JP2010090067A - Nitrogen-containing heterocyclic derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent for preventing or treating diseases such as dementia, Alzheimer's disease, attention deficit hyperactivity disorder, schizophrenia, eating disorder, adiposity, diabetes, hyperlipemia, sleep disorder, narcolepsy, sleep apnea syndrome, circa rhythm disorder, depression and allergic rhinitis. <P>SOLUTION: The nitrogen-containing heterocyclic derivative represented by formula (1), or the pharmaceutically acceptable salt thereof is provided. <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).

  A histamine H3 receptor antagonist having a benzimidazole structure or an azaindole structure has also been reported (see Patent Documents 11 to 13). However, there is no report about the compound having the structure disclosed in the present invention.

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  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 For 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 preventive or therapeutic agents.

As a result of intensive studies for the above purpose, the present inventors have found that a nitrogen-containing heterocyclic derivative has a strong inhibitory activity on the binding of histamine to the histamine H3 receptor, and completed the present invention. .
That is, the present invention
(I) Formula (1)

｛式（１）中、Ｑは、下記式（Ａ）又は（Ｂ）で表される基を示し、

{In formula (1), Q represents a group represented by the following formula (A) or (B);

Ｘ¹は、窒素原子又はＣＲ^5Aであり、
Ｘ²は、窒素原子又はＣＲ^5Bであり、
Ｘ³は、窒素原子又はＣＲ^5Cであり、
Ｘ⁴は、窒素原子又はＣＲ^5Dであり、
Ｘ⁵は、窒素原子又はＣＲ^5Eであり、
ただし、Ｘ¹〜Ｘ⁵のいずれか１つが窒素原子であり、
Ｒ^5A〜Ｒ^5Eは、同一又は異なって、水素原子、ハロゲン原子、Ｃ₁〜Ｃ₆アルキル又はＣ₁〜Ｃ₆アルコキシを示し、
Ｒ¹は、Ｃ₁〜Ｃ₆アルキル、Ｃ₃〜Ｃ₇環状アルキル、−Ｃ（Ｏ）Ｒ⁶又は−ＳＯ₂Ｒ⁷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〜Ｃ₇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３〜７員の飽和複素環（該飽和複素環は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Ｃ₃〜Ｃ₇環状アルキルで置換されてもよい）又はＣ₃〜Ｃ₇環状アルキル（該Ｃ₃〜Ｃ₇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、
Ｒ⁶は、Ｃ₁〜Ｃ₆アルキル、Ｃ₁〜Ｃ₆アルコキシ（該Ｃ₁〜Ｃ₆アルキル又はＣ₁〜Ｃ₆アルコキシは、ハロゲン、Ｃ₁〜Ｃ₆アルコキシ、アリール又はヘテロアリールで置換されてもよい）、Ｃ₃〜Ｃ₇環状アルキル（該Ｃ₃〜Ｃ₇環状アルキルは、ハロゲン、Ｃ₁〜Ｃ₆アルキル、Ｃ₁〜Ｃ₆アルコキシ、アリール又はヘテロアリールで置換されてもよい）、アリール、ヘテロアリール（該アリール又はヘテロアリールは、「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、環中に窒素、酸素、若しくは硫黄原子から選ばれる１つ以上のヘテロ原子を含む単環式飽和複素環が結合したカルボニル、カルバモイル、環中に窒素、酸素、若しくは硫黄原子から選ばれる１つ以上のヘテロ原子を含む単環式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）、環中に窒素、酸素、若しくは硫黄原子から選ばれる１つ以上のヘテロ原子を含む単環式飽和複素環（該単環式飽和複素環は、ハロゲン、Ｃ₁〜Ｃ₆アルキル、Ｃ₁〜Ｃ₆アルコキシ、アリール又はヘテロアリールで置換されてもよい）又は−ＮＲ⁸Ｒ⁹で示される基を示し、
Ｒ⁷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、アリール又はヘテロアリールで置換されてもよい）、Ｃ₃〜Ｃ₇環状アルキル（該Ｃ₃〜Ｃ₇環状アルキルは、ハロゲン、Ｃ₁〜Ｃ₆アルキル、Ｃ₁〜Ｃ₆アルコキシ、アリール又はヘテロアリールで置換されてもよい）、アリール又はヘテロアリール（該アリール又はヘテロアリールは、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、
Ｒ⁸及びＲ⁹は、同一又は異なって、水素原子、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、アリール又はヘテロアリールで置換されてもよい）、Ｃ₃〜Ｃ₇環状アルキル（該Ｃ₃〜Ｃ₇環状アルキルは、ハロゲン、Ｃ₁〜Ｃ₆アルキル、Ｃ₁〜Ｃ₆アルコキシ、アリール又はヘテロアリール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、
ｐ、ｑ及びｎは、同一又は異なって、０〜２の整数を示す｝
で表される含窒素複素環誘導体、又はその医薬上許容される塩であり、

X ¹ is a nitrogen atom or CR ^5A ,
X ² is a nitrogen atom or CR ^5B ,
X ³ is a nitrogen atom or CR ^5C ,
X ⁴ is a nitrogen atom or CR ^5D ,
X ⁵ is a nitrogen atom or CR ^5E ,
However, it is any one of nitrogen atom of X ¹ ~X ^5,
R ^{5A to} R ^5E are the same or different and each represents a hydrogen atom, a halogen atom, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;
R ¹ represents C ₁ -C ₆ alkyl, C ₃ -C ₇ cyclic alkyl, —C (O) R ⁶ or —SO ₂ R ⁷ ,
R ² and R ³ are the same or different and each represents C ₁ -C ₆ alkyl or C ₃ -C ₇ cyclic alkyl;
Or R ² and R ³ together with the adjacent nitrogen atom form a 3-7 membered saturated heterocycle bonded to each other (the saturated heterocycle may be substituted with C ₁ -C ₆ alkyl). ,
R ⁴ is, C ₁ -C ₆ alkyl (wherein C ₁ -C ₆ alkyl may be substituted with C ₃ -C ₇ cyclic alkyl) or C ₃ -C ₇ cycloalkyl (said C ₃ -C ₇ cycloalkyl May be substituted with C ₁ -C ₆ alkyl),
R ⁶ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy (the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy is substituted with halogen, C ₁ -C ₆ alkoxy, aryl or heteroaryl. may be), C ₃ -C ₇ cycloalkyl (said C ₃ -C ₇ cyclic alkyl, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy may be substituted by aryl or heteroaryl) , Aryl, heteroaryl (the aryl or heteroaryl is “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 di Alkylaminocarbonyl, carbonyl, carbamoyl, to which a monocyclic saturated heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur atoms in the ring is bonded, selected from nitrogen, oxygen, or sulfur atoms in the ring Optionally substituted with 1 to 3 identical or different substituents selected from "monocyclic saturated heterocyclic ring or heteroaryl containing one or more heteroatoms", nitrogen, oxygen or sulfur atoms in the ring monocyclic saturated heterocyclic ring (monocyclic saturated heterocyclic ring containing one or more hetero atoms selected from, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted aryl or heteroaryl Or a group represented by -NR ⁸ R ⁹ ,
R ⁷ is C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl may be substituted with halogen, C ₁ -C ₆ alkoxy, aryl or heteroaryl), C ₃ -C ₇ cyclic alkyl (which is C ₃ -C ₇ cyclic alkyl, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy may be substituted by aryl or heteroaryl), aryl or heteroaryl (wherein aryl or heteroaryl are halogen , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy or cyano may be substituted)
R ⁸ and R ⁹ are the same or different and each is a hydrogen atom, C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl may be substituted with halogen, C ₁ -C ₆ alkoxy, aryl or heteroaryl. ), C ₃ -C ₇ cyclic alkyl (the C ₃ -C ₇ cyclic alkyl may be substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, aryl or heteroaryl), aryl ( The aryl may be substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy or cyano, or heteroaryl (the heteroaryl is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy; may be substituted with hydroxy or cyano) indicates,
p, q and n are the same or different and represent an integer of 0 to 2}
A nitrogen-containing heterocyclic derivative represented by: or a pharmaceutically acceptable salt thereof,

(II) In formula (1),
Any one of X ^{1 to} X ⁵ is a nitrogen atom, the other is CH,
R ¹ is —C (O) R ⁶ ;
R ⁶ is C ₁ -C ₆ alkoxy, phenyl (the phenyl may be substituted with halogen or cyano) or a monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur atoms in the ring A saturated heterocyclic ring of formula,
The nitrogen-containing heterocyclic derivative according to claim 1, wherein p, q and n are 1, or a pharmaceutically acceptable salt thereof,

  (III) Dementia, Alzheimer's disease, attention deficit / hyperactivity characterized by containing the nitrogen-containing heterocyclic derivative according to (I) or (II) or a pharmaceutically acceptable salt thereof as an active ingredient Sexual disorders, schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorders, depression, or allergic rhinitis It is a prophylactic or therapeutic agent.

  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, the “halogen atom” refers to 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 ₇ cyclic alkyl” refers to a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

“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.

“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.

“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.

“Monocyclic saturated heterocycle containing one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms in the ring” means one or more heteroatoms selected from nitrogen, oxygen or sulfur atoms Represents a 3- to 7-membered monocyclic saturated heterocyclic ring containing 1 and 2 and may be substituted with 1 to 2 oxo groups. For example, 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-azepanyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-piperazinyl, 3-oxazolidinyl, morpholino, 1-thiomorpholinyl, 2-oxopyrrolidine -1-yl, 2-oxopiperidin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 4-tetrahydropyranyl, 4-tetrahydrothiopyranyl, 1 , 1-dioxo-4-tetrahydrothiopyranyl or 1,4,5,6-tetrahydropyridazin-3-yl.

  The “carbonyl having a monocyclic saturated heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur atoms in the ring” is selected from the above “nitrogen atoms, oxygen atoms, or sulfur atoms” A 3 to 7-membered monocyclic saturated heterocyclic ring containing one or more heteroatoms ”, for example, aziridine-1-carbonyl, azetidine-1-carbonyl, pyrrolidine-1-carbonyl, Piperidine-1-carbonyl, azepan-1-carbonyl, imidazolidine-1-carbonyl, pyrazolidine-1-carbonyl, piperazine-1-carbonyl, oxazolidine-1-carbonyl, morpholine-1-carbonyl, thiomorpholine-1-carbonyl, etc. The group of is shown.

The “3- to 7-membered saturated heterocycle bonded to each other together with adjacent nitrogen atoms” refers to a 1-aziridinyl, 1-azetidinyl, 1-pyrrolidinyl, piperidino or 1-azepanyl group.

  “Aryl” is a monocyclic to tetracyclic aromatic carbocyclic group composed of 6 to 18 carbon atoms, such as a phenyl group, a naphthyl group, an anthryl group, a phenanthrenyl group, a tetracenyl group. And pyrenyl 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.

  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.

