CN116768868A - 一种哒嗪酮硫代衍生物及其制备方法和应用 - Google Patents
一种哒嗪酮硫代衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种具有通式(I)的哒嗪酮硫代衍生物,其结构式为:本发明还提供了上述衍生物的制备方法以及上述哒嗪酮硫代衍生物或其异构体、或其可药用盐、或其前药分子在用于制备治疗癌症的药物中的用途。本发明的哒嗪酮硫代衍生物为具有高活性抗肿瘤的新化合物,该类化合物单用或与其他药物联合用药可用于抗肿瘤治疗。与具有类似结构的哒嗪酮衍生物相比,本发明的哒嗪酮的硫代衍生物具有硫化氢供体特征,在降低化合物的毒性同时、具有更好的cMET激酶活性和更强的抗肿瘤活性。
Description
技术领域
本发明属于药物化学领域,具体涉及一种哒嗪酮硫代衍生物及其制备方法和应用。
背景技术
c-Met全称cellular-mesenchymal epithelial transition factor(细胞间质上皮转换因子),为受体酪氨酸激酶家族成员。c-Met信号通路在多种类型的实体瘤中如肺癌、胃癌、肝癌、乳腺癌、皮肤癌、大肠癌等均存在异常表达或突变,在多种肿瘤的发生发展中发挥了重要的作用。
c-Met目前作为一个有实力的肿瘤治疗靶点,其抑制剂类药物的研究现已成抗肿瘤药物研究发展的热点领域。而小分子c-Met抑制剂类抗肿瘤药物以其作用机制清晰,合成简便易于修饰等优点成为是最具潜力的抗肿瘤药物。小分子c-Met抑制剂类药物通过作用于c-Met受体,达到抑制c-Met结合域磷酸化,从而阻止酪氨酸激酶活化达到抑制下游信号传导产生抗肿瘤作用。伴随着小分子c-Met抑制剂作用机制的不断探究,随之产生的抑制剂类药物较传统抗肿瘤药物具有的毒副作用性低,疗效功能更加确切等优点,支撑着小分子c-Met抑制剂类抗肿瘤药物的不断发展。
c-Met 通路抑制剂在临床上取得了令人鼓舞的结果,但仍有一些问题需要解决。首先是获得性耐药问题,这在靶向药物中很常见。c-Met 扩增和高表达是癌症发展的主要因素,耐药突变并不经常发生,但在药物开发中考虑耐药突变仍然很重要。其次,考虑到高度保守的三磷酸腺苷结合,设计创新的结构激酶抑制剂以识别和抑制 c-Met 以产生治疗效果已成为一项重大挑战。
针对c-Met通路的治疗策略主要包括靶向MET基因的小分子TKIs和大分子药物。其中小分子TKIs可分为多激酶MET抑制剂和选择性MET抑制剂,前者包括克唑替尼、卡博替尼,后者包括特泊替尼、赛沃替尼、卡马替尼等。卡马替尼是FDA于2020年5月批准上市的第一款选择性c-MET小分子抑制剂。
特泊替尼Tepmetko(tepotinib)是全球首个被批准用于治疗携带MET基因改变的晚期非小细胞肺癌患者的口服MET抑制剂,有效率高达43%。在非小细胞肺癌(NSCLC)患者中,MET外显子14跳跃突变发生率为3-4%,而MET扩增发生率为1-6%。2019年9月美国食品和药物管理局(FDA)授予tepotinib突破性治疗的称号,用于治疗接受含铂化疗后病情进展、携带METex14跳跃突变的转移性NSCLC患者。2021年2月3日,FDA批准靶向抗癌药特泊替尼Tepmetko(Tepotinib),用于治疗携带MET基因第14号外显子跳过改变(METex14skipping)的晚期非小细胞肺癌(NSCLC)成人患者。
特泊替尼毒性偏大,有一些不可忽视的副作用,比如间质性肺病/肺炎、肝毒性、外周水肿、肾毒性等。
特泊替尼(Tepotinib)结构式:
将哒嗪酮羰基硫代后所得的衍生物,进一步具备了硫化氢分子供体的特性。硫化氢是继一氧化氮和一氧化碳之后的第3种内源性气体信使分子,对人类的健康具有极其重要的作用,它可以在短时间内迅速地跨越细胞膜,不仅具有舒张血管、保护心脏、抗炎、抗氧化的生理学作用,还具有抗肿瘤的功能(Lee ZW, Zhou J, Chen CS, et al. The slow-releasing hydrogen sulfide donor, GYY4137, exhibits novel anti-cancer effectsin vitro and in vivo. PLoS One. 2011;6(6):e21077.;Kashfi K. Anti-canceractivity of new designer hydrogen sulfide-donating hybrids. Antioxid RedoxSignal. 2014;20(5):831-846.),其抗肿瘤细胞的钟状模型(bell-shapled model)已被广泛证实(Szabo C. Gasotransmitters in cancer: from pathophysiology toexperimental therapy. Nat Rev Drug Discov. 2016;15(3):185-203.;Cao X, Ding L,Xie ZZ, et al. A Review of Hydrogen Sulfide Synthesis, Metabolism, andMeasurement: Is Modulation of Hydrogen Sulfide a Novel Therapeutic forCancer?. Antioxid Redox Signal. 2019;31(1):1-38.)。含有硫化氢供体结构的化合物在水解后释放的硫化氢,不仅可以抑制NF-κB的激活,降低NF-κB靶向蛋白表达而诱导黑色素瘤B6F10细胞凋亡,还可以上调Fas相关死亡域蛋白(FADD)的表达而抑制体内黑色素瘤生长(Cai F, Xu H, Cao N, et al. ADT-OH, a hydrogen sulfide-releasing donor,induces apoptosis and inhibits the development of melanoma in vivo byupregulating FADD. Cell Death Dis. 2020;11(1):33.)。
也有报道认为,硫化氢可以通过促进肿瘤细胞摄取葡萄糖而加快糖酵解并产生乳酸,扰乱细胞内的酸外排,引起肿瘤细胞内的酸化,从而抑制肿瘤细胞生长。其还可以抑制线粒体功能,激活细胞凋亡通路,阻滞细胞周期于G1/S期而发挥抗肿瘤效果。(Lee ZW, TeoXY, Tay EY, et al. Utilizing hydrogen sulfide as a novel anti-cancer agent bytargeting cancer glycolysis and pH imbalance. Br J Pharmacol. 2014;171(18):4322-4336.)。
哒嗪酮羰基硫代后所得的衍生物,体外激酶抑制和抗肿瘤细胞增殖抑制活性测试显示,硫代后的衍生物具有更高的活性。Vero细胞系是从非洲绿猴的肾脏上皮细胞中分离培养出来的。这个细胞系由日本千叶大学的Yasumura 和 Kawakita 于1962年3月27日扩增出来。该细胞系取“Verda Reno”(世界语意为‘绿色的肾脏)的简写而命名为"Vero"。测试化合物对Vero细胞的体外增值抑制活性,可以反映出化合物的细胞毒性,试验测定的IC50值越大,说明化合物的细胞毒性就越低。体外抗Vero细胞增殖活性测试证明,哒嗪酮羰基衍生物经硫代后毒性明显降低。
发明内容
本发明的目的在于提供一种哒嗪酮硫代衍生物的制备及其应用,经体外激酶抑制和抗肿瘤细胞增殖抑制活性测试显示,哒嗪酮硫代衍生物具有更高的活性以及更低的毒性,具有较好的应用前景。本发明是通过以下技术方案实现的:
一种哒嗪酮硫代衍生物,其特征在于:具有通式()的哒嗪酮硫代衍生物或其异构体、或其可药用盐、或其前药分子,其通式(I)化学结构为:
其中,哒嗪酮的羰基氧被硫取代;
通式(I)中,X为NH或者O;
通式(I)中,n=1, 2, 3; m=1, 2, 3;
通式(I)中,R为H、1-15个碳的烷基、烯基、炔基或其衍生物;或/和3-8个碳的环烷基或其衍生物;或/和含1-6个卤素的1-15碳的卤代烷基、卤代烯基或卤代炔基或其衍生物;或/和6-20个碳原子的芳基、卤代芳基、酚或多元酚或其衍生物;或/和1-15个碳原子的酰基或其衍生物;或/和含有1-4个杂原子的5-8元的杂环或并杂环或其衍生物中的任意一种;
所述的一种哒嗪酮硫代衍生物,其通式(I)化学结构为以下任意一种结构:
。
本发明所述的一种哒嗪酮硫代衍生物的制备方法包括如下所示方法进行合成:
所述的硫代试剂为P2S5、劳森试剂、2, 4-二(甲硫基)-1, 3, 2, 4-二噻二磷杂丁环-2, 4-二硫醚、2, 4-双(苯基硫基) -1, 3-二硫-2, 4-二磷杂环丁烷-2, 4 二硫化物,或者2, 4-双(4-苯氧基苯基)-1, 3, 2, 4-二硫代二磷杂环丁烷-2, 4-二硫化物中的一种或者两种;硫代反应温度在-78~180oC范围。
所述的硫代反应所使用的溶剂为二氯甲烷,二氯乙烷,四氢呋喃,乙腈,乙二醇二甲醚,1,4-二氧六环,N,N-二甲基甲酰胺或者二甲亚砜中的一种或几种的混合物。
所述的一种药物或药物组合物为含有治疗有效量的哒嗪酮硫代衍生物或其异构体、或其可药用盐、或其前药分子;进一步地,所述的一种药物或药物组合物还包括含有一种或多种药学上可接受的载体、稀释剂或赋形剂的情况。
