JP2011088833A - Sulfamide derivative with npy y5 receptor antagonistic action - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel compound with NPY Y5 receptor antagonistic action. <P>SOLUTION: The compound is a compound represented by formula (I) (wherein R<SP>1</SP>and R<SP>2</SP>are each independently a particular substituent, provided that R<SP>1</SP>and R<SP>2</SP>may form an optionally substituted nitrogen-containing heterocyclic ring together with the adjacent nitrogen atom; X is a heterocyclic ring; a plurality of R<SP>3</SP>'s are each independently optionally substituted aryl, heteroaryl or heterocyclyl; m is an integer of 0-2; n is an integer of 0-5; a plurality of R's are each independently halogen, oxo, cyano, nitro, (non)substituted alkyl or the like; and p is an integer of 0-2), a pharmaceutically acceptable salt thereof or a solvate thereof. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a novel sulfamide derivative having NPY Y5 receptor antagonistic activity and useful as a pharmaceutical, particularly as an anti-obesity drug.

  Neuropeptide Y (hereinafter referred to as NPY) is a peptide consisting of 36 amino acid residues and was isolated from pig brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals.

  In previous reports, NPY has been found to have a feeding promoting action, an anticonvulsant action, a learning promoting action, an anxiolytic action, an antistress action, etc. in the central nervous system, and depression, It may be deeply involved in central nervous system diseases such as Alzheimer's dementia and Parkinson's disease. In peripheral tissues, NPY causes contraction of smooth muscles such as blood vessels and myocardium, and is thus considered to be involved in cardiovascular disorders. Furthermore, it is known to be involved in metabolic diseases such as obesity, diabetes, and hormonal abnormalities (see Non-Patent Document 1). Therefore, a pharmaceutical composition having an NPY receptor antagonistic action may be a prophylactic or therapeutic agent for various diseases involving the NPY receptor as described above.

  To date, subtypes Y1, Y2, Y3, Y4, Y5, and Y6 have been discovered for NPY receptors (see Non-Patent Document 2). The Y5 receptor is involved in at least the feeding function, and it has been suggested that the antagonist is an anti-obesity drug (see Non-Patent Documents 3 to 5).

Patent Document 1 describes a benzimidazole derivative and an imidazopyridine derivative having a sulfonyl group having an NPY Y5 receptor antagonistic action. Further, amine derivatives having a sulfonyl group having an NPY Y5 receptor antagonistic action are described in Patent Documents 2, 3 and the like. In addition, Patent Documents 4 and 5 describe that amide derivatives having a sulfonyl group have NPY Y5 antagonistic activity. These compounds differ in structure from the compounds of the present invention.
Further, a compound having a structure different from that of the compound of the present invention but having NPY Y5 antagonistic activity is disclosed in Patent Document 6 and the like.

Derivatives having a similar structure to the compound of the present application are described in Patents 7 to 9, but their actions are completely different and do not suggest the present invention.
Moreover, although the pyrazole derivative which has a similar structure with this invention compound is described in patent documents 10-13, an effect | action is completely different and does not suggest this invention.

International Publication No. 2005/080348 Pamphlet International Publication No. 2007/125595 International Publication No. 2009/054434 Pamphlet International Publication No. 01/037826 Pamphlet International Publication No. 2006/001318 Pamphlet International Publication No. 2003/104255 Pamphlet International Publication No. 2001/005770 Pamphlet International Publication No. 2004/043962 Pamphlet International Publication No. 2004/052862 Pamphlet WO 98/52940 pamphlet US Pat. No. 6,979,686 International Publication No. 2000/31063 Pamphlet International Publication No. 2004/072033 Pamphlet

Trends in Pharmacological Sciences, Vol. 15, 153 (1994) Trends in Pharmacological Sciences, Vol.18, 372 (1997) Peptides, Vol. 18, 445 (1997) Obesity, Vol.14, No.9, A235 (2006) Obesity, Vol.15, No.9, A57 (2007)

  An object of the present invention is to provide a novel sulfamide derivative having an excellent NPY Y5 receptor antagonistic action.

  As a result of intensive studies, the present inventors have succeeded in synthesizing a novel compound having an excellent NPY Y5 receptor antagonistic action. Moreover, it discovered that this compound showed the strong body weight suppression effect. Furthermore, the present inventors have also found that the compounds of the present invention have little inhibition on drug metabolizing enzymes, and have good metabolic stability and water solubility. The compound of the present invention has low toxicity and is sufficiently safe for use as a medicine.

（式中、
Ｒ^１およびＲ^２はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ^１およびＲ^２は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環または置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、または
Ｒ^１およびＲ^５は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、
Ｘは芳香族ヘテロ環または非芳香族へテロ環であり、
Ｒ^３はそれぞれ独立して、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ^４はそれぞれ独立して、ハロゲン、シアノ、ニトロ、ニトロソ、アジド、オキソ、
置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、
ヒドロキシ、置換若しくは非置換のアルコキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロサイクリルオキシ、
メルカプト、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のシクロアルキルチオ、置換若しくは非置換のシクロアルケニルチオ、置換若しくは非置換のアリールチオ、置換若しくは非置換のヘテロアリールチオ、置換若しくは非置換のヘテロサイクリルチオ、
カルボキシ、置換若しくは非置換のアルコキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換のヘテロサイクリルオキシカルボニル、置換若しくは非置換のカルバモイル、
ホルミル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換のヘテロサイクリルカルボニル、
スルフィノ、スルホ、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換のヘテロサイクリルスルホニル、置換若しくは非置換のスルファモイルまたは置換若しくは非置換のアミノであり、
Ｒ^５は水素、置換若しくは非置換のアルキルまたは置換若しくは非置換のアリールであり、
ｍは０〜２の整数であり、
ｎは０〜５の整数であり、
Ｒはそれぞれ独立して、ハロゲン、オキソ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルであり、
ｐは０〜２の整数である）で示される化合物、その製薬上許容される塩またはそれらの溶媒和物を含有するＮＰＹＹ５受容体拮抗作用を有する医薬組成物。
（２）式（Ｉ）：

（式中、
Ｒ^１およびＲ^２はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ^１およびＲ^２は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環または置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、または
Ｒ^１およびＲ^５は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよく、
Ｘは芳香族へテロ環または非芳香族ヘテロ環であり、
Ｒ^３はそれぞれ独立して、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ^４はそれぞれ独立して、ハロゲン、シアノ、ニトロ、ニトロソ、アジド、オキソ、
置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、
ヒドロキシ、置換若しくは非置換のアルコキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のシクロアルキルオキシ、置換若しくは非置換のシクロアルケニルオキシ、置換若しくは非置換のアリールオキシ、置換若しくは非置換のヘテロアリールオキシ、置換若しくは非置換のヘテロサイクリルオキシ、
メルカプト、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のシクロアルキルチオ、置換若しくは非置換のシクロアルケニルチオ、置換若しくは非置換のアリールチオ、置換若しくは非置換のヘテロアリールチオ、置換若しくは非置換のヘテロサイクリルチオ、
カルボキシ、置換若しくは非置換のアルコキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のシクロアルキルオキシカルボニル、置換若しくは非置換のシクロアルケニルオキシカルボニル、置換若しくは非置換のアリールオキシカルボニル、置換若しくは非置換のヘテロアリールオキシカルボニル、置換若しくは非置換のヘテロサイクリルオキシカルボニル、置換若しくは非置換のカルバモイル、
ホルミル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のシクロアルキルカルボニル、置換若しくは非置換のシクロアルケニルカルボニル、置換若しくは非置換のアリールカルボニル、置換若しくは非置換のヘテロアリールカルボニル、置換若しくは非置換のヘテロサイクリルカルボニル、
スルフィノ、スルホ、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のシクロアルキルスルホニル、置換若しくは非置換のシクロアルケニルスルホニル、置換若しくは非置換のアリールスルホニル、置換若しくは非置換のヘテロアリールスルホニル、置換若しくは非置換のヘテロサイクリルスルホニル、置換若しくは非置換のスルファモイルまたは置換若しくは非置換のアミノであり、
Ｒ^５は水素、置換若しくは非置換のアルキルまたは置換若しくは非置換のアリールであり、
ｍは０〜２の整数であり、
ｎは０〜５の整数であり、
Ｒはそれぞれ独立して、ハロゲン、オキソ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルであり、
ｐは０〜２の整数である）で示される化合物（但し、式：

で示される基が、

である化合物は除く。）、
その製薬上許容される塩またはそれらの溶媒和物。
（３）Ｘがインドール、ピロロピリジン、ピロロピリミジン、ピロロピラジン、イミダゾール、ピラゾール、ピロール、トリアゾール、ピリジン、イミダゾピリジンまたはベンゾイミダゾールである、（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（４）Ｘがピラゾールである、（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（５）式：

で示される基が、

で示される基であり、
ｎが０または１である、
（２）記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（６）ｍが１である、（２）〜（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（７）Ｒ^１およびＲ^２がそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである、（２）〜（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（８）Ｒ^２が置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである、（２）〜（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（９）Ｒ^１が水素または置換若しくは非置換のアルキルであり、
Ｒ^２が置換若しくは非置換のアルキル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキルまたは置換若しくは非置換のアリールである、（２）〜（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１０）Ｒ^１およびＲ^２が隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成している、（２）〜（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１１）Ｒ^３がそれぞれ独立して、置換または非置換のフェニルである、
（２）〜（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１２）Ｒ^４がそれぞれ独立して、ハロゲン、シアノまたは置換若しくは非置換のアルキルである、（２）〜（５）いずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。
（１３）（２）〜（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を有効成分とする医薬組成物。
（１４）ＮＰＹ Ｙ５受容体拮抗作用を有する、（１３）記載の医薬組成物。
（１５）上記（２）〜（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物を投与することを特徴とする、ＮＰＹ Ｙ５の関与する疾患の治療または予防方法。
（１６）ＮＰＹ Ｙ５の関与する疾患の治療または予防剤を製造するための、上記（２）〜（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物の使用。
（１７）ＮＰＹ Ｙ５受容体の関与する疾患を治療または予防するための、上記（２）〜（１２）のいずれかに記載の化合物、その製薬上許容される塩またはそれらの溶媒和物。 That is, the present invention relates to the following.
(1) Formula (I):

(Where
R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl,
R ¹ and R ² together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R ¹ and R ⁵ together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle,
X is an aromatic heterocycle or a non-aromatic heterocycle,
Each R ³ is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
Each R ⁴ is independently halogen, cyano, nitro, nitroso, azide, oxo,
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy,
Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclylthio,
Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or Unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl,
Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted hetero Arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl,
Sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted A heteroarylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino,
R ⁵ is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
m is an integer from 0 to 2,
n is an integer of 0 to 5,
Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
p is an integer of 0 to 2, and a pharmaceutical composition having an NPYY5 receptor antagonistic action, comprising a compound represented by the formula: a pharmaceutically acceptable salt thereof or a solvate thereof.
(2) Formula (I):

(Where
R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl,
R ¹ and R ² together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R ¹ and R ⁵ together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle,
X is an aromatic heterocycle or a non-aromatic heterocycle,
Each R ³ is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
Each R ⁴ is independently halogen, cyano, nitro, nitroso, azide, oxo,
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy,
Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclylthio,
Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or Unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl,
Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted hetero Arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl,
Sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted A heteroarylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino,
R ⁵ is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
m is an integer from 0 to 2,
n is an integer of 0 to 5,
Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
p is an integer of 0 to 2) (provided that the formula:

A group represented by

Is excluded. ),
The pharmaceutically acceptable salt or solvate thereof.
(3) The compound according to (2), pharmaceutically acceptable salt thereof, or the like, wherein X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, imidazole, pyrazole, pyrrole, triazole, pyridine, imidazopyridine or benzimidazole Solvates.
(4) The compound according to (2), pharmaceutically acceptable salt or solvate thereof, wherein X is pyrazole.
(5) Formula:

A group represented by

A group represented by
n is 0 or 1;
(2) The compound, its pharmaceutically acceptable salt or solvate thereof as described in (2).
(6) The compound according to any one of (2) to (5), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m is 1.
(7) R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, (2) (5) The compound according to any one of the above, a pharmaceutically acceptable salt thereof, or a solvate thereof.
(8) The compound according to any one of (2) to (5), wherein R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. , A pharmaceutically acceptable salt thereof or a solvate thereof.
(9) R ¹ is hydrogen or substituted or unsubstituted alkyl;
The compound according to any one of (2) to (5), wherein R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, its pharmaceutical Top acceptable salts or solvates thereof.
(10) The compound according to any one of (2) to (5), wherein R ¹ and R ² together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic ring, The pharmaceutically acceptable salt or solvate thereof.
(11) R ³ is each independently substituted or unsubstituted phenyl.
(2)-The compound in any one of (5), its pharmaceutically acceptable salt, or those solvates.
(12) The compound according to any one of (2) to (5), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein each R ⁴ is independently halogen, cyano, or substituted or unsubstituted alkyl. object.
(13) A pharmaceutical composition comprising the compound according to any one of (2) to (12), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
(14) The pharmaceutical composition according to (13), which has an NPY Y5 receptor antagonistic action.
(15) Treatment of a disease involving NPY Y5, comprising administering the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof, or Prevention method.
(16) Of the compound according to any one of (2) to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof, for producing a therapeutic or prophylactic agent for a disease involving NPY Y5 use.
(17) The compound according to any one of the above (2) to (12), a pharmaceutically acceptable salt thereof, or a solvate thereof, for treating or preventing a disease involving the NPY Y5 receptor.

  The compound of the present invention exhibits NPY Y5 receptor antagonistic action, and is associated with drugs, particularly diseases involving NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, It is very useful as a medicine for the treatment or prevention of hypertension, cerebral hyperemia, congestive heart failure or sleep disorder. In addition, since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity. Furthermore, it is very useful as a medicament for treating or preventing diseases in which obesity is a risk factor, such as diabetes, hypertension, hyperlipidemia, arteriosclerosis, and acute coronary syndrome.

  The terms used in this specification will be described below. In addition, in this specification, each term has the same meaning, whether used alone or in combination with other terms, unless otherwise specified.

  “Halogen” includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.

  “Alkyl” means a linear or branched hydrocarbon group having 1 to 10 carbon atoms. C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc. are included. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl , N-nonyl, n-decyl and the like.

  “Alkenyl” means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at any position. Including alkenyl having 2 to 8 carbon atoms, alkenyl having 3 to 6 carbon atoms and the like. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.

  “Alkynyl” means a linear or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at any position. C2-C6 alkynyl, C2-C4 alkynyl, etc. are included. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.

  “Cycloalkyl” means a C3-C8 cyclic saturated hydrocarbon group. Examples include cycloalkyl having 3 to 6 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, and the like. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.

  “Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl. Cycloalkenyl also includes bridged cyclic unsaturated aliphatic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.

  “Aryl” means a monocyclic or polycyclic aromatic carbocyclic group. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned. Further, a condensed aromatic hydrocarbon cyclic group in which a cycloalkane (ring derived from the above “cycloalkyl”) or a cycloalkene (ring derived from the “cycloalkenyl”) is condensed is also included. For example, indanyl, indenyl, biphenylenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned.

“Aromatic heterocycle” means an aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Includes monocyclic or polycyclic aromatic heterocycles.
The “monocyclic aromatic heterocycle” means a 4- to 8-membered monocyclic aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, furan, and thiophene. In particular, a 5-membered or 6-membered monocyclic aromatic heterocycle is preferable.
The “polycyclic aromatic heterocycle” refers to the above “monocyclic aromatic heterocycle”, an aromatic carbocycle (ring derived from the above “aryl”), an aromatic heterocycle, a cycloalkane (the above “cycloalkane”). A ring derived from “alkyl” or a ring fused with a cycloalkene (ring derived from “cycloalkenyl” above). For example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzo A bicyclic aromatic heterocycle such as thiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine; carbazole, Examples include tricyclic aromatic heterocycles such as acridine, xanthene, phenothiazine, phenoxathiin, phenoxazine, and dibenzofuran. It is.

The “nitrogen-containing aromatic heterocycle” means a monocyclic or polycyclic aromatic heterocycle having at least one nitrogen atom in the ring.
Examples of the “monocyclic nitrogen-containing aromatic heterocycle” include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, isoxazole, oxazole, oxadiazole, isothiazole, and thiazole. , Thiadiazole and the like.
Examples of the `` polycyclic nitrogen-containing aromatic heterocycle '' include, for example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benziso Two-ring nitrogen-containing compounds such as oxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzothiazole, benzothiadiazole, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine Aromatic heterocycles: 3-ring nitrogen-containing aromatic heterocycles such as carbazole, acridine, phenothiazine, phenoxazine and the like.

“Heteroaryl” means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring. For example, the group includes a group derived from the above “monocyclic aromatic heterocycle” and a group derived from the above “polycyclic aromatic heterocycle”.
Examples of the `` monocyclic aromatic heterocyclic group '' include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, Thienyl and the like can be mentioned.
Examples of the “polycyclic aromatic heterocyclic group” include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl , Benzoxazolyl, benzoxiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyra Bicyclic aromatic heterocyclic groups such as dinopyridazinyl, oxazolopyridyl, thiazolopyridyl; carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathi Le, phenoxazinyl, heterocyclic groups such as the aromatic tricyclic dibenzofuryl and the like. In the case of a polycyclic aromatic heterocyclic group, any ring may have a bond.

