JP2020509003A - スルホキシイミングリコシダーゼ阻害剤 - Google Patents
スルホキシイミングリコシダーゼ阻害剤 Download PDFInfo
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- JP2020509003A JP2020509003A JP2019545961A JP2019545961A JP2020509003A JP 2020509003 A JP2020509003 A JP 2020509003A JP 2019545961 A JP2019545961 A JP 2019545961A JP 2019545961 A JP2019545961 A JP 2019545961A JP 2020509003 A JP2020509003 A JP 2020509003A
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
Description
で表される化合物並びに/又はその生理学的に許容される塩、互変異性体、溶媒和物、立体異性体及び誘導体を含んでいる薬物に関する。式(I)で表される化合物は、グリコシダーゼ阻害剤として使用することができる。本発明の目的は、さらにまた、式(I)で表される化合物を含んでいる医薬組成物、並びに、1種類以上のタウオパシー及びアルツハイマー病を治療するための式(I)で表される化合物の使用である。
Xは、N又はCR’’’であり;
Yは、O、S、SO又はSO2であり;
R’、R’’は、それぞれ独立して、H、Halを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキルを表し;
R’’’、R’’’’は、独立して、H、Hal、NR3R4、CHR3R4、OR3、CNを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキルを表し、ここで、1〜3のCH2基は、O、NR3、S、SO、SO2、S(O)(NR3’)、N(SO)R3’、CO、COO、OCO、CONR3、NR3CO、
Z1は、S、O、NR3であり;
Z2、Z3は、独立して、CR5又はNを表し;
Z4は、N、CH、CON、COCHであり;
Z5は、NR8、CHR5、S(O)(NR3’)、N(SO)R3’、
Z7は、C(R3’)2、S、O、NR3’であり;
sは、0又は1を表し;
Tは、N、CH又はCR7であり;
R3’は、Hを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキル基を表し、ここで、1〜3のCH2基は、SO2、CO、Oから選択される基で置き換えられていてもよく、及び、ここで、1〜5個の水素原子は、Halで置き換えられていてもよく;
R5、R6、R7は、独立して、H、Hal、NR3R4、NO2を表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキルを表し、ここで、1〜3のCH2基は、O、NR3、S、SO、SO2、S(O)(NR3’)、N(SO)R3’、CO、COO、OCO、CONR3、NR3CO、
R8は、Hを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキルを表し、ここで、1〜3のCH2基は、SO、SO2、S(O)(NR3’)、N(SO)R3’、CO、COO、OCO、CONR3、NR3CO、及び、
Halは、F、Cl、Br又はIを表し;
Hetは、飽和、不飽和又は芳香族の環を表し、ここで、該環は、単環式若しくは二環式であるか又は縮合二環式であり、及び、該環は、3〜8員を有し且つN、O及びSから選択される1〜4個のヘテロ原子を含んでおり、ここで、該環は、R5、Hal及びOR3から選択される1〜3個の置換基で置換されていてもよく;
Arは、6員炭素環式芳香族環を表すか、又は、縮合若しくは非縮合の二環式芳香族環系を表し、ここで、該環は、R5、OR3及びHalから独立して選択される1〜3の置換基で置換されていてもよく;
Cycは、3〜8個の炭素原子を有する飽和又は不飽和の炭素環式環を表し、ここで、該環は、R5又はHal又はOHから独立して選択される1〜3の置換基で置換されていてもよく;
m及びnは、互いに独立して、0、1、2又は3を表し;
t及びqは、互いに独立して、0、1、2又は3を表し、但し、t+q≧1であり;
及び、
ここで、Z5とZ6のうちの少なくとも1は、基S(O)(NR3’)若しくはN(SO)R3’又は
又は、
ここで、R’’’、R’’’’、R5、R6、R7及びR8のうちの少なくとも1は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキル基(ここで、少なくとも1のCH2基は、基S(O)(NR3’)若しくはN(SO)R3’又は
及び、
ここで、
さらなるCH2基及びH原子は、R’’’、R’’’’、R5、R6、R7及びR8の定義に従う別の基で置き換えられていてもよい〕
で表される化合物、並びに、その薬学的に使用可能な誘導体、溶媒和物、塩、プロドラッグ、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)、並びに、1個以上のH原子がD(重水素)で置き換えられている式(I)で表される化合物に関する。
のうちの1つを表す。
のうちの1つである。
のうちの1つである。
又は、
式中、R’’’、R’’’’、R5、R6、R7及びR8のうちの少なくとも1は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキル基から選択され、ここで、少なくとも1のCH2基は、基
式中、R3’、Z7、t、qは、上記で定義されているとおりである〕で表される化合物、並びに、その薬学的に使用可能な誘導体、溶媒和物、塩、プロドラッグ、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)、並びに、1個以上のH原子がD(重水素)で置き換えられている式(I)で表される化合物が好ましい。
又は、
式中、R’’’、R’’’’、R5、R6、R7及びR8のうちの少なくとも1は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキル基から選択され、ここで、少なくとも1のCH2基は、基
式中、X、Y、R’、R’’、R’’’、R3’、R7、Z5、Z6、Z7、T、t、qは、上記で定義されているとおりである〕で表される化合物、並びに、その薬学的に使用可能な誘導体、溶媒和物、塩、プロドラッグ、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)、並びに、1個以上のH原子がD(重水素)で置き換えられている式(I)で表される化合物がさらに好ましい。
及び、
R’、R3’、R3、R4、Hal、Het、Ar及びCycは、上記で定義されているとおりである;
並びに、その薬学的に使用可能な誘導体、溶媒和物、塩、プロドラッグ、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)、並びに、1個以上のH原子がD(重水素)で置き換えられている式(I)で表される化合物。
R’、R7’及びT’は、上記で定義されているとおりである;
並びに、その薬学的に使用可能な誘導体、溶媒和物、塩、プロドラッグ、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)、並びに、1個以上のH原子がD(重水素)で置き換えられている式(I)で表される化合物。
R7’は、上記で定義されているとおりである;
並びに、その薬学的に使用可能な誘導体、溶媒和物、塩、プロドラッグ、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)、並びに、1個以上のH原子がD(重水素)で置き換えられている式(I)で表される化合物。
R7’及びT’は、上記で定義されているとおりである;
並びに、その薬学的に使用可能な誘導体、溶媒和物、塩、プロドラッグ、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)、並びに、1個以上のH原子がD(重水素)で置き換えられている式(I)で表される化合物。
以下の段階によって得ることができる化合物:
(a) ラセミ5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]チアゾールのキラル分割; ここで、該5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]チアゾールをエタノール中のD−ジ−p−アニソイル酒石酸で処理し、及び、それにより形成された固形D−ジ−p−アニソイル酒石酸塩を単離し、その後、塩基を用いて前記塩をエナンチオマー的に富化された又は純粋な遊離ピペラジン塩基に変換させる;
(b) 実施例において記載されている方法EによるPhenomenex Lux Amylose−1カラムでのキラルSFCクロマトグラフィーによるラセミ2−クロロ−5−(メチルスルフィニル)ピリミジンのキラル分割; それにより、溶出する2−クロロ−5−(メチルスルフィニル)ピリミジンの2種類のエナンチオマーの1番目がエナンチオマー的に富化された又は純粋な物質として得られ、その物質を、次に、MgO、酢酸ロジウム(II)二量体(Rh2(OAc)4)及び(ジアセトキシヨード)ベンゼン(PhI(OAc)2)の存在下でトリフルオロアセトアミドと反応させて、N−((2−クロロピリミジン−5−イル)(メチル)(オキソ)−λ6−スルファニリデン)−2,2,2−トリフルオロアセトアミドの対応するエナンチオマー的に富化された又は純粋なエナンチオマーを生成させる;
(c) 段階(a)で得られたエナンチオマー的に富化された又は純粋なピペラジン塩基と段階(b)で得られたN−((2−クロロピリミジン−5−イル)(メチル)(オキソ)−λ6−スルファニリデン)−2,2,2−トリフルオロアセトアミドのエナンチオマー的に富化された又は純粋なエナンチオマーの、塩基の存在下における反応; そのようにして得られた生成物を単離した後、脱保護して、(2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ6−スルファノンのエナンチオマー的に富化された又は純粋な単一のジアステレオ異性体が得られる。
以下の段階によって得ることができる化合物:
(a) ラセミ5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]チアゾールのキラル分割; ここで、該5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]チアゾールをエタノール中のD−ジ−p−アニソイル酒石酸で処理し、及び、それにより形成された固形D−ジ−p−アニソイル酒石酸塩を単離し、その後、塩基を用いて前記塩をエナンチオマー的に富化された又は純粋な遊離ピペラジン塩基に変換させる;