所述哒嗪酮硫代衍生物或其异构体、或其可药用盐、或其前药分子或所述药物组合物单独或联合其它抗癌剂在制备治疗癌症的药物中的应用。该应用的特征在于所述癌症包括包括脑癌、脑胶质瘤、子宫内膜癌、卵巢癌、宫颈癌、乳腺癌、结肠癌、肺癌、前列腺癌、肝癌、白血病、淋巴癌、皮肤癌、基底细胞瘤、血管瘤、子宫癌、喉癌、胃癌、唇癌、食道癌、鼻咽癌、胆囊癌、胰腺癌、肾癌、舌癌、膀胱癌、黑素瘤、脂肪瘤、甲状腺癌、胸腺癌、骨癌。
本发明所述的一种哒嗪酮硫代衍生物的应用,其特征在于所述哒嗪酮硫代衍生物或其异构体、或其可药用盐、或其前药分子至少一种与其它的抗癌剂联用在制备治疗癌症的药物中的应用。该应用的特征在于:所述其它抗癌剂包括阿霉素类、博莱霉素、长春碱类、紫杉烷类、依托泊苷、5-氟尿嘧啶、环磷酰胺、甲氨蝶呤、顺铂、维甲酸、替莫唑胺、放线菌素、伊马替尼、吉非替尼、索拉非尼、厄洛替尼、舒尼替尼、阿法替尼、卡博替尼、奥斯替尼、达拉非尼、利妥昔单抗、西妥昔单抗、曲妥珠单抗、尼伏单抗、潘利珠单抗、阿替珠单抗、度伐单抗、阿维单抗。
上述硫代反应粗产物可以用溶剂提取法、沉淀法、结晶法进一步纯化,也可以用柱层析法进行纯化,填料用硅胶、凝胶、大孔树脂或氧化铝,洗脱剂可以用石油醚-丙酮、石油醚-乙酸乙酯、石油醚-二氯甲烷等不同比例的混合。
本发明具有以下有益效果:
本发明哒嗪酮硫代衍生物和化合物特泊替尼(Tepotinib)及其类似物相比较,本发明的哒嗪酮硫代衍生物具有更高c-Met激酶活性和更强的抗肿瘤活性,而且其还是一种硫化氢供体分子,对抗肿瘤药物具有减毒增效的作用,从而该类化合物毒性更低,因而应用前景非常广阔。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例描述所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明具体实施例18所述的动物试验小鼠体重变化曲线图;
图2为本发明具体实施例18所述的动物试验小鼠肿瘤体积变化曲线图。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
实施例1:化合物1的制备
(1). 化合物1-1的合成:
氮气保护下,将2-溴-5-羟基嘧啶(6.0g, 34.3mmol)、1-Boc-3-羟甲基氮杂环丁烷(7.38g, 39.4mmol)、Ph3P (10.34g, 39.4mmol)在120ml无水THF中搅拌溶解,在0℃下缓慢滴加DIAD (7.97g, 39.4mmol)。滴加完毕后,自然升温至室温并继续搅拌约4.5小时。薄层硅胶色谱显示2-溴-5-羟基嘧啶消耗完毕(展开剂:PE/EA=1/1)后,反应液用300ml乙酸乙酯稀释,依次用100ml水洗涤两次、100ml饱和食盐水洗涤一次。有机相经无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:PE/EA=4/1),得到11.06g类白色油状物1-1,收率:78.4%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.25 (s, 2H), 4.17-4.19 (d, J = 6.57Hz, 2H), 4.08-4.12 (m, 2H), 3.76-3.80 (m, 2H), 2.94-3.04 (m, 1H), 1.43 (s,9H).
MS(+ESI): m/z [M+H]+ 344.1.
(2). 化合物1-2的合成:
氮气保护下,将化合物1-1 (20g, 58.3mmol )、3-羟甲基苯硼酸(9.75g,64.1mmol)、溶于200ml 1,4-Dioxane中,然后加入K2CO3水溶液(9.67g溶于10ml水,70.0mmol)及Pd(dppf)Cl2 (1.71g, 2.33mmol)。所得反应液在82℃搅拌2.5小时后,薄层硅胶色谱检测原料1-1消耗完毕。停止搅拌,浓缩除去溶剂,残余物中加入400ml乙酸乙酯后用200ml水洗涤。有机相用200ml饱和食盐水洗涤、经无水硫酸钠干燥后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂:PE/EA=1/1~1/2),得到16.8g类白色固体1-2,收率:77.63%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.45-8.46 (d, J = 1.18Hz, 2H), 8.33 (s,1H), 8.25-8.27 (m, 1H), 7.46-7.47 (d, J = 5.16Hz, 2H), 4.77-4.78 (d, J = 2.69Hz, 2H), 4.21-4.22 (d, J = 6.57 Hz, 2H), 4.09-4.14 (t, J = 8.56 Hz, 2H),3.80-3.83 (dt, J = 8.41, 16.84 Hz, 2H), 2.96-3.06 (m, 1H), 2.07-2.08 (m, 1H),1.45 (s, 9H).
MS(+ESI): m/z [M+Na]+: 394.2.
(3). 化合物1-3的合成:
在氮气保护及25℃下,向化合物1-2 (6.8g, 18.3mmol)和三乙胺(2.23g,22.0mmol)的150ml二氯甲烷溶液中缓慢滴加MsCl (2.11g, 21.5mmol)。滴毕,反应液继续搅拌1小时,薄层硅胶色谱显示原料1-2消耗完毕。减压浓缩反应液,残余物用硅胶柱层析纯化(洗脱剂:PE/EA=2/1~1/1),得到7.85g油状物1-3,收率:95.4%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.48 (s, 2H), 8.38-8.42 (m, 2H), 7.45-7.54 (m, 2H), 5.33 (s, 2H), 4.25-4.25 (d, J = 6.56 Hz, 2H), 4.11-4.15 (t, J =8.58 Hz, 2H), 3.81-3.85 (dd, J = 8.90, 5.18 Hz, 2H), 3.00-3.06 (m, 1H), 2.95(s, 3H), 1.45 (s, 9H).
(4). 化合物1-4的合成:
氮气保护下,将化合物1-3 (7.75g, 17.3mmol)、3-(6-羰基-1,6-二氢-3-哒嗪基)苯氰 (3.74g, 19.0mmol)、碳酸钾(2.86g, 20.7mmol)和50ml无水DMF的混合物在70℃搅拌5小时。当薄层硅胶色谱显示原料1-3消耗完毕,将反应液降至室温,保持搅拌,向其中缓慢加入300ml水,过滤收集析出的大量白色固体粗品,该粗品用硅胶柱层析纯化(洗脱剂:PE/EA=1/1~1/2),得到7.24g类白色固体1-4,收率:76.2%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.59-8.60 (t, J = 1.52Hz, 1H), 8.51 (s,2H), 8.28-8.31 (m, 1H), 8.17-8.19 (t, J = 1.52 Hz, 1H), 7.96-7.98 (ddd, J =1.20, 1.75, 7.99 Hz, 1H), 7.68-7.70 (dt, J = 1.29, 7.72 Hz, 1H), 7.61-7.64(d, J = 9.72 Hz, 1H), 7.54-7.58 (m, 2H), 7.43-7.47 (t, J = 7.70 Hz, 1H),7.05-7.05 (d, J = 9.70 Hz, 1H), 5.50 (s, 2H), 4.23-4.25 (d, J = 6.60 Hz, 2H),4.10-4.14 (t, J = 8.60 Hz, 2H), 3.81-3.84 (dd, J = 5.21, 8.91 Hz, 2H), 2.97-3.07 (m, 1H), 1.45 (s, 9H).
MS(+ESI): m/z [M+Na]+: 573.2.
(5). 化合物1-5的合成:
氮气保护下,化合物1-4 (3g, 5.5mmol)、P2S5·2Py (5.19g, 13.7mmol)和80ml吡啶的混合物在115℃搅拌9小时。薄层硅胶色谱监测原料1-4消耗完毕,将反应液降至室温并减压浓缩,残余物用300ml二氯甲烷稀释后用100ml柠檬酸水溶液洗涤两次、饱和食盐水洗涤一次。有机相用无水硫酸钠干燥后减压浓缩。残余物用硅胶柱层析纯化(洗脱剂:PE/EA=1/1),得到1.7g黄色固体1-5,收率:55.06%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.66 (s, 1H), 8.52 (s, 2H), 8.31-8.32(d, J = 7.85 Hz, 1H), 8.24 (s, 1H), 8.00-8.02 (d, J = 8.02 Hz, 1H), 7.89-7.91(dd, J = 0.94, 9.25 Hz, 1H), 7.73-7.75 (d, J = 7.71 Hz, 1H), 7.64-7.66 (d, J= 7.56 Hz, 1H), 7.58-7.62 (t, J = 7.86 Hz, 1H), 7.43-7.47 (t, J = 7.72 Hz,1H), 7.29-7.31 (d, J = 9.26 Hz, 1H), 6.06 (s, 2H), 4.24-4.25 (d, J = 6.59 Hz,2H), 4.10-4.14 (t, J = 8.58 Hz, 2H), 3.81-3.84 (dd, J = 5.21, 8.89 Hz, 2H),2.97-3.07 (m ,1H), 1.45 (s, 9H).
