JPWO2019148136A5 - - Google Patents

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JPWO2019148136A5
JPWO2019148136A5 JP2020541375A JP2020541375A JPWO2019148136A5 JP WO2019148136 A5 JPWO2019148136 A5 JP WO2019148136A5 JP 2020541375 A JP2020541375 A JP 2020541375A JP 2020541375 A JP2020541375 A JP 2020541375A JP WO2019148136 A5 JPWO2019148136 A5 JP WO2019148136A5
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本発明により提供される化合物はまた、生物学的および病理学的現象におけるＧＣＮ２酵素の研究；身体組織において起こる細胞内シグナル伝達経路の研究；ならびに新たなＧＣＮ２阻害剤またはキナーゼ、シグナル伝達経路、およびサイトカインレベルの他のレギュレーターの、インビトロまたはインビボでの比較評価のために有用である。
本発明の実施形態において、例えば以下の項目が提供される。
（項目１）
式Ｉ：

Figure 2019148136000060
またはその薬学的に受容可能な塩の化合物であって、式Ｉにおいて：
環Ａは、３員～８員の飽和もしくは部分不飽和の単環式炭素環式環、フェニル、８員～１０員の二環式芳香族炭素環式環、窒素、酸素、もしくは硫黄から独立して選択される０個～４個のヘテロ原子を有する５～６員の芳香環と必要に応じて縮合し、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する、４員～８員の部分不飽和単環式複素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する７員～１２員の部分不飽和スピロ環式複素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する７員～１２員の部分不飽和二環式複素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する７員～１２員の部分不飽和架橋二環式複素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員の単環式ヘテロ芳香環、窒素、酸素、もしくは硫黄から独立して選択される１個～５個のヘテロ原子を有する８員～１０員の二環式ヘテロ芳香環、または
Ｈｅｔから選択され、ここでＨｅｔは、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～８員の飽和単環式複素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する７員～１２員の飽和スピロ環式複素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する７員～１２員の飽和二環式複素環式環、または窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する７員～１２員の飽和架橋二環式複素環式環であり；
環Ｂは、
Figure 2019148136000061
 であり；
各Ｒは独立して、水素であるか、またはＣ １～６ 脂肪族、３員～８員の飽和もしくは部分不飽和の単環式炭素環式環、フェニル、８員～１０員の二環式芳香族炭素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～８員の飽和もしくは部分不飽和の単環式複素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員の単環式ヘテロ芳香環、または窒素、酸素、もしくは硫黄から独立して選択される１個～５個のヘテロ原子を有する８員～１０員の二環式ヘテロ芳香環から選択される必要に応じて置換された基であるか；あるいは
２個のＲ基は必要に応じて一緒になって、二価Ｃ ２～４ アルキレン鎖を形成し；
２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、窒素、酸素もしくは硫黄から独立して選択される０個～４個のヘテロ原子を有する必要に応じて置換された３員～７員の飽和もしくは部分不飽和の単環式環を形成し；
各Ｒ’は独立して、水素、またはハロゲンで必要に応じて置換されたＣ １～３ 脂肪族基であり；
Ｒ １ の各々は独立して、水素、ハロゲン、－ＣＮ、－ＮＯ ２ 、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ ２ 、－Ｃ（Ｏ）ＮＲＳ（Ｏ） ２ Ｒ、－Ｃ（Ｏ）Ｎ＝Ｓ（Ｏ）Ｒ ２ 、－ＮＲ ２ 、－ＮＲＣ（Ｏ）Ｒ、－ＮＲＣ（Ｏ）ＮＲ ２ 、－ＮＲＣ（Ｏ）ＯＲ、－ＮＲＳ（Ｏ） ２ Ｒ、－ＮＲＳ（Ｏ） ２ ＮＲ ２ 、－ＯＲ、－ＯＮ（Ｒ）ＳＯ ２ Ｒ、－Ｐ（Ｏ）Ｒ ２ 、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ） ２ Ｒ、－Ｓ（Ｏ）（ＮＨ）Ｒ、－Ｓ（Ｏ） ２ Ｎ（Ｒ） ２ 、－Ｓ（ＮＨ ２ ） ２ （Ｏ）ＯＨ、－Ｎ＝Ｓ（Ｏ）Ｒ ２ 、－ＣＨ ３ 、－ＣＨ ２ ＯＨ、－ＣＨ ２ ＮＨＳＯ ２ ＣＨ ３ 、－ＣＤ ３ 、－ＣＤ ２ ＮＲＳ（Ｏ） ２ Ｒ、またはＲであるか；あるいは：
２個のＲ １ 基は必要に応じて一緒になって、＝Ｏまたは＝ＮＨを形成するか；あるいは
２個のＲ １ 基は必要に応じて一緒になって、二価Ｃ ２～４ アルキレン鎖を形成し；
Ｒ ２ の各々は独立して、水素、ハロゲン、－ＣＮ、－Ｃ（Ｏ）Ｎ（Ｒ’） ２ 、－ＯＲ’、－Ｎ（Ｒ’） ２ 、－Ｓ（Ｏ） ２ Ｒ、－Ｓ（Ｏ） ２ Ｎ（Ｒ） ２ 、－Ｏ－フェニル、または必要に応じて置換された基であり、該必要に応じて置換された基は、Ｃ １～３ 脂肪族、フェニル、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員の単環式ヘテロ芳香環、または窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する４員～８員の飽和単環式複素環から選択され；
Ｒ ３ は、水素、ハロゲン、－ＣＮ、－ＯＲ’、－Ｎ（Ｒ’） ２ 、または必要に応じて置換された基であり、該必要に応じて置換された基は、Ｃ １～３ 脂肪族、フェニル、または窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員の単環式ヘテロ芳香環から選択され；
Ｒ ４ は、水素、ハロゲン、－ＣＮ、－ＯＲ、－Ｎ＝Ｓ（Ｏ）Ｒ ２ 、－Ｎ（Ｒ） ２ 、または必要に応じて置換された基であり、該必要に応じて置換された基は、Ｃ １～３ 脂肪族、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～８員の飽和もしくは部分不飽和の単環式複素環式環、または窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する７員～１２員の飽和もしくは部分不飽和のスピロ環式複素環式環から選択され；
ｍは、０、１、２、３、４または５であり；
ｎは、０、１、または２であり；
ｐは、０または１であり；そして
ｑは、０または１である、
化合物。
（項目２）
環ＡはＨｅｔである、項目１に記載の化合物。
（項目３）
Ｈｅｔは、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～８員の飽和単環式複素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する７員～１２員の飽和スピロ環式複素環式環、または窒素、酸素、もしくは硫黄から独立して選択される１個～３個のヘテロ原子を有する７員～１２員の飽和二環式複素環式環である、項目２に記載の化合物。
（項目４）
環Ｂは、
Figure 2019148136000062
 である、項目１に記載の化合物。
（項目５）
Ｒ １ の各々は独立して、水素、ハロゲン、－ＣＮ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ ２ 、－Ｃ（Ｏ）ＮＲＳ（Ｏ） ２ Ｒ、－Ｃ（Ｏ）Ｎ＝Ｓ（Ｏ）Ｒ ２ 、－ＮＲ ２ 、－ＮＲＣ（Ｏ）Ｒ、－ＮＲＣ（Ｏ）ＮＲ ２ 、－ＮＲＣ（Ｏ）ＯＲ、－ＮＲＳ（Ｏ） ２ Ｒ、－ＮＲＳ（Ｏ） ２ ＮＲ ２ 、－ＯＲ、－ＯＮ（Ｒ）ＳＯ ２ Ｒ、－Ｐ（Ｏ）Ｒ ２ 、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ） ２ Ｒ、－Ｓ（Ｏ）（ＮＨ）Ｒ、－Ｓ（Ｏ） ２ Ｎ（Ｒ） ２ 、－Ｓ（ＮＨ ２ ） ２ （Ｏ）ＯＨ、－Ｎ＝Ｓ（Ｏ）Ｒ ２ 、－ＣＨ ３ 、－ＣＨ ２ ＯＨ、－ＣＨ ２ ＮＨＳＯ ２ ＣＨ ３ 、－ＣＤ ３ 、－ＣＤ ２ ＮＲＳ（Ｏ） ２ Ｒ、またはＲである、項目１に記載の化合物。
