JP2010090075A - Indol or indoline derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a therapeutic agent for a disease such as cognitive disorder, Alzheimer's disease, attention-deficit or hyperactivity disorder and schizophrenia. <P>SOLUTION: The therapeutic agent comprises a compound represented by formula (1) [wherein a double line including a wavy line represents a single or double bond; Q is a group represented by structural formula (A) or (B); R is 1-6C alkyl or the like; and R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>are each 1-6C alkyl or the like] as an active ingredient. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  Histamine is usually stored in intracellular granules such as mast cells, lungs, liver, and gastric mucosa, and is released to the outside by external stimuli such as binding of antigens to cell surface antibodies. For example, when mast cells are stimulated with an antigen that has entered from the outside, histamine is released from the mast cells and causes an allergic reaction by stimulating histamine H1 (H1) receptors present on blood vessels and smooth muscles. Also, histamine released from ECL cells on the gastric mucosa stimulates histamine H2 (H2) receptors on mural cells and promotes gastric acid secretion. Based on these facts, H1 receptor antagonists or H2 receptor antagonists have been developed as therapeutic agents for allergic diseases or gastric ulcers, and are now widely used as pharmaceuticals.

  Furthermore, it has been clarified that histamine acts as a neurotransmitter on a histamine receptor (histamine H3 (H3) receptor) present in the central nerve and peripheral nerve and exhibits various physiological functions. This receptor was cloned in 1999 and its gene sequence and amino acid sequence were clarified, but the amino acid sequence homology with H1 receptor and H2 receptor was as low as 22% and 21.4%, respectively. (Refer nonpatent literature 1). It has been shown that the H3 receptor exists in the presynaptic membrane and functions as an autoreceptor that controls histamine synthesis and release (see Non-Patent Document 2). It has also been clarified that the H3 receptor controls the release of histamine and other neurotransmitters such as acetylcholine, serotonin, dopamine, and noradrenaline (see Non-Patent Document 3). These facts suggest that selective H3 receptor modulators can be therapeutic agents for various diseases related to abnormal neurotransmitter release in nerves.

  In fact, the results of studies in animal models using synthetic compounds show that H3 receptor antagonists or inverse agonists are dementia, Alzheimer's disease (see Non-Patent Documents 4 and 5), attention deficit / hyperactivity disorder ( It shows the possibility that it can be used as a therapeutic agent for non-patent document 6), schizophrenia (see non-patent document 7), epilepsy, central convulsions and the like.

  In addition, it has been shown that H3 receptor is involved in eating behavior (see Non-Patent Document 8), and as an adaptation disease of H3 receptor antagonist or inverse agonist, eating disorder, obesity, diabetes, high fat Metabolic diseases such as blood pressure are also envisaged.

  Histamine has been shown to regulate the daily rhythm in the brain and maintain a balance between arousal and sleep (see Non-Patent Documents 9 and 10), an H3 receptor antagonist, or an inverse agonist Diseases associated with sleep disorders such as sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, and depression are also assumed.

  Furthermore, it has been shown that the H3 receptor is present in the sympathetic nerve of the nasal mucosa, and it has been reported that nasal congestion is markedly improved by the combined use of the H3 receptor antagonist and the H1 receptor antagonist ( Non-patent document 11). This indicates that the H3 receptor antagonist or inverse agonist may be useful for the treatment of allergic rhinitis and the like alone or in combination with the H1 receptor antagonist.

  H3 receptor antagonists or inverse agonists are summarized in multiple reviews (see Non-Patent Documents 12 to 15), and these can be referred to. Initially, many imidazole compounds using histamine itself as a lead compound were reported, but concerns about the inhibitory action of the drug metabolizing enzyme cytochrome P450 (CYP) and the like have been shown, and they have not been developed as pharmaceutical products.

  Recently, many literatures and patents on non-imidazole H3 receptor antagonists or inverse agonists have been reported (see Patent Literatures 1 to 10).

  For example, a histamine H3 receptor antagonist having a structure in which a pyrrolidine ring and an indole ring represented by the following formula (a) are bonded via an oxygen atom has been reported (see Patent Document 11).

  A histamine H3 receptor antagonist having a structure in which a piperidine ring represented by the following formula (b) and a benzene ring are bonded via an oxygen atom has been reported (see Patent Document 12).

  A histamine H3 receptor antagonist having an indole ring structure represented by the following formula (c) has been reported (see Patent Document 13).

また、異なる作用機序、用途における類似構造の化合物として、下記式（ｄ）で表されるインドール構造を有したＦａｃｔｏｒＸａ阻害物質が報告されている（特許文献１４参照）。

In addition, a Factor Xa inhibitor having an indole structure represented by the following formula (d) has been reported as a compound having a similar structure in different action mechanisms and uses (see Patent Document 14).

しかし、本発明に開示された構造を有する化合物についての報告はない。

However, there is no report about the compound having the structure disclosed in the present invention.

WO20050977751 International Publication WO2005097778 International Publication WO2005118547 International Publication WO2006014136 International Publication WO2006045416 International Publication WO2006046131 International Publication WO20066059778 International Publication WO20060661193 International Publication WO2006107661 International Publication WO2006103057 International Publication WO2005123716 International Publication WO2002012190 International Publication WO2006035308 International Publication US6534535 Registration Gazette Lovenberg T.W., et al., Molecular pharmacology, 55, 1101-1107, 1999 Arrang J-M. Et al., Nature, 302, 832-837, 1983 Brown R.E., et al., Progress in Neurobiology, 63, 637-672, 2001 Huang Y-W. Et al., Behavioral Brain Research, 151, 287-293, 2004 Komater V.A., et al., Behavioral Brain Research, 159, 295-300, 2005 Passani M.B., et al., Neuroscience and Biobehavioral Reviews, 24, 107-113, 2000 Fox G.B., et al., J. Pharmacol. Exp. Ther., 313, 176-190, 2005 Hancock A.A. et al., Curr. Opin. Investig. Drug, 4, 1190-1197 Huang Z-L. Et al., Prog. Natr. Acad. Sci., 103, 4687-4692, 2006 Babier A.J. et al., Br. J. Pharmacol., 143, 649-661, 2004 McLeod R.L. et al., Am. J. Rhinol., 13, 391-399, 1999 Schwartz J.C., et al., Trends in Pharmacol. Sci., 7, 24-28, 1986 Passani M.B., et al., Trends in Pharmacol. Sci., 25, 618-625, 2004 Leurs R. et al., Nature Drug Discovery, 4, 107-122, 2005 Leurs R. et al., Drug Discovery Today, 10, 1613-1627, 2005

  The object of the present invention is to have a strong inhibitory action on the binding of histamine to the histamine H3 receptor, such as disorders caused by the histamine H3 receptor, such as dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, Prevention of diseases such as schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, depression or allergic rhinitis To find an agent or therapeutic agent.

As a result of intensive studies for the above purpose, the present inventors have found that an indole or indoline derivative has a strong inhibitory activity on the binding of histamine to the histamine H3 receptor, thereby completing the present invention.
That is, the present invention
(I) Formula (1)

｛式（１）中、波線を含む二重線は、単結合又は二重結合を示し、
Ｑは、下記式（Ａ）又は（Ｂ）で表される基を示し、

{In Formula (1), a double line including a wavy line indicates a single bond or a double bond,
Q represents a group represented by the following formula (A) or (B),

Ｒは、Ｃ₁〜Ｃ₆アルキル、Ｃ₃〜Ｃ₈環状アルキル、−Ｃ（Ｏ）Ｒ⁴又は−ＳＯ₂Ｒ⁵を示し、
Ｒ¹は、Ｃ₁〜Ｃ₆アルキル（該Ｃ₁〜Ｃ₆アルキルはＣ₃〜Ｃ₈環状アルキルで置換されてもよい）又はＣ₃〜Ｃ₈環状アルキル（該Ｃ₃〜Ｃ₈環状アルキルはＣ₁〜Ｃ₆アルキルで置換されてもよい）を示し、
Ｒ²及びＲ³は、同一又は異なって、Ｃ₁〜Ｃ₆アルキル又はＣ₃〜Ｃ₈環状アルキルを示し、
又はＲ²及びＲ³は、隣接する窒素原子と一緒になって互いに結合した４〜７員の飽和複素環（該飽和複素環は、ハロゲン又はＣ₁〜Ｃ₆アルキルで置換されてもよい）を形成し、
Ｒ⁴は、Ｃ₁〜Ｃ₆アルキル（該Ｃ₁〜Ｃ₆アルキルは、ハロゲン；Ｃ₃〜Ｃ₈環状アルキル；Ｃ₁〜Ｃ₆アルコキシ；シアノ；Ｃ₂〜Ｃ₇アルコキシカルボニル；Ｃ₂〜Ｃ₇アルキルアミノカルボニル；Ｃ₃〜Ｃ₁₃ジアルキルアミノカルボニル；カルバモイル；環中に１つ以上の窒素原子を含み、さらに酸素若しくは硫黄原子を含んでもよい３〜７員の飽和複素環が結合したカルボニル；トリフルオロメチル又はフェニルで置換されてもよい）、Ｃ₃〜Ｃ₈環状アルキル（該Ｃ₃〜Ｃ₈環状アルキルは、ハロゲン；Ｃ₁〜Ｃ₆アルキル又はＣ₁〜Ｃ₆アルコキシで置換されてもよい）、アリール（該アリールは、「ハロゲン；Ｃ₁〜Ｃ₆アルキル；Ｃ₁〜Ｃ₆アルコキシ；ヒドロキシ；トリフルオロメチル；トリフルオロメトキシ；アミノ；Ｃ₁〜Ｃ₆アルキルアミノ；Ｃ₂〜Ｃ₁₂ジアルキルアミノ；Ｃ₂〜Ｃ₇アルカノイル；Ｃ₁〜Ｃ₆アルキルスルホニル；ニトロ；シアノ；Ｃ₂〜Ｃ₇アルキルアミノカルボニル；Ｃ₃〜Ｃ₁₃ジアルキルアミノカルボニル；環中に１つ以上の窒素原子を含み、さらに酸素若しくは硫黄原子を含んでもよい３〜７員の飽和複素環が結合したカルボニル；カルバモイル；環中に１つ以上の窒素原子を含み、さらに酸素若しくは硫黄原子を含んでもよい３〜７員の飽和複素環又はヘテロアリール」より選ばれる同一又は異なる１〜３個の置換基で置換されてもよい）、ヘテロアリール（該ヘテロアリールは、「ハロゲン；Ｃ₁〜Ｃ₆アルキル；Ｃ₁〜Ｃ₆アルコキシ；ヒドロキシ；トリフルオロメチル；トリフルオロメトキシ；アミノ；Ｃ₁〜Ｃ₆アルキルアミノ；Ｃ₂〜Ｃ₁₂ジアルキルアミノ；Ｃ₂〜Ｃ₇アルカノイル；Ｃ₁〜Ｃ₆アルキルスルホニル；ニトロ；シアノ；Ｃ₂〜Ｃ₇アルキルアミノカルボニル；Ｃ₃〜Ｃ₁₃ジアルキルアミノカルボニル；環中に１つ以上の窒素原子を含み、さらに酸素若しくは硫黄原子を含んでもよい３〜７員の飽和複素環が結合したカルボニル；カルバモイル；環中に１つ以上の窒素原子を含み、さらに酸素若しくは硫黄原子を含んでもよい３〜７員の飽和複素環又はヘテロアリール」より選ばれる同一又は異なる１〜３個の置換基で置換されてもよい）、環中に１つ以上の窒素原子を含み、さらに酸素若しくは硫黄原子を含んでもよく、環中の一部に不飽和結合を含んでもよい飽和複素環、Ｃ₁〜Ｃ₆アルコキシ又は−ＮＲ⁶Ｒ⁷で示される基を示し、
Ｒ⁵は、Ｃ₁〜Ｃ₆アルキル、Ｃ₃〜Ｃ₈環状アルキル、アリール（該アリールは、ハロゲン；Ｃ₁〜Ｃ₆アルキル；Ｃ₁〜Ｃ₆アルコキシ；ヒドロキシ又はシアノで置換されてもよい）又はヘテロアリール（該ヘテロアリールは、ハロゲン；Ｃ₁〜Ｃ₆アルキル；Ｃ₁〜Ｃ₆アルコキシ；ヒドロキシ又はシアノで置換されてもよい）を示し、
Ｒ⁶及びＲ⁷は、同一又は異なって、水素原子又はＣ₁〜Ｃ₆アルキル（該Ｃ₁〜Ｃ₆アルキルは、ハロゲン；Ｃ₁〜Ｃ₆アルコキシ又はヒドロキシで置換されてもよい）を示し、
又はＲ⁶及びＲ⁷は、隣接する窒素原子と一緒になって互いに結合し、環中に前記窒素原子の他に１つ以上の窒素、酸素若しくは硫黄原子を含んでもよい４〜７員の飽和複素環（該飽和複素環は、ハロゲン又はＣ₁〜Ｃ₆アルキルで置換されてもよい）を形成し、
ｍ及びｎは、同一又は異なって、０〜２の整数を示す｝
で表されるインドール若しくはインドリン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、摂食障害、肥満、糖尿病、高脂血症、睡眠障害、ナルコレプシー、睡眠時無呼吸症候群、概日リズム障害、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（II）式（１）

