CN114008028A - 抑制癌细胞生长的嘧啶衍生物及其医药用途 - Google Patents
抑制癌细胞生长的嘧啶衍生物及其医药用途 Download PDFInfo
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- CN114008028A CN114008028A CN202080044951.2A CN202080044951A CN114008028A CN 114008028 A CN114008028 A CN 114008028A CN 202080044951 A CN202080044951 A CN 202080044951A CN 114008028 A CN114008028 A CN 114008028A
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- Prior art keywords
- amino
- phenyl
- pyrimidin
- dimethylamino
- methyl
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- 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
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- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
本发明提供了抑制癌细胞生长的新型嘧啶衍生物化合物及其药学上可接受的盐。本发明提供了一种包含这些化合物或其药学上可接受的盐的药物组合物。本发明还提供了一种治疗肺癌的医疗用途，其特征在于使用这些嘧啶衍生物化合物及其药学上可接受的盐作为活性成分。本发明还提供了一种治疗肺癌的方法，其包括施用根据本发明的化合物的有效剂量、其盐或包含它们的组合物。
Description
技术领域
本发明涉及有效抑制癌细胞生长的嘧啶衍生物化合物及其抗癌用途。
背景技术
在非小细胞肺癌患者中发现了表皮生长因子受体(EGFR)激酶域的各种突变为致癌基因，吉非替尼(Gefitinib)、厄洛替尼(Erlotinib)和奥希替尼(Osimertinib)等被用作表皮生长因子受体(EGFR)的小分子激酶抑制剂来治疗它们。
其中，由表皮生长因子受体外显子20插入突变(EGFR EXON 20Insertionmutation)引起的肺癌占所有突变的5％，各种表皮生长因子受体抑制剂(EGFRinhibitors)已被评估用于其治疗，但目前仍没有药物被批准作为治疗EGFR EXON 20插入突变肺癌的标准疗法，因此迫切需要开发一种可以治疗它的药物。
发明内容
相应地，本发明要解决的问题是提供对治疗肺癌，特别是对显示表皮生长因子受体突变特性的肺癌有用的化合物及其医药用途。
为了解决上述问题，本发明提供了以下化学式1的化合物或其药学上可接受的盐。
[化学式1]
在化学式1中，
A、B、D、E和G是A＝N、B＝C、D＝C、E＝C和G＝N的组合，或A＝N、B＝C、D＝N、E＝C和G＝C的组合，
W是氧或NH，
X和Y分别是CH、氧或氮，
当X或Y是氧时，Z1和Z2分别不存在，或当X或Y不是氧时，Z1和Z2分别是C1至C4烷基，或分别由碳原子组成并且相互连接以与X和Y一起形成5、6或7元环，
R1是C1至C4烷基，
R2是氢，或C1至C4烷基，
R3和R4分别是氢、卤素、OH、OMe、OEt、CN、CF3、C1至C4烷基或相互连接以形成5或6元(与苯基融合)杂芳环，且
R5是氢、卤素、OH、OMe、OEt、CN、CF3或C1至C4烷基，
R6和R7分别是氢、卤素、OH、OMe、OEt、CN、CF3、COOH、COO-C1-4烷基、COO-C1-5环烷基、C1至C4烷基或相互连接以形成5或6元杂芳环，R8是氢、卤素、OH、OMe、OEt、CN、CF3或C1至C4烷基，
R9是-C(O)-CH＝CH2或C1至C4烷基，并且
R10不存在或是氢、卤素、C1至C4烷基、OH、OMe、OEt、CN、CF3、NMe2、哌嗪、被C1至C3烷基取代的哌嗪、吗啉或被C1至C3烷基取代的吗啉。
本发明人已经证实，根据本发明的新型化合物对治疗肺癌是有效的，尤其是对显示有表皮生长因子受体突变的肺癌。特别地，本发明的化合物对治疗具有肺癌中显示表皮生长因子受体(EGFR)EXON 20插入突变特性的癌细胞的肺癌是有用的。
如本文所使用的术语”烷基”是指具有1至10个碳原子的饱和直链或支链非环状碳氢化合物(当碳原子的数量没有特别限制时)。“低级烷基”是指具有1至4个碳原子的直链或支链烷基。有代表性的饱和直链烷基包括：-甲基、-乙基、-正丙基、-正丁基、-正戊基、-正己基、-正庚基、-正辛基、-正壬基和-正癸基，而饱和支链烷基包括：-异丙基、-仲丁基、-异丁基、-叔丁基、异戊基、2-甲基己基、3-甲基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2-甲基己基、3-甲基己基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基丁基、2,3-二甲基戊基、2,4-二甲基戊基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基戊基、2,2-二甲基己基、3,3-二甲基戊基、3,3-二甲基己基、4,4-二甲基己基、2-乙基戊基、3-乙基戊基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、2-甲基-4-乙基戊基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2-甲基-4-乙基己基、2,2-二乙基戊基、3,3-二乙基己基、2,2-二乙基己基和3,3-二乙基己基。
如本文所使用的术语“环烷基”是指具有碳原子和氢原子且不具有碳-碳多键的单环或多环饱和环。环烷基的实例包括(C3-C7)环烷基(例如，环丙基、环丁基、环戊基、环己基和环庚基)，但不限于此。在本发明的一个方面，环烷基是(C3-C5)环烷基。在本发明的另一个方面，环烷基是环丙基。在一个实例中，环烷基团是单环或双环。
在此，当描述为“C1-6”或“C1至C6”时，这意味着碳原子的数量为1至6。例如，C1-6烷基是指具有1至6个碳原子的烷基。
如本文所使用的术语“卤素”和“卤”是指氟、氯、溴或碘。
如本文所使用的术语“芳基”是指含有5至10个环原子的碳环芳基团。代表性的实例包括苯基、甲苯基、二甲苯基、萘基、四氢萘基、蒽基、芴基、茚基和薁基等，但不限于此。碳环芳基团可以被选择性地取代。
