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含有吡咯并噠嗪衍生物的蛋白激酶抑制劑的制作方法_4

文檔序號:9915947閱讀:來源:國知局
20(m,3H),7.10(t,lH), 6.92(d J = 3.細z,lH),6.33(d,J = 7.細z,lH) ,5.75-5.74(q,lH) ,4.38-4.33(q,2H) ,2.94 (s,3H),1.58(t J = 7.2Hz,3H)
[0324] MS:657[M+W +
[0325] 實施例32 )4-乙氧基-N-( 3-氣-4-( (5-( 3-氨橫酷苯基川比咯并[1,2-b ]化嗦-4-基) 氧)苯基)-1-(4-氣苯基)-2-氧代-1,2-二氨化晚-3-甲酯胺的制備
[0326]
[0327] 1h NMR(400MHz,CDCl3)Sll.45(s,lH),8.17(t,lH),7.88-7.81(m,4H),7.78-7.75 (m,lH),7.49-7.45(m,2H),7.36-7.33(m,2H),7.26-7.20(m,3H),7.02(t,lH),6.91(d,J= 2.細z,lH),6.33(dJ = 8.0Hz,lH),5.79(dJ = 5.2Hz,lH),4.37-4.35(q,2H),2.52(dJ = 5.2Hz,3H),1.58(t,J = 6.8Hz,3H)
[032引 MS:658[M+扣 +
[0329] 實施例33)N-(3-氣-4-((5-(化晚-4-基川比咯并[l,2-b]化嗦-4-基)氧)苯基)-4- 甲氧基-2-氧代-1-苯基-l,2-二氨化晚-3-甲酯胺的制備
[0330]
[033。 iHNMR(400MHz,CDCl3)Sll.64(s,lH),8.27-8.26(m,lH),7.96-7.92(m,lH),7.86- 7.82(m,4H) ,7.51 (d,J = 7.細z,lH),7.44(t,J = 7.7Hz,1H) ,7.37-7.32(m,2H) ,7.24-7.22 (m,3H),7.06(t,J = 8.7Hz,lH),6.93(d,J = 2.細z,lH),6.37(d,J = 7.9Hz,lH),5.71(d,J = 5.0Hz,lH),4.37(q,J = 7.0Hz,2H),2.58(s,3H),1.59(t,J = 7.0Hz,3H)
[0332] MS:548[M+扣+
[0333] 實施例34)n-(4-((5-(3-乙酷基苯基川比咯并[l,2-b]化嗦-4-基)氧)-3-氣苯基)- 4-乙氧基-1-(4-氣苯基-2-氧代-1,2-二氨化晚-3-甲酯胺的制備
[0334]
[0335] 1h NMR(400MHz,CDCl3)Sll.85(s,lH),8.55(d,J=6.0Hz,2H),8.01-7.97(m,lH), 7.89(d,J = 5.4Hz,lH),7.83(d,J = 2.9Hz,lH),7.60-7.52(m,6H),7.39-7.37(m,2H),7.31- 7.28(m,lH),7.06(t,J = 8.7Hz,lH),6.96(d,J = 2.9Hz,lH),6.41(d,J = 7.9Hz,lH),5.78 (d,J = 5.3Hz,lH),4.12(s,3H)
[0336] MS:621[M+W +
[0337] 實施例35)N-(4-((5-(3-(N,N-二甲基氨橫酷)苯基)化咯并[l,2-b]化嗦-4-基) 氧)-3-氣苯基)-4-乙氧基-1-( 4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[033引
[0339] 1h NMR(400MHz,CDCl3)Sll.5(s,lH),8.14(t,lH),7.93-7.81(m,4H),7.73-7.67 (m,lH),7.50-7.46(m,2H),7.36-7.33(m,2H),7.26-7.23(m,2H),7.08(t,lH),6.91(d,J= 2.細z,lH),6.:M(d,J = 7.細z,lH),5.74(d,J = 6.4Hz,lH),4.37-4.35(q,2H),2.52(d,J = 5.2Hz,3H),1.58(t,J = 6.8Hz,3H)