MS(+ESI): m/z [M+Na]+: 589.2.
(6). 化合物1的合成:
将化合物1-5 (1.2g, 2.1mmol)溶于20ml二氯甲烷,氮气保护下缓慢加入6ml三氟乙酸,然后反应液在室温搅拌1小时。薄层硅胶色谱显示原料消耗完毕后,反应液用100ml二氯甲烷稀释,搅拌下向其中缓慢加入100ml饱和碳酸氢钠水溶液至无气泡产生。收集有机相,用50ml饱和食盐水洗涤后,经无水硫酸钠干燥后减压浓缩,得0.946g黄色固体粗品,收率:95.8%。取250mg粗品用硅胶制备板进行纯化(展开剂:DCM/MeOH=5/1),得到194mg黄色固体1。
1H-NMR (400 MHz, DMSO-d6) δ ppm: 9.29 (brs, 1H), 8.70 (s, 2H), 8.45(s, 2H), 8.30-8.32 (d, J = 8.0 Hz, 1H), 8.23-8.25 (d, J = 8.0 Hz, 1H), 7.88-8.00 (m, 3H), 7.76 (t, J = 8.0Hz, 1H), 7.47-7.54 (m, 2H), 6.04 (s, 2H), 4.39(d, J = 5.76 Hz, 2H), 4.06-4.11 (m, 2H), 3.84-3.88 (m, 2H), 3.20-3.27 (m,1H).
HRMS(+ESI): m/z [M+H]+: 467.2.
实施例2:化合物2的制备
化合物1 (0.38g, 0.82mmol)、0.2ml甲醛(30%水溶液, 4.9mmol)和NaBH3CN(0.307g, 4.9mmol)溶于20ml甲醇和10ml二氯甲烷中,随后室温搅拌2小时。薄层硅胶色谱显示反应结束,反应液用100ml二氯甲烷稀释,依次用100ml水和100ml饱和食盐水洗涤。有机相经无水硫酸钠干燥后减压浓缩,残余物用硅胶制备板进行纯化(展开剂:DCM/MeOH=6/1),得90mg黄色固体2,收率:22.99%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.64 (t, J = 1.6 Hz, 1H), 8.51 (s, 2H),8.31, 8.33 (dt, J = 1.2, 8.0 Hz, 1H), 8.22 (t, J = 1.2 Hz, 1H), 8.00-8.03 (m,1H), 7.91 (d, J = 9.2 Hz, 1H), 7.73, 7.75 (dt, J = 1.2, 8.0 Hz, 1H), 7.62-7.66 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0Hz, 1H), 7.30 (d, J =9.2 Hz, 1H), 6.07 (s, 2H), 4.26 (d, J = 6.8 Hz, 2H), 3.43 (t, J = 7.6 Hz,2H), 3.12-3.18 (m, 2H), 2.86-2.97 (m, 1H), 2.35 (s, 3H).
MS(+ESI): m/z [M+H]+: 481.2.
实施例3:化合物3的制备
化合物1 (0.4g, 0.86mmol)、乙醛(0.23g, 5.2mmol)和NaBH3CN (0.32g,5.2mmol)溶于12ml二氯甲烷和6ml甲醇种,反应液在25℃搅拌1.5小时。薄层硅胶色谱显示反应结束后,反应液用50ml二氯甲烷稀释,依次用50ml水和50ml饱和食盐水洗涤。有机相经无水硫酸钠干燥后减压浓缩,残余物用硅胶制备板进行纯化(展开剂:DCM/MeOH=4/1),得到180mg黄色固体3,收率:42.45%。
1H-NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.50 (s, 2H), 8.31 (d, J = 8.0Hz, 1H), 8.21 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H),7.73 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H),7.44 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 6.05 (s, 2H), 4.25 (d, J= 6.4 Hz, 2H), 3.48 (t, J = 8.0 Hz, 2H), 3.15-3.20 (m, 2H), 2.93-3.03 (m,1H), 2.52-5.58 (q, J = 7.2 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H).
HRMS(+ESI): m/z [M+H]+: 495.2.
实施例4:化合物4的制备
将化合物1 (0.4g, 8.6mmol)、0.5ml丙酮和NaBH3CN (0.32g, 5.2mmol) 溶于12ml二氯甲烷和6ml甲醇种,室温搅拌4小时。当薄层硅胶色谱显示反应结束,反应液用50ml二氯甲烷稀释,依次用50ml水和50ml饱和食盐水洗涤。有机相经无水硫酸钠干燥后减压浓缩,残余物用硅胶制备板进行纯化(展开剂:DCM/MeOH=5/1),得到150mg黄色固体4,收率:34.4%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.66 (s, 1H), 8.52 (s, 2H), 8.31 (dd, J= 1.2, 8.0 Hz, 1H), 8.22 (t, J = 1.2 Hz, 1H), 7.99-8.02 (m, 1H), 7.89 (d, J =9.2 Hz, 1H), 7.72-7.75 (m, 1H), 7.64-7.66 (d, J = 7.67 Hz, 1H), 7.58-7.62 (t,J = 7.86 Hz, 1H), 7.43-7.47 (t, J = 7.72 Hz, 1H), 7.29-7.31 (d, J = 9.27 Hz,1H), 6.05 (s, 2H), 4.23 (d, J = 5.6 Hz, 2H), 3.74-3.78 (m, 2H), 3.48-3.52 (m,2H), 3.07-3.14 (m, 1H), 2.74-2.80 (m, 1H), 1.10 (d, J = 6.0 Hz, 6H).
MS(ESI): m/z [M+H]+: 509.2.
实施例5:化合物5的制备
(1). 化合物5-1的制备:
氮气保护下,将2-溴-5-羟基嘧啶(10.0g, 57.1mmol)、1-Boc-3-羟甲基吡咯烷(13.2g, 65.7mmol)、Ph3P (17.2g, 65.7mmol)溶于120ml 无水THF中, 0℃度下保持搅拌,缓慢滴加DIAD (13.3g, 65.7mmol),滴加完毕后,自然升温到室温并继续搅拌5小时。当薄层硅胶色谱显示反应结束,反应液用300ml乙酸乙酯稀释,用150ml水洗涤两次、饱和食盐水洗涤一次。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:PE/EA=3/1),得到15.32g类白色油状物5-1,收率:75.74%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.14 (s, 2H), 3.92-3.93 (d, J = 6.54Hz, 2H), 3.26-3.51 (m, 3H), 3.09-3.12 (m, 1H ), 2.61 (s, 1H), 1.99-2.00 (m,1H), 1.70 (m, 1H), 1.32-1.34 (m, 9H).
(2). 化合物5-2的制备:
向化合物5-1 (15.32g, 42.9mmol)、3-羟甲基苯硼酸(7.82g, 51.5mmol)、K2CO3溶液(8.89g溶于7ml水,64.4mmol)和90ml 1,4-Dioxane的混合物中加入Pd(dppf)Cl2(1.25g, 1.72mmol)。在氮气保护下,反应混合物在80℃下加热搅拌3小时。薄层硅胶色谱显示反应结束后,反应液冷至室温,减压浓缩除去大部分溶剂,残余物中加入250ml二氯甲烷溶解和100ml ,搅拌后收集有机相。有机相用200ml饱和食盐水洗涤后,用无水硫酸钠干燥、减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:PE/EA=2/1~1/1),得到9.94g淡粉红色固体5-2,收率:60.14%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.42-8.43 (d, J = 3.32 Hz, 2H), 8.32(s, 1H), 8.24-8.26 (t, J = 4.06 Hz, 1H), 7.45-7.46 (d, J = 5.12 Hz, 2H),4.76-4.78 (d, J = 5.88 Hz, 2H), 3.98-4.08 (m, 2H), 3.58-3.63 (m, 1H), 3.37-3.52 (m, 2H), 3.17-3.25 (m, 1H), 2.68-2.71 (m, 1H), 2.29 (m, 1H), 2.08-2.11(m, 1H), 1.75-1.83 (m, 1H), 1.46 (s, 9H).
MS(+ESI): m/z [M+Na]+: 408.2.