R represents C ₁ -C ₆ alkyl, C ₃ -C ₈ cyclic alkyl, —C (O) R ⁴ or —SO ₂ R ⁵ ,
R ¹ is, C ₁ -C ₆ alkyl (wherein C ₁ -C ₆ alkyl may be substituted with C ₃ -C ₈ cyclic alkyl) or C ₃ -C ₈ cycloalkyl (said C ₃ -C ₈ cycloalkyl May be substituted with C ₁ -C ₆ alkyl),
R ² and R ³ are the same or different and represent C ₁ -C ₆ alkyl or C ₃ -C ₈ cyclic alkyl,
Or R ² and R ³ are 4- to 7-membered saturated heterocycles bonded together with adjacent nitrogen atoms (the saturated heterocycle may be substituted with halogen or C ₁ -C ₆ alkyl) Form the
R ⁴ is C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl is halogen; C ₃ -C ₈ cyclic alkyl; C ₁ -C ₆ alkoxy; cyano; C ₂ -C ₇ alkoxycarbonyl; C _2- C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl; carbamoyl; a carbonyl bonded to a 3-7 membered saturated heterocyclic ring containing one or more nitrogen atoms in the ring and further containing an oxygen or sulfur atom ; tri fluoromethyl or phenyl may be substituted), C ₃ -C ₈ cycloalkyl (said C ₃ -C ₈ cyclic alkyl, halogen; substituted with C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy may be), aryl (the aryl, "halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy, hydroxy, trifluoromethyl; trifluoromethoxy; amino; C ₁ ~ ₆ alkylamino; C ₂ -C ₁₂ dialkylamino; C ₂ -C ₇ alkanoyl; C ₁ -C ₆ alkylsulfonyl; nitro; cyano; C ₂ -C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl; ring A carbonyl having a 3- to 7-membered saturated heterocycle containing one or more nitrogen atoms and optionally further containing oxygen or sulfur atoms; carbamoyl; containing one or more nitrogen atoms in the ring and further oxygen or A 3-7 membered saturated heterocyclic ring or heteroaryl which may contain a sulfur atom, which may be substituted with 1 to 3 substituents which are the same or different, and a heteroaryl (which is a halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy, hydroxy, trifluoromethyl; trifluoromethoxy; amino; C ₁ -C ₆ alkylamino C ₂ -C ₁₂ dialkylamino; C ₂ -C ₇ alkanoyl; C ₁ -C ₆ alkylsulfonyl; nitro; cyano; C ₂ -C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl; one in the ring A carbonyl having a 3- to 7-membered saturated heterocycle containing the above nitrogen atom and further containing an oxygen or sulfur atom; carbamoyl; containing one or more nitrogen atoms in the ring and further containing an oxygen or sulfur atom May be substituted with the same or different 1 to 3 substituents selected from 3 to 7-membered saturated heterocycles or heteroaryls ”, which contains one or more nitrogen atoms in the ring, and oxygen or may contain a sulfur atom, partially unsaturated bond may include saturated heterocyclic rings in the ring, a group represented by C ₁ -C ₆ alkoxy or -NR ⁶ R ^7,
R ⁵ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cyclic alkyl, aryl (where the aryl is halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; optionally substituted with hydroxy or cyano) ) or heteroaryl (said heteroaryl, halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; indicates hydroxy or cyano may be substituted with)
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or C ₁ -C ₆ alkyl (wherein the C ₁ -C ₆ alkyl may be substituted with halogen; C ₁ -C ₆ alkoxy or hydroxy). ,
Or R ⁶ and R ⁷ are bonded to each other together with adjacent nitrogen atoms, and may contain one or more nitrogen, oxygen or sulfur atoms in addition to the nitrogen atoms in the ring. heterocyclic (saturated heterocyclic ring may be substituted with halogen or C ₁ -C ₆ alkyl) is formed,
m and n are the same or different and represent an integer of 0 to 2}
Containing an indole or indoline derivative represented by the above or a pharmaceutically acceptable salt thereof as an active ingredient, dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, Preventive or therapeutic agent for convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, depression, or allergic rhinitis,
(II) Formula (1)

｛式（１）中、波線を含む二重線は、単結合又は二重結合を示し、
Ｑは、下記式（Ａ）又は（Ｂ）で表される基を示し、

{In Formula (1), a double line including a wavy line indicates a single bond or a double bond,
Q represents a group represented by the following formula (A) or (B),

Ｒは、Ｃ₁〜Ｃ₆アルキル、Ｃ₃〜Ｃ₈環状アルキル、−Ｃ（Ｏ）Ｒ⁴又は−ＳＯ₂Ｒ⁵を示し、
Ｒ¹は、Ｃ₁〜Ｃ₆アルキル（Ｃ₁〜Ｃ₆該アルキルはＣ₃〜Ｃ₈環状アルキルで置換されてもよい）又はＣ₃〜Ｃ₈環状アルキル（該Ｃ₃〜Ｃ₈環状アルキルはＣ₁〜Ｃ₆アルキルで置換されてもよい）を示し、
Ｒ²及びＲ³は、同一又は異なって、Ｃ₁〜Ｃ₆アルキル又はＣ₃〜Ｃ₈環状アルキルを示し、
又は、Ｒ²及びＲ³は、隣接する窒素原子と一緒になって互いに結合した４〜７員の飽和複素環（該飽和複素環は、ハロゲン又はＣ₁〜Ｃ₆アルキルで置換されてもよい）を形成し、
Ｒ⁴は、Ｃ₁〜Ｃ₆アルキル（該Ｃ₁〜Ｃ₆アルキルは、ハロゲン；Ｃ₃〜Ｃ₈環状アルキル；Ｃ₁〜Ｃ₆アルコキシ；シアノ；Ｃ₂〜Ｃ₇アルコキシカルボニル；Ｃ₂〜Ｃ₇アルキルアミノカルボニル；Ｃ₃〜Ｃ₁₃ジアルキルアミノカルボニル；カルバモイル又は環中に１つ以上の窒素原子を含み、さらに酸素若しくは硫黄原子を含んでもよい３〜７員の飽和複素環が結合したカルボニルで置換されてもよい）、Ｃ₃〜Ｃ₈環状アルキル（該Ｃ₃〜Ｃ₈環状アルキルは、ハロゲン；Ｃ₁〜Ｃ₆アルキル又はＣ₁〜Ｃ₆アルコキシで置換されてもよい）、アリール（該アリールは、ハロゲン；Ｃ₁〜Ｃ₆アルキル；Ｃ₁〜Ｃ₆アルコキシ；ヒドロキシ；トリフルオロメチル；トリフルオロメトキシ；アミノ；Ｃ₁〜Ｃ₆アルキルアミノ；Ｃ₂〜Ｃ₁₂ジアルキルアミノ；Ｃ₂〜Ｃ₇アルカノイル；Ｃ₁〜Ｃ₆アルキルスルホニル；ニトロ；シアノ；Ｃ₂〜Ｃ₇アルコキシカルボニル；Ｃ₂〜Ｃ₇アルキルアミノカルボニル；Ｃ₃〜Ｃ₁₃ジアルキルアミノカルボニル；環中に１つ以上の窒素原子を含み、さらに酸素若しくは硫黄原子を含んでもよい３〜７員の飽和複素環が結合したカルボニル；カルバモイル又は環中に１つ以上の窒素原子を含み、さらに酸素若しくは硫黄原子を含んでもよい３〜７員の飽和複素環で置換されてもよい）、ヘテロアリール（該ヘテロアリールは、ハロゲン；Ｃ₁〜Ｃ₆アルキル；Ｃ₁〜Ｃ₆アルコキシ；ヒドロキシ；トリフルオロメチル；トリフルオロメトキシ；アミノ；Ｃ₁〜Ｃ₆アルキルアミノ；Ｃ₂〜Ｃ₁₂ジアルキルアミノ；Ｃ₂〜Ｃ₇アルカノイル；Ｃ₁〜Ｃ₆アルキルスルホニル；ニトロ；シアノ；Ｃ₂〜Ｃ₇アルコキシカルボニル；Ｃ₂〜Ｃ₇アルキルアミノカルボニル；Ｃ₃〜Ｃ₁₃ジアルキルアミノカルボニル；環中に１つ以上の窒素原子を含み、さらに酸素若しくは硫黄原子を含んでもよい３〜７員の飽和複素環が結合したカルボニル；カルバモイル又は環中に１つ以上の窒素原子を含み、さらに酸素、又は硫黄原子を含んでもよい３〜７員の飽和複素環で置換されてもよい）、Ｃ₁〜Ｃ₆アルコキシ、−ＮＲ⁶Ｒ⁷又は−（ＣＨ₂）_l−Ａｒで示される基を示し、
Ａｒは、アリール（該アリールは、ハロゲン；Ｃ₁〜Ｃ₆アルキル又はＣ₁〜Ｃ₆アルコキシで置換されてもよい）を示し、
Ｒ⁵は、Ｃ₁〜Ｃ₆アルキル、Ｃ₃〜Ｃ₈環状アルキル、アリール（該アリールは、ハロゲン；Ｃ₁〜Ｃ₆アルキル、Ｃ₁〜Ｃ₆アルコキシ又はヒドロキシで置換されてもよい）又はヘテロアリール（該ヘテロアリールは、ハロゲン；Ｃ₁〜Ｃ₆アルキル、Ｃ₁〜Ｃ₆アルコキシ又はヒドロキシで置換されてもよい）を示し、
Ｒ⁶及びＲ⁷は、同一又は異なって、水素原子又はＣ₁〜Ｃ₆アルキル（該Ｃ₁〜Ｃ₆アルキルは、ハロゲン；Ｃ₁〜Ｃ₆アルコキシ又はヒドロキシで置換されてもよい）を示し、
又は、Ｒ⁶及びＲ⁷は、隣接する窒素原子と一緒になって互いに結合し、環中に前記窒素原子の他に１つ以上の窒素、酸素若しくは硫黄原子を含んでもよい４〜７員の飽和複素環（該飽和複素環は、ハロゲン又はＣ₁〜Ｃ₆アルキルで置換されてもよい）を形成し、
ｍ及びｎは、同一又は異なって、０〜２の整数を示し、
ｌは、１〜３の整数を示す｝
で表されるインドール若しくはインドリン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、摂食障害、肥満、糖尿病、高脂血症、睡眠障害、ナルコレプシー、睡眠時無呼吸症候群、概日リズム障害、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（III）式（１）中、波線を含む二重線が二重結合である、（I）又は（II）に記載のインドール誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、摂食障害、肥満、糖尿病、高脂血症、睡眠障害、ナルコレプシー、睡眠時無呼吸症候群、概日リズム障害、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（IV）式（１）中、Ｑが式（Ａ）である、（I）〜（III）のいずれかに記載のインドール若しくはインドリン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、摂食障害、肥満、糖尿病、高脂血症、睡眠障害、ナルコレプシー、睡眠時無呼吸症候群、概日リズム障害、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（V）式（１）中、Ｑが式（Ｂ）である、（I）〜（III）のいずれかに記載のインドール若しくはインドリン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、摂食障害、肥満、糖尿病、高脂血症、睡眠障害、ナルコレプシー、睡眠時無呼吸症候群、概日リズム障害、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤、
（VI）式（１）中、Ｒが−Ｃ（Ｏ）Ｒ⁴である、（I）〜（V）のいずれかに記載のインドール若しくはインドリン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする、認知症、アルツハイマー病、注意欠陥・多動性症、統合失調症、てんかん、中枢性痙攣、摂食障害、肥満、糖尿病、高脂血症、睡眠障害、ナルコレプシー、睡眠時無呼吸症候群、概日リズム障害、うつ病、若しくはアレルギー性鼻炎の予防剤又は治療剤である。

R represents C ₁ -C ₆ alkyl, C ₃ -C ₈ cyclic alkyl, —C (O) R ⁴ or —SO ₂ R ⁵ ,
R ¹ is, C ₁ -C ₆ alkyl (C ₁ -C ₆ the alkyl may be substituted with C ₃ -C ₈ cyclic alkyl) or C ₃ -C ₈ cycloalkyl (said C ₃ -C ₈ cycloalkyl May be substituted with C ₁ -C ₆ alkyl),
R ² and R ³ are the same or different and represent C ₁ -C ₆ alkyl or C ₃ -C ₈ cyclic alkyl,
Or R ² and R ³ are 4-7 membered saturated heterocycles bonded together with adjacent nitrogen atoms (the saturated heterocycle may be substituted with halogen or C ₁ -C ₆ alkyl). )
R ⁴ is C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl is halogen; C ₃ -C ₈ cyclic alkyl; C ₁ -C ₆ alkoxy; cyano; C ₂ -C ₇ alkoxycarbonyl; C _2- C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl; carbamoyl or a carbonyl bonded to a 3-7 membered saturated heterocyclic ring containing one or more nitrogen atoms in the ring and further containing an oxygen or sulfur atom in which may be substituted), C ₃ -C ₈ cycloalkyl (said C ₃ -C ₈ cyclic alkyl, halogen; may be substituted with C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy), aryl (the aryl, halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy, hydroxy, trifluoromethyl; trifluoromethoxy; amino; C ₁ -C ₆ alkylamino; C ₂ -C ₁₂ Gia Alkylamino; in the ring; C ₂ -C ₇ alkanoyl; C ₁ -C ₆ alkylsulfonyl; nitro; cyano; C ₂ -C ₇ alkoxycarbonyl; C ₂ -C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl A carbonyl having a 3 to 7 membered saturated heterocycle containing one or more nitrogen atoms and optionally further containing oxygen or sulfur atoms; carbamoyl or one or more nitrogen atoms in the ring and further oxygen or sulfur atoms may be substituted with a comprise also be 3-7 membered saturated heterocyclic ring), heteroaryl (said heteroaryl, halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy, hydroxy, trifluoromethyl; trifluoromethoxy; amino; C ₁ -C ₆ alkylamino; C ₂ -C ₁₂ dialkylamino; C ₂ -C ₇ alkanoyl; C ₁ -C ₆ Alkylsulfonyl; nitro; cyano; C ₂ -C ₇ alkoxycarbonyl; C ₂ -C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl; includes one or more nitrogen atoms in the ring, further oxygen or sulfur atom A carbonyl bonded to a 3 to 7 membered saturated heterocyclic ring which may contain: a carbamoyl or a 3 to 7 membered saturated heterocyclic ring which contains one or more nitrogen atoms in the ring and may further contain an oxygen or sulfur atom may be substituted), C ₁ ~C ₆ alkoxy, -NR ⁶ R ⁷ or - (CH ₂₎ represents a group represented by _l -Ar,
Ar is aryl (the aryl, halogen; C ₁ -C ₆ alkyl or C ₁ -C ₆ may be substituted by alkoxy) indicates,
R ⁵ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cyclic alkyl, aryl (wherein the aryl may be substituted by halogen; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy) or heteroaryl (said heteroaryl, halogen; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy which may be substituted with) indicates,
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or C ₁ -C ₆ alkyl (wherein the C ₁ -C ₆ alkyl may be substituted with halogen; C ₁ -C ₆ alkoxy or hydroxy). ,
Or R ⁶ and R ⁷ are bonded to each other together with an adjacent nitrogen atom, and may contain one or more nitrogen, oxygen or sulfur atoms in addition to the nitrogen atom in the ring. saturated heterocyclic ring (saturated heterocycle, halogen or C ₁ which may be substituted with -C ₆ alkyl) forming a,
m and n are the same or different and represent an integer of 0 to 2,
l represents an integer of 1 to 3}
Containing an indole or indoline derivative represented by the above or a pharmaceutically acceptable salt thereof as an active ingredient, dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, Preventive or therapeutic agent for convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, depression, or allergic rhinitis,
(III) In the formula (1), the double line including the wavy line is a double bond, and contains the indole derivative according to (I) or (II) or a pharmaceutically acceptable salt thereof as an active ingredient. Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorder, narcolepsy, sleeplessness Preventive or therapeutic agent for respiratory syndrome, circadian rhythm disorder, depression, or allergic rhinitis,
(IV) In formula (1), Q is the formula (A), and contains an indole or indoline derivative according to any one of (I) to (III), or a pharmaceutically acceptable salt thereof as an active ingredient. Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep Preventive or therapeutic agent for apnea syndrome, circadian rhythm disorder, depression, or allergic rhinitis,
(V) In formula (1), Q is the formula (B), and contains the indole or indoline derivative according to any one of (I) to (III), or a pharmaceutically acceptable salt thereof as an active ingredient. Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep Preventive or therapeutic agent for apnea syndrome, circadian rhythm disorder, depression, or allergic rhinitis,
(VI) The indole or indoline derivative or the pharmaceutically acceptable salt thereof according to any one of (I) to (V), wherein R is —C (O) R ⁴ in formula (1), as an active ingredient Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy , A prophylactic or therapeutic agent for sleep apnea syndrome, circadian rhythm disorder, depression, or allergic rhinitis.

  It has been found that the compound of the present invention has an excellent histamine H3 receptor antagonistic action.

  Terms used herein are as defined below.

  In the present invention, “halogen” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

“C ₁ -C ₆ alkyl” refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec A group such as -butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl is shown.

