JP2016164154A - Condensed pyrazole derivative unsubstituted at 7-position with inhibitory activity on autotaxin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for treating or preventing diseases related to autotaxin that is characterized by administrating a compound having an inhibitory action on autotaxin.SOLUTION: A compound represented by formula (I), pharmaceuticals comprising the compound as an active ingredient and a method for treating or preventing diseases related to autotaxin by administrating the compound are provided. (Ris a 4- to 6-membered aromatic carbocyclic group having a substituent; R, R, Rand Rare each independently H, a substituted/unsubstituted alkyl, a substituted/unsubstituted alkenyl, a substituted/unsubstituted alkynyl, a substituted/unsubstituted nonaromatic carbocyclic group, a substituted/unsubstituted aromatic carbocyclic group, a substituted/unsubstituted nonaromatic heterocyclic group or a substituted/unsubstituted aromatic heterocyclic group, or the like)SELECTED DRAWING: None

Description

  The present invention relates to a 7-position unsubstituted condensed pyrazole derivative having autotaxin inhibitory activity and a pharmaceutical comprising the 7-position unsubstituted condensed pyrazole 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. G protein-coupled receptors ( Information is transmitted through 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 through a common mechanism, regardless of the type of trigger.
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.

  As prevention and treatment methods for chronic kidney disease, in addition to lifestyle guidance and dietary guidance, treatment with antihypertensive therapies such as angiotensin receptor antagonists and calcium antagonists is performed. 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 Documents 1 to 3 and 6 disclose dihydropyrazolopyrazinone derivatives which are mGluR5 receptor allosteric modulators.
Non-Patent Document 2 discloses a dihydropyrazolopyrazinone derivative having an MK2 inhibitory action.
Patent Documents 4 and 5 and Non-Patent Document 3 disclose dihydropyrazolopyrazinone derivatives having an HIV integrase inhibitory action.
On the other hand, Patent Document 7 and Non-Patent Document 4 disclose dihydropyrazolopyrazinone derivatives having anticancer activity.

However, there is no description or suggestion that the compound has an autotaxin inhibitory action and can be a therapeutic agent for chronic kidney disease.

On the other hand, Patent Document 8 discloses an imidazopyrimidinone derivative having autotaxin inhibitory activity.

International Publication No. 2013/192350 International Publication No. 2013/192346 International Publication No. 2012/83224 International Publication No. 2007/50510 International Publication No. 2005/120516 International Publication No. 2014/195311 China publication No. 101367819 International Publication No. 2014/133112

Nature, 411, 494-498, 2001. Bioorganic & Medicinal Chemistry Letters, Volume: 21, Issue: 12, 3818-3822 Bioorganic & Medicinal Chemistry Letters, Volume: 18, Issue: 2, 721-725 Bioorganic & Medicinal Chemistry, Volume: 16, Issue: 24, 10165-10171, 2008

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

  As a result of intensive studies, the present inventors have found a 7-position unsubstituted condensed pyrazole derivative having excellent autotaxin inhibitory activity, and achieved the present invention.

（式中、
Ｒ^１は以下のいずれかの式：

（環Ａは６員の芳香族炭素環、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、
環Ｂは５員の芳香族複素環、５員の非芳香族複素環または５員の非芳香族炭素環であり、
環Ｃは４員の非芳香族炭素環または４員の非芳香族複素環であり、
Ｒ^１ａはハロゲン、シアノ、置換アルキル、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、または置換もしくは非置換のアルキニルチオであり、
Ｒ^１ｂはハロゲン、シアノ、ヒドロキシ、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、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非芳香族複素環式基、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芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、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芳香族炭素環カルボニル、置換も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非芳香族炭素環カルボニル、置換も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芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、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芳香族炭素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、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芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、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、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換も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、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミノであり、
ｎは０〜６の整数である。）で示される基であり、
Ｒ^２は水素、ハロゲン、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^３は水素、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非芳香族炭素環式基、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複素環式基または置換もしくは非置換の芳香族複素環式基であり、
Ｒ^４ａおよびＲ^４ｂはそれぞれ独立して、水素、ハロゲン、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非芳香族炭素環式基、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複素環式基、置換もしくは非置換の芳香族複素環式基、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非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、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非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、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非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換も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非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、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非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、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、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルである。）で示される化合物、
（ただし、
（ｉ）Ｒ^３が水素または非置換アルキルであり、Ｒ^４ａおよびＲ^４ｂが同時に水素である化合物、および
（ｉｉ）以下に示す化合物を除く。

）またはその製薬上許容される塩。
（２）Ｒ^１が式：

（環Ａは６員の芳香族炭素環、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る。）で示される基である、上記（１）記載の化合物またはその製薬上許容される塩。
（３）環Aが６員の芳香族炭素環または６員の芳香族複素環である、上記（２）記載の化合物またはその製薬上許容される塩。
（４）環Aが６員の芳香族炭素環である、上記（２）記載の化合物またはその製薬上許容される塩。
（５）Ｒ^１が式：

（式中、ｍは０〜３の整数であり、その他の記号は上記（１）と同意義である。）で示される基である、上記（１）記載の化合物またはその製薬上許容される塩。
（６）Ｒ^２が水素である、上記（１）〜（５）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。
（７）Ｒ^３が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または置換もしくは非置換のアルキニルである、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）Ｒ^３が置換基群Ａから選択される１以上の基で置換されたアルキル（ここで置換基群Ａは、ヒドロキシ、カルボキシ、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非芳香族炭素環式基、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複素環式基、置換もしくは非置換の芳香族複素環式基、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芳香族炭素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換も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非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アミノ、置換もしくは非置換のカルバモイルおよび置換もしくは非置換のスルファモイルからなる）、置換基群Ａから選択される１以上の基で置換されたアルケニルまたは置換基群Ａから選択される１以上の基で置換されたアルキニルである、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^４ａおよびＲ^４ｂはそれぞれ独立して、水素、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非芳香族炭素環式基、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複素環式基または置換もしくは非置換の芳香族複素環式基である、上記（１）〜（８）のいずれか記載の化合物またはその製薬上許容される塩。
（１０）Ｒ^３が水素であり、
Ｒ^４ａおよびＲ^４ｂのいずれか一方が水素であり、他方が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非芳香族炭素環式基、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複素環式基または置換もしくは非置換の芳香族複素環式基である、上記（９）記載の化合物またはその製薬上許容される塩。
（１１）Ｒ^３が水素であり、
Ｒ^４ａおよびＲ^４ｂのいずれか一方が水素であり、他方が置換基群Ｂから選択される１以上の置換基で置換された非芳香族炭素環式基（ここで、置換基群Ｂは、ハロゲン、シアノ、ヒドロキシ、ホルミル、カルボキシ、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非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換も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芳香族複素環カルボニル、置換もしくは非置換のカルバモイルおよび置換もしくは非置換のスルファモイルである。）、置換基群Ｂから選択される１以上の置換基で置換された芳香族炭素環式基、置換基群Ｂから選択される１以上の置換基で置換された非芳香族複素環式基または置換基群Ｂから選択される１以上の置換基で置換された芳香族複素環式基である、上記（１０）記載の化合物またはその製薬上許容される塩。
（１２）Ｒ^３が水素であり、
Ｒ^４ａおよびＲ^４ｂのいずれか一方が水素であり、他方が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または置換もしくは非置換のアルケニルである、上記（１０）記載の化合物またはその製薬上許容される塩。
（１３）上記（１）〜（１２）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。
（１４）オートタキシン阻害剤である、上記（１３）記載の医薬組成物。
（１５）上記（１）〜（１２）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または予防方法。
（１６）オートタキシンの関与する疾患を治療または予防するための、上記（１）〜（１２）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。
（１７）オートタキシンの関与する疾患の治療剤または予防剤を製造するための、上記（１）〜（１２）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の使用。
（１８）式（Ｉ）：

（式中、
Ｒ^１は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芳香族複素環式基、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非芳香族複素環式基、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オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、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芳香族炭素環カルボニル、置換も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非芳香族炭素環カルボニル、置換も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芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、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芳香族炭素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、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芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、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ホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換も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、置換もしくは非置換のアルキニルスルホニル、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^２は水素、ハロゲン、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^３は水素、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非芳香族炭素環式基、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複素環式基または置換もしくは非置換の芳香族複素環式基であり、
Ｒ^４ａおよびＲ^４ｂはそれぞれ独立して、水素、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非芳香族炭素環式基、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複素環式基、置換もしくは非置換の芳香族複素環式基、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非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、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非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、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非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換も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非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、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非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、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、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルである。）で示される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、オートタキシン阻害作用を有する医薬組成物。
（１９）尿排泄障害、慢性腎臓病もしくは腎線維症、間質性肺炎もしくは肺線維症、強皮症、線維筋痛症、関節炎リウマチ、動脈硬化症、眼疾患、脈絡膜血管新生および糖尿病網膜症、関節炎、神経変性、再狭窄、創傷治癒もしくは移植片拒絶反応または子宮内膜症の予防または治療に用いられるものである、上記（１８）記載の医薬組成物。 That is, the present invention relates to the following.
(1) Formula (I):

(Where
R ¹ is ^one of the following formulas:

(Ring A is a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, a 6-membered non-aromatic carbocyclic ring or a 6-membered non-aromatic heterocyclic ring,
Ring B is a 5-membered aromatic heterocycle, a 5-membered non-aromatic heterocycle or a 5-membered non-aromatic carbocycle,
Ring C is a 4-membered non-aromatic carbocycle or 4-membered non-aromatic heterocycle,
R ^1a is halogen, cyano, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio Substituted or unsubstituted alkenylthio, or substituted or unsubstituted alkynylthio,
R ^1b 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 An aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted alkyloxy, a 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 alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic Aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylthio, substituted or unsubstituted The Arkeni Thio, substituted or unsubstituted alkynylthio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted non-substituted Aromatic heterocyclic thio, 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 alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, Substituted or unsubstituted fragrance Carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Sulfamoyl or substituted or unsubstituted amino of
n is an integer of 0-6. )
R ² is hydrogen, halogen, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, 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 Substituted 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 ³ is hydrogen, 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 A substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R ^4a and R ^4b are each independently hydrogen, halogen, cyano, formyl, carboxy, 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 oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkyl Thio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic hetero Ring 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 carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxy Carbonyl, substituted or unsubstituted alkynyloxy Sicarbonyl, 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 nonaromatic carbon Ring 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 Lucenylsulfonyl, substituted or 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 non-substituted Substituted aromatic heterocyclic sulfonyl. ), A compound represented by
(However,
(I) Excludes compounds in which R ³ is hydrogen or unsubstituted alkyl, and R ^4a and R ^4b are simultaneously hydrogen, and (ii) compounds shown below.

) Or a pharmaceutically acceptable salt thereof.
(2) R ¹ is the formula:

(Ring A is a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, a 6-membered non-aromatic carbocyclic ring or a 6-membered non-aromatic heterocyclic ring), 1) The described compound or a pharmaceutically acceptable salt thereof.
(3) The compound according to the above (2) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered aromatic carbocycle or a 6-membered aromatic heterocycle.
(4) The compound according to the above (2) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered aromatic carbocycle.
(5) R ¹ is the formula:

Wherein m is an integer of 0 to 3, and other symbols are as defined in (1) above, or a pharmaceutically acceptable compound thereof as described in (1) above. salt.
(6) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein R ² is hydrogen.
(7) The compound according to any one of (1) to (6) above or a pharmaceutically acceptable salt thereof, wherein R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. Salt.
(8) R ³ is alkyl substituted with one or more groups selected from substituent group A (wherein substituent group A is hydroxy, carboxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl) Oxy, substituted or unsubstituted alkynyloxy, 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 Non-aromatic 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 amino, substituted or unsubstituted carbamoyl and substituted or unsubstituted The compound according to (7), which is an alkenyl substituted with one or more groups selected from Substituent Group A or an alkynyl substituted with one or more groups selected from Substituent Group A Or a pharmaceutically acceptable salt thereof.
(9) R ^4a and R ^4b are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, Any of the above (1) to (8), which is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic group The described compound or a pharmaceutically acceptable salt thereof.
(10) R ³ is hydrogen,
Either one of R ^4a and R ^4b is hydrogen and the other is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, The compound according to (9) above, which is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof Acceptable salt.
(11) R ³ is hydrogen,
One of R ^4a and R ^4b is hydrogen, and the other is a non-aromatic carbocyclic group substituted with one or more substituents selected from Substituent Group B (wherein Substituent Group B is Halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted Or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted carbamoyl and substituted or unsubstituted sulfamoyl. An aromatic carbocycle substituted with one or more substituents selected from substituent group B Group, a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group B, or an aromatic heterocyclic group substituted with one or more substituents selected from substituent group B Or a pharmaceutically acceptable salt thereof.
(12) R ³ is hydrogen,
The compound according to the above (10) or a pharmaceutically acceptable salt thereof, wherein either one of R ^4a and R ^4b is hydrogen and the other is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkenyl. Acceptable salt.
(13) A pharmaceutical composition comprising the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof as an active ingredient.
(14) The pharmaceutical composition according to the above (13), which is an autotaxin inhibitor.
(15) A method for treating or preventing a disease involving autotaxin, which comprises administering the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof.
(16) The compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof for treating or preventing a disease involving autotaxin.
(17) Use of the compound according to any one of (1) to (12) above or a pharmaceutically acceptable salt thereof for producing a therapeutic or prophylactic agent for a disease involving autotaxin.
(18) Formula (I):

(Where
R ¹ represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted nonaromatic heterocyclic ring Formula group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, 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 alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic 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 alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or Unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocarbonyl oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or non-substituted Substituted non-aromatic heterocycle O, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted Substituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted alkyl sulfinyl, 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 unsubstituted alkyl sulfonyl, substituted Or unsubstituted Luque sulfonyl sulfonyl, substituted or unsubstituted alkynyl-sulfonyl, substituted or unsubstituted amino, a substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl,
R ² is hydrogen, halogen, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, 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 Substituted 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 ³ is hydrogen, 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 A substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R ^4a and R ^4b are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-substituted 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 oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or non-substituted Substituted alkylthio, substituted or unsubstituted alkenylthio, 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 carbocycle Carbonyl, substituted or unsubstituted aromatic carbocyclic 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 a Lucynyloxycarbonyl, 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 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 Is 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, or Substituted or unsubstituted aromatic heterocyclic sulfonyl. And a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition having an autotaxin inhibitory action.
(19) Urinary excretion disorder, chronic kidney disease or renal fibrosis, interstitial pneumonia or pulmonary fibrosis, scleroderma, fibromyalgia, rheumatoid arthritis, arteriosclerosis, eye disease, choroidal neovascularization and diabetic retinopathy The pharmaceutical composition according to (18), which is used for prevention or treatment of arthritis, neurodegeneration, restenosis, wound healing or graft rejection or endometriosis.

  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.

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

“Alkyl” means a straight or branched hydrocarbon group having 1 to 10 carbon atoms. C1-C6 alkyl, C1-C4 alkyl, C1-C3 alkyl, etc. are included. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl , N-nonyl, n-decyl and the like.
“Alkyl” in R ^1a and R ^1b includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyl and ethyl are preferable.
Examples of the “alkyl” in R ³ include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyl and ethyl are preferable.
^Examples of “alkyl” in R ^4a and R ^4b include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isohexyl and the like. In particular, methyl and ethyl are preferable.

Alkyl moieties such as “alkyloxy”, “alkyloxycarbonyl”, “alkylcarbonyl”, “alkyloxycarbonylalkyl”, “alkylthio”, “alkylsulfinyl”, “alkylsulfonyl”, “alkylamino” Is equivalent to.
Thus, for example, in the case of “alkyloxy”, methyloxy, ethyloxy, n-propyloxy, isopropyloxy, tert-butyloxy, n-octyloxy, isobutylmethylhexyloxy, n-nonyloxy and the like are mentioned. Examples include oxy, ethyloxy, n-propyloxy, isopropyloxy and the like.

“Haloalkyl” and “haloalkyloxy” are groups in which an alkyl moiety such as alkyl and alkyloxy is substituted at any position where 1 to 5 (preferably 1 to 3) of the above “halogen” can be substituted. Means.
For example, monohaloalkyl, dihaloalkyl, trihaloalkyl and the like can be mentioned. In particular, fluoromethyl, difluoromethyl, trifluoromethyl and the like are preferable.

“Alkenyl” means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at any position. Including alkenyl having 2 to 8 carbon atoms, alkenyl having 3 to 6 carbon atoms and the like. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.
The alkenyl moiety such as “alkenyloxy”, “alkenyloxycarbonyl”, “alkenylcarbonyl”, “alkenyloxycarbonylalkyl”, “alkenylthio”, “alkenylsulfinyl”, “alkenylsulfonyl”, “alkenylamino” It is synonymous with “alkenyl”.

“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.
Alkynyl moieties such as “alkynyloxy”, “alkynyloxycarbonyl”, “alkynylcarbonyl”, “alkenyloxycarbonylalkyl”, “alkynylthio”, “alkynylsulfinyl”, “alkynylsulfonyl”, “alkynylamino” It is synonymous with “alkynyl”.

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 preferred.
As the “6-membered aromatic carbocycle” in ring A, benzene is 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.
As the “aromatic carbocyclic group” in R ^4a and R ^4b , phenyl is preferable.

  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 and tetrahydronaphthalene.

“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 and the like.
“Cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. In particular, “cycloalkyl” having 3 to 6 carbon atoms and “cycloalkyl” having 5 or 6 carbon atoms are 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.

「非芳香族炭素環オキシ」、「非芳香族炭素環オキシカルボニル」、「非芳香族炭素環カルボニル」、「非芳香族炭素環チオ」、「非芳香族炭素環スルフィニル」、「非芳香族炭素環スルホニル」等の非芳香族炭素環部分は、上記「非芳香族炭素環」と同意義である。
「芳香族炭素環オキシ」、「芳香族炭素環オキシカルボニル」、「芳香族炭素環カルボニル」、「芳香族炭素環チオ」、「芳香族炭素環スルフィニル」、「芳香族炭素環スルホニル」、「芳香族炭素環アミノ」等の芳香族炭素環部分は、上記「芳香族炭素環」と同意義である。 “Non-aromatic carbocyclic group” means the above-mentioned “cycloalkyl” and “cycloalkenyl” as well as “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.

"Non-aromatic carbocyclic oxy", "non-aromatic carbocyclic oxycarbonyl", "non-aromatic carbocyclic carbonyl", "non-aromatic carbocyclic thio", "non-aromatic carbocyclic sulfinyl", "non-aromatic A non-aromatic carbocyclic moiety such as “carbocycle sulfonyl” has the same meaning as the above “non-aromatic carbocycle”.
"Aromatic carbocyclic oxy", "aromatic carbocyclic oxycarbonyl", "aromatic carbocyclic carbonyl", "aromatic carbocyclic thio", "aromatic carbocyclic sulfinyl", "aromatic carbocyclic sulfonyl", " An aromatic carbocyclic moiety such as “aromatic carbocyclic amino” has the same meaning as the above “aromatic carbocycle”.

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, pyrazine, pyrazole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, triazine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, etc. ring;
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 the like.
Examples of the “6-membered aromatic heterocycle” in ring A include rings represented by the following formulae.

  Examples of the “5-membered aromatic heterocycle” in ring A include tetrazole, furan, thiophene, imidazole, triazole, triazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole and the like.

The “aromatic heterocyclic group” includes a monovalent group derived from the above “aromatic heterocyclic ring”.
For example, pyrrolyl, pyrazinyl, pyrazolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, etc. A cyclic group;
For example, indolyl, isoindolyl, indazolyl, indolinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxazolyl Diazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazo And condensed aromatic heterocyclic groups such as linyl.
"Aromatic heterocyclic oxy", "Aromatic heterocyclic oxycarbonyl", "Aromatic heterocyclic carbonyl", "Aromatic heterocyclic thio", "Aromatic heterocyclic sulfinyl", "Aromatic heterocyclic sulfonyl", " An aromatic heterocyclic moiety such as “aromatic heterocyclic amino” has the same meaning as the above “aromatic heterocyclic ring”.

“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,
A ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring is condensed with one or more of the “cycloalkane” or the “cycloalkene”;
A 5- to 7-membered non-aromatic heterocyclic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is one or more of the above “aromatic carbocycle” or “non-aromatic carbocycle”. Includes fused rings.
For example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dihydropyrazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydro Monocyclic non-aromatic heterocycles such as thiazoline, tetrahydroisothiazoline,
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.

「非芳香族複素環オキシ」、「非芳香族複素環オキシカルボニル」、「非芳香族複素環カルボニル」、「非芳香族複素環チオ」、「非芳香族複素環スルフィニル」、「非芳香族複素環スルホニル」、「非芳香族複素環アミノ」等の非芳香族複素環部分は、上記「非芳香族複素環」と同意義である。 For example, the following groups are also included in the non-aromatic heterocyclic group.

"Non-aromatic heterocyclic oxy", "Non-aromatic heterocyclic oxycarbonyl", "Non-aromatic heterocyclic carbonyl", "Non-aromatic heterocyclic thio", "Non-aromatic heterocyclic sulfinyl", "Non-aromatic Non-aromatic heterocyclic moieties such as “heterocyclic sulfonyl” and “non-aromatic heterocyclic amino” have the same meaning as the above “non-aromatic heterocyclic ring”.

A substituted or unsubstituted non-aromatic carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group may be substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino.
"Non-aromatic heterocyclic oxy", "Non-aromatic heterocyclic oxycarbonyl", "Non-aromatic heterocyclic carbonyl", "Non-aromatic heterocyclic thio", "Non-aromatic heterocyclic sulfinyl", "Non-aromatic Non-aromatic heterocyclic moieties such as “heterocyclic sulfonyl” and “non-aromatic heterocyclic amino” have the same meaning as the above “non-aromatic heterocyclic ring”.

  A substituted or unsubstituted non-aromatic carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group may be substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino.

“Substituted alkyl”, “Substituted alkenyl”, “Substituted alkynyl”, “Substituted non-aromatic carbocyclic group”, “Substituted aromatic carbocyclic group”, “Substituted aromatic heterocyclic group” or “Substituted non-aromatic” Substituents for `` heterocyclic group '' include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, amino, carboxy, alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic group, aromatic Carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, substituted carbamoyl, substituted sulfamoyl, substituted amidino, group represented by formula: —O—R ^x , formula: —O—C (═O ) -R ^x group, formula: -C (= O) -R ^x group, formula: -C (= O) -O-R ^x group, formula: -S-R ^x a group represented by or the formula: represented by _-SO 2 -R ^x That group (wherein R ^x is alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, carbamoyl, sulfamoyl Or amidino). 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 oxycarbonyl, aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxy Carbonyl and the like are preferred. 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 Group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy C, 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 hetero Ring oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted Or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxy Carbonyl, substituted or unsubstituted a Quinyloxycarbonyl, 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 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 alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic Group carbocycle O, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, 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 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, substituted or unsubstituted amino, Substituted or unsubstituted cal Sulfamoyl the moil and substituted or unsubstituted and the like. 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, substituted carbamoyl, sulfamoyl, substituted sulfamoyl, amino, substituted 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 hetero Ring carbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic carbocyclic oxycarbonyl, aromatic Heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl and the like are preferable. With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.
As the substituent of “substituted alkyl” in R ³ ,
Halogen, cyano, hydroxy, carboxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, 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 nonaromatic heterocyclic ring Carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted Ku is unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, sulfamoyl carbamoyl and substituted or unsubstituted substituted or unsubstituted.
As the substituent of “substituted alkyl” in R ^3, an aromatic carbocyclic group optionally substituted with one or more groups selected from substituent group D (wherein substituent group D is cyano, hydroxy, , Carboxy, alkyloxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, dialkylaminoalkyloxy, hydroxy non-aromatic heterocyclic carbonyl, carbamoyl and oxo), one or more groups selected from substituent group D Selected from an optionally substituted aromatic heterocyclic group, a non-aromatic carbocyclic group optionally substituted with one or more groups selected from Substituent Group D, or Substituent Group D More preferred are non-aromatic heterocyclic groups which may be substituted with one or more groups.

Examples of the substituent of the “substituted aromatic carbocyclic group” in R ^4a and R ^4b include carboxy, alkyl, hydroxyalkyl, alkyloxycarbonyl, hydroxy non-aromatic heterocyclic carbonyl, cyanoalkyl non-aromatic heterocyclic carbonyl, carboxy Non-aromatic heterocyclic carbonyl, hydroxyalkyl non-aromatic heterocyclic alkyl, alkyloxycarbamoyl, cyanoalkylcarbamoyl, hydroxyalkylcarbamoyl, dihydroxyalkylcarbamoyl, hydroxyalkyloxyalkylcarbamoyl, carboxyalkylcarbamoyl, carbamoylalkylcarbamoyl, alkylcarbamoylalkylcarbamoyl , Dialkylcarbamoylalkylcarbamoyl, dialkylaminoalkylcarbamoyl, hydroxyalkyl Minoalkylcarbamoyl, aromatic carbocyclic (carboxy) alkylcarbamoyl, aromatic carbocyclic alkyl (hydroxyalkyl) non-aromatic heterocyclic alkyl carbamoyl, haloaromatic carbocyclic alkyl (hydroxy) non-aromatic heterocyclic alkyl carbamoyl, aromatic Carbocyclic alkyl non-aromatic carbocyclic alkyl (hydroxy) alkyl carbamoyl, cyano non-aromatic carbocyclic carbamoyl, non-aromatic heterocyclic carbamoyl, oxo non-aromatic heterocyclic carbamoyl, dioxo non-aromatic heterocyclic carbamoyl, non-aromatic hetero Ring alkylcarbamoyl, oxo non-aromatic heterocycle alkylcarbamoyl, alkyl nonaromatic heterocycle alkylcarbamoyl, aromatic heterocycle alkylcarbamoyl, N-alkylcarbonylaminoalkyl-N-alkylcarbamoyl, alkylcarboni Non-aromatic heterocyclic carbamoyl and the like.

Substituents for “substituted amino”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted amidino” or “substituted imino” include hydroxy, cyano, formyl, alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic Group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, carbamoyl, sulfamoyl, amidino, group represented by formula: —O—R, formula: —C (═O) — A group represented by R, a group represented by the formula: —C (═O) —O—R, or a group represented by the formula: —SO ₂ —R, wherein R is alkyl, haloalkyl, alkenyl, alkynyl, non- Aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group or non-aromatic heterocyclic group). With these substituents, 1 to 2 arbitrary positions that can be substituted 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, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted nonaromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl Substituted or unsubstituted carbamoyl and substituted or unsubstituted sulfamoyl. 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, substituted sulfamoyl, amino, substituted 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 carbocyclic oxycarbonyl, aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic carbocyclic oxycarbonyl, aromatic hetero Ring oxycarbonyl, non-aromatic heterocyclic oxycarbonyl and the like are preferable. With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.

Examples of the substituent of “substituted amino” in R ^1a and R ^1a include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted Examples include alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl and the like.
In particular, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, non-aromatic carbocyclic carbonyl, aromatic carbocyclic carbonyl, non-aromatic heterocyclic carbonyl, and aromatic heterocyclic carbonyl are preferable. One or two of these substituents may be substituted.