如本文所使用的“杂芳基”是5至10元杂环芳烃环，其有至少一个选自由氮、氧和硫所组成的组的至少一个杂原子，是包括至少一个碳原子和具有单环和双环系统的5-10元杂环芳环。代表性的杂芳基是三唑基、四唑基、噁二唑基、吡啶基、呋喃基、苯并呋喃基、苯硫基(thiophenyl)、苯并苯硫基(benzothiophenyl)、喹啉基、吡咯基、吲哚基、噁唑基、苯并噁唑基、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、异噁唑基、吡唑基、异噻唑基、哒嗪基、嘧啶基(pyrimidinyl)、吡嗪基、三嗪基、噌啉基、酞嗪基、喹唑啉基、嘧啶基(pyrimidyl)、氧杂环丁烷基、吖庚因基(azepinly)、哌嗪基、吗啉基、二噁烷基、噻丁基(thietanyl)和噁唑基。
在本文中，化学式1所代表的化合物可以以无机酸或有机酸诱导的盐的形式使用，例如，它可以以盐的形式使用，盐选自由盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、酒石酸、柠檬酸、甘道夫酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸等所组成的组中的一种或多种酸诱导。
如本文所使用的术语“本发明的化合物”是指化学式1的每种化合物，以及包合物、水合物、溶剂合物或其多晶型物物。此外，术语“本发明的化合物”的意思是本发明化合物的药学上可接受的盐，除非提及其药学上可接受的盐。在一个实例中，本发明的化合物可以作为立体异构纯化合物(例如，基本上不含其他立体异构体(例如，85％ee或以上，90％ee或以上，95％ee或以上，97％ee或以上，或99％ee或以上))存在。换句话说，当根据本发明的化学式1的化合物或其盐是互变异构体和/或立体异构体(例如几何异构体和构象异构体)时，它们的每个分离异构体和混合物也包括在本发明的化合物的范围内。当本发明的化合物或其盐在其结构中具有不对称碳时，它们的旋光化合物和外消旋混合物也包括在本发明化合物的范围内。
如本文所使用的术语“多晶型物”是指本发明的化合物或其复合物的固体结晶形式。同一化合物的不同多晶型物表现出不同的物理、化学和/或光谱特性。物理特性的差异包括稳定性(如，热稳定性或光稳定性)、压缩性和密度(对配方和产品制备很重要)以及溶解率(可能影响生物药效率)，但不限于此。稳定性的差异会引起化学反应性的变化(如，不同的氧化，例如由一种多晶型物组成时比由另一种多晶型物组成时变色更快)或机械性能的变化(如，储存为动力学上优选的多晶型物的纯化碎片被转化为热力学上更稳定的多晶型物)或其两者的变化(纯化的一种多晶型物对高湿度下的降解更敏感)。多晶型物的其他物理特性可能影响它们的加工。例如，一种多晶型物可能比另一种多晶型物更容易形成溶剂合物，例如，由于其形状或粒子大小分布，其可能更难过滤或洗涤。
如本文所使用的术语“溶剂化合物”是指本发明的化合物或其药学上可接受的盐，包括由非共价分子间力结合的化学或非化学计算量的溶剂。优选溶剂是挥发性的，无毒的，可对人类进行微量施用。
如本文所使用的术语“水合物”是指本发明的化合物或其药学上可接受的盐，包括由非共价分子间作用力结合的化学或非化学计算量的水。
如本文所使用的术语“包合物”是指本发明的化合物或其盐以晶格形式存在，其晶格形式含有限制客体分子(例如溶剂或水)的空间(例如通道)。
如本文所使用的术语“纯化”是指分离物在分离时至少有90％的纯度，在一个实例中，它是指95％或更高的纯度，在另一个实例中，它是指99％或更高的纯度，在其他实例中，它是指99.9％或更高的纯度。
如本文所使用的“治疗”包括根除、移除、改变或控制原发性、局部或转移性癌组织；以及最大限度地减少或延迟癌症的扩散。
非限制性的，根据本发明的化合物的实例包括以下化合物及其药学上可接受的盐。
-N-(2-((5-氯-2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)吡啶-4-基)氨基)苯基)-N-甲磺酸酰胺，
-N-(2-((2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)噻吩并[3,2-d]嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺，
-N-(2-((2-((4-(4-(二甲基氨基)哌啶-1-基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)噻吩并[3,2-d]嘧啶-4-基)氨基)苯基)-N-甲氧基甲磺酰胺，
-N-(2-((2-((5-(异丙基氨基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)噻吩并[3,2-d]嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺，
-N-(2-((5-氯-2-((5-(异丙基氨基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺，
-N-(2-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺，
-N-(4-甲氧基-5-((4-((2-(N-甲基甲磺酰氨基)苯基)氨基)噻吩并[3,2-d]嘧啶-2-基)氨基)-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)丙烯酰胺，
-N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((2-(N-甲基甲磺酰氨基)苯基)氨基)噻吩并[3,2-d]嘧啶-2-基)氨基)苯基)丙烯酰胺，
-N-(2-(4-(二甲基氨基)哌啶-1-基)-4-甲氧基-5-((4-((2-(N-甲基甲磺酰氨基)苯基)氨基)噻吩并[3,2-d]嘧啶-2-基)氨基)苯基)丙烯酰胺，
-N-(5-((5-氯-4-((2-(甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺，
-N-(5-((5-氯-4-((5-(N-甲基甲磺酰氨基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺，
-N-(5-((5-氯-4-((5-(甲磺酰氨基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺，
-N-(5-((5-氯-4-((5-氟-2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺，
-N-(5-((5-氯-4-((5-氟-2-(甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺，
-2-((5-丙烯酰胺基-4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-5-羧酸异丙酯，
