JP2012167027A - Condensed heterocyclic derivative having npy y5 receptor antagonism - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound having NPY Y5 receptor antagonism.SOLUTION: The compound is represented by formula (I) (wherein X is -SO- or the like; Yis =C(-R)- or the like; Yis -C(-R)= or the like; Yis =C(-R)- or the like; Z is -N= or the like; R, R, R, R, R, and Rare each hydrogen or the like; Ris an optionally substituted alkyl group or the like; Ris an optionally substituted aryl group or the like; Ris an optionally substituted aryl group; and n is 1 or the like) and has been found to have NPY Y5 receptor antagonism.

Description

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

Obesity is defined as the accumulation of excess fat or adipose tissue in the body relative to lean body mass, and is recognized as a major risk factor for health problems. The body mass index (BMI) is a simple index of the height-weight ratio that is commonly used to classify an adult (over 15 years old) group or individual as overweight or obese. It is defined as the body weight (kg / m ² ) expressed in kilograms divided by the height squared in meters. According to the World Health Organization, BMI of 25 kg / m ² or more is “overweight” and 30 kg / m ² or more is “obese”. On the other hand, the Japanese Society of Obesity considers BMI to be 25 kg / m ² or more as “obesity”. This is because the number of obesity-related diseases including diabetes and dyslipidemia increases according to BMI, and the average value of the number of diseases becomes 1.0 or more at a BMI of 25 kg / m ² . According to a 2005 survey by the World Health Organization, around 1.6 billion people worldwide are overweight and at least 400 million people are obese. Obesity is mainly caused by an increase in the ratio of caloric intake to physical activity and consumption in daily life. The number of obese people is increasing due to an increase in the intake of high fat and high sugar content foods in recent years, and more than 700 million people are expected to be diagnosed as obese worldwide in 2015.

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 is a preventive 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 discloses a benzimidazole derivative having a substituent containing sulfamide, which has a growth hormone secretion promoting action and can be used as an anti-obesity drug.

  Patent Document 2 discloses a benzimidazole derivative having a carboxyl group, which has an IL-8 and GROα chemokine inhibitory action and can be used as a therapeutic agent for inflammatory diseases. Patent Document 3 discloses a benzimidazole derivative having a carbonyl group, which has a β-secretase inhibitory action and can be used as an Alzheimer's therapeutic agent.

  Patent Document 4 discloses an arylalkyl acid compound having a substituent containing benzoxazole, which has a DGAT-1 inhibitory action and can be used as an antiobesity agent. Patent Document 5 discloses a bicycloamine derivative having a substituent including benzoxazole, which has an SSTR antagonistic action and can be used as a therapeutic agent for type II diabetes or obesity. Patent Document 6 discloses a benzoxazole derivative containing piperidine that has an SSTR antagonistic action and can be used as a therapeutic agent for type II diabetes and obesity.

  Patent Document 7 discloses a condensed heterocyclic derivative having a substituent containing benzoxazole, which has a glucokinase activating action and can be used as a diabetic drug. Patent Document 8 is a document relating to an optical brightener of an organic substance, and discloses a benzoxazole compound having a substituent containing benzoxazole.

  However, Patent Documents 1 to 8 do not describe NPY Y5 receptor antagonistic action.

US Pat. No. 6,525,203 International Publication No. 2007/009774 International Publication No. 2006/099379 International Publication No. 2004/100881 International Publication No. 2010/056717 International Publication No. 2006/094682 International Publication No. 2008/136444 US Pat. No. 3,272,805

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 condensed heterocyclic 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 eating 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、
Ｘは−ＳＯ_２−、−ＳＯ_２−Ｃ（−Ｒ^１４）（−Ｒ^１５）−、−Ｎ（−Ｒ^６）−ＳＯ_２−又は−ＳＯ_２−Ｎ（−Ｒ^７）−であり、
Ｙ^１は＝Ｃ（−Ｒ^８）−又は＝Ｎ−であり、
Ｙ^２は−Ｃ（−Ｒ^３）＝又は−Ｎ＝であり、
Ｙ^３は＝Ｃ（−Ｒ^１）−又は＝Ｎ−であり、

で示される部分は、

から選択される構造であり、
Ｗ^２は−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；
−Ａｋ−Ｓ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；又は
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−であり、
Ａｋはそれぞれ独立して、単結合、置換若しくは非置換のＣ１−Ｃ４アルキレン又は置換若しくは非置換のＣ２−Ｃ４アルケニレンであり、
Ｒ^１、Ｒ^３、Ｒ^８、Ｒ^１４及びＲ^１５はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
Ｒ^１０は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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又は置換若しくは非置換のアミジノであり、
Ｒ^２は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ミノ、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又は式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基であり、
Ｒ^４はシクロアルキル、シクロアルケニル、アリール、ヘテロアリール又は非芳香族複素環式基であり、
Ｒ^５はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
ｎは０〜３の整数であり、
Ｒ^６、Ｒ^７及びＲ^１３はそれぞれ独立して、水素又は置換若しくは非置換のアルキルであり又はＲ^６はＲ^２と共に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複素環を形成していてもよく、Ｒ^７はＲ^２と共に隣接する窒素原子及びＳＯ_２−と一緒になって置換若しくは非置換の複素環を形成していてもよい。
上記の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若しくは置換若しくは非置換の非芳香族複素環式基又はＲ^４のシクロアルキル、シクロアルケニル若しくは非芳香族複素環式基は、１又は２個のオキソ、チオキソ又は置換若しくは非置換のイミノで置換されていてもよい。但し、以下の化合物を除く。

で示される部分が、

であり、Ｗ^２が単結合である化合物、

で示される部分が、

であり、Ｘが−ＳＯ_２−Ｎ（−Ｒ^７）−であり、かつＲ^２がメチルである化合物、

で示される部分が、

から選択される構造であり、Ｗ^２が単結合であり、かつ

で示される部分が、

から選択される構造である化合物、

）で示される化合物又はその製薬上許容される塩を含有するＮＰＹ Ｙ５受容体拮抗作用を有する医薬組成物。
（２）Ｗ^２が−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；又は
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｏ−Ａｋ−；である、（１）記載の医薬組成物。
（３）Ｘが−ＳＯ_２−である、（１）記載の医薬組成物。
（４）Ｒ^２が置換若しくは非置換のアルキルである、（１）記載の医薬組成物。
（５）Ｒ^４がアリール又はヘテロアリールである、（１）記載の医薬組成物。
（６）Ｙ^１が＝Ｃ（−Ｒ^８）−であり、Ｙ^２が−Ｃ（−Ｒ^３）＝であり、Ｙ^３が＝Ｃ（−Ｒ^１）−である、（１）〜（５）のいずれかに記載の医薬組成物。
（７）式（Ｉａ）：

（式中、
Ｙ^１は＝Ｃ（−Ｒ^８）−又は＝Ｎ−であり、
Ｙ^２は−Ｃ（−Ｒ^３）＝又は−Ｎ＝であり、
Ｙ^３は＝Ｃ（−Ｒ^１）−又は＝Ｎ−であり、
Ｗ^２は−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；又は
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｏ−Ａｋ−；
Ａｋはそれぞれ独立して、単結合、置換若しくは非置換のＣ１−Ｃ４アルキレン又は置換若しくは非置換のＣ２−Ｃ４アルケニレンであり、
但し、Ｗ^２が−Ａｋ−である場合、Ａｋは単結合ではなく、
Ｒ^１、Ｒ^３及びＲ^８はそれぞれ独立して、水素、ハロゲン、シアノ、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であり、
Ｒ^２は炭素数２〜１０の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又は置換若しくは非置換のシクロアルケニルであり、
Ｒ^４はシクロアルキル、シクロアルケニル、アリール、ヘテロアリール又は非芳香族複素環式基であり、
Ｒ^５はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
ｎは０〜３の整数であり、
Ｒ^１０は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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又は置換若しくは非置換のアミジノである。
上記の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若しくは置換若しくは非置換の非芳香族複素環式基又はＲ^４のシクロアルキル、シクロアルケニル若しくは非芳香族複素環式基は、１又は２個のオキソ、チオキソ又は置換若しくは非置換のイミノで置換されていてもよい。）で示される化合物又はその製薬上許容される塩。
（８）Ｗ^２が−Ａｋ−；又は
−Ａｋ−Ｏ−Ａｋ−である、（７）記載の化合物又はその製薬上許容される塩。
（９）Ｒ^２が置換若しくは非置換の炭素数２〜１０のアルキルである、（７）記載の化合物又はその製薬上許容される塩。
（１０）Ｙ^１が＝Ｃ（−Ｒ^８）−であり、Ｙ^２が−Ｃ（−Ｒ^３）＝であり、かつＹ^３が＝Ｃ（−Ｒ^１）−である、（７）記載の化合物又はその製薬上許容される塩。
（１１）式（Ｉｂ）：

（式中、
Ｙ^１は＝Ｃ（−Ｒ^８）−又は＝Ｎ−であり、
Ｙ^２は−Ｃ（−Ｒ^３）＝又は−Ｎ＝であり、
Ｙ^３は＝Ｃ（−Ｒ^１）−又は＝Ｎ−であり、
Ｗ^２は−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；
−Ａｋ−Ｓ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；又は
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−であり、
Ａｋはそれぞれ独立して、単結合、置換若しくは非置換のＣ１−Ｃ４アルキレン又は置換若しくは非置換のＣ２−Ｃ４アルケニレンであり、
Ｒ^１、Ｒ^３及びＲ^８はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
Ｒ^１０は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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又は置換若しくは非置換のアミジノであり、
Ｒ^２は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ミノ、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又は式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基であり、
Ｒ^４はシクロアルキル、シクロアルケニル、アリール、ヘテロアリール又は非置換の非芳香族複素環式基であり、
Ｒ^５はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
ｎは０〜３の整数であり、
Ｒ^１３は水素又は置換若しくは非置換のアルキルである。
上記の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若しくは置換若しくは非置換の非芳香族複素環式基又はＲ^４のシクロアルキル、シクロアルケニル若しくは非芳香族複素環式基は、１又は２個のオキソ、チオキソ又は置換若しくは非置換のイミノで置換されていてもよい。但し、以下の化合物を除く。
Ｒ^４がフェニルである化合物、

で示される部分が、

から選択される構造である化合物、

）で示される化合物又はその製薬上許容される塩。
（１２）Ｒ^４がヘテロアリール又は非芳香族複素環式基である、請求項１１記載の化合物又はその製薬上許容される塩。
（１３）Ｒ^４が単環若しくは２環のヘテロアリール又は単環若しくは２環の非芳香族複素環式基である、（１１）記載の化合物又はその製薬上許容される塩。
（１４）Ｗ^２が−Ａｋ−；又は−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−である、（１１）記載の化合物又はその製薬上許容される塩。
（１５）Ｒ^２が置換若しくは非置換のアルキルである、（１１）記載の化合物又はその製薬上許容される塩。
（１６）Ｙ^１が＝Ｃ（−Ｒ^８）−であり、Ｙ^２が−Ｃ（−Ｒ^３）＝であり、かつＹ^３が＝Ｃ（−Ｒ^１）−である、（１１）記載の化合物又はその製薬上許容される塩。
（１７）（７）〜（１６）のいずれかに記載の化合物又はその製薬上許容される塩を含有する医薬組成物。
（１８）ＮＰＹ Ｙ５受容体拮抗作用を有する、（１７）記載の医薬組成物。
（１９）（１）〜（６）、（１７）又は（１８）のいずれかに記載の医薬組成物と併用するための、抗肥満作用を有する化合物を含有する肥満症の予防及び／又は治療用又は肥満症における体重管理用の医薬組成物。 That is, the present invention relates to the following.
(1) Formula (I):

(Where
X _-SO 2 is ^{_{-, - SO 2 -C (-R}} 14) (- R 15) -, - N (-R 6) -SO 2 - or _-SO 2 -N (-R ⁷⁾ - a and,
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,

The part indicated by

A structure selected from
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-N (R < ¹³ >)-Ak-;
-Ak-S-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-;
-Ak-C (= O) -Ak-O-Ak-;
-Ak-C (= O) -Ak-N (R < ¹³ >)-Ak-; or -Ak-N (R < ¹³ >)-Ak-C (= O) -Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
R ¹ , R ³ , R ⁸ , R ¹⁴ and R ¹⁵ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or non-substituted Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or an unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl, a substituted or unsubstituted amidino, a group represented by the formula: —O—R ¹⁰ , a formula: —O— C (= O) group represented by ^{-R 10,} represented by the formula: -C (= O) ^{-R 10} The formula: -C (= O) groups represented by ^{-O-R 10,} wherein: a group represented by ^{-S-R 10,} _wherein: group or formula represented by -SO 2 ^{-R 10:} -O-SO a group represented by ₂ -R ^10,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl or a substituted or unsubstituted amidino;
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or the formula: A group represented by C (═O) —O—R ¹⁰ ;
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ⁶ , R ⁷ and R ¹³ are each independently hydrogen or substituted or unsubstituted alkyl, or R ⁶ together with R ² together with the adjacent nitrogen atom forms a substituted or unsubstituted heterocycle. R ⁷ may be combined with the adjacent nitrogen atom and SO ₂ — together with R ² to form a substituted or unsubstituted heterocycle.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. However, the following compounds are excluded.

The part indicated by

A compound wherein W ² is a single bond,

The part indicated by

A compound wherein X is —SO ₂ —N (—R ⁷ ) — and R ² is methyl;

The part indicated by

And W ² is a single bond, and

The part indicated by

A compound having a structure selected from

) Or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having an NPY Y5 receptor antagonistic action.
^{(2) W} 2 is -Ak-;
-Ak-O-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-; or -Ak-C (= O) -Ak-O-Ak-; The pharmaceutical composition according to (1).
(3) The pharmaceutical composition according to (1), wherein X is —SO ₂ —.
(4) The pharmaceutical composition according to (1), wherein R ² is substituted or unsubstituted alkyl.
(5) The pharmaceutical composition according to (1), wherein R ⁴ is aryl or heteroaryl.
(6) Y ¹ is = C (-R ⁸ )-, Y ² is -C (-R ³ ) =, and Y ³ is = C (-R ¹ )-. The pharmaceutical composition according to any one of 5).
(7) Formula (Ia):

(Where
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-; or -Ak-C (= O) -Ak-O-Ak-;
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
However, when W ² is -Ak-, Ak is not a single bond,
R ¹ , R ³ and R ⁸ are each independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
R ² is substituted or unsubstituted alkyl having 2 to 10 carbon atoms, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl,
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. Or a pharmaceutically acceptable salt thereof.
(8) The compound according to (7) or a pharmaceutically acceptable salt thereof, wherein W ² is -Ak-; or -Ak-O-Ak-.
(9) The compound according to (7) or a pharmaceutically acceptable salt thereof, wherein R ² is substituted or unsubstituted alkyl having 2 to 10 carbon atoms.
(10) The description of (7), wherein Y ¹ is ═C (—R ⁸ ) —, Y ² is —C (—R ³ ) =, and Y ³ is ═C (—R ¹ ) —. Or a pharmaceutically acceptable salt thereof.
(11) Formula (Ib):

(Where
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-N (R < ¹³ >)-Ak-;
-Ak-S-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-;
-Ak-C (= O) -Ak-O-Ak-;
-Ak-C (= O) -Ak-N (R < ¹³ >)-Ak-; or -Ak-N (R < ¹³ >)-Ak-C (= O) -Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
R ¹ , R ³ and R ⁸ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic Group heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , formula: —O—C (═O) — Group represented by R ¹⁰ , Formula: —C (═O) —R ¹⁰ Group represented by Formula: —C (═O) A group represented by —O—R ¹⁰ , a group represented by formula: —S—R ¹⁰ , a group represented by formula: —SO ₂ —R ¹⁰ or a group represented by formula: —O—SO ₂ —R ^10; Yes,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl or a substituted or unsubstituted amidino;
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or the formula: A group represented by C (═O) —O—R ¹⁰ ;
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or unsubstituted non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ¹³ is hydrogen or substituted or unsubstituted alkyl.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. However, the following compounds are excluded.
A compound wherein R ⁴ is phenyl;

The part indicated by

A compound having a structure selected from

Or a pharmaceutically acceptable salt thereof.
(12) The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein R ⁴ is heteroaryl or a non-aromatic heterocyclic group.
(13) The compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic non-aromatic heterocyclic group.
(14) The compound according to (11) or a pharmaceutically acceptable salt thereof, wherein W ² is -Ak-; or -Ak-C (= O) -Ak-.
(15) The compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R ² is substituted or unsubstituted alkyl.
(16) The description of (11), wherein Y ¹ is = C (-R ⁸ )-, Y ² is -C (-R ³ ) =, and Y ³ is = C (-R ¹ )-. Or a pharmaceutically acceptable salt thereof.
(17) A pharmaceutical composition comprising the compound according to any one of (7) to (16) or a pharmaceutically acceptable salt thereof.
(18) The pharmaceutical composition according to (17), which has an NPY Y5 receptor antagonistic action.
(19) Prevention and / or treatment of obesity containing a compound having anti-obesity action for use in combination with the pharmaceutical composition according to any one of (1) to (6), (17) or (18) Or a pharmaceutical composition for weight management in obesity.

(20) The pharmaceutical composition according to any one of (1) to (6) or (17) above, which is used for prevention and / or treatment of obesity.
(21) The pharmaceutical composition according to any one of (1) to (6) or (17), which is used for weight management in obesity.
(22) A method for preventing and / or treating obesity, comprising administering the compound represented by the formula (I) according to (1) or a pharmaceutically acceptable salt thereof.
(23) A method for weight management in obesity, comprising administering a compound represented by the formula (I) described in (1) above or a pharmaceutically acceptable salt thereof.
(24) A compound represented by the formula (I) described in (1) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of obesity.
(25) A compound represented by the formula (I) described in (1) or a pharmaceutically acceptable salt thereof for weight management in obesity.
(26) A pharmaceutical composition containing a compound having an anti-obesity action is used in combination with the pharmaceutical composition according to any one of (1) to (6) or (17) above. Prophylactic and / or therapeutic methods.
(27) A pharmaceutical composition containing a compound having an anti-obesity action is used in combination with the pharmaceutical composition according to any one of (1) to (6) or (17) above, in obesity Weight management method.

