CN116768903A - 一种吡咯并嘧啶衍生物及其制备方法、药物组合物和应用 - Google Patents
一种吡咯并嘧啶衍生物及其制备方法、药物组合物和应用 Download PDFInfo
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Abstract
本发明涉及化药领域,具体涉及一种吡咯并嘧啶衍生物及其制备方法、药物组合物和应用。本发明获得了一种新型吡咯并嘧啶衍生物,制备过程简单易行,可得到多种吡咯并嘧啶衍生物,该化合物具有较好的治疗和预防癌症的效果,其对FGFR2具有选择性抑制作用,作用安全性良好;并可组成药物组合物,适合用于治疗多种癌症药物的开发。
Description
技术领域
本发明涉及化药领域,具体涉及一种吡咯并嘧啶衍生物及其制备方法、药物组合物和应用。
背景技术
多靶点抑制剂、泛FGFR抑制剂已经在临床研究中取得不俗的表现,仍然是FGFR异常疾病治疗的首要选择;不过,针对当前药物的不良事件,提高药物安全性、克服耐药以及提高患者临床获益是药物研究持续进步的动力;
FGFR2基因位于染色体10q26,编码2种亚型的蛋白(FGFR2b和FGFR2c),是FGF的功能性受体;在机体内,FGFR2与配体结合后被激活,引起相应效应细胞内结构域的自磷酸化;FGFR2的异常表达与多种人类癌症的发生和进展有关,FGFR2基因的错义突变已被证明发生在胃癌、肺癌、卵巢癌和子宫内膜癌中;因此,发现新型、有效、安全性良好的抗肿瘤药物是治疗癌症亟需解决的重要问题。
发明内容
本发明的目的是解决现有技术的不足,提供一种吡咯并嘧啶衍生物及其制备方法、药物组合物和应用,具体采用以下的技术方案:
根据本发明的第一方面,提供了一种吡咯并嘧啶衍生物,其结构如式I所示:
式I,
式I中,Linker取自烷基、烷氧基、杂原子取代基、取代氮杂环、芳基、取代芳基结构中的一种;
X取自N、O结构中的任意一种;
R取自烷基、烷氧基、杂原子取代基、取代氮杂环、芳基或-Ph-N(R1R2)N-中的一种。
优选地,式I中,Linker、R、X分别独立选自以下结构1-16中的一种:
结构1中,Linker为,R对应为/>,X对应为O;
结构2中,Linker为,R对应为/>,X对应为O;
结构3中,Linker为,R对应为/>,X对应为N;
结构4中,Linker为,R对应为/>,X对应为N;
结构5中,Linker为,R对应为/>,X对应为N;
结构6中,Linker为,R对应为/>,X对应为N;
结构7中,Linker为,R对应为/>,X对应为N;
结构8中,Linker为,R对应为/>,X对应为N;
结构9中,Linker为,R对应为/>,X对应为N;
结构10中,Linker为,R对应为/>,X对应为N;
结构11中,Linker为,R对应为/>,X对应为N;
结构12中,Linker为,R对应为/>,X对应为N;
结构13中,Linker为,R对应为/>,X对应为N;
结构14中,Linker为,R对应为/>,X对应为N;
结构15中,Linker为,R对应为/>,X对应为N;
结构16中,Linker为,R对应为/>,X对应为N。
更为优选地,吡咯并嘧啶衍生物结构为式II或式III所示:
式II,/>式III。
体外抗增殖实验表明,式II和式III均能对FGFR2高表达的SNU-16肿瘤细胞表现出抗增殖作用,其中,式III能以低纳摩尔浓度有效抑制FGFR2高表达的SNU-16肿瘤细胞的增殖。体内抗增殖实验,式II和式III均能显著抑制小鼠体内SNU-16肿瘤细胞生长,其中,式III的体内肿瘤生长抑制率达到87.3%,显示出强效的体内抑瘤作用效果,表明式III是一种有潜力的药物分子用于FGFR2异常的癌症的治疗。后续将会以此为先导化合物进行FGFR2选择性小分子抑制剂的开发。
根据本发明的第二方面,还提供了上述的吡咯并嘧啶衍生物的制备方法,其制备路线为:
。
根据本发明的第三方面,还提供了上述的吡咯并嘧啶衍生物或其在药学上可接受的盐在制备FGFR2抑制剂中的应用。
优选地,FGFR2抑制剂可用于制备治疗具有FGFR2异常的相关癌症的药物。优选地,相关癌症包括胃癌、肺癌、卵巢癌和子宫内膜癌。
根据本发明的第四方面,还提供了一种药物组合物,包括上述的吡咯并嘧啶衍生物或其药学上可接受的盐。
优选地,药物组合物包括赋形剂。优选地,赋形剂为阿拉伯胶、糖浆、羊毛脂和淀粉中的至少一种。该赋形剂性质稳定,与主药无配伍禁忌,不产生副作用,不影响疗效,在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用,不与主药产生化学或物理作用,不影响主药的含量测定。
本发明的有益效果为:本发明获得了一种吡咯并嘧啶衍生物,制备过程简单易行,可以获得多种吡咯并嘧啶衍生物,该化合物具有较好的治疗和预防癌症的效果,对FGFR2具有选择性抑制作用,并可组成药物组合物,适合用于治疗胃癌、肺癌、卵巢癌和子宫内膜癌等癌症药物的开发。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整的描述,以充分地理解本发明的目的、方案和效果。需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互组合。
实施例1
一种吡咯并嘧啶衍生物(记为化合物1)、化合物A1、化合物A2、化合物A3、化合物A4、化合物A5,其结构如下所示:
化合物1,/>化合物A1,
化合物A2,/>化合物A3,
化合物A4,/>化合物A5。
具体制备方法为:
1)化合物A1的制备:
将2-氯-7H-吡咯并[2,3-d]嘧啶(3.00 g,19.5 mmol)溶解于乙腈(60 mL)中,冰浴、氩气保护状态下加入N-碘代丁二酰亚胺(5.28 g,23.5 mmol),缓慢升至室温继续反应1h。将反应液进行浓缩,加少量乙腈进行抽滤,收集滤饼,并在真空下干燥,得白色固体化合物(4.75 g,85.7%)。
对化合物A1进行检测:1H NMR (400 MHz, DMSO-d 6)δ12.74 (s, 1H), 8.63 (s,1H), 7.83 (s, 1H).13C NMR (100 MHz,DMSO-d 6)δ153.6, 153.3, 151.7, 151.4, 133.3,120.3,54.2. HRMS (ESI): calculated for C6H4ClIN3 +[M+H]+: 279.9133, found279.9138。
2)化合物A2的制备
将化合物A1(4.75g,17.0 mmol),三乙胺(4.31 mL,17.0 mmol),4-二甲氨基吡啶(146 mg,1.19 mmol)溶于50 mLTHF中,冰浴、氩气保护条件下滴加二碳酸二叔丁酯(4.31mL,18.7 mmol),缓慢升至室温继续反应0.5 h。将反应液用饱和氯化钠溶液(100 mL)淬灭,乙酸乙酯(300 mL)萃取,收集有机相,并用无水硫酸钠干燥,减压浓缩后得到粗品。粗品经硅胶柱层析进行纯化(PE:EA = 8:1),得到白色固体化合物A2(5.20g,95.3%)。
对化合物A2进行检测:1H NMR (400 MHz, CDCl3)δ8.59 (s, 1H), 7.77 (s, 1H),1.66 (s, 9H).13C NMR (100 MHz,CDCl3)δ157.0, 152.7, 152.5, 145.9, 132.1, 122.0,86.5,58.4, 28.1, 27.9, 27.9. HRMS (ESI): calculated for C11H12ClIN3O2 +[M+H]+:379.9657, found 379.9658。