[0340] MS:672[M+扣 +
[0:341] 實施例36)N-(4-((5-(3-(N,N-二甲基氨橫酷)苯基)化咯并[l,2-b]化嗦-4-基) 氧)-3-氣苯基)-4-乙氧基-1-( 4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0;342]
[0;343] 1h NMR(400MHz,CDCl3)Sll.49(s,1H),8.09(t,lH) ,7.91-7.81 (m,4H) ,7.63-7.61 (m,lH),7.51-7.47(m,2H),7.37-7.33(m,2H),7.26-7.20(m,2H),7.08(t,lH),6.90(d,J= 3.2Hz,lH),6.:M(d J = 7.細z,lH),5.73(dJ = 3.細z,lH),4.38-4.33(q,2H),2.60(s,細), 1.58(t J = 6.細z,3H)
[0344] MS:686[M+扣 +
[0345] 實施例37)4-乙氧基-N-(3-氣-4-( (5-(4-硝基苯基)化咯并[l,2-b]化嗦-4-基) 氧)苯基)-1-(4-氣苯基)-2-氧代-1,2-二氨化晚-3-甲酯胺的制備
[0;346]
[0;347] 1h NMR(400MHz,CDCl3)Sll.68(s,lH),8.21-8.19(m,2H),7.91-7.93(m,lH),7.89 (d J = 5.細z,lH),7.83(dJ = 2.細z,lH) ,7.79-7.77(m,2H) ,7.51 (dj = 7.細z,lH),7.37- 7.34(m,2H),7.28-7.21(m,3H),7.05(t,J = 8.4Hz,lH),6.94(d,J = 2.細z,lH),6.36(d,J = 8.0Hz,lH),5.75(d,J = 5.2Hz,lH),4.39-4.34(q,2H),1.59(d,J = 6.8Hz,3H)
[0;34 引 MS:624[M+扣 +
[0349] 實施例38)N-(4-((5-(4-氨基苯基川比咯并[l,2-b]化嗦-4-基)氧)-3-氣苯基)-4- 乙氧基-1-( 4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0350]
[0;35。 1h NMR(400MHz,CDCl3)Sl 1.58(s,1H),7.92-7.88(m,1H),7.77-7.75(m,2H),7.50 (d,J = 8.0Hz,lH),7.45-7.43(m,2H),7.23-7.21(m,2H)7.37-7.34(m,2H),7.04(t,J = 8.4Hz,2H),6.81(d,J = 2.4Hz,lH),6.68(d,J = 8.4Hz,lH),6.36(d,J = 8.0Hz,lH),5.61(d, J = 5.2Hz,lH),5.4(br,2H),4.37-4.35(q,2H),1.59(d J = 6.8Hz,3H)
[0;352] MS:594[M+扣 +
[0353]實施例39)4-乙氧基-N-(3-氣-4-( (5-(3-( (2-甲氧基乙氧基)甲基)苯基)郵咯并 [l,2-b]惦嗦-4-基)氧)苯基)-1-(4-氣苯基)-2-氧代-1,2-二氨化晚-3-甲酯胺的制備
[0354]
[0;35 引 1h NMR(400MHz,CDCl3)Sll.60(s,1H) ,7.93-7.90(dd,2H),7.81 (d,J = 5.2Hz,lH), 7.79(d,J=2.8Hz,IH),7.69-7.63(m,3H),7.51-7.46(m,2H),7.37-7.30(m,3H),7.24-7.21 (m,2H)7.04(t,lH),6.88(d,J = 2.8Hz,lH),6.36(d,J = 8.0Hz,lH),5.61(d,J = 5.2Hz,lH), 4.57(s,2H),4.37-4.35(q,2H),3.56-3.53(m,2H),3.47-3.:M(m,2H),1.59(d,J = 6.8Hz, 3H)
[0;356] MS:667[M+W +
[0357] 實施例40)N-(3-氣-4-((5-(2-甲氧基化晚-4-基)化咯并[1,2-6]化嗦-4-基)氧) 苯基)-1-(4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[035引
