CN113651768A - 一种n-芳基邻氨基苯甲酰胺类化合物及其制备和应用 - Google Patents

一种n-芳基邻氨基苯甲酰胺类化合物及其制备和应用 Download PDF

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CN113651768A
CN113651768A CN202110311265.3A CN202110311265A CN113651768A CN 113651768 A CN113651768 A CN 113651768A CN 202110311265 A CN202110311265 A CN 202110311265A CN 113651768 A CN113651768 A CN 113651768A
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王震
石桃
李俊芳
张红花
王晓东
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University of South China
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Abstract

本发明涉及医药技术领域，具体涉及一种N‑芳基邻氨基苯甲酰胺类酸化合物抗脑内肿瘤活性化合物及其制备和应用，其结构通式为：
Figure 294064DEST_PATH_IMAGE001
其中：R1为卤素F或Cl或Br或I、烷基、杂烷烃、氨基、硝基的一种或几种，R1在苯环上的取代位置为2位、3位、4位，取代基数量为单取代或多取代；R2为卤素F或Cl或Br或I、烷基、杂烷烃、氨基、硝基的一种或几种；R2在苯环上的取代位置为2位、3位、4位，取代基数量为单取代或多取代；R3为杂环或苯并杂环；n为1‑3；X为N或CH。本发明的化合物具有显著COX‑2抑制作用和拓扑异构酶抑制作用，对于是多种肿瘤，特别是脑内肿瘤如胶质瘤等在体内外具有显著抑制增殖，侵袭，迁移，并具有阻滞周期阻滞等作用，是一类新型多靶点抗肿瘤药物。

Description

一种N-芳基邻氨基苯甲酰胺类化合物及其制备和应用
技术领域
本发明属于医药N-芳基邻氨基苯甲酰胺化合物技术领域，具体涉及一种N-芳基邻氨基苯甲酰胺类化合物及其制备和应用。
背景技术
胶质瘤，是成人最常见的原发性脑瘤，居颅内肿瘤发病率第一位，神经胶质瘤患者的中位生存期小于2年，且致死率高居颅内肿瘤首位。目前化疗是治疗胶质瘤尤其是恶性胶质瘤的重要手段。但是目前的化疗药物种类少，主要是替莫唑胺，也只能延长2.5个月的中位生存期，FDA最近批准的治疗复发胶质母细胞瘤药物贝伐单抗（avastin），也没有延长中位生存期。因此，迫切需要研发更为有效、作用机制独特的多靶点的抗胶质母细胞瘤治疗药物。临床试验证实COX-2抑制剂和拓扑异构酶联合使用可以显著延长生存期，提高辐射反应性。本次报道的N-芳基邻氨基苯甲酰胺类衍生物首次证明是拓扑酶和COX-2双重抑制剂，并具有良好的血脑屏障透过性，可高效低毒靶向治疗胶质瘤。
发明内容
本发明所要解决的技术问题是针对现有技术中的缺点而提供一种以N-芳基邻氨基苯甲酰胺系列衍生物，进行抗肿瘤尤其是胶质瘤生物活性研究，结果表明，该化合物具有很好的抗胶质瘤肿瘤活性，具有抗肿瘤药物开发潜力，可以用来制备抗肿瘤药物。
本发明的另一目的是提供上述N-芳基邻氨基苯甲酰胺类化合物的制备方法。
本发明的还有一目的是提供上述N-芳基邻氨基苯甲酰胺类化合物的应用。
一种N-芳基邻氨基苯甲酰胺衍生物，结构通式为：
Figure 717645DEST_PATH_IMAGE001
；
其中：R1为卤素F或 Cl或Br或I、烷基、杂烷烃、氨基、硝基的一种或几种，R1在苯环上的取代位置为2位、3位、4位，取代基数量为单取代或多取代；
R2为卤素F或 Cl或Br或I、烷基、杂烷烃、氨基、硝基的一种或几种；
R3为杂环或苯并杂环；
n为1-3；
X为N或CH。
所述R1或 R2的烷基为1-4个碳原子低级烷基，杂烷烃为甲氧基或三氟甲基或N,N二甲基。
上述N-芳基邻氨基苯甲酰胺衍生物，结构式为：
Figure 626695DEST_PATH_IMAGE002
Figure 915856DEST_PATH_IMAGE003
。
上述N-芳基邻氨基苯甲酰胺衍生物的制备方法，合成路线为：
Figure 51302DEST_PATH_IMAGE004
。
上述N-芳基邻氨基苯甲酰胺衍生物的制备方法，具体步骤如下：
在氩气条件下，将化合物IV和EDCI•HCl和HOBT溶解在二氯甲烷中，在室温下加入化合物I 或化合物II或化合物III，以及 Et3N搅拌反应8-12小时，通过TLC检测反应完成后减压旋转蒸发除去反应液，然后将得到的残余物通过硅胶快速柱色谱纯化得到式（一）化合物或式（二）化合物或式（三）化合物，其中化合物I 或化合物II或化合物III：EDCI•HCl：HOBT：Et3N：化合物IV摩尔比为1:1.2:1.1:2.5:1，化合物I 或化合物II或化合物III在二氯甲烷的浓度为0.5 mmol/mL。
上述N-芳基邻氨基苯甲酰胺衍生物作为活性物质在制备抗肿瘤药物中的应用。上述N-芳基邻氨基苯甲酰胺类化合物是抑制多种人肿瘤细胞株，优选人胶质瘤细胞株U87MG、U251、C6等的增殖、迁移、侵袭、愈合；诱导人胶质瘤细胞株U87MG、U251、C6等的凋亡，诱导人胶质瘤细胞株U87MG、U251、C6等的G2/M期周期阻滞，可用于治疗肿瘤，尤其是用于胶质瘤药物。用于COX-2抑制剂药物，在胶质瘤动物模型有效。用于拓扑异构酶多靶点抑制剂药物。
本发明公开了一类新型N-芳基邻氨基苯甲酰胺类化合物及其制备方法，本化合物合成路线绿色环保、简洁高效、原料易得。通过体内外实验证在体外抗肿瘤活性表明，该类化合物表现出良好的抗各类人肿瘤活性，优选胶质瘤，具有抗肿瘤药物开发潜力，可以用来制备抗肿瘤药物，给恶性胶质瘤的治疗提供了新思路，有助于开发新的高效低毒的抗胶质瘤药物。
附图说明
图1 为本发明化合物 I-1 和I-8本发明化合物I-1 和I-8显著拓扑异构酶I 和拓扑异构酶II, COX-2；
图2 为本发明化合物 I-1 和I-8显著减少U251、U87MG细胞增殖细胞比例与Control组相比较图，*p< 0.05；
图3为本发明化合物I-1 和I-8显著增加U251、U87MG细胞G2/M期细胞比例与Control组相比较图，*p< 0.05；
图4为本发明化合物I-1 和I-8显著抑制U251、U87MG细胞侵袭迁移的发生；
图5为本发明化合物I-1 和I-8显著抑制造模成功的大鼠胶质瘤原位模型的SD大鼠的肿瘤生长 *p< 0.05，**p< 0.01；
图6为本发明化合物I-1显著抑制造模成功的大鼠胶质瘤原位模型的SD大鼠的肿瘤的磷酸化STAT3的表达， *p< 0.05，**p< 0.01；
图7为本发明化合物I-1显著抑制造模成功的大鼠胶质瘤原位模型的SD大鼠的肿瘤的MMP-9的表达， *p< 0.05，**p< 0.01；
图 8为本发明化合物I-1显著抑制造模成功的U87MG裸鼠荷瘤模型的肿瘤生长，*p< 0.05，**p< 0.01。
具体实施方式
本发明N-芳基邻氨基苯甲酰胺化合物的合成路线：
Figure 661275DEST_PATH_IMAGE005
。
实施例1
一种N-芳基邻氨基苯甲酰胺类化合物，具体步骤如下：
在氩气条件下，将化合物IV（1.0 eq）、EDCI•HCl（1.2 eq）、HOBT（1.1 eq）溶解在二氯甲烷（3 mL）中，并在室温下加入Et3N（2.5 eq）和化合物I （1.0 eq），搅拌反应8小时，通过TLC检测反应完成后，通过减压旋转蒸发除去反应液，然后将得到的残余物通过硅胶快速柱色谱纯化，得到所需的固体产物式（一）化合物，两步的总产率为20-50％。
实施例2
一种N-芳基邻氨基苯甲酰胺类化合物，具体步骤如下：
在氩气条件下，将化合物IV（1.0 eq）、EDCI•HCl（1.2 eq）、HOBT（1.1 eq）溶解在二氯甲烷（3 mL）中，并在室温下加入Et3N（2.5 eq）和化合物II（1.0 eq），搅拌反应12小时，通过TLC检测反应完成后，通过减压旋转蒸发除去反应液，然后将得到的残余物通过硅胶快速柱色谱纯化，得到所需的固体产物式（二）化合物，两步的总产率为20-50％。
实施例3
一种N-芳基邻氨基苯甲酰胺类化合物，具体步骤如下：
在氩气条件下，将化合物IV（1.0 eq）、EDCI•HCl（1.2 eq）、HOBT（1.1 eq）溶解在二氯甲烷（3 mL）中，并在室温下加入Et3N（2.5 eq）和化合物III（1.0 eq），搅拌反应12小时，通过TLC检测反应完成后，通过减压旋转蒸发除去反应液，然后将得到的残余物通过硅胶快速柱色谱纯化，得到所需的固体产物式（三）化合物，两步的总产率为20-50％。
实施例4
一种Ｎ－苯基N-芳基邻氨基苯甲酰胺类化合物，为
N-(4-methoxyphenyl)-2-(phenylamino)benzamide (A-1)
white solid (30% yield), mp 133.0-134.1 ℃. 1H NMR (400 MHz, CD Cl3) δ9.16 (s, 1H), 7.86 (s, 1H), 7.57 (dd, J = 7.9, 1.5 Hz, 1H), 7.49 – 7.42 (m,2H), 7.41 – 7.35 (m, 1H), 7.35 – 7.26 (m, 3H), 7.22 – 7.15 (m, 2H), 7.06 –6.98 (m, 1H), 6.95 – 6.87 (m, 2H), 6.82 (t, J = 7.5 Hz, 1H), 3.81 (s, 3H). 13CNMR (101 MHz, CD Cl3) δ 167.73, 156.82, 145.62, 141.39, 132.46, 130.53,129.28, 127.55, 122.77, 122.54, 120.75, 118.73, 118.17, 115.80, 114.26,55.50. LC-MS m/z (ESI) m/z calcd for C20H19N2O2 (M + H): 319.1; found 319.1 (M+ H)+, 341.1 (M + Na)+.The purity was 95.07% by HPLC analysis。
实施例5
一种Ｎ－苯基N-芳基邻氨基苯甲酰胺类化合物，为
N-(4-methoxybenzyl)-2-(phenylamino)benzamide (B-1)
white solid (20% yield), mp 120.0-121.1 ℃. 1H NMR (400 MHz, CD Cl3) δ9.36 (s, 1H), 7.38 (dd, J = 7.9, 1.6 Hz, 1H), 7.35 – 7.19 (m, 6H), 7.19 –7.15 (m, 2H), 7.04 – 6.92 (m, 1H), 6.88 – 6.79 (m, 2H), 6.74 – 6.64 (m, 1H),6.56 – 6.34 (m, 1H), 4.49 (d, J = 5.5 Hz, 2H), 3.76 (s, 3H). 13C NMR (101 MHz,CD Cl3) δ 169.20, 159.03, 145.45, 141.46, 132.12, 130.02, 129.19, 129.09,127.46, 122.32, 120.69, 118.13, 117.84, 115.37, 114.11, 55.21, 43.27. LC-MSm/z (ESI) calcd for C21H21N2O2 (M + H): 333.2, found 333.1 (M + H)+, 355.2 (M +Na)+. The purity was 99.29% by HPLC analysis。
实施例6
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-hydroxybenzyl)-2-(phenylamino)benzamide (C-1)
white solid (40% yield), mp 139.0-140.1 ℃. 1H NMR (400 MHz, DMSO-d6)δ 9.75 (s, 1H), 9.29 (s, 1H), 9.02 (t, J = 6.0 Hz, 1H), 7.71 (dd, J = 7.9,1.4 Hz, 1H), 7.37 – 7.26 (m, 4H), 7.19 – 7.11 (m, 4H), 7.02 – 6.93 (m, 1H),6.87 – 6.79 (m, 1H), 6.77 – 6.68 (m, 2H), 4.36 (d, J = 5.9 Hz, 2H). 13C NMR(101 MHz, DMSO- d 6) δ 168.66, 156.32, 144.48, 141.54, 131.95, 129.66, 129.46,128.88, 128.67, 121.84, 119.57, 118.65, 118.11, 115.10, 114.95, 42.06. LC-MSm/z (ESI) calcd for C20H19N2O2 (M + H): 319.1, found 319.1 (M + H)+, 341.1 (M +Na)+. The purity was 99.34% by HPLC analysis。
实施例7
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-hydroxyphenyl)-2-(phenylamino)benzamide (D-1):
white solid (50% yield), mp 144.9-145.0 ℃. 1H NMR (400 MHz, DMSO- d 6)δ 10.18 – 10.09 (m, 1H), 9.35 – 9.16 (m, 2H), 7.81 – 7.68 (m, 1H), 7.55 –7.44 (m, 2H), 7.41 – 7.26 (m, 4H), 7.21 – 7.09 (m, 2H), 7.01 – 6.87 (m, 2H),6.80 – 6.69 (m, 2H). 13C NMR (101 MHz, DMSO-d 6) δ 167.20, 153.97, 143.94,141.73, 131.91, 130.33, 129.44, 129.32, 122.70, 121.68, 120.55, 119.22,118.55, 115.56, 115.03. LC-MS m/z (ESI) calcd for C19H17N2O2 (M + H): 305.1,found 305.1(M + H)+; 327.1 (M + Na)+. The purity was 99.10% by HPLC analysis。
