JP2017149693A - Condensed-ring pyrimidinone derivative having autotaxin inhibitory activity - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a condensed-ring pyrimidinone derivative having excellent autotaxin inhibitory activity.SOLUTION: The present invention provides a compound illustrated by the following formula and the like or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to a fused pyrimidinone derivative having autotaxin inhibitory activity, and a pharmaceutical comprising the fused pyrimidinone derivative as an active ingredient.

  Lysophosphatidic acid (Lysophosphatidic acid, LPA) is a lipid mediator that exhibits a variety of actions such as cell proliferation, intracellular calcium influx, cytoskeletal changes, and cell migration, and is a G protein-coupled receptor (expressed on the surface of the cell membrane). It is involved in signal transduction via LPA1-6). It has been reported that this lipid is involved in biological abnormalities such as fibrosis, pain, cancer, inflammation, arteriosclerosis (Non-patent Document 1).

LPA can be biosynthesized by several metabolic pathways, but the main pathway is due to the production of lysophosphatidylcholine hydrolyzed by autotaxin (autotaxin, ENPP2, ATX). Although ATX is also called ENPP2 be secretory proteins belonging to ENPP (E cto n ucleotide p yrophosphatase and p hosphodiesterase) Family (ENPP1-7), among the family, LPA production in a lysophospholipase D activity Only ATX is involved. It has been reported that inhibiting the enzyme activity of ATX to suppress the production of LPA is effective in treating fibrotic diseases (Non-patent Document 1).

Fibrosis can occur in any tissue, but can progress by a common mechanism, regardless of the type of trigger for its onset.
On the other hand, structures and structures of animal tissues and organs are maintained by fibers such as collagen. However, when the tissues are damaged in some way, they are restored to the original tissues by a wound healing process accompanied by collagen production. However, if the tissue is subjected to multiple immunological, chemical, mechanical, metabolic, or other injuries or the extent of the injuries is large, excessive fibrous connective tissue accumulation may occur. Such accumulation of connective tissue is irreversible, and when fibers increase abnormally, a fibrotic disease is caused in which tissues and organs do not function normally.

  For example, the pathological features of chronic kidney disease include fibrosis of the glomeruli and tubulointerstitium. The pathological features of end stage renal failure are markedly parenchymal cell loss and fibrosis. It is known that patients who show tubulointerstitial fibrosis in patients with chronic kidney disease progress more rapidly in renal function deterioration than patients who do not show fibrosis.

  In addition to lifestyle guidance and dietary guidance, treatment with antihypertensive therapies such as angiotensin receptor antagonists and calcium antagonists is being carried out as a preventive and therapeutic method for chronic kidney disease. However, the effects obtained by existing therapies cannot be said to be sufficient, and there is a demand for better preventive / therapeutic agents for renal dysfunction.

Patent Document 1 discloses a tetrahydropyrimidopyrimidinone derivative that is an interleukin-1 modulator.
Non-patent documents 2 and 3 disclose pyrimidothiadiazine derivatives.
Non-Patent Documents 4 and 5 disclose dihydrooxazolopyrimidinone derivatives.
Non-Patent Document 6 discloses a dihydroimidazopyrimidinone derivative.

International Publication No. 2005/70932

Nature, 411, 494-498, 2001. Journal of Heterocyclic Chemistry, Volume: 47, Issue: 6, Pages: 1294-1302 Russian Chemical Bulletin, Volume: 56, Issue: 7, Pages: 1437-1440, 2007 Journal of Fluorine Chemistry, Volume: 129, Issue: 9, Pages: 836-847, 2008 Chemical Communications (Cambridge, United Kingdom), Issue: 7, Pages: 844-845, 2003 Phosphorus, Sulfur and Silicon and the Related Elements, Volume: 113, Issue: 1-4, Pages: 67-77, 1996

  An object of the present invention is to provide a condensed pyrimidinone derivative having excellent autotaxin inhibitory activity.

  As a result of intensive studies, the present inventors have found a condensed pyrimidinone derivative having excellent autotaxin inhibitory activity, and achieved the present invention.

（式中、
環Ａは架橋を有していてもよい含窒素飽和複素環であり、
Ｒ^１は、水素、ハロゲン、シアノ、ヒドロキシ、ホルミル、置換も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非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、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芳香族複素環式基、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オキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の芳香族複素環オキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換の非芳香族炭素環チオ、置換若しくは非置換の芳香族炭素環チオ、置換若しくは非置換の非芳香族複素環チオ、置換若しくは非置換の芳香族複素環チオ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換の非芳香族炭素環カルボニル、置換若しくは非置換の芳香族炭素環カルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換若しくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換の非芳香族炭素環オキシカルボニル、置換若しくは非置換の芳香族炭素環オキシカルボニル、置換若しくは非置換の非芳香族複素環オキシカルボニル、置換若しくは非置換の芳香族複素環オキシカルボニル、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ルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換の非芳香族炭素環スルフィニル、置換若しくは非置換の芳香族炭素環スルフィニル、置換若しくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換の芳香族複素環スルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換若しくは非置換の非芳香族炭素環スルホニル、置換若しくは非置換の芳香族炭素環スルホニル、置換若しくは非置換の非芳香族複素環スルホニルまたは置換若しくは非置換の芳香族複素環スルホニルであり、
Ｒ^２は式：

（式中、
Ｘは単結合、Ｏ、Ｓ、ＮＲ^７Ａ、またはＣＲ^７ＢＲ^７Ｃであり、
Ｒ^７Ａは水素または置換もしくは非置換のアルキルであり、
Ｒ^７ＢおよびＲ^７Ｃはそれぞれ独立して、水素、ハロゲン、またはＲ^７ＢおよびＲ^７Ｃは一緒になってオキソを形成してもよく、
環Ｂはベンゼン、６員の芳香族複素環、６員の非芳香族炭素環または６員の非芳香族複素環であり、
Ｒ^５はハロゲン、ヒドロキシ、シアノ、ホルミル、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アミノ、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のカルバモイル、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ルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニルまたは置換若しくは非置換のアルキニルスルホニルであり、
Ｒ^６はそれぞれ独立して、ハロゲン、ヒドロキシ、シアノ、ホルミル、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アミノ、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のカルバモイル、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ルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニルまたは置換若しくは非置換のアルキニルスルホニルであり、
ｍは０〜４の整数である。）で示される基であり、
Ｒ^３は、ハロゲン、シアノ、ヒドロキシ、ホルミル、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芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族炭素環式基、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アルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換の芳香族炭素環カルボニル、置換若しくは非置換の芳香族複素環カルボニル、置換若しくは非置換の非芳香族炭素環カルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換若しくは非置換のアルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換の芳香族炭素環スルフィニル、置換若しくは非置換の芳香族複素環スルフィニル、置換若しくは非置換の非芳香族炭素環スルフィニルまたは置換若しくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換若しくは非置換の芳香族炭素環スルホニル、置換若しくは非置換の芳香族複素環スルホニル、置換若しくは非置換の非芳香族炭素環スルホニルまたは置換若しくは非置換の非芳香族複素環スルホニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルであり、
Ｒ^４はそれぞれ独立して、ハロゲン、シアノ、ヒドロキシ、ホルミル、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芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族炭素環式基、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アルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換の芳香族炭素環カルボニル、置換若しくは非置換の芳香族複素環カルボニル、置換若しくは非置換の非芳香族炭素環カルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換若しくは非置換のアルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換の芳香族炭素環スルフィニル、置換若しくは非置換の芳香族複素環スルフィニル、置換若しくは非置換の非芳香族炭素環スルフィニルまたは置換若しくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換若しくは非置換の芳香族炭素環スルホニル、置換若しくは非置換の芳香族複素環スルホニル、置換若しくは非置換の非芳香族炭素環スルホニルまたは置換若しくは非置換の非芳香族複素環スルホニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルであり、
ｎは０〜４の整数である）で示される化合物（ただし、下記（ｉ）〜（ｉｉｉ）の化合物を除く、
（ｉ）

で示される部分構造が、

で示される部分構造であり、Ｒ^１がシアノであり、Ｘが単結合であり、環Ｂがベンゼンである化合物、
（ｉｉ）

で示される部分構造が、

で示される部分構造であり、Ｒ^１が水素であり、Ｘが単結合であり、環Ｂがベンゼンであり、Ｒ^３が置換ピリミジルである化合物、および
（ｉｉｉ）以下に示す化合物

またはその製薬上許容される塩。
（２）Ｒ^１が水素である、上記（１）記載の化合物またはその製薬上許容される塩。
（３）Ｘが単結合であり、
環Ｂがベンゼンまたは６員の芳香族複素環である、上記（１）または（２）記載の化合物またはその製薬上許容される塩。
（４）環Ｂがベンゼンである、上記（３）記載の化合物またはその製薬上許容される塩。
（５）Ｒ^２が以下に示される基：

（式中、環Ｂはベンゼン、ピリジン、ピリミジンまたはピラジンである）であり、
Ｒ^５はハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニルまたは置換もしくは非置換のアルキニルスルホニルであり、
Ｒ^６はハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニルまたは置換もしくは非置換のアルキニルスルホニルであり、
Ｒ^６’はそれぞれ独立して、ハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニルまたは置換もしくは非置換のアルキニルスルホニルであり、
ｐは０〜３の整数である）である、上記（１）または（２）記載の化合物またはその製薬上許容される塩。
（６）Ｒ^５はハロゲン、シアノ、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルキルオキシであり、
Ｒ^６は、ハロゲン、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアミノまたは置換もしくは非置換のアルキルオキシであり、
Ｒ^６’はそれぞれ独立して、ハロゲン、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアミノまたは置換もしくは非置換のアルキルオキシである、上記（５）記載の化合物またはその製薬上許容される塩。
（７）

