CN114426541B - 氮杂芳基化合物及其用途 - Google Patents
氮杂芳基化合物及其用途 Download PDFInfo
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- CN114426541B CN114426541B CN202111255588.1A CN202111255588A CN114426541B CN 114426541 B CN114426541 B CN 114426541B CN 202111255588 A CN202111255588 A CN 202111255588A CN 114426541 B CN114426541 B CN 114426541B
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- hydrogen
- compound
- alkyl group
- pharmaceutically acceptable
- alkyl
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- C—CHEMISTRY; METALLURGY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供了一类氮杂芳基化合物，或其立体异构体、或其药学上可接受的盐。本发明还提供了该类化合物及其组合物在作为制备治疗与EED蛋白和/或PRC2蛋白复合物相关疾病的药物中的用途。
Description
技术领域
本发明涉及一类新的氮杂芳基化合物及其在作为制备治疗与EED蛋白和/或PRC2蛋白复合物相关疾病的药物中的用途。
背景技术
多梳基因家族PcG(Polycomb Group genes)是重要的表观遗传修饰基因，PRC2(Polycomb Repressive Complex 2)作为PcG复合体的重要复合物之一,主要包括EZH2(Enhancer of Zeste Homolog 2)、SUZ12(Suppressor of Zeste 12Homologue)、EED(Embryonic Ectoderm Development)和YYl(Yin Yang 1)。PRC2是通过对染色质中组蛋白3的27位赖氨酸(H3K27)的甲基化修饰来抑制相关基因的表达。其中EZH2具有酶催化活性，能够把底物SAM(S-adenosyl-L-methionine)的甲基转移到H3K27上，从而达到H3K27的一到三甲基化修饰。EZH2的酶催化活性也依赖于PRC2其他组成部分，比如属于WD40重复结构蛋白家族的EED蛋白。PRC2的功能异常与临床上许多肿瘤疾病相关，包括肺癌、乳腺癌、直肠癌、前列腺癌、膀胱癌、胰腺癌、肉瘤以及淋巴癌等等。因此研发抑制PRC2的药物具有重要价值。
抑制PRC2药物的研发目前有EZH2抑制剂以及EED抑制剂两个方向，其中EZH2抑制剂目前已有进入临床，例如EPZ-6438、GSK2816126等。EED抑制剂对EZH2酶功能有变构抑制的作用，可以达到与EZH2相同或类似的生物功能。并且EED抑制剂还可能会克服了EZH2抑制剂的耐药性问题，与EZH2抑制剂联用也可能达到更好的协同作用。
发明内容
本发明提供了一种式I所示的化合物、或其立体异构体、或其药学上可接受的盐：
其中，
A环选自5～6元杂环烷基、苯环、5～6元芳杂环或-(苯环)-(5～6元杂环烷基)；其中杂环烷基、苯环、芳杂环可进一步被一个、两个或三个RA1取代；
每个RA1分别独立选自氢、氘、卤素、氰基、硝基、C1～6烷基、卤素取代的C1～6烷基、-ORA2、-NRA2RA3、-C(O)RA2、-S(O)RA2、-S(O)2RA2、3～6元环烷基；
RA2、RA3分别独立选自氢、氘、C1～6烷基、3～6元环烷基；
R1选自氢、氘、C1～6烷基、氘取代的C1～6烷基；
R2、R3分别独立选自氢、氘、卤素、C1～6烷基、氘取代的C1～6烷基、卤素取代的C1～6烷基；且R2、R3不同时为氢；
或者，R2、R3相连形成3～6元环烷基、氘取代的3～6元环烷基；
R4、R5分别独立选自氢、C1～6烷基；
或者，R4、R5相连形成5～6元环烷基、氘取代的5～6元环烷基、5～6元杂环烷基、氘取代的5～6元杂环烷基、5～6元芳杂环、氘取代的5～6元芳杂环；
或者，R2、R4相连形成5～6元环烷基、氘取代的5～6元环烷基、5～6元杂环烷基、氘取代的5～6元杂环烷基；
R6选自氢、卤素、氰基、硝基、C1～6烷基、卤素取代的C1～6烷基、-OR62、-NR62R63、3～6元环烷基；
R62、R63分别独立选自氢、C1～6烷基。
进一步地，
A环选自吡啶、哌嗪、苯环或-(苯环)-(哌嗪)；其中吡啶、哌嗪、苯环可进一步被一个、两个或三个RA1取代；