（項目６）
Ｒ ２ の各々は独立して、水素、ハロゲン、－ＣＮ、－Ｃ（Ｏ）Ｎ（Ｒ’） ２ 、－ＯＲ’、－Ｎ（Ｒ’） ２ 、または必要に応じて置換された基であり、該必要に応じて置換された基は、Ｃ １～３ 脂肪族、または窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員の単環式ヘテロ芳香環から選択される、項目１に記載の化合物。
（項目７）
Ｒ ３ は、水素、ハロゲン、－ＣＮ、－ＯＲ’、－Ｎ（Ｒ’） ２ 、または必要に応じて置換された基であり、該必要に応じて置換された基は、Ｃ １～３ 脂肪族、または窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員の単環式ヘテロ芳香環から選択される、項目１に記載の化合物。
（項目８）
Ｒ ４ は、水素、ハロゲン、－ＣＮ、－ＯＲ、－Ｎ（Ｒ） ２ 、または必要に応じて置換された基であり、該必要に応じて置換された基は、Ｃ １～３ 脂肪族、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～８員の飽和もしくは部分不飽和の単環式複素環式環、または窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する７員～１２員の飽和もしくは部分不飽和のスピロ環式複素環式環から選択される、項目１に記載の化合物。
（項目９）
環Ｂは、
Figure 2019148136000063
 である、項目１に記載の化合物。
（項目１０）
式ＩＶ－ａ、ＩＶ－ｂ、もしくはＩＶ－ｃ：
Figure 2019148136000064
Figure 2019148136000065
 のうちの１つ、またはその薬学的に受容可能な塩の、項目９に記載の化合物。
（項目１１）
式ＸＩＩＩ－ａ、ＸＩＩＩ－ａ、もしくはＸＩＩＩ－ｃ：
Figure 2019148136000066
 のうちの１つ、またはその薬学的に受容可能な塩の、項目９に記載の化合物。
（項目１２）
式ＸＩＶ－ａ、ＸＩＶ－ａ、もしくはＸＩＶ－ｃ：
Figure 2019148136000067
 のうちの１つ、またはその薬学的に受容可能な塩の、項目９に記載の化合物。
（項目１３）
式ＸＶ－ａ、ＸＶ－ａ、もしくはＸＶ－ｃ：
Figure 2019148136000068
Figure 2019148136000069
 のうちの１つ、またはその薬学的に受容可能な塩の、項目９に記載の化合物。
（項目１４）
環Ｂは、
Figure 2019148136000070
 である、項目１に記載の化合物。
（項目１５）
式ＶＩ－ａ、ＶＩ－ｂ、もしくはＶＩ－ｃ：
Figure 2019148136000071
 のうちの１つ、またはその薬学的に受容可能な塩の、項目１４に記載の化合物。
（項目１６）
環Ｂは、
Figure 2019148136000072
 である、項目１に記載の化合物。
（項目１７）
式ＸＩＩ－ａ、ＸＩＩ－ｂ、もしくはＸＩＩ－ｃ：
Figure 2019148136000073
 のうちの１つ、またはその薬学的に受容可能な塩の、項目１６に記載の化合物。
（項目１８）
式ＸＶＩ－ａ、ＸＶＩ－ｂ、もしくはＸＶＩ－ｃ：
Figure 2019148136000074
 のうちの１つ、またはその薬学的に受容可能な塩の、項目１６に記載の化合物。
（項目１９）
式ＸＶＩＩ－ａ、ＸＶＩＩ－ｂ、もしくはＸＶＩＩ－ｃ：
Figure 2019148136000075
Figure 2019148136000076
 のうちの１つ、またはその薬学的に受容可能な塩の、項目１６に記載の化合物。
（項目２０）
式ＸＶＩＩＩ－ａ、ＸＶＩＩＩ－ｂ、もしくはＸＶＩＩＩ－ｃ：
Figure 2019148136000077
 のうちの１つ、またはその薬学的に受容可能な塩の、項目１６に記載の化合物。
（項目２１）
式ＸＩＸ－ａ、ＸＩＸ－ｂ、もしくはＸＩＸ－ｃ：
Figure 2019148136000078
 のうちの１つ、またはその薬学的に受容可能な塩の、項目１６に記載の化合物。
（項目２２）
式ＸＸ－ａ、ＸＸ－ｂ、もしくはＸＸ－ｃ：
Figure 2019148136000079
Figure 2019148136000080
 のうちの１つ、またはその薬学的に受容可能な塩の、項目１６に記載の化合物。
（項目２３）
式ＸＸＩ－ａ、ＸＸＩ－ｂ、もしくはＸＸＩ－ｃ：
Figure 2019148136000081
 のうちの１つ、またはその薬学的に受容可能な塩の、項目１６に記載の化合物。
（項目２４）
ｍは、１、２、３、４または５であり、特に、１、２または３である、項目１～２３のいずれか１項に記載の化合物。
（項目２５）
前記化合物は、表１に図示される化合物から選択される、項目１に記載の化合物。
（項目２６）
項目１～２５のいずれか１項に記載の化合物、および薬学的に受容可能なキャリア、アジュバント、またはビヒクルを含有する、薬学的組成物。
（項目２７）
患者または生物学的サンプルにおいて、ＧＣＮ２を阻害する方法であって、項目１～２５のいずれか１項に記載の化合物、またはその薬学的組成物を、該患者に投与する工程、または該生物学的サンプルと接触させる工程を包含する、方法。
（項目２８）
患者において、ＧＣＮ２媒介性の障害、疾患、または状態を処置する方法であって、該患者に、項目１～２５のいずれか１項に記載の化合物、またはその薬学的組成物を投与する工程を包含する、方法。
（項目２９）
前記ＧＣＮ２媒介性の障害、疾患、または状態は、炎症状態、免疫学的状態、自己免疫状態、アレルギー状態、リウマチ状態、血栓症状態、がん、感染、神経変性疾患、変性疾患、神経炎症疾患、心血管疾患、および代謝状態．からなる群より選択される、項目２８に記載の方法。
（項目３０）
前記がんは、固形腫瘍であって、ここで該固形腫瘍は、上皮、膀胱、胃、腎臓、頭頚部、食道、子宮頚部、甲状腺、腸管、肝臓、脳、前立腺、泌尿生殖路、リンパ系、胃、喉頭、軟骨肉腫およびユーイング肉腫が挙げられる骨、胎児組織腫瘍が挙げられる生殖細胞、および／または肺の腫瘍の群、単球性白血病、肺腺癌、小細胞肺癌、膵臓がん、グリア芽細胞腫、神経線維腫、血管肉腫、乳癌および／または悪性黒色腫の群を起源とする、固形腫瘍、ならびに血液および免疫系の腫瘍の群からなる群より選択される、項目２９に記載の方法。
（項目３１）
前記自己免疫状態は、関節リウマチ、全身性ループス、多発性硬化症、乾癬、シェーグレン症候群または移植器官拒絶である、項目２９に記載の方法。
（項目３２）
前記代謝状態は糖尿病である、項目２９に記載の方法。
（項目３３）
前記変性疾患は骨関節症である、項目２９に記載の方法。
（項目３４）
前記炎症状態は、喘息、炎症性腸疾患、または巨細胞関節炎である、項目２９に記載の方法。
（項目３５）
前記心血管疾患は虚血傷害である、項目２９に記載の方法。
（項目３６）
前記神経変性疾患は、アルツハイマー病、ダウン症候群、アミロイドーシスを伴う遺伝性大脳出血－オランダ型、脳のアミロイドアンギオパチー、クロイツフェルト－ヤコブ病、前頭側頭型痴呆、ハンチントン病、またはパーキンソン病である、項目２９に記載の方法。
（項目３７）
前記感染は、リーシュマニア、らい菌（Ｍ．ｌｅｐｒａｅ）、結核菌（Ｍ．ｔｕｂｅｒｃｕｌｏｓｉｓ）および／もしくはＭ．アビウム（Ｍ．ａｖｉｕｍ）が挙げられるマイコバクテリア、マラリア原虫、ヒト免疫不全ウイルス、エプスタイン－バーウイルス、単純ヘルペスウイルス、またはＣ型肝炎ウイルスにより引き起こされる、項目２９に記載の方法。
（項目３８）
前記ＧＣＮ２媒介性の障害、疾患、または状態は、がんであり、そして前記方法は、がんの処置のための第二の薬剤を投与する工程をさらに包含する、項目２８に記載の方法。 The compounds provided by the present invention also study GCN2 enzymes in biological and pathological phenomena; study intracellular signaling pathways that occur in body tissues; and new GCN2 inhibitors or kinases, signaling pathways, and. It is useful for comparative evaluation of other regulators of cytokine levels in vitro or in vivo.
In the embodiment of the present invention, for example, the following items are provided.
(Item 1)
Formula I:
Figure 2019148136000060
 Or a compound of its pharmaceutically acceptable salt, in Formula I:
Ring A is independent of 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic rings, phenyls, 8- to 10-membered heterocyclic aromatic carbocyclic rings, nitrogen, oxygen, or sulfur. 1 to 2 heteros selected independently of nitrogen, oxygen, or sulfur by condensing as needed with a 5 to 6 membered aromatic ring having 0 to 4 heteroatoms selected. A 7 to 12 member with 1 to 2 heteroatoms selected independently of a 4- to 8-membered partially unsaturated monocyclic heterocyclic ring with atoms, nitrogen, oxygen, or sulfur. Partially unsaturated spirocyclic heterocyclic ring, 7-12 membered partially unsaturated bicyclic heterocyclic ring with 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur , 7-12 membered partially unsaturated bridged bicyclic heterocyclic ring with 1-2 heteroatoms selected independently of nitrogen, oxygen, or sulfur, independent of nitrogen, oxygen, or sulfur A 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms selected from the above, 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Has 8 to 10 member bicyclic heteroaromatic rings, or
Selected from Het, where Het is a 4- to 8-membered saturated monocyclic heterocyclic ring, nitrogen, having 1 to 2 heteroatoms selected independently of nitrogen, oxygen, or sulfur. 7-12 member saturated spirocyclic heterocyclic rings with 1 to 4 heteroatoms selected independently of oxygen or sulfur, selected independently of nitrogen, oxygen, or sulfur 1 A 7 to 12 member saturated bicyclic heterocyclic ring with 3 to 3 heteroatoms, or a 7 member with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. It is a 12-membered saturated bridged bicyclic heterocyclic ring;
Ring B is
Figure 2019148136000061
 And;
Each R is independently hydrogen or C 1-6 aliphatic, 3-8 member saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 member bicycle. Formula Aromatic 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic rings with 1 to 2 heteroatoms independently selected from aromatic carbocyclic rings, nitrogen, oxygen, or sulfur , A 5- to 6-membered monocyclic heteroaromatic ring with 1 to 4 heteroatoms selected independently of nitrogen, oxygen, or sulfur, or independently selected from nitrogen, oxygen, or sulfur. Is it a optionally substituted group selected from 8- to 10-membered bicyclic heteroaromatic rings with 1 to 5 heteroatoms;
The two R groups can be combined together as needed to form a divalent C 2-4 alkylene chain;
The two R groups are optionally combined with the atoms between them and optionally substituted with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Form a saturated or partially unsaturated monocyclic ring with 3 to 7 members;
Each R'is an independent C 1-3 aliphatic group optionally substituted with hydrogen or halogen;
Each of R 1 is independently hydrogen, halogen, -CN, -NO 2 , -C (O) R, -C (O) OR, -C (O) NR 2 , -C (O) NRS (O). ) 2 R, -C (O) N = S (O) R 2 , -NR 2 , -NRC (O) R, -NRC (O) NR 2 , -NRC (O) OR, -NRS (O) 2 R, -NRS (O) 2 NR 2 , -OR, -ON (R) SO 2 R, -P (O) R 2 , -SR, -S (O) R, -S (O) 2 R,- S (O) (NH) R, -S (O) 2 N (R) 2 , -S (NH 2 ) 2 (O) OH, -N = S (O) R 2 , -CH 3 , -CH 2 OH, -CH 2 NHSO 2 CH 3 , -CD 3 , -CD 2 NRS (O) 2 R, or R; or:
Do the two R1s come together as needed to form = O or = NH; or
The two R1s can be combined together as needed to form a divalent C 2-4 alkylene chain;
Each of R 2 is independent of hydrogen, halogen, -CN, -C (O) N (R') 2 , -OR', -N (R') 2 , -S (O) 2 R, -S. (O) 2 N (R) 2 , -O-phenyl, or optionally substituted groups, the optionally substituted groups being C 1-3 aliphatic, phenyl, nitrogen, oxygen. Or a 5- to 6-membered monocyclic heteroaromatic ring with 1 to 4 heteroatoms selected independently of sulfur, or 1 to independently selected from nitrogen, oxygen, or sulfur. Selected from 4- to 8-membered saturated monocyclic heterocycles with 4 heteroatoms;
R 3 is hydrogen, halogen, -CN, -OR', -N (R') 2 , or a optionally substituted group, and the optionally substituted groups are C 1-3. Selected from 5- to 6-membered monocyclic heteroaromatic rings with 1 to 4 heteroatoms selected independently of aliphatic, phenyl, or nitrogen, oxygen, or sulfur;
