CN113278010A - 一类蛋白激酶降解剂及其用途 - Google Patents
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Abstract
本发明提供了一类蛋白激酶降解剂及其用途,具体地,本发明提供了一种具有式(Ⅰ)所示结构的化合物或者其药学上可接受的盐,或者其立体异构体或前药分子。所述的化合物能够靶向泛素化降解AXL、FLT3等蛋白,因此可以用于治疗AXL、FLT3激酶异常表达相关的适应症。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类靶向泛素化降解AXL、FLT3等蛋白的化合物及其药用组合物和应用。
背景技术
蛋白激酶是细胞功能的关键调节分子,构成了最大且功能最多样的基因家族之一。蛋白激酶通过底物蛋白的磷酸化,指导许多蛋白的活动、定位以及总体功能,并且参与几乎所有细胞活动。蛋白激酶的表达、活化、定位等异常,与多种疾病的发生、发展密切相关,是肿瘤、炎症等多种疾病的重要驱动因子。因此,人类激酶组是一个潜在治疗靶点资源库,针对激酶进行药物开发将是未来长时间内的重大科学和产业热点课题。截止到2020年12月31日,FDA共计批准了62个激酶抑制剂药物上市,集中在40多个激酶靶标,其中以EGFR(7个)、ABL(6个)、ALK(5个)、JAK(7)、VEGFR(6个)为靶标上市的药物最多。
研究发现,蛋白的非激酶功能在肿瘤等疾病中发挥重要作用。文献已经报道了EGFR、PIPK3、PDK1、BRAF、CRAF、CHK2、ZAP70、AKT、Aurora A等激酶的非激酶功能。单纯抑制剂激酶活性无法完全抑制剂激酶的非激酶功能,从而带来疗效低、耐药等潜在不利影响。因此,开发蛋白降解剂有望全面抑制激酶的酶活和非激酶功能,发挥强效治疗作用。而基于PROTAC原理的蛋白降解剂是目前最为成功和成熟的蛋白降解策略,并成功用于多个激酶及其他靶标的降解剂开发。
PROTAC特指一类可以特异性识别并诱导降解靶蛋白的小分子化合物;分子结构由靶蛋白识别配体、Linker和E3识别配体三部分组成。PROTAC的优点是不但有效抑制靶蛋白的活性,而且可以快速降解清除靶蛋白。理论上只需要催化量的药物,就可以降解细胞内几乎所有的蛋白质(包括膜蛋白),故具有较高的安全性、耐药性和广阔的应用前景。目前已经开发成功了针对ERR、ABL、BET、CDK4/6等靶蛋白的降解剂,结果表明其不但能治疗基因驱动型肿瘤的增殖,也能克服抑制剂耐药。2018年,辉瑞公司宣布投资8.3亿美元进行基于PROTAC技术的蛋白降解剂药物研发。2019年3月,药明康德的合作伙伴Arinas公司宣布,其开发的针对雄激素受体的蛋白降解剂ARV-110进入临床研究;这是全球首个进入临床研究阶段的蛋白降解剂。
AXL受体络氨酸激酶属于TAM受体酪氨酸激酶家族,广泛表达于大脑、免疫细胞、血小板、内皮细胞、骨骼肌、心脏、肝脏和肾脏等组织,能够促进AML等肿瘤细胞增殖、转移,与多种化疗、激酶抑制剂药物的耐药有关。R428(BGB324)是目前选择性最好的AXL抑制剂之一,已于2013年进入临床I期研究,其他多个AXL抑制剂处于不同研发阶段,但尚无AXL抑制剂上市。生物学研究发现AXL可能存在激酶非依赖的生物调节作用:1)BGB324显著抑制MDA-MB-231乳腺癌细胞中AXL及其下游蛋白AKT磷酸化,但对细胞侵袭的抑制作用明显小于AXL基因敲除的结果;2)Meyer等人发现AXL与EGFR共定位可以转激活下游信号导致肿瘤细胞对EGFR抑制剂的耐受,AXL基因敲除可以抑制AKT磷酸化以及EGF介导的信号通路,但BGB324对AKT磷酸化影响很小。
FMS样酪氨酸激酶3(FLT3)是一种Ⅲ型受体酪氨酸激酶,在造血细胞的存活、增殖和分化中起着重要作用,是AML的成熟治疗靶标。FLT3突变主要有两种类型:膜旁结构域(juxtamembrane)的内部串联重复突变(FLT3-ITD)和酪氨酸激酶结构域的点突变(FLT3-TKD)或缺失。两种突变的FLT3分子都可以非配体依赖的二聚和反式磷酸化被激活的。突变型FLT3诱导多种细胞内信号通路的激活导致细胞增殖和抗凋亡,主要包括STAT5、MAPK和AKT等。FLT3-ITD和FLT3-TKD分别发生在约20%和10%的AML中。由于FLT3突变是AML最常见的基因突变,并与预后不良有关;因此,突变型FLT3是治疗AML的一个很有前途的治疗靶标。目前,已经有多个非选择性FLT3抑制剂如米哚妥林(midostaurin),及选择性抑制剂如吉瑞替尼(Gilteritinib)、奎扎替尼(Quizartinib)和Crenolanib(CP-868596)等上市或者在研,但快速出现的FTT3突变耐药仍是临床尚未解决的医学难题。因此,设计合成AXL、FLT3等激酶降解剂用于肿瘤治疗,可以同时控制激酶的酶活和非激酶功能,产生强效治疗作用并克服耐药。
发明内容
本发明的目的是提供一种能够靶向泛素化降解AXL、FLT3等蛋白的化合物及其药用组合物。
本发明的第一方面,提供了一种具有式(Ⅰ)所示结构的化合物或者其药学上可接受的盐,或者其立体异构体或前药分子:
其中:
X不存在,或选自下组:-CH2-、-CF2-或-O-;
R1选自下组:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基;
R2选自:取代或未取代的C1-C6烷基;
Y选自:-CH2-,-C(=O)-;
L具有如下式所示的结构:-Z-(L1)m-;
其中,m为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30;
所述的Z选自下组:具有0-4个杂原子的3-12元环、-NH-、-O-、-C(O)-、-CONH-、-NHCO-、-S-、-CH2-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-;
L1选自下组:具有0-4个杂原子的3-12元环、-NH-、-O-、-C(O)-、-CONH-、-NHCO-、-S-、-CH2-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-;
且所述的L片段可以任选地包括一个或多个RL取代基,且所述的RL取代基选自下组:卤素、-OH、-CN、-CF3、-NH2、-COOH、氧原子(=O)、取代或未取代的C1-C6烷基或卤代烷基、取代或未取代的C1-C6烷氧基,或者2个RL基与它们所连接的原子共同形成含有0-4个杂原子的3-8元环;
其中,上述的取代指基团上的一个或多个H原子被选自下组的取代基替代:卤素,氘原子。
在另一优选例中,所述的式I化合物具有选自下组的结构:
在另一优选例中,R1选自下组:-H,-F,-Cl,-CH3,-CF3,-CD3,-CH2CH3,环丙基,环丁基,环戊基,异丙基,氟代乙基,氟代环丙基,氟代环丁基,氟代环戊基,氟代异丙基。
在另一优选例中,R2选自-CH3,-CD3。
在另一优选例中,L具有下式所示结构:
其中:
Z选自下组:具有0-4个杂原子的3-8元环、-NH-、-O-、-C(O)-、-CONH-、-NHCO-、-S-、-CH2-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-;
n为1、2、3、4、5、6、7、8、9或10;并且短划线表示接头部分的连接点。
在另一优选例中,L具有下式所示结构:
其中:
W1和W2不存在,或各自独立地为具有0-4个杂原子的3-12元环,其任选地被RL取代;
B不存在,或B选自下组:具有0-4个杂原子的3-12元环、-NH-、-O-、-CONH-、-NHCO-、-S-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-、C1-C6烷基或卤代烷基(直链、支链、任选地取代的)并且任选地一个或多个C原子被O、N替换;或C1-C6烷氧基(直链、支链、任选地取代的);
Z选自下组:含有0-4个杂原子的3-12元环、-NH-、-O-、-CONH-、-NHCO-、-S-、-CH2-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-;
n是0-10;并且
短划线表示接头部分的连接点。
在另一优选例中,所述的Z选自下组:-NHCO-、-CH2-、-C(O)-、含有0-4个杂原子的3-12元环、-NH-、-O-。
在另一优选例中,所述的L具有选自下组的结构:
其中,n,m各自独立地为0-6的整数。
在另一优选例中,所述的化合物选自下组:
本发明的第二方面,提供了一种治疗肿瘤的药用组合物,其特征在于包括本发明第一方面所述的式I化合物或其药学上可接受的盐,或立体异构体或其前药分子;和
药学上可接受的载体。
本发明的第三方面,提供了一种本发明第一方面所述的式I化合物或其药学上可接受的盐,或立体异构体或其前药分子在制备治疗或预防与AXL和/或FLT3的活性或表达量相关的疾病或病症的用途,其中,所述的疾病或病症选自下组:心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症、癌症。
在另一优选例中,所述肿瘤为血液性肿瘤、胃肠间质瘤、组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、鼻咽癌中的任意一种。
在另一优选例中,所述的药物组合物用于治疗选自下组的适应症:非小细胞肺癌、胃肠间质瘤、肝癌、恶性黑色素瘤、前列腺癌、肾癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、宫颈癌、肺癌、喉癌、鼻咽癌、胰腺癌、多发性骨髓瘤、B淋巴瘤、白血病,或用于防止肿瘤术后复发。
在另一优选例中,所述的药物组合物用于治疗AXL、FLT3、AuroraA等激酶异常表达相关的适应症。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1为MDA-MB-231细胞中AXL蛋白水平检测结果;
图2为MV4-11细胞中FLT3蛋白水平检测结果;
图3为化合物HS-28对不同细胞中不同蛋白的降解活性检测结果;
图4为化合物抑制MDA-MB-231细胞的迁移和侵袭实验结果。
具体实施方式
本发明人经过长期而深入的研究,制备了一类能够靶向泛素化降解AXL、FLT3等蛋白的化合物及其药用组合物。所述的化合物可以高效、高选择性地降解细胞中的AXL、FLT3等蛋白,因此具有潜在的治疗AXL、FLT3激酶异常表达相关的适应症的用途。基于上述发现,发明人完成了本发明。
术语
本发明所述化合物中,当任何变量(例如R1、R2等)在任何组分中出现超过一次,则其每次出现的定义独立于其它每次出现的定义。同样,允许取代基及变量的组合,只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环,其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代,应理解这些基团可在相同碳原子上或不同碳原子上,只要使结构稳定。
除非另外定义,否则本文所使用的所有技术和科学术语具有与本发明所属领域的技术人员通常理解的含义相同的含义。在描述中使用的术语仅出于描述具体实施方式的目的,并且其不意欲限制本发明。
以下术语用于描述本发明。在其中本文未具体定义术语的情况下,在术语用于描述本发明的背景中应用该术语的常规技术人员为该术语提供了本领域承认的含义。
本文所用术语“泛素连接酶(Ubiquitin Ligase)”表示促进泛素向特定底物蛋白的转移,从而靶向所述底物蛋白用于降解的蛋白家族。举例来说,Von Hippel-Lindau E3泛素连接酶或CRBN E3泛素连接酶是这样的蛋白:其单独或与E2泛素-缀合酶组合导致泛素向靶标蛋白上的赖氨酸的连接,并随后靶向特定蛋白底物用于被蛋白酶体降解。因而,单独或与E2泛素缀合酶形成复合物的E3泛素连接酶负责泛素向靶标蛋白的转移。一般而言,所述泛素连接酶参与聚泛素化,从而使得第二泛素连接至第一泛素;第三泛素连接至第二泛素,以此类推。聚泛素化标记蛋白以用于被蛋白酶体降解。但是,存在一些限于单泛素化的泛素化事件,其中通过泛素连接酶向底物分子仅添加单个泛素。单泛素化的蛋白未被靶向蛋白酶体以进行降解,但是相反可以在它们的细胞位置或功能方面进行改变,例如,通过结合具有能够结合泛素的结构域的其它蛋白。使情况进一步复杂化的是,可以通过E3靶向泛素上不同的赖氨酸以形成链。最常见的赖氨酸是泛素链上的Lys48。这是用于制备被蛋白酶体识别的多聚泛素的赖氨酸。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如,“C1-C6烷基”中“C1-C6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如,“C1-C6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。
本文所用术语“烷氧基”指具有-O-烷基结构的基团,如-OCH3、-OCH2CH3、-OCH2CH2CH3、-O-CH2CH(CH3)2、-OCH2CH2CH2CH3、-O-CH(CH3)2等。
本文所用术语“杂环烷基”指饱和或部分不饱和的单环、双环或多环环状取代基,其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子,其余环原子为碳,双环或多环包括螺环、稠环和桥环。例如:吗啉基、哌啶基、四氢吡咯基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基、四氢噻吩基、 等,及其N-氧化物。杂环取代基的连接可通过碳原子或通过杂原子实现。
正如本领域技术人员所理解的,本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。本发明提供了一种具有式(Ⅰ)所示结构的化合物:
其中:
X不存在,或选自下组:-CH2-、-CF2-或-O-;
R1选自下组:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基;
R2选自:取代或未取代的C1-C6烷基;
Y选自:-CH2-,-C(=O)-;
L具有如下式所示的结构:-Z-(L1)m-;
其中,m为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30;
所述的Z选自下组:具有0-4个杂原子的3-12元环、-NH-、-O-、-C(O)-、-CONH-、-NHCO-、-S-、-CH2-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-;
L1选自下组:具有0-4个杂原子的3-12元环、-NH-、-O-、-C(O)-、-CONH-、-NHCO-、-S-、-CH2-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-;
且所述的L片段可以任选地包括一个或多个RL取代基,且所述的RL取代基选自下组:卤素、-OH、-CN、-CF3、-NH2、-COOH、氧原子(=O)、取代或未取代的C1-C6烷基或卤代烷基、取代或未取代的C1-C6烷氧基,或者2个RL基与它们所连接的原子共同形成含有0-4个杂原子的3-8元环;
其中,上述的取代指基团上的一个或多个H原子被选自下组的取代基替代:卤素,氘原子。
在本发明的优选实施方式中,所述的化合物选自下组:
药学上可接受的盐