(3). 化合物5-3的制备:
将化合物5-2 (4.97g, 12.9mmol)、Ph3P (5.08g, 19.4mmol)溶于100ml二氯甲烷,在室温并保持搅拌下,分批缓慢加入CBr4 (6.43g, 19.4mmol)。加毕,继续室温搅拌4小时,直至薄层硅胶色谱显示原料5-2消耗完全。向反应液中加入100ml水,搅拌后收集有机相。有机相用100ml饱和食盐水洗涤,再用无水硫酸钠干燥、减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:PE/EA=3/1~2/1),得到5.5g类白色固体5-3,收率:95.4%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.46 (s, 2H), 8.38-8.39 (d, J = 1.76Hz, 1H), 8.28-8.33 (m, 1H), 7.43-7.50 (m, 2H), 4.59-4.68 (d, J =37.83 Hz,2H), 4.05-4.07 (m, 2H), 3.40-3.64 (m, 3H), 3.22-3.28 (m, 1H), 2.73-2.74 (m,1H), 2.12 (m, 1H), 1.83 (m, 1H), 1.48 (s, 9H).
(4). 化合物5-4的制备:
将化合物5-3 (12g, 26.8mmol)、3-(6-羰基-1,6-二氢-3-哒嗪基)苯氰 (5.82g,29.5mmol)、碳酸钾(4.45g, 32.2mmol)在120ml无水DMF中的混合物于72℃搅拌1小时,直至薄层硅胶色谱显示反应结束。反应液冷至室温,向反应液中缓慢加入300ml水,过滤收集析出的大量固体粗品,该粗品用硅胶柱层析进一步进行纯化(洗脱剂:PE/EA=1/1~1/2),得到9.94g类白色固体5-4,收率:65.6%。
1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.65 (s, 2H), 8.37-8.39 (m, 2H),8.22-8.26 (m, 2H), 8.16-8.19 (d, J = 9.80 Hz, 1H), 7.92-7.95 (dt, J = 7.68,7.76 Hz, 1H), 7.70-7.74 (t, J = 7.87 Hz, 1H), 7.48-7.49 (m, 2H), 7.15-7.18(d, J = 9.76 Hz, 1H), 5.45 (s, 2H), 4.13-4.21 (m, 2H), 4.01-4.06 (q, J = 7.12Hz, 1H), 3.38-3.51 (m, 2H), 3.24-3.28 (m, 1H), 3.08-3.13 (dd, J = 10.75, 7.13Hz, 1H), 2.63-2.70 (m, 1H), 2.02 (m, 1H), 1.67-1.79 (m, 1H), 1.40 (s, 9H).
(5). 化合物5-5的制备:
在氮气保护下,将化合物5-4 (3.44g, 6.1mmol)和劳森试剂(6.16g, 15.2mmol)的40ml无水THF的溶液在100ml密封耐压管中于66℃下搅拌反应8小时。将耐压管冷至室温,反应液用300ml乙酸乙酯稀释,随后依次用100ml饱和碳酸氢钠水溶液、100ml饱和食盐水洗涤。有机相用无水硫酸钠干燥,减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:PE/EA=3/1~2/1),得到1.24g黄色固体5-5,收率35%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.66 (s, 1H), 8.51 (s, 1H), 8.31-8.33(d, J = 7.96 Hz, 1H), 8.24 (s, 1H), 8.01-8.03 (d, J = 8.00Hz, 1H), 7.90-7.92(d, J = 9.24 Hz, 1H), 7.74-7.76 (dt, J = 7.84, 1.28 Hz, 1H), 7.64-7.66 (d, J= 7.56 Hz, 1H), 7.58-7.62 (t, J = 7.86 Hz, 1H), 7.44-7.48 (t, J = 7.73 Hz,1H), 7.30-7.32 (d, J = 9.27 Hz, 1H), 6.07 (s, 2H), 4.07 (m, 2H), 3.39-3.66(m, 3H), 3.19-3.28 (m, 1H), 2.71-2.76 (m, 1H), 2.11-2.12 (m, 1H), 1.76-1.88(m, 1H), 1.66 (m, 1H), 1.48 (s, 9H).
MS(+ESI): m/z [M+Na]+: 603.2.
(6). 化合物5的制备:
向0.84g化合物5-5 (0.85g, 1.5mmol)的10ml二氯甲烷溶液中缓慢加入4ml三氟乙酸,然后反应液在室温下继续搅拌0.5小时。当薄层硅胶色谱显示反应结束,反应液用50ml二氯甲烷稀释后,向其中滴加50ml饱和碳酸氢钠水溶液,搅拌后,收集有机相。有机相用50ml饱和食盐水洗涤、无水硫酸钠干燥后减压浓缩,得到0.5g黄色固体粗品5,收率:71.9%;取150mg粗品用硅胶制备板进行纯化(展开剂:DCM/MeOH=4/1),得到35mg黄色固体5。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.63 (s, 1H), 8.49 (s, 2H), 8.29 (d, J= 8.0 Hz, 1H), 8.21 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 9.2Hz,1H), 7.73 (d, J = 7.6 Hz, 1H), 7.55-7.65 (m, 2H), 7.41-7.46 (m, 1H), 7.25-7.32 (m, 1H), 6.05 (s, 2H), 4.00-4.09 (m, 2H), 3.18-3.25 (m, 1H), 2.99-3.08(m, 2H), 2.87-2.91 (m, 1H), 2.62-2.69 (m, 1H), 2.01-2.10 (m, 1H), 1.59-1.67(m, 1H).
HRMS(+ESI): m/z [M+H]+: 481.2.
实施例6:化合物6的制备
将化合物5 (0.2g, 0.42mmol)、30%甲醛溶液(0.072ml, 2.52mmol)溶解在10mlDCM和10ml MeOH中并于室温搅拌10分钟,然后加入NaBH3CN (0.157g, 2.52mmol)继续在室温搅拌30分钟。当薄层硅胶色谱显示反应结束后,反应液用100ml二氯甲烷稀释,随后依次用100ml水和100ml饱和食盐水洗涤。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶制备板进行纯化(展开剂:DCM/MeOH=5/1),得到75mg黄色固体6,收率:36.43%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.63 (s, 1H), 8.49 (s, 2H), 8.31 (d, J= 8.0Hz, 1H), 8.21 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 9.2 Hz,1H), 7.74 (d, J = 8.0Hz, 1H), 7.57-7.66 (m, 2H), 7.43-7.47 (t, J = 8.0 Hz,1H), 7. 30 (d, J = 9.2 Hz, 1H), 6.06 (s, 2H), 4.03 (d, J = 6.8 Hz, 2H), 2.62-2.78 (m, 3H), 2.48-2.59 (m, 2H), 2.38 (s, 3H), 2.04-2.15 (m, 1H), 1.58-1.68(m, 1H).
HRMS(+ESI): m/z [M+H]+: 495.2.
实施例7:化合物7的制备
将化合物5 (0.4g, 0.84mmol)和乙醛(0.22g, 5.04mmol)溶于10ml DCM和10mlMeOH中,室温搅拌10分钟后加入NaBH3CN (0.31g, 5.04mmol),然后继续在室温搅拌1小时。薄层硅胶色谱显示反应结束后,反应液用150ml二氯甲烷稀释,随后依次用150ml水和150ml饱和食盐水洗涤,有机相经无水硫酸钠干燥后减压浓缩。残余物用硅胶制备板进行纯化(展开剂:DCM/MeOH=5/1),得到47mg黄色固体7,收率:11.1%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.64 (s, 1H), 8.50 (s, 2H), 8.31 (dt, J= 1.2, 8.0Hz,, 1H), 8.22 (t, J = 1.2 Hz, 1H), 8.00 (dt: J = 1.2, 8.0Hz, 1H),7. 90 (d, J = 9.2 Hz, 1H), 7.74 (dt: J = 1.2, 8.0Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 9.2Hz, 1H), 6.06 (s, 2H), 4.08 (d, J = 6.8 Hz, 2H), 2.94-2.98 (m, 1H), 2.76-2.85(m, 3H), 2.62-2.73 (m, 3H), 2.13-2.23 (m, 1H), 1.70-1.80 (m, 1H), 1.22 (t, J= 7.2 Hz, 3H).
HRMS(+ESI): m/z [M+H]+: 509.2.
实施例8:化合物8的制备
将化合物5 (0.2g, 0.42mmol)、0.5ml丙酮、10ml DCM 和10ml MeOH混合物搅拌10分钟后,加入NaBH3CN (0.157g, 2.52mmol),继续室温搅拌1.5小时。薄层硅胶色谱显示反应结束,反应液用100ml二氯甲烷稀释,随后依次用100ml水和100ml饱和食盐水洗涤,有机相经无水硫酸钠干燥后减压浓缩。残余物用硅胶制备板进行纯化(展开剂:DCM/MeOH=6/1),得到100mg黄色固体8,收率:45.97%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.65 (s, 1H), 8.50 (s, 2H), 8.31 (dt, J= 1.2, 8.0Hz, 1H), 8.22 (t, J = 1.2 Hz, 1H), 8.01 (dt, J = 1.2, 8.0 Hz, 1H),7. 90 (d, J = 9.2 Hz, 1H), 7.74 (dt, J = 1.2, 8.0 Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 9.2Hz, 1H), 6.06 (s, 2H), 4.08 (d, J = 6.0Hz, 2H), 3.10-3.15 (m, 1H), 2.69-2.99(m, 5H), 2.16-2.25 (m, 1H), 1.75-1.83 (m, 1H), 1.23-1.25 (dd, J = 3.2, 6.0Hz, 6H).
