CN103619835B - 新型嘧啶衍生物 - Google Patents
新型嘧啶衍生物 Download PDFInfo
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- CN103619835B CN103619835B CN201280014101.3A CN201280014101A CN103619835B CN 103619835 B CN103619835 B CN 103619835B CN 201280014101 A CN201280014101 A CN 201280014101A CN 103619835 B CN103619835 B CN 103619835B
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- Prior art keywords
- methyl
- base
- indol
- pyrimidine
- ethyl
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 69
- -1 methoxyl group Chemical group 0.000 claims description 50
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 46
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Abstract
本发明提供了式(I)的新型嘧啶衍生物,制备该化合物的方法,含有该化合物的药物组合物,以及该化合物在治疗包括癌症的疾病中的用途;其中R1‑R11、Z和Y如说明书中定义。
Description
发明领域
本发明涉及新型嘧啶衍生物,涉及制备该化合物的方法,涉及包含该化合物的药物组合物,以及涉及使用该化合物治疗包括癌症的疾病的方法。
技术背景
癌症是一种主要的并且常常致命的疾病。因此,开发用于癌症的新疗法是一直以来最重要的过程。绝大多数癌症以实体瘤形式存在,例如肺癌、乳腺癌和前列腺癌,其他包括血液学和淋巴样恶性肿瘤,例如白血病和淋巴瘤。
癌症化疗的的一个重要靶标是微管蛋白。该疗法中的靶向药物阻断微管纺锤体-介导染色体分离,使得分裂的肿瘤细胞停留在有丝分裂继而诱导凋亡。现有的药物通过两种不同的机制靶向微管蛋白,例如紫杉烷类分子(稳定微管蛋白)和一些长春花属生物碱(去稳定剂)。这些天然来源的试剂在许多癌症,例如乳腺癌、卵巢癌、前列腺癌、肺癌、白血病和淋巴瘤中的效能、功效和广泛的临床应用遵循了微管蛋白的重要性及其在癌症生长过程中的作用。常常分离或合成这些植物化合物的衍生物和类似物以发现更有效的抗癌试剂。新型微管蛋白聚合抑制剂的示例参见,例如WO2009/070645、US2010/0279410、Mahindroo,N.等;Expert Opin.Ther.Patents2006,16,647-691,Carlson,R.;ExpertOpin.Ther.Patents2007,17,707-722和Chen,S-M.等;ExpertOpin.Investig.Drugs2010,19,329-343。
在临床癌症中,尝试采用化疗以治愈或减轻疾病。在大多数情况下,该疗法以组合化疗的形式递送,即两种或更多种具有不同作用模式的药物一起使用,以优化对癌细胞的作用和使副作用最小化。化疗获得的结果根据肿瘤类型而不同。一些肿瘤非常敏感,治疗具有非常高的可能性能够获得包括治愈疾病在内的有益效果。这种类型的肿瘤的例子是急性白血病,恶性淋巴瘤,睾丸癌,绒毛膜癌症和威尔曼瘤。其他类型的癌症化疗可导致有效缓解和延长的存活期。这类肿瘤的例子是乳腺癌、结肠直肠癌、卵巢癌、小细胞肺癌、膀胱癌、多发性骨髓瘤以及淋巴和髓细胞样的慢性白血病。对经典化疗响应较差的主要的耐药肿瘤包括:恶性胶质瘤、黑色素瘤、前列腺癌、肉瘤以及除结肠直肠癌之外的胃肠道肿瘤(参见例如DeVita,Hellman和Rosenberg:Cancer:Principles&Practice of Oncology(癌症原理和肿瘤学实践),第8版978-0-7817-7207-5)。
近年来,更多兴趣致力于涉及特异性靶分子的药物。调节细胞增殖和死亡的分子,例如生长因子的酪氨酸激酶受体(RTK)即这类治疗策略的靶分子之一。目前用于临床实践的两类靶向RTK的化合物是:单克隆抗体和酪氨酸激酶抑制剂。最早获批的靶向疗法是曲妥珠单抗(一种针对HER2的单克隆抗体,用于治疗转移性乳腺癌)和伊马替尼(一种靶向慢性髓细胞样白血病中的BCR-Ab1的小酪氨酸激酶抑制剂)。虽然治疗效果良好,但是常常因为RTK旁路途径的激活,许多受治忠者形成了耐药性。目前,普遍的认知是同时干扰多种RTS的分子可能比单一靶试剂更有效。目前有一些获批的药物,例如索拉非尼和舒尼替尼,它们显然是靶向多种途径,可作为这种新一代抗癌药物的代表(例如Gossage,L.等;ClinCancerRes.2010,第16卷,第1973-1978页)
某些嘧啶化合物及其在癌症治疗中的潜在应用参见例如WO2003/030909、WO2003/059913、WO2003/063794、WO2004/056807、WO2004/056786、WO2006/133426、WO2007/085833、WO2008/128231、WO2009/063240、WO2009/071535、US2009/142532、EP1506960和WO2007/071455。
本领域需要的是以特定方式起效的靶向药物,选择性消除参与肿瘤存活和进展的细胞亚群。本发明提供了具有意外的抗增殖活性效果的新型嘧啶化合物。因此,这些新型化合物可用于治疗增殖性疾病如癌症。
发明内容
在本发明的第一方面,提供了式I的化合物或其药学上可接受的酯、酰胺、溶剂合物或盐,
式中:
Z代表碳或氮;
Y代表碳或氮,其中Z和Y中的一个代表氮;
R1、R3和R8独立地选自氢和(C1-C4)烷基;
R2选自氢、(C1-C4)烷基、(C1-C4)烷基-NH(C1-C4)烷基、(C1-C4)烷基-N[(C1-C4)烷基]2和(CO)OH;
R4、R5、R6和R7独立地选自氢、卤素、羟基、氨基、硝基、氰基、(C1-C4)烷基、(C1-C4)烷基-OH、(C1-C4)烷基-NH2、(C1-C4)烷基-NH(C1-C4)烷基、(C1-C4)烷基-N[(C1-C4)烷基]2、(C1-C4)烷基-NH(CO)(C1-C4)烷基、(CO)OH、(CO)NH2、(CO)NH(C1-C4)烷基、(CO)N[(C1-C4)烷基]2、O(C1-C4)烷基、O(C1-C4)烷基(C2-C5)杂环基、O(C1-C4)烷基(C2-C5)杂环基(C1-C4)烷基、O(C1-C4)烷基(CO)OH、O(C1-C4)烷基(CO)NH(C1-C4)烷基、O(C1-C4)烷基(CO)N[(C1-C4)烷基]2、OCF3、NH(C1-C4)烷基、N[(C1-C4)烷基]2、NH(CO)(C1-C4)烷基、NHSO2(C1-C4)烷基、N[(C1-C4)烷基]SO2(C1-C4)烷基、SH、S(C1-C4)烷基、SO2NH2、SO2NH(C1-C4)烷基和SO2N[(C1-C4)烷基]2;
当Z或Y是碳时,R10选自氢、氨基和(C1-C4)烷基;
R11选自氢、氨基、(C1-C4)烷基、(C1-C4)烷基(C2-C5)杂环基、(C1-C4)烷基(C2-C5)杂环基(C1-C4)烷基、(CO)OH、(CO)NH2、(CO)NH(C1-C4)烷基、(CO)N[(C1-C4)烷基]2、(CO)(C1-C4)烷基、(C2-C5)杂环基、(C2-C5)杂环基(C1-C4)烷基、NH(C1-C4)烷基、N[(C1-C4)烷基]2、NH(CO)(C1-C4)烷基、NHSO2(C1-C4)烷基、N[(C1-C4)烷基]SO2(C1-C4)烷基、SO2NH2、SO2NH(C1-C4)烷基和SO2N[(C1-C4)烷基]2;
R9代表
或
R12、R13和R14独立地选自氢、卤素、羟基、(C1-C4)烷基、O(C1-C4)烷基、NH(C1-C4)烷基和N[(C1-C4)烷基]2;
R15选自氢和(C1-C4)烷基;以及
R16和R17独立地选自氢、卤素、(C1-C4)烷基、(C1-C4)烷基(C2-C5)杂环基、(C1-C4)烷基(C2-C5)杂环基(C1-C4)烷基、(C1-C4)烷基(CO)OH、(C1-C4)烷基(CO)NH2、(C1-C4)烷基(CO)NH(C1-C4)烷基、(C1-C4)烷基(CO)N[(C1-C4)烷基]2、(C1-C4)烷基-OH、(C1-C4)烷基-O(C1-C4)烷基、(C1-C4)烷基-NH(C1-C4)烷基、(C1-C4)烷基-N[(C1-C4)烷基]2、(C1-C4)烷基-NH(CO)(C1-C4)烷基、(CO)OH、(CO)NH2、(CO)NH(C1-C4)烷基、(CO)N[(C1-C4)烷基]2、(CO)(C1-C4)烷基、(CO)(C2-C5)杂环基和(CO)(C2-C5)杂环基)(C1-C4)烷基。
在本发明中,酯包括,如当R16是(CO)OH时,其形成的酯也包括在内,如(CO)OCH3和(CO)OC2H5OH。因此,在这个方面的一个实施方式中,R16代表(CO)OH的酯,选自(CO)OCH3和(CO)OC2H5OH。
在这个方面的另一个实施方式中,R1代表氢。
在这个方面的另一个实施方式中,R2、R3和R8独立地选自氢和甲基。
在这个方面的另一个实施方式中,R2、R3和R8代表氢。
在这个方面的另一个实施方式中,Z代表碳并且Y代表氮。
在这个方面的另一个实施方式中,R4、R5、R6和R7独立地选自氢、卤素、羟基、(C1-C4)烷基、O(C1-C4)烷基、O(C1-C4)烷基(C2-C5)杂环基和OCF3。
在这个方面的另一个实施方式中,R5代表O(C1-C4)烷基。
在这个方面的另一个实施方式中,R5选自甲氧基、乙氧基和丙氧基。
在这个方面的另一个实施方式中。当Z或Y是碳时,R10选自氢、(C1-C4)烷基和NH2。
在这个方面的另一个实施方式中。当Z或Y是碳时,R10选自氢和(C1-C4)烷基。
在这个方面的另一个实施方式中。当Z或Y是碳时,R10选自氢和甲基。
在这个方面的另一个实施方式中,R11选自氢、(C1-C4)烷基、(CO)NH2和(C2-C5)杂环基(C1-C4)烷基。
在这个方面的另一个实施方式中,R11选自氢和甲基。
在这个方面的另一个实施方式中,R9选自
和
在这个方面的另一个实施方式中,R9选自
和
在这个方面的另一个实施方式中,R11、R13和R14代表氢。
在这个方面的另一个实施方式中,R15选自氢和甲基。
在这个方面的另一个实施方式中,R16和R17独立地选自氢、(C1-C4)烷基、(C1-C4)烷基-OH和(CO)OH。
在这个方面的另一个实施方式中,R16和R17独立地选自氢、甲基、(C1-C4)烷基-OH和(CO)OH。
在这个方面的另一个实施方式中,R16和R17独立地选自氢、甲基和(C1-C4)烷基-OH。
在这个方面的另一个实施方式中,R16选自氢、甲基、(C1-C4)烷基-OH和(CO)OH。
在这个方面的另一个实施方式中,当R16是(CO)OH时,也包括由此形成的酯,如(CO)OCH3和(CO)OC2H5OH。
在这个方面的另一个实施方式中,R16选自氢、甲基和(C1-C4)烷基-OH。
在这个方面的另一个实施方式中,R16选自氢、甲基和羟甲基。
在这个方面的另一个实施方式中,R17选自氢和甲基。
在这个方面的另一个实施方式中,Y代表碳并且Z代表氮。
在这个方面的另一个实施方式中,
Z代表碳并且Y代表氮;
R1、R2、R3、R8、R12、R13和R14代表氢;
R4、R5、R6和R7独立地选自氢、卤素、羟基、(C1-C4)烷基、O(C1-C4)烷基、O(C1-C4)烷基(C2-C5)杂环基和OCF3;
当Z或Y是碳时,R10选自氢和(C1-C4)烷基;
R11选自氢、(C1-C4)烷基、(CO)NH2和(C2-C5)杂环基(C1-C4)烷基;
R9选自:
和
R15选自氢和甲基;
并且R16和R17独立地选自氢、(C1-C4)烷基、(C1-C4)烷基-OH和(CO)OH。优选地,R16是甲基并且R17选自氢和(C1-C4)烷基。
在这个方面的另一个实施方式中,
R4代表氢;
R5选自卤素,甲基、O(C1-C2)烷基和OCF3;
R6和R7独立地选自氢、甲基和甲氧基;
当Z或Y是碳时,R10选自氢和甲基;
R11选自氢、甲基和(CO)NH2;
R9选自:
和
R15选自氢和甲基;
并且R16和R17独立地选自氢、甲基和羟甲基。
在这个方面的另一个实施方式中,R16代表甲基。
在这个方面的另一个实施方式中,R5选自甲氧基、甲基和氟。
在这个方面的另一个实施方式中,R5选自甲氧基和甲基。
在这个方面的另一个实施方式中,R11选自氢、甲基和(CO)NH2。
在这个方面的另一个实施方式中,R9选自
和
其中R15和R17独立地选自氢和甲基;并且R16选自氢、甲基、羟甲基和(CO)OH。
在这个方面的另一个实施方式中,提供了式I的化合物,其中
Z代表碳并且Y代表氮;
R1、R10、R12、R13、R14和R17代表氢;
R2、R3、R7、R8和R11独立地选自氢和甲基;
R4、R5和R6独立地选自氢和O(C1-C4)烷基;
R9选自:
和
R15选自氢和甲基;并且
R16代表氢、甲基和羟甲基。
在这个方面的另一个实施方式中,提供了式I的化合物,其中
Z代表碳并且Y代表氮;
R1、R2、R3、R4、R6、R7、R8、R12、R13和R14代表氢;
R10、R11、R15和R17独立地选自氢和甲基;R5选自甲氧基和乙氧基;
R9选自:
和
和;
R16选自氢、甲基和羟甲基。
在这个方面的另一个实施方式中,提供了式I的化合物,其中
R1、R2、R3、R4、R6、R7、R8、R12、R14和R17代表氢;
R10选自氢和氨基;
R11选自氢、(CO)NH2和(C2-C5)杂环基(C1-C4)烷基;
R5选自甲氧基、乙氧基和羟基;
R15选自氢和甲基;
R16选自氢、甲基和羟甲基;以及
R9选自:
和
在这个方面的另一个实施方式中,提供了式I的化合物,其中
Z代表碳或氮;
Y代表碳或氮,其中Z和Y中的一个代表氮;
R1、R2、R3和R8独立地选自氢和(C1-C4)烷基;
R4、R5、R6和R7独立地选自氢、卤素、羟基、(C1-C4)烷基、O(C1-C4)烷基、O(C1-C4)烷基(C2-C5)杂环基和OCF3;
R9代表:
或
当Z或Y是碳时,R10选自氢、(C1-C4)烷基和氨基;
R11选自氢、(C1-C4)烷基、(C2-C5)杂环基(C1-C4)烷基和(CO)NH2;
R12、R13和R14是氢;
R15和R17独立地选自氢和(C1-C4)烷基;并且
R16选自氢、(C1-C4)烷基、(CO)OH和(C1-C4)烷基-OH。
在这个方面的另一个实施方式中,提供了式I的化合物,其中
Z代表碳或氮;
Y代表碳或氮,其中Z和Y中的一个代表氮;
R1、R2、R3和R8独立地选自氢和甲基;
R4、R5、R6和R7独立地选自氢、卤素、羟基、甲基、甲氧基、乙氧基、丙氧基、O(C1-C4)烷基(C2-C5)杂环基和OCF3;
