CN114957224B - 一种肿瘤低氧靶向的egfr抑制剂及其应用 - Google Patents
一种肿瘤低氧靶向的egfr抑制剂及其应用 Download PDFInfo
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- CN114957224B CN114957224B CN202210540714.6A CN202210540714A CN114957224B CN 114957224 B CN114957224 B CN 114957224B CN 202210540714 A CN202210540714 A CN 202210540714A CN 114957224 B CN114957224 B CN 114957224B
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- methyl
- imidazol
- indol
- pyrimidin
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Abstract
本发明设计并合成了一种具有肿瘤低氧靶向作用的EGFR抑制剂，具有通式(I)结构。本发明提供的肿瘤低氧靶向的EGFR抑制剂对EGFRL858R/T790M突变型激酶具有良好的抑制活性，并对H1975、HCC827细胞系具有良好的增殖抑制活性和低氧选择性，具有低氧和EGFR双重靶向作用。
Description
技术领域
本发明涉及药物化学领域，具体地，本发明涉及一类新型肿瘤低氧靶向的EGFR抑制剂，以及所述化合物作为EGFR抑制剂在制备抗肿瘤药物中的应用。
背景技术
肺癌是致死率最高的恶性肿瘤，约占全球癌症相关死亡人数的18％，包括小细胞肺癌(Small cell lung cancer，SCLC)和非小细胞肺癌(Non-small cell lung cancer，NSCLC)，NSCLC约占肺癌的80％-85％。表皮生长因子受体(Epidermal growth factorreceptor，EGFR)的高表达和突变是NSCLC最常见的驱动因素，在高达50％的亚洲NSCLC患者中被检测到。
EGFR是一种具有酪氨酸激酶活性的跨膜糖蛋白，由细胞外受体结合结构域、跨膜结构域和细胞内结构域组成。它的胞外受体结合区与表皮生长因子配体结合后发生二聚化，激活胞质内的酪氨酸激酶结构域，发生磷酸化，从而激活其下游的3条主要信号通路，发挥调节细胞生长、增殖、分化、凋亡等作用。当EGFR发生异常表达，会影响下游信号通路，诱发转移性结直肠癌、头颈部鳞状细胞癌、NSCLC等多种肿瘤的发生。整个EGFR激酶结构域由外显子18-24位编码，突变主要集中在外显子18-21位，包括激活突变和耐药突变，激活突变主要包括21位外显子上的L858R突变和19位外显子缺失，耐药突变主要包括20位外显子的T790M突变和C797S突变。
当前以EGFR为靶点设计的小分子抑制剂已经有三代被广泛用于临床，逐渐成为NSCLC治疗的首选药物。第一代EGFR抑制剂包括吉非替尼、厄洛替尼等，在治疗EGFR激活突变的NSCLC患者中取得了显著效果，但是大部分患者在治疗9-14个月后产生继发性的T790M突变(EGFRT790M)。第二代EGFR抑制剂包括达克替尼、阿法替尼等，虽然对T790M耐药突变体表现出一定的抑制效果，但是对野生型EGFR(EGFRWT)选择性较差，存在剂量限制性毒性，使其临床应用受到限制。第三代EGFR抑制剂，如奥西替尼(AZD9291)、奥莫替尼等，为非可逆抑制剂，用于治疗EGFRT790M阳性的NSCLC患者，并对EGFRWT具有良好的选择性。
第三代EGFR抑制剂的非可逆作用主要是通过结构中的丙烯酰胺和激酶797位半胱氨酸(C797)的共价结合实现的，当发生C797S突变时，共价键形成能力丧失，导致了新的耐药问题。尽管以三代EGFR抑制剂为代表的的酪氨酸激酶抑制剂在癌症治疗领域取得了显著成功，但是临床经验表明仍然存在不可避免的毒副作用，如发生在胃肠道、皮肤等器官的不良反应。通过增强药物在肿瘤组织的特异性蓄积，提高靶向能力，可以减少或规避不良反应，增加这些药物的适用范围。
低氧是实体瘤微环境的特征之一，会导致肿瘤的放疗抗性，促进肿瘤细胞的转移和侵袭，与EGFR的高表达和耐药性也有一定的联系，成为癌症研究中的一个非常有吸引力的靶点。针对肿瘤低氧的特点，低氧还原活化型分子被开发用来治疗实体瘤，如硝基咪唑类分子。从还原活化机制来看，在低氧组织中，硝基咪唑在单电子还原酶作用下，经过单电子还原途径，先生成硝基阴离子自由基，之后经过羟胺中间体进一步被还原成活性自由基，与组织周围具有亲核性的蛋白质、氨基酸等成分发生共价结合，达到细胞毒性作用。而在正常的组织中，由于氧分供应正常，活性自由基不能存在，药物以低毒的原型存在，从而保证对正常组织的安全性。目前，硝基咪唑基团被广泛用于生物还原前药、诊断试剂及乏氧显像剂等的研究，在肿瘤治疗领域有巨大的应用潜力。
发明内容
针对现有技术的不足，本发明所要解决的问题是：设计并合成了一种新型的能够靶向低氧肿瘤的EGFR抑制剂，并对该类化合物进行了体外激酶和细胞水平上的活性评价。结果表明，该类化合物对EGFRL858R/T790M激酶有效好的抑制活性，低氧条件下对H1975和HCC827细胞有较好的抗增殖活性，具有低氧和EGFR双重靶向作用。
本发明的目的是提供一种新的肿瘤低氧靶向的EGFR抑制剂化合物，所述化合物具有下述通式结构：
其中，
X选自NH或O；
Y选自O，N，NH，-CH2O-，-CONH-，-NHCO-，-COO-；
Z选自C或N；
Linker选自1至6个碳原子的直链烷烃基，-(CH2)2O(CH2)2-，R1选自H，F，CH3；
R2选自H，卤素，C1-C2烷基，C1-C2烷氧基，
R3选自NO2，H，CH3；
R4选自NO2，H；
R5选自NO2，H或缺失。
本发明所述“卤素”为氟，氯，溴，碘。
本发明所述“1至6个碳原子的直链烷烃基”为-CH2-，-(CH2)2-，-(CH2)3-，-(CH2)4-，-(CH2)5-，-(CH2)6-。
本发明所述“C1-C2烷基”为甲基，乙基。
本发明所述“C1-C2烷氧基”为甲氧基，乙氧基。
进一步地，X选自NH或O；
Y选自O，N，NH，-CH2O-，-CONH-；
Z选自C或N；
Linker选自-(CH2)2-，-(CH2)3-，-(CH2)4-，-(CH2)5-，-(CH2)2O(CH2)2-，
R1选自H，F，CH3；
R2选自H，F，Cl，CH3，OCH3，
R3选自NO2，H，CH3；
R4选自NO2，H；
R5选自NO2，H或缺失。
在其中一些实施例中，Z选自C，R3选自NO2，R4选自H，R5选自H。
在其中一些实施例中，Z选自C，R3选自H，R4选自NO2，R5选自H。
在其中一些实施例中，Z选自C，R3选自CH3，R4选自H，R5选自NO2。
在其中一些实施例中，Z选自N，R3选自H，R4选自NO2，R5缺失。
更具体的，本发明具有通式(I)结构的肿瘤低氧靶向的EGFR抑制剂化合物优选为：
N-(3-氟-4-(3-(2-硝基-1H-咪唑-1-基)丙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A01
N-(3-氟-4-(4-(2-硝基-1H-咪唑-1-基)丁氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A02
N-(3-氟-4-((5-(2-硝基-1H-咪唑-1-基)戊基)氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A03
N-(3-氟-4-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A04
4-(1-甲基-1H-吲哚-3-基)-N-(3-甲基-4-(4-(2-硝基-1H-咪唑-1-基)丁氧基)苯基)嘧啶-2-胺A05
4-(1-甲基-1H-吲哚-3-基)-N-(3-甲基-4-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)嘧啶-2-胺A06
4-(1-甲基-1H-吲哚-3-基)-N-(4-(4-(2-硝基-1H-咪唑-1-基)丁氧基)苯基)嘧啶-2-胺A07
4-(1-甲基-1H-吲哚-3-基)-N-(4-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)嘧啶-2-胺A08
N-(3-氟-4-(4-(4-硝基-1H-咪唑-1-基)丁氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A09
4-(1-甲基-1H-吲哚-3-基)-N-(3-(4-(4-硝基-1H-咪唑-1-基)丁氧基)苯基)嘧啶-2-胺A10
4-(1-甲基-1H-吲哚-3-基)-N-(3-(4-(2-硝基-1H-咪唑-1-基)丁氧基)苯基)嘧啶-2-胺A11
4-(1-甲基-1H-吲哚-3-基)-N-(3-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)嘧啶-2-胺A12
4-(1-甲基-1H-吲哚-3-基)-N-(4-甲基-3-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)嘧啶-2-胺A13
N-(4-甲氧基-3-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A14
N-(4-氯-3-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A15
1-(4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)乙酮A16
4-(1-甲基-1H-吲哚-3-基)-N-(2-甲基-5-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)嘧啶-2-胺A17
N-(2-氟-5-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A18
4-(1-甲基-1H-吲哚-3-基)-N-(3-((2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)甲基)苯基)嘧啶-2-胺A19
3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基))乙基)苯甲酰胺A20
2-甲基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)-N-(4-(2-硝基-1H-咪唑-1-基)丁基)苯胺A21
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)-N-(4-(2-硝基-1H-咪唑-1-基)丁基)苯胺A22
2-甲基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)-N,N-双(4-(2-硝基-1H-咪唑-1)-基)丁基)苯胺A23
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)-N,N-双(4-(2-硝基-1H-咪唑-1-基)丁基)苯胺A24
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(2-(2-硝基-1H-咪唑-1-基)乙基)苯甲酰胺B01
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B02
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(4-(2-硝基-1H-咪唑-1-基)丁基)苯甲酰胺B03
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(5-(2-硝基-1H-咪唑-1-基)戊基)苯甲酰胺B04
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(2-(2-(2-硝基-1H-咪唑-1)-基)乙氧基)乙基)苯甲酰胺B05
(4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯基)(4-((2-硝基-1H-咪唑-1-基)甲基)哌啶-1-基)甲酮B06
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙基)-2-吗啉苯甲酰胺B07
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-甲基-5-硝基-1H-咪唑-1-基)丙基)-2-吗啉苯甲酰胺B08
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(2-(3-硝基-1H-1,2,4-)三唑-1-基)乙基)苯甲酰胺B09
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(3-硝基-1H-1,2,4-)三唑-1-基)丙基)苯甲酰胺B10
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(4-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B11
5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(4-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B12
5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B13
2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B14
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-(4-甲基哌嗪-1-基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B15
2-(二乙氨基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-)基)丙基)苯甲酰胺B16
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)-2-(哌啶-1-基)苯甲酰胺B17
2-(3-(二甲基氨基)氮杂环丁烷-1-基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2)-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B18
