JP2021506916A - Keap1のBTBドメインの小分子モジュレータ - Google Patents
Keap1のBTBドメインの小分子モジュレータ Download PDFInfo
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- JP2021506916A JP2021506916A JP2020534443A JP2020534443A JP2021506916A JP 2021506916 A JP2021506916 A JP 2021506916A JP 2020534443 A JP2020534443 A JP 2020534443A JP 2020534443 A JP2020534443 A JP 2020534443A JP 2021506916 A JP2021506916 A JP 2021506916A
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
Description
本出願は、全体が参照により本明細書に援用される、2017年12月22日に出願された米国仮特許出願第62/609,463号に対する優先権の利益を主張するものである。
Xが、−C(O)−及び−S(O)2−から選択され;
R1及びR2がそれぞれ、独立して、H及びC1〜6アルキルから選択され;又はR1及びR2が、それらが結合される炭素と一緒になって、スピロシクロアルキル又はスピロヘテロシクロアルキル環を形成し;
R3が、ヒドロキシル及び任意に置換されるアルコキシから選択され;
R4が、任意に置換されるアリール及び任意に置換されるヘテロアリールから選択される)
の化合物、又はその薬学的に許容される塩を提供する。
R1及びR2がそれぞれ、独立して、C1〜6アルキルから選択され;又はR1及びR2が、それらが結合される炭素と一緒になって、スピロシクロアルキル又はスピロヘテロシクロアルキル環を形成し;
R3が、ヒドロキシル及び任意に置換されるアルコキシから選択され;
R4が、任意に置換されるアリール及び任意に置換されるヘテロアリールから選択される)
の化合物、又はその薬学的に許容される塩を提供する。
R1及びR2がそれぞれ、独立して、C1〜6アルキルから選択され;又はR1及びR2が、それらが結合される炭素と一緒になって、スピロシクロアルキル環を形成し;
R3が、ヒドロキシル及び任意に置換されるアルコキシから選択され;
R4が、任意に置換されるアリール及び任意に置換されるヘテロアリールから選択される)
の化合物、又はその薬学的に許容される塩を提供する。
R1及びR2がそれぞれ、独立して、C1〜6アルキルから選択され;又はR1及びR2が、それらが結合される炭素と一緒になって、スピロシクロアルキル又はスピロヘテロシクロアルキル環を形成し;
R3が、ヒドロキシル及び任意に置換されるアルコキシから選択され;
R5が、出現するごとに独立して、ハロゲン、CN、任意に置換されるアルキル、任意に置換されるアルケニル、任意に置換されるアルキニル、任意に置換されるアルキルスルホニル、任意に置換されるアルコキシル、任意に置換されるシクロアルキル、任意に置換されるシクロアルケニル、任意に置換されるヘテロシクロアルキル、任意に置換されるヘテロシクロアルケニル、任意に置換されるアリール、及び任意に置換されるヘテロアリールから選択され;
pが、0、1、2、3、及び4から選択される)
の化合物、又はその薬学的に許容される塩を提供する。
R1及びR2がそれぞれ、独立して、C1〜6アルキルから選択され;又はR1及びR2が、それらが結合される炭素と一緒になって、スピロシクロアルキル環を形成し;
R3が、ヒドロキシル及び任意に置換されるアルコキシから選択され;
R5が、出現するごとに独立して、ハロゲン、CN、任意に置換されるアルキル、任意に置換されるアルケニル、任意に置換されるアルキニル、任意に置換されるアルキルスルホニル、任意に置換されるアルコキシル、任意に置換されるシクロアルキル、任意に置換されるシクロアルケニル、任意に置換されるヘテロシクロアルキル、任意に置換されるヘテロシクロアルケニル、任意に置換されるアリール、及び任意に置換されるヘテロアリールから選択され;
pが、0、1、2、3、及び4から選択される)
の化合物、又はその薬学的に許容される塩を提供する。
