JP2012131708A - 4-substituted pyridazinone compound and p2x7 receptor inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel pyridazinone compound having an activity of inhibiting P2X7 receptor that is a kind of purine receptor, which is useful in preventing, treating or ameliorating diseases relating to inflammation or immunity.SOLUTION: Disclosed are a novel pyridazinone compound represented by a formula (I), a tautomer of the compound, a prodrug, a pharmaceutically acceptable salt, or a solvate of these compounds.

Description

  The present invention relates to a novel heterocyclic compound exhibiting a P2X7 receptor inhibitory action.

P2X7 receptor, a kind of purine receptor, is a ligand-gated ion channel that accepts purine nucleotides and allows ^ions such as Ca ²⁺ to pass through. Macrophages, mast cells, lymphocyte T cells, lymphocyte B cells, antigen presentation It is expressed in cells, osteoclasts, keratinocytes, etc., and is involved in diseases related to inflammation, immunity, etc. through production of inflammatory cytokines, particularly IL-1β (Interleukin-1β) and IL-18 (for example, Non-patent Document 1). To 3). It is also expressed in microglia and is also involved in pain (see Non-Patent Document 4, for example).
Thus, inhibitors of P2X7 receptors may be useful in the treatment of these diseases, indeed P2X7 knockout mice are resistant to rheumatoid arthritis development and pain, and P2X7 inhibitors are neurogenic. It is known to improve pain (see, for example, Non-Patent Documents 4 to 6).
P2X7 receptor inhibitors are known in the following reports and the like (see, for example, Patent Documents 1 and 2), but further drug development is desired.

International Publication No. 99/29660 International Publication No. 2007/109192

Physiological Review 2002: 82, p. 1013-1067 (Physiol Rev. 2002: 82, p.1013-1067) Journal of Immunology 2006: 176, p. 3877-3883 (J Immunol. 2006: 176, p.3877-3883) Journal of Biological Chemistry 2001: 276, p. 3820-3826 (J Biol Chem. 2001: 276, p.3820-3826) Pain 2005: 114, p. 386-396 (Pain. 2005: 114, p.386-396) Journal of Immunology 2002: 168, p. 6436-6445 (J Immunol. 2002: 168, p.6436-6445) Journal of Pharmacology and Experimental Therapeutics 2006: 319, p. 1376-1385 (J Pharmacol Exp Ther. 2006: 319, p.1376-1385)

  An object of the present invention is to provide a novel pyridazinone compound having P2X7 receptor inhibitory activity and useful for diseases involving inflammation and immunity.

［式中、Ｒ^１は水素原子、水酸基、ニトロ基、シアノ基、カルボキシル基、カルバモイル基、アミノ基、ハロゲン原子、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−６アルキニル基又はＣ_１−６アルコキシ基
（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−６アルキニル基及びＣ_１−６アルコキシ基は、無置換であるか又はハロゲン原子で置換されている。）
を意味し、
Ｒ^２はＣ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_１−６アルコキシ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルキルスルホニル基
（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_１−６アルコキシ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキルチオ基及びＣ_１−６アルキルスルホニル基は置換基群Ｖ^３より単独若しくは異なって選ばれる１つ以上の置換基で置換されており、ハロゲン原子で置換されていてもよい。）、
テトラゾリル基、Ｃ_２−９ヘテロシクリル基
（該テトラゾリル基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
又は式（ＩＩ）

（式中、Ｒ^ａはシアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味し、
Ｒ^ｂ及びＲ^ｃはそれぞれ独立して、水素原子、シアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味するか、
Ｒ^ａとＲ^ｂ又はＲ^ｂとＲ^ｃが一緒になって含窒素ヘテロシクリル基
（該含窒素へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味し、
T’及びU’はそれぞれ独立して、酸素原子、硫黄原子、ＮＲ^ｄ又はＮＯＲ^ｄ
（式中、Ｒ^ｄは水素原子、シアノ基又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味する。）
を意味し、
Ｌは単結合又はＣ_１−６アルキレン基
（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
の何れかで示される構造を意味し、
Ｑは式（ＩＩＩ）

（式中、
Ｒ^３及びＲ^５はそれぞれ独立して水素原子、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基又はＣ_２−６アルキニル基
（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基及びＣ_２−６アルキニル基は、無置換であるか又はハロゲン原子で置換されている。）
を意味し、
Ｒ^４はＣ_１−２０アルキル基、Ｃ_２−２０アルケニル基又はＣ_２−１９ヘテロシクリル基
（該Ｃ_１−２０アルキル基、Ｃ_２−２０アルケニル基及びＣ_２−１９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味するか、
Ｒ^３とＲ^４が一緒になって含窒素ヘテロシクリル基
（該含窒素へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基、若しくはＣ_１−２０アルキル基で置換されている。）
を意味し、
ｍは０，１又は２を意味し、
Ｔは酸素原子又は硫黄原子を意味する。）
の何れかで示される構造を意味し、
Ｘは単結合又はＣ_１−６アルキレン基
（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味し、
Ｙは単結合、Ｃ_２−１４アリーレン基、Ｃ_２−９ヘテロシクリレン基
（該Ｃ_２−１４アリーレン基及びＣ_２−９ヘテロシクリレン基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
又は式（ＩＶ）

（式中、Ｒ^６及びＲ^７はそれぞれ独立して、水素原子、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基（該Ｃ_１−６アルキル基及びＣ_２−６アルケニル基は、無置換であるか又は置換基群Ｖ¹より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）又はハロゲン置換Ｃ_１−３アルキル基を意味し、
Ｕ及びＷはそれぞれ独立して、酸素原子、硫黄原子又はＮＯＲ^１０
（式中、Ｒ^１０は水素原子、Ｃ_１−３アルキル基又はハロゲン置換Ｃ_１−３アル
キル基を意味する。）
を意味し、ｎは０，１又は２を意味する。）
の何れかで示される構造を意味し、
Ｚは水素原子、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_１−６アルコキシ基、Ｃ_３−１２シクロアルキル基、Ｃ_３−１２シクロアルケニル基
（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_１−６アルコキシ基、Ｃ_３−１２シクロアルキル基及びＣ_３−１２シクロアルケニル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）、
Ｃ_２−１４アリール基、縮合アリール基、Ｃ_２−１４アリールオキシ基又はＣ_２−９ヘテロシクリル基
（該Ｃ_２−１４アリール基、縮合アリール基、Ｃ_２−１４アリールオキシ基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を表し、
置換基群Ｖ^１は、カルボキシル基、カルバモイル基、スルファモイル基、ホスホノ基、スルホ基、テトラゾリル基、ホルミル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルチオ基及びＣ_１−６アルキルスルホニル基
（該モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルチオ基及びＣ_１−６アルキルスルホニル基は、無置換であるか又はカルボキシル基、カルバモイル基、スルファモイル基、ホスホノ基、スルホ基、テトラゾリル基、ホルミル基、ニトロ基、シアノ基、ハロゲン原子、Ｃ_１−６アルキル基、ハロゲン置換Ｃ_１−３アルキル基、Ｃ_１−６アルコキシ基、ハロゲン置換Ｃ_１−３アルコキシ基、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキルチオ基若しくはＣ_１−６アルキルスルホニル基で置換されている。）
により構成され、
置換基群Ｖ^２は、置換基群Ｖ^１、Ｃ_２−１４アリール基及び縮合アリール基
（該Ｃ_２−１４アリール基及び縮合アリール基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
により構成され、
置換基群Ｖ^３は、カルボキシル基、カルバモイル基、スルファモイル基、ホスホノ基、スルホ基、テトラゾリル基、ホルミル基、ニトロ基、シアノ基、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルキルスルホニル基
（該モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルチオ基及びＣ_１−６アルキルスルホニル基は、無置換であるか又はカルボキシル基、カルバモイル基、スルファモイル基、ホスホノ基、スルホ基、テトラゾリル基、ホルミル基、ニトロ基、シアノ基、ハロゲン原子、Ｃ_１−６アルキル基、ハロゲン置換Ｃ_１−３アルキル基、Ｃ_１−６アルコキシ基、ハロゲン置換Ｃ_１−３アルコキシ基、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキルチオ基若しくはＣ_１−６アルキルスルホニル基で置換されている。）、Ｃ_２−１４アリール基及び縮合アリール基
（該Ｃ_２−１４アリール基及び縮合アリール基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
により構成される。］
で表される化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（２）
Ｒ^１が水素原子、Ｃ_１−３アルコキシ基又はハロゲン置換Ｃ_１−３アルコキシ基である、（１）記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（３）
Ｒ^１が水素原子又はエトキシ基である（１）記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（４）
Ｒ^２がＣ_１−６アルキル基、Ｃ_１−６アルコキシ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基
（該Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、モノＣ_１−６アルキルアミノ基及びジＣ_１−６アルキルアミノ基は置換基群Ｖ^３より単独若しくは異なって選ばれる１つ以上の置換基で置換されており、ハロゲン原子で置換されていてもよい。）、
テトラゾリル基、Ｃ_２−９ヘテロシクリル基
（該テトラゾリル基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
又は式（Ｖ）

（式中、Ｒ^ａはシアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味し、
Ｒ^ｂは水素原子、シアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味するか、
Ｒ^ａとＲ^ｂが一緒になって含窒素ヘテロシクリル基
（該含窒素へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味し、
Ｔ’は酸素原子、ＮＲ^ｄ又はＮＯＲ^ｄ
（式中、Ｒ^ｄは水素原子、シアノ基、Ｃ_１−３アルキル基（該Ｃ_１−３アルキル基は、無置換であるか又はフェニル基で置換されている。）又はハロゲン置換Ｃ_１−３アルキル基を意味する。）
を意味し、
Ｌは単結合又はＣ_１−６アルキレン基
（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
である（１）乃至（３）のいずれか一項に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（５）
Ｒ^２がＣ_１−３アルキル基
（該Ｃ_１−３アルキル基はカルボキシル基又は水酸基で置換されている。）
又は式（ＶＩ）

（式中、Ｒ^aはＣ_１−３アルキル基を意味し、Ｒ^ｂは水素原子又はＣ_１−３アルキル基を意味し、
Ｔ’は酸素原子、ＮＲ^ｄ又はＮＯＲ^ｄ
（式中、Ｒ^ｄは水素原子、シアノ基又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は、無置換であるか又はフェニル基で置換されている。）を意味する。）
を意味する。）
である（４）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（６）
Ｑが式（ＶＩＩ）

（式中、
Ｒ^３は、水素原子又はＣ_１−６アルキル基
（該Ｃ_１−６アルキル基は、無置換であるか又はハロゲン原子で置換されている。）
を意味し、
Ｒ^４はＣ_１−２０アルキル基又はＣ_２−２０アルケニル基
（該Ｃ_１−２０アルキル基及びＣ_２−２０アルケニル基は、無置換であるか又は置換基群Ｖ^１より単独もしくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
である（１）乃至（５）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（７）
Ｑが式（ＶＩＩＩ）

（式中、
ｍは０，１又は２を意味し、
Ｒ^４はＣ_１−２０アルキル基又はＣ_２−２０アルケニル基
（該Ｃ_１−２０アルキル基及びＣ_２−２０アルケニル基は、無置換であるか又は置換基群Ｖ^１より単独もしくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
である（１）乃至（５）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（８）
Ｒ^３が水素原子を意味し、Ｒ^４がＣ_３−１２シクロアルキル基又はＣ_３−１２シクロアルケニル基
（該Ｃ_３−１２シクロアルキル基及びＣ_３−１２シクロアルケニル基は、無置換であるか又は置換基群Ｖ^１より単独もしくは異なって選ばれる１乃至３つの置換基によって置換されている。）
を意味する（６）又は（７）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（９）
Ｒ^３が水素原子を意味し、Ｒ^４がＣ_２−１９ヘテロシクリル基
（該Ｃ_２−１９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独もしくは異なって選ばれる１乃至３つの置換基によって置換されている。）
を意味する（６）又は（７）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（１０）
Ｒ^３が水素原子を意味し、Ｒ^４がＣ_２−１１ヘテロシクリル基
（該Ｃ_２−１１ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独もしくは異なって選ばれる１乃至３つの置換基によって置換されている。）
を意味する（６）又は（７）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（１１）
ＸがＣ_１−６アルキレン基
（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ又は２つの置換基によって置換されている。）
を意味し、
Ｙが単結合又は式（ＩＸ）

（式中、Ｒ^６は、水素原子又はＣ_１−６アルキル基
（該Ｃ_１−６アルキル基は、無置換であるか又はハロゲン原子で置換されている。）
を意味し、Ｕは酸素原子又は硫黄原子を意味する。）
の何れかで示される構造を意味し、
ＺがＣ_１−６アルキル基、Ｃ_１−６アルコキシ基
（該Ｃ_１−６アルキル基及びＣ_１−６アルコキシ基は、無置換であるか又は置換基群Ｖ^２より選ばれる１つ若しくは２つの置換基によって置換されている。）、
Ｃ_２−１４アリール基、Ｃ_２−１４アリールオキシ基又はＣ_２−９ヘテロシクリル基
（該Ｃ_２−１４アリール基、Ｃ_２−１４アリールオキシ基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より選ばれる１つの置換基で置換されている。）
を意味する（１）乃至（１０）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（１２）
ＺがＣ_１−６アルキル基
（該Ｃ_１−６アルキル基はＣ_２−９ヘテロアリール基
（該Ｃ_２−９ヘテロアリール基は、無置換であるか又は置換基群Ｖ^１より単独
若しくは異なって選ばれる１つ又は２つの置換基で置換されている。）
で置換されている。）
を意味する（１）乃至（１１）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。
（１３）
（１）乃至（１２）の何れか１項に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物を有効成分として含有するＰ２Ｘ７受容体阻害剤。
（１４）
（１３）記載のＰ２Ｘ７受容体阻害剤を有効成分として含有するＰ２Ｘ７受容体阻害作用が有効な疾患の予防・治療・改善薬。
（１５）
（１３）記載のＰ２Ｘ７受容体阻害剤を有効成分として含有する関節リウマチ治療剤。
（１６）
（１）乃至（１２）の何れか１項に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物を有効成分として含有する医薬。 The present inventors diligently studied to find a novel low molecular weight compound having P2X7 receptor antagonistic activity. As a result, the present inventors found that the compound of the present invention has a high antagonistic action and completed the present invention. That is, this invention is comprised by the following.
(1)
Formula (I)

[Wherein, R ¹ represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a carboxyl group, a carbamoyl group, an amino group, a halogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group. Or a C _1-6 alkoxy group (the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C _1-6 alkoxy group are unsubstituted or substituted with a halogen atom) Yes.)
Means
R ² is a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkoxy group, a mono C _1-6 alkylamino group, a diC _1-6 alkylamino group, a C _1-6 alkylthio group, a C _1-6 alkylsulfonyl group (the C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkoxy group, mono C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _{1- The 6} alkylthio group and the C _1-6 alkylsulfonyl group are substituted with one or more substituents selected from the substituent group V ³ alone or differently, and may be substituted with a halogen atom.
A tetrazolyl group, a C _2-9 heterocyclyl group (the tetrazolyl group and the C _2-9 heterocyclyl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ² alone or differently; Yes.)
Or formula (II)

(In the formula, R ^a is a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group, or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, The C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are one or more substituents that are unsubstituted or selected alone or differently from the substituent group V ² Is replaced by
R ^b and R ^c are each independently a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group or a C _2-9 heterocyclyl group The C _1-6 alkyl group, the C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are unsubstituted, or are selected alone or differently from the substituent group V ² Is substituted with one or more substituents
R ^a and R ^b or R ^b and R ^{c taken} together to form a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or one or more selected from the group of substituents V ¹ alone or differently Substituted with a substituent of
Means
T ′ and U ′ each independently represent an oxygen atom, a sulfur atom, NR ^d or NOR ^d
(In the formula, R ^d is a hydrogen atom, a cyano group or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or one or more selected from the substituent group V ² alone or differently). Substituted with a substituent of
Means
L is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). .)
Means. )
Means a structure represented by
Q is the formula (III)

(Where
R ³ and R ⁵ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group (the C _1-6 alkyl group, C _2-6 alkenyl group and C 2 _{The 2-6} alkynyl group is unsubstituted or substituted with a halogen atom.)
Means
R ⁴ represents a C _1-20 alkyl group, a C _2-20 alkenyl group, or a C _2-19 heterocyclyl group (the C _1-20 alkyl group, C _2-20 alkenyl group, and C _2-19 heterocyclyl group are unsubstituted. Or substituted with one or more substituents selected from the substituent group V ¹ alone or differently.
Or
R ³ and R ⁴ are taken together to form a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is one or more substituents that are unsubstituted or selected from the group of substituents V ¹ alone or differently, or C Substituted with a _1-20 alkyl group.)
Means
m means 0, 1 or 2;
T means an oxygen atom or a sulfur atom. )
Means a structure represented by
X is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from substituent group V ¹ alone or differently) .)
Means
Y is a single bond, a C _2-14 arylene group, a C _2-9 heterocyclylene group (the C _2-14 arylene group and the C _2-9 heterocyclylene group are unsubstituted or substituted by a substituent group V ^2. It is substituted with one or more substituents which are selected more individually or differently.)
Or formula (IV)

(Wherein R ⁶ and R ⁷ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group (the C _1-6 alkyl group and C _2-6 alkenyl group are unsubstituted) Or substituted with one or more substituents selected from the substituent group V ¹ alone or differently) or a halogen-substituted C _1-3 alkyl group,
U and W are each independently an oxygen atom, a sulfur atom or NOR ¹⁰
(In the formula, R ¹⁰ represents a hydrogen atom, a C _1-3 alkyl group or a halogen-substituted C _1-3 alkyl group.)
And n means 0, 1 or 2. )
Means a structure represented by
Z represents a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkoxy group, a C _3-12 cycloalkyl group, a C _3-12 cycloalkenyl group (the C _1-6 alkyl group, The C _2-6 alkenyl group, the C _1-6 alkoxy group, the C _3-12 cycloalkyl group and the C _3-12 cycloalkenyl group are unsubstituted or selected from the substituent group V ² alone or differently 1 Substituted with one or more substituents).
C _2-14 aryl group, condensed aryl group, C _2-14 aryloxy group or C _2-9 heterocyclyl group (the C _2-14 aryl group, condensed aryl group, C _2-14 aryloxy group and C _2-9 The heterocyclyl group is unsubstituted or substituted with one or more substituents selected from the substituent group V ² alone or differently.
Represents
Substituent group V ¹ was a carboxyl group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, a formyl group, a nitro group, a cyano group, a halogen atom, a hydroxyl group, an amino group, a mono C _1-6 alkylamino group , Di C _1-6 alkylamino group, C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylthio group and C _1-6 alkyl A sulfonyl group (the mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylthio and _{C 1-6} alkylsulfonyl group, unsubstituted or substituted with or carboxyl group, a carbamoyl group, a sulfamoyl group, phospho Group, a sulfo group, a tetrazolyl group, a formyl group, a nitro group, a cyano group, a halogen _{atom, C 1-6} alkyl group, a halogen-substituted _{C 1-3} alkyl _{group, C 1-6} alkoxy group, a halogen-substituted _{C 1-3} alkoxy Substituted with a group, a hydroxyl group, an amino group, a mono C _1-6 alkylamino group, a di C _1-6 alkylamino group, a C _1-6 alkylthio group or a C _1-6 alkylsulfonyl group.)
Composed of
Substituent group V ² is substituent group V ¹ , C _2-14 aryl group and condensed aryl group (the C _2-14 aryl group and condensed aryl group are unsubstituted or independent from substituent group V ^1. Or substituted with one or more substituents selected differently.)
Composed of
Substituent group V ³ includes a carboxyl group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, a formyl group, a nitro group, a cyano group, a hydroxyl group, an amino group, a mono C _1-6 alkylamino group, and a diC. _1-6 alkylamino group, C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylthio group, C _1-6 alkylsulfonyl group ( The mono C _1-6 alkylamino group, diC _1-6 alkylamino group, C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _{1- 6} alkylthio group and a C _1-6 alkylsulfonyl group, unsubstituted or substituted with or carboxyl group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, Torazoriru group, a formyl group, a nitro group, a cyano group, a halogen _{atom, C 1-6} alkyl group, a halogen-substituted _{C 1-3} alkyl _{group, C 1-6} alkoxy group, a halogen-substituted _{C 1-3} alkoxy group, hydroxyl group, amino Group, mono C _1-6 alkylamino group, diC _1-6 alkylamino group, C _1-6 alkylthio group or C _1-6 alkylsulfonyl group.), C _2-14 aryl group and condensation An aryl group (the C _2-14 aryl group and the condensed aryl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently).
Consists of. ]
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(2)
The compound according to (1), wherein R ¹ is a hydrogen atom, a C _1-3 alkoxy group or a halogen-substituted C _1-3 alkoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound Or a solvate thereof.
(3)
The compound according to (1), wherein R ¹ is a hydrogen atom or an ethoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(4)
R ² is a C _1-6 alkyl group, a C _1-6 alkoxy group, a mono C _1-6 alkylamino group, a di-C _1-6 alkylamino group (the C _1-6 alkyl group, a C _1-6 alkoxy group, The mono-C _1-6 alkylamino group and the di-C _1-6 alkylamino group are substituted with one or more substituents selected from the substituent group V ³ alone or differently, and may be substituted with a halogen atom Good),
A tetrazolyl group, a C _2-9 heterocyclyl group (the tetrazolyl group and the C _2-9 heterocyclyl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ² alone or differently; Yes.)
Or formula (V)

(In the formula, R ^a is a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group, or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, The C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are one or more substituents that are unsubstituted or selected alone or differently from the substituent group V ² Is replaced by
R ^b is a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group, or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, C _{The 2-6} alkenyl group, C _2-14 aryl group, condensed aryl group and C _2-9 heterocyclyl group are one or more substituents which are unsubstituted or selected alone or differently from the substituent group V ² Is replaced)
R ^a and R ^b are taken together to form a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or substituted with one or more substituents selected from substituent group V ¹ alone or differently. ing.)
Means
T ′ is an oxygen atom, NR ^d or NOR ^d
(Wherein R ^d is a hydrogen atom, a cyano group, a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with a phenyl group) or halogen-substituted C _{1- 3} means an alkyl group.)
Means
L is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). .)
Means. )
The compound according to any one of (1) to (3), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(5)
R ² is a C _1-3 alkyl group (the C _1-3 alkyl group is substituted with a carboxyl group or a hydroxyl group).
Or formula (VI)

(Wherein R ^a represents a C _1-3 alkyl group, R ^b represents a hydrogen atom or a C _1-3 alkyl group,
T ′ is an oxygen atom, NR ^d or NOR ^d
(Wherein R ^d represents a hydrogen atom, a cyano group, or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with a phenyl group).)
Means. )
The compound according to (4), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(6)
Q is the formula (VII)

(Where
R ³ is a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted with a halogen atom).
Means
R ⁴ represents a C _1-20 alkyl group or a C _2-20 alkenyl group (the C _1-20 alkyl group and C _2-20 alkenyl group are unsubstituted or selected alone or differently from the substituent group V ¹⁾ Substituted with one or more substituents.
Means. )
(1) to (5), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(7)
Q is the formula (VIII)

(Where
m means 0, 1 or 2;
R ⁴ represents a C _1-20 alkyl group or a C _2-20 alkenyl group (the C _1-20 alkyl group and C _2-20 alkenyl group are unsubstituted or selected alone or differently from the substituent group V ¹⁾ Substituted with one or more substituents.
Means. )
(1) to (5), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(8)
R ³ represents a hydrogen atom, and R ⁴ represents a C _3-12 cycloalkyl group or a C _3-12 cycloalkenyl group (the C _3-12 cycloalkyl group and the C _3-12 cycloalkenyl group are unsubstituted) Or substituted with 1 to 3 substituents selected from the substituent group V ¹ alone or differently.
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound according to (6) or (7), or a solvate thereof.
(9)
R ³ represents a hydrogen atom, and R ⁴ is a C _2-19 heterocyclyl group (the C _2-19 heterocyclyl group is unsubstituted or selected from 1 to 3 selected from the substituent group V ¹ alone or differently Substituted by substituents.)
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound according to (6) or (7), or a solvate thereof.
(10)
R ³ represents a hydrogen atom, and R ⁴ is a C _2-11 heterocyclyl group (the C _2-11 heterocyclyl group is unsubstituted or selected from 1 to 3 selected from the substituent group V ¹ alone or differently Substituted by substituents.)
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound according to (6) or (7), or a solvate thereof.
(11)
X represents a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or two substituents selected from the substituent group V ¹ alone or differently).
Means
Y is a single bond or formula (IX)

(Wherein R ⁶ represents a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted with a halogen atom).
U represents an oxygen atom or a sulfur atom. )
Means a structure represented by
Z is _{C 1-6 alkyl, C 1-6} alkoxy groups (the _{C 1-6} alkyl group and a _{C 1-6} alkoxy group, one selected from unsubstituted or substituted with a substituent group ^{V 2} or 2 Substituted by two substituents).
C _2-14 aryl group, C _2-14 aryloxy group or C _2-9 heterocyclyl group (the C _2-14 aryl group, C _2-14 aryloxy group and C _2-9 heterocyclyl group are unsubstituted) substituted with or one substituent selected from substituent group V ^2.)
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound according to any one of (1) to (10), or a solvate thereof.
(12)
Z is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _2-9 heteroaryl group (the C _2-9 heteroaryl group is unsubstituted or is independent or different from the substituent group V ¹⁾ Substituted with one or two substituents selected from
Has been replaced by )
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound according to any one of (1) to (11), or a solvate thereof.
(13)
The P2X7 receptor comprising the compound according to any one of (1) to (12), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient Body inhibitors.
(14)
(13) A prophylactic / therapeutic / ameliorating agent for a disease having an effective P2X7 receptor inhibitory action, comprising the P2X7 receptor inhibitor according to (13) as an active ingredient.
(15)
(13) A therapeutic agent for rheumatoid arthritis comprising the P2X7 receptor inhibitor according to (13) as an active ingredient.
(16)
(1) A medicament comprising the compound according to any one of (12), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient.

  According to the present invention, a novel pyridazinone compound having excellent P2X7 receptor inhibitory activity and useful for diseases involving inflammation, immunity and the like could be provided.

Hereinafter, the present invention will be described in more detail.
In the present invention, “n” is normal, “i” is iso, “s” is secondary, “t” or “tert” is tertiary, “c” is cyclo, “o” is ortho, and “m” is Meta, `` p '' means para, `` rac '' means racemic, `` Ph '' means phenyl, `` Py '' means pyridyl, `` Me '' means methyl, `` Et '' means ethyl, `` Pr '' means propyl, `` Bu “But” means tertiary butoxycarbonyl, “Ms” means methanesulfonyl, “Tf” means trifluoromethanesulfonyl, and “MOM” means methoxymethyl.

First, a description will be given terms in the respective substituents ^{R 1} ~R ^7, R ¹⁰ and ^R a to R ^d.

  Halogen atoms are fluorine, chlorine, bromine and iodine.

The C _1-3 alkyl group is an alkyl group having 1 to 3 carbon atoms, and may contain a linear, branched or C ₃ cycloalkyl group. Specific examples thereof include methyl, ethyl, n- And propyl, i-propyl and c-propyl.

The C _1-6 alkyl group is an alkyl group having 1 to 6 carbon atoms, and may contain a linear, branched, or C _3-6 cycloalkyl group. n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl, n-pentyl, 1-methyl-n-butyl, 2- Methyl-n-butyl, 3-methyl-n-butyl, 1,1-dimethyl-n-propyl, 1,2-dimethyl-n-propyl, 2,2-dimethyl-n-propyl, 1-ethyl-n- Propyl, c-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c-propyl, 2,3-dimethyl-c-propyl, 1-ethyl-c-propyl, 2-ethyl-c-propyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-n-pentyl, 3-methyl-n-pentyl, 4-methyl-n- Pentyl, 1,1-dimethyl-n-butyl, 1,2-dimethyl-n-butyl, 1,3-dimethyl-n-butyl, 2,2-dimethyl-n-butyl, 2,3-dimethyl-n-butyl, 3,3-dimethyl-n-butyl, 1-ethyl-n-butyl, 2- Ethyl-n-butyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 1-ethyl-1-methyl-n-propyl, 1-ethyl-2-methyl- n-propyl, c-hexyl, 1-methyl-c-pentyl, 2-methyl-c-pentyl, 3-methyl-c-pentyl, 1-ethyl-c-butyl, 2-ethyl-c-butyl, 3- Ethyl-c-butyl, 1,2-dimethyl-c-butyl, 1,3-dimethyl-c-butyl, 2,2-dimethyl-c-butyl, 2,3-dimethyl-c-butyl, 2,4- Dimethyl-c-butyl, 3,3-dimethyl-c-butyl, 1-n-propyl-c-propyl, 2-n-propyl-c-propyl, 1-i-propyl-c-propyl, 2-i- Propyl-c-propyl, 1,2,2-trimethyl-c-propyl, 1,2,3-trimethyl-c-propyl, 2,2,3-trimethyl-c-propyl, 1-ethyl-2-methyl- c-propyl, 2- Examples include ethyl-1-methyl-c-propyl, 2-ethyl-2-methyl-c-propyl and 2-ethyl-3-methyl-c-propyl.

The C _3-12 cycloalkyl group is a cycloalkyl group having 3 to 12 carbon atoms, and may contain a condensed polycyclic structure, a bridged ring structure, or a spiro ring structure. Propyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl, c-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c-propyl, 2,3-dimethyl-c-propyl, 1-ethyl-c-propyl, 2-ethyl-c-propyl, c-hexyl, 1-methyl-c-pentyl, 2- Methyl-c-pentyl, 3-methyl-c-pentyl, 1-ethyl-c-butyl, 2-ethyl-c-butyl, 3-ethyl-c-butyl, 1,2-dimethyl-c-butyl, 1, 3-dimethyl-c-butyl, 2,2-dimethyl-c-butyl, 2,3-dimethyl-c-butyl, 2,4-dimethyl-c-butyl, 3,3-dimethyl-c-butyl, 1- n-propyl-c-propyl, 2-n-propyl-c-propyl, 1-i-propyl -C-propyl, 2-i-propyl-c-propyl, 1,2,2-trimethyl-c-propyl, 1,2,3-trimethyl-c-propyl, 2,2,3-trimethyl-c- Propyl, 1-ethyl-2-methyl-c-propyl, 2-ethyl-1-methyl-c-propyl, 2-ethyl-2-methyl-c-propyl and 2-ethyl-3-methyl-c-propyl, Examples include c-heptyl, c-octyl, c-nonyl, c-decyl, c-undecyl, c-dodecyl, and the structures shown below.

The C _7-12 cycloalkyl group is a cycloalkyl group having 7 to 12 carbon atoms, and may contain a condensed polycyclic structure, a bridged ring structure, or a spiro ring structure. Preferable specific examples include the structures shown below.

The C _8-12 cycloalkyl group is a cycloalkyl group having 8 to 12 carbon atoms, and may contain a condensed polycyclic structure, a bridged ring structure, or a spiro ring structure. The structure shown in FIG.

The C _1-20 alkyl group is an alkyl group having 1 to 20 carbon atoms, and may include a straight chain, a branched chain, or a C _3-20 cycloalkyl group. Here, the C _3-20 cycloalkyl group is a cycloalkyl group containing 3 to 20 carbon atoms, and may contain a condensed polycyclic structure, a bridged ring structure, or a spiro ring structure. Specific examples of the C _1-20 alkyl group include, in addition to the above, 1-methyl-1-ethyl-n-pentyl, 1-heptyl, 2-heptyl, 1-ethyl-1,2-dimethyl-n-propyl, 1-ethyl-2,2-dimethyl-n-propyl, 1-octyl, 3-octyl, 4-methyl-3-n-heptyl, 6-methyl-2-n-heptyl, 2-propyl-1-n- Heptyl, 2,4,4-trimethyl-1-n-pentyl, 1-nonyl, 2-nonyl, 2,6-dimethyl-4-n-heptyl, 3-ethyl-2,2-dimethyl-3-n- Pentyl, 3,5,5-trimethyl-1-n-hexyl, 1-decyl, 2-decyl, 4-decyl, 3,7-dimethyl-1-n-octyl and 3,7-dimethyl-3-n -Octyl, n-nonyl, n-undecyl, n-dodecyl N-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-icosanyl, c-heptyl, c-octyl, c-nonyl, c-decyl, c -Undecyl, c-dodecyl, c-tridecyl, c-tetradecyl, c-pentadecyl, c-hexadecyl, c-heptadecyl, c-octadecyl, c-nonadecyl, c-icosanyl, and the structures shown below are exemplified.

The C _2-6 alkenyl group means a group in which any 1, 2 or 3 positions of the C _1-6 alkyl group (excluding the methyl group) shown above are converted to a double bond. , Branched and C _3-6 cycloalkenyl groups, specific examples include ethenyl, 1-propenyl, 2-propenyl, 1-methyl-1-ethenyl, 1-butenyl, 2-butenyl, 3- Butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-ethylethenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-n-propylethenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 2-ethyl-2-propenyl, 2-methyl-1- Butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3- Tenenyl, 1,1-dimethyl-2-propenyl, 1-i-propylethenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-c-pentenyl, 2-c- Pentenyl, 3-c-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 1-methyl-2-pentenyl, 1-methyl-3- Pentenyl, 1-methyl-4-pentenyl, 1-n-butylethenyl, 2-methyl-1-pentenyl, 2-methyl-2-pentenyl, 2-methyl-3-pentenyl, 2-methyl-4-pentenyl, 2- n-propyl-2-propenyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 3-methyl-3-pentenyl, 3-methyl-4-pentenyl, 3-ethyl-3-butenyl, 4- Methyl-1-pentenyl, 4-methyl-2-pentenyl, 4-methyl-3-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1-methyl-2-ethyl-2-propenyl, 1-s-butylethenyl, 1 , 3-Dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 1-i-butylethenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl -1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 2-i-propyl-2-propenyl, 3,3-dimethyl-1-butenyl, 1-ethyl-1 -Butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-n-propyl-1-propenyl, 1-n-propyl-2-propenyl, 2-ethyl-1-butenyl, 2-ethyl 2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-t-butylethenyl, 1-methyl-1-ethyl-2-propenyl, 1-ethyl-2-methyl -1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1-i-propyl-1-propenyl 1-i-propyl-2-propenyl, 1-methyl-2-c-pentenyl, 1-methyl-3-c-pentenyl, 2-methyl-1-c-pentenyl, 2-methyl-2-c-pentenyl, 2-methyl-3-c-pentenyl, 2-methyl-4-c-pentenyl, 2-methyl-5-c-pentenyl, 2-methylene-c-pentyl, 3-methyl-1-c-pentenyl, 3- Methyl-2-c-pentenyl, 3-methyl-3-c-pentenyl, 3-methyl-4-c-pentenyl, 3-methyl-5-c-pentenyl, 3-methylene-c-pentyl, 1-c- Examples include hexenyl, 2-c-hexenyl, and 3-c-hexenyl.

