CN108727285A - 增加氰基苯胺基取代喹唑啉类化合物的生物活性及其应用 - Google Patents
增加氰基苯胺基取代喹唑啉类化合物的生物活性及其应用 Download PDFInfo
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Abstract
本发明涉及增加的生物活性的化合物,特别涉及到增加的抗胃癌、皮肤癌、食管癌、宫颈癌、卵巢癌、白血病、骨髓瘤、肝癌、喉癌、直肠癌、结肠癌、人退行性癌细胞、甲状腺癌、胰腺癌、白血病、肾癌、黑色素瘤及其白癜风治疗、皮炎治疗、抗艾滋病、免疫抑制活性之类的药物活性的化合物。具体来讲本发明涉及到一种具有结构(Ⅰ)的氰基苯胺基取代喹唑啉类化合物,从而增加所述化合物及其药学上可接受的盐、溶剂合物的生物活性。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一类氰基苯胺基取代的喹唑啉化合物或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物的增加生物活性及其在药物中的应用。该类化合物或其药学上可接受的盐对多种实体肿瘤细胞增殖具有较好的抑制活性,未来有可能作为治疗药物得已应用。
背景技术
临床上,恶性肿瘤是一类以细胞增殖失控和分化异常且极易发生转移为特征的常见类疾病,其发病率及致死率均较高,成为严重威胁人类生命健康的重大疾病之一。手术治疗、放疗和化疗是目前临床治疗恶性肿瘤的常用传统方法,在临床治疗过程中,这些方法均具有一定的疗效,但是其副作用较大,对病患伤害较大,使生存质量大幅下降。传统的抗肿瘤药物主要是细胞毒类药物,其中大多数是非选择性的,毒副作用大,易产生耐药性。确切的特异性作用靶点的发现对于抗肿瘤药物的研发至关重要,受体酪氨酸蛋白激酶在恶性肿瘤致病机理中具有极其重要的作用,具有特异性的PTK抑制剂作为抗肿瘤治疗药物的研究与开发是当前生物和药物化学领域的热点话题之一。
研究发现,实体瘤的发病率在恶性肿瘤中占绝大多数,其发生发展以及侵袭与转移均与EGFR密切相关。以EGFR为药物作用靶点,对恶性肿瘤进行靶向分子治疗,可以提高临床治疗的特异性和选择性,同时降低毒副作用,被公认为是治疗恶性肿瘤的希望之星。EGFR是一种具有胞质区域的跨膜糖蛋白,属于酪氨酸蛋白激酶受体家族,与细胞信号转导密切相关,可以活化多个重要的下游信号级联,影响细胞的生长、增殖和分化等一系列活动。临床研究表明,EGFR广泛分布于人体各组织的细胞膜上,在多种肿瘤细胞中均表达或高表达,包括乳腺癌、头颈部癌、胃癌、结肠癌、食管癌、膀胱癌、肾癌、胰腺癌和卵巢癌等。EGFR的激活与恶性肿瘤的发生和生长密切相关,包括肿瘤细胞的增殖、细胞凋亡的抑制、细胞新生血管的生成和肿瘤细胞的浸润与转移等。目前,用于攻击恶性肿瘤中EFGR的手段主要有两种,其一为针对受体胞外配体结合区域,中和或阻止配体与受体的结合,从而阻断下游信号转导;其二为作用于受体胞内酪氨酸激酶区域的EGFR-TK抑制剂,该类抑制剂具有高效性和特异性,体内的抗肿瘤治疗效果为其临床研究铺平了道路。基于目前的研究成果,进一步探寻和研究EGFR-TK的抑制剂将是未来有效抗肿瘤新药研发的重要策略。
喹唑啉类化合物的药物开发引人关注,我们近期研究发现氰基苯胺基喹唑啉类化合物具有一些新的生物活性和潜在应用价值,不仅具有较高的肿瘤治疗活性,还有皮肤病的良好治疗作用。
发明内容
本发明的目的在于提供氰基苯胺基喹唑啉类化合物用于某些抗癌治疗药物和治疗白癜风皮肤病的药物和临床应用。
本发明公开了一种涉及如下结构(Ⅰ)的氰基苯胺基喹唑啉类化合物或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物在药物治疗中的应用。
根据本发明提供的式(Ⅰ)所示喹唑啉类化合物:
其中:氰基(CN)为2-氰基,3-氰基,4-氰基;
其中:X为H,F,Cl,Br,CF3
其中R为二甲氨基、二乙胺基、羟乙基甲氨基、二羟乙基氨基、苄基甲氨基、苄基羟乙基氨基、吡咯烷基、N-吗啉基、哌啶基、4-甲基哌啶基、4-羟基哌啶基、4-羟甲基哌啶基、2-羟乙基哌啶基、4-乙氧羰基哌啶基、4-苯基哌啶基、四氢异喹啉基、4-二甲氨基哌啶基、4-哌啶基哌啶基、4-甲基哌嗪基、4-乙基哌嗪基、4-羟乙基哌嗪基、4-吡啶基哌嗪基。
本发明在药物中的应用所涉及包括前述任一项式(Ⅰ)所示的化合物或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物,其中术语“含有该化合物或其药学上可接受的盐的药物组合物”表示为含有药学上有效治疗剂量的式(Ⅰ)所示的化合物或其药学上可接受的盐可以与一种或多种药学上可接受的载体、赋形剂或稀释剂共同制成药物组合物,该组合物可以制成固体口服剂、液体口服剂、注射剂等剂型。