“C ₃ -C ₈ cyclic alkyl” refers to a cyclic alkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

“C ₁ -C ₆ alkoxy” refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, A group such as sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy or n-hexyloxy is shown.

“C ₂ -C ₇ alkoxycarbonyl” refers to a carbonyl group to which a linear or branched alkoxy group having 1 to 6 carbon atoms is bonded. For example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, A group such as isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl or n-hexyloxycarbonyl is shown.

“C ₁ -C ₆ alkylamino” refers to an amino group substituted with a linear or branched alkyl group having 1 to 6 carbon atoms, such as methylamino, ethylamino, n-propylamino. , Isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, n-pentylamino, isopentylamino, neopentylamino or n-hexylamino.

“C ₂ -C ₁₂ dialkylamino” refers to an amino group substituted with two linear or branched alkyl groups having 1 to 6 carbon atoms, such as dimethylamino, diethylamino, di-n -Propylamino, N, N-isopropylmethylamino, di-n-butylamino, diisobutylamino, N, N-sec-butylethylamino, N, N-tert-butylmethylamino, di-n-pentylamino, N , N-isopentylmethylamino, N, N-neopentylmethylamino, or di-n-hexylamino.

    “A 3 to 7-membered saturated heterocyclic ring which contains one or more nitrogen atoms in the ring and may further contain oxygen or sulfur atoms” means one or more nitrogen atoms in the ring and further oxygen atoms or 1 represents a group consisting of a saturated 3 to 7 membered monocyclic heterocycle, which may contain one or more heteroatoms selected from sulfur atoms, and may be substituted with 1 to 2 oxo groups Good. For example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-azepanyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-piperazinyl, 3-oxazolidinyl, morpholino, 1-thiomorpholinyl, 2-oxopyrrolidin-1-yl , 2-oxopiperidin-1-yl or 2,5-dioxopyrrolidin-1-yl.

“C ₂ -C ₇ alkylaminocarbonyl” refers to a carbonyl group to which a linear or branched alkylamino group having 1 to 6 carbon atoms is bonded, and examples thereof include methylaminocarbonyl, ethylaminocarbonyl, n -Propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, isopentylaminocarbonyl, neopentylaminocarbonyl or n-hexyl A group such as aminocarbonyl is shown.

“C ₃ -C ₁₃ dialkylaminocarbonyl” refers to a carbonyl group to which a dialkylamino group having 2 to 12 carbon atoms is bonded, and examples thereof include dimethylaminocarbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, N, N-isopropylmethylaminocarbonyl, di-n-butylaminocarbonyl, diisobutylaminocarbonyl group, N, N-sec-butylethylaminocarbonyl, N, N-tert-butylmethylaminocarbonyl, di-n-pentylaminocarbonyl, A group such as N, N-isopentylmethylaminocarbonyl, N, N-neopentylmethylaminocarbonyl or di-n-hexylaminocarbonyl is shown.

    “A carbonyl having a 3- to 7-membered saturated heterocyclic ring containing one or more nitrogen atoms in the ring and further containing an oxygen or sulfur atom” means the above “one or more nitrogen atoms in the ring. A 3- to 7-membered saturated heterocyclic ring which may further contain an oxygen or sulfur atom ”, for example, aziridine-1-carbonyl, azetidine-1-carbonyl, pyrrolidine-1-carbonyl, piperidine- Groups such as 1-carbonyl, azepane-1-carbonyl, imidazolidine-1-carbonyl, pyrazolidine-1-carbonyl, piperazine-1-carbonyl, oxazolidine-1-carbonyl, morpholine-1-carbonyl or thiomorpholine-1-carbonyl Indicates.

“C ₂ -C ₇ alkanoyl” refers to a carbonyl group to which an alkyl group having 1 to 6 carbon atoms is bonded. For example, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, pentanoyl, 3-methylbutyryl, 4,4- A group such as dimethylpentanoyl or heptanoyl is shown.

“C ₁ -C ₆ alkylsulfonyl” refers to a sulfonyl group substituted with an alkyl group having 1 to 6 carbon atoms, such as methanesulfonyl, propanesulfonyl, butanesulfonyl, isobutanesulfonyl, tert-butylsulfonyl, pentane. A group such as sulfonyl or heptanesulfonyl is shown.

The “4- to 7-membered saturated heterocyclic ring bonded together with the adjacent nitrogen atom” refers to a 1-azetidinyl group, 1-pyrrolidinyl group, piperidino group or 1-azepanyl group.

  “A 4 to 7-membered saturated heterocyclic ring which is bonded together with adjacent nitrogen atoms and may contain one or more nitrogen, oxygen or sulfur atoms in addition to the nitrogen atom”. From a saturated 4- to 7-membered monocyclic heterocycle containing one nitrogen atom and further containing one or more heteroatoms selected from nitrogen, oxygen and sulfur atoms For example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 1-azepanyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-piperazinyl, 3-oxazolidinyl, morpholino or 1-thiomorpholinyl.

  “Aryl” refers to a phenyl group or a naphthyl group.

  “Heteroaryl” refers to a group consisting of a 5- to 6-membered monocyclic or 9- to 10-membered bicyclic aromatic heterocycle, such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl. , Quinazolinyl, quinoxalinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, indolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, indazolyl, benzoxazolyl, benzothiazolyl or benzotriazolyl Groups. More specifically, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2- Yl, quinolin-2-yl, quinolin-4-yl, quinolin-6-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-6-yl, quinazolin-2-yl, quinazolin-5-yl, Quinoxalin-2-yl, quinoxalin-6-yl, pyrrol-3-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, pyrazol-3-yl, pyrazole- 4-yl, imidazol-2-yl, oxazol-2-yl, oxazol-4-yl, isoxazol-3-yl, thiazole-2 Yl, thiazol-5-yl, isothiazol-4-yl, 1,2,4-triazol-3-yl, indol-2-yl, indol-5-yl, indol-7-yl, benzofuran-3-yl , Benzothiophen-3-yl, benzimidazol-2-yl, indazol-5-yl, benzoxazol-2-yl, benzothiazol-2-yl or benzotriazol-4-yl.

  “Saturated heterocycle containing one or more nitrogen atoms in the ring and further containing an oxygen or sulfur atom and optionally containing an unsaturated bond” means one or more rings in the ring. 5 to 6-membered monocyclic or 9 to 10-membered bicyclic saturated heterocycle that contains a nitrogen atom, may further contain an oxygen or sulfur atom, and may contain an unsaturated bond in a part of the ring A group consisting of a ring, such as 4-piperidinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 4-tetrahydropyranyl, 1,4,5,6-tetrahydropyridazin-3-yl, indoline-4-yl, Indoline-6-yl, isoindoline-4-yl, 1,2,3,4-tetrahydroquinolin-7-yl, 1,2,3,4-tetrahydroisoquinolin-6-yl, 2,3-dihydrobenzofuran- -Yl, 2,3-dihydrobenzofuran-7-yl, benzo [1,3] dioxol-5-yl, 2,3-dihydro [1,4] benzodioxin-5-yl, 2,3-dihydro [1 , 4] benzodioxin-6-yl or 3,4-dihydro [1,4] benzoxazin-7-yl.

In view of pharmacokinetics and safety, in the present invention, R is preferably —C (O) R ⁴ , more preferably R ⁴ is aryl or heteroaryl. A preferred aryl is phenyl, and a preferred heteroaryl is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or quinolinyl.

  In the present invention, pharmaceutically acceptable salts include, for example, salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid , Citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactal Salts with acids, organic acids such as naphthalene-2-sulfonic acid, salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion, ammonia Arginine, lysine, piperazine, choline, diethylamine, 4-phenylsilane B hexylamine, 2-aminoethanol, salts with amines such as benzathine.

  The compounds of the present invention may also exist as various solvates. Moreover, it may be a hydrate from the viewpoint of applicability as a medicine.

  The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like.

  The compounds of the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, and sulfur atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful in, for example, metabolism and pharmacokinetic studies, biological analysis as receptor ligands, and the like.

  The compounds of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients or diluents into a pharmaceutical formulation. Examples of the carrier, excipient, and diluent include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water Various oils such as syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like are included.

  In addition, additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary are mixed with the above carriers, excipients or diluents, and tablets are prepared by conventional formulation techniques. , Pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, skin patches and the like. The compound of the present invention can be orally or parenterally administered to an adult patient in an amount of 0.001 to 500 mg once a day or divided into several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.

  Desirable profiles of the compound of the present invention include excellent drug efficacy, excellent pharmacokinetics, excellent physical properties, low toxicity, and the like.

The compound of the present invention can be produced by the following method.
The compound of the present invention can be produced by a known organic chemical method, and can be produced, for example, according to the method according to the following reaction formula. In the following reaction formulas 1 to 13, R, R ¹ , R ² , R ³ , R ⁴ , m, and n are as defined above. X ¹ and X ² are the same or different, and are halogen atoms such as chlorine atom, bromine atom and iodine atom, or methanesulfonyloxy group, phenylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. And a leaving group such as an organic sulfonyloxy group.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 1 is demonstrated. This production process is a process for producing the compound (1-1) of the present invention from the compound (2) and the compound (3).
(Reaction Formula 1)

(Step 1a)
Step 1a is a step for obtaining compound (4) by condensing compound (2) and known compound (3) by a coupling reaction. Compound (2) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction includes Mitsunobu reaction, for example, a combination of an organic phosphorus compound such as triphenylphosphine and tributylphosphine and an azo compound such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, and ditertbutyl azodicarboxylate. Examples thereof include a method performed in a solvent in the presence of a reagent or a phosphorus ylide reagent such as cyanomethyltributylphosphorane. Examples of the solvent used in this reaction include ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; N, N-dimethylformamide; Amides such as N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile or a mixed solvent thereof includes, among these, tetrahydrofuran or toluene. preferable. The reaction temperature in this reaction is usually 0 ° C to 120 ° C, preferably 15 ° C to 80 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

(Process 2)
Step 2 is a step for obtaining the compound (1-1) of the present invention by condensing the compound (4) and the compound (5) by a coupling reaction. The coupling reaction can be carried out by a general method for introducing a substituent into the nitrogen atom of indole in the presence of a base in a solvent or without a solvent. Moreover, additives, such as potassium iodide and sodium bromide, can be added as needed. Examples of the base used in this reaction include sodium hydride, potassium hydride, n-butyllithium, diisopropylethylamine, tert-butoxypotassium, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and the like. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated carbonization such as chloroform and dichloromethane. Hydrogens; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof Among these, N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile is preferable. The reaction temperature in this reaction is usually 0 ° C. to 150 ° C., preferably 15 ° C. to 80 ° C., and the reaction time is usually 1 to 64 hours, preferably 1 to 12 hours.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 2 is demonstrated. This production process is a process for producing the compound (1-3) of the present invention from the compound (1-2) in which R ⁴ = methyl group in the compound (1-1) synthesized in the step 2.
(Reaction Formula 2)

(Step 3a)
Step 3a is a step for obtaining the compound (6) by deprotecting the acetyl group of the compound (1-2). The reaction can be carried out by a general amide hydrolysis method, for example, a method of reacting in the presence or absence of a strong acid in a solvent, a method of reacting in a solvent in the presence of a base, etc. (TW Greene and PGMGM Wuts Protective Groups in Organic Synthesis) or a method analogous thereto. Examples of the acid used here include hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like. Examples of the base used include sodium hydroxide and potassium hydroxide. Examples of the solvent used include alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof . The reaction temperature in this reaction is usually 0 ° C to 150 ° C, preferably 15 ° C to 80 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

(Step 4a)
Step 4a is a step for obtaining the compound (1-3) of the present invention by condensing the compound (6) and the compound (7) by a coupling reaction. Compound (7) is a known compound or a compound that can be easily synthesized from a known compound. Examples of the coupling reaction include a method of reacting compound (6) and compound (7) in a solvent in the presence or absence of a base. Moreover, additives, such as potassium iodide and sodium bromide, can be added as needed. Examples of the base used in this reaction include pyridine, triethylamine, diisopropylethylamine, tert-butoxypotassium, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated carbonization such as chloroform and dichloromethane. Hydrogens; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof Of these, tetrahydrofuran, N, N-dimethylformamide or acetonitrile is preferable. The reaction temperature in this reaction is usually 0 ° C to 150 ° C, preferably 15 ° C to 80 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 3 is demonstrated. This production process is a process for producing the compound (1-4) of the present invention from the compound (8) and the compound (9).
(Reaction Formula 3)

(Process 5)
Step 5 is a step for obtaining compound (10) by condensing known compound (8) and compound (9) by a coupling reaction. Compound (9) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction can be performed by a general method of reductive amination reaction, for example, reduction to a mixture of compound (8) and compound (9) in the presence or absence of an acid in a solvent or without solvent. The method of adding an agent is mentioned. Further, as a reduction method, for example, a catalytic reduction method by hydrogenation using a catalyst such as palladium-carbon, platinum, Raney nickel, rhodium-alumina or the like can be used. Examples of the reducing agent used in this reaction include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diborane, lithium aluminum hydride and the like. Examples of the acid used in this reaction include acetic acid, formic acid, hydrochloric acid and the like. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; acetonitrile; water or a mixed solvent thereof. Of these, methanol, ethanol, toluene or tetrahydrofuran is preferred. The reaction temperature in this reaction is usually 0 ° C. to 150 ° C., preferably 15 ° C. to 40 ° C., and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

(Step 1b)
Step 1b is a step for obtaining the compound (1-4) of the present invention by condensing the compound (10) and the compound (2) by a coupling reaction. The coupling reaction can be carried out by the same method as in Step 1a.

Hereinafter, the manufacturing method of the compound of this invention shown by Reaction formula 4 is demonstrated. In this production process, compounds (1-6) and (1-3) of the present invention are converted from compound (1-5) in which R ⁴ = tert-butoxy group in compound (1-4) synthesized in step 1b. It is a process for manufacturing.
(Reaction Formula 4)

(Step 3b)
Step 3b is a step for obtaining compound (11) by deprotecting the tert-butoxycarbonyl group of compound (1-5). The reaction can be carried out by a general method of deprotecting a tert-butoxycarbonyl group. For example, a method of reacting in the presence or absence of a strong acid in a solvent, a method of reacting in a solvent in the presence of a base, etc. (T. W. Greene and PMGM Wuts Protective Groups in Organic Synthesis) or a method analogous thereto. Examples of the acid used in this reaction include hydrochloric acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like. Examples of the base used in this reaction include sodium hydroxide and potassium hydroxide. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated carbonization such as chloroform and dichloromethane. Hydrogens; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof Is mentioned. The reaction temperature in this reaction is usually 0 ° C. to 150 ° C., preferably 15 ° C. to 40 ° C., and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

(Step 4b)
Step 4b is a step for condensing compound (11) and compound (7) by a coupling reaction to obtain compound (1-6) of the present invention. The coupling reaction can be carried out by the same method as in step 4a.