The C _2-20 alkenyl group means a group in which any 1, 2 or 3 positions of the C _1-20 alkyl group (excluding the methyl group) shown above are converted into double bonds, , Branched and C _3-20 cycloalkenyl groups. Here, the C _3-20 cycloalkenyl group means a group in which any 1, 2 or 3 positions of the C _3-20 cycloalkyl group shown above are converted into double bonds, It may contain a ring structure, a bridged ring structure or a spiro ring structure. Specific examples of the C _2-20 alkenyl group include, in addition to the above, 1-methyl-n-hexenyl, 1,2-dimethyl-n-hexenyl, 1-ethyl-n-hexenyl, 1-n-heptenyl, 2 -n-heptel, 3-n-heptenyl, 4-n-heptenyl, 1-n-octenyl, 2-n-octenyl, 3-n-octenyl, 1-methyl-c-hexenyl, 1,2-dimethyl- c-hexenyl, 1-ethyl-c-hexenyl, 1-c-heptenyl, 2-c-heptenyl, 3-c-heptenyl, 4-c-heptenyl, 1-c-octenyl, 2-c-octenyl, 3 -c-octenyl and 4-c-octenyl, 1-decenyl, 2-decenyl, 4-decenyl, 3,7-dimethyl-1-n-octenyl, 3,7-dimethyl-3-n-octenyl, 2-n -Nonenyl, 3-n-undecenyl, 1-n-dodecenyl, 3-n-tridecenyl, 2-n-tetradecenyl, 4,6-n-pentadecadienyl 2-n-hexadecenyl, 5-n-heptadecenyl, 10-n-octadecenyl, 2-n-nonadecenyl, 4-n-icocenyl, 2-c-nonenyl, 4-c-decenyl, 2-c-undecenyl, 5- c-dodecenyl, 3-c-tridecenyl, 6-c-tetradecenyl, 10-c-pentadecenyl, 5-c-hexadecenyl, 4-c-heptadecenyl, 1-c-octadecenyl, 3-c-nonadecenyl, 2-c- Examples include icocenyl and the structures shown below.

The C _3-12 cycloalkenyl group means a group in which any 1, 2 or 3 positions of the C _3-12 cycloalkyl group shown above are converted to a double bond, a condensed polycyclic structure, a bridged ring Or a spiro ring structure, specific examples include 1-c-pentenyl, 2-c-pentenyl, 3-c-pentenyl, 1-methyl-2-c-pentenyl, 1-methyl-3- c-pentenyl, 2-methyl-1-c-pentenyl, 2-methyl-2-c-pentenyl, 2-methyl-3-c-pentenyl, 2-methyl-4-c-pentenyl, 2-methyl-5- c-pentenyl, 2-methylene-c-pentyl, 3-methyl-1-c-pentenyl, 3-methyl-2-c-pentenyl, 3-methyl-3-c-pentenyl, 3-methyl-4-c- Pentenyl, 3-methyl-5-c-pentenyl, 3-methylene-c-pentyl, 1-c-hexenyl, 2-c-hexenyl and 3-c-hexenyl, 1-methyl-c-hexenyl, 1,2 -Dimethyl-c-hexenyl, 1-ethyl-c-hexenyl, 1-c-heptenyl, 2-c-heptenyl, 3-c-heptenyl, 4-c-heptenyl, 1-c-octenyl, 2-c-octenyl, 3-c-octenyl and 4-c-octenyl, 1-c-decenyl, 2-c-decenyl, 4-c-decenyl, 3,7-dimethyl-1-c-octenyl, 3,7-dimethyl-3-c-octenyl, 2 -C-nonenyl, 3-c-undecenyl, 1-c-dodecenyl, 3-c-tridecenyl, 2-c-tetradecenyl, 4,5-c-pentadecadienyl, 2-c-hexadecenyl, 5-c- Examples include heptadecenyl, 10-c-octadecenyl, 2-c-nonadecenyl, 2-c-undecenyl, 5-c-dodecenyl and the structures shown below.

The C _7-12 cycloalkenyl group means a group in which any 1, 2 or 3 positions of the C _7-12 cycloalkyl group shown above are converted to a double bond, and a condensed polycyclic structure, a bridged ring A structure or a spiro ring structure may be included, and preferred examples include the structures shown below.

The C _2-6 alkynyl group is an alkynyl group having 2 to 6 carbon atoms, and may include linear, branched, and C ₆ cycloalkynyl. Specific examples include ethynyl, 1-propynyl. 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1 -Methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5 -Hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butyn Nyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 1-n-propyl-2-propynyl, 2-ethyl-3-butynyl, 1-methyl-1-ethyl-2-propynyl, 1-c-propyl-2-propynyl and 1- i-propyl-2-propynyl and the like can be mentioned.

The halogen-substituted C _1-3 alkyl group, which alkyl group a C _1-3 alkyl group shown above is a fluorine atom, a chlorine atom, is 1 or more substituted with halogen atom such as bromine and / or iodine atom Specific examples include fluoromethyl group, difluoromethyl group, trifluoromethyl group, chlorofluoromethyl group, chlorodifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, Tribromomethyl group, iodomethyl group, diiodomethyl group, triiodomethyl group, fluoroethyl group, difluoroethyl group, trifluoroethyl group, tetrafluoroethyl group, pentafluoroethyl group, chloroethyl group, dichloroethyl group, trichloroethyl group, Tetrachloroethyl group, pentachrome Ethyl group, bromoethyl group, dibromoethyl group, tribromoethyl group, tetrabromoethyl group, pentabromoethyl group, perfluoro-n-propyl group, 2,2-difluoro-n-propyl group, 2,2,3, 3,3-pentafluoro-n-propyl group, perfluoro-i-propyl group, 2-fluoro-i-propyl group, 2,2,2,2,2,2-hexafluoro-i-propyl group, 2 , 2-difluoro-c-propyl group, 2,2,3,3-tetrafluoro-c-propyl group and the like.

The C _1-6 alkoxy group may include linear, branched and C _3-6 cycloalkoxy groups, and specific examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy, n -Butoxy, i-butoxy, s-butoxy, t-butoxy, c-butoxy, 1-methyl-c-propoxy, 2-methyl-c-propoxy, n-pentyloxy, 1-methyl-n-butoxy, 2 -Methyl-n-butoxy, 3-methyl-n-butoxy, 1,1-dimethyl-n-propoxy, 1,2-dimethyl-n-propoxy, 2,2-dimethyl-n-propoxy, 1-ethyl-n -Propoxy, c-pentyloxy, 1-methyl-c-butoxy, 2-methyl-c-butoxy, 3-methyl-c-butoxy, 1,2-dimethyl-c-propoxy, 2,3-dimethyl-c- Propoxy, 1-ethyl-c-propoxy, 2-ethyl-c-propoxy, n-hexyloxy, 1-methyl-n-pentyloxy, 2-methyl-n-pentyloxy , 3-methyl-n-pentyloxy, 4-methyl-n-pentyloxy, 1,1-dimethyl-n-butoxy, 1,2-dimethyl-n-butoxy, 1,3-dimethyl-n-butoxy, 2 , 2-Dimethyl-n-butoxy, 2,3-dimethyl-n-butoxy, 3,3-dimethyl-n-butoxy, 1-ethyl-n-butoxy, 2-ethyl-n-butoxy, 1,1,2 -Trimethyl-n-propoxy, 1,2,2-trimethyl-n-propoxy, 1-ethyl-1-methyl-n-propoxy, 1-ethyl-2-methyl-n-propoxy, c-hexyloxy, 1- Methyl-c-pentyloxy, 2-methyl-c-pentyloxy, 3-methyl-c-pentyloxy, 1-ethyl-c-butoxy, 2-ethyl-c-butoxy, 3-ethyl-c-butoxy, 1 , 2-Dimethyl-c-butoxy, 1,3-dimethyl-c-butoxy, 2,2-dimethyl-c-butoxy, 2,3-dimethyl-c-butoxy, 2,4-dimethyl-c-butoxy, 3 , 3-Dimethyl-c-butoxy, 1-n-propyl-c-propoxy, 2-n-propyl-c- Propoxy, 1-i-propyl-c-propoxy, 2-i-propyl-c-propoxy, 1,2,2-trimethyl-c-propoxy, 1,2,3-trimethyl-c-propoxy, 2,2, 3-trimethyl-c-propoxy, 1-ethyl-2-methyl-c-propoxy, 2-ethyl-1-methyl-c-propoxy, 2-ethyl-2-methyl-c-propoxy and 2-ethyl-3- And methyl-c-propoxy.

The C _1-3 alkoxy group is an alkoxy group having 1 to 3 carbon atoms and may contain a linear, branched or C ₃ cycloalkoxy group. Specific examples thereof include methoxy, ethoxy, n- Examples include propoxy, i-propoxy and c-propoxy.

The halogen-substituted C _1-3 alkoxy group is a group in which one or more alkyl groups in the C _1-3 alkoxy group shown above are substituted with a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and / or an iodine atom. Specific examples include fluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, chlorofluoromethoxy group, chlorodifluoromethoxy group, chloromethoxy group, dichloromethoxy group, trichloromethoxy group, bromomethoxy group, dibromomethoxy. Group, tribromomethoxy group, iodomethoxy group, diiodomethoxy group, triiodomethoxy group, fluoroethoxy group, difluoroethoxy group, trifluoroethoxy group, tetrafluoroethoxy group, pentafluoroethoxy group, chloroethoxy group, dichloroethoxy Group, bird Loroethoxy, tetrachloroethoxy, pentachloroethoxy, bromoethoxy, dibromoethoxy, tribromoethoxy, tetrabromoethoxy, pentabromoethoxy, perfluoro-n-propoxy, 2,2-difluoro- n-propoxy group, 2,2,3,3,3-pentafluoro-n-propoxy group, perfluoro-i-propoxy group, 2-fluoro-i-propoxy group, 2,2,2,2,2, Examples include 2-hexafluoro-i-propoxy group, 2,2-difluoro-c-propoxy group and 2,2,3,3-tetrafluoro-c-propoxy group.

The C _1-3 alkylene group means a linear, branched or cyclic alkylene group having 1 to 3 carbon atoms. For example, a methylene group, an ethylene group, a propylene group, an isopropylene group or a c-propylene group can give.

The C _1-6 alkylene group means a linear, branched alkylene group or cyclic alkylene group having 1 to 6 carbon atoms, such as methylene group, ethylene group, propylene group, isopropylene group, c-propylene. Group, ethylpropylene group, butylene group, isobutylene group, c-butylene group, ethylbutylene group, pentylene group, c-pentylene group, hexalene group and c-hexalene group.

The C _2-14 aryl group means a C _6-14 aryl group and a C _2-9 aromatic heterocyclic group not containing a hetero atom as a ring constituent atom.
The C _6-14 aryl group containing no hetero atom is an aryl group having 6 to 14 carbon atoms. Specific examples thereof include a phenyl group, a 1-indenyl group, a 2-indenyl group, a 3-indenyl group, 4 -Indenyl group, 5-indenyl group, 6-indenyl group, 7-indenyl group, α-naphthyl group, β-naphthyl group, 1-tetrahydronaphthyl group, 2-tetrahydronaphthyl group, 5-tetrahydronaphthyl group, 6-tetrahydro Naphthyl, o-biphenylyl, m-biphenylyl, p-biphenylyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4- Examples thereof include a phenanthryl group and a 9-phenanthryl group.
The C _2-9 aromatic heterocyclic group is a C _2-6 monocyclic heterocyclic ring having up to 5 to 7 membered rings which can contain 1 to 3 atoms alone or in combination of oxygen atom, nitrogen atom and sulfur atom. This means a C _5-9 fused bicyclic heterocyclic group having 8 to 10 groups and constituent atoms, and when it contains a nitrogen atom, it also includes an N-oxide.
Specific examples of the C _2-6 monocyclic heterocyclic group having 5 to 7 membered rings include 2-thienyl group, 3-thienyl group, 2-furyl group, 3-furyl group, 2-pyranyl group, 3- Pyranyl group, 4-pyranyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4- Pyrazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3- Isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrazinyl group, 2-pyrimidinyl group, 4 Pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-1,3,4-oxadiazolyl group, 2-1,3,4-thiadiazolyl group, 3-1,2,4-oxadiazolyl group 5-1, 2, 4-oxadiazolyl group, 3-1, 2, 4-thiadiazolyl group, 5-1, 2, 4-thiadiazolyl group, 3-1, 2, 5-oxadiazolyl group, 3-1, 2 , 5-thiadiazolyl group, 3-4H-1,2,4-triazolyl group, 3-1H-1,2,4-triazolyl group, 5-1H-1,2,4-triazolyl group, 4-2H-1 , 2,3-triazolyl group, 5-2H-1,2,3-triazolyl group, 4-1H-1,2,3-triazolyl group, 5-1H-1,2,3-triazolyl group and the like. .
Examples of the C _5-9 condensed bicyclic heterocyclic group having 8 to 10 constituent atoms include 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group, 7- Benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothienyl group, 3-benzothienyl group, 4-benzothienyl group, 5-benzothienyl group 6-benzothienyl group, 7-benzothienyl group, 1-isobenzothienyl group, 4-isobenzothienyl group, 5-isobenzothienyl group, 2-chromenyl group, 3-chromenyl group, 4-chromenyl group, 5 -Chromenyl group, 6-chromenyl group, 7-chromenyl group, 8-chromenyl group, 1-indolidinyl group, 2-indolidinyl group, 3-indolidyl group Group, 5-indolidinyl group, 6-indolidinyl group, 7-indolidinyl group, 8-indolidinyl group, 1-isoindolyl group, 2-isoindolyl group, 4-isoindolyl group, 5-isoindolyl group, 1-indolyl group, 2- Indolyl group, 3-indolyl group, 4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group, 1-indazolyl group, 2-indazolyl group, 3-indazolyl group, 4-indazolyl group, 5- Indazolyl group, 6-indazolyl group, 7-indazolyl group, 2- (7-aza) indazolyl group, 3- (7-aza) indazolyl group, 4- (7-aza) indazolyl group, 5- (7-aza) Indazolyl group, 6- (7-aza) indazolyl group, 2- (4-aza) indazolyl group, 3- (4-aza) indazoli Group, 5- (4-aza) indazolyl group, 6- (4-aza) indazolyl group, 7- (4-aza) indazolyl group, 1-purinyl group, 2-purinyl group, 3-purinyl group, 6-purinyl Group, 7-purinyl group, 8-purinyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group, 1-isoquinolyl group Group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 1-phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 1-2 7-naphthyridinyl group, 3-2,7-naphthyridinyl group, 4-2,7-naphthyridinyl group, 1-2,6-naphthyridinyl group, 3-2,6-naphthyridinyl group, 4-2,6-na Thyridinyl group, 2-1,8-naphthyridinyl group, 3-1,8-naphthyridinyl group, 4-1,8-naphthyridinyl group, 2-1,7-naphthyridinyl group, 3-1,7-naphthyridinyl group, 4- 1,7-naphthyridinyl group, 5-1,7-naphthyridinyl group, 6-1,7-naphthyridinyl group, 8-1,7-naphthyridinyl group, 2-1,6-naphthyridinyl group, 3-1,6-naphthyridinyl group Group, 4-1,6-naphthyridinyl group, 5-1,6-naphthyridinyl group, 7-1,6-naphthyridinyl group, 8-1,6-naphthyridinyl group, 2-1,5-naphthyridinyl group, 3-1 , 5-naphthyridinyl group, 4-1,5-naphthyridinyl group, 6-1,5-naphthyridinyl group, 7-1,5-naphthyridinyl group, 8-1,5-naphthyridinyl group, 2-quinoxalinyl group, 5-quinoxalinyl Group, 6- Noxalinyl group, 2-quinazolinyl group, 4-quinazolinyl group, 5-quinazolinyl group, 6-quinazolinyl group, 7-quinazolinyl group, 8-quinazolinyl group, 3-cinnolinyl group, 4-cinnolinyl group, 5-cinnolinyl group, 6- Examples include cinnolinyl group, 7-cinnolinyl group, 8-cinnolinyl group, 2-pteridinyl group, 4-pteridinyl group, 6-pteridinyl group, and 7-pteridinyl group.

The C _2-9 heteroaryl group is a C _2-6 monocyclic heterocyclic group or a structure having up to 5 to 7 membered rings which can contain 1 to 3 atoms alone or in combination of oxygen atom, nitrogen atom and sulfur atom. A C _5-9 condensed bicyclic heterocyclic group having 8 to 10 atoms is included, and when it contains a nitrogen atom, an N-oxide is also included.
Specific examples of the C _2-6 monocyclic heterocyclic group having 5 to 7 membered rings include 2-thienyl group, 3-thienyl group, 2-furyl group, 3-furyl group, 2-pyranyl group, 3- Pyranyl group, 4-pyranyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4- Pyrazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3- Isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrazinyl group, 2-pyrimidinyl group, 4 Pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-1,3,4-oxadiazolyl group, 2-1,3,4-thiadiazolyl group, 3-1,2,4-oxadiazolyl group 5-1, 2, 4-oxadiazolyl group, 3-1, 2, 4-thiadiazolyl group, 5-1, 2, 4-thiadiazolyl group, 3-1, 2, 5-oxadiazolyl group, and 3-1, 2 , 5-thiadiazolyl group and the like.
Specific examples of the C _5-9 condensed bicyclic heterocyclic group having 8 to 10 constituent atoms include 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl group, and 6-benzofuranyl group. 7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothienyl group, 3-benzothienyl group, 4-benzothienyl group, 5- Benzothienyl group, 6-benzothienyl group, 7-benzothienyl group, 1-isobenzothienyl group, 4-isobenzothienyl group, 5-isobenzothienyl group, 2-chromenyl group, 3-chromenyl group, 4-chromenyl group Group, 5-chromenyl group, 6-chromenyl group, 7-chromenyl group, 8-chromenyl group, 1-indolidinyl group, 2-indolidinyl group, 3-i Doridinyl group, 5-indolidinyl group, 6-indolidinyl group, 7-indolidinyl group, 8-indolidinyl group, 1-isoindolyl group, 2-isoindolyl group, 4-isoindolyl group, 5-isoindolyl group, 1-indolyl group, 2- Indolyl group, 3-indolyl group, 4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group, 3- (7-aza) indazolyl group, 4- (7-aza) indazolyl group, 5 -(7-aza) indazolyl group, 6- (7-aza) indazolyl group, 2- (4-aza) indazolyl group, 3- (4-aza) indazolyl group, 5- (4-aza) indazolyl group, 6 -(4-aza) indazolyl group, 7- (4-aza) indazolyl group, 1-indazolyl group, 2-indazolyl group, 3-indazolyl group, 4-indazolyl group, 5-indazolyl group, 6-indazolyl group, 7-indazolyl group, 1-purinyl group, 2-purinyl group, 3-purinyl group, 6-purinyl group, 7-purinyl group, 8-prinyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 1-phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 1-2, 7-naphthyridinyl group, 3-2,7- Naphthyridinyl group, 4-2,7-naphthyridinyl group, 1-2,6-naphthyridinyl group, 3-2,6-naphthyridinyl group, 4-2,6-naphthyridinyl group, 2- , 8-naphthyridinyl group, 3-1,8-naphthyridinyl group, 4-1,8-naphthyridinyl group, 2-1,7-naphthyridinyl group, 3-1,7-naphthyridinyl group, 4-1,7-naphthyridinyl group 5-1,7-naphthyridinyl group, 6-1,7-naphthyridinyl group, 8-1,7-naphthyridinyl group, 2-1,6-naphthyridinyl group, 3-1,6-naphthyridinyl group, 4-1, 6-naphthyridinyl group, 5-1,6-naphthyridinyl group, 7-1,6-naphthyridinyl group, 8-1,6-naphthyridinyl group, 2-1,5-naphthyridinyl group, 3-1,5-naphthyridinyl group, 4-1,5-naphthyridinyl group, 6-1,5-naphthyridinyl group, 7-1,5-naphthyridinyl group, 8-1,5-naphthyridinyl group, 2-quinoxalinyl group, 5-quinoxalinyl group, 6-quinoxalinyl group , 2- Quinazolinyl group, 4-quinazolinyl group, 5-quinazolinyl group, 6-quinazolinyl group, 7-quinazolinyl group, 8-quinazolinyl group, 3-cinnolinyl group, 4-cinnolinyl group, 5-cinnolinyl group, 6-cinnolinyl group, 7- Examples thereof include a cinnolinyl group, an 8-cinnolinyl group, a 2-pteridinyl group, a 4-pteridinyl group, a 6-pteridinyl group, and a 7-pteridinyl group.

The C _2-14 arylene group means a divalent group generated by removing one hydrogen atom from one ring atom of the above C _2-14 aryl group. For example, a phenylene group, an indenylene group, Naphthylene group, tetrahydronaphthylene group, biphenylene group, thienylene group, furylene group, pyranylene group, pyrrolylene group, imidazolylene group, pyrazolylene group, thiazolylene group, isothiazolylene group, oxazolylene group, pyridylene group, pyrazinylene group, pyrimidinylene group, pyridadinylene group, Oxadiazolylene group, thiadiazolylene group, triazolylene group, benzofuranylene group, isobenzofuranylene group, benzothienylene group, isobenzothienylene group, chromemenylene group, indolizinylene group, isoindolinylene group, indoleylene group, indazolylene Group, purinylene group, a quinolylene group, isoquinolylene group, phthalazinylene group, naphthyridinylene group, a quinoxalinylene group, a quinazolinylene group, Shin'noriniren group, Puterijiniren group and the like.

が挙げられる。 The heterocyclyl groups C _2-19, free from any one or more of the atoms of C _3-20 cycloalkyl group and C _3-20 cycloalkenyl groups shown above may in a nitrogen atom, an oxygen atom and a sulfur atom Means a group converted to a selected atom, and the carbon atoms constituting the ring may be carbonyl or thiocarbonyl.

Is mentioned.

が挙げられる。 The heterocyclyl groups C _2-11, free from any one or more of the atoms of C _3-12 cycloalkyl group and C _3-12 cycloalkenyl groups shown above may in a nitrogen atom, an oxygen atom and a sulfur atom Means a group converted to a selected atom, and the carbon atoms constituting the ring may be carbonyl or thiocarbonyl.

Is mentioned.

The C _2-9 heterocyclyl group is a monocyclic or condensed bicyclic heterocyclic group composed of one or more atoms freely selected from a nitrogen atom, an oxygen atom and a sulfur atom and 2 to 9 carbon atoms. And the carbon atoms constituting the ring may be carbonyl or thiocarbonyl, specifically,

が挙げられる。

Is mentioned.

The C _2-9 heterocyclylene group means a divalent group generated by removing one hydrogen atom from one ring atom of the above C _2-9 heterocyclyl group.

が挙げられる。

Is mentioned.

が挙げられる。 A nitrogen-containing heterocyclyl group has one or more nitrogen atoms, and may further contain one or more atoms selected from oxygen and sulfur atoms, and consists of 2 to 9 carbon atoms. Monocyclic and fused bicyclic heterocyclic groups, the carbon atoms constituting the ring may be carbonyl or thiocarbonyl, and specific examples include:

Is mentioned.

が挙げられる。 The condensed aryl group is a condensed bicyclic group or condensed tricyclic group in which the above C _2-14 aryl group and C _2-9 heterocyclyl group or C _3-6 cycloalkyl group are condensed. In

Is mentioned.

The C _2-14 aryloxy group includes a C _6-14 aryloxy group and a C _2-9 aromatic heterocyclic oxy group which do not contain a hetero atom as a ring constituent atom, but a C _2-9 aromatic group. The heterocyclic oxy group includes a C _2-6 monocyclic heterocyclic oxy group having 5 to 7 membered ring and oxygen atoms, nitrogen atoms and sulfur atoms which may contain 1 to 3 atoms alone or in combination. Of from 8 to 10 C _5-9 fused bicyclic heterocyclic oxy groups.

The C _6-14 aryloxy group containing no hetero atom includes a phenyloxy group, a 1-indenyloxy group, a 2-indenyloxy group, a 3-indenyloxy group, a 4-indenyloxy group, and a 5-indenyl group. Nyloxy group, 6-indenyloxy group, 7-indenyloxy group, α-naphthyloxy group, β-naphthyloxy group, 1-tetrahydronaphthyloxy group, 2-tetrahydronaphthyloxy group, 5-tetrahydronaphthyloxy group 6-tetrahydronaphthyloxy group, o-biphenylyloxy group, m-biphenylyloxy group, p-biphenylyloxy group, 1-anthryloxy group, 2-anthryloxy group, 9-anthryloxy group, 1-phenanthryloxy group, 2-phenanthryloxy group, 3-phenanthryloxy group, 4-phenanthryloxy group and 9-phenanthryl Alkoxy group and the like.

Examples of the C _2-6 monocyclic heterocyclic oxy group having 5 to 7 members include a 2-thienyloxy group, a 3-thienyloxy group, a 2-furyloxy group, a 3-furyloxy group, a 2-pyranyloxy group, 3-pyranyloxy group, 4-pyranyloxy group, 1-pyrrolyloxy group, 2-pyrrolyloxy group, 3-pyrrolyloxy group, 1-imidazolyloxy group, 2-imidazolyloxy group, 4-imidazolyloxy group, 1-pyrazolyloxy group, 3- Pyrazolyloxy group, 4-pyrazolyloxy group, 2-thiazolyloxy group, 4-thiazolyloxy group, 5-thiazolyloxy group, 3-isothiazolyloxy group, 4-isothiazolyloxy group, 5-isothiazolyloxy group, 2-oxa Zolyloxy group, 4-oxazolyloxy group, 5-oxazolyloxy group, 3-isooxy Sazolyloxy group, 4-isoxazolyloxy group, 5-isoxazolyloxy group, 2-pyridyloxy group, 3-pyridyloxy group, 4-pyridyloxy group, 2-pyrazinyloxy group, 2-pyrimidinyloxy group, 4-pyrimidinyloxy group, 5-pyrimidinyloxy group, 3-pyridazinyloxy group, 4-pyridazinyloxy group, 2-1,3,4-oxadiazolyloxy group, 2-1,3 4-thiadiazolyloxy group, 3-1,2,4-oxadiazolyloxy group, 5-1,2,4-oxadiazolyloxy group, 3-1,2,4-thiadiazolyloxy group, Examples include 5-1,2,4-thiadiazolyloxy group, 3-1,2,5-oxadiazolyloxy group, 3-1,2,5-thiadiazolyloxy group, and the like.

Examples of the C _5-9 fused bicyclic heterocyclic oxy group having 8 to 10 constituent atoms include 2-benzofuranyloxy group, 3-benzofuranyloxy group, 4-benzofuranyloxy group, 5- Benzofuranyloxy group, 6-benzofuranyloxy group, 7-benzofuranyloxy group, 1-isobenzofuranyloxy group, 4-isobenzofuranyloxy group, 5-isobenzofuranyloxy group, 2 -Benzothienyloxy group, 3-benzothienyloxy group, 4-benzothienyloxy group, 5-benzothienyloxy group, 6-benzothienyloxy group, 7-benzothienyloxy group, 1-isobenzothienyloxy group, 4 -Isobenzothienyloxy group, 5-isobenzothienyloxy group, 2-chromenyloxy group, 3-chromenyloxy group, 4-chromenyloxy group, 5 -Chromenyloxy group, 6-chromenyloxy group, 7-chromenyloxy group, 8-chromenyloxy group, 1-indolidinyloxy group, 2-indolidinyloxy group, 3-indolidinyloxy group 5-indolidinyloxy group, 6-indolidinyloxy group, 7-indolidinyloxy group, 8-indolidinyloxy group, 1-isoindolyloxy group, 2-isoindolyloxy group, 4 -Isoindolyloxy group, 5-isoindolyloxy group, 1-indolyloxy group, 2-indolyloxy group, 3-indolyloxy group, 4-indolyloxy group, 5-indolyloxy group, 6-indolyloxy group, 7-indolyloxy group, 1-indazolyloxy group, 2-indazolyloxy group, 3-indazolyloxy group, 4-indazolyloxy group Si group, 5-indazolyloxy group, 6-indazolyloxy group, 7-indazolyloxy group, 1-purinyloxy group, 2-prinyloxy group, 3-prinyloxy group, 6-purinyloxy group, 7-prinyloxy group Group, 8-purinyloxy group, 2-quinolyloxy group, 3-quinolyloxy group, 4-quinolyloxy group, 5-quinolyloxy group, 6-quinolyloxy group, 7-quinolyloxy group, 8-quinolyloxy group, 1-isoquinolyloxy group, 3-isoquinolyloxy group, 4-isoquinolyloxy group, 5-isoquinolyloxy group, 6-isoquinolyloxy group, 7-isoquinolyloxy group, 8-isoquinolyloxy group, 1- Phthalazinyloxy group, 5-phthalazinyloxy group, 6-phthalazinyloxy group, 1-2,7-naphthyridinyloxy group 3-2,7-naphthyridinyloxy group, 4-2,7-naphthyridinyloxy group, 1-2,6-naphthyridinyloxy group, 3-2,6-naphthyridinyloxy group, 4- 2,6-naphthyridinyloxy group, 2-1,8-naphthyridinyloxy group, 3-1,8-naphthyridinyloxy group, 4-1,8-naphthyridinyloxy group, 2-1, 7-naphthyridinyloxy group, 3-1,7-naphthyridinyloxy group, 4-1,7-naphthyridinyloxy group, 5-1,7-naphthyridinyloxy group, 6-1,7- Naphthyridinyloxy group, 8-1,7-naphthyridinyloxy group, 2-1,6-naphthyridinyloxy group, 3-1,6-naphthyridinyloxy group, 4-1,6-naphthyridinyl group Ruoxy group, 5-1,6-naphthyridinyloxy group, 7-1,6-naphthy Dinyloxy group, 8-1,6-naphthyridinyloxy group, 2-1,5-naphthyridinyloxy group, 3-1,5-naphthyridinyloxy group, 4-1,5-naphthyridinyloxy group 6-1,5-naphthyridinyloxy group, 7-1,5-naphthyridinyloxy group, 8-1,5-naphthyridinyloxy group, 2-quinoxalinyloxy group, 5-quinoxa Linyloxy group, 6-quinoxalinyloxy group, 2-quinazolinyloxy group, 4-quinazolinyloxy group, 5-quinazolinyloxy group, 6-quinazolinyloxy group, 7-quinazoly Nyloxy group, 8-quinazolinyloxy group, 3-cinnolinyloxy group, 4-cinnolinyloxy group, 5-cinnolinyloxy group, 6-cinnolinyloxy group, 7-cinnolinyloxy Group, 8-cinnolinyloxy group, 2 Examples include -pteridinyloxy group, 4-pteridinyloxy group, 6-pteridinyloxy group, and 7-pteridinyloxy group.

The mono C _1-6 alkylamino group is an amino group having one C _1-6 alkyl group, which may include linear, branched, and C _3-6 cycloalkylamino groups. Is methylamino, ethylamino, n-propylamino, i-propylamino, c-propylamino, n-butylamino, i-butylamino, s-butylamino, t-butylamino, c-butylamino, 1-methyl -c-propylamino, 2-methyl-c-propylamino, n-pentylamino, 1-methyl-n-butylamino, 2-methyl-n-butylamino, 3-methyl-n-butylamino, 1,1 -Dimethyl-n-propylamino, 1,2-dimethyl-n-propylamino, 2,2-dimethyl-n-propylamino, 1-ethyl-n-propylamino, c-pentylamino, 1-methyl-c- Butylamino, 2-methyl-c-butylamino, 3-methyl-c-butylamino, 1,2-dimethyl-c-propyl Pyramino, 2,3-dimethyl-c-propylamino, 1-ethyl-c-propylamino, 2-ethyl-c-propylamino, n-hexylamino, 1-methyl-n-pentylamino, 2-methyl-n -Pentylamino, 3-methyl-n-pentylamino, 4-methyl-n-pentylamino, 1,1-dimethyl-n-butylamino, 1,2-dimethyl-n-butylamino, 1,3-dimethyl- n-butylamino, 2,2-dimethyl-n-butylamino, 2,3-dimethyl-n-butylamino, 3,3-dimethyl-n-butylamino, 1-ethyl-n-butylamino, 2-ethyl -n-butylamino, 1,1,2-trimethyl-n-propylamino, 1,2,2-trimethyl-n-propylamino, 1-ethyl-1-methyl-n-propylamino, 1-ethyl-2 -Methyl-n-propylamino, c-hexylamino, 1-methyl-c-pentylamino, 2-methyl-c-pentylamino, 3-methyl-c-pentylamino, 1-ethyl-c-butylamino, 2 - Til-c-butylamino, 3-ethyl-c-butylamino, 1,2-dimethyl-c-butylamino, 1,3-dimethyl-c-butylamino, 2,2-dimethyl-c-butylamino, 2 , 3-Dimethyl-c-butylamino, 2,4-dimethyl-c-butylamino, 3,3-dimethyl-c-butylamino, 1-n-propyl-c-propylamino, 2-n-propyl-c -Propylamino, 1-i-propyl-c-propylamino, 2-i-propyl-c-propylamino, 1,2,2-trimethyl-c-propylamino, 1,2,3-trimethyl-c-propyl Amino, 2,2,3-trimethyl-c-propylamino, 1-ethyl-2-methyl-c-propylamino, 2-ethyl-1-methyl-c-propylamino, 2-ethyl-2-methyl-c -Propylamino, 2-ethyl-3-methyl-c-propylamino and the like.