3)化合物A3的制备
将化合物A2(1.00 g,2.64 mmol),3,5-二甲氧基苯硼酸(528 mg,2.90 mmol)溶解在1,4-二氧六环:水(10.0 mL:5.00 mL = 2∶1)的混合溶液中,然后加入碳酸钾(730 mg,5.28 mmol),[1,1'-双 (二苯基膦)二茂铁]二氯化钯 (II)(193 mg,0.260mmol)。体系用氩气置换3次,油浴升温至75 ℃,反应4 h,反应完成后用饱和氯化钠淬灭反应,乙酸乙酯萃取两次,有机相干燥浓缩,柱层析纯化(PE:EA = 5∶1至2∶1)得化合物A3(白色固体粉末,450mg,64.2%)。
对化合物A3进行检测:1H NMR (400 MHz, DMSO-d 6 )δ12.63 (s, 1H),9.23 (s,1H), 8.07 (d,J= 2.2 Hz, 1H), 6.89 (d,J= 2.3 Hz, 2H),6.46 (t,J= 2.2 Hz, 1H),3.83 (s,6H).13C NMR (100 MHz,DMSO- d6 )δ161.4, 153.7, 152.8, 151.3, 135.5,126.3,115.6, 115.5, 105.0, 99.2, 55.7. HRMS (ESI): calculatedfor C14H13ClIN3O2 +[M+H]+: 290.0691, found 290.0690。
4)化合物A4的制备
将化合物A3(500 mg, 1.73 mmol),三苯基膦(815 mg,3.11mmol),叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯(597 mg, 2.60 mmol)溶于干燥的二氯甲烷(17 mL)中,在冰浴、氩气保护条件下,缓慢滴加偶氮二甲酸二叔丁酯(716mg, 3.11 mmol)。随后,将体系缓慢升至室温继续反应1 h。用TLC检测原料,原料消失后停止反应,然后将反应液进行减压浓缩,粗品经硅胶柱层析纯化(CH2Cl2:MeOH = 45: 1 至 30:1)得白色固体化合物A4(460 mg, 53%)。
对化合物A4进行检测:1H NMR (400 MHz, CDCl3)δ9.05 (s,1H), 7.37 (s, 1H),6.71 (s, 2H), 6.46 (s, 1H), 4.27 (t,J= 7.2 Hz, 2H),3.85 (s, 6H), 3.41 (t,J=5.1 Hz, 4H), 2.34 (dt,J= 18.4, 6.3Hz, 6H), 1.92 (q,J= 7.5 Hz, 2H), 1.59 –1.53 (m, 2H), 1.45 (s, 9H),1.35 (t,J= 7.7 Hz, 2H).13C NMR (100 MHz, CDCl3)δ161.4, 161.4, 154.7, 153.8, 152.4, 150.7, 134.7, 126.2, 116.3, 115.9,105.3,105.3, 98.9, 79.6, 58.3, 55.4, 55.4, 53.0, 53.0, 44.5, 44.5, 30.0, 30.0,28.4,28.4, 28.4, 26.3, 24.5. HRMS (ESI): calculatedfor C28H39ClN5O4 +[M+H]+: 545.0930,found 545.0933。
5)化合物A5的制备
将化合物A4(250 mg,0.46 mmol)溶于1,4-二氧六环(5 mL),随后向反应体系中体系中加入N,N-二甲基乙醇胺(1.63 mL,13.78 mmol),N,N-二异丙基乙胺(400 μL,2.3mmol),升温至110 ℃反应5 h。将反应液用H2O(10 mL)淬灭,再用乙酸乙酯(30 mL)萃取,收集有机相,并用无水硫酸钠干燥并减压浓缩,粗品经硅胶柱层析分离纯化(CH2Cl2:MeOH =20:1),得到白色固体化合物A5(102 mg, 41 %)。
对化合物A5进行检测:1H NMR (400 MHz, CDCl3)δ8.94 (s, 1H), 7.20 (s, 1H),6.72 (s, 2H), 6.42 (s, 1H), 4.50 (t,J= 5.4Hz, 2H), 4.18 (t,J= 6.6 Hz, 2H),3.84 (s, 6H), 3.40 (t,J= 4.8Hz, 4H), 2.90 (d,J= 7.5 Hz, 2H), 2.55 (s, 6H),2.37 - 2.30 (m, 6H),2.24 (d,J= 8.0 Hz, 2H), 1.88 (t,J= 7.8 Hz, 2H), 1.53 (t,J= 7.8 Hz, 2H), 1.44 (d,J= 2.6 Hz, 12H), 1.35 (d,J= 7.9 Hz,2H).13C NMR (100MHz, CDCl3)δ161.7, 161.3,161.3, 154.7, 153.3, 150.7, 135.7, 123.9, 116.0,112.9, 105.0, 105.0, 98.7,79.6, 65.8, 65.8, 60.0, 58.4, 56.5, 55.4, 55.4,53.0, 53.0, 45.4, 45.4, 44.1,30.0, 29.7, 28.5, 28.4, 28.4, 27.2, 26.4, 24.7.HRMS (ESI): calculated for C33H51N6O5 +[M+H]+: 610.8000, found 610.8004。
6)化合物1的制备
将化合物A5(80 mg,0.14 mmol)的二氯甲烷(0.7 mL)溶液加入三氟乙酸(0.5mL),室温反应0.5 h,减压浓缩,即可得到粗产品。将上述实验获得的粗中间体化合物加入到干燥的二氯甲烷(1.5mL)溶液中,向体系中加入三乙胺(36 μL,0.26mmol),然后在0 ℃条件下缓慢滴加丙烯酰氯(11 μL,0.14 mmol)。将反应液在室温下搅拌反应0.5 h。TLC检测反应完全后,加H2O(1.4 mL)淬灭反应,并用二氯甲烷(4.2 mL)萃取,收集有机相,用无水硫酸钠进行干燥并减压浓缩即可得到粗产物。粗产品经硅胶柱层析分离纯化(CH2Cl2:MeOH =15:1),得到黄色固体化合物1(50 mg,56%)。
对化合物1进行检测:M.p.116.1-116.9 °C; IR (KBr): 3412, 3378, 2716,1537, 1072, 1067, 960 cm-1.1H NMR (400 MHz, CDCl3)δ8.80 (s, 1H), 7.08 (s,1H),6.71 (s, 2H), 6.59 – 6.49 (m, 1H), 6.40 (s, 1H), 6.26 (dd,J= 18.5Hz, 1H),5.67 (dd,J= 8.9 Hz, 1H), 4.26 (d,J= 6.3 Hz, 2H),3.83 (s, 6H), 3.65 (s, 2H),3.51 (s, 2H), 3.04 (d,J= 4.4 Hz, 3H), 2.83– 2.76 (m, 2H), 2.54 (d,J= 15.0 Hz,4H).13C NMR (100 MHz,CDCl3)δ165.3, 161.2, 161.2, 159.7, 153.7, 150.0, 136.1,127.9, 127.4, 122.2, 116.1, 109.7, 104.8, 104.8, 98.5, 57.4, 55.4, 55.4,53.5,52.7, 45.8, 41.9, 41.1, 28.7. HRMS (ESI): calculated for C24H31N6O3 +[M+H]+:451.5430, found 451.5433。