で示される化合物における、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４ａおよびＲ^４ｂ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。
Ｒ^１は以下のいずれかの式：

（環Ａは６員の芳香族炭素環、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、
環Ｂは５員の芳香族複素環、５員の非芳香族複素環または５員の非芳香族炭素環であり、
環Ｃは４員の非芳香族炭素環または４員の非芳香族複素環であり、
Ｒ^１ａはハロゲン、シアノ、置換アルキル、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、または置換もしくは非置換のアルキニルチオであり、
Ｒ^１ｂはハロゲン、シアノ、ヒドロキシ、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、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非芳香族複素環式基、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芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、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芳香族炭素環カルボニル、置換も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非芳香族炭素環カルボニル、置換も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ルキ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アルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、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芳香族炭素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、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芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、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、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換も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、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミノであり、
ｎは０〜６の整数である。）で示される基が挙げられる。
Ｒ^１の好ましい態様としては、式：

（環Ａは６員の芳香族炭素環、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る。）で示される基が挙げられる。
環Ａの好ましい態様としては、６員の芳香族炭素環または６員の芳香族複素環が挙げられる。
環Ａの好ましい態様としては、６員の芳香族炭素環が挙げられる。
Ｒ^１のさらに好ましい態様としては、式：

（式中、ｍは０〜３の整数であり、Ｒ^１ａはハロゲン、シアノ、置換アルキル、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、または置換もしくは非置換のアルキニルチオであり、
Ｒ^１ｂはハロゲン、シアノ、ヒドロキシ、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、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非芳香族複素環式基、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芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、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芳香族炭素環カルボニル、置換も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非芳香族炭素環カルボニル、置換も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ルキ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アルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、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芳香族炭素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、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芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、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、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換も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、置換もしくは非置換のスルファモイルまたは置換もしくは非置換のアミノである。）で示される基が挙げられる。
Ｒ^１ａの好ましい態様としては、ハロゲンまたはシアノが挙げられる。
Ｒ^１ｂの好ましい態様としては、ハロゲン、シアノ、ヒドロキシ、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または置換もしくは非置換のアルキニルが挙げられる。 Formula (I):

In the compounds ^represented, indicating preferred embodiments of ^{R 1, R 2, R 3} , R 4a and ^{R 4b} below. The following possible combinations of compounds are preferred:
R ¹ is ^one of the following formulas:

(Ring A is a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, a 6-membered non-aromatic carbocyclic ring or a 6-membered non-aromatic heterocyclic ring,
Ring B is a 5-membered aromatic heterocycle, a 5-membered non-aromatic heterocycle or a 5-membered non-aromatic carbocycle,
Ring C is a 4-membered non-aromatic carbocycle or 4-membered non-aromatic heterocycle,
R ^1a is halogen, cyano, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio Substituted or unsubstituted alkenylthio, or substituted or unsubstituted alkynylthio,
R ^1b 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 An aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted alkyloxy, a 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 alkyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic Aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylthio, substituted or unsubstituted The Arkeni Thio, substituted or unsubstituted alkynylthio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted non-substituted Aromatic heterocyclic thio, 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 alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, Substituted or unsubstituted fragrance Carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Sulfamoyl or substituted or unsubstituted amino of
n is an integer of 0-6. ).
In a preferred embodiment of R ¹ , the formula:

(Ring A is a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, a 6-membered non-aromatic carbocyclic ring or a 6-membered non-aromatic heterocyclic ring).
As a preferable embodiment of the ring A, a 6-membered aromatic carbocyclic ring or a 6-membered aromatic heterocyclic ring can be mentioned.
A preferred embodiment of ring A includes a 6-membered aromatic carbocycle.
In a further preferred embodiment of R ¹ , the formula:

Wherein m is an integer from 0 to 3 and R ^1a is halogen, cyano, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted alkyloxy, substituted or unsubstituted alkenyloxy, Substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, or substituted or unsubstituted alkynylthio,
R ^1b 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 An aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted alkyloxy, a 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 alkyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic Aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylthio, substituted or unsubstituted The Arkeni Thio, substituted or unsubstituted alkynylthio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted non-substituted Aromatic heterocyclic thio, 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 alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, Substituted or unsubstituted fragrance Carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted A sulfamoyl or a substituted or unsubstituted amino. ).
A preferred embodiment of R ^1a includes halogen or cyano.
Preferred embodiments of R ^1b include halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

R ² is hydrogen, halogen, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, 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 Substituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted Alternatively, unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, or substituted or unsubstituted alkynylsulfonyl can be mentioned.
Preferred embodiments of R ² include hydrogen, halogen, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted amino.
Another preferred embodiment of R ² includes hydrogen, halogen or cyano.
A more preferred embodiment of R ² includes hydrogen.

R ³ is hydrogen, 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 A substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group.
Preferred embodiments of R ³ include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
In a preferred embodiment of R ³ , alkyl substituted with one or more groups selected from Substituent Group A (wherein Substituent Group A is hydroxy, carboxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, 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 Substituted non-aromatic 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 amino, substituted or unsubstituted carbamoyl And alkynyl substituted with one or more groups selected from Substituent Group A, and alkynyl substituted with one or more groups selected from Substituent Group A.
A further preferred embodiment of R ³ includes alkyl substituted with one or more groups selected from substituent group A.

As a more preferred embodiment of R ^3, an aromatic carbocyclic alkyl optionally substituted with one or more groups selected from substituent group D (wherein substituent group D is cyano, carboxy, alkyloxycarbonyl, Alkyl, hydroxyalkyl, carboxyalkyl, dialkylaminoalkyl and carbamoyl.), Or aromatic heterocyclic alkyl which may be substituted with one or more groups selected from Substituent Group D.
As a more preferred embodiment of R ³ , non-aromatic heterocyclic alkyl optionally substituted with one or more groups selected from substituent group E (wherein substituent group E is carboxy, carboxyalkyl, aromatic Substituted with one or more groups selected from group carbocyclic (carboxy) alkyl, oxo non-aromatic heterocyclic group, non-aromatic heterocyclic carbonyl and alkyloxycarbonyl) or substituent group E Even better are non-aromatic carbon ring alkyls.

R ^4a and R ^4b are each independently hydrogen, halogen, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic 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 non-substituted Substituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted al Ruthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic hetero Ring 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 carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxy Carbonyl, substituted or unsubstituted alkynyl Xyloxycarbonyl, 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 nonaromatic carbon Ring 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 sulfonyl or substituted or unsubstituted And aromatic heterocyclic sulfonyl.
Preferred embodiments of R ^4a and R ^4b are each independently hydrogen, 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 or substituted or unsubstituted aromatic heterocyclic group.
As a preferred embodiment of R ^4a and R ^4b , either one is hydrogen and the other is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic Examples thereof include a carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, and a substituted or unsubstituted aromatic heterocyclic group.
As a preferred embodiment of R ^4a and R ^4b , a non-aromatic carbocyclic group in which either one is hydrogen and the other is substituted with one or more substituents selected from Substituent Group B (wherein substituted Group B is halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic Carbocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted carbamoyl and substituted or unsubstituted Sulfamoyl), one or more substituents selected from Substituent Group B Substituted with one or more substituents selected from a substituted aromatic carbocyclic group, a non-aromatic heterocyclic group substituted with one or more substituents selected from Substituent Group B, or Substituent Group B Aromatic heterocyclic group formed.
In a preferred embodiment of R ^4a and R ^4b , one of them is hydrogen and the other is hydrogen or substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkenyl.
The compound of the present invention is not limited to a specific isomer, but all possible isomers (for example, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer, etc.) ), Racemates or mixtures thereof.

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

The radioactive label of the compound of the present invention can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. 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.) and / or a crystal polymorph, and the present invention includes such various solvates and crystals. Also includes polymorphs. The “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound of the present invention. When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In addition, the crystalline polymorph may be formed by recrystallizing the compound of the present invention or a pharmaceutically acceptable salt thereof.

  The compound of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs. A prodrug is a derivative of a compound of the 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” means (1) kidney disorders (proteinuria including microalbuminuria, abnormal urine, abnormal urinary sediment, abnormal images such as single kidney and multiple cystic kidneys, increased serum creatinine level, etc. (2) GFR (glomerular filtration rate) less than 60 mL / min / 1.73 m ² 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、ＰＧはＢＯＣ等のアミノ基の保護基、その他の記号は上記と同意義。）
化合物ａ１に、アンモニウムヒドロキシドを反応させた後、保護化剤を反応させることにより、化合物ａ２を得ることができる。
反応溶媒としては、２−プロパノール、ジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、エタノール、水、トルエン、アセトニトリル、１，４−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。
アンモニウムヒドロキシドは、化合物ａ１に対して、１〜５０当量、好ましくは５〜３０当量用いることができる。
反応温度は、室温〜２００℃、好ましくは５０℃〜１５０℃であり、必要に応じて封管下で反応することも可能である。
反応時間は、０．１時間〜２４時間、好ましくは１時間〜１２時間である。
アミノ基の保護化剤としては、（Ｂｏｃ）_２Ｏ、Ｆｍｏｃ−Ｃｌベンジルオキシクロリド、ベンジルブロミド等が挙げられ、化合物ａ１に対して、１〜５０当量、好ましくは１〜１０当量用いることができる。
アミノ基の保護化の溶媒としては、ジクロロメタン、テトラヒドロフラン、酢酸エチル、水、１，２−ジメトキシエタン、Ｎ，Ｎ−ジメチルホルムアミド、アセトニトリル、１，４−ジオキサン、アセトン等が挙げられ、単独または混合して用いることができる。
アミノ基の保護化の反応温度は、０℃〜１００℃、好ましくは室温である。
アミノ基の保護化の反応時間は、０．１時間〜２４時間、好ましくは１時間〜５時間である。 Method for producing compound a2

(In the formula, PG is an amino-protecting group such as BOC, and other symbols are as defined above.)
Compound a2 can be obtained by reacting compound a1 with ammonium hydroxide and then with a protecting agent.
Examples of the reaction solvent include 2-propanol, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, ethanol, water, toluene, acetonitrile, 1,4-dioxane and the like, and these can be used alone or in combination.
Ammonium hydroxide can be used in an amount of 1 to 50 equivalents, preferably 5 to 30 equivalents, relative to compound a1.
The reaction temperature is room temperature to 200 ° C., preferably 50 ° C. to 150 ° C. If necessary, the reaction can be carried out under a sealed tube.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
Examples of the amino group protecting agent include (Boc) ₂ O, Fmoc-Cl benzyloxychloride, benzyl bromide and the like, and 1 to 50 equivalents, preferably 1 to 10 equivalents, can be used with respect to compound a1. .
Examples of the solvent for protecting the amino group include dichloromethane, tetrahydrofuran, ethyl acetate, water, 1,2-dimethoxyethane, N, N-dimethylformamide, acetonitrile, 1,4-dioxane, acetone, and the like. Can be used.
The reaction temperature for protecting the amino group is 0 ° C. to 100 ° C., preferably room temperature.
The reaction time for protecting the amino group is 0.1 hour to 24 hours, preferably 1 hour to 5 hours.

（式中、Ｒ^a1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または置換もしくは非置換のアルキニル、その他の記号は上記と同意義。）
化合物ａ３の溶液に、トリフェニルホスフィンおよび縮合剤の存在下、化合物ａ２を反応させることにより、化合物ａ４を得ることができる。
反応溶媒としては、テトラヒドロフラン、ジクロロメタン、酢酸エチル、水、メタノール、Ｎ，Ｎ−ジメチルホルムアミド、アセトニトリル、１，４−ジオキサン、トルエン等が挙げられ、単独または混合して用いることができる。
トリフェニルホスフィンは、化合物ａ３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。
縮合剤としては、アゾジカルボン酸 ジイソプロピル、アゾジカルボン酸 ジ−ｔｅｒｔ−ブチル、アゾジカルボン酸 ジエチル、酸化アルミニウム、硫酸、五酸化二リン、三酸化硫黄、ジシクロヘキシルカルボジイミド等が挙げられ、化合物ａ３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、０℃〜加熱還流下、好ましくは０℃〜室温である。
反応時間は、０．１時間〜２４時間、好ましくは１時間〜５時間である。 Method for producing compound a4

(Wherein R ^a1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, and other symbols are as defined above.)
Compound a4 can be obtained by reacting compound a3 with compound a2 in the presence of triphenylphosphine and a condensing agent.
Examples of the reaction solvent include tetrahydrofuran, dichloromethane, ethyl acetate, water, methanol, N, N-dimethylformamide, acetonitrile, 1,4-dioxane, toluene and the like, and these can be used alone or in combination.
Triphenylphosphine can be used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound a3.
Examples of the condensing agent include diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, diethyl azodicarboxylate, aluminum oxide, sulfuric acid, diphosphorus pentoxide, sulfur trioxide, and dicyclohexylcarbodiimide. 1 to 10 equivalents, preferably 1 to 3 equivalents can be used.
The reaction temperature is 0 ° C. to heating under reflux, preferably 0 ° C. to room temperature.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 5 hours.

（式中の記号は上記と同意義。）
化合物ａ４の溶液に、脱保護剤と反応させることにより、化合物ａ５を得ることができる。用いる脱保護剤の種類によって、種々の塩として得ることができる。
反応溶媒としては、酢酸エチル、メタノール、水、エタノール、２−プロパノール、ジクロロメタン、ＴＨＦ、１，４−ジオキサン、テトラヒドロフラン等が挙げられ、単独または混合して用いることができる。
脱保護剤としては、塩酸／酢酸エチル、水酸化ナトリウム、パラジウム炭素、トリクロロエチルクロロホルメート、ピペリジン、モルホリン、テトラブチルアンモニウムフルオリド等が挙げられ、化合物ａ４に対して、１〜１００当量、好ましくは１〜２０当量用いることができる。
反応温度は、０℃〜加熱還流下、好ましくは室温である。
反応時間は、０．１時間〜２４時間、好ましくは１時間〜５時間である。 Method for producing compound a5

(The symbols in the formula are as defined above.)
Compound a5 can be obtained by reacting a solution of compound a4 with a deprotecting agent. Depending on the type of deprotecting agent used, various salts can be obtained.
Examples of the reaction solvent include ethyl acetate, methanol, water, ethanol, 2-propanol, dichloromethane, THF, 1,4-dioxane, tetrahydrofuran and the like, and these can be used alone or in combination.
Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, sodium hydroxide, palladium carbon, trichloroethyl chloroformate, piperidine, morpholine, tetrabutylammonium fluoride, and the like. 1 to 20 equivalents can be used.
The reaction temperature is 0 ° C. to heating under reflux, preferably room temperature.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 5 hours.

（式中の記号は上記と同意義。）
化合物ａ５を加熱することにより、化合物ａ６を得ることができる。化合物ａ５が塩の場合は、塩基存在下で反応させることができる。
反応溶媒としては、エタノール、水、ジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、メタノール、１，４−ジオキサン、アセトニトリル、トルエン、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、トリエチルアミン、ジイソプロピルエチルアミン、水酸化ナトリウム、炭酸カリウム等が挙げられ、化合物ａ４に対して、１〜１０当量、好ましくは１〜５当量用いることができる。
反応温度は、５０℃〜加熱還流下、好ましくは加熱還流下である。
反応時間は、０．１時間〜２４時間、好ましくは１時間〜５時間である。 Method for producing compound a6

(The symbols in the formula are as defined above.)
Compound a6 can be obtained by heating compound a5. When compound a5 is a salt, it can be reacted in the presence of a base.
Examples of the reaction solvent include ethanol, water, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these can be used alone or in combination.
Examples of the base include triethylamine, diisopropylethylamine, sodium hydroxide, potassium carbonate and the like, and 1 to 10 equivalents, preferably 1 to 5 equivalents, can be used with respect to compound a4.
The reaction temperature is 50 ° C. to heating under reflux, preferably heating under reflux.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 5 hours.

（式中、Ｒ^３’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または置換もしくは非置換のアルキニル、その他の記号は上記と同意義。）
化合物ａ６を、塩基存在下、求電子剤と反応させることにより、化合物ａ７を得ることができる。
反応溶媒としては、テトラヒドロフラン、エタノール、水、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド、メタノール、１，４−ジオキサン、アセトニトリル、トルエン、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。
求電子剤としては、ハロゲン化物、メシレート、トシレート等が挙げられ、化合物ａ６に対して、１〜１０当量、好ましくは１〜５当量用いることができる。
塩基としては、ｔｅｒｔ−ブトキシカリウム、水素化ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、ＤＢＵ等が挙げられ、化合物ａ６に対して、１〜１０当量、好ましくは１〜５当量用いることができる。
反応温度は、氷冷下〜加熱還流下、好ましくは氷冷下〜室温である。
反応時間は、０．１時間〜２４時間、好ましくは０．１時間〜５時間である。 Method for producing compound a7

(Wherein R ^{3 ′} is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, and other symbols are as defined above.)
Compound a7 can be obtained by reacting compound a6 with an electrophile in the presence of a base.
Examples of the reaction solvent include tetrahydrofuran, ethanol, water, dichloromethane, N, N-dimethylformamide, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these can be used alone or in combination.
Examples of the electrophile include halides, mesylate, tosylate and the like, and 1 to 10 equivalents, preferably 1 to 5 equivalents, can be used with respect to compound a6.
Examples of the base include tert-butoxy potassium, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU, etc., and 1 to 10 equivalents, preferably 1 to 5 equivalents, are used relative to compound a6. it can.
The reaction temperature is from ice cooling to heating under reflux, preferably from ice cooling to room temperature.
The reaction time is 0.1 hour to 24 hours, preferably 0.1 hour to 5 hours.