本发明包括式Ⅰ化合物的游离形式,也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐,也包括所有式Ⅰ化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如,可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别,但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常,通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的,通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此,本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如,常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐,也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2一乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的,则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐,所述碱包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等,“Pharmaceutical Salts,”J.Pharm.Sci.’1977:66:1-19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
药物代谢物及前药
本发明所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本发明的权利要求中。
药物组合物及其用途
本发明还提供了一种药物组合物,它包含安全有效量范围内的活性成分,以及药学上可接受的载体或者辅料。由于本申请的活性成分式Ⅰ的化合物及其药学上可接受的盐对于AXL、FLT3等蛋白的异常表达有很好的抑制作用,因此所述的药物组合物能够用于治疗人或其它哺乳动物与AXL、FLT3等蛋白异常表达相关的肿瘤、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症等疾病。
本发明提供了一类蛋白激酶降解剂及其用途,具体地,本发明提供了一种具有式(Ⅰ)所示结构的化合物或者其药学上可接受的盐,或者其立体异构体或前药分子。所述的化合物能够靶向泛素化降解AXL、FLT3、AuroraA等蛋白,并广泛抑制非小细胞肺癌、胃肠间质瘤、肝癌、三阴性乳腺癌、白血病等肿瘤细胞的增殖,可以用于治疗AXL、FLT3、AuroraA等激酶异常表达相关的适应症及上述肿瘤。
在一个实施方案中,本申请的活性成分,或者含有该活性成分的药物组合物可以用于预防和/或治疗非小细胞肺癌、恶性黑色素瘤、前列腺癌、肾癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、宫颈癌、肺癌、喉癌、鼻咽癌、胰腺癌、多发性骨髓瘤、B淋巴瘤、白血病等肿瘤,或者用于防止肿瘤术后复发。
本发明所述的“活性成分”是指本发明所述的式I化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
本发明所述的“活性成分”和药物组合物可用作AXL、FLT3等蛋白降解剂,可用于制备预防和/或治疗肿瘤、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症等的药物。
“安全有效量”指的是:活性成分的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg活性成分/剂,更佳地,含有10-200mg活性成分/剂。较佳地,所述的“一剂”为一个药片。
“药学上可接受的载体或者辅料”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。
“相容性”在此指的是组合物中各组分能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。
药学上可以接受的载体或者辅料部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
在另一优选例中,本发明式I化合物可与大分子化合物或高分子通过非键合作用形成复合物。在另一优选例中,本发明式I化合物作为小分子还可通过化学键与大分子化合物或高分子相连接。所述大分子化合物可以是生物大分子如高聚糖、蛋白、核酸、多肽等。
本发明的活性成分或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中,活性成分与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:
(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;
(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;
(c)保湿剂,例如,甘油;
(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;
(e)缓溶剂,例如石蜡;
(f)吸收加速剂,例如,季胺化合物;
(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;
(h)吸附剂,例如,高岭土;和
(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他治疗药物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
联合用药
式Ⅰ化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时,原来药物的给药方式和剂量保持不变,而同时或随后服用式Ⅰ化合物。当式Ⅰ化合物与其它一种或几种药物同时服用时,优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式Ⅰ化合物与其它一种或几种已知药物。当式Ⅰ化合物与其它一种或几种药物进行药物联用时,式Ⅰ化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式Ⅰ化合物进行药物联用的药物或活性成分包括但不局限为:雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂,细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体、JAK抑制剂等。
在一个实施方案中,可以与式Ⅰ化合物进行药物联用的药物或活性成分包括但不局限为:阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
本发明的有益之处在于:提供了一种结构新颖的PROTAC化合物,该类化合物可以高效、高选择性地降解细胞中的AXL、FLT3等蛋白,可以有效抑制多种肿瘤细胞的生长,可用于制备抗肿瘤药物。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
以下实施例中的原料可以从商业途径获得,或者通过本领域已知的方法制备,或根据本文所述方法制备。
化合物的结构通过核磁共振(1H-NMR)和/或质谱(MS)来确定。NMR测定是用BrukerAV-400型核磁共振仪,测定溶剂为氘代氯仿(CDCl3)或氘代二甲亚砜(DMSO-D6),TMS为内标。MS的测定用LCQAD-40000型质谱仪。柱层析采用200-300目硅胶(青岛海洋化工厂生产)。
实施例1:N-(4-((7-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)-2-氧乙基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-1)
步骤1:制备2-(1-(((4-乙基苯基)氨基)亚乙基)丙二酸二乙酯(2)
对乙基苯胺(2.42g,20mmol),乙酰基丙二酸二甲酯(2.02g,10mmol)溶于50mL正戊烷,加入催化量对甲基苯磺酸(20mg),回流反应过夜。降至室温,加少量饱和NaHCO3,用EA萃取两次,合并有机相,用饱和食盐水洗涤一遍,无水Na2SO4干燥,过滤旋干,柱层析得固体2.68g(87.8%)。1H NMR(400MHz,d6-DMSO)δ10.98(s,1H),7.23(d,J=8.0Hz,2H),7.14(d,J=8.0Hz,2H),4.10(m,4H),2.63-2.58(q,J=8.0Hz,2H),2.00(s,3H),1.21-1.16(m,9H)。MS(ESI),m/z:306[M+H]+。
步骤2:制备6-乙基-2-甲基-4-氧代-1,4-二氢喹啉-3-羧酸乙酯(3)
2-(1-((4-乙基苯基)氨基)亚乙基)丙二酸二乙酯(2)(2.5g,8.2mmol)溶于25mL二苯醚,搅拌下加热至200℃反应2小时。降至室温,有固体析出,过滤,用PE洗涤,抽干得白色固体2g(94.3%)。1H NMR(400MHz,d6-DMSO)δ11.78(s,1H),7.86(s,1H),7.53(d,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),4.23(q,J=8.0Hz,2H),2.73-2.68(q,J=8.0Hz,2H),2.37(s,3H),1.26(t,J=8.0Hz,3H),1.21(t,J=8.0Hz,3H)。MS(ESI),m/z:260[M+H]+。
步骤3:制备6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酸乙酯(4)
6-乙基-2-甲基-4-氧-1,4-二氢喹啉-3羧酸乙酯(3)(2g,7.7mmol),K2CO3(3.18g,23.1mmol)溶于50mL DMF,搅拌下加入MeI(0.72mL,11.55mmol),50℃反应过夜。降至室温,加水淬灭,有固体析出,用水洗多次,固体用DCM多次萃取,合并有机相旋干,柱层析得白色固体1.52g(72.4%)。1H NMR(400MHz,CDCl3)δ8.23(s,1H),7.46(d,J=8.0Hz,1H),7.37(d,J=8.0Hz,1H),4.40(q,J=8.0Hz,2H),3.72(s,3H),2.76-2.71(q,J=8.0Hz,2H),2.48(s,3H),1.38(t,J=8.0Hz,3H),1.26(t,J=8.0Hz,3H)。MS(ESI),m/z:274[M+H]+。
步骤4:制备6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酸(5)
6-乙基-1,2-二甲基-4-氧-1,4-二氢喹啉-3-羧酸乙酯(4)(1.5g,5.5mmol),NaOH(880mg,22mmol)溶于30mL乙醇和15mL水中,回流反应过夜。降至室温,旋干大部分有机溶剂,加水,在冰浴下用稀HCl调节PH至7-8,有固体析出,过滤,抽干得白色固体1.25g(93.3%)。1H NMR(400MHz,d6-DMSO)δ8.11(s,1H),7.88(d,J=8.0Hz,1H),7.69(d,J=8.0Hz,1H),3.87(s,3H),2.87(s,3H),2.80-2.74(q,J=8.0Hz,2H),2.48(s,3H),1.24(t,J=8.0Hz,3H)。MS(ESI),m/z:246[M+H]+。
步骤5:制备4-(((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯胺(7)
向反应瓶中加入7-卞氧基-4-氯-6-甲氧基喹唑啉(6)(4.5g,15mmol)、4-氨基-2-氟苯酚(2.3g,18mmol)、叔丁醇钾(2.4g,21mmol)、DMF(250mL),加热至80℃反应2小时,停止反应,减压去除溶剂后,干法过柱,得到4-((7-(卞氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯胺3.6g(62%)。1H NMR(400MHz,d6-DMSO)δ8.53(s,1H),7.55(s,1H),7.52(m,2H),7.49(s,1H),7.44(t,J=7.2Hz,2H),7.37(t,J=7.2Hz,1H),7.04(t,J=8.8Hz,1H),6.50(dd,J1=2.4Hz,J2=13.2Hz,1H),6.42(dd,J1=2.4Hz,J2=8.8Hz,1H),5.39(s,2H),5.35(s,2H),3.97(s,3H)。MS(ESI),m/z:391[M+H]+。
步骤6:制备6-乙基-N-(3-氟-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(8)
向反应瓶中加入4-(((7-(苄氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯胺(7)(3.6g,9.19mmol)、6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酸(5)(2.25g,9.19mmol)、HATU(5.24g,13.8mmol)、DIPEA(3.56g,27.57mmol)、DMF(200mL),室温反应2小时,停止反应,减压除去溶剂后,干法过柱得到中间体,将中间体溶于甲醇中,加入Pd/C,在氢气环境下室温搅拌过夜,停止反应,减压出去溶剂后,干法过柱,得到6-乙基-N-(3-氟-4-((7-羟基-6-甲氧基喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺4.2g(87%)。1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.48(s,1H),8.58(s,1H),8.09(d,J=2.2Hz,1H),7.96(dd,J=12.9,2.4Hz,1H),7.83(d,J=8.9Hz,1H),7.67(dd,J=8.9,2.3Hz,1H),7.63(s,1H),7.51(dd,J=8.9,2.3Hz,1H),7.48-7.41(m,2H),4.02(s,3H),3.84(s,3H),2.82-2.72(m,2H),2.65(s,3H),1.25(t,J=7.5Hz,3H).MS(ESI),m/z:528[M+H]+
步骤7:制备2-溴-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚啉-4-基)乙酰胺(10a)
在烧瓶中,将溴乙酸(300mg,1.53mmol)溶于无水DCM(10mL)中。将反应冷却至0℃,然后逐滴加入草酰氯(410mL,4.61mmol)。加入催化量的DMF(10μL),并将反应搅拌3小时,真空蒸发溶剂并保持在氩气下。在另一个装有回流冷凝器的圆底烧瓶中,加入4-氨基-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮(334mg,1.22mmol),然后加入无水THF(5ml)。将溴乙酰氯溶解在THF中,并加入到反应烧瓶中,并回流过夜。在真空下蒸发溶剂,并将粗混合物溶解在乙酸乙酯中,并用饱和NaHCO3和盐水洗涤,MgSO4干燥。蒸发溶剂,并将粗混合物进行柱色谱分离,得到黄色固体状的2-溴-N-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚基-4-基)乙酰胺430mg(78%)。1H NMR(400MHz,DMSO-d6):δ11.15(s,1H),10.27(s,1H),8.47(d,J=6.0Hz,1H),7.88(t,J=12.0Hz,1H),7.69(d,J=6.0Hz,1H),5.17(dd,J=13.3Hz,1H),4.34(s,2H),2.90(m,1H),2.55(m,2H),2.08(m,1H).MS(ESI),m/z:392.99[M+H]+。
