JP5210174B2 - ヒストンデアセチラーゼ(hdac)阻害剤としてのヘテロ環置換ケトン誘導体 - Google Patents
ヒストンデアセチラーゼ(hdac)阻害剤としてのヘテロ環置換ケトン誘導体 Download PDFInfo
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- JP5210174B2 JP5210174B2 JP2008546643A JP2008546643A JP5210174B2 JP 5210174 B2 JP5210174 B2 JP 5210174B2 JP 2008546643 A JP2008546643 A JP 2008546643A JP 2008546643 A JP2008546643 A JP 2008546643A JP 5210174 B2 JP5210174 B2 JP 5210174B2
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- hydrogen
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- VLCYCQAOQCDTCN-ZCFIWIBFSA-N α-difluoromethylornithine Chemical compound NCCC[C@@](N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-ZCFIWIBFSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- A61P37/00—Drugs for immunological or allergic disorders
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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Description
bは、0、1、2、3、4、又は5であり;
qは、1、2、3、又は4であり;
Yは、C=O、(C=O)NR7、O(C=O)NR7、又は(CH2)aOであり;
aは、0、1、2、又は3であり;
Hetは、5員の不飽和ヘテロ環(これは、それぞれ独立にN、O、及びSから選ばれる1、2、3、又は4個のヘテロ原子を含むが、該ヘテロ原子のうち2個以上がO又はSであることはない)又は6員の不飽和ヘテロ環(これは、それぞれ独立にN及びOから選ばれる1、2、3、又は4個のヘテロ原子を含む)であり; これらの環は、シアノ、ハロゲン、ヒドロキシ、オキソ、ニトロ、アミノ、C1−6アルキルアミノ、ジ(C1−6アルキル)アミノ、C1−6アルキル、ハロC1−6アルキル、C1−6アルコキシ、ハロC1−6アルコキシ、C3−10シクロアルキル、C2−6アルケニル、C2−6アルキニル、及びC6−10アリールからそれぞれ独立に選ばれる1個以上の置換基で置換されていてもよく;
R1は、水素、C1−6アルキル、ハロC1−6アルキル、C6−10アリール、5員の不飽和ヘテロ環(これは、それぞれ独立にO、N、及びSから選ばれる1、2、3、又は4個のヘテロ原子を含むが、該ヘテロ原子のうち2個以上がO又はSであることはない)、6員の不飽和ヘテロ環(これは、1、2、又は3個の窒素原子を含む)、或いは8〜10員の不飽和又は部分飽和ヘテロ環(これは、それぞれ独立にO、N、及びSから選ばれるヘテロ原子を含む)であり; これらの環は、シアノ、ハロゲン、ニトロ、オキソ、ヒドロキシ、C1−6アルキル、ハロC1−6アルキル、C1−6アルコキシ、ハロC1−6アルコキシ、C1−6アルキルカルボニル、C1−6アルコキシカルボニル、カルボキシ、C6−10アリール、C6−10アリールオキシ、C6−10アリールカルボニル、及びN(Ra)2(Raはそれぞれ独立に水素、C1−6アルキル、C6−10アリール、C1−6アルキルカルボニル、及びC6−10アリールカルボニルから選ばれる)からそれぞれ独立に選ばれる1個以上の置換基で置換されていてもよく;
R2は、C1−6アルキルであり;
R3は、水素、ハロゲン、ヒドロキシ、シアノ、C1−6アルキル、ハロC1−6アルキル、C1−6アルコキシ、ハロC1−6アルコキシ、C3−10シクロアルキル、ハロC3−10シクロアルキル、C2−10アルケニル、C2−10アルキニル、ニトロ、N(Rd)2(Rdはそれぞれ独立に水素、C1−6アルキル、及びC1−6アルキルカルボニルから選ばれる)、C6−10アリール、C6−10アリールC1−6アルキル、C6−10アリールC1−6アルコキシ、4、5、又は6員の飽和又は部分飽和ヘテロ環(これは、それぞれ独立にN、O、及びSから選ばれる1、2、又は3個のヘテロ原子を含み、C1−4アルキル基で架橋されていてもよい)、5員の不飽和ヘテロ環(これは、それぞれ独立にN、O、及びSから選ばれる1、2、3、又は4個のヘテロ原子を含むが、該ヘテロ原子のうち2個以上がO又はSであることはない)、6員の不飽和ヘテロ環(これは、1、2、又は3個の窒素原子を含む)、或いは7〜13員の飽和、部分飽和、又は不飽和ヘテロ環(これは、それぞれ独立にN、O、又はSから選ばれるヘテロ原子を含む)であり; これらの環は、Rbからそれぞれ独立に選ばれる1個以上の置換基で置換されていてもよく;
R4は、水素又はC1−6アルキルであるか、或いはY−(CR5R6)b−R3と共にオキソ基を形成し;
R5及びR6は、それぞれ独立に水素又はC1−6アルキルであり;
R7は、水素又はC1−6アルキルであり;
それぞれのRbは、ハロゲン、ヒドロキシ、シアノ、C1−6アルキル、ハロC1−6アルキル、ハロC1−6アルキルカルボニル、ハロC1−6アルキルカルボニルオキシ、C1−6アルコキシ、ハロC1−6アルコキシ、カルボキシ、C1−6アルキルカルボニル、C1−6アルコキシカルボニル、ニトロ、オキソ、SO2N(Rc)2、N(Rc)2(Rcはそれぞれ独立に水素、C1−6アルキル、C1−6アルキルカルボニル、カルボキシ、及びC1−6アルコキシカルボニルから選ばれる)、C6−10アリール、C6−10アリールC1−6アルキル、5又は6員の飽和又は部分飽和ヘテロ環(これは、それぞれ独立にN、O、又はSから選ばれる1、2、又は3個のヘテロ原子を含み、C1−4アルキル基で架橋されていてもよい)、5員の不飽和ヘテロ環(これは、それぞれ独立にN、O、及びSから選ばれる1、2、3、又は4個のヘテロ原子を含むが、該ヘテロ原子のうち2個以上がO又はSであることはない)、或いは6員の不飽和ヘテロ環(これは、1、2、又は3個の窒素原子を含む)であり; これらの環は、ハロゲン、ヒドロキシ、アミノ、シアノ、C1−6アルキル、ハロC1−6アルキル、C1−6アルコキシ、及びハロC1−6アルコキシからそれぞれ独立に選ばれる1個以上の置換基で置換されていてもよい。