(b) 実施例において記載されている方法EによるPhenomenex Lux Amylose−1カラムでのキラルSFCクロマトグラフィーによるラセミ2−クロロ−5−(メチルスルフィニル)ピリミジンのキラル分割; それにより、溶出する2−クロロ−5−(メチルスルフィニル)ピリミジンの2種類のエナンチオマーの2番目がエナンチオマー的に富化された又は純粋な物資として得られ、その物質を、次に、MgO、酢酸ロジウム(II)二量体(Rh2(OAc)4)及び(ジアセトキシヨード)ベンゼン(PhI(OAc)2)の存在下でトリフルオロアセトアミドと反応させて、N−((2−クロロピリミジン−5−イル)(メチル)(オキソ)−λ6−スルファニリデン)−2,2,2−トリフルオロアセトアミドの対応するエナンチオマー的に富化された又は純粋なエナンチオマーを生成させる;
(c) 段階(a)で得られたエナンチオマー的に富化された又は純粋なピペラジン塩基と段階(b)で得られたN−((2−クロロピリミジン−5−イル)(メチル)(オキソ)−λ6−スルファニリデン)−2,2,2−トリフルオロアセトアミドのエナンチオマー的に富化された又は純粋なエナンチオマーの、塩基の存在下における反応; そのようにして得られた生成物を単離した後、脱保護して、(2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ6−スルファノンのエナンチオマー的に富化された又は純粋な単一のジアステレオ異性体が得られる。
+ 1〜10μM
++ 0.2〜1μM
+++ 0.2〜0.05μM
++++ 0.05μM未満。
うな好ましい化合物は、高い固体状態安定性、肝臓ミクロソームの存在下での高い安定性、高い酸化安定性及び適切な透過性を示す。さらに好ましい本発明の化合物は、強力な生物学的活性、例えば、脳抽出物で測定される総タンパク質のO−GlcNAc化レベルなどによって、薬物としての適合性を示す。そのようなパラメータを測定するための関連する試験は、当業者には知られており、例えば、固体状態安定性(Waterman K.C. (2007) Pharm Res 24(4);780−790)、肝臓ミクロソーム存在下での安定性(Obach R. S. (1999) Drug Metab Dispos 27(11);1350−135)及び浸透性(例えば、Caco−2浸透性アッセイ;Calcagno A. M. (2006) Mol Pharm 3(1);87−93)。あるいは、それらは、脳抽出物で測定される総タンパク質のO−GlcNAc化レベルの測定について記載している実施例B02などの、下記実施例において記載されている。OGA阻害アッセイにおいて高い効力及び上記特性のうちの1以上を示す本発明の化合物は、本明細書で挙げられた適応症に関する薬物として特に適している。
Ac(アセチル)、aq(水性)、h(時間)、g(グラム)、L(リットル)、mg(ミリグラム)、MHz(メガヘルツ)、μM(マイクロモル濃度)、min(分)、mm(ミリメートル)、mmol(ミリモル)、mM(ミリモル濃度)、m.p.(融点)、equiv(当量)、mL(ミリリットル)、μL(マイクロリットル)、ACN(アセトニトリル)、AcOH(酢酸)、BINAP(2,2’−ビス(ジスフェニルホスフィノ)−1,1’−ビナフタレン)、BOC(tert−ブトキシ−カルボニル)、CBZ(カルボベンゾキシ)、CDCl3(重クロロホルム)、CD3OD(重メタノール)、CH3CN(アセトニトリル)、c−hex(シクロヘキサン)、DCC(ジシクロヘキシルカルボジイミド)、DCM(ジクロロメタン)、DHP(O−(2,4−ジニトロフェニル)−ヒドロキシルアミン)、dppf(1,1’−ビス(ジフェニルホスフィノ)フェロセン)、DIC(ジイソプロピルカルボジイミド)、DIEA(ジイソプロピルエチル−アミン)、DMF(ジメチルホルムアミド)、DMSO(ジメチルスルホキシド)、DMSO−d6(重ジメチルスルホキシド)、EDC(1−(3−ジメチル−アミノ−プロピル)−3−エチルカルボジイミド)、ESI(エレクトロスプレーイオン化)、EtOAc(酢酸エチル)、Et2O(ジエチルエーテル)、EtOH(エタノール)、FMOC(フルオレニルメチルオキシカルボニル)、HATU(ジメチルアミノ−([1,2,3]トリアゾロ[4,5−b]ピリジン−3−イルオキシ)−メチレン]−ジメチル−アンモニウムヘキサフルオロホスフェート)、HPLC(高性能液体クロマトグラフィー)、i−PrOH(2−プロパノール)、K2CO3(炭酸カリウム)、LC(液体クロマトグラフィー)、MD Autoprep(質量分離Autoprep)、MeOH(メタノール)、MgSO4(硫酸マグネシウム)、MS(質量分析)、MTBE(メチルtert−ブチルエーテル)、Mtr.(4−メトキシ−2,3,6−トリメチルベンゼンスルホニル)、MW(マイクロ波)、NBS(N−ブロモスクシンイミド)、NaHCO3(重炭酸ナトリウム)、NaBH4(水素化ホウ素ナトリウム)、NMM(N−メチルモルホリン)、NMR(核磁気共鳴)、m−CPBA(3−クロロ過安息香酸)、MSH(O−メシチレンスルホニルヒドロキシルアミン)、POA(フェノキシアセテート)、Py(ピリジン)、PyBOP(登録商標)(ベンゾトリアゾール−1−イル−オキシ−トリス−ピロリジノ−ホスホニウムヘキサフルオロホスフェート)、RT(室温)、Rt(保持時間)、SFC(超臨界流体クロマトグラフィー)、SPE(固相抽出)、T3P(プロピルホスホン酸無水物)、TBAF(テトラ−n−ブチルアンモニウムフルオリド)、TBTU(2−(1−H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムテトラフルオロボレート)、TEA(トリエチルアミン)、TFA(トリフルオロ酢酸)、THF(テトラヒドロフラン)、TLC(薄層クロマトグラフィー)、UV(紫外線)。
・ アセチルコリンエステラーゼ阻害剤(AChEIs)、例えば、Aricept(登録商標)(ドネペジル)、Exelon(登録商標)(リバスティグミン)、Razadyne(登録商標)(Razadyne ER(登録商標)、Reminyl(登録商標)、Nivalin(登録商標)、ガランタミン)、Cognex(登録商標)(タクリン)、NMDA拮抗薬、例えば、メマンチン(Axura(登録商標)、Ebixa(登録商標))、Huperzine A、フェンセリン、Debio−9902 SR(ZT−1 SR)、ザナペジル(TAK0147)、ガンスチグミン、NP7557、α7ニコチン性アセチルコリン受容体作動薬、5−HT6受容体拮抗薬、M1ムスカリン性アセチルコリン受容体作動薬及びポジティブアロステリックモジュレーターなど;
・ タウ凝集阻害剤、例えば、メチレンブルーなど;
・ タウ凝集シーディング(seeding)及び増殖をブロックする薬剤、例えば、タウ抗体及びタウワクチンなど;
・ 微小管安定剤、例えば、AL−108、AL−208、パクリタキセルなど;
・ アミロイド−β(Aβ)ペプチド低下剤、例えば、β−セクレターゼ(BACE−1)阻害剤、老人斑消去生物剤、例えば、Aβ抗体及びAβワクチン。
該神経変性性の疾患又は状態は、さらに好ましくは、1以上のタウオパシー及びアルツハイマー病、筋萎縮性側索硬化症(ALS)、認知障害を伴う筋萎縮性側索硬化症(ALSci)、嗜銀顆粒病、行動異常型前頭側頭型認知症(bvFTD)、ブルーイト病(Bluit disease)、大脳皮質基底核変性症(CBP)、ボクサー認知症、レヴィー小体認知症、石灰化を伴うびまん性神経原線維変化病、ダウン症候群、家族性英国型認知症、家族性デンマーク型認知症、染色体17と関連したパーキンソニズムを伴う前頭側頭認知症(FTDP−17)、前頭側頭葉変性症(FTLD)、神経節膠腫、神経節細胞腫、ゲルストマン−シュトロイスラー−シャインカー病、球状グリアタウオパシー(Globular glial tauopathy)、グアドループパーキンソニズム、ハレルフォルデンスパッツ病(脳内の鉄蓄積1型を伴う神経変性)、鉛脳症、リポフスチン沈着症、髄膜血管腫症、多系統委縮症、筋強直性ジストロフィー、ニーマン・ピック病(C型)、淡蒼球−橋脳−黒質変性(Pallido−ponto−nigraldegeneration)、パーキンソン病、パーキンソン病認知症(PDD)、グアムのパーキンソン認知症症候群、ピック病(PiD)、脳炎後パーキンソニズム(PEP)、原発性進行性失語症、プリオン病(クロイツフェルト−ヤコブ病(GJD)、異型クロイツフェルト・ヤコブ病(vCJD)、致死性家族性不眠症、クールー病、進行性超皮質性グリオーシス(Progressive supercortical gliosis)、進行性核上まひ(PSP)、純粋自律神経失調症、リチャードソン症候群、亜急性硬化性全脳炎、神経原線維型老年認知症、結節硬化症、ハンチントン病の群から選択される。最も好ましいものは、1以上のタウオパシー及びアルツハイマー病である。
式(I)で表される化合物は、液相及び固相の両方の化学プロトコル又は混合液相及び固相プロトコルを用いて、容易に入手可能な出発物質から幾つかの合成アプローチによって調製することができる。合成経路の例は、実施例において、以下にを記載されている。報告されている全ての収率は、最適化されていない収率である。別途示されていない限り、ラセミ混合物として得られる式(I)及び関連する式で表される化合物は、分離して、エナンチオマー的に富化された混合物又は純粋なエナンチオマーを提供することができる。
機器名:Agilent Technologies 1290 infinity 11;
方法A:方法:A−H2O中0.1%TFA、B−ACN中0.1%TFA;流量:2.0mL/分;カラム:XBridge C8(50×4.6mm、3.5μm)、+veモード;
方法B:方法:A−H2O中10mM NH4HCO3、B−ACN;流量:1.0mL/分;カラム:XBridge C8(50×4.6mm、3.5μm)、+veモード;
方法C:方法:A−H2O中0.1%HCOOH、B−ACN;流量:1.5mL/分;カラム:ZORBAX Eclipse XDB−C18(50×4.6mm、3.5μm)、+veモード。
機器名:Agilent 1200 Series instruments;以下のように、UV検出による%を使用(maxplot);
方法A:方法:A−H2O中0.1%TFA、B−CAN中0.1%TFA;流量:2.0mL/分;カラム:XBridge C8(50×4.6mm、3.5μm);
方法B:方法:A−H2O中10mM NH4HCO3、B−ACN;流量:1.0mL/分;カラム:XBridge C8(50×4.6mm、3.5μm)。
機器名:Agilent 1260 infiinity II;