(S)-2-(3-(二甲基氨基)吡咯烷-1-基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B19
2-(4-(二甲基氨基)哌啶-1-基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2)-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B20
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B21
2-(环丙基氨基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-)基)丙基)苯甲酰胺B22
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-((1-(甲基磺酰基)哌啶-4-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B23
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-((2-吗啉代乙基)氨基)-N-(3-(2-硝基-1H)-咪唑-1-基)丙基)苯甲酰胺B24
本发明还提供了制备通式(I)结构及其药学可接受衍生物的方法，通过化合物的三个主要组分，本发明称为化合物的头部(V)、中心(III)和尾巴(II)的反应来制备通式(I)化合物。部分通式(I)化合物的合成路线如下：
如以上反应式所示，将中心(III)和尾巴(II)，在酸性条件下或者碱和催化剂条件下，于正丁醇或N,N-二甲基甲酰胺(DMF)等溶剂中加热反应，制得中间体(IV)，再与头部(V)结构在碳酸钾、DMF、加热条件下反应，得到目标化合物(I)。
其中：X选自NH或O；Y选自O，N，NH，-CH2O-，-CONH-；Z选自C或N；Linker选自-(CH2)2-，-(CH2)3-，-(CH2)4-，-(CH2)5-，-(CH2)2O(CH2)2-，R1选自H，F，CH3；
R2选自H，F，Cl，CH3，OCH3，
R3选自NO2，H，CH3；R4选自NO2，H；R5选自NO2，H或缺失。
本发明的另一目的是提供了一种药物组合物，所述药物组合物以本发明中具有通式(I)结构的化合物或其药学上可接受的盐或其立体异构体或其前药作为活性成分，并包括一种或多种药学上可接受的载体。
所述载体包括药学领域常规的稀释剂，赋形剂，填充剂，粘合剂，湿润剂，崩解剂，吸收促进剂，表面活性剂，吸附载体，润滑剂等。本发明药物可以制成片剂，粉剂，颗粒剂，胶囊，口服液、注射液等多种形式，上述各种剂型的药物均可以按照药学领域的常规方法制备。本发明的药物组合物可通过口服、注射、喷雾吸入等方式给药，优选口服给药和注射给药方式。
本发明的药物组合物和该组合物的各种制剂可使用常规的药用载体制备。
本发明化合物的药学上可接受的盐的实例包括但不限于无机或有机酸盐，例如氢卤酸盐、硫酸盐、磷酸盐、硝酸盐、枸橼酸盐、苹果酸盐、樟脑磺酸盐、对甲苯磺酸盐、甲磺酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐；以及与有机碱例如伯胺、氨基乙醇、葡萄糖胺等制备的有机碱盐，或钠盐、钾盐、镁盐、钙盐等无机碱盐。
本发明的另一目的是提供具有通式(I)所述结构的化合物，以及以上任意一种形式的优选化合物及其药物组合物，在制备治疗或预防与EGFR相关的癌症的药物中的应用。
其中，所述癌症选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、头颈癌、胃癌、胰腺癌、皮肤癌、结/直肠癌、宫颈癌、脑胶质瘤、膀胱癌、肾癌等。
实验结果表明，本发明所制得的化合物对EGFRL858R/T790M激酶具有较好的抑制活性，低氧条件下对HCC827和H1975细胞具有良好的增殖抑制活性，如化合物B20、B21的IC50值都在10nM以下。同时，本发明的化合物结构新颖，原料易得，操作简单，具有较好的抗肿瘤应用前景和潜在的商业价值。
具体实施方式
为了更好的理解本发明的实质，以下结合具体实施例对本发明进行进一步的描述，但是本发明的实施例用于说明本发明而非用于限制本发明的保护范围，根据本发明的实质对本发明进行简单的改进都属于本发明要求保护的范围。
实施例1：N-(3-氟-4-(3-(2-硝基-1H-咪唑-1-基)丙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A01
合成路线如下：
步骤a：2-氟-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯酚的合成
将3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(7.0mmol，1.71g)和4-氨基-2-氟苯酚(7.0mmol，0.89g)溶于15ml正丁醇中，加入1mL浓盐酸溶液，80℃加热，反应过夜。反应结束后冷却至室温，反应液浓缩，硅胶柱层析纯化，得黄色固体，产率为60％。1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),9.26(s,1H),8.58(d,J＝7.4Hz,1H),8.29(d,J＝5.1Hz,1H),8.25(s,1H),7.76(d,J＝14.0Hz,1H),7.52(d,J＝8.1Hz,1H),7.33-7.12(m,4H),6.90(t,J＝9.3Hz,1H),3.87(s,3H).ESI-MS:m/z＝335.1[M+H]+.
步骤b：N-(3-氟-4-(3-(2-硝基-1H-咪唑-1-基)丙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺的合成
将2-氟-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯酚(0.5mmol，0.17g)和1-(3-溴丙基)-2-硝基-1H-咪唑(0.6mmol，0.14g)溶于2mL的DMF中，加入碳酸钾(1.0mmol，0.14g)，80℃加热回流。反应结束后抽滤，滤液用乙酸乙酯萃取三次，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，残留物通过硅胶柱层析纯化得黄色固体，产率为69％。1HNMR(400MHz,DMSO-d6)δ9.42(s,1H),8.60(d,J＝8.0Hz,1H),8.33(d,J＝5.4Hz,1H),8.29(s,1H),7.88(dd,J＝14.3,2.4Hz,1H),7.68(s,1H),7.53(d,J＝8.1Hz,1H),7.44(d,J＝8.9Hz,1H),7.27(t,J＝7.4Hz,1H),7.24-7.15(m,3H),7.11(t,J＝9.3Hz,1H),4.59(t,J＝7.0Hz,2H),4.06(t,J＝5.9Hz,2H),3.88(s,3H),2.32-2.23(m,2H)；13C NMR(100MHz,DMSO-d6)δ162.19,159.88,156.77,151.61(d,J＝239.5Hz),144.74,140.18(d,J＝11.0Hz),137.64,135.29(d,J＝9.7Hz),132.86,127.89,127.79,125.54,122.30,122.27,120.83,116.03(d,J＝2.3Hz),114.88(d,J＝3.0Hz),112.47,110.38,107.53(d,J＝22.6Hz),107.34,66.66,46.84,33.04,29.48.ESI-MS:m/z＝488.2[M+H]+.
实施例2：N-(3-氟-4-(4-(2-硝基-1H-咪唑-1-基)丁氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A02
合成方法同实施例1，只是将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(4-溴丁基)-2-硝基-1H-咪唑。黄色固体，产率为62％。1H NMR(500MHz,DMSO-d6)δ9.41(s,1H),8.60(d,J＝8.0Hz,1H),8.33(d,J＝5.4Hz,1H),8.30(s,1H),7.87(dd,J＝14.3,2.4Hz,1H),7.73(s,1H),7.54(d,J＝8.2Hz,1H),7.45(d,J＝8.7Hz,1H),7.27(t,J＝7.2Hz,1H),7.22-7.17(m,3H),7.10(t,J＝9.4Hz,1H),4.47(t,J＝7.2Hz,2H),4.04(t,J＝6.3Hz,2H),3.88(s,3H),2.00-1.92(m,2H),1.78-1.69(m,2H)；13C NMR(125MHz,DMSO-d6)δ162.17,159.88,156.78,151.55(d,J＝239.3Hz),140.40(d,J＝11.1Hz),137.62,135.03(d,J＝9.5Hz),132.87,127.87,125.53,122.31,122.25,120.81,115.85(d,J＝2.0Hz),114.83(d,J＝2.9Hz),112.45,110.96,110.38,107.48(d,J＝22.6Hz),107.29,68.83,49.20,33.04,26.52,25.73.ESI-MS:m/z＝502.2[M+H]+.
实施例3：N-(3-氟-4-((5-(2-硝基-1H-咪唑-1-基)戊基)氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A03
合成方法同实施例1，只是将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(5-溴戊基)-2-硝基-1H-咪唑。黄色固体，产率为61％。1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.61(d,J＝7.6Hz,1H),8.33(d,J＝5.4Hz,1H),8.30(s,1H),7.87(dd,J＝14.3,2.2Hz,1H),7.71(s,1H),7.53(d,J＝8.1Hz,1H),7.44(d,J＝8.8Hz,1H),7.27(t,J＝7.4Hz,1H),7.23-7.15(m,3H),7.10(t,J＝9.4Hz,1H),4.41(t,J＝7.2Hz,2H),4.01(t,J＝6.3Hz,2H),3.88(s,3H),1.90-1.81(m,2H),1.81-1.69(m,2H),1.50-1.39(m,2H)；13C NMR(100MHz,DMSO-d6)δ162.16,159.88,156.75,151.46(d,J＝239.0Hz),144.53,140.53(d,J＝10.9Hz),137.61,134.85(d,J＝9.8Hz),132.84,127.85,127.82,125.53,122.31,122.23,120.79,115.61(d,J＝2.3Hz),114.83(d,J＝2.9Hz),112.44,110.37,107.49(d,J＝23.4Hz),107.25,68.94,49.31,33.03,29.47,28.22,22.37.ESI-MS:m/z＝516.2[M+H]+.
实施例4：N-(3-氟-4-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A04
合成方法同实施例1，只是将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑。黄色固体，产率为67％。1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.60(d,J＝7.8Hz,1H),8.33(d,J＝5.4Hz,1H),8.29(s,1H),7.87(dd,J＝14.3,2.4Hz,1H),7.63(d,J＝0.7Hz,1H),7.53(d,J＝8.2Hz,1H),7.44(d,J＝8.9Hz,1H),7.30-7.24(m,1H),7.23-7.17(m,2H),7.15(d,J＝0.8Hz,1H),7.08(t,J＝9.4Hz,1H),4.61(t,J＝5.1Hz,2H),4.09(t,J＝4.5Hz,2H),3.91-3.83(m,5H),3.75(t,J＝4.5Hz,2H)；13C NMR(100MHz,DMSO-d6)162.18,159.90,156.78,151.51(d,J＝239.3Hz),144.81,140.35(d,J＝11.2Hz),137.64,135.13(d,J＝9.7Hz),132.85,128.09,127.49,125.55,122.30,122.26,120.82,115.81(d,J＝2.5Hz),114.84(d,J＝2.4Hz),112.48,110.38,107.53(d,J＝22.7Hz),107.33,68.86,68.85,68.83,48.94,33.04.ESI-MS:m/z＝518.2[M+H]+.
实施例5：4-(1-甲基-1H-吲哚-3-基)-N-(3-甲基-4-(4-(2-硝基-1H-咪唑-1-基)丁氧基)苯基)嘧啶-2-胺A05
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为2-甲基-4-氨基苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(4-溴丁基)-2-硝基-1H-咪唑。黄色固体，产率为71％。1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.59(d,J＝7.8Hz,1H),8.28(s,2H),7.74(s,1H),7.63(s,1H),7.52(d,J＝8.2Hz,1H),7.46(d,J＝7.7Hz,1H),7.25(t,J＝7.6Hz,1H),7.22-7.06(m,3H),6.87(d,J＝8.6Hz,1H),4.48(t,J＝7.0Hz,2H),3.98(t,J＝5.8Hz,2H),3.87(s,3H),2.17(s,3H),2.05-1.93(m,2H),181-1.70(m,2H)；13C NMR(100MHz,DMSO-d6)δ162.04,160.35,156.89,151.56,144.62,137.61,133.64,132.71,127.90,125.60,125.57,122.55,122.48,122.20,120.74,118.20,112.65,111.64,110.31,106.55,67.26,49.32,33.03,26.72,25.93,16.21.ESI-MS:m/z＝498.2[M+H]+.