R9代表:
或
当Z或Y是碳时,R10选自氢、甲基和氨基;
R11选自氢、甲基、(C2-C5)杂环基(C1-C4)烷基和(CO)NH2;
R12、R13和R14是氢;
R15和R17独立地选自氢和甲基;并且
R16选自氢、甲基、(CO)OH和(C1-C4)烷基-OH。
在本发明的另一方面,提供了式I的化合物,所述化合物选自:
N2-[2-(1H-吲哚-3-基)乙基]-N4-(1H-吲哚-5-基)嘧啶-2,4-二胺;
N4-(1H-吲哚-5-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-[2-(1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N4-(2-甲基-1H-吲哚-5-基)-N2-{2-[5-(2-吗啉乙氧基)-1H-吲哚-3-基]乙基}嘧啶-2,4-二胺;
N4-(2-甲基-1H-吲哚-5-基)-N2-{2-[5-(三氟甲氧基)-1H-吲哚-3-基]乙基}嘧啶-2,4-二胺;
3-{2-[4-(2-甲基-1H-吲哚-5-基氨基)嘧啶-2-基氨基]乙基}-1H-吲哚-5-醇;
N2-[2-(5-甲基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-氟-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(6-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(7-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N4-(1,2-二甲基-1H-吲哚-5-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N4-(2,3-二甲基-1H-吲哚-5-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
(5-{2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]嘧啶-4-基氨基}-1H-吲哚-2-基)甲醇;
5-{2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]嘧啶-4-基氨基}-1H-吲哚-2-羧酸甲酯;
5-{2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]嘧啶-4-基氨基}-1H-吲哚-2-羧酸2-羟乙酯;
N4-(1H-苯并[d]咪唑-5-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-苯并[d]咪唑-5-基)嘧啶-2,4-二胺;
N4-(1H-吲哚-6-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N4-(1H-吲哚-4-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N4-[2-(1H-吲哚-3-基)乙基]-N2-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N4-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N2-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N4-[2-(1H-吲哚-3-基)乙基]-N2-(1H-吲哚-6-基)嘧啶-2,4-二胺;
N4-[2-(1H-吲哚-3-基)乙基]-N2-(1H-吲哚-4-基)嘧啶-2,4-二胺;
N2-[2-(1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]-6-(2-甲基-1H-吲哚-5-基氨基)嘧啶-4-羧酰胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-5-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;和
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;
及其药学上可接受的酯、酰胺、溶剂合物或盐。
在本发明的另一方面,提供了式I的化合物,所述化合物选自:
N2-[2-(4-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N4-(2-甲基-1H-吲哚-5-基)-N2-[2-(5-丙氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-[2-(5-异丙氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5,6-二甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-7-甲基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(1-甲基-1H-苯并[d]咪唑-5-基)嘧啶-2,4-二胺;
N4-(1,2-二甲基-1H-苯并[d]咪唑-5-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(1-甲基-1H-吲哚-4-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-2-甲基-1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-苯并[d]咪唑-5-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-苯并[d]咪唑-5-基)嘧啶-2,4-二胺;
[5-(2-{[2-(5-甲氧基-1H-吲哚-3-基)乙基][甲基]氨基}嘧啶-4-基氨基)-1H-吲哚-2-基]甲醇;
(5-{2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]嘧啶-4-基氨基}-I-甲基-1H-苯并[d]咪唑-2-基)甲醇;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;和
N4-(1,2-二甲基-1H-吲哚-5-基)-N2-[2-(5-甲氧基-lH-吲哚-5-基)乙基]-N4-甲基嘧啶-2,4-二胺;
及其药学上可接受的酯、酰胺、溶剂合物或盐。
在本发明的另一方面,提供了式I的化合物,所述化合物选自:
[5-({2-[2-(5-乙氧基-lH-吲哚-3-基)乙基氨基]嘧啶-4-基}氨基)-lH-吲哚-2-基]甲醇;
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-6-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-6-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(1-甲基吲哚-6-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(1-甲基吲哚-6-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-4-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-4-基)嘧啶-2,4-二胺;
3-[2-({4-[{1-甲基吲哚-4-基)氨基]嘧啶-2-基}氨基)乙基]-lH-吲哚-5-醇;
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(1-甲基吲哚-4-基)嘧啶-2,4-二胺;
N4-(1,2-二甲基吲哚-4-基)-N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-苯并咪唑-4-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-苯并咪唑-4-基)嘧啶-2,4-二胺;
N4-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N2-(1-甲基吲哚-4-基)嘧啶-2,4-二胺;
2-[2-(5-乙氧基-lH-吲哚-3-基)乙基氨基]-6-[(2-甲基-lH-吲哚-5-基)氨基]嘧啶-4-羧酰胺;
6-[{1,2-二甲基苯并咪唑-5-基)氨基]-2-[2-(5-甲氧基-lH-吲哚-3-基)乙基氨基]嘧啶-4-羧酰胺;
2-[2-(5-甲氧基-lH-吲哚-3-基)乙基氨基]-6-[(1-甲基吲哚-4-基)氨基]嘧啶-4-羧酰胺;
2-[2-(5-乙氧基-lH-吲哚-3-基)乙基氨基]-6-[(1-甲基吲哚-4-基)氨基]嘧啶-4-羧酰胺;
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(1-甲基吲哚-4-基)-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;和
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4,5-三胺;
及其药学上可接受的酯、酰胺、溶剂合物或盐。
在本发明的另一方面,提供了式I的化合物,用于治疗。
在本发明的另一方面,提供了式I的化合物,用于治疗癌症。
在本发明的另一方面,提供了式I的化合物,用于在选自白血病、淋巴瘤、骨髓瘤、乳腺癌、卵巢癌、前列腺癌、肺癌、胰腺癌和胶质瘤的癌症的治疗中使用。
本发明的化合物显示出抑制微管蛋白聚合和/或诱导凋亡。因此,在本发明的另一方面,提供了式I的化合物,用于疾病的治疗,其中对微管蛋白聚合的抑制是有益的。另外,在本发明的另一方面,提供了式I的化合物,用于疾病的治疗,其中对诱导凋亡是有益的。
在本发明的另一方面,提供了式I的化合物在制备用于治疗癌症的药物和药物组合物中的应用。
在本发明的另一方面,提供了式I的化合物在药物和药物组合物的制造中的用途,所述药物和药物组合物用于选自白血病、淋巴瘤、骨髓瘤、乳腺癌、卵巢癌、前列腺癌、肺癌、胰腺癌和胶质瘤的癌症的治疗。
在本发明的另一方面,提供了一种药物组合物,其包含式I的化合物以及药学上可接受的稀释剂和载体。
在本发明的另一方面,提供了一种癌症治疗方法,该方法包括给予需要的对象治疗有效量的式I的化合物。
在本发明的另一方面,提供了治疗选自白血病、淋巴瘤、骨髓瘤、乳腺癌、卵巢癌、前列腺癌、肺癌、胰腺癌和胶质瘤的癌症的方法,其包括向需要的对象给予药学有效量的式I的化合物。
在本发明的另一方面,提供了一种癌症治疗方法,该方法包括给予需要的对象治疗有效量的式I的化合物,联合另一种式I的化合物,联合放疗,或者联合另一种选自以下的抗癌试剂:烷化剂,抗代谢剂,抗癌类喜树碱衍生物,植物来源的抗癌试剂,抗生素,酶,铂配位络合物,微管蛋白抑制剂、酪氨酸激酶抑制剂,激素,激素拮抗剂,单克隆抗体,干扰素和生物反应修饰剂。
本申请中的化合物名称是按照ChemBioDraw Ultra11.0版的IUPAC产生的。
根拥式I化合物上存在的取代基,化合物可以形成酯、酰胺和/或盐,它们均包括在本发明的范围内。适用于医药用途的式I化合物的盐和溶剂合物中的抗衡离子或缔合溶剂是药学上可接受的。然而,具有非药学上可接受的抗衡离子或缔合溶剂的盐和溶剂合物也包括在本发明的范围内,例如,可以用作式I化合物及其药学上可接受的盐、溶剂合物和生理学功能衍生物的制备过程中的中间体。术语“生理学功能衍生物”是指例如通过体内转化,与游离的式I化合物相比具有相同的生理学功能的式I化合物的化学衍生物。酯和酰胺是生理学功能衍生物的例子。
给予接受者之后,化合物能够转化为上文所述的式I化合物或其活性代谢物或残留物的化合物称为“前药”。例如,前药可以在血液中例如通过水解在体内转化为具有医学作用的活性形式。药学上可接受的前药可参见T.Higuchi和V.Stella,作为新型递送系统的前药(Prodrugs as Novel Delivery Systems),A.C.S.学术讨论会丛刊第14卷(1976);前药设计(“Design of Prodrugs”),H.Bundgaard编,Elsevier,1985;和EdwardB.Roche编,Bioreversible Carriers in Drug Design,美国药学协会,Pergamon出版,1987,这些都通过引用纳入本文。
根拥本发明合适的盐包括用有机或无机酸或碱形成的盐。具体来说,根拥本发明用酸形成的合适的盐包括用以下酸形成的盐:无机酸,强有机羧酸,例如未取代或者被例如卤素取代的1-4个碳原子的链烷羧酸,例如饱和或不饱和二羧酸,例如羟基羧酸,例如氨基酸,或者有机磺酸,例如,未取代或者被例如卤素取代的(Cl-C4)烷基-磺酸或芳基-磺酸。药学上可接受的酸加成盐包括用以下酸形成的盐:盐酸、氢溴酸、硫酸、硝酸、柠檬酸、酒石酸、乙酸、磷酸、乳酸、丙酮酸、醋酸、三氟乙酸、琥珀酸、高氯酸、富马酸、马来酸、乙醇酸、乳酸、水杨酸、草酰乙酸、甲磺酸、乙磺酸、对甲苯磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸、羟乙磺酸、抗坏血酸、苹果酸、邻苯二甲酸、门冬氨酸、谷氨酸、赖氨酸和精氨酸。其他酸如草酸,虽然它们本身不是药学上可接受的,但是可以用作获得本发明化合物及其药学上可接受的酸加成盐的中间体。
药学上可接受的碱盐包括:铵盐,碱金属盐,例如钾盐和钠盐,碱土金属盐,例如钙盐和镁盐,有机碱的盐,例如二环己基胺,N-甲基-D-葡萄糖胺,吗啉,硫代吗啉,哌啶,吡咯烷,单、二-或三-低级烷基胺,例如乙基-、叔丁基-、二乙基-、二异丙基-、三乙基-、三丁基-或二甲基-丙基胺,或者单、二-或三羟基低级烷基胺,例如单、二-或三乙醇胺的盐。可进一步形成相应的内盐。
有机化学领域的技术人员将理解,许多有机化合物可与溶剂形成复合物,它们在这些溶剂中反应或者由这些溶剂沉淀或结晶出来。这些复合物称为“溶剂合物”。例如,与水的复合物称为“水合物”。
除非另有说明,下面的定义适用于通篇说明书所涉及的术语。
本文所用术语“烷基”表示直链和支链饱和烃基。烷基的例子包括:甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基和仲丁基。在直链烷基中,优选甲基、乙基、正丙基和正丁基。在支链烷基中,可涉及异丙基、叔丁基、异丁基和仲丁基。
本文所用术语“烷氧基”表示O-烷基基团,其中“烷基”如上所述。烷氧基的例子包括但不限于:甲氧基和乙氧基。其他例子包括丙氧基和丁氧基,如异丙氧基、正丙氧基、叔丁氧基、异丁氧基和仲丁氧基。
本文所用术语“卤素”表示氟、氯、溴或碘。氟、氯和溴是特别优选的。