本出願の化合物は、経口で、非経口、口腔、膣内、直腸、吸入、吹送、舌下に、筋肉内に、皮下に、局所に、鼻腔内に、腹腔内に、胸郭内に、静脈内、硬膜外に、髄腔内に、脳室内に及び注射によって関節中に投与され得る。
(1)抗鬱薬、例えばアゴメラチン、アミトリプチリン、アモキサピン、ブプロピオン、シタロプラム、クロミプラミン、デシプラミン、ドキセピンデュロキセチン、エルザソナン、エスシタロプラム、フルボキサミン、フルオキセチン、ゲピロン、イミプラミン、イプサピロン、マプロチリン、ノルトリプチリン、ネファゾドン、パロキセチン、フェネルジン、プロトリプチリン、ラメルテオン、レボキセチン、ロバルゾタン、セルトラリン、シブトラミン、チオニソキセチン、トラニルシプロミン、トラゾドン、トリミプラミン、ベンラファクシン並びにそれらの同等物及び薬学的に活性な異性体及び代謝産物。
本出願に記載される定義は、本出願全体を通して使用される用語を明確にすることが意図される。
本出願の組成物及び方法は、それを必要とする個体を治療するために用いられ得る。特定の実施形態において、個体は、ヒト、又は非ヒト哺乳動物などの哺乳動物である。ヒトなどの動物に投与されるとき、組成物又は化合物は、好ましくは、例えば、本出願の化合物及び薬学的に許容される担体を含む医薬組成物として投与される。薬学的に許容される担体は、当該技術分野において周知であり、例えば、水溶液、例えば、水若しくは緩衝生理食塩水又は他の溶媒若しくはビヒクル、例えば、グリコール、グリセロール、オリーブ油などの油、又は注射用有機酸エステルを含む。好ましい実施形態において、このような医薬組成物が、ヒトへの投与、特に、侵襲経路の投与(すなわち、上皮バリアを介した輸送又は拡散を回避する、注射又は注入(implantation)などの経路)のためのものである場合、水溶液は、発熱物質を含まない、又は発熱物質を実質的に含まない。賦形剤は、例えば、薬剤の遅延放出を行うように、又は1つ以上の細胞、組織又は器官を選択的に標的にするように選択され得る。医薬組成物は、錠剤、カプセル剤(スプリンクルカプセル及びゼラチンカプセルを含む)、顆粒剤、再構成用に凍結乾燥されたもの、散剤、液剤、シロップ剤、坐剤、注射などの単位剤形であり得る。組成物はまた、経皮送達系、例えば、皮膚パッチ中に存在し得る。組成物はまた、点眼剤などの、局所投与に好適な液剤中に存在し得る。
本出願の化合物のいくつかの非限定的な実施例が以下に続く。
全ての温度が、セ氏温度(℃)で示され、修正されない。試薬グレードの化学物質及び無水溶媒は、商業的供給源から購入し、特に記載されない限り、さらに精製せずに使用した。生成物の名称は、Dotmatics electronic lab notebookに含まれる命名ソフトウェアを用いて決定した。シリカゲルクロマトグラフィーは、15〜200mL/分の溶離剤流量範囲を有する予め充填された使い捨てSiO2固定相カラム、UV検出(254及び280nm)を用いて、Teledyne Isco機器において行った。逆相分取HPLCを、H2O(0.03%の(NH4)2CO3/0.375%のNH4OH)中のMeCN又はH2O(0.1%のHCOOH)中のMeCNの勾配で溶離しながら、C18カラム、UV検出(214及び254nm)を用いて行った。
順相又は逆相カラムクロマトグラフィーによって精製されたラセミ体化合物(>95%の純度)を、分取キラルHPLCカラムによってさらに精製した。典型的に使用されるキラルカラムは、以下のとおりであった:(a)CHIRALPAK IC、2・25cm、5μm;(b)CHIRALPAK AD−H、2.0cm I.D.2・25cm L、(R,R)Whelk−O 1、21.1・250mm、5μm;(c)CHIRALPAK IA、2・25cm、5μm;(d)CHIRAL ART Cellulose−SB、2*25cm、5μm。移動相A:Hex、移動相B:IPA又はEtOH;流量:20mL/分;勾配:化合物極性及びカラム条件に応じて10〜45分で5B〜95B;UV検出器:254/220nm。各鏡像異性体を含有する画分を、蒸発乾固させ、CH3CN及び水に溶解させ、次に、凍結乾燥させて、両方の鏡像異性体を固体化合物として得た。
順相又は逆相カラムクロマトグラフィーによって精製されたラセミ体化合物(>95%の純度)を、Lux C4カラム(150×4.6mm):移動相A(ヘプタン)、移動相B(EtOH)、典型的な勾配=10%のB、UV検出器:230nmを用いて、分取キラルHPLCによってさらに精製した。