[0;359] 1h NMR(400MHz,CDCl3)Sll.72(s,lH),8.09(d,J = 5.2Hz,lH),7.86(d,J = 5.2Hz, lH),7.80(d,J = 2.細z,lH),7.55(d,J = 7.細z,lH),7.37(d,J = 4.0Hz,lH),7.35-7.34(m, 2H)7.27-7.20(m,3H),7.18(t,lH),7.01(s,lH),6.93(d,J = 2.細z,lH),6.40(d,J = 8.0Hz, lH),5.75(d,J=5.2Hz,lH),4.11(s,3H),3.92(s,3H),3.56-3.53(m,2H),3.47-3.34(m, 2H),1.59(d,J = 6.8Hz,3H)
[0360] MS:596[M+扣+
[0361] 實施例41)N-(4-((5-(3-(二甲基氨基甲酯)苯基川比咯并[l,2-b]化嗦-4-基)氧)- 3-氣苯基)-4-乙氧基-1-( 4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0362]
[0363] iHNMR(400MHz,CDCl3)Sll.64(s,lH),7.95-7.91(m,lH),7.83-7.79(m,2H),7.68- 7.64(m,2H),7.51(d,J = 7.8Hz,lH),7.39-7.33(m,3H),7.28-7.21(m,4H),7.03(t,J = 8.7Hz,lH),6.88(d,J = 2.細z,lH),6.36(d,J = 7.9Hz,lH),5.69(d,J = 5.3Hz,lH),4.36(q, J = 7.0Hz,2H),3.10(s,3H),2.92(s,3H),1.58(t,J = 7.0Hz,3H)
[0364] MS:650[M+扣+
[0365] 實施例42)N-(3-氣-4-((5-(化晚-4-基川比咯并[l,2-b]化嗦-4-基)氧)苯基)-N- (4-氣苯基)環丙烷-1,1 -二甲酯胺的制備
[0366]
[0367] 1h NMR(400MHz,CDCl3)Sl0.13(s,lH),8.54(d,J = 5.4Hz,2H),8.23(s,lH),7.89 (d,J = 5.4Hz,lH),7.85(d,J = 2.9Hz,lH),7.77-7.73(m,lH),7.57(d,J = 6.0Hz,2H),7.46- 7.41(m,2H),7.23-7.21(m,lH),7.14-7.12(m,lH),7.09-7.03(m,2H),6.97(d,J=2.9Hz, lH),5.77(d J = 5.3Hz,IH) ,1.81 (qJ = 5.2Hz,2H),1.62(qJ = 4.6Hz,2H)
[036引 MS:526[M+扣 +
[0369] 實施例43)4-乙氧基-N-(3-氣-4-( (5-(3-(2-?基丙-2-基)苯基)化咯并[l,2-b] 化嗦-4-基)氧)苯基)-1-(4-氣苯基)-2-氧代-1,2-二氨化晚-3-甲酯胺的制備
[0370]
[0371] iHNMR(400MHz,CDCl3)Sll.59(s,lH),7.94-7.89(m,lH),7.82-7.78(m,3H),7.52- 7.48(m,2H),7.39-7.33(m,4H),7.25-7.21(m,3H),7.07-6.98(m,2H),6.90(d,J=2.細Z, lH),6.35(d,J = 8.0Hz,lH),5.67(d,J = 5.2Hz,lH),4.35(q,J = 7.2Hz,2H),1.57(t,J = 7.2Hz,3H),1.54(s,細)
[0372] MS:637[M+扣+
[0373] 實施例44)4-乙氧基-N-(3-氣-4-((5-(3-(甲基氨基甲酯)苯基川比咯并[l,2-b雌 嗦-4-基)氧)苯基)-1 -(4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0374]