]で表される化合物、又はその薬学的に許容される塩若しくは互変異性体を提供する。
b、q、R1、R2、R3、R4、R5、R6、及びYは、上記式I中のそれらと同義であり;
A及びBの一方はNであり、他方はCHであり;
Reは、水素又はC1−6アルキルである。
]で表される化合物、又はその薬学的に許容される塩若しくは互変異性体も提供する。
Y1は、(C=O)又は(C=O)NR7であり;
R1、R2、R3、R5、R6、b、及びqは、上記式I中のそれらと同義であり;
A及びBの一方はNであり、他方はCHであり;
R4は、水素又はC1−6アルキルである。
]で表される化合物、又はその薬学的に許容される塩若しくは互変異性体も提供する。
2−[5−(2−ナフチル)−1H−イミダゾール−2−イル]−8−オキソデカン酸;
5−(2−ナフチル)−2−(7−オキソ−1−{[(2−フェニルエチル)アミノ]カルボニル}ノニル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
2−[1−(ヒドロキシメチル)−7−オキソノニル]−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
5−(2−ナフチル)−2−{7−オキソ−1−[(ピリジン−3−イルメトキシ)メチル]ノニル}−1H−イミダゾール−1−イウムトリフルオロアセテート;
5−(2−ナフチル)−2−(8−オキソノナノイル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
9−ヒドロキシ−9−[5−(2−ナフチル)−1H−イミダゾール−2−イル]ノナン−3−オン;
(−)−9−ヒドロキシ−9−[5−(2−ナフチル)−1H−イミダゾール−2−イル]ノナン−3−オン;
2−(1−ヒドロキシ−1−メチル−7−オキソノニル)−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
2−(1−メトキシ−7−オキソノニル)−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
5−(2−ナフチル)−2−{7−オキソ−1−[({[(1S)−1−フェニルエチル]アミノ}カルボニル)オキシ]ノニル}−1H−イミダゾール−1−イウムトリフルオロアセテート;
2−[1−(アニリノカルボニル)−7−オキソノニル]−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
2−{1−[(ベンジルアミノ)カルボニル]−7−オキソノニル}−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
1−メチル−4−{2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}ピペラジン−1−イウムビス(トリフルオロアセテート);
4−{2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}−1−フェニルピペラジン−1−イウムビス(トリフルオロアセテート);
2−(1−{[メチル(キノリン−6−イルメチル)アミノ]カルボニル}−7−オキソノニル)−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
1−[2−({2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)エチル]ピペリジニウムビス(トリフルオロアセテート);
1−ベンジル−4−({2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)ピペリジニウムビス(トリフルオロアセテート);
2−[1−({[2−(3,4−ジヒドロキノリン−1(2H)−イル)エチル]アミノ}カルボニル)−7−オキソノニル]−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
1−[1,1−ジメチル−2−({2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)エチル]ピペリジニウムビス(トリフルオロアセテート);
5−(2−ナフチル)−2−(7−オキソ−1−{[(1,3−チアゾール−2−イルメチル)アミノ]カルボニル}ノニル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
5−(2−ナフチル)−2−(7−オキソ−1−{[(ピリジン−3−イルメチル)アミノ]カルボニル}ノニル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
5−(2−ナフチル)−2−{7−オキソ−1−[(ピリジン−3−イルアミノ)カルボニル]ノニル}−1H−イミダゾール−1−イウムトリフルオロアセテート;
5−(2−ナフチル)−2−{7−オキソ−1−[(1,3−チアゾール−2−イルアミノ)カルボニル]ノニル}−1H−イミダゾール−1−イウムトリフルオロアセテート;
5−(2−ナフチル)−2−(7−オキソ−1−{[(2−ピリジン−4−イルエチル)アミノ]カルボニル}ノニル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
5−(2−ナフチル)−2−(7−オキソ−1−{[(2−ピリジン−2−イルエチル)アミノ]カルボニル}ノニル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
4−[2−({2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)エチル]モルホリン−4−イウムビス(トリフルオロアセテート);
1−[2−({2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)エチル]−1H−ピラゾール−1−イウムビス(トリフルオロアセテート);
4−[2−({2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)エチル]−1H−ピラゾール−1−イウムビス(トリフルオロアセテート);
