JP2014520846A - Alk5及び/又はalk4の抑制剤としての2−ピリジル置換イミダゾール類 - Google Patents
Alk5及び/又はalk4の抑制剤としての2−ピリジル置換イミダゾール類 Download PDFInfo
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- JP2014520846A JP2014520846A JP2014520137A JP2014520137A JP2014520846A JP 2014520846 A JP2014520846 A JP 2014520846A JP 2014520137 A JP2014520137 A JP 2014520137A JP 2014520137 A JP2014520137 A JP 2014520137A JP 2014520846 A JP2014520846 A JP 2014520846A
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- imidazo
- dihydro
- pyridin
- alkyl group
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- BIHVICZBGYKDAI-UHFFFAOYSA-N 2-methoxy-7-[6-(6-methylpyridin-2-yl)-3,7-dihydro-2h-imidazo[1,2-a]imidazol-5-yl]quinoxaline Chemical compound C=1C2=NC(OC)=CN=C2C=CC=1C(N1CCNC1=N1)=C1C1=CC=CC(C)=N1 BIHVICZBGYKDAI-UHFFFAOYSA-N 0.000 claims description 3
- NDPIDAARYDRSAT-UHFFFAOYSA-N 2-methyl-6-[6-(6-methylpyridin-2-yl)-3,7-dihydro-2h-imidazo[1,2-a]imidazol-5-yl]quinoline Chemical compound CC1=CC=CC(C2=C(N3CCNC3=N2)C=2C=C3C=CC(C)=NC3=CC=2)=N1 NDPIDAARYDRSAT-UHFFFAOYSA-N 0.000 claims description 3
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- NDVJMDMHMYTYBX-UHFFFAOYSA-N 5-(3,5-dimethoxyphenyl)-6-(6-methylpyridin-2-yl)-3,7-dihydro-2h-imidazo[1,2-a]imidazole Chemical compound COC1=CC(OC)=CC(C=2N3CCNC3=NC=2C=2N=C(C)C=CC=2)=C1 NDVJMDMHMYTYBX-UHFFFAOYSA-N 0.000 claims description 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
【選択図】なし
Description
R1は1つの構造部分と縮合したフェニル基、ピリジル基又はチエニル基であり、その構造部分は、前記フェニル基、ピリジル基又はチエニル基の2つの環員と共に芳香族又は非芳香族の5〜7員環を形成し、前記環はO、N及びSから独立に選択された3つ以下のヘテロ原子を任意に含有し、前記縮合されたフェニル基、ピリジル基又はチエニル基は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C1−6ハロアルキル基、ニトリル基、−(CH2)p−OR4基、−O−(CH2)q−NR4R5基、−(CH2)p−NR4R5基、−NHCO−O−(CH2)q−NR4R5基、−NHCO−(CH2)p−NR4R5基、及び−C5−15ヘテロアリール基からなる群から独立に選択された1つ以上の基により任意に置換され、前記−C5−15ヘテロアリール基は、O、N及びSから独立に選択された3つ以下のヘテロ原子を含有し、又は、R1は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C1−6ハロアルキル基、ニトリル基、−(CH2)p−OR4基、−O−(CH2)q−NR4R5基、−NH−(CH2)q−NR4R5基、−(CH2)p−NR4R5基、−(CH2)p−NHCOR4基、−(CH2)p−NHCO2R4基、−(CH2)p−NHSO2R4基、及び−C5−15ヘテロ環基からなる群から独立に選択された1つ以上の基により任意に置換されるフェニル基又はピリジル基であり、前記−C5−15ヘテロ環基はO、N及びSから独立に選択された3つ以下のヘテロ原子を含有し、−C1−6アルキル基により任意に置換可能である。
本発明のさらに別の態様によれば、哺乳類においてALK5及び/又はALK4受容体により介在される疾患の予防又は治療のために、化学式(I)で示す化合物、又はその薬剤学的に許容可能な塩、又はその溶媒和化合物の、医薬品の製造における使用を提供する。
R1は1つの構造部分と縮合したフェニル基、ピリジル基又はチエニル基であり、当該構造部分は、前記フェニル基、ピリジル基又はチエニル基の2つの環員と共に、芳香族又は非芳香族の5〜7員環を形成し、前記環はO、N及びSから独立に選択された3つ以下のヘテロ原子を任意に含有し、前記縮合されたフェニル基、ピリジル基又はチエニル基は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C1−6ハロアルキル基、ニトリル基、−(CH2)p−OR4基、−O−(CH2)q−NR4R5基、−(CH2)p−NR4R5基、−NHCO−O−(CH2)q−NR4R5基、−NHCO−(CH2)p−NR4R5基、及び、−C5−15ヘテロアリール基からなる群から独立に選択された1つ以上の基により任意に置換され、前記−C5−15ヘテロアリール基は、O、N及びSから独立に選択された3つ以下のヘテロ原子を含有し、又は、R1は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C1−6ハロアルキル基、ニトリル基、−(CH2)p−OR4基、−O−(CH2)q−NR4R5基、−NH−(CH2)q−NR4R5基、−(CH2)p−NR4R5基、−(CH2)p−NHCOR4基、−(CH2)p−NHCO2R4基、−(CH2)p−NHSO2R4基、及び−C5−15ヘテロ環基からなる群から独立に選択された1つ以上の基により任意に置換されるフェニル基又はピリジル基であり、前記−C5−15ヘテロ環基はO、N及びSから独立に選択された3つ以下のヘテロ原子を含有し、−C1−6アルキル基により任意に置換可能である。
本発明の一実施形態において、R3は、水素原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C3−7シクロアルキル基、−(CH2)p−NR4R5、−O−(CH2)q−NR4R5、−(CH2)p−CONHOH、−(CH2)p−CN、−(CH2)p−CO2R4、−(CH2)p−CONR4R5、−(CH2)p−テトラゾール、−(CH2)p−OR4、−(CH2)p−NHCOR4、−(CH2)p−NHCO2R4、又は−(CH2)p−NHSO2R4である。
1) 1−[6−(6−メチル−ピリジン−2−イル)−5−キノキサリン−6−イル−2,3−ジヒドロ−イミダゾ[1,2−a]イミダゾール−1−イル]−エタノン、
2) 6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール3−イル]−キノキサリン、
3) 6−[2−(6−メチル−ピリジン−2−イル)−5,6,7,8−テトラヒドロ−イミダゾ[1,2−a]ピリミジン−3−イル]−キノキサリン、
4) 6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール3−イル]−キノリン、
5) 6−[2−(6−メチル−ピリジン−2−イル)−5,6,7,8−テトラヒドロ−イミダゾ[1,2−a]ピリミジン−3−イル]−キノリン、
6) 2−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−チエノ[3,2−c]ピリジン、
7) 6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−ベンゾチアゾール、
8) 5−(ベンゾ[b]チオフェン−5−イル)−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
9) 6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−[1,2,4]トリアゾロ[1,5−a]ピリジン、
10) 5−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−ベンゾオキサゾール、
11) 4−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノリン、
12) 5−ベンゾ[1,3]ジオキソール−5−イル−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
13) 5−(2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−6−イル)−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
14) 7−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−2−ピラゾ−ル−1−イル−キノキサリン、
15) ジメチル−(2−{7−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノキサリン−2−イルオキシ}−エチル)−アミン、
16) 2−メトキシ−7−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノキサリン、
17) 5−(3,5−ジメトキシフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
18) N,N−ジメチル−4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)アニリン、
19) 4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)ベンゾニトリル、
20) 2−メチル−6−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)キノリン、
21) 4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)アニリン、