方法A:移動相:n−ヘキサン:EtOH(60:40)の中の0.1%DEA;流量:1.0mL/分;カラム:Chiralcell OD−H(250×4.6mm、5μm)。
機器名:THAR−SFC 80、及び、THAR−SFC 200(分析的)
CO2と共溶媒の間の比率は、50:50〜90:10の範囲である;
方法A:移動相:IPA中20mMアンモニア、流量:4mL/分;カラム:Chiralpak ADH(250×4.6mm、5μm);
方法B:移動相:メタノール20mMアンモニア、流量:10mL/分;カラム:YMC Cellulose C(250×4.6mm、5μm);
方法C:移動相:IPA中20mMアンモニア、流量:4mL/分;カラム:Lux A1(250×4.6mm、5μm);
方法D:移動相:MeOH中20mMアンモニア、流量:4mL/分;カラム:Chiralpak ADH(250×4.6mm、5μm);
方法E:移動相:IPA、流量:3mL/分;カラム:Lux A1(250×4.6mm、5μm)。
方法A:A−H2O中0.1%TFA、B−MeOH又はCAN;カラム:Sunfire C8(19×250mm、5μm)、又は、Sunfire C18(30×250mm、10μm);
方法B:A−H2O中10mM NH4HCO3、B−MeOH又はACN、カラム:Sunfire C8(19×250mm、5μm)、又は、Sunfire C18(30×250mm、10μm)。
機器名:THAR−SFC 80、THAR−SFC 200、及び、PIC SFC 10−150
CO2と共溶媒の間の比率は、50:50〜90:10の範囲である;
方法A:移動相:IPA中20mMアンモニア;流量:3mL/分;カラム:Chiralpak ADH(250×30mm、5μm);
方法B:移動相:メタノール中20mMアンモニア;流量:5mL/分;カラム:YMC Cellulose C(250×30mm、5μm);
方法C:移動相:IPA中20mMアンモニア;流量:5mL/分;カラム:Lux A1(250×30mm、5μm);
方法D:移動相:MeOH中20mMアンモニア;流量:4mL/分;カラム:Chiralpak ADH(250×30mm、5μm);
方法E:移動相:IPA、流量:100mL/分;カラム:Phenomenex Lux Amylose−1(250×30mm、5μm)。
段階2: 1,4−ジブロモ−2−(2−ブロモエトキシ)ベンゼン
段階3: 2,3−ジヒドロベンゾフラン−6−カルバルデヒド
段階4: 1−(2,3−ジヒドロベンゾフラン−6−イル)エタン−1−オール
段階5: 6−(1−クロロエチル)−2,3−ジヒドロベンゾフラン
段階6: 4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−カルボン酸tert−ブチル
段階7: 1−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン
中間体2: (S)−1−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン、又は、(R)−1−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン
中間体3: 1−(1−(2,2−ジメチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン二塩酸塩
段階2: 5−ブロモ−2−(2−メチルアリル)フェノール、及び、3−ブロモ−2−(2−メチルアリル)フェノール
段階3: 6−ブロモ−2,2−ジメチル−2,3−ジヒドロベンゾフラン
段階4: 1−(2,2−ジメチル−2,3−ジヒドロベンゾフラン−6−イル)エタン−1−オン
異性体B分析:収率:15%(500mg、淡黄色の液体)。1H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 3.36 (s, 2H), 2.59 (s, 3H), 1.48 (s, 6H). LCMS: (方法 A) 191.0 (M+H), Rt. 4.2 分, 99.2%(Max).
段階5: 1−(2,2−ジメチル−2,3−ジヒドロベンゾフラン−6−イル)エタン−1−オール
段階6: 6−(1−クロロエチル)−2,2−ジメチル−2,3−ジヒドロベンゾフラン
段階8: 1−(1−(2,2−ジメチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン二塩酸塩
中間体4: 1−(1−(2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン二塩酸塩
段階2: 1−(4−アリル−3−ヒドロキシフェニル)エタン−1−オンと1−(2−アリル−3−ヒドロキシフェニル)エタン−1−オンの混合物
段階3: 1−(2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エタン−1−オン(異性体A)、及び、1−(2−メチル−2,3−ジヒドロベンゾフラン−4−イル)エタン−1−オン(異性体B)
異性体Bの分析:1H NMR (400 MHz, DMSO-d6): δ 7.37 (d, J = 7.60 Hz, 1H), 7.24-7.18 (m, 1H), 6.95 (d, J = 7.60 Hz, 1H), 5.00-4.94 (m, 1H), 3.72-3.65 (m, 1H), 3.18-3.11 (m, 1H), 2.60 (s, 3H), 1.49-1.47 (m, 3H). LCMS: (方法 A) 177.3 (M+H), Rt. 3.7 分, 74.5% (Max).
段階4: 1−(2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エタン−1−オール
段階5: 6−(1−クロロエチル)−2−メチル−2,3−ジヒドロベンゾフラン
段階6: 4−(1−(2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−カルボン酸tert−ブチル
段階7: 1−(1−(2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン二塩酸塩
中間体5: 1−(1−(クロマン−7−イル)エチル)ピペラジン二塩酸塩
段階2: 1,4−ジブロモ−2−(3−ブロモプロポキシ)ベンゼン
段階4: 1−(クロマン−7−イル)エタン−1−オール
段階5: 7−(1−クロロエチル)クロマン:
段階7: 1−(1−(クロマン−7−イル)エチル)ピペラジン二塩酸塩:
中間体6: 5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]チアゾール
段階2: 1−(ベンゾ[d]チアゾール−5−イル)エタン−1−オール:
段階3: 5−(1−クロロエチル)ベンゾ[d]チアゾール:
段階4: 4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−カルボン酸tert−ブチル:
段階5: 5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]チアゾール
中間体7: (S)−5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]チアゾール、又は、(R)−5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]チアゾール
中間体8: 2−メチル−5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]チアゾール
段階2: 1−(2−メチルベンゾ[d]チアゾール−5−イル)エタン−1−オール
段階3: 5−(1−クロロエチル)−2−メチルベンゾ[d]チアゾール
段階4: 2−メチル−5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]チアゾール
中間体9: 2−クロロ−5−(メチルスルフィニル)ピリミジン
段階2: 2−クロロ−5−(メチルスルフィニル)ピリミジン
中間体10: N−((2−クロロピリミジン−5−イル)(メチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド
中間体11及び中間体12: N−((2−クロロピリミジン−5−イル)−(R)−(メチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド、及び、N−((2−クロロピリミジン−5−イル)−(S)−(メチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド
2番目の溶出ピーク(250.0LのIPA)を40℃で濃縮した。収率:36%(180.0g、白色の固体)。1H NMR (400 MHz, DMSO-d6): δ 9.04 (s, 2H), 2.98 (s, 3H).LCMS: (方法 A) 177.0 (M+H), Rt. 0.8 分, 99.8% (Max). HPLC: (方法 A) Rt. 1.02 分, 98.8% (Max). キラル SFC: (方法 E) Rt 4.6 分, 99.7%.
段階2: N−((2−クロロピリミジン−5−イル)−(S)−(メチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド、及び、N−((2−クロロピリミジン−5−イル)−(R)−(メチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド
段階1で単離された最初に溶出した化合物(0.5g、2.8mmol)をDCM(5mL)に溶解させた溶液を撹拌しながら、それに、トリフルオロアセトアミド(0.64g、5.66mmol)、MgO(0.45g、11.3mmol)、Rh2(OAc)4(0.062g、0.14mmol)及びPhI(OAc)2(1.36g、4.20mmol)を添加し、その反応混合物を室温で一晩撹拌した。当該反応が完了したことを、TLCでモニターした。次いで、その反応混合物をセライトを通して濾過し、DCMで洗浄した。その有機層を減圧下で濃縮し、得られた粗製物質をフラッシュクロマトグラフィー(Biotage Isolera、溶離液:石油エーテル(pet ether)中25−28%EtOAc)で精製して、中間体11が得られた。収率:86%(0.69g、白色の固体)。1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 2H), 3.98 (s, 3H). LCMS: (方法 A) 191.9 (M-COCF3+H), Rt. 3.8 分, 73.8%.