1−メチル−3−[({2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)メチル]ピペリジニウムビス(トリフルオロアセテート);
1−メチル−4−[({2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)メチル]ピペリジニウムビス(トリフルオロアセテート);
1−メチル−2−[(メチル{2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)メチル]ピペリジニウムビス(トリフルオロアセテート);
2−[1−({[(1−メチルピロリジニウム−3−イル)メチル]アミノ}カルボニル)−7−オキソノニル]−5−(2−ナフチル)−1H−イミダゾール−1−イウムビス(トリフルオロアセテート);
2−(1−{[(2−メトキシエチル)アミノ]カルボニル}−7−オキソノニル)−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
2−[1−({[2−(ジメチルアンモニオ)エチル]アミノ}カルボニル)−7−オキソノニル]−5−(2−ナフチル)−1H−イミダゾール−1−イウムビス(トリフルオロアセテート);
2−[1−({[2−(アセチルアミノ)エチル]アミノ}カルボニル)−7−オキソノニル]−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
4−[2−({2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)エチル]−4H−1,2,4−トリアゾール−4−イウムビス(トリフルオロアセテート);
5−(2−ナフチル)−2−(7−オキソ−1−{[(2−ピロリジニウム−1−イルエチル)アミノ]カルボニル}ノニル)−1H−イミダゾール−1−イウムビス(トリフルオロアセテート);
1−メチル−4−({2−[5−(2−ナフチル)−1H−イミダゾール−1−イウム−2−イル]−8−オキソデカノイル}アミノ)ピペリジニウムビス(トリフルオロアセテート);
5−(2−ナフチル)−2−[7−オキソ−1−(1,3−チアゾリジン−3−イルカルボニル)ノニル]−1H−イミダゾール−1−イウムトリフルオロアセテート;
5−(2−ナフチル)−2−(7−オキソ−1−{[(2−ピリジン−3−イルエチル)アミノ]カルボニル}ノニル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
2−[1−(アミノカルボニル)−7−オキソノニル]−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
2−{1−[(メチルアミノ)カルボニル]−7−オキソノニル}−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
1−(2−フェニル−1,3−チアゾール−5−イル)オクタン−1,7−ジオン;
9−ヒドロキシ−9−(5−フェニル−1H−イミダゾール−2−イル)ノナン−3−オン;
9−メトキシ−9−[2−(2−ナフチル)−1H−イミダゾール−5−イル]ノナン−3−オン;
9−ヒドロキシ−9−[2−(2−ナフチル)−1H−イミダゾール−5−イル]ノナン−3−オン;
2−{1−[(アニリノカルボニル)オキシ]−7−オキソノニル}−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;
2−(1−{[(ベンジルアミノ)カルボニル]オキシ}−7−オキソノニル)−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート;並びに
これらの薬学的に許容される遊離塩基、塩、及び立体異性体が挙げられる。
心臓:肉腫(血管肉腫、線維肉腫、横紋筋肉腫、脂肪肉腫)、粘液腫、横紋筋腫、線維腫、脂肪腫、奇形腫;
肺:気管支癌(扁平上皮細胞癌、未分化小細胞癌、未分化大細胞癌、腺癌)、胞巣状癌(細気管支癌)、気管支腺腫、肉腫、リンパ腫、軟骨性過誤腫、中皮腫;
消化管:食道(扁平上皮細胞癌、腺癌、平滑筋肉腫、リンパ腫)、胃(癌腫、リンパ腫、平滑筋肉腫)、膵臓(導管腺癌、膵島細胞腺腫、グルカゴン産生腫瘍、ガストリン産生腫瘍、カルチノイド腫瘍、ビポーマ)、小腸(腺癌、リンパ腫、カルチノイド腫瘍、カポジ肉腫、平滑筋腫、血管腫、脂肪腫、神経繊維腫、線維腫)、大腸(腺癌、管状腺腫、絨毛腺腫、過誤腫、平滑筋腫);
泌尿生殖器:腎臓(腺癌、ウィルム腫瘍(腎芽腫)、リンパ腫、白血病)、膀胱及び尿道(扁平上皮細胞癌、移行細胞癌、腺癌)、前立腺(腺癌、肉腫)、精巣(精上皮腫、奇形腫、胎生期癌、奇形癌、絨毛癌、肉腫、間質細胞癌、線維腫、線維腺腫、腺腫瘍、脂肪腫);
肝臓:肝癌(肝細胞癌)、胆管癌、肝芽腫、血管肉腫、肝細胞腺腫、血管腫;
骨:骨肉腫、線維肉腫、悪性線維性組織球腫、軟骨肉腫、ユーイング肉腫、悪性リンパ腫(細網細胞肉腫)、多発骨髄腫、悪性巨細胞腫、脊索腫、骨軟骨腫、良性軟骨腫、軟骨芽細胞腫、軟骨粘液線維腫、類骨腫、巨大細胞腫瘍;
神経系:頭蓋骨(骨腫、血管腫、肉芽腫、黄色腫、変形性骨炎)、髄膜(髄膜腫、髄膜肉腫、神経膠腫症)、脳(星状細胞腫、髄芽腫、神経膠腫、上衣細胞腫、胚細胞腫(松果体腫)、多形性膠芽腫、乏突起膠腫、神経鞘腫、網膜芽腫、先天性腫瘍)、脊髄神経繊維腫、髄膜腫、神経膠腫、肉腫);
婦人科癌:子宮(子宮内膜癌)、頸部(頸癌、前腫瘍子宮頸部形成異常)、卵巣(卵巣癌(漿液性嚢胞腺癌、ムチン性嚢胞腺癌、未分類癌)、顆粒膜−莢膜細胞腫瘍、セルトリ・ライディック細胞腫瘍、未分化胚細胞腫、悪性奇形腫)、外陰(扁平上皮細胞癌、上皮内癌、腺癌、線維肉腫、黒色腫)、膣(明細胞癌、扁平上皮細胞癌、ブドウ状肉腫(胎児性横紋筋肉腫)、卵管(癌);
血液:血液((急性及び慢性)骨髄性白血病、急性リンパ芽球性白血病、慢性リンパ性白血病、骨髄増殖性疾患、多発骨髄腫、骨髄異形成症候群)、ホジキン病、非ホジキンリンパ腫(悪性リンパ腫);
皮膚:悪性黒色腫、基底細胞癌、扁平上皮細胞癌、カポジ肉腫、異形成母斑症、脂肪腫、血管腫、皮膚線維腫、ケロイド、乾癬;及び
副腎:神経芽細胞腫
が挙げられるが、これらに限定されない。ここで、用語「癌性細胞」は上記のいずれかの状態にある細胞を含む。
