JP2023174607A - Pharmaceutical composed of 5-heteroaryl-1h-pyrazole-3-amine derivative - Google Patents

Abstract

To provide a compound that exhibits anticancer action based on CHK1 inhibition.SOLUTION: This invention has been completed with the findings that a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof has strong inhibitory action on CHK1, exhibiting superior antitumor action [where X, Y and Z independently represent CR8 or a nitrogen atom, X, Y and Z are not simultaneously CR8, and R8's independently represent a hydrogen atom, a halogen atom, cyano, nitro, carboxyl, sulfonic acid, phosphoric acid or the like].SELECTED DRAWING: None

Description

The present disclosure provides 5-heteroaryl-1H-pyrazoles that inhibit Checkpoint Kinase 1 (CHK1) and are useful as medicaments for treating or preventing cancers characterized by defects in deoxyribonucleic acid (DNA) replication, chromosome segregation, or cell division. -3-amine derivatives and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these, liposomes containing these, or therapeutic agents or prophylaxis for pathological conditions involving CHK1 containing these compositions or liposomes Regarding drugs.

CHK1 is a serine/threonine protein kinase downstream of ATR in the DNA damage checkpoint signaling pathway in the cell cycle. In mammalian cells, CHK1 is phosphorylated in an ATR-dependent manner in response to DNA damage caused by ionizing radiation, etc., or DNA replication stress caused by excessive cell proliferation and genome instability in cancer cells. Patent Documents 1 to 5). This phosphorylation that activates CHK1 causes CHK1 to phosphorylate CDC25A, inhibiting dephosphorylation of cyclin E/CDK2 by CDC25A, and arresting progression from S phase. CHK1 also phosphorylates CDC25C, inhibits dephosphorylation of cyclin B/CDK1 by CDC25C, and halts progression from the G2M phase. In either case, regulation of CDK activity induces cell cycle arrest and prevents cell division in the presence of DNA damage, thereby promoting repair of DNA damage. CHK1 inhibition suppresses the DNA damage checkpoint function in the cell cycle in cancer cells, causing DNA repair failure and uncontrolled DNA synthesis in the presence of DNA damage, resulting in DNA fragmentation and replication. induces catastrophe and cell death (Patent Documents 1 and 2).

Various inhibitors of CHK1 (Patent Documents 1 to 3) have been reported.

International Publication No. 2010/077758 International Publication No. 2012/064548 International Publication No. 2017/132928

Dai Y and Grant S, Clin Cancer Res, 16(2):376-383 (2010) Benada J and Macurek L, Biomolecules, 5:1912-1937 (2015) King C, Mol Cancer Ther, 14(9):2004-2013 (2015) Dent P, Expert Opinion on Investigational drugs, 28(12):1095-1100 (2019) Evangelisti G. et al, Expert Opinion on Investigational Drugs, 29(8):779-792 (2020) David H. et al. J Clin Oncol, 34:1764-1771 (2016)

The present disclosure provides compounds that exhibit anticancer effects based on CHK1 inhibition. Preferably, compounds that have a wide disparity between the compound concentration that suppresses CHK1 inhibitory activity and the compound concentration that suppresses hERG current, compounds that do not exhibit CYP inhibition based on MBI that causes serious side effects such as hepatotoxicity, and compounds that do not exhibit CHK1 inhibitory activity. Provided is a compound that has a wide range of disparity between the concentration of the compound that suppresses the concentration of the compound and the concentration of the compound that causes toxicity to blood cells, and/or a compound that is encapsulated in liposomes and is released from the liposomes in a sustained manner. That is, the present invention provides an antitumor agent that has high therapeutic effects while reducing side effects.

As a result of extensive studies, the present inventors found that the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "compound of the present disclosure") The present disclosure has been completed based on the discovery that it exhibits an excellent antitumor effect by having a strong inhibitory effect on .

That is, the present disclosure is as follows.

［式中、
Ｒ^１は、水素原子、置換されていてもよいＣ_１－６アルキル、置換されていてもよいＣ_３－１０シクロアルキル、置換されていてもよい３～１０員の飽和複素環基、置換されていてもよいＣ_６－１０アリール、又は置換されていてもよい５～１２員のヘテロアリールを表し、
Ｒ^２は、水素原子、ハロゲン原子、シアノ、ニトロ、カルボキシル、スルホン酸、リン酸、－ＯＲ^３、－ＳＲ^３、－ＣＯＲ^４、－ＣＯ_２Ｒ^４、－ＣＯＮＲ^５Ｒ^６、－ＳＯ_２Ｒ^４、－ＳＯ_２ＮＲ^５Ｒ^６、－ＯＣＯＲ^４、－ＯＣＯ_２Ｒ^４、－ＯＣＯＮＲ^５Ｒ^６、－ＮＲ^５Ｒ^６、－ＮＲ^７ＣＯＲ^４、－ＮＲ^７ＣＯ_２Ｒ^４、－ＮＲ^７ＣＯＮＲ^５Ｒ^６、－ＮＲ^７ＳＯ_２Ｒ^４、－ＮＲ^７ＳＯ_２ＮＲ^５Ｒ^６、置換されていてもよいＣ_１－６アルキル、置換されていてもよいＣ_２－６アルケニル、置換されていてもよいＣ_２－６アルキニル、置換されていてもよいＣ_３－１０シクロアルキル、置換されていてもよい３～１０員の飽和複素環基、置換されていてもよいＣ_６－１０アリール、又は置換されていてもよい５～１２員のヘテロアリールを表し、
Ｒ^３は、水素原子又はＣ_１－６アルキルを表し、
Ｒ^４は、Ｃ_１－６アルキルを表し、
Ｒ^５、Ｒ^６及びＲ^７は、それぞれ独立して、水素原子、又はＣ_１－６アルキルを表し、ここにおいて、同一の窒素原子と結合するＲ^５及びＲ^６が共にＣ_１－６アルキルのとき、これらはそれぞれが結合する窒素原子と一緒になって、３～８員の含窒素飽和複素環を形成していてもよく、
Ｘ、Ｙ及びＺは、それぞれ独立して、ＣＲ^８又は窒素原子を表し、ここにおいて、Ｘ、Ｙ及びＺは同時にＣＲ^８ではなく、
Ｒ^８は、複数ある場合はそれぞれ独立して、水素原子、ハロゲン原子、シアノ、ニトロ、カルボキシル、スルホン酸、リン酸、－ＯＲ^９、－ＳＲ^９、－ＣＯＲ^１０、－ＣＯ_２Ｒ^１０、－ＣＯＮＲ^１１Ｒ^１２、－ＳＯ_２Ｒ^１０、－ＳＯ_２ＮＲ^１１Ｒ^１２、－ＯＣＯＲ^１０、－ＯＣＯ_２Ｒ^１０、－ＯＣＯＮＲ^１１Ｒ^１２、－ＮＲ^１１Ｒ^１２、－ＮＲ^１３ＣＯＲ^１０、－ＮＲ^１３ＣＯ_２Ｒ^１０、－ＮＲ^１３ＣＯＮＲ^１１Ｒ^１２、－ＮＲ^１３ＳＯ_２Ｒ^１０、－ＮＲ^１３ＳＯ_２ＮＲ^１１Ｒ^１２、置換されていてもよいＣ_１－６アルキル、置換されていてもよいＣ_２－６アルケニル、置換されていてもよいＣ_２－６アルキニル、置換されていてもよいＣ_３－１０シクロアルキル、置換されていてもよい３～１０員の飽和複素環基、置換されていてもよいＣ_６－１０アリール、又は置換されていてもよい５～１２員のヘテロアリールを表し、
Ｒ^９は、水素原子又はＣ_１－６アルキルを表し、
Ｒ^１０は、Ｃ_１－６アルキルを表し、
Ｒ^１１、Ｒ^１２及びＲ^１３は、それぞれ独立して、水素原子又はＣ_１－６アルキルを表し、ここにおいて、同一の窒素原子と結合するＲ^１１及びＲ^１２が共にＣ_１－６アルキルのとき、これらはそれぞれが結合する窒素原子と一緒になって、３～８員の含窒素飽和複素環を形成していてもよく、
Ｌは、単結合又は置換されていてもよいＣ_１－６アルキレンを表し、
Ｖは、単結合、置換されていてもよいＣ_３－１０シクロアルキレン又は置換されていてもよい３～１０員の二価飽和複素環基を表し、
Ｗは、単結合又は置換されていてもよいＣ_１－６アルキレンを表し、
Ｑは、水素原子又はＮＨＲ^１４を表し、
Ｒ^１４は、水素原子、置換されていてもよいＣ_１－６アルキル、置換されていてもよいＣ_３－１０シクロアルキル、又は置換されていてもよい３～１０員の飽和複素環基を表す］で表される、
化合物又はその製薬学的に許容される塩を含有する医薬。
〔項２〕
Ｒ^１、Ｒ^２、Ｒ^８、Ｒ^１４、Ｌ、Ｖ、及びＷにおける置換されていてもよいＣ_１－６アルキル、置換されていてもよいＣ_２－６アルケニル、置換されていてもよいＣ_２－６アルキニル、置換されていてもよいＣ_３－１０シクロアルキル、置換されていてもよい３～１０員の飽和複素環基、置換されていてもよいＣ_６－１０アリール、置換されていてもよい５～１２員のヘテロアリール、置換されていてもよいＣ_１－６アルキレン、置換されていてもよいＣ_３－１０シクロアルキレン、又は置換されていてもよい３～１０員の二価飽和複素環基が、それぞれ独立して
（１）ハロゲン原子、
（２）水酸基、
（３）Ｃ_６－１０アリール、
（４）５～１２員のヘテロアリール、
（５）Ｃ_１－６アルキル、
（６）Ｃ_２－６アルケニル、
（７）Ｃ_２－６アルキニル、
（８）Ｃ_１－６アルコキシ、
（９）Ｃ_１－６アルキルチオ
（１０）Ｃ_３－１０シクロアルキル、
（１１）３～１０員の飽和複素環基、
（１２）カルボキシル、
（１３）－ＣＯＲ^１５、
（１４）－ＣＯ_２Ｒ^１５、
（１５）－ＣＯＮＲ^１６Ｒ^１７、
（１６）－ＮＲ^１６Ｒ^１７、
（１７）－ＮＲ^１８ＣＯＲ^１５、
（１８）－ＮＲ^１８ＣＯ_２Ｒ^１５、
（１９）－ＮＲ^１８ＳＯ_２Ｒ^１５、
（２０）－ＮＲ^１８ＣＯＮＲ^１６Ｒ^１７、
（２１）－ＮＲ^１８ＳＯ_２ＮＲ^１６Ｒ^１７、
（２２）－ＳＯ_２Ｒ^１５、
（２３）－ＳＯ_２ＮＲ^１６Ｒ^１７、
（２４）－ＯＣＯＲ^１５、
（２５）－ＯＣＯ_２Ｒ^１５、
（２６）－ＯＣＯＮＲ^１６Ｒ^１７、
（２７）スルホン酸、
（２８）リン酸、
（２９）シアノ、及び
（３０）ニトロ
からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよく、
ここにおいて、前記（３）Ｃ_６－１０アリール、（４）５～１２員のヘテロアリール、（５）Ｃ_１－６アルキル、（６）Ｃ_２－６アルケニル、（７）Ｃ_２－６アルキニル、（８）Ｃ_１－６アルコキシ、（９）Ｃ_１－６アルキルチオ、（９）Ｃ_３－１０シクロアルキル及び（１０）３～１０員の飽和複素環基に示す基が、
（ａ）ハロゲン原子、
（ｂ）水酸基、
（ｃ）Ｃ_６－１０アリール、
（ｄ）５～１２員のヘテロアリール、
（ｅ）Ｃ_１－６アルキル、
（ｆ）Ｃ_２－６アルケニル、
（ｇ）Ｃ_２－６アルキニル、
（ｈ）Ｃ_１－６アルコキシ、
（ｉ）Ｃ_３－１０シクロアルキル、
（ｊ）３～１０員の飽和複素環基、
（ｋ）カルボキシル、
（ｌ）－ＣＯＲ^１５、
（ｍ）－ＣＯ_２Ｒ^１５、
（ｎ）－ＣＯＮＲ^１６Ｒ^１７、
（ｏ）－ＮＲ^１６Ｒ^１７、
（ｐ）－ＮＲ^１８ＣＯＲ^１５、
（ｑ）－ＮＲ^１８ＳＯ_２Ｒ^１５、
（ｒ）－ＳＯ_２Ｒ^１５、
（ｓ）－ＳＯ_２ＮＲ^１６Ｒ^１７、
（ｔ）スルホン酸、
（ｕ）リン酸、
（ｖ）シアノ、及び
（ｗ）ニトロ
からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよく、
Ｒ^１５が、複数ある場合はそれぞれ独立して、Ｃ_１－６アルキルであり、
Ｒ^１６及びＲ^１７が、それぞれ独立して、水素原子又はＣ_１－６アルキルであり、Ｒ^１６又はＲ^１７が複数ある場合は、Ｒ^１６又はＲ^１７のそれぞれは同一でも異なってもよく、ここにおいて、同一の窒素原子と結合するＲ^１６及びＲ^１７が共にＣ_１－６アルキルのとき、これらはそれぞれが結合する窒素原子と一緒になって、３～８員の含窒素飽和複素環を形成していてもよく、
Ｒ^１８が、水素原子又はＣ_１－６アルキルである、
項１に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３〕
Ｒ^１、Ｒ^２、Ｒ^８、Ｒ^１４、Ｌ、Ｖ、及びＷにおける置換されていてもよいＣ_１－６アルキル、置換されていてもよいＣ_２－６アルケニル、置換されていてもよいＣ_２－６アルキニル、置換されていてもよいＣ_３－１０シクロアルキル、置換されていてもよい３～１０員の飽和複素環基、置換されていてもよいＣ_６－１０アリール、置換されていてもよい５～１２員のヘテロアリール、置換されていてもよいＣ_１－６アルキレン、置換されていてもよいＣ_３－１０シクロアルキレン、又は置換されていてもよい３～１０員の二価飽和複素環基が、それぞれ独立して
（１）ハロゲン原子、
（２）水酸基、
（３）Ｃ_６－１０アリール、
（４）５～１２員のヘテロアリール、
（５）ハロゲン原子、及び水酸基からなる群から選択される１～３の置換基で置換されていてもよいＣ_１－６アルキル、
（６）Ｃ_２－６アルケニル、
（７）Ｃ_２－６アルキニル、
（８）Ｃ_１－６アルコキシ、
（９）Ｃ_３－１０シクロアルキル、
（１０）３～１０員の飽和複素環基、
（１１）カルボキシル、
（１２）－ＣＯＲ^１５、
（１３）－ＣＯ_２Ｒ^１５、
（１４）－ＣＯＮＲ^１６Ｒ^１７、
（１５）－ＮＲ^１６Ｒ^１７、
（１６）－ＳＯ_２Ｒ^１５、
（１７）－ＳＯ_２ＮＲ^１６Ｒ^１７、
（１８）スルホン酸、
（１９）リン酸、
（２０）シアノ、及び
（２１）ニトロ
からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよく、
Ｒ^１５が、複数ある場合はそれぞれ独立して、Ｃ_１－６アルキルであり、
Ｒ^１６及びＲ^１７が、それぞれ独立して、水素原子又はＣ_１－６アルキルを表し、Ｒ^１６又はＲ^１７が複数ある場合は、Ｒ^１６又はＲ^１７のそれぞれは同一でも異なってもよく、ここにおいて、同一の窒素原子と結合するＲ^１６及びＲ^１７が共にＣ_１－６アルキルのとき、これらはそれぞれが結合する窒素原子と一緒になって、３～８員の含窒素飽和複素環を形成していてもよい、
項１～２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４〕
Ｒ^１、Ｒ^２、Ｒ^８、Ｌ、Ｖ、及びＷにおける置換されていてもよいＣ_１－６アルキル、置換されていてもよいＣ_２－６アルケニル、置換されていてもよいＣ_２－６アルキニル、置換されていてもよいＣ_３－１０シクロアルキル、置換されていてもよい３～１０員の飽和複素環基、置換されていてもよいＣ_６－１０アリール、置換されていてもよい５～１２員のヘテロアリール、置換されていてもよいＣ_１－６アルキレン、置換されていてもよいＣ_３－１０シクロアルキレン、又は置換されていてもよい３～１０員の二価飽和複素環基が、それぞれ独立して
（１）ハロゲン原子、
（２）水酸基、
（３）フェニル、
（４）５～６員のヘテロアリール、
（５）ハロゲン原子、及び水酸基からなる群から選択される１～３の置換基で置換されていてもよいＣ_１－６アルキル、
（６）Ｃ_１－６アルコキシ、
（７）Ｃ_３－７シクロアルキル、
（８）３～７員の飽和複素環基、
（９）－ＣＯＲ^１５、
（１０）－ＣＯ_２Ｒ^１５、
（１１）－ＣＯＮＲ^１６Ｒ^１７、
（１２）－ＮＲ^１６Ｒ^１７、
（１３）－ＳＯ_２Ｒ^１５、
（１４）－ＳＯ_２ＮＲ^１６Ｒ^１７、及び
（１５）シアノ
からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよく、
Ｒ^１５が、複数ある場合はそれぞれ独立して、Ｃ_１－６アルキルであり、
Ｒ^１６及びＲ^１７が、それぞれ独立して、水素原子又はＣ_１－６アルキルであり、Ｒ^１６又はＲ^１７が複数ある場合は、Ｒ^１６又はＲ^１７のそれぞれは同一でも異なってもよく、ここにおいて、同一の窒素原子と結合するＲ^１６及びＲ^１７が共にＣ_１－６アルキルのとき、これらはそれぞれが結合する窒素原子と一緒になって、３～８員の含窒素飽和複素環を形成していてもよい、
項１～３のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項５〕
Ｒ^１が、水素原子、又は１～３個のフッ素原子で置換されていてもよいＣ_１－６アルキルである、
項１～４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項６〕
Ｒ^１が、１～３個のフッ素原子で置換されていてもよいメチル基、又はエチル基である、
項１～４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項７〕
Ｒ^１が、１～３個のフッ素原子で置換されていてもよいメチル基である、
項１～４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項８〕
Ｒ^１が、メチル基である、
項１～４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項９〕
Ｒ^２が、水素原子、ハロゲン原子、シアノ、－ＯＲ^３、Ｃ_１－６アルキル、Ｃ_３－１０シクロアルキル、又は３～１０員の飽和複素環基である、
項１～８のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項１０〕
Ｒ^２が、ハロゲン原子、シアノ、又は１～３個のハロゲン原子で置換されていてもよいＣ_１－６アルキルである、
項１～８のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項１１〕
Ｒ^２が、シアノである、
項１～８のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項１２〕
Ｒ^８が、複数ある場合はそれぞれ独立して、水素原子、ハロゲン原子、シアノ、－ＯＲ^９、－ＣＯ_２Ｒ^１０、－ＣＯＮＲ^１１Ｒ^１２、－ＮＲ^１１Ｒ^１２、－ＮＲ^１３ＣＯＲ^１０、Ｃ_１－６アルキル（該アルキルは、フッ素原子、塩素原子、臭素原子、水酸基、フェニル、５～６員のヘテロアリール、Ｃ_１－６アルコキシ、Ｃ_３－７シクロアルキル、３～７員の飽和複素環基、－ＣＯＮＲ^１６Ｒ^１７、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、Ｃ_３－１０シクロアルキル（該シクロアルキルは、フッ素原子、塩素原子、臭素原子、水酸基、フェニル、５～６員のヘテロアリール、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_３－７シクロアルキル、３～７員の飽和複素環基、－ＣＯＮＲ^１６Ｒ^１７、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、３～１０員の飽和複素環基（該飽和複素環基は、フッ素原子、塩素原子、臭素原子、水酸基、フェニル、５～６員のヘテロアリール、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_３－７シクロアルキル、３～７員の飽和複素環基、－ＣＯＮＲ^１６Ｒ^１７、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、フェニル（該フェニルは、フッ素原子、塩素原子、臭素原子、水酸基、フェニル、５～６員のヘテロアリール、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_３－７シクロアルキル、３～７員の飽和複素環基、－ＣＯＮＲ^１６Ｒ^１７、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、又は５～６員のヘテロアリール（該ヘテロアリールは、フッ素原子、塩素原子、臭素原子、水酸基、フェニル、５～６員のヘテロアリール、Ｃ_１－６アルキル、Ｃ_１－６アルコキシ、Ｃ_３－７シクロアルキル、３～７員の飽和複素環基、－ＣＯＮＲ^１６Ｒ^１７、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）である、
項１～１１のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項１３〕
Ｒ^８が、複数ある場合はそれぞれ独立して、
水素原子、
ハロゲン原子
－ＯＲ^９、
Ｃ_１－６アルキル（該アルキルは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、
Ｃ_３－７シクロアルキル（該シクロアルキルは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、
３～７員の飽和複素環基（該飽和複素環基は、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、
フェニル（該フェニルは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、又は
５～６員のヘテロアリール（該ヘテロアリールは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）である、
項１～１１のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項１４〕
Ｒ^８が、複数ある場合はそれぞれ独立して、
水素原子、
フッ素原子、
塩素原子、
臭素原子、
Ｃ_１－６アルキル（該アルキルは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）、又は
５～６員のヘテロアリール（該ヘテロアリールは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）である、
項１～１１のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項１５〕
Ｌが、
単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）である、項１～１４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項１６〕
Ｖが、
単結合、
Ｃ_３－１０シクロアルキレン（該シクロアルキレンは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、又は
３～１０員の二価飽和複素環基（該飽和複素環基は、フッ素原子、水酸基、１～２個の水酸基又はフッ素原子で置換されていてもよいＣ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）である、
項１～１５のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項１７〕
Ｗが、
単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）である、
項１～１６のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項１８〕
Ｒ^１４が、
水素原子、
Ｃ_１－６アルキル（該アルキルは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、
Ｃ_３－１０シクロアルキル（該シクロアルキルは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、又は
３～１０員の飽和複素環基（該飽和複素環基は、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）である、
項１～１７のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項１９〕
Ｒ^１が、
１～３個のフッ素原子で置換されていてもよいＣ_１－６アルキルであり、
Ｒ^２が、
ハロゲン原子、
シアノ、又は
１～３個のフッ素原子で置換されていてもよいＣ_１－６アルキルであり、
Ｘ、Ｙ及びＺが、それぞれ独立して、ＣＲ^８又は窒素原子であり、ここにおいて、Ｘ、Ｙ及びＺは同時にＣＲ^８ではなく、
Ｒ^８が、複数ある場合はそれぞれ独立して、
水素原子、
フッ素原子、
塩素原子、
臭素原子、
Ｃ_１－６アルキル（該アルキルは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）、又は
５～６員のヘテロアリール（該ヘテロアリールは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）であり
Ｌが、
単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）であり、
Ｖが、
単結合、
Ｃ_３－１０シクロアルキレン（該シクロアルキレンは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、又は
３～１０員の二価飽和複素環基（該飽和複素環基は、フッ素原子、水酸基、１～２個の水酸基又はフッ素原子で置換されていてもよいＣ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）であり、
Ｗが、
単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）であり、
Ｑが、水素原子、又はＮＨＲ^１４であり、
Ｒ^１４が、
水素原子、
Ｃ_１－６アルキル（該アルキルは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、
Ｃ_３－１０シクロアルキル（該シクロアルキルは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、又は
３～１０員の飽和複素環基（該飽和複素環基は、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）であり、
Ｒ^１６及びＲ^１７が、それぞれ独立して、水素原子、又はＣ_１－６アルキルであり、Ｒ^１６又はＲ^１７が複数ある場合は、Ｒ^１６又はＲ^１７のそれぞれは同一でも異なってもよく、ここにおいて、同一の窒素原子と結合するＲ^１６及びＲ^１７がともにＣ_１－６アルキルのとき、これらはそれぞれが結合する窒素原子と一緒になって、３～８員の含窒素飽和複素環を形成していてもよい、
項１に記載の化合物又はその製薬学的に許容される塩を含有する医薬。
〔項２０〕
式（１）が、下記式（２）：

［式中、
Ｘ、Ｙ及びＺは、それぞれ独立して、ＣＲ^８又は窒素原子を表し、ここにおいて、Ｘ、Ｙ及びＺは同時にＣＲ^８ではなく、
Ｒ^８は、複数ある場合はそれぞれ独立して、
水素原子、
フッ素原子、
塩素原子、
臭素原子、
Ｃ_１－６アルキル（該アルキルは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）、又は
５～６員のヘテロアリール（該ヘテロアリールは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）を表し、
Ｌは、
単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）を表し、
Ｖは、
単結合、
Ｃ_３－１０シクロアルキレン（該シクロアルキレンは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、又は
３～１０員の二価飽和複素環基（該飽和複素環基は、フッ素原子、水酸基、１～２個の水酸基又はフッ素原子で置換されていてもよいＣ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）を表し、
Ｗは、
単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）を表し、
Ｑは、水素原子、又はＮＨＲ^１４を表し、
Ｒ^１４は、
水素原子、
Ｃ_１－６アルキル（該アルキルは、フッ素原子、水酸基、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、
Ｃ_３－１０シクロアルキル（該シクロアルキルは、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）、又は
３～１０員の飽和複素環基（該飽和複素環基は、フッ素原子、水酸基、Ｃ_１－３アルキル、Ｃ_１－３アルコキシ、－ＮＲ^１６Ｒ^１７、及びシアノからなる群から選択される同一又は異なる１～３個の置換基で置換されていてもよい）を表し、
Ｒ^１６及びＲ^１７は、それぞれ独立して、水素原子、又はＣ_１－６アルキルを表し、Ｒ^１６又はＲ^１７が複数ある場合は、Ｒ^１６又はＲ^１７のそれぞれは同一でも異なってもよく、ここにおいて、同一の窒素原子と結合するＲ^１６及びＲ^１７がともにＣ_１－６アルキルのとき、これらはそれぞれが結合する窒素原子と一緒になって、３～８員の含窒素飽和複素環を形成していてもよい］で表される、
項１に記載の化合物又はその製薬学的に許容される塩を含有する医薬。
〔項２１〕
Ｘ、Ｙ及びＺのうちの１つまたは２つは、窒素原子を表す、項１～２０のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項２２〕
Ｘが、窒素原子であり、
Ｙ及びＺが、ＣＲ^８である、
項１～２１のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項２３〕
Ｙが、窒素原子であり、
Ｘ及びＺが、ＣＲ^８である、
項１～２１のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項２４〕
Ｚが、窒素原子であり、
Ｘ及びＹが、ＣＲ^８である、
項１～２１のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項２５〕
Ｒ^８は、複数ある場合はそれぞれ独立して、
水素原子、
フッ素原子、
塩素原子、
臭素原子、又は
Ｃ_１－６アルキル（該アルキルは、フッ素原子、水酸基、及びＣ_１－３アルコキシからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）である、
項１～２４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項２６〕
Ｒ^８が、複数ある場合はそれぞれ独立して、水素原子、フッ素原子、塩素原子、臭素原子、又はＣ_１－３アルキルである、
項１～２４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項２７〕
Ｌが、単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）である、
項１～２６のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項２８〕
Ｌが、
単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、及びシアノからなる群から選択される１個の置換基で置換されていてもよい）である、
項１～２６のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項２９〕
Ｌが、
単結合、又は
１個の水酸基又はフッ素原子で置換されていてもよいＣ_１－６アルキレンである、
項１～２６のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３０〕
Ｖが、
単結合、
Ｃ_３－７シクロアルキレン（該シクロアルキレンは、フッ素原子、水酸基、１～２個の水酸基で置換されていてもよいＣ_１－３アルキル、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）、又は
３～７員の二価飽和複素環基（該飽和複素環基は、フッ素原子、水酸基、１～２個の水酸基又はフッ素原子で置換されていてもよいＣ_１－３アルキル、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）である、
項１～２９のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３１〕
Ｖが、
単結合、
Ｃ_３－７シクロアルキレン（該シクロアルキレンは、フッ素原子、水酸基、１～２個の水酸基で置換されていてもよいＣ_１－３アルキル、及びシアノからなる群から選択される１個の置換基で置換されていてもよい）、又は
３～７員の二価飽和複素環基（該飽和複素環基は、フッ素原子、水酸基、１～２個の水酸基又はフッ素原子で置換されていてもよいＣ_１－３アルキル、及びシアノからなる群から選択される１個の置換基で置換されていてもよい）である、
項１～２９のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３２〕
Ｖが、
単結合、
Ｃ_３－７シクロアルキレン（該シクロアルキレンは、水酸基、及びＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）、又は
３～７員の二価飽和複素環基（該飽和複素環基は、フッ素原子、水酸基、及び１～２個の水酸基又はフッ素原子で置換されていてもよいＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）である、
項１～２９のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３３〕
Ｗが、
単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）である、
項１～３２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３４〕
Ｗが、
単結合、又は
Ｃ_１－３アルキレン（該アルキレンは、フッ素原子、水酸基、及びシアノからなる群から選択される１個の置換基で置換されていてもよい）である、
項１～３２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３５〕
Ｗが、
単結合、又は
１個の水酸基で置換されていてもよいＣ_１－３アルキレンである、
項１～３２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３６〕
Ｒ^１４が、
水素原子、又は
Ｃ_１－６アルキル（該アルキルは、フッ素原子、水酸基、及びシアノからなる群から選択される同一又は異なる１～２個の置換基で置換されていてもよい）である、
項１～３５のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３７〕
Ｒ^１４が、
水素原子、又は
Ｃ_１－３アルキル（該アルキルは、フッ素原子、水酸基、及びシアノからなる群から選択される１個の置換基で置換されていてもよい）である、
項１～３５のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３８〕
Ｑが、
水素原子、
ＮＨ_２、又は
ＮＨＭｅである、
項１～３７のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項３９〕
式（１）が、下記式（３）：

［式中、
Ｒ^８ａ及びＲ^８ｂは、それぞれ独立して、水素原子、フッ素原子、塩素原子、臭素原子、又はＣ_１－３アルキルを表し、
Ｌは、単結合、又は１個の水酸基で置換されていてもよいＣ_１－６アルキレンを表し、
Ｖは、
単結合、
Ｃ_３－７シクロアルキレン（該シクロアルキレンは、水酸基、及びＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）、又は
３～７員の二価飽和複素環基（該飽和複素環基は、フッ素原子、シアノ、水酸基、及びＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）を表し、
Ｗは、
単結合、又は
１個の水酸基で置換されていてもよいＣ_１－３アルキレンを表し、
Ｑは、水素原子又はＮＨ_２である］で表される
項１に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４０〕
Ｒ^８ａ及びＲ^８ｂが、それぞれ独立して、水素原子、フッ素原子又は塩素原子である、
項３９に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４１〕
Ｒ^８ａ及びＲ^８ｂが、それぞれ独立して、水素原子、又は塩素原子である、
項３９に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４２〕
Ｌが、Ｃ_１－３アルキレンである、
項３９～４１のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４３〕
Ｖが、単結合である、
項３９～４２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４４〕
Ｖが、Ｃ_３－７シクロアルキレンである、
項３９～４２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４５〕
Ｗが、単結合である、
項３９～４４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４６〕
Ｗが、Ｃ_１－３アルキレンである、
項３６～４４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４７〕
Ｑが、ＮＨ_２である、
項３６～４６のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４８〕
式（１）が、下記式（４）：

［式中、
Ｒ^８ｂ及びＲ^８ｃは、それぞれ独立して、水素原子、フッ素原子、塩素原子、臭素原子、又はＣ_１－３アルキルを表し、
Ｌは、
単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、及びシアノからなる群から選択される１個の置換基で置換されていてもよい）を表し、
Ｖは、
単結合、
Ｃ_３－７シクロアルキレン（該シクロアルキレンは、水酸基、及びＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）、又は
３～７員の二価飽和複素環基（該飽和複素環基は、フッ素原子、シアノ、水酸基、及び１～３個の水酸基及びフッ素原子で置換されていてもよいＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）を表し、
Ｗは、
単結合、又は
１個の水酸基で置換されていてもよいＣ_１－３アルキレンを表し、
Ｑは、水素原子、ＮＨ_２、又はＮＨＭｅである］で表される
項１に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項４９〕
Ｒ^８ｂ及びＲ^８ｃが、水素原子である、
項４８に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項５０〕
Ｌが、
単結合、又は
１個の水酸基又はフッ素原子で置換されていてもよいＣ_１－６アルキレンである、
項４８又は４９のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項５１〕
Ｌが、１個の水酸基又はフッ素原子で置換されていてもよいＣ_１－４アルキレンである、
項４８又は４９のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項５２〕
Ｌが、単結合である、
項４８又は４９のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項５３〕
Ｖが、
単結合、
Ｃ_３－７シクロアルキレン、又は
３～７員の二価飽和複素環基（該飽和複素環基は、フッ素原子、水酸基及びＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）である、
項４８～５２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項５４〕
Ｗが、
単結合、又は
Ｃ_１－３アルキレンである、
項４８～５３のいずれか一項に記載の化合物、またはその製薬学的に許容される塩を含有する医薬。
〔項５５〕
Ｗが、単結合である、
項４８～５３のいずれか一項に記載の化合物、またはその製薬学的に許容される塩を含有する医薬。
〔項５６〕
Ｗが、Ｃ_１－３アルキレンである、
項４８～５３のいずれか一項に記載の化合物、またはその製薬学的に許容される塩を含有する医薬。
〔項５７〕
Ｑが、水素原子である、
項４８～５６のいずれか一項に記載の化合物、またはその製薬学的に許容される塩を含有する医薬。
〔項５８〕
Ｑが、ＮＨ_２である、
項４８～５６のいずれか一項に記載の化合物、またはその製薬学的に許容される塩を含有する医薬。
〔項５９〕
Ｑが、ＮＨＭｅである、
項４８～５６のいずれか一項に記載の化合物、またはその製薬学的に許容される塩を含有する医薬。
〔項６０〕
式（１）が、下記式（５）：

［式中、
Ｒ^８ａ及びＲ^８ｃは、それぞれ独立して、水素原子、フッ素原子、塩素原子、臭素原子、又はＣ_１－３アルキルを表し、
Ｌは、単結合、又は１個の水酸基で置換されていてもよいＣ_１－6アルキレンを表し、
Ｖは、
単結合、
Ｃ_３－７シクロアルキレン（該シクロアルキレンは、水酸基、及びＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）、又は
３～７員の二価飽和複素環基（該飽和複素環基は、フッ素原子、シアノ、水酸基、及び１個の水酸基で置換されていてもよいＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）を表し、
Ｗは、
単結合、又は
１個の水酸基で置換されていてもよいＣ_１－３アルキレンを表し、
Ｑは、水素原子、又はＮＨ_２である］で表される
項１に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項６１〕
Ｒ^８ａ及びＲ^８ｃが、水素原子である、
項６０に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項６２〕
Ｌが、１個の水酸基で置換されていてもよいＣ_１－6アルキレンである、
項６０又は６１のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項６３〕
Ｖが、
単結合、
Ｃ_３－７シクロアルキレン又は
３～７員の二価飽和複素環基（該飽和複素環基は、水酸基、及び１個の水酸基で置換されていてもよいＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）である、
項６０～６２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項６４〕
Ｖが、単結合である、
項６０～６２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項６５〕
Ｖが、Ｃ_３－７シクロアルキレンである、
項６０～６２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項６６〕
Ｖが、３～７員の二価飽和複素環基（該飽和複素環基は、水酸基、及びＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）である、
項６０～６２のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項６７〕
Ｗが、
単結合、又は
Ｃ_１－３アルキレンである、
項６０～６６のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項６８〕
Ｗが、単結合である、
項６０～６６のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項６９〕
Ｗが、Ｃ_１－３アルキレンである、
項６０～６６のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項７０〕
Ｑが、水素原子である、
項６０～６９のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項７１〕
Ｑが、ＮＨ_２である、
項６０～６９のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項７２〕
式（１）が、下記式（６）：