22) N−(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)アセトアミド、
23) N−(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)メタンスルホンアミド、
24) t−ブチル(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)カルバメート、
25) 5−(4−(4−メチルピペラジン−1−イル)フェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
26) 4−(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)モルホリン、
27) 6−(6−メチルピリジン−2−イル)−5−(m−トリル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
28) 5−(4−メトキシフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
29) 6−(6−メチルピリジン−2−イル)−5−(4−(トリフルオロメチル)フェニル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
30) 6−(6−メチルピリジン−2−イル)−5−(4−(メチルチオ)フェニル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
31) 5−(3−フルオロ−4−メトキシフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
32) 5−(4−フルオロフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
33) 1−アセチル−6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸エチルエステル、
34) 6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸エチルエステル、
35) [6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−イル]−メタノール、
36) 1−アセチル−6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボニトリル
37) 6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボニトリル、
38) 6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸アミド、
39) (6−(6−メチルピリジン−2−イル)−5−(チエノ[3,2−c] ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−イル)メタンアミン、
40) N−((6−(6−メチルピリジン−2−イル)−5−(チエノ[3,2−c]ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−イル)メチル)アセトアミド、
及び、
41) 6−(6−メチルピリジン−2−イル)−5−(チエノ[3,2−c]ピリジン−2−イル)−2,3−ジヒドロイミダゾ[2,1−b]オキサゾール
である。
[反応スキーム1]
[反応スキーム4]
2−トリブチルスタナニル−チエノ[3,2−c]ピリジンの合成
1H NMR (300 MHz, CDCl3) δ 9.13(d, 1H), 8.38 (d, 1H), 7.81 (d, 1H), 7.50 (m, 1H), 1.59(m, 6H), 1.37 (m, 6H),1.20 (m, 6H), 0.92 (t, 9H).
[中間体2]
6−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−ベンゾチアゾールの合成
1H NMR (300 MHz, CDCl3) δ 9.06(s, 1H), 8.46 (s, 1H), 8.13 (d, 1H), 7.94 (d, 1H), 1.38 (s, 12H).
[中間体3]
2−ベンゾ[b]チオフェン−5−イル−4,4,5,5−テトラメチル−[1,3,2]ジオキサボロランの合成
1H NMR (300 MHz, CDCl3) δ 8.31(s, 1H), 7.88 (d, 1H), 7.74 (d, 1H), 7.41 (d, 1H), 7.34 (d, 1H), 1.37 (s, 12H).
[中間体4]
6−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−[1,2,4]トリアゾロ[1,5−a]ピリジンの合成
1H NMR (300 MHz, CDCl3) δ 8.95(s, 1H), 8.35 (s, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 1.36 (s, 12H).
[中間体5]
5−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−ベンゾオキサゾールの合成
1H NMR (300 MHz, CDCl3) δ 8.25(s, 1H), 8.09 (s, 1H), 7.85 (d, 1H), 7.58 (d, 1H), 1.37 (s, 12H).
[中間体6]
4−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−キノリンの合成
1H NMR (300 MHz, CDCl3) δ 8.93(d, 1H), 8.64 (dd, 1H), 8.11 (dd, 1H), 7.85 (d, 1H), 7.71 (m, 1H), 7.58 (m,1H), 1.44 (s, 12H).
[中間体7]
5−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−ベンゾ[1,3]ジオキソールの合成
1H NMR (300 MHz, CDCl3) δ 7.35(d, 1H), 7.23 (s, 1H), 6.82 (d, 1H), 5.95 (s, 2H), 1.32 (s, 12H).
[中間体8]
6−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−2,3−ジヒドロ−ベンゾ[1,4]ジオキシンの合成
1H NMR (300 MHz, CDCl3) δ 7.31(d, 1H), 7.29 (dd, 1H), 6.85 (d, 1H), 4.22 (m, 4H), 1.31 (s, 12H).
[中間体9]
2−イミダゾール−1−イル−7−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−キノキサリンの合成
1H NMR (300 MHz, CDCl3) δ 9.10(s, 1H), 8.56 (d, 1H), 8.12 (s, 1H), 8.10 (dd, 1H), 7.89 (s, 1H), 7.81 (dd,1H), 7.31 (s, 1H), 1.41 (s, 12H).
[中間体10]
2−ピラゾ−ル−1−イル−7−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−キノキサリンの合成
1H NMR (300 MHz, CDCl3) δ 9.71(s, 1H), 8.70 (d, 1H), 8.51 (s, 1H), 8.08 (d, 1H), 8.08 (d, 1H), 7.85 (d, 1H),6.57 (dd, 1H), 1.41 (s, 12H).
[中間体11]
1−[6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−イミダゾ[1,2−a]イミダゾール−1−イル]−エタノンの合成
1H NMR (300 MHz, CDCl3) δ 7.68(d, 1H), 7.57 (t, 1H), 7.46 (s, 1H), 6.98 (d, 1H), 4.46 (m, 2H), 4.15 (m, 2H),2.70 (s, 3H), 2.54 (s, 3H).
[中間体12]
1−[5−ブロモ−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−イミダゾ[1,2−a]イミダゾール−1−イル]−エタノンの合成
1H NMR (300 MHz, CDCl3) δ 7.68(d, 1H), 7.59 (t, 1H), 7.03 (d, 1H), 4.48 (m, 2H), 4.12 (m, 2H), 2.67 (s, 3H),2.60 (s, 3H).
[中間体13]
2−[2−(ベンジルスルホニル)−1H−イミダゾール4−イル]−6−メチルピリジンの合成
MS(ESI) m/z 314.05 (MH+).
1H NMR (300 MHz, CDCl3) δ 7.64 (m,2H), 7.26 (m, 3H), 7.16 (m, 3H), 7.06 (d, 1H), 4.61 (s, 2H), 2.50 (s, 3H).
[中間体14]
5−ブロモ−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロイミダゾ[2,1−b]オキサゾールの合成
1H NMR (300 MHz, CDCl3) δ 7.64(d, 1H), 7.56 (t, 1H), 7.00 (dd, 1H), 5.03 (dd, 2H), 4.18 (dd, 2H), 2.58 (s,3H).
[中間体15]
1−アセチル−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸エチルエステルの合成
1H NMR (300 MHz, CDCl3) δ 7.69 (d,1H), 7.57 (t, 1H), 7.42 (s, 1H), 6.97 (d, 1H), 5.36 (dd, 1H), 4.40 (t, 2H), 4.25(q, 2H), 4.14 (dd, 2H), 2.73 (s, 3H), 2.53 (s, 3H), 1.28 (t, 3H).
[中間体16]
1−アセチル−5−臭化−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸エチルエステルの合成
1H NMR (300 MHz, CDCl3) δ 7.68 (d,1H), 7.59 (t, 1H), 7.03 (d, 1H), 5.37 (dd, 1H), 4.35 (t, 2H), 4.27 (q, 2H), 4.12(dd, 2H), 2.71 (s, 3H), 2.59 (s, 3H), 1.30 (t, 3H).