“Non-aromatic heterocycle” means a non-aromatic ring having one or more heteroatoms arbitrarily selected from O, S and N in the ring. Includes monocyclic or polycyclic non-aromatic heterocycles.
The “monocyclic non-aromatic heterocycle” means a 4- to 8-membered monocyclic non-aromatic ring having one or more hetero atoms arbitrarily selected from O, S and N in the ring. For example, dioxane, thiirane, oxirane, oxathiolane, azetidine, thiane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, oxadiazine, dihydropyridine, thiomorpholine, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroiso Examples include thiazole, oxazolidine, thiazolidine and the like. In particular, a 5-membered or 6-membered monocyclic non-aromatic heterocycle is preferable.
“Polycyclic non-aromatic heterocycle” refers to the above “monocyclic non-aromatic heterocycle”, aromatic carbocycle (ring derived from the above “aryl”), aromatic heterocycle, monocyclic A non-aromatic heterocycle, a cycloalkane (ring derived from the above “cycloalkyl”) or a cycloalkene (ring derived from the “cycloalkenyl”) is condensed. For example, indoline, isoindoline, chroman, isochroman and the like can be mentioned.

The “nitrogen-containing non-aromatic heterocycle” means a monocyclic or polycyclic non-aromatic heterocycle having at least one nitrogen atom in the ring.
`` Monocyclic nitrogen-containing non-aromatic heterocycle '' includes, for example, azetidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, oxadiazine, dihydropyridine, thiomorpholine, tetrahydrothiazole, tetrahydro Examples include isothiazole, oxazolidine, thiazolidine and the like.
Examples of the “polycyclic nitrogen-containing non-aromatic heterocycle” include indoline, isoindoline, dihydrobenzothiadiazole and the like.

“Heterocyclyl” means a non-aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring. A monocyclic non-aromatic heterocyclic group (a group derived from the above “monocyclic non-aromatic heterocyclic ring”) or a polycyclic non-aromatic heterocyclic group (the above “polycyclic non-aromatic heterocyclic group”); Group derived from “aromatic heterocycle”.
Specific examples of `` monocyclic non-aromatic heterocyclic group '' include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidino, piperidino, piperazinyl, piperazinoyl , Morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and the like.
Specific examples of the “polycyclic non-aromatic heterocyclic group” include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like. In the case of a polycyclic non-aromatic heterocyclic group, any ring may have a bond.

  “Alkoxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, pentoxy, neopentoxy, hexoxy, isohexoxy, n-heptoxy, isoheptoxy, n -Octoxy, isooctoxy and the like.

  “Haloalkyl” and “haloalkoxy” mean a group in which the above “halogen” is bonded to the above “alkyl” and “alkoxy”.

  “Aryloxy” means a group in which the above “aryl” is bonded to an oxygen atom. Specific examples include phenoxy, naphthoxy, anthryloxy, phenanthryloxy, indanyloxy, indenyloxy, biphenylyloxy, acenaphthyloxy, tetrahydronaphthyloxy, fluorenyloxy and the like.

  "Alkenyloxy", "cycloalkyloxy", "cycloalkenyloxy", "heteroaryloxy" and "heterocyclyloxy" are the above "alkenyl", "cycloalkyl", "cycloalkenyl", "heteroaryl" And “heterocyclyl” means a group bonded to an oxygen atom.

  “Alkylthio”, “alkenylthio”, “cycloalkylthio”, “cycloalkenylthio”, “arylthio”, “heteroarylthio” and “heterocyclylthio” are the above-mentioned “alkyl”, “alkenyl”, “cycloalkyl” ”,“ Cycloalkenyl ”,“ aryl ”,“ heteroaryl ”and“ heterocyclyl ”mean a group bonded to a sulfur atom.

  “Alkoxycarbonyl”, “alkenyloxycarbonyl”, “cycloalkyloxycarbonyl”, “cycloalkenyloxycarbonyl”, “aryloxycarbonyl”, “heteroaryloxycarbonyl” and “heterocyclyloxycarbonyl” Means a group in which the oxygen atom of “alkoxy”, “alkenyloxy”, “cycloalkyloxy”, “cycloalkenyloxy”, “aryloxy”, “heteroaryloxy” and “heterocyclyloxy” is bonded to a carbonyl group .

  “Alkylcarbonyl”, “alkenylcarbonyl”, “cycloalkylcarbonyl”, “cycloalkenylcarbonyl”, “arylcarbonyl”, “heteroarylcarbonyl” and “heterocyclylcarbonyl” are the above “alkyl”, “alkenyl”. , “Cycloalkyl”, “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a carbonyl group.

  “Alkylsulfonyl”, “alkenylsulfonyl”, “cycloalkylsulfonyl”, “cycloalkenylsulfonyl”, “arylsulfonyl”, “heteroarylsulfonyl” and “heterocyclylsulfonyl” are the above “alkyl”, “alkenyl”. , “Cycloalkyl”, “cycloalkenyl”, “aryl”, “heteroaryl” and “heterocyclyl” mean a group bonded to a sulfonyl group.

"Substituted or unsubstituted alkyl", "substituted or unsubstituted alkenyl", "substituted or unsubstituted alkynyl", "substituted or unsubstituted alkoxy", "substituted or unsubstituted alkenyloxy", "substituted or unsubstituted "Substituted alkylthio", "Substituted or unsubstituted alkenylthio", "Substituted or unsubstituted alkoxycarbonyl", "Substituted or unsubstituted alkenyloxycarbonyl", "Substituted or unsubstituted alkylcarbonyl", "Substituted or unsubstituted Substituents of “substituted alkenylcarbonyl”, “substituted or unsubstituted alkylsulfonyl” or “substituted or unsubstituted alkenylsulfonyl” include halogen, cyano, nitro, nitroso, azide, acyl, acyloxy, imino, hydroxy, alkoxy , Haloal Alkoxy, alkynyloxy, cycloalkyl, cycloalkyloxy, cycloalkenyl, cycloalkenyloxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy,
Mercapto, alkylthio, alkenylthio, cycloalkylthio, cycloalkenylthio, arylthio, heteroarylthio, heterocyclylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, heteroaryloxy Carbonyl, heterocyclyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, cycloalkyl Sulfonyl, cycloalkenylsulfoni , Arylsulfonyl, heteroarylsulfonyl, heterocyclyl sulfonyl, sulfamoyl, amino, oxo and the like. Any position may be substituted with one or more groups selected from these.

“Substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted aryl”, “substituted or unsubstituted heteroaryl”, “substituted or unsubstituted heterocyclyl”, "Substituted or unsubstituted nitrogen-containing aromatic heterocycle", "Substituted or unsubstituted nitrogen-containing non-aromatic heterocycle", "Substituted or unsubstituted cycloalkyloxy", "Substituted or unsubstituted cycloalkenyloxy" , “Substituted or unsubstituted aryloxy”, “substituted or unsubstituted heteroaryloxy”, “substituted or unsubstituted heterocyclyloxy”, “substituted or unsubstituted cycloalkylthio”, “substituted or unsubstituted Cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted Heteroarylthio ”,“ substituted or unsubstituted heterocyclylthio ”,“ substituted or unsubstituted cycloalkyloxycarbonyl ”,“ substituted or unsubstituted cycloalkenyloxycarbonyl ”,“ substituted or unsubstituted aryloxycarbonyl ” , “Substituted or unsubstituted heteroaryloxycarbonyl”, “substituted or unsubstituted heterocyclyloxycarbonyl”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted cycloalkylcarbonyl”, “substituted or "Unsubstituted cycloalkenylcarbonyl", "substituted or unsubstituted arylcarbonyl", "substituted or unsubstituted heteroarylcarbonyl", "substituted or unsubstituted heterocyclylcarbonyl", "substituted or unsubstituted cycloaryl" Killsulfonyl "," substituted or unsubstituted cycloalkenylsulfonyl "," substituted or unsubstituted arylsulfonyl "," substituted or unsubstituted heteroarylsulfonyl "," substituted or unsubstituted heterocyclylsulfonyl "," substituted Alternatively, the substituent of “unsubstituted sulfamoyl” or “substituted or unsubstituted amino” includes alkyl, haloalkyl, alkenyl, alkynyl, halogen, cyano, nitro, nitroso, azide, acyl, acyloxy, imino, hydroxy, alkoxy, halo. Alkoxy, alkynyloxy, cycloalkyl, cycloalkyloxy, cycloalkenyl, cycloalkenyloxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyl Oxy, mercapto, alkylthio, alkenylthio, cycloalkylthio, cycloalkenylthio, arylthio, heteroarylthio, heterocyclylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, cycloalkyloxycarbonyl, cycloalkenyloxycarbonyl, aryloxycarbonyl, hetero Aryloxycarbonyl, heterocyclyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, Cycloalkylsulfonyl, cycloalkenyl Ruhoniru, arylsulfonyl, heteroarylsulfonyl, heterocyclyl sulfonyl, sulfamoyl, amino, oxo, alkylene, alkylenedioxy, formula: -N ^(R 7) - ^(alkylene) -O- a group represented the formula: -N And a group represented by (R ⁷ )-(alkylene) -N (R ⁷ ) — (R ⁷ is independently hydrogen or alkyl). In the case of substitution with a divalent group, the bond of the divalent group may be bonded to the same or different atom. The divalent group may be bonded so as to form a bicyclo ring or a spiro ring as well as a case where the bond of the divalent group is bonded to an adjacent atom. Any position may be substituted with one or more groups selected from these.

For example, when the substituent of “substituted or unsubstituted cycloalkyl (eg, cyclohexyl)” is alkylene (eg, —CH ₂ —CH ₂ —), it may be substituted as follows.

For example, when the substituent of “substituted or unsubstituted aryl” is alkylenedioxy, the following groups are exemplified.

置換基が他の二価の基の場合も、上記と同様に置換されていてもよい。 For example, when the substituent of “substituted or unsubstituted aryl” is a group represented by the formula: —N (R ⁷ )-(alkylene) -O—, the following groups are exemplified.

When the substituent is another divalent group, it may be substituted in the same manner as described above.

“Acyl” means (1) a linear or branched alkylcarbonyl or alkenylcarbonyl having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms,
(2) cycloalkylcarbonyl having 4 to 9 carbon atoms, preferably 4 to 7 carbon atoms, and (3) arylcarbonyl having 7 to 11 carbon atoms are included. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.

  “Acyloxy” means a group in which the above “acyl” is bonded to an oxygen atom.

  All of the compounds of the present invention have NPY Y5 receptor antagonistic action, and particularly preferred compounds include the following compounds in the formula (I).

で示される基が、
式：

で示される基である化合物。 R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or A compound that is unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.

A compound wherein R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.

A compound wherein R ¹ and R ² are each independently hydrogen; alkyl; alkyl substituted with halogen or cyano; alkoxy;

A compound wherein R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl.

R ¹ is hydrogen or substituted or unsubstituted alkyl;
A compound wherein R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl.

R ¹ is hydrogen; alkyl; or alkyl substituted with cyano;
A compound wherein R ² is alkyl; alkyl substituted with halogen or cyano; alkoxy; cycloalkyl; aryl.

A compound in which R ¹ and R ² together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing aromatic heterocyclic ring or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic ring.

A compound in which R ¹ and R ² together with an adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle.

A compound in which R ¹ and R ² together with the adjacent nitrogen atom form piperidine, oxo substituted oxazolidine or morpholine.

A compound in which R ¹ and R ⁵ together with an adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle.

formula:

A group represented by
formula:

The compound which is group shown by these.

A compound wherein R ³ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

R ³ is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Morpholinyl, substituted or unsubstituted morpholino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted dihydrobenzoxazinyl Or a compound that is substituted or unsubstituted indazolyl.

R ³ is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted Morpholinyl, substituted or unsubstituted morpholino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted benzodioxolyl, substituted or unsubstituted dihydrobenzoxazinyl Or substituted or unsubstituted indazolyl (each substituted group is halogen, cyano, nitro, nitroso, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkenyloxy, Lucapto, alkylthio, alkenylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, sulfamoyl, aminoalkylenedioxy, morpholino and formula: -N ( R ⁷ )-(alkylene) -O— is one or more groups selected from the group represented by:

R ³ is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl (the substituents are each selected from halogen, cyano, nitro, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy and haloalkoxy A compound which is the above group).

A compound in which R ³ is substituted or unsubstituted phenyl or pyridyl (the substituent is one or more groups selected from halogen, cyano, and alkoxy).

A compound in which R ³ is substituted or unsubstituted phenyl (the substituent is one or more groups selected from halogen, cyano, and alkoxy).

R ⁴ is halogen, cyano, nitro, nitroso, azide, oxo,
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy,
Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclylthio,
Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or Unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl,
Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted hetero Arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl,
Sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted Or a substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino.

A compound wherein R ⁴ is halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted aryloxy.

R ⁴ is halogen, cyano, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy or substituted or unsubstituted aryloxy (the substituents are halogen, cyano, nitro, Nitroso, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkenyloxy, mercapto, alkylthio, alkenylthio, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, carbamoyl, formyl, alkylcarbonyl, alkenylcarbonyl, And one or more groups selected from sulfino, sulfo, alkylsulfonyl, alkenylsulfonyl, sulfamoyl and amino).

A compound wherein R ⁴ is halogen, cyano or substituted or unsubstituted alkyl.

R ⁴ is halogen, cyano, or substituted or unsubstituted alkyl (the substituents are one or more groups selected from halogen, cyano, nitro, azide, oxo, alkyl, haloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, and haloalkoxy, respectively) Compound).

A compound in which R ⁴ is halogen, cyano, or alkyl.

A compound wherein R ⁵ is hydrogen or substituted or unsubstituted alkyl.

A compound in which R ⁵ is hydrogen or alkyl having 1 to 3 carbon atoms.

A compound wherein R ⁵ is hydrogen.

A compound wherein m is 1 or 2.

A compound wherein m is 1.

A compound wherein n is 0-2.

A compound wherein n is 0 or 1.

A compound wherein R is halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.

The compound whose p is an integer of 0-2.

（なお、シクロヘキサン、（Ｒ^３）ｍおよび（Ｒ^４）ｎからの結合手は上記環上の置換可能ないずれの原子に結合していてもよい。） A compound wherein X is an aromatic heterocycle or a non-aromatic heterocycle.

A compound in which X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, imidazole, pyrazole, pyrrole, triazole, pyridine, imidazopyridine or benzimidazole.

A compound wherein X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, pyrazole, pyrrole or benzimidazole.

A compound wherein X is pyrazole.

A compound in which X is a group selected from the following.

(The bond from cyclohexane, (R ³ ) m, and (R ⁴ ) n may be bonded to any substitutable atom on the ring.)

で示される基が、

（Ｘ’はシクロヘキサン環との結合手を環内の窒素原子の隣接位に有する芳香族ヘテロ環または非芳香族へテロ環である。）
で示される基である化合物。 formula:

A group represented by

(X ′ is an aromatic heterocycle or non-aromatic heterocycle having a bond to the cyclohexane ring adjacent to the nitrogen atom in the ring.)
The compound which is group shown by these.

で示される基が、式：

で示される基である化合物。

式：

で示される基が、式：

で示される基である化合物。 formula:

A group represented by the formula:

The compound which is group shown by these.

formula:

A group represented by the formula:

The compound which is group shown by these.

で示される基は、以下の式で示される基と同意義である。
式：

式：

で示される基は、以下の式で示される基と同意義である。
式：

The formula:

The group represented by is the same as the group represented by the following formula.
formula:

formula:

The group represented by is the same as the group represented by the following formula.
formula:

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物、および／または
式：

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物を意味する。特に好ましくは、
式：

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物である。 The compound represented by the formula (I) is
formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
And / or the formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
Means a compound represented by Particularly preferably,
formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
It is a compound shown by these.

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。） The above compounds can also be described as follows.

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)

  The compound of the present invention can produce each compound, and includes pharmaceutically acceptable salts. “Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, Examples include salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; and salts of alkaline earth metals such as calcium or magnesium.

  The compounds of the present invention include solvates thereof. Preferable examples include hydrates and alcohol hydrates. For example, monohydrate, dihydrate, monoalcohol hydrate, dialcohol solvate and the like.

  When the compound of the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers and all stereoisomers (geometric isomers, epimers, enantiomers, etc.). Moreover, when this invention compound has a double bond, when E body and Z body may exist, both are included.

  Prodrugs of the compounds of the present invention are included within the scope of the compounds contained in the pharmaceutical composition of the present invention. Prodrugs of the compounds of the present invention are functional derivatives of the compounds of the present invention and are easily converted into the compounds of the present invention in vivo. Therefore, the “compound” of the present invention is a specifically disclosed compound or a compound that is not specifically disclosed in some cases, but is administered in vivo to a patient with a disease involving NPY Y5. Including compounds that convert to Conventional procedures for selection and formulation of suitable prodrug derivatives are described, for example, in Design of Prodrugs (ed. H. Bundgaard, Elsevier, 1985).

