JP2013010719A - Benzimidazolone and oxindole derivative, and pharmaceutical application of them - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent or a prophylactic agent of various kinds of diseases or symptoms (particularly neuropsychiatric disease such as Alzheimer's dementia) involving a serotonin 4 receptor.SOLUTION: There is provided a compound represented by formula (1) or a pharmaceutically acceptable salt thereof [in the formula, A represents formula (A-1) or else, B represents formula (B-2) or else, D represents (R-1) or else, U represents carbon atom or nitrogen atom, X, Y and Z represent oxygen atom, nitrogen atom, sulfur atom or carbon atom, V represents oxygen atom or sulfur atom, W represents N-Ror CRR, R, R, Rand Rrepresent hydrogen atom, halogen atom, alkyl group or else, R, R, Rand Rrepresent hydrogen atom, halogen atom, hydroxy group, alkyl group or else, Rrepresents hydrogen atom, alkyl group, -CORand -COORor else, l represents an integer of 0 to 4, r, r', s and s' represent integers of 0 to 3].

Description

The present invention relates to a novel benzimidazolone derivative or oxindole 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 It relates to a pharmaceutical composition containing it.

From the study of the mechanism of action of metoclopramide [4-amino-5-chloro-N- (2-diethylaminoethyl) -2-methoxybenzamide], a gastrointestinal motility promoter or a gastrointestinal function-improving drug widely used in clinical practice, serotonin A 5-HT ₄ receptor, which is 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 a cognitive function improving action by acetylcholine release enhancing action and a relative beta amyloid protein (Aβ) lowering action associated with an increase in soluble APPα by α secretase activation. Has been reported (see Non-Patent Document 2). PRX-03140 having a partial agonist action on 5-HT ₄ receptors (see Non-Patent Document 1) in animal experiments using rats, which have been reported to show cognitive improvement effect and Aβ lowering effect. 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). From the above, 5-HT ₄ receptor agonists are expected as therapeutic agents for novel mechanisms for various dementias associated with Alzheimer-type dementia (AD) and 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 a urea derivative having a benzimidazolone skeleton is useful as a gastrointestinal motility promoting agent or a gastrointestinal function improving agent (see Patent Document 1, Patent Document 2, and Patent Document 3). In addition, urea derivatives having an oxindole skeleton have a gastrointestinal function enhancing action and an antiemetic action, and are known to be useful as a therapeutic agent for digestive system diseases (see Patent Document 4). However, no compound has been reported in which the nitrogen atom of benzimidazolone or oxindole is bonded to an oxadiazole ring or the like.

US Patent Application Publication No. 2005148573 U.S. Patent Application Publication No. 2006276482 US Patent Application Publication No. 2007117796 US Patent Application Publication No. 2010173939

37th SFN Meeting (2007) Abstract of presentation (Poster presentation number 745.10 / CCC12) International Conference on Alzheimer's Disease (ICAD) 2008 Abstract of presentation, presentation number 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 extensive research, the present inventors have determined that the aromatic ring moiety is benzimidazolone, benzimidazol-2-thione, or oxindole, and the oxadiazole ring is used as a linker moiety that connects the aromatic ring moiety and the amine side chain. The present inventors have found that a group of compounds having a bioequivalent structure of an amide bond, for example, exhibits excellent agonist activity for the 5-HT ₄ receptor and is useful as a therapeutic agent for Alzheimer's dementia, etc. Was completed. According to the present invention, there are provided a benzimidazolone derivative and an oxindole derivative (hereinafter sometimes referred to as “the compound of the present invention”) represented by the following formula (1).

[Claim 1] Formula (1):

［式中、
Ａは下記の式（Ａ−１）、式（Ａ−２）、式(Ａ−３)、又は式（Ａ−４）：

[Where:
A is the following formula (A-1), formula (A-2), formula (A-3), or formula (A-4):

（式中、
ｌは０〜４の整数を意味し、
ｍは０〜２の整数を意味し、
ｎは０〜２の整数を意味し、
ｏおよびｐは、それぞれ独立して、０又は１を意味し、
ｑは０〜５の整数を意味し、
（Ａ−１）〜（Ａ−４）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、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良い）
を意味し、
Ｂは下記の式（Ｂ−１）、式（Ｂ−２）、又は式（Ｂ−３）：

(Where
l means an integer of 0 to 4;
m means an integer of 0 to 2;
n means an integer of 0 to 2,
o and p each independently represent 0 or 1,
q means an integer of 0 to 5;
(A-1) to (A-4) are substitutable positions, and 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, And may be substituted with one or more substituents selected from the group consisting of an oxo group and a halogen atom)
Means
B is the following formula (B-1), formula (B-2), or formula (B-3):

（式中、
（Ｂ−２）および（Ｂ−３）は環内の可能な位置に不飽和結合があってもよく、Ｂが式（Ｂ−１）を意味する場合、Ｄは存在しない）を意味し、
Ｄは以下の（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_３−６アルケニル基、置換されていてもよいＣ_３−６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、および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、
ここにおいて、Ｃ_１−６アルキル基、Ｃ_３−６アルケニル基、Ｃ_３−６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、およびＣ_５−８単環性もしくはＣ_７−１０２環性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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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_２−６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良い；
（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アルキレン鎖は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）を意味し、

(Where
(B-2) and (B-3) may have an unsaturated bond at a possible position in the ring, and D does not exist when B means formula (B-1)),
D means a group selected from the group consisting of the following groups (1) and (2):
(1) hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _3-6 alkenyl group, optionally substituted C _3-6 alkynyl group, optionally substituted Good C _3-8 monocyclic, C _7-10 bicyclic or C _7-12 tricyclic cycloalkyl group, and optionally substituted C _5-8 monocyclic or C _7-10 bicyclic A cycloalkenyl group,
Here, a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 monocyclic, a C _7-10 bicyclic or a C _7-12 tricyclic cycloalkyl group , And a C _5-8 monocyclic or C _7-10 bicyclic cycloalkenyl group, each independently at a substitutable position, a C _1-4 alkyl group, a hydroxy group, a C _1-4 alkoxy group, Selected from the group consisting of C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _2-6 alkanoyl group, phenacyl group, and halogen atom Optionally substituted with one or more substituents;
_{(2) - (CH 2)} u -R 12
Here, u means an integer of 0 to 4, and when u means an integer of 1 to 4, the alkylene chain is a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, May be substituted with one or more substituents selected from the group consisting of 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), the formula ^(R 12 -7), or refers to the formula ^(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_３−６アルケニル基、置換されていてもよいＣ_３−６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_３−６アルケニル基、Ｃ_３−６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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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、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良い；
（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_３−６アルケニル基、置換されていてもよいＣ_３−６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_３−６アルケニル基、Ｃ_３−６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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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良く、
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_１−４アルキル基、Ｃ_１−４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_２−６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良い）；
（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_３−６アルケニル基又はＣ_３−６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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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）、
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_３−６アルケニル基、置換されていてもよいＣ_３−６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）、Ｃ_２−６アルカノイル基、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_３−６アルケニル基、Ｃ_３−６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_２−６アルカノイル基、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、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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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良く、
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_１−４アルキル基、Ｃ_１−４アルコキシ基、シアノ基、ニトロ基、Ｃ_２−６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良く、
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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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、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）を形成しても良く、
（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い）、
前記Ｒ^８、Ｒ^８’、Ｒ^９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_３−６アルケニル基、置換されていてもよいＣ_３−６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_３−６アルケニル基、Ｃ_３−６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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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_２−６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良く、
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_１−４アルキル基、Ｃ_１−４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_２−６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良く、
或いは、Ｒ^８およびＲ^９、並びにＲ^８’およびＲ^９’は、それぞれ独立して、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良く、
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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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、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、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、およびＣ_１−６アルコキシ基は、それぞれ独立して、置換可能な位置で、Ｃ_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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_２−６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良く、
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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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_２−６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良く、
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、
前記ｖは０〜２の整数を意味し（但しｒおよびｓは同時に０ではない）、
Ｖは酸素原子、又は硫黄原子を意味し、
Ｗは、Ｎ−Ｒ^１、又はＣＲ^１Ｒ^２を意味し、
Ｒ^１およびＲ^２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（Ｒ^１が窒素原子と結合している場合、当該へテロ環基上の炭素原子が窒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（Ｒ^１が窒素原子と結合している場合、当該へテロ環基上の炭素原子が窒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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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_２−６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良く、
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_１−４アルキル基、Ｃ_１−４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_２−６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良く、
或いはＲ^１とＲ^２は互いに結合して１個の酸素原子を含んでもよい３〜６員の飽和環（該飽和環は、置換可能な位置で、Ｃ_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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、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、
Ｕは炭素原子、又は窒素原子を意味し、
Ｘ、ＹおよびＺは、それぞれ独立して、酸素原子、窒素原子、硫黄原子および炭素原子からなる群から選択され、Ｘ、Ｙ、Ｚのうち少なくともひとつは酸素原子、硫黄原子、又は窒素原子のいずれかを意味し、
Ｒ^４は、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、ニトロ基、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、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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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_２−６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良く、
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_１−４アルキル基、Ｃ_１−４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_２−６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良く、
或いはＲ^４とＲ^１は互いに結合して飽和あるいは不飽和の１個の酸素原子を含んでもよい６〜９員の環（該環は、置換可能な位置で、Ｃ_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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、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^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、ニトロ基、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、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_１−４アルキル基、ヒドロキシ基、Ｃ_１−４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_２−６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良く、
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_１−４アルキル基、Ｃ_１−４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_２−６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良い]
で表される化合物又はその製薬学的に許容される塩。

(Where
R ¹³ means a group selected from the group consisting of the groups included in the following (1) to (5),
(1) a hydrogen atom and a formyl group;
(2) C _1-6 alkyl group which may be substituted, C _3-6 alkenyl group which may be substituted, C _3-6 alkynyl group which may be substituted, C ₃ which may be substituted _{A -8} cycloalkyl group, and an _optionally substituted C _5-8 cycloalkenyl group,
Here, the C _1-6 alkyl group, the C _3-6 alkenyl group, the C _3-6 alkynyl group, the C _3-8 cycloalkyl group, and the C _5-8 cycloalkenyl group can be independently substituted. Selected from the group consisting of a C _1-4 alkyl group, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, an oxo group, and a halogen atom. Optionally 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 _3-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 A cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an 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 _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a 5-9 membered monocyclic or 7 A 10-membered bicyclic non-aromatic unsaturated heterocyclic group and a 4-9-membered monocyclic or 7-10-membered bicyclic saturated heterocyclic group are each independently In the substitutable position, C _1-4 alkyl group, hydroxy group, C _1-4 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl And may be substituted with one or more substituents selected from the group consisting of a group and a halogen atom,
Aryl, and heteroaryl groups, independently, at substitutable positions, halogen atom, hydroxy _{group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4} haloalkyl _{group, C 1- 4} haloalkoxy group, cyano group, nitro group, C _2-6 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 _3-6 alkenyl group or a C _3-6 alkynyl group);
^{(5) -CONR} 19 R 20, or ^-CSNR 19 ^{R 20} and _{^{-SO 2 NR 19 R 20 (R}} 19 and ^{R 20} are each independently means any group in the hydrogen atom or the ^{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 (the heterocyclic group is a C _1-4 alkyl group, hydroxy group, C _1-4 at a substitutable position). And optionally substituted with one or more substituents selected from the group consisting of an alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, an oxo group, and a halogen atom),
R ¹⁴ and R ¹⁵ each independently represent a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 alkenyl group, or an _optionally substituted C _{3− 6} alkynyl groups, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 cycloalkenyl group, an _optionally substituted aryl group, an optionally substituted heteroaryl A 5- to 9-membered monocyclic or 7 to 10-membered bicyclic non-aromatic unsaturated hetero ring group which may be substituted (the hetero ring group has carbon atoms on the ring; 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group (bonded to the adjacent nitrogen atom), which is substituted on the ring is bonded to the nitrogen atom adjacent the carbon atom), C _2-6 alk Yl _{group, C 1-6} alkoxycarbonyl group means a carbamoyl group, a sulfamoyl group, or a _{C 1-6} alkylsulfonyl group,
Here, a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 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 _2-6 alkanoyl group , C _1-6 alkoxycarbonyl group, carbamoyl group, sulfamoyl group, and C _1-6 alkylsulfonyl group are each independently a C _1-4 alkyl group, a hydroxy group, C _1-4 at a substitutable position. May be substituted with one or more substituents selected from the group consisting of an alkoxy 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 _1-4 alkyl group, a C _1-4 alkoxy group, a cyano group, a nitro group, or a C _{2-6 at} a substitutable position. May be substituted with one or more substituents selected from the group consisting of an alkanoyl group and an optionally substituted amino group,
Alternatively, 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 A saturated or unsaturated 4- to 9-membered monocyclic or 7- to 10-membered bicyclic nitrogen-containing heterocyclic group (the heterocyclic group is a C _1-4 alkyl group at a substitutable position) Substituted with one or more substituents selected from the group consisting of: a hydroxy group, a C _1-4 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 formed),
^{(R 12 -1) ~ (R} 12 -4) may be at the unsaturated bond in position within a ring),
R ⁸ , R ^{8 ′} , R ⁹ and R ^{9 ′} are each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 alkenyl group, An optionally substituted C _3-6 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 heteroaryl group, an optionally substituted 5- to 9-membered monocyclic or 7 to 10-membered bicyclic non-aromatic unsaturated heterocyclic group (the heterocyclic ring) Group is a carbon atom on the ring bonded to the adjacent nitrogen atom), or an optionally substituted 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group ( The heterocyclic group means that the carbon atom on the ring is bound to the adjacent nitrogen atom) Taste,
Here, a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a 5-9 membered monocyclic or 7 A 10-membered bicyclic non-aromatic unsaturated heterocyclic group and a 4-9-membered monocyclic or 7-10-membered bicyclic saturated heterocyclic group are each independently C _1-4 alkyl group, hydroxy group, C _1-4 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 _2-6 alkanoyl groups, phenacyl groups, and halogen atoms,
Aryl, and heteroaryl groups, independently, at substitutable positions, halogen atom, hydroxy _{group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4} haloalkyl _{group, C 1- 4} haloalkoxy group, cyano group, nitro group, C _2-6 alkanoyl group, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted amino groups,
Alternatively, R ⁸ and R ⁹ , and R ^{8 ′} and R ^{9 ′} are each independently bonded to each other, and in addition to the adjacent nitrogen atom, 1 to 2 nitrogen atoms, 1 oxygen atom, and 1 A saturated or unsaturated 4 to 9-membered monocyclic or 7 to 10-membered bicyclic nitrogen-containing heterocyclic group containing 0 to 2 heteroatoms selected from the group consisting of 1 sulfur atom May be formed,
Here, the nitrogen-containing heterocyclic group is a substitutable position, and is a C _1-4 alkyl group, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano. May be substituted with one or more substituents selected from the group consisting of a group, an oxo group, and a halogen atom,
R ¹⁰ , R ^{10 ′} , R ¹¹ and R ^{11 ′} each independently represent a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkyl group, or an _optionally substituted C. _{A 2-6} alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _1-6 alkoxy group, a cyano group, or an oxo group;
Here, the C _1-6 alkyl group, the C _2-6 alkenyl group, the C _2-6 alkynyl group, and the C _1-6 alkoxy group are each independently a C _1-4 alkyl group at a substitutable position. , Hydroxy group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _2-6 alkanoyl group, phenacyl group, and halogen atom May be substituted with one or more substituents selected from the group consisting of:
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 the ring to which R ¹⁰ and R ¹¹ are bonded,
Here, the saturated or unsaturated 3- to 8-membered ring is a C _1-4 alkyl group, a hydroxy group, a C _1-4 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 groups, cyano groups, oxo groups, aryl groups, heteroaryl groups, aryloxy groups, C _2-6 alkanoyl groups, phenacyl groups, and halogen atoms 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;
T and t ′ each independently represents 1 or 2;
V represents an integer of 0 to 2 (provided that r and s are not 0 at the same time);
V means an oxygen atom or a sulfur atom,
W represents N—R ¹ or CR ¹ R ² ;
R ¹ and R ² are each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or 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 (when R ¹ is bonded to a nitrogen atom, A carbon atom on the heterocyclic group is bound to a nitrogen atom), or an optionally substituted 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group (R ^{If 1} is bonded to a nitrogen atom, a carbon atom on the heterocyclic group the Bonded to the nitrogen atom) 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 A 10-membered bicyclic non-aromatic unsaturated heterocyclic group and a 4-9-membered monocyclic or 7-10-membered bicyclic saturated heterocyclic group are each independently In the substitutable position, C _1-4 alkyl group, hydroxy group, C _1-4 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl May be substituted with one or more substituents selected from the group consisting of a group, an aryloxy group, a C _2-6 alkanoyl group, a phenacyl group, and a halogen atom,
Aryl, and heteroaryl groups, independently, at substitutable positions, halogen atom, hydroxy _{group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4} haloalkyl _{group, C 1- 4} haloalkoxy group, cyano group, nitro group, C _2-6 alkanoyl group, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted amino groups,
Alternatively, R ¹ and R ² may be bonded to each other to contain one oxygen atom, a 3 to 6 membered saturated ring (the saturated ring is a substitutable position, a C _1-4 alkyl group, a hydroxy group, C It may be substituted with one or more substituents selected from the group consisting of _1-4 alkoxy groups, C _1-4 haloalkyl groups, C _1-4 haloalkoxy groups, cyano groups, oxo groups, and halogen atoms. )
U means a carbon atom or a nitrogen atom;
X, Y and Z are each independently selected from the group consisting of an oxygen atom, a nitrogen atom, a sulfur atom and a carbon atom, and at least one of X, Y and Z is an oxygen atom, a sulfur atom or a nitrogen atom. Means either
R ⁴ 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 an _optionally substituted C _2-6 alkynyl. A group, 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 haloalkyl group, optionally substituted C _1-4 haloalkoxy group, cyano group, nitro group, optionally substituted aryl group, optionally substituted heteroaryl group, or optionally substituted Means a good amino 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 _1-6 alkoxy group, a C _{1- 4} haloalkyl group and C _1-4 haloalkoxy group are each independently at a substitutable position, C _1-4 alkyl group, hydroxy group, C _1-4 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _2-6 alkanoyl group, phenacyl group, and one or more substituents selected from the group consisting of halogen atoms May be replaced with
Aryl, and heteroaryl groups, independently, at substitutable positions, halogen atom, hydroxy _{group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4} haloalkyl _{group, C 1- 4} haloalkoxy group, cyano group, nitro group, C _2-6 alkanoyl group, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted amino groups,
Alternatively, R ⁴ and R ¹ may be bonded to each other to contain a saturated or unsaturated oxygen atom, a 6 to 9 membered ring (the ring is a C _1-4 alkyl group, hydroxy group at a substitutable position). Substituted with one or more substituents selected from the group consisting of a group, a C _1-4 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 formed)
R ⁵ , R ⁶ , and R ⁷ 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. , 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 -6} alkoxy group, C _1-4 haloalkyl group which may be substituted, C _1-4 haloalkoxy group which may be substituted, cyano group, nitro group, aryl group which may be substituted, substituted An optionally substituted heteroaryl group, or an optionally substituted amino 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 _1-6 alkoxy group, a C _{1- 4} haloalkyl group and C _1-4 haloalkoxy group are each independently at a substitutable position, C _1-4 alkyl group, hydroxy group, C _1-4 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _2-6 alkanoyl group, phenacyl group, and one or more substituents selected from the group consisting of halogen atoms May be replaced with
Aryl, and heteroaryl groups, independently, at substitutable positions, halogen atom, hydroxy _{group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4} haloalkyl _{group, C 1- And} 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 _2-6 alkanoyl group, and an optionally substituted amino group]
Or a pharmaceutically acceptable salt thereof.

[Section 2]
(A-1) to (A-4) are substitutable positions, 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, Item 2. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents selected from the group consisting of halogen atoms.

[Section 3]
Item 3. The compound according to Item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein V is an oxygen atom.

[Section 4]
W is N—R ¹ , R ¹ 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, 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 (the carbon atom on the heterocyclic group is a nitrogen atom) 4-9-membered monocyclic or 7-10-membered bicyclic saturated heterocyclic group (which is bonded), or a carbon atom on the heterocyclic group is a nitrogen atom The compound according to any one of Items 1 to 3, or a pharmaceutical product thereof Acceptable salt.

[Section 5]
Item ^5. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to ⁴ , wherein R ⁴ , R ⁵ , and R ⁷ are a hydrogen atom, and R ⁶ is a hydrogen atom or a halogen atom.

[Section 6]
Item 6. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 5, wherein U is a carbon atom.

[Section 7]
Item 7. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6, wherein X is a nitrogen atom, Y is an oxygen atom, and Z is a nitrogen atom.

[Section 8]
Item 8. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 7, wherein A is (A-1) and l is 0 or 1.

[Section 9]
Item 9. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 8, wherein B is (B-2), s is 1, and r is 2.

[Section 10]
D is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 monocyclic, C _7-10 bicyclic or C _7-12 tricyclic cycloalkyl group Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.

[Section 11]
D is _{- (CH} 2) u ^{-R 12,} compound or a pharmaceutically acceptable salt thereof according to any one ^{R 12} is a section 1-9 is of formula ^(R 12 -3).

[Section 12]
Item 10. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 9, wherein D is — (CH ₂ ) _u —R ¹² and R ¹² is the formula (R ¹² -1).

[Section 13]
Formula (11)

で表される項１〜９および項１２のいずれかに記載の化合物又はその製薬学的に許容される塩。

Item 13. The compound according to any one of Items 1 to 9 and Item 12 or a pharmaceutically acceptable salt thereof.

[Section 14]
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following compounds:
(01) 1-ethyl-5-fluoro-3- {5- [1- (propan-2-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1, 3-dihydro-2H-benzimidazol-2-one,
(02) 3- {5- [1- (butan-2-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1-ethyl-5-fluoro-1, 3-dihydro-2H-benzimidazol-2-one,
(03) 1-ethyl-5-fluoro-3- {5- [1- (tetrahydrofuran-3-ylmethyl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1, 3-dihydro-2H-benzimidazol-2-one,
(04) 1-ethyl-5-fluoro-3- {5- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl } -1,3-dihydro-2H-benzimidazol-2-one,
(05) 3- [5- (1-Cyclobutylpiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1-ethyl-5-fluoro-1,3-dihydro-2H -Benzimidazol-2-one,
(06) 3- [5- (1-Cyclopentylpiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1-ethyl-5-fluoro-1,3-dihydro-2H- Benzimidazol-2-one,
(07) 5-Fluoro-1- (propan-2-yl) -3- {5- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxa Diazol-3-yl} -1,3-dihydro-2H-benzimidazol-2-one,
(08) 1-ethyl-5-fluoro-3- {5- [1- (tetrahydro-2H-pyran-4-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl } -1,3-dihydro-2H-benzimidazol-2-one,
(09) 1-ethyl-3- {5- [1- (1-hydroxy-2-methylpropan-2-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H-benzimidazol-2-one,
(10) 3- [5- (1-tert-Butylpiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1-ethyl-5-fluoro-1,3-dihydro- 2H-benzimidazol-2-one,
(11) 1-ethyl-5-fluoro-3- {5- [1- (4-methyltetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazole- 3-yl} -1,3-dihydro-2H-benzimidazol-2-one,
(12) Methyl 4- {3- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazole -5-yl] azetidin-1-yl} piperidine-1-carboxylate,
(13) 1-ethyl-5-fluoro-3- {5- [1 ′-(methylsulfonyl) -1,4′-bipiperidin-4-yl] -1,2,4-oxadiazol-3-yl } -1,3-dihydro-2H-benzimidazol-2-one,
(14) Methyl 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazole-5 Yl] -1,4′-bipiperidine-1′-carboxylate,
(15) Methyl 2-({4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadi Azol-5-yl] piperidin-1-yl} methyl) morpholine-4-carboxylate,
(16) 1-ethyl-5-fluoro-3- {5- [cis-4- (pyrrolidin-1-yl) cyclohexyl] -1,2,4-oxadiazol-3-yl} -1,3- Dihydro-2H-benzimidazol-2-one,
(17) 1-ethyl-5-fluoro-3- {5- [cis-4- (3-methoxyazetidin-1-yl) cyclohexyl] -1,2,4-oxadiazol-3-yl}- 1,3-dihydro-2H-benzimidazol-2-one,
(18) 1-ethyl-3- [5- (cis-4- {ethyl [2- (tetrahydro-2H-pyran-4-yl) ethyl] amino} cyclohexyl) -1,2,4-oxadiazole- 3-yl] -5-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
(19) 1-ethyl-5-fluoro-3- (5- {cis-4- [methyl (tetrahydrofuran-3-yl) amino] cyclohexyl} -1,2,4-oxadiazol-3-yl)- 1,3-dihydro-2H-benzimidazol-2-one,
(20) 1-ethyl-5-fluoro-3- {5- [cis-3- (3-methoxyazetidin-1-yl) cyclobutyl] -1,2,4-oxadiazol-3-yl}- 1,3-dihydro-2H-benzimidazol-2-one,
(21) 1-ethyl-3- {5-3- (ethylamino) cyclobutyl] -1,2,4-oxadiazol-3-yl} -5-fluoro-1,3-dihydro-2H-benzimidazole -2-one,
(22) 3- {5- [cis-3- (cyclopentylamino) cyclobutyl] -1,2,4-oxadiazol-3-yl} -1-ethyl-5-fluoro-1,3-dihydro-2H -Benzimidazol-2-one,
(23) 1-ethyl-5-fluoro-3- (5- {cis-3- [methyl (tetrahydrofuran-3-ylmethyl) amino] cyclobutyl} -1,2,4-oxadiazol-3-yl)- 1,3-dihydro-2H-benzimidazol-2-one.