[中間体17]
1−アセチル−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボニトリルの合成
1H NMR (300 MHz, CDCl3) δ 7.67 (d,1H), 7.59 (t, 1H), 7.49 (s, 1H), 7.01 (d, 1H), 5.61 (dd, 1H), 4.47 (m, 2H), 2.74(s, 3H), 2.54 (s, 3H).
[中間体18]
1−アセチル−5−ブロモ−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボニトリルの合成
1H NMR (300 MHz, CDCl3) δ 7.63 (d,1H), 7.59 (t, 1H), 7.04 (dd, 1H), 5.61 (dd, 1H), 4.40 (m, 2H), 2.70 (s, 3H),2.56 (s, 3H).
(実施例)
[実施例1]
1−[6−(6−メチル−ピリジン−2−イル)−5−キノキサリン−6−イル−2,3−ジヒドロ−イミダゾ[1,2−a]イミダゾール−1−イル]−エタノンの合成
MS(ESI) m/z 371.68 (MH+).
1H NMR (300 MHz, CDCl3) δ 8.84(d, 2H), 8.15 (d, 1H), 8.03 (d, 1H), 7.97 (dd, 1H), 7.62 (d, 1H), 7.55 (t, 1H),7.00 (d, 1H), 4.55 (t, 2H), 4.27 (t, 2H), 2.76 (s, 3H), 2.36 (s, 3H).
[実施例2]
6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノキサリンの合成
MS(ESI) m/z 329.64 (MH+).
1H NMR (300 MHz, CDCl3) δ 8.82(d, 1H), 8.80 (d, 1H), 8.12 (t, 1H), 7.98 (m, 2H), 7.50 (d, 1H), 7.49 (t, 1H),6.97 (dd, 1H), 4.57 (br s, 1H), 4.24 (m, 2H), 4.09 (t, 2H), 2.39 (s, 3H).
[実施例3]
6−[2−(6−メチル−ピリジン−2−イル)−5,6,7,8−テトラヒドロ−イミダゾ[1,2−a]ピリミジン−3−イル]−キノキサリンの合成
MS(ESI) m/z 343.69 (MH+).
1H NMR (300 MHz, CDCl3) δ 8.84(d, 1H), 8.83 (d, 1H), 8.09 (d, 1H), 8.02 (d, 1H), 7.84 (dd, 1H), 7.40 (t, 1H),7.27 (d, 1H), 6.90 (d, 1H), 4.97 (br s, 1H), 3.90 (t, 2H), 3.49 (m, 2H), 2.38(s, 3H), 2.09 (quintet, 2H).
[実施例4]
6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノリンの合成
MS(ESI) m/z 329.64 (MH+).
1H NMR (300 MHz, CDCl3) δ 8.89(dd, 1H), 8.11 (m, 1H), 8.03 (d, 1H), 7.94 (d, 1H), 7.82 (dd, 1H), 7.45 (t,1H), 7.41 (d, 1H), 7.39 (t, 1H), 6.92 (dd, 1H), 4.44 (br t, 1H), 4.16 (m, 2H),4.07 (m, 2H), 2.40 (s, 3H).
[実施例5]
6−[2−(6−メチル−ピリジン−2−イル)−5,6,7,8−テトラヒドロ−イミダゾ[1,2−a]ピリミジン−3−イル]−キノリンの合成
MS(ESI) m/z 342.86 (MH+).
1H NMR (300 MHz, CDCl3) δ 8.92(dd, 1H), 8.13 (d, 1H), 8.08 (d, 1H), 7.86 (d, 1H), 7.73 (dd, 1H), 7.42 (dd,1H), 7.33 (t, 1H), 7.14 (d, 1H), 6.87 (d, 1H), 4.90 (br s, 1H), 3.81 (t, 2H),3.48 (m, 2H), 2.40 (s, 3H), 2.09 (quintet, 2H).
[実施例6]
2−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−チエノ[3,2−c]ピリジンの合成
MS(ESI) m/z 334.77 (MH+).
1H NMR (300 MHz, CDCl3+CD3OD)δ 8.89 (s, 1H), 8.27 (d, 1H), 7.67 (d, 1H), 7.63 (s, 1H), 7.55 (t, 1H),7.43 (d, 1H), 7.02 (d, 1H), 4.26 (m, 2H), 4.04 (m, 2H), 2.52 (s, 3H).
[実施例7]
6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−ベンゾチアゾールの合成
MS(ESI) m/z 334.70 (MH+).
1H NMR (300 MHz, CDCl3) δ 9.00(s, 1H), 8.17 (d, 1H), 8.10 (d, 1H), 7.60 (dd, 1H), 7.42 (t, 1H), 7.34 (d, 1H),6.92 (d, 1H), 4.10 (m, 4H), 2.40 (s, 3H).
[実施例8]
5−ベンゾ[b]チオフェン−5−イル−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 333.71 (MH+).
1H NMR (300 MHz, CDCl3) δ 7.95(d, 1H), 7.84 (d, 1H), 7.46 (d, 1H), 7.43 (dd, 1H), 7.38 (d, 1H), 7.32 (t, 1H),7.26 (d, 1H), 6.90 (d, 1H), 4.35 (br s, 1H), 4.06 (m, 4H), 2.46 (s, 3H).
[実施例9]
6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−[1,2,4]トリアゾロ[1,5−a]ピリジンの合成
MS(ESI) m/z 318.71 (MH+).
1H NMR (300 MHz, CDCl3) δ 9.01(t, 1H), 8.31 (s, 1H), 7.66 (m, 1H), 7.56 (d, 1H), 7.52 (t, 1H), 6.94 (dd, 1H),5.39 (br s, 1H), 4.03 (m, 4H), 2.37 (s, 3H).
[実施例10]
5−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−ベンゾオキサゾールの合成
MS(ESI) m/z 318.69 (MH+).
1H NMR (300 MHz, CDCl3) δ 8.12(s, 1H), 7.90 (s, 1H), 7.55 (d, 2H), 7.41 (t, 1H), 7.30 (d, 1H), 6.90 (d, 1H),4.07 (m, 4H), 2.42 (s, 3H).
[実施例11]
4−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノリンの合成
MS(ESI) m/z 328.74 (MH+).
1H NMR (300 MHz, CDCl3) δ 8.94(d, 1H), 8.14 (d, 1H), 7.82 (d, 1H), 7.69 (m, 1H), 7.45 (d, 1H), 7.39 (m, 1H),7.33 (t, 1H), 7.22 (d, 1H), 6.79 (d, 1H), 4.57 (br s, 1H), 4.06 (t, 2H), 3.90(m, 2H), 2.09 (s, 3H).
[実施例12]
5−ベンゾ[1,3]ジオキソール−5−イル−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 321.61 (MH+).
1H NMR (300 MHz, CDCl3) δ 7.40(t, 1H), 7.26 (d, 1H), 6.98 (d, 1H), 6.91 (m, 2H), 6.80 (d, 1H), 5.98 (s, 2H),4.35 (br s, 1H), 4.02 (m, 4H), 2.48 (s, 3H).