The di-C _1-6 alkylamino group means an amino group having two C _1-6 alkyl groups, and the two alkyl groups may be symmetric or asymmetric. Symmetric diC _1-6 alkylamino groups may include linear, branched and C _3-6 cycloalkylamino groups, specific examples being dimethylamino, diethylamino, di-n-propylamino, di- -i-propylamino, di-c-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, di-c-butylamino, di- (1-methyl-c-propyl) amino, di- (2-methyl-c-propyl) amino, di-n-pentylamino, di- (1-methyl-n-butyl) amino, di- (2-methyl -n-butyl) amino, di- (3-methyl-n-butyl) amino, di- (1,1-dimethyl-n-propyl) amino, di- (1,2-dimethyl-n-propyl) amino, Di- (2,2-dimethyl-n-propyl) amino, di- (1-ethyl-n-propyl) amino, di-c-pentylamino, di- (1-methyl-c-butyl) amino, di- (2-Methyl-c-butyl) amino, di- (3-Methyl-c-butyl) amino, di- (1,2-dimethyl-c-propyl) amino, di- (2,3-dimethyl-c-propyl) amino, di- (1-ethyl-c- Propyl) amino, di- (2-ethyl-c-propyl) amino, di-n-hexylamino, di- (1-methyl-n-pentyl) amino, di- (2-methyl-n-pentyl) amino, Di- (3-methyl-n-pentyl) amino, di- (4-methyl-n-pentyl) amino, di- (1,1-dimethyl-n-butyl) amino, di- (1,2-dimethyl- n-butyl) amino, di- (1,3-dimethyl-n-butyl) amino, di- (2,2-dimethyl-n-butyl) amino, di- (2,3-dimethyl-n-butyl) amino , Di- (3,3-dimethyl-n-butyl) amino, di- (1-ethyl-n-butyl) amino, di- (2-ethyl-n-butyl) amino, di- (1,1,2 -Trimethyl-n-propyl) amino, di- (1,2,2-trimethyl-n-propyl) amino, di- (1-ethyl-1-methyl-n-propyl) amino, di- (1-ethyl- 2-Methyl-n-propyl) a Di-c-hexylamino, di- (1-methyl-c-pentyl) amino, di- (2-methyl-c-pentyl) amino, di- (3-methyl-c-pentyl) amino, di- (1-ethyl-c-butyl) amino, di- (2-ethyl-c-butyl) amino, di- (3-ethyl-c-butyl) amino, di- (1,2-dimethyl-c-butyl) Amino, di- (1,3-dimethyl-c-butyl) amino, di- (2,2-dimethyl-c-butyl) amino, di- (2,3-dimethyl-c-butyl) amino, di- ( 2,4-Dimethyl-c-butyl) amino, di- (3,3-dimethyl-c-butyl) amino, di- (1-n-propyl-c-propyl) amino, di- (2-n-propyl) -c-propyl) amino, di- (1-i-propyl-c-propyl) amino, di- (2-i-propyl-c-propyl) amino, di- (1,2,2-trimethyl-c- Propyl) amino, di- (1,2,3-trimethyl-c-propyl) amino, di- (2,2,3-trimethyl-c-propyl) amino, di- (1-ethyl-2-methyl-c) -Propyl) amino, di- (2-ethyl-1 -Methyl-c-propyl) amino, di- (2-ethyl-2-methyl-c-propyl) amino, di- (2-ethyl-3-methyl-c-propyl) amino and the like.
The asymmetric di C _1-6 alkylamino group may include linear, branched and C _3-6 cycloalkylamino groups. Specific examples include (methyl, ethyl) amino, (methyl, n-propyl). ) Amino, (methyl, i-propyl) amino, (methyl, c-propyl) amino, (methyl, n-butyl) amino, (methyl, i-butyl) amino, (methyl, s-butyl) amino, (methyl , T-butyl) amino, (methyl, n-pentyl) amino, (methyl, c-pentyl) amino, (methyl, n-hexyl) amino, (methyl, c-hexyl) amino, (ethyl, n-propyl) Amino, (ethyl, i-propyl) amino, (ethyl, c-propyl) amino, (ethyl, n-butyl) amino, (ethyl, i-butyl) amino, (ethyl, s-butyl) amino, (ethyl, t-butyl) amino, (ethyl, n- Pentyl) amino, (ethyl, c-pentyl) amino, (ethyl, n-hexyl) amino, (ethyl, c-hexyl) amino, (n-propyl, i-propyl) amino, (n-propyl, c-propyl) ) Amino, (n-propyl, n-butyl) amino, (n-propyl, i-butyl) amino, (n-propyl, s-butyl) amino, (n-propyl, t-butyl) amino, (n- Propyl, n-pentyl) amino, (n-propyl, c-pentyl) amino, (n-propyl, n-hexyl) amino, (n-propyl, c-hexyl) amino, (i-propyl, c-propyl) Amino, (i-propyl, n-butyl) amino, (i-propyl, i-butyl) amino, (i-propyl, s-butyl) amino, (i-propyl, t-butyl) amino, (i-propyl) , N-pentyl) amino, (i-propyl, c-pentyl) amino, (i-propyl) Pill, n-hexyl) amino, (i-propyl, c-hexyl) amino, (c-propyl, n-butyl) amino, (c-propyl, i-butyl) amino, (c-propyl, s-butyl) Amino, (c-propyl, t-butyl) amino, (c-propyl, n-pentyl) amino, (c-propyl, c-pentyl) amino, (c-propyl, n-hexyl) amino, (c-propyl) , C-hexyl) amino, (n-butyl, i-butyl) amino, (n-butyl, s-butyl) amino, (n-butyl, t-butyl) amino, (n-butyl, n-pentyl) amino , (N-butyl, c-pentyl) amino, (n-butyl, n-hexyl) amino, (n-butyl, c-hexyl) amino, (i-butyl, s-butyl) amino, (i-butyl, t-butyl) amino, (i-butyl, n-pentyl) amino, (i-butyl, c-pentyl) amino, (i-butyl, n-hexyl) amino , (I-butyl, c-hexyl) amino, (s-butyl, t-butyl) amino, (s-butyl, n-pentyl) amino, (s-butyl, c-pentyl) amino, (s-butyl, n-hexyl) amino, (s-butyl, c-hexyl) amino, (t-butyl, n-pentyl) amino, (t-butyl, c-pentyl) amino, (t-butyl, n-hexyl) amino, (T-butyl, c-hexyl) amino, (n-pentyl, c-pentyl) amino, (n-pentyl, n-hexyl) amino, (n-pentyl, c-hexyl) amino, (c-pentyl, n -Hexyl) amino, (c-pentyl, c-hexyl) amino, (n-hexyl, c-hexyl) amino and the like.

The C _1-6 alkylthio group is a thio group having a C _1-6 alkyl group, and may include linear, branched, and C _3-6 cycloalkylthio groups. Specific examples include methylthio, ethylthio, n-propylthio, i-propylthio, c-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio, c-butylthio, 1-methyl-c-propylthio, 2-methyl-c-propylthio, n- Pentylthio, 1-methyl-n-butylthio, 2-methyl-n-butylthio, 3-methyl-n-butylthio, 1,1-dimethyl-n-propylthio, 1,2-dimethyl-n-propylthio, 2,2- Dimethyl-n-propylthio, 1-ethyl-n-propylthio, c-pentylthio, 1-methyl-c-butylthio, 2-methyl-c-butylthio, 3-methyl-c-butylthio, 1,2-dimethyl-c- Propylthio, 2,3-dimethyl-c-propylthio, 1-ethyl-c-propylthio, 2- Tyl-c-propylthio, n-hexylthio, 1-methyl-n-pentylthio, 2-methyl-n-pentylthio, 3-methyl-n-pentylthio, 4-methyl-n-pentylthio, 1,1-dimethyl-n- Butylthio, 1,2-dimethyl-n-butylthio, 1,3-dimethyl-n-butylthio, 2,2-dimethyl-n-butylthio, 2,3-dimethyl-n-butylthio, 3,3-dimethyl-n- Butylthio, 1-ethyl-n-butylthio, 2-ethyl-n-butylthio, 1,1,2-trimethyl-n-propylthio, 1,2,2-trimethyl-n-propylthio, 1-ethyl-1-methyl- n-propylthio, 1-ethyl-2-methyl-n-propylthio, c-hexylthio, 1-methyl-c-pentylthio, 2-methyl-c-pentylthio, 3-methyl-c-pentylthio, 1-ethyl-c- Butylthio, 2-ethyl-c-butylthio, 3-ethyl-c-butylthio, 1,2-dimethyl-c-butylthio, 1,3-dimethyl-c-butylthio, 2,2-dimethyl-c-butylthio, 2 , 3-Dimethyl-c-butylthio, 2,4-dimethyl-c-butylthio, 3,3-dimethyl-c-butylthio, 1-n-propyl-c-propylthio, 2-n-propyl-c-propylthio, 1 -i-propyl-c-propylthio, 2-i-propyl-c-propylthio, 1,2,2-trimethyl-c-propylthio, 1,2,3-trimethyl-c-propylthio, 2,2,3-trimethyl -c-propylthio, 1-ethyl-2-methyl-c-propylthio, 2-ethyl-1-methyl-c-propylthio, 2-ethyl-2-methyl-c-propylthio, 2-ethyl-3-methyl-c -Propylthio and the like.

The C _1-3 alkylthio group is an alkylthio group having 1 to 3 carbon atoms, and may include a straight chain, branched chain or C ₃ cycloalkylthio group. Specific examples thereof include methylthio, ethylthio, n- Examples include propylthio, i-propylthio and c-propylthio.

The C _1-6 alkylsulfonyl group is a sulfonyl group having a C _1-6 alkyl group, and may include linear, branched, and C _3-6 cycloalkylsulfonyl groups. , Ethylsulfonyl, n-propylsulfonyl, i-propylsulfonyl, c-propylsulfonyl, n-butylsulfonyl, i-butylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, c-butylsulfonyl, 1-methyl-c- Propylsulfonyl, 2-methyl-c-propylsulfonyl, n-pentylsulfonyl, 1-methyl-n-butylsulfonyl, 2-methyl-n-butylsulfonyl, 3-methyl-n-butylsulfonyl, 1,1-dimethyl- n-propylsulfonyl, 1,2-dimethyl-n-propylsulfonyl, 2,2-dimethyl-n-propylsulfonyl, 1-ethyl-n-propylsulfonyl, c-pentylsulfonyl 1-methyl-c-butylsulfonyl, 2-methyl-c-butylsulfonyl, 3-methyl-c-butylsulfonyl, 1,2-dimethyl-c-propylsulfonyl, 2,3-dimethyl-c-propylsulfonyl, 1 -Ethyl-c-propylsulfonyl, 2-ethyl-c-propylsulfonyl, n-hexylsulfonyl, 1-methyl-n-pentylsulfonyl, 2-methyl-n-pentylsulfonyl, 3-methyl-n-pentylsulfonyl, 4 -Methyl-n-pentylsulfonyl, 1,1-dimethyl-n-butylsulfonyl, 1,2-dimethyl-n-butylsulfonyl, 1,3-dimethyl-n-butylsulfonyl, 2,2-dimethyl-n-butyl Sulfonyl, 2,3-dimethyl-n-butylsulfonyl, 3,3-dimethyl-n-butylsulfonyl, 1-ethyl-n-butylsulfonyl, 2-ethyl-n-butylsulfonyl, 1,1,2-trimethyl- n-propylsulfonyl, 1,2,2-trimethyl-n-propylsulfonyl, 1-ethyl-1- Tyl-n-propylsulfonyl, 1-ethyl-2-methyl-n-propylsulfonyl, c-hexylsulfonyl, 1-methyl-c-pentylsulfonyl, 2-methyl-c-pentylsulfonyl, 3-methyl-c-pentyl Sulfonyl, 1-ethyl-c-butylsulfonyl, 2-ethyl-c-butylsulfonyl, 3-ethyl-c-butylsulfonyl, 1,2-dimethyl-c-butylsulfonyl, 1,3-dimethyl-c-butylsulfonyl 2,2-dimethyl-c-butylsulfonyl, 2,3-dimethyl-c-butylsulfonyl, 2,4-dimethyl-c-butylsulfonyl, 3,3-dimethyl-c-butylsulfonyl, 1-n-propyl -c-propylsulfonyl, 2-n-propyl-c-propylsulfonyl, 1-i-propyl-c-propylsulfonyl, 2-i-propyl-c-propylsulfonyl, 1,2,2-trimethyl-c-propyl Sulfonyl, 1,2,3-trimethyl-c-propylsulfonyl, 2,2,3-trimethyl-c-propyl Ruphonyl, 1-ethyl-2-methyl-c-propylsulfonyl, 2-ethyl-1-methyl-c-propylsulfonyl, 2-ethyl-2-methyl-c-propylsulfonyl and 2-ethyl-3-methyl-c -Propylsulfonyl and the like.

The C _1-3 alkylsulfonyl group is an alkylsulfonyl group having 1 to 3 carbon atoms, and may include a linear, branched, or C ₃ cycloalkylsulfonyl group. Specific examples include methylsulfonyl, Examples include ethylsulfonyl, n-propylsulfonyl, i-propylsulfonyl and c-propylsulfonyl.

Next, a preferred structure of each substituent in the present invention is listed.
The substituent R ¹ is preferably a hydrogen atom, a C _1-3 alkoxy group or a halogen-substituted C _1-3 alkoxy group.
The substituent R ¹ is more preferably a hydrogen atom or an ethoxy group, and still more preferably a hydrogen atom.

（式中、Ｒ^aはシアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味し、
Ｒ^ｂ及びＲ^ｃはそれぞれ独立して、水素原子、シアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、
及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味するか、
Ｒ^aとＲ^ｂ又はＲ^ｂとＲ^ｃが一緒になって含窒素ヘテロシクリル基
（該含窒素へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味し、
T’及びU’はそれぞれ独立して、酸素原子、ＮＲ^ｄ又はＮＯＲ^ｄ
（式中、Ｒ^ｄは水素原子、シアノ基又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味する。）
を意味し、
Ｌは単結合又はＣ_１−６アルキレン基
（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
である。
置換基Ｒ^２は、より好ましくは、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基
（該Ｃ_１−６アルキル基及びＣ_１−６アルコキシ基は置換基群Ｖ^３より単独若しくは異なって選ばれる１つ以上の置換基で置換されており、ハロゲン原子で置換されていてもよい。）、
テトラゾリル基、Ｃ_２−９ヘテロシクリル基
（該テトラゾリル基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
又は式（Ｖ）

（式中、Ｒ^aはシアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味し、
Ｒ^ｂは水素原子、シアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味するか、
Ｒ^aとＲ^ｂが一緒になって含窒素ヘテロシクリル基
（該含窒素へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味し、
T’は酸素原子、ＮＲ^ｄ又はＮＯＲ^ｄ
（式中、Ｒ^ｄは水素原子、シアノ基又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は、無置換であるか又はフェニル基で置換されている。）を意味する。）
を意味し、
Ｌは単結合又はＣ_１−６アルキレン基
（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
である。
置換基Ｒ^２は、さらに好ましくはＣ_１−３アルキル基
（該Ｃ_１−３アルキル基はカルボキシル基又は水酸基で置換されている。）
又は式（ＶＩ）

（式中、Ｒ^aはＣ_１−３アルキル基を意味し、Ｒ^ｂは水素原子又はＣ_１−３アルキル基を意味し、
Ｔ’は酸素原子、ＮＲ^ｄ又はＮＯＲ^ｄ
（式中、Ｒ^ｄは水素原子、シアノ基又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は、無置換であるか又はフェニル基で置換されている。）を意味する。）
を意味する。）
である。 The substituent R ² is preferably a C _1-6 alkyl group, a C _1-6 alkoxy group, a mono C _1-6 alkylamino group, a diC _1-6 alkylamino group, a C _1-6 alkylthio group, a C _{1- 6} alkylsulfonyl groups (the C _1-6 alkyl group, C _1-6 alkoxy group, mono C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkylthio group and C _1-6 alkyl) The sulfonyl group is substituted with one or more substituents selected from the substituent group V ³ alone or differently, and may be substituted with a halogen atom).
A tetrazolyl group, a C _2-9 heterocyclyl group (the tetrazolyl group and the C _2-9 heterocyclyl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ² alone or differently; Yes.)
Or formula (X)

(In the formula, R ^a is a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, The C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are one or more substituents that are unsubstituted or selected alone or differently from the substituent group V ² Is replaced by
R ^b and R ^c are each independently a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group or a C _2-9 heterocyclyl group A C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group,
And C _2-9 heterocyclyl group is substituted with one or more substituents selected as or singly or different from Substituent group V ² unsubstituted. ) Or
R ^a and R ^b or R ^b and R ^{c taken} together to form a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or one or more selected from the group of substituents V ¹ alone or differently Substituted with a substituent of
Means
T ′ and U ′ each independently represent an oxygen atom, NR ^d or NOR ^d
(In the formula, R ^d is a hydrogen atom, a cyano group or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or one or more selected from the substituent group V ² alone or differently). Substituted with a substituent of
Means
L is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). .)
Means. )
It is.
The substituent R ² is more preferably a C _1-6 alkyl group, a C _1-6 alkoxy group (the C _1-6 alkyl group and the C _1-6 alkoxy group are selected from the substituent group V ³ alone or differently). Substituted with one or more substituents, which may be substituted with a halogen atom)
A tetrazolyl group, a C _2-9 heterocyclyl group (the tetrazolyl group and the C _2-9 heterocyclyl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ² alone or differently; Yes.)
Or formula (V)

(In the formula, R ^a is a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, The C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are one or more substituents that are unsubstituted or selected alone or differently from the substituent group V ² Is replaced by
R ^b is a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group, or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, C _{The 2-6} alkenyl group, C _2-14 aryl group, condensed aryl group and C _2-9 heterocyclyl group are one or more substituents which are unsubstituted or selected alone or differently from the substituent group V ² Is replaced)
R ^a and R ^{b taken} together are a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently. ing.)
Means
T ′ is an oxygen atom, NR ^d or NOR ^d
(Wherein R ^d represents a hydrogen atom, a cyano group, or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with a phenyl group).)
Means
L is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). .)
Means. )
It is.
The substituent R ² is more preferably a C _1-3 alkyl group (the C _1-3 alkyl group is substituted with a carboxyl group or a hydroxyl group).
Or formula (VI)

(Wherein R ^a represents a C _1-3 alkyl group, R ^b represents a hydrogen atom or a C _1-3 alkyl group,
T ′ is an oxygen atom, NR ^d or NOR ^d
(Wherein R ^d represents a hydrogen atom, a cyano group, or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with a phenyl group).)
Means. )
It is.

（式中、Ｒ^３及びＲ^５は水素原子を意味し、Ｒ^４はＣ_７−１2シクロアルキル基又はＣ_７−１2シクロアルケニル基を意味する。）、
式（ＶＩＩ）

（式中、Ｒ^３は、水素原子又はＣ_１−６アルキル基
（該Ｃ_１−６アルキル基は、無置換であるか又はハロゲン原子で置換されている。）
を意味し、Ｒ^４はＣ_１−２０アルキル基、Ｃ_２−２０アルケニル基又はＣ_２−１９へテロシクリル基
（該Ｃ_１−２０アルキル基、Ｃ_２−２０アルケニル基及びＣ_２−１９へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
又は、式（ＶＩＩＩ）

（式中、ｍは０，１又は２を意味し、Ｒ^４はＣ_１−２０アルキル基、Ｃ_２−２０アルケニル基又はＣ_２−１９へテロシクリル基
（該Ｃ_１−２０アルキル基、Ｃ_２−２０アルケニル基又はＣ_２−１９へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
である。
置換基Ｑは、より好ましくは式（ＶＩＩ）

（式中、Ｒ^３は水素原子を意味し、Ｒ^４はＣ_３−１2シクロアルキル基、Ｃ_３−１2シクロアルケニル基又はＣ_２−１９へテロシクリル基
（該Ｃ_３−12シクロアルキル基、Ｃ_３−１2シクロアルケニル基及びＣ_２−１９へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独もしくは異なって選ばれる１乃至３つの置換基によって置換されている。）
を意味する。）
又は、式（ＶＩＩＩ）

（式中、ｍは０，１又は２を意味し、Ｒ^４はＣ_３−１2シクロアルキル基、Ｃ_３−１2シクロアルケニル基又はＣ_２−１９へテロシクリル基
（該Ｃ_３−12シクロアルキル基、Ｃ_３−１2シクロアルケニル基及びＣ_２−１９へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独もしくは異なって選ばれる１乃至３つの置換基によって置換されている。）
を意味する。）
である。
置換基Ｑは、さらに好ましくは式（ＶＩＩ）

（式中、Ｒ^３は水素原子を意味し、Ｒ^４はＣ_７−１2シクロアルキル基又はＣ_７−１2シクロアルケニル基
（該Ｃ_７−１2シクロアルキル基及びＣ_７−１2シクロアルケニル基は、無置換であるか又はカルボキシル基、カルバモイル基、スルファモイル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルキルスルホニル基、ハロゲン置換Ｃ_１−３アルキル基及びハロゲン置換Ｃ_１−３アルコキシ基より単独若しくは異なって選ばれる１つ又は２つの置換基で置換されている。）
を意味する。）
又は、式（ＶＩＩＩ）

（式中、ｍは０，１又は２を意味し、Ｒ^４はＣ_７−１2シクロアルキル基又はＣ_７−１2シクロアルケニル基
（該Ｃ_７−１2シクロアルキル基及びＣ_７−１2シクロアルケニル基は、無置換であるか又はカルボキシル基、カルバモイル基、スルファモイル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルキルスルホニル基、ハロゲン置換Ｃ_１−３アルキル基及びハロゲン置換Ｃ_１−３アルコキシ基より単独若しくは異なって選ばれる１つ又は２つの置換基で置換されている。）
を意味する。）
である。
置換基Ｑは、特に好ましくは式（ＶＩＩ）

（式中、Ｒ^３は水素原子を意味し、Ｒ^４はＣ_８−１2シクロアルキル基
（該Ｃ_８−１2シクロアルキル基は、無置換であるか又はカルボキシル基、カルバモイル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルスルホニル基、ハロゲン置換Ｃ_１−３アルキル基及びハロゲン置換Ｃ_１−３アルコキシ基より単独若しくは異なって選ばれる１つ又は２つの置換基で置換されている。）
を意味する。）
である。
置換基Ｑは、さらに特に好ましくは式（ＶＩＩ）

（式中、Ｒ^３は水素原子を意味し、Ｒ^４は以下に示す構造である。）である。

置換基Ｑは、さらに特に好ましくは式（ＶＩＩ）

（式中、Ｒ^３は水素原子を意味し、Ｒ^４は以下に示す構造である。）である。

The substituent Q is preferably of the formula (XI)

(Wherein R ³ and R ⁵ represent a hydrogen atom, and R ⁴ represents a C _7-12 cycloalkyl group or a C _7-12 cycloalkenyl group),
Formula (VII)

(In the formula, R ³ is a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted with a halogen atom).
R ⁴ represents a C _1-20 alkyl group, a C _2-20 alkenyl group or a C _2-19 heterocyclyl group (the C _1-20 alkyl group, a C _2-20 alkenyl group and a C _2-19 heterocyclyl group). The group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently.
Means. )
Or formula (VIII)

(In the formula, m represents 0, 1 or 2, and R ⁴ represents a C _1-20 alkyl group, a C _2-20 alkenyl group or a C _2-19 heterocyclyl group (the C _1-20 alkyl group, C _{2 The -20} alkenyl group or the C _2-19 heterocyclyl group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently.
Means. )
It is.
Substituent Q is more preferably of formula (VII)

(Wherein R ³ represents a hydrogen atom, R ⁴ represents a C _3-12 cycloalkyl group, a C _3-12 cycloalkenyl group or a C _2-19 heterocyclyl group (the C _3-12 cycloalkyl group, C _{The 3-12} cycloalkenyl group and the C _2-19 heterocyclyl group are unsubstituted or substituted by 1 to 3 substituents selected from the substituent group V ¹ alone or differently.
Means. )
Or formula (VIII)

(In the formula, m represents 0, 1 or 2, and R ⁴ represents a C _3-12 cycloalkyl group, a C _3-12 cycloalkenyl group or a C _2-19 heterocyclyl group (the C _3-12 cycloalkyl group). , C _3-12 cycloalkenyl group and C _2-19 heterocyclyl group are unsubstituted or substituted by 1 to 3 substituents selected from substituent group V ¹ alone or differently.
Means. )
It is.
Substituent Q is more preferably of formula (VII)

(In the formula, R ³ represents a hydrogen atom, R ⁴ represents a C _7-12 cycloalkyl group or a C _7-12 cycloalkenyl group (the C _7-12 cycloalkyl group and the C _7-12 cycloalkenyl group are Unsubstituted or carboxyl group, carbamoyl group, sulfamoyl group, nitro group, cyano group, halogen atom, hydroxyl group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1- Selected from ₆ alkoxy groups, C _2-9 heterocyclyl groups, C _1-6 alkylthio groups, C _1-6 alkylsulfonyl groups, halogen-substituted C _1-3 alkyl groups and halogen-substituted C _1-3 alkoxy groups. Substituted with one or two substituents.)
Means. )
Or formula (VIII)

(In the formula, m represents 0, 1 or 2, and R ⁴ represents a C _7-12 cycloalkyl group or a C _7-12 cycloalkenyl group (the C _7-12 cycloalkyl group and C _7-12 cycloalkenyl group). Is unsubstituted or carboxyl group, carbamoyl group, sulfamoyl group, nitro group, cyano group, halogen atom, hydroxyl group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylthio group, C _1-6 alkylsulfonyl group, halogen-substituted C _1-3 alkyl group and halogen-substituted C _1-3 alkoxy group alone or differently Substituted with one or two selected substituents.)
Means. )
It is.
The substituent Q is particularly preferably of the formula (VII)

(In the formula, R ³ represents a hydrogen atom, R ⁴ represents a C _8-12 cycloalkyl group (the C _8-12 cycloalkyl group is unsubstituted or a carboxyl group, a carbamoyl group, a nitro group, a cyano group) Group, halogen atom, hydroxyl group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylsulfonyl group, It is substituted with one or two substituents selected from a halogen-substituted C _1-3 alkyl group and a halogen-substituted C _1-3 alkoxy group alone or differently.
Means. )
It is.
The substituent Q is more particularly preferably of the formula (VII)

(Wherein R ³ represents a hydrogen atom, and R ⁴ has a structure shown below).

The substituent Q is more particularly preferably of the formula (VII)

(Wherein R ³ represents a hydrogen atom, and R ⁴ has a structure shown below).

Substituent X is preferably a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted, or one or two substituents selected from substituent group V ¹ alone or differently). Is replaced by.)
It is.
The substituent X is more preferably a C _1-3 alkylene group, still more preferably a methylene group, 1,2-ethylene group, or 1,1-ethylene group, and particularly preferably a methylene group.

（式中、Ｒ^６は、水素原子又はＣ_１−３アルキル基
（該Ｃ_１−３アルキル基は、無置換であるか又はハロゲン原子で置換されている。）を意味し、Ｕは酸素原子又は硫黄原子を意味する。）である。
置換基Ｙは、より好ましくは式(ＩＸ)
（式中、Ｒ^６は、水素原子を意味し、Ｕは酸素原子を意味する。）
である。

Substituent Y is preferably a single bond or formula (IX)

(In the formula, R ⁶ represents a hydrogen atom or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with a halogen atom), and U represents an oxygen atom. Or a sulfur atom.).
Substituent Y is more preferably of formula (IX)
(In the formula, R ⁶ represents a hydrogen atom, and U represents an oxygen atom.)
It is.

（式中、各構造は無置換であるか又はカルボキシル基、カルバモイル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルスルホニル基、ハロゲン置換Ｃ_１−３アルキル基及びハロゲン置換Ｃ_１−３アルコキシ基で置換されている。）
で示される置換基群から選ばれる1つの置換基で置換されている。）
又は、Ｃ_１−３アルキル基
（該Ｃ_１−３アルキル基は置換基群（ＸＩＩＩ）

（式中、各構造は無置換であるか又はカルボキシル基、カルバモイル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルスルホニル基、ハロゲン置換Ｃ_１−３アルキル基及びハロゲン置換Ｃ_１−３アルコキシ基で置換されている。）
で示される置換基群から選ばれる1つの置換基で置換されている。）
である。
置換基Ｚは、さらに特に好ましくは、（３−メチルピリジル）メチル基、（３−メチルピリジル）エチル基、ピリジルメチル基、ピリジルエチル基、（２−フルオロピリジル）エチル基、（３−クロロピリジル）エチル基、(３−ジメチルアミノピリジル)メチル基、ピリダジニルエチル基、ピリダジニルプロピル基、ピリミジニルエチル基、（４−メチルピリダジニル）メチル基、（３−ジメチルアミノピリダジニル）メチル基、（３−メチルピリダジニル）エチル基、（３−クロロピリダジニル）エチル基、（３−メトキシピリダジニル）エチル基、（３−メタンスルホニルピリジル）エチル基又はピリミジニルプロピル基である。 The substituent Z is preferably a C _1-6 alkyl group, a C _1-6 alkoxy group (the C _1-6 alkyl group and the C _1-6 alkoxy group are unsubstituted or selected from the substituent group V ^2). Substituted by one or two substituents).
C _2-14 aryl group, C _2-14 aryloxy group or C _2-9 heterocyclyl group (the C _2-14 aryl group, C _2-14 aryloxy group and C _2-9 heterocyclyl group are unsubstituted) substituted with or one or two substituents selected independently or different from substituent group V ^2.)
It is.
The substituent Z is more preferably a C _1-6 alkyl group (the C _1-6 alkyl group is a C _2-9 heteroaryl group or a C _2-9 heterocyclyl group (the C _2-9 heteroaryl group and C _{2-6 The 9} heterocyclyl group is unsubstituted or substituted with one or two substituents selected from the substituent group V ¹ alone or differently.
Has been replaced by )
It is.
The substituent Z is more preferably a C _1-6 alkyl group (the C _1-6 alkyl group is a C _2-9 heteroaryl group or a C _2-9 heterocyclyl group (the C _2-9 heteroaryl group and C _{2-6 9} Heterocyclyl group is unsubstituted or carboxyl group, carbamoyl group, sulfamoyl group, nitro group,
A cyano group, a halogen atom, a hydroxyl group, an amino group, a C _1-6 alkyl group,
A mono C _1-6 alkylamino group, a di C _1-6 alkylamino group,
A C _1-6 alkoxy group, a C _2-9 heterocyclyl group, a C _1-6 alkylthio group,
1 selected independently or differently from a C _1-6 alkylsulfonyl group, a halogen-substituted C _1-3 alkyl group and a halogen-substituted C _1-3 alkoxy group
Substituted with one or two substituents. )
Has been replaced by )
It is.
The substituent Z is particularly preferably a C _1-3 alkyl group (the C _1-3 alkyl group is a substituent group (XII)).

(In the formula, each structure is unsubstituted or carboxyl group, carbamoyl group, nitro group, cyano group, halogen atom, hydroxyl group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group , C _1-6 alkyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylsulfonyl group, halogen substituted C _1-3 alkyl group and halogen substituted C _1-3 alkoxy group ing.)
Is substituted with one substituent selected from the group of substituents represented by )
Or a C _1-3 alkyl group (the C _1-3 alkyl group is a substituent group (XIII))

(In the formula, each structure is unsubstituted or carboxyl group, carbamoyl group, nitro group, cyano group, halogen atom, hydroxyl group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group , C _1-6 alkyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylsulfonyl group, halogen substituted C _1-3 alkyl group and halogen substituted C _1-3 alkoxy group ing.)
Is substituted with one substituent selected from the group of substituents represented by )
It is.
Substituent Z is more preferably (3-methylpyridyl) methyl group, (3-methylpyridyl) ethyl group, pyridylmethyl group, pyridylethyl group, (2-fluoropyridyl) ethyl group, (3-chloropyridyl) ) Ethyl group, (3-dimethylaminopyridyl) methyl group, pyridazinylethyl group, pyridazinylpropyl group, pyrimidinylethyl group, (4-methylpyridazinyl) methyl group, (3-dimethylaminopyridyl) Dazinyl) methyl group, (3-methylpyridazinyl) ethyl group, (3-chloropyridazinyl) ethyl group, (3-methoxypyridazinyl) ethyl group, (3-methanesulfonylpyridyl) An ethyl group or a pyrimidinylpropyl group.

  Preferable compounds used in the present invention for P2X7 receptor inhibitors, preventive / treating / ameliorating drugs for diseases for which P2X7 receptor inhibitory action is effective, and rheumatoid arthritis therapeutic agents include the following.

（式中、Ｒ^aはシアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味し、
Ｒ^ｂ及びＲ^ｃはそれぞれ独立して、水素原子、シアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味するか、
Ｒ^aとＲ^ｂ又はＲ^ｂとＲ^ｃが一緒になって含窒素ヘテロシクリル基
（該含窒素へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味し、
T‘及びU’はそれぞれ独立して、酸素原子、ＮＲ^ｄ又はＮＯＲ^ｄ
（式中、Ｒ^ｄは水素原子、シアノ基又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味する。）
を意味し、
Ｌは単結合又はＣ_１−６アルキレン基
（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）であり、
Ｑが式（ＸＩ）

（式中Ｒ^３及びＲ^５は水素原子を意味し、Ｒ^４はＣ_７−１2シクロアルキル基又はＣ_７−１2シクロアルケニル基を意味する。）
、式（ＶＩＩ）

（式中、Ｒ^３は、水素原子又はＣ_１−６アルキル基
（該Ｃ_１−６アルキル基は、無置換であるか又はハロゲン原子で置換されている。）
を意味し、Ｒ^４はＣ_１−２０アルキル基、Ｃ_２−２０アルケニル基又はＣ_２−１９へテロシクリル基
（該Ｃ_１−２０アルキル基、Ｃ_２−２０アルケニル基及びＣ_２−１９へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
又は、式（ＶＩＩＩ）

（式中、ｍは０，１又は２を意味し、Ｒ^４はＣ_１−２０アルキル基、Ｃ_２−２０アルケニル基又はＣ_２−１９へテロシクリル基
（該Ｃ_１−２０アルキル基、Ｃ_２−２０アルケニル基及びＣ_２−１９へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
であり、
ＸがＣ_１−６アルキレン基
（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる置換基１つ又は２つの置換基によって置換されている。）
であり、
Ｙが単結合又は式(ＩＸ)

（式中、Ｒ^６は、水素原子又はＣ_１−６アルキル基
（該Ｃ_１−6アルキル基は、無置換であるか又はハロゲン原子で置換されている。）を意味し、Ｕは酸素原子又は硫黄原子を意味する。）
であり、
Ｚが、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基
（該Ｃ_１−６アルキル基及びＣ_１−６アルコキシ基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる１つ又は２つの置換基で置換されている。）、Ｃ_２−１４アリール基又はＣ_２−９ヘテロシクリル基
（該Ｃ_２−１４アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より選ばれる１つの置換基で置換されている。）
である式(I)で表される化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。 1) R ¹ is a hydrogen atom, a C _1-3 alkoxy group or a halogen-substituted C _1-3 alkoxy group,
R ² is a C _1-6 alkyl group, a C _1-6 alkoxy group, a mono C _1-6 alkylamino group, a diC _1-6 alkylamino group, a C _1-6 alkylthio group, a C _1-6 alkylsulfonyl group ( The C _1-6 alkyl group, C _1-6 alkoxy group, mono C _1-6 alkylamino group, diC _1-6 alkylamino group, C _1-6 alkylthio group and C _1-6 alkylsulfonyl group are substituents. Substituted with one or more substituents selected from the group V ³ singly or differently, and may be substituted with a halogen atom).
A tetrazolyl group, a C _2-9 heterocyclyl group (the tetrazolyl group and the C _2-9 heterocyclyl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ² alone or differently; Yes.)
Or formula (X)

(In the formula, R ^a is a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, The C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are one or more substituents that are unsubstituted or selected alone or differently from the substituent group V ² Is replaced by
R ^b and R ^c are each independently a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group or a C _2-9 heterocyclyl group The C _1-6 alkyl group, the C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are unsubstituted, or are selected alone or differently from the substituent group V ² Is substituted with one or more substituents
R ^a and R ^b or R ^b and R ^{c taken} together to form a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or one or more selected from the group of substituents V ¹ alone or differently Substituted with a substituent of
Means
T ′ and U ′ each independently represent an oxygen atom, NR ^d or NOR ^d
(In the formula, R ^d is a hydrogen atom, a cyano group or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or one or more selected from the substituent group V ² alone or differently). Substituted with a substituent of
Means
L is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). .)
Means. ) And
Q is the formula (XI)

(In the formula, R ³ and R ⁵ represent a hydrogen atom, and R ⁴ represents a C _7-12 cycloalkyl group or a C _7-12 cycloalkenyl group.)
, Formula (VII)

(In the formula, R ³ is a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted with a halogen atom).
R ⁴ represents a C _1-20 alkyl group, a C _2-20 alkenyl group or a C _2-19 heterocyclyl group (the C _1-20 alkyl group, a C _2-20 alkenyl group and a C _2-19 heterocyclyl group). The group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently.
Means. )
Or formula (VIII)

(In the formula, m represents 0, 1 or 2, and R ⁴ represents a C _1-20 alkyl group, a C _2-20 alkenyl group or a C _2-19 heterocyclyl group (the C _1-20 alkyl group, C _{2 The -20} alkenyl group and the C _2-19 heterocyclyl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently.
Means. )
And
X is a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or two substituents selected from substituent group V ¹ alone or differently) .)
And
Y is a single bond or formula (IX)

Wherein R ⁶ represents a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted with a halogen atom), and U is an oxygen atom Or it means a sulfur atom.)
And
Z is a C _1-6 alkyl group, a C _1-6 alkoxy group (the C _1-6 alkyl group and the C _1-6 alkoxy group are unsubstituted or selected alone or differently from the substituent group V ²⁾ Or a C _2-14 aryl group or a C _2-9 heterocyclyl group (the C _2-14 aryl group and the C _2-9 heterocyclyl group are unsubstituted). substituted with or one substituent selected from substituent group V ^2.)
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound represented by formula (I) or a solvate thereof.