［式中、
Ｒ^８ａは、水素原子、フッ素原子、塩素原子、臭素原子、又はＣ_１－３アルキルを表し、
Ｌは、
単結合、又は
Ｃ_１－６アルキレン（該アルキレンは、フッ素原子、水酸基、及びシアノからなる群から選択される１個の置換基で置換されていてもよい）を表し、
Ｖは、
単結合、
Ｃ_３－７シクロアルキレン（該シクロアルキレンは、水酸基、及びＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）、又は
３～７員の二価飽和複素環基（該飽和複素環基は、フッ素原子、シアノ、水酸基及び１～３個のフッ素原子で置換されていてもよいＣ_１－３アルキルからなる群から選択される１個の置換基で置換されていてもよい）を表し、
Ｗは、
単結合、又は
１個の水酸基で置換されていてもよいＣ_１－３アルキレンを表し、
Ｑは、水素原子、ＮＨ_２、又はＮＨＭｅである］で表される
項１に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項７３〕
Ｒ^８ａが、水素原子である、
項７２に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項７４〕
Ｌが、Ｃ_１－４アルキレンである、
項７２又は７３のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項７５〕
Ｖが、
単結合、又は
Ｃ_３－７シクロアルキレンである、
項７２～７４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項７６〕
Ｖが、単結合である、
項７２～７４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項７７〕
Ｖが、Ｃ_３－７シクロアルキレンである、
項７２～７４のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を含有する医薬。
〔項７８〕
Ｗが、
単結合、又は、
Ｃ_１－３アルキレンである、
項７２～７７のいずれか一項に記載の化合物、またはその製薬学的に許容される塩を含有する医薬。
〔項７９〕
Ｗが、単結合である、
項７２～７７のいずれか一項に記載の化合物、またはその製薬学的に許容される塩を含有する医薬。
〔項８０〕
Ｗが、Ｃ_１－３アルキレンである、
項７２～７７のいずれか一項に記載の化合物、またはその製薬学的に許容される塩を含有する医薬。
〔項８１〕
Ｑが、ＮＨ_２である、
項７２～８０のいずれか一項に記載の化合物、またはその製薬学的に許容される塩を含有する医薬。
〔項８２〕
以下の化合物から選択される、化合物又はその製薬学的に許容される塩を含有する、項１に記載の医薬：５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例１）、
５－（｛５－［２－（３－アミノプロポキシ）－６－クロロ－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例２）、
５－（｛５－［３－（３－アミノプロポキシ）－５－メトキシピリジン－４－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例３）、
５－（｛５－［４－（３－アミノプロポキシ）－２－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例４）、
５－［（５－｛３－［（３－フルオロアゼチジン－３－イル）メトキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例５）、
５－［（５－｛２－メトキシ－４－［（３－メチルアゼチジン－３－イル）メトキシ］ピリジン－３－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例６）、
５－［（５－｛４－［（３－ヒドロキシアゼチジン－３－イル）メトキシ］－２－メトキシピリジン－３－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例７）、
５－｛［５－（４－｛［３－（ヒドロキシメチル）アゼチジン－３－イル］メトキシ｝－２－メトキシピリジン－３－イル）－１Ｈ－ピラゾール－３－イル］アミノ｝ピラジン－２－カルボニトリル（実施例８）、
５－［（５－｛３－［（３Ｒ）－３－アミノブトキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例９）、
５－［（５－｛３－［（３Ｓ）－３－アミノブトキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例１０）、
５－｛［５－（３－｛［１－（アミノメチル）シクロプロピル］メトキシ｝－５－メトキシピリジン－４－イル）－１Ｈ－ピラゾール－３－イル］アミノ｝ピラジン－２－カルボニトリル（実施例１１）、
５－［（５－｛３－メトキシ－５－［（モルホリン－２－イル）メトキシ］ピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例１２）、
５－［（５－｛３－メトキシ－５－［（モルホリン－２－イル）メトキシ］ピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例１３）、
５－［（５－｛３－［（２Ｓ）－３－アミノ－２－ヒドロキシプロポキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例１４）、
Ｎ－｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝－５－クロロピラジン－２－アミン（実施例１５）、
Ｎ－｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝－５－（トリフルオロメチル）ピラジン－２－アミン（実施例１６）、
５－（｛５－［４－（３－アミノプロポキシ）－６－メトキシピリミジン－５－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例１７）、５－（｛５－［３－（アゼチジン－３－イル）メトキシ－５－メトキシピリジン－４－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例１８）、
５－｛［５－（３－｛［（１Ｒ，３Ｓ）－３－アミノシクロヘキシル］オキシ｝－５－メトキシピリジン－４－イル）－１Ｈ－ピラゾール－３－イル］アミノ｝ピラジン－２－カルボニトリル（実施例１９）、
（Ｓ）－５－［（５－｛３－［（３－フルオロピロリジン－３－イル）メトキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例２０）、
（Ｓ）－５－［（５－｛３－メトキシ－［５－（ピロリジン－３－イル）メトキシ］ピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例２１）、
（Ｒ）－５－［（５－｛３－［（３－フルオロピロリジン－３－イル）メトキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例２２）、
５－｛［５－（４－｛［１－（アミノメチル）シクロプロピル］メトキシ｝－６－メトキシピリミジン－－イル）－１Ｈ－ピラゾール－３－イル］アミノ｝ピラジン－２－カルボニトリル（実施例２３）、
５－（｛５－［３－（３－アミノプロポキシ）－５－（フルオロメトキシ）ピリジン－４－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例２４）、
５－［（５－｛３－メトキシ－５－［（３－メチルアゼチジン－３－イル）メトキシ］ピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例２５）、
５－｛［５－（３－｛［３－（ジフルオロメチル）アゼチジン－３－イル］メトキシ｝－５－メトキシピリジン－４－イル）－１Ｈ－ピラゾール－３－イル］アミノ｝ピラジン－２－カルボニトリル（実施例２６）、
５－［（５－｛３－［（２Ｓ）－３－アミノ－２－メチルプロポキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例２７）、
５－［（５－｛３－［（２Ｒ）－３－アミノ－２－メチルプロポキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例２８）、
５－［（５－｛３－［（２Ｓ）－３－アミノ－２－フルオロプロポキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例２９）、
５－［（５－｛３－［（２Ｒ）－３－アミノ－２－フルオロプロポキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例３０）、
５－［（５－｛３－メトキシ－５－［３－（メチルアミノ）プロポキシ］ピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例３１）、
５－｛［５－（３－｛［（１Ｒ，３Ｒ）－３－アミノシクロペンチル］オキシ｝－５－メトキシピリジン－４－イル）－１Ｈ－ピラゾール－３－イル］アミノ｝ピラジン－２－カルボニトリル（実施例３２）、
５－［（５－｛３－［（１Ｒ）－１－（アゼチジン－３－イル）エトキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例３３）、
５－［（５－｛３－［（１Ｒ）－１－（３－ヒドロキシアゼチジン－３－イル）エトキシ］－５－メトキシピリジン－４－イル｝－１Ｈ－ピラゾール－３－イル）アミノ］ピラジン－２－カルボニトリル（実施例３４）、
５－｛［５－（３－メトキシ－５－｛［（１Ｒ，３Ｒ）－３－（メチルアミノ）シクロペンチル］オキシ｝ピリジン－４－イル）－１Ｈ－ピラゾール－３－イル］アミノ｝ピラジン－２－カルボニトリル（実施例３５）、
５－｛［５－（３－｛［（１Ｒ，２Ｓ，４Ｓ，５Ｓ）－４－アミノビシクロ［３．１．０］ヘキサン－２－イル］オキシ｝－５－メトキシピリジン－４－イル）－１Ｈ－ピラゾール－３－イル］アミノ｝ピラジン－２－カルボニトリル（実施例３６）、
５－｛［５－（２－｛［１－（アミノメチル）シクロプロピル］メトキシ｝－４－メトキシピリジン－３－イル）－１Ｈ－ピラゾール－３－イル］アミノ｝ピラジン－２－カルボニトリル（実施例３７）、
５－｛［５－（４－｛［１－（アミノメチル）シクロプロピル］メトキシ｝－２－メトキシピリジン－３－イル）－１Ｈ－ピラゾール－３－イル］アミノ｝ピラジン－２－カルボニトリル（実施例３８）。
〔項８３〕
以下の化合物から選択される、化合物又はその製薬学的に許容される塩を含有する、項１に記載の医薬：５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例１）、
５－（｛５－［３－（３－アミノプロポキシ）－５－メトキシピリジン－４－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例３）、
５－（｛５－［４－（３－アミノプロポキシ）－２－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例４）。
〔項８４〕
以下の化合物から選択される、化合物又はその製薬学的に許容される塩を含有する、項１に記載の医薬：５－（｛５－［４－（３－アミノプロポキシ）－２－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例４）。
〔項８５〕
以下の化合物又はその製薬学的に許容される塩を含有する、項１に記載の医薬：
５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例１）。
〔項８６〕
以下の化合物又はその製薬学的に許容される塩を含有する、項１に記載の医薬：
５－（｛５－［３－（３－アミノプロポキシ）－５－メトキシピリジン－４－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル（実施例３）。
〔項８７〕
項１～８６のいずれか一項に記載の医薬を有効成分として含有する医薬組成物。
〔項８８〕
項１～８６のいずれか一項に記載の医薬、プレキサセルチブ、又はその製薬学的に許容される塩を内封したリポソームを含有する医薬組成物。
〔項８９〕
項１～８６のいずれか一項に記載の医薬を内封したリポソームを含有する医薬組成物。
〔項９０〕
項１～８６のいずれか一項に記載の医薬であって、該医薬はそれを内封したリポソームに含まれる医薬。
〔項９１〕
前記リポソームが、リン脂質をさらに含む、項８８又は８９に記載の医薬組成物又は項９０に記載の医薬。
〔項９２〕
前記リポソームが、
（１）項１～８６のいずれか一項に記載の医薬、及び
（２）リン脂質、
を含む、項８８～９１のいずれか一項に記載の医薬組成物又は医薬。
〔項９３〕
前記リン脂質が、ホスファチジルコリン、ホスファチジルグリセロール、ホスファチジン酸、ホスファチジルエタノールアミン、ホスファチジルセリン、ホスファチジルイノシトール、スフィンゴミエリン、大豆レシチン、卵黄レシチン、水素添加卵黄レシチン、及び水素添加大豆レシチンからなる群より選択される一種又はそれらの二種以上の組み合わせ物である、項９１又は９２に記載の医薬組成物又は医薬。
〔項９４〕
前記リポソームが、さらにステロール類を含む、項８８～９３のいずれか一項に記載の医薬組成物又は医薬。
〔項９５〕
前記ステロール類が、コレステロールである、項９４に記載の医薬組成物又は医薬。
〔項９６〕
前記リポソームが、さらにポリマー修飾脂質を含む、項８８～９５のいずれか一項に記載の医薬組成物又は医薬。
〔項９７〕
前記ポリマー修飾脂質のポリマー部分が、ポリエチレングリコール、ポリプロピレングリコール、ポリビニルアルコール、ポリビニルピロリドン、メトキシポリエチレングリコール、メトキシポリプロピレングリコール、メトキシポリビニルアルコール、メトキシポリビニルピロリドン、エトキシポリエチレングリコール、エトキシポリプロピレングリコール、エトキシポリビニルアルコール、エトキシポリビニルピロリドン、プロポキシポリエチレングリコール、プロポキシポリプロピレングリコール、プロポキシポリビニルアルコール、又はプロポキシポリビニルピロリドンである、項９６に記載の医薬組成物又は医薬。
〔項９８〕
ポリマー修飾脂質の脂質部分が、ホスファチジルエタノールアミン又はジアシルグリセロールである、項９６又は９７に記載の医薬組成物又は医薬。
〔項９９〕
前記ポリマー修飾脂質が、ポリマー部分としてポリエチレングリコール、ポリプロピレングリコール、ポリビニルアルコール、ポリビニルピロリドン、メトキシポリエチレングリコール、メトキシポリプロピレングリコール、メトキシポリビニルアルコール、メトキシポリビニルピロリドン、エトキシポリエチレングリコール、エトキシポリプロピレングリコール、エトキシポリビニルアルコール、エトキシポリビニルピロリドン、プロポキシポリエチレングリコール、プロポキシポリプロピレングリコール、プロポキシポリビニルアルコール、又はプロポキシポリビニルピロリドンを含み、脂質部分としてホスファチジルエタノールアミン又はジアシルグリセロールを含む、項９６又は９７に記載の医薬組成物又は医薬。
〔項１００〕
前記リポソームが、
（１）項１～８６のいずれか一項に記載の医薬、
（２）４０～７０モル％のリン脂質、
（３）３０～５０モル％のコレステロール、及び
（４）１～１０モル％のポリマー修飾脂質、
を含む、項８９～９１のいずれか一項に記載の医薬組成物又は医薬。
〔項１０１〕
前記リポソームが、さらに、無機酸、無機酸塩、有機酸、有機酸塩、糖類、緩衝剤、酸化防止剤、及びポリマー類からなる群から選択される添加物を含む、項８９～１００のいずれか一項に記載の医薬組成物又は医薬。
〔項１０２〕
項１～８６のいずれか一項に記載の医薬を有効成分として含有する、癌の治療剤及び／又は予防剤。
〔項１０３〕
前記癌が、扁平上皮がん、メラノーマ、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、骨髄異形成症候群、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、脳腫瘍、頭頸部がん、頭頸部扁平上皮癌、食道がん、甲状腺がん、肺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、トリプルネガティブ乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、結腸がん、直腸がん、ＭＳＩ－ｈｉｇｈ大腸がん、肛門がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、白金製剤抵抗性卵巣がん、ＰＡＲＰ阻害剤抵抗性卵巣がん、膀胱がん、尿路上皮がん、腎がん、腎細胞がん、前立腺がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、悪性黒色腫、神経芽細胞腫、骨肉種、ユーイング肉腫、軟骨肉腫、軟部肉腫、又は皮膚がんからなる群から選択される少なくとも一種の癌である、項１０２に記載の治療剤及び／又は予防剤。
〔項１０４〕
前記癌が、頭頚部がん、扁平上皮がん、非小細胞肺がん、肛門がん、乳がん、トリプルネガティブ乳がん、卵巣がん、白金製剤抵抗性卵巣がん、又は子宮体がんからなる群から選択される少なくとも一種の癌である、項１０２に記載の治療剤及び／又は予防剤。
〔項１０５〕
治療及び／又は予防が必要な患者に、治療及び／又は予防上の有効量の項１～８６のいずれか一項に記載の医薬、或いは項８７～１０１に記載の医薬組成物又は医薬、或いは項１０２～１０４に記載の治療剤及び／又は予防剤を投与することを含む、癌の治療及び／又は予防するための方法。
〔項１０６〕
前記癌が、扁平上皮がん、メラノーマ、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、骨髄異形成症候群、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、脳腫瘍、頭頸部がん、頭頸部扁平上皮癌、食道がん、甲状腺がん、肺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、トリプルネガティブ乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、結腸がん、直腸がん、ＭＳＩ－ｈｉｇｈ大腸がん、肛門がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、白金製剤抵抗性卵巣がん、ＰＡＲＰ阻害剤抵抗性卵巣がん、膀胱がん、尿路上皮がん、腎がん、腎細胞がん、前立腺がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、悪性黒色腫、神経芽細胞腫、骨肉種、ユーイング肉腫、軟骨肉腫、軟部肉腫、又は皮膚がんからなる群から選択される少なくとも一種の癌である、項１０５に記載の治療及び／又は予防するための方法。
〔項１０７〕
癌の治療剤及び／又は予防剤を製造するための、項１～８６のいずれか一項に記載の医薬、或いは項８７～１０１に記載の医薬組成物又は医薬、或いは項１０２～１０４に記載の治療剤及び／又は予防剤の使用。
〔項１０８〕
前記癌が、扁平上皮がん、メラノーマ、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、骨髄異形成症候群、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、脳腫瘍、頭頸部がん、頭頸部扁平上皮癌、食道がん、甲状腺がん、肺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、トリプルネガティブ乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、結腸がん、直腸がん、ＭＳＩ－ｈｉｇｈ大腸がん、肛門がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、白金製剤抵抗性卵巣がん、ＰＡＲＰ阻害剤抵抗性卵巣がん、膀胱がん、尿路上皮がん、腎がん、腎細胞がん、前立腺がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、悪性黒色腫、神経芽細胞腫、骨肉種、ユーイング肉腫、軟骨肉腫、軟部肉腫、又は皮膚がんからなる群から選択される少なくとも一種の癌である、項１～８６のいずれか一項に記載の医薬、或いは医薬組成物、或いは治療剤及び／又は予防剤の使用。
〔項１０９〕
癌の治療及び／又は予防に使用するための、項１～８６のいずれか一項に記載の医薬、或いは項８７～１０１に記載の医薬組成物又は医薬、或いは項１０２～１０４に記載の治療剤及び／又は予防剤。
〔項１１０〕
前記癌が、扁平上皮がん、メラノーマ、急性白血病、慢性リンパ性白血病、慢性骨髄性白血病、骨髄異形成症候群、真性多血症、悪性リンパ腫、形質細胞腫瘍、多発性骨髄腫、脳腫瘍、頭頸部がん、頭頸部扁平上皮癌、食道がん、甲状腺がん、肺がん、小細胞肺がん、非小細胞肺がん、胸腺腫・胸腺がん、乳がん、トリプルネガティブ乳がん、胃がん、胆のう・胆管がん、肝がん、肝細胞がん、膵がん、結腸がん、直腸がん、ＭＳＩ－ｈｉｇｈ大腸がん、肛門がん、消化管間質腫瘍、絨毛上皮がん、子宮体がん、子宮頸がん、卵巣がん、白金製剤抵抗性卵巣がん、ＰＡＲＰ阻害剤抵抗性卵巣がん、膀胱がん、尿路上皮がん、腎がん、腎細胞がん、前立腺がん、睾丸腫瘍、精巣胚細胞腫瘍、卵巣胚細胞腫瘍、ウイルムス腫瘍、悪性黒色腫、神経芽細胞腫、骨肉種、ユーイング肉腫、軟骨肉腫、軟部肉腫、又は皮膚がんからなる群から選択される少なくとも一種の癌である、項１～８６のいずれか一項に記載の医薬、或いは医薬組成物、或いは治療剤及び／又は予防剤。
〔項１１１〕
併用薬物又はその製薬学的に許容される塩と併用して、がんを治療するための、項１～８６のいずれか一項に記載の医薬であって、当該併用薬物が、ホルモン療法剤、化学療法剤、免疫療法剤ならびに細胞増殖因子およびその受容体作用を阻害する薬剤からなる群から選択される少なくとも１種以上である、項１～８６のいずれか一項に記載の医薬。
〔項１１２〕
併用薬物又はその製薬学的に許容される塩と併用して、がんを治療するための、項１～８６のいずれか一項に記載の医薬であって、当該併用薬物が、５－ＦＵ系薬剤、シタラビン、塩酸ドキソルビシン、ゲムシタビン、メソトレキセート、ペメトレキセド、エトポシド、イリノテカン、トポテカン、シスプラチン、カルボプラチン、オキサリプラチン、パクリタキセル、ドセタキセル、電離放射線、ベバシズマブ、リポソーム化ドキソルビシン、ルカパリブ、オラパリブ、ニラパリブ、トラベクテジン、パゾパニブ、ペンブロリズマブ、ニボルマブ、イピリムマブ、デュルバルマブ、アベルマブ、アテゾリズマブ、ラロトレクチニブ、エントレクチニブ、ナブパクリタキセル、エルロチニブ、リポソーム化イリノテカン、ロイコボリン、セツキシマブ、エリブリン、イホスファミド、ダカルバジンからなる群から選択される少なくとも１種以上である、項１～８６のいずれか一項に記載の医薬。
〔項１１３〕
併用薬物又はその製薬学的に許容される塩と併用して、がんを治療するための、項１～８６のいずれか一項に記載の医薬であって、当該併用薬物が、５－ＦＵ系薬剤、イリノテカン、ゲムシタビン、シスプラチン、カルボプラチン、オキサリプラチン、パクリタキセル、電離放射線、ルカパリブ、オラパリブ、ニラパリブ、ペンブロリズマブ、ニボルマブからなる群から選択される少なくとも１種以上である、項１～８６のいずれか一項に記載の医薬。
〔項１１４〕
併用薬物又はその製薬学的に許容される塩と併用して、がんを治療するための、（ａ）項１～８６のいずれか一項に記載の医薬であって、（ｂ）当該併用薬物が、ホルモン療法剤、化学療法剤、免疫療法剤ならびに細胞増殖因子およびその受容体作用を阻害する薬剤からなる群から選択される少なくとも１種以上であり、
（１）（ａ）が（ｂ）と同時に投与される、
（２）（ａ）が (ｂ)の投与後に投与される、又は
（３）（ｂ）が (ａ)の投与後に投与されること、を特徴とする、
項１～８６のいずれか一項に記載の医薬。
〔項１１５〕
前記併用薬物（ｂ）が、化学療法剤又は免疫療法剤である、
項１１４に記載の医薬。
〔項１１６〕
前記併用薬物（ｂ）が、ゲムシタビンである、
項１１４又は１１５に記載の医薬。
〔項１１７〕
前記（ａ）医薬が、前記（ｂ）ゲムシタビンと同時に投与される項１１６に記載の医薬。
〔項１１８〕
前記（ａ）医薬が、前記（ｂ）ゲムシタビンの投与後約２４～４８時間以内に投与される項１１６に記載の医薬。
〔項１１９〕
前記（ｂ）ゲムシタビンが、前記（ａ）化合物、又はその製薬学的に許容される塩、或いはリポソームの投与後約２４～４８時間以内に投与される項１１６に記載の医薬。
〔項１２０〕
前記併用薬物（ｂ）が、抗ＰＤ－１抗体である、
項１１４又は１１５に記載の医薬。
〔項１２１〕
前記（ａ）化合物、又はその製薬学的に許容される塩、或いはリポソームが、前記（ｂ）抗ＰＤ－１抗体と同時に投与される項１２０に記載の医薬。
〔項１２２〕
前記（ｂ）抗ＰＤ－１抗体が、前記（ａ）化合物、又はその製薬学的に許容される塩、或いはリポソームの投与後約７２～９６時間以内に投与される、項１２０に記載の医薬。
〔項１２３〕
前記（ａ）化合物、又はその製薬学的に許容される塩、或いはリポソームが、前記（ｂ）抗ＰＤ－１抗体の投与後約７２～９６時間以内に投与される項１１６に記載の医薬。
〔項１２４〕
併用薬物と組み合わせてなる、項１～８６のいずれか一項に記載の医薬を含む医薬組成物、或いは項８７～１０１のいずれか一項に記載の医薬組成物又は医薬であって、当該併用薬物が、ホルモン療法剤、化学療法剤、免疫療法剤ならびに細胞増殖因子およびその受容体作用を阻害する薬剤からなる群から選択される少なくとも１種以上である、医薬組成物。
〔項１２５〕
併用薬物と組み合わせてなる、項１～８６のいずれか一項に記載の医薬医薬を含む医薬組成物、或いは項８７～１０１のいずれか一項に記載の医薬組成物又は医薬であって、当該併用薬物が、５－ＦＵ系薬剤、シタラビン、塩酸ドキソルビシン、ゲムシタビン、メソトレキセート、ペメトレキセド、エトポシド、イリノテカン、トポテカン、シスプラチン、カルボプラチン、オキサリプラチン、パクリタキセル、ドセタキセル、電離放射線、ベバシズマブ、リポソーム化ドキソルビシン、ルカパリブ、オラパリブ、ニラパリブ、トラベクテジン、パゾパニブ、ペンブロリズマブ、ニボルマブ、イピリムマブ、デュルバルマブ、アベルマブ、アテゾリズマブ、ラロトレクチニブ、エントレクチニブ、ナブパクリタキセル、エルロチニブ、リポソーム化イリノテカン、ロイコボリン、セツキシマブ、エリブリン、イホスファミド、ダカルバジンからなる群から選択される少なくとも１種以上である、医薬組成物。
〔項１２６〕
併用薬物と組み合わせてなる、項１～８６のいずれか一項に記載の医薬を含む医薬組成物、或いは項８７～１０１のいずれか一項に記載の医薬組成物又は医薬であって、当該併用薬物が、５－ＦＵ系薬剤、イリノテカン、ゲムシタビン、シスプラチン、カルボプラチン、オキサリプラチン、パクリタキセル、電離放射線、ルカパリブ、オラパリブ、ニラパリブ、ペンブロリズマブ、ニボルマブからなる群から選択される少なくとも１種以上である、医薬組成物。
〔項１２７〕
Ｘ線粉末回折において、７．２°±０．２°、及び８．８°±０．２°に回折角（２θ°）ピークを有する、形態Ｉの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル 塩酸塩。
〔項１２８〕
Ｘ線粉末回折において、７．２°±０．２°、８．８°±０．２°、９．８°±０．２°、１０．２°±０．２°、１０．７°±０．２°、１６．７°±０．２°、１８．５°±０．２°、２６．２°±０．２°、及び２７．０°±０．２°および２６．４°±０．２°から選択される４つ以上の回折角（２θ°）ピークを有する、形態Ｉの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル 塩酸塩。
〔項１２９〕
Ｘ線粉末回折において、６．８°±０．２°、及び１３．０°±０．２°に回折角（２θ°）ピークを有する、形態ＩＩの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル リン酸塩。
〔項１３０〕
Ｘ線粉末回折において、６．８°±０．２°、７．５°±０．２°、１１．７°±０．２°、１１．９°±０．２°、１３．０°±０．２°、１６．４°±０．２°、１９．３°±０．２°、２０．４°±０．２°、２２．７°±０．２°、及び２４．３°±０．２°から選択される４つ以上の回折角（２θ°）ピークを有する、形態ＩＩの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル リン酸塩。
〔項１３１〕
Ｘ線粉末回折において、６．０°±０．２°、及び１７．０°±０．２°に回折角（２θ°）ピークを有する、形態ＩＩＩの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル トシル酸塩。
〔項１３２〕
Ｘ線粉末回折において、６．０°±０．２°、９．０°±０．２°、１２．１°±０．２°、１４．４°±０．２°、１６．２°±０．２°、１７．０°±０．２°、２２．８°±０．２°、及び２６．３°±０．２°から選択される４つ以上の回折角（２θ°）ピークを有する、形態ＩＩＩの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル トシル酸塩。
〔項１３３〕
Ｘ線粉末回折において、９．３°±０．２°、及び１０．２°±０．２°に回折角（２θ°）ピークを有する、形態ＩＶの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル。
〔項１３４〕
Ｘ線粉末回折において、９．３°±０．２°、１０．２°±０．２°、１０．７°±０．２°、１３．６°±０．２°、１６．７°±０．２°、１７．１°±０．２°、１７．８°±０．２°、１８．６°±０．２°、２６．１°±０．２°及び２６．４°±０．２°から選択される４つ以上の回折角（２θ°）ピークを有する、形態ＩＶの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル。
〔項１３５〕
Ｘ線粉末回折において、７．９°±０．２°、及び８．７°±０．２°に回折角（２θ°）ピークを有する、形態Ｖの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル。
〔項１３６〕
Ｘ線粉末回折において、７．９°±０．２°、８．７°±０．２°、１２．２°±０．２°、１３．１°±０．２°、１５．９°±０．２°、１７．６°±０．２°、１９．９°±０．２°、２１．９°±０．２°、２２．８°±０．２°、及び２６．６°±０．２°から選択される４つ以上の回折角（２θ°）ピークを有する、形態Ｖの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル。
〔項１３７〕
Ｘ線粉末回折において、５．３°±０．２°、及び５．７°±０．２°に回折角（２θ°）ピークを有する、形態ＶＩの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル。
〔項１３８〕
Ｘ線粉末回折において、５．３°±０．２°、５．７°±０．２°、７．０°±０．２°、７．３°±０．２°、７．８°±０．２°、８．４°±０．２°、９．３°±０．２°、１０．５°±０．２°、１１．５°±０．２°、及び１４．１°±０．２°から選択される４つ以上の回折角（２θ°）ピークを有する、形態ＶＩの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル。
〔項１３９〕
Ｘ線粉末回折において、８．２°±０．２°、及び２７．０°±０．２°に回折角（２θ°）ピークを有する、形態ＶＩＩの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル 塩酸塩。
〔項１４０〕
Ｘ線粉末回折において、７．０°±０．２°、８．２°±０．２°、９．７°±０．２°、１１．５°±０．２°、１４．０°±０．２°、１４．６°±０．２°、１６．３°±０．２°、１８．０°±０．２°、１９．８°±０．２°、２１．２°±０．２°、２１．５°±０．２°、２４．１°±０．２°、及び２７．０°±０．２°から選択される４つ以上の回折角（２θ°）ピークを有する、形態ＶＩＩの結晶形態の５－（｛５－［２－（３－アミノプロポキシ）－４－メトキシピリジン－３－イル］－１Ｈ－ピラゾール－３－イル｝アミノ）ピラジン－２－カルボニトリル 塩酸塩。 [Section 1]

[In the formula,
R¹is a hydrogen atom, optionally substituted C_1-6Alkyl, optionally substituted C_3-10Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C_6-10represents aryl or optionally substituted 5- to 12-membered heteroaryl,
R²is hydrogen atom, halogen atom, cyano, nitro, carboxyl, sulfonic acid, phosphoric acid, -OR³,-SR³,-COR⁴,-CO₂R⁴,-CONR⁵R⁶,-SO₂R⁴,-SO₂N.R.⁵R⁶,-OCOR⁴,-OCO₂R⁴,-OCONR⁵R⁶,-NR⁵R⁶,-NR⁷C.O.R.⁴,-NR⁷C.O.₂R⁴,-NR⁷CONR⁵R⁶,-NR⁷S.O.₂R⁴,-NR⁷S.O.₂N.R.⁵R⁶, optionally substituted C_1-6Alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-10Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C_6-10represents aryl or optionally substituted 5- to 12-membered heteroaryl,
R³is a hydrogen atom or C_1-6represents alkyl,
R⁴is C_1-6represents alkyl,
R⁵,R⁶and R⁷are each independently a hydrogen atom or C_1-6represents alkyl, where R bonded to the same nitrogen atom⁵and R⁶are both C_1-6When alkyl, these may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded,
X, Y and Z are each independently CR⁸or represents a nitrogen atom, where X, Y and Z are simultaneously CR⁸not,
R⁸If there is more than one, each independently represents hydrogen atom, halogen atom, cyano, nitro, carboxyl, sulfonic acid, phosphoric acid, -OR⁹,-SR⁹,-COR¹⁰,-CO₂R¹⁰,-CONR¹¹R¹²,-SO₂R¹⁰,-SO₂N.R.¹¹R¹²,-OCOR¹⁰,-OCO₂R¹⁰,-OCONR¹¹R¹²,-NR¹¹R¹²,-NR¹³C.O.R.¹⁰,-NR¹³C.O.₂R¹⁰,-NR¹³CONR¹¹R¹²,-NR¹³S.O.₂R¹⁰,-NR¹³S.O.₂N.R.¹¹R¹², optionally substituted C_1-6Alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-10Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C_6-10represents aryl or optionally substituted 5- to 12-membered heteroaryl,
R⁹is a hydrogen atom or C_1-6represents alkyl,
R¹⁰is C_1-6represents alkyl,
R¹¹,R¹²and R¹³are each independently a hydrogen atom or C_1-6represents alkyl, where R bonded to the same nitrogen atom¹¹and R¹²are both C_1-6When alkyl, these may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded,
L is a single bond or optionally substituted C_1-6represents alkylene,
V is a single bond, optionally substituted C_3-10Represents cycloalkylene or an optionally substituted 3- to 10-membered divalent saturated heterocyclic group,
W is a single bond or optionally substituted C_1-6represents alkylene,
Q is a hydrogen atom or NHR¹⁴represents,
R¹⁴is a hydrogen atom, optionally substituted C_1-6Alkyl, optionally substituted C_3-10cycloalkyl or an optionally substituted 3- to 10-membered saturated heterocyclic group],
A medicament containing a compound or a pharmaceutically acceptable salt thereof.
[Section 2]
R¹,R²,R⁸,R¹⁴, L, V, and optionally substituted C in W_1-6Alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-10Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C_6-10Aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C_1-6alkylene, optionally substituted C_3-10cycloalkylene or an optionally substituted 3- to 10-membered divalent saturated heterocyclic group, each independently
(1) Halogen atom,
(2) hydroxyl group,
(3)C_6-10aryl,
(4) 5-12 membered heteroaryl,
(5)C_1-6alkyl,
(6)C_2-6alkenyl,
(7)C_2-6alkynyl,
(8)C_1-6alkoxy,
(9)C_1-6Alkylthio
(10)C_3-10cycloalkyl,
(11) 3- to 10-membered saturated heterocyclic group,
(12) carboxyl,
(13)-COR¹⁵,
(14)-CO₂R¹⁵,
(15)-CONR¹⁶R¹⁷,
(16)-NR¹⁶R¹⁷,
(17)-NR¹⁸C.O.R.¹⁵,
(18)-NR¹⁸C.O.₂R¹⁵,
(19)-NR¹⁸S.O.₂R¹⁵,
(20)-NR¹⁸CONR¹⁶R¹⁷,
(21)-NR¹⁸S.O.₂N.R.¹⁶R¹⁷,
(22)-SO₂R¹⁵,
(23)-SO₂N.R.¹⁶R¹⁷,
(24)-OCOR¹⁵,
(25)-OCO₂R¹⁵,
(26)-OCONR¹⁶R¹⁷,
(27) sulfonic acid,
(28) phosphoric acid,
(29) Cyano, and
(30) Nitro
may be substituted with the same or different 1 to 5 substituents selected from the group consisting of;
Here, the above (3)C_6-10Aryl, (4) 5-12 membered heteroaryl, (5) C_1-6Alkyl, (6)C_2-6alkenyl, (7)C_2-6Alkynyl, (8)C_1-6Alkoxy, (9)C_1-6Alkylthio, (9)C_3-10The group shown in cycloalkyl and (10) 3- to 10-membered saturated heterocyclic group is
(a) halogen atom,
(b) hydroxyl group,
(c)C_6-10aryl,
(d) 5-12 membered heteroaryl,
(e)C_1-6alkyl,
(f)C_2-6alkenyl,
(g)C_2-6alkynyl,
(h)C_1-6alkoxy,
(i)C_3-10cycloalkyl,
(j) 3- to 10-membered saturated heterocyclic group,
(k) carboxyl,
(l)-COR¹⁵,
(m)-CO₂R¹⁵,
(n)-CONR¹⁶R¹⁷,
(o)-NR¹⁶R¹⁷,
(p)-NR¹⁸C.O.R.¹⁵,
(q)-NR¹⁸S.O.₂R¹⁵,
(r)-SO₂R¹⁵,
(s)-SO₂N.R.¹⁶R¹⁷,
(t) sulfonic acid,
(u) phosphoric acid,
(v) cyano, and
(w) Nitro
may be substituted with the same or different 1 to 5 substituents selected from the group consisting of;
R¹⁵However, if there are multiple, each independently, C_1-6is alkyl,
R¹⁶and R¹⁷are each independently a hydrogen atom or C_1-6is alkyl, R¹⁶or R¹⁷If there are multiple R¹⁶or R¹⁷may be the same or different, and here, R bonded to the same nitrogen atom¹⁶and R¹⁷are both C_1-6When alkyl, these may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded,
R¹⁸is a hydrogen atom or C_1-6is an alkyl,
Item 1. A medicament containing the compound according to item 1 or a pharmaceutically acceptable salt thereof.
[Section 3]
R¹,R²,R⁸,R¹⁴, L, V, and optionally substituted C in W_1-6Alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-10Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C_6-10Aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C_1-6alkylene, optionally substituted C_3-10cycloalkylene or an optionally substituted 3- to 10-membered divalent saturated heterocyclic group, each independently
(1) Halogen atom,
(2) hydroxyl group,
(3)C_6-10aryl,
(4) 5-12 membered heteroaryl,
(5) C optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-6alkyl,
(6)C_2-6alkenyl,
(7)C_2-6alkynyl,
(8)C_1-6alkoxy,
(9)C_3-10cycloalkyl,
(10) 3- to 10-membered saturated heterocyclic group,
(11) carboxyl,
(12)-COR¹⁵,
(13)-CO₂R¹⁵,
(14)-CONR¹⁶R¹⁷,
(15)-NR¹⁶R¹⁷,
(16)-SO₂R¹⁵,
(17)-SO₂N.R.¹⁶R¹⁷,
(18) sulfonic acid,
(19) phosphoric acid,
(20) Cyano, and
(21) Nitro
may be substituted with the same or different 1 to 5 substituents selected from the group consisting of;
R¹⁵However, if there are multiple, each independently, C_1-6is alkyl,
R¹⁶and R¹⁷are each independently a hydrogen atom or C_1-6Represents alkyl, R¹⁶or R¹⁷If there are multiple R¹⁶or R¹⁷may be the same or different, and here, R bonded to the same nitrogen atom¹⁶and R¹⁷are both C_1-6When alkyl, these may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded,
A medicament containing the compound according to any one of Items 1 to 2, or a pharmaceutically acceptable salt thereof.
[Section 4]
R¹,R²,R⁸, L, V, and optionally substituted C in W_1-6Alkyl, optionally substituted C_2-6alkenyl, optionally substituted C_2-6Alkynyl, optionally substituted C_3-10Cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C_6-10Aryl, optionally substituted 5- to 12-membered heteroaryl, optionally substituted C_1-6alkylene, optionally substituted C_3-10cycloalkylene or an optionally substituted 3- to 10-membered divalent saturated heterocyclic group, each independently
(1) Halogen atom,
(2) hydroxyl group,
(3) phenyl,
(4) 5- to 6-membered heteroaryl,
(5) C optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a hydroxyl group_1-6alkyl,
(6)C_1-6alkoxy,
(7)C_3-7cycloalkyl,
(8) 3- to 7-membered saturated heterocyclic group,
(9)-COR¹⁵,
(10)-CO₂R¹⁵,
(11)-CONR¹⁶R¹⁷,
(12)-NR¹⁶R¹⁷,
(13)-SO₂R¹⁵,
(14)-SO₂N.R.¹⁶R¹⁷,as well as
(15) Cyano
may be substituted with the same or different 1 to 5 substituents selected from the group consisting of;
R¹⁵However, if there are multiple, each independently, C_1-6is alkyl,
R¹⁶and R¹⁷are each independently a hydrogen atom or C_1-6is alkyl, R¹⁶or R¹⁷If there are multiple R¹⁶or R¹⁷may be the same or different, and here, R bonded to the same nitrogen atom¹⁶and R¹⁷are both C_1-6When alkyl, these may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded,
A medicament containing the compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
[Section 5]
R¹is optionally substituted with a hydrogen atom or 1 to 3 fluorine atoms_1-6is an alkyl,
Item 5. A medicament containing the compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
[Section 6]
R¹is a methyl group or an ethyl group optionally substituted with 1 to 3 fluorine atoms,
Item 5. A medicament containing the compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
[Section 7]
R¹is a methyl group optionally substituted with 1 to 3 fluorine atoms,
Item 5. A medicament containing the compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
[Section 8]
R¹is a methyl group,
Item 5. A medicament containing the compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
[Section 9]
R²is hydrogen atom, halogen atom, cyano, -OR³, C_1-6alkyl, C_3-10cycloalkyl, or a 3- to 10-membered saturated heterocyclic group,
Item 9. A medicament containing the compound according to any one of items 1 to 8, or a pharmaceutically acceptable salt thereof.
[Section 10]
R²is optionally substituted with a halogen atom, cyano, or 1 to 3 halogen atoms_1-6is an alkyl,
Item 9. A medicament containing the compound according to any one of items 1 to 8, or a pharmaceutically acceptable salt thereof.
[Section 11]
R²is cyano,
Item 9. A medicament containing the compound according to any one of items 1 to 8, or a pharmaceutically acceptable salt thereof.
[Section 12]
R⁸If there is more than one, each independently hydrogen atom, halogen atom, cyano, -OR⁹,-CO₂R¹⁰,-CONR¹¹R¹²,-NR¹¹R¹²,-NR¹³C.O.R.¹⁰, C_1-6Alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- to 6-membered heteroaryl, a C_1-6Alkoxy, C_3-7cycloalkyl, 3- to 7-membered saturated heterocyclic group, -CONR¹⁶R¹⁷,-NR¹⁶R¹⁷, and cyano), C_3-10Cycloalkyl (cycloalkyl includes fluorine atom, chlorine atom, bromine atom, hydroxyl group, phenyl, 5- to 6-membered heteroaryl, C_1-6alkyl, C_1-6Alkoxy, C_3-7cycloalkyl, 3- to 7-membered saturated heterocyclic group, -CONR¹⁶R¹⁷,-NR¹⁶R¹⁷, and cyano), a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group includes a fluorine atom, a chlorine atom, atom, bromine atom, hydroxyl group, phenyl, 5- to 6-membered heteroaryl, C_1-6alkyl, C_1-6Alkoxy, C_3-7cycloalkyl, 3- to 7-membered saturated heterocyclic group, -CONR¹⁶R¹⁷,-NR¹⁶R¹⁷, and cyano), phenyl (which may be substituted with 1 to 3 same or different substituents selected from the group consisting of 6-membered heteroaryl, C_1-6alkyl, C_1-6Alkoxy, C_3-7cycloalkyl, 3- to 7-membered saturated heterocyclic group, -CONR¹⁶R¹⁷,-NR¹⁶R¹⁷, and cyano), or a 5- to 6-membered heteroaryl (the heteroaryl is a fluorine atom, a chlorine atom, a bromine atom, Atom, hydroxyl group, phenyl, 5-6 membered heteroaryl, C_1-6alkyl, C_1-6Alkoxy, C_3-7cycloalkyl, 3- to 7-membered saturated heterocyclic group, -CONR¹⁶R¹⁷,-NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
Item 12. A medicament containing the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
[Section 13]
R⁸However, if there are multiple, each independently,
hydrogen atom,
halogen atom
-OR⁹,
C_1-6Alkyl (the alkyl is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano),
C_3-7Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano),
A 3- to 7-membered saturated heterocyclic group (the saturated heterocyclic group includes a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano),
Phenyl (the phenyl is a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), or
5- to 6-membered heteroaryl (the heteroaryl includes a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
Item 12. A medicament containing the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
[Section 14]
R⁸However, if there are multiple, each independently,
hydrogen atom,
fluorine atom,
chlorine atom,
bromine atom,
C_1-6Alkyl (the alkyl is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), or
5- to 6-membered heteroaryl (the heteroaryl includes a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano),
Item 12. A medicament containing the compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
[Section 15]
L is
single bond, or
C_1-6Alkylene (the alkylene is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷The compound according to any one of Items 1 to 14, or its pharmaceutical Medicinal products containing salts acceptable to.
[Section 16]
V is
single bond,
C_3-10Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), or
A 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, a C which may be substituted with 1 to 2 hydroxyl groups, or a fluorine atom)_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
Item 16. A medicament containing the compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof.
[Section 17]
W is
single bond, or
C_1-6Alkylene (the alkylene is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
Item 17. A medicament containing the compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof.
[Section 18]
R¹⁴but,
hydrogen atom,
C_1-6Alkyl (the alkyl is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano),
C_3-10Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), or
A 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group includes a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
Item 18. A medicament containing the compound according to any one of Items 1 to 17, or a pharmaceutically acceptable salt thereof.
[Section 19]
R¹but,
C optionally substituted with 1 to 3 fluorine atoms_1-6is alkyl,
R²but,
halogen atom,
Cyano or
C optionally substituted with 1 to 3 fluorine atoms_1-6is alkyl,
X, Y and Z are each independently CR⁸or a nitrogen atom, where X, Y and Z are simultaneously CR⁸not,
R⁸However, if there are multiple, each independently,
hydrogen atom,
fluorine atom,
chlorine atom,
bromine atom,
C_1-6Alkyl (the alkyl is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), or
5- to 6-membered heteroaryl (the heteroaryl includes a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano);
L is
single bond, or
C_1-6Alkylene (the alkylene is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
V is
single bond,
C_3-10Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), or
A 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, a C which may be substituted with 1 to 2 hydroxyl groups, or a fluorine atom)_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
W is
single bond, or
C_1-6Alkylene (the alkylene is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
Q is a hydrogen atom or NHR¹⁴and
R¹⁴but,
hydrogen atom,
C_1-6Alkyl (the alkyl is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano),
C_3-10Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), or
A 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group includes a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
R¹⁶and R¹⁷are each independently a hydrogen atom or a C_1-6is alkyl, R¹⁶or R¹⁷If there are multiple R¹⁶or R¹⁷may be the same or different, and here, R bonded to the same nitrogen atom¹⁶and R¹⁷are both C_1-6When alkyl, these may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded,
Item 1. A medicament containing the compound according to item 1 or a pharmaceutically acceptable salt thereof.
[Section 20]
Formula (1) becomes the following formula (2):

[In the formula,
X, Y and Z are each independently CR⁸or represents a nitrogen atom, where X, Y and Z are simultaneously CR⁸not,
R⁸If there are multiple, each independently,
hydrogen atom,
fluorine atom,
chlorine atom,
bromine atom,
C_1-6Alkyl (the alkyl is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), or
5- to 6-membered heteroaryl (the heteroaryl includes a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 2 substituents selected from the group consisting of
L is
single bond, or
C_1-6Alkylene (the alkylene is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
V is
single bond,
C_3-10Cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), or
A 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, a C which may be substituted with 1 to 2 hydroxyl groups, or a fluorine atom)_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
W is
single bond, or
C_1-6Alkylene (the alkylene is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
Q is a hydrogen atom, or NHR¹⁴represents,
R¹⁴teeth,
hydrogen atom,
C_1-6Alkyl (the alkyl is a fluorine atom, a hydroxyl group, a C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano),
C_3-10Cycloalkyl (the cycloalkyl is a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), or
A 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group includes a fluorine atom, a hydroxyl group, a C_1-3alkyl, C_1-3alkoxy, -NR¹⁶R¹⁷, and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
R¹⁶and R¹⁷are each independently a hydrogen atom or C_1-6Represents alkyl, R¹⁶or R¹⁷If there are multiple R¹⁶or R¹⁷may be the same or different, and here, R bonded to the same nitrogen atom¹⁶and R¹⁷are both C_1-6When alkyl, these may be combined with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing saturated heterocycle],
Item 1. A medicament containing the compound according to item 1 or a pharmaceutically acceptable salt thereof.
[Section 21]
Item 21. A medicament containing the compound according to any one of Items 1 to 20, or a pharmaceutically acceptable salt thereof, wherein one or two of X, Y, and Z represent a nitrogen atom.
[Section 22]
X is a nitrogen atom,
Y and Z are CR⁸is,
Item 22. A medicament containing the compound according to any one of Items 1 to 21, or a pharmaceutically acceptable salt thereof.
[Section 23]
Y is a nitrogen atom,
X and Z are CR⁸is,
Item 22. A medicament containing the compound according to any one of Items 1 to 21, or a pharmaceutically acceptable salt thereof.
[Section 24]
Z is a nitrogen atom,
X and Y are CR⁸is,
Item 22. A medicament containing the compound according to any one of Items 1 to 21, or a pharmaceutically acceptable salt thereof.
[Section 25]
R⁸If there are multiple, each independently,
hydrogen atom,
fluorine atom,
chlorine atom,
Bromine atom, or
C_1-6Alkyl (the alkyl is a fluorine atom, a hydroxyl group, and a C_1-3(optionally substituted with the same or different 1 to 2 substituents selected from the group consisting of alkoxy),
Item 25. A medicament containing the compound according to any one of Items 1 to 24, or a pharmaceutically acceptable salt thereof.
[Section 26]
R⁸If there are multiple atoms, each independently represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C_1-3is an alkyl,
Item 25. A medicament containing the compound according to any one of Items 1 to 24, or a pharmaceutically acceptable salt thereof.
[Section 27]
L is a single bond, or
C_1-6alkylene (the alkylene may be substituted with the same or different 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano),
Item 27. A medicament containing the compound according to any one of Items 1 to 26, or a pharmaceutically acceptable salt thereof.
[Section 28]
L is
single bond, or
C_1-6alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano);
Item 27. A medicament containing the compound according to any one of Items 1 to 26, or a pharmaceutically acceptable salt thereof.
[Section 29]
L is
single bond, or
C optionally substituted with one hydroxyl group or fluorine atom_1-6is alkylene,
Item 27. A medicament containing the compound according to any one of Items 1 to 26, or a pharmaceutically acceptable salt thereof.
[Section 30]
V is
single bond,
C_3-7Cycloalkylene (the cycloalkylene is a C which may be substituted with a fluorine atom, a hydroxyl group, or one or two hydroxyl groups)_1-3alkyl, and cyano), or
3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, a C which may be substituted with 1 to 2 hydroxyl groups, or a fluorine atom)_1-3(optionally substituted with 1 to 2 same or different substituents selected from the group consisting of alkyl and cyano),
Item 30. A medicament containing the compound according to any one of Items 1 to 29, or a pharmaceutically acceptable salt thereof.
[Section 31]
V is
single bond,
C_3-7Cycloalkylene (the cycloalkylene is a C which may be substituted with a fluorine atom, a hydroxyl group, or one or two hydroxyl groups)_1-3optionally substituted with one substituent selected from the group consisting of alkyl, and cyano), or
3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, a C which may be substituted with 1 to 2 hydroxyl groups, or a fluorine atom)_1-3optionally substituted with one substituent selected from the group consisting of alkyl, and cyano),
Item 30. A medicament containing the compound according to any one of Items 1 to 29, or a pharmaceutically acceptable salt thereof.
[Section 32]
V is
single bond,
C_3-7Cycloalkylene (the cycloalkylene has a hydroxyl group and a C_1-3optionally substituted with one substituent selected from the group consisting of alkyl), or
3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, and a C which may be substituted with 1 to 2 hydroxyl groups or fluorine atoms)_1-3optionally substituted with one substituent selected from the group consisting of alkyl),
Item 30. A medicament containing the compound according to any one of Items 1 to 29, or a pharmaceutically acceptable salt thereof.
[Section 33]
W is
single bond, or
C_1-6alkylene (the alkylene may be substituted with the same or different 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano),
Item 33. A medicament containing the compound according to any one of Items 1 to 32, or a pharmaceutically acceptable salt thereof.
[Section 34]
W is
single bond, or
C_1-3alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano);
Item 33. A medicament containing the compound according to any one of Items 1 to 32, or a pharmaceutically acceptable salt thereof.
[Section 35]
W is
single bond, or
C optionally substituted with one hydroxyl group_1-3is alkylene,
Item 33. A medicament containing the compound according to any one of Items 1 to 32, or a pharmaceutically acceptable salt thereof.
[Section 36]
R¹⁴but,
hydrogen atom, or
C_1-6Alkyl (the alkyl may be substituted with the same or different 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano),
Item 36. A medicament containing the compound according to any one of Items 1 to 35, or a pharmaceutically acceptable salt thereof.
[Section 37]
R¹⁴but,
hydrogen atom, or
C_1-3an alkyl (the alkyl may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano group);
Item 36. A medicament containing the compound according to any one of Items 1 to 35, or a pharmaceutically acceptable salt thereof.
[Section 38]
Q is
hydrogen atom,
N.H.₂, or
NHMe,
Item 38. A medicament containing the compound according to any one of Items 1 to 37, or a pharmaceutically acceptable salt thereof.
[Section 39]
Formula (1) becomes the following formula (3):