One preferred embodiment of the compound of the present invention is the above formula (1):
Any one of X ^{1 to} X ⁵ is a nitrogen atom, the other is CH,
R ¹ is —C (O) R ⁶ ;
R ⁶ is C ₁ -C ₆ alkoxy, phenyl (the phenyl may be substituted with halogen or cyano) or a monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur atoms in the ring A saturated heterocyclic ring of formula,
A nitrogen-containing heterocyclic derivative in which p, q and n are 1, or a pharmaceutically acceptable salt thereof.

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, for example, according to the method shown in the following reaction formula. In the following reaction formulas 1 to 13, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , n, p, and q are as defined above. R ⁵ represents R ^5A , R ^5B , R ^5C , R ^5D or R ^5E (R ^{5A to} R ^5E are as defined above), and Y ¹ , Y ² , Y ³ and Y ⁴ are Elimination of halogen atoms such as chlorine atom, bromine atom and iodine atom or organic sulfonyloxy group such as methanesulfonyloxy group, phenylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group, etc. A group or a hydroxyl group, Z ¹ and Z ² represent a leaving group such as a halogen atom or an organic sulfonyloxy group, and R ^A and R ^B are the same or different and represent a hydrogen atom, C ₁ -C ₅ alkyl; group or (wherein C ₁ -C ₅ alkyl groups are C ₃ -C ₇ cyclic alkyl may be substituted with group), or C ₃ -C ₇ cyclic alkyl group, or R ^a and R ^B, adjacent carbonyl Bond together with the group 3-7 membered saturated cyclic alkyl ketones that (saturated cyclic alkyl ketones C ₁ may be substituted with -C ₆ alkyl) to form a.

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).
(Reaction Formula 1)

(Step 1a)
Step 1a is a step for obtaining compound (4) by condensing compound (2) and compound (3) by a coupling reaction. Compound (2) and compound (3) are known compounds or compounds that can be easily synthesized from known compounds.
When Y ¹ is a leaving group such as a halogen atom or an organic sulfonyloxy group, the coupling reaction generally involves alkylation of the hydroxyl group of phenol in the presence or absence of a base in a solvent or without a solvent. It can be implemented by a conventional method. Moreover, additives, such as potassium iodide and sodium bromide, can be added as needed. Examples of the base used in this reaction include organic bases such as pyridine, triethylamine, diisopropylethylamine; tert-butoxy potassium, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like. Inorganic bases. 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 200 ° C, preferably 15 ° C to 120 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.
When Y ¹ is a hydroxyl group, the coupling reaction includes Mitsunobu reaction. For example, organic phosphorus compounds such as triphenylphosphine and tributylphosphine and diethyl azodicarboxylate, diisopropyl azodicarboxylate, diazodicarboxylate Examples thereof include a method in which a reagent combined with an azo compound such as tertbutyl or a phosphorus ylide reagent such as cyanomethyltributylphosphorane is present in a solvent. 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 compound (6) by condensing compound (4) and compound (5) by a coupling reaction. Compound (5) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction can be carried out by reacting in a solvent or without a solvent in the presence or absence of a base. Moreover, additives, such as potassium fluoride, can be added as needed. Examples of the base used in this reaction include organic bases such as pyridine, triethylamine, diisopropylethylamine; tert-butoxy potassium, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like. Inorganic bases. 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 300 ° C, preferably 40 ° C to 180 ° C.
(Process 3)
Step 3 is a step for obtaining the compound (7) by reducing the nitro group of the compound (6). This step can be performed by a general reduction reaction in which a nitro group is converted to an amino group. For example, catalytic reduction reaction by hydrogenation using a catalyst such as palladium-carbon, platinum, Raney nickel, rhodium-alumina, zinc, iron, etc. , Reduction reaction under acidic conditions using tin or tin (II) chloride, and reduction reaction using a metal hydride such as lithium aluminum hydride. As a specific example, for example, it can be carried out by using palladium-carbon as a catalyst and performing a catalytic reduction reaction by hydrogenation in an ethanol solvent.
(Process 4)
Step 4 is a step for obtaining the compound (1-1) of the present invention from the compound (7). The reaction can be carried out by a general method for synthesizing a benzimidazole derivative from a benzene-1,2-diamine derivative. For example, formic acid or an equivalent thereof can be obtained in a solvent or without a solvent in the presence or absence of an acid. In addition, the method of making it react is mentioned. Examples of formic acid equivalents used in this reaction include trialkoxymethanes such as triethyl orthoformate; dialkoxyaminomethanes such as dimethylformamide dimethyl acetal; alkoxydiaminomethanes such as tert-butoxybis (dimethylamino) methane; Formic acid esters such as methyl formimidate; formamide; formamidine; triazine. Examples of the acid used in this reaction include organic acids such as acetic acid and p-toluenesulfonic acid; inorganic acids such as hydrochloric acid and sodium hydrogensulfate; Lewis acids such as trimethylsilane chloride and triphenyl phosphite. 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 300 ° C, preferably 15 ° C to 180 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.
The compound (1-1) of the present invention can also be produced from the compound (6) by a one-step reaction. The reaction can be carried out by combining the reaction conditions of step 3 and step 4, for example, reaction in the presence of formic acid or its equivalent in the reduction reaction under acidic conditions using iron or tin (II) chloride. The method of letting it be mentioned.

Further, the compound (1-1) of the present invention is a compound (1-2) in which R ¹ = tert-butoxycarbonyl group in the compound (1-1) produced by the reaction formula 1, as shown in the reaction formula 2. Can also be manufactured.
(Reaction Formula 2)

(Step 5a)
Step 5a is a step for obtaining compound (8) by deprotecting the tert-butoxycarbonyl group of compound (1-2). 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, and trifluoromethanesulfonic acid. 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 6)
Step 6 is a step for obtaining the compound (1-1) of the present invention by condensing the compound (8) and the compound (9) by a coupling reaction. Compound (9) is a known compound or a compound that can be easily synthesized from a known compound.
When Y ² is a leaving group such as a halogen atom or an organic sulfonyloxy group, the coupling reaction includes reacting compound (8) and compound (9) in a solvent in the presence or absence of a base. The method of letting it be mentioned. Moreover, additives, such as potassium iodide and sodium bromide, can be added as needed. Examples of the base used in this reaction include organic bases such as pyridine, triethylamine, diisopropylethylamine; tert-butoxy potassium, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like. Inorganic bases. 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.
When R ¹ is —C (O) R ⁶ and Y ² is a hydroxyl group, the coupling reaction can be carried out by a general method of amidation of carboxylic acid. For example, carboxylic acid is converted to carboxylic acid chloride. And a method of reacting with an amine after being led to a carboxylic acid halide such as carboxylic acid bromide, a method of reacting a mixed acid anhydride obtained from carboxylic acid and chlorocarbonate, etc. with an amine, a carboxylic acid with 1-benzotriazolyl ester, Examples thereof include a method of reacting with an amine after being led to an active ester such as succinimidyl ester, and a method of reacting a carboxylic acid with an amine in the presence of a condensing agent. 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 organic bases such as pyridine, triethylamine and diisopropylethylamine; inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogencarbonate. 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.

Moreover, the compound (1-1) of this invention can also be manufactured from a compound (10) as shown in Reaction formula 3.
(Reaction Formula 3)

(Step 1b)
Step 1b is a step for condensing compound (10) and compound (3) by a coupling reaction to obtain compound (11). Compound (10) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction can be carried out by the same method as in step 1a of reaction scheme 1.

(Step 7a)
Step 7a is a step for obtaining the compound (1-1) of the present invention by condensing the compound (11) and the compound (12) by a coupling reaction. 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 method for introducing a substituent into the nitrogen atom of benzimidazole in the presence or absence 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-butyl lithium, diisopropylethylamine, tert-butoxy potassium, potassium carbonate, cesium carbonate, 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 Among these, N, N-dimethylformamide, dimethyl sulfoxide or acetonitrile is preferable. The reaction temperature in this reaction is usually 0 ° C to 300 ° C, preferably 15 ° C to 160 ° C, and the reaction time is usually 1 to 64 hours, preferably 1 to 12 hours.

Compound (11) can also be produced from compound (10) as shown in Reaction Scheme 4.
(Reaction Formula 4)

(Step 8)
Step 8 is a step for obtaining compound (14) by condensing compound (10) and known compound (13) by a coupling reaction. Compound (10) 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 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 organic bases such as pyridine, triethylamine, diisopropylethylamine; tert-butoxy potassium, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like. Inorganic bases. 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, acetonitrile, and 2-butanone are 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 9a)
Step 9a is a step for obtaining compound (11) by condensing compound (14) and compound (15) by a coupling reaction. Compound (15) 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 method for obtaining a tertiary amine by reacting a secondary amine with an alkyl halide in the presence or absence 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 organic bases such as pyridine, triethylamine, diisopropylethylamine; tert-butoxy potassium, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like. Inorganic bases. 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, and acetonitrile are preferable. The reaction temperature in this reaction is usually 0 ° C to 200 ° C, preferably 15 ° C to 120 ° 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 5 is demonstrated. This production process is a process for producing the compound (1-3) of the present invention from the compound (17).
(Reaction Formula 5)

(Step 7b)
Step 7b is a step for obtaining the compound (1-3) of the present invention by condensing the compound (17) and the compound (12) by a coupling reaction. Compound (17) can be produced from compound (16) by a method similar to the method shown in Reaction Scheme 3, Step 1b or Reaction Scheme 4. Compound (16) can be produced, for example, according to the method described in (Bioorganic and Medicinal Chemistry, 2007, 350-364). The coupling reaction can be carried out by a general method for introducing a substituent into the nitrogen atom of indazole. For example, the same method as in Step 7a of Reaction Scheme 3 can be mentioned.

The compounds of the present invention (1-3), as shown in Scheme 6, R ¹ = tert-butoxy compound is a carbonyl group in the compounds of the present invention prepared in step 7b (1-3) (1- It can also be manufactured from 4). This production can be carried out by the same method as shown in Reaction Scheme 2.
(Reaction Formula 6)

以下、反応式７で示される本発明の化合物の製造方法について説明する。この製造工程は、化合物（１９）から本発明の化合物（１−５）を製造するための工程である。
（反応式７）

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 7 is demonstrated. This production process is a process for producing the compound (1-5) of the present invention from the compound (19).
(Reaction Formula 7)

(Step 7c)
Step 7c is a step for obtaining the compound (1-5) of the present invention by condensing the compound (19) and the compound (12) by a coupling reaction. Compound (19) can be produced from compound (18) by the same method as shown in Reaction Scheme 3, Step 1b or Reaction Scheme 4. Compound (18) can be produced, for example, according to the method described in (Tetrahedron Letters, 2004, 2317-2319). The coupling reaction can be carried out by a general method for introducing a substituent into the 1-position nitrogen atom of 7-azaindole, and for example, can be carried out by the same method as in step 7a of Reaction Scheme 3.