R4 is a hydrogen, halogen, -CN, -OR, -N = S (O) R 2 , -N (R) 2 , or optionally substituted group, which is optionally substituted. The group is a 4- to 8-membered saturated or partially unsaturated monocyclic complex having 1 to 2 heteroatoms independently selected from C 1-3 aliphatic, nitrogen, oxygen, or sulfur. Selected from a cyclic ring or a 7-12 member saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. ;
m is 0, 1, 2, 3, 4 or 5;
n is 0, 1, or 2;
p is 0 or 1; and
q is 0 or 1,
Compound.
(Item 2)
The compound according to item 1, wherein the ring A is Het.
(Item 3)
Het is independent of 4- to 8-membered saturated monocyclic heterocyclic rings, nitrogen, oxygen, or sulfur with 1 to 2 heteroatoms selected independently of nitrogen, oxygen, or sulfur. 7 to 12 member saturated spirocyclic heterocyclic rings with 1 to 4 heteroatoms selected from each, or 1 to 3 heterocycles independently selected from nitrogen, oxygen, or sulfur. The compound according to item 2, which is a 7 to 12-membered saturated bicyclic heterocyclic ring having an atom.
(Item 4)
Ring B is
Figure 2019148136000062
 The compound according to item 1.
(Item 5)
Each of R 1 is independently hydrogen, halogen, -CN, -C (O) R, -C (O) OR, -C (O) NR 2 , -C (O) NRS (O) 2 R, -C (O) N = S (O) R 2 , -NR 2 , -NRC (O) R, -NRC (O) NR 2 , -NRC (O) OR, -NRS (O) 2 R, -NRS (O) 2 NR 2 , -OR, -ON (R) SO 2 R, -P (O) R 2 , -SR, -S (O) R, -S (O) 2 R, -S (O) (NH) R, -S (O) 2 N (R) 2 , -S (NH 2 ) 2 (O) OH, -N = S (O) R 2 , -CH 3 , -CH 2 OH, -CH 2 The compound according to item 1, which is NHSO 2 CH 3 , -CD 3 , -CD 2 NRS (O) 2 R, or R.
(Item 6)
Each of R 2 is independently substituted with hydrogen, halogen, -CN, -C (O) N (R') 2 , -OR', -N (R') 2 , or optionally substituted groups. Yes, the optionally substituted group is a 5- to 6-membered group having 1 to 4 heteroatoms selected independently of C 1-3 aliphatic or nitrogen, oxygen, or sulfur. The compound according to item 1, which is selected from a monocyclic heteroaromatic ring.
(Item 7)
R 3 is hydrogen, halogen, -CN, -OR', -N (R') 2 , or a optionally substituted group, and the optionally substituted groups are C 1-3. The compound according to item 1, which is selected from a 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms selected independently of an aliphatic or nitrogen, oxygen, or sulfur. ..
(Item 8)
R4 is a hydrogen, halogen, -CN, -OR, -N (R) 2 , or a optionally substituted group, the optionally substituted group being a C1-3 fatty group . , A 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring with 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or nitrogen, oxygen, or The compound according to item 1, wherein the compound is selected from a 7 to 12 member saturated or partially unsaturated spirocyclic heterocyclic ring having 1 to 2 heteroatoms selected independently of sulfur.
(Item 9)
Ring B is
Figure 2019148136000063
 The compound according to item 1.
(Item 10)
Formula IV-a, IV-b, or IV-c:
Figure 2019148136000064
Figure 2019148136000065
 Item 9. The compound according to item 9, one of the following, or a pharmaceutically acceptable salt thereof.
(Item 11)
Formulas XIII-a, XIII-a, or XIII-c:
Figure 2019148136000066
 Item 9. The compound according to item 9, one of the following, or a pharmaceutically acceptable salt thereof.
(Item 12)
Formula XIV-a, XIV-a, or XIV-c:
Figure 2019148136000067
 Item 9. The compound according to item 9, one of the following, or a pharmaceutically acceptable salt thereof.
(Item 13)
Formula XV-a, XV-a, or XV-c:
Figure 2019148136000068
Figure 2019148136000069
 Item 9. The compound according to item 9, one of the following, or a pharmaceutically acceptable salt thereof.
(Item 14)
Ring B is
Figure 2019148136000070
 The compound according to item 1.
(Item 15)
Formula VI-a, VI-b, or VI-c:
Figure 2019148136000071
 The compound according to item 14, one of the following, or a pharmaceutically acceptable salt thereof.