[Section 15]
Item 15. A pharmaceutical composition comprising the compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof.

[Section 16]
Item 15. A serotonin 4 receptor agonist comprising the compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Section 17]
Item 15. A therapeutic agent for Alzheimer-type dementia comprising the compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention can provide a compound having an agonist (agonist) action or a partial agonist (partial agonist) action on a serotonin 4 receptor, and therefore provides a therapeutic or preventive agent for a disease or condition involving serotonin 4 receptor. Can do. The following (i) to (v) are mentioned as diseases or symptoms in which the involvement of serotonin 4 receptor is suggested:
(I) neuropsychiatric disorders 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 diseases, scleroderma, diabetes mellitus, nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain, chest Gastrointestinal symptoms such as burns or ambiguity;
(V) Urinary system diseases accompanied by dysuria due to urinary tract obstruction or enlarged prostate.
In addition, since the compound of the present invention exhibits excellent 5-HT ₄ receptor operability 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 “optionally 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.

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, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl Group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group and the like. Preferred is a C _1-4 alkyl group, 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, an 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, and 2-methyl- A 2-propenyl group is mentioned.

Examples of the “C _2-6 alkynyl group” include linear or branched alkynyl groups having 2 to 6 carbon atoms, and 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, 5-hexynyl group etc. are mentioned. 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 _1-6 alkoxy group” include linear or branched alkoxy groups having 1 to 6 carbon atoms, specifically, methoxy group, ethoxy group, propoxy group, isopropoxy group, Examples include butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like. Preferably, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group are exemplified.

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

_{Examples of the} “C _3-6 alkenyl group” include a linear or branched alkenyl group having 3 to 6 carbon atoms, and an alkenyl group containing 1 to 2 double bonds. Specifically, 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- Examples thereof include a methyl-2-propenyl group, 1-methyl-3-methyl-3-butenyl group, 4-methyl-4-pentenyl group, 1,3-butadienyl group, 1,5-hexadienyl group and the like. Preferably 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, and 2-methyl-3-butenyl group. It is done.

Examples of the “C _3-6 alkynyl group” include linear or branched alkynyl groups having 2 to 6 carbon atoms, and include 1 to 2 triple bonds, more preferably 1 triple bond. An alkynyl group is mentioned. Specifically, 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, 5-hexynyl Groups and the like. Preferably 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, Examples include 4-pentynyl group, 3-pentynyl group, 2-pentynyl group, and 1-methyl-2-butynyl group.

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

_{Examples of the} “C _5-8 cycloalkenyl group” include 5- to 8-membered cycloalkenyl groups, and specifically include 1-cyclopentenyl group, 3-cyclopentenyl group, 4-cyclopentenyl group, 1-cyclohexenyl group. 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 -A cyclooctenyl group etc. are mentioned. Preferred examples include 1-cyclopentenyl group, 3-cyclopentenyl group, 4-cyclopentenyl group, 1-cyclohexenyl group, 3-cyclohexenyl group, and 4-cyclohexenyl group.

  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 containing 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 an indolyl group, a benzofuryl group, a benzothienyl group, a quinolinyl group, and a 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 and nitrogen atom. Preferably an indolyl group and a quinolinyl group are mentioned.

The “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 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. Non-aromatic unsaturated heterocyclic groups can be mentioned, 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 and 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, and as a saturated heterocyclic group substituted with an oxo group, specifically, a 2-oxopyrrolidinyl group, and A 2-oxotetrahydrofuryl group is mentioned.
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 and nitrogen atom.

_{Examples of the} “C _1-4 alkyl group” include a linear or branched alkyl group having 1 to 4 carbon atoms, and specifically include a methyl group, an ethyl group, a propyl group, an isopropyl group, and butyl. Group, isobutyl group, sec-butyl group, tert-butyl group and the like. Preferred are methyl group, ethyl group, propyl group, and isopropyl group.

_{Examples of the} “C _1-4 alkoxy group” include a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, Examples include butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group and the like. Preferable examples include methoxy group, ethoxy group, propoxy group, isopropoxy group, and tert-butoxy group.

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

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

Examples of the “C _2-6 alkanoyl group” include a linear or branched alkanoyl group having 2 to 6 carbon atoms, and specifically include an acetyl group, a propanoyl group, a 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 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 cycloalkylC _1-4 alkyl) amino” (eg, 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” (eg, methylcyclopropylamino, methylcyclobutylamino, methylcyclopentylamino, methylcyclohexylamino, methylcycloheptylamino, etc.) ,
Examples of the “4- to 7-membered cyclic amino group” include the same or different hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as the atoms constituting the ring in addition to the nitrogen atom of the cyclic amino group. 4-membered to 7-membered monocyclic amino group which may contain 1 to 3. Specific examples include azetidino, pyrrolidino, piperazino, piperidino, morpholino, thiomorpholino, azepano, oxoazepano and the like. Preferred examples include amino, methylamino, ethylamino, cyclopropylamino, cyclobutylamino, dimethylamino, di-1-methylethylamino, methylcyclopropylamino, azetidino, pyrrolidino, piperazino, piperidino, and morpholino, and more preferred. Include amino, methylamino, dimethylamino, azetidino, pyrrolidino, and piperidino.

  "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 adjacent nitrogen atoms 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, hexahydroaze Pinyl 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 a decahydroquinoxalinyl group, an octahydrobenzo-1,4-oxazinyl group, an 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, a 1,2,3,4-tetrahydroisoquinolinyl group, and a 3,4-dihydrobenzo-1,4-oxazinyl group. More preferred are pyrrolidinyl group, piperazinyl group, piperidinyl group, and 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, and preferably a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring.
Specific examples of the “bicyclic or spiro compound formed with the ring to which 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, octahydrocyclopenta [b] pyrrole, octa Mud cyclopenta [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 preferable examples include 7-azabicyclo [2.2.1] heptane, 8-azabicyclo [3.2.1] octane, and 3-azabicyclo [3.2.1] octane.

The “C _3-8 monocyclic, C _7-10 bicyclic or C _7-12 tricyclic cycloalkyl group” includes a 3-8-membered monocyclic cycloalkyl group and a 7-10-membered 2 cycloalkyl 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. Preferred examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. 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 3-8 membered monocyclic cycloalkenyl group and a 7-10 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 -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 can be mentioned. Preferred examples include 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.

"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 adjacent nitrogen atoms Specific examples of the saturated monocyclic nitrogen-containing heterocyclic group in the “8-membered monocyclic nitrogen-containing heterocyclic group” include azetidinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, hexahydro Examples thereof include an azepinyl 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- A 1H-pyrrolyl group is mentioned.

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. Preferable 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, and 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 “3- to 6-membered saturated ring optionally containing one oxygen atom” include a 3- to 6-membered cycloalkane not containing an oxygen atom and a 3- to 6-membered cyclic ether containing an oxygen atom. Specific examples of the 3- to 6-membered cycloalkane include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring. Examples of the 3- to 6-membered cyclic ether containing an oxygen atom include an oxirane ring and an oxetane. A ring, a tetrahydrofuran ring, and a tetrahydropyran ring.

“R ⁴ and R ¹ may be bonded to each other and may contain a saturated or unsaturated oxygen atom and a 6-9 membered ring” specifically means the following formulas (E-1) to (E— 16):

で示される６〜９員の環等が挙げられる。好ましくは式（Ｅ−１）、（Ｅ−４）、（Ｅ−５）、（Ｅ−８）、（Ｅ−９）、（Ｅ−１０）、および（Ｅ−１４）が挙げられる。

6-9 membered ring etc. which are shown by these, etc. are mentioned. Preferred examples include the formulas (E-1), (E-4), (E-5), (E-8), (E-9), (E-10), and (E-14).

“A partial structure in formula (1), wherein U means a carbon atom or a nitrogen atom, and X, Y and Z are each independently a group consisting of an oxygen atom, a nitrogen atom, a sulfur atom and a carbon atom. And at least one of X, Y, and Z is a 5-membered heteroaryl, which means either an oxygen atom, a sulfur atom, or a nitrogen atom. The following formula (F):

としては、下記式（Ｆ−１）〜（Ｆ−１６）：

As the following formulas (F-1) to (F-16):

のヘテロアリールが挙げられ、ヘテロアリールの結合位置は、化学的に安定であれば特に限定は無く、任意の炭素原子上もしくは窒素原子上で結合していてよい。ただし、ベンズイミダゾロン環等の窒素原子との結合位置は、任意の炭素原子上であり、Ａとの結合位置は、ベンズイミダゾロン環等の窒素原子との結合位置を基に、上記式（Ｆ）に記載の位置関係の炭素原子又は窒素原子である。好ましくは式（Ｆ−４）〜（Ｆ−７）、（Ｆ−１０）〜（Ｆ−１３）のへテロアリールが挙げられる。さらに好ましくは（Ｆ−１０）〜（Ｆ−１３）のへテロアリールが挙げられる。
本発明における各基について説明する。

The bonding position of the heteroaryl is not particularly limited as long as it is chemically stable, and may be bonded on any carbon atom or nitrogen atom. However, the bonding position with a nitrogen atom such as a benzimidazolone ring is on an arbitrary carbon atom, and the bonding position with A is based on the bonding position with a nitrogen atom such as a benzimidazolone ring based on the above formula ( It is a carbon atom or a nitrogen atom in the positional relationship described in F). Preferably, heteroaryls of the formulas (F-4) to (F-7) and (F-10) to (F-13) are used. More preferably, the heteroaryl of (F-10)-(F-13) is mentioned.
Each group in the present invention will be described.

  A is preferably formula (A-1) or (A-3), more preferably formula (A-1).

  B is preferably the formula (B-1) or the formula (B-2), more preferably the formula (B-2).

D is preferably a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 monocyclic, C _7-10 bicyclic or C _7-12 tricyclic. cycloalkyl group, or _{- (CH} 2) u ^{-R 12} and the like.

Preferred examples of R ¹² include formula (R ¹² -1), formula (R ¹² -3), and 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} can be mentioned, more preferably, optionally substituted _{C 1-6} alkyl group, an optionally substituted _{C 3-8} cycloalkyl _^group, -COR ^16, -SO ^{2 R} 16 Or —COOR ¹⁶ is more preferable, and —COR ¹⁶ , —SO ₂ R ¹⁶ , or —COOR ¹⁶ is more preferable.

R ¹⁶ is preferably a C _1-6 alkyl group which may be substituted, a C _3-8 cycloalkyl group which may be substituted, or an aryl group which may be substituted, or may be substituted. It includes heteroaryl groups, more preferably, optionally substituted C _1-6 alkyl group, and a good C _3-8 cycloalkyl group which may be substituted.

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. Examples thereof include an 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. It is done.

Preferably, R ¹ and R ² are each independently a hydrogen 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 and C _5-8 cycloalkenyl group which may be substituted may be mentioned, more preferably, C _1-6 alkyl group which may be substituted, C _{2 2} which may be substituted. ₆ alkenyl group is mentioned.

R ⁴ , R ⁵ , R ⁶ and R ⁷ 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 C. _{A 3-8} cycloalkyl group, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _1-4 haloalkyl group, an optionally substituted C _1-4 haloalkoxy group, a cyano group, Examples thereof include a nitro group, an optionally substituted aryl group, an optionally substituted heteroaryl group, and an optionally substituted amino group, and more preferably a hydrogen atom, a halogen atom, and an optionally substituted C atom. _1-6 alkyl group, optionally substituted C _1-6 alkoxy group, optionally substituted C _1-4 haloalkyl group, or optionally substituted C _1-4 haloal Examples thereof include a alkoxy group, more preferably a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkyl group.

R ⁸ , R ^{8 ′} , R ⁹ and R ^{9 ′} are preferably each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, or an _optionally substituted C _3-8 cycloalkyl. Group, an optionally substituted C _5-8 cycloalkenyl group, an _optionally substituted aryl group, or an optionally substituted heteroaryl group, and more preferably an optionally substituted C _{1. And a -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. Examples thereof include a preferable C _1-6 alkoxy group, and more preferable examples include a hydrogen atom, an optionally substituted C _1-6 alkyl group, and an optionally substituted C _1-6 alkoxy group.

  l is preferably 0 or 1.

  Preferably, m is 0 or 1.

  n is preferably 0 or 1.

  o is preferably 0 or 1.

  Preferably q is 1-3.

  Preferably, r and r ′ are each independently 1-2.

  Preferably, s and s ′ are each independently 0 or 1.

  Preferably, t and t ′ are each independently 1.

  u is preferably 0 to 2, and more preferably 0 or 1.

  Preferably 1 or 2 is mentioned as v.

(A-1) to (A-4) are each independently a substitutable position, preferably selected from the group consisting of a C _1-6 alkyl group, a hydroxy group, and a C _1-6 alkoxy group. May be substituted with one or more substituents.

D is a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 monocyclic, a C _7-10 bicyclic or a C _7-12 tricyclic cycloalkyl group, Or each group in the case of representing a C _5-8 monocyclic or C _7-10 bicyclic cycloalkenyl group is independently a substitutable position, preferably a C _1-4 alkyl group, hydroxy It may be substituted with one or more substituents selected from the group consisting of a group, a C _1-4 alkoxy group, a C _1-4 haloalkyl group, and an aryl group.

When D represents — (CH ₂ ) _u —R ¹² , and u represents an integer of 1 to 4, the alkylene chain is preferably a substitutable position, preferably a C _1-6 alkyl group, a hydroxy group, and It may be substituted with one or more substituents selected from the group consisting of C _1-6 alkoxy groups.

Each group when R ¹³ represents a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 cycloalkyl group, or a C _5-8 cycloalkenyl group, Independently, at a substitutable position, preferably consists of a _C1-4 alkyl group, a hydroxy group, a _C1-4 alkoxy group, a _C1-4 haloalkyl group, a _C1-4 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 _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a 5-9 membered monocyclic group or 7 Each of which represents a 10-membered bicyclic non-aromatic unsaturated heterocyclic group, or a 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group Each group is independently a substitutable position, preferably a _C1-4 alkyl group, a hydroxy group, a _C1-4 alkoxy group, a _C1-4 haloalkyl group, a _C1-4 haloalkoxy group, oxo. May be substituted with one or more substituents selected from the group consisting of a group, an aryl group, a heteroaryl group, and a halogen atom, and more preferably a C _1-4 alkyl group, a hydroxy group, and a C _1-4 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 _1-4 alkyl group, or a C _1-4 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 _1-4 alkyl group, a C _1-4 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, and an optionally substituted amino group. or it may be substituted with a substituent, more preferably a halogen atom, C _1-4 alkyl, C _1-4 alkoxy groups, and optionally substituted amino group 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, in addition to the adjacent nitrogen atom, and 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 _1-4 alkyl group, a hydroxy group, C It may be substituted with one or more substituents selected from the group consisting of _1-4 alkoxy groups, oxo groups and halogen atoms.

R ¹⁴ and R ¹⁵ are each independently a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, 5 -9-membered monocyclic or 7-10 membered bicyclic non-aromatic unsaturated heterocyclic group, 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocycle Each group 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 is independently a substitutable position, preferably C It may be substituted with one or more substituents selected from the group consisting of _1-4 alkyl groups, hydroxy groups, C _1-4 alkoxy groups, oxo groups, aryl groups, heteroaryl groups, and halogen atoms; Preferably C _1-4 a It may be substituted with one or more substituents selected from the group consisting of an alkyl group, a hydroxy group, a C _1-4 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 a substitutable position, preferably C _1- Substituted with one or more substituents selected from the group consisting of ₄ alkyl groups, hydroxy groups, C _1-4 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 C _1-4 alkyl groups, hydroxy groups, C _1-4 alkoxy groups, oxo groups, and halogen atoms. .

R ⁸ , R ^{8 ′} , R ⁹ and R ^{9 ′} are each independently a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 cycloalkyl group, 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 Each group in the case of representing a membered bicyclic saturated heterocyclic group is independently a substitutable position, preferably a C _1-4 alkyl group, a hydroxy group, or a C _1-4 alkoxy group. , A C _1-4 haloalkoxy group, an oxo group, an aryl group, a heteroaryl group, an aryloxy group, and one or more substituents selected from the group consisting of halogen atoms, more preferably C _1-4 alkyl group, hydroxy _{group, C 1-} Alkoxy group, oxo group, and may be substituted with one or more substituents selected from the group consisting of halogen atoms.

R ⁸ and R ⁹ , and R ^{8 ′} and R ^{9 ′} are each independently bonded to each other, in addition to the adjacent nitrogen atom, 1 to 2 nitrogen atoms, 1 oxygen atom and 1 When representing a saturated or unsaturated 4 to 9-membered monocyclic or 7 to 10-membered bicyclic nitrogen-containing heterocyclic group containing 0 to 2 heteroatoms selected from the group consisting of sulfur atoms Each of these groups may be independently substituted at a substitutable position, preferably with one or more substituents selected from the group consisting of C _1-4 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 _1-4 alkyl group, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 haloalkoxy group, an oxo group, an aryl. 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 _1-4 alkyl group, a hydroxy group, C _1- It may be substituted with one or more substituents selected from the group consisting of ₄ 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 3-8 that may contain one oxygen atom. In the case of forming a member ring and representing a bicyclic ring or a spiro compound together with the ring to which R ¹⁰ and R ¹¹ are bonded, each group is independently at a substitutable position, preferably C _1- It may be substituted with one or more substituents selected from the group consisting of ₄ alkyl groups, hydroxy groups, C _1-4 alkoxy groups, oxo groups, and halogen atoms.

When R ¹ 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, a C _5-8 cycloalkenyl group, an aryl group, and a heteroaryl group Each group independently represents a substitutable position, preferably a _C1-4 alkyl group, a hydroxy group, a _C1-4 alkoxy group, a _C1-4 haloalkyl group, a _C1-4 haloalkoxy. And may be substituted with one or more substituents selected from the group consisting of a group and a halogen atom, more preferably selected from the group consisting of a C _1-4 alkyl group, a hydroxy group, and a C _1-4 alkoxy group May be substituted with one or more substituents.

When R ² 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, a C _5-8 cycloalkenyl group, an aryl group, and a heteroaryl group Each group independently represents a substitutable position, preferably a _C1-4 alkyl group, a hydroxy group, a _C1-4 alkoxy group, a _C1-4 haloalkyl group, a _C1-4 haloalkoxy. And may be substituted with one or more substituents selected from the group consisting of a group and a halogen atom, more preferably selected from the group consisting of a C _1-4 alkyl group, a hydroxy group, and a C _1-4 alkoxy group May be substituted with one or more substituents.

R ⁴ 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 C _1-6 alkoxy group, a C _{1- In the} case of representing a ₄ haloalkyl group, a C _1-4 haloalkoxy group, an aryl group, and a heteroaryl group, each group is independently a substitutable position, preferably a C _1-4 alkyl group, a hydroxy group May be substituted with one or more substituents selected from the group consisting of a group, a C _1-4 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, and a halogen atom, and more preferably It may be substituted with one or more substituents selected from the group consisting of a C _1-4 alkyl group, a hydroxy group, a C _1-4 alkoxy group and a halogen atom.

When R ¹ and R ⁴ are bonded to each other to represent a 6 to 9 membered ring which may contain a saturated or unsaturated oxygen atom, the group is preferably a substitutable position, preferably C _1- It may be substituted with one or more substituents selected from the group consisting of ₄ alkyl groups, hydroxy groups, C _1-4 alkoxy groups, oxo groups, and halogen atoms.

R ⁵ , R ⁶ and R ⁷ 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. Group, a C _1-6 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, an aryl group and a heteroaryl group, each independently represents a substitutable position. And preferably one or more selected from the group consisting of a C _1-4 alkyl group, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, and a halogen atom. may be substituted with a substituent, more preferably a C _1-4 alkyl group, hydroxy group, C _1-4 alkoxy groups, and one or more selected from the group consisting of halogen atoms It may be substituted with a substituent.

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 and isolated isomers of these diastereomers and optical isomers exist. Are also included in the present invention.

The present invention also replaces the fact that one or more atoms in a compound of formula (1) have been 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 agent for confirming 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 they are easy to produce and detect. In this regard, such compounds are also useful in 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.

  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 salts thereof. 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.

Process for producing the compound of the present invention

In the following, the formula (1) in 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。

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.

(Manufacturing method 1)
The compound represented by formula (1) may, for example, D is _(CH 2) _u - For ^(R 12 -1), the compound V is an oxygen atom (1 ') can be prepared by the following method .

（式中、ｒ、ｓ、ｒ’、ｓ’、ｕ、Ａ、Ｂ、Ｕ、Ｗ、Ｘ、Ｙ、Ｚ、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、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）

(Wherein, r, s, r ′, s ′, u, A, B, U, W, X, Y, Z, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ ′, R ¹¹ ′ and R ¹³ means the same as described above, and L ¹ means 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 an appropriate 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 a reactive derivative represented by formula (1-2), L ¹ represents a hydroxyl group. Formula (1-3): R < ¹⁶ > -COOH
(Wherein R ¹⁶ means the same as above)
And alkyl esters (particularly methyl esters), active esters, acid anhydrides or carboxylic acid halides (particularly carboxylic acid chlorides) of the carboxylic acid compounds.
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 represents the same as described above), the reactive derivative represented by the formula (1-2) is:
Formula ^{(1-4): R 16 O-} CO-L 1
(In the formula, L ¹ and R ¹⁶ are the same as those described above.)
The compound represented by these can be mentioned.
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 represents the same as the above), the reactive derivative represented by the formula (1-2) Is
Formula _{^{(1-5): R 16 -SO 2}} -L 1
(In the formula, L ¹ and R ¹⁶ are the same as those described above.)
The compound represented by these can be mentioned.

In the formula (1 ′), when —R ¹³ represents —CONR ¹⁹ R ²⁰ (wherein R ¹⁹ and R ²⁰ are the same as described above), the reactivity represented by the formula (1-2) As derivatives,
Formula ^{(1-6): R 19 R 20} N-CO-L 1
(In the formula, L ¹ , R ¹⁹ and R ²⁰ mean the same as above)
The compound represented by these can be mentioned.

  The reaction between the compound represented by the formula (1-1) and the reactive derivative represented by the formula (1-2) is performed in a solvent or under no 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. Two or more kinds may be mixed and 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 type 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, especially chlorine and bromine, or methanesulfonyloxy and p-toluenesulfonyloxy are preferred

The compound of the formula (1-1) described in the production method 1 is, for example, a compound in which B is (B-2), D is (CH ₂ ) _u- (R ¹² -1), and u is 1 (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), D is (CH ₂ ) _u- (R ¹² -1), and u is 0, the compound (1-1 '') is produced by the method shown in Production Method 3. I can do it.
(Manufacturing method 2)

〔式中、ｒ、ｓ、ｒ’、ｓ’、Ａ、Ｕ、Ｗ、Ｘ、Ｙ、Ｚ、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は前掲と同じものを意味し、Ｒ^１０、Ｒ^１１、Ｒ^１０’およびＲ^１１’は、それぞれ独立して前掲より選択される置換基を意味し、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〕

[Wherein, r, s, r ′, s ′, A, U, W, X, Y, Z, R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as described above, and R ¹⁰ , R ¹¹ , R ¹⁰ ′ and R ¹¹ ′ each independently represent a substituent selected from the above, L ² represents a protecting group which can be eliminated by hydrolysis or hydrogenolysis, and L ³ represents —CH _2- L ⁴ (L ⁴ means a leaving group) or formyl group]

(Manufacturing method 3)

〔式中、ｒ、ｓ、ｒ’、ｓ’、Ａ、Ｕ、Ｗ、Ｘ、Ｙ、Ｚ、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は前掲と同じものを意味し、Ｒ^１０、Ｒ^１１、Ｒ^１０’およびＲ^１１’は、それぞれ独立して前掲より選択される置換基を意味し、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〕

[Wherein, r, s, r ′, s ′, A, U, W, X, Y, Z, R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as described above, and R ¹⁰ , R ¹¹ , R ¹⁰ ′ and R ¹¹ ′ each independently represents a substituent selected from the above, L ² represents a protecting group which can be eliminated by hydrolysis or hydrogenolysis, and L ⁵ represents an oxo group Or a leaving group)

Hereinafter, step 1 to step 4 in the production method 2 or 3 will be described.
1) Alkylation step by substitution reaction 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 When L ⁵ represents a leaving group in the compound of formula (3-1), which is a production intermediate of production method 3, steps 1 and 3 are alkylation steps by a substitution reaction, and are performed in a solvent or without a solvent. Done. 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. , An alkali bicarbonate such as potassium bicarbonate, or an organic base such as triethylamine, tributylamine, diisopropylethylamine, or N-methylmorpholine, but the compound represented by the formula (2-1) as an excess 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. Among them, halogen atoms, particularly chlorine and bromine, or methanesulfonyloxy and p-toluenesulfonyloxy are preferable. 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 type of raw material compound used, it is generally about 0 ° C to about 200 ° C, preferably about 20 ° C to about 150 ° C.

  Compounds of formula (2-2) and formula (3-1) are commercially available or can be prepared by known methods. That is, the corresponding alcohol derivative of formula (2-2a) or formula (3-1a) is converted into a leaving group by a conventional method to obtain a compound represented by formula (2-2b) or formula (3-1b). Can be manufactured.

