CN114539246A - 一种哌啶并嘧啶类化合物及其用途 - Google Patents
一种哌啶并嘧啶类化合物及其用途 Download PDFInfo
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- CN114539246A CN114539246A CN202111662801.0A CN202111662801A CN114539246A CN 114539246 A CN114539246 A CN 114539246A CN 202111662801 A CN202111662801 A CN 202111662801A CN 114539246 A CN114539246 A CN 114539246A
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- C07D471/02—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 system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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Abstract
本发明提供了一种哌啶并嘧啶类化合物及其用途,哌啶并嘧啶类化合物为下式(I)表示的化合物及其异构体或其药学上可接受的盐。本发明化合物能够应用于针对KRASG12C突变蛋白相关癌症的治疗药物中,KRASG12C突变蛋白相关癌症疾病选自:肺癌、结直肠癌、胰腺癌、胰腺癌、肝癌、胃癌、食道癌、胆管癌、乳腺癌、卵巢癌、子宫颈癌、黑色素瘤、脑胶质瘤、淋巴癌、白血病。
Description
技术领域
本发明涉及药物合成技术领域,具体涉及一种哌啶并嘧啶类化合物及其在制备针对KRASG12C突变蛋白相关癌症的治疗药物中的用途。
背景技术
RAS突变经常在恶性肿瘤中观察到并且支持癌症的各种标志,包括基因组不稳定性,细胞增殖,细胞凋亡的抑制,代谢的重编程,微环境的改变,免疫应答的逃避和转移的促进。与其对癌细胞功能的普遍影响一致,许多已建立的肿瘤模型中致癌KRAS的消退导致肿瘤消退,因此,RAS是一个潜在的非常有效的癌症治疗靶点。RAS突变看起来有多种功能类别,可能需要针对每个功能类别制定策略。
在RAS家族成员中,致癌突变最常见于KRAS(85%),而NRAS(12%)和HRAS(3%)则较为少见。大多数RAS家族突变发生在氨基酸残基12、13和61处,在三维空间构象中,这些氨基酸残基多与GTP有直接相互作用。比如,氨基酸残基12处的甘氨酸突变为除脯氨酸以外的任何其它氨基酸均会产生空间阻断,阻止GAP蛋白进入KRAS,从而抑制GTP水解并导致高活性的GTP结合形式的KRAS显著增加。变异的KRAS占肺癌的30%,97%的KRAS变异发生在外显子2和3,包括氨基酸G12(39%),G13和Q61。KRAS G12C是非小细胞肺癌中最常见的RAS突变,是美国癌症死亡的主要原因,临床上仍然没有直接和有效的药物,但近年该领域开始有了显著的进展。
2013年,Shokat等在《Nature》报道了突破性的结果,他们筛选设计的活性小分子能够在G12C处不可逆地与突变体半胱氨酸结合到KRAS效应区附近的一个小口袋,结合到这个口袋的小分子可以通过将蛋白质锁定在GDP结合的非活性状态来抑制KRAS活性。2016年,Wellspring公司在《癌症发现》上报道了靶向KRAS G12C小分子抑制剂ARS-853,虽然活性仍在微摩尔级,但完成了细胞及动物试验的概念验证。2018年,该公司又在《细胞》上公开了新一代靶向KRAS G12C小分子抑制剂ARS-1620。
发明内容
为解决以上技术问题,本发明采取如下技术方案:
根据本发明的一个方面,本发明提供了一种哌啶并嘧啶类化合物,为下式(I)表示的化合物及其异构体或其药学上可接受的盐,
其中,
R1a为氢;
R2选自氢、卤素或-OC1-3烷基;
R3a、R3b、R3c和R3d各自独立地选自氢或C1-3烷基;所述C1-3烷基可被1个或多个R9取代;所述R9为氰基或卤素;
R4选自C1-3烷基;所述C1-3烷基可被1个-N(C1-2烷基)2取代;
R5选自苯基或萘基;所述苯基或萘基可被1个或多个R10取代;所述R10选自卤素、羟基、-CF3、-OCF3、-NH2、C1-6烷基或C1-6烷氧基;
R6选自-COC1-4烷基、C1-6烷基、C1-6烷氧基、C1-6氘代烷基、C1-6卤烷基、C3-6环烷基;
R7选自氢、卤素原子、C1-3烷基、C1-3卤烷基、氧代;
L选自-O-、-S-或-NR11;所述R11选自氢或C1-3烷基。
根据本发明的另一个方面,优选地,在式(I)所示的结构中,R1a和R1b各自独立地选自氢、氟、氯或-CH3;所述-CH3可被一个或多个氟、氯、羟基、-OCH3、含有1至3个选自N、O和S的杂原子的C5-6杂芳基、-NR6aR6b取代基取代;所述的R6a、R6b独立地选自C1-3烷基或者R6a、R6b与其共同相连的-N-一起组成一个饱和或不饱和含有1至3个选自N、O和S的杂原子的四至六元杂环;R6a和R6b中所述的C1-3烷基或者饱和或不饱和含有1至3个选自N、O和S的杂原子的四至六元杂环可被1个或多个氟或氯取代。
更进一步优选地,R1a为氢;R1b为氢。
根据本发明的另一个方面,优选地,在式(I)所示的结构中,R2选自氢、卤素或-OC1-3烷基。
进一步优选地,R2选自氢或氟。
进一步优选地,R3a、R3b、R3c和R3d各自独立地选自氢或C1-3烷基;所述C1-3烷基可被1个或多个R9取代;所述R9为氰基或卤素;
进一步优选地,R3a选自氢或C1-3烷基;所述C1-3烷基可被1个或多个R9取代;所述R9为氰基或卤素;R3b、R3c和R3d都选自氢;
更进一步优选地,R3a选自-CH2CN;R3b、R3c和R3d都选自氢。
优选地,在式(I)所示的结构中,R3a、R3b、R3c和R3d中任意的一个或两个为-CH3,其余都是氢。
