CN112236422B - 喹唑啉类化合物作为egfr三突变抑制剂及其应用 - Google Patents
喹唑啉类化合物作为egfr三突变抑制剂及其应用 Download PDFInfo
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- CN112236422B CN112236422B CN201980025718.7A CN201980025718A CN112236422B CN 112236422 B CN112236422 B CN 112236422B CN 201980025718 A CN201980025718 A CN 201980025718A CN 112236422 B CN112236422 B CN 112236422B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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Abstract
涉及喹唑啉类化合物作为EGFR三突变抑制剂及其应用。具体而言,公开了下式(I)所示化合物、含有下式(I)化合物的药物组合物及所述化合物在治疗EGFR介导的相关疾病以及制备治疗EGFR介导的相关疾病的药物中的用途。
Description
技术领域
本发明属于医药以及药物合成领域,具体地,本发明涉及一种喹唑啉类化合物作为EGFR三突变抑制剂及其应用。
背景技术
表皮生长因子受体(epidermal growth factor receptor,EGFR,也称作HER-1或c-erbB-1)是由1186个氨基酸组成的,170-kDa的跨膜糖蛋白。EGFR由三部分组成:细胞外受体区域;跨膜区域;细胞内酪氨酸激酶区域。EGFR是受体酪氨酸激酶c-erbB家族中的一员,与HER2(c-erbB-2),HER3(c-erbB-3)和HER4(c-erbB-4)共同组成c-erbB家族。已经确认的可以与EGFR结合的配体有:表皮生长因子(EGF)、转化生长因子α(TGFα)、双向调节因子、肝素结合EGF、细胞调节素等。在人体组织中,EGF和TGFα被认为是EGFR两种最重要的配体[2]。当配体与EGFR在胞外结合域结合后,ErbB家族成员会形成同源或异源二聚体,引起胞浆内酪氨酸激酶区蛋白构象改变,与ATP结合而自身磷酸化,进而活化下游信号分子(Ras-Raf-MEK/MAPK,Ras-Raf-促分裂原活化蛋白激酶通路;PI3K/Akt,磷脂酰肌醇3激酶/Akt通路),发挥维持细胞生长增殖、细胞移动、血管生成、抑制凋亡等多种生理功能。
由于EGFR在控制细胞增殖、存活、及代谢方面的关键作用,干扰它的活动就可以阻断信号的转导,从而使得EGFR成为一种引人注目的肿瘤靶向治疗分子靶标,靶向EGFR药物也已成为肿瘤治疗的热点。目前针对EGFR的肿瘤分子靶向药物,按其性质主要分为两大类:一类是直接作用于细胞外受体区域的单克隆抗体;另一类是干扰细胞内EGFR酪氨酸激酶活性的小分子抑制剂。单克隆抗体药物通过与EGFR的膜外配体结合域作用,使EGF等内源性配体无法与EGFR结合,从而阻止信号传入细胞;小分子药物则通过与胞内酪氨酸激酶催化区结合,抑制其催化活性,从而阻断细胞增殖信号。
EGFR的突变主要集中在18-21号外显子上,这几个外显子负责编码EGFR酪氨酸激酶域。其中19号外显子缺失占据了EGFR酪氨酸激酶敏感性突变的44%。在21号外显子上的点突变-L858R突变,占据了EGFR酪氨酸激酶敏感性突变的41%。719号残基从甘氨酸突变到丝氨酸,丙氨酸或者半胱氨酸占据了总突变的10%,而20号外显子的插入或复制突变占据了剩余的5%。其中19号外显子缺失和L858R点突变是最普遍的敏感性突变。这些突变会增强EGFR激酶的活性,从而提高下游信号通路。另外报道发现,由EGFR酪氨酸激酶抑制剂治疗产生的耐药性中,50%的病人发现了20号外显子上的T790M点突变。这种突变被认为是在治疗期间产生的,因为在未治疗病人中并未检测到这种突变。针对这些不同的突变衍生出了一系列的小分子抑制剂。
首先是第一代EGFR小分子抑制剂,例如Gefitinib、Erlotinib。这些抑制剂主要针对的是敏感性突变,但随着T790M抗性突变的发现,患者逐渐产生耐药性。因此衍生出了第二代及第三代EGFR抑制剂,该类抑制剂主要通过分子上的迈克尔受体与蛋白的半胱氨酸797残基发生共价结合来提高抑制活性。
虽然利用第三代EGFR抑制剂治疗携带有T790M突变的非小细胞肺癌病人有希望,但耐药性也逐渐产生。经过研究发现其耐药性的发生主要是由于Cys797残基发生突变形成Ser797残基,导致第三代抑制剂没办法共价结合到蛋白激酶上。
因此急切需要开发新一代的抑制剂来克服EGFR L858R/T790M/C797S三突变。
发明内容
本发明的目的是提供一类结构新颖的可作用ECFR抑制剂的化合物。
本发明第一方面提供了通式I所示的化合物或其立体异构体或光学异构体,或其药学上可接受的盐:
式中,
X是CH2、NH、O或S;
Z是N或CH;
Y是无、-O-、-NHCO-、-CONH-、-NHSO-、-SONH-、-NHCONH-或-NHSONH-;
R1是氢、卤素(氟、氯、溴、碘)、C1-4烷基、卤代C1-4烷基、C1-4烷氧基、卤代C1-4烷氧基、C1-4烷基硫基、(C1-4烷基)(C1-4烷基)P(=O)-、硝基或氨基;
R2选自下组:氢、取代或未取代的苯基、取代或未取代的苯基C1-4烷基、取代或未取代的苯基并C4-7环烷基、取代或未取代的C4-7环烷基C1-4烷基、含N或O的5或6元杂环,所述取代是指上述基团中的一个或多个氢原子被选自下组的基团所取代:卤素、C1-4烷基、苯基、
R3、R4各自选自独立地选自下组:氢、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基、取代或未取代的哌嗪基C1-6烷氧基、取代或未取代的哌啶基C1-6烷氧基、取代或未取代的吗啉基C1-6烷氧基,或R3、R4形成-O-C1-6烷基-O-;所述取代是指上述基团中的一个或多个氢原子被选自下组的基团所取代:卤素、C1-4烷基、C1-4烷氧基、苯基;
R5是氢、卤素、羟基或氨基。
在另一优选例中,R2选自下组:
在另一优选例中,所述化合物如通式II所示:
式中,R1、R2、R3、R4、Y如前所限定。
在另一优选例中,所述化合物如通式III所示:
式中,R3、R4、R1和Y如权利要求1所述;
R6、R7各自独立地选自下组:
其中,R11选自下组:氢、卤素、羟基;
m为0、1或2;
t为0、1或2。
在另一优选例中,R6和R7之一选自下组:
在另一优选例中,R11选自下组:氢、卤素(较佳地,为F)。
在另一优选例中,当Y是-O-时,R2是苯基或苯基C1-4烷基;较佳地,苯基。
在另一优选例中,R3、R4各自独立选自下列:
n为1、2或3。
在另一优选例中,所述化合物如通式IV所示:
式中,R8、R9、R10各自独立地选自下组:氢、卤素、羟基。
在另一优选例中,R8为羟基或氟。
在另一优选例中,R9为氢。
在另一优选例中,R10为氟。
在另一优选例中,所述化合物选自下组:
本发明第二方面提供了一种药物组合物,所述药物组合物含有第一方面所述的化合物或其立体异构体或光学异构体,或其药学上可接受的盐,以及药学上可接受的载体或赋形剂。
本发明第三方面提供了本发明第一方面所述的化合物或其立体异构体或光学异构体,或其药学上可接受的盐在制备治疗或预防EGFR介导的疾病或抑制EGFR的药物中的用途。
在另一优选例中,所述EGFR介导的疾病为癌症。
在另一优选例中,所述癌症选自下组:非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头劲部鳞癌、宫颈癌、食管癌、肝癌、肾癌、胰腺癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌、多发性骨髓癌和实体瘤。
本发明提供了一种治疗方法,所述方法包括步骤:给需要的对象施用本发明第一方面所述的化合物或其立体异构体或光学异构体,或其药学上可接受的盐。
在另一优选例中,所述需要的对象患有EGFR介导的疾病。
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。
具体实施方式
本发明人通过广泛而深入的研究,意外发现一类具有优异的EGFR抑制活性的喹唑啉类化合物。在此基础上完成了本发明。
术语定义
本文中涉及到的一些基团定义如下:
本文中,“烷基”指碳链长度为1-10个碳原子的饱和的支链或直链烷基,优选的烷基包括长1-6个、1-4个或1-3个碳原子不等的烷基。烷基的例子包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、庚基等。烷基可以被1个或多个取代基取代,例如被卤素或卤代烷基取代。例如,烷基可以是被1-4个氟原子取代的烷基,或者烷基可以是被氟代烷基取代的烷基。
本文中,“烷氧基”指被烷基取代的氧基。优选的烷氧基是长1-6个碳原子的烷氧基,更优选为长1-4个碳原子的烷氧基。烷氧基的例子包括但不限于甲氧基、乙氧基、丙氧基等。在具体的实施方式中,烷氧基可以是取代的烷氧基,例如,烷氧基取代的烷氧基。在具体的实施方式中,优选C1-C3烷氧基取代的C1-C3烷氧基。
本文中,“环烷基”指包含3-10个,优选4-7个环碳原子的饱和的环状烷基。环烷基的例子包括但不限于环丙基、环丁基、环己基、环庚基等。环烷基可以被1个或多个取代基取代,例如被卤素或卤代烷基取代。例如,环烷基可以是被1-4个氟原子取代。在优选的实施方式中,本发明中的环烷基是环己基。
本文中,“卤素”指氟、氯、溴和碘。
本文中,“芳基”指含有6到14个碳原子的单环、双环或三环芳族基团,包括苯基、萘基、菲基、蒽基、茚基、茀基、四氢化萘基、二氢化茚基等。芳基可任选地被1-5个(例如,1、2、3、4或5个)选自以下的取代基取代:卤素、C1-4醛基、C1-6烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基等、杂环基或杂芳基等。
本文所用“杂环基”包括但不限于含有1-3个选自O、S和N的杂原子的5元或6元杂环基团,包括但不限于呋喃基、噻吩基、吡咯基、吡咯烷基、吡唑基、咪唑基、三唑基、噁唑基、吡喃基、吡啶基、嘧啶基、吡嗪基、哌啶基、吗啉基等。
本文中,“任选取代的”指其所修饰的取代基可任选地被1-5个(例如,1、2、3、4或5个)选自以下的取代基取代:卤素、C1-4醛基、C1-6直链或支链烷基、氰基、硝基、氨基、羟基、羟甲基、卤素取代的烷基(例如三氟甲基)、卤素取代的烷氧基(例如三氟甲氧基)、羧基、C1-4烷氧基、乙氧甲酰基、N(CH3)和C1-4酰基。
活性成分
本发明提供了一系列结构新颖的喹啉类化合物,如通式I所示,并进行了结构表征。
本发明化合物还可以是式I所示化合物的立体异构体或光学异构体,或其药学上可接受的盐。
本发明化合物的药学上可接受的盐的例子包括但不限于本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
药物组合物
由于本发明化合物具有优异的EGFR激酶的抑制活性(尤其是EGFR三突变抑制活性),因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)EGFR激酶相关疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物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本发明化合物/剂,更佳地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物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本发明化合物/剂,更佳地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”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份能和本发明化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体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。
本发明化合物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、肠胃外(静脉内、肌肉内或皮下)。
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,活性化合物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。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂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,这种组合物中活性化合物或化合物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。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
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。除了活性化合物外,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。
除了活性化合物外,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,或者与其他药学上可接受的化合物联合给药。
联合给药时,所述药物组合物还包括与一种或多种(2种,3种,4种,或更多种)其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种可与本发明的化合物同时、分开或顺序地施用。
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。
制备方法
本发明的化合物的制备方法可以是本领域常规的方法,也可以采用本发明的合成路线。
其中,各个步骤的反应试剂和条件如下所示:
(a)4-((甲苯磺酰氧基)甲基)哌啶-1-羧酸叔丁酯,DMF,K2CO3;120℃,5h;
(b)HCHO,HCOOH,120℃,8h;
(c)发烟硝酸,DCM,25℃,过夜;
(d)Pd/C,MeOH/DCM,H2,25℃,4h;
(e)甲脒乙酸盐,CH3OCH2CH2OH,120℃,8h;
(f)SOCl2,DMF,80℃,3h;
(g)THF,Et3N,60℃,5h;
(h)Pd/C,H2,MeOH/DCM,25℃,5h;
(i)i-PrOH,HCl,80℃,8h。
其中,化合物2h的制备方法可以如下所示:
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,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1:化合物1的合成
4-(N-Boc-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯的合成
称取三草酸甲酯(1g,5.49mmol)于100mL茄型瓶中,加入无水碳酸钾(1.52g,10.98mmol),加入约50mL的DMF,常温搅拌约15min。加入叔丁基-4-((甲苯磺酰氧基)甲基)哌啶-1-羧酸叔丁酯(2.75g,7.41mmol),升温至95℃回流反应3h。TLC确定反应完全。用饱和氯化钠/乙酸乙酯萃取,并用无水硫酸钠干燥,水泵旋蒸除去大部分溶剂,隔膜泵70℃旋蒸约20min除去残余的DMF。粗品经硅胶柱层析(石油醚/乙酸乙酯=8∶1)分离,得到4-(N-Boc-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯2g,产率86%。1H NMR(400MHz,DMSO):δ7.57(d,J=8.4Hz,1H),7.45(s,1H),7.07(d,J=8.4Hz,1H),3.97(d,J=12Hz,2H),3.9(d,J=6.4Hz,2H),3.82(s,3H),3.81(s,3H),2.74(s,2H),1.95-1.85(m,1H),1.75(d,J=8.4Hz,2H),1.4(s,9H),1.15(m,2H)。
4-(N-甲基-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯的合成
称取4-(N-Boc-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯(1g,2.64mmol)于100mL茄型瓶中,加入约12mL甲酸,常温搅拌约30min,使其溶解。后缓慢滴加甲醛溶液(4mL,47.44mmol,37%),95℃回流加热,氩气保护,反应约6h后,TLC确定反应完毕。隔膜泵旋蒸除去溶剂。粗品经硅胶柱层析(二氯甲烷/甲醇=30∶1)分离,得到4-(N-甲基-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯白色固体730mg,收率94%。1H NMR(400MHz,DMSO):δ7.57(d,J=8.4Hz,1H),7.42(s,1H),7.10(d,J=8.4Hz,1H),3.94(d,J=6Hz,2H),3.82(s,3H),3.81(s,3H),3.25(d,J=12Hz,2H),2.70(dd,J1=11.2Hz,J2=22.8Hz,2H),2.6(s,3H),1.97-1.80(m,1H),1.88(d,J=21.6Hz,2H),1.49-1.40(m,2H)。