HRMS(+ESI): m/z [M+H]+: 523.2.
实施例9:化合物9的制备
(1). 化合物9-1的制备:
氮气保护下,将2-溴-5-羟基嘧啶(20g, 114.3mmol)、N-Boc-4-哌啶甲醇(27g,125.7mmol)和Ph3P (33g, 125.7mmol)溶于150ml 无水THF中。保持搅拌,于0℃缓慢滴加DIAD (25g, 125.7mmol),滴加完毕后,自然升温到室温并继续搅拌1小时。薄层硅胶色谱显示2-溴-5-羟基嘧啶消耗完毕,反应液用400ml乙酸乙酯稀释,依次用300ml水和饱和食盐水洗涤。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(PE/EA=6/1),得到32.4g白色固体9-1,收率:76.4%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.23 (s, 2H), 3.87-3.88 (d, J = 6.32Hz, 2H), 2.71-2.77 (t, J =11.54 Hz, 2H), 1.93-2.04 (m, 1H),1.78-1.81 (d, J =12.88 Hz, 2H), 1.46 (s, 9H), 1.26 (s, 2H), 1.25 (s, 2H).
(2). 化合物9-2的制备:
氮气保护下,3-羟甲基苯硼酸(4.65g, 30.6mmol)、化合物9-1 (10.82g,29mmol)、Pd(dppf)Cl2 (0.849g, 1.16mmol)、K2CO3 (4.8g溶于6ml水,34.8mmol)和130ml 1,4-Dioxane的混合物在85℃下搅拌约2小时。薄层硅胶色谱显示反应结束,将反应液降温至室温后减压浓缩,残余物中加入250ml乙酸乙酯,用100ml水洗涤两次。有机相用100ml饱和食盐水洗涤一次后用无水硫酸钠干燥、减压浓缩,残余物经硅胶柱层析纯化(洗脱剂:PE/EA=2/1),得到6.31g类白色固体9-2,收率54.21%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.45 (s, 2H), 8.34 (s, 1H), 8.26-8.28(m, 1H), 7.47-7.48 (m, 2H), 4.79-4.80 (d, J = 5.52 Hz, 2H), 3.94-3.96 (d, J =6.32 Hz, 2H), 2.74-2.79 (t, J = 11.02 Hz, 2H), 1.96-2.07 (m, 1H), 1.83-1.86(m, 2H), 1.62 (s, 2H), 1.47 (s, 9H), 1.25-1.37 (m, 3H).
(3). 化合物9-3的制备:
将化合物9-2 (6.81g, 17mmol) 和Ph3P(8.9g, 34mmol)溶于150ml二氯甲烷,室温搅拌下缓慢分批加入CBr4(11.3g, 34mmol)。加毕,反应液在室温下搅拌40分钟。薄层硅胶色谱显示反应结束后,反应液依次用100ml水、100ml饱和食盐水洗涤。有机相经无水硫酸钠干燥后减压浓缩,残余物经硅胶柱层析纯化(洗脱剂:PE/EA=4/1),得到4.23g白色固体9-3,收率:49.17%。
1H-NMR (400 MHz, CDCl3) δ 8.46 ppm: (s, 2H), 8.38 (m, 1H), 8.27-8.30(m, 1H), 7.43-7.49 (m, 2H), 4.59 (s, 2H), 3.94-3.96 (d, J = 6.32 Hz, 2H),2.74-2.79 (t, J = 11.8 Hz, 2H), 1.97-2.07 (m, 1H), 1.83-1.86 (d, J = 12.84Hz, 2H), 1.63 (s, 1H), 1.48 (s, 9H), 1.27-1.37 (m, 3H).
MS(+ESI): m/z [M+Na]+: 484.1.
(4). 化合物9-4的制备:
将3-(6-羰基-1,6-二氢-3-哒嗪基)苯氰(1.38g, 7mmol)、化合物9-3 (3.54g,7.7mmol)、K2CO3 (1.45g, 10.5mmol)和60ml 无水DMF的混合物在65℃搅拌5小时。当薄层硅胶色谱显示反应结束后,将反应液降温至室温,搅拌下加入250ml水,过滤收集析出的大量类白色固体粗品,该粗品用30ml无水乙醇进行重结晶,得到1.95g类白色固体9-4,收率:48.16%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.57-8.58 (t, J = 1.50 Hz, 1H), 8.48(s, 2H), 8.28-8.30 (dt, J = 7.80, 1.34 Hz, 1H), 8.17-8.18 (t, J = 1.52 Hz,1H), 7.96-7.99 (m, 1H), 7.68-7.70 (dt, J = 7.72, 1.29 Hz, 1H), 7.62-7.64 (m,1H), 7.54-7.58 (t, J = 7.91 Hz, 2H), 7.43-7.46 (t, J = 7.70 Hz, 1H), 7.05-7.07 (d, J = 9.70 Hz, 1H), 5.50 (s, 2H), 3.94-3.96 (d, J = 6.33 Hz, 2H),2.73-2.78 (t, J = 11.10 Hz, 2H), 1.82-1.86 (d, J = 12.74 Hz, 2H), 1.68 (s,3H), 1.47 (s, 9H), 1.24-1.36 (m, 3H).
MS(+ESI): m/z [M+H]+: 579.3.
(5). 化合物9-5的制备:
氮气保护下,在100ml耐压封管中依次加入化合物9-4 (1.6g, 2.8mmol),Lawesson,s Reagent (2.24g, 5.5mmol)和50ml无水THF,密封后,反应液在66℃搅拌约9小时。反应液温度降至室温后用200ml乙酸乙酯稀释,依次用100ml饱和碳酸氢钠水溶液、100ml水及100ml饱和食盐水洗涤。有机相用无水硫酸钠干燥、减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:PE/EA=2/1),得到0.86g黄色固体9-5,收率:52.30%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.64-8.65 (t, J = 1.54 Hz, 1H), 8.49(s, 2H), 8.30-8.33 (dt, J = 8.00, 1.28 Hz, 1H), 8.23-8.24 (t, J = 1.49 Hz,1H), 8.00-8.03 (ddd, J = 1.18, 1.79, 8.00 Hz, 1H), 7.90-7.92 (d, J = 9.24 Hz,1H), 7.73-7.76 (dt, J = 7.84, 1.32 Hz, 1H), 7.64-7.65 (d, J = 7.86 Hz, 1H),7.58-7.62 (m, 1H), 7.43-7.47 (t, J = 7.73 Hz, 1H), 7.29-7.32 (d, J = 9.27 Hz,1H), 6.07 (s, 2H), 3.95-3.96 (d, J = 6.34 Hz, 2H), 2.73-2.79 (t, J = 11.4 Hz,2H), 1.96-2.03 (m, 1H), 1.83-1.86 (d, J = 12.77Hz, 2H), 1.61 (s, 2H), 1.47(s, 9H), 1.24-1.36 (m, 3H).
MS(+ESI): m/z [M+Na]+: 617.2.
(6). 化合物9的制备:
将化合物9-5 (0.22g, 0.37mmol)溶于15ml二氯甲烷,然后在室温下缓慢加入2.5ml三氟乙酸。加毕,反应液继续在室温下搅拌1小时。薄层硅胶色谱显示反应结束后,反应液用100ml二氯甲烷稀释,用50ml饱和碳酸氢钠水溶液洗涤2次。有机相用100ml饱和食盐水洗涤后,经无水硫酸钠干燥、减压浓缩。残余物用硅胶制备板进行纯化(展开剂: DCM/MeOH=2/1),得到92mg黄色固体9,收率:50.28%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.67 (s, 1H), 8.50 (s, 2H), 8.31 (d, J= 8.0 Hz, 1H), 8.24 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 9.2 Hz,1H), 7.74 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz,1H), 7.45 (t, J = 8.0 Hz, 1H), 7.29 (d, J =9.2 Hz, 1H), 6.06 (s, 2H), 4.00(d, J = 6.0 Hz, 2H), 3.46-3.51 (m, 2H), 2.90-2.96 (m, 2H), 2.10-2.26 (m, 1H),1.98-2.08 (m, 3H), 1.71-1.83 (m, 2H).
MS(+ESI): m/z [M+H]+: 495.2.
实施例10:化合物10的制备
将劳森试剂 (100 mg, 0.255 mmol)和特泊替尼(100 mg, 0.255 mmol)溶于100ml的 1, 4-Dioxane,然后反应液在100℃下搅拌3小时。薄层硅胶色谱显示反应结束后,反应液冷却至室温,减压浓缩,残余物用50ml毫升乙酸乙酯稀释后依次用40ml 饱和碳酸氢钠水溶液和40ml饱和食盐水洗涤,有机相经无水硫酸钠干燥后减压浓缩。残余物用制备液相进行纯化,得到24.3 mg类白色固体产品10,收率23.5%。
1H NMR (400 MHz, DMSO-d6) δ ppm:8.64 (s, 2H), 8.45-8.47 (m, 2H), 8.31(dt, J = 1.2,8.0 Hz, 1H), 7.87 (s, 1H), 8.23 (dt, J = 1.2, 8.0 Hz, 1H), 7.94-8.02 (m, 3H), 7.77 (t, J = 8.0 Hz, 1H), 7.46-7.54 (m, 2H), 6.04 (s, 2H), 4.05(d, J = 5.6 Hz, 2H), 2.94-2.99 (m, 2H), 2.33 (s, 3H), 2.16-2.21 (m, 2H),1.78-1.83 (m, 3H), 1.36-1.40 (m, 2H).