（式中、
Ｙ^１は＝Ｃ（−Ｒ^８）−又は＝Ｎ−であり、
Ｙ^２は−Ｃ（−Ｒ^３）＝又は−Ｎ＝であり、
Ｙ^３は＝Ｃ（−Ｒ^１）−又は＝Ｎ−であり、
Ｗ^２は−Ａｋ−；−Ｏ−；−Ｏ−Ａｋ−；又は−Ａｋ−Ｏ−；
Ａｋはそれぞれ独立して、置換若しくは非置換のＣ１−Ｃ４アルキレン又は置換若しくは非置換のＣ２−Ｃ４アルケニレンであり、
Ｒ^１、Ｒ^３及びＲ^８はそれぞれ独立して、水素、ハロゲン、シアノ、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であり、
Ｒ^２は炭素数２〜１０の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又は置換若しくは非置換のシクロアルケニルであり、
Ｒ^４はシクロアルキル、シクロアルケニル、アリール、ヘテロアリール又は非芳香族複素環式基であり、
Ｒ^５はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
ｎは０〜３の整数であり、
Ｒ^１０は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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又は置換若しくは非置換のアミジノである。
上記の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若しくは置換若しくは非置換の非芳香族複素環式基又はＲ^４のシクロアルキル、シクロアルケニル若しくは非芳香族複素環式基は、１又は２個のオキソ、チオキソ又は置換若しくは非置換のイミノで置換されていてもよい。）で示される化合物又はその製薬上許容される塩。
（２９）式（Ｉｂ）：

（式中、
Ｙ^１は＝Ｃ（−Ｒ^８）−又は＝Ｎ−であり、
Ｙ^２は−Ｃ（−Ｒ^３）＝又は−Ｎ＝であり、
Ｙ^３は＝Ｃ（−Ｒ^１）−又は＝Ｎ−であり、
Ｗ^２は−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；
−Ａｋ−Ｓ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；又は
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−であり、
Ａｋはそれぞれ独立して、単結合、置換若しくは非置換のＣ１−Ｃ４アルキレン又は置換若しくは非置換のＣ２−Ｃ４アルケニレンであり、
Ｒ^１、Ｒ^３及びＲ^８はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
Ｒ^１０は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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又は置換若しくは非置換のアミジノであり、
Ｒ^２は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ミノ、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又は式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基であり、
Ｒ^４はシクロプロピル、シクロペンチル、シクロヘキシル、インダゾリル、キノリル、キノキサリニル、ベンズオキサゾリル、ピラゾリル、ピリジル、チアゾリル、ピリミジニル、ピラジニル、アゼチジニル、ピロリジニル、テトラヒドロピラニル、ジヒドロベンゾフリル、ピペリジル、テトラヒドロフラニル、アザスピロヘプタニルであり、
Ｒ^５はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
ｎは０〜３の整数であり、
Ｒ^１３は水素又は置換若しくは非置換のアルキルである。
上記の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若しくは置換若しくは非置換の非芳香族複素環式基又はＲ^４のシクロアルキル、シクロアルケニル若しくは非芳香族複素環式基は、１又は２個のオキソ、チオキソ又は置換若しくは非置換のイミノで置換されていてもよい。）で示される化合物又はその製薬上許容される塩。
（３０）式（Ｉｃ）：

（式中、
Ｙ^１は＝Ｃ（−Ｒ^８）−又は＝Ｎ−であり、
Ｙ^２は−Ｃ（−Ｒ^３）＝又は−Ｎ＝であり、
Ｙ^３は＝Ｃ（−Ｒ^１）−又は＝Ｎ−であり、
Ｗ^２は−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；
−Ａｋ−Ｓ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；又は
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−であり、
Ａｋはそれぞれ独立して、単結合、置換若しくは非置換のＣ１−Ｃ４アルキレン又は置換若しくは非置換のＣ２−Ｃ４アルケニレンであり、
Ｒ^１、Ｒ^３及びＲ^８はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
Ｒ^１０は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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又は置換若しくは非置換のアミジノであり、
Ｒ^２は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ミノ、置換若しくは非置換のシクロアルキル又は置換若しくは非置換のシクロアルケニルであり、
Ｒ^４はシクロアルキル、シクロアルケニル、アリール、ヘテロアリール又は非置換の非芳香族複素環式基であり、
Ｒ^５はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
ｎは０〜３の整数であり、
Ｒ^１３は水素又は置換若しくは非置換のアルキルであり、
上記の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若しくは置換若しくは非置換の非芳香族複素環式基又はＲ^４のシクロアルキル、シクロアルケニル若しくは非芳香族複素環式基は、１又は２個のオキソ、チオキソ又は置換若しくは非置換のイミノで置換されていてもよい。）で示される化合物又はその製薬上許容される塩。
（３１）式（ＩＩＩ）：

（式中、Ｈａｌはハロゲン、各記号は上記（１）と同意義である。）
で示される化合物又はその製薬上許容される塩。
（３２）式（ＶＩＩ）：

（式中、各記号は上記（１）と同意義である。）
で示される化合物又はその製薬上許容される塩。
（３３）式（Ｘ）：

（式中、各記号は上記（１）と同意義である。）
で示される化合物又はその製薬上許容される塩。
（３４）上記（７）〜（１６）のいずれかに記載の化合物又はその製薬上許容される塩の製造方法。
（３５）上記（７）〜（１６）のいずれかに記載の化合物又はその製薬上許容される塩の結晶化することを特徴とする、上記（３４）記載の製造方法。
（３６）上記（３１）〜（３３）のいずれかの化合物を用いる工程を含むことを特徴とする、上記（３４）記載の製造方法。 (28)
Formula (Ia):

(Where
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,
W ² represents -Ak-; -O-; -O-Ak-; or -Ak-O-;
Each Ak is independently substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
R ¹ , R ³ and R ⁸ are each independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
R ² is substituted or unsubstituted alkyl having 2 to 10 carbon atoms, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl,
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. Or a pharmaceutically acceptable salt thereof.
(29) Formula (Ib):

(Where
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-N (R < ¹³ >)-Ak-;
-Ak-S-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-;
-Ak-C (= O) -Ak-O-Ak-;
-Ak-C (= O) -Ak-N (R < ¹³ >)-Ak-; or -Ak-N (R < ¹³ >)-Ak-C (= O) -Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
R ¹ , R ³ and R ⁸ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic Group heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , formula: —O—C (═O) — Group represented by R ¹⁰ , Formula: —C (═O) —R ¹⁰ Group represented by Formula: —C (═O) A group represented by —O—R ¹⁰ , a group represented by formula: —S—R ¹⁰ , a group represented by formula: —SO ₂ —R ¹⁰ or a group represented by formula: —O—SO ₂ —R ^10; Yes,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl or a substituted or unsubstituted amidino;
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or the formula: A group represented by C (═O) —O—R ¹⁰ ;
R ⁴ is cyclopropyl, cyclopentyl, cyclohexyl, indazolyl, quinolyl, quinoxalinyl, benzoxazolyl, pyrazolyl, pyridyl, thiazolyl, pyrimidinyl, pyrazinyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, dihydrobenzofuryl, piperidyl, tetrahydrofuranyl, azaspiro Heptanil,
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ¹³ is hydrogen or substituted or unsubstituted alkyl.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. Or a pharmaceutically acceptable salt thereof.
(30) Formula (Ic):

(Where
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-N (R < ¹³ >)-Ak-;
-Ak-S-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-;
-Ak-C (= O) -Ak-O-Ak-;
-Ak-C (= O) -Ak-N (R < ¹³ >)-Ak-; or -Ak-N (R < ¹³ >)-Ak-C (= O) -Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
R ¹ , R ³ and R ⁸ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic Group heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , formula: —O—C (═O) — Group represented by R ¹⁰ , Formula: —C (═O) —R ¹⁰ Group represented by Formula: —C (═O) A group represented by —O—R ¹⁰ , a group represented by formula: —S—R ¹⁰ , a group represented by formula: —SO ₂ —R ¹⁰ or a group represented by formula: —O—SO ₂ —R ^10; Yes,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl or a substituted or unsubstituted amidino;
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl,
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or unsubstituted non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ¹³ is hydrogen or substituted or unsubstituted alkyl;
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. Or a pharmaceutically acceptable salt thereof.
(31) Formula (III):

(In the formula, Hal is halogen, and each symbol has the same meaning as in (1) above.)
Or a pharmaceutically acceptable salt thereof.
(32) Formula (VII):

(In the formula, each symbol has the same meaning as (1) above.)
Or a pharmaceutically acceptable salt thereof.
(33) Formula (X):

(In the formula, each symbol has the same meaning as (1) above.)
Or a pharmaceutically acceptable salt thereof.
(34) A method for producing the compound according to any one of (7) to (16) above or a pharmaceutically acceptable salt thereof.
(35) The production method according to (34), wherein the compound according to any one of (7) to (16) or a pharmaceutically acceptable salt thereof is crystallized.
(36) The production method according to (34) above, which comprises a step of using any one of the compounds (31) to (33).

  The compound of the present invention exhibits an 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, sleep disorder and the like. 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 the treatment or prevention of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis, and acute coronary syndromes.

（式中、
Ｘは−ＳＯ_２−、−ＳＯ_２−Ｃ（−Ｒ^１４）（−Ｒ^１５）−、−Ｎ（−Ｒ^６）−ＳＯ_２−又は−ＳＯ_２−Ｎ（−Ｒ^７）−であり、
Ｙ^１は＝Ｃ（−Ｒ^８）−又は＝Ｎ−であり、
Ｙ^２は−Ｃ（−Ｒ^３）＝又は−Ｎ＝であり、
Ｙ^３は＝Ｃ（−Ｒ^１）−又は＝Ｎ−であり、

で示される部分は、

から選択される構造であり、
Ｗ^２は−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；
−Ａｋ−Ｓ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；又は
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−であり、
Ａｋはそれぞれ独立して、単結合、置換若しくは非置換のＣ１−Ｃ４アルキレン又は置換若しくは非置換のＣ２−Ｃ４アルケニレンであり、
Ｒ^１、Ｒ^３、Ｒ^８、Ｒ^１４及びＲ^１５はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
Ｒ^１０は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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又は置換若しくは非置換のアミジノであり、
Ｒ^２は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ミノ、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又は式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基であり、
Ｒ^４はシクロアルキル、シクロアルケニル、アリール、ヘテロアリール又は非芳香族複素環式基であり、
Ｒ^５はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
ｎは０〜３の整数であり、
Ｒ^６、Ｒ^７及びＲ^１３はそれぞれ独立して、水素又は置換若しくは非置換のアルキルであり、又はＲ^６はＲ^２と共に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複素環を形成していてもよく、Ｒ^７はＲ^２と共に隣接する窒素原子及び−ＳＯ_２−と一緒になって置換若しくは非置換の複素環を形成していてもよい。
上記の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若しくは置換若しくは非置換の非芳香族複素環式基又はＲ^４のシクロアルキル、シクロアルケニル若しくは非芳香族複素環式基は、１又は２個のオキソ、チオキソ又は置換若しくは非置換のイミノで置換されていてもよい。但し、以下の化合物を除く。

で示される部分が、

であり、Ｗ^２が単結合である化合物、

で示される部分が、

であり、Ｘが−ＳＯ_２−Ｎ（−Ｒ^７）−であり、かつＲ^２がメチルである化合物、

で示される部分が、

から選択される構造であり、W^２が単結合であり、かつ

で示される部分が、

から選択される構造である化合物、及び

）で示される化合物、又はその製薬上許容される塩に関する。 The present invention will be described below. The present invention relates to a compound of formula (I):
Formula (I):

(Where
X _-SO 2 is ^{_{-, - SO 2 -C (-R}} 14) (- R 15) -, - N (-R 6) -SO 2 - or _-SO 2 -N (-R ⁷⁾ - a and,
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,

The part indicated by

A structure selected from
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-N (R < ¹³ >)-Ak-;
-Ak-S-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-;
-Ak-C (= O) -Ak-O-Ak-;
-Ak-C (= O) -Ak-N (R < ¹³ >)-Ak-; or -Ak-N (R < ¹³ >)-Ak-C (= O) -Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
R ¹ , R ³ , R ⁸ , R ¹⁴ and R ¹⁵ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or non-substituted Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or an unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl, a substituted or unsubstituted amidino, a group represented by the formula: —O—R ¹⁰ , a formula: —O— C (= O) group represented by ^{-R 10,} represented by the formula: -C (= O) ^{-R 10} The formula: -C (= O) groups represented by ^{-O-R 10,} wherein: a group represented by ^{-S-R 10,} _wherein: group or formula represented by -SO 2 ^{-R 10:} -O-SO a group represented by ₂ -R ^10,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl or a substituted or unsubstituted amidino;
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or the formula: A group represented by C (═O) —O—R ¹⁰ ;
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ⁶ , R ⁷ and R ¹³ are each independently hydrogen or substituted or unsubstituted alkyl, or R ⁶ together with R ² together with the adjacent nitrogen atom forms a substituted or unsubstituted heterocycle R ⁷ may be combined with the adjacent nitrogen atom and —SO ₂ — together with R ² to form a substituted or unsubstituted heterocycle.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. However, the following compounds are excluded.

The part indicated by

A compound wherein W ² is a single bond,

The part indicated by

A compound wherein X is —SO ₂ —N (—R ⁷ ) — and R ² is methyl;

The part indicated by

And W ² is a single bond, and

The part indicated by

A compound having a structure selected from

) Or a pharmaceutically acceptable salt thereof.

で示される化合物において、

で示される部分が、

である場合、以下の（Ｉｄ）又は（Ｉｅ）のいずれの構造をも意味する。

（式中、各記号は式（Ｉ）と同意義である。） Formula (I):

In the compound represented by

The part indicated by

Means any of the following structures (Id) or (Ie):

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

（式中、各記号は式（Ｉ）と同意義である。） In the compound represented by the formula (I), when X is —N (—R ⁶ ) —SO ₂ —, R ⁶ together with R ² together with the adjacent nitrogen atom forms a substituted or unsubstituted heterocyclic ring. When formed, the compound of formula (I) is represented by the following formula (If). Note that when X is —N (—R ⁶ ) —SO ₂ —, a nitrogen atom is bonded to R ² .

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

（式中、各記号は式（Ｉ）と同意義である。） In the compound represented by the formula (I), when X is —SO ₂ —N (—R ⁷ ) —, R ⁷ together with R ² and the adjacent nitrogen atom and —SO ₂ — is substituted or non-substituted. When a substituted heterocyclic ring is formed, the compound represented by the formula (I) is represented by the following formula (Ig). Note that when X is —SO ₂ —N (—R ⁷ ) —, a sulfur atom is bonded to R ² .

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

  In the compound represented by the formula (I), the following embodiments are preferable.

X is ^{_{-SO 2 -, - SO 2 -C}} (-R 14) (- R 15) -, - N (-R 6) -SO 2 - or _-SO 2 -N (-R ⁷⁾ - a. R ⁶ may form a heterocyclic ring substituted or unsubstituted together with the nitrogen atom adjacent with R ^2, R ⁷ is a nitrogen atom and -SO 2 adjacent with R ² _- and together A substituted or unsubstituted heterocyclic ring may be formed. X is preferably —SO ₂ — or —SO ₂ —N (—R ⁷ ) —, and more preferably —SO ₂ —.
When X is —N (—R ⁶ ) —SO ₂ —, it is preferable that R ^{6 and} R ² together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle.

（式中、各記号は式（Ｉ）と同意義である。）
上記「複素環」は、芳香族であってもよく、非芳香族であってもよい。また、環の構成原子に上記式に示された窒素原子以外に、窒素原子、酸素原子、硫黄原子を含んでいてもよい。好ましくは、３〜８員の非芳香族又は芳香族の複素環である。また、他の環が縮合していてもよい。例えば、１〜３個の３〜８員の炭素環又は複素環が縮合していてもよい。上記「複素環」としては、好ましくは、５〜７員の非芳香族又は芳香族の複素環、又はそれらに５〜７員の炭素環又は複素環が縮合した環である。例えば、式：

で示される基の好ましい態様としては、以下の基、又はこれらの基に１個の５員又は６員の炭素環又は複素環が縮合した基が例示される。なお、これらの基は置換可能な任意の位置で置換されていてもよい。

特に好ましくは、

又は、これらにベンゼン環若しくはシクロヘキサン環が縮合した基である。 When R ^{6 and} R ² together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic ring, the compound represented by the formula (I) is represented by the following formula (If).

(In the formula, each symbol has the same meaning as in formula (I).)
The “heterocycle” may be aromatic or non-aromatic. In addition to the nitrogen atom represented by the above formula, the ring constituting atom may contain a nitrogen atom, an oxygen atom, or a sulfur atom. Preferably, it is a 3-8 membered non-aromatic or aromatic heterocycle. Further, other rings may be condensed. For example, 1 to 3 3 to 8 membered carbocyclic or heterocyclic rings may be condensed. The “heterocycle” is preferably a 5- to 7-membered non-aromatic or aromatic heterocycle, or a ring in which a 5- to 7-membered carbon ring or heterocycle is condensed. For example, the formula:

Preferable embodiments of the group represented by are exemplified by the following groups, or groups in which one 5-membered or 6-membered carbocyclic or heterocyclic ring is condensed to these groups. These groups may be substituted at any substitutable position.

Particularly preferably,

Or it is the group which the benzene ring or the cyclohexane ring condensed to these.

（式中、各記号は式（Ｉ）と同意義である。）
上記「複素環」は、環の構成原子に上記式に示された窒素原子及び硫黄原子以外に、窒素原子、酸素原子、硫黄原子を含んでいてもよい。好ましくは、３〜８員の非芳香族複素環である。また、他の環が縮合していてもよい。例えば、１〜３個の３〜８員の炭素環又は複素環が縮合していてもよい。上記「複素環」としては、好ましくは、５〜７員の非芳香族複素環又はそれらに５〜７員の炭素環若しくは複素環が縮合した環である。例えば、式：

で示される基の好ましい態様としては、以下の基又はこれらの基に１個の５員若しくは６員の炭素環若しくは複素環が縮合した基が例示される。なお、これらの基は置換可能な任意の位置で置換されていてもよい。

When R ^{7 and} R ² together with the adjacent nitrogen atom and —SO ₂ — form a substituted or unsubstituted heterocycle, the compound represented by the formula (I) is represented by the following formula (Ig) Indicated by

(In the formula, each symbol has the same meaning as in formula (I).)
The “heterocycle” may contain a nitrogen atom, an oxygen atom, or a sulfur atom in addition to the nitrogen atom and the sulfur atom shown in the above formula as constituent atoms of the ring. Preferably, it is a 3-8 membered non-aromatic heterocyclic ring. Further, other rings may be condensed. For example, 1 to 3 3 to 8 membered carbocyclic or heterocyclic rings may be condensed. The “heterocycle” is preferably a 5- to 7-membered non-aromatic heterocyclic ring or a ring in which a 5- to 7-membered carbon ring or heterocyclic ring is condensed. For example, the formula:

Preferable embodiments of the group represented by are exemplified by the following groups or groups obtained by condensing one 5-membered or 6-membered carbon ring or heterocyclic ring to these groups. These groups may be substituted at any substitutable position.

Y ¹ is ═C (—R ⁸ ) — or ═N—. Preferred is ═C (—R ⁸ ) —, and particularly preferred is ═C (—H) —.
Y ² is —C (—R ³ ) ═ or —N═. -C (-R < ³ >) = is preferable, and -C (-H) = is particularly preferable.
Y ³ is ═C (—R ¹ ) — or ═N—. Preferred is ═C (—R ¹ ) —, and particularly preferred is ═C (—H) —.

で示される部分は、

から選択される構造である。

The part indicated by

Is a structure selected from

W ² is -Ak-;
-Ak-O-Ak-;
-Ak-N (R < ¹³ >)-Ak-;
-Ak-S-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-;
-Ak-C (= O) -Ak-O-Ak-;
-Ak-C (= O) -Ak-N (R < ¹³ >)-Ak-; or -Ak-N (R < ¹³ >)-Ak-C (= O) -Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene.
Preferably, -Ak-;
-Ak-O-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-; or -Ak-C (= O) -Ak-O-Ak-;
Ak is preferably a single bond or a substituted or unsubstituted C1-C2 alkylene.
The substituent of “C1-C4 alkylene” or “C2-C4 alkenylene” is preferably hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy or cyano.

R ¹ , R ³ , R ⁸ , R ¹⁴ and R ¹⁵ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or non-substituted Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or an unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl, a substituted or unsubstituted amidino, a group represented by the formula: —O—R ¹⁰ , a formula: —O— C (= O) group represented by ^{-R 10,} represented by the formula: -C (= O) ^{-R 10} The formula: -C (= O) groups represented by ^{-O-R 10,} wherein: group or formula represented by ^{-S-R _10:} is a group represented by -SO 2 ^{-R 10.}
R ¹ , R ³ , R ⁸ , R ¹⁴ and R ¹⁵ are preferably hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, formula : A group represented by —O—R ¹⁰ , a group represented by formula: —O—C (═O) —R ¹⁰ , a group represented by formula: —C (═O) —R ¹⁰ , a formula: —C ( ═O) A group represented by —O—R ¹⁰ or a group represented by the formula: —SO ₂ —R ¹⁰ .
Particularly preferred substituents for R ¹ are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
Particularly preferred substituents for R ³ are hydrogen, alkyl, alkenyl, alkyloxy, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
Particularly preferred substituents for R ⁸ are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.
Preferred substituents for R ¹⁴ or R ¹⁵ are hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy, cyano.

R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino.
Preferred embodiments of R ¹⁰ include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted A non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl or a substituted or unsubstituted sulfamoyl.