本文所用术语“杂环基”表示其中1-3个碳原子被一个或多个独立地选自氮、氧或硫的杂原子取代的碳原子的环状基团。杂环基的例子包括但不限于:四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基和二噁烷基。
本发明化合物可直接用于预防和治疗,或者优选地以药物组合物的形式。尽管活性成份能够单独给药,但优选为药物制剂或组合物的形式。因此,本发明提供了一种药物制剂,其包含本发明的化合物以及药学上可接受的稀释剂、赋形剂或载体(在这里统称为“载体”材料)。本发明的药物组合物可采取下文所述的药物制剂的形式。因此,本发明涉及一种药物组合物,其包含至少一种式I的化合物以及常规的赋形剂。
用于口服给药的示例性组合物包括:悬浮剂,其可包含例如微晶纤维素用于赋予体积,藻酸或藻酸钠作为助悬剂,甲基纤维素作为粘度增强剂,以及甜味剂或调味剂,例如本领域已知的那些;和速释片剂,其可包含例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁、硫酸钙、山梨糖醇、葡萄糖和/或乳糖和/或其他赋形剂、粘合剂、膨胀剂、崩解剂、稀释剂和润滑剂,例如本领域已知的那些。合适的粘合剂包括:淀粉、明胶、天然的糖如葡萄糖或β-乳糖、玉米甜味剂、天然和合成树胶如阿拉伯胶、黄芪胶或藻酸钠、羧甲基纤维素、聚乙二醇和蜡等。崩解剂包括但不限于:淀粉、甲基纤维素、琼脂、膨润土和黄原胶等。式I的化合物也可通过舌下和/或含服方式经口腔递送。模制片、压制片或冻干片是可使用的示例性形式。示例性的组合物包括将本发明化合物与快速溶解的稀释剂如甘露醇、乳糖、蔗糖和/或环糊精配制的那些。这些制剂中还可包括高分子量赋形剂如纤维素(微晶粉末纤维素)或聚乙二醇(PEG)。这些制剂也可包括有助于粘膜粘附的赋形剂,例如羟丙基纤维素(HPC),羟丙基甲基纤维素(HPMC),羧甲基纤维素钠(SCMC),马来酸酐共聚物(例如,Gantrez)和控制释放的试剂如聚丙烯酸类共聚物(例如Carbopo1934)。还可加入润滑剂,助流剂,调味剂,着色剂和稳定剂以便于制备和使用。这些剂型中使用的润滑剂包括:油酸钠,硬脂酸钠,硬脂酸镁,苯甲酸钠,乙酸钠和氯化钠等。对于液体形式的口服给药,口服药物组分可以与任何口服、非毒性的药学上可接受的惰性载体如乙醇、甘油和水等组合。
本发明的药物制剂包括适用于口服、胃肠外[包括皮下、皮内、肌内、静脉内(推注或输注)和关节内],吸入(包括可通过各种类型的计量加压气溶胶的方式产生的细颗粒粉剂或喷雾剂),喷雾器或吸入器,直肠、腹膜内和局部(包括皮肤、含服、舌下和眼内)给药的制剂,虽然最合适的途径可能取决于例如接受者的病症和状态。
适用于口服给药的本发明的制剂可以是各种含有预定量的活性成分的独立单位的形式,例如胶囊、扁胶囊、丸剂或片剂;粉末或颗粒;在水性液体或非水性液体的溶液或悬液,例如酏剂、酊剂、混悬剂或糖浆剂;或水包油乳液剂或油包水乳液剂。该活性成分也可制成大丸剂、药糖剂或糊剂。
片剂可以通过与任选的一种或多种辅助成份压缩或模塑来制作。压缩片剂的制作方法可以是在合适的机器中将任选与粘结剂、润滑剂、惰性稀释剂、润滑剂、表面活性剂或分散剂混合的诸如粉末或颗粒等自由流动形式的活性成份进行压缩。模塑片剂可通过在合适的机器中对用惰性液态稀释剂湿润的粉末状化合物的混合物进行模塑。片剂可任选地包衣或刻痕,并可配制成能够提供其中活性成分的缓释或控释。本发明化合物可例如以适用于速释或缓释的形式给予。速释或缓释可通过利用包含本发明化合物的合适的药物组合物来实现,或者尤其是在缓释的情况下,利用例如皮下植入物或渗透泵的装置来实现。本发明化合物也可以脂质体方式给予。优选的单位剂量制剂是包含有效剂量(如下文所述)或者其合适部分的活性成分的制剂。
应该理解的是,除上述特别提到的成分,本发明的制剂还可以包括与所研究制剂类型有关领域的其他常规药剂,例如,适宜于口服的制剂可以包括调味剂。
所述制剂可以作为单位剂型方便地提供,且可通过药学领域熟知的任何方法制造。所有方法均包括使活性成分与构成一种或多种附加成分的载体结合的步骤。通常,使活性成分与液体载体和/或细分固体载体均匀且密切地结合以制备制剂,然后,如果需要,将该产物成型,得到所需制剂。
本发明的化合物也可脂质体递送系统,例如小单室囊泡、大单室囊泡和多室囊泡的形式给予。脂质体可以由各种磷脂、1,2-二棕榈酰磷脂酰胆碱、磷脂酰乙醇胺(脑磷脂)、磷脂酰丝氨酸、磷脂酰肌醇、二磷脂酰甘油(心磷脂)或磷脂酰胆碱(卵磷脂)形成。
用于胃肠外给药的制剂包括水性和非水性无菌注射溶液,其可包含抗氧化剂、缓冲剂、抑菌剂以及使得制剂与指定接受者的血液等渗的溶质;以及水性和非水性无菌混悬液,其可包含助悬剂和增稠剂。可以用单位剂量或多剂量容器,例如密封的安瓿和药瓶提供该制剂,也可通过冷冻干燥(冻干)条件保存该组合物,临用前只需要加入无菌液体载体如盐水或注射用水即可使用。临时用的注射溶液和混悬液可以由前文描述的无菌粉末、颗粒和片剂进行制备。用于胃肠外给药的示例性组合物包括:可注射溶液剂或悬浮剂,其可包含例如合适的非毒性胃肠外可接受的稀释剂或溶剂,例如聚乙二醇、乙醇、1,3-丁二醇、水、林格溶液、氯化钠等渗溶液、或其他合适的分散剂或润湿剂以及助悬剂,包括合成的单或二甘油酯和脂肪酸,包括油酸和Cremaphor。
用于鼻腔、气溶胶或吸入给药的示例性组合物包括盐水中的溶液,其可包含例如苄基醇或其他合适的防腐剂,吸收促进剂以提高生物利用度,和/或其他增溶剂或分散剂如本领域已知的那些。
用于直肠给药的制剂可以用常规载体如可可油/合成甘油酯或聚乙二醇制成栓剂形式。这些载体在常温条件下通常为固体,但在直肠管腔内液化和/或溶解以释放药物。
口腔内局部给药例如含服或舌下给药的制剂,包括锭剂,其包含在调味基质如蔗糖和阿拉伯胶或西黄蓍胶中的活性成分,和软锭剂,其包含在明胶和甘油或蔗糖和阿拉伯胶中的基质中的活性成分。局部给药的示例性组合物包括局部载体如Plastibase(用聚乙烯胶化的矿物油)。
当然,实现治疗效果所需的活性成分的量将根拥具体化合物、给药途径、受治对象,包括对象的类型、物种、年龄、体重、性别和医学状态以及对象的肝肾功能,待治疗的具体病症或疾病以及严重性而变化。普通有经验的内科医师、兽医或临床医师可容易地确定和处方用于防止、逆转或阻止疾病进程所需的药物的有效量。
当用于指定效果时,对于成人而言,本发明的口服剂量在约0.01毫克/千克体重/天(毫克/千克/天)至约100毫克/千克/天的范围内,优选为0.01毫克/千克体重/天(毫克/千克/天)至10毫克/千克/天,最优选为0.1-5.0毫克/千克/天。对于口服给药,组合物优选以片剂或以独立单位提供的其他呈现形式提供,所述独立单位包含0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0,50.0,100和500毫克活性成分,用于系统性调节给予受治患者的剂量。药物通常包括约0.01-500毫克活性成分,优选约1-100毫克活性成分。对于静脉内给药,恒定速率输注期间,最优选的剂量将在约0.1至约10毫克/千克/分钟的范围内变化。优选地,本发明化合物可每天给药一次,或者将全天剂量分成每天两次、三次或四次给药。而且,本发明的优选化合物可通过外用合适的鼻内运载体以鼻内形式给药,或使用本领域普通技术人员公知的透皮贴剂形式通过透皮途径给药。以透皮递送系统的形式给药时,当然,在整个给药方案中可以连续给药,而非间歇式给药。
本发明还提供了式I的化合物在制备用于治疗或预防癌症的药物中的应用。
本发明的化合物和药物组合物可以在预防和治疗疾病中使用,例如癌症、寄生虫所致疾病、过敏性疾病、克罗恩病、风湿性疾病,结核病,糖尿病,阿耳茨海默病,炎性疾病,多发性硬化(MS),肌萎缩侧索硬化(ALS),帕金森病以及细菌、病毒和真菌导致的疾病。
本发明的化合物和药物组合物尤其适用于治疗或预防各种增殖性疾病和癌症,包括但不限于骨癌、乳腺癌、呼吸道癌症、脑癌、生殖器的癌症、消化道癌症、尿道癌、眼睛、肝脏、皮肤、头部、颈部、甲状腺、甲状旁腺癌症以及上述癌症的转移形式。乳腺癌的增殖性疾病包括但不限于:浸润性导管癌、浸润性小叶癌、导管癌、原位小叶癌和转移性乳腺癌。皮肤的增殖性疾病包括但不限于:基底细胞癌,鳞状细胞癌,恶性黑色素瘤和卡波济氏肉瘤。呼吸道的增殖性疾病包括但不限于:小细胞和非小细胞肺癌,支气管腺瘤,胸膜肺母细胞瘤和恶性间皮瘤。脑的增殖性疾病包括但不限于:脑干和下丘脑胶质瘤,小脑和大脑星形细胞瘤,髓母细胞瘤,室管膜肿瘤,少突胶质细胞瘤,脑膜瘤以及神经外胚层和松果体瘤。男性生殖器官的增殖性疾病包括但不限于:前列腺、睾丸和阴茎癌症。
女性生殖器官的增殖性疾病包括但不限于:子宫癌,宫颈癌,卵巢癌,阴道癌症,外阴癌症,子宫肉瘤和卵巢生殖细胞瘤。消化道的增殖性疾病包括但不限于:肛门,结肠,结肠直肠,食管,胆囊,胃,胰腺,直肠,小肠和唾液腺的癌症。肝脏的增殖性疾病包括但不限于:肝细胞癌、胆管癌和原发性肝癌。眼睛的增殖性疾病包括但不限于:眼内黑色素瘤、视网膜母细胞瘤和横纹肌肉瘤。头部的增殖性疾病包括但不限于:喉头,下咽,鼻咽,口咽,唇,口腔和转移性鼻旁窦癌症。
淋巴瘤的增殖性疾病包括但不限于:T细胞和B细胞淋巴瘤,非霍奇金淋巴瘤,皮肤T细胞淋巴瘤,霍奇金疾病和中枢神经系统的淋巴瘤。白血病包括但不限于:急性骨髓性白血病、慢性髓细胞性白血病和多毛细胞白血病。甲状腺的增殖性疾病包括但不限于:甲状腺癌,胸腺瘤和恶性胸腺瘤。泌尿道的增殖性疾病包括但不限于:肾癌和膀胱癌。肉瘤包括但不限于:软组织的肉瘤,骨肉瘤,恶性纤维组织细胞瘤,淋巴肉瘤和横纹肌肉瘤。
优选地,本发明的化合物和药物组合物尤其适用于治疗与预防下列疾病:乳腺癌、白血病、肺癌、骨髓瘤、淋巴瘤、卵巢癌、胰腺癌、前列腺癌和胶质瘤。
虽然本发明的化合物可单独使用,但是化合物之间也可以相互组合,与放疗或者与其他抗癌药组合使用。各种类型的抗癌和抗肿瘤化合物包括但不限于:烷化剂,抗代谢剂,抗癌喜树碱衍生物,植物衍生的抗癌药,抗生素,酶,铂配位络合物,微管蛋白抑制剂、酪氨酸激酶抑制剂,激素和激素拮抗剂,单克隆抗体,干扰素,生物反应修饰剂和其他抗癌药。烷化剂的例子包括但不限于:氮芥,环磷酰胺,异环磷酰胺,美法仑,苯丁酸氮芥,白消安,二溴甘露醇,雷莫司汀,尼莫司汀,替莫唑胺和卡莫司汀;抗代谢剂的例子包括但不限于:甲氨蝶呤,氟尿嘧啶,阿糖胞苷,吉西他滨,氟达拉滨,巯基嘌呤,硫鸟嘌呤和硫唑嘌呤;喜树碱衍生物的例子包括但不限于:伊立替康,拓扑替康和喜树碱;植物衍生试剂的例子包括但不限于:长春碱和长春新碱,多西他赛,紫杉醇,和秋水仙素;抗生素的例子包括但不限于:放线菌素D,道诺霉素和博来霉素。作为抗肿瘤药有效的酶的一个例子包括L-天冬酰胺酶。
配位化合物的例子包括但不限于:顺铂和卡铂;微管蛋白抑制剂的例子包括但不限于:上述涉及的植物衍生试剂;酪氨酸激酶抑制剂的例子包括但不限于:吉非替尼,伊马替尼,舒尼替尼,尼洛替尼,达沙替尼,埃罗替尼和帕佐替尼(pazopanib);激素和激素相关化合物的例子包括但不限于:氯泼尼松,地塞米松,福美坦,氨鲁米特,阿那曲唑,羟基孕酮己酸酯,甲羟孕酮和他莫昔芬;干扰素的例子包括但不限于:干扰素α,干扰素α-2a,干扰素α-2b,干扰素β,干扰素γ-la和干扰素γ-nl;生物反应修饰剂的例子包括但不限于:云芝素(krestin),蘑菇多糖,西佐喃,皮西巴尼(picibanil)和乌苯美司。其他抗癌药的例子包括但不限于:米托蒽醌,丙卡巴肼,达卡巴嗪,羟基服,喷司他丁,维A酸,亮丙瑞林,氟他胺和阿地白介素。
本发明化合物的各种合成路径可以由本领域技术人员设计并且下文所述的可能的合成路径并不限制本发明。
用于合成通式I的化合物的过程
方法A
将合适的胺(II或V)溶解于异丙醇(0.2g/mL)。加入1.1当量嘧啶(III)和1.2当量N,N-二异丙基乙基胺(DIPEA),将混合物在25-80℃之间的温度搅拌1小时。将反应混合物溶解在EtOAc/MeOH9:1中,用NaHCO3的饱和水溶液、水和盐水洗涤。真空除去溶剂,在硅胶上用柱色谱纯化残留物,用庚烷/EtOAc、EtOAc和/或EtOAc/MeOH作为洗脱剂,得到中间体(IV'或IV")。
中间体(IV'或IV")溶解于乙二醇中(0.2g/mL,在一些情况下为了完全溶解反应物,单独使用或作为助溶剂使用NMP)并且加入1.3当量的胺(II或V)和1.3当量N,N-二异丙基乙基胺(DIPEA)。然后将混合物在100-150℃之间的温度搅拌1-3小时。将反应混合物溶解在EtOAc/MeOH9:1中,并用NaHCO3的饱和水溶液、水和盐水洗涤。真空除去溶剂,在硅胶上用柱色谱纯化残留物,用庚烷/EtOAc、EtOAc和/或EtOAc/MeOH/TEA和/或CH2Cl2/MeOH作为洗脱剂,得到式I的化合物。该过程如方案1所示。
方案1
实施例1-14,16-21,26-29,47-58,73-78,79-83,以及85-88的化合物通过方法A的途径(i)合成,而实施例22-25和85的化合物通过方法A途径(ii)合成(如方案1所示)。实施例15、59、60和72的化合物通过方法A的途径(i)合成,但是在第一步后还通过硅烷化(叔丁基二甲基氯甲硅烷,咪唑,DMF)进行保护以及在第二步后去保护(四丁基氟化铵,THF)。实施例61和62的化合物通过方法A的途径(i)合成,但是在第一步之后还进行烷基化(按照方案3)。实施例90的化合物通过方法A的途径(i)合成,但是必须进行中间体99的额外还原步骤(在甲醇中10%Pd/C下氢化)。R1-R11如式I定义。
方法B
将合适的胺(V)溶解于异丙醇/N-甲基-2-吡咯烷酮(0.2g/mL)。加入1.0当量嘧啶(III)、1.0当量N,N-二异丙基乙基胺(DIPEA)和1.2当量的NaI,将混合物在150℃搅拌12小时。将反应混合物溶解在EtOAc/MeOH9:1中,用NaHCO3的饱和水溶液、水和盐水洗涤。真空除去溶剂,在硅胶上用柱色谱纯化残留物,用EtOAc/MeOH/TEA作为洗脱剂,得到中间体(IV"′)。
在氮气气氛下,向在N-甲基-2-吡咯烷酮(NMP)(0.2g/mL)中0.10当量Pd(OAc)2、0.15当量的2,2'-双(二苯基磷基)-1,1'-联萘(BINAP)和1.5当量的CsCO3的溶液加入中间体(IV"′)。然后将混合物在150℃搅拌1小时。将反应混合物溶解在EtOAc/MeOH9:1中,并用NaHCO3的饱和水溶液、水和盐水洗涤。真空除去溶剂,在硅胶上用柱色谱纯化残留物,用EtOAc/MeOH/TEA作为洗脱剂,得到式I的化合物。该过程如方案2所示。
方案2
实施例30和89通过方法B合成(如方案2所示)。R1-R10如式I定义。
用于合成通式VI″的中间体的过程
为了得到某些甲基化类似物,将合适的单取代的嘧啶(VI')溶解于二甲基甲酰胺(0.lg/mL)中。加入2当量的Cs2CO3和2当量的碘代甲烷,混合物在室温下搅拌24小时。将反应混合物溶解在EtOAc中,用水洗涤。真空除去溶剂,在硅胶上用柱色谱纯化残留物,用庚烷/EtOAc作为洗脱剂,得到化合物(VI")。该过程如方案3所示。
方案3
中间体化合物70和71通过该反应过程合成(如方案3所示)。
用于合成式X的色胺衍生物的过程