(Item 16)
Ring B is
Figure 2019148136000072
 The compound according to item 1.
(Item 17)
Formula XII-a, XII-b, or XII-c:
Figure 2019148136000073
 16. The compound of item 16 of one of, or a pharmaceutically acceptable salt thereof.
(Item 18)
Formula XVI-a, XVI-b, or XVI-c:
Figure 2019148136000074
 16. The compound of item 16 of one of, or a pharmaceutically acceptable salt thereof.
(Item 19)
Formula XVII-a, XVII-b, or XVII-c:
Figure 2019148136000075
Figure 2019148136000076
 16. The compound of item 16 of one of, or a pharmaceutically acceptable salt thereof.
(Item 20)
Formula XVIII-a, XVIII-b, or XVIII-c:
Figure 2019148136000077
 16. The compound of item 16 of one of, or a pharmaceutically acceptable salt thereof.
(Item 21)
Formula XIX-a, XIX-b, or XIX-c:
Figure 2019148136000078
 16. The compound of item 16 of one of, or a pharmaceutically acceptable salt thereof.
(Item 22)
Formula XX-a, XX-b, or XX-c:
Figure 2019148136000079
Figure 2019148136000080
 16. The compound of item 16 of one of, or a pharmaceutically acceptable salt thereof.
(Item 23)
Formula XXI-a, XXI-b, or XXI-c:
Figure 2019148136000081
 16. The compound of item 16 of one of, or a pharmaceutically acceptable salt thereof.
(Item 24)
The compound according to any one of items 1 to 23, wherein m is 1, 2, 3, 4 or 5, and in particular, 1, 2 or 3.
(Item 25)
The compound according to item 1, wherein the compound is selected from the compounds shown in Table 1.
(Item 26)
A pharmaceutical composition comprising the compound according to any one of items 1 to 25, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
(Item 27)
A method of inhibiting GCN2 in a patient or biological sample, wherein the compound according to any one of items 1 to 25, or a pharmaceutical composition thereof, is administered to the patient, or the biology. A method comprising contacting a target sample.
(Item 28)
A method for treating a GCN2-mediated disorder, disease, or condition in a patient, wherein the patient is administered with the compound according to any one of items 1 to 25, or a pharmaceutical composition thereof. Including, method.
(Item 29)
The GCN2-mediated disorders, diseases, or conditions include inflammatory, immunological, autoimmune, allergic, rheumatic, thrombotic, cancer, infection, neurodegenerative, degenerative, and neuroinflammatory disorders. , Cardiovascular disease, and metabolic status. 28. The method of item 28, selected from the group consisting of.
(Item 30)
The cancer is a solid tumor, wherein the solid tumor is epithelial, bladder, stomach, kidney, head and neck, esophagus, cervical, thyroid, intestinal, liver, brain, prostate, urogenital tract, lymphatic system. , Stomach, throat, bones such as chondrosarcoma and Ewing sarcoma, germ cells such as fetal tissue tumors, and / or a group of lung tumors, monocytic leukemia, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, 29. Item 29, selected from the group consisting of solid tumors originating from the group of gria blastoma, neurofibromas, angiosarcoma, breast cancer and / or malignant melanoma, and tumors of the blood and immune system. the method of.
(Item 31)
29. The method of item 29, wherein the autoimmune state is rheumatoid arthritis, systemic lupus, multiple sclerosis, psoriasis, Sjogren's syndrome or transplant organ rejection.
(Item 32)
29. The method of item 29, wherein the metabolic state is diabetes.
(Item 33)
29. The method of item 29, wherein the degenerative disease is osteoarthritis.
(Item 34)
29. The method of item 29, wherein the inflammatory condition is asthma, inflammatory bowel disease, or giant cell arthritis.
(Item 35)
29. The method of item 29, wherein the cardiovascular disease is an ischemic injury.
(Item 36)
The neurodegenerative diseases are Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis-Dutch type, amyloid angiopathy in the brain, Kreuzfeld-Jakob's disease, frontal temporal dementia, Huntington's disease, or Parkinson's disease. The method according to item 29.
(Item 37)
The infections include Leishmania, Mycobacterium leprae, Mycobacterium tuberculosis (M. tuberculosis) and / or M. leprae. 29. The method of item 29, which is caused by mycobacteria such as M. avium, Plasmodium malaria, human immunodeficiency virus, Epstein-Bar virus, herpes simplex virus, or hepatitis C virus.
(Item 38)