(Step 6a)
Step 6a is a step for producing the compound (1-3) of the present invention by converting the indoline ring of the compound (1-6) to an indole ring. Examples of the conversion method include a general oxidation reaction method. For example, the reaction is carried out in a solvent in the presence of an oxidizing agent, in the presence or absence of a metal catalyst, in a solvent or without a solvent. And a method of performing oxygen oxidation or air oxidation. Examples of the oxidizing agent used in this reaction include manganese dioxide, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and the like. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated carbonization such as chloroform and dichloromethane. Hydrogens; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof Is mentioned. The reaction temperature in this reaction is usually 0 ° C. to 150 ° C., preferably 15 ° C. to 40 ° C., and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

(Reaction Formula 5)

  Moreover, the compound (1-1) of this invention can also be obtained by the conversion reaction (step 6b) of the indoline ring of the compound (1-4) to the indole ring, as shown in Reaction Scheme 5. The conversion reaction can be carried out by the same method as in Step 6a.

(Reaction Formula 6)

  Moreover, the compound (1-1) of this invention can also be obtained by the coupling reaction (process 7a) of a compound (6) and a compound (12) as shown in Reaction formula 6. Compound (12) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction can be carried out by a general amine amidation method, for example, a method in which a carboxylic acid is led to a carboxylic acid halide such as carboxylic acid chloride or carboxylic acid bromide and then reacted with an amine, or carboxylic acid and chloro A method of reacting a mixed acid anhydride obtained from a carbonate ester with an amine, a method of reacting a carboxylic acid with an amine after introducing the carboxylic acid to an active ester such as 1-benzotriazolyl ester or succinimidyl ester, and a carboxylic acid as a condensing agent Examples thereof include a method of reacting with an amine in the presence. These reactions can all be performed in a solvent in the presence or absence of a base. Examples of the condensing agent used in this reaction include 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, diphenylphosphoryl azide, carbonyldiimidazole, and the like. Activating agents such as hydroxybenzotriazole and hydroxysuccinimide can be used. Examples of the base used in this reaction include pyridine, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like. Examples of the solvent used in this reaction include ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; N, N-dimethylformamide; Amides such as N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof. Among these, toluene, Tetrahydrofuran or N, N-dimethylformamide is preferred. The reaction temperature in this reaction is usually 0 ° C to 120 ° C, preferably 15 ° C to 40 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

(Reaction Formula 7)

  Moreover, the compound (1-4) of this invention can also be obtained by the coupling reaction (process 7b) of a compound (11) and a compound (12) as shown in Reaction formula 7. The coupling reaction can be carried out by the same method as in Step 7a.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 8 is demonstrated. This production process is a process for producing the compound (1-7) of the present invention from the compound (10).
(Reaction Formula 8)

(Step 8)
Step 8 is a step for obtaining compound (14) by a coupling reaction between compound (10) and known compound (13). The coupling reaction can be carried out by a general method in which phenol and an alkyl halide are reacted in the presence of a base in a solvent or without a solvent. Moreover, additives, such as potassium iodide and sodium bromide, can be added as needed. Examples of the base used in this reaction include pyridine, triethylamine, diisopropylethylamine, tert-butoxypotassium, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated carbonization such as chloroform and dichloromethane. Hydrogens; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof Of these, tetrahydrofuran, toluene, N, N-dimethylformamide, 2-butanone or acetonitrile is preferable. The reaction temperature in this reaction is usually 0 ° C to 150 ° C, preferably 15 ° C to 80 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

(Step 6c)
Step 6c is a step for obtaining the compound (15) by converting the indoline ring of the compound (14) into an indole ring. The conversion reaction can be carried out by the same method as in Step 6a.

(Step 9a)
Step 9a is a step for obtaining the compound (1-7) of the present invention by condensing the compound (15) and the compound (16) by a coupling reaction. Compound (16) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction can be performed by a general method in which an amine and an alkyl halide are reacted in a solvent or without a solvent in the presence or absence of a base. Moreover, additives, such as potassium iodide and sodium bromide, can be added as needed. Examples of the base used in this reaction include pyridine, triethylamine, diisopropylethylamine, tert-butoxypotassium, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; halogenated carbonization such as chloroform and dichloromethane. Hydrogens; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; Ketones such as acetone and 2-butanone; Dimethyl sulfoxide; Acetonitrile; Water or a mixed solvent thereof Of these, ethanol, isopropanol, tetrahydrofuran, N, N-dimethylformamide or acetonitrile is preferable. The reaction temperature in this reaction is usually 0 ° C to 150 ° C, preferably 15 ° C to 80 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

Hereinafter, the manufacturing method of the compound of this invention shown by Reaction formula 9 is demonstrated. This production step is a step for producing the compound (1-9) of the present invention from the compound (1-8) in which R ⁴ = methyl group in the compound (1-7) synthesized in the step 9a.
(Reaction Formula 9)

(Step 3c)
Step 3c is a step for obtaining compound (17) by deprotecting the acetyl group of compound (1-8). This reaction can be carried out by the same method as in Step 3a.

(Step 4c)
Step 4c is a step for obtaining the compound (1-9) of the present invention by condensing the compound (17) and the compound (7) by a coupling reaction. The coupling reaction can be carried out by the same method as in step 4a.

Hereinafter, the manufacturing method of the compound of this invention shown by Reaction formula 10 is demonstrated. This production process is a process for producing the compound (1-10) of the present invention from the compound (14).
(Reaction Formula 10)

(Step 9b)
Step 9b is a step for condensing compound (14) and compound (16) by a coupling reaction to obtain compound (1-10) of the present invention. The coupling reaction can be carried out by the same method as in Step 9a.

Hereinafter, the manufacturing method of the compound of this invention shown by Reaction formula 11 is demonstrated. In this production step, the compounds (1-12) and (1-9) of the present invention are converted from the compound (1-11) in which R ⁴ = tert-butoxy group in the compound (1-10) synthesized in step 9b. It is a process for manufacturing.
(Scheme 11)

(Step 3d)
Step 3d is a step for obtaining the compound (18) by deprotecting the tert-butoxycarbonyl group of the compound (1-11). This reaction can be carried out in the same manner as in Step 3b.

(Step 4d)
Step 4d is a step for condensing compound (18) and compound (7) by a coupling reaction to obtain compound (1-12) of the present invention. The coupling reaction can be carried out by the same method as in step 4a.

(Step 6d)
Step 6d is a step for converting the indoline ring of compound (1-12) to an indole ring to obtain compound (1-9) of the present invention. The conversion reaction can be carried out by the same method as in Step 6a.

(Scheme 12)

  Moreover, the compound (1-7) of this invention can also be obtained by the coupling reaction (process 7c) of a compound (17) and a compound (12) as shown in Reaction formula 12. The coupling reaction can be carried out by the same method as in Step 7a.

(Scheme 13)

  Moreover, the compound (1-10) of this invention can also be obtained by the coupling reaction (process 7d) of a compound (18) and a compound (12) as shown in Reaction formula 13. The coupling reaction can be carried out by the same method as in Step 7a.

  EXAMPLES Examples and test examples are shown below to specifically describe the present invention, but the present invention is not limited to these.

(Example 1)

Preparation of 1- (1-acetylpiperidin-4-yl) -5-[(1-cyclobutylpiperidin-4-yl) oxy] -1H-indole (Compound No. 1)

(1) Preparation of 1-acetylpiperidin-4-yl ester of methanesulfonic acid Methanesulfonyl chloride (60.9 g) was added to a chloroform (700 mL) solution of N-acetyl-4-hydroxypiperidine (35.8 g) and pyridine (56 g). And stirred at room temperature for 16 hours. Chloroform was added to the reaction mixture, washed with 0.1 M aqueous hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-diethyl ether to obtain the title compound (26.2 g) as a colorless solid.

(2) Production of N-cyclobutyl-4-hydroxypiperidine To a solution of 4-hydroxypiperidine (100 g) and acetic acid (59.4 g) in chloroform (1500 mL) was added cyclobutanone (104 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled in an ice bath, sodium triacetoxyhydroborate (314 g) was added over 30 minutes, and the mixture was stirred at room temperature for 16 hours. 2M aqueous sodium hydroxide solution (750 mL) was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (developing solvent: ethyl acetate) to obtain the title compound (161 g) as a brown oil.

(3) Preparation of 5- (1-cyclobutylpiperidin-4-yloxy) -1H-indole N-cyclobutyl-4-hydroxypiperidine (12.8 g) obtained in Example 1- (2), 5-hydroxy A 40% toluene solution (37.6 mL) of diethyl azodicarboxylate was added dropwise to a tetrahydrofuran (150 mL) solution of indole (10 g) and triphenylphosphine (21.7 g), and the mixture was stirred at room temperature for 40 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent: chloroform) and NH-type silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1 to 2: 1). And purified. The obtained pale yellow amorphous was crystallized from diisopropyl ether-n-hexane to obtain the title compound (8.35 g) as a colorless solid.

(4) Production of 1- (1-acetylpiperidin-4-yl) -5-[(1-cyclobutylpiperidin-4-yl) oxy] -1H-indole (Compound No. 1)

水素化ナトリウム（ミネラルオイル中５５％以上含有、０．３９ｇ）をＮ，Ｎ−ジメチルホルムアミド（２７ｍＬ）に加えて懸濁液とし、室温にて実施例１−（３）で得られた５−（１−シクロブチルピペリジン−４−イルオキシ）−１Ｈ−インドール（２．２０ｇ）を加え、４０℃にて３０分間撹拌した。反応混合物を氷浴にて冷却し、実施例１−（１）で得られたメタンスルホン酸 １−アセチルピペリジン−４−イルエステル（２．５２ｇ）を加え、９０℃にて１６時間撹拌した。反応混合物を室温まで放冷し、水素化ナトリウム（０．３９ｇ）及びメタンスルホン酸 １−アセチルピペリジン−４−イルエステル（２．５２ｇ）を加え、９０℃にて４０時間撹拌した。反応混合物を室温まで放冷し、水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して減圧下濃縮した。得られた残渣をＮＨ型シリカゲルカラムクロマトグラフィー（展開溶媒：ｎ−ヘキサン：酢酸エチル＝７：３〜酢酸エチル）にて精製して淡黄色アモルファスの表題化合物（０．８６ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.56 - 1.75 (m, 2 H), 1.80 - 2.20 (m, 14 H), 2.16 (s, 3 H), 2.60 - 2.77 (m, 4 H), 3.25 - 3.31 (m, 1 H), 3.97 - 4.03 (m, 1 H), 4.27 (br.s., 1 H), 4.35 - 4.42 (m, 1 H), 4.84 - 4.90 (m, 1 H), 6.43 (d, J=3.2 Hz, 1 H), 6.89 (dd, J=9.2, 2.3 Hz, 1 H), 7.12 (d, J=3.2 Hz, 1 H), 7.14 (d, J=2.3 Hz, 1 H), 7.25 (d, J=9.2 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 396(M+H)⁺

Sodium hydride (containing 55% or more in mineral oil, 0.39 g) was added to N, N-dimethylformamide (27 mL) to form a suspension, which was obtained in Example 1- (3) at room temperature. (1-Cyclobutylpiperidin-4-yloxy) -1H-indole (2.20 g) was added and stirred at 40 ° C. for 30 minutes. The reaction mixture was cooled in an ice bath, methanesulfonic acid 1-acetylpiperidin-4-yl ester (2.52 g) obtained in Example 1- (1) was added, and the mixture was stirred at 90 ° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, sodium hydride (0.39 g) and methanesulfonic acid 1-acetylpiperidin-4-yl ester (2.52 g) were added, and the mixture was stirred at 90 ° C. for 40 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH-type silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 7: 3-ethyl acetate) to obtain a pale yellow amorphous title compound (0.86 g).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.56-1.75 (m, 2 H), 1.80-2.20 (m, 14 H), 2.16 (s, 3 H), 2.60-2.77 (m, 4 H), 3.25-3.31 (m, 1 H), 3.97-4.03 (m, 1 H), 4.27 (br.s., 1 H), 4.35-4.42 (m, 1 H), 4.84-4.90 (m, 1 H) , 6.43 (d, J = 3.2 Hz, 1 H), 6.89 (dd, J = 9.2, 2.3 Hz, 1 H), 7.12 (d, J = 3.2 Hz, 1 H), 7.14 (d, J = 2.3 Hz , 1 H), 7.25 (d, J = 9.2 Hz, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 396 (M + H) ⁺

(Example 2)

Preparation of 1- {4- [5- (1-cyclobutylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} 2,2-dimethylpropan-1-one (Compound No. 2)

(1) Preparation of methanesulfonic acid 1- (2,2-dimethylpropionyl) piperidin-4-yl ester In the same manner as in Example 1- (1), N The title compound was obtained as a colorless solid using tert-butanoyl-4-hydroxypiperidine.

(2) 1- {4- [5- (1-cyclobutylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} 2,2-dimethylpropan-1-one (Compound No. 2) Manufacturing

実施例１−（４）と同様の方法により、メタンスルホン酸 １−アセチルピペリジン−４−イルエステルの代わりに実施例２−（１）で得られたメタンスルホン酸 １−（２，２−ジメチルプロピオニル）ピペリジン−４−イルエステルを用いて無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 9 H), 1.50 - 2.16 (m, 16 H), 2.59 - 2.78 (m, 3 H), 2.93 - 3.01 (m, 2 H), 4.22 - 4.30 (m, 1 H), 4.36 - 4.43 (m, 1 H), 4.60 - 4.68 (m, 2 H), 6.40 - 6.43 (m, 1 H), 6.85 - 6.90 (m, 1 H), 7.10 - 7.14 (m, 2 H), 7.23 (s, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 438(M+H)⁺

In the same manner as in Example 1- (4), methanesulfonic acid 1- (2,2-dimethyl) obtained in Example 2- (1) instead of methanesulfonic acid 1-acetylpiperidin-4-yl ester The title compound was obtained as a colorless solid using propionyl) piperidin-4-yl ester.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 9 H), 1.50-2.16 (m, 16 H), 2.59-2.78 (m, 3 H), 2.93-3.01 (m, 2 H), 4.22-4.30 (m, 1 H), 4.36-4.43 (m, 1 H), 4.60-4.68 (m, 2 H), 6.40-6.43 (m, 1 H), 6.85-6.90 (m, 1 H), 7.10-7.14 (m, 2 H), 7.23 (s, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 438 (M + H) ⁺

(Example 3)

Preparation of {4- [5- (1-cyclobutylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} cyclopentylmethanone (Compound No. 3)

(1) Preparation of 1-cyclopentanoylpiperidin-4-yl ester of methanesulfonic acid N-cyclopentanoyl-4 instead of N-acetyl-4-hydroxypiperidine was prepared in the same manner as in Example 1- (1). -The title compound was obtained as a light brown solid using hydroxypiperidine.

