CN112300194B - 一类稠环吡啶酮类化合物、制备方法和用途 - Google Patents
一类稠环吡啶酮类化合物、制备方法和用途 Download PDFInfo
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- CN112300194B CN112300194B CN202010747468.2A CN202010747468A CN112300194B CN 112300194 B CN112300194 B CN 112300194B CN 202010747468 A CN202010747468 A CN 202010747468A CN 112300194 B CN112300194 B CN 112300194B
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
Abstract
本发明公开了一类稠环吡啶酮类化合物、制备方法和用途。具体为一种如通式I所示的稠环吡啶酮类化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药、其制备方法及在药学上的应用,其中各基团的定义如说明书中所述。
Description
技术领域
本发明属于药物化学领域,具体地,涉及一类稠环吡啶酮类化合物,具有抑制Ras突变蛋白活性的化合物、制备方法和用途。
背景技术
RAS是第一个在人类肿瘤中被鉴定出来的致癌基因,最早在两种鼠肉瘤病毒中被发现。RAS基因家族有三个成员,分别是Hras、Kras、Nras。在人类肿瘤中,Kras突变最为常见,约占85%。先前研究表明,Kras突变之所以能致癌,是因为第12号密码子发生了错义突变,改变了Kras蛋白质的结构并使其一直处于激活状态。Ras在信号通路传递中的作用主要是活化控制基因转录的激酶,从而调节细胞分化和增生,与肿瘤细胞的生存、增殖、迁移、转移和血管生成密切相关。据统计,有11%-16%的肺腺癌病例中存在Kras G12C突变,胰腺癌、结直肠癌、卵巢癌、胆管癌里也有一部分是Kras突变导致。然而,距离首次发现Kras致癌基因已过去三十余年,EGFR、BCL等常见原癌基因的靶向药物已历经数代,针对Kras的靶向药却始终未能成功研发出来。一直以来,针对KRas通路突变型肿瘤的靶向药物主要集中在法尼基转移酶抑制剂和Raf-MEK通路抑制剂上,但是收效甚微。近年来,针对KRas特定基因突变的抑制剂研发成为热点,部分抑制剂逐渐由临床前孵化走向临床研究,如KRas G12C抑制剂AMG510,MRTX1257等,并且在早期临床实验中显示了一定的疗效。全球首款KRASG12C抑制剂AMG 510的第一项临床数据终于在2019年6月举行的美国临床肿瘤学会正式公布,在这项临床研究中,安进药物AMG 510显示出能够阻止大多数具有KRas突变的非小细胞肺癌和结直肠癌患者的肿瘤生长。因此,发现和寻找特异性高、成药性优异的针对KRas特定突变基因的靶向药物成为工业界一大热点。
发明内容
本发明需要解决的技术问题之一是提供一种新型的KRas G12C抑制剂,用于制备肿瘤治疗药物。
解决上述技术问题的方案如下:
一种具有如通式I所示的稠环吡啶酮类化物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,
式中:
R1独立地选自氢、氘、卤素、氰基、硝基、C1-C6烷基、C1-C6烷基-SO2-、C1-C6烷基-SO-、或C1-C6卤代烷基;
R2、R3独立地选自氢、卤素、氰基、硝基、C1-C6烷基、C1-C6烷基-SO2-、C1-C6烷基-SO-、N(R2a)(R2b)-(CH2)x-;或者,R9和R10共同构成一个5-10元的被C1-C6烷基取代的含氮杂环烷基;其中,R2a和R2b各自独立地选自氢或C1-C6烷基,x选自0-5中的任一整数;
W,W1,W2独立地选自CR4或N,R4独立地选自H、氘、卤素、氰基、羟基、氨基、C1-C6烷基、C1-C6烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、3-8元环烷基或杂环烷基等;
Ra,Rb,Rc,Rd,Re,Rf,Rg分别独立地选自氢、氘、C1-C6烷基、烷氧基、卤代烷基等,或者Ra,Rb,Rc,Rd,Re,Rf和Rg两两之间形成3-8元的饱和或部分不饱和环系;
Ar独立地选自5-12元芳香环或芳香稠环、5-12元芳香杂环或芳香稠杂环;并且Ar环可以被一个或多个以下基团所取代:氢、氘、卤素、C1-C6烷基、烷氧基、3-8元环烷基或杂环烷基、C1-C6卤代烷氧基、C2-C6烯基、C2-C6炔基、取代或未取代的氨基、酰胺基、磺酰胺基等;