根据本发明的另一个方面,优选地,在式(I)所示的结构中,R4选自C1-3烷基;所述C1-3烷基可被1个-N(C1-2烷基)2取代;
根据本发明的另一个方面,优选地,在式(I)所示的结构中,R4选自C1-3烷基;所述C1-3烷基可被1个含有1至3个选自N、O和S的杂原子的四至八元饱和或不饱和杂环取代;所述含有1至3个选自N、O和S的杂原子的四至八元饱和或不饱和杂环可被1个或多个氟、氯、甲基、甲氧基或苄基取代;
根据本发明的另一个方面,优选地,在式(I)所示的结构中,L为-O-。
根据本发明的另一个方面,优选地,在式(I)所示的结构中,R5为C6-10芳基;所述C6-10芳基可被1个或多个R10取代;所述R10选自卤素、羟基、-CF3、-OCF3、-NH2、-NHC1-4烷基、-N(C1-4烷基)2、-CONH2、-CONHC1-4烷基、-CON(C1-4烷基)2、-NHCOC1-4烷基、C1-6烷基、C1-6烷氧基、C2-6炔基、C2-6烯基、C3-6环烷基、饱和或不饱和的五至八元碳环、或者含有1至3个选自N、O和S的杂原子的五至八元饱和或不饱和杂环。
进一步优选地,R5选自苯基或萘基;所述苯基或萘基可被1个或多个R10取代;所述R10选自卤素、羟基、-CF3、-OCF3、-NH2、C1-6烷基或C1-6烷氧基。
更进一步优选地,R10选自氟、氯、溴、-CF3、-NH2、甲基、乙基、正丙基、异丙基或甲氧基。
根据本发明的另一个方面,优选地,在式(I)所示的结构中,R6选自-COC1-4烷基、C1-6烷基、C1-6烷氧基、C1-6氘代烷基、C1-6卤烷基、C3-6环烷基;
进一步优选地,R6选自C1-3烷基、C1-3氘代烷基、C3-6环烷基。
根据本发明的另一个方面,优选地,在式(I)所示的结构中,R7为氢。
根据本发明的另一个方面,优选地,由式(I)表示的化合物及其异构体或其药学上可接受的盐由选自以下化合物中:
根据本发明的另一个方面,本发明提供了由式(I)表示的化合物及其药学上可接受的盐及其异构体或其药学上可接受的盐在制备针对KRASG12C突变蛋白相关癌症治疗药物中的用途。
优选地,根据所述用途,所述KRASG12C突变蛋白相关癌症疾病选自:肺癌、结直肠癌、胰腺癌、胰腺癌、肝癌、胃癌、食道癌、胆管癌、乳腺癌、卵巢癌、子宫颈癌、黑色素瘤、脑胶质瘤、淋巴癌、白血病。
根据本发明的另一个方面,本发明提供了一种用于治疗KRASG12C突变蛋白相关癌症的药物,所述药物包括治疗有效量的根据本发明的由式(I)表示的化合物及其药学上可接受的盐及其异构体或其药学上可接受的盐作为活性成分,以及药学上可接受的辅料。
优选地,根据所述药物,所述KRASG12C突变蛋白相关癌症疾病选自:肺癌、结直肠癌、胰腺癌、胰腺癌、肝癌、胃癌、食道癌、胆管癌、乳腺癌、卵巢癌、子宫颈癌、黑色素瘤、脑胶质瘤、淋巴癌、白血病。
根据本发明的另一个方面,本发明提供了一种KRASG12C突变蛋白相关癌症的治疗方法,所述治疗方法包括向受试者施用有效量的根据本发明的所述化合物或包含所述化合物及其药学上可接受的盐作为活性成分的药物组合物。
优选地,根据所述治疗方法,所述KRASG12C突变蛋白相关癌症的治疗方法,所述癌症疾病选自:肺癌、结直肠癌、胰腺癌、胰腺癌、肝癌、胃癌、食道癌、胆管癌、乳腺癌、卵巢癌、子宫颈癌、黑色素瘤、脑胶质瘤、淋巴癌、白血病。
根据本发明的另一个方面,本发明提供了式((I)表示的所述化合物的制备方法,以X=-CH2CH2-时的结构化合物为例,所述制备方法如下:
1)将原料I-1溶于MeOH(30mL)中,N2氛围下加入NaOMe和S-甲基异硫脲硫酸盐,室温搅拌过夜。关环得到并环I-2;
2)将化合物I-2溶于DCM(10mL),降温至0℃,加入DIEA和Tf2O,升至室温搅拌2h。得到活化酯I-3;
3)将化合物I-3和哌嗪类似物I-4、DIEA溶于DMF中,升温至100℃,搅拌反应2h,经取代反应生成中间体I-5;
4)将甲硫醚I-5用m-CPBA氧化得到亚砜类似物I-6;
5)将亚砜类似物I-6、脯氨醇类似物溶于甲苯中,加入t-BuONa,降温至0℃搅拌反应2h,R4-YH与中间体I-6发生取代反应得到中间体I-7;
6)将化合物I-7溶于溶剂中,针对不同的保护基采取不同的脱保护方法,脱去哌嗪上的保护基得到中间体I-8;
7)将化合物I-8溶于DCM,加入TEA,降温至0℃以下,开始递加烯丙基酰氯反应2h。哌嗪类似物I-8与酰氯缩合得到I-9;
8)将中间体I-9溶于DCM,加入三氟醋酸,室温下搅拌3h,脱去Boc保护基得到I-10;
9)将I-10溶于甲醇,加入R6的醛或酮,继续加入氰基硼氢化钠等还原剂发生还原氨化反应得到终产品I,或加入R6的卤代物发生取代反应生成终产品I。
具体实施方式
以下,将详细地描述本发明。在进行描述之前,应当理解的是,在本说明书和所附的权利要求书中使用的术语不应解释为限制于一般含义和字典含义,而应当在允许发明人适当定义术语以进行最佳解释的原则的基础上,根据与本发明的技术方面相应的含义和概念进行解释。因此,这里提出的描述仅仅是出于举例说明目的的优选实例,并非意图限制本发明的范围,从而应当理解的是,在不偏离本发明的精神和范围的情况下,可以由其获得其他等价方式或改进方式。
根据本发明,如果无另外说明,这里引用的所有术语具有与那些本领域的熟练人员理解本发明相同的含义。
如本文所用的术语“盐”是指含阳离子和阴离子的化合物,其可通过可接受质子部位的质子化和/或可供质子部位的去质子化来产生。值得注意的是,可接受质子部位的质子化导致形成阳离子类物质,其电荷通过生理阴离子的存在而平衡,而可供质子部位的去质子化导致形成阴离子类物质,其电荷通过生理阳离子的存在而平衡。