（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

化合物（ＩＩＩ−１）に、式：Ｒ^１（Ｒ^２）ＮＳＯ_２Ｈａｌで示される化合物を反応させ、式（Ｉ）で示される化合物を得る。また、式（ＩＩＩ−２）で示される化合物に、式：Ｒ^５Ｈａｌで示される化合物を反応させ、式（Ｉ）で示される化合物を得る。
上記反応は、塩基を用いて行うことができる。塩基としては、ピリジン、トリエチルアミン、Ｎ‐メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等を使用することができる。
上記反応は、０℃〜５０℃で数分〜数時間反応させればよい。溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、ヘキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等を用いることができる。
Ｘ上のＲ^３やＲ^４を保護して上記反応を行い、反応後に脱保護してもよい。 The compound represented by formula (I) which is the compound of the present invention can be synthesized, for example, by the following method.

(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Compound (III-1) is reacted with a compound represented by the formula: R ¹ (R ² ) NSO ₂ Hal to obtain a compound represented by formula (I). In addition, the compound represented by the formula (III-2) is reacted with the compound represented by the formula: R ⁵ Hal to obtain the compound represented by the formula (I).
The above reaction can be performed using a base. As the base, pyridine, triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride and the like can be used.
The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours. Use solvents such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof. Can do.
The above reaction may be carried out while protecting R ³ and R ⁴ on X, and may be deprotected after the reaction.

（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

化合物（ＩＩＩ−１）に、式：Ｒ^１（Ｒ^２）ＮＳＯＨａｌで示される化合物を反応させ、化合物（ＩＩＩ−３）を得る。さらに、得られた化合物（ＩＩＩ−３）を酸化し、式（Ｉ）で示される化合物を得る。
式：Ｒ^１（Ｒ^２）ＮＳＯＨａｌで示される化合物を使用する工程は、塩基存在下で行うことができる。塩基としては、ピリジン、トリエチルアミン、Ｎ−メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を使用することができる。
上記反応は、０℃〜５０℃で数分〜数時間反応させればよい。溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、ヘキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリルおよびそれらの混合溶媒等を用いることができる。
酸化工程は、酸化剤を用いて行うことができる。酸化剤としては、ｍ−クロロ過安息香酸、過酢酸、過酸化水素、過トリフルオロ酢酸、過ヨウ素酸ナトリウム、次亜塩素酸ナトリウム、過マンガン酸カリウム、タングステン酸ナトリウム等が挙げられる。
Ｘ上のＲ^３やＲ^４を保護して上記反応を行い、反応後に脱保護してもよい。 The compound of the present invention can be synthesized as follows.

(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Compound (III-3) is obtained by reacting compound (III-1) with a compound represented by the formula: R ¹ (R ² ) NSOHal. Furthermore, the obtained compound (III-3) is oxidized to obtain a compound represented by the formula (I).
The step of using the compound represented by the formula: R ¹ (R ² ) NSOHal can be performed in the presence of a base. As the base, pyridine, triethylamine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used.
The reaction may be performed at 0 ° C. to 50 ° C. for several minutes to several hours. Use solvents such as tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixed solvents thereof. Can do.
The oxidation step can be performed using an oxidizing agent. Examples of the oxidizing agent include m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, pertrifluoroacetic acid, sodium periodate, sodium hypochlorite, potassium permanganate, and sodium tungstate.
The above reaction may be carried out while protecting R ³ and R ⁴ on X, and may be deprotected after the reaction.

（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程Ａ
目的化合物に対応する置換基Ｒ^５を有する化合物（Ｘ−１）と式：Ｒ^１（Ｒ^２）ＮＳＯ_２Ｈａｌで示される化合物を適当な溶媒中、塩基で処理し、化合物（Ｘ−２）を得る。０℃〜５０℃で数分〜数時間反応させればよい。
溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン（塩化メチレン）、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、ジクロロメタンである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。
塩基としては、トリエチルアミン、ピリジン、Ｎ−メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくはトリエチルアミンである。化合物（Ｘ−１）に対して、１〜５等量の塩基を用いるのが好ましい。

工程Ｂ
化合物（Ｘ−２）を適当な溶媒中、塩基で処理し、化合物（Ｘ−３）を得る。０℃〜５０℃で数分〜数時間反応させればよい。
塩基としては、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等を用いることができる。好ましくは、水酸化ナトリウムである。
溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、テトラヒドロフランおよび／またはエタノールである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。

工程Ｃ
化合物（Ｘ−３）を適当な溶媒中、ハロゲン化剤で処理し、０℃〜５０℃で数分〜数時間反応させ、酸ハロゲン化物を得る。
ハロゲン化剤としては、オキサリルクロリド、チオニルクロリド、チオニルブロミド、五塩化リン、オキシ塩化リン等が挙げられる。好ましくはオキサリルクロリドである。化合物（Ｘ−３）に対して、１〜５等量のハロゲン化剤を用いるのが好ましい。また、触媒としてジメチルホルムアミドを加えても良い。
溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、Ｎ−メチルピロリドン、ジエチルエーテル、１，２−ジクロロエタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、塩化メチレンおよび／またはジメチルホルムアミドである。これらの溶媒は、ハロゲン化剤との組み合わせで適宜選択して使用すればよい。
なお、ハロゲン化剤の代わりに、無水酢酸、メタンスルホニルクロリド、クロロ炭酸エチルを用いて、酸ハロゲン化物の代わりに活性エステルを得て、次の工程Ｄに使用してもよい。

工程Ｄ
工程Ｃで得られた酸ハロゲン化物または活性エステルと酢酸エチルを適当な溶媒中、ルイス酸とＮ-アルキルイミダゾール存在下、−１００℃〜０℃で数分〜数時間反応させた後、塩基を加えると、化合物（Ｘ−４）を得る。
ルイス酸としては、四塩化チタン、四塩化スズ、三塩化アルミニウム、三フッ化ホウ素エーテル錯体、三塩化ホウ素、トリメチルシリルトリフルオロメタンスルホナート（ＴＭＳＯＴｆ）、二塩化亜鉛等を用いることができる。好ましくは、四塩化チタンである。
Ｎ−アルキルイミダゾールとしては、Ｎ−メチルイミダゾール、Ｎ−エチルイミダゾール等を用いることができる。好ましくは、Ｎ−メチルイミダゾールである。
塩基としては、Ｎ，Ｎ’−ジイソプロピルエチルアミン、ジエチルアミン、トリエチルアミン、ピリジン、Ｎ−メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくは、Ｎ，Ｎ’−ジイソプロピルエチルアミンである。
溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、塩化メチレンおよび／または酢酸エチルである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。 When X is pyrazole, the compound (X-4), which is an intermediate of the compound of the present invention, can be synthesized using the synthesis method shown below.

(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Process A
The compound (X-1) having the substituent R ⁵ corresponding to the target compound and the compound represented by the formula: R ¹ (R ² ) NSO ₂ Hal are treated with a base in an appropriate solvent to give the compound (X-2) Get. What is necessary is just to make it react for several minutes-several hours at 0 to 50 degreeC.
Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixtures thereof A solvent or the like can be used. Preferably, it is dichloromethane. These solvents may be appropriately selected and used in combination with a base.
As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred. It is preferable to use 1 to 5 equivalents of a base with respect to compound (X-1).

Process B
Compound (X-2) is treated with a base in a suitable solvent to give compound (X-3). What is necessary is just to make it react for several minutes-several hours at 0 to 50 degreeC.
As the base, barium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide or the like can be used. Sodium hydroxide is preferable.
As the solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, mixed solvents thereof, etc. are used. Is possible. Tetrahydrofuran and / or ethanol are preferred. These solvents may be appropriately selected and used in combination with a base.

Process C
Compound (X-3) is treated with a halogenating agent in a suitable solvent and reacted at 0 ° C. to 50 ° C. for several minutes to several hours to obtain an acid halide.
Examples of the halogenating agent include oxalyl chloride, thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus oxychloride and the like. Oxalyl chloride is preferred. It is preferable to use 1 to 5 equivalents of a halogenating agent with respect to compound (X-3). Further, dimethylformamide may be added as a catalyst.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof and the like can be used. Methylene chloride and / or dimethylformamide are preferable. These solvents may be appropriately selected and used in combination with a halogenating agent.
Instead of the halogenating agent, an active ester may be obtained instead of the acid halide using acetic anhydride, methanesulfonyl chloride, or ethyl chlorocarbonate, and used in the next step D.

Process D
The acid halide or active ester obtained in Step C and ethyl acetate are reacted in a suitable solvent in the presence of Lewis acid and N-alkylimidazole at −100 ° C. to 0 ° C. for several minutes to several hours. Addition gives compound (X-4).
As the Lewis acid, titanium tetrachloride, tin tetrachloride, aluminum trichloride, boron trifluoride ether complex, boron trichloride, trimethylsilyl trifluoromethanesulfonate (TMSOTf), zinc dichloride, or the like can be used. Titanium tetrachloride is preferable.
As N-alkylimidazole, N-methylimidazole, N-ethylimidazole and the like can be used. N-methylimidazole is preferable.
As the base, N, N′-diisopropylethylamine, diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. N, N′-diisopropylethylamine is preferable.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preference is given to methylene chloride and / or ethyl acetate. These solvents may be appropriately selected and used in combination with a base.

（式中、Ｈａｌはハロゲン、Ｒ^６はＲ^３、Ｒ^４またはＲ^３若しくはＲ^４に誘導できる基である。その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程Ｅ
化合物（Ｘ−４）を適切な溶媒中、ヒドラジン（例えば、ヒドラジンモノハイドレート）と反応させ、化合物（Ｘ−５）を得る。０℃〜１００℃で数分〜数時間反応させればよい。
溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、メタノールである。
ヒドラジンのかわりに、式：ＮＨ_２ＮＨＲ^６で示される化合物を用いることもできる。この場合、ヒドラジン環に、ヒドロキシ基と同時にＲ^６を導入することができる。

工程Ｆ
定法により、化合物（Ｘ−５）を用いて、目的化合物に対応する置換基Ｒ^３およびＲ^４を付し、式（Ｉ）で示される化合物を得ることができる。 When X is pyrazole, the compound of the present invention can be synthesized from compound (X-4) using the synthesis method shown below.

(In the formula, Hal is halogen, R ⁶ is a group derivable to R ³ , R ⁴ or R ³ or R ^4. Each other symbol has the same meaning as each symbol in the compound represented by the formula (I). .)

Process E
Compound (X-4) is reacted with hydrazine (for example, hydrazine monohydrate) in a suitable solvent to obtain compound (X-5). What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is methanol.
Instead of hydrazine, a compound represented by the formula: NH ₂ NHR ⁶ can also be used. In this case, R ⁶ can be introduced into the hydrazine ring simultaneously with the hydroxy group.

Process F
The compound represented by the formula (I) can be obtained by adding the substituents R ³ and R ⁴ corresponding to the target compound using the compound (X-5) by a conventional method.

Moreover, as a method of obtaining the compound represented by the formula (I) from the compound (X-4), the following method can also be used.

Process G
Compound (X-4) wherein: a suitable solvent a compound represented by Hal-C (= O) -R 6, it is treated with a base to give compound (X-6). What is necessary is just to make it react for several minutes-several hours at 0 to 50 degreeC.
Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, and mixtures thereof A solvent or the like can be used. Preferably, it is dichloromethane.
As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, metallic sodium and the like can be used. Pyridine is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (X-4).
The step can also be performed in the presence of an activator. As the activator, magnesium chloride, magnesium bromide, magnesium iodide and the like can be used. Preferably, it is magnesium chloride. It is preferable to use 1 to 5 equivalents of an activator with respect to compound (X-4).

Process H
Compound (X-6) is treated with a base in a suitable solvent to give compound (X-7). What is necessary is just to make it react for several minutes-several hours at 0 to 50 degreeC.
Solvents include dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane (methylene chloride), toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, A mixed solvent thereof or the like can be used. Preferred is dimethyl sulfoxide. These solvents may be appropriately selected and used in combination with a base.
As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Sodium chloride is preferred. It is preferable to use 1 to 5 equivalents of a base relative to compound (X-6).

Process I
Compound (X-7) is reacted with hydrazine (for example, hydrazine monohydrate) in a suitable solvent to obtain a compound represented by formula (I). What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is methanol.

（式中、Ｂは保護基、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物（Ｘａ−１）を得、工程Ｂ〜工程Ｉを行うこともできる。
保護基としては、ベンジルオキシカルボニル、ｔｅｒｔ−ブトキシカルボニル、フルオレニルメトキシカルボニル等が挙げられる。好ましくは、ベンジルオキシカルボニルである。 In Step A, the amino group of the compound (X-1) having the substituent R ⁵ corresponding to the target compound is protected by a conventional method, and the formula:

(In the formula, B is a protecting group, and other symbols are the same as the symbols in the compound represented by formula (I).)
The compound (Xa-1) shown by these is obtained, and the process B-the process I can also be performed.
Examples of the protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl and the like. Preferably, it is benzyloxycarbonyl.

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）
で示される化合物（Ｘａ−２）を得る。 After step I, deprotection is carried out by a conventional method, and the formula:

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I).)
The compound (Xa-2) shown by is obtained.

Compound (Xa-2) can be treated with a base represented by the formula: R ¹ (R ² ) —N—SO ₂ -Hal in a suitable solvent to give a compound represented by formula (I). . The reaction conditions are the same as in step A.

（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程 a
目的化合物に対応する置換基Ｒ^１、Ｒ^２、Ｒ^５を有する化合物（ＩＶ−１）（合成法はＷＯ２００７／１２５９５２に記載）とトリハロ酢酸ハライドおよびそのＮａ塩を適当な溶媒中、０℃〜５０℃で数分〜数時間反応させ、化合物（ＩＶ−２）を得る。
溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、ジメチルホルムアミドである。

工程ｂ
化合物（ＩＶ−２）とスルホニルハライドを適当な溶媒中で、塩基存在下で反応させ、化合物（ＩＶ−３）を得る。０℃〜１００℃で数分〜数時間反応させればよい。
スルホニルハライドとしては、ｐ−トルエンスルホニルクロリド、ベンゼンスルホニルクロリド、メタンスルホニルクロリド、トリフルオロメタンスルホニルクロリド等を用いることができる。
塩基としては、トリエチルアミン、ピリジン、N-メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくはトリエチルアミンである。化合物（ＩＶ−２）に対して、１〜５等量の塩基を用いるのが好ましい。
溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、N-メチルピロリドン、ジエチルエーテル、１，２−ジクロロエタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、塩化メチレンである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。
触媒としては、DABCO (1,4-Diazabicyclo[2,2,2]octane)、HCl、H₂SO₄、酢酸、CF₃COOH、トルエンスルホン酸、ｐ−トルエンスルホン酸等が挙げられる。好ましくは、DABCOである。

工程c
化合物（ＩＶ−３）を適当な溶媒中、塩基で処理し、化合物（ＩＶ−４）を得る。−５０℃〜５０℃で数分〜数時間反応させればよい。
塩基としては、ｎ−ブチルリチウム、ｓｅｃ−ブチルリチウム、ｔｅｒｔ−ブチルリチウム、メチルリチウム、ヒドラジン、プロパンチオールリチウム塩等を用いることができる。強塩基が好ましく、例えば、ｎ−ブチルリチウム等が好ましい。
溶媒としては、塩化メチレン、テトラヒドロフラン、ジエチルエーテル、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、ペンタン、ヘプタン、ジオキサン、アセトン等が使用可能である。好ましくは、テトラヒドロフランおよび／またはヘキサンである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。 Depending on X, compound (IV-4), which is an intermediate of the compound of the present invention, can be synthesized using the synthesis method shown below.

(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Process a
A compound (IV-1) having substituents R ¹ , R ² , R ⁵ corresponding to the target compound (the synthesis method is described in WO2007 / 125595), trihaloacetic acid halide and its Na salt in an appropriate solvent at 0 ° C. to The reaction is carried out at 50 ° C. for several minutes to several hours to obtain compound (IV-2).
Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, Acetonitrile, water, a mixed solvent thereof or the like can be used. Preferred is dimethylformamide.

Step b
Compound (IV-3) is reacted with sulfonyl halide in a suitable solvent in the presence of a base to give compound (IV-3). What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
As the sulfonyl halide, p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride and the like can be used.
As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred. It is preferable to use 1 to 5 equivalents of a base with respect to compound (IV-2).
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, acetonitrile, a mixed solvent thereof and the like can be used. Preferably, it is methylene chloride. These solvents may be appropriately selected and used in combination with a base.
Examples of the catalyst include DABCO (1,4-Diazabicyclo [2,2,2] octane), HCl, H ₂ SO ₄ , acetic acid, CF ₃ COOH, toluenesulfonic acid, p-toluenesulfonic acid and the like. DABCO is preferable.

Process c
Compound (IV-3) is treated with a base in a suitable solvent to give compound (IV-4). What is necessary is just to make it react for several minutes-several hours at -50 degreeC-50 degreeC.
As the base, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium, hydrazine, propanethiol lithium salt and the like can be used. Strong bases are preferred, such as n-butyllithium.
As the solvent, methylene chloride, tetrahydrofuran, diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, acetone and the like can be used. Tetrahydrofuran and / or hexane are preferable. These solvents may be appropriately selected and used in combination with a base.

