JP5602729B2 - キナゾリン化合物、同化合物を含む医薬組成物及び同化合物を含む治療薬 - Google Patents
キナゾリン化合物、同化合物を含む医薬組成物及び同化合物を含む治療薬 Download PDFInfo
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Description
本発明の1つの態様は、下式:
本発明の化合物の例を以下に示す。
本発明のキナゾリン化合物は、EGFRと接触するとこのレセプターの活性を阻害する。したがって、有効な量の1つ以上のこの化合物は、EGFRの過剰発現および過剰活性に関連したがんを治療するために使用することができる。
化合物1の合成経路を以下に示す:
化合物2〜59を実施例1に記載の方法に類似した方法で調製した。
化合物2:
1H NMR(DMSO−d6,400MHz):δ9.83(s,1H),8.88(s,1H),8.79(s,1H)8.43(d,J=8Hz,2H),8.10(s,1H),7.94(t,J=2.4Hz,1H),7.82(t,J=2.0Hz,1H),7.80(d,J=2.0Hz,1H),7.42〜7.36(m,3H),7.09〜7.06(m,3H),4.48(s,2H),3.53(s,1H);MS(m/e):412(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.42(s,1H),8.93(s,1H),8.63(s,1H),8.53(s,1H),8.44(d,J=3.2Hz,2H),8.21(s,1H),7.35(t,J=2.4Hz,1H),7.32〜6.88(m,5H),6.80(d,J=2.0Hz 1H),6.68(d,J=2.4Hz,1H),6.65(s,1H),4.44(s,2H),4.04(s,1H);MS(m/e):395(M+1)。
1H NMR(DMSO−d6,400MHz):9.68(s,1H),9.14(s,1H),8.51(s,1H),8.51(d,J=2.0Hz,1H),8.11(s,1H),7.89(t,J=2.0Hz,2H),7.72(d,J=8Hz,1H),7.40(t,J=3.6Hz,1H),7.21(d,J=4Hz,1H),4.24(s,1H),3.46(s,4H),1.53(s,6H):MS(m/e):372(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.83(s,1H),8.88(s,1H),8.79(s,1H)8.43(d,J=8Hz,2H),8.10(s,1H),7.94(t,J=2.4Hz,1H),7.82(t,J=2.0Hz,1H),7.80(d,J=2.0Hz,1H),7.42〜7.36(m,3H),7.09〜7.06(m,3H),4.48(s,2H),3.53(s,1H);MS(m/e):412(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.83(s,1H),8.87(d,1H),8.79(s,1H)8.43(d,J=8Hz,2H),8.10(s,1H),7.94(t,J=2.4Hz,1H),7.80(d,J=2.0Hz,1H),7.42〜7.36(m,3H),7.09〜7.06(m,3H),4.48(s,2H),3.53(s,1H);MS(m/e):430(M+1)。
1H NMR (DMSO−d6,400MHz):δ9.77(s,1H),8.57(d,J=10.8Hz,1H),8.50(s,1H),8.04(s,1H),7.96(d,J=2Hz,1H),7.89(d,J=8Hz,1H),7.69(d,J=20Hz,1H),7.35(t,J=8.0Hz,1H),4.20(s,1H),2.49(s,4H),1.86(s,4H);MS(m/e):358(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.77(s,1H),9.02(s,1H),8.53(s,1H),8.51(d,J=2Hz,1H),8.05(s,1H),7.88(t,J=8Hz,2H),7.72(d,J=8Hz,1H),7.38(d,J=8Hz,1H),7.20(d,J=7.2Hz,1H),4.18(s,1H),3.65(t,J=4.4Hz,4H),3.51(t,J=4.8Hz,4H);MS(m/e):374(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.77(s,1H),8.99(s,1H),8.52(s,2H),8.05(s,1H),7.93(m,2H),7.69(d,J=8.8Hz,1H),7.38(t,J=8Hz,1H),7.19(d,J=8Hz,1H),4.23(s,1H),2.23−0.91(m,8H),0.91(m,J=2.8Hz,6H);MS(m/e):400(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.83(s,1H),8.75(s,1H),8.52(s,1H),8.44(s,1H),7.90(m,2H),7.71(d,J=8.4Hz,2H),7.39(t,J=8Hz,1H),7.20(d,J=8Hz,1H),4.20(s,1H),3.59(s,4H),3.53(s,4H),3.53(s,6H);MS(m/e):420(M+1)。
1H NMR(CD3OD,400MHz):δ8.5(s 1H),8.06(s 1H),8.05(s,1H),7.68−7.80(d,J=9.2Hz,3H),7.39−7.42(t,J=8.0Hz 1H),7.29−7.31(d,J=3.2Hz,1H),7.20−7.20(d,J=0.4Hz,1H),4.08−4.12(t,J=8.0Hz,2H),3.67−3.73(m,4H),3.21−3.25(m,6H),1.65−1.85(m,6H);MS(m/e):459.3(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.81(s,1H),8.63(s,1H),8.54(s,1H),8.49(s,1H),8.51(s,1H),8.05(s,1H),7.92(m,2H),7.70(d,J=12Hz,1H),7.37(t,J=2.4Hz,1H),7.19(d,J=4Hz,1H),4.17(s,1H),3.71(m,2H),3.76(m,2H),3.16(m,1H),2.70(m,1H),2.18−2.07(m,8H),1.73(m,1H),1.31(m,1H);MS(m/e):441(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.76(s,1H),8.97(s,1H),8.51(d,J=8.8,2H),8.05(s,1H),7.89(t,J=8.8Hz,2H),7.71(d,J=8.8Hz,1H),7.38(t,J=8.0Hz,1H),7.20(d,J=8Hz,1H),4.19(s,1H),3.54(s,4H),2.26(t,J=2Hz,2H),0.87(d,J=4Hz,1H),0.49(d,J=8Hz,2H),0.11(s,2H);MS(m/e):427(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.95(s,1H),8.87(s,1H),8.51(s,1H),8.47(s,1H),8.03(s,1H),7.85(m,2H),7.69(d,J=8.8Hz,1H),7.37(t,J=8.0Hz,1H),7.19(d,J=8Hz,1H),4.41(s,1H),4.08(s,1H),4.05(s,1H),2.94(t,J=10.8Hz,2H),2.17(t,J=4Hz,1H),1.86(t,J=6Hz,2H),1.66(s,4H),1.33(m,2H);MS(m/e):401(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.96(s,1H),9.44(s,1H),8.50(s,1H),8.45(s,1H),8.00(s,1H),7.88(t,J=2.8Hz,1H),7.70(d,J=8.8Hz,1H),7.36(t,J=8.0Hz,1H),7.19(d,J=7.6Hz,1H),6.85(d,J=6Hz,1H),4.19(s,1H),3.33(m,4H),3.22(s,3H);MS(m/e):362(M+1)。
1H NMR(CD3OD,400MHz):δ8.51(s,1H),8.47〜8.46(d,J=2.4Hz,1H),7.97(s,1H),7.93〜7.91(dd,J=2.4Hz,8.8Hz,1H),7.83〜7.81(dd,J=1.6Hz,8.4Hz,1H),7.77〜7.74(d,J=8.8Hz,1H),7.40〜7.36(t,J=8.0Hz,1H),7.28〜7.26(dd,J=1.2Hz,8Hz,1H),3.78〜7.74(t,J=6.4Hz,2H),3.52(s,1H),2.93〜2.90(m,1H),2.86〜2.82(t,J=6.0Hz,2H),1.13〜1.10(m,2H),0.97〜0.95(m,2H);MS(m/e):397.4(M+1)
化合物19:
1H NMR(DMSO−d6,400MHz):δ9.77(s,1H),8.90(s,1H),8.55〜8.55(d,J=2Hz,1H),8,44(s,1H),8.18〜8,17(d,J=1.2Hz,1H),8.07(s,1H),7.94〜7.91(dd,J=2Hz,9.2Hz,1H),7.70〜7.65(m,2H),7.56〜7.54(d,J=8.8Hz,1H),7.43〜7.40(m,1H),7.17〜7.09(m,3H),4.64(s,2H),3.03(s,3H);MS(m/e):417.5(M+1)
化合物20:
1H NMR(DMSO−d6,400MHz):δ9.78(s,1H),8.71(s,1H),8.54〜8.53(d,J=1.6Hz,1H),8.52(s,1H),8.06(s,1H),7.96〜7.90(m,2H).7.71〜7.69(d,J=9.2Hz,1H),7.40〜7.36(t,J=8Hz,1H),7.20〜7.19(d,J=7.2Hz,1H),4.20(s,1H),3.43〜3.41(m,2H),2.99(s,3H),1.13〜1.09(t,J=7.2Hz,3H);MS(m/e):346.4(M+1)
化合物22:
1H NMR(CD3OD,400MHz):δ8.49(s,1H),8.40〜8.39(d,J=2.4Hz,1H),7.99(s,1H),7.94(s,1H),7.80〜7.77(d,J=8.8Hz,1H),7.74〜7.72(d,J=8.8Hz,1H),7.62〜7.57(m,1H),7.39〜7.35(t,J=7.6Hz,1H),7.28〜7.26(d,J=7.6Hz,1H),3.55(s,1H),3.56〜3.49(m,4H),2.85〜2.78(m,6H),1.28〜1.25(t,J=6.8Hz,3H),1.19〜1.15(t,J=6.8Hz,6H);MS(m/e):431.5(M+1)
化合物23:
1H NMR(CD3OD,400MHz):δ8.51(s,1H),8.39〜8.39(d,J=2.4Hz,1H),7.98(s,1H),7.83(s,1H),7.81〜7.78(dd,J=2Hz,9.6Hz,1H),7.75〜7.73(d,J=9.4Hz,1H),7.41〜7.37(t,J=8Hz,1H),7.30〜7.27(m,1H),3.53(s,1H),3.46〜3.43(t,J=7.2Hz,4H),1.68〜1.65(m,4H),1.45〜1.40(m,4H),1.03〜0.99(t,J=7.2Hz,6H);MS(m/e):416.5(M+1)
化合物24:
1H NMR(CD3OD,400MHz):δ8.50(s,1H),8.40〜8.39(d,J=2.0Hz,1H),7.97(s,1H),7.83〜7.81(d,J=8.4Hz,1H),7.75〜7.68(m,2H),7.41〜7.37(t,J=8.4Hz,1H),7.29〜7.27(m,1H),3.61〜3.58(t,J=6.0Hz,2H),3.53(s,1H),3.12(s,1H),2.72〜2.69(t,J=6.0Hz,2H),2.45(s,6H);MS(m/e):389.5(M+1)。
1H NMR(CD3OD,400MHz):δ8.51(s,1H),8.40〜8.39(d,J=2Hz,1H),7.98(s,1H),7.83〜7.80(dd,J=2.4Hz,9.2Hz,1H),7.75〜7.73(d,J=9.2Hz,1H),7.41〜7.27(t,J=8Hz,1H),7.29〜7.27(d,J=7.6Hz,1H),3.53(s,1H),3.53〜3.48(t,J=7.6Hz,2H),3.39〜3.36(t,J=6.8Hz,2H),1.77〜1.71(m,2H),1.15〜1.14(m,1H),1.02〜0.98(t,J=7.2Hz,3H),0.62〜0.58(m,2H),0.37〜0.34(m,2H);MS(m/e):400.5(M+1)
化合物26:
1H NMR(CD3OD,400MHz):δ8.75(s,1H),8.73〜8.72(d,J=2Hz,1H),8.08〜8.05(dd,J=2.4Hz,9.2Hz,1H),7.92〜7.92(d,J=1.2Hz,1H),7.83(s,1H),7.81(s,1H),7.78〜7.75(m,1H),7.50〜7.47(m,2H),3.80〜3.77(t,J=6.4Hz,2H),3.63(s,1H),3.24(s,3H),2.86〜2.83(t,J=6.4Hz,2H);MS(m/e):371.4(M+1)
化合物27:
1H NMR(CD3OD,400MHz):δ8.50(s,1H),8.40〜8.39(d,J=2.4Hz,1H),7.79(s,1H),7.82〜7.79(dd,J=2.0Hz,8.8Hz,2H),7.73〜7.71(d,J=8.8Hz,1H),7.40〜7.36(t,J=8.0Hz,1H),7.28〜7.26(d,J=8.4Hz,1H),3.53(s,1H),3.51〜3.4(q,J=7.2Hz,2H),3.46〜3.42(t,J=7.6Hz,2H),1.68〜1.64(m,2H),1.45〜1.40(m,2H),1.28〜1.25(t,J=7.2Hz,3H),1.02〜0.99(t,J=7.6Hz,3H);MS(m/e):388.5(M+1)
化合物28:
1H NMR(DMSO−d6,400MHz):δ9.76(s,1H),8.91(s,1H),8.53(s,1H),8.49(s,1H),8.04(s,1H),7.90(d,J=8Hz,1H),7.75(d,J=8.8Hz,1H),7.39(t,J=8.0Hz,1H),7.20(d,J=7.6Hz,1H),4.19(s,1H),3.50(s,8H),2.43(s,4H),2.16(s,6H);MS(m/e):444(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.78(s,1H),9.11(s,1H),8.52(s,2H),8.04(s,1H),7.91(d,J=8Hz,2H),7.69(t,J=8.0Hz,1H),7.37(d,J=7.6Hz,1H),7.18(d,J=7.6Hz,1H),4.19(s,1H),3.65−3.23(m,12H),3.14(s,3H);MS(m/e):431(M+1)
化合物30:
1H NMR(DMSO−d6,400MHz):δ9.78(s,1H),9.15(s,1H),8.50(s,1H),8.41(s,1H),8.03(s,1H),7.88(d,J=8Hz,1H),7.84(d,J=8.8Hz,1H),7.70(d,J=8.8Hz,1H),7.38(t,J=8.0Hz,1H),7.20(d,J=7.6Hz,1H),6.45(t,J=2.4Hz,1H),4.19(s,1H),2.38(t,J=6.4Hz,6H),1.52(m,J=5.2,4H),1.40(m,2H),1.23(s,2H);MS(m/e):415(M+1)
化合物32:
1H NMR(DMSO−d6,400MHz):δ9.77(s,1H),9.01(s,1H),8.50(s,1H),8.40(s,1H),8.02(s,1H),7.85(t,J=8.0Hz,2H),7.71(d,J=8.8Hz,1H),7.39(t,J=8.0Hz,1H),7.20(d,J=6.8Hz,1H),6.44(t,J=2.4Hz,1H),4.19(s,1H),3.27(m,4H),2.54(m,4H),1.70(s,4H);MS(m/e):401(M+1)
化合物33:
1H NMR(DMSO−d6,400MHz):δ9.46(s,1H),8.87(s,1H),8.50(s,1H),8.44(s,1H),8.03(s,1H),7.88(d,J=8Hz,2H),7.70(d,J=5.2Hz,1H),7.38(t,J=8.0Hz,2H),7.20(d,J=8Hz,2H),4.21(s,1H),3.20(m,2H),2.95(m,2H);MS(m/e):398(M+1)
化合物34:
1H NMR(CDCl3,400MHz):δ9.79(s,1H),8.50(s,1H),8.45〜8.36(m,2H),8.05(s,1H),7.97〜7.95(d,J=8.4Hz,1H),7.92〜7.90(d,J=8.4Hz,1H),7.68〜7.65(d,J=8.8Hz,1H),7.38〜7.34(t,J=7.6Hz,1H),7.19〜7.17(d,J=7.6Hz,1H),4.19(s,1H),3.58〜3.56(m,2H),1.74〜1.60(m,4H),1.26〜1.23(m,6H),0.91〜0.86(m,6H);MS(m/e):416.5(M+1)
化合物35:
1H NMR(CDCl3,400MHz):δ9.86(s,1H),9.20(s,1H),8,56〜8.56(d,J=2Hz,1H),8.53(s,1H),8.06(s,1H),7.98〜7.95(dd,J=2Hz,8.8Hz,1H),7.93〜7.91(d,J=8.4Hz,1H),7.73〜7.70(d,J=8.8Hz,1H),7.39〜7.35(t,J=7.2Hz,1H),7.20〜7.18(d,J=7.6,1H),4.20(s,1H),3.79〜3.75(t,J=6.8Hz,4H),2.85〜2.82(t,J=6.8Hz,4H);MS(m/e):410.4(M+1)
化合物36:
1H NMR(CDCl3 MHz):δ9.77(s,1H),8,69(s,1H),8,53〜8.51(m,2H),8.05(s,1H),7.95〜7.89(m,2H),7.69〜7.67(d,J=8.8,1H),7.39〜7.35(t,J=7.2Hz,1H),7.19〜7.17(d,J=7.2Hz,1H),4.19(s,1H),2.98(s,3H),1.51〜1.50(m,2H),1.26〜1.25(m,6H),0.84(s,3H);MS(m/e):402.5(M+1)
化合物37:
1H NMR(CD3OD,400MHz):δ8.50(s,1H),8.40〜8.40(d,J=2.0Hz,1H),7.97(s,1H),7.80〜7.77(m,2H),7.74〜7.71(d,J=9.2Hz,1H),7.38〜7.36(t,J=8.0Hz,1H),7.28〜7.27(d,J=7.6Hz,1H),4.29〜4.29(d,J=2.4Hz,2H),3.53(s,1H),3.18(s,3H),2.75〜2.73(t,J=2.4Hz,1H);MS(m/e):356.4(M+1)
化合物38:
1H NMR(DMSO−d6,400MHz):δ8.51(s,1H),8.49(s,1H),7.94(s,1H),7.91〜7.88(dd,J=1.6Hz,9.2Hz,1H),7.80〜7.78(d,J=8.8Hz,1H),7.76〜7.76(d,J=0.8Hz,1H),7.46〜7.44(t,J=8.8Hz,1H),7.38〜7.36(t,J=7.6Hz,1H),7.29〜7.28(m,1H),7.27〜7.24(t,J=8.4Hz,1H),4.60(s,4H),3.51(s,1H);MS(m/e):382.4(M+1)
化合物39:
1H NMR(CDCl3,400MHz):δ9.78(s,1H),8.77(s,1H),8.53〜8.52(d,J=2Hz,1H),8.51(s,1H),8.04(s,1H),7.94〜7.88(m,2H),7.70〜7.68(d,J=8.8Hz,1H),7.39〜7.353(t,J=8Hz,1H),7.19〜7.17(d,J=7.6Hz,1H),5.84〜5.79(m,1H),5.22〜5.16(m,2H),4,19(s,1H),4.02〜4.01(d,J=4.8Hz,2H),2,97(s,1H);MS(m/e):357.4(M+1)
化合物40:
1H NMR(DMSO−d6,400MHz):δ9.81(s,1H),9.23(s,1H),8.52(s,2H),8.49(s,1H),8.04(s,1H),7.90(m,2H),7.70(d,J=8.8Hz,1H),7.37(t,J=7.6Hz,1H),7.18(d,J=7.6Hz,1H),4.19(s,1H),3.87(t,J=8Hz,2H),3.59(s,2H),2.06(m,2H)1.72(s,2H);MS(m/e):408(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.78(s,1H),9.11(s,1H),8.51(s,2H),8.04(s,1H),7.90(d,J=8.8Hz,2H),7.69(d,J=8.8Hz,1H),7.37(t,J=8.0Hz,1H),7.18(d,J=8.8Hz,1H),4.19(s,1H),3.68(m,4H),2.59(m,6H),1.07(m,3H);MS(m/e):401(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.77(s,1H),9.13(s,1H),8.51(s,2H),8.04(s,1H),7.92(t,J=7.6Hz,2H),7.69(d,J=8.8Hz,1H),7.37(t,J=8.0Hz,1H),7.18(d,J=6.0Hz,1H),4.19(s,1H),3.88(s,4H),3.59(t,J=5.2Hz,4H),1.64(t,J=5.2Hz,4H);MS(m/e):430(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.76(s,1H),9.92(s,1H),8.51(s,2H),8.04(s,1H),7.90(d,J=8Hz,2H),7.68(d,J=8.8Hz,1H),7.37(t,J=8.0Hz,1H),7.17(d,J=8.8Hz,1H),4.19(s,1H),2.76(t,J=12Hz,1H),2.41(t,J=10.8Hz,6H),1.66−1.42(m,6H),1.22−1.07(m,8H);MS(m/e):428(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.77(s,1H),8.90(s,1H),8.51(d,J=6.8,2H),8.03(s,1H),7.87(t,J=8.8Hz,2H),7.71(d,J=8.8Hz,1H),7.37(t,J=8.0Hz,1H),7.18(d,J=8Hz,1H),4.18(s,1H),3.67(m,8H),1.15(d,J=2.0Hz,1H),0.79(m,4H);MS(m/e):441(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.79(s,1H),9.18(s,1H),8.54(d,J=4.4Hz,2H),8.05(s,1H),7.89(m,2H),7.74〜7.71(d,J=8.8Hz,1H),7.41〜7.37(t,J=8.0Hz,1H),7.21〜7.19(d,J=7.6Hz,1H),4.20(s,1H),3.65(bs,4H),3.18(bs,4H),2.94(s,3H);MS(m/e):451.5(M+1)。