[In the formula,
R^8aand R^8bare each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C_1-3represents alkyl,
L is a single bond or C optionally substituted with one hydroxyl group_1-6represents alkylene,
V is
single bond,
C_3-7Cycloalkylene (the cycloalkylene has a hydroxyl group and a C_1-3optionally substituted with one substituent selected from the group consisting of alkyl), or
A 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group includes a fluorine atom, a cyano group, a hydroxyl group, and a C_1-3optionally substituted with one substituent selected from the group consisting of alkyl),
W is
single bond, or
C optionally substituted with one hydroxyl group_1-3represents alkylene,
Q is a hydrogen atom or NH₂is expressed as
Item 1. A medicament containing the compound according to item 1 or a pharmaceutically acceptable salt thereof.
[Section 40]
R^8aand R^8bare each independently a hydrogen atom, a fluorine atom or a chlorine atom,
A medicament containing the compound according to item 39 or a pharmaceutically acceptable salt thereof.
[Section 41]
R^8aand R^8bare each independently a hydrogen atom or a chlorine atom,
A medicament containing the compound according to item 39 or a pharmaceutically acceptable salt thereof.
[Section 42]
L is C_1-3is alkylene,
Item 42. A medicament containing the compound according to any one of Items 39 to 41, or a pharmaceutically acceptable salt thereof.
[Section 43]
V is a single bond,
A medicament containing the compound according to any one of Items 39 to 42, or a pharmaceutically acceptable salt thereof.
[Section 44]
V is C_3-7is cycloalkylene,
A medicament containing the compound according to any one of Items 39 to 42, or a pharmaceutically acceptable salt thereof.
[Section 45]
W is a single bond,
A medicament containing the compound according to any one of Items 39 to 44, or a pharmaceutically acceptable salt thereof.
[Section 46]
W is C_1-3is alkylene,
A medicament containing the compound according to any one of Items 36 to 44, or a pharmaceutically acceptable salt thereof.
[Section 47]
Q is NH₂is,
A medicament containing the compound according to any one of Items 36 to 46, or a pharmaceutically acceptable salt thereof.
[Section 48]
Formula (1) becomes the following formula (4):

[In the formula,
R^8band R^8care each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C_1-3represents alkyl,
L is
single bond, or
C_1-6represents alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano),
V is
single bond,
C_3-7Cycloalkylene (the cycloalkylene has a hydroxyl group and a C_1-3optionally substituted with one substituent selected from the group consisting of alkyl), or
3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a cyano group, a hydroxyl group, and a C which may be substituted with 1 to 3 hydroxyl groups and a fluorine atom)_1-3optionally substituted with one substituent selected from the group consisting of alkyl),
W is
single bond, or
C optionally substituted with one hydroxyl group_1-3represents alkylene,
Q is a hydrogen atom, NH₂, or NHMe]
Item 1. A medicament containing the compound according to item 1 or a pharmaceutically acceptable salt thereof.
[Section 49]
R^8band R^8cis a hydrogen atom,
49. A medicament containing the compound according to Item 48 or a pharmaceutically acceptable salt thereof.
[Section 50]
L is
single bond, or
C optionally substituted with one hydroxyl group or fluorine atom_1-6is alkylene,
Item 49. A medicament containing the compound according to any one of Item 48 or 49, or a pharmaceutically acceptable salt thereof.
[Section 51]
C where L may be substituted with one hydroxyl group or fluorine atom_1-4is alkylene,
Item 49. A medicament containing the compound according to any one of Item 48 or 49, or a pharmaceutically acceptable salt thereof.
[Section 52]
L is a single bond,
Item 49. A medicament containing the compound according to any one of Item 48 or 49, or a pharmaceutically acceptable salt thereof.
[Section 53]
V is
single bond,
C_3-7cycloalkylene, or
A 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group includes a fluorine atom, a hydroxyl group, and a C_1-3optionally substituted with one substituent selected from the group consisting of alkyl),
A medicament containing the compound according to any one of Items 48 to 52, or a pharmaceutically acceptable salt thereof.
[Section 54]
W is
single bond, or
C_1-3is alkylene,
A medicament containing the compound according to any one of Items 48 to 53, or a pharmaceutically acceptable salt thereof.
[Section 55]
W is a single bond,
A medicament containing the compound according to any one of Items 48 to 53, or a pharmaceutically acceptable salt thereof.
[Section 56]
W is C_1-3is alkylene,
A medicament containing the compound according to any one of Items 48 to 53, or a pharmaceutically acceptable salt thereof.
[Section 57]
Q is a hydrogen atom,
Item 57. A medicament containing the compound according to any one of Items 48 to 56, or a pharmaceutically acceptable salt thereof.
[Section 58]
Q is NH₂is,
Item 57. A medicament containing the compound according to any one of Items 48 to 56, or a pharmaceutically acceptable salt thereof.
[Section 59]
Q is NHMe,
Item 57. A medicament containing the compound according to any one of Items 48 to 56, or a pharmaceutically acceptable salt thereof.
[Section 60]
Formula (1) becomes the following formula (5):

[In the formula,
R^8aand R^8care each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C_1-3represents alkyl,
L is a single bond or C optionally substituted with one hydroxyl group_1-6represents alkylene,
V is
single bond,
C_3-7Cycloalkylene (the cycloalkylene has a hydroxyl group and a C_1-3optionally substituted with one substituent selected from the group consisting of alkyl), or
3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a cyano group, a hydroxyl group, and a C which may be substituted with one hydroxyl group)_1-3optionally substituted with one substituent selected from the group consisting of alkyl),
W is
single bond, or
C optionally substituted with one hydroxyl group_1-3represents alkylene,
Q is a hydrogen atom or NH₂is expressed as
Item 1. A medicament containing the compound according to item 1 or a pharmaceutically acceptable salt thereof.
[Section 61]
R^8aand R^8cis a hydrogen atom,
Item 61. A medicament containing the compound according to Item 60 or a pharmaceutically acceptable salt thereof.
[Section 62]
C where L may be substituted with one hydroxyl group_1-6is alkylene,
A medicament containing the compound according to any one of Item 60 or 61, or a pharmaceutically acceptable salt thereof.
[Section 63]
V is
single bond,
C_3-7cycloalkylene or
3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group includes a hydroxyl group and a C which may be substituted with one hydroxyl group)_1-3optionally substituted with one substituent selected from the group consisting of alkyl),
Item 63. A medicament containing the compound according to any one of Items 60 to 62, or a pharmaceutically acceptable salt thereof.
[Section 64]
V is a single bond,
Item 63. A medicament containing the compound according to any one of Items 60 to 62, or a pharmaceutically acceptable salt thereof.
[Section 65]
V is C_3-7is cycloalkylene,
Item 63. A medicament containing the compound according to any one of Items 60 to 62, or a pharmaceutically acceptable salt thereof.
[Section 66]
V is a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a hydroxyl group, and a C_1-3optionally substituted with one substituent selected from the group consisting of alkyl),
Item 63. A medicament containing the compound according to any one of Items 60 to 62, or a pharmaceutically acceptable salt thereof.
[Section 67]
W is
single bond, or
C_1-3is alkylene,
Item 67. A medicament containing the compound according to any one of Items 60 to 66, or a pharmaceutically acceptable salt thereof.
[Section 68]
W is a single bond,
Item 67. A medicament containing the compound according to any one of Items 60 to 66, or a pharmaceutically acceptable salt thereof.
[Section 69]
W is C_1-3is alkylene,
Item 67. A medicament containing the compound according to any one of Items 60 to 66, or a pharmaceutically acceptable salt thereof.
[Section 70]
Q is a hydrogen atom,
Item 69. A medicament containing the compound according to any one of Items 60 to 69, or a pharmaceutically acceptable salt thereof.
[Section 71]
Q is NH₂is,
Item 69. A medicament containing the compound according to any one of Items 60 to 69, or a pharmaceutically acceptable salt thereof.
[Section 72]
Formula (1) becomes the following formula (6):

[In the formula,
R^8ais a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C_1-3represents alkyl,
L is
single bond, or
C_1-6represents alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano),
V is
single bond,
C_3-7Cycloalkylene (the cycloalkylene has a hydroxyl group and a C_1-3optionally substituted with one substituent selected from the group consisting of alkyl), or
A 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a cyano group, a hydroxyl group, and a C which may be substituted with 1 to 3 fluorine atoms)_1-3optionally substituted with one substituent selected from the group consisting of alkyl),
W is
single bond, or
C optionally substituted with one hydroxyl group_1-3represents alkylene,
Q is a hydrogen atom, NH₂, or NHMe]
Item 1. A medicament containing the compound according to item 1 or a pharmaceutically acceptable salt thereof.
[Section 73]
R^8ais a hydrogen atom,
73. A medicament containing the compound according to Item 72 or a pharmaceutically acceptable salt thereof.
[Section 74]
L is C_1-4is alkylene,
A medicament containing the compound according to any one of Item 72 or 73, or a pharmaceutically acceptable salt thereof.
[Section 75]
V is
single bond, or
C_3-7is cycloalkylene,
A medicament containing the compound according to any one of Items 72 to 74, or a pharmaceutically acceptable salt thereof.
[Section 76]
V is a single bond,
Item 75. A medicament containing the compound according to any one of Items 72 to 74, or a pharmaceutically acceptable salt thereof.
[Section 77]
V is C_3-7is cycloalkylene,
Item 75. A medicament containing the compound according to any one of Items 72 to 74, or a pharmaceutically acceptable salt thereof.
[Section 78]
W is
single bond, or
C_1-3is alkylene,
Item 78. A medicament containing the compound according to any one of items 72 to 77, or a pharmaceutically acceptable salt thereof.
[Section 79]
W is a single bond,
Item 78. A medicament containing the compound according to any one of items 72 to 77, or a pharmaceutically acceptable salt thereof.
[Section 80]
W is C_1-3is alkylene,
Item 78. A medicament containing the compound according to any one of items 72 to 77, or a pharmaceutically acceptable salt thereof.
[Section 81]
Q is NH₂is,
Items 72 to 80. A medicament containing the compound according to any one of items 72 to 80, or a pharmaceutically acceptable salt thereof.
[Section 82]
The medicament according to item 1, which contains a compound or a pharmaceutically acceptable salt thereof selected from the following compounds: 5-({5-[2-(3-aminopropoxy)-4-methoxypyridine) -3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 1),
5-({5-[2-(3-aminopropoxy)-6-chloro-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 2 ),
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 3),
5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 4),
5-[(5-{3-[(3-fluoroazetidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 5),
5-[(5-{2-methoxy-4-[(3-methylazetidin-3-yl)methoxy]pyridin-3-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 6),
5-[(5-{4-[(3-hydroxyazetidin-3-yl)methoxy]-2-methoxypyridin-3-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 7),
5-{[5-(4-{[3-(hydroxymethyl)azetidin-3-yl]methoxy}-2-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2- carbonitrile (Example 8),
5-[(5-{3-[(3R)-3-aminobutoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 9 ),
5-[(5-{3-[(3S)-3-aminobutoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 10 ),
5-{[5-(3-{[1-(aminomethyl)cyclopropyl]methoxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile ( Example 11),
5-[(5-{3-methoxy-5-[(morpholin-2-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 12 ),
5-[(5-{3-methoxy-5-[(morpholin-2-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 13 ),
5-[(5-{3-[(2S)-3-amino-2-hydroxypropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 14),
N-{5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}-5-chloropyrazin-2-amine (Example 15),
N-{5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}-5-(trifluoromethyl)pyrazin-2-amine (Example 16 ),
5-({5-[4-(3-aminopropoxy)-6-methoxypyrimidin-5-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 17), 5- ({5-[3-(azetidin-3-yl)methoxy-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 18),
5-{[5-(3-{[(1R,3S)-3-aminocyclohexyl]oxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbo Nitrile (Example 19),
(S)-5-[(5-{3-[(3-fluoropyrrolidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2 - carbonitrile (Example 20),
(S)-5-[(5-{3-methoxy-[5-(pyrrolidin-3-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 21),
(R)-5-[(5-{3-[(3-fluoropyrrolidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2 - carbonitrile (Example 22),
5-{[5-(4-{[1-(aminomethyl)cyclopropyl]methoxy}-6-methoxypyrimidin--yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (implemented) Example 23),
5-({5-[3-(3-aminopropoxy)-5-(fluoromethoxy)pyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 24) ,
5-[(5-{3-methoxy-5-[(3-methylazetidin-3-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 25),
5-{[5-(3-{[3-(difluoromethyl)azetidin-3-yl]methoxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2- carbonitrile (Example 26),
5-[(5-{3-[(2S)-3-amino-2-methylpropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 27),
5-[(5-{3-[(2R)-3-amino-2-methylpropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 28),
5-[(5-{3-[(2S)-3-amino-2-fluoropropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 29),
5-[(5-{3-[(2R)-3-amino-2-fluoropropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 30),
5-[(5-{3-methoxy-5-[3-(methylamino)propoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile (Example 31) ,
5-{[5-(3-{[(1R,3R)-3-aminocyclopentyl]oxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbo Nitrile (Example 32),
5-[(5-{3-[(1R)-1-(azetidin-3-yl)ethoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2- carbonitrile (Example 33),
5-[(5-{3-[(1R)-1-(3-hydroxyazetidin-3-yl)ethoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino] pyrazine-2-carbonitrile (Example 34),
5-{[5-(3-methoxy-5-{[(1R,3R)-3-(methylamino)cyclopentyl]oxy}pyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine- 2-carbonitrile (Example 35),
5-{[5-(3-{[(1R,2S,4S,5S)-4-aminobicyclo[3.1.0]hexan-2-yl]oxy}-5-methoxypyridin-4-yl) -1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile (Example 36),
5-{[5-(2-{[1-(aminomethyl)cyclopropyl]methoxy}-4-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile ( Example 37),
5-{[5-(4-{[1-(aminomethyl)cyclopropyl]methoxy}-2-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile ( Example 38).
[Section 83]
The medicament according to item 1, which contains a compound or a pharmaceutically acceptable salt thereof selected from the following compounds: 5-({5-[2-(3-aminopropoxy)-4-methoxypyridine) -3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 1),
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 3),
5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 4).
[Section 84]
The medicament according to item 1, which contains a compound or a pharmaceutically acceptable salt thereof selected from the following compounds: 5-({5-[4-(3-aminopropoxy)-2-methoxypyridine) -3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 4).
[Section 85]
The medicament according to item 1, which contains the following compound or a pharmaceutically acceptable salt thereof:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 1).
[Section 86]
The medicament according to item 1, which contains the following compound or a pharmaceutically acceptable salt thereof:
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Example 3).
[Section 87]
Item 87. A pharmaceutical composition containing the medicament according to any one of Items 1 to 86 as an active ingredient.
[Section 88]
Item 87. A pharmaceutical composition containing a liposome encapsulating the medicament according to any one of items 1 to 86, prexasertib, or a pharmaceutically acceptable salt thereof.
[Section 89]
Item 87. A pharmaceutical composition containing a liposome encapsulating the medicament according to any one of Items 1 to 86.
[Section 90]
87. The medicament according to any one of items 1 to 86, wherein the medicament is contained in a liposome encapsulating the medicament.
[Section 91]
91. The pharmaceutical composition according to item 88 or 89 or the medicament according to item 90, wherein the liposome further contains a phospholipid.
[Section 92]
The liposome is
(1) The medicament according to any one of items 1 to 86, and
(2) phospholipid,
The pharmaceutical composition or medicament according to any one of Items 88 to 91, comprising:
[Section 93]
The phospholipid is one selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin. or a combination of two or more thereof, the pharmaceutical composition or medicament according to item 91 or 92.
[Section 94]
94. The pharmaceutical composition or medicament according to any one of Items 88 to 93, wherein the liposome further contains a sterol.
[Section 95]
95. The pharmaceutical composition or medicament according to item 94, wherein the sterol is cholesterol.
[Section 96]
96. The pharmaceutical composition or medicament according to any one of Items 88 to 95, wherein the liposome further comprises a polymer-modified lipid.
[Section 97]
The polymer portion of the polymer-modified lipid is polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinylpyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxy 97. The pharmaceutical composition or medicament according to item 96, which is polyvinylpyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinylpyrrolidone.
[Section 98]
98. The pharmaceutical composition or medicament according to item 96 or 97, wherein the lipid moiety of the polymer-modified lipid is phosphatidylethanolamine or diacylglycerol.
[Section 99]
The polymer-modified lipid includes polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinylpyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxy as a polymer moiety. Item 98. The pharmaceutical composition or medicament according to item 96 or 97, which contains polyvinylpyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinylpyrrolidone, and contains phosphatidylethanolamine or diacylglycerol as the lipid moiety.
[Section 100]
The liposome is
(1) The medicament according to any one of items 1 to 86,
(2) 40 to 70 mol% phospholipids;
(3) 30-50 mol% cholesterol, and
(4) 1 to 10 mol% polymer-modified lipid;
The pharmaceutical composition or medicament according to any one of Items 89 to 91, comprising:
[Section 101]
Any of Items 89 to 100, wherein the liposome further comprises an additive selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, saccharides, buffers, antioxidants, and polymers. The pharmaceutical composition or medicament according to item 1.
[Section 102]
Item 87. A therapeutic and/or prophylactic agent for cancer, comprising the medicament according to any one of Items 1 to 86 as an active ingredient.
[Section 103]
The cancer is squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell tumor, multiple myeloma, brain tumor, head and neck cancer. Cancer, head and neck squamous cell carcinoma, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma/thymic cancer, breast cancer, triple negative breast cancer, stomach cancer, gallbladder/bile duct cancer, liver Cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, MSI-high colon cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, endometrial cancer, cervical cancer Ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial cancer, renal cancer, renal cell cancer, prostate cancer, testicular tumor, testis At least one type of cancer selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer. , the therapeutic agent and/or prophylactic agent according to item 102.
[Section 104]
The cancer is from the group consisting of head and neck cancer, squamous cell carcinoma, non-small cell lung cancer, anal cancer, breast cancer, triple negative breast cancer, ovarian cancer, platinum-resistant ovarian cancer, or endometrial cancer. Item 103. The therapeutic and/or preventive agent according to item 102, which is at least one selected type of cancer.
[Section 105]
A therapeutically and/or prophylactically effective amount of the medicament according to any one of items 1 to 86, or a pharmaceutical composition or medicament according to items 87 to 101, to a patient in need of treatment and/or prevention; A method for treating and/or preventing cancer, which comprises administering the therapeutic agent and/or preventive agent according to items 102 to 104.
[Section 106]
The cancer is squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell tumor, multiple myeloma, brain tumor, head and neck cancer. Cancer, head and neck squamous cell carcinoma, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma/thymic cancer, breast cancer, triple negative breast cancer, stomach cancer, gallbladder/bile duct cancer, liver Cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, MSI-high colon cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, endometrial cancer, cervical cancer Ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial cancer, renal cancer, renal cell cancer, prostate cancer, testicular tumor, testis At least one type of cancer selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer. , the method for treatment and/or prevention according to item 105.
[Section 107]
The medicament according to any one of Items 1 to 86, or the pharmaceutical composition or medicament according to Items 87 to 101, or the pharmaceutical composition or medicament according to Items 102 to 104, for producing a therapeutic and/or preventive agent for cancer. Use of therapeutic and/or prophylactic agents.
[Section 108]
The cancer is squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell tumor, multiple myeloma, brain tumor, head and neck cancer. Cancer, head and neck squamous cell carcinoma, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma/thymic cancer, breast cancer, triple negative breast cancer, stomach cancer, gallbladder/bile duct cancer, liver Cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, MSI-high colon cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, endometrial cancer, cervical cancer Ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial cancer, renal cancer, renal cell cancer, prostate cancer, testicular tumor, testis At least one type of cancer selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer. , use of the medicament, or pharmaceutical composition, or therapeutic and/or prophylactic agent according to any one of Items 1 to 86.
[Section 109]
The medicament according to any one of Items 1 to 86, or the pharmaceutical composition or medicament according to Items 87 to 101, or the treatment according to Items 102 to 104, for use in the treatment and/or prevention of cancer. agent and/or preventive agent.
[Section 110]
The cancer is squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell tumor, multiple myeloma, brain tumor, head and neck cancer. Cancer, head and neck squamous cell carcinoma, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma/thymic cancer, breast cancer, triple negative breast cancer, stomach cancer, gallbladder/bile duct cancer, liver Cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, MSI-high colon cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, endometrial cancer, cervical cancer Ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial cancer, renal cancer, renal cell cancer, prostate cancer, testicular tumor, testis At least one type of cancer selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer. , the medicament or pharmaceutical composition, or a therapeutic and/or prophylactic agent according to any one of Items 1 to 86.
[Section 111]
87. The medicament according to any one of Items 1 to 86, for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug is a hormone therapy agent. 87. The medicament according to any one of Items 1 to 86, which is at least one selected from the group consisting of , chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of cell growth factors and their receptors.
[Section 112]
87. The medicament according to any one of Items 1 to 86, for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug contains 5-FU Cytarabine, doxorubicin hydrochloride, gemcitabine, methotrexate, pemetrexed, etoposide, irinotecan, topotecan, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, ionizing radiation, bevacizumab, liposomal doxorubicin, rucaparib, olaparib, niraparib, trabectedin, pasopani Bu, Item 1: at least one selected from the group consisting of pembrolizumab, nivolumab, ipilimumab, durvalumab, avelumab, atezolizumab, larotrectinib, entrectinib, nab-paclitaxel, erlotinib, liposomal irinotecan, leucovorin, cetuximab, eribulin, ifosfamide, and dacarbazine. -86. The medicament according to any one of 86.
[Section 113]
87. The medicament according to any one of Items 1 to 86, for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug contains 5-FU Any one of Items 1 to 86, which is at least one selected from the group consisting of irinotecan, gemcitabine, cisplatin, carboplatin, oxaliplatin, paclitaxel, ionizing radiation, rucaparib, olaparib, niraparib, pembrolizumab, and nivolumab. Medicines listed in section.
[Section 114]
(a) The medicament according to any one of items 1 to 86, for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, and (b) the combination the drug is at least one selected from the group consisting of hormone therapy agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of cell growth factors and their receptors;
(1) (a) is administered at the same time as (b);
(2) (a) is administered after the administration of (b), or
(3) characterized in that (b) is administered after the administration of (a);
87. The medicament according to any one of items 1 to 86.
[Section 115]
The concomitant drug (b) is a chemotherapeutic agent or an immunotherapeutic agent,
The medicament according to item 114.
[Section 116]
the concomitant drug (b) is gemcitabine;
The medicament according to item 114 or 115.
[Section 117]
117. The medicament according to paragraph 116, wherein the (a) medicament is administered simultaneously with the (b) gemcitabine.
[Section 118]
117. The medicament of paragraph 116, wherein said (a) medicament is administered within about 24-48 hours after administration of said (b) gemcitabine.
[Section 119]
117. The medicament according to item 116, wherein the (b) gemcitabine is administered within about 24 to 48 hours after administration of the (a) compound, or a pharmaceutically acceptable salt thereof, or liposome.
[Section 120]
the concomitant drug (b) is an anti-PD-1 antibody;
The medicament according to item 114 or 115.
[Section 121]
121. The medicament according to item 120, wherein the (a) compound, its pharmaceutically acceptable salt, or liposome is administered simultaneously with the (b) anti-PD-1 antibody.
[Section 122]
121. The medicament according to item 120, wherein the (b) anti-PD-1 antibody is administered within about 72 to 96 hours after administration of the (a) compound, or a pharmaceutically acceptable salt thereof, or a liposome. .
[Section 123]
117. The medicament according to item 116, wherein the (a) compound, or a pharmaceutically acceptable salt thereof, or liposome is administered within about 72 to 96 hours after the administration of the (b) anti-PD-1 antibody.
[Section 124]
A pharmaceutical composition comprising the medicament according to any one of Items 1 to 86, or a pharmaceutical composition or medicament according to any one of Items 87 to 101, which is in combination with a concomitant drug. A pharmaceutical composition, wherein the drug is at least one selected from the group consisting of hormone therapy agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of cell growth factors and their receptors.
[Section 125]
A pharmaceutical composition comprising the pharmaceutical according to any one of Items 1 to 86 in combination with a concomitant drug, or a pharmaceutical composition or medicament according to any one of Items 87 to 101, Concomitant drugs include 5-FU drugs, cytarabine, doxorubicin hydrochloride, gemcitabine, methotrexate, pemetrexed, etoposide, irinotecan, topotecan, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, ionizing radiation, bevacizumab, liposomal doxorubicin, rucaparib, olaparib , niraparib, trabectedin, pazopanib, pembrolizumab, nivolumab, ipilimumab, durvalumab, avelumab, atezolizumab, larotrectinib, entrectinib, nab-paclitaxel, erlotinib, liposomal irinotecan, leucovorin, cetuximab, eribulin, ifosfamide, dacarbazine. A pharmaceutical composition that is more than one species.
[Section 126]
A pharmaceutical composition comprising the medicament according to any one of Items 1 to 86, or a pharmaceutical composition or medicament according to any one of Items 87 to 101, which is in combination with a concomitant drug. A pharmaceutical composition in which the drug is at least one selected from the group consisting of 5-FU drugs, irinotecan, gemcitabine, cisplatin, carboplatin, oxaliplatin, paclitaxel, ionizing radiation, rucaparib, olaparib, niraparib, pembrolizumab, and nivolumab. thing.
[Section 127]
In X-ray powder diffraction, 5-({5-[ 2-(3-Aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride.
[Section 128]
In X-ray powder diffraction, 7.2°±0.2°, 8.8°±0.2°, 9.8°±0.2°, 10.2°±0.2°, 10.7° ±0.2°, 16.7°±0.2°, 18.5°±0.2°, 26.2°±0.2°, and 27.0°±0.2° and 26.4 5-({5-[2-(3-aminopropoxy)-4-methoxypyridine) in the crystalline form of Form I with four or more diffraction angle (2θ°) peaks selected from °±0.2° -3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride.
[Section 129]
In X-ray powder diffraction, 5-({5-[ 2-(3-Aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile phosphate.
[Section 130]
In X-ray powder diffraction, 6.8°±0.2°, 7.5°±0.2°, 11.7°±0.2°, 11.9°±0.2°, 13.0° ±0.2°, 16.4°±0.2°, 19.3°±0.2°, 20.4°±0.2°, 22.7°±0.2°, and 24.3 5-({5-[2-(3-aminopropoxy)-4-methoxypyridine) in the crystalline form of Form II with four or more diffraction angle (2θ°) peaks selected from °±0.2° -3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile phosphate.
[Section 131]
In X-ray powder diffraction, 5-({5-[ 2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile tosylate.
[Section 132]
In X-ray powder diffraction, 6.0°±0.2°, 9.0°±0.2°, 12.1°±0.2°, 14.4°±0.2°, 16.2° Four or more diffraction angles (2θ°) selected from ±0.2°, 17.0°±0.2°, 22.8°±0.2°, and 26.3°±0.2° 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2- in the crystalline form of Form III with the peak Carbonitrile tosylate.
[Section 133]
In X-ray powder diffraction, 5-({5-[ 2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.
[Section 134]
In X-ray powder diffraction, 9.3°±0.2°, 10.2°±0.2°, 10.7°±0.2°, 13.6°±0.2°, 16.7° ±0.2°, 17.1°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 26.1°±0.2° and 26.4° 5-({5-[2-(3-aminopropoxy)-4-methoxypyridine- 3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.
[Section 135]
In X-ray powder diffraction, the 5-({5-[ 2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.
[Section 136]
In X-ray powder diffraction, 7.9°±0.2°, 8.7°±0.2°, 12.2°±0.2°, 13.1°±0.2°, 15.9° ±0.2°, 17.6°±0.2°, 19.9°±0.2°, 21.9°±0.2°, 22.8°±0.2°, and 26.6° 5-({5-[2-(3-aminopropoxy)-4-methoxypyridine) in the crystalline form of Form V, having four or more diffraction angle (2θ°) peaks selected from °±0.2° -3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.
[Section 137]
In X-ray powder diffraction, 5-({5-[ 2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.
[Section 138]
In X-ray powder diffraction, 5.3°±0.2°, 5.7°±0.2°, 7.0°±0.2°, 7.3°±0.2°, 7.8° ±0.2°, 8.4°±0.2°, 9.3°±0.2°, 10.5°±0.2°, 11.5°±0.2°, and 14.1 5-({5-[2-(3-aminopropoxy)-4-methoxypyridine) in the crystalline form of Form VI with four or more diffraction angle (2θ°) peaks selected from °±0.2° -3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile.
[Section 139]
In X-ray powder diffraction, 5-({5-[ 2-(3-Aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride.
[Section 140]
In X-ray powder diffraction, 7.0°±0.2°, 8.2°±0.2°, 9.7°±0.2°, 11.5°±0.2°, 14.0° ±0.2°, 14.6°±0.2°, 16.3°±0.2°, 18.0°±0.2°, 19.8°±0.2°, 21.2° Four or more diffraction angles (2θ°) selected from ±0.2°, 21.5°±0.2°, 24.1°±0.2°, and 27.0°±0.2° 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2- in the crystalline form of Form VII with the peak Carbonitrile hydrochloride.

The present disclosure provides a CHK1 inhibitor comprising a 5-heteroaryl-1H-pyrazol-3-amine derivative or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure have both excellent CHK1 inhibitory activity and high safety. By being encapsulated in liposomes and released from the liposome in a sustained manner, it acts on cancer continuously and exhibits strong antitumor effects. The compounds of the present disclosure are useful as therapeutic agents for diseases involving CHK1, and are specifically applicable to patients with pancreatic cancer, ovarian cancer, osteosarcoma, Ewing's sarcoma, chondrosarcoma, or soft tissue sarcoma. It is.

The present disclosure has been shown to have a pharmacological effect in Phase 2 trials for ovarian cancer patients, and compared to Prexasertib, a 5-phenyl-1H-pyrazol-3-amine derivative, it has been inferred from non-clinical studies. It has been found that while maximal efficacy was not achieved with sustained exposure for 72 hours, the compounds of the present disclosure or salts thereof may further improve this. Furthermore, when administered in a single dose, the compounds or salts of the present disclosure did not cause such side effects compared to prexasertib, which causes side effects due to high peak blood concentrations. With continuous administration for three days, side effects resulting from long-term drug exposure were observed, whereas such side effects were not observed with the compound or salt of the present disclosure (Non-patent Document 3, Non-Patent Document 6). ). In addition, the present inventors have newly found that prexasertib has a risk of hepatotoxicity, and the compound of the present invention has a reduced risk of hepatotoxicity. From the above, the compound of the present disclosure has both excellent CHK1 inhibitory activity and high safety.

In particular, the compound represented by formula (3), which has a pyridine ring with a nitrogen atom at a specific position, is characterized by both high antitumor activity and safety, as well as excellent pharmacokinetics.

In particular, the compound of Example 1, which is included in formula (3), exhibits higher CHK1 inhibitory activity compared to prexasertib, has a strong cell proliferation inhibitory effect, and is characterized by high safety. Furthermore, the compound of Example 1 exhibits good pharmacokinetics and is characterized by being efficiently encapsulated in liposomes. The liposome preparation of the compound of Example 1 has excellent antitumor effects and high safety, and exhibits even more exceptional antitumor effects when used in combination with existing anticancer drugs.

Figure 3 shows the powder X-ray diffraction pattern of Form I of the compound of Example 39. The horizontal axis shows the diffraction angle 2θ (°), and the vertical axis shows the count number (the same applies to FIGS. 2 to 6 below). Figure 4 shows the powder X-ray diffraction pattern of Form II of the compound of Example 40. Figure 4 shows the powder X-ray diffraction pattern of Form III of the compound of Example 41. Figure 4 shows the powder X-ray diffraction pattern of Form IV of the compound of Example 42. Figure 4 shows the powder X-ray diffraction pattern of Form V of the compound of Example 43. Figure 4 shows the powder X-ray diffraction pattern of Form VI of the compound of Example 44. Figure 4 shows the powder X-ray diffraction pattern of Form VII of the compound of Example 45. FIG. 7 is a diagram showing the tumor PD response effect of Test A of Test Example 11, a solution formulation or a liposome formulation of prexasertib, using ES-2 tumor-bearing mice. PD response was evaluated by detecting the expression levels of γH2AX and Tubulin by Western blotting, quantifying the intensity of each band using ImageJ software, and calculating the relative value of the expression level of γH2AX based on the expression level of Tubulin. The vertical axis indicates the relative value of γH2AX. FIG. 8 is a diagram showing the tumor PD response effect of Test B of Test Example 11, the solution formulation of prexasertib, or the liposome formulation of Example 1 using ES-2 tumor-bearing mice. PD response was evaluated by detecting the expression levels of γH2AX and Tubulin by Western blotting, quantifying the intensity of each band using ImageJ software, and calculating the relative value of the expression level of γH2AX based on the expression level of Tubulin. The vertical axis indicates the relative value of γH2AX. FIG. 9 is a diagram showing the tumor PD response effect of Test C of Test Example 11 and the liposome formulation of Example 1 using ES-2 tumor-bearing mice. PD response was evaluated by detecting the expression levels of γH2AX and Tubulin by Western blotting, quantifying the intensity of each band using ImageJ software, and calculating the relative value of the expression level of γH2AX based on the expression level of Tubulin. The vertical axis indicates the relative value of γH2AX.

The present disclosure will be described in more detail below. Throughout this specification, references to the singular should be understood to include the plural unless specifically stated otherwise. Accordingly, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to also include the plural concept, unless specifically stated otherwise. Further, it should be understood that the terms used herein have the meanings commonly used in the art unless otherwise specified. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present specification (including definitions) will control.

Terms used in this specification will be explained below.

In this specification, the number of substituents in the group defined as "optionally substituted" is not particularly limited as long as they are substitutable. Furthermore, unless otherwise specified, the description of each group also applies when the group is a part or substituent of another group.

Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably it is a fluorine atom or a chlorine atom.

"C _1-6 alkyl" means an alkyl having 1 to 6 carbon atoms, and "C ₆ alkyl" means an alkyl having 6 carbon atoms. The same applies to other numbers.

"C _1-6 alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred examples of C _1-6 alkyl include "C _1-4 alkyl", more preferably "C _1-3 alkyl". Specific examples of "C _1-3 alkyl" include methyl, ethyl, propyl, 1-methylethyl, and the like. Specific examples of "C _1-4 alkyl" include butyl, 1,1 _- dimethylethyl, 1-methylpropyl, 2-methyl Examples include propyl. Specific examples of "C _1-6 alkyl" include pentyl, 1,1 _- dimethylpropyl, 1,2-dimethylpropyl, 1 -Methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.

"C _2-6 alkenyl" means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. Preferred examples of "C _2-6 alkenyl" include "C _2-4 alkenyl." Specific examples of "C _2-4 alkenyl" include vinyl, propenyl, methylpropenyl, butenyl, and the like. Specific examples of "C _2-6 alkenyl" include pentenyl, hexenyl, and the like, in addition to those listed above as specific examples of "C _2-4 alkenyl."

"C _2-6 alkynyl" means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one triple bond. “C _2-6 alkynyl” is preferably “C _2-4 alkynyl”. Specific examples of "C _2-4 alkynyl" include propynyl, methylpropynyl, butynyl, and the like. Specific examples of "C _2-6 alkynyl" include methylbutynyl, pentynyl, hexynyl, and the like, in addition to those listed above as specific examples of "C _2-4 alkynyl."

"C _1-6 alkoxy" means "C _1-6 alkyloxy", and the "C _1-6 alkyl" moiety has the same meaning as the above-mentioned "C _1-6 alkyl". "C _1-6 alkoxy" preferably includes "C _1-4 alkoxy", and more preferably "C _1-3 alkoxy". Specific examples of "C _1-3 alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, and the like. Specific examples of "C _1-4 alkoxy" include, in addition to those listed above as specific examples of "C _1-3 alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methyl Examples include propoxy. Specific examples of “C _1-6 alkoxy” include pentyloxy _, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1 -methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy and the like.

The "C _1-6 alkyl" part of "C _1-6 alkylthio" has the same meaning as the above "C _1-6 alkyl". "C _1-6 alkylthio" preferably includes "C _1-4 alkylthio", and more preferably "C _1-3 alkylthio". Specific examples of "C _1-3 alkylthio" include methylthio, ethylthio, propylthio, 1-methylethylthio, and the like. Specific examples of “C _1-4 alkylthio” include butylthio, 1,1 _- dimethylethylthio, 1-methylpropylthio, 2 -Methylpropylthio and the like. Specific examples of "C _1-6 alkylthio" include pentylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, in addition to those listed above as specific examples of "C _1-4 alkylthio". , 1-methylbutylthio, 2-methylbutylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, hexylthio, and the like.

"C _1-6 alkylene" means a straight or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms. As "C _1-6 alkylene", preferably "C _1-4 alkylene" is mentioned, and more preferably "C _1-3 alkylene" is mentioned. Specific examples of "C _1-3 alkylene" include methylene, ethylene, propylene, trimethylene, and the like. Specific examples of “C _1-4 alkylene” include butylene, 1,1 _- dimethylethylene, 1,2-dimethylethylene, 1 -methyltrimethylene, 2-methyltrimethylene and the like. Specific examples of "C _1-6 alkylene" include pentylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, in addition to those listed as specific examples of "C _1-4 alkylene" above. , 1-methylbutylene, 2-methylbutylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, hexylene, and the like.

"C _3-10 cycloalkyl" means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure. "C _3-10 cycloalkyl" preferably includes "C _3-7 cycloalkyl." Specific examples of "C _3-7 cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Specific examples of "C _3-10 cycloalkyl" include, for example, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and the like, in addition to those listed above as specific examples of "C _3-7 cycloalkyl."

Furthermore, "C _3-10 cycloalkyl" includes a bicyclic ring in which the C _3-10 cycloalkyl and an aromatic hydrocarbon ring are condensed. Specific examples of the ring-fused compound include the structures shown below.

Specific examples of the above-mentioned crosslinked structure include the structures shown below.

"C _3-10 cycloalkylene" means a cyclic divalent saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure. Preferred examples of "C _3-10 cycloalkylene" include "C _3-7 cycloalkylene". Specific examples of "C _3-7 cycloalkylene" include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like. Specific examples of "C _3-10 cycloalkyl" include, in addition to those listed above as specific examples of "C _3-7 cycloalkyl", cyclooctylene, cyclononylene, cyclodecylene, adamantylene, and the like.

Specific examples of the above-mentioned crosslinked structure include the structures shown below.

The term "3- to 10-membered saturated carbocycle" means a cyclic saturated hydrocarbon having 3 to 10 carbon atoms. The "3- to 10-membered saturated carbocycle" preferably includes "4- to 6-membered saturated carbocycle." Specific examples of the "4- to 6-membered saturated carbocycle" include, for example, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, and the like. Specific examples of the "3- to 10-membered saturated carbocycle" include, in addition to the specific examples of the "4- to 6-membered saturated carbocycle", a cyclopropane ring, a cycloheptane ring, a cyclooctane ring, Examples include cyclononane and cyclodecane.

A "3- to 10-membered saturated heterocyclic group" is composed of 1 to 2 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and 2 to 9 carbon atoms. It means a monovalent saturated heterocyclic group, and also includes those having a partially unsaturated bond and those having a crosslinked structure. The atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO ₂ -. The "3- to 10-membered saturated heterocyclic group" preferably includes "4- to 7-membered monocyclic saturated heterocyclic group." Specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group" include oxetanyl, azetidinyl, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneyl, Examples include minyl, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. Examples of the "3- to 10-membered saturated heterocyclic group" include, in addition to those listed as specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group", oxiranyl, aziridinyl, and the like.
In addition, the "3- to 10-membered saturated heterocyclic group" includes a fused ring formed by the 3- to 10-membered saturated heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring. Bicyclic types are also included. Examples of the 6-membered aromatic hydrocarbon ring forming the condensed ring include a benzene ring. Examples of the 6-membered aromatic heterocycle forming the condensed ring include pyridine, pyrimidine, and pyridazine. Specific examples of the bicyclic "3- to 10-membered saturated heterocyclic group" forming a condensed ring include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxa Nyl, isoindolyl, indazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, and the like.

The term "3- to 8-membered nitrogen-containing saturated heterocycle" means a saturated heterocycle composed of one nitrogen atom and 2 to 7 carbon atoms. The "3- to 8-membered nitrogen-containing saturated heterocycle" preferably includes "4- to 6-membered nitrogen-containing saturated heterocycle." Specific examples of the "4- to 6-membered nitrogen-containing saturated heterocycle" include, for example, an azetidine ring, a pyrrolidine ring, a piperidine ring, and the like. Specific examples of the "3- to 8-membered nitrogen-containing saturated heterocycle" include, in addition to the specific examples of the "4- to 6-membered nitrogen-containing saturated heterocycle", an aziridine ring, an azepane ring, an azocane ring, etc. Examples include rings.

"3- to 10-membered divalent saturated heterocyclic group" means 1 to 2 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and 2 to 9 carbon atoms. It means a divalent saturated heterocyclic group consisting of, and also includes those having a partially unsaturated bond and those having a crosslinked structure. The atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO ₂ -. The "3- to 10-membered saturated heterocyclic group" preferably includes "4- to 7-membered monocyclic saturated heterocyclic group." Specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group" include oxetanylene, azetidinylene, tetrahydrofurylene, pyrrolidinylene, imidazolidinylene, piperidinylene, morpholinylene, thiomorpholinylene, dioxothiomol Holinylene, hexamethylene iminilene, oxazolidinylene, thiazolidinylene, oxoimidazolidinylene, dioxoimidazolidinylene, oxooxazolidinylene, dioxooxazolidinylene, dioxothiazolidinylene, tetrahydrofuranylene, Examples include tetrahydropyranylene. Examples of the "3- to 10-membered saturated heterocyclic group" include, in addition to those listed as specific examples of the "4- to 7-membered monocyclic saturated heterocyclic group", oxiranylene, aziridinylene, and the like.

In addition, the "3- to 10-membered saturated heterocyclic group" includes a fused ring formed by the 3- to 10-membered saturated heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring. Bicyclic types are also included. Examples of the 6-membered aromatic hydrocarbon ring forming the condensed ring include a benzene ring. Examples of the 6-membered aromatic heterocycle forming the condensed ring include pyridine, pyrimidine, and pyridazine. Specific examples of the bicyclic "3- to 10-membered saturated heterocyclic group" forming a condensed ring include dihydroindolylene, dihydroisoindolylene, dihydropurinylene, dihydrothiazolopyrimidinylene, dihydrobenzo Examples include dioxanylene, isoindolylene, indazolylene, tetrahydroquinolinylene, tetrahydroisoquinolinylene, and tetrahydronaphthyridinylene.

"C _6-10 aryl" means an aromatic hydrocarbon ring group having 6 to 10 carbon atoms. Specific examples of "C _6-10 aryl" include phenyl, 1-naphthyl, 2-naphthyl, and the like. Preferred is phenyl.
Furthermore, "C _6-10 aryl" includes a bicyclic ring in which the C _6-10 aryl and a C _4-6 cycloalkyl or a 5- to 6-membered saturated heterocycle form a condensed ring. Specific examples of the bicyclic "C _6-10 aryl" forming a condensed ring include the groups shown below.

"Aromatic hydrocarbon ring" means the ring portion of the above "C _6-10 aryl".

"5- to 12-membered heteroaryl" means a monocyclic 5- to 7-membered aromatic group containing 1 to 4 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. It means a cyclic heterocyclic group or a bicyclic 8- to 12-membered aromatic heterocyclic group. Preferably, it is a "5- to 7-membered monocyclic heteroaryl." More preferred are pyridyl, pyrimidinyl, quinolyl, or isoquinolyl. More preferred is pyridyl. Specific examples of "5- to 7-membered monocyclic heteroaryl" include pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, and triazinyl. , triazolyl, oxadiazolyl, triazolyl, tetrazolyl and the like. Specific examples of "5- to 12-membered heteroaryl" include indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl, in addition to those listed above as "5- to 7-membered monocyclic heteroaryl". , benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, and the like.

"Aromatic heterocycle" means the ring portion of the above-mentioned "5- to 12-membered heteroaryl."

"Cancer" and "tumor" are synonymous in this disclosure and both refer to a malignant tumor, including cancer, sarcoma, and hematological malignancy. Specific examples of "cancer" or "tumor" include acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell tumor, and multiple myeloma. , brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, thymoma/thymic cancer, breast cancer, stomach cancer, gallbladder/bile duct cancer, liver cancer, hepatocellular carcinoma , pancreatic cancer, colon cancer, rectal cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer. Renal cancer, renal cell cancer, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue Examples include sarcoma or skin cancer.

Prexasertib is a compound having the following structure.

In the compound of the present disclosure represented by formula (1), (2), (3), (4) or (5), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^8a , R ^8b , R ^8c , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R 15 , R ¹⁶ , R ¹⁷ , ^{R 18 ,} X, Y, Z, L , V, W, Q and Y are as follows, but the technical scope of the present disclosure is not limited to the range of the compounds listed below.