Z独立地选自O或NR5,R5独立地选自H、氘、C1-C6烷基、C1-C6烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、3-8元环烷基或杂环烷基等;
Ri和Rj独立地选自H、氘、卤素、C1-C6烷基、C1-C6烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、3-8元环烷基或杂环烷基等,或者当Z为NR5时,Ri和Rj可以为氧代;或者Ri和Rj两者可以相互形成3-8元饱和或部分不饱和或不饱和环系;或者Ri和Rj可以分别与Z形成3-8元饱和或部分不饱和或不饱和环系;
R独立地选自氢、氘、C1-C20烷基,C2-12的烯基,C2-C12的炔基、3-12元环烷基或杂环烷基,5-10元芳基或杂芳基等;
其中,所述的杂芳基包含1-3个选自下组的杂原子:N、O、P或S,所述的杂环烷基包含1-3个选自下组的杂原子:N、O、P或S,所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
在一些实施方式中,具有通式(I)所述的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,其优选为通式(IIA)、(IIB)、(IIC)所示的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药:
其中R6独立地选自氢、氘、C1-C6烷基、烷氧基、卤代烷基、卤代烷氧基等;R、R1、R2、R3、Ra、Rb、Rc、Rd、Re、Rf、Rg、W、W1、W2、Ri、Rj如上文所定义。
在另一些实施方式中,具有通式(1)所述的化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,其特征在于:
R1优选自氢、氘、氟、甲基、氰基等;
Ra、Rb、Rc、Rd、Re、Rf、Rg分别独立第优选自氢、氘、氟、甲基;
W1和W分别独立地优选自CR4,R4独立地选自氢、氘、卤素、氰基、羟基、氨基、C1-C4烷基、C1-C4烷氧基、C2-C4烯基、C2-C4炔基、C1-C4的烷氧基、3-6元环烷基、C1-C4卤代烷基、C1-C4卤代烷氧基等;
W2独立地优选自N或CH、C-F、C-Cl、C-Me、C-OMe等;
Ar独立地优选自取代或未取代的苯基和吡啶基等单环芳香基团,或者取代或未取代的萘基、萘啶基、吲唑基、苯并咪唑基、苯并噻唑基等双环芳香基团;所述的一个或多个取代基优选自下组:氢、氘、卤素、C1-C4的烷基、羟基、氨基、氰基、C1-C4烷氧基、C1-C4卤代烷基、C1-C4卤代烷氧基等;
R独立地优选自取代或未取代的C6-C20烷基、取代或未取代的3-8元的环烷基或杂环烷基、取代或未取代的5-10元芳基或杂芳基;进一步优选为C6-C20的支链烷基,5-8元的环烷基或杂环烷基,苯基或吡啶基等;
其它基团的范围如上文所定义。
一种制备式I化合物的方法,其特征在于,所述方法包括步骤a-c:
a)将通式(A)化合物与芳基硼酸或芳基硼酸酯或芳基金属试剂(Ar-M)通过过渡金属催化偶联反应转化成中间体(B);和
b)将通式(B)化合物通过常规官能团脱除保护基团PG,得到通式(C)化合物;
c)将通式(C)化合物和丙烯酸或者丙烯酰氯在适当条件下发生缩合反应生成通式(I)。
所示各基团的定义如上所述;
优选地,所述步骤a)、b)、c)各自在溶剂中进行,且所述溶剂选自下组:水、甲醇、乙醇、异丙醇、丁醇、乙二醇、乙二醇甲醚、N-甲基吡咯烷酮、二甲基亚砜,四氢呋喃、甲苯、二氯甲烷、1,2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环,或其组合物。
优选地,所述过渡金属催化剂选自下组:三(二亚苄基丙酮)二钯(Pd2(dba)3)、四(三苯基膦)钯(Pd(PPh3)4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、1,2-二(二苯基膦基)乙烷二氯化钯,或其组合物;所述催化剂配体选自下组:三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、三邻苯甲基膦,或其组合物。
优选地,所述缩合试剂选自下组:DCC、DIC、CDI、EDCI、HOAt、HOBt、BOP、PyBOP、HATU、TBTU等,或其组合物。
优选地,所述无机碱选自下组:氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠,或其组合物;所述有机碱选自下组:吡啶,三乙胺,N,N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶,或其组合物。