步骤1:将盐酸5-羟色胺(VII)溶解在水(20mg/mL)中。加入3当量的碳酸钾和1当量的二碳酸二叔丁酯,将混合物在室温下搅拌24小时。水性反应混合物用EtOAc萃取并且有机相用水、lMHCl(水溶液)和盐水洗涤。真空除去溶剂,在硅胶上用柱色谱纯化残留物,用CH2Cl2/MeOH作为洗脱剂,得到2-(5-羟基-lH-吲哚-3-基)乙基氨基甲酸叔丁酯(VIII)。
步骤2:将2-(5-羟基-lH-吲哚-3-基)乙基氨基甲酸叔丁酯(VIII),3-9当量的碳酸钾和0-1当量的NaI在2-丁酮或丙酮中预先混合(25mg/mL)。5分钟后,加入3-5当量的烷基卤(R'-X分别=溴乙烷或4-(2-氯乙基)吗啉×HCl或1-碘代丙烷或2-碘代丙烷),将混合物在60-90℃搅拌1-5天。将反应混合物溶解在EtOAc中,用NaHCO3饱和水溶液洗涤。真空除去溶剂,在硅胶上用柱色谱纯化残留物,用CH2Cl2/丙酮或庚烷/EtOAc作为洗脱剂,得到烷基化衍生物(IX)。
步骤3:烷基化衍生物(IX)溶解于甲醇(l0mg/mL)中,在0℃下滴加加入10当量的甲醇中的乙酰氯溶液并且在室温下放置过夜。将反应混合物浓缩,加入小部分的丙酮并且滤去沉淀,得到需要的胺作为盐酸盐(X)。
该过程如方案4所示。
方案4
式X的色胺衍生物通过该过程生产(如方案4所示)并且在实施例5、6、48、49、55、58、72、74、76、78、80、83、85、88和90的合成中使用。
实施例1
N2-[2-(lH-吲哚-3-基)乙基]-N4-(lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.77(s,1H),10.61(s,1H),8.58(s,1H),7.81(s,1H),7.79(d,1H),7.57(d,1H),7.34(d,1H),7.30(d,1H),7.25(m,1H),7.20(d,1H),7.14(s,1H),7.06(t,1H),6.96(t,1H),6.30(s,1H),6.24(m,1H),5.93(d,1H),3.60(q,2H),3.00(t,2H).
MS(ESI+)m/z369.3[M+H]+.
实施例2
N4-(lH-吲哚-5-基)-N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.77(s,1H),10.45(s,1H),8.57(s,1H),7.82(s,1H),7.79(d,1H),7.29(d,1H),7.25-7.18(m,3H),7.10(s,1H),7.08(s,1H),6.72(dd,1H),6.30(s,1H),6.22(m,1H),5.94(d,1H),3.75(s,3H),3.58(q,2H),2.95(t,2H).
MS(ESI+)m/z399.3[M+H]+.
实施例3
N2-[2-(lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6)δ10.37(s,1H),10.34(s,1H),8.18(br s,1H),7.76(d,1H),7.58(d,1H),7.56(br s,1H),7.36(d,1H),7.20(d,1H),7.09-7.06(m,3H),7.00(t,1H),6.02(s,1H),5.94(d,1H),5.54(br s,1H);3.67(q,2H),3.04(t,2H),2.41(s,3H).
MS(ESI+)m/z383.2[M+H]+.
实施例4
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.45(s,1H),8.50(s,1H),7.77(d,1H),7.65(s,1H),7.23(d,1H),7.17(d,1H),7.11-7.07(m,3H),6.72(dd,1H),6.20(m,1H),5.97(s,1H),5.91(d,1H),3.75(s,3H),3.58(q,2H),2.95(t,2H),2.36(s,3H).
MS(ESI+)m/z413.4[M+H]+.
实施例5
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.56(s,1H),10.43(s,1H),8.50(s,1H),7.77(d,1H),7.65(s,1H),7.22(d,1H),7.15(d,1H),7.09-7.06(m,3H),6.71(dd,1H),6.19(m,1H),5.97(s,1H),5.91(d,1H),4.01(q,2H),3.57(q,2H),2.93(t,2H),2.36(s,3H),1.31(t,3H).
MS(ESI+)m/z427.3[M+H]+.
实施例6
N4-(2-甲基-lH-吲哚-5-基)-N2-{2-[5-(2-吗啉乙氧基)-lH-吲哚-3-基]乙基}嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.56(s,1H),10.45(s,1H),8.50(s,1H),7.77(d,1H),7.66(s,1H),7.22(d,1H),7.15(d,1H),7.10-7.07(m,3H),6.72(dd,1H),6.19(m,1H),5.96(s,1H),5.91(d,1H),4.07(t,2H),3.57(m,6H),2.94(t,2H),2.68(t,2H),2.47(m,4H),2.35(s,3H).
MS(ESI+)m/z512.4[M+H]+.
实施例7
N4-(2-甲基-lH-吲哚-5-基)-N2-{2-[5-(三氟甲氧基)-lH-吲哚-3-基]乙基}嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.93(s,1H),10.56(s,1H),8.50(s,1H),7.77(d,1H),7.64(s,1H),7.53(s,1H),7.42(d,1H),7.28(s,1H),7.16(d,1H),7.08(dd,1H),7.02(d,1H),6.26(br s,1H),5.97(s,1H),5.92(d,1H),3.57(q,2H),2.97(t,2H),2.36(s,3H).
MS(ESI+)m/z467.2[M+H]+.
实施例8
3-{2-[4-(2-甲基-lH-吲哚-5-基氨基)嘧啶-2-基氨基]乙基}-lH-吲哚-5-醇
1H NMR(500MHz,CD3OD)δ7.66(d,1H),7.52(br s,1H),7.20-7.14(m,2H),7.03(brs,1H),7.01(s,1H),6.97(s,1H),6.66(dd,1H),6.01(s,1H),5.90(d,1H),3.63(t,2H),2.96(t,2H),2.38(s,3H).
MS(ESI+)m/z399.3[M+H]+.
实施例9
N2-[2-(5-甲基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.56(s,1H),10.46(s,1H),8.50(s,1H),7.77(d,1H),7.65(s,1H),7.34(s,1H),7.23(d,1H),7.15(d,1H),7.11-7.08(m,2H),6.89(d,1H),6.18(m,1H),5.97(s,1H),5.91(d,1H),3.58(q,2H),2.95(t,2H),2.37(s,3H),2.36(s,3H).
MS(ESI+)m/z397.3[M+H]+.
实施例10
N2-[2-(5-氟-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,)δ10.90(s,1H),10.73(s,1H),8.75(br s,1H),7.74(m,2H),7.32(m,2H),7.24(s,1H),7.13(d,1H),7.08(d,1H),6.90(t,1H),6.53(br s,1H),5.90(d,2H),3.53(m,2H),2.92(m,1H),2.33(s,3H).
MS(ESI+)m/z401.3[M+H]+.
实施例11
N2-[2-(6-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.56(s,1H),10.40(s,1H),8.50(s,1H),7.77(d,1H),7.64(s,1H),7.42(d,1H),7.16(d,1H),7.09(d,1H),6.99(s,1H),6.86(s,1H),6.63(d,1H),6.17(t,1H),5.98(s,1H),5.90(d,1H),3.77(s,3H),3.57(q,2H),2.92(t,2H),2.36(s,3H).
MS(ESI+)m/z413.3[M+H]+.
实施例12
N2-[2-(7-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.65(s,1H),10.57(s,1H),8.50(s,1H),7.76(d,1H),7.64(s,1H),7.18-7.15(m,2H),7.10(m,1H),7.06(m,1H),6.89(t,1H),6.64(d,1H),6.19(m,1H),5.97(s,1H),5.90(d,1H),3.91(s,3H),3.57(q,2H),2.95(t,2H),2.36(s,3H).
MS(ESI+)m/z413.3[M+H]+.
实施例13
N4-(1,2-二甲基-lH-吲哚-5-基)-N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.45(s,1H),8.56(s,1H),7.78(d,1H),7.70(s,1H),7.25-7.20(m,3H),7.10(d,1H),7.07(d,1H),6.73(dd,1H),6.23(br s,1H),6.05(s,1H),5.92(d,1H),3.74(s,3H),3.62(s,3H),3.58(q,2H),2.95(t,2H),2.37(s,3H).
MS(ESI+)m/z427.3[M+H]+.
实施例14
N4-(2,3-二甲基-lH-吲哚-5-基)-N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.44(s,1H),10.31(s,1H),8.52(s,1H),7.77(d,1H),7.63(s,1H),7.23(d,1H),7.13-7.05(m,4H),6.72(dd,1H),6.15(m,1H),5.91(d,1H),3.74(s,3H),3.60(q,2H),2.95(t,2H),2.29(s,3H),2.07(s,3H).MS(ESI+)m/z427.3[M+H]+.
实施例15
(5-{2-[2-(5-甲氧基-lH-吲哚-3-基)乙基氨基]嘧啶-4-基氨基)-lH-吲哚-2-基)甲醇
1H NMR(500MHz,DMSO-d6,75℃)δ10.65(s,1H),10.44(s,1H),8.53(s,1H),7.78(d,1H),7.72(s,1H),7.23(d,2H),7.15(dd,1H),7.10(d,1H),7.08(d,1H),6.72(dd,1H),6.20(t,1H),6.15(s,1H),5.92(d,1H),4.95(t,1H),4.59(d,2H),3.75(s,3H),3.58(q,2H),2.95(t,2H).
MS(ESI+)m/z429.4[M+H]+.
实施例16
5-{2-[2-(5-甲氧基-lH-吲哚-3-基)乙基氨基]嘧啶-4-基氨基)-lH-吲哚-2-羧酸甲酯
1H NMR(500MHz,DMSO-d6,75℃)δ11.56(s,1H),10.44(s,1H),8.74(s,1H),
8.03(s,1H),7.82(d,1H),7.41-7.35(m,2H),7.23(d,1H),7.10(d,1H),7.07(d,1H),6.96(s,1H),6.72(dd,1H),6.30(t,1H),5.97(d,1H),3.87(s,3H),3.73(s,3H),3.60(q,2H),2.96(t,2H).
MS(ESI+)m/z457.3[M+H]+.
实施例17
5-{2-[2-(5-甲氧基-lH-吲哚-3-基)乙基氨基]嘧啶-4-基氨基}-lH-吲哚-2-羧酸2-羟乙基酯
1H NMR(500MHz,DMSO-d6,75℃)δ11.51(s,1H),10.44(s,1H),8.75(s,1H),8.04(s,1H),7.82(d,1H),7.42-7.36(m,2H),7.23(d,1H),7.10(d,1H),7.07(d,1H),7.01(s,1H),6.72(dd,1H),6.31(m,1H),5.97(d,1H),4.71(m,1H),4.32(t,2H),3.75(m,2H),3.74(s,3H),3.60(q,2H),2.96(t,2H).
MS(ESI+)m/z487.2[M+H]+.
实施例18
N4-(lH-苯并[d]咪唑-5-基)-N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ12.07(br s,1H),10.45(s,1H),8.84(br s,1H),8.05(s,1H),8.00-7.88(m,1H),7.83(d,1H),7.47(m,1H),7.38(d,1H),7.22(d,1H),7.12(br s,1H),7.07(s,1H),6.71(d,1H),6.29(br s,1H),6.00(d,1H),3.74(s,3H),3.59(q,2H),2.95(t,3H).
MS(ESI+)m/z400.3[M+H]+.
实施例19
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-苯并[d]咪唑-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ11.76(br s,1H),10.45(s,1H),8.75(br s,1H),7.82(d,1H),7.78(br s,1H),7.34-7.28(m,2H),7.23(d,1H),7.13(br s,1H),7.07(d,1H),6.72(dd,1H),6.26(br s,1H),5.97(d,1H),3.74(s,3H),3.59(q,2H),2.95(t,2H),2.46(s,3H).
MS(ESI+)m/z414.3[M+H]+.
实施例20
N4-(lH-吲哚-6-基)-N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.66(s,1H),10.45(s,1H),8.71(s,1H),7.82(d,1H),7.71(s,1H),7.41(d,1H),7.23(d,1H),7.21-7.19(m,2H),7.10(d,1H),7.08(d,1H),6.72(dd,1H),6.35(s,1H),6.18(m,1H),6.00(d,1H),3.75(s,3H),3.61(q,2H),2.96(t,2H).
MS(ESI+)m/z399.2[M+H]+.