实施例6：4-(1-甲基-1H-吲哚-3-基)-N-(3-甲基-4-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)嘧啶-2-胺A06
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为2-甲基-4-氨基苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑。黄色固体，产率为53％。1H NMR(500MHz,DMSO-d6)δ9.13(s,1H),8.59(d,J＝7.6Hz,1H),8.28(t,J＝2.5Hz,2H),7.64(s,2H),7.52(d,J＝8.2Hz,1H),7.46(d,J＝7.1Hz,1H),7.26(t,J＝7.5Hz,1H),7.17(d,J＝7.7Hz,1H),7.16(s,1H),7.12(d,J＝5.3Hz,1H),6.86(d,J＝8.8Hz,1H),4.62(t,J＝5.0Hz,2H),4.03(t,J＝4.3Hz,2H),3.91-3.84(m,5H),3.75(t,J＝4.4Hz,2H),2.15(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.05,160.34,156.90,151.47,137.62,133.85,132.73,128.12,127.54,125.76,125.60,122.52,122.49,122.22,120.76,118.18,114.82,112.65,111.95,110.34,106.60,69.08,68.95,67.80,49.04,33.05,16.21.ESI-MS:m/z＝514.2[M+H]+.
实施例7：4-(1-甲基-1H-吲哚-3-基)-N-(4-(4-(2-硝基-1H-咪唑-1-基)丁氧基)苯基)嘧啶-2-胺A07
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合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为4-氨基苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(4-溴丁基)-2-硝基-1H-咪唑。黄色固体，产率为74％。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.59(d,J＝7.3Hz,1H),8.28(d,J＝5.2Hz,2H),7.74(s,1H),7.69(d,J＝8.6Hz,2H),7.52(d,J＝8.1Hz,1H),7.26(t,J＝7.5Hz,1H),7.22-7.15(m,2H),7.13(d,J＝5.2Hz,1H),6.90(d,J＝8.6Hz,2H),4.47(t,J＝7.0Hz,2H),3.97(t,J＝5.9Hz,2H),3.87(s,3H),2.01-1.90(m,2H),1.79-1.66(m,2H)；13CNMR(100MHz,DMSO-d6)δ162.09,160.28,156.85,153.37,144.60,137.61,134.09,132.70,127.90,125.59,122.46,122.20,120.99,120.77,114.36,112.60,110.34,106.71,67.13,49.28,33.04,26.67,25.77.ESI-MS:m/z＝484.2[M+H]+.
实施例8：4-(1-甲基-1H-吲哚-3-基)-N-(4-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)嘧啶-2-胺A08
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为4-氨基苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑。黄色固体，产率为66％。1H NMR(500MHz,DMSO-d6)δ9.21(s,1H),8.58(d,J＝6.8Hz,1H),8.28(d,J＝5.0Hz,2H),7.69(d,J＝8.7Hz,2H),7.65(s,1H),7.52(d,J＝8.1Hz,1H),7.26(t,J＝7.4Hz,1H),7.19(d,J＝7.5Hz,2H),7.17(s,1H),7.14(d,J＝5.2Hz,1H),6.88(d,J＝8.7Hz,2H),4.61(t,J＝4.8Hz,2H),4.02(t,J＝4.3Hz,2H),3.88(s,3H),3.85(t,J＝5.0Hz,2H),3.73(t,J＝4.5Hz,2H)；13C NMR(125MHz,DMSO-d6)δ162.11,160.28,156.85,153.21,144.88,137.62,134.19,132.73,128.16,127.56,125.60,122.47,122.21,120.98,120.78,116.48,114.36,112.60,110.35,106.74,68.95,68.83,67.21,48.96,33.05.ESI-MS:m/z＝500.2[M+H]+.
实施例9：N-(3-氟-4-(4-(4-硝基-1H-咪唑-1-基)丁氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A09
合成方法同实施例1，只是将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(4-溴丁基)-4-硝基-1H-咪唑。黄色固体，产率为78％。1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.61(d,J＝7.7Hz,1H),8.49(s,1H),8.33(d,J＝5.3Hz,1H),8.30(s,1H),7.92(s,1H),7.88(d,J＝14.3Hz,1H),7.53(d,J＝8.0Hz,1H),7.45(d,J＝8.6Hz,1H),7.27(t,J＝7.4Hz,1H),7.23-7.16(m,2H),7.11(t,J＝9.3Hz,1H),4.16(t,J＝6.9Hz,2H),4.04(t,J＝5.9Hz,2H),3.88(s,3H),2.01-1.90(m,2H),1.74-1.63(m,2H)；13C NMR(100MHz,DMSO-d6)δ162.20,159.90,156.79,151.54(d,J＝239.2Hz),147.04,140.43(d,J＝11.0Hz),137.65,137.43,135.04(d,J＝10.0Hz),132.89,125.56,122.35,122.28,121.58,120.84,115.79(d,J＝1.2Hz),114.84(d,J＝2.7Hz),112.47,110.41,107.51(d,J＝23.3Hz),107.31,68.71,47.12,33.07,26.88,25.64.ESI-MS:m/z＝502.2[M+H]+.
实施例10：4-(1-甲基-1H-吲哚-3-基)-N-(3-(4-(4-硝基-1H-咪唑-1-基)丁氧基)苯基)嘧啶-2-胺A10
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为3-氨基苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(4-溴丁基)-4-硝基-1H-咪唑。黄色固体，产率为59％。1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.62(d,J＝7.9Hz,1H),8.46(s,1H),8.34(d,J＝5.3Hz,1H),8.30(s,1H),7.90(s,1H),7.60(s,1H),7.52(d,J＝8.1Hz,1H),7.34(d,J＝7.7Hz,1H),7.25(t,J＝7.5Hz,1H),7.22-7.14(m,3H),6.53(d,J＝6.5Hz,1H),4.13(t,J＝7.0Hz,2H),3.97(t,J＝6.2Hz,2H),3.87(s,3H),1.98-1.87(m,2H),1.73-1.61(m,2H)；13C NMR(100MHz,DMSO-d6)δ162.14,160.04,158.87,156.83,147.03,142.11,137.64,137.41,132.86,129.11,125.55,122.45,122.23,121.56,120.81,112.54,111.58,110.36,107.39,106.85,105.47,66.61,47.15,33.05,26.95,25.67.ESI-MS:m/z＝484.2[M+H]+.
实施例11：4-(1-甲基-1H-吲哚-3-基)-N-(3-(4-(2-硝基-1H-咪唑-1-基)丁氧基)苯基)嘧啶-2-胺A11
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为3-氨基苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(4-溴丁基)-2-硝基-1H-咪唑。黄色固体，产率为83％。1H NMR(400MHz,DMSO-d6)δ9.38(s,1H),8.62(d,J＝7.9Hz,1H),8.34(d,J＝5.3Hz,1H),8.29(s,1H),7.71(s,1H),7.60(s,1H),7.52(d,J＝8.1Hz,1H),7.36(d,J＝8.1Hz,1H),7.24(t,J＝7.2Hz,1H),7.22-7.14(m,4H),6.53(dd,J＝8.1,1.8Hz,1H),4.44(t,J＝7.2Hz,2H),3.97(t,J＝6.2Hz,2H),3.87(s,3H),1.97-1.87(m,2H),1.79-1.67(m,2H)；13C NMR(100MHz,DMSO-d6)δ162.10,160.02,158.86,156.80,144.56,142.09,137.61,132.79,129.06,127.85,127.80,125.52,122.40,122.19,120.76,112.53,111.53,110.30,107.36,106.91,105.41,66.70,49.20,33.00,26.63,25.74.ESI-MS:m/z＝484.2[M+H]+.
实施例12：4-(1-甲基-1H-吲哚-3-基)-N-(3-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)嘧啶-2-胺A12
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为3-氨基苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑。黄色固体，产率为64％。1H NMR(500MHz,DMSO-d6)δ9.39(s,1H),8.63(d,J＝7.6Hz,1H),8.34(d,J＝5.1Hz,1H),8.30(s,1H),7.62(s,1H),7.56(s,1H),7.53(d,J＝8.1Hz,1H),7.38(d,J＝7.7Hz,1H),7.27(t,J＝7.4Hz,1H),7.23-7.16(m,3H),7.14(s,1H),6.52(d,J＝7.4Hz,1H),4.59(t,J＝4.2Hz,2H),4.03(s,2H),3.88(s,3H),3.84(t,J＝4.5Hz,2H),3.74(s,2H)；13C NMR(125MHz,DMSO-d6)δ162.18,160.04,158.73,156.81,142.13,137.65,132.89,129.16,128.15,127.54,125.56,122.47,122.28,120.86,112.52,111.68,110.39,107.42,106.86,105.42,68.89,68.79,66.75,48.94,33.07.ESI-MS:m/z＝500.2[M+H]+.
实施例13：4-(1-甲基-1H-吲哚-3-基)-N-(4-甲基-3-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)嘧啶-2-胺A13
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为5-氨基-2-甲基苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑。黄色固体，产率为71％。1H NMR(500MHz,DMSO-d6)δ9.27(s,1H),8.60(d,J＝7.8Hz,1H),8.32(d,J＝5.3Hz,1H),8.28(s,1H),7.61(s,1H),7.53(d,J＝8.2Hz,1H),7.46(d,J＝1.3Hz,1H),7.34(d,J＝8.0Hz,1H),7.26(t,J＝7.3Hz,1H),7.20-7.15(m,2H),7.14(s,1H),7.04(d,J＝8.2Hz,1H),4.60(t,J＝5.1Hz,2H),4.02(t,J＝4.5Hz,2H),3.90-3.83(m,5H),3.75(t,J＝4.4Hz,2H),2.09(s,3H)；13C NMR(125MHz,DMSO-d6)δ162.08,160.12,156.88,156.37,139.92,137.63,132.75,130.00,128.09,127.52,125.56,122.40,122.25,120.79,118.39,112.58,111.15,110.39,107.10,103.27,68.95,68.90,67.18,49.01,33.04,15.46.ESI-MS:m/z＝514.2[M+H]+.
实施例14：N-(4-甲氧基-3-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A14
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为2-甲氧基-5-氨基苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑。黄色固体，产率为86％。1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.58(d,J＝7.8Hz,1H),8.30(d,J＝5.4Hz,1H),8.28(s,1H),7.64(d,J＝0.9Hz,1H),7.52(d,J＝8.2Hz,1H),7.47(d,J＝2.4Hz,1H),7.34(dd,J＝8.7,2.3Hz,1H),7.29-7.22(m,1H),7.20-7.12(m,3H),6.92(d,J＝8.8Hz,1H),4.59(t,J＝5.1Hz,2H),4.04-3.99(m,2H),3.87(s,3H),3.84(t,J＝5.1Hz,2H),3.78-3.72(m,5H)；13C NMR(125MHz,DMSO-d6)δ162.05,160.20,156.85,147.67,143.88,137.59,134.56,132.69,128.21,127.49,125.56,122.41,122.20,120.74,112.65,112.58,111.75,110.34,106.82,106.30,68.76,67.66,56.00,48.94,33.01.ESI-MS:m/z＝530.2[M+H]+.