で示される部分構造が、

である、上記（１）〜（６）のいずれかに記載の化合物、またはその製薬上許容される塩。
（８）

で示される部分構造が、

（式中の記号は、上記と同意義である。）
である、上記（７）記載の化合物、またはその製薬上許容される塩。
（９）Ｒ^３が置換若しくは非置換のアルキル、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族炭素環式基、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アルキルカルボニル、置換若しくは非置換の芳香族炭素環カルボニル、置換若しくは非置換の芳香族複素環カルボニル、置換若しくは非置換の非芳香族炭素環カルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換もしくは非置換のアミノまたは置換もしくは非置換のカルバモイルである、上記（８）記載の化合物、またはその製薬上許容される塩。
（１０）上記（１）〜（９）のいずれかに記載の化合物またはその製薬上許容される塩を有効成分として含有する医薬組成物。
（１１）オートタキシン阻害剤である、上記（１０）記載の医薬組成物。
（１２）オートタキシンが関与する疾患の予防または治療のための、上記（１０）記載の医薬組成物。
（１３）オートタキシンの関与する疾患の治療剤又は予防剤を製造するための、上記（１）〜（１０）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使用。
（１４）上記（１）〜（１０）のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とするオートタキシンの関与する疾患の治療又は予防方法。 That is, the present invention relates to the following.
(1) Formula (I):

(Where
Ring A is a nitrogen-containing saturated heterocyclic ring which may have a bridge,
R ¹ is hydrogen, halogen, cyano, hydroxy, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or An unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted amino, a substituted or unsubstituted alkyloxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy Substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted al Kenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted Aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbon Ring carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyl Oxycarbonyl, substituted or non-substituted Non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted Aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted Is substituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, or substituted or unsubstituted aromatic heterocyclic A ring sulfonyl,
R ² is the formula:

(Where
X is a single bond, O, S, NR ^7A , or CR ^7B R ^7C ;
R ^7A is hydrogen or substituted or unsubstituted alkyl;
R ^7B and R ^7C are each independently hydrogen, halogen, or R ^7B and R ^7C may together form an oxo,
Ring B is benzene, a 6-membered aromatic heterocycle, a 6-membered non-aromatic carbocycle or a 6-membered non-aromatic heterocycle,
R ⁵ is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
Each R ⁶ is independently halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl Substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxy Xyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
m is an integer of 0-4. )
R ³ is halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy Substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Heterocyclic oxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl Substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic Heterocyclic carbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl Substituted or unsubstituted non-aromatic carbocyclic sulfinyl or substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl Substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or non-substituted Substituted carbamoyl or substituted or unsubstituted sulfamoyl,
Each R ⁴ is independently halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group; Substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or non-substituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or non-substituted Substituted non-aromatic heterocyclic oxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted al Kenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted Non-aromatic heterocyclic carbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic Heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl or substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted a Quinylsulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic carbocyclic sulfonyl, or substituted or unsubstituted nonaromatic heterocyclic sulfonyl, Substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl,
n is an integer of 0 to 4) (excluding the following compounds (i) to (iii)),
(I)

The partial structure indicated by

A compound in which R ¹ is cyano, X is a single bond, and ring B is benzene,
(Ii)

The partial structure indicated by

Wherein R ¹ is hydrogen, X is a single bond, ring B is benzene, and R ³ is substituted pyrimidyl, and (iii) compounds shown below

Or a pharmaceutically acceptable salt thereof.
(2) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen.
(3) X is a single bond,
The compound or a pharmaceutically acceptable salt thereof according to the above (1) or (2), wherein Ring B is benzene or a 6-membered aromatic heterocyclic ring.
(4) The compound according to (3) or a pharmaceutically acceptable salt thereof, wherein ring B is benzene.
(5) R ² is a group shown below:

Wherein ring B is benzene, pyridine, pyrimidine or pyrazine.
R ⁵ is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
R ⁶ is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
Each R ^{6 ′} is independently halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted Substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkyl Carbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyl Xyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
(p is an integer of 0 to 3) or a pharmaceutically acceptable salt thereof according to (1) or (2) above.
(6) R ⁵ is halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy,
R ⁶ is halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino or substituted or unsubstituted alkyloxy,
R ^{6 ′} is each independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino, or substituted or unsubstituted alkyloxy, or a pharmaceutically acceptable salt thereof. Salt.
(7)

The partial structure indicated by

The compound according to any one of (1) to (6) above, or a pharmaceutically acceptable salt thereof.
(8)

The partial structure indicated by

(The symbols in the formula are as defined above.)
The compound according to (7) above, or a pharmaceutically acceptable salt thereof.
(9) R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic The compound according to (8) above, which is an aromatic carbocyclic carbonyl, a substituted or unsubstituted non-aromatic heterocyclic carbonyl, a substituted or unsubstituted amino or a substituted or unsubstituted carbamoyl, or a pharmaceutically acceptable salt thereof.
(10) A pharmaceutical composition comprising the compound according to any one of (1) to (9) above or a pharmaceutically acceptable salt thereof as an active ingredient.
(11) The pharmaceutical composition according to the above (10), which is an autotaxin inhibitor.
(12) The pharmaceutical composition according to (10) above, for the prevention or treatment of a disease involving autotaxin.
(13) Use of the compound according to any one of (1) to (10) above or a pharmaceutically acceptable salt thereof for producing a therapeutic or prophylactic agent for a disease involving autotaxin.
(14) A method for treating or preventing a disease involving autotaxin, comprising administering the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof.

  The compound of the present invention exhibits excellent autotaxin inhibitory activity, and is particularly useful in the treatment or prevention of diseases involving autotaxin.

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.
The application “consisting of” means having only the configuration requirements.
The term “comprising” is not limited to the constituent elements and means that elements not described are not excluded.

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

“Alkyl” means a linear or branched hydrocarbon group having 1 to 10 carbon atoms. C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc. are included. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl , N-nonyl, n-decyl and the like.
“Alkyl” in R ⁴ includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like. In particular, methyl, ethyl and the like are preferable.

“Alkylcarbonyl” includes methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl and the like.
Examples of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl and the like. Particularly, methyloxycarbonyl, ethyloxycarbonyl and the like can be mentioned.

“Haloalkyl” and “haloalkyloxy” are a group in which 1 to 5 (preferably 1 to 3) of the above “halogen” is substituted at any position where alkyl and alkyloxy can be substituted. means.
Examples of “haloalkyl” for R ⁵ include monohaloalkyl, dihaloalkyl, trihaloalkyl and the like. In particular, monotrifluoromethyl, monochloromethyl, dichloromethyl, difluoromethyl, monotrifluoromonochloromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, and trifluoropentyl are preferable.
Examples of “haloalkyloxy” for R ⁵ include monohaloalkyloxy, dihaloalkyloxy, trihaloalkyloxy and the like. In particular, monotrifluoromethyloxy, monochloromethyloxy, dichloromethyloxy, difluoromethyloxy, monotrifluoromonochloromethyloxy, trifluoromethyloxy, trifluoroethyloxy, trifluoropropyloxy, trifluorobutyloxy, trifluoropentyl Oxy is preferred.

  “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 2 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.

  The “aromatic carbocycle” includes a monocyclic or condensed aromatic hydrocarbon ring. For example, a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, etc. are mentioned. A benzene ring is particularly preferable.

  “Aromatic carbocyclic group” means a monovalent group derived from the above “aromatic carbocyclic group”. For example, phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl and the like can be mentioned. Particularly preferred is phenyl.

  The “cycloalkane” includes a monocyclic or polycyclic saturated carbocyclic ring having 3 to 10 carbon atoms. Examples of the monocyclic cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane. Examples of the polycyclic cycloalkane include norbornane, tetrahydronaphthalene, adamantane and the like.

“Cycloalkyl” includes a monovalent group derived from the above “cycloalkane”. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Examples of polycyclic cycloalkyl include norbornyl, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl, adamantyl and the like.
As the “cycloalkyl”, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like are preferable. Particularly, “cycloalkyl” having 3 to 6 carbon atoms and “cycloalkyl” having 5 or 6 carbon atoms are preferable. preferable.

  “Cycloalkene” includes a non-aromatic monocyclic or polycyclic ring having 3 to 10 carbon atoms and containing at least one carbon-carbon double bond. Examples of the monocyclic cycloalkene include cyclopentene and cyclohexene. Examples of the polycyclic cycloalkene include norbornene and indene.

  “Cycloalkenyl” includes a monovalent group derived from the above “cycloalkene”. Examples of monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl and the like. Examples of polycyclic cycloalkenyl include norbornenyl, inden-1-yl, inden-2-yl, inden-3-yl and the like. “Cycloalkenyl” having 5 or 6 carbon atoms is particularly preferable.

“Non-aromatic carbocyclic group” means one or two of the above “cycloalkyl” and “cycloalkenyl”, and “cycloalkyl”, “cycloalkenyl” and / or “aromatic carbocycle”. Includes fused groups. The bond may exit from any ring.
For example, the following groups are also included in the non-aromatic carbocyclic group.

The “aromatic heterocycle” includes a 5- to 6-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring.
For example, monocyclic aromatics such as pyrrole, pyrazole, tetrazole, furan, thiophene, tetrazole, imidazole, triazole, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, triazine, pyridine, pyridazine, pyrimidine, pyrazine Heterocycle;
Indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzothiazole, Examples thereof include condensed aromatic heterocycles such as benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazoline, and benzopyran.
Examples of the “6-membered aromatic heterocycle” in ring B include pyridine, pyridazine, pyrimidine, pyrazine and the like, and pyridine is particularly preferable.