In addition, as shown in Reaction Scheme 8, the compound (1-5) of the present invention is a compound (1-) wherein R ¹ = tert-butoxycarbonyl group in the compound (1-5) of the present invention produced in Step 7c. It can also be produced from 6). This production can be carried out by the same method as shown in Reaction Scheme 2.
(Reaction Formula 8)

以下、反応式９で示される本発明の化合物の製造方法について説明する。この製造工程は、化合物（２０）から本発明の化合物（１−７）を製造するための工程である。
（反応式９）

Hereinafter, the manufacturing method of the compound of this invention shown by Reaction formula 9 is demonstrated. This production process is a process for producing the compound (1-7) of the present invention from the compound (20).
(Reaction Formula 9)

(Step 7d)
Step 7d is a step for condensing compound (20) and compound (12) by a coupling reaction to obtain compound (1-7) of the present invention. Compound (20) can be produced, for example, according to the method described in (Journal of Organic Chemistry, 1968, 3762-3766). The coupling reaction can be carried out by a general method for introducing a substituent into the 1-position nitrogen atom of 6-azaindole, and for example, can be carried out by the same method as in Step 7a of Reaction Scheme 3.

Further, as shown in Reaction Scheme 10, compound (1-7) of the present invention is R ¹ = tert-butoxycarbonyl group in Compound (1-7) of the present invention prepared in Step 7d of Reaction Scheme 9. It can also be produced from compound (1-8). This production can be carried out by the same method as shown in Reaction Scheme 2.
(Reaction Formula 10)

Hereinafter, the manufacturing method of the compound of this invention shown by Reaction formula 11 is demonstrated. This production process is a process for producing the compound (1-9) of the present invention from the compound (21).
(Scheme 11)

(Step 10a)
Step 10a is a step for condensing compound (21) and compound (22) by a coupling reaction to obtain compound (23). Compound (21) and compound (22) are known compounds or compounds that can be easily synthesized from known compounds. The coupling reaction can be carried out by reacting compound (21) with compound (22) in the presence or absence 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 organic bases such as pyridine, triethylamine, diisopropylethylamine; tert-butoxy potassium, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like. Inorganic bases. 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. The reaction temperature in this reaction is usually 0 ° C to 200 ° C, preferably 15 ° C to 120 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.

(Step 9b)
Step 9b is a step for obtaining compound (24) by condensing compound (23) and compound (15) by a coupling reaction. The coupling reaction can be carried out in the same manner as in Step 9a of Reaction Scheme 4.
(Step 11)
Step 11 is a step for obtaining compound (25) from compound (24). The reaction can be carried out by the same method as described in (Journal of Medicinal Chemistry, 1990, 2087-2093).
(Step 12)
Step 12 is a step for obtaining compound (26) from compound (25). The reaction can be carried out by the same method as described in (Journal of Medicinal Chemistry, 1990, 2087-2093).
(Step 7e)
Step 7e is a step for condensing compound (26) and compound (12) by a coupling reaction to obtain compound (1-9) of the present invention. The coupling reaction can be carried out by a general method for introducing a substituent into the 1-position nitrogen atom of 4-azaindole, and can be carried out, for example, by the same method as in Step 7a of Reaction Scheme 3.

In addition, as shown in Reaction Scheme 12, Compound (1-9) of the present invention is R ¹ = tert-butoxycarbonyl group in Compound (1-9) of the present invention prepared in Step 7e of Reaction Formula 11. It can also be produced from compound (1-10). This production can be carried out by the same method as shown in Reaction Scheme 2.
(Scheme 12)

Hereinafter, the manufacturing method of the compound of this invention shown by Reaction formula 13 is demonstrated. This production process is a process for producing the compound (1-11) of the present invention from the compound (2).
(Scheme 13)

(Step 13a)
Step 13a is a step for obtaining compound (28) by condensing compound (2) and compound (27) by a coupling reaction. Compound (27) is a known compound or a compound that can be easily synthesized from a known compound.
When Y ³ is a leaving group such as a halogen atom or an organic sulfonyloxy group, the coupling reaction generally involves alkylation of the hydroxyl group of phenol in the presence or absence of a base in a solvent or without a solvent. It can be implemented by a conventional method. Moreover, additives, such as potassium iodide and sodium bromide, can be added as needed. Examples of the base used in this reaction include organic bases such as pyridine, triethylamine, diisopropylethylamine; tert-butoxy potassium, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride and the like. Inorganic bases. 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 200 ° C, preferably 15 ° C to 120 ° C, and the reaction time is usually 1 to 48 hours, preferably 1 to 12 hours.
When Y ³ is a hydroxyl group, the coupling reaction includes Mitsunobu reaction. For example, organic phosphorus compounds such as triphenylphosphine and tributylphosphine and diethyl azodicarboxylate, diisopropyl azodicarboxylate, diazodicarboxylate Examples thereof include a method in which a reagent in combination with an azo compound such as tertbutyl or a phosphorus ylide reagent such as cyanomethyltributylphosphorane is present in a solvent. 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.

Compound (1-11) of the present invention can be produced from compound (28) by a method similar to the method shown in Reaction Scheme 1 and Reaction Scheme 2.

The compound (1-11) of the present invention can also be produced by the method shown in Reaction Scheme 14.
(Scheme 14)

(Step 13b)
Step 13b is a step for obtaining compound (30) by condensing compound (2) and compound (29) by a coupling reaction. The compound (29) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction can be performed in the same manner as in Step 13a of Reaction Scheme 13.

(Step 5b)
Step 5b is a step for obtaining the compound (32) by deprotecting the tert-butoxycarbonyl group of the compound (31). The deprotection reaction can be carried out by the same method as in Step 5a of Reaction Scheme 2. Compound (31) can be produced from compound (30) by a method similar to the method shown in Reaction Scheme 1.

(Step 14)
Step 14 is a step for obtaining the compound (1-11) of the present invention by condensing the compound (32) and the compound (33) by a reductive amination reaction. Compound (33) is a known compound or a compound that can be easily synthesized from a known compound. The reaction can be carried out by a general method of reductive amination reaction in which a carbonyl compound and an amine are condensed. For example, compound (32) and compound (33) can be used in the presence or absence of an acid in a solvent or without solvent. ) And a method in which a reducing agent is added to the mixture. 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, and lithium aluminum hydride. Examples of the acid used in this reaction include acetic acid, formic acid, and hydrochloric acid. Examples of the solvent used in this reaction include alcohols such as methanol, ethanol and isopropanol; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; chloroform, dichloromethane and the like. Halogenated hydrocarbons; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone; dimethyl sulfoxide; acetonitrile; acetone; water or a mixed solvent thereof. 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.

The compound (1-11) of the present invention can also be produced by the method shown in Reaction Scheme 15.
(Scheme 15)

（工程９ｃ）
工程９ｃは、化合物（３２）と化合物（３４）とをカップリング反応により縮合して本発明の化合物（１−１１）を得るための工程である。化合物（３４）は、公知化合物であるか、公知化合物から容易に合成できる化合物である。該カップリング反応は、反応式４の工程９ａに示す方法と同様の方法により製造できる。

(Step 9c)
Step 9c is a step for condensing compound (32) and compound (34) by a coupling reaction to obtain compound (1-11) of the present invention. The compound (34) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction can be produced by a method similar to the method shown in Step 9a of Reaction Scheme 4.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 16 is demonstrated. This production process is a process for producing the compound (1-12) of the present invention from the compound (16).
(Scheme 16)

本発明の化合物（１−１２）は、化合物（３５）から、反応式５の工程７ｂ及び反応式６に示す方法と同様の方法により製造できる。また、化合物（１−１２）は、化合物（３６）から、反応式５の工程７ｂ、反応式１４の工程５ｂ、工程１４及び反応式１５に示す方法と同様の方法により製造できる。化合物（３５）及び化合物（３６）は、化合物（１６）から、反応式１３の工程１３ａ及び反応式１４の工程１３ｂに示す方法と同様の方法により製造できる。

Compound (1-12) of the present invention can be produced from compound (35) by a method similar to the method shown in Reaction Scheme 5, Step 7b and Reaction Scheme 6. In addition, compound (1-12) can be produced from compound (36) by a method similar to the method shown in step 7b of reaction formula 5, step 5b of reaction formula 14, step 14 and reaction formula 15. Compound (35) and compound (36) can be produced from compound (16) by a method similar to the method shown in Step 13a of Reaction Formula 13 and Step 13b of Reaction Formula 14.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 17 is demonstrated. This production process is a process for producing the compound (1-13) of the present invention from the compound (18).
(Reaction Scheme 17)

本発明の化合物（１−１３）は、化合物（３７）から、反応式７の工程７ｃ及び反応式８に示す方法と同様の方法により製造できる。また、化合物（１−１３）は、化合物（３８）から、反応式５の工程７ｂ、反応式１４の工程５ｂ、工程１４及び反応式１５に示す方法と同様の方法により製造できる。化合物（３７）及び化合物（３８）は、化合物（１８）から、反応式１３の工程１３ａ及び反応式１４の工程１３ｂに示す方法と同様の方法により製造できる。

Compound (1-13) of the present invention can be produced from compound (37) by a method similar to the method shown in Reaction Scheme 7, Step 7c and Reaction Scheme 8. In addition, compound (1-13) can be produced from compound (38) by a method similar to the method shown in step 7b in reaction formula 5, step 5b in reaction formula 14, step 14 and reaction formula 15. Compound (37) and compound (38) can be produced from compound (18) by a method similar to the method shown in Step 13a of Reaction Formula 13 and Step 13b of Reaction Formula 14.

Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 18 is demonstrated. This production process is a process for producing the compound (1-14) of the present invention from the compound (39).
(Scheme 18)

Compound (1-14) of the present invention can be produced from compound (39) by a method similar to the method shown in Reaction Scheme 9, Step 7d and Reaction Scheme 10. Compound (39) can be produced in the same manner as in compound (20).
Hereafter, the manufacturing method of the compound of this invention shown by Reaction formula 17 is demonstrated. This production process is a process for producing the compound (1-15) of the present invention from the compound (21).
(Reaction Scheme 17)

Step 10b is a step for obtaining compound (41) by condensing compound (21) and compound (40) by a coupling reaction. Compound (40) is a known compound or a compound that can be easily synthesized from a known compound. The coupling reaction can be performed in the same manner as in Step 10a of Reaction Scheme 11.
Compound (1-15) of the present invention can be produced from compound (41) by a method similar to the method shown in Reaction Scheme 11 and Reaction Scheme 12.