1H NMR(CD3OD,400MHz):δ8.51(s 1H),8.06(s 1H),8.05(s,1H),7.68−7.80(d,J=9.2Hz,3H),7.39−7.42(t,J=8.0Hz,1H),7.29−7.31(d,J=3.2Hz,1H),7.20−7.20(d,J=0.4Hz,1H),4.08−4.12(t,J=8.0Hz,2H),3.67−3.73(t,J=8.0Hz,2H);MS(m/e):348.1(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.82(s,1H),8.93(s,1H),8.52〜8.46(m,4H),8.03(s,1H),7.90〜7.88(m,2H),7.72〜7.70(m,2H),7.37(s,2H),7.19〜7.18(m,1H),4.74(s,2H),4.20(s,1H),3.33〜3.35(m,2H),1.07〜1.05(m,1H),0.42〜0.41(m,2H),0.23〜0.19(m,2H);MS(m/e):449.5(M+1)
化合物48:
1H NMR(CDCl3,400MHz):δ9.78(s,1H),8.70(s,1H),8.53〜8.48(m,4H),8.02〜7.97(m,2H),7.88〜7.84(m,1H),7.74〜7.65(m,2H),7.32(s,2H),7.19(s,1H),4.54(s,2H),4.19(s,1H),2.65〜2.58(m,1H),0.96〜0.89(m,2H),0.76〜0.75(m,2H);MS(m/e):435.5(M+1)
化合物49:
1H NMR(DMSO−d6,400MHz):δ9.79(s,1H),9.04(s,1H),8.50(s,1H),8.41(s,1H),8.03(s,1H),7.90〜7.84(m,2H),7.71〜7.69(d,J=8.8Hz,1H),7.41〜7.37(t,J=8.0Hz,1H),7.21〜7.19(d,J=7.6Hz,1H),6.82〜6.80(d,J=8.0Hz,1H),4.20(s,1H),3.87〜3.82(m,2H),3.75〜3.73(bs,1H),3.43〜3.38(t,J=9.2Hz,2H),1.85〜1.81(d,J=5.6Hz,2H),1.44〜1.40(m,2H);MS(m/e):388.4(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.79(s,1H),9.09〜9.05(m,1H),8.50(s,1H),8.41(s,1H),8.03(s,1H),7.89〜7.84(m,2H),7.72〜7.70(d,J=9.2Hz,1H),7.41〜7.37(t,J=8.0Hz,1H),7.21〜7.19(d,J=7.2Hz,1H),6.69〜6.65(m,1H),4.20(s,1H),3.73〜3.40(t,J=7.2Hz,2H),2.62〜2.59(t,J=7.2Hz,2H),2.10(s,3H);MS(m/e):378.4(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.79(s,1H),9.02(s,1H),8.50(s,1H),8.41(s,1H),8.03(s,1H),7.89〜7.84(m,2H),7.71〜7.69(d,J=8.8Hz,1H),7.41〜7.37(t,J=8.8Hz,1H),7.21〜7.19(d,J=7.2Hz,1H),6.69(m,1H),4.20(s,1H),3.24〜3.20(t,J=6.8Hz,2H),2.55〜2.53(t,J=7.2Hz,2H),2.06(s,3H),2.55〜2.53(tt,J=6.8Hz,7.2Hz,2H);MS(m/e):392.5(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.83(s,1H),9.37(s,1H),8.54(d,J=8.8,2H),8.08(s,1H),7.93(t,J=8.8Hz,2H),7.74(d,J=9.2Hz,1H),7.39(t,J=8.0Hz,1H),7.20(d,J=7.6Hz,1H),4.23(s,1H),3.55(m,8H);MS(m/e):469(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.77(s,1H),9.01(s,1H),8.52(d,J=6.8,2H),8.05(s,1H),7.88(m,2H),7.72(d,J=7.2Hz,1H),7.39(t,J=8.4Hz,1H),7.20(d,J=7.6Hz,1H),4.20(s,1H),3.66(d,J=6.4Hz,2H),3.54(t,J=5.2Hz,4H),2.66(t,J=4.8Hz,4H);MS(m/e):455(M+1)。
1H NMR(CD3OD,400MHz):δ8.49(s,1H),8.37(s,1H),7.96(s,1H),7.81〜7.79(d,J=7.2Hz,1H),7.74〜7.73(m,2H),7.40〜7.36(t,J=8.0Hz,1H),7.27〜7.25(d,J=7.2Hz,1H),3.64〜3.62(bs,4H),3.52(s,1H),2.53〜2.51(bs,4H),2.35(s,3H);MS(m/e):387.5(M+1)。
1H NMR(CD3OD,400MHz):δ8.48(s,1H),8.37(s,1H),7.96(s,1H),7.81〜7.79(d,J=7.2Hz,1H),7.74〜7.73(m,2H),7.40〜7.36(t,J=8.0Hz,1H),7.27〜7.25(d,J=7.2Hz,1H),3.64〜3.61(bs,4H),3.52(s,1H),2.77〜2.74(m,1H),2.64〜2.62(bs,4H),1.12〜1.10(d,J=6.4Hz,3H);MS(m/e):415.5(M+1)。
1H NMR(CD3OD,400MHz):δ8.48(s,1H),8.37(s,1H),7.96(s,1H),7.81〜7.79(d,J=7.2Hz,1H),7.74〜7.73(m,2H),7.40〜7.36(t,J=8.0Hz,1H),7.27〜7.25(d,J=7.2Hz,1H),4.34〜4.31(d,J=13.6Hz,2H),3.51(s,1H),2.97〜2.91(t,J=12.4Hz,2H),2.52〜2.48(m,1H),2.33(s,6H),2.00〜1.97(d,J=11.6Hz,2H),1.49〜1.45(m,2H);MS(m/e):415.5(M+1)。
1H NMR(CD3OD,400MHz):δ8.48(s,1H),8.37(s,1H),7.96(s,1H),7.81〜7.79(d,J=7.2Hz,1H),7.74〜7.73(m,2H),7.40〜7.36(t,J=8.0Hz,1H),7.27〜7.25(d,J=7.2Hz,1H),4.34〜4.31(d,J=13.6Hz,2H),3.51(s,1H),2.98〜2.91(t,J=13.2Hz,3H),2.73(m,4H),1.96〜1.93(d,J=12.4Hz,2H),1.56〜1.53(m,2H),1.14〜1.10(t,J=7.6Hz,6H);MS(m/e):443.5(M+1)。
MS(m/e):443(M+1)。
化合物59:
MS(m/e):45.2(M+1)。
化合物60の合成経路を以下に示す:
化合物61〜65は実施例60に記載した方法に類似の方法で調製した。
化合物61:
1H NMR(DMSO−d6,400MHz):δ9.88(s,1H),8.71(s,1H),8.59(d,J=6.4Hz,2H),8.05(s 1H),7.90(d,J=9.2Hz,1H),7.61(d,J=7.6Hz,1H),7.41(t,J=8.0Hz,1H),7.24(d,J=8.8Hz,1H),4.22(s,1H),3.65(m,4H),3.49(m,6H);MS(m/e):392(M+1)。
1H NMR(DMSO−d6,400MHz):δ10.04(s,1H),8.79(s,1H),8.67(d,J=0.4Hz,1H),8.56(s,1H),8.07(s,1H),7.92(d,J=8.8Hz,1H),7.60(d,J=10.8Hz,H),7.41(m,2H),7.23(d,J=7.6Hz,1H),7.12(m,3H),4.62(s,1H),4.23(s,1H),3.01(s,1H);MS(m/e):444(M+1)。
1H NMR(DMSO−d6,400MHz):δ10.00(s,1H),8.83(s,1H),8.73(d,J=4Hz,1H),8.56(s,1H),8.00(s,1H),7.78(d,J=8Hz,1H),7.61(d,J=12Hz,1H),7.40(m,J=7.6Hz,1H),7.23(d,J=7.2Hz,1H),4.22(s,1H),3.57(s,8H),3.37(s,6H);MS(m/e):438(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.96(s,1H),8.67(s,1H),8.59(s,1H),8.60(s,1H),8.39(s,1H),8.05(d,J=8.4Hz,1H),7.91(d,J=8.8Hz,1H),7.59(d,J=10.8Hz,1H),7.39(d,J=7.6Hz,1H),7.22(d,J=6Hz,1H),7.13(d,J=2.0Hz,1H),4.22(s,1H),3.68(m,4H),2.22(s,6H),1.80(m,2H);MS(m/e):419(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.93(s,1H),8.73(s,1H),8.58(s,2H),8.06(s,1H),7.91(d,J=8.0Hz,1H),7.58(d,J=8.8Hz,1H),7.40(t,J=6.8Hz,1H),7.23(d,J=8Hz,1H),4.22(s,1H),2.92(t,J=5.2Hz,2H),2.51(m,4H),1.99−1.91(m,4H),1.72−1.42(m,4H),1.23−1.16(m,4H);MS(m/e):459(M+1)。
化合物66の合成経路を以下に示す:
1H NMR(DMSO−d6,400MHz):9.81(s,1H),8.59(s,1H),8.53(s,1H),8.02(s,1H),7.98(s,1H),7.89(d,J=8.8Hz,1H),7.38(t,J=8Hz,1H),7.25(s,1H),7.19(d,J=7.6Hz,1H),4.21(s,1H),3.98(s,3H),3.53−3.51(m,4H),1.60−1.53(s,6H);MS(m/e):402(M+1)。
化合物67〜84は実施例66に記載した方法に類似の方法で調製した。
化合物67:
1H NMR(DMSO−d6,400MHz):9.69(s,1H),8.58(s,1H),8.54(s,1H),8.10(s,1H),8.04(s,1H),7.90(d,J=8.8Hz,1H),7.38(t,J=8Hz,1H),7.26(s,1H),7.19(d,J=7.2Hz,1H),4.19(s,1H),3.99(s,3H),3.64(t,J=4.8Hz,4H),3.49(s,J=4.8Hz,4H);MS(m/e):404(M+1)。
1H NMR(DMSO−d6,400MHz):9.71(s,1H),8.57(s,1H),8.52(s,1H),8.07(s,1H),8.04(s,1H),7.91(d,J=8.8Hz,1H),7.37(t,J=6.4Hz,1H),7.24(s,1H),7.18(d,J=5.2Hz,1H),4.19(s,1H),3.98(s,3H),3.50(m,4H),2.48(m,6H),1.04(s,3H);MS(m/e):431(M+1)。