The “aromatic heterocyclic group” includes a monovalent group derived from the above “aromatic heterocyclic ring”.
For example, monocyclic aromatic heterocyclic groups such as pyrrolyl, pyrazolyl, tetrazolyl, furyl, thienyl, tetrazolyl, imidazolyl, triazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazinyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. ;
For example, indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxazolyl, benzoxazolyl , Benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazolothiazolyl, pyrazinopyridazinyl, benzimidazolinyl And condensed aromatic heterocyclic groups such as benzopyranyl.

“Non-aromatic heterocycle” means a 5- to 7-membered non-aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring,
A non-aromatic ring in which two or more of them are independently fused,
The 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is one or more of the “cycloalkane”, the “cycloalkene” or the “non-aromatic heterocycle”. A ring fused with
A 5- to 7-membered non-aromatic heterocycle having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycle” or “non-aromatic carbocycle” Included rings.
For example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dihydropyrazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazoline, tetrahydro Monocyclic non-aromatic heterocycles such as isothiazoline,
Examples thereof include condensed non-aromatic heteroaromatic rings such as indoline, isoindoline, benzopyran, benzodioxane, tetrahydroquinoline, benzo [d] oxazol-2 (3H) -one, tetrahydrobenzothiophene and the like.

The “non-aromatic heterocyclic group” includes a monovalent group derived from the above “non-aromatic heterocyclic ring”.
For example, pyrrolinyl, pyrrolidino, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydropyridyl, dihydropyridinyl, dihydropyridinyl, dihydropyridinyl Monocyclic non-aromatic heterocyclic groups such as, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl,
Examples thereof include condensed heterocyclic groups such as benzodioxane, tetrahydroquinoline, benzo [d] oxazol-2 (3H) -one, and tetrahydrobenzothiophene.
Specific examples of the “polycyclic non-aromatic heterocyclic group” include indolinyl, isoindolinyl, chromanyl, isochromanyl, isomannyl 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 aromatic carbocyclic group or substituted non-aromatic heterocyclic group may be substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino.

Substituents for “substituted alkyl”, “substituted alkenyl” and “substituted alkynyl” include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, carboxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynyl Rubonyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, Substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted Non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Non-aromatic carbocycle Xy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or Unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted Aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxyoxy, substituted or unsubstituted Aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, Preferred is a substituted or unsubstituted non-aromatic heterocyclic carbonyloxy. With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.
Substituents for “substituted alkyl”, “substituted alkenyl” and “substituted alkynyl” include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, carboxy, alkyloxy, alkenyloxy, alkynyloxy, alkylcarbonyl, Alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylsulfonyl, Alkenylsulfonyl, alkynylsulfonyl, carbamoyl, substituted carbamoyl, sulfamo , Substituted sulfamoyl, amino, substituted amino, non-aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, non-aromatic carbocyclic oxy, aromatic carbon Ring oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, non-aromatic carbocyclic carbonyl, aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, non-aromatic carbocyclic oxycarbonyl, Aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, non-aromatic carbocyclic carbonyloxy, aromatic carbocyclic carbonyloxy, aromatic heterocyclic carbonyloxy, non-aromatic heterocyclic carbonyl Oxy and the like are preferable. With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.
Substituents of “substituted non-aromatic carbocyclic group”, “substituted aromatic carbocyclic group”, “substituted aromatic heterocyclic group” or “substituted non-aromatic heterocyclic group” include halogen, cyano , Hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyl Oxy, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group A group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or Substituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylcarbonyl Substituted, unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl Substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocycle Oxycarbonyl, substituted or non-substituted Aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy Substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or Unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted nonaromatic carbocyclic thio, substituted or unsubstituted Aromatic carbocyclic thio, Substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted Substituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl Substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic ring Sulfonyl, substituted or Substituted aromatic heterocyclic sulfonyl, substituted or unsubstituted amino, sulfamoyl carbamoyl and substituted or unsubstituted substituted or unsubstituted. With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.
Substituents of “substituted non-aromatic carbocyclic group”, “substituted aromatic carbocyclic group”, “substituted aromatic heterocyclic group” or “substituted non-aromatic heterocyclic group” include halogen, hydroxy , Mercapto, nitro, nitroso, cyano, azide, formyl, carboxy, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl , Alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylsulfonyl Alkenylsulfonyl, alkynylsulfonyl, carbamoyl, carbamoyl, sulfamoyl, amino, non-aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, non-aromatic carbocyclic oxy , Aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, non-aromatic carbocyclic carbonyl, aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, non-aromatic carbon Ring oxycarbonyl, aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, non-aromatic carbocyclic carbonyloxy, aromatic carbocyclic carbonyloxy, aromatic heterocyclic carbonyloxy, non-aromatic Group heterocyclic carbonyloxy and the like are preferable. With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.

The substituents of “substituted amino”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted amidino” or “substituted imino” include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group Substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or Unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbon Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocycle Oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynyl Sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, unsubstituted aromatic heterocyclic sulfinyl, substituted or Unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted Non-aromatic heterocyclic sulfonyl, unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl and the like can be mentioned. One or two of these substituents may be substituted.
Substituents for “substituted amino”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted amidino” or “substituted imino” include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azido, formyl, carboxy, alkyl Alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylthio, alkenylthio , Alkynylthio, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylsulfonyl, alkenyl Sulfonyl, alkynylsulfonyl, carbamoyl, substituted carbamoyl, sulfamoyl, amino, non-aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, non-aromatic carbocyclic oxy , Aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, non-aromatic carbocyclic carbonyl, aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, non-aromatic carbon Ring oxycarbonyl, aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, non-aromatic carbocyclic carbonyloxy, aromatic carbocyclic carbonyloxy, aromatic heterocyclic carbonyloxy, non-aromatic Group heterocyclic carbonyloxy and the like are preferable. With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.

で示される化合物が挙げられる。
環Ａ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびｎの好ましい態様を以下に示す。下記の可能な組合せの化合物が好ましい。
環Ａは架橋を有していてもよい含窒素飽和複素環が挙げられる。
環Ａの好ましい態様としては、ピペラジン、ピペリジン、モルホリン、チオモルホリンが挙げられる。

で示される部分構造としては、

で示される部分構造が好ましく、

で示される部分構造が特に好ましい。 The compound of the present invention has the formula:

The compound shown by these is mentioned.
Preferred embodiments of ring A, R ¹ , R ² , R ³ , R ⁴ and n are shown below. The following possible combinations of compounds are preferred:
Ring A includes a nitrogen-containing saturated heterocyclic ring which may have a bridge.
Preferred embodiments of ring A include piperazine, piperidine, morpholine, and thiomorpholine.

As a partial structure shown by

A partial structure represented by

The partial structure represented by is particularly preferable.

（式中、
Ｘは単結合、Ｏ、Ｓ、ＮＲ^７Ａ、またはＣＲ^７ＢＲ^７Ｃであり、
Ｒ^７Ａは水素または置換もしくは非置換のアルキルであり、
Ｒ^７ＢまたはＲ^７Ｃはそれぞれ独立して、水素、ハロゲン、またはＲ^７ＢおよびＲ^７Ｃは一緒になってオキソを形成してもよく、
環Ｂはベンゼン、６員の芳香族複素環、６員の非芳香族炭素環または６員の非芳香族複素環であり、
Ｒ^５はハロゲン、ヒドロキシ、シアノ、ホルミル、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アミノ、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のカルバモイル、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ルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニルまたは置換若しくは非置換のアルキニルスルホニルであり、
Ｒ^６はそれぞれ独立して、ハロゲン、ヒドロキシ、シアノ、ホルミル、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アミノ、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のカルバモイル、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ルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニルまたは置換若しくは非置換のアルキニルスルホニルであり、
ｍは０〜４の整数である。）で示される基が挙げられる。
Ｘの好ましい態様としては、単結合、Ｏ、Ｓが挙げられる。
Ｘのさらに好ましい態様としては、単結合が挙げられる。
Ｒ^７Ａの好ましい態様としては、水素が挙げられる。
Ｒ^７ＢおよびＲ^７Ｃの好ましい態様としては、それぞれ独立して、水素またはハロゲンが挙げられる。
環Ｂの好ましい態様としては、ベンゼンまたは６員の芳香族複素環が挙げられる。
環Ｂのさらに好ましい態様としては、ベンゼン、ピリジン、ピリミジンまたはピラジンが挙げられる。
環Ｂの特に好ましい態様としては、ベンゼンが挙げられる。
Ｒ^５の好ましい態様としては、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キルオキシが挙げられる。
Ｒ^５のさらに好ましい態様としては、ハロゲン、シアノ、ハロゲンで置換されていてもよいアルキルまたはハロゲンで置換されていてもよいアルキルオキシが挙げられる。
Ｒ^５の特に好ましい態様としては、ハロゲン、シアノ、トリフルオロメチルまたはトリフルオロメチルオキシが挙げられる。
Ｒ^６の好ましい態様としては、それぞれ独立して、ハロゲン、ヒドロキシ、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ミノ、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のカルバモイル、置換若しくは非置換のスルファモイルまたは置換若しくは非置換のアルキルスルホニルが挙げられる。
Ｒ^６のさらに好ましい態様としては、それぞれ独立して、ハロゲン、シアノ、ヒドロキシアルキル、アルキルオキシアミノアルキルまたはアルキルオキシカルボニルアミノが挙げられる。
ｍの好ましい態様としては、０〜２の整数が挙げられる。
ｍのさらに好ましい態様としては、１が挙げられる。 R ² is the formula:

(Where
X is a single bond, O, S, NR ^7A , or CR ^7B R ^7C ;
R ^7A is hydrogen or substituted or unsubstituted alkyl;
R ^7B or R ^7C each independently represents hydrogen, halogen, or R ^7B and R ^7C together may form an oxo;
Ring B is benzene, a 6-membered aromatic heterocycle, a 6-membered non-aromatic carbocycle or a 6-membered non-aromatic heterocycle,
R ⁵ is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
Each R ⁶ is independently halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl Substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxy Xyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
m is an integer of 0-4. ).
Preferred examples of X include a single bond, O, and S.
A more preferred embodiment of X includes a single bond.
A preferred embodiment of R ^7A includes hydrogen.
As a preferable aspect of R ^7B and R ^7C , hydrogen or halogen can be mentioned independently.
Preferred embodiments of ring B include benzene or a 6-membered aromatic heterocyclic ring.
Further preferred embodiments of ring B include benzene, pyridine, pyrimidine or pyrazine.
A particularly preferred embodiment of ring B includes benzene.
Preferred embodiments of R ⁵ include halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy.
More preferable embodiments of R ⁵ include halogen, cyano, alkyl optionally substituted with halogen, or alkyloxy optionally substituted with halogen.
Particularly preferred embodiments of R ⁵ include halogen, cyano, trifluoromethyl or trifluoromethyloxy.
As preferred embodiments of R ⁶ , each independently represents halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylcarbonyl, substituted Or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or substituted or unsubstituted alkylsulfonyl.
Further preferred embodiments of R ⁶ include, independently, halogen, cyano, hydroxyalkyl, alkyloxyaminoalkyl or alkyloxycarbonylamino.
As a preferable aspect of m, the integer of 0-2 is mentioned.
As a more preferred embodiment of m, 1 is exemplified.