段階1で単離された2番目に溶出した化合物(2.0g、0.01mmol)をDCM(20mL、10V)に溶解させた溶液を撹拌しながら、それに、トリフルオロアセトアミド(2.56g、0.226mol)、MgO(1.83g、0.05mol)、Rh2(OAC)4(250mg、0.56mol)及びPhI(OAC)2(5.49g、0.016mol)を添加し、室温で一晩撹拌した。当該反応が完了したことをTLCでモニターし、次いで、その反応混合物をセライトを通して濾過した。その濾液を減圧下で濃縮し、得られた粗製物質をフラッシュクロマトグラフィー(Biotage Isolera、溶離液:石油エーテル(pet ether)中15−25%EtOAc)で精製して、中間体12が得られた。収率:62%(2.0g、白色の固体)。1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 2H), 4.04 (s, 3H). LCMS: (方法 A) 288.0 (M+H), Rt. 1.9 分, 92.8% (Max). HPLC: (方法 A) Rt. 3.8 分, 96.1% (Max).
中間体13: N−((2−クロロピリミジン−5−イル)(エチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド
段階2: 2−クロロ−5−(エチルスルフィニル)ピリミジン
段階3: N−((2−クロロピリミジン−5−イル)(エチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド
段階2: 2−クロロ−5−(プロピルスルフィニル)ピリミジン
段階3: N−((2−クロロピリミジン−5−イル)(オキソ)(プロピル)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド
中間体15: N−((6−クロロピリジン−3−イル)(メチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド
段階2: 2−クロロ−5−(メチルスルフィニル)ピリジン
段階3: N−((6−クロロピリジン−3−イル)(メチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド
中間体16: N−((6−クロロピリジン−3−イル)(エチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド
段階2: 2−クロロ−5−(エチルスルフィニル)ピリジン
段階3: N−((6−クロロピリジン−3−イル)(エチル)(オキソ)−λ 6 −スルファニリデン)−2,2,2−トリフルオロアセトアミド
中間体17: 2−(ピペラジン−1−イル)ピリミジン−5−カルボン酸メチル
段階2: 2−(4−(λ 2 −クロラニル)−4λ 4 −ピペラジン−1−イル)ピリミジン−5−カルボン酸メチル
中間体18: 1−(4−(メチルチオ)フェニル)ピペラジン塩酸塩
段階2: 1−(4−(メチルチオ)フェニル)ピペラジン塩酸塩
中間体19: 7−(1−(ピペラジン−1−イル)エチル)キノリン
段階2: キノリン−7−カルバルデヒド
段階3: 1−(キノリン−7−イル)エタン−1−オール
段階4: 7−(1−クロロエチル)キノリン
段階5: 4−(1−(キノリン−7−イル)エチル)ピペラジン−1−カルボン酸tert−ブチル
段階6: 7−(1−(ピペラジン−1−イル)エチル)キノリン
中間体20: 6−イミノ−2−(ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−6l4−チオピラノ[4,3−d]ピリミジン 6−オキシド塩酸塩
段階2: (E)−3−((ジメチルアミノ)メチレン)テトラヒドロ−4H−チオピラン−4−オン
段階3: 4−(7,8−ジヒドロ−5H−チオピラノ[4,3−d]ピリミジン−2−イル)ピペラジン−1−カルボン酸tert−ブチル
段階4: 4−(6−オキシド−7,8−ジヒドロ−5H−チオピラノ[4,3−d]ピリミジン−2−イル)ピペラジン−1−カルボン酸tert−ブチル
段階5: 4−(6−イミノ−6−オキシド−5,6,7,8−テトラヒドロ−6l4−チオピラノ[4,3−d]ピリミジン−2−イル)ピペラジン−1−カルボン酸tert−ブチル
段階6: 6−イミノ−2−(ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−6l4−チオピラノ[4,3−d]ピリミジン 6−オキシド塩酸塩
中間体21: 6−(1−(ピペラジン−1−イル)エチル)キノキサリン
段階2: 1−(キノキサリン−6−イル)エタン−1−オール
段階3: 6−(1−クロロエチル)キノキサリン
段階4: 4−(1−(キノキサリン−6−イル)エチル)ピペラジン−1−カルボン酸tert−ブチル
段階5: 6−(1−(ピペラジン−1−イル)エチル)キノキサリン塩酸塩
中間体22: 2−メチル−5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]オキサゾール塩酸塩
段階2: 1−(2−メチルベンゾ[d]オキサゾール−5−イル)エタン−1−オン
段階3: 1−(2−メチルベンゾ[d]オキサゾール−5−イル)エタン−1−オール
段階4: 5−(1−クロロエチル)−2−メチルベンゾ[d]オキサゾール
段階5: 4−(1−(2−メチルベンゾ[d]オキサゾール−5−イル)エチル)ピペラジン−1−カルボン酸tert−ブチル
段階6: 2−メチル−5−(1−(ピペラジン−1−イル)エチル)ベンゾ[d]オキサゾール塩酸塩
中間体23: 1−(1−((R)−2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン二塩酸塩
段階2: (R)−((2−(2,5−ジブロモフェノキシ)プロポキシ)メタントリイル)トリベンゼン
段階3: (R)−2−(2,5−ジブロモフェノキシ)プロパン−1−オール
段階4: (R)−1,4−ジブロモ−2−((1−ブロモプロパン−2−イル)オキシ)ベンゼン
段階5: (R)−2−メチル−2,3−ジヒドロベンゾフラン−6−カルバルデヒド
段階6: 1−((R)−2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エタン−1−オール
段階7: (2R)−6−(1−クロロエチル)−2−メチル−2,3−ジヒドロベンゾフラン
段階8: 4−(1−((R)−2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−カルボン酸tert−ブチル
段階9: 1−(1−((R)−2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン二塩酸塩
実施例1: (2−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
段階2: (2−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例2: イミノ(メチル)(2−(4−(1−(2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
実施例3: (2−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(エチル)(イミノ)−λ 6 −スルファノン
実施例4: (2−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(プロピル)−λ 6 −スルファノン
実施例5: (2−(4−(1−(2,2−ジメチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例6: (6−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(エチル)(イミノ)−λ 6 −スルファノン
実施例7: (6−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例8: (2−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン
実施例9: ((2−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)イミノ)ジメチル−λ 6 −スルファノン
段階2: ((2−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)イミノ)ジメチル−λ 6 −スルファノン:
実施例10: 2−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)−N−(ジメチル(オキソ)−λ 6 −スルファニリデン)ピリミジン−5−カルボキサミド
段階2: 2−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)−N−(ジメチル(オキソ)−λ 6 −スルファニリデン)ピリミジン−5−カルボキサミド
実施例11: (4−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)フェニル)(イミノ)(メチル)−λ 6 −スルファノン
段階2: 1−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)−4−(4−(メチルスルフィニル)フェニル)ピペラジン
実施例12、実施例13、実施例14及び実施例15: (S)−(2−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、(S)−(2−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、(R)−(2−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、及び、(R)−(2−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
2番目に溶出したフラクション(実施例13)の分析;収率:17%(22mg、白色の固体)。1H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 2.4 Hz, 2H), 7.15 (d, J = 7.2 Hz, 1H), 6.75 (t, J = 7.6 Hz, 2H), 4.51 (t, J = 8.8 Hz, 2H), 4.24 (s, 1H), 3.83-3.81 (m, 4H), 3.38 (d, J = 6.4 Hz, 1H), 3.16-3.76 (m, 5H), 2.38-2.33 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 388.3 (M+H), Rt. 2.0 分, 99.7% (Max). HPLC: (方法 A) Rt. 2.1 分, 99.1% (Max). キラル SFC: (方法 A) Rt. 4.5 分, 98.6% (Max).
