JP2021526517A - ビスフルオロアルキル−1,4−ベンゾジアゼピノン化合物および免疫療法剤を含む組成物ならびにそれらの使用方法 - Google Patents
ビスフルオロアルキル−1,4−ベンゾジアゼピノン化合物および免疫療法剤を含む組成物ならびにそれらの使用方法 Download PDFInfo
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Abstract
Description
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、ゼロ、1、または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3がHまたは−CH3であり、
各Raは独立して、F、Cl、−CN、−OCH3、および/または−NHCH2CH2OCH3であり、
yは、ゼロ、1、または2である。
R1は、−CH2CF3であり、
R2は、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、Cl、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、および/または−O(シクロプロピル)であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zはゼロ、1、または2であり、
環Aがフェニルであり、zがゼロであり、yが1または2である場合、少なくとも1つのRaは、
C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、または−O(シクロプロピル)であることを条件とし、
R3がRxである場合、R4はHであることを条件とし、
R4がRyである場合、R3は、Hまたは−CH3であることを条件とする。
R1は、−CH2CH2CF3であり、
R2は、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OCH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、Cl、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、および/または−O(シクロプロピル)であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。
R3は、Hまたは−CH3であり、
各Raは独立して、F、Cl、−CN、−OCH3、および/または−NHCH2CH2OCH3である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、ゼロ、1、または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、ゼロ、1、または2である。
MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR(配列番号1)。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、ゼロ、1、または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3がHまたは−CH3であり、
各Raは独立して、F、Cl、−CN、−OCH3、および/または−NHCH2CH2OCH3であり、
zは、ゼロ、1、または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、ゼロ、1、または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、ゼロ、1、または2である。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、ゼロ、1、または2である。
多発性骨髄腫(MM)細胞株におけるB細胞成熟抗原(BCMA)発現に対するγ−セクレターゼ阻害剤の効果
BCMA標的CAR−T細胞と化合物(1)のインビトロでの抗腫瘍活性
BCMA標的CAR−T細胞と化合物(1)のインビボでの抗腫瘍活性
BCMA標的CAR−T細胞と化合物(1)を組み合わせたインビボでの抗腫瘍活性−ヒト
すべての患者は、300mgの/m2のシクロホスファミドの3用量および30mg/m2のフルダラビンの3用量を受ける。レシピエントの白血球の枯渇が養子移入されたT細胞の活性を高めるため、化学療法が実施される。両方の化学療法剤は、0日目のCAR−BCMA T細胞注入の前の−5、−4、および−3日目に毎日投与される。CAR−BCMA T細胞は、化合物(1)を含む組成物と共に各患者に投与される。用量漸増計画では、0.3×106CAR+T細胞/kgの初期用量を必要とし、その後の各用量レベルまで3倍に増加する。
γ−セクレターゼ阻害剤は、リンパ腫細胞株ではB細胞成熟抗原(BCMA)レベルを増加させたが、B−ALL細胞株では増加させなかった。
Claims (42)
- 1つ以上のB細胞成熟抗原(BCMA)標的化免疫療法剤と、
式(I)の構造によって表される1つ以上の化合物および/またはその少なくとも1つの塩と、を含む組成物。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。 - R1が−CH2CH2CF3であり、
R2が−CH2CH2CF3または−CH2CH2CH2CF3であり、
各Raが独立して、Cl、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、および/または−O(シクロプロピル)である、請求項1に記載の組成物。 - 環Aがフェニルであり、R3がHである、請求項4に記載の組成物。
- R2が−CH2CH2CF3であり、環Aがフェニルである、請求項4に記載の組成物。
- R2が−CH2CH2CF3であり、
環Aがフェニルであり、
RaがC1〜3アルキルまたは−CH2OHであり、
各Rbが独立して、Fおよび/またはClであり、yが1である、請求項4に記載の組成物。 - 前記1つ以上の化合物が、
(2R,3S)−N−((3S)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(22)、(2R,3S)−N−((3S)−5−(3−クロロフェニル)−9−エチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(23)、(2R,3S)−N−((3S)−5−(3−クロロフェニル)−9−イソプロピル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(24)、(2R,3S)−N−(9−クロロ−5−(3,4−ジメチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(25)、(2R,3S)−N−(9−クロロ−5−(3,5−ジメチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(26)、(2R,3S)−N−((3S)−9−エチル−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(27)、(2R,3S)−N−((3S)−5−(3−クロロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(28)、(2R,3S)−N−((3S)−5−(3−クロロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(29)、(2R,3S)−N−((3S)−5−(3−メチルフェニル)−2−オキソ−9−(トリフルオロメチル)−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(30)、(2R,3S)−N−((3S)−9−クロロ−5−(3,5−ジメチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(31)、(2R,3S)−N−((3S)−5−(3−メチルフェニル)−2−オキソ−9−(トリフルオロメチル)−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(32)、(2R,3S)−N−((3S)−9−イソプロピル−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(33)、(2R,3S)−N−((3S)−9−(シクロプロピルオキシ)−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(34)、(2R,3S)−N−((3S)−9−(シクロプロピルオキシ)−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(35)、(2R,3S)−N−((3S)−9−クロロ−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(36)、(2R,3S)−N−((3S)−9−メチル−2−オキソ−5−(3−(トリフルオロメチル)フェニル)−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(37)、(2R,3S)−N−((3S)−9−メチル−2−オキソ−5−(3−(トリフルオロメチル)フェニル)−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(38)、(2R,3S)−N−((3S)−9−クロロ−5−(2−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(39)、(2R,3S)−N−((3S)−5−(4−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(40)、(2R,3S)−N−((3S)−9−クロロ−5−(3−シクロプロピルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(41)、(2R,3S)−N−((3S)−5−(3−クロロフェニル)−9−メトキシ−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(42)、(2R,3S)−N−((3S)−5−(4−クロロフェニル)−9−メトキシ−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(43)、(2R,3S)−N−((3S)−9−クロロ−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(44)、(2R,3S)−N−((3S)−5−(3−メチルフェニル)−9−メトキシ−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(45)、(2R,3S)−N−((3S)−5−(4−(ヒドロキシメチル)フェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(46)、(2R,3S)−N−((3S)−5−(2−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(47)、(2R,3S)−N−((3S)−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(48)、(2R,3S)−N−((3S)−9−メトキシ−2−オキソ−5−(5−(トリフルオロメチル)−2−ピリジニル)−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(49)、(2R,3S)−N−((3S)−5−(5−クロロ−2−ピリジニル)−9−メトキシ−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(50)、(2R,3S)−N−((3S)−5−(4−メトキシフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(51)、(2R,3S)−N−((3S)−5−(4−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(52)、(2R,3S)−N−((3S)−5−(3−フルオロフェニル)−9−(ヒドロキシメチル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(53)、((3S)−3−(((2R,3S)−3−カルバモイル−6,6,6−トリフルオロ−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−1−イル)メチルL−バリネート(54)、((3S)−3−(((2R,3S)−3−カルバモイル−6,6,6−トリフルオロ−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−1−イル)メチルL−アラニネート(55)、S−(((2S,3R)−6,6,6−トリフルオロ−3−(((3S)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)カルバモイル)−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−L−システイン(56)、tert−ブチルS−(((2S,3R)−6,6,6−トリフルオロ−3−(((3S)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)カルバモイル)−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−L−システイネート(57)、メチルS−(((2S,3R)−6,6,6−トリフルオロ−3−(((3S)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)カルバモイル)−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−L−システイネート(58)、((3S)−3−(((2R,3S)−3−カルバモイル−6,6,6−トリフルオロ−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−1−イル)メチル(4−(ホスホノオキシ)フェニル)アセテート(59)、((3S)−3−(((2R,3S)−3−カルバモイル−6,6,6−トリフルオロ−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−1−イル)メチルL−バリル−L−バリネート(60)、およびこれらの塩、から選択される、請求項4に記載の組成物。 - 前記B細胞成熟抗原(BCMA)標的化免疫療法剤が、キメラ抗原受容体T(CAR−T)細胞を含む、請求項1〜10のいずれか一項に記載の組成物。
- 前記B細胞成熟抗原(BCMA)標的化免疫療法剤が、抗体薬物複合体、二重特異性抗体、三重特異性抗体、三機能性抗体(trifunctional antibody)、化学的に連結されたFab、または二重特異性T細胞エンゲージャー(BiTE)を含む、請求項1〜10のいずれか一項に記載の組成物。
- 対象における、B細胞成熟抗原(BCMA)関連障害またはBCMA発現に関連する疾患を治療、抑制または阻害する方法であって、
1つ以上のB細胞成熟抗原(BCMA)標的化免疫療法剤を含む第1の組成物と、
式(I)の構造によって表される1つ以上の化合物および/またはその少なくとも1つの塩を含む第2の組成物と、を含む医薬組成物を、前記対象に投与するステップを含む方法。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。 - 前記B細胞成熟抗原(BCMA)関連障害が、増殖性疾患を含む、請求項13に記載の方法。
- 対象における増殖性疾患を治療、抑制または阻害する方法であって、
1つ以上のB細胞成熟抗原(BCMA)標的化免疫療法剤を含む第1の組成物と、式(I)の構造によって表される1つ以上の化合物および/またはその少なくとも1つの塩を含む第2の組成物と、を含む医薬組成物を、前記対象に投与するステップを含む方法。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。 - 前記増殖性疾患が、前癌状態または良性増殖性障害である、請求項14〜15のいずれか一項に記載の方法。
- 前記増殖性疾患が、癌である、請求項14〜15のいずれか一項に記載の方法。
- 対象における抗B細胞成熟抗原(BCMA)療法の有効性を改善する方法であって、
1つ以上のB細胞成熟抗原(BCMA)標的化免疫療法剤を含む第1の組成物と、
式(I)の構造によって表される1つ以上の化合物および/またはその少なくとも1つの塩を含む第2の組成物と、を含む医薬組成物を、前記対象に投与するステップを含む方法。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。 - 前記抗B細胞成熟抗原(BCMA)療法が抗癌療法を含む、請求項18に記載の方法。
- 前記B細胞成熟抗原(BCMA)標的化免疫療法剤が、キメラ抗原受容体T(CAR−T)細胞を含む、請求項13〜19のいずれか一項に記載の方法。
- 前記B細胞成熟抗原(BCMA)標的化免疫療法剤が、抗体薬物複合体、二重特異性抗体、三重特異性抗体、三機能性抗体、化学的に連結されたFab、または二重特異性T細胞エンゲージャー(BiTE)を含む、請求項13〜19のいずれか一項に記載の方法。
- 前記第1の組成物および/または前記第2の組成物が、前記対象に静脈内投与される、請求項13〜21のいずれか一項に記載の方法。
- 前記第1の組成物および/または前記第2の組成物が、前記対象に経口投与される、請求項13〜21のいずれか一項に記載の方法。
- 前記第1の組成物および前記第2の組成物が、一緒に投与される、請求項13〜21のいずれか一項に記載の方法。
- 前記第1の組成物および前記第2の組成物が、別個の部位または別個の時間に投与される、請求項13〜21のいずれか一項に記載の方法。
- 式(I)を含む前記組成物が、前記1つ以上のB細胞成熟抗原(BCMA)標的化免疫療法剤を含む前記組成物の投与の前に、そしてその後再び投与される、請求項13〜21のいずれか一項に記載の方法。
- 対象の癌細胞から脱落するB細胞成熟抗原(BCMA)を減少させる方法であって、式(I)の構造によって表される1つ以上の化合物および/またはその少なくとも1つの塩を含む組成物を、前記対象に投与するステップを含む方法。
R1は、−CH2CF3または−CH2CH2CF3であり、
R2は、−CH2CF3、−CH2CH2CF3、または−CH2CH2CH2CF3であり、
R3は、H、−CH3またはRxであり、
R4は、HまたはRyであり、
Rxは、−CH2OC(O)CH(CH3)NH2、−CH2OC(O)CH(NH2)CH(CH3)2、−CH2OC(O)CH((CH(CH3)2)NHC(O)CH(NH2)CH(CH3)2、
Ryは、−SCH2CH(NH2)C(O)OH、−SCH2CH(NH2)C(O)OH3、または−SCH2CH(NH2)C(O)OC(CH3)3であり、
環Aは、フェニルまたはピリジニルであり、
各Raは独立して、F、Cl、−CN、−OCH3、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、−O(シクロプロピル)および/または−NHCH2CH2OCH3であり、
各Rbは独立して、F、Cl、−CH3、−CH2OH、−CF3、シクロプロピル、および/または−OCH3であり、
yは、ゼロ、1、または2であり、
zは、1または2である。 - 前記組成物が、前記対象に静脈内または経口投与される、請求項27に記載の方法。
- 前記癌が、多発性骨髄腫を含む、請求項17および19〜28のいずれか一項に記載の方法。
- 前記癌が、白血病を含む、請求項17および19〜28のいずれか一項に記載の方法。
- 前記白血病が、T細胞急性リンパ芽球性白血病(T−ALL)を含む、請求項30に記載の方法。
- 前記癌が、リンパ腫を含む、請求項17および19〜28のいずれか一項に記載の方法。
- 前記癌が、固形腫瘍を含む、請求項17および19〜28のいずれか一項に記載の方法。
- R1が−CH2CH2CF3であり、
R2が−CH2CH2CF3または−CH2CH2CH2CF3であり、
各Raが独立して、Cl、C1〜3アルキル、−CH2OH、−CF3、シクロプロピル、−OCH3、および/または−O(シクロプロピル)である、請求項34に記載の方法。 - 環Aがフェニルであり、R3がHである、請求項36に記載の方法。
- R2が−CH2CH2CF3であり、環Aがフェニルである、請求項36に記載の方法。
- R2が−CH2CH2CF3であり、環Aがフェニルであり、RaがC1〜3アルキルまたは−CH2OHであり、各Rbが独立して、Fおよび/またはClであり、yが1である、請求項36に記載の方法。
- 前記1つ以上の化合物が、
(2R,3S)−N−((3S)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(22)、(2R,3S)−N−((3S)−5−(3−クロロフェニル)−9−エチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(23)、(2R,3S)−N−((3S)−5−(3−クロロフェニル)−9−イソプロピル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(24)、(2R,3S)−N−(9−クロロ−5−(3,4−ジメチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(25)、(2R,3S)−N−(9−クロロ−5−(3,5−ジメチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(26)、(2R,3S)−N−((3S)−9−エチル−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(27)、(2R,3S)−N−((3S)−5−(3−クロロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(28)、(2R,3S)−N−((3S)−5−(3−クロロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(29)、(2R,3S)−N−((3S)−5−(3−メチルフェニル)−2−オキソ−9−(トリフルオロメチル)−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(30)、(2R,3S)−N−((3S)−9−クロロ−5−(3,5−ジメチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(31)、(2R,3S)−N−((3S)−5−(3−メチルフェニル)−2−オキソ−9−(トリフルオロメチル)−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(32)、(2R,3S)−N−((3S)−9−イソプロピル−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(33)、(2R,3S)−N−((3S)−9−(シクロプロピルオキシ)−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(34)、(2R,3S)−N−((3S)−9−(シクロプロピルオキシ)−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(35)、(2R,3S)−N−((3S)−9−クロロ−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(36)、(2R,3S)−N−((3S)−9−メチル−2−オキソ−5−(3−(トリフルオロメチル)フェニル)−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−3−(4,4,4−トリフルオロブチル)−2−(3,3,3−トリフルオロプロピル)スクシンアミド(37)、(2R,3S)−N−((3S)−9−メチル−2−オキソ−5−(3−(トリフルオロメチル)フェニル)−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(38)、(2R,3S)−N−((3S)−9−クロロ−5−(2−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(39)、(2R,3S)−N−((3S)−5−(4−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(40)、(2R,3S)−N−((3S)−9−クロロ−5−(3−シクロプロピルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(41)、(2R,3S)−N−((3S)−5−(3−クロロフェニル)−9−メトキシ−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(42)、(2R,3S)−N−((3S)−5−(4−クロロフェニル)−9−メトキシ−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(43)、(2R,3S)−N−((3S)−9−クロロ−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(44)、(2R,3S)−N−((3S)−5−(3−メチルフェニル)−9−メトキシ−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(45)、(2R,3S)−N−((3S)−5−(4−(ヒドロキシメチル)フェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(46)、(2R,3S)−N−((3S)−5−(2−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(47)、(2R,3S)−N−((3S)−5−(3−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(48)、(2R,3S)−N−((3S)−9−メトキシ−2−オキソ−5−(5−(トリフルオロメチル)−2−ピリジニル)−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(49)、(2R,3S)−N−((3S)−5−(5−クロロ−2−ピリジニル)−9−メトキシ−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(50)、(2R,3S)−N−((3S)−5−(4−メトキシフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(51)、(2R,3S)−N−((3S)−5−(4−メチルフェニル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(52)、(2R,3S)−N−((3S)−5−(3−フルオロフェニル)−9−(ヒドロキシメチル)−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)−2,3−ビス(3,3,3−トリフルオロプロピル)スクシンアミド(53)、((3S)−3−(((2R,3S)−3−カルバモイル−6,6,6−トリフルオロ−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−1−イル)メチルL−バリネート(54)、((3S)−3−(((2R,3S)−3−カルバモイル−6,6,6−トリフルオロ−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−1−イル)メチルL−アラニネート(55)、S−(((2S,3R)−6,6,6−トリフルオロ−3−(((3S)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)カルバモイル)−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−L−システイン(56)、tert−ブチルS−(((2S,3R)−6,6,6−トリフルオロ−3−(((3S)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)カルバモイル)−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−L−システイネート(57);メチルS−(((2S,3R)−6,6,6−トリフルオロ−3−(((3S)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−3−イル)カルバモイル)−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−L−システイネート(58)、((3S)−3−(((2R,3S)−3−カルバモイル−6,6,6−トリフルオロ−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−1−イル)メチル(4−(ホスホノオキシ)フェニル)アセテート(59)、((3S)−3−(((2R,3S)−3−カルバモイル−6,6,6−トリフルオロ−2−(3,3,3−トリフルオロプロピル)ヘキサノイル)アミノ)−5−(3−フルオロフェニル)−9−メチル−2−オキソ−2,3−ジヒドロ−1H−1,4−ベンゾジアゼピン−1−イル)メチルL−バリル−L−バリネート(60)、およびこれらの塩、から選択される、請求項36に記載の方法。
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JP2003523932A (ja) * | 1998-12-24 | 2003-08-12 | デュポン ファーマシューティカルズ カンパニー | Aβタンパク質生成の阻害剤としてのスクシノイルアミノベンゾジアゼピン |
JP2015530411A (ja) * | 2012-09-21 | 2015-10-15 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Notch阻害剤としてのビス(フルオロアルキル)−1,4−ベンゾジアゼピノン化合物 |
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WO2019226329A1 (en) | 2019-11-28 |
US20200085839A1 (en) | 2020-03-19 |
AU2019275284A1 (en) | 2021-01-14 |
CN112203661A (zh) | 2021-01-08 |
EP3801551A1 (en) | 2021-04-14 |
MX2020012561A (es) | 2021-01-29 |
SG11202011589WA (en) | 2020-12-30 |
IL278829A (en) | 2021-01-31 |
EP3801551A4 (en) | 2022-04-06 |
BR112020023975A2 (pt) | 2021-02-23 |
US20220288088A1 (en) | 2022-09-15 |
KR20210013184A (ko) | 2021-02-03 |
CA3101340A1 (en) | 2019-11-28 |
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