（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程ｄ
化合物（Ｖ−１）に適当な溶媒中、Ｎ−ブロモスクシンイミドを加え、化合物（Ｖ−２）を得る。−５０℃〜室温で数分〜数時間反応させればよい。
溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、ジクロロメタンおよび／またはメタノールである。

工程ｅ
化合物（Ｖ−２）に適当な溶媒中、ハロゲノ炭酸エチルを加え、化合物（Ｖ−３）を得る。０℃〜１００℃で数分〜数時間反応させればよい。
溶媒としてはテトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、Ｎ-メチルピロリドン、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、ピリジン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能であるが、無溶媒でも実施可能である。好ましくは、テトラヒドロフランおよび／またはピリジンである。
塩基の存在下で行ってもよい。塩基としては、ピリジン、Ｎ-メチルモルホリン、ジメチルアニリン等を使用することができる。 When X is indole, the compound of the present invention can be synthesized as follows.

(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Step d
N-bromosuccinimide is added to compound (V-1) in a suitable solvent to give compound (V-2). The reaction may be performed at −50 ° C. to room temperature for several minutes to several hours.
As the solvent, tetrahydrofuran, dimethylformamide, dichloromethane, toluene, benzene, xylene, cyclohexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, mixed solvents thereof, etc. are used. Is possible. Preferred is dichloromethane and / or methanol.

Process e
Compound (V-3) is obtained by adding halogenoethyl carbonate to compound (V-2) in a suitable solvent. What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, dichloromethane, toluene, benzene, pyridine, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, Acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used, but the present invention can also be performed without a solvent. Tetrahydrofuran and / or pyridine are preferable.
The reaction may be performed in the presence of a base. As the base, pyridine, N-methylmorpholine, dimethylaniline and the like can be used.

Process f
Compound (V-4) and compound (IV-4) are reacted in a suitable solvent in the presence of a base to obtain compound (V-4). What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
As the base, triethylamine, DBU, sodium carbonate, potassium carbonate, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Preferred are triethylamine, potassium carbonate and the like.
Solvents include tetrahydrofuran, dimethylformamide, dimethylacetamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, Propanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Preferred is dimethylformamide.
Examples of the catalyst include Pd (PPh3) 4 (tetrakistriphenylphosphine palladium), PdCl2 (PPh3) 2 (dichlorobistriphenylphosphine palladium), Pd (DBA) (bisdibenzylideneacetone palladium), copper iodide, DABCO and the like. It is done. Preferred is dichlorobistriphenylphosphine palladium and / or copper iodide.

Process g
Compound (V-4) is treated with a base in a suitable solvent to give compound (I-3). What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
Use as bases tetrabutylammonium fluoride, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, hydrazine, propanethiol lithium salt, etc. Can do. Tetrabutylammonium fluoride is preferred.
Solvents include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, etc. A mixed solvent or the like can be used. Tetrahydrofuran is preferable. These solvents may be appropriately selected and used in combination with a base.

（式中、Ｈａｌはハロゲン、その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程ｈ
化合物（ＶＩ−１）を適当な溶媒中、塩基の存在下で、シアノギ酸エチルと反応させることにより、化合物（ＶＩ−２）を得る。−１００℃〜０℃で数分〜数時間反応させればよい。
塩基としては、リチウムジイソプロピルアミン、リチウムテトラメチルピペリジド、ｎ−ブチルリチウム、ｓｅｃ−ブチルリチウム、ｔｅｒｔ−ブチルリチウム、メチルリチウム、メチルリチウム等を用いることができる。好ましくは、リチウムジイソプロピルアミンである。
溶媒としては、テトラヒドロフラン、ジエチルエーテル、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、ペンタン、ヘプタン、ジオキサン、それらの混合溶媒等が使用可能である。好ましくは、テトラヒドロフランである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。

工程ｉ
化合物（ＶＩ−２）を適当な溶媒中、塩基で処理し、化合物（ＶＩ−３）を得る。０℃〜５０℃で数分〜数時間反応させればよい。
塩基としては、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム等を用いることができる。好ましくは、水酸化ナトリウムである。
溶媒としては、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、エタノールである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。 When X is pyrrolopyrimidine, the compound of the present invention can be synthesized as follows.

(In the formula, Hal is halogen, and other symbols have the same meanings as those in the compound represented by the formula (I).)

Process h
Compound (VI-2) is obtained by reacting compound (VI-1) with ethyl cyanoformate in a suitable solvent in the presence of a base. The reaction may be performed at −100 ° C. to 0 ° C. for several minutes to several hours.
As the base, lithium diisopropylamine, lithium tetramethylpiperide, n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, methyllithium, or the like can be used. Lithium diisopropylamine is preferable.
As the solvent, tetrahydrofuran, diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, a mixed solvent thereof or the like can be used. Tetrahydrofuran is preferable. These solvents may be appropriately selected and used in combination with a base.

Step i
Compound (VI-2) is treated with a base in a suitable solvent to give compound (VI-3). What is necessary is just to make it react for several minutes-several hours at 0 to 50 degreeC.
As the base, barium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide or the like can be used. Sodium hydroxide is preferable.
As the solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, mixed solvents thereof, etc. are used. Is possible. Preferably, it is ethanol. These solvents may be appropriately selected and used in combination with a base.

Step j
Compound (VI-4) is obtained by treating compound (VI-3) with a base in a suitable solvent and reacting with diphenylphosphoric acid azide. What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
As the base, diisopropylamine, triethylamine, dimethylaminopyridine and the like can be used. Triethylamine is preferable.
As the solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, chloroform, dioxane, acetone, acetonitrile, butanol, a mixed solvent thereof or the like can be used. T-butanol is preferable. These solvents may be appropriately selected and used in combination with a base.

Process k
Compound (VI-4) and compound (IV-4) are reacted in an appropriate solvent in the presence of a base to obtain compound (VI-5). What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC. The reaction conditions are the same as in step f.

Process l
Compound (VI-5) is treated with a base in a suitable solvent to give compound (I-4). What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
As the base, 1,8-diazabicyclo [5,4,0] -7-undecene, tetrabutylammonium fluoride, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, metal alkoxide and the like can be used. 1,8-diazabicyclo [5,4,0] -7-undecene is preferred.
As the solvent, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. is there. Methanol and / or water are preferred. These solvents may be appropriately selected and used in combination with a base.
In the compounds (VI-1), (VI-2), (VI-3), (VI-4), and (VI-5) in steps h to l, compounds having different nitrogen atom positions and numbers are used. Thus, the compound represented by the formula (I) in which X is various aromatic heterocycles can be synthesized.

（式中、Ｙは式（Ｉ）のＲ^３、Ｒ^４または水素を示す。その他各記号は式（Ｉ）で示される化合物における各記号と同意義である。）

工程ｍ
目的化合物に対応する置換基Ｒ^１、Ｒ^２、Ｒ^５を有する化合物（ＶＩＩ−１）（合成法はＷＯ２００１／０３７８２６に記載）を適当な溶媒中、脱水剤で処理し、０℃〜５０℃で数分〜数時間反応させて、酸ハロゲン化物に変換した後、さらに、Ｎ，Ｏ−ジメチルヒドロキシアミン塩酸塩を加え、適当な溶媒中、塩基存在下、０℃〜５０℃で数分〜数時間反応させ、化合物（ＶＩＩ−２）を得る。
脱水剤としては、オキサリルクロリド、チオニルクロリド、五塩化リン、オキシ塩化リン、無水酢酸、メタンスルホニルクロリド、クロロ炭酸エチル等が挙げられる。好ましくはオキサリルクロリドである。化合物（ＶＩＩ−１）に対して、１〜５等量の脱水剤を用いるのが好ましい。また、触媒としてジメチルホルムアミドを加えても良い。
塩基としては、トリエチルアミン、ピリジン、N-メチルモルホリン、ジメチルアニリン、炭酸カリウム、炭酸ナトリウム、水酸化バリウム、水酸化ナトリウム、水酸化カリウム等を用いることができる。好ましくはトリエチルアミンである。
溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジメチルアセタミド、Ｎ−メチルピロリドン、ジエチルエーテル、１，２−ジクロロエタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、塩化メチレンおよび／またはジメチルホルムアミドである。これらの溶媒は、塩基との組み合わせで適宜選択して使用すればよい。

工程ｎ
化合物（ＶＩＩ−２）で示される化合物を適当な溶媒中、メチル化試薬で処理し、化合物（ＶＩＩ−３）を得る。−８０℃〜１００℃で数分〜数時間反応させればよい。
メチル化試薬としては、メチルマグネシウムブロミド、メチルマグネシウムクロリド、メチルマグネシウムヨージド、メチルリチウムを用いることができる。好ましくは、メチルマグネシウムブロミド、メチルマグネシウムクロリドである。化合物（ＶＩＩ−２）に対して、１〜５等量のグリニャール試薬を用いるのが好ましい。
溶媒としては、テトラヒドロフラン、ジエチルエーテル、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、ペンタン、ヘプタン、ジオキサン、それらの混合溶媒等が使用可能である。好ましくは、テトラヒドロフランおよび／またはジエチルエーテルである。これらの溶媒は、メチル化試薬との組み合わせで適宜選択して使用すればよい。 When X is pyrrole, the compound of the present invention can be synthesized as follows.

(In the formula, Y represents R ³ , R ⁴ or hydrogen in formula (I). Other symbols are the same as those in the compound represented by formula (I).)

Process m
A compound (VII-1) having substituents R ¹ , R ² , and R ⁵ corresponding to the target compound (the synthesis method is described in WO2001 / 037826) is treated with a dehydrating agent in an appropriate solvent, and 0 ° C. to 50 ° C. For several minutes to several hours to convert to acid halide, and further, N, O-dimethylhydroxyamine hydrochloride is added, and in a suitable solvent in the presence of a base at 0 ° C. to 50 ° C. for several minutes to Reaction is carried out for several hours to obtain compound (VII-2).
Examples of the dehydrating agent include oxalyl chloride, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, acetic anhydride, methanesulfonyl chloride, ethyl chlorocarbonate and the like. Oxalyl chloride is preferred. It is preferable to use 1 to 5 equivalents of a dehydrating agent with respect to compound (VII-1). Further, dimethylformamide may be added as a catalyst.
As the base, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, potassium carbonate, sodium carbonate, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Triethylamine is preferred.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, Pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, a mixed solvent thereof and the like can be used. Methylene chloride and / or dimethylformamide are preferable. These solvents may be appropriately selected and used in combination with a base.

Process n
The compound represented by compound (VII-2) is treated with a methylating reagent in an appropriate solvent to obtain compound (VII-3). The reaction may be performed at −80 ° C. to 100 ° C. for several minutes to several hours.
As the methylating reagent, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, or methyllithium can be used. Preferred are methylmagnesium bromide and methylmagnesium chloride. It is preferable to use 1 to 5 equivalents of a Grignard reagent with respect to compound (VII-2).
As the solvent, tetrahydrofuran, diethyl ether, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, a mixed solvent thereof or the like can be used. Tetrahydrofuran and / or diethyl ether are preferred. These solvents may be appropriately selected and used in combination with a methylating reagent.

Process o
Compound (VII-3) and an aldehyde having a substituent R ³ corresponding to the target compound are treated with a base in an appropriate solvent to obtain compound (VII-4). What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
As the base, triethylamine, pyridine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, butyllithium, LDA, sodium methoxide and the like can be used. Sodium hydroxide is preferred.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, pentane, heptane, dioxane, methanol, Ethanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Preferably, it is methanol. These solvents may be appropriately selected and used in combination with a base.

Process p
Compound (VII-4) and nitromethane are treated with a base in an appropriate solvent to obtain compound (VII-5). What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
As the base, tetrabutylammonium fluoride, potassium fluoride, cesium fluoride, diethylamine, triethylamine, pyridine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Preferred is diethylamine.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, water, Those mixed solvents can be used. Preferably, it is methanol. These solvents may be appropriately selected and used in combination with a base.

Process q
Compound (VII-5) is treated with a base at 0 ° C. to 100 ° C. for several minutes to several hours in a suitable solvent, further treated with methanol at 0 ° C. to 65 ° C. for several minutes to several hours, and then treated with acid. By doing this, compound (VII-6) is obtained.
As the base, diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Preferably, it is potassium hydroxide.
As the acid, concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid and the like can be used. Preferably, it is concentrated sulfuric acid.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, Ethanol, propanol, acetonitrile, water, a mixed solvent thereof or the like can be used. Methanol and / or tetrahydrofuran are preferred. These solvents may be appropriately selected and used in combination with a base or an acid.

Process r
Compound (VII-6) is reacted with ammonium acetate in a suitable solvent to give compound (I-5). What is necessary is just to make it react for several minutes-several hours at room temperature -150 degreeC.
Solvents include acetic acid, methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, diethyl ether, diisopropyl ether, 1,2-dichloroethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, acetic acid. Ethyl, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, propanol, acetonitrile, water, a mixed solvent thereof and the like can be used. Preferably, it is acetic acid.

（式中、Ｈａｌはハロゲン、ＹおよびＺはそれぞれ式（Ｉ）のＲ^３、Ｒ^４または水素を示す。その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程ｓ
目的化合物に対応するＲ^３を有する化合物（ＶＩＩＩ−１）とテトラブチルアンモニウムハライドを適当な溶媒中、１００℃〜２００℃で(場合によってはマイクロウェーブ反応装置を用いて)数分〜数時間反応させ、化合物（ＶＩＩＩ−２）を得る。
溶媒としては、酢酸、塩化メチレン、テトラヒドロフラン、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、メタノール、エタノール、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、アセトニトリルである。

工程ｔ
化合物（ＶＩＩＩ−２）を適当な溶媒中、ヘキサメチレンテトラミンと反応させることにより、化合物（ＶＩＩＩ−３）を得る。室温〜１００℃で数分〜数時間反応させればよい。
溶媒としては、酢酸、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、アセトニトリル、それらの混合溶媒等が使用可能である。好ましくは、クロロホルムである。 When X is imidazole, the compound of the present invention can be synthesized as follows.

(In the formula, Hal represents halogen, Y and Z each represent R ³ , R ⁴ or hydrogen in formula (I). The other symbols have the same meanings as those in the compound represented by formula (I). )

Process s
Reaction of compound (VIII-1) having R ³ corresponding to the target compound and tetrabutylammonium halide in a suitable solvent at 100 ° C. to 200 ° C. (possibly using a microwave reactor) for several minutes to several hours To give compound (VIII-2).
Solvents include acetic acid, methylene chloride, tetrahydrofuran, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, methanol, ethanol, acetonitrile, and mixtures thereof A solvent or the like can be used. Acetonitrile is preferred.

Process t
Compound (VIII-3) is obtained by reacting compound (VIII-2) with hexamethylenetetramine in a suitable solvent. What is necessary is just to make it react for several minutes-several hours at room temperature-100 degreeC.
Solvents include acetic acid, methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, acetonitrile, those A mixed solvent or the like can be used. Preferably, it is chloroform.

Step u
Compound (VIII-3) is reacted with an acid in a suitable solvent to give compound (VIII-4). What is necessary is just to make it react for several minutes-several hours at room temperature-100 degreeC.
As the acid, concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid and the like can be used. Concentrated hydrochloric acid is preferred.
As the solvent, acetic acid, methylene chloride, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, pentane, heptane, dioxane, methanol, ethanol, acetonitrile, a mixed solvent thereof or the like can be used. Preferably, it is ethanol.

Process v
Compound (VIII-5) is obtained by reacting compound (VII-1) having substituents R ¹ , R ² and R ⁵ corresponding to the target compound and compound (VIII-4). The reaction conditions are the same as in step m above.

Process w
Compound (I-6) can be obtained by subjecting compound (VIII-5) to the same method as in step r above.

（式中、Ｙは式（Ｉ）のＲ^３、Ｒ^４または水素を示す。その他各記号は、式（Ｉ）で示される化合物における各記号と同意義である。）

工程ｘ
目的化合物に対応する置換基Ｒ^３、Ｒ^４を有する化合物（ＩＸ−１）を適切な溶媒中、ハロゲノメチルと反応させ、化合物（ＩＸ−２）で示される化合物を得る。０℃〜１００℃で数分〜数時間反応させればよい。
溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、アセトニトリルである。

工程ｙ
目的化合物に対応する置換基Ｒ^１、Ｒ^２、Ｒ^５を有する化合物（ＶＩＩ−１）を適当な溶媒中、脱水剤で処理し、０℃〜５０℃で数分〜数時間反応させ、さらに、ヒドラジン一水和物を加え、適当な溶媒中、０℃〜５０℃で数分〜数時間反応させ、化合物（ＩＸ-３）を得る。
脱水剤としては、カルボニルジイミダゾール、ジシクロヘキシルカルボジイミド、トリフルオロベンゼンボロニックアシッド、ビス（ビストリメチルシリルアミノ）スズ等が挙げられる。好ましくはカルボニルジイミダゾールである。化合物（ＶＩＩ−１）に対して、１〜５等量の脱水剤を用いるのが好ましい。
溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、テトラヒドロフランである。

工程ｚ
化合物（Ｘ-３）と化合物（Ｘ−２）を適切な溶媒中、塩基で処理することによって、化合物（ＶＩ−７）を得る。５０℃〜１５０℃で数分〜数時間反応させればよい。
塩基としては、ジエチルアミン、トリエチルアミン、ピリジン、N-メチルモルホリン、ジメチルアニリン、水酸化バリウム、水酸化ナトリウム、水酸化カリウム、ヒドラジン、プロパンチオールリチウム塩等を用いることができる。好ましくは、トリエチルアミンである。
溶媒としては、塩化メチレン、テトラヒドロフラン、ジメチルホルムアミド、ジエチルエーテル、ジクロロメタン、トルエン、ベンゼン、キシレン、シクロヘキサン、へキサン、クロロホルム、酢酸エチル、酢酸ブチル、ペンタン、ヘプタン、ジオキサン、アセトン、メタノール、エタノール、アセトニトリル、水、それらの混合溶媒等が使用可能である。好ましくは、エタノールである。
Ｘが上記に示した芳香族ヘテロ環以外の環であっても、有機化学の知識を用いて、Ｘが各種の芳香族ヘテロ環または非芳香族へテロ環である化合物についても、製造することができる。
Ｒ^１およびＲ^５が隣接する窒素原子と一緒になって置換若しくは非置換の含窒素非芳香族ヘテロ環を形成している化合物についても、以下のように合成することができる。

（式中、各記号は、式（Ｉ）で示される化合物における各記号と同意義である。式中のベンゼン環は置換基を有していてもよいし、ベンゼン環の代わりに他の環であってもよい。）
化合物（Ｘ−１）とＨ_２ＮＳＯ_２ＮＨ_２を塩基の存在下で反応させ、化合物（Ｉ−８）を得る。塩基としては、ピリジンなどを用いることができる。 When X is triazole, the compound of the present invention can be synthesized as follows.