术语“药学上可接受的盐”指所述盐是药学上可接受的。药学上可接受的盐的例子包括但不限于:(1)酸加成盐,与无机酸形成,如盐酸、氢溴酸、硫酸、硝酸、磷酸等等;或与有机酸形成,如羟基乙酸、丙酮酸、乳酸、丙二酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙烷-二磺酸、2-羟基乙烷磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4对甲苯磺酸、樟脑酸、十二烷基硫酸、葡萄糖酸、谷氨酸、水杨酸、顺式-已二烯二酸等等;或(2)碱加成盐,和上述无机酸的任一种的共轭碱形成,其中共轭碱包含选自Na+、K+、Mg2+、Ca2+、NHxR4-x +中的阳离子组分,其中NHxR4-x +(R是C1-4烷基,下标x是选自0、1、2、3或4的整数)表示季铵盐中的阳离子。应该理解,所有涉及药学上可接受的盐都包括相同酸加成盐的本文中所定义的溶剂加成形式(溶剂化物)或晶体形式(多晶型物)。
术语“C1-M烷基”是指包含1-M个碳原子的烷基,例如其中M是具有下列数值的整数: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。例如术语“C1-6烷基”是指含有1-6个碳原子的烷基。烷基的例子包括但不限于低级烷基,包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基或戊基、异戊基、新戊基、己基、庚基和辛基。
术语“芳香基”指芳族体系,可以是单环或原本稠合的或连接在一起的多芳环,从而使至少一部分稠合或连接的环形成共轭的芳系。芳基基团包括但不限制于:苯基、萘基、四氢萘基。芳基可被任选取代,如可被1-4个选自下组的基团所取代的芳基或杂环:卤素、-CN、-OH、-NO2、氨基、烷基、环烷基、链烯基、炔基、烷氧基、芳氧基、取代的烷氧基、烷基羰基、烷基羧基、烷基氨基或芳硫基。
术语“取代”指参考基团可以被一个或多个额外基团所取代,额外基团单独地且独立的选自于,烷基,环烷基,芳基,杂芳基,杂脂环烃,羟基,烷氧基,烷硫基,芳硫基,烷亚砜基,芳亚砜基,烷砜基,芳砜基,氰基,卤基,羰基,硫代羰基,硝基,卤烷基,氟烷基和氨基,包括单取代和双取代的氨基基团及其被保护的衍生物。
本发明所提供的由式(I)表示的化合物或其药学上可接受的盐,和包含该化合物的药物组合物可以是多种形式,如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等,并可以存在于适宜的固体或液体的载体或稀释液中以及适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。例如其制剂配方的单位剂量中包含0.05-200mg式(I)的化合物或其药学上可接受的盐,优选地,制剂配方的单位剂量中包含0.1mg-100mg式(I)的化合物。
本发明的由通式(I)表示的化合物和药物组合物可对哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径。最优选为口服。最佳优选日剂量为0.01-200mg/kg体重,一次性服用,或0.01-100mg/kg体重分次服用。不管用何种服用方法,个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。
本发明中,术语“有效量”可指为实现预期的效果所需的剂量和时段的有效的量。此有效量可能因某些因子而产生不同的变化,如疾病的种类或治疗时疾病的病症、被施用的特定标的器官的构造、病人个体大小、或疾病或症状的严重性。本领域具有通常知识者不需要过度实验即可凭经验决定特定化合物的有效量。
典型的配方是通过混合本发明的通式(I)表示的化合物及载体、稀释剂或赋形剂制备而成。适宜的载体、稀释剂或赋形剂是本领域技术人员所熟知的,包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。
所用的特定载体、稀释剂或赋形剂,将根据本发明的化合物的使用方式和目的而定。一般以本领域技术人员认为可安全有效地给药至哺乳类动物的溶剂为基础而选择溶剂。一般而言,安全的溶剂是无毒性含水溶剂诸如水,以及其他可溶于水或与水混溶的无毒性溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中的一种或多种。该配方也可包括一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂,使该药物以可被接受的形式制造或使用。
本发明所述的如式(I)的化合物与至少一种其它药物的组合使用时,两种药物或多种药物可以分开使用也可以组合使用,优选以药学组合物的形式给药。本发明的如式(I)的化合物或药物组合物能以任一已知的口服、静脉注射、直肠给药、阴道给药、透皮吸收、其它局部或全身给药形式,分开或一起给药至受试者。
这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂,使该药物组合物以可被接受的形式制造或使用。
本发明药物优选口服给药途径。用于口服给药的固态剂型可包括胶囊、片剂、粉末或颗粒制剂。在固态剂型中,本发明的化合物或药物组合物与至少一种惰性赋形剂、稀释剂或载剂混合。适宜的赋形剂、稀释剂或载剂包括诸如柠檬酸钠或磷酸二钙的物质,或淀粉、乳糖、蔗糖、甘露糖醇、硅酸等;粘合剂如羧甲基纤维素、褐藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等;湿润剂如甘油等;崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、特定的络合硅酸盐、碳酸钠等;溶液阻滞剂如石蜡等;吸收促进剂如季铵化合物等;吸附剂如高岭土、膨润土等;润滑剂如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠等。在胶囊与片剂的情况下,该剂型亦可包括缓冲剂。类似类型的固态组合物亦可作为软式与硬式填充明胶胶囊中的填料,其使用乳糖以及高分子量聚乙二醇等作为赋形剂。