R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or the formula: It is a group represented by C (═O) —O—R ¹⁰ .
As a preferable embodiment of R ² , substituted or unsubstituted alkyl (substituents are halogen, alkyloxy, hydroxy, cyano, oxetanyl), substituted or unsubstituted amino (substituent is alkyl), or a formula: It is a group represented by C (═O) —O—R ¹⁰ (wherein R ¹⁰ is alkyl). Preferred is alkyl having 2 to 10 carbons, more preferred is alkyl having 2 to 4 carbons, and particularly preferred is alkyl having 2 carbons.

R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group.
Preferable embodiments of R ⁴ are cycloalkyl, aryl, heteroaryl and non-aromatic heterocyclic group, and particularly preferably aryl, heteroaryl or non-aromatic heterocyclic group.
When R ⁴ is a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group, it may be substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino. These oxo, thioxo or imino are substituted with carbon atoms or sulfur atoms constituting the ring. In this case, a cyclic group having —C (═O) —, —S (═O) —, —S (═O) ₂ —, —C (═S) —, —C (═NH) — in the ring. Means group. The imino may have a substituent.

R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10.} Here, R ¹⁰ has the same meaning as described above.
Preferred examples of R ⁵ include halogen, cyano, substituted or unsubstituted amino (the substituent is a group represented by the formula: —SO ₂ —R ¹⁰ (wherein R ¹⁰ is alkyl)), substituted or non-substituted. Substituted alkyl (substituents are halogen, hydroxy, cyano, aryl, alkyloxy, aryloxy or the formula: —C (═O) —R ¹⁰ , where R ¹⁰ is a non-aromatic heterocyclic group) Group), substituted or unsubstituted aryl (substituent is halogen or haloalkyl), substituted or unsubstituted heteroaryl (substituent is halogen or haloalkyl), substituted or unsubstituted non-aromatic heterocycle Formula groups (halogen, cyano or alkyl as substituents), substituted or unsubstituted carbamoyl (substituents are Le), wherein: (In the ^formula, the ^{R 10} is a substituted or unsubstituted alkyl (substituent, halogen, cyano or alkylamino) ^{-O-R 10} or aryl) groups represented by the formula: -C (= O) -R ¹⁰ (as the substituent, a non-aromatic heterocyclic group), represented by the formula: —C (═O) —O—R ¹⁰ (wherein the substituent is alkyl or arylalkyl) A group represented by the formula: —S—R ¹⁰ (wherein R ¹⁰ is haloalkyl) or a formula: —SO ₂ —R ¹⁰ (wherein R ¹⁰ is an alkyl, haloalkyl, aryl or non-aromatic heterocyclic ring) Group represented by the formula group).

n is an integer of 0-3. Preferably it is 1 or 2.
R ⁶ , R ⁷ and R ¹³ are each independently hydrogen or substituted or unsubstituted alkyl. Preferably, it is hydrogen or alkyl. R ⁶ may be combined with an adjacent nitrogen atom together with R ² to form a substituted or unsubstituted heterocycle. R ⁷ together with R ² and the adjacent nitrogen atom and —SO ₂ — may form a substituted or unsubstituted heterocycle.

で示される化合物において、

で示される部分が、

である場合、特に、以下の様態が好ましい。 Formula (I):

In the compound represented by

The part indicated by

In particular, the following embodiments are preferable.

（式中、
Ｙ^１は＝Ｃ（−Ｒ^８）−又は＝Ｎ−であり、
Ｙ^２は−Ｃ（−Ｒ^３）＝又は−Ｎ＝であり、
Ｙ^３は＝Ｃ（−Ｒ^１）−又は＝Ｎ−であり、
Ｗ^２は−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；又は
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｏ−Ａｋ−；
Ａｋはそれぞれ独立して、単結合、置換若しくは非置換のＣ１−Ｃ４アルキレン又は置換若しくは非置換のＣ２−Ｃ４アルケニレンであり、
但し、Ｗ^２が−Ａｋ−である場合、Ａｋは単結合ではなく、
Ｒ^１、Ｒ^３及びＲ^８はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、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であり、
Ｒ^２は炭素数２〜１０の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又は置換若しくは非置換のシクロアルケニルであり、
Ｒ^４はシクロアルキル、シクロアルケニル、アリール、ヘテロアリール又は非芳香族複素環式基であり、
Ｒ^５はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
ｎは０〜３の整数であり、
Ｒ^１０は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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又は置換若しくは非置換のアミジノである。
上記の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若しくは置換若しくは非置換の非芳香族複素環式基又はＲ^４のシクロアルキル、シクロアルケニル若しくは非芳香族複素環式基は、１又は２個のオキソ、チオキソ又は置換若しくは非置換のイミノで置換されていてもよい。）で示される化合物又はその製薬上許容される塩。 Formula (Ia):

(Where
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-; or -Ak-C (= O) -Ak-O-Ak-;
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
However, when W ² is -Ak-, Ak is not a single bond,
R ¹ , R ³ and R ⁸ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl,
R ² is substituted or unsubstituted alkyl having 2 to 10 carbon atoms, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl,
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. Or a pharmaceutically acceptable salt thereof.

  In the compound represented by the formula (Ia), the following modes are more preferable.

W ² is -Ak-;
-Ak-O-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-; or -Ak-C (= O) -Ak-O-Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene. However, when W ² is -Ak-, Ak is not a single bond.
-Ak-; -O-; -O-Ak-; -Ak-O-
Ak is substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene.
The substituent of “C1-C4 alkylene” or “C2-C4 alkenylene” is preferably hydrogen, alkyl, hydroxy, halogen, haloalkyl, haloalkyloxy or cyano.

R ² is substituted or unsubstituted alkyl having 2 to 10 carbon atoms, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl. More preferably, it is a substituted or unsubstituted alkyl having 2 to 10 carbon atoms. In particular, an alkyl having 2 to 4 carbon atoms is preferable, and an alkyl having 2 carbon atoms is more preferable.

R ⁴ is particularly preferably cyclopropyl, cyclohexyl, phenyl, dihydrobenzofuranyl, isoindolinyl, piperidyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, pyridyl, quinuclidinyl, tetrahydroquinolinyl, chromenyl, isoxazolyl, oxazolyl, thiazolyl or benzoimidazolyl. is there. More preferred is phenyl.
R ⁵ is particularly preferably halogen, cyano, substituted or unsubstituted amino (the substituent is a group represented by the formula: —SO ₂ —R ¹⁰ (wherein R ¹⁰ is alkyl)), substituted or unsubstituted Alkyl (substituent is halogen or phenyl), substituted or unsubstituted phenyl (substituent is halogen, haloalkyl or alkyloxy), substituted or unsubstituted azetidinyl (substituent is halogen), substituted or Unsubstituted piperidyl (substituent is halogen), substituted or unsubstituted benzothiazolyl (substituent is halogen) or a group represented by the formula: —O—R ¹⁰ (wherein R ¹⁰ is alkyl or haloalkyl) It is.
Other preferred embodiments of each symbol are the same as the preferred embodiments of each symbol in the compound represented by formula (I).

で示される化合物において、

で示される部分が、

である場合、特に、以下の様態が好ましい。 Formula (I):

In the compound represented by

The part indicated by

In particular, the following embodiments are preferable.

（式中、
Ｙ^１は＝Ｃ（−Ｒ^８）−又は＝Ｎ−であり、
Ｙ^２は−Ｃ（−Ｒ^３）＝又は−Ｎ＝であり、
Ｙ^３は＝Ｃ（−Ｒ^１）−又は＝Ｎ−であり、
Ｗ^２は−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；
−Ａｋ−Ｓ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；又は
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−であり、
Ａｋはそれぞれ独立して、単結合、置換若しくは非置換のＣ１−Ｃ４アルキレン又は置換若しくは非置換のＣ２−Ｃ４アルケニレンであり、
Ｒ^１、Ｒ^３及びＲ^８はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
Ｒ^１０は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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又は置換若しくは非置換のアミジノであり、
Ｒ^２は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又は置換若しくは非置換のシクロアルケニルであり、
Ｒ^４はシクロアルキル、シクロアルケニル、アリール、ヘテロアリール又は非置換の非芳香族複素環式基であり、
Ｒ^５はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
ｎは０〜３の整数であり、
Ｒ^１３は水素又は置換若しくは非置換のアルキルであり、
上記の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若しくは置換若しくは非置換の非芳香族複素環式基又はＲ^４のシクロアルキル、シクロアルケニル若しくは非芳香族複素環式基は、１又は２個のオキソ、チオキソ又は置換若しくは非置換のイミノで置換されていてもよい。但し、以下の化合物を除く。
Ｒ^４がフェニルである化合物、

で示される部分が、

から選択される構造である化合物、

）で示される化合物又はその製薬上許容される塩。 Formula (Ib):

(Where
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-N (R < ¹³ >)-Ak-;
-Ak-S-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-;
-Ak-C (= O) -Ak-O-Ak-;
-Ak-C (= O) -Ak-N (R < ¹³ >)-Ak-; or -Ak-N (R < ¹³ >)-Ak-C (= O) -Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
R ¹ , R ³ and R ⁸ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic Group heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , formula: —O—C (═O) — Group represented by R ¹⁰ , Formula: —C (═O) —R ¹⁰ Group represented by Formula: —C (═O) A group represented by —O—R ¹⁰ , a group represented by formula: —S—R ¹⁰ , a group represented by formula: —SO ₂ —R ¹⁰ or a group represented by formula: —O—SO ₂ —R ^10; Yes,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl or a substituted or unsubstituted amidino;
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl,
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or unsubstituted non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ¹³ is hydrogen or substituted or unsubstituted alkyl;
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. However, the following compounds are excluded.
A compound wherein R ⁴ is phenyl;

The part indicated by

A compound having a structure selected from

Or a pharmaceutically acceptable salt thereof.

  In the compound represented by the formula (Ib), the following modes are more preferable.

R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or unsubstituted non-aromatic heterocyclic group. Preferable embodiments of R ⁴ are cycloalkyl, aryl, heteroaryl, non-aromatic heterocyclic group, more preferably heteroaryl or non-aromatic heterocyclic group, particularly preferably monocyclic or Bicyclic heteroaryl or monocyclic or bicyclic non-aromatic heterocyclic group. However, R ⁴ is not phenyl, piperidyl or octahydrocyclopenta [b] pyrrolyl.
Particularly preferably R ⁴ is cyclopropyl, cyclopentyl, cyclohexyl, indazolyl, quinolyl, quinoxalinyl, benzoxazolyl, pyrazolyl, pyridyl, thiazolyl, pyrimidinyl, pyrazinyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl, dihydrobenzofuryl, piperidyl, tetrahydrofura Nil and azaspiroheptanyl.
R ⁵ is particularly preferably halogen, hydroxy, cyano, substituted or unsubstituted alkyl (substituent is halogen, phenyl or phenyloxy), substituted or unsubstituted phenyl (substituent is halogen), morpholino, Tetrahydropyranyl, group represented by formula: —O—R ¹⁰ (wherein R ¹⁰ is alkyl, haloalkyl or phenyl) or formula: —C (═O) —O—R ¹⁰ (substituent is phenylalkyl ).

  Other preferred embodiments of each symbol are the same as the preferred embodiments of each symbol in the compound represented by formula (I).

で示される化合物において、

で示される部分が、

である場合、特に、以下の様態が好ましい。 Formula (I):

In the compound represented by

The part indicated by

In particular, the following embodiments are preferable.

（式中、
Ｙ^１は＝Ｃ（−Ｒ^８）−又は＝Ｎ−であり、
Ｙ^２は−Ｃ（−Ｒ^３）＝又は−Ｎ＝であり、
Ｙ^３は＝Ｃ（−Ｒ^１）−又は＝Ｎ−であり、
Ｗ^２は−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；
−Ａｋ−Ｓ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｏ−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｏ−Ａｋ−；
−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−；又は
−Ａｋ−Ｎ（Ｒ^１３）−Ａｋ−Ｃ（＝Ｏ）−Ａｋ−であり、
Ａｋはそれぞれ独立して、単結合、置換若しくは非置換のＣ１−Ｃ４アルキレン又は置換若しくは非置換のＣ２−Ｃ４アルケニレンであり、
Ｒ^１、Ｒ^３及びＲ^８はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
Ｒ^１０は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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル又は置換若しくは非置換のアミジノであり、
Ｒ^２は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ミノ、置換若しくは非置換のシクロアルキル又は置換若しくは非置換のシクロアルケニルであり、
Ｒ^４はシクロアルキル、シクロアルケニル、アリール、ヘテロアリール又は非置換の非芳香族複素環式基であり、
Ｒ^５はハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、置換若しくは非置換のアミノ、カルボキシ、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、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、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイル、置換若しくは非置換のアミジノ、式：−Ｏ−Ｒ^１０で示される基、式：−Ｏ−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｒ^１０で示される基、式：−Ｃ（＝Ｏ）−Ｏ−Ｒ^１０で示される基、式：−Ｓ−Ｒ^１０で示される基、式：−ＳＯ_２−Ｒ^１０で示される基又は式：−Ｏ−ＳＯ_２−Ｒ^１０で示される基であり、
ｎは０〜３の整数であり、
Ｒ^１３は水素又は置換若しくは非置換のアルキルであり、
上記の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若しくは置換若しくは非置換の非芳香族複素環式基又はＲ^４のシクロアルキル、シクロアルケニル若しくは非芳香族複素環式基は、１又は２個のオキソ、チオキソ又は置換若しくは非置換のイミノで置換されていてもよい。）で示される化合物又はその製薬上許容される塩。 Formula (Ic):

(Where
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-N (R < ¹³ >)-Ak-;
-Ak-S-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-;
-Ak-C (= O) -Ak-O-Ak-;
-Ak-C (= O) -Ak-N (R < ¹³ >)-Ak-; or -Ak-N (R < ¹³ >)-Ak-C (= O) -Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
R ¹ , R ³ and R ⁸ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic Group heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , formula: —O—C (═O) — Group represented by R ¹⁰ , Formula: —C (═O) —R ¹⁰ Group represented by Formula: —C (═O) A group represented by —O—R ¹⁰ , a group represented by formula: —S—R ¹⁰ , a group represented by formula: —SO ₂ —R ¹⁰ or a group represented by formula: —O—SO ₂ —R ^10; Yes,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl or a substituted or unsubstituted amidino;
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl,
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or unsubstituted non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ¹³ is hydrogen or substituted or unsubstituted alkyl;
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. Or a pharmaceutically acceptable salt thereof.

In the compound represented by the formula (Ic), the following embodiments are more preferable.
R ² is particularly preferably substituted or unsubstituted alkyl (substituted group is cyano) or substituted or unsubstituted amino (substituted group is alkyl).
W ² is particularly preferably -Ak-; -Ak-O-Ak-, and each Ak is independently a single bond, C1-C4 alkylene or C2-C4 alkenylene. More preferably, it is a single bond.
R ⁴ is particularly preferably aryl, pyridyl, pyrazolyl or azetidinyl. More preferred is phenyl.
R ⁵ is particularly preferably halogen, cyano, substituted or unsubstituted alkyl (substituent is halogen, hydroxy or cyano), aryl, substituted or unsubstituted morpholino (substituent is alkyl), piperidino, pyrrolidinyl , Pyrazolyl, imidazolyl, substituted or unsubstituted azetidinyl (substituent is halogen), substituted or unsubstituted carbamoyl (substituent is alkyl), formula: —O—R ¹⁰ (wherein R ¹⁰ is substituted) Or a group represented by unsubstituted alkyl (the substituent is cyano or alkylamino) or a group represented by the formula: —C (═O) —O—R ¹⁰ (wherein R ¹⁰ is alkyl). .
Other preferred embodiments of each symbol are the same as the preferred embodiments of each symbol in the compound represented by formula (I).

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

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

“Alkyl” means a straight 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.

  “Haloalkyl” and “haloalkyloxy” mean a group in which 1 to 5 (preferably 1 to 3) of the above “halogens” are substituted on the alkyl part of alkyl and alkyloxy.

  “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.

  “C1-C4 alkylene” includes a divalent group in which 1 to 3 methylenes are continuous, and specifically includes methylene, ethylene and trimethylene.

  The “C2-C4 alkenylene” includes a divalent group in which 2 or 3 methylenes are continuous and at least one of carbon-carbon bonds is a double bond.

“Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic saturated hydrocarbon groups. Examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, a cycloalkyl having 3 to 6 carbon atoms and a cycloalkyl having 5 or 6 carbon atoms are preferable.
Examples of the ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring, Cyclopentene ring) and the like, and non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
For example, the following groups are also exemplified by cycloalkyl and are included in cycloalkyl. These groups may be substituted at any substitutable position.

“Cycloalkenyl” refers to a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, and a group obtained by further condensing one or two rings of 3 to 8 members to these cyclic unsaturated aliphatic hydrocarbon groups. Means. Examples of the cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like. In particular, a C3-C6 cycloalkenyl and a C5-C6 cycloalkenyl are preferable.
Examples of the ring condensed with the C3-C8 cyclic unsaturated aliphatic hydrocarbon group include carbocycles (aromatic carbocycles (for example, benzene rings, naphthalene rings)), non-aromatic carbocycles (for example, cycloalkane rings). (Example: cyclohexane ring, cyclopentane ring, etc.), cycloalkene ring (example: cyclohexene ring, cyclopentene ring, etc.)), heterocycle (aromatic heterocycle (pyridine ring, pyrimidine ring, pyrrole ring, imidazole ring, etc.) And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.) The bond is derived from a C3-C8 cyclic unsaturated aliphatic hydrocarbon group. .
For example, the following groups are also exemplified as cycloalkenyl and are included in cycloalkenyl. These groups may be substituted at any substitutable position.

“Aryl” is a monocyclic or polycyclic aromatic carbocyclic group, or a group obtained by further condensing one or two rings of 3 to 8 members to these monocyclic or polycyclic aromatic carbocyclic groups. Means. Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
Rings condensed with monocyclic or polycyclic aromatic carbocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring). And non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to come from a monocyclic or polycyclic aromatic carbocyclic group.
For example, the following groups are also exemplified as aryl and are included in aryl. These groups may be substituted at any substitutable position.

“Heteroaryl” means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and monocyclic or polycyclic It means a group obtained by further condensing one or two 3- to 8-membered rings on an aromatic heterocyclic group.
As the “monocyclic aromatic heterocyclic group”, a 5- or 6-membered heteroaryl is particularly preferable. For example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, Examples include oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
As the “polycyclic aromatic heterocyclic group”, a heteroaryl fused with a 5-membered or 6-membered ring is particularly preferable. Naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Bicyclic aromatic heterocyclic groups such as zolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl; carbazolyl, a Lysinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, cycloalkenyl, 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.
Rings condensed with monocyclic or polycyclic aromatic heterocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene). Ring, cyclopentene ring, etc.)) and non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to be from a monocyclic or polycyclic aromatic heterocyclic group.
For example, the following groups are also exemplified as heteroaryl, and are included in heteroaryl. These groups may be substituted at any substitutable position.

“Non-aromatic heterocyclic group” means a non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and these non-aromatic heterocyclic groups It means a group obtained by further condensing one or two 3- to 8-membered rings to the formula group.
It contains a monocyclic non-aromatic heterocyclic group or a polycyclic non-aromatic heterocyclic group.
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.
For example, the following groups are also included in the non-aromatic heterocyclic group.

  A substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group is substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino Also good.

“Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted aryl”, “substituted heteroaryl”, “substituted non-aromatic heterocyclic group”, “ “C1-C4 alkylene”, “C2-C4 alkenylene”, “substituted heterocycle formed by combining R ⁶ and R ² together with adjacent nitrogen atom”, “nitrogen atom where R ⁷ and R ² are both adjacent and Examples of the substituent of “substituted heterocycle formed together with —SO ₂ —” or “substituted alkyl having 2 to 10 carbon atoms” include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, amino, Carboxy, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, non-aromatic heterocyclic group Carbamoyl, sulfamoyl, amidino, formula: a group represented by ^{-O-R 10,} wherein: -O-C (= O) group represented by ^{-R 10,} represented by the formula: -C (= O) ^{-R 10} A group represented by the formula: —C (═O) —O—R ¹⁰ , a group represented by the formula: —S—R ¹⁰ , or a group represented by the formula: —SO ₂ —R ¹⁰ (where R ¹⁰ represents , Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, non-aromatic heterocyclic group, carbamoyl, sulfamoyl or amidino). With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.
“Substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl”, “substituted or unsubstituted non-aromatic heterocyclic group”, “R ⁶ and R ² together with the adjacent nitrogen atom A substituted or unsubstituted heterocyclic ring formed as “, or a substituted or unsubstituted heterocyclic ring formed by R ⁷ and R ² together with the adjacent nitrogen atom and —SO ₂ —” can be substituted. Any position may be substituted with oxo, thioxo or substituted or unsubstituted imino.