MS(+ESI) : m/z [M+H]+:509.2.
实施例11:化合物11的制备
将化合物9 (0.69g, 1.4mmol)、NaBH(OAc)3 (1.82g, 5.6mmol)、50ml二氯甲烷和10ml丙酮的混合物在室温下搅拌6小时。薄层硅胶色谱显示反应结束后,反应液依次用40ml水、40ml饱和食盐水洗涤。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:DCM/MeOH=25/1)得到640mg黄色固体产物,收率:90.2%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.67 (s, 1H), 8.49 (s, 2H), 8.31 (d, J= 8.0 Hz, 1H), 8.24 (t, J = 1.2 Hz, 1H), 8.01 (dt, J = 1.2, 8.0 Hz, 1H), 7.90(d, J = 9.2 Hz, 1H), 7.75 (dt, J = 1.2, 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz,1H), 7.61 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 9.2 Hz,1H), 6.07 (s, 2H), 4.04 (d, J = 5.6 Hz, 2H), 3.39-3.45 (m, 3H), 2.71-2.77 (m,2H), 2.08-2.22 (m, 5H), 1.40 (d, J = 6.8 Hz, 6H).
MS(+ESI): m/z [M+H]+: 537.2.
实施例12:化合物12的制备
(1) . 化合物12-1的合成:
氮气保护下,将3-{1-[3-(5-溴嘧啶-2-基)苄基]-6-氧代-1,6-二氢哒嗪-3-基}苯甲腈 (CAS: 1103506-77-9; 10g, 22.6mmol)、NaI (13.5g, 90.3mmol)、CuI (0.43g,2.3mmol)、乙二胺四乙酸(DEEA) (0.27g, 2.3mmol)和100ml 1,4-Dioxane的混合物在120℃下搅拌18小时。反应液温度降至室温,过滤除去不溶物,滤液减压浓缩,残余物用200ml二氯甲烷稀释后依次用200ml水和200ml饱和食盐水洗涤。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:DCM/MeOH=100/1),得到10.08g类白色固体12-1,收率:90.95%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.84 (s, 1H), 8.60 (s, 1H), 8.34-8.36(d, J = 7.86 Hz, 1H), 8.14 (s, 1H), 7.98-8.00 (d, J = 8.00 Hz, 1H), 7.68-7.70(d, J = 7.74 Hz, 1H), 7.61-7.65 (t, J = 8.58 Hz, 2H), 7.54-7.58 (t, J = 7.85Hz, 1H), 7.45-7.49 (t, J = 7.73 Hz, 1H), 7.05-7.08 (d, J = 9.71 Hz, 1H), 5.50(s, 2H).
MS(+ESI): m/z [M+H]+: 492.0.
(2) . 化合物12-2的合成:
氮气保护下,将化合物12-1 (1.5g, 3.05mmol)、CuI (0.1162g, 0.61mmol)、L-Proline (0.14g, 1.22mmol)、Cs2CO3 (1.99g, 6.1mmol)、1-甲基-4-哌啶甲胺(0.587g,4.6mmol)和14ml无水DMF的混合物在25毫升密封的耐压管中于100℃搅拌24小时。反应液降温至室温后,过滤除去不溶物,滤液减压浓缩,残余物用100ml二氯甲烷稀释,随后用100ml饱和食盐水洗涤。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:DCM/MeOH=9/1~6/1),得到1.81g粗产物,收率:56.56%。取200mg粗品进一步用硅胶制备板纯化(展开剂:DCM/MeOH=4/1),得到100mg类白色固体12-2。
1H-NMR (400 MHz, CD3OD) δ ppm: 8.29 (s, 1H), 8.12-8.14 (d, J = 7.88Hz, 3H), 8.01-8.07 (dd, J = 17.05, 7.61 Hz, 2H), 7.82-7.84 (d, J = 9.69 Hz,1H), 7.66-7.68 (dd, J = 7.68, 0.79 Hz, 1H), 7.49-7.53 (t, J = 7.86 Hz, 1H),7.39-7.41 (d, J = 7.25 Hz, 1H), 7.3-7.37 (t, J = 7.61 Hz, 1H), 6.97-6.99 (d,J = 7.88 Hz, 1H), 5.39 (s, 2H), 3.99-3.00 (d, J = 6.72 Hz, 2H), 2.83-2.86 (d,J = 11.61 Hz, 2H), 2.23 (s, 3H), 1.94-1.99 (t, J = 11.16 Hz, 2H), 1.76-1.79(d, J = 12.60 Hz, 2H), 1.53-1.60 (m, 1H), 1.24-1.34 (m, 3H).
MS(ESI): m/z [M+H]+: 492.2.
(3). 化合物12的合成:
氮气保护下,将化合物12-5 (0.4g, 0.814mmol)、P2S5·2Py (0.62g, 1.63mmol)、8ml吡啶的混合物在密封的25毫升耐压管中于 100℃下搅拌24小时。反应液温度降至室温,减压浓缩反应液,残余物用100ml二氯甲烷稀释,随后用100ml饱和食盐水洗涤。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化 (洗脱剂: DCM/MeOH=10/1~6/1),得到的180mg粗产物进一步用制备液相纯化,得到33mg黄色固体12,收率:8.0%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.59 (s, 1H), 8.25(dd, J = 1.2, 8.0Hz,1H), 8.22-8.26(m, 3H), 8.01 (dt, J = 1.2, 8.0 Hz, 1H), 7.91 (d, J = 9.2 Hz,1H), 7.74 (dt, J = 1.2, 8.0 Hz, 1H), 7.56-7.62 (m, 2H), 7.42 (t, J = 8.0 Hz,1H), 7.29 (d, J = 9.2 Hz, 1H), 6.06 (s, 2H), 3.12 (t, J = 6.0 Hz, 2H), 2.91(d, J = 11.2 Hz, 2H), 2.29 (s, 3H), 1.90-2.01 (m, 2H), 1.72-1.84 (m, 2H),1.56-1.68 (m, 1H), 1.32-1.49 (m, 2H).
MS(+ESI): m/z [M+H]+: 508.2.
实施例13:化合物13的制备
(1) . 化合物13-1的合成:
氮气保护下,将化合物12-1 (1.5g, 3.05mmol)、CuI (0.1162g, 0.61mmol)、L-Proline (0.14g, 1.2mmol)、Cs2CO3 (1.99g, 6.1mmol)、1-乙基-4-哌啶甲胺(0.65g,4.58mmol)和12ml 无水DMF的混合物在密封的耐药管中于100℃下搅拌24小时。将反应液温度降至室温,过滤除去不溶物,滤液减压浓缩。残余物用200ml二氯甲烷稀释后用200ml饱和食盐水洗涤。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:DCM/MeOH=9/1),得到0.75g淡黄色固体粗产物,收率:48.59%;取100mg粗产物进一步用硅胶制备板纯化(展开剂:DCM/MeOH=6/1),得到60mg类白色固体13-1。
1H-NMR (400 MHz, CD3OD) δ ppm: 8.28-8.32 (d, J = 15.86 Hz, 2H), 8.16-8.19 (m, 3H), 8.09-8.11 (d, J = 7.69 Hz, 1H), 8.00-8.02 (d, J = 9.71 Hz, 1H),7.77-7.79 (d, J = 7.74 Hz, 1H), 7.62-7.65 (t, J = 7.87 Hz, 1H), 7.45-7.47 (d,J = 7.66 Hz, 1H), 7.38-7.42 (t, J = 7.64 Hz, 1H), 7.08-7.10 (d, J = 9.71 Hz,1H), 5.48 (s, 2H), 3.03-3.09 (m ,4H), 2.47-2.52 (q, J = 7.20 Hz, 2H), 2.04-2.10 (t, J = 11.57 Hz, 2H), 1.85-1.89 (d, J = 13.12 Hz, 2H), 1.67-1.73 (m,1H), 1.27-1.40 (m, 3H), 1.10-1.14 (t, J = 7.25 Hz, 3H).
MS(+ESI): m/z [M+H]+: 506.3.