6-硝基-4-(N-甲基-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯的合成
称取4-(N-甲基-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯(500mg,1.7mmol)于100mL茄型瓶中,加入约20mLDCM使其溶解。冰浴冷却下缓慢滴加约2mL三氟乙酸,15min内滴加24M的发烟硝酸(400uL,8.52mmol)。室温反应约6h。反应完毕,用饱和碳酸氢钠水溶液调节pH至7,用饱和氯化钠/乙酸乙酯萃取,用无水硫酸钠干燥。旋蒸除去溶剂,粗品经硅胶柱层析(二氯甲烷/甲醇=30∶1)分离,得到6-硝基-4-(N-甲基-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯淡黄色油状物450mg,收率78%。1H NMR(400MHz,DMSO):δ7.62(s,1H),7.31(s,1H),3.97(d,J=6Hz),3.92(s,3H),3.83(s,3H),2.77(d,J=11.2Hz,2H),2.15(s,3H),1.86(t,J=11.2Hz,2H),1.76-1.74(m,1H),1.72(d,J=10.4Hz,2H),1.30-1.25(m,2H)。
6-氨基-4-(N-甲基-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯的合成
称取6-硝基-4-(N-甲基-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯(400mg,1.36mmol)于250mL的茄型瓶中,加约100mL甲醇使其溶解,加Pd/C(40mg,10%),氢气状态下反应约6h,TLC显示反应完毕。用硅藻土过滤除去Pd/C,旋蒸除去溶剂,得6-氨基-4-(N-甲基-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯油状液体约350mg,收率96%。直接投下一步。
6-甲氧基-7-(N-甲基4-哌啶甲氧基)-3,4-二氢喹唑啉-4-酮的合成
称取6-氨基-4-(N-甲基-4-哌啶甲氧基)-3-甲氧基苯甲酸甲酯(350mg,1.13mmol)于250mL茄型瓶中,加入乙二醇单甲醚约100mL使其溶解,分批加入醋酸甲脒(355mg,3.4mmol),40min内加完。120℃下回流反应约3h,TLC跟踪发现原料未反应完,再次分两批加入醋酸甲醚(240mg,2.27mmol),每隔1h加一次。反应约5h后,TLC跟踪仍有少量原料微反应完。停止反应,旋蒸除去溶剂,用饱和碳酸氢钠水溶液调节pH至9,用饱和氯化钠/二氯甲烷萃取若干次,用无水硫酸钠干燥,旋蒸除去溶剂。粗品经硅胶柱层析(二氯甲烷/甲醇=10∶1)分离,得6-甲氧基-7-(N-甲基-4-哌啶甲氧基)-3,4-二氢喹唑啉-4-酮淡黄色固体100mg,收率30%。1H NMR(400MHz,DMSO):δ7.98(s,1H),7.45(s,1H),7.13(s,1H),3.98(d,J=6.0Hz,2H),3.87(s,3H),2.92(d,J=10.8Hz,2H),2.29(s,3H),2.13(t,J=10.4Hz,2H),1.85-1.81(m,1H),1.79(d,J=12Hz,2H),1.39-1.32(m,2H)。
4-氯-6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉
向50mL茄型瓶中加入二氯亚砜约5mL,加N,N-二甲基甲酰胺约1滴,冰浴下搅拌约30min;称取6-甲氧基-7-(N-甲基-4-哌啶甲氧基)-3,4-二氢喹唑啉-4-酮淡黄色固体100mg投入上述茄型瓶中,常温搅拌约12h。取少量样品点板,原料反应完毕,旋蒸除去溶剂。用饱和碳酸氢钠水溶液调节pH至9,用饱和氯化钠/二氯甲烷萃取若干次,用无水硫酸钠干燥,旋蒸除去溶剂。粗品经硅胶柱层析(二氯甲烷/甲醇=10∶1)分离,得4-氯-6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉淡黄色固体75mg,收率75%。1H NMR(400MHz,DMSO):δ8.87(s,1H),7.45(s,1H),7.40(s,1H),4.00(d,J=6.4Hz,2H),4.00(s,3H),2.78(d,J=11.2Hz,2H),2.16(s,3H),1.90(t,J=13.2Hz,2H),1.79(d,J=12Hz,3H),1.35-1.32(m,2H)。
N-(3-氟-4-硝基苯基)-4-甲氧基苯甲酰胺
称取3-氟-4-硝基苯胺(2g,12.55mmol)于250mL茄型瓶中,加入乙酸乙酯使其溶解。滴加苯磺酰氯(2mL,15.07mmol),三乙胺(2.2mL,15.07mmol)。氩气保护下,常温搅拌1h后,回流反应6h后,TLC跟踪原料反应完毕,旋蒸除去溶剂。粗品经硅胶柱层析(二氯甲烷/石油醚=3∶1)分离,得N-(3-氟-4-硝基苯基)-4-甲氧基苯甲酰胺淡黄色固体2.78g,收率80%。1H NMR(400MHz,DMSO):δ11.03(s,1H),8.22(t,J=9.2Hz,1H),8.10(d,J=14.4Hz,1H),8.00(d,J=7.2Hz,1H),7.82(d,J=9.2Hz,1H),7.65(t,J=7.2Hz,1H),7.57(t,J=7.6Hz,1H)。
N-(4-氨基-3-氟苯基)苯甲酰胺
称取N-(3-氟-4-硝基苯基)-4-甲氧基苯甲酰胺(500mg,1.92mmol)于250mL茄型瓶中,加入甲醇使其溶解。加钯碳(50mg,10%)。抽真空,氢气状态下常温搅拌3h后,TLC跟踪原料反应完毕。用硅藻土过滤除去Pd/C,旋蒸除去溶剂,得N-(4-氨基-3-氟苯基)苯甲酰胺约430mg,收率97%。直接投下一步。
N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)
称取N-(4-氨基-3-氟苯基)苯甲酰胺(180mg,0.56mmol)投入上述茄型瓶中,加异丙醇约15mL使其溶解,取4-氯-6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉(196mg,0.75mmol)于试管中加异丙醇使其溶解,将其滴加入茄型瓶中,常温反应约1h,反应液微红,加入2N盐酸2滴,80℃回流约6h,有白色沉淀产生。TLC跟踪原料反应完。抽滤,用少量异丙醇洗涤固体沉淀。将沉淀溶于二氯甲烷中,用碳酸氢钠饱和溶液调节pH至9,用饱和氯化钠/二氯甲烷萃取若干次,用无水硫酸钠干燥,旋蒸除去溶剂。粗品经硅胶柱层析(二氯甲烷/甲醇=10∶1)分离,得N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)白色固体180mg,收率62%。1H NMR(400MHz,DMSO):δ10.49(s,1H),9.48(s,1H),8.34(s,1H),7.98(d,J=7.2Hz,2H),7.87(d,J=12.8Hz,1H),7.83(s,1H),7.6(s,1H),7.57(t,J=7.6Hz,2H),7.53(t,J=8.8Hz,1H),7.6(s,1H),4.99(d,J=6Hz,2H),3.95(s,3H),2.79(d,J=11.2Hz,2H),2.17(s,3H),1.89(t,J=11.2Hz,3H),1.37-1.34(m,2H).13C NMR(100MHz,DMSO-d6)δ165.69,157.37,153.60,153.10,148.94,148.77,138.04,137.94,134.64,131.75,128.43,127.67,121.81,121.68,115.86,108.45,107.61,102.01,72.70,56.12,54.83,46.16,34.57,28.45.HRMS(ESI)(m/z):[M+H]+calcd for C29H33N8O3,516.2433;found,516.2410.HPLC纯度纯度:96.92%,保留时间=11.06min.