2) The compound according to 1) above, wherein R ¹ is a hydrogen atom or an ethoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

（式中、Ｒ^aはシアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味し、
Ｒ^ｂは水素原子、シアノ基、Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基又はＣ_２−９ヘテロシクリル基（該Ｃ_１−６アルキル基、Ｃ_２−６アルケニル基、Ｃ_２−１４アリール基、縮合アリール基及びＣ_２−９ヘテロシクリル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味するか、
Ｒ^aとＲ^ｂが一緒になって含窒素ヘテロシクリル基
（該含窒素へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味し、
T’は酸素原子、ＮＲ^ｄ又はＮＯＲ^ｄ
（式中、Ｒ^ｄは水素原子、シアノ基又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は、無置換であるか又はフェニル基で置換されている。）を意味する。）
を意味し、
Ｌは単結合又はＣ_１−６アルキレン基
（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
を意味し、
T‘及びU’はそれぞれ独立して、酸素原子、ＮＲ^ｄ又はＮＯＲ^ｄ
（式中、Ｒ^ｄは水素原子、シアノ基又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は、無置換であるか又は置換基群Ｖ^２より単独若しくは異なって選ばれる1つ以上の置換基で置換されている。）を意味する。）
を意味し、
Ｌは単結合又はＣ_１−６アルキレン基
（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）
を意味する。）
である上記１）又は２）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。 3) R ² is a C _1-6 alkyl group, a C _1-6 alkoxy group (the C _1-6 alkyl group and the C _1-6 alkoxy group are one or more selected from substituent group V ³ independently or differently) Substituted with a substituent and optionally substituted with a halogen atom).
A tetrazolyl group, a C _2-9 heterocyclyl group (the tetrazolyl group and the C _2-9 heterocyclyl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ² alone or differently; Yes.)
Or formula (V)

(In the formula, R ^a is a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, The C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are one or more substituents that are unsubstituted or selected alone or differently from the substituent group V ² Is replaced by
R ^b is a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group, or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, C _{The 2-6} alkenyl group, C _2-14 aryl group, condensed aryl group and C _2-9 heterocyclyl group are one or more substituents which are unsubstituted or selected alone or differently from the substituent group V ² Is replaced)
R ^a and R ^{b taken} together are a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently. ing.)
Means
T ′ is an oxygen atom, NR ^d or NOR ^d
(Wherein R ^d represents a hydrogen atom, a cyano group, or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with a phenyl group).)
Means
L is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). .)
Means. )
Means
T ′ and U ′ each independently represent an oxygen atom, NR ^d or NOR ^d
(In the formula, R ^d is a hydrogen atom, a cyano group or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or one or more selected from the substituent group V ² alone or differently). Substituted with a substituent of
Means
L is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). .)
Means. )
The compound according to 1) or 2), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

（式中、Ｒ^３は水素原子を意味し、Ｒ^４はＣ_３−１2シクロアルキル基、Ｃ_３−１2シクロアルケニル基又はＣ_２−１９へテロシクリル基
（該Ｃ_３−12シクロアルキル基、Ｃ_３−１2シクロアルケニル基及びＣ_２−１９へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独もしくは異なって選ばれる１乃至３つの置換基によって置換されている。）
を意味する。）
又は、式（ＶＩＩＩ）

（式中、ｍは０，１又は２を意味し、Ｒ^４はＣ_３−１2シクロアルキル基、Ｃ_３−１2シクロアルケニル基又はＣ_２−１９へテロシクリル基
（該Ｃ_３−12シクロアルキル基、Ｃ_３−１2シクロアルケニル基及びＣ_２−１９へテロシクリル基は、無置換であるか又は置換基群Ｖ^１より単独もしくは異なって選ばれる１乃至３つの置換基によって置換されている。）
を意味する。）
である上記１）乃至３）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。 4) Q is the formula (VII)

(Wherein R ³ represents a hydrogen atom, R ⁴ represents a C _3-12 cycloalkyl group, a C _3-12 cycloalkenyl group or a C _2-19 heterocyclyl group (the C _3-12 cycloalkyl group, C _{The 3-12} cycloalkenyl group and the C _2-19 heterocyclyl group are unsubstituted or substituted by 1 to 3 substituents selected from the substituent group V ¹ alone or differently.
Means. )
Or formula (VIII)

(In the formula, m represents 0, 1 or 2, and R ⁴ represents a C _3-12 cycloalkyl group, a C _3-12 cycloalkenyl group or a C _2-19 heterocyclyl group (the C _3-12 cycloalkyl group). , C _3-12 cycloalkenyl group and C _2-19 heterocyclyl group are unsubstituted or substituted by 1 to 3 substituents selected from substituent group V ¹ alone or differently.
Means. )
The compound according to the above 1) to 3), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

5) The compound according to the above 1) to 4), wherein X is a C _1-3 alkylene group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

（式中、Ｒ^６は、水素原子を意味し、Ｕは酸素原子を意味する。）
である上記１）乃至５）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。 6) Substituent Y is represented by formula (IX)

(In the formula, R ⁶ represents a hydrogen atom, and U represents an oxygen atom.)
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

7) Substituent Z is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _2-9 heteroaryl group (the C _2-9 heteroaryl group is unsubstituted or independently from substituent group V ¹⁾ Or substituted with one or two substituents selected differently.)
Has been replaced by )
The compound according to 1) to 6) above, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

8) The compound according to 1) to 7), wherein R ¹ is a hydrogen atom, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

（式中、Ｒ^aはＣ_１−３アルキル基を意味し、Ｒ^ｂは水素原子又はＣ_１−３アルキル基を意味し、
Ｔ’は酸素原子、ＮＲ^ｄ又はＮＯＲ^ｄ
（式中、Ｒ^ｄは水素原子、シアノ基又はＣ_１−３アルキル基（該Ｃ_１−３アルキル基は、無置換であるか又はフェニル基で置換されている。）を意味する。）
を意味する。）
であるである上記１）乃至８）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。 9) R ² is a C _1-3 alkyl group (the C _1-3 alkyl group is substituted with a carboxyl group or a hydroxyl group)
Or formula (VI)

(Wherein R ^a represents a C _1-3 alkyl group, R ^b represents a hydrogen atom or a C _1-3 alkyl group,
T ′ is an oxygen atom, NR ^d or NOR ^d
(Wherein R ^d represents a hydrogen atom, a cyano group, or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with a phenyl group).)
Means. )
The compound according to the above 1) to 8), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

（式中Ｒ^３は水素原子を意味し、Ｒ^４はＣ_７−１2シクロアルキル基又はＣ_７−１2シクロアルケニル基
（該Ｃ_７−１2シクロアルキル基及びＣ_７−１2シクロアルケニル基は、無置換であるか又はカルボキシル基、カルバモイル基、スルファモイル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルキルスルホニル基、ハロゲン置換Ｃ_１−３アルキル基及びハロゲン置換Ｃ_１−３アルコキシ基より単独若しくは異なって選ばれる１つ又は２つの置換基で置換されている。）
を意味する。）
又は、式（ＶＩＩＩ）

（式中ｍは０，１又は２を意味し、Ｒ^４はＣ_７−１2シクロアルキル基又はＣ_７−１2シクロアルケニル基
（該Ｃ_７−１2シクロアルキル基及びＣ_７−１2シクロアルケニル基は、無置換であるか又はカルボキシル基、カルバモイル基、スルファモイル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルチオ基、Ｃ_１−６アルキルスルホニル基、ハロゲン置換Ｃ_１−３アルキル基及びハロゲン置換Ｃ_１−３アルコキシ基より単独若しくは異なって選ばれる１つ又は２つの置換基で置換されている。）
を意味する。）
である上記１）乃至９）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。 10) Q is the formula (VII)

(Wherein R ³ represents a hydrogen atom, R ⁴ represents a C _7-12 cycloalkyl group or a C _7-12 cycloalkenyl group (the C _7-12 cycloalkyl group and the C _7-12 cycloalkenyl group are Substituted or carboxyl group, carbamoyl group, sulfamoyl group, nitro group, cyano group, halogen atom, hydroxyl group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 1 selected from an alkoxy group, a C _2-9 heterocyclyl group, a C _1-6 alkylthio group, a C _1-6 alkylsulfonyl group, a halogen-substituted C _1-3 alkyl group and a halogen-substituted C _1-3 alkoxy group. Substituted with one or two substituents.)
Means. )
Or formula (VIII)

(In the formula, m means 0, 1 or 2, and R ⁴ represents a C _7-12 cycloalkyl group or a C _7-12 cycloalkenyl group (the C _7-12 cycloalkyl group and the C _7-12 cycloalkenyl group are , Unsubstituted or carboxyl group, carbamoyl group, sulfamoyl group, nitro group, cyano group, halogen atom, hydroxyl group, amino group, mono C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _{1 -6} alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylthio group, C _1-6 alkylsulfonyl group, halogen-substituted C _1-3 alkyl group and halogen-substituted C _1-3 alkoxy group are selected alone or differently Substituted with one or two substituents.
Means. )
The compound according to the above 1) to 9), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

11) The compound according to 1) to 10) above, wherein X is a methylene group, 1,2-ethylene group or 1,1-ethylene group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound Obtained salts or solvates thereof.

12) Substituent Z is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _2-9 heteroaryl group or a C _2-9 heterocyclyl group (the C _2-9 heteroaryl group and C _2-9 heterocyclyl). Group is unsubstituted or carboxyl, carbamoyl, sulfamoyl, nitro,
A cyano group, a halogen atom, a hydroxyl group, an amino group, a C _1-6 alkyl group,
A mono C _1-6 alkylamino group, a di C _1-6 alkylamino group,
A C _1-6 alkoxy group, a C _2-9 heterocyclyl group, a C _1-6 alkylthio group,
1 selected independently or differently from a C _1-6 alkylsulfonyl group, a halogen-substituted C _1-3 alkyl group and a halogen-substituted C _1-3 alkoxy group
Substituted with one or two substituents. )
Has been replaced by )
The compound according to 1) to 11) above, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

（式中Ｒ^３は水素原子を意味し、Ｒ^４はＣ_８−１2シクロアルキル基
（該Ｃ_８−１2シクロアルキル基は、無置換であるか又はカルボキシル基、カルバモイル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルスルホニル基、ハロゲン置換Ｃ_１−３アルキル基及びハロゲン置換Ｃ_１−３アルコキシ基より単独若しくは異なって選ばれる１つ又は２つの置換基で置換されている。）
を意味する。）
である上記１）乃至１２）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。 13) Substituent Q is represented by formula (VII)

(Wherein R ³ represents a hydrogen atom, R ⁴ represents a C _8-12 cycloalkyl group (the C _8-12 cycloalkyl group is unsubstituted or is a carboxyl group, a carbamoyl group, a nitro group, a cyano group) , Halogen atom, hydroxyl group, amino group, mono C _1-6 alkylamino group, diC _1-6 alkylamino group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylsulfonyl group, halogen It is substituted with one or two substituents selected from a substituted C _1-3 alkyl group and a halogen-substituted C _1-3 alkoxy group alone or differently.
Means. )
The compound according to 1) to 12) above, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

（式中、各構造は無置換であるか又はカルボキシル基、カルバモイル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルスルホニル基、ハロゲン置換Ｃ_１−３アルキル基及びハロゲン置換Ｃ_１−３アルコキシ基より単独若しくは異なって選ばれる１つ又は２つの置換基で置換されている。）
で示される置換基群から選ばれる1つの置換基で置換されている。）
又は、Ｃ_１−３アルキル基
（該Ｃ_１−３アルキル基は置換基群（ＸＩＩＩ）

（式中、各構造は無置換であるか又はカルボキシル基、カルバモイル基、ニトロ基、シアノ基、ハロゲン原子、水酸基、アミノ基、モノＣ_１−６アルキルアミノ基、ジＣ_１−６アルキルアミノ基、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_２−９ヘテロシクリル基、Ｃ_１−６アルキルスルホニル基、ハロゲン置換Ｃ_１−３アルキル基及びハロゲン置換Ｃ_１−３アルコキシ基より単独若しくは異なって選ばれる１つ又は２つの置換基で置換されている。）
で示される置換基群から選ばれる1つの置換基で置換されている。）
である上記１）乃至１３）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。 14) The substituent Z is a C _1-3 alkyl group (the C _1-3 alkyl group is a substituent group (XII)).

(In the formula, each structure is unsubstituted or carboxyl group, carbamoyl group, nitro group, cyano group, halogen atom, hydroxyl group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group A C _1-6 alkyl group, a C _1-6 alkoxy group, a C _2-9 heterocyclyl group, a C _1-6 alkylsulfonyl group, a halogen-substituted C _1-3 alkyl group and a halogen-substituted C _1-3 alkoxy group or Substituted with one or two substituents selected differently.)
Is substituted with one substituent selected from the group of substituents represented by )
Or a C _1-3 alkyl group (the C _1-3 alkyl group is a substituent group (XIII))

(In the formula, each structure is unsubstituted or carboxyl group, carbamoyl group, nitro group, cyano group, halogen atom, hydroxyl group, amino group, mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group A C _1-6 alkyl group, a C _1-6 alkoxy group, a C _2-9 heterocyclyl group, a C _1-6 alkylsulfonyl group, a halogen-substituted C _1-3 alkyl group and a halogen-substituted C _1-3 alkoxy group or Substituted with one or two substituents selected differently.)
Is substituted with one substituent selected from the group of substituents represented by )
The compound according to 1) to 13) above, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

（式中Ｒ^３が水素原子を意味し、Ｒ^４が以下に示す構造である。）

又は、式（ＶＩＩ）

（式中、Ｒ^３は水素原子を意味し、Ｒ^４は以下に示す構造である。）

である上記１）乃至１４）に記載の化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。 15) Q is the formula (VII)

(In the formula, R ³ represents a hydrogen atom, and R ⁴ has a structure shown below.)

Or formula (VII)

(In the formula, R ³ represents a hydrogen atom, and R ⁴ has the structure shown below.)

The compound according to 1) to 14) above, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

16) Z is (3-methylpyridyl) methyl, pyridylmethyl, (3-methylpyridyl) ethyl, pyridylethyl, (2-fluoropyridyl) ethyl, (3-chloropyridyl) ethyl, (3 -Dimethylaminopyridyl) methyl group, pyridazinylethyl group, pyridazinylpropyl group, pyrimidinylethyl group, (4-methylpyridazinyl) methyl group, (3-dimethylaminopyridazinyl) methyl group , (3-methylpyridazinyl) ethyl group, (3-chloropyridazinyl) ethyl group, (3-methoxypyridazinyl) ethyl group, (3-methanesulfonylpyridyl) ethyl group or pyrimidinylpropyl group The compounds according to 1) to 15) above, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof

第１表
−−−−− −−−−− −−−−− −−−−− −−−−――
Ｑ Ｚ Ｑ Ｚ Ｑ Ｚ Ｑ Ｚ Ｑ Ｚ
−−−−− −−−−− −−−−− −−−−− −−−−――
Ｑ１ Ｚ１ Ｑ２ Ｚ１ Ｑ３ Ｚ１ Ｑ４ Ｚ１ Ｑ５ Ｚ１
Ｑ６ Ｚ１ Ｑ７ Ｚ１ Ｑ８ Ｚ１ Ｑ９ Ｚ１ Ｑ１０ Ｚ１
Ｑ１ Ｚ２ Ｑ２ Ｚ２ Ｑ３ Ｚ２ Ｑ４ Ｚ２ Ｑ５ Ｚ２
Ｑ６ Ｚ２ Ｑ７ Ｚ２ Ｑ８ Ｚ２ Ｑ９ Ｚ２ Ｑ１０ Ｚ２
Ｑ１ Ｚ３ Ｑ２ Ｚ３ Ｑ３ Ｚ３ Ｑ４ Ｚ３ Ｑ５ Ｚ３
Ｑ６ Ｚ３ Ｑ７ Ｚ３ Ｑ８ Ｚ３ Ｑ９ Ｚ３ Ｑ１０ Ｚ３
Ｑ１ Ｚ４ Ｑ２ Ｚ４ Ｑ３ Ｚ４ Ｑ４ Ｚ４ Ｑ５ Ｚ４
Ｑ６ Ｚ４ Ｑ７ Ｚ４ Ｑ８ Ｚ４ Ｑ９ Ｚ４ Ｑ１０ Ｚ４
Ｑ１ Ｚ５ Ｑ２ Ｚ５ Ｑ３ Ｚ５ Ｑ４ Ｚ５ Ｑ５ Ｚ５
Ｑ６ Ｚ５ Ｑ７ Ｚ５ Ｑ８ Ｚ５ Ｑ９ Ｚ５ Ｑ１０ Ｚ５
Ｑ１ Ｚ６ Ｑ２ Ｚ６ Ｑ３ Ｚ６ Ｑ４ Ｚ６ Ｑ５ Ｚ６
Ｑ６ Ｚ６ Ｑ７ Ｚ６ Ｑ８ Ｚ６ Ｑ９ Ｚ６ Ｑ１０ Ｚ６
Ｑ１ Ｚ７ Ｑ２ Ｚ７ Ｑ３ Ｚ７ Ｑ４ Ｚ７ Ｑ５ Ｚ７
Ｑ６ Ｚ７ Ｑ７ Ｚ７ Ｑ８ Ｚ７ Ｑ９ Ｚ７ Ｑ１０ Ｚ７
Ｑ１ Ｚ８ Ｑ２ Ｚ８ Ｑ３ Ｚ８ Ｑ４ Ｚ８ Ｑ５ Ｚ８
Ｑ６ Ｚ８ Ｑ７ Ｚ８ Ｑ８ Ｚ８ Ｑ９ Ｚ８ Ｑ１０ Ｚ８
Ｑ１ Ｚ９ Ｑ２ Ｚ９ Ｑ３ Ｚ９ Ｑ４ Ｚ９ Ｑ５ Ｚ９
Ｑ６ Ｚ９ Ｑ７ Ｚ９ Ｑ８ Ｚ９ Ｑ９ Ｚ９ Ｑ１０ Ｚ９
Ｑ１ Ｚ１０ Ｑ２ Ｚ１０ Ｑ３ Ｚ１０ Ｑ４ Ｚ１０ Ｑ５ Ｚ１０
Ｑ６ Ｚ１０ Ｑ７ Ｚ１０ Ｑ８ Ｚ１０ Ｑ９ Ｚ１０ Ｑ１０ Ｚ１０
Ｑ１ Ｚ１１ Ｑ２ Ｚ１１ Ｑ３ Ｚ１１ Ｑ４ Ｚ１１ Ｑ５ Ｚ１１
Ｑ６ Ｚ１１ Ｑ７ Ｚ１１ Ｑ８ Ｚ１１ Ｑ９ Ｚ１１ Ｑ１０ Ｚ１１
Ｑ１ Ｚ１２ Ｑ２ Ｚ１２ Ｑ３ Ｚ１２ Ｑ４ Ｚ１２ Ｑ５ Ｚ１２
Ｑ６ Ｚ１２ Ｑ７ Ｚ１２ Ｑ８ Ｚ１２ Ｑ９ Ｚ１２ Ｑ１０ Ｚ１２
Ｑ１ Ｚ１３ Ｑ２ Ｚ１３ Ｑ３ Ｚ１３ Ｑ４ Ｚ１３ Ｑ５ Ｚ１３
Ｑ６ Ｚ１３ Ｑ７ Ｚ１３ Ｑ８ Ｚ１３ Ｑ９ Ｚ１３ Ｑ１０ Ｚ１３
Ｑ１ Ｚ１４ Ｑ２ Ｚ１４ Ｑ３ Ｚ１４ Ｑ４ Ｚ１４ Ｑ５ Ｚ１４
Ｑ６ Ｚ１４ Ｑ７ Ｚ１４ Ｑ８ Ｚ１４ Ｑ９ Ｚ１４ Ｑ１０ Ｚ１４
Ｑ１ Ｚ１５ Ｑ２ Ｚ１５ Ｑ３ Ｚ１５ Ｑ４ Ｚ１５ Ｑ５ Ｚ１５
Ｑ６ Ｚ１５ Ｑ７ Ｚ１５ Ｑ８ Ｚ１５ Ｑ９ Ｚ１５ Ｑ１０ Ｚ１５
Ｑ１ Ｚ１６ Ｑ２ Ｚ１６ Ｑ３ Ｚ１６ Ｑ４ Ｚ１６ Ｑ５ Ｚ１６
Ｑ６ Ｚ１６ Ｑ７ Ｚ１６ Ｑ８ Ｚ１６ Ｑ９ Ｚ１６ Ｑ１０ Ｚ１６
Ｑ１ Ｚ１７ Ｑ２ Ｚ１７ Ｑ３ Ｚ１７ Ｑ４ Ｚ１７ Ｑ５ Ｚ１７
Ｑ６ Ｚ１７ Ｑ７ Ｚ１７ Ｑ８ Ｚ１７ Ｑ９ Ｚ１７ Ｑ１０ Ｚ１７
Ｑ１ Ｚ１８ Ｑ２ Ｚ１８ Ｑ３ Ｚ１８ Ｑ４ Ｚ１８ Ｑ５ Ｚ１８
Ｑ６ Ｚ１８ Ｑ７ Ｚ１８ Ｑ８ Ｚ１８ Ｑ９ Ｚ１８ Ｑ１０ Ｚ１８
Ｑ１ Ｚ１９ Ｑ２ Ｚ１９ Ｑ３ Ｚ１９ Ｑ４ Ｚ１９ Ｑ５ Ｚ１９
Ｑ６ Ｚ１９ Ｑ７ Ｚ１９ Ｑ８ Ｚ１９ Ｑ９ Ｚ１９ Ｑ１０ Ｚ１９
Ｑ１ Ｚ２０ Ｑ２ Ｚ２０ Ｑ３ Ｚ２０ Ｑ４ Ｚ２０ Ｑ５ Ｚ２０
Ｑ６ Ｚ２０ Ｑ７ Ｚ２０ Ｑ８ Ｚ２０ Ｑ９ Ｚ２０ Ｑ１０ Ｚ２０
Ｑ１ Ｚ２１ Ｑ２ Ｚ２１ Ｑ３ Ｚ２１ Ｑ４ Ｚ２１ Ｑ５ Ｚ２１
Ｑ６ Ｚ２１ Ｑ７ Ｚ２１ Ｑ８ Ｚ２１ Ｑ９ Ｚ２１ Ｑ１０ Ｚ２１
Ｑ１ Ｚ２２ Ｑ２ Ｚ２２ Ｑ３ Ｚ２２ Ｑ４ Ｚ２２ Ｑ５ Ｚ２２
Ｑ６ Ｚ２２ Ｑ７ Ｚ２２ Ｑ８ Ｚ２２ Ｑ９ Ｚ２２ Ｑ１０ Ｚ２２
Ｑ１ Ｚ２３ Ｑ２ Ｚ２３ Ｑ３ Ｚ２３ Ｑ４ Ｚ２３ Ｑ５ Ｚ２３
Ｑ６ Ｚ２３ Ｑ７ Ｚ２３ Ｑ８ Ｚ２３ Ｑ９ Ｚ２３ Ｑ１０ Ｚ２３
Ｑ１ Ｚ２４ Ｑ２ Ｚ２４ Ｑ３ Ｚ２４ Ｑ４ Ｚ２４ Ｑ５ Ｚ２４
Ｑ６ Ｚ２４ Ｑ７ Ｚ２４ Ｑ８ Ｚ２４ Ｑ９ Ｚ２４ Ｑ１０ Ｚ２４
Ｑ１ Ｚ２５ Ｑ２ Ｚ２５ Ｑ３ Ｚ２５ Ｑ４ Ｚ２５ Ｑ５ Ｚ２５
Ｑ６ Ｚ２５ Ｑ７ Ｚ２５ Ｑ８ Ｚ２５ Ｑ９ Ｚ２５ Ｑ１０ Ｚ２５
Ｑ１ Ｚ２６ Ｑ２ Ｚ２６ Ｑ３ Ｚ２６ Ｑ４ Ｚ２６ Ｑ５ Ｚ２６
Ｑ６ Ｚ２６ Ｑ７ Ｚ２６ Ｑ８ Ｚ２６ Ｑ９ Ｚ２６ Ｑ１０ Ｚ２６
Ｑ１ Ｚ２７ Ｑ２ Ｚ２７ Ｑ３ Ｚ２７ Ｑ４ Ｚ２７ Ｑ５ Ｚ２７
Ｑ６ Ｚ２７ Ｑ７ Ｚ２７ Ｑ８ Ｚ２７ Ｑ９ Ｚ２７ Ｑ１０ Ｚ２７
Ｑ１ Ｚ２８ Ｑ２ Ｚ２８ Ｑ３ Ｚ２８ Ｑ４ Ｚ２８ Ｑ５ Ｚ２８
Ｑ６ Ｚ２８ Ｑ７ Ｚ２８ Ｑ８ Ｚ２８ Ｑ９ Ｚ２８ Ｑ１０ Ｚ２８
Ｑ１ Ｚ２９ Ｑ２ Ｚ２９ Ｑ３ Ｚ２９ Ｑ４ Ｚ２９ Ｑ５ Ｚ２９
Ｑ６ Ｚ２９ Ｑ７ Ｚ２９ Ｑ８ Ｚ２９ Ｑ９ Ｚ２９ Ｑ１０ Ｚ２９
Ｑ１ Ｚ３０ Ｑ２ Ｚ３０ Ｑ３ Ｚ３０ Ｑ４ Ｚ３０ Ｑ５ Ｚ３０
Ｑ６ Ｚ３０ Ｑ７ Ｚ３０ Ｑ８ Ｚ３０ Ｑ９ Ｚ３０ Ｑ１０ Ｚ３０
−−−−―― −−−――― −−−――― −−−−−− ――−−−−− 17) R ¹ is a hydrogen atom, R ² is a formyl group, X is a methylene group, Y is —CONH—, and Q and Z are combinations of the combinations described in Table 1 below. , Tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
In addition, the symbol in Table 1 shows the following substituents.

Table 1 ----- ----- ------ ----- -----
Q Z Q Z Q Z Q Q Z Q Z
---------- ------ ------ -----
Q1 Z1 Q2 Z1 Q3 Z1 Q4 Z1 Q5 Z1
Q6 Z1 Q7 Z1 Q8 Z1 Q9 Z1 Q10 Z1
Q1 Z2 Q2 Z2 Q3 Z2 Q4 Z2 Q5 Z2
Q6 Z2 Q7 Z2 Q8 Z2 Q9 Z2 Q10 Z2
Q1 Z3 Q2 Z3 Q3 Z3 Q4 Z3 Q5 Z3
Q6 Z3 Q7 Z3 Q8 Z3 Q9 Z3 Q10 Z3
Q1 Z4 Q2 Z4 Q3 Z4 Q4 Z4 Q5 Z4
Q6 Z4 Q7 Z4 Q8 Z4 Q9 Z4 Q10 Z4
Q1 Z5 Q2 Z5 Q3 Z5 Q4 Z5 Q5 Z5
Q6 Z5 Q7 Z5 Q8 Z5 Q9 Z5 Q10 Z5
Q1 Z6 Q2 Z6 Q3 Z6 Q4 Z6 Q5 Z6
Q6 Z6 Q7 Z6 Q8 Z6 Q9 Z6 Q10 Z6
Q1 Z7 Q2 Z7 Q3 Z7 Q4 Z7 Q5 Z7
Q6 Z7 Q7 Z7 Q8 Z7 Q9 Z7 Q10 Z7
Q1 Z8 Q2 Z8 Q3 Z8 Q4 Z8 Q5 Z8
Q6 Z8 Q7 Z8 Q8 Z8 Q9 Z8 Q10 Z8
Q1 Z9 Q2 Z9 Q3 Z9 Q4 Z9 Q5 Z9
Q6 Z9 Q7 Z9 Q8 Z9 Q9 Z9 Q10 Z9
Q1 Z10 Q2 Z10 Q3 Z10 Q4 Z10 Q5 Z10
Q6 Z10 Q7 Z10 Q8 Z10 Q9 Z10 Q10 Z10
Q1 Z11 Q2 Z11 Q3 Z11 Q4 Z11 Q5 Z11
Q6 Z11 Q7 Z11 Q8 Z11 Q9 Z11 Q10 Z11
Q1 Z12 Q2 Z12 Q3 Z12 Q4 Z12 Q5 Z12
Q6 Z12 Q7 Z12 Q8 Z12 Q9 Z12 Q10 Z12
Q1 Z13 Q2 Z13 Q3 Z13 Q4 Z13 Q5 Z13
Q6 Z13 Q7 Z13 Q8 Z13 Q9 Z13 Q10 Z13
Q1 Z14 Q2 Z14 Q3 Z14 Q4 Z14 Q5 Z14
Q6 Z14 Q7 Z14 Q8 Z14 Q9 Z14 Q10 Z14
Q1 Z15 Q2 Z15 Q3 Z15 Q4 Z15 Q5 Z15
Q6 Z15 Q7 Z15 Q8 Z15 Q9 Z15 Q10 Z15
Q1 Z16 Q2 Z16 Q3 Z16 Q4 Z16 Q5 Z16
Q6 Z16 Q7 Z16 Q8 Z16 Q9 Z16 Q10 Z16
Q1 Z17 Q2 Z17 Q3 Z17 Q4 Z17 Q5 Z17
Q6 Z17 Q7 Z17 Q8 Z17 Q9 Z17 Q10 Z17
Q1 Z18 Q2 Z18 Q3 Z18 Q4 Z18 Q5 Z18
Q6 Z18 Q7 Z18 Q8 Z18 Q9 Z18 Q10 Z18
Q1 Z19 Q2 Z19 Q3 Z19 Q4 Z19 Q5 Z19
Q6 Z19 Q7 Z19 Q8 Z19 Q9 Z19 Q10 Z19
Q1 Z20 Q2 Z20 Q3 Z20 Q4 Z20 Q5 Z20
Q6 Z20 Q7 Z20 Q8 Z20 Q9 Z20 Q10 Z20
Q1 Z21 Q2 Z21 Q3 Z21 Q4 Z21 Q5 Z21
Q6 Z21 Q7 Z21 Q8 Z21 Q9 Z21 Q10 Z21
Q1 Z22 Q2 Z22 Q3 Z22 Q4 Z22 Q5 Z22
Q6 Z22 Q7 Z22 Q8 Z22 Q9 Z22 Q10 Z22
Q1 Z23 Q2 Z23 Q3 Z23 Q4 Z23 Q5 Z23
Q6 Z23 Q7 Z23 Q8 Z23 Q9 Z23 Q10 Z23
Q1 Z24 Q2 Z24 Q3 Z24 Q4 Z24 Q5 Z24
Q6 Z24 Q7 Z24 Q8 Z24 Q9 Z24 Q10 Z24
Q1 Z25 Q2 Z25 Q3 Z25 Q4 Z25 Q5 Z25
Q6 Z25 Q7 Z25 Q8 Z25 Q9 Z25 Q10 Z25
Q1 Z26 Q2 Z26 Q3 Z26 Q4 Z26 Q5 Z26
Q6 Z26 Q7 Z26 Q8 Z26 Q9 Z26 Q10 Z26
Q1 Z27 Q2 Z27 Q3 Z27 Q4 Z27 Q5 Z27
Q6 Z27 Q7 Z27 Q8 Z27 Q9 Z27 Q10 Z27
Q1 Z28 Q2 Z28 Q3 Z28 Q4 Z28 Q5 Z28
Q6 Z28 Q7 Z28 Q8 Z28 Q9 Z28 Q10 Z28
Q1 Z29 Q2 Z29 Q3 Z29 Q4 Z29 Q5 Z29
Q6 Z29 Q7 Z29 Q8 Z29 Q9 Z29 Q10 Z29
Q1 Z30 Q2 Z30 Q3 Z30 Q4 Z30 Q5 Z30
Q6 Z30 Q7 Z30 Q8 Z30 Q9 Z30 Q10 Z30
---------------------- -------

１９）Ｒ^１が水素原子であり、Ｒ^２がホルミル基であり、Ｘがメチレン基であり、Ｙが−ＣＯＮＨ−であり、Ｑ、Ｚが以下に示す上記第１表（但し、１９）の場合、表中のＱ１〜Ｑ１０及びＺ１〜Ｚ３０は下記の置換基を表す。）に記載の組み合わせからなる化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。

２０）Ｒ^１が水素原子であり、Ｒ^２がホルミル基であり、Ｘがメチレン基であり、Ｙが−ＣＯＮＨ−であり、Ｑ、Ｚが以下に示す上記第１表（但し、２０）の場合、表中のＱ１〜Ｑ１０及びＺ１〜Ｚ３０は下記の置換基を表す。）に記載の組み合わせからなる化合物、該化合物の互変異性体、プロドラッグ若しくはその医薬的に許容され得る塩又はそれらの溶媒和物。

18) R ¹ is a hydrogen atom, R ² is a formyl group, X is a methylene group, Y is -CONH-, and Q and Z are those shown in Table 1 (note 18) shown below. In the case, Q1 to Q10 and Z1 to Z30 in the table represent the following substituents. ), A tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

19) R ¹ is a hydrogen atom, R ² is a formyl group, X is a methylene group, Y is -CONH-, and Q and Z are those shown in Table 1 (note 19) shown below. In the case, Q1 to Q10 and Z1 to Z30 in the table represent the following substituents. ), A tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

20) R ¹ is a hydrogen atom, R ² is a formyl group, X is a methylene group, Y is -CONH-, and Q and Z are those shown in Table 1 (note 20) shown below. In the case, Q1 to Q10 and Z1 to Z30 in the table represent the following substituents. ), A tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

21) A compound comprising the combination according to 17) to 20), wherein R ¹ is an ethoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
22) A compound comprising the combination described in 17) to 20) above, wherein R ¹ is a trifluoromethyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. object.

23) A compound comprising the combination according to 17) to 20), wherein R ¹ is a trifluoromethoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. object.

24) A compound comprising the combination described in 17) to 23) above, wherein R ² is an acetyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

25) A compound comprising the combination according to 17) to 23), wherein R ² is a hydroxymethyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. .

26) A compound comprising the combination described in 17) to 23) above, wherein R ² is a 1-hydroxyethyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound, or a solvent thereof Japanese products.

27) A compound comprising the combination described in 17) to 23) above, wherein R ² is a (hydroxyimino) methyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a compound thereof Solvate.

28) A compound comprising a combination according to the above 17) to 23), wherein R ² is a (methoxyimino) methyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a compound thereof Solvate.

29) A compound comprising the combination described in 17) to 23) above, wherein R ² is a (cyanoimino) methyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvent thereof Japanese products.

30) A compound comprising a combination according to the above 17) to 23), wherein R2 is an N-methoxyethaneimidoyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a compound thereof Solvate.

31) A compound comprising a combination according to the above 17) to 23), wherein R2 is an N-hydroxyethaneimidoyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a salt thereof Solvate.

32) A compound comprising a combination according to the above 17) to 23), wherein R2 is an N-cyanoethaneimidoyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a compound thereof Solvate.

33) A compound comprising the combination of the above 17) to 23), wherein R ² is a dimethylcarbamoyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .

34) A compound comprising the combination described in 17) to 23) above, wherein R ² is a methylcarbamoyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. .

35) The compound comprising the combination according to 17) to 23), wherein R ² is a methoxycarbonyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .

36) A compound comprising the combination according to 17) to 23), wherein R ² is a 2- (methoxycarbonyl) ethyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound, Their solvates.

37) A compound comprising the combination according to the above 17) to 23), wherein R ² is a methylimino group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

38) A compound comprising the combination described in 17) to 23) above, wherein R ² is an isopropylimino group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound, or a solvate thereof. .

39) A compound comprising the combination according to the above 17) to 23), wherein R ² is a benzylimino group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .

40) A compound comprising the combination according to the above 17) to 23), wherein R ² is a tetrazolyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

41) The compound comprising the combination according to 17) to 23), wherein R ² is a 2-oxazolinyl group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof object.

42) A compound comprising the combination according to 17) to 41), wherein X is an ethylene group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

43) A compound comprising the combination according to the above 17) to 41), wherein X is a structure shown below, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .

44) A compound comprising the combination according to 17) to 41), wherein X is a structure shown below, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .

45) A compound comprising the combination according to the above 17) to 41), wherein X is a structure shown below, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .

46) A compound comprising the combination according to 17) to 41), wherein X is a single bond, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

47) A compound comprising the combination according to 17) to 46) above, wherein Y is -CSNH-, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

48) A compound comprising the combination according to the above 17) to 46), wherein Y is —CO—, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
49) A compound comprising the combination according to the above 17) to 46), wherein Y is -CS-, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

50) A compound comprising the combination according to the above 17) to 46), wherein Y is methylene, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

51) A compound comprising the combination according to the above 17) to 46), wherein Y is —NH—, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

52) A compound comprising the combination according to the above 17) to 46), wherein Y is a structure shown below, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .

53) A compound comprising the combination according to the above 17) to 46), wherein Y is a structure shown below, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .

54) A compound comprising the combination according to the above 17) to 46), wherein Y is a structure shown below, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof .

55) A compound comprising the combination according to 17) to 46) above, wherein Y is —NHCO—, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

56) A compound comprising the combination according to the above 17) to 46), wherein Y is —O—, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

57) A compound comprising the combination according to the above 17) to 46), wherein Y is -S-, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

58) A compound comprising the combination according to the above 17) to 46), wherein Y is a single bond, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.

59) A P2X7 receptor inhibitor comprising the compound according to 1) to 58) above, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient.

60) A prophylactic / therapeutic / ameliorating agent for a disease having an effective P2X7 receptor inhibitory action, comprising the P2X7 receptor inhibitor described in 59) as an active ingredient.

61) A therapeutic agent for rheumatoid arthritis comprising the P2X7 receptor inhibitor described in 59) above as an active ingredient.

62) A medicament comprising the compound according to 1) to 61) above, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient.

  In the present invention, the compound represented by the formula (I) of the present invention exists, for example, via the tautomerism and geometric isomerism, both inside and outside the ring, in addition to a mixture thereof, It also exists as a mixture of isomers. Further, when an asymmetric center is present, or when an asymmetric center is formed as a result of isomerization, it includes the presence of each optical isomer and a mixture in an arbitrary ratio. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism also exist. The compounds of the present invention also include those containing all these types in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can.

  The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can exist as an arbitrary crystal form depending on production conditions, and can exist as an arbitrary hydrate. And hydrates and mixtures thereof are also included within the scope of the present invention. Moreover, although it may exist as a solvate containing organic solvents, such as acetone, ethanol, and tetrahydrofuran, all of these forms are contained in the scope of the present invention.

The compound represented by the formula (I) of the present invention can be converted into a pharmaceutically acceptable salt, or can be liberated from the formed salt, if necessary. Examples of the pharmaceutically acceptable salt of the present invention include salts with alkali metals (such as lithium, sodium and potassium), alkaline earth metals (such as magnesium and calcium), ammonium, organic bases and amino acids. In addition, inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) Other salts are also possible.
A prodrug is a derivative of the present invention having a group that can be chemically or metabolically decomposed, and becomes a compound that forms the present invention pharmacologically active by solvolysis or in vivo under physiological conditions It is. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs (Elsevier, Amsterdam 1985). In the case of the present invention, when it has a hydroxyl group, a prodrug such as an acyloxy derivative produced by reacting the compound with an appropriate acyl halide or an appropriate acid anhydride is exemplified. Particularly preferred acyloxy as a prodrug includes -OCOC ₂ H ₅ , -OCO (t-Bu), -OCOC ₁₅ H ₃₁ , -OCO (m-CO ₂ Na-Ph), -OCOCH ₂ CH ₂ CO ₂ Na,- OCOCH (NH ₂ ) CH ₃ , —OCOCH ₂ N (CH ₃ ) _{2 and the} like can be mentioned. In the case where the compound forming the present invention has an amino group, a prodrug such as an amide derivative produced by reacting a compound having an amino group with an appropriate acid halide or an appropriate mixed acid anhydride is exemplified. Is done. Particularly preferred amides as prodrugs include —NHCO (CH ₂ ) ₂₀ OCH ₃ , —NHCOCH (NH ₂ ) CH _{3 and the} like.

  P2X7 receptor inhibitor containing the P2X7 receptor inhibitor of the present invention as an active ingredient is a preventive / treating / ameliorating agent for diseases having an effective P2X7 receptor inhibitory action, such as tablets, capsules, powders, granules, pills, syrups, etc. It can be administered as an oral administration agent, rectal administration agent, transdermal absorption agent or injection. The agent can be administered as a single therapeutic agent or as a mixture with other therapeutic agents. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be produced by a conventional method with addition of pharmacologically and pharmaceutically acceptable additives. That is, additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, plasticizers, and coating agents can be used for oral preparations. Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or provided as dry syrups prepared with water or other suitable solvent prior to use. Good. The liquid preparation may contain conventional additives such as suspending agents, fragrances, diluents or emulsifiers. When administered rectally, it can be administered as a suppository. Suppositories are based on suitable substances such as cacao butter, lauric fat, macrogol, glycerogelatin, witepsol, sodium stearate or mixtures thereof, and emulsifiers, suspending agents, preservatives, etc. as necessary Can be added. Injections include aqueous or injectable distilled water, physiological saline, 5% glucose solution, propylene glycol and other solubilizers or solubilizers, pH adjusters, isotonic agents, Pharmaceutical ingredients such as stabilizers are used.

  When the drug of the present invention is administered to humans, the dosage is determined according to the age and condition of the patient. In general, in the case of adults, 0.1 to 1000 mg / human / day for oral or rectal administration, injection 0.05 mg to 500 mg / person / day. These numerical values are merely examples, and the dosage is determined according to the symptoms of the patient.

  As a scene using this invention, the scene which can expect improvement of a disease state by using the compound which has P2X7 receptor inhibitory activity is mentioned. Specifically, prevention / treatment of swelling / pain increase / bone metabolism in rheumatoid arthritis, prevention / treatment of inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), osteoarthritis, etc., or inflammatory pain and cancer Prevention and treatment of pain, etc., and other diseases related to IL-1β such as Crohn's disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, bronchitis, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis Allergic reaction, allergic contact hypersensitivity, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, bone resorption disease, relaxation of artificial joint implant, Atherosclerosis, aortic aneurysm, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head injury, neurotrauma, spinal cord injury, neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, eccentric Depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, psychotropism or cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular neovascularization, corneal damage, macular degeneration, corneal scar formation, strong Meningitis, abnormal wound healing, burn, autoimmune disorder, Huntington's disease, diabetes, AIDS, cachexia, sepsis, septic shock, endotoxin shock, conjunctivitis shock, gram-negative sepsis, toxic shock syndrome, cerebral malaria, heart And reperfusion injury of the kidney, thrombosis, glomerulonephritis, graft-versus-host reaction, allograft rejection, organ transplant toxicity, ulcerative colitis, or muscle degeneration, etc. However, it is not limited to these.

  The compound of the present invention can be synthesized by the method shown below, but the following production method is an example of a general production method and does not limit the production method.

  The compound of the present invention can usually be purified by column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC), high performance liquid chromatography-mass spectrometry (LC / MS), etc. For example, a high purity product can be obtained by recrystallization or washing with a solvent.

Examples of the base in the description of the general production method of the compound of the present invention include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, lithium hydride. Alkali metal salts such as sodium amide, t-butoxy potassium, t-butoxy sodium, n-butyl lithium, lithium diisopropylamide, amines such as pyridine, triethylamine, diisopropylethylamine, pyrrolidine, N-methylpiperidine, hexamethyldisilazane And silane reagents, sodium acetate, and potassium acetate.
The solvent in the description of the general production method of the compound of the present invention is not particularly limited as long as it is stable under the reaction conditions and is inert and does not interfere with the reaction. For example, dimethyl sulfoxide is representative. Sulfoxide solvents, amide solvents typified by dimethylformamide or dimethylacetamide, ether solvents typified by ethyl ether, dimethoxyethane or tetrahydrofuran, dioxane, cyclopentylmethyl ether, halogens typified by dichloromethane, chloroform, dichloroethane Solvent, acetonitrile, nitrile solvent represented by propionitrile, aromatic hydrocarbon solvent represented by benzene, toluene, hydrocarbon solvent represented by hexane, heptane, Ester solvents such as ethyl, methanol, ethanol, 1-propanol, 2-propanol, alcoholic solvents such as ethylene glycol, water. In addition, the reaction can be carried out under conditions where the above-mentioned solvents are arbitrarily mixed or without solvent.
The reaction temperature in the general production method of the compound of the present invention can be selected from an appropriate temperature in the range of -78 ° C. to the boiling point of the solvent used in the reaction, and this production method is conducted under atmospheric pressure, under pressure, and microwave irradiation. It can be implemented in the lower class.
In the following general production method of the compound of the present invention, general formulas of intermediates and final products in each step are shown, and these intermediates and final products also include their precursors. Here, the precursor means a compound that can be derived into a target product by hydrolysis, deprotection group, reduction, oxidation, alkylation, etc., if necessary. Includes those protected with an acceptable protecting group. Protection and deprotection are commonly known protection and deprotection reactions (eg, Protective Groups in Organic Synthesis, Fourth Edition, by TWGreene). For example, John Wiley & Sons Inc. (2006)).

The following synthesis methods are known as general synthesis methods for pyridazinone compounds.
New edition Heterocyclic compounds Basic edition (Kodansha 2004) 1-14 pages, 69-132 pages, 176-207 pages.
Journal of Heterocyclic Chemistry 33 (6), 1579-1582; 1996 (Journal of Heterocyclic Chemistry, 33 (6), 1579-1582; 1996)
Comprehensive Heterocyclic Chemistry Vol. 3, Part 2B, Pergamon Press. (Comprehensive Heterocyclic Chemistry., Vol.3, Part 2B, Pergamon Press.)
Journal of Heterocyclic Chemistry 42,427-435; 2005 (Journal of Heterocyclic Chemistry, 42, 427-435; 2005)
WO9501343 etc.

（１）−Ｉに対し、（１）−ＩＩ、（１）−ＩＶ又は（１）−Ｖで示されるアミンを、溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基の存在下、必要に応じて加熱することにより、それぞれ（１）−ＩＩＩ、（１）−ＶＩＩＩ、（１）−ＩＸあるいはこれらの前駆体を得ることができる（工程（１）−１及び（１）−２）。
次いで（１）−ＶＩＩＩに対し（１）−ＶＩを、又は（１）−ＩＸに対し（１）−ＶＩＩを、溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基の存在下、必要に応じて加熱することにより、（１）−ＩＩＩあるいはこれらの前駆体を得ることができる。（工程（１）−３）。 In the formula (I), a compound in which Q is represented by the following structure can be produced, for example, by the production method of the following formula (1).

(1) -I with respect to (I) -II, (1) -IV or (1) -V, the catalyst and / or potassium carbonate, triethylamine, etc. (1) -III, (1) -VIII, (1) -IX or a precursor thereof can be obtained by heating in the presence of a base as necessary (step (1) -1). And (1) -2).
Next, (1) -VI with respect to (1) -VIII, or (1) -VII with respect to (1) -IX, while stirring in a solvent, if necessary, such as a catalyst and / or potassium carbonate, triethylamine, etc. (1) -III or a precursor thereof can be obtained by heating as necessary in the presence of a base. (Step (1) -3).

（２）−Ｉと（２）−ＩＩで示される化合物を溶媒中攪拌下で必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基の存在下、必要に応じて加熱することにより、（２）−ＩＩＩあるいはこれらの前駆体を得ることができる（工程（２）−１）。（２）−ＩＩＩを溶媒中攪拌下で塩酸等の酸存在下、必要に応じて加熱することにより、（２）−ＩＶあるいはこれらの前駆体を得ることができる（工程（２）−２）。（２）−ＩＶと（２）−Ｖで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又はＷＳＣ等の縮合剤を用い、必要に応じて加熱することにより、（２）−ＶＩあるいはこれらの前駆体を得ることができる（工程（２）−３）。（２）−ＩＶとＲ^４ＮＣＳ又はＲ^４ＮＣＯで示される化合物を溶媒中攪拌下で、必要に応じて触媒を用い、必要に応じて加熱することにより、（２）−ＶＩＩあるいはこれらの前駆体を得ることができる（工程（２）−４）。（２）−ＩＶで示される化合物を溶媒中攪拌下でチオホスゲン、ホスゲン又はその等価体を用い、必要に応じて加熱することにより、（２）−ＶＩＩＩあるいはこれらの前駆体を得ることができる（工程（２）−５）。続いて、（２）−ＶＩＩＩと（２）−ＩＸで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基の存在下、必要に応じて加熱することにより、（２）−Ｘあるいはこれらの前駆体を得ることができる（工程（２）−６）。
式（２）に示す化合物のうち、Ｔが硫黄原子である化合物は、Ｔが酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することでも得ることができる。 A compound in which Q is represented by the following structure in formula (I) can be synthesized, for example, by the method of formula (2) below.

By heating the compound represented by (2) -I and (2) -II with stirring in a solvent, if necessary, in the presence of a catalyst and / or a base such as potassium carbonate or triethylamine, as necessary ( 2) -III or a precursor thereof can be obtained (step (2) -1). (2) -IV or a precursor thereof can be obtained by heating (2) -III, if necessary, in the presence of an acid such as hydrochloric acid with stirring in a solvent (step (2) -2). . (2) The compound represented by -IV and (2) -V is stirred in a solvent, and if necessary, a catalyst and / or a base such as potassium carbonate or triethylamine and / or a condensing agent such as WSC are used as necessary. By heating accordingly, (2) -VI or a precursor thereof can be obtained (step (2) -3). (2) -VII and a precursor thereof are prepared by heating a compound represented by -IV and R ⁴ NCS or R ⁴ NCO in a solvent with stirring, if necessary, using a catalyst, if necessary. A body can be obtained (step (2) -4). (2) -VIII or a precursor thereof can be obtained by heating the compound represented by -IV using thiophosgene, phosgene or an equivalent thereof while stirring in a solvent, if necessary, and heating ( Step (2) -5). Subsequently, the compounds represented by (2) -VIII and (2) -IX are heated as necessary in the presence of a catalyst and / or a base such as potassium carbonate or triethylamine while stirring in a solvent. As a result, (2) -X or a precursor thereof can be obtained (step (2) -6).
Of the compounds represented by formula (2), a compound in which T is a sulfur atom can also be obtained by heating a compound in which T is an oxygen atom while stirring in a solvent using a Lawson reagent or an equivalent thereof as necessary. be able to.

（３）−Ｉと（３）−ＩＩで示される化合物を溶媒中攪拌下で必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基の存在下、必要に応じて加熱することにより、（３）−ＩＩＩを得ることができる（工程（３）−１）。（３）−ＩＩＩと（３）−ＩＶで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又はＷＳＣ等の縮合剤を用い、必要に応じて加熱することにより、（３）−ＶＩあるいはこれらの前駆体を得ることができる（工程（３）−２）。（３）−ＩＩＩで示される化合物を溶媒中攪拌下でホスゲン、チオホスゲン又はその等価体を用い、必要に応じて加熱し、続いて、（３）−Ｖと反応させることで（３）−ＶＩＩあるいはこれらの前駆体を得ることができる（工程（３）−３）。
式（３）に示す化合物のうち、Ｔが硫黄原子である化合物は、Ｔが酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することでも得ることができる。 A compound in which Q is represented by the following structure in formula (I) can be synthesized, for example, by the method of formula (3) below.

By heating the compound represented by (3) -I and (3) -II with stirring in a solvent, if necessary, in the presence of a catalyst and / or a base such as potassium carbonate or triethylamine, as necessary ( 3) -III can be obtained (step (3) -1). The compounds represented by (3) -III and (3) -IV are stirred in a solvent, and if necessary, a catalyst and / or a base such as potassium carbonate or triethylamine and / or a condensing agent such as WSC are used as necessary. By heating accordingly, (3) -VI or a precursor thereof can be obtained (step (3) -2). The compound represented by (3) -III is heated as necessary using phosgene, thiophosgene or an equivalent thereof while stirring in a solvent, and then reacted with (3) -V to (3) -VII. Alternatively, these precursors can be obtained (step (3) -3).
Of the compounds represented by formula (3), a compound in which T is a sulfur atom can also be obtained by heating a compound in which T is an oxygen atom while stirring in a solvent using a Lawson reagent or an equivalent thereof as necessary. be able to.

（４）−Ｉと（４）−ＩＩで示される化合物を溶媒中攪拌下で必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又は光延反応の条件下、必要に応じて加熱することにより、（４）−ＩＩＩあるいはこれらの前駆体を得ることができる（工程（４）−１）。 Among the compounds represented by the formula (I), a compound in which X is a C _1-6 alkylene group can be produced, for example, by the production method of the following formula (4).

(4) The compound represented by -I and (4) -II is heated as necessary under the conditions of a catalyst and / or a base such as potassium carbonate and triethylamine and / or Mitsunobu reaction as necessary under stirring in a solvent. By doing so, (4) -III or a precursor thereof can be obtained (step (4) -1).

又はＸが単結合又はＣ_１−６アルキレン基であり、Ｙが以下に示す構造

でありＺがヘテロシクリル基である化合物は、例えば以下の式（５）の製造法により製造することができる。

（５）−Ｉ又は（５）−ＩＩと（５）−ＩＩＩで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又はＷＳＣ等の縮合剤を用い、必要に応じて加熱することにより、（５）−ＩＶ又は（５）−Ｖあるいはこれらの前駆体を得ることができる（工程（５）−１）。
（５）−Ｉ又は（５）−ＩＩとＺＨ（この場合、Ｚはヘテロシクリル基を意味する。）で示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又はＷＳＣ等の縮合剤を用い、必要に応じて加熱することにより、（５）−ＶＩ又は（５）−ＶＩＩあるいはこれらの前駆体を得ることができる（工程（５）−２）。
式（５）に示す化合物のうち、Ｕが硫黄原子である化合物は、Ｕが酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することでも得ることができる。
式（５）に示す化合物のうち、ＵがＮＯＲ^１０である化合物はＵが酸素原子である化合物を溶媒中攪拌下でＨ_２ＮＯＲ^１０又はその等価体を用い、必要に応じて酸又は塩基存在下、必要に応じて加熱することでも得ることができる。 Of the compounds represented by formula (I), X is a single bond or a C _1-6 alkylene group, and Y and Z are the structures shown below.

Or X is a single bond or a C _1-6 alkylene group, and Y is a structure shown below

And Z is a heterocyclyl group can be produced, for example, by the production method of the following formula (5).

(5) The compound represented by -I or (5) -II and (5) -III is stirred in a solvent, and if necessary, a catalyst and / or a base such as potassium carbonate or triethylamine and / or a condensation such as WSC. (5) -IV or (5) -V or a precursor thereof can be obtained by using an agent and heating as necessary (step (5) -1).
(5) -I or (5) -II and ZH (in this case, Z means a heterocyclyl group) with stirring in a solvent, if necessary, catalyst and / or potassium carbonate, triethylamine, etc. (5) -VI or (5) -VII or a precursor thereof can be obtained by heating using a base and / or a condensing agent such as WSC as necessary (step (5) -2). ).
Of the compounds represented by formula (5), a compound in which U is a sulfur atom can also be obtained by heating a compound in which U is an oxygen atom while stirring in a solvent using a Lawson reagent or an equivalent thereof as necessary. be able to.
Among the compounds represented by formula (5), a compound in which U is NOR ¹⁰ is a compound in which U is an oxygen atom, and H ₂ NOR ¹⁰ or an equivalent thereof is used under stirring in a solvent, and an acid or a base is present as necessary. It can also be obtained by heating as necessary.

である化合物は例えば以下の式（６）の製造法により製造することができる。

（６）−Ｉと（６）−ＩＩ〜（６）−ＶＩで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又は光延反応の条件下、必要に応じて加熱することにより、（６）−ＶＩＩ〜（６）−ＸＩあるいはこれらの前駆体を得ることができる（工程（６）−１）。
式（６）に示す化合物のうち、Ｕが硫黄原子である化合物は、Ｕが酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することでも得ることができる。
（６）―ＩＸで示される化合物は溶媒中攪拌下でメタクロロ過安息香酸等の酸化剤を用い、必要に応じて加熱することで−Ｓ−を−ＳＯ−及び−ＳＯ_２−に変換することもできる。 Of the compounds represented by formula (I), X is a C _1-6 alkylene group, and Y and Z are the structures shown below.

The compound which is can be manufactured, for example with the manufacturing method of following formula | equation (6).

(6) -I and the compounds represented by (6) -II to (6) -VI with stirring in a solvent, if necessary, a catalyst and / or a base such as potassium carbonate or triethylamine and / or conditions for Mitsunobu reaction Then, (6) -VII to (6) -XI or a precursor thereof can be obtained by heating as necessary (step (6) -1).
Of the compounds represented by formula (6), a compound in which U is a sulfur atom can also be obtained by heating a compound in which U is an oxygen atom while stirring in a solvent using a Lawson reagent or an equivalent thereof as necessary. be able to.
(6) the compound represented by -IX is using an oxidizing agent such as metachloroperbenzoic acid under stirring in a solvent, heating if necessary -S- the -SO- and -SO 2 _- can be converted to You can also.

（この場合、ＬはＣ_１−６アルキレン基（該Ｃ_１−６アルキレン基は、無置換であるか又は置換基群Ｖ^１より単独若しくは異なって選ばれる１つ以上の置換基で置換されている。）を意味する。）
である化合物は例えば式（７）の製造法により製造することができる。

（７）−Ｉと（７）−ＩＩで示される有機ボロン酸、有機ボロン酸エステル、有機スズ化合物又は有機マグネシウム化合物等の有機金属化合物を溶媒中攪拌下で、必要に応じてテトラキストリフェニルホスフィノパラジウム又は(１,１‘−ビス(ジフェニルホスフィノ)フェロセン)ジクロロパラジウム等の遷移金属触媒及び／又は炭酸カリウム、トリエチルアミン又は炭酸ナトリウム等の塩基を用い、必要に応じて加熱することにより、（７）−ＩＩＩあるいはこれらの前駆体を得ることができる（工程（７）−１）。（例えば、遷移金属が拓く有機合成，辻二郎著，1997年，（株）化学同人、クロス−カップリングリアクションズ、ア プラクティカルガイド、シリーズ トピックス イン カレントケミストリ、Ｖｏｌ．２１９ 宮浦憲夫著、スプリンガー(Cross-Coupling Reactions A Practical Guide，Series:Topics in Current Chemistry , Vol.219, Miyaura, Norio, Springer） Among the compounds represented by the formula (I), R ² is a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkoxy group, a C _2-14 aryl group, a C _2-9 heterocyclyl group or The structure shown below

(In this case, L is a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). Means.)
The compound which is can be manufactured by the manufacturing method of Formula (7), for example.

(7) An organometallic compound such as an organic boronic acid, an organic boronic acid ester, an organic tin compound or an organic magnesium compound represented by (I)-(I) and (7) -II is stirred in a solvent, and if necessary, tetrakistriphenylphosphine By using a transition metal catalyst such as finopalladium or (1,1′-bis (diphenylphosphino) ferrocene) dichloropalladium and / or a base such as potassium carbonate, triethylamine or sodium carbonate, and heating as necessary, ( 7) -III or a precursor thereof can be obtained (step (7) -1). (For example, organic synthesis pioneered by transition metals, by Jiro Jiro, 1997, Doujin Chemical Co., Ltd., Cross-Coupling Reactions, Practical Guide, Series Topics in Current Chemistry, Vol. 219 by Norio Miyaura, Springer (Cross -Coupling Reactions A Practical Guide, Series: Topics in Current Chemistry, Vol.219, Miyaura, Norio, Springer)

（８）−Ｉで示される化合物と対応するＣ_１−６アルキルアルコール、Ｃ_１−６アルキルチオールを溶媒中攪拌下で必要に応じて触媒及び／又は水素化ナトリウム、トリエチルアミン又は炭酸ナトリウム等の塩基を用い、必要に応じて加熱することにより、（８）−ＩＩあるいはこれらの前駆体を得ることができる（工程（８）−１）。
（８）−ＩＩＩで示される化合物と対応するＣ_１−６アルキルハロゲン化合物、Ｃ_１−６アルキルトリフレート又はＣ_１−６アルコールを、溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又は光延反応の条件下、必要に応じて加熱することにより、（８）−ＩＩあるいはこれらの前駆体を得ることができる（工程（８）−２）。 Among the compounds represented by formula (I), a compound in which R ² is a C _1-6 alkoxy group or a C _1-6 alkylthio group can be produced, for example, by the production method of formula (8).

(8) A compound represented by -I and a corresponding C _1-6 alkyl alcohol or C _1-6 alkyl thiol under stirring in a solvent, if necessary, a catalyst and / or a base such as sodium hydride, triethylamine or sodium carbonate (8) -II or a precursor thereof can be obtained (step (8) -1) by heating as necessary.
(8) The compound represented by -III and the corresponding C _1-6 alkyl halogen compound, C _1-6 alkyl triflate, or C _1-6 alcohol are stirred in a solvent and, if necessary, a catalyst and / or carbonic acid. (8) -II or a precursor thereof can be obtained by heating as necessary under the conditions of a base such as potassium or triethylamine and / or Mitsunobu reaction (step (8) -2).

Among the compounds represented by the formula (I), a compound in which R ² is a C _1-6 alkylsulfonyl group is, for example, a compound represented by the formula (8) -II, in which R ² is a C _1-6 alkylthio group. A certain compound can be obtained by heating as necessary using an oxidizing agent such as metachloroperbenzoic acid with stirring in a solvent.

（９）−Ｉで示される化合物を、Ｎ，Ｎ−ジメチルホルムアミドとオキシ塩化リン又はその等価体の混合物中で、必要に応じて加熱することにより、（９）−ＩＩあるいはこれらの前駆体を得ることができる（工程（９）−１）。
（９）−ＩＩＩで示される化合物とＮ−ブロモスクシンイミド等のハロゲン化剤を溶媒中攪拌下で必要に応じて過酸化ベンゾイルや２，２‘−アゾビスイソブチロニトリル等のラジカル開始剤を用い、必要に応じて加熱することにより、（９）−ＩＶあるいはこれらの前駆体を得ることができる（工程（９）−２）。（９）−ＩＶで示される化合物と硝酸銀を溶媒中攪拌下で必要に応じて加熱することにより、（９）−ＩＩあるいはこれらの前駆体を得ることができる（工程（９）−３）。 Among the compounds represented by the formula (I), a compound in which R ² is a formyl group can be produced, for example, by the production method of the formula (9).

The compound represented by (9) -I is heated in a mixture of N, N-dimethylformamide and phosphorus oxychloride or an equivalent thereof as necessary, to thereby obtain (9) -II or a precursor thereof. Can be obtained (step (9) -1).
(9) A radical initiator such as benzoyl peroxide or 2,2′-azobisisobutyronitrile is optionally added to the compound represented by -III and a halogenating agent such as N-bromosuccinimide with stirring in a solvent. By using and heating as necessary, (9) -IV or a precursor thereof can be obtained (step (9) -2). (9) -II or a precursor thereof can be obtained by heating the compound represented by (9) -IV and silver nitrate as necessary under stirring in a solvent (step (9) -3).

（１０）−Iで示される化合物とシアン化銅等のシアン化剤を溶媒中攪拌下で、必要に応じて加熱することにより、（１０）−ＩＩあるいはこれらの前駆体を得ることができる（工程（１０）−１）。（１０）−ＩＩで示される化合物とアジ化ナトリウムを、溶媒中攪拌下で、必要に応じて加熱することにより、（１０）−ＩＩＩあるいはこれらの前駆体を得ることができる（工程（１０）−２）。 Among the compounds represented by the formula (I), a compound in which R ² is a tetrazolyl group can be produced, for example, by the production method of the formula (10).

(10) -II or a precursor thereof can be obtained by heating a compound represented by (10) -I and a cyanating agent such as copper cyanide in a solvent while stirring as necessary ( Step (10) -1). (10) -III or a precursor thereof can be obtained by heating the compound represented by (10) -II and sodium azide as necessary under stirring in a solvent (step (10)). -2).

（１１）−Iで示される化合物と硝酸又はその等価体を、必要に応じて濃硫酸の存在下で、必要に応じて加熱することにより、（１１）−ＩＩあるいはこれらの前駆体を得ることができる（工程（１１）−１）。（１１）−ＩＩで示される化合物を溶媒中攪拌下で、水素又はギ酸塩を用いてパラジウム−炭素等の存在下又は塩化スズや還元鉄等の還元剤を用いて、必要に応じて加熱することにより、（１１）−ＩＩＩあるいはこれらの前駆体を得ることができる（工程（１１）−２）。（１１）−ＩＩＩと（１１）−ＩＶ又は（１１）−Ｖで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又はＷＳＣ等の縮合剤を用い、必要に応じて加熱することにより、（１１）−ＶＩ、（１１）−ＶＩＩあるいはこれらの前駆体を得ることができる（工程（１１）−３）。（１１）−ＩＩＩとＲ^aＮＣＳ又はＲ^aＮＣＯで示される化合物を溶媒中攪拌下で、必要に応じて触媒を用い、必要に応じて加熱することにより、（１１）−ＶＩＩＩあるいはこれらの前駆体を得ることができる（工程（１１）−４）。（１１）−ＩＩＩで示される化合物を溶媒中攪拌下でチオホスゲン、ホスゲン又はその等価体を用い、必要に応じて加熱することにより、（１１）−ＩＸあるいはこれらの前駆体を得ることができる（工程（１１）−５）。続いて、（１１）−ＩＸと（１１）−Ｘ又は（１１）−ＸＩで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基の存在下、必要に応じて加熱することにより、（１１）−ＸＩＩ、（１１）−ＸＩＩＩあるいはこれらの前駆体を得ることができる（工程（１１）−６）。
式（１１）に示す化合物のうち、Ｔ’が硫黄原子である化合物は、Ｔ’が酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することでも得ることができる。 Among the compounds represented by the formula (I), a compound in which R ² has the structure shown below can be produced, for example, by the production method of the formula (11).

(11) -II or a precursor thereof is obtained by heating the compound represented by (11) -I and nitric acid or an equivalent thereof, if necessary, in the presence of concentrated sulfuric acid, if necessary. (Step (11) -1). (11) The compound represented by -II is heated as necessary using hydrogen or a formate in the presence of palladium-carbon or a reducing agent such as tin chloride or reduced iron while stirring in a solvent. Thus, (11) -III or a precursor thereof can be obtained (step (11) -2). The compound represented by (11) -III and (11) -IV or (11) -V is stirred in a solvent, and if necessary, a catalyst and / or a base such as potassium carbonate or triethylamine and / or a condensation such as WSC. (11) -VI, (11) -VII or a precursor thereof can be obtained by using an agent and heating as necessary (step (11) -3). (11) -VIII or a precursor thereof can be prepared by heating the compound represented by (11) -III and R ^a NCS or R ^a NCO in ^a solvent while using a catalyst, if necessary, and if necessary. A body can be obtained (step (11) -4). (11) -IX or a precursor thereof can be obtained by heating the compound represented by (11) -III using thiophosgene, phosgene, or an equivalent thereof while stirring in a solvent, if necessary ( Step (11) -5). Subsequently, the compound represented by (11) -IX and (11) -X or (11) -XI is stirred in a solvent, and if necessary, in the presence of a catalyst and / or a base such as potassium carbonate or triethylamine, (11) -XII, (11) -XIII, or these precursors can be obtained by heating as needed (process (11) -6).
Among the compounds represented by formula (11), a compound in which T ′ is a sulfur atom is heated as necessary using a Lawson reagent or an equivalent thereof while stirring the compound in which T ′ is an oxygen atom in a solvent. But you can get it.

（１２）−ＩとＲ^ｂＮＨ_２又はＲ^ｃＮＨ_２で示される化合物を溶媒中攪拌下で必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基の存在下、必要に応じて加熱することにより、（１２）−ＩＩ又は（１２）−ＩＩＩを得ることができる（工程（１２）−１）。（１２）−ＩＩと（１２）−ＩＶで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又はＷＳＣ等の縮合剤を用い、必要に応じて加熱することにより、（１２）−Ｖあるいはこれらの前駆体を得ることができる（工程（１２）−２）。（１２）−ＩＩ又は（１２）−ＩＩＩで示される化合物を溶媒中攪拌下でホスゲン、チオホスゲン又はその等価体を用い、必要に応じて加熱し、続いて、（１２）−ＶＩ又は（１２）−ＶＩＩと反応させることで（１２）−ＶＩＩＩまたは（１２）−ＩＸあるいはこれらの前駆体を得ることができる（工程（１２）−３）。
式（１２）に示す化合物のうち、Ｔ’が硫黄原子である化合物は、Ｔ’が酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することでも得ることができる。 Among the compounds represented by the formula (I), a compound in which R ² has the structure shown below can be produced, for example, by the production method of the formula (12).

(12) The compound represented by -I and R ^b NH ₂ or R ^c NH ₂ is heated as necessary in the presence of a catalyst and / or a base such as potassium carbonate or triethylamine while stirring in a solvent. Thus, (12) -II or (12) -III can be obtained (step (12) -1). The compounds represented by (12) -II and (12) -IV are stirred in a solvent, and if necessary, a catalyst and / or a base such as potassium carbonate or triethylamine and / or a condensing agent such as WSC are used as necessary. By heating accordingly, (12) -V or a precursor thereof can be obtained (step (12) -2). The compound represented by (12) -II or (12) -III is heated as necessary using phosgene, thiophosgene or an equivalent thereof while stirring in a solvent, and subsequently, (12) -VI or (12) (12) -VIII or (12) -IX or a precursor thereof can be obtained by reacting with -VII (step (12) -3).
Of the compounds represented by formula (12), a compound in which T ′ is a sulfur atom is heated as necessary using a Lawson reagent or an equivalent thereof while stirring the compound in which T ′ is an oxygen atom in a solvent. But you can get it.

（１３）−ＩとＲ^ｂ-Ｖ^１０で示される化合物を溶媒中攪拌下で必要に応じて加熱することにより、（１３）−ＩＩを得ることができる（工程（１３）−１）。（１３）−ＩＩで示される化合物と二酸化マンガン等の酸化剤を溶媒中攪拌下で必要に応じて加熱することにより、（１３）−ＩＩＩあるいはこれらの前駆体を得ることができる（工程（１３）−２）。
（１３）−ＩＶと（１３）−Ｖで示される化合物を溶媒中攪拌下で必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基の存在下、必要に応じて加熱することにより、（１３）−ＩＩＩあるいはこれらの前駆体を得ることができる（工程（１３）−３）。
式（１３）に示す化合物のうち、Ｔ’が硫黄原子である化合物は、Ｔ’が酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することで得ることができる。
式（１３）に示す化合物のうち、Ｔ’がＮＲ^ｄ又はＮＯＲ^ｄである化合物はＴ’が酸素原子である化合物を溶媒中攪拌下でＨ_２ＮＲ^ｄ、Ｈ_２ＮＯＲ^ｄ又はその等価体を用い、必要に応じて酸又は塩基存在下、必要に応じて加熱することで得ることができる。 Among the compounds represented by the formula (I), a compound in which R ² has the structure shown below can be produced, for example, by the production method of the formula (13).

(13) -II can be obtained by heating the compound represented by -I and R ^b -V ¹⁰ under agitation in a solvent as necessary (step (13) -1). (13) -III or a precursor thereof can be obtained by heating the compound represented by (13) -II and an oxidizing agent such as manganese dioxide as necessary under stirring in a solvent (step (13)). ) -2).
By heating the compound represented by (13) -IV and (13) -V with stirring in a solvent, if necessary, in the presence of a catalyst and / or a base such as potassium carbonate or triethylamine as necessary, ( 13) -III or a precursor thereof can be obtained (step (13) -3).
Of the compounds represented by formula (13), a compound in which T ′ is a sulfur atom is heated as necessary using a Lawson reagent or an equivalent thereof while stirring the compound in which T ′ is an oxygen atom in a solvent. Can be obtained at
Of the compounds represented by the formula (13), a compound in which T ′ is NR ^d or NOR ^d is a compound in which T ′ is an oxygen atom, and H ₂ NR ^d , H ₂ NOR ^d or an equivalent thereof is stirred under stirring in a solvent. It can be obtained by heating, if necessary, in the presence of an acid or a base as necessary.