（式中、Ｒ^ａ２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非芳香族炭素環式基、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複素環式基または置換もしくは非置換の芳香族複素環式基、Ｒ^ａ３は、置換もしくは非置換のアルキレン、置換もしくは非置換のアルケニレン、置換もしくは非置換のアルキニレン、置換もしくは非置換の非芳香族炭素環、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の非芳香族複素環、置換もしくは非置換の芳香族複素環、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非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換も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芳香族複素環カルボニル、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ホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、その他の記号は上記と同意義。）
化合物ａ８を、加水分解することにより、化合物ａ９を得ることができる。
反応溶媒としては、テトラヒドロフラン、エタノール、水、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド、メタノール、１，４−ジオキサン、アセトニトリル、トルエン、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、水酸化ナトリウム、水酸化リチウム、水酸化カリウム等が挙げられ、化合物ａ８に対して、１〜１０当量、好ましくは１〜５当量用いることができる。
反応温度は、氷冷下〜加熱還流下、好ましくは室温である。
反応時間は、０．１時間〜２４時間、好ましくは０．１時間〜５時間である。 Method for producing compound a9

Wherein R ^a2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocycle Formula group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group, R ^a3 is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted Alkynylene, substituted or unsubstituted non-aromatic carbocyclic ring, substituted or unsubstituted aromatic carbocyclic ring, substituted or unsubstituted non-aromatic heterocyclic ring, substituted or unsubstituted aromatic heterocyclic ring, substituted or unsubstituted Alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted Aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted carbamoyl, substituted or non-substituted (Substituted sulfamoyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, and other symbols are as defined above.)
Compound a9 can be obtained by hydrolyzing compound a8.
Examples of the reaction solvent include tetrahydrofuran, ethanol, water, dichloromethane, N, N-dimethylformamide, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these can be used alone or in combination.
Examples of the base include sodium hydroxide, lithium hydroxide, potassium hydroxide and the like, and 1 to 10 equivalents, preferably 1 to 5 equivalents, can be used with respect to compound a8.
The reaction temperature is from ice cooling to heating under reflux, preferably room temperature.
The reaction time is 0.1 hour to 24 hours, preferably 0.1 hour to 5 hours.

（式中、Ｒ^ａ４およびＲ^ａ５は、それぞれ独立して、水素、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非芳香族炭素環式基、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複素環式基、置換もしくは非置換の芳香族複素環式基、またはＲ^ａ４およびＲ^ａ５が結合する窒素原子と一緒になって、置換もしくは非置換の含窒素非芳香族複素環式基、その他の記号は上記と同意義。）
化合物ａ９を、塩基および縮合剤の存在下、アミンと反応させることにより、化合物ａ１０を得ることができる。
反応溶媒としては、Ｎ，Ｎ−ジメチルホルムアミド、エタノール、水、ジクロロメタン、テトラヒドロフラン、メタノール、１，４−ジオキサン、アセトニトリル、トルエン、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、トリエチルアミン、ｔｅｒｔ−ブトキシカリウム、炭酸カリウム、炭酸セシウム、ジイソプロピルエチルアミン、ＤＢＵ等が挙げられ、化合物ａ９に対して、１〜１０当量、好ましくは１〜５当量用いることができる。
縮合剤としては、ＨＡＴＵ、ＷＳＣ、ＤＣＣ等が挙げられ、化合物ａ９に対して、１〜１０当量、好ましくは１〜５当量用いることができる。
アミンは、化合物ａ９に対して、１〜１０当量、好ましくは１〜５当量用いることができる。
反応温度は、氷冷下〜加熱還流下、好ましくは室温である。
反応時間は、０．１時間〜２４時間、好ましくは１時間〜５時間である。 Method for producing compound a10

Wherein R ^a4 and R ^a5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted Substituted with an aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, or a nitrogen atom to which R ^a4 and R ^a5 are attached Or an unsubstituted nitrogen-containing non-aromatic heterocyclic group, and other symbols are as defined above.)
Compound a10 can be obtained by reacting compound a9 with an amine in the presence of a base and a condensing agent.
Examples of the reaction solvent include N, N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these can be used alone or in combination.
Examples of the base include triethylamine, tert-butoxy potassium, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU, and the like, and 1 to 10 equivalents, preferably 1 to 5 equivalents, can be used with respect to compound a9.
Examples of the condensing agent include HATU, WSC, DCC and the like, and 1 to 10 equivalents, preferably 1 to 5 equivalents, can be used with respect to compound a9.
The amine can be used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound a9.
The reaction temperature is from ice cooling to heating under reflux, preferably room temperature.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 5 hours.

（式中の記号は上記と同意義。）
化合物ａ９を、塩基存在下、ＤＰＰＡと反応させることにより、化合物ａ１１を得ることができる。
反応溶媒としては、ｔｅｒｔ−ブタノール、水、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド、エタノール、テトラヒドロフラン、メタノール、１，４−ジオキサン、アセトニトリル、トルエン、酢酸エチル、ベンゼン等が挙げられ、単独または混合して用いることができる。
塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、等が挙げられ、化合物ａ９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。
ＤＰＰＡは、化合物ａ９に対して、１〜１０当量、好ましくは１〜５当量用いることができる。
反応温度は、室温〜加熱還流下、好ましくは加熱還流下である。
反応時間は、１時間〜２４時間、好ましくは１時間〜５時間である。 Method for producing compound a11

(The symbols in the formula are as defined above.)
Compound a11 can be obtained by reacting compound a9 with DPPA in the presence of a base.
Examples of the reaction solvent include tert-butanol, water, dichloromethane, N, N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate, benzene, and the like. Can be used.
Examples of the base include triethylamine, diisopropylethylamine, and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a9.
DPPA can be used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound a9.
The reaction temperature is from room temperature to heating under reflux, preferably under heating under reflux.
The reaction time is 1 hour to 24 hours, preferably 1 hour to 5 hours.

（式中、Ｒ^ａ６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非芳香族炭素環式基、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複素環式基または置換もしくは非置換の芳香族複素環式基、その他の記号は上記と同意義。）
化合物ａ１１を、脱保護剤と反応させた後に、塩基存在下、酸無水物または酸ハロゲン化物と反応させることにより、化合物ａ１２を得ることができる。
脱保護の溶媒としては、酢酸エチル、水、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド、エタノール、テトラヒドロフラン、メタノール、１，４−ジオキサン、アセトニトリル、トルエン、等が挙げられ、単独または混合して用いることができる。
脱保護剤としては、塩酸／酢酸エチル、メタンスルホン酸、トリフルオロ酢酸、硫酸、ヨードトリメチルシラン、三塩化アルミニウム、ブロモカテコールボラン、トリメチルシリルクロリド、トリメチルシリルトリフレート等が挙げられ、化合物ａ１１に対して、１〜１００当量、好ましくは１〜５０当量用いることができる。
塩基としては、トリエチルアミン、炭酸セシウム、炭酸カリウム、ジイソプロピルエチルアミン、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム等が挙げられ、化合物ａ１１に対して、１〜１０当量、好ましくは１〜５当量用いることができる。
酸無水物または酸ハロゲン化物は、化合物ａ１１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。
反応溶媒としては、メタノール、水、ジクロロメタン、Ｎ，Ｎ−ジメチルホルムアミド、エタノール、テトラヒドロフラン、１，４−ジオキサン、アセトニトリル、トルエン、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。
反応温度は、０℃〜加熱還流下、好ましくは室温である。
反応時間は、１時間〜２４時間、好ましくは１時間〜１２時間である。 Method for producing compound a12

Wherein R ^a6 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or non-substituted (Substituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group, and other symbols are as defined above.)
Compound a12 can be obtained by reacting compound a11 with a deprotecting agent and then reacting with an acid anhydride or acid halide in the presence of a base.
Examples of the deprotection solvent include ethyl acetate, water, dichloromethane, N, N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, and the like. These may be used alone or in combination. it can.
Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, methanesulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminum trichloride, bromocatecholborane, trimethylsilyl chloride, trimethylsilyl triflate and the like. 1 to 100 equivalents, preferably 1 to 50 equivalents can be used.
Examples of the base include triethylamine, cesium carbonate, potassium carbonate, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, etc., and 1 to 10 equivalents, preferably 1 to 5 equivalents, are used with respect to compound a11. it can.
The acid anhydride or acid halide can be used in an amount of 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound a11.
Examples of the reaction solvent include methanol, water, dichloromethane, N, N-dimethylformamide, ethanol, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these can be used alone or in combination.
The reaction temperature is 0 ° C. to heating under reflux, preferably room temperature.
The reaction time is 1 hour to 24 hours, preferably 1 hour to 12 hours.

（式中の記号は上記と同意義。）
化合物ａ９を、塩基およびエチルクロロホルメート存在下、還元剤と反応させることにより、化合物ａ１３を得ることができる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル、１，４−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、トリエチルアミン、ジイソプロピルエチルアミン、炭酸水素ナトリウム、水酸化ナトリウム等が挙げられ、化合物ａ９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。
還元剤としては、水素化ホウ素ナトリウム、水素化アルミニウムリチウム、トリアセトキシ水素化ホウ素ナトリウム等が挙げられ、化合物ａ９に対して、１〜１０当量、好ましくは１〜５当量用いることができる。
エチルクロロホルメートは、化合物ａ９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、氷冷下〜加熱還流下、氷冷下〜室温である。
反応時間は、０．１時間〜２４時間、好ましくは０．１時間〜５時間である。 Method for producing compound a13

(The symbols in the formula are as defined above.)
Compound a13 can be obtained by reacting compound a9 with a reducing agent in the presence of a base and ethyl chloroformate.
Examples of the reaction solvent include tetrahydrofuran, diethyl ether, 1,4-dioxane and the like, and these can be used alone or in combination.
Examples of the base include triethylamine, diisopropylethylamine, sodium hydrogen carbonate, sodium hydroxide and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a9.
Examples of the reducing agent include sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride and the like, and 1 to 10 equivalents, preferably 1 to 5 equivalents, can be used with respect to compound a9.
Ethyl chloroformate can be used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound a9.
The reaction temperature is from ice-cooling to heating under reflux, from ice-cooling to room temperature.
The reaction time is 0.1 hour to 24 hours, preferably 0.1 hour to 5 hours.

（式中、Ｒ^ａ７は、ハロゲン等の脱離基、Ｒ^ａ８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^ａ８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、その他の記号は上記と同意義である。）
化合物ａ１４を、金属触媒および塩基存在下、化合物ａ１５と反応させることにより、化合物ａ１６を得ることができる。
反応溶媒としては、ＤＭＦ、ＴＨＦ、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、炭酸カリウム、炭酸セシウム等が挙げられ、化合物ａ１４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ａ１５は、化合物ｂ９１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、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、酢酸パラジウム等が挙げられ、化合物ｂ９１に対して、０．０１〜０．５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、室温〜加熱還流下、好ましくは室温〜１００℃である。
反応時間は、０．１時間〜２４時間、好ましくは１時間〜１２時間である。

(Wherein R ^a7 is a leaving group such as halogen, and R ^a8 is independently hydroxy, substituted or unsubstituted alkyloxy, or two R ^{a8 taken} together to form a substituted or unsubstituted alkylenedioxy. And other symbols are as defined above.)
Compound a16 can be obtained by reacting compound a14 with compound a15 in the presence of a metal catalyst and a base.
Examples of the reaction solvent include DMF, THF, dioxane and the like, and these can be used alone or in combination.
Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a14.
Compound a15 can be used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound b91.
Examples of the metal catalyst include 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, palladium acetate and the like, and 0.01 to 0 with respect to compound b91. 0.5 equivalent, preferably 0.05 to 0.2 equivalent can be used.
The reaction temperature is from room temperature to heating under reflux, preferably from room temperature to 100 ° C.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 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 urinary excretion disorder, chronic kidney disease or renal fibrosis, interstitial pneumonia or pulmonary 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 endometriosis, etc. Known pharmaceutical compositions containing the compounds of the present invention are useful as therapeutic and / or prophylactic agents for these diseases. More preferably, the pharmaceutical composition containing the compound of the present invention comprises urinary drainage disorder, interstitial pneumonia or pulmonary fibrosis, renal fibrosis, liver fibrosis, scleroderma, pain, fibromyalgia, rheumatoid arthritis It is useful as an agent for treating and / or preventing multiple sclerosis or endometriosis. 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 PdCl ₂ (dppf) -DCM: 1,1′-bis (diphenyl) Phosphino) ferrocene-palladium (II) dichloride-dichloromethane complex (DHQ) 2PHAL: hydroquinine-1,4-phthalazine diyl diether (DHQD) 2PHAL: hydroquinidine-1,4-phthalazine diyl diether

The NMR analysis obtained in each example was performed at 300 MHz and measured using d ₆ -DMSO and CDCl ₃ .
In the specification, RT represents a retention time in LC / MS: liquid chromatography / mass spectrometry.
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: Perform a linear gradient of 10% -100% solvent [B] 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.
(Method C)
Column: ACQUITY UPLC (registered trademark) BEH C18
Flow rate: 0.55 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 5% -100% solvent [B] is performed in 3 minutes. 100% solvent [B] was maintained for 5 minutes.