Keap1のBTBドメインに結合されたいくつかの化合物の結晶構造を決定し、それにより、分子の絶対配置の割り当てが得られた。例示的なプロトコルについては実施例2を参照されたい。X線が決定された化合物は、S配置にあることが分かり、鏡像異性体対のうちより活性な方に相当していた。鏡像異性体が分離されたが、絶対配置が割り当てられていない化合物については、データが、試験された単一の鏡像異性体について示される。規定の立体化学なしで描かれ、「鏡像異性体A」と表示される化合物については、その化合物について本出願全体を通して提供される全てのデータは、より活性な鏡像異性体についてのものである。規定の立体化学なしで描かれ、「鏡像異性体B」と表示される化合物については、その化合物について本出願全体を通して提供される全てのデータは、より活性の低い鏡像異性体についてのものである。規定の立体化学なしで描かれ、「鏡像異性体A」とも「鏡像異性体B」とも表示されない化合物については、その化合物について本出願全体を通して提供される全てのデータは、ラセミ体についてのものである。
N末端ヘキサヒスチジンタグ及びTEV切断配列に融合されたKeap1(G48−D180)[S172A](以後、「Keap1N−BTB」と呼ばれる)プラスミドを、大腸菌(Escherichia coli)(BL21 Gold DE3コンピテントセル)において形質転換し、一晩、37℃で、100μg/mlのカナマイシン及び50μg/mlのテトラサイクリンが補充された50mlのTeriffic Broth(TB)中で成長させた。この一晩培養物が、50μg/mLのカナマイシン及び50μg/mLのテトラサイクリンが補充された3LのTBを接種するために使用され、OD600が約0.6に達するまで37℃で成長させた後、0.2mMのIPTGで誘導した。発現を、18℃で一晩続けさせ、細胞を、遠心分離(4,400×g、10分、4℃)によって収集した。得られた細胞ペレット(50gの細胞重量)を、2000 U Benzonase(Merck)、完全EDTAフリープロテアーゼ阻害剤(Roche Applied Science)の4つの錠剤、及び2.5mg/mLのリゾチーム(Sigma Aldrich)が補充された200mLの溶解緩衝液(40mMのHEPES pH8.0、300mMのNaCl、20mMのイミダゾール、1mMのTCEP)中で再懸濁させた。
アッセイの目的
このアッセイの目的は、Nrf2へのKeap1の結合を防ぎ、したがって、HEK−293 ARE蛍ルシフェラーゼで一過性にトランスフェクトされた細胞内のNrf2シグナル伝達経路を活性化する、Keap1の小分子阻害剤を特定することである。HEK−293細胞は、野生型Keap1タンパク質を発現し、したがって、低い構成レベルのNrf2タンパク質及びNrf2依存的転写を有する。細胞株は、一過性トランスフェクションによって社内で生成され、蛍ルシフェラーゼの上流にARE転写応答要素の2×縦列反復を有していた。Keap1が阻害されるとき、Nrf2シグナル伝達が活性化され、ルシフェラーゼ発現及び発光の増加がある。
凍結保存されたHEK AREルシフェラーゼ細胞を、37℃の水浴中で急速に解凍し、アッセイ培養培地(DMEM、10%のFCS、2mMのL−グルタミン)中で再懸濁させた。細胞懸濁液を、Heraeus卓上遠心分離機を用いて遠心分離(5分;300g)によってペレット化した。上清を除去し、ペレットを、バイアル当たり5mLの培養培地中で徐々に再懸濁させた。細胞生存及び細胞数を、Invitrogen Countess自動セルカウンター(典型的な生存率80%)を用いて測定し、細胞を5.0×105個の細胞/mLの密度に希釈した。
化合物を、100μMの最高濃度で10ptの用量曲線を用いて、Labcyte Echoを用いて音響的に分注した。アッセイウェルに、合計60nLになるまでDMSOを戻し充填して、アッセイを通して0.3%(v/v)のDMSOを維持した。
刺激因子(Stimulator)シグナルを、30μMのtert−ブチルヒドロキノン(tBHQ)を用いて定義し、ニュートラル(Neutral)シグナルをDMSOビヒクル対照によって定義した。全ての計算を、GeneDataを用いて行った。