  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 Tert-butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indazol-1-yl) piperidine-1-carboxylate (Compound No. 1) ( 1) Production of (2R) -1- (3-chloropropyl) -2-methylpyrrolidine

（Ｒ）−２−メチルピロリジン（１８．０ｇ）と１−ブロモ−３−クロロプロパン（１００．０ｇ）のアセトン（３６０ｍＬ）溶液に、氷浴下５Ｍ水酸化ナトリウム水溶液（５０ｍＬ）を滴下して加えた。８０℃まで昇温し、４時間撹拌した。反応混合物をジエチルエーテルで抽出し、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＝４：１〜１：１）及びシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム：メタノール＝９：１）にて精製して黄色油状の表題化合物（１７．８ｇ、５２％）を得た。
（２）５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−インダゾールの製造

To a solution of (R) -2-methylpyrrolidine (18.0 g) and 1-bromo-3-chloropropane (100.0 g) in acetone (360 mL) was added dropwise 5M aqueous sodium hydroxide solution (50 mL) in an ice bath. It was. It heated up to 80 degreeC and stirred for 4 hours. The reaction mixture was extracted with diethyl ether, and 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 type silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1 to 1: 1) and silica gel column chromatography (developing solvent: chloroform: methanol = 9: 1). To give the title compound (17.8 g, 52%) as a yellow oil.
(2) Preparation of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indazole

１Ｈ−インダゾール−５−オール（２．００ｇ）のアセトニトリル（３０ｍＬ）溶液に、炭酸カリウム（３．１０ｇ）、ヨウ化ナトリウム（１．１０ｇ）及び実施例１−（１）で製造した（Ｒ）−１−（３−クロロプロピル）−２−メチルピロリジン（２．７０ｇ）を順次加え、９０℃にて５時間撹拌した。反応混合物を室温まで放冷し、不溶物を濾過して濾液を減圧下濃縮した。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＝４：１〜１：９）にて精製して無色固体の表題化合物（０．７８ｇ、２０％）を得た。
（３）Ｔｅｒｔ−ブチル ４−（５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−インダゾール−１−イル）ピペリジン−１−カルボキシラート（化合物番号１）の製造

Prepared in a solution of 1H-indazol-5-ol (2.00 g) in acetonitrile (30 mL) with potassium carbonate (3.10 g), sodium iodide (1.10 g) and Example 1- (1) (R) -1- (3-Chloropropyl) -2-methylpyrrolidine (2.70 g) was sequentially added, and the mixture was stirred at 90 ° C. for 5 hours. The reaction mixture was allowed to cool to room temperature, insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-type silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1 to 1: 9) to give the title compound (0.78 g, 20%) as a colorless solid. It was.
(3) Tert-butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indazol-1-yl) piperidine-1-carboxylate (Compound No. 1) Manufacturing of

実施例１−（２）で製造した５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−インダゾール（０．３０ｇ）のＮ，Ｎ−ジメチルホルムアミド（３ｍＬ）溶液に、氷浴下水素化ナトリウム（ミネラルオイル中５５％以上含有、０．０８ｇ）を加え、室温にて１５分間撹拌した。反応混合物にｔｅｒｔ−ブチル １−（メチルスルホニルオキシ）ピペリジン−４−カルボキシラート（０．９７ｇ）を加え、９０℃で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、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＝４：１〜１：４）にて精製して無色非晶質の表題化合物（０．２０ｇ，４３％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.4 Hz, 3 H), 1.32 - 1.51 (m, 10 H), 1.55 - 1.85 (m, 6 H), 1.87 - 2.08 (m, 3 H), 2.09 - 2.26 (m, 3 H), 2.26 - 2.36 (m, 1 H), 2.85 - 3.03 (m, 2 H), 3.14 - 3.23 (m, 1 H), 4.00 - 4.10 (m, 2 H), 4.15 - 4.38 (m, 2 H), 4.43 - 4.57 (m, 1 H), 7.03 - 7.11 (m, 2 H), 7.33 (d, J=9.2 Hz, 1 H), 7.88 (s, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 443(M+H)⁺

N, N-dimethylformamide (3 mL) of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indazole (0.30 g) prepared in Example 1- (2) Sodium hydride (containing 55% or more in mineral oil, 0.08 g) was added to the solution in an ice bath and stirred at room temperature for 15 minutes. To the reaction mixture, tert-butyl 1- (methylsulfonyloxy) piperidine-4-carboxylate (0.97 g) was added and stirred at 90 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, 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 = 4: 1 to 1: 4) to give a colorless amorphous title compound (0.20 g, 43%). Got.
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J = 6.4 Hz, 3 H), 1.32-1.51 (m, 10 H), 1.55-1.85 (m, 6 H), 1.87-2.08 ( m, 3 H), 2.09-2.26 (m, 3 H), 2.26-2.36 (m, 1 H), 2.85-3.03 (m, 2 H), 3.14-3.23 (m, 1 H), 4.00-4.10 ( m, 2 H), 4.15-4.38 (m, 2 H), 4.43-4.57 (m, 1 H), 7.03-7.11 (m, 2 H), 7.33 (d, J = 9.2 Hz, 1 H), 7.88 (s, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 443 (M + H) ⁺

(Example 2)
(4-Fluorophenyl) [4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indazol-1-yl) piperidin-1-yl] methanone (Compound No. Preparation of 2) (1) Preparation of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-indazole hydrochloride

実施例１−（３）で製造したｔｅｒｔ−ブチル ４−（５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−インダゾール−１−イル)ピペリジン−１−カルボキシラート（０．２０ｇ）の酢酸エチル（０．６ｍＬ）溶液に、室温にて４Ｍ塩酸―酢酸エチル溶液（０．６ｍＬ）を滴下して加え、３時間撹拌した。反応混合物を減圧下濃縮して無色固体の表題化合物（０．１８ｇ，８０％）を得た。
（２）（４−フルオロフェニル）［４−（５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−インダゾール−１−イル）ピペリジン−１−イル］メタノン（化合物番号２）の製造

Tert-Butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indazol-1-yl) piperidine-1-prepared in Example 1- (3) To a solution of carboxylate (0.20 g) in ethyl acetate (0.6 mL) was added dropwise 4M hydrochloric acid-ethyl acetate solution (0.6 mL) at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (0.18 g, 80%) as a colorless solid.
(2) (4-Fluorophenyl) [4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indazol-1-yl) piperidin-1-yl] methanone Production of (Compound No. 2)

実施例２−（１）で製造した５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ}−１−(ピペリジン−４−イル)−１Ｈ−インダゾール（０．０４６ｇ）及びピリジン（０．０４４ｇ）のクロロホルム（０．５ｍＬ）溶液に、氷浴下４−フルオロベンゾイルクロリド（０．０１７ｇ）を加え、室温にて２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＝４：１〜０：１０）にて精製して、無色非晶質の表題化合物（０．０１５ｇ，３０％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.07 - 1.14 (m, 3 H), 1.40 - 1.46 (m, 1 H), 1.65 - 2.37 (m, 12 H), 2.97 - 3.04 (m, 1 H), 3.09 - 4.01 (m, 4 H), 4.02 - 4.09 (m, 2 H), 4.59 - 4.66 (m, 1 H), 4.96 - 5.02 (m, 1 H), 7.06 - 7.14 (m, 2 H), 7.31 - 7.35 (m, 1 H), 7.39 - 7.43 (m, 2 H), 7.46 - 7.50 (m, 2 H), 7.89 - 7.91 (m, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 465(M+H)⁺

5- {3-[(2R) -2-Methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-indazole (0.046 g) prepared in Example 2- (1) 4-Fluorobenzoyl chloride (0.017 g) was added to a chloroform (0.5 mL) solution of pyridine (0.044 g) in an ice bath and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1 to 0:10) to give a colorless amorphous title. A compound (0.015 g, 30%) was obtained.
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.07-1.14 (m, 3 H), 1.40-1.46 (m, 1 H), 1.65-2.37 (m, 12 H), 2.97-3.04 (m, 1 H), 3.09-4.01 (m, 4 H), 4.02-4.09 (m, 2 H), 4.59-4.66 (m, 1 H), 4.96-5.02 (m, 1 H), 7.06-7.14 (m, 2 H), 7.31-7.35 (m, 1 H), 7.39-7.43 (m, 2 H), 7.46-7.50 (m, 2 H), 7.89-7.91 (m, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 465 (M + H) ⁺

(Example 3)
Preparation of Tert-butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-benzimidazol-1-yl) piperidine-1-carboxylate (Compound No. 3) (1) Preparation of (2R) -1- [3- (4-chloro-3-nitrophenoxy) propyl] -2-methylpyrrolidine

実施例１−（２）と同様の方法により、１Ｈ−インダゾール−５−オールの代わりに４−クロロ−３−ニトロフェノール（３．０ｇ）を用いて、黄色油状の表題化合物（３．３ｇ、６４％）を得た。
（２）Ｔｅｒｔ−ブチル ４−［（４−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−２−ニトロフェニル）アミノ］ピペリジン−１−カルボキシラートの製造

In a manner similar to Example 1- (2), substituting 4-chloro-3-nitrophenol (3.0 g) for 1H-indazol-5-ol, the title compound (3.3 g, 64%).
(2) Preparation of Tert-butyl 4-[(4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -2-nitrophenyl) amino] piperidine-1-carboxylate

実施例３−（１）で製造した（２Ｒ）−１−［３−（４−クロロ−３−ニトロフェノキシ）プロピル］−２−メチルピロリジン（３．０ｇ）にｔｅｒｔ-ブチル ４−アミノピペリジン−１−カルボキシラート（２０．０ｇ）を加え、１４０℃にて４日間撹拌した。反応混合物に酢酸エチル（２０ｍＬ）を加えて撹拌し、不溶物を濾過後、濾液を減圧下濃縮した。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＝４：１）及びシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム：メタノール＝２４：１）にて精製して赤褐色油状の表題化合物（１．９ｇ、４１％）を得た。
（３）Ｔｅｒｔ−ブチル ４−［（２−アミノ−４−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝フェニル）アミノ］ピペリジン−１−カルボキシラートの製造

Example 2 (2R) -1- [3- (4-Chloro-3-nitrophenoxy) propyl] -2-methylpyrrolidine (3.0 g) prepared in (1) was added to tert-butyl 4-aminopiperidine- 1-Carboxylate (20.0 g) was added and stirred at 140 ° C. for 4 days. Ethyl acetate (20 mL) was added to the reaction mixture and stirred, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH type silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1) and silica gel column chromatography (developing solvent: chloroform: methanol = 24: 1) to obtain a reddish brown oil. Of the title compound (1.9 g, 41%).
(3) Preparation of Tert-butyl 4-[(2-amino-4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) amino] piperidine-1-carboxylate

実施例３−（２）で製造したｔｅｒｔ−ブチル ４−［（４−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−２−ニトロフェニル）アミノ］ピペリジン−１−カルボキシラート（０．７ｇ）のエタノール（３０ｍＬ）溶液にパラジウム炭素（０．７ｇ）を加え、水素雰囲気下室温にて２４時間撹拌した。反応混合物をセライト濾過し、濾液を減圧濃縮して赤褐色非晶質の表題化合物（０．５０ｇ、７６％）を得た。
（４）Ｔｅｒｔ−ブチル ４−（５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−ベンゾイミダゾール−１−イル）ピペリジン−１−カルボキシラート（化合物番号３）の製造