3番目に溶出したフラクション(実施例14)の分析;収率:18%(26mg、白色の固体)。1H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 2.4 Hz, 2H), 7.15 (d, J = 7.2 Hz, 1H), 6.75 (t, J = 7.6 Hz, 2H), 4.51 (t, J = 8.8 Hz, 2H), 4.24 (s, 1H), 3.83-3.81 (m, 3H), 3.38 (d, J = 6.4 Hz, 1H), 3.16-3.76(m, 6H), 2.38-2.33 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 388.3 (M+H), Rt. 2.0 分, 99.7% (Max). HPLC: (方法 A) Rt. 2.1 分, 99.1% (Max). キラル SFC: (方法 A) Rt. 5.4 分, 96.6% (Max)
4番目に溶出したフラクション(実施例15)の分析;収率:18%(25mg、白色の固体)。1H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 2.4 Hz, 2H), 7.15 (d, J = 7.2 Hz, 1H), 6.75 (t, J = 7.6 Hz, 2H), 4.51 (t, J = 8.8 Hz, 2H), 4.24 (s, 1H), 3.83-3.81 (m, 3H), 3.38 (d, J = 6.4 Hz, 1H), 3.16-3.76 (m, 6H), 2.38-2.33 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H). LCMS: (方法 A) 388.3 (M+H), Rt. 2.0 分, 99.7% (Max). HPLC: (方法 A) Rt. 2.1 分, 99.1% (Max). キラル SFC: (方法 A) Rt. 7.4 分, 96.6% (Max)
実施例12の代替え的な合成:
中間体2(7.5g、32.3mmol)をDMF(75.0mL、10V)に溶解させた溶液を撹拌しながら、それに、室温で、TEA(13.5mL、96.98mmol)及び中間体10(10.2g、35.56mmol)を添加し、同温度で一晩撹拌した。当該反応が完了したことをTLCでモニターし、次いで、その反応混合物を減圧下で濃縮した。得られた粗製物質をフラッシュクロマトグラフィー(Biotage Isolera、溶離液:石油エーテル(pet ether)中40%EtOAc)で精製して、中間体N−((2−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(メチル)(オキソ)−λ6−スルファニリデン)−2,2,2−トリフルオロアセトアミド又はN−((2−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(メチル)(オキソ)−λ6−スルファニリデン)−2,2,2−トリフルオロアセトアミドが得られた。収率:60%(9.0g、オフホワイト色の固体)。
実施例16: (2−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(2−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例17: (S)−(2−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)((2−メトキシエチル)イミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)((2−メトキシエチル)イミノ)(メチル)−λ 6 −スルファノン、又は、(S)−(2−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)((2−メトキシエチル)イミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)((2−メトキシエチル)イミノ)(メチル)−λ 6 −スルファノン
実施例18: (S)−(2−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(エチルイミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(エチルイミノ)(メチル)−λ 6 −スルファノン、又は、(S)−(2−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(エチルイミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(エチルイミノ)(メチル)−λ 6 −スルファノン
実施例19: (S)−(2−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イソプロピルイミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イソプロピルイミノ)(メチル)−λ 6 −スルファノン、又は、(S)−(2−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イソプロピルイミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イソプロピルイミノ)(メチル)−λ 6 −スルファノン
実施例20: (6−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン、又は、(6−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン
中間体2(500mg、2.15mmol)をACN(10mL)に溶解させた溶液を撹拌しながら、それに、TEA(0.6mL、4.29mmol)及び中間体15(611mg、2.01mmol)を添加し、その反応混合物を45℃で一晩撹拌した。当該反応が完了したことをTLCでモニターし、次いで、その反応混合物を減圧下で蒸発させた。得られた混合物に、水(10mL)を添加し,その水層をEtOAc(2×25mL)で抽出した。その有機層を合して無水Na2SO4で脱水し、そして、減圧下で濃縮して、標題化合物が得られた。収率:53%(550mg、オフホワイト色の固体)。1H NMR (400 MHz, DMSO-d6): δ 8.48 (d, J = 3.2 Hz, 1H), 7.93-7.89 (m, 1H), 7.15 (d, J = 10.0 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 6.77-6.72 (m, 2H), 4.50 (t, J = 8.8 Hz, 2H), 3.62-3.59 (m, 4H), 3.18-3.11 (m, 2H), 3.45-3.37 (m, 1H), 2.50-2.28 (m, 4H), 1.30 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 482.9 (M+H), Rt. 2.4 分, 99.7% (Max).
段階2: (6−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(6−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(イミノ)(メチル)−λ 6 −スルファノン
段階1で得られた生成物(550mg、1.14mmol)をEtOH(10mL)に溶解させた溶液を撹拌しながら、それに、K2CO3(354mg、2.28mmol)を添加し、室温で2時間撹拌した。当該反応が完了したことをTLCでモニターし、次いで、その反応混合物を減圧下で蒸発させた。得られた混合物に、水(10mL)を添加し、その水層をEtOAc(2×10mL)で抽出した。その有機層を合して水(10mL)で洗浄し、無水Na2SO4で脱水し、そして、減圧下で濃縮して、標題化合物が得られた。収率:90%(400mg、オフホワイト色の固体)。1H NMR (400 MHz, DMSO-d6): δ 8.49 (d, J = 2.4 Hz, 1H), 7.88-7.85 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 4.04 (s, 1H), 3.6-3.51 (m, 4H), 3.14 (t, J = 8.4 Hz, 2H), 3.02 (s, 3H), 2.48-2.45 (m, 2H), 2.39-2.33 (m, 2H), 1.30 (d, J = 8.4 Hz, 3H). LCMS: (方法 A) 387.2 (M+H), Rt. 1.7 分, 99.7% (Max).
段階3: (6−(4−((S)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン、又は、(6−(4−((R)−1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン
段階2で得られた生成物(200mg、0.52mmol)をDMF(5mL)に溶解させた溶液を撹拌しながら、それに、0℃で、NaH(60%)(24mg、1.04mmol)を添加し、その混合物を10分間撹拌した。次いで、MeI(0.004mL、0.78mmol)を添加し、その混合物を室温で一晩撹拌した。当該反応が完了したことをTLCでモニターし、次いで、その反応混合物を減圧下で蒸発させた。得られた混合物に、水(5mL)を添加し、その水層をEtOAc(2×25mL)で抽出した。その有機層を合してNa2SO4で脱水し、減圧下で濃縮した。得られた粗製物質を分取HPLC(方法B)で精製して、標題化合物が得られた。収率:20%(40mg、オフホワイト色の固体)。1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 1.6 Hz, 1H), 7.76 (t, J = 2.4 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 6.77 (d, J = 6.8 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.62 (s, 4H), 3.37 (s, 1H), 3.14 (t, J = 8.4 Hz, 2H), 3.05 (s, 3H), 2.39 (s, 5H), 2.34 (s, 2H), 1.30 (s, 3H). LCMS: (方法 A) 401.2 (M+H), Rt. 2.2 分, 98.9% (Max). HPLC: (方法 A) Rt. 2.2 分, 99.1% (Max).
実施例21: (2−(4−(1−(クロマン−7−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例22: (2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例23: (2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(エチル)(イミノ)−λ 6 −スルファノン
実施例24: (2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(プロピル)−λ 6 −スルファノン
実施例25: (2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン
実施例26: (6−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例27: (2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(エチルイミノ)(メチル)−λ 6 −スルファノン
実施例28: (2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イソプロピルイミノ)(メチル)−λ 6 −スルファノン
実施例29: (2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)((2−メトキシエチル)イミノ)(メチル)−λ 6 −スルファノン
実施例30: (6−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン
実施例31: ((2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)イミノ)ジメチル−λ 6 −スルファノン
段階2: ((2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)イミノ)ジメチル−λ 6 −スルファノン
実施例32: 2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)−N−(ジメチル(オキソ)−λ 6 −スルファニリデン)ピリミジン−5−カルボキサミド
段階2: 2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−カルボン酸
段階3: 2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)−N−(ジメチル(オキソ)−λ 6 −スルファニリデン)ピリミジン−5−カルボキサミド
実施例33: (4−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)フェニル)(イミノ)(メチル)−λ 6 −スルファノン
段階2: 5−(1−(4−(4−(メチルスルフィニル)フェニル)ピペラジン−1−イル)エチル)ベンゾ[d]チアゾール
段階3: (4−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)フェニル)(イミノ)(メチル)−λ 6 −スルファノン
実施例34: (2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例35: (S)−(2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(S)−(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
MeOH(930.0mL、10V)とDCM(186.0mL、2V)の中のこの中間体(93.0g、0.18mol)に、室温で、K2CO3(25.7g、0.18mol)を添加し、その混合物を同温度で1時間撹拌した。当該反応が完了したことをTLCで確認した。その反応混合物を減圧下で濃縮した。得られた粗製生成物をDCM中1−4%MeOHを使用するカラムクロマトグラフィー(シリカゲル 60−120メッシュ)で精製して、標題化合物が得られた。収率:83%(60g、白色の固体)。1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.64 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.49 (dd, J = 8.2, 1.2 Hz, 1H), 4.23 (s, 1H), 3.85-3.82 (m, 4H), 3.65 (q, J = 6.4 Hz, 1H), 3.06 (s, 3H), 2.54-2.41 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 403.1 (M+H), Rt. 1.65 分, 99.89% (Max). HPLC: (方法 A) Rt. 1.90 分, 99.70% (Max), 99.58% (220 nm). キラル SFC: (方法 B) Rt 9.1 分, 97.68% (Max).