A preferred embodiment of R ¹ includes C _1-6 alkyl optionally substituted with 1 to 3 fluorine atoms.
More preferred embodiments of R ¹ include a methyl group or an ethyl group which may be substituted with 1 to 3 fluorine atoms.
A more preferred embodiment of R ¹ is a methyl group optionally substituted with 1 to 3 fluorine atoms.
An even more preferred embodiment of R ¹ is a methyl group.

Preferred embodiments of R ² include hydrogen atom, halogen atom, cyano, -OR ³ , C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms, C _3-10 cycloalkyl, or 3 to 3 halogen atoms. Examples include 10-membered saturated heterocyclic groups.
More preferred embodiments of R ² include hydrogen atom, halogen atom, cyano, or C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms.
More preferred embodiments of R ² include C _1-6 alkyl optionally substituted with a halogen atom, cyano, or 1 to 3 halogen atoms.
An even more preferred embodiment of R ² is cyano.

Preferred embodiments of R ³ include a hydrogen atom or C _1-6 alkyl.
A more preferred embodiment of R ³ is C _1-6 alkyl.
A more preferred embodiment of R ³ is C _1-3 alkyl.
An even more preferred embodiment of R ³ is a methyl group.

A preferred embodiment of R ⁴ is C _1-3 alkyl.
A more preferred embodiment of R ⁴ is a methyl group.

Preferred embodiments of R ⁵ , R ⁶ and R ⁷ include a hydrogen atom or C _1-6 alkyl.
A more preferred embodiment of R ⁵ , R ⁶ and R ⁷ is C _1-6 alkyl.
A more preferred embodiment of R ⁵ , R ⁶ and R ⁷ is C _1-3 alkyl.
An even more preferred embodiment of R ⁵ , R ⁶ and R ⁷ is a methyl group.

Preferred embodiments of R ⁸ include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano). ), or a 5- to 6-membered heteroaryl (the heteroaryl is a fluorine atom, a hydroxyl group, a C _1-3 alkyl, (optionally substituted with 1 to 2 same or different substituents selected from the group consisting of C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano).
More preferred embodiments of R ⁸ include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C _1-6 alkyl (the alkyl is a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and a cyano atom). may be substituted with one to two identical or different substituents selected from the group consisting of).
More preferred embodiments of R ⁸ include hydrogen atom, fluorine atom, chlorine atom, bromine atom, or C _1-3 alkyl.
An even more preferred embodiment of R ⁸ is a hydrogen atom or a chlorine atom.

Preferred embodiments of R ^8a , R ^8b and R ^8c include a hydrogen atom, a fluorine atom, a chlorine atom, and a bromine atom.
More preferable embodiments of R ^8a , R ^8b and R ^8c include a hydrogen atom and a chlorine atom.
A more preferred embodiment of R ^8a , R ^8b and R ^8c is a hydrogen atom.

Preferred embodiments of R ⁹ include a hydrogen atom or C _1-6 alkyl.
A more preferred embodiment of R ⁹ is C _1-3 alkyl.
A more preferred embodiment of R ⁹ is a methyl group.

A preferred embodiment of R ¹⁰ is C _1-3 alkyl.
A more preferred embodiment of R ¹⁰ is a methyl group.

Preferred embodiments of R ¹¹ , R ¹² and R ¹³ include a hydrogen atom or C _1-6 alkyl.
A more preferred embodiment of R ¹¹ , R ¹² and R ¹³ is C _1-3 alkyl.
A more preferred embodiment of R ¹¹ , R ¹² and R ¹³ is a methyl group.

Preferred embodiments of R ¹⁴ include a hydrogen atom, a C _1-6 alkyl (the alkyl is the same or different selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano). (optionally substituted with 1 to 3 substituents), C _3-10 cycloalkyl (the cycloalkylene is a fluorine atom, a hydroxyl group, a C _1-3 alkyl, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano), or a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, hydroxyl group, C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano, which may be substituted with the same or different 1 to 3 substituents). .
A more preferred embodiment of R ¹⁴ is a hydrogen atom, C _1-6 alkyl (the alkyl is the same or the same selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano). (optionally substituted with 1 to 3 different substituents).
A more preferred embodiment of R ¹⁴ is a hydrogen atom or C _1-3 alkyl (the alkyl may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano). can be mentioned.
An even more preferred embodiment of R ¹⁴ is a hydrogen atom or a methyl group.

A preferred embodiment of R ¹⁵ is C _1-6 alkyl.
A more preferred embodiment of R ¹⁵ is C _1-3 alkyl.
A more preferred embodiment of R ¹⁵ is a methyl group.

Preferred embodiments of R ¹⁶ and R ¹⁷ include a hydrogen atom or C _1-6 alkyl.
A more preferred embodiment of R ¹⁶ and R ¹⁷ is C _1-6 alkyl.
A more preferred embodiment of R ¹⁶ and R ¹⁷ is C _1-3 alkyl.
An even more preferred embodiment of R ¹⁶ and R ¹⁷ is a methyl group.

Preferred embodiments of R ¹⁸ include a hydrogen atom or C _1-6 alkyl.
A more preferred embodiment of R ¹⁸ is C _1-6 alkyl.
A more preferred embodiment of R ¹⁸ is C _1-3 alkyl.
An even more preferred embodiment of R ¹⁸ is a methyl group.

Preferred embodiments of X, Y and Z include CR ⁸ or a nitrogen atom. In the present disclosure, when referring to a compound of the present disclosure or a pharmaceutically acceptable salt, X, Y and Z are not simultaneously ^CR8 .
Another preferred embodiment of X, Y and Z is that one or two of X, Y and Z represent a nitrogen atom.
Another preferred embodiment of X, Y and Z is that X is CR ⁸ and Y and Z are nitrogen atoms.
Another preferred embodiment of X, Y and Z is that Y is CR ⁸ and X and Z are nitrogen atoms.
Further different preferable embodiments of X, Y and Z include that Z is CR ⁸ and X and Y are nitrogen atoms.

A preferred embodiment of L is a single bond, or C _1-6 alkylene (the alkylene is the same or different selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano). (optionally substituted with 1 to 3 substituents).
A more preferred embodiment of L is a single bond or C _1-6 alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano group). Can be mentioned.
More preferred embodiments of L include a single bond or C _1-6 alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom and a hydroxyl group).
Even more preferred embodiments of L include C _1-6 alkylene which may be substituted with a single bond or one hydroxyl group.

Preferred embodiments of V include a single bond, C _3-10 cycloalkylene (the cycloalkylene is a group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkyl, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano). or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group may be substituted with the same or different 1 to 3 substituents selected from 1 to 3 same or different substituents selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano, which may be substituted with two hydroxyl groups or fluorine atoms; may be substituted with a group).
More preferred embodiments of V include a single bond, C _3-7 cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, a C _1-3 alkyl optionally substituted with 1 to 2 hydroxyl groups, and cyano). or a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group may be substituted with the same or different 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, C _1-3 alkyl optionally substituted with 1 to 2 hydroxyl groups or fluorine atoms, and cyano) may be substituted with the same or different 1 to 2 substituents selected from the group consisting of Can be mentioned.
More preferred embodiments of V include a single bond, a C _3-7 cycloalkylene (the cycloalkylene is a fluorine atom, a hydroxyl group, and a C _1-3 alkyl optionally substituted with 1 to 2 hydroxyl groups or a fluorine atom). or a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group may be substituted with the same or different 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, (optionally substituted with 1 to 2 same or different substituents selected from the group consisting of C _1-3 alkyl optionally substituted with 1 to 2 hydroxyl groups).
Even more preferred embodiments of V include a single bond, C _3-7 cycloalkylene (even if the cycloalkylene is substituted with one substituent selected from the group consisting of hydroxyl group and C _1-3 alkyl). or a 3- to 7-membered divalent saturated heterocyclic group (the 3- to 7-membered saturated heterocyclic group is one selected from the group consisting of fluorine atom, cyano, hydroxyl group, and C _1-3 alkyl) may be substituted with a substituent).

A preferred embodiment of W is a single bond, or C _1-6 alkylene (the alkylene is the same or different selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano). (optionally substituted with 1 to 3 substituents).
A more preferred embodiment of W is a single bond or a C _1-3 alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano group). Can be mentioned.
More preferred embodiments of W include a single bond or C _1-3 alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom and a hydroxyl group).
Even more preferred embodiments of W include C _1-3 alkylene which may be substituted with a single bond or one hydroxyl group.

A preferred embodiment of Q is a hydrogen atom or NHR ¹⁴ .
More preferred embodiments of Q include a hydrogen atom, NH ₂ , or NHMe.
A more preferable embodiment of Q is a hydrogen atom or NH ₂ .
An even more preferred embodiment of Q is a hydrogen atom.
Another even more preferred embodiment of Q includes _NH2 .

One embodiment of the compound represented by formula (1) includes the following (A).
(A)
R ¹ is a methyl group or an ethyl group optionally substituted with 1 to 3 fluorine atoms,
R ² is hydrogen atom, halogen atom, cyano, -OR ³ , C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms, C _3-10 cycloalkyl, or 3- to 10-membered saturated is a heterocyclic group,
R ³ is a hydrogen atom or C _1-6 alkyl,
X, Y and Z each independently represent CR ⁸ or a nitrogen atom, where X, Y and Z are not CR ⁸ at the same time;
R ⁸ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C _1-6 alkyl (the alkyl is selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) may be substituted with the same or different 1 to 2 substituents), or 5- to 6-membered heteroaryl (the heteroaryl is a fluorine atom, a hydroxyl group, a C _1-3 alkyl, a C _1-3 (optionally substituted with 1 to 2 same or different substituents selected from the group consisting of alkoxy, -NR ¹⁶ R ¹⁷ , and cyano),
L is a single bond, or C _1-6 alkylene (the alkylene is the same or different 1 to 3 selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) (optionally substituted with a substituent),
V is a single bond, C _3-10 cycloalkylene (the cycloalkylene is selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) may be substituted with the same or different 1 to 3 substituents), or a 3 to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, a hydroxyl group, a 1 to 2 hydroxyl group), or substituted with the same or different 1 to 3 substituents selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano, which may be substituted with a fluorine atom. ), and
W is a single bond, or C _1-6 alkylene (the alkylene is the same or different 1 to 3 atoms selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) (optionally substituted with a substituent),
Q is a hydrogen atom or NHR ¹⁴ ,
R ¹⁴ is a hydrogen atom, C _1-6 alkyl (the alkyl is the same or different 1 to 3 selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ⁽ optionally substituted _{with a} ^substituent _of or a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C _{1 -3} alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano, which may be substituted with the same or different 1 to 3 substituents),
R ¹⁶ and R ¹⁷ are hydrogen atoms or C _1-6 alkyl,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (1) includes the following (B).
(B)
R ¹ is a methyl group optionally substituted with 1 to 3 fluorine atoms,
R ² is a halogen atom, cyano, or C _1-6 alkyl optionally substituted with 1 to 3 halogen atoms,
X, Y and Z each independently represent CR ⁸ or a nitrogen atom, where X, Y and Z are not CR ⁸ at the same time;
R ⁸ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C _1-3 alkyl,
L is a single bond, or C _1-6 alkylene (the alkylene is the same or different 1 to 3 selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) (optionally substituted with a substituent),
V is a single bond, C _3-10 cycloalkylene (the cycloalkylene is selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) may be substituted with the same or different 1 to 3 substituents), or a 3 to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group may be a fluorine atom, a hydroxyl group, a 1 to 2 hydroxyl group), or substituted with the same or different 1 to 3 substituents selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano, which may be substituted with a fluorine atom. ), and
W is a single bond, or C _1-6 alkylene (the alkylene is the same or different 1 to 3 atoms selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) (optionally substituted with a substituent),
Q is a hydrogen atom or NHR ¹⁴ ,
R ¹⁴ is a hydrogen atom, C _1-6 alkyl (the alkyl is the same or different 1 to 3 selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ⁽ optionally substituted _{with a} ^substituent _of ), or a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group includes a fluorine atom, a hydroxyl group, a C _{1 -3} alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
R ¹⁶ and R ¹⁷ are hydrogen atoms or C _1-6 alkyl,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (1) includes the following (C).
(C)
R ¹ is a methyl group or a fluoromethyl group,
R ² is a chlorine atom, cyano, or trifluoromethyl group,
X, Y and Z each independently represent CR ⁸ or a nitrogen atom, where X, Y and Z are not CR ⁸ at the same time;
R ⁸ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C _1-3 alkyl,
L is a single bond, or C _1-6 alkylene (the alkylene is the same or different 1 to 3 selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) (optionally substituted with a substituent),
V is a single bond, C _3-10 cycloalkylene (the cycloalkylene is selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) may be substituted with the same or different 1 to 3 substituents), or a 3 to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group may be a fluorine atom, a hydroxyl group, a 1 to 2 hydroxyl group), or substituted with the same or different 1 to 3 substituents selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano, which may be substituted with a fluorine atom. ), and
W is a single bond, or C _1-6 alkylene (the alkylene is the same or different 1 to 3 atoms selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) (optionally substituted with a substituent),
Q is a hydrogen atom or NHR ¹⁴ ,
R ¹⁴ is a hydrogen atom or C _1-3 alkyl (the alkyl may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and cyano),
A compound or a pharmaceutically acceptable salt thereof, wherein R ¹⁶ and R ¹⁷ are a hydrogen atom or C _1-6 alkyl.

One embodiment of the compound represented by formula (1) includes the following (D).
(D)
R ¹ is a methyl group,
R ² is cyano,
X, Y and Z each independently represent CR ⁸ or a nitrogen atom, where X, Y and Z are not CR ⁸ at the same time;
R ⁸ is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C _1-3 alkyl,
L is a single bond or C _1-6 alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano),
V is a single bond, C _3-7 cycloalkylene (the cycloalkylene is selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkyl optionally substituted with 1 to 2 hydroxyl groups, and cyano); may be substituted with the same or different 1 to 2 substituents), or a 3 to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group may be substituted with a fluorine atom, a hydroxyl group, 1 to 2 C _1-3 alkyl optionally substituted with a hydroxyl group or a fluorine atom, and cyano, which may be substituted with the same or different 1 to 2 substituents),
W is a single bond or C _1-3 alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano),
Q is a hydrogen atom, NH ₂ or NHMe,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (1) or (2) includes the following (E).
(E)
X, Y and Z each independently represent CR ⁸ or a nitrogen atom, where X, Y and Z are not CR ⁸ at the same time;
R ⁸ is a hydrogen atom or a chlorine atom,
L is a single bond or C _1-6 alkylene optionally substituted with one hydroxyl group or fluorine atom,
V is a single bond, C _3-7 cycloalkylene (the cycloalkylene may be substituted with one substituent selected from the group consisting of hydroxyl group and C _1-3 alkyl), or 3 to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is from the group consisting of fluorine atom, cyano, hydroxyl group, and C _1-3 alkyl optionally substituted with 1 to 2 hydroxyl groups or fluorine atoms) optionally substituted with one selected substituent),
W is a single bond or C _1-3 alkylene optionally substituted with one hydroxyl group,
Q is a hydrogen atom, NH ₂ or NHMe,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (3) includes the following (F).
(F)
R ^8a and R ^8b are each independently a hydrogen atom or a chlorine atom,
L is a single bond or C _1-3 alkylene optionally substituted with one hydroxyl group,
V is a single bond, C _3-7 cycloalkylene (the cycloalkylene may be substituted with one substituent selected from the group consisting of hydroxyl group and C _1-3 alkyl), or 3 to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group may be substituted with one substituent selected from the group consisting of fluorine atom, cyano, hydroxyl group, and C _1-3 alkyl) and
W is a single bond or C _1-3 alkylene optionally substituted with one hydroxyl group,
Q is a hydrogen atom or _NH2 ,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (3) includes the following (G).
(G)
R ^8a and R ^8b are each independently a hydrogen atom or a chlorine atom,
L is C _1-3 alkylene optionally substituted with one hydroxyl group,
V is a single bond,
W is a single bond or C _1-3 alkylene optionally substituted with one hydroxyl group,
Q is _NH2 ,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (3) includes the following (H).
(H)
R ^8a and R ^8b are each independently a hydrogen atom,
L is C _1-3 alkylene optionally substituted with one hydroxyl group,
V is C _3-7 cycloalkylene,
W is C _1-3 alkylene optionally substituted with one hydroxyl group,
Q is _NH2 ,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (4) includes the following (I).
(I)
R ^8b and R ^8c are hydrogen atoms,
L is a single bond or C _1-3 alkylene optionally substituted with one hydroxyl group or fluorine atom,
V is a single bond, C _3-7 cycloalkylene (the cycloalkylene may be substituted with one substituent selected from the group consisting of hydroxyl group and C _1-3 alkyl), or 3 to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is from the group consisting of fluorine atom, cyano, hydroxyl group, and C _1-3 alkyl optionally substituted with 1 to 3 hydroxyl groups or fluorine atoms) optionally substituted with one selected substituent),
W is a single bond or C _1-3 alkylene optionally substituted with one hydroxyl group,
Q is a hydrogen atom, NH ₂ or NHMe,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (4) includes the following (J).
(J)
R ^8b and R ^8c are each independently a hydrogen atom,
L is C _1-3 alkylene optionally substituted with one hydroxyl group or fluorine atom,
V is a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is a fluorine atom, cyano, a hydroxyl group, and C _1-3 which may be substituted with 1 to 3 hydroxyl groups and a fluorine atom) (optionally substituted with one substituent selected from the group consisting of alkyl),
W is a single bond,
Q is a hydrogen atom,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (4) includes the following (K).
(K)
R ^8b and R ^8c are each independently a hydrogen atom,
L is C _1-3 alkylene optionally substituted with one hydroxyl group or fluorine atom,
V is C _3-7 cycloalkylene (the cycloalkylene may be substituted with one substituent selected from the group consisting of a hydroxyl group and C _1-3 alkyl),
W is C _1-3 alkylene optionally substituted with one hydroxyl group,
Q is _NH2 ,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (4) includes the following (L).
(L)
R ^8b and R ^8c are each independently a hydrogen atom,
L is a single bond,
V is C _3-7 cycloalkylene (the cycloalkylene may be substituted with one substituent selected from the group consisting of hydroxyl group and C _1-3 alkyl),
W is a single bond,
Q is NH ₂ or NHMe;
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (4) includes the following (M).
(M)
R ^8b and R ^8c are each independently a hydrogen atom,
L is C _1-3 alkylene optionally substituted with one hydroxyl group or fluorine atom,
V is a single bond,
W is a single bond or C _1-3 alkylene optionally substituted with one hydroxyl group,
Q is NH ₂ or NHMe;
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (5) includes the following (N).
(N)
R ^8a and R ^8c are each independently a hydrogen atom,
L is a single bond or C _1-3 alkylene optionally substituted with one hydroxyl group,
V is a single bond, C _3-7 cycloalkylene (the cycloalkylene may be substituted with one substituent selected from the group consisting of hydroxyl group and C _1-3 alkyl), or 3 to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from the group consisting of fluorine atom, cyano, hydroxyl group, and C _1-3 alkyl optionally substituted with 1 to 2 hydroxyl groups) optionally substituted with one substituent),
W is a single bond or C _1-3 alkylene optionally substituted with one hydroxyl group,
Q is a hydrogen atom or _NH2 ,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (5) includes the following (O).
(O)
R ^8a and R ^8c are each independently a hydrogen atom,
L is C _1-3 alkylene optionally substituted with one hydroxyl group,
V is a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is one selected from the group consisting of a hydroxyl group and a C _1-3 alkyl optionally substituted with one hydroxyl group) (optionally substituted with a substituent),
W is a single bond,
Q is a hydrogen atom,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (5) includes the following (P).
(P)
R ^8a and R ^8c are each independently a hydrogen atom,
L is C _1-3 alkylene optionally substituted with one hydroxyl group,
V is a single bond,
W is a single bond or C _1-3 alkylene optionally substituted with one hydroxyl group,
Q is _NH2 ,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (5) includes the following (Q).
(Q)
R ^8a is each independently a hydrogen atom,
L is C _1-3 alkylene optionally substituted with one hydroxyl group,
V is C _3-7 cycloalkylene,
W is C _1-3 alkylene optionally substituted with one hydroxyl group,
Q is _NH2 ,
A compound or a pharmaceutically acceptable salt thereof.

One embodiment of the compound represented by formula (6) includes the following (R).
(R)
R ^8a is a hydrogen atom,
L is C _1-3 alkylene,
V is a single bond or C _3-7 cycloalkylene,
W is a single bond or C _1-3 alkylene,
Q is _NH2 ,
A compound or a pharmaceutically acceptable salt thereof.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile A crystalline form (Form I) of the hydrochloride salt having a powder X-ray diffraction pattern having a characteristic peak at at least 7.2°±0.2° expressed in 2θ is mentioned.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile A crystalline form (Form I) of the hydrochloride salt having a powder X-ray diffraction pattern having a characteristic peak at at least 8.8°±0.2° expressed in 2θ is mentioned.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride salt, which has a crystalline form (form I).

A further aspect of the invention is a crystalline form of Form I of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino) Pyrazine-2-carbonitrile hydrochloride, expressed in 2θ: 7.2°±0.2°, 8.8°±0.2°, 9.8°±0.2°, 10.2 °±0.2°, 10.7°±0.2°, 16.7°±0.2°, 18.5°±0.2°, 26.2°±0.2°, and 27. Those having a powder X-ray diffraction pattern with characteristic peaks at 0°±0.2° and 26.4°±0.2° are mentioned. The crystal is identified by having four or five peaks selected from these ten peaks.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile Mention is made of a crystalline form (Form II) of a phosphate salt having a powder X-ray diffraction pattern having a characteristic peak at at least 6.8°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile Mention is made of a crystalline form (Form II) of a phosphate salt having a powder X-ray diffraction pattern having a characteristic peak at at least 13.0°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile A crystalline form of a phosphate salt having a powder X-ray diffraction pattern having characteristic peaks at at least 6.8° ± 0.2° and 13.0° ± 0.2°, expressed in 2θ. Form II).

A further aspect of the invention is the crystalline form of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino) Pyrazine-2-carbonitrile phosphate, expressed in 2θ, 6.8°±0.2°, 7.5°±0.2°, 11.7°±0.2°, 11. 9°±0.2°, 13.0°±0.2°, 16.4°±0.2°, 19.3°±0.2°, 20.4°±0.2°, 22. Examples include those having a powder X-ray diffraction pattern with characteristic peaks at 7°±0.2° and 24.3°±0.2°. The crystal is identified by having four or five peaks selected from these ten peaks.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile Mention is made of the crystalline form (Form III) of the tosylate salt, which has a powder X-ray diffraction pattern with characteristic peaks at at least 6.0°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile and a crystalline form (Form III) having a powder X-ray diffraction pattern having a characteristic peak at at least 17.0°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile A crystalline form of a tosylate salt having a powder X-ray diffraction pattern having characteristic peaks at at least 6.0° ± 0.2° and 17.0° ± 0.2°, expressed in 2θ. Form III).

A further aspect of the invention is a crystalline form of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino) of Form III. Pyrazine-2-carbonitrile tosylate, expressed in 2θ, 6.0°±0.2°, 9.0°±0.2°, 12.1°±0.2°, 14. Characterized by 4°±0.2°, 16.2°±0.2°, 17.0°±0.2°, 22.8°±0.2°, and 26.3°±0.2° Examples include those having a powder X-ray diffraction pattern with a typical peak. The crystal is identified by having four or five peaks selected from these ten peaks.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Form IV), which has a powder X-ray diffraction pattern with characteristic peaks at at least 9.3°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Form IV), which has a powder X-ray diffraction pattern having a characteristic peak at at least 10.2°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Form IV) having a powder X-ray diffraction pattern having characteristic peaks at at least 9.3° ± 0.2° and 10.2° ± 0.2°, expressed in 2θ. can be mentioned.

A further aspect of the invention is a crystalline form of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino) of Form IV. Pyrazine-2-carbonitrile, expressed in 2θ, 9.3°±0.2°, 10.2°±0.2°, 10.7°±0.2°, 13.6°± 0.2°, 16.7°±0.2°, 17.1°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 26.1°± Examples include those having a powder X-ray diffraction pattern with characteristic peaks at 0.2° and 26.4°±0.2°. The crystal is identified by having four or five peaks selected from these ten peaks.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Form V) having a powder X-ray diffraction pattern with characteristic peaks at at least 7.9°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Form V), which has a powder X-ray diffraction pattern with characteristic peaks at at least 8.7°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Form V) having a powder X-ray diffraction pattern having characteristic peaks at at least 7.9° ± 0.2° and 8.7° ± 0.2°, expressed in 2θ. can be mentioned.

A further aspect of the invention is a crystalline form of Form V of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino) Pyrazine-2-carbonitrile, expressed in 2θ, 7.9°±0.2°, 8.7°±0.2°, 12.2°±0.2°, 13.1°± 0.2°, 15.9°±0.2°, 17.6°±0.2°, 19.9°±0.2°, 21.9°±0.2°, 22.8°± Examples include those having a powder X-ray diffraction pattern having characteristic peaks at 0.2° and 26.6°±0.2°. The crystal is identified by having four or five peaks selected from these ten peaks.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Form VI) having a powder X-ray diffraction pattern with characteristic peaks at at least 5.3°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Form VI) having a powder X-ray diffraction pattern with characteristic peaks at at least 5.7°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile (Form VI) having a powder X-ray diffraction pattern having characteristic peaks at at least 5.3° ± 0.2° and 5.7° ± 0.2°, expressed in 2θ. can be mentioned.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino) in the crystalline form of Form VI Pyrazine-2-carbonitrile, expressed in 2θ, 5.3°±0.2°, 5.7°±0.2°, 7.0°±0.2°, 7.3°± 0.2°, 7.8°±0.2°, 8.4°±0.2°, 9.3°±0.2°, 10.5°±0.2°, 11.5°± Examples include those having a powder X-ray diffraction pattern having characteristic peaks at 0.2° and 14.1°±0.2°. The crystal is identified by having four or five peaks selected from these ten peaks.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile A crystalline form (Form VII) of the hydrochloride salt having a powder X-ray diffraction pattern having a characteristic peak at at least 8.2°±0.2° expressed in 2θ is mentioned.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile Mention is made of the crystalline form (Form VII) of the hydrochloride salt, which has a powder X-ray diffraction pattern with a characteristic peak at at least 27.0°±0.2°, expressed in 2θ.

In a further aspect of the invention, 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride salt, which has a crystalline form (form VII).

A further aspect of the invention is a crystalline form of 5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino) of Form VII. Pyrazine-2-carbonitrile hydrochloride, expressed in 2θ: 7.0°±0.2°, 8.2°±0.2°, 9.7°±0.2°, 11.5 °±0.2°, 14.0°±0.2°, 14.6°±0.2°, 16.3°±0.2°, 18.0°±0.2°, 19.8 characteristic of °±0.2°, 21.2°±0.2°, 21.5°±0.2°, 24.1°±0.2° and 27.0°±0.2° Examples include those having a powder X-ray diffraction pattern with peaks. The crystal is identified by having four or five peaks selected from these 13 peaks.

When administering the compound of the present disclosure, the amount used varies depending on the symptoms, age, administration method, etc., but for example, in the case of intravenous injection, the lower limit is 0.01 mg per day for adults ( Effects are expected by administering 1000 mg (preferably 100 mg) once or in several doses depending on the symptoms. Examples of the administration schedule include single administration, once a day for three consecutive days, or twice a day for one week. Furthermore, each of the administration methods described above can be repeated at intervals of about 1 day to about 60 days.

Compounds of the disclosure may be administered parenterally or orally, but are preferably administered parenterally, more preferably by intravenous injection. The compounds of the present disclosure are also preferably formulated and administered in a pharmaceutically acceptable carrier, such as a liposome.

Liposomes encapsulating compounds of the present disclosure include at least one or more phospholipids. Examples of phospholipids include phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and sphingomyelin.

The fatty acid residue in the phospholipid is not particularly limited, but includes, for example, saturated or unsaturated fatty acid residues having 14 to 18 carbon atoms, and specifically, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, etc. Examples include acyl groups derived from fatty acids such as acids. In addition, phospholipids derived from natural products such as egg yolk lecithin and soybean lecithin, and hydrogenated egg yolk lecithin in which the unsaturated fatty acid residues thereof are hydrogenated, hydrogenated soybean lecithin (also called hydrogenated soybean phospholipid or hydrogenated soybean phosphatidylcholine). ) etc. can also be used.

The amount (mole fraction) of phospholipid to be blended with respect to the entire liposome membrane component is not particularly limited, but is preferably 30 to 80%, more preferably 40 to 70%.

Liposomes encapsulating compounds of the present disclosure can include sterols. Examples of sterols include cholesterol, β-sitosterol, stigmasterol, campesterol, brassicasterol, ergosterol, and fucosterol. Preferable examples of sterols include cholesterol. The amount (mole fraction) of sterols to be added to the entire liposome membrane component is not particularly limited, but is preferably 0 to 60%, more preferably 10 to 50%, and still more preferably 30 to 50%. Can be mentioned.

Liposomes encapsulating compounds of the present disclosure can include polymer-modified lipids to improve retention in vivo. The amount (mole fraction) of the polymer-modified lipid to be blended with respect to the entire liposome membrane component is not particularly limited, but is preferably 0 to 20%, more preferably 1 to 10%. The polymer portion of the polymer-modified lipid preferably includes a hydrophilic polymer, and more preferably includes a hydrophilic polymer in which the terminal of the polymer that is not bonded to a lipid is alkoxylated. The polymer moiety of the polymer-modified lipid is not particularly limited, but includes, for example, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinylpyrrolidone, and ethoxy. Examples include polyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxypolyvinylpyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, and propoxypolyvinylpyrrolidone. The polymer portion of the polymer-modified lipid preferably includes polyethylene glycol, methoxypolyethylene glycol, methoxypolypropylene glycol, ethoxypolyethylene glycol, ethoxypolypropylene glycol, propoxypolyethylene glycol, and propoxypolypropylene glycol. More preferred examples of the polymer moiety of the polymer-modified lipid include polyethylene glycol, methoxypolyethylene glycol, ethoxypolyethylene glycol, ethoxypolypropylene glycol, and propoxypolyethylene glycol. Even more preferred polymer moieties of polymer-modified lipids include polyethylene glycol and methoxypolyethylene glycol. The polymer moiety of the polymer-modified lipid most preferably includes methoxypolyethylene glycol. The molecular weight of the polymer moiety of the polymer-modified lipid is not particularly limited, but examples include 100 to 10,000 Daltons, preferably 1,000 to 7,000 Daltons, more preferably 1,500 to 5,000 Daltons, and most preferably 1,500 to 7,000 Daltons. An example is 3000 Daltons.

The lipid moiety of the polymer-modified lipid is not specifically limited, but includes, for example, phosphatidylethanolamine and diacylglycerol. The lipid moiety of the polymer-modified lipid is preferably phosphatidylethanolamine having a saturated or unsaturated fatty acid residue having 14 to 18 carbon atoms, and diacylglycerol having a saturated or unsaturated fatty acid residue having 14 to 18 carbon atoms. and more preferably phosphatidylethanolamine having a saturated fatty acid residue having 14 to 18 carbon atoms, and diacylglycerol having a saturated fatty acid residue having 14 to 18 carbon atoms, and more preferably a palmitoyl group or a stearoyl group. and diacylglycerols having a palmitoyl group or a stearoyl group. The most preferred lipid moiety of the polymer-modified lipid is distearoyl phosphatidylethanolamine.

Liposomes encapsulating compounds of the present disclosure can include pharmaceutically acceptable additives. Examples of additives include inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers.

Examples of inorganic acids include phosphoric acid, hydrochloric acid, and sulfuric acid.

Examples of inorganic acid salts include sodium hydrogen phosphate, sodium chloride, ammonium sulfate, and magnesium sulfate.

Examples of organic acids include citric acid, acetic acid, succinic acid, and tartaric acid.

Examples of organic acid salts include sodium citrate, sodium acetate, disodium succinate, and sodium tartrate.

Examples of sugars include glucose, sucrose, mannitol, sorbitol, and trehalose.

Examples of the buffer include L-arginine, L-histidine, trometamol (Trishydroxymethylaminomethane, Tris), and salts thereof.

Antioxidants include, for example, sodium sulfite, L-cysteine, sodium thioglycolate, sodium thiosulfate, ascorbic acid, and tocopherol.

Examples of polymers include polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, and sodium carboxymethylcellulose.

The method for producing the compound of the present disclosure represented by formula (1) will be described below by giving examples, but the method for producing the compound of the present disclosure is not limited thereto. The compounds used in the following production methods may form salts as long as they do not interfere with the reaction.

The compounds of the present disclosure can be produced using known compounds as starting materials, for example, by the following production methods A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, It can be produced by appropriately combining the methods of Q and R, methods analogous thereto, or synthetic methods well known to those skilled in the art. Compounds of the present disclosure other than formula (a2) can also be produced by methods similar to these or by appropriately combining synthesis methods well known to those skilled in the art.

［式中、Ｒ^１、Ｒ^２、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基を意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。］ Manufacturing method A
The compound of the present disclosure represented by formula (a2) can be produced, for example, by the following method.

[In the formula, R ¹ , R ² , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, and P ¹ means an amino protecting group. Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

[Step 1]
Compound (a2) can be produced by removing the protecting group P ¹ of compound (a1) obtained by the following production method. This step can be performed, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

［式中、Ｒ^１、Ｒ^２、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基を意味し、Ｐ^２はフェノールの保護基を意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられ、Ｐ^２としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のフェノールの保護基等が挙げられる。］ Manufacturing method B
The compound of the present disclosure represented by formula (a1) can be produced, for example, by the following method.

[Wherein, R ¹ , R ² , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, P ¹ means an amino protecting group, and P ² means a phenol protecting group. means a protecting group. Examples of P ¹ include the amino protecting group described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999), and as P ² , Examples include the phenol protecting group described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

Compound (b3) is available as a commercial product.

[Step 1]
Compound (b2) can be produced by removing the protecting group P ² of compound (b1) obtained by the following production method. This step can be carried out, for example, according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[Step 2]
Compound (a1) can be produced by a Mitsunobu reaction between compound (b2) and compound (b3) in a suitable solvent in the presence of a Mitsunobu reagent.

Examples of the Mitsunobu reagent include diethyl azodicarboxylate (DEAD), isopropyl azodicarboxylate (DIAD), N,N,N',N'-tetraisopropylazodicarboxamide (TIPA), and 1,1'-(azodicarboxylate). carbonyl)dipiperidine (ADDP), N,N,N',N'-tetramethylazodicarboxamide (TMAD), triphenylphosphine, tributylphosphine, etc., cyanomethylenetrimethylphosphorane (CMMP), cyano Methylenebutylphosphorane (CMBP) can also be used.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane. ; Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; Ester solvents such as ethyl acetate and methyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, Examples include aprotic solvents such as 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide; or mixed solvents thereof. Preferred solvents include toluene, benzene, THF, 1,4-dioxane, and mixed solvents thereof.

The reaction time is usually 5 minutes to 72 hours, preferably 12 hours to 24 hours.

The reaction temperature is usually 0°C to 100°C, preferably 0°C to 50°C.

［式中、Ｒ^１、Ｒ^２、Ｘ、Ｙ及びＺは項１の記載と同義であり、Ｐ^２はフェノールの保護基を意味する。Ｐ^２としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のフェノールの保護基等が挙げられる。］ Manufacturing method C
The compound of the present disclosure represented by formula (b1) can be produced, for example, by the following method.

[In the formula, R ¹ , R ² , X, Y and Z have the same meanings as described in Item 1, and P ² means a phenol protecting group. Examples of P ² include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

[Step 1]
Compound (c2) can be produced by reacting compound (c1) with hydrazine monohydrate in a suitable solvent in the presence or absence of a suitable acid.

Examples of acids include acetic acid, propionic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, camphorsulfonic acid, and the like. Preferred acids include acetic acid, p-toluenesulfonic acid, and the like.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; Ester solvents such as ethyl acetate and methyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide; alcoholic solvents such as methanol, ethanol, isopropyl alcohol, butanol; or mixtures thereof. Preferable examples of the solvent include 1,4-dioxane, toluene, and ethanol.

The reaction time is usually 5 minutes to 72 hours, preferably 12 hours to 24 hours.

The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[Step 2]
Compound (b1) can be produced by reacting compound (c2) with a 5-chloropyrazine derivative in a suitable solvent in the presence of a suitable base. Compound (b1) can also be produced by reacting compound (c2) with a 5-chloropyrazine derivative in a suitable solvent in the presence of a suitable palladium catalyst, a ligand and a base.

Examples of the base include triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7 -ene (DBU), pyridine, dimethylaminopyridine, picoline, N-methylmorpholine (NMM), organic bases such as N-ethylmorpholine, or sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, Examples include inorganic bases such as sodium hydroxide and potassium hydroxide. Preferred examples of the base include triethylamine, diisopropylethylamine, N-ethylmorpholine, potassium carbonate, and cesium carbonate.

Examples of the palladium catalyst include salts such as palladium chloride and palladium acetate, and zero-valent palladium complexes such as tris(dibenzylideneacetone) dipalladium (0) chloroform adduct.

Examples of the ligand include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xanthos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) , 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), and other phosphine ligands. . Preferred examples of the ligand include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantophos).

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; Ester solvents such as ethyl acetate and methyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, and other aprotic solvents; or mixtures thereof. Preferred solvents include tetrahydrofuran, 1,4-dioxane, toluene, dimethyl sulfoxide and the like.

The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 6 hours.

The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

Manufacturing method D
The compound of the present disclosure represented by formula (c1) can be produced, for example, by the following method.

［式中、Ｒ^１、Ｘ、Ｙ及びＺは項１の記載と同義であり、Ｐ^２はフェノールの保護基を意味する。Ｐ^２としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のフェノールの保護基等が挙げられる。］

[In the formula, R ¹ , X, Y and Z have the same meanings as described in Item 1, and P ² means a phenol protecting group. Examples of P ² include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

[Step 1]
Compound (c1) can be produced by reacting compound (d1) with acetonitrile in an appropriate solvent in the presence of an appropriate base.

As the base, an inorganic base can be used. Inorganic bases include hydrides such as sodium hydride, alkali halides such as potassium fluoride, alkali hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydrogen carbonate. Examples include alkali, alkali alkoxides such as sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and alkali metals such as n-butyllithium, methyllithium and isopropylmagnesium bromide. Preferred bases include sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, n-butyllithium, and the like.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; Ester solvents such as ethyl acetate and methyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide; alcoholic solvents such as methanol, ethanol, isopropyl alcohol, butanol; or mixtures thereof. Preferred solvents include tetrahydrofuran, toluene, and the like.

The reaction time is usually 5 minutes to 72 hours, preferably 12 hours to 24 hours.
The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

［式中、Ｒ^１、Ｒ^２、Ｘ、Ｙ及びＺは項１の記載と同義であり、Ｐ^２はフェノールの保護基を意味する。Ｐ^２としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のフェノールの保護基等が挙げられる。］ Manufacturing method E
The compound of the present disclosure represented by formula (b1) can be produced, for example, by the following method.

[In the formula, R ¹ , R ² , X, Y and Z have the same meanings as described in Item 1, and P ² means a phenol protecting group. Examples of P ² include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

[Step 1]
Compound (e2) can be produced by reacting compound (e1) with carbon disulfide and iodomethane in a suitable solvent in the presence of a suitable base.

As the base, an inorganic base can be used. Inorganic bases include hydrides such as sodium hydride, alkali halides such as potassium fluoride, alkali hydroxides such as sodium hydroxide and potassium hydroxide, carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydrogen carbonate. Examples include alkali, alkali alkoxides such as sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, and alkali metals such as n-butyllithium, methyllithium and isopropylmagnesium bromide. Preferred bases include sodium hydride, potassium tert-butoxide, and the like.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; Ester solvents such as ethyl acetate and methyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide; alcoholic solvents such as methanol, ethanol, isopropyl alcohol, butanol; or mixtures thereof. Preferred solvents include tetrahydrofuran, toluene, N,N-dimethylformamide, and the like.

The reaction time is usually 5 minutes to 72 hours, preferably 30 minutes to 2 hours.

The reaction temperature is usually -78°C to 200°C, preferably 0°C to 25°C.

[Step 2]
Compound (e3) can be produced by reacting compound (e2) with a 5-aminopyrazine derivative in an appropriate solvent in the presence of an appropriate base.

Examples of the base include triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7 -Ene (DBU), pyridine, dimethylaminopyridine, picoline, N-methylmorpholine (NMM), organic bases such as N-ethylmorpholine, or sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and inorganic bases such as potassium hydroxide. Preferred bases include triethylamine, diisopropylethylamine, and the like.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; Ester solvents such as ethyl acetate and methyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, and other aprotic solvents; or mixtures thereof. Preferred solvents include tetrahydrofuran, toluene, dimethyl sulfoxide, and the like.

The reaction time is usually 5 minutes to 48 hours, preferably 2 hours to 8 hours.

The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

[Step 3]
Compound (b1) can be produced by reacting compound (e3) with hydrazine monohydrate in a suitable solvent in the presence or absence of a suitable acid.

Examples of acids include acetic acid, propionic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, hydrochloric acid, sulfuric acid, camphorsulfonic acid, and the like. Preferably, the acid is acetic acid.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; Ester solvents such as ethyl acetate and methyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide; alcoholic solvents such as methanol, ethanol, isopropyl alcohol, butanol; or mixtures thereof. Preferable examples of the solvent include 1,4-dioxane and ethanol.

The reaction time is usually 5 minutes to 72 hours, preferably 12 hours to 24 hours.

The reaction temperature is usually 0°C to 200°C, preferably 50°C to 100°C.

［式中、Ｒ^１、Ｘ、Ｙ及びＺは項１の記載と同義であり、Ｐ^２はフェノールの保護基を意味する。Ｐ^２としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のフェノールの保護基等が挙げられる。］ Manufacturing method F
The compound of the present disclosure represented by formula (c1) can be produced, for example, by the following method.

[In the formula, R ¹ , X, Y and Z have the same meanings as described in Item 1, and P ² means a phenol protecting group. Examples of P ² include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

[Step 1]
Compound (f1) can be produced by reacting compound (e1) with dimethylformamide dimethyl acetal in a suitable solvent.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; Ester solvents such as ethyl acetate and methyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, and other aprotic solvents; or mixtures thereof. Preferred solvents include N,N-dimethylformamide and the like.

The reaction time is usually 5 minutes to 48 hours, preferably 24 hours to 48 hours.

The reaction temperature is usually 0°C to 200°C, preferably 60°C to 120°C.

[Step 2]
Compound (f2) can be produced by reacting compound (f1) with hydroxyamine hydrochloride in a suitable solvent.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; Ester solvents such as ethyl acetate and methyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide; alcoholic solvents such as methanol, ethanol, isopropyl alcohol, butanol; or mixtures thereof. Preferable examples of the solvent include ethanol, isopropyl alcohol, and the like.

The reaction time is usually 5 minutes to 48 hours, preferably 6 hours to 12 hours.

The reaction temperature is usually 0°C to 200°C, preferably 40°C to 80°C.

[Step 3]
Compound (c1) can be produced by reacting compound (f2) with a base in an appropriate solvent.

Examples of the base include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Preferred examples of the base include sodium hydroxide and potassium hydroxide.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, and 1,4-dioxane; Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, and xylene; Ester solvents such as ethyl acetate and methyl acetate; N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, dimethyl sulfoxide; protic solvents such as water, methanol, ethanol, isopropyl alcohol, butanol; or mixtures thereof. Preferably, the solvent includes a mixed solvent of water and ethanol.

The reaction time is usually 5 minutes to 48 hours, preferably 1 hour to 6 hours.

The reaction temperature is usually 0°C to 200°C, preferably 20°C to 50°C.

［式中、Ｒ^１、Ｒ^２、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基をを意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。］ Manufacturing method G
The compound of the present disclosure represented by formula (a1) can be produced, for example, by the following method.

[In the formula, R ¹ , R ² , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, and P ¹ means an amino protecting group. Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

[Step 1]
Compound (g2) can be produced from compound (g1) obtained by the following production method by the method described in Step 1 of Production Method C or a method similar thereto.