R ³ is halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy Substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Heterocyclic oxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl Substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic Heterocyclic carbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl Substituted or unsubstituted non-aromatic carbocyclic sulfinyl or substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl Substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or non-substituted Substituted carbamoyl or substituted or unsubstituted sulfamoyl.
Preferred embodiments of R ³ include halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted Non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl Substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted fragrance Aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl or substituted or unsubstituted aromatic Examples include aromatic heterocyclic sulfonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl.
Further preferred embodiments of R ³ include substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted alkyl Sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or And unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl. The
As another more preferable embodiment of R ³ , substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted aromatic heterocyclic alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Aromatic heterocyclic groups, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl.
Particularly preferred embodiments of R ³ include carboxy aromatic carbocyclic alkyl carbamoyl, carboxy non-aromatic carbocyclic carbamoyl, hydroxyalkyl carbamoyl or alkyl carbamoyl.

R ⁴ is halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy Substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Heterocyclic oxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl Substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic Heterocyclic carbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl Substituted or unsubstituted non-aromatic carbocyclic sulfinyl or substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl Substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or non-substituted Substituted carbamoyl or substituted or unsubstituted sulfamoyl.
Preferred embodiments of R ⁴ include halogen, cyano, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or non-substituted Substituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic Ring oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted Aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbon Rubonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl or substituted or unsubstituted non-substituted Aromatic heterocyclic sulfonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl.
More preferred embodiments of R ⁴ include haloalkyl, hydroxyalkyl or haloalkyloxyalkyl.

As for n, the integer of 0-4 is mentioned.
A preferable embodiment of n includes an integer of 0 to 1.
A more preferable embodiment of n includes 0.
1 is mentioned as another preferable aspect of n.

The following compound group is also a preferred embodiment.

  The compounds of the present invention are not limited to a specific isomer, but all possible isomers (eg, keto-enol isomer, imine-enamine isomer, geometric isomer, diastereoisomer, optical isomer, Rotamers 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. This method reacts a tritium gas with a precursor in which the compound of 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, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids Salts, 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, trifluoroacetic acid, Citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, Le 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.), a co-crystal and / or a crystal polymorph. Products, co-crystals and polymorphs are also included. 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. “Co-crystal” means that the compound or salt represented by the formula (I) and the counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules.

  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 invention that has a group that can be chemically or metabolically degraded and is a compound that becomes a pharmaceutically active compound of the invention in vivo by solvolysis or under physiological conditions. 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.

“Chronic kidney disease” refers to: (1) kidney disorders (urinary abnormalities such as proteinuria including microalbuminuria, abnormal urinary sediments, abnormal images such as single kidney and multiple cystic kidneys, increased serum creatinine level, etc. (2) GFR (glomerular filtration rate) is less than 60 mL / min / 1.73 m ² (reduced renal function, electrolyte abnormalities such as hypokemia due to tubular damage, abnormalities in histopathological examinations such as renal biopsy) In this case, one or both of the above-mentioned decrease in renal function lasts 3 months or more.

  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.

（式中、環Ａは架橋を有していてもよい含窒素飽和複素環であり、Ｒ^３はハロゲン、シアノ、ヒドロキシ、ホルミル、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芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族炭素環式基、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アルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換の芳香族炭素環カルボニル、置換若しくは非置換の芳香族複素環カルボニル、置換若しくは非置換の非芳香族炭素環カルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換若しくは非置換のアルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換の芳香族炭素環スルフィニル、置換若しくは非置換の芳香族複素環スルフィニル、置換若しくは非置換の非芳香族炭素環スルフィニルまたは置換若しくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換若しくは非置換の芳香族炭素環スルホニル、置換若しくは非置換の芳香族複素環スルホニル、置換若しくは非置換の非芳香族炭素環スルホニルまたは置換若しくは非置換の非芳香族複素環スルホニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルであり、
Ｒ^４は、ハロゲン、シアノ、ヒドロキシ、ホルミル、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芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族炭素環式基、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アルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の芳香族複素環オキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換の芳香族炭素環カルボニル、置換若しくは非置換の芳香族複素環カルボニル、置換若しくは非置換の非芳香族炭素環カルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換若しくは非置換のアルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換の芳香族炭素環スルフィニル、置換若しくは非置換の芳香族複素環スルフィニル、置換若しくは非置換の非芳香族炭素環スルフィニルまたは置換若しくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換若しくは非置換の芳香族炭素環スルホニル、置換若しくは非置換の芳香族複素環スルホニル、置換若しくは非置換の非芳香族炭素環スルホニルまたは置換若しくは非置換の非芳香族複素環スルホニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルであり、
ｎは０〜４の整数であり、Ｒ^１ａは置換もしくは非置換のアルキルである。）

化合物１ａを、トリアルキルオキソニウムテトラフルオロボレートと反応させることにより、化合物２ａを得ることができる。
反応溶媒としては、塩化メチレン、クロロホルム、ＴＨＦ、ジオキサン、水等が挙げられ、単独または混合して用いることができる。
トリアルキルオキソニウムテトラフルオロボレートとしては、トリメチルオキソニウムテトラフルオロボレート、トリエチルオキソニウムテトラフルオロボレート等が挙げられ、化合物１ａに対して、１〜１０当量、好ましくは１〜３当量用いることができる。
反応温度は、室温〜加熱還流下、好ましくは室温〜５０℃である。
反応時間は、１時間〜２４０時間、好ましくは１２時間〜２００時間である。 Process 1 Production method of compound 2a

(In the formula, ring A is a nitrogen-containing saturated heterocyclic ring which may have a bridge, and R ³ is halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-substituted Aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic hetero Ring oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted a Alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted nonaromatic carbon Ring carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, Substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted a Kenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic carbocyclic sulfonyl, substituted or unsubstituted A non-aromatic heterocyclic sulfonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl,
R ⁴ is halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy Substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Heterocyclic oxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl Substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic Heterocyclic carbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl Substituted or unsubstituted non-aromatic carbocyclic sulfinyl or substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl Substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or non-substituted Substituted carbamoyl or substituted or unsubstituted sulfamoyl,
n is an integer of 0 to 4, and R ^1a is a substituted or unsubstituted alkyl. )

Compound 2a can be obtained by reacting compound 1a with trialkyloxonium tetrafluoroborate.
Examples of the reaction solvent include methylene chloride, chloroform, THF, dioxane, water and the like, and these can be used alone or in combination.
Examples of the trialkyloxonium tetrafluoroborate include trimethyloxonium tetrafluoroborate, triethyloxonium tetrafluoroborate and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound 1a.
The reaction temperature is from room temperature to heating under reflux, preferably from room temperature to 50 ° C.
The reaction time is 1 hour to 240 hours, preferably 12 hours to 200 hours.

（式中の記号は上記と同意義である。）
化合物２ａを、塩化アンモニウムと反応させることにより、化合物３ａを得ることができる。
反応溶媒としては、エタノール、メタノール、ＤＭＦ等が挙げられ、単独または混合して用いることができる。
塩化アンモニウムは、化合物２ａに対して、１〜５当量、好ましくは１〜３当量用いることができる。
反応温度は、室温〜加熱還流下、好ましくは５０℃〜加熱還流下である。
反応時間は、１時間〜２４時間、好ましくは６時間〜１２時間である。 Process 2 Production method of compound 3a

(The symbols in the formula are as defined above.)
Compound 3a can be obtained by reacting compound 2a with ammonium chloride.
Examples of the reaction solvent include ethanol, methanol, DMF and the like, and these can be used alone or in combination.
Ammonium chloride can be used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound 2a.
The reaction temperature is room temperature to heating under reflux, preferably 50 ° C. to heating under reflux.
The reaction time is 1 to 24 hours, preferably 6 to 12 hours.