实施例21
N4-(lH-吲哚-4-基)-N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.89(s,1H),10.45(s,1H),8.51(s,1H),7.85(d,1H),7.66(d,1H),7.24-7.22(m,2H),7.11-7.07(m,3H),6.98(t,1H),6.72(dd,1H),6.64(m,1H),6.30(m,1H),6.13(d,1H),3.75(s,3H),3.58(q,2H),2.94(t,2H).
MS(ESI+)m/z399.3[M+H]+.
实施例22
N4-[2-(lH-吲哚-3-基)乙基]-N2-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(300MHz,DMSO-d6)δ10.81(br s,1H),10.57(br s,1H),8.47(s,1H),7.85(s,1H),7.73(br s,1H),7.52(d,1H),7.33(d,1H),7.22(d,1H),7.16(s,1H),7.11(br s,1H),7.06(t,2H),6.95(t,1H),5.84(d,2H),3.61(br s,2H),2.96(t,1H),2.30(s,3H).
MS(ESI+)m/z383.3[M+H]+.
实施例23
N。-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N'-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.48(s,1H),10.40(s,1H),8.18(s,1H),7.83(d,1H),7.76(d,1H),7.24(d,2H),7.12(d,1H),7.07(d,1H),7.02(d,1H),6.80(br s,1H),6.73(dd,1H),5.90(s,1H),5.87(d,1H),3.74(s,3H),3.61(q,2H),2.97(t,2H),2.34(s,3H).
MS(ESI+)m/z413.3[M+H]+.
实施例24
N4-[2-(lH-吲哚-3-基)乙基]-N2-(lH-吲哚-6-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6)δ10.82(s,1H),10.78(s,1H),8.72(s,1H),8.06(s,1H),7.78(br s,1H),7.54(d,1H)7.35-7.30(m,2H),7.26(d,1H),7.20-7.10(m,3H),7.06(t,1H),6.95(t,1H),6.29(s,1H),5.90(d,1H),3.65(br s,2H),2.99(t,2H).
MS(ESI+)m/z369.2[M+H]+.
实施例25
N4-[2-(lH-吲哚-3-基)乙基l-N2-(lH-吲哚-4-基)嘧啶-2,4-二胺
1H NMR(500MHz,CDC13)δ8.21(s,1H),8.06(s,1H),8.02(d,1H),7.95(d,1H),7.63(d,1H),7.38(d,1H),7.24-7.07(m,6H),7.03(s,1H),6.58(s,1H),5.82(d,1H),4.85(br s,1H),3.72(br s,2H),3.10(t,2H).
MS(ESI+)m/z369.2[M+H]+.
实施例26
N2-[2-(lH-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.61(s,1H),10.55(s,1H),8.35(s,1H),7.59(m,2H),7.35(d,1H),7.18-7.13(m,2H),7.09-7.06(m,2H),6.96(t,1H),6.12(m,1H),5.97(s,1H),5.78(s,1H),3.59(q,2H),2.97(t,2H),2.36(s,3H),2.08(s,3H).MS(ESI+)m/z397.4[M+H]+.
实施例27
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.55(s,1H),10.45(s,1H),8.35(s,1H),7.61(s,1H),7.23(d,1H),7.15(d,1H),7.11(d,1H),7.08-7.06(m,2H),6.72(dd,1H),6.10(m,1H),5.97(s,1H),5.78(s,1H),3.75(s,3H),3.58(q,2H),2.94(t,2H),2.35(s,3H),2.08(s,3H).
MS(ESI+)m/z427.3[M+H]+.
实施例28
2-[2-(5-甲氧基-lH-吲哚-3-基)乙基氨基]-6-(2-甲基-lH-吲哚-5-基氨基)嘧啶-4-羧酰胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.60(s,1H),10.46(s,1H),8.88(s,1H),7.68(s,1H),7.56(br s,1H),7.24(m,1H),7.23(d,1H),7.18(d,1H),7.11(m,2H),7.03(s,1H),6.73(d,1H),6.56(s,1H),6.42(m,1H),5.99(br s,1H),3.74(s,3H),3.34(q,2H),2.97(t,2H),2.36(s,3H).
MS(ESI+)m/z456.3[M+H]+.
实施例29
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-5-甲基-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.51(s,1H),10.41(s,1H),7.75(s,1H),7.66(s,1H),7.63(s,1H),7.25(d,1H),7.22(d,1H),7.13(d,1H),7.04(s,2H),6.71(dd,1H),5.95(m,2H),3.73(s,3H),3.51(q,2H),2.89(t,2H),2.36(s,3H),2.04(s,3H).
MS(ESI+)m/z427.3[M+H]+.
实施例30
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.51(s,1H),10.44(s,1H),7.94(s,1H),7.53(s,1H),7.23(d,1H),7.13(d,1H),7.10(d,1H),7.05-7.02(m,2H),6.72(dd,1H),5.97(s,1H),5.79(t,1H),5.26(s,1H),3.75(s,3H),3.55(q,2H),3.39(t,4H),2.94(t,2H),2.35(s,3H),2.32(t,4H),2.20(s,3H).
MS(ESI+)m/z511.5[M+H]+.
中间体31
N-(lH-吲哚-5-基)-2-氯嘧啶-4-胺
1H NMR(500MHz,DMSO-d6)δ11.12(s,1H),9.81(s,1H),8.04(d,1H),7.67(br s,1H),7.40(d,1H),7.36(t,1H),7.11(br s,1H),6.61(br s,1H),6.42(s,1H).
MS(ESI+)m/z245.3[M+H]+.
中间体32
N-(2-甲基-lH-吲哚-5-基)-2-氯嘧啶-4-胺
1H-NMR(500MHz,DMSO-d6,75℃)δ10.76(s,1H),9.54(s,1H),8.01(d,1H),7.47(s,1H),7.26(d,1H),7.01(d,1H),6.56(d,1H),6.11(s,1H),2.39(s,3H).
MS(ESI+)m/z259.1[M+H]+.
中间体33
N-(2-氯嘧啶-4-基)-1,2-二甲基-lH-吲哚-5-胺
1H-NMR(500MHz,DMSO-d6,75℃)δ9.57(s,1H),8.02(d,1H),7.51(s,1H),7.35(d,1H),7.10(d,1H),6.58(d,1H),6.20(s,1H),3.66(s,3H),2.41(s,3H).
MS(ESI+)m/z273.1[M+H]+.
中间体34
N-(2-氯嘧啶-4-基)-2,3-二甲基-lH-吲哚-5-胺
1H-NMR(500MHz,DMSO-d6,75℃)δ10.52(s,1H),9.55(s,1H),8.01(d,1H),7.42(s,1H),7.23(d,1H),7.02(d,1H),6.56(d,1H),2.32(s,3H),2.14(s,3H).
MS(ESI+)m/z273.2[M+H]+.
中间体35
[5-(2-氯嘧啶-4-基氨基)-lH-吲哚-2-基]甲醇
1H-NMR(500MHz,DMSO-d6,75℃)δ10.84(s,1H),9.56(s,1H),8.02(d,1H),7.55(s,1H),7.34(d,1H),7.07(dd,1H),6.58(d,1H),6.27(s,1H),5.01(m,1H),4.62(d,2H).
中间体36
5-(2-氯嘧啶-4-基氨基)-lH-吲哚-2-羧酸甲酯
1H-NMR(500MHz,DMSO-d6,75℃)δ11.76(s,1H),9.70(s,1H),8.07(d,1H),7.80(s,1H),7.47(d,1H),7.32(dd,1H),7.14(s,1H),6.65(d,1H),3.89(s,3H).
MS(ESI+)m/z303.1[M+H]+.
中间体37
N-(2-氯嘧啶-4-基)-lH-苯并[d]咪唑-5-胺
1H NMR(500MHz,DMSO-d6)δ12.38(br s,1H),10.00(br s,1H),8.19(s,1H),8.10(d,1H),7.94(br s,1H),7.58(d,1H),7.22(d,1H),6.71(d,1H).
MS(ESI+)m/z246.1[M+H]+.
中间体38
N-(2-氯嘧啶-4-基)-2-甲基-lH-苯并[d]咪唑-5-胺
1H-NMR(500MHz,DMSO-d6,75℃)δ12.01(s,1H),9.72(m,1H),8.07(s,1H),7.72(m,1H),7.46-7.36(m,1H),7.18-7.11(m,1H),6.66(m,1H),2.48(s,3H).
MS(ESI+)m/z260.1[M+H]+.
中间体39
N-(2-氯嘧啶-4-基)-lH-吲哚-6-胺
1H-NMR(500MHz,DMSO-d6)δ11.13(s,1H),9.95(s,1H),8.08(d,1H),7.77(br s,1H),7.50(d,1H),7.31(s,1H),7.03(d,1H),6.71(d,1H),6.39(d,1H).
MS(ESI+)m/z245.1[M+H]+.
中间体40
N-(2-氯嘧啶-4-基)-lH-吲哚-4-胺
1H-NMR(500MHz,DMSO-d6,75℃)δ11.06(br s,1H),9.64(s,1H),8.08(d,1H),7.31(t,1H),7.9-7.25(m,2H),7.10(t,1H),6.67(d,1H),6.48(s,1H).
MS(ESI+)m/z245.1[M+H]+.
中间体41
N-[2-(lH-吲哚-3-基)乙基]-2-氯嘧啶-4-胺
1H-NMR(500MHz,DMSO-d6,75℃)δ10.66(s,1H),7.90(d,1H),7.79(br s,1H),7.59(d,1H),7.35(d,1H),7.15(s,1H),7.07(t,1H),6.99(t,1H),6.44(d,1H),3.56(m,2H),2.96(t,2H).
MS(ESI+)m/z273.2[M+H]+.
中间体42
2-氯-N-[2-(5-甲氧基-lH-吲哚-3-基)乙基]嘧啶-4-胺
1H-NMR(500MHz,DMSO-d6,75℃)δ10.50(s,1H),7.90(d,1H),7.79(br s,1H),7.24(d,1H),7.11(s,1H),7.04(s,1H),6.73(dd,1H),6.45(d,1H)3.78(s,3H),3.56(br s,2H),2.93(t,2H).
MS(ESI+)m/z303.1[M+H]+.
中间体43
N-(2-甲基-lH-吲哚-5-基)-2-氯-6-甲基嘧啶-4-胺
1H NMR(500MHz,CD3OD)δ7.43(br s,1H),7.26(d,1H),6.98(br s,1H),6.34(s,1H),6.02(s,1H),2.41(s,3H),2.22(s,3H).
MS(ESI+)m/z273.2[M+H]+.
中间体44
2-氯-6-(2-甲基-lH-吲哚-5-基氨基)嘧啶-4-羧酰胺
1H-NMR(500MHz,DMSO-d6,105℃)δ10.68(s,1H),9.76(s,1H),7.50(m,3H),7.29(d,1H),7.15(s,1H),7.05(d,1H),6.13(s,1H),2.36(s,3H).
MS(ESI+)m/z302.1[M+H]+.
中间体45
N-(2-氯-5-甲基嘧啶-4-基)-2-甲基-lH-吲哚-5-胺
1H-NMR(500MHz,DMSO-d6,75℃)δ10.71(s,1H),8.56(s,1H),7.92(s,1H),7.52(d,1H),7.24(d,1H),7.12(dd,1H),6.11(s,1H),2.39(s,3H),2.15(s,3H).
MS(ESI+)m/z273.1[M+H]+.
中间体46
4-氯-N-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-6-(4-甲基哌嗪-1-基)嘧啶-2-胺
1H-NMR(500MHz,DMSO-d6)δ10.62(s,1H),7.22(d,1H),7.13-6.96(m,3H),6.71(dd,1H),6.06(br s,1H),3.75(s,3H),3.55(br s,4H),3.46(q,2H),2.87(t,2H),2.31(t,4H),2.19(m,3H).
MS(ESI+)m/z401.2[M+H]+.
实施例47
N2-[2-(4-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1HNMR(500MHz,DMSO-d6,105℃)61051(brs,lH),10.48(brs,
1H),8.37(s,1H).7.75(d,1H),7.63(d,lH),7.l6(d,1H),7.06(dd,1H),
6.98-6.94(m,3H),6.45(dd,1H),5.98(brs,2H),5.89(d,lH),3.96(s,3H),3.59(q,2H),3.11(t,2H),2.36(s3H).
MS(ESI+)m/z413.4[M+H]+
实施例48
N4-(2-甲基-lH-吲哚-5-基)-N2-[2-(5-丙氧基-lH-吲哚-3-基)乙基]嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.56(s,1H),10.43(s,1H),8.50(s,1H),7.78(d,1H),7.65(s,1H),7.22(d,1H),7.12(d,1H),7.07(m,3H),6.71(dd,1H),6.18(m,1H),5.97(s,1H),5.91(d,1H),3.91(t,2H),3.56(q,2H),2.94(t,2H),2.36(s,3H),1.71(dt,2H),0.98(t,3H).
MS(ESI+)m/z441.2[M+H]+.
实施例49
N2-[2-(5-异丙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.56(s,1H),10.43(s,1H),8.49(s,1H),7.77(d,1H),7.65(s,1H),7.21(d,1H),7.12(d,1H),7.08(m,3H),6.70(dd,1H),6.19(m,1H),5.98(s,1H),5.91d,1H),4.46(dq,1H),3.56(q,2H),2.93(t,2H),2.49(s,3H),1.25(d,6H).
MS(ESI+)m/z441.2[M+H]+.
实施例50
N2-[2-(5,6-二甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.56(s,1H),10.29(s,1H),8.53(s,1H),7.77(d,1H),7.65(s,1H),7.16(d,1H),7.09(d,1H),7.08(s,1H),6.97(d,1H),6.91(s,1H),6.20(brs,1H),5.97(s,1H),5.92(d,1H),3.77(s,3H),3.74(s,3H),3.57(q,2H),2.92(t,2H),2.36(s,3H).
MS(ESI+)m/z443.2[M+H]+.
实施例51
N2-[2-(5-甲氧基-7-甲基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.56(s,1H),10.41(s,1H),8.50(s,1H),7.77(d,1H),7.65(s,1H),7.15(d,1H),7.09-7.07(m,2H),6.90(s,1H),6.55(s,1H),6.17(m,1H),5.96(s,1H),5.91(d,1H),3.73(s,3H),3.57(q,2H),2.93(t,2H),2.41(s,3H),2.36(s,3H).
MS(ESI+)m/z427.5[M+H]+.