以下化合物的合成均采用与实施例1合成步骤相同或相似的路线合成
实施例2 N-(4-氟-3-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)苯甲酰胺
浅黄色固体,收率45%。1H NMR(400MHz,DMSO-d6):δ10.38(s,1H),9.58(s,1H),8.36(s,1H),8.05(d,J=7.2Hz,1H),7.87(d,J=7.2Hz,2H),7.84(s,1H),7.67-7.53(m,4H),7.31(t,J=12Hz,1H),7.18(s,1H),4.01(d,J=6Hz,2H),3.95(s,3H),2.83(d,J=11.2Hz,2H),2.21(s,3H),1.96(t,J=12Hz,3H),1.78(d,J=10.4Hz,2H),1.30-1.58(m,2H).13C NMR(100MHz,DMSO-d6)δ170.74,157.40,153.54,153.10,148.90,146.73,142.50,128.62,126.13,124.39,114.60,108.43,107.62,102.02,72.58,56.12,54.65,48.55,45.86,42.02,38.30,36.20,34.37,28.22.HRMS(ESI)(m/z):[M+H]+,calcd forC29H33N8O3,516.2433;found,516.2410.HPLC纯度:95.36%,保留时间=10.78min.
实施例3 N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-苯基乙酰胺
白色固体,收率40%。1H NMR(400MHz,DMSO-d6):δ10.42(s,1H),10.41(s,1H),8.30(s,1H),7.80(s,1H),7.73(dd,J1=12.4Hz,J2=2Hz,1H),7.46(t,J=8.4Hz,1H),7.37-7.32(m,5H),7.26(m,1H),4.00(d,J=6Hz,2H),3.96(s,3H),3.68(s,2H),2.80(d,J=12Hz,2H),2.17(s,3H),1.89(t,J=11.2Hz,2H),1.78-1.76(m,3H).13C NMR(100MHz,DMSO-d6):δ169.32,157.36,153.58,153.08,148.92146.75,135.73,129.10,128.31,126.57,114.67,108.42,107.61,106.75,102.00,72.67,56.11,54.81,48.56,46.11,43.26,34.54,28.42.HRMS(ESI)(m/z):[M+H]+calcd for C29H33N8O3,530.2567;found,530.2543.HPLC纯度:95.00%,保留时间=11.20min.
实施例4 N-(4-氟-3-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-苯基乙酰胺
白色固体,收率43%。1H NMR(400MHz,DMSO-d6):δ10.29(s,1H),9.50(s,1H),8.35(s,1H),7.87(dd,J1=7.2Hz,J2=2.8Hz,1H),7.80(s,1H),7.44-7.45(m,1H),7.34-7.24(m,6H),7.17(s,1H),4.00(d,J=6Hz,2H),3.94(s,3H),3.65(s,2H),2.80(d,J=12Hz,2H),2.17(s,3H),1.89(t,J=11.2Hz,2H),1.78-1.76(m,3H).13C NMR(100MHz,DMSO-d6):δ169.06,157.03,153.67,153.00,149.00146.85,135.90,129.00,128.29,126.52,118.55,115.90,108.51,107.60,102.00,72.71,56.10,54.83,46.16,43.26,34.56,26.44.HRMS(ESI)(m/z):[M+H]+calcd for C29H33N8O3,530.2567;found,530.2543.HPLC纯度:97.22%,保留时间=11.05min.
实施例5.2-(2,3-二氢-1H-茚-2-基)-N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)乙酰胺
浅黄色固体,收率48%。1H NMR(400MHz,DMSO-d6):δ10.2(s,1H),9.44(s,1H),8.31(s,1H),7.82(s,1H),7.74(s,1H),7.41(s,1H),7.35(d,J=8.8Hz,1H),7.23(t,J=3.2Hz,2H),7.18(s,1H),7.14-7.11(m,2H),4.01(d,J=6Hz,2H),3.94(s,3H),3.17(s,2H),3.13-3.05(m,3H),2.90-2.83(m,2H),2.87(s,1H),2.83(s,1H),2.22(s,3H),1.98(t,J=10.8Hz,2H),1.78(d,J=10.4Hz,2H),1.30-1.58(m,2H).13C NMR(100MHz,DMSO-d6):δ170.74,157.40,153.54,153.10,148.90,146.73,142.50,126.13,124.39,114.60,108.43,107.62,106.71,106.46,102.02,72.58,56.12,54.65,46.55,45.86,42.02,36.30,36.20,34.37,28.22.HRMS(ESI)(m/z):[M+H]+calcd for C29H33N8O3,570.2880;found,570.2889.HPLC纯度:96.71%,保留时间=12.41min.
实施例6 2-(2,3-二氢-1H-茚-2-基)-N-(4-氟-3-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)乙酰胺
白色固体,收率32%。1H NMR(400MHz,DMSO-d6):δ10.2(s,1H),9.67(s,1H),8.35(s,1H),7.90(s,1H),7.50(s,1H),7.25-7.20(m,4H),7.12-7.10(m,2H),4.03(d,J=6Hz,2H),3.96(s,3H),3.08-3.02(m,4H),2.90-2.82(m,2H),2.87(s,1H),2.83(s,1H),2.42(s,5H),2.02-1.86(m,4H),1.52-1.48(m,2H).13C NMR(100MHz,DMSO-d6):δ170.48,157.08,153.62,153.03,148.98,146.80,142.50,126.12,124.37,118.52,115.86,115.67,108.52,107.60,102.05,72.58,56.11,54.60,45.80,41.95,38.28,36.28,34.31,26.15.HRMS(ESI)(m/z):[M+H]+calcd for C31H31F4N5O3,570.2880;found,570.2879.HPLC纯度:95.33%,保留时间=12.20min.
实施例7 N-(4-(苄氧基)苯基)-6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-胺
白色固体(收率45%)。1H NMR(400MHz,DMSO):δ9.53(s,1H),8.38(s,1H),7.91(s,1H),7.68(s,1H),7.66(s,1H),7.18(s,1H),7.47(d,J=7.2Hz,1H),7.46(s,1H),7.42-7.38(m,2H),7.35-7.32(m,1H),7.15(s,1H),7.05(s,1H),7.03(s,1H),5.11(s,2H),4.99(d,J=6.0Hz,2H),3.96(s,3H),2.96(d,J=11.6Hz,2H),2.32(s,3H),2.23-2.17(m,2H),1.84-1.81(m,3H),1.48-1.39(m,2H).13C NMR(100MHz,DMSO-d6)δ158.55,154.58,153.29,152.98,148.77,146.87,137.20,132.47,128.38,127.75,127.64,124.30,114.52,108.68,107.75,102.27,72.27,69.33,56.33,54.03,44.99,33.83,27.53.HRMS(ESI)(m/z):[M+H]+calcd for C29H32N4O3,485.2553;found,485.2556.HPLC纯度:99.64%,保留时间=12.54min.
实施例8 6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)-N-(4-苯氧基苯基)喹唑啉-4-胺
白色固体(收率45%)。1H NMR(400MHz,DMSO):δ9.57(s,1H),8.43(s,1H),7.89(s,1H),7.79(d,J=8.8Hz,2H),7.40(t,J=8.4Hz,2H),7.18(s,1H),7.13(t,J=7.2Hz,1H),7.07(d,J=8.0Hz,2H),7.02(d,J=8.0Hz,2H),4.01(d,J=6.0Hz,2H),3.97(s,3H),2.96(d,J=11.2Hz,2H),2.32(s,2H),2.18(m,2H),1.90-1.88(m,1H),1.83(d,J=12.0Hz,2H),1.48-1.39(m,2H).13C NMR(100MHz,DMSO-d6)δ157.82,156.83,153.94,153.38,152.48,149.39,147.34,135.70,130.47,124.64,123.50,119.53,118.45,109.22,108.31,102.61,72.84,56.81,54.72,45.70,34.42,29.50,28.18.HRMS(ESI)(m/z):[M+H]+calcd forC28H31N4O3,471.2396;found,471.2412.HPLC纯度:97.93%,保留时间=12.41min.