步骤8:制备N-(4-((7-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)-2-氧乙基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-1)
在圆底烧瓶中,将化合物8(105mg,0.2mmol,1.0equiv)溶解在DMF(10mL)中。将KI(4mg,0.02mmol,0.1equiv)和KHCO 3(60mg,0.6mmol,3equiv)加入溶液中,然后加入化合物11a(95mg,0.24mmol,1.2equiv)。将所得混合物在60℃下搅拌12h。用EtOAc和饱和盐水处理后,将合并的有机层经Na2SO4干燥。过滤并蒸发后,将残余物通过快速柱色谱法用DCM/MeOH纯化,得到白色固体产物67mg(40%)。1H NMR(600MHz,DMSO)δ11.19(s,1H),11.03(s,1H),10.47(s,1H),8.76(d,J=8.3Hz,1H),8.58(s,1H),8.10(s,1H),7.96(d,J=12.8Hz,1H),7.89(t,J=7.8Hz,1H),7.84(d,J=8.8Hz,1H),7.67(dd,J=9.6,7.0Hz,3H),7.55(s,1H),7.52(d,J=9.6Hz,1H),7.46(t,J=8.7Hz,1H),5.20(dd,J=12.9,5.4Hz,1H),5.12(s,2H),4.09(s,3H),3.85(s,3H),2.94-2.91(m,1H),2.80-2.75(m,2H),2.66(s,3H),2.60-2.55(m,1H),2.13(d,J=5.8Hz,1H),1.91(s,1H),1.25(d,J=7.6Hz,3H).13C NMR(151MHz,DMSO)δ173.95,173.21,170.34,167.36,167.16,166.22,164.64,154.90,153.16,152.71,152.26,150.77,149.03,144.71,140.00,139.70,138.97,134.82(d,J=13.0Hz,1C),133.36(d,J=13.8Hz,1C),126.28,125.98,125.26,124.58,124.16,119.22,117.58,115.97,113.74,110.17,108.57,108.00,107.84,101.61,68.12,56.70,49.50,35.67,31.42,27.94,23.54,22.52,19.50,15.98,13.94.HRMS(ESI)for C44H36FN7O10[M+H]+,calcd:842.2580;found,842.2565.HPLC purity=97.14%,Rt 6.03min.
实施例2:N-(4-((7-((6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-6-氧己基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-2)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.02(d,J=7.3Hz,2H),9.80(s,1H),8.56(s,1H),8.09(d,J=2.2Hz,1H),7.96(dd,J=12.9,2.3Hz,1H),7.86-7.78(m,2H),7.67(dd,J=8.9,2.3Hz,1H),7.59(s,1H),7.51(d,J=1.7Hz,3H),7.48-7.40(m,2H),5.15(dd,J=13.3,5.1Hz,1H),4.46-4.31(m,2H),4.24(t,J=6.5Hz,2H),3.98(s,3H),3.84(s,3H),2.91(ddd,J=17.7,13.4,5.4Hz,1H),2.78(q,J=7.6Hz,2H),2.65(s,3H),2.60(d,J=17.5Hz,1H),2.43(t,J=7.4Hz,2H),2.35(dd,J=13.1,4.5Hz,1H),2.02(dd,J=12.0,6.5Hz,1H),1.88(t,J=7.4Hz,2H),1.79-1.67(m,2H),1.60-1.49(m,2H),1.25(t,J=7.5Hz,3H).13C NMR(151MHz,DMSO)δ173.93,173.28,171.77,171.51,168.30,166.19,164.55,155.75,154.79,153.17,152.55,152.23,150.84,149.43,139.98,139.69,138.88(d,J=9.9Hz,1C),134.85(d,J=12.9Hz,1C),134.27,134.14,133.13,129.06,126.27,125.69,124.83,124.14,119.43,119.22,117.57,115.94,109.47,107.98,107.81(d,J=4.9Hz,1C),101.09,69.16,56.58,52.03,46.97,36.23,35.66,31.67,28.62,27.94,25.66,25.31,23.11,19.50,15.98.HRMS(ESI)for C48H46FN7O9[M+H]+,calcd:884.3414;found,884.3401.HPLC purity=96.57%,Rt 5.41min.
实施例3:N-(4-((7-((6-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)-6-氧己基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-3)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.99(s,1H),10.31(s,1H),8.55(s,1H),8.33(d,J=8.3Hz,1H),8.09(d,J=2.2Hz,1H),7.97(dd,J=13.0,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.68(dd,J=8.9,2.3Hz,1H),7.62-7.54(m,2H),7.53-7.39(m,3H),7.31-7.23(m,1H),5.09(dd,J=13.2,5.2Hz,1H),4.47(d,J=17.7Hz,1H),4.36(d,J=17.7Hz,1H),4.22(t,J=6.5Hz,2H),3.98(s,3H),3.84(s,3H),2.89(ddd,J=17.2,13.6,5.5Hz,1H),2.77(q,J=7.6Hz,2H),2.64(s,4H),2.49-2.34(m,3H),2.06-1.99(m,1H),1.88(t,J=7.4Hz,2H),1.76(t,J=7.6Hz,2H),1.56(d,J=7.5Hz,2H),1.25(s,3H).13CNMR(151MHz,DMSO)δ173.92,173.24,171.72,171.22,169.68,166.19,164.53,155.76,154.79,153.18,152.52,152.24,150.84,149.42,143.08,139.98,138.87(d,J=9.9Hz,1C),137.54,134.85(d,J=12.8Hz,1C),133.62,133.39,126.27,124.82,124.15,119.21,118.07,117.54(d,J=8.3Hz,1C),117.24,115.92,109.46,107.88(d,J=28.6Hz,1C),107.72-107.51(m,1C),101.05,69.11,56.55,52.10,47.98,37.44,35.66,31.64,28.54,27.94,25.53,25.00,22.81,19.50,15.98,13.95.HRMS(ESI)for C48H46FN7O9[M+H]+,calcd:884.3414;found,884.3384.HPLC purity=97.32%,Rt 6.59min.
实施例4:N-(4-((7-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)-2-氧乙基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-4)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),11.03(s,1H),10.99(s,1H),8.57(s,1H),8.27(d,J=1.8Hz,1H),8.08(d,J=2.3Hz,1H),8.01-7.91(m,3H),7.83(d,J=8.9Hz,1H),7.68(d,J=9.0Hz,2H),7.54-7.41(m,3H),5.18-5.10(m,3H),4.05(s,3H),3.84(s,3H),2.90(ddd,J=17.0,13.8,5.4Hz,1H),2.77(q,J=7.6Hz,2H),2.66-2.53(m,5H),2.11-2.02(m,1H),1.24(d,J=7.5Hz,3H).13C NMR(151MHz,DMSO)δ173.95,173.21,170.34,167.36,167.16,166.22,164.64,154.90,153.16,152.71,152.26,150.77,149.03,144.71,140.00,139.70,138.97,134.82(d,J=13.0Hz,1C),133.36(d,J=13.8Hz,1C),126.28,125.98,125.26,124.58,124.16,119.22,117.58,115.97,113.74,110.17,108.57,108.00,107.84,101.61,68.12,56.70,49.50,35.67,31.42,27.94,23.54,22.52,19.50,15.98,13.94.HRMS(ESI)for C44H36FN7O10[M+H]+,calcd:842.2580;found,842.2574.HPLC purity=98.65%,Rt 11.70min.:
实施例5:N-(4-((7-((10-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)-10-氧代癸基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-5)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.99(s,1H),10.28(s,1H),8.56(s,1H),8.32(d,J=8.1Hz,1H),8.09(d,J=2.2Hz,1H),7.97(dd,J=13.0,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.67(dd,J=8.9,2.2Hz,1H),7.62-7.36(m,5H),7.25(d,J=7.3Hz,1H),5.09(dd,J=13.3,5.1Hz,1H),4.48(d,J=17.7Hz,1H),4.36(d,J=17.7Hz,1H),4.19(t,J=6.5Hz,2H),3.99(s,3H),3.84(s,3H),2.90(ddd,J=17.2,13.6,5.3Hz,1H),2.77(q,J=7.6Hz,2H),2.64(s,4H),2.42(dd,J=9.0,5.9Hz,3H),2.03(ddd,J=9.3,4.7,2.3Hz,1H),1.81(t,J=7.4Hz,2H),1.65(t,J=6.8Hz,2H),1.45(d,J=7.4Hz,2H),1.36-1.31(m,6H),1.25(t,J=7.5Hz,5H).13C NMR(151MHz,DMSO)δ173.93,173.24,171.79,171.22,169.69,166.18,164.54,155.78,154.80,153.18,152.53,152.26,150.85,149.44,143.07,139.98,139.69,138.87(d,J=9.8Hz,1C),137.55,134.85(d,J=13.0Hz,1C),133.62,133.38,130.10,126.27,124.82,124.15,119.20,118.04,117.51(d,J=17.0Hz,1C),117.18,115.91,109.45,107.90(d,J=23.4Hz,1C),107.75,101.06,69.27,56.57,52.09,47.98,37.55,35.66,31.64,29.42-29.31(m,1C),29.12(t,J=23.8Hz,1C),28.90-28.82(m,1C),28.79,27.94,25.92,25.29,22.82,19.50,15.98.HRMS(ESI)for C52H54FN7O9[M+H]+,calcd:940.4040;found,940.4019.HPLC purity=97.54%,Rt8.56min.
实施例6:N-(4-((7-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)氨基)-2-氧乙氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-6)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ10.99(s,2H),10.70(s,1H),8.56(s,1H),8.09(d,J=2.2Hz,1H),8.04-8.01(m,1H),7.97(dd,J=13.0,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.75-7.62(m,4H),7.54-7.39(m,3H),5.14-5.05(m,3H),4.45(d,J=17.4Hz,1H),4.31(d,J=17.4Hz,1H),4.05(s,3H),3.84(s,3H),3.22-3.10(m,2H),2.92(ddd,J=16.9,13.5,5.3Hz,1H),2.77(q,J=7.6Hz,2H),2.64(s,4H),2.38(qd,J=13.0,4.4Hz,1H),1.99(dd,J=10.1,4.6Hz,1H),1.57(dd,J=10.6,6.3Hz,2H),0.94(t,J=7.3Hz,3H).13C NMR(151MHz,DMSO)δ173.88,173.35,171.54,168.19,166.51,164.60,154.96,153.13,152.68,152.10,150.74,149.01,143.86,142.06,139.96,138.96,134.78(d,J=12.9Hz,1C),133.40,127.30,126.24,124.82,124.19(d,J=22.5Hz,1C),124.09-123.93(m,1C),119.51,117.58,115.93,114.06,110.06,108.41,107.95,107.79,101.51,68.13,57.98,56.67,52.02,47.64,35.66,31.68,27.94,23.52,19.68,16.00,13.96.HRMS(ESI)for C44H38FN7O9[M+H]+,calcd:828.2788;found,828.2789.HPLC purity=98.74%,Rt 9.69min.