実施例36: (S)−(2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(S)−(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例37: (S)−(2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン、又は、(R)−(2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン、又は、(S)−(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン、又は、(R)−(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(メチル)(メチルイミノ)−λ 6 −スルファノン
実施例38: (R)−(2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(S)−(2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
中間体6(0.47g、1.46mmol)をACN(2.0mL,)に溶解させた溶液を撹拌しながら、それに、TEA(0.88mL、5.8mmol)及び中間体12(464mg、1.6mmol)を添加し、その反応混合物を室温で30分間撹拌した。当該反応が完了したことをTLCでモニターし、次いで、その反応混合物を減圧下で濃縮した。得られた粗製物質をフラッシュクロマトグラフィー(Biotage Isolera、石油エーテル(pet ether)中60−80%EtOAc)で精製して、標題化合物が得られた。収率:44%(320mg、白色の固体)。1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.75 (s, 2H), 8.13 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.89 (t, J = 4.8 Hz, 4H), 3.76 (s, 3H), 3.70 (d, J = 6.8 Hz, 1H), 2.58-2.43 (m, 4H), 1.41 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 268.0 (M+H), Rt. 1.9 分, 92.8% (Max). HPLC: (方法 A) Rt. 3.8 分, 96.1% (Max).
段階2: (R)−(2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(S)−(2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
段階1の生成物(310mg、0.62mmol)をメタノール(2mL)とDCM(1mL)に溶解させた溶液を撹拌しながら、それに、K2CO3(200mg、1.0mmol)を添加し、1時間撹拌した。当該反応が完了したことをTLCでモニターし、次いで、その反応混合物を減圧下で濃縮した。得られた粗製物質をフラッシュクロマトグラフィー(Biotage Isolera、勾配:DCM中3−4%メタノール)で精製して、標題化合物が得られた。収率:84%(210g、白色の固体)。1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.64 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.49 (dd, J = 8.2, 1.2 Hz, 1H), 4.23 (s, 1H), 3.84 (t, J = 4.8 Hz, 4H), 3.06 (s, 3H), 2.54-2.41 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 403.1 (M+H), Rt. 1.6 分, 99.9% (Max). HPLC: (方法 A) Rt. 1.9 分, 99.7% (Max).
実施例39: (R)−(2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(S)−(2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
この中間体(310mg、0.62mol)をメタノール(2mL)とDCM(1mL)に溶解させた溶液を撹拌しながら、それに、K2CO3(200mg、1.0mol)を添加し、室温で1時間撹拌した。当該反応が完了したことをTLCでモニターし、次いで、その反応混合物を減圧下で濃縮した。得られた粗製物質をフラッシュクロマトグラフィー(Biotage Isolera、勾配:DCM中3−4%メタノール)で精製して、標題化合物が得られた。収率:84%(210g、白色の固体)。1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.64 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.49 (dd, J = 8.2, 1.2 Hz, 1H), 4.23 (s, 1H), 3.84 (t, J = 4.8 Hz, 4H), 3.06 (s, 3H), 2.54-2.41 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). LCMS: (方法 A) 403.1 (M+H), Rt. 1.6 分, 99.9% (Max). HPLC: (方法 A) Rt. 1.9 分, 99.7% (Max).
実施例40: (S)−(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(S)−(2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例41: (S)−(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((R)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(S)−(2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン、又は、(R)−(2−(4−((S)−1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(イミノ)(メチル)−λ 6 −スルファノン
実施例42: イミノ(メチル)(2−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
実施例43: エチル(イミノ)(2−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
実施例44: イミノ(2−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(プロピル)−λ 6 −スルファノン
実施例45: メチル(2−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)(メチルイミノ)−λ 6 −スルファノン
実施例46: イミノ(メチル)(6−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)−λ 6 −スルファノン
実施例47: メチル(6−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリジン−3−イル)(メチルイミノ)−λ 6 −スルファノン
実施例48: (エチルイミノ)(メチル)(2−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
実施例49: (イソプロピルイミノ)(メチル)(2−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
実施例50: イミノ(メチル)(4−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)フェニル)−λ 6 −スルファノン
段階2: 2−メチル−5−(1−(4−(4−(メチルスルフィニル)フェニル)ピペラジン−1−イル)エチル)ベンゾ[d]チアゾール
段階3: イミノ(メチル)(4−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)フェニル)−λ 6 −スルファノン
実施例51、実施例52、実施例53及び実施例54: (S)−イミノ(メチル)(2−(4−((S)−1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン、及び、(R)−イミノ(メチル)(2−(4−((S)−1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン、及び、(S)−イミノ(メチル)(2−(4−((R)−1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン、及び、(R)−イミノ(メチル)(2−(4−((R)−1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
2番目に溶出したフラクション(実施例52)の分析;収率:11%(46mg、オフホワイト色の固体)。1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.23 (s, 1H), 3.85-3.84 (m, 4H), 3.66-3.64 (m, 1H), 3.07 (s, 3H), 2.79 (s, 3H), 2.50-2.43 (m, 4H), 1.39 (d, J = 6.80 Hz, 3H). LCMS: (方法 A) 416.8 (M+H), Rt. 2.1 分, 99.2% (Max). HPLC: (方法 A) Rt. 2.0 分, 99.7% (Max). キラル SFC: (方法 C) Rt. 4.5 分, 97.6% (Max).
3番目に溶出したフラクション(実施例53)の分析;収率:15%(65mg、オフホワイト色の固体)。1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.23 (s, 1H), 3.85-3.84 (m, 4H), 3.66-3.64 (m, 1H), 3.07 (s, 3H), 2.79 (s, 3H), 2.50-2.43 (m, 4H), 1.39 (d, J = 6.80 Hz, 3H). LCMS: (方法 A) 416.8 (M+H), Rt. 2.1 分, 99.4% (Max). HPLC: (方法 A) Rt. 2.0 分, 99.4% (Max). キラル SFC: (方法 C) Rt. 4.9 分, 97.4% (Max).
4番目に溶出したフラクション(実施例54)の分析;収率:17%(75mg、オフホワイト色の固体)。1H NMR (400 MHz, DMSO-d6): δ 8.65 (s, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.23 (s, 1H), 3.85-3.84 (m, 4H), 3.66-3.64 (m, 1H), 3.07 (s, 3H), 2.79 (s, 3H), 2.50-2.43 (m, 4H), 1.39 (d, J = 6.80 Hz, 3H). LCMS: (方法 A) 416.8 (M+H), Rt. 2.1 分, 98.2% (Max). HPLC: (方法 A) Rt. 2.0 分, 97.9% (Max). キラル SFC: (方法 C) Rt. 8.5 分, 98.9% (Max).