实施例9 N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-苯基丙酰胺
浅黄色固体(收率35%),熔点:199.6-199.8℃。1H NMR(400MHz,DMSO-d6):δ10.67(s,1H),9.58(s,1H),8.31(s,1H),7.91(s,1H),7.77(d,J=8.8Hz,1H),7.46-7.42(m,4H),7.34(t,J=7.6Hz,2H),7.27-7.20(m,2H),4.17-4.15(m,1H),4.05(d,J=6.0Hz,2H),3.95(s,3H),3.28(d,J=10.4Hz,2H),2.85-2.83(m,2H),2.62(s,3H),2.07-1.98(m,3H),1.67-1.64(m,2H),1.45-1.43(d,J=6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ173.04,157.91,155.86,153.77,153.63,149.29,147.16,142.23,138.74,129.00,128.84,127.81,127.20,115.17,109.10,108.29,107.25,107.00,102.85,72.16,58.73,53.22,49.04,46.23,33.03,26.42,18.97.HRMS(ESI)(m/z):[M+H]+calcd for C31H34FN5O3,544.2724;found,544.2709.HPLC纯度:98.56%,保留时间=12.02min.
实施例10 N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-3-甲基-2-苯基丁酰胺
白色固体(收率37%),熔点:196.0-196.2℃。1H NMR(400MHz,DMSO-d6):δ10.52(s,1H),9.49(s,1H),8.30(s,1H),7.85(s,1H),7.75(dd,J1=2.0Hz,J2=13.2Hz,1H),7.45-7.38(m,4H),7.33(t,J=7.6Hz,2H),7.24(m,1H),7.18(s,1H),4.01(d,J=6.4Hz,2H),3.94(s,3H),3.33(d,J=10.4Hz,1H),3.03(d,J=11.6Hz,2H),2.37(s,3H),2.34-2.24(m,3H),1.91-1.84(m,3H),1.50-1.45(m,2H),1.04(d,J=6.4Hz,1H),0.88(d,J=6.4Hz,1H).13C NMR(100MHz,DMSO-d6)δ172.48,157.89,155.86,153.93,153.59,149.35,147.21,140.04,128.77,128.68,127.37,115.19,108.99,108.17,107.26,107.00,102.63,72.70,60.98,56.65,54.43,45.27,34.14,31.47,27.65,21.70,20.68.HRMS(ESI)(m/z):[M+H]+calcd for C33H38FN5O3,572.3037;found,572.3047.HPLC纯度:97.51%,保留时间=13.00min.
实施例11 N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2,2-二苯基
白色固体(收率30%)熔点:257.0-257.2℃。1H NMR(400MHz,DMSO-d6):δ10.83(s,1H),9.50(s,1H),8.31(s,1H),7.85(s,1H),7.78(d,J=12.8Hz,1H),7.47-7.34(m,10H),7.29-7.26(m,2H),7.18(s,1H),5.27(s,1H),4.01(d,J=5.6Hz,2H),3.94(s,3H),3.02(d,J=10.8Hz,2H),2.38(s,3H),2.33-2.25(m,2H),1.90-1.84(m,3H),1.91-1.84(m,3H),1.50-1.42(m,2H).13C NMR(100MHz,DMSO-d6)δ170.64,157.86,155.86,153.94,153.60,149.37,147.22,140.26,129.04,128.89,127.38,115.33,109.00,108.19,107.41,102.62,72.69,57.74,56.65,54.43,45.25,34.12,27.84.HRMS(ESI)(m/z):[M+H]+calcd forC36H36FN5O3,606.2880;found,606.2888.HPLC纯度:98.61%,保留时间=13.25min.
实施例12 N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)基)-2-苯基乙酰胺
称取4-氯-6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉(100mg,0.32mmol)投入100mL茄型瓶中,加异丙醇约15mL使其溶解,加入N-(4-氨基-3-氟苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺(120mg,0.32mmol)加入6N盐酸2滴,80℃回流约6h,有白色沉淀产生。TLC跟踪原料反应完。抽滤,用少量异丙醇洗涤固体沉淀。将沉淀溶于二氯甲烷中,用碳酸氢钠饱和溶液调节pH至9,用饱和氯化钠/二氯甲烷萃取若干次,用无水硫酸钠干燥,旋蒸除去溶剂。粗品经硅胶柱层析(二氯甲烷/甲醇=10∶1)分离,得N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)基)-2-苯基乙酰胺90mg,收率42%。1H NMR(400MHz,DMSO-d6):δ10.80(s,1H),9.45(s,1H),8.32(s,1H),7.82(s,1H),7.78(s,1H),7.75(d,J=4.4Hz 1H),7.64-7.57(m,2H),7.54-7.43(m,7H),7.39(d,J=8.4Hz,1H),7.17(s,1H),7.26(s,1H),4.85(d,J=18Hz,1H),4.02-3.87(m,3H),3.96(s,3H),2.82(d,J=12.0Hz,2H),2.18(s,3H),2.03(t,J=11.2Hz,2H),1.81-1.78(m,3H),1.38-1.35(m,2H).13C NMR(100MHz,DMSO-d6):δ168.34,167.73,157.33,153.60,153.06,148.95,146.77,142.38,135.18,131.70,131.42,129.09,128.54,127.95,123.64,122.94,108.45,107.63,102.02,72.66,58.54,56.13,54.76,48.35,46.05,34.50,28.37.HRMS(ESI)(m/z):[M+H]+calcd for C38H37FN6O4,661.2939;found,661.2929.HPLC纯度:95.64%,保留时间=12.42min.
实施例13(2-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)二甲基氧化膦
白色固体(收率43%),熔点:150.5-150.8℃。1H NMR(400MHz,DMSO-d6):δ12.09(s,1H),9.10-9.03(m,1H),8.57(s,1H),7.45(s,1H),7.66-7.57(m,2H),7.18(s,1H),7.15(t,J=7.2Hz,1H),3.98(d,J=6Hz,2H),3.92(s,3H),2.78(d,J=12Hz,2H),2.16(s,3H),1.91-1.89(m,5H),1.86(s,3H),1.76-1.74(m,3H).13C NMR(100MHz,DMSO-d6):δ155.61,153.63,152.62,149.27,146.73,144.51,132.43,130.95,120.46,109.38,107.94,101.17,72.77,55.88,54.80,48.56,46.12,34.53,26.41,18.89,18.19.HRMS(ESI)(m/z):[M+H]+calcd for C29H33N8O3,455.2212;found,455.2207.HPLC纯度:97.49%,保留时间=9.23min.
实施例14(2-((7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)氧化膦
白色固体(收率45%),熔点:170.7-172.4℃。1H NMR(400MHz,DMSO-d6):δ12.36(s,1H),9.11(s,1H),8.65(s,1H),8.29(d,J=9.2Hz,1H),7.68-7.58(m,2H),7.25(dd,J1=2.4Hz,J2=9.2Hz,1H),7.23-7.15(m,2H),4.02(d,J=6Hz,2H),2.97(d,J=11.2Hz,2H),2.33(s,3H),2.20(t,J=10.8Hz,2H),1.89(s,3H),1.88(s,3H),1.83(d,J=10.8Hz,3H),1.48-1.39(m,2H).13C NMR(100MHz,DMSO-d6):δ162.05,158.68,154.77,151.93,144.19,132.40,131.04,123.71,122.14,121.02,120.95,1118.48,109.92,107.79,72.04,54.16,45.07,33.95,27.57,18.85,18.14.HRMS(ESI)(m/z):[M+H]+calcd for C23H30N4O2P,425.2106;found,425.2110.HPLC纯度:98.02%,保留时间=8.75min.