28. The method of item 28, wherein the GCN2-mediated disorder, disease, or condition is cancer, and the method further comprises the step of administering a second agent for the treatment of cancer.

Claims (39)

式ＸＶ－ａ、ＸＶ－ｂ、もしくはＸＶ－ｃ：Formula XV-a, XV-b, or XV-c:
Figure 2019148136000001
Figure 2019148136000001
Figure 2019148136000002
Figure 2019148136000002
 のうちの１つの化合物またはその薬学的に受容可能な塩であって、式中、One of the compounds or a pharmaceutically acceptable salt thereof in the formula,
Ｒ R １1 の各々は独立して、水素、ハロゲン、－ＣＮ、－ＮＯEach of them is independent of hydrogen, halogen, -CN, -NO. ２2 、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲ, -C (O) R, -C (O) OR, -C (O) NR ２2 、－Ｃ（Ｏ）ＮＲＳ（Ｏ）, -C (O) NRS (O) ２2 Ｒ、－Ｃ（Ｏ）Ｎ＝Ｓ（Ｏ）ＲR, -C (O) N = S (O) R ２2 、－ＮＲ, -NR ２2 、－ＮＲＣ（Ｏ）Ｒ、－ＮＲＣ（Ｏ）ＮＲ, -NRC (O) R, -NRC (O) NR ２2 、－ＮＲＣ（Ｏ）ＯＲ、－ＮＲＳ（Ｏ）, -NRC (O) OR, -NRS (O) ２2 Ｒ、－ＮＲＳ（Ｏ）R, -NRS (O) ２2 ＮＲNR ２2 、－ＯＲ、－ＯＮ（Ｒ）ＳＯ, -OR, -ON (R) SO ２2 Ｒ、－Ｐ（Ｏ）ＲR, -P (O) R ２2 、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）, -SR, -S (O) R, -S (O) ２2 Ｒ、－Ｓ（Ｏ）（ＮＨ）Ｒ、－Ｓ（Ｏ）R, -S (O) (NH) R, -S (O) ２2 Ｎ（Ｒ）N (R) ２2 、－Ｓ（ＮＨ, -S (NH) ２2 ）) ２2 （Ｏ）ＯＨ、－Ｎ＝Ｓ（Ｏ）Ｒ(O) OH, -N = S (O) R ２2 、－ＣＨ, -CH ３3 、－ＣＨ, -CH ２2 ＯＨ、－ＣＨOH, -CH ２2 ＮＨＳＯNHSO ２2 ＣＨCH ３3 、－ＣＤ, -CD ３3 、－ＣＤ, -CD ２2 ＮＲＳ（Ｏ）NRS (O) ２2 Ｒ、またはＲであるか；あるいはR, or R; or
２個のＲ 2 R １1 基は必要に応じて一緒になって、＝Ｏまたは＝ＮＨを形成するか；あるいはDo the groups come together as needed to form = O or = NH; or
２個のＲ 2 R １1 基は必要に応じて一緒になって、二価ＣGroup together as needed, divalent C ２～４2-4 アルキレン鎖を形成し；Forming an alkylene chain;
各Ｒは独立して、水素であるか、またはＣ Each R is independently hydrogen or C １～６1-6 脂肪族、３員～８員の飽和もしくは部分不飽和の単環式炭素環式環、フェニル、８員～１０員の二環式芳香族炭素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～８員の飽和もしくは部分不飽和の単環式複素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員の単環式ヘテロ芳香環、または窒素、酸素、もしくは硫黄から独立して選択される１個～５個のヘテロ原子を有する８員～１０員の二環式ヘテロ芳香環から選択される必要に応じて置換された基であるか；あるいはHeteroatom, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic ring, independent of nitrogen, oxygen, or sulfur One selected independently of a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms, nitrogen, oxygen, or sulfur. A 5- to 6-membered monocyclic heteroaromatic ring with 4 heteroatoms, or an 8- to 10-membered heteroatom with 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Is it a optionally substituted group selected from bicyclic heteroaromatic rings; or
２個のＲ基は必要に応じて一緒になって、二価Ｃ The two R groups are combined as needed to form a divalent C. ２～４2-4 アルキレン鎖を形成するか；あるいはDo you form an alkylene chain; or
２個のＲ基は、これらの間にある原子と必要に応じて一緒になって、窒素、酸素もしくは硫黄から独立して選択される０個～４個のヘテロ原子を有する必要に応じて置換された３員～７員の飽和もしくは部分不飽和の単環式環を形成し； The two R groups are optionally combined with the atoms between them and optionally substituted with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Form a saturated or partially unsaturated monocyclic ring with 3 to 7 members;
ｍは、０、１、２、３、４または５である、 m is 0, 1, 2, 3, 4 or 5,
化合物またはその薬学的に受容可能な塩。A compound or a pharmaceutically acceptable salt thereof. Ｒ R １1 は、水素、ハロゲン、－ＣＮ、－Ｃ（Ｏ）Ｒ、－Ｃ（Ｏ）ＯＲ、－Ｃ（Ｏ）ＮＲIs hydrogen, halogen, -CN, -C (O) R, -C (O) OR, -C (O) NR ２2 、－Ｃ（Ｏ）ＮＲＳ（Ｏ）, -C (O) NRS (O) ２2 Ｒ、－Ｃ（Ｏ）Ｎ＝Ｓ（Ｏ）ＲR, -C (O) N = S (O) R ２2 、－ＮＲ, -NR ２2 、－ＮＲＣ（Ｏ）Ｒ、－ＮＲＣ（Ｏ）ＮＲ, -NRC (O) R, -NRC (O) NR ２2 、－ＮＲＣ（Ｏ）ＯＲ、－ＮＲＳ（Ｏ）, -NRC (O) OR, -NRS (O) ２2 Ｒ、－ＮＲＳ（Ｏ）R, -NRS (O) ２2 ＮＲNR ２2 、－ＯＲ、－ＯＮ（Ｒ）ＳＯ, -OR, -ON (R) SO ２2 Ｒ、－Ｐ（Ｏ）ＲR, -P (O) R ２2 、－ＳＲ、－Ｓ（Ｏ）Ｒ、－Ｓ（Ｏ）, -SR, -S (O) R, -S (O) ２2 Ｒ、－Ｓ（Ｏ）（ＮＨ）Ｒ、－Ｓ（Ｏ）R, -S (O) (NH) R, -S (O) ２2 Ｎ（Ｒ）N (R) ２2 、－Ｓ（ＮＨ, -S (NH) ２2 ）) ２2 （Ｏ）ＯＨ、－Ｎ＝Ｓ（Ｏ）Ｒ(O) OH, -N = S (O) R ２2 、－ＣＨ, -CH ３3 、－ＣＨ, -CH ２2 ＯＨ、－ＣＨOH, -CH ２2 ＮＨＳＯNHSO ２2 ＣＨCH ３3 、－ＣＤ, -CD ３3 、－ＣＤ, -CD ２2 ＮＲＳ（Ｏ）NRS (O) ２2 Ｒ、またはＲである、請求項１に記載の化合物またはその薬学的に受容可能な塩。R, or R, the compound of claim 1 or a pharmaceutically acceptable salt thereof. ２個のＲ 2 R １1 基は一緒になって、二価ＣThe groups are together, divalent C ２～４2-4 アルキレン鎖を形成する、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which forms an alkylene chain. ２個のＲ 2 R １1 基は一緒になって、＝Ｏまたは＝ＮＨを形成する、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the groups together form = O or = NH. ｍは、１、２または３である、請求項１～４のいずれか１項に記載の化合物またはその薬学的に受容可能な塩。 m is 1, 2 or 3, the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof. 各Ｒは独立して、水素であるか、またはＣ Each R is independently hydrogen or C １～６1-6 脂肪族、３員～８員の飽和もしくは部分不飽和の単環式炭素環式環、フェニル、８員～１０員の二環式芳香族炭素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する４員～８員の飽和もしくは部分不飽和の単環式複素環式環、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する５員～６員の単環式ヘテロ芳香環、または窒素、酸素、もしくは硫黄から独立して選択される１個～５個のヘテロ原子を有する８員～１０員の二環式ヘテロ芳香環から選択される必要に応じて置換された基である、請求項２に記載の化合物またはその薬学的に受容可能な塩。