[037引 1h NMR(400MHz,CDCl3)δll.68(s,lH),7.99(d,J = 4.細z,lH),7.97-7.96(m,lH), 7.84(d,J = 5.2Hz,lH),7.81(d,J = 2.Wz,lH),7.77-7.69(m,2H),7.50(d,J = 7.Wz,lH), 7.41(t,J = 7.細z,lH) ,7.36-7.33(m,2H) ,7.25-7.21 (m,3H),7.03(t,J = 8.細z,lH) ,6.91 (d,J = 3.2Hz,lH),6.35(d,J = 8.0Hz,lH),6.2(br,lH),5.71(d,J = 5.2Hz,lH),4.38-4.33 (q,2H),2.95(d J = 5.2Hz,3H),1.58(t J = 6.8Hz,3H)
[0376] MS:636[M+扣+
[0377] 實施例45)3-(4-(4-(4-乙氧基-1-(4-氣苯基)-2-氧代-1,2-二氨化晚-3-甲酯胺 基)-2-氣苯氧基川比咯并[1,2-b ]化嗦-5-基)芐基氨基甲酸醋的制備
[037引
[0379] 1h NMR(400MHz,CDCl3)Sll.60(s,lH),7.91(d,J = 2.4Hz,lH),7.88(d,J = 2.4Hz, lH),7.82(d,J = 5.2Hz,lH),7.79(d,J = 2.Wz,lH),7.68(s,lH),7.61-7.59(m,lH),7.50 (d,J = 8.OHz,IH),7.37-7.32(m,3H),7.26-7.20(m,4H),7.05(t,J = 8.8Hz,lH),6.89(d,J =2.細z,lH),6.36(d,J = 7.細z,lH),5.69(d,J = 5.細z,lH),5.09(s,2H),4.48(br,2H), 4.38-4.35(q,2H),1.59(d,J = 6.8Hz,3H)
[0380] MS:652[M+扣+
[0381] 實施例46)4-乙氧基-N-(3-氣-4-( (5-(3-( 1-?基乙基)苯基)化咯并[l,2-b]化 嗦-4-基)氧)苯基)-1 -(4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0382]
[0383] 1h NMR(400MHz,CDCl3)Sll.59(s,lH),7.93-7.89(m,lH),7.82-7.79(m,2H),7.67 (s,IH),7.56-7.53(m,IH),7.49(d,J=7.8Hz,lH),7.37-7.31(m,3H),7.25-7.21(m,4H), 7.04(t,J = 8.7Hz,lH),6.89(d,J = 2.8Hz,lH),6.35(d,J = 7.9Hz,lH),5.69-5.68(m,lH), 4.89(q J = 6.4Hz,lH),1.57(t J = 7.0Hz,3H),1.45(d J = 6.4Hz,3H)
[0384] MS:623[M+扣+
[0385] 實施例47)N-(3-氣-4-((5-(3-(1-?基乙基)苯基川比咯并[l,2-b]化嗦-4-基)氧) 苯基)-1-( 4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0386]
[0387] iHNMR(400MHz,CDCl3)Sll.99(s,lH),8.75-8.73(m,lH),7.94-7.91(m,lH),7.85- 7.82(m,2H),7.69(s,lH),7.64-7.55(m,2H),7.43-7.26(m,7H),7.11(t,J=8.6Hz,lH), 6.92(d J = 2.7Hz,lH),6.62(t J = 6.細z,lH),5.72(dJ = 5.3Hz,lH),4.92(q,J = 6.2Hz, lH),1.48(q J = 6.4Hz,3H)
[038引 MS:579[M+扣 +
[0389]實施例48)N-(3-氣-4-((5-(3-(1-?基乙基)苯基)郵咯并[l,2-b]腳i-4-基)氧) 苯基)-4-甲氧基-2-氧代-1-苯基-1,2-二氨化晚-3-甲酯胺的制備
[0390]
[0391] 1h NMR(400MHz,CDCl3)Sll.77(s,lH),7.95-7.91(m,lH),7.83-7.79(m,2H),7.66 (s,lH),7.58-7.49(m,5H),7.37-7.31(m,3H),7.24-7.18(m,2H),7.04(t,J=8.7Hz,lH), 6.91-6.88(m,lH),6.39(d,J = 7.細z,lH),5.70(d,J = 5.3Hz,lH),4.87(q,J = 6.4Hz,lH), 4.10(s,3H),1.49-1.43(m,3H)