(In the formula, Y represents R ³ , R ⁴ or hydrogen in formula (I). Each other symbol has the same meaning as each symbol in the compound represented by formula (I).)

Process x
Compound (IX-1) having substituents R ³ and R ⁴ corresponding to the target compound is reacted with halogenomethyl in an appropriate solvent to obtain a compound represented by compound (IX-2). What is necessary is just to make it react for several minutes-several hours at 0 to 100 degreeC.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Acetonitrile is preferred.

Process y
The compound (VII-1) having substituents R ¹ , R ² and R ⁵ corresponding to the target compound is treated with a dehydrating agent in a suitable solvent, reacted at 0 ° C. to 50 ° C. for several minutes to several hours, Then, hydrazine monohydrate is added, and the mixture is reacted in an appropriate solvent at 0 ° C. to 50 ° C. for several minutes to several hours to obtain compound (IX-3).
Examples of the dehydrating agent include carbonyldiimidazole, dicyclohexylcarbodiimide, trifluorobenzeneboronic acid, bis (bistrimethylsilylamino) tin, and the like. Preferred is carbonyldiimidazole. It is preferable to use 1 to 5 equivalents of a dehydrating agent with respect to compound (VII-1).
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Tetrahydrofuran is preferable.

Step z
Compound (VI-7) is obtained by treating compound (X-3) and compound (X-2) with a base in a suitable solvent. What is necessary is just to make it react for several minutes-several hours at 50 to 150 degreeC.
As the base, diethylamine, triethylamine, pyridine, N-methylmorpholine, dimethylaniline, barium hydroxide, sodium hydroxide, potassium hydroxide, hydrazine, propanethiol lithium salt and the like can be used. Triethylamine is preferable.
Solvents include methylene chloride, tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane, hexane, chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane, acetone, methanol, ethanol, acetonitrile, Water, a mixed solvent thereof or the like can be used. Preferably, it is ethanol.
Even if X is a ring other than the aromatic heterocycle shown above, using the knowledge of organic chemistry, also producing compounds in which X is various aromatic heterocycles or non-aromatic heterocycles Can do.
A compound in which R ¹ and R ⁵ together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle can also be synthesized as follows.

(In the formula, each symbol has the same meaning as each symbol in the compound represented by formula (I). The benzene ring in the formula may have a substituent, or another ring instead of the benzene ring. It may be.)
Compound (I-1) is reacted with H ₂ NSO ₂ NH ₂ in the presence of a base to give compound (I-8). As the base, pyridine or the like can be used.

（式中、Ｒ^５は水素または置換若しくは非置換のアルキルである。好ましくは、Ｒ^５が水素である。その他各記号は式（Ｉ）で示される化合物における各記号と同意義である。）で示される化合物。なお、シクロヘキサン環に置換している−≡は、式：−Ｃ≡ＣＨで示される基を表す。 In the above steps, the following intermediates are useful.
formula:

(In the formula, R ⁵ is hydrogen or substituted or unsubstituted alkyl. Preferably, R ⁵ is hydrogen. Other symbols are as defined in the compound represented by formula (I).) A compound represented by Note that —≡ substituted on the cyclohexane ring represents a group represented by the formula: —C≡CH.

（式中、Ｒ^５は水素または置換若しくは非置換のアルキルである。その他各記号は式（Ｉ）で示される化合物における各記号と同意義である。好ましくは、Ｒ^５が水素である。）で示される化合物。 formula:

(In the formula, R ⁵ is hydrogen or substituted or unsubstituted alkyl. The other symbols have the same meanings as those in the compound represented by formula (I). Preferably, R ⁵ is hydrogen.) A compound represented by

（式中、Ｒ^５は水素または置換若しくは非置換のアルキルであり、Ｒ^８は置換若しくは非置換のアルキルである。好ましくは、Ｒ^５が水素であり、Ｒ^８がメチル、エチル、イソプロピルまたはｔｅｒｔ−ブチルである。その他各記号は式（Ｉ）で示される化合物における各記号と同意義である。）で示される化合物。 formula:

Wherein R ⁵ is hydrogen or substituted or unsubstituted alkyl and R ⁸ is substituted or unsubstituted alkyl. Preferably, R ⁵ is hydrogen and R ⁸ is methyl, ethyl, isopropyl or tert -Butyl, and other symbols are the same as those in the compound represented by formula (I).

（式中、Ｒ^５は水素または置換若しくは非置換のアルキルである。好ましくは、Ｒ^５が水素である。その他各記号は式（Ｉ）で示される化合物における各記号と同意義である。）で示される化合物。 formula:

(In the formula, R ⁵ is hydrogen or substituted or unsubstituted alkyl. Preferably, R ⁵ is hydrogen. Other symbols are as defined in the compound represented by formula (I).) A compound represented by

The compounds of the present invention are effective for all diseases involving NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders It is particularly useful for the prevention and / or treatment of obesity and weight management in obesity. It is also effective for the prevention and / or treatment of diseases in which obesity is a risk factor, such as diabetes, hypertension, hyperlipidemia, arteriosclerosis, and acute coronary syndrome.
Furthermore, the compound of the present invention has not only NPY Y5 receptor antagonistic activity but also usefulness as a pharmaceutical, and has any or all of the following excellent characteristics.
a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP3A4, etc.) is weak.
b) It is difficult to induce drug metabolizing enzymes.
c) Good pharmacokinetics such as high bioavailability and moderate clearance.
d) Low toxicity such as anemia-inducing action.
e) High metabolic stability.
f) High Y5 receptor selectivity.
g) High water solubility.
h) High brain transferability.
i) Does not cause reproductive toxicity (eg, teratogenicity).
j) Does not cause gastrointestinal disorders (for example, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).

  Furthermore, the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and high Y5 receptor selectivity. NPY induces a sustained vasoconstrictive action in the periphery, but this action is mainly mediated by the Y1 receptor. Since the Y5 receptor is not involved in such an action at all, the possibility of inducing side effects based on peripheral vasoconstriction is low, and a pharmaceutical composition containing the compound of the present invention as an active ingredient can be preferably used as a safe medicine. It is considered possible.

  A pharmaceutical composition comprising the compound of the present invention as an active ingredient suppresses food intake and exhibits an anti-obesity effect. Therefore, side effects such as indigestion as seen in drugs that exhibit anti-obesity effects by inhibiting digestion and absorption, and central side effects such as antidepressant effects such as serotonin transporter inhibitors that exhibit anti-obesity effects Not doing so is one of the features of the pharmaceutical composition.

  When the pharmaceutical composition of the present invention is administered, it can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods. For parenteral administration, any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorption agents, inhalants and the like can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.

  Various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.

  Examples of the excipient include lactose, sucrose, glucose, starch, calcium carbonate, or crystalline cellulose. Examples of the binder include methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, and polyvinyl pyrrolidone. Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate. Examples of the lubricant include talc, magnesium stearate or macrogol. As a suppository base, cacao butter, macrogol, methyl cellulose or the like can be used. In addition, when preparing as liquid or emulsion or suspension injections, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are added as appropriate. You may do it. In the case of oral administration, flavoring agents, fragrances and the like may be added.

  The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc. 100 mg / kg / day, preferably in the range of 0.1-10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.

  The pharmaceutical composition of the present invention can also be used in combination with other known anti-obesity drugs (agents that can be used for weight management in obesity or obesity). Moreover, the administration therapy of the pharmaceutical composition of the present invention can also be used in combination with known diet therapy, drug therapy, exercise and the like.

The present invention will be described in more detail with reference to the following examples, but these are not intended to limit the present invention.
Moreover, the symbol used in this specification represents the following meaning.
Me: methyl Et: ethyl Pr: propyl Bu: butyl THF: tetrahydrofuran DMF: N, N-dimethylformamide DMA: dimethylacetamide DMSO: dimethyl sulfoxide TMSOTf: trimethylsilyl triflate Cbz: benzyloxycarbonyl NMM: N-methylmorpholine NIS: N- Iodosuccinimide

化合物１(10 g, 48.1 mmol)に塩化メチレン(50 ml)を加えた後、氷冷下でジメチルスルファモイルクロリド (10.4 ml, 96.0 mmol)とトリエチルアミン(26.7 ml , 193 mmol)を加え、氷冷下のまま４時間攪拌した。反応液を水へあけ、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去することにより化合物２を得た。
¹H-NMR (CDCl₃) δ: 4.39 (1.0H, d, J = 7.60 Hz), 4.11 (2.0H, q, J = 7.1 Hz), 3.20-3.11 (1.0H, m), 2.97 (6.0H, s), 2.25-2.12 (3.0H, m), 2.03 (2.0H, br-d, J = 15.7 Hz), 1.56-1.46 (2.0H, m), 1.30-1.20 (5.0H, m).

第２工程

化合物２をエタノール(15 ml)とテトラヒドロフラン(30 ml)に溶解させた後、水10mlに溶解した水酸化ナトリウム(2.89 g, 72.2 mmol)を加え、５時間室温で攪拌した。有機溶媒の一部を減圧留去した後、反応液を希塩酸水へあけ、酸性とし、クロロホルムで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去することにより化合物３を定量的に得た。

第３工程

化合物３ (10.7 g, 42.7 mmol)に塩化メチレン(50 ml)を加えた後、氷冷下でオキザリルクロリド(3.85 ml, 44.0 mmol)とＮ，Ｎ’−ジメチルホルムアミド(0.1 ml, 1.28 mmol)を加えた。室温で１時間攪拌した後、反応液を減圧下濃縮して酸クロリドを得た。
Ｎ−メチルイミダゾール(4.09 ml, 51.3 mmol)の塩化メチレン(50 ml)−酢酸エチル(6.70 mL, 68.4 mmol)溶液に、-60℃で酸クロリド(42.7 mmol)の塩化メチレン(50 ml)溶液を加え、さらに同温度で四塩化チタン(15.6 ml, 141 mmol)を滴下し、30分間攪拌した。反応液にＮ，Ｎ’−ジイソプロピルエチルアミン(26.9 ml, 154 mmol)を加え、-40℃で40分間攪拌した後、水を加え、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物４ (9.61 g, 収率70%)を得た。
¹H-NMR (CDCl₃) δ: 4.19 (2.0H, q, J = 7.1 Hz), 4.12 (1.0H, d, J = 8.1 Hz), 3.47 (2.0H, s), 3.19-3.11 (1.0H, m), 2.79 (6.0H, s), 2.47-2.39 (1.0H, m), 2.19-2.16 (2.0H, m), 1.99 (2.0H, br-d, J = 13.69 Hz), 1.51-1.40 (2.0H, m), 1.31-1.19 (5.0H,m). Example 1 First Step of Synthesis of Compound Ia-1

Methylene chloride (50 ml) was added to compound 1 (10 g, 48.1 mmol), and then dimethylsulfamoyl chloride (10.4 ml, 96.0 mmol) and triethylamine (26.7 ml, 193 mmol) were added under ice-cooling. The mixture was stirred for 4 hours with cooling. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 2.
¹ H-NMR (CDCl ₃ ) δ: 4.39 (1.0H, d, J = 7.60 Hz), 4.11 (2.0H, q, J = 7.1 Hz), 3.20-3.11 (1.0H, m), 2.97 (6.0H , s), 2.25-2.12 (3.0H, m), 2.03 (2.0H, br-d, J = 15.7 Hz), 1.56-1.46 (2.0H, m), 1.30-1.20 (5.0H, m).

Second step

Compound 2 was dissolved in ethanol (15 ml) and tetrahydrofuran (30 ml), sodium hydroxide (2.89 g, 72.2 mmol) dissolved in 10 ml of water was added, and the mixture was stirred at room temperature for 5 hours. After part of the organic solvent was distilled off under reduced pressure, the reaction solution was poured into dilute hydrochloric acid, acidified, and extracted with chloroform. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain Compound 3 quantitatively.

Third step

Methylene chloride (50 ml) was added to compound 3 (10.7 g, 42.7 mmol), and then oxalyl chloride (3.85 ml, 44.0 mmol) and N, N′-dimethylformamide (0.1 ml, 1.28 mmol) were added under ice cooling. Was added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to obtain acid chloride.
To a solution of N-methylimidazole (4.09 ml, 51.3 mmol) in methylene chloride (50 ml) -ethyl acetate (6.70 mL, 68.4 mmol) was added a solution of acid chloride (42.7 mmol) in methylene chloride (50 ml) at -60 ° C. In addition, titanium tetrachloride (15.6 ml, 141 mmol) was further added dropwise at the same temperature, followed by stirring for 30 minutes. N, N′-diisopropylethylamine (26.9 ml, 154 mmol) was added to the reaction mixture, and the mixture was stirred at −40 ° C. for 40 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 4 (9.61 g, yield 70%).
¹ H-NMR (CDCl ₃ ) δ: 4.19 (2.0H, q, J = 7.1 Hz), 4.12 (1.0H, d, J = 8.1 Hz), 3.47 (2.0H, s), 3.19-3.11 (1.0H , m), 2.79 (6.0H, s), 2.47-2.39 (1.0H, m), 2.19-2.16 (2.0H, m), 1.99 (2.0H, br-d, J = 13.69 Hz), 1.51-1.40 (2.0H, m), 1.31-1.19 (5.0H, m).

塩化マグネシウム(1.48 g, 15.6 mmol)に塩化メチレン(20 ml)を加えた後、化合物４(5.0 g, 15.6 mmol)を加えた。この懸濁液に氷冷下にてピリジン(2.52 ml, 31.2 mmol)を加え、15分間攪拌した。その後、氷冷下のまま3-フルオロベンゾイルクロリド(1.90ml, 15.6 mmol)の塩化メチレン(5 ml)溶液を加えた後、室温で４時間攪拌した。反応液を希塩酸水へあけ、酸性とし酢酸エチルで抽出した。有機層を水洗し更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去することにより化合物５(6.68 g, 収率97%)を得た。

第５工程

化合物５ (6.68 g, 15.1 mmol)にジメチルスルホキシド(25ml)を加えた後、塩化ナトリウム(970 mg, 16.6 mmol)と水(0.54ml, 30.2 mmol)を加え、140℃で1時間攪拌した。反応液を水へあけ酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物６ (942 mg, 収率17%)を得た。
¹H-NMR (CDCl₃) δ: 7.65 (1.0H, d, J = 7.6 Hz), 7.57 (1.0H, d, J = 9.6 Hz), 7.45-7.40 (1.0H, m), 7.24-7.20 (1.0H, m), 6.13 (1.0H, s), 4.07 (1.0H, d, J = 8.1 Hz), 3.25-3.18 (1.0H, m), 2.81 (6.0H, s), 2.31-2.17 (3.0H, m), 2.02 (2.0H, br-d, J = 13.2 Hz), 1.64-1.55 (2.0H, m), 1.34-1.24 (2.0H, m).

第６工程

化合物６ (433 mg, 1.17 mmol)にメタノール(6 ml)を加えた後、ヒドラジン一水和物(0.068 ml, 1.40 mmol)を加え、室温で４時間攪拌した。反応液を水へあけ酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物Ｉａ−１(320 mg, 収率75%)を得た。
¹H-NMR (CDCl₃) δ: 7.49-7.33 (3.0H, m), 7.01 (1.0H, td, J = 8.4, 2.5 Hz), 4.14 (1.0H, d, J = 7.6 Hz), 3.30-3.23 (1.0H, m), 2.82 (6.0H, s), 2.68-2.62 (1.0H, m), 2.18 (4.0H, dd, J = 42.6, 13.2 Hz), 1.58 (2.0H, q, J = 13.0 Hz), 1.36 (2.0H, q, J = 12.5 Hz). Fourth step

Methylene chloride (20 ml) was added to magnesium chloride (1.48 g, 15.6 mmol), and then compound 4 (5.0 g, 15.6 mmol) was added. Pyridine (2.52 ml, 31.2 mmol) was added to this suspension under ice cooling, and the mixture was stirred for 15 minutes. Thereafter, a solution of 3-fluorobenzoyl chloride (1.90 ml, 15.6 mmol) in methylene chloride (5 ml) was added with ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into dilute hydrochloric acid, acidified and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 5 (6.68 g, yield 97%).