实施例2
一种吡咯并嘧啶衍生物(记为化合物2),其结构如下所示:
化合物2,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A5制备所用N,N-二甲基乙醇胺改为N,N-二甲基丙醇胺,得到黄色固体,产率60%。
对化合物2进行检测:M.p.161.3-162.3 °C; IR (KBr): 3148, 2834, 1680,1532, 1435, 1302, 1234, 1170, 859, 802cm-1.1H NMR (400 MHz, CDCl3)δ8.96 (s,1H), 7.21 (s, 1H), 6.73 (s, 2H), 6.54 (dd,J= 16.8, 10.5 Hz, 1H), 6.43(t,J=2.1 Hz, 1H), 6.27 (dt,J= 16.9, 1.7 Hz, 1H), 5.68 (dt,J= 10.6, 1.6 Hz, 1H),4.51 (t,J= 6.1 Hz, 2H), 4.20 (t,J= 7.1Hz, 2H), 3.85 (s, 6H), 3.67 (t,J= 4.9Hz, 2H), 3.53 (t,J= 4.9Hz, 2H), 2.91 (d,J= 8.7 Hz, 2H), 2.56 (s, 6H), 2.40(t,J= 5.0Hz, 5H), 2.30 (dt,J= 21.3, 7.5 Hz, 4H), 1.89 (p,J= 7.3 Hz,2H), 1.54(p,J= 7.6 Hz, 2H), 1.35 (p,J= 7.9 Hz, 2H).13CNMR (100 MHz, CDCl3)δ165.3,161.3, 161.3, 153.2, 150.8,135.6, 127.8, 127.4, 124.1, 116.0, 113.0, 105.0,105.0, 98.6, 98.6, 65.0, 58.1,58.1, 56.3, 55.4, 55.4, 53.5, 52.7, 45.7, 44.3,44.2, 41.9, 29.9, 26.4, 25.8,24.6. HRMS (ESI): calculated for C31H45N6O4 +[M+H]+:565.7310, found 565.7314。
实施例3
一种吡咯并嘧啶衍生物(记为化合物3),其结构如下所示:
化合物3,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A5制备所用N,N-二甲基乙醇胺改为苯胺,得到黄色固体,产率63%。
对化合物3进行检测:M.p.161.3-162.6 °C; IR (KBr): 2948, 2833, 1679,1531, 1434.8, 1301, 1233, 1169, 869,801 cm-1.1H NMR (400 MHz, CDCl3)δ8.94 (s,1H), 7.79 – 7.72 (m, 2H), 7.36 (d,J= 7.4 Hz, 2H), 7.13 (s,1H), 7.01 (t,J= 7.3Hz, 1H), 6.75 (d,J= 2.2 Hz, 2H), 6.51(dd,J= 16.8, 10.5 Hz, 1H), 6.43 (t,J=2.3 Hz, 1H), 6.27 (dd,J= 16.9, 1.9 Hz, 1H), 5.68 (dd,J= 10.5, 2.0 Hz, 1H),4.22 (t,J= 6.9 Hz, 2H), 3.86 (s, 6H), 3.73 – 3.61 (m, 2H), 3.59 – 3.47 (m,2H), 2.42 (s,4H), 2.35 (t,J= 7.6 Hz, 2H), 1.93 (q,J= 7.2 Hz, 2H), 1.59 (q,J=8.1, 7.1 Hz, 2H), 1.37 (p,J= 7.8 Hz, 2H).13CNMR (100 MHz, CDCl3)δ165.3, 161.4,161.3, 155.9, 152.6,150.3, 140.4, 135.9, 128.9, 128.9, 127.9, 127.4, 122.99,121.7, 118.3, 118.3,116.3, 111.1, 104.9, 104.9, 98.6, 58.1, 55.4, 55.4, 53.2,52.7, 45.4, 43.9,41.5, 29.8, 25.9, 24.4. HRMS (ESI): calculated for C32H39N6O3 +[M+H]+: 555.6950, found 555.6953。
实施例4
一种吡咯并嘧啶衍生物(记为化合物4),其结构如下所示:
化合物4,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A5制备所用N,N-二甲基乙醇胺改为3-氨基-9-乙基咔唑。黄色固体,产率60%。
对化合物4进行检测:M.p.181.3-182.1 °C; IR (KBr): 3248, 2813, 1639,1551, 1424,1302,1253, 1159, 849, 791 cm-1.1H NMR (400 MHz, CDCl3)δ8.97 (s,1H), 8.66 (d,J= 2.1 Hz, 1H), 8.05 (d,J= 7.7 Hz, 1H),7.62 (dd,J= 8.7, 2.1 Hz,1H), 7.49 – 7.42 (m, 1H), 7.38 (dd,J= 11.6, 8.4 Hz, 2H), 7.22 – 7.16 (m, 1H),7.11 (s, 1H), 6.77 (d,J= 2.3Hz, 2H), 6.47 – 6.36 (m, 2H), 6.24 (dd,J= 16.8,2.1 Hz, 1H), 5.63 (dd,J= 10.5, 2.0 Hz, 1H), 4.35 (q,J= 7.2 Hz, 2H), 4.22 (t,J= 6.9 Hz, 2H), 3.85 (s, 6H), 3.61 (s, 2H), 3.39 (t,J= 5.1 Hz, 2H),2.30 (dt,J=15.2, 7.2 Hz, 6H), 1.96 (p,J= 7.1 Hz, 2H), 1.57(p,J= 7.6 Hz, 2H), 1.42 (t,J=7.2 Hz, 3H), 1.40 – 1.34 (m,2H).13C NMR (100 MHz, CDCl3)δ165.2, 161.3,161.3,156.7, 152.9, 150.3, 140.4, 136.1, 136.0, 132.5, 127.9, 127.3, 125.6,123.0,122.9, 122.7, 120.3, 119.1, 118.4, 116.2, 111.2, 110.7, 108.6, 108.5,104.8,104.8, 98.6, 58.0, 55.4, 55.4, 53.0, 52.6, 45.2, 44.0, 41.4, 37.6, 29.8,25.8,24.5, 13.9. HRMS (ESI): calculated for C40H46N7O3 +[M+H]+: 672.8460, found672.8462。
实施例5