实施例15 N-(4-((6,7-二甲氧基吡啶-4-基)氨基)-3-氟苯基)苯甲酰胺
白色固体,收率40%。1H NMR(400MHz,DMSO-d6):δ10.80(s,1H),9.45(s,1H),8.33(s,1H),7.81(s,1H),7.78(s,1H),7.75(d,J=4.4Hz 1H),7.64-7.57(m,2H),7.54-7.43(m,7H),7.39(d,J=8.4Hz,1H),7.17(s,1H),6.26(s,1H),4.85(d,J=18Hz,1H),4.02-3.87(m,3H),3.96(s,3H),2.82(d,J=12Hz,2H),2.18(s,3H),2.03(t,J=11.2Hz,2H),1.81-1.78(m,3H),1.38-1.35(m,2H).13C NMR(100MHz,DMSO-d6):δ165.70,157.41,154.21,153.13,148.81,146.80,134.65,131.75,128.43,127.67,115.87,108.54,107.01,101.90,56.05,55.76.HRMS(ESI)(m/z):[M+H]+calcd for C29H33N8O3,516.2407;found,516.2410.
实施例16 N-(3-((6,7-二甲氧基吡啶-4-基).氨基)-4-氟苯基)苯甲酰胺
白色固体,收率30%。1H NMR(400MHz,DMSO):δ11.90(s,1H),10.59(s,1H),8.83(s,1H),8.47(s,1H),7.25(dd,J1=2.8Hz,J2=7.2Hz,1H),8.01(s,1H),8.00(s,1H),7.83-7.79(m,2H),7.61(t,J=4.8Hz,1H),7.56-7.52(m,2H),7.47(s,1H),7.40(t,J=9.6Hz,1H),4.03(s,3H),4.00(s,J=3H).13C NMR(100MHz,DMSO-d6):δ106.03,157.73,154.81,153.49,152.36,149.36,135.24,132.11,128.88,128.14,120.39,109.10,107.33,102.57,56.60,56.30.HRMS(ESI)(m/z):[M+H]+calcd for C23H20FN4O3,419.1508;found,419.1524.
实施例17 N-(4-((6,7-二甲氧基吡啶-4-基)氨基)-3-氟苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺
白色固体,收率45%。1H NMR(400MHz,DMSO):δ10.80(s,1H),9.45(s,1H),8.33(s,1H),7.81(s,1H),7.78(s,1H),7.75(d,J=4.4Hz 1H),7.64-7.57(m,2H),7.54-7.43(m,7H),7.39(d,J=8.4Hz,1H),7.17(s,1H),6.26(s,1H),4.85(d,J=18Hz,1H),4.00(d,J=18Hz,1H),3.94(s,3H),3.93(s,3H).13C NMR(100MHz,DMSO-d6):δ168.35,157.36,154.22,153.07,148.81,146.81,142.39,137.28,135.17,131.71,131.42,129.09,128.54,127.95,123.65,122.93,108.53,107.01,101.90,58.54,56.04,55.76,48.57.HRMS(ESI)(m/z):[M+H]+calcd for C27H25FN4O3,564.2012;found,564.2045.HPLC纯度:96.86%,保留时间=14.16min.
实施例18 N-(4-氟-3-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)基)-2-苯基乙酰胺
白色固体(收率20%)。1H NMR(400MHz,DMSO):δ10.77(s,1H),9.70(s,1H),8.36(s,1H),7.90(s,1H),7.76(d,J=7.6Hz,1H),7.64-7.62(m,2H),7.53-7.49(m,2H),7.47-7.41(m,4H),7.28(t,J=10.0Hz,1H),7.21(s,1H),6.26(s,1H),4.82(d,J=17.6Hz,1H),4.03(d,J=17.6Hz,1H),4.00(d,J=6.0Hz,2H),3.96(s,3H),3.12(d,J=11.6Hz,2H),2.48(s,3H),2.02-1.95(m,1H),1.94-1.91(m,4H),1.56-1.49(m,2H).13C NMR(100MHz,DMSO-d6)δ168.64,168.19,157.70,153.89,149.45,142.86,135.81,135.28,132.17,131.92,129.53129.02,128.43,124.12,123.41,119.39,109.15,108.11,105.63,103.00,62.07,58.96,56.81,56.28,53.27,48.89,46.99.HRMS(ESI)(m/z):[M+H]+calcd forC38H37FN6O4,661.2913;found,661.2943.HPLC纯度:95.85%,保留时间=12.42min.
实施例19(S)-N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺
白色固体(收率45%)。1H NMR(400MHz,DMSO):δ10.37(s,1H),9.54(s,1H),8.33(s,1H),7.85(s,1H),7.80(dd,J1=2Hz,J2=5.6Hz,1H),7.77(s,1H),7.62-7.58(m,2H),7.54-7.44(m,7H),7.39(dd,J1=1.6Hz,J2=8.8Hz,2H),7.18(s,1H),6.27(s,1H),4.85(d,J=17.6Hz,1H),4.02(d,J=5.6Hz,2H),4.00(d,J=17.6Hz,2H),3.96(s,3H),2.93(d,J=11.2Hz,2H),2.29(s,3H),2.13(t,J=11.2Hz,2H).1.82-1.80(m,3H),1.48-1.38(m,2H).13C NMR(100MHz,DMSO-d6)δ168.86,168.23,157.83,155.87,154.01,153.57,149.39,147.24,142.88,135.86,132.21,129.59,129.19,128.45,124.15,123.44,115.45,108.98,108.12,107.59,102.57,72.89,59.03,58.48,56.64,54.79,49.07,48.88,45.82,34.50,28.28.HRMS(ESI)(m/z):[M+H]+calcd for C38H38FN6O4,661.2912;found,661.2938.HPLC纯度:97.68%,保留时间=12.48min.
实施例20(R)-N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺
白色固体(收率45%)。1H NMR(400MHz,DMSO):δ10.96(s,1H),9.73(s,1H),8.32(s,1H),7.96(s,1H),7.79-7.78(m,1H),7.77(s,1H),7.64-7.58(m,2H),7.52(t,J=14Hz,1H),7.49(s,1H),7.47-7.43(m,5H),7.39(dd,J1=1.6Hz,J2=8.8Hz,1H),7.22(s,1H),6.28(s,1H),4.84(d,J=17.6Hz,1H),4.02(d,J=5.6Hz,2H),4.00(d,J=17.6Hz,1H),3.96(s,3H),3.22(d,J=11.2Hz,2H),2.74(t,J=9.6Hz,2H),2.57(s,3H),1.96-1.92(m,3H),1.86-1.80(m,2H).13C NMR(100MHz,DMSO-d6)δ168.92,168.19,158.14,154.06,149.49,142.87,135.71,132.20,131.93,129.55,129.09,128.99,124.45,123.42,115.45,108.12,107.59,102.57,72.90,60.42,59.05,58.48,56.98,53.14,49.94,43.05,33.00,26.31.HRMS(ESI)(m/z):[M+H]+calcd for C38H38FN6O4,661.2925;found,661.2935.