实施例15：N-(4-氯-3-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A15
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为4-氯-3-羟基苯胺，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑。黄色固体，产率为92％。1H NMR(500MHz,DMSO-d6)δ9.52(s,1H),8.59(d,J＝7.8Hz,1H),8.36(d,J＝5.4Hz,1H),8.31(s,1H),7.71(d,J＝2.3Hz,1H),7.62(d,J＝0.9Hz,1H),7.54(d,J＝8.2Hz,1H),7.49(dd,J＝8.7,2.2Hz,1H),7.32(d,J＝8.7Hz,1H),7.29-7.25(m,1H),7.23(d,J＝5.4Hz,1H),7.22-7.18(m,1H),7.13(d,J＝1.0Hz,1H),4.60(t,J＝5.1Hz,2H),4.10(t,J＝4.6Hz,2H),3.90-3.86(m,5H),3.78(t,J＝4.5Hz,2H)；13C NMR(125MHz,DMSO-d6)δ162.20,159.81,156.87,153.59,141.18,137.66,132.96,129.45,128.14,127.52,125.52,122.32,122.26,120.90,112.84,112.43,111.94,110.47,107.73,104.56,68.99,68.56,68.07,49.00,33.07.ESI-MS:m/z＝534.2[M+H]+.
实施例16：1-(4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)乙酮A16
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为4'-氨基-2'-羟基苯乙酮，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑。黄色固体，产率为62％。1H NMR(500MHz,DMSO-d6)δ9.81(s,1H),8.61(d,J＝7.9Hz,1H),8.42(d,J＝5.4Hz,1H),8.34(s,1H),7.73(d,J＝1.7Hz,1H),7.68(d,J＝8.7Hz,1H),7.60(d,J＝0.9Hz,1H),7.57-7.50(m,2H),7.33-7.26(m,2H),7.25-7.18(m,1H),7.13(d,J＝0.9Hz,1H),4.60(t,J＝5.1Hz,2H),4.15(t,J＝4.4Hz,2H),3.89(s,3H),3.84(t,J＝5.1Hz,2H),3.80(t,J＝4.4Hz,2H),2.43(s,3H)；13C NMR(125MHz,DMSO-d6)δ196.07,162.28,159.59,159.42,156.92,146.80,144.84,137.70,133.12,130.84,128.08,127.53,125.49,122.38,122,23,120.98,119.86,112.33,110.53,110.50,108.44,101.97,68.82,68.73,67.32,49.03,33.10,31.83.ESI-MS:m/z＝542.2[M+H]+.
实施例17：4-(1-甲基-1H-吲哚-3-基)-N-(2-甲基-5-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)嘧啶-2-胺A17
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为3-氨基-4-甲基苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑。黄色固体，产率为75％。1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.34(d,J＝8.0Hz,1H),8.25(d,J＝6.6Hz,2H),7.57(s,1H),7.48(d,J＝8.2Hz,1H),7.24(d,J＝2.4Hz,1H),7.20(t,J＝7.6Hz,1H),7.14(d,J＝1.6Hz,1H),7.11(d,J＝7.8Hz,2H),7.04(t,J＝7.5Hz,1H),6.66(dd,J＝8.3,2.5Hz,1H),4.55(t,J＝5.1Hz,2H),4.00(t,J＝5.2Hz,2H),3.85(s,3H),3.79(t,J＝5.1Hz,2H),3.72-3.65(t,J＝4.4Hz,2H),2.19(s,3H)；13C NMR(100MHz,DMSO-d6)δ162.18,160.92,157.00,156.64,139.17,137.52,132.60,130.58,128.07,127.47,125.62,123.80,122.64,122.10,120.61,112.49,111.10,110.16,109.89,106.55,68.87,68.72,66.89,48.89,32.99,17.39.ESI-MS:m/z＝514.2[M+H]+.
实施例18：N-(2-氟-5-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A18
合成方法同实施例1，将步骤a中的原料4-氨基-2-氟苯酚替换为3-氨基-4-氟苯酚，将步骤b中的原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑。黄色固体，产率为79％。1H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.47(d,J＝8.0Hz,1H),8.31(d,J＝4.4Hz,2H),7.60(d,J＝0.8Hz,1H),7.55-7.48(m,2H),7.26-7.08(m,5H),6.66(dt,J＝8.9,3.3Hz,1H),4.57(t,J＝5.1Hz,2H),4.02(t,J＝4.5Hz,2H),3.87(s,3H),3.82(t,J＝5.2Hz,2H),3.71(t,J＝4.4Hz,2H)；13C NMR(100MHz,DMSO-d6)δ162.33,160.25,156.89,154.39(d,J＝1.5Hz),149.30(d,J＝235.9Hz),137.56,132.86,128.56(d,J＝13.0Hz),128.08,127.48,125.58,122.57,122.19,120.74,115.44(d,J＝21.1Hz),112.34,110.93,110.24,109.70,108.85(d,J＝6.7Hz),107.48,68.81,68.74,67.43,48.89,33.02.ESI-MS:m/z＝518.2[M+H]+.
实施例19：4-(1-甲基-1H-吲哚-3-基)-N-(3-((2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)甲基)苯基)嘧啶-2-胺A19
合成路线如下：
步骤a：(3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)甲醇的合成
合成方法同实施例1中的步骤a，将原料4-氨基-2-氟苯酚替换为3-氨基苯甲醇。黄色固体，产率为61％。1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.62(d,J＝7.9Hz,1H),8.34(d,J＝5.7Hz,2H),7.91(s,1H),7.65(d,J＝8.2Hz,1H),7.53(d,J＝8.1Hz,1H),7.31-7.17(m,4H),6.94(d,J＝7.5Hz,1H),4.52(d,J＝5.4Hz,2H),3.88(s,3H).ESI-MS:m/z＝331.2[M+H]+.
步骤b：4-(1-甲基-1H-吲哚-3-基)-N-(3-((2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)甲基)苯基)嘧啶-2-胺的合成
将(3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯基)甲醇(0.3mmol，0.10g)置于两口瓶中，氮气保护，加入2mL的DMF，冰浴搅拌，加入钠氢(0.9mmol，0.02g)，继续搅拌1h；将1-(2-(2-溴乙氧基)乙基)-2-硝基-1H-咪唑(0.6mmol，0.16g)溶于1mL的DMF中，滴入上述反应体系，室温反应2h。反应液加水淬灭，乙酸乙酯萃取，浓缩，柱层析纯化得黄色固体，产率为34％。1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.20(d,J＝5.3Hz,1H),7.86(d,J＝7.7Hz,1H),7.47(d,J＝0.8Hz,1H),7.45(d,J＝8.4Hz,1H),7.38(t,J＝7.7Hz,1H),7.32-7.23(m,2H),7.20-7.13(m,2H),7.11-.02(m,2H),6.91(t,J＝7.5Hz,1H),4.58-4.49(m,4H),4.13(t,J＝6.0Hz,2H),3.83(s,3H),3.75(t,J＝5.1Hz,2H),3.70(t,J＝6.1Hz,2H)；13CNMR(100MHz,DMSO-d6)δ161.78,161.49,156.60,144.58,143.54,137.47,132.60,128.65,128.12,127.42,126.30,125.96,125.62,123.55,122.35,122.03,120.52,112.54,110.09,105.75,68.56,67.82,62.67,49.24,49.10,32.98.ESI-MS:m/z＝514.2[M+H]+.
实施例20：3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基))乙基)苯甲酰胺A20
合成路线如下：
步骤a：3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯甲酸甲酯的合成
合成方法同实施例1中的步骤a，将原料4-氨基-2-氟苯酚替换为3-氨基苯甲酸甲酯。白色固体，产率为65％。1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.64-8.56(m,2H),8.38(d,J＝5.4Hz,1H),8.35(s,1H),8.09(d,J＝8.1Hz,1H),7.55(dd,J＝9.8,8.5Hz,2H),7.46(t,J＝7.9Hz,1H),7.27(dd,J＝10.9,6.3Hz,2H),7.18(t,J＝7.4Hz,1H),3.89(s,3H),3.84(s,3H).ESI-MS:m/z＝359.2[M+H]+.
步骤b：3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯甲酸的合成
将3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯甲酸甲酯(1.5mmol，0.54g)溶于甲醇/水溶液中，加入5M的氢氧化钠溶液3mL，80℃回流，反应4h。反应结束后浓缩反应液，加2M的稀盐酸溶液调节PH至3-4，有固体析出，过滤出固体为粗产品，不经纯化直接进行下一步。
步骤c：3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基))乙基)苯甲酰胺的合成
将3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯甲酸(0.5mmol，0.17g)溶解在DMF中，加入HATU(1.0mmol，0.38g)和DIPEA(1.0mmol，0.13g)，搅拌20分钟；2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙胺三氟乙酸盐(0.75mmol，0.24g)溶于DMF中，加入DIPEA(1.5mmol，0.20g)搅拌后加入上述反应体系，室温搅拌至反应结束，水洗，乙酸乙酯萃取，浓缩，柱层析纯化得黄色固体，产率为58％。1H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.58(d,J＝8.0Hz,1H),8.39-8.31(m,4H),7.95-7.90(m,1H),7.60(d,J＝0.9Hz,1H),7.53(d,J＝8.2Hz,1H),7.39-7.34(m,2H),7.29-7.21(m,2H),7.17(t,J＝7.5Hz,1H),7.09(d,J＝0.9Hz,1H),4.56(t,J＝5.1Hz,2H),3.89(s,3H),3.77(t,J＝5.1Hz,2H),3.51(t,J＝6.0Hz,2H),3.40-3.36(m,2H)；13C NMR(100MHz,DMSO-d6)δ166.84,162.09,159.99,156.97,141.00,137.64,135.09,133.09,128.22,128.16,127.47,125.54,122.38,122.21,121.66,120.88,119.54,118.58,112.45,110.36,107.44,68.74,68.41,48.96,33.07.ESI-MS:m/z＝527.2[M+H]+.
实施例21：2-甲基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)-N-(4-(2-硝基-1H-咪唑-1-基)丁基)苯胺A21
合成路线如下：
步骤a：2-甲基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)苯胺的合成
依次将3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(8.0mmol，1.95g)、2-甲基-4-氨基苯酚(8.0mmol，0.99g)、碳酸铯(12.0mmol，3.91g)、Xantphos(1.3mmol，0.75g)、Pd2(dba)3(0.4mmol，0.37g)加入100mL两口瓶中，氮气保护条件下，加入40mL的1,4-二氧六环，80℃加热回流，反应过夜。反应结束后，冷却至室温，硅藻土过滤，滤液用乙酸乙酯萃取三次，合并有机相，干燥，浓缩，柱层析纯化得黄色固体，产率为30％。1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝5.3Hz,1H),8.34(s,1H),7.92(d,J＝8.0Hz,1H),7.49-7.43(m,2H),7.20(t,J＝7.6Hz,1H),7.02(t,J＝7.5Hz,1H),6.81(d,J＝8.4Hz,1H),6.55(d,J＝2.4Hz,1H),6.50(dd,J＝8.4,2.6Hz,1H),4.96(s,2H),3.84(s,3H),1.96(s,3H).ESI-MS:m/z＝331.2[M+H]+.