优选地,所述酸选自下组:盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸、乙酸,三氟甲磺酸或其组合物。
优选地,所述还原剂选自下组:铁粉、锌粉、氯化亚锡、硫代硫酸钠、亚硫酸钠、氢气等。
本发明提供的一类通式(I)优选化合物,包括但不限于以下结构:
本发明的另一目的是提供一种治疗或预防肿瘤的药物及其组合物。实现上述目的的技术方案如下:
一种***的药物组合物,其由上述通式(I)所示的稠环吡啶酮类化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药与药学上可接受的载体组成。
本发明的另一目的是提供一种上述化合物的用途。实现上述目的的技术方案如下:
所述通式(I)所示的稠环吡啶酮类化合物,或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药用于制备治疗与Ras突变蛋白活性或表达量相关的疾病的药物,特别是肿瘤的治疗药物。所述的肿瘤独立地选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、***癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌、胰腺癌等。
本发明涉及具有通式(I)结构特征的化合物,可以抑制多种肿瘤细胞,尤其是能高效地杀死KRas G12C突变蛋白信号通路异常相关的肿瘤,是一类全新作用机制的治疗药物。
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
发明人经过长期而深入的研究,制备了一类具有式I所示结构新颖的化合物,并发现其具有较好的抑制KRas G12C蛋白抑制活性,且所述的化合物在极低浓度(可低至小于100nM)下,即对KRas G12C蛋白产生特异性抑制作用,并且对KRas G12C相关的细胞增殖抑制活性相当优异,且所述的化合物在极低浓度(可低至小于10nM)下,即对KRas G12C阳性的肿瘤细胞具有较强的杀伤作用,因而可以用于治疗与KRas G12C突变或表达量异常引起的相关疾病如肿瘤。基于上述发现,发明人完成了本发明。
术语
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本发明主题作任何限制。在本申请中,除非另有具体说明,否则使用单数时也包括复数。必须注意,除非文中另有清楚的说明,否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
在本申请中,术语“卤素”是指氟、氯、溴或碘;“羟基”是指-OH基团;“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基;“羰基”是指-C(=O)-基团;“硝基”是指-NO2;“氰基”是指-CN;“氨基”是指-NH2;“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基;“羧基”是指-COOH。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个,更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。
在本申请中,作为基团或是其它基团的一部分,术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3至15个碳原子,优选具有3至10个碳原子,更优选具有3至8个碳原子,且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明,环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系;其杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言,杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言,芳基可以为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中,术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。