（式中、Ｒ^１は水素、ハロゲン、ヒドロキシ、ホルミル、置換も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非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、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芳香族複素環式基、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オキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の芳香族複素環オキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換の非芳香族炭素環チオ、置換若しくは非置換の芳香族炭素環チオ、置換若しくは非置換の非芳香族複素環チオ、置換若しくは非置換の芳香族複素環チオ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換の非芳香族炭素環カルボニル、置換若しくは非置換の芳香族炭素環カルボニル、置換若しくは非置換の非芳香族複素環カルボニル、置換若しくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換の非芳香族炭素環オキシカルボニル、置換若しくは非置換の芳香族炭素環オキシカルボニル、置換若しくは非置換の非芳香族複素環オキシカルボニル、置換若しくは非置換の芳香族複素環オキシカルボニル、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ルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換の非芳香族炭素環スルフィニル、置換若しくは非置換の芳香族炭素環スルフィニル、置換若しくは非置換の非芳香族複素環スルフィニル、置換若しくは非置換の芳香族複素環スルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニル、置換若しくは非置換のアルキニルスルホニル、置換若しくは非置換の非芳香族炭素環スルホニル、置換若しくは非置換の芳香族炭素環スルホニル、置換若しくは非置換の非芳香族複素環スルホニルまたは置換若しくは非置換の芳香族複素環スルホニルであり、Ｒ^２ａは置換もしくは非置換のアルキルであり、その他の記号は上記と同意義である。）
化合物３ａを、塩基存在下、化合物４ａと反応させることにより、化合物５ａを得ることができる。
塩基としては、トリエチルアミン、ｔｅｒｔ−ブトキシカリウム、ナトリウムメトキシド、ナトリウムエトキシド、炭酸カリウム、水素化ナトリウム等が挙げられ、化合物３ａに対して、１〜１０当量、好ましくは１．５〜５当量用いることができる。
化合物化４ａは、化合物３ａに対して、１〜５当量、好ましくは１〜２当量用いることができる。
反応温度は、室温〜加熱還流下、好ましくは５０℃〜加熱還流下である。
反応時間は、１時間〜２４時間、好ましくは６時間〜１２時間である。 Process 3 Production method of compound 5a

Wherein R ¹ is hydrogen, halogen, hydroxy, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted Or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic ring Oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenyl Nilthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted Aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbon Ring carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyl Oxycarbonyl, substituted or unsubstituted Non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted Aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted Unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, or substituted or unsubstituted aromatic heterocyclic Sulfonyl, R ^2a is substituted or unsubstituted alkyl, and other symbols are as defined above. )
Compound 5a can be obtained by reacting compound 3a with compound 4a in the presence of a base.
Examples of the base include triethylamine, tert-butoxypotassium, sodium methoxide, sodium ethoxide, potassium carbonate, sodium hydride and the like, and 1 to 10 equivalents, preferably 1.5 to 5 equivalents, are used with respect to compound 3a. be able to.
Compound 4a can be used in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound 3a.
The reaction temperature is room temperature to heating under reflux, preferably 50 ° C. to heating under reflux.
The reaction time is 1 to 24 hours, preferably 6 to 12 hours.

（式中、Ｒ^３ａはトリフラート等の脱離基、その他の記号は上記と同意義である。）
化合物５ａを、塩基存在下、スルホンアミド、スルホン酸無水物またはスルホニルクロリドと反応させることにより、化合物６ａを得ることができる。
反応溶媒としては、ＤＭＦ、塩化メチレン、ＴＨＦ等が挙げられ、単独または混合して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、炭酸カリウム等が挙げられ、化合物５ａに対して、１〜１０当量、好ましくは１〜２当量用いることができる。
スルホンアミド、スルホン酸無水物またはスルホニルクロリドとしては、1，1，1‐トリフルオロ‐Ｎ‐フェニル‐（（トリフルオロメチル）スルホニル）メタンスルホンアミド、無水トリフルオロメタンスルホン酸、トリフルオロメタンスルホン酸クロリド等が挙げられ、化合物５ａに対して、１〜５当量、好ましくは１〜２当量用いることができる。
反応温度は、０℃〜５０℃、好ましくは室温である。
反応時間は、０．１時間〜６時間、好ましくは０．５時間〜２時間である。 Process 4 Production method of compound 6a

(Wherein R ^3a is a leaving group such as triflate, and other symbols are as defined above.)
Compound 6a can be obtained by reacting compound 5a with sulfonamide, sulfonic anhydride or sulfonyl chloride in the presence of a base.
Examples of the reaction solvent include DMF, methylene chloride, THF and the like, and these can be used alone or in combination.
Examples of the base include triethylamine, pyridine, potassium carbonate and the like, and 1 to 10 equivalents, preferably 1 to 2 equivalents, can be used with respect to compound 5a.
Examples of sulfonamides, sulfonic anhydrides or sulfonyl chlorides include 1,1,1-trifluoro-N-phenyl-((trifluoromethyl) sulfonyl) methanesulfonamide, trifluoromethanesulfonic anhydride, trifluoromethanesulfonic acid chloride, etc. 1 to 5 equivalents, preferably 1 to 2 equivalents, can be used with respect to compound 5a.
The reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.
The reaction time is 0.1 to 6 hours, preferably 0.5 to 2 hours.

（式中、Ｒ^４aはそれぞれ独立してヒドロキシ、置換もしくは非置換のアルキルオキシまたは２つのＲ^４aが一緒になって置換もしくは非置換のアルキレンジオキシを形成してもよく、Ｒ^２は式：

（式中、
Ｘは単結合、Ｏ、Ｓ、ＮＲ^７Ａ、またはＣＲ^７ＢＲ^７Ｃであり、
Ｒ^７Ａは水素または置換もしくは非置換のアルキルであり、
Ｒ^７ＢまたはＲ^７Ｃはそれぞれ独立して、水素、ハロゲン、またはＲ^７ＢおよびＲ^７Ｃは一緒になってオキソを形成してもよく、
環Ｂはベンゼン、６員の芳香族複素環、６員の非芳香族炭素環または６員の非芳香族複素環であり、
Ｒ^５はハロゲン、ヒドロキシ、シアノ、ホルミル、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アミノ、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のカルバモイル、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ルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニルまたは置換若しくは非置換のアルキニルスルホニルであり、
Ｒ^６はそれぞれ独立して、ハロゲン、ヒドロキシ、シアノ、ホルミル、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アミノ、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニル、置換若しくは非置換のアルキニルカルボニル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のカルバモイル、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ルキルスルフィニル、置換若しくは非置換のアルケニルスルフィニル、置換若しくは非置換のアルキニルスルフィニル、置換若しくは非置換のアルキルスルホニル、置換若しくは非置換のアルケニルスルホニルまたは置換若しくは非置換のアルキニルスルホニルであり、
ｍは０〜４の整数であり、その他の記号は上記と同意義である。）
化合物６ａを、金属触媒および塩基存在下、化合物７ａと反応させることにより、化合物８ａを得ることができる。
反応溶媒としては、ＤＭＦ、ＴＨＦ、トルエン、メタノール、エタノール、ジオキサン等が挙げられ、単独または混合して用いることができる。
塩基としては、炭酸ナトリウム、炭酸セシウム、炭酸カリウム、水酸化ナトリウム、リン酸カリウム、ｔｅｒｔ−ブトキシカリウム等が挙げられ、化合物６aに対して１〜１０当量、好ましくは１〜３当量用いることができる。
化合物７ａは、化合物６ａに対して、１〜１０当量、好ましくは１〜３当量用いることができる。
金属触媒としては、１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロリド−ジクロロメタン錯体、クロロ（２−ジシクロヘキシルホスフィノ−２’，４’，６’−トリイソプロピル−１，１’−ビフェニル）［２−（２’−アミノ−１，１’−ビフェニル）］パラジウム（ＩＩ）、テトラキス（トリフェニルホスフィン）パラジウム等が挙げられ、化合物６ａに対して、０．０１〜１当量、好ましくは０．０５〜０．２当量用いることができる。
反応温度は、５０〜２００℃、好ましくは５０〜１５０℃である。場合によってはマイクロウェーブ照射下の温度で行ってもよい。
反応時間は、０．１時間〜１２時間、好ましくは０．１時間〜６時間である。 Process 5 Production method of compound 8a

Wherein R ^4a is independently hydroxy, substituted or unsubstituted alkyloxy, or two R ^4a together can form a substituted or unsubstituted alkylenedioxy, wherein R ² has the formula:

(Where
X is a single bond, O, S, NR ^7A , or CR ^7B R ^7C ;
R ^7A is hydrogen or substituted or unsubstituted alkyl;
R ^7B or R ^7C each independently represents hydrogen, halogen, or R ^7B and R ^7C together may form an oxo;
Ring B is benzene, a 6-membered aromatic heterocycle, a 6-membered non-aromatic carbocycle or a 6-membered non-aromatic heterocycle,
R ⁵ is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
Each R ⁶ is independently halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl Substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxy Xyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
m is an integer of 0 to 4, and other symbols are as defined above. )
Compound 8a can be obtained by reacting compound 6a with compound 7a in the presence of a metal catalyst and a base.
Examples of the reaction solvent include DMF, THF, toluene, methanol, ethanol, dioxane and the like, and these can be used alone or in combination.
Examples of the base include sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, potassium phosphate, tert-butoxypotassium and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound 6a. .
Compound 7a can be used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to Compound 6a.
Examples of the metal catalyst include 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, chloro (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1. '-Biphenyl) [2- (2'-amino-1,1'-biphenyl)] palladium (II), tetrakis (triphenylphosphine) palladium and the like, and 0.01 to 1 equivalent to compound 6a , Preferably 0.05 to 0.2 equivalents can be used.
The reaction temperature is 50 to 200 ° C, preferably 50 to 150 ° C. In some cases, it may be performed at a temperature under microwave irradiation.
The reaction time is 0.1 hour to 12 hours, preferably 0.1 hour to 6 hours.