BSA(ウシ血清アルブミン);n−BuLi(n−ブチルリチウム);DCM(ジクロロメタン);DEA(ジエチルアミン);DMEM(ダルベッコ改変イーグル培地);DMF(ジメチルホルムアミド);DMSO(ジメチルスルホキシド);EDC.HCl(1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩);EDTA(エチレンジアミン四酢酸);em(エミッション);EtOAc(酢酸エチル);EtOH(エタノール);ex(励起(exitation));HOBt(1−ヒドロキシベンゾトリアゾール);HPLC(高速液体クロマトグラフィー);KCl(塩化カリウム);MeCN(アセトニトリル);MS(質量分析);NMR(核磁気共鳴);PBS(リン酸緩衝生理食塩水);RP(逆相);RT(室温);THF(テトラヒドロフラン);TFA(トリフルオロ酢酸);SEM−Cl([2−(クロロメトキシ)エチル](トリメチル)シラン);TBAF(テトラブチルアンモニウムフルオライド);TBTU(2−(1H−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);TFAA(無水トリフルオロ酢酸);Tris−HCl(トリスヒドロキシメチルアミノエタン);TSA(トリコスタチンA);TsCl(パラトルエンスルホン酸クロライド)。
Hetがイミダゾールである式Iの化合物を調製する方法は、スキーム1に示される。水素化ナトリウム等の塩基の存在下、マロン酸tert−ブチルメチルエステルを、適当なハロゲン化アルキルでアルキル化して、ホモロゲートしたマロン酸エステル誘導体を得る。このメチルエステルを通常の条件下で水酸化リチウムを用いて加水分解してモノエステルを得て、該モノエステルは、Cs2CO3等の塩基の存在下、α−ハロケトンでアルキル化できる。トルエン等の高沸点溶媒中で、過剰の酢酸アンモニウムの存在下でこれを加熱し、イミダゾール化合物が生成する。これをトリフルオロ酢酸等の酸で処理することにより、カルボン酸を遊離させ、カルボニル部位のケタール保護基などの付加の保護基を除去する。例えば、EDCIやHOBtを用いて通常の手順により、このカルボン酸をアミンとカップリングさせ、アミドを得る。
アッセイ条件:
HDAC1アッセイにより、ヒストンデアセチラーゼ(HDAC)活性を定量化する。96ウェルのマイクロタイタープレート中、精製したHDAC1の濃度を固定して化合物の連続希釈物を前培養し、その後脱アセチル化の際に蛍光発光するアセチル化リジン含有基質/展開剤を添加して、アッセイを行う。デアセチラーゼ反応を37℃で60分間行い、展開剤溶液を加えて反応を停止し、プレートリーダーで蛍光(ex360nM、em460nM)を測定する。
HDAC蛍光活性アッセイの試薬はバイオモル・リサーチ・ラボラトリーズ社(BioMol Research Laboratories、ペンシルバニア州プリマスミーティング)から購入し、特にFluor−de−Lys(商標)基質/展開剤系であることを特徴とする。この試薬は、50mMのストック溶液(KI−104)として独自開発の蛍光基質を含み、また展開剤濃縮物(KI−105)を含む。Fluor−de−Lys基質のリジン残基の脱アセチル化は、専売の展開剤を加えた後に蛍光(ex360nM、em460nM)を測定することで定量する。
TSAストック:100%ジメチルスルホキシド(DMSO)中10mMのストック溶液としてTSAを用いる。
アッセイ緩衝液:25mMのトリス/HCl(pH8)、137mMのNaCl、2.7mMのKCl、1mMのMgCl2、0.1mg/mlのBSA
希釈基質液:市販の50mMのFluor−de−Lys基質(KI−104)を、使用前に、HDAC分析緩衝液で150μMに希釈する。分析中の最終濃度は30μMである。
希釈展開剤液:市販の20X展開剤濃縮物(KI−105)を、HDAC分析緩衝液中に1:167の比率で加え、希釈する。2μM[最終]TSAをこの溶液に加えると、反応が停止させやすくなる。
HDAC1作用液:新鮮なアリコートの酵素から、HDAC1酵素を、使用前にアッセイ緩衝液中に希釈する。アッセイ中の最終濃度は1〜2nMである。
化合物:試験化合物を、アッセイ緩衝液中の10×5%DMSO溶液として調製すべきである。反応中の最終DMSO濃度は0.5%である。
96ウェルマイクロプレートを用い、最終容積50μl/ウェルで、以下の条件下で反応を行う。
5μlのDMSO/化合物溶液を添加
アッセイ緩衝液中35μlHeLa HDAC1溶液を添加(或いはネガティブコントロール中の35μlアッセイ緩衝液を添加)
室温で10’インキュベート
150μM基質溶液10μlを添加し反応開始
37℃で1時間インキュベート
50μlの展開剤/4μMTSA溶液を添加して停止
室温で10分間インキュベート
Ex.360nM及びEm.460nMで蛍光を測定
一時的にpCDNA3−HDAC1−FLAGでトランスフェクションしたHeLa細胞を、DMEM、抗生物質及びグルタミンを加えた10%のウシ胎仔血清中、10cm培養皿上で80%群まで成長させる。細胞を10mlの冷PBSで洗浄し、2mlのPBS中に回収する。細胞を800×g、4℃で5分間遠心分離し、30mlのPBSで洗浄し、10mlのPBS中に懸濁させ、その数を数え、再度遠心分離し、−80℃で凍結する。
2−[5−(2−ナフチル)−1H−イミダゾール−2−イル]−8−オキソデカン酸(A4)
ステップ1:[5−(2−エチル−1,3−ジオキソラン−2−イル)ペンチル]マロン酸tert−ブチルメチルエステル(A1)
THF中のNaH(60%、1当量)の0℃の懸濁液(0.1M溶液)に、マロン酸tert−ブチルメチル(1当量)を滴下し、得られた混合物をRTで1時間撹拌し、これをTHF中の2−エチル−2−(5−ヨードペンチル)−1,3−ジオキソラン(0.9当量)の溶液(0.3M)に加えた。得られた混合物を60℃で1時間撹拌し、NH4Cl溶液を加え、有機層を分離し、Na2SO4で乾燥し、減圧濃縮して、無色のオイルを得、これを、更に精製することなく使用した。
1H NMR(400MHz,CDCl3)δ:3.81(4H,s),3.61(3H,s),3.12(1H,t,J=7.4Hz),1.80−1.67(2H,m),1.56−1.43(4H,m),1.34(9H,s),1.29−1.17(6H,m),0.79(3H,t,J=7.5Hz)。
MS(ES)C18H32O6要求値:344,実測値:367(M+Na)+。
THF/H2O(2:1)中のA1(1当量)の溶液(0.09M溶液)をLiOH(1.1当量)で処理し、その溶液をRTで3時間撹拌した。6NのHClで反応を停止し、生成物をEtOAcで抽出した。有機層をNa2SO4で乾燥し、減圧下で溶媒を除去して、白色固体を得、これは、更に精製することなく使用した。
1H NMR(400MHz,CDCl3)δ:3.86(4H,s),3.16(1H,t,J=7.3Hz),1.90−1.68(2H,m),1.63−1.46(4H,m),1.39(9H,s),1.33−1.15(6H,m),0.84(3H,t,J=7.5Hz)。