就本发明的目的而言,杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中,术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中,“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选地被取代的芳基”表示芳基被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成,通过相同的键键合,但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体),例如可参见GeraldGübitz and Martin G.Schmid(Eds.),Chiral Separat ions,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004;A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010;Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and TechnicalLtd.,Essex,1991,809-816;Heller,Acc.Chem.Res.1990,23,128。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型,本发明旨在包括各种晶型及其混合物。
通常,结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水,该情况下的溶剂化物为水合物。或者,溶剂可以是有机溶剂。因此,本发明的化合物可以以水合物存在,包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等,以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物,但在某些情况下,也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中,术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此,术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时,前药可以不具有活性,但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化,而产生本发明的母体化合物,例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990;Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”,“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物***的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,ThePharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。
本领域技术人员还应当理解,在下文所述的方法中,中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in OrganicSynthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
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。
中间体制备方法一:稠环吡啶酮类化合物的合成
参照专利WO2019110751A1和WO2018217651A1的合成路线和方法,制备得到稠环吡啶酮类中间体化合物1A-1H。
中间体制备方法二:哌嗪类化合物的合成
参照专利WO2019110751A1和US20190062330A1的合成路线和方法,制备得到哌嗪类中间体化合物2A-2C
实施例通用制备方法一
第一步:将稠环吡啶酮类中间体(1eq.)溶于无水四氢呋喃中,依次加入N,N-二异丙基乙胺(DIPEA)(1.6eq.)和哌嗪类中间体(1.5eq.),氮气保护下加热回流18小时。薄层层析(TLC)监测反应完全,冷却至室温,减压浓缩,剩余物加入水和二氯甲烷分相,水相用二氯甲烷萃取三次,萃取液无水硫酸钠干燥,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第二步:将上述第一步产物(1eq.)溶于N,N-二甲基甲酰胺(DMF)中,加入双(三甲基硅基)胺基锂(LiHMDS)(3eq.),氮气保护下加热至100度搅拌8小时。TLC监测反应完全,冷却至室温,倒入饱和氯化铵水溶液中,有固体析出,过滤,滤饼真空干燥得到目标产物,采用核磁和质谱确认结构。