（式中、Ｒ^９はクロロ、ブロモ等のハロゲン、メシル、トシル等の脱離基、その他の記号は上記と同意義である。）
化合物９ａを、還元剤と反応させることにより、化合物１０ａを得ることができる。
反応溶媒としては、エタノール、メタノール、酢酸エチル、ＴＨＦ、ジクロロメタン等が挙げられ、単独または混合して用いることができる。
還元剤としては、塩化スズ、鉄、パラジウム−炭素等が挙げられ、化合物９ａに対して、０．０１〜１０当量、好ましくは０．０５〜５当量用いることができる。
反応温度は、氷冷下〜加熱還流下、好ましくは室温〜加熱還流下である。
反応時間は、０．１時間〜２４時間、好ましくは０．５時間〜６時間である。 Process 6 Production method of compound 10a

(Wherein R ⁹ is a halogen such as chloro and bromo, a leaving group such as mesyl and tosyl, and other symbols are as defined above.)
Compound 10a can be obtained by reacting compound 9a with a reducing agent.
Examples of the reaction solvent include ethanol, methanol, ethyl acetate, THF, dichloromethane and the like, and these can be used alone or in combination.
Examples of the reducing agent include tin chloride, iron, palladium-carbon, and the like, and 0.01 to 10 equivalents, preferably 0.05 to 5 equivalents, can be used with respect to compound 9a.
The reaction temperature is from ice cooling to heating under reflux, preferably from room temperature to heating under reflux.
The reaction time is 0.1 hour to 24 hours, preferably 0.5 hour to 6 hours.

（式中、Ｒ^１０は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基または置換もしくは非置換の非芳香族複素環式基、その他の記号は上記と同意義である。）
化合物１０ａを、塩基存在下、ハロゲン化アシルと反応させることにより、化合物ｂ２６を得ることができる。
反応溶媒としては、ピリジン、ジクロロメタン、ＴＨＦ、酢酸エチル等が挙げられ、単独または混合して用いることができる。
塩基としては、水素化ナトリウム、水酸化ナトリウム、炭酸カリウム等が挙げられ、化合物１０ａに対して、１〜５当量、好ましくは１〜３当量用いることができる。
反応温度は、氷冷下〜加熱還流下、好ましくは室温〜加熱還流下である。
反応時間は、０．１時間〜１２時間、好ましくは０．５時間〜３時間である。 Compound 11a production method

Wherein R ¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocycle A formula group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, and other symbols are as defined above.)
Compound b26 can be obtained by reacting compound 10a with an acyl halide in the presence of a base.
Examples of the reaction solvent include pyridine, dichloromethane, THF, ethyl acetate and the like, and these can be used alone or in combination.
Examples of the base include sodium hydride, sodium hydroxide, potassium carbonate and the like, and 1 to 5 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound 10a.
The reaction temperature is from ice cooling to heating under reflux, preferably from room temperature to heating under reflux.
The reaction time is 0.1 hour to 12 hours, preferably 0.5 hour to 3 hours.

  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 may be gradually lowered and the precipitated solid or crystals may be collected by filtration.

The compound according to the present invention has autotaxin inhibitory activity. Therefore, the pharmaceutical composition containing the compound according to the present invention is useful as a therapeutic and / or prophylactic agent for diseases involving autotaxin. Examples of diseases involving autotaxin include chronic kidney disease, urinary excretion disorder, chronic kidney disease or renal fibrosis, interstitial pneumonia or lung fibrosis, scleroderma, pain, fibromyalgia, rheumatoid arthritis, Angiogenesis, cancer, tumor formation, growth and spread, arteriosclerosis, eye disease, choroidal neovascularization and diabetic retinopathy, inflammatory disease, arthritis, neurodegeneration, restenosis, wound healing or graft rejection or in utero Examples include membrane disease. More preferred are urinary drainage disorder, interstitial pneumonia or pulmonary fibrosis, renal fibrosis, liver fibrosis, scleroderma, pain, fibromyalgia, chronic obstructive pulmonary disease or rheumatoid arthritis and the like. The pharmaceutical composition containing the compound according to the present invention is useful as a therapeutic and / or prophylactic agent for these diseases.
The compound of the present invention has not only autotaxin inhibitory activity but also usefulness as a pharmaceutical, and may have any or all of the following excellent characteristics.
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 ENPP1, 3-7 receptors and may have high ENPP2 receptor selectivity.

  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.

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

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

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

  EXAMPLES The present invention will be described in more detail below with reference to examples and test examples of the present invention, but the present invention is not limited thereto.

Moreover, the abbreviation used in this specification represents the following meaning.
Me: methyl Et: ethyl Bu: butyl Ph: phenyl _PPh 3, TPP: triphenylphosphine AcOEt: ethyl acetate DMF: N, N-dimethylformamide TFA: trifluoroacetic acid DMSO: dimethylsulfoxide THF: Tetrahydrofuran DIEA, Hunig's Base : N, N-diisopropylethylamine TBAF: tetrabutylammonium fluoride SEM: 2- (trimethylsilyl) ethoxymethyl OAc: acetate group mCPBA: metachloroperbenzoic acid NMP: 1-methylpyrrolidin-2-one LAH: lithium aluminum hydride DBU : 1,8-diazabicyclo [5.4.0] undec-7-ene DCM: methylene chloride TEA: triethylamine TMS: tetramethylsilane HATU: O- (7-azaben Zotriazol-1-yl) -N, N, N ′, N ′,-tetramethyluronium hexafluorophosphate DPPA: diphenyl phosphate azide

The NMR analysis obtained in each example was carried out at 400 MHz and measured using deuterated dimethyl sulfoxide (d ₆ -DMSO) or deuterated chloroform (CDCl ₃ ).
LC / MS was measured under the following conditions.

(Method A)
Column: ACQUITY UPLC BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 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: A linear gradient of 5% -100% solvent [B] is performed in 3.5 minutes 100% solvent [B] was maintained for 0.5 minutes.
(Method B)
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, 100% solvent [B] was maintained for 5 minutes.

化合物１（３．０４ｇ，１９．３ｍｍｏｌ）の塩化メチレン（３０ｍＬ）溶液に、１ｍｏｌ／Ｌトリエチルオキソニウムテトラフルオロボレートの塩化メチレン溶液（２９ｍＬ、２９．０ｍｍｏｌ）を加え、室温で７日間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液加え抽出した。有機層を無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）で精製することにより、化合物２（２．０ｇ，収率：５６％）を淡黄色油状物として得た。
¹H-NMR (CDCl₃) δ: 4.52 (1H, t, J = 7.0 Hz), 4.28-4.23 (4H, m), 2.65-2.57 (1H, m), 2.50-2.46 (1H, m), 2.36-2.27 (1H, m), 2.17-2.12 (1H, m), 1.34-1.27 (6H, m). Example 1 First Step of Synthesis of Compound I-002 Production Method of Compound 2

To a solution of compound 1 (3.04 g, 19.3 mmol) in methylene chloride (30 mL) was added 1 mol / L triethyloxonium tetrafluoroborate in methylene chloride (29 mL, 29.0 mmol), and the mixture was stirred at room temperature for 7 days. The reaction solution was extracted with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give compound 2 (2.0 g, yield: 56%) as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 4.52 (1H, t, J = 7.0 Hz), 4.28-4.23 (4H, m), 2.65-2.57 (1H, m), 2.50-2.46 (1H, m), 2.36 -2.27 (1H, m), 2.17-2.12 (1H, m), 1.34-1.27 (6H, m).

化合物２（２．０ｇ，１０．７８ｍｍｏｌ）のエタノール（２０ｍＬ）溶液に、塩化アンモニウム（０．７５ｇ，１４．０１ｍｍｏｌ）を加え、１２時間加熱還流した。反応液を減圧濃縮することにより、化合物３の粗生成物を得た。
Second Step: Method for Producing Compound 3

To a solution of compound 2 (2.0 g, 10.78 mmol) in ethanol (20 mL) was added ammonium chloride (0.75 g, 14.01 mmol), and the mixture was heated to reflux for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product of compound 3.

化合物３の１，４‐ジオキサン（４０ｍＬ）溶液に、トリエチルアミン（３．７４ｍＬ，２７ｍｍｏｌ）およびエチル３‐クロロ‐３‐オキソプロピオネート（１．３６ｍＬ，１０．７８ｍｍｏｌ）を加え、８０℃で１時間３０分攪拌した。反応液を減圧濃縮することにより、化合物４の粗生成物（１５．８３ｇ）を得た。
Step 3 Production Method of Compound 4

To a solution of compound 3 in 1,4-dioxane (40 mL) was added triethylamine (3.74 mL, 27 mmol) and ethyl 3-chloro-3-oxopropionate (1.36 mL, 10.78 mmol). Stir for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain a crude product of compound 4 (15.83 g).

化合物４（５．６ｇ，１０．４２ｍｍｏｌ）のＤＭＦ（１００ｍＬ）溶液に、トリエチルアミン（１．７３ｍＬ，１２．５ｍｍｏｌ）および１，１，１−トリフルオロ−Ｎ−フェニル−（（トリフルオロメチル）スルホニル）メタンスルホンアミド（４．０１ｇ，１１．４６ ｍｍｏｌ）を加え、室温で２時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）で精製することにより、化合物５（６５４ｍｇ，収率：１８％）を黄色油状物として得た。
LC-MS: m/z=357. [M+H]⁺ メソッド Ａ, 1.98 min
Step 4 Production Method of Compound 5

To a solution of compound 4 (5.6 g, 10.42 mmol) in DMF (100 mL) was added triethylamine (1.73 mL, 12.5 mmol) and 1,1,1-trifluoro-N-phenyl-((trifluoromethyl) sulfonyl. ) Methanesulfonamide (4.01 g, 11.46 mmol) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give Compound 5 (654 mg, yield: 18%) as a yellow oil.
LC-MS: m / z = 357. [M + H] ⁺ method A, 1.98 min

化合物５（６５４ｍｇ，１．８４ｍｍｏｌ）のＤＭＦ（６ｍＬ）溶液に、３−アミノ−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ベンゾニトリル（６７２ｍｇ，２．７５ｍｍｏｌ）、ＰｄＣｌ２（ｄｐｐｆ）ジクロロメタン錯体（３８１ｍｇ，０．５３５ｍｍｏｌ）および２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（１．８４ｍＬ，３．６７ｍｍｏｌ）を加え、６０℃で８０分間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥して減圧濃縮することにより、化合物６の粗生成物（５４０．４ｍｇ）を得た。
LC-MS: m/z=325. [M+H]⁺ メソッド Ａ, 1.56 min
Step 5: Method for producing compound 6