实施例8
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-methoxyphenethyl)-2-(phenylamino)benzamide (E-1)
white solid (43% yield), mp 127.1-128.0 ℃. 1H NMR (400 MHz, CD Cl3) δ9.26 (s, 1H), 7.34 – 7.09 (m, 9H), 6.98 (t, J = 7.3 Hz, 1H), 6.87 – 6.79 (m,2H), 6.73 – 6.65 (m, 1H), 6.22 (s, 1H), 3.75 (s, 3H), 3.65 – 3.54 (m, 2H),2.83 (t, J = 6.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 169.38, 158.26, 145.22,141.51, 131.96, 130.68, 129.65, 129.19, 127.33, 122.24, 120.54, 118.62,117.91, 115.42, 114.06, 55.17, 41.04, 34.64. LC-MS m/z (ESI) calcd forC22H23N2O2 (M + H): 347.2, found 347.2 (M + H)+; 369.2 (M + Na)+. The purity was98.50% by HPLC analysis。
实施例9
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-hydroxyphenethyl)-2-(phenylamino)benzamide (F-1)
white solid (50% yield), mp 124.0-125.1 ℃. 1H NMR (400 MHz,Methanol- d 4) δ 7.51 – 7.43 (m, 1H), 7.35 – 7.19 (m, 4H), 7.16 – 7.00 (m,4H), 6.99 – 6.90 (m, 1H), 6.83 – 6.74 (m, 1H), 6.74 – 6.63 (m, 2H), 3.62 –3.34 (m, 2H), 2.85 – 2.65 (m, 2H). 13C NMR (101 MHz, Methanol- d 4) δ 171.62,156.87, 145.74, 143.40, 143.38, 132.93, 131.34, 130.81, 130.79, 130.35,130.33, 129.64, 123.11, 121.37, 120.91, 119.71, 116.90, 116.26, 116.24,42.65, 35.66. LC-MS m/z (ESI) calcd for C21H21N2O2 (M + H): 333.2, found 333.2(M + H)+; 355.1 (M + Na)+. The purity was 96.71% by HPLC analysis。
实施例10
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(3-(4-methoxyphenyl)propyl)-2-(phenylamino)benzamide (G-1)
white solid (40% yield), mp 140.1-141.0 ℃. 1H NMR (400 MHz, CD Cl3) δ9.45 (s, 1H), 7.49 – 7.29 (m, 7H), 7.28 – 7.21 (m, 2H), 7.17 – 7.09 (m, 1H),7.02 – 6.91 (m, 2H), 6.88 – 6.81 (m, 1H), 6.37 – 6.16 (m, 1H), 3.91 (s, 3H),3.61 – 3.50 (m, 2H), 2.80 (t, J = 7.5 Hz, 2H), 2.13 – 1.94 (m, 2H). 13C NMR(101 MHz, CDCl3) δ 169.37, 157.94, 145.26, 141.53, 133.35, 131.98, 129.24,129.21, 127.33, 122.25, 120.57, 118.53, 117.81, 115.40, 113.96, 55.22, 39.52,32.60, 31.18. LC-MS m/z (ESI) calcd for C23H25N2O2 (M + H): 361.2, found 361.2(M + H)+; 383.1 (M + Na)+. The purity was 99.40% by HPLC analysis。
实施例11
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(3-(4-hydroxyphenyl)propyl)-2-(phenylamino)benzamide (H-1)
white solid (45% yield), mp 139.9-140.2 ℃. 1H NMR (400 MHz,Methanol- d 4) δ 7.56 – 7.49 (m, 1H), 7.33 – 7.21 (m, 4H), 7.14 – 7.08 (m,2H), 7.03 – 6.92 (m, 3H), 6.86 – 6.79 (m, 1H), 6.71 – 6.64 (m, 2H), 3.37 –3.32 (m, 2H), 2.63 – 2.51 (m, 2H), 1.90 – 1.79 (m, 2H). 13C NMR (101 MHz,DMSO- d 6) δ 168.95, 155.43, 144.19, 141.74, 131.91, 131.88, 129.55, 129.30,128.94, 128.80, 121.80, 119.46, 119.37, 118.38, 115.22, 38.90, 31.97, 31.14.LC-MS m/z (ESI) calcd for C22H23N2O2 (M + H): 347.2, found 347.2 (M + H)+;369.2 (M + Na)+. The purity was 98.90% by HPLC analysis。
实施例12
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(4-methoxyphenyl)benzamide (I-1)
white solid (30% yield), mp 133.9-134.1 ℃. 1H NMR (400 MHz, CDCl3) δ9.16 (s, 1H), 7.82 (s, 1H), 7.55 (dd, J = 7.9, 1.5 Hz, 1H), 7.51 – 7.41 (m,2H), 7.33 – 7.18 (m, 2H), 7.18 – 7.02 (m, 2H), 7.01 – 6.93 (m, 1H), 6.94 –6.86 (m, 2H), 6.86 – 6.68 (m, 1H), 3.79 (s, 3H), 2.33 (s, 3H). 13C NMR (101MHz, CDCl3) δ 167.77, 156.85, 146.44, 141.04, 135.45, 132.58, 130.43, 130.08,127.36, 126.70, 124.54, 122.81, 120.76, 117.79, 117.75, 115.40, 114.27,55.47, 14.88. LC-MS m/z (ESI) calcd for C21H20ClN2O2 (M + H): 367.1, found367.1(M + H)+; 389.1 (M + Na)+. The purity was 98.44% by HPLC analysis。
实施例13
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((2,3-dimethylphenyl)amino)-N-(4-methoxyphenyl)benzamide (J-1)
white solid (42% yield), mp 127.0-128.0 ℃. 1H NMR (400 MHz, CDCl3) δ9.05 (s, 1H), 7.80 (s, 1H), 7.56 – 7.42 (m, 3H), 7.26 – 7.19 (m, 1H), 7.14(d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.97 – 6.86 (m, 4H), 6.72 (t,J = 7.5 Hz, 1H), 3.79 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H). 13C NMR (101 MHz,CDCl3) δ 167.93, 156.73, 147.49, 139.27, 138.03, 132.53, 131.13, 130.62,127.31, 125.84, 125.74, 122.76, 121.25, 116.95, 116.80, 115.03, 114.23,55.47, 20.61, 13.91. LC-MS m/z (ESI) calcd for C22H23N2O2 (M + H): 347.2, found347.1 (M + H)+; 369.1 (M + Na)+. The purity was 99.67% by HPLC analysis。
实施例14
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((2,3-dimethylphenyl)amino)-N-(4-hydroxyphenyl)benzamide (K-1)
white solid (30% yield), mp 125.0-126.1 ℃. 1H NMR (400 MHz,Methanol-d 4) δ 7.68 (dd, J = 7.9, 1.6 Hz, 1H), 7.45 – 7.33 (m, 2H), 7.25 –7.17 (m, 1H), 7.11 – 6.96 (m, 2H), 6.92 (d, J = 7.3 Hz, 1H), 6.86 – 6.69 (m,4H), 3.35 (s, 1H), 2.28 (s, 3H), 2.15 (s, 3H). 13C NMR (101 MHz, Methanol-d 4)δ170.45, 155.74, 148.24, 140.82, 139.11, 133.26, 131.74, 131.40, 129.75,126.95, 126.79, 124.81, 122.07, 119.34, 118.23, 116.27, 115.70, 20.70, 14.02.LC-MS m/z (ESI) calcd for C21H21N2O2 (M + H): 333.2, found 333.1 (M + H)+;355.1 (M + Na)+. The purity was 99.90% by HPLC analysis。
实施例15
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chlorophenyl)amino)-N-(4-hydroxyphenyl)benzamide (L-1)
white solid (35% yield), mp 190.1-191.4 ℃. 1H NMR (400 MHz,Methanol-d 4) δ 7.72 (d, J = 7.8 Hz, 1H), 7.41 – 7.33 (m, 4H), 7.20 (t, J =8.0 Hz, 1H), 7.11 (t, J = 2.0 Hz, 1H), 7.04 – 6.94 (m, 2H), 6.93 – 6.87 (m,1H), 6.80 – 6.70 (m, 2H). 13C NMR (75 MHz, Methanol-d 4) δ 169.69, 156.43,145.43, 144.51, 135.96, 133.13, 131.60, 130.98, 130.18, 124.60, 123.42,122.29, 121.17, 119.41, 118.37, 118.15, 116.45. LC-MS m/z (ESI) calcd forC19H16ClN2O2 (M + H): 339.1, found 339.0(M + H)+; 361.1(M + Na)+. The purity was99.18% by HPLC analysis。
实施例16
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-methoxyphenyl)-2-((3-(trifluoromethyl)phenyl)amino)benzamide (M-1)
white solid (30% yield), mp 136.5 -137.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.36 (s, 1H), 7.84 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.48 – 7.28 (m, 7H),7.20 (d, J = 7.6 Hz, 1H), 6.93 – 6.85 (m, 3H), 3.90 – 3.51 (m, 3H). 13C NMR(75 MHz, CDCl3) δ 167.60, 156.94, 144.36, 142.15, 132.57, 131.63 (q, J = 32.1Hz), 130.26, 129.79, 127.61, 123.99 (d, J = 272.4 Hz), 122.81, 119.62,119.26, 118.44 (q, J = 3.9 Hz), 116.21, 116.13 (d, J = 4.0 Hz), 116.06,114.26, 55.44. LC-MS m/z (ESI) calcd for C21H18F3N2O2 (M + H): 387.1, found387.1 (M + H)+; 409.1 (M + Na)+. The purity was 99.79% by HPLC analysis。