第三步:将上述第二步产物(1eq.)溶于无水二氧六环/水(4/1)的混合溶剂中,依次加入硼酸或三氟硼酸钾盐(2eq.),无水碳酸钾粉末(2.5eq.)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl2)(0.1eq.),氮气保护下加热回流2小时。TLC监测反应完全,冷却至室温,减压浓缩,剩余物用二氯甲烷稀释,依次用饱和氯化铵溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第四步:将上述第三步产物(1eq.)溶于甲醇中,加入4M(氯化氢)HCl/甲醇溶液(20eq.),室温下搅拌3小时。TLC监测反应完全,减压浓缩,剩余物溶于二氯甲烷中,0度下依次加入DIPEA(3eq.)和丙烯酰氯(1eq.),搅拌0.5小时,反应液用饱和氯化铵溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标化合物,采用核磁和质谱确认结构。
实施例通用制备方法二
第一步:将稠环吡啶酮类中间体(1eq.)溶于无水四氢呋喃中,依次加入DIPEA(1.6eq.)和哌嗪类中间体(1.5eq.),氮气保护下加热回流18小时。TLC监测反应完全,冷却至室温,减压浓缩,剩余物加入水和二氯甲烷分相,水相用二氯甲烷萃取三次,萃取液无水硫酸钠干燥,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第二步:将上述第一步产物(1eq.)溶于无水冰醋酸中,慢慢加入还原铁粉(3eq.),氮气保护下加热至80度搅拌0.5小时。反应完毕,硅藻土过滤,乙酸乙酯洗涤,滤液浓缩。剩余物用二氯甲烷稀释,依次用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第三步:将上述第二步产物(1eq.)溶于DMF中,0度下加入钠氢(1.5eq.),搅拌0.5小时,加入碘甲烷(1.1eq.),室温下反应过夜。反应完毕,反应液减压浓缩,剩余物用二氯甲烷稀释,依次用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第四步:将上述第三步产物(1eq.)溶于无水二氧六环/水(4/1)的混合溶剂中,依次加入硼酸或三氟硼酸钾盐(2eq.),无水碳酸钾粉末(2.5eq.)和Pd(dppf)Cl2(0.1eq.),氮气保护下加热回流2小时。TLC监测反应完全,冷却至室温,减压浓缩,剩余物用二氯甲烷稀释,依次用饱和氯化铵溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第五步:将上述第四步产物(1eq.)溶于甲醇中,加入4M氯化氢/甲醇溶液(20eq.),室温下搅拌3小时。TLC监测反应完全,减压浓缩,剩余物溶于二氯甲烷中,0度下依次加入DIPEA(3eq.)和丙烯酰氯(1eq.),搅拌0.5小时,反应液用饱和氯化铵溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标化合物,采用核磁和质谱确认结构。
实施例通用制备方法三
第一步:将稠环吡啶酮类酰胺中间体(1eq.)溶于乙腈/三乙胺(3/1)的混合溶剂中,分批加入五硫化二磷(1eq.),氮气保护下加热回流3小时。反应完毕,冷却至室温,有固体析出,过滤,滤饼真空干燥得到目标产物,采用核磁和质谱确认结构。
第二步:将上述第一步产物(1eq.)溶于乙醇/DIPEA(5/1)的混合溶剂中,加入2,2-二甲氧基乙胺(1eq.),氮气保护下加热回流6小时。反应完毕,冷却至室温,减压浓缩,剩余物溶于冰醋酸中,加热至100度搅拌2小时。冷却至室温,减压浓缩,剩余物用二氯甲烷稀释,依次用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第三步:将上述第二步产物(1eq.)溶于无水二氧六环/水(4/1)的混合溶剂中,依次加入硼酸或三氟硼酸钾盐(2eq.),无水碳酸钾粉末(2.5eq.)和Pd(dppf)Cl2(0.1eq.),氮气保护下加热回流2小时。TLC监测反应完全,冷却至室温,减压浓缩,剩余物用二氯甲烷稀释,依次用饱和氯化铵溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第四步:将上述第三步产物(1eq.)溶于甲醇中,加入4MHCl甲醇溶液(20eq.),室温下搅拌3小时。TLC监测反应完全,减压浓缩,剩余物溶于二氯甲烷中,0度下依次加入DIPEA(3eq.)和丙烯酰氯(1eq.),搅拌0.5小时,反应液用饱和氯化铵溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标化合物,采用核磁和质谱确认结构。