HEK293ルシフェラーゼアッセイにおいて評価された化合物の平均EC50値が、表10に示される。平均値を、1〜20の個々の測定からのあらゆるところから計算した。
本明細書において言及される全ての刊行物及び特許は、それぞれの個々の刊行物又は特許が具体的に及び個別に参照により援用されていることが示されているかのように、全体が参照により本明細書に援用される。矛盾がある場合、本明細書における任意の定義を含む本出願が優先される。
本出願の特定の実施形態が記載されてきたが、上記の明細書は、例示的なものであり、限定的なものではない。本出願の主題の多くの変形が、本明細書及び以下の特許請求の範囲の検討により当業者に明らかになるであろう。本出願の全範囲は、特許請求の範囲を、それらの均等物の全範囲とともに参照し、及び本明細書を、このような変形とともに参照することによって決定されるべきである。
Claims (77)
- 式(I’)
Xが、−C(O)−及び−S(O)2−から選択され;
R1及びR2がそれぞれ、独立して、H及びC1〜6アルキルから選択され;又はR1及びR2が、それらが結合される炭素と一緒になって、スピロシクロアルキル又はスピロヘテロシクロアルキル環を形成し;
R3が、ヒドロキシル及び任意に置換されるアルコキシから選択され;
R4が、任意に置換されるアリール及び任意に置換されるヘテロアリールから選択される)
の化合物、又はその薬学的に許容される塩。 - Xが−C(O)−である、請求項1に記載の化合物、又はその薬学的に許容される塩。
- Xが−S(O)2−である、請求項1に記載の化合物、又はその薬学的に許容される塩。
- R1及びR2がそれぞれHである、請求項3に記載の化合物、又はその薬学的に許容される塩。
- 式(I)
R1及びR2がそれぞれ、独立して、C1〜6アルキルから選択され;又はR1及びR2が、それらが結合される炭素と一緒になって、スピロシクロアルキル又はスピロヘテロシクロアルキル環を形成し;
R3が、ヒドロキシル及び任意に置換されるアルコキシから選択され;
R4が、任意に置換されるアリール及び任意に置換されるヘテロアリールから選択される)
の化合物、又はその薬学的に許容される塩。 - 式(I)
R1及びR2がそれぞれ、独立して、C1〜6アルキルから選択され;又はR1及びR2が、それらが結合される炭素と一緒になって、スピロシクロアルキル環を形成し;
R3が、ヒドロキシル及び任意に置換されるアルコキシから選択され;
R4が、任意に置換されるアリール及び任意に置換されるヘテロアリールから選択される)
の化合物、又はその薬学的に許容される塩。 - R4が、任意に置換されるフェニル、任意に置換されるピリジニル、任意に置換されるイソキノリニル、任意に置換されるピラジニル、任意に置換されるチオフェニル、及び任意に置換されるチアゾリルから選択される、請求項1〜6のいずれか一項に記載の化合物、又はその薬学的に許容される塩。
- R4が、任意に置換されるピリジニルである、請求項7に記載の化合物、又はその薬学的に許容される塩。
- R4が、1つ以上のR5で任意に置換され;
R5が、出現するごとに独立して、ハロゲン、CN、任意に置換されるアルキル、任意に置換されるアルケニル、任意に置換されるアルキニル、任意に置換されるアルキルスルホニル、任意に置換されるアルコキシル、任意に置換されるシクロアルキル、任意に置換されるシクロアルケニル、任意に置換されるヘテロシクロアルキル、任意に置換されるヘテロシクロアルケニル、任意に置換されるアリール、及び任意に置換されるヘテロアリールから選択される、請求項1〜8のいずれか一項に記載の化合物、又はその薬学的に許容される塩。 - R4が、1つ又は2つのR5で置換される、請求項9に記載の化合物、又はその薬学的に許容される塩。
- R4が、2つのR5で置換される、請求項9に記載の化合物、又はその薬学的に許容される塩。
- R5が、出現するごとに独立して、ハロゲン、任意に置換されるアルキル、任意に置換されるアルケニル、任意に置換されるアルキニル、任意に置換されるアルコキシル、任意に置換されるシクロアルキル、任意に置換されるシクロアルケニル、任意に置換されるヘテロシクロアルキル、任意に置換されるヘテロシクロアルケニル、任意に置換されるフェニル、任意に置換されるピラゾリル、任意に置換されるピリジニル、任意に置換されるチアゾリル、任意に置換されるイミダゾリル、任意に置換されるピリミジニル、任意に置換されるイソオキサゾリル、任意に置換されるイソチアゾリル、及び任意に置換されるトリアゾロピリジニルから選択される、請求項9〜11のいずれか一項に記載の化合物、又はその薬学的に許容される塩。