每个RA1分别独立选自氢、氘、卤素、氰基、硝基、C1～4烷基、卤素取代的C1～4烷基、-ORA2、-NRA2RA3、-C(O)RA2、-S(O)RA2、-S(O)2RA2、环丙基；
RA2、RA3分别独立选自氢、氘、C1～4烷基、环丙基；
R1选自氢、氘、C1～4烷基、氘取代的C1～4烷基；
R2、R3分别独立选自氢、氘、卤素、C1～4烷基、氘取代的C1～4烷基、卤素取代的C1～4烷基；且R2、R3不同时为氢；
或者，R2、R3相连形成环丙烷、氘取代的环丙烷；
R4、R5分别独立选自氢、C1～4烷基；
或者，R4、R5相连形成二氢呋喃、呋喃、氘取代的二氢呋喃、氘取代的呋喃；
或者，R2、R4相连形成环戊烯、氘取代的环戊烯；
R6选自氢、卤素、氰基、硝基、C1～4烷基、卤素取代的C1～4烷基、-OR62、-NR62R63、环丙烷；
R62、R63分别独立选自氢、C1～4烷基。
更进一步地，
A环选自
更进一步地，式I所示的化合物如下所示：
更进一步地，式I所示的化合物如下所示：
在本发明的一些具体实施方案中，所述化合物具体为：
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐在制备药物中的用途。
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐在制备治疗与EED蛋白和/或PRC2蛋白复合物相关疾病的药物中的用途。
进一步地，所述与EED和/或PRC2蛋白复合物活性相关的疾病为肿瘤、癌症、癌前期综合征相关的疾病中的一种或几种。
本发明还提供了一种药物组合物，以前述的化合物、或其立体异构体、或其药学上可接受的盐，加上药学上可接受的辅料制备而成的制剂。
“癌症”或“肿瘤”是指以不受控制的细胞异常增殖为特征的多种疾病中的任何一种，受影响的细胞在局部或通过血流和淋巴系统扩散到其他部位的能力的身体(即转移)以及许多特征结构和/或分子特征中的任何一个。“癌细胞”是指经历多步骤肿瘤进展的早期，中期或晚期阶段的细胞。癌症包括肉瘤、乳腺癌、肺癌、脑癌、骨癌、肝癌、肾癌、结肠癌和前列腺癌。在一些实施方案中，式I的化合物用于治疗选自结肠癌、脑癌、乳腺癌、纤维肉瘤和鳞状细胞癌的癌症。在一些实施方案中，癌症选自黑素瘤、乳腺癌、结肠癌、肺癌和卵巢癌。在一些实施方案中，所治疗的癌症是转移性癌症。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或基团所替换。
“可进一步被取代”是指“取代”可以但不必须发生，该说明包括发生或不发生的情形。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca～b烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，C1～4烷基是指包含1～4个碳原子的烷基。
“烷基”是指具有指定数目的成员原子的饱和烃链。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分，所述其他基团为例如C1～C6烷氧基。
本发明中Ca～b烷氧基、Ca～b烷酯基、Ca～b烷氨基、Ca～b酰基分别是指含有“a”至“b”个碳原子的烷基与对应的氧原子、酯基、氨基、酰基相连得到的基团。
本发明中所述的“环烷基”、“环烷烃”是指具有多个碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连和螺环体系)的饱和或部分饱和的环状基团。对于具有不含环杂原子的芳族和非芳族环的多环体系，当连接点位于非芳族碳原子时，适用术语“环烷基”(例如5,6,7,8,-四氢化萘-5-基)。术语“环烷基”包括环烯基基团，诸如环己烯基。环烷基基团的实例包括例如，金刚烷基、环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。包括多双环烷基环体系的环烷基基团的实例是双环己基、双环戊基、双环辛基等。下面例举并命名两种此类双环烷基多环结构：
双环己基和/>
双环己基。
本发明中所述的“杂环”、“杂环烷基”、“杂环烷烃”是指包含至少一个杂原子的饱和环或非芳香性的不饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常表示多个环原子的一价饱和或部分不饱和单环或二环环系统、优选3至9个环原子的一价饱和或部分不饱和单环或二环环系统，其包含1、2或3个选自N、O和S的环杂原子，其余的环原子是碳。二环表示由共有两个环原子的两个环组成的，即将两个环分开的桥是单键或是一个或两个环原子的链。单环饱和杂环烷基的实例是氧杂环丁基、氮杂环丁基、吡咯烷基、2-氧代-吡咯烷-3-基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、