化合物１（４４５ｍｇ，１．７７５ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液に、トリフェニルホスフィン（５５９ｍｇ，２．１３０ｍｍｏｌ）およびＮ−ｔｅｒｔブトキシカルボニル−２−アミノエタノール（３３０ｕＬ，２．１３０ｍｍｏｌ）を加えた。氷冷下、アゾジカルボン酸ジイソプロピル（４１４ｕＬ，２．１３０ｍｍｏｌ）を加え、室温で１時間２０分攪拌した。反応液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（６９０ｍｇ，収率：９９％）を白色固体として得た。
¹H-NMR (CDCl₃)δ:. 1.37-1.44 (m, 12H), 3.64 (dt, J = 5.6, 5.6 Hz, 2H), 4.37 (q, J = 7.2 Hz, 2H), 4.71 (t, J = 5.6 Hz, 2H), 4.93 (br s, 1H), 7.11 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H). Example 1 Production Method 1 of Compound 4 First Step Production Method of Compound 2

To a solution of Compound 1 (445 mg, 1.775 mmol) in tetrahydrofuran (5 mL) was added triphenylphosphine (559 mg, 2.130 mmol) and N-tertbutoxycarbonyl-2-aminoethanol (330 uL, 2.130 mmol). Under ice cooling, diisopropyl azodicarboxylate (414 uL, 2.130 mmol) was added, and the mixture was stirred at room temperature for 1 hour and 20 minutes. The reaction solution was purified by silica gel chromatography (hexane / ethyl acetate) to give compound 2 (690 mg, yield: 99%) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: 1.37-1.44 (m, 12H), 3.64 (dt, J = 5.6, 5.6 Hz, 2H), 4.37 (q, J = 7.2 Hz, 2H), 4.71 (t, J = 5.6 Hz, 2H), 4.93 (br s, 1H), 7.11 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H).

化合物２（４８５ｍｇ，１．２３１ｍｍｏｌ）の酢酸エチル（３ｍＬ）溶液に、４ｍｏｌ／Ｌ塩酸／酢酸エチル溶液（１．５３９ｍＬ，６．１６ｍｍｏｌ）を加え、室温で５時間攪拌した。析出した固体を濾取することにより、化合物３（５４５ｍｇ）の粗生成物を白色固体として得た。
¹H-NMR (DMSO-D₆)δ:. 1.35 (t, J = 7.2 Hz, 3H), 3.34 (t, J = 6.1 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 4.79 (t, J = 6.1 Hz, 2H), 7.50 (dt, J = 9.0, 2.2 Hz, 3H), 7.94 (dt, J = 9.0, 2.2 Hz, 2H), 8.08 (s, 3H). Second Step: Method for Producing Compound 3

To a solution of compound 2 (485 mg, 1.231 mmol) in ethyl acetate (3 mL) was added 4 mol / L hydrochloric acid / ethyl acetate solution (1.539 mL, 6.16 mmol), and the mixture was stirred at room temperature for 5 hours. The precipitated solid was collected by filtration to give a crude product of compound 3 (545 mg) as a white solid.
¹ H-NMR (DMSO-D ₆ ) δ: 1.35 (t, J = 7.2 Hz, 3H), 3.34 (t, J = 6.1 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 4.79 (t, J = 6.1 Hz, 2H), 7.50 (dt, J = 9.0, 2.2 Hz, 3H), 7.94 (dt, J = 9.0, 2.2 Hz, 2H), 8.08 (s, 3H).

化合物３（１．４２ｇ，４．３０ｍｍｏｌ）のエタノール（２５ｍＬ）溶液に、トリエチルアミン（２．３８ｍＬ，１７．２０ｍｍｏｌ）を加え、５０℃で５時間攪拌した。反応液を減圧濃縮した後、水（３０ｍＬ）を加え、析出した固体を濾過することにより、化合物４（１．０５ｇ，収率：９９％）を白色固体として得た。
¹H-NMR (DMSO-D₆)δ:. 3.62-3.66 (m, 2H), 4.33-4.38 (m, 2H), 7.26 (s, 1H), 7.48 (dt, J = 9.0, 2.2 Hz, 2H), 7.89 (dt, J = 9.0, 2.2 Hz, 2H), 8.26 (s, 1H). Step 3 Production Method of Compound 4

Triethylamine (2.38 mL, 17.20 mmol) was added to a solution of compound 3 (1.42 g, 4.30 mmol) in ethanol (25 mL), and the mixture was stirred at 50 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water (30 mL) was added, and the precipitated solid was filtered to give compound 4 (1.05 g, yield: 99%) as a white solid.
¹ H-NMR (DMSO-D ₆ ) δ: 3.62-3.66 (m, 2H), 4.33-4.38 (m, 2H), 7.26 (s, 1H), 7.48 (dt, J = 9.0, 2.2 Hz, 2H ), 7.89 (dt, J = 9.0, 2.2 Hz, 2H), 8.26 (s, 1H).

化合物４（３０ｍｇ，０．１２１ｍｍｏｌ）のテトラヒドロフラン（０．５ｍＬ）溶液に、氷冷下、ｔｅｒｔ−ブトキシカリウム（１６．３ｍｇ，０．１４５ｍｍｏｌ）を加え、１０分間攪拌した。２−ブロモプロピオン酸エチル（１９ｕＬ，０．１４５ｍｍｏｌ）を加え、室温で４時間３０分攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して減圧濃縮した。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（１５ｍｇ，収率：３６％）を白色固体として得た。
¹H-NMR (CDCl₃)δ: . 1.29 (t, J = 7.2 Hz, 3H), 1.54 (d, J = 7.4 Hz, 2H), 3.75-3.93 (m, 2H), 4.16-4.28 (m, 2H), 4.39-4.54 (m, 2H), 5.44 (q, J = 7.4 Hz, 1H), 7.14 (s, 1H), 7.39 (dt, J = 9.0, 2.1 Hz, 2H), 7.74 (dt, J = 9.0, 2.2 Hz, 2H). Example 2 Production Method 1 of Compound 5 Step 1 Production Method of Compound 5

To a tetrahydrofuran (0.5 mL) solution of compound 4 (30 mg, 0.121 mmol) was added tert-butoxypotassium (16.3 mg, 0.145 mmol) under ice cooling, and the mixture was stirred for 10 minutes. Ethyl 2-bromopropionate (19 uL, 0.145 mmol) was added, and the mixture was stirred at room temperature for 4 hours 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give compound 5 (15 mg, yield: 36%) as a white solid.
¹ H-NMR (CDCl ₃ ) δ: .1.29 (t, J = 7.2 Hz, 3H), 1.54 (d, J = 7.4 Hz, 2H), 3.75-3.93 (m, 2H), 4.16-4.28 (m, 2H), 4.39-4.54 (m, 2H), 5.44 (q, J = 7.4 Hz, 1H), 7.14 (s, 1H), 7.39 (dt, J = 9.0, 2.1 Hz, 2H), 7.74 (dt, J = 9.0, 2.2 Hz, 2H).

化合物４（２００ｍｇ，０．８０７ｍｍｏｌ）のテトラヒドロフラン（２ｍＬ）溶液に、氷冷下、ｔｅｒｔ−ブトキシカリウム（１０９ｍｇ，０．９６９ｍｍｏｌ）を加え、１０分間攪拌した。ブロモ酢酸エチル（１０７ｕＬ，０．１４５ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液にエタノール（２ｍＬ）および２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１．２１１ｍＬ，２．４２２ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応液を減圧濃縮後、２ｍｏｌ／Ｌ塩酸水溶液を１．７ｍＬ加え、酢酸エチルで２回抽出した。有機層を無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣を酢酸エチル／ヘキサンにて懸濁精製することにより、化合物６（２３５ｍｇ，収率：９５％）を白色固体として得た。
¹H-NMR (DMSO-D₆)δ: . 3.90 (t, J = 6.8 Hz, 2H), 4.24 (s, 2H), 4.46 (t, J = 6.8 Hz, 2H), 7.33 (s, 1H), 7.48 (dt, J = 9.0, 2.2 Hz, 2H), 7.90 (dt, J = 9.0, 2.2 Hz, 2H), 12.92 (s, 1H). Example 3 Production Method 1 of Compound 6 Step 1 Production Method of Compound 6

To a solution of compound 4 (200 mg, 0.807 mmol) in tetrahydrofuran (2 mL) was added tert-butoxypotassium (109 mg, 0.969 mmol) under ice cooling, and the mixture was stirred for 10 minutes. Ethyl bromoacetate (107 uL, 0.145 mmol) was added and stirred at room temperature for 1 hour. Ethanol (2 mL) and a 2 mol / L aqueous sodium hydroxide solution (1.211 mL, 2.422 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, 1.7 mL of 2 mol / L hydrochloric acid aqueous solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by suspension in ethyl acetate / hexane to give Compound 6 (235 mg, yield: 95%) as a white solid.
¹ H-NMR (DMSO-D ₆ ) δ: 3.90 (t, J = 6.8 Hz, 2H), 4.24 (s, 2H), 4.46 (t, J = 6.8 Hz, 2H), 7.33 (s, 1H) , 7.48 (dt, J = 9.0, 2.2 Hz, 2H), 7.90 (dt, J = 9.0, 2.2 Hz, 2H), 12.92 (s, 1H).

化合物６（１３０ｍｇ，０．４２５ｍｍｏｌ）のｔｅｒｔ−ブタノール（２ｍＬ）溶液に、トリエチルアミン（８８ｕＬ，０．６３８ｍｍｏｌ）およびＤＰＰＡ（１３７ｕＬ，０．６３８ｍｍｏｌ）を加え、８０℃で４時間３０分攪拌した。反応液を減圧濃縮し、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（６２ｍｇ，収率：３９％）を白色固体として得た。
¹H-NMR (DMSO-D₆)δ: . 1.40 (s, 9H), 3.81 (t, J = 6.0 Hz, 2H), 4.41 (t, J = 6.0 Hz, 2H), 4.73 (d, J = 5.8 Hz, 2H), 7.32 (s, 1H), 7.45-7.50 (m, 2H), 7.68 (br s, 1H), 7.87-7.92 (m, 2H). Example 4 Production Method 1 of Compound 8 First Step Production Method of Compound 7

Triethylamine (88 uL, 0.638 mmol) and DPPA (137 uL, 0.638 mmol) were added to a tert-butanol (2 mL) solution of compound 6 (130 mg, 0.425 mmol), and the mixture was stirred at 80 ° C. for 4 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give compound 7 (62 mg, yield: 39%) as a white solid.
¹ H-NMR (DMSO-D ₆ ) δ: .1.40 (s, 9H), 3.81 (t, J = 6.0 Hz, 2H), 4.41 (t, J = 6.0 Hz, 2H), 4.73 (d, J = 5.8 Hz, 2H), 7.32 (s, 1H), 7.45-7.50 (m, 2H), 7.68 (br s, 1H), 7.87-7.92 (m, 2H).

化合物７（６０ｍｇ，０．１５９ｍｍｏｌ）のエタノール（１ｍＬ）およびクロロホルム（１ｍＬ）の混合溶液に、４ｍｏｌ／Ｌ塩酸／酢酸エチル溶液（０．５ｍＬ，２．０００ｍｍｏｌ）を加え、室温で１時間攪拌した。反応液を減圧濃縮し、得られた残渣のメタノール（２ｍＬ）溶液に、トリエチルアミン（６６．２ｕＬ，０．４７８ｍｍｏｌ）および無水酢酸（２２．６ｕＬ，０．２３９ｍｍｏｌ）を加え、室温で２時間攪拌した。析出した固体を濾過し、得られた固体をシリカゲルクロマトグラフィー（クロロホルム／メタノール）で精製することにより、化合物８（３０ｍｇ，収率：５９％）を白色固体として得た。
¹H-NMR (DMSO-D₆)δ: . 1.87 (s, 3H), 3.85 (t, J = 6.9 Hz, 2H), 4.41 (t, J = 6.9 Hz, 2H), 4.80 (d, J = 6.3 Hz, 2H), 7.33 (s, 1H), 7.48 (dt, J = 9.0, 2.2 Hz, 2H), 7.90 (dt, J = 9.0, 2.2 Hz, 2H), 8.67 (t, J = 6.3 Hz, 1H). Second Step: Method for Producing Compound 8

To a mixed solution of compound 7 (60 mg, 0.159 mmol) in ethanol (1 mL) and chloroform (1 mL) was added 4 mol / L hydrochloric acid / ethyl acetate solution (0.5 mL, 2.000 mmol), and the mixture was stirred at room temperature for 1 hour. . The reaction mixture was concentrated under reduced pressure, triethylamine (66.2 uL, 0.478 mmol) and acetic anhydride (22.6 uL, 0.239 mmol) were added to a methanol (2 mL) solution of the obtained residue, and the mixture was stirred at room temperature for 2 hours. . The precipitated solid was filtered, and the obtained solid was purified by silica gel chromatography (chloroform / methanol) to obtain Compound 8 (30 mg, yield: 59%) as a white solid.
¹ H-NMR (DMSO-D ₆ ) δ: 1.87 (s, 3H), 3.85 (t, J = 6.9 Hz, 2H), 4.41 (t, J = 6.9 Hz, 2H), 4.80 (d, J = 6.3 Hz, 2H), 7.33 (s, 1H), 7.48 (dt, J = 9.0, 2.2 Hz, 2H), 7.90 (dt, J = 9.0, 2.2 Hz, 2H), 8.67 (t, J = 6.3 Hz, 1H).

化合物６（５０ｍｇ，０．１６４ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．５ｍＬ）溶液に、トリエチルアミン（２７ｕＬ，０．１９６ｍｍｏｌ）、ＨＡＴＵ（７４．６ｍｇ，０．１９６ｍｍｏｌ）およびエチルピペリジン−４−カルボキシレート（３０ｕＬ，０．１９６ｍｍｏｌ）を加え、室温で攪拌した。反応液に１０％クエン酸水溶液を加え、酢酸エチルで２回抽出した。有機層を１０％クエン酸水溶液、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をヘキサン／酢酸エチルで懸濁精製することにより、化合物９（６８ｍｇ，収率：９４％）を白色固体として得た。
¹H-NMR (DMSO-D₆)δ: . 1.19 (t, J = 7.0 Hz, 3H), 1.34-1.47 (m, 1H), 1.52-1.66 (m, 1H), 1.86 (t, J = 13.2 Hz, 2H), 2.59-2.66 (m, 1H), 2.78 (t, J = 11.4 Hz, 1H), 3.14 (t, J = 11.4 Hz, 1H), 3.75-3.86 (m, 3H), 4.09 (q, J = 7.1 Hz, 2H), 4.15-4.24 (m, 1H), 4.39-4.48 (m, 4H), 7.30 (s, 1H), 7.48 (dd, J = 6.8, 2.0 Hz, 2H), 7.90 (dd, J = 6.8, 2.0 Hz, 2H). Example 5 Production Method 1 of Compound 10 First Step Production Method of Compound 9

To a solution of compound 6 (50 mg, 0.164 mmol) in N, N-dimethylformamide (0.5 mL) was added triethylamine (27 uL, 0.196 mmol), HATU (74.6 mg, 0.196 mmol) and ethylpiperidine-4-carboxyl. The rate (30 uL, 0.196 mmol) was added and stirred at room temperature. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by suspension in hexane / ethyl acetate to give Compound 9 (68 mg, yield: 94%) as a white solid.
¹ H-NMR (DMSO-D ₆ ) δ: 1.19 (t, J = 7.0 Hz, 3H), 1.34-1.47 (m, 1H), 1.52-1.66 (m, 1H), 1.86 (t, J = 13.2 Hz, 2H), 2.59-2.66 (m, 1H), 2.78 (t, J = 11.4 Hz, 1H), 3.14 (t, J = 11.4 Hz, 1H), 3.75-3.86 (m, 3H), 4.09 (q , J = 7.1 Hz, 2H), 4.15-4.24 (m, 1H), 4.39-4.48 (m, 4H), 7.30 (s, 1H), 7.48 (dd, J = 6.8, 2.0 Hz, 2H), 7.90 ( dd, J = 6.8, 2.0 Hz, 2H).