- R5が、出現するごとに独立して、ハロゲン、任意に置換されるアルキル、任意に置換されるアルコキシル、任意に置換されるアリール、及び任意に置換されるヘテロアリールから選択される、請求項9〜11のいずれか一項に記載の化合物、又はその薬学的に許容される塩。
- R5が、出現するごとに独立して、ハロゲン、任意に置換されるアルキル、任意に置換されるアルコキシル、任意に置換されるフェニル、任意に置換されるピラゾリル、任意に置換されるピリジニル、及び任意に置換されるチアゾリルから選択される、請求項13に記載の化合物、又はその薬学的に許容される塩。
- R5が、出現するごとに独立して、ハロゲン及び任意に置換されるアルキルから選択される、請求項14に記載の化合物、又はその薬学的に許容される塩。
- R5が、出現するごとに独立して、1つ以上のR6で任意に置換され;
R6が、出現するごとに独立して、ハロゲン、CN、オキソ、アルキル、アルケニル、アルキニル、アルコキシ、アルキルスルホニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、及びヘテロアリールから選択される、請求項9〜14のいずれか一項に記載の化合物、又はその薬学的に許容される塩。 - R6が、出現するごとに独立して、ハロゲン、CN、オキソ、アルキル、アルコキシ、アルキルスルホニル、及びシクロアルキルから選択される、請求項16に記載の化合物、又はその薬学的に許容される塩。
- R6が、出現するごとに独立して、ハロゲン、アルキル、及びアルキルスルホニルから選択される、請求項17に記載の化合物、又はその薬学的に許容される塩。
- 式(Ia)
R1及びR2がそれぞれ、独立して、C1〜6アルキルから選択され;又はR1及びR2が、それらが結合される炭素と一緒になって、スピロシクロアルキル又はスピロヘテロシクロアルキル環を形成し;
R3が、ヒドロキシル及び任意に置換されるアルコキシから選択され;
R5が、出現するごとに独立して、ハロゲン、CN、任意に置換されるアルキル、任意に置換されるアルケニル、任意に置換されるアルキニル、任意に置換されるアルキルスルホニル、任意に置換されるアルコキシル、任意に置換されるシクロアルキル、任意に置換されるシクロアルケニル、任意に置換されるヘテロシクロアルキル、任意に置換されるヘテロシクロアルケニル、任意に置換されるアリール、及び任意に置換されるヘテロアリールから選択され;
pが、0、1、2、3、及び4から選択される)
の化合物、又はその薬学的に許容される塩。 - 式(Ia)
R1及びR2がそれぞれ、独立して、C1〜6アルキルから選択され;又はR1及びR2が、それらが結合される炭素と一緒になって、スピロシクロアルキル環を形成し;
R3が、ヒドロキシル及び任意に置換されるアルコキシから選択され;
R5が、出現するごとに独立して、ハロゲン、CN、任意に置換されるアルキル、任意に置換されるアルケニル、任意に置換されるアルキニル、任意に置換されるアルキルスルホニル、任意に置換されるアルコキシル、任意に置換されるシクロアルキル、任意に置換されるシクロアルケニル、任意に置換されるヘテロシクロアルキル、任意に置換されるヘテロシクロアルケニル、任意に置換されるアリール、及び任意に置換されるヘテロアリールから選択され;
pが、0、1、2、3、及び4から選択される)
の化合物、又はその薬学的に許容される塩。 - pが、1及び2から選択される、請求項19又は20に記載の化合物、又はその薬学的に許容される塩。
- pが2である、請求項21に記載の化合物、又はその薬学的に許容される塩。
- R5が、出現するごとに独立して、ハロゲン、任意に置換されるアルキル、任意に置換されるアルケニル、任意に置換されるアルキニル、任意に置換されるアルコキシル、任意に置換されるシクロアルキル、任意に置換されるシクロアルケニル、任意に置換されるヘテロシクロアルキル、任意に置換されるヘテロシクロアルケニル、任意に置換されるフェニル、任意に置換されるピラゾリル、任意に置換されるピリジニル、任意に置換されるチアゾリル、任意に置換されるイミダゾリル、任意に置換されるピリミジニル、任意に置換されるイソオキサゾリル、任意に置換されるイソチアゾリル、及び任意に置換されるトリアゾロピリジニルから選択される、請求項19〜22のいずれか一項に記載の化合物、又はその薬学的に許容される塩。