本发明涉及的化学合成药物的药效学实验证明:本发明涉及的喹唑啉类化合物具有靶向性高、特异性强、毒副作用小等优点,具有广阔的临床应用前景。本发明的目的在于提供上述任一项式(Ⅰ)所示的喹唑啉类化合物对其增加在抗肿瘤药物中的应用,如抗胃癌、皮肤癌、食管癌、宫颈癌、卵巢癌、白血病、骨髓瘤、喉癌、人盲肠腺癌、膀胱癌、直肠癌、结肠癌、人退行性癌细胞、甲状腺癌、胰腺癌、白血病、肾癌、黑色素瘤药物方面;在抗肝癌(如SMMC7721、MHCC97L、MHCC97H、Bel7402、Bel7404、Bel7405、HB611、Huh7、HCC-LM3、HHCC、Li-7、Hep3B、HEPA-6、Hep3B2.1-7、HepB1.2、HL7702(LO2)、HAb18、F11、HTB-52SK-HEP-1、HepaRG、HepG2.2.15、HepG2-RHBV、HUH-6、HUH-7、SNU-182、SNU-387、MCA-RH7777、PLC/PRF/5、QSG7701、QGY-7701、QGY-7703、SK-HEP-1以及未发现的新型肝癌细胞)药物中的应用;在制备白癜风治疗、皮炎治疗、免疫抑制药物方面的应用;在抗艾滋病药物方面的应用。
具体实施方式
下面是本发明涉及的具体化合物实施例。所述的实施例用于描述本发明使本领域技术人员能更清楚地理解和实施本发明涉及的化合物但并不以任何方式局限于于此,仅为其例证和代表。
本发明涉及的取代喹唑啉类化合物实施例
实施例1
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-二甲氨基)丙氧基)喹唑啉-4-胺(Ⅰ-1)
粉末状固体;m.p.:170-172℃;1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.12(d,J=8.5Hz,2H,ArH),8.04(m,3H,ArH),7.27(s,1H,ArH),4.28(m,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),2.69(m,2H,-NCH2 CH2CH2O-),2.18(s,6H,-CH3),1.85(m,2H,-OCH2 CH2 CH2N-);ESI-MS:m/z calcd found 378.13[M+H]+.
实施例2
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-二乙氨基)丙氧基)喹唑啉-4-胺(Ⅰ-2)
粉末状固体;m.p.:178-181℃;1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.12(d,J=8.5Hz,2H,ArH),8.03(m,3H,ArH),7.23(s,1H,ArH),4.28(m,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),2.89(m,4H,-NCH2 CH3),2.59(m,2H,-NCH2 CH2CH2O-),1.87(m,2H,-OCH2 CH2 CH2N-),1.01(t,6H,-NCH2 CH3 );ESI-MS:m/z calcd found 406.33[M+H]+.
实施例3
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-羟乙基甲氨基)丙氧基)喹唑啉-4-胺(Ⅰ-3)
粉末状固体;m.p.:218-220℃;1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.11(d,J=8.5Hz,2H,ArH),8.03(m,3H,ArH),7.23(s,1H,ArH),4.18(m,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),3.46(t,2H,-CH2 OH),2.45-2.61(m,4H,-NCH2 -),2.21(s,3H,-NCH3),1.89(m,2H,-OCH2 CH2 CH2N-);ESI-MS:m/z calcd found 408.23[M+H]+.
实施例4
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-二羟乙基氨基)丙氧基)喹唑啉-4-胺(Ⅰ-4)
粉末状固体;m.p.:162-164℃;1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.11(d,J=8.5Hz,2H,ArH),8.03(m,3H,ArH),7.23(s,1H,ArH),4.18(m,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),3.46-3.52(m,4H,-CH2 CH2 OH),2.45-2.63(m,6H,-NCH2 -),1.87(m,2H,-OCH2 CH2 CH2N-);ESI-MS:m/z calcd found 438.20[M+H]+.