5th process

Dimethyl sulfoxide (25 ml) was added to compound 5 (6.68 g, 15.1 mmol), sodium chloride (970 mg, 16.6 mmol) and water (0.54 ml, 30.2 mmol) were added, and the mixture was stirred at 140 ° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 6 (942 mg, yield 17%).
¹ H-NMR (CDCl ₃ ) δ: 7.65 (1.0H, d, J = 7.6 Hz), 7.57 (1.0H, d, J = 9.6 Hz), 7.45-7.40 (1.0H, m), 7.24-7.20 ( 1.0H, m), 6.13 (1.0H, s), 4.07 (1.0H, d, J = 8.1 Hz), 3.25-3.18 (1.0H, m), 2.81 (6.0H, s), 2.31-2.17 (3.0 H, m), 2.02 (2.0H, br-d, J = 13.2 Hz), 1.64-1.55 (2.0H, m), 1.34-1.24 (2.0H, m).

6th process

Methanol (6 ml) was added to compound 6 (433 mg, 1.17 mmol), hydrazine monohydrate (0.068 ml, 1.40 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound Ia-1 (320 mg, yield 75%).
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.33 (3.0H, m), 7.01 (1.0H, td, J = 8.4, 2.5 Hz), 4.14 (1.0H, d, J = 7.6 Hz), 3.30- 3.23 (1.0H, m), 2.82 (6.0H, s), 2.68-2.62 (1.0H, m), 2.18 (4.0H, dd, J = 42.6, 13.2 Hz), 1.58 (2.0H, q, J = 13.0 Hz), 1.36 (2.0H, q, J = 12.5 Hz).

化合物１ (10 g, 48.1 mmol)にアセトニトリル(40 ml)と水(20 ml)を加えた後、氷冷下でベンジルオキシカルボニルクロリド (8.25 ml, 57.8 mmol)とトリエチルアミン(26.7 ml , 193 mmol)を加え、氷冷下のまま４時間攪拌した。反応液を希塩酸水へあけ、酸性とし、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去することにより化合物８ (11.9 g, 収率81%)を得た。
¹H-NMR (CDCl₃) δ: 7.36-7.31 (5.0H, m), 5.09 (2.0H, s), 4.12 (2.0H, q, J = 7.1 Hz), 2.21 (1.0H, tt, J = 12.2, 3.5 Hz), 2.10-2.00 (4.0H, m), 1.59-1.49 (2.0H, m), 1.24 (3.0H, t, J = 7.1 Hz), 1.14 (2.0H, q, J = 12.5 Hz).

第２工程

化合物８(14.7 g, 48.1 mmol)をエタノール(60 ml)とテトラヒドロフラン(30 ml)に溶解させた後、2規定水酸化ナトリウム水溶液(120 ml, 240 mmol)を加え、室温で4時間攪拌した。反応液を希塩酸水へあけ、酸性とし、クロロホルムで抽出し、有機層を水洗し、更に飽和食塩水で洗浄した。この時目的物の一部が結晶として析出したため、それらを濾取した。濾液の有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去することにより結晶を得た。先に濾取した結晶と合わせ、酢酸エチル―ヘキサンの混合溶媒から再結晶精製することで、化合物９ (5.49 g, 収率41%)を得た。
¹H-NMR (DMSO-d₆) δ: 7.38-7.29 (5.0H, m), 7.19 (1H, d, J = 8.1 Hz), 4.99 (2.0H, s), 3.25-3.22 (1.0H, m), 2.12-2.06 (1.0H, m), 1.90-1.82 (4.0H, m), 1.33 (2.0H, dd, J = 25.1, 10.4 Hz), 1.17 (2.0H, q, J = 11.3 Hz). Example 2 First Step of Synthesis of Compound Ia-9 and Compound IIa-3

Acetonitrile (40 ml) and water (20 ml) were added to compound 1 (10 g, 48.1 mmol), and then benzyloxycarbonyl chloride (8.25 ml, 57.8 mmol) and triethylamine (26.7 ml, 193 mmol) under ice-cooling. And stirred for 4 hours with ice cooling. The reaction solution was poured into dilute hydrochloric acid, acidified, and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 8 (11.9 g, yield 81%).
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.31 (5.0H, m), 5.09 (2.0H, s), 4.12 (2.0H, q, J = 7.1 Hz), 2.21 (1.0H, tt, J = 12.2, 3.5 Hz), 2.10-2.00 (4.0H, m), 1.59-1.49 (2.0H, m), 1.24 (3.0H, t, J = 7.1 Hz), 1.14 (2.0H, q, J = 12.5 Hz ).

Second step

Compound 8 (14.7 g, 48.1 mmol) was dissolved in ethanol (60 ml) and tetrahydrofuran (30 ml), 2N aqueous sodium hydroxide solution (120 ml, 240 mmol) was added, and the mixture was stirred at room temperature for 4 hr. The reaction solution was poured into dilute hydrochloric acid, acidified, extracted with chloroform, the organic layer was washed with water, and further washed with saturated brine. At this time, some of the target product was precipitated as crystals, and they were collected by filtration. The organic layer of the filtrate was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain crystals. Compound 9 (5.49 g, yield 41%) was obtained by combining with the crystals collected earlier and recrystallizing from a mixed solvent of ethyl acetate-hexane.
¹ H-NMR (DMSO-d ₆ ) δ: 7.38-7.29 (5.0H, m), 7.19 (1H, d, J = 8.1 Hz), 4.99 (2.0H, s), 3.25-3.22 (1.0H, m ), 2.12-2.06 (1.0H, m), 1.90-1.82 (4.0H, m), 1.33 (2.0H, dd, J = 25.1, 10.4 Hz), 1.17 (2.0H, q, J = 11.3 Hz).

化合物９ (3.00 g, 10.8 mmol)に塩化メチレン(50 ml)を加えた後、氷冷下でオキザリルクロリド(0.975 ml, 11.1 mmol)とＮ，Ｎ’−ジメチルホルムアミド(0.025 ml, 0.325 mmol)を加えた。室温で１時間攪拌した後、反応液を減圧下濃縮して酸クロリドを得た。
Ｎ−メチルイミダゾール(1.04 ml, 13.0 mmol)の塩化メチレン(50 ml)−酢酸エチル(1.69 mL, 17.3 mmol)溶液に、-60℃で酸クロリド(10.8 mmol)の塩化メチレン(50 ml)溶液を加え、さらに同温度で四塩化チタン(3.94 ml, 35.7 mmol)を滴下し、30分間攪拌した。反応液にN,N’-ジイソプロピルエチルアミン(6.80 ml, 38.9 mmol)を加え、-40℃で40分間攪拌した後、水を加え、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物１０ (1.75 g, 収率47%)を得た。
¹H-NMR (CDCl₃) δ: 7.37-7.31 (5.0H, m), 5.08 (2.0H, s), 4.70 (1.0H, d, J = 5.6 Hz), 4.19 (2.0H, q, J = 7.10 Hz), 3.47-3.44 (3.0H, m), 2.45-2.39 (1.0H, m), 2.12 (2.0H, br-d, J = 10.1 Hz), 1.97 (2.0H, br-d, J = 13.2 Hz), 1.52-1.42 (2.0H, br-d, J = 13.7 Hz), 1.29-1.24 (3.0H, m), 1.15 (2.0H, dd, J = 24.8, 9.6 Hz).

第４工程

塩化マグネシウム(1.03 g, 10.8 mmol)に塩化メチレン(20 ml)を加えた後、化合物１０(3.12 g, 8.98 mmol)を加えた。この懸濁液に氷冷下にてピリジン(1.45 ml, 18.0 mmol)を加え、15分間攪拌した。その後、氷冷下のまま3-フルオロベンゾイルクロリド(1.31 ml, 10.8 mmol)の塩化メチレン(5 ml)溶液を加えた後、室温で２時間攪拌した。反応液を希塩酸水へあけ、酸性とし、酢酸エチルで抽出した。有機層を水洗し、更に飽和食塩水で洗浄して無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物１１ (3.04 g, 収率72%)を得た。

第５工程

化合物１１ (3.04 g, 6.47 mmol)にジメチルスルホキシド(20ml)を加えた後、塩化ナトリウム(416 mg, 7.12 mmol)と水(0.23ml, 13.0 mmol)を加え、140℃で1時間攪拌した。反応液を水へあけ、酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、β-ジケトンを定量的(2.57 g)に得た。
得られたβ-ジケトン(2.57 g, 6.47 mmol)にメタノール(30 ml)を加えた後、ヒドラジン一水和物(0.377 ml, 7.76 mmol)を加え、室温で２時間攪拌した。反応液を水へあけ、酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物１２ (1.41g, 収率55%)を得た。
¹H-NMR (DMSO-d₆) δ: 12.67 (0.9H, s), 7.59-7.24 (9.0H, m), 7.08 (1.0H, s), 6.53 (1.0H, s), 5.02 (2.0H, s), 3.38-3.34 (1.0H, m), 2.61-2.55 (1.0H, s), 2.01-1.90 (4.0H, m), 1.50-1.29 (4.0H, m).

第６工程

化合物１２ (1.41 g, 3.58 mmol)にメタノール(50ml)を加えた後、水酸化パラジウム触媒(282 mg, 2.01 mmol)を加え、常圧室温にて3時間攪拌しながら水素添加反応を行なった。反応液をセライト濾過した後、濾液の溶媒を減圧下留去し、残渣をジオキサン(50 ml)に再度溶解した。氷冷下にて４規定塩酸のジオキサン溶液(1.34 ml, 5.38 mmol)を加え30分間攪拌した後、溶媒を減圧下留去することにより化合物１３を定量的(1.06 g)に得た。
¹H-NMR (DMSO-d₆) δ: 7.61-7.54 (2.0H, m), 7.43 (1.0H, dd, J = 14.2, 8.1 Hz), 7.11 (1.0H, td, J = 8.4, 2.5 Hz), 6.57 (1.0H, s), 3.03 (1.0H, br-s), 2.61 (1.0H, t, J = 8.4 Hz), 2.05 (4.0H, br-d, J = 8.6 Hz), 1.55-1.42 (4.0H, m). Third step

Methylene chloride (50 ml) was added to compound 9 (3.00 g, 10.8 mmol), and then oxalyl chloride (0.975 ml, 11.1 mmol) and N, N′-dimethylformamide (0.025 ml, 0.325 mmol) were added under ice cooling. Was added. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to obtain acid chloride.
To a solution of N-methylimidazole (1.04 ml, 13.0 mmol) in methylene chloride (50 ml) -ethyl acetate (1.69 mL, 17.3 mmol) was added a solution of acid chloride (10.8 mmol) in methylene chloride (50 ml) at -60 ° C. In addition, titanium tetrachloride (3.94 ml, 35.7 mmol) was further added dropwise at the same temperature, followed by stirring for 30 minutes. N, N′-diisopropylethylamine (6.80 ml, 38.9 mmol) was added to the reaction mixture, and the mixture was stirred at −40 ° C. for 40 minutes, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 10 (1.75 g, yield 47%).
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.31 (5.0H, m), 5.08 (2.0H, s), 4.70 (1.0H, d, J = 5.6 Hz), 4.19 (2.0H, q, J = 7.10 Hz), 3.47-3.44 (3.0H, m), 2.45-2.39 (1.0H, m), 2.12 (2.0H, br-d, J = 10.1 Hz), 1.97 (2.0H, br-d, J = 13.2 Hz), 1.52-1.42 (2.0H, br-d, J = 13.7 Hz), 1.29-1.24 (3.0H, m), 1.15 (2.0H, dd, J = 24.8, 9.6 Hz).

Fourth step

Methylene chloride (20 ml) was added to magnesium chloride (1.03 g, 10.8 mmol), and then compound 10 (3.12 g, 8.98 mmol) was added. Pyridine (1.45 ml, 18.0 mmol) was added to this suspension under ice cooling, and the mixture was stirred for 15 minutes. Thereafter, a solution of 3-fluorobenzoyl chloride (1.31 ml, 10.8 mmol) in methylene chloride (5 ml) was added with ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into dilute hydrochloric acid, acidified, and extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 11 (3.04 g, yield 72%).

5th process

Dimethyl sulfoxide (20 ml) was added to compound 11 (3.04 g, 6.47 mmol), sodium chloride (416 mg, 7.12 mmol) and water (0.23 ml, 13.0 mmol) were added, and the mixture was stirred at 140 ° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain β-diketone quantitatively (2.57 g).
Methanol (30 ml) was added to the obtained β-diketone (2.57 g, 6.47 mmol), hydrazine monohydrate (0.377 ml, 7.76 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 12 (1.41 g, yield 55%).
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.9H, s), 7.59-7.24 (9.0H, m), 7.08 (1.0H, s), 6.53 (1.0H, s), 5.02 (2.0H , s), 3.38-3.34 (1.0H, m), 2.61-2.55 (1.0H, s), 2.01-1.90 (4.0H, m), 1.50-1.29 (4.0H, m).

6th process

Methanol (50 ml) was added to compound 12 (1.41 g, 3.58 mmol), palladium hydroxide catalyst (282 mg, 2.01 mmol) was added, and a hydrogenation reaction was performed with stirring at normal pressure and room temperature for 3 hours. The reaction solution was filtered through Celite, and then the solvent of the filtrate was distilled off under reduced pressure. The residue was dissolved again in dioxane (50 ml). Under ice-cooling, 4N hydrochloric acid in dioxane (1.34 ml, 5.38 mmol) was added and stirred for 30 minutes, and then the solvent was distilled off under reduced pressure to obtain compound 13 quantitatively (1.06 g).
¹ H-NMR (DMSO-d ₆ ) δ: 7.61-7.54 (2.0H, m), 7.43 (1.0H, dd, J = 14.2, 8.1 Hz), 7.11 (1.0H, td, J = 8.4, 2.5 Hz ), 6.57 (1.0H, s), 3.03 (1.0H, br-s), 2.61 (1.0H, t, J = 8.4 Hz), 2.05 (4.0H, br-d, J = 8.6 Hz), 1.55- 1.42 (4.0H, m).

2-クロロエタノール(0.374 ml, 5.58 mmol)にアセトニトリル(20 ml)を加えた後、氷冷下でクロロスルホニルイソシアナート (0.484 ml, 5.58 mmol)を加え、同温度にて30分間攪拌し、反応活性種を得た。
化合物１３(1.50 g, 5.07 mmol)にアセトニトリル(100 ml)を加えた後、氷冷下でN-メチルモルフォリン(2.79 ml, 25.4 mmol)を加え、さらに同温度にて上記で調製した反応活性種を滴下した。室温で３時間攪拌後、反応液の溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物Ｉａ−９ (1.68g, 収率81%)を得た。
¹H-NMR (DMSO-d₆) δ: 12.7(1H, s), 8.45 (1H, s), 7.50 (3H, m), 7.07 (1H, s), 6.52 (1H, s), 4.39 (2.6H, t, J = 7.60 Hz), 3.96 (2.6H, t, J = 7.6 Hz), 3.36 (1H, m), 2.63 (1H,m)), 1.97 (4H,m), 1.43 (4H, m).

第８工程

化合物Ｉａ−９ (50.0 mg, 0.122 mmol)にジオキサン(5 ml)を加えた後、プロパン-1-アミン(0.012 ml, 0.147 mmol)、トリエチルアミン(0.051 ml, 0.367 mmol)、トリメチルシリルトリフラート(0.015 ml, 0.122 mmol)を順次加え、80℃で8時間攪拌した。反応液を水へあけ酢酸エチルで抽出した。有機層を水、飽和塩化ナトリウム水溶液で洗浄した後、硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製し、化合物ＩＩａ−３ (33.0 mg, 収率71%)を得た。
¹H-NMR (DMSO-d₆) δ: 12.67 (0.8H, s), 7.57 (2.0H, m), 7.42 (1.0H, m), 7.08 (1.0H, m), 6.80 (1.0H, m), 6.73 (1.0H,m), 6.53 (0.9H, s), 3.00 (1.0H, m), 2.78 (2.0H, q, J = 6.76 Hz), 2.57 (1.0H,m), 2.00 (4.0H,m), 1.52-1.29 (6.0H, m), 0.87 (3.0H, t, J = 7.60 Hz). 7th process

Acetonitrile (20 ml) was added to 2-chloroethanol (0.374 ml, 5.58 mmol), then chlorosulfonyl isocyanate (0.484 ml, 5.58 mmol) was added under ice cooling, and the mixture was stirred at the same temperature for 30 min. Active species were obtained.
Acetonitrile (100 ml) was added to compound 13 (1.50 g, 5.07 mmol), then N-methylmorpholine (2.79 ml, 25.4 mmol) was added under ice cooling, and the reaction activity prepared above at the same temperature. Seeds were dripped. After stirring at room temperature for 3 hours, the solvent of the reaction solution was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound Ia-9 (1.68 g, yield 81%).
¹ H-NMR (DMSO-d ₆ ) δ: 12.7 (1H, s), 8.45 (1H, s), 7.50 (3H, m), 7.07 (1H, s), 6.52 (1H, s), 4.39 (2.6 H, t, J = 7.60 Hz), 3.96 (2.6H, t, J = 7.6 Hz), 3.36 (1H, m), 2.63 (1H, m)), 1.97 (4H, m), 1.43 (4H, m ).