用于口服给药的液态剂型包括药学上可接受的乳化液、溶液、悬浮液、糖浆液与酏剂。除了本发明的化合物或其药物组合物之外,该液态剂型可含有本领域中常用的惰性稀释剂,诸如水或其他溶剂;增溶剂及乳化剂诸如乙醇、异丙基醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺;油类(如棉籽油、落花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油等);甘油;四氢糠基醇;聚乙二醇与脱水山梨糖醇的脂肪酸酯;或这些物质中的几种的混合物等。
除了这些惰性稀释剂之外,该组合物也可包括赋形剂,诸如润湿剂、乳化剂、悬浮剂、增甜剂、调味剂与香料剂中的一种或多种。
就悬浮液而言,除了本发明的由通式(I)表示的化合物或其药学上可接受的盐或者包含其的药物组合物之外,可进一步含有载剂诸如悬浮剂,如乙氧基化异硬脂醇、聚氧乙烯山梨醣醇、脱水山梨醣醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄耆胶,或这些物质中几种的混合物等。
本发明的由通式(I)表示的化合物或其药学上可接受的盐或者包含其的药物组合物可采用其它局部给药剂型给药,包括膏、粉末、喷剂及吸入剂。该药物可在无菌条件下与药学上可接受的赋形剂、稀释剂或载剂以及所需要的任一防腐剂、缓冲剂或推进剂混合。眼用配方、眼用油膏、粉末与溶液,亦意欲涵盖于本发明的范围内。
此外,本公开还涵盖了试剂盒(例如制药包装)。提供的试剂盒可以包含本文所述的药物组合物或化合物和容器(例如,药瓶、安瓿、瓶子、注射器和/或分装包装或其它合适的容器)。在一些实施方式中,提供的试剂盒可以任选地进一步包括第二容器,其包含用于稀释或悬浮本文所述的药物组合物或化合物的药用赋形剂。在一些实施方式中,设置在第一容器和第二容器中的本文所述的药物组合物或化合物组合形成一个单元剂量形式。
在某些实施方式中,本文所述试剂盒进一步包括包含于试剂盒中的用于使用所述化合物或药物组合物的用法说明。本文所述的试剂盒还可以包括管理机构(如美国食品药品监督管理局(FDA))所要求的信息。在某些实施方式中,在试剂盒中包括的信息为处方信息。在某些实施方式中,试剂盒和用法说明提供用于治疗需要其的受试者的增殖性疾病和/或预防需要其的受试者的增殖性疾病。本文所述的试剂盒可以包含一种或多种额外的药物制剂作为单独的组合物。
以下结合具体的实施例对本发明做进一步详细的说明,但本发明不限于以下实施例,实施例是为了更好的阐释本发明的某些具体体现而不能被解释为以任何方式限定本发明的范围。实施例中未注明的条件为常规条件。除非特别说明,以下实施例中使用的试剂和仪器均为市售可得产品。
以下实施例中化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定使用BrukerAVANCE-400核磁仪,测定溶剂为氘代二甲亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号:Finnigan LCQadvantage MAX)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.2mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例中无特殊说明,反应的温度为室温,为20℃-30℃。
实施例中的反应进程的检测采用薄层色谱法(TLC),所使用的展开剂体系,以及纯化化合物采用的柱层析的洗脱机体系包括有:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:石油醚和乙酸乙酯体系,D:丙酮和石油醚体系,溶剂的体积比例根据化合物的极性不同而进行调节。
实验中所用缩写语:Boc,叔丁氧羰基;Me,甲基;Et,乙基;tBuOK,叔丁醇钾;THF,四氢呋喃;EA,乙酸乙酯;DCM,二氯甲烷;DIPEA,二异丙基乙胺;D,氘;Tf2O,三氟甲磺酸酐;Alloc,烯丙基氧羰基;DMF,N,N-二甲基酰胺;TFA,三氟醋酸;小时,h;TEA,三乙胺;TMS,三甲基硅烷。
中间体的制备:
中间体1-1:
步骤1:
将化合物A(29.36g,0.188mol)、丙二酸(20g,0.192mol)、醋酸铵(30g,0.39mol)加入乙醇(70mL)中,回流搅拌6h。反应结束后,冷却至室温,过滤,滤饼加入50%醋酸(200mL),升温至80℃,搅拌0.5h,冷却,过滤,烘干得化合物B(7g,白色固体)。
步骤2:
将化合物B(3.2g,5mmol)溶于MeOH(8mL)中,加入SOCl2(7.14g,20mmol),室温搅拌1h后浓缩,加入饱和NaHCO3(50mL)、EA(50mL*3)萃取,食盐水(50mL)洗涤,干燥,浓缩得化合物C(2.9g,无水油状物)。
MS m/z(ES(I):230.1[M+1]。
步骤3:
将化合物C(6.3g,27.5mmol)、丙烯酸甲酯(2.6g,30.1mmol)溶于MeOH(10mL)中,室温搅拌过夜。浓缩,柱层析得化合物D(6.9g,无水油状物)。
MS m/z(ES(I):316.2[M+1]。
步骤4:
将化合物D(3.15g,10mmol)溶于30mLTHF中,依次加入Boc酸酐(4.36g,20mmol),DIPEA(5.2g,20mmol),65℃反应过夜,柱层析纯化得无色油状液体E(4g,收率96%)。
1H NMR(400MHz,CDCl3):8.11-8.08(m,1H),7.89-7.85(m,2H),7.62-7.45(m,4H),6.49-6.30(m,1H),3.66(s,3H),3.48(s,3H),3.46-3.37(m,2H),3.25-3.12(m,3H),2.42-1.98(m,2H),1.55(s,9H);
MS m/z(ES(I):416.2[M+1].
步骤5:
化合物E(2.9g,7mmol)溶于50mLTHF中,冷却至0℃后加入叔丁醇钾(1.6g,14mmol),搅拌5min后加入EA直至析出固体后加入10mL水,水相EA萃取(50×2),合并有机相,无水硫酸钠干燥,浓缩柱层析纯化得无色油状液体1-1(1.4g,收率53.8%)。
MS m/z(ES(I):384.2[M+1].