実施例55: イミノ(メチル)(2−(4−(1−(2−メチルベンゾ[d]オキサゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
段階2: イミノ(メチル)(2−(4−(1−(2−メチルベンゾ[d]オキサゾール−5−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
実施例56: イミノ(メチル)(2−(4−(1−(キノリン−7−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
段階2: イミノ(メチル)(2−(4−(1−(キノリン−7−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
実施例57: イミノ(メチル)(2−(4−(1−(キノキサリン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
段階2: イミノ(メチル)(2−(4−(1−(キノキサリン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
実施例58: 6−イミノ−2−(4−(1−(2−メチルベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−6λ 4 −チオピラノ[4,3−d]ピリミジン 6−オキシド
実施例59: 2−(4−(1−(ベンゾ[d]チアゾール−5−イル)エチル)ピペラジン−1−イル)−6−イミノ−5,6,7,8−テトラヒドロ−6λ 4 −チオピラノ[4,3−d]ピリミジン 6−オキシド
実施例60: 4−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)−6−イミノ−6,7−ジヒドロ−5H−6λ 4 −チエノ[3,4−d]ピリミジン 6−オキシド
段階2: 5,7−ジヒドロチエノ[3,4−d]ピリミジン−2,4(1H,3H)−ジオン
段階3: 2,4−ジクロロ−5,7−ジヒドロチエノ[3,4−d]ピリミジン
段階4: 2,4−ジクロロ−5,7−ジヒドロチエノ[3,4−d]ピリミジン 6−オキシド
段階5: N−(2,4−ジクロロ−6−オキシド−5,7−ジヒドロ−6λ 4 −チエノ[3,4−d]ピリミジン−6−イリデン)−2,2,2−トリフルオロアセトアミド
段階6: 2−クロロ−4−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)シクロヘキシル)−6−イミノ−6,7−ジヒドロ−5H−6λ 4 −チエノ[3,4−d]ピリミジン 6−オキシド
段階7: 4−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)シクロヘキシル)−6−イミノ−6,7−ジヒドロ−5H−6l4−チエノ[3,4−d]ピリミジン 6−オキシド
実施例61: 2−(4−(1−(2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)−6−イミノ−5,6,7,8−テトラヒドロ−6λ 4 −チオピラノ[4,3−d]ピリミジン 6−オキシド
実施例62: 6−イミノ−2−(4−(1−(キノリン−7−イル)エチル)ピペラジン−1−イル)−5,6,7,8−テトラヒドロ−6−λ 4 −チオピラノ[4,3−d]ピリミジン 6−オキシド
実施例63: イミノ(メチル)(2−(4−(1−((R)−2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
段階2: イミノ(メチル)(2−(4−(1−((R)−2−メチル−2,3−ジヒドロベンゾフラン−6−イル)エチル)ピペラジン−1−イル)ピリミジン−5−イル)−λ 6 −スルファノン
実施例B01: ヒトO−GlcNAcase酵素阻害アッセイ
2%DMSO中の適切な濃度の阻害剤のマッキルベイン緩衝液(pH6.5)中溶液(用量応答曲線計算用)の5μLを、384ウェルプレート(Greiner、781900)の各ウェルに加える。次いで、20nMのHis標識hOGA及び10μMのFL−GlcNAc(フルオレセインモノ−β−D−(2−デオキシ−2−N−アセチル)グルコピラノシド;Marker Gene Technologies Inc, M1485)を、384ウェルプレートに最終体積が20μLとなるように加えた。室温で60分インキュベートした後、10μLの停止緩衝液(200mMグリシン、pH10.75)を添加することによって反応を停止させた。蛍光(λexc485nm;(λemm520nm)のレベルをPHERAstar装置で読み取った。測定された蛍光の量を、阻害剤濃度に対してプロットして、IC50を計算するためのS字用量応答曲線を生成させた。全ての個々のデータを、バックグラウンド(Thiamet 3μM=100%阻害)を減算することで補正し、0.5%DMSOを対照値(阻害無)と見なした。
被験化合物を、C57BL/6Jマウスに経口投与した。化合物を投与した後、所定の時間間隔で、典型的には2〜48時間の範囲の時間で、好ましくは4〜24時間の範囲の時間で、採血及び前脳解剖のために断頭によってマウスを殺した。右脳半球を2mL容プリセリーズ(Precellys)管の中に入れ、ドライアイスで急速冷凍し、−80℃で保存した。左半球を2mL容エッペンドルフ管の中に入れ、ドライアイスで急速冷凍し、さらなる処理まで−80℃で保存した。血液サンプルを35IUのヘパリンを含んでいるSarstedt管の中に採取し、4℃で維持した。3800×g、4℃で10分間遠心分離した後、50μLの血漿を各サンプルから1.5mL容エッペンドルフ管に移し、−80℃で保存した。
サンプルを無作為化し、そして、120μg/mL(25μL/ウェル)の可溶性脳タンパク質を、4℃で一晩、マルチアレイ96ウェル高結合プレート(L15XB−3 High bind − Meso Scale Discovery)に直接コーティングした。洗浄(PBS−T緩衝液で3回)後、そのプレートを、MSDブロッカーA溶液を用いて、撹拌しながら室温(RT)で1時間ブロックした。洗浄(PBS−T緩衝液で3回)後、そのプレートを、O−GlcNAc部分に対する0.1μg/mLのマウスモノクローナル抗体(RL2;MA1−072 − Thermo Scientific)と一緒に、撹拌しながら室温で1時間インキュベートした。ECLアッセイのために、洗浄(PBS−T緩衝液で3回)後、1μg/mLのSULFO−TAGTM標識抗マウス二次抗体(Meso Scale Discovery)を加え、そして、該プレートを室温で撹拌しながら1時間インキュベートし、光から保護した。洗浄(PBS−T緩衝液で3回)後、該プレートに150μL/ウェルの1×Read Buffer Tを加えた後、Sector Imager 6000(Meso Scale Discovery)で読み取った。
(A)注射用バイアル: 100gの本発明による活性成分及び5gのリン酸水素二ナトリウムを3Lの2回蒸留水に溶解させた溶液を、2N塩酸を用いてpH6.5に調節し、滅菌濾過し、注射用バイアルに移し入れ、無菌条件下で凍結乾燥させ、そして、無菌条件下で密閉した。各注射用バイアルは、5mgの活性成分を含んでいた。
材料
・ CD1マウス血漿: プールされた雄、K2−EDTA(MSEPLEDTA2、Bioreclammation, USA)
・ リン酸緩衝生理食塩水(1XPBS)、pH7.4、100mM(Sigma, Cat No.P4417)
・ REDインサート(Pierce, Cat No.9006, 8 kDa MWCO)
・ サンプル分析:LC−MS/MS。
・ DMSOストック溶液の調製
参照化合物及び被験化合物の20mM DMSOストック溶液から、1mM DMSO中間ワーキング溶液を調製する。1mM 中間ワーキング溶液から、100μM DMSOワーキング溶液を調製する。
選択した血漿を、使用前に、水浴を用いて−20℃から37℃とする。参照化合物又は被験化合物のDMSOワーキング溶液(2μL;100μM)を選択した血漿(198μL)に加えることにより、試験溶液を調製する。スパイクされた血漿(200μL)を、テフロンプレートに配置されたREDインサートのサンプルコンパートメントに移す。REDインサートの緩衝液コンパートメントに、350μLの1×PBSを添加する。該テフロンプレートをシーリングマットで覆い、サーモミキサー内で、500RPMで、37℃で5時間撹拌する。インキュベーション時間が経過した後、サンプルコンパートメントからの血漿のアリコート(50μL)をブランク1×PBS(50μL)と混合させる。同様に、緩衝液コンパートメントからの緩衝液のアリコート(50μL)をブランク血漿(50μL)と混合させる。クエンチング溶液(200μL、内部標準トルブタミド(0.5μg/mL)を含んでいるアセトニトリル)を添加し、得られた溶液を、ボルテックスミキサーを使用して混合させ、遠心分離する(Eppendorf 5415, 13792 g)。上清を、質量分析計を用いて分析する。サンプル(上清画分、5μL)をLC−MS/MS機器に注入する。
このアッセイでは、被験化合物をマウス、ラット及びヒトの肝臓ミクロソームと一緒にインキュベートし、LC−MS/MSを使用して、薬物の消失率を測定する。このアッセイで使用する条件を、以下に要約する。
・ CD−1マウスの肝臓ミクロソーム、プールされた雄(Life Technologies, Cat No.MSMC−PL)(20mg/mL)
・ SD Ratの肝臓ミクロソーム、プールされた雄(Life Technologies, Cat No.RTMCL−PL)(20mg/mL)
・ ヒトの肝臓ミクロソーム、プールされた性別混合(Life Technologies, Cat No. HMMC−PL)(20mg/mL)
・ NADPH(SRL Mumbai, Cat No.99197)
・ ベラパミル(Sigma, Cat No.V4629)
・ アテノロール(Sigma, Cat No.A7655)
・ トルブタミド(Sigma Cat. No. T0891)
・ アッセイ緩衝液: 50mM リン酸カリウム緩衝液、pH7.4
・ 被験化合物及び参照化合物: DMSOストック溶液(濃度10mM)を調製し、室温で保存する。10μLの10mM DMSOストック溶液を90μLのDMSOと混合させることによって、被験化合物及び参照化合物の中間1mM溶液を調製する。内容物をボルテックスミキサーの中で激しく混合させる。
・ 被験化合物及び参照化合物のワーキング溶液の調製:
被験化合物又は参照化合物の1mM DMSO溶液10μLを90μLのアッセイ緩衝液と混合させることによって、ワーキング溶液(濃度100μM)調製する。該混合物をボルテックスミキサーの中で激しく混合させる。これによって得られる溶液は、10%のDMSOを含んでいる。代謝安定性アッセイでは、この100μMワーキング溶液10μLを最終アッセイ体積1mLに添加して、最終試験濃度1μM及びDMSO濃度0.1%とする。
代謝安定性アッセイは、50mMアッセイ緩衝液、リン酸カリウム緩衝液(pH7.4)の最終体積1mLで実施する。アッセイは2反復(n=2)で実施する。955μLのアッセイ緩衝液、25μLの肝臓ミクロソーム及び10μLの100μMの被験化合物溶液を含んでいる混合物を、37℃に維持した水浴の中で10分間プレインキュベートする。プレインキュベーション後、10μLの100mM NADPH溶液を添加して、反応を開始させる。その溶液を混合させ、水浴中で37℃でインキュベートする。該アッセイにおける種々の成分の最終濃度は、以下のとおりである:DMSO 0.1%、被験化合物1μM、肝臓ミクロソームタンパク質0.5mg/mL、及び、NADPH 1mM。