As the substituents of “substituted amino”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted amidino” or “substituted imino”, hydroxy, cyano, formyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Aryl, heteroaryl, non-aromatic heterocyclic group, carbamoyl, sulfamoyl, amidino, group represented by formula: —O—R, group represented by formula: —C (═O) —R, formula: —C ( ═O) —O—R, or a group represented by the formula: —SO ₂ —R, wherein R is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or non- Aromatic heterocyclic group). With these substituents, 1 to 2 arbitrary positions that can be substituted may be substituted.

  The compound of the present invention is not limited to a specific isomer, but all possible isomers (for example, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer, etc.) ), Racemates or mixtures thereof.

One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with hydrogen, carbon and / or isotopes of other atoms, respectively. Examples of such isotopes are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ^{Like 36} Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compounds of the present invention also include compounds substituted with such isotopes. The compound substituted with the isotope is useful as a pharmaceutical and includes all radiolabeled compounds of the present invention. A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.

The radioactive label of the compound of the present invention can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. In this method, a tritium gas is reacted with a precursor in which a compound of the formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ^{The 14} C-labeled compound can be prepared by using a raw material having ¹⁴ C carbon.

  Examples of the pharmaceutically acceptable salt of the compound of the present invention include a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, calcium, barium, etc.). , Magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) And salts with amino acids, or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (eg, formic acid, acetic acid, propionic acid, trifluoro) Acetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, Maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, and salts with ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

  The compound of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystal polymorph, and the present invention is applicable to such various solvates and crystals. Also includes polymorphs. The “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound of the present invention. When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In addition, the crystalline polymorph may be formed by recrystallizing the compound of the present invention or a pharmaceutically acceptable salt thereof.

  The compound of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed and converted to the compounds of the present invention under physiological conditions in vivo, compounds that are hydrolyzed by gastric acid, etc., and converted to the compounds of the present invention, etc. Include. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.

When the compound of the present invention or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anion. Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with hydride or reacting with a condensing agent. For example _{CH 3 COO-, C 2 H 5} COO-, t-BuCOO-, C 15 H 31 COO-, PhCOO -, (m-NaOOCPh) COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH (NH 2) _{COO-, CH 2 N (CH 3} ) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p- CH ₃ —O—PhSO ₃ —, PhSO ₃ —, and p-CH ₃ PhSO ₃ — can be mentioned.

（式中、Ｈａｌはハロゲン、その他の各記号は式（Ｉ）と同意義である。） Below, the general manufacturing method of this invention compound is demonstrated. In addition, this invention compound can be manufactured based on the knowledge of organic chemistry also by methods other than the synthesis method shown below.

(In the formula, Hal is halogen, and other symbols are as defined in formula (I).)

Process 1
In this step, the compound represented by the formula (III) is produced from the compound represented by the formula (II) via a diazonium salt.
The diazonium salt can be produced by reacting the compound represented by the formula (II) with NaNO ₂ and HCl at a low temperature.
As the reaction solvent, water or a mixed solvent of water and alcohol (for example, methanol) can be used.
After the formation of the diazonium salt, the diazonium salt can be reacted with a copper halide (eg, copper bromide, copper chloride, copper iodide, etc.) to produce a compound represented by the formula (III). The reaction can be carried out at 0 ° C. to room temperature. Moreover, it can also heat to 40-60 degreeC.

Process 2
In this step, the compound represented by formula (I) is produced from the compound represented by formula (III). The compound represented by the formula (III) is useful as a synthetic intermediate for the compound represented by the formula (I).

Step 2-1
A compound having a reactive amino group (-NH-), by reaction with a halogen compound represented by the formula ^(III), the linker moiety to the ring containing ^{V 1, V 2 (-W 1} -W 2 A compound represented by formula (I) to which a nitrogen atom of-) is bonded can be produced. The substituent on R ⁴ may be introduced prior to step 2-1, or may be introduced after step 2-1.
As the reaction solvent, acetonitrile, tetrahydrofuran, toluene, benzene, 2-propanol and the like can be used.
The reaction can also be performed at room temperature. Moreover, you may heat suitably, seeing progress of reaction. For example, it can carry out by heating to 100-120 degreeC in acetonitrile.
It can be performed under microwave irradiation.

Step 2-2
In Step 2, a compound having a reactive hydroxy group (—OH) is reacted with a halogen of the compound represented by the formula (III), whereby a linker moiety (—W ¹ ) is added to the ring containing V ¹ and V ^2. A compound represented by the formula (I) to which an oxygen atom of —W ² — is bonded can be produced. The substituent on R ⁴ may be introduced prior to Step 2-2 or may be introduced after Step 2-2.
As the reaction solvent, N, N-dimethylformamide or the like can be used.
The reaction can also be performed at room temperature. Moreover, you may heat suitably, seeing progress of reaction.
Moreover, you may add a cesium carbonate etc. as a catalyst.

（式中、Ｘは−ＳＯ_２、Ｐｒｏはアミノ保護基、その他の各記号は式（Ｉ）と同意義である。） The compound represented by the formula (II) used in the above step 1 can be produced as follows.

(Wherein X is —SO ₂ , Pro is an amino protecting group, and other symbols are the same as those in formula (I).)

Process 3
In this step, the compound represented by the formula (V) is produced by oxidizing the -S- group of the compound represented by the formula (IV).
As the oxidizing agent, mCPBA (metachloroperbenzoic acid), KMnO ₄ (potassium permanganate), Oxone, NaIO ₄ (sodium periodate), NaBO ₃ (sodium perborate), hydrogen peroxide, etc. may be used. it can.
As the reaction solvent, dichloromethane, chloroform, acetonitrile, acetone, water and the like can be used.
The reaction can be performed at room temperature, or may be appropriately heated while watching the progress of the reaction.

Process 4
In this step, the amino protecting group of the compound represented by formula (IV) is removed to produce the compound represented by formula (II).
As the amino protecting group, methoxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl, trichloroethoxycarbonyl and the like can be used.
What is necessary is just to select deprotection conditions suitably according to a protecting group. For example, the protecting group may be eliminated under alkaline conditions.

（式中、各記号は式（Ｉ）と同意義である。） The compound represented by the formula (I) can also be produced as follows.

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

で示される化合物を塩基存在下で反応させ、アミド化を行い、式（ＶＩＩ）で示される化合物を製造する工程である。
反応溶媒としては、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド、テトラヒドロフラン、１−メチルピロリジン−２−オン、Ｎ，Ｎ−ジメチルアセトアミド、アセトニトリル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、ジメチルアミノピリジン、Ｎ，Ｎ−ジイソプロピルエチルアミン等を用いることができる。
本工程において、ＨＡＴＵ（２−（１Ｈ−７−アザベンゾトリアゾール−１−イル）−１，１，３，３−テトラメチル ウロニウム ヘキサフルオロリン酸 メタンアミニウム）を縮合剤として用いることができる。 Process 5
The compound of formula (VI) has the formula:

In this step, the compound represented by formula (VII) is produced by reacting the compound represented by formula (II) in the presence of a base and performing amidation.
As the reaction solvent, dichloromethane, N, N-dimethylformamide, tetrahydrofuran, 1-methylpyrrolidin-2-one, N, N-dimethylacetamide, acetonitrile and the like can be used.
As the base, triethylamine, pyridine, dimethylaminopyridine, N, N-diisopropylethylamine and the like can be used.
In this step, HATU (2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium) can be used as a condensing agent.

Step 6
In this step, the compound represented by the formula (VII) is cyclized to produce the compound represented by the formula (I).
Acetic acid, hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, 10-camphorsulfonic acid and the like can be used as a reaction solvent at 100 to 150 ° C.
The step 5 and step 6, the formula: is shown in compounds having a group represented by -X-R ^2, as in step 5 and 6 using a compound having a group represented by -S-R ² May be reacted, and then -S- may be oxidized.
In addition, the substituent on R ⁴ may be introduced after Step 5 or 6, or may be introduced prior to Step 5.
The compound represented by the formula (VII) is useful as a synthetic intermediate for the compound represented by the formula (I).

（式中、Ｘは−ＳＯ_２−、Ｈａｌはハロゲン、その他の各記号は式（Ｉ）と同意義である。） The compound represented by the formula (I) can also be produced by the following steps.

(In the formula, X is —SO ₂ —, Hal is halogen, and other symbols are the same as those in formula (I).)

Step 7
In this step, the compound represented by the formula (VIII) is reacted with a compound having a reactive amino group (—NH—) or a hydroxyl group (—OH) to produce a compound represented by the formula (IX).
This step can be performed according to step 2.
The reaction can be carried out in the presence of DIEA (N, N-diisopropylethylamine), triethylamine or the like. It can be performed at room temperature, or may be performed by heating to 150 to 200 ° C.
As a reaction solvent, IPA (isopropyl alcohol), dioxane, toluene, tetrahydrofuran, ethanol, 1-methylpyrrolidin-2-one, N, N-dimethylformamide and the like can be used.

Process 8
A step of producing a compound represented by the formula (X) by reacting a compound represented by the formula (IX) with a compound represented by the formula: R ² SH (wherein R ² is as defined in the formula (I)). It is.
In the presence of Pd ₂ (dba) ₃ (tris (dibenzylideneacetone) dipalladium (0)), Pd (OAc) ₂ (palladium acetate), copper iodide, Pd (PPh ₃ ) ₄ (tetrakistriphenylphosphine palladium, etc. As the base, DIEA (N, N-diisopropylethylamine) can be used, and in the presence of Xantphos (xantphos), DOX (dioxane) can be used as the solvent. The reaction can be carried out at room temperature or by heating to 100 to 120 ° C.
This step can be performed under microwave irradiation.
In addition, instead of the compound represented by the formula: R ² SH (wherein R ² is as defined in the formula (I)), the formula: R ² SSR ² (wherein R ² is as defined in the formula (I)) ) Can be used.
Further, instead of the compound represented by the formula: R ² SH (wherein R ² is as defined in the formula (I)), the formula: R ² S (═O) O—R (for example, R is 2-naphthyl) A compound represented by formula (I) can be produced by producing a compound having -S (= O)-by using a compound represented by (methyl) and then oxidizing the compound.
In these cases, prior to the reaction, the —NH— of the condensed ring of the formula (IX) may be protected with an SEM group (2- (trimethylsilyl) ethoxymethyl group). The SEM group can be eliminated by heating in the presence of TBAF (tetrabutylammonium fluoride).

Step 9
In this step, the -S- group of the compound represented by formula (X) is oxidized to produce a compound represented by formula (I).
This step can be performed according to step 3.
The substituent on R ⁴ may be introduced after each of the steps 7 to 9 or may be introduced prior to the step 7.
The compound represented by the formula (X) is useful as a synthetic intermediate for the compound represented by the formula (I).

（式中、Ｈａｌはハロゲン、その他の各記号は式（Ｉ）と同意義である。） The compound represented by the formula (IX) used in the above step 8 can also be produced as follows.

(In the formula, Hal is halogen, and other symbols are as defined in formula (I).)

Step 10
A compound having a reactive amino group (-NH), by reaction with the carboxyl group of the compound represented by the formula ^(XII), the linker moiety to the ring containing ^{V 1, V 2 (-W 1} -W 2 A compound represented by the formula (IX) to which a carbonyl group of-) is bonded can be produced. The substituent on R ⁴ may be introduced prior to Step 10 or after Step 10.
As the reaction solvent, N, N-dimethylformamide or the like can be used.
As the base, triethylamine, pyridine, dimethylaminopyridine, N, N-diisopropylethylamine and the like can be used.
In this step, HATU (2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium) can be used as a condensing agent.

  The compound of the present invention thus obtained can be purified by crystallization in various solvents. Solvents used include alcohol (methanol, ethanol, isopropyl alcohol, n-butanol, etc.), ether (diethyl ether, diisopropyl ether, etc.), acetic acid methyl ester, acetic acid ethyl ester, chloroform, methylene chloride, tetrahydrofuran, N, N- Examples include dimethylformamide, toluene, benzene, xylene, acetonitrile, hexane, dioxane, dimethoxyethane, water, or a mixed solvent thereof. After dissolving in these solvents under heating to remove impurities, the temperature is gradually lowered and the precipitated solid or crystals may be collected by filtration.

The compounds of the present invention prevent NPY Y5 related diseases in general, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders And / or effective treatment. 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, dyslipidemia, arteriosclerosis, and acute coronary syndrome.
Furthermore, the compound of the present invention has not only an NPY Y5 receptor antagonistic action but also a usefulness as a medicine, and has any or all of the following excellent features.
a) The inhibitory action against CYP enzymes (for example, CYP1A2, CYP2C9, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) Low toxicity such as anemia-inducing action.
d) High metabolic stability.
e) High water solubility.
f) High brain transferability.
g) Does not cause gastrointestinal disorders (eg, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).

  Furthermore, the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and is considered to have 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, it is unlikely to induce side effects based on peripheral vasoconstriction, and the compound of the present invention considered to have high Y5 receptor selectivity is used as an active ingredient. The pharmaceutical composition to be used can be suitably used as a safe medicine.

  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, percutaneous 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, crystalline cellulose and the like. 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 anti-obesity drugs (pharmaceutical compositions containing compounds having an anti-obesity action, drugs that can be used for weight management in obesity or obesity, etc.). For example, by using a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention, it can be used for prevention and / or treatment of obesity, weight management in obesity, and the like. The pharmaceutical composition containing the compound of the present invention can be used in combination with a pharmaceutical composition containing a compound having an anti-obesity action for the prevention and / or treatment of obesity or weight management in obesity. it can. Moreover, the administration therapy of the pharmaceutical composition of the present invention can be used in combination with diet therapy, drug therapy, exercise and the like.

For example, the following methods are also within the scope of the present invention.
Prevention of obesity or obesity-related diseases, comprising administering a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof. Or a method of weight management in treatment or obesity.
A pharmaceutical composition containing a compound having an anti-obesity action is administered to a patient undergoing prevention or treatment by administration of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof. A method for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity;

で示される化合物。
ＧＰＲ１１９アゴニスト：式：

で示される化合物。
カンナビノイドＣＢ１受容体拮抗剤：リモナバン塩酸塩。
ニューロキニンＮＫ３受容体拮抗薬：リモナバン塩酸塩。
モノアミン取り込み阻害剤：シブトラミン塩酸塩。
メラニン凝集ホルモンＭＣＨ受容体（ＳＬＣ−１）の選択的アンタゴニスト：式：

で示される化合物。
ステアロイル・コエンザイムＡ・デサチュラーゼ−１阻害剤：式：

で示される化合物。
ノルアドレナリン及びドパミン再取り込み阻害薬：テソフェンシン。
また、ノルアドレナリン及びドパミン再取り込み阻害薬であるブプロピオンとオピオイド受容体アンタゴニストであるナルトレキソンの配合剤、ＮＥ分泌促進作用を有するフェンタミンとＧＡＢＡアゴニストであるトピラマートの配合剤等も抗肥満作用を有する化合物を含有する医薬組成物として例示される。 As a pharmaceutical composition containing a compound having an anti-obesity action, a compound having an appetite suppressing action (a selective serotonin reuptake inhibitor such as fenfluramine and fluoxetine; mazindol, etc.), a compound having an action to suppress digestion and absorption of nutrients (Compounds having a saccharide absorption inhibitory effect (α-glucosidase inhibitors such as acarbose and voglibose; SGLT-2 inhibitors such as dapagliflozin, remogliflozin and KGT-1075), compounds having a fat absorption inhibitory activity (lipase inhibitors (stomach Compounds having lipase inhibitory action; compounds having pancreatic lipase inhibitory action such as orlistat, lipstatin, pancricin, cetiristat, etc.), bile acid adsorbing resins such as cholestyramine, cholestyramide, etc.), 5HT transporter inhibitor, NE transporter Inhibitor, CB-1 antagonist / inverse agonist, ghrelin antagonist, H3 antagonist / inverse agonist, MCH R1 antagonist, MCH R2 agonist / antagonist, NPY Y1 receptor antagonist, NPY Y2 receptor agonist, NPY Y4 receptor agonist, NPY Y5 Receptor antagonist, mGluR5 antagonist, leptin, leptin agonist, leptin derivative, opioid antagonist, orexin antagonist, BRS3 agonist, CCK-A agonist, CNTF, CNTF agonist, CNTF derivative, GHS agonist, 5HT2C agonist, Mc4r agonist, monoamine reuptake inhibition Agent, GLP-1 agonist, UCP-1, 2, and 3 activator, β3A Contains gonists, thyroid hormone β agonists, PDE inhibitors, FAS inhibitors, DGAT1 inhibitors, DGAT2 inhibitors, ACC2 inhibitors, glucocorticoid antagonists, acyl-estrogens, fatty acid transporter inhibitors, dicarboxylic acid transporter inhibitors, etc. Pharmaceutical composition to be used.
Although not limited to the following, examples of the pharmaceutical composition containing a compound having an anti-obesity action include the following.
Pancreatic lipase inhibitor: Orlistat.
Gastrointestinal function regulator: 6-chloro-2-phenyl-8,8a-dihydro-indenol [1,2-d] thiazol-3a-ol.
Serotonin 2C agonist: lorcaserine hydrochloride.
Carboxypeptidase inhibitor: Formula:

A compound represented by
GPR119 agonist: Formula:

A compound represented by
Cannabinoid CB1 receptor antagonist: rimonabant hydrochloride.
Neurokinin NK3 receptor antagonist: rimonabant hydrochloride.
Monoamine uptake inhibitor: sibutramine hydrochloride.
Selective antagonist of melanin-concentrating hormone MCH receptor (SLC-1): Formula:

A compound represented by
Stearoyl coenzyme A desaturase-1 inhibitor: Formula:

A compound represented by
Noradrenaline and dopamine reuptake inhibitors: Tesofensin.
In addition, a combination of bupropion, a noradrenaline and dopamine reuptake inhibitor, and naltrexone, an opioid receptor antagonist, a combination of fentamine, which has an NE secretion promoting action, and topiramate, a GABA agonist, also contain compounds having anti-obesity effects. Exemplified as a pharmaceutical composition.

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 Bu: butyl Ph: phenyl PPh ₃ , TPP: triphenylphosphine DMF: N, N-dimethylformamide TFA: trifluoroacetic acid DMSO: dimethyl sulfoxide THF: tetrahydrofuran HATU: 2- (1H-7-aza Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate Methanaminium DIEA: N, N-diisopropylethylamine IPA: 2-propanol TBAF: tetrabutylammonium fluoride SEM: 2- (trimethylsilyl) ethoxymethyl DOX: dioxane _Pd 2 _{(dba) 3:} tris (dibenzylideneacetone) dipalladium OAc: acetate groups xantphos: Xantphos Hunig's base: N, N- diisopropyl Propylethylamine mCPBA: metachloroperbenzoic acid NMP: 1-methylpyrrolidin-2-one LAH: lithium aluminum hydride DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene Dess-Martin Periodinane: 1, 1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one DCM: methylene chloride, dichloromethane TEA: triethylamine DEOXOFLUOR: bis (2-methoxyethyl) aminosulfur trifluoride DAST: N, N-diethylaminosulfur trifluoride

In addition, the NMR analysis obtained in each Example was measured using d6-DMSO and CDCl ₃ . DCl is deuterated hydrochloric acid.
“RT” in the NMR data column represents the retention time in LC / MS: liquid chromatography / mass spectrometry and was measured under the following conditions.
Measurement conditions (1): Column: Gemini-NX (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing methanol solution gradient: A linear gradient of 5% -100% solvent [B] is performed in 3.5 minutes, 100% solvent [B] was maintained for 0.5 minutes.
Measurement conditions (2): Column: Gemini-NX (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 10 mM ammonium carbonate-containing aqueous solution, [B] is an acetonitrile gradient: linear gradient of 5% -100% solvent [B] is performed for 3.5 minutes, and 100% solvent [B] is added for 0.5 minutes. B] was maintained.
Measurement conditions (3): Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution Gradient: linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.