[Step 2]
Compound (a1) can be produced from compound (g2) by the method described in Step 2 of Production Method C or a method analogous thereto.

［式中、Ｒ^１、Ｒ^２、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基をを意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。］ Manufacturing method H
The compound represented by formula (a1) can be produced, for example, by the following method.

[Wherein, R ¹ , R ² , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, and P ¹ means an amino protecting group. Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

[Step 1]
Compound (h2) can be produced from compound (h1) obtained by the following production method by the method described in Step 1 of Production Method E or a method analogous thereto.

[Step 2]
Compound (h3) can be produced from compound (h2) by the method described in Step 2 of Production Method E or a method analogous thereto.
[Step 3]
Compound (a1) can be produced from compound (h3) by the method described in Step 3 of Production Method E or a method analogous thereto.

［式中、Ｒ^１、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基をを意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。］ Manufacturing method I
The compound represented by formula (g1) can be produced, for example, by the following method.

[In the formula, R ¹ , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, and P ¹ means an amino protecting group. Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

[Step 1]
Compound (i1) can be produced from compound (h1) obtained by the following production method by the method described in Step 1 of Production Method F or a method analogous thereto.

[Step 2]
Compound (i2) can be produced from compound (i1) by the method described in Step 2 of Production Method F or a method analogous thereto.

[Step 3]
Compound (g1) can be produced from compound (i2) by the method described in Step 3 of Production Method F or a method analogous thereto.

［式中、Ｒ^１、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基をを意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。］ Manufacturing method J
The compound represented by formula (g1) can also be produced, for example, by the following method.

[In the formula, R ¹ , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, and P ¹ means an amino protecting group. Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

[Step 1]
Compound (g1) can be produced from compound (j1) obtained by the following production method by the method described in Step 1 of Production Method D or a method analogous thereto.

［式中、Ｒ^１、Ｘ、Ｙ及びＺは項１の記載と同義であり、Ｐ^２はフェノールの保護基をを意味する。Ｐ^２としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のフェノールの保護基等が挙げられる。］ Manufacturing method K
The compound of the present disclosure represented by formula (d1) can be produced, for example, by the following method.

[In the formula, R ¹ , X, Y and Z have the same meanings as described in Item 1, and P ² means a phenol protecting group. Examples of P ² include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

Compound (k1) is available as a commercial product.

[Step 1]
Compound (d1) is produced from compound (k1), for example, by the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). can do.

［式中、Ｒ^１、Ｘ、Ｙ及びＺは項１の記載と同義であり、Ｐ^２はフェノールの保護基を意味する。Ｐ^２としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のフェノールの保護基等が挙げられる。］ Manufacturing method L
The compound of the present disclosure represented by formula (e1) can be produced, for example, by the following method.

[In the formula, R ¹ , X, Y and Z have the same meanings as described in Item 1, and P ² means a phenol protecting group. Examples of P ² include the phenol protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

Compound (l1) is available as a commercial product.

[Step 1]
Compound (e1) can be produced from compound (l1) by the method described in Step 1 of Production Method K or a method analogous thereto.

［式中、Ｒ^１、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基を意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。］ Manufacturing method M
The compound of the present disclosure represented by formula (j1) can be produced, for example, by the following method.

[Wherein, R ¹ , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, and P ¹ means an amino protecting group. Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

Compound (k1) and compound (b3) are available as commercial products.

[Step 1]
Compound (j1) can be produced from compound (k1) and compound (b3) by the method described in Step 2 of Production Method B or a method analogous thereto.

［式中、Ｒ^１、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基を意味し、ＬＧは脱離基を意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。
ＬＧとしては、例えば、ハロゲン、メタンスルホニルオキシ、ｐ－トルエンスルホン酸オキシ、トリフルオロメタンスルホン酸オキシ等が挙げられる。］ Manufacturing method N
The compound of the present disclosure represented by formula (j1) can be produced, for example, by the following method.

[In the formula, R ¹ , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, P ¹ means an amino protecting group, and LG means a leaving group . Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).
Examples of LG include halogen, methanesulfonyloxy, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. ]

Compound (k1) and compound (n1) are available as commercial products.

[Step 1]
Compound (j1) can be produced by reacting compound (k1) and compound (n1) in an appropriate solvent in the presence or absence of an appropriate base.

Examples of the base include triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7 -Ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, organic bases such as N-methylmorpholine (NMM), or sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydroxide Examples include inorganic bases such as potassium. Preferable examples of the base include triethylamine, diisopropylethylamine, potassium carbonate, and sodium hydroxide.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include alcoholic solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), and tert-butanol; diethyl ether, diisopropyl Ether solvents such as ether, tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; acetonitrile, Aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide; or mixtures thereof. . Preferred solvents include 2-propanol, tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, and the like.

The reaction temperature is usually -80°C to heating under reflux, preferably 25°C to 90°C.

The reaction time is usually 30 minutes to 48 hours, preferably 6 to 12 hours.

［式中、Ｒ^１、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基を意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。］ Manufacturing method O
The compound of the present disclosure represented by formula (h1) can be produced, for example, by the following method.

[Wherein, R ¹ , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, and P ¹ means an amino protecting group. Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999). ]

Compound (l1) and compound (b3) are available as commercial products.

[Step 1]
Compound (h1) can be produced from compound (l1) and compound (b3) by the method described in Step 2 of production method B or a method analogous thereto.

［式中、Ｒ^１、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基を意味し、ＬＧは脱離基を意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。
ＬＧとしては、例えば、ハロゲン、メタンスルホニルオキシ、ｐ－トルエンスルホン酸オキシ、トリフルオロメタンスルホン酸オキシ等が挙げられる。］ Manufacturing method P
The compound of the present disclosure represented by formula (h1) can be produced, for example, by the following method.

[In the formula, R ¹ , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, P ¹ means an amino protecting group, and LG means a leaving group . Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).
Examples of LG include halogen, methanesulfonyloxy, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. ]

Compound (l1) and compound (n1) are available as commercial products.

[Step 1]
Compound (h1) can be produced from compound (l1) and compound (n1) by the method described in Step 2 of production method B or a method analogous thereto.

［式中、Ｒ^１、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基を意味し、ＬＧは脱離基を意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。
ＬＧとしては、例えば、ハロゲン、メタンスルホニルオキシ、ｐ－トルエンスルホン酸オキシ、トリフルオロメタンスルホン酸オキシ等が挙げられる。］ Manufacturing method Q
The compound of the present disclosure represented by formula (h1) can be produced, for example, by the following method.

[In the formula, R ¹ , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, P ¹ means an amino protecting group, and LG means a leaving group . Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).
Examples of LG include halogen, methanesulfonyloxy, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. ]

Compound (q1), compound (q2) and compound (b3) are available as commercial products.

[Step 1]
Compound (q3) can be produced from compound (q1) and compound (q2) by the method described in Step 1 of Production Method N or a method analogous thereto.

[Step 2]
Compound (q4) can be produced by reacting compound (q3) and acetaldehyde in an appropriate solvent in the presence of an appropriate base.

Examples of the base include n-butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium tetramethylpiperidide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide. Examples include silazide, isopropylmagnesium chloride-lithium chloride complex, and the like.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, and 1,4-dioxane; benzene, Aromatic hydrocarbon solvents such as toluene, chlorobenzene, anisole, xylene; halogen solvents such as methylene chloride, chloroform, 1,2-dichloroethane; acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N- Examples include aprotic solvents such as methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethyl sulfoxide; or mixtures thereof. Preferred solvents include tetrahydrofuran.

The reaction temperature is usually -80°C to heating under reflux, preferably -80°C to 25°C.

The reaction time is usually 30 minutes to 48 hours, preferably 6 to 12 hours.

[Step 3]
Compound (q5) can be produced by reacting compound (q4) with an appropriate oxidizing agent in an appropriate solvent in the presence or absence of an appropriate base.

Examples of the oxidizing agent include manganese dioxide, Dess-Martin reagent, dimethyl sulfoxide-oxalyl chloride, dimethyl sulfoxide-trifluoroacetic anhydride, sulfur trioxide-pyridine complex, 2,2,6,6-tetramethylpiperidine-1 -Oxyradical-sodium hypochlorite and the like.
Examples of the base include triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7 -Ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, organic bases such as N-methylmorpholine (NMM), or sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydroxide Examples include inorganic bases such as potassium.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include halogenated solvents such as methylene chloride, chloroform, and 1,2-dichloroethane; diethyl ether, diisopropyl ether, tetrahydrofuran, and methyl. Ether solvents such as cyclopentyl ether and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; acetonitrile, N,N-dimethyl Examples include aprotic solvents such as formamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethylsulfoxide; or mixtures thereof. Preferred solvents include methylene chloride, tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide and the like.

The reaction temperature is usually -80°C to heating under reflux, preferably -80°C to 25°C.
The reaction time is usually 30 minutes to 48 hours, preferably 6 to 12 hours.

[Step 4]
Compound (h1) can be produced from compound (q5) and compound (b3) by the method described in Step 2 of Production Method B or a method analogous thereto.

［式中、Ｒ^１、Ｒ^１４、Ｘ、Ｙ、Ｚ、Ｌ、Ｖ及びＷは項１の記載と同義であり、Ｐ^１はアミノの保護基を意味し、ＬＧは脱離基を意味する。Ｐ^１としては、例えば、Protective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載のアミノの保護基等が挙げられる。
ＬＧとしては、例えば、ハロゲン、メタンスルホニルオキシ、ｐ－トルエンスルホン酸オキシ、トリフルオロメタンスルホン酸オキシ等が挙げられる。］ Manufacturing method R
The compound of the present disclosure represented by formula (i2) can be produced, for example, by the following method.

[In the formula, R ¹ , R ¹⁴ , X, Y, Z, L, V and W have the same meanings as described in Item 1, P ¹ means an amino protecting group, and LG means a leaving group . Examples of P ¹ include the amino protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).
Examples of LG include halogen, methanesulfonyloxy, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. ]

Compound (l1) and compound (b3) are available as commercial products.

[Step 1]
Compound (r1) can be produced from compound (l1) by the method described in Step 1 of Production Method F or a method analogous thereto.

[Step 2]
Compound (r2) can be produced from compound (r1) by the method described in Step 2 of Production Method F or a method analogous thereto.

[Step 3]
Compound (r3) can be produced by reacting compound (r2) with a suitable halogenating agent or sulfonylating agent in the presence or absence of a suitable base, in a suitable solvent or without a solvent. .

Examples of the halogenating agent or sulfonylating agent include thionyl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus tribromide, methanesulfonyl chloride, N-phenylbis(trifluoromethanesulfonimide), trifluoromethanesulfonic anhydride, etc. Can be mentioned.

Examples of the base include triethylamine, diisopropylethylamine, tributylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7 -Ene (DBU), pyridine, 4-dimethylaminopyridine, picoline, organic bases such as N-methylmorpholine (NMM), or sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydroxide Examples include inorganic bases such as potassium.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include halogenated solvents such as methylene chloride, chloroform, and 1,2-dichloroethane; diethyl ether, diisopropyl ether, tetrahydrofuran, and methyl. Ether solvents such as cyclopentyl ether and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; acetonitrile, N,N-dimethyl Examples include aprotic solvents such as formamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethylsulfoxide; or mixtures thereof. Preferred solvents include methylene chloride, tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide and the like.

The reaction temperature is usually -80°C to reflux, preferably 0°C to reflux.

The reaction time is usually 30 minutes to 48 hours, preferably 30 minutes to 12 hours.

[Step 4]
Compound (i2) can be produced by a reaction of compound (r3) and compound (b3) in an appropriate solvent in the presence of an appropriate base, catalyzed by an appropriate palladium source and a ligand.

Examples of the base include organic bases such as triethylamine, diisopropylethylamine, tributylamine, pyridine, 4-dimethylaminopyridine, picoline, and N-methylmorpholine (NMM), or sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydroxide. and inorganic bases such as potassium hydroxide. Preferred bases include diisopropylethylamine, cesium carbonate, and the like.

Examples of the palladium source include salts such as palladium chloride and palladium acetate, and zero-valent palladium complexes such as tris(dibenzylideneacetone) dipalladium (0) chloroform adduct.
As a ligand, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantophos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 2- Examples include phosphine ligands such as dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos). As a ligand, preferably 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantophos)
can be mentioned.

The solvent is not particularly limited as long as it does not react under the reaction conditions of this step, but examples include halogenated solvents such as methylene chloride, chloroform, and 1,2-dichloroethane; diethyl ether, diisopropyl ether, tetrahydrofuran, and methyl. Ether solvents such as cyclopentyl ether and 1,4-dioxane; aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene, anisole, and xylene; ester solvents such as ethyl acetate and methyl acetate; acetonitrile, N,N-dimethyl Examples include aprotic solvents such as formamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, and dimethylsulfoxide; or mixtures thereof. Preferred solvents include tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, N,N-dimethylformamide and the like.

The reaction temperature is usually 0°C to reflux, preferably 50°C to reflux. The reaction time is usually 5 minutes to 72 hours, preferably 2 to 12 hours.

In the production methods explained above, those that do not describe the production method of starting materials or intermediates are available as commercial products, or can be obtained from commercially available compounds by methods known to those skilled in the art or methods similar thereto. Can be synthesized.

In each reaction of the production method described above, a protecting group can be used as necessary, even when the use of a protecting group is not specifically specified. For example, if any functional group other than the reactive site changes under the described reaction conditions or is inappropriate in the absence of a protecting group to carry out the described method, other functional groups other than the reactive site may be protected as necessary. Then, the target compound can be obtained by deprotecting the compound after the completion of the reaction or after performing a series of reactions.

As the protecting group, for example, the protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999) can be used. Specific examples of amino protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like. Specific examples of the hydroxyl protecting group include trialkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, and benzyl.

The introduction and removal of a protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see the above-mentioned Protective Groups in Organic Synthesis) or a method analogous thereto.

In this specification, protecting groups, condensing agents, etc. are sometimes represented by abbreviations according to IUPAC-IUB (Biochemical Nomenclature Committee) commonly used in this technical field. Note that the compound names used herein do not necessarily follow IUPAC nomenclature.

The intermediates or target compounds in the production method explained above should be modified as appropriate by converting their functional groups (e.g., protecting and deprotecting the functional groups as necessary, and using amino, hydroxyl, carbonyl, halogen, etc. as a foothold). Various transformations can also lead to other compounds included in this disclosure. Transformation of the functional group can be performed by a commonly used method (see, for example, Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999), etc.).

The intermediates and target compounds in the production method explained above are isolated by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc.). Can be purified. Furthermore, the intermediate can be used in the next reaction without being particularly purified.

"Pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, or citrate, oxalate, phthalate, etc. Fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonic acid Examples include organic acid salts such as salts and camphorsulfonates. In addition, base addition salts include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, and aluminum salts, or trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, and diethanolamine. , triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylamine, and other organic base salts. Furthermore, examples of "pharmaceutically acceptable salts" include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

Suitable salts and pharmaceutically acceptable salts of the starting materials and intermediates are the customary non-toxic salts. These include, for example, organic acid salts (e.g. acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate). salts, etc.) and acid addition salts such as inorganic acid salts (e.g. hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, etc.), amino acids (e.g. arginine, aspartic acid, glutamic acid, etc.) ), metal salts such as alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g. calcium salts, magnesium salts, etc.), ammonium salts, organic base salts (e.g. trimethylamine salts, triethylamine salts) , pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), and can be appropriately selected by those skilled in the art.

In the present disclosure, deuterium converters obtained by converting any one or more of ¹ H of the compounds represented by formulas (1) to (5) to ² H (D) also include deuterium converted products of formulas (1) to (5). It is included in the compounds represented by 5).

The present disclosure includes compounds represented by formulas (1) to (5) or pharmaceutically acceptable salts thereof. Furthermore, since the compounds of the present disclosure may exist in the form of hydrates and/or solvates with various solvents (ethanolates, etc.), these hydrates and/or solvates are also included in the present disclosure. Included in the disclosed compounds.

Furthermore, the compounds of the present disclosure include optical isomers based on optically active centers, atropisomers based on axial or planar chirality caused by intramolecular rotation constraints, other stereoisomers, tautomers, It includes all possible isomers such as geometric isomers and all forms of crystalline forms, as well as mixtures thereof.

In particular, optical isomers and atropisomers can be obtained as racemates or as optically active forms when optically active starting materials or intermediates are used. In addition, if necessary, at an appropriate stage of the production method, the corresponding raw material, intermediate, or racemic form of the final product may be separated by a known separation method such as a method using an optically active column or a fractional crystallization method. They can be physically or chemically separated into their optical antipodes. These resolution methods include, for example, reacting a racemate with an optically active resolving agent to synthesize two diastereomers, and then taking advantage of their different physical properties to resolve the diastereomers by methods such as fractional crystallization. Examples include the stereomer method.

When it is desired to obtain a pharmaceutically acceptable salt of the compound of the present disclosure, when the compounds represented by formulas (1) to (5) are obtained in the form of a pharmaceutically acceptable salt, It may be purified as it is, or if it is obtained in a free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or base may be added to form a salt by a conventional method.

Liposomes encapsulating the compound of the present disclosure can be produced, for example, by the method described below.

[Step 1]
Membrane components such as phospholipids and cholesterol are dissolved in an organic solvent such as chloroform, and the organic solvent is distilled off within the flask to form a thin film of the lipid mixture on the inner wall of the flask. Instead of the above, the lipid mixture may be obtained as a freeze-dried product by dissolving it in t-butyl alcohol or the like and then freeze-drying it. Alternatively, after dissolving membrane components such as phospholipids and cholesterol in an organic solvent, a lipid mixture can be obtained by using an instant vacuum dryer CRUX (manufactured by Hosokawa Micron Corporation) to obtain a powdered lipid mixture. It can be obtained from Nippon Fine Chemical Co., Ltd.

[Step 2]
A crude liposome dispersion is obtained by adding an internal aqueous phase solution such as an aqueous ammonium sulfate solution to the lipid mixture obtained in Step 1 and dispersing it.

[Step 3]
Using an extruder, the crude liposome dispersion obtained in step 2 is passed through a filter to obtain a desired particle size. Alternatively, the crude liposome dispersion obtained in step 2 is discharged from a nozzle at high pressure using a high-pressure homogenizer to obtain a desired particle size. The particle size of the liposome is not particularly limited, but is, for example, 10 nm to 200 nm, preferably 30 nm to 150 nm, more preferably 40 nm to 140 nm, even more preferably 50 to 120 nm, and most preferably 60 to 100 nm. The particle size of the liposome is an average value measured by a dynamic light scattering method, and can be measured using, for example, Zetasizer Nano ZS (Malvern Instruments).

[Step 4]
The external aqueous phase of the liposome solution obtained in step 3 is replaced by gel filtration, dialysis, tangential flow filtration, ultracentrifugation, or the like.

[Step 5]
The compound is encapsulated in the liposome by incubating the liposome solution obtained in step 4 with the external aqueous phase replaced with the compound to be encapsulated.

[Step 6]
The resulting compound-encapsulated liposome is subjected to gel filtration, dialysis, tangential flow filtration, ultracentrifugation, or the like to remove unencapsulated compounds. Note that if the desired encapsulation rate is obtained in step 5, step 6 can be omitted.

The compounds of the present disclosure can be used in combination with other drugs to enhance their effects. Specifically, the compounds of the present disclosure can be used in combination with drugs such as hormonal therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, or agents that inhibit the action of cell growth factors and their receptors. Hereinafter, a drug that can be used in combination with the compound of the present disclosure will be abbreviated as a concomitant drug.

The compound of the present disclosure exhibits excellent anticancer activity even when used as a single agent, but when used in combination with one or more of the above-mentioned concomitant drugs (multidrug combination), the compound can further enhance its effect or improve the patient's health. QOL can be improved.

Examples of "hormone therapy agents" include fosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol, Rinone, Nomegestol, Tadenane, Mepartricin, Raloxifene, Ormeloxifene, Levormeloxifene, Antiestrogens (e.g. Tamoxifen citrate, Toremifene citrate, etc.), Pill preparations, Mepithiostane, Testrolactone, Aminoglutethimide, LH- RH derivatives (LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin, etc.), LH-RH antagonists), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anadrozole, etc.), Strozole, letrozole, exemestane, vorozole, formestane, etc.), antiandrogens (e.g., flutamide, enzalutamide, apalutamide, bicalutamide, nilutamide, etc.), corticosteroids (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), Examples include androgen synthesis inhibitors (eg, abiraterone, etc.), retinoids, and drugs that slow the metabolism of retinoids (eg, liarozole, etc.).

Examples of "chemotherapeutic agents" include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, molecular target therapeutic agents, immunomodulators, and other chemotherapeutic agents. Typical examples are listed below.

Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, mer Faran, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptozodin, pipobroman, etogluside, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine , prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trophosfamide, dinostatin stimaramer, adozelesin, systemstin, vizeresin, trabectedin and their DDS formulations.

Examples of "antimetabolites" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, eocitabine, cytarabine, cytarabine oxphosphate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emitefur, capecitabine, etc.), aminopterin, nerzarabine, leucoporin calcium, tabloid, butocin, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarpamide, pentostatin , pyritrexime, idoxyuridine, mitoguazone, tiazofurin, ambamustine, bendamustine, and DDS formulations thereof.

Examples of "anticancer antibiotics" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, and epirubicin hydrochloride. , neocarzinostatin, mithramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, eribulin, and DDS preparations thereof.

Examples of "plant-derived anticancer drugs" include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, DJ-927, vinorelbine, irinotecan, topotecan, and DDS preparations thereof. .

Examples of "molecular target therapeutic agents" include imatinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, nilotinib, lapatinib, pazopanib, ruxolitinib, crizotinib, vemurafenib, vandetanib, ponatinib, cabozantinib, tofacitinib, regorafenib, bosutinib, Axitinib, dabrafenib , trametinib, nintedanib, idelalisib, ceritinib, lenvatinib, palbociclib, alectinib, afatinib, osimertinib, ribociclib, abemaciclib, brigatinib, neratinib, copanlisib, cobimetinib, ibrutinib, acalabrutinib, encorafenib, binimetinib, vari Citinib, fostamatinib, lorlatinib, erdafitinib, entrectinib, dacomitinib , sirolimus, everolimus, temsirolimus, olaparib, rucaparib, niraparib, venetoclax, azacitidine, decitabine, vorinostat, panobinostat, romidepsin, bortezomib, carfilzomib, larotrectinib, and ixazomib.

Examples of "immunomodulators" include lenalidomide and pomalidomide.

Examples of "other chemotherapeutic agents" include sobuzoxane.

Examples of "immunotherapeutic agents (BRM)" include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium Umparvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, Toll-like Receptors agonist (e.g., TLR7 agonist, TLR8 agonist, TLR9 agonist, etc.) can be mentioned.

The cell growth factor in a drug that inhibits the action of cell growth factors and their receptors may be any substance as long as it promotes cell growth, and is usually a peptide with a molecular weight of 20,000 or less. There are factors that exert their effects at low concentrations due to their binding with the body. Specifically, EGF (epidermal growth factor) or a substance having substantially the same activity as EGF (e.g., TGFalpha, etc.), insulin or a substance having substantially the same activity as EGF (e.g., insulin, IGF (insulin- like growth factor)-1, IGF-2, etc.), FGF (fibroblast growth factor), or a substance having an assay substantially the same as it (e.g., acidic FGF, basic FGF, KGK (keratinocyte growth factor), FGF- 10 ), and other cell growth factors (e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet -derived growth factor), TGF-beta (transforming growth factor beta), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), heregulin, angiopolymer ethine, etc.).

The administration period of the compound of the present disclosure and the concomitant drug is not limited, and they may be administered to the subject at the same time or at staggered intervals. It may also be a combination of the compound of the present disclosure and a concomitant drug. The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. Further, the compounding ratio of the compound of the present disclosure and the concomitant drug can be appropriately selected depending on the subject of administration, administration route, target disease, symptoms, combination, etc. For example, when the subject to be administered is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present disclosure. In addition, for the purpose of suppressing side effects, it can be used in combination with drugs (concomitant drugs) such as antiemetics, sleep-inducing drugs, and anticonvulsants.

In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same goes for "or." In this specification, when a term is specified as "within two values," the range includes the two values themselves.

All references, including scientific literature, patents, patent applications, etc., cited herein are herein incorporated by reference in their entirety to the same extent as if each were specifically indicated.

The present disclosure has been described above with reference to preferred embodiments for ease of understanding. The present disclosure will now be described based on examples, but the above description and the following examples are provided for illustrative purposes only and are not provided for the purpose of limiting the present disclosure. Therefore, the scope of the invention is not limited to the embodiments or examples specifically described herein, but is limited only by the scope of the claims.

The present disclosure will be explained in more detail below using reference examples, examples, and test examples, but the present invention is not limited thereto.

In this specification, the following abbreviations may be used.
Ts: p-Toluenesulfonyl THF: Tetrahydrofuran TFA: Trifluoroacetic acid DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide MeCN: Acetonitrile Me: Methyl Boc: tert-butoxycarbonyl Dess-Martin reagent: Dess-Martin periodinane ( 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one)

NMR (Nuclear Magnetic Resonance) data used for compound identification was obtained using a JNM-ECS400 nuclear magnetic resonance apparatus (400 MHz) manufactured by JEOL Ltd.
Symbols used in NMR include s for singlet, d for doublet, dd for doublet, t for triplet, td for triplet doublet, q for quartet, m stands for multiplet, br for broad, brs for broad singlet, brm for broad multiplet and J for coupling constant.

The LC/MS (Liquid Chromatography-Mass Spectrometry) analysis conditions used for compound identification are as follows. Among the observed mass spectrometry values [MS (m/z)], the value corresponding to the monoisotopic mass (accurate mass consisting only of the main isotope) is expressed as [M+H] ⁺ , [MH] ^- or [M+2H] ²⁺ etc., and the retention time is indicated as Rt (minutes).

Measurement conditions A
Detection device: ACQUITY (registered trademark) SQ detector (Waters)
HPLC: ACQUITY UPLC (registered trademark) system
Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm x 30 mm)
Solvent: A solution: 0.06% formic acid/H ₂ O, B solution: 0.06% formic acid/MeCN
Gradient condition: 0.0-1.3min Linear gradient from B 2% to 96%
Flow rate: 0.8mL/min
UV: 220nm and 254nm
Column temperature: 40℃

Measurement condition B
Detection equipment: APCI 6120 Quadrupole LC/MS (Agilent Technologies)
HPLC: Agilent Technologies 1260 Infinity® system
Column: Agilent Technologies (registered trademark) ZORBAX SB-C18 (1.8 μm, 2.1 mm x 50 mm)
Solvent: A solution: 0.1% formic acid/H ₂ O, B solution: MeCN
Gradient condition: 0.0-5.0min Linear gradient from B 5% to 90%
Flow rate: 0.6mL/min
UV: 210nm, 254nm, and 280nm
Column temperature: 40℃

Measurement conditions C
Detection equipment: Shimadzu LCMS-2020
Column: L-column-2 ODS (4.6mm x 35mm)
Gradient condition: MeCN/H ₂ O/HCO ₂ H=10/90/0.1 → 100/0/0.1 (0-2 min), 100/0/0.1 (2-4 min)
Flow rate: 2mL/min
Column temperature: 40℃

Reference example 1:
tert-butyl 3-{[(4-acetyl-5-methoxypyridin-3-yl)oxy]methyl}-3-fluoroazetidine-1-carboxylate

Production of tert-butyl 3-{[(4-acetyl-5-methoxypyridin-3-yl)oxy]methyl}-3-fluoroazetidine-1-carboxylate (Reference Example 1) 1-(3-hydroxy- To a solution of 5-methoxy-4-pyridinyl)ethanone (1.00 g) in THF (50.0 mL) was added tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (1.85 g) and triphenyl. Phosphine (3.15g) was added at room temperature and cooled to 0°C. Diisopropyl azodicarboxylate (2.5 mL) was added and stirred at 0°C for 12 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, it was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain Reference Example 1 (720 mg).
LC-MS; [M+H] ⁺ 355.2/Rt (min) 0.886 (measurement conditions A)

Reference example 2:
tert-Butyl 3-{[(3-acetyl-2-methoxypyridin-4-yl)oxy]methyl}-3-(hydroxymethyl)azetidine-1-carboxylate

a) Production of tert-butyl 3-(hydroxymethyl)-3-{[(4-methylbenzene-1-sulfonyl)oxy]methyl}azetidine-1-carboxylate tert-butyl 3,3-bis(hydroxymethyl) To a solution of azetidine-1-carboxylate (1.50 g) in methylene chloride (20.0 mL) were added pyridine (5.60 mL), trimethylamine hydrochloride (0.13 g), and para-toluenesulfonyl chloride (1.45 g). C. and stirred at room temperature for 12 hours. Saturated brine was added to the reaction mixture to quench it, followed by extraction with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, it was filtered off and the solvent was distilled off under reduced pressure to obtain the title compound (2.30 g). The obtained residue was used in the next reaction without being purified.
LC-MS; [M+H] ⁺ 372.1/Rt (min) 0.928 (measurement conditions A)

b) Production of tert-butyl 3-{[(3-acetyl-2-methoxypyridin-4-yl)oxy]methyl}-3-(hydroxymethyl)azetidine-1-carboxylate (Reference Example 2) tert-butyl 1-(4- Hydroxy-2-methoxy-3-pyridinyl)ethanone (1.00 g) and cesium carbonate (7.80 g) were added, and the mixture was stirred at room temperature for 12 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, it was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain Reference Example 2 (1.01 g).
LC-MS; [M+H] ⁺ 367.3/Rt (min) 0.796 (measurement conditions A)

Reference example 3:
tert-butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate

a) Preparation of tert-butyl {3-[(3-acetyl-4-methoxypyridin-2-yl)oxy]propyl}carbamate 1-(2-hydroxy-4-methoxypyridin-3-yl)ethanone (2. Cesium carbonate (7.80 g) and 3-(Boc-amino)propyl bromide (4.27 g) were added to a solution of 00 g) in DMF (40.0 mL) at 0° C., and the mixture was stirred at room temperature for 12 hours. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, it was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.25 g).
LC-MS; [M+H] ⁺ 325.2/Rt (min) 0.959 (measurement conditions A)
1H-NMR (CDCl ₃ ) δ: 8.06 (1H, d, J = 6.0 Hz), 6.55 (1H, d, J = 6.0 Hz), 4.97 (1H, brs), 4.40 (2H, t, J = 6.4 Hz ), 3.86 (3H, s), 3.27-3.24 (2H, m), 2.49 (3H, s), 1.96-1.90 (2H, m), 1.44 (9H, s).

b) Production of tert-butyl [3-({3-[(2E)-3-(dimethylamino)prop-2-enyl]-4-methoxypyridin-2-yl}oxy)propyl]carbamate tert-butyl { To a solution of 3-[(3-acetyl-4-methoxypyridin-2-yl)oxy]propyl}carbamate (2.25 g) in DMF (10.0 mL) was added N,N-dimethylformamide dimethyl acetal (10.0 mL). The mixture was added and stirred at 115°C for 24 hours. After cooling, the solvent of the reaction solution was distilled off under reduced pressure to obtain the title compound (4.30 g) as a crude product.
LC-MS; [M+H] ⁺ 380.3/Rt (min) 0.722 (measurement conditions A)

c) Production of tert-butyl (3-{[4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate tert-butyl [3-({3- Hydroxyamine hydrochloride was added to a solution of [(2E)-3-(dimethylamino)prop-2-enyl]-4-methoxypyridin-2-yl}oxy)propyl]carbamate (4.30 g) in ethanol (30.0 mL). (5.49g) was added and stirred at 65°C for 2 hours. After cooling, the reaction solution was added to a saturated aqueous sodium bicarbonate solution to quench. The resulting aqueous solution was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.63 g).
LC-MS; [M+H] ⁺ 350.2/Rt (min) 0.722 (measurement conditions A)
1H-NMR (CDCl ₃ ) δ: 8.32 (1H, d, J = 1.6 Hz), 8.12 (1H, d, J = 6.0 Hz), 6.64 (1H, d, J = 6.0 Hz), 6.59 (1H, d , J = 1.6 Hz), 4.87 (1H, brs), 4.45 (2H, t, J = 6.4 Hz), 3.92 (3H, s), 3.28-3.24 (2H, m), 1.99-1.93 (2H, m) , 1.44 (9H, s).

d) Production of tert-butyl (3-{[3-(cyanoacetyl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate tert-butyl (3-{[4-methoxy-3-(1, Potassium hydroxide (0.29 g) was added to a mixed solution of 2-oxazol-5-yl)pyridin-2-yl]oxy}propyl) carbamate (1.63 g) in ethanol (20.0 mL) and water (5.00 mL). ) and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to saturated brine for quenching. The resulting aqueous solution was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.50 g).
LC-MS; [M+H] ⁺ 350.2/Rt (min) 0.872 (measurement conditions A)
1H-NMR (CDCl ₃ ) δ: 8.14 (1H, d, J = 6.0 Hz), 6.59 (1H, d, J = 6.0 Hz), 4.94 (1H, brs), 4.44 (2H, t, J = 6.0 Hz ), 3.92 (3H, s), 3.29-3.23 (2H, m), 1.99-1.93 (2H, m), 1.43 (9H, s).

e) Production of tert-butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate (Reference Example 3) tert-butyl (3-{[3-(cyanoacetyl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate (1.99 g) in ethanol (20.0 mL), acetic acid (3.28 mL), hydrazine monohydrate 2.78 mL) was added at 0°C, and the mixture was stirred at 90°C for 24 hours. After cooling, the reaction solution was added to a saturated aqueous sodium bicarbonate solution to quench. The resulting aqueous solution was extracted twice with chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain Reference Example 3 (1.60 g).
LC-MS; [M+H] ⁺ 364.0/Rt (min) 0.684 (measurement conditions A)
1H-NMR (DMSO-D6) δ: 11.61-10.91 (1H, brs), 8.01 (1H, d, J = 12.0 Hz), 6.93-6.89 (1H, m), 6.84 (1H, d, J = 6.0 Hz ), 5.93 (1H, brs), 4.50 (1H, brs), 4.32 (2H, t, J = 6.4 Hz), 3.89 (3H, s), 3.09-3.04 (2H, m), 1.86-1.79 (2H, m), 1.37 (9H, s).

Reference example 4:
tert-Butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-6-chloro-4-methoxypyridin-2-yl]oxy}propyl)carbamate

a) Production of 1-{6-chloro-4-methoxy-2-[(4-methoxyphenyl)methoxy]pyridin-3-yl}ethane-1-ol 2-chloro-4-methoxy-6-[(4 -Methoxybenzyl)oxy]pyridine (10.0 g) in THF (100 mL) was cooled to -78°C. 2.8 mol/L n-butyllithium (15.3 mL) was added, and the mixture was stirred at -78°C for 3 hours. Acetamide (6.30 mL) was added and stirred at -78°C for 6 hours. The reaction mixture was quenched by adding saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, it was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (4.25 g).
LC-MS; [M+H] ⁺ 324.2/Rt (min) 1.118 (measurement conditions A)
1H-NMR (CDCl ₃ ) δ: 7.36 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.8 Hz), 6.55 (1H, s), 5.32 (2H, s), 5.16-5.11 (1H, m), 3.85 (3H, s), 3.80 (3H, s), 3.30 (1H, s), 1.41 (3H, d, J = 6.8 Hz).
13C-NMR (CDCl ₃ ) δ: 165.2, 159.6, 147.6, 130.1, 128.6, 114.1, 112.6, 101.8, 68.7, 62.9, 56.3, 55.4, 23.1.

b) Production of 1-{6-chloro-4-methoxy-2-[(4-methoxyphenyl)methoxy]pyridin-3-yl}ethane-1-one 1-{6-chloro-4-methoxy-2- Dess-Martin reagent (6.19 g) was added to a solution of [(4-methoxyphenyl)methoxy]pyridin-3-yl}ethane-1-ol (3.15 g) in methylene chloride (100 mL), and the mixture was stirred at room temperature for 12 hours. did. The reaction solution was quenched by adding to a saturated aqueous sodium hydrogen carbonate solution. The resulting aqueous solution was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.50 g).
LC-MS; [M+H] ⁺ 322.2/Rt (min) 1.081 (measurement conditions A)

c) Production of 1-(6-chloro-2-hydroxy-4-methoxypyridin-3-yl)ethane-1-one 1-{6-chloro-4-methoxy-2-[(4-methoxyphenyl)methoxy ] TFA (6.00 mL) was added to a solution of pyridin-3-yl}ethan-1-one (2.50 g) in methylene chloride (30.0 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by amine silica gel column chromatography (chloroform/methanol) to obtain the title compound (2.00 g).
LC-MS; [M+H] ⁺ 202.1/Rt (min) 0.773 (measurement conditions A)

d) Production of tert-butyl {3-[(3-acetyl-6-chloro-4-methoxypyridin-2-yl)oxy]propyl}carbamate 1-(6-chloro-2-hydroxy-4-methoxypyridine- To a solution of 3-yl)ethane-1-one (3.00 g) in DMF (50.0 mL) were added cesium carbonate (9.70 g) and 3-(Boc-amino)propyl bromide (5.63 g) at 0°C. and stirred at room temperature for 12 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, it was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.01 g).
LC-MS; [M+H] ⁺ 359.3/Rt (min) 1.123 (measurement conditions A)

e) Production of tert-butyl [3-({6-chloro-3-[(2E)-3-(dimethylamino)prop-2-enyl]-4-methoxypyridin-2-yl}oxy)propyl]carbamate N,N-dimethylformamide dimethylacetal was added to a solution of tert-butyl {3-[(3-acetyl-6-chloro-4-methoxypyridin-2-yl)oxy]propyl}carbamate (840 mg) in DMF (10.0 mL). (3.00 mL) was added and stirred at 115°C for 24 hours. After cooling, the solvent of the reaction solution was distilled off under reduced pressure to obtain the title compound (0.97 g) as a crude product.
LC-MS; [M+H] ⁺ 414.4/Rt (min) 0.944 (measurement conditions A)

f) Production of tert-butyl (3-{[6-chloro-4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate tert-butyl [3- ({6-chloro-3-[(2E)-3-(dimethylamino)prop-2-enyl]-4-methoxypyridin-2-yl}oxy)propyl]carbamate (0.97 g) in ethanol (30. Hydroxyamine hydrochloride (1.70 g) was added to the solution (0 mL) and stirred at 65° C. for 2 hours. After cooling, the reaction solution was added to a saturated aqueous sodium bicarbonate solution to quench. The resulting aqueous solution was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (677 mg).
LC-MS; [M+H] ⁺ 384.3/Rt (min) 1.132 (measurement conditions A)

g) Production of tert-butyl (3-{[6-chloro-3-(cyanoacetyl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate tert-butyl (3-{[6-chloro-4 -Methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate (677 mg) in a mixed solution of ethanol (20.0 mL) and water (5.00 mL). Potassium oxide (100 mg) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to saturated brine for quenching. The resulting aqueous solution was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (470 mg).
LC-MS; [M+H] ⁺ 384.3/Rt (min) 1.064 (measurement conditions A)

h) tert-butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-6-chloro-4-methoxypyridin-2-yl]oxy}propyl)carbamate (Reference Example 4) Production: To a solution of tert-butyl (3-{[6-chloro-3-(cyanoacetyl)-4-methoxypyridin-2-yl]oxy}propyl) carbamate (470 mg) in ethanol (20.0 mL) was added acetic acid (0. 71 mL) and hydrazine monohydrate (0.77 mL) were added at 0°C, and the mixture was stirred at 90°C for 24 hours. After cooling, the reaction solution was added to a saturated aqueous sodium bicarbonate solution to quench. The resulting aqueous solution was extracted twice with chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain Reference Example 4 (350 mg).
LC-MS; [M+H] ⁺ 398.3/Rt (min) 0.911 (measurement conditions A)

Reference example 5:
1-(4-hydroxy-6-methoxypyrimidin-5-yl)ethane-1-one

a) Production of 1-(4-hydroxy-6-methoxypyrimidin-5-yl)ethane-1-one 1-(4,6-dimethoxypyrimidin-5-yl)ethane-1-one (2.00 g) A dichloromethane solution (1.0 mol/L, 54.9 mL) of boron tribromide (1.0 mol/L, 54.9 mL) was added to a dichloromethane (30.0 mL) solution at -60°C, and the mixture was stirred at -50°C or lower for 3 hours. The reaction solution was quenched by adding saturated saline, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol/chloroform) to obtain the title compound (220 mg).
LC-MS; [M+H] ⁺ 169.1/Rt (min) 0.367 (measurement conditions A)
1H-NMR (CDCl ₃ ) δ: 14.31 (1H, brs), 8.36 (1H, s), 4.10 (3H, s), 2.65
(3H, s).

Reference example 6:
tert-butyl (3-{[4-acetyl-5-(fluoromethoxy)pyridin-3-yl]oxy}propyl)carbamate

a) Production of 3-fluoro-5-(fluoromethoxy)pyridine To a solution of 5-fluoropyridin-3-ol (1.00 g) in DMF (30.0 mL), add cesium carbonate (4.32 g), fluoromethyl 4-methyl Benzene sulfonate (2.17 g) was added at room temperature, and the mixture was heated and stirred at 80° C. for 8 hours. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. After drying the organic layer over anhydrous sodium sulfate, it was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (538 mg).
LC-MS; [M+H] ⁺ 146.0/Rt (min) 0.574 (measurement conditions A)

b) Production of 1-[3-fluoro-5-(fluoromethoxy)pyridin-4-yl]ethan-1-ol A solution of N,N-diisopropylethylamine (0.687 mL) in THF (15 mL) was heated at -78°C. After cooling, n-butyllithium (1.58 mol/L, 3.05 mL) was added and stirred at 0° C. for 15 minutes. The reaction solution was cooled again to -78°C, 3-fluoro-5-(fluoromethoxy)pyridine (538 mg) was added, and after stirring for 1 hour, acetaldehyde (0.419 mL) was added. After the reaction solution was gradually heated to room temperature and stirred overnight, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, it was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (475 mg).
LC-MS; [M+H] ⁺ 190.1/Rt (min) 0.494 (measurement conditions A)
1H-NMR (CDCl3) δ:8.30 (1H, d, J = 1.8 Hz),8.26 (1H, s), 5.85 (1H, dd, J = 6.7,3.1 Hz), 5.71 (1H,dd, J = 7.2 , 3.2 Hz),5.31-5.22 (1H, m), 2.60 (1H, dd, J = 9.8, 1.8 Hz), 1.59(3H, d, J = 6.7 Hz).

c) Production of 1-[3-fluoro-5-(fluoromethoxy)pyridin-4-yl]ethane-1-one 1-[3-fluoro-5-(fluoromethoxy)pyridin-4-yl]ethane A solution of -1-ol (475 mg) in dichloromethane (10.0 mL) was ice-cooled, Dess-Martin reagent (1.60 g) was added, and the mixture was stirred at room temperature overnight. A sodium thiosulfate aqueous solution and a saturated sodium bicarbonate aqueous solution were added to the reaction mixture, and the mixture was extracted with chloroform. After drying the obtained organic layer over anhydrous sodium sulfate, it was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (407 mg).
LC-MS; [M+H] ⁺ 188.0/Rt (min) 0.618 (measurement conditions A)

d) Production of tert-butyl (3-{[4-acetyl-5-(fluoromethoxy)pyridin-3-yl]oxy}propyl)carbamate 1-[3-fluoro-5-(fluoromethoxy)pyridine-4 Tert-butyl (3-hydroxypropyl) carbamate (762 mg) was added to a solution of DMF (10.0 mL) containing cesium carbonate (1.42 g) and 407 mg of ethane-1-one (407 mg), and the mixture was heated at 80°C for 8 hours. Stirred. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. After drying the organic layer over anhydrous sodium sulfate, it was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (67 mg).
LC-MS; [M+H] ⁺ 343.2/Rt (min) 0.832 (measurement conditions A)
1H-NMR (CDCl3) δ:8.22 (1H, d, J = 1.8 Hz),8.16 (1H, s), 5.68 (2H, d, J = 53.6 Hz), 4.70 (1H, brs), 4.15 (2H, t, J = 6.1Hz), 3.32-3.21 (2H, m), 2.50 (3H, s), 2.00-1.93 (2H,m), 1.41 (9H, s).