一种吡咯并嘧啶衍生物(记为化合物5),其结构如下所示:
化合物5,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A5制备所用N,N-二甲基乙醇胺改为4-(4-乙基哌嗪-1-基)苯胺,得到黄色固体,产率63%。
对化合物5进行检测:M.p.174.2-174.9 °C; IR (KBr): 3251, 2832, 1676,1531, 1435, 1322, 1231, 1163, 879, 802cm-1.1H NMR (400 MHz, CDCl3)δ8.89 (s,1H), 7.63 (dd,J= 8.8, 2.2 Hz, 2H), 7.09 (d,J= 2.0Hz, 1H), 6.94 (dd,J= 8.9,2.2 Hz, 2H), 6.73 (d,J= 2.2 Hz,2H), 6.51 (dd,J= 16.8, 10.6, 2.0 Hz, 1H), 6.40(q,J= 2.3 Hz,1H), 6.24 (dt,J= 16.9, 2.1 Hz, 1H), 5.66 (dt,J= 10.4, 2.1 Hz,1H), 4.17 (dt,J= 7.0, 3.5 Hz, 2H), 3.83 (d,J= 2.1 Hz, 6H),3.70 – 3.61 (m,2H), 3.55 – 3.45 (m, 2H), 3.36 (t,J= 4.7 Hz, 4H), 2.94(d,J= 5.3 Hz, 4H), 2.79(q,J= 7.6 Hz, 2H), 2.38 (t,J= 4.8 Hz, 4H), 2.34 – 2.28 (m, 2H), 1.91 (q,J=7.5 Hz, 2H), 1.55 (p,J= 7.8 Hz, 2H), 1.37 – 1.28 (m, 5H).13C NMR (100 MHz,CDCl3)δ165.2, 161.3, 161.3, 156.2, 152.7, 150.3, 145.5, 135.9, 134.3, 127.8,127.4, 122.7, 119.8, 119.8, 117.9, 117.9, 116.1, 110.8, 104.8, 104.8, 98.5,58.1, 55.4, 55.4, 53.4, 52.6, 52.3, 52.1, 52.1, 49.0, 49.0, 45.5, 43.9, 41.7,29.8, 26.1, 24.5, 10.6. HRMS (ESI): calculated for C38H51N8O3 +[M+H]+: 667.8710,found 667.8711。
实施例6
一种吡咯并嘧啶衍生物(记为化合物6),其结构如下所示:
化合物6,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A5制备所用N,N-二甲基乙醇胺改为4-(4-甲基哌嗪-1-基)苯胺,得到黄色固体,产率60%。
对化合物6进行检测:M.p.163.3-163.9 °C; IR (KBr): 3245, 2823, 1659,1532, 1435, 1302, 1231, 1159, 879, 811cm-1.1H NMR (400 MHz, CDCl3)δ8.89 (s,1H), 7.62 (d,J= 8.9 Hz, 2H), 7.09 (s, 1H), 6.95 (d,J= 8.9 Hz, 2H), 6.73 (d,J=2.3 Hz, 2H), 6.52 (dd,J= 16.8, 10.5Hz, 1H), 6.41 (t,J= 2.3 Hz, 1H), 6.26 (dd,J= 16.9, 2.0 Hz,1H), 5.67 (dd,J= 10.5, 2.0 Hz, 1H), 4.17 (t,J= 6.9 Hz, 2H),3.84 (s, 6H), 3.65 (d,J= 5.5 Hz, 2H), 3.49 (t,J= 5.0 Hz, 2H),3.24 (t,J= 4.9Hz, 4H), 2.73 (t,J= 4.8 Hz, 4H), 2.45 (s, 3H),2.37 (q,J= 5.4 Hz, 4H), 2.30(t,J= 7.5 Hz, 2H), 1.91 (p,J= 7.1 Hz, 2H), 1.55 (p,J= 7.6 Hz, 2H), 1.35 (h,J=7.4, 6.5Hz, 2H).13C NMR (100 MHz, CDCl3)δ165.2, 161.3,161.3, 156.3, 152.8,150.3, 146.1, 136.0, 133.8, 127.8, 127.5, 122.6, 119.9,119.9, 117.5, 117.5,116.1, 104.8, 104.8, 98.5, 58.1, 55.4, 55.4, 54.9, 54.9,53.4, 52.7, 49.67,49.7, 45.6, 45.6, 43.9, 41.8, 29.8, 26.2, 24.5. HRMS (ESI): calculated forC37H49N8O3 +[M+H]+: 653.8440, found 653.8442。
实施例7
一种吡咯并嘧啶衍生物(记为化合物7),其结构如下所示:
化合物7,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A4制备所用的叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯改为叔丁基-4-(2-羟乙基)哌嗪-1-羧酸酯,将化合物A5制备所用N,N-二甲基乙醇胺改为4-(4-甲基哌嗪-1-基)苯胺,得到黄色固体,产率60%。
对化合物7进行检测:M.p.141.3-142.6 °C; IR (KBr): 3235, 2813, 1649,1512, 1425, 1352, 1232, 1176, 880, 812cm-1.1H NMR (400 MHz, CDCl3)δ8.89 (s,1H), 7.65 – 7.47 (m, 2H), 7.15 (s, 1H), 7.00 – 6.86 (m, 2H), 6.73 (d,J= 2.3Hz, 2H), 6.51 (dd,J= 16.8, 10.5 Hz, 1H), 6.42 (t,J= 2.3Hz, 1H), 6.26 (dd,J=16.8, 2.0 Hz, 1H), 5.67 (dd,J= 10.5, 2.0Hz, 1H), 4.28 (t,J= 6.4 Hz, 2H), 3.84(s, 6H), 3.73 – 3.37 (m, 4H),3.23 (t,J= 5.0 Hz, 4H), 2.81 (t,J= 6.5 Hz, 2H),2.70 (t,J= 4.9 Hz, 4H), 2.53 (dt,J= 10.4, 5.0 Hz, 4H), 2.42 (s, 3H).13CNMR(100 MHz, CDCl3)δ165.3, 161.3, 161.3, 156.4, 152.9,150.4, 146.5, 136.0,133.4, 127.9, 127.4, 122.8, 120.4, 120.4, 117.2, 117.2,116.2, 110.8, 104.9,104.9, 98.5, 57.55, 55.4, 55.4, 55.0, 55.0, 53.4, 52.8,49.7, 49.7, 45.8,45.7,41.9, 41.5. HRMS (ESI):calculated for C34H43N8O3 +[M+H]+: 611.7630, found611.7633.