To a solution of compound 5 (654 mg, 1.84 mmol) in DMF (6 mL), 3-amino-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile ( 672 mg, 2.75 mmol), PdCl 2 (dppf) dichloromethane complex (381 mg, 0.535 mmol) and 2 mol / L aqueous sodium carbonate solution (1.84 mL, 3.67 mmol) were added, and the mixture was stirred at 60 ° C. for 80 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of compound 6 (540.4 mg).
LC-MS: m / z = 325. [M + H] ⁺ method A, 1.56 min

化合物６（５４０．４ｍｇ，１．６７ｍｍｏｌ）のジクロロメタン（５ｍＬ）溶液に、氷冷下、ピリジン（０．２７ｍＬ，３．３３ｍｍｏｌ）およびクロロギ酸メチル（０．１９３ｍＬ，２．５０ｍｍｏｌ）を加え、１時間攪拌した。反応液にメタノールを加え減圧濃縮した後、得られた残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）で精製することにより、化合物７（１１８ｍｇ，収率：１９％）を淡黄色アモルファスとして得た。
LC-MS: m/z=383. [M+H]⁺ メソッド Ａ, 1.76 min

第７工程 化合物８の製造方法

化合物７（１１８ｍｇ，０．３１ｍｍｏｌ）のメタノール（１ｍＬ）／テトラヒドロフラン（１ｍＬ）混合溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１．００ｍＬ，２．００ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液に２ｍｏｌ／Ｌ塩酸水溶液を加えｐＨ３とした後、減圧濃縮し、残渣に水を加え酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥して減圧濃縮することにより、化合物８（１０３．５ｍｇ，収率：９５％）を淡褐色アモルファスとして得た。
LC-MS: m/z=355. [M+H]⁺ メソッド Ａ, 1.42 min

第８工程 化合物９の製造方法

化合物８（２１ｍｇ，０．０５９ｍｍｏｌ）のＤＭＦ（２００μＬ）溶液に、トリエチルアミン（２４．７μＬ，０．１７８ｍｍｏｌ）、２‐メチルプロパン‐２‐アミン（８．１μＬ，０．０７７ｍｍｏｌ）およびＨＡＴＵ（２９．３ｍｇ，０．０７７ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）で精製することにより、化合物９（１３．２ｍｇ，収率：５４％）を黄色アモルファスとして得た。
LC-MS: m/z=410. [M+H]⁺ メソッド Ａ, 1.74 min
¹H-NMR (CDCl₃) δ: 10.55 (1H, s), 8.64 (1H, s), 7.58 (1H, d, J = 8.2 Hz), 7.35 (1H, dd, J = 8.2, 1.6 Hz), 6.76 (1H, s), 6.62 (1H, s), 5.02 (1H, d, J = 7.8 Hz), 3.79 (3H, s), 3.60-3.50 (1H, m), 3.15-3.10 (1H, m), 2.74-2.71 (1H, m), 2.45-2.34 (1H, m), 1.36 (9H, s).

本化合物の物理恒数を以下に示す。ＲＴは保持時間（分）、ＭＳは［Ｍ＋Ｈ］^＋を示す。 Step 6: Method for producing compound 7

Pyridine (0.27 mL, 3.33 mmol) and methyl chloroformate (0.193 mL, 2.50 mmol) were added to a solution of compound 6 (540.4 mg, 1.67 mmol) in dichloromethane (5 mL) under ice cooling. Stir for hours. Methanol was added to the reaction mixture and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane / ethyl acetate) to give Compound 7 (118 mg, yield: 19%) as a pale yellow amorphous product.
LC-MS: m / z = 383. [M + H] ⁺ method A, 1.76 min

Step 7: Method for producing compound 8

To a mixed solution of compound 7 (118 mg, 0.31 mmol) in methanol (1 mL) / tetrahydrofuran (1 mL) was added 2 mol / L aqueous sodium hydroxide solution (1.00 mL, 2.00 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 3 by adding a 2 mol / L hydrochloric acid aqueous solution and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Compound 8 (103.5 mg, yield: 95%) as a light brown amorphous.
LC-MS: m / z = 355. [M + H] ⁺ method A, 1.42 min

Step 8: Method for producing compound 9

To a solution of compound 8 (21 mg, 0.059 mmol) in DMF (200 μL), triethylamine (24.7 μL, 0.178 mmol), 2-methylpropan-2-amine (8.1 μL, 0.077 mmol) and HATU (29. 3 mg, 0.077 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give Compound 9 (13.2 mg, yield: 54%) as a yellow amorphous.
LC-MS: m / z = 410. [M + H] ⁺ method A, 1.74 min
¹ H-NMR (CDCl ₃ ) δ: 10.55 (1H, s), 8.64 (1H, s), 7.58 (1H, d, J = 8.2 Hz), 7.35 (1H, dd, J = 8.2, 1.6 Hz), 6.76 (1H, s), 6.62 (1H, s), 5.02 (1H, d, J = 7.8 Hz), 3.79 (3H, s), 3.60-3.50 (1H, m), 3.15-3.10 (1H, m) , 2.74-2.71 (1H, m), 2.45-2.34 (1H, m), 1.36 (9H, s).

The physical constants of this compound are shown below. RT indicates retention time (minutes), and MS indicates [M + H] ⁺ .

ＬＣ−ＭＳ： ｍ／ｚ＝４１０． ［Ｍ＋Ｈ］^＋ メソッド Ｂ， １．６５ ｍｉｎ

化合物Ｉ−００２

ＬＣ−ＭＳ： ｍ／ｚ＝４１０． ［Ｍ＋Ｈ］^＋ メソッド Ａ， １．７４ ｍｉｎ

化合物Ｉ−００３

ＬＣ−ＭＳ： ｍ／ｚ＝４２６． ［Ｍ＋Ｈ］^＋ メソッド Ａ， １．３９ ｍｉｎ

化合物Ｉ−００４

ＬＣ−ＭＳ： ｍ／ｚ＝４８８． ［Ｍ＋Ｈ］^＋ メソッド Ａ， １．６４ ｍｉｎ

化合物Ｉ−００５

ＬＣ−ＭＳ： ｍ／ｚ＝５０６． ［Ｍ＋Ｈ］^＋ メソッド Ａ， １．６３ ｍｉｎ

化合物Ｉ−００６

ＬＣ−ＭＳ： ｍ／ｚ＝４８８． ［Ｍ＋Ｈ］^＋ メソッド Ｂ， １．４３ ｍｉｎ

化合物Ｉ−００７

ＬＣ−ＭＳ： ｍ／ｚ＝５０６． ［Ｍ＋Ｈ］^＋ メソッド Ｂ， １．４５ ｍｉｎ

化合物Ｉ−００８

ＬＣ−ＭＳ： ｍ／ｚ＝４１０． ［Ｍ＋Ｈ］^＋ メソッド Ｂ， １．６４ ｍｉｎ

化合物Ｉ−００９

ＬＣ−ＭＳ： ｍ／ｚ＝４２６． ［Ｍ＋Ｈ］^＋ メソッド Ｂ， １．２３ ｍｉｎ

化合物Ｉ−０１０

ＬＣ−ＭＳ： ｍ／ｚ＝４８４． ［Ｍ＋Ｈ］^＋ メソッド Ｂ， １．３３ ｍｉｎ
Compound I-001

LC-MS: m / z = 410. [M + H] ⁺ method B, 1.65 min

Compound I-002

LC-MS: m / z = 410. [M + H] ⁺ method A, 1.74 min

Compound I-003

LC-MS: m / z = 426. [M + H] ⁺ method A, 1.39 min

Compound I-004

LC-MS: m / z = 488. [M + H] ⁺ method A, 1.64 min

Compound I-005

LC-MS: m / z = 506. [M + H] ⁺ method A, 1.63 min

Compound I-006

LC-MS: m / z = 488. [M + H] ⁺ method B, 1.43 min

Compound I-007

LC-MS: m / z = 506. [M + H] ⁺ method B, 1.45 min

Compound I-008

LC-MS: m / z = 410. [M + H] ⁺ method B, 1.64 min

Compound I-009

LC-MS: m / z = 426. [M + H] ⁺ method B, 1.23 min

Compound I-010

LC-MS: m / z = 484. [M + H] ⁺ method B, 1.33 min

Test Example 1 Evaluation of autotaxin inhibitor
A solution A consisting of 25 mM Tris-HCl buffer (pH 7.5), 100 mM NaCl, 5 mM MgCl ₂ , and 0.1% BSA was prepared. 5 μl) is added. Further, 5 μl of 0.5 μM TG-mTMP diluted with Solution A is added and reacted at room temperature for 2 hours. After completion of the reaction, 5 μl of 150 mM EDTA diluted with solution A is added to the reaction solution to stop the reaction, and the fluorescent dye TokyoGreen produced by the reaction is detected.
For the detection of TokyoGreen, a measurement instrument ViewLux (manufactured by PerkinElmer) is used, and fluorescence is measured under conditions of excitation wavelength 480 nm / fluorescence wavelength 540 nm.
A concentration-dependent curve is prepared by plotting the inhibition rate at each concentration of the compound, assuming that the value when no compound is contained is 0% inhibition and the value when no enzyme is added is 100% inhibition. The compound concentration showing 50% inhibition is taken as the IC50 value.