- R5が、出現するごとに独立して、ハロゲン、任意に置換されるアルキル、任意に置換されるアルコキシル、任意に置換されるアリール、及び任意に置換されるヘテロアリールから選択される、請求項19〜22のいずれか一項に記載の化合物、又はその薬学的に許容される塩。
- R5が、出現するごとに独立して、ハロゲン、任意に置換されるアルキル、任意に置換されるアルコキシル、任意に置換されるフェニル、任意に置換されるピラゾリル、任意に置換されるピリジニル、及び任意に置換されるチアゾリルから選択される、請求項24に記載の化合物、又はその薬学的に許容される塩。
- R5が、出現するごとに独立して、ハロゲン及び任意に置換されるアルキルから選択される、請求項25に記載の化合物、又はその薬学的に許容される塩。
- pが2であり、R5が、出現するごとに独立して、ハロゲン及び任意に置換されるアルキルから選択される、請求項19又は20に記載の化合物、又はその薬学的に許容される塩。
- R5の1つの出現がハロゲンであり、R5の他方の出現が、任意に置換されるアルキルである、請求項27に記載の化合物、又はその薬学的に許容される塩。
- R5の1つの出現が−Fであり、R5の他方の出現が、−CH(F)2である、請求項28に記載の化合物、又はその薬学的に許容される塩。
- R5が、出現するごとに独立して、1つ以上のR6で任意に置換され;
R6が、出現するごとに独立して、ハロゲン、CN、オキソ、アルキル、アルケニル、アルキニル、アルコキシ、アルキルスルホニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、ヘテロシクロアルケニル、アリール、及びヘテロアリールから選択される、請求項19〜25のいずれか一項に記載の化合物、又はその薬学的に許容される塩。 - R6が、出現するごとに独立して、ハロゲン、CN、オキソ、アルキル、アルコキシ、アルキルスルホニル、及びシクロアルキルから選択される、請求項30に記載の化合物、又はその薬学的に許容される塩。
- R6が、出現するごとに独立して、ハロゲン、アルキル、及びアルキルスルホニルから選択される、請求項31に記載の化合物、又はその薬学的に許容される塩。
- R1及びR2がそれぞれ、独立して、C1〜4アルキルから選択される、請求項1〜3及び5〜32のいずれか一項に記載の化合物、又はその薬学的に許容される塩。
- R1及びR2がそれぞれ、独立して、メチル及びエチルから選択される、請求項33に記載の化合物、又はその薬学的に許容される塩。
- R1及びR2が両方ともメチルである、請求項34に記載の化合物、又はその薬学的に許容される塩。
- R1及びR2が、それらが結合される炭素と一緒になって、スピロシクロプロピル、スピロシクロブチル、又はスピロシクロペンチル環を形成する、請求項1〜3及び5〜32のいずれか一項に記載の化合物、又はその薬学的に許容される塩。
- R1及びR2が、それらが結合される炭素と一緒になって、スピロシクロプロピル又はスピロシクロペンチル環を形成する、請求項36に記載の化合物、又はその薬学的に許容される塩。
- R1及びR2が、それらが結合される炭素と一緒になって、スピロシクロプロピル環を形成する、請求項37に記載の化合物、又はその薬学的に許容される塩。
- R3が、任意に置換されるアルコキシである、請求項1〜38のいずれか一項に記載の化合物、又はその薬学的に許容される塩。
- R3がメトキシである、請求項39に記載の化合物、又はその薬学的に許容される塩。
- R3がトリフルオロメトキシである、請求項39に記載の化合物、又はその薬学的に許容される塩。
- R3がメトキシ−d3である、請求項39に記載の化合物、又はその薬学的に許容される塩。
- 化合物1〜57、59〜94、96、98〜120、122〜137、139〜158、160〜212、及び214〜240のいずれか1つから選択される化合物、並びにその薬学的に許容される塩。
- 化合物14、
- 化合物42、
- 化合物163、
- 化合物186、
- 化合物194、
- (a)請求項1〜48のいずれか一項に記載の化合物と;(b)薬学的に許容される賦形剤とを含む医薬組成物。
- 薬剤として使用するための、請求項1〜48のいずれか一項に記載の化合物又は請求項49に記載の医薬組成物。