MS(ES)C17H30O6要求値:330,実測値:331(M+H)+。
EtOH中のA2(1当量)及びCs2CO3(0.5当量)の溶液(0.47M溶液)をRTで45分間撹拌し、減圧濃縮した。得られた塩の混合物のDMF溶液(0.27M溶液)に、2−ブロモ−1−(2−ナフチル)エタノン(1当量)を加え、その混合物をN2下、RTで2時間撹拌した。DMFを減圧下でトルエンと共沸し、除去した。EtOAcを加え、混合物をろ過し、残渣をEtOAcで洗浄し、合わせたろ液を減圧濃縮した。トルエン中の得られたオイルとNH4OAc(20当量)の混合液(0.1M溶液)を還流温度で2時間加熱し、過剰なNH4OAc及びH2Oをディーン・スターク・トラップで除去した。得られた混合物をRTに冷却し、EtOAcで希釈し、飽和NaHCO3水溶液及び食塩水で洗浄した。この溶液をNa2SO4で乾燥し、減圧濃縮し、得られた茶色オイルをシリカゲルクロマトグラフィー(20〜50%のEtOAc/石油エーテル)で精製して、淡褐色の泡状物として表題化合物を得た。
1H NMR(400MHz,CDCl3)δ:8.15(1H,s),7.89−7.71(4H,m),7.49−7.37(2H,m),7.35(1H,s),3.97(1H,t,J=7.2Hz),3.89(4H,s),2.06−1.87(2H,m),1.65−1.52(4H,m),1.49(9H,s),1.41−1.27(6H,m),0.87(3H,t,J=7.5Hz)。
MS(ES)C29H38N2O4要求値:478,実測値:479(M+H)+。
エステル(A3)を0℃でTFA/DCM(3:7、0.2M溶液)で処理し、冷却槽を取り除き、得られた混合物をRTで4時間撹拌した。その溶媒を減圧除去した。得られた粗酸生成物の多くは更なる精製を行うことなく使用し、一部のみRP−HPLCで精製した。
1H NMR(400MHz,DMSO)δ:8.37(1H,s),8.15(1H,s),8.12−8.03(1H,m),8.03−7.90(3H,m),7.70−7.53(2H,m),4.03(1H,t,J=7.7Hz),2.48−2.34(4H,m),2.25−2.00(2H,m),1.58−1.42(2H,m),1.39−1.17(4H,s),0.92(3H,t,J=7.3Hz)。
MS(ES)C23H26N2O3要求値:378,実測値:379(M+H)+。
5−(2−ナフチル)−2−(7−オキソ−1−{[(2−フェニルエチル)アミノ]カルボニル}ノニル)−1H−イミダゾール−1−イウムトリフルオロアセテート(B1)
EDC.HCl(1.5当量)、HOBt(1.5当量)、及び実施例1(1当量)のDMF溶液をRTで30分間撹拌し、2−フェニルエチルアミン(1.5当量)を加え、この混合物をRTで一晩撹拌した。得られた反応混合物を、分取RP−HPLC(カラム:C18、溶離液:H2O(0.1%TFA)及びMeCN(+0.1%TFA))で精製し、所望の化合物のフラクションを凍結乾燥し、表題化合物B1を白色粉末として得た。
1H NMR(400MHz,DMSO−d6)δ:14.45(1H,bs),8.55(1H,bs),8.41(1H,s),8.17(1H,s),8.13−8.05(1H,m),8.04−7.91(3H,m),7.68−7.57(2H,m),7.36−7.17(5H,m),4.03(1H,t,J=7.7Hz),3.48−3.38(2H,m),2.82(2H,t,J=8.1Hz),2.47−2.36(4H,m),2.08−1.94(2H,m),1.53−1.41(2H,m),1.30−1.05(4H,m),0.93(3H,t,J=7.2Hz)。
MS(ES)C31H35N3O2要求値:481,実測値:482(M+H)+。
2−[1−(ヒドロキシメチル)−7−オキソノニル]−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート(C2)
ステップ1:7−(2−エチル−1,3−ジオキソラン−2−イル)−2−[5−(2−ナフチル)−1H−イミダゾール−2−イル]ヘプタン−1−オール(C1)
無水THF中の実施例1のA3(1当量)の溶液(0.07M溶液)をLiAlH4(2.0当量)で処理し、得られた混合物をRTで2時間撹拌し、飽和NH4Cl水溶液を加えて反応を停止した。この混合物をEtOAcで抽出し、有機層を食塩水で洗浄し、Na2SO4で乾燥し、減圧濃縮した。この粗残渣を更に精製することなく使用した。
MS(ES)C25H32N2O3要求値:408,実測値:409(M+H)+。
アルコールC1をDCM/TFA(8:2、0.03M溶液)に溶解し、その溶液を2時間撹拌し、その溶媒を減圧除去し、粗残渣を分取RP−HPLC(カラム:C18、溶離液:H2O(0.1%TFA)及びMeCN(+0.1%TFA))で精製した。所望のフラクションを凍結乾燥し、白色粉末を得た。
1H NMR(400MHz,DMSO−d6)δ:14.41(1H,bs),8.40(1H,s),8.22(1H,s),8.15−8.06(1H,m),8.03−7.92(3H,m),7.70−7.54(2H,m),3.70(2H,d,J=5.9Hz),3.32−3.19(1H,m),2.47−2.32(4H,m),1.88−1.72(2H,m),1.56−1.40(2H,m),1.35−1.15(4H,m),0.92(3H,t,J=7.2Hz)。
MS(ES)C23H28N2O2要求値:364,実測値:365(M+H)+。
5−(2−ナフチル)−2−{7−オキソ−1−[(ピリジン−3−イルメトキシ)メチル]ノニル}−1H−イミダゾール−1−イウムトリフルオロアセテート(D3)
ステップ1:tert−ブチル 7−(2−エチル−1,3−ジオキソラン−2−イル)−2−(5−(2−ナフチル)−1−{[2−(トリメチルシリル)エトキシ]メチル}−1H−イミダゾール−2−イル)ヘプタノエート(D1)
無水THF中の実施例1のA3の0℃溶液(0.06M溶液)にNaH(60%、1.5当量)を段階的に加え、得られた混合物を1時間撹拌し、これにSEM−Cl(1.5当量)を滴下した。この溶液をRTまで温め、更に3時間撹拌した。飽和NH4Cl水溶液を加えて反応を停止し、得られた混合物をEtOAcで抽出した。有機層を食塩水で洗浄し、Na2SO4で乾燥し、減圧濃縮した。粗残渣をシリカゲルカラムクロマトグラフィー(20〜50%のEtOAc/石油エーテル)で精製して、淡褐色の泡状物としてD1を得た。