硫代吗啉基、1，1-二氧代-硫代吗啉-4-基、氮杂环庚基、二氮杂环庚基、高哌嗪基或氧杂氮杂环庚基。二环饱和杂环烷基的实例是8-氮杂-二环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-二环[3.2.1]辛基、9-氮杂-二环[3.3.1]壬基、
部分不饱和杂环烷基的实例是二氢呋喃基、咪唑啉基、四氢-吡啶基或二氢吡喃基。
本发明中所述的“芳环”是指具有多个碳原子的芳烃基团。芳基通常是具有6-20个碳原子的单环、二环或三环芳基。此外，本文所用的术语“芳基”是指可以是单个芳环或稠合在一起的多个芳环的芳族取代基。非限制性实例包括苯基、萘基或四氢萘基。
本发明中所述的“芳杂环”是指包含至少一个杂原子的芳香性不饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常包含多个环原子的、其中一个或多个环原子选自O、N、S的杂原子的芳族单环或双环烃。优选地有一到三个杂原子。杂环芳基例如代表：吡啶基、吲哚基、喹噁啉基、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、苯并噻吩基、苯并吡喃基、苯并噻吡喃基、呋喃基、吡咯基、噻唑基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、咪唑基、噻吩基、噁二唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基。
本发明中所述的“卤素”是指氟、氯、溴或碘。
本发明中所述的“卤素取代的烷基”、“氘取代的烷基”、“氘取代的环烷基”是指烷基中的一个或多个氢原子被卤素或氘取代；例如三氟甲基。
本发明中所述的“-OR”、“-NRR”等是指R基团与氧原子或氮原子以单键相连。
本发明中所述的“-C(O)R”、“-S(O)2R”等中的氧原子是与碳原子或硫原子以双键相连。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同时、分别或有序地对受试对象进行给药。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
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)的的单位给出。NMR的测定是用(Bruker AvanceIII 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3),氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
LC-MS的测定使用岛津液质联用仪(Shimadzu LC-MS 2020(ESI))。HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。MPLC(中压制备色谱)使用Gilson GX-281反相制备色谱仪。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，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。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于安耐吉化学、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例中无特殊说明，反应在氮气氛围下进行。实施例中无特殊说明，溶液是指水溶液。实施例中无特殊说明，反应的温度为室温。实施例中无特殊说明，M是摩尔每升。室温通常为20℃～30℃。过夜为12±1h。
中间体M1、8-溴-5-甲基磺酰-[1,2,4]三唑[4,3-c]嘧啶的合成
步骤1、化合物M1-2的合成
在干燥的250ml单口瓶中加入底物5-溴-4-氯-2-甲基磺酰-嘧啶(1g，4.38mmol)，加入乙醇(20ml)溶解，搅拌下缓慢滴加N2H4 H2O(440mg,9.21mmol)搅拌反应4小时，LC-MS监测。反应结束后用水和乙酸乙酯萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物M1-1(5-溴-2-甲基磺酰-嘧啶-4-基)肼(1.03g,99.9％)LC-MC：m/z 236.1[M+H]+
步骤2、化合物M1的合成