（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）
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。

(Wherein r ′, s ′, R ¹⁰ ′, R ¹¹ ′ and L ² mean the same as above)
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 When L ³ represents a formyl group in the compound of formula (2-2) which is a production intermediate of production method 2, and formula (3-1) which is a production intermediate of production method 3 In the above compound, when L ⁵ represents an oxo group, Step 1 and Step 3 are reductive alkylation steps. For example, the reaction can be carried out under the following conditions. That is, (I) catalytic reduction using platinum oxide or palladium carbon as a catalyst in the presence of a catalytic amount of acid as required, and (II) pyridine-borane in the presence of a catalytic amount or an excess amount of acid as required. And borane complexes such as triethylamine-borane, reduction using sodium borohydride, sodium triacetoxyhydroborate or sodium cyanoborohydride, and the like. 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.

The compounds of formula (2-2) and formula (3-1) used here are commercially available or can be prepared by known methods. That is, a corresponding formyl derivative of formula (2-2c) and an oxo derivative of formula (3-1c) are produced by oxidizing corresponding alcohol derivatives of formula (2-2a) and formula (3-1a) by a conventional method. Can do. 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 (2-2c) 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 (2-2d) with DIBAH (diisobutylaluminum hydride).

（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（２−２ｄ）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。

(Wherein r ′, s ′, R ¹⁰ ′, R ¹¹ ′ and L ² mean the same as above)
In addition, the compound represented by Formula (2-2d) used at the said process is marketed, or can be manufactured by a well-known method.

3) Deprotecting group step Steps 2 and 4 are deprotecting group reaction steps. In production method 2 and 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 include acetyl group, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, triphenylmethyl group, methanesulfonyl group, p-toluenesulfonyl group and the like.
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, isopropanol, acetonitrile, dioxane, water, or a mixture thereof can be 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 eliminated by hydrogenolysis include, for example, benzyloxycarbonyl group, 3- or 4-chlorobenzyloxycarbonyl group, benzyl group, 4-methoxybenzyl group. Etc.
Deprotection by hydrogenolysis can be carried out 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 the reaction 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.

(Manufacturing method 4)
For example, a formula (2- The compound of 1 ′) has the following production method:

（式中、ｌ、ｒ、ｓ、Ｗ、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^１０、Ｒ^１１及びＬ^２は前掲と同じものを意味し、Ｌ^６は脱離基を意味し、Ｌ^７は水酸基か脱離基を意味する）
で製造する事ができる。

(Wherein, l, r, s, W, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ and L ² are the same as described above, and L ⁶ is a leaving group. , L ⁷ means a hydroxyl group or a leaving group)
Can be manufactured.

Step 1 is a cyanation step. In this step, examples of the leaving group represented by L ⁶ include bromine and p-toluenesulfonyl group. As the base used in this reaction, for example, trimethylamine, triethylamine, DMAP (4-N, N-dimethylaminopyridine), pyridine, butyllithium, sodium hydride, lithium hexamethyldisilazide or the like alone or A combination of two or more bases is used. The reaction temperature is generally about −80 ° C. to about 100 ° C., preferably about 0 ° C. to about 80 ° C. 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, and dimethyl sulfoxide. These solvents may be used alone or in combination of two or more. Used.

Step 2 is a reaction in which a hydroxylamine is allowed to act on a cyano group to obtain an amidinooxime 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 the formula (4-7) can be produced by reacting with the reactive derivative represented by 6).

Step 3-1 (condensation step)
Examples of the reactive derivative include a carboxylic acid compound represented by (4-6), an alkyl ester (particularly methyl ester), an active ester, an acid anhydride, and an acid halide (particularly acid chloride) of the carboxylic acid compound. it can.
Case (4-6) is a carboxylic acid compound ^{(L 7} are hydroxyl groups),
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, propanephosphonic anhydride and the like. it can. 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.
As a specific example when (4-6) is an active ester,
p-nitrophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester, etc. It is done.
As a specific example when (4-6) is an acid anhydride,
Symmetric acid anhydrides or mixed acid anhydrides are used. Specific examples of mixed acid anhydrides include mixed acid anhydrides with chlorocarbonic acid alkyl esters such as ethyl chlorocarbonate and isobutyl chlorocarbonate, and chlorocarbons such as benzyl chlorocarbonate. Examples thereof include mixed acid anhydrides with carbonic acid aralkyl esters, mixed acid anhydrides with chlorocarbonic acid aryl esters such as phenyl chlorocarbonate, and mixed acid anhydrides with alkanoic acids such as isovaleric acid and pivalic acid.

This reaction is carried out 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, 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. 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.

  While the reaction temperature varies depending on the type 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 ⁷ include halogen atoms such as chlorine, bromine and iodine, alkylsulfonyloxy groups such as methanesulfonyloxy group, and arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy. A halogen atom, in particular chlorine and bromine, or a methanesulfonyloxy and trifluoromethanesulfonyloxy group.

This reaction is carried out 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, 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. 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.

While the reaction temperature varies depending on the type of raw material compound used, it is generally about 0 ° C to about 200 ° C, preferably about 20 ° C to about 150 ° C.

Step 3-2 (Cyclization step)
The compound of formula (4-7) is reacted in the presence or absence of a suitable additive such as a base as described in the literature (for example, Current Organic Chemistry, (2008), 12 (10), 850). By the thing, the compound of Formula (4-8) can be manufactured.

This reaction is carried out 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, 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 N-methylmorpholine and tetrabutylammonium fluoride are used. While the reaction temperature varies depending on the type 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. A 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.

(Manufacturing method 5)
The compound of the formula (4-1) described in the production method 4 can be produced by a commercially available method. For example, when W is a compound (4-1 ′) in which N—R ¹ is represented, the following production method:

（式中、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｌ^２およびＬ^４は前掲と同じものを意味し、Ｌ^８はハロゲン原子等の脱離基、Ｌ^９はメチル、エチル基等のアルキル基を意味し、Ｌ^１０は加水分解、加水素分解、もしくは加チオール分解により脱離し得る保護基を意味する）
で製造する事ができる。
なお、工程１〜６は文献（例えば、Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ， １９９９， Ｖｏｌ． ４２， Ｎｏ． １５, ２８７０）記載の方法を参考にすることができる。

(In the formula, R ⁴ , R ⁵ , R ⁶ , R ⁷ , L ² and L ⁴ are the same as described above, L ⁸ is a leaving group such as a halogen atom, L ⁹ is a methyl, ethyl group, etc. L ¹⁰ represents an alkyl group, and L ¹⁰ represents a protective group that can be removed by hydrolysis, hydrogenolysis, or thiol decomposition)
Can be manufactured.
Steps 1 to 6 can refer to methods described in literature (for example, Journal of Medicinal Chemistry, 1999, Vol. 42, No. 15, 2870).

Step 1 is a substitution reaction, a compound of formula (5-1) (preferably L ⁸ is fluorine or chlorine atom) with a compound of the formula (5-2), the presence or absence of a base such as a suitable additive The compound of Formula (5-3) can be manufactured by making it react under.

This reaction is carried out 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, 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 the like. Or it mixes and uses 2 or more types.

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, An organic base such as N-methylmorpholine is used. The reaction temperature is generally about 0 ° C to about 200 ° C, preferably about 20 ° C to about 150 ° C.

In step 2, the compound of formula (5-3) is also produced by reacting the compound of formula (5-5) in the same manner as 2) reductive alkylation reaction in production methods 2 and 3. Means you can.

Step 3 is a step of reducing a nitro group to an amino group in the presence of a metal. The reduction reaction can be performed in an inert solvent in the presence of a metal such as palladium-carbon, palladium hydroxide, rhodium-carbon in a hydrogen atmosphere. Examples of the solvent include ether solvents such as tetrahydrofuran, diethyl ether, dioxane, and cyclopentyl methyl ether, hydrocarbon solvents such as toluene and benzene, alcohol solvents such as methanol and ethanol, and mixed solvents thereof. The reduction reaction is usually performed at −10 ° C. to heating reflux temperature, for 0.5 to 6 hours, in the presence of a metal such as zinc or iron, with an organic acid such as acetic acid acting as an acid, or hydrogen chloride, It can also be carried out by reacting an inorganic acid such as ammonium chloride. Examples of the solvent include ether solvents such as tetrahydrofuran and dioxane, hydrocarbon solvents such as toluene and benzene, alcohol solvents such as methanol and ethanol, water, or a mixed solvent thereof.

Step 4 is a cyclization reaction. The compound of formula (4-1 ′) can be produced by reacting the compound of formula (5-4) with a urea agent in the presence of a suitable additive such as a base.
Examples of urea agents include 1,3-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, N, N′-carbonyldisuccinic acid imide, phosgene, diphosgene, triphosgene, and chloro such as ethyl chlorocarbonate and ethyl chlorocarbonate. And carbonyl equivalents such as carbonic acid alkyl esters.

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 are 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, N-methylmorpholine. The reaction temperature is generally about 0 ° C to about 150 ° C, preferably 20 ° C to about 80 ° C.

Step 5 is an alkylation reaction. A compound of formula (5-8) is produced by reacting a compound of formula (5-6) with a compound of formula (5-7) in the same manner as in 1) alkylation reaction in production methods 2 and 3. be able to.

Step 6 is a deprotection reaction. The compound of the formula (4-1 ′) can be produced by reacting the compound of the formula (5-8) in the same manner as the 3) deprotection reaction in the production methods 2 and 3.

Step 7 is a protection reaction. The amino group of the compound of formula (5-9) is protected by a conventional method with a tert-butoxycarbonyl group, acetyl group, benzoyl group, trifluoroacetyl group, benzyloxycarbonyl group, 2-nitrobenzenesulfonyl group, etc. 5-10) can be produced.

Step 8 is an alkylation reaction. In the same manner as in Step 5, the compound of formula (5-10) and the compound of formula (5-7) are reacted in the same manner as in 1) alkylation reaction in production methods 2 and 3, to thereby formula (5-11) Can be produced.

Step 9 is a deprotection reaction. Conditions of the compound of formula (5-11) mentioned in 3) deprotection reaction in production methods 2 and 3 or conditions described in the literature (for example, Synlet, 1999, 1301., Tetrahedron, 2002, 58, 6267.) For example, a compound of formula (5-12) can be produced by deprotecting the 2-nitrobenzenesulfonyl group.

Step 10 is a deprotection reaction. This step is a step of producing a carboxylic acid compound (5-13) by deprotecting the ester group of the compound of formula (5-12) by hydrolysis. To implement this process, Protective Groups in Organic Synthesis, Green, John Wiley & Sons Inc. (1981) ) And the like.
Specifically, for example, the following method is used. When L ⁹ is, for example, a methyl group or an ethyl group, it can be led to a carboxylic acid by alkaline hydrolysis or acid hydrolysis. That is, for example, in the presence of an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, or magnesium hydroxide, in water, or such as methanol, ethanol, 2-propanol, or Usually in an alcohol solvent such as butanol, an ether solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon solvent such as benzene, toluene or xylene, or a mixed solvent thereof. The compound of the formula (5-13) can be produced by reacting in the temperature range of room temperature to heating reflux for 0.5 to 48 hours.

Step 11 is a cyclization reaction. In this step, the carboxyl group of the compound of the formula (5-13) is converted into an azide compound and an inert organic solvent by a method described in the literature (for example, Bioorganic & Medicinal Chemistry Letters 18, (2008), 5010-5014). The base is reacted at room temperature to the boiling point of the solvent, preferably at 100 ° C. inside or outside for 1 hour to 24 hours, preferably several hours to 10 to several hours, thereby converting it into an isocyanate group by a Curtius rearrangement reaction, This is a step for producing a compound of the formula (4-1 ′) by the intramolecular cyclization reaction.
Examples of the azide compound include diarylphosphoryl azide such as diphenylphosphoryl azide, alkali metal azide such as sodium azide, and trialkylsilyl azide such as trimethylsilyl azide, among which diphenylphosphoryl azide is preferable. is there.

The inert organic solvent is not particularly limited as long as it does not adversely affect the reaction, and specific examples include toluene, 1,4-dioxane, tetrahydrofuran, and the like, and toluene is particularly preferable.
Examples of the base used in the reaction include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N-dimethylaniline, 1,8-diazabicyclo [5. 4.0] undec-7-ene (DBU), tertiary aliphatic amines such as 1,5-azabicyclo [4.3.0] non-5-ene (DBN); for example, pyridine, 4-dimethylamino Aromatic amines such as pyridine, picoline, lutidine, quinoline and isoquinoline; alkali metals such as metal potassium, metal sodium and metal lithium; alkali metal hydrides such as sodium hydride and potassium hydride; alkalis such as butyl lithium Metal alkylates; for example potassium-tert-butyler , Sodium ethylate, alkali metal alkoxides such as sodium methylate; and alkali metal carbonates such as for example potassium carbonate; for example potassium hydroxide, alkali metal hydroxides such as sodium hydroxide. Triethylamine, N, N-diisopropylethylamine and the like are particularly suitable.

(Manufacturing method 6)
The compound of the formula (4-1) described in the production method 4 can be produced by a commercially available method. For example, when W is a compound (4-1 ″) in which CR ¹ R ² is represented, commercially available and known methods, or the following production methods:

（式中、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｌ^２およびＬ^４は前掲と同じものを意味する）
で製造する事ができる。

(In the formula, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , L ² and L ⁴ are the same as described above)
Can be manufactured.

Step 1 is a protection reaction. L ² can be introduced by a conventional method. Preferably, L ² is an acetyl group, and the compound of formula (6-2) can be produced according to the method described in the literature (for example, Journal of Organic Chemistry, 2005, vol. 70, 5, 1828-1834). .

  Step 2 is an alkylation reaction. A compound of formula (6-4) is produced by reacting a compound of formula (6-2) with a compound of formula (6-3) in the same manner as in 1) alkylation reaction in production methods 2 and 3. be able to.

  Step 3 is a deprotection reaction. A compound of formula (4-1 ″) can be produced by reacting the compound of formula (6-4) in the same manner as 3) deprotection reaction in Production Methods 2 and 3.

(Manufacturing method 7)
In addition, in the compound represented by the formula (1), for example, B is the formula (B-2), D is an optionally substituted C _1-6 alkyl group, and an optionally substituted C _3-6 alkenyl. Groups, optionally substituted C _3-6 alkynyl groups, optionally substituted C _3-8 monocyclic, C _7-10 bicyclic or C _7-12 tricyclic cycloalkyl groups, and substituted In the case of the C _5-8 monocyclic or C _7-10 bicyclic cycloalkenyl group which may be prepared, and the compound (1 ″) in which V is an oxygen atom, it can also be produced by the following method.

〔式中、ｒ、ｓ、Ａ、Ｕ、Ｗ、Ｘ、Ｙ、Ｚ、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、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（Ｄ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〕

[Wherein, r, s, A, U, W, X, Y, Z, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ and R ¹¹ are the same as those described above, and L ⁵ represents An oxo group (when L ⁵ is present on the primary carbon atom of D, 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 a compound of formula (2-1) and a compound of formula (7-1) are converted into the same as 1) alkylation reaction in production methods 2 and 3. The compound of the formula (1 ″) can be produced by reacting by a method.

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

(Manufacturing method 8)
In addition, for example, when the compound represented by the formula (1) is a compound (1 ′ ″) in which B is the formula (B-2), D is the formula (R ¹² -3), and V is an oxygen atom, It can also be produced by the following method.

〔式中、ｒ、ｓ、ｒ’ 、ｓ’ 、ｕ、Ａ、Ｕ、Ｗ、Ｘ、Ｙ、Ｚ、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、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（８−１）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〕

[Wherein, r, s, r ′, s ′, u, A, U, W, X, Y, Z, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ , R ¹⁰ ′ and R ¹¹ ′ means the same as described above, and L ⁵ represents an oxo group (when L ⁵ is present on the primary carbon atom of the formula (8-1), forms a formyl group together with the carbon atom) or (Means 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 (8-1) are converted into the same method as 1) alkylation reaction in production methods 2 and 3. The compound of the formula (1 ′ ″) can be produced by reacting by a method.

When L ⁵ is an oxo group, step 1 is a reductive alkylation reaction, and the compound of formula (2-1) and the compound of formula (8-1) are converted into 2) reductive alkylation reaction in production methods 2 and 3. The compound of the formula (1 ′ ″) can be produced by reacting in the same manner as described above.

(Manufacturing method 9)
The compound represented by the formula (1) is, for example, a compound (1 ″ ″) in which X is a nitrogen atom, Z is a nitrogen atom, Y is an oxygen atom, V is an oxygen atom, and U is a carbon atom. In this case, it can also be produced by the following method.

（式中、Ａ、Ｂ、Ｄ、Ｗ、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７およびＬ^７は前掲と同じものを意味する）

(In the formula, A, B, D, W, R ⁴ , R ⁵ , R ⁶ , R ⁷ and L ⁷ mean the same as the above).

  Step 1-1 is a condensation reaction, and step 1-2 is a subsequent cyclization reaction. In the same manner as in Steps 3-1 and 3-2 in Production Method 4, the compound of formula (4-5) and the compound of formula (9-1) are subjected to a condensation reaction and subjected to a cyclization reaction, thereby obtaining a compound of formula (1). '' '') Can be produced.

(Manufacturing method 10)
The compound represented by the formula (1) includes, for example, X is a nitrogen atom, Z is a nitrogen atom, Y is an oxygen atom, V is an oxygen atom, U is a carbon atom, A is a formula (A-3), B In the case of the compound formula (1 ′ ″ ″) representing the formula (B-1), it can also be produced by the following method.

（式中、ｏ、ｐ、ｑ、Ｗ、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、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）

(Wherein, o, p, q, W, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , L ² and L ⁷ are the same as the above, and L ⁵ and L ¹¹ are Each independently an oxo group (when L ⁵ or L ¹¹ is on the primary carbon atom, it forms a formyl group with the carbon atom) or a leaving group)

Steps 1 and 1 'are a condensation reaction followed by a cyclization reaction. By reacting the compound of formula (4-5) with the compound of formula (10-1) or formula (10-9) by the same method as in steps 3-1 and 3-2 in production method 4, respectively The compound of (10-2) and Formula (10-4) can be manufactured.

When L ¹¹ is a leaving group, Step 2 and Step 2 ′ are alkylation reactions, and the compound of Formula (10-2) and the compound of Formula (10-3) or Formula (10-8) are produced in Production Method 2. 1 and 3, the compounds of formula (1 ′ ″ ″) and formula (1-2) can be produced by reacting in the same manner as in the alkylation reaction.

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 (10-2) and a compound of formula (10-3) or formula (10-8) By reacting in the same manner as 2) reductive alkylation reaction in 2 and 3, compounds of formula (1 ′ ″ ″) and formula (1-2) can be produced, respectively.

Step 3 is a deprotection reaction. A compound of formula (10-5) can be produced by performing a deprotection reaction on the compound of formula (10-4) 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. The compound of the formula (10-5) and the compound of the formula (10-6), or the compound of the formula (1-2) and the compound of the formula (10-7) are the same as in 1) alkylation reaction in the production methods 2 and 3. The compounds of formula (1-2) and formula (1 ′ ″ ″) can be produced by reacting by the method of

When L ⁵ is an oxo group, Step 4 and Step 5 are reductive alkylation reactions, and a compound of formula (10-5) and a compound of formula (10-6) or a compound of formula (1-2) By reacting the compound of the formula (10-7) in the same manner as the 2) reductive alkylation reaction in the production methods 2 and 3, the compounds of the formula (1-2) and the formula (1 ′ ″ ″) are obtained, respectively. Compounds can be produced.

(Manufacturing method 11)
The compound represented by the formula (2-1) is

（式中、ｒ、ｓ、Ａ、Ｒ^４、Ｒ^５、Ｒ^６およびＲ^７は、前掲と同じものを意味する）
例えば、
式中、Ｘ及びＹが窒素原子、Ｚが酸素原子、Ｕが炭素原子を表す場合、参考例９９に示す方法と同様にして製造でき、
式中、Ｘが酸素原子、Ｙ及びＺが窒素原子、Ｕが炭素原子を表す場合、参考例１００に示す方法と同様にして製造でき、
式中、Ｘが窒素原子、Ｚが硫黄原子、Ｙ及びＵが炭素原子を表す場合、参考例１０１に示す方法と同様にして製造でき、
式中、Ｘが酸素原子、Ｚが窒素原子、Ｙ及びＵが炭素原子を表す場合、参考例１０２に示す方法と同様にして製造でき、
式中、Ｘ、Ｙ及びＵが窒素原子、Ｚが炭素原子を表す場合、参考例１０３に示す方法と同様にして製造でき、
式中、Ｘが酸素原子、Ｙが窒素原子、Ｚ及びＵが炭素原子を表す場合、参考例１０４に示す方法と同様にして製造できる。

(Wherein, r, s, A, R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as described above)
For example,
In the formula, when X and Y are a nitrogen atom, Z is an oxygen atom, and U is a carbon atom, it can be produced in the same manner as in Reference Example 99,
In the formula, when X represents an oxygen atom, Y and Z represent a nitrogen atom, and U represents a carbon atom, it can be produced in the same manner as the method shown in Reference Example 100,
In the formula, when X represents a nitrogen atom, Z represents a sulfur atom, and Y and U represent a carbon atom, they can be produced in the same manner as in Reference Example 101,
In the formula, when X represents an oxygen atom, Z represents a nitrogen atom, and Y and U represent a carbon atom, it can be produced in the same manner as the method shown in Reference Example 102,
In the formula, when X, Y and U represent a nitrogen atom and Z represents a carbon atom, it can be produced in the same manner as the method shown in Reference Example 103,
In the formula, when X is an oxygen atom, Y is a nitrogen atom, and Z and U are carbon atoms, they can be produced in the same manner as the method shown in Reference Example 104.

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 protective 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 each of 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, 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 (for example, 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), and salts thereof.
In addition, 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 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 necessary (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 functional group present in the structural formula, selection of the raw material compound, and reaction treatment conditions. Can be converted to compounds.

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.

The following (i) to (v) may be mentioned as diseases or symptoms in which agonistic (agonist) action, partial agonistic (partial agonist) action on serotonin 4 receptor is desired and / or required:
(I) neuropsychiatric disorders 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 diseases, scleroderma, diabetes mellitus, nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain, chest Gastrointestinal symptoms such as burns or ambiguity;
(V) Urinary system diseases accompanied by dysuria due to 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 agonistic 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 cross-linked 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; sulfates 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.
Stabilizers include, for example, 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 disorders described in i), particularly Alzheimer's 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), α4β2nACh receptor agonist (AZD-1446, CHANTIX (varenicline), etc.), nAChR agonist (ABT-089, etc.), AMPA receptor agonist (CX-717, LY-451395, etc.), histamine H3 receptor Antagonists (ABT-288, SAR-110894, PF-03654746, etc.), muscarinic M1 receptor agonists (MCD-386, GSK-1034702, etc.), PDE4 inhibitors (etazolate, etc.), PDE9 inhibitors (PF-04447943) ), Histone deacetylase inhibitor (EVP-0334, etc.), σ1 receptor agonist (Anavex-2-73, etc.), γ-secretase inhibitor (GSI) (BMS-708163, NIC5-15, ELND-006, MK) -0752), γ-secretase inhibitor (GSM) (E-2212, CH F-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) ), 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.) and other agents with neuroprotective action (SK-PC-B70M, T-817MA, davunetide, HF-0220, PF-4494700, PYM-50028, CERE-110, ASP-0777, TAK-065, AAD- 2004, etc.), combined with other drugs used to treat various types of dementia, 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 : Triacetoxy sodium borohydride
(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 CDCl ₃ : deuterated chloroform CD ₃ OD: deuterated methanol DMSO-d ₆ : deuterated dimethyl sulfoxide
Me: methyl
Et: ethyl
nPr: Normal propyl
iPr: Isopropyl
cPr: Cyclopropyl
nBu: Normal butyl
iBu: Isobutyl
cBu: Cyclobutyl
Ph: Phenyl Ac: Acetyl Ms: Mesyl
Boc: tert-butoxycarbonyl
Pd-C: Palladium-carbon
NaBH ₃ (CN): Sodium cyanoborohydride
Cbz or Z: benzyloxycarbonyl s: singlet d: doublet t: triplet q: quadruple line m: multiple line br: wide dd: double doublet td: triplet doublet J: Coupling constant
Hz: Hertz
N: Normal (for example, 2NHCl indicates 2N hydrochloric acid)
M: Molar concentration (mol / L) (Example: 2M methylamine indicates a 2 mol / L methylamine solution)
min: minutes
atm: atmospheric pressure

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 MH ⁺ .
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: Liquid A: 0.05% TFA / H ₂ O, Liquid 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: 2.4mL / min
UV: 220nm

Measurement method B:
LC-MS: Waters ACQUITY ^TM UltraPerformance LC
Column: Waters ACQUITY UPLC BEH Phenyl 1.7μm, 2.1 × 50 mm
Solvent: A solution: 0.05% formic acid / H ₂ O, B solution: 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 minutes; A / B = 90: 10
Flow rate: 0.75 mL / min UV: 220, 254 nm
Column temperature: 40 ° C

NMR in this specification was measured using JEOL JNM-AL series AL300 and AL400.
Unless otherwise specified, commercially available materials were used for the raw material compounds, reaction reagents, and solvents.

Reference example 001:
Preparation of 1- (propan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one:

(1) 2-Nitroaniline (6.91 g) is dissolved in 1,2-dichloroethane (80 ml), 2-methoxypropene (7.13 ml), acetic acid (2.86 ml), sodium triacetoxyborohydride (15. 9 g) was added and stirred at room temperature for 27 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 6/1) to give 2-nitro-N- (propan-2-yl) aniline (7.97 g) as yellow crystals. Obtained.
LC-MS, m / z; 181 (MH ⁺ ).

(2) The product (7.97 g) was dissolved in methanol (60 ml), 10% palladium / carbon (50% wet, 6 g) was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours. After completion of the reaction, the mixture was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to obtain N- (propan-2-yl) benzene-1,2-diamine (5.91 g) as a dark purple oily substance. It was.
LC-MS, m / z; 151 (MH ⁺ ).