[実施例13]
5−(2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−6−イル)−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 335.69 (MH+).
1H NMR (300 MHz, CDCl3) δ 7.39 (t,1H), 7.17 (d, 1H), 6.90 (d, 1H), 6.88 (d, 1H), 6.83 (dd, 1H), 6.77 (d, 1H),4.23 (m, 4H), 3.97 (m, 4H), 2.42 (s, 3H).
[実施例14]
7−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール3−イル]−2−ピラゾール−1−イル−キノキサリンの合成
MS(ESI) m/z 395.78 (MH+).
1H NMR (300 MHz, CDCl3+CD3OD)δ 9.56 (s, 1H), 8.67 (d, 1H), 8.02 (d, 1H), 7.96 (d, 1H), 7.84 (m, 1H),7.77 (dd, 1H), 7.51 (t, 1H), 7.41 (d, 1H), 6.97 (d, 1H), 6.56 (m, 1H), 4.23 (m,2H), 4.06 (m, 2H), 2.36 (s, 3H).
[実施例15]
ジメチル−(2−{7−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール3−イル]−キノキサリン−2−イルオキシ}−エチル)−アミンの合成
MS(ESI) m/z 416.57 (MH+).
1H NMR (300 MHz, CDCl3) δ 8.48(s, 1H), 7.91 (s, 1H), 7.89 (d, 1H), 7.68 (dd, 1H), 7.46 (t, 1H), 7.40 (d, 1H),6.95 (d, 1H), 4.89 (br s, 1H), 4.58 (t, 2H), 4.22 (m, 2H), 4.09 (m, 2H), 2.79(t, 2H), 2.42 (s, 3H), 2.37 (s, 6H).
[実施例16]
2−メトキシ−7−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノキサリンの合成
MS(ESI) m/z 359.74.
1H NMR (400 MHz, CDCl3) δ 8.42(s, 1H), 7.93 (d, 1H), 7.90 (d, 1H), 7.68 (dd, 1H), 7.46 (t, 1H), 7.40 (d, 1H),6.95 (d, 1H), 4.46 (br s, 1H), 4.22 (m, 2H), 4.09 (s, 3H), 4.07(m, 2H), 2.43(s, 3H).
[実施例17]
5−(3,5−ジメトキシフェニル)−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 337.27 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.41(t, 1H), 7.29 (d, 1H), 6.92 (d, 1H), 6.61 (d, 2H), 6.41 (t, 1H), 4.09 (dd, 2H),4.00 (dd, 2H), 3.74 (s, 6H), 2.51 (s, 3H).
[実施例18]
N,N−ジメチル−4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)アニリンの合成
MS(ESI) m/z 320.34 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.33(m, 3H), 7.21 (m, 1H), 6.88 (m, 1H), 6.71 (m, 2H), 4.00 (ddt, 4H), 2.98 (s,6H), 2.49 (s, 3H).
[実施例19]
4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)ベンゾニトリの合成
MS(ESI) m/z 302.31 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.57(m, 5H), 7.39 (d, 1H), 7.01 (d, 1H), 4.09 (m, 4H), 2.40 (s, 3H).
[実施例20]
2−メチル−6−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)キノリンの合成
MS(ESI) m/z 342.35 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.94(m, 3H), 7.77 (dd, 1H), 7.43 (m, 2H), 7.28 (d, 1H), 6.93 (d, 1H), 4.10 (m, 4H),2.75 (s, 3H), 2.38 (s, 3H).
[実施例21]
4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)アニリンの合成
MS(ESI) m/z 292.30 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.41(t, 1H), 7.19 (m, 3H), 6.91 (d, 1H), 6.68 (m, 2H), 4.00 (m, 4H), 3.29 (br s,2H, NH2), 2.46 (s, 3H).
[実施例22]
N−(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)アセトアミドの合成
MS(ESI) m/z 334.30 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.44(m, 5H), 7.27 (d, 1H), 6.92 (d, 1H), 4.02 (m, 4H), 2.44 (s, 3H), 2.17 (s, 3H).
[実施例23]
N−(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)メタンスルホンアミドの合成
MS(ESI) m/z 370.07 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.42(t, 1H), 7.30 (m, 2H), 7.21 (d, 1H), 7.14 (m, 2H), 6.89 (d, 1H), 3.98 (m, 4H),2.94 (s, 3H), 2.34 (s, 3H).
[実施例24]
t−ブチル(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)カルバメートの合成
MS(ESI) m/z 392.16 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.42(t, 2H), 7.35 (m, 4H), 7.24 (d, 1H), 6.92 (d, 1H), 4.01 (m, 4H), 2.45 (s, 3H),1.53 (s, 9H).
[実施例25]
5−(4−(4−メチルピペラジン−1−イル)フェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 375.37 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.40(t, 1H), 7.32 (m, 2H), 7.22 (d, 1H), 6.90 (m, 3H), 3.99 (m, 4H), 3.25 (dd, 4H),2.60 (dd, 4H), 2.47 (s, 3H), 2.36 (s, 3H).
[実施例26]
4−(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)モルホリンの合成
MS(ESI) m/z 362.42 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.41(t, 1H), 7.33 (m, 2H), 7.22 (d, 1H), 6.89 (m, 3H), 4.01 (m, 4H), 3.88 (dd, 4H),3.20 (dd, 4H), 2.47 (s, 3H).
[実施例27]
6−(6−メチルピリジン−2−イル)−5−(m−トリル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 291.32 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.41(t, 1H), 7.26 (m, 4H), 7.10 (m, 1H), 6.91 (d, 1H), 4.03 (m, 4H), 2.46 (s, 3H),2.34 (t, 3H).
[実施例28]
5−(4−メトキシフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 307.30 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.39(m, 3H), 7.26 (m, 1H), 6.90 (m, 3H), 4.02 (m, 4H), 3.84 (s, 3H), 2.46 (s, 3H).
[実施例29]
6−(6−メチルピリジン−2−イル)−5−(4−(トリフルオロメチル)フェニル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 345.37 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.59(m, 4H), 7.49 (t, 1H), 7.38 (d, 1H), 6.96 (d, 1H), 4.06 (m, 4H), 2.42 (s, 3H).
[実施例30]
6−(6−メチルピリジン−2−イル)−5−(4−(メチルチオ)フェニル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 323.29 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.41(m, 3H), 7.27 (m, 3H), 6.92 (d, 1H), 4.03 (m, 4H), 2.51 (s, 3H), 2.46 (s, 3H).
[実施例31]
5−(3−フルオロ−4−メトキシフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 325.36 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.45(t, 1H), 7.31 (m, 2H), 7.17 (ddd, 1H), 6.93 (m, 2H), 4.03 (m, 4H), 3.92 (s,3H), 2.45 (s, 3H).
[実施例32]
5−(4−フルオロフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾールの合成
MS(ESI) m/z 295.38 (MH+)
1H NMR (300 MHz, CDCl3) δ 7.45(m, 3H), 7.31 (d, 1H), 7.04 (m, 2H), 6.90 (d, 1H), 4.03 (m, 4H), 2.43 (s, 3H).