实施例通用制备方法四
第一步:将稠环吡啶酮类硫酰胺中间体(1eq.)溶于四氢呋喃中,加入水合肼(1.5eq.),氮气保护下加热回流6小时。反应完毕,冷却至室温,减压浓缩,有固体析出,过滤,滤饼真空干燥得到目标产物,采用核磁和质谱确认结构。
第二步:将上述第一步产物(1eq.)溶于二氯甲烷中,加入原甲酸三甲酯(4eq.),搅拌十分钟后,再加入三氟乙酸(1eq.)。室温继续搅拌一小时后,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第三步:将上述第二步产物(1eq.)溶于无水二氧六环/水(4/1)的混合溶剂中,依次加入硼酸或三氟硼酸钾盐(2eq.),无水碳酸钾粉末(2.5eq.)和Pd(dppf)Cl2(0.1eq.),氮气保护下加热回流2小时。TLC监测反应完全,冷却至室温,减压浓缩,剩余物用二氯甲烷稀释,依次用饱和氯化铵溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第四步:将上述第三步产物(1eq.)溶于甲醇中,加入4MHCl甲醇溶液(20eq.),室温下搅拌3小时。TLC监测反应完全,减压浓缩,剩余物溶于二氯甲烷中,0度下依次加入DIPEA(3eq.)和丙烯酰氯(1eq.),搅拌0.5小时,反应液用饱和氯化铵溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标化合物,采用核磁和质谱确认结构。
实施例通用制备方法五
第一步:将稠环吡啶酮类硫酰胺中间体(1eq.)溶于甲醇/浓氨水(1/1)的混合溶剂,置于闷罐中,加入催化量的对甲苯磺酸,加热至100度搅拌6小时。反应完毕,反应液减压浓缩。剩余物用二氯甲烷稀释,依次用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物直接用于下一步反应。
第二步:将上述第一步粗品产物(1eq.)悬浮于异丙醇中,室温下滴加二甲基甲酰胺-二甲缩醛(1.2eq.)。滴加完毕,反应液加热回流三小时,冷却至室温,再向反应液中加入盐酸羟胺(1.2eq.),50度加热搅拌过夜。反应液冷却至室温,减压浓缩、干燥,剩余物悬浮于无水四氢呋喃中,冰浴冷却,然后缓慢滴加三氟乙酸酐(1.5eq.)。滴加完毕,移去冰浴,室温搅拌过夜。将饱和碳酸氢钠溶液缓慢滴加到上述反应液中,二氯甲烷萃取,依次用水和饱和食盐水洗涤,无水硫酸钠干燥,过滤、减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第三步:将上述第二步产物(1eq.)溶于无水二氧六环/水(4/1)的混合溶剂中,依次加入硼酸或三氟硼酸钾盐(2eq.),无水碳酸钾粉末(2.5eq.)和Pd(dppf)Cl2(0.1eq.),氮气保护下加热回流2小时。TLC监测反应完全,冷却至室温,减压浓缩,剩余物用二氯甲烷稀释,依次用饱和氯化铵溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标产物,采用核磁和质谱确认结构。
第四步:将上述第三步产物(1eq.)溶于甲醇中,加入4MHCl甲醇溶液(20eq.),室温下搅拌3小时。TLC监测反应完全,减压浓缩,剩余物溶于二氯甲烷中,0度下依次加入DIPEA(3eq.)和丙烯酰氯(1eq.),搅拌0.5小时,反应液用饱和氯化铵溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析分离纯化得到目标化合物,采用核磁和质谱确认结构。
实施例
采用中间体1-2以及其它商品化的试剂为原料,分别采用实施例通用制备方法一到五的合成方法制备得到如下实施例化合物。
测试例1:本发明化合物对NCI-H358、MiaPaca-2细胞增殖和下游信号ERK磷酸化能力的影响试验
测试方法一(2D):分别将NCI-H358(肺癌)和MiaPaca-2细胞(胰腺癌)细胞(100μL/孔,20000个细胞/mL)接种在96孔培养板中,并补充有10%胎牛血清和1%青霉素/硫酸链霉素。用0.5%二甲亚砜作为空白对照,用起始浓度为10μM,八梯度三倍稀释的待测化合物溶液处理细胞,并在5%CO2培养箱中孵育一定的时间(3-7天)。在孵育结束时,向每个孔中加入10μL的MTT储备溶液(5mg/mL)。将培养板在37℃下孵育4小时,然后去除培养基。将二甲亚砜(100μL)加入每个孔中,然后充分摇动。在Thermo Scientific Varioskan Flash多模式阅读器上,在570nm处测量甲臜产物的吸光度。通过使用GraphPad Prism 6.0软件将剂量反应数据拟合到三参数非线性回归模型中获得IC50值。