1H NMR(DMSO−d6,400MHz):9.65(s,1H),8.73(s,1H),8.57(s,1H),8.49(s,1H),8.00(s,1H),7.87(d,J=7.6Hz,1H),7.37(t,J=8Hz,1H),7.24(s,1H),7.17(d,J=7.6Hz,1H),4.19(s,1H),4.01(s,3H),3.56(s,8H),3.36(s,6H);MS(m/e):450(M+1)。
1H NMR(DMSO−d6,400MHz):9.73(s,1H),8.66(s,1H),8.53(s,1H),8.49(s,1H),8.03(s,1H),7.98(s,1H),7.89(d,J=7.2Hz,1H),7.46−7.36(m,3H),7.25−7.13(m,6H),4.63(s,2H),4.19(s,1H),3.98(s,3H),3.04(s,3H);MS(m/e):456(M+1)。
1H NMR(DMSO−d6,400MHz):9.66(s,1H),8.88(s,1H),8.48(s,1H),8.41(s,1H),7.98(s,1H),7.85(d,J=8.0Hz,1H),7.37(t,J=8.0Hz,1H),7.12(s,1H),7.15(d,J=7.2Hz,1H),4.18(s,1H),4.03(s,3H),3.43−3.30(m,7H);MS(m/e):392(M+1)。
1H NMR(DMSO−d6,400MHz):9.76(s,1H),8.62(s,1H),8.51(s,1H),8.36(s,1H),8.00(s,1H),7.87(d,J=7.6Hz,1H),7.37(t,J=8.0Hz,1H),7.26(s,1H),7.18(d,J=7.6Hz,1H),4.21(s,1H),4.01(s,3H),3.54(dd,J=4.0Hz,4.0Hz,4H),3.46(s,3H),3.16(s,3H);MS(m/e):406(M+1)。
1H NMR(DMSO−d6,400MHz):9.68(s,1H),8.57(s,1H),8.50(s,1H),8.04(s,1H),8.00(s,1H),7.89(d,J=7.6Hz,1H),7.35(t,J=8.0Hz,1H),7.24(s,1H),7.17(d,J=7.6Hz,1H),4.20(s,1H),3.98(s,3H),3.42−3.40(m,2H),2.99(s,3H),2.80−2.74(m,6H),1.09(m,6H);MS(m/e):447(M+1)。
1H NMR(DMSO−d6,400MHz):9.69(s,1H),8.56(s,1H),8.53(s,1H),8.05(s,1H),8.04(s,1H),7.90(d,J=7.6Hz,1H),7.38(t,J=8Hz,1H),7.26(s,1H),7.19(d,J=7.6Hz,1H),4.21(s,1H),3.99(s,3H),3.58(m,4H),2.36(m,4H),2.23(s,3H);MS(m/e):417(M+1)。
1H NMR(DMSO−d6,400MHz):9.70(s,1H),8.57(s,1H),8.53(s,1H),8.04(s,2H),7.90(d,J=8.0Hz,1H),7.38(t,J=8.0Hz,1H),7.25(s,1H),7.19(d,J=8.0Hz,1H),4.21(s,1H),3.99(s,3H),3.50(m,4H),2.49(m,4H),2.24(m,2H),0.85−0.11(m,5H);MS(m/e):457(M+1)。
1H NMR(DMSO−d6,400MHz):9.69(s,1H),8.56(s,1H),8.53(s,1H),8.04(s,2H),7.90(d,J=8.0Hz,1H),7.38(t,J=8.0Hz,1H),7.25(s,1H),7.19(d,J=7.6Hz,1H),4.21(s,1H),4.11(m,2H),4.03(s,3H),2.95(m,2H),2.73(m,4H),2.21(m,1H),1.88(m,2H),1.71(m,4H),1.41(m,2H);MS(m/e):458(M+1)。
1H NMR(DMSO−d6,400MHz):9.69(s,1H),8.56(s,1H),8.53(s,1H),8.04(s,2H),7.90(d,J=7.6Hz,1H),7.38(t,J=8.0Hz,1H),7.25(s,1H),7.19(d,J=7.6Hz,1H),4.21(s,1H),4.14(m,2H),3.99(s,3H),2.86(m,2H),2.20(s,6H),1.78(m,2H),1.35(m,2H),1.24(m,1H);MS(m/e):445(M+1)。
1H NMR(DMSO−d6,400MHz):9.66(s,1H),8.61(s,1H),8.52(s,2H),8.04(s,1H),7.91(d,J=7.2Hz,1H),7.38(t,J=8.0Hz,1H),7.22(s,1H),7.21(d,J=7.2Hz,1H),4.26(m,2H),4.18(s,1H),3.50(m,4H),2.51(m,2H),2.41(m,4H),1.49(m,3H),1.04(m,3H);MS(m/e):445(M+1)。
1H NMR(DMSO−d6,400MHz):8.53(s,1H),8.34−8.31(m,3H),7.83(dd,J=2.0Hz,J=1.6Hz,1H),7.60(d,J=9.2Hz,1H),7.47(s,1H),7.7.45(s,1H),7.31(t,J=7.6Hz,2H),7.21(t,J=7.2Hz,1H),5.61−5.58(m,1H),3.79−3.77(m,1H),3.66−3.64(m,1H),3.39−3.37(m,2H),3.18−3.17(m,2H),2.40(s,6H),2.25−2.24(m,1H),1.58(d,J=7.6Hz,3H);MS(m/e):405(M+1)。
1H NMR(DMSO,400MHz):8.52(s,1H),8.28(s,2H),7.63(s,1H),7.48(d,J=7.6Hz,2H),7.24−7.14(m,4H),5.80−5.77(m,1H),3.99(s,3H),3.78−3.89(m,4H),3.29−3.22(m,2H),2.33(s,6H),2.25−2.24(m,1H),1.56(d,J=7.2Hz,3H);MS(m/e):453(M+1)。
1H NMR(DMSO−d6,400MHz):8.74(s,1H),8.48(s,1H),8.29(s,1H),7.56(s,1H),7.23−7.15(m,6H),3.96(s,3H),3.72−3.57(m,3H),3.32−3.29(m,2H),2.82−2.78(m,2H),2.23(s,6H),1.34(s,4H);MS(m/e):447(M+1)。
1H NMR(DMSO−d6,400MHz):9.54(s,1H),8.61(s,1H),8.44(s,1H),7.69(s,2H),7.48(d,J=8.0Hz,2H),7.23−7.19(m,3H),3.99(s,3H),3.80−3.66(m,2H),3.45−3.40(m,2H),3.18−3.06(m,3H),2.90−2.83(m,6H),2.08−2.01(m,3H),1.24−1.18(m,3H);MS(m/e):447(M+1)。
化合物85の合成経路を以下に示す:
実施例86〜90:化合物86〜90の合成
化合物86〜90は実施例85に記載した方法に類似の方法で調製した。
1H NMR(DMSO−d6,400MHz):δ9.85(s,1H),8.56〜8.54(d,J=9.2,1H),8.52(s,1H),8.13(s,1H),7.98〜7.96(d,J=8.8Hz,1H),7.84(s,1H),7.69〜7.66(d,J=9.6Hz,1H),7.40〜7.36(t,J=7.6Hz,1H),7.20〜7.18(d,J=7.5Hz,1H),4.20(s,1H),2.99(s,3H),2.87〜2.85(m,2H),2.66〜2.56(m,6H),1.03〜0.99(t,J=7.2Hz,6H);MS(m/e):417.5(M+1)。
1H NMR(DMSO−d6,400Hz):δ9.90(s,1H),8.97(s,1H),8.59〜8.457(d,J=9.2Hz,1H),8.53(s,1H),8.15(s,1H),8.02〜8.02(d,J=1.6Hz,1H),8.00〜7.98(d,J=7.6Hz,1H),7.85〜7.83(dd,J=1.6Hz,8.8Hz,1H),7.39〜7.35(t,J=8.0Hz,1H),7.20〜7.18(d,J=7.6Hz,1H),5.88〜5.79(m,1H),5.21〜5.16(m,2H),4.20(s,1H),4.03〜4.02(d,J=5.2Hz,2H),3.15(s,3H);MS(m/e):358.4(M+1)。
1H NMR(DMSO−d6,400MHz):δ10.13(s,1H),9.86(s,1H),8.56〜8.54(d,J=9.2Hz,1H),8.52(s,1H),8.12(s,1H),7.97(s,1H),7.95(s,1H),7.58〜7.56(d,J=9.2Hz,1H),7.49〜7.46(t,J=6.4Hz,1H),7.39〜7.33(m,5H),7.27〜7.23(m,1H),7.20〜7.18(d,J=7.2Hz,1H),4.36〜4.34(d,J=6.0Hz,2H),4.21(s,1H);MS(m/e):394.4(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.91(s,1H),8.59〜8.57(d,J=9.2Hz,1H),8.53(s,1H),8.14(s,1H),8.02〜8.01(d,J=2.0Hz,1H),7.99〜7.98(d,J=7.6Hz,1H),7.85〜7.82(dd,J=1.6Hz,8.8Hz,1H),7.39〜7.35(t,J=8Hz,1H),7.20〜7.18(d,J=8Hz,1H),4.21(s,1H),3.64〜3.62(m,4H),3.54〜3.52(m,4H);MS(m/e):374.4(M+1)
化合物90:
1H NMR(DMSO−d6,400MHz):δ9.73(s,1H),8.79(s,1H),8.54(s,1H),8.46〜8.44(d,J=9.6Hz,1H),8.11(s,1H),7.96(s,1H),7.95〜7.93(d,J=8Hz,1H),7.80〜7.77(t,J=1.2Hz,9.2),7.41〜7.37(t,J=15.2Hz,1H),7.21〜7.19(d,J=8Hz,1H),4.21(s,1H),3.55〜3.51(m,2H),3.30(s,1H),3.04(s,1H);MS(m/e):376.4(M+1)。
化合物91の合成経路を以下に示す。
化合物92〜125は実施例91に記載の方法に類似した方法で調製した。
化合物92:
1H NMR(CD3OD,400MHz):8.59(d,J=2.0Hz,1H),8.37(s,1H),7.93(dd,J=2.4Hz,J=2.4Hz,1H),7.72(d,J=8.8Hz,1H),7.47(t,J=6.8Hz,1H),7.28−7.25(m,1H),7.11(q,1H),5.87−5.84(m,1H),3.38(s,2H),3.04(m,4H),2.86(m,4H),2.66(s,3H),1.71(d,J=7.2Hz,3H),MS(m/e):423(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.99(s,1H),9.88(s,1H),8.66(s,1H),8.57(s,1H),8.06(d,J=9.2Hz,1H),8.03(s,1H),7.89(d,J=8.0Hz,1H),7.78(d,J=8.8Hz,1H),7.41(t,J=8.0Hz,1H),7.23(d,J=7.2Hz,1H),4.23(s,1H),3.20(d,2H),3.17(d,J=4.4Hz,1H),2.60(m,8H),2.6(m,8H),2.35(t,J=6.8Hz,3H);MS(m/e):415(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.97(s,1H),9.88(s,1H),8.66(d,J=1.6Hz,1H),8.57(s,1H),8.06(d,J=9.2Hz,1H),8.03(s,1H),7.89(d,J=8.0Hz,1H),7.78(d,J=9.2Hz,1H),7.41(t,J=8.0Hz,1H),7.23(d,J=8.0Hz,1H),4.23(s,1H),3.19(d,2H),2.6(m,8H),0.99(d,J=6.8Hz,6H);MS(m/e):429(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.96(s,1H),8.79(s,1H),8.58(s,1H),8.12(d,J=8.8Hz,1H),8.07(s,1H),7.92(d,J=7.6Hz,1H),7.80(d,J=8.4Hz,1H),7.40(t,J=7.2Hz,1H),7.22(d,J=7.2Hz,1H),4.23(s,1H),3.39(s,2H),2.98(m,8H),1.13(s,6H);MS(m/e):417(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.94(s,1H),8.73(s,1H),8.57(s,1H),8.11(d,J=6.4Hz,1H),8.05(s,1H),7.90(d,J=8.0Hz,1H),7.79(d,J=9.2Hz,1H),7.39(t,J=7.6Hz,1H),7.21(d,J=7.6Hz,1H),4.21(s,1H),3.39(s,2H),3.34(m,4H),2.79(s,6H);MS(m/e):389(M+1)。
MS(m/e):413.2(M+1)。
化合物98:
1H NMR(DMSO,400MHz):δ10.09(s,1H),9.92(s,1H),8.62(s,1H),8.57(s,1H),8.10(d,J=8.8Hz,1H),8.02(s,1H),7.99(d,J=8.0Hz,1H),7.81(d,J=8.8Hz,1H),7.41(t,J=8.0Hz,1H),7.22(d,J=7.6Hz,1H),4.21(s,1H),3.47(t,J=4.2Hz,4H),3.39(s,2H),3.26(s,6H),2.85(t,J=3.9Hz,4H);MS(m/e):434(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.98(s,1H),9.85(s,1H),8.62(d,J=2.0Hz,1H),8.57(s,1H),8.10(dd,J=8.8,2.0Hz 1H),8.03(s,1H),7.88(dd,J=8.4,1.2Hz 1H),7.78(d,J=9.2Hz,1H),7.41(t,J=7.6Hz,1H),7.23(d,J=8.0Hz,1H),4.23(s,1H),3.18(s,2H),2.90(d,J=12.0Hz,2H),2.48(s,3H),2.22(t,J=11.2Hz,2H),1.97(t,J=9.6Hz,1H),1.85(d,J=12.0Hz,2H),1.67(d,4H),1.55(m,2H);MS(m/e):455(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.98(s,1H),9.86(s,1H),8.64(d,J=1.6Hz,1H),8.57(s,1H),8.05(dd,J=8.8,2.0Hz 1H),8.03(s,1H),7.89(dd,J=8.4,1.2Hz 1H),7.78(d,J=9.2Hz,1H),7.41(t,J=8.0Hz,1H),7.23(d,J=8.0Hz,1H),4.23(s,1H),3.20(s,2H),2.56(m,8H),2.37(m,4H),2.14(s,6H);MS(m/e):458(M+1)。
MS(m/e):475(M+1)。
化合物103:
1H NMR(DMSO−d6,400MHz):δ9.97(s,1H),9.86(s,1H),8.64(d,J=1.6Hz,1H),8.57(s,1H),8.06(dd,J=9.2,2.0Hz 1H),8.03(s,1H),7.89(dd,J=8.4,1.2Hz 1H),7.78(d,J=8.4Hz,1H),7.41(t,J=8.0Hz,1H),7.23(d,J=7.6Hz,1H),4.23(s,1H),3.21(s,2H),2.56(m,8H),2.20(d,J=6.4Hz,2H),1.24(s,1H),0.83(m,1H),0.46(m,2H),0.80(m,2H);MS(m/e):441(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.99(s,1H),9.86(s,1H),8.65(d,J=1.2Hz,1H),8.57(s,1H),8.06(dd,J=8.8,2.0Hz 1H),8.03(s,1H),7.89(dd,J=8.4,1.2Hz 1H),7.79(d,J=9.2Hz,1H),7.41(t,J=8.0Hz,1H),7.23(d,J=7.6Hz,1H),4.23(s,1H),3.38(s,2H),3.17(d,J=5.2Hz,1H),2.86(t,J=5.6Hz,4H),2.62(d,J=4.8Hz,4H)2.31(s,3H),1.80(m,2H),1.24(s,1H);MS(m/e):415(M+1)
化合物105:
MS(m/e):431(M+1)。
MS(m/e):427.2(M+1)。
化合物107:
1H NMR(DMSO−d6,400MHz):δ9.94(s,1H),9.84(s,1H),8.63(s,1H),8.55(s,1H),8.03(m,2H),7.88(d,J=8.0Hz,1H),7.77(d,j=9.2Hz,1H),7.37(t,J=8.0Hz,1H),7.20(d,j=7.6Hz,1H),4.20(s,1H),3.16(s,2H),2.95(d,j=11.2Hz,2H),2.39(m,5H),2.17(t,j=8.8Hz,2H),1.62(m,4H),1.35(m,4H),0.83(t,j=7.6Hz,6H);MS(m/e):485.3(M+1)。
1H NMR(DMSO−d6,400MHz):δ10.09(s,1H),9.86(s,1H),8.68(s,1H),8.57(s,1H),8.02(m,2H),7.88(d,J=8.0Hz,1H),7.79(d,j=9.2Hz,1H),7.41(t,J=8.0Hz,1H),7.23(d,J=7.6Hz,1H),4.20(s,1H),3.78(s,2H),3.58(s,2H),3.28(s,2H),2.63(s,2H),2.51(s,2H),1.99(s,1H),0.73(m,4H);MS(m/e):455.2(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.96(s,1H),9.84(s,1H),8.62(s,1H),8.57(s,1H),8.09(d,J=8.8Hz,1H),8.02(s,1H),7.88(d,J=8.0Hz,1H),7.79(t,J=8.8Hz,1H),7.41(t,J=8.0Hz,1H),7.23(d,J=8.0Hz,1H),4.22(s,1H),3.57(m,1H),3.17(s,2H),2.80(m,2H),2.30(m,2H),1.78(m,2H),1.54(m,2H);MS(m/e):402.1(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.95(s,1H),9.84(s,1H),8.61(s,1H),8.55(s,1H),8.09(m,2H),7.86(d,j=8.8Hz,1H),7.76(d,j=9.2Hz,1H),7.79(t,j=8.0Hz,1H),7.21(d,j=7.6Hz,1H),4.21(s,1H),3.42(t,j=6.0Hz,2H),3.22(s,3H),3.17(s,2H),2.49(m,10H);MS(m/e):445.2(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.95(s,1H),9.84(s,1H),8.64(s,1H),8.57(s,1H),8.08(d,j=8.8Hz,1H),8.03(s,1H),7.89(d,j=8.1Hz,1H),7.78(d,j=9.2Hz,1H),7.40(t,j=8.4Hz,1H),7.23(d,j=7.6Hz,1H),4.21(s,1H),3.18(s,2H),2.95(d,j=10.8Hz,2H),2.40(s,3H),2.30(m,4H),2.18(m,7H),1.76(m,2H),1.56(m,2H);MS(m/e):484.0(M+1)。
1H NMR(CD3OD,400MHz):δ8.69(s,1H),8.51(s,1H),7.94(s,1H),7.81〜7.75(m,3H),7.40〜7.36(t,J=8.0Hz,1H),7.28〜7.26(d,J=8.0Hz,1H),3.51(s,1H),2.86〜2.82(m,2H),2.69〜2.65(m,10H),1.11〜1.09(d,J=6.0Hz,6H);MS(m/e):443.5(M+1)。
1H NMR(CD3OD,400MHz):δ8.65(s,1H),8.52(s,1H),7.95〜7.89(m,2H),7.81〜7.77(m,2H),7.40〜7.36(t,J=8.0Hz,1H),7.29〜7.27(d,J=8.0Hz,1H),3.50(s,1H),2.72(m,8H),1.38〜1.36(d,J=6.8Hz,3H),1.12〜1.01(d,J=6.4Hz,6H);MS(m/e):443.5(M+1)。
1H NMR(DMSO−d6,400MHz):10.27(s,1H),10.04(s,1H),9.28(s,1H),8.58(s,1H),8.44(d,J=7.2Hz,1H),8.29(s,1H),8.16(d,J=7.6Hz,1H),7.78(d,J=8.8Hz,1H),7.39(t,J=7.6Hz,1H),7.21(d,J=7.2Hz,1H),4.22(s,1H),2.51(s,8H),1.26(s,6H),1.21(s,3H);MS(m/e):429(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.97(s,1H),9.84(s,1H),8.78(s,1H),8.56(s,1H),8.16(d,J=9.2Hz,1H),8.07(s,1H),7.93(d,J=8.4Hz,1H),7.78(d,J=9.2Hz,1H),7.41(t,J=8.4Hz,1H),7.22(d,J=8.0Hz,1H),4.23(s,1H),2.61(s,8H),1.24(s,6H),1.01(d,J=10.8Hz,1H),0.98−0.96(m,1H);MS(m/e):457(M+1)。
1H NMR(DMSO−d6,400MHz):9.99(s,1H),9.87(s,1H),8.73(s,1H),8.56(s,1H),8.15(d,J=7.6Hz,1H),8.08(s,1H),8.7.95(d,J=7.2Hz,1H),7.78(d,J=10.2Hz,1H),7.41(t,J=7.6Hz,1H),7.22(d,J=8.0Hz,1H),4.23(s,1H),3.15(d,J=4.8Hz,1H)2.55(s,8H),1.25(s,6H),1.02−0.971(m,3H);MS(m/e):443(M+1)。
1H NMR(DMSO−d6,400MHz):δ9.86(s,1H),9.42(s,1H),8.68(s,1H),8.57(s,1H),8.18(d,J=7.2Hz,1H),8.05(s,1H),7.92(d,J=7.6Hz,1H),7.58(d,J=7.2Hz,1H),7.39(t,J=6.0Hz,1H),7.22(d,J=7.6Hz,1H),6.14(s,1H),4.22(s,1H),3.09−3.06(m,2H),1.49(s,3H),1.32(s,6H);MS(m/e):374(M+1)。