[実施例33]
1−アセチル−6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸エチルエステルの合成
MS(ESI) m/z 448.31 (MH+)
1H NMR (300 MHz, CDCl3) δ 9.05(s, 1H), 8.43 (d, 1H), 7.80 (s, 1H), 7.72 (d, 1H), 7.67 (d, 1H), 7.61 (t, 1H), 7.07(d, 1H), 5.44 (dd, 1H), 4.59 (t, 1H), 4.33 (dd, 1H), 4.29 (q, 2H), 2.76 (s, 3H),2.56 (s, 3H), 1.32 (t, 3H).
[実施例34]
6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸エチルエステルの合成
MS(ESI) m/z 406.19 (MH+)
1H NMR (300 MHz, CDCl3) δ 9.02(d, 1H), 8.40 (d, 1H), 7.74 (s, 1H), 7.70 (d, 2H), 7.58 (s, 1H), 7.56 (d, 1H),7.03 (t, 1H), 4.94 (br s, 1H), 4.83 (dd, 1H), 4.57 (t, 1H), 4.54 (d, 1H), 4.30(q, 2H), 2.58 (s, 3H), 1.34 (t, 3H).
[実施例35]
[6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−イル]−メタノールの合成
MS(ESI) m/z 364.32 (MH+)
1H NMR (300 MHz, CDCl3) δ 8.83(s, 1H), 8.22 (d, 1H), 7.64 (d, 1H), 7.55 (s, 1H), 7.53 (t, 1H), 7.36 (d, 1H), 7.00(d, 1H), 4.40 (m, 1H), 4.30 (t, 1H), 4.03 (dd, 1H), 4.68 (dd, 1H), 3.61 (dd,1H), 2.50 (s, 3H).
[実施例36]
1−アセチル−6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボニトリルの合成
MS(ESI) m/z 401.19 (MH+)
1H NMR (300 MHz, CDCl3) δ 8.97(s, 1H), 8.34 (d, 1H), 7.73 (d, 1H), 7.72 (s, 1H), 7.59 (m, 2H), 7.07 (m, 1H), 5.69(dd, 1H), 4.61 (m, 2H), 2.71 (s, 3H), 2.50 (s, 3H).
[実施例37]
6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボニトリルの合成
MS(ESI) m/z 359.23 (MH+)
1H NMR (300 MHz, CDCl3) δ 8.86(s, 1H), 8.24 (d, 1H), 7.66 (d, 1H), 7.56 (s, 1H), 7.51 (d, 1H), 7.36 (d, 1H),7.02 (d, 1H), 5.10 (dd, 1H), 4.49 (m, 2H), 2.47 (s, 3H).
[実施例38]
6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸アミドの合成
MS(ESI) m/z 359.27 (M-H2O)
1H NMR (300 MHz, CDCl3) δ 8.85(d, 1H), 8.24 (d, 1H), 7.66 (d, 1H), 7.56 (s, 1H), 7.51 (d, 1H), 7.36 (d, 1H),7.02 (d, 1H), 5.10 (dd, 1H), 4.49 (m, 2H), 2.47 (s, 3H).
[実施例39]
(6−(6−メチルピリジン−2−イル)−5−(チエノ[3,2−c]ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−イル)メタンアミンの合成
MS(ESI) m/z 363.28 (MH+)
1H NMR (300 MHz, CDCl3) δ 9.00(d, 1H), 8.39 (m, 1H), 7.70 (m, 2H), 7.56 (m, 2H), 7.03 (m, 1H), 4.40 (m, 2H),4.09 (m, 1H), 3.04 (dd, 1H), 2.92 (dd, 1H), 2.59 (s, 3H).
[実施例40]
N−((6−(6−メチルピリジン−2−イル)−5−(チエノ[3,2−c]ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−イル)メチル)アセトアミドの合成
MS(ESI) m/z 405.24 (MH+)
1H NMR (300 MHz, CDCl3) δ 8.95(s, 1H), 8.34 (d, 1H), 7.72 (d, 1H), 7.60 (m, 2H), 7.44 (d, 1H), 7.08 (d, 1H),4.54 (m, 1H), 4.37 (dd, 1H), 4.00 (dd, 1H), 3.52 (m, 2H), 2.58 (s, 3H), 1.99(s, 3H).
[実施例41]
6−(6−メチルピリジン−2−イル)−5−(チエノ[3,2−c]ピリジン−2−イル)−2,3−ジヒドロイミダゾ[2,1−b]オキサゾールの合成
MS(ESI) m/z 335.17 (MH+)
1H NMR (300 MHz, CDCl3) δ 9.03(d, 1H), 8.42 (d, 1H), 7.86 (d, 1H), 7.72 (dt, 1H), 7.63 (m, 2H), 7.05 (ddd,1H), 5.13 (dd, 2H), 4.44 (dd, 2H), 2.58 (s, 3H).
[生物学データ]
本発明の化合物の生物学的な活性は、下記の試験法により評価した。
ALK5のキナーゼ活性は、一般的な基質、カゼインに放射標識されたリン酸[33P]を配合することで測定した。ヒトALK5のキナーゼドメイン(200番目から503番目までのアミノ酸)を、GSTタグ又はヒスチジンタグのN末端に結合させ、そのキナーゼ構造体を操作して昆虫細胞内で発現させる。精製されたALK5タンパク質をカゼイン基質(最終濃度,2mg/mL)と混合させた後、反応バッファー[20mM HEPES(pH7.5)、10mM MgCl2、1mM EGTA、0.02%Brij35、0.02mg/mlBSA、0.1mM Na3VO4、2mM DTT及び1% DMSOを含み]を添加した。異なる濃度を有する前記化学式(I)の化合物の各種DMSO溶液を調製するために純DMSOを使用しており、調製されたDMSO溶液を反応混合液に添加した。さらに、33P−ATP、比活性0.01μCi/μl、最終)を反応混合物に添加したことにより、反応を開始させた。さらに、室温で2時間放置した後、反応液をP81イオン交換クロマトグラフィー用ペーパーにスポットし、0.75%リン酸で広範囲にわたって洗浄た。その後、ペーパーを風乾して測定した。
ALK4のキナーゼ活性は、一般的な基質、カゼインに放射標識されたリン酸[33P]を配合することで測定した。ヒトALK4のキナーゼドメイン(150番目から505番目までのアミノ酸)をGSTタグに結合させ、そのキナーゼ構造体を操作して昆虫細胞内で発現させた。
本発明による前記化学式(I)で示す化合物の生物学的活性は、HaCaT細胞においてTGF−β1誘発のスマッド結合配列ルシフェラーゼ(略SBE−Lux)リポーターの活性及びPAI−1ールシフェラーゼ(PAI−1−luciferase、略p3TP−Lux)リポーターの活性を阻害する能力で評価された。HaCaT細胞は37℃で5%CO2の培養器にDMEM培地(10%FBS,100U/mLペニシリン、及び100μg/mLストレプトマイシンを含み)で培養した。これらの細胞は2.5×104 セル/ウェルの96ウェルプレートに撒き、それぞれに対して、p3TP−Lux及びSBE−Luxリポーターを0.6μg形質移入した。形質移入してから24時間経った後、各種の濃度(5、10、50、00及び500nM)でALK5抑制剤を2時間前処理した。さらに、これらの細胞を5ng/mlのTGF−β1リガンド(PEPROTECH、100−21C)で刺激させ、37℃で5%CO2の培養器に24時間培養した。培地を洗い出し、細胞溶解物中のルシフェラーゼ活性をルシフェラーゼ定量システム(Promega)で測定した。
Claims (12)
-