[0392] MS:591[M+W +
[0393] 實施例49)4-乙氧基-N-(3-氣-4-(巧-(喀晚-5-基川比咯并[l,2-b]化嗦-4-基)氧) 苯基)-1-( 4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0394]
[03巧]咕 NMR(400MHz,DMS0-d6)Sl0.61(s,lH),9.04(d,J = 2.8Hz,3H) ,8. ll(t,J = 3.2Hz,2H),7.93-7.90(m,lH),7.86(d,J = 7.6Hz,lH),7.53-7.44(m,4H),7.39-7.:M(m, 2H),7.21(d,J = 2.Wz,lH),6.51(d,J = 8.0Hz,lH),5.96(d,J = 5.2Hz,lH),4.25(q,J = 6.8Hz,2H),1.30(t,J = 7.2Hz,3H)
[0396] MS:678[M+扣+
[0397] 實施例50)4-乙氧基-N-(3-氣-4-((5-(3-嗎嘟-4-幾基苯基川比咯并[l,2-b]化嗦- 4-基)氧)苯基)-1-(4-氣苯基)-2-氧代-l,2-二氨化晚-3-甲酯胺的制備
[039引
[0399] 1h NMR(400MHz,CDCl3)Sll.6(s,lH),7.94(d,J = 2.4Hz,lH),7.83(s,lH),7.65(m, 2H),7.50(d,J = 8.0Hz,lH),7.40-7.15(m,7H),6.04(t,J = 8.細z,lH),6.86(d,J = 2.細z, lH),6.35(d,J = 7.Wz,lH),5.68(d,J = 5.2Hz,lH),4.36(q,J = 7.3Hz,2H),1.58(t,J = 7.3Hz,3H)
[0400] MS:692[M+扣+
[0401 ]實施例 51 )4-乙氧基-N-(3-氣-4-( (5-(2-嗎嘟燒 R 比晚(mor 地 olidinpy;ridin)-4- 基川比咯并[l,2-b]化嗦-4-基)氧)苯基)-1-(4-氣苯基)-2-氧代-1,2-二氨化晚-3-甲酯胺 的制備
[0402]
[0403] 1h NMR(400MHz,CDCl3)Sll.70(s,lH),8.15(d,J = 5.2Hz,lH),7.99(d,J = 2.4Hz, lH),7.96(d,J = 2.4Hz,lH),7.85(d,J = 5.Wz,lH),7.80(d,J = 2.4Hz,lH),7.51(d,J = 8Hz,IH),7.37-7. :M(m,2H),7.26-7.21(m,2H),7.05-7.00(m,2H),6.96-6.94(m,2H),6.36 (d,J = 8.0Hz,lH),5.73(d,J = 5.細z,lH) ,4.39-4.34(q,2H),3.75(t,J = 4.8Hz,4H) ,3.47 (t J = 5.2Hz,4H),1.59(d J = 6.細z,3H)
[0404] MS:665[M+扣 +
[0405] 實施例52)4-乙氧基-N-(3-氣-4-( (5-(3-硝基苯基)化咯并[l,2-b]化嗦-4-基) 氧)苯基)-1-( 4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0406]
[0407] 1h 醒R(400MHz,DMS0-d6)Sl0.59(s,lH),8.49(d,J = 2.0Hz,lH),8.09-8.07(m, 4H),7.94-7.89(m,lH),7.85(d,J = 8.0Hz,lH),7.66(t,J = 8.0Hz,lH),7.48-7.43(m,4H), 7.39-7.34(m,2H),7.17(d,J = 3.2Hz,lH),6.51(d,J = 8.0Hz,lH),5.95(d,J = 5.Wz,lH), 4.25(q J = 7.2Hz,2H),1.30(t J = 7.2Hz,3H)
[040引 MS:624[M+扣 +