(2) Production of {4- [5- (1-cyclobutylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} cyclopentylmethanone (Compound No. 3)

実施例１−（４）と同様の方法により、メタンスルホン酸 １−アセチルピペリジン−４−イルエステルの代わりに実施例３−（１）で得られたメタンスルホン酸 １−シクロペンタノイルピペリジン−４−イルエステルを用いて淡灰色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.43 - 2.21 (m, 20 H), 2.60 - 2.77 (m, 4 H), 2.87 - 2.98 (m, 2 H), 3.12 - 3.27 (m, 2 H), 3.80 - 3.95 (m, 1 H), 4.11 - 4.21 (m, 2 H), 4.23 - 4.30 (m, 1 H), 4.36 - 4.43 (m, 1 H), 4.87 - 4.93 (m, 1 H), 6.43 (d, J=2.8 Hz, 1 H), 6.89 (dd, J=8.7, 2.3 Hz, 1 H), 7.12 (d, J=3.2 Hz, 1 H), 7.14 (d, J=2.3 Hz, 1 H), 7.23 - 7.28 (m, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 450(M+H)⁺

In the same manner as in Example 1- (4), methanesulfonic acid 1-cyclopentanoylpiperidine-4 obtained in Example 3- (1) instead of methanesulfonic acid 1-acetylpiperidin-4-yl ester -The title compound was obtained as a light gray solid using the yl ester.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.43-2.21 (m, 20 H), 2.60-2.77 (m, 4 H), 2.87-2.98 (m, 2 H), 3.12-3.27 (m, 2 H ), 3.80-3.95 (m, 1 H), 4.11-4.21 (m, 2 H), 4.23-4.30 (m, 1 H), 4.36-4.43 (m, 1 H), 4.87-4.93 (m, 1 H ), 6.43 (d, J = 2.8 Hz, 1 H), 6.89 (dd, J = 8.7, 2.3 Hz, 1 H), 7.12 (d, J = 3.2 Hz, 1 H), 7.14 (d, J = 2.3 Hz, 1 H), 7.23-7.28 (m, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 450 (M + H) ⁺

Example 4

Preparation of {4- [5- (1-cyclobutylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} pyrrolidin-1-ylmethanone (Compound No. 4)

(1) Preparation of 5- (1-cyclobutylpiperidin-4-yloxy) -1- (piperidin-4-yl) -1H-indole 1- (1-acetylpiperidine obtained in Example 1- (4) -4-yl) -5-{(1-cyclobutylpiperidin-4-yl) oxy} -1H-indole (0.86 g) in ethanol (7.2 mL) and 6 M aqueous sodium hydroxide solution (1.8 mL) And stirred at 80 ° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, neutralized with 6M aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (developing solvent: chloroform: methanol = 99: 1) to give the title compound (0 .60 g) was obtained.

(2) Production of {4- [5- (1-cyclobutylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} pyrrolidin-1-ylmethanone (Compound No. 4)

実施例４−（１）で得られた５−（１−シクロブチルピペリジン−４−イルオキシ）−1−（ピペリジン−４−イル）−１Ｈ−インドール（０．１２９ｇ）及びトリエチルアミン（０．０７３ｇ）のクロロホルム（１．２ｍＬ）溶液にピロリジン−１−カルボニルクロリド（０．０７２ｇ）を加え、室温にて１６時間撹拌した。反応混合物を減圧下濃縮し、得られた残渣をＮＨ型シリカゲルカラムクロマトグラフィー（展開溶媒：ｎ−ヘキサン：酢酸エチル＝４：１〜３：７）にて精製し、得られた無色固体をジイソプロピルエーテルから再結晶して無色固体の表題化合物（０．１０８ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.63 - 1.75 (m, 2 H), 1.80 - 2.16 (m, 18 H), 2.60 - 2.77 (m, 3 H), 2.91 - 2.98 (m, 2 H), 3.37 - 3.44 (m, 4 H), 3.93 - 3.99 (m, 2 H), 4.23 - 4.35 (m, 2 H), 6.42 (d, J=3.2 Hz, 1 H), 6.88 (dd, J=8.7, 2.3 Hz, 1 H), 7.13 (d, J=2.3 Hz, 1 H), 7.16 (d, J=3.2 Hz, 1 H), 7.26 (d, J=9.2 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 451(M+H)⁺

5- (1-Cyclobutylpiperidin-4-yloxy) -1- (piperidin-4-yl) -1H-indole (0.129 g) and triethylamine (0.073 g) obtained in Example 4- (1) Pyrrolidine-1-carbonyl chloride (0.072 g) was added to a chloroform (1.2 mL) solution, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1 to 3: 7), and the resulting colorless solid was diisopropyl. Recrystallization from ether gave the title compound (0.108 g) as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.63-1.75 (m, 2 H), 1.80-2.16 (m, 18 H), 2.60-2.77 (m, 3 H), 2.91-2.98 (m, 2 H ), 3.37-3.44 (m, 4 H), 3.93-3.99 (m, 2 H), 4.23-4.35 (m, 2 H), 6.42 (d, J = 3.2 Hz, 1 H), 6.88 (dd, J = 8.7, 2.3 Hz, 1 H), 7.13 (d, J = 2.3 Hz, 1 H), 7.16 (d, J = 3.2 Hz, 1 H), 7.26 (d, J = 9.2 Hz, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 451 (M + H) ⁺

(Example 5)

Preparation of 4- [5- (1-cyclobutylpiperidin-4-yloxy) indol-1-yl] piperidine-1-carboxylic acid tert-butyl ester (Compound No. 5)

実施例１−（４）と同様の方法により、メタンスルホン酸 １−アセチルピペリジン−４−イルエステルの代わりに４−メタンスルホニルオキシピペリジン−１−カルボン酸 ｔｅｒｔ−ブチルエステルを用いて黄色油状の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9 H), 1.58 - 2.17 (m, 16 H), 2.61 - 2.78 (m, 3 H), 2.85 - 2.96 (m, 2 H), 4.23 - 4.36 (m, 4 H), 6.42 (d, J=3.2 Hz, 1 H), 6.88 (dd, J=8.7, 2.3 Hz, 1 H), 7.13 (d, J=2.3 Hz, 1 H), 7.14 (d, J=3.2 Hz, 1 H), 7.25 (d, J=9.2 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 454(M+H)⁺

In the same manner as in Example 1- (4), instead of methanesulfonic acid 1-acetylpiperidin-4-yl ester, 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester was used to give the title as a yellow oil. A compound was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9 H), 1.58-2.17 (m, 16 H), 2.61-2.78 (m, 3 H), 2.85-2.96 (m, 2 H), 4.23-4.36 (m, 4 H), 6.42 (d, J = 3.2 Hz, 1 H), 6.88 (dd, J = 8.7, 2.3 Hz, 1 H), 7.13 (d, J = 2.3 Hz, 1 H) , 7.14 (d, J = 3.2 Hz, 1 H), 7.25 (d, J = 9.2 Hz, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 454 (M + H) ⁺

(Example 6)

Preparation of 5- (1-cyclobutylpiperidin-4-yloxy) -1- (1-methanesulfonylpiperidin-4-yl) -1H-indole (Compound No. 6)

実施例４−（２）と同様の方法により、ピロリジン−１−カルボニルクロリドの代わりにメタンスルホニルクロリドを用いて無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.60 - 2.28 (m, 14 H), 2.52 - 2.82 (m, 4 H), 2.86 (s, 3 H), 2.87 - 2.96 (m, 3 H), 3.98 - 4.07 (m, 2 H), 4.20 - 4.33 (m, 2 H), 6.40 - 6.48 (m, 1 H), 6.84 - 6.91 (m, 1 H), 7.10 - 7.18 (m, 2 H), 7.19 - 7.23 (m, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 432(M+H)⁺

In the same manner as in Example 4- (2), methanesulfonyl chloride was used in place of pyrrolidine-1-carbonyl chloride to give the title compound as a colorless solid.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.60-2.28 (m, 14 H), 2.52-2.82 (m, 4 H), 2.86 (s, 3 H), 2.87-2.96 (m, 3 H), 3.98-4.07 (m, 2 H), 4.20-4.33 (m, 2 H), 6.40-6.48 (m, 1 H), 6.84-6.91 (m, 1 H), 7.10-7.18 (m, 2 H), 7.19-7.23 (m, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 432 (M + H) ⁺

(Example 7)

Preparation of 5- (1-cyclobutylpiperidin-4-yloxy) -1- (1-methylpiperidin-4-yl) -1H-indole (Compound No. 7)

5- (1-Cyclobutylpiperidin-4-yloxy) -1- (piperidin-4-yl) -1H-indole (138 mg) of 1,2-dichloroethane obtained in Example 4- (1) (1. 3 mL) solution was added 37% aqueous formaldehyde solution (0.060 mL) and stirred at room temperature for 20 minutes. Sodium triacetoxyhydroborate (0.13 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 16 hours. To the reaction mixture was added 2M aqueous sodium hydroxide solution (3 mL), stirred for 15 minutes, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 7: 3-5: 5), and the resulting colorless solid was washed with diisopropyl ether to give a colorless powder. The title compound (0.070 g) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.63-2.22 (m, 18 H), 2.36 (s, 3 H), 2.59-2.80 (m, 3 H), 3.00-3.05 (m, 2 H), 4.11-4.20 (m, 1 H), 4.26 (br.s., 1 H), 6.39 6.43 (m, 1 H), 6.87 (dd, J = 8.5, 1.6 Hz, 1 H), 7.13 (d, J = 2.3 Hz, 1 H), 7.19 (d, J = 3.2 Hz, 1 H), 7.24-7.27 (m, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 368 (M + H) ⁺

(Example 8)

Preparation of 1- (1-acetylpiperidin-4-yl) -5-[(1-cyclopentylpiperidin-4-yl) oxy] -1H-indole (Compound No. 8)

(1) Production of N-cyclopentyl-4-hydroxypiperidine By the same method as in Example 1- (2), the title compound was obtained as an orange solid using cyclopentanone instead of cyclobutanone.

(2) Preparation of 5- (1-cyclopentylpiperidin-4-yloxy) -1H-indole In the same manner as in Example 1- (3), instead of N-cyclobutyl-4-hydroxypiperidine, Example 8- ( Using the N-cyclopentyl-4-hydroxypiperidine obtained in 1), the title compound was obtained as a dark brown oil.

(3) Production of 1- (1-acetylpiperidin-4-yl) -5-[(1-cyclopentylpiperidin-4-yl) oxy] -1H-indole (Compound No. 8)

実施例１−（４）と同様の方法により、５−（１−シクロブチルピペリジン−４−イルオキシ）−１Ｈ−インドールの代わりに実施例８−（２）で得られた５−（１−シクロペンチルピペリジン−４−イルオキシ）−１Ｈ−インドールを用いて無色固体の表題化合物を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.37 - 1.48 (m, 2 H), 1.51 - 1.59 (m, 2 H), 1.65 - 1.74 (m, 2 H), 1.82 - 1.95 (m, 6 H), 1.99 - 2.06 (m, 2 H), 2.11 - 2.20 (m, 2 H), 2.16 (s, 3 H), 2.25 - 2.36 (m, 2 H), 2.48 - 2.56 (m, 1 H), 2.70 - 2.76 (m, 1 H), 2.80 - 2.89 (m, 2 H), 3.24 - 3.31 (m, 1 H), 3.98 - 4.03 (m, 1 H), 4.23 - 4.30 (m, 1 H), 4.36 - 4.42 (m, 1 H), 4.85 - 4.90 (m, 1 H), 6.43 (d, J=3.2 Hz, 1 H), 6.89 (dd, J=8.7, 2.3 Hz, 1 H), 7.12 (d, J=3.2 Hz, 1 H), 7.14 (d, J=2.3 Hz, 1 H), 7.25 (d, J=9.2 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 410(M+H)⁺

In the same manner as in Example 1- (4), 5- (1-cyclopentyl) obtained in Example 8- (2) instead of 5- (1-cyclobutylpiperidin-4-yloxy) -1H-indole The title compound was obtained as a colorless solid using piperidin-4-yloxy) -1H-indole.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.37-1.48 (m, 2 H), 1.51-1.59 (m, 2 H), 1.65-1.74 (m, 2 H), 1.82-1.95 (m, 6 H ), 1.99-2.06 (m, 2 H), 2.11-2.20 (m, 2 H), 2.16 (s, 3 H), 2.25-2.36 (m, 2 H), 2.48-2.56 (m, 1 H), 2.70-2.76 (m, 1 H), 2.80-2.89 (m, 2 H), 3.24-3.31 (m, 1 H), 3.98-4.03 (m, 1 H), 4.23-4.30 (m, 1 H), 4.36-4.42 (m, 1 H), 4.85-4.90 (m, 1 H), 6.43 (d, J = 3.2 Hz, 1 H), 6.89 (dd, J = 8.7, 2.3 Hz, 1 H), 7.12 ( d, J = 3.2 Hz, 1 H), 7.14 (d, J = 2.3 Hz, 1 H), 7.25 (d, J = 9.2 Hz, 1 H)
MS (ESI / APCI Dual) ( Positive) m / z; 410 (M + H) +

Example 9

Preparation of {4- [5- (1-cyclopentylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} cyclopentylmethanone (Compound No. 9)

(1) Production of 5- (1-cyclopentylpiperidin-4-yloxy) -1- (piperidin-4-yl) -1H-indole In the same manner as in Example 4- (1), 1- (1-acetyl 1- (1-acetylpiperidine-4) obtained in Example 8- (3) instead of piperidin-4-yl) -5-[(1-cyclobutylpiperidin-4-yl) oxy] -1H-indole The title compound was obtained as a yellow oil using -yl) -5-[(1-cyclopentylpiperidin-4-yl) oxy] -1H-indole.

(2) Production of {4- [5- (1-cyclopentylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} cyclopentylmethanone (Compound No. 9)

実施例９−（１）で得られた５−（１−シクロペンチルピペリジン−４−イルオキシ）−1−（ピペリジン−４−イル）−１Ｈ−インドール（０．１０５ｇ）及びトリエチルアミン（０．０５８ｇ）のクロロホルム（１ｍＬ）溶液にシクロペンタンカルボン酸クロリド（０．０６０ｇ）を氷浴下加え、室温にて１６時間攪拌した。反応混合物に水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して減圧下濃縮した。得られた残渣をＮＨ型シリカゲルカラムクロマトグラフィー（展開溶媒：ｎ−ヘキサン：酢酸エチル＝７：３）にて精製し、得られた無色固体をジイソプロピルエーテルで洗浄して無色粉末の表題化合物（０．０９２ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.38 - 1.47 (m, 2 H), 1.51 - 1.64 (m, 4 H), 1.65 - 1.80 (m, 4 H), 1.81 - 1.95 (m, 10 H), 1.99 - 2.06 (m, 2 H), 2.11 - 2.20 (m, 2 H), 2.24 - 2.35 (m, 2 H), 2.48 - 2.56 (m, 1 H), 2.69 - 2.77 (m, 1 H), 2.79 - 2.89 (m, 2 H), 2.91 - 2.99 (m, 1 H), 3.19 - 3.27 (m, 1 H), 4.14 - 4.20 (m, 1 H), 4.23 - 4.30 (m, 1 H), 4.36 - 4.43 (m, 1 H), 4.86 - 4.93 (m, 1 H), 6.43 (d, J=3.2 Hz, 1 H), 6.89 (dd, J=8.7, 2.3 Hz, 1 H), 7.12 (d, J=3.2 Hz, 1 H), 7.14 (d, J=2.3 Hz, 1 H), 7.23 - 7.28 (m, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 464(M+H)⁺

Of 5- (1-cyclopentylpiperidin-4-yloxy) -1- (piperidin-4-yl) -1H-indole (0.105 g) and triethylamine (0.058 g) obtained in Example 9- (1) Cyclopentanecarboxylic acid chloride (0.060 g) was added to a chloroform (1 mL) solution in an ice bath, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 7: 3), and the obtained colorless solid was washed with diisopropyl ether to give the title compound (0 .092 g) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.38-1.47 (m, 2 H), 1.51-1.64 (m, 4 H), 1.65-1.80 (m, 4 H), 1.81-1.95 (m, 10 H ), 1.99-2.06 (m, 2 H), 2.11-2.20 (m, 2 H), 2.24-2.35 (m, 2 H), 2.48-2.56 (m, 1 H), 2.69-2.77 (m, 1 H ), 2.79-2.89 (m, 2 H), 2.91-2.99 (m, 1 H), 3.19-3.27 (m, 1 H), 4.14-4.20 (m, 1 H), 4.23-4.30 (m, 1 H ), 4.36-4.43 (m, 1 H), 4.86-4.93 (m, 1 H), 6.43 (d, J = 3.2 Hz, 1 H), 6.89 (dd, J = 8.7, 2.3 Hz, 1 H), 7.12 (d, J = 3.2 Hz, 1 H), 7.14 (d, J = 2.3 Hz, 1 H), 7.23-7.28 (m, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 464 (M + H) ⁺

(Example 10)

Preparation of 1- (1-acetylpiperidin-4-yl) -5-[(1-cyclobutylpiperidin-4-yl) oxy] indoline (Compound No. 10)

(1) Production of indoline-5-ol To a solution of 5-hydroxyindole (1.0 g) in tetrahydrofuran (5 mL) was added dropwise an 8M borane-pyridine complex solution (3.8 mL) at 0-5 ° C. The reaction mixture was stirred at the same temperature for 30 minutes, 6M aqueous hydrochloric acid solution (10 mL) was added, and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was cooled in an ice bath, 6M aqueous sodium hydroxide solution was added to adjust the pH to 9, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform: methanol = 10: 1) to obtain the title compound (0.78 g) as a light brown solid.