实施例17
一种Ｎ－苯基N-芳基邻氨基苯甲酰胺类化合物，为
N-(4-hydroxyphenyl)-2-((3-(trifluoromethyl)phenyl)amino)benzamide (N-1)
white solid (30% yield), mp 133.9-141.5 ℃. 1H NMR (400 MHz,Methanol-d 4) δ 7.72 (d, J = 7.9 Hz, 1H), 7.42 – 7.29 (m, 7H), 7.16 (d, J =7.6 Hz, 1H), 7.03 – 6.95 (m, 1H), 6.81 – 6.72 (m, 2H). 13C NMR (101 MHz,Methanol-d 4) δ 169.62, 155.83, 144.71, 144.19, 133.16, 132.64 (q, J = 32.0Hz), 131.23, 131.19, 130.25, 125.59 (q, J = 271.5 Hz), 124.54, 123.67,122.83, 121.45, 118.57 (q, J = 4.0 Hz), 118.35, 116.25, 115.72 (d, J = 4.0Hz). LC-MS m/z (ESI) calcd for C20H16F3N2O2 (M + H): 373.1, found 373.1 (M + H)+;395.1 (M + Na)+. The purity was 99.42% by HPLC analysis。
实施例18
一种Ｎ－苯基N-芳基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(4-methoxyphenyl)nicotinamide(O-1)
white solid (20% yield), mp 196.0-197.5 ℃. 1H NMR (400 MHz, CDCl3) δ10.06 (s, 1H), 8.29 (dd, J = 4.9, 1.8 Hz, 1H), 7.95 – 7.72 (m, 3H), 7.54 –7.35 (m, 2H), 7.17 – 7.05 (m, 2H), 6.96 – 6.85 (m, 2H), 6.72 (dd, J = 7.7,4.8 Hz, 1H), 3.81 (s, 3H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.49,157.15, 155.80, 151.75, 139.40, 135.50, 134.78, 129.99, 128.66, 126.41,124.55, 123.08, 121.43, 114.35, 113.12, 111.42, 55.50, 15.12. LC-MS m/z (ESI)calcd for C20H19ClN3O2 (M + H): 368.1, found 368.1 (M + H)+; 390.1 (M + Na)+.The purity was 95.95% by HPLC analysis。
实施例19
一种Ｎ－苯基N-芳基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(4-hydroxyphenyl)nicotinamide(P-1)
white solid (40% yield), mp 160.2-161.4 ℃. 1H NMR (400 MHz, DMSO-d 4)δ 8.30 (dd, J = 4.8, 1.8 Hz, 1H), 8.25 (dd, J = 7.7, 1.9 Hz, 1H), 8.13 (d, J= 6.9 Hz, 1H), 7.54 – 7.41 (m, 2H), 7.21 – 7.07 (m, 2H), 6.92 (dd, J = 7.7,4.8 Hz, 1H), 6.84 – 6.72 (m, 2H), 2.32 (s, 3H). 13C NMR (101 MHz, DMSO-d 4) δ166.18, 154.64, 154.40, 150.56, 140.12, 137.57, 133.44, 129.64, 126.81,126.06, 123.19, 122.94, 120.22, 115.09, 113.82, 112.21, 14.71. LC-MS m/z(ESI) calcd for C19H17ClN3O2 (M + H): 354.1, found 354.1 (M + H)+; 376.1 (M +Na)+. The purity was 95.24% by HPLC analysis。
实施例20
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((2,6-dichloro-3-methylphenyl)amino)-N-(4-methoxyphenyl)benzamide(Q-1)
white solid (25% yield), mp 168.5-169.3 ℃. 1H NMR (400 MHz, CDCl3) δ9.07 (s, 1H), 7.88 (s, 1H), 7.64 – 7.46 (m, 3H), 7.31 – 7.24 (m, 2H), 7.06(d, J = 8.2 Hz, 1H), 6.96 – 6.78 (m, 3H), 6.41 (d, J = 8.3 Hz, 1H), 3.81 (s,3H), 2.40 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.58, 156.74, 145.46, 136.38,135.53, 133.14, 132.27, 130.68, 130.03, 127.71, 127.29, 122.55, 118.24,118.04, 115.14, 114.25, 55.51, 20.63. LC-MS m/z (ESI) calcd for C21H19Cl2N2O2(M + H): 401.1, found 401.0 (M + H)+; 423.1 (M + Na)+. The purity was 98.05%by HPLC analysis。
实施例21
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((2,6-dichloro-3-methylphenyl)amino)-N-(4-hydroxyphenyl)benzamide(R-1)
white solid (30% yield), mp 166.0-167.0 ℃. 1H NMR (400 MHz,Methanol-d 4) δ 7.61 (d, J = 7.9 Hz, 1H), 7.38 –7.30 (m, 2H), 7.28 – 7.22 (m,1H), 7.17 – 7.00 (m, 2H), 6.79 – 6.65 (m, 3H), 6.27 – 6.16 (m, 1H), 2.31 –2.26 (m, 3H). 13C NMR (101 MHz, Methanol-d 4) δ 170.24, 155.80, 146.46, 137.85,137.01, 134.07, 132.98, 131.41, 131.17, 129.51, 129.07, 129.04, 124.74,119.97, 119.30, 116.29, 115.49, 20.67. LC-MS m/z (ESI) calcd for C20H17Cl2N2O2(M + H): 401.1, found 387.1 (M + H)+; 409.0 (M + Na)+. The purity was 98.80%by HPLC analysis。
实施例22
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chlorophenyl)amino)-N-(4-methoxyphenyl)benzamide (S-1)
white solid (30% yield), mp 147.0-148.5 ℃. 1H NMR (400 MHz, CDCl3) δ9.23 (s, 1H), 7.99 – 7.73 (m, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.47 – 7.32 (m,4H), 7.23 – 7.15 (m, 2H), 7.02 (d, J = 8.2 Hz, 1H), 6.97 – 6.82 (m, 4H), 3.81(s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.58, 156.90, 144.51, 142.92, 134.79,132.51, 130.34, 130.27, 127.56, 122.77, 122.04, 119.59, 119.52, 119.06,118.15, 116.36, 114.26, 55.47. LC-MS m/z (ESI) calcd for C20H18ClN2O2 (M + H):353.1, found 353.1(M + H)+; 375.1 (M + Na)+. The purity was 96.75% by HPLCanalysis。
实施例23
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(4-hydroxyphenyl)benzamide (T-1)
white solid (30% yield), mp 123.9-124.2 ℃. 1H NMR (400 MHz,Methanol-d 4) δ 7.71 (dd, J = 7.9, 1.6 Hz, 1H), 7.45 – 7.34 (m, 2H), 7.34 –7.26 (m, 1H), 7.24 – 7.16 (m, 1H), 7.14 – 7.05 (m, 2H), 6.97 (d, J = 8.4 Hz,1H), 6.86 (t, J = 7.5 Hz, 1H), 6.81 – 6.72 (m, 2H), 2.30 (s, 3H). 13C NMR (101MHz, Methanol-d 4) δ 170.15, 155.96, 146.74, 143.02, 136.40, 133.27, 131.24,130.08, 129.92, 128.11, 125.03, 124.77, 121.00, 120.75, 119.54, 116.56,116.32, 14.94. LC-MS m/z (ESI) calcd for C21H18ClN2O2 (M + H): 353.1, found353.1 (M + H)+; 375.1 (M + Na)+. The purity was 98.82% by HPLC analysis。
实施例24
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-methoxyphenyl)-2-((3-(trifluoromethyl)phenyl)amino)nicotinamide(U-1)
white solid (30% yield), mp 192.2-193.0 ℃. 1H NMR (400 MHz, CDCl3) δ10.53 (s, 1H), 8.41 (dd, J = 4.8, 1.8 Hz, 1H), 8.08 (t, J = 2.0 Hz, 1H), 7.93– 7.82 (m, 2H), 7.72 (s, 1H), 7.54 – 7.35 (m, 3H), 7.26 – 7.21 (m, 1H), 7.01– 6.90 (m, 2H), 6.82 (dd, J = 7.7, 4.8 Hz, 1H), 3.83 (s, 3H). 13C NMR (75 MHz,DMSO-d 6) δ 166.21, 156.23, 154.07, 150.63, 141.09, 137.85, 131.40, 129.87,129.63 (q, J = 31.2 Hz), 124.44 (d, J = 272.4 Hz), 123.08, 117.84 (d, J = 4.2Hz), 115.27 (d, J = 4.3 Hz), 114.61, 113.92, 112.96, 55.35. LC-MS m/z (ESI)calcd for C20H17F3N3O2 (M + H): 388.1, found 388.1 (M + H)+; 410.1 (M + Na)+.The purity was 96.16% by HPLC analysis。
实施例25
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-hydroxyphenyl)-2-((3-(trifluoromethyl)phenyl)amino)nicotinamide(W-1)
white solid (25% yield), mp 216.0-217.0 ℃. 1H NMR (400 MHz,Methanol-d 4) δ 8.34 (dd, J = 4.8, 1.8 Hz, 1H), 8.27 – 8.21 (m, 1H), 8.15 (dd,J = 7.7, 1.9 Hz, 1H), 7.74 (dd, J = 8.2, 2.2 Hz, 1H), 7.48 – 7.39 (m, 3H),7.27 – 7.19 (m, 1H), 6.91 (dd, J = 7.7, 4.9 Hz, 1H), 6.87 – 6.77 (m, 2H). 13CNMR (101 MHz, DMSO-d 6) δ 166.11, 154.51, 154.09, 150.53, 141.12, 137.78,129.88, 129.83, 129.65 (q, J = 31.4 Hz), 123.39, 123.02, 124.45 (q, J = 272.3Hz), 117.79 (d, J = 4.0 Hz), 115.24, 115.18 (d, J = 3.9 Hz), 114.60, 113.00.HRMS (ESI-TOF) calcd for C19H15F3N3O2 (M + H)+: 374.1111, found 374.1133 (M + H)+.The purity was 99.54% by HPLC analysis。