中间体2-1:
步骤1:
将化合物F(12.8g,67mmol)溶于DCM(70mL)中,加入化合物G(27g,80mmol),室温搅拌过夜。后处理后柱层析得化合物H(17g,无水油状物)。
步骤2:
将化合物H(17g,69mmol)溶于MeOH(75mL)中,加入NaOH(27g,690mmol)的水溶液(75mL),室温搅拌2h。反应结束后,浓缩,加入稀HCl调节pH至1,EA(100mL*3)萃取,食盐水(100mL)洗涤,干燥,浓缩得化合物I(12.1g,白色固体)。
MS m/z(ES(I):231.0[M-1].
步骤3:
将Na(3.13g,136mmol)加入无水EtOH(110mL)中,形成乙醇钠,加入热的盐酸羟胺盐酸盐(9.45g,136mmol)溶液(6mL),迅速冷却过滤,滤液倒回反应瓶中,加入化合物I(12.1g),回流过夜。冷却至室温,过滤,干燥得化合物J(3.268g,白色固体)。
MS m/z(ES(I):250.1[M+1].
步骤4:
将化合物J(3.268g,13mmol)加入MeOH(40mL)中,加入SOCl2(6.2g,52.5mmol),室温搅拌1h后浓缩,加入饱和Na2CO3溶液(50mL),EA(50mL*3)萃取,食盐水(50mL)洗涤。干燥,浓缩得化合物K(3.25g,类白色固体)。
MS m/z(ES(I):264.1[M+1].
步骤5:
将化合物K(1.6g,6mmol)、丙烯酸甲酯(0.568g,6.6mmol)溶于MeOH(2mL)和DCM(2mL)中,室温搅拌过夜。浓缩,柱层析得化合物L(1.1g,无水油状物)。
MS m/z(ES(I):350.1[M+1].
步骤6:
将化合物L(3.50g,10mmol)溶于30mLTHF中,依次加入Boc酸酐(4.36g,20mmol),DIPEA(5.2g,20mmol),65℃反应过夜后直接柱层析纯化得无色油状液体M(4g,收率89%)。
1H NMR(400MHz,CDCl3):7.81-7.75(m,2H),7.67-7.59(m,2H),7.47-7.43(m,1H),7.36-7.32(m,1H),3.60(s,3H),3.50(s,3H),3.40-3.00(m,5H),2.47-2.18(m,2H),1.45(s,9H);
MS m/z(ES(I):450.1[M+1].
步骤7:
将化合物M(3.15g,7mmol)溶于50mLTHF中,冷却至0℃后加入叔丁醇钾(1.6g,14mmol),搅拌反应5min后加入EA直至析出固体后加入10mL水,EA萃取(50×2),合并有机相,无水硫酸钠干燥,浓缩后柱层析纯化得无色油状液体2-1(1.5g,收率51.7%)。
MS m/z(ES(I):418.1[M+1].
实施例1:化合物1的制备
按照如下路线利用中间体1-1作为原料制备化合物1。
步骤1:中间体1-2的合成
将化合物1-1(1.340g,3.5mmol)溶于无水甲醇(15mL)中,氮气氛围下加入NaOMe(0.945g,17.5mmol),S-甲基异硫脲硫酸盐(1.75g,6.3mmol),室温搅拌过夜。反应结束后,加入稀盐酸调节pH到6,浓缩干甲醇,加入水(30mL)和乙酸乙酯(10mL),充分搅拌震荡,过滤固体,干燥得中间体1-2(0.7g,白色固体)。
MS m/z(ES(I):424.2[M+1].
步骤2:中间体1-3的合成
将化合物1-2(0.7g,1.65mmol)溶于二氯甲烷(10mL),降温至0℃,加入二异丙基乙基胺(0.638g,4.95mmol)、三氟乙酸酸酐(0.7g,2.48mmol),升至室温搅拌2h。反应结束后,浓缩,柱层析(石油醚:乙酸乙酯=100:1~15:1)得中间体1-3(300mg,类白色固体)。
1H NMR(400MHz,CDCl3):8.24(d,J=8.0Hz,1H),7.89(d,J=8.0Hz,1H),7.81(d,J=8.0Hz,1H),7.58-7.52(m,2H),7.38-7.28(m,1H),6.96-6.95(m,1H),3.53-3.36(m,3H),2.58(s,3H),2.30-2.20(m,2H),1.53(s,9H).
步骤3:中间体1-5的合成
将化合物1-3(43mg,0.07mmol)、1-4(15mg,0.07mmol)和二异丙基乙基胺(50mg,0.39mmol)溶于二氧六环(6mL)中,升温至50℃,搅拌反应3h。反应结束后,加入水(10mL),并用乙酸乙酯(10mL)萃取,水相再用乙酸乙酯(10mL*2)萃取,合并有机相,并用饱和食盐水(10mL)洗涤,干燥,浓缩得中间体1-5(44mg,类白色固体)。
MS m/z(ES(I):531.3[M+1]。
步骤4:中间体1-6的合成
将化合物1-5(44mg,0.08mmol)溶于二氯甲烷(5mL)中,降温至0℃,加入三乙胺(11mg,0.10mmol),冰浴下滴加Alloc-Cl(12mg,0.10mmol),搅拌反应1h。反应结束后,加入水淬灭反应,分液得有机相,干燥,浓缩得中间体1-6(55mg,类白色固体)。
MS m/z(ES(I):615.3[M+1].
步骤5:中间体1-7的合成
将化合物1-5(55mg,0.09mmol)溶于EA(5mL)中,降温至0℃,加入间氯过氧苯甲酰氯(18mg,0.09mmol),冰浴下搅拌反应1h。反应结束后,加入饱和硫代硫酸钠水溶液淬灭反应,分液得有机相,干燥,浓缩得中间体1-7(60mg,黄色固体)。
步骤6:中间体1-9的合成
将化合物1-8(22mg,0.19mmol)、叔丁醇钠(27mg,0.28mmol)溶于甲苯(5mL)中,冰浴下加入1-7(60mg,0.09mmol)的甲苯溶液(2mL),搅拌反应2h。反应结束后,EA和水萃取,浓缩干溶剂,柱层析纯化得中间体1-9(70mg,类白色固体)。
MS m/z(ES(I):682.4[M+1].