Tert-Butyl 4-[(4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -2-nitrophenyl) amino] piperidine-1- prepared in Example 3- (2) To a solution of carboxylate (0.7 g) in ethanol (30 mL) was added palladium carbon (0.7 g), and the mixture was stirred at room temperature for 24 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a reddish brown amorphous title compound (0.50 g, 76%).
(4) Tert-butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-benzimidazol-1-yl) piperidine-1-carboxylate (Compound No. 3) )Manufacturing of

実施例３−（３）で製造したｔｅｒｔ−ブチル ４−［（２−アミノ−４−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝フェニル）アミノ］ピペリジン−１−カルボキシラート（０．１ｇ）のトルエン（０．２ｍＬ）溶液にＮ，Ｎ‐ジメチルホルムアミドジメチルアセタール（０．１６ｍＬ）を加え、１００℃にて２日間撹拌した。反応混合物を減圧下濃縮し、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）にて精製して褐色油状の表題化合物（０．０２７ｇ、２６％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J=6.0 Hz, 3 H) 1.40 - 1.46 (m, 1 H) 1.49 (s, 9 H) 1.54 - 2.45 (m, 12 H) 2.86 - 2.96 (m, 2 H) 2.98 - 3.06 (m, 1 H) 3.16 - 3.24 (m, 1 H) 4.02 - 4.11 (m, 2 H) 4.22 - 4.45 (m, 3 H) 6.94 (dd, J=9.2, 2.3 Hz, 1 H) 7.24 - 7.29 (m, 2 H) 7.89 (s, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 443(M+H)⁺

Tert-Butyl 4-[(2-amino-4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) amino] piperidine-1- prepared in Example 3- (3) N, N-dimethylformamide dimethylacetal (0.16 mL) was added to a toluene (0.2 mL) solution of carboxylate (0.1 g), and the mixture was stirred at 100 ° C. for 2 days. The reaction mixture was concentrated under reduced pressure and purified by NH silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1) to give the title compound (0.027 g, 26%) as a brown oil. .
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J = 6.0 Hz, 3 H) 1.40-1.46 (m, 1 H) 1.49 (s, 9 H) 1.54-2.45 (m, 12 H) 2.86-2.96 (m, 2 H) 2.98-3.06 (m, 1 H) 3.16-3.24 (m, 1 H) 4.02-4.11 (m, 2 H) 4.22-4.45 (m, 3 H) 6.94 (dd, J = 9.2, 2.3 Hz, 1 H) 7.24-7.29 (m, 2 H) 7.89 (s, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 443 (M + H) ⁺

Example 4
4-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-benzimidazol-1-yl) piperidin-1-yl] carbonyl} benzonitrile (compound Production of number 4) (1) Production of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-benzimidazole

実施例３−（３）で製造したｔｅｒｔ−ブチル ４−［（２−アミノ−４−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝フェニル）アミノ］ピペリジン−１−カルボキシラート（０．４ｇ）にギ酸（２ｍＬ）を加え、１３０℃にて４時間撹拌した。反応混合物に氷浴下６Ｍ水酸化ナトリウム水溶液を加え、ｐＨを１０とし、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。得られた残渣のエタノール（２ｍＬ）溶液に、６Ｍ水酸化ナトリウム水溶液（０．２ｍＬ）を加え、１００℃にて１時間撹拌した。反応混合物に飽和食塩水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮して褐色油状の表題化合物（０．０９４ｇ、７４％）を得た。
（２）４−｛［４−（５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−ベンゾイミダゾール−１−イル）ピペリジン−１−イル］カルボニル｝ベンゾニトリル（化合物番号４）の製造

Tert-Butyl 4-[(2-amino-4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) amino] piperidine-1- prepared in Example 3- (3) Formic acid (2 mL) was added to carboxylate (0.4 g), and the mixture was stirred at 130 ° C. for 4 hours. To the reaction mixture was added 6M aqueous sodium hydroxide solution in an ice bath to adjust the pH to 10, 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. To a solution of the obtained residue in ethanol (2 mL) was added 6M aqueous sodium hydroxide solution (0.2 mL), and the mixture was stirred at 100 ° C. for 1 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.094 g, 74%) as a brown oil.
(2) 4-{[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-benzimidazol-1-yl) piperidin-1-yl] carbonyl} benzo Production of nitrile (compound no. 4)

４−シアノ安息香酸（０．１７ｇ）のクロロホルム溶液（１．０ｍＬ）に１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（０．２３ｇ）及び１−ヒドロキシベンゾトリアゾール一水和物（０．１６ｇ）を加え、室温にて３０分間撹拌した。反応混合物に実施例４−（１）で製造した５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１−（ピペリジン−４−イル）−１Ｈ−ベンゾイミダゾール（０．２５ｇ）のクロロホルム（０．５ｍＬ）溶液を滴下して加え、室温にて２４時間撹拌した。反応混合物を減圧下濃縮し、ＮＨ型シリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム〜クロロホルム：メタノール＝９７：３）にて精製して黄色非晶質の表題化合物（化合物番号４）（０．２１ｇ、６１％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.0 Hz, 3 H) 1.38 - 1.47 (m, 1 H) 1.65 - 2.37 (m, 12 H) 2.97 - 3.05 (m, 2 H) 3.17 - 3.22 (m, 1 H) 3.22 - 3.37 (m, 1 H) 3.79 - 3.92 (m, 1 H) 4.04 - 4.11 (m, 2 H) 4.40 - 4.46 (m, 1 H) 4.86 - 5.04 (m, 1 H) 6.97 (dd, J=9.2, 2.3 Hz, 1 H) 7.27 - 7.30 (m, 2 H) 7.57 (d, J=8.7 Hz, 2 H) 7.75 (d, J=8.7 Hz, 2 H) 7.90 (s, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 472(M+H)⁺

1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g) and 1-hydroxybenzotriazole monohydrate in chloroform solution (1.0 mL) of 4-cyanobenzoic acid (0.17 g) (0.16 g) was added and stirred at room temperature for 30 minutes. To the reaction mixture, 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-benzimidazole prepared in Example 4- (1) ( 0.25 g) in chloroform (0.5 mL) was added dropwise and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and purified by NH type silica gel column chromatography (developing solvent: chloroform to chloroform: methanol = 97: 3) to give a yellow amorphous title compound (Compound No. 4) (0.21 g, 61%).
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J = 6.0 Hz, 3 H) 1.38-1.47 (m, 1 H) 1.65-2.37 (m, 12 H) 2.97-3.05 (m, 2 H) 3.17-3.22 (m, 1 H) 3.22-3.37 (m, 1 H) 3.79-3.92 (m, 1 H) 4.04-4.11 (m, 2 H) 4.40-4.46 (m, 1 H) 4.86-5.04 (m, 1 H) 6.97 (dd, J = 9.2, 2.3 Hz, 1 H) 7.27-7.30 (m, 2 H) 7.57 (d, J = 8.7 Hz, 2 H) 7.75 (d, J = 8.7 Hz, 2 H) 7.90 (s, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 472 (M + H) ⁺

(Example 5)
[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-benzimidazol-1-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4- Yl) methanone (Compound No. 5)

実施例４−（２）と同様の方法により、４−シアノ安息香酸の代わりにテトラヒドロ−２Ｈ−ピラン−４−カルボン酸（０．０１７ｇ）を用いて、褐色非晶質の表題化合物（化合物番号５）（０．０１７ｇ、４７％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.0 Hz, 3 H) 1.37 - 1.47 (m, 1 H) 1.61 - 2.07 (m, 12 H) 2.09 - 2.16 (m, 1 H) 2.21 - 2.34 (m, 4 H) 2.70 - 2.83 (m, 2 H) 2.97 - 3.03 (m, 1 H) 3.15 - 3.21 (m, 1 H) 3.22 - 3.31 (m, 1 H) 3.43 - 3.50 (m, 2 H) 4.01 - 4.11 (m, 3 H) 4.11 - 4.19 (m, 1 H) 4.34 - 4.42 (m, 1 H) 4.87 - 4.95 (m, 1 H) 6.96 (dd, J=8.7, 2.3 Hz, 1 H) 7.26 (d, J=8.7 Hz, 1 H) 7.28 (d, J=2.3 Hz, 1 H) 7.88 (s, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 455(M+H)⁺

Using a method similar to that in Example 4- (2), substituting tetrahydro-2H-pyran-4-carboxylic acid (0.017 g) for 4-cyanobenzoic acid, the title compound (compound number) 5) (0.017 g, 47%) was obtained.
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J = 6.0 Hz, 3 H) 1.37-1.47 (m, 1 H) 1.61-2.07 (m, 12 H) 2.09-2.16 (m, 1 H) 2.21-2.34 (m, 4 H) 2.70-2.83 (m, 2 H) 2.97-3.03 (m, 1 H) 3.15-3.21 (m, 1 H) 3.22-3.31 (m, 1 H) 3.43-3.50 (m, 2 H) 4.01-4.11 (m, 3 H) 4.11-4.19 (m, 1 H) 4.34-4.42 (m, 1 H) 4.87-4.95 (m, 1 H) 6.96 (dd, J = 8.7, 2.3 Hz, 1 H) 7.26 (d, J = 8.7 Hz, 1 H) 7.28 (d, J = 2.3 Hz, 1 H) 7.88 (s, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 455 (M + H) ⁺

(Example 6)
[4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-benzimidazol-1-yl) piperidin-1-yl] (pyrrolidin-1-yl) methanone ( Production of Compound No. 6)

実施例２−（２）と同様の方法により、５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１−（ピペリジン−４−イル）−１Ｈ−インダゾールの代わりに実施例４−（１）で製造した５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１−（ピペリジン−４−イル）−１Ｈ−ベンゾイミダゾール（０．０２９ｇ）を、４−フルオロベンゾイルクロリドの代わりにピロリジン−１−カルボニルクロリド（０．０１５ｇ）をそれぞれ用いて、黄色非晶質の表題化合物（化合物番号６）（０．００５ｇ、１４％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.53 (d, J=5.5 Hz, 3 H) 1.83 - 1.89 (m, 4 H) 1.90 - 2.34 (m, 12 H) 2.47 - 2.55 (m, 1 H) 2.92 - 2.99 (m, 2 H) 3.28 - 3.33 (m, 1 H) 3.37 - 3.44 (m, 5 H) 3.95 - 4.00 (m, 2 H) 4.07 - 4.12 (m, 1 H) 4.12 - 4.17 (m, 1 H) 4.28 - 4.35 (m, 1 H) 6.92 (dd, J=8.7, 2.3 Hz, 1 H) 7.25 (d, J=2.3 Hz, 1 H) 7.31 (d, J=8.7 Hz, 1 H) 7.94 (s, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 440(M+H)⁺