-2-((5-丙烯酰胺基-4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-5-羧酸环丙酯，或
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((6-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺。
在另一个方面，本发明提供了一种药物组合物，包括化学式1的化合物的治疗有效剂量或根据本发明的其药学上可接受的盐，以及药学上可接受的载体。
如本文所使用的“有效剂量”是指足以破坏、改变、控制或清除原发性、局部或转移性癌细胞或癌组织的本发明的化合物的量；减缓或尽量减少癌症的扩散；或在治疗或管理癌症、肿瘤性疾病或肿瘤中提供治疗益处。“有效剂量”也指足以导致癌症或肿瘤细胞死亡的本发明的化合物的量。“有效剂量”也指足以在体外或体内抑制或降低肺癌细胞活性的量。
在另一个方面，本发明提供了一种治疗疾病或病症的方法，包括向需要的受试者施用治疗有效剂量的化学式1的化合物或其药学上可接受的盐，并且该疾病或病症是肺癌。在另一个方面，该受试者是人。在另一个方面，该肺癌是显示表皮生长因子受体(EGFR)突变特性的肺癌。在另一方面，该肺癌是具有显示表皮生长因子受体EXON 20插入突变(EGFREXON 20插入突变)特性的癌细胞的肺癌。
换句话说，本发明提供了一种医疗用途，其特征是将根据本发明的化学式1的化合物或其药学上可接受的盐作为活性成分。在一个方面，本发明的医疗用途是用于治疗或预防本文所述的疾病或病症的用途。
因此，在另一个方面，本发明提供了一种药物组合物，其用于治疗或预防肺癌，特别是表皮生长因子受体突变表达的肺癌，该药物组合物包括根据本发明的化合物或其药学上可接受的盐作为活性成分。
本发明的化合物或其药学上可接受的盐一般以治疗有效剂量进行给药。本发明的化合物可以通过任何适当的途径以适合该途径的药物组合物形式的有效剂量给药，并进行预期的治疗。有效剂量一般可以是约0.0001至约200mg/kg(体重)/天，最好是约0.001至约100mg/kg/天，通过单次或分次给药。根据年龄、物种和要治疗的疾病或病症，低于该范围下限的剂量水平可能是合适的。在其他情况下，可以使用更大的剂量而不产生有害的副作用。较大的剂量可以分成几个较小的剂量，在一天内施用。确定适当剂量的方法在本领域是众所周知的，例如，文件雷明顿(Remington):《药学的科学与实践》，麦克出版公司，第20版，2000可被使用。
对于肺癌的治疗，本文所述的化合物或其药学上可接受的盐可通过以下各种方法给药。
口服给药
本发明的化合物可以口服给药，口服是一个包括吞咽的概念。通过口服给药，本发明的化合物可以进入胃肠道，也可以直接从口腔吸收进入血流，例如口腔或舌下给药。
适合口服的组合物可以是固体、液体、凝胶或粉末的形式，可以有片剂、锭剂、胶囊、颗粒剂和粉末等配方。
用于口服的组合物可选择性地进行肠溶，并可通过肠溶表现出延迟或持续释放。换句话说，根据本发明的口服施用组合物可以是具有即时或改良释放模式的制剂。
该液体制剂可包括溶液、糖浆和悬浮液，该液体组合物可以是包含在软胶囊或硬胶囊中的形式。该制剂可包括药学上可接受的载体，例如，水、乙醇、聚乙二醇、纤维素或油。该制剂还可包括一种或多种乳化剂和/或悬浮剂。
在片剂中，作为活性成分的药物量可以基于片剂总重量的约0.05重量％至约95重量％，通常是约2重量％至约50重量％的量存在。此外，片剂可包括用量约为制剂的0.5重量％至约35重量％，通常是约为2重量％至约25重量％的崩解剂。作为崩解剂的实例，可以使用乳糖、淀粉、甘醇酸淀粉钠、聚乙烯聚吡咯烷酮、交联羧甲基纤维素钠、麦芽糊精或其混合物，但不限于此。
用于制备成片剂而组成的适当的助流剂(glydent)可以以约0.1重量％至约重量5％的量存在，且滑石、二氧化硅、硬脂酸、钙、锌或镁硬脂酸和硬脂酰富马酸钠等可用作助流剂，但本发明不受这些种类的添加剂限制。
作为制备成片剂的粘合剂，可使用明胶、聚乙二醇、糖、树胶、淀粉、聚乙烯吡咯烷酮、羟丙基纤维素和羟丙基甲基纤维素等。且作为制备成片剂的合适稀释剂，可使用甘露醇、木糖醇、乳糖、葡萄糖、蔗糖、山梨醇、淀粉和微晶纤维素等，但本发明不限于这些种类的添加剂。
可选择性地包含在片剂中的增溶剂的用量可为基于片剂总重量的约0.1重量％至约3重量％，例如，聚山梨酯、月桂硫酸钠、十二烷基硫酸钠、碳酸丙烯酯、二甘醇单乙醚、二甲基异山梨酯、聚氧乙烯甘醇酸化天然或氢化蓖麻油、HCORTM(Nikkol)。油酯、GelucireTM、辛酸/辛酸单/双甘油酯、山梨糖醇脂肪酸酯和Solutol HSTM等可用于根据本发明的药物组合物，但本发明不限于这些特定种类的增溶剂。
胃肠外给药
本发明的化合物可以直接给药到血液、肌肉或肠道。适当的胃肠外给药方法包括静脉内、肌肉内、皮下动脉内、腹腔内、鞘内和颅内注射等。合适的胃肠外给药装置包括注射器(包括针头和无针注射器)和输液方法。
用于胃肠外给药的组合物可以是具有即时或改良释放模式的制剂，且改良释放模式可以是延迟释放或持续释放模式。
大多数胃肠外制剂是液体组合物，这些液体组合物是包含根据本发明的药物成分、盐、缓冲剂和等渗剂等的水溶液。
胃肠外制剂也可以制备成干燥形式(例如冻干)或无菌非水溶液。这些制剂可与适当的载体如无菌水一起使用。溶解性增强剂也可用于制备胃肠外溶液。
局部给药
本发明的化合物可通过皮肤或经皮肤的方式进行局部给药。局部给药的制剂包括洗剂、溶液、乳膏、凝胶、水凝胶、软膏、泡沫、植入物和贴片等。用于局部给药制剂的药学上可接受的载体可包括水、酒精、矿物油、甘油和聚乙二醇等。局部给药也可以通过电穿孔、离子电渗疗法和声透疗法等方式进行。
用于局部给药的组合物可以是具有即时或改良释放模式的制剂，而改良释放模式可以是延迟或持续释放模式。
优势效果
本发明提供了具有癌细胞抑制活性的新的嘧啶衍生物化合物及其药学上可接受的盐。根据本发明的嘧啶衍生物或其药学上可接受的盐可以有效地抑制表皮生长因子受体突变表达的癌细胞的生长，特别是，存在于肺癌中的癌细胞。因此，根据本发明的化合物及其药学上可接受的盐对治疗肺癌是有用的。
具体实施方式
下面，为了帮助理解本发明，将通过实施例等对其进行详细描述。然而，根据本发明的实施例可以以各种其他形式进行修改，而且本发明的范围不应理解为仅限于以下实施例。提供本发明的实施例是为了向具有本发明所涉及领域的一般知识的人更完整地描述本发明。
根据本发明，上述化学式1所代表的化合物可以很容易地制备，例如，参照下面反应图式1、2、3和4所示方法。
[反应图式1]
[反应图式2]
[反应图式3]
[反应图式4]
合成实施例：合成N-(2-((5-氯-2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)吡啶-4-基)氨基)苯基)-N-甲磺酸酰胺和N-((5-氯-4-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺
步骤1：
在上述反应图式1中，将结构A1-P3(3g，21.262mmol)溶于乙腈(150mL)。在室温下，加入CS2CO3(10.4g，31.892mmol)和N-甲基甲磺酰胺，然后在80℃搅拌12小时。反应后剩余的固体被过滤，减压蒸馏除去有机溶剂，得到Al-P2。没有单独的分离过程，其被用于下一反应。
步骤2：
将步骤1中得到的结构A1-P2(4.5g，19.545mmol)溶解在MeOH(100mL)和DCM(50mL)的混合溶剂中，然后加入10％Pd/C(0.416g，3.909mmol)。在氢气环境下，搅拌2小时，然后用铁铝酸四钙过滤，减压蒸馏，除去溶剂，得到粗制A1-P1。该固体用乙醚和正戊烷洗涤，用于下一步反应，不需要单独的分离过程。
步骤3：
将前述反应得到的结构A1-P1(8.3g，41.446mmol)溶于IPA(200mL)，然后在室温下加入2,5,6-三氯嘧啶(12.163g，66.314mmol)和DIPEA(21.428g，166mmol)，在90℃搅拌12小时。反应完成后，减压蒸馏，除去溶剂，然后加水，用DCM提取。混合溶液再次用2N HCl洗涤，分离有机层并减压蒸馏，得到粗制A1。没有单独的分离过程，其被用于下一反应。
步骤4：
在上述反应图式2中，将结构B1-P5(4g，21.489mmol)溶于DCM(100mL)，然后在室温下，加入Boc酸酐(4.690g，21.489mmol)和DMAP(0.262g，2.149mmol)，并搅拌12小时。当反应完成后，反应混合物用2N HCl洗涤，然后用Na2SO4干燥并过滤，再减压蒸馏，得到粗制的B1-P4。采用柱色谱法，得到纯的B1-P4目标化合物(5.8g，97.5％)。
步骤5：
在上述反应图式2中，将结构B1-P4(2.2g，7.685mmol)溶于乙腈(50mL)，然后在室温下加入K2CO3(2.124g，15.371mmol)和N,N,N'-三甲基二胺，然后在80℃搅拌12小时。反应完成后，过滤反应产物，减压蒸馏，得到粗制B1-P3。没有单独的分离过程，其被用于下一反应。
步骤6：
在上述反应图式2中，将结构B1-P3(2.8g，7.6mmol)溶解在MeOH(50mL)和DCM(20mL)的混合溶剂中，在氢气环境下搅拌4小时。当反应完成后，用铁铝酸四钙过滤，减压蒸馏除去溶剂，得到粗制的B1-P2。没有单独的分离过程，其被用于下一反应。
步骤7：
在上述反应图式2中，向B1-P3(580.8mg，1.00mmol)中加入丙酮20mL，然后加入锌粉(653.9mg，10.0mmol)和饱和溶液NH4Cl(10mL)并在6小时回流下完成反应。在室温下冷却后，用铁铝酸四钙除去锌粉，减压除去溶剂，然后用EtOAc提取得到的水层。在得到的有机层中，在减压下除去溶剂，用柱色谱法进行纯化。
步骤8：
在上述反应图式2中，将B1-P1(300mg，0.764mmol)溶于DCM(15mL)，然后冷却到0℃。然后，加入TFA(0.6mL，7.643mmol)，并将温度提高到室温，搅拌3小时。反应完成后，减压蒸馏，除去溶剂，用DCM和饱和NaHCO3溶液清洗，然后将有机层分离并干燥，再减压蒸馏。没有单独的分离过程，其被用于下一反应。
步骤9：
在上述反应图式3中，将丙烯酸(75mg，1.034mmol)溶于DMF(4mL)，然后冷却到0℃。然后，加入HATU(393mg，1.034mmol)和DIPEA(400mg，3.103mmol)，再加入B1-P2(350mg，1.034mmol)，将反应物在室温下搅拌12小时。当反应完成后，用H2O和DCM提取。分离出的有机层用Na2SO4干燥，并过滤，然后减压蒸馏。使用柱色谱法，得到纯化得B1-P1目标化合物(220mg，55％)。
步骤10：
在上述反应图式3中，将C1-P1(300mg，0.764mmol)溶于DCM(15mL)，然后冷却到0℃。加入TFA(0.6mL，7.643mmol)，将温度升高到室温，搅拌3小时。反应完成后，减压蒸馏，除去溶剂，用DCM和饱和NaHCO3溶液洗涤，然后分离有机层，干燥，再减压蒸馏。没有单独的分离过程，其被用于下一反应。
步骤11：
在上述反应图式4中，将结构B1(50mg，0.178mmol)溶于异丙醇(3mL)，然后在室温下加入A1(71mg，0.205mmol)和PTSA(48.8mg，0.257mmol)，在90℃搅拌12小时。反应完成后，减压蒸馏，除去溶剂，用水和10％MeOH/DCM提取。分离有机层并干燥，减压蒸馏，得到粗制的化合物1。使用柱色谱法，得到纯化的化合物1(60mg，58％)。
1H NMR(400MHz；CDCl3):δ(ppm):8.26-8.49(2H,m),8.16(1H,s)8.09-8.08(1H,d),7.83(1H,s),7.55-7.52(1H,dd),6.98(1H,s),6.97-6.77(1H,dd),5.72(1H,dd),4.76(1H,m),3.67(3H,s),3.14(3H,s),3.06(3H,s),2.79(2H,m),2.70(3H,s),2.20(8H,br s),1.11(6H,d).[M+H]+:m/z 591.17实测592.2 HPLC纯度：97.9％
步骤12：
在上述反应方案4中，将结构C1(50mg，0.171mmol)溶于异丙醇(3mL)，然后在室温下加入A1(71mg，0.205mmol)和PTSA(49.1mg，0.258mmol)，在90℃搅拌12小时。反应完成后，减压蒸馏，除去溶剂，用水和10％MeOH/DCM提取。分离有机层并干燥，减压蒸馏，得到粗制的化合物12。使用柱色谱法，得到纯化的化合物12(65mg，63％)。
1H NMR(400MHz；CDCl3):δ(ppm):10.02(1H,br s),8.35-8.31(2H,m),8.26(1H,s)8.21-8.19(1H,d),8.09(1H,s),7.53-7.50(1H,dd),6.95(1H,s),6.18-6.14(1H,dd),5.72-5.68(1H,dd),4.31(1H,m),3.72(3H,s),3.14(3H,s),3.05(3H,s),2.86(2H,m),2.66(3H,s),2.19(8H,br s),1.12(6H,d).[M+H]+:m/z 591.17实测592.2 HPLC纯度：98.1％
实施例1.N-(2-((5-氯-2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)吡啶-4-基)氨基)苯基)-N-甲磺酸酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz；CDCl3):δ(ppm):8.26-8.49(2H,m),8.16(1H,s)8.09-8.08(1H,d),7.83(1H,s),7.55-7.52(1H,dd),6.98(1H,s),6.97-6.77(1H,dd),5.72(1H,dd),4.76(1H,m),3.67(3H,s),3.14(3H,s),3.06(3H,s),2.79(2H,m),2.70(3H,s),2.20(8H,br s),1.11(6H,d).[M+H]+:m/z 591.17实测592.2HPLC纯度：97.9％