实施例8
一种吡咯并嘧啶衍生物(记为化合物8),其结构如下所示:
化合物8,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A4制备所用的叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯改为叔丁基-4-(3-羟丙基)哌嗪-1-羧酸酯,将化合物A5制备所用N,N-二甲基乙醇胺改为4-(4-甲基哌嗪-1-基)苯胺,得到黄色固体,产率60%。
对化合物8进行检测:M.p.151.3-152.1 °C; IR (KBr): 3246, 2813, 1661,1542, 1415, 1362, 1232, 1156, 877, 801cm-1.1H NMR (400 MHz, CDCl3)δ8.88 (s,1H), 7.62 (d,J= 8.9 Hz, 2H), 7.12 (s, 1H), 6.95 (d,J= 9.0 Hz, 2H), 6.72 (d,J=2.3 Hz, 2H), 6.53 (dd,J= 16.8, 10.5Hz, 1H), 6.42 (t,J= 2.3 Hz, 1H), 6.26 (dd,J= 16.8, 2.0 Hz,1H), 5.68 (dd,J= 10.5, 1.9 Hz, 1H), 4.25 (t,J= 6.7 Hz, 2H),3.85 (s, 6H), 3.66 (d,J= 6.6 Hz, 2H), 3.49 (s, 2H), 3.33 – 3.19 (m,4H), 2.80(d,J= 5.4 Hz, 4H), 2.49 (s, 3H), 2.40 (q,J= 7.1,5.9 Hz, 6H), 2.08 (p,J= 6.8Hz, 2H).13C NMR (100 MHz, CDCl3)δ165.3, 161.3, 161.3, 156.2, 152.8, 150.2,146.1, 135.9, 127.9, 127.4,123.5, 122.9, 120.1, 120.1, 117.5, 117.5, 116.2,110.9, 104.9, 104.9, 98.5,55.4, 55.4, 55.1, 54.7, 54.75, 53.4, 49.4, 49.4,45.7, 45.4, 42.3, 41.8, 40.9,26.9. HRMS (ESI): calculated for C35H44N8O3 +[M+H]+:625.7900, found 625.7904。
实施例9
一种吡咯并嘧啶衍生物(记为化合物9),其结构如下所示:
化合物9,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A4制备所用的叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯改为叔丁基-4-(4-羟丁基)哌嗪-1-羧酸酯,将化合物A5制备所用N,N-二甲基乙醇胺改为4-(4-甲基哌嗪-1-基)苯胺,得到黄色固体,产率59%。
对化合物9进行检测:M.p.171.1-171.9 °C; IR (KBr): 3241, 2822, 1655,1537, 1436, 1301, 1232, 1139, 889, 791cm-1.1H NMR (400 MHz, CDCl3)δ8.89 (s,1H), 7.61 (d,J= 8.5 Hz, 2H), 7.10 (s, 1H), 6.95 (d,J= 8.6 Hz, 2H), 6.73 (s,2H), 6.53 (dd,J= 16.8, 10.5 Hz, 1H), 6.42 (d,J= 2.2 Hz, 1H), 6.27 (dd,J=16.7, 1.9 Hz, 1H), 5.68 (dd,J=10.5, 1.9 Hz, 1H), 4.20 (t,J= 6.9 Hz, 2H), 3.85(s, 6H), 3.64 (s, 2H),3.49 (d,J= 6.6 Hz, 2H), 3.34 – 3.23 (m, 4H), 2.79 (s,4H), 2.49 (s,3H), 2.38 (dt,J= 12.1, 6.5 Hz, 6H), 1.92 (q,J= 7.3 Hz, 2H),1.54(q,J= 7.7 Hz, 2H).13C NMR (100 MHz, CDCl3)δ165.2, 161.3, 161.3, 156.3, 152.8,150.3, 146.1, 136.0, 133.7, 127.8,127.4, 122.5, 120.1, 120.1, 117.5, 117.5,116.3, 110.9, 104.9, 104.9, 98.5,57.6, 57.6, 55.4, 55.4, 54.8, 54.8, 53.3,52.7, 49.5, 49.5, 45.5, 43.8, 29.7,27.8, 23.8. HRMS (ESI): calculated forC36H47N8O3 +[M+H]+: 639.8170, found 639.8173。
实施例10
一种吡咯并嘧啶衍生物(记为化合物10),其结构如下所示:
化合物10,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A4制备所用的叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯改为叔丁基-4-(6-羟己基)哌嗪-1-羧酸酯,将A5制备所用N,N-二甲基乙醇胺改为4-(4-甲基哌嗪-1-基)苯胺,得到黄色固体,产率61%。
对化合物10进行检测:M.p.171.8-172.3 °C; IR (KBr): 3262, 2925, 1646,1581, 1428, 1316, 1234, 1173, 856, 805cm-1.1H NMR (400 MHz, CDCl3)δ8.90 (s,1H), 7.63 (d,J= 9.0 Hz, 2H), 7.10 (s, 1H), 6.95 (d,J= 9.0 Hz, 2H), 6.74 (d,J=2.3 Hz, 2H), 6.53 (dd,J= 16.8, 10.5Hz, 1H), 6.42 (t,J= 2.3 Hz, 1H), 6.27 (dd,J= 16.8, 2.0 Hz,1H), 5.68 (dd,J= 10.5, 2.0 Hz, 1H), 4.17 (t,J= 7.0 Hz, 2H),3.85 (s, 6H), 3.60 (d,J= 54.8 Hz, 4H), 3.28 (t,J= 5.0 Hz,4H), 2.80 (t,J= 5.0Hz, 4H), 2.50 (s, 3H), 2.39 (t,J= 5.0 Hz,4H), 2.34 – 2.26 (m, 2H), 1.93 –1.84 (m, 2H), 1.47 (s, 2H), 1.39 – 1.29 (m,4H).13C NMR (100 MHz, CDCl3)δ165.3,161.3,161.3, 156.2, 152.7, 150.3, 145.9, 136.0, 133.9, 127.9, 127.4, 122.7,119.9,119.9, 117.6, 117.6, 116.1, 110.9, 104.8, 104.8, 98.5, 58.33, 58.3,55.4, 55.4,54.8, 54.8, 53.4, 52.7, 49.5, 49.5, 45.5, 44.1, 41.7, 29.9, 26.9,26.6, 26.5. HRMS (ESI): calculated for C38H51N8O3 +[M+H]+: 667.8710, found667.8713。