(前記化学式(I)において、
R1は、1つの構造部分と縮合したフェニル基、ピリジル基又はチエニル基であり、その構造部分は、前記フェニル基、ピリジル基又はチエニル基の2つの環員と共に、5〜7員の芳香族又は非芳香族環を形成し、前記環はO、N及びSから独立に選択された3つ以下のヘテロ原子を任意に含有し、前記縮合されたフェニル基、ピリジル基又はチエニル基は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C1−6ハロアルキル基、ニトリル基、−(CH2)p−OR4基、−O−(CH2)q−NR4R5基、−(CH2)p−NR4R5基、−NHCO−O−(CH2)q−NR4R5基、−NHCO−(CH2)p−NR4R5基、及び−C5−15ヘテロアリール基からなる群から独立に選択された一つ以上の基により任意に置換され、前記−C5−15ヘテロアリール基はO、N及びSから独立に選択された3つ以下のヘテロ原子を含有し、又は、R1は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C1−6ハロアルキル基、ニトリル基、−(CH2)p−OR4基、−O−(CH2)q−NR4R5基、−NH−(CH2)q−NR4R5基、−(CH2)p−NR4R5基、−(CH2)p−NHCOR4基、−(CH2)p−NHCO2R4基、−(CH2)p−NHSO2R4基、及び−C5−15ヘテロ環基からなる群から独立に選択された一つ以上の基により任意に置換されるフェニル基又はピリジル基であり、前記−C5−15ヘテロ環基はO、N及びSから独立に選択された3つ以下のヘテロ原子を含有し、−C1−6アルキル基により任意に置換可能であり、
R2は、水素原子、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C3−7シクロアルキル基、−C5−15ヘテロアリール基、−C1−6ハロアルキル基、−(CH2)p−OR4基、−O−(CH2)p−NR4R5基、−(CH2)p−NR4R5基、ニトリル基、−CONHR4基、又は−SO2NHR4基であり、
R3は、水素原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C3−7シクロアルキル基、−(CH2)p−NR4R5基、−O−(CH2)q−NR4R5基、−(CH2)p−CONHOH基、−(CH2)p−CN基、−(CH2)p−CO2R4基、−(CH2)p−CONR4R5基、−(CH2)p−テトラゾール基、−(CH2)p−COR4基、−(CH2)q−(OR6)2基、−(CH2)p−OR4基、−(CH2)p−CH=CH−CN基、−(CH2)p−CH=CH−CO2R4基、−(CH2)p−CH=CH−CONR4R5基、−(CH2)p−NHCOR4基、−(CH2)p−NHCO2R4基、−(CH2)p−NHSO2R4基又は−(CH2)p−CH=CH−テトラゾール基であり、
R4及びR5は、それぞれ独立して水素原子、もしくはC1−6アルキル基であり、又は、R4及びR5は窒素原子に連結しながら、窒素原子と共に3〜6員の芳香族又は非芳香族の環を形成し、前記環はO、N及びSから独立に選択された3つ以下のヘテロ原子を任意に含有し、
R6は−C1−6アルキル基であり、
pは0〜4の整数であり、
qは2〜5の整数であり、
nは1〜3の整数であり、
XはNR7、O、又はSであり、
R7は、水素原子、ヒドロキシル基、−C1−6アルキル基、−C3−7シクロアルキル基又は−CO−C1−6アルキル基である。)
上記化学式(I)で示す化合物、その薬剤学的に許容可能な塩、又はその溶媒和化合物。 - R1は1つの構造部分と縮合したフェニル基、ピリジル基又はチエニル基であり、その構造部分は、前記フェニル基、ピリジル基又はチエニル基の2つの環員と共に、芳香族又は非芳香族の5又は6員環を形成し、前記環はO、N及びSから独立に選択された1つ又は2つのヘテロ原子を任意に含有し、前記縮合されたフェニル基、ピリジル基又はチエニル基は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C1−6ハロアルキル基、ニトリル基、−(CH2)p−OR4基、−O−(CH2)q−NR4R5基、−(CH2)p−NR4R5基、−NHCO−O−(CH2)q−NR4R5基、−NHCO−(CH2)p−NR4R5基、及び−C5−15ヘテロアリール基からなる群から独立に選択された1つ以上の基により任意に置換され、前記−C5−15ヘテロアリール基は、O、N及びSから独立に選択された3つ以下のヘテロ原子を含有し、又は、R1は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C1−6ハロアルキル基、ニトリル基、−NH−(CH2)q−NR4R5基、−(CH2)p−NR4R5基、−(CH2)p−NHCOR4基、−(CH2)p−NHCO2R4基、−(CH2)p−NHSO2R4基、及び−C5−15ヘテロ環基からなる群から独立に選択された1つ以上の基により任意に置換されるフェニル基であり、前記−C5−15ヘテロ環基はO、N及びSから独立に選択された3つ以下のヘテロ原子を含有し、−C1−6アルキル基により任意に置換可能であり、
R2は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C3−7シクロアルキル基、−C5−15ヘテロアリール基、−C1−6ハロアルキル基、−(CH2)p−OR4基、−O−(CH2)p−NR4R5基、−(CH2)p−NR4R5基、ニトリル基、−CONHR4基、又は−SO2NHR4基であり、
R3は、水素原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C3−7シクロアルキル基、−(CH2)p−NR4R5、−O−(CH2)q−NR4R5、−(CH2)p−CONHOH、−(CH2)p−CN、−(CH2)p−CO2R4、−(CH2)p−CONR4R5、−(CH2)p−テトラゾール、−(CH2)p−OR4、−(CH2)p−NHCOR4、−(CH2)p−NHCO2R4、又は−(CH2)p−NHSO2R4基であり、
R4及びR5は、それぞれ独立して水素原子もしくは−C1−4アルキル基であり、又は、R4及びR5は窒素原子に連結しながら、窒素原子と共に3〜6員の芳香族又は非芳香族のヘテロ環を形成し、前記ヘテロ環は、O、N及びSから独立に選択される3つ以下のヘテロ原子を任意に含有し、
pは0〜2の整数であり、
qは2〜4の整数であり、
nは1又は2の整数であり、
XはNR7、O又はSであり、
R7は、水素原子、ヒドロキシル基、−C1−6アルキル基又は−CO−C1−6アルキル基である、請求項1に記載の化合物。 - 前記R1は、キノキサリニル、キノリニル、チエノピリジニル、ベンゾチアゾリル、ベンゾチオフェニル、トリアゾロピリジニル、ベンゾオキサゾリル、キノリニル、ベンゾジオキソリル、及びベンゾジオキシニルからなる群から選択された縮合環であり、前記縮合環は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C1−6ハロアルキル基、ニトリル基、−(CH2)p−OR4基、−O−(CH2)q−NR4R5基、−(CH2)p−NR4R5基、及び、−C5−15ヘテロアリール基からなる群から独立に選択された一つ以上の基により任意に置換され、前記−C5−15ヘテロアリール基は、O、N及びSから独立に選択された1つ又は2つのヘテロ原子を含有し、又は、R1は、ハロゲン原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−C1−6ハロアルキル基、ニトリル基、−(CH2)p−OR4基、−O−(CH2)q−NR4R5基、−NH−(CH2)q−NR4R5基、−(CH2)p−NR4R5基、−(CH2)p−NHCOR4基、−(CH2)p−NHCO2R4基、−(CH2)p−NHSO2R4、及び−C5−15ヘテロ環基からなる群から独立に選択された一つ又は二つの基により任意に置換されるフェニル基であり、前記−C5−15ヘテロ環基はO、N及びSから独立に選択された1つ又は2つのヘテロ原子を含有し、−C1−6アルキル基により任意に置換可能であり、
R2は、ハロゲン原子、−C1−6アルキル基、−C1−6ハロアルキル基、又は−NH2基であり、ピリジン環の窒素原子の隣位に位置し、
R3は、水素原子、−O−C1−6アルキル基、−S−C1−6アルキル基、−C1−6アルキル基、−(CH2)p−NR4R5基、−(CH2)p−CN基、−(CH2)p−CO2R4、−(CH2)p−CONR4R5基、−(CH2)p−COR4基、−(CH2)p−OR4基、又は−(CH2)p−NHCOR4基であり、