In the same manner as in Example 2- (2), instead of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-indazole 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-benzimidazole (0. 029 g), respectively, using pyrrolidine-1-carbonyl chloride (0.015 g) instead of 4-fluorobenzoyl chloride to give the yellow amorphous title compound (Compound No. 6) (0.005 g, 14%). It was.
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.53 (d, J = 5.5 Hz, 3 H) 1.83-1.89 (m, 4 H) 1.90-2.34 (m, 12 H) 2.47-2.55 (m, 1 H) 2.92-2.99 (m, 2 H) 3.28-3.33 (m, 1 H) 3.37-3.44 (m, 5 H) 3.95-4.00 (m, 2 H) 4.07-4.12 (m, 1 H) 4.12-4.17 (m, 1 H) 4.28-4.35 (m, 1 H) 6.92 (dd, J = 8.7, 2.3 Hz, 1 H) 7.25 (d, J = 2.3 Hz, 1 H) 7.31 (d, J = 8.7 Hz, 1 H) 7.94 (s, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 440 (M + H) ⁺

(Example 7)
Preparation of 1- (1-methylpiperidin-4-yl) -5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-benzimidazole (Compound No. 7)

実施例４−（１）で製造した５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１−（ピペリジン−４−イル）−１Ｈ−ベンゾイミダゾール（０．０９５ｇ）と水（０．０５ｍＬ）の二層系混合液に氷浴下ギ酸（０．０７６ｍＬ）及びホルマリン（３７％水溶液、０．０５７ｍＬ）を加え、１１０℃にて４時間撹拌した。反応混合物に氷浴下６Ｍ水酸化ナトリウム水溶液を加え、ｐＨを１０とし、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：酢酸エチル：メタノール＝９９：１）にて精製して褐色非晶質の表題化合物（化合物番号７）（０．０６０ｇ、６１％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.0 Hz, 3 H) 1.37 - 1.47 (m, 1 H) 1.65 - 1.74 (m, 2 H) 1.74 - 1.80 (m, 1 H) 1.87 - 1.95 (m, 1 H) 1.96 - 2.08 (m, 2 H) 2.09 - 2.20 (m, 6 H) 2.20 - 2.26 (m, 1 H) 2.27 - 2.33 (m, 1 H) 2.37 (s, 3 H) 2.97 - 3.03 (m, 1 H) 3.03 - 3.08 (m, 2 H) 3.16 - 3.22 (m, 1 H) 4.03 - 4.11 (m, 2 H) 4.11 - 4.18 (m, 1 H) 6.94 (dd, J=8.7, 2.3 Hz, 1 H) 7.28 (d, J=2.3 Hz, 1 H) 7.30 (d, J=8.7 Hz, 1 H) 7.92 (s, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 357(M+H)⁺

5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-benzimidazole (0.095 g) prepared in Example 4- (1) ) And water (0.05 mL) were added formic acid (0.076 mL) and formalin (37% aqueous solution, 0.057 mL) in an ice bath and stirred at 110 ° C. for 4 hours. To the reaction mixture was added 6M aqueous sodium hydroxide solution in an ice bath to adjust the pH to 10, 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: ethyl acetate: methanol = 99: 1) to give a brown amorphous title compound (Compound No. 7) (0.060 g, 61%). Obtained.
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J = 6.0 Hz, 3 H) 1.37-1.47 (m, 1 H) 1.65-1.74 (m, 2 H) 1.74-1.80 (m, 1 H) 1.87-1.95 (m, 1 H) 1.96-2.08 (m, 2 H) 2.09-2.20 (m, 6 H) 2.20-2.26 (m, 1 H) 2.27-2.33 (m, 1 H) 2.37 (s , 3 H) 2.97-3.03 (m, 1 H) 3.03-3.08 (m, 2 H) 3.16-3.22 (m, 1 H) 4.03-4.11 (m, 2 H) 4.11-4.18 (m, 1 H) 6.94 (dd, J = 8.7, 2.3 Hz, 1 H) 7.28 (d, J = 2.3 Hz, 1 H) 7.30 (d, J = 8.7 Hz, 1 H) 7.92 (s, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 357 (M + H) ⁺

(Example 8)
Tert-butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo [2,3-b] pyridin-1-yl) piperidine-1-carboxylate Preparation of (Compound No. 8) (1) Preparation of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo [2,3-b] pyridine

実施例１−（２）と同様の方法により、１Ｈ−インダゾール−５−オールの代わりに５−ヒドロキシ−７−アザインドール（２．０ｇ）を用いて、褐色非晶質の表題化合物（２．３５ｇ、６１％）を得た。
（２）ｔｅｒｔ−ブチル ４−（５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−ピロロ［２，３−ｂ］ピリジン−１−イル）ピペリジン−１−カルボキシラート（化合物番号８）の製造

In the same manner as in Example 1- (2), 5-hydroxy-7-azaindole (2.0 g) was used instead of 1H-indazol-5-ol, and the title compound (2. 35 g, 61%).
(2) tert-butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo [2,3-b] pyridin-1-yl) piperidine-1 -Preparation of carboxylate (Compound No. 8)

実施例１−（３）と同様の方法により、５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−インダゾールの代わりに実施例８−（１）で製造した５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−ピロロ［２，３−ｂ］ピリジンを用いて、褐色非晶質の表題化合物（化合物番号８）（０．４４ｇ、２６％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.0 Hz, 3 H) 1.35 - 1.45 (m, 1 H) 1.49 (s, 9 H) 1.65 - 1.73 (m, 1 H) 1.73 - 1.82 (m, 1 H) 1.82 - 1.96 (m, 3 H) 1.97 - 2.09 (m, 4 H) 2.09 - 2.16 (m, 1 H) 2.18 - 2.26 (m, 1 H) 2.27 - 2.35 (m, 1 H) 2.90 - 2.99 (m, 2 H) 2.98 - 3.06 (m, 1 H) 3.14 - 3.24 (m, 1 H) 4.02 - 4.13 (m, 2 H) 4.19 - 4.42 (m, 2 H) 4.85 - 4.92 (m, 1 H) 6.39 (d, J=3.2 Hz, 1 H) 7.23 (d, J=3.2 Hz, 1 H) 7.43 (d, J=2.8 Hz, 1 H) 8.08 (d, J=2.8 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 443(M+H)⁺

Prepared in Example 8- (1) by the same method as in Example 1- (3), instead of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indazole. 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo [2,3-b] pyridine was used to give a brown amorphous title compound (Compound No. 8) (0.44 g, 26%) was obtained.
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J = 6.0 Hz, 3 H) 1.35-1.45 (m, 1 H) 1.49 (s, 9 H) 1.65-1.73 (m, 1 H) 1.73-1.82 (m, 1 H) 1.82-1.96 (m, 3 H) 1.97-2.09 (m, 4 H) 2.09-2.16 (m, 1 H) 2.18-2.26 (m, 1 H) 2.27-2.35 (m , 1 H) 2.90-2.99 (m, 2 H) 2.98-3.06 (m, 1 H) 3.14-3.24 (m, 1 H) 4.02-4.13 (m, 2 H) 4.19-4.42 (m, 2 H) 4.85 -4.92 (m, 1 H) 6.39 (d, J = 3.2 Hz, 1 H) 7.23 (d, J = 3.2 Hz, 1 H) 7.43 (d, J = 2.8 Hz, 1 H) 8.08 (d, J = (2.8 Hz, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 443 (M + H) ⁺

Example 9
(4-Fluorophenyl) [4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo [2,3-b] pyridin-1-yl) piperidine- Preparation of 1-yl] methanone (Compound No. 9) (1) 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-pyrrolo Production of [2,3-b] pyridine

実施例２−（１）と同様の方法により、ｔｅｒｔ−ブチル ４−（５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−インダゾール−１−イル)ピペリジン−１−カルボキシラートの代わりに実施例８−（２）で製造したｔｅｒｔ−ブチル ４−（５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−ピロロ［２，３−ｂ］ピリジン−１−イル）ピペリジン−１−カルボキシラート（０．４４ｇ）を用いて、褐色非晶質の表題化合物（０．２６ｇ、７６％）を得た。
（２）（４−フルオロフェニル）［４−（５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−ピロロ［２，３−ｂ］ピリジン−１−イル）ピペリジン−１−イル］メタノン（化合物番号９）の製造

In the same manner as in Example 2- (1), tert-butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indazol-1-yl) piperidine Tert-Butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo prepared in Example 8- (2) instead of -1-carboxylate [ 2,3-b] pyridin-1-yl) piperidine-1-carboxylate (0.44 g) was used to give the brown amorphous title compound (0.26 g, 76%).
(2) (4-Fluorophenyl) [4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo [2,3-b] pyridin-1-yl ) Piperidin-1-yl] methanone (Compound No. 9)

実施例２−（２）と同様の方法により、５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１−（ピペリジン−４−イル）−１Ｈ−インダゾールの代わりに実施例９−（１）で製造した５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１−（ピペリジン−４−イル）−１Ｈ−ピロロ［２，３−ｂ］ピリジン（０．０８ｇ）を用いて、褐色非晶質の表題化合物（０．０４ｇ、３７％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.0 Hz, 3 H) 1.37 - 1.46 (m, 1 H) 1.65 - 1.73 (m, 1 H) 1.74 - 1.83 (m, 1 H) 1.87 - 2.36 (m, 14 H) 2.96 - 3.05 (m, 1 H) 3.14 - 3.23 (m, 1 H) 4.04 - 4.13 (m, 2 H) 4.94 - 5.05 (m, 1 H) 6.40 (d, J=3.7 Hz, 1 H) 7.08 - 7.15 (m, 2 H) 7.24 (d, J=3.7 Hz, 1 H) 7.43 (d, J=2.8 Hz, 1 H) 7.45 - 7.51 (m, 2 H) 8.08 (d, J=2.8 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 465(M+H)⁺

In the same manner as in Example 2- (2), instead of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-indazole 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-pyrrolo [2,3] prepared in Example 9- (1). -B] Brown amorphous title compound (0.04 g, 37%) was obtained using pyridine (0.08 g).
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J = 6.0 Hz, 3 H) 1.37-1.46 (m, 1 H) 1.65-1.73 (m, 1 H) 1.74-1.83 (m, 1 H) 1.87-2.36 (m, 14 H) 2.96-3.05 (m, 1 H) 3.14-3.23 (m, 1 H) 4.04-4.13 (m, 2 H) 4.94-5.05 (m, 1 H) 6.40 (d , J = 3.7 Hz, 1 H) 7.08-7.15 (m, 2 H) 7.24 (d, J = 3.7 Hz, 1 H) 7.43 (d, J = 2.8 Hz, 1 H) 7.45-7.51 (m, 2 H ) 8.08 (d, J = 2.8 Hz, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 465 (M + H) ⁺

(Example 10)
Tert-butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo [3,2-b] pyridin-1-yl) piperidine-1-carboxylate Production of (Compound No. 10) (1) Production of 2- (3-chloropropoxy) -5-nitropyridine