实施例11
一种吡咯并嘧啶衍生物(记为化合物11),其结构如下所示:
化合物11,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A4制备所用的叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯改为1-Boc-3-羟甲基吡咯烷,将化合物A5制备所用N,N-二甲基乙醇胺改为4-(4-甲基哌嗪-1-基)苯胺,得到黄色固体,产率61%。
对化合物11进行检测:M.p.170.3-170.6 °C; IR (KBr): 3256, 2924, 1643,1565, 1422, 1313, 1246, 1175, 865, 811cm-1.1H NMR (400 MHz, CDCl3)δ8.91 (s,1H), 7.57 (d,J= 13.8 Hz, 2H), 7.08 (s, 1H), 6.94 (d,J= 12.7 Hz, 2H), 6.72 (s,2H), 6.45 – 6.37 (m, 2H), 6.32 (s, 1H), 5.74 – 5.56(m, 1H), 4.47 – 4.12 (m,2H), 3.85 (s, 6H), 3.80 – 3.40 (m, 5H), 3.31 (dt,J= 9.8, 4.6 Hz, 4H), 3.05 –2.71 (m, 5H), 2.51 (s, 3H), 2.12 – 2.00 (m, 1H),1.80 (dt,J= 12.4, 6.1 Hz,1H).13C NMR (100 MHz, CDCl3)δ164.6, 161.3, 161.3, 156.5, 152.9, 150.6, 146.0,135.7, 133.6, 128.3,127.9, 122.4, 120.4, 120.2, 117.6, 117.5, 116.8, 110.7,104.9, 104.9, 98.8,77.4, 77.2, 77.0, 76.7, 55.4, 55.4, 54.7, 49.9, 49.3,46.0, 45.7, 45.0, 40.3,38.2, 29.6, 27.9. HRMS (ESI): calculated for C33H40N7O3 +[M+H]+: 582.7210, found 582.7214。
实施例12
一种吡咯并嘧啶衍生物(记为化合物12),其结构如下所示:
化合物12,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A4制备所用的叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯改为N-Boc-4-哌啶甲醇,将化合物A5制备所用N,N-二甲基乙醇胺改为4-(4-甲基哌嗪-1-基)苯胺,得到黄色固体,产率61%。
对化合物12进行检测:M.p.151.3-152.1 °C; IR (KBr): 3228, 2931, 1642,1561, 1438, 1356, 1214, 1163, 852, 803cm-1.1H NMR (400 MHz, CDCl3)δ8.91 (s,1H), 7.60 (d,J= 7.3 Hz, 2H), 7.05 (s, 1H), 6.95 (d,J= 7.5 Hz, 2H), 6.73 (s,2H), 6.55 (ddd,J= 16.9, 10.6, 2.0 Hz, 1H),6.42 (s, 1H), 6.26 (dd,J= 16.9, 2.1Hz, 1H), 5.66 (dd,J=10.5, 2.0 Hz, 1H), 4.06 (d,J= 6.8 Hz, 2H), 3.85 (s, 6H),3.22 – 3.14(m, 4H), 3.02 (d,J= 12.9 Hz, 1H), 2.63 – 2.58 (m, 4H), 2.37 (s,3H).13CNMR (100 MHz, CDCl3)δ165.4, 162.5, 161.3, 161.3, 156.5,152.9, 150.4,146.3, 135.8, 133.5, 127.8, 122.9, 120.1, 120.1, 117.3, 117.3,116.3, 110.7,104.8, 104.8, 98.6, 55.4, 55.4, 54.9, 49.6, 49.5, 45.7, 45.6,41.8, 37.2,36.5, 31.4, 30.7, 29.6. HRMS (ESI):calculated for C34H42N7O3 +[M+H]+: 596.7480,found 596.7484。
实施例13
一种吡咯并嘧啶衍生物(记为化合物13),其结构如下所示:
化合物13,
具体制备方法为:与化合物1的制备方法类似,仅将化合物A4制备所用的叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯改为3-羟甲基氮杂环丁烷-1-羧酸叔丁酯,将化合物A5制备所用N,N-二甲基乙醇胺改为4-(4-甲基哌嗪-1-基)苯胺,得到黄色固体,产率60%。
对化合物13进行检测:M.p.142.5-143.1 °C; IR (KBr): 3262, 2915, 1656,1580, 1427, 1326, 1224, 1143, 836, 801cm-1.1H NMR (400 MHz, CDCl3)δ8.90 (s,1H), 7.65 – 7.49 (m, 2H), 7.05 (s, 1H), 6.97 – 6.88 (m, 2H), 6.71 (d,J= 2.3Hz, 2H), 6.43 (t,J= 2.2 Hz, 1H), 6.33 (dd,J= 16.9, 1.9Hz, 1H), 6.13 (dd,J=17.0, 10.3 Hz, 1H), 5.65 (dd,J= 10.3,1.8 Hz, 1H), 4.48 (dd,J= 14.1, 8.5 Hz,1H), 4.39 – 4.09 (m, 4H), 3.97(dd,J= 10.5, 5.2 Hz, 1H), 3.84 (s, 6H), 3.24(q,J= 8.7, 6.8Hz, 5H), 2.73 (t,J= 4.8 Hz, 4H), 2.45 (s, 3H).13C NMR (100MHz,CDCl3)δ165.8, 161.3, 161.2, 156.6, 153.0, 150.7,146.4, 135.6, 133.2, 127.6,125.6, 122.0, 120.4, 120.4, 117.3, 117.3, 116.9,110.8, 104.9, 104.9, 98.8,55.4, 55.4, 54.9, 54.9, 53.6, 51.1, 49.4, 49.4,47.3, 45.6, 29.4. HRMS (ESI):calculated for C32H38N7O3 +[M+H]+: 568.6940, found 568.6943。
实施例14
一种吡咯并嘧啶衍生物(记为化合物14),其结构如下所示:
化合物14
具体制备方法为:与化合物1的制备方法类似,仅将化合物A4制备所用的叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯改为N-Boc-4-羟基哌啶,将化合物A5制备所用N,N-二甲基乙醇胺改为4-(4-甲基哌嗪-1-基)苯胺,得到黄色固体,产率58%。
对化合物14进行检测:M.p.161.3-162.1 °C; IR (KBr): 3232, 2925, 1676,1523, 1426, 1316, 1214, 1134, 846, 802cm-1.1H NMR (400 MHz, CDCl3)δ8.90 (s,1H), 7.58 (d,J= 9.0 Hz, 2H), 7.10 (s, 1H), 6.95 (d,J= 9.0 Hz, 2H), 6.71 (d,J=2.3 Hz, 2H), 6.65 (dd,J= 16.8, 10.6Hz, 1H), 6.42 (t,J= 2.2 Hz, 1H), 6.34 (dd,J= 16.8, 2.0 Hz,1H), 5.75 (dd,J= 10.5, 2.0 Hz, 1H), 4.94 (d,J= 13.4 Hz, 1H),4.77 (tt,J= 10.7, 4.5 Hz, 1H), 4.20 (d,J= 13.7 Hz, 1H), 3.84(s, 6H), 3.27 (t,J= 5.1 Hz, 5H), 2.77 (t,J= 4.9 Hz, 5H), 2.48(s, 3H), 2.23 – 1.97 (m, 4H).13CNMR (100 MHz, CDCl3)δ165.51, 161.29, 161.29, 156.13, 152.28, 150.60, 146.15,135.78, 133.54, 128.30,127.50, 120.22, 120.16, 119.59, 117.45, 117.45,116.66, 111.20, 104.79, 104.79,98.83, 55.43, 55.43, 54.83, 54.83, 52.08,49.42, 49.42, 45.53, 45.32, 41.71,32.58, 31.36. HRMS (ESI): calculated forC33H40N7O3 +[M+H]+: 582.7210, found 582.7213。
实施例15
一种吡咯并嘧啶衍生物(记为化合物15),其结构如下所示:
化合物15
具体制备方法为:与化合物1的制备方法类似,仅将化合物A4制备所用的叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯改为BOC-3-氨基苄醇,将化合物A5制备所用N,N-二甲基乙醇胺改为4-(4-甲基哌嗪-1-基)苯胺,得到黄色固体,产率61%。
对化合物15进行检测:M.p.201.3-202.1 °C; IR (KBr): 3247, 2933, 1676,1521, 1435, 1302, 1214, 1167, 872, 805cm-1.1H NMR (400 MHz, CDCl3)δ8.88 (s,1H), 7.83 (s, 1H), 7.59 (s, 1H), 7.53 (d,J= 8.6 Hz, 2H), 7.18(s, 1H), 7.09(s, 1H), 7.00 (d,J= 7.9 Hz, 1H), 6.88 (d,J= 8.7Hz, 2H), 6.71 (d,J= 2.3 Hz,2H), 6.40 (ddd,J= 8.2, 6.9, 1.5Hz, 2H), 6.27 (dd,J= 16.8, 10.1 Hz, 1H), 5.71(dd,J= 10.0,1.5 Hz, 1H), 3.82 (s, 6H), 3.22 (t,J= 4.9 Hz, 4H), 2.75 (t,J=4.9Hz, 4H), 2.46 (s, 3H).13C NMR (100 MHz, CDCl3)δ163.7, 161.2, 161.2, 156.4,152.8, 150.4, 145.9, 138.4, 137.9, 135.8, 133.7,131.1, 129.5, 127.9, 123.5,122.7, 120.1, 120.1, 119.5, 119.1, 117.5, 117.5,116.7, 110.8, 104.8, 104.8,98.7, 55.4, 55.4, 54.8, 54.7, 49.3, 49.3, 47.7,45.4. HRMS (ESI): calculatedfor C35H38N7O3 +[M+H]+: 604.7270, found 604.7274。
实施例16
一种吡咯并嘧啶衍生物(记为化合物16),其结构如下所示:
化合物16
具体制备方法为:与化合物1的制备方法类似,仅将化合物A4制备所用的叔丁基-4-(5-羟戊基)哌嗪-1-羧酸酯改为BOC-3-氨基苄醇,将化合物A5制备所用N,N-二甲基乙醇胺改为N-BOC-2-(4-氨基苯基)乙醇,得到黄色固体,产率60%。