(2) Preparation of 1- (1-acetylpiperidin-4-yl) indoline-5-ol Indoline-5-ol (0.3 g) obtained in Example 10- (1), 1-acetylpiperidin-4 To a suspension of -one (0.375 g) and acetic acid (0.2 g) in chloroform (10 mL) was added sodium triacetoxyhydroborate (0.564 g) in an ice bath and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 10: 1) to give the title compound (0.36 g) as a pale brown oil.

(3) Production of 1- (1-acetylpiperidin-4-yl) -5-{(1-cyclobutylpiperidin-4-yl) oxy} indoline (Compound No. 10)

To a solution of triphenylphosphine (0.26 g) in tetrahydrofuran (5 mL) was added a 40% toluene solution of diethyl azodicarboxylate (0.45 mL) in an ice bath, and the mixture was stirred at the same temperature for 30 min. 1-Cyclobutylpiperidin-4-ol (0.155 g) was added to the reaction mixture, stirred at room temperature for 30 minutes, and further 1- (1-acetylpiperidin-4-yl) indoline-5-ol (0.26 g). ) And stirred at 50 ° C. for 4 hours. The reaction mixture was cooled in an ice bath, 2M aqueous hydrochloric acid was added to adjust the pH to 1, and ethyl acetate was added to separate the layers. The aqueous layer was neutralized with 2M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 1: 1) to obtain the title compound (0.038 g) as a light brown oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.45-2.17 (m, 17 H), 2.50-2.77 (m, 6 H), 2.89 (t, J = 8.5 Hz, 2 H), 3.06-3.18 (m , 1 H), 3.20-3.31 (m, 2 H), 3.44-3.55 (m, 1 H), 3.86-3.94 (m, 1 H), 4.08 (br.s., 1 H), 4.72-4.81 ( m, 1 H), 6.31 (d, J = 8.6 Hz, 1 H), 6.63 (dd, J = 8.6, 2.4 Hz, 1 H), 6.73 (d, J = 2.4 Hz, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 398 (M + H) ⁺

(Example 11)

Preparation of 5-[(1-cyclobutylpiperidin-4-yl) oxy] -1- [1- (phenylcarbonyl) piperidin-4-yl] -2,3-dihydro-1H-indole (Compound No. 11)

(1) Preparation of 5- (1-cyclobutylpiperidin-4-yloxy) -1-piperidin-4-yl-2,3-dihydro-1H-indole In the same manner as in Example 4- (1), 1 1- (1) obtained in Example 10- (3) instead of-(1-acetylpiperidin-4-yl) -5-[(1-cyclobutylpiperidin-4-yl) oxy] -1H-indole The title compound was obtained using -acetylpiperidin-4-yl) -5-{(1-cyclobutylpiperidin-4-yl) oxy} indoline.

(2) 5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (phenylcarbonyl) piperidin-4-yl] -2,3-dihydro-1H-indole (Compound No. 11) Manufacturing of

In the same manner as in Example 9- (2), instead of 5- (1-cyclopentylpiperidin-4-yloxy) -1- (piperidin-4-yl) -1H-indole, Example 11- (1) The resulting 5- (1-cyclobutylpiperidin-4-yloxy) -1-piperidin-4-yl-2,3-dihydro-1H-indole was replaced with benzoyl chloride instead of cyclopentanecarboxylic acid chloride. The title compound was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.62-2.16 (m, 16 H), 2.56-2.94 (m, 6 H), 3.09 (br.s., 1 H), 3.26-3.36 (m, 2 H), 3.56 (tt, J = 11.7, 3.4 Hz, 1 H), 3.88 (br.s., 1 H), 4.08 (br.s., 1 H), 4.87 (br.s., 1 H) , 6.33 (d, J = 8.7 Hz, 1 H), 6.64 (dd, J = 8.5, 2.5 Hz, 1 H), 6.74 (d, J = 2.3 Hz, 1 H), 7.41 (br.s, 5 H )
MS (ESI / APCI Dual) (Positive) m / z; 460 (M + H) ⁺

Example 12

5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (pyridin-4-ylcarbonyl) piperidin-4-yl] -2,3-dihydro-1H-indole (Compound No. 12) )Manufacturing of

In the same manner as in Example 9- (2), instead of 5- (1-cyclopentylpiperidin-4-yloxy) -1- (piperidin-4-yl) -1H-indole, Example 11- (1) The obtained 5- (1-cyclobutylpiperidin-4-yloxy) -1-piperidin-4-yl-2,3-dihydro-1H-indole was replaced with isonicotinoyl chloride instead of cyclopentanecarboxylic acid chloride, respectively. Used to obtain the title compound.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.48-2.17 (m, 16 H), 2.56-2.95 (m, 6 H), 3.09-3.16 (m, 1 H), 3.26-3.36 (m, 2 H ), 3.57 (tt, J = 11.6, 3.7 Hz, 1 H), 3.73 (d, J = 12.4 Hz, 1 H), 4.09 (br.s., 1 H), 4.87 (d, J = 12.8 Hz, 1 H), 6.32 (d, J = 8.3 Hz, 1 H), 6.64 (dd, J = 8.3, 2.3 Hz, 1 H), 6.74 (d, J = 2.8 Hz, 1 H), 7.29 (d, J = 6.0 Hz, 2 H), 8.70 (d, J = 6.0 Hz, 2 H)
MS (ESI / APCI Dual) (Positive) m / z; 461 (M + H) ⁺

(Example 13)

Preparation of 5-[(1-cyclopentylpiperidin-4-yl) oxy] -1- [1- (phenylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 13)

In the same manner as in Example 9- (2), the title compound was obtained using benzoyl chloride in place of cyclopentanecarboxylic acid chloride.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.33-1.46 (m, 2 H), 1.46-1.62 (m, 4 H), 1.62-1.73 (m, 2 H), 1.74-2.41 (m, 9 H ), 2.45-2.55 (m, 1 H), 2.83 (br.s, 2 H), 2.97 (br.s, 1 H), 3.21 (br.s, 2 H), 3.97 (br.s, 1 H ), 4.26 (br.s, 1 H), 4.37-4.46 (m, 1 H), 4.95 (br.s, 1 H), 6.43 (d, J = 3.2 Hz, 1 H), 6.89 (dd, J = 8.7, 2.3 Hz, 1 H), 7.13 (d, J = 2.3 Hz, 1 H), 7.15 (d, J = 3.2 Hz, 1 H), 7.23-7.26 (m, 1 H), 7.40-7.46 ( m, 5 H)
MS (ESI / APCI Dual) (Positive) m / z; 472 (M + H) ⁺

(Example 14)

Preparation of 5-[(1-cyclobutylpiperidin-4-yl) oxy] -1- [1- (1H-pyrazol-4-ylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 14)

5- (1-cyclobutylpiperidin-4-yloxy) -1- (piperidin-4-yl) -1H-indole (0.1 g), 4-pyrazolecarboxylic acid (0.1 g) obtained in Example 4- (1) 0.04 g), 1-hydroxybenzotriazole monohydrate (0.065 g) and 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (0.081 g) N, N-dimethylformamide (1 mL) ) The suspension was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography to obtain the colorless amorphous title compound (0.112 g).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.11 (t, J = 7.3 Hz, 1 H), 1.24 (t, J = 7.1 Hz, 1 H), 1.59-2.07 (m, 12 H), 2.07- 2.20 (m, 4 H), 2.66 (br.s, 2 H), 2.71-2.78 (m, 1 H), 3.12-3.24 (m, 1 H), 4.27 (br.s, 1 H), 4.38- 4.46 (m, 1 H), 5.50 (br.s, 1 H), 6.42 (d, J = 3.2 Hz, 1 H), 6.88 (dd, J = 8.9, 2.5 Hz, 1 H), 7.10-7.13 ( m, 2 H), 7.22-7.26 (m, 1 H), 7.83 (s, 2 H)
MS (ESI / APCI Dual) (Positive) m / z; 448 (M + H) ⁺

The following compounds were synthesized by a method similar to the method shown in Example 14.
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (phenylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 15)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (3-phenylpropanoyl) piperidin-4-yl] -1H-indole (Compound No. 16)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (4-phenylbutanoyl) piperidin-4-yl] -1H-indole (Compound No. 17)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- {1-[(4-fluorophenyl) carbonyl] piperidin-4-yl} -1H-indole (Compound No. 18)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- {1-[(3-fluorophenyl) carbonyl] piperidin-4-yl} -1H-indole (Compound No. 19)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- {1-[(2-fluorophenyl) carbonyl] piperidin-4-yl} -1H-indole (Compound No. 20)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- {1-[(2,4-difluorophenyl) carbonyl] piperidin-4-yl} -1H-indole (Compound No. 21)
1- {1-[(4-Chlorophenyl) carbonyl] piperidin-4-yl} -5-[(1-cyclobutylpiperidin-4-yl) oxy] -1H-indole (Compound No. 22)
1- {1-[(3-chlorophenyl) carbonyl] piperidin-4-yl} -5-[(1-cyclobutylpiperidin-4-yl) oxy] -1H-indole (Compound No. 23)
1- {1-[(2-chlorophenyl) carbonyl] piperidin-4-yl} -5-[(1-cyclobutylpiperidin-4-yl) oxy] -1H-indole (Compound No. 24)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- (1-{[4- (trifluoromethyl) phenyl] carbonyl} piperidin-4-yl) -1H-indole (Compound No. 25)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- (1-{[4- (trifluoromethoxy) phenyl] carbonyl} piperidin-4-yl) -1H-indole (Compound No. 26)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- {1-[(4-methylphenyl) carbonyl] piperidin-4-yl} -1H-indole (Compound No. 27)
1- {1-[(4-tert-butylphenyl) carbonyl] piperidin-4-yl} -5-[(1-cyclobutylpiperidin-4-yl) oxy] -1H-indole (Compound No. 28)
4-[(4- {5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1H-indol-1-yl} piperidin-1-yl) carbonyl] -N, N-dimethylaniline (Compound No. 29)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- {1-[(4-nitrophenyl) carbonyl] piperidin-4-yl} -1H-indole (Compound No. 30)
4-[(4- {5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1H-indol-1-yl} piperidin-1-yl) carbonyl] benzonitrile (Compound No. 31)
1- {4-[(4- {5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1H-indol-1-yl} piperidin-1-yl) carbonyl] phenyl} ethanone (Compound No. 32 )
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- (1-{[4- (methylsulfonyl) phenyl] carbonyl} piperidin-4-yl) -1H-indole (Compound No. 33)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (pyridin-4-ylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 34)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (pyridin-2-ylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 35)
6-[(4- {5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1H-indol-1-yl} piperidin-1-yl) carbonyl] -4,5-dihydropyridazine-3 ( 2H) -one (Compound No. 36)
1- {1-[(1-acetylpiperidin-4-yl) carbonyl] piperidin-4-yl} -5-[(1-cyclobutylpiperidin-4-yl) oxy] -1H-indole (Compound No. 37)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- {1-[(1-methylpiperidin-4-yl) carbonyl] piperidin-4-yl} -1H-indole (Compound No. 38)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (tetrahydrofuran-3-ylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 39)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (cyclohexylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 40)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- {1-[(4-methoxycyclohexyl) carbonyl] piperidin-4-yl} -1H-indole (Compound No. 41)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (cyclopentylacetyl) piperidin-4-yl] -1H-indole (Compound No. 42)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (3-cyclopentylpropanoyl) piperidin-4-yl] -1H-indole (Compound No. 43)
3- (4- {5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1H-indol-1-yl} piperidin-1-yl) -3-oxopropanenitrile (Compound No. 44)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (methoxyacetyl) piperidin-4-yl] -1H-indole (Compound No. 45)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- (1-propanoylpiperidin-4-yl) -1H-indole (Compound No. 46)
5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1- [1- (4,4,4-trifluorobutanoyl) piperidin-4-yl] -1H-indole (Compound No. 47).
The structural formulas and instrument data of compound numbers 15 to 47 are shown in Table 1-1 to Table 1-5.

(Example 15)

Preparation of 1- {4- [5- (1-tert-butylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} ethanone (Compound No. 48)

(1) Preparation of 5- (1-tert-butylpiperidin-4-yloxy) -1H-indole In the same manner as in Example 1- (3), instead of N-cyclobutyl-4-hydroxypiperidine, 1-tert The title compound was obtained using -butyl-4-hydroxypiperidine (which can be synthesized according to the method described in Journal of Organic Chemistry, 2005, 70, 1930-1933).