化合物２(307mg, 2.21mmol)に、窒素気流下でＮ，Ｎ−ジメチルホルムアミド(1.0ml)、トリエチルアミン(418ul, 3.02mmol)、化合物１(500mg, 2.01mmol)及びＨＡＴＵ(918mg, 2.42mmol)を加え、１時間程度攪拌した。反応液に酢酸エチルを加え、２Ｍの炭酸カリウム水溶液及び水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、化合物３ (586.4mg, 収率81.8%)を個体物として得た。
LCMS(MS、測定条件(1))=357.60 (M+H) Example 1 First Step of Synthesis of Compound Ia-4-1

Compound 2 (307 mg, 2.21 mmol) was mixed with N, N-dimethylformamide (1.0 ml), triethylamine (418 ul, 3.02 mmol), compound 1 (500 mg, 2.01 mmol) and HATU (918 mg, 2.42 mmol) under a nitrogen stream. In addition, it was stirred for about 1 hour. Ethyl acetate was added to the reaction mixture, washed with 2M aqueous potassium carbonate solution and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give Compound 3 (586.4 mg, yield 81.8%) as a solid. Obtained.
LCMS (MS, measurement condition (1)) = 357.60 (M + H)

ＸａｎｔＰｈｏｓ(16.2mg, 0.028mmol)及びＰｄ_２（ｄｂａ）_３(12.9mg, 0.014mmol)に窒素気流下で１，４−ジオキサン(1.0ml)、化合物３ (100.0mg, 0.281mmol)及びＮ，Ｎ−ジイソプロピルエチルアミン(123ul, 0.702mmol)を加えた。さらにｎ−プロパンチオール(32.1mg, 0.421mmol)の１，４−ジオキサン溶液(1.0ml)を加えて、マイクロウェーブ反応装置(１３０℃, １時間)により反応を行なった。溶媒を減圧下留去し、残渣に酢酸エチルを加え、水で洗浄して無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、シリカゲルクロマトグラフィーにより精製し、化合物４(70.6mg, 収率71.6%)を得た。
LCMS(MS)=351.90 (M+H) Second step

XantPhos (16.2 mg, 0.028 mmol) and Pd ₂ (dba) ₃ (12.9 mg, 0.014 mmol) under 1,2 dioxane (1.0 ml), compound 3 (100.0 mg, 0.281 mmol) and N, N -Diisopropylethylamine (123ul, 0.702mmol) was added. Further, a 1,4-dioxane solution (1.0 ml) of n-propanethiol (32.1 mg, 0.421 mmol) was added, and the reaction was carried out using a microwave reactor (130 ° C., 1 hour). The solvent was evaporated under reduced pressure, ethyl acetate was added to the residue, washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and purified by silica gel chromatography to obtain compound 4 (70.6 mg, yield). The rate was 71.6%).
LCMS (MS) = 351.90 (M + H)

化合物４(70mg, 0.20mmol)に塩化メチレン(1.0ml)を加えた後、氷冷下でｍＣＰＢＡ
(110mg, 0.44mmol)の塩化メチレン溶液(1.0m)を加え、氷冷下のまま１時間弱攪拌した。反応液に２Ｍの炭酸カリウム水溶液を加え、塩化メチレンで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。
得られた残渣をシリカゲルクロマトグラフィーにより精製し、化合物Ia-4-1 (49.4mg, 収率64.7%)を得た。
1H-NMR (DMSO-d6) δ: 0.91 (t, J = 7.35 Hz, 3H), 1.56 (td, J = 14.95, 7.60 Hz, 2H), 2.98 (dt, J = 20.28, 5.83 Hz, 2H), 3.29-3.33 (m, 2H), 3.95 (t, J = 6.08 Hz, 1H), 4.55 (t, J = 5.83 Hz, 1H), 4.89 (s, 1H), 5.53 (s, 1H), 7.19-7.31 (m, 4H), 7.78-7.87 (m, 2H), 8.20 (s, 1H), 13.73 (s, 1H).
LCMS(RT、測定条件(3))=1.86
LCMS(MS)=383.9 (M+H) Third step

After adding methylene chloride (1.0 ml) to compound 4 (70 mg, 0.20 mmol), mCPBA was added under ice cooling.
A solution of (110 mg, 0.44 mmol) in methylene chloride (1.0 m) was added, and the mixture was stirred slightly for 1 hour with ice cooling. To the reaction solution was added 2M aqueous potassium carbonate solution, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
The obtained residue was purified by silica gel chromatography to obtain compound Ia-4-1 (49.4 mg, yield 64.7%).
1H-NMR (DMSO-d6) δ: 0.91 (t, J = 7.35 Hz, 3H), 1.56 (td, J = 14.95, 7.60 Hz, 2H), 2.98 (dt, J = 20.28, 5.83 Hz, 2H), 3.29-3.33 (m, 2H), 3.95 (t, J = 6.08 Hz, 1H), 4.55 (t, J = 5.83 Hz, 1H), 4.89 (s, 1H), 5.53 (s, 1H), 7.19-7.31 (m, 4H), 7.78-7.87 (m, 2H), 8.20 (s, 1H), 13.73 (s, 1H).
LCMS (RT, measurement condition (3)) = 1.86
LCMS (MS) = 383.9 (M + H)

Example 2 First Step of Synthesis of Compound Ib-1-67

チオカルボジイミダゾール(0.950 g, 5.33 mmol)を塩化メチレン(10 ml)に溶解させ、そこに化合物６( 1 g, 4.85 mmol)の塩化メチレン(10 ml)溶液を滴下し、室温で１時間攪拌した。続いて、トリエチルアミン(2.02 ml, 14.54 mmol)と化合物７ (1.18 g, 4.85 mmol)を加え、さらに１７時間室温で攪拌した。その後、エバポレーターにて溶媒を減圧下留去し、そこへテトラヒドロフラン (10 ml), 水酸化リチウム一水和物(0.305 g, 7.27 mmol)を加え、最後に３０％ 過酸化水素水 (0.743 ml, 7.27 mmol)をゆっくり滴下し、室温で１時間半攪拌した。反応液に水を加えた後、酢酸エチルで２度抽出し、有機層を硫酸マグネシウムで乾燥した後、溶媒を減圧下留去した。得られた粗生成物をクロロホルムと酢酸エチルで溶解させ、そこへヘキサンを加え、析出した白色固体をろ取することで化合物８ (1.20 g, 収率 58.9%)を得た。
LCMS(MS)=421.90 (M+H)

Thiocarbodiimidazole (0.950 g, 5.33 mmol) is dissolved in methylene chloride (10 ml), and a solution of compound 6 (1 g, 4.85 mmol) in methylene chloride (10 ml) is added dropwise and stirred at room temperature for 1 hour. did. Subsequently, triethylamine (2.02 ml, 14.54 mmol) and compound 7 (1.18 g, 4.85 mmol) were added, and the mixture was further stirred at room temperature for 17 hours. Then, the solvent was distilled off under reduced pressure using an evaporator, tetrahydrofuran (10 ml) and lithium hydroxide monohydrate (0.305 g, 7.27 mmol) were added thereto, and finally 30% hydrogen peroxide solution (0.743 ml, 7.27 mmol) was slowly added dropwise and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was dissolved in chloroform and ethyl acetate, hexane was added thereto, and the precipitated white solid was collected by filtration to obtain Compound 8 (1.20 g, yield 58.9%).
LCMS (MS) = 421.90 (M + H)

化合物８ (600mg, 1.428 mmol)をテトラヒドロフラン (10 ml)に溶解させ、水素化ナトリウム(74.2mg, 1.856 mmol)、ＳＥＭＣｌ (329 mg, 1.856 mmol)を加え、室温で１７時間攪拌した。反応液に水を加えた後、有機層を酢酸エチルで２度抽出し、硫酸マグネシウムで乾燥後、溶媒を減圧下留去し、化合物９を粗生成物として定量的に得た。得られた化合物９のうち500mg (0.790 mmol)をジオキサン(3.3 ml)、Ｐｄ_２（ｄｂａ）_３(36.2mg, 0.040 mmol)、ｘａｎｔｐｈｏｓ(45.7mg, 0.079 mmol)、ジイソプロピルエチルアミン(0.345 ml, 1.975 mmol)、エタンチオール(0.064ml, 0.869 mmol)を加えて密封し、マイクロウェーブで１３０℃,４０分間照射した。反応液に水を加えた後、酢酸エチルで２度抽出し、有機層を硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルクロマトグラフィーにより精製し、化合物１０ (352mg, 収率83.8%)を透明なオイルで得た。
LCMS(MS)=532.20 (M+H) Second step

Compound 8 (600 mg, 1.428 mmol) was dissolved in tetrahydrofuran (10 ml), sodium hydride (74.2 mg, 1.856 mmol) and SEMCl (329 mg, 1.856 mmol) were added, and the mixture was stirred at room temperature for 17 hours. After adding water to the reaction solution, the organic layer was extracted twice with ethyl acetate, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to quantitatively obtain Compound 9 as a crude product. Of the obtained compound 9, 500 mg (0.790 mmol) was added to dioxane (3.3 ml), Pd ₂ (dba) ₃ (36.2 mg, 0.040 mmol), xantphos (45.7 mg, 0.079 mmol), diisopropylethylamine (0.345 ml, 1.975 mmol). ), Ethanethiol (0.064 ml, 0.869 mmol) was added and sealed, and irradiated with microwave at 130 ° C. for 40 minutes. Water was added to the reaction solution, followed by extraction twice with ethyl acetate, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 10 (352 mg, yield 83.8%) as a clear oil.
LCMS (MS) = 532.20 (M + H)

化合物１０ (352mg, 0.662 mmol)に塩化メチレン(5 ml)、 メタクロロ過安息香酸(166mg, 0.662 mmol)を加え、室温で攪拌し、１０分後にさらにメタクロロ過安息香酸(182mg, 0.728 mmol)を加えて室温で１時間程攪拌した。反応液に水と飽和重曹水を加えた後、クロロホルムで２度抽出し、有機層を硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。得られた残渣に、酢酸エチル(4.0 ml)、 0.4 Ｍ重亜硫酸ナトリウム水溶液(4 ml)、２８％アンモニア水(0.5 ml)を加え、室温にて１５分間攪拌後、酢酸エチルを加え２度抽出した。得られた有機層を硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣に再度塩化メチレン(5 ml)とメタクロロ過安息香酸(300mg, 1.20 mmol)を加え、１０分攪拌後、飽和重曹水を加えて酢酸エチルで２度抽出し、有機層を硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。得られた残渣に、テトラヒドロフラン(4 ml)、０．４Ｍ重亜硫酸ナトリウム水溶液(4 ml)、２８％アンモニア水(0.5 ml)を加え、３時間半攪拌した。反応液に水を加え、クロロホルムで２度抽出し、有機層を硫酸マグネシウムで乾燥後溶媒を減圧下留去した。これにより化合物１１ (325 mg, 収率87.1%)を白色固体で得た。
LCMS(MS)=564.25 (M+H) Third step

Methylene chloride (5 ml) and metachloroperbenzoic acid (166 mg, 0.662 mmol) were added to compound 10 (352 mg, 0.662 mmol), stirred at room temperature, and after 10 minutes, further metachloroperbenzoic acid (182 mg, 0.728 mmol) was added. And stirred at room temperature for about 1 hour. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, ethyl acetate (4.0 ml), 0.4 M aqueous sodium bisulfite solution (4 ml) and 28% aqueous ammonia (0.5 ml) were added. After stirring for 15 minutes at room temperature, ethyl acetate was added and extracted twice. did. The obtained organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue, methylene chloride (5 ml) and metachloroperbenzoic acid (300 mg, 1.20 mmol) were added again. After stirring for 10 minutes, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. Tetrahydrofuran (4 ml), 0.4 M aqueous sodium bisulfite solution (4 ml) and 28% aqueous ammonia (0.5 ml) were added to the resulting residue, and the mixture was stirred for 3.5 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. This gave compound 11 (325 mg, 87.1% yield) as a white solid.
LCMS (MS) = 564.25 (M + H)

化合物１１(40.0mg, 0.071 mmol)に塩化メチレン(1.0 ml)とトリフルオロ酢酸(0.20 ml, 2.60 mmol)を加え、室温で５時間攪拌した。反応液に２mol/L 水酸化ナトリウム水溶液を加え、塩化メチレンにて２度抽出した。有機層を硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。得られた残渣をカラムクロマトグラフィーで精製し、化合物Ib-1-67を白色固体 (19.4 mg, 収率63.1%)として得た。
1H-NMR (CDCl3) δ: 1.29 (9H, m), 2.42 (2H, t, J = 11.2 Hz), 3.33 (2H, q, J = 7.4 Hz), 3.43 (2H, d, J = 10.7 Hz), 3.82 (2H, t, J = 7.4 Hz), 6.96 (3H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.97 (1H, d, J = 6.1 Hz) Fourth step

Methylene chloride (1.0 ml) and trifluoroacetic acid (0.20 ml, 2.60 mmol) were added to compound 11 (40.0 mg, 0.071 mmol), and the mixture was stirred at room temperature for 5 hours. A 2 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted twice with methylene chloride. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography to give compound Ib-1-67 as a white solid (19.4 mg, yield 63.1%).
1H-NMR (CDCl3) δ: 1.29 (9H, m), 2.42 (2H, t, J = 11.2 Hz), 3.33 (2H, q, J = 7.4 Hz), 3.43 (2H, d, J = 10.7 Hz) , 3.82 (2H, t, J = 7.4 Hz), 6.96 (3H, d, J = 8.6 Hz), 7.21 (1H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.6 Hz), 7.97 (1H, d, J = 6.1 Hz)

２１％ナトリウムエトキシドのエタノール溶液(0.581 ml, 1.556 mmol)に化合物１３(200mg, 1.556 mmol)とＮ−メチルピロリジン-２-オン(2 ml)を加え、マイクロウェーブにて１２０℃で４０分間照射した後、さらに１５０℃で１時間半照射した。反応液に水を加えて酢酸エチルで２度抽出した後、有機層を硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、淡黄色の非晶質である化合物１４(106mg, 収率49.3%)を得た。
LCMS(MS)=138.90 (M+H) Example 3 First Step of Synthesis of Compound Ic-2-65

Compound 13 (200 mg, 1.556 mmol) and N-methylpyrrolidin-2-one (2 ml) were added to an ethanol solution of 21% sodium ethoxide (0.581 ml, 1.556 mmol) and irradiated with microwave at 120 ° C. for 40 minutes. After that, it was further irradiated at 150 ° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain pale yellow amorphous compound 14 (106 mg, yield 49.3%).
LCMS (MS) = 138.90 (M + H)

チオカルボニルジイミダゾール(163 mg, 0.915 mmol)にアセトニトリル(3 ml)、化合物１４ (105mg, 0.760 mmol)を加え、トリエチルアミン (0.136ml, 0.982 mmol)を加え、室温で９時間程攪拌した。続いてこの反応液の３分の１を用いトリエチルアミン(0.045 ml, 0.325 mmol)、 アセトニトリル(3 ml)、化合物１５ (40mg, 0.164 mmol)を加え、室温で２８時間攪拌した。反応液に蒸留水を加えてクロロホルムで２度抽出し、有機層を硫酸マグネシウムで乾燥後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物Ic-2-65を(13.0 mg, 収率20.3%)を白色固体で得た。
1H-NMR (CDCl3) δ: 1.40-1.43 (12H, m), 4.38 (2H, q, J = 7.1 Hz), 6.26 (1H, s), 7.02-7.06 (2H, m), 7.16 (1H, d, J = 2.0 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 2.0 Hz), 8.08 (1H, d, J = 5.6 Hz)
LCMS(RT、測定条件(3))=1.47
LCMS(MS) =391.00 (M+H) Second step

Acetonitrile (3 ml) and compound 14 (105 mg, 0.760 mmol) were added to thiocarbonyldiimidazole (163 mg, 0.915 mmol), triethylamine (0.136 ml, 0.982 mmol) was added, and the mixture was stirred at room temperature for about 9 hours. Subsequently, triethylamine (0.045 ml, 0.325 mmol), acetonitrile (3 ml) and compound 15 (40 mg, 0.164 mmol) were added using one third of the reaction solution, and the mixture was stirred at room temperature for 28 hours. Distilled water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound Ic-2-65 (13.0 mg, yield 20.3%) as a white solid.
1H-NMR (CDCl3) δ: 1.40-1.43 (12H, m), 4.38 (2H, q, J = 7.1 Hz), 6.26 (1H, s), 7.02-7.06 (2H, m), 7.16 (1H, d , J = 2.0 Hz), 7.44 (1H, d, J = 8.6 Hz), 7.57 (1H, d, J = 2.0 Hz), 8.08 (1H, d, J = 5.6 Hz)
LCMS (RT, measurement condition (3)) = 1.47
LCMS (MS) = 391.00 (M + H)

化合物１８(1.36 g, 3.63 mmol)をＤＭＦ(14 ml)に溶解させ、化合物１７(621 mg, 3.63 mmol)を加えた後、炭酸セシウム (1.77g, 5.44 mmol) を加え、３時間、５０℃で攪拌した。その後、反応混合物に水を加え、酢酸エチルで抽出し、飽和食塩水による洗浄を行った。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィーにより精製することで化合物１９(1.70 g, 収率92%)を得た。
LCMS(MS)=510.00 (M+H) Example 4 First Step of Synthesis of Compound Ia-5-19

Compound 18 (1.36 g, 3.63 mmol) was dissolved in DMF (14 ml), compound 17 (621 mg, 3.63 mmol) was added, cesium carbonate (1.77 g, 5.44 mmol) was added, and 3 hours at 50 ° C. And stirred. Then, water was added to the reaction mixture, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give compound 19 (1.70 g, yield 92%).
LCMS (MS) = 510.00 (M + H)

第１工程で得られた化合物１９(1.50 g, 2.94 mmol)を塩化メチレン(10 ml)に溶解させた後、トリフルオロ酢酸 (10 ml) を加え３時間、室温下で攪拌した。その後、メタノール (5 ml) を加え３０分間、室温下で攪拌した。その後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、飽和食塩水による洗浄を行った。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィーにより精製した。最後に、再結晶による精製を行うことで化合物Ia-5-19 (816 mg, 収率73%)を得た。
1H-NMR (CDCl3) δ: 1.23-1.29 (3.0H,m), 3.10-3.18 (2.0H, m), 7.35-8.09 (10.0H, m), 8.75 (1.0H, d, J = 2.03 Hz), 10.36 (1.0H, m).
LCMS(RT、測定条件(3))=1.59
LCMS(MS)=379.9 (M+H) Second step

Compound 19 (1.50 g, 2.94 mmol) obtained in the first step was dissolved in methylene chloride (10 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 3 hours. Then, methanol (5 ml) was added and stirred at room temperature for 30 minutes. Thereafter, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography. Finally, purification by recrystallization gave Compound Ia-5-19 (816 mg, yield 73%).
1H-NMR (CDCl3) δ: 1.23-1.29 (3.0H, m), 3.10-3.18 (2.0H, m), 7.35-8.09 (10.0H, m), 8.75 (1.0H, d, J = 2.03 Hz) , 10.36 (1.0H, m).
LCMS (RT, measurement condition (3)) = 1.59
LCMS (MS) = 379.9 (M + H)

化合物２１(500 mg, 5.74 mmol)をアセトニトリル(1.0 ml)に溶解させ、ヨードベンゼン(0.64 ml, 5.74 mmol)、ヨウ化銅 (109 mg, 0.57 mmol)、炭酸セシウム (2.81 g, 8.61 mmol) を加え、２７時間、室温下で攪拌した。その後、反応混合物をセイラトを用いてろ過し、ろ液を濃縮した。その後、残渣をシリカゲルクロマトグラフィーにより精製することで化合物２２(192 mg, 収率21%)を得た。
¹H-NMR (CDCl₃) δ: 2.07-2.09 (1.0H, m), 2.14-2.22 (1.0H, m), 3.27-3.29 (1.0H, m), 3.32-3.38 (1.0H, td, J = 8.87, 3.72 Hz), 3.48-3.53 (2.0H, m), 4.60 (1.0H, br-s), 6.58 (2.0H, d, J = 8.11 Hz), 6.70 (1.0H, t, J = 7.35 Hz), 7.22-7.26 (2.0H, m). Example 5 First Step of Synthesis of Compound Ia-5-14

Compound 21 (500 mg, 5.74 mmol) was dissolved in acetonitrile (1.0 ml), and iodobenzene (0.64 ml, 5.74 mmol), copper iodide (109 mg, 0.57 mmol), cesium carbonate (2.81 g, 8.61 mmol) were added. In addition, the mixture was stirred at room temperature for 27 hours. Thereafter, the reaction mixture was filtered using Seirato, and the filtrate was concentrated. Then, the residue was purified by silica gel chromatography to obtain compound 22 (192 mg, yield 21%).
¹ H-NMR (CDCl ₃ ) δ: 2.07-2.09 (1.0H, m), 2.14-2.22 (1.0H, m), 3.27-3.29 (1.0H, m), 3.32-3.38 (1.0H, td, J = 8.87, 3.72 Hz), 3.48-3.53 (2.0H, m), 4.60 (1.0H, br-s), 6.58 (2.0H, d, J = 8.11 Hz), 6.70 (1.0H, t, J = 7.35 Hz), 7.22-7.26 (2.0H, m).