（１４）−Ｉと（１４）−ＩＩで示される化合物を溶媒中攪拌下で必要に応じて酸又は塩基存在下、必要に応じて加熱することにより、（１４）−ＩＩＩあるいはこれらの前駆体を得ることができる（工程（１４）−１）。 Among the compounds represented by the formula (I), a compound in which R ² has the structure shown below can be produced, for example, by the production method of the formula (14).

(14) -III or a precursor thereof by heating the compound represented by (14) -I and (14) -II with stirring in a solvent, if necessary, in the presence of an acid or a base as necessary Can be obtained (step (14) -1).

（１５）−Ｉで示される化合物を溶媒中攪拌下で、一酸化炭素又はその等価体を用いて、必要に応じて酢酸パラジウム等の遷移金属触媒及び／又はホスフィンリガンド及び／又は炭酸カリウム、トリエチルアミン又は炭酸ナトリウム等の塩基の存在下、必要に応じて加熱することにより、（１５）−ＩＩあるいはこれらの前駆体を得ることができる（工程（１５）−１）。
（１５）−ＩＩＩで示される化合物を溶媒中攪拌下で、過マンガン酸カリウム、亜塩素酸ナトリウムや過酸化水素等の酸化剤及び必要に応じて酸、塩基又は触媒を用い、必要に応じて加熱することにより、（１５）−ＩＩあるいはこれらの前駆体を得ることができる（工程（１５）−２）。
（１５）−ＩＩと（１５）−ＩＶ又は（１５）−Ｖで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又はＷＳＣ等の縮合剤を用い、必要に応じて加熱することにより、（１５）−ＶＩ又は（１５）−ＶＩＩあるいはこれらの前駆体を得ることができる（工程（１５）−３）。
式（１５）に示す化合物のうち、Ｔ’が硫黄原子である化合物は、Ｔ’が酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することで得ることができる。 Among the compounds represented by the formula (I), a compound in which R ² has the structure shown below can be produced, for example, by the production method of the formula (15).

(15) The compound represented by -I is stirred in a solvent, using carbon monoxide or an equivalent thereof, and if necessary, a transition metal catalyst such as palladium acetate and / or a phosphine ligand and / or potassium carbonate, triethylamine Alternatively, (15) -II or a precursor thereof can be obtained by heating as necessary in the presence of a base such as sodium carbonate (step (15) -1).
(15) The compound represented by -III is stirred in a solvent, using an oxidizing agent such as potassium permanganate, sodium chlorite or hydrogen peroxide and, if necessary, an acid, a base or a catalyst. By heating, (15) -II or a precursor thereof can be obtained (step (15) -2).
The compound represented by (15) -II and (15) -IV or (15) -V is stirred in a solvent, and if necessary, a catalyst and / or a base such as potassium carbonate or triethylamine and / or a condensation such as WSC. (15) -VI or (15) -VII or a precursor thereof can be obtained by using an agent and heating as necessary (step (15) -3).
Of the compounds represented by formula (15), a compound in which T ′ is a sulfur atom is heated as necessary using a Lawson reagent or an equivalent thereof while stirring the compound in which T ′ is an oxygen atom in a solvent. Can be obtained at

（１６）−Ｉ、（１６）−ＩＩ及び（１６）−ＩＩＩで示される化合物を溶媒中攪拌下で必要に応じてトリエチルアミン等の塩基存在下、必要に応じて加熱することにより、（１６）−ＩＶあるいはこれらの前駆体を得ることができる（工程（１６）−１）。
式（１６）に示す化合物のうち、Ｔ’又はＵ’が硫黄原子である化合物は、Ｔ’又はＵ’が酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することで得ることができる。 Among the compounds represented by the formula (I), a compound in which R ² has the structure shown below can be produced, for example, by the production method of the formula (16).

By heating the compound represented by (16) -I, (16) -II and (16) -III in a solvent with stirring in a solvent, if necessary, in the presence of a base such as triethylamine as necessary, (16) -IV or a precursor thereof can be obtained (step (16) -1).
Of the compounds represented by formula (16), a compound in which T ′ or U ′ is a sulfur atom is required to use a compound in which T ′ or U ′ is an oxygen atom while stirring in a solvent using Lawson's reagent or an equivalent thereof. It can obtain by heating according to.

（１７）−Ｉで示される化合物を溶媒中攪拌下で、水酸化カリウム又はその等価体を用いて、必要に応じてトリス（ジベンジリデンアセトン）ジパラジウム等の遷移金属触媒及び／又はホスフィンリガンドの存在下、必要に応じて加熱することにより、（１７）−ＩＩあるいはこれらの前駆体を得ることができる（工程（１７）−１）。
（１７）−ＩＩで示される化合物を溶媒中攪拌下で、（１７）−ＩＩＩ、（１７）−ＩＶ又は（１７）−Ｖで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又はＷＳＣ等の縮合剤を用い、必要に応じて加熱することにより、（１７）−ＶＩ、（１７）−ＶＩＩ又は（１７）−ＶＩＩＩあるいはこれらの前駆体を得ることができる（工程（１７）−２）。
式（１７）に示す化合物のうち、Ｔ’が硫黄原子である化合物は、Ｔ’が酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することで得ることができる。 Among the compounds represented by the formula (I), a compound in which R ² has the structure shown below can be produced, for example, by the production method of the formula (17).

(17) A compound represented by -I is stirred in a solvent, using potassium hydroxide or an equivalent thereof, and if necessary, a transition metal catalyst such as tris (dibenzylideneacetone) dipalladium and / or a phosphine ligand. (17) -II or a precursor thereof can be obtained by heating in the presence as necessary (step (17) -1).
The compound represented by (17) -II is stirred in a solvent, the compound represented by (17) -III, (17) -IV or (17) -V is stirred in a solvent, and if necessary, a catalyst and (17) -VI, (17) -VII or (17) -VIII or a precursor thereof by using a base such as potassium carbonate or triethylamine and / or a condensing agent such as WSC and heating as necessary. A body can be obtained (step (17) -2).
Of the compounds represented by formula (17), a compound in which T ′ is a sulfur atom is heated as necessary using a Lawson reagent or an equivalent thereof while stirring the compound in which T ′ is an oxygen atom in a solvent. Can be obtained at

（１８）−Ｉと（１８）−ＩＩで示される化合物を溶媒中攪拌下で、必要に応じてブチルリチウムやトリエチルアミン等の塩基の存在下、必要に応じて加熱することにより、（１８）−ＩＩＩあるいはこれらの前駆体を得ることができる（工程（１８）−１）。
（１８）−ＩＩＩで示される化合物を化合物を溶媒中攪拌下で、水素又はギ酸塩を用いてパラジウム−炭素等の存在下、必要に応じて加熱することにより、（１８）−ＩＶあるいはこれらの前駆体を得ることができる（工程（１８）−２）。
（１８）−ＩＶで示される化合物を溶媒中攪拌下で、必要に応じて水酸化ナトリウム等の塩基を用い、必要に応じて加熱することにより、（１８）−Ｖあるいはこれらの前駆体を得ることができる（工程（１８）−３）。
（１８）−Ｖと（１８）−ＶＩ又は（１８）−ＶＩＩで示される化合物を溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基及び／又はＷＳＣ等の縮合剤を用い、必要に応じて加熱することにより、（１８）−ＶＩＩＩ又は（１８）−ＩＸあるいはこれらの前駆体を得ることができる（工程（１８）−４）。
式（１８）に示す化合物のうち、Ｔ’が硫黄原子である化合物は、Ｔ’が酸素原子である化合物を溶媒中攪拌下でローソン試薬又はその等価体を用い、必要に応じて加熱することで得ることができる。 Among the compounds represented by the formula (I), a compound in which R ² has the structure shown below can be produced, for example, by the production method of the formula (18).

(18) -I and (18) -II are heated in the presence of a base such as butyllithium or triethylamine, if necessary, while stirring the compound shown in (18) -II. III or a precursor thereof can be obtained (step (18) -1).
The compound represented by (18) -III is heated as necessary in the presence of palladium-carbon or the like using hydrogen or formate under stirring of the compound in a solvent, to thereby obtain (18) -IV or a compound thereof. A precursor can be obtained (step (18) -2).
(18) -V or a precursor thereof is obtained by heating the compound represented by (IV) -IV while stirring in a solvent, using a base such as sodium hydroxide, if necessary, and if necessary. (Step (18) -3).
The compound represented by (18) -V and (18) -VI or (18) -VII is stirred in a solvent, and if necessary, a catalyst and / or a base such as potassium carbonate or triethylamine and / or a condensation such as WSC. (18) -VIII or (18) -IX or a precursor thereof can be obtained by using an agent and heating as necessary (step (18) -4).
Of the compounds represented by formula (18), a compound in which T ′ is a sulfur atom is heated as necessary using a Lawson reagent or an equivalent thereof while stirring the compound in which T ′ is an oxygen atom in a solvent. Can be obtained at

  Formula (1) -II, (1) -IV, (1) -V, (2) -IX, (3) -II, (3) -V, (5) -III, (6) -II, ( 11) -X, (12) -VII, (15) -V, (16) -III or amine compound represented by (18) -VII is a corresponding nitrile compound, acid amide compound, oxime compound, halogen compound, It can be synthesized from ketone compounds, aldehyde compounds, alcohol compounds, boron compounds, epoxide compounds, acid imide compounds, carbamate compounds, and the like. (For example, 4th edition, Experimental Chemistry Lecture 20, Organic Synthesis II, The Chemical Society of Japan, 1992, Maruzen Co., Ltd., Bioorganic and Medicinal Chemistry, 13, 4022, 2005, Kuramochi et al. (Bioorganic & Medicinal Chemistry, 13 , 4022, 2005, Kuramoti T. et al.), Journal of Medicinal Chemistry 50, 149, 2007 (Journal of Medicinal Chemistry, 50, 149, 2007), Journal of Organic Chemistry 46, 4296, 1981 (Journal of Organic Chemistry, 46, 4296, 1981), Journal of Organic Chemistry 44, 2081, 1979 (Journal of Organic Chemistry, 44, 2081, 1979), Acta Chemica Scandinavia 19, 1741, 1965 (Acta Chemica Scandinavica, 19, 1741, 1965) ), Organic Letter 5,44 97, 2003 (Organic Letters, 5, 4497, 2003))

（１９）−Ｉに対し、（１９）−ＩＩ又は（１９）−ＩＶで示されるアルコール又はチオールを、溶媒中攪拌下で、必要に応じて触媒及び／又は炭酸カリウムやトリエチルアミン等の塩基の存在下、必要に応じて加熱することにより、それぞれ（１９）−ＩＩＩ又は（１９）−Ｖあるいはこれらの前駆体を得ることができる（工程（１９）−１及び（１９）−２）。
次いで（１９）−Ｖに対し、（１９）−ＶＩで示される化合物は溶媒中攪拌下でメタクロロ過安息香酸等の酸化剤を用い、必要に応じて加熱することで−Ｓ−を−ＳＯ−及び−ＳＯ_２−に変換することもできる。 In the formula (I), a compound in which Q is represented by the following structure can be produced, for example, by the production method of the following formula (19).

(19) -I with respect to alcohol or thiol represented by (19) -II or (19) -IV, with stirring in a solvent, and presence of a catalyst and / or a base such as potassium carbonate or triethylamine, if necessary Then, (19) -III or (19) -V or a precursor thereof can be obtained by heating as necessary (steps (19) -1 and (19) -2).
Next, with respect to (19) -V, the compound represented by (19) -VI uses an oxidizing agent such as metachloroperbenzoic acid with stirring in a solvent, and is heated as necessary to convert -S- to -SO-. and -SO ₂ - can be converted into.

The present invention will be described in more detail with reference synthesis examples, synthesis examples, test examples, and formulation examples below, but the present invention is not limited to these examples.
In Examples, NMR means nuclear magnetic resonance spectrum, LC / MS means liquid chromatography mass spectrometry, and (v / v) means (volume / volume).
¹ H-NMR was measured at 300 MHz, and LC / MS was measured under the following conditions.
LC / MS condition 1
Column: Waters SunFire C18 (3.5μm, 4.6x30mm)
Eluent: acetonitrile / 0.1% formic acid aqueous solution (10/90 → 30/70)
LC / MS condition 2
Column: Waters SunFire C18 (3.5μm, 4.6x30mm)
Eluent: Acetonitrile / 0.1% formic acid aqueous solution (10/90 → 85/15)
LC / MS condition 3
Column: Waters Xterra MSC18 (3.5μm, 2.1x20mm)
Eluent: Acetonitrile / 0.2% formic acid aqueous solution (20/80 → 90/10)
LC / MS condition 4
Column: Waters Xterra MSC18 (3.5μm, 4.6x30mm)
Eluent: acetonitrile / 0.2% formic acid aqueous solution (15/85 → 85/15)
LC / MS condition 5
Column: Waters SunFire C18 (3.5μm, 2.1x20mm)
Eluent: acetonitrile / 0.1% formic acid aqueous solution (10/90 → 30/70)
LC / MS condition 6
Column: Waters SunFire C18 (3.5μm, 2.1x20mm)
Eluent: acetonitrile / 0.1% formic acid aqueous solution (10/90 → 60/40)
LC / MS condition 7
Column: Waters SunFire C18 (3.5μm, 2.1x20mm)
Eluent: Acetonitrile / 0.1% formic acid aqueous solution (10/90 → 85/15)
LC / MS condition 8
Column: Waters SunFire C18 (3.5μm, 2.1x20mm)
Eluent: Acetonitrile / 0.1% formic acid aqueous solution (20/80 → 100/0)
LC / MS condition 9
Column: Waters SunFire C18 (3.5μm, 2.1x20mm)
Eluent: acetonitrile / 0.1% formic acid aqueous solution (40/60 → 100/0)

Ｎ−メトキシ−Ｎ−メチルピリダジン−４−カルボキサミド

４−ピリダジンカルボン酸(1.61 g, 13.0 mmol)、Ｎ−メチル−Ｎ−メトキシアミン 塩酸塩 (2.54 g, 26.0 mmol)、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩（6.23 g, 32.5 mmol）、１−ヒドロキシベンゾトリアゾール 無水物（触媒量）、トリエチルアミン（9.06 mL, 65.0 mmol）のＮ，Ｎ−ジメチルホルムアミド溶液（16 mL）を室温で3日間攪拌した。反応終了後、溶媒を減圧留去し、水及びクロロホルムを加え、セライトろ過した。ろ液をクロロホルムで抽出、無水硫酸ナトリウムで乾燥、減圧留去した。得られた反応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）で精製し目的物を得た。（94%収率）

形状：淡茶色油状物
LC/MS：条件７ 保持時間0.71分
LC/MS(ESI⁺) m/z; 168 [M+1]^+
１H-NMR(CDCl_３)
δ：3.42 (s, 3H), 3.58 (s, 3H), 7.76 (dd, J = 5.4, 2.0 Hz, 1H), 9.35 (d, J = 5.4 Hz, 1H), 9.45 (d, J = 2.0 Hz, 1H).

1−（ピリダジン−４−イル）エタノン

Ｎ−メトキシ−Ｎ−メチルピリダジン−４−カルボキサミド(1.13 g, 6.76 mmol)のテトラヒドロフラン溶液 (22 mL) に、窒素雰囲気下、0℃でメチルマグネシウムブロミド（10.1 mL, 10.1 mmol, 1Mジエチルエーテル溶液）を滴下し、1時間攪拌した。反応終了後、飽和食塩水を加え、クロロホルムで抽出、無水硫酸ナトリウムで乾燥、減圧留去した。得られた反応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＝１／２（ｖ／ｖ）→０／１（ｖ／ｖ））で精製し目的物を得た。（42%収率）

形状：淡黄色固体
LC/MS：条件７ 保持時間0.75分
LC/MS(ESI⁺) m/z; 123 [M+1]^+
１H-NMR(CDCl_３)
δ：2.70 (s, 3H), 7.86 (dd, J= 0.8, 5.4 Hz, 1H), 9.48 (d, J = 5.4 Hz, 1H), 9.61 (d, J = 0.8 Hz, 1H).

Ｎ−ヒドロキシ−１−（ピリダジン−４−イル）エタンイミン 塩酸塩

1−（ピリダジン−４−イル）エタノン (1.00 g, 8.19 mmol) とヒドロキシルアミン 塩酸塩 (598 mg, 8.60 mmol） のエタノール溶液 (20 mL) を90℃で10分間攪拌した。反応終了後、減圧留去して、得られた反応粗物を次工程に用いた。

形状：茶色固体
LC/MS：条件７ 保持時間0.75分
LC/MS(ESI⁺) m/z; 138 [M+1]^+
１H-NMR(CDCl_３)
δ：2.69 (s, 3H), 7.86 (dd, J= 0.8, 5.3 Hz, 1H), 9.46 (d, J = 5.3 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H).

１−（ピリダジン−４−イル）エタンアミン 塩酸塩

Ｎ−ヒドロキシ−１−（ピリダジン−４−イル）エタンイミン 塩酸塩 (1.48 g, 8.53 mmol) と10%パラジウム−炭素 (0.15 g) のエタノール溶液 (30 mL) を水素雰囲気下、室温で1日攪拌した。反応終了後、反応液をセライトろ過し、得られたろ液を減圧留去して、得られた反応粗物を次工程に用いた。

形状：茶色無定形物
LC/MS：条件５ 保持時間0.71分
LC/MS(ESI⁺) m/z; 124 [M+1]^+
１H-NMR(CDCl_３)
δ：1.56 (d, J = 7.0 Hz, 3H), 4.52 (br d, J = 7.0 Hz, 1H), 7.89 (dd, J = 2.5, 5.4 Hz, 1H), 8.8-9.1 (br s, 3H), 9.31 (d, J = 5.4 Hz, 1H), 9.43 (d, J = 2.5Hz, 1H). Reference synthesis example 1
1- (Pyridazin-4-yl) ethanamine hydrochloride

N-methoxy-N-methylpyridazine-4-carboxamide

4-Pyridazinecarboxylic acid (1.61 g, 13.0 mmol), N-methyl-N-methoxyamine hydrochloride (2.54 g, 26.0 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (6.23 g , 32.5 mmol), 1-hydroxybenzotriazole anhydride (catalytic amount), triethylamine (9.06 mL, 65.0 mmol) in N, N-dimethylformamide (16 mL) was stirred at room temperature for 3 days. After completion of the reaction, the solvent was distilled off under reduced pressure, water and chloroform were added, and the mixture was filtered through celite. The filtrate was extracted with chloroform, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product. (94% yield)

Shape: light brown oil
LC / MS: Condition 7 Retention time 0.71 minutes
LC / MS (ESI ⁺ ) m / z; 168 [M + 1] ^+
1 H-NMR (CDCl ₃ )
δ: 3.42 (s, 3H), 3.58 (s, 3H), 7.76 (dd, J = 5.4, 2.0 Hz, 1H), 9.35 (d, J = 5.4 Hz, 1H), 9.45 (d, J = 2.0 Hz , 1H).

1- (pyridazin-4-yl) ethanone

To a tetrahydrofuran solution (22 mL) of N-methoxy-N-methylpyridazine-4-carboxamide (1.13 g, 6.76 mmol) at 0 ° C. in a nitrogen atmosphere, methylmagnesium bromide (10.1 mL, 10.1 mmol, 1M diethyl ether solution) Was added dropwise and stirred for 1 hour. After completion of the reaction, saturated brine was added, extracted with chloroform, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2 (v / v) → 0/1 (v / v)) to obtain the desired product. (42% yield)

Shape: pale yellow solid
LC / MS: Condition 7 Retention time 0.75 minutes
LC / MS (ESI ⁺ ) m / z; 123 [M + 1] ^+
1 H-NMR (CDCl ₃ )
δ: 2.70 (s, 3H), 7.86 (dd, J = 0.8, 5.4 Hz, 1H), 9.48 (d, J = 5.4 Hz, 1H), 9.61 (d, J = 0.8 Hz, 1H).

N-hydroxy-1- (pyridazin-4-yl) ethanimine hydrochloride

An ethanol solution (20 mL) of 1- (pyridazin-4-yl) ethanone (1.00 g, 8.19 mmol) and hydroxylamine hydrochloride (598 mg, 8.60 mmol) was stirred at 90 ° C. for 10 minutes. After completion of the reaction, the reaction crude product was distilled off under reduced pressure and used in the next step.

Shape: Brown solid
LC / MS: Condition 7 Retention time 0.75 minutes
LC / MS (ESI ⁺ ) m / z; 138 [M + 1] ^+
1 H-NMR (CDCl ₃ )
δ: 2.69 (s, 3H), 7.86 (dd, J = 0.8, 5.3 Hz, 1H), 9.46 (d, J = 5.3 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H).

1- (Pyridazin-4-yl) ethanamine hydrochloride

N-hydroxy-1- (pyridazin-4-yl) ethanimine hydrochloride (1.48 g, 8.53 mmol) and ethanol solution (30 mL) of 10% palladium-carbon (0.15 g) were stirred at room temperature for 1 day in a hydrogen atmosphere. did. After completion of the reaction, the reaction solution was filtered through Celite, the resulting filtrate was distilled off under reduced pressure, and the resulting reaction crude was used in the next step.

Shape: brown amorphous
LC / MS: Condition 5 Retention time 0.71 minutes
LC / MS (ESI ⁺ ) m / z; 124 [M + 1] ^+
1 H-NMR (CDCl ₃ )
δ: 1.56 (d, J = 7.0 Hz, 3H), 4.52 (br d, J = 7.0 Hz, 1H), 7.89 (dd, J = 2.5, 5.4 Hz, 1H), 8.8-9.1 (br s, 3H) , 9.31 (d, J = 5.4 Hz, 1H), 9.43 (d, J = 2.5Hz, 1H).

４，５−ジクロロピリダジン−３（２H）−オン（3.00 g, 18.2 mmol 、Journal of Heterocyclic Chemistry, 33(6), 1579-1582;1996記載の方法により合成した。）のジオキサン−水混合溶液（1:1（体積比）、30 mL）にトリエチルアミン（4.94 mL, 35.5 mmol）、（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−イソピノカンフェイルアミン（2.41 mL, 14.2 mmol）を加え、120℃で17時間攪拌した。放冷後、１M 塩酸を加え、クロロホルムで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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／酢酸エチル＝５／１（ｖ／ｖ））で精製し目的物を得た。(5.1 g, 100%収率)

形状：淡黄色固体
LC/MS：条件３ 保持時間4.09分
LC/MS(ESI⁺)：282, 284 [M+1]⁺
LC/MS(ESI^-)：280, 282 [M-1]^- Reference synthesis example 2
4-Chloro-5-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazin-3 (2H) -one

4,5-dichloropyridazin-3 (2H) -one (3.00 g, 18.2 mmol, synthesized by the method described in Journal of Heterocyclic Chemistry, 33 (6), 1579-1582; 1996) in a dioxane-water mixed solution ( Triethylamine (4.94 mL, 35.5 mmol) and (1R, 2R, 3R, 5S) -isopinoccamphoylamine (2.41 mL, 14.2 mmol) were added to 1: 1 (volume ratio, 30 mL), and the mixture was stirred at 120 ° C. Stir for hours. After allowing to cool, 1M hydrochloric acid was added, extracted with chloroform, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 5/1 (v / v)) to obtain the desired product. (5.1 g, 100% yield)

Shape: pale yellow solid
LC / MS: Condition 3 Retention time 4.09 minutes
LC / MS (ESI ⁺ ): 282, 284 [M + 1] ^{+
LC / MS (ESI -):} 280, 282 [M-1] -

４−クロロ−５−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−３（２H）-オン(600 mg, 2.13 mmol)のＮ，Ｎ-ジメチルホルムアミド溶液(6 mL)に室温でブロモ酢酸エチル (306 μL, 2.76 mmol), 炭酸カリウム (381 mg, 2.76 mmol)を加え、80℃で1.5時間攪拌した。放冷後、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。得られた有機層を飽和塩化アンモニウム水溶液及び飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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／酢酸エチル＝8／1（ｖ／ｖ））で精製し目的物を得た。（258 mg，33%収率）

形状：無色固体
LC/MS：条件７ 保持時間4.62分
LC/MS(ESI⁺) m/z; 368, 370 [M+1]⁺
LC/MS(ESI^-) m/z; 366, 368 [M-1]^-
1H-NMR(CDCl₃)
δ: 0.97 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J = 7.2 Hz, 3H), 1.23 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.68-1.80 (m, 1H), 1.89-2.00 (m, 2H), 2.00-2.10 (m, 1H), 2.41-2.55 (m, 1H), 2.58-2.70 (m, 1H), 3.80-3.90 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.65 (br d, J = 7.8 Hz, 1H), 4.86 (s, 2H), 7.62 (s, 1H). Reference synthesis example 3
Ethyl [5-chloro-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine- 1 (6H) -yl] acetate

4-Chloro-5-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazin-3 (2H) -one (600 mg, 2.13 mmol) in N, N-dimethylformamide solution (6 mL) at room temperature was added ethyl bromoacetate (306 μL, 2.76 mmol) and potassium carbonate (381 mg, 2.76 mmol) at 80 ° C. for 1.5 hours. Stir. After allowing to cool, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 8/1 (v / v)) to obtain the desired product. (258 mg, 33% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 4.62 minutes
LC / MS (ESI ⁺ ) m / z; 368, 370 [M + 1] ^{+
LC / MS (ESI -) m} / z; 366, 368 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 0.97 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J = 7.2 Hz, 3H), 1.23 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H ), 1.68-1.80 (m, 1H), 1.89-2.00 (m, 2H), 2.00-2.10 (m, 1H), 2.41-2.55 (m, 1H), 2.58-2.70 (m, 1H), 3.80-3.90 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.65 (br d, J = 7.8 Hz, 1H), 4.86 (s, 2H), 7.62 (s, 1H).

エチル ［５−クロロ−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］アセテート（20 g, 54.4 mmol）、トリエチルアミン(15.1 mL, 108.8 mmol)、5% パラジウム−炭素（4 g）のテトラヒドロフラン溶液(140 mL)を水素雰囲気下、室温で24時間攪拌した。反応終了後、反応液をセライトろ過し、得られたろ液を減圧留去して得られた反応残渣を酢酸エチルに溶解させ、有機層を水で洗浄後、無水硫酸マグネシウムで乾燥、減圧留去した。酢酸エチルを加え、加熱溶解した後に0℃に冷却し、析出した固体をろ取し、目的物(13.78 g)を得た。ろ液をシリカゲルカラムクロマトグラフィー（クロロホルム／酢酸エチル＝１／１（ｖ／ｖ））で精製し、目的物(4.04 g)を得た。(17.82 g, 98%収率）

形状：無色固体
LC/MS：条件７ 保持時間4.24分
LC/MS(ESI⁺) m/z; 334 [M+1]⁺
LC/MS(ESI^-) m/z; 332 [M-1]^-
1H-NMR(CDCl₃)
δ: 0.89 (d, J = 10.2 Hz, 1H), 1.02 (s, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.55-1.65 (m, 1H), 1.78-1.92 (m, 2H), 1.95-2.05 (m, 1H), 2.38-2.50 (m, 1H), 2.58-2.70 (m, 1H), 3.50-3.70 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.28 (br d, J = 7.8 Hz, 1H), 4.79 (s, 2H), 5.73 (d, J = 2.7 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H). Reference synthesis example 4
Ethyl [6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine-1 (6H) -Il] acetate

Ethyl [5-chloro-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine- 1 (6H) -yl] acetate (20 g, 54.4 mmol), triethylamine (15.1 mL, 108.8 mmol), 5% palladium-carbon (4 g) in tetrahydrofuran (140 mL) at room temperature under hydrogen atmosphere for 24 hours. Stir. After completion of the reaction, the reaction solution was filtered through Celite, and the resulting filtrate was distilled off under reduced pressure. The resulting reaction residue was dissolved in ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. did. Ethyl acetate was added and dissolved by heating, and then cooled to 0 ° C. The precipitated solid was collected by filtration to obtain the desired product (13.78 g). The filtrate was purified by silica gel column chromatography (chloroform / ethyl acetate = 1/1 (v / v)) to obtain the desired product (4.04 g). (17.82 g, 98% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 4.24 minutes
LC / MS (ESI ⁺ ) m / z; 334 [M + 1] ^{+
LC / MS (ESI -) m} / z; 332 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 0.89 (d, J = 10.2 Hz, 1H), 1.02 (s, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H ), 1.55-1.65 (m, 1H), 1.78-1.92 (m, 2H), 1.95-2.05 (m, 1H), 2.38-2.50 (m, 1H), 2.58-2.70 (m, 1H), 3.50-3.70 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.28 (br d, J = 7.8 Hz, 1H), 4.79 (s, 2H), 5.73 (d, J = 2.7 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H).

Ｎ，Ｎ−ジメチルホルムアミド(50 mL)に、オキシ塩化リン（4.66 mL, 50 mmol）を0℃でゆっくり加え、室温で10分間撹拌した。エチル ［６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］アセテート（8.28 g, 25 mmol）を0℃でゆっくり加え、室温で10分間撹拌した。反応終了後、反応液を飽和炭酸水素ナトリウム水溶液（200 mL）にゆっくり注ぎ、酢酸エチルで抽出した。有機層を飽和塩化アンモニウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥、減圧留去し、目的物を得た。（8.84 g, 98%収率）

形状：無色固体
LC/MS：条件７ 保持時間4.63分
LC/MS(ESI⁺) m/z; 362 [M+1]⁺
LC/MS(ESI^-) m/z; 360 [M-1]^-
1H-NMR(CDCl₃)
δ: 1.15 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.15 (d, J = 7.2 Hz, 3H), 1.28 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H), 1.75-1.83 (m, 1H), 1.90-1.98 (m, 1H), 2.00-2.14 (m, 2H), 2.42-2.52 (m, 1H), 2.56-2.67 (m, 1H), 3.95-4.05 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.79 (s, 2H), 7.71 (s, 1H), 10.2 (br d, J = 7.8 Hz, 1H), 10.3 (s, 1H). Synthesis example 1
Ethyl [5-formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine- 1 (6H) -yl] acetate

To N, N-dimethylformamide (50 mL), phosphorus oxychloride (4.66 mL, 50 mmol) was slowly added at 0 ° C., and the mixture was stirred at room temperature for 10 minutes. Ethyl [6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine-1 (6H) -Il] acetate (8.28 g, 25 mmol) was added slowly at 0 ° C. and stirred at room temperature for 10 minutes. After completion of the reaction, the reaction solution was slowly poured into a saturated aqueous sodium hydrogen carbonate solution (200 mL) and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain the desired product. (8.84 g, 98% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 4.63 minutes
LC / MS (ESI ⁺ ) m / z; 362 [M + 1] ^{+
LC / MS (ESI -) m} / z; 360 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 1.15 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.15 (d, J = 7.2 Hz, 3H), 1.28 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H ), 1.75-1.83 (m, 1H), 1.90-1.98 (m, 1H), 2.00-2.14 (m, 2H), 2.42-2.52 (m, 1H), 2.56-2.67 (m, 1H), 3.95-4.05 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.79 (s, 2H), 7.71 (s, 1H), 10.2 (br d, J = 7.8 Hz, 1H), 10.3 (s, 1H ).

［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］酢酸

エチル ［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］アセテート（723 mg, 2.0 mmol）のテトラヒドロフラン溶液（5 mL）に、1M水酸化ナトリウム水溶液（5 mL, 5 mmol）を加え、室温で40分間攪拌した。反応終了後、酢酸エチルを加えて希釈したのち、1M塩酸で中和後、有機層を抽出し、無水硫酸ナトリウムで乾燥、減圧留去し、目的物を得た。（667 mg, 100％収率）

形状：無色固体
LC/MS：条件７ 保持時間4.22分
LC/MS(ESI⁺) m/z; 334 [M+1]⁺
LC/MS(ESI^-) m/z; 332 [M-1]^-

［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］アセテート

［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］酢酸（666.7 mg, 2.0 mmol）、ｔ−ブタノール（0.226 mL, 2.4 mmol）、Ｎ,Ｎ−ジメチル−４−アミノピリジン（24.4 mg, 0.2 mmol）のジクロロメタン溶液（10 mL）に、Ｎ,Ｎ'−ジシクロヘキシルカルボジイミド（495.1 mg, 2.4 mmol）を加え、室温で1時間攪拌した。反応終了後、酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧留去した。得られた反応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＝４／１（ｖ／ｖ））で精製し目的物を得た。（633.8 mg, 81%収率）

形状：無色固体
LC/MS：条件７ 保持時間4.95分
LC/MS(ESI⁺) m/z; 390 [M+1]^+
1H-NMR(CDCl₃)
δ: 1.02 (d, J = 10.2 Hz, 1H), 1.04 (s, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.49 (s, 9H), 1.75-1.83 (m, 1H), 1.90-1.98 (m, 1H), 2.00-2.14 (m, 2H), 2.42-2.52 (m, 1H), 2.56-2.67 (m, 1H), 3.90-4.05 (m, 1H), 4.70 (s, 2H), 7.71 (s, 1H), 10.2 (br d, J = 7.8 Hz, 1H), 10.3 (s, 1H). Synthesis example 2
t-butyl [5-formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} Pyridazine-1 (6H) -yl] acetate

[5-Formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine-1 (6H) -yl] acetic acid

Ethyl [5-formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine- To a tetrahydrofuran solution (5 mL) of 1 (6H) -yl] acetate (723 mg, 2.0 mmol) was added 1M aqueous sodium hydroxide solution (5 mL, 5 mmol), and the mixture was stirred at room temperature for 40 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, neutralized with 1M hydrochloric acid, the organic layer was extracted, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the desired product. (667 mg, 100% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 4.22 minutes
LC / MS (ESI ⁺ ) m / z; 334 [M + 1] ^{+
LC / MS (ESI -) m} / z; 332 [M-1] -

[5-Formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine-1 (6H) -yl] acetate

[5-Formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine-1 (6H) -yl] acetic acid (666.7 mg, 2.0 mmol), t-butanol (0.226 mL, 2.4 mmol), N, N-dimethyl-4-aminopyridine (24.4 mg, 0.2 mmol) in dichloromethane (10 mL) N, N′-dicyclohexylcarbodiimide (495.1 mg, 2.4 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 (v / v)) to obtain the desired product. (633.8 mg, 81% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 4.95 minutes
LC / MS (ESI ⁺ ) m / z; 390 [M + 1] ^+
1 H-NMR (CDCl ₃ )
δ: 1.02 (d, J = 10.2 Hz, 1H), 1.04 (s, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.49 (s, 9H), 1.75-1.83 (m, 1H), 1.90-1.98 (m, 1H), 2.00-2.14 (m, 2H), 2.42-2.52 (m, 1H), 2.56-2.67 (m, 1H), 3.90-4.05 (m, 1H) , 4.70 (s, 2H), 7.71 (s, 1H), 10.2 (br d, J = 7.8 Hz, 1H), 10.3 (s, 1H).