实施例7:N-(4-((7-((8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-8-氧辛基)氧基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-7)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),11.02(d,J=3.8Hz,1H),9.70(s,1H),8.55(s,1H),8.48(d,J=8.4Hz,1H),8.13-8.04(m,1H),8.00-7.91(m,1H),7.83(dd,J=9.1,5.3Hz,2H),7.67(dd,J=8.7,2.4Hz,1H),7.63-7.54(m,2H),7.54-7.48(m,1H),7.48-7.34(m,2H),5.15(dd,J=12.9,5.2Hz,1H),4.20(t,J=6.6Hz,2H),3.99(s,3H),3.83(d,J=2.6Hz,3H),2.90(t,J=14.7Hz,1H),2.77(q,J=7.6Hz,2H),2.65(s,3H),2.57(d,J=10.4Hz,2H),2.47(s,1H),2.07(d,J=12.5Hz,1H),1.89-1.77(m,2H),1.70-1.62(m,2H),1.48(s,2H),1.41(s,4H),1.25(t,J=7.5Hz,3H).13C NMR(151MHz,DMSO)δ173.90,173.22,172.51,170.25,168.16,167.13,166.20,164.52,155.75,154.79,153.17,152.53,152.16,150.81,149.41,139.97,139.66,138.87(d,J=10.0Hz,1C),137.01,136.55,134.82(d,J=12.9Hz,1C),133.39,131.89,126.70,126.24,124.83,124.12,119.27,118.72,117.57,117.39,115.92,109.42,107.95,107.76(d,J=13.1Hz,1C),101.02,69.24,56.56,55.38,49.38,36.96,35.65,31.40,29.05-28.60(m,1C),27.94,25.83,25.20,22.45,19.51,15.99.HRMS(ESI)for C50H48FN7O10[M+H]+,calcd:926.3508;found,926.3513.HPLC purity=96.72%,Rt 4.64min.
实施例8:N-(4-((7-((8-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)-8-氧辛基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-8)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.99(s,1H),10.29(s,1H),8.56(s,1H),8.33(d,J=8.3Hz,1H),8.08(d,J=2.2Hz,1H),7.97(dd,J=12.9,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.67(dd,J=8.9,2.2Hz,1H),7.60-7.53(m,2H),7.53-7.37(m,3H),7.25(d,J=7.6Hz,1H),5.09(dd,J=13.2,5.1Hz,1H),4.48(d,J=17.7Hz,1H),4.36(d,J=17.7Hz,1H),4.20(t,J=6.5Hz,2H),3.99(s,3H),3.84(s,3H),2.90(ddd,J=16.7,13.5,5.4Hz,1H),2.77(q,J=7.6Hz,2H),2.64(s,4H),2.43(dt,J=10.1,6.3Hz,3H),2.03(ddd,J=7.5,5.5,2.4Hz,1H),1.90-1.77(m,2H),1.67(t,J=7.1Hz,2H),1.52-1.36(m,6H),1.25(t,J=7.5Hz,3H).13C NMR(151MHz,DMSO)δ173.93,173.24,171.81,171.23,169.69,166.18,164.54,155.78,154.80,153.18,152.53,152.26,150.85,149.43,143.08,139.98,139.68,138.87(d,J=9.9Hz,1C),137.55,134.85(d,J=12.9Hz,1C),133.63,133.38,126.27,124.83,124.15,119.19,118.05,117.52(d,J=14.7Hz,1C),117.19,115.92,109.45,107.98,107.79(d,J=11.2Hz,1C),101.05,69.25,56.57,52.09,47.98,37.50,35.66,31.64,28.91,28.85,28.74,27.94,25.81,25.24,22.82,19.50,15.97.HRMS(ESI)forC50H50FN7O9[M+H]+,calcd:912.3727;found,912.3729.HPLC purity=95.74%,Rt6.59min.
实施例9:N-(4-((7-((6-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)氨基)-6-氧己基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-9)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.00(d,J=12.3Hz,2H),10.18(s,1H),8.56(s,1H),8.13(d,J=1.9Hz,1H),8.09(d,J=2.2Hz,1H),7.97(dd,J=13.0,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.70(ddd,J=16.2,8.5,2.2Hz,2H),7.58(s,1H),7.54-7.44(m,3H),7.42(d,J=3.6Hz,1H),5.11(dd,J=13.3,5.1Hz,1H),4.40(d,J=17.3Hz,1H),4.31-4.20(m,3H),3.99(s,3H),3.84(s,3H),2.98-2.85(m,1H),2.78(q,J=7.6Hz,2H),2.64(s,4H),2.44-2.36(m,3H),2.03-1.98(m,1H),1.88(t,J=7.4Hz,2H),1.78-1.69(m,2H),1.58-1.51(m,2H),1.25(s,3H).13C NMR(151MHz,DMSO)δ173.92,173.30,171.91,171.46,168.51,166.19,164.54,155.76,154.80,153.18,152.54,152.23,150.85,149.44,139.98,139.71(d,J=3.6Hz,1C),138.91,136.77,134.85(d,J=12.9Hz,1C),133.39,132.58,126.28,124.83,124.16(d,J=2.5Hz,1C),123.10,119.22,117.57,115.93,113.48,109.47,107.98,107.81,101.07,69.17,56.57,52.18,47.44,36.86,35.67,31.69,28.65,27.94,25.69,25.29,22.96,19.50.HRMS(ESI)for C48H46FN7O9[M+H]+,calcd:884.3414;found,884.3410.HPLC purity=96.39%,Rt 9.39min.
实施例10:N-(4-((7-((8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)氨基)-8-氧辛基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-10)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.97(s,1H),10.23(s,1H),8.56(s,1H),8.09(d,J=2.2Hz,1H),8.02-7.93(m,2H),7.83(d,J=8.9Hz,1H),7.70-7.63(m,2H),7.59(d,J=7.7Hz,2H),7.50(d,J=8.3Hz,1H),7.47-7.39(m,2H),5.08(dd,J=13.2,5.1Hz,1H),4.42(d,J=17.3Hz,1H),4.28(d,J=17.2Hz,1H),4.21(t,J=6.5Hz,2H),3.99(s,3H),3.84(s,3H),2.97-2.85(m,1H),2.77(q,J=7.6Hz,2H),2.65(s,3H),2.60(d,J=17.9Hz,1H),2.38(t,J=7.3Hz,3H),2.02-1.95(m,1H),1.83(t,J=7.2Hz,2H),1.64(t,J=7.2Hz,2H),1.48(s,2H),1.39(s,4H),1.24(d,J=7.4Hz,3H).13C NMR(151MHz,DMSO)δ173.88,173.36,172.28,171.57,168.32,166.21,164.53,155.76,154.78,153.16,152.54,152.11,150.82,149.42,143.74,143.02,139.96,139.68,138.91,134.82(d,J=13.0Hz,1C),133.40,126.54,126.25,124.84,124.10(d,J=9.5Hz,1C),119.42-119.37(m,1C),119.21(d,J=34.1Hz,1C),117.58,115.91,113.54,109.43,108.23-107.96(m,1C),107.96-107.63(m,1C),101.04,69.23,56.57,51.99,47.59,36.96,35.66,31.69,28.99(d,J=15.9Hz,1C),28.76,27.94,25.85,25.44,23.00,19.51,16.01.HRMS(ESI)forC50H50FN7O9[M+H]+,calcd:912.3727;found,912.3732.HPLC purity=96.09%,Rt7.06min.
实施例11:N-(4-((7-((10-((2-(2,6-二氧代哌啶-3-基)1-氧代异吲哚啉-4-基)氨基)-10-氧十二烷基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-11)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.99(s,1H),9.80(s,1H),8.56(s,1H),8.08(d,J=2.2Hz,1H),7.97(dd,J=12.9,2.3Hz,1H),7.86-7.79(m,2H),7.67(dd,J=8.9,2.3Hz,1H),7.59(s,1H),7.54-7.48(m,3H),7.46(d,J=8.6Hz,1H),7.40(s,1H),5.16(dd,J=13.3,5.1Hz,1H),4.44-4.30(m,2H),4.20(t,J=6.6Hz,2H),4.00(s,3H),3.84(s,3H),3.01-2.87(m,1H),2.77(q,J=7.6Hz,2H),2.64(s,4H),2.37(dd,J=8.8,6.1Hz,3H),2.08-1.97(m,1H),1.87-1.78(m,2H),1.63(d,J=8.4Hz,2H),1.47(s,2H),1.34(s,6H),1.24(d,J=7.5Hz,5H).13C NMR(151MHz,DMSO)δ173.93,173.29,171.84,171.51,168.29,166.19,164.54,155.78,154.80,153.18,152.55,152.25,150.85,149.44,139.98,139.69,138.88(d,J=9.8Hz,1C),134.85(d,J=13.0Hz,1C),134.23(d,J=17.8Hz,1C),133.39,133.13,129.06,126.27,125.71,124.82,124.15,119.42,119.20,117.57,115.94,109.46,107.91(d,J=23.3Hz,1C),107.76,101.08,69.27,56.58,52.02,46.96,36.30,35.67,31.68,29.37,29.22,29.18,29.14,28.81,27.94,25.96,25.58,23.13,19.50,15.98.HRMS(ESI)for C52H54FN7O9[M+H]+,calcd:940.4040;found,940.4003.HPLC purity=98.60%,Rt5.95min.
实施例12:N-(4-((7-((8-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)氨基)-8-氧辛基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-12)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),10.99(s,1H),10.15(s,1H),8.56(s,1H),8.12(d,J=2.0Hz,1H),8.08(d,J=2.2Hz,1H),7.97(dd,J=13.0,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.69(ddd,J=17.0,8.5,2.1Hz,2H),7.58(s,1H),7.54-7.48(m,2H),7.45(t,J=8.7Hz,1H),7.40(s,1H),5.11(dd,J=13.3,5.1Hz,1H),4.40(d,J=17.1Hz,1H),4.27(d,J=17.1Hz,1H),4.21(t,J=6.5Hz,2H),4.00(s,3H),3.84(s,3H),2.98-2.84(m,1H),2.77(q,J=7.6Hz,2H),2.64(s,4H),2.38(dt,J=14.9,6.1Hz,3H),2.01(dt,J=7.2,2.2Hz,1H),1.83(t,J=7.2Hz,2H),1.65(t,J=7.2Hz,2H),1.48(d,J=8.1Hz,2H),1.44-1.33(m,4H),1.25(t,J=7.6Hz,3H).13C NMR(151MHz,DMSO)δ173.93,173.30,172.00,171.46,168.51,166.19,164.54,155.78,154.80,153.18,152.54,152.25,150.86,149.44,139.98,139.71(d,J=7.3Hz,1C),138.87(d,J=9.8Hz,1C),136.74,134.85(d,J=13.0Hz,1C),133.39,132.58,126.27,124.83,124.16(d,J=2.6Hz,1C),123.08,119.21,117.57,115.92,113.45,109.46,107.98,107.79(d,J=9.6Hz,1C),101.07,69.25,56.58,52.17,47.43,36.90,35.66,31.69,29.08,28.95,28.77,27.94,25.86,25.48,22.96,19.50,15.98.HRMS(ESI)for C50H50FN7O9[M+H]+,calcd:912.3727;found,912.3736.HPLCpurity=96.81%,Rt 8.99min.