化合物２２(19.6 mg, 0.12 mmol)をＤＭＦ(1 ml)に溶解させ、水素化ナトリウム(6.4 mg, 0.16 mmol)を加えた後、室温下、１０分間攪拌した。その後、化合物１８(30.0 mg, 0.08 mmol) をＤＭＦ（1 ml)に溶解させた溶液を加え、室温下、１．５時間攪拌した。その後、反応混合物に水を加え、酢酸エチルで抽出し、飽和食塩水による洗浄を行った。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィーにより簡易精製した。
次に、先に合成した化合物をテトラヒドロフラン(5 ml)に溶解させ、テトラブチルアンモニウムフルオライド・１水和物(223 mg, 0.799 mmol)を加え、８０℃にて２．５時間攪拌した。その後、反応溶液を濃縮し、残渣をシリカゲルクロマトグラフィーにより精製することで化合物Ia-5-14(19.5 mg, 収率66%)を得た。
1H-NMR (CDCl3) δ: 1.26 (3.0H, t, J = 7.60 Hz), 2.45 (2.0H, m), 3.14 (2.0H, q, J = 7.44 Hz), 3.49-3.56 (2.0H, m), 3.66 (1.0H, m), 3.79 (1.0H, dd, J = 11.66, 4.56 Hz), 5.84 (1.0H, br-s), 6.61 (2.0H, d, J = 8.11 Hz), 6.73 (1.0H, t, J = 7.35 Hz), 7.25 (3.0H, m).
LCMS(RT、測定条件(3))=1.87
LCMS(MS)=372.0 (M+H) Second step

Compound 22 (19.6 mg, 0.12 mmol) was dissolved in DMF (1 ml), sodium hydride (6.4 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 10 min. Thereafter, a solution of compound 18 (30.0 mg, 0.08 mmol) dissolved in DMF (1 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. Then, water was added to the reaction mixture, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was simply purified by silica gel chromatography.
Next, the compound synthesized previously was dissolved in tetrahydrofuran (5 ml), tetrabutylammonium fluoride monohydrate (223 mg, 0.799 mmol) was added, and the mixture was stirred at 80 ° C. for 2.5 hours. Thereafter, the reaction solution was concentrated, and the residue was purified by silica gel chromatography to obtain compound Ia-5-14 (19.5 mg, yield 66%).
1H-NMR (CDCl3) δ: 1.26 (3.0H, t, J = 7.60 Hz), 2.45 (2.0H, m), 3.14 (2.0H, q, J = 7.44 Hz), 3.49-3.56 (2.0H, m ), 3.66 (1.0H, m), 3.79 (1.0H, dd, J = 11.66, 4.56 Hz), 5.84 (1.0H, br-s), 6.61 (2.0H, d, J = 8.11 Hz), 6.73 ( 1.0H, t, J = 7.35 Hz), 7.25 (3.0H, m).
LCMS (RT, measurement condition (3)) = 1.87
LCMS (MS) = 372.0 (M + H)

化合物２４(100 mg, 0.575 mmol)をジオキサン(1.0 ml)に溶解させ、化合物２５ (99.0 mg, 0.69 mmol)、化合物２６(26.8 mg, 0.057 mmol)、Ｐｄ_２（ｄｂａ）_３ (26.3 mg, 0.029 mmol)、ｔ−ＢｕＯＮａ（166mg, 1.72 mmol)を加え、１２０℃の条件下、３０分間マイクロウェーブを照射した。その後、反応溶液を濃縮し、残渣をシリカゲルクロマトグラフィーにより精製することで化合物２７(78.6 mg, 収率68%)を得た。
¹H-NMR (CDCl₃) δ: 2.42-2.49 (2.0H, m), 3.63 (2.0H, t, J = 7.10 Hz), 3.76 (2.0H, t, J = 12.93 Hz), 5.73 (1.0H, d, J = 2.03 Hz), 6.17 (1.0H, dd, J = 6.59, 2.03 Hz), 7.63 (1.0H, d, J = 6.59 Hz). Example 6 First Step of Synthesis of Compound Ia-5-16

Compound 24 (100 mg, 0.575 mmol) was dissolved in dioxane (1.0 ml), compound 25 (99.0 mg, 0.69 mmol), compound 26 (26.8 mg, 0.057 mmol), Pd ₂ (dba) ₃ (26.3 mg, 0.029 mmol) and t-BuONa (166 mg, 1.72 mmol) were added, and microwave irradiation was performed at 120 ° C. for 30 minutes. Thereafter, the reaction solution was concentrated, and the residue was purified by silica gel chromatography to obtain Compound 27 (78.6 mg, yield 68%).
¹ H-NMR (CDCl ₃ ) δ: 2.42-2.49 (2.0H, m), 3.63 (2.0H, t, J = 7.10 Hz), 3.76 (2.0H, t, J = 12.93 Hz), 5.73 (1.0H , d, J = 2.03 Hz), 6.17 (1.0H, dd, J = 6.59, 2.03 Hz), 7.63 (1.0H, d, J = 6.59 Hz).

化合物１８(30.0 mg, 0.08 mmol)をＤＭＦ(2 ml)に溶解させ、化合物２７(16.0 mg, 0.08 mmol)を加えた後、炭酸セシウム (39.1mg, 0.12 mmol) を加え、４時間、５０℃で攪拌した。その後、反応混合物に水を加え、酢酸エチルで抽出し、飽和食塩水による洗浄を行った。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィーにより精製することで化合物２８(44.4 mg, 収率103%)を得た。
LCMS(MS)=539.10 (M+H) Second step

Compound 18 (30.0 mg, 0.08 mmol) was dissolved in DMF (2 ml), compound 27 (16.0 mg, 0.08 mmol) was added, cesium carbonate (39.1 mg, 0.12 mmol) was added, and 4 hours at 50 ° C. And stirred. Then, water was added to the reaction mixture, extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give compound 28 (44.4 mg, yield 103%).
LCMS (MS) = 539.10 (M + H)

化合物２８(44.4 mg, 0.082 mmol)をテトラヒドロフラン(5 ml)に溶解させ、テトラブチルアンモニウムフルオライド・１水和物(230 mg, 0.824 mmol)を加え、５０℃にて５時間攪拌した。その後、反応溶液を濃縮し、残渣をシリカゲルクロマトグラフィーにより精製することで化合物Ia-5-16(20.2 mg, 収率60%)を得た。
1H-NMR (CDCl3) δ: 1.28 (3.0H, t, J = 7.10 Hz), 2.45-2.55 (2.0H, m), 3.15 (2.0H, br-s), 3.69 (2.0H, t, J = 7.10 Hz), 3.86 (2.0H, t, J = 12.93 Hz), 6.48-6.72 (2.0H, m), 7.47-8.22 (4.0H, m), 9.47 (1.0H, m).
LCMS(RT、測定条件(3))=1.17
LCMS(MS)=408.9 (M+H) Third step

Compound 28 (44.4 mg, 0.082 mmol) was dissolved in tetrahydrofuran (5 ml), tetrabutylammonium fluoride monohydrate (230 mg, 0.824 mmol) was added, and the mixture was stirred at 50 ° C. for 5 hours. Thereafter, the reaction solution was concentrated, and the residue was purified by silica gel chromatography to obtain compound Ia-5-16 (20.2 mg, yield 60%).
1H-NMR (CDCl3) δ: 1.28 (3.0H, t, J = 7.10 Hz), 2.45-2.55 (2.0H, m), 3.15 (2.0H, br-s), 3.69 (2.0H, t, J = 7.10 Hz), 3.86 (2.0H, t, J = 12.93 Hz), 6.48-6.72 (2.0H, m), 7.47-8.22 (4.0H, m), 9.47 (1.0H, m).
LCMS (RT, measurement condition (3)) = 1.17
LCMS (MS) = 408.9 (M + H)

化合物３０(1000 mg, 10.4 mmol)をトルエン(10 ml)に溶解させ、炭酸セシウム (3390 mg, 10.4 mmol)、化合物３１(2540mg, 20.8mmol)、トリフェニルホスフィン(273mg, 1.04mmol)、酢酸パラジウム(117mg, 0.52mmol)、クロロホルム(124mg、1.04mmol)を加えた１００℃で９時間還流を行った。不溶物をセライトろ過し、ろ液を留去した。残渣をカラムクロマトグラフィーで精製し化合物３２(1430mg, 収率79%)を得た。
¹H-NMR (DMSO-d₆) δ: 2.02-2.05 (1H, m), 2.23-2.35 (2H, m), 2.41-2.46 (1H, m), 2.63 (1H, t, J = 10.0 Hz), 2.95-3.02 (1H, m), 7.22-7.31 (5H, m). Example 7 First Step of Synthesis of Compound Ib-2-22

Compound 30 (1000 mg, 10.4 mmol) is dissolved in toluene (10 ml), cesium carbonate (3390 mg, 10.4 mmol), compound 31 (2540 mg, 20.8 mmol), triphenylphosphine (273 mg, 1.04 mmol), palladium acetate (117 mg, 0.52 mmol) and chloroform (124 mg, 1.04 mmol) were added and refluxed at 100 ° C. for 9 hours. The insoluble material was filtered through Celite, and the filtrate was distilled off. The residue was purified by column chromatography to obtain compound 32 (1430 mg, yield 79%).
¹ H-NMR (DMSO-d ₆ ) δ: 2.02-2.05 (1H, m), 2.23-2.35 (2H, m), 2.41-2.46 (1H, m), 2.63 (1H, t, J = 10.0 Hz) , 2.95-3.02 (1H, m), 7.22-7.31 (5H, m).

ヒドロキシアミン(５０％水溶液, 1190mg)のメタノール(2ml)と水(5ml)の溶液に第１工程で得られた化合物３２(1430 mg, 8.21 mmol)のメタノール溶液(20ml)を加えた。そこに炭酸カリウム(1130mg, 8.21mmol)の水溶液(5ml)を加え、室温で１．５時間攪拌した。メタノールを減圧下留去し水溶液を酢酸エチルで２回抽出した。有機層を硫酸マグネシウムで乾燥し、濾過後、留去し、化合物３３(1490mg, 収率96%)を得た。
LCMS(MS)=189.95 (M+H) Second step

To a solution of hydroxyamine (50% aqueous solution, 1190 mg) in methanol (2 ml) and water (5 ml) was added a methanol solution (20 ml) of compound 32 (1430 mg, 8.21 mmol) obtained in the first step. Thereto was added an aqueous solution (5 ml) of potassium carbonate (1130 mg, 8.21 mmol), and the mixture was stirred at room temperature for 1.5 hours. Methanol was distilled off under reduced pressure, and the aqueous solution was extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated to give compound 33 (1490 mg, yield 96%).
LCMS (MS) = 189.95 (M + H)

第２工程で得られた化合物３３(1490mg, 7.87mmol)をテトラヒドロフラン(20ml)に溶解させ、０℃で水素化リチウムアルミニウムを加えた。室温に昇温し、２時間攪拌した。硫酸ナトリウム１０水和物を注意深く加え、室温で２時間攪拌した。不溶物を濾別し、ろ液を留去することで化合物３４(1160mg, 収率84%)を得た。
LCMS(MS)=176.00 (M+H) Third step

Compound 33 (1490 mg, 7.87 mmol) obtained in the second step was dissolved in tetrahydrofuran (20 ml), and lithium aluminum hydride was added at 0 ° C. The mixture was warmed to room temperature and stirred for 2 hours. Sodium sulfate decahydrate was carefully added and stirred at room temperature for 2 hours. The insoluble material was filtered off, and the filtrate was evaporated to give compound 34 (1160 mg, 84% yield).
LCMS (MS) = 176.00 (M + H)

化合物３５(100mg, 0.407mmol)をイソプロパノール(2ml)に溶解させ、第３工程で得られた化合物３４(214mg, 1.22mmol)を加え、マイクロウェーブを１００℃で３０分間照射させた。溶媒を留去し、残渣をカラムクロマトグラフィーで精製し、化合物Ib-2-22(25.7mg, 収率16%)を得た。
LCMS(RT、測定条件(3))=2.21
LCMS(MS)=385.00 (M+H) Fourth step

Compound 35 (100 mg, 0.407 mmol) was dissolved in isopropanol (2 ml), compound 34 (214 mg, 1.22 mmol) obtained in the third step was added, and the microwave was irradiated at 100 ° C. for 30 minutes. The solvent was distilled off, and the residue was purified by column chromatography to give compound Ib-2-22 (25.7 mg, yield 16%).
LCMS (RT, measurement condition (3)) = 2.21
LCMS (MS) = 385.00 (M + H)

化合物３７ (200 mg, 0.817 mmol) 及び２-(メチルアミノ)-1-フェニルエタノール (124 mg, 0.817 mmol) を２−プロパノール (4.0 ml) に溶解させ、Ｎ，Ｎ−ジイソプロピルエチルアミン (171 ul, 0.981 mmol) を加え、マイクロウェーブ反応装置(180℃, 30分間)により反応を行なった。反応液中に水と飽和食塩水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィーにより精製し、化合物Ia-1-10(205.8 mg, 収率70.1%)を得た。
¹H-NMR (DMSO-d₆) δ: 1.08 (3H, t, J = 6.84 Hz), 3.09 (3H, s), 3.19 (2H, m), 3.62 (2H, m), 4.95 (1H, q, J = 4.56 Hz), 5.62 (1H, dd, J = 10.00, 5.00 Hz), 7.27 (1H, m), 7.34-7.42 (6H, m), 7.54, 7.59 (1H, ds), 11.54, 11.66 (1H, ds).
LCMS(RT、測定条件(3))=1.1
LCMS(MS)=359.95 (M+H) Example 8 First Step of Synthesis of Compound Ia-1-10 and Compound Ia-1-12

Compound 37 (200 mg, 0.817 mmol) and 2- (methylamino) -1-phenylethanol (124 mg, 0.817 mmol) were dissolved in 2-propanol (4.0 ml), and N, N-diisopropylethylamine (171 ul, 0.981 mmol) was added, and the reaction was carried out using a microwave reactor (180 ° C., 30 minutes). Water and saturated brine were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give compound Ia-1-10 (205.8 mg, yield 70.1%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.08 (3H, t, J = 6.84 Hz), 3.09 (3H, s), 3.19 (2H, m), 3.62 (2H, m), 4.95 (1H, q , J = 4.56 Hz), 5.62 (1H, dd, J = 10.00, 5.00 Hz), 7.27 (1H, m), 7.34-7.42 (6H, m), 7.54, 7.59 (1H, ds), 11.54, 11.66 ( 1H, ds).
LCMS (RT, measurement condition (3)) = 1.1
LCMS (MS) = 359.95 (M + H)

第１工程で得られた化合物３８ (100 mg, 0.278 mmol) を塩化メチレン (1 ml) に溶解させ、ＤＭＰ（128mg，0.292 mmol）を加えた後、１時間、室温で攪拌した。反応液中に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、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ーにより精製し、化合物Ia-1-12 (80.2 mg, 収率80.7%) を得た。
¹H-NMR (CDCl₃) δ: 1.19 (3H, t, J = 7.60 Hz), 3.05 (2H, q, J = 7.44 Hz), 3.21 (3H, s), 5.01 (2H, s), 7.25-7.28 (1H, br m), 7.38-7.54 (4H, m), 7.69 (1H, s), 7.88 (2H, d, J = 7.10 Hz).
LCMS(RT、測定条件(3))=1.02
LCMS(MS)=357.95 (M+H) Second step

Compound 38 (100 mg, 0.278 mmol) obtained in the first step was dissolved in methylene chloride (1 ml), DMP (128 mg, 0.292 mmol) was added, and the mixture was stirred for 1 hour at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give compound Ia-1-12 (80.2 mg, yield 80.7%).
¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.60 Hz), 3.05 (2H, q, J = 7.44 Hz), 3.21 (3H, s), 5.01 (2H, s), 7.25- 7.28 (1H, br m), 7.38-7.54 (4H, m), 7.69 (1H, s), 7.88 (2H, d, J = 7.10 Hz).
LCMS (RT, measurement condition (3)) = 1.02
LCMS (MS) = 357.95 (M + H)

化合物４０ (5 g, 21.36 mmol)をＴＨＦ (40 ml) に溶解させ、水素化ナトリウム(1.0 g, 25.6 mmol)をゆっくり加えた後、１時間、室温で攪拌した。臭化アリル(2.2 ml, 25.6 mmol) を滴下した後、室温で一晩攪拌した。反応液中に水を加え、ジエチルエーテルで抽出し、有機層を水で洗浄した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、化合物４１ (6.19 g, 収率105.7%) を得た。得られた化合物は精製する事無く次反応に使用した。 Example 9 First Step of Synthesis of Compound Ia-6-22

Compound 40 (5 g, 21.36 mmol) was dissolved in THF (40 ml), sodium hydride (1.0 g, 25.6 mmol) was slowly added, and the mixture was stirred for 1 hour at room temperature. After allyl bromide (2.2 ml, 25.6 mmol) was added dropwise, the mixture was stirred overnight at room temperature. Water was added to the reaction solution, extracted with diethyl ether, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain Compound 41 (6.19 g, yield 105.7%). The obtained compound was used in the next reaction without purification.

第１工程で得られた化合物４１ (1 g, 3.65 mmol) をアセトニトリル (5 ml) に溶解させた後、酢酸パラジウム (41 mg, 0.182 mmol)、トリフェニルホスフィン (96 mg, 0.365 mmol) 及びトリエチルアミン (3 ml) を加え、窒素気流下、３時間、８０℃で攪拌した。反応液中に１ mol/L塩酸を加え、ジエチルエーテルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、化合物４２(1.03 g, 収率129.0%) を得た。得られた化合物は精製する事無く次反応に使用した。 Second step

Compound 41 (1 g, 3.65 mmol) obtained in the first step was dissolved in acetonitrile (5 ml), followed by palladium acetate (41 mg, 0.182 mmol), triphenylphosphine (96 mg, 0.365 mmol) and triethylamine. (3 ml) was added, and the mixture was stirred at 80 ° C. for 3 hours under a nitrogen stream. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give compound 42 (1.03 g, yield 129.0%). The obtained compound was used in the next reaction without purification.