1H NMR(DMSO−d6,400MHz):δ10.00(s,1H),9.82(s,1H),9.04(s,1H),8.52(s,1H),7.96(s,1H),7.85〜7.83(d,J=7.2Hz,1H),7.40〜7.36(t,J=8.0Hz,1H),7.19(s,1H),4.20(s,1H),4.07(s,3H),3.34(s,2H),2.61〜2.58(m,4H),2.48〜2.36(m,4H),1.05〜1.02(t,J=9.6Hz,3H);MS(m/e):445.5(M+1)。
1H NMR(DMSO−d6,400MHz):δ10.04(s,1H),9.82(s,1H),9.04(s,1H),8.52(s,1H),7.96(s,1H),7.85〜7.83(d,J=7.2Hz,1H),7.40〜7.36(t,J=8.0Hz,1H),7.19(s,1H),4.20(s,1H),4.07(s,3H),3.2(s,2H),2.61〜2.58(m,4H),2.48〜2.36(m,8H),1.10(bs,6H);MS(m/e):459.5(M+1)。
1H NMR(DMSO−d6,400MHz):10.00(s,1H),9.83(s,1H),9.04(s,1H),8.53(s,1H),7.96(s,1H),7.84(d,J=7.6Hz,1H),7.38(t,J=8.0Hz,1H),7.32(s,1H),7.20(d,J=7.6Hz,1H),4.21(s,1H),4.08(s,3H),3.22(s,2H),2.60(m,8H),2.23(s,3H);MS(m/e):431(M+1)。
1H NMR(DMSO−d6,400MHz):δ10.16(s,1H),9.81(s,1H),9.08(s,1H),8.52(s,1H),7.97(s,1H),7.84(d,J=8.8Hz,1H),7.38(t,J=8.0Hz,1H),7.32(s,1H),7.20(d,J=8.0Hz,1H),4.21(s,1H),4.06(s,3H),3.46(t,J=5.2Hz,1H),3.26(s,3H),2.76(t,J=5.2Hz,1H),1.24(s,1H);MS(m/e):406(M+1)。
1H NMR(CD3OD,400MHz):δ8.93(s,1H),8.48(s,1H),7.93(s,1H),7.77(d,J=8.0Hz,1H),7.38(t,J=7.6Hz,1H),7.27(t,J=7.2Hz,2H),4.14(s,3H),3.37(s,1H),3.25(s,2H),3.12−3.09(m,3H),2.42−2.37(m,2H),2.02−2.00(m,2H),1.80−1.77(m,2H),1.31−1.25(m,4H),1.20(s,6H);MS(m/e):487(M+1)。
1H NMR(DMSO−d6,400MHz):δ10.04(s,1H),9.81(s,1H),9.02(s,1H),8.53(s,1H),7.97(s,1H),7.85(d,J=8.0Hz,1H),7.38(t,J=8.0Hz,1H),7.32(s,1H),7.20(d,J=7.6Hz,1H),4.19(s,1H),4.07(s,3H),3.21(s,2H),2.68−2.60(m,4H),1.22(s,3H),1.02−0.97(m,6H);MS(m/e):445(M+1)。
1H NMR(DMSO−d6,400MHz):δ10.52(s,1H),9.94(s,1H),8.95(s,1H),8.57(s,1H),7.99(s,1H),7.86(d,J=9.2Hz,1H),7.39(t,J=8.4Hz,1H),7.33(s,1H),6.76(d,J=7.6Hz,1H),4.23(s,1H),4.04(s,3H),2.98(s,8H),2.78−2.75(m,3H),2.34−2.30(m,2H),1.37(s,6H);MS(m/e):473(M+1)。
化合物127は実施例126に記載の方法に類似した方法で調製した。
化合物128の合成経路を以下に示す:
化合物129〜156は実施例128に記載の方法に類似した方法で調製した。
化合物129:
1H NMR(DMSO−d6,400MHz):10.06(s,1H),8.71(s,1H),8.7−0(s,1H),8.51〜8.48(dd,J=1.6Hz,8.4Hz,1H),8.09(s,1H),7.99〜7.97(d,J=8.0Hz,1H),7.89〜7.8 7(d,J=8.8Hz,1H),7.45〜7.41(t,J=8.0Hz,1H),7.34〜7.33(d,J=3.2Hz,1H),7.26〜7.24(d,J=7.2Hz,1H),6.93〜6.92(d,J=3.2Hz,1H),4.23(s,1H),3.77〜3.74(t,J=6.4Hz,2H),3.61〜3.55(m,4H),2.61〜2.56(t,J=6.4Hz,2H),2.48〜2.24(m,4H);MS(m/e):441.5(M+1)。
1H NMR(DMSO−d6,400MHz):10.04(s,1H),8.69(s,1H),8.63(s,1H),8.49〜8.46(dd,J=1.6Hz,8.4Hz,1H),8.08(s,1H),7.99〜7.97(d,J=8.0Hz,1H),7.89〜7.8 7(d,J=8.8Hz,1H),7.45〜7.41(t,J=8.0Hz,1H),7.34〜7.33(d,J=3.2Hz,1H),7.26〜7.24(d,J=7.2Hz,1H),6.96〜6.95(d,J=3.2Hz,1H),4.23(s,1H),3.86〜3.83(t,J=6.8Hz,2H),2.84〜2.80(t,J=6.8Hz,2H),2.12(s,3H);MS(m/e):402.5(M+1)。
1H NMR(DMSO−d6,400MHz):9.74(s,1H),8.67(s,1H),8.63(s,1H),8.45〜8.43(dd,J=2.4Hz,8.8Hz,1H),8.07(s,1H),7.97〜7.95(d,J=8.0Hz,1H),7.89〜7.87(d,J=8.8Hz,1H),7.45〜7.41(t,J=8.0Hz,1H),7.31〜7.30(d,J=3.2Hz,1H),7.26〜7.24(d,J=7.2Hz,1H),7.08〜7.07(d,J=3.2Hz,1H),4.23(s,1H),4.14〜4.10(m,1H),3.99〜3.96(m,2H),3.50〜3.45(t,J=8.4Hz,2H),1.91〜1.86(m,2H),1.79〜1.75(m,2H);MS(m/e):412.4(M+1)。
1H NMR(DMSO−d6,400MHz):9.74(s,1H),8.67(s,1H),8.63(s,1H),8.45〜8.43(dd,J=2.4Hz,8.8Hz,1H),8.07(s,1H),7.97〜7.95(d,J=8.0Hz,1H),7.89〜7.87(d,J=8.8Hz,1H),7.45〜7.41(t,J=8.0Hz,1H),7.31〜7.30(d,J=3.2Hz,1H),7.26〜7.24(d,J=7.2Hz,1H),7.08〜7.07(d,J=3.2Hz,1H),4.23(s,1H),3.98〜3.97(m,1H),3.25〜3.24(m,2H),3.03〜2.99(m,2H),2.29(s,3H),1.95〜1.80(m,4H);MS(m/e):425.2(M+1)。
1H NMR(DMSO−d6,400MHz):9.93(s,1H),8.63(s,2H),8.46〜8.43(dd,J=2.8Hz,8.8Hz,1H),8.06(s,1H),7.96〜7.94(d,J=8.4Hz,2H),7.45〜7.41(t,J=8.0Hz,1H),7.26〜7.24(m,2H),6.93(s,1H),4.24(s,1H),3.65〜3.62(t,J=6.8Hz,2H),1.67〜1.64(m,2H),1.35〜1.24(m,2H),0.95〜0.91(t,J=7.2Hz,3H);MS(m/e):384.4(M+1)。
MS(m/e):466.5(M+1)。
化合物135:
1H NMR(CD3OD,400MHz):8.79(s,1H),8.62(s,1H),8.55〜8.33(d,J=8.8Hz,1H),8.13(s,1H),8.04〜8.02(d,J=8.0Hz,1H),7.88〜7.85(d,J=8.0Hz,1H),7.46〜7.40(m,2H),6.91〜6.90(d,J=3.2Hz,1H),4.23(s,1H),3.74〜3.71(t,J=6.4Hz,2H),2.57〜2.54(t,J=6.4Hz,2H),2.27(s,6H);MS(m/e):399.4(M+1)。
1H NMR(DMSO−d6,400MHz):10.41(s,1H),8.84(s,1H),8.62(s,1H),8.06(s,1H),8.57〜8.54(dd,J=2.4Hz,8.8Hz,1H),8.17(s,1H),8.07〜8.05(d,J=8.8Hz,1H),7.87〜7.85(d,J=9.2Hz,1H),7.58〜7.57(d,J=3.6Hz,1H),7.42〜7.39(t,J=8.0Hz,1H),7.24〜7.18(m,2H),6.90(s,1H),6.61(d,J=3.2Hz,1H),4.35〜4.32(t,J=6.0Hz,2H),4.24(s,1H),4.02〜3.99(t,J=6.0Hz,2H);MS(m/e):422.5(M+1)。
1H NMR(CD3OD,400MHz):8.66〜8.53(m,4H),8.27〜8.24(dd,J=2.0Hz,9.2Hz,1H),7.91〜7.79(m,4H),7.50(m,1H),7.43〜7.39(t,J=8.0Hz,1H),7.31〜7.29(d,J=7.6Hz,1H),7.18〜7.17(d,J=3.2Hz,1H),6.90〜6.89(d,J=3.2Hz,1H),5.02(s,2H),3.38(s,1H);MS(m/e):419.5(M+1)。
1H NMR(DMSO−d6,400MHz):9.96(s,1H),8.66(s,1H),8.63(s,1H),8.45〜8.43(d,J=8.4Hz,1H),8.05(s,1H),7.95〜7.87(m,2H),7.45〜6.99(m,8H),6.99(s,1H),6.61(d,J=3.2Hz,1H),4.88(s,2H),4.24(s,1H);MS(m/e):436.5(M+1)。
1H NMR(DMSO−d6,400MHz):10.04(s,1H),8.68(s,1H),8.62(s,1H),8.46〜8.44(d,J=9.2Hz,1H),8.07(s,1H),7.97〜7.95(d,J=7.6Hz,1H),7.88−7.86(d,J=9.2Hz,1H),7.44〜7.40(t,J=8.0Hz,1H),7.28(s,1H),7.25〜7.23(d,J=7.2Hz,1H),6.81(s,1H),4.24(s,1H),3.07(s,1H),0.90(bs,4H);MS(m/e):368.4(M+1)。
1H NMR(CD3OD,400MHz):8.60(s,1H),8.58〜8.57(d,J=2.4Hz,1H),8.25〜8.22(dd,J=2.0Hz,9.2Hz,1H),8.01(s,1H),7.90〜7.88(d,J=9.2Hz,1H),7.86〜7.84(d,J=8.4Hz,1H),7.43〜7.39(t,J=8.0Hz,1H),7.31〜7.29(d,J=7.6Hz,1H),7.12(s,1H),6.86(s,1H),4.59〜4.57(m,1H),3.56(s,1H),2.16〜2.12(m,2H),1.92〜1.76(m,6H);MS(m/e):396.4(M+1)。