Reference example 7:
tert-butyl (3-{[4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate

a) Production of (2E)-3-(dimethylamino)-1-(2-hydroxy-4-methoxypyridin-3-yl)prop-2-en-1-one 1-(2-hydroxy-4-methoxy Tert-butoxybis(dimethylamino)methane (5.21 g) was added to a mixture of pyridin-3-yl)ethanone (2.50 g) and toluene (6.23 ml), and the mixture was heated and stirred at 55° C. for 6 hours. After cooling, toluene (18.6 ml) was added dropwise, and the resulting crystals were collected by filtration and washed with toluene. The crystals were dried in vacuo to obtain the title compound (2.87 g). The filtrate was concentrated under reduced pressure, and the crystals precipitated from the ethanol/toluene mixed solvent were washed with the ethanol/toluene mixed solvent and dried in vacuo to obtain the second crystal of the title compound (0.20 g).
LC-MS; [M+H] ⁺ 223.1/Rt (min) 1.564
1H-NMR (DMSO-D6)δ: 11.25 (1H, brs), 7.39 (1H, d, J = 6.7 Hz), 7.11 (1H, br s),6.21 (1H, d, J =7.9 Hz), 5.00 (1H, d, J = 11.0 Hz), 3.73 (3H, s), 3.00 (3H, br s), 2.75 (3H, brs).

b) Production of 4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-ol (2E)-3-(dimethylamino)-1-(2-hydroxy-4-methoxypyridin-3 Hydroxyamine hydrochloride (1.56 g) was added to a mixture of prop-2-en-1-one (2.50 g) and ethanol (37.5 ml), and the mixture was stirred at room temperature for 16 hours. Water (37.5 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to 28.5 g, then further water (9.0 ml) was added, and the mixture was stirred at 0°C. The resulting crystals were collected by filtration, washed with cold water, and dried under vacuum to obtain the title compound (1.53 g).
LC-MS; [M+H] ⁺ 193.1/Rt (min) 0.928
1H-NMR(DMSO-D6) δ: 11.83 (1H, br s), 8.51 (1H, d, J = 1.8 Hz), 7.61 (1H, d, J=7.3Hz), 6.83 (1H, d, J = 1.8 Hz), 6.38 (1H, d, J = 7.3 Hz), 3.93 (3H, s).

c) Production of 4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl trifluoromethanesulfonate 4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2- Trifluoromethanesulfonic anhydride (2.16 g) was added dropwise to a mixture of ol (1.23 g) and pyridine (6.1 ml) at 0°C. The reaction mixture was warmed up and stirred at room temperature for 16 hours. The reaction mixture was cooled to 0°C, water (16ml) was added dropwise, and the mixture was stirred at 0°C for 1.5 hours. The resulting crystals were collected by filtration, washed with a water/pyridine mixed solvent, then with water, and dried under vacuum to obtain the title compound (1.91 g).
LC-MS; [M+H] ⁺ 325.0/Rt (min) 4.781
1H-NMR (CDCl3) δ:8.37 (1H, d, J = 1.8 Hz), 8.32 (1H, d, J = 6.1 Hz), 7.01(1H, d, J = 6.1 Hz),6,67 (1H, d, J = 1.8 Hz), 4.00 (3H, s).

d) Production of tert-butyl (3-{[4-methoxy-3-(1,2-oxazol-5-yl)pyridin-2-yl]oxy}propyl)carbamate 4-methoxy-3-(1,2 -oxazol-5-yl)pyridin-2-yl trifluoromethanesulfonate (50 mg) and tert-butyl (3-hydroxypropyl) carbamate (54 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg), tris(dibenzylideneacetone) dipalladium (0) chloroform adduct (16 mg), and toluene (1.5 ml) was added diisopropylethylamine (72 mg), and the mixture was heated and stirred at 100° C. for 4 hours. After the reaction mixture was allowed to cool, insoluble materials were filtered off through Celite and washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (30 mg).
LC-MS; [M+H] ⁺ 350.2/Rt (min) 4.647

Reference examples 8 to 41:
Compounds of Reference Examples 8 to 41 shown in the table below were obtained by the same method as described in Reference Examples 1 to 7 using the corresponding raw material compounds.

Reference example 42:
tert-Butyl {3-[(3-{3-[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl}-4-methoxypyridin-2-yl)oxy]propyl}carbamate

A solution of tert-butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate (600 mg) in DMSO (10.0 mL) 4-ethylmorpholine (1.00 mL) and 5-chloropyrazine-2-carbonitrile (461 mg) were added at room temperature, and the mixture was stirred at 80°C for 12 hours. Saturated brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, it was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.01 g).
LC-MS; [M+H] ⁺ 467.3/Rt (min) 0.885 (measurement conditions A)
1H-NMR (DMSO-D6) δ: 12.4 (1H, s), 10.7 (1H, s), 8.61 (1H, s), 8.50 (1H, brs), 8.07 (1H, d, J = 5.2 Hz), 7.06 (1H, brs), 6.90 (1H, d, J = 6.0 Hz), 4.34 (2H, t, J = 6.4 Hz), 3.93 (3H, s), 3.14-3.08 (2H, m), 1.87-1.84 (2H, m), 1.35 (9H, s).

Reference examples 43 to 78:
Compounds of Reference Examples 43 to 78 shown in the table below were obtained by a method similar to that described in Reference Example 42 using the corresponding raw material compounds.

Reference example 79:
tert-Butyl {3-[(3-{3-[(5-chloropyrazin-2-yl)amino]-1H-pyrazol-5-yl}-4-methoxypyridin-2-yl)oxy]propyl}carbamate

tert-Butyl (3-{[3-(3-amino-1H-pyrazol-5-yl)-4-methoxypyridin-2-yl]oxy}propyl)carbamate (60 mg) in 1,4-dioxane (825 μL) 2,5-dichloropyrazine (32.9 μL), tris(dibenzylideneacetone) dipalladium (0) (15.1 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 .1 mg) and cesium carbonate (108 mg) were added at room temperature, and the mixture was stirred at 150° C. for 2 hours under microwave irradiation. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound.
LC-MS; [M+H] ⁺ 476.3/Rt (min) 0.969 (measurement conditions A)

Example 1:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile

tert-Butyl {3-[(3-{3-[(5-cyanopyrazin-2-yl)amino]-1H-pyrazol-5-yl}-4-methoxypyridin-2-) obtained in Reference Example 42 yl)oxy]propyl}carbamate (200 mg) in methylene chloride (20.0 mL) was added TFA (2.00 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by amine silica gel column chromatography (ethyl acetate/methanol) to obtain Example 1 (112 mg).
LC-MS; [M+H] ⁺ 367.2/Rt (min) 0.671 (measurement conditions A)
1H-NMR (DMSO-D6) δ: 8.65 (1H, s), 8.50 (1H, brs), 8.06 (1H, d, J = 6.4 Hz), 7.04 (1H, brs), 6.89 (1H, d, J = 6.4 Hz), 4.41 (2H, t, J = 6.0 Hz), 3.92 (3H, s), 2.75 (1H, t, J = 6.8 Hz), 1.85-1.76 (2H, m).

Examples 2-38:
Compounds of Examples 2 to 38 shown in the table below were obtained in the same manner as in Example 1 using the corresponding starting compounds.

Powder X-ray diffraction measurements of Examples 39 to 45 were performed under the conditions shown below. The obtained diffraction patterns (XRD spectra) are shown in FIGS. 1 to 6A. Examples 39 to 41 are crystals of various salts of the compound of Example 1, and Examples 42 to 45 are crystal polymorphs of the compound of Example 1.

The crystal form may be determined based on the characteristic diffraction peaks of each crystal shown in the diffraction diagrams of FIGS. 1 to 6A.

The main diffraction peaks and characteristic diffraction peaks identified from the diffraction patterns of FIGS. 1 to 6A are listed below. It should be noted that the diffraction peak values at the diffraction angle 2θ (°) described in the following examples may have some measurement error depending on the measuring equipment or measurement conditions. Specifically, the measurement error may be within the range of ±0.2, preferably ±0.1.

Powder X-ray diffraction measurement method (Example 39-44):
Detection equipment: Spectris Power X-ray diffraction system Empyrian
X-ray tube: CuKα (wavelength: 1.54 angstroms)
Tube voltage: 45kV
Tube current: 40mA
Measurement range: 4 to 40 degrees (2θ)
Step width: 0.013 degrees Integral time: 100 seconds/step Powder X-ray diffraction measurement method (Example 45):
Detection equipment: Bruker AXS D8 ADVANCE
X-ray tube: CuKα (wavelength: 1.54 angstroms)
Tube voltage: 40kV
Tube current: 40mA
Measurement range: 4 to 40 degrees (2θ)
Step width: 0.015 degrees

Example 39:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride

Methanol (0.6 mL) was added to the compound of Example 1 (30.0 mg), and a 5-10% (W/V) hydrochloric acid-methanol solution (60 μL) was added, followed by stirring at a set temperature of 60° C. for 2 hours. After cooling, the mixture was allowed to stand overnight, and the precipitated solid was collected by filtration and dried to obtain the title compound as crystals (Form I).
[Form I] The powder X-ray diffraction pattern is shown in FIG.
Main diffraction peaks: 2θ (°) = 7.2, 8.8, 9.8, 10.2, 10.7, 16.7, 18.5, 26.2, 27.0
Characteristic diffraction peaks: 2θ (°) = 7.2, 8.8, 9.8, 10.2, 10.7

Example 40:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile phosphate

A 13.4 mg/mL phosphoric acid-methanol solution (1200 μL) was added to the compound of Example 1 (30.0 mg), and the mixture was stirred at a set temperature of 60° C. for 4 hours. After cooling, the mixture was allowed to stand overnight, and the precipitated solid was collected by filtration and dried to obtain the title compound as crystals (Form II).
[Form II] The powder X-ray diffraction pattern is shown in FIG.
Main diffraction peaks: 2θ (°) = 6.8, 7.5, 11.7, 11.9, 13.0, 16.4, 19.3, 20.4, 22.7, 24.3
Characteristic diffraction peaks: 2θ (°) = 6.8, 7.5, 11.7, 11.9, 13.0

Example 41:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile tosylate

Methanol (0.6 mL) was added to the compound of Example 1 (30.0 mg), and further a 26.0 mg/mL tosylic acid-methanol solution (0.6 mL) was added, followed by stirring at a set temperature of 60° C. for 2 hours. After cooling, the mixture was allowed to stand overnight, and the precipitated solid was collected by filtration and dried to obtain the title compound as crystals (Form III).
[Form III] The powder X-ray diffraction pattern is shown in FIG.
Main diffraction peaks: 2θ (°) = 6.0, 9.0, 12.1, 14.4, 16.2, 17.0, 22.8, 26.3
Characteristic diffraction peaks: 2θ (°) = 6.0, 9.0, 12.1, 14.4, 16.2, 17.0

Example 42:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile

[Form IV] The powder X-ray diffraction pattern is shown in FIG.
According to Example 1, the title compound was obtained as crystals (Form IV).
Main diffraction peaks: 2θ (°) = 9.3, 10.2, 10.7, 13.6, 16.7, 17.1, 17.8, 18.6, 26.1, 26.4
Characteristic diffraction peaks: 2θ (°) = 9.3, 10.2, 10.7, 16.7, 26.1, 26.4

Example 43:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile

[Form V] The powder X-ray diffraction pattern is shown in FIG.
A solution of the compound of Example 1 (5 mg) in tetrahydrofuran/water (10/1, 0.5 mL) was added and heated at a set temperature of 105° C. for 1 hour. After cooling, it was sealed and left to stand for 4 days, then opened and left to stand for 3 days, and the solvent was distilled off. The precipitated solid gave the title compound as crystals (Form V).
Main diffraction peaks: 2θ (°) = 7.9, 8.7, 12.2, 13.1, 15.9, 17.6, 19.9, 21.9, 22.8, 26.6
Characteristic diffraction peaks: 2θ (°) = 7.9, 8.7, 12.2, 13.1, 15.9, 26.6

Example 44:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile

[Form VI] The powder X-ray diffraction pattern is shown in FIG.
A solution of the compound of Example 1 (5 mg) in acetone/water (10/1, 0.5 mL) was added and heated at a set temperature of 105° C. for 1 hour. After cooling, it was sealed and left to stand for 4 days, then opened and left to stand for 3 days, and the solvent was distilled off. The precipitated solid gave the title compound as crystals (Form VI). Main diffraction peaks: 2θ (°) = 5.3, 5.7, 7.0, 7.3, 7.8, 8.4, 9.3, 10.5, 11.5, 14.1
Characteristic diffraction peaks: 2θ (°) = 5.3, 5.7, 7.0, 7.3, 8.4, 9.3

Example 45:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile hydrochloride

[Form VII] The powder X-ray diffraction pattern is shown in Figure 6A.
The compound of Example 1 (36 mg) was suspended in a water (6 mL) solution, and 1 mol/L hydrochloric acid was gradually added to adjust the pH to 6.5. After standing at room temperature for 1 hour, the precipitated title compound was obtained as crystals (Form VII). Main diffraction peaks: 2θ (°) = 7.0, 8.2, 9.7, 11.5, 14.0, 14.6, 16.3, 18.0, 19.8, 21.2, 21 .5, 24.1, 27.0
Characteristic diffraction peaks: 2θ (°) = 8.2, 14.6, 21.2, 21.5, 24.1, 27.0

Test example
Test Example 1: CHK1 inhibitory activity test IMAP TR-FRET Screening Express Kit (R8160) was obtained from Molecular Devices. CHK1 kinase (02-117, CarnaBio Inc.), FAM-labeled CHK1tide (R7185, Molecular Devices Inc.), and ATP were diluted with assay buffer to final concentrations of 4 μg/mL, 2 μM, and 20 μM, respectively. FAM-PKAtide (R7255, Molecular Devices) and FAM-Phospho-PKAtide (R7304, Molecular Devices) were diluted and mixed, followed by a standard series of calibrations with phosphorylation levels from 0 to 100%. Created. Add 5 μL of the compound dissolved in 0.4% DMSO solution to a 384-well plate, and create a compound study group in which 5 μL each of CHK1, CHK1tide, and ATP were added, and a standard group in which 20 μL each of standard was added. Kinase reaction was carried out for an hour. Thereafter, 60 μL of Binding Reagent (80% Buffer A, 20% Buffer B, 1:600 Binding Reagent, 1:400 Tb-Donor) was added, and a binding reaction was performed at room temperature for 2 hours. Fluorescence intensities at 520 nm and 490 nm upon excitation at 340 nm were obtained using SpectraMax Paradigm (Molecular Devices). The phosphorylation level of CHK1tide was calculated using standard, the phosphorylation level was set as 100% in the DMSO-treated group, and the kinase activity was determined using the formula shown below, and the concentration corresponds to the concentration of the evaluation compound showing 50% kinase activity. _IC50 values were calculated.

Kinase inhibition (%) = 100-A/B x 100
A: Signal in the presence of evaluation compound B: Signal in negative control (DMSO treatment group)

The test shown in Test Example 1 was conducted on the compounds obtained in the examples and prexasertib purchased from MedChemExpress (the source is the same in the following test examples). The IC ₅₀ values (nM) of test results for each test substance are shown in the table below.

As shown in the table above, Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 15, 17, 18, 19, 20, 21, 22, 24 , 26, 28, 30 and 37 showed a stronger inhibitory effect on CHK1 activity than prexasertib. Among them, the compounds of Examples 1 and 8 have an exceptional effect of particularly strongly suppressing CHK1 activity.

Test Example 2: Cell proliferation inhibition experiment ES-2 cells were obtained from the American Type Culture Collection (ATCC). The cells were cultured in McCoy's 5a medium containing 10% fetal bovine serum and 1% penicillin/streptomycin at 37° C. in the presence of 5% CO ₂ .
500 cells per well were seeded in a 384-well plate, the evaluation compound was added to the plate so that the final concentration of DMSO was 0.1%, and the cells were cultured for 2 days. After completion of the culture, cell viability was calculated using CellTiter-Glo (registered trademark) 3D Reagent (Promega, G968B). From the survival rate curve, an IC ₅₀ value corresponding to the concentration of the evaluation compound at which the inhibition rate of cell proliferation was 50% was calculated. Note that ES-2 cells are known to exhibit resistance to cisplatin.

The test shown in Test Example 2 was conducted on the compounds obtained in Examples and prexasertib. The table below shows the concentration (IC ₅₀ value; nM) of each test substance that inhibits cell proliferation by 50%. The table below lists the results of cell growth inhibition tests for representative compounds of the present disclosure based on the ratings of I, II, III, IV, and V (1000 nM<I, 1000 nM>II> 300nM, 300nM>III>100nM, 100nM>IV>30nM, 30nM>V).

As shown in the table above, Examples 1, 3, 4, 5, 6, 11, 15, 17, 19, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32 , 33, 35, 36, 37, and 38 showed good cell proliferation inhibitory effects comparable to prexasertib.

Test Example 3: hERG current inhibition test A test substance was added to cultured CHO cell line cells stably expressing hERG (human ether-a-go-go related gene) gene at a concentration of 0.27 to 100 μM. The hERG current under voltage stimulation was measured using Qube384 (Sophion Bioscience), and the concentration (IC ₅₀ value; μM) at which each test substance inhibited the hERG current by 50% was calculated.

The test shown in Test Example 3 was conducted on the compounds obtained in Examples and prexasertib. Furthermore, for the compounds of each Example, the value obtained by dividing the hERG IC ₅₀ obtained in Test Example 3 by the CHK1 inhibition IC ₅₀ obtained in Test Example 1 was calculated as hERG/CHK1. The results are shown in the table below.

As shown in the table above, the compounds of Examples 1, 3, 4, 7 to 10, 14, 24, 32, and 34 have a deviation width of 50,000 times or more between the IC ₅₀ of CHK1 inhibition and the IC ₅₀ of hERG. It was shown that Among them, the compounds of Examples 1, 3, 7, 8, 14, and 24 were shown to have a deviation width of 100,000 times or more between the IC ₅₀ of CHK1 inhibition and the IC ₅₀ of hERG.
These six compounds exhibit disparity that is 18 times or more greater than prexasertib and have heterogeneous effects with high safety.

Test Example 4: CYP3A4 MBI and Enzyme Inactivation Clearance Evaluation Cytochrome P450 (hereinafter referred to as CYP) is the most important enzyme group involved in drug metabolism, and many pharmacokinetic interactions are based on inhibition of these CYP activities. There are multiple molecular species of CYP, and in particular, CYP3A4 is most involved in the metabolism of pharmaceuticals in the oxidation reaction by CYP, and also accounts for the majority of the CYPs present in the liver.

There are two main types of CYP inhibition: "reversible inhibition" and "mechanism-based inhibition (MBI)." In particular, MBI-based CYP inhibition can cause not only drug interactions but also serious side effects (hepatic side effects). (Curr Opin Drug Discov Devel. 2010 January, 13(1), 66-77, Therapeutics and Clinical Risk Management, 2005, 1(1), 3-13).

MBI of CYP3A4 and enzyme inactivation clearance were evaluated using the compound of this example and prexasertib.

Using human liver microsomes as the enzyme source and midazolam or testosterone as the substrate, the inhibitory effect and inhibition mode of the test compound on CYP3A4 was evaluated. After metabolic reaction at 37°C for 30 minutes, the substrate-derived metabolic products of the test compound addition group (4 concentrations) and the substrate-derived metabolic products of the non-addition group were measured by LC-MS/MS, and the inhibition rate was calculated from the ratio. was calculated. In addition, IC ₅₀ values were calculated from the concentration plots. It is known that when a test compound has an MBI effect, the IC ₅₀ is lowered by starting the reaction by adding a substrate after preincubation in the presence of NADPH (cofactor) (Xenobiotica, 2009 , 39(2), 99-112), when the change in IC ₅₀ value due to preincubation was 2 times or more, it was determined that there was an MBI effect.

If an MBI effect was observed, _kinact (maximum enzyme inactivation rate constant) and K _I (concentration of inhibitor resulting in a rate of 50% of the maximum enzyme inactivation rate) were calculated by nonlinear least squares method. . Furthermore, enzyme inactivation clearance was calculated according to the method described in Drug Metabolism and Disposition, 2011, 39(7), 1247-1254 (CL _{int =} k _inact /K _I (ml/min/mmol) x CYP contents (pmol/mg protein)).

The table below shows the fold change in IC ₅₀ value and enzyme inactivation clearance due to preincubation, which are indicators of the MBI action of each example compound and prexasertib on CYP3A4.

The inventors of the present invention newly discovered that prexasertib inhibits MBI-based CYP3A4, which poses a risk of causing serious side effects such as hepatotoxicity.

As shown in the table above, although prexasertib exhibits MBI-based inhibition of CYP3A4, the compounds of Examples 1, 2, 4, 6-8, 14, 29-31, 34, 37, and 38 It was revealed that MBI-based inhibition of CYP3A4 was not shown. These results show that the compounds of Examples 1, 2, 4, 6-8, 14, 29-31, 34, 37, and 38 have a risk of causing not only drug interactions but also serious side effects such as hepatotoxicity. It has the unique effect of having reduced high safety. Among them, the compound represented by formula (3) shows particularly high safety and has unique effects.

Test example 5. Human bone marrow cell colony formation test (blood toxicity evaluation test)
Human bone marrow CD34-positive hematopoietic stem cells were obtained from Lonza Corporation. The frozen cells were thawed in a 9:1 mixture of Methocult Express medium, RPMI1640 medium containing 10% fetal bovine serum, and 1% penicillin/streptomycin, and 5000 cells were seeded per well in a 6-well plate. The cells were then cultured overnight at 37°C in the presence of 5% _CO2 . The evaluation compound was added at a final DMSO concentration of 0.1%, 100 nM, and cultured for 48 hours. Cells were collected and washed with PBS. 1/6 amount of cells were seeded in a 12-well plate and cultured at 37° C. in the presence of 5% CO ₂ for about 2 weeks. After completion of the culture, the number of colonies formed was calculated using Thiazolyl blue tetrazolium bromide (MTT).

The test shown in Test Example 5 was conducted on the representative compounds obtained in Examples and plexasertib. The results are shown in the table below.

As shown in the table above, although 100 nM prexasertib shows a suppressive effect on human bone marrow cell colony formation, 100 nM Example 1 does not show a suppressive effect on human bone marrow cell colony formation. became clear. The results show that the compound of Example 1 has a different effect with high safety on hematologic toxicity.

Test example 6. Liposome Encapsulation Test A liposome encapsulation test was conducted for representative example compounds and prexasertib.

Hydrogenated soybean phosphatidylcholine (COATSOME NC-21E, manufactured by NOF Corporation) 6.48 g, cholesterol (manufactured by Sigma) 2.32 g, and distearoyl phosphatidylethanolamine-methoxypolyethylene glycol 2000 (SUNBRIGHT DSPE-020CN, NOF Corporation) 2.06 g of t-butyl alcohol was dissolved in 560 mL of t-butyl alcohol heated to 65°C. After freezing this solution in a dry ice/acetone bath, t-butyl alcohol was removed by distillation under reduced pressure to obtain a lipid mixture.

200 mL of 250 mM ammonium sulfate solution was added to the above lipid mixture, heated to 65° C., and dispersed with a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed at a pressure of 100 MPa using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo) to obtain liposomes with an average particle size (Z-average) of about 80 nm. By using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the aqueous phase outside the liposomes was replaced with 10 mM L-histidine buffer/10% sucrose solution (pH 6.5), An empty liposome solution was obtained. Filter with a 0.22 μm membrane filter, add 10 mM L-histidine buffer/10% sucrose solution (pH 6.5), and adjust the total lipid concentration to 75 mM (75 μmol/mL) or 50 mM (50 μmol/mL). did. Note that the amount prepared was increased or decreased as appropriate.

Weigh out 2 to 3 mg of the test compound, add 1 mL of empty liposome solution with a total lipid concentration of 50 mM, adjust the pH to 5.5 to 7 by adding 1 mol/L hydrochloric acid or 1 mol/L aqueous sodium hydroxide solution, and place in a water bath at 65°C. After heating for 10 to 30 minutes, the mixture was cooled on ice. If there were any insoluble materials, they were removed by centrifugation at 15,000 xg for 5 minutes.

The liposome encapsulation rate was calculated as follows.
100 μL of the liposome solution was placed on an ultrafiltration filter (Amicon Ultra, 100K, 0.5 mL, manufactured by Merck & Co.), and centrifuged at 4° C. and 15,000×g for 10 minutes. The compound concentration in the filtrate after ultrafiltration was measured by HPLC, and was defined as the unencapsulated compound concentration.
The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and left at 5° C. for 10 minutes or more. Insoluble matter was removed by centrifugation at 15,000 xg for 5 minutes, and the compound concentration of the supernatant was measured by HPLC, which was taken as the compound concentration in the liposome solution.
The encapsulation rate and encapsulation efficiency were calculated using the following formula.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100 / Compound concentration in liposome solution Encapsulation efficiency (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration )×100/concentration at the time of compound introduction

The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 3μL or 5μL

It was confirmed that Prexasertib Examples 1, 3, 4, 5, and 6 could achieve high encapsulation efficiency of 80% or more. In addition, in the liposome encapsulation operation of Example 4, when the pH was adjusted by adding 1 mol/L hydrochloric acid, a significant increase in liquid viscosity was observed. This increase in viscosity can be a problem when producing liposomes on a large scale. On the other hand, in Examples 1, 3, 5, and 6, no increase in viscosity was observed during the liposome encapsulation operation. Therefore, the compounds represented by formulas (3) and (4) showed particularly good liposome encapsulation operability.

Test example 6A. Liposome Encapsulation Test of Example 1 The compound of Example 1 was subjected to a liposome encapsulation test.

Presome ACD-1 (a pre-prepared mixture consisting of hydrogenated soybean phosphatidylcholine, cholesterol and distearoyl phosphatidylethanolamine-methoxypolyethylene glycol 2000 in a mass ratio of 3:1:1, manufactured by Nippon Fine Chemical Co., Ltd.) 11.08 g It was weighed out, 200 mL of 250 mM ammonium sulfate solution was added, heated to 65° C., and dispersed with a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 80 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the aqueous phase outside the liposomes was replaced with 10 mM L-histidine buffer/10% sucrose solution (pH 6.5), and 0. By filtering through a 22 μm membrane filter, an empty liposome solution with a total lipid concentration of 75 mM (75 μmol/mL) was obtained.

The compound of Example 1 was weighed out, and about 0.4 mL of 10 mM L-histidine buffer/10% sucrose solution (pH 6.5), about 0.1 mL of 0.1 mol/L hydrochloric acid, and 1 mL of the above empty liposome solution were added. , 1 mol/L hydrochloric acid was added to adjust the pH to 6 to 6.5, heated in a 65° C. water bath for 30 minutes, and then cooled on ice. Thereafter, it was filtered using a 0.22 μm membrane filter.

The liposome encapsulation rate was calculated as follows.
Unencapsulated compound concentration: The compound concentration was measured by HPLC for a solution obtained by adding 100 μL of a 4% phosphoric acid aqueous solution to 100 μL of the liposome solution. The HPLC measurement conditions are as follows.
HPLC conditions
Column: MonoSelect nPEC (GL Sciences Inc.)
Column temperature: 30℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 95/5 (1) → 70/30 (6) → 70/30 (7 ) → 95/5 (7.01) → 95/5 (10)
Flow rate: 1mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 2μL

Compound concentration in liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and left at 5° C. for 10 minutes or more. Insoluble matter was removed by centrifugation at 15,000×g for 5 minutes, and the compound concentration of the supernatant was measured by HPLC. The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL

The encapsulation rate and encapsulation efficiency were calculated using the following formula.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100 / Compound concentration in liposome solution Encapsulation efficiency (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration )×100/concentration at the time of compound introduction

It was confirmed that Example 1 could achieve a high liposome encapsulation efficiency of 90% or more.

Test example 6B. Liposome encapsulation test of Example 1 The compound of Example 1 was subjected to a liposome encapsulation test.

Presome ACD-1 (a pre-prepared mixture consisting of hydrogenated soybean phosphatidylcholine, cholesterol and distearoyl phosphatidylethanolamine-methoxypolyethylene glycol 2000 in a mass ratio of 3:1:1, manufactured by Nippon Fine Chemical Co., Ltd.) 11.08 g It was weighed out, 200 mL of 250 mM ammonium sulfate solution was added, heated to 65° C., and dispersed with a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 81 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the aqueous phase outside the liposomes was replaced with 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), By filtering through a 0.22 μm membrane filter, an empty liposome solution with a total lipid concentration of 53.1 mg/mL was obtained.

120 mg of the compound of Example 1 was weighed out, and 18.3 mL of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), 0.3 mL of 1 mol/L hydrochloric acid, and 41.7 mL of the above empty liposome solution were added. In addition, the pH was adjusted to 6.5 with 1 mol/L hydrochloric acid or 1 mol/L sodium hydroxide. This liquid was heated in a 50°C water bath for 30 minutes, cooled on ice, and filtered through a 0.22 μm membrane filter. The compound concentration in the liposome solution of Example 1 was 2.00 mg/mL, the encapsulation rate was 98.0%, and the average particle size (Z-average) was 84 nm.

The liposome encapsulation rate was calculated as follows.
Unencapsulated compound concentration: Mix 100 μL of liposome solution, 100 μL of 4% phosphoric acid aqueous solution, and 300 μL of physiological saline, centrifuge at 100,000 x g for 60 minutes to remove insoluble matter, and measure the compound concentration of the supernatant by HPLC. did.
Compound concentration in liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and left at 5° C. for 10 minutes or more. Insoluble matter was removed by centrifugation at 15,000×g for 5 minutes, and the compound concentration of the supernatant was measured by HPLC.
The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL

The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution

Liposomes encapsulating the compound of Example 1 were stored at 5°C, and changes in compound concentration, encapsulation rate, and average particle diameter were confirmed. As shown in Table 11, the liposomes encapsulating Example 1 showed no major changes in compound concentration, encapsulation rate, or average particle diameter, and were found to have excellent storage stability.

Test example 7. Pharmacokinetic study The solution formulations of prexasertib, Examples 1, 3, and 6, and the liposome formulations of prexasertib were administered intravenously to mice, and the concentration of the test substance in the blood was measured.

For solution formulations, it was dissolved in 10mM glycine/5% mannitol solution (pH 2) or 10mM glycine/5% mannitol solution (pH 2) containing 20% sulfobutylether-β-cyclodextrin, and then filtered with a 0.22 μm membrane filter. I used something.

For the liposome preparation, liposomes encapsulating the test compound were prepared in the same manner as in Test Example 6, and the aqueous phase outside the liposome was mixed with 10 mM L-histidine buffer using a gel filtration column PD-10 (manufactured by GE Healthcare). /10% sucrose solution (pH 6.5), filtered through a 0.22 μm membrane filter, and adjusted the concentration by adding 10mM L-histidine buffer/10% sucrose solution (pH 6.5). did.

<Administration test>
The solution formulation or liposome formulation was instantaneously administered intravenously to 7-week-old female BALB/c mice, and blood was collected over time from the jugular vein up to 72 hours after administration without anesthesia. Immediately after blood collection, 4 times the volume of methanol was added to the blood, which was then centrifuged, and the concentration of the test compound in the resulting supernatant was determined by LC-MS/MS.

The measurement conditions for LC-MS/MS are as follows.
HPLC: Prominence system (Shimadzu Corporation)
MS/MS:4000 QTRAP(SCIEX)
Column: Cadenza CD-C18, 3 μm, 50 x 2 mm (Intact Co., Ltd.) Column temperature: 40°C
Mobile phase: A: Water containing 0.1% formic acid B: Acetonitrile containing 0.1% formic acid A/B (min): 90/10 (0) → 10/90 (2.5) → 10/90 (3. 5) → 90/10 (3.6) → 90/10 (5.0)
Flow rate: 0.4mL/min
Detection: ESI (positive mode)
Injection volume: 0.1-5μL

The test results are shown in the table below. In the table, "mean" means the average, and "S.D." means the standard deviation. Tables 12, 13, 14, 15 and 16 show the test compound concentrations in plasma from 0 hours after administration to 72 hours after administration.

Regarding the AUC for Examples 1, 3, and 6 and the liposome formulation of prexasertib, the AUC was calculated using the trapezoidal method from 0 hours after administration to the time (t) when the plasma test compound concentration could be quantified, and is shown in Table 17. show.

From the above results, when the encapsulated liposomes of Example 1 and Example 3, which were formulated into liposome formulations, were administered intravenously, high blood retention was confirmed. The present results demonstrated the achievement of the 72-hour sustained exposure critical to maximizing efficacy reported in prexasertib non-clinical studies. Therefore, Examples 1 and 3 have excellent pharmacokinetic profiles and are extremely useful as anticancer agents. It was shown that it is important that the nitrogen atom on the pyridine ring is present at a specific position, which is a characteristic of the compound represented by formula (3).

Test example 8. Drug efficacy evaluation test using tumor-bearing mice transplanted with ES-2 cells Antitumor effects were evaluated using prexasertib, a liposome preparation containing prexasertib, and a liposome preparation containing Example 1.

For the solution formulation of prexasertib, prexasertib was dissolved in a 10 mM glycine/5% mannitol solution (pH 2) containing 20% sulfobutylether-β-cyclodextrin, and then filtered through a 0.22 μm membrane filter.

A liposome formulation was prepared in the same manner as in Test Example 6. The test compound was weighed out, an empty liposome solution with a total lipid concentration of 50 mM was added so that the compound concentration was 2 mg/mL, and the pH was adjusted to 6 to 7 by adding 1 mol/L hydrochloric acid. Alternatively, add 10mM L-histidine buffer/10% sucrose solution (pH 6.5) and hydrochloric acid to the test compound to dissolve or disperse the compound, and prepare an empty liposome solution with a total lipid concentration of 75mM so that the compound concentration is 2mg/mL. was added to adjust the pH to 6-7. This solution was heated in a 65°C water bath for 10 to 30 minutes and then cooled on ice. After standing in a refrigerator at 5° C. for at least one night, it was filtered with a 0.22 μm membrane filter. The liposome encapsulation rate calculated by the method described in Test Example 6 was 99% or more.

ES-2 cells (ATCC) were added to 4-7 week old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan) at 1×10 ⁶ cells/mouse. It was implanted intradermally around the ventral region. After confirming the engraftment of ES-2 cells 5 to 14 days after transplantation, intravenous injection was performed once a week at a dose of 30 mg/kg for the solution formulation or 3 mg/kg, 7.5 mg/kg, or 20 mg/kg for the liposome formulation. or subcutaneously administered twice a day for 3 consecutive days (total of 6 doses per week). The tumor volume is measured over time from the start of administration, and the tumor volume reduction effect due to compound administration is evaluated. The tumor volume was calculated by the following formula using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo).

Tumor volume [mm ³ ] = 0.5 x (breadth axis [mm]) ² x long axis [mm]

A control group in which only the solvent was administered and a group in which the compound of the present disclosure was administered were compared, T/C was calculated using the following formula, and the antitumor effect was evaluated. In addition, the rate of complete tumor regression (CR) at the end of administration of the solution formulation or liposome formulation was recorded. For the control administration group, an empty liposome solution prepared in the same manner as in Test Example 6 was used.

T/C (%) = (Tumor volume at the end of administration of the compound administration group of the present disclosure - Tumor volume at the start of administration of the compound administration group of the present disclosure) / (Tumor volume at the end of administration of the control administration group - Control Tumor volume at the start of administration in the administration group) x 100

Table 18 shows the T/C (%) and CR individual rate for tumor-bearing mice transplanted with ES-2 cells at each dose and administration period of the test compound.

In a drug efficacy evaluation test using tumor-bearing mice, it was revealed that Example 1 formulated into liposomes exhibited excellent antitumor effects similar to prexasertib formulated into liposomes at any dose. Ta. These liposomal formulations have achieved tumor regression in evaluation studies using a dose of 20 mg/kg that cannot be achieved with prexasertib in solution formulation. From the results of this test, Example 1 is a promising compound that exhibits excellent antitumor effects and has exceptional effects.

Test example 9. Measurement of neutrophil counts using tumor-bearing mice transplanted with ES-2 cells 4-7 week old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan) ES-2 cells (ATCC) were intradermally transplanted around the ventral region at 1×10 ⁶ cells/mouse. After confirming the engraftment of ES-2 cells 5 to 14 days after transplantation, a single dose of each dose of the liposome preparation containing prexasertib and the liposome preparation containing Example 1 was administered intravenously. Blood was collected 72 hours after administration, and the number of neutrophils was measured. For comparison in this test, an empty liposome solution prepared by the same method as Test Example 6 was used.

A control group administered with empty liposome solution was compared with a group administered with liposome-formulated Example 1 and liposome-formulated prexasertib, and the residual rate of neutrophils was calculated using the following formula, The safety of each formulation was evaluated.

Neutrophil residual rate (%) = (Number of neutrophils 72 hours after administration in the administration group) / (Number of neutrophils 72 hours after administration in the control administration group) x 100

Table 19 shows the survival rate of neutrophils in tumor-bearing mice to which ES-2 cells were transplanted.

Example 1 formulated in liposomes shows comparable antitumor efficacy at the same dosage as prexasertib formulated in liposomes. At the minimum effective dose of 3 mg/kg, liposome-formulated prexasertib has a neutrophil survival rate of 15%, and antitumor effects and hematologic toxicity have been observed simultaneously. On the other hand, in Example 1, which was formulated into a liposome formulation, at the minimum effective dose of 3 mg/kg, the residual rate of neutrophils was 61%, and the side effects of blood toxicity were reduced. Furthermore, as shown in Test Example 8, liposome-formulated prexasertib in Example 1 was administered at a dose of 7.5 mg/kg even at a dose of 20 mg/kg at which tumor regression was observed. This shows a higher neutrophil survival rate than in the case. From the above, Example 1 is an excellent compound that has both higher safety and efficacy than prexasertib, and has exceptional effects. Similarly, the liposome preparation of Example 1 is an excellent compound having both high safety and efficacy, and has exceptional effects.

Test example 10. Human bone marrow cell Myeloid differentiation induction test (blood toxicity evaluation test)
Human bone marrow CD34-positive hematopoietic stem cells were obtained from Lonza Corporation. The frozen cells were thawed in IMDM medium containing 1% fetal bovine serum, suspended in Complete hemaTox (registered trademark) Myeloid Medium, and 1000 cells per well were seeded in a 96-well plate. The evaluation compound was added so that the final concentration of DMSO was 0.1%, 3 nM, and the cells were cultured for 7 days at 37° C. in the presence of 5% CO ₂ . After culturing, half the cell suspension per well was collected, the luminescence value was measured using CellTiter-Glo (registered trademark) 3D Reagent (Promega, G968B), and the cell survival ratio was calculated using the following formula. did.

Cell survival ratio (%) = (measured luminescence value after 7 days of evaluation compound) / (measured luminescence value after 7 days of control group) × 100

The test shown in Test Example 10 was conducted on the representative compounds obtained in Examples and plexasertib. The results are shown in the table below.

As shown in the table above, although 3 nM prexasertib shows a suppressive effect on Myeloid cells induced to differentiate from human bone marrow cells, 3 nM Example 1 suppresses Myeloid cells induced to differentiate from human bone marrow cells. It was revealed that the drug had no suppressive effect on cells. From these results, compared to prexasertib, Example 1 is a compound with high safety in terms of blood toxicity, and has exceptional and different effects.

Test example 11. Tumor PD test using tumor-bearing mice transplanted with ES-2 cells Using prexasertib, a liposome formulation encapsulating prexasertib, and a liposome formulation encapsulating Example 1, pharmacodynamics (PD) in tumors was investigated. ) The response effect was evaluated.

For the solution formulation of prexasertib, prexasertib was dissolved in a 10 mM glycine/5% mannitol solution (pH 2) containing 20% sulfobutylether-β-cyclodextrin, and then filtered through a 0.22 μm membrane filter.

A liposome formulation was prepared in the same manner as in Test Example 6. The test compound was weighed out, an empty liposome solution with a total lipid concentration of 50 mM was added so that the compound concentration was 2 mg/mL, and the pH was adjusted to 6 to 7 by adding 1 mol/L hydrochloric acid. Alternatively, add 10mM L-histidine buffer/10% sucrose solution (pH 6.5) and hydrochloric acid to the test compound to dissolve or disperse the compound, and prepare an empty liposome solution with a total lipid concentration of 75mM so that the compound concentration is 2mg/mL. was added to adjust the pH to 6-7. This solution was heated in a 65°C water bath for 10 to 30 minutes and then cooled on ice. After standing in a refrigerator at 5° C. for at least one night, it was filtered with a 0.22 μm membrane filter. The liposome encapsulation rate calculated by the method described in Test Example 6 was 99% or more.

Ovarian cancer ES-2 cells (ATCC) were injected into 4- to 7-week-old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan) at 1×10 ⁶ cells/mouse. It was implanted intradermally around the ventral region. After confirming the engraftment of ES-2 cells 5 to 14 days after transplantation, each test was administered under the following conditions:
Test A: A single intravenous dose of 30 mg/kg for the solution formulation or 7.5 mg/kg, 3 mg/kg, 1 mg/kg, 0.3 mg/kg for the liposome formulation was administered intravenously. Test B: A single intravenous dose of 30 mg/kg for the solution formulation or 7.5 mg/kg, 3 mg/kg, 1 mg/kg, 0.3 mg/kg for the liposome formulation was administered intravenously. Study C: Liposomal formulations were administered intravenously in a single dose at 20 mg/kg, 7.5 mg/kg, 3 mg/kg, 1 mg/kg, 0.3 mg/kg. Tumors were collected 1, 3, or 6 days after administration, and the PD response of the tumors to compound administration was evaluated.

PD response effects in tumors were evaluated by Western blotting. The intensity of each band detected by anti-anti-γH2AX antibody (05-636, Merck) and anti-Tubulin antibody (3873, Cell Signaling Technology) was calculated using ImageJ software.

A control administration group in which only the solvent was administered and a compound administration group of the present disclosure were compared, and the relative value of each band intensity was calculated using the following formula to evaluate the PD response effect on the tumor. For the control administration group, an empty liposome solution prepared in the same manner as in Test Example 6 was used.

Intensity of γH2AX = {(band intensity of γH2AX in the tumor of the compound administration group of the present disclosure)/(band intensity of Tubulin in the tumor of the compound administration group of the present disclosure)}/{(band intensity of γH2AX in the tumor of the control administration group) /Tubulin band intensity in tumor of control administration group)}×100

FIG. 7-9 shows the intensity of γH2AX in tumor-bearing mice transplanted with ES-2 cells at each dose and administration period of the test compound.

From the above results, as shown in Test Example 11 Test A, when liposome-formulated prexasertib was administered, a strong PD response effect was confirmed at a dose of 7.5 mg/kg 3 days after administration, and a solution-formulated prexasertib was confirmed. It achieved a PD response effect that cannot be achieved with prexasertib. Test Example 11 As shown in Test B, when the liposome formulation of Example 1 was administered, a strong PD response effect was confirmed at a dose of 7.5 mg/kg one day after administration, and the solution formulation of prexasertib showed a strong PD response effect. A previously unattainable PD response effect was achieved. Test Example 11 As shown in Test C, when the liposome-formulated Example 1 was administered, a strong PD response effect was confirmed at doses of 7.5 mg/kg and 20 mg/kg 3 days and 6 days after administration. Ta. These liposome formulations, as shown in Test Example 7, demonstrated the achievement of sustained exposure for 72 hours, which is important for maximizing the efficacy reported in non-clinical studies of prexasertib. Therefore, Example 1 has an excellent pharmacokinetic and pharmacodynamic profile and is extremely useful as an anticancer agent.

Test example 12. Drug efficacy evaluation test using peritoneally disseminated tumor-bearing mice transplanted with ES-2 cells Antitumor effects were evaluated using prexasertib, a liposome preparation containing prexasertib, and a liposome preparation containing Example 1.