实施例2.N-(2-((2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)噻吩并[3,2-d]嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),9.20(s,1H),8.02(s,1H),7.63(d,J＝7.6Hz,1H),7.45(dd,J＝7.5,1.5Hz,1H),7.39-7.32(m,2H),7.04(td,J＝7.5,1.5Hz,1H),6.76(td,J＝7.5,1.5Hz,1H),6.46(s,1H),5.51(d,J＝8.4Hz,1H),4.31(m,1H),3.85(s,3H),3.44-3.34(bs,2H),3.32(s,3H),3.26(s,3H),3.00(s,3H),2.57-2.50(m,8H),1.12(d,J＝6.9Hz,6H).MS:ESI m/z 613.1[M+H]+HPLC纯度：99.0％
实施例3.N-(2-((2-((4-(4-(二甲基氨基)哌啶-1-基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)噻吩并[3,2-d]嘧啶-4-基)氨基)苯基)-N-甲氧基甲磺酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),9.20(s,1H),8.02(s,1H),7.63(d,J＝7.6Hz,1H),7.45(dd,J＝7.5,1.5Hz,1H),7.39-7.32(m,2H),7.04(td,J＝7.5,1.5Hz,1H),6.76(td,J＝7.5,1.5Hz,1H),6.46(s,1H),5.51(d,J＝8.4Hz,1H),4.31(m,1H),3.72(s,3H),3.14(s,3H),3.06(s,3H),3.00(d,J＝11.2Hz,2H),2.62(dd,J＝12.4,10.2Hz,2H),2.19(m,8H),1.80(d,J＝11.4Hz,2H),1.65(q,J＝11.3Hz,2H),1.12(d,J＝6.9Hz,6H).MS:ESI m/z 639.0[M+H]+HPLC纯度：98.5％
实施例4.N-(2-((2-((5-(异丙基氨基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)噻吩并[3,2-d]嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.22(s,1H),8.00(s,1H),7.61(d,J＝7.6Hz,1H),7.45(dd,J＝7.5,1.5Hz,1H),7.37-7.33(m,2H),7.04(td,J＝7.5,1.5Hz,1H),6.76(td,J＝7.5,1.5Hz,1H),6.46(s,1H),5.51(d,J＝8.4Hz,1H),4.32(m,1H),3.70(s,3H),3.15(s,3H),3.04(s,3H),3.01(d,J＝11.2Hz,2H),.69-2.57(m,2H),2.55-2.48(m,4H),2.25(m,5H),2.12(s,3H),1.81(d,J＝11.9Hz,2H),1.67(q,J＝11.4,10.7Hz,2H),1.10(d,J＝6.9Hz,6H).MS:ESI m/z 694.1[M+H]+HPLC纯度：97.9％
实施例5.N-(2-((5-氯-2-((5-(异丙基氨基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz；CDCl3):δ(ppm):10.02(1H,br s),8.35-8.31(2H,m),8.26(1H,s)8.21-8.19(1H,d),8.09(1H,s),7.53-7.50(1H,dd),6.95(1H,s),6.18-6.14(1H,dd),5.72-5.68(1H,dd),4.31(1H,m),3.72(s,3H),3.14(s,3H),3.06(s,3H),3.00(2H,d),2.69-2.57(2H,m),2.55-2.48(4H,m),2.25(5H,m),2.12(3H,s),1.81(2H,d),1.67(2H,q),1.12(d,6H).MS:ESI m/z 672.0[M+H]+HPLC纯度：98.2％
实施例6.N-(2-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz；CDCl3):δ(ppm):10.02(1H,br s),8.37-8.33(2H,m),8.23(1H,s)8.20-8.17(1H,d),8.09(1H,s),7.53-7.50(1H,dd),6.95(1H,s),6.18-6.14(1H,dd),5.72-5.68(1H,dd),4.31(1H,m),3.72(s,3H),3.14(s,3H),3.06(s,3H),3.00(d,J＝11.2Hz,2H),2.62(2H,dd),2.19(8H,m),1.80(2H,d),1.65(2H,q),1.12(6H,d).MS:ESI m/z 617.0[M+H]+HPLC纯度：97.6％
实施例7.N-(4-甲氧基-5-((4-((2-(N-甲基甲磺酰氨基)苯基)氨基)噻吩并[3,2-d]嘧啶-2-基)氨基)-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)丙烯酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.75(s,1H),8.36(s,1H),8.03(d,J＝5.3Hz,1H),8.00(dd,J＝8.1,1.6Hz,1H),7.70(s,1H),7.52(dd,J＝7.9,1.6Hz,1H),7.24(td,J＝7.7,1.6Hz,1H),7.20-7.11(m,2H),6.93(s,1H),6.37(m,1H),6.18(dd,J＝16.9,2.1Hz,1H),5.74-5.66(m,1H),3.72(s,3H),3.14(s,3H),3.06(s,3H),3.00(d,J＝11.2Hz,2H),2.69-2.57(m,2H),2.55-2.48(m,4H),2.25(m,5H),2.12(s,3H),1.81(d,J＝11.9Hz,2H),1.67(q,J＝11.4,10.7Hz,2H).MS:ESI m/z 706.2[M+H]+,HPLC纯度：98.5％.