LC−MS/MSデータから、種々の時点において残っている薬物の量を決定した(%PCR)。%PCRの対数を時間に対してプロットして、勾配値を得た。その勾配値から、インビトロT1/2を求めた。インビトロ固有クリアランス(Clint)は、次の式を用いて計算した。
Claims (18)
- 式(I)
Rは、1〜6個の炭素原子を有する直鎖又は分枝鎖のアルキルであり、ここで、1〜5個の水素原子は、Hal又はOHで置き換えられていてもよく;
Wは、CH又はNであり;
Aは、以下の基:
Xは、N又はCR’’’であり;
Yは、O、S、SO又はSO2であり;
R’、R’’は、それぞれ独立して、H、Halを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキルを表し;
R’’’、R’’’’は、独立して、H、Hal、NR3R4、CHR3R4、OR3、CNを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキルを表し、ここで、1〜3のCH2基は、O、NR3、S、SO、SO2、S(O)(NR3’)、N(SO)R3’、CO、COO、OCO、CONR3、NR3CO、
R’’’、R’’’’は、独立して、以下の基:
R3、R4は、それぞれ独立して、Hを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキル基を表し;
Qは、以下の基:
Z1は、S、O、NR3であり;
Z2、Z3は、独立して、CR5又はNを表し;
Z4は、N、CH、CON、COCHであり;
Z5は、NR8、CHR5、S(O)(NR3’)、N(SO)R3’、
Z6は、CH2、CO、S(O)(NR3’)、N(SO)R3’、
Z7は、C(R3’)2、S、O、NR3’であり;
sは、0又は1を表し;
Tは、N、CH又はCR7であり;
R3’は、Hを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキル基を表し、ここで、1〜3のCH2基は、SO2、CO、Oから選択される基で置き換えられていてもよく、及び、ここで、1〜5個の水素原子は、Halで置き換えられていてもよく;
R5、R6、R7は、独立して、H、Hal、NR3R4、NO2を表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキルを表し、ここで、1〜3のCH2基は、O、NR3、S、SO、SO2、S(O)(NR3’)、N(SO)R3’、CO、COO、OCO、CONR3、NR3CO、
R5、R6、R7は、Ar、Het若しくはCycを表すか、又は、以下の基:
R8は、Hを表すか、又は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキルを表し、ここで、1〜3のCH2基は、SO、SO2、S(O)(NR3’)、N(SO)R3’、CO、COO、OCO、CONR3、NR3CO、及び、
R8は、以下の基:
Halは、F、Cl、Br又はIを表し;
Hetは、飽和、不飽和又は芳香族の環を表し、ここで、該環は、単環式若しくは二環式であるか又は縮合二環式であり、及び、該環は、3〜8員を有し且つN、O及びSから選択される1〜4個のヘテロ原子を含んでおり、ここで、該環は、R5、Hal及びOR3から選択される1〜3個の置換基で置換されていてもよく;
Arは、6員炭素環式芳香族環を表すか、又は、縮合若しくは非縮合の二環式芳香族環系を表し、ここで、該環は、R5、OR3及びHalから独立して選択される1〜3の置換基で置換されていてもよく;
Cycは、3〜8個の炭素原子を有する飽和又は不飽和の炭素環式環を表し、ここで、該環は、R5又はHal又はOHから独立して選択される1〜3の置換基で置換されていてもよく;
m及びnは、互いに独立して、0、1、2又は3を表し;
t及びqは、互いに独立して、0、1、2又は3を表し、但し、t+q≧1であり;
及び、
ここで、Z5とZ6のうちの少なくとも1は、基S(O)(NR3’)若しくはN(SO)R3’又は
又は、
ここで、R’’’、R’’’’、R5、R6、R7及びR8のうちの少なくとも1は、
又は、
ここで、R’’’、R’’’’、R5、R6、R7及びR8のうちの少なくとも1は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキル基(ここで、少なくとも1のCH2基は、基S(O)(NR3’)若しくはN(SO)R3’又は
で表される化合物、並びに、その医薬として使用可能な誘導体、溶媒和物、塩、プロドラッグ、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)、並びに、1個以上のH原子がD(重水素)で置き換えられている式(I)で表される化合物、但し、以下の化合物は除外される:
- 同一の基A、R、W、Q、n及びmを有する請求項2に記載されている化合物(Ia)及び化合物(Ib)を等量で又は非等量で含んでいる混合物。
- Rがメチルであり、及び/又は、WがNである、請求項1、2又は3の1項に記載の式(I)で表される化合物。
- R5、R6、R7は、独立して、H、SO2CH3、SO2CH2CH3、SO2CH2CH2OH、SO2CH2CH2OCH3、S(O)(NR3’)CH3、S(O)(NR3’)CH2CH3、S(O)(NR3’)CH2CH2OH、S(O)(NR3’)CH2CH2OCH3、N(SO)R3’CH3、N(SO)R3’CH2CH3、N(SO)R3’CH2CH2OH、N(SO)R3’CH2CH2OCH3、
から選択され;及び、
R3、R4、Z7及びR3’は、請求項1において与えられている意味を有する;
請求項1〜請求項6に記載の式(I)で表される化合物。 - Z5及びZ6のうちの少なくとも1は、基
又は、
R’’’、R’’’’、R5、R6、R7及びR8のうちの少なくとも1は、
又は、
R’’’、R’’’’、R5、R6、R7及びR8のうちの少なくとも1は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキル基から選択され、ここで、少なくとも1のCH2基は、基
R3’、Z7、t、qは、請求項1で定義されているとおりである;
請求項1に記載の式(I)で表される化合物、並びに、その医薬として使用可能な誘導体、溶媒和物、塩、プロドラッグ、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)、並びに、1個以上のH原子がD(重水素)で置き換えられている式(I)で表される化合物。 - 式(C)
A’は、以下の基:
T’は、N、CHであり;
R7’は、1〜12個の炭素原子を有する直鎖若しくは分枝鎖のアルキルを表し、ここで、1〜3のCH2基は、
又は、
R7’は、
及び、
R’、R3’、R3、R4、Hal、Het、Ar及びCycは、請求項1で定義されているとおりである〕
で表される化合物、並びに、その医薬として使用可能な誘導体、溶媒和物、塩、プロドラッグ、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)、並びに、1個以上のH原子がD(重水素)で置き換えられている式(I)で表される化合物。 - m及びnが、同時に1を表す、請求項1〜請求項10のいずれか1項に記載の式(I)で表される化合物。
- 薬物として使用するための、請求項1〜12のいずれか1項に記載の式(I)で表される化合物。
- 神経変性疾患、糖尿病、癌、心血管疾患及び卒中から選択される状態の治療において使用するための、請求項1〜12のいずれか1項に記載の式(I)で表される化合物、並びに、その医薬として使用可能な誘導体、溶媒和物、塩、互変異性体、エナンチオマー、ラセミ化合物及び立体異性体(全ての比率におけるこれらの混合物を包含する)。
- 前記状態が、1以上のタウオパシー及びアルツハイマー病、認知症、筋萎縮性側索硬化症(ALS)、認知障害を伴う筋萎縮性側索硬化症(ALSci)、嗜銀顆粒病、行動異常型前頭側頭型認知症(BvFTD)、ブルーイト病(Bluit disease)、慢性外傷性脳症、大脳皮質基底核変性症(CBP)、ボクサー認知症、石灰化を伴うびまん性神経原線維変化病、ダウン症候群、家族性英国型認知症、家族性デンマーク型認知症、染色体17と関連したパーキンソニズムを伴う前頭側頭認知症(FTDP−17)、前頭側頭葉変性症(FTLD)、神経節膠腫、神経節細胞腫、ゲルストマン−シュトロイスラー−シャインカー病、球状グリアタウオパシー(Globular glia tauopathy)、グアドループパーキンソニズム、ハレルフォルデンスパッツ病(脳内の鉄蓄積1型を伴う神経変性)、鉛脳症、リポフスチン沈着症、髄膜血管腫症、多系統委縮症、筋強直性ジストロフィー、ニーマン・ピック病(C型)、淡蒼球−橋脳−黒質変性(Pallido−ponto−nigral degeneration)、グアムのパーキンソン認知症症候群、ピック病(PiD)、パーキンソン病認知症、脳炎後パーキンソニズム(PEP)、原発性進行性失語症、プリオン病(クロイツフェルト−ヤコブ病(GJD)、進行性非能弁的失語症、異型クロイツフェルト・ヤコブ病(vCJD)、致死性家族性不眠症、クールー病、進行性超皮質性グリオーシス(Progressive supercortical gliosis)、進行性核上まひ(PSP)、意味認知症、スティール−リチャードソン−オルスゼフスキー症候群、亜急性硬化性全脳炎、神経原線維型老年認知症、結節硬化症、ハンチントン病及びパーキンソン病の群からから、好ましくは、1以上のタウオパシー及びアルツハイマー病の群から選択される、請求項14に記載の状態の治療において使用するための化合物。
- タウオパシーを治療する方法であって、請求項1〜12のいずれか1項において定義されている化合物を、そのような治療を必要とする哺乳動物に投与する、前記方法。
- グリコシダーゼを阻害する方法であって、グリコシダーゼを発現している系を、該グリコシダーゼが阻害されるようなインビトロ条件下で請求項1〜12のいずれか1項において定義されている化合物と接触させる、前記方法。
- 医薬組成物であって、活性成分として、薬学的に許容される補助剤及び/又は賦形剤と一緒に請求項1〜12のいずれか1項に記載の化合物を、場合により1種類以上のさらなる活性成分と組み合わせて、含んでいる、前記医薬組成物。
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US11612599B2 (en) | 2023-03-28 |
ZA201905405B (en) | 2021-08-25 |
AU2017222958A1 (en) | 2018-08-02 |
CN108884077A (zh) | 2018-11-23 |
JP2019510006A (ja) | 2019-04-11 |
JP7082446B2 (ja) | 2022-06-08 |
KR20180132629A (ko) | 2018-12-12 |
AU2017222958B2 (en) | 2019-07-18 |
EP3419971A1 (en) | 2019-01-02 |
CA3012560A1 (en) | 2017-08-31 |
MA43677A (fr) | 2018-11-28 |
WO2017144633A1 (en) | 2017-08-31 |
EA201991697A1 (ru) | 2020-03-04 |
CN110770226B (zh) | 2023-11-10 |
MX2018010192A (es) | 2019-01-31 |
CN110770226A (zh) | 2020-02-07 |
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US20210186958A1 (en) | 2021-06-24 |
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