化合物９（５８ｍｇ，０．１３０ｍｍｏｌ）のエタノール（１ｍＬ）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１９６ｕＬ，０．３９１ｍｍｏｌ）を加え、室温で２時間攪拌した。反応液に２ｍｏｌ／Ｌ塩酸水溶液（２００ｕＬ，０．４００ｍｍｏｌ）を加え、減圧濃縮した。得られた残渣に水（５ｍＬ）を加えて、室温で３０分攪拌した。析出した固体を濾取することにより、化合物１０（４８ｍｇ，収率：８８％）を白色固体として得た。
¹H-NMR (DMSO-D6)δ:. 1.39 (dd, J = 20.1, 10.8 Hz, 1H), 1.57 (q, J = 10.5 Hz, 1H), 1.85 (t, J = 12.7 Hz, 2H), 2.46-2.57 (m, 1H), 2.77 (t, J = 11.4 Hz, 1H), 3.13 (t, J = 11.4 Hz, 1H), 3.75-3.87 (m, 3H), 4.14-4.22 (m, 1H), 4.38-4.48 (m, 4H), 7.30 (s, 1H), 7.48 (dd, J = 6.8, 2.0 Hz, 2H), 7.90 (dd, J = 6.8, 2.0 Hz, 2H), 12.32 (s, 1H). Second Step: Method for Producing Compound 10

To a solution of compound 9 (58 mg, 0.130 mmol) in ethanol (1 mL) was added 2 mol / L aqueous sodium hydroxide solution (196 uL, 0.391 mmol), and the mixture was stirred at room temperature for 2 hours. A 2 mol / L aqueous hydrochloric acid solution (200 uL, 0.400 mmol) was added to the reaction solution, and the mixture was concentrated under reduced pressure. Water (5 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration to give compound 10 (48 mg, yield: 88%) as a white solid.
¹ H-NMR (DMSO-D6) δ: 1.39 (dd, J = 20.1, 10.8 Hz, 1H), 1.57 (q, J = 10.5 Hz, 1H), 1.85 (t, J = 12.7 Hz, 2H), 2.46-2.57 (m, 1H), 2.77 (t, J = 11.4 Hz, 1H), 3.13 (t, J = 11.4 Hz, 1H), 3.75-3.87 (m, 3H), 4.14-4.22 (m, 1H) , 4.38-4.48 (m, 4H), 7.30 (s, 1H), 7.48 (dd, J = 6.8, 2.0 Hz, 2H), 7.90 (dd, J = 6.8, 2.0 Hz, 2H), 12.32 (s, 1H ).

化合物１（１．２５ｇ，４．９９ｍｍｏｌ）のアセトニトリル（７．５ｍＬ）溶液に、炭酸カリウム（２．７６ｇ，１９．９５ｍｍｏｌ）、１，２−ジブロモエタン（４．３０ｍＬ， ４９．８６ｍｍｏｌ）およびヨウ化カリウム（４１４ｍｇ，２．４９３ｍｍｏｌ）を加え、一晩加熱還流した。反応液に水を加え、クロロホルムで２回抽出した。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１１（８９３ｍｇ，収率：５０％）を白色固体として得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｃ、LC-MS: m/z=367. [M+H]⁺、保持時間：2.87分 Example 6 Production Method 1 of Compound 12 First Step Production Method of Compound 11

To a solution of compound 1 (1.25 g, 4.99 mmol) in acetonitrile (7.5 mL) was added potassium carbonate (2.76 g, 19.95 mmol), 1,2-dibromoethane (4.30 mL, 49.86 mmol) and iodine. Potassium chloride (414 mg, 2.493 mmol) was added, and the mixture was heated to reflux overnight. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. 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 11 (893 mg, yield: 50%) as a white solid.
LC / MS Method: C, LC-MS: m / z = 367. [M + H] ⁺ , retention time: 2.87 minutes

化合物１１（２０ｍｇ，０．０５６ｍｍｏｌ）のアセトニトリル（７．５ｍＬ）溶液に、２−エトキシエチルアミン（４９．８ｍｇ，０．５５９ｍｍｏｌ）およびヨウ化カリウム（１．９ｍｇ，０．０１１ｍｍｏｌ）を加え、一晩加熱還流した。反応液に水を加え、クロロホルムで２回抽出した。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１２（５．６ｍｇ，収率：３１％）を黄色固体として得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｃ、LC-MS: m/z=320. [M+H]⁺、保持時間：1.97分 Second Step: Method for Producing Compound 12

To a solution of compound 11 (20 mg, 0.056 mmol) in acetonitrile (7.5 mL), 2-ethoxyethylamine (49.8 mg, 0.559 mmol) and potassium iodide (1.9 mg, 0.011 mmol) were added overnight. Heated to reflux. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. 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 12 (5.6 mg, yield: 31%) as a yellow solid.
LC / MS Method: C, LC-MS: m / z = 320. [M + H] ⁺ , retention time: 1.97 minutes

化合物１３（１５０ｍｇ，０．５７３ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（３ｍＬ）溶液に、水素化ナトリウム（２７．５ｍｇ，０．６８８ｍｍｏｌ）を加え、室温で２０分間攪拌した。反応液にメチル ３−（ブロモメチル）ベンゾエート（１７１ｍｇ，０．７４５ｍｍｏｌ）を加え、室温で１時間３０分攪拌した。反応液に１ｍｏｌ／Ｌ塩酸水溶液を加え、酢酸エチルで抽出した。有機層を水で洗浄後、無水硫酸マグネシウムで乾燥して減圧濃縮した。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１４（２３５ｍｇ，収率：ｑｕａｎｔ．）を淡白色固体として得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｃ、LC-MS: m/z=401. [M+H]⁺、保持時間：2.41分 Example 7 Production Method 1 of Compound 15 First Step Production Method of Compound 14

To a solution of compound 13 (150 mg, 0.573 mmol) in N, N-dimethylformamide (3 mL) was added sodium hydride (27.5 mg, 0.688 mmol), and the mixture was stirred at room temperature for 20 minutes. Methyl 3- (bromomethyl) benzoate (171 mg, 0.745 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr 30 min. A 1 mol / L aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give Compound 14 (235 mg, yield: quant.) As a pale white solid.
LC / MS Method: C, LC-MS: m / z = 401. [M + H] ⁺ , retention time: 2.41 minutes

化合物１４（２３５ｍｇ，０．５７３ｍｍｏｌ）のテトラヒドロフラン（２．５ｍＬ）およびメタノール（２．５ｍＬ）混合溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１．４３３ｍＬ，２．８７ｍｍｏｌ）を加え、室温で２時間３０分攪拌した。反応液を減圧濃縮し、得られた残渣に２ｍｏｌ／Ｌ塩酸水溶液と水を加えｐＨ２とした。析出した固体を濾過することにより、化合物１５（２１０ｍｇ，収率：９３％）を白色固体として得た。
¹H-NMR (δppm TMS/ DMSO-D6)δ: 7.93-7.87 (m, 4H), 7.62 (d, 1H, J = 7.3 Hz), 7.50-7.47 (m, 3H), 7.35 (s, 1H), 5.11 (d, 1H, J = 15.3 Hz), 4.46-4.42 (m, 2H), 4.30 (d, 1H, J = 13.3 Hz), 4.01-3.99 (m, 1H), 1.16 (d, 3H, J = 6.5 Hz). Second Step: Method for Producing Compound 15

To a mixed solution of compound 14 (235 mg, 0.573 mmol) in tetrahydrofuran (2.5 mL) and methanol (2.5 mL) was added 2 mol / L aqueous sodium hydroxide solution (1.433 mL, 2.87 mmol), and at room temperature for 2 hours. Stir for 30 minutes. The reaction solution was concentrated under reduced pressure, and a 2 mol / L hydrochloric acid aqueous solution and water were added to the resulting residue to adjust to pH 2. The precipitated solid was filtered to obtain Compound 15 (210 mg, yield: 93%) as a white solid.
¹ H-NMR (δppm TMS / DMSO-D6) δ: 7.93-7.87 (m, 4H), 7.62 (d, 1H, J = 7.3 Hz), 7.50-7.47 (m, 3H), 7.35 (s, 1H) , 5.11 (d, 1H, J = 15.3 Hz), 4.46-4.42 (m, 2H), 4.30 (d, 1H, J = 13.3 Hz), 4.01-3.99 (m, 1H), 1.16 (d, 3H, J = 6.5 Hz).

化合物１６（１８．６ｇ，１２６ｍｍｏｌ）のｔｅｒｔ−ブタノール（１８０ｍＬ）溶液に、ジ−ｔｅｒｔ−ブチルカーボネート（８７．６ｍＬ，３７７ｍｍｏｌ）およびＤＭＡＰ（１．５４ｇ，１２．６ｍｍｏｌ）を加え、５０℃で３時間攪拌した。反応液に２ｍｏｌ／Ｌ塩酸水溶液を加え、酢酸エチルで抽出した。有機層を２ｍｏｌ／Ｌ水酸化ナトリウム水溶液および水で洗浄後、無水硫酸マグネシ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１７（２４．０ｇ，収率：９３％）を淡黄色油状物として得た。
¹H-NMR (δppm TMS/ CDCl3)δ: 7.93-7.87 (m, 4H), 7.62 (d, 1H, J = 7.3 Hz), 7.50-7.47 (m, 3H), 7.35 (s, 1H), 5.11 (d, 1H, J = 15.3 Hz), 4.46-4.42 (m, 2H), 4.30 (d, 1H, J = 13.3 Hz), 4.01-3.99 (m, 1H), 1.16 (d, 3H, J = 6.5 Hz). Example 8 Production Method 1 of Compound 18 First Step Production Method of Compound 17

To a solution of compound 16 (18.6 g, 126 mmol) in tert-butanol (180 mL) was added di-tert-butyl carbonate (87.6 mL, 377 mmol) and DMAP (1.54 g, 12.6 mmol). Stir for hours. A 2 mol / L aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 2 mol / L aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give Compound 17 (24.0 g, yield: 93%) as a pale yellow oil.
¹ H-NMR (δppm TMS / CDCl3) δ: 7.93-7.87 (m, 4H), 7.62 (d, 1H, J = 7.3 Hz), 7.50-7.47 (m, 3H), 7.35 (s, 1H), 5.11 (d, 1H, J = 15.3 Hz), 4.46-4.42 (m, 2H), 4.30 (d, 1H, J = 13.3 Hz), 4.01-3.99 (m, 1H), 1.16 (d, 3H, J = 6.5 Hz).

Ｔｅｒｔ−ブチルカーバメート（１．７２ｇ，１４．６９ｍｍｏｌ）の１−プロパノール（５ｍＬ）溶液に０．６ｍｏｌ／Ｌ水酸化ナトリウム水溶液（２４．５ｍＬ，１４．６９ｍｍｏｌ）および次亜塩素酸ｔｅｒｔ−ブチル（１．６６ｍＬ，１４．６９ｍｍｏｌ）を加え、氷冷下に冷却した。反応液に（ＤＨＱ）２ＰＨＡＬ（２２９ｍｇ，０．２９４ｍｍｏｌ）の１−プロパノール（５ｍＬ）溶液、化合物１７（１ｇ，４．９０ｍｍｏｌ）の１−プロパノール（５ｍＬ）溶液およびオスミウム（ＶＩ）酸カリウム二水和物（７２．２ｍｇ，０．１９６ｍｍｏｌ）を加え、氷冷下４時間攪拌した。反応液を減圧濃縮後、水を加え、酢酸エチルで抽出した。有機層を１ｍｏｌ／Ｌ塩酸水溶液および飽和食塩水で洗浄後、無水硫酸マグネシ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１８（８６５ｍｇ，収率：５２％）を白色固体として得た。
¹H-NMR (MeOD)δ: 7.91 (2H, d, J = 7.8 Hz), 7.40 (2H, d, J = 8.0 Hz), 4.70 (1H, s), 3.72-3.62 (2H, m), 1.58 (9H, s), 1.43 (9H, s). Second Step: Production Method of Compound 18

A solution of Tert-butyl carbamate (1.72 g, 14.69 mmol) in 1-propanol (5 mL) was added with a 0.6 mol / L aqueous sodium hydroxide solution (24.5 mL, 14.69 mmol) and tert-butyl hypochlorite (1 .66 mL, 14.69 mmol) was added, and the mixture was cooled under ice cooling. (DHQ) 2PHAL (229 mg, 0.294 mmol) in 1-propanol (5 mL), Compound 17 (1 g, 4.90 mmol) in 1-propanol (5 mL) and osmium (VI) potassium dihydrate The product (72.2 mg, 0.196 mmol) was added and stirred for 4 hours under ice cooling. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol / L hydrochloric acid aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give Compound 18 (865 mg, yield: 52%) as a white solid.
¹ H-NMR (MeOD) δ: 7.91 (2H, d, J = 7.8 Hz), 7.40 (2H, d, J = 8.0 Hz), 4.70 (1H, s), 3.72-3.62 (2H, m), 1.58 (9H, s), 1.43 (9H, s).