- 疾患を治療する方法であって、有効量の、請求項1〜48のいずれか一項に記載の少なくとも1つの化合物又は請求項49に記載の医薬組成物を含むNrf2転写の活性化因子を、それを必要とする対象に投与することを含む、方法。
- Keap1タンパク質を阻害する方法であって、細胞を、有効量の、請求項1〜48のいずれか一項に記載の少なくとも1つの化合物又は請求項49に記載の医薬組成物と接触させることを含む、方法。
- 対象における神経変性疾患を治療する方法であって、有効量の、請求項1〜48のいずれか一項に記載の少なくとも1つの化合物又は請求項49に記載の医薬組成物を、それを必要とする対象に投与することを含む、方法。
- 前記神経変性疾患が、アルツハイマー病(AD)、パーキンソン病(PD)、ハンチントン病(HD)及び他のCAGトリプレットリピート(又はポリグルタミン)病、筋萎縮性側索硬化症(ALS;ルー・ゲーリック病)、びまん性レヴィー小体病、有棘赤血球舞踏病、原発性側索硬化症、多発性硬化症(MS)、前頭側頭認知症、フリードライヒ運動失調症、急性頭部外傷、及びてんかん(ミクログリア活性化の抑制)から選択される、請求項53に記載の方法。
- 前記疾患が、パーキンソン病である、請求項54に記載の方法。
- 対象における炎症性疾患を治療する方法であって、有効量の、請求項1〜48のいずれか一項に記載の少なくとも1つの化合物又は請求項49に記載の医薬組成物を、それを必要とする対象に投与することを含む、方法。
- 前記炎症性疾患が、(i)呼吸器疾患;(ii)心血管疾患;(iii)代謝性疾患;(iv)全身性敗血症及び/又は大外傷の結果として起こる多臓器不全;(v)炎症性関節炎、(vi)炎症性腸疾患(IBD)、及び(vii)炎症性皮膚疾患から選択される、請求項56に記載の方法。
- 前記呼吸器疾患が、慢性閉塞性肺疾患(COPD)、喘息、特発性肺線維症及び放射線肺臓炎から選択される、請求項57に記載の方法。
- 前記心血管疾患が、アテローム性動脈硬化症から選択される、請求項57に記載の方法。
- 前記代謝性疾患が、急性腎障害、慢性腎疾患、急性肝障害及び慢性肝不全から選択される、請求項57に記載の方法。
- 前記炎症性関節炎が、痛風である、請求項57に記載の方法。
- 前記炎症性腸疾患が、クローン病又は潰瘍性大腸炎である、請求項57に記載の方法。
- 前記炎症性皮膚疾患が、アトピー性皮膚炎である、請求項57に記載の方法。
- 対象における自己免疫疾患を治療する方法であって、有効量の、請求項1〜48のいずれか一項に記載の少なくとも1つの化合物又は請求項49に記載の医薬組成物を、それを必要とする対象に投与することを含む、方法。
- 前記自己免疫疾患が、全身性エリテマトーデス(SLE)、シェーグレン症候群、関節リウマチ、乾癬性関節炎、乾癬、及び筋炎から選択される、請求項64に記載の方法。
- 対象における癌を治療する方法であって、有効量の、請求項1〜48のいずれか一項に記載の少なくとも1つの化合物又は請求項49に記載の医薬組成物を、それを必要とする対象に投与することを含む、方法。
- 前記癌が、肺癌、乳癌、胃癌、大腸癌、結腸癌、前立腺癌、胆嚢癌、卵巣癌、肝臓癌、食道癌、神経膠腫、食道扁平上皮細胞癌、膵臓癌、子宮内膜癌、乳頭癌、頭頸部癌、皮膚癌、肝細胞癌、並びに腎臓癌及び膀胱癌から選択される、請求項66に記載の方法。
- 活性酸素種(ROS)の発生又は酸化損傷に起因する、対象における合併症又は有害な後遺症を治療する方法であって、有効量の、請求項1〜48のいずれか一項に記載の少なくとも1つの化合物又は請求項49に記載の医薬組成物を、それを必要とする対象に投与することを含む、方法。
- 前記活性酸素種(ROS)の発生又は酸化損傷が、体外式膜型人工肺(ECMO)、心肺バイパス法(CBP)、体外循環路を必要とする腎代替療法、又は心臓、腎臓若しくは肝臓移植の結果である、請求項68に記載の方法。
- 前記体外循環路を必要とする腎代替療法が、腎臓透析、血液ろ過及び血液透析ろ過から選択される、請求項69に記載の方法。
- 神経変性疾患の治療のための薬剤の調製における、請求項1〜48のいずれか一項に記載の化合物又は請求項49に記載の医薬組成物の使用。