Heteroatom, 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8- to 10-membered bicyclic aromatic carbocyclic ring, independent of nitrogen, oxygen, or sulfur One selected independently of a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms, nitrogen, oxygen, or sulfur. A 5- to 6-membered monocyclic heteroaromatic ring with 4 heteroatoms, or an 8- to 10-membered with 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, which is a optionally substituted group selected from a bicyclic heteroaromatic ring. Ｒは水素である、請求項２に記載の化合物またはその薬学的に受容可能な塩。 R is hydrogen, the compound of claim 2 or a pharmaceutically acceptable salt thereof. Ｒは必要に応じて置換されたＣ R is replaced as needed C １～６1-6 脂肪族である、請求項２に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 2, which is an aliphatic, or a pharmaceutically acceptable salt thereof. Ｒは必要に応じて置換された３員～８員の飽和もしくは部分不飽和の単環式炭素環式環である、請求項２に記載の化合物またはその薬学的に受容可能な塩。 The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R is a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring optionally substituted. 各Ｒは必要に応じて置換されたフェニルである、請求項２に記載の化合物またはその薬学的に受容可能な塩。 The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein each R is optionally substituted phenyl. Ｒは必要に応じて置換された８員～１０員の二環式芳香族炭素環式環である、請求項２に記載の化合物またはその薬学的に受容可能な塩。 The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R is an 8- to 10-membered bicyclic aromatic carbocyclic ring substituted as needed. Ｒは、窒素、酸素、もしくは硫黄から独立して選択される１個～２個のヘテロ原子を有する必要に応じて置換された４員～８員の飽和もしくは部分不飽和の単環式複素環式環である、請求項２に記載の化合物またはその薬学的に受容可能な塩。 R is a optionally substituted 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The compound according to claim 2, which is a cyclic ring, or a pharmaceutically acceptable salt thereof. Ｒは、窒素、酸素、もしくは硫黄から独立して選択される１個～４個のヘテロ原子を有する必要に応じて置換された５員～６員の単環式ヘテロ芳香環である、請求項２に記載の化合物またはその薬学的に受容可能な塩。 R is a optionally substituted 5- to 6-membered monocyclic heteroaromatic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 2. The compound according to 2 or a pharmaceutically acceptable salt thereof. Ｒは、窒素、酸素、もしくは硫黄から独立して選択される１個～５個のヘテロ原子を有する必要に応じて置換された８員～１０員の二環式ヘテロ芳香環である、請求項２に記載の化合物またはその薬学的に受容可能な塩。 R is an optionally substituted 8- to 10-membered bicyclic heteroaromatic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 2. The compound according to 2 or a pharmaceutically acceptable salt thereof. ２個のＲ基は一緒になって、二価Ｃ Two R groups together, divalent C ２～４2-4 アルキレン鎖を形成する、請求項２に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 2 or a pharmaceutically acceptable salt thereof, which forms an alkylene chain. ２個のＲ基は、これらの間にある原子と一緒になって、窒素、酸素もしくは硫黄から独立して選択される０個～４個のヘテロ原子を有する必要に応じて置換された３員～７員の飽和もしくは部分不飽和の単環式環を形成する、請求項２に記載の化合物またはその薬学的に受容可能な塩。 The two R groups, together with the atoms between them, have 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur and are optionally substituted 3 members. The compound of claim 2 or a pharmaceutically acceptable salt thereof, which forms a ~ 7-membered saturated or partially unsaturated monocyclic ring. Ｒ R １1 基は、フルオロ、クロロ、メチル、エチル、－ＯＨ、－ＯＣＨThe groups are fluoro, chloro, methyl, ethyl, -OH, -OCH. ３3 、－ＣＨ, -CH ２2 ＯＨ、－ＣＨOH, -CH ２2 ＣＮ、－ＣＦCN, -CF ３3 、－ＣＨ, -CH ２2 ＮＨNH ２2 、－ＣＯＯＨ、－ＮＨ, -COOH, -NH ２2 、,
Figure 2019148136000003
Figure 2019148136000003
 からなる群から選択される、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. Ｒ R １1 基は、The basis is
Figure 2019148136000004
Figure 2019148136000004
 からなる群から選択される、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. Ｒ R １1 基は、The basis is
Figure 2019148136000005
Figure 2019148136000005
 からなる群から選択される、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. Ｒ R １1 基は、The basis is
Figure 2019148136000006
Figure 2019148136000006
 からなる群から選択される、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. Ｒ R １1 基は、The basis is
Figure 2019148136000007
Figure 2019148136000007
 からなる群から選択される、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. Ｒ R １1 基は、The basis is
Figure 2019148136000008
Figure 2019148136000008
 からなる群から選択される、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. Ｒ R １1 基は、The basis is
Figure 2019148136000009
Figure 2019148136000009
 からなる群から選択される、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. Ｒ R １1 基は、The basis is
Figure 2019148136000010
Figure 2019148136000010
 からなる群から選択される、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of. 前記化合物は、 The compound is
Figure 2019148136000011
Figure 2019148136000011
Figure 2019148136000012
Figure 2019148136000012
 からなる群から選択される、請求項１に記載の化合物またはその薬学的に受容可能な塩。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of.