２−クロロ−５−ニトロピリジン（５．００ｇ）及び３−クロロプロパノール（４．５０ｇ）のＮ，Ｎ−ジメチルホルムアミド（１００ｍＬ）溶液に、−１０℃にてカリウム ｔｅｒｔ−ブトキシド（３．９０ｇ）を加え、室温にて一晩撹拌した。反応混合物に氷水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、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＝９：１〜７：３）にて精製して黄色油状の表題化合物（５．９０ｇ，８６％）を得た。
（２）２−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−５−ニトロピリジンの製造

To a solution of 2-chloro-5-nitropyridine (5.00 g) and 3-chloropropanol (4.50 g) in N, N-dimethylformamide (100 mL) at −10 ° C. potassium tert-butoxide (3.90 g) And stirred at room temperature overnight. Ice 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 anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 9: 1-7: 3) to give the title compound (5.90 g, 86%) as a yellow oil.
(2) Preparation of 2- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -5-nitropyridine

実施例１０―（１）で製造した２−（３−クロロプロポキシ）−５−ニトロピリジン（５．００ｇ）のアセトニトリル（５０ｍＬ）溶液に、炭酸カリウム（６．４０ｇ）、ヨウ化ナトリウム（１．７０ｇ）、（Ｒ）−２−メチルピロリジン（３．００ｇ）を順次加え、９０℃にて８時間撹拌した。反応混合物を室温まで放冷し、濾過後濾液を減圧下濃縮した。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＝４：１）及びシリカゲルカラムクロマトグラフィー（展開溶媒：クロロホルム：メタノール＝９：１）にて精製して、茶色油状の表題化合物（４．４０ｇ，７１％）を得た。
（３）（６−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−３−ニトロピリジン−２−イル）アセトニトリルの製造

To a solution of 2- (3-chloropropoxy) -5-nitropyridine (5.00 g) prepared in Example 10- (1) in acetonitrile (50 mL), potassium carbonate (6.40 g) and sodium iodide (1. 70 g) and (R) -2-methylpyrrolidine (3.00 g) were sequentially added, and the mixture was stirred at 90 ° C. for 8 hours. The reaction mixture was allowed to cool to room temperature, and after filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH type silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1) and silica gel column chromatography (developing solvent: chloroform: methanol = 9: 1), and brown. The title compound (4.40 g, 71%) was obtained as an oil.
(3) Preparation of (6- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -3-nitropyridin-2-yl) acetonitrile

カリウム ｔｅｒｔ−ブトキシド（３．７０ｇ）のテトラヒドロフラン（３０ｍＬ）溶液に、実施例１０―（２）で製造した２−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−５−ニトロピリジン（４．００ｇ）及び４−クロロフェノキシアセトニトリル（３．８０ｇ）のテトラヒドロフラン（５０ｍＬ）溶液を−１０℃にて滴下して加え、同温下４時間撹拌した。反応混合物に水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥して減圧下濃縮し、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：クロロホルム）にて精製して赤色油状の表題化合物（１．９０ｇ，４１％）を得た。
（４）５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−ピロロ［３，２−ｂ］ピリジンの製造

2- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -5 prepared in Example 10- (2) was added to a solution of potassium tert-butoxide (3.70 g) in tetrahydrofuran (30 mL). A solution of -nitropyridine (4.00 g) and 4-chlorophenoxyacetonitrile (3.80 g) in tetrahydrofuran (50 mL) was added dropwise at -10 ° C, and the mixture was stirred at the same temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (developing solvent: chloroform) to give the title compound (1.90 g, 41%) as a red oil. Got.
(4) Preparation of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo [3,2-b] pyridine

実施例１０―（３）で製造した（６−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−３−ニトロピリジン−２−イル）アセトニトリル（１．１０ｇ）、パラジウム−炭素（１０％）（０．２０ｇ）及び酢酸（１０ｍＬ）をエタノール（３０ｍＬ）に加えて懸濁液とし、水素雰囲気下室温にて一晩撹拌した。反応混合物を濾過して濾液を減圧下濃縮した。得られた残渣に水及び飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮して無色油状の表題化合物（０．４８ｇ，４６％）を得た。
（５）ｔｅｒｔ−ブチル ４−（５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−ピロロ［３，２−ｂ］ピリジン−１−イル）ピペリジン−１−カルボキシラート（化合物番号１０）の製造

(6- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -3-nitropyridin-2-yl) acetonitrile (1.10 g), palladium prepared in Example 10- (3) -Carbon (10%) (0.20 g) and acetic acid (10 mL) were added to ethanol (30 mL) to form a suspension and stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water and saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.48 g, 46%) as a colorless oil.
(5) tert-butyl 4- (5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo [3,2-b] pyridin-1-yl) piperidine-1 -Preparation of carboxylate (Compound No. 10)

実施例１−（３）と同様の方法により、５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−インダゾールの代わりに実施例１０−（４）で製造した５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１Ｈ−ピロロ［３，２−ｂ］ピリジン（０．２５ｇ）を用いて、無色固体の表題化合物（化合物番号１０）（０．１１ｇ，２５％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J=5.5 Hz, 3 H), 1.46 - 1.51 (m, 10 H), 1.53 - 2.39 (m, 12 H), 2.80 - 3.06 (m, 3 H), 3.21 (br. s., 1 H), 4.21 - 4.45 (m, 5 H), 6.54 (d, J=3.2 Hz, 1 H), 6.60 (d, J=8.7 Hz, 1 H), 7.25 - 7.26 (m, 1 H), 7.57 (d, J=9.2 Hz, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 443(M+H)⁺

Prepared in the same manner as in Example 1- (3) but in Example 10- (4) instead of 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-indazole. 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1H-pyrrolo [3,2-b] pyridine (0.25 g) was used to give the title compound (compound No. 10) (0.11 g, 25%) was obtained.
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 5.5 Hz, 3 H), 1.46-1.51 (m, 10 H), 1.53-2.39 (m, 12 H), 2.80-3.06 ( m, 3 H), 3.21 (br. s., 1 H), 4.21-4.45 (m, 5 H), 6.54 (d, J = 3.2 Hz, 1 H), 6.60 (d, J = 8.7 Hz, 1 H), 7.25-7.26 (m, 1 H), 7.57 (d, J = 9.2 Hz, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 443 (M + H) ⁺

(Example 11)
Preparation of (4- {5-[(1-cyclobutylpiperidin-4-yl) oxy] -1H-benzimidazol-1-yl} piperidin-1-yl) (4-fluorophenyl) methanone (Compound No. 11) (1) Production of tert-butyl 4- (4-chloro-3-nitrophenoxy) piperidine-1-carboxylate

４−クロロ−３−ニトロフェノール（２５．０ｇ）、Ｎ，Ｎ−ジメチルホルムアミド（５００ｍＬ）及び炭酸セシウム（９４．０ｇ）の懸濁液にｔｅｒｔ−ブチル ４−［（メチルスルホニル）オキシ］ピペリジン−１−カルボキシラート（６０．０ｇ）を加え、１００℃にて１０時間撹拌した。反応混合物を室温まで放冷し、ｔｅｒｔ−ブチル ４−［（メチルスルホニル）オキシ］ピペリジン−１−カルボキシラート（３０．０ｇ）を加えて１００℃にて１０時間撹拌した。反応混合物を室温まで放冷し、不溶物を濾過して濾液を減圧下濃縮した。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＝４：１〜１：１）、にて精製して褐色油状の表題化合物（２７．６ｇ、５４％）を得た。
（２）４−（４−クロロ−３−ニトロフェノキシ）ピペリジン塩酸塩の製造

To a suspension of 4-chloro-3-nitrophenol (25.0 g), N, N-dimethylformamide (500 mL) and cesium carbonate (94.0 g), tert-butyl 4-[(methylsulfonyl) oxy] piperidine- 1-carboxylate (60.0 g) was added and stirred at 100 ° C. for 10 hours. The reaction mixture was allowed to cool to room temperature, tert-butyl 4-[(methylsulfonyl) oxy] piperidine-1-carboxylate (30.0 g) was added, and the mixture was stirred at 100 ° C. for 10 hr. The reaction mixture was allowed to cool to room temperature, insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-type silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1 to 1: 1) to give the title compound (27.6 g, 54%) as a brown oil. Obtained.
(2) Production of 4- (4-chloro-3-nitrophenoxy) piperidine hydrochloride

実施例１１−（１）で製造したｔｅｒｔ−ブチル ４−（４−クロロ−３−ニトロフェノキシ）ピペリジン−１−カルボキシラート（２７．６ｇ）の酢酸エチル（１００ｍＬ）溶液に、氷浴下４Ｍ塩酸−酢酸エチル溶液（１００ｍＬ）を滴下して加えた。反応混合物を室温にて１時間撹拌し、生成した結晶を濾過し乾燥して白色結晶の表題化合物（１０．６ｇ、４７％）を得た。
（３）４−（４−クロロ−３−ニトロフェノキシ）−１−シクロブチルピペリジンの製造

To a solution of tert-butyl 4- (4-chloro-3-nitrophenoxy) piperidine-1-carboxylate (27.6 g) prepared in Example 11- (1) in ethyl acetate (100 mL) was added 4M hydrochloric acid in an ice bath. -An ethyl acetate solution (100 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, and the resulting crystals were filtered and dried to give the title compound (10.6 g, 47%) as white crystals.
(3) Production of 4- (4-chloro-3-nitrophenoxy) -1-cyclobutylpiperidine

実施例１１−（２）で製造した４−（４−クロロ−３−ニトロフェノキシ）ピペリジン塩酸塩（１０．６ｇ）のクロロホルム（３５ｍＬ）溶液にトリエチルアミン（２．５ｍＬ）を加え、１０分間撹拌した。反応混合物にシクロブタノン（２．５４ｇ）及び酢酸（２ｍＬ）を加え、室温にて３０分間撹拌した後、ナトリウムトリアセトキシボロヒドリド（１０．８ｇ）を加え、室温にて２時間撹拌した。反応混合物に氷浴下６Ｍ水酸化ナトリウム水溶液を加え、ｐＨを９とし、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＝４：１〜１：１）にて精製して白色結晶の表題化合物（１０．２ｇ、９１％）を得た。
（４）ｔｅｒｔ−ブチル ４−（｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］−２−ニトロフェニル｝アミノ）ピペリジン−１−カルボキシラートの製造

Triethylamine (2.5 mL) was added to a solution of 4- (4-chloro-3-nitrophenoxy) piperidine hydrochloride (10.6 g) prepared in Example 11- (2) in chloroform (35 mL) and stirred for 10 minutes. . Cyclobutanone (2.54 g) and acetic acid (2 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (10.8 g) was added, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 6M aqueous sodium hydroxide solution in an ice bath 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 NH-type silica gel column chromatography (developing solvent: n-hexane: ethyl acetate = 4: 1 to 1: 1) to obtain the title compound (10.2 g, 91%) as white crystals. It was.
(4) Preparation of tert-butyl 4-({4-[(1-cyclobutylpiperidin-4-yl) oxy] -2-nitrophenyl} amino) piperidine-1-carboxylate