结果:本发明提供的实施例化合物对NCI-H358和MiaPaca-2细胞的增值抑制活性,IC50值均小于5000nM,部分实施例如1、3、6、7、8、12、13、14、15等IC50值小于500nM。
测试方法二(3D):将处于对数生长期的肿瘤细胞用培养液稀释至一定的浓度接种于超低附着表面的96孔板,培养介质为80μL/孔。细胞在湿度室中以37℃孵育过夜。第二天板中加入系列稀释的受试化合物(10个浓度,3倍稀释),20μL/孔,培养箱孵育96h。取出板放置室温后加入等体积的3D试剂孵育1h,En VisionTM读板器检测信号。使用以下公式将信号转换为百分比抑制:%抑制=100-[(测试化合物信号-中位最小信号)/(中位最大信号-中位最小信号)x 100]。最大信号是无抑制剂孔的信号值,最小信号是含有足以完全抑制细胞增殖的参考抑制剂的孔的信号值,对化合物各个浓度的百分比抑制率进行四参数非线性回归拟合曲线并计算IC50。
结果:本发明提供的实施例化合物对NCI-H358和MiaPaca-2细胞的增值抑制活性,IC50均小于1000nM,部分实施例如实施例1、3,8、12、13、15等对NCI-H358和MiaPaca-2的细胞增殖抑制活性IC50小于200nM。
测试方法三(ERK磷酸化):将Miapaca-2或H358细胞按照一定的浓度接种于96孔板放置于37℃,5%CO2的细胞培养箱培养过夜,第二天板中加入系列稀释的受试化合物(5个浓度,3倍稀释)作用24h(Miapaca-2)或3h(H358),然后加入含蛋白酶和磷酸酶抑制剂的裂解液裂解细胞提取蛋白,western blot方法检测p-ERK的水平。
结果:本发明提供的部分实施例化合物如实施例1,3,8、12、13、15等对NCI-H358和MiaPaca-2的磷酸化ERK水平抑制作用明显,IC50小于500nM。
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 (7)
1.一种如通式I所示的稠环吡啶酮类化合物或其药学上可接受的盐,
式中:
R1独立地选自氢、卤素、氰基、C1-C6烷基;
R2、R3独立地选自氢、卤素、C1-C6烷基;
W2为CH或N;
W,W1独立地选自CR4或N,R4独立地选自卤素、烯基或3-5元环烷基;
Ra,Rb,Rc,Rd,Re,Rf,Rg分别独立地选自氢、C1-C6烷基;且当Ra与Rb不同时,与Ra和Rb相连的碳原子为R构型;
Ar独立地选自5-12元芳香环或芳香稠环基、5-12元芳香杂环或芳香稠杂环基;所述5-12元芳香杂环或芳香稠杂环基含有1-3个独立地选自N、O、P、S的杂原子;进一步地Ar上的一个或多个氢原子可以被以下基团所取代:卤素、羟基、C1-C6烷基或氨基;
Z独立地选自NR5,R5独立地选自H、C1-C6烷基;
当Z为NR5时,Ri和Rj为氧代;
R独立地选自未取代的5-10元芳基、未取代的5-10元杂芳基、取代的5-10元芳基或取代的5-10元杂芳基;所述5-10元杂芳基分别含有1-3个独立地选自N、O、P、S的杂原子;R被取代时,所述取代基独立地选自C1-C6烷基,所述取代基的个数为一个或多个。
2.如权利要求1所述的化合物或其药学上可接受的盐,其特征在于:
R1选自氢;
Ra、Rb、Rc、Rd、Re、Rf、Rg分别独立地选自氢、甲基;
W2为CH;
W1独立地选自CR4,R4独立地选自卤素、C2-C4烯基、3-5元环烷基;
W独立地选自N或CR4,R4独立地选自卤素;
Ar独立地选自取代的苯基、取代的吡啶基、取代的萘基、取代的吲唑基、取代的苯并咪唑基、取代的苯并噻唑基;所述的一个或多个取代基独立地选自下组:卤素、羟基、C1-C4的烷基、氨基;
R独立地选自取代的5-10元芳基或杂芳基;所述取代基独立地选自甲基、异丙基。
3.如权利要求2所述的化合物或其药学上可接受的盐,其特征在于:
W1为CR4,R4独立地选自卤素、乙烯基或环丙基;
W为N或C-F;
R为取代的吡啶基,所述取代基独立地选自甲基、异丙基。
5.如权利要求1-4中任一项所述的化合物或其药学上可接受的盐的用途,其特征在于,用于制备治疗与Ras蛋白突变相关的疾病的药物。
6.如权利要求5所述的用途,其特征在于,所述疾病为肿瘤,所述的肿瘤选自肺癌、胰腺癌、肝癌、结直肠癌、胆管癌、脑癌、白血病、淋巴癌、黑色素瘤、甲状腺癌或鼻咽癌。
7.一种药物组合物,其特征在于,所述的药物组合物包括:
(i)有效量的如权利要求1-4中任一项所述的化合物或其药学上可接受的盐;和
(ii)药学上可接受的载体。
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