实施例52
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(1-甲基-lH-苯并[d]咪唑-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.44(s,1H),8.81(s,1H),8.05(s,1H),8.02(d,1H),7.83(d,1H),7.46(dd,1H),7.39(d,1H),7.22(d,1H),7.15(d,1H),7.07(d,1H),6.72(dd,1H),6.34(br s,1H),5.99(d,1H),3.81(s,3H),3.74(s,3H),3.58(q,2H),2.95(t,2H).
MS(ESI+)m/z414.4[M+H]+.
实施例53
N4-(1,2-二甲基-lH-苯并[d]咪唑-5-基)-N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.44(s,1H),8.74(s,1H),7.88(d,1H),7.80(d,1H),7.37(dd,1H),7.28(d,1H),7.23(d,1H),7.17(d,1H),7.07(d,1H),6.72(dd,1H),6.30(br s,1H),5.96(d,1H),3.75(s,3H),3.69(s,3H),3.57(q,2H),2.95(t,2H),2.51(s,3H).
MS(ESI+)m/z428.2[M+H]+.
实施例54
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(1-甲基-lH-吲哚-4-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.45(s,1H),8.55(s,1H),7.86(d,1H),7.72(d,1H),7.25-7.20(m,2H),7.12-7.02(m,4H),6.72(dd,1H),6.64(d,1H),6.31(br s,1H),6.14(d,1H),3.77(s,3H),3.75(s,3H),3.58(q,2H),2.94(t,2H).
MS(ESI+)m/z413.4[M+H]+.
实施例55
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.56(s,1H),10.44(s,1H),8.44(s,1H),7.61(s,1H),7.22(d,1H),7.16(d,1H),7.11-7.05(m,3H),6.72(dd,1H),6.16(br s,1H),5.97(s,1H),5.80(s,1H),4.00(q,2H),3.57(q,2H),2.94(t,2H),2.36(s,3H),2.09(s,3H),1.31(t,3H).
MS(ESI+)m/z441.4[M+H]+.
实施例56
N2-[2-(5-甲氧基-2-甲基-lH-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.59(s,1H),10.32(s,1H),8.54(br s,1H),7.59(s,1H),7.17(d,1H),7.11(d,1H),7.08(dd,1H),6.98(d,1H),6.62(dd,1H),6.16(br s,1H),6.00(s,1H),5.81(s,1H),3.73(s,3H),3.46(q,2H),2.88(t,2H),2.36(s,3H),2.29(s,3H),2.10(s,3H).
MS(ESI+)m/z441.3[M+H]+.
实施例57
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-lH-苯并[d]咪唑-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,CD3OD)δ7.94(br s,1H),7.35(m,1H),7.25(br s,1H),7.21(d,1H),7.04(s,1H),6.99(d,1H),6.72(dd,1H),5.87(s,1H),3.73-3.69(m,5H),3.03(t,2H),2.51(s,3H),2.13(s,3H).
MS(ESI+)m/z428.2[M+H]+.
实施例58
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-lH-苯并[d]咪唑-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,CD3OD)δ7.96(br s,1H),7.35(m,1H),7.25(br s,1H),7.20(d,1H),7.03(s,1H),6.98(d,1H),6.72(dd,1H),5.87(s,1H),3.89(m,2H),3.71(t,2H),3.03(t,2H),2.51(s,3H),2.13(s,3H),1.30(t,3H).
MS(ESI+)m/z442.2[M+H]+.
实施例59
[5-(2-{[2-(5-甲氧基-lH-吲哚-3-基)乙基][甲基]氨基}嘧啶-4-基氨基)-lH-吲哚-2-基]甲醇
1H NMR(500MHz,DMSO-d6,75℃)δ10.63(s,1H),10.43(s,1H),8.60(s,1H),7.87(d,1H),7.75(d,1H),7.25-7.20(m,2H),7.17(dd,1H),7.09(d,1H),7.06(d,1H),6.72(dd,1H),6.11(s,1H),5.94(d,1H),4.94(t,1H),4.58(d,2H),3.86(m,2H),3.75(s,3H),3.08(s,3H),2.97(t,2H).
MS(ESI+)m/z443.4[M+H]+.
实施例60
(5-{2-[2-(5-甲氧基-lH-吲哚-3-基)乙基氨基]嘧啶-4-基氨基}-1-甲基-lH-苯并[d]咪唑-2-基)甲醇
1H NMR(500MHz,DMSO-d6,75℃)δ10.44(s,1H),8.80(s,1H),7.97(d,1H),7.82(d,1H),7.43(dd,1H),7.34(d,1H),7.23(d,1H),7.17(d,1H),7.07(d,1H),6.72(dd,1H),6.32(br s,1H),5.97(d,1H),5.32(t,1H),4.72(d,2H),3.80(s,3H),3.75(s,3H),3.58(q,2H),2.97(t,2H).
MS(ESI+)m/z444.2[M+H]+.
实施例61
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-甲基-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.85(s,1H),10.45(s,1H),7.60(d,1H),7.32(d,1H),7.26(s,1H),7.23(d,1H),7.12-7.07(m,2H),6.85(dd,1H),6.72(dd,1H),6.26(br s,1H),6.14(s,1H),5.41(d,1H),3.77(s,3H),3.58(q,2H),3.39(s,3H),2.95(t,2H),2.40(s,3H).
MS(ESI+)m/z427.4[M+H]+.
实施例62
N4-(1,2-二甲基-lH-吲哚-5-基)-N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-甲基嘧啶-2,4-二胺
1H NMR(500MHz,DMSO-d6,75℃)δ10.51(s,1H),7.59(d,1H),7.45(d,1H),7.34(d,1H),7.25(d,1H),7.12(d,1H),7.11(br s,1H),7.07(d,1H),6.96(dd,1H),6.74(dd,1H),6.26(s,1H),5.52(d,1H),3.77(s,3H),3.70(s,3H),3.64(q,2H),3.45(s,3H),2.98(t,2H),2.43(s,3H).
MS(ESI+)m/z441.4[M+H]+.
中间体63
N-(2-氯嘧啶-4-基)-1-甲基-1H-苯并[d]咪唑-5-胺
1H NMR(500MHz,DMSO-d6,75℃)δ9.77(br s,1H),8.13(s,1H),8.09(d,1H),7.87(s,1H),7.54(d,1H),7.34(d,1H),6.68(d,1H),3.84(s,3H).
中间体64
N-(2-氯嘧啶-4-基)-1,2-二甲基-lH-苯并[d]咪唑-5-胺
1H NMR(500MHz,DMSO-d6,75℃)δ9.71(s,1H),8.07(d,1H),7.72(s,1H),7.43(d,1H),7.25(dd,1H),6.65(d,1H),3.73(s,3H),2.52(s,3H).
MS(ESI+)m/z274.2[M+H]+.
中间体65
N-(2-氯嘧啶-4-基)-1-甲基-lH-吲哚-4-胺
1H NMR(500MHz,DMSO-d6,75℃)δ9.66(s,1H),8.09(d,1H),7.34-7.28(m,3H),7.17(dd,1H),6.68(d,1H),6.48(d,1H),3.81(s,3H).
MS(ESI+)m/z259.2[M+H]+.
中间体66
N-(2-氯-6-甲基嘧啶-4-基)-2-甲基-lH-苯并[dl咪唑-5-胺
1H NMR(500MHz,DMSO-d6,75℃)δ12.00(s,1H),9.60-9.52(m,1H),7.70-7.65(m,1H),7.46-7.36(m,1H),7.16-7.10(m,1H),6.52-6.47(m,1H),2.47(s,3H),2.25(s,3H).
MS(ESI+)m/z274.2[M+H]+.
中间体67
2-[(叔丁基二甲基甲硅烷氧基)甲基]-N-(2-氯嘧啶-4-基)-lH-吲哚-5-胺
1H-NMR(500MHz,DMSO-d6,75℃)δ10.86(s,1H),9.57(s,1H),8.02(d,1H),7.57(s,1H),7.36(d,1H),7.09(dd,1H),6.59(d,1H),6.31(s,1H),4.80(s,2H),0.92(s,9H),0.10(s,6H).
MS(ESI+)m/z389.2[M+H]+.
中间体68
[5-(2-氯嘧啶-4-基氨基)-1-甲基-lH-苯并[d]咪唑-2-基]甲醇
1H-NMR(500MHz,DMSO-d6,75℃)δ9.75(s,1H),8.08(d,1H),7.81(s,1H),7.50(d,1H),7.32(dd,1H),6.66(d,1H),5.35(m,1H),4.73(d,2H),3.83(s,3H).
MS(ESI+)m/z290.2[M+H]+.
中间体69
2-[(叔丁基二甲基甲硅烷氧基)甲基]-N-(2-氯嘧啶-4-基)-1-甲基-lH-苯并[d]咪唑-5-胺
1H-NMR(500MHz,DMSO-d6,75℃)δ8.08(d,1H),7.96(s,1H),7.84(s,1H),7.52(d,1H),7.33(dd,1H),6.67(d,1H),4.93(s,2H),3.83(s,3H),0.90(s,9H),0.10(s,6H).
中间体70
N-(2-氯嘧啶-4-基)-N,2-二甲基-lH-吲哚-5-胺
1H-NMR(500MHz,DMSO-d6)δ11.14(s,1H),7.86(d,1H),7.37(d,1H),7.34(s,1H),6.89(dd,1H),6.16(s,1H),6.07(br s,1H),3.39(s,3H).
MS(ESI+)m/z273.2[M+H]+.
中间体71
N-(2-氯嘧啶-4-基)-N,1,2-三甲基-lH-吲哚-5-胺
1H-NMR(500MHz,DMSO-d6,25℃)δ7.86(d,1H),7.50(d,1H),7.38(s,1H),6.98(dd,1H),6.26(s,1H),6.06(br s,1H),3.69(s,3H),3.40(s,3H).
MS(ESI+)m/z287.2[M+H]+.
实施例72
[5-({2-[2-(5-乙氧基-lH-吲哚-3-基)乙基氨基]嘧啶-4-基}氨基)-lH-吲哚-2-基]甲醇
1H NMR(400MHz,DMSO-d6,75℃)δ10.62(s,1H),10.40(s,1H),8.49(s,1H),7.78(d,1H),7.71(s,1H),7.25-7.22(m,2H),7.15(m,1H),7.08(m,2H),6.72(dd,1H),6.16-6.24(m,2H),5.93(d,1H),4.91(m,1H),4.60(d,2H),4.02(q,2H),3.58(q,2H),2.95(t,2H),1.32(t,3H).
MS(ESI+)m/z443.2[M+H]+.
实施例73
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-6-基)嘧啶-2,4-二胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.40(d,2H),8.59(s,1H),7.80(d,1H),7.55(s,1H),7.25(t,2H),7.10(td,3H),6.73(dd,1H),6.10(t,1H),6.03(s,1H),5.97(d,1H),3.75(s,3H),3.61(q,2H),2.96(t,2H),2.36(s,3H).
MS(ESI+)m/z413.2[M+H]+.
实施例74
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-6-基)嘧啶-2,4-二胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.40(d,2H),8.59(s,1H),7.80(d,1H),7.56(s,1H),7.26(d,1H),7.27(d,1H),7.13-7.06(m,3H),6.72(dd,1H),6.10(t,1H),6.03(s,1H),5.97(d,1H),4.01(q,2H),3.60(q,2H),2.95(t,2H),2.36(s,3H),1.32(t,3H).
MS(ESI+)m/z427.2[M+H]+.
实施例75
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(1-甲基吲哚-6-基)嘧啶-2,4-二胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.42(s,1H),8.80(s,1H),7.99(s,1H),7.83(d,1H),7.40(d,1H),7.24(d,1H),7.13-7.05(m,4H),6.72(dd,1H),6.33(d,1H),6.29(t,1H),6.03(d,1H),3.73(s,3H),3.66(q,2H),3.58(s,3H),2.98(t,2H).
MS(ESI+)m/z413.2[M+H]+.
实施例76
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(1-甲基吲哚-6-基)嘧啶-2,4-二胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.41(s,1H),8.80(s,1H),8.00(s,1H),7.83(d,1H),7.41(d,1H),7.23(d,1H),7.13-7.05(m,4H),6.71(dd,1H),6.32(d,1H),6.28(t,1H),6.03(d,1H),3.98(q,2H),3.64(q,2H),3.57(s,3H),2.97(t,2H),1.30(t,3H).
MS(ESI+)m/z427.2[M+H]+.
实施例77
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-4-基)嘧啶-2,4-二胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.68(s,1H),10.42(s,1H),8.34(s,1H),7.83(d,1H),7.51(d,1H),7.24(d,1H),7.09(dd,2H),7.01(d,1H),6.90(dd,1H),6.73(dd,1H),6.29(s,1H),6.20(m,1H),6.07(d,1H),3.76(s,3H),3.59(q,2H),2.94(t,2H),2.38(s,3H).
MS(ESI+)m/z413.2[M+H]+.
实施例78
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-4-基)嘧啶-2,4-二胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.68(s,1H),10.40(s,1H),8.34(s,1H),7.83(d,1H),7.51(d,1H),7.23(d,1H),7.10-7.07(m,2H),7.01(d,1H),6.91(t,1H),6.72(dd,1H),6.29(s,1H),6.19(t,1H),6.07(d,1H),4.02(q,2H),3.58(q,2H),2.94(t,2H),2.38(s,3H),1.32(t,3H).
MS(ESI+)m/z427.2[M+H]+.
实施例79
3-[2-({4-[(1-甲基吲哚-4-基)氨基]嘧啶-2-基}氨基)乙基]-lH-吲哚-5-醇
1H NMR(400MHz,DMSO-d6,75℃)δ10.26(s,1H),8.51(s,1H),8.28(br s,1H),7.86(d,1H),7.69(d,1H),7.21(d,1H),7.15-7.03(m,4H),6.91(d,1H),6.64-6.61(m,2H),6.24(t,1H),6.13(d,1H),3.78(s,3H),3.57(q,2H),2.90(t,2H).
MS(ESI+)m/z399.2[M+H]+.
实施例80
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(1-甲基吲哚-4-基)嘧啶-2,4-二胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.41(s,1H),8.51(s,1H),7.86(d,1H),7.71(d,1H),7.24-7.21(m,2H),7.13-7.04(m,4H),6.72(dd,1H),6.65(d,1H),6.26(t,1H),6.14(d,1H),4.02(q,2H),3.78(s,3H),3.58(q,2H),2.94(t,2H),1.32(t,3H).
MS(ESI+)m/z427.2[M+H]+.