8th step

After adding dioxane (5 ml) to compound Ia-9 (50.0 mg, 0.122 mmol), propan-1-amine (0.012 ml, 0.147 mmol), triethylamine (0.051 ml, 0.367 mmol), trimethylsilyl triflate (0.015 ml, 0.122 mmol) was sequentially added, and the mixture was stirred at 80 ° C. for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound IIa-3 (33.0 mg, yield 71%).
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.8H, s), 7.57 (2.0H, m), 7.42 (1.0H, m), 7.08 (1.0H, m), 6.80 (1.0H, m ), 6.73 (1.0H, m), 6.53 (0.9H, s), 3.00 (1.0H, m), 2.78 (2.0H, q, J = 6.76 Hz), 2.57 (1.0H, m), 2.00 (4.0 H, m), 1.52-1.29 (6.0H, m), 0.87 (3.0H, t, J = 7.60 Hz).

（Ｒ^１およびＲ^２はそれぞれ独立して、水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルコキシ、置換若しくは非置換のシクロアルキル、置換若しくは非置換のシクロアルケニル、置換若しくは非置換のアリール、置換若しくは非置換のヘテロアリールまたは置換若しくは非置換のヘテロサイクリルであり、
Ｒ^１およびＲ^２は隣接する窒素原子と一緒になって置換若しくは非置換の含窒素芳香族ヘテロ環または置換若しくは非置換の含窒素非芳香族ヘテロ環を形成してもよい。）
化合物１６ (１当量)をジオキサンに溶解させ、Ｎ-ヨードスクシンイミド(1.2当量)を加え80℃で数時間攪拌する。その後、反応液をチオ硫酸ナトリウム水溶液へあけ酢酸エチルで抽出する。有機層を水洗し無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去することで化合物１７を得る。

第２工程

（Ｒ^１およびＲ^２は前記と同意義である。）
化合物１７(1当量)、亜鉛粉末(0.2当量)、青酸亜鉛(0.6当量) をジメチルアセトアミドに溶解させ、窒素気流下Pd(P^tBu₃)₂(0.1当量)を加え95℃で数時間攪拌する。その後、反応液を水へあけ酢酸エチルで抽出する。有機層を水洗し無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィにより精製することで目的物１８を得る。
これら化合物１６〜１８も本発明化合物である。 Example 3
First step

(R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
R ¹ and R ² may be combined with an adjacent nitrogen atom to form a substituted or unsubstituted nitrogen-containing aromatic heterocyclic ring or a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic ring. )
Compound 16 (1 equivalent) is dissolved in dioxane, N-iodosuccinimide (1.2 equivalent) is added, and the mixture is stirred at 80 ° C. for several hours. The reaction mixture is then poured into an aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to obtain Compound 17.

Second step

(R ¹ and R ² are as defined above.)
Compound 17 (1 eq), zinc powder (0.2 eq), zinc cyanide (0.6 eq) are dissolved in dimethylacetamide, Pd (P ^t Bu ₃ ) ₂ (0.1 eq) is added under a nitrogen stream, and the mixture is stirred at 95 ° C. for several hours. To do. The reaction mixture is then poured into water and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel chromatography to obtain the desired product 18.
These compounds 16-18 are also this invention compounds.

Hereinafter, the compound represented by the formula (I) can be synthesized in the same manner.

Ia-1
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.33 (2.9H, m), 7.01 (1.0H, td, J = 8.36, 2.53 Hz), 4.14 (1.0H, d, J = 7.60 Hz), 3.30- 3.23 (1.1H, m), 2.82 (5.9H, s), 2.68-2.62 (1.2H, m), 2.18 (4.5H, dd, J = 42.58, 13.18 Hz), 1.58 (2.2H, q, J = 13.01 Hz), 1.36 (2.2H, q, J = 12.50 Hz).

Ia-2
¹ H-NMR (CDCl ₃ ) δ: 7.54 (1.0H, t, J = 9.38 Hz), 7.43 (1.0H, s), 7.18 (1.0H, dt, J = 14.53, 5.07 Hz), 6.29 (1.0H , s), 4.04 (1.0H, d, J = 8.11 Hz), 3.29-3.25 (1.1H, m), 2.82 (6.2H, s), 2.68-2.62 (1.2H, m), 2.24 (2.2H, d, J = 13.18 Hz), 2.12 (2.2H, d, J = 12.67 Hz), 1.58 (6.1H, dd, J = 23.83, 11.66 Hz), 1.37 (2.8H, dd, J = 24.59, 9.38 Hz) .

Ia-3
¹ H-NMR (CDCl ₃ ) δ: 7.83 (0.9H, s), 7.55 (1.3H, dd, J = 12.42, 8.36 Hz), 7.46 (1.0H, d, J = 8.11 Hz), 6.33 (0.9H , s), 4.06 (1.1H, d, J = 7.60 Hz), 3.28 (1.0H, dt, J = 13.01, 4.82 Hz), 2.82 (5.9H, s), 2.65 (1.1H, dd, J = 13.43 , 10.39 Hz), 2.18 (4.2H, dd, J = 48.67, 11.66 Hz), 1.58 (7.4H, dd, J = 24.08, 11.41 Hz), 1.37 (3.2H, dd, J = 24.33, 9.63 Hz).

Ia-4
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.33 (3H, m), 7.02 (1H, m), 6.34 (1H, s), 4.21 (1H, d, J = 8.11 Hz), 3.28 (1H, m ), 2.85 (3H, s), 2.64 (1H, m), 2.34 (1H, m), 2.24 (2H, br-d, J = 11.66 Hz), 2.13 (2H, br-d, J = 13.18 Hz) , 1.59 (2H, m), 1.39 (2H, m), 0.76 (4.H, m).

Ia-5
¹ H-NMR (CDCl ₃ ) δ: 7.41 (3H, m), 7.00 (1.0H, m), 6.34 (1H, s), 4.47 (1H, t, J = 7.86 Hz), 4.13 (1H, d, J = 8.11 Hz), 3.65 (1H, t, J = 7.86 Hz), 3.31-3.20 (5H, m), 2.63 (1H, m), 2.17 (4H, m), 1.58 (2H, m), 1.36 ( 2H, m), 1.20 (6H, t, J = 7.10 Hz).

Ia-6
¹ H-NMR (CDCl ₃ ) δ: 7.46-7.37 (3.1H, m), 7.01 (1.0H, td, J = 8.24, 2.20 Hz), 6.35 (1.0H, s), 4.06-4.05 (1.1H, br m), 3.24 (5.3H, dq, J = 10.00, 5.00 Hz), 2.66-2.63 (1.2H, m), 2.23-2.12 (4.9H, m), 1.66-1.55 (10.6H, m), 1.38 -1.29 (4.2H, m).

Ia-7
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.34 (3H, m), 7.02 (1H, t, J = 8.36 Hz), 6.35 (1.0H, s), 4.28 (1.0H, d, J = 8.62 Hz ), 4.16 (2.0H, s), 3.32 (1.0H, m), 2.98 (3H, s), 2.66 (1H, m), 2.28 (2H, d, J = 10.65 Hz), 2.15 (2H, d, J = 12.67 Hz), 1.60 (2H, m), 1.43 (2H, m).

Ia-8
¹ H-NMR (CDCl ₃ ) δ: 7.41 (3H, m), 7.01 (1.0H, t, J = 8.36 Hz), 6.35 (1.0H, s), 4.18 (1.0H, d, J = 8.11 Hz) , 3.50 (2H, t, J = 6.59 Hz), 3.30 (1.0H, m), 2.94 (3H, s), 2.72-2.63 (3H, m), 2.24 (2H, d, J = 12.67 Hz), 2.14 (2H, d, J = 12.17 Hz), 1.61 (2H, dd, J = 24.59, 12.42 Hz), 1.38 (2H, dd, J = 26.11, 11.41 Hz).

Ia-9
¹ H-NMR (DMSO-d ₆ ) δ: 12.7 (1H, s), 8.45 (1H, s), 7.50 (3H, m), 7.07 (1H, s), 6.52 (1H, s), 4.39 (2.6 H, t, J = 7.60 Hz), 3.96 (2.6H, t, J = 7.6 Hz), 3.36 (1H, m), 2.63 (1H, m)), 1.97 (4H, m), 1.43 (4H, m )

Ia-10
¹ H-NMR (CDCl ₃ ) δ: 7.42 (3.0H, m), 7.01 (1.0H, m), 6.35 (1.0H, s), 4.00 (1.0H, d, J = 8.11 Hz), 3.77 (4.0 H, t, J = 4.56 Hz), 3.32-3.28 (1.0H, m), 3.21 (4.0H, t, J = 4.56 Hz), 2.66 (1.0H, m), 2.25 (2.0H, m), 2.14 (2.0H, m), 1.61 (2.0H, m), 1.40 (2.0H, m).

Ia-11
¹ H-NMR (CDCl ₃ ) δ: 7.47-7.35 (3.0H, m), 7.01 (1.0H, m), 6.36 (1.0H, s), 4.19 (1.0H, d, J = 8.11 Hz), 3.82 (2.0H, q, J = 8.62 Hz), 3.27 (1.0H, m), 2.99 (3H, s), 2.66 (1.0H, m), 2.23 (2.0H, m), 2.12 (2.0H, m) , 1.59 (2.0H, m), 1.38 (2.0H, m).

Ia-12
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.9H, s), 7.56 (2.0H, t, J = 13.43 Hz), 7.40-7.30 (7H, m), 7.09 (1.0H, s), 6.54 (1.0H, s), 4.22 (2.0H, s), 3.11-3.07 (1.0H, m), 2.58 (1.0H, m), 2.00 (4.0H, m), 1.43 (4.0H, m).

Ia-13
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.35 (3.0H, m), 7.02 (1.0H, d, J = 6.59 Hz), 6.35 (1.0H, s), 4.46 (1.0H, d, J = 8.11 Hz), 3.50 (2.0H, t, J = 6.59 Hz), 3.30 (3.0H, m), 2.69 (3.0H, m), 2.17 (4.0H, m), 1.58 (2.0H, m), 1.33 (5.0H, m).

Ia-14
¹ H-NMR (CDCl ₃ ) δ: 7.49 (1.0H, d, J = 7.60 Hz), 7.37 (7.0H, m), 7.01 (1.0H, m), 6.35 (1.0H, s), 4.41 (2.0 H, s), 4.13 (1.0H, d, J = 8.11 Hz), 3.22 (3.0H, m), 2.63 (1.0H, tt, J = 12.17, 3.46 Hz), 2.14 (4.0H, dd, J = 26.87, 12.17 Hz), 1.54 (2.0H, dd, J = 25.35, 10.65 Hz), 1.32 (2.0H, dd, J = 26.36, 11.66 Hz), 1.16 (3.0H, t, J = 7.10 Hz).

Ia-15
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (1.0H, s), 7.56 (3.0H, m), 7.42 (1.0H, dd, J = 13.43, 5.83 Hz), 7.09 (1.0H, t, J = 8.11 Hz), 6.51 (1.0H, s), 3.45 (4.0H, t, J = 6.59 Hz), 3.10 (1.0H, m), 2.82 (4.0H, t, J = 6.84 Hz), 2.58 ( 1.0H, m), 2.01 (4.0H, m), 1.42 (4.0H, m).

Ia-16
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.9H, s), 7.61-7.41 (3.0H, m), 7.09 (1.0H, t, J = 7.60 Hz), 6.77-6.70 (2.0H, m), 6.54 (1.0H, s), 3.07-3.00 (1.0H, m), 2.59 (2.0H, d, J = 6.59 Hz), 2.01 (4.0H, br-t, J = 10.90 Hz), 1.48 -1.28 (4.0H, m), 0.88 (9.0H, s).

IIa-1
¹ H-NMR (DMSO-d ₆ ) δ: 8.31 (0.6H, s), 7.57 (2.0H, m), 7.42 (1.0H, m), 7.08 (1.0H, m), 6.86 (1.0H, d , J = 7.60 Hz), 6.61 (1.0H, d, J = 5.07 Hz), 6.52 (1.0H, s), 2.99 (1.0H, m), 2.57 (1.0H, m), 2.46 (3.0H, d , J = 4.56 Hz), 2.00 (4.0H, m), 1.39 (4.0 H, dq, J = 44.10, 12.25 Hz).

IIa-2
¹ H-NMR (DMSO-d ₆ ) δ: 12.68 (0.7H, s), 7.56 (2.0H, m), 7.42 (1.0H, q, J = 7.27 Hz), 7.09 (1.0H, t, J = 8.11 Hz), 6.82 (1.0H, d, J = 7.60 Hz), 6.71 (1.0H, t, J = 5.83 Hz), 6.54 (1.0H, s), 2.99 (1.0H, m), 2.89-2.82 ( 2.0H, m), 2.57 (1.0H, m), 2.00 (4.0H, m), 1.39 (4.0H, m), 1.07 (3.8H, t, J = 7.35 Hz).

IIa-3
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.8H, s), 7.57 (2.0H, m), 7.42 (1.0H, m), 7.08 (1.0H, m), 6.80 (1.0H, m ), 6.73 (1.0H, m), 6.53 (0.9H, s), 3.00 (1.0H, m), 2.78 (2.0H, q, J = 6.76 Hz), 2.57 (1.0H, m), 2.00 (4.0 H, m), 1.52-1.29 (6.0H, m), 0.87 (3.0H, t, J = 7.60 Hz).

IIa-4
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.9H, s), 7.51 (3.0H, m), 7.08 (1.0H, m), 6.70 (2.0H, m), 6.53 (1.0H, s ), 3.00 (1.0H, br-s), 2.54 (2.0H, m), 2.01 (4.0H, m), 1.50-1.32 (4.0H, m), 1.11 (6.0H, d, J = 6.08 Hz) .

IIa-5
¹ H-NMR (DMSO-d ₆ ) δ: 12.68 (0.9H, s), 7.61-7.42 (3.0H, m), 7.11 (2.0H, m), 6.94 (1.0H, d, J = 7.10 Hz) , 6.53 (1.0H, s), 3.06-3.02 (1.0H, m), 2.58 (1.0H, t, J = 10.39 Hz), 2.30 (1.0H, td, J = 6.34, 2.37 Hz), 2.05 (4.0 H, m), 1.50-1.31 (4.0H, m), 0.53 (4.0H, m).

IIa-6
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.8H, s), 7.57 (2.0H, dd, J = 25.85, 8.62 Hz), 7.42 (1.0H, t, J = 7.86 Hz), 7.08 ( 1.0H, t, J = 8.62 Hz), 6.77 (2.0H, dd, J = 6.59, 3.55 Hz), 6.53 (1.0H, s), 3.48 (1.0H, m), 3.02-2.99 (1.0H, m ), 2.57 (1.0H, m), 2.01 (4.0H, m), 1.81 (2.0H, m), 1.61 (2.0H, m), 1.37 (10.0H, m).

IIa-7
¹ H-NMR (DMSO-d ₆ ) δ: 12.63 (0.8H, s), 9.65 (1.0H, s), 7.50 (4.0H, m), 7.28 (2.1H, t, J = 7.86 Hz), 7.17 (2.0H, d, J = 7.60 Hz), 7.07 (1.0H, s), 6.98 (1.0H, t, J = 7.35 Hz), 6.50 (1.0, s), 3.05 (1.0H, dt, J = 13.52 , 4.44 Hz), 2.55 (1.0H, m), 1.93 (2.0H, d, J = 11.66 Hz), 1.83 (2.0H, d, J = 10.65 Hz), 1.38 (2.0H, q, J = 12.67 Hz ), 1.25 (2.0H, dd, J = 22.31, 12.67 Hz).

IIa-8
¹ H-NMR (DMSO-d ₆ ) δ: 9.42 (1.0H, s), 7.50 (6.0H, m), 7.15 (4.0H, m), 6.52 (1.0H, s), 3.15-3.12 (1.0H , m), 2.56 (1.0H, m), 1.93 (4.0H, dd, J = 25.85, 12.17 Hz), 1.47-1.26 (4.0H, m).

IIa-9
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (1.0H, s), 7.50 (3.0H, ddd, J = 64.89, 20.53, 8.11 Hz), 7.08 (1.0H, t, J = 7.60 Hz), 6.81 (1.0H, d, J = 7.10 Hz), 6.71 (1.0H, t, J = 5.58 Hz), 6.53 (1.0H, s), 3.04-2.97 (1.0H, m), 2.81 (2.0H, q , J = 6.76 Hz), 2.58 (1.0H, t, J = 11.91 Hz), 2.00 (4.0H, m), 1.49-1.27 (8.0H, m), 0.88 (3.0H, t, J = 7.35 Hz) .

IIa-10
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.8H, s), 7.57 (2.0H, dd, J = 27.88, 9.12 Hz), 7.41 (1.0H, dd, J = 14.45, 7.35 Hz), 7.08 (1.0H, t, J = 8.62 Hz), 6.81 (1.0H, d, J = 7.60 Hz), 6.71 (1.0H, t, J = 5.32 Hz), 6.52 (1.0H, s), 2.99 (1.0 H, dq, J = 14.83, 3.55 Hz), 2.80 (2.0H, q, J = 6.76 Hz), 2.58 (1.0H, t, J = 11.41 Hz), 2.00 (4.0H, d, J = 10.14 Hz) , 1.46-1.26 (10.0H, m), 0.87 (3.0H, t, J = 6.59 Hz).