Figure 2019148136000013
Figure 2019148136000013
Figure 2019148136000014
Figure 2019148136000014
Figure 2019148136000015
Figure 2019148136000015
Figure 2019148136000016
Figure 2019148136000016
Figure 2019148136000017
Figure 2019148136000017
Figure 2019148136000018
Figure 2019148136000018
Figure 2019148136000019
Figure 2019148136000019
Figure 2019148136000020
Figure 2019148136000020
Figure 2019148136000021
Figure 2019148136000021
Figure 2019148136000022
Figure 2019148136000022
Figure 2019148136000023
Figure 2019148136000023
Figure 2019148136000024
Figure 2019148136000024
Figure 2019148136000025
Figure 2019148136000025
Figure 2019148136000026
Figure 2019148136000026
Figure 2019148136000027
Figure 2019148136000027
Figure 2019148136000028
Figure 2019148136000028
Figure 2019148136000029
Figure 2019148136000029
Figure 2019148136000030
Figure 2019148136000030
Figure 2019148136000031
Figure 2019148136000031
Figure 2019148136000032
Figure 2019148136000032
Figure 2019148136000033
Figure 2019148136000033
Figure 2019148136000034
Figure 2019148136000034
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Figure 2019148136000035
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Figure 2019148136000036
Figure 2019148136000037
Figure 2019148136000037
Figure 2019148136000038
Figure 2019148136000038
Figure 2019148136000039
Figure 2019148136000039
Figure 2019148136000040
Figure 2019148136000040
Figure 2019148136000041
Figure 2019148136000041
Figure 2019148136000042
Figure 2019148136000042
Figure 2019148136000043
Figure 2019148136000043
Figure 2019148136000044
Figure 2019148136000044
Figure 2019148136000045
Figure 2019148136000045
Figure 2019148136000046
Figure 2019148136000046
Figure 2019148136000047
Figure 2019148136000047
Figure 2019148136000048
Figure 2019148136000048
Figure 2019148136000049
Figure 2019148136000049
Figure 2019148136000050
Figure 2019148136000050
Figure 2019148136000051
Figure 2019148136000051
Figure 2019148136000052
Figure 2019148136000052
Figure 2019148136000053
Figure 2019148136000053
Figure 2019148136000054
Figure 2019148136000054
Figure 2019148136000055
Figure 2019148136000055
Figure 2019148136000056
Figure 2019148136000056
Figure 2019148136000057
Figure 2019148136000057
Figure 2019148136000058
Figure 2019148136000058
Figure 2019148136000059
Figure 2019148136000059
 からなる群から選択される化合物またはその薬学的に受容可能な塩。A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. 請求項１～２６のいずれか１項に記載の化合物またはその薬学的に受容可能な塩、および薬学的に受容可能なキャリア、アジュバント、またはビヒクルを含有する、薬学的組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 患者または生物学的サンプルにおいて、ＧＣＮ２を阻害するための、請求項１～２６のいずれか１項に記載の化合物またはその薬学的に受容可能な塩を含む薬学的組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof for inhibiting GCN2 in a patient or a biological sample. ＧＣＮ２媒介性の障害、疾患、または状態を処置するための、請求項１～２６のいずれか１項に記載の化合物またはその薬学的に受容可能な塩を含む組成物。 A composition comprising the compound according to any one of claims 1-26 or a pharmaceutically acceptable salt thereof for treating a GCN2-mediated disorder, disease, or condition. 前記ＧＣＮ２媒介性の障害、疾患、または状態は、炎症状態、免疫学的状態、自己免疫状態、アレルギー状態、リウマチ状態、血栓症状態、がん、感染、神経変性疾患、変性疾患、神経炎症疾患、心血管疾患、および代謝状態．からなる群より選択される、請求項２９に記載の組成物。 The GCN2-mediated disorders, diseases, or conditions include inflammatory, immunological, autoimmune, allergic, rheumatic, thrombotic, cancer, infection, neurodegenerative, degenerative, and neuroinflammatory disorders. , Cardiovascular disease, and metabolic status. 29. The composition of claim 29 , selected from the group consisting of. 前記がんは、固形腫瘍であって、ここで該固形腫瘍は、上皮、膀胱、胃、腎臓、頭頚部、食道、子宮頚部、甲状腺、腸管、肝臓、脳、前立腺、泌尿生殖路、リンパ系、胃、喉頭、軟骨肉腫およびユーイング肉腫が挙げられる骨、胎児組織腫瘍が挙げられる生殖細胞、および／または肺の腫瘍の群、単球性白血病、肺腺癌、小細胞肺癌、膵臓がん、グリア芽細胞腫、神経線維腫、血管肉腫、乳癌および／または悪性黒色腫の群を起源とする、固形腫瘍、ならびに血液および免疫系の腫瘍の群からなる群より選択される、請求項３０に記載の組成物。 The cancer is a solid tumor, wherein the solid tumor is epithelial, bladder, stomach, kidney, head and neck, esophagus, cervical, thyroid, intestinal, liver, brain, prostate, urogenital tract, lymphatic system. , Stomach, throat, bones such as chondrosarcoma and Ewing sarcoma, germ cells such as fetal tissue tumors, and / or a group of lung tumors, monocytic leukemia, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, 30 is selected from the group consisting of solid tumors originating from the group of gria blastoma, neurofibromas, angiosarcoma, breast cancer and / or malignant melanoma, and tumors of the blood and immune system. The composition described. 前記自己免疫状態は、関節リウマチ、全身性ループス、多発性硬化症、乾癬、シェーグレン症候群または移植器官拒絶である、請求項３０に記載の組成物。 30. The composition of claim 30 , wherein the autoimmune condition is rheumatoid arthritis, systemic lupus, multiple sclerosis, psoriasis, Sjogren's syndrome or transplant organ rejection. 前記代謝状態は糖尿病である、請求項３０に記載の組成物。 30. The composition of claim 30 , wherein the metabolic state is diabetic. 前記変性疾患は骨関節症である、請求項３０に記載の組成物。 30. The composition of claim 30 , wherein the degenerative disease is osteoarthritis. 前記炎症状態は、喘息、炎症性腸疾患、または巨細胞関節炎である、請求項３０に記載の組成物。 30. The composition of claim 30 , wherein the inflammatory condition is asthma, inflammatory bowel disease, or giant cell arthritis. 前記心血管疾患は虚血傷害である、請求項３０に記載の組成物。 30. The composition of claim 30 , wherein the cardiovascular disease is an ischemic injury. 前記神経変性疾患は、アルツハイマー病、ダウン症候群、アミロイドーシスを伴う遺伝性大脳出血－オランダ型、脳のアミロイドアンギオパチー、クロイツフェルト－ヤコブ病、前頭側頭型痴呆、ハンチントン病、またはパーキンソン病である、請求項３０に記載の組成物。 The neurodegenerative diseases are Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis-Dutch type, amyloid angiopathy in the brain, Kreuzfeld-Jakob's disease, frontal temporal dementia, Huntington's disease, or Parkinson's disease. The composition according to claim 30 . 前記感染は、リーシュマニア、らい菌（Ｍ．ｌｅｐｒａｅ）、結核菌（Ｍ．ｔｕｂｅｒｃｕｌｏｓｉｓ）および／もしくはＭ．アビウム（Ｍ．ａｖｉｕｍ）が挙げられるマイコバクテリア、マラリア原虫、ヒト免疫不全ウイルス、エプスタイン－バーウイルス、単純ヘルペスウイルス、またはＣ型肝炎ウイルスにより引き起こされる、請求項３０に記載の組成物。 The infections include Leishmania, Mycobacterium leprae, Mycobacterium tuberculosis (M. tuberculosis) and / or M. leprae. 30. The composition of claim 30 , which is caused by mycobacteria such as M. avium, Plasmodium malaria, human immunodeficiency virus, Epstein-Bar virus, herpes simplex virus, or hepatitis C virus. 前記ＧＣＮ２媒介性の障害、疾患、または状態は、がんであり、そして前記組成物は、がんの処置のための第二の薬剤と組み合わせて投与されることを特徴とする、請求項２９に記載の組成物。

29. The GCN2-mediated disorder, disease, or condition is cancer, and the composition is administered in combination with a second agent for the treatment of cancer, claim 29 . The composition described.
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