实施例81
N4-(1,2-二甲基吲哚-4-基)-N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]嘧啶-2,4-二胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.42(s,1H),8.39(s,1H),7.83(d,1H),7.58(d,1H),7.24(d,1H),7.11-7.04(m,3H),6.98(dd,1H),6.73(dd,1H),6.38(s,1H),6.22(m,1H),6.08(d,1H),3.76(s,3H),3.65(s,3H),3.58(q,2H),2.94(t,2H),2.40(s,3H).
MS(ESI+)m/z427.2[M+H]+.
实施例82
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-苯并咪唑-4-基)嘧啶-2,4-二胺
1H NMR(400MHz,CD3OD,45℃)δ7.83(d,1H),7.23(d,2H),7.12(dd,1H),7.05(d,1H),7.02(br s,1H),6.76(dd,1H),6.09(br d,1H),3.78(s,3H),3.66(br t,2H),3.01(brt,2H),2.53(s,3H).
MS(ESI+)m/z414.2[M+H]+.
实施例83
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-苯并咪唑-4-基)嘧啶-2,4-二胺
1H NMR(400MHz,CD3OD,45℃)δ7.83(d,1H),7.23(d,2H),7.12(dd,1H),7.05(d,1H),7.02(br s,1H),6.76(dd,1H),6.09(br d,1H),4.01(q,2H),3.64(br t,2H),3.00(brt,2H),2.53(s,3H),1.43(t,3H).
MS(ESI+)m/z428.2[M+H]+.
实施例84
N4-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N2-(1-甲基吲哚-4-基)嘧啶-2,4-二胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.46(s,1H),7.98(s,1H),7.92(dd,1H),7.83(d,1H),7.25(d,1H),7.15(d,1H),7.11(s,1H),7.04-6.99(m,3H),6.92(m,1H),6.75-6.71(m,2H),5.98(d,1H),4.06(q,2H),3.75(ds,6H),3.62(q,2H).
MS(ESI+)m/z413.2[M+H]+.
实施例85
2-[2-(5-乙氧基-lH-吲哚-3-基)乙基氨基]-6-[(2-甲基-lH-吲哚-5-基)氨基]嘧啶-4-羧酰胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.58(s,1H),10.43(s,1H),8.85(s,1H),7.68(s,1H),7.55(br s,1H),7.24-7.18(m,3H),7.12(m,2H),7.03(d,1H),6.72(dd,1H),6.57(s,1H),6.37(t,1H),6.01(s,1H),4.01(q,2H),3.65(q,2H),2.98(t,2H),2.37(s,3H),1.31(t,3H).
MS(ESI+)m/z470.2[M+H]+.
实施例86
6-[(1,2-二甲基苯并咪唑-5-基)氨基]-2-[2-(5-甲氧基-lH-吲哚-3-基)乙基氨基]嘧啶-4-羧酰胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.43(s,1H),9.07(s,1H),7.90(s,1H),7.56(brs,1H),7.38(dd,1H),7.32(d,1H),7.24(d,1H),7.23(br s,1H),7.19(d,1H),7.03(d,1H),6.73(dd,1H),6.62(s,1H),6.49(m,1H),3.75(s,3H),3.71(s,3H),3.66(q,2H),2.99(t,2H),2.52(s,3H).
MS(ESI+)m/z471.2[M+H]+.
实施例87
2-[2-(5-甲氧基-lH-吲哚-3-基)乙基氨基]-6-[(1-甲基吲哚-4-基)氨基]嘧啶-4-羧酰胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.44(s,1H),8.88(s,1H),7.74(d,1H),7.58(brs,1H),7.25-7.22(m,3H),7.16-7.04(m,4H),6.81(s,1H),6.73(dd,1H),6.67(d,1H),6.49(t,1H),3.79(s,3H),3.75(s,3H),3.66(q,2H),2.98(t,2H).
MS(ESI+)m/z456.2[M+H]+.
实施例88
2-[2-(5-乙氧基-lH-吲哚-3-基)乙基氨基]-6-[(1-甲基吲哚-4-基)氨基]嘧啶-4-羧酰胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.43(s,1H),8.88(s,1H),7.75(d,1H),7.57(brs,1H),7.25-7.21(m,3H),7.16-7.06(m,3H),7.03(d,1H),6.81(s,1H),6.72(dd,1H),6.68(d,1H),6.48(t,1H),4.01(q,2H),3.79(s,3H),3.65(q,2H),2.97(t,2H),1.31(t,3H).
MS(ESI+)m/z470.2[M+H]+.
实施例89
N2-[2-(5-甲氧基-lH-吲哚-3-基)乙基]-N4-(1-甲基吲哚-4-基)-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺
1H NMR(400MHz,CD3OD)δ7.24-7.12(m,5H),7.06(m,2H),6.76(dd,1H),6.46(d,1H),3.81(s,3H),3.80(s,3H),3.66(t,2H),3.49(m,4H),1.95(t,2H),3.95(m,4H),2.32(s,3H).
MS(ESI+)m/z511.3[M+H]+.
实施例90
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)嘧啶-2,4,5-三胺
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),10.60(s,1H),7.93(s,1H),7.78(s,1H),7.47(s,1H),7.25-7.03(m,5H),6.69(dd,1H),5.91(s,1H),5.82(t,1H),3.96(q,2H),3.46(q,2H),2.88(t,2H),2.34(s,3H),1.31(t,3H).
MS(ESI+)m/z442.2[M+H]+.
中间体91
N-(2-氯嘧啶-4-基)-2-甲基-lH-吲哚-6-胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.73(s,1H),9.61(s,1H),8.05(d,1H),7.55(s,1H),7.36(d,1H),6.97(dd,1H),6.65(d,1H),6.10(s,1H),2.38(s,3H).
中间体92
N-(2-氯嘧啶-4-基)-1-甲基-吲哚-6-胺
1H NMR(400MHz,DMSO-d6,75℃)δ9.73(s,1H),8.08(d,1H),7.65(s,1H),7.53(d,1H),7.27(d,1H),7.09(dd,1H),6.70(d,1H),6.41(d,1H),3.77(s,3H).
中间体93
N-(2-氯嘧啶-4-基)-2-甲基-lH-吲哚-4-胺
1H-NMR(400MHz,DMSO-d6,75℃)δ10.87(s,1H),9.52(s,1H),8.06(d,1H),7.17(d,1H),7.16(d,1H),7.01(dd,1H),6.59(d,1H),6.13(s,1H),2.39(s,3H).
中间体94
N-(2-氯嘧啶-4-基)-1,2-二甲基-吲哚-4-胺
1H-NMR(400MHz,DMSO-d6,75℃)δ9.54(s,1H),8.06(d,1H),7.25(d,1H),7.22(d,1H),7.09(dd,1H),6.60(d,1H),6.23(s,1H),3.69(s,3H),2.42(s,3H).
中间体95
N-(2-氯嘧啶-4-基)-2-甲基-lH-苯并咪唑-4-胺
1H-NMR(400MHz,DMSO-d6,115℃)δ8.10(d,1H),7.48(br s,1H),7.27(br d,1H),7.13(dd,1H),6.81(br m,1H),2.52(s,3H).
中间体96
2-氯-6-[(1,2-二甲基苯并咪唑-5-基)氨基]嘧啶-4-羧酰胺
1H NMR(400MHz,DMSO-d6,115℃)δ9.84(s,1H),7.73(d,1H),7.46(br s,2H),7.44(d,1H),7.29(dd,1H),7.23(s,1H),3.74(s,3H),2.54(s,3H).
中间体97
2-氯-6-[(1-甲基吲哚-4-基)氨基]嘧啶-4-羧酰胺
1H NMR(400MHz,DMSO-d6,75℃)δ9.96(s,1H),7.72(br s,1H),7.57(br s,1H),7.39-7.28(m,4H),7.20(t,1H),6.51(d,1H),3.83(s,3H).
中间体98
N-(2-氯-5-硝基-嘧啶-4-基)-2-甲基-lH-吲哚-5-胺
1H NMR(400MHz,DMSO-d6,75℃)δ10.84(s,1H),10.26(s,1H),9.08(s,1H),7.54(s,1H),7.31(d,1H),7.11(dd,1H),6.17(s,1H),2.41(s,3H).
中间体99
N2-[2-(5-乙氧基-lH-吲哚-3-基)乙基]-N4-(2-甲基-lH-吲哚-5-基)-5-硝基-嘧啶-2,4-二胺
1H NMR(400MHz,DMSO-d6,125℃)δ10.49(br s,1H),10.19(br s,2H),8.96(s,1H),7.76(br s,2H),7.25-7.20(m,3H),7.00(s,1H),6.73(dd,1H),6.02(s,1H),4.01(q,2H),3.65(q,2H),2.97(t,2H),2.39(s,3H),1.32(t,3H).
生物学试验
微培养细胞毒荧光分析FMCA(Larsson,R.等;AnticancerRes,1989,9,第1111-1119页)是一种三天的非克隆原性基于微板的细胞活力试验,用于在体外衡量化合物的细胞毒和/或抑制细胞效应(Lindhagen,E.等,NatProtoc,2008.3,第1364-1369页)。FMCA代表了一种可评价的方法,用于在多种细胞类型中衡量细胞毒作用,包括细胞系和来自忠者的原代细胞(Larsson,R.等,IntJCancer,1992.50,第177-185页;Fridborg,H.等,EurJCancer,1999.35,第424-432页;Dhar,S.等,BrJCancer,1996.74,第888-896页)
FMCA是基于以下原理:二乙酸荧光素(FDA)在活细胞质膜中的酯酶作用下转化为荧光探针荧光素。在实验中,制备含化合物的96或384-孔微板并储存在-70℃备用。然后将细胞接种到含药微板中,置于培养箱中培养72小时。培养的最后一天,板洗涤,加入含FDA的缓冲液,与细胞培养45分钟。最后,在荧光计中测量每孔荧光,用以下公式计算每种化合物处理孔的存活指数%(SI):化合物-处理的细胞减去空白除以对照细胞减去空白。高的SI-值表示大的活细胞百分比,反之亦然。
在本发明化合物的实验中,96-孔培养板的制备如下:
将化合物溶解在DMSO中至l0mM,-20℃储存。将297μl无菌PBS加入各孔,制备96-孔微板。将测试化合物解冻,避光,混合,将3μl储备溶液加入96-孔板中,实现浓度100μM。然后,将20μl化合物溶液转移至V-形底的96-孔板中,准备试验板。100μM的化合物用PBS稀释至10μM,准备含20μl的试验板。将板在-70℃储存备用。
细胞接种当天,在两块试验板中,向各孔中加入180μl细胞悬液。因而测试的化合物的最终浓度为10μM和lμM。
在后续实验中,如上所述,与一些批准的癌症药物(达沙替尼,帕佐替尼,索拉非尼和舒尼替尼)一起,测试化合物。首先,全部使用急性淋巴母细菌白血病细胞系CCRF-CEM。在试验板中,在六个空的孔(空白孔)中加入培养液,在孔中加入PBS和细胞悬液,用作对照孔。然后如上所述,计算每个化合物处理的孔的SI-值。所有实验进行两次,每次实验准备一批新的板。所得数拥显示出实施例化合物相比比较化合物的活性。
在剂量响应实验中,如下制备384-孔培养板:
将本发明的化合物以及比较的激酶抑制剂索拉非尼、舒尼替尼、达沙替尼、帕佐替尼,和WO2009/071535中揭示的参比化合物(化合物#107)用PBS稀释至比所需的起始浓度高10倍的浓度。然后,采用Biomek2000液体处理系统在深孔384孔板中连续稀释化合物。在该板中,用Biomek2000制备每孔含5μl化合物的试验板。当用PBS稀释时某些化合物发生沉淀,因此如上所述这些化合物在96孔板中用培养基RPMI1640代替PBS手动制备。
化合物还在5个浓度进行测试,在以下细胞类型中5倍连续稀释:CCRF-CEM,hTERT-RPEl(正常视网膜上皮细胞),hRPTEpiC(正常肾脏细胞)和外周血单核细胞(PBMC)。每次实验进行三次,除了PBMC和hRPTEpiC,这两种进行两次。计算SI-值,用GraphPadPrism5.0(加利福尼亚州拉由拉市的图形软件有限公司(GraphPad Software Inc.))绘图,由曲线确定对于每种细胞类型和化合物的EC50-值。
本发明的示例性化合物在CCRF-CEM细胞测定中有活性,显示EC50值小于10μM。本发明优选的化合物的EC50值小于1μM。本发明更优选的化合物的EC50值小于0.1μM,该试验中参比化合物索拉非尼舒尼替尼、达沙替尼、帕佐替尼和WO2009/071535化合物#107的EC50值分别为8.3μM,14.1μM,9.7μM,25.9μM和1-10μM。大多数本发明化合物的EC50值比参比化合物小,数拥如表1所示。
表1.CCRF-CEM癌细胞-白血病中的EC50(μM)
参比1表示参比化合物索拉非尼
参比2表示参比化合物舒尼替尼
参比3表示参比化合物达沙替尼
参比4表示参比化合物帕佐替尼
参比5WO2009/071535化合物#107
此外,原代结果还显示与测试的hTERT-RPE1(正常视网膜上皮细胞),hRPTEpiC(正常肾脏细胞)和外周血单核细胞(PBMC)相比,本发明的化合物对CCRF-CEM细胞的选择性提高。
还在与以下癌症相关的其他癌症细胞系中测定本发明化合物:乳腺癌(MDA-MB-231;参见例如Cailleau,R.,等;J.Natl.CancerInst.,1974,53,661-674),替尼泊苷耐受性白血病(CEM/VMl;参见例如Danks,M.,等;Cancer Res.,1987,47,1297-1301),白血病(HL-60;参见例如Collins,S.,等;Nature,1977,270,347-349),阿霉素耐受性肺癌(H69AR;参见例如Mirski,S.,等;CancerRes.,1987,47,2594-2598),骨髓瘤(RPMI8226;参见例如Matsuoka,Y.,等;Proc.Soc.Exp.Biol.Med.,1967,125,1246-1250),阿霉素耐受性骨髓瘤(8226/Dox40;参见例如Dalton,W.,等;Blood,1989,15,747-752),淋巴瘤(U-937,参见例如Sundstrom,C,等;Int.J.Cancer,1976,17,565-577),长春新碱耐受性淋巴瘤(U-937-vcr;参见例如Botling,J.,等;Int.J.Cancer,1994,58,269-274),卵巢癌(A2780;参见例如Hamilton,T.,等;Semin.Oncol,1984,11,285-298),多柔比星耐受性卵巢癌(A2780/Adr)顺铂耐受性卵巢癌(A2780/Cis;参见例如Behrens,B.,等;CancerRes.1987,47,414-418),胰腺癌(PANC-l,BxPC-3,和MIAPaCa-2;参见例如Lieber,M.,等;Int.J.Cancer,1975,15,741-747;Loor,R.,等;Clin.Lab.Med.,1982,2,567-578;和Yunis,A,等;Int.J.Cancer,1977,19,128-135)以及前列腺癌(PC-3;参见例如Kaighn,M.,等;Invest.Urol,1979,17,16-23)。这些测试的代表性结果如表2和表3所示。
表2.各种癌症细胞系中的EC50(μM)
“nt”表示“尚未测定”。
表3.各种癌症细胞系中的EC50(μM)
“nt”表示“尚未测定”。