1H NMR(DMSO−d6,400MHz):9.92(s,1H),8.63(s,2H),8.42〜8.39(dd,J=2.4Hz,9.2Hz,1H),8.01(s,1H),7.95〜7.93(d,J=9.2Hz,1H),7.88〜7.86(d,J=9.2Hz,1H),7.44〜7.40(t,J=8.0Hz,1H),7.25〜7.23(m,2H),7.03(s,1H),4.23(s,1H),4.10(bs,1H),3.04(s,2H),1.88(bs,8H),1.03(bs,3H);MS(m/e):439.4(M+1)。
1H NMR(CD3OD,400MHz):9.88(s,1H),8.64(s,1H),8.61(s,1H),8.42〜8.40(d,J=8.8Hz,1H),8.04(s,1H),7.93〜7.88(m,2H),7.50〜7.49(d,J=4.8Hz,1H),7.45〜7.41(t,J=7.6Hz,1H),7.26〜7.24(d,J=7.6Hz,1H),7.23〜7.22(d,J=2.8Hz,1H),7.15(s,1H),7.04〜7.02(t,J=4.0Hz,1H),6.97〜6.96(d,J=2.8Hz,1H),5.04(s,2H),4.24(s,1H);MS(m/e):424.5(M+1)。
1H NMR(DMSO−d6,400MHz):9.93(s,1H),8.64(s,1H),8.63(s,1H),8.44〜8.42(dd,J=2.0Hz,8.8Hz,1H),8.05(s,1H),7.95〜7.93(d,J=8.4Hz,1H),7.90〜7.88(d,J=8.8Hz,1H),7.45〜7.43(t,J=8.0Hz,1H),7.27〜7.25(m,2H),6.86〜6.85(d,J=3.2Hz,1H),6.00〜5.93(m,1H),5.24〜5.16(m,2H),4.29〜4.27(d,J=5.2Hz,2H),4.24(s,1H);MS(m/e):368.4(M+1)。
1H NMR(DMSO−d6,400MHz):9.89(s,1H),8.62(bs,2H),8.42(bs,1H),8.05(s,1H),7.91〜7.80(m,2H),7.44(bs,1H),7.25〜7.14(m,2H),6.99(s,1H),4.25(s,1H),3.61(bs,2H),3.26(bs,2H),3.04〜2.90(m,2H),2.08(bs,2H),1.93〜1.88(m,4H);MS(m/e):453.5(M+1)。
1H NMR(CD3OD,400MHz):9.91(s,1H),8.64(s,1H),8.63〜8.62(d,J=2.0Hz,1H),8.39〜8.36(dd,J=1.6Hz,9.2Hz,1H),8.04(s,1H),7.93〜7.89(m,2H),7.46〜7.42(t,J=8.0Hz,1H),7.27(s,1H),7.25〜7.24(d,J=3.2Hz,1H),6.97〜6.96(d,J=3.2Hz,1H),4.52〜4.51(d,J=2.0Hz,2H),4.25(s,1H),3.44(s,1H);MS(m/e):366.4(M+1)。
1H NMR(CD3OD,400MHz):9.88(s,1H),8.63(s,1H),8.60(s,1H),8.43〜8.41(d,J=8.8Hz,1H),8.03(s,1H),7.93〜7.87(m,2H),7.46〜7.42(t,J=7.6Hz,1H),7.26〜7.24(d,J=8.0Hz,1H),7.21〜7.20(d,J=3.2Hz,1H),6.94〜6.93(d,J=2.8Hz,1H),4.25(s,1H),3.66〜3.63(t,J=6.8Hz,2H),2.48〜2.39(m,6H),1.79〜1.76(m,2H),0.96〜0.93(t,J=7.2Hz,6Hz);MS(m/e):441.5(M+1)。
1H NMR(DMSO−d6,400MHz):10.11(s,1H),8.72(d,J=2.0Hz,1H),8.63(s,1H),8.59(dd,J=2.0Hz,J=2.0Hz,1H),8.10(s,1H),7.99(d,J=8.0Hz,1H),7.88(d,J=9.2Hz,1H),7.43(t,J=8.0Hz,1H),7.35(d,J=2.8Hz,1H),7.24(d,J=7.6Hz,1H),6.88(d,J=2.8Hz,1H),4.23(s,1H),3.80−3.78(m,2H),3.65−3.62(m,2H),3.51−3.48(m,2H),1.14−1.08(m,3H);MS(m/e):400(M+1)。
1H NMR(CD3OD,400MHz):9.88(s,1H),8.62(s,1H),8.60(s,1H),8.03(s,1H),7.93〜7.91(d,J=8.0Hz,1H),7.89〜7.87(d,J=9.2Hz,1H),7.45〜7.43(t,J=8.0Hz,1H),7.26〜7.24(d,J=7.2Hz,1H),7.18〜7.17(d,J=3.2Hz,1H),6.91〜6.90(d,J=2.8Hz,1H),4.23(s,1H),3.75〜3.72(t,J=6.4Hz,2H),2.59〜2.56(t,J=6.4Hz,2H),2.51〜2.40(m,4H),2.38〜2.32(m,4H),2.14(s,3H);MS(m/e):454.5(M+1)。
1H NMR(CD3OD,400MHz):9.92(s,1H),8.63(s,1H),8.60(s,1H),8.44〜8.42(d,J=8.8Hz,1H),8.04(s,1H),7.96〜7.87(m,2H),7.46〜7.42(t,J=7.6Hz,1H),7.26〜7.24(d,J=7.6Hz,1H),7.18〜7.17(d,J=2.8Hz,1H),6.91〜6.90(d,J=2.4Hz,1H),4.25(s,1H),3.37〜3.69(m,1H),3.52〜3.47(m,1H),2.30〜2.26(m,2H),2.19〜2.06(m,2H),1.78〜1.71(m,2H),1.65〜1.59(m,2H),1.42〜1.45(m,1H),1.07〜1.10(m,3H);MS(m/e):439.5(M+1)。
1H NMR(CD3OD,400MHz):8.57(s,1H),8.53(s,1H),8.22〜8.20(dd,J=1.6Hz,9.2Hz,1H),7.99(s,1H),7.89〜7.87(d,J=8.8Hz,1H),7.84〜7.82(d,J=8.0Hz,1H),7.39〜7.37(t,J=7.6Hz,1H),7.29〜7.27(d,J=7.2Hz,1H),7.03〜7.02(d,J=2.8Hz,1H),6.82〜6.81(d,J=3.2Hz,1H),4.16〜4.12(t,J=6.8Hz,2H),3.56(s,1H),2.59〜2.56(t,J=6.4Hz,2H);MS(m/e):400.4(M+1)。
1H NMR(CD3OD,400MHz):8.58〜8.57(m,2H),8.25〜8.22(dd,J=2.0Hz,8.8Hz,1H),7.98(s,1H),7.92〜7.89(d,J=8.8Hz,1H),7.86〜7.84(d,J=8.0Hz,1H),7.43〜7.39(t,J=7.6Hz,1H),7.31〜7.29(d,J=7.2Hz,1H),7.09〜7.08(d,J=2.8Hz,1H),6.80〜6.79(d,J=3.2Hz,1H),3.86〜3.83(t,J=6.4Hz,2H),3.53(s,1H),2.91〜2.88(t,J=6.8Hz,2H),2.26〜2.22(m,2H),1.85〜1.66(m,5H);MS(m/e):425.1(M+1)。
1H NMR(CD3OD,400MHz):8.61(s,1H),8.53(s,1H),8.22〜8.20(dd,J=1.6Hz,9.2Hz,1H),7.99(s,1H),7.89〜7.87(d,J=8.8Hz,1H),7.84〜7.82(d,J=8.0Hz,1H),7.39〜7.37(t,J=7.6Hz,1H),7.29〜7.27(d,J=7.2Hz,1H),7.03〜7.02(d,J=2.8Hz,1H),6.83〜6.82(d,J=2.8Hz,1H),4.08〜4.05(t,J=6.8Hz,2H),3.55(s,1H),3.52〜3.40(m,4H),2.85〜2.82(t,J=6.8Hz,2H),2.00〜1.89(m,4H);MS(m/e):453.4(M+1)。
1H NMR(CD3OD,400MHz):8.59(s,1H),8.57〜8.56(d,J=2.0Hz,1H),8.24〜8.21(dd,J=2.4Hz,8.8Hz,1H),7.99(s,1H),7.90〜7.88(d,J=8.8Hz,1H),7.84〜7.82(d,J=7.2Hz,1H),7.42〜7.38(t,J=8.0Hz,1H),7.30〜7.28(d,J=7.6Hz,1H),7.10〜7.09(d,J=3.2Hz,1H),6.81〜6.80(d,J=3.6Hz,1H),3.90〜3.87(t,J=5.6Hz,2H),3.54(s,1H),3.45〜3.42(t,J=6.0Hz,2H),2.94(s,3H);MS(m/e):449.5(M+1)。
1H NMR(CD3OD,400MHz):8.58(s,1H),8.56〜8.55(d,J=2.0Hz,1H),8.23〜8.20(dd,J=2.4Hz,8.8Hz,1H),7.99(s,1H),7.89〜7.87(d,J=8.8Hz,1H),7.84〜7.82(d,J=8.0Hz,1H),7.41〜7.37(t,J=8.0Hz,1H),7.29〜7.27(d,J=7.6Hz,1H),7.08〜7.07(d,J=2.8Hz,1H),6.80〜6.79(d,J=3.6Hz,1H),3.96〜3.93(t,J=5.6Hz,2H),3.53(s,1H),3.52〜3.48(t,J=5.6Hz,2H),2.94(s,3H),2.84(s,3H);MS(m/e):463.5(M+1)。
1H NMR(CD3OD,400MHz):8.58(s,1H),8.56〜8.55(d,J=2.0Hz,1H),8.23〜8.20(dd,J=2.0Hz,8.8Hz,1H),7.98(s,1H),7.89〜7.87(d,J=9.2Hz,1H),7.84〜7.82(d,J=8.0Hz,1H),7.41〜7.37(t,J=7.6Hz,1H),7.29〜7.27(d,J=8.0Hz,1H),7.07〜7.06(d,J=2.8Hz,1H),6.73〜6.72(d,J=2.8Hz,1H),3.85〜3.82(t,J=5.6Hz,2H),3.55〜3.52(t,J=6.0Hz,2H),3.52(s,1H),1.56〜1.52(m,1H),0.83〜0.81(m,2H),074〜0.71(m,2H);MS(m/e):439.5(M+1)。
1H NMR(CD3OD,400MHz):8.61(d,J=2.0Hz,1H),8.60〜8.56(dd,J=2.0Hz,1H),8.24〜8.21(dd,J=2.0Hz,9.2Hz,1H),8.01〜7.99(dd,J=2.0Hz,4.4Hz,1H),7.92〜7.91(dd,J=2.4Hz,9.2Hz,1H),7.86〜7.84(d,J=8.0Hz,1H),7.43〜7.39(t,J=8.0Hz,1H),7.32〜7.30(d,J=8.0Hz,1H),4.05〜4.02(t,J=5.6Hz,1H),3.98〜3.96(t,J=5.6Hz,1H),3.94〜3.92(t,J=5.6Hz,1H),3.78〜3.75(t,J=5.6Hz,1H),3.55(s,1H),3.27(s,1.5H),3.05(s,1.5H),1.92〜1.85(m,1H),0.82〜0.77(m,3H),0.69〜0.65(m,1H);MS(m/e):453.5(M+1)。
化合物157の合成経路を以下に示す:
化合物158〜163は実施例157に記載の方法に類似した方法で調製した。
化合物158:
1H NMR(CD3OD,400MHz):8.59(s,1H),8.52〜8.49(d,J=8.8Hz,1H),8.11〜8.08(d,J=2.4Hz,1H),8.09〜8.08(d,J=2.4Hz,1H),7.98(s,1H),7.83〜7.81(d,J=8.0Hz,1H),7.43〜7.39(t,J=7.6Hz,1H),7.32〜7.30(d,J=7.6Hz,1H),7.18〜7.17(d,J=2.8Hz,1H),6.85〜6.84(d,J=3.2Hz,1H),3.81〜3.77(t,J=6.8Hz,2H),3.56(s,1H),2.74〜2.67(m,6H),2.02〜1.95(m,2H),1.14〜1.10(t,J=7.2Hz,6H);MS(m/e):441.5(M+1)。