実施例３−（２）と同様の方法により、（２Ｒ）−１−［３−（４−クロロ−３−ニトロフェノキシ）プロピル］−２−メチルピロリジンの代わりに実施例１１−（３）で製造した４−（４−クロロ−３−ニトロフェノキシ）−１−シクロブチルピペリジン（２．５０ｇ）を用いて、赤褐色油状の表題化合物（０．６ｇ、１６％）を得た。
（５）ｔｅｒｔ−ブチル ４−（｛２−アミノ−４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝アミノ）ピペリジン−１−カルボキシラートの製造

In the same manner as in Example 3- (2), instead of (2R) -1- [3- (4-chloro-3-nitrophenoxy) propyl] -2-methylpyrrolidine, Example 11- (3) Using the prepared 4- (4-chloro-3-nitrophenoxy) -1-cyclobutylpiperidine (2.50 g), the title compound (0.6 g, 16%) as a reddish brown oil was obtained.
(5) Preparation of tert-butyl 4-({2-amino-4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} amino) piperidine-1-carboxylate

実施例３−（３）と同様の方法により、ｔｅｒｔ−ブチル ４−［（４−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−２−ニトロフェニル）アミノ］ピペリジン−１−カルボキシラートの代わりに実施例１１−（４）で製造したｔｅｒｔ−ブチル ４−（｛４−［（１−シクロブチルピペリジン−４−イル）オキシ］−２−ニトロフェニル｝アミノ）ピペリジン−１−カルボキシラート（０．４ｇ）を用いて、褐色非晶質の表題化合物（０．１１ｇ、２９％）を得た。
（６）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−ベンゾイミダゾールの製造

In the same manner as in Example 3- (3), tert-butyl 4-[(4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -2-nitrophenyl) amino] piperidine Tert-Butyl 4-({4-[(1-cyclobutylpiperidin-4-yl) oxy] -2-nitrophenyl} amino) piperidine prepared in Example 11- (4) instead of -1-carboxylate The brown amorphous title compound (0.11 g, 29%) was obtained using -1-carboxylate (0.4 g).
(6) Preparation of 5-[(1-cyclobutylpiperidin-4-yl) oxy] -1- (piperidin-4-yl) -1H-benzimidazole

実施例４−（１）と同様の方法により、ｔｅｒｔ−ブチル ４−［（２−アミノ−４−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝フェニル）アミノ］ピペリジン−１−カルボキシラートの代わりに実施例１１−（５）で製造したｔｅｒｔ−ブチル ４−（｛２−アミノ−４−［（１−シクロブチルピペリジン−４−イル）オキシ］フェニル｝アミノ）ピペリジン−１−カルボキシラート（０．１１ｇ）を用いて、褐色非晶質の表題化合物（０．０６３ｇ、７４％）を得た。
（７）（４−｛５−［（１−シクロブチルピペリジン−４−イル）オキシ］−１Ｈ−ベンゾイミダゾール−１−イル｝ピペリジン−１−イル）（４−フルオロフェニル）メタノン（化合物番号１１）の製造

In a manner similar to that in Example 4- (1), tert-butyl 4-[(2-amino-4- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} phenyl) amino] piperidine Tert-Butyl 4-({2-amino-4-[(1-cyclobutylpiperidin-4-yl) oxy] phenyl} amino) piperidine prepared in Example 11- (5) instead of -1-carboxylate The brown amorphous title compound (0.063 g, 74%) was obtained using -1-carboxylate (0.11 g).
(7) (4- {5-[(1-Cyclobutylpiperidin-4-yl) oxy] -1H-benzimidazol-1-yl} piperidin-1-yl) (4-fluorophenyl) methanone (Compound No. 11) )Manufacturing of

実施例４−（２）と同様の方法により、５−｛３−［（２Ｒ）−２−メチルピロリジン−１−イル］プロポキシ｝−１−（ピペリジン−４−イル）−１Ｈ−ベンゾイミダゾールの代わりに実施例１１−（６）で製造した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−ベンゾイミダゾール（０．０５ｇ）を用いて、褐色非晶質の表題化合物（化合物番号１１）（０．０４５ｇ、６７％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.59 - 1.80 (m, 2 H) 1.85 - 2.42 (m, 14 H) 2.65 - 2.77 (m, 2 H) 2.79 - 2.90 (m, 1 H) 2.93 - 3.41 (m, 2 H) 3.76 - 4.28 (m, 1 H) 4.30 - 4.49 (m, 2 H) 4.59 - 5.45 (m, 1 H) 6.96 (dd, J=2.3, 8.7 Hz, 1 H) 7.11 - 7.16 (m, 2 H) 7.29 (d, J=8.7 Hz, 1 H) 7.31 (d, J=2.3 Hz, 1 H) 7.45 - 7.51 (m, 2 H) 7.93 (s, 1 H)
MS (ESI/APCI Dual) (Positive) m/z; 477(M+H)⁺

In the same manner as in Example 4- (2), 5- {3-[(2R) -2-methylpyrrolidin-1-yl] propoxy} -1- (piperidin-4-yl) -1H-benzimidazole was synthesized. Instead, 5-[(1-cyclobutylpiperidin-4-yl) oxy] -1- (piperidin-4-yl) -1H-benzimidazole (0.05 g) prepared in Example 11- (6) was used. To obtain the brown amorphous title compound (Compound No. 11) (0.045 g, 67%).
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.59-1.80 (m, 2 H) 1.85-2.42 (m, 14 H) 2.65-2.77 (m, 2 H) 2.79-2.90 (m, 1 H) 2.93 -3.41 (m, 2 H) 3.76-4.28 (m, 1 H) 4.30-4.49 (m, 2 H) 4.59-5.45 (m, 1 H) 6.96 (dd, J = 2.3, 8.7 Hz, 1 H) 7.11 -7.16 (m, 2 H) 7.29 (d, J = 8.7 Hz, 1 H) 7.31 (d, J = 2.3 Hz, 1 H) 7.45-7.51 (m, 2 H) 7.93 (s, 1 H)
MS (ESI / APCI Dual) (Positive) m / z; 477 (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 washing solution (pH 7.4) containing 5 mM EDTA. Washed twice. 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 50% inhibition of R (−)-α-methyl [ ³ H] histamine binding was determined from the inhibition curve. The evaluation results are shown in Table 1.

（N.T.：試験未実施）

(NT: not tested)

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 compound 2 1.2 nM, IC ₅₀ values of compound 4 was 0.55 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 In addition, it has become possible to provide a novel nitrogen-containing heterocyclic derivative useful for treatment.

Claims (3)

Formula (1)

{In formula (1), Q represents a group represented by the following formula (A) or (B);

X ¹ is a nitrogen atom or CR ^5A ,
X ² is a nitrogen atom or CR ^5B ,
X ³ is a nitrogen atom or CR ^5C ,
X ⁴ is a nitrogen atom or CR ^5D ,
X ⁵ is a nitrogen atom or CR ^5E ,
However, it is any one of nitrogen atom of X ¹ ~X ^5,
R ^{5A to} R ^5E are the same or different and each represents a hydrogen atom, a halogen atom, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;
R ¹ represents C ₁ -C ₆ alkyl, C ₃ -C ₇ cyclic alkyl, —C (O) R ⁶ or —SO ₂ R ⁷ ,
R ² and R ³ are the same or different and each represents C ₁ -C ₆ alkyl or C ₃ -C ₇ cyclic alkyl;
Or R ² and R ³ together with the adjacent nitrogen atom form a 3-7 membered saturated heterocycle bonded to each other (the saturated heterocycle may be substituted with C ₁ -C ₆ alkyl). ,
R ⁴ is, C ₁ -C ₆ alkyl (wherein C ₁ -C ₆ alkyl may be substituted with C ₃ -C ₇ cyclic alkyl) or C ₃ -C ₇ cycloalkyl (said C ₃ -C ₇ cycloalkyl May be substituted with C ₁ -C ₆ alkyl),
R ⁶ is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy (the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy is substituted with halogen, C ₁ -C ₆ alkoxy, aryl or heteroaryl. may be), C ₃ -C ₇ cycloalkyl (said C ₃ -C ₇ cyclic alkyl, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy; may be substituted by aryl or heteroaryl) , Aryl, heteroaryl (the aryl or heteroaryl is “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 di Alkylaminocarbonyl, carbonyl, carbamoyl, to which a monocyclic saturated heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur atoms in the ring is bonded, selected from nitrogen, oxygen, or sulfur atoms in the ring Optionally substituted with 1 to 3 identical or different substituents selected from "monocyclic saturated heterocyclic ring or heteroaryl containing one or more heteroatoms", nitrogen, oxygen or sulfur atoms in the ring monocyclic saturated heterocyclic ring (monocyclic saturated heterocyclic ring containing one or more hetero atoms selected from, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, substituted aryl or heteroaryl Or a group represented by -NR ⁸ R ⁹ ,
R ⁷ is C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl may be substituted with halogen, C ₁ -C ₆ alkoxy, aryl or heteroaryl), C ₃ -C ₇ cyclic alkyl (which is C ₃ -C ₇ cyclic alkyl, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy may be substituted by aryl or heteroaryl), aryl or heteroaryl (wherein aryl or heteroaryl are halogen , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy or cyano may be substituted)
R ⁸ and R ⁹ are the same or different and each is a hydrogen atom, C ₁ -C ₆ alkyl (the C ₁ -C ₆ alkyl may be substituted with halogen, C ₁ -C ₆ alkoxy, aryl or heteroaryl. ), C ₃ -C ₇ cyclic alkyl (the C ₃ -C ₇ cyclic alkyl may be substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, aryl or heteroaryl), aryl ( The aryl may be substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, hydroxy or cyano, or heteroaryl (the heteroaryl is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, shows a hydroxy or cyano may be substituted with)
p, q and n are the same or different and represent an integer of 0 to 2}
Or a pharmaceutically acceptable salt thereof. In equation (1),
Any one of X ^{1 to} X ⁵ is a nitrogen atom, the other is CH,
R ¹ is —C (O) R ⁶ ;
R ⁶ is C ₁ -C ₆ alkoxy, phenyl (the phenyl may be substituted with halogen or cyano) or a monocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur atoms in the ring A saturated heterocyclic ring of formula,
The nitrogen-containing heterocyclic derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein p, q and n are 1. A dementia, Alzheimer's disease, attention deficit / hyperactivity disorder, comprising the nitrogen-containing heterocyclic derivative according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof as an active ingredient, Preventive agent for schizophrenia, epilepsy, central convulsions, eating disorders, obesity, diabetes, hyperlipidemia, sleep disorders, narcolepsy, sleep apnea syndrome, circadian rhythm disorder, depression, or allergic rhinitis Therapeutic agent.