实施例13:N-(4-((7-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氨基)-2-氧乙氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-13)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),10.29(s,1H),8.55(s,1H),8.09(d,J=2.2Hz,1H),7.97(dd,J=12.9,2.3Hz,1H),7.83(d,J=8.6Hz,2H),7.70-7.64(m,2H),7.61-7.49(m,3H),7.49-7.39(m,2H),5.18(dd,J=13.3,5.1Hz,1H),5.10(s,2H),4.45-4.30(m,2H),4.05(s,3H),3.84(s,3H),3.02-2.88(m,1H),2.78(q,J=7.5Hz,2H),2.64(s,4H),2.32-2.20(m,1H),2.09-1.95(m,1H),1.25(s,3H).13C NMR(151MHz,DMSO)δ173.95,173.27,171.46,168.20,166.28(d,J=16.1Hz,1C),164.64,154.92,153.16,152.71,152.26,150.79,149.01,140.00,139.71,138.98,134.82(d,J=13.2Hz,1C),133.70-133.22(m,1C),129.37,126.29,126.14,124.83,124.16,120.25,119.23,117.59,115.97,110.11,108.47,108.24-108.07(m,1C),107.92(d,J=23.2Hz,1C),101.57,67.87,56.69,55.37,51.99,46.78,35.67,31.68,27.95,23.14,19.51,15.98.HRMS(ESI)for C44H38FN7O9[M+H]+,calcd:828.2788;found,828.2804.HPLC purity=95.05%,Rt 9.26min.
实施例14:N-(4-((7-(2-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)氨基)-2-氧乙氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-14)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.01(s,2H),10.58(s,1H),8.56(s,1H),8.10(d,J=10.4Hz,2H),7.96(d,J=12.7Hz,1H),7.80(dd,J=16.4,8.5Hz,2H),7.67(d,J=8.5Hz,2H),7.59(d,J=8.2Hz,1H),7.55-7.37(m,3H),5.18-5.00(m,3H),4.43(d,J=17.2Hz,1H),4.30(d,J=17.2Hz,1H),4.05(s,3H),3.84(s,3H),2.96-2.86(m,1H),2.77(q,J=7.5Hz,2H),2.65(s,4H),2.40(d,J=13.0Hz,1H),2.08-1.96(m,1H),0.93(t,J=7.4Hz,3H).13CNMR(151MHz,DMSO)δ173.88,171.46,168.33,166.26(d,J=12.9Hz,1C),164.60,154.98,154.76,153.14,152.68,150.75,149.02,139.96,138.95,138.79,137.56,134.79(d,J=13.0Hz,1C),133.40,132.72,126.25,124.83,124.49,123.48,119.33,117.58,115.92,113.83,110.07,108.44,107.79,101.51,68.21,57.98,56.67,52.17,49.06,47.49,35.66,31.68,27.94,23.52,22.93,19.68,16.01,13.96.HRMS(ESI)for C44H38FN7O9[M+H]+,calcd:828.2788;found,828.2772.HPLC purity=95.18%,Rt9.93min.
实施例15:N-(4-((7-((5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-5-氧戊基)氧基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-15)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),10.99(s,1H),9.76(s,1H),8.56(s,1H),8.46(d,J=8.4Hz,1H),8.08(d,J=2.2Hz,1H),7.97(dd,J=12.9,2.3Hz,1H),7.86-7.79(m,2H),7.67(dd,J=8.9,2.3Hz,1H),7.64-7.59(m,1H),7.58(s,1H),7.54-7.40(m,3H),5.16(dd,J=12.8,5.4Hz,1H),4.27(t,J=6.1Hz,2H),3.99(s,3H),3.84(s,3H),2.90(ddd,J=16.7,13.8,5.5Hz,1H),2.77(q,J=7.6Hz,2H),2.67-2.54(m,7H),2.13-2.03(m,1H),1.96-1.89(m,2H),1.88-1.81(m,2H),1.25(d,J=4.0Hz,3H).13C NMR(151MHz,DMSO)δ173.93,173.19,172.36,170.22,168.15,167.13,166.20,164.54,155.70,154.79,153.17,152.25,150.84,149.41,139.99,139.69,138.87(d,J=9.9Hz,1C),136.97,134.85(d,J=12.9Hz,1C),133.40,131.90,126.77,126.27,124.82,124.15,119.21,118.76,117.53(d,J=13.5Hz,1C),115.93,109.49,107.99,107.83,101.07,68.92,56.60,49.41,36.44,35.67,31.62,31.40,30.31,28.19,27.94,22.47,21.90,19.50,15.98.HRMS(ESI)forC47H42FN7O10[M+H]+,calcd:884.3050;found,884.3025.HPLC purity=98.21%,Rt5.36min.
实施例16:N-(4-((7-((5-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)氨基)-5-氧戊基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-16)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.01(d,J=11.5Hz,2H),10.21(s,1H),8.57(s,1H),8.13(d,J=2.0Hz,1H),8.08(d,J=2.2Hz,1H),7.97(dd,J=12.9,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.73(dd,J=8.2,2.0Hz,1H),7.67(dd,J=8.8,2.2Hz,1H),7.60(s,1H),7.55-7.41(m,4H),5.11(dd,J=13.3,5.1Hz,1H),4.40(d,J=17.1Hz,1H),4.31-4.22(m,3H),4.00(s,3H),3.84(s,3H),2.98-2.86(m,1H),2.77(q,J=7.6Hz,2H),2.64(s,4H),2.49-2.33(m,3H),2.07-1.96(m,1H),1.94-1.80(m,4H),1.25(s,3H).13C NMR(151MHz,DMSO)δ173.93,173.31,171.79,171.46,168.50,166.19,164.55,155.73,154.80,153.18,152.56,152.24,150.85,149.43,139.98,139.69,138.88(d,J=9.7Hz,1C),136.80,134.85(d,J=12.9Hz,1C),133.39,132.59,130.10,126.27,124.83,124.17(d,J=6.3Hz,1C),123.12,119.21,117.57,115.94,113.50,109.50,107.90(d,J=24.4Hz,1C),107.80-107.67(m,1C),101.10,68.96,56.60,52.18,47.44,36.45,35.66,31.69,28.41,27.94,22.96,22.18,19.50,15.98.HRMS(ESI)for C47H44FN7O9[M+H]+,calcd:870.3257;found,870.3248.HPLCpurity=95.84%,Rt 6.69min.
实施例17:N-(4-((7-((10-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)-10-氧癸基)氧基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-17)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),11.01(s,1H),10.54(s,1H),8.55(s,1H),8.26(d,J=1.8Hz,1H),8.09(d,J=2.2Hz,1H),7.96(dd,J=12.9,2.3Hz,1H),7.87(ddd,J=20.8,11.3,8.5Hz,3H),7.67(dd,J=8.9,2.2Hz,1H),7.58(s,1H),7.50(dd,J=9.1,2.3Hz,1H),7.47-7.37(m,2H),5.12(dd,J=12.9,5.3Hz,1H),4.20(t,J=6.5Hz,2H),4.00(s,3H),3.84(s,3H),2.89(ddd,J=17.6,14.2,5.3Hz,1H),2.77(q,J=7.6Hz,2H),2.65(s,3H),2.64-2.53(m,2H),2.40(t,J=7.5Hz,2H),2.11-2.01(m,1H),1.82(t,J=7.3Hz,2H),1.63(s,2H),1.47(s,2H),1.33(s,6H),1.25(t,J=7.6Hz,5H).13C NMR(151MHz,DMSO)δ173.93,173.18,172.80,170.35,167.49,167.22,166.18,164.54,155.77,154.79,153.17,152.54,152.26,150.85,149.43,145.61,139.98,139.69,138.87(d,J=9.8Hz,1C),134.85(d,J=12.8Hz,1C),133.39,133.25,126.27,125.13(d,J=12.3Hz,1C),124.82,124.15,123.94,119.19,117.57,115.93,113.29,109.45,108.26-108.07(m,1C),108.07-107.61(m,1C),101.07,69.27,56.58,49.44,37.03,35.67,31.42,29.18(dd,J=22.1,15.6Hz,1C),28.80,27.94,25.94,25.29,22.53,19.50,15.98.HRMS(ESI)forC52H52FN7O10[M+H]+,calcd:954.3832;found,954.3830.HPLC purity=97.21%,Rt5.47min.
实施例18:N-(4-((7-((12-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-12-氧十二烷基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-18)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),11.02(s,1H),9.68(s,1H),8.56(s,1H),8.48(d,J=8.4Hz,1H),8.09(d,J=2.2Hz,1H),7.96(dd,J=12.9,2.3Hz,1H),7.86-7.78(m,2H),7.67(dd,J=8.9,2.3Hz,1H),7.62-7.56(m,2H),7.51(dd,J=8.9,2.3Hz,1H),7.44(t,J=8.7Hz,1H),7.39(s,1H),5.15(dd,J=12.8,5.4Hz,1H),4.20(t,J=6.5Hz,2H),3.99(s,3H),3.84(s,3H),2.90(ddd,J=16.7,13.7,5.4Hz,1H),2.82-2.73(m,2H),2.65(s,3H),2.63-2.52(m,2H),2.46(t,J=7.4Hz,2H),2.12-2.03(m,1H),1.81(t,J=7.3Hz,2H),1.67-1.57(m,2H),1.45(d,J=7.7Hz,2H),1.30-1.28(m,4H),1.27(s,3H),1.25(s,2H),1.23(s,2H).13C NMR(151MHz,DMSO)δ173.93,173.18,172.49,170.21,168.18,167.12,166.18,164.55,155.80,154.79,153.17,152.51,152.28,150.86,149.34,139.99,139.68,138.88(d,J=9.9Hz,1C),137.05,136.54,134.84(d,J=12.9Hz,1C),133.39,131.89,126.64,126.26,124.81,124.14,119.17,118.70,117.75-117.21(m,1C),115.92,109.45,108.00,107.91(d,J=23.2Hz,1C),107.68,101.07,69.27,56.58,49.40,37.02,35.67,31.41,29.60-29.21(m,1C),29.21-28.93(m,1C),28.88,28.79,27.94,25.94,25.24,22.46,19.50,15.97.HRMS(ESI)for C54H56FN7O10[M+H]+,calcd:982.4145;found,982.4123.HPLCpurity=99.07%,Rt 10.00min.
实施例19:N-(4-((7-((5-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)-5-氧戊基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-19)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.02(d,J=26.3Hz,2H),9.86(s,1H),8.57(s,1H),8.09(d,J=2.2Hz,1H),7.97(dd,J=12.9,2.3Hz,1H),7.86-7.81(m,2H),7.68(dd,J=8.8,2.2Hz,1H),7.60(s,1H),7.54-7.48(m,3H),7.48-7.42(m,2H),5.16(dd,J=13.3,5.1Hz,1H),4.39(d,J=8.5Hz,2H),4.27(t,J=6.1Hz,2H),4.00(s,3H),3.84(s,3H),2.99-2.87(m,1H),2.78(q,J=7.6Hz,2H),2.64(s,3H),2.63-2.56(m,1H),2.48(s,2H),2.35(qd,J=13.2,4.4Hz,1H),2.02(ddd,J=12.5,6.4,3.8Hz,1H),1.95-1.78(m,4H),1.24(d,J=7.4Hz,3H).13C NMR(151MHz,DMSO)δ173.92,173.25,171.67,171.23,169.64,166.19,164.53,155.70,154.80,153.18,152.52,152.23,150.85,149.42,143.08,139.97,139.70,138.88(d,J=10.2Hz,1C),137.50,134.85(d,J=12.9Hz,1C),133.58,133.39,126.28,124.83,124.15,119.22,118.08,117.55(d,J=7.1Hz,1C),117.27,115.92,109.49,107.91(d,J=20.2Hz,1C),107.71-107.59(m,1C),101.05,68.96,58.03,56.58,52.14,36.91,35.67,31.65,28.24,27.94,23.54,19.68,15.98,13.95.HRMS(ESI)for C47H44FN7O9[M+H]+,calcd:870.3257;found,870.3263.HPLC purity=96.42%,Rt7.13min.