还在来自美国科罗拉多州丹佛市的细胞骨架有限公司(Cytoskeleton Inc)的微管蛋白聚合试验中进一步测定示例性化合物。由于当聚合发生时荧光报告子掺入微管蛋白中,所以聚合之后发生荧光增强。3μM的长春新碱和紫杉醇分别用作用于微管蛋白聚合抑制和稳定的阳性对照。所有化合物溶解在DMSO中,DMSO用作溶剂对照。在实验中,将示例性化合物和对照化合物与牛微管蛋白在无细胞环境中培养,然后在荧光计中测定荧光(Fluostar Optima,BMG Labtech,奥芬堡,德国),每分钟360/450nm,总共60分钟。测试选择的示例性化合物并显示出对微管蛋白聚合的抑制效果。
在细胞循环实验中进一步测试一些示例性化合物。在这些实验中,按照生产商的说明书使用Cl记k-iTOEdUAssay(分子探针/英骏公司)。HCTl16细胞在每孔6000个细胞的密度下接种并且放置使其附着于黑玻璃底的96孔帕金埃尔默板(PerkinElmerplate)的底部。然后加入化合物并与细胞孵育24小时。使用10μM的环吡酮(ciclopirox)作为G1期阻滞的阳性对照以及使用10μM的长春新碱作为G2/M期阻滞的阳性对照。在加入化合物之后直接加入用于定量新合成的DNA的EdU(5-乙炔基-2'-脱氧尿苷)溶液。第二天,细胞用甲醛固定和透化并且实施Click-iT反应。最后,加入DNA染料以标记细胞核。
然后在ArrayScanVTIHCS读数仪(赛默飞世尔细胞学公司(Thermo FischerCellomics))中使用Target Activation Bioapplication软件实施定量分析。每个孔总共1500个细胞在细胞水平被分析并且每个处理条件的代表DNA含量的数拥用柱状图作图。每个细胞中核染色的平均荧光密度,组距为20,在X轴上作图而细胞的数量在Y轴上表示。在这个柱状图中,在Gl期阻滞的细胞位于左侧的第一个峰而在G2/M期阻滞的细胞位于右侧的第二个峰。选择的示例性化合物被测试并且它们中的大多数显示G2/M期阻滞,G2/M期阻滞对于微管蛋白抑制剂是常见的。示例性化合物还在活细胞成像设备中被测试诱导凋亡。采用针对活细胞的NucViewTM488胱冬酶-3试验试剂盒(美国加利福尼亚州海达德的Biotium有限公司)。在实验前一天将HCT116细胞接种到黑色玻璃底PerkinElmer板中,然后加入选定浓度的化合物。最后,加入DEVD-NucView488胱冬酶-3底物,将板置于IncuCyteFLR中进行活细胞成像。当底物被活化的胱冬酶-3剪切时,释放染料,结合DNA后形成荧光(参见Cen,H.,等;FASEBJ.,2008,22,2243-2252)。1μM的星形孢菌素用作凋亡的阳性对照。测定选择的实施例化合物,所有化合物在各个时间点选择的浓度下诱导凋亡。
Claims (30)
1.一种式I的化合物,或其药学上可接受的盐
式中:
Z代表碳而Y代表氮;
R1、R3和R8是氢;
R2选自氢和(C1-C4)烷基;
R4、R6和R7独立地选自氢和O(C1-C4)烷基;
R5选自氢、卤素、羟基、O(C1-C4)烷基、O(C1-C4)烷基(C2-C5)杂环基和OCF3;
R10选自氢、氨基和(C1-C4)烷基;
R11选自氢、(C1-C4)烷基、(C1-C4)烷基(C2-C5)杂环基和(CO)NH2;
R9代表
R12、R13和R14是氢;
R15选自氢和(C1-C4)烷基;以及
R16选自氢、(C1-C4)烷基、(C1-C4)烷基-OH和(CO)OH、(CO)NH2、(CO)NH(C1-C4)烷基、(CO)N[(C1-C4)烷基]2、(CO)(C1-C4)烷基、(CO)(C2-C5)杂环基和(CO)(C2-C5)杂环基)(C1-C4)烷基;并且
R17选自氢和(C1-C4)烷基。
2.如权利要求1所述的化合物,其特征在于,R2选自氢和甲基。
3.如权利要求1或2所述的化合物,其特征在于,R2是氢。
4.如权利要求1所述的化合物,其特征在于,R5代表O(C1-C4)烷基。
5.如权利要求1所述的化合物,其特征在于R5选自甲氧基、乙氧基或丙氧基。
6.如权利要求1所述的化合物,其特征在于R5是甲氧基。
7.如权利要求1所述的化合物,其特征在于,R10选自氢和甲基。
8.如权利要求1所述的化合物,其特征在于,R11选自氢和甲基。
9.如权利要求1所述的化合物,其特征在于,R15选自氢和甲基。
10.如权利要求1所述的化合物,其特征在于,R16选自氢、甲基和(C1-C4)烷基-OH,并且R17选自氢和甲基。
11.如权利要求1所述的化合物,其特征在于,R16选自氢、甲基和(C1-C4)烷基-OH。
12.如权利要求1所述的化合物,其特征在于,R16选自氢、甲基和羟甲基。
13.如权利要求1所述的化合物,其特征在于,R17选自氢和甲基。
14.如权利要求1所述的化合物,其特征在于,
R4代表氢;
R5选自卤素、甲基、O(C1-C2)烷基和OCF3;
R6和R7独立地选自氢和甲氧基;
R10选自氢和甲基;
R11选自氢、甲基和(CO)NH2;
R9选自:
R15选自氢和甲基;
R16选自氢、甲基和羟甲基;并且
R17选自氢和甲基。
15.如权利要求14所述的化合物,其特征在于,R16表示甲基。
16.如权利要求1所述的化合物,其特征在于,
Z代表碳并且Y代表氮;
R1、R2、R3、R8、R12、R13和R14代表氢;
R4、R6和R7独立地选自氢和O(C1-C4)烷基;
R5选自氢、卤素、羟基、(C1-C4)烷基、O(C1-C4)烷基、O(C1-C4)烷基(C2-C5)杂环基和OCF3;
R10选自氢和(C1-C4)烷基;
R11选自氢、(C1-C4)烷基、(CO)NH2和(C1-C4)烷基(C2-C5)杂环基;
R9选自:
R15选自氢和甲基;
R16选自氢、(C1-C4)烷基、(C1-C4)烷基-OH和(CO)OH;并且
R17选自氢和(C1-C4)烷基。
17.如权利要求16所述的化合物,其特征在于,R16代表甲基。
18.如权利要求16或17所述的化合物,其特征在于,R5选自甲氧基和氟。
19.如权利要求16所述的化合物,其特征在于,R11选自氢、甲基和(CO)NH2。
20.如权利要求1所述的化合物,其特征在于,
Z代表碳并且Y代表氮;
R1、R3、R7、R8、R10、R12、R13、R14和R17代表氢;
R2和R11独立地选自氢和甲基;
R4、R5和R6独立地选自氢和O(C1-C4)烷基;
R9选自:
R15选自氢和甲基;并且
R16代表氢、甲基和羟甲基。
21.如权利要求1所述的化合物,其特征在于,
Z代表碳并且Y代表氮;
R1、R2、R3、R4、R6、R7、R8、R12、R13和R14代表氢;
R10、R11、R15和R17独立地选自氢和甲基;
R5选自甲氧基和乙氧基;
R9选自:
R16选自氢、甲基和羟甲基。
22.如权利要求1所述的化合物,其特征在于,
R1、R2、R3、R4、R6、R7、R8、R12、R14和R17代表氢;
R10选自氢和氨基;
R11选自氢、(CO)NH2和(C1-C4)烷基(C2-C5)杂环基;
R5选自甲氧基、乙氧基和羟基;
R15选自氢和甲基;
R16选自氢、甲基和羟甲基;并且
R9选自:
23.如权利要求1所述的化合物,所述化合物选自:
N2-[2-(1H-吲哚-3-基)乙基]-N4-(1H-吲哚-5-基)嘧啶-2,4-二胺;
N4-(1H-吲哚-5-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-[2-(1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N4-(2-甲基-1H-吲哚-5-基)-N2-{2-[5-(2-吗啉乙氧基)-1H-吲哚-3-基]乙基}嘧啶-2,4-二胺;
N4-(2-甲基-1H-吲哚-5-基)-N2-{2-[5-(三氟甲氧基)-1H-吲哚-3-基]乙基}嘧啶-2,4-二胺;
3-{2-[4-(2-甲基-1H-吲哚-5-基氨基)嘧啶-2-基氨基]乙基}-1H-吲哚-5-醇;
N2-[2-(5-甲基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-氟-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(6-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(7-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N4-(1,2-二甲基-1H-吲哚-5-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N4-(2,3-二甲基-1H-吲哚-5-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
(5-{2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]嘧啶-4-基氨基}-1H-吲哚-2-基)甲醇;
5-{2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]嘧啶-4-基氨基}-1H-吲哚-2-羧酸甲酯;
5-{2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]嘧啶-4-基氨基}-1H-吲哚-2-羧酸2-羟乙基酯;
N4-(1H-苯并[d]咪唑-5-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-苯并[d]咪唑-5-基)嘧啶-2,4-二胺;
N4-(1H-吲哚-6-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N4-(1H-吲哚-4-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-[2-(1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]-6-(2-甲基-1H-吲哚-5-基氨基)嘧啶-4-羧酰胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-5-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;和
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;
及其药学上可接受的盐。
24.如权利要求1所述的化合物,所述化合物选自:
N2-[2-(4-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N4-(2-甲基-1H-吲哚-5-基)-N2-[2-(5-丙氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-[2-(5-异丙氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5,6-二甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-7-甲基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(l-甲基-1H-苯并[d]咪唑-5-基)嘧啶-2,4-二胺;
N4-(l,2-二甲基-1H-苯并[d]咪唑-5-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(l-甲基-1H-吲哚-4-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-2-甲基-1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-苯并[d]咪唑-5-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-1H-吲哚-3-基)乙基]-6-甲基-N4-(2-甲基-1H-苯并[d]咪唑-5-基)嘧啶-2,4-二胺;和
(5-{2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]嘧啶-4-基氨基}-1-甲基-1H-苯并[d]咪唑-2-基)甲醇;
及其药学上可接受的盐。
25.如权利要求1所述的化合物,所述化合物选自:
[5-({2-[2-(5-乙氧基-1H-吲哚-3-基)乙基氨基]嘧啶-4-基}氨基)-1H-吲哚-2-基]甲醇;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-6-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-6-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(l-甲基吲哚-6-基)嘧啶-2,4-二胺;
N2-2-(5-乙氧基-1H-吲哚-3-基)乙基]-N4-(l-甲基吲哚-6-基)嘧啶-2,4-二胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-4-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-4-基)嘧啶-2,4-二胺;
3-[2-({4-[(1-甲基吲哚-4-基)氨基]嘧啶-2-基}氨基)乙基]-1H-吲哚-5-醇;
N2-2-(5-乙氧基-1H-吲哚-3-基)乙基]-N4-(l-甲基吲哚-4-基)嘧啶-2,4-二胺;
N4-(l,2-二甲基吲哚-4-基)-N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]嘧啶-2,4-二胺;
N2-2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-苯并咪唑-4-基)嘧啶-2,4-二胺;
N2-[2-(5-乙氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-苯并咪唑-4-基)嘧啶-2,4-二胺;
2-[2-(5-乙氧基-1H-吲哚-3-基)乙基氨基]-6-[(2-甲基-1H-吲哚-5-基)氨基]嘧啶-4-羧酰胺;
6-[(l,2-二甲基苯并咪唑-5-基)氨基]-2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]嘧啶-4-羧酰胺;
2-[2-(5-甲氧基-1H-吲哚-3-基)乙基氨基]-6-[(1-甲基吲哚-4-基)氨基]嘧啶-4-羧酰胺;
2-[2-(5-乙氧基-1H-吲哚-3-基)乙基氨基]-6-[(l-甲基吲哚-4-基)氨基]嘧啶-4-羧酰胺;
N2-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N4-(l-甲基吲哚-4-基)-6-(4-甲基哌嗪-1-基)嘧啶-2,4-二胺;和
N2-[2-(5-乙氧基-1H-吲哚-3-基)乙基]-N4-(2-甲基-1H-吲哚-5-基)嘧啶-2,4,5-三胺;
及其药学上可接受的盐。
26.N4-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N2-(2-甲基-1H-吲哚-5-基)嘧啶-2,4-二胺或其药学上可接受的盐。
27.N4-[2-(5-甲氧基-1H-吲哚-3-基)乙基]-N2-(1-甲基吲哚-4-基)嘧啶-2,4-二胺或其药学上可接受的盐。
28.如权利要求1-27中任一项所述的化合物在制备用于治疗癌症的药物中的用途。
29.如权利要求1-27中任一项所述的化合物在制备用于治疗癌症的药物中的用途,所述癌症选自白血病、淋巴瘤、骨髓瘤、乳腺癌、卵巢癌、前列腺癌、肺癌、胰腺癌和胶质瘤。
30.一种药物组合物,其包含如权利要求1-27中任一项所述的化合物以及药学上可接受的稀释剂和载体。
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EP11159589A EP2502924A1 (en) | 2011-03-24 | 2011-03-24 | Novel pyrimidine derivatives |
EP11159589.8 | 2011-03-24 | ||
EP11189572 | 2011-11-17 | ||
EP11189572.8 | 2011-11-17 | ||
PCT/EP2012/055216 WO2012127032A1 (en) | 2011-03-24 | 2012-03-23 | Novel pyrimidine derivatives |
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EP1506960A1 (en) * | 2003-08-07 | 2005-02-16 | National Health Research Institutes | Indole compounds as inhibitors of tubulin polymerisation for the treatment of angiogenesis-related disorders |
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EP1506960A1 (en) * | 2003-08-07 | 2005-02-16 | National Health Research Institutes | Indole compounds as inhibitors of tubulin polymerisation for the treatment of angiogenesis-related disorders |
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