实施例26
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-(benzylamino)-N-(4-methoxyphenyl)benzamide (Z-1)
white solid (30% yield), mp 123.0-124.2 ℃. 1H NMR (400 MHz, CDCl3) δ7.93 (t, J = 5.6 Hz, 1H), 7.71 (s, 1H), 7.51 – 7.38 (m, 3H), 7.38 – 7.16 (m,6H), 6.93 – 6.80 (m, 2H), 6.69 – 6.55 (m, 2H), 4.38 (d, J = 5.5 Hz, 2H), 3.78(s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.09, 156.62, 149.66, 138.91, 133.05,130.71, 128.56, 127.26, 127.11, 127.00, 122.71, 115.37, 115.07, 114.19,112.26, 55.46, 47.13. LC-MS m/z (ESI) calcd for C21H21N2O2 (M + H): 333.1,found 333.1 (M + H)+; 355.1 (M + Na)+. The purity was 99.13% by HPLC analysis。
实施例27
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-(benzylamino)-N-(4-hydroxyphenyl)benzamide (1-A)
white solid (40% yield), mp 147.0-148.2 ℃. 1H NMR (400 MHz,Methanol-d 4) δ 7.62 (dd, J = 7.8, 1.6 Hz, 1H), 7.50 – 7.34 (m, 4H), 7.33 –7.17 (m, 4H), 6.83 – 6.72 (m, 2H), 6.72 – 6.56 (m, 2H), 4.39 (s, 2H). 13C NMR(101 MHz, Methanol-d 4) δ 170.73, 155.67, 150.57, 140.80, 133.68, 131.54,129.59, 129.57, 128.26, 128.02, 124.77, 117.83, 116.40, 116.24, 113.16,48.07. LC-MS m/z (ESI) calcd for C20H19N2O2 (M + H): 319.1, found 319.1 (M + H)+;341.1 (M + Na)+. The purity was 95.28% by HPLC analysis。
实施例28
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-bromo-3-methoxyphenyl)-2-((2,3-dimethylphenyl)amino)benzamide(J-5)
white solid (30% yield), mp 164.0-165.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.11 (s, 1H), 8.45 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 7.9, 1.6Hz, 1H), 7.27 – 7.23 (m, 1H), 7.18 – 7.12 (m, 2H), 7.11 – 7.03 (m, 2H), 6.97(d, J = 7.4 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.79 – 6.72 (m, 1H), 3.92 (s,3H), 2.32 (s, 3H), 2.20 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.59, 148.90,147.84, 139.18, 138.09, 132.75, 131.42, 127.44, 126.94, 126.07, 125.83,123.97, 121.62, 120.95, 116.84, 116.80, 116.05, 115.09, 113.59, 56.13, 20.63,13.96. LC-MS m/z (ESI) calcd for C22H22BrN2O2 (M + H): 425.1, found 425.1 (M +H)+; 447.1 (M + Na)+. The purity was 95.19% by HPLC analysis。
实施例29
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(3,4-dimethoxyphenyl)-2-((2,3-dimethylphenyl)amino)benzamide (J-7)
white solid (40% yield), mp 174.9-175.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.01 (s, 1H), 7.79 (s, 1H), 7.55 (d, J = 6.4 Hz, 1H), 7.31 (d, J = 2.4 Hz,1H), 7.27 – 7.22 (m, 1H), 7.16 – 7.04 (m, 2H), 7.03 – 6.80 (m, 4H), 6.77 –6.67 (m, 1H), 3.89 (d, J = 11.7 Hz, 6H), 2.32 (s, 3H), 2.20 (s, 3H). 13C NMR(101 MHz, CDCl3) δ 167.89, 149.13, 147.57, 146.24, 139.27, 138.08, 132.61,131.31, 131.17, 127.26, 125.98, 125.81, 121.47, 116.96, 116.84, 115.15,113.02, 111.38, 105.79, 56.13, 55.96, 20.62, 13.97. LC-MS m/z (ESI) calcd forC23H25BrN2O3 (M + H): 377.2, found 377.2 (M + H)+; 399.1 (M + Na)+. The puritywas 99.12% by HPLC analysis。
实施例30
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-(dimethylamino)phenyl)-2-((2,3-dimethylphenyl)amino)benzamide(J-8)
white solid (50% yield), mp 150.2-151.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.09 (s, 1H), 7.71 (s, 1H), 7.53 (dd, J = 7.9, 1.6 Hz, 1H), 7.47 – 7.33 (m,2H), 7.28 – 7.19 (m, 1H), 7.15 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H),6.99 – 6.87 (m, 2H), 6.76 – 6.68 (m, 3H), 2.93 (s, 6H), 2.31 (s, 3H), 2.19(s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.86, 148.32, 147.37, 139.41, 137.99,132.29, 131.09, 127.28, 127.19, 125.71, 122.78, 121.17, 117.32, 116.76,114.94, 113.03, 40.86, 20.61, 13.92. LC-MS m/z (ESI) calcd for C23H26BrN3O (M +H): 360.2, found 360.2 (M + H)+; 382.2 (M + Na)+. The purity was 95.08% byHPLC analysis。
实施例31
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(3,4-dimethoxybenzyl)benzamide(I-2)
white solid (30% yield), mp 118.9-119.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.13 (s, 1H), 7.78 (s, 1H), 7.57 (dd, J = 7.9, 1.6 Hz, 1H), 7.32 – 7.26 (m,2H), 7.23 – 7.19 (m, 1H), 7.17 – 7.05 (m, 2H), 7.02 – 6.94 (m, 2H), 6.89 –6.78 (m, 2H), 3.90 (d, J = 11.8 Hz, 6H), 2.35 (s, 3H). 13C NMR (101 MHz,CDCl3) δ 167.72, 149.16, 146.52, 146.36, 141.04, 135.49, 132.65, 130.98,130.27, 127.34, 126.75, 124.69, 121.00, 117.82, 117.76, 115.50, 113.09,111.39, 105.81, 56.12, 55.97, 14.94. LC-MS m/z (ESI) calcd for C22H22ClN2O3 (M+ H): 397.1, found 397.1 (M + H)+; 419.1 (M + Na)+. The purity was 98.26% byHPLC analysis。
实施例32
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(3,4,5-trimethoxyphenyl)benzamide (I-4)
white solid (50% yield), mp 192.9-193.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.10 (s, 1H), 8.04 (s, 1H), 7.60 (dd, J = 8.0, 1.6 Hz, 1H), 7.32 – 7.24 (m,1H), 7.19 (d, J = 7.7 Hz, 1H), 7.17 – 7.02 (m, 2H), 6.94 (d, J = 8.5 Hz, 1H),6.86 (s, 2H), 6.80 – 6.73 (m, 1H), 3.82 (d, J = 2.6 Hz, 9H), 2.34 (s, 3H). 13CNMR (101 MHz, CDCl3) δ 167.76, 153.24, 146.43, 140.94, 135.40, 134.93,133.66, 132.67, 130.18, 127.44, 126.72, 124.67, 121.00, 117.81, 117.63,115.45, 98.58, 60.89, 55.98, 55.74, 14.86. LC-MS m/z (ESI) calcd forC23H24ClN2O4 (M + H): 397.1, found 427.1 (M + H)+; 449.1(M + Na)+. The puritywas 95.04% by HPLC analysis。
实施例33
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((3-chloro-2-methylphenyl)amino)benzamide (I-8)
white solid (35% yield), mp 172.9-173.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.15 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 6.2 Hz, 1H), 7.32 – 7.19 (m, 3H),7.16 – 7.05 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 6.91 – 6.72 (m, 3H), 5.97 (s,2H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.74, 147.94, 146.54, 144.80,140.99, 135.49, 132.71, 131.60, 130.16, 127.30, 126.73, 124.64, 120.85,117.80, 117.56, 115.46, 114.26, 108.16, 103.70, 101.38, 14.90. LC-MS m/z(ESI) calcd for C21H18ClN2O3 (M + H): 381.1, found 381.1 (M + H)+; 403.0 (M +Na)+. The purity was 97.29% by HPLC analysis。
实施例34
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(3,5-dimethoxybenzyl)benzamide(I-10)