第２工程で得られた化合物４２(1 g, 6.84 mmol) をテトラヒドロフラン (25 ml) に溶解させた後、１Ｍ ボラン−テトラヒドロフラン 錯体 (3.42 ml, 3.42 mmol) を滴下し、３時間、室温で攪拌した。反応液中に３Ｍ 水酸化ナトリウム水溶液を滴下し、次いで３０％ 過酸化水素水を滴下後、室温で一晩攪拌した。飽和食塩水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、化合物４３ (1.01 g, 収率90.3%) を得た。得られた化合物は精製する事無く次反応に使用した。 Third step

Compound 42 (1 g, 6.84 mmol) obtained in the second step was dissolved in tetrahydrofuran (25 ml), 1M borane-tetrahydrofuran complex (3.42 ml, 3.42 mmol) was added dropwise, and the mixture was stirred for 3 hours at room temperature. did. 3M aqueous sodium hydroxide solution was added dropwise to the reaction solution, and then 30% hydrogen peroxide solution was added dropwise, followed by stirring overnight at room temperature. Saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain Compound 43 (1.01 g, yield 90.3%). The obtained compound was used in the next reaction without purification.

第3工程で得られた化合物４３ (131 mg, 0.800 mmol) をＮ，Ｎ−ジメチルホルムアミド (1 ml) に溶解させた後、化合物１８ (100 mg, 0.267 mmol) を加え溶解した。水素化ナトリウム (21.3 mg, 0.533 mmol) をゆっくり加え、３時間、室温で攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣を逆層クロマトグラフィーにより精製し、化合物４４ (33.1 mg, 収率24.7%) を得た。
LCMS(MS)=503.15 (M+H) Fourth step

Compound 43 (131 mg, 0.800 mmol) obtained in the third step was dissolved in N, N-dimethylformamide (1 ml), and then compound 18 (100 mg, 0.267 mmol) was added and dissolved. Sodium hydride (21.3 mg, 0.533 mmol) was slowly added and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by reverse layer chromatography to give compound 44 (33.1 mg, yield 24.7%).
LCMS (MS) = 503.15 (M + H)

第４工程で得られた化合物４４ (33.1 mg, 0.066 mmol)をテトラヒドロフラン (2 ml) に溶解させた後、テトラブチルアンモニウムフルオライド (138 mg, 0.527 mmol) を加え、５時間、５０℃ で攪拌した。テトラブチルアンモニウムフルオライド (138 mg, 0.527 mmol) をさらに加え、１時間、５０℃ で攪拌した。反応混合物に水を加え、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。残渣をアミノシリカゲルクロマトグラフィーにより精製し、化合物Ia-6-22 (14.3 mg, 収率58.3%) を得た。
1H-NMR (CDCl₃) δ: 1.08 (3H, t, J = 7.35 Hz), 3.24 (2H, q, J = 7.27 Hz), 3.86 (1H, dd, J = 11.66, 3.55 Hz), 4.11 (1H, dd, J = 11.66, 2.53 Hz), 4.67-4.74 (4H, m), 5.56 (1H, s), 7.10 (1H, dd, J = 4.56, 2.28 Hz), 7.25 (2H, dd, J = 5.83, 3.30 Hz), 7.38-7.42 (2H, m), 7.52-7.58 (2H, m), 7.78 (1H, s).
LCMS(RT、測定条件(3))=1.65
LCMS(MS)=372.95 (M+H) 5th process

Compound 44 (33.1 mg, 0.066 mmol) obtained in the fourth step was dissolved in tetrahydrofuran (2 ml), tetrabutylammonium fluoride (138 mg, 0.527 mmol) was added, and the mixture was stirred at 50 ° C. for 5 hours. did. Tetrabutylammonium fluoride (138 mg, 0.527 mmol) was further added, and the mixture was stirred at 50 ° C. for 1 hour. Water was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel chromatography to obtain compound Ia-6-22 (14.3 mg, yield 58.3%).
1H-NMR (CDCl ₃ ) δ: 1.08 (3H, t, J = 7.35 Hz), 3.24 (2H, q, J = 7.27 Hz), 3.86 (1H, dd, J = 11.66, 3.55 Hz), 4.11 (1H , dd, J = 11.66, 2.53 Hz), 4.67-4.74 (4H, m), 5.56 (1H, s), 7.10 (1H, dd, J = 4.56, 2.28 Hz), 7.25 (2H, dd, J = 5.83 , 3.30 Hz), 7.38-7.42 (2H, m), 7.52-7.58 (2H, m), 7.78 (1H, s).
LCMS (RT, measurement condition (3)) = 1.65
LCMS (MS) = 372.95 (M + H)

化合物４６ (1 g, 4.97 mmol) 及び酢酸銅 (903 mg, 4.97 mmol) をジメチルスルホキシド (10 ml) に溶解させ、ヨウ化ベンゼン (834 ul, 7.45 mmol) 及び１，８−ジアザビシクロ［５．４．０］ウンデカ−７−エン (1.5 ml, 9.94 mmol) を加えた後、マイクロウェーブ反応装置 (１３０℃, ３０分間) により反応を行なった。反応液中に水を加え、酢酸エチルで抽出した。有機層を水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去した。塩化メチレンを加え、不溶物をろ去し、溶媒を減圧下留去後、シリカゲルクロマトグラフィーにより精製し、化合物４７ (356.3 mg, 収率25.9%) を得た。
¹H-NMR (DMSO-d₆) δ: 5.14 (2H, s), 5.98 (1H, d, J = 3.04 Hz), 6.10 (1H, dd, J = 7.60, 2.53 Hz), 7.34-7.49 (10H, m), 7.56 (1H, d, J = 7.60 Hz). Example 10 First Step of Synthesis of Compound Ia-5-20

Compound 46 (1 g, 4.97 mmol) and copper acetate (903 mg, 4.97 mmol) were dissolved in dimethyl sulfoxide (10 ml), and benzene iodide (834 ul, 7.45 mmol) and 1,8-diazabicyclo [5.4. 0.0] undec-7-ene (1.5 ml, 9.94 mmol) was added and the reaction was carried out in a microwave reactor (130 ° C., 30 minutes). Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Methylene chloride was added, insolubles were removed by filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give compound 47 (356.3 mg, yield 25.9%).
¹ H-NMR (DMSO-d ₆ ) δ: 5.14 (2H, s), 5.98 (1H, d, J = 3.04 Hz), 6.10 (1H, dd, J = 7.60, 2.53 Hz), 7.34-7.49 (10H , m), 7.56 (1H, d, J = 7.60 Hz).

第１工程で得られた化合物４７ (356.3 mg, 1.285 mmol) をメタノール (5 ml) 及びテトラヒドロフラン (5 ml) に溶解させた後、５０％パラジウム炭素 (35.5 mg, 0.167 mmol) を加え、水素雰囲気下、一晩、攪拌した。反応液をセライトろ過後、溶媒を減圧下留去し、化合物４８ (241.4 mg, 収率100%)を得た。
¹H-NMR (DMSO-d₆) δ: 5.65 (1H, d, J = 2.53 Hz), 5.96 (1H, dd, J = 7.60, 2.53 Hz), 7.33 (2H, m), 7.41 (1H, m), 7.48 (3H, m), 10.75 (1H, br s). Second step

Compound 47 (356.3 mg, 1.285 mmol) obtained in the first step was dissolved in methanol (5 ml) and tetrahydrofuran (5 ml), 50% palladium carbon (35.5 mg, 0.167 mmol) was added, and hydrogen atmosphere was added. Under stirring overnight. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give compound 48 (241.4 mg, yield 100%).
¹ H-NMR (DMSO-d ₆ ) δ: 5.65 (1H, d, J = 2.53 Hz), 5.96 (1H, dd, J = 7.60, 2.53 Hz), 7.33 (2H, m), 7.41 (1H, m ), 7.48 (3H, m), 10.75 (1H, br s).

第２工程で得られた化合物４８ (100 mg, 0.533 mmol)、化合物１８ (100 mg, 0.267 mmol) 及び炭酸セシウム (174 mg, 0.533 mmol) をＮ，Ｎ−ジメチルホルムアミド (2 ml) に溶解させ、３時間、５０℃で攪拌した。さらに４時間、８０℃で攪拌後、反応液中に水を加え、酢酸エチルで抽出した。有機層を水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧下留去し、化合物４９ (126.0 mg, 収率89.9%) を得た。得られた化合物は精製する事無く次反応に使用した。 Third step

Compound 48 (100 mg, 0.533 mmol), compound 18 (100 mg, 0.267 mmol) and cesium carbonate (174 mg, 0.533 mmol) obtained in the second step were dissolved in N, N-dimethylformamide (2 ml). Stir for 3 hours at 50 ° C. After further stirring at 80 ° C. for 4 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain Compound 49 (126.0 mg, yield 89.9%). The obtained compound was used in the next reaction without purification.

第３工程で得られた化合物４９ (44 mg, 0.084 mmol) を塩化メチレン (1 ml) に溶解させた後、トリフルオロ酢酸 (1 ml) を加え、一晩、室温で攪拌した。反応液中に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧下留去し、残渣を逆層クロマトグラフィーにより精製し、ジイソプロピルエーテルより再結晶することにより、化合物Ia-5-20 (3.5 mg, 収率10.6%) を得た。
LCMS(RT、測定条件(3))=1.34
LCMS(MS)=395.90 (M+H) Fourth step

Compound 49 (44 mg, 0.084 mmol) obtained in the third step was dissolved in methylene chloride (1 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by reverse layer chromatography and recrystallized from diisopropyl ether to give compound Ia-5-20 (3.5 mg, yield). 10.6%).
LCMS (RT, measurement condition (3)) = 1.34
LCMS (MS) = 395.90 (M + H)

化合物５２ (330 mg, 1.498 mmol)をＤＭＦ (3 ml)に溶解させ、ＨＡＴＵ (627 mg, 1.648 mmol)を加えた後、トリエチルアミン (311 μl, 2.247 mmol) を滴下し、２分間、室温で攪拌した。これを化合物５１(300 mg, 1.498 mmol)のＤＭＦ (3 mL)溶液に滴下し、室温で７時間攪拌した。反応液中に水を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去することで化合物５３を得た。これ以上の精製はせずに第２工程の反応に用いた。 Example 11 Synthesis Step 1 of Compound Ia-3-1, Compound Ia-4-8, Compound Ia-3-23

Compound 52 (330 mg, 1.498 mmol) was dissolved in DMF (3 ml), HATU (627 mg, 1.648 mmol) was added, then triethylamine (311 μl, 2.247 mmol) was added dropwise, and the mixture was stirred for 2 minutes at room temperature. did. This was added dropwise to a DMF (3 mL) solution of Compound 51 (300 mg, 1.498 mmol) and stirred at room temperature for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, Compound 53 was obtained by removing the solvent under reduced pressure. It was used for the reaction in the second step without further purification.

第１工程で得られた化合物５３ (603 mg, 1.499 mmol)を酢酸(5 ml)に溶解させた後、１時間、加熱還流下で攪拌した。溶媒を減圧留去した後、反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィーにより精製することで化合物Ia-3-1(332 mg, 2工程収率58%)を得た。
1H-NMR (DMSO-d6) δ: 1.08 (3H, t, J = 7.4 Hz), 3.26 (2H, q, J = 7.3 Hz), 4.30 (2H, s), 7.34 (2H, d, J = 7.6 Hz), 7.48 (2H, d, J = 8.6 Hz), 7.65-7.69 (2H, m), 8.02 (1H, s), 12.88 (1H, s). Second step

Compound 53 (603 mg, 1.499 mmol) obtained in the first step was dissolved in acetic acid (5 ml), and then stirred for 1 hour under heating and refluxing. After the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound Ia-3-1 (332 mg, two-step yield 58%).
1H-NMR (DMSO-d6) δ: 1.08 (3H, t, J = 7.4 Hz), 3.26 (2H, q, J = 7.3 Hz), 4.30 (2H, s), 7.34 (2H, d, J = 7.6 Hz), 7.48 (2H, d, J = 8.6 Hz), 7.65-7.69 (2H, m), 8.02 (1H, s), 12.88 (1H, s).

化合物Ia-3-1 (100 mg, 0.260 mmol)と二酸化セレン(87 mg, 0.780 mmol)の混合物をジオキサン(4 ml)中、８０℃で１時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィーにより精製した。酢酸エチルとジイソプロピルエーテルより再結晶することで化合物Ia-4-8(86 mg, 収率83%)を得た。
1H-NMR (DMSO-d6) δ: 1.12 (3H, t, J = 7.4 Hz), 3.37-3.38 (2H, m), 7.64 (2H, d, J = 8.1 Hz), 7.86-7.88 (2H, m), 8.69-8.71 (2H, m), 14.09 (1H, s). Third step

A mixture of compound Ia-3-1 (100 mg, 0.260 mmol) and selenium dioxide (87 mg, 0.780 mmol) was stirred in dioxane (4 ml) at 80 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography. Recrystallization from ethyl acetate and diisopropyl ether gave Compound Ia-4-8 (86 mg, yield 83%).
1H-NMR (DMSO-d6) δ: 1.12 (3H, t, J = 7.4 Hz), 3.37-3.38 (2H, m), 7.64 (2H, d, J = 8.1 Hz), 7.86-7.88 (2H, m ), 8.69-8.71 (2H, m), 14.09 (1H, s).

化合物Ia-4-8 (55 mg, 0.138 mmol)を塩化メチレン(3 ml)に懸濁させ、ＤＥＯＸＯＦＬＵＯＲ (305 mg, 1.381 mmol)を滴下し、４０分間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィーにより精製した。酢酸エチルとジイソプロピルエーテルより再結晶することで化合物Ia-3-23 (30 mg, 収率52%)を得た。
1H-NMR (DMSO-d6) δ: 1.09 (3H, t, J = 7.4 Hz), 3.29-3.32 (2H, m), 7.57-7.59 (2H, m), 7.80-7.88 (4H, m), 8.18 (1H, s), 14.15 (1H, s). Fourth step

Compound Ia-4-8 (55 mg, 0.138 mmol) was suspended in methylene chloride (3 ml), DEOXOFLUOR (305 mg, 1.381 mmol) was added dropwise, and the mixture was stirred for 40 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography. Recrystallization from ethyl acetate and diisopropyl ether gave Compound Ia-3-23 (30 mg, 52% yield).
1H-NMR (DMSO-d6) δ: 1.09 (3H, t, J = 7.4 Hz), 3.29-3.32 (2H, m), 7.57-7.59 (2H, m), 7.80-7.88 (4H, m), 8.18 (1H, s), 14.15 (1H, s).

マグネシウム(417 mg, 17.14 mmol) を減圧下、加熱した後、室温でジエチルエーテル (10 ml) を加え、攪拌した。ここに化合物６４ (1 g, 5.71 mmol)と微量のヨウ素を加え、室温で２時間攪拌した。これを−７８℃に冷却したシュウ酸ジエチル (2.341 ml, 17.14 mmol) のジエチルエーテル(10 ml) 溶液に滴下し、１時間攪拌した。
反応混合物に塩酸水溶液を加え、酢酸エチルで抽出し、有機層を塩酸水溶液と飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィーにより精製することで化合物６５ (495 mg, 収率44%)を得た。 Example 12 First Step of Synthesis of Compound Ia-6-16

Magnesium (417 mg, 17.14 mmol) was heated under reduced pressure, diethyl ether (10 ml) was added at room temperature, and the mixture was stirred. Compound 64 (1 g, 5.71 mmol) and a small amount of iodine were added thereto, and the mixture was stirred at room temperature for 2 hours. This was added dropwise to a solution of diethyl oxalate (2.341 ml, 17.14 mmol) in diethyl ether (10 ml) cooled to −78 ° C. and stirred for 1 hour.
An aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous hydrochloric acid solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain Compound 65 (495 mg, yield 44%).

化合物６５ (460 mg, 2.345 mmol)を塩化メチレン(2 ml)に溶解し、氷冷下、ＤＡＳＴ(929 μｌ, 7.03 mmol)を滴下し、６０℃で１時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィーにより精製することで化合物６６ (268 mg, 収率52%)を得た。
¹H-NMR (DMSO-d₆) δ: 1.23 (3H, t, J = 7.1 Hz), 4.32 (2H, q, J = 7.1 Hz), 7.39-7.41 (2H, m), 7.65-7.69 (2H, m). Second step

Compound 65 (460 mg, 2.345 mmol) was dissolved in methylene chloride (2 ml), and DAST (929 μl, 7.03 mmol) was added dropwise under ice cooling, followed by stirring at 60 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 66 (268 mg, yield 52%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.23 (3H, t, J = 7.1 Hz), 4.32 (2H, q, J = 7.1 Hz), 7.39-7.41 (2H, m), 7.65-7.69 (2H , m).

化合物６６ (260 mg, 1.192 mmol) をエタノール (5 ml)に溶解させ、水素化ホウ素ナトリウム(63 mg, 1.668 mmol) を加え、室温で１時間攪拌した。反応混合物にクエン酸水溶液を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィーにより精製することで化合物６７ (157 mg,収率75%)を得た。
¹H-NMR (DMSO-d₆) δ: 3.83-3.86 (2H, m), 5.63 (1H, t, J = 6.3 Hz), 7.31-7.33 (2H, m), 7.57-7.59 (2H, m). Third step

Compound 66 (260 mg, 1.192 mmol) was dissolved in ethanol (5 ml), sodium borohydride (63 mg, 1.668 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound 67 (157 mg, yield 75%).
¹ H-NMR (DMSO-d ₆ ) δ: 3.83-3.86 (2H, m), 5.63 (1H, t, J = 6.3 Hz), 7.31-7.33 (2H, m), 7.57-7.59 (2H, m) .

化合物６７ (45 mg, 0.258 mmol) をＤＭＦ (5 ml)に溶解させ、水素化ナトリウム (10 mg, 0.258 mmol) を氷冷下加え、室温で３０分間攪拌した後、化合物６８ (90 mg, 0.215 mmol) を加え、室温で３０分間攪拌した。反応液中に水を加え、析出した結晶をろ取することで化合物６９ (111 mg)を得た。 Fourth step

Compound 67 (45 mg, 0.258 mmol) was dissolved in DMF (5 ml), sodium hydride (10 mg, 0.258 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 min, and then compound 68 (90 mg, 0.215). mmol) was added and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration to obtain Compound 69 (111 mg).

第４工程で得られた化合物６９ (110 mg, 0.214 mmol)をＴＨＦ (5 ml)に溶解させた後、ＴＢＡＦ (279 mg, 1.069 mmol)を加え、加熱還流下で２時間攪拌した。反応液中に水を加え、酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィーにより精製した。ヘキサンとジイソプロピルエーテルより再結晶することで化合物Ia-6-16 (43 mg, 収率52%)を得た。
1H-NMR (DMSO-d6) δ: 1.03-1.09 (3H, m), 3.25 (2H, q, J = 7.4 Hz), 5.12-5.19 (2H, m), 7.40 (2H, t, J = 8.9 Hz), 7.55-7.61 (2H, m), 7.74-7.83 (3H, m), 12.75-12.83 (1H, m). 5th process

Compound 69 (110 mg, 0.214 mmol) obtained in the fourth step was dissolved in THF (5 ml), TBAF (279 mg, 1.069 mmol) was added, and the mixture was stirred for 2 hours with heating under reflux. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography. Recrystallization from hexane and diisopropyl ether gave Compound Ia-6-16 (43 mg, yield 52%).
1H-NMR (DMSO-d6) δ: 1.03-1.09 (3H, m), 3.25 (2H, q, J = 7.4 Hz), 5.12-5.19 (2H, m), 7.40 (2H, t, J = 8.9 Hz ), 7.55-7.61 (2H, m), 7.74-7.83 (3H, m), 12.75-12.83 (1H, m).