(3) The product (5.91 g) was dissolved in tetrahydrofuran (130 ml), N, N′-carbonylimidazole (7.96 g) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, the organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give the titled compound (6.26 g) as white crystals.
LC-MS, m / z; 177 (MH ⁺ ).

  Instead of 2-nitroaniline in Reference Example 001, the corresponding raw material compound was used to produce the compounds shown in the following table (Reference Examples 002 to 004) by the same method as Reference Example 001.

Reference example 005:
Preparation of 1-cyclopropyl-1,3-dihydro-2H-benzimidazol-2-one:

(1) Cyclopropylamine (20 ml) was added to 1-chloro-2-nitrobenzene (9.45 g), and the mixture was stirred at 110 ° C. for 2 days in a sealed tube. After allowing to cool to room temperature, saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was then dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 10/1) to obtain N-cyclopropyl-2-nitroaniline (7.84 g) as a crude product.

(2) The crude product (7.84 g) was dissolved in acetic acid (150 ml), iron powder (12.29 g) was added, and the mixture was stirred at 70 ° C. for 3 hours. After cooling to room temperature, the iron powder was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 6/1) to obtain N-cyclopropylbenzene-1,2-diamine (0.76 g).
LC-MS, m / z; 149 (MH ⁺ ).

(3) Using the product (0.76 g), the title compound (0.43 g) was obtained in the same manner as in Reference Example 001 (3).
LC-MS, m / z; 175 (MH ⁺ ).

Reference Example 006:
Preparation of 4-chloro-1- (propan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one:

(1) 3-Chloro-2-N- (propan-2-yl) -2-nitroaniline using 3-chloro-2-nitroaniline (3.45 g) in the same manner as in Reference Example 001 (1) (2.6 g) was obtained.
LC-MS, m / z; 215 (MH ⁺ ).

(2) Using the above product (2.6 g), 3-chloro-N- (propan-2-yl) benzene-1,2-diamine (1. 69 g) was obtained.
LC-MS, m / z; 185 (MH ⁺ ).

(3) Using the product (1.69 g), the title compound (1.84 g) was obtained in the same manner as in Reference Example 001 (3).
LC-MS, m / z; 211 (MH ⁺ ).

Reference example 007:
Preparation of 1-ethyl-1,3-dihydro-2H-benzimidazol-2-one:

(1) 1,3-dihydro-2H-benzimidazol-2-one (6.71 g) and N, N-dimethylaminopyridine (0.61 g) were dissolved in THF (200 ml), and di-tert-butyl dicarbonate was dissolved. (24 g) was slowly added and then heated to reflux for 1 hour. After cooling to room temperature, THF was distilled off by concentration under reduced pressure, and the resulting residue was dissolved in ethyl acetate (150 ml). Next, the organic layer was washed with an ice-cooled 0.5N aqueous hydrochloric acid solution (50 ml) and then with a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain di-tert-butyl 2-oxo-1H-benzimidazole-1,3 (2H) -dicarboxylate. The obtained crude product was dissolved in acetonitrile (170 ml), 1,3-dihydro-2H-benzimidazol-2-one (6.7 g) and potassium carbonate (8.29 g) were added, and the mixture was heated to reflux for 3 hours. The reaction mixture was allowed to cool at room temperature, and then acetonitrile was mostly distilled off by concentration under reduced pressure. Then, 1N aqueous hydrochloric acid (510 ml) was added dropwise with stirring at room temperature, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and washed with water and then with hexane. The obtained solid was dried at 50 ° C. under reduced pressure to obtain tert-butyl 2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (23.1 g) as a solid.
LC-MS, m / z; 235 (MH ⁺ ).

(2) The product (44.13 g) was dissolved in acetonitrile (630 ml), ethyl iodide (18.1 ml) and potassium carbonate (33.8 g) were added, and the mixture was stirred at 80 ° C. for 8 hours. After allowing to cool to room temperature, acetonitrile was distilled off by concentration under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed with saturated brine. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (56.6 g). Was obtained as a crude product.
LC-MS, m / z; 263 (MH ⁺ ).

(3) The above product (56.6 g) was dissolved in methylene chloride (70 ml), trifluoroacetic acid (70 ml) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, methylene chloride and trifluoroacetic acid were removed by concentration under reduced pressure, and toluene (30 ml × 3) was further added and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate (1000 ml). The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (33.1 g) as a crude product.
LC-MS, m / z; 163 (MH ⁺ ).

Reference Example 008:
Preparation of 1-propyl-1,3-dihydro-2H-benzimidazol-2-one:

(1) In tert-butyl 2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 007 (1), 2.34 g) as a raw material in Reference Example 007 (2) Using 1-bromopropane (1.85 g) and sodium iodide (0.15 g) in place of ethyl iodide, tert-butyl 2-oxo-3-propyl-2,3-dihydro-1H- Benzimidazole-1-carboxylate (2.39 g) was obtained.
LC-MS, m / z; 277 (MH ⁺ ).

(2) Using the product (2.39 g), the title compound (2.17 g) was obtained in the same manner as in Reference Example 007 (3).
LC-MS, m / z; 177 (MH ⁺ ).

Reference Example 009:
Preparation of 1-cyclobutyl-1,3-dihydro-2H-benzimidazol-2-one:

(1) tert-Butyl 2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 007 (1), 2.34 g) was dissolved in THF (50 ml) and cyclobutanol (2 .16 g), triphenylphosphine (3.93 g) and diethyl azodicarboxylate (40% toluene solution, 6.8 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/1) to give tert-butyl 3-cyclobutyl-2-oxo-2,3-dihydro-1H. -Benzimidazole-1-carboxylate (0.3 g) was obtained.
LC-MS, m / z; 289 (MH ⁺ ).

(2) Using the product (0.3 g), the title compound (0.21 g) was obtained in the same manner as in Reference Example 007 (3).
LC-MS, m / z; 189 (MH ⁺ ).

Reference example 010:
Preparation of 1- (2-fluoroethyl) -1,3-dihydro-2H-benzimidazol-2-one:

(1) In tert-butyl 2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 007 (1), 2.34 g) as a raw material in Reference Example 009 (1) 2-Fluoroethanol (1.92 g) was used instead of cyclobutanol, and tert-butyl 3- (2-fluoroethyl) -2-oxo-2,3-dihydro-1H-benzimidazole-1- Carboxylate (1.06 g) was obtained.
LC-MS, m / z; 281 (MH ⁺ ).

(2) Using the product (1.06 g), the title compound (0.77 g) was obtained in the same manner as in Reference Example 007 (3).
LC-MS, m / z; 181 (MH ⁺ ).

Reference Example 011:
Preparation of 1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one:

(1) 1,4-Difluoro-2-nitrobenzene (63.6 g) is dissolved in THF (800 ml), 70% ethylamine aqueous solution (51.5 g) and potassium carbonate (111 g) are added, and the mixture is stirred at 50 ° C. for 5 hours. did. After completion of the reaction, insoluble matters were removed by filtration, and after washing with THF, the filtrate was concentrated under reduced pressure to obtain N-ethyl-4-fluoro-2-nitroaniline (75.6 g) as a yellow solid.
LC-MS, m / z; 185 (MH ⁺ ).

(2) N ¹ -ethyl-4-fluorobenzene-1,2-diamine (4.58 g) was obtained by the same method as in Reference Example 001 (2) using the product (5.53 g). It was.
LC-MS, m / z; 155 (MH ⁺ ).

(3) Using the product (75.6 g), the title compound (62.1 g) was obtained as light gray crystals in the same manner as in Reference Example 001 (3).
¹ H NMR (CDCl ₃ , δppm); 1.36 (3H, t, J = 7.2 Hz), 3.95 (2H, q, J = 7.3 Hz), 6.78-6.92 (3H, m), 10.37 (1H, s). LC-MS, m / z; 181 (MH ⁺ ).

  Instead of 1,4-difluoro-2-nitrobenzene in Reference Example 011, the compounds shown in the following table (Reference Examples 012 to 016) were produced in the same manner as in Reference Example 011 using the corresponding raw material compounds.

Reference Example 017:
Production of 1,7-dimethyl-1,3-dihydro-2H-benzimidazol-2-one:

(1) 2-Amino-3-methylbenzoic acid (4.41 g) was dissolved in methanol (100 ml), thionyl chloride (5.3 ml) was added under ice cooling, and the mixture was heated to reflux overnight. After allowing to cool to room temperature, methanol was removed by concentration under reduced pressure, 1N aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with ethyl acetate (1000 ml). The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, and then the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give methyl 2-amino-3-methylbenzoate (2 0.01 g) was obtained.
LC-MS, m / z; 166 (MH ⁺ ).

(2) The product (4.26 g) was dissolved in pyridine (50 ml), 2-nitrobenzenesulfonyl chloride (6.29 g) was added under ice cooling, and the mixture was stirred overnight at room temperature. After completion of the reaction, pyridine was distilled off by concentration under reduced pressure, 1N aqueous hydrochloric acid was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was then dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 2/1) to give methyl 3-methyl-2-{[(2-nitrophenyl) sulfonyl] amino} benzoate (7 .87 g) was obtained.
LC-MS, m / z; 351 (MH ⁺ ).

(3) The product (3.92 g) was dissolved in DMF (30 ml), methyl iodide (3.18 g) and potassium carbonate (3.1 g) were added, and the mixture was stirred at room temperature for 1 hour. Water (60 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was then washed with water and saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product 3-methyl-2- {methyl [(2-nitrophenyl) sulfonyl]. Amino} methyl benzoate (4.12 g) was obtained.

(4) The product (4.12 g) was dissolved in DMF (30 ml), mercaptoacetic acid (4.16 g) and lithium hydroxide monohydrate (3.56 g) were added, and the mixture was stirred at 80 ° C. for 6 hours. After allowing to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. Next, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 6/1) to obtain methyl 3-methyl-2- (methylamino) benzoate (0.95 g).
LC-MS, m / z; 180 (MH ⁺ ).

(5) The above product (0.95 g) was dissolved in ethanol (20 ml), 1N aqueous sodium hydroxide solution (20 ml) was added, and the mixture was stirred at 60 ° C. for 1 hr. After completion of the reaction, ethanol was distilled off by concentration under reduced pressure, and the resulting residue was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 3-methyl-2- (methylamino) benzoic acid (0.63 g).
LC-MS, m / z; 166 (MH ⁺ ).

(6) The product (0.63 g) was dissolved in toluene (15 ml), diphenylphosphoric acid azide (0.78 ml) and triethylamine (0.55 ml) were added, and the mixture was heated to reflux overnight under a nitrogen atmosphere. After allowing to cool to room temperature, toluene was distilled off by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/1) to give the title compound (0.52 g )
LC-MS, m / z; 163 (MH ⁺ ).

Reference Example 018:
Preparation of 6-methoxy-1- (propan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one:

(1) 4-Methoxy-2- (propan-2-ylamino) benzoic acid in the same manner as in Reference Example 001 (1) using methyl 2-amino-4-methoxybenzoate (6.11 g) Methyl (7.33 g) was obtained as a pale yellow oil.

(2) Using the product (7.33 g), 4-methoxy-2- (propan-2-ylamino) benzoic acid (6.43 g) was converted to white in the same manner as in Reference Example 017 (5). Obtained as crystals.
LC-MS, m / z; 210 (MH ⁺ ).

(3) Using the product (6.43 g), the title compound (6.07 g) was obtained in the same manner as in Reference Example 017 (6).
LC-MS, m / z; 207 (MH ⁺ ).

Reference Example 019:
Preparation of 4-methyl-1- (propan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one:

(1) Using 2-amino-6-methylbenzoic acid (1.51 g) in the same manner as (1) in Reference Example 001, 2-methyl-6- (propan-2-ylamino) benzoic acid ( 0.68 g) was obtained.
LC-MS, m / z; 194 (MH ⁺ ).

(2) Using the product (0.68 g), the title compound (0.55 g) was obtained in the same manner as in Reference Example 017 (6).
LC-MS, m / z; 191 (MH ⁺ ).

Reference Example 020:
Preparation of 4-methoxy-1- (propan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one:

The title compound (0.42 g) was obtained in the same manner as in Reference Example 019 using 2-amino-6-methoxybenzoic acid (1.67 g).
LC-MS, m / z; 207 (MH ⁺ ).

Reference Example 021:
Preparation of 4,5-dihydroimidazo [1,5,4-de] [1,4] benzoxazin-2 (1H) -one:

(1) 3- (benzyloxy) benzene-1,2-diamine (DR Buckle, et al., J. Med. Chem., 1987 (30) 12 , 221-2221) (17.4 g) was added to tetrahydrofuran (150 ml). ), N, N′-carbonylimidazole (11.4 g) was added, and the mixture was stirred at room temperature overnight. N, N′-carbonylimidazole (3.0 g) was added to the reaction solution, and the mixture was heated to reflux for 3 hours, and then the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the resulting residue, and a solid insoluble in both phases was collected by filtration. The ethyl acetate layer was concentrated under reduced pressure, and the resulting residue (crude crystals) was combined with the previously obtained solid to produce a small amount. Was washed with ethyl acetate, and the desired product was collected by filtration. The mother liquor was concentrated under reduced pressure, and the resulting residue (crude crystals) was treated in the same manner to give 4-benzyloxy-1,3-dihydro-2H-benzimidazol-2-one (16.6 g in total) as white crystals. Obtained.
1H NMR (DMSO-d ₆ , δppm); 5.18 (2H, s), 6.56 (1H, d, J = 7.8 Hz), 6.69 (1H, d, J = 8.4 Hz), 6.83 (1H, t, J = 8.0 Hz), 7.27-7.40 (3H, m), 7.51-7.53 (2H, m), 10.56 (1H, s), 10.78 (1H, s).

(2) Di-tert-butyl dicarbonate (6.43 g) and potassium carbonate (3.88 g) were added to a solution of the above product (6.75 g) in tetrahydrofuran (120 ml), and the mixture was heated and stirred at 55 ° C. for 6 hours. . The reaction mixture was concentrated under reduced pressure, and chloroform and water were added to the resulting residue for liquid separation, and the organic phase was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude crystals were washed with hexane. The crystals were collected by filtration, and tert-butyl 4-benzyloxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyl. The rate (9.25 g) was obtained as a white solid.
1H NMR (CDCl ₃ , δppm); 1.67 (9H, s), 5.16 (2H, s), 6.79 (1H, d, J = 8.4 Hz), 7.02 (1H, t, J = 8.3 Hz), 7.31-7.45 (6H, m), 8.15 (1H, s).

(3) The product (4.9 g), benzyloxyethanol (2.4 g) and triphenylphosphine (4.1 g) were dissolved in tetrahydrofuran (70 ml), and diethyl azodicarboxylate (2.2 mol / l) was dissolved. 7.2 ml) was added dropwise as a toluene solution and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give tert-butyl-4- (benzyloxy) -3- (2- Benzyloxy) ethyl) -2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (5.3 g) was obtained as an oil.
LC-MS, m / z; 375 ([MH-Boc] ⁺ ).

(4) The above product (4.15 g) was dissolved in ethanol (100 ml), 5% palladium carbon (0.5 g) was added, and hydrogenated overnight at room temperature and normal pressure. 5% palladium carbon (0.5 g) was added, and the reaction was further continued for 5 hours to confirm the disappearance of the raw materials. The reaction mixture was heated to dissolve the product, the catalyst was removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (60 ml), triphenylphosphine (2.3 g) and diethyl azodicarboxylate (4.0 ml as a 2.2 mol / l toluene solution) were added, and the mixture was stirred at room temperature overnight. . The reaction mixture was diluted with ethyl acetate, washed with water and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3/2) to give tert-butyl 2-oxo-4,5-dihydroimidazo [1, 5,4-de] [1,4] benzoxazine-1 (2H) -carboxylate (2.7 g) was obtained as an oil.
1H NMR (CDCl ₃ , δppm); 1.67 (9H, s), 3.99 (2H, t, J = 4.8 Hz), 4.37 (2H, t, J = 4.8 Hz), 6.75 (1H, d, J = 8.1 Hz ), 6.99 (1H, t, J = 8.3 Hz), 7.24 (1H, d, J = 7.8 Hz).

(5) To the above product (2.67 g) was added 4N hydrogen chloride in ethyl acetate (30 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed in turn with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the solvent was evaporated under reduced pressure. The obtained residue (crude crystals) was washed with diisopropyl ether and then filtered to obtain the title compound (1.05 g) as white cotton-like crystals.
1H NMR (CDCl ₃ , δppm); 4.03 (2H, t, J = 4.8 Hz), 4.41 (2H, t, J = 4.8 Hz), 6.65 (1H, dd, J = 9.3, 0.8 Hz), 6.71 (1H , d, J = 7.8 Hz), 6.94 (1H, t, J = 8.1 Hz), 8.92 (1H, brs). LC-MS, m / z; 177 (MH ⁺ ).

Reference Example 022:
Preparation of N′-hydroxy-2-oxo-3- (propan-2-yl) -2,3-dihydro-1H-benzimidazole-1-carboxyimidamide:

(1) 1- (propan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one (Reference Example 001, 880 mg) was dissolved in DMF (10 ml), and 55% hydrogenated under ice cooling. Sodium (458 mg) was added. After stirring for 30 minutes under ice cooling, DMF (10 ml solution) of cyanogen bromide (1.06 g) was added dropwise and stirred overnight at room temperature. After completion of the reaction, water (40 ml) was slowly added dropwise to the reaction mixture with stirring, and the precipitated solid was collected by filtration and washed with water and then with hexane. The obtained solid was dried at 50 ° C. under reduced pressure to give 2-oxo-3- (propan-2-yl) -2,3-dihydro-1H-benzimidazole-1-carbonitrile (769 mg). Obtained as a light brown solid.
LC-MS, m / z; 202 (MH ⁺ ).

(2) The product (1.03 g) was dissolved in ethanol (25 ml), hydroxylamine hydrochloride (1.07 g), potassium carbonate (1.13 g) and water (5 ml) were added, and the mixture was heated to reflux for 17 hours. After allowing to cool to room temperature, ethanol was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.21 g) as an oil.
LC-MS, m / z; 235 (MH ⁺ ).

  In the same manner as in Reference Example 022 except that 1- (propan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one in Reference Example 022 was used, the following table was prepared. Of the compound (Reference Examples 023 to 042).

Reference Example 043
1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one Production of hydrochloride:

(1) 1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid (0.50 g) was dissolved in DMF (4 ml), N, N′-carbonylimidazole (0.36 g) was added, and the mixture was stirred at room temperature for 1 hour. Stir. Subsequently, 3-ethyl-6-fluoro-N′-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide (0.57 g) was added and stirred at 110 ° C. for 20 hours. . The reaction mixture was allowed to cool to room temperature, and water (20 ml) was slowly added dropwise with stirring. The precipitated solid was collected by filtration and washed with water and then with hexane. The obtained solid was dried at 50 ° C. under reduced pressure to give 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl). -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate (0.52 g) was obtained.

(2) The product (0.52 g) was dissolved in 1,4-dioxane (10 ml), 4N hydrochloric acid / 1,4-dioxane solution (10 ml) was added, and the mixture was stirred at room temperature overnight. Hexane (20 ml) was added dropwise to the reaction mixture, and the precipitated solid was collected by filtration and washed with hexane to obtain the title compound (0.44 g) as a white solid.
LC-MS, m / z; 332 (MH ⁺ ).

Reference Example 044
1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one Production of trifluoroacetate:

(1) 1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid (10.6 g) is dissolved in THF (100 ml), N, N′-carbonylimidazole (8.17 g) is added, and 1 degree at 60 degrees. Stir for hours. Subsequently, 3-ethyl-6-fluoro-N′-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide (10.0 g) was added and stirred at 60 ° C. for 2 hours. did. Then, 1N tetrabutylammonium fluoride / THF solution (10 ml) was added to the reaction solution, and the mixture was stirred at 60 ° C. overnight. After completion of the reaction, THF was distilled off by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1/1) to obtain tert-butyl 4- [3- ( 3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazol-5-yl] piperidine-1-carboxylate (17 0.0 g) was obtained.
LC-MS, m / z; 432 (MH ⁺ ).

(2) The product (17.0 g) was dissolved in methylene chloride (50 ml), trifluoroacetic acid (25 ml) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off by concentration under reduced pressure. The obtained residue was dissolved in methylene chloride (15 ml), and ethyl acetate (75 ml) was added dropwise with stirring at room temperature. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure at 50 ° C. to obtain the title compound (16.9 g) as a white solid.
LC-MS, m / z; 332 (MH ⁺ ).

  Instead of 3-ethyl-6-fluoro-N′-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide in Reference Example 043 and Reference Example 044, the corresponding starting compound was used. In the same manner as in Reference Example 043 or Reference Example 044, the compounds shown in the following table (Reference Examples 045 to 064) were produced. (In the table below, HX means hydrochloric acid or trifluoroacetic acid)

  Instead of 3-ethyl-6-fluoro-N′-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide in Reference Example 043 and Reference Example 044, 3-ethyl-N '-Hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide (Reference Example 028) was used instead of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid Using the carboxylic acid to be prepared, the compounds shown in the following table (Reference Examples 065 to 072) were produced in the same manner as in Reference Example 043 or Reference Example 044.

  Compounds in the following table were prepared in the same manner as in Reference Example 043 or Reference Example 044 using the corresponding carboxylic acid instead of 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid in Reference Example 043 and Reference Example 044. (Reference Examples 073 to 074) were produced.

Reference Example 075
Preparation of 2- (tetrahydrofuran-2-yl) ethyl 4-methylbenzenesulfonate:

(1) Lithium aluminum hydride (4.20 g) was stirred in THF (100 ml) at −40 ° C. in a nitrogen atmosphere, and a solution of ethyl tetrahydrofuran-2-acetate (7.0 g) in THF (63 ml) was slowly added dropwise. did. After completion of the dropwise addition, the mixture was stirred at −40 ° C. for 2.5 hours, sodium fluoride (18.58 g) and water (8.0 ml) were added to complete the reaction, and after filtration, the solvent was concentrated under reduced pressure to give 2- (Tetrahydrofuran-2-yl) ethanol (4.40 g) was obtained as a colorless oil.
LC-MS, m / z; 117 (MH ⁺ ).

(2) Triethylamine (10.6 ml), trimethylamine hydrochloride (0.362 g) and paratoluenesulfonic acid chloride (7.94 g) were added to a dichloromethane solution (160 ml) of the above product (4.40 g) at 0 ° C. Stir. After completion of the reaction, water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered, and the solvent was concentrated under reduced pressure to give 2- (tetrahydrofuran-2-yl) ethyl 4-methylbenzenesulfonate (10 .19 g) was obtained as a colorless oil.
LC-MS, m / z; 271 (MH ⁺ ).

Reference Example 076
Preparation of (tetrahydro-2H-pyran-3-yl) methyl 4-methylbenzenesulfonic acid:

Using (tetrahydro-2H-pyran-3-yl) methanol instead of 2- (tetrahydrofuran-2-yl) ethanol in Reference Example 075 (2), in the same manner as in Reference Example 075 (2), The title compound was prepared.
LC-MS, m / z; 271 (MH ⁺ ).

Reference Example 077
Production of 1-tert-butylpiperidine-4-carboxylic acid:

(1) 1-ethyl-4-piperidone (6.36 g) was dissolved in acetone (50 ml), methyl iodide (8.52 g) was added, and the mixture was stirred at room temperature overnight. Subsequently, after stirring for 1 hour under ice cooling, the precipitated solid was collected by filtration to obtain 1-ethyl-1-methyl-4-oxopiperidinium iodide (13.06 g) as a white solid.

(2) Under a nitrogen atmosphere, water (4 ml) and sodium carbonate (106 mg) were added to tert-butylamine (3.66 g), then toluene (25 ml) and the above product (2.68 g) were added, and at 80 ° C. Stir for 6 hours. The mixture was allowed to cool to room temperature, extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 1-tert-butylpiperidin-4-one (1.31 g) as a yellow oil.
¹ H NMR (CDCl ₃ , δppm); 1.14 (9H, s), 2.44 (4H, t, J = 6.1 Hz), 2.85 (4H, t, J = 6.1 Hz).

(3) Under a nitrogen atmosphere, the above product (466 mg) was dissolved in THF (12 ml), N-phenylbis (trifluoromethanesulfonimide) (1.18 g) was added, and the temperature was adjusted to −78 ° C. with an acetone-dry ice bath. Cooled down. Subsequently, 1.6 N lithium hexamethyldisilazide / THF solution (2.1 ml) was added, and the mixture was stirred at −78 ° C. for 1 hour. After warming to room temperature, the mixture was further stirred for 1 hour, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer is dried over sodium sulfate and filtered, the filtrate is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (developing solvent: chloroform / methanol = 95/5) to give 1-tert-butyl- 1,2,3,6-Tetrahydropyridin-4-yl trifluoromethanesulfonate (1.22 g) was obtained as a yellow solid.
¹ H NMR (CDCl ₃ , δppm); 1.10 (9H, s), 2.40-2.47 (2H, m), 2.76 (2H, t, J = 5.5 Hz), 3.26 (2H, q, J = 3.2 Hz), 5.74 (1H, m). LC-MS, m / z; 288 (MH ⁺ ).