实施例8.N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((2-(N-甲基甲磺酰氨基)苯基)氨基)噻吩并[3,2-d]嘧啶-2-基)氨基)苯基)丙烯酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.74(s,1H),8.36(s,1H),8.03(d,J＝5.3Hz,1H),8.00(dd,J＝8.1,1.6Hz,1H),7.71(s,1H),7.52(dd,J＝7.9,1.6Hz,1H),7.24(td,J＝7.7,1.6Hz,1H),7.20-7.11(m,2H),6.93(s,1H),6.37(m,1H),6.18(dd,J＝16.9,2.1Hz,1H),5.74-5.66(m,1H),3.75(s,3H),3.13(s,3H),3.01(s,3H),2.84(bs,2H),2.65(s,3H),2.37-2.07(m,8H).MS:ESI m/z 625.1[M+H]+,HPLC纯度：97.9％.
实施例9.N-(2-(4-(二甲基氨基)哌啶-1-基)-4-甲氧基-5-((4-((2-(N-甲基甲磺酰氨基)苯基)氨基)噻吩并[3,2-d]嘧啶-2-基)氨基)苯基)丙烯酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),8.74(s,1H),8.35(s,1H),8.03(d,J＝5.3Hz,1H),8.00(dd,J＝8.1,1.6Hz,1H),7.70(s,1H),7.52(dd,J＝7.9,1.6Hz,1H),7.24(td,J＝7.7,1.6Hz,1H),7.20-7.11(m,2H),6.93(s,1H),6.37(m,1H),6.18(dd,J＝16.9,2.1Hz,1H),5.74-5.66(m,1H),3.72(s,3H),3.14(s,3H),3.06(s,3H),3.00(d,J＝11.2Hz,2H),2.62(dd,J＝12.4,10.2Hz,2H),2.19(s,7H),1.80(d,J＝11.4Hz,2H),1.65(q,J＝11.3Hz,2H).MS:ESI m/z650.0[M+H]+,HPLC纯度：98.1％.
实施例10.N-(5-((5-氯-4-((2-(甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz；DMSO-d6):δ(ppm):10.02(1H,br s),8.35-8.31(2H,m),8.26(1H,s)8.21-8.19(1H,d),8.09(1H,s),7.53-7.50(1H,dd),7.12-7.04(2H,m),6.95(1H,s),6.37(1H,br s),6.18-6.14(1H,dd),5.72-5.68(1H,dd),3.72(3H,s),3.14(3H,s),2.86(2H,m),2.66(3H,s),2.19(8H,br s).[M+H]+:m/z 588.20,实测589.1 HPLC纯度：98.2％
实施例11.N-(5-((5-氯-4-((5-(N-甲基甲磺酰氨基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ9.51(d,J＝7.3Hz,2H),9.43(s,1H),9.34(d,J＝7.5Hz,1H),8.58(d,J＝7.5Hz,1H),8.52(s,1H),7.58(d,J＝7.5Hz,1H),7.53(d,J＝7.3Hz,2H),6.41(s,1H),6.34(dd,J＝16.7,10.0Hz,1H),6.03(dd,J＝10.0,3.1Hz,1H),5.93(dd,J＝16.7,3.1Hz,1H),3.72(s,3H),3.14(s,3H),3.05(s,3H),2.86(m,2H),2.66(s,3H),2.19(m,8H).MS:ESI m/z 655.1[M+H]+,HPLC纯度：98.7％
实施例12.N-(5-((5-氯-4-((5-(甲磺酰氨基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ9.50(d,J＝7.3Hz,2H),9.43(s,1H),9.36(d,J＝7.5Hz,1H),8.58(d,J＝7.5Hz,1H),8.52(s,1H),7.56(d,J＝7.5Hz,1H),7.53(d,J＝7.3Hz,2H),6.41(s,1H),6.34(dd,J＝16.7,10.0Hz,1H),6.03(dd,J＝10.0,3.1Hz,1H),5.93(dd,J＝16.7,3.1Hz,1H),3.72(s,3H),3.12(s,3H),2.86(m,2H),2.66(s,3H),2.19(m,8H).MS:ESI m/z 641.0[M+H]+,HPLC纯度：97.3％.
实施例13.N-(5-((5-氯-4-((5-氟-2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),9.42(d,J＝8.2Hz,2H),8.52(s,1H),7.75(dd,J＝8.0,1.5Hz,1H),7.54(s,1H),7.31(dd,J＝7.5,5.0Hz,1H),6.93-6.84(m,1H),6.41(s,1H),6.34(dd,J＝16.7,10.0Hz,1H),6.03(dd,J＝10.0,3.1Hz,1H),5.93(dd,J＝16.7,3.1Hz,1H),3.72(s,3H),3.14(s,3H),3.05(s,3H),2.86(bs,2H),2.63(s,3H),2.20(m,8H).MS:ESI m/z 621.0[M+H]+HPLC纯度：98.9％.
实施例14.N-(5-((5-氯-4-((5-氟-2-(甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.54(s,1H),9.43(d,J＝2.5Hz,2H),8.52(s,1H),7.56-7.48(m,3H),6.84(ddd,J＝8.0,7.5,1.5Hz,1H),6.41(s,1H),6.34(dd,J＝16.7,10.0Hz,1H),6.03(dd,J＝10.0,3.1Hz,1H),5.93(dd,J＝16.7,3.1Hz,1H),3.70(s,3H),3.16(s,3H),2.83(bs,2H),2.63(s,3H),2.18(m,8H).MS:ESI m/z 607.0[M+H]+HPLC纯度：98.7％.
实施例15. 2-((5-丙烯酰胺基-4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-5-羧酸异丙酯的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.59-9.48(m,2H),8.84(s,1H),7.54(s,1H),7.18(dd,J＝7.4,1.5Hz,1H),7.08-6.99(m,2H),6.95(td,J＝7.1,2.1Hz,1H),6.41(s,1H),6.34(dd,J＝16.7,10.1Hz,1H),6.03(dd,J＝9.9,3.1Hz,1H),5.93(dd,J＝16.7,3.1Hz,1H),5.09(h,J＝6.2Hz,1H),3.81(s,3H),3.26(t,J＝6.8Hz,2H),3.12(s,3H),3.08(s,3H),2.83(s,3H),2.43(m,2H),2.11(s,6H),1.28(d,J＝6.2Hz,6H),MS:ESI m/z 655.0[M+H]+HPLC纯度：98.9％.