实施例5
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-苄基甲氨基)丙氧基)喹唑啉-4-胺(Ⅰ-5)
粉末状固体;m.p.:234-236℃;1H NMR(400MHz,DMSO-d6):δ9.71(s,1H,NH),8.48(s,1H,ArH),8.03(q,2H,ArH),7.79(s,1H,ArH),7.73(q,2H,ArH),7.42(t,2H,ArH),7.34(m,2H,ArH),7.26(m,2H,ArH),5.21(s,2H,ArCH2 -),4.18(m,2H,-OCH2 CH2CH2N-),3.89(s,3H,-OCH3),2.63(m,2H,-NCH2 -),2.56(s,3H,-NCH3),1.87(m,2H,-OCH2 CH2 CH2N-);ESI-MS:m/z calcd found 454.22[M+H]+.
实施例6
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-苄基羟乙基氨基)丙氧基)喹唑啉-4-胺(Ⅰ-6)
粉末状固体;m.p.:215-218℃;1H NMR(400MHz,DMSO-d6):δ9.83(s,1H,NH),8.48(s,1H,ArH),8.03(d,2H,ArH),7.83(s,1H,ArH),7.73(d,2H,ArH),7.41(t,2H,ArH),7.34(m,2H,ArH),7.26(m,2H,ArH),5.19(s,2H,ArCH2 -),4.18(m,2H,-OCH2 CH2CH2N-),3.89(s,3H,-OCH3),2.45-2.63(m,4H,-NCH2-),3.46-3.52(m,2H,-CH2 CH2 OH),1.89(m,2H,-OCH2 CH2 CH2N-);ESI-MS:m/z calcd found 484.21[M+H]+.
实施例7
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺(Ⅰ-7)
粉末状固体;m.p.:160-162℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.12(d,J=8.5Hz,2H,ArH),8.04(m,3H,ArH),7.23(s,1H,ArH),4.20(m,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),2.58(m,2H,-NCH2-),2.50(m,2H,-NCH2-),2.10–1.93(m,2H,-NCH2 CH2CH2O-),1.91(m,2H,-OCH2 CH2 CH2N-),1.70(m,4H,-CH2CH2-).ESI-MS:m/z calcdfound 404.33[M+H]+.
实施例8
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺(Ⅰ-8)
粉末状固体;m.p.:172-174℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.12(d,J=8.5Hz,2H,ArH),7.92–7.78(m,3H,ArH),7.23(s,1H,ArH),4.19(t,2H,-OCH 2CH2CH2N-),3.99(s,3H,-OCH3),1.95(dd,J=17.5,10.8Hz,6H,-NCH2-),1.60–1.38(m,8H,-OCH2 CH2 CH2N-and-CH2CH2CH2-).ESI-MS:m/z calcd found 418.33[M+H]+.
实施例9
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺(Ⅰ-9)
粉末状固体;m.p.:170-172℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.13(d,J=8.6Hz,2H,ArH),7.97–7.77(m,3H,ArH),7.23(s,1H,ArH),4.18(t,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),2.88(t,J=10.6Hz,2H,-NCH2 CH2CH2O-),1.58(t,J=12.6Hz,4H,-NCH2-),1.38–1.13(m,10H,-OCH2 CH2 CH2N-and piperidine-H,-CH3).ESI-MS:m/z calcd found 432.42[M+H]+.
实施例10
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-羟基哌啶基))丙氧基)喹唑啉-4-胺(Ⅰ-10)
粉末状固体;m.p.:194-196℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.11(d,J=8.6Hz,2H,ArH),7.97(m,3H,ArH),7.23(s,1H,ArH),4.18(t,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),3.67(m,1H,-CHOH),2.82-2.77(m,4H,-NCH2-),2.31-2.55(m,2H,-NCH2-),1.91-1.61(m,6H,-OCH2 CH2 CH2N-and-NCH2 CH2 -).ESI-MS:m/z calcdfound 434.32[M+H]+.
实施例11
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(2-羟乙基哌啶基))丙氧基)喹唑啉-4-胺(Ⅰ-11)
粉末状固体;m.p.:194-194℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.11(d,J=8.5Hz,2H,ArH),7.96–7.78(m,3H,ArH),7.23(s,1H,ArH),4.17(t,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),3.87(t,2H,-CH2 CH2 OH),2.87-2.57(m,5H,-NCH2-),1.99(m,2H,-OCH2 CH2 CH2N-),1.65–1.37(m,8H,-CH2 CH2OH and-CH2CH2CH2-).ESI-MS:m/zcalcd found 462.34[M+H]+.
实施例12
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-乙氧羰基哌啶基))丙氧基)喹唑啉-4-胺(Ⅰ-12)
粉末状固体;m.p.:192-194℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.13(d,J=8.6Hz,2H,ArH),7.97–7.77(m,3H,ArH),7.23(s,1H,ArH),4.18(t,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),2.87(m,6H,-NCH2 CH2-),2.28(m,1H,-CHCO-),2.21-2.12(m,8H,-NCH2 CH2 -,-OCH2 CH2 CH2N-and-OCH2 CH3),1.38(t,3H,-OCH2CH3).ESI-MS:m/zcalcd found 490.24[M+H]+.