(4) Under a carbon monoxide atmosphere, the above product (1.22 g) was dissolved in DMF (10 ml), and triphenylphosphine (473 mg), triethylamine (843 μl), benzyl alcohol (935 μl), and palladium acetate (135 mg) were added. And stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (column; Hi-Flash ^TM amino). The crude product was obtained by purifying with Column, developing solvent: hexane / ethyl acetate = 1/1). The crude product was then dissolved in ethyl acetate (30 ml) and extracted with 1N aqueous hydrochloric acid. The aqueous layer was neutralized with 1N sodium hydroxide, extracted with ethyl acetate, the organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give benzyl 1-tert-butyl-1,2, 3,6-Tetrahydropyridine-4-carboxylate (86 mg) was obtained.
¹ H NMR (CDCl ₃ , δppm); 1.11 (9H, s), 2.41-2.47 (2H, m), 2.65 (2H, t, J = 5.6 Hz), 3.31 (2H, q, J = 3.1 Hz), 5.19 (2H, s), 6.99 (1H, m), 7.31-7.39 (5H, m). LC-MS, m / z; 274 (MH ⁺ ).

(5) The product (86 mg) was dissolved in methanol (10 ml), 10% palladium / carbon (50% wet, 60 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1 hr. After completion of the reaction, the mixture was filtered through celite, washed with methanol, and the filtrate was concentrated under reduced pressure to obtain the title compound (71 mg) as a yellow solid.
LC-MS, m / z; 186 (MH ⁺ ).

Reference Example 078
Preparation of 1- (4-methyltetrahydro-2H-pyran-4-yl) piperidine-4-carboxylic acid:

(1) Tetrahydro-4H-pyran-4-one (6.01 g) was dissolved in diethyl ether (100 ml), and a 1.12N methylmagnesium bromide / THF solution (70 ml) was added dropwise over 30 minutes under ice cooling. . After warming to room temperature, the mixture was stirred overnight, saturated aqueous ammonium chloride was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain 4-methyltetrahydro-2H-pyran-4-ol (6.14 g).

(2) The above product (6.14 g) was dissolved in acetic acid (30 ml), and chloroacetonitrile (6.5 ml) was added. Next, concentrated sulfuric acid (30 ml) was added dropwise under ice cooling, and the mixture was warmed to room temperature and stirred overnight. Ice water (150 ml) was added, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1/2) to give 2-chloro-N- (4-methyltetrahydro-2H-pyran-4-yl) acetamide ( 6.39 g) was obtained as a pale yellow solid.
¹ H NMR (CDCl ₃ , δppm); 1.46 (3H, s), 1.68-1.79 (2H, m), 2.02-2.11 (2H, m), 3.57-3.67 (2H, m), 3.71-3.79 (2H, m), 4.00 (2H, s), 6.36 (1H, brs).

(3) The above product (6.39 g) was dissolved in ethanol (55 ml), acetic acid (5 ml) and thiourea (2.79 g) were added, and the mixture was heated to reflux for 5 hours. After allowing to cool to room temperature, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (20 ml) was added to the obtained residue, and the mixture was stirred at room temperature. The insoluble material was collected by filtration to give 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (4.5 g).
¹ H NMR (DMSO-d ₆ , δppm); 1.35 (3H, s), 1.56-1.66 (2H, m), 1.74-1.85 (2H, m), 3.43-3.54 (2H, m), 3.76 (2H, dt, J = 12.0, 4.5 Hz), 8.33 (3H, brs). LC-MS, m / z; 116 (MH ⁺ ).

(4) In a nitrogen atmosphere, ethanol (25 ml), water (12.5 ml) and potassium carbonate (1.38 g) were added to the product (1.10 g), and the mixture was stirred at 85 ° C. for 10 minutes. A solution prepared by dissolving 1-methyl-4-oxopiperidinium iodide (1.34 g, (1) of Reference Example 077) in ethanol / water (4 ml / 4 ml) was added and heated to reflux for 5 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 9/1) to give 1- (4-methyltetrahydro-2H-pyran-4-yl) piperidin-4-one (491 mg) Got.
¹ H NMR (CDCl ₃ , δppm); 1.00 (3H, s), 1.54-1.64 (2H, m), 1.77-1.87 (2H, m), 2.44 (4H, t, J = 6.1 Hz), 2.82 (4H , t, J = 6.1 Hz), 3.54-3.61 (2H, m), 3.87-3.94 (2H, m). LC-MS, m / z; 198 (MH ⁺ ).

(5) The above product was reacted in the same manner as in Reference Example 077 (3) to (5) to give the title compound as a yellow solid.
LC-MS, m / z; 228 (MH ⁺ ).

Reference Example 079:
1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro-2H-benz Preparation of imidazol-2-one 2 trifluoroacetate:

(1) 1- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one Fluoroacetate (800 mg) was suspended in 1,2-dichloroethane (10 ml) and tert-butyl 3-formylazetidine-1-carboxylate (556 mg), sodium triacetoxyborohydride (1.14 g), triethylamine ( 0.75 ml) was added and stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over 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 = 3/2) to tert-butyl 3-({3- [3- (3 -Ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazol-5-yl] azetidin-1-yl} methyl) azetidine-1-carboxy The rate (880 mg) was obtained.
LC-MS, m / z; 455 (MH ⁺ ).

(2) tert-butyl 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1, in (2) of Reference Example 044, The above compound was used in place of 2,4-oxadiazol-5-yl] piperidine-1-carboxylate, and the title compound was obtained in the same manner as in Reference Example 044 (2).
LC-MS, m / z; 355 (MH ⁺ ).

  1- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one in Reference Example 079 Using the corresponding raw materials instead of trifluoroacetate and tert-butyl 3-formylazetidine-1-carboxylate, the compounds shown in the following table (Reference Examples 080 to 082) were produced in the same manner as Reference Example 079. did.

Reference Example 083:
1-ethyl-5-fluoro-3- [5- (3-methylazetidin-3-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole Preparation of 2-one trifluoroacetate:

(1) tert-butyl 3- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazole- 5-yl] azetidine-1-carboxylate (161 mg) was dissolved in THF (2 ml) and cooled to −78 ° C. in an acetone-dry ice bath. Then, 2N lithium diisopropylamide / THF solution (0.26 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. Methyl iodide (85 mg) was added, and the mixture was further stirred for 1 hr, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1/1) to tert-butyl 3- [3- (3-Ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazol-5-yl] -3-methyl Azetidine-1-carboxylate (106 mg) was obtained.
LC-MS, m / z; 835 (2M + H ⁺ ).

(2) tert-butyl 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1, in (2) of Reference Example 044, The above compound was used in place of 2,4-oxadiazol-5-yl] piperidine-1-carboxylate, and the title compound was obtained in the same manner as in Reference Example 044 (2).
LC-MS, m / z; 318 (MH ⁺ ).

Reference Example 084:
1-ethyl-5-fluoro-3- [5- (3-fluoroazetidin-3-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole Preparation of 2-one trifluoroacetate:

(1) tert-butyl 3- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazole- 5-yl] azetidine-1-carboxylate (807 mg) was dissolved in THF (10 ml) and cooled to −78 ° C. in an acetone-dry ice bath. Then, 2N lithium diisopropylamide / THF solution (2 ml) was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. N-fluorobenzenesulfonimide (1.39 g) was added, and the mixture was further stirred for 1 hour, and then stirred overnight at room temperature. Next, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 1/1) to tert-butyl 3- [3- (3-Ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazol-5-yl] -3-fluoro Azetidine-1-carboxylate (75 mg) was obtained.
LC-MS, m / z; 843 (2M + H ⁺ ).

(2) tert-butyl 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1, in (2) of Reference Example 044, The above compound was used in place of 2,4-oxadiazol-5-yl] piperidine-1-carboxylate, and the title compound was obtained in the same manner as in Reference Example 044 (2).
LC-MS, m / z; 322 (MH ⁺ ).

  1- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one in Reference Example 079 Similar to Reference Example 079, using the corresponding starting material instead of trifluoroacetate and tert-butyl 4-formylpiperidine-1-carboxylate instead of tert-butyl 3-formylazetidine-1-carboxylate By the method, the compounds shown in the following table (Reference Examples 085 to 086) were produced.

Reference Example 087:
1-ethyl-3- {5- [1- (piperidin-4-ylmethyl) pyrrolidin-3-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H-benz Preparation of imidazol-2-one 2 trifluoroacetate:

参考例０７９における１−［５−（アゼチジン−３−イル）−１，２，４−オキサジアゾール−３−イル］−３−エチル−１，３−ジヒドロ−２Ｈ−ベンズイミダゾール−２−オン トリフルオロ酢酸塩の代わりに１−エチル−３−［５−（ピロリジン−３−イル）−１，２，４−オキサジアゾール−３−イル］−１，３−ジヒドロ−２Ｈ−ベンズイミダゾール−２−オン 塩酸塩を用い、ｔｅｒｔ−ブチル ３−ホルミルアゼチジン−１−カルボキシレートの代わりにｔｅｒｔ−ブチル ４−ホルミルピペリジン−１−カルボキシレートを用いて、参考例０７９と同様の方法により、標記化合物を製造した。
LC-MS, m/z; 397 (MH⁺).

1- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one in Reference Example 079 1-ethyl-3- [5- (pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole- instead of trifluoroacetate In the same manner as in Reference Example 079, using 2-one hydrochloride and using tert-butyl 4-formylpiperidine-1-carboxylate instead of tert-butyl 3-formylazetidine-1-carboxylate, The compound was prepared.
LC-MS, m / z; 397 (MH ⁺ ).

  1- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one in Reference Example 079 A method similar to the step of Reference Example 079 (1) and then Reference Example 043 (2) using the corresponding starting materials instead of trifluoroacetate and tert-butyl 3-formylazetidine-1-carboxylate Produced the compounds shown in the following table (Reference Examples 088 to 091).

Reference Example 092:
1-ethyl-5-fluoro-3- {5- [1- (morpholin-2-ylmethyl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro Preparation of -2H-benzimidazol-2-one dihydrochloride:

(1) tert-Butyl 2- (hydroxymethyl) morpholine-4-carboxylate (2.33 g), imidazole (1.10 g) and triphenylphosphine (3.66 g) are dissolved in methylene chloride (43 mL) and iodine ( 3.27 g) was added in portions and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (column; Hi-Flash ^™ Silica Column, developing solvent: hexane / ethyl acetate) to give tert-butyl 2- (iodomethyl) morpholine- 4-carboxylate (3.08 g) was obtained as white crystals.
LC-MS, m / z; 655 ([2M + H] ⁺ ).

(2) 1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole- 2-one trifluoroacetate (801 mg) was suspended in acetonitrile (10 ml), the above product (1.00 g), potassium carbonate (276 mg) and sodium iodide (20 mg) were added, and the mixture was heated to reflux overnight. After allowing to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over 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 = 1/1), whereby tert-butyl 2-({4- [3- ( 3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazol-5-yl] piperidin-1-yl} methyl) Morpholine-4-carboxylate (873 mg) was obtained as a colorless viscous solid.

(3) A 4N hydrogen chloride dioxane solution (15 ml) was added to the product (873 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure to obtain the title compound as a white solid.
LC-MS, m / z; 431 (MH ⁺ ).

Reference Example 093:
Preparation of 1-ethyl-3- [5- (4-oxocyclohexyl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one:

4-oxocyclohexanecarboxylic acid (2.35 g) was dissolved in THF (50 mL), 1,1′-carbonyldimidazole (2.68 g) was added, and the mixture was stirred at room temperature for 1 hour. Subsequently, 3-ethyl-N′-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide (3.30 g) was added and stirred at 50 ° C. for 4 hours. Next, tetrabutylammonium fluoride (1M THF solution, 15 ml) was added, and the mixture was further stirred at 50 ° C. overnight. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (4.41 g) as a white solid.
¹ H NMR (CDCl ₃ , δppm); 1.39 (3H, t, J = 7.5 Hz), 2.23-2.38 (2H, m), 2.44-2.67 (6H, m), 3.54 (1H, m), 4.01 (2H , q, J = 7.2 Hz), 7.07 (1H, d, J = 7.5 Hz), 7.15-7.28 (2H, m), 7.87 (1H, d, J = 7.8 Hz). LC-MS, m / z; 327 (MH ⁺ ).

  The same method as in Reference Example 093, using the corresponding starting material instead of 3-ethyl-N′-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide in Reference Example 093 The compounds shown in the following table (Reference Examples 094 to 095) were produced.

Reference Example 096:
Preparation of 1-ethyl-3- [5- (3-oxocyclobutyl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one:

3-oxocyclobutanecarboxylic acid (4.11 g) was dissolved in THF (60 mL), 1,1′-carbonyldimidazole (5.84 g) was added, and the mixture was stirred at room temperature for 1 hour. Subsequently, 3-ethyl-N-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide (6.61 g) was added and stirred at 50 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, ethanol (147 mL) and sodium acetate (2.71 g) were added, and the mixture was stirred at 85 ° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (column; Hi-Flash ^™ silica Column, developing solvent: hexane / ethyl acetate). The title compound was obtained as white crystals.
LC-MS, m / z; 299 (MH ⁺ ).

Reference Example 097:
1-ethyl-5-fluoro-3- [5- (3-oxocyclobutyl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one Manufacturing of:

3-oxocyclobutanecarboxylic acid (1.21 g) was dissolved in DMF (30 mL), 1,1′-carbonyldimidazole (1.72 g) was added, and the mixture was stirred at room temperature for 1 hour. Subsequently, 3-ethyl-6-fluoro-N′-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide (2.11 g) was added and stirred at 50 ° C. for 3 hours. Then, it heated up at 120 degreeC and stirred for further 4 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is subjected to silica gel column chromatography (column; Hi-Flash ^™ Silica Column, developing solvent: hexane / ethyl acetate). The title compound (1.75 g) was obtained as white crystals.
LC-MS, m / z; 317 (MH ⁺ ).

Reference Example 098:
3- [5- (cis-4-aminocyclohexyl) -1,2,4-oxadiazol-3-yl] -1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazole-2- Production of on-trifluoroacetate:

Reference Example 043 (1), (1), (1), (1), (1), (1), (1), (1), (1), (1) The title compound was obtained in the same manner as in 2).
LC-MS, m / z; 346 (MH ⁺ ).

Reference Example 099:
1- [5- (Piperidin-4-yl) -1,3,4-oxadiazol-2-yl] -3- (propan-2-yl) -1,3-dihydro-2H-benzimidazole-2 -Production of on-trifluoroacetate:

(1) 1- (propan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one (881 mg) was dissolved in THF (20 ml), and 55% sodium hydride (328 mg) was cooled with ice. Was added. After stirring for 30 minutes under ice cooling, p-nitrophenyl chloroformate (665 mg) was added, and the mixture was stirred at room temperature for 1 hour. Then, a solution of tert-butyl 4- (hydrazinecarbonyl) piperidine-1-carboxylate (1.46 g) and triethylamine (1.4 ml) in THF (10 ml) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over 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 = 3/2) to thereby tert-butyl 4-[(2-{[2-oxo -3- (Propan-2-yl) -2,3-dihydro-1H-benzimidazol-1-yl] carbonyl} hydrazinyl) carbonyl] piperidine-1-carboxylate (1.28 g) was obtained as an oil.
LC-MS, m / z; 446 (MH ⁺ ).

(2) Dissolve the above product (1.19 g) in methylene chloride (25 ml), add triphenylphosphine (1.05 g), carbon tetrachloride (0.385 ml), triethylamine (1.5 ml) and heat for 8 hours. Refluxed. After allowing to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3/2) to give tert-butyl 4- {5- [2-oxo-3- (propan-2-yl)- 2,3-Dihydro-1H-benzimidazol-1-yl] -1,3,4-oxadiazol-2-yl} piperidine-1-carboxylate (0.819 g) was obtained as an oil.
LC-MS, m / z; 428 (MH ⁺ ).

(3) tert-butyl 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1, in (2) of Reference Example 044, The title compound was produced in the same manner as in Reference Example 044 (2) using the above product in place of 2,4-oxadiazol-5-yl] piperidine-1-carboxylate.
LC-MS, m / z; 328 (MH ⁺ ).

Reference Example 100:
1- [5- (Piperidin-4-yl) -1,3,4-oxadiazol-2-yl] -3- (propan-2-yl) -1,3-dihydro-2H-benzimidazole-2 -Production of on-trifluoroacetate:

(1) tert-Butyl 4-[(Hydroxylimino) methyl] piperidine-1-carboxylate (2.59 g) was dissolved in DMF (25 ml), N-chlorosuccinimide (1.47 g) was added, and at room temperature. After stirring for 2 hours, water (40 ml) was slowly added dropwise with stirring. The precipitated solid was collected by filtration and washed with water. The obtained solid was dried at 50 ° C. under reduced pressure to obtain tert-butyl 4- [chloro (hydroxyoximino) methyl] piperidine-1-carboxylate (2.31 g) as white crystals.

(2) The above product (631 mg) and 2-oxo-3- (propan-2-yl) -2,3-dihydro-1H-benzimidazole-1-carbonitrile (402 mg) were dissolved in toluene (20 ml), Sodium hydrogen carbonate (672 mg) was added, and the mixture was stirred at 80 ° C. for 5 hours. After allowing to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 5/1) to give tert-butyl 4- {5- [2-oxo-3- (propan-2-yl)- 2,3-Dihydro-1H-benzimidazol-1-yl] -1,2,4-oxadiazol-3-yl} piperidine-1-carboxylate (411 mg) was obtained as white crystals.
LC-MS, m / z; 428 (MH ⁺ ).

(3) tert-Butyl 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1, in (2) of Reference Example 043, The title compound was produced in the same manner as in Reference Example 043 (2) using the above product in place of 2,4-oxadiazol-5-yl] piperidine-1-carboxylate.
LC-MS, m / z; 328 (MH ⁺ ).

Reference Example 101:
Preparation of 1-ethyl-3- [5- (piperidin-4-yl) -1,3-thiazol-2-yl] -1,3-dihydro-2H-benzimidazol-2-one trifluoroacetate:

(1) Under a nitrogen atmosphere, 1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (811 mg) was dissolved in dioxane (50 ml), and trans-N, N′-dimethylcyclohexane-1,2- Diamine (142 mg), copper (I) iodide (95 mg) and potassium carbonate (760 mg) were added, and the mixture was stirred at 90 ° C. Next, a solution of 2,5-dibromothiazole (1.37 g) in dioxane was added dropwise to the reaction solution, and the mixture was stirred at 90 ° C. overnight. The mixture was allowed to cool to room temperature, filtered through Celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 15/1) to give 1- (5- Bromo-1,3-thiazol-2-yl) -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (880 mg) was obtained.
LC-MS, m / z; 324 (MH ⁺ ).

(2) The above product (324 mg) was dissolved in DME (6 ml) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6 -Dihydropyridine-1 (2H) -carboxylate (371 mg), tetrakistriphenylphosphine palladium (116 mg), sodium carbonate (212 mg) and water (3 ml) were added, and the mixture was stirred at 70 ° C. for 4 hours. After allowing to cool to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4/1) to give tert-butyl 4- [2- (3-ethyl-2-oxo-2,3-dihydro -1H-benzimidazol-1-yl) -1,3-thiazol-5-yl] -3,6-dihydropyridine-1 (2H) -carboxylate (379 mg) was obtained.
LC-MS, m / z; 427 (MH ⁺ ).

(3) The product (312 mg) was dissolved in methanol (5 ml), 10% palladium / carbon (50% wet, 100 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered through Celite, washed with methanol, and the filtrate was concentrated under reduced pressure to give tert-butyl 4- [2- (3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazole- 1-yl) -1,3-thiazol-5-yl] piperidine-1-carboxylate (317 mg) was obtained.
LC-MS, m / z; 429 (MH ⁺ ).

(4) tert-butyl 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1, in (2) of Reference Example 044, The title compound was produced in the same manner as in Reference Example 044 (2) using the above product in place of 2,4-oxadiazol-5-yl] piperidine-1-carboxylate.
LC-MS, m / z; 329 (MH ⁺ ).

Reference Example 102:
Preparation of 1-ethyl-5-fluoro-3- [4- (piperidin-4-yl) -1,3-oxazol-2-yl] -1,3-dihydro-2H-benzimidazol-2-one:

(1) Benzyl 4-acetylpiperidine-1-carboxylate (2.61 g) was dissolved in methanol (71 mL), and bromine (0.52 mL) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer is concentrated, and the residue is purified by silica gel column chromatography (column; Hi-Flash ^™ Silicagel Column, developing solvent: hexane / ethyl acetate) to obtain benzyl 4- (2-bromoacetyl) piperidine-1-carboxyl. The rate (1.80 g) was obtained as a colorless oil.
LC-MS, m / z; 681 ([2M + H] ⁺ ).

(2) The above product (340 mg) was mixed with formamide (1.0 mL) and stirred at 130 ° C. for 1 hour using a microwave. By purifying the obtained reaction mixture as it is with silica gel column chromatography (column; Hi-Flash ^™ silica column, developing solvent: hexane / ethyl acetate), benzyl 4- (1,3-oxazol-4-yl) piperidine -1-carboxylate (132 mg) was obtained as a colorless oil.
LC-MS, m / z; 287 (MH ⁺ ).

(3) The product (132 mg) was dissolved in THF (2.1 mL) and cooled to -78 ° C. Lithium hexamethyldisilazide (1M THF solution, 0.55 mL) was added dropwise thereto, and the mixture was stirred at −78 ° C. for 30 minutes. Next, hexachloroethane (298 mg) was added, and the mixture was further stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride 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 ^™ silica column, developing solvent: hexane / ethyl acetate) to thereby prepare benzyl 4- (2-chloro-1,3-oxazol-4-yl). ) Piperidine-1-carboxylate (117 mg) was obtained as a colorless oil.
LC-MS, m / z; 321 (MH ⁺ ).

(4) 1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one (135 mg) was dissolved in DMF (2.5 mL), 55% sodium hydride (42 mg) was added, and 50 Stir at 15 ° C. for 15 minutes. A solution of the above product (200 mg) in DMF (2.5 mL) was added thereto, and the mixture was further stirred at 90 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 ^™ silica column, developing solvent: chloroform / methanol), whereby benzyl 4- [2- (3-ethyl-6-fluoro-2-oxo -2,3-Dihydro-1H-benzimidazol-1-yl) -1,3-oxazol-4-yl] piperidine-1-carboxylate (124 mg) was obtained as a colorless oil.
LC-MS, m / z; 465 (MH ⁺ ).

(5) The product (124 mg) was dissolved in methanol, 10% palladium on carbon (12 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The obtained reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to produce the title compound.
LC-MS, m / z; 331 (MH ⁺ ).

Reference Example 103:
1-ethyl-3- [1- (piperidin-4-yl) -1H-1,2,3-triazol-4-yl] -1,3-dihydro-2H-benzimidazol-2-one trifluoroacetate Manufacturing of:

(1) 1-ethyl-1,3-dihydro-2H-benzimidazol-2-one (2.09 g) and (bromoethynyl) (tripropan-2-yl) silane (3.70 g) in toluene (13 mL) Into the solution, potassium carbonate (3.55 g), copper (II) sulfate pentahydrate (321 mg) and 1,10-phenanthroline (464 mg) were added and stirred at 65 ° C. for 1 day under nitrogen. The reaction mixture was allowed to cool and then filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (column; Hi-Flash ^™ silica column, developing solvent: hexane / ethyl acetate) to give 1-ethyl-3-[(tripropan-2-ylsilyl) ethynyl] -1,3-Dihydro-2H-benzimidazol-2-one (811 mg) was obtained as a colorless oil.

(2) The above product (811 mg) was dissolved in THF (55 mL), tetrabutylammonium fluoride (1M THF solution, 2.6 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (column; Hi-Flash ^™ silica column, developing solvent: hexane / ethyl acetate) to give 1-ethyl-3-ethynyl-1, 3-Dihydro-2H-benzimidazol-2-one (396 mg) was obtained as colorless crystals.
LC-MS, m / z; 187 (MH ⁺ ).

(3) The above product (200 mg) and tert-butyl 4-azidopiperidine-1-carboxylate (267 mg) were dissolved in tert-butyl alcohol (1.1 mL), and copper (11 mg) and copper sulfate II) An aqueous solution (1.1 mL) of hydrate (13 mg) was added, and the mixture was stirred at 110 ° C. for 2 hours under nitrogen atmosphere. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride 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 ^™ Amino column, developing solvent: hexane / ethyl acetate) to give tert-butyl 4- [4- (3-ethyl-2-oxo- 2,3-Dihydro-1H-benzimidazol-1-yl) -1H-1,2,3-triazol-1-yl] piperidine-1-carboxylate (430 mg) was obtained as a white solid.
LC-MS, m / z; 413 (MH ⁺ ).

(4) tert-butyl 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1, in (2) of Reference Example 044, The title compound was produced in the same manner as in Reference Example 044 (2) using the above product in place of 2,4-oxadiazol-5-yl] piperidine-1-carboxylate.
LC-MS, m / z; 313 (MH ⁺ ).

Reference Example 104:
Preparation of 1-ethyl-3- [3- (piperidin-4-yl) isoxazol-5-yl] -1,3-dihydro-2H-benzimidazol-2-one trifluoroacetate:

(1) 1-ethyl-3-ethynyl-1,3-dihydro-2H-benzimidazol-2-one (200 mg) and tert-butyl 4- (chloro (hydroxyimino) methyl) piperidine-1-carboxylate (567 mg) ) Was dissolved in toluene (12 mL mL), sodium hydrogen carbonate (588 mg) was added, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride 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 ^™ silica column, developing solvent: hexane / ethyl acetate) to give tert-butyl 4- [5- (3-ethyl-2-oxo- 2,3-Dihydro-1H-benzimidazol-1-yl) isoxazol-3-yl] piperidine-1-carboxylate (419 mg) was obtained as a colorless oil.