1H NMR(400MHz,CDCl3)δ:8.32(1H,s),7.91−7.75(5H,m),7.49−7.37(2H,m),5.43(1H,d,J=10.9Hz),5.26(1H,d,J=10.9Hz),3.90(4H,s),3.86(2H,t,J=7.4Hz),3.57(1H,t,J=8.1Hz),2.27−2.14(2H,m),1.67−1.57(4H,m),1.49(9H,s),1.41−1.27(6H,m),0.96(2H,t,J=7.4Hz),0.87(3H,t,J=7.5Hz),0.07(9H,s)。
MS(ES)C35H52N2O5Si要求値:608,実測値:609(M+H)+。
実施例3のステップ1と同様の手法でエステルD1を還元し、アルコールD2を得た。
MS(ES)C31H46N2O4Si要求値:538,実測値:539(M+H)+。
D2(1.0当量)の無水THF溶液に、0℃でNaH(60%、1.3当量)を段階的に加えた。得られた混合物をRTで40分間撹拌し、3−ブロモメチルピリジン(1.3当量)を加え、その混合物をRTで1時間撹拌した。溶媒を減圧留去し、残渣をTFA/DCM(1:1)に溶解し、RTで3時間撹拌した。溶媒の減圧留去の後、粗生成物を分取RP−HPLC(カラム:C18、溶離液:H2O(0.1%TFA)及びMeCN(+0.1%TFA))で精製し、所望の化合物のフラクションを凍結乾燥し、D3を白色粉末として得た。
1H NMR(400MHz,CDCl3)δ:8.20(1H,s),8.04(1H,s),7.89−7.71(4H,m),7.67−7.37(6H,m),4.70−4.50(2H,m),4.10−3.95(1H,m),3.75−3.42(2H,m),2.48−2.22(4H,m),2.00−1.80(2H,m),1.55−1.40(2H,m),1.34−1.15(4H,m),1.00(3H,t,J=7.5Hz)。
MS(ES)C29H33N3O2要求値:455,実測値:456(M+H)+。
5−(2−ナフチル)−2−(8−オキソノナノイル)−1H−イミダゾール−1−イウムトリフルオロアセテート(E4)
ステップ1:4−ブロモ−1−{[2−(トリメチルシリル)エトキシ]メチル}−1H−イミダゾール(E1)
無水THF中の5−ブロモ−1H−イミダゾール(1.0当量)の溶液(0.4M溶液)に、0℃でNaH(60%、1.2当量)を段階的に加えた。その混合物を0℃で2時間撹拌し、SEMCl(1.2当量)を加え、RTで12時間撹拌した。飽和NH4Cl水溶液を加えて反応を停止し、その混合物をEtOAcで抽出した。有機層を食塩水で洗浄し、Na2SO4で乾燥し、減圧濃縮した。粗残渣をシリカゲルカラムクロマトグラフィー(20〜50%のEtOAc/石油エーテル)で精製して、オイル状のE1を得た。
1H NMR(300MHz,CDCl3)δ:7.45(1H,s),7.00(1H,s),5.21(2H,s),3.47(2H,t,J=8.2Hz),0.89(2H,t,J=8.2Hz),0.00(9H,s)。
MS(ES)C9H17BrN2OSi要求値:276/278,実測値:277/279(M+H)+。
ベンゼン中のE1(1.0当量)の溶液(0.1M溶液)、2−ナフチルボロン酸(1.5当量)、及び飽和Na2CO3水溶液に、アルゴン下でPdCl2((PPh)3)2を加えた。その混合物を60℃で72時間撹拌し、冷却し、EtOAcで抽出した。有機層を食塩水で洗浄し、Na2SO4で乾燥し、減圧濃縮した。粗残渣をシリカゲルカラムクロマトグラフィー(20〜50%のEtOAc/石油エーテル)で精製して、E2を黄色固体として得た。
1H NMR(300MHz,CDCl3)δ:8.31(1H,s),7.88−7.70(5H,m),7.48−7.39(3H,m),5.28(2H,s),3.54(2H,t,J=8.2Hz),0.94(2H,t,J=8.2Hz),0.00(9H,s)。
MS(ES)C19H24N2OSi要求値:324,実測値:325(M+H)+。
THF中のE2(1.0当量)の−78℃の溶液(0.1M溶液)に、n−BuLi(1.3当量)のヘキサン溶液を加えた。この溶液を30分間撹拌し、THF中のN−メトキシ−N−メチル−7−(2−メチル−1,3−ジオキソラン−2−イル)ヘプタンアミド(1.5当量)溶液をゆっくり加えた。反応混合物を−78℃で1時間、RTで1時間撹拌した。次いで、水を加え、EtOAcで水相を抽出した。有機抽出物を併せてMgSO4で乾燥し、溶媒を減圧除去した。粗残渣をシリカゲルカラムクロマトグラフィー(20〜50%のEtOAc/石油エーテル)で精製して、E3を黄色固体として得た。
1H NMR(300MHz,CDCl3)δ:8.32(1H,s),7.96−7.81(4H,m),7.68(1H,s)7.53−7.42(2H,m),5.85(2H,s),3.92(4H,s),3.64(2H,t,J=8.2Hz),3.26(2H,t,J=8.2Hz),1.77(2H,m),1.69−1.36(8H,m),1.31(3H,s),0.97(2H,t,J=8.2Hz),0.19(9H,s)。
MS(ES)C30H42N2O4Si要求値:522,実測値:523(M+H)+。
ケトンE3をTFA/DCM(1:1)に溶解し、RTで4時間撹拌した。その溶媒を減圧留去した後、粗生成物を分取RP−HPLC(カラム:C18、溶離液:H2O(0.1%TFA)及びMeCN(+0.1%TFA)使用)で精製し、所望の化合物のフラクションを凍結乾燥し、E4を白色固体として得た。
1H NMR(300MHz,DMSO)δ:8.17(1H,s),7.92−7.79(3H,m),7.76−7.64(2H,m),7.55−7.45(2H,m),3.15(2H,t,J=7.4Hz),2.44(2H,t,J=7.4Hz),2.15(3H,s),1.74(2H,m),1.58(2H,m),1.37(4H,m)。
MS(ES)C22H24N2O2要求値:348,実測値:349(M+H)+。
9−ヒドロキシ−9−[5−(2−ナフチル)−1H−イミダゾール−2−イル]ノナン−3−オン(F3)
ステップ1:6−(2−エチル−1,3−ジオキソラン−2−イル)−1−(4−(2−ナフチル)−1−{[2−(トリメチルシリル)エトキシ]メチル}−1H−イミダゾール−2−イル)ヘキサン−1−オン(F1)
THF中の実施例5のE2(1.0当量)の溶液(0.1M溶液)に、−78℃でn−BuLi(1.3当量)のヘキサン溶液を加えた。この溶液を30分間撹拌し、これにTHF中の6−(2−エチル−1,3−ジオキソラン−2−イル)−N−メトキシ−N−メチルヘキサンアミド(1.5当量)溶液をゆっくりと加えた。反応混合物を−78℃で1時間、更にRTで1時間撹拌した。次いで、水を加え、水相をEtOAcで抽出した。有機抽出物を併せてMgSO4で乾燥し、溶媒を減圧除去した。粗生成物を更に精製することなく次のステップに使用した。