实施例13
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-苯基哌啶基))丙氧基)喹唑啉-4-胺(Ⅰ-13)
粉末状固体;m.p.:194-196℃.1H NMR(400MHz,DMSO-d6):δ9.69(s,1H,NH),8.47(d,1H,ArH),8.03(d,J=8.7Hz,2H,ArH),7.85–7.71(m,4H,ArH),7.56(m,3H,ArH),7.24-7,03(m,2H,ArH),4.13(t,2H,-OCH2 CH2CH2N-),3.89(s,3H,-OCH3),2.85(m,1H,-CHAr),2.12(m,2H,-OCH2 CH2 CH2N-),1.88-1.855(m,6H,-NCH2-),1.68–1.41(m,4H,-NCH2 CH2 -).ESI-MS:m/z calcd found 494.25[M+H]+.
实施例14
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-四氢异喹啉基)丙氧基)喹唑啉-4-胺(Ⅰ-14)
粉末状固体;m.p.:234-236℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.11(d,J=8.6Hz,2H,ArH),7.97–7.68(m,3H,ArH),7.23(s,1H,ArH),7.03-7.12(m,4H,ArH),4.22(t,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),3.60(s,2H,-NCH2-),3.17(d,2H,-NCH2 CH2 -),2.85-2.70(m,4H,-NCH2-),2.12-2.03(m,2H,-OCH2 CH2 CH2N-).ESI-MS:m/z calcd found 466.25[M+H]+.
实施例15
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-N,N-二甲氨基)哌啶基)丙氧基)喹唑啉-4-胺(Ⅰ-15)
粉末状固体;m.p.:180-182℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.11(d,J=8.6Hz,2H,ArH),7.97(m,3H,ArH),7.23(s,1H,ArH),4.19(t,2H,-OCH2 CH2CH2N-),3.97(s,3H,-OCH3),2.82-2.77(m,4H,-NCH2-),2.27(s,6H,-NCH3),2.21-2.05(m,3H,-NCH2-and-CH-),1.81(m,4H,-OCH2 CH2 CH2N-and-NCH2 CH2 -),1.51(m,2H,-NCH2 CH2-).ESI-MS:m/z calcd found 461.42[M+H]+.
实施例16
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-哌啶基)哌啶基)丙氧基)喹唑啉-4-胺(Ⅰ-16)
粉末状固体;m.p.:176-178℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.13(d,J=8.6Hz,2H,ArH),7.91(m,3H,ArH),7.23(s,1H,ArH),4.21(t,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),2.82-2.47(m,10H,-NCH2-),2.17-2.05(m,3H,-OCH2 CH2 CH2N-and-CH-),1.81(m,2H,-NCH2 CH2 -),1.61-1.51(m,8H,-CH2CH2CH2-and-NCH2 CH2 -).ESI-MS:m/z calcd found 501.32[M+H]+.
实施例17
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺(Ⅰ-17)
粉末状固体;m.p.:162-164℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.12(d,J=8.5Hz,2H,ArH),7.84(m,3H,ArH),7.23(s,1H,ArH),4.18(t,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),2.55–2.45(m,6H,-NCH2-),2.17(s,3H,-NCH3),2.02–1.80(m,6H,-NCH2-and-OCH2 CH2 CH2N-).ESI-MS:m/z calcd found 433.23[M+H]+.
实施例18
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺(Ⅰ-18)
粉末状固体;m.p.:164-166℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.13(d,J=8.7Hz,2H,ArH),7.89-7.81(m,3H,ArH),7.23(s,1H,ArH),4.19(t,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),1.95(m,6H,-NCH2-,-NCH2 CH3,-OCH2 CH2 CH2N-),1.41-1.07(m,6H,-NCH2-),1.05(m,5H,-NCH2-and-NCH2 CH3 ).ESI-MS:m/z calcd found447.25[M+H]+.
实施例19
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-羟乙基哌嗪基))丙氧基)喹唑啉-4-胺(Ⅰ-19)
粉末状固体;m.p.:168-171℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.11(d,J=8.7Hz,2H,ArH),7.81(m,3H,ArH),7.23(s,1H,ArH),4.09(t,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),3.49(t,2H,-NCH2 CH2 OH),3.25-2.89(m,12H,-NCH2-),1.95(m,2H,-OCH2 CH2 CH2N-).ESI-MS:m/z calcd found 463.25[M+H]+.
实施例20
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(4-吡啶基哌嗪基))丙氧基)喹唑啉-4-胺(Ⅰ-20)
粉末状固体;m.p.:166-168℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.23(d,2H,ArH),8.12(d,J=8.5Hz,2H,ArH),7.84(m,3H,ArH),7.23(s,1H,ArH),7.09(d,2H,ArH),4.22(t,2H,-OCH2 CH2CH2N-),3.99(s,3H,-OCH3),3.15–2.55(m,8H,-NCH2-),2.37(m,2H,-NCH2-),1.89(m,2H,-OCH2 CH2 CH2N-).ESI-MS:m/z calcd found 496.25[M+H]+.