步骤b：2-甲基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)-N-(4-(2-硝基-1H-咪唑-1-基)丁基)苯胺的合成
合成方法同实施例1中的步骤b，将原料2-氟-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯酚替换为本实施例中步骤a制得的2-甲基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)苯胺，将原料1-(3-溴丙基)-2-硝基-1H-咪唑替换为1-(4-溴丁基)-2-硝基-1H-咪唑。黄色固体，产率为65％。1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝5.3Hz,1H),8.35(s,1H),7.89(d,J＝8.0Hz,1H),7.72(s,1H),7.46(t,J＝7.0Hz,2H),7.23-7.14(m,2H),6.95(t,J＝7.4Hz,1H),6.87(d,J＝8.5Hz,1H),6.53(s,1H),6.48(dd,J＝8.6,2.2Hz,1H),5.50(t,J＝5.2Hz,1H),4.46(t,J＝7.1Hz,2H),3.84(s,3H),3.09(q,J＝6.1Hz,2H),1.99(s,3H),1.96-1.86(m,2H),1.65-1.53(m,2H)；13C NMR(100MHz,DMSO-d6)δ165.53,163.99,158.49,146.56,144.62,142.05,137.55,133.35,130.35,127.88,125.65,122.60,122.53,122.31,120.92,113.82,111.76,110.30,110.26,109.90,49.37,42.85,33.10,27.65,25.71,16.45.ESI-MS:m/z＝498.2[M+H]+.
实施例22：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)-N-(4-(2-硝基-1H-咪唑-1-基)丁基)苯胺A22
合成方法同实施例21，将步骤a中的原料2-甲基-4-氨基苯酚替换为4-氨基苯酚。黄色固体，产率为59％。1H NMR(400MHz,DMSO-d6)δ8.42(d,J＝5.3Hz,1H),8.38(s,1H),8.00(d,J＝8.0Hz,1H),7.74(s,1H),7.49(t,J＝6.1Hz,2H),7.25-7.17(m,2H),7.03-6.94(m,3H),6.66(d,J＝8.5Hz,2H),5.63(t,J＝5.0Hz,1H),4.48(t,J＝7.0Hz,2H),3.87(s,3H),3.16-3.05(m,2H),1.99-1.88(m,2H),1.68-1.57(m,2H)；13C NMR(100MHz,DMSO-d6)δ165.94,163.94,158.37,146.45,144.61,143.26,137.57,133.41,127.89,127.89,125.60,122.60,122.53,122.34,120.93,112.34,111.76,110.30,110.08,49.37,42.85,33.12,27.65,25.68.ESI-MS:m/z＝484.2[M+H]+.
实施例23：2-甲基-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)-N,N-双(4-(2-硝基-1H-咪唑-1)-基)丁基)苯胺A23
合成方法同实施例21。黄色固体，产率为15％。1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝5.4Hz,1H),8.37(s,1H),7.84(d,J＝8.0Hz,1H),7.68(s,2H),7.50-7.44(m,2H),7.22-7.14(m,3H),6.93(d,J＝8.7Hz,1H),6.89(t,J＝7.4Hz,1H),6.62-6.53(m,2H),4.42(t,J＝7.1Hz,4H),3.85(s,3H),3.31-3.28(m,4H),2.03(s,3H),1.90-1.80(m,4H),1.62-1.49(m,4H)；13C NMR(100MHz,DMSO)δ165.47,164.02,158.48,145.30,144.56,141.98,137.57,133.42,130.55,127.85,125.62,122.70,122.52,122.32,120.81,113.90,111.73,110.35,110.26,109.94,49.97,49.36,33.11,27.34,23.76,16.68.ESI-MS:m/z＝665.3[M+H]+.
实施例24：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氧基)-N,N-双(4-(2-硝基-1H-咪唑-1-基)丁基)苯胺A24
合成方法同实施例21，将步骤a中的原料2-甲基-4-氨基苯酚替换为4-氨基苯酚。黄色固体，产率为20％。1H NMR(400MHz,DMSO-d6)δ8.40(d,J＝5.4Hz,1H),8.37(s,1H),7.94(d,J＝8.0Hz,1H),7.68(s,2H),7.53-7.43(m,2H),7.25-7.13(m,3H),7.03(d,J＝8.9Hz,2H),6.92(t,J＝7.6Hz,1H),6.72(d,J＝9.0Hz,2H),4.42(t,J＝7.1Hz,4H),3.85(s,3H),3.33-3.26(m,4H),1.91-1.77(m,4H),1.63-1.48(m,4H)；13C NMR(100MHz,DMSO-d6)δ165.89,163.96,158.35,145.14,144.55,143.10,137.58,133.45,127.85,125.57,122.71,122.53,122.34,120.82,112.35,111.72,110.30,110.11,50.01,49.37,33.11,27.33,23.74.ESI-MS:m/z＝651.3[M+H]+.
实施例25：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(2-(2-硝基-1H-咪唑-1-基)乙基)苯甲酰胺B01
合成路线如下：
步骤a：2-氟-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯甲酸甲酯的合成
取250mL两口烧瓶，依次加入3-(2-氯嘧啶-4-基)-1-甲基-1H-吲哚(21.0mmol，5.12g)、4-氨基-2-氟苯甲酸甲酯(20.0mmol，3.38g)、碳酸铯(40.0mmol，13.03g)、Xantphos(6.0mmol，3.11g)、Pd2(dba)3(2.0mmol，1.83g)，氮气保护条件下，加入80mL的1,4-二氧六环，120℃加热回流24h。反应结束后，冷却至室温，硅藻土过滤，滤液用乙酸乙酯萃取，合并有机相，干燥，浓缩，柱层析纯化。白色固体，产率为42％。1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.62(d,J＝7.8Hz,1H),8.44(d,J＝5.4Hz,1H),8.35(s,1H),8.07(d,J＝14.8Hz,1H),7.85(t,J＝8.7Hz,1H),7.66(d,J＝8.8Hz,1H),7.55(d,J＝8.0Hz,1H),7.34(d,J＝5.4Hz,1H),7.32-7.20(m,2H),3.89(s,3H),3.82(s,3H).ESI-MS:m/z＝377.1[M+H]+.
步骤b：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯甲酸甲酯的合成
2-氟-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯甲酸甲酯(1.5mmol，0.57g)溶于8mL的DMF中，加入碳酸钾(6.0mmol，0.83g)和吗啉(6.0mmol，0.60g)，120℃回流48h，反应结束后用乙酸乙酯萃取三次，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，浓缩，硅胶柱层析纯化。黄色固体，产率为41％。1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.60(d,J＝7.8Hz,1H),8.40(d,J＝5.4Hz,1H),8.33(s,1H),7.73(d,J＝8.6Hz,1H),7.66-7.58(m,2H),7.55(d,J＝8.1Hz,1H),7.32-7.19(m,3H),3.89(s,3H),3.77(s,3H),3.72(t,J＝4.2Hz,4H),2.97(t,J＝4.2Hz,4H).ESI-MS:m/z＝444.2[M+H]+.
步骤c：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯甲酸的合成
合成方法同实施例20中的步骤b，将原料3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯甲酸甲酯替换为4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯甲酸甲酯，粗产物不经纯化直接进行下一步。
步骤d：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(2-(2-硝基-1H-咪唑-1-基)乙基)苯甲酰胺的合成
合成方法同实施例20中的步骤c，将原料3-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)苯甲酸替换为4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯甲酸，将原料2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙胺三氟乙酸盐替换为2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐。黄色固体，产率为45％。1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.46(t,J＝5.9Hz,1H),8.59(d,J＝7.8Hz,1H),8.40(d,J＝5.4Hz,1H),8.32(s,1H),7.78(s,1H),7.73(s,2H),7.54(d,J＝6.4Hz,2H),7.32-7.20(m,3H),7.14(s,1H),4.61(t,J＝5.6Hz,2H),3.89(s,3H),3.79(q,J＝5.7Hz,2H),3.69-3.60(t,J＝4.2Hz,4H),2.87-2.80(t,J＝4.2Hz,4H)；13C NMR(100MHz,DMSO-d6)δ166.60,162.23,159.74,156.98,151.64,144.84,144.45,137.70,133.01,131.16,128.37,127.75,125.51,122.38,122.24,121.01,119.96,113.65,112.43,110.51,109.94,108.11,66.29,53.04,49.40,38.68,33.09.ESI-MS:m/z＝568.2[M+H]+.
实施例26：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B02
合成方法同实施例25，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为53％。1H NMR(400MHz,CDCl3)δ10.07(t,J＝5.9Hz,1H),8.40(d,J＝5.3Hz,1H),8.35(d,J＝7.8Hz,1H),8.17(d,J＝8.6Hz,1H),7.94(d,J＝1.9Hz,1H),7.87(s,1H),7.52(s,1H),7.45(dd,J＝8.6,2.0Hz,1H),7.42-7.37(m,2H),7.36-7.27(m,2H),7.16(d,J＝5.4Hz,1H),7.14(s,1H),4.52(t,J＝6.9Hz,2H),3.89(s,3H),3.84(t,J＝4.3Hz,4H),3.57(q,J＝6.3Hz,2H),3.04(t,J＝4.5Hz,4H),2.22-2.14(m,2H)；13C NMR(100MHz,CDCl3)δ167.17,162.67,159.72,157.41,152.13,144.27,138.15,132.69,131.60,128.64,126.81,125.97,122.98,121.72,121.66,120.40,115.25,113.98,110.69,110.15,109.28,67.66,53.78,48.25,36.18,33.53,31.84.ESI-MS:m/z＝582.3[M+H]+.
实施例27：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(4-(2-硝基-1H-咪唑-1-基)丁基)苯甲酰胺B03
合成方法同实施例25，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为4-(2-硝基-1H-咪唑-1-基)丁-1-胺三氟乙酸盐。黄色固体，产率为40％。1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.27(t,J＝5.7Hz,1H),8.60(d,J＝7.8Hz,1H),8.40(d,J＝5.4Hz,1H),8.34(s,1H),7.77(s,1H),7.74(s,2H),7.73(s,1H),7.55(d,J＝8.1Hz,1H),7.32-7.18(m,4H),4.44(t,J＝7.1Hz,2H),3.90(s,3H),3.74(t,J＝4.0Hz,4H),3.41-3.37(m,2H),2.91(t,J＝4.0Hz,4H),1.91-1.79(m,2H),1.61-1.50(m,2H)；13C NMR(100MHz,DMSO-d6)δ166.04,162.20,159.74,156.95,151.41,144.11,137.67,133.01,131.05,127.95,127.89,125.50,122.33,122.27,120.97,120.69,113.44,112.41,110.49,109.67,108.00,66.37,53.00,45.69,38.20,33.08,27.57,26.43.ESI-MS:m/z＝596.3[M+H]+.
实施例28：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(5-(2-硝基-1H-咪唑-1-基)戊基)苯甲酰胺B04
合成方法同实施例25，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为5-(2-硝基-1H-咪唑-1-基)戊-1-胺三氟乙酸盐。黄色固体，产率为27％。1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.28(t,J＝5.6Hz,1H),8.61(d,J＝7.7Hz,1H),8.40(d,J＝5.4Hz,1H),8.34(s,1H),7.78(s,3H),7.76(s,2H),7.70(s,1H),7.55(d,J＝8.1Hz,1H),7.31-7.20(m,3H),7.17(s,1H),4.40(t,J＝7.2Hz,2H),3.90(s,3H),3.75(t,J＝4.0Hz,4H),3.33-3.28(m,2H),2.91(t,J＝4.0Hz,4H),1.88-1.78(m,2H),1.63-1.54(m,2H),1.39-1.30(m,2H)；13C NMR(100MHz,DMSO-d6)δ165.84,162.19,159.74,156.94,151.40,144.56,144.10,137.66,132.99,131.08,127.83,125.49,122.32,122.24,120.96,120.68,113.53,112.41,110.47,109.75,107.99,66.42,53.03,49.37,38.56,33.07,29.52,28.89,23.52.ESI-MS:m/z＝610.3[M+H]+.