实施例20:N-(4-((7-(2-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-4-基)氨基)-2-氧乙氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-20)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.05(s,2H),11.02(s,1H),8.57(s,1H),8.47(d,J=8.3Hz,1H),8.09(d,J=2.2Hz,1H),7.97(dd,J=12.9,2.3Hz,1H),7.82(d,J=8.9Hz,1H),7.70-7.57(m,3H),7.55-7.49(m,2H),7.47(d,J=8.6Hz,1H),7.30(d,J=7.6Hz,1H),5.08(q,J=5.2,3.9Hz,3H),4.49(d,J=17.6Hz,1H),4.37(d,J=17.6Hz,1H),4.08(s,3H),3.84(s,3H),2.93(ddd,J=18.3,9.7,3.7Hz,1H),2.77(q,J=7.5Hz,2H),2.65(s,4H),2.42(td,J=13.1,4.5Hz,1H),2.06(dd,J=14.8,9.0Hz,1H),1.25(s,3H).13C NMR(151MHz,DMSO)δ173.90,171.42,168.35,166.22(d,J=12.9Hz,1C),164.61,154.98,154.75,153.14,152.65,150.77,149.02,139.97,138.95,138.75,137.53,134.79(d,J=13.0Hz,1C),133.41,132.72,126.31,124.83,124.39,123.48,119.36,117.58,116.64,113.83,110.07,108.44,107.79,101.52,68.21,57.98,56.62,52.17,49.09,47.49,35.66,31.62,27.94,23.52,22.91,19.68,16.01,13.96.HRMS(ESI)for C44H38FN7O9[M+H]+,calcd:828.2788;found,828.2790.HPLC purity=97.88%,Rt 6.97min.
实施例21:N-(4-((7-((8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)-8-氧辛基)氧基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-21)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),11.01(s,1H),10.68(s,1H),8.55(s,1H),8.27(d,J=1.7Hz,1H),8.09(d,J=2.3Hz,1H),7.99-7.90(m,2H),7.87-7.80(m,2H),7.67(dd,J=8.7,2.3Hz,1H),7.58(s,1H),7.53-7.47(m,1H),7.45(d,J=8.7Hz,1H),7.41(d,J=7.6Hz,1H),5.12(dd,J=13.0,5.3Hz,1H),4.21(t,J=6.5Hz,2H),3.99(s,3H),3.84(s,3H),2.90(td,J=13.5,12.9,7.1Hz,1H),2.77(d,J=7.6Hz,2H),2.65(s,3H),2.58(td,J=14.6,4.4Hz,2H),2.43(t,J=7.4Hz,2H),2.32(s,1H),2.09-1.95(m,2H),1.83(t,J=7.2Hz,2H),1.68-1.62(m,2H),1.48(s,2H),1.41-1.38(m,2H),1.25(s,3H).13C NMR(151MHz,DMSO)δ173.93,173.20,172.86,170.36,167.50,167.24,166.20,164.54,155.78,154.80,153.18,152.54,152.23,150.85,149.44,145.67,139.98,139.69,138.88(d,J=10.0Hz,1C),134.85(d,J=12.8Hz,1C),133.32(d,J=23.0Hz,1C),130.11,126.27,125.11(d,J=11.2Hz,1C),124.83,124.15,123.97,119.23,117.57,115.94,113.32,109.46,108.18-108.03(m,1C),108.03-107.66(m,1C),101.07,69.25,56.58,49.45,36.99,35.67,31.43,28.96(d,J=12.8Hz,1C),28.76,27.95,25.83,25.25,22.55,19.51,15.98.HRMS(ESI)for C50H48FN7O10[M+H]+,calcd:926.3519;found,926.3525.HPLC purity=96.56%,Rt 5.28min.
实施例22:N-(4-((7-((10-((2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚啉-5-基)氨基)-10-氧代癸基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-22)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.00(d,J=9.9Hz,2H),10.14(s,1H),8.56(s,1H),8.10(dd,J=12.1,2.1Hz,2H),7.97(dd,J=13.0,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.69(ddd,J=15.8,8.6,2.1Hz,2H),7.59(s,1H),7.54-7.48(m,2H),7.47-7.38(m,2H),5.11(dd,J=13.3,5.1Hz,1H),4.40(d,J=17.1Hz,1H),4.27(d,J=17.0Hz,1H),4.20(t,J=6.5Hz,2H),4.00(s,3H),3.84(s,3H),2.91(ddd,J=17.2,13.6,5.4Hz,1H),2.77(q,J=7.6Hz,2H),2.64(s,3H),2.63-2.56(m,1H),2.46-2.37(m,1H),2.35(t,J=7.4Hz,2H),2.00(dp,J=10.5,3.2Hz,1H),1.82(t,J=7.4Hz,2H),1.63(t,J=7.0Hz,2H),1.51-1.42(m,2H),1.33(s,6H),1.24(d,J=7.5Hz,5H).13C NMR(151MHz,DMSO)δ173.93,173.30,172.00,171.46,168.51,166.19,164.54,155.78,154.80,153.18,152.54,152.25,150.86,149.44,139.98,139.71(d,J=7.3Hz,1C),138.87(d,J=9.8Hz,1C),136.73,134.85(d,J=13.0Hz,1C),133.39,132.57,126.27,124.83,124.16,123.08,119.20,117.57,115.92,113.45,109.45,108.07-107.62(m,1C),101.07,69.28,56.58,52.17,47.43,36.93,35.67,31.69,29.22(dd,J=19.5,12.3Hz),28.81,27.94,25.95,25.52,22.96,19.50,15.98.HRMS(ESI)for C52H54FN7O9[M+H]+,calcd:940.4040;found,940.4009.HPLC purity=98.33%,Rt11.07min.
实施例23:N-(4-((7-((5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-5-氧戊基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-23)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.02(d,J=7.0Hz,2H),9.84(s,1H),8.56(s,1H),8.09(d,J=2.3Hz,1H),7.96(dd,J=12.9,2.3Hz,1H),7.88-7.79(m,2H),7.67(dd,J=8.9,2.2Hz,1H),7.59(s,1H),7.48(ddd,J=25.2,10.2,5.9Hz,5H),5.15(dd,J=13.2,5.1Hz,1H),4.46-4.32(m,2H),4.27(t,J=6.2Hz,2H),4.00(s,3H),3.84(s,3H),2.99-2.86(m,1H),2.77(q,J=7.6Hz,2H),2.65(s,3H),2.58(s,1H),2.50-2.45(m,2H),2.41-2.27(m,1H),2.07-1.98(m,1H),1.96-1.78(m,4H),1.25(t,J=7.5Hz,3H).13C NMR(151MHz,DMSO)δ173.93,173.28,171.63,171.50,168.29,166.19,164.55,155.72,154.79,153.17,152.57,152.24,150.84,149.42,139.98,139.69,138.88(d,J=9.9Hz,1C),134.84(d,J=13.0Hz,1C),134.20(d,J=12.0Hz,1C),133.39,133.15,129.08,126.27,125.71,124.83,124.14,119.46,119.22,117.57,115.94,109.50,107.98,107.82,101.12,68.95,56.60,52.03,46.98,35.81,35.66,31.68,28.37,27.94,23.11,22.20,19.50,15.98.HRMS(ESI)forC50H43FN7O8[M+H]+,calcd:870.3246;found,870.3260.HPLC purity=97.86%,Rt 6.9min.
实施例24:N-(4-((7-((8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氨基)-8-氧辛基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-24)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.99(s,1H),9.81(s,1H),8.56(s,1H),8.09(d,J=2.2Hz,1H),8.00-7.94(m,1H),7.86-7.80(m,2H),7.67(dd,J=8.8,2.3Hz,1H),7.59(s,1H),7.54-7.39(m,5H),5.16(dd,J=13.3,5.1Hz,1H),4.44-4.30(m,2H),4.21(t,J=6.6Hz,2H),4.00(s,3H),3.84(s,3H),2.98-2.90(m,1H),2.77(q,J=7.6Hz,2H),2.64(s,4H),2.37(dt,J=13.6,6.2Hz,3H),2.02(dd,J=13.8,7.1Hz,1H),1.84(t,J=7.2Hz,2H),1.65(t,J=7.2Hz,2H),1.53-1.36(m,6H),1.24(d,J=7.4Hz,3H).13CNMR(151MHz,DMSO)δ173.93,173.29,171.84,171.51,168.29,166.19,164.54,162.75,155.77,154.80,153.18,152.54,152.24,150.84,149.43,139.98,139.69,138.88(d,J=9.8Hz,1C),134.85(d,J=12.8Hz,1C),134.22(d,J=17.6Hz,1C),133.39,133.13,129.06,126.27,125.70,124.83,124.15,119.42,119.21,117.57,115.92,109.46,107.90(d,J=23.3Hz,1C),107.76,101.08,69.25,56.58,52.02,46.97,36.26(d,J=4.6Hz,1C),35.66,31.68,29.01(d,J=22.7Hz,1C),28.77,27.94,25.87,25.52,23.12,19.50,15.98.HRMS(ESI)for C50H50FN7O9[M+H]+,calcd:912.3727;found,912.3714.HPLC purity=98.56%,Rt6.40min.
实施例25:N-(4-((7-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)-6-氧己基)氧基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-25)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),10.59(s,1H),8.55(s,1H),8.27(s,1H),8.09(s,1H),8.00-7.93(m,1H),7.93-7.80(m,3H),7.67(d,J=8.8Hz,1H),7.58(s,1H),7.51(d,J=8.6Hz,1H),7.47-7.39(m,2H),5.13(dd,J=13.0,5.3Hz,1H),4.23(s,2H),3.98(s,3H),3.84(s,3H),2.89(s,1H),2.77(q,J=7.5Hz,2H),2.65(s,3H),2.58(s,2H),2.45(d,J=7.6Hz,2H),2.05(d,J=13.0Hz,1H),1.88(t,J=7.3Hz,2H),1.74(t,J=7.6Hz,2H),1.54(t,J=7.7Hz,2H),1.24(d,J=7.2Hz,3H).13C NMR(151MHz,DMSO)δ173.93,173.19,172.73,170.35,167.49,167.22,166.19,164.54,155.74,154.79,153.17,152.54,152.24,150.84,149.43,145.59,139.98,139.69,138.87(d,J=9.9Hz,1C),134.85(d,J=13.0Hz,1C),133.39,133.25,126.27,125.14(d,J=15.6Hz,1C),124.82,124.15,123.96,119.21,117.57,115.92,113.32,109.47,107.98,107.80,101.08,69.14,56.57,49.45,36.97,35.66,31.42,28.60,27.94,25.62,25.04,22.53,19.50,15.98.HRMS(ESI)for C48H44FN7O10[M+H]+,calcd:898.3206;found,898.3188.HPLC purity=98.42%,Rt 5.50min.
实施例26:N-(4-((7-((12-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氨基)-12-氧十二烷基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-26)
合成方法如实施例1。
1H NMR(600MHz,DMSO)δ11.03(s,1H),10.57(s,1H),8.55(s,1H),8.26(s,1H),8.09(s,1H),7.96(d,J=12.8Hz,1H),7.92(d,J=8.1Hz,1H),7.84(dd,J=18.2,8.5Hz,2H),7.67(d,J=8.7Hz,1H),7.59(s,1H),7.51(d,J=8.8Hz,1H),7.43(t,J=8.8Hz,1H),7.39(s,1H),5.12(dd,J=12.8,5.3Hz,1H),4.20(t,J=6.3Hz,2H),4.00(s,3H),3.84(s,3H),3.18(s,1H),2.88(dd,J=21.8,9.1Hz,1H),2.79-2.75(m,2H),2.66(s,3H),2.60(d,J=17.7Hz,1H),2.40(t,J=7.3Hz,2H),2.07-2.02(m,1H),1.86-1.78(m,2H),1.65-1.59(m,2H),1.45(d,J=6.7Hz,2H),1.29(s,12H),1.25(s,3H).13C NMR(151MHz,DMSO)δ173.93,173.18,172.82,170.34,167.49,167.22,166.19,164.54,155.78,154.79,153.17,152.53,152.25,150.85,149.43,145.63,139.98,139.69,138.87(d,J=10.0Hz,1C),134.85(d,J=12.9Hz,1C),133.31(d,J=22.7Hz,1C),130.10,126.27,125.11(d,J=11.5Hz,1C),124.81,124.15,123.94,119.20,117.57,115.93,113.29,109.45,107.98,107.79(d,J=11.8Hz,1C),101.06,69.27,56.57,55.36,49.44,49.06,37.02,35.66,31.42,29.56-28.88(m,1C),28.80,27.94,25.95,25.28,22.53,19.50,15.98.HRMS(ESI)for C54H56FN7O10[M+H]+,calcd:982.4145;found,982.4158.HPLC purity=98.45%,Rt 8.09min.