实施例21
化合物N-(4-氰基苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺(Ⅰ-21)
粉末状固体;m.p.:276-278℃.1H NMR(400MHz,DMSO-d6):δ9.78(s,1H,NH),8.58(s,1H,ArH),8.12(d,J=8.5Hz,2H,ArH),7.92–7.78(m,3H,ArH),7.23(s,1H,ArH),4.19(t,2H,-OCH2 CH2CH2N-),3.95(s,3H,-OCH3),3.58(m,4H,-OCH2 CH2-),2.47–2.32(m,6H,-NCH2-),1.99(m,2H,-OCH2 CH2 CH2N-).ESI-MS:m/zcalcd found 419.32[M+H]+.
实施例22
化合物N-(3-氰基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺(Ⅰ-22)
粉末状固体;m.p.:172-174℃.1H NMR(400MHz,DMSO-d6):δ9.68(s,1H,NH),8.54(s,1H,ArH),8.38(s,1H,ArH),8.15(d,J=8.1Hz,1H,ArH),7.83(s,1H,ArH),7.67–7.44(m,2H,ArH),7.21(s,1H,ArH),4.19(t,2H,-OCH2 CH2CH2N-),3.98(s,3H,-OCH3),2.58(t,J=7.1Hz,2H,-NCH2-),2.51(s,2H,-NCH2-),2.48(s,2H,-NCH2-),2.04–1.93(m,2H,-OCH2 CH 2CH2N-),1.70(s,4H,-CH2CH2-).ESI-MS:m/z 404.30[M+H]+.
实施例23
化合物N-(3-氰基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺(Ⅰ-23)
粉末状固体;m.p.:146-148℃.1H NMR(400MHz,DMSO-d6):δ9.67(s,1H,NH),8.55(s,1H,ArH),8.38(s,1H,ArH),8.15(d,J=8.0Hz,1H,ArH),7.83(s,1H,ArH),7.65–7.52(m,2H,ArH),7.21(s,1H,ArH),4.18(s,2H,-OCH2 CH2CH2N-),3.98(s,3H,-OCH3),2.48–2.41(m,2H,-OCH2 CH2 CH2N-),2.37(s,4H,-NCH2-),1.94(m,4H,-NCH2-,-CH2 CH2CH2-),1.56–1.48(m,4H,-CH2CH2CH2-).ESI-MS:m/z 418.38[M+H]+.
实施例24
化合物N-(3-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺(Ⅰ-24)
粉末状固体;m.p.:142-144℃.1H NMR(400MHz,DMSO-d6):δ9.67(s,1H,NH),8.54(s,1H,ArH),8.38(s,1H,ArH),8.15(dd,J=5.1,4.0Hz,1H,ArH),7.83(s,1H,ArH),7.67–7.49(m,2H,ArH),7.20(s,1H,ArH),4.17(s,2H,-OCH2 CH2CH2N-),3.98(s,3H,-OCH3),2.85(d,J=11.2Hz,2H,-NCH2-),2.53–2.50(m,2H,-OCH2CH2 CH2 N-),2.43(t,J=7.0Hz,2H,-NCH2-),1.93(ddd,J=28.7,17.0,8.2Hz,4H,-OCH2 CH2 CH2N-,-NCH2 CH2 -),1.57(m,3H,-NCH2 CH2 -,-CHCH3),0.88(d,J=6.5Hz,3H,-CHCH3 ).ESI-MS:m/z 432.32[M+H]+.
实施例25
化合物N-(3-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺(Ⅰ-25)
粉末状固体;m.p.:152-154℃.1H NMR(400MHz,DMSO-d6):δ9.67(s,1H,NH),8.55(s,1H,ArH),8.38(s,1H,ArH),8.15(d,J=7.9Hz,1H,ArH),7.83(s,1H,ArH),7.76–7.45(m,2H,ArH),7.20(s,1H,ArH),4.18(s,2H,-OCH2 CH2CH2N-),3.98(s,3H,-OCH3),2.51(s,2H,-OCH2CH2 CH2 N-),2.42(dd,J=28.5,21.5Hz,8H,-NCH2-),2.16(s,3H,-NCH3),2.03–1.89(m,2H,-OCH2 CH2 CH2N-).ESI-MS:m/z 433.37[M+H]+.