(2) Production of 1- {4- [5- (1-tert-butylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} ethanone (Compound No. 48)

5- (1-tert-) synthesized in Example 15- (1) instead of 5- (1-cyclobutylpiperidin-4-yloxy) -1H-indole in the same manner as in Example 1- (4) The title compound was obtained using butylpiperidin-4-yloxy) -1H-indole.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.09 (s, 9 H), 1.74-2.22 (m, 8 H), 2.16 (s, 3 H), 2.33-2.45 (m, 2 H), 2.72 ( td, J = 13.1, 2.3 Hz, 1 H), 2.79-2.94 (m, 2 H), 3.23-3.32 (m, 1 H), 3.95-4.03 (m, 1 H), 4.23 (br.s, 1 H), 4.32-4.42 (m, 1 H), 4.82-4.91 (m, 1 H), 6.42 (d, J = 2.8 Hz, 1 H), 6.88 (dd, J = 9.2, 2.3 Hz, 1 H) , 7.10 (d, J = 3.2 Hz, 1 H), 7.13 (d, J = 2.3 Hz, 1 H), 7.24 (d, J = 8.7 Hz, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 398 (M + H) ⁺

(Example 16)

Preparation of 4- {4- [5- (1-tert-butylpiperidin-4-yloxy) indol-1-yl] piperidine-1-carbonyl} benzonitrile (Compound No. 49)

In the same manner as in Example 4- (1) and 9- (2), 1- (1-acetylpiperidin-4-yl) -5-{(1-cyclobutylpiperidin-4-yl) oxy} indoline Instead, 1- {4- [5- (1-tert-butylpiperidin-4-yloxy) indol-1-yl] piperidin-1-yl} ethanone synthesized in Example 15- (2) was replaced with benzoyl chloride. Instead the title compound was obtained using 4-cyanobenzoyl chloride respectively.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.09 (s, 9 H), 1.75-2.43 (m, 10 H), 2.83-2.93 (m, 2 H), 2.99 (br.s, 1 H), 3.27 (br.s, 1 H), 3.80 (br.s, 1 H), 4.19-4.26 (m, 1 H), 4.39-4.47 (m, 1 H), 4.95 (br.s, 1 H), 6.42-6.45 (m, 1 H), 6.87-6.91 (m, 1 H), 7.13 (t, J = 3.0 Hz, 2 H), 7.21-7.24 (m, 1 H), 7.56 (d, J = 8.7 Hz, 2 H), 7.74 (d, J = 8.7 Hz, 2 H)
MS (ESI / APCI Dual) (Positive) m / z; 485 (M + H) ⁺

(Example 17)

Preparation of 1- (1-acetylpiperidin-4-yl) -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 50)

(1) Production of 1- {4- [5- (3-chloropropoxy) -2,3-dihydroindol-1-yl] piperidin-1-yl} ethanone 1 obtained in Example 10- (2) A suspension of-(1-acetylpiperidin-4-yl) indoline-5-ol (3 g), 1-bromo-3-chloropropane (2.36 g), cesium carbonate (7.51 g) in acetonitrile (30 mL) was added. Stir at 1.5 ° C. for 1.5 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 was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 1: 9 to ethyl acetate) to obtain the title compound (3.25 g) as a light brown oil.

(2) Production of 1- {4- [5- (3-chloropropoxy) indol-1-yl] piperidin-1-yl} ethanone 1- {4- [5 obtained in Example 17- (1) A suspension of (3-chloropropoxy) -2,3-dihydroindol-1-yl] piperidin-1-yl} ethanone (0.4 g) and manganese dioxide (0.2 g) in chloroform (8 mL) at 60 ° C. For 18 hours. The reaction mixture was diluted with chloroform and filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (0.41 g) as a pale yellow oil.

(3) Production of 1- (1-acetylpiperidin-4-yl) -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 50)

1- {4- [5- (3-Chloropropoxy) indol-1-yl] piperidin-1-yl} ethanone (0.2 g), pyrrolidine (0.085 g) obtained in Example 17- (2) A suspension of cesium carbonate (0.389 g) in acetonitrile (0.6 mL) was stirred at 80 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to NH silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 1: 1 to ethyl acetate). To give the title compound (0.147 g) as a pale yellow oil.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.75-1.83 (m, 4 H), 1.85-1.95 (m, 2 H), 1.98-2.05 (m, 2 H), 2.09-2.19 (m, 2 H ), 2.15 (s, 3 H), 2.50-2.55 (m, 4 H), 2.63 (t, J = 7.8 Hz, 2 H), 2.69-2.76 (m, 1 H), 3.25-3.31 (m, 1 H), 4.00 (dd, J = 13.8, 4.1 Hz, 1 H), 4.05 (t, J = 6.4 Hz, 2 H), 4.34-4.42 (m, 1 H), 4.86 (dd, J = 13.5, 4.4 Hz, 1 H), 6.42 (d, J = 3.2 Hz, 1 H), 6.87 (dd, J = 8.9, 2.5 Hz, 1 H), 7.10 (t, J = 2.8 Hz, 2 H), 7.24 (d , J = 8.7 Hz, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 370 (M + H) ⁺

(Example 18)

Preparation of 3-({4- [5- (3-pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) benzonitrile (Compound No. 51) (1) 1- Preparation of (piperidin-4-yl) -5- [3- (pyrrolidin-1-yl) propoxy] -1H-indole 1- (1-acetylpiperidin-4-yl obtained in Example 17- (3) ) -5- (3-Pyrrolidin-1-ylpropoxy) -1H-indole (2.02 g) in ethanol (30 mL) was added 6M aqueous sodium hydroxide solution (7.3 mL) and stirred at 80 ° C. for 16 hours. did. The reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the resulting residue for liquid separation, and the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (developing solvent: ethyl acetate) to give the title compound (1.29 g) as a brown oil. Got.

(2) Preparation of 3-({4- [5- (3-pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) benzonitrile (Compound No. 51)

1- (Piperidin-4-yl) -5- (3- (pyrrolidin-1-yl) propoxy) -1H-indole (0.2 g) and 3-cyanobenzoic acid obtained in Example 18- (1) 1-hydroxybenzotriazole monohydrate (0.14 g) and 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide hydrochloride (0.18 g) in chloroform (0.5 mL) solution of (0.14 g) Of N, N-dimethylformamide (0.5 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1 to n-hexane: ethyl acetate = 1: 4), The resulting colorless solid was washed with ethyl acetate to give the title compound (0.15 g) as a colorless powder.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.55-3.55 (m, 18 H), 3.72-3.93 (m, 1 H), 4.06 (d, J = 6.4 Hz, 2 H), 4.40-4.49 (m , 1 H), 4.90 (br.s, 1 H), 6.45 (d, J = 2.8 Hz, 1 H), 6.88 (dd, J = 8.7, 2.5 Hz, 1 H), 7.09-7.15 (m, 2 H), 7.24 (d, J = 8.7 Hz, 1 H), 7.57 (t, J = 7.8 Hz, 1 H), 7.68-7.76 (m, 3 H)
MS (ESI / APCI Dual) (Positive) m / z; 457 (M + H) ⁺

The following compounds were synthesized by the same method as shown in Example 18.
4-({4- [5- (3-Pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) benzonitrile (Compound No. 52)
1- {1-[(6-Methoxypyridin-3-yl) carbonyl] piperidin-4-yl} -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 53)
5- (3-Pyrrolidin-1-ylpropoxy) -1- (1-{[6- (trifluoromethyl) pyridin-3-yl] carbonyl} piperidin-4-yl) -1H-indole (Compound No. 54)
5-({4- [5- (3-Pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) pyridine-2-carbonitrile (Compound No. 55)
1- {1-[(6-Methylpyridin-3-yl) carbonyl] piperidin-4-yl} -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 56)
1- {1-[(4,6-Dimethylpyridin-3-yl) carbonyl] piperidin-4-yl} -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 57)
1- (1-{[6- (1H-pyrazol-1-yl) pyridin-3-yl] carbonyl} piperidin-4-yl) -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole ( Compound No. 58)
1- {1-[(5-Methylpyridin-3-yl) carbonyl] piperidin-4-yl} -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 59)
1- {1-[(4-Methylpyridin-3-yl) carbonyl] piperidin-4-yl} -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 60)
1- (1-{[2-Methyl-6- (trifluoromethyl) pyridin-3-yl] carbonyl} piperidin-4-yl) -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole ( Compound No. 61)
1- [4-({4- [5- (3-Pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) phenyl] pyrrolidin-2-one (Compound No. 62 )
1- [3-({4- [5- (3-Pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) phenyl] pyrrolidin-2-one (Compound No. 63 )
N-methyl-3-({4- [5- (3-pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) benzamide (Compound No. 64)
N, N-dimethyl-3-({4- [5- (3-pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) benzamide (Compound No. 65)
1- {1-[(3-Methylpyridin-2-yl) carbonyl] piperidin-4-yl} -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 66)
N, N-dimethyl-4-({4- [5- (3-pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) benzamide (Compound No. 67)
5-({4- [5- (3-Pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) pyridin-2-ol (Compound No. 68)
1- {1-[(5-Methylpyrazin-2-yl) carbonyl] piperidin-4-yl} -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 69)
1- [1- (Pyrimidin-5-ylcarbonyl) piperidin-4-yl] -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 70)
1- [1- (Pyrazin-2-ylcarbonyl) piperidin-4-yl] -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 71).
The structural formulas and instrument data of compound numbers 52 to 71 are shown in Tables 2-1 to 2-3.

(Example 19)

Preparation of 1- (1-acetylpiperidin-4-yl) -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 72)

In the same manner as in Example 17- (3), the title compound was obtained using (R) -2-methylpyrrolidine instead of pyrrolidine.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J = 6.0 Hz, 3 H), 1.39-1.47 (m, 1 H), 1.55-1.83 (m, 2 H), 1.84-1.95 (m , 3 H), 1.96-2.07 (m, 2 H), 2.10-2.34 (m, 8 H), 2.73 (td, J = 13.1, 2.8 Hz, 1 H), 3.01 (ddd, J = 11.7, 9.2, 7.1 Hz, 1 H), 3.19 (td, J = 8.6, 2.5 Hz, 1 H), 3.24-3.31 (m, 1 H), 3.97-4.10 (m, 3 H), 4.39 (tt, J = 11.9, 4.1 Hz, 1 H), 4.88 (br.s., 1 H), 6.44 (d, 1 H), 6.89 (dd, J = 8.9, 2.5 Hz, 1 H), 7.09-7.12 (m, 2 H) , 7.25 (d, J = 8.7 Hz, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 384 (M + H) ⁺

(Example 20)

3-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl} benzonitrile (Compound No. 73) Preparation (1) Preparation of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-indole Obtained in Example 19. 1- (1-acetylpiperidin-4-yl) -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (2.55 g) in ethanol (30 mL) Was added with 6M aqueous sodium hydroxide solution (10 mL) and stirred at 80 ° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the resulting residue for liquid separation, and the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.23 g) as a brown oil.

(2) 3-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl} benzonitrile Production of (Compound No. 73)

5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-indole (0.2 g) obtained in Example 20- (1) ) And 3-cyanobenzoic acid (0.12 g) in chloroform (0.5 mL), 1-hydroxybenzotriazole monohydrate (0.11 g) and 3- (3-dimethylaminopropyl) -1-ethylcarbodiimide A solution of hydrochloride (0.14 g) in N, N-dimethylformamide (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1 to n-hexane: ethyl acetate = 1: 1), The obtained colorless crystals were washed with diethyl ether to give the title compound (0.17 g) as colorless crystals.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (br.s, 3 H), 1.34-1.47 (m, 1 H), 1.59-2.37 (m, 12 H), 2.92-3.41 (m, 4 H ), 3.84 (br.s, 1 H), 4.01-4.10 (m, 2 H), 4.39-4.49 (m, 1 H), 4.92 (br.s, 1 H), 6.45 (d, J = 3.2 Hz , 1 H), 6.88 (dd, J = 8.7, 2.3 Hz, 1 H), 7.09-7.15 (m, 2 H), 7.24 (d, J = 9.2 Hz, 1 H), 7.57 (t, J = 7.3 Hz, 1 H), 7.68-7.76 (m, 3 H)
MS (ESI / APCI Dual) (Positive) m / z; 471 (M + H) ⁺

The following compounds were synthesized by a method similar to the method shown in Example 20.
4-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl} benzonitrile (Compound No. 74)
5-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl} pyridine-2-carbohydrate Nitrile (Compound No. 75)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- [1- (tetrahydro-2H-pyran-4-ylcarbonyl) piperidin-4-yl] -1H-indole ( Compound No. 76)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- [1- (pyridin-4-ylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 77)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- [1- (pyridin-3-ylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 78)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- {1-[(4-morpholin-4-ylphenyl) carbonyl] piperidin-4-yl} -1H-indole (Compound No. 79)
1- {1-[(4-methoxyphenyl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 80 )
1- {1-[(2,6-dimethoxypyridin-3-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H -Indole (Compound No. 81)
1- {1-[(6-Methoxypyridin-3-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 82)
1- {1-[(6-methoxypyridin-2-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 83)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (1-{[6- (trifluoromethyl) pyridin-3-yl] carbonyl} piperidin-4-yl) -1H-indole (Compound No. 84)
1- [1- (2,3-Dihydro-1-benzofuran-5-ylcarbonyl) piperidin-4-yl] -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy}- 1H-indole (Compound No. 85)
1- [1- (2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl) piperidin-4-yl] -5- {3-[(2R) -2-methylpyrrolidin-1-yl] Propoxy} -1H-indole (Compound No. 86)
1- {1-[(4-Bromophenyl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 87 )
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- [1- (pyrimidin-2-ylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 88)
1- {1-[(6-Methylpyridin-3-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 89)
2,6-dimethoxy-4-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl } Phenol (Compound No. 90)
1- {1-[(3,5-difluoropyridin-2-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H -Indole (Compound No. 91)
1- {1-[(5-methylpyridin-3-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 92)
1- {1-[(2,6-dimethoxypyrimidin-4-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H Indole (compound no. 93)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (1-{[4- (1H-pyrazol-1-yl) phenyl] carbonyl} piperidin-4-yl) -1H-indole (Compound No. 94)
1- {1-[(6-methoxypyrazin-2-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 95)
4-Methyl-7-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl}- 3,4-Dihydro-2H-1,4-benzoxazine (Compound No. 96)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- [1- (phenylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 97)
1- {1-[(2-fluorophenyl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 98 )
1- {1-[(3-methylphenyl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 99 )
N, N-dimethyl-4-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl } Benzamide (Compound No. 100)
N, N-dimethyl-3-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl } Benzamide (Compound No. 101)
1- (3-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl} phenyl) Etanone (Compound No. 102)
1- {1-[(2-methoxypyridin-3-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 103)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (1-{[4- (trifluoromethyl) pyridin-3-yl] carbonyl} piperidin-4-yl) -1H-indole (Compound No. 104)
1- {1-[(2,6-dimethoxyphenyl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (compound Number 105)
1- {1-[(3-methoxyphenyl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 106 )
1- {1-[(4,6-Dimethylpyridin-3-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H -Indole (compound no. 107)
1- {1-[(2-Fluoro-6-methoxyphenyl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 108)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (1-{[2-methyl-6- (trifluoromethyl) pyridin-3-yl] carbonyl} piperidine- 4-yl) -1H-indole (Compound No. 109)
1- [1- (2,3-Dihydro-1-benzofuran-7-ylcarbonyl) piperidin-4-yl] -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy}- 1H-indole (Compound No. 110)
1- {1-[(2-ethoxypyridin-3-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 111)
1- [1- (2,3-dihydro-1,4-benzodioxin-5-ylcarbonyl) piperidin-4-yl] -5- {3-[(2R) -2-methylpyrrolidin-1-yl] Propoxy} -1H-indole (Compound No. 112)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- {1-[(2,4,6-trimethoxyphenyl) carbonyl] piperidin-4-yl} -1H- Indole (Compound No. 113)
1- {1-[(3-Fluoro-4-methoxyphenyl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 114)
1- {1-[(4-Fluoro-3-methoxyphenyl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 115)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (1-{[6- (1H-pyrazol-1-yl) pyridin-3-yl] carbonyl} piperidine- 4-yl) -1H-indole (Compound No. 116)
1- {1-[(5-methylpyrazin-2-yl) carbonyl] piperidin-4-yl} -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indole (Compound No. 117)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- [1- (pyrimidin-5-ylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 118)
5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- [1- (pyrazin-2-ylcarbonyl) piperidin-4-yl] -1H-indole (Compound No. 119)
4-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl} quinoline (Compound No. 120 )
6-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] carbonyl} quinoline (Compound No. 121 )
1- {1-[(4-Methylpyridin-3-yl) carbonyl] piperidin-4-yl} -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 122)
1- {1-[(3-Methylpyridin-2-yl) carbonyl] piperidin-4-yl} -5- (3-pyrrolidin-1-ylpropoxy) -1H-indole (Compound No. 123)
1- [4-({4- [5- (3-Pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) phenyl] pyrrolidin-2-one (Compound No. 124 )
1- [3-({4- [5- (3-Pyrrolidin-1-ylpropoxy) -1H-indol-1-yl] piperidin-1-yl} carbonyl) phenyl] pyrrolidin-2-one (Compound No. 125 ).
The structural formulas and instrument data of compound numbers 74 to 125 are shown in Tables 3-1 to 3-9.