实施例27:N-(4-((7-((10-((2-(2,6-二氧代哌啶-3-基)1-氧代异吲哚基-5-基)氨基)-10-氧十二烷基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-27)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.00(d,J=5.3Hz,2H),10.24(s,1H),8.56(s,1H),8.09(d,J=2.2Hz,1H),8.02-7.94(m,2H),7.83(d,J=8.9Hz,1H),7.70-7.63(m,2H),7.60(d,J=6.2Hz,2H),7.51(dd,J=9.0,2.2Hz,1H),7.45(t,J=8.7Hz,1H),7.40(s,1H),5.09(dd,J=13.3,5.1Hz,1H),4.42(d,J=17.3Hz,1H),4.28(d,J=17.2Hz,1H),4.20(t,J=6.6Hz,2H),4.00(s,3H),3.84(s,3H),2.92(ddd,J=17.2,13.6,5.4Hz,1H),2.78(q,J=7.6Hz,2H),2.64(s,3H),2.63-2.55(m,1H),2.36(t,J=7.6Hz,3H),2.02-1.95(m,1H),1.82(t,J=7.4Hz,2H),1.61(d,J=8.8Hz,2H),1.47(s,2H),1.33(s,6H),1.24(d,J=7.5Hz,5H).13C NMR(151MHz,DMSO)δ173.93,173.31,172.26,171.55,168.32,166.19,164.54,155.78,154.79,153.17,152.54,152.25,150.86,149.43,143.73,143.03,139.98,139.69,138.88(d,J=10.0Hz,1C),134.85(d,J=12.9Hz),133.39,126.56,126.27,124.82,124.10(d,J=14.8Hz,1C),119.16(d,J=14.2Hz,1C),117.57,115.92,113.55,109.45,108.06-107.56(m,1C),101.08,69.27,56.58,52.02,47.61,37.00,35.67,31.69,29.20(dd,J=21.5,12.4Hz,1C),28.80,27.94,25.94,25.50,23.01,19.50,15.98.HRMS(ESI)forC52H54FN7O9[M+H]+,calcd:940.4040;found,940.4013.HPLC purity=99.42%,Rt5.25min.
实施例28:N-(4-((7-((6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)氨基)-6-氧己基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-28)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.00(d,J=5.4Hz,2H),10.28(s,1H),8.56(s,1H),8.08(d,J=2.2Hz,1H),8.01(d,J=1.7Hz,1H),7.97(dd,J=12.9,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.70-7.64(m,2H),7.60(d,J=12.3Hz,2H),7.51(dd,J=8.7,2.1Hz,1H),7.48-7.39(m,2H),5.10(dd,J=13.3,5.1Hz,1H),4.43(d,J=17.3Hz,1H),4.29(d,J=17.3Hz,1H),4.23(t,J=6.5Hz,2H),3.98(s,3H),3.84(s,3H),2.92(ddd,J=17.2,13.6,5.4Hz,1H),2.77(q,J=7.6Hz,2H),2.64(s,3H),2.63-2.56(m,1H),2.43(t,J=7.4Hz,2H),2.36(td,J=13.2,4.5Hz,1H),1.99(td,J=6.3,5.3,2.3Hz,1H),1.88(p,J=6.5Hz,2H),1.73(p,J=7.4Hz,2H),1.53(qd,J=8.5,5.7Hz,2H),1.25(t,J=7.6Hz,3H).13C NMR(151MHz,DMSO)δ173.93,173.32,172.19,171.55,168.32,166.19,164.54,155.75,154.79,153.17,152.54,152.25,150.84,149.43,143.74,143.02,139.98,139.68,138.88(d,J=10.1Hz,1C),134.85(d,J=13.0Hz,1C),133.39,126.59,126.26,124.83,124.10(d,J=12.5Hz,1C),119.17(d,J=9.9Hz,1C),117.57,115.94,113.58,109.47,107.98,107.81,101.08,69.16,56.57,52.02,47.62,36.94,35.66,31.69,28.63,27.94,25.67,25.25,23.01,19.50,15.97.HRMS(ESI)for C48H46FN7O9[M+H]+,calcd:884.3414;found,884.3405.HPLCpurity=97.67%,Rt 7.46min.
实施例29:N-(4-((7-((5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)氨基)-5-氧戊基)氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-29)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ10.99(d,J=11.7Hz,2H),10.28(s,1H),8.56(s,1H),8.09(d,J=2.2Hz,1H),8.04-7.93(m,2H),7.82(d,J=8.9Hz,1H),7.72-7.63(m,2H),7.62-7.57(m,2H),7.51(dd,J=8.5,2.3Hz,1H),7.47-7.40(m,2H),5.09(dd,J=13.3,5.1Hz,1H),4.42(d,J=17.3Hz,1H),4.33-4.22(m,3H),4.00(s,3H),3.84(s,3H),3.17(d,J=5.2Hz,1H),2.91(ddd,J=18.2,13.6,5.4Hz,1H),2.77(q,J=7.6Hz,2H),2.65(s,4H),2.38(qd,J=13.1,4.3Hz,2H),2.05-1.94(m,1H),1.88(dt,J=22.5,7.8Hz,4H),1.25(t,J=7.5Hz,3H).13C NMR(151MHz,DMSO)δ173.88,173.36,172.07,171.57,168.32,166.21,164.53,155.70,154.78,153.16,152.56,150.81,149.40,143.75,142.96,139.96,139.68,138.89(d,J=9.8Hz,1C),134.82(d,J=12.9Hz,1C),133.39,126.60,126.25,124.84,124.10(d,J=6.4Hz,1C),119.32,119.13,117.58,115.92,113.58,109.47,107.95,107.79,101.06,68.93,56.58,51.99,49.06,47.59,36.52,35.65,31.69,28.37,27.94,22.99,22.14,19.51,16.00.HRMS(ESI)for C47H44FN7O9[M+H]+,calcd:870.3257;found,870.3253.HPLC purity=98.00%,Rt 5.70min.
实施例30:N-(4-((7-((6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-6-氧己基)氧基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-30)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),11.00(s,1H),9.74(s,1H),8.55(s,1H),8.48(d,J=8.4Hz,1H),8.09(d,J=2.2Hz,1H),7.96(dd,J=13.0,2.3Hz,1H),7.87-7.81(m,2H),7.68(dd,J=8.9,2.3Hz,1H),7.62(d,J=7.3Hz,1H),7.58(s,1H),7.54-7.48(m,1H),7.45(d,J=8.7Hz,1H),7.42(d,J=4.1Hz,1H),5.15(dd,J=12.9,5.4Hz,1H),4.23(t,J=6.5Hz,2H),3.98(s,3H),3.85(s,3H),2.89(ddd,J=17.5,14.1,5.5Hz,1H),2.78(q,J=7.5Hz,2H),2.65(s,3H),2.64-2.53(m,4H),2.11-2.02(m,1H),1.88(t,J=7.5Hz,2H),1.80-1.70(m,2H),1.55(t,J=7.6Hz,2H),1.25(d,J=4.7Hz,3H).13CNMR(151MHz,DMSO)δ173.89,173.25,172.49,170.26,168.11,167.13,166.25,164.53,155.74,152.54,152.06,150.81,149.37,139.99,139.69,136.96,136.56,134.84(d,J=13.0Hz,1C),133.43,131.89,126.83,126.23,124.84,119.36,118.80,117.54(d,J=12.6Hz,1C),115.95,109.44,107.71,101.03,69.12,56.56,49.37,40.43,36.88,35.65,31.38,28.50,27.94,25.47,24.95,22.43,19.50,16.00.HRMS(ESI)for C48H44FN7O10[M+H]+,calcd:898.3193;found,898.3195.HPLC purity=95.41%,Rt 4.57min.
实施例31:N-(4-((7-((5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧异吲哚啉-5-基)氨基)-5-氧戊基)氧基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-31)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.99(s,1H),10.64(s,1H),8.56(s,1H),8.27(d,J=1.8Hz,1H),8.08(d,J=2.2Hz,1H),7.97(dd,J=12.9,2.3Hz,1H),7.93-7.80(m,3H),7.67(dd,J=8.9,2.3Hz,1H),7.59(s,1H),7.54-7.39(m,3H),5.14(dd,J=12.9,5.4Hz,1H),4.27(s,2H),4.00(s,3H),3.84(s,3H),2.90(ddd,J=17.4,14.0,5.5Hz,1H),2.77(q,J=7.6Hz,2H),2.64(s,3H),2.63-2.57(m,1H),2.55(d,J=6.5Hz,3H),2.06(dq,J=11.0,3.3Hz,1H),1.96-1.80(m,4H),1.24(d,J=7.6Hz,3H).13C NMR(151MHz,DMSO)δ173.93,173.19,172.61,170.35,167.48,167.22,166.19,164.54,155.70,154.79,153.17,152.55,152.25,150.84,149.41,145.56,139.98,139.69,138.88(d,J=10.0Hz,1C),134.85(d,J=12.9Hz,1C),133.39,133.24,126.27,125.15(d,J=18.4Hz,1C),124.82,124.15,123.98,119.21,117.57,115.93,113.33,109.50,107.98,107.82,101.09,68.92,56.60,49.45,36.56,35.66,31.42,28.33,27.94,22.53,21.94,19.50,15.98.HRMS(ESI)for C47H42FN4O10[M+H]+,calcd:884.3055;found,884.2567.HPLC purity=97.86%,Rt 5.58min.
实施例32:N-(4-((7-((10-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-10-氧十二烷基)氧基)-6-甲基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酰胺(HS-32)
合成方法如实施例1。
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),11.02(s,1H),9.69(s,1H),8.55(s,1H),8.48(d,J=8.4Hz,1H),8.09(d,J=2.2Hz,1H),7.96(dd,J=12.9,2.3Hz,1H),7.82(dt,J=8.5,3.5Hz,2H),7.67(dd,J=8.8,2.3Hz,1H),7.64-7.56(m,2H),7.51(dd,J=8.9,2.3Hz,1H),7.44(t,J=8.7Hz,1H),7.39(s,1H),5.15(dd,J=12.7,5.4Hz,1H),4.20(t,J=6.5Hz,2H),4.00(s,3H),3.84(s,3H),3.17(d,J=5.2Hz,1H),2.97-2.84(m,1H),2.78(t,J=7.6Hz,2H),2.65(s,3H),2.59(s,3H),2.47(t,J=7.4Hz,2H),2.12-2.03(m,1H),1.82(t,J=7.4Hz,2H),1.69-1.58(m,2H),1.46(d,J=8.1Hz,2H),1.36-1.32(m,5H),1.25(t,J=7.5Hz,6H).13C NMR(151MHz,DMSO)δ173.93,173.18,172.48,170.21,168.18,167.12,166.18,164.53,155.77,154.79,153.17,152.53,152.28,150.85,149.43,139.98,139.68,138.87(d,J=9.7Hz,1C),137.05,136.54,134.85(d,J=13.0Hz,1C),133.38,131.89,130.10,126.66,126.26,124.81,124.15,119.17,118.70,117.56,117.37,115.92,109.45,107.98,107.79(d,J=12.2Hz,1C),101.06,69.27,56.57,55.36,49.40,49.06,37.02,35.66,31.40,29.29,28.96,28.80,27.94,25.93,25.25,22.46,19.50,15.97.HRMS(ESI)for C52H52FN7O10[M+H]+,calcd:954.3832;found,954.3822.HPLC purity=95.95%,Rt9.42min.