MS(ES)C30H42N2O4Si要求値:523,実測値:524(M+H)+。
EtOH中のケトンF1の0℃の溶液(0.04M溶液)にNaBH4(2.0当量)を加え、その合わせた混合物を1時間撹拌した。これに水をゆっくり加え、水相をEtOAcで抽出した。有機抽出物をMgSO4で乾燥し、溶媒を減圧除去した。粗生成物を精製することなく、そのまま次のステップで使用した。
MS(ES)C30H44N2O4Si要求値:525,実測値:526(M+H)+。
アルコールF2をTFA/DCM(1:1)に溶解し、RTで4時間撹拌した。飽和NaHCO3水溶液で反応を停止し、水相をEtOAcで抽出した。有機抽出物を併せてMgSO4で乾燥し、溶媒を減圧除去した。粗生成物をフラッシュクロマトグラフィー(EtOAc/石油エーテル溶離液)で精製し、生成物を白色固体として得た。
1H NMR(300MHz,DMSO)δ:8.30(1H,s),7.97−7.75(6H,m),7.58−7.41(2H,m),5.81(1H,brs),4.75(1H,m),2.37(4H,m),1.80(2H,m),1.51−1.19(6H,m),0.88(3H,t,J=7.3Hz)。
MS(ES)C22H26N2O2要求値:350,実測値:351(M+H)+。
(−)−9−ヒドロキシ−9−[5−(2−ナフチル)−1H−イミダゾール−2−イル]ノナン−3−オン(G1)
実施例6のエナンチオマー(F2)を、超臨界流体キラルカラムクロマトグラフィー(カラム:キラルセルOJ−H、流速:9.99ml/分、モディファイヤー:30%MeOH及び0.2%DEA、Tcol=35℃、Pcol=100bar)で分離した。(+)−アルコールをTFA/DCM(1:1)に溶解し、RTで4時間撹拌した。飽和NaHCO3水溶液で反応を停止し、水相をEtOAcで抽出した。合わせた有機抽出物をMgSO4で乾燥し、溶媒を減圧除去した。粗生成物をフラッシュクロマトグラフィー(EtOAc/石油エーテル溶離液を使用)で精製し、G1を白色固体として得た。
[α]D 22=−12.6(EtOAc中、c=1.0)。
MS(ES)C22H26N2O2要求値:350,実測値:351(M+H)+。
2−(1−ヒドロキシ−1−メチル−7−オキソノニル)−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート(H1)
THF中の実施例6のF1(1.0当量)の溶液(0.03M溶液)に、−78℃、アルゴン下で、メチルリチウム(1.2当量)を加えた。2時間後、水を加え、水相をEtOAcで抽出した。合わせた有機抽出物をMgSO4で乾燥し、溶媒を減圧除去した。残渣をTFA/DCM(1:1)に溶解し、4時間撹拌した。溶媒を減圧除去し、所望の物質を分取RP−HPLC(カラム:C18、溶離液:H2O(+0.1%TFA)及びMeCN(+0.1%TFA))により単離させた。所望の化合物のフラクションを凍結乾燥し、H1を白色固体として得た。
1H NMR(300MHz,CDCl3)δ:8.23(1H,s),7.86−7.29(8H,m),2.26(4H,m),2.07−1.80(2H,m),1.63(3H,s),1.45−1.06(6H,m),0.95(3H,t,J=7.5Hz)。
MS(ES)C23H29N2O2要求値:365,実測値:365(M)+。
2−(1−メトキシ−7−オキソノニル)−5−(2−ナフチル)−1H−イミダゾール−1−イウムトリフルオロアセテート(I1)
THF中の実施例6のF2(1.0当量)の溶液に、0℃で、NaH(60%、2.5当量)を加え、その5分後にMeI(2.0当量)を加え、反応混合物を12時間撹拌した。続いて、溶媒を減圧除去し、残渣をTFA/DCM(1:1)に溶解し、4時間撹拌した。飽和NaHCO3水溶液で反応を停止し、水相をEtOAcで抽出した。合わせた有機抽出物をMgSO4で乾燥し、溶媒を減圧除去した。所望の物質を分取RP−HPLC(カラム:C18、溶離液:H2O(+0.1%TFA)及びMeCN(+0.1%TFA))により単離させた。所望の化合物のフラクションを凍結乾燥し、イミダゾール化合物を白色固体として得た。
1H NMR(300MHz,CDCl3)δ:8.23(1H,s),7.89−7.73(3H,m),7.59(1H,d,J=8.8Hz),7.52−7.39(3H,m),4.68(1H,m),3.24(3H,s),2.30(4H,m),1.85(2H,m),1.42(2H,m),1.32−1.09(4H,m),0.88(3H,t,J=7.3Hz)。
MS(ES)C23H28N2O2要求値:365,実測値:366(M+H)+。
5−(2−ナフチル)−2−{7−オキソ−1−[({[(1S)−1−フェニルエチル]アミノ}カルボニル)オキシ]ノニル}−1H−イミダゾール−1−イウムトリフルオロアセテート(H1)
トルエン中の実施例6のF2(1.0当量)の溶液に、(S)−メチルベンジルイソシアネート(1.3当量)及びピリジン(0.2当量)を加え、その反応混合物を40℃で60時間撹拌した。水を加え、水相をEtOAcで抽出した。合わせた有機抽出物をMgSO4で乾燥し、溶媒を減圧除去した。粗残渣をTFA/DCM(1:1)に溶解し、RTで4時間撹拌した。溶媒を減圧除去し、所望の物質を分取RP−HPLC(カラム:C18、溶離液:H2O(+0.1%TFA)及びMeCN(+0.1%TFA))により単離させた。所望の化合物のフラクションを凍結乾燥し、イミダゾール化合物を白色固体として得た。
1H NMR(300MHz,CDCl3)δ:8.05(0.5H,s),7.97(0.5H,s),7.71(3H,m),7.53−7.03(9H,m),6.99(0.5H,d,J=7.3Hz),6.68(0.5H,d,J=7.3Hz),5.95(1H,m),4.69(1H,m),2.29(4H,m),1.93(2H,m),1.54−1.09(10H,m),0.99(1.5H,t,J=7.3Hz),0.97(1.5H,t,J=7.3Hz)。
MS(ES)C31H35N3O3要求値:498,実測値:499(M+H)+。
Claims (7)
- 式I:
qは、1、2、3、又は4であり;
Yは、C=O、(C=O)NR7、O(C=O)NR7、又は(CH2)aOであり;
aは、0、1、2、又は3であり;