エチル ［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］アセテート（72.3 mg, 0.2 mmol）、ヒドロキシルアミン 塩酸塩（27.8 mg, 0.4 mmol）のエタノール溶液（2 mL）を３時間還流した。放冷後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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＝2／1（ｖ／ｖ））で精製し目的物を得た。（62.2 mg，83%収率）

形状：無色固体
LC/MS：条件７ 保持時間4.47分
LC/MS(ESI⁺) m/z; 377 [M+1]⁺
LC/MS(ESI^-) m/z; 375 [M-1]^-
1H-NMR(CDCl₃)
δ: 1.00 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.17 (d, J = 7.2 Hz, 3H), 1.28 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H), 1.75-1.83 (m, 1H), 1.85-1.93 (m, 1H), 1.95-2.05 (m, 2H), 2.39-2.52 (m, 1H), 2.56-2.67 (m, 1H), 3.85-3.95 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.81 (s, 2H), 7.69 (s, 1H), 7.70 (br s, 1H), 8.39 (br d, J = 7.5 Hz, 1H), 8.66 (s, 1H). Synthesis example 3
Ethyl {5-[(E)-(hydroxyimino) methyl] -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] Put-3-yl] amino} pyridazin-1 (6H) -yl} acetate

Ethyl [5-formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine- A solution of 1 (6H) -yl] acetate (72.3 mg, 0.2 mmol) and hydroxylamine hydrochloride (27.8 mg, 0.4 mmol) in ethanol (2 mL) was refluxed for 3 hours. After allowing to cool, saturated aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 (v / v)) to obtain the desired product. (62.2 mg, 83% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 4.47 minutes
LC / MS (ESI ⁺ ) m / z; 377 [M + 1] ^{+
LC / MS (ESI -) m} / z; 375 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 1.00 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.17 (d, J = 7.2 Hz, 3H), 1.28 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H ), 1.75-1.83 (m, 1H), 1.85-1.93 (m, 1H), 1.95-2.05 (m, 2H), 2.39-2.52 (m, 1H), 2.56-2.67 (m, 1H), 3.85-3.95 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.81 (s, 2H), 7.69 (s, 1H), 7.70 (br s, 1H), 8.39 (br d, J = 7.5 Hz, 1H), 8.66 (s, 1H).

｛５−［（Ｅ）−（ヒドロキシイミノ）メチル］−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル｝酢酸

エチル ｛５−［（Ｅ）−（ヒドロキシイミノ）メチル］−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル｝アセテート（37.6 mg, 0.1 mmol）のテトラヒドロフラン溶液（1 mL）に、1M水酸化ナトリウム水溶液（100 μL, 0.1 mmol）を加え、50℃で20分間攪拌した。反応終了後、酢酸エチルを加えて希釈したのち、水、1M塩酸で中和した後、有機層を抽出し、無水硫酸マグネシウムで乾燥、減圧留去し、目的物を得た。（34.8 mg, 100％収率）

形状：無色無定形物

２−{５−［（Ｅ）−（ヒドロキシイミノ）メチル］−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル}−Ｎ−[１−（ピリダジン−４−イル）エチル]アセトアミド

｛５−［（Ｅ）−（ヒドロキシイミノ）メチル］−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝酢酸（34.8 mg, 0.1 mmol）、１−（ピリダジン−４−イル）エタンアミン（18.5 mg, 0.15 mmol）のジクロロメタン溶液（2 mL）に、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩（28.8 mg, 0.15 mmol）、１−ヒドロキシベンゾトリアゾール 無水物（1.35 mg, 0.01 mmol）、トリエチルアミン（27.9 μL, 0.2 mmol）を加え室温で24時間攪拌した。反応終了後、クロロホルムを加え、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧留去した。得られた反応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＝８／１（ｖ／ｖ））で精製し目的物を得た。（20.1 mg, 44%収率）

形状：無色固体
LC/MS：条件７ 保持時間3.85分
LC/MS(ESI⁺) m/z; 454 [M+1]⁺
LC/MS(ESI^-) m/z; 452 [M-1]^- Synthesis example 4
2- {5-[(E)-(hydroxyimino) methyl] -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] Hept-3-yl] amino} pyridazin-1 (6H) -yl} -N- [1- (pyridazin-4-yl) ethyl] acetamide

{5-[(E)-(hydroxyimino) methyl] -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept -3-yl] amino} pyridazin-1 (6H) -yl} acetic acid

Ethyl {5-[(E)-(hydroxyimino) methyl] -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] To a tetrahydrofuran solution (1 mL) of [pt-3-yl] amino} pyridazin-1 (6H) -yl} acetate (37.6 mg, 0.1 mmol) was added 1M aqueous sodium hydroxide solution (100 μL, 0.1 mmol), and 50 Stir at 20 ° C. for 20 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, neutralized with water and 1M hydrochloric acid, the organic layer was extracted, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain the desired product. (34.8 mg, 100% yield)

Shape: colorless amorphous

2- {5-[(E)-(hydroxyimino) methyl] -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] Hept-3-yl] amino} pyridazin-1 (6H) -yl} -N- [1- (pyridazin-4-yl) ethyl] acetamide

{5-[(E)-(hydroxyimino) methyl] -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept -3-yl] amino} acetic acid (34.8 mg, 0.1 mmol), 1- (pyridazin-4-yl) ethanamine (18.5 mg, 0.15 mmol) in dichloromethane (2 mL), 1- (3-dimethylaminopropyl). ) -3-Ethylcarbodiimide hydrochloride (28.8 mg, 0.15 mmol), 1-hydroxybenzotriazole anhydride (1.35 mg, 0.01 mmol) and triethylamine (27.9 μL, 0.2 mmol) were added and stirred at room temperature for 24 hours. After completion of the reaction, chloroform was added, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (chloroform / methanol = 8/1 (v / v)) to obtain the desired product. (20.1 mg, 44% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 3.85 minutes
LC / MS (ESI ⁺ ) m / z; 454 [M + 1] ^{+
LC / MS (ESI -) m} / z; 452 [M-1] -

［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］酢酸(75 mg, 0.224 mmol)、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩 (65 mg, 0.339 mmol)、１−ヒドロキシベンゾトリアゾール 無水物 (3.0 mg, 0.0222 mmol）、トリエチルアミン (62 μL, 0.445 mmol) のＮ，Ｎ−ジメチルホルムアミド溶液 (2.0 mL) に１−（ピリダジン−４−イル）エタンアミン (36 mg, 0.292 mmol) を加え室温で96時間攪拌した。反応終了後、酢酸エチルを加え、飽和塩化アンモニウム水溶液で洗浄、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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＝９／１（ｖ／ｖ））で精製し目的物を得た。(15mg, 15%収率)

形状：無色無定形物
LC/MS：条件７ 保持時間3.97分
LC/MS(ESI⁺) m/z; 439 [M+1]⁺
LC/MS(ESI^-) m/z; 437 [M-1]^-
1H-NMR(CDCl₃)
δ: 1.01 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.54 (d, J = 7.5 Hz, 3H), 1.76-1.84 (m, 1H), 1.90-1.97 (m, 1H), 2.02-2.10 (m, 2H), 2.44-2.53 (m, 1H), 2.58-2.68 (m, 1H), 3.92-4.03 (m, 1H), 4.74 (s, 2H), 5.02-5.13 (m, 1H), 7.05 (br d, J = 7.5 Hz, 1H), 7.41 (dd, J = 5.7, 2.1 Hz, 1H), 7.75 (s, 1H), 9.09-9.16 (m, 2H), 10.18 (br d, J = 8.4 Hz, 1H), 10.25 (s, 1H). Synthesis example 5
2- [5-Formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine -1 (6H) -yl] -N- [1- (pyridazin-4-yl) ethyl] acetamide

[5-Formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine-1 (6H) -yl] acetic acid (75 mg, 0.224 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (65 mg, 0.339 mmol), 1-hydroxybenzotriazole anhydride (3.0 mg, 0.0222 mmol) and triethylamine (62 μL, 0.445 mmol) in N, N-dimethylformamide (2.0 mL) were added 1- (pyridazin-4-yl) ethanamine (36 mg, 0.292 mmol) and stirred at room temperature for 96 hours. . After completion of the reaction, ethyl acetate was added, washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (chloroform / methanol = 9/1 (v / v)) to obtain the desired product. (15mg, 15% yield)

Shape: colorless amorphous
LC / MS: Condition 7 Retention time 3.97 minutes
LC / MS (ESI ⁺ ) m / z; 439 [M + 1] ^{+
LC / MS (ESI -) m} / z; 437 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 1.01 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.54 (d, J = 7.5 Hz, 3H ), 1.76-1.84 (m, 1H), 1.90-1.97 (m, 1H), 2.02-2.10 (m, 2H), 2.44-2.53 (m, 1H), 2.58-2.68 (m, 1H), 3.92-4.03 (m, 1H), 4.74 (s, 2H), 5.02-5.13 (m, 1H), 7.05 (br d, J = 7.5 Hz, 1H), 7.41 (dd, J = 5.7, 2.1 Hz, 1H), 7.75 (s, 1H), 9.09-9.16 (m, 2H), 10.18 (br d, J = 8.4 Hz, 1H), 10.25 (s, 1H).

２−[５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル]−Ｎ−[１−（ピリダジン−４−イル）エチル]アセトアミド (13 mg, 0.0295 mmol) のメタノール溶液(1 mL)に0℃で水素化ホウ素ナトリウム (1.5 mg, 0.0431 mmol) を加え室温で40分間攪拌した。反応終了後、水を加え、酢酸エチルで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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＝９／１（ｖ／ｖ））で精製し目的物を得た。(8mg, 62%収率)

形状：無色固体
LC/MS：条件７ 保持時間3.75分
LC/MS(ESI⁺) m/z; 441 [M+1]⁺
LC/MS(ESI^-) m/z; 439 [M-1]^-
1H-NMR(CDCl₃)
δ: 0.95 (d, J = 10.2 Hz, 1H), 1.03 (s, 3H), 1.15 (d, J = 7.5 Hz, 3H), 1.25 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H), 1.65-2.05 (m, 4H), 2.38-2.63 (m, 2H), 3.50 (br s, 1H), 3.68-3.78 (m, 1H), 4.65 (d, J = 14.4 Hz, 2H), 4.80-4.90 (m, 2H), 5.00-5.12 (m, 1H), 5.70 (br d, J = 8.1 Hz, 1H), 7.39 (dd, J = 5.4, 2.7 Hz, 1H), 7.65 (s, 1H), 7.72 (br s, 1H), 9.44 (d, J = 5.4 Hz, 1H), 9.10-9.16 (m, 1H). Synthesis Example 6
2- [5- (hydroxymethyl) -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] Amino} pyridazin-1 (6H) -yl] -N- [1- (pyridazin-4-yl) ethyl] acetamide

2- [5-Formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine -1 (6H) -yl] -N- [1- (pyridazin-4-yl) ethyl] acetamide (13 mg, 0.0295 mmol) in methanol (1 mL) at 0 ° C. sodium borohydride (1.5 mg, 0.0431 mmol) was added and stirred at room temperature for 40 minutes. After completion of the reaction, water was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (chloroform / methanol = 9/1 (v / v)) to obtain the desired product. (8mg, 62% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 3.75 minutes
LC / MS (ESI ⁺ ) m / z; 441 [M + 1] ^{+
LC / MS (ESI -) m} / z; 439 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 0.95 (d, J = 10.2 Hz, 1H), 1.03 (s, 3H), 1.15 (d, J = 7.5 Hz, 3H), 1.25 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H ), 1.65-2.05 (m, 4H), 2.38-2.63 (m, 2H), 3.50 (br s, 1H), 3.68-3.78 (m, 1H), 4.65 (d, J = 14.4 Hz, 2H), 4.80 -4.90 (m, 2H), 5.00-5.12 (m, 1H), 5.70 (br d, J = 8.1 Hz, 1H), 7.39 (dd, J = 5.4, 2.7 Hz, 1H), 7.65 (s, 1H) , 7.72 (br s, 1H), 9.44 (d, J = 5.4 Hz, 1H), 9.10-9.16 (m, 1H).

エチル ［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］アセテート (400 mg, 1.11 mmol) のジクロロメタン溶液 (16 mL) に2Mトリメチルアルミニウム−トルエン溶液 (2.8 mL, 5.60 mmol) を加え、20時間還流した。放冷後、エタノールを加え減圧留去し、水とエタノールを加え、セライトろ過し、得られたろ液を酢酸エチルで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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＝２／１→１／１（ｖ／ｖ））で精製し目的物を得た。(134mg, 32%収率)

形状：無色油状物
LC/MS：条件７ 保持時間4.52分
LC/MS(ESI⁺) m/z; 378 [M+1]⁺
LC/MS(ESI^-) m/z; 376 [M-1]^- Synthesis example 7
Ethyl [5- (1-hydroxyethyl) -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl Amino} pyridazin-1 (6H) -yl] acetate

Ethyl [5-formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine- To a dichloromethane solution (16 mL) of 1 (6H) -yl] acetate (400 mg, 1.11 mmol) was added 2M trimethylaluminum-toluene solution (2.8 mL, 5.60 mmol), and the mixture was refluxed for 20 hours. After allowing to cool, ethanol was added and evaporated under reduced pressure. Water and ethanol were added and filtered through Celite, and the resulting filtrate was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 → 1/1 (v / v)) to obtain the desired product. (134 mg, 32% yield)

Shape: colorless oil
LC / MS: Condition 7 Retention time 4.52 minutes
LC / MS (ESI ⁺ ) m / z; 378 [M + 1] ^{+
LC / MS (ESI -) m} / z; 376 [M-1] -

[５−（１−ヒドロキシエチル）−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル]酢酸エチル (130 mg, 0.344 mmol) と二酸化マンガン (350 mg, 3.42 mmol) のクロロホルム溶液 (6.0 mL) を12時間還流した。反応終了後、反応液をセライトろ過し、得られたろ液を減圧留去して得られた反応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＝７／３（ｖ／ｖ））で精製し目的物を得た。(75 mg, 58%収率)

形状：無色油状物
LC/MS：条件７ 保持時間4.87分
LC/MS(ESI⁺) m/z; 376 [M+1]⁺
LC/MS(ESI^-) m/z; 374 [M-1]^-
1H-NMR(CDCl₃)
δ: 1.02 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.74-1.83 (m, 1H), 1.88-1.95 (m, 1H), 2.00-2.14 (m, 2H), 2.42-2.52 (m, 1H), 2.56-2.67 (m, 1H), 2.67 (s, 3H), 3.88-4.00 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.78 (s, 2H), 7.68 (s, 1H), 10.95 (br d, J = 7.8 Hz, 1H). Synthesis Example 8
Ethyl [5-acetyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine- 1 (6H) -yl] acetate

[5- (1-hydroxyethyl) -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] Amino} pyridazin-1 (6H) -yl] ethyl acetate (130 mg, 0.344 mmol) and manganese dioxide (350 mg, 3.42 mmol) in chloroform (6.0 mL) were refluxed for 12 hours. After completion of the reaction, the reaction solution was filtered through Celite, the obtained filtrate was distilled off under reduced pressure, and the resulting reaction residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7/3 (v / v)). I got a thing. (75 mg, 58% yield)

Shape: colorless oil
LC / MS: Condition 7 Retention time 4.87 minutes
LC / MS (ESI ⁺ ) m / z; 376 [M + 1] ^{+
LC / MS (ESI -) m} / z; 374 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 1.02 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.16 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H ), 1.74-1.83 (m, 1H), 1.88-1.95 (m, 1H), 2.00-2.14 (m, 2H), 2.42-2.52 (m, 1H), 2.56-2.67 (m, 1H), 2.67 (s , 3H), 3.88-4.00 (m, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.78 (s, 2H), 7.68 (s, 1H), 10.95 (br d, J = 7.8 Hz, 1H ).

[５−アセチル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル]酢酸

エチル [５−アセチル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル]アセテート (70 mg, 0.187 mmol) の1, 4-ジオキサン溶液 (2.0 mL) に１M水酸化ナトリウム水溶液 (206 μL, 0.206 mmol) を加え、室温で2時間攪拌した。反応終了後、反応液を1M塩酸で中和し (pH 4)、酢酸エチルで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応粗物を次反応に用いた。

形状：無色無定形物
LC/MS：条件７ 保持時間4.38分
LC/MS(ESI⁺) m/z; 348 [M+1]⁺
LC/MS(ESI^-) m/z; 346 [M-1]^-

２−[５−アセチル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル]−Ｎ−[１−（ピリダジン−４−イル）エチル]アセトアミド

[５−アセチル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル]酢酸 (68 mg, 0.187 mmol)、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩 (54 mg, 0.282 mmol)、１−ヒドロキシベンゾトリアゾール 無水物 (3.0 mg, 0.0222 mmol）、トリエチルアミン (52 μL, 0.373 mmol) のジクロロメタン溶液 (2.0 mL) に１−（ピリダジン−４−イル）エタンアミン (51 mg, 0.414 mmol) を加え室温で6時間攪拌した。反応終了後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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＝９／１（ｖ／ｖ））で精製し目的物を得た。(67 mg, 79%収率)

形状：無色無定形物
LC/MS：条件７ 保持時間4.10分
LC/MS(ESI⁺) m/z; 453 [M+1]⁺
LC/MS(ESI^-) m/z; 451 [M-1]^-
1H-NMR(CDCl₃)
δ: 1.01 (d, J = 10.2 Hz, 1H), 1.04 (s, 3H), 1.15 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H), 1.72-1.81 (m,1 H), 1.90-1.97 (m, 1H), 2.00-2.12 (m, 2H), 2.42-2.54 (m, 1H), 2.57-2.68 (m, 1H), 2.69 (s, 3H), 3.90-4.00 (m, 1H), 4.69-4.78 (m, 2H), 5.02-5.12 (m, 1H), 6.90 (br d, J = 6.6 Hz, 1H), 7.39-7.45 (m, 1H), 7.73 (s, 1H), 9.11 (d, J = 5.1 Hz, 1H), 9.16 (s, 1H), 10.95 (br d, J= 8.4 Hz, 1H). Synthesis Example 9
2- [5-acetyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine -1 (6H) -yl] -N- [1- (pyridazin-4-yl) ethyl] acetamide

[5-acetyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine-1 (6H) -yl] acetic acid

Ethyl [5-acetyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine- To a 1,4-dioxane solution (2.0 mL) of 1 (6H) -yl] acetate (70 mg, 0.187 mmol) was added 1M aqueous sodium hydroxide solution (206 μL, 0.206 mmol), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was neutralized with 1M hydrochloric acid (pH 4), extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting reaction crude was used for the next reaction.

Shape: colorless amorphous
LC / MS: Condition 7 Retention time 4.38 minutes
LC / MS (ESI ⁺ ) m / z; 348 [M + 1] ^{+
LC / MS (ESI -) m} / z; 346 [M-1] -

2- [5-acetyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine -1 (6H) -yl] -N- [1- (pyridazin-4-yl) ethyl] acetamide

[5-acetyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine-1 (6H) -yl] acetic acid (68 mg, 0.187 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (54 mg, 0.282 mmol), 1-hydroxybenzotriazole anhydride (3.0 mg, 0.0222 mmol) and triethylamine (52 μL, 0.373 mmol) in dichloromethane solution (2.0 mL) were added 1- (pyridazin-4-yl) ethanamine (51 mg, 0.414 mmol) and stirred at room temperature for 6 hours. After completion of the reaction, saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (chloroform / methanol = 9/1 (v / v)) to obtain the desired product. (67 mg, 79% yield)

Shape: colorless amorphous
LC / MS: Condition 7 Retention time 4.10 minutes
LC / MS (ESI ⁺ ) m / z; 453 [M + 1] ^{+
LC / MS (ESI -) m} / z; 451 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 1.01 (d, J = 10.2 Hz, 1H), 1.04 (s, 3H), 1.15 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.54 (d, J = 6.9 Hz, 3H ), 1.72-1.81 (m, 1 H), 1.90-1.97 (m, 1H), 2.00-2.12 (m, 2H), 2.42-2.54 (m, 1H), 2.57-2.68 (m, 1H), 2.69 ( s, 3H), 3.90-4.00 (m, 1H), 4.69-4.78 (m, 2H), 5.02-5.12 (m, 1H), 6.90 (br d, J = 6.6 Hz, 1H), 7.39-7.45 (m , 1H), 7.73 (s, 1H), 9.11 (d, J = 5.1 Hz, 1H), 9.16 (s, 1H), 10.95 (br d, J = 8.4 Hz, 1H).

２−[５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル]−Ｎ−[１−（ピリダジン−４−イル）エチル]アセトアミド (31 mg, 0.0707 mmol) のジクロロメタン (2.0 mL) 溶液にメトキシルアミン 塩酸塩 (6.0 mg, 0.0718 mmol) を加え、室温で15時間攪拌した。反応終了後、水を加え、酢酸エチルで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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＝１５／１（ｖ／ｖ））で精製し目的物を得た。(23 mg, 70%収率)

形状：無色無定形物
LC/MS：条件７ 保持時間4.27分
LC/MS(ESI⁺) m/z; 468 [M+1]⁺
LC/MS(ESI^-) m/z; 466 [M-1]^-
1H-NMR(CDCl₃)
δ: 0.97 (d, J = 9.9 Hz, 1H), 1.05 (s, 3H), 1.20 (dd, J = 7.1, 2.0 Hz, 3H), 1.28 (s, 3H), 1.50 (d, J = 6.9 Hz, 3H), 1.74-1.82 (m, 1H), 1.91-2.08 (m,3 H), 2.42-2.54 (m, 1H), 2.60-2.71 (m, 1H), 3.90-3.96 (m, 4H), 4.76 (q, J = 13.8 Hz, 2H), 4.99-5.08 (m, 1H), 7.38 (dd, J = 5.4, 2.4 Hz, 1H), 7.73 (s, 1H), 8.65 (s, 1H), 8.69 (br d, J = 7.5 Hz, 1H), 9.08-9.13 (m, 2H). Synthesis Example 10
2- {5-[(E)-(methoxyimino) methyl] -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] Hept-3-yl] amino} pyridazin-1 (6H) -yl} -N- [1- (pyridazin-4-yl) ethyl] acetamide

2- [5-Formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine -1 (6H) -yl] -N- [1- (pyridazin-4-yl) ethyl] acetamide (31 mg, 0.0707 mmol) in dichloromethane (2.0 mL) solution in methoxylamine hydrochloride (6.0 mg, 0.0718 mmol) And stirred at room temperature for 15 hours. After completion of the reaction, water was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (chloroform / methanol = 15/1 (v / v)) to obtain the desired product. (23 mg, 70% yield)

Shape: colorless amorphous
LC / MS: Condition 7 Retention time 4.27 minutes
LC / MS (ESI ⁺ ) m / z; 468 [M + 1] ^{+
LC / MS (ESI -) m} / z; 466 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 0.97 (d, J = 9.9 Hz, 1H), 1.05 (s, 3H), 1.20 (dd, J = 7.1, 2.0 Hz, 3H), 1.28 (s, 3H), 1.50 (d, J = 6.9 Hz , 3H), 1.74-1.82 (m, 1H), 1.91-2.08 (m, 3 H), 2.42-2.54 (m, 1H), 2.60-2.71 (m, 1H), 3.90-3.96 (m, 4H), 4.76 (q, J = 13.8 Hz, 2H), 4.99-5.08 (m, 1H), 7.38 (dd, J = 5.4, 2.4 Hz, 1H), 7.73 (s, 1H), 8.65 (s, 1H), 8.69 (br d, J = 7.5 Hz, 1H), 9.08-9.13 (m, 2H).

２−[５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル]−Ｎ−[１−（ピリダジン−４−イル）エチル]アセトアミド (14 mg, 0.0319 mmol) の１，２−ジクロロエタン (1.0 mL) 溶液にシアナミド (8.1 mg, 0.193 mmol) とモレキュラーシーブスを加え、10時間還流した。反応終了後、水を加え、酢酸エチルで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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＝１０／１（ｖ／ｖ））で精製し目的物を得た。(1.5 mg, 10%収率)

形状：淡黄色油状物
LC/MS：条件７ 保持時間4.05分
LC/MS(ESI⁺) m/z; 463 [M+1]⁺
LC/MS(ESI^-) m/z; 461 [M-1]^-
1H-NMR(CDCl₃)
δ: 0.98 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J = 7.5 Hz, 3H), 1.28 (s, 3H), 1.52-1.60 (m, 3H), 1.76-1.84 (m,1 H), 1.92-1.99 (m, 1H), 2.00-2.12 (m, 2H), 2.46-2.57 (m, 1H), 2.60-2.72 (m, 1H), 3.98-4.10 (m, 1H), 4.74 (s, 2H), 5.01-5.14 (m, 1H), 6.74 (br d, J = 7.5 Hz, 0.75H), 6.95 (m, 0.25H), 7.40 (dd, J= 5.4, 2.4 Hz, 1H), 7.75 (s, 1H), 9.10-9.16 (m, 2H), 9.35 (s, 1H), 9.95 (br d, J = 8.4 Hz, 0.75H), 10.19 (m, 0.25H). Synthesis Example 11
2- {5-[(E / Z)-(cyanoimino) methyl] -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1 ] Hept-3-yl] amino} pyridazin-1 (6H) -yl} -N- [1- (pyridazin-4-yl) ethyl] acetamide

2- [5-Formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine -1 (6H) -yl] -N- [1- (pyridazin-4-yl) ethyl] acetamide (14 mg, 0.0319 mmol) in 1,2-dichloroethane (1.0 mL) in a solution of cyanamide (8.1 mg, 0.193 mmol) ) And molecular sieves were added and refluxed for 10 hours. After completion of the reaction, water was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (chloroform / methanol = 10/1 (v / v)) to obtain the desired product. (1.5 mg, 10% yield)

Shape: pale yellow oil
LC / MS: Condition 7 Retention time 4.05 minutes
LC / MS (ESI ⁺ ) m / z; 463 [M + 1] ^{+
LC / MS (ESI -) m} / z; 461 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 0.98 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J = 7.5 Hz, 3H), 1.28 (s, 3H), 1.52-1.60 (m, 3H), 1.76 -1.84 (m, 1 H), 1.92-1.99 (m, 1H), 2.00-2.12 (m, 2H), 2.46-2.57 (m, 1H), 2.60-2.72 (m, 1H), 3.98-4.10 (m , 1H), 4.74 (s, 2H), 5.01-5.14 (m, 1H), 6.74 (br d, J = 7.5 Hz, 0.75H), 6.95 (m, 0.25H), 7.40 (dd, J = 5.4, 2.4 Hz, 1H), 7.75 (s, 1H), 9.10-9.16 (m, 2H), 9.35 (s, 1H), 9.95 (br d, J = 8.4 Hz, 0.75H), 10.19 (m, 0.25H) .

２−（２−エトキシ−２−オキソエチル）−３−オキソ−５−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝−２，３−ジヒドロピリダジン−４−カルボン酸

エチル ［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］アセテート (100 mg, 0.276 mmol) とスルファミン酸 (38 mg, 0.391 mmol) の酢酸溶液 (2.0 mL)に亜塩素酸ナトリウム (43 mg, 0.475 mmol) の水溶液 (0.3 mL) を加え、室温で12時間攪拌した。反応終了後、水 (約3 mL) を加え、析出物をろ取、減圧乾燥し目的物を得た。(72 mg, 69%収率)

形状：無色固体
LC/MS：条件７ 保持時間4.74分
LC/MS(ESI⁺) m/z; 378 [M+1]⁺
LC/MS(ESI^-) m/z; 376 [M-1]^-

エチル［５−（ジメチルカルバモイル）−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル］アセテート

２−（２−エトキシ−２−オキソエチル）−３−オキソ−５−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝−２，３−ジヒドロピリダジン−４−カルボン酸 (14 mg, 0.0371 mmol) の１，２−ジクロロエタン溶液 (1.5 mL) に塩化オキサリル (10 μL, 0.115 mmol) とＮ，Ｎ−ジメチルホルムアミド (1 μL) を加え、１時間還流した。反応液を減圧濃縮し、ジクロロメタン(1.0 mL)、トリエチルアミン (16 μL, 0.115 mmol) とジメチルアミン 塩酸塩 (3.6 mg, 0.0442 mmol) を加え、室温で4時間攪拌した。反応終了後、水を加え、酢酸エチルで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応粗物を次反応に用いた。

形状：無色油形物
LC/MS：条件７ 保持時間4.18分
LC/MS(ESI⁺) m/z; 405 [M+1]⁺
LC/MS(ESI^-) m/z; 403 [M-1]

［５−（ジメチルカルバモイル）−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル］酢酸

上記で得られたエチル［５−（ジメチルカルバモイル）−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル］アセテートの1, 4-ジオキサン溶液 (1.0 mL) に１M水酸化ナトリウム水溶液 (80 μL, 0.080 mmol) を加え、室温で9時間攪拌した。反応終了後、1M塩酸で中和し (pH 4)、酢酸エチルで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応粗物を次反応に用いた。

形状：無色油状物
LC/MS：条件７ 保持時間3.84分
LC/MS(ESI⁺) m/z; 377 [M+1]⁺
LC/MS(ESI^-) m/z; 375 [M-1]^-

Ｎ，Ｎ−ジメチル−３−オキソ−２−（２−オキソ−２−{［１−（ピリダジン−４−イル）エチル］アミノ}エチル）−５−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝｝−２，３−ジヒドロピリダジン−４−カルボキシアミド

上記で得られた［５−（ジメチルカルバモイル）−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル］酢酸のジクロロメタン溶液 (2.0 mL) に、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩 (11 mg, 0.057 mmol)、１−ヒドロキシベンゾトリアゾール 無水物 (1.5 mg, 0.0111 mmol）、トリエチルアミン (20 μL, 0.143 mmol)、１−（ピリダジン−４−イル）エタンアミン (6.8 mg, 0.0553 mmol) を加え室温で16時間攪拌した。反応終了後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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＝９／１（ｖ／ｖ））で精製し目的物を得た。(11 mg, 62%収率、3工程)

形状：無色無定形物
LC/MS：条件７ 保持時間3.67分
LC/MS(ESI⁺) m/z; 482 [M+1]⁺
LC/MS(ESI^-) m/z; 480 [M-1]^-
1H-NMR(CDCl₃)
δ: 0.95 (d, J = 9.9 Hz, 1H), 1.04 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H), 1.25 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H), 1.62-1.75 (m, 1H), 1.85-2.05 (m, 3H), 2.38-2.48 (m, 1H), 2.54-2.64 (m, 1H), 2.93 (s, 3H), 3.09 (s, 3H), 3.78-3.91 (m, 1H), 4.69-4.82 (m, 2H), 4.99-5.09 (m, 1H), 6.41 (br d, J = 7.5 Hz, 1H), 7.35-7.42 (m, 2H), 7.68 (s, 1H), 9.08 (d, J = 5.4 Hz, 1H), 9.14 (d, J = 1.5 Hz, 1H). Synthesis Example 12
N, N-dimethyl-3-oxo-2- (2-oxo-2-{[1- (pyridazin-4-yl) ethyl] amino} ethyl) -5-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} -2,3-dihydropyridazine-4-carboxamide

2- (2-Ethoxy-2-oxoethyl) -3-oxo-5-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3- Yl] amino} -2,3-dihydropyridazine-4-carboxylic acid

Ethyl [5-formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine- 1 (6H) -yl] acetate (100 mg, 0.276 mmol) and sulfamic acid (38 mg, 0.391 mmol) in acetic acid (2.0 mL) in aqueous solution of sodium chlorite (43 mg, 0.475 mmol) (0.3 mL) And stirred at room temperature for 12 hours. After completion of the reaction, water (about 3 mL) was added, and the precipitate was collected by filtration and dried under reduced pressure to obtain the desired product. (72 mg, 69% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 4.74 minutes
LC / MS (ESI ⁺ ) m / z; 378 [M + 1] ^{+
LC / MS (ESI -) m} / z; 376 [M-1] -

Ethyl [5- (dimethylcarbamoyl) -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino } Pyridazine-1 (6H) -yl] acetate

2- (2-Ethoxy-2-oxoethyl) -3-oxo-5-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3- Yl] amino} -2,3-dihydropyridazine-4-carboxylic acid (14 mg, 0.0371 mmol) in 1,2-dichloroethane solution (1.5 mL) and oxalyl chloride (10 μL, 0.115 mmol) and N, N-dimethyl. Formamide (1 μL) was added and refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure, dichloromethane (1.0 mL), triethylamine (16 μL, 0.115 mmol) and dimethylamine hydrochloride (3.6 mg, 0.0442 mmol) were added, and the mixture was stirred at room temperature for 4 hr. After completion of the reaction, water was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting reaction crude was used for the next reaction.

Shape: colorless oil form
LC / MS: Condition 7 Retention time 4.18 minutes
LC / MS (ESI ⁺ ) m / z; 405 [M + 1] ^{+
LC / MS (ESI -) m} / z; 403 [M-1]

[5- (Dimethylcarbamoyl) -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} Pyridazine-1 (6H) -yl] acetic acid

Ethyl [5- (dimethylcarbamoyl) -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-] obtained above To a 1,4-dioxane solution (1.0 mL) of 3-yl] amino} pyridazin-1 (6H) -yl] acetate was added 1M aqueous sodium hydroxide solution (80 μL, 0.080 mmol), and the mixture was stirred at room temperature for 9 hours. After completion of the reaction, the mixture was neutralized with 1M hydrochloric acid (pH 4), extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The resulting reaction crude was used for the next reaction.

Shape: colorless oil
LC / MS: Condition 7 Retention time 3.84 minutes
LC / MS (ESI ⁺ ) m / z; 377 [M + 1] ^{+
LC / MS (ESI -) m} / z; 375 [M-1] -

N, N-dimethyl-3-oxo-2- (2-oxo-2-{[1- (pyridazin-4-yl) ethyl] amino} ethyl) -5-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino}}-2,3-dihydropyridazine-4-carboxamide

[5- (Dimethylcarbamoyl) -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3 obtained above. -Il] amino} pyridazin-1 (6H) -yl] acetic acid in dichloromethane (2.0 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11 mg, 0.057 mmol), 1- Hydroxybenzotriazole anhydride (1.5 mg, 0.0111 mmol), triethylamine (20 μL, 0.143 mmol) and 1- (pyridazin-4-yl) ethanamine (6.8 mg, 0.0553 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (chloroform / methanol = 9/1 (v / v)) to obtain the desired product. (11 mg, 62% yield, 3 steps)

Shape: colorless amorphous
LC / MS: Condition 7 Retention time 3.67 minutes
LC / MS (ESI ⁺ ) m / z; 482 [M + 1] ^{+
LC / MS (ESI -) m} / z; 480 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 0.95 (d, J = 9.9 Hz, 1H), 1.04 (s, 3H), 1.15 (d, J = 6.9 Hz, 3H), 1.25 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H ), 1.62-1.75 (m, 1H), 1.85-2.05 (m, 3H), 2.38-2.48 (m, 1H), 2.54-2.64 (m, 1H), 2.93 (s, 3H), 3.09 (s, 3H ), 3.78-3.91 (m, 1H), 4.69-4.82 (m, 2H), 4.99-5.09 (m, 1H), 6.41 (br d, J = 7.5 Hz, 1H), 7.35-7.42 (m, 2H) , 7.68 (s, 1H), 9.08 (d, J = 5.4 Hz, 1H), 9.14 (d, J = 1.5 Hz, 1H).