实施例21 2-环己基-N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)乙酰胺
白色固体(收率26%)。1H NMR(400MHz,DMSO):δ10.78(s,1H),9.51(s,1H),8.32(s,1H),7.84(s,1H),7.77(d,J=6.8Hz,1H),7.75(s,1H),7.67-7.63(m,2H),7.53-7.41(m,3H),7.18(s,1H),4.87(d,J=18.4Hz,1H),4.83(s,1H),4.61(d,J=18.4Hz,1H),4.00(d,J=6Hz,2H),3.95(s,3H),2.91(d,J=11.2Hz,2H),2.26(s,3H),2.11(t,J=10.8Hz,3H),1.83-1.76(m,4H),1.62-1.64(m,3H),1.48-1.37(m,3H),1.26-1.22(m,5H).13C NMR(100MHz,DMSO-d6)δ169.29,168.32,158.23,157.83,155.79,154.00,153.56,149.38,147.23,142.79,137.68,137.57,129.08,128.36,124.04,123.43,122.43,122.31,115.85,108.96,108.11,107.72,107.47,102.54,72.91,60.24,56.63,54.84,47.70,45.90,37.54,34.55,29.67,29.58,28.35,26.27,25.56,25.41.HRMS(ESI)(m/z):[M+H]+calcd forC38H43FN6O4,667.3412;found,667.3406.HPLC纯度:96.75%,保留时间=13.09min.
实施例22 N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(3-氟苯基)-2-(1-氧代异吲哚啉-2-基)乙酰胺
白色固体(收率41%)。1H NMR(400MHz,DMSO):δ10.95(s,1H),9.63(s,1H),8.32(s,1H),7.90(s,1H),7.78(s,1H),7.76(d,J=4.8Hz,1H),7.65-7.59(m,2H),7.57-7.50(m,2H),7.46(d,J=8.8Hz,1H),7.38(d,J=8.8Hz,1H),7.31-7.26(m,3H),7.22(s,1H),6.26(s,1H),4.82(d,J=17.6Hz,1H),4.02(d,J=5.6Hz,2H),4.00(d,J=17.6Hz,1H),3.95(s,3H),3.31(d,J=11.2Hz,2H),2.84(t,J=9.6Hz,2H),2.64(s,3H),1.96-1.92(m,3H),1.66-1.58(m,2H).13C NMR(100MHz,DMSO-d6)δ168.25,163.96,161.52,157.81,155.84,154.00,153.57,149.39,147.24,142.92,132.28,131.79,129.16,128.48,125.18,124.18,123.47,108.98,108.12,102.58,74.35,72.87,60.47,58.48,56.64,54.76,48.92,45.77,34.54,28.25.HRMS(ESI)(m/z):[M+H]+calcd for C38H37F2N6O4,679.2837;found,679.2845.HPLC纯度:97.51%,保留时间=12.72min.
实施例23 N-(3-氟-4-((7-甲氧基-6-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)基)-2-苯基乙酰胺
称取((4-((2-氟-4-(2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰氨基)苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)甲基)哌啶-1-甲酸叔丁酯(600mg,0.80mmol)于100mL茄型瓶中,加入约12mL甲酸,常温搅拌约30min,使其溶解。后缓慢滴加约甲醛溶液(4mL47.44mmol,37%),95℃回流加热,氩气保护,反应约6h后,TLC点板确定反应完毕。隔膜泵旋蒸除去溶剂。粗品经硅胶柱层析(二氯甲烷/甲醇=10∶1)分离,得到N-(3-氟-4-((7-甲氧基-6-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)基)-2-苯基乙酰胺白色固体120mg,收率22%。白色固体(收率21%)。1H NMR(400MHz,DMSO):δ10.87(s,1H),9.59(s,1H),8.31(s,1H),7.91(s,1H),7.77(s,1H),7.75(d,J=3.2Hz,1H),7.64-7.57(m,2H),7.54-7.43(m,7H),7.37(d,J=8.8Hz,1H),7.19(s,1H),6.25(s,1H),4.24(d,J=17.6Hz,1H),4.04-4.03(m,2H),3.98(d,J=17.6Hz,1H),3.94(s,3H),3.01-2.90(m,2H),2.69(s,3H),2.16-2.08(m,1H),2.03-1.96(m,3H),1.67-1.64(m,2H).13C NMR(100MHz,DMSO-d6)δ168.87,168.23,158.36,157.88,155.92,154.79,153.60,148.52,147.22,142.88,135.65,132.21,131.91,129.59,129.29,129.05,128.46,124.15,123.43,115.48,109.01,107.59,107.34,103.29,73.09,59.05,56.33,54.03,49.06,44.57,33.94,27.52.HRMS(ESI)(m/z):[M+H]+calcd for C38H37FN6O4,661.2908;found,661.2932.HPLC纯度:95.95%,保留时间=12.32min.
实施例24(3-氟-4-((7-甲氧基-6-((4-甲基哌嗪-1-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)基)-2-苯基乙酰胺
称取3-氟-4-((6-羟基-7-甲氧基喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺(300mg,0.54mmol)于100mL茄型瓶中,加入乙醇使其溶解,加乙醇钠(100mg,1.36mmol),加多聚甲醛(50mg,1.09mmol),N-甲基哌嗪(140mg,1.36mmol),浓HCl2-3滴,回流反应约3h后,TLC点板确定反应完毕。水泵旋蒸除去溶剂。粗品经硅胶柱层析(二氯甲烷/甲醇=10∶1)分离,得到N-(3-氟-4-((7-甲氧基-6-((4-甲基哌嗪-1-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)基)-2-苯基乙酰胺120mg,收率33%。白色固体(收率25%)。1H NMR(400MHz,DMSO):δ10.78(s,1H),9.49(s,1H),8.22(s,1H),7.96(s,1H),7.78-7.72(m,2H),7.63-7.56(m,3H),7.52(d,J=7.6Hz,2H),7.48-7.43(m,5H),7.33(d,J=8.8Hz,1H),7.15(s,1H),6.25(s,1H),4.23(d,J=17.6Hz,1H),3.98(d,J=17.6Hz,1H),3.98(s,3H),3.92(s,2H),2.89(s,2H),2.73(s,2H),2.67-2.58(m,4H),2.15(s,3H).13C NMR(100MHz,DMSO-d6)δ168.75,168.19,158.66,153.08,147.81,146.35,142.88,135.77,132.18,131.93,129.55,129.03,128.44,124.13,123.43,114.77,111.46,107.56,107.31,107.08,59.98,56.52,54.48,51.67,48.87,45.90,45.70,43.14.HRMS(ESI)(m/z):[M+H]+calcd for C37H36FN7O4,662.2883;found,662.2885.HPLC纯度:98.81%,保留时间=12.00min.
实施例25(3-氟-4-((7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺
白色固体(收率25%)。1H NMR(400MHz,DMSO):δ10.87(s,1H),9.55(s,1H),8.33(s,1H),7.85(s,1H),7.77(d,J=8.4Hz,2H),7.64-7.58(m,2H),7.54-7.44(m,7H),7.38(d,J=8.8Hz,1H),7.19(s,1H),6.27(s,1H),4.84(d,J=18.0Hz,1H),4.17(t,J=6.4Hz,2H),4.00(d,J=18.0Hz,1H),3.94(s,3H),3.79-3.74(m,4H),2.47-2.44(m,2H),2.42-2.41(m,4H),2.02-1.97(m,2H).13C NMR(100MHz,DMSO-d6)δ168.32,168.03,157.16,156.97,154.62,152.71,148.42,142.36,136.46,134.68,131.43,131.39,128.70,128.67,128.37,127.59,127.27,123.06,122.76,114.96,108.58,107.31,107.06,106.86,101.59,66.86,66.98,59.25,55.36,54.83,53.12,48.24,25.48.HRMS(ESI)(m/z):[M+H]+calcd forC38H37FN6O5,677.2908;found,677.2912.HPLC纯度:95.91%,保留时间=12.25min.