(2) . 化合物13的合成:
氮气保护下,将化合物13-1 (0.49g, 0.97mmol)、P2S5·2Py (0.74g, 1.94mmol)、10ml吡啶的混合物在密封的耐压管中于100℃下搅拌26小时。将反应液冷至室温,反应液用150ml二氯甲烷稀释后,用饱和食盐水洗涤三次。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:DCM/MeOH=20/1),得到150mg粗产物,进一步用制备液相纯化,得到22mg黄色固体13,收率:4.4%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.58 (s, 1H), 8.25 (dt, J = 1.2, 8.0Hz, 1H), 8.21-8.23(m, 3H), 8.01 (dt, J = 1.2, 8.0 Hz, 1H), 7.90 (d, J = 9.2Hz, 1H), 7.74 (dt, J = 1.2, 8.0 Hz, 1H), 7.56-7.61 (m, 2H), 7.42 (t, J = 8.0Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H), 6.05 (s, 2H), 3.12 (t, J = 6.0 Hz, 2H),3.00-3.07 (m, 2H), 2.45 (q, J = 7.2 Hz, 2H), 1.91-2.05 (m, 2H), 1.76-1.86 (m,2H), 1.63-1.73 (m, 1H), 1.37-1.51 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H).
MS(+ESI): m/z [M+H]+: 522.2.
实施例14:化合物14的制备
(1) . 化合物14-1的合成:
氮气保护下,将化合物12-1 (4.0g, 8.15mmol)、CuI (0.31g, 1.63mmol)、L-Proline (0.38g, 3.26mmol)、Cs2CO3 (5.31g, 16.3mmol)、1-Boc-4-氮甲基哌啶(2.6g,12.2mmol)和50ml 无水DMF的混合物在密封的耐药管中于100℃下搅拌24小时。将反应液温度降至室温,过滤除去不溶物,滤液减压浓缩。残余物用200ml乙酸乙酯稀释后用200ml饱和食盐水洗涤。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:PE/EA=2~1/1),得到1.89g类白色固体产物14-1,收率:40.14%。
1H-NMR (400 MHz, CDCl3) δ ppm: 8.49 (s, 1H), 8.26 – 8.07 (m, 4H), 7.93(d, J = 7.9 Hz, 1H), 7.65 (dd, J = 7.7, 1.1 Hz, 1H), 7.59 (d, J = 9.7 Hz,1H), 7.51 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 7.1 Hz, 1H), 7.39 (t, J = 7.6 Hz,1H), 7.01 (dd, J = 9.7, 1.2 Hz, 1H), 5.46 (s, 2H), 4.22 – 4.05 (m, 3H), 3.06(s, 2H), 2.67 (t, J = 11.7 Hz, 2H), 1.74 (d, J = 10.9 Hz, 3H), 1.44 (s, 9H),1.26 – 1.08 (m, 3H).
MS(+ESI): m/z [M+H]+: 578.3.
(2) . 化合物14-2的合成:
氮气保护下,将化合物14-1 (0.46g, 0.8mmol)、P2S5·2Py (0.61g, 1.6mmol)、5ml吡啶的混合物在密封的耐压管中于120℃下搅拌7小时。将反应液冷至室温,反应液用200ml乙酸乙酯稀释后,用稀柠檬酸水溶液洗涤三次。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:DCM),得到158mg黄色固体14-2,收率:32.2%。
1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.45 (s, 1H), 8.35 (s, 1H), 8.30 (d,J = 8.1 Hz, 1H), 8.24 (d, J = 7.2 Hz, 2H), 8.17 – 8.10 (m, 1H), 7.99 (d, J =7.8 Hz, 1H), 7.94 (t, J = 6.2 Hz, 2H), 7.74 (t, J = 7.9 Hz, 1H), 7.41 (d, J =5.1 Hz, 2H), 6.35 (t, J = 5.8 Hz, 1H), 6.01 (s, 2H), 4.05 – 3.90 (m, 2H),3.02 (t, J = 5.8 Hz, 2H), 2.73 – 2.67 (m, 2H), 1.72 (d, J = 10.8 Hz, 3H),1.39 (s, 9H), 1.06 (dt, J = 12.2, 9.1 Hz, 2H).
MS(+ESI): m/z [M+H]+: 594.3.
(3) . 化合物14的合成:
将化合物14-2 (0.21g, 0.35mmol)溶于10ml二氯甲烷,氮气保护下缓慢加入1ml三氟乙酸,然后反应液在室温搅拌6小时。薄层硅胶色谱显示原料消耗完毕后,反应液用100ml二氯甲烷稀释,搅拌下向其中缓慢加入饱和碳酸氢钠水溶液至无气泡产生。收集有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得黄色固体粗品,制备液相分离纯化得化合物14 125mg,收率:72.4%。
1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.45 (t, J = 1.4 Hz, 1H), 8.35 (s,1H), 8.30 (ddd, J = 8.0, 1.7, 1.1 Hz, 1H), 8.22 (d, J = 4.1 Hz, 2H), 8.13(ddd, J = 5.1, 3.7, 1.7 Hz, 1H), 8.03 – 7.90 (m, 3H), 7.74 (t, J = 7.9 Hz,1H), 7.48 – 7.35 (m, 2H), 6.33 (t, J = 5.8 Hz, 1H), 6.01 (s, 2H), 2.98 (dd, J= 11.8, 5.7 Hz, 4H), 2.47 (dd, J = 16.6, 6.0 Hz, 2H), 1.76 – 1.58 (m, 3H),1.18 – 1.03 (m, 2H).
MS(+ESI): m/z [M+H]+: 494.2.
实施例15:化合物15的制备
(1) . 化合物15-1的合成:
氮气保护下,将化合物12-1 (2.95g, 6.0mmol)、CuI (0.23g, 1.2mmol)、L-Proline (0.27g, 2.4mmol)、Cs2CO3 (3.9g, 12.0mmol)、1-甲基-吡咯烷-3-甲胺(1.03g,9mmol)和30ml 无水DMF的混合物在密封的耐压管中于100℃下搅拌24小时。将反应液温度降至室温,过滤除去不溶物,滤液减压浓缩。残余物用200ml二氯甲烷稀释后用200ml饱和食盐水洗涤。有机相用无水硫酸钠干燥后减压浓缩,残余物用硅胶柱层析纯化(洗脱剂:DCM/MeOH=100~20/1),得到1.05g类白色固体产物15-1,收率:36.7%。
1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.30 (d, J = 1.5 Hz, 1H), 8.23 (d, J= 5.5 Hz, 1H), 8.21 – 8.12 (m, 3H), 8.11 – 8.05 (m, 2H), 7.89 – 7.82 (m, 1H),7.64 (t, J = 7.9 Hz, 1H), 7.39 – 7.28 (m, 2H), 7.08 (d, J = 9.8 Hz, 1H), 6.26(t, J = 5.5 Hz, 1H), 5.35 (s, 2H), 2.98 (t, J = 6.1 Hz, 2H), 2.51 – 2.44 (m,2H), 2.33 (dt, J = 15.4, 5.1 Hz, 2H), 2.22 (dd, J = 9.0, 5.1 Hz, 1H), 2.17(s, 3H), 1.93 – 1.85 (m, 1H), 1.38 (ddd, J = 13.0, 7.9, 6.3 Hz, 1H).
MS(+ESI): m/z [M+H]+:478.3.
(2) . 化合物15的合成:
氮气保护下,将化合物15-1 (0.72g, 1.5mmol)、P2S5·2Py (1.33g, 3mmol)、15ml吡啶的混合物在密封的耐压管中于120℃下搅拌7小时。将反应液冷至室温,反应液用200ml乙酸乙酯稀释后,用饱和食盐水洗涤三次。有机相用无水硫酸钠干燥后减压浓缩,残余物用中性氧化铝柱层析纯化(洗脱剂:DCM/MeOH=100~50:1),得黄色固体15粗产物,进一步制备液相纯化得目标产物121mg,收率:16.3%。
1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.45 (d, J = 1.5 Hz, 1H), 8.35 (s,1H), 8.29 (d, J = 8.1 Hz, 1H), 8.22 (s, 2H), 8.17 – 8.11 (m, 1H), 8.01 – 7.90(m, 3H), 7.74 (t, J = 7.9 Hz, 1H), 7.41 (dd, J = 4.0, 1.3 Hz, 2H), 6.32 (t, J= 5.5 Hz, 1H), 6.01 (s, 2H), 3.05 (dd, J = 9.7, 3.6 Hz, 2H), 2.57 – 2.50 (m,2H), 2.44 – 2.34 (m, 2H), 2.27 (dd, J = 9.0, 5.1 Hz, 1H), 2.23 (s, 3H), 1.98– 1.90 (m, 1H), 1.44 (ddd, J = 13.0, 7.9, 6.2 Hz, 1H).
MS(+ESI): m/z [M+H]+: 494.2.