实施例16. 2-((5-丙烯酰胺基-4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-5-羧酸环丙酯的制备
最终的化合物是通过上述反应图式4制备的。
1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.58-9.47(m,2H),8.82(s,1H),7.54(s,1H),7.18(dd,J＝7.4,1.5Hz,1H),7.08-6.99(m,2H),6.95(td,J＝7.1,2.1Hz,1H),6.41(s,1H),6.34(dd,J＝16.7,10.1Hz,1H),6.03(dd,J＝9.9,3.1Hz,1H),5.93(dd,J＝16.7,3.1Hz,1H),5.06(m,1H),3.79(s,3H),3.26(t,J＝6.8Hz,2H),3.15(s,3H),3.09(s,3H),2.80(s,3H),2.43(m,2H),2.11(s,6H),0.98-0.95(m,2H),0.88-0.85(m,2H),MS:ESI m/z653.0[M+H]+HPLC纯度：98.6％.
实施例17的合成实施例
[反应图式5]
步骤1：合成N-甲基-N-(2-硝基苯基)甲磺酰胺
将1-氟-2-硝基苯(1.0eq.)溶解在乙腈中，在室温下加入碳酸钾(2.0eq.)和N-甲基甲磺酰胺(1.4eq.)。然后，在80℃下搅拌过夜。完成反应后，将温度降至室温，并过滤。滤液在减压下蒸发，得到化合物。没有分离过程，其被用于下一反应。
步骤2：N-(2-氨基苯基)-N-甲基甲磺酰胺的合成
将N-甲基-N-(2-硝基苯基)甲磺酰胺(1.0eq.)溶于甲醇，并加入和乙酸乙酯(1:1)和10％钯/炭(0.2eq.)。在氢气下，搅拌2小时。反应完成后，用铁铝酸四钙过滤，然后减压蒸发滤液。用乙醚和戊烷将其固化并过滤，得到目标化合物。没有分离过程，其被用于下一反应。
步骤3：合成N-(2-((6-氯嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺
将N-(2-氨基苯基)-N-甲基甲磺酰胺(1.0eq.)溶于异丙醇，并在室温下加入2,4,5-三氯吡喃(1.1eq.)和N,N-二异丙基乙胺(2.5eq.)。在80℃下搅拌过夜。完成反应后，减压蒸发，用水和二氯甲烷提取。有机层用2N盐酸清洗。有机层在减压下蒸发，并进行柱色谱分析，得到目标化合物。(50％己烷/乙酸乙酯)
步骤4：合成N-(2-((6-((4-氟-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺
将嘧啶衍生物(1.0eq.)溶于异丙醇，在室温下加入苯胺衍生物(1.0eq.)和甲磺酸(1.3eq.)。在80℃下搅拌过夜。反应完成后，减压蒸发，用水和10％甲醇/二氯甲烷混合溶液提取。有机层减压蒸发，进行柱色谱分析，得到目标化合物。(50％己烷/乙酸乙酯)
步骤5：合成N-(2-((6-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺
将N-(2-((6-((4-氟-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(1.0eq.)溶于乙腈，在室温下加入碳酸钾(3.0eq.)和胺链(1.2eq.)。通过回流搅拌过夜。完成反应后，将温度降至室温，并进行过滤。滤液在减压下蒸发，得到目标化合物。没有分离过程，其被用于下一反应。
步骤6：合成N-(2-((6-((5-氨基-4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺
将N-(2-((6-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(1.0eq.)溶于1,4-二氧六环，在室温下加入锌(10.0eq.)和氯化铵(10.0eq.)，并搅拌一夜。完成反应后，将温度降至室温，经铁铝酸四钙过滤后，减压蒸发滤液，得到化合物。没有分离过程，其被用于下一反应。
步骤7：合成N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((6-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺
将N-(2-((6-((5-氨基-4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺(1.0eq.)溶于四氢呋喃和水中，在0±5℃下加入3-氯丙酰氯(1.2eq.)。在同一温度下，搅拌15分钟。完成反应后，在相同温度下加入氢氧化钠(4.0eq.)。通过提高反应器温度，在65℃下搅拌过夜。反应完成后，减压蒸发除去溶剂，用水和10％甲醇/二氯甲烷混合溶液提取。在减压下蒸发有机层，进行柱色谱分析，得到目标化合物。(10％甲醇/二氯甲烷)
实施例17.N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((6-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺
产量：23.0％，白色固体，1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.42(s,1H),8.29(s,1H),8.09(d,J＝0.9Hz,1H),8.00(s,1H),7.79(dd,J＝8.2,1.5Hz,1H),7.46(dd,J＝8.0,1.5Hz,1H),7.26(ddd,J＝8.4,7.4,1.6Hz,1H),7.07(td,J＝7.6,1.5Hz,1H),6.93(s,1H),6.34(dd,J＝16.9,10.0Hz,1H),6.19(dd,J＝16.9,2.2Hz,1H),6.04(d,J＝1.1Hz,1H),5.71(dd,J＝10.0,2.2Hz,1H),3.74(s,3H),3.10(s,3H),2.99(s,3H),2.80(t,J＝5.9Hz,2H),2.66(s,3H),2.26(t,J＝5.8Hz,2H),2.16(s,6H).MS:ESI m/z 569.14[M+H]+
实验实施例1：癌细胞生长抑制作用的测量
由于具有EGFR插入突变的肺癌细胞系不能从商业上获得，因此尝试了一种利用位点直接诱变法在野生型EGFR表达载体的每个位点插入3-4个氨基酸的方法。首先，本发明使用了一种载体，在最常发生改变的D770_N771位点加入3个氨基酸的NPG，并使用Ba/F3细胞系来表达这些基因。Ba/F3细胞系是Murine IL3依赖性亲B细胞系，仅在加入IL-3时显示细胞生长，在没有IL-3的情况下，表达致癌突变的EGFR时，具有突变的EGFR依赖性的细胞生长和死亡。因为对突变的EGFR显示有效抑制作用的物质会抑制细胞生长和诱导细胞凋亡，所以通过MTT法分析细胞的抗癌作用。
将预先构建好的1×104个细胞的稳定细胞置于96孔板中并培养过夜，然后以剂量依赖的方式处理实施例中的化合物。72小时后，加入MTT试剂，3小时后，加入终止缓冲液(10％SDS)。培养24小时后，在595nm处读取分析结果，并在每个化合物抑制细胞生长50％的浓度下计算IC50的值。结果在表1中显示为A、B、C和D。在本文中，A表示IC50≤100nM，B表示IC50＝100-300nM，C表示IC50＝300-1,000nM，D表示IC50>1,000nM。作为对照药物，使用奥希替尼。