R4及びR5は、それぞれ独立して水素原子又はC1−6アルキル基であり、
pは0〜2の整数であり、
qは2〜4の整数であり、
nは1〜3の整数であり、
XはNR7、O又はSであり、
R7は、水素原子又は−CO−C1−6アルキル基である、請求項1に記載の化合物。 - 1) 1−[6−(6−メチル−ピリジン−2−イル)−5−キノキサリン−6−イル−2,3−ジヒドロ−イミダゾ[1,2−a] イミダゾール−1−イル]−エタノン、
2) 6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノキサリン、
3) 6−[2−(6−メチル−ピリジン−2−イル)−5,6,7,8−テトラヒドロ−イミダゾ[1,2−a]ピリミジン−3−イル]−キノキサリン、
4) 6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノリン、
5) 6−[2−(6−メチル−ピリジン−2−イル)−5,6,7,8−テトラヒドロ−イミダゾ[1,2−a]ピリミジン−3−イル]−キノリン、
6) 2−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−チエノ[3,2−c]ピリジン、
7) 6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−ベンゾチアゾール、
8) 5−(ベンゾ[b]チオフェン−5−イル)−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
9) 6−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−[1,2,4]トリアゾロ[1,5−a]ピリジン、
10) 5−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−ベンゾオキサゾール、
11) 4−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノリン、
12) 5−ベンゾ[1,3]ジオキソール−5−イル−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
13) 5−(2,3−ジヒドロ−ベンゾ[1,4]ジオキシン−6−イル)−6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
14) 7−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−2−ピラゾ−ル−1−イル−キノキサリン、
15) ジメチル−(2−{7−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノキサリン−2−イルオキシ}−エチル)−アミン、
16) 2−メトキシ−7−[2−(6−メチル−ピリジン−2−イル)−6,7−ジヒドロ−5H−イミダゾ[1,2−a]イミダゾール−3−イル]−キノキサリン、
17) 5−(3,5−ジメトキシフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
18) N,N−ジメチル−4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)アニリン、
19) 4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)ベンゾニトリル、
20) 2−メチル−6−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)キノリン、
21) 4−(6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)アニリン、
22) N−(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)アセトアミド、
23) N−(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)メタンスルホンアミド、
24) t−ブチル(4−(6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)カルバメート、
25) 5−(4−(4−メチルピペラジン−1−イル)フェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
26) 4−(4−(6−(6−メチル−ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−5−イル)フェニル)モルホリン、
27) 6−(6−メチルピリジン−2−イル)−5−(m−トリル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
28) 5−(4−メトキシフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
29) 6−(6−メチルピリジン−2−イル)−5−(4−(トリフルオロメチル)フェニル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
30) 6−(6−メチル−ピリジン−2−イル)−5−(4−(メチルチオ)フェニル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
31) 5−(3−フルオロ−4−メトキシフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
32) 5−(4−フルオロフェニル)−6−(6−メチルピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール、
33) 1−アセチル−6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸エチルエステル、
34) 6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸エチルエステル、
35) [6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−イル]−メタノール、
36) 1−アセチル−6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボニトリル、
37) 6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボニトリル、
38) 6−(6−メチル−ピリジン−2−イル)−5−チエノ[3,2−c]ピリジン−2−イル−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−カルボン酸アミド、
39) (6−(6−メチルピリジン−2−イル)−5−(チエノ[3,2−c]ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−イル)メタンアミン、
40) N−((6−(6−メチルピリジン−2−イル)−5−(チエノ[3,2−c]ピリジン−2−イル)−2,3−ジヒドロ−1H−イミダゾ[1,2−a]イミダゾール−2−イル)メチル)アセトアミド、
及び、
41) 6−(6−メチルピリジン−2−イル)−5−(チエノ[3,2−c]ピリジン−2−イル)−2,3−ジヒドロイミダゾ[2,1−b]オキサゾール
からなる群より選択される、請求項1に記載の化合物。 - 請求項1に記載の前記化学式(I)で示す化合物の、哺乳類においてトランスフォーミング増殖因子β(TGF−β)第I型受容体(ALK5)又はアクチビン第I型受容体(ALK4)、又はこれらの両方により介在される疾患を治療するための医薬品の製造における使用。
- ALK5受容体又はALK4受容体、又はこれらの両方により介在される前記疾患は、腎線維症、肝線維症、肺線維症、糸球体腎炎、糖尿病性腎障害、ループス腎炎、高血圧による腎障害、腎間質線維化、薬物曝露合併症による腎線維症、HIV関連腎臓病、臓器移植懐死、あらゆる病因による肝線維症、感染による肝機能障害、アルコール性肝炎、胆道系疾患、肺線維症、急性肺障害、成人性呼吸促迫症候群、特発性肺線維症、慢性閉塞性肺疾患、感染因子又は毒物による肺線維症、梗塞後の心臓線維症、うっ血性心不全、拡張型心筋症、心筋炎、血管狭窄症、再狭窄、粥状動脈硬化、眼球損傷、角膜損傷、増殖性硝子体網膜症、真皮における外傷又は手術痕による創傷治癒中の過剰又は肥厚性の瘢痕又はケロイドの生成、腹膜又は真皮下の癒着、皮膚硬化症、線維性硬化症、全身性進行性硬化症、皮膚炎、多発筋炎、関節炎、骨粗鬆症、潰瘍、神経機能障害、男性勃起機能障害、アルツハイマー病、レイノー症候群、線維性癌、腫瘍転移及び増殖、放射線線維症及び血栓症からなる群より選択される、請求項5に記載の使用。