(Example 21)

4-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indol-1-yl) piperidin-1-yl] sulfonyl} benzonitrile (Compound No. 126)

5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-indole (0.2 g) obtained in Example 20- (1) ) And pyridine (0.070 g) in chloroform (1 mL) were added 4-cyanobenzenesulfonyl chloride (0.13 g) and stirred at room temperature for 16 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 anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 1: 1), and the resulting brown solid was washed with diethyl ether to give the title compound (0 .13 g) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.08 (d, J = 6.0 Hz, 3 H), 1.35-2.32 (m, 13 H), 2.51-2.58 (m, 2 H), 2.93-3.02 (m , 1 H), 3.17 (br.s, 1 H), 3.98-4.16 (m, 5 H), 6.43 (d, J = 3.2 Hz, 1 H), 6.83 (dd, J = 8.9, 2.5 Hz, 1 H), 7.07-7.11 (m, 3 H), 7.86 7.94 (m, 4 H)
MS (ESI / APCI Dual) (Positive) m / z; 507 (M + H) ⁺

Test Example 1: H3 receptor binding test Membrane preparation of human-type H3 receptor-expressing CHO-K1 cells (Euroscreen, ES-392-M, protein 15 μg / 200 μl), R (−)-α-methyl [ ³ H] histamine (Amersham, TRK-1017, specific activity 1.74 TBq / mmol, 2 nM) and the test drug were allowed to react for 1 hour at room temperature. After completion of the reaction, the reaction mixture was suction filtered through a glass filter (GF / C) treated with 0.3% polyethyleneimine, and the glass filter was washed with 50 mM Tris-HCl containing 0.1% BSA and 5 mM magnesium chloride. Washed 5 times with (pH 7.4). After washing, the glass filter was dried, a scintillator was added, and the radioactivity on the filter was measured with a liquid scintillation counter.

The amount of R (−)-α-methyl [ ³ H] histamine binding when the reaction was carried out in the presence of 10 μM R (−)-α-methylhistamine was defined as the nonspecific binding degree, and total R (−)-α -The difference between the degree of methyl [ ³ H] histamine binding and the degree of non-specific binding was defined as the degree of specific R (−)-α-methyl [ ³ H] histamine binding. Inhibition curves were obtained by reacting a constant concentration (2 nM) of R (−)-α-methyl [ ³ H] histamine with various concentrations of each test drug under the conditions described above. The test drug concentration (IC ₅₀ ) at which the binding of R (−)-α-methyl [ ³ H] histamine was inhibited by 50% was determined from the inhibition curve. As a result, the IC ₅₀ values of Compound 1 to Compound 126 were 100 nM or less. A part of the results is shown in Table 4.

Test Example 2: [35S] GTP-γ-S binding test The test was conducted with reference to the method described in The Journal of Pharmaceutical and Experimental Therapeutics, 313, 1, 165-175, 2005. Specifically, it is as follows.
Membrane preparation of human-type H3 receptor-expressing CHO-K1 cells (Euroscreen, ES-392-M, protein 7.5 μg / 100 μl), R (−)-α-methyl [ ³ H] histamine (Amersham, TRK-1017, specific activity 1.74 TBq / mmol, 2 nM), and the test compound were reacted at room temperature for 30 minutes. After completion of the reaction, [ ³⁵ S] GTP-γ-S (0.2 nM) was further added, and the reaction was continued for 30 minutes. After completion of the reaction, the reaction mixture was suction filtered through a glass filter (GF / C), and the glass filter was washed three times with a 20 mM HEPES washing solution (pH 7.4) containing 100 mM sodium chloride and 1 mM magnesium chloride. After washing, the glass filter was dried, a scintillator was added, and the radioactivity on the filter was measured with a liquid scintillation counter.

The amount of [ ³⁵ S] GTP-γ-S binding when the reaction is carried out in the absence of R (−)-α-methylhistamine is defined as nonspecific binding, and is obtained in the presence of R (−)-α-methylhistamine. The difference from the total binding was defined as the specific [ ³⁵ S] GTP-γ-S binding degree. Inhibition by reacting constant concentrations of [ ³⁵ S] GTP-γ-S (0.2 nM) and R (−)-α-methylhistamine (100 μM) with various concentrations of each test drug under the conditions described above. A curve was obtained. From the inhibition curve, the test drug concentration (IC ₅₀ ) at which [ ³⁵ S] GTP-γ-S binding was inhibited by 50% was determined.
As a result, IC ₅₀ values of the compounds 1 3 nM, IC ₅₀ value of Compound 74 was 2 nM.

According to the present invention, it has a strong binding inhibitory action on the binding of histamine to histamine H3 receptor, and is a disorder caused by histamine H3 receptor such as dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, integration Prevention of diseases such as ataxia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, depression or allergic rhinitis It has become possible to provide novel indole or indoline derivatives that are useful in therapy.

Claims (6)

Formula (1)

{In Formula (1), a double line including a wavy line indicates a single bond or a double bond,
Q represents a group represented by the following formula (A) or (B),

R represents C ₁ -C ₆ alkyl, C ₃ -C ₈ cyclic alkyl, —C (O) R ⁴ or —SO ₂ R ⁵ ,
R ¹ is, C ₁ -C ₆ alkyl (wherein C ₁ -C ₆ alkyl may be substituted with C ₃ -C ₈ cyclic alkyl) or C ₃ -C ₈ cycloalkyl (said C ₃ -C ₈ cycloalkyl May be substituted with C ₁ -C ₆ alkyl),
R ² and R ³ are the same or different and represent C ₁ -C ₆ alkyl or C ₃ -C ₈ cyclic alkyl,
Or R ² and R ³ are 4- to 7-membered saturated heterocycles bonded together with adjacent nitrogen atoms (the saturated heterocycle may be substituted with halogen or C ₁ -C ₆ alkyl) Form the
R ⁴ is C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl is halogen; C ₃ -C ₈ cyclic alkyl; C ₁ -C ₆ alkoxy; cyano; C ₂ -C ₇ alkoxycarbonyl; C _2- C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl; carbamoyl; a carbonyl bonded to a 3-7 membered saturated heterocyclic ring containing one or more nitrogen atoms in the ring and further containing an oxygen or sulfur atom ; tri fluoromethyl or phenyl may be substituted), C ₃ -C ₈ cycloalkyl (said C ₃ -C ₈ cyclic alkyl, halogen; substituted with C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy may be), aryl (the aryl, "halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy, hydroxy, trifluoromethyl; trifluoromethoxy; amino; C ₁ ~ ₆ alkylamino; C ₂ -C ₁₂ dialkylamino; C ₂ -C ₇ alkanoyl; C ₁ -C ₆ alkylsulfonyl; nitro; cyano; C ₂ -C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl; ring A carbonyl having a 3- to 7-membered saturated heterocycle containing one or more nitrogen atoms and optionally further containing oxygen or sulfur atoms; carbamoyl; containing one or more nitrogen atoms in the ring and further oxygen or A 3-7 membered saturated heterocyclic ring or heteroaryl which may contain a sulfur atom, which may be substituted with 1 to 3 substituents which are the same or different, and a heteroaryl (which is a halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy, hydroxy, trifluoromethyl; trifluoromethoxy; amino; C ₁ -C ₆ alkylamino C ₂ -C ₁₂ dialkylamino; C ₂ -C ₇ alkanoyl; C ₁ -C ₆ alkylsulfonyl; nitro; cyano; C ₂ -C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl; one in the ring A carbonyl having a 3- to 7-membered saturated heterocycle containing the above nitrogen atom and further containing an oxygen or sulfur atom; carbamoyl; containing one or more nitrogen atoms in the ring and further containing an oxygen or sulfur atom May be substituted with the same or different 1 to 3 substituents selected from 3 to 7-membered saturated heterocycles or heteroaryls ”, which contains one or more nitrogen atoms in the ring, and oxygen or may contain a sulfur atom, partially unsaturated bond may include saturated heterocyclic rings in the ring, a group represented by C ₁ -C ₆ alkoxy or -NR ⁶ R ^7,
R ⁵ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cyclic alkyl, aryl (where the aryl is halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; optionally substituted with hydroxy or cyano) ) or heteroaryl (said heteroaryl, halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; indicates hydroxy or cyano may be substituted with)
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or C ₁ -C ₆ alkyl (wherein the C ₁ -C ₆ alkyl may be substituted with halogen; C ₁ -C ₆ alkoxy or hydroxy). ,
Or R ⁶ and R ⁷ are bonded to each other together with adjacent nitrogen atoms, and may contain one or more nitrogen, oxygen or sulfur atoms in addition to the nitrogen atoms in the ring. heterocyclic (saturated heterocyclic ring may be substituted with halogen or C ₁ -C ₆ alkyl) is formed,
m and n are the same or different and represent an integer of 0 to 2}
Containing an indole or indoline derivative represented by the above or a pharmaceutically acceptable salt thereof as an active ingredient, dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central Preventive or therapeutic agent for convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, depression, or allergic rhinitis. Formula (1)

{In Formula (1), a double line including a wavy line indicates a single bond or a double bond,
Q represents a group represented by the following formula (A) or (B),

R represents C ₁ -C ₆ alkyl, C ₃ -C ₈ cyclic alkyl, —C (O) R ⁴ or —SO ₂ R ⁵ ,
R ¹ is, C ₁ -C ₆ alkyl (C ₁ -C ₆ the alkyl may be substituted with C ₃ -C ₈ cyclic alkyl) or C ₃ -C ₈ cycloalkyl (said C ₃ -C ₈ cycloalkyl May be substituted with C ₁ -C ₆ alkyl),
R ² and R ³ are the same or different and represent C ₁ -C ₆ alkyl or C ₃ -C ₈ cyclic alkyl,
Or R ² and R ³ are 4-7 membered saturated heterocycles bonded together with adjacent nitrogen atoms (the saturated heterocycle may be substituted with halogen or C ₁ -C ₆ alkyl). )
R ⁴ is C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl is halogen; C ₃ -C ₈ cyclic alkyl; C ₁ -C ₆ alkoxy; cyano; C ₂ -C ₇ alkoxycarbonyl; C _2- C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl; carbamoyl or a carbonyl bonded to a 3-7 membered saturated heterocyclic ring containing one or more nitrogen atoms in the ring and further containing an oxygen or sulfur atom in which may be substituted), C ₃ -C ₈ cycloalkyl (said C ₃ -C ₈ cyclic alkyl, halogen; may be substituted with C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy), aryl (the aryl, halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy, hydroxy, trifluoromethyl; trifluoromethoxy; amino; C ₁ -C ₆ alkylamino; C ₂ -C ₁₂ Gia Alkylamino; in the ring; C ₂ -C ₇ alkanoyl; C ₁ -C ₆ alkylsulfonyl; nitro; cyano; C ₂ -C ₇ alkoxycarbonyl; C ₂ -C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl A carbonyl having a 3 to 7 membered saturated heterocycle containing one or more nitrogen atoms and optionally further containing oxygen or sulfur atoms; carbamoyl or one or more nitrogen atoms in the ring and further oxygen or sulfur atoms may be substituted with a comprise also be 3-7 membered saturated heterocyclic ring), heteroaryl (said heteroaryl, halogen; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy, hydroxy, trifluoromethyl; trifluoromethoxy; amino; C ₁ -C ₆ alkylamino; C ₂ -C ₁₂ dialkylamino; C ₂ -C ₇ alkanoyl; C ₁ -C ₆ Alkylsulfonyl; nitro; cyano; C ₂ -C ₇ alkoxycarbonyl; C ₂ -C ₇ alkylaminocarbonyl; C ₃ -C ₁₃ dialkylaminocarbonyl; includes one or more nitrogen atoms in the ring, further oxygen or sulfur atom Substituted with a carbamoyl or a 3-7 membered saturated heterocycle containing one or more nitrogen atoms in the ring and further containing an oxygen or sulfur atom and may be), C ₁ ~C ₆ alkoxy, -NR ⁶ R ⁷ or - (CH ₂₎ represents a group represented by _l -Ar,
Ar is aryl (the aryl, halogen; C ₁ -C ₆ alkyl or C ₁ -C ₆ may be substituted by alkoxy) indicates,
R ⁵ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cyclic alkyl, aryl (wherein the aryl may be substituted by halogen; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy) or heteroaryl (said heteroaryl, halogen; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or hydroxy which may be substituted with) indicates,
R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or C ₁ -C ₆ alkyl (wherein the C ₁ -C ₆ alkyl may be substituted with halogen; C ₁ -C ₆ alkoxy or hydroxy). ,
Or R ⁶ and R ⁷ are bonded to each other together with an adjacent nitrogen atom, and may contain one or more nitrogen, oxygen or sulfur atoms in addition to the nitrogen atom in the ring. saturated heterocyclic ring (saturated heterocycle, halogen or C ₁ which may be substituted with -C ₆ alkyl) forming a,
m and n are the same or different and represent an integer of 0 to 2,
l represents an integer of 1 to 3}
Containing an indole or indoline derivative represented by the above or a pharmaceutically acceptable salt thereof as an active ingredient, dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central Preventive or therapeutic agent for convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, depression, or allergic rhinitis. In the formula (1), the double line including a wavy line is a double bond, the indole derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, as an active ingredient, Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian Preventive or therapeutic agent for rhythm disorder, depression, or allergic rhinitis. The indole or indoline derivative according to any one of claims 1 to 3, wherein Q is the formula (A) in the formula (1), or a pharmaceutically acceptable salt thereof as an active ingredient Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome , Preventive or therapeutic agent for circadian rhythm disorder, depression, or allergic rhinitis. It contains the indole or indoline derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof as an active ingredient, wherein Q in formula (1) is formula (B). Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome , Preventive or therapeutic agent for circadian rhythm disorder, depression, or allergic rhinitis. In the formula (1), R is -C (O) R ^4, containing indole or indoline derivative of any one of claims 1-5, or a pharmaceutically acceptable salt thereof as an active ingredient Dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep A prophylactic or therapeutic agent for apnea syndrome, circadian rhythm disorder, depression, or allergic rhinitis.