对化合物16进行检测:M.p.213.3-213.9 °C; IR (KBr): 3238, 2865, 1673,1535, 1436, 1302, 1231, 1168, 870, 792cm-1.1H NMR (400 MHz, CDCl3)δ8.88 (s,1H), 7.61 (t,J= 9.2 Hz, 4H), 7.24 – 7.09 (m, 4H), 7.03 – 6.94(m, 3H), 6.69(d,J= 2.2 Hz, 2H), 6.52 – 6.25 (m, 4H), 5.75 (d,J= 10.1 Hz, 1H), 4.40 – 4.30(m, 2H), 3.84 (s, 6H), 3.28 (t,J= 4.8 Hz,4H), 3.12 (s, 2H), 2.82 (d,J= 5.6Hz, 4H), 2.50 (s, 3H).13CNMR (100 MHz, CDCl3)δ163.6, 161.2, 161.2, 156.4,152.8,150.3, 145.9, 138.4, 137.9, 135.8, 133.7, 131.1, 129.5,127.9, 123.5,122.7,120.1, 120.1, 119.4, 119.1, 117.5, 117.5, 116.6, 110.8, 104.8, 104.8,98.7,55.4, 55.4, 54.7, 54.7, 49.3, 49.3, 47.7, 47.7,45.3.HRMS (ESI):calculated for C36H40N7O3 +[M+H]+: 618.7540, found 618.7543。
实施例17
本实施例对实施例1-16制得的化合物进行酶活测试实验。
本发明以AZD4547为阳性对照,采用均相时间分辨荧光(HIRF)评估化合物1-16对FGFR1,2,3三种亚型的激酶抑制活性。
表1基于酶活结果的构效关系研究
结果如表1所示,化合物1-16均可不同程度的抑制FGFR1/2/3的蛋白活性,其中化合物6和化合物10对FGFR1、FGFR2抑制效果最优,因此对这两种化合物展开了一系列检测。
实施例18
本实施例对化合物6和化合物10对特定癌细胞系的抗增殖活性进行了检测。
检测方法:取对数生长期的细胞,将SNU-16细胞以8000个/孔的密度,每孔90 uL接种于96孔板中,将待测化合物6和化合物10配置成所需的不同浓度加入,置于5%CO2,37 ℃培养箱中孵育48 h。向每孔中加入10 μLCCK-8溶液,在培养箱中继续培养6 h。使用酶标仪测定在450 nm处的OD值,通过GraphPad Prizm7统计并计算出相应的IC50值。
表2体外抗增殖活性测定
化合物编号 | SNU-16/IC50(μM) |
6 | 0.255 |
10 | 0.097 |
如表2体外抗增殖实验表明,化合物6和化合物10均能对FGFR2高表达的SNU-16肿瘤细胞表现出抗增殖作用,其中,化合物10能以低纳摩尔浓度有效抑制FGFR2高表达的SNU-16肿瘤细胞的增殖。
实施例19
本实施例对化合物6和化合物10抑制小鼠体内肿瘤生长进行了检测。
为了评估化合物6和化合物10在体内抗肿瘤功效,用FGFR2高表达的的人胃癌细胞SNU-16建立了小鼠皮下移植瘤模型。
检测方法:胰酶消化收集处于对数生长期的细胞,1×PBS洗涤三次,细胞沉淀用重悬液(1640培养基:Matrigel=1:1)稀释至1×108/mL,按5×106个/只的数量将细胞接种至5-周龄的雌性Balb/c Nude小鼠前肢腋窝下。待肿瘤体积长至50-100 mm3时,随机将小鼠分为三组(对照组、100 mg/kg化合物6、100mg/kg化合物10组),每组6只小鼠,化合物6和化合物10每天分别口服给药,并量取肿瘤体积和小鼠体重,给药17天后处理小鼠,剖取肿瘤组织,固定于福尔马林溶液备用。
表3肿瘤生长抑制效果测定
化合物编号 | 肿瘤生长抑制率(TGI%) |
6 | 60.6% |
10 | 87.3% |
如表3体内抗增殖实验结果所示,化合物6和化合物10均能显著抑制小鼠体内SNU-16肿瘤细胞生长,其中,化合物10的体内肿瘤生长抑制率达到87.3%,显示出强效的体内抑瘤作用效果,表明化合物10是一种有潜力的药物分子用于FGFR2异常的癌症的治疗。后续将会以此为先导化合物进行FGFR2选择性小分子抑制剂的开发。
综上所述,本发明合成的7H-吡咯并[2,3-d]嘧啶的新型衍生物可以作为对FGFR2的有效和选择性抑制剂。
以上所述,只是本发明的较佳实施例而已,本发明并不局限于上述实施方式,只要其以相同的手段达到本发明的技术效果,都应属于本发明的保护范围。在本发明的保护范围内其技术方案和/或实施方式可以有各种不同的修改和变化。
Claims (10)
1.一种吡咯并嘧啶衍生物,其特征在于,其结构如式I所示:
式I,
式I中,Linker取自烷基、烷氧基、杂原子取代基、取代氮杂环、芳基、取代芳基结构中的一种;
X取自N、O结构中的任意一种;
R取自烷基、烷氧基、杂原子取代基、取代氮杂环、芳基或-Ph-N(R1R2)N-中的一种。
2.根据权利要求1所述的吡咯并嘧啶衍生物,其特征在于,式I中,Linker、R、X分别独立选自以下结构1-16中的一种:
结构1中,Linker为,R对应为/>,X对应为O;
结构2中,Linker为,R对应为/>,X对应为O;
结构3中,Linker为,R对应为/>,X对应为N;
结构4中,Linker为,R对应为/>,X对应为N;
结构5中,Linker为,R对应为/>,X对应为N;
结构6中,Linker为,R对应为/>,X对应为N;
结构7中,Linker为,R对应为/>,X对应为N;
结构8中,Linker为,R对应为/>,X对应为N;
结构9中,Linker为,R对应为/>,X对应为N;
结构10中,Linker为,R对应为/>,X对应为N;
结构11中,Linker为,R对应为/>,X对应为N;
结构12中,Linker为,R对应为/>,X对应为N;
结构13中,Linker为,R对应为/>,X对应为N;
结构14中,Linker为,R对应为/>,X对应为N;
结构15中,Linker为,R对应为/>,X对应为N;
结构16中,Linker为,R对应为/>,X对应为N。
3.根据权利要求1所述的吡咯并嘧啶衍生物,其特征在于,其结构为式II或式III所示:
式II,/>式III。
4.一种权利要求1-3所述任一项的吡咯并嘧啶衍生物的制备方法,其特征在于,其制备路线为:
。
5.权利要求1-3任一项所述的吡咯并嘧啶衍生物或其在药学上可接受的盐在制备FGFR2抑制剂中的应用。
6.根据权利要求5所述的应用,其特征在于,所述FGFR2抑制剂可用于制备治疗具有FGFR2异常的相关癌症的药物。
7.根据权利要求6所述的应用,其特征在于,所述相关癌症包括胃癌、肺癌、卵巢癌和子宫内膜癌。
8.一种药物组合物,其特征在于,包括权利要求1-3任一项所述的吡咯并嘧啶衍生物或其药学上可接受的盐。
9.根据权利要求8所述的药物组合物,其特征在于,所述药物组合物包括赋形剂。
10.根据权利要求9所述的药物组合物,其特征在于,所述赋形剂为阿拉伯胶、糖浆、羊毛脂和淀粉中的至少一种。
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