步骤7:中间体1-10的合成
将化合物1-9(70mg,0.10mmol)溶于DCM(5mL)中,加入吗啡啉(18mg,0.20mmol)及四(三苯基膦)钯(7mg),氮气保护室温反应,过滤浓缩柱层析纯化得到固体1-10(20mg)。
1H NMR(400MHz,CDCl3):8.17-8.12(m,1H),7.84-7.82(m,1H),7.75-7.72(m,1H),7.51-7.47(m,2H),7.33-7.29(m,1H),7.17-7.12(m,1H),4.89-4.80(m,1H),4.41-4.30(m,1H),3.94-3.90(m,1H),3.57-3.50(m,2H),3.42-2.75(m,13H),2.55-2.44(m,2H),2.19-2.12(m,2H),1.99-1.95(m,2H),1.53-1.48(m,2H),1.35(s,9H);
MS m/z(ES(I):598.3[M+1].
步骤8:中间体1-12的合成
将化合物1-10(20mg,0.033mmol)溶于DMF(4mL),加入DIPEA(13mg,0.10mmol),降温至0℃,开始加入化合物1-11(5mg,0.050mmol),50%PPAA(43mg,0.067mmol)后反应1h。浓缩干溶剂,制备纯化得到化合物1-12(10mg,淡黄色固体)。
1H NMR(400MHz,CDCl3):8.17-8.12(m,1H),7.88-7.82(m,1H),7.80-7.76(m,1H),7.56-7.51(m,2H),7.36-7.29(m,2H),5.41(brs,1H),5.28-5.21(m,1H),5.20-5.18(m,1H),4.57-4.51(m,1H),4.02-3.97(m,2H),3.85-3.80(m,1H),3.71-3.64(m,2H),3.45-3.44(m,2H),3.27-3.23(m,2H),2.98-2.95(m,3H),2.84-2.73(m,2H),2.24-2.13(m,4H),2.08-1.97(m,4H),1.60-1.45(m,2H),1.35(s,9H);
MS m/z(ES(I):670.5[M+1].
步骤9:化合物1的合成
将化合物1-12(10mg)溶于DCM(2mL)中,N2保护,冷至0℃,缓慢滴加TFA(0.2mL),加完室温反应2h。浓缩,加入饱和的NaHCO3溶液淬灭反应,调节pH=7-8,EA(2mL)萃取3次,合并有机相,干燥,制备纯化得淡黄色固体化合物1(6mg)。
MS m/z(ES(I):570.3[M+1].
实施例2:化合物2的制备
按照如下路线利用中间体1-1作为原料制备化合物2。
将化合物1(5mg)溶于乙腈(2mL)中,氮气保护,降温至0℃,加37%甲醛(0.5mL)和氰基硼氢化钠(0.6mg)反应0.5h,反应结束后,制备纯化得淡白色固体(3.4mg)。
1H NMR(400MHz,CDCl3):8.15-8.13(m,1H),7.88-7.87(m,1H),7.81-7.78(m,1H),7.53-7.52(m,1H),7.49-7.43(m,3H),5.43(brs,1H),5.32-5.31(m,1H),5.25-5.20(m,1H),4.97-4.92(m,1H),4.58-4.52(m,1H),4.31-4.21(m,3H),4.09-4.03(m,3H),3.82-3.79(m,2H),3.63-3.56(m,1H),3.28-3.24(m,3H),2.98-2.97(m,3H),2.88-2.78(m,2H),2.30-2.21(m,5H),2.20-2.07(m,3H),1.60-1.45(m,2H);
MS m/z(ES(I):584.4[M+1].
实施例3:化合物3的制备
按照实施例1和实施例2的合成路线,利用中间体2-1作为原料制备得到化合物3。
1H NMR(400MHz,CDCl3):7.93(d,J=4.0Hz,1H),7.82-7.80(m,2H),7.61(d,J=4.0Hz,1H),7.56-7.52(m,1H),7.37-7.33(m,1H),5.63-5.77(m,1H),5.50-5.42(m,1H),5.35-5.31(m,1H),5.27-5.22(m,1H),4.91-4.77(m,2H),4.54-4.48(m,1H),4.11-4.03(m,1H),3.90-3.81(m,2H),3.70-3.58(m,2H),3.52-3.43(m,2H),3.29-3.19(m,1H),3.15-3.03(m,1H),3.00-2.75(m,5H),2.20-2,00(m,8H),1.62-1.40(m,2H);
MS m/z(ES(I):618.3[M+1].
实施例4:化合物4的制备
按照实施例1和实施例2的合成路线,利用中间体2-1作为原料制备得到化合物4。
1H NMR(400MHz,CDCl3):7.91-7.89(m,1H),7.87-7.80(m,2H),7.59(d,J=4.0Hz,1H),7.50-7.48(m,1H),7.36-7.31(m,1H),5.80-5.77(m,1H),5.43-5.42(m,1H),5.33-5.30(m,1H),5.25-5.20(m,1H),4.84-4.81(m,2H),4.49-4.47(m,1H),4.08-4.043(m,1H),3.92-3.88(m,2H),3.62-3.57(m,2H),3.50-3.45(m,2H),3.23-3.20(m,1H),3.13-3.04(m,1H),2.90-2.87(m,3H),2.82-2.80(m,1H),2.62-2.52(m,1H),2.25-2.20(m,4H),2.02-2.01(m,3H),1.62-1.45(m,2H),1.03-0.99(m,3H);
MS m/z(ES(I):632.4[M+1].
实施例5:化合物5的制备
按照实施例1和实施例2的合成路线,利用中间体2-1作为原料制备得到化合物5。
1H NMR(400MHz,CDCl3):8.09-7.95(m,1H),7.81-7.79(m,2H),7.61(d,J=8.0Hz,1H),7.54-7.47(m,1H),7.37-7.33(m,1H),5.47(brs,1H),5.38-5.31(m,1H),5.28-5.21(m,1H),5.07-4.98(m,1H),4.59-4.43(m,2H),4.07-4.00(m,1H),3.86-3.70(m,2H),3.56-3.42(m,3H),3.31-3.07(m,3H),2.99-2.88(m,4H),2.84-2.72(m,2H),2.32-2.00(m,6H),1.65-1.50(m,2H),1.15-1.05(m,6H);
MS m/z(ES(I):646.4[M+1].