实施例26(4-((6,7-双(2-甲氧基乙氧基)喹唑啉-4-基)氨基)-3-氟苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺
白色固体(收率22%)。1H NMR(400MHz,DMSO):δ10.83(s,1H),9.47(s,1H),8.33(s,1H),7.85(s,1H),7.77(d,J=8.0Hz,2H),7.62-7.58(m,2H),7.54-7.44(m,7H),7.38(dd,J1=1.6Hz,J2=8.8Hz,3H),7.22(s,1H),6.26(s,1H),4.84(d,J=18.4Hz,1H),4.27(m,4H),4.99(d,J=18.4Hz,1H),3.79-3.74(m,4H),3.37(s,3H),3.36(s,3H).13C NMR(100MHz,DMSO-d6)δ168.86,168.24,157.82,155.83,154.02,153.63,148.44,147.18,142.88,135.64,132.22,131.90,129.00,129.05,128.46,124.16,123.44,115.43,109.04,108.45,103.58,70.52,68.63,68.43,59.03,58.84,58.80,48.87.HRMS(ESI)(m/z):[M+H]+calcd for C36H34FN5O6,652.2527;found,642.2567.HPLC纯度:97.77%,保留时间=14.36min.
实施例27(4-((2-氨基-6,7-二甲氧基喹唑啉-4-基)氨基)-3-氟苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺
称取4-氯-6,7-二甲氧基-2-胺(100mg,0.41mmol)投入100mL茄型瓶中,加异丙醇约15mL使其溶解,加入N-(4-氨基-3-氟苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺(190mg,0.50mmol)加入6N盐酸2滴,80℃回流约6h,有白色沉淀产生。TLC跟踪原料反应完。抽滤,用少量异丙醇洗涤固体沉淀。将沉淀溶于二氯甲烷中,用碳酸氢钠饱和溶液调节pH至9,用饱和氯化钠/二氯甲烷萃取若干次,用无水硫酸钠干燥,旋蒸除去溶剂。粗品经硅胶柱层析(二氯甲烷/甲醇=10∶1)分离,得(4-((2-氨基-6,7-二甲氧基喹唑啉-4-基)氨基)-3-氟苯基)-2-(1-氧代异吲哚啉-2-基)-2-苯基乙酰胺90mg,收率37%。1H NMR(400MHz,DMSO):δ10.66(s,1H),8.18(t,J=8.8Hz,1H),7.79(s,1H),7.76(d,J=8.0Hz,1H),7.70(d,J=12.8Hz,1H),7.62-7.56(m,2H),7.52-7.44(m,5H),7.27-7.25(m,3H),6.80(s,1H),6.24(s,1H),4.85(d,J=17.6Hz,1H),4.97(d,J=17.6Hz,1H),3.84(s,3H),3.82(s,3H),3.38(s,2H).13C NMR(100MHz,DMSO-d6)δ168.70,168.20,162.05,155.24,146.58,142.88,135.72,132.19,131.93,129.55,129.05,128.45,124.15,123.41,115.47,107.34,107.09,104.74,103.88,107.08,59.03,56.53,56.22,48.91.HRMS(ESI)(m/z):[M+H]+calcd forC32H27FN6O4,579.2134;found,579.2155.HPLC纯度:98.12%,保留时间=14.71min.
实施例28 2-(2,5-二氟苯基)-N-(3-氟-4-((6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)氨基)苯基)-2-(1-氧代异吲哚啉-2-基)乙酰胺
白色固体(收率38%),熔点:202.2-202.4℃。1H NMR(400MHz,DMSO-d6):δ10.85(s,1H),9.53(s,1H),8.33(s,1H),7.85(s,1H),7.79-7.73m,2H),7.66-7.29(m,9H),7.18(s,1H),6.42(s,1H),4.82(d,J=17.6Hz,1H),4.14(d,J=17.6Hz,1H),4.01(d,J=6.0Hz,2H),3.95(s,3H),2.96(d,J=10.4Hz,2H),2.32(s,3H),2.19(t,J=11.2Hz,2H),1.85-1.75(m,3H),1.48-1.36(m,2H).13C NMR(100MHz,DMSO-d6):δ168.00,167.40,157.82,155.92,154.01,153.57,149.40,147.25,142.82,132.38,131.63,129.14,128.53,124.23,123.53,115.73,108.99,108.15,102.59,72.84,56.65,56.68,53.35,48.77,45.64,34.38,28.14.HRMS(ESI)(m/z):[M+H]+calcd for C38H35F3N6O4,697.2750;found,679.2759.HPLC纯度:95.36%,保留时间=10.78min.
生物评价方法:
酪氨酸激酶:EGFR(WT)
EGFRT790M/L858R(LR/TM)
EGFRT790M/L858R/C797S(LR/TM/CS)
ELISA激酶活性检测
用酶联免疫吸附法(Enzyme-Linked Immunosorbent Assay,ELISA)检测激酶磷酸化底物的能力,计算化合物对激酶活性的抑制作用。激酶采用EGFR L858R/T790M/C797S(购自BPS Bioscience)。
ELISA主要步骤如下:酶反应底物Poly(Glu,Tyr)4∶1用无钾离子的PBS稀释成2.5μg/孔,37℃反应12-16h包被酶标板,备用。每孔加入用反应缓冲液(50mM HEPES pH 7.4,20mM MgCl2,0.1mM MnCl2,0.2mM Na3VO4,1mM DTT)稀释的ATP(终浓度5μM)溶液,加入化合物或溶剂对照,然后加入激酶启动反应,37℃摇床反应1h。T-PBS洗板三次,加入抗体PY99(含5mg/mL BSA的T-PBS,1∶500稀释)100μL于37℃摇床反应0.5h。T-PBS洗板后,加入辣根过氧化物酶标记的羊抗鼠的IgG(含5mg/mL BSA的T-PBS,1∶2000稀释)100μL,37℃摇床反应0.5h。再次洗板后,加入含0.03%H2O2,2mg/mL的OPD(0.1mol/L,pH 5.4柠檬酸盐缓冲液配制)显色液100μL/孔,25℃避光反应1-10min。加入50μL/孔2M H2SO4终止反应,用可调波长式微孔板酶标仪(SpectraMax Plus384,Molecular Devices)读数,波长为490nm。IC50值由抑制曲线得到。
酶活性测试结果如下表:
a激酶活性测试通过使用ELISA基EGFR-TK测试进行。数据是至少两次独立测定的平均值并以平均值±SD(标准偏差)表示。b二突变体(EGFRL858R/T790M).c三突变体(EGFRL858R /T790M/C797S)。
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 (9)
2.如权利要求1所述化合物或其立体异构体或光学异构体,或其药学上可接受的盐,其特征在于,所述卤素是氟、氯、溴或碘。
7.一种药物组合物,其特征在于,所述药物组合物含有权利要求1-6中任一项所述的化合物或其立体异构体或光学异构体,或其药学上可接受的盐,以及药学上可接受的载体或赋形剂。
8.权利要求1-6中任一项所述的化合物或其立体异构体或光学异构体,或其药学上可接受的盐在制备治疗或预防EGFR介导的疾病或抑制EGFR的药物中的用途。
9.如权利要求8所述的用途,其特征在于,所述EGFR介导的疾病为癌症。
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PCT/CN2019/082498 WO2019196938A1 (zh) | 2018-04-13 | 2019-04-12 | 喹唑啉类化合物作为egfr三突变抑制剂及其应用 |
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