[0409] 實施例53)4-乙氧基-N-(3-氣-4-( (5-(3-氨基苯基)化咯并[l,2-b]化嗦-4-基) 氧)苯基)-1-( 4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0410]
[0411] iHMlR(400MHz,DMS0-d6)Sl0.57(s,lH),7.96(d,J = 5.6Hz,lH),7.96(d,J = 2.8Hz,lH),7.89(dd,J=11.6和2.0Hz,lH),7.85(d,J = 8.0Hz,lH),7.48-7.43(m,4H), 7.69-7.34(m,2H),6.97(t,J = 8.0Hz,lH),6.86(d,J = 2.8Hz,lH),6.82-6.74(m,2H),6.51 (d,J = 8.0Hz,lH),6.45-6.43(m,2H),5.78(d,J = 4.8Hz,lH),4.94(s,2H),4.25(q,J = 7.2Hz,2H),1.30(t,J = 7.2Hz,3H)
[0412] MS:594[M+扣+
[OW] 實施例54)4-乙氧基-N-(3-氣-4-((5-(3-(1-甲氧基乙基)苯基)郵咯并[l,2-b]惦 嗦-4-基)氧)苯基)-1 -(4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0414]
[0415] 1h NMR(400MHz,DMS0-d6)Sl0.56(s,lH),8.01(d,J = 4.8Hz,lH),7.90(m,2H), 7.70-7.30(m,9H),7.16(d,J = 8.0Hz,lH),6.99(d,J = 2.細z,lH),6.52(d,J = 8.0Hz,lH), 5.84(d,J = 4.細z,lH),4.28(q,J = 7.1Hz,2H),3.28(m,lH),2.99(s,3H),1.27(m,6H)
[0416] MS:637[M+W +
[0417] 實施例55)n-(3-氣-4-((5-(3-(1-?基乙基)苯基川比咯并[l,2-b]化嗦-4-基)氧) 苯基)-N-(4-氣苯基)環丙烷-1,1-二甲酯胺的制備
[0418]
[0419] 1h NMR(400MHz,CDCl3)S9.91(s,lH),8.14(s,lH),7.83-7.81(m,2H),7.72-7.68 (m,lH),7.66(s,lH),7.53(d,J = 7.6Hz,lH),7.45-7.42(m,2H),7.34(t,J = 7.Wz,lH), 7.19-7.16(m,lH),7.12-7.04(m,3H),7.53(d J = 2.細z,lH),5.68(dJ = 5.2Hz,lH),4.89 (q J = 6.4Hz,lH),2.35(t J = 8.0Hz,lH),1.78(q,J = 5.2Hz,2H),1.60(q,J = 4.4Hz,2H), 1.46(d J = 6.4Hz,3H)
[0420] MS:569[M+扣+
[042。 實施例56)N-(4-((5-(3-((二甲氨基)甲基)苯基)郵咯并[l,2-b]惦嗦-4-基)氧)- 3-氣苯基)-4-乙氧基-1-( 4-氣苯基)-2-氧代-1,2-二氨R比晚-3-甲酯胺的制備
[0422]
[0423] 1h NMR(400MHz,CDCl3)Sll.62(s,lH),7.94-7.90(m,lH),7.81-7.78(m,2H),7.61 (s,lH),7.55-7.52(m,lH),7.50(d,J=8.0Hz,lH),7.36-7.30(m,3H),7.25-7.18(m,4H), 7.05(t,J = 8.細z,lH),6.89(d,J = 2.細z,lH),6.35(d,J = 8.0Hz,lH),5.67-5.66(m,lH), 4.35(q J = 6.細z,2H),3.45(s,2H),2.18(s,細),1.57(tJ = 7.2Hz,3H)
[0424] MS:636[M+扣+
[0425] 實施例57州-(3-氣-4-((5-川比晚-4-基川比咯并[1,2-6]化嗦-4-基)氧)-苯基)-1-
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