(2) tert-butyl 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1, in (2) of Reference Example 044, The title compound was produced in the same manner as in Reference Example 044 (2) using the above product in place of 2,4-oxadiazol-5-yl] piperidine-1-carboxylate.
LC-MS, m / z; 313 (MH ⁺ ).

Reference Example 105:
Preparation of spiro [cyclopropane-1,3′-indole] -2 ′ (1′H) -one:

(1) Oxindole (6.78 g) was dissolved in acetic anhydride (17 ml) and stirred at 140 ° C. for 6 hours. After cooling to room temperature, water (20 ml) was added dropwise, and the precipitated solid was collected by filtration and washed with water. The obtained solid was dried at 70 ° C. under reduced pressure to obtain 1-acetylindoline-2-one (8.11 g).
LC-MS, m / z; 181 (MH ⁺ ).

(2) The above product (4.81 g) was dissolved in DMF (90 ml), 1,2-dibromoethane (3.1 ml) was added, and then 55% sodium hydride (2.64 g) was added under ice cooling. It was. After raising the temperature to room temperature and stirring for 7 hours, water (180 ml) was added dropwise, and the precipitated solid was collected by filtration. The obtained solid was washed with water and then with hexane, and then dried under reduced pressure at 70 ° C., whereby 1′-acetylspiro [cyclopropane-1,3′-indole] -2 ′ (1′H) -one ( 1.75 g) was obtained as a pale pink solid.
¹ H NMR (CDCl ₃ , δppm); 1.57-1.64 (2H, m), 1.82-1.87 (2H, m), 2.71 (3H, s), 6.85 (1H, m), 7.18 (1H, dt, J = 7.5, 1.0 Hz), 7.31 (1H, m), 8.31 (1H, m).

(3) The product (1.75 g) was dissolved in methanol (35 ml), 1N aqueous sodium hydroxide solution (35 ml) was added, and the mixture was stirred at 60 ° C. for 6 hours and then at room temperature for 15 hours. Next, after neutralizing with 1N aqueous hydrochloric acid, methanol was distilled off under reduced pressure, followed by extraction with chloroform. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1 .41 g) was obtained as a solid.
LC-MS, m / z; 160 (MH ⁺ ).

Reference Example 106:
Production of 3,3-dimethyl-1,3-dihydro-2H-indol-2-one:

(1) 1-acetyl-3,3-dimethylindolin-2-one was obtained by using methyl iodide instead of 1,2-dibromoethane by the same method as in Reference Example 105 (2). .
LC-MS, m / z; 204 (MH ⁺ ).

(2) Using the above product, the title compound was obtained in the same manner as in Reference Example 105 (3).
LC-MS, m / z; 162 (MH ⁺ ).

In the same manner as in Reference Example 105, instead of the oxindole in Reference Example 105, the corresponding raw material compounds were used to produce the compounds shown in the following table (Reference Examples 107 to 110).

In the same manner as in Reference Example 022 except that 1- (propan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one in Reference Example 022 was used, the following table was prepared. (Reference Examples 111 to 116) were produced.

Instead of 3-ethyl-6-fluoro-N′-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide in Reference Example 043 and Reference Example 044, the corresponding starting compound was used. In the same manner as in Reference Example 043 or Reference Example 044, the compounds shown in the following table (Reference Examples 117 to 122) were produced.

Reference Example 123:
1- [5- (1,4′-bipiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -3,3-dimethyl-1,3-dihydro-2H-indole-2 -ON Production of dihydrochloride:

1- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one in Reference Example 079 Instead of trifluoroacetate and tert-butyl 3-formylazetidine-1-carboxylate the corresponding raw material 3,3-dimethyl-1- [5- (piperidin-4-yl) -1,2,4-oxa Reference Example 079 (1) and Reference Example using diazol-3-yl] -1,3-dihydro-2H-indol-2-one hydrochloride and tert-butyl 4-oxopiperidine-1-carboxylate The title compound was produced in the same manner as in (92) of 092.

Reference example 124:
1 ′-[5- (piperidin-4-yl) -1,3,4-oxadiazol-2-yl] spiro [cyclopropane-1,3′-indole] -2 ′ (1′H) -one Production of trifluoroacetate:

Spiro [cyclopropane-1,3′-indole] -2 ′ (1′H instead of 1- (propan-2-yl) -1,3-dihydro-2H-benzimidazol-2-one in Reference Example 099 ) -One was used to produce the title compound in the same manner as in Reference Example 099.
LC-MS, m / z; 311 (MH ⁺ ).

Reference Example 125:
1 ′-[3- (piperidin-4-yl) -1,2,4-oxadiazol-5-yl] spiro [cyclopropane-1,3′-indole] -2 ′ (1′H) -one Production of hydrochloride:

Instead of 2-oxo-3- (propan-2-yl) -2,3-dihydro-1H-benzimidazole-1-carbonitrile in Reference Example 100, 2′-oxospiro obtained during the synthesis of Reference Example 111 [ The title compound was produced in the same manner as in Reference Example 100 using cyclopropane-1,3′-indole] -1 ′ (2′H) -carbonitrile.
LC-MS, m / z; 311 (MH ⁺ ).

Example 001
1- {5- [1- (3-methoxypropyl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -3- (propan-2-yl) -1,3- Preparation of dihydro-2H-benzimidazol-2-one:

1- [5- (Piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -3- (propan-2-yl) -1,3-dihydro-2H-benzimidazole 2-one trifluoroacetate (170 mg) was suspended in acetonitrile (5 ml), 1-bromo-3-methoxypropane (74 mg) and cesium carbonate (195 mg) were added, and the mixture was stirred at room temperature overnight. Subsequently, after stirring for 4 hours at 60 degrees, it was allowed to cool to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over 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 = 1/1) to obtain the title compound (111 mg) as a colorless oil.
¹ H NMR (CDCl ₃ , δppm); 1.58 (6H, d, J = 7.2 Hz), 1.75-1.87 (2H, m), 1.99-2.27 (6H, m), 2.43-2.53 (2H, m), 2.95 -3.13 (3H, m), 3.34 (3H, s), 3.44 (2H, t, J = 6.4 Hz), 4.70-4.81 (1H, m), 7.12-7.22 (3H, m), 7.88 (1H, dt , J = 7.4, 1.2 Hz).
LC-MS, m / z; 400 (MH ⁺ ).

  1- [5- (Piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -3- (propan-2-yl) -1,3-dihydro-2H- in Example 001 The compounds shown in the following table (Examples 002 to 026) were produced in the same manner as in Example 001 using the corresponding starting materials instead of benzimidazol-2-one trifluoroacetate.

１）得られた化合物を塩化メチレンに溶解し、１規定 塩酸／ジエチルエーテル溶液で処理する事により、塩酸塩とした。

1) The obtained compound was dissolved in methylene chloride and treated with 1N hydrochloric acid / diethyl ether solution to obtain hydrochloride.

１）得られた化合物を塩化メチレンに溶解し、１規定 塩酸／ジエチルエーテル溶液で処理する事により、塩酸塩とした。

1) The obtained compound was dissolved in methylene chloride and treated with 1N hydrochloric acid / diethyl ether solution to obtain hydrochloride.

Example 027:
1-ethyl-5-fluoro-3- {5- [1- (propan-2-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro Production of -2H-benzimidazol-2-one:

1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one Trifluoroacetate (267 mg) was suspended in acetonitrile (20 ml), isopropyl iodide (122 mg) and potassium carbonate (166 mg) were added, and the mixture was heated to reflux overnight. After allowing to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over 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 = 1/1) to obtain the title compound (113 mg) as a white solid.
¹ H NMR (CDCl ₃ , δppm); 1.08 (6H, d, J = 6.4 Hz), 1.37 (3H, t, J = 7.2 Hz), 1.96-2.11 (2H, m), 2.15-2.24 (2H, m ), 2.35 (2H, t, J = 11.1 Hz), 2.75-2.86 (1H, m), 2.94-3.11 (3H, m), 3.99 (2H, q, J = 7.2 Hz), 6.94-6.97 (2H, m), 7.72 (1H, dt, J = 8.8, 1.5 Hz). LC-MS, m / z; 374 (MH ⁺ ).

1-Ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 027 The compounds shown in the following table (Examples 028 to 032) were produced in the same manner as in Example 027 using the corresponding starting materials instead of -2-one trifluoroacetate and isopropyl iodide.

１）ハロゲン化アルキル
２）得られた化合物を塩化メチレンに溶解し、１規定 塩酸／ジエチルエーテル溶液で処理する事により、塩酸塩とした。

1) Alkyl halide 2) The obtained compound was dissolved in methylene chloride and treated with 1N hydrochloric acid / diethyl ether solution to obtain hydrochloride.

１）ハロゲン化アルキル

1) Alkyl halide

Example 033:
1-ethyl-3- {5- [2- (piperidin-1-yl) ethyl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H-benzimidazole-2- On-manufacturing:

3-piperidinepropanoic acid (121 mg) and 3-ethyl-N′-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide (154 mg) were dissolved in THF (1.4 ml). 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (201 mg) and 1-hydroxybenzotriazole (118 mg) were added, and the mixture was stirred at 50 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The residue was dissolved in THF (2.8 ml), tetrabutylammonium fluoride in THF (1M, 0.07 ml) was added, and the mixture was stirred at 50 ° C. overnight. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol) to obtain the title compound.
¹ H NMR (CDCl ₃ , δppm); 1.32-1.51 (5H, m), 1.51-1.71 (4H, m), 2.47 (4H, m), 2.91 (2H, t, J = 7.5 Hz), 3.19 (2H , t, J = 7.6 Hz), 4.01 (2H, q, J = 7.2 Hz), 7.06 (1H, m), 7.14-7.26 (2H, m), 7.88 (1H, m) .LC-MS, m / z; 342 (MH ⁺ ).

  The compounds shown in the following table (Examples 034 to 035) were produced in the same manner as in Example 033 using the corresponding carboxylic acid instead of 3-piperidinepropanoic acid in Example 033.

Examples 036-059
1- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one trifluoroacetate (30 mg, 0.075 mmol) was dissolved in DMF (1 ml) and the corresponding alkyl halide (RX) (0.15 mmol, 2 eq), potassium carbonate (15.6 mg, 0.113 mmol, 1.5 eq) was added. The mixture was stirred at 60 ° C. for 4 to 12 hours. After completion of the reaction, the mixture was allowed to cool to room temperature, chloroform (4 ml) was added to the reaction mixture, and the organic layer was washed with water (2 ml × 3). After concentrating the organic layer under reduced pressure, the resulting residue was purified by Gilson HPLC to produce the compounds shown in the following table (Examples 036 to 059).

Example 060:
1-ethyl-3- (5- {1- [2- (4-fluorophenyl) ethyl] azetidin-3-yl} -1,2,4-oxadiazol-3-yl) -1,3-dihydro Production of -2H-benzimidazol-2-one:

１−［５−（アゼチジン−３−イル）−１，２，４−オキサジアゾール−３−イル］−３−エチル−１，３−ジヒドロ−２Ｈ−ベンズイミダゾール−２−オン トリフルオロ酢酸塩（０．１２５ｇ）をアセトニトリル（２．０ｍｌ）に溶解し、１−（２−ブロモエチル）−４−フルオロベンゼン（０．１４６ｇ）、炭酸カリウム（０．１２４ｇ）を加え、６０℃にて終夜撹拌した。反応混合物にクロロホルムを加え、水、飽和食塩水にて洗浄後、有機層を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Ｇｉｌｓｏｎ ＨＰＬＣにて精製することで標記化合物（０．０６６ｇ）を固体として得た。
¹H NMR (DMSO-d₆, δppm); 1.25 (3H, t, J = 7.1 Hz), 2.58 (2H, t, J = 6.1 Hz), 2.65(2H, t, J = 6.1 Hz), 3.39 (2H, t, J = 7.1 Hz), 3.64 (2H, t, J = 7.7 Hz), 3.94 (2H, q, J = 7.1 Hz), 4.03(1H, m), 7.08 (2H, m), 7.18 (1H, dt, J = 7.8, 1.9 Hz), 7.23-7.27 (3H, m), 7.35 (1H, d, J = 7.1 Hz), 7.72 (1H, d, J = 7.8 Hz). LC-MS, m/z; 408 (MH⁺).

1- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one trifluoroacetate (0.125 g) was dissolved in acetonitrile (2.0 ml), 1- (2-bromoethyl) -4-fluorobenzene (0.146 g) and potassium carbonate (0.124 g) were added, and the mixture was stirred at 60 ° C. overnight. did. Chloroform was added to the reaction mixture, washed with water and saturated brine, the organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by Gilson HPLC to obtain the title compound (0.066 g) as a solid.
¹ H NMR (DMSO-d ₆ , δppm); 1.25 (3H, t, J = 7.1 Hz), 2.58 (2H, t, J = 6.1 Hz), 2.65 (2H, t, J = 6.1 Hz), 3.39 ( 2H, t, J = 7.1 Hz), 3.64 (2H, t, J = 7.7 Hz), 3.94 (2H, q, J = 7.1 Hz), 4.03 (1H, m), 7.08 (2H, m), 7.18 ( 1H, dt, J = 7.8, 1.9 Hz), 7.23-7.27 (3H, m), 7.35 (1H, d, J = 7.1 Hz), 7.72 (1H, d, J = 7.8 Hz). LC-MS, m / z; 408 (MH ⁺ ).

  Using the corresponding phenethyl bromide instead of 1- (2-bromoethyl) -4-fluorobenzene in Example 060, the compounds shown in the following table (Examples 061 to 064) were produced in the same manner as in Example 060. .

Examples 065-082
1-ethyl-3- [5- (pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one trifluoroacetate (48 mg, 0.117 mmol) dissolved in DMF (1 ml), corresponding alkyl halide (RX) (0.16 mmol, 1.4 eq), potassium carbonate (24.3 mg, 0.175 mmol, 1.5 eq) ), Sodium iodide (1.8 mg, 0.01 mmol, 0.1 equivalent) was added, and the mixture was stirred at room temperature to 60 ° C. for 4 to 12 hours. After completion of the reaction, the mixture was allowed to cool to room temperature, chloroform (4 ml) was added to the reaction mixture, and the organic layer was washed with water (2 ml × 3). After concentrating the organic layer under reduced pressure, the resulting residue was purified by Gilson HPLC to produce the compounds shown in the following table (Examples 065-082).

Example 083:
1-ethyl-3- (5- {1- [3- (2-oxopyrrolidin-1-yl) propyl] pyrrolidin-3-yl} -1,2,4-oxadiazol-3-yl) -1 Preparation of 1,3-dihydro-2H-benzimidazol-2-one:

1-ethyl-3- [5- (pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one trifluoroacetate (66 mg) was dissolved in acetonitrile (2.0 ml), 1- (3-bromopropyl) pyrrolidin-2-one (44 mg), potassium carbonate (60.2 mg), sodium iodide (21.8 mg) were added, The mixture was stirred for 5 hours with heating under reflux. The reaction mixture was cooled, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over 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 = 1/1) to obtain the title compound (13 mg) as a colorless oil.
¹ H NMR (CDCl ₃ , δppm); 1.38 (3H, t, J = 7.2 Hz), 1.70-1.84 (3H, m), 2.02 (2H, m), 2.28-2.44 (3H, m), 2.53 (2H , m), 2.75 (2H, m), 2.92 (1H, m), 3.10 (1H, t, J = 8.7 Hz), 3.37 (4H, m), 3.73 (1H, m), 4.00 (2H, q, J = 7.2 Hz), 7.05 (1H, d, J = 7.2 Hz), 7.14-7.26 (2H, m), 7.86 (1H, d, J = 8.4 Hz) .LC-MS, m / z; 425 (MH ⁺ ).

Example 084:
1-ethyl-3- (5- {1- [2- (tetrahydro-2H-pyran-4-yl) ethyl] pyrrolidin-3-yl} -1,2,4-oxadiazol-3-yl)- Preparation of 1,3-dihydro-2H-benzimidazol-2-one:

The title compound was produced in the same manner as in Example 083 using 4- (2-bromoethyl) tetrahydropyran in place of 1- (3-bromopropyl) pyrrolidin-2-one in Example 083.
¹ H NMR (CDCl ₃ , δppm); 1.22-1.43 (5H, m), 1.43-1.66 (5H, m), 2.38 (2H, m), 2.54 (2H, m), 2.67 (1H, m), 2.76 -2.91 (2H, m), 3.14 (1H, t, J = 8.7 Hz), 3.37 (2H, t, J = 11.4 Hz), 3.73 (1H, m), 3.89-4.05 (4H, m), 7.05 ( 1H, d, J = 7.5 Hz), 7.13-7.26 (2H, m), 7.86 (1H, d, J = 7.7 Hz). LC-MS, m / z; 412 (MH ⁺ ).

1-ethyl-3- [5- (pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one in Example 084 The compounds shown in the following table (Examples 085 to 088) were produced in the same manner as in Example 084 using the corresponding starting materials instead of trifluoroacetate.

Examples 089-097
1-ethyl-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one trifluoroacetate (50 mg, 0.117 mmol) in DMF (1 ml), the corresponding alkyl halide (RX) (0.16 mmol, 1.4 eq), potassium carbonate (24.3 mg, 0.175 mmol, 1.5 eq) ), Sodium iodide (1.8 mg, 0.01 mmol, 0.1 equivalent) was added, and the mixture was stirred at room temperature to 60 ° C. for 4 to 12 hours. After completion of the reaction, the mixture was allowed to cool to room temperature, chloroform (4 ml) was added to the reaction mixture, and the organic layer was washed with water (2 ml × 3). After concentrating the organic layer under reduced pressure, the resulting residue was purified by Gilson HPLC to produce the compounds shown in the following table (Examples 089 to 097).

Example 098
1-ethyl-3- {5- [1- (propan-2-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H-benz Production of imidazol-2-one:

Instead of 2-nitroaniline in Reference Example 001 (1), 1-ethyl-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3- The title compound (30 mg) was obtained in the same manner as in Reference Example 001 using dihydro-2H-benzimidazol-2-one trifluoroacetate (103 mg).
¹ H NMR (CDCl ₃ , δppm); 1.05 (6H, d, J = 6.6 Hz), 1.36 (3H, t, J = 7.2 Hz), 1.91-2.10 (2H, m), 2.10-2.23 (2H, m ), 2.30 (2H, m), 2.75 (1H, m), 2.88-3.11 (3H, m), 3.98 (2H, q, J = 7.2 Hz), 7.03 (1H, d, J = 7.7 Hz), 7.09 -7.25 (2H, m), 7.87 (1H, d, J = 7.5 Hz). LC-MS, m / z; 356 (MH ⁺ ).

Example 099
1-ethyl-3- {5- [1- (propan-2-yl) pyrrolidin-3-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H-benz Production of imidazol-2-one:

Instead of 2-nitroaniline in Reference Example 001 (1), 1-ethyl-3- [5- (pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -1,3- The title compound (51 mg) was obtained in the same manner as in Reference Example 001 using dihydro-2H-benzimidazol-2-one trifluoroacetate (100 mg).
¹ H NMR (CDCl ₃ , δppm); 1.14 (6H, dd, J = 6.2, 1.7 Hz), 1.38 (3H, t, J = 7.2 Hz), 2.26-2.54 (3H, m), 2.70 (1H, dd , J = 15.6, 8.6 Hz), 2.83-2.97 (2H, m), 3.29 (1H, t, J = 8.8 Hz), 3.70-3.81 (1H, m), 4.00 (2H, q, J = 7.2 Hz) , 7.04-7.07 (1H, m), 7.14-7.26 (2H, m), 7.86 (1H, m). LC-MS, m / z; 342 (MH ⁺ ).

Example 100
1-ethyl-5-fluoro-3- {5- [1- (tetrahydrofuran-3-ylmethyl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro Production of -2H-benzimidazol-2-one:

1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one Trifluoroacetate (0.100 g) was dissolved in dichloromethane (3.0 ml), tetrahydrofuran-3-carbaldehyde (50% aqueous solution) (64 μl) and sodium triacetoxyborohydride (0.143 g) were added, and the mixture was brought to room temperature. And stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over 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 = 1/1) to obtain the title compound (0.118 g) as a colorless oil. .
¹ H NMR (CDCl ₃ , δppm); 1.37 (3H, t, J = 7.2 Hz), 2.00-2.10 (2H, m), 2.13-2.17 (4H, m), 2.34-2.38 (1H, m) 2.45 ( 1H, br), 2.90-3.15 (3H, m), 3.60-3.92 (7H, m), 6.91-6.97 (2H, m), 7.13-7.25 (2H, m), 7.71 (1H, d, J = 8.6 Hz). LC-MS, m / z; 416 (MH ⁺ ).

Using the corresponding aldehyde or ketone instead of tetrahydrofuran-3-carbaldehyde in Example 100, the compounds shown in the following table (Examples 101 to 114) were produced in the same manner as in Example 100.

Example 115
1-ethyl-5-fluoro-3- {5- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1 Preparation of 1,3-dihydro-2H-benzimidazol-2-thione hydrochloride:

Under a nitrogen atmosphere, 1-ethyl-5-fluoro-3- {5- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazole-3- Il} -1,3-dihydro-2H-benzimidazol-2-one (52 mg) was dissolved in toluene (10 ml), Lawesson's reagent (30 mg) was added, and the mixture was heated to reflux for 4 days. After cooling to room temperature, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (column; Hi-Flash ^TM amino column, developing solvent: hexane / ethyl acetate = 1/1). A crude product was obtained. This was dissolved in methylene chloride (1 ml), 1N hydrochloric acid / diethyl ether solution (1 ml) was added dropwise, and the precipitated solid was collected by filtration to obtain the title compound (15 mg).
LC-MS, m / z; 432 (MH ⁺ ).

Example 116
3- {5- [1- (4,4-Difluorocyclohexyl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1-ethyl-5-fluoro-1,3- Preparation of dihydro-2H-benzimidazol-2-one:

1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one Trifluoroacetate (147 mg) was suspended in 1,2-dichloroethane (5 ml), triethylamine (141 μl), 4,4-difluorocyclohexanone (135 mg), sodium triacetoxyborohydride (212 mg), titanium tetraisopropoxide (375 mg) was added and stirred at 60 ° C. overnight. After allowing to cool to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride. The organic layer was dried over 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 = 1/1) to obtain the title compound (87 mg) as a white solid.
¹ H NMR (CDCl ₃ , δppm); 1.37 (3H, t, J = 7.2 Hz), 1.60-1.91 (6H, m), 1.94-2.23 (6H, m), 2.29-2.52 (3H, m), 2.95 -3.11 (3H, m), 3.98 (2H, q, J = 7.2 Hz), 6.93-6.98 (2H, m), 7.71 (1H, d, J = 8.8 Hz). LC-MS, m / z; 450 (MH ⁺ ).

Using the corresponding ketone instead of 4,4-difluorocyclohexanone in Example 116, the compounds shown in the following table (Examples 117 to 119) were produced in the same manner as in Example 116.

1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 100 1-ethyl-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H instead of 2-one trifluoroacetate -Benzimidazol-2-one Using trifluoroacetate and using the corresponding aldehyde or ketone instead of tetrahydrofuran-3-carbaldehyde, the compounds in the following table (Examples 121 to 121) were prepared in the same manner as in Example 100. 127) was produced.

Example 128
Of 1- [5- (1-cyclohexylpyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one Manufacturing:

1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 100 1-ethyl-3- [5- (pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H instead of 2-one trifluoroacetate -The title compound was prepared in the same manner as in Example 100 using benzimidazol-2-one trifluoroacetate and using cyclohexanone instead of tetrahydrofuran-3-carbaldehyde.
¹ H NMR (CDCl ₃ , δppm); 1.14-1.32 (5H, m), 1.38 (3H, t, J = 7.2 Hz), 1.61 (1H, m), 1.73-1.82 (2H, m), 1.90-2.00 (2H, m), 2.14 (1H, m), 2.24-2.48 (2H, m), 2.70 (1H, m), 2.84-2.99 (2H, m), 3.31 (1H, t, J = 8.8 Hz), 3.74 (1H, m), 4.00 (2H, q, J = 7.2 Hz), 7.06 (1H, m), 7.15-7.26 (2H, m), 7.87 (1H, m). LC-MS, m / z; 382 (MH ⁺ ).

1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 100 In the same manner as in Example 100, using the corresponding starting material instead of -2-one trifluoroacetate and tetrahydro-4H-pyran-4-one instead of tetrahydrofuran-3-carbaldehyde, the following table was obtained. Of the compound (Examples 129 to 130).

1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 100 In the same manner as in Example 100, using the corresponding raw materials instead of 2-one trifluoroacetate and tetrahydropyran-4-carbaldehyde instead of tetrahydrofuran-3-carbaldehyde, the compounds shown in the following table (Examples 132 to 133) were produced.

Example 134
1-ethyl-3- (5- {1-[(4-hydroxytetrahydro-2H-pyran-4-yl) methyl] piperidin-4-yl} -1,2,4-oxadiazol-3-yl) Preparation of -1,3-dihydro-2H-benzimidazol-2-one:

1-ethyl-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one trifluoroacetate (256 mg) was suspended in ethanol (1 ml), N, N-diisopropylethylamine (0.5 ml) and 1,6-dioxaspiro [2.5] octane (898 mg) were added, and the mixture was stirred at 80 ° C. for 1 day. After allowing to cool to room temperature, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (column; Hi-Flash ^™ Amino Column, developing solvent: hexane / ethyl acetate = 1/3). The title compound (222 mg) was obtained.
¹ H NMR (CDCl ₃ , δppm); 1.38 (3H, t, J = 7.2 Hz), 1.44-1.51 (2H, m), 1.56-1.66 (3H, m), 2.00-2.18 (4H, m), 2.38 (2H, s), 2.54 (2H, dt, J = 11.4, 2.8 Hz), 2.94-3.12 (3H, m), 3.73-3.85 (4H, m), 4.00 (2H, q, J = 7.2 Hz), 7.06 (1H, d, J = 7.7 Hz), 7.15-7.24 (2H, m), 7.88 (1H, m). LC-MS, m / z; 428 (MH ⁺ ).