实施例26
化合物N-(3-氰基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺(Ⅰ-26)
粉末状固体;m.p.:142-144℃.1H NMR(400MHz,DMSO-d6):δ9.67(s,1H,NH),8.54(s,1H,ArH),8.38(s,1H,ArH),8.15(d,J=8.4Hz,1H,ArH),7.83(s,1H,ArH),7.68–7.53(m,2H,ArH),7.20(s,1H,ArH),4.18(t,J=6.4Hz,2H,-OCH2 CH2CH2N-),3.98(s,3H,-OCH3),2.53–2.49(m,2H,-NCH2-),2.47–2.42(m,2H,-NCH2 CH3),2.31(dt,J=14.3,7.2Hz,4H,-NCH2-),1.94(m,2H,-OCH2 CH2 CH2N-),0.98(t,J=7.2Hz,3H,-NCH2 CH3 ).ESI-MS:m/z 447.30[M+H]+.
实施例27
化合物N-(3-氰基苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺(Ⅰ-27)
粉末状固体;m.p.:266-268℃.1H NMR(400MHz,DMSO-d6):δ9.68(s,1H,NH),8.58(s,1H,ArH),8.38(s,1H,ArH),8.15(d,J=8.4Hz,1H,ArH),7.81(s,1H,ArH),7.69–7.51(m,2H,ArH),7.23(s,1H,ArH),4.19(m,2H,-OCH2 CH2CH2N-),3.97(s,3H,-OCH3),3.59(m,4H,-OCH2 CH2-),2.50-2.42(m,6H,-NCH2-),1.99(m,2H,-OCH2 CH2 CH2N-).ESI-MS:m/z calcdfound 419.33[M+H]+.
实施例28
化合物N-(2-氰基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺(Ⅰ-28)
粉末状固体;m.p.:142-144℃.1H NMR(400MHz,DMSO-d6):δ8.46(s,1H,ArH),8.06(d,J=8.7Hz,2H,ArH),7.92–7.87(m,2H,ArH),7.27-7.23(m,2H,ArH),4.12(m,2H,-OCH2 CH2CH2N-),3.81(s,3H,-OCH3),2.65-2.21(m,6H,-NCH2-),1.80(m,2H,-OCH2 CH2 CH2N-),1.60(m,4H,-CH2CH2-).ESI-MS:m/z calcd found 404.22[M+H]+.
实施例29
化合物N-(2-氰基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺(Ⅰ-29)
粉末状固体;m.p.:156-158℃.1H NMR(400MHz,DMSO-d6):δ8.47(s,1H,ArH),8.12(d,J=8.7Hz,1H,ArH),8.06(d,J=8.7Hz,1H,ArH),7.92(m,1H,ArH),7.52(m,1H,ArH),7.24(s,1H,ArH),7.16(m,1H,ArH),4.12(m,2H,-OCH2 CH2CH2N-),3.82(s,3H,-OCH3),2.65-2.21(m,6H,-NCH2-),1.95(m,2H,-OCH2 CH2 CH2N-),1.32-1.30(m,6H,-CH2CH2CH2-).ESI-MS:m/z calcd found 418.24[M+H]+.
实施例30
化合物N-(2-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺(Ⅰ-30)
粉末状固体;m.p.:162-164℃.1H NMR(400MHz,DMSO-d6):δ8.48(s,1H,ArH),8.13(d,J=8.7Hz,1H,ArH),8.06(d,J=8.04Hz,1H,ArH),7.62-7.58(m,2H,ArH),7.26(s,1H,ArH),7.20(s,1H,ArH),4.19(m,2H,-OCH2CH2CH2N-),3.82(s,3H,-OCH3),2.10(m,2H,-OCH2CH2 CH2 N-),1.83(m,2H,-NCH2 CH2 -),1.37(m,3H,-NCH2 CH2 -,-CHCH3),0.74(d,J=6.5Hz,3H,-CHCH3 ).ESI-MS:m/z 432.25[M+H]+.
实施例31
化合物N-(2-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺(Ⅰ-31)
粉末状固体;m.p.:154-157℃.1H NMR(400MHz,DMSO-d6):δ8.48(s,1H,ArH),8.13(d,J=8.7Hz,1H,ArH),8.06(d,J=8.04Hz,1H,ArH),7.91(m,1H,ArH),7.62-7.58(m,1H,ArH),7.25(s,1H,ArH),7.08(s,1H,ArH),4.03(m,2H,-OCH2 CH2CH2N-),3.87(s,3H,-OCH3),2.51-2.22(m,8H,-NCH2-),2.16(s,3H,-NCH3),2.08(m,2H,-OCH2CH2 CH2 N-),1.80(m,2H,-OCH2 CH2 CH2N-).ESI-MS:m/z calcd found 433.25[M+H]+.