测试实施例1:化合物对KRAS G12C突变细胞活性试验
本实验旨在验证本发明化合物对KRAS G12C突变的NCI-H358人非小细胞肺癌细胞中ERK磷酸化的抑制。
主要试剂:
细胞株NCI-H358、RPMI1640培养基、FBS、TrypLETM Express Enzyme、PBS、8%固定液、阻断溶液、100%甲醇、兔抗pERK、鼠抗GAPDH、IRDye 800CW山羊抗兔IgG、IRDye680RD山羊抗鼠IgG
主要耗材与仪器:
T75细胞培养瓶、384细胞培养微孔板、CO2恒温培养箱、Eppendorf离心机、Echo550液体工作站、红外激光成像系统Odyssey CLx
实验方法:
4 x 106NCI-H358细胞(购自ATCC)接种于T75培养瓶,用加10%FBS(购自Transgene)和1%青霉素链霉素的RPMI 1640(均购自Gibco)培养2天,37℃,5%CO2。第3天时,倒去培养基,并用DPBS洗一次。加入2mL TrypLETM Express Enzyme(购自Gibco)在室温消化至细胞变圆。加入5mL新鲜培养基,吹打并收集细胞。1000rpm离心5min。弃去上清,用新鲜培养基重悬细胞并计数。在384孔板中每孔接种40μl 6000个细胞,37℃,5%CO2培养过夜。第二天,用Echo 550加入200nl每孔的梯度稀释化合物(0.5%DMSO,起始浓度1000nm,3倍稀释,共10个浓度点),继续培养3h。在每孔中加入40μl 8%固定液(购自Solarbio),室温孵育20min。加入40μl PBS洗涤一次。然后加入40μl 100%冷甲醇室温孵育10min。用40μlPBS洗涤一次。每孔加入20μl阻断溶液(购自Licor)室温孵育1h。吸去阻断溶液并加入20μl一抗混合物,兔抗pERK(购自CST,1:1000稀释)和鼠抗GAPDH(购自CST,1:2000稀释),4℃孵育过夜。40μl每孔的含0.05%吐温的PBST洗涤3次。每孔加入20μl二抗混合液,IRDye 800CW山羊抗兔IgG和IRDye 680RD山羊抗鼠IgG(均购自Li-COR,均按1:2000稀释),室温孵育45min。每孔加入40μl PBST洗涤3次。将孔板在1000rpm离心1min,并用Odyssey CLx读板。
数据分析:IC50结果由GraphPad Prism 5.0软件进行分析。
具体测试数据见下表1。
其中对照化合物MRTX849(WO2019099524)结构如下:
结论:本发明中大多数化合物显示了良好的抑制活性。
测试实施例2:化合物对KRAS-G12C修饰的评价
实验目的:
该实施例说明本发明的实施例化合物共价结合到KRAS G12C,使用LCMS测定本发明化合物与KRas G12C的共价加成物
实验步骤:
1、将GDP load到KRAS-4B-G12C蛋白上
1)将KRAS-4B-G12C蛋白用低镁缓冲液稀释一倍至浓度为103uM。
2)在1mL 103uM KRAS-4B-G12C蛋白中加入1mL 2*GDP loadingbuffer,轻柔缓慢混匀。
3)将2mL的混合物在室温下反应1.5h。
4)分装成100uL/管,用液氮速冻并存储到-80℃条件下。
2、小分子化合物对KRAS-4B-G12C蛋白的共价修饰分析
1)将KRAS-4B-G12C蛋白用10X反应缓冲液稀释,如下表所示配制反应体系:
成分 | 体积 |
GDP-loaded KRAS-4B-G12C(20uM) | 5uL |
小分子化合物(10%DMSO) | 5uL |
10X反应缓冲液 | 5uL |
MilliQ水 | 35uL |
共计 | 50uL |
2)分别在室温下反应5min和30min。
3)加入5uL的5%甲酸终止反应。
3、质谱检测
在质谱检测前将总共55uL的反应体系15000rpm离心10min。
4、计算与Kras-G12C的耦联率
耦联率(%)=蛋白-化合物复合物峰面积/(复合物峰面积+单体蛋白峰面积)*100。
每种蛋白质的质量计算为该蛋白质总信号的百分比,然后将该百分比与不加反应性化合物的蛋白质信号标准化。这些归一化的信号报告为归一化对照百分比(normalizedpercent of control,POC)。POC值增加表示化合物显示出更高的KRASG12C修饰程度。式(I)的示例化合物在3μM浓度下测试3min的结果如表2所示。“A”表示<25%POC;“B”表示>25%POC-<50%POC;“C”表示>50%POC;ND表示未测。
具体测试数据见下表2。
实施例 | POC | 实施例 | POC | 实施例 | POC |
1 | A | 2 | B | 3 | C |
4 | C | 5 | B | MRTX849 | C |
结论:本发明中化合物显示了良好的KRASG12C共价结合能力。
测试实施例3:化合物在小鼠全血中的稳定性试验
本实验旨在考察本发明化合物在全血样品中的稳定性。
以ICR雄性EDTA-K2全血为空白基质在室温条件下分别配制100ng/mL的样品(n=3)。在预定考察时间点(例如配制后即刻、1h、4h)取出稳定性样品,进行离心处理(离心条件:1500±20g,温度:2~8℃,离心10min),获取血浆样品。
取上述血浆样本加入内标溶液,涡旋1min,15400g,4℃,离心10min,取上清液进样分析,以分析物与内标的峰面积比值来计算结果,将每个时间点稳定性样品的响应平均峰面积的比值与配制后即刻样品比较,稳定性样品测定值与配制后即刻样品的偏差应不超过±15.0%。