For the solution formulation of prexasertib, prexasertib was dissolved in a 10 mM glycine/5% mannitol solution (pH 2) containing 20% sulfobutylether-β-cyclodextrin, and then filtered through a 0.22 μm membrane filter.

A liposome formulation encapsulating prexasertib was prepared as follows.
11.08 g of Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.) and 200 mL of a 250 mM ammonium sulfate solution were mixed and dispersed with a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 80 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the aqueous phase outside the liposomes was replaced with 10 mM L-histidine buffer/10% sucrose solution (pH 6.5). By filtering through a 22 μm membrane filter, an empty liposome solution with a total lipid concentration of 75 mM was obtained. 60 mg of prexasertib, 10 mL of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), and 20 mL of the above empty liposome solution were added, and the pH was adjusted to 6.5. This liquid was heated in a 50°C water bath for 30 minutes, cooled on ice, and filtered through a 0.22 μm membrane filter. The concentration of prexasertib in the liposome solution was 1.97 mg/mL, and the encapsulation rate was 98%.

The compound concentration and encapsulation rate in the liposome solution were calculated as follows.
Unencapsulated compound concentration: Mix 100 μL of liposome solution, 100 μL of 4% phosphoric acid aqueous solution, and 300 μL of physiological saline, centrifuge at 100,000 x g for 60 minutes to remove insoluble matter, and measure the compound concentration of the supernatant by HPLC. did.

Compound concentration in the liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC.
The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 90/10 (0) → 70/30 (3) → 0/100 (3.5) → 0/100 (4) → 90/10 (4.01) → 90/10 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution

A liposome formulation containing Example 1 was prepared as follows.
11.08 g of Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.) and 200 mL of a 250 mM ammonium sulfate solution were mixed and dispersed with a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 81 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the aqueous phase outside the liposomes was replaced with 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), By filtering through a 0.22 μm membrane filter, an empty liposome solution with a total lipid concentration of 53.1 mg/mL was obtained. 80 mg of the compound of Example 1, 12.2 mL of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), and 27.8 mL of the above empty liposome solution were added, and the pH was adjusted to 6.5. This liquid was heated in a 50°C water bath for 30 minutes, cooled on ice, and filtered with a 0.22 μm membrane filter. The compound concentration in the liposome solution of Example 1 was 1.99 mg/mL, and the encapsulation rate was 97%.

The liposome encapsulation rate was calculated as follows.
Unencapsulated compound concentration: The compound concentration was measured by HPLC for a solution obtained by adding 100 μL of a 4% phosphoric acid aqueous solution to 100 μL of the liposome solution. The HPLC measurement conditions are as follows.
HPLC conditions
Column: MonoSelect nPEC (GL Sciences Inc.)
Column temperature: 30℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 95/5 (1) → 70/30 (6) → 70/30 (7 ) → 95/5 (7.01) → 95/5 (10)
Flow rate: 1mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 2μL
Compound concentration in the liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC. The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution

Five-week-old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan) were injected with 1× ovarian cancer ES-2 cells (ATCC), a cell line in which Luciferase was expressed. The cells were transplanted intraperitoneally at 10 ⁶ cells/mouse. After confirming the engraftment of ES-2 cells using the IVIS Imaging System (PerkinElmer) 5 to 14 days after transplantation, the solution formulation was administered at a dose of 30 mg/kg or the liposome formulation at a dose of 4.5 mg/kg or 20 mg/kg for one week. One dose was administered intravenously. The luminescence caused by Luciferase is measured over time from the start of administration to evaluate the tumor shrinkage effect caused by compound administration. Mice were observed based on tumor size, systemic symptoms, and body weight changes estimated from luminescence caused by Luciferase, and the survival period of mice that showed a healthy condition without any serious findings was measured.

The median survival period of the control administration group in which only the vehicle was administered and the compound administration group of the present disclosure was calculated, and the antitumor effect was evaluated. Empty liposome solution was used for the control administration group.

Table 21 shows the median survival time for peritoneally disseminated tumor-bearing mice transplanted with ES-2 cells at each dose and administration period of the test compound.

In a drug efficacy evaluation test using peritoneal disseminated tumor-bearing mice, liposome-formulated Example 1 was found to exhibit the same excellent antitumor effect as liposome-formulated prexasertib at a dose of 20 mg/kg. It became clear. These liposome formulations have achieved survival extensions that cannot be achieved with solution-formulated prexasertib in evaluation studies using a dose of 20 mg/kg. From the results of this test, Example 1 is a promising compound that exhibits excellent antitumor effects and has exceptional effects.

Test example 13. Drug efficacy evaluation test using ovarian orthotopic tumor-bearing mice transplanted with ES-2 cells Antitumor effects were evaluated using prexasertib, a liposome preparation containing prexasertib, and a liposome preparation containing Example 1.

For the solution formulation of prexasertib, prexasertib was dissolved in a 10 mM glycine/5% mannitol solution (pH 2) containing 20% sulfobutylether-β-cyclodextrin, and then filtered through a 0.22 μm membrane filter.

A liposome formulation encapsulating prexasertib was prepared as follows.
11.08 g of Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.) and 200 mL of a 250 mM ammonium sulfate solution were mixed and dispersed with a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 80 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the aqueous phase outside the liposomes was replaced with 10 mM L-histidine buffer/10% sucrose solution (pH 6.5), and 0. By filtering through a 22 μm membrane filter, an empty liposome solution with a total lipid concentration of 75 mM was obtained. 60 mg of prexasertib, 10 mL of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), and 20 mL of the above empty liposome solution were added, and the pH was adjusted to 6.5. This liquid was heated in a 50°C water bath for 30 minutes, cooled on ice, and filtered through a 0.22 μm membrane filter. The concentration of prexasertib in the liposome solution was 1.97 mg/mL, and the encapsulation rate was 98%.

The compound concentration and encapsulation rate in the liposome solution were calculated as follows.
Unencapsulated compound concentration: Mix 100 μL of liposome solution, 100 μL of 4% phosphoric acid aqueous solution, and 300 μL of physiological saline, centrifuge at 100,000 x g for 60 minutes to remove insoluble matter, and measure the compound concentration of the supernatant by HPLC. did.

Compound concentration in the liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC.
The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 90/10 (0) → 70/30 (3) → 0/100 (3.5) → 0/100 (4) → 90/10 (4.01) → 90/10 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution

A liposome formulation containing Example 1 was prepared as follows.
11.08 g of Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.) and 200 mL of a 250 mM ammonium sulfate solution were mixed and dispersed with a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 81 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the aqueous phase outside the liposomes was replaced with 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), By filtering through a 0.22 μm membrane filter, an empty liposome solution with a total lipid concentration of 53.1 mg/mL was obtained. 80 mg of the compound of Example 1, 12.2 mL of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), and 27.8 mL of the above empty liposome solution were added, and the pH was adjusted to 6.5. This liquid was heated in a 50°C water bath for 30 minutes, cooled on ice, and filtered through a 0.22 μm membrane filter. The compound concentration in the liposome solution of Example 1 was 1.99 mg/mL, and the encapsulation rate was 97%.

The liposome encapsulation rate was calculated as follows.
Unencapsulated compound concentration: The compound concentration was measured by HPLC for a solution obtained by adding 100 μL of a 4% phosphoric acid aqueous solution to 100 μL of the liposome solution. The HPLC measurement conditions are as follows.
HPLC conditions
Column: MonoSelect nPEC (GL Sciences Inc.)
Column temperature: 30℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 95/5 (1) → 70/30 (6) → 70/30 (7 ) → 95/5 (7.01) → 95/5 (10)
Flow rate: 1mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 2μL
Compound concentration in the liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC. The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution

Five-week-old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan) were injected with 1× ovarian cancer ES-2 cells (ATCC), a cell line in which Luciferase was expressed. The cells were transplanted into the right ovary at 10 ⁶ cells/mouse. After confirming the engraftment of ES-2 cells using the IVIS Imaging System (PerkinElmer) 5 to 14 days after transplantation, the solution preparation was administered at a dose of 30 mg/kg or the liposome preparation at a dose of 4.5 mg/kg or 20 mg/kg for one week. One dose was administered intravenously. Luminescence due to Luciferase is measured over time from the start of administration to evaluate tumor shrinkage effect due to compound administration. Mice were observed based on tumor size, systemic symptoms, and weight changes estimated from luminescence caused by Luciferase, and the survival period of mice that showed a healthy condition without any serious findings was measured.

The median survival period of the control administration group in which only the vehicle was administered and the compound administration group of the present disclosure was calculated, and the antitumor effect was evaluated. Empty liposome solution was used for the control administration group.

Table 22 shows the median survival time of ovarian orthotopic tumor-bearing mice transplanted with ES-2 cells at each dose and administration period of the test compound.

In a drug efficacy evaluation test using ovarian orthotopic tumor-bearing mice, liposome-formulated Example 1 exhibited excellent antitumor effects similar to liposome-formulated prexasertib at a dose of 20 mg/kg. became clear. These liposome formulations have achieved survival extensions that cannot be achieved with solution-formulated prexasertib in evaluation studies using a dose of 20 mg/kg. From the results of this test, Example 1 is a promising compound that exhibits excellent antitumor effects and has exceptional effects.

Test example 14. Drug efficacy evaluation test using cancer-bearing mice transplanted with various cancer cells The antitumor effect was evaluated using a liposome preparation containing Example 1.

The liposome preparation encapsulating Example 1 was the one used in Test Example 12 or the one prepared by the following method.

Weighed 138.4 g of Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.), added 2437 g of 250 mM ammonium sulfate solution, dispersed with a homogenizer (CLEARMIX, manufactured by M TECHNIQUE), and defoamed by vacuum degassing. A crude liposome dispersion was obtained. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Microfluidizer M-110 EH-30, manufactured by Microfluidics) at a pressure of 14,500 Psi to obtain liposomes with an average particle size (Z-average) of 73 nm. Using a Tangential Flow Filtration system equipped with five Pellicon cassettes (Pellicon 2 Mini 300kD 0.1m2, manufactured by Merck & Co., Ltd.), the aqueous phase outside the liposomes was mixed with 10mM L-histidine buffer/9.4% sucrose solution (pH 6.5). ) and filtered through a 0.2 μm membrane filter to obtain an empty liposome solution with a total lipid concentration of 58.2 mg/mL. 3.0 g of the compound of Example 1 was weighed out, and 562 g of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5) and 980 g of the empty liposome solution were added to adjust the pH to 6.5. . The mixture was heated at 45° C. for 60 minutes and then cooled. Using a Tangential Flow Filtration system equipped with five Pellicon cassettes (Pellicon 2 Mini 300kD 0.1m2, manufactured by Merck & Co., Ltd.), the aqueous phase outside the liposomes was mixed with 10mM L-histidine buffer/9.4% sucrose solution (pH 6.5). ) and filtered with a 0.2 μm membrane filter. This liquid was dispensed into glass vials in an amount of 50 mL each, which was capped and sealed. The compound concentration in the liposome solution of Example 1 was 1.98 mg/mL, and the encapsulation rate was 97%.

The compound concentration and encapsulation rate in the liposome solution were calculated as follows.
Unencapsulated compound concentration: Mix 100 μL of liposome solution, 100 μL of 4% phosphoric acid aqueous solution, and 300 μL of physiological saline, centrifuge at 100,000 x g for 60 minutes to remove insoluble matter, and measure the compound concentration of the supernatant by HPLC. did.

Compound concentration in liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC.
The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: 0.1% trifluoroacetic acid-containing water B: Acetonitrile A/B (min): 95/5 (0) → 60/40 (3) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution or Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.) 11.08 g and 250 mM ammonium sulfate solution 200 mL were mixed and dispersed using a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 81 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the aqueous phase outside the liposomes was replaced with 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), By filtering through a 0.22 μm membrane filter, an empty liposome solution with a total lipid concentration of 53.1 mg/mL was obtained. 60 mg of the compound of Example 1, 9.16 mL of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), and 20.8 mL of the above empty liposome solution were added, and the pH was adjusted to 6.5. This liquid was heated in a 50°C water bath for 30 minutes, cooled on ice, and filtered through a 0.22 μm membrane filter. The compound concentration in the liposome solution of Example 1 was 2.08 mg/mL, and the encapsulation rate was 98%.

The compound concentration and encapsulation rate in the liposome solution were calculated as follows.
Unencapsulated compound concentration: Mix 100 μL of liposome solution, 100 μL of 4% phosphoric acid aqueous solution, and 300 μL of physiological saline, centrifuge at 100,000 x g for 60 minutes to remove insoluble matter, and measure the compound concentration of the supernatant by HPLC. did.

Compound concentration in liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC.
The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (concentration of compound in liposome solution - concentration of unencapsulated compound) x 100/concentration of compound in liposome solution.

4-7 week old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan) or NODSCID mice (NOD.CB17-Prkdc ^scid /J, female, Charles River, Japan) Ovarian cancer SKOV-3 cells (ATCC) or sarcoma SJCRH30 cells (ATCC) or sarcoma HT-1080 cells (ATCC) or pancreatic cancer AsPC-1 cells (ATCC) or pancreatic cancer BxPC-3 cells (ATCC) or Lung cancer Calu-6 cells (ATCC) or ovarian cancer OV5304 cells (Crown Bioscience) at 5×10 ⁵ cells/mouse or 1×10 ⁶ cells/mouse or 3×10 ⁶ cells/mouse or 5×10 ⁶ cells/mouse Alternatively, it was intradermally implanted around the ventral region to give a tumor mass of 8 mm ³ to 27 mm ³ per mouse. After confirming the engraftment of various cancer cells 5 to 27 days after transplantation, the liposome preparation was administered intravenously once a week at a dose of 4.5 mg/kg, 10 mg/kg, or 20 mg/kg. The tumor volume is measured over time from the start of administration, and the tumor volume reduction effect due to compound administration is evaluated. The tumor volume was calculated using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo) using the following formula. It is known that BxPC-3 cells exhibit resistance to gemcitabine, and OV5304 exhibits resistance to PARP inhibitors.

Tumor volume [mm ³ ] = 0.5 x (breadth axis [mm]) ² x long axis [mm]

A control group in which only the solvent was administered and a group in which the compound of the present disclosure was administered were compared, T/C was calculated using the following formula, and the antitumor effect was evaluated. Empty liposome solution was used for the control administration group.

T/C (%) = (Tumor volume at the end of administration of the compound administration group of the present disclosure - Tumor volume at the start of administration of the compound administration group of the present disclosure) / (Tumor volume at the end of administration of the control administration group - Control Tumor volume at the start of administration in the administration group) x 100

Table 23 shows the T/C (%) for tumor-bearing mice transplanted with various cancer cells at each dose and administration period of the test compound.

In a combination efficacy evaluation test using tumor-bearing mice, it was revealed that Example 1 formulated into liposomes exhibited excellent antitumor effects against various cancer cell lines. From the results of this test, Example 1 is a promising compound that exhibits excellent antitumor effects and has exceptional effects.

Test Example 14A. Drug efficacy evaluation test using cancer-bearing mice transplanted with various cancer cells The antitumor effect was evaluated using a liposome preparation containing Example 1.

A liposome formulation containing Example 1 was prepared as follows.
Weighed 498.2 g of Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.), added 8772 g of 250 mM ammonium sulfate solution, dispersed with a homogenizer (CLEARMIX, manufactured by M TECHNIQUE), and defoamed by vacuum degassing. A crude liposome dispersion was obtained. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Microfluidizer M-110 EH-30, manufactured by Microfluidics) at a pressure of 14,500 Psi to obtain liposomes with an average particle size (Z-average) of 73 nm. Using a Tangential Flow Filtration system equipped with five Pellicon cassettes (Pellicon 2 Mini 300kD 0.1m2, manufactured by Merck & Co., Ltd.), the liposome external aqueous phase was replaced with water for injection, and then 10mM L-histidine/9.4% sucrose was added. Add L-histidine and sucrose to form a solution, adjust the pH to 6.5 using 1 mol/L hydrochloric acid, and filter through a 0.2 μm membrane filter to obtain an empty solution with a total lipid concentration of 50.2 mg/mL. A liposome solution was obtained.

10.0 g of the compound of Example 1 was weighed out, and 1354 g of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), 27 g of 1 mol/L hydrochloric acid, and 3786 g of the above empty liposome solution were added to give 1 mol/L of the compound. The pH was adjusted to 6.5 with L-hydrochloric acid. After heating at 45° C. for 60 minutes, the mixture was cooled, adjusted to pH 6.5, and filtered through a 0.2 μm membrane filter. This liquid was dispensed into glass vials in an amount of 50 mL each, which was capped and sealed. The concentration of the compound of Example 1 in the liposome solution was 2.01 mg/mL, the encapsulation rate was 97.5%, and the average particle size (Z-average) was 74 nm.

The compound concentration and encapsulation rate in the liposome solution were calculated as follows.
Unencapsulated compound concentration: Mix 100 μL of liposome solution, 100 μL of 4% phosphoric acid aqueous solution, and 300 μL of physiological saline, centrifuge at 100,000 x g for 60 minutes to remove insoluble matter, and measure the compound concentration of the supernatant by HPLC. did.

Compound concentration in liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC.
The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: 0.1% trifluoroacetic acid-containing water B: Acetonitrile A/B (min): 95/5 (0) → 60/40 (3) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution

A2780 cells (ECACC) or HCC1806 cells (ATCC) or An3CA cells (ATCC) or Detroit562 cells were injected into 4-7 week old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan). cells (ATCC) or FaDu cells (ATCC) or NCI-H460 cells (ATCC) at 1x10 ⁶ cells/mouse or 2x10 ⁶ cells/mouse or 1.2x10 ⁶ cells/mouse or 1x10 ⁶ cells/mouse or 3x10 ⁶ c. ells/mouse Alternatively, the cells were intradermally transplanted around the ventral region at 3×10 ⁶ cells/mouse. After confirming the engraftment of various cancer cells 5 to 27 days after transplantation, the liposome preparation was intravenously administered at a dose of 20 mg/kg once a week. The tumor volume is measured over time from the start of administration, and the tumor volume reduction effect due to compound administration is evaluated. The tumor volume was calculated by the following formula using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo). It is known that BxPC-3 cells exhibit resistance to gemcitabine, and OV5304 exhibits resistance to PARP inhibitors.

Tumor volume [mm ³ ] = 0.5 x (breadth axis [mm]) ² x long axis [mm]

A control group in which only the solvent was administered and a group in which the compound of the present disclosure was administered were compared, T/C was calculated using the following formula, and the antitumor effect was evaluated. Empty liposome solution was used for the control group.

T/C (%) = (Tumor volume at the end of administration of the compound administration group of the present disclosure - Tumor volume at the start of administration of the compound administration group of the present disclosure) / (Tumor volume at the end of administration of the control administration group - Control Tumor volume at the start of administration in the administration group) x 100

Table 23A shows the T/C (%) for tumor-bearing mice transplanted with various cancer cells at each dose and administration period of the test compound.

Test example 15. Combination drug efficacy evaluation test using tumor-bearing mice transplanted with PA-1 cells The antitumor effect was evaluated using a liposome preparation containing cisplatin and a liposome preparation containing Example 1.

Cisplatin (Randa Injection 50 mg/100 mL, Nippon Kayaku Co., Ltd.) was used.

A liposome formulation containing Example 1 was prepared as follows.

Weighed 138.4 g of Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.), added 2437 g of 250 mM ammonium sulfate solution, dispersed with a homogenizer (CLEARMIX, manufactured by M TECHNIQUE), and defoamed by vacuum degassing. A crude liposome dispersion was obtained. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Microfluidizer M-110 EH-30, manufactured by Microfluidics) at a pressure of 14,500 Psi to obtain liposomes with an average particle size (Z-average) of 73 nm. Using a Tangential Flow Filtration system equipped with five Pellicon cassettes (Pellicon 2 Mini 300kD 0.1m2, manufactured by Merck & Co., Ltd.), the aqueous phase outside the liposomes was mixed with 10mM L-histidine buffer/9.4% sucrose solution (pH 6.5). ) and filtered through a 0.2 μm membrane filter to obtain an empty liposome solution with a total lipid concentration of 58.2 mg/mL. 3.0 g of the compound of Example 1 was weighed out, and 562 g of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5) and 980 g of the empty liposome solution were added to adjust the pH to 6.5. . The mixture was heated at 45° C. for 60 minutes and then cooled. Using a Tangential Flow Filtration system equipped with five Pellicon cassettes (Pellicon 2 Mini 300kD 0.1m2, manufactured by Merck & Co., Ltd.), the aqueous phase outside the liposomes was mixed with 10mM L-histidine buffer/9.4% sucrose solution (pH 6.5). ) and filtered with a 0.2 μm membrane filter. This liquid was dispensed into glass vials in an amount of 50 mL each, which was capped and sealed. The compound concentration in the liposome solution of Example 1 was 1.98 mg/mL, and the encapsulation rate was 97%.

The compound concentration and encapsulation rate in the liposome solution were calculated as follows.
Unencapsulated compound concentration: Mix 100 μL of liposome solution, 100 μL of 4% phosphoric acid aqueous solution, and 300 μL of physiological saline, centrifuge at 100,000 x g for 60 minutes to remove insoluble matter, and measure the compound concentration of the supernatant by HPLC. did.

Compound concentration in liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC.
The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: 0.1% trifluoroacetic acid-containing water B: Acetonitrile A/B (min): 95/5 (0) → 60/40 (3) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution

Ovarian cancer PA-1 cells (ATCC) were injected into 4-7 week old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan) at 5×10 ⁶ cells/mouse. It was implanted intradermally around the ventral region. After confirming the engraftment of PA-1 cells 5 to 14 days after transplantation, administer intravenously once a week at a dose of 20 mg/kg of liposome preparation, 2.5 mg/kg of cisplatin, or a combination thereof, or for 1 week. The drug was administered intraperitoneally twice or in combination. The tumor volume is measured over time from the start of administration, and the tumor volume reduction effect due to compound administration is evaluated. The tumor volume was calculated by the following formula using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo).

Tumor volume [mm ³ ] = 0.5 x (breadth axis [mm]) ² x long axis [mm]

A control group in which only the solvent was administered and a group in which the compound of the present disclosure was administered were compared, T/C was calculated using the following formula, and the antitumor effect was evaluated. In addition, the rate of complete tumor regression (CR) at the end of administration with liposome preparations, cisplatin, or combination administration was described. Empty liposome solution was used for the control group.

T/C (%) = (Tumor volume at the end of administration of the compound administration group of the present disclosure - Tumor volume at the start of administration of the compound administration group of the present disclosure) / (Tumor volume at the end of administration of the control administration group - Control Tumor volume at the start of administration in the administration group) x 100

Table 24 shows the T/C (%) and CR individual rate for tumor-bearing mice transplanted with PA-1 cells at each dose and administration period of the test compound.

In a combination drug efficacy evaluation test using tumor-bearing mice, it was revealed that Example 1, which was formulated into liposomes, exhibited excellent antitumor effects when used in combination with cisplatin. From the results of this test, Example 1 is a promising compound that exhibits excellent antitumor effects and has exceptional effects.

Test example 16. Combination drug efficacy evaluation test using tumor-bearing mice transplanted with ES-2 cells The antitumor effect was evaluated using a liposome preparation containing encapsulated Example 1 and gemcitabine.

Gemcitabine (Gemzar injection 200 mg, Eli Lilly Japan) was dissolved in physiological saline (Otsuka saline injection, Otsuka Pharmaceutical Factory).

A liposome formulation was prepared in the same manner as in Test Example 6. The test compound was weighed out, an empty liposome solution with a total lipid concentration of 50 mM was added so that the compound concentration was 2 mg/mL, and the pH was adjusted to 6 to 7 by adding 1 mol/L hydrochloric acid. Alternatively, add 10mM L-histidine buffer/10% sucrose solution (pH 6.5) and hydrochloric acid to the test compound to dissolve or disperse the compound, and prepare an empty liposome solution with a total lipid concentration of 75mM so that the compound concentration is 2mg/mL. was added to adjust the pH to 6-7. This solution was heated in a 65°C water bath for 10 to 30 minutes and then cooled on ice. After standing in a refrigerator at 5° C. for at least one night, it was filtered with a 0.22 μm membrane filter. The liposome encapsulation rate calculated by the method described in Test Example 6 was 99% or more.

Ovarian cancer ES-2 cells (ATCC) were injected into 4- to 7-week-old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan) at 1×10 ⁶ cells/mouse. It was implanted intradermally around the ventral region. After confirming the engraftment of ES-2 cells 5 to 14 days after transplantation, administer intravenously once a week at a dose of 4.5 mg/kg of liposome preparation, 30 mg/kg of gemcitabine, or a combination thereof, or for 1 week. The drug was administered intraperitoneally twice or in combination. The tumor volume is measured over time from the start of administration, and the tumor volume reduction effect due to compound administration is evaluated. The tumor volume was calculated by the following formula using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo).

Tumor volume [mm ³ ] = 0.5 x (breadth axis [mm]) ² x long axis [mm]

A control group in which only the solvent was administered and a group in which the compound of the present disclosure was administered were compared, T/C was calculated using the following formula, and the antitumor effect was evaluated. In addition, the percentage of individuals with complete tumor regression (CR) at the end of treatment with liposome preparations, gemcitabine, or combination administration was described. For the control administration group, an empty liposome solution prepared in the same manner as in Test Example 6 was used.

T/C (%) = (Tumor volume at the end of administration of the compound administration group of the present disclosure - Tumor volume at the start of administration of the compound administration group of the present disclosure) / (Tumor volume at the end of administration of the control administration group - Control Tumor volume at the start of administration in the administration group) x 100

Table 25 shows the T/C (%) and CR individual rate for tumor-bearing mice transplanted with ES-2 cells at each dose and administration period of the test compound.

In a combination drug efficacy evaluation test using tumor-bearing mice, it was revealed that Example 1 formulated into liposomes exhibited excellent antitumor effects when used in combination with gemcitabine. From the results of this test, Example 1 is a promising compound that exhibits excellent antitumor effects and has exceptional effects.

Test example 17. Measurement of the number of neutrophils using tumor-bearing mice transplanted with ES-2 cells The number of neutrophils was measured using a liposome preparation containing Example 1 and gemcitabine.

Gemcitabine (Gemzar injection 200 mg, Eli Lilly Japan) was dissolved in physiological saline (Otsuka saline injection, Otsuka Pharmaceutical Factory).

A liposome formulation was prepared in the same manner as in Test Example 6. The test compound was weighed out, an empty liposome solution with a total lipid concentration of 50 mM was added so that the compound concentration was 2 mg/mL, and the pH was adjusted to 6 to 7 by adding 1 mol/L hydrochloric acid. Alternatively, add 10mM L-histidine buffer/10% sucrose solution (pH 6.5) and hydrochloric acid to the test compound to dissolve or disperse the compound, and prepare an empty liposome solution with a total lipid concentration of 75mM so that the compound concentration is 2mg/mL. was added to adjust the pH to 6-7. This solution was heated in a 65°C water bath for 10 to 30 minutes and then cooled on ice. After standing in a refrigerator at 5° C. for at least one night, it was filtered with a 0.22 μm membrane filter. The liposome encapsulation rate calculated by the method described in Test Example 6 was 99% or more.

Ovarian cancer ES-2 cells (ATCC) were injected into 4- to 7-week-old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan) at 1×10 ⁶ cells/mouse. It was implanted intradermally around the ventral region. After confirming the engraftment of ES-2 cells 5 to 14 days after transplantation, administer intravenously once a week at a dose of 4.5 mg/kg of liposome preparation, 30 mg/kg of gemcitabine, or a combination thereof, or for 1 week. The drug was administered intraperitoneally twice or in combination. Blood was collected 96 hours after the final administration, and the number of neutrophils was measured. For comparison in this test, an empty liposome solution prepared by the same method as Test Example 6 was used.

The control group administered with empty liposome solution was compared with the administration group administered with liposome formulation Example 1, gemcitabine, and the combination, and the residual rate of neutrophils was calculated using the following formula. We evaluated the safety of

Neutrophil residual rate (%) = (Number of neutrophils 96 hours after administration in the administration group) / (Number of neutrophils 96 hours after administration in the control group) x 100

Table 26 shows the residual rate of neutrophils in tumor-bearing mice to which ES-2 cells were transplanted.

Example 1, which was formulated into a liposome formulation, had a neutrophil survival rate of 87% at 4.5 mg/kg, and as shown in Test Example 17, it exhibited antitumor effects and exhibited no side effects of hematologic toxicity. Not shown. Furthermore, as shown in Test Example 17, the liposome-formulated Example 1 did not exacerbate the side effects of hematologic toxicity caused by gemcitabine when administered in combination with gemcitabine, in which tumor regression was observed, and increased neutrophils. It shows the survival rate of From the above, Example 1 formulated into a liposome formulation is an excellent compound having both high safety and efficacy, and has exceptional effects.

Test example 18. Drug efficacy evaluation test regarding combination administration order using tumor-bearing mice transplanted with ES-2 cells The antitumor effect was evaluated using the liposome preparation containing Example 1 and gemcitabine.

Gemcitabine (Gemzar injection 200 mg, Eli Lilly Japan) was dissolved in physiological saline (Otsuka saline injection, Otsuka Pharmaceutical Factory).

A liposome formulation containing Example 1 was prepared as follows.
11.08 g of Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.) and 200 mL of a 250 mM ammonium sulfate solution were mixed and dispersed with a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 81 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the aqueous phase outside the liposomes was replaced with 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), By filtering through a 0.22 μm membrane filter, an empty liposome solution with a total lipid concentration of 53.1 mg/mL was obtained. 60 mg of the compound of Example 1, 9.16 mL of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), and 20.8 mL of the above empty liposome solution were added, and the pH was adjusted to 6.5. This liquid was heated in a 50°C water bath for 30 minutes, cooled on ice, and filtered through a 0.22 μm membrane filter. The compound concentration in the liposome solution of Example 1 was 2.08 mg/mL, and the encapsulation rate was 98%.

The compound concentration and encapsulation rate in the liposome solution were calculated as follows.
Unencapsulated compound concentration: Mix 100 μL of liposome solution, 100 μL of 4% phosphoric acid aqueous solution, and 300 μL of physiological saline, centrifuge at 100,000 x g for 60 minutes to remove insoluble matter, and measure the compound concentration of the supernatant by HPLC. did.

Compound concentration in liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC.
The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution

Ovarian cancer ES-2 cells (ATCC) were injected into 4- to 7-week-old BALB/c-nu/nu mice (CAnN.Cg-Foxn1nu/CrlCrlj, female, Charles River, Japan) at 1×10 ⁶ cells/mouse. It was implanted intradermally around the ventral region. After confirming the engraftment of ES-2 cells 5 to 14 days after transplantation, a single intravenous administration and a single intraperitoneal administration of the liposome preparation and gemcitabine were administered at a dose of 4.5 mg/kg and 30 mg/kg, respectively. The tumor volume is measured over time from the start of administration, and the tumor volume reduction effect due to compound administration is evaluated. The tumor volume was calculated by the following formula using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo).

Tumor volume [mm ³ ] = 0.5 x (breadth axis [mm]) ² x long axis [mm]

A control group in which only the solvent was administered and a group in which the compound of the present disclosure was administered were compared, T/C was calculated using the following formula, and the antitumor effect was evaluated. In addition, the percentage of individuals with complete tumor regression (CR) at the end of treatment with liposome preparations, gemcitabine, or combination administration was described. Empty liposome solution was used for the control administration group.

T/C (%) = (Tumor volume at the end of administration of the compound administration group of the present disclosure - Tumor volume at the start of administration of the compound administration group of the present disclosure) / (Tumor volume at the end of administration of the control administration group - Control Tumor volume at the start of administration in the administration group) x 100

Table 27 shows the T/C (%) and CR individual rate for tumor-bearing mice transplanted with ES-2 cells at each dose and administration period of the test compound.

In a combination drug efficacy evaluation test using tumor-bearing mice, it was revealed that Example 1 formulated into liposomes exhibited excellent antitumor effects when used in combination with gemcitabine. As shown in Test Example 18, the antitumor effect of the combination of liposome formulation Example 1 and gemcitabine was most effective when the liposome formulation of Example 1 was administered the day after gemcitabine administration, followed by It was shown that simultaneous administration or administration of gemcitabine on the day after administration of the liposome preparation of Example 1 was highly effective. From the results of this test, Example 1 is a promising compound that exhibits excellent antitumor effects and has exceptional effects.

Test example 19. Combination drug efficacy evaluation test using tumor-bearing mice transplanted with MC38 cells The antitumor effect was evaluated using a liposome preparation containing Example 1 and an anti-PD-1 antibody.

Anti-PD-1 antibody (114116, Biolegend) was used diluted with PBS (Invitrogen).

A liposome formulation was prepared in the same manner as in Test Example 6. The test compound was weighed out, an empty liposome solution with a total lipid concentration of 50 mM was added so that the compound concentration was 2 mg/mL, and the pH was adjusted to 6 to 7 by adding 1 mol/L hydrochloric acid. Alternatively, add 10mM L-histidine buffer/10% sucrose solution (pH 6.5) and hydrochloric acid to the test compound to dissolve or disperse the compound, and prepare an empty liposome solution with a total lipid concentration of 75mM so that the compound concentration is 2mg/mL. was added to adjust the pH to 6-7. This solution was heated in a 65°C water bath for 10 to 30 minutes and then cooled on ice. After standing in a refrigerator at 5° C. for at least one night, it was filtered with a 0.22 μm membrane filter. The liposome encapsulation rate calculated by the method described in Test Example 6 was 99% or more.

Mouse colon cancer MC38 cells (Kerafast) were injected around the ventral region of 4- to 7-week-old c57BL/6J mice (C57BL/6J, female, Charles River, Japan) at 5×10 ⁵ cells/mouse. It was implanted intradermally. After confirming the engraftment of MC38 cells 5 to 14 days after transplantation, administer intravenously once a week at a dose of 10 mg/kg of liposome preparation, 200 μg/head of anti-PD-1 antibody, or a combination thereof, or for 1 week. The drug was administered intraperitoneally twice or in combination. The tumor volume is measured over time from the start of administration, and the tumor volume reduction effect due to compound administration is evaluated. The tumor volume was calculated by the following formula using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo).

Tumor volume [mm ³ ] = 0.5 x (breadth axis [mm]) ² x long axis [mm]

A control group in which only the solvent was administered and a group in which the compound of the present disclosure was administered were compared, T/C was calculated using the following formula, and the antitumor effect was evaluated. In addition, the rate of complete tumor regression (CR) at the end of administration of the liposome preparation, anti-PD-1 antibody, or combination administration was described. For the control administration group, an empty liposome solution prepared in the same manner as in Test Example 6 was used.

T/C (%) = (Tumor volume at the end of administration of the compound administration group of the present disclosure - Tumor volume at the start of administration of the compound administration group of the present disclosure) / (Tumor volume at the end of administration of the control administration group - Control Tumor volume at the start of administration in the administration group) x 100

Table 28 shows the T/C (%) and CR individual rate for tumor-bearing mice transplanted with MC38 cells at each dose and administration period of the test compound.

In a combination drug efficacy evaluation test using tumor-bearing mice, liposome formulation Example 1 was found to exhibit excellent antitumor effects when used in combination with liposome formulation Example 1 and anti-PD-1 antibody. It became clear. As shown in Test Example 19, tumor-bearing mice to which MC38 cells were transplanted are a model in which anti-PD-1 antibodies exhibit antitumor effects. From the results of this test, Example 1 is a promising compound that exhibits excellent antitumor effects in a model in which anti-PD-1 antibodies exhibit antitumor effects, and has exceptional effects.

Test example 20. Combination drug efficacy evaluation test using tumor-bearing mice transplanted with EMT6 cells The antitumor effect was evaluated using a liposome preparation encapsulating Example 1 and an anti-PD-1 antibody.

Anti-PD-1 antibody (114116, Biolegend) was used diluted with PBS (Invitrogen).

A liposome formulation containing Example 1 was prepared as follows.
11.08 g of Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.) and 200 mL of a 250 mM ammonium sulfate solution were mixed and dispersed with a homogenizer (ULTRA-TURRAX, manufactured by IKA) to obtain a crude liposome dispersion. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Nano-Mizer NM2, manufactured by Yoshida Kikai Kogyo) at a pressure of 100 MPa to obtain liposomes with an average particle size (Z-average) of 81 nm. Using a dialysis cassette (Slide-A-Lyzer G2 Dialysis Cassettes 20K MWCO, manufactured by Thermo Scientific), the aqueous phase outside the liposomes was replaced with 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), By filtering through a 0.22 μm membrane filter, an empty liposome solution with a total lipid concentration of 53.1 mg/mL was obtained. 60 mg of the compound of Example 1, 9.16 mL of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), and 20.8 mL of the above empty liposome solution were added, and the pH was adjusted to 6.5. This liquid was heated in a 50°C water bath for 30 minutes, cooled on ice, and filtered through a 0.22 μm membrane filter. The compound concentration in the liposome solution of Example 1 was 2.08 mg/mL, and the encapsulation rate was 98%.

The compound concentration and encapsulation rate in the liposome solution were calculated as follows.
Unencapsulated compound concentration: Mix 100 μL of liposome solution, 100 μL of 4% phosphoric acid aqueous solution, and 300 μL of physiological saline, centrifuge at 100,000 x g for 60 minutes to remove insoluble matter, and measure the compound concentration of the supernatant by HPLC. did.

Compound concentration in liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC.
The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A/B (min): 95/5 (0) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution

Mouse breast cancer EMT6 cells (ATCC) were implanted intradermally around the ventral region of 4-7 week old BALB/c mice (BALB/cAnNCrlCrlj, female, Charles River, Japan) at 5 x 10 ⁵ cells/mouse. did. After confirming the engraftment of EMT6 cells 5 to 14 days after transplantation, administer intravenously once a week at 10 mg/kg of liposome preparation, 200 μg/head of anti-PD-1 antibody, or a combination thereof, or for 1 week. The drug was administered intraperitoneally twice or in combination. The tumor volume is measured over time from the start of administration, and the tumor volume reduction effect due to compound administration is evaluated. The tumor volume was calculated by the following formula using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo).

Tumor volume [mm ³ ] = 0.5 x (breadth axis [mm]) ² x long axis [mm]

A control group in which only the solvent was administered and a group in which the compound of the present disclosure was administered were compared, T/C was calculated using the following formula, and the antitumor effect was evaluated. In addition, the rate of complete tumor regression (CR) at the end of administration of the liposome preparation, anti-PD-1 antibody, or combination administration was described. Empty liposome solution was used for the control administration group.

T/C (%) = (Tumor volume at the end of administration of the compound administration group of the present disclosure - Tumor volume at the start of administration of the compound administration group of the present disclosure) / (Tumor volume at the end of administration of the control administration group - Control Tumor volume at the start of administration in the administration group) x 100

Table 29 shows the T/C (%) and CR individual rate for tumor-bearing mice transplanted with EMT6 cells at each dose and administration period of the test compound.

In a combination drug efficacy evaluation test using tumor-bearing mice, liposome formulation Example 1 was found to exhibit excellent antitumor effects when used in combination with liposome formulation Example 1 and anti-PD-1 antibody. It became clear. As shown in Test Example 20, tumor-bearing mice to which EMT6 cells were transplanted are a model in which anti-PD-1 antibodies do not exhibit antitumor effects. From the results of this test, Example 1 showed excellent antitumor effects when used in combination with Example 1 formulated into liposomes and anti-PD-1 antibodies against a model in which anti-PD-1 antibodies did not show antitumor effects. It is a promising compound with exceptional effects.

Test example 21. Drug efficacy evaluation test regarding combination administration order using tumor-bearing mice transplanted with EMT6 cells The antitumor effect was evaluated using the liposome preparation containing Example 1 and the anti-PD-1 antibody.

Anti-PD-1 antibody (114116, Biolegend) was used diluted with PBS (Invitrogen).

A liposome formulation containing Example 1 was prepared as follows.
Weighed 498.2 g of Presome ACD-1 (manufactured by Nippon Fine Chemical Co., Ltd.), added 8772 g of 250 mM ammonium sulfate solution, dispersed with a homogenizer (CLEARMIX, manufactured by M TECHNIQUE), and defoamed by vacuum degassing. A crude liposome dispersion was obtained. Furthermore, the crude liposome dispersion was dispersed using a high-pressure homogenizer (Microfluidizer M-110 EH-30, manufactured by Microfluidics) at a pressure of 14,500 Psi to obtain liposomes with an average particle size (Z-average) of 73 nm. Using a Tangential Flow Filtration system equipped with five Pellicon cassettes (Pellicon 2 Mini 300kD 0.1m2, manufactured by Merck & Co., Ltd.), the liposome external aqueous phase was replaced with water for injection, and then 10mM L-histidine/9.4% sucrose was added. Add L-histidine and sucrose to form a solution, adjust the pH to 6.5 using 1 mol/L hydrochloric acid, and filter through a 0.2 μm membrane filter to obtain an empty solution with a total lipid concentration of 50.2 mg/mL. A liposome solution was obtained.

10.0 g of the compound of Example 1 was weighed out, and 1354 g of 10 mM L-histidine buffer/9.4% sucrose solution (pH 6.5), 27 g of 1 mol/L hydrochloric acid, and 3786 g of the above empty liposome solution were added to give 1 mol/L of the compound. The pH was adjusted to 6.5 with L-hydrochloric acid. After heating at 45° C. for 60 minutes, the mixture was cooled, adjusted to pH 6.5, and filtered through a 0.2 μm membrane filter. This liquid was dispensed into glass vials in an amount of 50 mL each, which was capped and sealed. The concentration of the compound of Example 1 in the liposome solution was 2.01 mg/mL, the encapsulation rate was 97.5%, and the average particle size (Z-average) was 74 nm.

The compound concentration and encapsulation rate in the liposome solution were calculated as follows.
Unencapsulated compound concentration: Mix 100 μL of liposome solution, 100 μL of 4% phosphoric acid aqueous solution, and 300 μL of physiological saline, centrifuge at 100,000 x g for 60 minutes to remove insoluble matter, and measure the compound concentration of the supernatant by HPLC. did.
Compound concentration in liposome solution: The liposome solution was diluted with a trifluoroacetic acid/water/methanol mixture (0.1/25/75) and centrifuged at 15,000 x g for 10 minutes at 4°C to remove insoluble matter. Compound concentration in the supernatant was determined by HPLC.
The HPLC measurement conditions are as follows.
HPLC conditions
Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm
Column temperature: 40℃
Mobile phase: A: 0.1% trifluoroacetic acid-containing water B: Acetonitrile A/B (min): 95/5 (0) → 60/40 (3) → 0/100 (3.5) → 0/100 (4) → 95/5 (4.01) → 95/5 (5)
Flow rate: 0.8mL/min
Detection: UV-visible detector Measurement wavelength 254nm
Injection volume: 5μL
The encapsulation rate was calculated using the formula below.
Encapsulation rate (%) = (Compound concentration in liposome solution - Unencapsulated compound concentration) x 100/Compound concentration in liposome solution

Mouse breast cancer EMT6 cells (ATCC) were intradermally implanted around the ventral region of a 5-week-old BALB/c mouse (BALB/cAnNCrlCrlj, female, Charles River, Japan) at 5×10 ⁵ cells/mouse. After confirming the engraftment of EMT6 cells 5 days after transplantation, the liposome preparation was administered at a dose of 6 mg/kg and the anti-PD-1 antibody at a dose of 200 μg/head once a week intravenously and once a week intraperitoneally. The tumor volume is measured over time from the start of administration, and the tumor volume reduction effect due to compound administration is evaluated. The tumor volume was calculated by the following formula using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo).

Tumor volume [mm ³ ] = 0.5 x (breadth axis [mm]) ² x long axis [mm]

A control group in which only the solvent was administered and a group in which the compound of the present disclosure was administered were compared, T/C was calculated using the following formula, and the antitumor effect was evaluated. Additionally, the rate of complete tumor regression (CR) at the end of administration with the liposome preparation and anti-PD-1 antibody was described. Empty liposome solution was used for the control administration group.

T/C (%) = (Tumor volume at the end of administration of the compound administration group of the present disclosure - Tumor volume at the start of administration of the compound administration group of the present disclosure) / (Tumor volume at the end of administration of the control administration group - Control Tumor volume at the start of administration in the administration group) x 100

Table 30 shows the T/C (%) and CR individual rate for tumor-bearing mice transplanted with EMT6 cells at each dose and administration period of the test compound.