IIa-11
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (1.0H, s), 7.57 (2.0, dd, J = 26.87, 8.62 Hz), 7.41 (1.0H, dd, J = 14.19, 7.10 Hz), 7.08 (1.0H, s), 6.78 (2.0H, dd, J = 15.46, 6.84 Hz), 6.53 (1.0H, s), 3.01 (1.0H, tt, J = 10.65, 3.89 Hz), 2.64-2.55 (3.0 H, m), 2.00 (4.0H, t, J = 4.31 Hz), 1.77-1.67 (1.0H, m), 1.38 (4.0H, dq, J = 45.62, 11.74 Hz), 0.88 (6.0H, d, (J = 6.60 Hz)

IIa-12
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.8H, s), 7.57 (2.0H, dd, J = 27.63, 9.38 Hz), 7.41 (1.0H, dd, J = 14.19, 7.60 Hz), 7.08 (1.0H, s), 6.87-6.78 (2.0H, m), 6.53 (1.0H, s), 3.04-3.00 (1.0H, m), 2.71 (2.0H, t, J = 6.34 Hz), 2.57 (1.0H, t, J = 10.90 Hz), 2.02-1.98 (4.0H, m), 1.39 (4.0H, dq, J = 49.81, 12.34 Hz), 0.98-0.92 (1.0H, m), 0.43 (2.0 H, q, J = 6.08 Hz), 0.17 (2.0H, q, J = 4.90 Hz).

IIa-13
¹ H-NMR (DMSO-d ₆ ) δ: 12.68 (0.9H, s), 7.74 (1.0H, s), 7.57 (2.0H, dd, J = 26.87, 8.62 Hz), 7.41 (1.0H, dd, J = 14.45, 7.35 Hz), 7.16-7.06 (2.0H, m), 6.53 (1.0H, s), 3.61 (2.0H, ddd, J = 15.84, 9.76, 6.46 Hz), 3.04 (1.0H, tt, J = 11.41, 3.46 Hz), 2.58 (1.0H, t, J = 11.66 Hz), 2.01 (4.0H, t, J = 9.12 Hz), 1.39 (4.0H, dq, J = 47.40, 11.74 Hz).

IIa-14
¹ H-NMR (DMSO-d ₆ ) δ: 12.68 (0.8H, s), 7.62-7.41 (4.0H, m), 7.10 (2.0H, d, J = 7.1 Hz), 6.53 (1.0H, s) , 6.19-5.89 (1.0H, m), 3.27-3.17 (2.0H, m), 3.08-3.00 (1.0H, m), 2.62-2.56 (1.0H, m), 2.02-2.00 (4.0H, m) , 1.50-1.29 (4.0H, m).

IIa-15
¹ H-NMR (DMSO-d ₆ ) δ: 12.68 (0.7H, s), 7.56 (2.0H, m), 7.42 (1.0H, m), 7.12 (3.0H, m), 6.52 (1.0H, s ), 3.06 (3.0H, m), 2.69 (2.0H, t, J = 6.59 Hz), 2.58 (1.0H, t, J = 11.15 Hz), 2.02 (4.0H, t, J = 11.15 Hz), 1.39 (4.0H, dq, J = 45.37, 11.74 Hz).

IIa-16
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.9H, s), 7.61-7.41 (3.0H, m), 7.09 (1.0H, t, J = 7.60 Hz), 6.77-6.70 (2.0H, m), 6.54 (1.0H, s), 3.07-3.00 (1.0H, m), 2.59 (2.0H, d, J = 6.59 Hz), 2.01 (4.0H, br-t, J = 10.90 Hz), 1.48 -1.28 (4.0H, m), 0.88 (9.0H, s).

IIa-18
¹ H-NMR (DMSO-d ₆ ) δ: 12.68 (0.8H, s), 9.65 (1.0H, s), 7.61-7.39 (4.0H, m), 7.09 (1.0H, t, J = 7.9 Hz) , 6.53 (1.0H, s), 3.64 (3.0H, s), 3.11-3.06 (1.0H, m), 2.58-2.54 (1.0H, m), 2.00-1.97 (4.0H, m), 1.48-1.31 (4.0H, m).

IIa-19
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (1.0H, s), 9.51 (1.0H, s), 7.62-7.38 (4.0H, m), 7.08 (1.0H, t, J = 7.9 Hz) , 6.52 (1.0H, s), 3.87 (2.0H, q, J = 7.1 Hz), 3.12-3.06 (1.0H, m), 2.59-2.54 (1.0H, m), 1.99 (4.0H, br-d , J = 10.7 Hz), 1.45-1.24 (4.0H, m), 1.15 (3.0H, t, J = 7.1 Hz).

IIa-20
¹ H-NMR (DMSO-d ₆ ) δ: 12.67 (0.8H, s), 9.33 (0.9H, s), 7.61-7.40 (4.0H, m), 7.08 (1.0H, t, J = 7.4 Hz) , 6.53 (1.0H, s), 4.06-4.00 (1.0H, m), 3.14-3.07 (1.0H, m), 2.59-2.53 (1.0H, d, J = 12.2 Hz), 2.00-1.98 (4.0H , m), 1.48-1.31 (4.0H, m), 1.14 (6.0H, d, J = 6.08 Hz).

Test Example 1-1 Affinity for Mouse NPY Y5 Receptor A cDNA sequence encoding the mouse NPY Y5 receptor (see Biochim. Biophys. Acta 1328: 83-89, 1997) was expressed in the expression vector pME18S (Takebe et al. Mol. Cell.Biol.8, 466-472). The obtained expression vector was transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual, and NPY Y5 receptor stably expressing cells were obtained.
Membrane preparations prepared from CHO cells expressing mouse NPY Y5 receptor were assay buffer together with the compounds of the present invention and 30,000 cpm [ ¹²⁵ I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare). The solution was incubated in a liquid (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filtered through a glass filter GF / C treated with 1% polyethyleneimine. After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter was determined with a gamma counter. Non-specific binding was measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC ₅₀ value) of the test compound for specific peptide YY binding was determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)]. The results are shown in Table 1.
The compound according to the present invention inhibited the binding of peptide YY (NPY and homologous substances) to the mouse NPY Y5 receptor. That is, this compound showed affinity for the mouse NPY Y5 receptor.

Test Example 1-2 Affinity for Human NPY Y5 Receptor A cDNA sequence encoding the human NPY Y5 receptor (see WO96 / 16542) was obtained by expressing the expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466-). 472). The obtained expression vector is transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual to obtain NPY Y5 receptor stably expressing cells.
Membrane preparation prepared from CHO cells expressing human NPY Y5 receptor is assay buffer together with the compound of the present invention and 30,000 cpm [ ¹²⁵ I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare). Incubate in a liquid (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filter through a glass filter GF / C treated with 1% polyethyleneimine. . After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter is determined with a gamma counter. Non-specific binding is measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC ₅₀ value) of the test compound for specific peptide YY binding is determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].

Test Example 2 Rat and Mouse Brain Migration Evaluation Using the cassette dosing method (Drug. Metab. Dispos. (2001); 29, 957-966), the rat (Crl; CD (SD), ♂, 8weeks) 30 minutes after intravenous administration (0.5 mg / mL / kg), for mice (Jcl; C57BL / 6J, Ｊ, 8weeks), plasma and brain 3 hours or 5 hours after oral administration (2 mg / 10 mL / kg) From the concentration, brain migration (brain / plasma partition coefficient; Kp) was evaluated.

Test Example 3 Pharmacokinetic Evaluation in Rats Using the cassette dosing method, the half-life was determined from the change in plasma concentration after intravenous administration (0.5 mg / mL / kg) in rats (Crl; CD (SD), ♂, 8 weeks). (T1 / 2) and systemic clearance (CLtot) were evaluated.

Test Example 4 cAMP Production Inhibitory Action in CHO Cells After CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), the compounds according to the present invention Was added and incubated for 5 minutes, after which 50 nMNPY and 10 μM forskolin (Sigma) were added and incubated for 30 minutes. After stopping the reaction by adding 1N HCl, the amount of cAMP in the supernatant was measured using EIA kit (manufactured by Amersham LIFE SIENCE). The inhibitory action of NPY on cAMP production by forskolin stimulation was taken as 100%, and the 50% inhibitory concentration (IC ₅₀ value) of the compound according to the present invention for this NPY action was determined.

Test Example 5 NPY Y5 Receptor Selectivity Test Examples 1-2 and Y1-expressing cells (human neuroblastoma, SK-N-MC) membrane samples and Y2-expressing cells (human neuroblastoma, SMS-KAN) membrane samples were used. The test is performed in the same manner, and the affinity of the compound of the present invention for the NPY Y1 receptor and the NPY Y2 receptor is measured. From the result, it can be confirmed that the compound according to the present invention has NPY Y5 receptor selectivity.

Test Example 6 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the outer occipital crest to the back of the nose of male C57BL / 6J mice (12-14 weeks old, 25-30 g) to expose the upper skull. . A hole having a diameter of about 1 mm was formed using an electric drill at a position about 1 mm rearward from the exposed part bregma toward lamda, about 1 mm from the midline to the left side. A 0.5% hydroxypropylmethylcellulose aqueous solution (manufactured by Shin-Etsu Chemical Co., Ltd.) or a test substance suspended in this aqueous solution is forcibly orally administered to an anesthetized mouse and an NPY Y5 receptor-specific agonist 1 hour after administration. ([CPP ^1-7 , NPY ^19-23 , Ala ³¹ , Aib ³² , Gln ³⁴ ] -hPanalytic Polypeptide: manufactured by Tocris Co.) 0.1 nmol was injected from the head opening provided previously using a cannula. The food intake of mice was measured 2 hours and 4 hours after the injection, and the difference in food intake between the group administered with 0.5% hydroxypropylmethylcellulose solution and the group administered with the test substance was investigated. As a result, when the compound of the present invention was administered at a dose of 12.5 mg / kg, the amount of food intake was significantly suppressed compared to the case where 0.5% hydroxypropylmethylcellulose was administered.
For example, in the group (Group A) administered at a dose of 12.5 mg / kg of Compound Ia-3, the food intake after 2 hours and 4 hours after injection was 0.28 ± 0.05 g and 0.57 ± 0.08 g, respectively. Met. On the other hand, the amount of food consumed 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group B) was 0.62 ± 0.06 g and 1.37 ± 0.08 g, respectively. In addition, the amount of food consumed in the 0.5% hydroxypropylmethylcellulose solution administration group (Group C) in which no NPY Y5 receptor-specific agonist was injected was 0.10 ± 0.03 g, 0.13 ± 0.02 g, and Group C If the value of A is subtracted from the A and B groups and converted, the feeding suppression rates for the B group at 2 hours and 4 hours after the injection in the A group are 65.1% and 64.1%, respectively.

Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) The degree to which the metabolite production was inhibited by the test compound was evaluated.

  The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan ( CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsomes 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 μmol / L (4 points).

  As a reaction solution in a 96-well plate, 5 kinds of each substrate, human liver microsome, and test drug are added in the above composition in 50 mM Hepes buffer, and NADPH as a coenzyme is added to start a metabolic reaction as an index. The mixture was reacted at 37 ° C. for 15 minutes, and then the reaction was stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant of the centrifugation was analyzed with a fluorescent multilabel counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.

The control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated. The IC ₅₀ was calculated by inverse estimation using a logistic model.
The results are shown below.
Compound Ia-1: 5 species> 20 μM
Compound Ia-4: 5 types> 20 μM
Compound IIa-6: 5 species> 20 μM
Compound IIa-11: 5 species> 20 μM

Test Example 8 Metabolic stability Metabolic stability evaluation by human liver microsomes: NADPH (final concentration 1 mM, in the case of oxidative metabolism), liver microsomes (final concentration 0.5 mg protein / in) in Tris-HCl buffer (pH 7.4) ml) and each compound (final concentration 2 μM) were added and reacted at 37 ° C. for 0 and 30 minutes. In the case of glucuronidation, UDPGA (final concentration 5 mM) was added instead of NADPH. The reaction was stopped by adding acetonitrile / methanol = 1/1 (v / v) twice the amount of the reaction solution, and then the compound in the centrifugal supernatant was measured by HPLC. The amount of disappearance due to metabolic reaction was calculated from the comparison of the values of 0 minute and 30 minutes, and the metabolic stability of the compound of the present invention was confirmed.
The remaining rate at a compound concentration of 0.5 μM is shown below.
Compound Ia-1: 87.4%
Compound Ia-11: 76.4%
Compound IIa-3: 92.7%
Compound IIa-5: 99.3%

Test Example 9 Powder Solubility Test An appropriate amount of specimen is put into a 96-well plate, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to make 1000 mL), JP-2 solution (phosphorus of pH 6.8). 200 mL of water is added to 500 mL of the acid buffer, and 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL). When dissolving after adding the test solution, add bulk powder as appropriate. Seal and shake at 37 ° C. for 1 hour. Filter, add 100 μL of methanol to 100 μL of each filtrate and dilute 2 times. Change the dilution factor as necessary. Check for bubbles and precipitates, seal and shake. Quantification is performed using HPLC by the absolute calibration curve method.

Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet Compound (I) 15 mg
Starch 15mg
Lactose 15mg
Crystalline cellulose 19mg
Polyvinyl alcohol 3mg
30ml distilled water
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.

Formulation Example 2 Capsule Compound (I) 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to make a powder as a fine powder or powder. It is filled into a capsule container to form a capsule.

Formulation Example 3 Granules Compound (I) 30 g
Lactose 265g
Magnesium stearate 5g
After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.

  As is clear from the above test examples, the compound of the present invention exhibits NPY Y5 receptor antagonistic action. Therefore, the compound of the present invention is used as a medicament for the prevention or treatment of eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure, sleep disorders, etc. Very useful. In addition, since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity. Furthermore, it is very useful as a medicament for treating or preventing diseases in which obesity is a risk factor, such as diabetes, hypertension, hyperlipidemia, arteriosclerosis, and acute coronary syndrome.

Claims (14)

Formula (I):

(Where
R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl,
R ¹ and R ² together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R ¹ and R ⁵ together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle,
X is an aromatic heterocycle or a non-aromatic heterocycle,
Each R ³ is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
Each R ⁴ is independently halogen, cyano, nitro, nitroso, azide, oxo,
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy,
Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclylthio,
Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or Unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl,
Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted hetero Arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl,
Sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted A heteroarylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino,
R ⁵ is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
m is an integer from 0 to 2,
n is an integer of 0 to 5,
Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
p is an integer of 0 to 2, and a pharmaceutical composition having an NPYY5 receptor antagonistic action, comprising a compound represented by the formula: a pharmaceutically acceptable salt thereof or a solvate thereof. Formula (I):

(Where
R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted Or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl,
R ¹ and R ² together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing aromatic heterocycle or a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, or R ¹ and R ⁵ together with the adjacent nitrogen atom may form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle,
X is an aromatic heterocycle or a non-aromatic heterocycle,
Each R ³ is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl;
Each R ⁴ is independently halogen, cyano, nitro, nitroso, azide, oxo,
Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,
Hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryl Oxy, substituted or unsubstituted heterocyclyloxy,
Mercapto, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted cycloalkylthio, substituted or unsubstituted cycloalkenylthio, substituted or unsubstituted arylthio, substituted or unsubstituted heteroarylthio, Substituted or unsubstituted heterocyclylthio,
Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or Unsubstituted heteroaryloxycarbonyl, substituted or unsubstituted heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl,
Formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted hetero Arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl,
Sulfino, sulfo, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted cycloalkylsulfonyl, substituted or unsubstituted cycloalkenylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted A heteroarylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amino,
R ⁵ is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
m is an integer from 0 to 2,
n is an integer of 0 to 5,
Each R is independently halogen, oxo, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
p is an integer of 0 to 2) (provided that the formula:

A group represented by

Is excluded. ),
The pharmaceutically acceptable salt or solvate thereof. The compound according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein X is indole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyrazine, imidazole, pyrazole, pyrrole, triazole, pyridine, imidazopyridine or benzimidazole. object. The compound according to claim 2, wherein X is pyrazole, a pharmaceutically acceptable salt thereof, or a solvate thereof. formula:

A group represented by

A group represented by
n is 0 or 1;
The compound according to claim 2, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 2 to 5, wherein m is 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. R ¹ and R ² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. Or a pharmaceutically acceptable salt or solvate thereof. The compound according to any one of claims 2 to 5, wherein R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, or a pharmaceutically acceptable salt thereof. Salts or solvates thereof. R ¹ is hydrogen or substituted or unsubstituted alkyl;
The compound according to any one of claims 2 to 5, wherein R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl, or a pharmaceutically acceptable salt thereof. Salts or solvates thereof. The compound according to any one of claims 2 to 5, wherein R ¹ and R ² together with the adjacent nitrogen atom form a substituted or unsubstituted nitrogen-containing non-aromatic heterocycle, the pharmaceutically acceptable product thereof Salts or solvates thereof. Each R ³ is independently substituted or unsubstituted phenyl;
The compound according to any one of claims 2 to 5, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 2 to 5, its pharmaceutically acceptable salt, or a solvate thereof, wherein each R ⁴ is independently halogen, cyano, or substituted or unsubstituted alkyl. The pharmaceutical composition which uses the compound in any one of Claims 2-12, its pharmaceutically acceptable salt, or those solvates as an active ingredient. 14. The pharmaceutical composition according to claim 13, which has an NPY Y5 receptor antagonistic action.