［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］酢酸（80 mg, 0.24 mmol）のジクロロメタン溶液 (0.8 mL) に、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩 (92 mg, 0.48 mmol)、１−ヒドロキシベンゾトリアゾール 無水物 (3 mg, 0.024 mmol）、トリエチルアミン (100 μL, 0.72 mmol)、イソプロピルアミン（51 μL, 0.60 mmol）を加え室温で16時間攪拌した。反応終了後、飽和食塩水を加え、ジクロロメタンで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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＝２／１→１／２（ｖ／ｖ））で精製し目的物を得た。(60 mg, 60%収率)

形状：無色固体
LC/MS：条件７ 保持時間3.74分
LC/MS(ESI⁺) m/z; 416 [M+1]⁺
LC/MS(ESI^-) m/z; 414 [M-1]^- Synthesis Example 13
2- {6-oxo-5-[(E)-(propan-2-ylimino) methyl] -4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1 .1] Hept-3-yl] amino} pyridazin-1 (6H) -yl} -N- (propan-2-yl) acetamide

[5-Formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine-1 (6H) -yl] acetic acid (80 mg, 0.24 mmol) in dichloromethane (0.8 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol), 1-hydroxy. Benzotriazole anhydride (3 mg, 0.024 mmol), triethylamine (100 μL, 0.72 mmol) and isopropylamine (51 μL, 0.60 mmol) were added and stirred at room temperature for 16 hours. After completion of the reaction, saturated brine was added, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 → 1/2 (v / v)) to obtain the desired product. (60 mg, 60% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 3.74 minutes
LC / MS (ESI ⁺ ) m / z; 416 [M + 1] ^{+
LC / MS (ESI -) m} / z; 414 [M-1] -

イソプロピルアミンの代わりにベンジルアミン（66 μL, 0.60 mmol）を用い、合成例１３と同様にして合成した。（74%収率）
形状：無色無定形物
LC/MS：条件７ 保持時間4.57分
LC/MS(ESI⁺) m/z; 512 [M+1]⁺ Synthesis Example 14
N-benzyl-2- {5-[(E)-(benzylimino) methyl] -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3. 1.1] Hept-3-yl] amino} pyridazin-1 (6H) -yl} acetamide

Synthesis was performed in the same manner as in Synthesis Example 13 using benzylamine (66 μL, 0.60 mmol) instead of isopropylamine. (74% yield)
Shape: colorless amorphous
LC / MS: Condition 7 Retention time 4.57 minutes
LC / MS (ESI ⁺ ) m / z; 512 [M + 1] ⁺

［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］酢酸（80 mg, 0.24 mmol）のジクロロメタン溶液 (0.8 mL) に、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩 (92 mg, 0.48 mmol)、１−ヒドロキシベンゾトリアゾール 無水物 (3 mg, 0.024 mmol）、トリエチルアミン (100 μL, 0.72 mmol)、モルホリン（52 μL, 0.60 mmol）を加え室温で16時間攪拌した。反応終了後、飽和食塩水を加え、ジクロロメタンで抽出、無水硫酸マグネシウムで乾燥、減圧留去した。得られた反応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＝２／１→１／２（ｖ／ｖ））で精製し目的物を得た。（65 mg, 67%収率）

形状：無色無定形物
LC/MS：条件７ 保持時間4.17分
LC/MS(ESI⁺) m/z; 403 [M+1]⁺
LC/MS(ESI^-) m/z; 401 [M-1]^- Synthesis Example 15
2- [2- (morpholino-4-yl) -2-oxoethyl] -3-oxo-5-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1 ] Heptan-3-yl] amino} -2,3-dihydropyridazine-4-carbaldehyde

[5-Formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine-1 (6H) -yl] acetic acid (80 mg, 0.24 mmol) in dichloromethane (0.8 mL) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol), 1-hydroxy. Benzotriazole anhydride (3 mg, 0.024 mmol), triethylamine (100 μL, 0.72 mmol) and morpholine (52 μL, 0.60 mmol) were added and stirred at room temperature for 16 hours. After completion of the reaction, saturated brine was added, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 → 1/2 (v / v)) to obtain the desired product. (65 mg, 67% yield)

Shape: colorless amorphous
LC / MS: Condition 7 Retention time 4.17 minutes
LC / MS (ESI ⁺ ) m / z; 403 [M + 1] ^{+
LC / MS (ESI -) m} / z; 401 [M-1] -

２−［２−（モルホリノ−４−イル）−２−オキソエチル］−３−オキソ−５−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２，６，６−トリメチルビシクロ[３．１．１]ヘプタン−３−イル］アミノ｝−２，３−ジヒドロピリダジン−４−カルボアルデヒドを用い、合成例３と同様にして合成した。（67%収率）

形状：無色無定形物
LC/MS：条件７ 保持時間4.02分
LC/MS(ESI⁺) m/z; 418 [M+1]⁺
LC/MS(ESI^-) m/z; 416 [M-1]^- Synthesis Example 16
4-[(E)-(hydroxyimino) methyl] -2- [2- (morpholino-4-yl) 2-oxoethyl] -5-{[(1R, 2R, 3R, 5S) -2,6,6 -Trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazin-3 (2H) -one

2- [2- (morpholino-4-yl) -2-oxoethyl] -3-oxo-5-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1 [Heptane-3-yl] amino} -2,3-dihydropyridazine-4-carbaldehyde was synthesized in the same manner as in Synthesis Example 3. (67% yield)

Shape: colorless amorphous
LC / MS: Condition 7 Retention time 4.02 minutes
LC / MS (ESI ⁺ ) m / z; 418 [M + 1] ^{+
LC / MS (ESI -) m} / z; 416 [M-1] -

２−[５−アセチル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２，６，６−トリメチルビシクロ［３．１．１］ヘプト−３−イル］アミノ｝ピリダジン−１（６Ｈ）−イル]−Ｎ−[１−（ピリダジン−４−イル）エチル]アセトアミド (9 mg, 0.0199 mmol) のエタノール溶液(1.0 mL)にヒドロキシルアミン 塩酸塩 (5.0 mg, 0.0720 mmol) を加え、モレキュラーシーブス存在下90℃で4時間攪拌した。反応終了後、溶媒を減圧留去し、得られた反応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＝１０／１（ｖ／ｖ））で精製し目的物を得た。(2 mg, 21%収率)

形状：無色油状物
LC/MS：条件７ 保持時間3.87分
LC/MS(ESI⁺) m/z; 468 [M+1]⁺
LC/MS(ESI^-) m/z; 466 [M-1]^-
1H-NMR(CDCl₃)
δ: 0.81-0.88 (m, 1H), 1.06 (s, 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.18 (s, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.50-1.62 (m, 1H), 1.78-1.87 (m, 2H), 1.92-1.98 (m, 1H), 2.30 (s, 3H), 2.31-2.40 (m, 1H), 2.48-2.59 (m, 1H), 3.70-3.82 (m, 1H), 4.69 (m, 2H), 4.95-5.04 (m, 1H), 7.32-7.38 (m, 2H), 7.63 (s, 1H), 7.93 (br s, 1H), 8.08 (br d, J = 8.1 Hz, 1H), 9.09 (d, J = 5.1 Hz, 1H), 9.05 (s, 1H). Synthesis Example 17
2- {5-[(1E) -N-hydroxyethaneimidoyl] -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1 ] Hept-3-yl] amino} pyridazin-1 (6H) -yl} -N- [1- (pyridazin-4-yl) ethyl] acetamide

2- [5-acetyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} pyridazine- Hydroxylamine hydrochloride (5.0 mg, 0.0720 mmol) was added to an ethanol solution (1.0 mL) of 1 (6H) -yl] -N- [1- (pyridazin-4-yl) ethyl] acetamide (9 mg, 0.0199 mmol). In addition, the mixture was stirred at 90 ° C. for 4 hours in the presence of molecular sieves. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting reaction residue was purified by silica gel column chromatography (chloroform / methanol = 10/1 (v / v)) to obtain the desired product. (2 mg, 21% yield)

Shape: colorless oil
LC / MS: Condition 7 Retention time 3.87 minutes
LC / MS (ESI ⁺ ) m / z; 468 [M + 1] ^{+
LC / MS (ESI -) m} / z; 466 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 0.81-0.88 (m, 1H), 1.06 (s, 3H), 1.07 (d, J = 6.9 Hz, 3H), 1.18 (s, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.50 -1.62 (m, 1H), 1.78-1.87 (m, 2H), 1.92-1.98 (m, 1H), 2.30 (s, 3H), 2.31-2.40 (m, 1H), 2.48-2.59 (m, 1H) , 3.70-3.82 (m, 1H), 4.69 (m, 2H), 4.95-5.04 (m, 1H), 7.32-7.38 (m, 2H), 7.63 (s, 1H), 7.93 (br s, 1H), 8.08 (br d, J = 8.1 Hz, 1H), 9.09 (d, J = 5.1 Hz, 1H), 9.05 (s, 1H).

水素化ナトリウム（鉱油中６３重量%分散物, 380.9 mg, 10 mmol）のテトラヒドロフラン溶液(15 mL）を0℃に冷却し、トリメチルホスホノアセテート（1.434 mL, 10 mmol）のテトラヒドロフラン溶液（5mL）をゆっくり加えた。0℃で10分間撹拌し、ｔ−ブチル ［５−ホルミル−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］アセテート（390 mg, 1 mmol）を室温でゆっくり加え、1分間撹拌した。反応終了後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出、有機層を無水硫酸ナトリウムで乾燥、減圧留去した。得られた反応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＝４／１（ｖ／ｖ））で精製した。得られた無色固体の酢酸エチル溶液（10 mL）に、5% パラジウム−炭素（50 mg）を加え、水素（1気圧）雰囲気下、室温で16時間攪拌した。反応終了後、反応液をセライトろ過し、得られたろ液を減圧留去して得られた反応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＝２／１（ｖ／ｖ））で精製し、目的物を得た。(337 mg, 75%収率, ２段階）

形状：無色無定形物
LC/MS：条件７ 保持時間4.99分
LC/MS(ESI⁺) m/z; 448 [M+1]⁺
LC/MS(ESI^-) m/z; 446 [M-1]^-
1H-NMR(CDCl₃)
δ: 1.04 (s, 3H), 1.05 (d, J = 10.2 Hz, 1H), 1.16 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.48 (s, 9H), 1.72-1.83 (m, 1H), 1.88-1.95 (m, 1H), 1.95-2.05 (m, 2H), 2.39-2.49 (m, 1H), 2.50-2.63 (m, 1H), 2.63-2.70 (m, 2H), 2.70-2.80 (m, 2H), 3.65 (s, 3H), 3.67-3.80 (m, 1H), 4.72 (dd, J = 16.5Hz, 22.5 Hz, 2H), 5.53 (br d, J = 7.8 Hz, 1H), 7.58 (s, 1H). Synthesis Example 18
Methyl 3- [2- (2-t-butoxy-2-oxoethyl) -3-oxo-5-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1 ] Hept-3-yl] amino} -2,3-dihydropyridazin-4-yl] propionate

A tetrahydrofuran solution (15 mL) of sodium hydride (63 wt% dispersion in mineral oil, 380.9 mg, 10 mmol) was cooled to 0 ° C., and a tetrahydrofuran solution (5 mL) of trimethylphosphonoacetate (1.434 mL, 10 mmol) was added. Slowly added. Stir at 0 ° C. for 10 minutes and turn to t-butyl [5-formyl-6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1]. [Pept-3-yl] amino} pyridazin-1 (6H) -yl] acetate (390 mg, 1 mmol) was slowly added at room temperature and stirred for 1 minute. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 (v / v)). To the obtained colorless solid ethyl acetate solution (10 mL), 5% palladium-carbon (50 mg) was added, and the mixture was stirred at room temperature for 16 hours in an atmosphere of hydrogen (1 atm). After completion of the reaction, the reaction solution was filtered through Celite, and the obtained filtrate was distilled off under reduced pressure. The resulting reaction residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 (v / v)), The desired product was obtained. (337 mg, 75% yield, 2 steps)

Shape: colorless amorphous
LC / MS: Condition 7 Retention time 4.99 minutes
LC / MS (ESI ⁺ ) m / z; 448 [M + 1] ^{+
LC / MS (ESI -) m} / z; 446 [M-1] -
¹ H-NMR (CDCl ₃ )
δ: 1.04 (s, 3H), 1.05 (d, J = 10.2 Hz, 1H), 1.16 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.48 (s, 9H), 1.72-1.83 (m, 1H), 1.88-1.95 (m, 1H), 1.95-2.05 (m, 2H), 2.39-2.49 (m, 1H), 2.50-2.63 (m, 1H), 2.63-2.70 (m, 2H) , 2.70-2.80 (m, 2H), 3.65 (s, 3H), 3.67-3.80 (m, 1H), 4.72 (dd, J = 16.5Hz, 22.5 Hz, 2H), 5.53 (br d, J = 7.8 Hz , 1H), 7.58 (s, 1H).

［５−（３−メトキシ−３−オキソプロピル）−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］酢酸

メチル ３−［２−（２−ｔ−ブトキシ−２−オキソエチル）−３−オキソ−５−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝−２,３−ジヒドロピリダジン−４−イル］プロピオネート(53.5 mg, 0.12 mmol)のトリフルオロ酢酸溶液（1 mL）を１時間還流した。反応終了後、濃縮し目的物を得た。（46.8 mg, 100%収率）

形状：無色無定形物
LC/MS：条件７ 保持時間4.27分
LC/MS(ESI⁺) m/z; 392 [M+1]⁺
LC/MS(ESI^-) m/z; 390 [M-1]^-

メチル ３−［３−オキソ−２−（２−オキソ−２−｛［１−（ピリダジン−４−イル）エチル］アミノ｝エチル）−５−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝−２,３−ジヒドロピリダジン−４−イル］プロピオネート

［５−（３−メトキシ−３−オキソプロピル）−６−オキソ−４−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝ピリダジン−１（６H）−イル］酢酸（46.8 mg, 0.12 mmol）、１−（ピリダジン−４−イル）エタンアミン（18.5 mg, 0.15 mmol）のジクロロメタン溶液（2 mL）に、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩（28.8 mg, 0.15 mmol）、１−ヒドロキシベンゾトリアゾール 無水物（1.35 mg, 0.01 mmol）、トリエチルアミン（27.9 μL, 0.2 mmol）を加え室温で24時間攪拌した。反応終了後、酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥、減圧留去した。得られた反応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＝２０／１（ｖ／ｖ））で精製し目的物を得た。（48.0 mg, 81%収率）

形状：無色無定形物
LC/MS：条件７ 保持時間4.09分
LC/MS(ESI⁺) m/z; 497 [M+1]⁺
LC/MS(ESI^-) m/z; 495 [M-1]^- Synthesis Example 19
Methyl 3- [3-oxo-2- (2-oxo-2-{[1- (pyridazin-4-yl) ethyl] amino} ethyl) -5-{[(1R, 2R, 3R, 5S) -2 , 6,6-Trimethylbicyclo [3.1.1] hept-3-yl] amino} -2,3-dihydropyridazin-4-yl] propionate

[5- (3-Methoxy-3-oxopropyl) -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept- 3-yl] amino} pyridazin-1 (6H) -yl] acetic acid

Methyl 3- [2- (2-t-butoxy-2-oxoethyl) -3-oxo-5-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1 ] Hept-3-yl] amino} -2,3-dihydropyridazin-4-yl] propionate (53.5 mg, 0.12 mmol) in trifluoroacetic acid (1 mL) was refluxed for 1 hour. After completion of the reaction, the product was concentrated to obtain the desired product. (46.8 mg, 100% yield)

Shape: colorless amorphous
LC / MS: Condition 7 Retention time 4.27 minutes
LC / MS (ESI ⁺ ) m / z; 392 [M + 1] ^{+
LC / MS (ESI -) m} / z; 390 [M-1] -

Methyl 3- [3-oxo-2- (2-oxo-2-{[1- (pyridazin-4-yl) ethyl] amino} ethyl) -5-{[(1R, 2R, 3R, 5S) -2 , 6,6-Trimethylbicyclo [3.1.1] hept-3-yl] amino} -2,3-dihydropyridazin-4-yl] propionate

[5- (3-Methoxy-3-oxopropyl) -6-oxo-4-{[(1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo [3.1.1] hept- To a dichloromethane solution (2 mL) of 3-yl] amino} pyridazin-1 (6H) -yl] acetic acid (46.8 mg, 0.12 mmol), 1- (pyridazin-4-yl) ethanamine (18.5 mg, 0.15 mmol), Add 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (28.8 mg, 0.15 mmol), 1-hydroxybenzotriazole anhydride (1.35 mg, 0.01 mmol), triethylamine (27.9 μL, 0.2 mmol) to room temperature For 24 hours. After completion of the reaction, ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography (chloroform / methanol = 20/1 (v / v)) to obtain the desired product. (48.0 mg, 81% yield)

Shape: colorless amorphous
LC / MS: Condition 7 Retention time 4.09 minutes
LC / MS (ESI ⁺ ) m / z; 497 [M + 1] ^{+
LC / MS (ESI -) m} / z; 495 [M-1] -

メチル ３−［３−オキソ−２−（２−オキソ−２−｛［１−（ピリダジン−４−イル）エチル］アミノ｝エチル）−５−｛［（１Ｒ，２Ｒ，３Ｒ，５Ｓ）−２,６,６−トリメチルビシクロ［３．１．１］へプト−３−イル］アミノ｝−２,３−ジヒドロピリダジン−４−イル］プロピオネート(27.0 mg, 0.054 mmol)のテトラヒドロフラン溶液（1 mL）に、1M水酸化ナトリウム水溶液（1 mL, 1 mmol）を加え、室温で60分間攪拌した。反応終了後、ジクロロメタンを加えて希釈したのち、1M塩酸で中和後、有機層を抽出し、無水硫酸ナトリウムで乾燥、減圧留去し、目的物を得た。（22.9 mg, 87％収率）

形状：無色固体
LC/MS：条件７ 保持時間3.82分
LC/MS(ESI⁺) m/z; 483 [M+1]⁺
LC/MS(ESI^-) m/z; 481 [M-1]^- Synthesis Example 20
3- [3-oxo-2- (2-oxo-2-{[1- (pyridazin-4-yl) ethyl] amino} ethyl) -5-{[(1R, 2R, 3R, 5S) -2, 6,6-trimethylbicyclo [3.1.1] hept-3-yl] amino} -2,3-dihydropyridazin-4-yl] propionic acid

Methyl 3- [3-oxo-2- (2-oxo-2-{[1- (pyridazin-4-yl) ethyl] amino} ethyl) -5-{[(1R, 2R, 3R, 5S) -2 , 6,6-Trimethylbicyclo [3.1.1] hept-3-yl] amino} -2,3-dihydropyridazin-4-yl] propionate (27.0 mg, 0.054 mmol) in tetrahydrofuran (1 mL) To the solution, 1M aqueous sodium hydroxide solution (1 mL, 1 mmol) was added, and the mixture was stirred at room temperature for 60 minutes. After completion of the reaction, the reaction mixture was diluted with dichloromethane and neutralized with 1M hydrochloric acid. The organic layer was extracted, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the desired product. (22.9 mg, 87% yield)

Shape: colorless solid
LC / MS: Condition 7 Retention time 3.82 minutes
LC / MS (ESI ⁺ ) m / z; 483 [M + 1] ^{+
LC / MS (ESI -) m} / z; 481 [M-1] -

Pharmacological analysis

Test Example 1: Dye assay
Primers were designed based on the human P2X7 (hP2X7) sequence registered in GENBANK, reverse transcription (using SuperScriptII kit (Invitrogen)) from normal human brain total RNA library, PCR (enzyme is KOD plus (Toyobo) HP2X7 was cloned by The deduced amino acid sequence is 595 amino acid residues. The DNA sequence was reinserted into pcDNA3.1 / myc-HisA vector (Invitrogen), and the nucleotide sequence was confirmed again.
HEK293 cells were transfected with hP2X7 / pcDNA3.1 / myc-HisA by the lipofection method. One day later, treatment with 1 mg / mL G418 was started, and replated as appropriate to select resistant cells. A clone was obtained by replating at low density by trypsin treatment. Each clone was subjected to a dye assay (see the next paragraph) and screened using one clone highly reactive to benzoylbenzoyladenosine triphosphate (BzATP), a ligand highly selective for the P2X7 receptor.
P2X7 receptor inhibitors were screened using a dye uptake assay with hP2X7 stably expressing HEK293. Cells were seeded at 20000 cells / well in collagen-coated black / clear 96-well plates. One day later, various test compounds were treated with various concentrations for 30 minutes, treated with dye (Yo-Pro-1) (final concentration 2 μM) and BzATP (final concentration 0.1 mM), and incubated for 90 minutes. Thereafter, the fluorescence of the cells (indicating Yo-Pro-1 uptake via BzATP-inducible P2X7 receptor) was measured with a fluorescence plate reader (excitation wavelength: 485 nm, fluorescence wavelength: 535 nm). The percent inhibition was calculated and the IC ₅₀ value determined by plotting against the logarithm of concentration. The results are shown in Table 2.

Table 2─────────────────────
Synthesis example IC ₅₀
Number (μM)
─────────────────────
4 0.0012
5 0.0029
6 0.17
9 0.0026
10 0.0057
11 0.013
12 0.32
13 0.17
14 0.56
15 0.25
17 0.0097
18 0.22
20 0.18
─────────────────────

Test Example 2: IL-1β assay Whole human blood collected from healthy volunteers was diluted 2-fold with physiological saline, and peripheral blood mononuclear cells were collected with a lymphoprep tube (Cosmo Bio). After washing with physiological saline, 10 ng / mL LPS (SIGMA) was added to the medium and seeded in a 96-well plate. After 30 minutes, various compounds were treated with various concentrations and incubated for 30 minutes. Thereafter, the cells were treated with BzATP (final concentration 1 mM) or ATP (final concentration 5 mM) and incubated for 120 minutes. The supernatant was collected from the cells by centrifugation, and IL-1β in the supernatant was measured using an HTRF kit (CIS bio international). The percent inhibition was calculated and the IC ₅₀ value determined by plotting against the logarithm of concentration. Table 3 shows the results.
Table 3 ─────────────────────
Synthesis example IC ₅₀
Number (μM)
─────────────────────
4 0.0032
5 0.013
─────────────────────

Formulation Example 1
A granule containing the following ingredients is produced.
Component Compound represented by formula (I) 10 mg
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
---------------------------
1000mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. Add low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution to the mixed powder, knead and granulate (extruded granulation pore size 0.5-1mm), then dry. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) to obtain granules.

Formulation Example 2
A powder for capsule filling containing the following components is produced.
Component Compound represented by formula (I) 10 mg
Lactose 79mg
Corn starch 10mg
Magnesium stearate 1mg
---------------------------
100mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These and magnesium stearate are mixed in a V-type mixer. Fill 10 mg powder into a No. 5 hard gelatin capsule.

Formulation Example 3
A capsule filling granule containing the following ingredients is produced.
Component Compound represented by formula (I) 15 mg
Lactose 90mg
Corn starch 42mg
HPC-L 3mg
---------------------------
150mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated, and dried. The obtained dried granule is sieved with a vibrating screen (12/60 mesh) and the size is adjusted, and 150 mg of the dried granule is filled into a No. 4 hard gelatin capsule.

Formulation Example 4
A tablet containing the following ingredients is produced.
Component Compound represented by formula (I) 10 mg
Lactose 90mg
Microcrystalline cellulose 30mg
Magnesium stearate 5mg
CMC-Na 15mg
---------------------------
150mg total
The compound represented by the formula (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a 150 mg tablet.

Formulation Example 5
The intravenous formulation is produced as follows.
Compound represented by formula (I) 100 mg
Saturated fatty acid glyceride 1000mL
A solution of the above components is usually administered intravenously to the patient at a rate of 1 mL per minute.

The compound of the present invention inhibits P2X7 receptor activation, so that the prevention, treatment and amelioration of diseases in which suppression of P2X7 receptor activation is effective, particularly anti-rheumatoid arthritis drugs which have both anti-inflammatory, anti-pain and bone metabolism improvement As such, it can be used as an anti-inflammatory bowel disease drug, an anti-pain drug such as inflammatory and cancer pain, and is useful as a pharmaceutical.

Claims (16)

Formula (I)

[Wherein, R ¹ represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, a carboxyl group, a carbamoyl group, an amino group, a halogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group. Or a C _1-6 alkoxy group (the C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C _1-6 alkoxy group are unsubstituted or substituted with a halogen atom) Yes.)
Means
R ² is a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkoxy group, a mono C _1-6 alkylamino group, a diC _1-6 alkylamino group, a C _1-6 alkylthio group, a C _1-6 alkylsulfonyl group (the C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkoxy group, mono C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _{1- The 6} alkylthio group and the C _1-6 alkylsulfonyl group are substituted with one or more substituents selected from the substituent group V ³ alone or differently, and may be substituted with a halogen atom.
A tetrazolyl group, a C _2-9 heterocyclyl group (the tetrazolyl group and the C _2-9 heterocyclyl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ² alone or differently; Yes.)
Or formula (II)

(In the formula, R ^a is a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group, or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, The C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are one or more substituents that are unsubstituted or selected alone or differently from the substituent group V ² Is replaced by
R ^b and R ^c are each independently a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group or a C _2-9 heterocyclyl group The C _1-6 alkyl group, the C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are unsubstituted, or are selected alone or differently from the substituent group V ² Is substituted with one or more substituents
R ^a and R ^b or R ^b and R ^{c taken} together to form a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or one or more selected from the group of substituents V ¹ alone or differently Substituted with a substituent of
Means
T ′ and U ′ each independently represent an oxygen atom, a sulfur atom, NR ^d or NOR ^d
(In the formula, R ^d is a hydrogen atom, a cyano group or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or one or more selected from the substituent group V ² alone or differently). Substituted with a substituent of
Means
L is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). .)
Means. )
Means a structure represented by
Q is the formula (III)

(Where
R ³ and R ⁵ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group (the C _1-6 alkyl group, C _2-6 alkenyl group and C 2 _{The 2-6} alkynyl group is unsubstituted or substituted with a halogen atom.)
Means
R ⁴ represents a C _1-20 alkyl group, a C _2-20 alkenyl group, or a C _2-19 heterocyclyl group (the C _1-20 alkyl group, C _2-20 alkenyl group, and C _2-19 heterocyclyl group are unsubstituted. Or substituted with one or more substituents selected from the substituent group V ¹ alone or differently.
Or
R ³ and R ⁴ are taken together to form a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted, or one or more substituents selected from the substituent group V ¹ alone or differently, or Substituted with a C _1-20 alkyl group.)
Means
m means 0, 1 or 2;
T means an oxygen atom or a sulfur atom. )
Means a structure represented by
X is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from substituent group V ¹ alone or differently) .)
Means
Y is a single bond, a C _2-14 arylene group, a C _2-9 heterocyclylene group (the C _2-14 arylene group and the C _2-9 heterocyclylene group are unsubstituted or substituted by a substituent group V ^2. It is substituted with one or more substituents which are selected more individually or differently.)
Or formula (IV)

(Wherein R ⁶ and R ⁷ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group (the C _1-6 alkyl group and C _2-6 alkenyl group are unsubstituted) Or substituted with one or more substituents selected from the substituent group V ¹ alone or differently) or a halogen-substituted C _1-3 alkyl group,
U and W are each independently an oxygen atom, a sulfur atom or NOR ¹⁰
(In the formula, R ¹⁰ represents a hydrogen atom, a C _1-3 alkyl group or a halogen-substituted C _1-3 alkyl group.)
And n means 0, 1 or 2. )
Means a structure represented by
Z represents a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkoxy group, a C _3-12 cycloalkyl group, a C _3-12 cycloalkenyl group (the C _1-6 alkyl group, The C _2-6 alkenyl group, the C _1-6 alkoxy group, the C _3-12 cycloalkyl group and the C _3-12 cycloalkenyl group are unsubstituted or selected from the substituent group V ² alone or differently 1 Substituted with one or more substituents).
C _2-14 aryl group, condensed aryl group, C _2-14 aryloxy group or C _2-9 heterocyclyl group (the C _2-14 aryl group, condensed aryl group, C _2-14 aryloxy group and C _2-9 The heterocyclyl group is unsubstituted or substituted with one or more substituents selected from the substituent group V ² alone or differently.
Represents
Substituent group V ¹ was a carboxyl group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, a formyl group, a nitro group, a cyano group, a halogen atom, a hydroxyl group, an amino group, a mono C _1-6 alkylamino group , Di C _1-6 alkylamino group, C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylthio group and C _1-6 alkyl A sulfonyl group (the mono-C _1-6 alkylamino group, di-C _1-6 alkylamino group, C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylthio and _{C 1-6} alkylsulfonyl group, unsubstituted or substituted with or carboxyl group, a carbamoyl group, a sulfamoyl group, phospho Group, a sulfo group, a tetrazolyl group, a formyl group, a nitro group, a cyano group, a halogen _{atom, C 1-6} alkyl group, a halogen-substituted _{C 1-3} alkyl _{group, C 1-6} alkoxy group, a halogen-substituted _{C 1-3} alkoxy Substituted with a group, a hydroxyl group, an amino group, a mono C _1-6 alkylamino group, a di C _1-6 alkylamino group, a C _1-6 alkylthio group or a C _1-6 alkylsulfonyl group.)
Composed of
Substituent group V ² is substituent group V ¹ , C _2-14 aryl group and condensed aryl group (the C _2-14 aryl group and condensed aryl group are unsubstituted or independent from substituent group V ^1. Or substituted with one or more substituents selected differently.)
Composed of
Substituent group V ³ includes a carboxyl group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, a tetrazolyl group, a formyl group, a nitro group, a cyano group, a hydroxyl group, an amino group, a mono C _1-6 alkylamino group, and a diC. _1-6 alkylamino group, C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _1-6 alkylthio group, C _1-6 alkylsulfonyl group ( The mono C _1-6 alkylamino group, diC _1-6 alkylamino group, C _1-6 alkyl group, C _2-6 alkenyl group, C _1-6 alkoxy group, C _2-9 heterocyclyl group, C _{1- 6} alkylthio group and a C _1-6 alkylsulfonyl group, unsubstituted or substituted with or carboxyl group, a carbamoyl group, a sulfamoyl group, a phosphono group, a sulfo group, Torazoriru group, a formyl group, a nitro group, a cyano group, a halogen _{atom, C 1-6} alkyl group, a halogen-substituted _{C 1-3} alkyl _{group, C 1-6} alkoxy group, a halogen-substituted _{C 1-3} alkoxy group, hydroxyl group, amino Group, mono C _1-6 alkylamino group, diC _1-6 alkylamino group, C _1-6 alkylthio group or C _1-6 alkylsulfonyl group.), C _2-14 aryl group and condensation An aryl group (the C _2-14 aryl group and the condensed aryl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently).
Consists of. ]
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. The compound according to claim 1, wherein R ¹ is a hydrogen atom, a C _1-3 alkoxy group or a halogen-substituted C _1-3 alkoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound Or a solvate thereof. The compound according to claim 1, wherein R ¹ is a hydrogen atom or an ethoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. R ² is a C _1-6 alkyl group, a C _1-6 alkoxy group, a mono C _1-6 alkylamino group, a di-C _1-6 alkylamino group (the C _1-6 alkyl group, a C _1-6 alkoxy group, The mono-C _1-6 alkylamino group and the di-C _1-6 alkylamino group are substituted with one or more substituents selected from the substituent group V ³ alone or differently, and may be substituted with a halogen atom Good),
A tetrazolyl group, a C _2-9 heterocyclyl group (the tetrazolyl group and the C _2-9 heterocyclyl group are unsubstituted or substituted with one or more substituents selected from the substituent group V ² alone or differently; Yes.)
Or formula (V)

(In the formula, R ^a is a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group, or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, The C _2-6 alkenyl group, the C _2-14 aryl group, the fused aryl group, and the C _2-9 heterocyclyl group are one or more substituents that are unsubstituted or selected alone or differently from the substituent group V ² Is replaced by
R ^b is a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-14 aryl group, a condensed aryl group, or a C _2-9 heterocyclyl group (the C _1-6 alkyl group, C _{The 2-6} alkenyl group, C _2-14 aryl group, condensed aryl group and C _2-9 heterocyclyl group are one or more substituents which are unsubstituted or selected alone or differently from the substituent group V ² Is replaced)
R ^a and R ^b are combined together to form a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently Has been.)
Means
T ′ is an oxygen atom, NR ^d or NOR ^d
(Wherein R ^d is a hydrogen atom, a cyano group, a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with a phenyl group) or halogen-substituted C _{1- 3} means an alkyl group.)
Means
L is a single bond or a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or more substituents selected from the substituent group V ¹ alone or differently). .)
Means. )
The compound according to any one of claims 1 to 3, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. R ² is a C _1-3 alkyl group (the C _1-3 alkyl group is substituted with a carboxyl group or a hydroxyl group).
Or formula (VI)

(Wherein R ^a represents a C _1-3 alkyl group, R ^b represents a hydrogen atom or a C _1-3 alkyl group,
T ′ is an oxygen atom, NR ^d or NOR ^d
(Wherein R ^d represents a hydrogen atom, a cyano group, or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with a phenyl group).)
Means. )
The compound according to claim 4, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. Q is the formula (VII)

(Where
R ³ is a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted with a halogen atom).
Means
R ⁴ represents a C _1-20 alkyl group or a C _2-20 alkenyl group (the C _1-20 alkyl group and C _2-20 alkenyl group are unsubstituted or selected alone or differently from the substituent group V ¹⁾ Substituted with one or more substituents.
Means. )
6. The compound according to claim 1, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. Q is the formula (VIII)

(Where
m means 0, 1 or 2;
R ⁴ represents a C _1-20 alkyl group or a C _2-20 alkenyl group (the C _1-20 alkyl group and C _2-20 alkenyl group are unsubstituted or selected alone or differently from the substituent group V ¹⁾ Substituted with one or more substituents.
Means. )
6. The compound according to claim 1, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. R ³ represents a hydrogen atom, and R ⁴ represents a C _3-12 cycloalkyl group or a C _3-12 cycloalkenyl group (the C _3-12 cycloalkyl group and the C _3-12 cycloalkenyl group are unsubstituted) Or substituted with 1 to 3 substituents selected from the substituent group V ¹ alone or differently.
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound according to claim 6 or 7, or a solvate thereof. R ³ represents a hydrogen atom, and R ⁴ is a C _2-19 heterocyclyl group (the C _2-19 heterocyclyl group is unsubstituted or selected from 1 to 3 selected from the substituent group V ¹ alone or differently Substituted by substituents.)
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound according to claim 6 or 7, or a solvate thereof. R ³ represents a hydrogen atom, and R ⁴ is a C _2-11 heterocyclyl group (the C _2-11 heterocyclyl group is unsubstituted or selected from 1 to 3 selected from the substituent group V ¹ alone or differently Substituted by substituents.)
Or a tautomer, prodrug or pharmaceutically acceptable salt of the compound according to claim 6 or 7, or a solvate thereof. X represents a C _1-6 alkylene group (the C _1-6 alkylene group is unsubstituted or substituted with one or two substituents selected from the substituent group V ¹ alone or differently).
Means
Y is a single bond or formula (IX)

(Wherein R ⁶ represents a hydrogen atom or a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted with a halogen atom).
U represents an oxygen atom or a sulfur atom. )
Means a structure represented by
Z is _{C 1-6 alkyl, C 1-6} alkoxy groups (the _{C 1-6} alkyl group and a _{C 1-6} alkoxy group, one selected from unsubstituted or substituted with a substituent group ^{V 2} or 2 Substituted by two substituents).
C _2-14 aryl group, C _2-14 aryloxy group or C _2-9 heterocyclyl group (the C _2-14 aryl group, C _2-14 aryloxy group and C _2-9 heterocyclyl group are unsubstituted) substituted with or one substituent selected from substituent group V ^2.)
11. The compound according to claim 1, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. Z is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _2-9 heteroaryl group (the C _2-9 heteroaryl group is unsubstituted or is independent or different from the substituent group V ¹⁾ Substituted with one or two substituents selected from
Has been replaced by )
12. The compound according to claim 1, meaning a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.   P2X7 receptor inhibition containing the compound according to any one of claims 1 to 12, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient Agent.   A prophylactic / therapeutic / ameliorating agent for a disease having an effective P2X7 receptor inhibitory action, comprising the P2X7 receptor inhibitor according to claim 13 as an active ingredient.   A therapeutic agent for rheumatoid arthritis comprising the P2X7 receptor inhibitor according to claim 13 as an active ingredient.   A medicament comprising the compound according to any one of claims 1 to 12, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient.