JP2021502386A - Ash1l分解剤及びそれを用いた治療方法 - Google Patents
Ash1l分解剤及びそれを用いた治療方法 Download PDFInfo
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- JP2021502386A JP2021502386A JP2020526059A JP2020526059A JP2021502386A JP 2021502386 A JP2021502386 A JP 2021502386A JP 2020526059 A JP2020526059 A JP 2020526059A JP 2020526059 A JP2020526059 A JP 2020526059A JP 2021502386 A JP2021502386 A JP 2021502386A
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Abstract
Description
関連出願の相互参照
本発明は、2017年11月10日に出願された米国仮特許出願62/584,473の優先権の利益を主張し、これは参照によりその全体が組み込まれる。
ASH1L(Absent small and homeotic disksタンパク質1相同体;EC:2.1.1.43)は、ヒストン3のリジン36(H3K36)をメチル化するヒストン−リジンN−メチルトランスフェラーゼ(KMTase)である。ASH1Lは、重要な白血病標的遺伝子におけるMLL融合タンパク質のクロマチン結合のため及びMLL融合タンパク質が媒介性する発がん性形質転換のために必要とされ、このことは、ASH1LがMLL白血病及び高いHOX発現を有する他の白血病における治療標的を表すことを示唆している(参考文献1;それらの全体が参照により組み込まれる)。ASH1Lはまた、甲状腺及び乳癌を含む様々な固形腫瘍で過剰発現する(参考文献2、3;それらの全体が参照により組み込まれる)。甲状腺癌では、ASH1Lは、腫瘍特異的切断型で過剰発現する。腫瘍抑制因子であるマイクロRNAのmiR−142−3pは、ASH1Lの3’UTRに結合することによってASH1Lタンパク質発現を阻害し、コロニー形成の阻害及び甲状腺癌細胞成長の遅延化と相関する効果を示す(参考文献2;その全体が参照により組み込まれる)。また、ASH1L遺伝子は、侵攻性基底様乳癌においてコピー数増幅を頻繁に受け、ASH1LのmRNAの高発現は、乳癌患者のより短い生存期間と関連している(参考文献3;その全体が参照により組み込まれる)。最後に、肝細胞癌(HCC)では、ASH1L遺伝子付近に構造変化が見られ、HCC細胞におけるASH1Lのノックダウンは、増殖を遅延させる(参考文献4;その全体が参照により組み込まれる)。
本明細書では、ASH1Lに結合する第1のドメイン及びASH1Lの分解を促進する第2のドメインを含む小分子が提供される。特に、ASH1L標的タンパク質分解標的キメラ(PROTAC)ならびに疾患(例えば、急性白血病、固形がん及びASH1Lの活性に依存する他の疾患)の治療のためのその使用方法が提供される。
またはその塩が本明細書で提供される。いくつかの実施形態では、式(Ic)の化合物は、式(Ia)について本明細書で記載される任意の部分及び置換基を含む。
またはその塩が本明細書で提供される。いくつかの実施形態では、式(Id)の化合物は、式(Ib)について本明細書で記載される任意の部分及び置換基を含む。
またはその塩が本明細書で提供される。いくつかの実施形態では、式(IIc)の化合物は、式(IIa)について本明細書で記載される任意の部分及び置換基を含む。
またはその塩が本明細書で提供される。いくつかの実施形態では、式(IId)の化合物は、式(IIb)について本明細書で記載される任意の部分及び置換基を含む。
またはその塩が本明細書で提供される。いくつかの実施形態では、式(IIIc)の化合物は、式(IIIa)について本明細書で記載される任意の部分及び置換基を含む。
またはその塩が本明細書で提供される。いくつかの実施形態では、式(IIId)の化合物は、式(IIIb)について本明細書で記載される任意の部分及び置換基を含む。
Zは、OまたはSであり;
R1は、H、アルキル、置換アルキル(例えば、ハロゲン置換アルキル)、分岐状アルキル、置換分岐状アルキル(例えば、ハロゲン置換分岐状アルキル)、アルコキシ、アミン、置換アミン、チオアルキル、ケトン、アミド、置換アミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環式環、置換炭素環式環、芳香族環、置換芳香族環、複素環式芳香族環、置換複素環式芳香族環、置換または非置換複素環式非芳香族環(例えば、ピペリジン、メチルピペリジン、架橋ピペリジン、テトラヒドロピラン、アルキルスルホニル置換ピペリジン、スルホンアミド置換ピペリジン、アリールスルホニル置換ピペリジン、1−((トリフルオロメチル)スルホニル)ピペリジン)、ジフルオロシクロヘキサン、モノフルオロシクロヘキサン、シクロヘキサン、置換ジフルオロシクロヘキサン、ビシクロオクタン、シクロヘプタン、別の芳香族環に縮合した炭素環式または複素環式芳香族環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから選択され;
R2、R3、R4、R5、及びR7は、独立して、H、ハロゲン(例えば、Cl、F、Br、I)、CH3、OH、SH、NH2、CN、CF3、CCl3、−CH2−CH3、−CH2−OH、−CH2NH2、CH3SH、CH2Cl、CH2Br、CH2F、CHF2、CH2CN、CH2CF3、及びCH2Cl3、アルキル、ハロアルキル、アルコールから選択され;
Aは、共有結合(すなわち、原子が存在しない)であるか、または表1に列挙された構造(式中、nは、0、1、2、3、4、5、6、7、8、9または10であり;mは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14もしくは15またはそれらの間の範囲であり;kは、存在する場合、0、1、2、3、4、5、6、7、8、9または10であり;lは、存在する場合、0、1、2、3、4、5、6、7、8、9または10である)から選択され;
リンカーは、表2に列挙された構造(式中、nは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15であり;mは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14もしくは15またはそれらの間の範囲であり);kは、存在する場合、0、1、2、3、4、5、6、7、8、9または10であり;lは、存在する場合、0、1、2、3、4、5、6、7、8、9または10である)から選択され;リガーゼリガンドは、表3に列挙されたものから選択される)を含むASH1L分解を誘導する化合物が本明細書で提供される。
各J、J1、J2、J3、及びJ4は、存在する場合、独立して、共有結合、H、アルキル1−15、アルケニル1−6、アルキニル1−6、(CH2)0−6C(S)NH2、(CH2)0−6C(O)NH2、O、S、NH、(CH2)0−6C(O)NH(CH2)1−6、(CH2)0−6NHC(O)(CH2)1−6、アルキニスルホニル、スルホンアミド、アルキルスルホンアミド、(CH2)0−6C(S)NH(CH2)1−6、(CH2)0−6O(CH2)1−6、(CH2)0−6OH、(CH2)0−6S(CH2)1−6、(CH2)0−6SH、(CH2)0−6NH(CH2)1−6、(CH2)0−6N(CH2)1−6(CH2)1−6、(CH2)0−6NH2、(CH2)0−6SO2(CH2)1−6、(CH2)0−6NHSO2(CH2)1−6、(CH2)0−6SO2NH2、ハロゲン(例えば、F、Cl、Br、またはI)、ハロアルキル(例えば、(CH2)0−6CH2F、(CH2)0−3CHF(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、ジハロアルキル(例えば、(CH2)0−6CF2H、(CH2)0−3CF2(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、トリハロアルキル(例えば、(CH2)0−6CF3、またはBr、Cl、もしくはIを有する類似物)、その長さに沿って2つ以上の位置で1〜3個のハロゲンを有するアルキル、(CH2)1−4SP(Ph)2=S、(CH2)0−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−5SH、(CH2)0−6O(CH2)1−6NH(CH2)1−5OH、(CH2)0−6O(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6O(CH2)1−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−6O(CH2)1−5SH、(CH2)0−6O(CH2)1−6S(CH2)1−5OH、(CH2)0−6O(CH2)1−6S(CH2)1−5NH2、(CH2)0−6O(CH2)1−6S(CH2)1−5SH、(CH2)0−6S(CH2)1−6NH(CH2)1−5OH、(CH2)0−6S(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6S(CH2)1−6NH(CH2)1−5SH、(CH2)0−6S(CH2)1−6O(CH2)1−5OH、(CH2)0−6S(CH2)1−6O(CH2)1−5NH2、(CH2)0−6S(CH2)1−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−6S(CH2)1−5SH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6NH(CH2)1−5SH、(CH2)0−6NH(CH2)1−6O(CH2)1−5OH、(CH2)0−6NH(CH2)1−6O(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6O(CH2)1−5SH、(CH2)0−6NH(CH2)1−6S(CH2)1−5OH、(CH2)0−6NH(CH2)1−6S(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6S(CH2)1−5SH、(CH2)0−3C(O)O(CH2)0−3、(CH2)0−3C(S)O(CH2)0−3、(CH2)0−3C(O)S(CH2)0−3、(CH2)0−3C(S)S(CH2)0−3、(CH2)0−3C(O)NH(CH2)0−3、(CH2)0−3C(S)NH(CH2)0−3、(CH2)0−3NHC(O)(CH2)0−3、(CH2)0−3NHC(S)(CH2)0−3、(CH2)0−3OC(O)(CH2)0−3、(CH2)0−3OC(S)(CH2)0−3、(CH2)0−3SC(O)(CH2)0−3、(CH2)0−3SC(S)(CH2)0−3、(CH2)0−3NHC(O)NH(CH2)0−3、(CH2)0−3NHC(S)NH(CH2)0−3、(CH2)0−3OC(O)NH(CH2)0−3、(CH2)0−3OC(S)NH(CH2)0−3、(CH2)0−3SC(O)NH(CH2)0−3、(CH2)0−3SC(S)NH(CH2)0−3、(CH2)0−3NHC(O)O(CH2)0−3、(CH2)0−3NHC(S)O(CH2)0−3、(CH2)0−3OC(O)O(CH2)0−3、(CH2)0−3OC(S)O(CH2)0−3、(CH2)0−3SC(O)O(CH2)0−3、(CH2)0−3SC(S)O(CH2)0−3、(CH2)0−3NHC(O)S(CH2)0−3、(CH2)0−3NHC(S)S(CH2)0−3、(CH2)0−3OC(O)S(CH2)0−3、(CH2)0−3OC(S)S(CH2)0−3、(CH2)0−3SC(O)S(CH2)0−3、(CH2)0−3SC(S)S(CH2)0−3、(CH2O)1−6、及びトリメチルメタンからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、独立して、フラン、ベンゾフラン、イソベンゾフラン、ピロール、インドール、イソインドール、チオフェン、ベンゾチオフェン、ベンゾ[c]チオフェン、イミダゾール、ベンズイミダゾール、プリン、ピラゾール、インダゾール、オキサゾール、ベンゾオキサゾール、イソキサゾール、ベンズイソキサゾール、チアゾール、ベンゾチアゾール、ベンゼン、ナフタレン、ピリジン、キノロン、イソキノリン、ピラジン、キノキサリン、ピリミジン、キナゾリン、ピリダジン、シンノリン、フタラジン、サリドマイド、トリアジン(例えば、1,2,3−トリアジン;1,2,4−トリアジン;1,3,5トリアジン)、チアジアゾール、アジリジン、チイラン(エピスルフィド)、オキシラン(エチレンオキシド、エポキシド)、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、オキサン、チアン、ペピエラジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、チチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3−シクロヘキサジエン、1,4−シクロヘキサジエン、1,5−シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3〜C7シクロアルキル基、及び表4で示される環構造のいずれかからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、Q環上の任意の位置で1つ以上の追加のJ基を示し得;
上記の任意のアルキルまたは(CH2)x−y基は、直鎖または分岐状であり得;
上記の任意のアルキルまたは(CH2)x−y基は追加的に、1つ以上の炭素上でOH、=O、NH2、CN、ジハロアルキル(例えば、CF2H)、トリハロアルキル(例えば、CF3)、またはハロゲン(例えば、F)置換基を含み得;
上記の基の末端位置上の水素の数は、基が追加の基に連結している場合に調整され得(例えば、CH3はCH2に調整される、OHはOに調整されるなど)、または基が末端である場合に調整され得る(例えば、CH2はCH3に調整される、OはOHに調整されるなど))。
R1は、H、アルキル、置換アルキル(例えば、ハロゲン置換アルキル)、分岐状アルキル、置換分岐状アルキル(例えば、ハロゲン置換分岐状アルキル)、アルコキシ、アミン、置換アミン、チオアルキル、ケトン、アミド、置換アミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環式環、置換炭素環式環、芳香族環、置換芳香族環、複素環式芳香族環、置換複素環式芳香族環、置換または非置換複素環式非芳香族環(例えば、ピペリジン、メチルピペリジン、架橋ピペリジン、テトラヒドロピラン、アルキルスルホニル置換ピペリジン、スルホンアミド置換ピペリジン、アリールスルホニル置換ピペリジン、1−((トリフルオロメチル)スルホニル)ピペリジン)、ジフルオロシクロヘキサン、モノフルオロシクロヘキサン、シクロヘキサン、置換ジフルオロシクロヘキサン、ビシクロオクタン、シクロヘプタン、別の芳香族環に縮合した炭素環式または複素環式芳香族環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから選択され;
Aは、共有結合(すなわち、原子が存在しない)であるか、または表1に列挙された構造(式中、nは、0、1、2、3、4、5、6、7、8、9または10であり;mは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14もしくは15またはそれらの間の範囲であり;kは、存在する場合、0、1、2、3、4、5、6、7、8、9または10であり;lは、存在する場合、0、1、2、3、4、5、6、7、8、9または10である)から選択され;
リンカーは、表2に列挙された構造(式中、nは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15であり;mは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14もしくは15またはそれらの間の範囲であり;kは、存在する場合、0、1、2、3、4、5、6、7、8、9または10であり;lは、存在する場合、0、1、2、3、4、5、6、7、8、9または10である)から選択され;
リガーゼリガンドは、表3に列挙されたものから選択される)を含むASH1L分解を誘導する化合物である。
(式中、J、Q1、またはJ1のうちの1つは、存在する場合、主骨格に連結されており;
各J、J1、J2、J3、及びJ4は、存在する場合、独立して、共有結合、H、アルキル1−15、アルケニル1−6、アルキニル1−6、(CH2)0−6C(S)NH2、(CH2)0−6C(O)NH2、O、S、NH、(CH2)0−6C(O)NH(CH2)1−6、(CH2)0−6NHC(O)(CH2)1−6、アルキニスルホニル、スルホンアミド、アルキルスルホンアミド、(CH2)0−6C(S)NH(CH2)1−6、(CH2)0−6O(CH2)1−6、(CH2)0−6OH、(CH2)0−6S(CH2)1−6、(CH2)0−6SH、(CH2)0−6NH(CH2)1−6、(CH2)0−6N(CH2)1−6(CH2)1−6、(CH2)0−6NH2、(CH2)0−6SO2(CH2)1−6、(CH2)0−6NHSO2(CH2)1−6、(CH2)0−6SO2NH2、ハロゲン(例えば、F、Cl、Br、またはI)、ハロアルキル(例えば、(CH2)0−6CH2F、(CH2)0−3CHF(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、ジハロアルキル(例えば、(CH2)0−6CF2H、(CH2)0−3CF2(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、トリハロアルキル(例えば、(CH2)0−6CF3、またはBr、Cl、もしくはIを有する類似物)、その長さに沿って2つ以上の位置で1〜3個のハロゲンを有するアルキル、(CH2)1−4SP(Ph)2=S、(CH2)0−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−5SH、(CH2)0−6O(CH2)1−6NH(CH2)1−5OH、(CH2)0−6O(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6O(CH2)1−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−6O(CH2)1−5SH、(CH2)0−6O(CH2)1−6S(CH2)1−5OH、(CH2)0−6O(CH2)1−6S(CH2)1−5NH2、(CH2)0−6O(CH2)1−6S(CH2)1−5SH、(CH2)0−6S(CH2)1−6NH(CH2)1−5OH、(CH2)0−6S(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6S(CH2)1−6NH(CH2)1−5SH、(CH2)0−6S(CH2)1−6O(CH2)1−5OH、(CH2)0−6S(CH2)1−6O(CH2)1−5NH2、(CH2)0−6S(CH2)1−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−6S(CH2)1−5SH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6NH(CH2)1−5SH、(CH2)0−6NH(CH2)1−6O(CH2)1−5OH、(CH2)0−6NH(CH2)1−6O(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6O(CH2)1−5SH、(CH2)0−6NH(CH2)1−6S(CH2)1−5OH、(CH2)0−6NH(CH2)1−6S(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6S(CH2)1−5SH、(CH2)0−3C(O)O(CH2)0−3、(CH2)0−3C(S)O(CH2)0−3、(CH2)0−3C(O)S(CH2)0−3、(CH2)0−3C(S)S(CH2)0−3、(CH2)0−3C(O)NH(CH2)0−3、(CH2)0−3C(S)NH(CH2)0−3、(CH2)0−3NHC(O)(CH2)0−3、(CH2)0−3NHC(S)(CH2)0−3、(CH2)0−3OC(O)(CH2)0−3、(CH2)0−3OC(S)(CH2)0−3、(CH2)0−3SC(O)(CH2)0−3、(CH2)0−3SC(S)(CH2)0−3、(CH2)0−3NHC(O)NH(CH2)0−3、(CH2)0−3NHC(S)NH(CH2)0−3、(CH2)0−3OC(O)NH(CH2)0−3、(CH2)0−3OC(S)NH(CH2)0−3、(CH2)0−3SC(O)NH(CH2)0−3、(CH2)0−3SC(S)NH(CH2)0−3、(CH2)0−3NHC(O)O(CH2)0−3、(CH2)0−3NHC(S)O(CH2)0−3、(CH2)0−3OC(O)O(CH2)0−3、(CH2)0−3OC(S)O(CH2)0−3、(CH2)0−3SC(O)O(CH2)0−3、(CH2)0−3SC(S)O(CH2)0−3、(CH2)0−3NHC(O)S(CH2)0−3、(CH2)0−3NHC(S)S(CH2)0−3、(CH2)0−3OC(O)S(CH2)0−3、(CH2)0−3OC(S)S(CH2)0−3、(CH2)0−3SC(O)S(CH2)0−3、(CH2)0−3SC(S)S(CH2)0−3、(CH2O)1−6、及びトリメチルメタンからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、独立して、フラン、ベンゾフラン、イソベンゾフラン、ピロール、インドール、イソインドール、チオフェン、ベンゾチオフェン、ベンゾ[c]チオフェン、イミダゾール、ベンズイミダゾール、プリン、ピラゾール、インダゾール、オキサゾール、ベンゾオキサゾール、イソキサゾール、ベンズイソキサゾール、チアゾール、ベンゾチアゾール、ベンゼン、ナフタレン、ピリジン、キノロン、イソキノリン、ピラジン、キノキサリン、ピリミジン、キナゾリン、ピリダジン、シンノリン、フタラジン、サリドマイド、トリアジン(例えば、1,2,3−トリアジン;1,2,4−トリアジン;1,3,5トリアジン)、チアジアゾール、アジリジン、チイラン(エピスルフィド)、オキシラン(エチレンオキシド、エポキシド)、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、オキサン、チアン、ペピエラジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、チチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3−シクロヘキサジエン、1,4−シクロヘキサジエン、1,5−シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3〜C7シクロアルキル基、及び表4で示される環構造のいずれかからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、Q環上の任意の位置で1つ以上の追加のJ基を示し得;
上記の任意のアルキルまたは(CH2)x−y基は、直鎖または分岐状であり得;
上記の任意のアルキルまたは(CH2)x−y基は追加的に、1つ以上の炭素上でOH、=O、NH2、CN、ジハロアルキル(例えば、CF2H)、トリハロアルキル(例えば、CF3)、またはハロゲン(例えば、F)置換基を含み得;
上記の基の末端位置上の水素の数は、基が追加の基に連結している場合に調整され得(例えば、CH3はCH2に調整される、OHはOに調整されるなど)、または基が末端である場合に調整され得る(例えば、CH2はCH3に調整される、OはOHに調整されるなど))。
Zは、OまたはSであり;
R2、R3、R4、R5、及びR7は、独立して、H、ハロゲン(例えば、Cl、F、Br、I)、CH3、OH、SH、NH2、CN、CF3、CCl3、−CH2−CH3、−CH2−OH、−CH2NH2、CH3SH、CH2Cl、CH2Br、CH2F、CHF2、CH2CN、CH2CF3、及びCH2Cl3から選択され;
R6は、H、アルキル、置換アルキル(例えば、ハロゲン置換アルキル)、分岐状アルキル、置換分岐状アルキル(例えば、ハロゲン置換分岐状アルキル)ヒドロキシ、アルコキシ、アミン、置換アミン、チオアルキル、ハロゲン、ケトン、アミド、置換アミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環式環、置換炭素環式環、芳香族環、置換芳香族環、複素環式芳香族環、置換複素環式芳香族環、置換または非置換複素環式非芳香族環(例えば、ピペリジン、メチルピペリジン、架橋ピペリジン、テトラヒドロピラン、アルキルスルホニル置換ピペリジン、スルホンアミド置換ピペリジン、アリールスルホニル置換ピペリジン)、別の芳香族環に縮合した炭素環式または複素環式芳香族環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから選択され;
R22及びR23は、独立して、H、ハロゲン(例えば、Cl、F、Br、I)、CH3、OH、SH、NH2、CN、CF3、CCl3、−CH2−CH3、−CH2−OH、−CH2NH2、CH3SH、CH2Cl、CH2Br、CH2F、CHF2、CH2CN、CH2CF3、及びCH2Cl3から選択され;
リンカーは、表6に列挙された構造(式中、nは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15であり;mは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14もしくは15またはそれらの間の範囲であり;kは、存在する場合、0、1、2、3、4、5、6、7、8、9または10であり;lは、存在する場合、0、1、2、3、4、5、6、7、8、9または10である)から選択され;
リガーゼリガンドは、表7に列挙されたものから選択される)を含むASH1L分解化合物が本明細書で提供される。
(式中、J、Q1、またはJ1のうちの1つは、存在する場合、主骨格に連結されており;
各J、J1、J2、J3、及びJ4は、存在する場合、独立して、共有結合、H、アルキル1−15、アルケニル1−6、アルキニル1−6、(CH2)0−6C(S)NH2、(CH2)0−6C(O)NH2、O、S、NH、(CH2)0−6C(O)NH(CH2)1−6、(CH2)0−6NHC(O)(CH2)1−6、アルキニスルホニル、スルホンアミド、アルキルスルホンアミド、(CH2)0−6C(S)NH(CH2)1−6、(CH2)0−6O(CH2)1−6、(CH2)0−6OH、(CH2)0−6S(CH2)1−6、(CH2)0−6SH、(CH2)0−6NH(CH2)1−6、(CH2)0−6N(CH2)1−6(CH2)1−6、(CH2)0−6NH2、(CH2)0−6SO2(CH2)1−6、(CH2)0−6NHSO2(CH2)1−6、(CH2)0−6SO2NH2、ハロゲン(例えば、F、Cl、Br、またはI)、ハロアルキル(例えば、(CH2)0−6CH2F、(CH2)0−3CHF(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、ジハロアルキル(例えば、(CH2)0−6CF2H、(CH2)0−3CF2(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、トリハロアルキル(例えば、(CH2)0−6CF3、またはBr、Cl、もしくはIを有する類似物)、その長さに沿って2つ以上の位置で1〜3個のハロゲンを有するアルキル、(CH2)1−4SP(Ph)2=S、(CH2)0−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−5SH、(CH2)0−6O(CH2)1−6NH(CH2)1−5OH、(CH2)0−6O(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6O(CH2)1−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−6O(CH2)1−5SH、(CH2)0−6O(CH2)1−6S(CH2)1−5OH、(CH2)0−6O(CH2)1−6S(CH2)1−5NH2、(CH2)0−6O(CH2)1−6S(CH2)1−5SH、(CH2)0−6S(CH2)1−6NH(CH2)1−5OH、(CH2)0−6S(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6S(CH2)1−6NH(CH2)1−5SH、(CH2)0−6S(CH2)1−6O(CH2)1−5OH、(CH2)0−6S(CH2)1−6O(CH2)1−5NH2、(CH2)0−6S(CH2)1−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−6S(CH2)1−5SH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6NH(CH2)1−5SH、(CH2)0−6NH(CH2)1−6O(CH2)1−5OH、(CH2)0−6NH(CH2)1−6O(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6O(CH2)1−5SH、(CH2)0−6NH(CH2)1−6S(CH2)1−5OH、(CH2)0−6NH(CH2)1−6S(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6S(CH2)1−5SH、(CH2)0−3C(O)O(CH2)0−3、(CH2)0−3C(S)O(CH2)0−3、(CH2)0−3C(O)S(CH2)0−3、(CH2)0−3C(S)S(CH2)0−3、(CH2)0−3C(O)NH(CH2)0−3、(CH2)0−3C(S)NH(CH2)0−3、(CH2)0−3NHC(O)(CH2)0−3、(CH2)0−3NHC(S)(CH2)0−3、(CH2)0−3OC(O)(CH2)0−3、(CH2)0−3OC(S)(CH2)0−3、(CH2)0−3SC(O)(CH2)0−3、(CH2)0−3SC(S)(CH2)0−3、(CH2)0−3NHC(O)NH(CH2)0−3、(CH2)0−3NHC(S)NH(CH2)0−3、(CH2)0−3OC(O)NH(CH2)0−3、(CH2)0−3OC(S)NH(CH2)0−3、(CH2)0−3SC(O)NH(CH2)0−3、(CH2)0−3SC(S)NH(CH2)0−3、(CH2)0−3NHC(O)O(CH2)0−3、(CH2)0−3NHC(S)O(CH2)0−3、(CH2)0−3OC(O)O(CH2)0−3、(CH2)0−3OC(S)O(CH2)0−3、(CH2)0−3SC(O)O(CH2)0−3、(CH2)0−3SC(S)O(CH2)0−3、(CH2)0−3NHC(O)S(CH2)0−3、(CH2)0−3NHC(S)S(CH2)0−3、(CH2)0−3OC(O)S(CH2)0−3、(CH2)0−3OC(S)S(CH2)0−3、(CH2)0−3SC(O)S(CH2)0−3、(CH2)0−3SC(S)S(CH2)0−3、(CH2O)1−6、及びトリメチルメタンからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、独立して、フラン、ベンゾフラン、イソベンゾフラン、ピロール、インドール、イソインドール、チオフェン、ベンゾチオフェン、ベンゾ[c]チオフェン、イミダゾール、ベンズイミダゾール、プリン、ピラゾール、インダゾール、オキサゾール、ベンゾオキサゾール、イソキサゾール、ベンズイソキサゾール、チアゾール、ベンゾチアゾール、ベンゼン、ナフタレン、ピリジン、キノロン、イソキノリン、ピラジン、キノキサリン、ピリミジン、キナゾリン、ピリダジン、シンノリン、フタラジン、サリドマイド、トリアジン(例えば、1,2,3−トリアジン;1,2,4−トリアジン;1,3,5トリアジン)、チアジアゾール、アジリジン、チイラン(エピスルフィド)、オキシラン(エチレンオキシド、エポキシド)、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、オキサン、チアン、ペピエラジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、チチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3−シクロヘキサジエン、1,4−シクロヘキサジエン、1,5−シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3〜C7シクロアルキル基、及び表4で示される環構造のいずれかからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、Q環上の任意の位置で1つ以上の追加のJ基を示し得;
上記の任意のアルキルまたは(CH2)x−y基は、直鎖または分岐状であり得;
上記の任意のアルキルまたは(CH2)x−y基は追加的に、1つ以上の炭素上でOH、=O、NH2、CN、ジハロアルキル(例えば、CF2H)、トリハロアルキル(例えば、CF3)、またはハロゲン(例えば、F)置換基を含み得;
上記の基の末端位置上の水素の数は、基が追加の基に連結している場合に調整され得(例えば、CH3はCH2に調整される、OHはOに調整されるなど)、または基が末端である場合に調整され得る(例えば、CH2はCH3に調整される、OはOHに調整されるなど))。
R6は、H、アルキル、置換アルキル、ヒドロキシ、アルコキシ、アミン、置換アミン、アルキルアミン、置換アルキルアミン、チオアルキル、ハロゲン、ケトン、アミド、置換アミド、アルキルアミド、置換アルキルアミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環式環、置換炭素環式環、芳香族環、置換芳香族環、複素環式芳香族環、置換複素環式芳香族環、置換または非置換複素環式非芳香族環、別の芳香族環に縮合した炭素環式または複素環式芳香族環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから選択され;
リンカーは、表6に列挙された構造(式中、nは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15であり;mは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14もしくは15またはそれらの間の範囲であり);kは、存在する場合、0、1、2、3、4、5、6、7、8、9または10であり;lは、存在する場合、0、1、2、3、4、5、6、7、8、9または10である)から選択され;リガーゼリガンドは、表7に列挙されたものから選択される)を含むASH1L分解化合物が本明細書で提供される。
(式中、J、Q1、またはJ1のうちの1つは、存在する場合、主骨格に連結されており;
各J、J1、J2、J3、及びJ4は、存在する場合、独立して、共有結合、H、アルキル1−15、アルケニル1−6、アルキニル1−6、(CH2)0−6C(S)NH2、(CH2)0−6C(O)NH2、O、S、NH、(CH2)0−6C(O)NH(CH2)1−6、(CH2)0−6NHC(O)(CH2)1−6、アルキニスルホニル、スルホンアミド、アルキルスルホンアミド、(CH2)0−6C(S)NH(CH2)1−6、(CH2)0−6O(CH2)1−6、(CH2)0−6OH、(CH2)0−6S(CH2)1−6、(CH2)0−6SH、(CH2)0−6NH(CH2)1−6、(CH2)0−6N(CH2)1−6(CH2)1−6、(CH2)0−6NH2、(CH2)0−6SO2(CH2)1−6、(CH2)0−6NHSO2(CH2)1−6、(CH2)0−6SO2NH2、ハロゲン(例えば、F、Cl、Br、またはI)、ハロアルキル(例えば、(CH2)0−6CH2F、(CH2)0−3CHF(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、ジハロアルキル(例えば、(CH2)0−6CF2H、(CH2)0−3CF2(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、トリハロアルキル(例えば、(CH2)0−6CF3、またはBr、Cl、もしくはIを有する類似物)、その長さに沿って2つ以上の位置で1〜3個のハロゲンを有するアルキル、(CH2)1−4SP(Ph)2=S、(CH2)0−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−5SH、(CH2)0−6O(CH2)1−6NH(CH2)1−5OH、(CH2)0−6O(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6O(CH2)1−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−6O(CH2)1−5SH、(CH2)0−6O(CH2)1−6S(CH2)1−5OH、(CH2)0−6O(CH2)1−6S(CH2)1−5NH2、(CH2)0−6O(CH2)1−6S(CH2)1−5SH、(CH2)0−6S(CH2)1−6NH(CH2)1−5OH、(CH2)0−6S(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6S(CH2)1−6NH(CH2)1−5SH、(CH2)0−6S(CH2)1−6O(CH2)1−5OH、(CH2)0−6S(CH2)1−6O(CH2)1−5NH2、(CH2)0−6S(CH2)1−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−6S(CH2)1−5SH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6NH(CH2)1−5SH、(CH2)0−6NH(CH2)1−6O(CH2)1−5OH、(CH2)0−6NH(CH2)1−6O(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6O(CH2)1−5SH、(CH2)0−6NH(CH2)1−6S(CH2)1−5OH、(CH2)0−6NH(CH2)1−6S(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6S(CH2)1−5SH、(CH2)0−3C(O)O(CH2)0−3、(CH2)0−3C(S)O(CH2)0−3、(CH2)0−3C(O)S(CH2)0−3、(CH2)0−3C(S)S(CH2)0−3、(CH2)0−3C(O)NH(CH2)0−3、(CH2)0−3C(S)NH(CH2)0−3、(CH2)0−3NHC(O)(CH2)0−3、(CH2)0−3NHC(S)(CH2)0−3、(CH2)0−3OC(O)(CH2)0−3、(CH2)0−3OC(S)(CH2)0−3、(CH2)0−3SC(O)(CH2)0−3、(CH2)0−3SC(S)(CH2)0−3、(CH2)0−3NHC(O)NH(CH2)0−3、(CH2)0−3NHC(S)NH(CH2)0−3、(CH2)0−3OC(O)NH(CH2)0−3、(CH2)0−3OC(S)NH(CH2)0−3、(CH2)0−3SC(O)NH(CH2)0−3、(CH2)0−3SC(S)NH(CH2)0−3、(CH2)0−3NHC(O)O(CH2)0−3、(CH2)0−3NHC(S)O(CH2)0−3、(CH2)0−3OC(O)O(CH2)0−3、(CH2)0−3OC(S)O(CH2)0−3、(CH2)0−3SC(O)O(CH2)0−3、(CH2)0−3SC(S)O(CH2)0−3、(CH2)0−3NHC(O)S(CH2)0−3、(CH2)0−3NHC(S)S(CH2)0−3、(CH2)0−3OC(O)S(CH2)0−3、(CH2)0−3OC(S)S(CH2)0−3、(CH2)0−3SC(O)S(CH2)0−3、(CH2)0−3SC(S)S(CH2)0−3、(CH2O)1−6、及びトリメチルメタンからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、独立して、フラン、ベンゾフラン、イソベンゾフラン、ピロール、インドール、イソインドール、チオフェン、ベンゾチオフェン、ベンゾ[c]チオフェン、イミダゾール、ベンズイミダゾール、プリン、ピラゾール、インダゾール、オキサゾール、ベンゾオキサゾール、イソキサゾール、ベンズイソキサゾール、チアゾール、ベンゾチアゾール、ベンゼン、ナフタレン、ピリジン、キノロン、イソキノリン、ピラジン、キノキサリン、ピリミジン、キナゾリン、ピリダジン、シンノリン、フタラジン、サリドマイド、トリアジン(例えば、1,2,3−トリアジン;1,2,4−トリアジン;1,3,5トリアジン)、チアジアゾール、アジリジン、チイラン(エピスルフィド)、オキシラン(エチレンオキシド、エポキシド)、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、オキサン、チアン、ペピエラジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、チチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3−シクロヘキサジエン、1,4−シクロヘキサジエン、1,5−シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3〜C7シクロアルキル基、及び表4で示される環構造のいずれかからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、Q環上の任意の位置で1つ以上の追加のJ基を示し得;
上記の任意のアルキルまたは(CH2)x−y基は、直鎖または分岐状であり得;
上記の任意のアルキルまたは(CH2)x−y基は追加的に、1つ以上の炭素上でOH、=O、NH2、CN、ジハロアルキル(例えば、CF2H)、トリハロアルキル(例えば、CF3)、またはハロゲン(例えば、F)置換基を含み得;
上記の基の末端位置上の水素の数は、基が追加の基に連結している場合に調整され得(例えば、CH3はCH2に調整される、OHはOに調整されるなど)、または基が末端である場合に調整され得る(例えば、CH2はCH3に調整される、OはOHに調整されるなど)。
Zは、OまたはSであり;
R1は、H、アルキル、置換アルキル(例えば、ハロゲン 置換アルキル)、分岐状アルキル、置換分岐状アルキル(例えば、ハロゲン置換分岐状アルキル)、アルコキシ、アミン、置換アミン、チオアルキル、ケトン、アミド、置換アミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環式環、置換炭素環式環、芳香族環、置換芳香族環、複素環式芳香族環、置換複素環式芳香族環、置換または非置換複素環式非芳香族環(例えば、ピペリジン、メチルピペリジン、架橋ピペリジン、テトラヒドロピラン、アルキルスルホニル置換ピペリジン、スルホンアミド置換ピペリジン)、1−((トリフルオロメチル)スルホニル)ピペリジン)、ジフルオロシクロヘキサン、モノフルオロシクロヘキサン、シクロヘキサン、置換ジフルオロシクロヘキサン、ビシクロオクタン、シクロヘプタン、別の芳香族環に縮合した炭素環式または複素環式芳香族環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから選択され;
R2、R3、R4、及びR5は、独立して、H、ハロゲン(例えば、Cl、F、Br、I)、CH3、OH、SH、NH2、CN、CF3、CCl3、−CH2−CH3、−CH2−OH、−CH2NH2、CH3SH、CH2Cl、CH2Br、CH2F、CHF2、CH2CN、CH2CF3、CH2Cl3、アルキル、ハロアルキル、及びアルコールから選択され;
R6は、H、アルキル、置換アルキル、ヒドロキシ、アルコキシ、アミン、置換アミン、アルキルアミン、置換アルキルアミン、チオアルキル、ハロゲン、ケトン、アミド、置換アミド、アルキルアミド、置換アルキルアミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環式環、置換炭素環式環、芳香族環、置換芳香族環、複素環式芳香族環、置換複素環式芳香族環、置換または非置換複素環式非芳香族環(例えば、アゼチジン)、別の芳香族環に縮合した炭素環式または複素環式芳香族環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから選択される)を含むASH1L阻害化合物が本明細書で提供される。
(式中、J、Q1、またはJ1のうちの1つは、存在する場合、主骨格に連結されており;
各J、J1、J2、J3、及びJ4は、存在する場合、独立して、共有結合、H、アルキル1−15、アルケニル1−6、アルキニル1−6、(CH2)0−6C(S)NH2、(CH2)0−6C(O)NH2、O、S、NH、(CH2)0−6C(O)NH(CH2)1−6、(CH2)0−6NHC(O)(CH2)1−6、アルキニスルホニル、スルホンアミド、アルキルスルホンアミド、(CH2)0−6C(S)NH(CH2)1−6、(CH2)0−6O(CH2)1−6、(CH2)0−6OH、(CH2)0−6S(CH2)1−6、(CH2)0−6SH、(CH2)0−6NH(CH2)1−6、(CH2)0−6N(CH2)1−6(CH2)1−6、(CH2)0−6NH2、(CH2)0−6SO2(CH2)1−6、(CH2)0−6NHSO2(CH2)1−6、(CH2)0−6SO2NH2、ハロゲン(例えば、F、Cl、Br、またはI)、ハロアルキル(例えば、(CH2)0−6CH2F、(CH2)0−3CHF(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、ジハロアルキル(例えば、(CH2)0−6CF2H、(CH2)0−3CF2(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、トリハロアルキル(例えば、(CH2)0−6CF3、またはBr、Cl、もしくはIを有する類似物)、その長さに沿って2つ以上の位置で1〜3個のハロゲンを有するアルキル、(CH2)1−4SP(Ph)2=S、(CH2)0−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−5SH、(CH2)0−6O(CH2)1−6NH(CH2)1−5OH、(CH2)0−6O(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6O(CH2)1−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−6O(CH2)1−5SH、(CH2)0−6O(CH2)1−6S(CH2)1−5OH、(CH2)0−6O(CH2)1−6S(CH2)1−5NH2、(CH2)0−6O(CH2)1−6S(CH2)1−5SH、(CH2)0−6S(CH2)1−6NH(CH2)1−5OH、(CH2)0−6S(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6S(CH2)1−6NH(CH2)1−5SH、(CH2)0−6S(CH2)1−6O(CH2)1−5OH、(CH2)0−6S(CH2)1−6O(CH2)1−5NH2、(CH2)0−6S(CH2)1−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−6S(CH2)1−5SH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6NH(CH2)1−5SH、(CH2)0−6NH(CH2)1−6O(CH2)1−5OH、(CH2)0−6NH(CH2)1−6O(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6O(CH2)1−5SH、(CH2)0−6NH(CH2)1−6S(CH2)1−5OH、(CH2)0−6NH(CH2)1−6S(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6S(CH2)1−5SH、(CH2)0−3C(O)O(CH2)0−3、(CH2)0−3C(S)O(CH2)0−3、(CH2)0−3C(O)S(CH2)0−3、(CH2)0−3C(S)S(CH2)0−3、(CH2)0−3C(O)NH(CH2)0−3、(CH2)0−3C(S)NH(CH2)0−3、(CH2)0−3NHC(O)(CH2)0−3、(CH2)0−3NHC(S)(CH2)0−3、(CH2)0−3OC(O)(CH2)0−3、(CH2)0−3OC(S)(CH2)0−3、(CH2)0−3SC(O)(CH2)0−3、(CH2)0−3SC(S)(CH2)0−3、(CH2)0−3NHC(O)NH(CH2)0−3、(CH2)0−3NHC(S)NH(CH2)0−3、(CH2)0−3OC(O)NH(CH2)0−3、(CH2)0−3OC(S)NH(CH2)0−3、(CH2)0−3SC(O)NH(CH2)0−3、(CH2)0−3SC(S)NH(CH2)0−3、(CH2)0−3NHC(O)O(CH2)0−3、(CH2)0−3NHC(S)O(CH2)0−3、(CH2)0−3OC(O)O(CH2)0−3、(CH2)0−3OC(S)O(CH2)0−3、(CH2)0−3SC(O)O(CH2)0−3、(CH2)0−3SC(S)O(CH2)0−3、(CH2)0−3NHC(O)S(CH2)0−3、(CH2)0−3NHC(S)S(CH2)0−3、(CH2)0−3OC(O)S(CH2)0−3、(CH2)0−3OC(S)S(CH2)0−3、(CH2)0−3SC(O)S(CH2)0−3、(CH2)0−3SC(S)S(CH2)0−3、(CH2O)1−6、及びトリメチルメタンからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、独立して、フラン、ベンゾフラン、イソベンゾフラン、ピロール、インドール、イソインドール、チオフェン、ベンゾチオフェン、ベンゾ[c]チオフェン、イミダゾール、ベンズイミダゾール、プリン、ピラゾール、インダゾール、オキサゾール、ベンゾオキサゾール、イソキサゾール、ベンズイソキサゾール、チアゾール、ベンゾチアゾール、ベンゼン、ナフタレン、ピリジン、キノロン、イソキノリン、ピラジン、キノキサリン、ピリミジン、キナゾリン、ピリダジン、シンノリン、フタラジン、サリドマイド、トリアジン(例えば、1,2,3−トリアジン;1,2,4−トリアジン;1,3,5トリアジン)、チアジアゾール、アジリジン、チイラン(エピスルフィド)、オキシラン(エチレンオキシド、エポキシド)、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、アゼチジン、オキサン、チアン、ペピエラジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、チチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3−シクロヘキサジエン、1,4−シクロヘキサジエン、1,5−シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3〜C7シクロアルキル基、及び表4で示される環構造のいずれかからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、Q環上の任意の位置で1つ以上の追加のJ基を示し得;
上記の任意のアルキルまたは(CH2)x−y基は、直鎖または分岐状であり得;
上記の任意のアルキルまたは(CH2)x−y基は追加的に、1つ以上の炭素上でOH、=O、NH2、CN、ジハロアルキル(例えば、CF2H)、トリハロアルキル(例えば、CF3)、またはハロゲン(例えば、F)置換基を含み得;
上記の基の末端位置上の水素の数は、基が追加の基に連結している場合に調整され得(例えば、CH3はCH2に調整される、OHはOに調整されるなど)、または基が末端である場合に調整され得る(例えば、CH2はCH3に調整される、OはOHに調整されるなど))。
R1は、H、アルキル、置換アルキル(例えば、ハロゲン 置換アルキル)、分岐状アルキル、置換分岐状アルキル(例えば、ハロゲン置換分岐状アルキル)、アルコキシ、アミン、置換アミン、チオアルキル、ケトン、アミド、置換アミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環式環、置換炭素環式環、芳香族環、置換芳香族環、複素環式芳香族環、置換複素環式芳香族環、置換または非置換複素環式非芳香族環(例えば、ピペリジン、メチルピペリジン、架橋ピペリジン、テトラヒドロピラン、アルキルスルホニル置換ピペリジン、スルホンアミド置換ピペリジン)、1−((トリフルオロメチル)スルホニル)ピペリジン)、ジフルオロシクロヘキサン、モノフルオロシクロヘキサン、シクロヘキサン、置換ジフルオロシクロヘキサン、ビシクロオクタン、シクロヘプタン、別の芳香族環に縮合した炭素環式または複素環式芳香族環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから選択され;
R6は、H、アルキル、置換アルキル、ヒドロキシ、アルコキシ、アミン、置換アミン、アルキルアミン、置換アルキルアミン、チオアルキル、ハロゲン、ケトン、アミド、置換アミド、アルキルアミド、置換アルキルアミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環式環、置換炭素環式環、芳香族環、置換芳香族環、複素環式芳香族環、置換複素環式芳香族環、置換または非置換複素環式非芳香族環(例えば、アゼチジン)、別の芳香族環に縮合した炭素環式または複素環式芳香族環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから選択され;
Aは、共有結合(すなわち、原子が存在しない)であるか、または表1に列挙された構造(式中、nは、0、1、2、3、4、5、6、7、8、9または10である)から選択され;
リンカーは、表2に列挙された構造(式中、nは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15であり;mは、存在する場合、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14もしくは15またはそれらの間の範囲であり;kは、存在する場合、0、1、2、3、4、5、6、7、8、9または10であり;lは、存在する場合、0、1、2、3、4、5、6、7、8、9または10である)から選択され;
リガーゼリガンドは、表3に列挙されたものから選択される)を含むASH1L分解化合物が本明細書で提供される。
(式中、J、Q1、またはJ1のうちの1つは、存在する場合、主骨格に連結されており;
各J、J1、J2、J3、及びJ4は、存在する場合、独立して、共有結合、H、アルキル1−15、アルケニル1−6、アルキニル1−6、(CH2)0−6C(S)NH2、(CH2)0−6C(O)NH2、O、S、NH、(CH2)0−6C(O)NH(CH2)1−6、(CH2)0−6NHC(O)(CH2)1−6、アルキニスルホニル、スルホンアミド、アルキルスルホンアミド、(CH2)0−6C(S)NH(CH2)1−6、(CH2)0−6O(CH2)1−6、(CH2)0−6OH、(CH2)0−6S(CH2)1−6、(CH2)0−6SH、(CH2)0−6NH(CH2)1−6、(CH2)0−6N(CH2)1−6(CH2)1−6、(CH2)0−6NH2、(CH2)0−6SO2(CH2)1−6、(CH2)0−6NHSO2(CH2)1−6、(CH2)0−6SO2NH2、ハロゲン(例えば、F、Cl、Br、またはI)、ハロアルキル(例えば、(CH2)0−6CH2F、(CH2)0−3CHF(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、ジハロアルキル(例えば、(CH2)0−6CF2H、(CH2)0−3CF2(CH2)0−2CH3、またはBr、Cl、もしくはIを有する類似物)、トリハロアルキル(例えば、(CH2)0−6CF3、またはBr、Cl、もしくはIを有する類似物)、その長さに沿って2つ以上の位置で1〜3個のハロゲンを有するアルキル、(CH2)1−4SP(Ph)2=S、(CH2)0−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−5SH、(CH2)0−6O(CH2)1−6NH(CH2)1−5OH、(CH2)0−6O(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6O(CH2)1−6NH(CH2)1−5SH、(CH2)0−6O(CH2)1−6O(CH2)1−5OH、(CH2)0−6O(CH2)1−6O(CH2)1−5NH2、(CH2)0−6O(CH2)1−6O(CH2)1−5SH、(CH2)0−6O(CH2)1−6S(CH2)1−5OH、(CH2)0−6O(CH2)1−6S(CH2)1−5NH2、(CH2)0−6O(CH2)1−6S(CH2)1−5SH、(CH2)0−6S(CH2)1−6NH(CH2)1−5OH、(CH2)0−6S(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6S(CH2)1−6NH(CH2)1−5SH、(CH2)0−6S(CH2)1−6O(CH2)1−5OH、(CH2)0−6S(CH2)1−6O(CH2)1−5NH2、(CH2)0−6S(CH2)1−6O(CH2)1−5SH、(CH2)0−6S(CH2)1−6S(CH2)1−5OH、(CH2)0−6S(CH2)1−6S(CH2)1−5NH2、(CH2)0−6S(CH2)1−6S(CH2)1−5SH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5OH、(CH2)0−6NH(CH2)1−6NH(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6NH(CH2)1−5SH、(CH2)0−6NH(CH2)1−6O(CH2)1−5OH、(CH2)0−6NH(CH2)1−6O(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6O(CH2)1−5SH、(CH2)0−6NH(CH2)1−6S(CH2)1−5OH、(CH2)0−6NH(CH2)1−6S(CH2)1−5NH2、(CH2)0−6NH(CH2)1−6S(CH2)1−5SH、(CH2)0−3C(O)O(CH2)0−3、(CH2)0−3C(S)O(CH2)0−3、(CH2)0−3C(O)S(CH2)0−3、(CH2)0−3C(S)S(CH2)0−3、(CH2)0−3C(O)NH(CH2)0−3、(CH2)0−3C(S)NH(CH2)0−3、(CH2)0−3NHC(O)(CH2)0−3、(CH2)0−3NHC(S)(CH2)0−3、(CH2)0−3OC(O)(CH2)0−3、(CH2)0−3OC(S)(CH2)0−3、(CH2)0−3SC(O)(CH2)0−3、(CH2)0−3SC(S)(CH2)0−3、(CH2)0−3NHC(O)NH(CH2)0−3、(CH2)0−3NHC(S)NH(CH2)0−3、(CH2)0−3OC(O)NH(CH2)0−3、(CH2)0−3OC(S)NH(CH2)0−3、(CH2)0−3SC(O)NH(CH2)0−3、(CH2)0−3SC(S)NH(CH2)0−3、(CH2)0−3NHC(O)O(CH2)0−3、(CH2)0−3NHC(S)O(CH2)0−3、(CH2)0−3OC(O)O(CH2)0−3、(CH2)0−3OC(S)O(CH2)0−3、(CH2)0−3SC(O)O(CH2)0−3、(CH2)0−3SC(S)O(CH2)0−3、(CH2)0−3NHC(O)S(CH2)0−3、(CH2)0−3NHC(S)S(CH2)0−3、(CH2)0−3OC(O)S(CH2)0−3、(CH2)0−3OC(S)S(CH2)0−3、(CH2)0−3SC(O)S(CH2)0−3、(CH2)0−3SC(S)S(CH2)0−3、(CH2O)1−6、及びトリメチルメタンからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、独立して、フラン、ベンゾフラン、イソベンゾフラン、ピロール、インドール、イソインドール、チオフェン、ベンゾチオフェン、ベンゾ[c]チオフェン、イミダゾール、ベンズイミダゾール、プリン、ピラゾール、インダゾール、オキサゾール、ベンゾオキサゾール、イソキサゾール、ベンズイソキサゾール、チアゾール、ベンゾチアゾール、ベンゼン、ナフタレン、ピリジン、キノロン、イソキノリン、ピラジン、キノキサリン、ピリミジン、キナゾリン、ピリダジン、シンノリン、フタラジン、サリドマイド、トリアジン(例えば、1,2,3−トリアジン;1,2,4−トリアジン;1,3,5トリアジン)、チアジアゾール、アジリジン、チイラン(エピスルフィド)、オキシラン(エチレンオキシド、エポキシド)、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、アゼチジン、オキサン、チアン、ペピエラジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、チチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3−シクロヘキサジエン、1,4−シクロヘキサジエン、1,5−シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3〜C7シクロアルキル基、及び表4で示される環構造のいずれかからなる群から選択され;
各Q、Q1、及びQ2は、存在する場合、Q環上の任意の位置で1つ以上の追加のJ基を示し得;
上記の任意のアルキルまたは(CH2)x−y基は、直鎖または分岐状であり得;
上記の任意のアルキルまたは(CH2)x−y基は追加的に、1つ以上の炭素上でOH、=O、NH2、CN、ジハロアルキル(例えば、CF2H)、トリハロアルキル(例えば、CF3)、またはハロゲン(例えば、F)置換基を含み得;
上記の基の末端位置上の水素の数は、基が追加の基に連結している場合に調整され得(例えば、CH3はCH2に調整される、OHはOに調整されるなど)、または基が末端である場合に調整され得る(例えば、CH2はCH3に調整される、OはOHに調整されるなど)。
〔図1〕化合物1によって誘導されるAsh1Lの分解。
本明細書に記載されるものと類似または同等である任意の方法及び材料は、本明細書に記載の実施形態の実施または試験に使用され得るが、いくつかの好ましい方法、組成物、装置、及び材料が本明細書に記載されている。しかしながら、本材料及び方法を記載する前に、本発明は本明細書に記載される特定の分子、組成物、方法論またはプロトコルに限定されず、その理由は、これらは日常的な実験及び最適化に応じて変わり得るからであることが理解されるべきである。また、本明細書で使用される用語は、特定のバージョンまたは実施形態の記載のみを目的としており、本明細書に記載の実施形態の範囲を限定することは意図されていないことが理解されるべきである。
本明細書では、ASH1Lに結合する第1のドメイン及びASH1Lの分解を促進する第2のドメインを含む小分子が提供される。特に、ASH1L標的タンパク質分解標的キメラ(PROTAC)ならびに疾患(例えば、急性白血病、固形がん及びASH1Lの活性に依存する他の疾患)の治療のためのその使用方法が提供される。
、オキサジリジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、オキサン、チアン、ピペラジン、アゼチジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、チチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3−シクロヘキサジエン、1,4−シクロヘキサジエン、1,5−シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3〜C7シクロアルキル基、及び表4で示される環構造のいずれかからなる群から選択され;各Q、Q1、及びQ2は、存在する場合、Q環上の任意の位置で1つ以上の追加のJ基を示し得;上記の任意のアルキルまたは(CH2)x−yは、直鎖または分岐状であり得;上記の任意のアルキルまたは(CH2)x−y基は追加的に、1つ以上の炭素上でOH、=O、NH2、CN、ジハロアルキル(例えば、CF2H)、トリハロアルキル(例えば、CF3)、またはハロゲン(例えば、F)置換基を含み得;上記の基の末端位置上の水素の
いくつかの実施形態では、R6は、存在する場合(例えば、式(IIa)、(IIb)、(IIIa)、及び(IIIb)において)、H、アルキル、置換アルキル(例えば、ハロゲン置換アルキル)、分岐状アルキル、置換分岐状アルキル(例えば、ハロゲン置換分岐状アルキル)ヒドロキシ、アルコキシ、アミン、置換アミン、チオアルキル、ハロゲン、ケトン、アミド、置換アミド、シアノ、スルホニル、カルボキシ、ジアルキルホスフィンオキシド、炭素環式環、置換炭素環式環、芳香族環、置換芳香族環、複素環式芳香族環、置換複素環式芳香族環、置換または非置換複素環式非芳香族環(例えば、ピペリジン、メチルピペリジン、架橋ピペリジン、テトラヒドロピラン、アルキルスルホニル置換ピペリジン、スルホンアミド置換ピペリジン)、別の芳香族環に縮合した炭素環式または複素環式芳香族環、水素結合供与体、水素結合受容体、及びそれらの組み合わせから選択され;特定の実施形態では、R6は、表14に示される置換基から選択される:
リジン、ジオキシラン、アゼチジン、オキセタン、チエタン、ジアゼチジン、ジオキセタン、ジチエタン、ピロリジン、テトラヒドロフラン、チオラン、イミダゾリジン、ピラゾリジン、オキサゾリジン、イソキサゾリジン、チアゾリジン、イソチアゾリジン、ジオキソラン、ジチオラン、ピペリジン、オキサン、チアン、ピペラジン、アゼチジン、モルホリン、チオモルホリン、ジオキサン、ジチアン、トリオキサン、チチアン、アゼパン、オキセパン、チエパン、ホモピペラジン、アゾカン、テトラヒドロピラン、シクロブテン、シクロペンテン、シクロヘキセン、シクロヘプテン、1,3−シクロヘキサジエン、1,4−シクロヘキサジエン、1,5−シクロオクタジエン、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、任意の好適なC3〜C7シクロアルキル基、及び表4で示される環構造のいずれかからなる群から選択され;各Q、Q1、及びQ2は、存在する場合、Q環上の任意の位置で1つ以上の追加のJ基を示し得;上記の任意のアルキルまたは(CH2)x−yは、直鎖または分岐状であり得;上記の任意のアルキルまたは(CH2)x−y基は追加的に、1つ以上の炭素上でOH、=O、NH2、CN、ジハロアルキル(例えば、CF2H)、トリハロアルキル(例えば、CF3)、またはハロゲン(例えば、F)置換基を含み得;上記の基の末端位置上の水素の数は、基が
いくつかの実施形態では、R22及びR23は、存在する場合(例えば、式IIa)は、独立して、H、ハロゲン(例えば、Cl、F、Br、I)、CH3、OH、SH、NH2、CN、CHF2、CF3、CCl3、−CH2−CH3、−CH2−OH、−CH2NH2、CH3SH、CH2Cl、CH2Br、CH2F、CHF2、CH2CN、CH2CF3、及びCH2Cl3から選択される。
所定の実施形態では、本明細書に開示される任意の好適な置換基及び官能基を有する、式(Ia)、(Ib)、(IIa)、(IIb)、(IIIa)、及び(IIIb)のうちいずれか1つの化合物または塩は、1つ以上の追加の薬剤と組み合わされて薬学的組成物を形成する。薬学的組成物は、活性化合物の薬学的に使用され得る調製剤への処理を容易にする賦形剤及び補助剤を含む1つ以上の生理学的に許容可能な担体を使用して従来の手法で製剤化され得る。適切な製剤は、選択された投与経路に依存する。本明細書に記載の薬学的組成物に好適な賦形剤に関するさらなる詳細については、例えば、Remington:The Science and Practice of Pharmacy,Nineteenth Ed(Easton,Pa.:Mack Publishing Company,1995);Hoover,John E.,Remington’s Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania 1975;Liberman,H.A.and Lachman,L.,Eds.,Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.,1980;及びPharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed.(Lippincott Williams & Wilkins1999)で見ることができ、そのような開示について参照により本明細書に組み込まれる。
本開示は、ASH1Lに結合し、ASH1Lタンパク質の分解を促進するための化合物及び方法を提供する。所定の実施形態では、本開示は、結合時にASH1Lの阻害もする化合物を提供する。ASH1L分解/阻害の機構の十分な理解は、本発明の実施には必要とされない。
本明細書では、他の経路を調節することが知られている薬剤、もしくは同じ経路の他の成分、またはさらに重複する一連の標的酵素が、本明細書に開示される任意の好適な置換基及び官能基を有する、式(Ia)、(Ib)、(IIa)、(IIb)、(IIIa)、及び(IIIb)のいずれか1つの化合物または塩と併用される併用療法のための方法が提供される。一態様では、そのような療法は、相乗的または追加的な治療効果を提供するための、本発明の1つ以上の化合物と化学療法剤、標的薬剤、治療抗体、及び放射線治療との組み合わせを含むがこれらに限定されない。
本明細書に記載の治療用途での使用のために、キット及び製造品も提供される。いくつかの実施形態では、そのようなキットは、バイアル、チューブなどの1つ以上の容器を受け取るように区画化されたキャリア、パッケージ、または容器を含み、容器(複数可)の各々は、本明細書に記載の方法で使用される別々の要素のうちの1つを含む。好適な容器には、例えば、ボトル、バイアル、シリンジ、及び試験管が含まれる。容器は、ガラスまたはプラスチックなどの様々な材料から形成される。
実施例1:N−(3−(3−カルバモチオイルフェニル)−1−(3−フルオロ−2−(フルオロメチル)プロピル)−1H−インドール−6−イル)−3−(2−(2−(2−((2−(2,6−ジオキソピペリジン−3−イル)−1,3−ジオキソイソインドリン−4−イル)オキシ)エトキシ)エトキシ)エトキシ)プロパンアミド(化合物1)の合成。
工程B:3−(6−ニトロ−1H−インドール−3−イル)ベンゾニトリル(1−2)の調製。(3−シアノフェニル)ボロン酸(805mg、5.5mmol)、3−ブロモ−6−ニトロ−1H−インドール(660mg、2.7mmol)Pd2(dba)3(512mg0.6mmol)、トリ−t−ブチルホスホニウムテトラフルロルボレート(157mg、0.5mmol)及びKF(477mg、8.2mmol)をTHF中で組み合わせた。混合物を脱気した。反応物をアルゴン雰囲気下で維持し、40oCに加熱した。反応混合物を室温に冷却し、セライトパッドを通して濾過し、これを酢酸エチル(60mL)で洗浄した。濾液を濃縮して暗赤色の固体を生成した。カラムクロマトグラフィによって精製した。1H NMR (600 MHz, アセトニトリル−d3) δ ppm 7.63 − 7.71 (m, 2 H) 7.93 − 7.96 (m, 1 H) 7.99 − 8.05 (m, 2 H) 8.05 − 8.09 (m, 2 H) 8.47 − 8.50 (m, 1 H) 10.00 − 10.40 (bs, 1 H);
工程C:3−(1−((2,2−ジメチル−1,3−ジオキサン−5−イル)メチル)−6−ニトロ−1H−インドール−3−イル)ベンゾニトリル(1−3)の調製。3−(6−ニトロ−1H−インドール−3−イル)ベンゾニトリル(540mg)及び炭酸セシウムを乾燥DMF(4mL)中で組み合わせた。暗赤色の反応混合物を室温で数分間撹拌した。次いでDMF(3mL)中のメシレートの懸濁液を添加した。フラスコをアルゴン下で撹拌し、60oCに加熱した。水及び化合物を酢酸エチルによって抽出した。水相を酢酸エチルで2回抽出し、組み合わされた有機相を硫酸ナトリウムで乾燥させた。蒸発後、粗化合物をカラムクロマトグラフィ(シリカゲル、ヘキサン−酢酸エチル)を使用して精製した。470mg(50%)の黄色の固体が得られた。1H NMR (600 MHz, CDCl3) δ ppm 1.51 (s, 3H) 1.55 (s, 3H) 2.06 − 2.13 (m, 1H) 3.59 (d, J = 11.4 Hz, 2H) 4.13 (dd, J = 12.3, 2.8 Hz, 2H) 4.61 (d, J=8.4 Hz, 2H) 7.55 − 7.67 (m, 3H) 7.86 (d, J = 7.7 Hz, 1H) 7.88 − 7.95 (m, 2H) 8.12 (dd, J = 8.8, 2.2 Hz, 1H) 8.46 (d, J = 1.5 Hz, 1H);13C NMR (150 MHz, CDCl3) δ ppm 19.6, 28.3, 34.8, 46.1, 61.0, 98.9, 107.2, 113.3, 116.1, 116.1, 118.7, 119.6, 129.8, 130.1, 130.2, 130.8, 131.6, 132.0, 135.4, 135.8, 143.7;
工程D:3−(1−(3−ヒドロキシ−2−(ヒドロキシメチル)プロピル)−6−ニトロ−1H−インドール−3−イル)ベンゾニトリル(1−4)の調製。3−(1−((2,2−ジメチル−1,3−ジオキサン−5−イル)メチル)−6−ニトロ−1H−インドール−3−イル)ベンゾニトリル(350mg、0.9mmol)をTHF(4.5mL)に溶解し、3MのHCl(水性、0.6mL)を添加した。反応混合物を室温で1.5時間撹拌した。混合物を濃縮してTHFを除去し、水で希釈し、いくつかの部分の酢酸エチルで抽出した。組み合わされた有機層を硫酸ナトリウムで乾燥させ、濾過し、濃縮して鮮やかな橙色の固体(280mg、89%の収率)を生成した。1H NMR (600 MHz, アセトニトリル−d3) δ ppm 2.23 (td, J=12.0, 6.1 Hz, 1H) 2.96 (br. s., 2H) 3.51 − 3.63 (m, 4H) 4.45 (d, J = 7.0 Hz, 2H) 7.62 − 7.72 (m, 2H) 7.96 (m, 1H) 7.99 − 8.11 (m, 4H) 8.60 (d, J = 1.8 Hz, 1H);13C NMR (150 MHz, アセトニトリル−d3) δ ppm 45.5, 46.2, 61.7, 109.1, 114.2, 116.4, 116.7, 120.2, 120.8, 131.1, 131.2, 131.8, 132.9, 135.3, 136.9, 137.4, 144.7;
工程E:3−(1−(3−フルオロ−2−(フルオロメチル)プロピル)−6−ニトロ−1H−インドール−3−イル)ベンゾニトリル(1−5)の調製。乾燥DCM(0.9mL)中のTEA.HF(93uL、0.57mmol)の溶液に、XtalfluorE(97mg、0.42mmol)を0oCで添加した。次いでDCM(0.5mL)中の3−(1−(3−ヒドロキシ−2−(ヒドロキシメチル)プロピル)−6−ニトロ−1H−インドール−3−イル)ベンゾニトリル(50mg、014mmol)の溶液を0oCで少量ずつ添加した。混合物を0oCで30分間及び室温で2時間撹拌した。次いで反応物を飽和NaHCO3でクエンチし、水相をDCMで抽出し、有機相を硫酸ナトリウムで乾燥させた。揮発性物質を蒸発させ、残渣をカラムクロマトグラフィ(シリカゲル、ヘキサン−酢酸エチル)によって精製し、29mgの生成物(57%の収率)を得た。1H NMR (600 MHz, DMSO−d6) δ ppm 2.71 − 2.87 (m, 1H) 4.45 − 4.52 (m, 1H) 4.53 − 4.59 (m, 4H) 4.60 − 4.66 (m, 1H) 7.68 − 7.73 (m, 1H) 7.78 (d, J = 7.7 Hz, 1H) 8.05 (dd, J = 8.8, 1.8 Hz, 1H) 8.09 (d, J = 8.1 Hz, 1H) 8.13 − 8.19 (m, 2H) 8.37 (m, 1H) 8.66 (d, J = 1.8 Hz, 1H);
工程F:3−(6−アミノ−1−(3−フルオロ−2−(フルオロメチル)プロピル)−1H−インドール−3−イル)ベンゾニトリル(1−6)の調製。アセトン(1.6m)中の3−(1−(3−フルオロ−2−(フルオロメチル)プロピル)−6−ニトロ−1H−インドール−3−イル)ベンゾニトリル(29mg、0.082mmol)の溶液に水を添加し(320μL)、続いて塩化アンモニウム(176mg)及び亜鉛粉末(106mg)を添加した。混合物を60分間撹拌した。アセトンを蒸発させ、残渣を酢酸エチルと濃アンモニア溶液の間で分配した。混合物をセライトを通して濾過し、有機相をMgSO4で乾燥させ、蒸発させた。化合物を次の工程にさらなる精製をせずに使用した。[M+H+AcCN]+に対するLR−MS計算値:367、実測値367.10
工程G:3−(6−アミノ−1−(3−フルオロ−2−(フルオロメチル)プロピル)−1H−インドール−3−イル)ベンゾチオアミド(1−7)の調製。DMF(0.2mL)中の3−(6−アミノ−1−(3−フルオロ−2−(フルオロメチル)プロピル)−1H−インドール−3−イル)ベンゾニトリル(23mg、0.072mmol)の溶液にヒドロ亜硫酸ナトリウム(60mg、1mmol)及び塩化マグネシウム(101mg、0.5mmol)を室温で添加した。混合物を2時間撹拌した。水を添加し(0.4mL)、生成物を酢酸エチル(3×5mL)によって抽出した。有機相を硫酸ナトリウムで乾燥させ、蒸発させた。黄色の残渣をカラムクロマトグラフィ(シリカゲル、ヘキサン−酢酸エチル)を使用して精製し、10mg(39%)のチオアミドを得た。1H NMR (600 MHz, DMSO−d6) δ ppm 2.50 − 2.64 (m, 1H) 4.10 (d, J = 7.7 Hz, 2H) 4.35 − 4.53 (m, 4H) 4.88 (s, 2H) 6.48 (dd, J = 8.6, 1.7 Hz, 1H) 6.54 (d, J=1.1 Hz, 1H) 7.33 − 7.39 (m, 2H) 7.53 (d, J = 8.4 Hz, 1H) 7.62 (d, J = 8.1 Hz, 1H) 7.66 (d, J = 8.1 Hz, 1 H) 8.05 (m, 1H) 9.47 (br. s., 1H) 9.81 (br. s., 1H);13C NMR (150 MHz, DMSO−d6) δ ppm 40.7 (J = 18 Hz), 42.2, 80.7, 81.8, 93.4, 110.7, 115.0, 117.0, 119.8, 124.0, 124.2, 124.9, 128.3, 128.6, 135.4, 138.6, 140.1, 144.8, 200.6。C19H19F2N3Sに対するHR−MS[ESI,M+H+]計算値:360.1346、実測値:360.1341。
工程J:N−(3−(3−カルバモチオイルフェニル)−1−(3−フルオロ−2−(フルオロメチル)プロピル)−1H−インドール−6−イル)−3−(2−(2−(2−((2−(2,6−ジオキソピペリジン−3−イル)−1,3−ジオキソイソインドリン−4−イル)オキシ)エトキシ)エトキシ)エトキシ)−プロパンアミド(1)の調製.化合物1−7(26mg、0.08mmol、1当量)をDCM(0.6mL)中の酸1−10(38.1mg、0.08mmol、1.1当量)の溶液に添加した。次いでジソプロピルエチルアミン(19μl、0.1mmol、1.2当量)を添加し、続いて1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム3−オキシドヘキサフルオロホスフェート(HATU、34mg、0.08mmol、1.1当量)を添加した。混合物を15分間撹拌し、シリカゲルカラム(4g、カートリッジ)に直接装填した。化合物をカラムクロマトグラフィ(ヘキサン:酢酸エチル、シリカゲル、100%の酢酸エチルで洗浄)を使用して精製した。化合物を黄色の固体(54mg、77%の収率)として得た。1H NMR (600 MHz, DMSO−d6) δ 11.06 (s, 1H), 9.96 (s, 1H), 9.84 − 9.92 (m, 1H), 9.54 (br. s., 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.83 (d, J = 8.44 Hz, 1H), 7.70 − 7.80 (m, 4H), 7.40 − 7.51 (m, 3H), 7.23 (d, J = 8.44 Hz, 1H), 5.07 (dd, J = 5.13, 12.84 Hz, 1H), 4.54 − 4.61 (m, 1H), 4.47 − 4.54 (m, 2H), 4.39 − 4.47 (m, 1H), 4.25 − 4.33 (m, 4H), 3.75 − 3.81 (m, 2H), 3.72 (t, J = 6.05 Hz, 2H), 3.59 − 3.63 (m, 2H), 3.51 − 3.56 (m, 6H), 2.82 − 2.93 (m, 1H), 2.62 − 2.76 (m, 1H), 2.53 − 2.62 (m, 3H), 1.99 − 2.05 (m, 1H);13C NMR (151 MHz, DMSO−d6) δ 200.5, 172.7, 169.9, 168.9, 166.8, 165.2, 155.8, 140.2, 136.9, 136.8, 134.8, 134.5, 133.2, 128.8, 128.4, 127.0, 125.0, 124.4, 121.4, 120.0, 119.4, 116.3, 115.3, 115.0, 113.4, 100.5, 81.8, 80.7, 70.1, 69.8, 69.7, 69.6, 68.8, 68.6, 66.7, 59.7, 48.7, 47.7, 37.2, 30.9, 22.0, 20.7, 14.0;C41H43F2N5O9SNaに対するHR−MS[M+Na+]m/z計算値:842.2647、実測値842.2637。
工程B:3−(6−ホルミル−1H−インドール−3−イル)ベンゾニトリル(2−2)の調製.無水THF(75mL)中の3−ブロモ−1H−インドール−6−カルバルデヒド(5000mg、22.422mmol)、(3−シアノフェニル)ボロン酸(6589mg、44.843mmol)、トリス(ジベンジリデンアセトン)ジパラジウム(0)(2669mg、2.915mmol)、トリ−tert−ブチルホスホニウムテトラフルオロボレート(1952mg、6.726mmol)及び無水KF(5211mg、89.686mmol)の混合物をアルゴン雰囲気下で40oCで一晩撹拌した。混合物を室温に冷却し、セライトを通して濾過し、酢酸エチル(100mL)によって洗浄した。濾液を真空中で濃縮し、残渣(シリカゲル固体装填)をヘキサン及び酢酸エチル(0〜50%)を用いたシリカゲルでのフラッシュクロマトグラフィによって精製して標記化合物(3g、54%の収率)を淡黄色の固体として得た。1H NMR (400 MHz, CD3OD) δ 10.0 (s, 1H), 8.02 (m, 4H), 7.91 (m, 1H), 7.72 (dd, J = 8.0, 1.3 Hz, 1H), 7.62 (m, 2H);
工程C:3−(6−ホルミル−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−3−イル)ベンゾニトリル(2−3)の調製。21oCの3−(6−ホルミル−1H−インドール−3−イル)ベンゾニトリル(420mg、1.707mmol)の無水DMF溶液(5mL)に炭酸セシウム(1668mg、5.120mmol)を添加し、5分間撹拌した。テトラヒドロ−2H−ピラン−4−イルメタンスルホネート(1228mg、6.826mmol)を上記混合物に添加した。混合物を100oCで13時間撹拌した。水を添加し(15mL)、生成物を酢酸エチル(2×20mL)によって抽出した。有機相を分離し、蒸発させて粗製物を得、これをカラムクロマトグラフィ(シリカゲル12g、ヘキサン中0〜40%の酢酸エチル)によって精製して生成物を黄色の固体(420mg、74%の収率)として得た。1H NMR (600 MHz, クロロホルム−d) δ 10.14 (s, 1H), 8.06 (s, 1H), 7.99 (d, J = 8.44 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J = 7.70 Hz, 1H), 7.75 (d, J = 8.44 Hz, 1H), 7.65 (s, 1H), 7.54 − 7.62 (m, 2H), 4.62 − 4.72 (m, 1H), 4.20 − 4.26 (m, 2H), 3.70 (dt, J = 2.57, 11.55 Hz, 2H), 2.12 − 2.24 (m, 4H);
工程D:3−(6−(ヒドロキシメチル)−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−3−イル)ベンゾニトリル(2−4)の調製。0oCのメタノール(20mL)及びアセトニトリル(30mL)中の3−(6−ホルミル−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−3−イル)ベンゾニトリル(310mg、0.939mmol)の混合物に水素化ホウ素ナトリウム(200mg、5.271mmol)を添加した。混合物を22oCでさらに5時間撹拌した。水性NH4Clを添加して(5mL)反応物をクエンチした。15分間撹拌した後、溶媒メタノールを回転蒸発によって除去した。生成物を酢酸エチル(2×20mL)によって抽出した。有機相を分離し、無水Na2SO4で乾燥させた。濾過及び濃縮後、粗生成物(310mg)を得、これを次の工程で直接使用した。[M−H2O+H]+に対するLC−MS計算値315、実測値315;
工程E:3−(6−(アジドメチル)−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−3−イル)ベンゾニトリル(2−5)の調製。磁気撹拌棒を備える25mLの丸底フラスコに3−(6−(ヒドロキシメチル)−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−3−イル)ベンゾニトリル(310mg、0.933mmol)、ジフェニルホスホリルアジド(DPPA)(334mg、1.213mmol)、及びTHF(5mL)を添加した。混合物を0℃で10分間撹拌した後、1,8−ジアザビシクロウンデス−7−エン(DBU)(170.5mg、1.120mmol)を一度に添加した。得られた混合物を室温で一晩撹拌した。水性NaHCO3(5mL)を添加した。有機層を分離し、水層を酢酸エチル(10mL×3)で抽出した。組み合わされた有機層を水(10mL×2)で洗浄し、無水Na2SO4で乾燥させ、濾過し、濃縮した。粗製物をシリカゲルでのフラッシュクロマトグラフィ(4g、ヘキサン中0〜40%の酢酸エチル)によって精製して生成物を白色の固体(234mg、70%の収率)として得た。1H NMR (600 MHz, クロロホルム−d) δ 7.92 (s, 1H), 7.86 − 7.91 (m, 2H), 7.52 − 7.59 (m, 2H), 7.46 (s, 1H), 7.42 (s, 1H), 7.19 (d, J = 8.07 Hz, 1H), 4.54 − 4.58 (m, J = 4.77, 4.77 Hz, 1H), 4.52 (s, 2H), 4.19 − 4.24 (m, 2H), 3.64 − 3.72 (m, 2H), 2.10 − 2.22 (m, 4H);
工程F:3−(6−(アミノメチル)−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−3−イル)ベンゾニトリル(2−6)の調製。THF(6mL)中の3−(6−(アジドメチル)−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−3−イル)ベンゾニトリル(234mg、0.655mmol)の溶液にPPh3(516mg、1.966mmol)を0oCで添加した。反応物を氷浴から除去し、水(0.2mL)を添加した。反応混合物を室温で18時間撹拌した。混合物を1NのHClでpH=1に酸性化し、EtOAc(100mL)で抽出した。水層を分離し、1NのNaOHでpH=10に塩基性化した。得られた溶液をEtOAc(30mL)で抽出した。有機層を分離し、無水Na2SO4で乾燥させた。濾過及び濃縮後、生成物を白色の固体(210mg、97%の収率)として得た。1H NMR (600 MHz, クロロホルム−d) δ 7.93 (s, 1H), 7.81 − 7.89 (m, 2H), 7.50 − 7.56 (m, 2H), 7.46 (s, 1H), 7.41 (br. s., 0H), 7.19 (d, J = 8.07 Hz, 1H), 4.51 − 4.60 (m, 1H), 4.17 − 4.23 (m, 2H), 4.06 (s, 2H), 3.67 (t, J = 11.55 Hz, 2H), 2.08 − 2.20 (m, 4H);
工程G:3−(6−(アミノメチル)−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−3−イル)ベンゾチオアミド(2−7)の調製。DMF(2mL)及び水(0.1mL)中の3−(6−(アミノメチル)−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−3−イル)ベンゾニトリル(25mg)の溶液にヒドロ亜硫酸ナトリウム(200mg)及び塩化マグネシウム(190mg)を室温で添加した。混合物を18時間撹拌した。LCMSは、反応が完了したこと示していた。水(20mL)を添加し、生成物を酢酸エチル(2×20mL)によって抽出した。有機相を分離し、蒸発させた。粗製物をカラムクロマトグラフィ(シリカゲル4g、DCM中0〜20%のメタノール(w/5%水性アンモニア溶液))を使用して精製し、生成物(25mg、91%の収率)を黄色の固体として得た。1H NMR (600 MHz, アセトン) δ 9.01 (br. s., 1H), 8.92 (br. s., 1H), 8.33 (br. s., 1H), 7.83 − 7.94 (m, 3H), 7.76 − 7.83 (m, 1H), 7.63 (s, 1H), 7.44 − 7.52 (m, 1H), 7.18 (d, J = 8.44 Hz, 1H), 4.68 − 4.79 (m, 1H), 4.58 (s, 2H), 4.06 − 4.15 (m, 2H), 3.69 (t, J = 11.37 Hz, 2H), 3.32 (d, J = 4.77 Hz, 1H), 2.13 − 2.25 (m, 3H);
工程H:N−((3−(3−カルバモチオイルフェニル)−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−6−イル)メチル)−3−(2−(2−(2−((2−(2,6−ジオキソピペリジン−3−イル)−1,3−ジオキソイソインドリン−4−イル)オキシ)エトキシ)エトキシ)エトキシ)プロパンアミド(2)の調製。DMF(2mL)中の3−(6−(アミノメチル)−1−(テトラヒドロ−2H−ピラン−4−イル)−1H−インドール−3−イル)ベンゾチオアミド(25mg、0.068mmol)、3−(2−(2−(2−((2−(2,6−ジオキソピペリジン−3−イル)−1,3−ジオキソイソインドリン−4−イル)オキシ)エトキシ)エトキシ)エトキシ)プロパン酸(化合物1−10、36mg、0.075mmol)、HATU(42mg、0.110mmol)及びDIPEA(24uL、0.137mmol)の混合物を22oCで1時間撹拌した。LCMSは、所望の生成物が形成し、反応が完了したことを示していた。反応混合物を酢酸エチル(30mL)及び水(20mL)によって分配した。水層をEtOAc(10mL)で抽出した。有機層を組み合わせ、水及びブラインで洗浄した。濃縮後、粗製物をカラムクロマトグラフィ(シリカゲル4g、DCM中0〜8.8%のメタノール)によって精製して生成物を黄色の固体(20mg、36%の収率)として得た。1H NMR (600 MHz, メタノール−d4) δ 8.22 (s, 1H), 7.86 (d, J = 8.44 Hz, 1H), 7.78 (d, J = 7.70 Hz, 1H), 7.71 (d, J = 7.70 Hz, 1H), 7.67 (s, 1H), 7.62 (t, J = 7.89 Hz, 1H), 7.49 (s, 1H), 7.42 (t, J = 7.70 Hz, 1H), 7.34 (d, J = 7.34 Hz, 1H), 7.25 (d, J = 8.44 Hz, 1H), 7.11 (d, J = 8.07 Hz, 1H), 5.03 (dd, J = 5.50, 12.47 Hz, 1H), 4.58 − 4.68 (m, J = 8.07, 15.41 Hz, 1H), 4.52 (s, 2H), 4.17 (br. s., 2H), 4.11 (dd, J = 2.93, 11.37 Hz, 2H), 3.64 − 3.79 (m, 6H), 3.48 − 3.61 (m, 8H), 2.57 − 2.85 (m, 3H), 2.50 (t, J = 5.69 Hz, 2H), 1.98 − 2.20 (m, 5H);13C NMR (151 MHz, メタノール−d4) δ 204.3, 174.6, 174.0, 171.4, 168.6, 167.3, 157.6, 141.7, 138.0, 137.8, 137.2, 134.9, 133.8, 130.8, 129.5, 127.2, 126.6, 125.1, 124.1, 121.5, 120.9, 120.7, 118.1, 117.2, 116.5, 110.3, 72.0, 71.6, 71.4, 70.3, 68.4, 68.3, 53.4, 50.4, 44.8, 37.9, 34.4, 32.1, 23.6;C43H47N5O10SNaに対するHR−MS[M+Na+]m/z計算値:848.2936、実測値:848.2932。
工程B:3−(4−ブロモ−1−オキソイソインドリン−2−イル)ピペリジン−2,6−ジオン(34−2)の調製。3−アミノピペリジン−2,6−ジオン(614mg、4.793mmol、1.22当量)及びトリエチルアミン(730uL、5.225mmol、1.33当量)をMeCN(20mL)中のメチル3−ブロモ−2−(ブロモメチル)ベンゾエート(1210mg、3.929mmol、1.0当量)の撹拌溶液に添加した。溶液を80℃で12時間撹拌し、次いで室温に冷却し、溶媒のほとんどを蒸発させた。酢酸エチル(20mL)及びH2O(50mL)を残渣に添加した。混合物を濾過して生成物を淡紫色の固体(750mg、59%の収率)として得た;1H NMR (600 MHz, DMSO−d6) δ 10.98 (s, 1H), 7.87 (dd, J = 7.9, 0.9 Hz, 1H), 7.77 (dd, J = 7.5, 0.9 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (d, J = 17.5 Hz, 1H), 4.27 (d, J = 17.5 Hz, 1H), 2.91 (ddd, J = 17.3, 13.7, 5.4 Hz, 1H), 2.63 − 2.58 (m, 1H), 2.48 − 2.43 (m, 1H), 2.03 (dtd, J = 12.7, 5.3, 2.2 Hz, 1H);
工程C:tert−ブチル(E)−3−(2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−4−イル)アクリレート(34−3)の調製。Tert−ブチルアクリレート(225uL、1.548mmol)及びビス(トリフェニルホスプリン)−パラジウム(II)クロライド(22mg、0.031mmol)をトリエチルアミン(1mL)及びN,N−ジメチルホルムアミド(1mL)中で1時間加熱して還流した。3−(4−ブロモ−1−オキソイソインドリン−2−イル)ピペリジン−2,6−ジオン(100mg、0.310mmol)を混合物に添加し、還流下で一晩加熱した。反応混合物をセライトの床を通して濾過し、酢酸エチル(30mL)で洗浄した。有機溶液を水(2×10mL)、及びブライン(10mL)で洗浄した。その後Na2SO4で乾燥させ、真空中で溶媒を除去して粗生成物を得、これを0〜100%のEtOAc/ヘキサンを使用するカラムクロマトグラフィによって精製して生成物(70mg、61%の収率)を黄色の固体として得た;1H NMR (600 MHz, DMSO−d6) δ 10.98 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.65 − 7.52 (m, 2H), 6.51 (dd, J = 16.1, 1.4 Hz, 1H), 5.15 (dd, J = 13.4, 5.1 Hz, 1H), 4.69 (d, J = 17.6 Hz, 1H), 4.51 (d, J = 17.6 Hz, 1H), 2.97 − 2.88 (m, 1H), 2.62 (d, J = 9.1 Hz, 1H), 2.45 − 2.35 (m, 1H), 2.05 − 2.00 (m, 1H), 1.50 (s, 9H);
工程D:tert−ブチル3−(2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−4−イル)プロパノエート(34−4)の調製。MeOH(20mL)中のtert−ブチル(E)−3−(2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−4−イル)アクリレート(100mg、0.270mmol)及び10%のPd/C(20mg)の撹拌溶液にトリエチルシラン(430uL、2.7mmol)を添加し、反応混合物を室温で50分間撹拌した。その後、それをセライトを通して濾過し、溶媒を真空中で除去した。粗生成物をさらなる精製をせずに次の工程で直接使用した;1H NMR (600 MHz, DMSO−d6) δ 10.97 (s, 1H), 7.66 − 7.60 (m, 1H), 7.60 − 7.54 (m, 1H), 7.50 − 7.45 (m, 1H), 5.13 (dd, J = 13.3, 5.3 Hz, 1H), 4.50 (d, J = 17.1 Hz, 1H), 4.35 (d, J = 17.1 Hz, 1H), 2.96 − 2.86 (m, 3H), 2.61 (qd, J = 8.0, 3.6 Hz, 3H), 2.44 (qd, J = 13.3, 5.2 Hz, 1H), 2.01 (dtd, J = 10.3, 5.3, 2.7 Hz, 1H), 1.35 (s, 9H);
工程E:(E)−3−(2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−4−イル)アクリル酸(34−5)の調製。DCM(2mL)中のtert−ブチル3−(2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−4−イル)プロパノエート(化合物34−4)の混合物にTFA(0.5mL)を添加し、これを22oCで2時間撹拌した。反応混合物を真空下で濃縮して生成物(165mg、59%の収率(2工程で))を白色の固体として得た;1H NMR (600 MHz, DMSO−d6) δ 10.99 (s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.81 − 7.78 (m, 1H), 7.66 − 7.54 (m, 2H), 6.55 (d, J = 16.2 Hz, 1H), 5.16 (dd, J = 13.3, 5.2 Hz, 1H), 4.70 (d, J = 17.6 Hz, 1H), 4.51 (d, J = 17.6 Hz, 1H), 2.94 (ddd, J = 17.3, 13.8, 5.5 Hz, 1H), 2.65 − 2.59 (m, 2H), 2.02 (dtd, J = 12.6, 5.3, 2.3 Hz, 1H);
工程F:N−(3−(3−カルバモチオイルフェニル)−1−(4,4−ジフルオロシクロヘキシル)−1H−インドール−6−イル)−9−(3−(2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−4−イル)プロパンアミド)ノナンアミド(34)の調製。THF(2mL)及びDMF(2mL)中の9−アミノ−N−(3−(3−カルバモチオイルフェニル)−1−(4,4−ジフルオロシクロヘキシル)−1H−インドール−6−イル)ノナンアミド(50mg、0.092mmol)、3−(2−(2,6−ジオキソピペリジン−3−イル)−1−オキソイソインドリン−4−イル)プロパン酸(35mg、0.111mmol)、HATU(42mg、0.111mmol)及びDIPEA(50uL、0.277mmol)の混合物を0oCで10分間撹拌した。反応混合物を酢酸エチル(30mL)及び水(20mL)の間で分配した。水層を酢酸エチル(10mL)で抽出した。有機層を組み合わせ、水及びブラインで洗浄した。濃縮後、粗製物をカラムクロマトグラフィ(シリカゲル4g、DCM中0〜10%のメタノール)によって精製して生成物(20mg、26%の収率)を黄色の固体として得た;1H NMR (600 MHz, アセトニトリル−d3) δ 8.17 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.74 (dd, J = 7.8, 1.6 Hz, 1H), 7.69 (dd, J = 8.1, 1.7 Hz, 1H), 7.63 − 7.57 (m, 2H), 7.44 − 7.36 (m, 3H), 7.07 (dd, J = 8.5, 1.8 Hz, 1H), 5.08 (dd, J = 13.3, 5.2 Hz, 1H), 4.49 − 4.39 (m, 3H), 3.03 (hept, J = 6.6 Hz, 2H), 2.91 (q, J = 7.3, 6.5 Hz, 2H), 2.80 (ddd, J = 18.4, 13.6, 5.4 Hz, 1H), 2.75 − 2.66 (m, 1H), 2.50 − 2.41 (m, 3H), 2.37 (t, J = 7.4 Hz, 2H), 2.24 − 2.01 (m, 9H), 1.69 (p, J = 7.6 Hz, 2H), 1.30 (dddt, J = 31.8, 24.5, 15.7, 8.4 Hz, 8H), 1.14 − 1.06 (m, 2H);13C NMR (151 MHz, アセトニトリル−d3) δ 204.26, 174.65, 174.60, 174.53, 172.08, 171.70, 142.23, 141.68, 138.09, 137.43, 137.07, 134.77, 133.31, 132.71, 130.82, 129.71, 129.55, 127.09, 125.24, 124.19, 123.82, 122.55, 120.84, 117.46, 115.32, 103.13, 61.53, 54.07, 53.65, 49.85, 40.31, 38.04, 37.19, 33.91 (t, J = 25.0 Hz), 32.35, 30.22, 30.15, 30.10, 30.08 − 29.87 (m), 28.79, 27.67, 26.93, 24.13, 20.84, 14.45;C46H53F2N6O5Sに対するHR−MS[M+Na+]m/z計算値:839.3761、実測値:839.3757。