实施例32
化合物N-(2-氰基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺(Ⅰ-32)
粉末状固体;m.p.:160-163℃.1H NMR(400MHz,DMSO-d6):δ8.48(s,1H,ArH),8.13(d,J=8.7Hz,1H,ArH),8.06(d,J=8.04Hz,1H,ArH),7.91(m,1H,ArH),7.62-7.58(m,1H,ArH),7.25(s,1H,ArH),7.08(s,1H,ArH),4.03(m,2H,-OCH2 CH2CH2N-),3.87(s,3H,-OCH3),2.51-2.22(m,8H,-NCH2-),2.16(s,3H,-NCH2 CH3),2.08(m,2H,-OCH2CH2 CH2 N-),1.80(m,2H,-OCH2 CH2 CH2N-),0.94(t,J=6.52Hz,3H,-NCH2 CH3 ).ESI-MS:m/z calcd found 447.26[M+H]+.
实施例33
化合物N-(2-氰基苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺(Ⅰ-33)
m.p.:272-274℃.1H NMR(400MHz,DMSO-d6):δ8.48(s,1H,ArH),8.13(d,J=8.7Hz,1H,ArH),8.06(d,J=8.7Hz,1H,ArH),7.91(m,1H,ArH),7.52(m,1H,ArH),7.23(s,1H,ArH),7.16(m,1H,ArH),4.11(m,2H,-OCH2 CH2CH2N-),3.87(s,3H,-OCH3),3.64-3.58(m,4H,-OCH2 CH2-),2.54–2.42(m,6H,-NCH2-),1.98(m,2H,-OCH2 CH2 CH2N-).ESI-MS:m/z calcdfound 419.34[M+H]+.
本发明涉及化合物的部分药效学实验实施例
实施例34
式(Ⅰ)所示化合物对五种人源肿瘤细胞增殖的体外抑制作用
对式(Ⅰ)所示化合物进行了部分癌细胞的体外抑制活性测定,同时设置已上市药物索拉非尼为阳性对照药物。实验结果见表1。化合物Ⅰ-11对胃癌BGC-823细胞和结肠癌GEO细胞具有较好的选择性,且具有较高的活性;化合物Ⅰ-18对BGC-823、SMMC7721、Bel7402细胞具有较好的选择性和较高的活性;化合物Ⅰ-21、Ⅰ-27、Ⅰ-29、Ⅰ-30、Ⅰ-32、Ⅰ-33对所有癌细胞都有较高的杀伤作用,尤其是Ⅰ-21、Ⅰ-27、Ⅰ-32、Ⅰ-33对所试验癌细胞的抑制IC50,在1μM左右。
表1本发明式(Ⅰ)所示部分实施例化合物及阳性药物对抑制肿瘤细胞增殖活性测试结果
Claims (9)
1.一种包含具有如下结构(Ⅰ)的取代喹唑啉类化合物或其药学上可接受的盐:
其中:氰基(CN)为2-氰基,3-氰基,4-氰基;
其中:X为H,F,Cl,Br,CF3
其中R为二甲氨基、二乙胺基、羟乙基甲氨基、二羟乙基氨基、苄基甲氨基、苄基羟乙基氨基、吡咯烷基、N-吗啉基、哌啶基、4-甲基哌啶基、4-羟基哌啶基、4-羟甲基哌啶基、2-羟乙基哌啶基、4-乙氧羰基哌啶基、4-苯基哌啶基、四氢异喹啉基、4-二甲氨基哌啶基、4-哌啶基哌啶基、4-甲基哌嗪基、4-乙基哌嗪基、4-羟乙基哌嗪基、4-吡啶基哌嗪基。
2.根据权利要求1所述的化合物(Ⅰ)或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物,其特征在于:其中氰基(CN)分别为2-、3-和4-位的单取代氰基;其中:X为H,F,CF3;其中R更优选为二甲氨基、二乙胺基、羟乙基甲氨基、二羟乙基氨基、苄基甲氨基、苄基羟乙基氨基、吡咯烷基、N-吗啉基、哌啶基、4-甲基哌啶基、4-羟基哌啶基、4-羟甲基哌啶基、2-羟乙基哌啶基、4-乙氧羰基哌啶基、4-苯基哌啶基、4-二甲氨基哌啶基、4-哌啶基哌啶基、4-甲基哌嗪基、4-乙基哌嗪基、4-吡啶基哌嗪基。
3.根据权利要求1所述的化合物(Ⅰ)或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物,其中所述的化合物优选自:
N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-二甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-二乙氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-羟乙基甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-二羟乙基氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-苄基甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(N,N-苄基羟乙基氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-羟基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(2-羟乙基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-乙氧羰基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-苯基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-四氢异喹啉基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-N,N-二甲氨基)哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-哌啶基)哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-羟乙基)哌嗪基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(1-(4-吡啶基)哌嗪基)丙氧基)喹唑啉-4-胺;
N-(4-氰基苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺;
N-(3-氰基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(3-氰基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(3-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(3-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(3-氰基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(3-氰基苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺;
N-(2-氰基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(2-氰基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(2-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(2-氰基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(2-氰基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(2-氰基苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺。
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(N,N-二甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(N,N-二乙氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(N,N-羟乙基甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(N,N-二羟乙基氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(N,N-苄基甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(N,N-苄基羟乙基氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-羟基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-羟甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(2-羟乙基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-乙氧羰基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-苯基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-四氢异喹啉基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-N,N-二甲氨基)哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-哌啶基)哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-羟乙基)哌嗪基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-吡啶基)哌嗪基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-氟苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺;