white solid (40% yield), mp 127.9-128.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.25 (s, 1H), 8.42 – 8.18 (m, 2H), 7.58 (d, J = 7.9 Hz, 1H), 7.31 – 7.19 (m,2H), 7.16 – 7.03 (m, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.86 – 6.76 (m, 1H), 6.62– 6.39 (m, 2H), 3.83 (d, J = 27.7 Hz, 6H), 2.36 (s, 3H). 13C NMR (101 MHz,CDCl3) δ 167.15, 156.70, 149.79, 146.35, 141.17, 135.39, 132.32, 130.02,127.49, 126.67, 124.40, 121.03, 120.92, 120.70, 118.37, 117.81, 115.36,103.81, 98.66, 55.75, 55.51, 14.89. LC-MS m/z (ESI) calcd for C22H22ClN2O3 (M +H): 381.1, found 397.1 (M + H)+; 419.1 (M + Na)+. The purity was 95.04% byHPLC analysis。
实施例35
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-(methylthio)phenyl)-2-((3-(trifluoromethyl)phenyl)amino)benzamide (N-2)
white solid (30% yield), mp 150.9-151.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.29 (s, 1H), 7.95 (s, 1H), 7.61 – 7.52 (m, 1H), 7.50 – 7.44 (m, 2H), 7.43 –7.32 (m, 4H), 7.30 – 7.19 (m, 4H), 6.92 – 6.82 (m, 1H), 2.45 (s, 3H). 13C NMR(101 MHz, CDCl3) δ 167.51, 144.52, 142.07, 134.89, 134.54, 132.79, 131.69 (q,J = 32.1 Hz), 129.83, 127.84, 127.57, 123.97 (q, J = 272.5 Hz), 122.97,121.32, 119.43, 119.31, 118.63 (q, J = 3.9 Hz), 116.30 (q, J = 3.8 Hz).,116.17, 16.49. LC-MS m/z (ESI) calcd for C21H18F3N2O S (M + H): 403.1, found403.1 (M + H)+; 425.0 (M + Na)+. The purity was 96.56% by HPLC analysis。
实施例36
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-(trifluoromethyl)phenyl)amino)-N-(3,4,5-trimethoxyphenyl)benzamide (N-3)
white solid (60% yield), mp 141.9-142.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.28 (s, 1H), 7.86 (s, 1H), 7.67 – 7.56 (m, 1H), 7.46 – 7.31 (m, 5H), 7.23(d, J = 7.4 Hz, 1H), 6.94 – 6.88 (m, 1H), 6.86 (s, 2H), 3.86 (s, 6H), 3.83(s, 3H). 13C NMR (75 MHz, CDCl3) δ 167.55, 153.35, 144.39, 142.13, 135.15,135.11, 133.48, 132.74, 131.68 (q, J = 32.1 Hz), 129.83, 127.60, 123.96 (d, J= 272.4 Hz), 122.93, 119.65, 119.37, 118.60 (q, J = 3.9 Hz), 116.28 (d, J =3.5 Hz)., 116.20, 98.53, 98.50, 60.95, 56.08. LC-MS m/z (ESI) calcd forC23H22F3N2O4 (M + H): 447.1, found 447.1 (M + H)+; 469.1 (M + Na)+. The puritywas 98.07% by HPLC analysis。
实施例37
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(4-(dimethylamino)phenyl)-2-((3-(trifluoromethyl)phenyl)amino)benzamide (N-4)
white solid (40% yield), mp 157.9-158.6 ℃. 1H NMR (400 MHz, CDCl3) δ9.43 (s, 1H), 7.74 (s, 1H), 7.57 (dd, J = 7.9, 1.5 Hz, 1H), 7.43 – 7.28 (m,7H), 7.19 (d, J = 7.5 Hz, 1H), 6.92 – 6.84 (m, 1H), 6.77 – 6.68 (m, 2H), 2.93(s, 6H). 13C NMR (101 MHz, CDCl3) δ 167.51, 148.47, 144.28, 142.29, 132.33,131.62 (q, J = 32.0 Hz), 129.75, 127.60, 127.57, 126.75, 126.73 (d, J = 272.6Hz), 122.81, 122.71, 119.99, 119.96, 119.23, 118.28 (q, J = 3.9 Hz), 116.09,116.03 (d, J = 4.5 Hz), 112.91, 40.76. LC-MS m/z (ESI) calcd for C22H21F3N3O (M+ H): 400.2, found 400.2 (M + H)+; 422.1 (M + Na)+. The purity was 99.00% byHPLC analysis。
实施例38
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(benzo[d][1,3]dioxol-5-yl)-2-((3-(trifluoromethyl)phenyl)amino)benzamide (N-6)
white solid (40% yield), mp 137.9-138.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.34 (s, 1H), 7.76 (s, 1H), 7.57 (dd, J = 7.8, 1.4 Hz, 1H), 7.44 – 7.30 (m,5H), 7.25 – 7.18 (m, 2H), 6.93 – 6.88 (m, 1H), 6.85 (dd, J = 8.3, 2.1 Hz,1H), 6.79 (d, J = 8.3 Hz, 1H), 5.97 (s, 2H). 13C NMR (101 MHz, CDCl3) δ167.55, 147.97, 144.91, 144.50, 142.14, 132.71, 131.45, 131.72 (q, J = 32.2Hz), 129.83, 127.53, 123.99 (q, J = 272.5 Hz), 122.95, 119.49, 119.29, 118.58(q, J = 3.9 Hz), 116.27 (q, J = 4.1 Hz)., 116.16, 114.27, 108.17, 103.65,101.41. LC-MS m/z (ESI) calcd for C21H16F3N2O3 (M + H): 401.1, found 401.1 (M +H)+; 423.1 (M + Na)+. The purity was 97.56% by HPLC analysis。
实施例39
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(3,4-dimethoxyphenyl)-2-((3-(trifluoromethyl)phenyl)amino)benzamide (N-9)
white solid (30% yield), mp 138.9-139.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.34 (s, 1H), 7.80 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.46 – 7.30 (m, 6H),7.22 (d, J = 7.5 Hz, 1H), 7.00 – 6.84 (m, 3H), 3.89 (d, J = 11.7 Hz, 6H). 13CNMR (75 MHz, CDCl3) δ 167.55, 148.98, 146.28, 144.21, 142.13, 132.50, 131.56(q, J = 32.2 Hz), 130.85, 129.75, 127.65, 123.93 (d, J = 272.5 Hz), 122.73,119.67, 119.26, 118.39 (q, J = 3.9 Hz), 116.04 (d, J = 4.1 Hz), 115.97,113.11, 111.25, 105.74, 55.94, 55.77. HRMS (ESI-TOF) Calcd for C22H19NaF3N2O3[M + Na]+ 439.1240, found 439.1259. The purity was 98.82% by HPLC analysis。
实施例40
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(4-methoxybenzyl)benzamide (2-G)
white solid (30% yield), mp 138.9-139.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.38 (s, 1H), 7.43 (dd, J = 7.9, 1.6 Hz, 1H), 7.32 – 7.20 (m, 4H), 7.16 –7.06 (m, 2H), 7.01 (dd, J = 8.4, 1.1 Hz, 1H), 6.96 – 6.84 (m, 2H), 6.77 –6.66 (m, 1H), 6.49 (t, J = 5.5 Hz, 1H), 4.56 (d, J = 5.6 Hz, 2H), 3.81 (s,3H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.19, 159.09, 146.12, 141.23,135.40, 132.29, 129.92, 129.77, 129.14, 127.35, 126.64, 124.24, 120.37,117.66, 117.40, 115.23, 114.15, 55.25, 43.32, 14.84。
实施例41
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-(2-fluoro-[1,1'-biphenyl]-4-yl)-N-(4-hydroxyphenyl)propanamide (CN-1)
white solid (30% yield), mp 128.9-129.2 ℃. 1H NMR (400 MHz, MeOD-d 4)δ 7.50 (d, J = 8.4 Hz, 2H), 7.45 – 7.36 (m, 3H), 7.36 – 7.21 (m, 5H), 6.77 –6.68 (m, 2H), 3.82 (q, J = 7.0 Hz, 1H), 1.52 (d, J = 7.0 Hz, 3H). 13C NMR (101MHz, MeOD-d 4) δ 174.37, 162.20, 159.75, 156.19, 144.84, 144.76, 136.92,131.87, 131.83, 131.22, 129.97, 129.94, 129.45, 128.92, 128.79, 128.66,124.72, 124.68, 123.55, 116.47, 116.08, 115.84, 47.47, 19.05。
实施例42
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-(2-fluoro-[1,1'-biphenyl]-4-yl)-N-(4-methoxyphenyl)propanamide (CM-1)
white solid (30% yield), mp 130.9-131.2 ℃. 1H NMR (400 MHz, CDCl3) δ7.53 (d, J = 8.2 Hz, 2H), 7.48 – 7.32 (m, 6H), 7.30 – 7.15 (m, 3H), 6.85 –6.76 (m, 2H), 3.75 (s, 3H), 3.70 (q, J = 7.1 Hz, 1H), 1.60 (d, J = 7.1 Hz,3H). 13C NMR (101 MHz, CDCl3) δ 171.49, 158.59, 156.50, 142.45, 142.38,135.27, 131.16, 130.76, 128.90, 128.87, 128.45, 128.14, 128.00, 127.73,123.59, 123.56, 121.80, 115.43, 115.20, 114.06, 55.43, 47.34, 18.63。
实施例43
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(benzyloxy)-2-((2,3-dimethylphenyl)amino)benzamide (WZ-1)
white solid (30% yield), mp 131.9-131.2 ℃. 1H NMR (400 MHz, CDCl3) δ8.90 (s, 1H), 8.46 (s, 1H), 7.49 – 7.35 (m, 5H), 7.21 (t, J = 7.6 Hz, 2H),7.14 (d, J = 7.9 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H),6.88 (d, J = 8.1 Hz, 1H), 6.68 – 6.56 (m, 1H), 5.04 (s, 2H), 2.33 (s, 3H),2.20 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.71, 147.47, 139.01, 138.13,135.29, 132.99, 131.23, 129.35, 128.84, 128.69, 127.14, 126.02, 125.78,121.33, 116.61, 114.84, 113.53, 78.45, 20.66, 13.89。
实施例44
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(3,4-dimethoxyphenyl)-2-((3-(trifluoromethyl)phenyl)amino)benzamide (X-1)
white solid (30% yield), mp 132.9-133.2 ℃. 1H NMR (400 MHz, CDCl3) δ9.27 (s, 1H), 7.40 (dd, J = 7.9, 1.6 Hz, 1H), 7.33 – 7.27 (m, 2H), 7.24 –7.16 (m, 2H), 7.09 (t, J = 7.7 Hz, 1H), 7.01 – 6.87 (m, 4H), 6.71 – 6.61 (m,1H), 6.47 – 6.38 (m, 1H), 4.56 (d, J = 5.5 Hz, 2H), 3.81 (s, 3H), 2.34 (s,3H), 2.23 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.39, 159.06, 147.20, 139.45,138.00, 132.26, 130.89, 130.11, 129.16, 127.26, 125.69, 125.59, 120.94,116.65, 116.59, 114.82, 114.13, 55.26, 43.29, 20.63, 13.88。
实施例45
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(benzo[d]oxazol-6-yl)-2-((3-chloro-2-methylphenyl)amino)benzamide(化合物1)
1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.39 (s, 1H), 8.25 (s, 1H),8.07 (s, 1H), 7.65 (dd, J = 24.3, 7.7 Hz, 2H), 7.36 – 7.23 (m, 2H), 7.20 (d,J = 7.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.10 – 7.04 (m, 1H), 6.99 (d, J =8.4 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3)δ 167.88, 152.93, 150.24, 146.45, 140.74, 136.57, 135.64, 135.41, 132.92,129.99, 127.51, 126.72, 124.64, 120.73, 120.25, 117.90, 117.82, 117.26,115.47, 103.94, 14.84。
实施例46
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(quinoxalin-6-yl)benzamide (化合物2)：
1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.90 (s, 2H), 8.40 (d, J =30.4 Hz, 2H), 8.18 – 7.97 (m, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.7Hz, 1H), 7.24 – 7.19 (m, 1H), 7.17 – 7.12 (m, 1H), 7.12 – 7.05 (m, 1H), 7.00(d, J = 8.4 Hz, 1H), 6.80 (t, J = 7.3 Hz, 1H), 2.35 (s, 3H). 13C NMR (101 MHz,CDCl3) δ 167.94, 146.75, 145.59, 144.08, 140.62, 139.15, 135.45, 133.22,130.33, 130.14, 127.61, 126.75, 124.78, 124.54, 120.88, 118.03, 117.81,116.75, 115.49, 14.87。
实施例47
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(pyridin-2-yl)benzamide (化合物4)：
1H NMR (400 MHz, CDCl3) δ 9.16 (d, J = 10.4 Hz, 2H), 8.25 (d, J = 8.4Hz, 1H), 8.07 (d, J = 4.9 Hz, 1H), 7.70 – 7.62 (m, 1H), 7.62 – 7.54 (m, 1H),7.23 – 7.17 (m, 1H), 7.17 – 7.12 (m, 1H), 7.09 – 7.04 (m, 1H), 7.04 – 6.97(m, 1H), 6.97 – 6.92 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 7.5 Hz,1H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.09, 151.54, 147.83, 146.81,140.79, 138.40, 135.44, 133.08, 130.26, 127.97, 126.76, 124.75, 121.10,119.79, 117.72, 116.80, 115.28, 114.31, 14.92。
实施例48
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(1H-benzo[d]imidazol-6-yl)-2-((3-chloro-2-methylphenyl)amino)benzamide (化合物5)：
1H NMR (400 MHz, CDCl3) δ 8.40 (s, 2H), 8.20 (s, 2H), 7.89 (d, J = 8.6Hz, 1H), 7.50 (dd, J = 7.9, 1.6 Hz, 1H), 7.43 – 7.32 (m, 1H), 7.24 – 7.19 (m,1H), 7.19 – 7.14 (m, 1H), 7.11 (d, J = 7.9 Hz, 2H), 7.08 (d, J = 2.1 Hz, 1H),7.02 – 6.97 (m, 1H), 6.88 – 6.82 (m, 1H), 6.80 (dd, J = 8.7, 2.2 Hz, 1H),3.75 (s, 2H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.46, 147.56, 145.35,144.40, 143.64, 139.93, 135.60, 134.45, 131.82, 130.31, 126.95, 125.41,125.38, 121.36, 117.87, 115.63, 115.52, 115.47, 114.46, 105.20, 14.87。
实施例49
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(quinolin-8-yl)benzamide (化合物6)：
1H NMR (400 MHz, CDCl3) δ 10.72 (s, 1H), 9.55 (s, 1H), 8.85 (dd, J =7.6, 1.4 Hz, 1H), 8.79 (dd, J = 4.3, 1.7 Hz, 1H), 8.11 (dd, J = 8.2, 1.7 Hz,1H), 7.85 (dd, J = 8.0, 1.5 Hz, 1H), 7.56 – 7.46 (m, 2H), 7.41 (dd, J = 8.3,4.2 Hz, 1H), 7.32 – 7.23 (m, 2H), 7.13 – 6.98 (m, 3H), 6.90 – 6.84 (m, 1H),2.40 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.71, 148.19, 146.75, 141.06,138.65, 136.26, 135.37, 134.39, 132.65, 130.11, 127.90, 127.88, 127.24,126.69, 124.47, 121.64, 121.62, 120.86, 117.83, 117.71, 116.27, 115.28,14.95。
实施例50
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(pyridin-4-yl)benzamide (化合物8)：
1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 8.60 – 8.51 (m, 2H), 8.47 (s,1H), 7.65 – 7.58 (m, 3H), 7.37 – 7.29 (m, 1H), 7.26 – 7.16 (m, 2H), 7.15 –7.07 (m, 1H), 7.01 – 6.94 (m, 1H), 6.85 – 6.78 (m, 1H), 2.37 (s, 3H). 13C NMR(101 MHz, CDCl3) δ 168.22, 150.66, 147.01, 145.12, 140.54, 135.54, 133.48,130.46, 127.63, 126.85, 125.09, 121.34, 117.76, 116.43, 115.56, 114.02,14.93。
实施例51
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(benzo[d]thiazol-6-yl)-2-((3-chloro-2-methylphenyl)amino)benzamide(化合物9)：
1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.91 (s, 1H), 8.56 (s, 1H),8.34 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.50 – 7.39(m, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 6.6Hz, 1H), 7.11 – 7.05 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 7.4 Hz,1H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.93, 153.72, 150.05, 146.51,140.76, 135.44, 135.35, 134.76, 132.95, 130.05, 127.49, 126.74, 124.69,123.55, 120.81, 119.81, 117.85, 117.30, 115.49, 113.35, 14.88。
实施例52
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(pyridazin-3-yl)benzamide (化合物11)：
1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 9.30 (s, 1H), 8.97 (d, J = 4.5Hz, 1H), 8.55 (d, J = 8.9 Hz, 1H), 7.90 – 7.79 (m, 1H), 7.59 – 7.47 (m, 1H),7.34 – 7.28 (m, 1H), 7.25 – 7.20 (m, 1H), 7.19 – 7.14 (m, 1H), 7.14 – 7.07(m, 1H), 6.98 – 6.93 (m, 1H), 6.80 (t, J = 7.4 Hz, 1H), 2.35 (s, 3H). 13C NMR(101 MHz, CDCl3) δ 168.59, 155.48, 148.44, 147.36, 140.51, 135.46, 133.71,130.52, 128.30, 128.21, 126.81, 125.06, 121.54, 119.39, 117.78, 115.38,115.27, 14.90。
实施例53
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(pyridin-3-yl)benzamide (化合物12)：