Ｔｅｒｔ−ブチルカーバメート（１．７２ｇ，１４．６９ｍｍｏｌ）の１−プロパノール（５ｍＬ）溶液に０．６ｍｏｌ／Ｌ水酸化ナトリウム水溶液（２４．５ｍＬ，１４．６９ｍｍｏｌ）および次亜塩素酸ｔｅｒｔ−ブチル（１．６６ｍＬ，１４．６９ｍｍｏｌ）を加え、氷冷下に冷却した。反応液に（ＤＨＱＤ）２ＰＨＡＬ（２２９ｍｇ，０．２９４ｍｍｏｌ）の１−プロパノール（５ｍＬ）溶液、化合物１７（１ｇ，４．９０ｍｍｏｌ）の１−プロパノール（５ｍＬ）溶液およびオスミウム（ＶＩ）酸カリウム二水和物（７２．２ｍｇ，０．１９６ｍｍｏｌ）を加え、氷冷下４時間攪拌した。反応液を減圧濃縮後、水を加え、酢酸エチルで抽出した。有機層を１ｍｏｌ／Ｌ塩酸水溶液および飽和食塩水で洗浄後、無水硫酸マグネシ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１９（９２０ｍｇ，収率：５６％）を白色固体として得た。
¹H-NMR (MeOD)δ: 7.91 (2H, d, J = 7.8 Hz), 7.40 (2H, d, J = 8.0 Hz), 4.70 (1H, s), 3.72-3.62 (2H, m), 1.58 (9H, s), 1.43 (9H, s).. Example 9 Production Method 1 of Compound 19 First Step Production Method of Compound 19

A solution of Tert-butyl carbamate (1.72 g, 14.69 mmol) in 1-propanol (5 mL) was added with a 0.6 mol / L aqueous sodium hydroxide solution (24.5 mL, 14.69 mmol) and tert-butyl hypochlorite (1 .66 mL, 14.69 mmol) was added, and the mixture was cooled under ice cooling. (DHQD) 2PHAL (229 mg, 0.294 mmol) in 1-propanol (5 mL), Compound 17 (1 g, 4.90 mmol) in 1-propanol (5 mL) and osmium (VI) potassium dihydrate The product (72.2 mg, 0.196 mmol) was added and stirred for 4 hours under ice cooling. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol / L hydrochloric acid aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give Compound 19 (920 mg, yield: 56%) as a white solid.
¹ H-NMR (MeOD) δ: 7.91 (2H, d, J = 7.8 Hz), 7.40 (2H, d, J = 8.0 Hz), 4.70 (1H, s), 3.72-3.62 (2H, m), 1.58 (9H, s), 1.43 (9H, s) ..

化合物２０（４９４．４ｍｇ，１．１６６ｍｍｏｌ）のトリフルオロ酢酸（２ｍＬ）溶液を室温で１時間攪拌した。反応液を減圧濃縮し、トルエンで共沸した。得られた残渣をジイソプロピルエーテルで懸濁精製することにより、化合物２１（４４０．５ｍｇ，収率：ｑｕａｎｔ．）を白色固体として得た。
¹H-NMR (DMSO-D6)δ: 12.95 (s, 1H), 8.84 (s, 1H), 7.94 (d, 2H, J = 8.0 Hz), 7.86 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.2 Hz), 7.46 (d, 2H, J = 8.3 Hz), 7.34 (s, 1H), 5.23 (s, 1H), 4.72 (dd, 1H, J = 13.2, 4.8 Hz), 4.52 (dd, 1H, J = 13.2, 6.0 Hz). Example 10 Production Method 1 of Compound 22 First Step Production Method of Compound 21

A solution of compound 20 (494.4 mg, 1.166 mmol) in trifluoroacetic acid (2 mL) was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and azeotroped with toluene. The resulting residue was purified by suspension with diisopropyl ether to obtain Compound 21 (440.5 mg, yield: quant.) As a white solid.
¹ H-NMR (DMSO-D6) δ: 12.95 (s, 1H), 8.84 (s, 1H), 7.94 (d, 2H, J = 8.0 Hz), 7.86 (d, 2H, J = 8.4 Hz), 7.52 (d, 2H, J = 8.2 Hz), 7.46 (d, 2H, J = 8.3 Hz), 7.34 (s, 1H), 5.23 (s, 1H), 4.72 (dd, 1H, J = 13.2, 4.8 Hz) , 4.52 (dd, 1H, J = 13.2, 6.0 Hz).

化合物２１（２０ｍｇ，０．０５４ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．２ｍＬ）溶液に、トリエチルアミン（２２．６ｕＬ，０．１６３ｍｍｏｌ）、ＨＡＴＵ（３１．０ｍｇ，０．０８２ｍｍｏｌ）および２−モルホリノエタンアミン（１０．７ｕＬ，０．０８２ｍｍｏｌ）を加え、室温で１５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し、得られた残渣をシリカゲルクロマトグラフィー（クロロホルム／メタノール）で精製後、イソプロピルエーテルで懸濁精製することにより、化合物２２（１４．５ｍｇ，収率：５６％）を白色固体として得た。
¹H-NMR (DMSO-D6)δ: 8.82 (s, 1H), 8.38 (s, 1H), 7.83 (dd, 4H, J = 20.2, 7.7 Hz), 7.47-7.46 (m, 4H), 7.33 (s, 1H), 5.19 (s, 1H), 4.71 (dd, 1H, J = 6.7, 3.3 Hz), 4.51 (dd, 1H, J = 13.2, 5.9 Hz), 3.55 (s, 4H), 3.36-3.33 (m, 2H), 2.43-2.40 (m, 6H). . Second Step: Method for Producing Compound 22

To a solution of compound 21 (20 mg, 0.054 mmol) in N, N-dimethylformamide (0.2 mL) was added triethylamine (22.6 uL, 0.163 mmol), HATU (31.0 mg, 0.082 mmol) and 2-morpholinoethane. Amine (10.7 uL, 0.082 mmol) was added and stirred at room temperature for 15 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. The obtained residue was purified by silica gel chromatography (chloroform / methanol) and then suspended and purified with isopropyl ether to give compound 22 (14.5 mg, yield). : 56%) as a white solid.
¹ H-NMR (DMSO-D6) δ: 8.82 (s, 1H), 8.38 (s, 1H), 7.83 (dd, 4H, J = 20.2, 7.7 Hz), 7.47-7.46 (m, 4H), 7.33 ( s, 1H), 5.19 (s, 1H), 4.71 (dd, 1H, J = 6.7, 3.3 Hz), 4.51 (dd, 1H, J = 13.2, 5.9 Hz), 3.55 (s, 4H), 3.36-3.33 (m, 2H), 2.43-2.40 (m, 6H) ...

化合物２３（１．３ｇ，３．５７ｍｍｏｌ）のテトラヒドロフラン（１５ｍＬ）溶液に、５−クロロ−２−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）アニリン（１．８１ｇ，０．１９ｍｍｏｌ）、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）（３８１ｍｇ，０．５３５ｍｍｏｌ）および１ｍｍｏｌ／Ｌリン酸三カリウム水溶液（１０．７１ｍＬ，１０．７１ｍｍｏｌ）を加え、５５℃で４０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した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）にて精製することにより、化合物２４（１．０３ｇ，収率：７０％）を白色固体として得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、LC-MS: m/z=411. [M+H]+、保持時間：2.12分 Example 11 Production Method 1 of Compound 25 First Step Production Method of Compound 24

To a solution of compound 23 (1.3 g, 3.57 mmol) in tetrahydrofuran (15 mL) was added 5-chloro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline. (1.81 g, 0.19 mmol), chloro (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) [2- (2′-amino-1,1 ′ -Biphenyl)] palladium (II) (381 mg, 0.535 mmol) and 1 mmol / L tripotassium phosphate aqueous solution (10.71 mL, 10.71 mmol) were added, and the mixture was stirred at 55 ° C. for 40 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. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give compound 24 (1.03 g, yield: 70%) as a white solid.
LC / MS Method: B, LC-MS: m / z = 411. [M + H] +, Retention time: 2.12 minutes

化合物２４（１ｇ，２．４３４ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に、氷冷下、ピリジン（９８０ｕＬ，１２．１７ｍｍｏｌ）および塩化アセチル（２６１ｕＬ，３．６５ｍｍｏｌ）を加え、１時間３０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した。得られた残渣を酢酸エチル／ヘキサンにて懸濁精製することにより、化合物２５（６９０ｍｇ，収率：６３％）を黄色固体として得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、LC-MS: m/z=453. [M+H]+、保持時間：2.11分
¹H-NMR (CDCl₃)δ: 10.94 (1H, s), 8.72 (1H, s), 8.01 (2H, d, J = 7.8 Hz), 7.56 (2H, t, J = 9.2 Hz), 7.47 (1H, t, J = 7.7 Hz), 7.24 (1H, s), 7.10 (1H, dd, J = 8.5, 2.0 Hz), 4.85 (2H, s), 4.41 (2H, t, J = 6.1 Hz), 3.93 (3H, s), 3.76 (2H, t, J = 6.1 Hz), 2.19 (3H, s). Second Step: Method for Producing Compound 25

Pyridine (980 uL, 12.17 mmol) and acetyl chloride (261 uL, 3.65 mmol) were added to a solution of compound 24 (1 g, 2.434 mmol) in dichloromethane (10 mL) under ice cooling, and the mixture was stirred for 1 hour 30 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. The obtained residue was purified by suspension in ethyl acetate / hexane to give Compound 25 (690 mg, yield: 63%) as a yellow solid.
LC / MS Method: B, LC-MS: m / z = 453. [M + H] +, Retention time: 2.11 minutes
¹ H-NMR (CDCl ₃ ) δ: 10.94 (1H, s), 8.72 (1H, s), 8.01 (2H, d, J = 7.8 Hz), 7.56 (2H, t, J = 9.2 Hz), 7.47 ( 1H, t, J = 7.7 Hz), 7.24 (1H, s), 7.10 (1H, dd, J = 8.5, 2.0 Hz), 4.85 (2H, s), 4.41 (2H, t, J = 6.1 Hz), 3.93 (3H, s), 3.76 (2H, t, J = 6.1 Hz), 2.19 (3H, s).

化合物２６（２ｇ，８．０２ｍｍｏｌ）のテトラヒドロフラン（８００ｕＬ）溶液に、−１０℃で硫酸（２０ｍＬ，８．０２ｍｍｏｌ）を加え、４０分間攪拌した。反応液を氷水に注ぎ、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カラムクロマトグラフィー（酢酸エチル／ヘキサン）にて精製することにより、化合物２７（２．２ｇ，収率：９３％）を得た。
Shimazu 4 min LC-MS: R.T. = 2.18
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、保持時間：2.18分 Example 12 Production Method 1 of Compound 29 First Step Production Method of Compound 29

To a solution of compound 26 (2 g, 8.02 mmol) in tetrahydrofuran (800 uL) was added sulfuric acid (20 mL, 8.02 mmol) at −10 ° C. and stirred for 40 minutes. The reaction mixture was poured into ice water and 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 column chromatography (ethyl acetate / hexane) to give Compound 27 (2.2 g, yield: 93%).
Shimazu 4 min LC-MS: RT = 2.18
LC / MS Method: B, Retention time: 2.18 minutes

化合物２７（１．７ｇ，５．７７ｍｍｏｌ）のテトラヒドロフラン（２０ｍＬ）溶液に、−７８℃で水素化ジイソブチルアルミニウム（１４．４ｍＬ，１４．４ｍｍｏｌ）を加え、徐々に０℃まで昇温した。反応液を酢酸エチルとメタノールの混合溶媒に注ぎ、その後ロッシェル塩水溶液を加えた。分液後、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カラムクロマトグラフィー（酢酸エチル／ヘキサン）にて精製することにより、化合物２８（１．６５ｇ，収率：ｑｕａｎｔ）を得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、保持時間：1.79, 1.87分 Second Step: Method for Producing Compound 28

To a solution of compound 27 (1.7 g, 5.77 mmol) in tetrahydrofuran (20 mL) was added diisobutylaluminum hydride (14.4 mL, 14.4 mmol) at −78 ° C., and the temperature was gradually raised to 0 ° C. The reaction solution was poured into a mixed solvent of ethyl acetate and methanol, and then an aqueous Rochelle salt solution was added. After separation, 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 column chromatography (ethyl acetate / hexane) to give compound 28 (1.65 g, yield: quant).
LC / MS Method: B, Retention time: 1.79, 1.87 minutes

化合物２８（１．５５ｇ，５．８２ｍｍｏｌ）のエタノール（１０ｍＬ）および水（２．５ｍＬ）の混合溶液に、塩化アンモニウム（９３３ｍｇ，１７．４５ｍｍｏｌ）および鉄（９７４ｍｇ，１７．４５ｍｍｏｌ）を加え、８０℃で２０分間攪拌した。反応液を濾過し、濾液に水を加え、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。得られた残渣を酢酸エチル／ヘキサンにて懸濁精製することにより、化合物２９（６２０ｍｇ，収率：４５％）を白色固体として得た。
¹H-NMR (DMSO-D₆)δ: 6.74 (1H, d, J = 2.8 Hz), 6.69 (1H, d, J = 2.5 Hz), 5.58 (2H, s), 5.41 (1H, t, J = 5.6 Hz), 4.40 (2H, d, J = 5.0 Hz).
LC-MS: m/z=235. [M+H]⁺ Step 3 Process for Producing Compound 29

To a mixed solution of compound 28 (1.55 g, 5.82 mmol) in ethanol (10 mL) and water (2.5 mL) was added ammonium chloride (933 mg, 17.45 mmol) and iron (974 mg, 17.45 mmol). Stir at 20 ° C. for 20 minutes. The reaction mixture was filtered, water was added to the filtrate, 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 suspension in ethyl acetate / hexane to give Compound 29 (620 mg, yield: 45%) as a white solid.
¹ H-NMR (DMSO-D ₆ ) δ: 6.74 (1H, d, J = 2.8 Hz), 6.69 (1H, d, J = 2.5 Hz), 5.58 (2H, s), 5.41 (1H, t, J = 5.6 Hz), 4.40 (2H, d, J = 5.0 Hz).
LC-MS: m / z = 235. [M + H] ⁺

化合物２３（２００ｍｇ，０．５４９ｍｍｏｌ）の１，４−ジオキサン（２ｍＬ）溶液に、ピナコールジボロン（３３４ｍｇ，１．３１８ｍｍｏｌ）、ＰｄＣｌ２（ｄｐｐｆ）−ＤＣＭ（８９．６ｍｇ，０．１１０ｍｍｏｌ）および酢酸カリウム（１６２ｍｇ，１．６４７ｍｍｏｌ）を加え、１０５℃で４時間攪拌した。反応液を濾過し、濾液を減圧濃縮した。得られた残渣をジオールシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）にて精製することにより、化合物３０の粗生成物を褐色油状物として得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、LC-MS: m/z=328. [M+H]+、保持時間：1.34分 Example 13 Production Method 1 of Compound 34 First Step Production Method of Compound 30

To a solution of compound 23 (200 mg, 0.549 mmol) in 1,4-dioxane (2 mL), pinacol diboron (334 mg, 1.318 mmol), PdCl 2 (dppf) -DCM (89.6 mg, 0.110 mmol) and potassium acetate (162 mg, 1.647 mmol) was added, and the mixture was stirred at 105 ° C. for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by diol silica gel column chromatography (ethyl acetate / hexane) to give a crude product of compound 30 as a brown oil.
LC / MS Method: B, LC-MS: m / z = 328. [M + H] +, Retention time: 1.34 minutes

化合物３０（２２０ｍｇ，０．５３５ｍｍｏｌ）のテトラヒドロフラン（２．５ｍＬ）溶液に、化合物２９（１２７ｍｇ，０．５３５ｍｍｏｌ）、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）（３８ｍｇ，０．０５３ｍｍｏｌ）および１ｍｍｏｌ／Ｌリン酸三カリウム水溶液（１．０７ｍＬ，１．０７ｍｍｏｌ）を加え、５０℃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カラムクロマトグラフィー（クロロホルム／メタノール）にて精製することにより、化合物３１（２５０ｍｇ，収率：ｑｕａｎｔ．）を黒色油状物として得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、LC-MS: m/z=441. [M+H]+、保持時間：1.71分 Second Step: Method for Producing Compound 31