实施例29：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(2-(2-(2-硝基-1H-咪唑-1)-基)乙氧基)乙基)苯甲酰胺B05
合成方法同实施例25，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙胺三氟乙酸盐。黄色固体，产率为34％。1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),9.45(t,J＝5.4Hz,1H),8.61(d,J＝7.8Hz,1H),8.41(d,J＝5.4Hz,1H),8.35(s,1H),7.85-7.75(m,3H),7.61(s,1H),7.55(d,J＝8.1Hz,1H),7.31-7.20(m,3H),7.12(s,1H),4.60(t,J＝5.2Hz,2H),3.90(s,3H),3.83(t,J＝5.2Hz,2H),3.71(t,J＝4.1Hz,4H),3.58(t,J＝5.4Hz,2H),3.46(q,J＝5.3Hz,2H),2.88(t,J＝4.2Hz,4H)；13C NMR(100MHz,DMSO-d6)δ165.67,162.19,159.72,156.93,151.65,144.86,144.34,137.66,133.00,131.29,127.98,127.55,125.49,122.32,122.22,120.97,120.09,113.64,112.40,110.48,109.81,108.05,69.15,68.50,66.25,53.15,48.80,38.57,33.07.ESI-MS:m/z＝612.3[M+H]+.
实施例30：(4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯基)(4-((2-硝基-1H-咪唑-1-基)甲基)哌啶-1-基)甲酮B06
合成方法同实施例25，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为4-((2-硝基-1H-咪唑-1-基)甲基)哌啶三氟乙酸盐。黄色固体，产率为22％。1HNMR(400MHz,DMSO-d6)δ9.51(d,J＝4.9Hz,1H),8.59(d,J＝7.9Hz,1H),8.36(d,J＝5.2Hz,1H),8.33(s,1H),7.69(d,J＝38.8Hz,1H),7.62-7.50(m,3H),7.28(t,J＝7.5Hz,1H),7.24-7.15(m,3H),7.07(dd,J＝43.8,8.2Hz,1H),4.61-4.50(m,1H),4.46-4.33(m,1H),4.32-4.26(m,1H),3.89(s,3H),3.78-3.67(m,2H),3.66-3.59(m,2H),3.22-3.11(m,2H),3.05-2.96(m,1H),2.83-2.75(m,2H),2.74-2.60(m,2H),2.23-2.02(m,1H),1.65-1.44(m,2H),1.06-0.97(m,2H)；13C NMR(100MHz,DMSO-d6)δ168.82,162.14,159.92,156.90,149.15,144.63,142.41,137.64,132.91,128.60,128.30,127.73,125.50,124.30,123.20,122.30,120.85,112.46,110.42,108.58,108.19,107.62,66.37,64.91,52.13,51.99,51.71,46.01,45.69,40.42,36.19,33.06,29.47.ESI-MS:m/z＝622.3[M+H]+.
实施例31：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(2-(2-甲基-5-硝基-1H-咪唑-1-基)乙基)-2-吗啉苯甲酰胺B07
合成方法同实施例25，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为2-(2-甲基-5-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐。黄色固体，产率为65％。1HNMR(400MHz,DMSO-d6)δ9.69(s,1H),9.49(t,J＝5.3Hz,1H),8.60(d,J＝7.5Hz,1H),8.40(d,J＝5.2Hz,1H),8.34(d,J＝2.4Hz,2H),7.79(s,1H),7.76(s,2H),7.55(d,J＝8.1Hz,1H),7.32-7.18(m,3H),4.22(t,J＝5.1Hz,2H),3.89(s,3H),3.75-3.67(m,2H),3.62(s,4H),2.84(s,4H),2.34(s,3H)；13C NMR(100MHz,DMSO-d6)δ166.68,162.18,159.69,156.93,151.57,145.41,145.29,144.48,137.66,132.97,131.01,125.47,122.35,122.32,122.20,120.95,119.97,113.66,112.40,110.46,109.96,108.08,66.18,53.01,45.96,33.05,12.53.ESI-MS:m/z＝582.3[M+H]+.
实施例32：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-甲基-5-硝基-1H-咪唑-1-基)丙基)-2-吗啉苯甲酰胺B08
合成方法同实施例25，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-甲基-5-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为60％。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),9.26(t,J＝5.7Hz,1H),8.61(d,J＝7.9Hz,1H),8.43(s,1H),8.40(d,J＝5.4Hz,1H),8.33(s,1H),7.77(s,1H),7.75(s,2H),7.55(d,J＝8.2Hz,1H),7.31-7.20(m,3H),4.07(t,J＝7.0Hz,2H),3.90(s,3H),3.77(t,J＝4.2Hz,4H),3.41-3.34(m,2H),2.93(t,J＝4.1Hz,4H),2.37(s,3H),2.08-1.99(m,2H)；13C NMR(100MHz,DMSO-d6)δ166.45,162.20,159.74,156.93,151.43,145.34,144.99,144.17,137.67,133.00,131.02,125.49,122.32,122.23,120.96,120.63,113.35,112.41,110.48,109.56,108.00,66.39,52.99,44.47,35.96,33.08,29.75,12.64.ESI-MS:m/z＝596.3[M+H]+.
实施例33：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(2-(3-硝基-1H-1,2,4-)三唑-1-基)乙基)苯甲酰胺B09
合成方法同实施例25，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为2-(3-硝基-1H-1,2,4-三唑-1-基)乙胺三氟乙酸盐。黄色固体，产率为32％。1HNMR(400MHz,DMSO-d6)δ9.69(s,1H),9.48(t,J＝5.9Hz,1H),8.91(s,1H),8.60(d,J＝7.9Hz,1H),8.40(d,J＝5.4Hz,1H),8.34(s,1H),7.78(s,1H),7.74(s,2H),7.55(d,J＝8.1Hz,1H),7.31-7.19(m,3H),4.54(t,J＝5.6Hz,2H),3.89(s,3H),3.82(q,J＝5.7Hz,2H),3.65(t,J＝4.2Hz,4H),2.87(t,J＝4.3Hz,4H)；13C NMR(100MHz,DMSO-d6)δ166.57,162.20,162.10,159.69,156.92,151.64,147.15,144.45,137.66,133.01,131.13,125.48,122.33,122.24,120.97,119.96,113.49,112.39,110.48,109.81,108.06,66.20,52.99,50.49,38.54,33.07.ESI-MS:m/z＝569.2[M+H]+.
实施例34：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(3-硝基-1H-1,2,4-)三唑-1-基)丙基)苯甲酰胺B10
合成方法同实施例25，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(3-硝基-1H-1,2,4-三唑-1-基)丙烷-1-胺三氟乙酸盐。黄色固体，产率为37％。1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.32(t,J＝5.5Hz,1H),8.92(s,1H),8.61(d,J＝7.6Hz,1H),8.40(d,J＝5.3Hz,1H),8.34(s,1H),7.78(s,1H),7.75(s,2H),7.55(d,J＝8.0Hz,1H),7.32-7.19(m,3H),4.41(t,J＝6.8Hz,2H),3.90(s,3H),3.77(s,4H),3.13-3.04(m,2H),2.93(s,4H),2.20-2.09(m,2H)；13CNMR(100MHz,DMSO-d6)δ166.41,162.20,159.74,156.93,151.47,146.85,144.21,137.67,133.00,131.07,125.50,122.33,122.26,120.97,120.52,113.38,112.41,110.48,109.61,108.01,66.37,53.02,45.68,35.85,33.08,29.38.ESI-MS:m/z＝583.3[M+H]+.
实施例35：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(4-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B11
合成方法同实施例25，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(4-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为48％。1H NMR(400MHz,DMSO-d6)δ9.65(s,1H),9.27(t,J＝5.7Hz,1H),8.61(d,J＝7.7Hz,1H),8.51(s,1H),8.40(d,J＝5.3Hz,1H),8.33(s,1H),7.94(s,1H),7.78(s,1H),7.75(s,2H),7.55(d,J＝8.1Hz,1H),7.32-7.19(m,3H),4.16(t,J＝6.8Hz,2H),3.90(s,3H),3.76(t,J＝3.9Hz,4H),3.34-3.33(m,2H),2.93(t,J＝4.1Hz,4H),2.12-2.04(m,2H)；13C NMR(100MHz,DMSO-d6)δ166.42,162.20,159.74,156.93,151.45,147.00,144.17,137.67,137.53,132.99,131.06,125.49,122.33,122.25,121.71,120.97,120.60,113.36,112.41,110.47,109.58,108.00,66.38,53.00,45.49,35.89,33.07,30.52.ESI-MS:m/z＝582.3[M+H]+.
实施例36：5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(4-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B12
合成路线如下：
步骤a：5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯甲酸甲酯的合成
合成方法同实施例25中的步骤a，将原料4-氨基-2-氟苯甲酸甲酯替换为5-氨基-2-吗啉代苯甲酸甲酯。白色固体，产率为65％。1H NMR(400MHz,DMSO-d6)δ9.45(s,1H),8.56(d,J＝7.7Hz,1H),8.32(d,J＝7.6Hz,2H),8.19(d,J＝1.9Hz,1H),7.84(d,J＝7.0Hz,1H),7.53(d,J＝8.1Hz,1H),7.27(t,J＝7.5Hz,1H),7.22-7.10(m,3H),3.88(s,3H),3.79(s,3H),3.71(s,4H),2.92(s,4H).ESI-MS:m/z＝444.2[M+H]+.
步骤b：5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯甲酸的合成
合成方法同实施例25中的步骤c，将原料4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯甲酸甲酯替换为5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯甲酸甲酯，粗产物不经纯化直接进行下一步。
步骤c：5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(4-硝基-1H-咪唑-1-基)丙基)苯甲酰胺的合成
合成方法同实施例25中的步骤d，将原料4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯甲酸替换为5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代苯甲酸，将原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(4-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为73％。1H NMR(400MHz,DMSO-d6)δ9.58(t,J＝5.6Hz,1H),9.52(s,1H),8.57(d,J＝7.4Hz,1H),8.52(s,1H),8.39(s,1H),8.33(d,J＝5.3Hz,2H),7.94(s,1H),7.90(dd,J＝8.6,2.1Hz,1H),7.52(d,J＝8.1Hz,1H),7.30-7.16(m,4H),4.17(t,J＝6.7Hz,2H),3.88(s,3H),3.75(s,4H),3.34-3.29(m,2H),2.91(s,4H),2.13-2.03(m,2H)；13C NMR(100MHz,DMSO-d6)δ166.75,161.98,159.95,156.99,147.01,144.18,137.63,137.52,137.29,133.11,129.26,125.52,122.31,122.17,121.92,121.70,120.91,120.75,120.73,112.46,110.35,107.18,66.56,53.08,45.39,35.88,33.04,30.43.ESI-MS:m/z＝582.3[M+H]+.