- 前記神経変性疾患が、アルツハイマー病(AD)、パーキンソン病(PD)、ハンチントン病(HD)及び他のCAGトリプレットリピート(又はポリグルタミン)病、筋萎縮性側索硬化症(ALS;ルー・ゲーリック病)、びまん性レヴィー小体病、有棘赤血球舞踏病、原発性側索硬化症、多発性硬化症(MS)、前頭側頭認知症、フリードライヒ運動失調症、急性頭部外傷、及びてんかん(ミクログリア活性化の抑制)からなる群から選択される、請求項71に記載の使用。
- 必要とする患者における疾患を治療するための薬剤の調製における、請求項1〜48のいずれか一項に記載の化合物又は請求項49に記載の医薬組成物の使用。
- 前記疾患が、アルツハイマー病(AD)、パーキンソン病(PD)、ハンチントン病(HD)及び他のCAGトリプレットリピート(又はポリグルタミン)病、筋萎縮性側索硬化症(ALS;ルー・ゲーリック病)、びまん性レヴィー小体病、有棘赤血球舞踏病、原発性側索硬化症、多発性硬化症(MS)、前頭側頭認知症、フリードライヒ運動失調症、急性頭部外傷、及びてんかん(ミクログリア活性化の抑制)から選択される、請求項73に記載の使用。
- 必要とする患者における疾患又は障害を治療する方法であって、請求項1〜48のいずれか一項に記載の化合物又は請求項49に記載の医薬組成物を投与することを含む、方法。
- 前記疾患又は障害が、アルツハイマー病(AD)、パーキンソン病(PD)、ハンチントン病(HD)及び他のCAGトリプレットリピート(又はポリグルタミン)病、筋萎縮性側索硬化症(ALS;ルー・ゲーリック病)、びまん性レヴィー小体病、有棘赤血球舞踏病、原発性側索硬化症、多発性硬化症(MS)、前頭側頭認知症、フリードライヒ運動失調症、急性頭部外傷、及びてんかん(ミクログリア活性化の抑制)から選択される、請求項75に記載の方法。
- 前記疾患が、パーキンソン病である、請求項76に記載の方法。
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US20230257371A1 (en) * | 2020-07-16 | 2023-08-17 | Merck Sharp & Dohme Llc | Cyclic cyanoenone derivatives as modulators of keap1 |
WO2024073587A1 (en) * | 2022-09-29 | 2024-04-04 | Vividion Therapeutics, Inc. | N-acryloylmorpholine derivatives as keap1 modulators and uses thereof |
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WO2013067036A1 (en) * | 2011-10-31 | 2013-05-10 | Rutgers, The State University Of New Jersey | Direct inhibitors of keap1-nrf2 interaction as antioxidant inflammation modulators |
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CA3085097A1 (en) | 2019-06-27 |
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US20210094931A1 (en) | 2021-04-01 |
AR113995A1 (es) | 2020-07-08 |
RU2020124097A (ru) | 2022-01-24 |
CN111491922A (zh) | 2020-08-04 |
KR20200104335A (ko) | 2020-09-03 |
AU2018386464A1 (en) | 2020-07-30 |
UY38027A (es) | 2019-07-31 |
US11479539B2 (en) | 2022-10-25 |
EP3728190A1 (en) | 2020-10-28 |
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AU2018386464B2 (en) | 2021-08-05 |
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