癌细胞生长抑制作用的实测(GI50)
表1
| 实施例 | EXON 20插入(NPG)Ba/F3细胞 |
| 1 | C |
| 2 | C |
| 3 | C |
| 4 | C |
| 5 | C |
| 6 | C |
| 7 | B |
| 8 | B |
| 9 | B |
| 10 | A |
| 11 | A |
| 12 | A |
| 13 | A |
| 14 | A |
| 15 | A |
| 16 | A |
| 17 | A |
| 奥希替尼 | C |
如表1所示，根据本发明的化合物对表达表皮生长因子受体的EXON 20插入突变的肺癌细胞系表现出优异的活性。特别是，实施例10-17化合物的活性更为出色。另一方面，对照药物奥希替尼的活性则相对较弱。
因此，本发明提出了一种新型的嘧啶衍生物，其可治疗表达表皮生长因子受体EXON 20插入突变的肺癌。
Claims (6)
1.下述化学式1的化合物或其药学上可接受的盐：
[化学式1]
在化学式1中，
A、B、D、E和G是A＝N、B＝C、D＝C、E＝C和G＝N的组合，或A＝N、B＝C、D＝N、E＝C和G＝C的组合，
W是氧或NH，
X和Y分别是CH、氧或氮，
Z1和Z2分别是C1至C4烷基，或分别由碳原子组成并且相互连接以与X和Y一起形成5、6或7元环，
当X或Y是氧时，Z1和Z2分别不存在；或当X或Y不是氧时，Z1和Z2分别是C1至C4烷基，或分别由碳原子组成并且相互连接以与X和Y一起形成5、6或7元环，
R1是C1至C4烷基，
R2是氢，或C1至C4烷基，
R3和R4分别是氢、卤素、OH、OME、OEt、CN、CF3、C1至C4烷基，或相互连接以形成5或6元杂芳环，
R5是氢、卤素、OH、OMe、OEt、CN、CF3或C1至C4烷基，
R6和R7分别是氢、卤素、OH、OMe、OEt、CN、CF3、COOH、COO-C1-4烷基、COO-C1-5环烷基、C1至C4烷基，或相互连接以形成5或6元杂芳环，
R8是氢、卤素、OH、OMe、OEt、CN、CF3或C1至C4烷基，
R9是-C(O)-CH＝CH2或C1至C4烷基，并且
R10不存在或是氢、卤素、C1至C4烷基、OH、OME、OEt、CN、CF3、NMe2、哌嗪、被C1至C3烷基取代的哌嗪、吗啉或被C1至C3烷基取代的吗啉。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其中，所述化合物为：
N-(2-((5-氯-2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)吡啶-4-基)氨基)苯基)-N-甲磺酸酰胺，
N-(2-((2-((4-((2-(二甲基氨基)乙基)(甲基)氨基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)噻吩并[3,2-d]嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺，
N-(2-((2-((4-(4-(二甲基氨基)哌啶-1-基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)噻吩并[3,2-d]嘧啶-4-基)氨基)苯基)-N-甲氧基甲磺酰胺，
N-(2-((2-((5-(异丙基氨基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)噻吩并[3,2-d]嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺，
N-(2-((5-氯-2-((5-(异丙基氨基)-2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺，
N-(2-((5-氯-2-((4-(4-(二甲基氨基)哌啶-1-基)-5-(异丙基氨基)-2-甲氧基苯基)氨基)嘧啶-4-基)氨基)苯基)-N-甲基甲磺酰胺，
N-(4-甲氧基-5-((4-((2-(N-甲基甲磺酰氨基)苯基)氨基)噻吩并[3,2-d]嘧啶-2-基)氨基)-2-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)丙烯酰胺，
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((2-(N-甲基甲磺酰氨基)苯基)氨基)噻吩并[3,2-d]嘧啶-2-基)氨基)苯基)丙烯酰胺，
N-(2-(4-(二甲基氨基)哌啶-1-基)-4-甲氧基-5-((4-((2-(N-甲基甲磺酰氨基)苯基)氨基)噻吩并[3,2-d]嘧啶-2-基)氨基)苯基)丙烯酰胺，
N-(5-((5-氯-4-((2-(甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺，
N-(5-((5-氯-4-((5-(N-甲基甲磺酰氨基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺，
N-(5-((5-氯-4-((5-(甲磺酰氨基)喹喔啉-6-基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺，
N-(5-((5-氯-4-((5-氟-2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺，
N-(5-((5-氯-4-((5-氟-2-(甲磺酰氨基)苯基)氨基)嘧啶-2-基)氨基)-2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺，
2-((5-丙烯酰胺基-4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-5-羧酸异丙酯，
2-((5-丙烯酰胺基-4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基苯基)氨基)-4-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-5-羧酸环丙酯，或
N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((6-((2-(N-甲基甲磺酰氨基)苯基)氨基)嘧啶-4-基)氨基)苯基)丙烯酰胺。
3.一种组合物，包含权利要求1或权利要求2所述的化合物或其药学上可接受的盐，以及药学上可接受的载体。
4.一种用于治疗或预防肺癌的药物组合物，其特征在于，包括权利要求1或权利要求2所述的化合物或其药学上可接受的盐作为活性成分。
5.根据权利要求4所述的用于治疗或预防肺癌的药物组合物，其中，所述肺癌是表达表皮生长因子受体突变的肺癌。
6.根据权利要求4所述的用于治疗或预防肺癌的药物组合物，其中，所述突变是EXON20插入突变。
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| US20220227781A1 (en) | 2022-07-21 |
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| WO2020256477A1 (ko) | 2020-12-24 |
| EP3988542A4 (en) | 2023-06-28 |
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