Example 135
tert-Butyl 2- {4- [3- (3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazol-5-yl] Production of piperidin-1-yl} -2-methylpropanoate:

1-ethyl-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one trifluoroacetate (855 mg) was suspended in acetonitrile (5 ml), tert-butyl 2-bromoisobutyrate (580 mg), potassium carbonate (553 mg) and sodium iodide (50 mg) were added, and the mixture was heated to reflux for 12 hours. After allowing to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over 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 = 1/1) to obtain the title compound (641 mg).
¹ H NMR (CDCl ₃ , δppm); 1.30 (6H, s), 1.38 (3H, t, J = 7.2 Hz), 1.47 (9H, s), 1.92-2.07 (2H, m), 2.11-2.21 (2H , m), 2.35-2.46 (2H, m), 2.98-3.17 (3H, m), 4.00 (2H, q, J = 7.3 Hz), 7.05 (1H, d, J = 7.3 Hz), 7.13-7.24 ( 2H, m), 7.89 (1H, m). LC-MS, m / z; 456 (MH ⁺ ).

Example 136
2- {4- [3- (3-Ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazol-5-yl] piperidine-1 Preparation of -yl} -2-methylpropionic acid hydrochloride:

tert-Butyl 2- {4- [3- (3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazol-5-yl] Piperidin-1-yl} -2-methylpropanoate (630 mg) was dissolved in methanol (10 ml), 4N hydrochloric acid / dioxane solution (12 ml) was added, and the mixture was stirred at 60 ° C. for 5 hr. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure to obtain the title compound (524 mg).
¹ H NMR (CD ₃ OD, δppm); 1.36 (3H, t, J = 7.2 Hz), 1.68 (6H, s), 2.23-2.65 (4H, m), 3.35-3.75 (5H, m), 4.02 ( 2H, q, J = 7.2 Hz), 7.20 (1H, m), 7.25-7.33 (2H, m), 7.88 (1H, d, J = 7.9 Hz) .LC-MS, m / z; 400 (MH ⁺ ).

Example 137
1-ethyl-3- {5- [1- (1-hydroxy-2-methylpropan-2-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1, Preparation of 3-dihydro-2H-benzimidazol-2-one hydrochloride:

2- {4- [3- (3-Ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazol-5-yl] piperidine-1 -Il} -2-methylpropionic acid hydrochloride (507 mg) was dissolved in THF (12 ml), triethylamine (174 μl) was added, and then ice-cooled isobutyl chloroformate (159 μl) was added and stirred for 1 hour. The insoluble material was filtered off, and the insoluble material was further washed with THF, and then a solution of sodium borohydride (48 mg) dissolved in water (1.5 ml) was added dropwise to the filtrate under ice cooling. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over 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 = 1/1) to obtain a crude product. The obtained crude product was dissolved in methylene chloride (2 ml), 1N hydrochloric acid / diethyl ether solution (2 ml) was added dropwise, and the precipitated solid was collected by filtration to give the title compound (398 mg) as a white solid.
¹ H NMR (DMSO-d ₆ , δppm); 1.23-1.33 (10H, m), 2.25-2.40 (4H, m), 3.11-3.27 (2H, m), 3.48-3.68 (5H, m), 3.90- 4.01 (2H, m), 7.19 (1H, dt, J = 7.7, 1.2 Hz), 7.27 (1H, dt, J = 7.7, 1.2 Hz), 7.38 (1H, d, J = 7.9 Hz), 7.74 (1H , dd, J = 7.8, 0.8 Hz) .LC-MS, m / z; 386 (MH ⁺ )

Example 138:
1-ethyl-5-fluoro-3- (5- {1- [2- (tetrahydrofuran-2-yl) ethyl] piperidin-4-yl} -1,2,4-oxadiazol-3-yl) 1 Preparation of 1,3-dihydro-2H-benzimidazol-2-one:

1-ethyl-3- [5- (pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one in Example 083 1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H instead of trifluoroacetate -Benzimidazol-2-one Trifluoroacetate was used instead of 1- (3-bromopropyl) pyrrolidin-2-one 2- (tetrahydrofuran-2-yl) ethyl 4-methylbenzenesulfonate (Reference Example 075) Was used to prepare the title compound in the same manner as in Example 083.
¹ H NMR (CDCl ₃ , δppm); 1.37 (3H, t, J = 7.2 Hz), 1.46-1.20 (12H, m), 2.40-2.58 (2H, m), 2.92-3.12 (3H, m) 3.73 ( 1H, m), 3.83-3.88 (2H, m), 3.95-4.02 (2H, m), 6.94-6.96 (2H, m), 7.71 (1H, d, J = 8.8 Hz). LC-MS, m / z; 430 (MH ⁺ ).

Example 139:
1-ethyl-3- {5- [1- (tetrahydro-2H-pyran-3-ylmethyl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro Production of -2H-benzimidazol-2-one:

1-ethyl-3- [5- (pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one in Example 083 1-ethyl-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole- instead of trifluoroacetate 2-one trifluoroacetic acid salt was used, and (tetrahydro-2H-pyran-3-yl) methyl 4-methylbenzenesulfonate (Reference Example 076) was used instead of 1- (3-bromopropyl) pyrrolidin-2-one. In the same manner as in Example 083, the title compound was produced.
¹ H NMR (CDCl ₃ , δppm); 1.38 (3H, t, J = 7.3 Hz), 1.80-2.20 (14H, m), 2.80-3.20 (4H, m), 3.41 (1H, br) 3.83 (1H, m), 3.95-4.03 (2H, m), 7.05 (1H, d, J = 7.1 Hz), 7.17 (1H, t, J = 7.8 Hz), 7.22 (1H, d, J = 7.6 Hz), 7.89 ( 1H, d, J = 8.0 Hz) .LC-MS, m / z; 412 (MH ⁺ ).

Example 140:
trans-1-ethyl-5-fluoro-3- {5- [1- (2-hydroxycyclopentyl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1,3- Preparation of dihydro-2H-benzimidazol-2-one:

1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one Trifluoroacetate (223 mg) was suspended in ethanol (4 ml), cyclopentene oxide (400 mg) and N, N-diisopropylethylamine (258 μl) were added, and the mixture was stirred at 80 ° C. for 2 days. After allowing to cool to room temperature, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (column; Hi-Flash ^TM amino column, developing solvent: ethyl acetate / methanol = 98/2). The title compound (163 mg) was obtained.
¹ H NMR (CDCl ₃ , δppm); 1.37 (3H, t, J = 7.2 Hz), 1.44-1.78 (4H, m), 1.82-2.12 (5H, m), 2.15-2.39 (4H, m), 2.58 (1H, m), 3.00-3.14 (2H, m), 3.21 (1H, m), 3.98 (2H, q, J = 7.2 Hz), 4.14 (1H, dd, J = 12.9, 5.6 Hz), 6.94- 6.97 (2H, m), 7.71 (1H, m). LC-MS, m / z; 416 (MH ⁺ ).

Example 141:
3- [5- (1-tert-Butylpiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1-ethyl-5-fluoro-1,3-dihydro-2H-benz Preparation of imidazol-2-one hydrochloride:

1-tert-Butylpiperidine-4-carboxylic acid (71 mg, Reference Example 077) was dissolved in DMF (2 ml), and N, N′-carbonylimidazole (92 mg), N, N-dimethyl-4-aminopyridine (4 mg) was dissolved. And stirred at 80 ° C. for 2 hours. Subsequently, 3-ethyl-6-fluoro-N′-hydroxy-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxyimidamide (71 mg) was added and stirred at 80 ° C. for 1 hour. Next, 1N tetrabutylammonium fluoride / THF solution (0.5 ml) was added to the reaction solution, and the mixture was stirred at 80 ° C. overnight. After allowing to cool to room temperature, water was added dropwise to the reaction solution, the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain a crude product (32 mg). Next, the crude product was dissolved in ethyl acetate (2 ml), 1N hydrochloric acid / diethyl ether solution (0.2 ml) was added dropwise, and the precipitated hydrochloride (30 mg) was collected by filtration. This was dissolved in ethanol (4.5 ml) at 90 ° C. and allowed to cool to room temperature. The precipitated solid was collected by filtration to give the title compound (21 mg) as a white solid.
¹ H NMR (CD ₃ OD, δppm); 1.34 (3H, t, J = 7.2 Hz), 1.47 (9H, s), 2.15-2.30 (2H, m), 2.52-2.61 (2H, m), 3.16- 3.26 (2H, m), 3.47-3.55 (1H, m), 3.76-3.84 (2H, m), 4.01 (2H, q, J = 7.2 Hz), 7.05 (1H, ddd, J = 10.4, 7.9, 1.8 Hz), 7.26 (1H, dd, J = 8.8, 4.4 Hz), 7.71 (1H, m). LC-MS, m / z; 388 (MH ⁺ ).

Example 142:
1-ethyl-5-fluoro-3- {5- [1- (4-methyltetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl } Preparation of 1,3-dihydro-2H-benzimidazol-2-one:

Using 1- (4-methyltetrahydro-2H-pyran-4-yl) piperidine-4-carboxylic acid (Reference Example 078) instead of 1-tert-butylpiperidine-4-carboxylic acid in Example 141 The title compound was obtained by reacting in the same manner as in Example 141.
¹ H NMR (CDCl ₃ , δppm); 0.94-1.05 (2H, m), 1.36 (3H, t, J = 7.3 Hz), 1.49-2.39 (11H, m), 2.99 (3H, br), 3.49-3.57 (2H, m), 3.83-3.92 (2H, m), 3.97 (2H, q, J = 7.2 Hz), 6.93-6.97 (2H, m), 7.70 (1H, m). LC-MS, m / z ; 430 (MH ⁺ ).

Examples 143-144
1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro-2H-benz Imidazole-2-one 2 trifluoroacetate (233 mg, 0.4 mmol) was dissolved in methylene chloride (4 ml) and triethylamine (224 μl, 1.6 mmol) was added. To this solution was added the corresponding alkyl chlorocarbonate (1.3 eq, 0.52 mmol) and stirred at room temperature overnight. Subsequently, water was added and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. By purifying the obtained residue by silica gel column chromatography (column; Hi-Flash ^™ Amino Column, developing solvent: hexane / ethyl acetate = 1/1 to 3/1 and chloroform / methanol = 9/1), The compounds in the table (Examples 143 to 144) were prepared.

Examples 145-146
1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro in Example 143 -2H-benzimidazol-2-one The compounds shown in the following table (Examples 145 to 146) were produced in the same manner as in Example 143 using the corresponding starting materials instead of 2trifluoroacetate.

Examples 147-150
1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro in Example 143 -2H-benzimidazol-2-one 1-ethyl-3- {5- [1- (piperidin-4-ylmethyl) azetidin-3-yl] -1,2,4-oxa instead of 2trifluoroacetate Diazol-3-yl} -1,3-dihydro-2H-benzimidazol-2-one 2-trifluoroacetate was used in the same manner as in Example 143 to obtain the compounds shown in the following table (Examples 147 to 150). Manufactured.

Examples 151-152
1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro in Example 143 -H-benzimidazol-2-one The compounds shown in the following table (Examples 151 to 152) were produced in the same manner as in Example 143 using the corresponding starting materials instead of 2trifluoroacetate.

Example 153:
1-ethyl-3- (5- {1-[(1-ethylpiperidin-4-yl) methyl] azetidin-3-yl} -1,2,4-oxadiazol-3-yl) -1,3 -Production of dihydro-2H-benzimidazol-2-one:

1-ethyl-3- {5- [1- (piperidin-4-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H-benz Imidazole-2-one 2 trifluoroacetate (350 mg) was suspended in THF (10 ml), acetaldehyde (100 μl) and sodium triacetoxyborohydride (399 mg) were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform / methanol (9/1). The organic layer was dried over 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: ethyl acetate / methanol = 9/1) to give the title compound (234 mg) as a yellow oil.
¹ H NMR (CDCl ₃ , δppm); 1.08 (3H, t, J = 7.2 Hz), 1.21-1.42 (6H, m), 1.68-1.94 (4H, m), 2.33-2.45 (4H, m), 2.94 (2H, d, J = 11.7 Hz), 3.48 (2H, t, J = 7.5 Hz), 3.79 (2H, t, J = 7.8 Hz), 3.97-4.07 (3H, m), 7.06 (1H, m) , 7.15-7.27 (2H, m), 7.87 (1H, m). LC-MS, m / z; 411 (MH ⁺ ).

Example 154:
1-ethyl-3- [5- (1-{[1- (methylsulfonyl) piperidin-4-yl] methyl} pyrrolidin-3-yl) -1,2,4-oxadiazol-3-yl]- Preparation of 1,3-dihydro-2H-benzimidazol-2-one:

1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro in Example 143 -2H-benzimidazol-2-one 1-ethyl-3- {5- [1- (piperidin-4-ylmethyl) pyrrolidin-3-yl] -1,2,4-oxa instead of 2trifluoroacetate Diazol-3-yl} -1,3-dihydro-2H-benzimidazol-2-one The same method as Example 143, using 2 trifluoroacetate and using methanesulfonyl chloride instead of alkyl chlorocarbonate Produced the title compound.
¹ H NMR (DMSO-d ₆ , δppm); 1.13 (2H, q, J = 12.0 Hz), 1.25 (3H, t, J = 7.2 Hz), 1.58 (1H, m), 1.81 (2H, t, J = 12.0 Hz), 2.16 (1H, m), 2.28-2.39 (3H, m), 2.58 (1H, m), 2.64-2.72 (3H, m), 2.82 (3H, m), 2.91 (2H, m) , 3.51 (2H, d, J = 12.4 Hz), 3.80 (1H, m), 3.93 (2H, q, J = 7.2 Hz), 7.17 (1H, dt, J = 7.8, 1.3 Hz), 7.25 (1H, dt, J = 7.8, 1.3 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.71 (1H, d, J = 7.3 Hz). LC-MS, m / z; 475 (MH ⁺ ).

Examples 155-156
1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro in Example 143 -2H-benzimidazol-2-one 1-ethyl-5-fluoro-3- (5- {1-[(2R) pyrrolidin-2-ylmethyl] piperidin-4-yl}-instead of 2trifluoroacetate 1,2,4-oxadiazol-3-yl) -1,3-dihydro-2H-benzimidazol-2-one dihydrochloride and the corresponding acid chloride or acid anhydride was allowed to act The compounds shown in the following table (Examples 155 to 156) were produced in the same manner as in Example 143.

Example 157:
Methyl (3S) -3-({4- [3- (6-chloro-3-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxa Preparation of [Diazol-5-yl] piperidin-1-yl} methyl) pyrrolidine-1-carboxylate:

1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro in Example 143 -2H-benzimidazol-2-one instead of 2-trifluoroacetate salt 5-chloro-1-ethyl-3- (5- {1-[(3R) -pyrrolidin-3-ylmethyl] piperidin-4-yl} The title compound was prepared in the same manner as in Example 143 using -1,2,4-oxadiazol-3-yl) -1,3-dihydro-2H-benzimidazol-2-one dihydrochloride.
¹ H NMR (CDCl ₃ , δppm); 1.37 (3H, t, J = 7.2 Hz), 1.65 (1H, m), 1.95-2.24 (7H, m), 2.29-2.49 (3H, m), 2.90-3.15 (4H, m), 3.28-3.64 (3H, m), 3.70 (3H, d, J = 2.6 Hz), 3.98 (2H, q, J = 7.2 Hz), 6.97 (1H, d, J = 8.3 Hz) , 7.21 (1H, dd, J = 8.3, 2.0 Hz), 7.92 (1H, d, J = 1.8 Hz). LC-MS, m / z; 489 (MH ⁺ ).

Examples 158-160
1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro in Example 143 -2H-benzimidazol-2-one instead of 2trifluoroacetate salt 3- [5- (1,4′-bipiperidin-4-yl) -1,2,4-oxadiazol-3-yl]- Using 1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazol-2-one dihydrochloride and reacting the corresponding acid chloride, in the same manner as in Example 143, Compounds (Examples 158-160) were prepared.

Examples 161-163
1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro in Example 143 -2H-benzimidazol-2-one 1-ethyl-5-fluoro-3- {5- [1- (piperidin-4-ylmethyl) piperidin-4-yl] -1,2 instead of 2trifluoroacetate , 4-oxadiazol-3-yl} -1,3-dihydro-2H-benzimidazol-2-one dihydrochloride and reacting the corresponding acid chloride by the same method as in Example 143 The compounds shown in the following table (Examples 161 to 163) were produced.

Example 164:
Methyl 2-({4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazole-5 Preparation of -yl] piperidin-1-yl} methyl) morpholine-4-carboxylate:

1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro in Example 143 -2H-benzimidazol-2-one 1-ethyl-5-fluoro-3- {5- [1- (morpholin-2-ylmethyl) piperidin-4-yl] -1,2 instead of 2trifluoroacetate , 4-oxadiazol-3-yl} -1,3-dihydro-2H-benzimidazol-2-one dihydrochloride was used to prepare the title compound in the same manner as in Example 143.
¹ H NMR (CDCl ₃ , δppm); 1.37 (3H, t, J = 7.2 Hz), 2.07-2.41 (7H, m), 2.51-2.77 (2H, m), 2.95-3.12 (4H, m), 3.46 -3.67 (2H, m), 3.73 (3H, s), 3.86-4.06 (5H, m), 6.92-6.99 (2H, m), 7.71 (1H, d, J = 8.8 Hz). LC-MS, m / z; 489 (MH ⁺ ).

Example 165:
1-ethyl-3- {5- [cis-4- (pyrrolidin-1-yl) cyclohexyl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H-benzimidazole- 2-one production:

Example 166:
1-ethyl-3- {5- [trans-4- (pyrrolidin-1-yl) cyclohexyl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H-benzimidazole 2-one production:

1-ethyl-3- [5- (4-oxocyclohexyl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one (0.41 g) Pyrrolidine (103 μl) was dissolved in dichloromethane (15 ml) and stirred at room temperature for 10 minutes. Next, acetic acid (90 μl) was added and stirred for another 30 minutes, then sodium triacetoxyborohydride (0.40 g) was added and stirred overnight at room temperature. A 1N aqueous potassium hydroxide solution was added to the reaction solution, and the mixture was partitioned. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is purified by silica gel column chromatography (column; Hi-Flash ^™ Amino Column, developing solvent: hexane / ethyl acetate) to give the cis isomer of the title compound as a colorless oil, and the trans isomer as a pale yellow solid. Got as.
(Example 165: cis-form)
¹ H NMR (CDCl ₃ , δppm); 1.38 (3H, t, J = 7.2 Hz), 1.72-1.93 (10H, m), 2.19 (1H, m), 2.34 (2H, m), 2.50-2.60 (4H , m), 3.21 (1H, m), 4.00 (2H, q, J = 7.5 Hz), 7.05 (1H, d, J = 7.5 Hz), 7.13-7.26 (2H, m), 7.86 (1H, d, J = 7.5 Hz) .LC-MS, m / z; 382 (MH ⁺ ).
(Example 166: Trans form)
¹ H NMR (CDCl ₃ , δppm); 1.38 (3H, t, J = 7.2 Hz), 1.68-1.86 (8H, m), 2.04-2.32 (5H, m), 2.55-2.70 (4H, m), 3.03 (1H, m), 4.00 (2H, q, J = 7.5 Hz), 7.05 (1H, d, J = 8.1 Hz), 7.13-7.26 (2H, m), 7.88 (1H, d, J = 7.2 Hz) LC-MS, m / z; 382 (MH ⁺ ).

Examples 167-172
1-ethyl-3- [5- (4-oxocyclohexyl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one in Example 165 and The compounds shown in the following table (Examples 167 to 172) were produced in the same manner as in Example 165 using the corresponding starting materials instead of pyrrolidine.

Example 173:
1-ethyl-5-fluoro-3- [5- (cis-4-{[2- (tetrahydro-2H-pyran-4-yl) ethyl] amino} cyclohexyl) -1,2,4-oxadiazole- Preparation of 3-yl] -1,3-dihydro-2H-benzimidazol-2-one:

Of 1-ethyl-3- [5- (4-oxocyclohexyl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one in Example 165 Instead 1-ethyl-5-fluoro-3- [5- (4-oxocyclohexyl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole-2 The title compound was prepared in a manner similar to Example 165 using -one and 2- (tetrahydro-2H-pyran-4-yl) ethamine in place of pyrrolidine.
¹ H NMR (CDCl ₃ , δppm); 1.24-1.64 (13H, m), 1.73-1.96 (4H, m), 2.22-2.34 (2H, m), 2.63 (2H, t, J = 7.4 Hz), 2.73 (1H, m), 3.22 (1H, m), 3.37 (2H, td, J = 11.7, 1.5 Hz), 3.90-4.03 (4H, m), 6.93-6.98 (2H, m), 7.70 (1H, m LC-MS, m / z; 458 (MH ⁺ ).

Example 174:
1-ethyl-3- [5- (cis-4- {ethyl [2- (tetrahydro-2H-pyran-4-yl) ethyl] amino} cyclohexyl) -1,2,4-oxadiazol-3-yl Preparation of -5-fluoro-1,3-dihydro-2H-benzimidazol-2-one:

1-ethyl-3- {5- [1- (piperidin-4-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro in Example 153 -2H-benzimidazol-2-one 1-ethyl-5-fluoro-3- [5- (cis-4-{[2- (tetrahydro-2H-pyran-4-yl) instead of 2 trifluoroacetate] Ethyl] amino} cyclohexyl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one in the same manner as in Example 153. The compound was prepared.
¹ H NMR (CDCl ₃ , δppm); 1.02 (3H, t, J = 7.1 Hz), 1.19-1.91 (16H, m), 2.35-2.71 (7H, m), 3.28-3.39 (3H, m), 3.91 (2H, dd, J = 11.2, 3.9 Hz), 3.99 (2H, q, J = 7.2 Hz), 6.94-6.98 (2H, m), 7.73 (1H, m). LC-MS, m / z; 486 (MH ⁺ ).

Example 175:
1-ethyl-5-fluoro-3- {5- [cis-4- (tetrahydrofuran-3-ylamino) cyclohexyl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H -Preparation of benzimidazol-2-one:

1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 100 2- [5- (cis-4-aminocyclohexyl) -1,2,4-oxadiazol-3-yl] -1-ethyl-5-fluoro-1, instead of 2-one trifluoroacetate The title compound was prepared in the same manner as in Example 100 using 3-dihydro-2H-benzimidazol-2-one trifluoroacetate and using 3-oxotetrahydrofuran instead of tetrahydrofuran-3-carbaldehyde. .
LC-MS, m / z; 416 (MH ⁺ ).

Example 176:
1-ethyl-5-fluoro-3- (5- {cis-4- [methyl (tetrahydrofuran-3-yl) amino] cyclohexyl} -1,2,4-oxadiazol-3-yl) -1,3 -Production of dihydro-2H-benzimidazol-2-one:

1-ethyl-3- {5- [1- (piperidin-4-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro in Example 153 -2H-benzimidazol-2-one 1-ethyl-5-fluoro-3- {5- [cis-4- (tetrahydrofuran-3-ylamino) cyclohexyl] -1,2,4 instead of 2trifluoroacetate The title compound was prepared in the same manner as in Example 153 using -oxadiazol-3-yl} -1,3-dihydro-2H-benzimidazol-2-one and using 37% aqueous formaldehyde instead of acetaldehyde. Manufactured.
¹ H NMR (CDCl ₃ , δppm); 1.38 (3H, t, J = 7.2 Hz), 1.61-1.92 (7H, m), 2.02 (1H, m), 2.19 (3H, s), 2.40-2.49 (2H , m), 2.56 (1H, m), 3.34-3.47 (2H, m), 3.59 (1H, t, J = 7.8 Hz), 3.73-3.89 (2H, m), 3.91-4.03 (3H, m), 6.94-6.99 (2H, m), 7.73 (1H, m). LC-MS, m / z; 430 (MH ⁺ ).

Examples 177-183
1-ethyl-3- [5- (4-oxocyclohexyl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazol-2-one in Example 165 and The compounds shown in the following table (Examples 177 to 183) were produced in the same manner as in Example 165 using the corresponding starting materials instead of pyrrolidine.

Examples 184-185
1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 100 1-ethyl-5-fluoro-3- {5- [cis-3- (methylamino) cyclobutyl] -1,2,4-oxadiazol-3-yl} instead of 2-one trifluoroacetate -1,3-dihydro-2H-benzimidazol-2-one (Example 181) or 1-ethyl-3- {5-3- (ethylamino) cyclobutyl] -1,2,4-oxadiazole-3 -Il} -5-fluoro-1,3-dihydro-2H-benzimidazol-2-one (Example 182) and in the same manner as in Example 100, the compounds in the following tables (Examples 184 to 185) ) Manufactured.

Examples 186-187
1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 100 3- {5- [cis-3- (cyclopentylamino) cyclobutyl] -1,2,4-oxadiazol-3-yl} -1-ethyl-5-fluoro instead of 2-one trifluoroacetate -1,3-dihydro-2H-benzimidazol-2-one (Example 183) was used in the same manner as in Example 100 except that formaldehyde aqueous solution or acetaldehyde was used instead of tetrahydrofuran-3-carbaldehyde. The compounds in the table (Examples 186 to 187) were prepared.