工程B:tert−ブチル3−((6−((tert−ブチルジメチルシリル)オキシ)ヘキシル)オキシ)プロパノエート(41−2)の調製。無水THF(10ml)中の41−1(1g、4.3mmol)の溶液にNaH(17mg、60%、0.43mmol)を添加し、混合物を室温で20分間撹拌し、tert−ブチルアクリレート(1.1g、8.6mmol)を添加した。得られた混合物を室温で24時間撹拌し、次いで水及びブラインで洗浄し、Na2SO4で乾燥させ、シリカで濃縮した。残渣を、EtOAc/ペンタンを溶離液として使用するカラムクロマトグラフィによって精製してtert−ブチル3−((6−((tert−ブチルジメチルシリル)オキシ)ヘキシル)オキシ)プロパノエートを無色の油(1.2g、80%)として得た。1H NMR (600 MHz, CDCl3) δ 7.76 (d, J = 2.0 Hz, 2H), 7.63 (d, J = 2.9 Hz, 2H), 4.03 (d, J = 6.3 Hz, 2H), 3.66 (t, J = 6.1 Hz, 2H), 3.38 (t, J = 6.4 Hz, 2H), 2.50 (t, J = 6.1 Hz, 2H), 1.55−1.45 (4H, m), 1.37 (s, 9 H), 1.33−1.28 (4H, m), 0.85−0.83 (9H, m), 0.009 (6H, s);
工程C及びD:tert−ブチル3−((6−((2−(2,6−ジオキソピペリジン−3−イル)−1,3−ジオキソイソインドリン−4−イル)オキシ)ヘキシル)オキシ)プロパノエート(41−4)の調製。THF(20mL)中の41−2(1g、2.7mmol)の撹拌溶液にTBAF(5.5ml、THF中1M、5.5mmol)を添加し、混合物を室温で3時間撹拌し、水性NH4Clを混合物に添加し、EtOAcで抽出した。組み合わせた有機層をブラインで洗浄し、無水Na2SO4で乾燥させて化合物41−3を黄色の油(680mg、98%)として得、化合物41−3をさらなる精製をせずに次の工程で直接使用した。化合物41−3(88mg、95μl、0.36mmol)をTHF(2ml)中のトリフェニルホスフィン(113mg、0.43mmol)の溶液に添加した。混合物を0℃に冷却し、THF(200μl)中のDIAD(86μL、0.43mmol)を少量ずつ添加した。15分後、2−(2,6−ジオキソピペリジン−3−イル)−4−ヒドロキシイソインドリン−1,3−ジオン(1−8、99mg、0.36mmol)を一度に添加した。反応物を室温に温めた。2時間後、溶媒を真空中で除去し、残渣をDCM/MeOHを溶離液として使用するカラムクロマトグラフィで精製して化合物41−4を黄色の油(108mg、60%)として得た。LC−MS:503[M+H+];
工程E:N−(3−(3−カルバモチオイルフェニル)−1−(4,4−ジフルオロシクロヘキシル)−1H−インドール−6−イル)−3−((6−((2−(2,6−ジオキソピペリジン−3−イル)−1,3−ジオキソイソインドリン−4−イル)オキシ)ヘキシル)オキシ)プロパンアミド(化合物41)の調製。化合物41−4(35mg、0.07mmol)をDCM(2.0mL)及びTFA(1.0mL)に溶解した。1時間撹拌した後、溶媒を蒸発させて粗酸化合物を得、これをさらなる精製をせずに次の工程で使用した。HATU(27mg、0.07mmol)、DIPEA(27μL、0.15mmol)、及び上記の粗酸化合物(0.07mmol)をDMF(2.0mL)中の化合物24−4(19mg、0.05mmol)の撹拌溶液に逐次添加した。溶液を室温で2時間撹拌した。次いで混合物をH2Oに注ぎ、EtOAcで2回抽出した。組み合わせた有機層をブラインで洗浄し、無水Na2SO4で乾燥させ、次いでシリカで濃縮した。残渣をDCM/MeOHを溶離液として使用するカラムクロマトグラフィによって精製して化合物41(12mg、30%)を得た。1H NMR (600 MHz, アセトン) δ 9.72 (s, 1H), 9.03 (s, 1H), 8.86 (s, 1H), 8.75 (s, 1H), 8.20 − 8.13 (m, 2H), 7.75 − 7.68 (m, 3H), 7.64 (s, 1H), 7.58 (dd, J = 8.3, 7.4 Hz, 1H), 7.31 (t, J = 7.7 Hz,1H), 7.23 (dd, J = 11.5, 7.9 Hz, 2H), 7.00 (dd, J = 8.6, 1.6 Hz, 1H), 5.01 − 4.92 (m, 1H), 4.56 − 4.49 (m, 1H), 4.03 (t, J = 6.3 Hz, 2H), 3.66 (t, J = 6.1 Hz, 2H), 3.38 (t, J = 6.4 Hz, 2H), 3.20 − 3.16 (m, 1H), 2.72 − 2.80−2.81 (m, 2H), 2.67 − 2.71 (m, 2H), 2.50 (t, J = 6.1 Hz, 2H), 2.21 − 1.99 (m, 8 H), 1.71 − 1.62 (m, 2H), 1.49 (dd, J = 14.0, 7.0 Hz, 2H), 1.43 (td, J = 14.5, 7.3 Hz, 2H), 1.34 (dd, J = 15.0, 8.1 Hz, 2H). 13C NMR (151 MHz, アセトン) δ 202.23, 171.70, 171.63, 169.13, 166.91, 165.35, 156.57, 140.41, 136.95, 136.51, 135.73, 134.60, 129.33, 128.34, 125.30, 124.45, 122.64, 122.16, 119.54, 119.26, 117.07, 115.95, 114.87, 113.43, 113.33, 100.86, 70.46, 69.02, 66.62, 54.00, 52.33, 49.11, 37.82, 35.29, 32.94, 32.72, 32.40, 31.11, 25.69, 25.49, 22.37。C43H46F2N5O7Sに対するHR−MS[M+H+]m/z計算値:814.3081、実測値:814.3079。
ウェスタンブロット
2.5×105のHeLa細胞を化合物で24時間処置し、続いてRIPA緩衝液中で溶解した。タンパク質試料を3〜8%のトリス−アセテートゲルに入れ、実行した。タンパク質をPVDFメンブレンに転写した後、ブロッキングのために5%ウシ血清アルブミン溶液を室温で2時間使用した。メンブレンをASH1L特異的抗体(Bethyl A301−749A)を用いて4℃で一晩インキュベートし、その後、抗ウサギ二次抗体(Cell signaling technology,7074S)を用いてインキュベートした。ブロットは、ECL検出システム(Amersham,RPN2236)によって検出した。
ヒト白血病細胞を24ウェルプレートに1×105細胞/mlでプレーティングし、0.25%DMSOまたは化合物で処置し、37℃で7〜14日間培養した。4日ごとに、1×105細胞のDMSO処置細胞に相当する量をスピンダウンし、新鮮な化合物を有する新鮮な培地に再懸濁した。0日目及び各4日の間隔で、細胞懸濁液の100μlのアリコートを4連で96ウェルプレートに移した。4連の試料を37℃で3〜4日間インキュベートし、次いでMTT細胞増殖アッセイキット(Roche)を使用して生細胞を測定した。吸光度をPHERAstar(BMG)マイクロプレートリーダーを使用して570nmで読み取った。
RNeasyミニキット(QIAGEN)を使用して細胞からトータルRNAを抽出し、次いで100〜2000ngのトータルRNAを高容量cDNA逆転写キット(Applied Biosystems)を使用して製造者のプロトコルに従って逆転写した。CFX96リアルタイムPCR検出システム(Biorad)を使用してリアルタイムPCRを実施した。TaqMan遺伝子発現マスターミックス及びTaqMan遺伝子発現アッセイをThermo Fisherから購入した。各遺伝子転写物の相対定量は、BioradリアルタイムPCR適用ガイドに記載されているようにΔΔCt法を使用して行った。
化合物またはDMSOで処置された1×105の白血病細胞を採取し、Shandon EZ Single Cytofunnel(Thermo Fisher)に入れた。試料を600rpmで5分間遠心分離した。スライドをHema−3キット(Thermo Fisher)で染色する前に空気乾燥させた。
本明細書に開示される例示的な化合物をマウスでインビボ試験に使用した。免疫不全の8〜10週齢の雌のNSGマウスをIACUCガイドラインに従ってインビボでの有効性試験に使用した。ルシフェラーゼを発現するヒトMV4;11白血病細胞(MV4;11−luc)を尾静脈注射(1×107細胞/動物)により静脈内に移植した。移植から5日後に、マウスをビヒクル対照または化合物処置群(1群あたり6〜7匹の動物)に無作為に割り当てた。処置群の各々の動物に腹腔内(i.p.)注射によってビヒクルまたは本開示の化合物Aを投与した。処置を17日間継続した。体重を毎日測定した一方で、平均発光シグナルを処置の開始後10日目及び17日目にすべてのマウスで測定した。実験の終了時に、脾臓、骨髄及び末梢血試料を収集し、白血病性芽球(hCD34+細胞)のレベルをフローサイトメトリーによって測定した。
Claims (22)
- 構造:
(式中、X、Z、A、リンカー、リガーゼリガンド、及びR1〜R7は、本明細書に記載及び/または図示される好適な置換基及び部分の任意の組み合わせから選択される)を含む化合物;
またはその塩。 - 構造:
(式中、Z、A、リンカー、リガーゼリガンド、及びR1は、本明細書に記載及び/または図示される好適な置換基及び部分の任意の組み合わせから選択される)を含む化合物;
またはその塩。 - 構造:
(式中、X、Z、A、リンカー、リガーゼリガンド、R1〜R7、及びR22〜R23は、本明細書に記載及び/または図示される好適な置換基及び部分の任意の組み合わせから選択される)を含む化合物;
またはその塩。 - 構造:
(式中、Z、リンカー、リガーゼリガンド、及びR6は、本明細書に記載及び/または図示される好適な置換基及び部分の任意の組み合わせから選択される)を含む化合物;
またはその塩。 - 構造:
(式中、X、Z、A、リンカー、リガーゼリガンド、及びR1〜R7は、本明細書に記載及び/または図示される好適な置換基及び部分の任意の組み合わせから選択される)を含む化合物;
またはその塩。 - 構造:
(式中、Z、A、リンカー、リガーゼリガンド、R1、及びR6は、本明細書に記載及び/または図示される好適な置換基及び部分の任意の組み合わせから選択される)を含む化合物;
またはその塩。 - 化合物1〜182から選択される、請求項1〜6のうちの1項に記載の化合物。
- X、Z、A、前記リンカー、前記リガーゼリガンド、及びR1〜R7は、存在する場合、化合物1〜91のX、Z、A、リンカー、リガーゼリガンド、及びR1〜R7基から任意の組み合わせで選択される、請求項1〜6のうちの1項に記載の化合物。
- 先行請求項のいずれか1項に記載の化合物及び薬学的に許容可能な担体を含む薬学的組成物。
- 前記薬学的組成物は、経口投与のために製剤化されている、請求項9に記載の薬学的組成物。
- 前記薬学的組成物は、注射のために製剤化されている、請求項9に記載の薬学的組成物。
- ASH1Lを分解する方法であって、ASH1Lを有効量の請求項1〜8のうちの1項の化合物または請求項9〜11のうちの1項の薬学的組成物と接触させることを含む、前記方法。
- ASH1Lの活性を阻害する方法であって、ASH1Lを有効量の請求項1〜8のうちの1項の化合物または請求項9〜11のうちの1項の薬学的組成物と接触させることを含む、前記方法。
- ASH1L活性は、前記化合物または薬学的組成物のASH1Lへの結合及び/または前記化合物または薬学的組成物によるASH1Lの分解の促進の任意の組み合わせによって阻害される、請求項13に記載の方法。
- ASH1Lの活性を阻害する及び/またはASH1Lの分解を促進するために、請求項9〜11のうちの1項に記載の薬学的組成物を有効量で対象に投与することを含む、疾患を治療する方法。
- 前記疾患は、がんである、請求項15に記載の方法。
- 前記疾患または病態は、白血病、血液学的悪性腫瘍、固形腫瘍癌、乳癌、前立腺癌、卵巣癌、肝臓癌、または甲状腺癌を含む、請求項16に記載の方法。
- 前記疾患または病態は、AML、ALL、混合系統白血病またはMLLの部分的タンデム重複を有する白血病を含む、請求項17に記載の方法。
- 染色体11q23上の染色体再構成によって媒介される障害の治療をそれを必要とする対象において行う方法であって、治療的有効量の請求項9〜11のいずれか1項に記載の薬学的組成物を前記対象に投与することを含む、前記方法。
- 前記薬学的組成物は、追加の治療剤と共投与される、請求項19に記載の方法。
- 前記対象は、ヒトである、請求項19に記載の方法。
- 請求項1〜8のうちの1項の化合物または請求項9〜11のうちの1項の薬学的組成物の疾患の治療のための使用。
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US20190142961A1 (en) | 2019-05-16 |
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US11147885B2 (en) | 2021-10-19 |
CA3082086A1 (en) | 2019-05-16 |
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