To a solution of compound 30 (220 mg, 0.535 mmol) in tetrahydrofuran (2.5 mL), compound 29 (127 mg, 0.535 mmol), chloro (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1 , 1′-biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II) (38 mg, 0.053 mmol) and 1 mmol / L tripotassium phosphate aqueous solution (1.07 mL, 1. 07 mmol) and stirred at 50 ° C. 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 column chromatography (chloroform / methanol) to give compound 31 (250 mg, yield: quant.) As a black oil.
LC / MS Method: B, LC-MS: m / z = 441. [M + H] +, Retention time: 1.71 minutes

化合物３１（７０ｍｇ，０．１５９ｍｍｏｌ）のアセトニトリル（１ｍＬ）溶液に、亜硝酸ｔｅｒｔ−ブチル（５７．１ｕＬ，０．４７６ｍｍｏｌ）およびヨウ化銅（Ｉ）（９１ｍｇ，０．４７６ｍｍｏｌ）を加え、５０℃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カラムクロマトグラフィー（酢酸エチル／ヘキサン）にて精製することにより、化合物３２（３５ｍｇ，収率：４０％）を褐色油状物として得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、LC-MS: m/z=552. [M+H]+、保持時間：2.11分 Third Step: Method for Producing Compound 32

To a solution of compound 31 (70 mg, 0.159 mmol) in acetonitrile (1 mL) was added tert-butyl nitrite (57.1 uL, 0.476 mmol) and copper (I) iodide (91 mg, 0.476 mmol), and 50 ° C. 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 column chromatography (ethyl acetate / hexane) to give compound 32 (35 mg, yield: 40%) as a brown oil.
LC / MS Method: B, LC-MS: m / z = 552. [M + H] +, Retention time: 2.11 minutes

化合物３２（３０ｍｇ，０．１５９ｍｍｏｌ）のＮ，Ｎ−ジメチルアセトアミド（０．８ｍＬ）溶液に、シアン化銅（Ｉ）（１４．６ｍｇ，０．１６３ｍｍｏｌ）を加え、１５０℃で１時間１５分攪拌した。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カラムクロマトグラフィー（メタノール／クロロホルム）にて精製することにより、化合物３３（１３ｍｇ，収率：５３％）を白色固体として得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、LC-MS: m/z=451. [M+H]+、保持時間：1.81分 Fourth Step: Method for Producing Compound 33

To a solution of compound 32 (30 mg, 0.159 mmol) in N, N-dimethylacetamide (0.8 mL) was added copper (I) cyanide (14.6 mg, 0.163 mmol), and the mixture was stirred at 150 ° C. for 1 hour and 15 minutes. did. 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 column chromatography (methanol / chloroform) to give compound 33 (13 mg, yield: 53%) as a white solid.
LC / MS Method: B, LC-MS: m / z = 451. [M + H] +, Retention time: 1.81 minutes

化合物３３（１３ｍｇ，０．０２９ｍｍｏｌ）のテトラヒドロフラン（３００ｕＬ）およびメタノール（３００ｕＬ）混合溶液に、氷冷下、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１４４ｕＬ，０．２８８ｍｍｏｌ）を加え、３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。得られた残渣を逆相カラムクロマトグラフィー（アセトニトリル／水）にて精製することにより、化合物３４（５ｍｇ，収率：４０％）を無色油状物として得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、LC-MS: m/z=436. [M+H]+、保持時間：1.85分
¹H-NMR (CDCl₃)δ: 8.07 (2H, d, J = 7.3 Hz), 7.72 (2H, dd, J = 8.7, 2.1 Hz), 7.64 (1H, d, J = 7.5 Hz), 7.52-7.50 (1H, m), 7.36 (1H, s), 4.86 (2H, s), 4.46-4.44 (4H, m), 3.81-3.75 (3H, m). Step 5: Method for producing compound 34

To a mixed solution of compound 33 (13 mg, 0.029 mmol) in tetrahydrofuran (300 uL) and methanol (300 uL) was added 2 mol / L sodium hydroxide aqueous solution (144 uL, 0.288 mmol) under ice cooling, and the mixture was stirred for 3 hours. 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 reverse phase column chromatography (acetonitrile / water) to give Compound 34 (5 mg, yield: 40%) as a colorless oil.
LC / MS Method: B, LC-MS: m / z = 436. [M + H] +, Retention time: 1.85 minutes
¹ H-NMR (CDCl ₃ ) δ: 8.07 (2H, d, J = 7.3 Hz), 7.72 (2H, dd, J = 8.7, 2.1 Hz), 7.64 (1H, d, J = 7.5 Hz), 7.52- 7.50 (1H, m), 7.36 (1H, s), 4.86 (2H, s), 4.46-4.44 (4H, m), 3.81-3.75 (3H, m).

化合物３５（２ｇ，１４．５８ｍｍｏｌ）のヘキサン（１０ｍＬ）溶液に、（Ｒ）−２−（クロロメチル）オキシラン（１．７２ｍＬ，２１．８７ｍｍｏｌ）を加え、４０℃で１時間３０分攪拌した。反応液を減圧濃縮し、化合物３６（４．０ｇ，収率：ｑｕａｎｔ．）を得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、LC-MS: m/z=230. [M+H]+、保持時間：0.82分 Example 14 Production Method 1 of Compound 37 First Step Production Method of Compound 36

(R) -2- (chloromethyl) oxirane (1.72 mL, 21.87 mmol) was added to a solution of compound 35 (2 g, 14.58 mmol) in hexane (10 mL), and the mixture was stirred at 40 ° C. for 1 hour 30 minutes. The reaction solution was concentrated under reduced pressure to obtain Compound 36 (4.0 g, yield: quant.).
LC / MS Method: B, LC-MS: m / z = 230. [M + H] +, Retention time: 0.82 min

化合物３６（３．３ｇ，１４．３７ｍｍｏｌ）のアセトニトリル（１０ｍＬ）溶液に、カルボニルジイミダゾール（５．６０ｇ，３４．４８ｍｍｏｌ）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カラムクロマトグラフィー（酢酸エチル／ヘキサン）にて精製することにより、化合物３７（１．５ｇ，収率：４１％）を得た。
ＬＣ／ＭＳ Ｍｅｔｈｏｄ：Ｂ、LC-MS: m/z=256. [M+H]+、保持時間：1.67分

同様にして、以下の化合物を合成した。 Second Step: Method for Producing Compound 37

Carbonyldiimidazole (5.60 g, 34.48 mmol) was added to a solution of compound 36 (3.3 g, 14.37 mmol) in acetonitrile (10 mL), and the mixture was 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 dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give Compound 37 (1.5 g, yield: 41%).
LC / MS Method: B, LC-MS: m / z = 256. [M + H] +, Retention time: 1.67 minutes

Similarly, the following compounds were synthesized.

Test Example 1 (Method A) 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) was added. Further, 5 μl of 0.5 μM TG-mTMP diluted with solution A was added and reacted at room temperature for 2 hours. After completion of the reaction, 5 μl of 150 mM EDTA diluted with solution A was added to the reaction solution to stop the reaction, and the fluorescent dye TokyoGreen produced by the reaction was detected.
For detection of TokyoGreen, fluorescence was measured under the conditions of an excitation wavelength of 480 nm / fluorescence wavelength of 540 nm using a measuring device ViewLux (manufactured by PerkinElmer).
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.

Test Example 2 (Method B) 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) was added. Further, 5 μl of 0.5 μM TG-mTMP diluted with solution A was added and reacted at room temperature for 2 hours. After completion of the reaction, 5 μl of 150 mM EDTA diluted with solution A was added to the reaction solution to stop the reaction, and the fluorescent dye TokyoGreen produced by the reaction was detected.
For detection of TokyoGreen, fluorescence was measured under the conditions of an excitation wavelength of 480 nm / fluorescence wavelength of 540 nm using a measuring device ViewLux (manufactured by PerkinElmer).
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.

Test Example 3 (Method C) Evaluation of autotaxin inhibitor
A solution B consisting 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 (diluted with solution B) was added to the compound dissolved in DMSO. 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 3 is shown in the following tables.
Assay method:
Method A: Test Example 1; Method B: Test Example 2; Method C: Test Example 3
Enzyme inhibitory activity:
A: IC50 <10 nM, B: 10 nM ≤ IC50 <100 nM, C: 100 nM ≤ IC50 <1000 nM,
D: 1000 nM ≤ IC50 ≤10000 nM

Test Example 4 CYP Inhibition Test Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) ( 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 5 Evaluation of metabolic stability Metabolic stability evaluation by human liver microsomes: NADPH (final concentration 1 mM, in the case of oxidative metabolism), liver microsomes (final concentration 0.5 mg protein) in 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 6 Powder Solubility Test An appropriate amount of specimen is put in a suitable container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to make 1000 mL), JP-2 solution (phosphorus of pH 6.8). 200 mL of water was added to 500 mL of an acid buffer, and 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (water was added to 1.08 g of TCA to make 100 mL). When dissolved after adding the test solution, a bulk powder was added as appropriate. Sealed and shaken at 37 ° C. for 1 hour. After filtration, 100 μL of methanol was added to 100 μL of each filtrate to perform 2-fold dilution. The dilution factor was changed as necessary. After confirming that there were no bubbles and precipitates, the mixture was sealed and shaken. Quantification was performed using HPLC by the absolute calibration curve method.

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 30 g of the present compound
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 (16)

Formula (I):

(Where
R ¹ is ^one of the following formulas:

(Ring A is a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, a 6-membered non-aromatic carbocyclic ring or a 6-membered non-aromatic heterocyclic ring,
Ring B is a 5-membered aromatic heterocycle, a 5-membered non-aromatic heterocycle or a 5-membered non-aromatic carbocycle,
Ring C is a 4-membered non-aromatic carbocycle or 4-membered non-aromatic heterocycle,
R ^1a is halogen, cyano, substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio Substituted or unsubstituted alkenylthio, or substituted or unsubstituted alkynylthio,
R ^1b 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 An aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted alkyloxy, a 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 alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic Aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkylthio, substituted or unsubstituted The Arkeni Thio, substituted or unsubstituted alkynylthio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted non-substituted Aromatic heterocyclic thio, 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 alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, Substituted or unsubstituted fragrance Carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Sulfamoyl or substituted or unsubstituted amino of
n is an integer of 0-6. )
R ² is hydrogen, halogen, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, 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 Substituted 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 ³ is hydrogen, 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 A substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R ^4a and R ^4b are each independently hydrogen, halogen, cyano, formyl, carboxy, 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 oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkyl Thio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic hetero Ring 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 carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxy Carbonyl, substituted or unsubstituted alkynyloxy Sicarbonyl, 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 nonaromatic carbon Ring 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 Lucenylsulfonyl, substituted or 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 non-substituted Substituted aromatic heterocyclic sulfonyl. ), A compound represented by
(However,
(I) Excludes compounds in which R ³ is hydrogen or unsubstituted alkyl, and R ^4a and R ^4b are simultaneously hydrogen, and (ii) compounds shown below.

) Or a pharmaceutically acceptable salt thereof. R ¹ is the formula:

(Ring A is a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, a 6-membered non-aromatic carbocyclic ring, or a 6-membered non-aromatic heterocyclic ring). 1. The compound according to 1 or a pharmaceutically acceptable salt thereof. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered aromatic carbocycle or a 6-membered aromatic heterocycle. The compound according to claim 2, wherein ring A is a 6-membered aromatic carbocycle, or a pharmaceutically acceptable salt thereof. R ¹ is the formula:

(Wherein m is an integer of 0 to 3, and other symbols are as defined in claim 1), or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ² is hydrogen. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ³ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. R ³ is alkyl substituted with one or more groups selected from substituent group A (wherein substituent group A is hydroxy, carboxy, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or unsubstituted alkynyloxy, 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 ring From carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl and substituted or unsubstituted sulfamoyl The compound according to claim 7, which is alkenyl substituted with one or more groups selected from substituent group A or alkynyl substituted with one or more groups selected from substituent group A Top acceptable salt. R ^4a and R ^4b are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted The compound according to any one of claims 1 to 8, which is a substituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutical thereof Top acceptable salt. R ³ is hydrogen;
Either one of R ^4a and R ^4b is hydrogen and the other is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, The compound according to claim 9, which is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof. Salt. R ³ is hydrogen;
One of R ^4a and R ^4b is hydrogen, and the other is a non-aromatic carbocyclic group substituted with one or more substituents selected from Substituent Group B (wherein Substituent Group B is Halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted Or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted carbamoyl and substituted or unsubstituted sulfamoyl. An aromatic carbocycle substituted with one or more substituents selected from substituent group B Group, a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group B, or an aromatic heterocyclic group substituted with one or more substituents selected from substituent group B The compound according to claim 10 or a pharmaceutically acceptable salt thereof. R ³ is hydrogen;
^11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein one of R ^4a and R ^4b is hydrogen and the other is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkenyl. Salt.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient.   The pharmaceutical composition according to claim 13, which is an autotaxin inhibitor. Formula (I):

(Where
R ¹ represents a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, a substituted or unsubstituted nonaromatic heterocyclic ring Formula group, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, 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 alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic 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 alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or Unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocarbonyl oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or non-substituted Substituted non-aromatic heterocycle O, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted Substituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted alkyl sulfinyl, 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 unsubstituted alkyl sulfonyl, substituted Or unsubstituted Luque sulfonyl sulfonyl, substituted or unsubstituted alkynyl-sulfonyl, substituted or unsubstituted amino, a substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl,

R ² is hydrogen, halogen, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, 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 Substituted 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 ³ is hydrogen, 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 A substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R ^4a and R ^4b are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-substituted 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 oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or non-substituted Substituted alkylthio, substituted or unsubstituted alkenylthio, 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 carbocycle Carbonyl, substituted or unsubstituted aromatic carbocyclic 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 a Lucynyloxycarbonyl, 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 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 Is 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, or Substituted or unsubstituted aromatic heterocyclic sulfonyl. And a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition having an autotaxin inhibitory action. Urinary excretion disorder, chronic kidney disease or renal fibrosis, interstitial pneumonia or pulmonary fibrosis, scleroderma, fibromyalgia, rheumatoid arthritis, arteriosclerosis, eye disease, choroidal neovascularization and diabetic retinopathy, arthritis, The pharmaceutical composition according to claim 15, which is used for prevention or treatment of neurodegeneration, restenosis, wound healing or graft rejection or endometriosis.