N-(3-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(3-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(3-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(3-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(3-氰基,2-氟苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(N,N-二甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(N,N-二乙氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(N,N-羟乙基甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(N,N-二羟乙基氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(N,N-苄基甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(N,N-苄基羟乙基氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-羟基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-羟甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(2-羟乙基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-乙氧羰基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-苯基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-四氢异喹啉基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-N,N-二甲氨基)哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-哌啶基)哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-羟乙基)哌嗪基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-吡啶基)哌嗪基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-氟苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-氟苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-氟苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺。
N-(2-氰基,4-氟苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(2-氰基,4-氟苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(2-氰基,4-氟苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,4-氟苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,4-氟苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,4-氟苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺。
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-二甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-二乙氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-羟乙基甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-二羟乙基氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-苄基甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-苄基羟乙基氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-羟基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-羟甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(2-羟乙基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-乙氧羰基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-苯基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-四氢异喹啉基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-N,N-二甲氨基)哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-哌啶基)哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-羟乙基)哌嗪基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-吡啶基)哌嗪基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺;
N-(3-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(3-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(3-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(3-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(3-氰基,2-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-二甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-二乙氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-羟乙基甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-二羟乙基氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-苄基甲氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(N,N-苄基羟乙基氨基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-羟基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-羟甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(2-羟乙基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-乙氧羰基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-苯基哌啶基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-四氢异喹啉基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-N,N-二甲氨基)哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-哌啶基)哌啶基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-羟乙基)哌嗪基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-吡啶基)哌嗪基)丙氧基)喹唑啉-4-胺;
N-(4-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,3-三氟甲基苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺。
N-(2-氰基,4-三氟甲基苯基)-6-甲氧基-7-(3-(1-吡咯烷基)丙氧基)喹唑啉-4-胺;
N-(2-氰基,4-三氟甲基苯基)-6-甲氧基-7-(3-(1-哌啶基)丙氧基)喹唑啉-4-胺;
N-(2-氰基,4-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌啶基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,4-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-甲基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,4-三氟甲基苯基)-6-甲氧基-7-(3-(1-(4-乙基哌嗪基))丙氧基)喹唑啉-4-胺;
N-(2-氰基,4-三氟甲基苯基)-6-甲氧基-7-(3-(4-吗啉基)丙氧基)喹唑啉-4-胺。
4.根据权利要求1所述的化合物(Ⅰ)或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物,其相应的药学上可接受的盐表示为式Ⅰ化合物·HqX,其中X表示卤素、硫酸根、磷酸根、磺酸根和有机酸根,q为1,或2,或3。
5.根据权利要求1所述的化合物(Ⅰ)或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物,所述的含有该化合物或其药学上可接受的盐的药物组合物表示为含有药学上有效治疗剂量的权利要求1~4中任何一项所述的化合物或其药学上可接受的盐以及药学上可接受的适当的载体、稀释剂或赋形剂,该组合物可以制成固体口服剂、液体口服剂、注射剂等剂型。
6.根据权利要求1~5中所述的化合物(Ⅰ)或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物,在制备白癜风治疗、皮炎治疗、免疫抑制药物方面的应用。
7.根据权利要求1~5中所述的化合物(Ⅰ)或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物,在如下抗肿瘤药物中的应用,如抗胃癌、皮肤癌、食管癌、宫颈癌、卵巢癌、白血病、骨髓瘤、喉癌、人盲肠腺癌、膀胱癌、直肠癌、结肠癌、人退行性癌细胞、甲状腺癌、胰腺癌、白血病、肾癌、黑色素瘤药物方面。
8.根据权利要求1~5中所述的化合物(Ⅰ)或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物,在抗肝癌(如SMMC7721、MHCC97L、MHCC97H、Bel7402、Bel7404、Bel7405、HB611、Huh7、HCC-LM3、HHCC、Li-7、Hep3B、HEPA-6、Hep3B2.1-7、HepB1.2、HL7702(LO2)、HAb18、F11、HTB-52SK-HEP-1、HepaRG、HepG2.2.15、HepG2-RHBV、HUH-6、HUH-7、SNU-182、SNU-387、MCA-RH7777、PLC/PRF/5、QSG7701、QGY-7701、QGY-7703、SK-HEP-1以及未发现的新型肝癌细胞)药物中的应用。
9.根据权利要求1~5中所述的化合物(Ⅰ)或其药学上可接受的盐、溶剂合物、含有该化合物或其药学上可接受的盐的药物组合物,在抗艾滋病药物方面的应用。
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