实施例33:体外肿瘤细胞增殖抑制活性
化合物对细胞的增殖抑制作用以CCK-8细胞计数试剂盒(Dojindo)检测。具体步骤如下:
1)细胞接种:处于细胞对数生长期的MDA-MB-231、MV4-11等肿瘤细胞分别按同样密度接种在不同96孔板中(3000-10000个细胞/100μl/孔)。
2)工作液配制:以细胞培养所需相应培养基作为稀释液(含或不含溶媒DMSO),稀释受试化合物和对照化合物储备液,获得所需浓度为终浓度3倍的系列浓度的工作液,各浓度组中的溶媒DMSO含量与溶媒对照组相一致。
3)共孵育:接种24hr后,向96孔板加入化合物系列浓度的母液100μl/孔,混匀后共培养72hr。所有组别至少3个复孔,每个化合物6个浓度。空白对照组:只加培养基,不加细胞和药物,排除培养基对比色的干扰。
4)吸光度测定:从96孔板吸走培养基后,每孔加入10μlCCK-8溶液,共培养4hr后,充分振荡使其均匀,在酶标仪上测定A450及A650处的吸光值。
5)数据处理:得到的A450-A650原始数据,得到各处理孔的细胞存活率(计算方法如下);然后将细胞存活率数据及其对应的化合物浓度输入GraphPad Prism 8.0Demo软件,使用非线性回归模型计算化合物对不同细胞的IC50值。
细胞存活率的计算:细胞存活率(%)=[(As-Ac)/(Ab-Ac)]×100%](As:实验孔;Ab:溶媒对照孔;Ac:空白孔)。
结果见下表,其中各个化合物对于MV4-11和MDA-MB-231的活性均较好,部分化合物对于MV4-11和MDA-MB-231的的半数抑制浓度均小于1μM。
表1.化合物对肿瘤细胞的增殖抑制活性
HS-28对多种肿瘤细胞表现出增殖抑制活性,具体数据见下表:
表2 HS-28的体外增殖抑制活性
实施例34:激酶抑制剂活性分析
用Z-lyte荧光共振能量转移法检测化合物的AXL激酶抑制活性。所用的蛋白激酶AXL、FLT3及其相应的底物试剂均购自Life technologies公司。所有反应在384微孔板上进行,酶反应体积10微升。反应缓冲液成分为50mM HEPES pH 7.5,10mM MgCl2,1mM EGTA,0.01%BRIJ-35。具体操作过程为:首先在微孔板内加入5ul适量的蛋白激酶与5ul相应底物(反应终浓度为2uM)混合液,然后用Echo520超声波微量液体转移系统(美国Labcyte公司)加入一系列梯度稀释的化合物,最后加入相应浓度的ATP(反应浓度为25μM),振荡混匀5min后,置于29度恒温箱内反应1.5h;然后加入5ul相应浓度的检测液(Development Reagent),振荡混匀5min,置于29度恒温箱内反应1h;最后加入5ul终止液(Stop Reagent),振荡混匀后用PE公司的Envision MultilabelReader多功能酶标仪进行检测,激发光波长为400nm,发射光波长分别为445nm和520nm。实验分别设置测试孔(加化合物,酶,底物和ATP),0%磷酸化孔(加DMSO,底物和ATP)100%磷酸化孔(只加磷酸化底物),0%抑制率孔(加DMSO,酶,底物和ATP)。根据荧光比值计算化合物对酶反应的抑制率,用GraphPad软件进行分析计算出化合物的IC50值。
激酶活性见下表,其中各个化合物均表现出较好的浓度,实施例10、28化合物的活性最佳。
表3.化合物的AXL、FLT3激酶抑制剂活性
实施例35:化合物对细胞中AXL(MDA-MB-231模型)、FLT3(MV4-11模型)表达的影响
实验方法:细胞株:MDA-MB-231细胞株、MV4-11细胞株均购自美国标准生物品收藏中心(ATCC)。使用常规Western Blot(免疫印迹法)进行检测,具体如下。将MDA-MB-231、MV4-11按一定数量种于12孔板,培养箱内贴壁培养过夜后,加入一定浓度的化合物作用24h,用裂解液裂解细胞收样。然后取适量样品进行SDS-PAGE电泳,电泳结束后用半干电转移系统将蛋白转移至硝酸纤维素膜,将硝酸纤维素膜置于封闭液(5%脱脂奶粉稀释于含0.1%Tween 20的TBS)中室温封闭2h,然后将膜分别置于一抗溶液(1:1000稀释于含0.1%Tween 20的TBS)中4℃孵育过夜。用含0.1%Tween 20的TBS洗涤三次,每次15min。将膜置于二抗溶液(辣根过氧化物酶标记羊抗兔的IgG,1:1000稀释于含0.1%Tween 20的TBS)中室温反应1h。同上洗膜三次后,用ECL plus试剂发色,Amersham Imager 600system拍照。
图1结果表明,化合物可以选择性剂量依赖性降解MDA-MB-231细胞中的AXL蛋白,以HS-10、HS-28的活性最好,在0.016μM水平即可显著下调AXL的蛋白水平。
图2结果表明,化合物可以选择性剂量依赖性降解MV4-11细胞中的FLT3蛋白,以HS-10、HS-28的活性最好,在0.016μM水平即可显著下调AXL的蛋白水平。
表4汇总了由图1和图2的定量分析结果,以上化合物中,实施例10、28等均能显著降解MDA-MB-231细胞中AXL蛋白水平和MV4-11细胞中FLT3蛋白水平,其中实施例28具有最优的AXL、FLT3蛋白降解活性。
表4 MDA-MB-231细胞中AXL蛋白水平和MV4-11细胞中FLT3蛋白水平
实施例36:化合物HS-28对患者来源AML细胞的增殖抑制作用
方法:患者骨髓样本用PBS以1:1比例稀释,然后缓慢平铺于等体积的人外周血淋巴细胞分离液中(P8610,Solarbio)。1000g条件下室温水平离心30min,小心吸取淋巴细胞到新的离心管中,加入10ml PBS,250g离心10min,弃上清,重复两次,收集细胞以5×104个/孔的密度铺于96孔板中。后续药物加样、孵育、测OD及IC50计算方法等同上。
结果显示(表3),化合物HS-28对分离获得的6个AML患者血样均表现出较好的体外增殖抑制活性,IC50小于50nM。
表5化合物HS-28对患者来源AML细胞的体外活性
注:SZX-2546347等所有患者均病理诊断为急性随性白血病(AML)。
实施例37:化合物HS-28对肿瘤细胞中多种蛋白的降解作用
方法:200μl密度为5×106个/ml的细胞接种6孔板中,然后加入不同浓度的药物;37℃处理4-12小时,取上清,PBS洗2次;然后加入100-200μl 1×SDS裂解液,收集细胞裂解液到离心管中,超声10-20s破碎细胞,煮沸10min。蛋白样品以90V电压进行SDS-PAGE电泳,110V电压转到PVDF膜上,5%BSA封闭4小时,4℃孵育一抗(Flt3、p-Flt3、GAPDH)过夜,室温孵育二抗(anti-Rabbit IgG、anti-Mouse IgG),TBST缓冲液洗膜,加入ELC显影液,然后成像获得蛋白条带信号。
结果如下图,发现HS-28可以nM水平在不同细胞里显著降解AXL、FLT3、AURORA-A、ARURORA-B、LCK等蛋白。
实施例38:化合物HS-28对乳腺癌细胞MDA-MB-231的体外迁移和侵袭抑制作用
方法:Tanswell小室购自美国Corning公司,孔径为8μm。使用前先在上层小室中加入相同数量的MDA-MB-231细胞,其置于200μL含有不同化合物浓度的无血清的PRMI-1640培养基中,下层小室中加入800μL含2%胎牛血清和10ng/ml TGFβ1的培养基,将小室置于37℃,5%CO2培养箱中培养24h后,取出小室,将细胞浸入结晶紫中20分钟染色并固定小室底部的细胞,用棉签轻轻擦去小室上层未穿过孔的细胞,后用清水洗净。在200倍显微镜下观察、拍照,计算每个小室中6个不同视野中迁移细胞数,计算平均值。
结果表明(图4),实施例28化合物能显著抑制MDA-MB-231细胞的迁移和侵袭,其在0.1μM的抑制率均为30%。
以上所述实施例仅表达了本发明的几种实施方式,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。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.具有式(Ⅰ)所示结构的化合物或者其药学上可接受的盐,或者其立体异构体或前药分子:
其中:
X不存在,或选自下组:-CH2-、-CF2-或-O-;
R1选自下组:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基;
R2选自:取代或未取代的C1-C6烷基;
Y选自:-CH2-,-C(=O)-;
L具有如下式所示的结构:-Z-(L1)m-;
其中,m为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30;
所述的Z选自下组:具有0-4个杂原子的3-12元环、-NH-、-O-、-C(O)-、-CONH-、-NHCO-、-S-、-CH2-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-;
L1选自下组:具有0-4个杂原子的3-12元环、-NH-、-O-、-C(O)-、-CONH-、-NHCO-、-S-、-CH2-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-;
且所述的L片段可以任选地包括一个或多个RL取代基,且所述的RL取代基选自下组:卤素、-OH、-CN、-CF3、-NH2、-COOH、氧原子(=O)、取代或未取代的C1-C6烷基或卤代烷基、取代或未取代的C1-C6烷氧基,或者2个RL基与它们所连接的原子共同形成含有0-4个杂原子的3-8元环;
其中,上述的取代指基团上的一个或多个H原子被选自下组的取代基替代:卤素,氘原子。
3.如权利要求1所述的化合物或者其药学上可接受的盐,或者其立体异构体或其前药分子,其特征在于,R1选自下组:-H,-F,-Cl,-CH3,-CF3,-CD3,-CH2CH3,环丙基,环丁基,环戊基,异丙基,氟代乙基,氟代环丙基,氟代环丁基,氟代环戊基,氟代异丙基。
4.如权利要求1所述的化合物或者其药学上可接受的盐,或者其立体异构体或其前药分子,其特征在于,R2选自-CH3,-CD3。
6.如权利要求1-4任一所述的化合物或者其药学上可接受的盐,或者其立体异构体或其前药分子,其特征在于,L具有下式所示结构:
其中:
W1和W2不存在,或各自独立地为具有0-4个杂原子的3-12元环,其任选地被RL取代;
B不存在,或B选自下组:具有0-4个杂原子的3-12元环、-NH-、-O-、-CONH-、-NHCO-、-S-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-、C1-C6烷基或卤代烷基(直链、支链、任选地取代的)并且任选地一个或多个C原子被O、N替换;或C1-C6烷氧基(直链、支链、任选地取代的);
Z选自下组:含有0-4个杂原子的3-12元环、-NH-、-O-、-CONH-、-NHCO-、-S-、-CH2-、-C≡C-、-CH=CH-、-P=O-、-S(O)2-、-S(O)-、-P(O)2(OH)-、-NH-S(O)-NH-、-C(O)O-、-OC(O)-;
n是0-10;并且
短划线表示接头部分的连接点。
8.一种治疗肿瘤的药用组合物,其特征在于包括权利要求1~7任一项所述的式I化合物或其药学上可接受的盐,或立体异构体或其前药分子;和
药学上可接受的载体。
9.如权利要求1~7任一项所述的式I化合物或其药学上可接受的盐,或立体异构体或其前药分子在制备治疗或预防与AXL和/或FLT3的活性或表达量相关的疾病或病症的用途,具体地,所述的疾病或病症选自下组:心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症、癌症。
10.如权利要求9所述的应用,其特征在于所述肿瘤为血液性肿瘤、胃肠间质瘤、组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、鼻咽癌中的任意一种。
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