Hetは、イミダゾリル、オキサゾリル、チエニル、チアゾリルまたはピラゾリルであり; これらの環は、シアノ、ハロゲン、ヒドロキシ、オキソ、ニトロ、アミノ、C1−6アルキルアミノ、ジ(C1−6アルキル)アミノ、C1−6アルキル、ハロC1−6アルキル、C1−6アルコキシ、ハロC1−6アルコキシ、C3−10シクロアルキル、C2−6アルケニル、C2−6アルキニル、及びC6−10アリールからそれぞれ独立に選ばれる1個以上の置換基で置換されていてもよく;
R1は、シアノ、ハロゲン、ニトロ、オキソ、ヒドロキシ、C1−6アルキル、ハロC1−6アルキル、C1−6アルコキシ、ハロC1−6アルコキシ、C1−6アルキルカルボニル、C1−6アルコキシカルボニル、カルボキシ、C6−10アリール、C6−10アリールオキシ、C6−10アリールカルボニル、及びN(Ra)2(Raはそれぞれ独立に水素、C1−6アルキル、C6−10アリール、C1−6アルキルカルボニル、及びC6−10アリールカルボニルから選ばれる)からそれぞれ独立に選ばれる1個以上の置換基で置換されていてもよいC 6−10 アリールであり;
R2は、C1−6アルキルであり;
R3は、水素、ハロゲン、ヒドロキシ、シアノ、C1−6アルキル、ハロC1−6アルキル、C1−6アルコキシ、ハロC1−6アルコキシ、C3−10シクロアルキル、ハロC3−10シクロアルキル、C2−10アルケニル、C2−10アルキニル、ニトロ、N(Rd)2(Rdはそれぞれ独立に水素、C1−6アルキル、及びC1−6アルキルカルボニルから選ばれる)、C6−10アリール、C6−10アリールC1−6アルキル、C6−10アリールC1−6アルコキシ、4、5、又は6員の飽和又は部分飽和ヘテロ環(これは、それぞれ独立にN、O、及びSから選ばれる1、2、又は3個のヘテロ原子を含み、C1−4アルキル基で架橋されていてもよい)、5員の不飽和ヘテロ環(これは、それぞれ独立にN、O、及びSから選ばれる1、2、3、又は4個のヘテロ原子を含むが、該ヘテロ原子のうち2個以上がO又はSであることはない)、6員の不飽和ヘテロ環(これは、1、2、又は3個の窒素原子を含む)、或いは7〜13員の飽和、部分飽和、又は不飽和ヘテロ環(これは、それぞれ独立にN、O、及びSから選ばれるヘテロ原子を含む)であり; これらの環は、Rbからそれぞれ独立に選ばれる1個以上の置換基で置換されていてもよく;
R4は、水素又はC1−6アルキルであり;
R5及びR6は、それぞれ独立に水素又はC1−6アルキルであり;
R7は、水素又はC1−6アルキルであり;
それぞれのRbは、ハロゲン、ヒドロキシ、シアノ、C1−6アルキル、ハロC1−6アルキル、ハロC1−6アルキルカルボニル、ハロC1−6アルキルカルボニルオキシ、C1−6アルコキシ、ハロC1−6アルコキシ、カルボキシ、C1−6アルキルカルボニル、C1−6アルコキシカルボニル、ニトロ、オキソ、SO2N(Rc)2、N(Rc)2(Rcはそれぞれ独立に水素、C1−6アルキル、C1−6アルキルカルボニル、カルボキシ、及びC1−6アルコキシカルボニルから選ばれる)、C6−10アリール、C6−10アリールC1−6アルキル、5又は6員の飽和又は部分飽和ヘテロ環(これは、それぞれ独立にN、O、又はSから選ばれる1、2、又は3個のヘテロ原子を含み、C1−4アルキル基で架橋されていてもよい)、5員の不飽和ヘテロ環(これは、それぞれ独立にN、O、及びSから選ばれる1、2、3、又は4個のヘテロ原子を含むが、該ヘテロ原子のうち2個以上がO又はSであることはない)、或いは6員の不飽和ヘテロ環(これは、1、2、又は3個の窒素原子を含む)であり; これらの環は、ハロゲン、ヒドロキシ、アミノ、シアノ、C1−6アルキル、ハロC1−6アルキル、C1−6アルコキシ、及びハロC1−6アルコキシからそれぞれ独立に選ばれる1個以上の置換基で置換されていてもよい。]で表される化合物、又はその薬学的に許容される塩若しくは互変異性体。 - YがC=O、(C=O)NH、(C=O)NMe、O(C=O)NH、O、又は(CH2)Oである、請求項1又は2に記載の化合物。
- R1がC6−10アリール、5員の不飽和ヘテロ環(これは、それぞれ独立にN、O、及びSから選ばれる1、2、又は3個のヘテロ原子を含むが、該ヘテロ原子のうち2個以上がO又はSであることはない)、6員の不飽和ヘテロ環(これは、1、2、又は3個の窒素原子を含む)、或いは8、9、又は10員の不飽和又は部分飽和ヘテロ環(これは、それぞれ独立にO、N、及びSから選ばれる1、2、3、又は4個のヘテロ原子を含む)から選択される、置換されてもよい環である、請求項1ないし4のいずれか1項に記載の化合物。
- R3が水素、ジメチルアミノ、フェニル、ナフチル、ピロリジニル、ピペリジニル、アゾニアビシクロ[2.2.1]ヘプタニル、アゾニアビシクロ[2.2.2]オクタニル、ピペラジニル、モルホリニル、チエニル、チアゾリル、イミダゾリル、ピラゾリル、イソオキサゾリル、チアジアゾリル、ピリジニル、インドリル、ベンゾチエニル、ベンゾチアジアゾリル、ベンゾオキサジアゾリル、ジヒドロベンゾフリル、ジヒドロチアゾロピリミジニル、イソキノリル、ジヒドロベンゾジオキシニル、ジヒドロベンゾオキサジニル、tert−ブトキシ、シクロペンチル、メチル、トリフルオロメチル、メトキシ、ジエチルアミノ、ヒドロキシ、ベンズイミダゾリル、ベンゾフラニル、トリアゾロピリミジニル、ジヒドロベンゾオキサゾリル、ジヒドロインドリル、ジヒドロキナゾリニル、ジヒドロフタラジニル、インダゾリル、キノリニル、ベンズイソオキサゾリル、ベンゾトリアゾリル、テトラヒドロベータカルボリニル、ジヒドロイソインドリル、テトラヒドロナフチリジニル、テトラゾリル、ベンジルオキシ、チオモルホリニル、アゼチジニル、テトラヒドロキノリニル、アセチルアミノ、トリアゾリル、チアゾリジニル、又はアミノであり、これらの環は、Rbからそれぞれ独立に選ばれる1個以上の置換基で置換されていてもよく、
Rbがハロゲン、シアノ、C1−6アルキル、C1−6アルコキシ、ハロC1−6アルコキシ、カルボキシ、C1−6アルコキシカルボニル、ニトロ、アミノスルホニル、(C1−6アルキルカルボニル)アミノ、モルホリニル、ピペラジニル、チアゾリル、ピラゾリル、イソオキサゾリル、ピリジニル、オキソ、ハロC1−6アルキル、フェニル、ピロリジニル、又はベンジルであり、これらの環は、C1−6アルキル及びハロC1−6アルキルからそれぞれ独立に選ばれる1個以上の置換基で置換されていてもよい、
請求項1ないし5のいずれか1項に記載の化合物。 - 治療に用いられるための請求項1ないし6のいずれか1項に記載の化合物、又はその薬学的に許容される塩若しくは互変異性体。
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