WinNonlin7.0软件非房室模型方法(NCA)进行t1/2药代动力学参数的计算。具体测试数据见下表3。
实施例 | T<sub>1/2</sub>(h) | 实施例 | T<sub>1/2</sub>(h) | 实施例 | T<sub>1/2</sub>(h) |
1 | >40 | 2 | >40 | 3 | >40 |
4 | >40 | 5 | 21 | MRTX849 | 20 |
结论:同公开的对比化合物MRTX849相比,本发明中的化合物在小鼠全血中出乎意料的显示了更高的半衰期,说明本发明的化合物具有更好的代谢稳定性。
测试实施例4:药代动力学评价:
以小鼠为受试动物,测试了小鼠鼠灌胃给予实施例1、实施例2化合物后不同时刻血浆中药物浓度。研究本发明化合物在小鼠鼠体内药物代谢动力学行为,评价其药物代谢特征。每组实施例选用12只体重相近的小鼠,口服给予剂量为10mg/kg,单次给药。动物给药后在15min、30min、1h、2h、4h、6h、10h、24h时间点采集血液。采用LC-MS/MS分析方法检测血浆中化合物含量,方法的定量下限均为20ng/mL。使用代谢动力学数据分析软件WinNonlin7.0对血浆中的浓度数据进行统计,利用非房室模型法(NCA)计算药代参数,具体见下表2。
实验方案:
实验药品:实施例3、实施例4化合物。
药物配置:取一定量药物,加入2%Klucel LF+0.1%Tween 80水溶液,配制成呈澄清溶液或均匀悬浮液。
给药:小鼠禁食过夜后灌胃给药,给药剂量为10mg/kg,给药体积均为10mL/kg。
操作:小鼠灌胃给药实施例3化合物,于给药前及给药后15min、30min、1h、2h、4h、6h、10h、24h尾静脉采血至少0.2mL,置于肝素化样品管中,4℃,3500转/min离心10min分离血浆,于-20℃保存,给药后2h进食。
测定不同浓度药物灌胃给药后小鼠血浆中待测化合物的含量:血浆样品室温解冻后分别取50μL,加入130μL的内标工作液(1000ng/mL,乙腈,甲苯磺丁脲),涡旋1min后,4℃,13000rpm条件下离心10min。取50μL上清液与100μL 50%乙腈水混合后进样LC/MS/MS分析。
药代动力学参数结果见表4。
表4:小鼠药物代谢数据
结论:本发明的化合物药代吸收良好,具有明显的药代动力学优势。
上述实施例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
Claims (9)
1.一种哌啶并嘧啶类化合物,其特征在于,为下式(I)表示的化合物及其异构体或其药学上可接受的盐,
其中,
R1a为氢;
R2选自氢、卤素或-OC1-3烷基;
R3a、R3b、R3c和R3d各自独立地选自氢或C1-3烷基;所述C1-3烷基可被1个或多个R9取代;所述R9为氰基或卤素;
R4选自C1-3烷基;所述C1-3烷基可被1个-N(C1-2烷基)2取代;
R5选自苯基或萘基;所述苯基或萘基可被1个或多个R10取代;所述R10选自卤素、羟基、-CF3、-OCF3、-NH2、C1-6烷基或C1-6烷氧基;
R6选自-COC1-4烷基、C1-6烷基、C1-6烷氧基、C1-6氘代烷基、C1-6卤烷基、C3-6环烷基;
R7选自氢、卤素原子、C1-3烷基、C1-3卤烷基、氧代;
L选自-O-、-S-或-NR11;所述R11选自氢或C1-3烷基。
2.根据权利要求1所述的一种哌啶并嘧啶类化合物,其特征在于,所述R1a和R1b各自独立地选自氢、氟、氯或-CH3;所述-CH3可被一个或多个氟、氯、羟基、-OCH3、含有1至3个选自N、O和S的杂原子的C5-6杂芳基、-NR6aR6b取代基取代;所述的R6a、R6b独立地选自C1-3烷基或者R6a、R6b与其共同相连的-N-一起组成一个饱和或不饱和含有1至3个选自N、O和S的杂原子的四至六元杂环;R6a和R6b中所述的C1-3烷基或者饱和或不饱和含有1至3个选自N、O和S的杂原子的四至六元杂环可被1个或多个氟或氯取代。
6.根据权利要求1-5任一项所述的一种哌啶并嘧啶类化合物在制备针对KRASG12C突变蛋白相关癌症治疗药物中的用途。
7.根据权利要求6所述的一种哌啶并嘧啶类化合物在制备针对KRASG12C突变蛋白相关癌症的治疗药物中的用途,其特征在于,所述KRASG12C突变蛋白相关癌症疾病选自:肺癌、结直肠癌、胰腺癌、胰腺癌、肝癌、胃癌、食道癌、胆管癌、乳腺癌、卵巢癌、子宫颈癌、黑色素瘤、脑胶质瘤、淋巴癌、白血病。
8.一种针对KRASG12C突变蛋白相关癌症的治疗药物,其特征在于,所述药物包括治疗有效量的根据权利要求1-5中任意一项所述由式(I)表示的化合物及其药学上可接受的盐及其异构体或其药学上可接受的盐作为活性成分,以及药学上可接受的辅料,所述KRASG12C突变蛋白相关癌症疾病选自:肺癌、结直肠癌、胰腺癌、胰腺癌、肝癌、胃癌、食道癌、胆管癌、乳腺癌、卵巢癌、子宫颈癌、黑色素瘤、脑胶质瘤、淋巴癌、白血病。
9.一种KRASG12C突变蛋白相关癌症的治疗方法,所述治疗方法包括向受试者施用有效量的根据权利要求1-5中任意一项所述由式(I)表示的化合物及其药学上可接受的盐及其异构体或其药学上可接受的盐作为活性成分的药物组合物,所述KRASG12C突变蛋白相关癌症疾病选自:肺癌、结直肠癌、胰腺癌、胰腺癌、肝癌、胃癌、食道癌、胆管癌、乳腺癌、卵巢癌、子宫颈癌、黑色素瘤、脑胶质瘤、淋巴癌、白血病。
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