In a combination drug efficacy evaluation test using tumor-bearing mice, it was revealed that Example 1, which was formulated into a liposome, exhibited excellent antitumor effects when used in combination with an anti-PD-1 antibody. As shown in Test Example 21, the antitumor effect of the combination of liposome-formulated Example 1 and anti-PD-1 antibody was strongest when administered simultaneously, followed by anti-PD-1 antibody after administration of the liposome preparation of Example 1. It was shown that the combination order of administering one antibody was strong. From the results of this test, Example 1 is a promising compound that exhibits excellent antitumor effects and has exceptional effects.

Test example 22. Kinase selectivity test HotSpot Full Panel Kinase profiling (Reaction Biology) was used to evaluate the selectivity of plexasertib, Example 1, and Example 3 against 370 wild-type kinases.

Buffer: 20mM HEPES, pH 7.5, 10mM _MgCl2 , 2mM _MnCl2 (as needed), 1mM EGTA, 0.02% Brij35, 0.02mg/mL BSA, _{0.1mM Na3VO4} , 2mM DTT ,1% DMSO
ATP concentration: 10μM
Reaction time: 2 hours ATP conversion rate in 2 hours: 5-20%
Compound concentration: 100nM

Tables 31 to 33 show the name of the kinase and the residual activity (%) at 100 nM for prexasertib, Example 1 and Example 3, for the kinases whose residual activity was less than 25% at 100 nM among 370 wild-type kinases. ) is shown.

As shown in the table above, the compounds of Examples 1 and 3 showed higher CHK1 selectivity than prexasertib. Among them, Example 1 had an exceptional effect of selectively inhibiting CHK1 activity, and thus exhibited an excellent antitumor effect due to CHK1 inhibition while avoiding the toxicity caused by non-selective kinase inhibition. .

Test example 23. CHK1/CHK2 selectivity test The test substance was dissolved in dimethylsulfoxide (DMSO) and further diluted with DMSO to prepare a solution with a concentration 100 times the test concentration. The solution was further diluted 25 times with assay buffer to obtain a test substance solution. A positive control substance solution was prepared in the same manner as above. A 4-fold concentrated test substance solution was prepared in assay buffer (20mM HEPES, 0.01% Triton X-100, 1mM DTT, pH 7.5). A 4x substrate/ATP/metal solution was prepared in kit buffer (20mM HEPES, 0.01% Triton X-100, 5mM DTT, pH 7.5). A double concentration kinase solution was prepared in assay buffer. 5 μL of 4-times concentration test substance solution, 5 μL of 4-times concentration substrate/ATP/metal solution, and 10 μL of 2-times concentration kinase solution were mixed in the wells of a 384-well polypropylene plate, and reacted for 1 hour at room temperature. The reaction was stopped by adding 70 μL of Termination Buffer (QuickScout Screening Assist MSA; Carna Biosciences). The substrate peptide and phosphorylated peptide in the reaction solution were separated and quantified using a LabChip ^™ system (Perkin Elmer). The kinase reaction was evaluated using the product ratio (P/(P+S)) calculated from the substrate peptide peak height (S) and the phosphorylated peptide peak height (P). The average signal of control wells containing all reaction components was defined as 0% Inhibition, and the average signal of background wells (no enzyme added) was defined as 100% Inhibition, and the inhibition rate was calculated from the average signal of each test substance test well. The IC ₅₀ value was determined by approximating a plot of test substance concentration and inhibition rate to a four-parameter logistic curve using the nonlinear least squares method.

Table 34 shows the _IC50 values for CHK1 and CHK2 for prexasertib and Example 1.

As shown in the table above, the compound of Example 1 showed higher CHK1 selectivity compared to prexasertib. From this, Example 1 exhibited excellent antitumor effects due to CHK1 inhibition while avoiding toxicity due to CHK2 inhibition.

From the results of Test Examples 1 to 13, the compound of the present invention exhibited high CHK1 inhibitory activity (Test Example 1) and high cancer cell proliferation inhibitory effect (Test Example 2). Furthermore, the compound of the present invention has the characteristic of having a low risk of cardiotoxicity (Test Example 3) and has the characteristic of being efficiently encapsulated in liposomes (Test Examples 6, 6A, and 6B).

The present inventors newly discovered the problem that prexasertib has a concern about hepatotoxicity, and in particular, the compound represented by formula (3) (a pyridine derivative having a nitrogen atom at a specific position) overcomes this problem, It was found that it has high safety (Test Example 4). In addition, the compound represented by formula (3) in particular has excellent pharmacokinetics (Test Example 7).

The compound of Example 1, which is a representative compound contained in formula (3), has a CHK1 inhibitory activity that is more than 5 times higher than that of prexasertib (Test Example 1), and has an exceptional effect showing a strong cell proliferation inhibitory effect. (Test Example 2). In addition, the compound of Example 1 has extremely low cardiotoxicity compared to prexasertib (Test Example 3). It was found that prexasertib does not show any concerns about hepatotoxicity, which is a new issue with prexasertib (Test Example 4), and has a unique effect in which the risk of hematotoxicity is significantly reduced compared to prexasertib (Test Example 5, and Test Example 10). Furthermore, the compound of Example 1 exhibits good pharmacokinetics (Test Example 7), is efficiently encapsulated in liposomes, and exhibits good liposome encapsulation operability (Test Examples 6, 6A, and 6B).

Furthermore, the liposome-formulated compound of Example 1 has an exceptional effect showing excellent antitumor effects in vitro and in vivo, and at the same time has a heterogeneous effect with high safety (Test Example 8, Test Example 9, Test Example 11 to Test Example 14). The combination of existing anticancer drugs and the compound of Example 1 has the characteristics of having both extremely excellent antitumor effects and high safety (Test Examples 15 to 21). In addition, the compound of Example 1 has an exceptional effect of selectively inhibiting CHK1 compared to prexasertib, and thus exhibits excellent anti-CHK1 inhibition while avoiding toxicity due to non-selective kinase inhibition. Demonstrates tumor effect (Test Examples 22 to 23).

From the above, the compound of Example 1 has an exceptional effect with high efficacy compared to prexasertib, and at the same time has a different effect that shows high safety, so it has unpredictable effects. Furthermore, the liposome preparation of Example 1 is an excellent drug that has excellent blood retention, antitumor effects, and high safety, and has unexpected effects.

The present disclosure relates to a CHK1 inhibitor, and relates to an antitumor agent that has high therapeutic effects while reducing side effects. As a result of intensive studies, the present inventors found that the compound represented by formula (1) has a strong inhibitory effect on CHK1 and has an excellent antitumor effect. Among them, it was confirmed that a series of compounds having a pyridine ring having a nitrogen atom at a specific position represented by formula (3) exhibited special and unique effects, and the present invention was completed.

Specifically, the present inventors created compounds according to Examples 1 to 38, and a series of compounds exhibited extremely high CHK1 inhibitory activity (Test Example 1) and high cancer cytotoxicity (Test Example 1). Example 2). Since hERG inhibition is weak, it has a unique effect with high safety (Test Example 3). Furthermore, the present inventors found that prexasertib has the problem of hepatotoxicity, and the compound of the present invention found a unique effect that overcomes this problem (Test Example 4). Among them, "a compound represented by formula (3) having a pyridine ring in which a nitrogen atom is present at a specific substitution position" represented by Example 1 etc. had extremely special and unique effects.

Compounds such as Example 1 represented by formula (3), unlike prexasertib, do not inhibit human bone marrow cell colony formation, exhibit high safety in terms of blood toxicity (Test Example 5), and have extremely high liposome encapsulation efficiency. , showed good liposome encapsulation operability (Test Examples 6, 6A, 6B), and showed high blood retention due to liposome formulation (Test Example 7). Although the liposome preparation has a tumor regression effect that cannot be achieved with prexasertib in a cancer-bearing model (Test Example 8), it has extremely high safety (Test Examples 9 and 10). Example 1 itself has an excellent pharmacokinetic and pharmacodynamic profile (Test Example 11), and its liposome formulation shows an effect of prolonging survival time that cannot be achieved with prexasertib (Test Examples 12 and 13). It showed efficacy against a wide variety of cancers (Test Examples 14 and 14A). When the liposome formulation of Example 1 was used in combination with various anticancer drugs (cisplatin, gemcitabine, or PD-1 antibody), exceptional effects were shown (Test Example 15-21). In addition, the compound of Example 1 has an exceptional effect of selectively suppressing CHK1 activity compared to prexasertib, and therefore, the compound of Example 1 has an excellent effect of inhibiting CHK1 while avoiding the toxicity caused by non-selective kinase inhibition. Shows antitumor effects (Test Examples 22-23).

As described above, although the present disclosure has been illustrated using the preferred embodiments thereof, it is understood that the scope of the present disclosure should be interpreted only by the claims. This application claims priority to Japanese Patent Application No. 2022-87171 (filed on May 27, 2022), the entire content of which is incorporated herein by reference. The patents, patent applications, and publications cited herein are hereby incorporated by reference to the same extent as if the contents were specifically set forth herein. be understood.

Compounds of the present disclosure potently inhibit Checkpoint Kinase 1 (CHK1). These liposome preparations achieve sustained drug exposure due to their sustained release effect, and thus exhibit strong antitumor effects based on the inhibitory effect of CHK1. Therefore, the compounds of the present disclosure, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and liposome preparations containing them are useful as therapeutic or preventive agents for pathological conditions involving CHK1.

Claims (89)

[In the formula,
R ¹ is a hydrogen atom, an optionally substituted C _1-6 alkyl, an optionally substituted C _3-10 cycloalkyl, an optionally substituted 3- to 10-membered saturated heterocyclic group, a substituted represents an optionally substituted C _6-10 aryl, or an optionally substituted 5- to 12-membered heteroaryl,
R ² is a hydrogen atom, a halogen atom, cyano, nitro, carboxyl, sulfonic acid, phosphoric acid, -OR ³ , -SR ³ , -COR ⁴ , -CO ₂ R ⁴ , -CONR ⁵ R ⁶ , -SO ₂ R ⁴ , -SO ₂ NR ⁵ R ⁶ , -OCOR ⁴ , -OCO ₂ R ⁴ , -OCONR ⁵ R ⁶ , -NR ⁵ R ⁶ , -NR ⁷ COR ⁴ , -NR ⁷ CO ₂ R ⁴ , -NR ⁷ CONR ⁵ R ⁶ , -NR ⁷ SO ₂ R ⁴ , -NR ⁷ SO ₂ NR ⁵ R ⁶ , optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, substituted optionally substituted C _2-6 alkynyl, optionally substituted C _3-10 cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C _6-10 aryl, or represents an optionally substituted 5- to 12-membered heteroaryl,
R ³ represents a hydrogen atom or C _1-6 alkyl,
R ⁴ represents C _1-6 alkyl,
R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom or C _1-6 alkyl, where R ⁵ and R ⁶ bonded to the same nitrogen atom are both C _1-6 alkyl. When these are combined with the nitrogen atoms to which they are bonded, they may form a 3- to 8-membered nitrogen-containing saturated heterocycle,
X, Y and Z each independently represent CR ⁸ or a nitrogen atom, where X, Y and Z are not CR ⁸ at the same time;
If there is more than one R ⁸ , each independently represents a hydrogen atom, a halogen atom, cyano, nitro, carboxyl, sulfonic acid, phosphoric acid, -OR ⁹ , -SR ⁹ , -COR ¹⁰ , -CO ₂ R ¹⁰ , - CONR ¹¹ R ¹² , -SO ₂ R ¹⁰ , -SO ₂ NR ¹¹ R ¹² , -OCOR ¹⁰ , -OCO ₂ R ¹⁰ , -OCONR ¹¹ R ¹² , -NR ¹¹ R ¹² , -NR ¹³ COR ¹⁰ , -NR ¹³ CO ₂ R ¹⁰ , -NR ¹³ CONR ¹¹ R ¹² , -NR ¹³ SO ₂ R ¹⁰ , -NR ¹³ SO ₂ NR ¹¹ R ¹² , optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-10 cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, substituted represents an optional C _6-10 aryl, or an optionally substituted 5- to 12-membered heteroaryl,
R ⁹ represents a hydrogen atom or C _1-6 alkyl,
R ¹⁰ represents C _1-6 alkyl,
R ¹¹ , R ¹² and R ¹³ each independently represent a hydrogen atom or C _1-6 alkyl, where R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl; , these may form a 3- to 8-membered nitrogen-containing saturated heterocycle together with the nitrogen atom to which they are bonded,
L represents a single bond or optionally substituted C _1-6 alkylene,
V represents a single bond, an optionally substituted C _3-10 cycloalkylene, or an optionally substituted 3- to 10-membered divalent saturated heterocyclic group,
W represents a single bond or optionally substituted C _1-6 alkylene,
Q represents a hydrogen atom or NHR ¹⁴ ,
R ¹⁴ represents a hydrogen atom, an optionally substituted C _1-6 alkyl, an optionally substituted C _3-10 cycloalkyl, or an optionally substituted 3- to 10-membered saturated heterocyclic group ], represented by
A medicament containing a compound or a pharmaceutically acceptable salt thereof. R ¹ , R ² , R ⁸ , R ¹⁴ , L, V, and W, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-10 cycloalkyl, optionally substituted 3- to 10-membered saturated heterocyclic group, optionally substituted C _6-10 aryl, substituted optionally substituted 5- to 12-membered heteroaryl, optionally substituted C _1-6 alkylene, optionally substituted C _3-10 cycloalkylene, or optionally substituted 3- to 10-membered divalent saturated Each of the heterocyclic groups independently includes (1) a halogen atom,
(2) hydroxyl group,
(3) C _6-10 aryl,
(4) 5-12 membered heteroaryl,
(5) C _1-6 alkyl,
(6) C _2-6 alkenyl,
(7) C _2-6 alkynyl,
(8) C _1-6 alkoxy,
(9) C _1-6 alkylthio (10) C _3-10 cycloalkyl,
(11) 3- to 10-membered saturated heterocyclic group,
(12) carboxyl,
(13)-COR ¹⁵ ,
(14)-CO ₂ R ¹⁵ ,
(15)-CONR ¹⁶ R ¹⁷ ,
(16)-NR ¹⁶ R ¹⁷ ,
(17)-NR ¹⁸ COR ¹⁵ ,
(18)-NR ¹⁸ CO ₂ R ¹⁵ ,
(19)-NR ¹⁸ SO ₂ R ¹⁵ ,
(20)-NR ¹⁸ CONR ¹⁶ R ¹⁷ ,
(21)-NR ¹⁸ SO ₂ NR ¹⁶ R ¹⁷ ,
(22)-SO ₂ R ¹⁵ ,
(23)-SO ₂ NR ¹⁶ R ¹⁷ ,
(24)-OCOR ¹⁵ ,
(25)-OCO ₂ R ¹⁵ ,
(26)-OCONR ¹⁶ R ¹⁷ ,
(27) sulfonic acid,
(28) phosphoric acid,
(29) cyano, and (30) may be substituted with 1 to 5 different substituents selected from the group consisting of nitro;
Here, the above (3) C _6-10 aryl, (4) 5-12 membered heteroaryl, (5) C _1-6 alkyl, (6) C _2-6 alkenyl, (7) C _2-6 alkynyl , (8) C _1-6 alkoxy, (9) C _1-6 alkylthio, (9) C _3-10 cycloalkyl, and (10) 3- to 10-membered saturated heterocyclic group,
(a) halogen atom,
(b) hydroxyl group,
(c) C _6-10 aryl,
(d) 5-12 membered heteroaryl,
(e) C _1-6 alkyl,
(f) C _2-6 alkenyl,
(g) C _2-6 alkynyl,
(h) C _1-6 alkoxy,
(i) C _3-10 cycloalkyl,
(j) 3- to 10-membered saturated heterocyclic group,
(k) carboxyl,
(l)-COR ¹⁵ ,
(m)-CO ₂ R ¹⁵ ,
(n)-CONR ¹⁶ R ¹⁷ ,
(o)-NR ¹⁶ R ¹⁷ ,
(p)-NR ¹⁸ COR ¹⁵ ,
(q)-NR ¹⁸ SO ₂ R ¹⁵ ,
(r)-SO ₂ R ¹⁵ ,
(s)-SO ₂ NR ¹⁶ R ¹⁷ ,
(t) sulfonic acid,
(u) phosphoric acid,
(v) cyano, and (w) nitro, which may be substituted with 1 to 5 same or different substituents;
When there are multiple R ^15s , each independently represents C _1-6 alkyl;
R ¹⁶ and R ¹⁷ are each independently a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ¹⁶ or R ¹⁷ , each of R ¹⁶ or R ¹⁷ may be the same or different; In, when R ¹⁶ and R ¹⁷ bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 8-membered nitrogen-containing saturated heterocycle. It is okay to do
R ¹⁸ is a hydrogen atom or C _1-6 alkyl,
A medicament containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof. R ¹ is a hydrogen atom or C _1-6 alkyl optionally substituted with 1 to 3 fluorine atoms,
A medicament containing the compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof. R ¹ is a methyl group,
A medicament containing the compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. R ² is a hydrogen atom, a halogen atom, cyano, -OR ³ , C _1-6 alkyl, C _3-10 cycloalkyl, or a 3- to 10-membered saturated heterocyclic group,
A medicament containing the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof. R ² is cyano,
A medicament containing the compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. When there is more than one R ⁸ , each independently represents a hydrogen atom, a halogen atom, cyano, -OR ⁹ , -CO ₂ R ¹⁰ , -CONR ¹¹ R ¹² , -NR ¹¹ R ¹² , -NR ¹³ COR ¹⁰ , C _1-6 alkyl (the alkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- to 6-membered heteroaryl, a C _1-6 alkoxy, a C _3-7 cycloalkyl, a 3- to 7-membered saturated hetero cyclic group, -CONR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , and cyano), C _3-10 cycloalkyl (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of The cycloalkyl is a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, phenyl, a 5- to 6-membered heteroaryl, a C _1-6 alkyl, a C _1-6 alkoxy, a C _3-7 cycloalkyl, a 3- to 7-membered a saturated heterocyclic group, a 3- ^{to 10 - membered} Saturated heterocyclic group (Saturated heterocyclic group includes fluorine atom, chlorine atom, bromine atom, hydroxyl group, phenyl, 5- to 6-membered heteroaryl, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cyclo Optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl, 3- to 7-membered saturated heterocyclic group, -CONR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , and cyano ), phenyl (the phenyl is a fluorine atom, chlorine atom, bromine atom, hydroxyl group, phenyl, 5- to 6-membered heteroaryl, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, 3- to a 7-membered saturated heterocyclic group, -CONR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , and cyano (optionally substituted with 1 to 3 substituents that are the same or different), or 5 ~6-membered heteroaryl (the heteroaryl includes fluorine atom, chlorine atom, bromine atom, hydroxyl group, phenyl, 5-6 membered heteroaryl, C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cyclo Optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl, 3- to 7-membered saturated heterocyclic group, -CONR ¹⁶ R ¹⁷ , -NR ¹⁶ R ¹⁷ , and cyano ) is,
A medicament containing the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. L is
A single bond, or C _1-6 alkylene (the alkylene is the same or different 1 to 3 substituents selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) A medicament containing the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, which is optionally substituted with . V is
single bond,
C _3-10 cycloalkylene (the cycloalkylene is the same or different 1-3 selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group may be substituted with a fluorine atom, a hydroxyl group, 1 to 2 hydroxyl groups, or a fluorine atom) optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano). be,
A medicament containing the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof. W is
A single bond, or C _1-6 alkylene (the alkylene is the same or different 1 to 3 substituents selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ), which may be replaced with
A medicament containing the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. ^R14 is
hydrogen atom,
C _1-6 alkyl (the alkyl is substituted with the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ),
C _3-10 cycloalkyl (the cycloalkyl is the same or different 1 to 3 selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ), or a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group includes a fluorine atom, a hydroxyl group, a C _1-3 alkyl, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ and cyano), which may be substituted with 1 to 3 same or different substituents selected from the group consisting of
A medicament containing the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. Formula (1) becomes the following formula (2):

[In the formula,
X, Y and Z each independently represent CR ⁸ or a nitrogen atom, where X, Y and Z are not CR ⁸ at the same time;
If there are multiple ^R8s , each independently,
hydrogen atom,
fluorine atom,
chlorine atom,
bromine atom,
C _1-6 alkyl (the alkyl is substituted with the same or different 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ), or a 5- to 6-membered heteroaryl (the heteroaryl is selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkyl, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano); may be substituted with the same or different 1 to 2 substituents),
L is
A single bond, or C _1-6 alkylene (the alkylene is the same or different 1 to 3 substituents selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ), which may be replaced with
V is
single bond,
C _3-10 cycloalkylene (the cycloalkylene is the same or different 1-3 selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ), or a 3- to 10-membered divalent saturated heterocyclic group (the saturated heterocyclic group may be substituted with a fluorine atom, a hydroxyl group, 1 to 2 hydroxyl groups, or a fluorine atom) optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) represents,
W is
A single bond, or C _1-6 alkylene (the alkylene is the same or different 1 to 3 substituents selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ), which may be replaced with
Q represents a hydrogen atom or NHR ¹⁴ ,
^R14 is
hydrogen atom,
C _1-6 alkyl (the alkyl is substituted with the same or different 1 to 3 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ),
C _3-10 cycloalkyl (the cycloalkyl is the same or different 1 to 3 selected from the group consisting of fluorine atom, hydroxyl group, C _1-3 alkyl, C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano) ), or a 3- to 10-membered saturated heterocyclic group (the saturated heterocyclic group includes a fluorine atom, a hydroxyl group, a C _1-3 alkyl, a C _1-3 alkoxy, -NR ¹⁶ R ¹⁷ , and cyano), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of
R ¹⁶ and R ¹⁷ each independently represent a hydrogen atom or C _1-6 alkyl, and when there is a plurality of R ¹⁶ or R ¹⁷ , each of R ¹⁶ or R ¹⁷ may be the same or different, Here, when R ¹⁶ and R ¹⁷ bonded to the same nitrogen atom are both C _1-6 alkyl, these together with the nitrogen atom bonded to each form a 3- to 8-membered nitrogen-containing saturated heterocycle. may be formed],
A medicament containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof. A medicament containing the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein one or two of X, Y and Z represent a nitrogen atom. X is a nitrogen atom,
Y and Z are CR ⁸ ;
A medicament containing the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof. Y is a nitrogen atom,
X and Z are CR ⁸ ;
A medicament containing the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof. Z is a nitrogen atom,
X and Y are CR ⁸ ;
A medicament containing the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof. If there are multiple ^R8s , each independently,
hydrogen atom,
fluorine atom,
chlorine atom,
Bromine atom, or C _1-6 alkyl (the alkyl may be substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atom, hydroxyl group, and C _1-3 alkoxy) is,
A medicament containing the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof. L is a single bond or C _1-6 alkylene (the alkylene may be substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atoms, hydroxyl groups, and cyano); be,
A medicament containing the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof. V is
single bond,
C _3-7 cycloalkylene (the cycloalkylene is the same or different 1- to 7-cycloalkylene selected from the group consisting of a fluorine atom, a hydroxyl group, a C _1-3 alkyl optionally substituted with 1 to 2 hydroxyl groups, and cyano) (optionally substituted with 2 substituents), or 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is substituted with a fluorine atom, a hydroxyl group, 1-2 hydroxyl groups, or a fluorine atom) C _1-3 alkyl, which may be substituted with the same or different 1-2 substituents selected from the group consisting of cyano)
A medicament containing the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof. W is
a single bond, or C _1-6 alkylene (the alkylene may be substituted with the same or different 1 to 2 substituents selected from the group consisting of fluorine atoms, hydroxyl groups, and cyano),
A medicament containing the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof. ^R14 is
a hydrogen atom, or a C _1-6 alkyl (the alkyl may be substituted with the same or different 1 to 2 substituents selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano),
A medicament containing the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof. Q is
hydrogen atom,
NH ₂ or NHMe;
A medicament containing the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof. Formula (1) becomes the following formula (3):

[In the formula,
R ^8a and R ^8b each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C _1-3 alkyl,
L represents a single bond or C _1-6 alkylene optionally substituted with one hydroxyl group,
V is
single bond,
C _3-7 cycloalkylene (the cycloalkylene may be substituted with one substituent selected from the group consisting of a hydroxyl group and C _1-3 alkyl), or a 3- to 7-membered divalent saturated represents a heterocyclic group (the saturated heterocyclic group may be substituted with one substituent selected from the group consisting of fluorine atom, cyano, hydroxyl group, and C _1-3 alkyl),
W is
Represents a C _1-3 alkylene optionally substituted with a single bond or one hydroxyl group,
Q is a hydrogen atom or _NH2 ] A medicament containing the compound according to claim 1, or a pharmaceutically acceptable salt thereof. R ^8a and R ^8b are each independently a hydrogen atom, a fluorine atom or a chlorine atom,
A medicament containing the compound according to claim 23 or a pharmaceutically acceptable salt thereof. R ^8a and R ^8b are each independently a hydrogen atom or a chlorine atom,
A medicament containing the compound according to claim 24 or a pharmaceutically acceptable salt thereof. L is C _1-3 alkylene,
A medicament containing the compound according to any one of claims 23 to 25, or a pharmaceutically acceptable salt thereof. V is a single bond,
A medicament containing the compound according to any one of claims 23 to 26, or a pharmaceutically acceptable salt thereof. V is C _3-7 cycloalkylene,
A medicament containing the compound according to any one of claims 23 to 26, or a pharmaceutically acceptable salt thereof. W is a single bond,
A medicament containing the compound according to any one of claims 23 to 28, or a pharmaceutically acceptable salt thereof. W is C _1-3 alkylene,
A medicament containing the compound according to any one of claims 23 to 28, or a pharmaceutically acceptable salt thereof. Q is _NH2 ,
A medicament containing the compound according to any one of claims 23 to 30, or a pharmaceutically acceptable salt thereof. Formula (1) becomes the following formula (4):

[In the formula,
R ^8b and R ^8c each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C _1-3 alkyl,
L is
represents a single bond, or C _1-6 alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano),
V is
single bond,
C _3-7 cycloalkylene (the cycloalkylene may be substituted with one substituent selected from the group consisting of a hydroxyl group and C _1-3 alkyl), or a 3- to 7-membered divalent saturated Heterocyclic group (the saturated heterocyclic group is one selected from the group consisting of fluorine atom, cyano, hydroxyl group, and C _1-3 alkyl optionally substituted with 1 to 3 hydroxyl groups and fluorine atom) (optionally substituted with a substituent),
W is
Represents a C _1-3 alkylene optionally substituted with a single bond or one hydroxyl group,
Q is a hydrogen atom, NH ₂ , or NHMe] A medicament containing the compound according to item 1, or a pharmaceutically acceptable salt thereof. R ^8b and R ^8c are hydrogen atoms,
A medicament containing the compound according to claim 32 or a pharmaceutically acceptable salt thereof. L is
C _1-6 alkylene which may be substituted with a single bond or one hydroxyl group or fluorine atom,
A medicament containing the compound according to claim 32 or 33, or a pharmaceutically acceptable salt thereof. V is
single bond,
C _3-7 cycloalkylene, or a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a C _1-3 alkyl group) may be substituted),
A medicament containing the compound according to any one of claims 32 to 34, or a pharmaceutically acceptable salt thereof. W is
is a single bond or C _1-3 alkylene,
A medicament containing the compound according to any one of claims 32 to 35, or a pharmaceutically acceptable salt thereof. Q is a hydrogen atom,
A medicament containing the compound according to any one of claims 32 to 36, or a pharmaceutically acceptable salt thereof. Q is _NH2 ,
A medicament containing the compound according to any one of claims 32 to 36, or a pharmaceutically acceptable salt thereof. Q is NHMe,
A medicament containing the compound according to any one of claims 32 to 36, or a pharmaceutically acceptable salt thereof. Formula (1) becomes the following formula (5):

[In the formula,
R ^8a and R ^8c each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C _1-3 alkyl,
L represents a single bond or C _1-6 alkylene optionally substituted with one hydroxyl group,
V is
single bond,
C _3-7 cycloalkylene (the cycloalkylene may be substituted with one substituent selected from the group consisting of a hydroxyl group and C _1-3 alkyl), or a 3- to 7-membered divalent saturated Heterocyclic group (the saturated heterocyclic group is substituted with one substituent selected from the group consisting of a fluorine atom, cyano, hydroxyl group, and C _1-3 alkyl optionally substituted with one hydroxyl group) ),
W is
Represents a C _1-3 alkylene optionally substituted with a single bond or one hydroxyl group,
Q is a hydrogen atom or _NH2 . A medicament containing the compound according to claim 1, or a pharmaceutically acceptable salt thereof. R ^8a and R ^8c are hydrogen atoms,
A compound according to claim 40, or a pharmaceutically acceptable salt thereof. L is C _1-6 alkylene optionally substituted with one hydroxyl group,
A medicament containing the compound according to claim 40 or 41, or a pharmaceutically acceptable salt thereof. V is
single bond,
C _3-7 cycloalkylene or a 3- to 7-membered divalent saturated heterocyclic group (the saturated heterocyclic group is selected from the group consisting of a hydroxyl group and a C _1-3 alkyl optionally substituted with one hydroxyl group) optionally substituted with one substituent),
A medicament containing the compound according to any one of claims 40 to 42, or a pharmaceutically acceptable salt thereof. W is
is a single bond or C _1-3 alkylene,
A medicament containing the compound according to any one of claims 40 to 43, or a pharmaceutically acceptable salt thereof. Q is a hydrogen atom,
A medicament containing the compound according to any one of claims 40 to 44, or a pharmaceutically acceptable salt thereof. Q is _NH2 ,
A medicament containing the compound according to any one of claims 40 to 44, or a pharmaceutically acceptable salt thereof. Formula (1) becomes the following formula (6):

[In the formula,
R ^8a represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, or a C _1-3 alkyl,
L is
represents a single bond, or C _1-6 alkylene (the alkylene may be substituted with one substituent selected from the group consisting of a fluorine atom, a hydroxyl group, and a cyano),
V is
single bond,
C _3-7 cycloalkylene (the cycloalkylene may be substituted with one substituent selected from the group consisting of a hydroxyl group and C _1-3 alkyl), or a 3- to 7-membered divalent saturated Heterocyclic group (the saturated heterocyclic group is one substituent selected from the group consisting of fluorine atom, cyano, hydroxyl group, and C _1-3 alkyl optionally substituted with 1 to 3 fluorine atoms) ), which may be substituted with
W is
Represents a C _1-3 alkylene optionally substituted with a single bond or one hydroxyl group,
Q is a hydrogen atom, NH ₂ , or NHMe. A medicament containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof. R ^8a is a hydrogen atom,
A medicament containing the compound according to claim 47, or a pharmaceutically acceptable salt thereof. L is C _1-4 alkylene,
A medicament containing the compound according to claim 47 or 48, or a pharmaceutically acceptable salt thereof. V is
is a single bond or C _3-7 cycloalkylene,
A medicament containing the compound according to any one of claims 47 to 49, or a pharmaceutically acceptable salt thereof. W is
single bond, or
C _1-3 alkylene,
A medicament containing the compound according to any one of claims 47 to 50, or a pharmaceutically acceptable salt thereof. Q is _NH2 ,
A medicament containing the compound according to any one of claims 47 to 51, or a pharmaceutically acceptable salt thereof. The medicament according to claim 1, containing a compound selected from the following compounds or a pharmaceutically acceptable salt thereof:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-({5-[2-(3-aminopropoxy)-6-chloro-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-[(5-{3-[(3-fluoroazetidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile ,
5-[(5-{2-methoxy-4-[(3-methylazetidin-3-yl)methoxy]pyridin-3-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile ,
5-[(5-{4-[(3-hydroxyazetidin-3-yl)methoxy]-2-methoxypyridin-3-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile ,
5-{[5-(4-{[3-(hydroxymethyl)azetidin-3-yl]methoxy}-2-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2- carbonitrile,
5-[(5-{3-[(3R)-3-aminobutoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,
5-[(5-{3-[(3S)-3-aminobutoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,
5-{[5-(3-{[1-(aminomethyl)cyclopropyl]methoxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,
5-[(5-{3-methoxy-5-[(morpholin-2-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,
5-[(5-{3-methoxy-5-[(morpholin-2-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,
5-[(5-{3-[(2S)-3-amino-2-hydroxypropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile ,
N-{5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}-5-chloropyrazin-2-amine,
N-{5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}-5-(trifluoromethyl)pyrazin-2-amine,
5-({5-[4-(3-aminopropoxy)-6-methoxypyrimidin-5-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-({5-[3-(azetidin-3-yl)methoxy-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-{[5-(3-{[(1R,3S)-3-aminocyclohexyl]oxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbo nitrile,
(S)-5-[(5-{3-[(3-fluoropyrrolidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2 - carbonitrile,
(S)-5-[(5-{3-methoxy-[5-(pyrrolidin-3-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile ,
(R)-5-[(5-{3-[(3-fluoropyrrolidin-3-yl)methoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2 - carbonitrile,
5-{[5-(4-{[1-(aminomethyl)cyclopropyl]methoxy}-6-methoxypyrimidin--yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,
5-({5-[3-(3-aminopropoxy)-5-(fluoromethoxy)pyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-[(5-{3-methoxy-5-[(3-methylazetidin-3-yl)methoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile ,
5-{[5-(3-{[3-(difluoromethyl)azetidin-3-yl]methoxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2- carbonitrile,
5-[(5-{3-[(2S)-3-amino-2-methylpropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile ,
5-[(5-{3-[(2R)-3-amino-2-methylpropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile ,
5-[(5-{3-[(2S)-3-amino-2-fluoropropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile ,
5-[(5-{3-[(2R)-3-amino-2-fluoropropoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile ,
5-[(5-{3-methoxy-5-[3-(methylamino)propoxy]pyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2-carbonitrile,
5-{[5-(3-{[(1R,3R)-3-aminocyclopentyl]oxy}-5-methoxypyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbo nitrile,
5-[(5-{3-[(1R)-1-(azetidin-3-yl)ethoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino]pyrazine-2- carbonitrile,
5-[(5-{3-[(1R)-1-(3-hydroxyazetidin-3-yl)ethoxy]-5-methoxypyridin-4-yl}-1H-pyrazol-3-yl)amino] pyrazine-2-carbonitrile,
5-{[5-(3-methoxy-5-{[(1R,3R)-3-(methylamino)cyclopentyl]oxy}pyridin-4-yl)-1H-pyrazol-3-yl]amino}pyrazine- 2-carbonitrile,
5-{[5-(3-{[(1R,2S,4S,5S)-4-aminobicyclo[3.1.0]hexan-2-yl]oxy}-5-methoxypyridin-4-yl) -1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,
5-{[5-(2-{[1-(aminomethyl)cyclopropyl]methoxy}-4-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile,
5-{[5-(4-{[1-(aminomethyl)cyclopropyl]methoxy}-2-methoxypyridin-3-yl)-1H-pyrazol-3-yl]amino}pyrazine-2-carbonitrile. The medicament according to claim 1, containing a compound selected from the following compounds or a pharmaceutically acceptable salt thereof:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile,
5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile. The medicament according to claim 1, containing a compound selected from the following compounds or a pharmaceutically acceptable salt thereof:
5-({5-[4-(3-aminopropoxy)-2-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile. The medicament according to claim 1, containing the following compound or a pharmaceutically acceptable salt thereof:
5-({5-[2-(3-aminopropoxy)-4-methoxypyridin-3-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile. The medicament according to claim 1, containing the following compound or a pharmaceutically acceptable salt thereof:
5-({5-[3-(3-aminopropoxy)-5-methoxypyridin-4-yl]-1H-pyrazol-3-yl}amino)pyrazine-2-carbonitrile. A pharmaceutical composition containing the medicament according to any one of claims 1 to 57 as an active ingredient. A pharmaceutical composition containing a liposome encapsulating the medicament according to any one of claims 1 to 57. 58. The medicament according to any one of claims 1 to 57, wherein the medicament is contained in a liposome encapsulating the medicament. 61. The pharmaceutical composition according to claim 59 or the medicament according to claim 60, wherein the liposome further comprises a phospholipid. The liposome is
(1) the medicament according to any one of claims 1 to 60; and (2) a phospholipid;
The pharmaceutical composition or medicament according to any one of claims 59 to 61, comprising: The phospholipid is one selected from the group consisting of phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, soybean lecithin, egg yolk lecithin, hydrogenated egg yolk lecithin, and hydrogenated soybean lecithin. or a combination of two or more thereof, the pharmaceutical composition or medicament according to claim 61 or 62. The pharmaceutical composition or medicament according to any one of claims 59 to 63, wherein the liposome further contains a sterol. 65. The pharmaceutical composition or medicament according to claim 64, wherein the sterol is cholesterol. The pharmaceutical composition or medicament according to any one of claims 59 to 65, wherein the liposome further comprises a polymer-modified lipid. The polymer portion of the polymer-modified lipid is polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, methoxypolyethylene glycol, methoxypolypropylene glycol, methoxypolyvinyl alcohol, methoxypolyvinylpyrrolidone, ethoxypolyethylene glycol, ethoxypolypropylene glycol, ethoxypolyvinyl alcohol, ethoxy 67. The pharmaceutical composition or medicament according to claim 66, which is polyvinylpyrrolidone, propoxypolyethylene glycol, propoxypolypropylene glycol, propoxypolyvinyl alcohol, or propoxypolyvinylpyrrolidone. 68. The pharmaceutical composition or medicament according to claim 66 or 67, wherein the lipid moiety of the polymer-modified lipid is phosphatidylethanolamine or diacylglycerol. The liposome is
(1) the medicament according to any one of claims 1 to 57;
(2) 40 to 70 mol% phospholipids;
(3) 30-50 mol% cholesterol, and (4) 1-10 mol% polymer-modified lipid,
The pharmaceutical composition or medicament according to any one of claims 59 to 61, comprising: 70. The liposome of claims 59-69, wherein the liposome further comprises an additive selected from the group consisting of inorganic acids, inorganic acid salts, organic acids, organic acid salts, sugars, buffers, antioxidants, and polymers. Pharmaceutical composition or medicament according to any one of the above. A therapeutic and/or preventive agent for cancer, which contains the medicament according to any one of claims 1 to 57 as an active ingredient. The cancer is squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell tumor, multiple myeloma, brain tumor, head and neck cancer. Cancer, head and neck squamous cell carcinoma, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma/thymic cancer, breast cancer, triple negative breast cancer, stomach cancer, gallbladder/bile duct cancer, liver Cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, MSI-high colon cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, endometrial cancer, cervical cancer Ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial cancer, renal cancer, renal cell cancer, prostate cancer, testicular tumor, testis At least one type of cancer selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer. 72. The therapeutic and/or prophylactic agent according to claim 71. The cancer is from the group consisting of head and neck cancer, squamous cell carcinoma, non-small cell lung cancer, anal cancer, breast cancer, triple negative breast cancer, ovarian cancer, platinum-resistant ovarian cancer, or endometrial cancer. Item 103. The therapeutic and/or preventive agent according to item 102, which is at least one selected type of cancer. The medicament according to any one of claims 1 to 57, or the pharmaceutical composition or medicament according to claims 58 to 70, or the pharmaceutical composition or medicament according to claims 71 to 73, for use in the treatment and/or prevention of cancer. The therapeutic agent and/or prophylactic agent according to any one of the above. The cancer is squamous cell carcinoma, melanoma, acute leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, polycythemia vera, malignant lymphoma, plasma cell tumor, multiple myeloma, brain tumor, head and neck cancer. Cancer, head and neck squamous cell carcinoma, esophageal cancer, thyroid cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, thymoma/thymic cancer, breast cancer, triple negative breast cancer, stomach cancer, gallbladder/bile duct cancer, liver Cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, MSI-high colon cancer, anal cancer, gastrointestinal stromal tumor, chorioepithelial carcinoma, endometrial cancer, cervical cancer Ovarian cancer, platinum-resistant ovarian cancer, PARP inhibitor-resistant ovarian cancer, bladder cancer, urothelial cancer, renal cancer, renal cell cancer, prostate cancer, testicular tumor, testis At least one type of cancer selected from the group consisting of germ cell tumor, ovarian germ cell tumor, Wilms tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer. , the medicament or pharmaceutical composition according to any one of claims 1 to 57, or a therapeutic and/or prophylactic agent. 58. The medicament according to any one of claims 1 to 57, for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug is hormonal therapy. 58. The medicament according to any one of claims 1 to 57, which is at least one selected from the group consisting of agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of cell growth factors and their receptors. . 58. The medicament according to any one of claims 1 to 57, for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug comprises 5- FU drugs, cytarabine, doxorubicin hydrochloride, gemcitabine, methotrexate, pemetrexed, etoposide, irinotecan, topotecan, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, ionizing radiation, bevacizumab, liposomal doxorubicin, rucaparib, olaparib, niraparib, trabectedin, pazo Panib , pembrolizumab, nivolumab, ipilimumab, durvalumab, avelumab, atezolizumab, larotrectinib, entrectinib, nab-paclitaxel, erlotinib, liposomal irinotecan, leucovorin, cetuximab, eribulin, ifosfamide, dacarbazine. Item 58. The medicament according to any one of Items 1 to 57. 58. The medicament according to any one of claims 1 to 57, (a) for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof; The concomitant drug is at least one selected from the group consisting of hormone therapy agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of cell growth factors and their receptors,
(1) (a) is administered at the same time as (b);
(2) (a) is administered after administration of (b), or (3) (b) is administered after administration of (a),
The medicament according to any one of claims 1 to 57. The concomitant drug (b) is a chemotherapeutic agent or an immunotherapeutic agent,
The medicament according to claim 78. the concomitant drug (b) is gemcitabine;
The medicament according to claim 78 or 79. 81. The medicament according to claim 80, wherein the (a) compound, a pharmaceutically acceptable salt thereof, or a liposome is administered simultaneously with the (b) gemcitabine. 81. The medicament of claim 80, wherein the (a) compound, or a pharmaceutically acceptable salt thereof, or liposome is administered within about 24 to 48 hours after administration of the (b) gemcitabine. 81. The medicament of claim 80, wherein the (b) gemcitabine is administered within about 24 to 48 hours after administration of the (a) compound, or a pharmaceutically acceptable salt thereof, or liposome. the concomitant drug (b) is an anti-PD-1 antibody;
The medicament according to claim 78 or 80. 85. The medicament according to claim 84, wherein the (a) compound, its pharmaceutically acceptable salt, or liposome is administered simultaneously with the (b) anti-PD-1 antibody. 85. The anti-PD-1 antibody of claim 84, wherein the (b) anti-PD-1 antibody is administered within about 72 to 96 hours after administration of the (a) compound, or a pharmaceutically acceptable salt thereof, or liposome. Medicine. 85. The medicament according to claim 84, wherein the (a) compound, or a pharmaceutically acceptable salt thereof, or liposome is administered within about 72 to 96 hours after administration of the (b) anti-PD-1 antibody. . A pharmaceutical composition comprising the medicament according to any one of claims 1 to 57, or a pharmaceutical composition or medicament according to any one of claims 58 to 70, in combination with a concomitant drug, A pharmaceutical composition in which the concomitant drug is at least one selected from the group consisting of hormonal therapy agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of cell growth factors and their receptors. A pharmaceutical composition comprising the medicament according to any one of claims 1 to 57, or a pharmaceutical composition or medicament according to any one of claims 58 to 70, in combination with a concomitant drug, The concomitant drugs include 5-FU drugs, cytarabine, doxorubicin hydrochloride, gemcitabine, methotrexate, pemetrexed, etoposide, irinotecan, topotecan, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, ionizing radiation, bevacizumab, liposomal doxorubicin, rucaparib, At least one selected from the group consisting of olaparib, niraparib, trabectedin, pazopanib, pembrolizumab, nivolumab, ipilimumab, durvalumab, avelumab, atezolizumab, larotrectinib, entrectinib, nab-paclitaxel, erlotinib, liposomal irinotecan, leucovorin, cetuximab, eribulin, ifosfamide, dacarbazine one or more pharmaceutical compositions.

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