1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.67 (s, 1H), 8.42 – 8.28 (m,2H), 8.29 – 8.21 (m, 1H), 7.64 (dd, J = 8.0, 1.5 Hz, 1H), 7.38 – 7.28 (m,2H), 7.21 (dd, J = 7.8, 1.4 Hz, 1H), 7.15 (dd, J = 8.0, 1.5 Hz, 1H), 7.12 –7.06 (m, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.81 (t, J = 7.5 Hz, 1H), 2.34 (s,3H). 13C NMR (101 MHz, CDCl3) δ 168.18, 146.79, 145.38, 141.72, 140.69,135.50, 134.73, 133.23, 130.31, 128.16, 127.64, 126.81, 124.90, 123.81,121.12, 117.82, 116.62, 115.50, 14.93。
实施例54
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
N-(1H-benzo[d][1,2,3]triazol-6-yl)-2-((3-chloro-2-methylphenyl)amino)benzamide (化合物13)：
1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.10 (dd, J = 8.1, 1.6 Hz,1H), 7.89 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.42 – 7.37 (m, 1H),7.28 – 7.25 (m, 1H), 7.21 – 7.18 (m, 1H), 7.15 – 7.10 (m, 1H), 6.99 (dd, J =8.6, 1.1 Hz, 1H), 6.90 – 6.84 (m, 2H), 4.29 (s, 2H), 2.38 (s, 3H). 13C NMR(101 MHz, CDCl3) δ 168.03, 149.02, 148.69, 140.11, 139.92, 135.56, 134.90,134.66, 134.45, 130.56, 126.98, 125.45, 121.82, 121.00, 117.56, 116.28,114.98, 114.31, 96.93, 14.92。
实施例55
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(2-oxoindolin-5-yl)benzamide (化合物14)：
1H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 10.25 (s, 1H), 9.23 (s,1H), 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.59 (s, 1H), 7.44 (dd, J = 8.4, 2.2 Hz,1H), 7.38 – 7.31 (m, 1H), 7.26 – 7.21 (m, 1H), 7.19 – 7.09 (m, 2H), 7.02 (d,J = 8.4 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 3.49 (s,2H), 2.25 (s, 3H). 13C NMR (101 MHz, DMSO-d 6 ) δ 176.43, 167.51, 144.63,141.57, 140.10, 134.43, 132.66, 132.23, 129.39, 127.58, 127.49, 126.02,123.36, 120.55, 119.65, 119.08, 118.46, 118.33, 115.31, 108.86, 36.12, 14.59。
实施例56
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(pyrimidin-4-yl)benzamide (化合物15)：
1H NMR (400 MHz, CDCl3) δ 9.23 (s, 2H), 8.77 (s, 1H), 8.67 (d, J = 5.8Hz, 1H), 8.30 (d, J = 5.7 Hz, 1H), 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.36 –7.30 (m, 1H), 7.25 – 7.21 (m, 1H), 7.21 – 7.17 (m, 1H), 7.14 – 7.08 (m, 1H),6.99 – 6.93 (m, 1H), 6.83 – 6.77 (m, 1H), 2.36 (s, 3H). 13C NMR (101 MHz,CDCl3) δ 168.55, 158.33, 157.39, 147.49, 140.27, 135.54, 134.01, 130.71,128.00, 126.87, 125.32, 121.73, 117.66, 115.39, 115.22, 110.35, 14.92。
实施例57
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(1H-indol-5-yl)benzamide (化合物16)：
1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.23 (s, 1H), 7.90 (s, 1H),7.87 (d, J = 2.1 Hz, 1H), 7.62 (dd, J = 8.0, 1.6 Hz, 1H), 7.37 (d, J = 8.6Hz, 1H), 7.34 – 7.25 (m, 3H), 7.29 – 7.19 (m, 4H), 7.12 (dd, J = 8.0, 1.6 Hz,1H), 7.12 – 7.05 (m, 2H), 7.02 (dd, J = 8.4, 1.1 Hz, 1H), 6.87 – 6.79 (m,1H), 6.57 – 6.51 (m, 1H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.00,146.30, 141.10, 135.40, 133.50, 132.45, 129.96, 129.78, 128.08, 127.42,126.68, 125.27, 124.38, 120.57, 118.15, 117.81, 117.17, 115.35, 113.78,111.31, 102.88, 14.93。
实施例58
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(pyridazin-4-yl)benzamide (化合物17)：
1H NMR (400 MHz, DMSO) δ 10.85 (s, 1H), 9.45 (d, J = 2.7 Hz, 1H),9.06 (d, J = 6.0 Hz, 1H), 8.96 (s, 1H), 8.02 (dd, J = 5.9, 2.7 Hz, 1H), 7.89– 7.75 (m, 1H), 7.45 – 7.35 (m, 1H), 7.22 – 7.08 (m, 3H), 6.99 – 6.87 (m,2H), 2.26 (s, 3H). 13C NMR (101 MHz, DMSO-d 6 ) δ 169.15, 151.43, 145.38,144.15, 141.32, 138.12, 134.43, 133.40, 129.84, 128.74, 127.54, 124.17,120.54, 118.32, 118.12, 115.65, 114.49, 14.70。
实施例59
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(1H-pyrazol-5-yl)benzamide (化合物20)：
1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.12 (d, J = 3.0 Hz, 1H), 7.94(dd, J = 7.9, 1.7 Hz, 1H), 7.38 – 7.30 (m, 1H), 7.20 (dd, J = 7.6, 1.7 Hz,1H), 7.13 – 7.01 (m, 3H), 6.89 – 6.83 (m, 1H), 5.97 (d, J = 3.0 Hz, 1H), 4.20(s, 2H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.96, 158.12, 146.56,140.79, 135.32, 133.39, 133.18, 132.33, 128.94, 126.75, 124.20, 119.84,117.81, 116.45, 115.71, 100.95, 14.66。
实施例60
一种Ｎ－苯基邻氨基苯甲酰胺类化合物，为
2-((3-chloro-2-methylphenyl)amino)-N-(isoxazol-5-yl)benzamide (化合物21)：
1H NMR (400 MHz, CDCl3) δ 9.94 (d, J = 23.3 Hz, 1H), 9.35 (s, 1H),8.36 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.28 – 7.20(m, 2H), 7.17 (d, J = 7.3 Hz, 1H), 7.13 – 7.04 (m, 1H), 6.94 (d, J = 8.5 Hz,1H), 6.85 (t, J = 7.5 Hz, 1H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3) δ167.50, 158.93, 157.82, 147.52, 140.56, 135.52, 133.71, 130.84, 128.30,126.85, 125.20, 121.84, 117.69, 115.16, 114.97, 99.71, 15.00。
实施例 61
CCK8法测试肿瘤药物敏感试验的方法学研究
精密称定目标化合物，分别稀释至浓度为100 mmol/L作为母液，过滤除菌，4℃密封保存备用。
预先培养胶质瘤肿瘤细胞（U251, U87MG, C6）生长至对数生长期，再把对数生长期的贴壁细胞用胰蛋白酶消化液消化后（悬浮细胞不需要消化），每孔100μl细胞悬浮液，每孔1000-10000个细胞，接种于96孔板中，周围一圈孔加入100μl的PBS缓冲液；
37℃细胞培养箱（5%CO2，90%H2O）中培养至细胞贴壁；之后加入含待测目标化合物的培养液，实验组加入按浓度梯度稀释，每个浓度均设置三个平行对照孔；空白对照组加入100μl培养液，继续培养72h；
每孔加入10μl的CCK8溶液，继续培养1h；之后终止培养，吸去孔内培养液；
置于酶标仪中450 nm下测定吸光度值，根据公式计算出目标化合物的抑制率，再用软件计算出IC50的值。结果见表1，结果表明N-芳基邻氨基苯甲酰胺类化合物具有显著的抗癌细胞增殖作用。
表 1. 代表性化合物胶质瘤细胞的增殖抑制作用
Compd. U87MG U251 C6
A-1 >100 >100 >100
B-1 >100 >100 >100
C-1 62.78 ± 2.75 >100 65.87 ± 3.19
D-1 53.99 ± 3.05 28.49 ± 12.76 46.34 ± 5.55
E-1 >100 >100 >100
F-1 38.24 ± 2.00 33.29 ± 6.12 43.89 ± 4.81
G-1 >100 >100 >100
H-1 >100 >100 >100
I-1 4.77 ± 0.15 5.36 ± 0.77 10.11 ± 3.15
J-1 >100 >100 >100
K-1 10.18 ± 1.03 25.18 ± 8.44 21.64 ± 1.46
L-1 17.96 ± 2.84 26.72 ± 3.95 28.24 ± 1.08
M-1 >100 >100 >100
N-1 22.46 ± 0.16 39.62 ± 6.80 27.74 ± 1.23
O-1 >100 >100 >100
P-1 21.84 ± 3.11 35.15 ± 3.28 52.16 ± 4.49
Q-1 79.13 ± 2.09 >100 >100
R-1 14.79 ± 1.45 33.78 ± 5.77 45.63 ± 8.64
S-1 >100 >100 >100
T-1 34.08 ± 0.19 14.27 ± 1.15 33.66 ± 1.53
U-1 >100 >100 >100
W-1 44.40 ± 3.11 >100 >100
Z-1 >100 >100 >100
1-A 60.89 ± 3.20 24.93 ± 4.80 51.51 ± 0.64
J-5 >100 >100 >100
J-7 >100 >100 >100
J-8 >100 >100 >100
I-2 >100 >100 43.96 ± 5.34
I-4 54.50 ± 6.57 >100 >100
I-8 6.46±0.63 9.91±1.12 16.89 ± 2.48
I-10 >100 >100 >100
N-2 >100 >100 >100
N-3 52.13 ± 4.46 50.73 ± 2.43 >100
N-4 44.38 ± 2.48 >100 >100
N-6 26.01 ± 3.21 12.87 ± 2.43 15.62 ± 1.37
N-9 72.35 ± 5.80 86.24 ± 8.98 36.48 ± 2.40
CM-1 50.92±4.20 >100 >100
CN-1 5.32±0.34 2.19±0.11 2.02±0.22
X-1 >100 >100 >100
Y-1 4.87±0.23 34.90±1.03 45.02±3.21
2-G >100 >100 >100
1-H 6.94±0.36 6.38±1.09 9.00±0.92
WZ-1 44.04±1.58 >100 >100
1 4.62±0.32 27.10±2.89 12.89±1.29
2 17.20±2.92 90.88±2.94 32.27±4.02
3 15.00±1.03 28.02±2.30 12.99±0.20
4 40.06±2.03 >100 >100
5 69.43±4.21 87.38±9.28 35.28±3.92
6 61.14±3.40 >100 17.53±3.92