实施例37：5-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B13
合成方法同实施例36，只是将步骤c中的原料3-(4-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为69％。1H NMR(400MHz,DMSO-d6)δ9.60(t,J＝5.5Hz,1H),9.48(s,1H),8.55(d,J＝7.9Hz,1H),8.38(s,1H),8.35(d,J＝2.1Hz,1H),8.33(d,J＝5.3Hz,1H),7.88(dd,J＝8.6,2.2Hz,1H),7.76(s,1H),7.52(d,J＝8.1Hz,1H),7.30-7.16(m,5H),4.48(t,J＝6.9Hz,2H),3.89(s,3H),3.75(s,4H),3.42-3.35(m,2H),2.92(s,4H),2.15-2.06(m,2H)；13C NMR(100MHz,DMSO-d6)δ166.67,161.94,159.95,157.02,144.65,144.21,137.63,137.30,133.11,129.21,127.87,127.83,125.51,122.26,122.15,121.94,120.91,120.78,120.76,112.47,110.36,107.18,66.55,53.08,47.56,36.01,33.05,30.12.ESI-MS:m/z＝582.3[M+H]+.
实施例38：2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B14
合成方法同实施例25，将步骤b中的原料吗啉替换为N,N,N′-三甲基乙二胺，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为47％。1H NMR(500MHz,DMSO-d6)δ9.63(s,1H),8.61(d,J＝7.9Hz,1H),8.39(d,J＝5.4Hz,1H),8.33(s,1H),7.82(d,J＝1.2Hz,1H),7.80-7.70(m,3H),7.55(d,J＝8.2Hz,1H),7.31-7.27(m,1H),7.26(d,J＝5.4Hz,1H),7.24-7.20(m,2H),4.48(t,J＝7.1Hz,2H),3.89(s,3H),3.32-3.29(m,2H),3.10(s,2H),2.65(s,3H),2.20(s,6H),2.09-2.03(m,2H)；13C NMR(125MHz,DMSO-d6)δ162.20,159.74,156.88,144.63,144.07,137.66,132.97,130.82,127.90,127.87,125.49,122.30,122.24,120.94,113.72,112.42,111.32,110.45,107.96,47.58,43.47,35.90,33.07,30.28.ESI-MS:m/z＝597.3[M+H]+.
实施例39：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-(4-甲基哌嗪-1-基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B15
合成方法同实施例25，将步骤b中的原料吗啉替换为N-甲基哌嗪，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为51％。1H NMR(400MHz,DMSO-d6)δ8.74(t,J＝5.8Hz,1H),8.54(d,J＝7.8Hz,1H),8.34(d,J＝5.4Hz,1H),8.23(s,1H),7.73(d,J＝8.6Hz,1H),7.67(s,1H),7.63(d,J＝8.6Hz,1H),7.59(s,1H),7.52(d,J＝8.1Hz,1H),7.30-7.15(m,4H),4.44(t,J＝7.0Hz,2H),3.44-3.00(m,10H),2.82(s,3H),2.11-2.00(m,2H)；13C NMR(100MHz,DMSO-d6)δ166.73,162.29,159.74,156.84,149.87,144.69,144.06,137.70,133.02,131.17,127.91,125.54,122.36,122.29,120.97,113.32,112.36,110.49,109.25,108.05,52.66,49.36,47.65,42.22,36.07,33.11,30.38.ESI-MS:m/z＝595.3[M+H]+.
实施例40：2-(二乙氨基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-)基)丙基)苯甲酰胺B16
合成方法同实施例25，将步骤b中的原料吗啉替换为二乙胺，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为37％。1H NMR(500MHz,DMSO-d6)δ10.35(t,J＝5.8Hz,1H),9.65(s,1H),8.63(d,J＝7.8Hz,1H),8.39(d,J＝5.4Hz,1H),8.33(s,1H),7.95(d,J＝8.7Hz,1H),7.88(dd,J＝8.7,2.0Hz,1H),7.79(d,J＝2.0Hz,1H),7.77(d,J＝1.0Hz,1H),7.55(d,J＝8.2Hz,1H),7.31-7.22(m,3H),7.21(d,J＝1.0Hz,1H),4.46(t,J＝7.1Hz,2H),3.89(s,3H),3.40-3.36(m,2H),3.02(q,J＝7.1Hz,4H),2.10-2.03(m,2H),0.98(t,J＝7.1Hz,6H)；13CNMR(125MHz,DMSO-d6)δ165.82,162.26,159.74,156.85,149.78,144.66,144.20,137.67,132.98,130.79,127.91,127.82,125.52,122.36,122.33,122.28,120.93,114.46,112.69,112.39,110.46,108.01,48.68,47.64,35.71,33.08,30.40,12.10.ESI-MS:m/z＝568.3[M+H]+.
实施例41：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)-2-(哌啶-1-基)苯甲酰胺B17
合成方法同实施例25，将步骤b中的原料吗啉替换为哌啶，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为52％。1H NMR(500MHz,DMSO-d6)δ9.72(t,J＝5.8Hz,1H),9.66(s,1H),8.61(d,J＝7.9Hz,1H),8.40(d,J＝5.4Hz,1H),8.33(s,1H),7.84-7.81(m,2H),7.78(d,J＝0.9Hz,1H),7.72(dd,J＝8.7,1.8Hz,1H),7.55(d,J＝8.2Hz,1H),7.31-7.20(m,3H),7.20(d,J＝1.0Hz,1H),4.47(t,J＝7.0Hz,2H),3.89(s,3H),3.39(q,J＝6.5Hz,2H),2.88(t,J＝5.1Hz,4H),2.13-2.05(m,2H),1.71-1.63(m,4H),1.55-1.47(m,2H)；13C NMR(125MHz,DMSO-d6)δ166.11,162.18,159.74,156.94,153.01,144.65,144.24,137.66,132.98,131.02,127.87,127.83,125.49,122.30,122.26,120.98,120.11,113.43,112.44,110.47,110.09,107.99,54.20,47.59,35.87,33.08,30.36,26.07,23.41.ESI-MS:m/z＝580.3[M+H]+.
实施例42：2-(3-(二甲基氨基)氮杂环丁烷-1-基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2)-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B18
合成方法同实施例25，将步骤b中的原料吗啉替换为3-(二甲氨基)氮杂环丁烷二盐酸盐，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为54％。1H NMR(500MHz,DMSO-d6)δ9.42(s,1H),8.63(d,J＝7.8Hz,1H),8.36(d,J＝5.4Hz,1H),8.31(s,1H),8.17(t,J＝5.7Hz,1H),7.78(d,J＝0.9Hz,1H),7.54(d,J＝8.1Hz,1H),7.30-7.17(m,6H),7.07(d,J＝1.7Hz,1H),4.46(t,J＝7.0Hz,2H),3.92-3.85(m,5H),3.55(s,2H),3.24(q,J＝6.2Hz,2H),3.10-3.01(m,1H),2.11(s,6H),2.06-2.00(m,2H)；13C NMR(125MHz,DMSO-d6)δ168.72,162.14,159.95,156.86,149.52,144.64,142.71,137.64,132.84,129.41,127.89,127.87,125.53,122.42,122.29,120.91,115.65,112.50,110.40,107.69,107.54,102.85,56.62,55.42,52.00,47.56,45.55,41.39,36.04,33.06,29.90.ESI-MS:m/z＝595.3[M+H]+.
实施例43：(S)-2-(3-(二甲基氨基)吡咯烷-1-基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B19
合成方法同实施例25，将步骤b中的原料吗啉替换为(S)-N,N'-(二甲基)-3-吡咯烷胺双盐酸盐，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为35％。1HNMR(500MHz,DMSO-d6)δ9.37(s,1H),8.62(d,J＝7.9Hz,1H),8.35(d,J＝5.4Hz,1H),8.34-8.29(m,2H),7.78(d,J＝0.9Hz,1H),7.53(d,J＝8.2Hz,1H),7.35(dd,J＝8.4,1.6Hz,1H),7.29-7.25(m,2H),7.23-7.19(m,4H),4.47(t,J＝7.1Hz,2H),3.88(s,3H),3.31-3.25(m,2H),3.24-3.17(m,3H),3.14(t,J＝8.7Hz,1H),2.69-2.61(m,1H),2.10(s,6H),2.07-1.99(m,3H),1.75-1.63(m,1H)；13C NMR(125MHz,DMSO-d6)δ169.87,162.09,159.99,156.86,146.65,144.61,142.65,137.63,132.78,129.79,127.90,127.84,125.51,122.39,122.26,120.85,117.47,112.52,110.37,107.46,107.35,104.03,65.01,54.40,48.92,47.52,45.66,43.76,36.05,33.03,29.96,29.58.ESI-MS:m/z＝609.3[M+H]+.
实施例44：2-(4-(二甲基氨基)哌啶-1-基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2)-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B20
合成方法同实施例25，将步骤b中的原料吗啉替换为4-二甲氨基哌啶二盐酸盐，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为26％。1H NMR(500MHz,DMSO-d6)δ9.66(s,1H),9.49(s,1H),8.60(d,J＝7.0Hz,1H),8.39(d,J＝4.9Hz,1H),8.32(s,1H),7.85-7.75(m,3H),7.71(d,J＝8.0Hz,1H),7.55(d,J＝8.1Hz,1H),7.31-7.17(m,4H),4.48(t,J＝6.2Hz,2H),3.89(s,3H),3.17(d,J＝10.6Hz,2H),2.70(t,J＝11.1Hz,2H),2.45-2.32(m,1H),2.28(s,6H),2.14-2.05(m,2H),1.94-1.85(m,2H),1.65-1.54(m,2H)；13C NMR(125MHz,DMSO-d6)δ166.21,162.18,159.74,156.94,152.08,144.64,144.15,137.67,132.97,130.97,127.87,127.83,125.49,122.30,122.23,120.98,120.30,113.39,112.45,110.47,109.79,108.02,60.94,52.33,47.58,41,03,35.96,33.08,30.33,29.02.ESI-MS:m/z＝623.3[M+H]+.
实施例45：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B21
合成方法同实施例25，将步骤b中的原料吗啉替换为1-甲基-4-(4-哌啶基)哌嗪，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为24％。1H NMR(500MHz,DMSO-d6)δ9.66(s,1H),9.46(t,J＝5.6Hz,1H),8.59(d,J＝7.8Hz,1H),8.39(d,J＝5.4Hz,1H),8.32(s,1H),7.83-7.75(m,3H),7.72-7.67(m,1H),7.55(d,J＝8.2Hz,1H),7.32-7.19(m,4H),4.47(t,J＝7.0Hz,2H),3.89(s,3H),3.16(d,J＝11.4Hz,2H),2.80-2.55(m,10H),2.42-2.32(m,4H),2.13-2.05(m,2H),1.92-1.84(m,2H),1.65-1.54(m,2H)；13C NMR(125MHz,DMSO-d6)δ166.68,162.65,160.21,157.41,152.55,145.12,144.60,138.14,133.44,131.44,128.35,128.32,125.95,122.77,122.71,121.46,120.74,113.83,112.91,110.94,110.21,108.49,60.68,54.46,53.02,52.48,48.06,47.92,36.42,33.55,30.82,28.70.ESI-MS:m/z＝678.4[M+H]+.