Test Example 2 Evaluation of autotaxin inhibitor
A solution B composed of 100 mM Tris-HCl buffer (pH 7.5), 150 mM NaCl, 5 mM MgCl ₂ , 0.05% Triton X-100 was prepared, and a human autotaxin enzyme ( 2.5 μl of R & D systems) was added. Further, 200 μM 18: 0 Lyso PC diluted by solution B (manufactured by Avanti Polar Lipids) was added by 2.5 μl and reacted at room temperature for 2 hours. After completion of the reaction, 100 mM Tris-HCl buffer (pH 7.5), 5 mM MgCl ₂ , 77 μg / ml choline oxidase, 10 μg / ml peroxidase, 25 μM 10-acetyl-3,7-dihydroxyphenoxazine, excess autotaxin inhibitor 15 μl of a choline assay reagent consisting of was added and reacted at room temperature for 20 minutes. The fluorescent dye resorufin produced by the reaction was detected.
For the detection of resorufin, a measuring instrument ViewLux (manufactured by PerkinElmer) was used, and fluorescence was measured under conditions of excitation wavelength 531 nm / fluorescence wavelength 598 nm.
A concentration-dependent curve was prepared by plotting the inhibition rate at each concentration of the compound, assuming that the value when no compound was contained was 0% inhibition and the value when no enzyme was added was 100% inhibition. The compound concentration showing 50% inhibition was defined as the IC50 value.
About this invention compound, the result obtained by the test method described in the said Test example 2 is shown in the following tables.
Enzyme inhibitory activity:
A: IC50 <10 nM, B: 10 nM ≦ IC50 <100 nM, C: 100 nM ≦ IC50 <1000 nM, D: 1000 nM ≦ IC50

I-001: D
I-002: B
I-003: B
I-004: B
I-005: B

Test Example 3 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human 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 compound 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 compound are added in the above composition in 50 mM Hepes buffer solution, 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 system (100%) was obtained by adding only DMSO, which is the solvent in which the test compound was dissolved, to the reaction system, and calculated the residual activity (%) at each concentration with the test compound solution added. Using the rate, IC ₅₀ was calculated by inverse estimation with a logistic model.

Test Example 4 Metabolic Stability Evaluation 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 Tris-HCl buffer (pH 7.4) / Ml) and a test 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 the values of 0 minute and 30 minutes, and the metabolic stability of the compound of the present invention was confirmed.

Test Example 5 Powder Solubility Test An appropriate amount of specimen is placed in an appropriate 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 (pH 6.8 phosphorus) 200 mL of water is added to 500 mL of an acid buffer, and 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (water is added to 1.08 g of TCA to make 100 mL). If dissolved after adding the test solution, add bulk powder as appropriate. Seal and shake at 37 ° C. for 1 hour. Filter, add 100 μL of methanol to 100 μL of each filtrate and dilute 2 times. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. Quantification is performed using HPLC by the absolute calibration curve method.

Test Example 6 DMSO Method Solubility Test The solubility of the compound of the present invention was determined under the condition of addition of 1% DMSO. A 10 mmol / L compound solution was prepared in DMSO, and 2 μL of the compound solution of the present invention was added to 198 uL of JP-1 solution or JP-2 solution. After allowing to stand at 25 ° C. for 16 hours, the mixed solution was subjected to suction filtration. The filtrate was diluted 10-fold with methanol / water = 1/1 (V / V), and the concentration in the filtrate was measured using LC / MS by the absolute calibration curve method.

Test Example 7 BA Test Oral Absorbability Examination Materials and Methods (1) Animals used: Mice or SD rats are used.
(2) Breeding conditions: Mice or SD rats are allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral administration and intravenous administration are administered at a predetermined dosage. Set the group as follows. (Dose may vary for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization.
(5) Administration method: Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention is calculated from the AUC of the group.

Test Example 8 Metabolic Stability Test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree to which the compound of the present invention is metabolized in the liver cirrhosis. .
In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH React at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution is added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant is quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction is calculated with the compound amount at 0 minute reaction as 100%. The hydrolysis reaction is carried out in the absence of NADPH, the glucuronic acid conjugation reaction is carried out in the presence of 5 mmol / L UDP-glucuronic acid instead of NADPH, and the same operation is carried out thereafter.

Test Example 9 CYP3A4 Fluorescence MBI Test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).
The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate. A part of the solution was transferred so as to be diluted to 1/10, and NADPH as a coenzyme was added to start a reaction as an index (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L Tris The reaction is stopped by adding (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, is measured using a fluorescent plate reader on the plate on which each index reaction has been performed. (Ex = 420nm, Em = 535nm)
A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated. Is used to calculate IC ₅₀ by inverse estimation using a logistic model. A case where the difference in IC ₅₀ values is 5 μmol / L or more is (+), and a case where the difference is 3 μmol / L or less is (−).

Test Example 10: Fluctuation Ames Test
The mutagenicity of the compound of the present invention is evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which has been cryopreserved, is inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For TA98 strain, 9 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. 9 mL of Micro F buffer (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: 0. MicroF containing 110 mL Exposure medium (Biotin: 8 μg / mL, Histidine: 0.2 μg / mL, Glucose: 8 mg / mL) suspended in 25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L) Buffer). The TA100 strain is added to 120 mL of Exposure medium with respect to the 3.16 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as negative control, and non-metabolic activation condition as a positive control. Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (under metabolic activation conditions, 498 μL of the test bacterial solution and S9 mix 90 μL of the mixture) and incubate with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer solution containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL each and dispense into 48 wells / dose of the microplate, followed by static culture at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation is made in comparison with the negative control group. Negative mutagenicity is (-) and positive mutagenicity is (+).

Test Example 11 hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, HEK293 cells expressing a human ether-a-go-related gene (hERG) channel are used, and are important for ventricular repolarization process. Consider the action of the compounds of the present invention on the delayed rectifier K ⁺ current (I _Kr ) that plays a role.
Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.) and holding the cells at a membrane potential of −80 mV by whole cell patch clamp method, a +40 mV depolarization stimulus was applied for 2 seconds, followed by a −50 mV repolarization. Record the I _Kr elicited when the stimulus is applied for 2 seconds. After the generated current is stabilized, an extracellular fluid (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH ₂ PO ₄ : 0.3 mmol / L, in which the compound of the present invention is dissolved at a target concentration, CaCl ₂ · 2H ₂ O: 1.8 mmol / L, MgCl ₂ · 6H ₂ O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid, 4- (2- Hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) is applied to the cells for 10 minutes at room temperature. From the obtained I _Kr , the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 1, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I _Kr is evaluated.

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
The above ingredients are uniformly mixed to form a powder as a powder or fine granules. 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
The above ingredients are mixed well, compression molded, pulverized, sized, and sieved to give granules of appropriate size.

  The present invention can be used in the field of pharmaceuticals, for example, in the field of development and production of therapeutic agents for fibrotic diseases and the like.

Claims (11)

Formula (I):

(Where
Ring A is a nitrogen-containing saturated heterocyclic ring which may have a bridge,
R ¹ is hydrogen, halogen, cyano, hydroxy, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or An unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted amino, a substituted or unsubstituted alkyloxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy Substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted al Kenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted Aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbon Ring carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyl Oxycarbonyl, substituted or non-substituted Non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted Aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted Is substituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, or substituted or unsubstituted aromatic heterocyclic A ring sulfonyl,
R ² is the formula:

(Where
X is a single bond, O, S, NR ^7A , or CR ^7B R ^7C ;
R ^7A is hydrogen or substituted or unsubstituted alkyl;
R ^7B and R ^7C are each independently hydrogen, halogen, or R ^7B and R ^7C may together form an oxo,
Ring B is benzene, a 6-membered aromatic heterocycle, a 6-membered non-aromatic carbocycle or a 6-membered non-aromatic heterocycle,
R ⁵ is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
Each R ⁶ is independently halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl Substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxy Xyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
m is an integer of 0-4. )
R ³ is halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy Substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Heterocyclic oxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl Substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic Heterocyclic carbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl Substituted or unsubstituted non-aromatic carbocyclic sulfinyl or substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl Substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or non-substituted Substituted carbamoyl or substituted or unsubstituted sulfamoyl,
Each R ⁴ is independently halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group; Substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or non-substituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or non-substituted Substituted non-aromatic heterocyclic oxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted al Kenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted Non-aromatic heterocyclic carbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic Heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl or substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted a Quinylsulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted nonaromatic carbocyclic sulfonyl, or substituted or unsubstituted nonaromatic heterocyclic sulfonyl, Substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl,
n is an integer of 0 to 4) (excluding the following compounds (i) to (iii)),
(I)

The partial structure indicated by

A compound in which R ¹ is cyano, X is a single bond, and ring B is benzene,
(Ii)

The partial structure indicated by

Wherein R ¹ is hydrogen, X is a single bond, ring B is benzene, and R ³ is substituted pyrimidyl, and (iii) compounds shown below

Or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein R ¹ is hydrogen, or a pharmaceutically acceptable salt thereof. X is a single bond,
The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring B is benzene or a 6-membered aromatic heterocyclic ring. The compound according to claim 3, wherein Ring B is benzene, or a pharmaceutically acceptable salt thereof. R ² is the group shown below:

Wherein ring B is benzene, pyridine, pyrimidine or pyrazine.
R ⁵ is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
R ⁶ is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, Substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted Alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
Each R ^{6 ′} is independently halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted Substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkyl Carbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyl Xyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein p is an integer of 0 to 3. R ⁵ is halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy,
R ⁶ is halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino or substituted or unsubstituted alkyloxy,
^6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein each R ^{6 ′} is independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino, or substituted or unsubstituted alkyloxy. salt.

The partial structure indicated by

The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

The partial structure indicated by

(The symbols in the formula are as defined above.)
The compound according to claim 7, or a pharmaceutically acceptable salt thereof. R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or non-substituted Substituted non-aromatic heterocyclic group, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocycle 9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, which is carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted amino or substituted or unsubstituted carbamoyl. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 10, which is an autotaxin inhibitor.