7 86.23±3.29 >100 45.92±3.99
8 13.94±4.92 42.18±3.59 16.56±0.03
9 11.89±3.32 29.80±3.32 9.20±2.09
10 89.49±3.91 >100 >100
11 96.80±3.49 >100 23.43±4.21
12 61.74±1.82 >100 >100
13 63.56±0.92 >100 9.18±1.00
14 46.21±2.29 >100 >100
15 32.57±2.38 >100 >100
16 20.85±4.20 59.23±2.00 >100
17 39.63±4.29 >100 >100
18 >100 >100 >100
19 >100 >100 >100
b-1 >100 >100 >100
b-2 >100 >100 >100
Tolfenamic Acid >100 >100 >100
Topotecan 0.06 ± 0.01 0.37 ± 0.01 5.80 ± 0.12
实施例62
拓扑异构酶和COX-2抑制剂筛选实验
该实验参考说明书Inspiralis 公司的试剂盒（货号：HT101，拓扑异构酶 I）和（货号：HT20，拓扑异构酶 II)进行实验，COX-2活性测试按照Cayman 公司的试剂盒（货号：701080）进行。实验结果见附图1。
实施例63
克隆实验和Edu实验
1、取对数生长期的各组细胞，分别用0.25%胰蛋白酶消化并吹打成单个细胞，并把细胞悬浮在10%胎牛血清的DMEM培养液中备用。
2、将细胞悬液作梯度倍数稀释，每组细胞分别以每皿50、100、200个细胞的梯度密度分别接种含10mL 37℃预温培养液的皿中，并轻轻转动，使细胞分散均匀。置37℃ 5% CO2及饱和湿度的细胞培养箱中培养2-3周。
3、经常观察，当培养皿中出现肉眼可见的克隆时，终止培养。弃去上清液，用PBS小心浸洗2次。加4%多聚甲醛固定细胞5mL固定15分钟。然后去固定液，加适量GIMSA应用染色液染10～30分钟，然后用流水缓慢洗去染色液，空气干燥。
4、将平皿倒置并叠加一张带网格的透明胶片，用肉眼直接计数克隆，或在显微镜（低倍镜）计数大于10个细胞的克隆数。最后计算克隆形成率。
克隆形成率 =（克隆数/接种细胞数）×100%
Edu实验按照试剂盒说明书（锐博生物公司，货号：C10310-1）进行。实验结果见附图2。
实施例64
肿瘤细胞周期检测实验
细胞周期是指连续分裂细胞从一次有丝分裂结束到下一次有丝分裂结束所经历的整个过程。在这个过程中，细胞遗传物质复制并加倍，且在分裂结束时平均分配到两个子细胞中去。细胞周期又可以分为间期和有丝分裂期，细胞间期常划分为休眠期（G0），DNA 合成前期（G1），DNA 合成期（S），DNA 合成后期（G2），整个周期可表示为 G1→S→G2→M。DNA周期检测可用来反应细胞周期的各个期的状况，即细胞增殖状况。利用细胞内 DNA 能够和荧光染料（如碘化丙啶 PI）结合的特性，细胞各个时期其 DNA 量不同从而结合的荧光染料不同，流式细胞仪检测的荧光强度也不一样。
具体方法为：1、用I-1和I-8 (2， 4，8 μM) 处理胶质瘤细胞U251和U87MG，同时设立阴性对照组，48小时后消化并收集细胞。2、用 PBS 洗涤细胞一次，1500rpm，5min 离心收集，调整细胞浓度为 1×106/ml,取1mL 单细胞悬液。3、制备的单细胞悬液离心后，去除上清，在细胞中加入70%预冷乙醇 500uL固定2小时至过夜，4℃保存，染色前用PBS洗去固定液；如需要，细胞悬液可用200目细胞筛网过滤一次。4、细胞沉淀中加 100µl RNase A 溶液，重悬细胞，37℃水浴 30min。5、再加入 400µlPI 染色液混匀，4℃避光孵育 30min。6、上机检测，记录激发波长 488nm 处红色荧光。结果见附图4，表明化合物I-1 和I-8 对胶质瘤细胞U251和U87MG有较强的G2/M 周期阻滞作用。
实施例65
胶质瘤细胞侵袭和迁移实验
Matrigel 是从小鼠EHS肉瘤中提取的基质成分，含有LN、IV型胶原、接触蛋白和肝素硫酸多糖，铺在无聚乙烯吡硌烷酮的聚碳酸酯滤膜上，能在DMEM培养基中重建形成膜结构，这种膜结构与天然基质膜结构极为相似。
滤膜孔径一般为8um，而且膜孔都被Matrigel覆盖，细胞不能自由穿过，必须分泌水解酶，并通过变形运动才能穿过这种铺有Martrigel 的滤膜，这与体内情况较为相似。
铺有Martrigel的滤膜放在以Blind Well腔或MICS腔上下室之间，铺有Martrigel面朝向上室，在下室中加有趋化剂，如一定浓度的LN、FN或小鼠3T3条件培养液或人睾丸上皮成纤维细胞培养液，上室加入重悬的U87MG, U251细胞，具有侵袭能力的细胞在趋化剂15%的血清诱导下开始穿膜运动。细胞穿膜所用的时间与Martrigel的用量有关，选择25ugMartrigell铺膜，16小时后观察结果较为合适。穿过滤膜的细胞多数粘附在滤膜下表面，可用棉签将上表面的细胞拭去，然后用甲醇固定滤膜，1%结晶紫染色，迁移实验不加Matrigel，其余步骤与侵袭相同。结果见附图4。
实施例66
对C6胶质瘤原位模型的作用
建立脑胶质瘤动物模型的方法有很多种，目前应用最广泛的是大鼠C6 胶质瘤模型。该模型通过立体定向的方式将C6 胶质瘤细胞植入大鼠右侧尾状核，具有成瘤快,成瘤率高,实验周期短,重复性好,没有明显的颅外生长和转移等优点，便于各种实验的研究。本实验将建立胶质肿瘤模型后的大鼠分为建模后1 周、建模后2 周、建模后3周三组，利用MRI、病理诊断等技术，验证移植瘤的生长情况。并采用免疫组化，HE 染色，Western blot和RT-PCR 等方法，研究化合物I-1和I-8在大鼠C6胶质肿瘤增殖过程中的表达变化，探讨其在胶质肿瘤增殖过程中的作用。
C6 细胞系及其移植瘤模型被广泛应用于脑胶质瘤的实验研究。C6 细胞是经N-亚硝基甲脲 (N-nitrosomethylurea)诱导的非纯种Wistar 大鼠脑胶质瘤细胞，是目前国际上通用的胶质瘤细胞系。当使用SD大鼠进行造模时，由于同种异体性导致的宿主排斥反应，C6模型不能实现100%的成功率。当C6 细胞移植于新生大鼠成瘤后，其组织学特性与人类脑胶质母细胞瘤（星形细胞肿瘤，WHO Ⅳ级）病理特征一致，当其移植于大鼠脑内时，具有较好的组织相容性，能在大鼠脑内成功接种建立胶质瘤模型，并能稳定生长，具有胶质瘤特异性标志物GFAP 等的特征。李维方等通过MRI 检查发现C6 胶质瘤模型建立成功后仅1 周肿瘤已基本形成，随接种时的延长，其肿瘤体积不断增大，逐渐产生压迫及颅内高压症状。接种2周时大鼠即有明显的颅内高压症状，2 周后即有死亡，3 周时肿瘤鼠大多处于濒危状态。提示部分大鼠的C6 胶质瘤可能因自身免疫活性较高而自然消亡。
研究发现，注入鼠脑的细胞悬液体积和细胞量均影响此模型的成功率，并证实最适合的接种体积为10μL，细胞数为106个/mL。这为本实验接种细胞的量和密度提供了参考。胶质瘤细胞在鼠脑内变化过程大致可分为三期，即①胶质瘤细胞在脑组织内分散、聚集期；②胶质瘤细胞增殖期；③肿瘤组织形成期；前两个阶段一般在１周左右出现，肿瘤形成期多数在荷瘤两周前后。
1 实验动物
健康成年SD大鼠，全部为雄性，体质量 190-220g，由兰州牧药研究所实验动物中心提供，符合清洁级标准。在实验饲养和实验中，遵守实验动物管理与保护的有关准则。（2）细胞培养大鼠C6 星形胶质瘤细胞于10%胎牛血清、青霉素100U/mL、链霉素50U/mL 的DMEM培养基中、5%二氧化碳、37℃条件下培养传代生长，在细胞生长处于对数生长期大约80%时，以0.25%胰酶消化，收集消化液离心后去上清液，PBS 液洗涤两次后以DMSM液配制成细胞悬液待接种，待接种的细胞活力应>90%，接种的细胞量配制成1×106/10 μL 备用。之后分装于500 μL的离心管中；用保温箱的冰袋保存运输。（冰袋温度以-20摄氏度为宜；-80摄氏度会使细胞冻住，存活率降低）。
2 模型制作
SD 大鼠腹腔内注射10%水合氯醛 (5 g,50 mL；0.6 mL/200g 体重的水合氯醛)后，固定于脑立体定位仪上，用剪刀剪去大鼠头顶部毛发，纵向切开头皮，用止血钳和剪刀剪开多层筋膜；暴露前囟颅骨标志begama 点（在两耳中点旁边）；用10mL注射器刮点做标记；之后用脑立体定位仪定位begama点前1mm，右旁开3mm 处用颅骨钻钻一骨孔，用注射器再次刮取做标记；用电钻钻孔1 mm；快钻开时；用注射器稍微挑掉一层薄膜（注意不要穿破硬膜）。用5μL 微量注射器抽取细胞悬液5μL（吸取之前一定要弹散细胞，否则聚团导致注射细胞数降低），垂直固定于立体定位仪上（设置参数：mode: infuse only; syringe:Hamilton 5.00 μL; RATES: I:0.001 ml/min，TARGET: No Target No target set）经骨孔处进针（注意针头不能沾染碘酒，否则细胞存活率降低），针头锐性刺破硬膜，进针至硬脑膜下5mm，后退1mm，于5 min 内将细胞悬液注入右侧尾状核区 (1μL/min)，注射完毕后按stop, reset后；留针5min，缓慢退针，骨蜡封闭骨孔，1 号丝线缝合头皮切口，碘酒涂抹伤口。对照组大鼠以相同剂量的生理盐水，同样方法注入相同部位。实验进行后要观察C6 细胞的活力，再次保证模型的成功。
给药需要灭菌的注射器，防止大鼠感染；造模后使用灭菌的垫料防止感染。对于状态不好的大鼠，可以给双抗（青霉素-链霉素：是40万U/Kg，q.d.连用三日；手术时撒在伤口缝合处，之后前三天每天两次肌注青链霉素，剂量大点没关系，一支青霉素80万单位打一次）。
3 MRI 影像学观察
分别于建模后1 周、2 周、3 周对大鼠进行头颅MRI 检查，活体观察肿瘤的生长情况。MRI 常规扫描：层厚2mm，层间距0mm，FOV，矩阵，2NEX. SE 序列，T1WI： TR/TE＝800ms/26ms，T2WI： TR/TE＝3000ms/80ms，增强扫描：尾静脉注射造影剂GD-DTAP(0.2-0.3ml/Kg)后，TR/TE＝800ms/26ms。
4 肿瘤组织的获取：将大鼠分别于MRI 检查后取材，用于病理检验及免疫组化实验的组织：在各相应时间点用10％水合氯醛（350mg/kg）腹腔注射麻醉动物，打开胸腔暴露其心脏，经左心室插管至升主动脉起始处，剪开右心耳，用注射器进行灌流固定：首先用0.9％的生理盐水（normal saline，NS）（4 ℃）约200 ml 快速冲洗血液，用4％多聚甲醛（Paraformaldehyde, PFA. 0.1M PBS 配置，pH 7.4）300-400 ml 作灌注固定，直到大鼠发生四肢抽搐。术毕，迅速取出肿瘤组织。放入 4％ PFA中后固定 24 h (4 ℃)。对照组大鼠以相同方式处理后，取右脑尾状核区组织作为对照。用于Western blot 及RT-PCR 实验的组织：将各实验组的大鼠麻醉后，冰上直接断头快速取出肿瘤组织，用EP 管分装后置-80℃保存备用。取右脑尾状核周围组织作为对照。并进行p-STAT3, MMP-9免疫荧光染色。
经上述实验证实，I-1和I-8 对C6胶质瘤原位模型具有显著抑制侵袭的作用，显著改善大鼠的焦虑行为，显著延长大鼠的生存期，结果见附图5，6，7。
实施例67
裸鼠U87MG异种移植瘤模型
细胞株移植瘤模型（cell derived xenograft, CDX)，即将体外传代培养的肿瘤细胞接种至免疫缺陷小鼠，也就是我们平时所说的裸鼠成瘤。裸鼠成瘤实验，即在裸鼠皮下注入肿瘤细胞，观察肿瘤的形成、发展及抗肿瘤药物的效果。
动物选择
一般选择4-6周龄Nude裸鼠，需要提前到SPF环境中适应1周。
接种部位与接种细胞量
接种部位常为皮下，静脉或原位；细胞量一般是5*106个/200ul，但是不同的细胞系的接种量略有差别。
成瘤时间
皮下接种的细胞一般会在1-2周成瘤，一般不会超过1个月；尾静脉和腹腔接种的细胞一般也是1周左右，需要密切观察动物的体重与状态进行判断，结果见附图8。

Claims (9)

1.一种N-芳基邻氨基苯甲酰胺类衍生物，其特征在于结构通式为：
Figure 298895DEST_PATH_IMAGE001
；
其中：R1为卤素F或 Cl或Br或I、烷基、杂烷烃、氨基、硝基的一种或几种，R1在苯环上的取代位置为2位、3位、4位，取代基数量为单取代或多取代；
R2为卤素F或 Cl或Br或I、烷基、杂烷烃、氨基、硝基的一种或几种；R2在苯环上的取代位置为2位、3位、4位，取代基数量为单取代或多取代；
R3为杂环或苯并杂环；
n为1-3；
X为N或CH。
2.根据权利要求1所述的一种N-芳基邻氨基苯甲酰胺衍生物，其特征在于：所述R1 或R2 的烷基为1-4个碳原子低级烷基，杂烷烃为甲氧基或三氟甲基或N，N二甲基。
3.根据权利要求1或2所述的一种N-芳基邻氨基苯甲酰胺衍生物，其特征在于具体结构式为：
Figure 34770DEST_PATH_IMAGE002
Figure 76413DEST_PATH_IMAGE003
。
4.根据权利要求1或2所述的一种N-芳基邻氨基苯甲酰胺衍生物的制备方法，其特征在于合成路线为：
Figure 214133DEST_PATH_IMAGE004
。
5.根据权利要求4所述的一种N-芳基邻氨基苯甲酰胺衍生物的制备方法，其特征在于具体步骤如下：
在氩气条件下，将化合物IV和EDCI•HCl和HOBT溶解在二氯甲烷中，在室温下加入化合物I 或化合物II或化合物III，以及Et3N搅拌反应8-12小时，通过TLC检测反应完成后减压旋转蒸发除去反应液，然后将得到的残余物通过硅胶快速柱色谱纯化得到式一化合物或式二化合物或式三化合物，其中化合物I 或化合物II或化合物III：EDCI•HCl：HOBT：Et3N：化合物IV摩尔比为1:1.2:1.1:2.5:1，化合物I 或化合物II或化合物III在二氯甲烷的浓度为0.5 mmol/mL。
6.根据权利要求1或2所述的一种N-芳基邻氨基苯甲酰胺衍生物作为活性物质在制备抗肿瘤药物中的应用。
7.根据权利要求6所述的一种N-芳基邻氨基苯甲酰胺衍生物，其特征在于：用于制备抗胶质瘤药物。
8.根据权利要求6所述的一种N-芳基邻氨基苯甲酰胺衍生物，其特征在于：用于COX-2抑制剂药物。
9.根据权利要求6所述的一种N-芳基邻氨基苯甲酰胺衍生物，其特征在于：用于拓扑异构酶多靶点抑制剂药物。
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