实施例46；2-(环丙基氨基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-)基)丙基)苯甲酰胺B22
合成方法同实施例25，将步骤b中的原料吗啉替换为环丙胺，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为37％。1H NMR(500MHz,DMSO-d6)δ9.52(s,1H),8.65(d,J＝7.8Hz,1H),8.38(d,J＝5.3Hz,1H),8.31(s,1H),8.22(s,1H),8.18(t,J＝5.6Hz,1H),7.76(d,J＝0.7Hz,1H),7.65(d,J＝1.9Hz,1H),7.53(t,J＝8.4Hz,2H),7.30-7.26(m,1H),7.25-7.19(m,4H),4.44(t,J＝7.0Hz,2H),3.88(s,3H),3.24(q,J＝6.2Hz,2H),2.42(s,1H),2.07-2.00(m,2H),0.73-0.67(m,2H),0.45-0.39(m,2H)；13C NMR(125MHz,DMSO-d6)δ169.08,162.16,159.93,156.81,151.08,144.67,137.63,132.85,128.63,127.85,127.80,125.53,122.45,122.28,120.90,112.49,110.39,107.81,107.77,106.04,101.40,99.53,47.51,35.81,33.04,29.99,24.25,15.17,7.21.ESI-MS:m/z＝552.2[M+H]+.
实施例47：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-((1-(甲基磺酰基)哌啶-4-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B23
合成方法同实施例25，将步骤b中的原料吗啉替换为1-(甲基磺酰基)哌啶-4-胺，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为21％。1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.62(d,J＝7.3Hz,1H),8.38(d,J＝4.8Hz,1H),8.30(s,1H),8.24-8.12(m,2H),7.75(s,1H),7.54(t,J＝6.3Hz,2H),7.44(s,1H),7.33-7.15(m,4H),7.07(d,J＝8.1Hz,1H),4.45(t,J＝6.0Hz,2H),3.89(s,3H),3.46-3.38(m,3H),3.27-3.21(m,2H),2.81(s,3H),2.66(t,J＝10.9Hz,2H),2.13-2.00(m,4H),1.50-1.35(m,2H)；13C NMR(100MHz,DMSO-d6)δ169.18,162.21,159.88,156.87,149.26,144.82,144.68,137.63,132.84,129.04,127.85,127.75,125.51,122.41,122.33,120.87,112.53,110.42,107.95,107.61,105.40,100.31,47.68,47.50,44.15,35.82,34.10,33.03,30.92,29.99.ESI-MS:m/z＝673.3[M+H]+.
实施例48：4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-((2-吗啉代乙基)氨基)-N-(3-(2-硝基-1H)-咪唑-1-基)丙基)苯甲酰胺B24
合成方法同实施例25，将步骤b中的原料吗啉替换为N-(2-氨基乙基)吗啉，将步骤d中的原料2-(2-硝基-1H-咪唑-1-基)乙胺三氟乙酸盐替换为3-(2-硝基-1H-咪唑-1-基)丙-1-胺三氟乙酸盐。黄色固体，产率为30％。1H NMR(500MHz,DMSO-d6)δ9.43(s,1H),8.62(d,J＝7.9Hz,1H),8.36(d,J＝5.4Hz,1H),8.31(s,1H),8.13(q,J＝4.9Hz,2H),7.79(d,J＝0.9Hz,1H),7.54(d,J＝8.2Hz,1H),7.50(d,J＝8.8Hz,1H),7.34(d,J＝1.9Hz,1H),7.30-7.25(m,1H),7.24-7.19(m,3H),7.05(dd,J＝8.7,1.7Hz,1H),4.46(t,J＝7.0Hz,2H),3.89(s,3H),3.54(t,J＝4.4,4H),3.26(q,J＝6.2Hz,2H),3.20-3.14(m,2H),2.52(t,J＝6.3Hz,2H),2.35(s,4H),2.10-2.00(m,2H)；13C NMR(125MHz,DMSO-d6)δ169.10,162.11,159.89,156.86,150.40,144.75,144.65,137.64,132.82,128.86,127.84,127.81,125.50,122.36,122.28,120.90,112.51,110.39,108.09,107.77,105.25,99.98,66.19,56.79,53.19,47.54,35.78,33.06,30.06.ESI-MS:m/z＝625.3[M+H]+.
除以上实施例化合物外，本发明对实施例部分化合物进行了体外EGFR激酶抑制活性评价和人肺腺癌细胞增殖抑制活性评价。
生物学试验实施例1：化合物的体外EGFR激酶抑制活性评价
实验目的：以AZD9291为阳性对照，利用迁移率改变法(Mobility shift assay)对化合物进行激酶水平上的活性筛选，检测目标化合物在EGFR激酶上的抑制率或IC50值。
实验方法：
(1)激酶：EGFRL858R/T790M双突变型激酶、野生型EGFR激酶(EGFRWT)
(2)化合物溶解在100％的DMSO中，配制成10mM储存液低温避光储存。配制浓度梯度的受试化合物，以10μM浓度起始，4倍稀释，复孔检测。在384孔板中稀释成100倍终浓度的溶液，用Echo转移到目的板的化合物孔；阴性对照孔和阳性对照孔中分别加等体积的DMSO。用配制好的1×Kinase buffer配制激酶溶液；向受试化合物孔中加入激酶溶液，同时向阴性对照孔加入等体积的1×Kinase buffer；离心机离心，振荡混匀，室温孵育；用1×Kinasebuffer配制Kinase substrate 22和ATP的混合溶液，加到反应板起始反应；离心机离心，振荡混匀，室温孵育；加入终止液终止反应，离心，振荡混匀；使用Caliper EZ Reader II读取转化率数据。用转化率数据计算百分比抑制率数据，以浓度的log值作为横坐标，百分比抑制率为纵坐标，使用GraphPad Prism 5分析软件拟合量效曲线，计算出各化合物的IC50值。
实验结果：见表1。
表1化合物的EGFR激酶抑制活性评价结果
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注：选择性数值为EGFRL858R/T790M的IC50值除以EGFRWT的IC50值。
从表1中数据可以看出本发明中绝大部分化合物对EGFRL858R/T790M激酶具有纳摩尔级别的抑制活性，与EGFRWT相比，对EGFRL858R/T790M激酶具有良好的选择性。
生物学试验实施例2：化合物在低氧和常氧条件下的细胞增殖抑制活性评价
实验目的：以AZD9291为阳性对照，利用磺酰罗丹明B比色法(SRB assay)对部分化合物进行细胞水平上的活性评价，检测目标化合物在常氧和低氧条件下对肿瘤细胞的增殖抑制活性(IC50)。
实验方法：
(1)细胞株：人肺腺癌细胞H1975(EGFRL858R/T790M双突变)、人肺腺癌细胞HCC827(EGFRdel19突变)
(2)实验分组：目标化合物、阳性对照组、阴性对照组；化合物浓度：浓度50μM起始，5倍稀释，8个浓度；常氧孵育条件：37℃，5％CO2孵育72h；低氧孵育条件：37℃，94％N2、1％O2、5％CO2孵育72h。
(3)细胞培养：H1975和HCC827细胞传代培养，培养条件均为含有青霉素(终浓度为100U/mL)、链霉素(终浓度为100μg/mL)以及10％FBS的RPMI-1640培养基。当细胞融合至90％时，弃去旧培养基，用PBS洗涤细胞2次，吸去PBS，加入0.25％胰蛋白酶-0.02％EDTA混合液消化细胞，当细胞变圆后立即加入完全培养基终止消化，轻轻吹打避免细胞成团，收集细胞。800rpm，4℃，离心5min，弃去上清，用完全培养基重悬细胞，分瓶培养，隔天换液。
(4)SRB测试：细胞融合至80％时，调整密度为5000个/孔，接种于96孔板中，按照实验分组方式加入受试化合物，分别在常氧和低氧条件下培养72小时；不去除培养基，加入固定液，4℃孵育1小时；去除固定液，平板用蒸馏水冲洗3次；加入SRB溶液，避光，室温下孵育15分钟；取出染色液，加入1×洗涤液，冲洗4次；加入1×固化溶液，室温下孵育10分钟；酶标仪检测每个孔在565nm处的吸光度；使用Graphpad 5.0统计分析数据，计算出受试化合物的IC50值。
实验结果：见表2
表2化合物对H1975和HCC827细胞的增殖抑制活性评价结果
注：选择性数值为常氧条件下的IC50值除以低氧条件下的IC50值。
从表2中数据可以看出，制得的化合物对含EGFRL858R/T790M双突变的H1975细胞和含EGFRdel19突变的HCC827细胞具有良好的增殖抑制活性。部分化合物低氧条件下IC50值达到10nM以下，优于阳性对照AZD9291；抑制活性是常氧条件下的4-6倍，表现出良好的低氧选择性，从而提示化合物可能对正常氧气浓度下的正常细胞毒性降低。综上，本发明涉及的化合物具有靶向肿瘤低氧组织的潜力和较好的突变EGFR抑制活性，有望发展成为低氧和EGFR双重靶向的新型激酶抑制剂，有较好的抗肿瘤应用前景。
Claims (4)
1.一种化合物或其药学上可接受的盐，其特征在于，选自如下化合物：
N-(4-甲氧基-3-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A14
N-(2-氟-5-(2-(2-(2-硝基-1H-咪唑-1-基)乙氧基)乙氧基)苯基)-4-(1-甲基-1H-吲哚-3-基)嘧啶-2-胺A18
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(2-硝基-1H-咪唑-1-基) 丙基)苯甲酰胺B02
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(2-(2-甲基-5-硝基-1H-咪唑-1-基) 乙基)-2-吗啉苯甲酰胺B07
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-甲基-5-硝基-1H-咪唑-1-基) 丙基)-2-吗啉苯甲酰胺B08
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(2-(3-硝基-1H-1,2,4-)三唑-1-基)乙基)苯甲酰胺B09
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-吗啉代-N-(3-(4-硝基-1H-咪唑-1-基) 丙基)苯甲酰胺B11
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-(4-甲基哌嗪-1-基)-N-(3-(2-硝基- 1H-咪唑-1-基)丙基)苯甲酰胺B15
(S)-2-(3-(二甲基氨基)吡咯烷-1-基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B19
2-(4-(二甲基氨基)哌啶-1-基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2) -硝基-1H-咪唑-1-基)丙基)苯甲酰胺B20
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-N-（3-(2-硝基-1H-咪唑-1-基)丙基）苯甲酰胺B21
2-(环丙基氨基)-4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-N-(3-(2-硝基-1H-咪唑-1-)基)丙基)苯甲酰胺B22
4-((4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基)氨基)-2-((1-(甲基磺酰基)哌啶-4-基)氨基)-N-(3 -(2-硝基-1H-咪唑-1-基)丙基)苯甲酰胺B23。
2.一种药物组合物，其特征在于，所述药物组合物包含权利要求1所述的化合物或其药学上可接受的盐作为活性成分，以及药学上可接受的载体。
3.权利要求1所述的化合物或其药学上可接受的盐，或权利要求2中所述的药物组合物，在制备治疗或预防与EGFR相关的癌症的药物中的应用。
4.根据权利要求3所述的应用，其特征在于，所述癌症为肺腺癌。
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