Examples 188-189
1- [5- (azetidin-3-yl) -1,2,4-oxadiazol-3-yl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one in Example 060 The corresponding raw materials were used in place of trifluoroacetate, and phenethyl bromide was used in place of 1- (2-bromoethyl) -4-fluorobenzene. 188-189) were produced.

１）ＨＸは、塩酸またはトリフルオロ酢酸を意味する。

1) HX means hydrochloric acid or trifluoroacetic acid.

Examples 190-193
1- [5- (Piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -3- (propan-2-yl) -1,3-dihydro-2 H in Example 001 -Benzimidazol-2-one The compounds shown in the following table (Examples 190 to 193) were produced in the same manner as in Example 001 using the corresponding starting materials instead of trifluoroacetate.

Examples 194-196
1-Ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 027 The compounds shown in the following table (Examples 194 to 196) were produced in the same manner as in Example 027 using the corresponding starting materials and alkyl halides instead of 2-one trifluoroacetate and isopropyl iodide.

１）ＨＸは、塩化水素かトリフルオロ酢酸を意味する。

1) HX means hydrogen chloride or trifluoroacetic acid.

１）得られた化合物を塩化メチレンに溶解し、１規定塩酸／ジエチルエーテル溶液で処理する事により、塩酸塩とした。

1) The obtained compound was dissolved in methylene chloride and treated with 1N hydrochloric acid / diethyl ether solution to obtain hydrochloride.

Examples 197-200
1-ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 100 Using the corresponding raw materials and aldehydes or ketones instead of 2-one trifluoroacetate and tetrahydrofuran-3-carbaldehyde, the compounds shown in the following table (Examples 197 to 200) were prepared in the same manner as in Example 100. Manufactured.

１）ＨＸは、塩化水素またはトリフルオロ酢酸を意味する。

1) HX means hydrogen chloride or trifluoroacetic acid.

Example 201:
1 ′-{5- [1- (2-Phenylethyl) piperidin-4-yl] -1,3,4-oxadiazol-2-yl} spiro [cyclopropane-1,3′-indole] -2 Production of '(1'H) -one:

1-Ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 027 1 '-[5- (piperidin-4-yl) -1,3,4-oxadiazol-2-yl] spiro [cyclopropane-1 instead of -2-one trifluoroacetate and isopropyl iodide , 3′-indole] -2 ′ (1′H) -one The title compound was prepared in the same manner as in Example 027 using trifluoroacetate and phenethyl bromide.
¹ H NMR (CDCl ₃ , δppm); 1.65-1.70 (2H, m), 1.89-1.94 (2H, m), 1.99-2.13 (2H, m), 2.15-2.33 (4H, m), 2.61-2.70 ( 2H, m), 2.80-2.89 (2H, m), 2.97-3.12 (3H, m), 6.90 (1H, m), 7.16-7.39 (7H, m), 7.98 (1H, m). LC-MS, m / z; 415 (MH ⁺ ).

Example 202:
1 ′-{3- [1- (3-methoxypropyl) piperidin-4-yl] -1,2,4-oxadiazol-5-yl} spiro [cyclopropane-1,3′-indole] -2 Production of '(1'H) -one hydrochloride:

1-Ethyl-5-fluoro-3- [5- (piperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzimidazole in Example 027 1 '-[3- (piperidin-4-yl) -1,2,4-oxadiazol-5-yl] spiro [cyclopropane-1 instead of -2-one trifluoroacetate and isopropyl iodide , 3′-indole] -2 ′ (1′H) -one The title compound was prepared in the same manner as in Example 027 using hydrochloride and 3-methoxypropyl bromide.
¹ H NMR (CDCl ₃ , δppm); 1.68-1.74 (2H, m), 1.94-2.01 (2H, m), 2.15-2.30 (2H, m), 2.35-2.44 (2H, m), 2.66-3.19 ( 7H, m), 3.33-3.36 (3H, d), 3.44-3.55 (4H, m), 6.92 (1H, t, J = 8.4 Hz), 7.25 (1H, m), 7.39 (1H, t, J = 7.9 Hz), 8.09 (1H, t, J = 8.3 Hz). LC-MS, m / z; 383 (MH ⁺ ).

Example 203:
4- [3- (3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) -1,2,4-oxadiazol-5-yl] -N, N- Preparation of dimethyl-1,4′-bipiperidine-1′-carboxamide:

1- {5- [1- (azetidin-3-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl} -3-ethyl-1,3-dihydro in Example 143 1- [5- (1,4′-bipiperidin-4-yl) -1,2,4-oxadiazol-3-yl]-in place of -2H-benzimidazol-2-one ditrifluoroacetate The title compound was produced in the same manner as in Example 143 by using 3,3-dimethyl-1,3-dihydro-2H-indol-2-one dihydrochloride and reacting with dimethylcarbamoyl chloride.
LC-MS, m / z; 467 (MH ⁺ ).

Pharmacological Tests Hereinafter, pharmacological test methods and results for representative compounds of the present invention will be shown, 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. 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 contained 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 a Whatman GF / B filter 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.
A 50% inhibitory concentration (IC ₅₀ ) was determined from the inhibition rate of the test compound for specific binding obtained by subtracting non-specific binding from the total binding amount of [ ³ H] -GR113808.
Table 64 shows the results of the serotonin 4 (5-HT ₄ ) receptor binding test.

Test Example 2 Serotonin 4 (5-HT ₄ ) Receptor Agonist Activity Measurement Test The cAMP measurement test was carried out 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. After replacing with medium 2 (DMEM / 10000 cut FBS, G-418, P / S, NEAA) 1-2 hours later, the cells were collected by trypsin treatment with EDTA. 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.
Table 65 shows the results of the serotonin 4 (5-HT ₄ ) receptor agonist activity measurement test.

The compound of the present invention is useful as a therapeutic or prophylactic agent for diseases or conditions involving serotonin 4 receptor. The following (i) to (v) are mentioned as diseases or symptoms in which the involvement of serotonin 4 receptor is suggested:
(I) neuropsychiatric disorders 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 diseases, scleroderma, diabetes mellitus, nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain, chest Gastrointestinal symptoms such as burns or ambiguity;
(V) Urinary system diseases accompanied by dysuria due to urinary tract obstruction or enlarged prostate.
In addition, since the compound of the present invention exhibits excellent 5-HT ₄ receptor operability and brain transferability, the therapeutic agent for neuropsychiatric diseases such as Alzheimer's dementia described in (i) above, Useful as a preventive agent.

Claims (16)

Formula (1):

[Where:
A is the following formula (A-1), formula (A-2), formula (A-3), or formula (A-4):

(Where
l means an integer of 0 to 4;
m means an integer of 0 to 2;
n means an integer of 0 to 2,
o and p each independently represent 0 or 1,
q means an integer of 0 to 5;
(A-1) to (A-4) are substitutable positions, and 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, And may be substituted with one or more substituents selected from the group consisting of an oxo group and a halogen atom)
Means
B is the following formula (B-1), formula (B-2), or formula (B-3):

(Where
(B-2) and (B-3) may have an unsaturated bond at a possible position in the ring, and D does not exist when B means formula (B-1)),
D means a group selected from the group consisting of the following groups (1) and (2):
(1) hydrogen atom, optionally substituted C _1-6 alkyl group, optionally substituted C _3-6 alkenyl group, optionally substituted C _3-6 alkynyl group, optionally substituted Good C _3-8 monocyclic, C _7-10 bicyclic or C _7-12 tricyclic cycloalkyl group, and optionally substituted C _5-8 monocyclic or C _7-10 bicyclic A cycloalkenyl group,
Here, a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 monocyclic, a C _7-10 bicyclic or a C _7-12 tricyclic cycloalkyl group , And a C _5-8 monocyclic or C _7-10 bicyclic cycloalkenyl group, each independently at a substitutable position, a C _1-4 alkyl group, a hydroxy group, a C _1-4 alkoxy group, Selected from the group consisting of C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _2-6 alkanoyl group, phenacyl group, and halogen atom Optionally substituted with one or more substituents;
_{(2) - (CH 2)} u -R 12
Here, u means an integer of 0 to 4, and when u means an integer of 1 to 4, the alkylene chain is a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, May be substituted with one or more substituents selected from the group consisting of 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), the formula ^(R 12 -7), or refers to the formula ^(R 12 -8),

(Where
R ¹³ means a group selected from the group consisting of the groups included in the following (1) to (5),
(1) a hydrogen atom and a formyl group;
(2) C _1-6 alkyl group which may be substituted, C _3-6 alkenyl group which may be substituted, C _3-6 alkynyl group which may be substituted, C ₃ which may be substituted _{A -8} cycloalkyl group, and an _optionally substituted C _5-8 cycloalkenyl group,
Here, the C _1-6 alkyl group, the C _3-6 alkenyl group, the C _3-6 alkynyl group, the C _3-8 cycloalkyl group, and the C _5-8 cycloalkenyl group can be independently substituted. Selected from the group consisting of a C _1-4 alkyl group, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, an oxo group, and a halogen atom. Optionally 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 _3-6 alkenyl group, an optionally substituted C _3-6 alkynyl group, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 A cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an 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 _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a 5-9 membered monocyclic or 7 A 10-membered bicyclic non-aromatic unsaturated heterocyclic group and a 4-9-membered monocyclic or 7-10-membered bicyclic saturated heterocyclic group are each independently In the substitutable position, C _1-4 alkyl group, hydroxy group, C _1-4 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl And may be substituted with one or more substituents selected from the group consisting of a group and a halogen atom,
Aryl, and heteroaryl groups, independently, at substitutable positions, halogen atom, hydroxy _{group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4} haloalkyl _{group, C 1- 4} haloalkoxy group, cyano group, nitro group, C _2-6 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 _3-6 alkenyl group or a C _3-6 alkynyl group);
^{(5) -CONR} 19 R 20, or ^-CSNR 19 ^{R 20} and _{^{-SO 2 NR 19 R 20 (R}} 19 and ^{R 20} are each independently means any group in the hydrogen atom or the ^{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 (the heterocyclic group is a C _1-4 alkyl group, hydroxy group, C _1-4 at a substitutable position). And optionally substituted with one or more substituents selected from the group consisting of an alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano group, an oxo group, and a halogen atom),
R ¹⁴ and R ¹⁵ each independently represent a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 alkenyl group, or an _optionally substituted C _{3− 6} alkynyl groups, an optionally substituted C _3-8 cycloalkyl group, an _optionally substituted C _5-8 cycloalkenyl group, an _optionally substituted aryl group, an optionally substituted heteroaryl A 5- to 9-membered monocyclic or 7 to 10-membered bicyclic non-aromatic unsaturated hetero ring group which may be substituted (the hetero ring group has carbon atoms on the ring; 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group (bonded to the adjacent nitrogen atom), which is substituted on the ring is bonded to the nitrogen atom adjacent the carbon atom), C _2-6 alk Yl _{group, C 1-6} alkoxycarbonyl group means a carbamoyl group, a sulfamoyl group, or a _{C 1-6} alkylsulfonyl group,
Here, a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 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 _2-6 alkanoyl group , C _1-6 alkoxycarbonyl group, carbamoyl group, sulfamoyl group, and C _1-6 alkylsulfonyl group are each independently a C _1-4 alkyl group, a hydroxy group, C _1-4 at a substitutable position. May be substituted with one or more substituents selected from the group consisting of an alkoxy 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 _1-4 alkyl group, a C _1-4 alkoxy group, a cyano group, a nitro group, or a C _{2-6 at} a substitutable position. May be substituted with one or more substituents selected from the group consisting of an alkanoyl group and an optionally substituted amino group,
Alternatively, 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 A saturated or unsaturated 4- to 9-membered monocyclic or 7- to 10-membered bicyclic nitrogen-containing heterocyclic group (the heterocyclic group is a C _1-4 alkyl group at a substitutable position) Substituted with one or more substituents selected from the group consisting of: a hydroxy group, a C _1-4 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 formed),
^{(R 12 -1) ~ (R} 12 -4) may be at the unsaturated bond in position within a ring),
R ⁸ , R ^{8 ′} , R ⁹ and R ^{9 ′} are each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-6 alkenyl group, An optionally substituted C _3-6 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 heteroaryl group, an optionally substituted 5- to 9-membered monocyclic or 7 to 10-membered bicyclic non-aromatic unsaturated heterocyclic group (the heterocyclic ring) Group is a carbon atom on the ring bonded to the adjacent nitrogen atom), or an optionally substituted 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group ( The heterocyclic group means that the carbon atom on the ring is bound to the adjacent nitrogen atom) Taste,
Here, a C _1-6 alkyl group, a C _3-6 alkenyl group, a C _3-6 alkynyl group, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a 5-9 membered monocyclic or 7 A 10-membered bicyclic non-aromatic unsaturated heterocyclic group and a 4-9-membered monocyclic or 7-10-membered bicyclic saturated heterocyclic group are each independently C _1-4 alkyl group, hydroxy group, C _1-4 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 _2-6 alkanoyl groups, phenacyl groups, and halogen atoms,
Aryl, and heteroaryl groups, independently, at substitutable positions, halogen atom, hydroxy _{group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4} haloalkyl _{group, C 1- 4} haloalkoxy group, cyano group, nitro group, C _2-6 alkanoyl group, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted amino groups,
Alternatively, R ⁸ and R ⁹ , and R ^{8 ′} and R ^{9 ′} are each independently bonded to each other, and in addition to the adjacent nitrogen atom, 1 to 2 nitrogen atoms, 1 oxygen atom, and 1 A saturated or unsaturated 4 to 9-membered monocyclic or 7 to 10-membered bicyclic nitrogen-containing heterocyclic group containing 0 to 2 heteroatoms selected from the group consisting of 1 sulfur atom May be formed,
Here, the nitrogen-containing heterocyclic group is a substitutable position, and is a C _1-4 alkyl group, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 haloalkyl group, a C _1-4 haloalkoxy group, a cyano. May be substituted with one or more substituents selected from the group consisting of a group, an oxo group, and a halogen atom,
R ¹⁰ , R ^{10 ′} , R ¹¹ and R ^{11 ′} each independently represent a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkyl group, or an _optionally substituted C. _{A 2-6} alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _1-6 alkoxy group, a cyano group, or an oxo group;
Here, the C _1-6 alkyl group, the C _2-6 alkenyl group, the C _2-6 alkynyl group, and the C _1-6 alkoxy group are each independently a C _1-4 alkyl group at a substitutable position. , Hydroxy group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _2-6 alkanoyl group, phenacyl group, and halogen atom May be substituted with one or more substituents selected from the group consisting of:
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 the ring to which R ¹⁰ and R ¹¹ are bonded,
Here, the saturated or unsaturated 3- to 8-membered ring is a C _1-4 alkyl group, a hydroxy group, a C _1-4 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 groups, cyano groups, oxo groups, aryl groups, heteroaryl groups, aryloxy groups, C _2-6 alkanoyl groups, phenacyl groups, and halogen atoms 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;
T and t ′ each independently represents 1 or 2;
V represents an integer of 0 to 2 (provided that r and s are not 0 at the same time);
V means an oxygen atom or a sulfur atom,
W represents N—R ¹ or CR ¹ R ² ;
R ¹ and R ² are each independently a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _2-6 alkenyl group, or 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 (when R ¹ is bonded to a nitrogen atom, A carbon atom on the heterocyclic group is bound to a nitrogen atom), or an optionally substituted 4-9 membered monocyclic or 7-10 membered bicyclic saturated heterocyclic group (R ^{If 1} is bonded to a nitrogen atom, a carbon atom on the heterocyclic group the Bonded to the nitrogen atom) 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 A 10-membered bicyclic non-aromatic unsaturated heterocyclic group and a 4-9-membered monocyclic or 7-10-membered bicyclic saturated heterocyclic group are each independently In the substitutable position, C _1-4 alkyl group, hydroxy group, C _1-4 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl May be substituted with one or more substituents selected from the group consisting of a group, an aryloxy group, a C _2-6 alkanoyl group, a phenacyl group, and a halogen atom,
Aryl, and heteroaryl groups, independently, at substitutable positions, halogen atom, hydroxy _{group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4} haloalkyl _{group, C 1- 4} haloalkoxy group, cyano group, nitro group, C _2-6 alkanoyl group, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted amino groups,
Alternatively, R ¹ and R ² may be bonded to each other to contain one oxygen atom, a 3 to 6 membered saturated ring (the saturated ring is a substitutable position, a C _1-4 alkyl group, a hydroxy group, C It may be substituted with one or more substituents selected from the group consisting of _1-4 alkoxy groups, C _1-4 haloalkyl groups, C _1-4 haloalkoxy groups, cyano groups, oxo groups, and halogen atoms. )
U means a carbon atom or a nitrogen atom;
X, Y and Z are each independently selected from the group consisting of an oxygen atom, a nitrogen atom, a sulfur atom and a carbon atom, and at least one of X, Y and Z is an oxygen atom, a sulfur atom or a nitrogen atom. Means either
R ⁴ 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 an _optionally substituted C _2-6 alkynyl. A group, 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 haloalkyl group, optionally substituted C _1-4 haloalkoxy group, cyano group, nitro group, optionally substituted aryl group, optionally substituted heteroaryl group, or optionally substituted Means a good amino 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 _1-6 alkoxy group, a C _{1- 4} haloalkyl group and C _1-4 haloalkoxy group are each independently at a substitutable position, C _1-4 alkyl group, hydroxy group, C _1-4 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _2-6 alkanoyl group, phenacyl group, and one or more substituents selected from the group consisting of halogen atoms May be replaced with
Aryl, and heteroaryl groups, independently, at substitutable positions, halogen atom, hydroxy _{group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4} haloalkyl _{group, C 1- 4} haloalkoxy group, cyano group, nitro group, C _2-6 alkanoyl group, and optionally substituted with one or more substituents selected from the group consisting of optionally substituted amino groups,
Alternatively, R ⁴ and R ¹ may be bonded to each other to contain a saturated or unsaturated oxygen atom, a 6 to 9 membered ring (the ring is a C _1-4 alkyl group, hydroxy group at a substitutable position). Substituted with one or more substituents selected from the group consisting of a group, a C _1-4 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 formed)
R ⁵ , R ⁶ , and R ⁷ 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. , 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 -6} alkoxy group, C _1-4 haloalkyl group which may be substituted, C _1-4 haloalkoxy group which may be substituted, cyano group, nitro group, aryl group which may be substituted, substituted An optionally substituted heteroaryl group, or an optionally substituted amino 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 _1-6 alkoxy group, a C _{1- 4} haloalkyl group and C _1-4 haloalkoxy group are each independently at a substitutable position, C _1-4 alkyl group, hydroxy group, C _1-4 alkoxy group, C _1-4 haloalkyl group, C _1-4 haloalkoxy group, cyano group, oxo group, aryl group, heteroaryl group, aryloxy group, C _2-6 alkanoyl group, phenacyl group, and one or more substituents selected from the group consisting of halogen atoms May be replaced with
Aryl, and heteroaryl groups, independently, at substitutable positions, halogen atom, hydroxy _{group, C 1-4 alkyl, C 1-4 alkoxy, C 1-4} haloalkyl _{group, C 1- And} 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 _2-6 alkanoyl group, and an optionally substituted amino group]
Or a pharmaceutically acceptable salt thereof. (A-1) to (A-4) are substitutable positions, 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, And a compound or a pharmaceutically acceptable salt thereof according to claim 1, which may be substituted with one or more substituents selected from the group consisting of: and halogen atoms. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein V is an oxygen atom. W is N—R ¹ , R ¹ 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, 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 (the carbon atom on the heterocyclic group is a nitrogen atom) 4-9-membered monocyclic or 7-10-membered bicyclic saturated heterocyclic group (which is bonded), or a carbon atom on the heterocyclic group is a nitrogen atom The compound according to any one of claims 1 to 3, or a pharmaceutical product thereof A chemically acceptable salt. R < ⁴ >, R < ⁵ >, and R < ⁷ > are hydrogen atoms, R < ⁶ > is a hydrogen atom or a halogen atom, The compound in any one of Claims 1-4, or its pharmaceutically acceptable salt. U is a carbon atom, The compound or its pharmaceutically acceptable salt in any one of Claims 1-5. X is a nitrogen atom, Y is an oxygen atom, Z is a nitrogen atom, The compound in any one of Claims 1-6, or its pharmaceutically acceptable salt. A is (A-1), l is 0 or 1, The compound in any one of Claims 1-7, or its pharmaceutically acceptable salt. B is (B-2), s is 1, and r is 2, The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof. D is a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 monocyclic, C _7-10 bicyclic or C _7-12 tricyclic cycloalkyl group The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. D is _{- (CH} 2) u ^{-R 12,} compound or a pharmaceutically acceptable salt thereof according to any one ^{R 12} is of claims 1 to 9 is a formula ^(R 12 -3). D is _{- (CH} 2) u ^{-R 12,} compound or a pharmaceutically acceptable salt thereof according to any one ^{R 12} is of claims 1 to 9 is a formula ^(R 12 -1). The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is selected from the group consisting of the following compounds:
(01) 1-ethyl-5-fluoro-3- {5- [1- (propan-2-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1, 3-dihydro-2H-benzimidazol-2-one,
(02) 3- {5- [1- (butan-2-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1-ethyl-5-fluoro-1, 3-dihydro-2H-benzimidazol-2-one,
(03) 1-ethyl-5-fluoro-3- {5- [1- (tetrahydrofuran-3-ylmethyl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1, 3-dihydro-2H-benzimidazol-2-one,
(04) 1-ethyl-5-fluoro-3- {5- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl } -1,3-dihydro-2H-benzimidazol-2-one,
(05) 3- [5- (1-Cyclobutylpiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1-ethyl-5-fluoro-1,3-dihydro-2H -Benzimidazol-2-one,
(06) 3- [5- (1-Cyclopentylpiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1-ethyl-5-fluoro-1,3-dihydro-2H- Benzimidazol-2-one,
(07) 5-Fluoro-1- (propan-2-yl) -3- {5- [1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxa Diazol-3-yl} -1,3-dihydro-2H-benzimidazol-2-one,
(08) 1-ethyl-5-fluoro-3- {5- [1- (tetrahydro-2H-pyran-4-ylmethyl) azetidin-3-yl] -1,2,4-oxadiazol-3-yl } -1,3-dihydro-2H-benzimidazol-2-one,
(09) 1-ethyl-3- {5- [1- (1-hydroxy-2-methylpropan-2-yl) piperidin-4-yl] -1,2,4-oxadiazol-3-yl} -1,3-dihydro-2H-benzimidazol-2-one,
(10) 3- [5- (1-tert-Butylpiperidin-4-yl) -1,2,4-oxadiazol-3-yl] -1-ethyl-5-fluoro-1,3-dihydro- 2H-benzimidazol-2-one,
(11) 1-ethyl-5-fluoro-3- {5- [1- (4-methyltetrahydro-2H-pyran-4-yl) piperidin-4-yl] -1,2,4-oxadiazole- 3-yl} -1,3-dihydro-2H-benzimidazol-2-one,
(12) Methyl 4- {3- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazole -5-yl] azetidin-1-yl} piperidine-1-carboxylate,
(13) 1-ethyl-5-fluoro-3- {5- [1 ′-(methylsulfonyl) -1,4′-bipiperidin-4-yl] -1,2,4-oxadiazol-3-yl } -1,3-dihydro-2H-benzimidazol-2-one,
(14) Methyl 4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadiazole-5 Yl] -1,4′-bipiperidine-1′-carboxylate,
(15) Methyl 2-({4- [3- (3-ethyl-6-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) -1,2,4-oxadi Azol-5-yl] piperidin-1-yl} methyl) morpholine-4-carboxylate,
(16) 1-ethyl-5-fluoro-3- {5- [cis-4- (pyrrolidin-1-yl) cyclohexyl] -1,2,4-oxadiazol-3-yl} -1,3- Dihydro-2H-benzimidazol-2-one,
(17) 1-ethyl-5-fluoro-3- {5- [cis-4- (3-methoxyazetidin-1-yl) cyclohexyl] -1,2,4-oxadiazol-3-yl}- 1,3-dihydro-2H-benzimidazol-2-one,
(18) 1-ethyl-3- [5- (cis-4- {ethyl [2- (tetrahydro-2H-pyran-4-yl) ethyl] amino} cyclohexyl) -1,2,4-oxadiazole- 3-yl] -5-fluoro-1,3-dihydro-2H-benzimidazol-2-one,
(19) 1-ethyl-5-fluoro-3- (5- {cis-4- [methyl (tetrahydrofuran-3-yl) amino] cyclohexyl} -1,2,4-oxadiazol-3-yl)- 1,3-dihydro-2H-benzimidazol-2-one,
(20) 1-ethyl-5-fluoro-3- {5- [cis-3- (3-methoxyazetidin-1-yl) cyclobutyl] -1,2,4-oxadiazol-3-yl}- 1,3-dihydro-2H-benzimidazol-2-one,
(21) 1-ethyl-3- {5-3- (ethylamino) cyclobutyl] -1,2,4-oxadiazol-3-yl} -5-fluoro-1,3-dihydro-2H-benzimidazole -2-one,
(22) 3- {5- [cis-3- (cyclopentylamino) cyclobutyl] -1,2,4-oxadiazol-3-yl} -1-ethyl-5-fluoro-1,3-dihydro-2H -Benzimidazol-2-one,
(23) 1-ethyl-5-fluoro-3- (5- {cis-3- [methyl (tetrahydrofuran-3-ylmethyl) amino] cyclobutyl} -1,2,4-oxadiazol-3-yl)- 1,3-dihydro-2H-benzimidazol-2-one. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. A serotonin 4 receptor agonist comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for Alzheimer-type dementia comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.