1H NMR(MeOD,400MHz):8.58(s,1H),8.48〜8.45(dd,J=1.6Hz,8.0Hz,1H),8.09〜8.08(d,J=2.4Hz,1H),8.07(s,1H),7.98(s,1H),7.83〜7.81(d,J=8.0Hz,1H),7.42〜7.38(t,J=8.0Hz,1H),7.31〜7.29(d,J=7.2Hz,1H),7.12〜7.11(d,J=2.8Hz,1H),6.84〜6.83(d,J=3.2Hz,1H),3.90〜3.85(m,1H),3.67〜3.64(m,1H),3.55(s,1H),3.23〜3.18(m,1H),3.01〜2.94(m,1H),2.86〜2.82(m,1H),2.44〜2.38(m,1H),2.32〜2.26(m,1H),1.98〜1.91(m,1H),1.75〜1.69(m,1H),1.18(s,3H);MS(m/e):439.5(M+1)。
1H NMR(CD3OD,400MHz):8.59(s,1H),8.51〜8.49(dd,J=2.0Hz,7.6Hz,1H),8.13〜8.12(d,J=2.0Hz,1H),8.11〜8.10(d,J=2.0Hz,1H),7.98(s,1H),7.83〜7.81(d,J=8.0Hz,1H),7.43〜7.39(t,J=8.4Hz,1H),7.32〜7.30(d,J=8.0Hz,1H),7.16〜7.15(d,J=3.6Hz,1H),6.82〜6.81(d,J=3.2Hz,1H),3.82〜3.78(t,J=7.2Hz,2H),3.61(s,1H),2.73〜2.33(m,10H),2.28(s,3H),2.00〜1.93(m,2H);MS(m/e):468.5(M+1)。
1H NMR(CD3OD,400MHz):8.59(s,1H),8.51〜8.49(d,J=9.6Hz,1H),8.11〜8.08(m,2H),7.98(s,1H),7.83〜7.81(d,J=8.0Hz,1H),7.43〜7.39(t,J=7.6Hz,1H),7.32〜7.30(dd,J=1.6Hz,6.8Hz,1H),7.17〜7.16(d,J=3.2Hz,1H),6.86〜6.85(d,J=2.8Hz,1H),3.85〜3.78(t,J=6.8Hz,2H),3.55(s,1H),3.12〜3.07(m,1H),2.38(s,3H),2.30〜2.12(m,4H),1.85〜1.78(m,2H),1.69〜1.55(m,2H);MS(m/e):439.5(M+1)。
1H NMR(CD3OD,400MHz):8.59(s,1H),8.51〜8.48(d,J=10.0Hz,1H),8.11〜8.09(m,2H),7.98(s,1H),7.84〜7.81(d,J=8.8Hz,1H),7.43〜7.39(t,J=8.0Hz,1H),7.32〜7.30(d,J=7.6Hz,1H),7.15〜7.14(d,J=3.2Hz,1H),6.88〜6.87(d,J=2.8Hz,1H),3.77〜3.73(t,J=7.2Hz,2H),3.54(s,1H),3.54〜3.50(t,J=7.2Hz,2H),3.42〜3.39(t,J=7.2Hz,1H),2.44〜2.40(t,J=7.6Hz,2H),2.12〜2.07(m,2H),2.04〜1.99(m,2H);MS(m/e):453.5(M+1)。
1H NMR(CD3OD,400MHz):8.60(s,1H),8.53〜8.50(d,J=10.0Hz,1H),8.12〜8.10(m,2H),7.99(s,1H),7.84〜7.82(d,J=8.0Hz,1H),7.84〜7.82(d,J=8.0Hz,1H),7.44〜7.41(t,J=7.6Hz,1H),7.33〜7.31(d,J=7.2Hz,1H),7.19〜7.18(d,J=2.8Hz,1H),6.86〜6.85(d,J=3.6Hz,1H),3.94〜3.91(t,J=6.8Hz,2H),3.56(s,1H),3.26〜3.23(m,2H),3.03(s,3H),2.30〜2.26(m,2H);MS(m/e):448.4(M+1)。
化合物164の合成経路を以下に示す:
化合物165の合成経路を以下に示す:
1H NMR(DMSO−d6,400MHz):9.98(s,1H),8.69(s,1H),8.63(s,1H),8.05(s,1H),7.92(d,J=7.2Hz,1H),7.35−7.29(m,2H),7.21(d,J=7.6Hz,1H),6.75(d,J=2.0Hz,1H),6.58(d,J=2.8Hz,1H),4.15(s,1H),3.91(s,3H),3.64(t,J=7.6Hz,2H),2.65(t,J=7.2Hz,2H),2.58(m,4H),0.97(m,6H);MS(m/e):457(M+1)。
化合物166〜170を実施例165に記載の方法と類似した方法で調製した。
化合物166:
1H NMR(DMSO−d6,400MHz):9.90(s,1H),8.67(s,1H),8.62(s,1H),8.08(s,1H),7.92(d,J=8.4Hz,1H),7.42−7.37(m,2H),7.21(d,J=7.6Hz,1H),6.72(s,2H),4.22(s,1H),3.95(s,3H),3.77(t,J=2.8Hz,2H),3.59(t,J=4.8Hz,2H),3.31(s,3H);MS(m/e):416(M+1)。
1H NMR(DMSO−d6,400MHz):9.94(s,1H),8.69(s,1H),8.62(s,1H),8.09(s,1H),7.93(d,J=7.6Hz,1H),7.42−7.37(m,2H),7.21(d,J=7.6Hz,1H),6.79(d,J=2.4Hz,1H),6.73(d,J=2.4Hz,1H),4.22(s,1H),3.94(s,3H),3.75(t,J=2.8Hz,2H),3.68−3.57(m,4H),3.59(t,J=4.8Hz,2H),2.51−2.48(m,4H);MS(m/e):471(M+1)。
1H NMR(DMSO−d6,400MHz):9.90(s,1H),8.66(s,1H),8.62(s,1H),8.08(s,1H),7.92(d,J=8.0Hz,1H),7.42−7.37(m,2H),7.21(d,J=7.2Hz,1H),6.76(d,J=2.8Hz,1H),6.70(d,J=2.8Hz,1H),4.24(s,1H),3.94(s,3H),3.71(t,J=6.0Hz,2H),2.56(t,J=8.4Hz,2H),2.42(s,8H),2.34(s,3H);MS(m/e):484(M+1)。
1H NMR(DMSO−d6,400MHz):9.94(s,1H),8.69(s,1H),8.62(s,1H),8.08(s,1H),7.92(d,J=8.0Hz,1H),7.41−7.35(m,2H),7.21(d,J=7.6Hz,1H),6.76(d,J=2.4Hz,1H),6.72(d,J=2.4Hz,1H),4.24(s,1H),3.93(s,3H),3.72(t,J=6.8Hz,2H),2.46−2.50(m,6H),1.80(t,J=7.2Hz,2H),1.00−0.96(m,6H);MS(m/e):471(M+1)。
1H NMR(DMSO−d6,400MHz):9.92(s,1H),8.67(s,1H),8.65(s,1H),8.07(s,1H),7.91(d,J=8.8Hz,1H),7.43−7.39(m,2H),7.22(d,J=7.2Hz,1H),6.78(s,2H),4.49(d,J=2.0Hz,2H),4.23(s,1H),3.95(s,3H);MS(m/e):396(M+1)。
A431細胞(ヒト類表皮がん)を96ウェルプレートに細胞数2.5×104個/ウェルとしてDMEM中に播種し、一晩インキュベートした。DMEM培地を廃棄し、プレートを200μLの無血清DMEM培地で洗浄した。この培地を廃棄した後、90μLの無血清DMEM培地を各ウェルに加えた。プレートを再び一晩インキュベートした。
阻害率を下式:
阻害(%)=100−{(化合物ウェルのシグナル−細胞ウェルのシグナル)/(EGFウェルのシグナル−細胞ウェルのシグナル)}×100%
のようにして計算したが、上記式中、「化合物ウェルのシグナル」は、細胞、試験化合物、およびEGFを含んだウェルから検出された蛍光を表し;「細胞ウェルのシグナル」は、細胞を含むが試験化合物およびEGFは含まないウェルから検出された蛍光を表し;「EGFウェルのシグナル」は、細胞およびEGFを含むが試験化合物は含まないウェルから検出された蛍光を表す。
結果は、化合物1〜170すべてがEGFR活性を阻害したことを示している。該化合物のIC50値は0.001μM〜10μMに及んだ。
本明細書に開示された特徴はすべて任意の組み合わせに組み合わせることが可能である。本明細書に開示された特徴はそれぞれ、同一、等価であるかまたは類似の目的を提供する代替の特徴に置き換えることができる。したがって、別途明白な記載のないかぎり、開示された各特徴は、総括的な一連の等価または類似の特徴のうちの一例にすぎない。
Claims (22)
- 下式:
R1、R2、およびR5はそれぞれ独立に、H、ハロ、ニトロ、アミノ、シアノ、ヒドロキシ、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、アルコキシ、アルキルチオ、アルキルカルボニル、カルボキシ、アルコキシカルボニル、カルボニルアミノ、スルホニルアミノ、アミノカルボニル、またはアミノスルホニルであり;
R3およびR4のうちの一方は
XはO、S、またはNRfであって、Rfは、H、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、アルキルカルボニル、アルコキシカルボニル、アミノカルボニル、もしくはアミノスルホニルであり;
Yはアルキニルで置換されているフェニルか、もしくは別の3〜8員環と融合しているフェニルであるか、あるいは、Yはフェニルで置換されたアルキルか、ハロ、ニトロ、シアノ、アルキル、アルケニルもしくはアルキニルで置換されているフェニルで置換されたアルキルか、もしくは別の3〜8員環と融合しているフェニルで置換されたアルキルであり;
ZはNである、化合物またはその薬学的に許容可能な塩またはそれらの混合物。 - R3およびR4のうちの一方が
- R3およびR4のうちの一方が
- RbおよびRcは、結合している窒素原子と一緒になって、下式:
- R3およびR4のうちの一方が
- R3およびR4のうちの一方が
- R3およびR4のうちの一方が
- XはO、NHまたはN−CH3であることを特徴とする、請求項1に記載の化合物またはその薬学的に許容可能な塩またはそれらの混合物。
- Yは
- Yは
- Yは
- R3およびR4のうちの一方が
- R3およびR4のうちの一方が
- RbおよびRcは、結合している窒素原子と一緒になって、下式:
- R3およびR4のうちの一方が
- R3およびR4のうちの一方が
- R3およびR4のうちの一方が
- 化合物は、以下の化合物1〜170
- 以下の化合物1〜170
- 請求項1もしくは19に記載の化合物またはその薬学的に許容可能な塩またはそれらの混合物と、該化合物の薬学的に許容可能な担体とを含んでなる医薬組成物。
- がんを治療するための治療薬であって、有効な量の請求項1もしくは19に記載の化合物またはその薬学的に許容可能な塩またはそれらの混合物を含む、治療薬。
- がんは、肺がん、頭頸部がん、結腸直腸がん、または膵臓がんである、請求項21に記載の治療薬。
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