- 前記哺乳類はヒトである、請求項5に記載の使用。
- 有効成分としての、請求項1に記載の前記化学式(I)で示す化合物、又はその薬剤学的に許容可能な塩又はその溶媒化合物と、薬剤学的に許容可能な賦形剤又は担体とを含み、ALK5受容体又はALK4受容体、又はこれらの両方により介在される疾患を予防又は治療する医薬組成物。
- ALK5受容体又はALK4受容体、又はこれらの両方により介在される前記疾患は、腎線維症、肝線維症、肺線維症、糸球体腎炎、糖尿病性腎障害、ループス腎炎、高血圧による腎障害、腎間質線維化、薬物曝露合併症による腎線維症、HIV関連腎臓病、臓器移植懐死、あらゆる病因による肝線維症、感染による肝機能障害、アルコール性肝炎、胆道系疾患、肺線維症、急性肺障害、成人性呼吸促迫症候群、特発性肺線維症、慢性閉塞性肺疾患、感染因子又は毒物による肺線維症、梗塞後の心臓線維症、うっ血性心不全、拡張型心筋症、心筋炎、血管狭窄症、再狭窄、粥状動脈硬化、眼球損傷、角膜損傷、増殖性硝子体網膜症、真皮における外傷又は手術痕による創傷治癒中の過剰又は肥厚性の瘢痕又はケロイドの生成、腹膜又は真皮下の癒着、皮膚硬化症、線維性硬化症、全身性進行性硬化症、皮膚炎、多発筋炎、関節炎、骨粗鬆症、潰瘍、神経機能障害、男性勃起機能障害、アルツハイマー病、レイノー症候群、線維性癌、腫瘍転移及び増殖、放射線線維症及び血栓症からなる群から選択される、請求項8に記載の医薬組成物。
- 哺乳類において、請求項1に記載の化学式(I)で示す化合物、又はその薬剤学的に許容可能な塩、又はその溶媒和化合物を必要とされる哺乳類に投与する方法を含み、ALK5受容体又はALK4受容体、又はこれらの両方により介在される疾患を予防又は治療する方法。
- ALK5受容体又はALK4受容体、又はこれらの両方により介在される前記疾患は、腎線維症、肝線維症、肺線維症、糸球体腎炎、糖尿病性腎障害、ループス腎炎、高血圧による腎障害、腎間質線維化、薬物曝露合併症による腎線維症、HIV関連腎臓病、臓器移植懐死、あらゆる病因による肝線維症、感染による肝機能障害、アルコール性肝炎、胆道系疾患、肺線維症、急性肺障害、成人性呼吸促迫症候群、特発性肺線維症、慢性閉塞性肺疾患、感染因子又は毒物による肺線維症、梗塞後の心臓線維症、うっ血性心不全、拡張型心筋症、心筋炎、血管狭窄症、再狭窄、粥状動脈硬化、眼球損傷、角膜損傷、増殖性硝子体網膜症、真皮における外傷又は手術痕による創傷治癒中の過剰又は肥厚性の瘢痕又はケロイドの生成、腹膜又は真皮下の癒着、皮膚硬化症、線維性硬化症、全身性進行性硬化症、皮膚炎、多発筋炎、関節炎、骨粗鬆症、潰瘍、神経機能障害、男性勃起機能障害、アルツハイマー病、レイノー症候群、線維性癌、腫瘍転移及び増殖、放射線線維症及び血栓症からなる群から選択される、請求項10に記載の方法。
- 哺乳類はヒトである、請求項10に記載の方法。
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KR20190022735A (ko) * | 2016-06-29 | 2019-03-06 | 브리스톨-마이어스 스큅 컴퍼니 | [1,2,4]트리아졸로[1,5-a]피리디닐 치환된 인돌 화합물 |
JP2021534203A (ja) * | 2018-08-22 | 2021-12-09 | クラヴィウス ファーマシューティカルズ,エルエルシー | Tgf−ベータを阻害するための置換イミダゾールおよび処置方法 |
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JP2018501209A (ja) * | 2014-11-21 | 2018-01-18 | ライジェル ファーマシューティカルズ, インコーポレイテッド | Tgf−ベータ阻害剤としての縮合イミダゾール誘導体 |
KR20190022735A (ko) * | 2016-06-29 | 2019-03-06 | 브리스톨-마이어스 스큅 컴퍼니 | [1,2,4]트리아졸로[1,5-a]피리디닐 치환된 인돌 화합물 |
JP2019523241A (ja) * | 2016-06-29 | 2019-08-22 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | [1,2,4]トリアゾロ[1,5−a]ピリジニル置換インドール化合物 |
JP6995067B2 (ja) | 2016-06-29 | 2022-01-14 | ブリストル-マイヤーズ スクイブ カンパニー | [1,2,4]トリアゾロ[1,5-a]ピリジニル置換インドール化合物 |
KR102473482B1 (ko) | 2016-06-29 | 2022-12-01 | 브리스톨-마이어스 스큅 컴퍼니 | [1,2,4]트리아졸로[1,5-a]피리디닐 치환된 인돌 화합물 |
JP6995067B6 (ja) | 2016-06-29 | 2023-12-14 | ブリストル-マイヤーズ スクイブ カンパニー | [1,2,4]トリアゾロ[1,5-a]ピリジニル置換インドール化合物 |
US11845745B2 (en) | 2017-03-23 | 2023-12-19 | Clavius Pharmaceuticals, LLC. | Tri-substituted imidazoles for the inhibition of TGF beta and methods of treatment |
JP2021534203A (ja) * | 2018-08-22 | 2021-12-09 | クラヴィウス ファーマシューティカルズ,エルエルシー | Tgf−ベータを阻害するための置換イミダゾールおよび処置方法 |
JP7147048B2 (ja) | 2018-08-22 | 2022-10-04 | クラヴィウス ファーマシューティカルズ,エルエルシー | Tgf-ベータを阻害するための置換イミダゾールおよび処置方法 |
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RU2612958C2 (ru) | 2017-03-14 |
EP2731949B1 (en) | 2018-04-04 |
WO2013009140A2 (en) | 2013-01-17 |
AU2012281281B2 (en) | 2017-06-01 |
TR201808033T4 (tr) | 2018-06-21 |
KR101938368B1 (ko) | 2019-01-14 |
US20130018052A1 (en) | 2013-01-17 |
DK2731949T3 (en) | 2018-06-14 |
BR112014000774A8 (pt) | 2017-10-10 |
AU2012281281A1 (en) | 2014-03-06 |
PL2731949T3 (pl) | 2018-10-31 |
JP6094975B2 (ja) | 2017-03-15 |
US10155763B2 (en) | 2018-12-18 |
EP2731949A4 (en) | 2014-12-17 |
CN103764655A (zh) | 2014-04-30 |
KR20140050048A (ko) | 2014-04-28 |
WO2013009140A3 (en) | 2013-04-11 |
EP2731949A2 (en) | 2014-05-21 |
ES2671581T3 (es) | 2018-06-07 |
RU2014105169A (ru) | 2015-08-20 |
CA2841252A1 (en) | 2013-01-17 |
BR112014000774A2 (pt) | 2016-08-23 |
NO2861601T3 (ja) | 2018-07-07 |
CA2841252C (en) | 2019-02-26 |
PT2731949T (pt) | 2018-06-15 |
BR112014000774B1 (pt) | 2022-03-29 |
MX2014000309A (es) | 2014-02-27 |
MX369576B (es) | 2019-11-13 |
CN103764655B (zh) | 2017-04-12 |
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