实施例16:化合物c-MET酶活性抑制评价试验
实验目的:通过激酶活性测试试验评估化合物1-15的c-MET酶抑制活性;
实验方法: 酶反应底物多聚谷氨酸酪氨酸钠盐 (Glu:Tyr=4:1) 用无钾离子的PBS (10mM磷酸钠缓冲液,150mM NaCl, pH=7.2-7.4) 稀释成20μg/mL, 125μL/孔包被酶标板,在37℃反应12小时后,弃去孔中液体,然后用200μL/孔的T-PBS (含0.1%Tween-20的无钾离子PBS) 洗板三次,每次5分钟。然后在37℃下在烘箱中干燥酶标板2小时。
化合物最高浓度设置为3.0μM, 用DMSO向下3倍稀释,一共10个浓度:3.0μM, 1.0μM, 0.33μM, 0.11μM, 0.037μM, 0.012μM, 0.0041μM, 0.0014μM,0.00045μM,0.00015μΜ,按照三复孔方式测试。每孔先加入用反应缓冲液稀释的ATP溶液80μL,然后加入10μL各化合物(阴性对照孔加入10μL空白DMSO溶液),最后加入10μL用缓冲溶液稀释的酶溶液,在37℃的摇床上处理1小时。反应缓冲液的终浓度为HEPES (Ph=7.4)50mM,MgCl2 50Mm, MnCl20.5mM, Na3VO4 0.2mM, DTT 1mM;ATP的终浓度为4μM,酶量为1μL/孔。T-PBS洗板三次。
加入100μL/孔的抗体PY99 (抗体用含BSA 5mg/mL的T-PBS稀释,浓度为0.4μ/mL),37℃下在摇床上处理0.5小时。T-PBS洗板三次。
加入100μL /孔的辣根过氧化物酶标记羊抗鼠IgG (抗体用含BSA 5mg/mL的T-PBS稀释,浓度为0.5μg/mL),37℃下在摇床上处理0.5小时。T-PBS洗板三次。
加入100μL /孔的2mg/mL的OPD显色液 (用含有0.03%H2O2的0.1M、pH = 5.4 的柠檬酸-柠檬酸钠缓冲液稀释),在25℃下避光反应5分钟。
加入50μL /孔的2M H2SO4溶液终止反应,用酶标仪VERSAmax读数,波长为490nM。
样品的抑制率通过下列公式计算:
样品抑制率(%) = (1-(化合物OD值-无酶对照孔OD值)/(阴性对照孔OD值-无酶对照孔OD值)) ×100
结果如表1所示:
结果显示,化合物1~15作为c-MET抑制剂,其活性是Tepotinib的5倍以上,具有更好的激酶活性。
实施例17:化合物对肿瘤细胞的增殖抑制作用
实验目的:利用CTG法验证化合物1~15及Tepotinib对MKN-45细胞、EBC-1细胞、Hs746T细胞及Vero细胞的增殖抑制活性。
实验方法:将样品配成4μM,向下依次稀释4倍,得到10个浓度:4000nM,1000nM,250nM, 62nM, 16nM, 4nM, 1nM, 0.24nM, 0.06nM, 0.015nM。采用三复孔方式进行试验。
在培养板每孔中制备50μL密度为2*104个细胞/mL的细胞悬浮液,在空白对照孔中加入50 μL不含细胞的培养液。然后在培养箱中预培养24小时(37℃,5%CO2,100%相对湿度)。向每个孔中添加50μL上述各浓度的样品溶液,培养板放回培养箱中继续培养48小时后,向每个孔中加入每孔中加入50 µL的CellTiter-Glo 工作液。用铝箔纸包裹细胞板以避光。将培养板在轨道摇床上振摇2分钟以诱导细胞裂解。培养板在室温放置10分钟以稳定发光信号, 在2014 EnVision 读板器上检测发光信号。用GraphPad Prism 7处理数据以计算IC50。
实验结果如表2所示。
结果显示,对于所测试的5个肿瘤细胞,化合物1~15在体外肿瘤细胞增殖抑制活性都高于参比化合物曲美替尼。
实施例18:化合物体内抗肿瘤实验
实验目的:研究化合物对人EBC-1 细胞(人肺鳞癌细胞) 皮下异种移植瘤在BALB/c 裸小鼠模型体内的药效。
实验方法: 采用人EBC-1 细胞裸小鼠皮下移植瘤模型,通过测量动物瘤径,计算肿瘤体积(Tumor Volume,TV)、相对肿瘤体积(Relative Tumor Volume,RTV)和相对肿瘤增殖率T/C(%)、化合物的抑瘤疗效TGI(%),评价供试品灌胃给药对人肺鳞癌细胞EBC-1裸鼠皮下移植瘤生长的抑制作用。实验分组及给药方案如表3所示:
化合物在5mg/kg剂量下,连续灌胃给药30天后,小鼠体重变化如附图1所示。
附图1显示,试验终点时特泊替尼组体重降低幅度明显高于其他组,说明特泊替尼的毒副作用高于化合物6、10、14。
化合物的抑瘤疗效用TGI(%)或相对肿瘤增殖率T/C(%)评价。TGI(%),反映肿瘤生长抑制率。TGI(%)的计算:TGI(%)=【1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)】×100%。
相对肿瘤增殖率T/C(%):计算公式如下:T/C % = TRTV / CRTV × 100 %(TRTV:治疗组RTV;CRTV:阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relativetumor volume,RTV),计算公式为 RTV = Vt / V0,其中V0是分组给药时(即d0)测量所得平均肿瘤体积,Vt为某一次测量时的平均肿瘤体积,TRTV与CRTV取同一天数据。
特泊替尼及化合物6、10、14对异种移植瘤模型的抑瘤药效评价如表4所示:
小鼠肿瘤体积变化如附图2所示。
附图2显示,试验终点时特泊替尼组和化合物6、10、14均能有效抑制小鼠肿瘤的增长,但化合物6、10、14的抑制效果更好。
以上所述实施例仅表达了本发明的实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (9)
1.一种哒嗪酮硫代衍生物,其特征在于:具有通式(I)的哒嗪酮硫代衍生物或其异构体、或其可药用盐、或其前药分子,其通式(I)化学结构为:
其中,哒嗪酮的羰基氧被硫取代;
通式(I)中,X为NH或者O;
通式(I)中,n=1, 2, 3;m=1, 2, 3;
通式(I)中,R为H、1-15个碳的烷基、烯基、炔基或其衍生物;或/和3-8个碳的环烷基或其衍生物;或/和含1-6个卤素的1-15碳的卤代烷基、卤代烯基或卤代炔基或其衍生物;或/和6-20个碳原子的芳基、卤代芳基、酚或多元酚或其衍生物;或/和1-15个碳原子的酰基或其衍生物;或/和含有1-4个杂原子的5-8元的杂环或并杂环或其衍生物中的任意一种。
2.根据权利要求1所述的一种哒嗪酮硫代衍生物,其特征在于:通式(I)化学结构为下述任意一种结构:
。
3.根据权利要求1-2任一项所述的一种哒嗪酮硫代衍生物,其特征在于,该哒嗪酮硫代衍生物的制备方法包括如下所示方法进行合成:
所述的硫代试剂为P2S5、劳森试剂、2, 4-二(甲硫基)-1, 3, 2, 4-二噻二磷杂丁环-2, 4-二硫醚、2, 4-双(苯基硫基) -1, 3-二硫-2, 4-二磷杂环丁烷-2, 4 二硫化物,或者2, 4-双(4-苯氧基苯基)-1, 3, 2, 4-二硫代二磷杂环丁烷-2, 4-二硫化物中的一种或者两种;硫代反应温度在-78~180oC范围。
4.根据权利要求3所述的一种哒嗪酮硫代衍生物,其特征在于,所述的硫代反应所使用的溶剂为二氯甲烷,二氯乙烷,四氢呋喃,乙腈,乙二醇二甲醚,1, 4-二氧六环,N, N-二甲基甲酰胺或者二甲亚砜中的一种或几种。
5.一种药物或药物组合物,其特征在于:包含有权利要求1-2任一项所述的哒嗪酮硫代衍生物或其异构体、或其可药用盐、或其前药分子,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
6.一种权利要求1-2任一项所述哒嗪酮硫代衍生物或其异构体、或其可药用盐、或其前药分子或权利要求5所述药物或药物组合物在制备治疗癌症的药物中的应用。
7.一种权利要求1-2任一项所述哒嗪酮硫代衍生物或其异构体、或其可药用盐、或其前药分子或权利要求5所述药物或药物组合物中的一种或多种与其它抗癌剂在制备治疗癌症的药物中的应用。
8.根据权利要求6-7任一项所述的应用,其特征在于:所述癌症包括脑癌、脑胶质瘤、子宫内膜癌、卵巢癌、宫颈癌、乳腺癌、结肠癌、肺癌、前列腺癌、肝癌、白血病、淋巴癌、皮肤癌、基底细胞瘤、血管瘤、子宫癌、喉癌、胃癌、唇癌、食道癌、鼻咽癌、胆囊癌、胰腺癌、肾癌、舌癌、膀胱癌、黑素瘤、脂肪瘤、甲状腺癌、胸腺癌、骨癌。
9.根据权利要求7所述的一种哒嗪酮硫代衍生物的应用,其特征在于:所述其它抗癌剂包括阿霉素类、博莱霉素、长春碱类、紫杉烷类、依托泊苷、5-氟尿嘧啶、环磷酰胺、甲氨蝶呤、顺铂、维甲酸、替莫唑胺、放线菌素、伊马替尼、吉非替尼、索拉非尼、厄洛替尼、舒尼替尼、阿法替尼、卡博替尼、奥斯替尼、达拉非尼、利妥昔单抗、西妥昔单抗、曲妥珠单抗、尼伏单抗、潘利珠单抗、阿替珠单抗、度伐单抗、阿维单抗。
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