化合物７１ (500 mg, 3.08 mmol) をＴＨＦ (10 ml)に溶解させ、トリエチルアミン(513 μl, 3.70 mmol) を加えた後、氷冷下、クロロギ酸イソブチル (486 μl, 3.70 mmol) を滴下した。これを、氷冷下、水素化ホウ素ナトリウム (140 mg, 3.70 mmol) のエタノール (5 ml) 溶液に滴下し、室温で１５時間攪拌した。反応液中にクエン酸水溶液を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去することで化合物７２ (371 mg,収率81%)を得た。
¹H-NMR (DMSO-d₆) δ: 0.70-0.71 (2H, m), 0.82-0.83 (2H, m), 3.52 (2H, d, J = 5.6 Hz), 4.63 (1H, t, J = 5.6 Hz), 7.14-7.18 (1H, m), 7.24-7.31 (4H, m). Example 13 First Step of Synthesis of Compound Ia-6-18

Compound 71 (500 mg, 3.08 mmol) was dissolved in THF (10 ml), triethylamine (513 μl, 3.70 mmol) was added, and then isobutyl chloroformate (486 μl, 3.70 mmol) was added dropwise under ice cooling. This was added dropwise to a solution of sodium borohydride (140 mg, 3.70 mmol) in ethanol (5 ml) under ice cooling and stirred at room temperature for 15 hours. An aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain Compound 72 (371 mg, yield 81%).
¹ H-NMR (DMSO-d ₆ ) δ: 0.70-0.71 (2H, m), 0.82-0.83 (2H, m), 3.52 (2H, d, J = 5.6 Hz), 4.63 (1H, t, J = 5.6 Hz), 7.14-7.18 (1H, m), 7.24-7.31 (4H, m).

化合物７２ (47 mg, 0.320 mmol) をＤＭＦ (3 ml)に溶解させ、水素化ナトリウム (13 mg, 0.320 mmol) を氷冷下加え、室温で３０分間攪拌した後、化合物１８ (100 mg, 0.267 mmol) を加え、室温で２時間攪拌した。反応液中にクエン酸水溶液を加え、酢酸エチルで抽出し、有機層を飽和炭酸水素ナトリウム水溶液と飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去することで化合物７３を得た。これ以上の精製はせずに第３工程の反応に用いた。 Second step

Compound 72 (47 mg, 0.320 mmol) was dissolved in DMF (3 ml), sodium hydride (13 mg, 0.320 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes, and then compound 18 (100 mg, 0.267). mmol) was added and stirred at room temperature for 2 hours. An aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying with anhydrous magnesium sulfate, Compound 73 was obtained by distilling off the solvent under reduced pressure. It was used for the reaction in the third step without further purification.

第２工程で得られた化合物７３ (130 mg, 0.214 mmol)をＴＨＦ (5 ml)に溶解させた後、ＴＢＡＦ (349 mg, 1.336 mmol)を加え、加熱還流下で１．５時間攪拌した。反応液中に水を加え、酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィーにより精製することで化合物Ia-6-18 (54 mg, 2工程収率57%)を得た。
1H-NMR (DMSO-d6) δ: 0.98-1.18 (7H, m), 3.23 (2H, q, J = 7.3 Hz), 4.67 (2H, s), 7.18-7.22 (1H, m), 7.32-7.36 (4H, m), 7.48-7.54 (2H, m), 7.73 (1H, s), 12.46 (1H, s). Third step

Compound 73 (130 mg, 0.214 mmol) obtained in the second step was dissolved in THF (5 ml), TBAF (349 mg, 1.336 mmol) was added, and the mixture was stirred for 1.5 hours with heating under reflux. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound Ia-6-18 (54 mg, 2 step yield 57%).
1H-NMR (DMSO-d6) δ: 0.98-1.18 (7H, m), 3.23 (2H, q, J = 7.3 Hz), 4.67 (2H, s), 7.18-7.22 (1H, m), 7.32-7.36 (4H, m), 7.48-7.54 (2H, m), 7.73 (1H, s), 12.46 (1H, s).

３−（トリフルオロメトキシ）フェノール(5.32g, 29.9 mmol)をＤＭＦ(100 ml)に溶解させ、炭酸セシウム(16.2 g, 49.8 mmol)、化合物７５ (9.0 g, 24.9 mmol)を添加し、８０℃で３時間過熱攪拌した。反応液に水とジエチルエーテルを加えて、分液、抽出、有機層は無水硫酸マグネシウムで乾燥、減圧濃縮した。残渣をシリカゲルクロマトグラフィーにより精製することで化合物７６ (12.0 g, 収率73％)を得た。
LCMS(MS)=504.8 (M+H) Example 14 Synthesis of Compound Ia-5-45 First Step

3- (Trifluoromethoxy) phenol (5.32 g, 29.9 mmol) was dissolved in DMF (100 ml), cesium carbonate (16.2 g, 49.8 mmol), compound 75 (9.0 g, 24.9 mmol) were added, and 80 ° C. For 3 hours. Water and diethyl ether were added to the reaction solution, followed by liquid separation, extraction, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound 76 (12.0 g, yield 73%).
LCMS (MS) = 504.8 (M + H)

化合物７６ (200 mg, 0.397 mmol)のトルエン溶液(10 ml)に、２−メチルプロパン−２−スルホンアミド (82 mg, 0.596 mmol)、Ｐｄ_２（ｄｂａ）_３ (36.4 mg, 0.040 mmol)、２−（ジ−ｔｅｒｔ−ブチルホスフィノ）ビフェニル (35.6 mg, 0.119 mmol)、ｔ−ＢｕＯＮａ (95 mg, 0.993 mmol)を添加し、過熱還流下４時間攪拌した。反応液に水とジエチルエーテルを加えて、分液、抽出、有機層は無水硫酸マグネシウムで乾燥、減圧濃縮した。残渣をシリカゲルクロマトグラフィーにより精製することで化合物７７(195 mg, 収率87%)を得た。
LCMS(MS)=560.1 (M+H) Second step

To a toluene solution (10 ml) of compound 76 (200 mg, 0.397 mmol), 2-methylpropane-2-sulfonamide (82 mg, 0.596 mmol), Pd ₂ (dba) ₃ (36.4 mg, 0.040 mmol), 2 -(Di-tert-butylphosphino) biphenyl (35.6 mg, 0.119 mmol) and t-BuONa (95 mg, 0.993 mmol) were added, and the mixture was stirred for 4 hours under reflux with heating. Water and diethyl ether were added to the reaction solution, followed by liquid separation, extraction, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound 77 (195 mg, yield 87%).
LCMS (MS) = 560.1 (M + H)

化合物７８ (90 mg, 0.161 mmol)のテトラヒドロフラン (2.0 ml)溶液に、１Ｍテトラブチルアンモニウムフルオライド テトラヒドロフラン溶液 (1.6 ml)を添加。過熱還流下４時間攪拌した。反応液に水とジエチルエーテルを加えて、分液、抽出、有機層は無水硫酸マグネシウムで乾燥、減圧濃縮した。残渣をシリカゲルクロマトグラフィーにより精製することで化合物Ia-5-45 (57.2 mg, 収率 83%)を得た。
1H-NMR (CDCl3) δ: 1.40 (s, 9H), 7.07-7.11 (m, 3H), 7.27-7.49 (m, 6H).
LCMS(RT、測定条件(3))=2.00
LCMS(MS)=430.4 (M+H) Third step

To a solution of compound 78 (90 mg, 0.161 mmol) in tetrahydrofuran (2.0 ml) was added 1M tetrabutylammonium fluoride tetrahydrofuran solution (1.6 ml). The mixture was stirred for 4 hours under reflux. Water and diethyl ether were added to the reaction solution, followed by liquid separation, extraction, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give compound Ia-5-45 (57.2 mg, yield 83%).
1H-NMR (CDCl3) δ: 1.40 (s, 9H), 7.07-7.11 (m, 3H), 7.27-7.49 (m, 6H).
LCMS (RT, measurement condition (3)) = 2.00
LCMS (MS) = 430.4 (M + H)

  According to the above Example, the following compounds were synthesized. In the table, Rac means a racemate, and Abs means an optically active substance. In the structural formula, Me is methyl, Et is ethyl, Ph is phenyl, and Bn is benzyl.

Moreover, according to the said Example, the following compounds are compoundable. In the structural formula, Rac means a racemate. Ph in the structural formula is phenyl.

で示される化合物における各置換基について、以下に例示する。 The compound of the present invention, formula (I):

Examples of each substituent in the compound represented by the formula:

Examples of the combination of Y ¹ , Y ² , and Y ³ in the compound of the present invention include the combinations described in Table 80 below.

Examples of combinations of R ² and X in the compounds of the present invention include the combinations described in Tables 81 and 82 below.

Examples of combinations of V ¹ , V ² , W ¹ and W ^{2 in} the compounds of the present invention include the combinations described in Tables 83 and 84 below.

Examples of R ^{4 in} the compound of the present invention include the examples described in Table 85 below.

Examples of R ^{5 in} the compound of the present invention include the combinations described in Table 86 below.

  All the individual compounds formed by combinations arbitrarily selected from the above-mentioned groups A, B, C, D and E are also included in the present invention.

Hereinafter, biological test examples of the compound of the present invention will be described.
Test Example 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 28.
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 2 Affinity for human NPY Y5 receptor A cDNA sequence encoding human NPY Y5 receptor (see WO96 / 16542) was expressed in expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466-472). Cloning into 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 was 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 3 Rat Brain Migration Evaluation Intravenous to rats (Crl; CD (SD), ♂, 8weeks) using the cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) From the plasma and brain concentration 30 minutes after administration (0.5 mg / mL / kg), brain transferability (brain / plasma partition coefficient; Kp) was evaluated.
As a result, the compound of the present invention showed good brain migration. For example, Compound Ia-5-29 had a brain Kp: 0.93.

Test Example 4 Evaluation of Mouse Brain Transferability Using a cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966), oral administration to mice (Jcl; C57BL / 6J, ♂, 8weeks) ( 2 mg / 10 mL / kg) From the plasma and brain concentrations after 3 or 5 hours, the brain transferability (brain / plasma partition coefficient; Kp) can be evaluated.

Test Example 5 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. As a result, the compound of the present invention showed good pharmacokinetics such as high bioavailability and appropriate clearance.

Test Example 6 Inhibition of cAMP production in CHO cells CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), and then the compound 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.
The results are shown below.
Compound Ia-1-11: 35 nM
Compound Ia-4-1: 146 nM
Compound Ic-2-65: 30nM

Test Example 7 NPY Y5 Receptor Selectivity Test Examples 1-2 and Y1-expressing cells (human neuroblastoma, SK-N-MC) membrane preparation and Y2-expressing cells (human neuroblastoma, SMS-KAN) membrane sample 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 NPY Y2 receptor is measured. As a result, it can be confirmed that the compound according to the present invention has NPY Y5 receptor selectivity.

Test Example 8 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the external occipital crest to the back of the nose of male C57BL / 6J mice (12-14 weeks old, 28-35 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 mice after waking up from anesthesia, and received physiological saline or NPY Y5 one hour after administration. Body-specific agonist ([cPP ^1-7 , NPY ^19-23 , Ala ³¹ , Aib ³² , Gln ³⁴ ] -h Pancreatic Polypeptide: manufactured by Tocris) 0.1 nmol using a cannula from the head opening previously provided Injected. The food intake of the mice was measured 2 hours and 4 hours after the injection, and the difference in food intake between the 0.5% hydroxypropylmethylcellulose solution administration group and the test substance administration group was investigated.
As a result, when the compound of the present invention was administered at a dose of 25 mg / kg, the amount of food intake was significantly suppressed as compared with 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-4-5, the food intake after 2 hours and 4 hours after injection was 0.31 ± 0.04 g and 0.71 ± 0. It was 06 g. On the other hand, the amount of food intake 2 hours and 4 hours after injection in the 0.5% hydroxypropylmethylcellulose solution administration group (Group B) was 0.58 ± 0.06 g and 1.20 ± 0.17 g, respectively. The 0.5% hydroxypropyl methylcellulose solution administration group (Group C) to which no NPY Y5 receptor specific agonist was injected was 0.03 ± 0.02 g, 0.07 ± 0.03 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 49.2% and 43.2%, respectively.

Test Example 9 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 multi-label 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-1-11: 5 species> 20 μM
Compound Ia-6-22: 5 species> 20 μM
Compound Ib-1-5: 5 types> 20 μM

Test Example 10 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. After the reaction was stopped by adding acetonitrile / methanol = 1/1 (v / v) twice the amount of the reaction solution, the compound in the centrifugal supernatant was measured by HPLC. The amount of disappearance due to metabolic reaction was calculated from the comparison of 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-4-8: 96.5%
Compound Ia-5-19: 98.6%
Compound Ia-6-7: 97.9%
Compound Ib-1-26: 96.4%
Compound Ic-2-30: 97.7%

Test Example 11 Powder Solubility Test An appropriate amount of a sample is put in a suitable container, 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 was added to 500 mL of an acid buffer, and 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (water was added to 1.08 g of TCA to make 100 mL). When dissolved after adding the test solution, a bulk powder was added as appropriate. Sealed and shaken at 37 ° C. for 1 hour. After filtration, 100 μL of methanol was added to 100 μL of each filtrate to perform 2-fold dilution. The dilution factor was changed as necessary. After confirming that there were no bubbles and precipitates, the mixture was sealed and shaken. Quantification was performed using HPLC by the absolute calibration curve method.
For example, the results of Compound Ib-1-5 are as follows.
JP-1 solution; 313 μg / mL
JP-2 solution: 6.82 μg / mL
TCA / JP-2 solution: 35.0 μg / mL

Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet 15 mg of the present compound
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 of the present invention 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.

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

Claims (19)

Formula (I):

(Where
X _-SO 2 is ^{_{-, - SO 2 -C (-R}} 14) (- R 15) -, - N (-R 6) -SO 2 - or _-SO 2 -N (-R ⁷⁾ - a and,
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,

The part indicated by

A structure selected from
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-N (R < ¹³ >)-Ak-;
-Ak-S-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-;
-Ak-C (= O) -Ak-O-Ak-;
-Ak-C (= O) -Ak-N (R < ¹³ >)-Ak-; or -Ak-N (R < ¹³ >)-Ak-C (= O) -Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
R ¹ , R ³ , R ⁸ , R ¹⁴ and R ¹⁵ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or non-substituted Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or an unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl, a substituted or unsubstituted amidino, a group represented by the formula: —O—R ¹⁰ , a formula: —O— C (= O) group represented by ^{-R 10,} represented by the formula: -C (= O) ^{-R 10} The formula: -C (= O) groups represented by ^{-O-R 10,} wherein: a group represented by ^{-S-R 10,} _wherein: group or formula represented by -SO 2 ^{-R 10:} -O-SO a group represented by ₂ -R ^10,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl or a substituted or unsubstituted amidino;
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or the formula: A group represented by C (═O) —O—R ¹⁰ ;
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ⁶ , R ⁷ and R ¹³ are each independently hydrogen or substituted or unsubstituted alkyl, or R ⁶ together with R ² together with the adjacent nitrogen atom forms a substituted or unsubstituted heterocycle R ⁷ may be combined with the adjacent nitrogen atom and SO ₂ — together with R ² to form a substituted or unsubstituted heterocycle.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. However, the following compounds are excluded.

The part indicated by

A compound wherein W ² is a single bond,

The part indicated by

A compound wherein X is —SO ₂ —N (—R ⁷ ) — and R ² is methyl;

The part indicated by

And W ² is a single bond, and

The part indicated by

A compound having a structure selected from

) Or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having an NPY Y5 receptor antagonistic action. W ² is -Ak-;
-Ak-O-Ak-;
-Ak-C (= O) -Ak-;
The pharmaceutical composition according to claim 1, which is -Ak-O-Ak-C (= O) -Ak-; or -Ak-C (= O) -Ak-O-Ak-. X is -SO ₂ - is, pharmaceutical composition of claim 1. The pharmaceutical composition according to claim 1, wherein R ² is substituted or unsubstituted alkyl. The pharmaceutical composition according to claim 1, wherein R ⁴ is aryl or heteroaryl. Y ¹ is = C (-R ⁸ )-, Y ² is -C (-R ³ ) =, and Y ³ is = C (-R ¹ )-. A pharmaceutical composition according to 1. Formula (Ia):

(Where
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-; or -Ak-C (= O) -Ak-O-Ak-;
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
However, when W ² is -Ak-, Ak is not a single bond,
R ¹ , R ³ and R ⁸ are each independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
R ² is substituted or unsubstituted alkyl having 2 to 10 carbon atoms, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl,
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted amidino.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. Or a pharmaceutically acceptable salt thereof. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein W ² is -Ak-; or -Ak-O-Ak-. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R ² is substituted or unsubstituted alkyl having 2 to 10 carbon atoms. The compound according to claim 7, wherein Y ¹ is = C (-R ⁸ )-, Y ² is -C (-R ³ ) =, and Y ³ is = C (-R ¹ )-. Its pharmaceutically acceptable salt. Formula (Ib):

(Where
Y ¹ is ═C (—R ⁸ ) — or ═N—,
Y ² is —C (—R ³ ) ═ or —N═,
Y ³ is ═C (—R ¹ ) — or ═N—,
W ² is -Ak-;
-Ak-O-Ak-;
-Ak-N (R < ¹³ >)-Ak-;
-Ak-S-Ak-;
-Ak-C (= O) -Ak-;
-Ak-O-Ak-C (= O) -Ak-;
-Ak-C (= O) -Ak-O-Ak-;
-Ak-C (= O) -Ak-N (R < ¹³ >)-Ak-; or -Ak-N (R < ¹³ >)-Ak-C (= O) -Ak-
Each Ak is independently a single bond, substituted or unsubstituted C1-C4 alkylene or substituted or unsubstituted C2-C4 alkenylene,
R ¹ , R ³ and R ⁸ are each independently hydrogen, halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or Unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic Group heterocyclic group, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , formula: —O—C (═O) — Group represented by R ¹⁰ , Formula: —C (═O) —R ¹⁰ Group represented by Formula: —C (═O) A group represented by —O—R ¹⁰ , a group represented by formula: —S—R ¹⁰ , a group represented by formula: —SO ₂ —R ¹⁰ or a group represented by formula: —O—SO ₂ —R ^10; Yes,
R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted A substituted heteroaryl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted carbamoyl, a substituted or unsubstituted sulfamoyl or a substituted or unsubstituted amidino;
R ² is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or the formula: A group represented by C (═O) —O—R ¹⁰ ;
R ⁴ is a cycloalkyl, cycloalkenyl, aryl, heteroaryl or unsubstituted non-aromatic heterocyclic group;
R ⁵ is halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, Substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C (= O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: -S-R Groups represented by ^0, the _formula: group, or the formula represented by -SO 2 ^{-R 10:} is a group represented by _-O-SO 2 ^{-R 10,}
n is an integer from 0 to 3,
R ¹³ is hydrogen or substituted or unsubstituted alkyl.
The above substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted non-aromatic heterocyclic group or R ⁴ cycloalkyl, cycloalkenyl or non-aromatic heterocyclic group is 1 Alternatively, it may be substituted with two oxo, thioxo or substituted or unsubstituted imino. However, the following compounds are excluded.
A compound wherein R ⁴ is phenyl;

The part indicated by

A compound having a structure selected from

Or a pharmaceutically acceptable salt thereof. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a heteroaryl or a non-aromatic heterocyclic group. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a monocyclic or bicyclic heteroaryl or a monocyclic or bicyclic non-aromatic heterocyclic group. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein W ² is -Ak-; or -Ak-C (= O) -Ak-. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R ² is substituted or unsubstituted alkyl. The compound according to claim 11, wherein Y ¹ is = C (-R ⁸ )-, Y ² is -C (-R ³ ) =, and Y ³ is = C (-R ¹ )-. Its pharmaceutically acceptable salt. A pharmaceutical composition comprising the compound according to any one of claims 7 to 16 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 17, which has an NPY Y5 receptor antagonistic action. Use for prevention and / or treatment of obesity containing a compound having an anti-obesity action for use in combination with the pharmaceutical composition according to any one of claims 1 to 6, 17 or 18, or for weight management in obesity Pharmaceutical composition.