在干燥的250ml单口瓶中加入底物(5-溴-2-甲基磺酰-嘧啶-4-基)肼(750mg，3.19mmol)，加入CH(OMe)3(10ml)溶解，升温至100℃，搅拌反应2.5小时，LC-MS监测。反应结束后用水和乙酸乙酯萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物M1 8-溴-5-甲基磺酰-[1,2,4]三唑[4,3-c]嘧啶(700g,89.5％)LC-MC：m/z 246.1[M+H]+
实施例1、N-(1-(2-氟苯基)环丙基)-8-(2-甲基吡啶-3-基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺的合成
步骤1、化合物1-2的合成
在干燥的250ml单口瓶中加入底物2-氟苯腈(1.21g，9.99mmol)，加入Et2O(40ml)溶解，加入溴(乙基)镁(2.93g，21.98mmol)，Ti(OiPr)4(3.12g，10.99mmol)和BF3OEt2(2.84g，19.98mmol)室温搅拌反应4小时，LC-MS监测。反应结束后用水和乙酸乙酯萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物1-(2-氟苯基)氨基环丙烷(260mg,17.2％)LC-MC：m/z 152.2[M+H]+
步骤2、化合物1-4的合成
在干燥的50ml单口瓶中加入底物8-溴-5-甲基磺酰-[1,2,4]三唑[4,3-c]嘧啶(40mg，0.16mmol)，加入THF(6ml)溶解，加入1-(2-氟苯基)氨基环丙烷(65mg，0.25mmol)，MCPBA(54.8mg，0.32mmol)和TEA(50mg，0.49mmol)室温搅拌反应4小时，LC-MS监测。反应结束后用水和乙酸乙酯萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物8-溴-N-[1-(2-氟苯基)环丙基]-[1,2,4]三唑[4,3-c]嘧啶-5-胺(26mg,45.7％)LC-MC：m/z348[M+H]+
步骤3、化合物1的合成
在干燥的50ml单口瓶中加入底物8-溴-N-[1-(2-氟苯基)环丙基]-[1,2,4]三唑[4,3-c]嘧啶-5-胺(12.8mg，0.036mmol)，加入1,4二氧六环(3ml)和水(1ml)溶解，加入2-甲基-3-(4,4,5,5-四甲基-1,3,2-二恶硼硼烷-2-基)吡啶(10.4mg，0.047mmol)，Pd(dppf)Cl2(2mg，0.036mmol)和碳酸钠(13mg，0.036mmol)，升温至110℃，在氮气保护下搅拌反应4小时，LC-MS监测。反应结束后用水和乙酸乙酯萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物N-[1-(2-氟苯基)环丙基]-8-(2-甲基-3-吡啶基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺(9.16mg,69.2％)LC-MC：m/z 361[M+H]+
1H NMR(400MHz,Methanol-d4)δ9.42(s,1H),8.75(dd,J＝5.9,1.6Hz,1H),8.54(dd,J＝8.0,1.6Hz,1H),7.96(dd,J＝8.0,5.8Hz,1H),7.83(s,1H),7.79(td,J＝7.7,1.8Hz,1H),7.27(tdd,J＝7.5,5.1,1.8Hz,1H),7.14–7.02(m,2H),2.67(s,3H),1.44(d,J＝2.2Hz,4H),1.31–1.28(m,2H).
实施例2、8-(2-甲基吡啶-3-基)-N-(1-苯乙基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺的合成
步骤1、化合物2-2的合成
按照实施例1中步骤2的合成方法，将步骤2中的1-(2-氟苯基)氨基环丙烷替换为1-苯乙胺，合成方法相同，得到化合物8-溴-N-(1-苯乙基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺LC-MC：m/z 319[M+H]+
步骤2、化合物2的合成
按照实施例1中步骤3的合成方法，将步骤3中的8-溴-N-[1-(2-氟苯基)环丙基]-[1,2,4]三唑[4,3-c]嘧啶-5-胺替换为8-溴-N-(1-苯乙基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺，合成方法相同，得到化合物8-(2-甲基吡啶-3-基)-N-(1-苯乙基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺LC-MC：m/z 331[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.84(d,J＝8.4Hz,1H),8.57(s,1H),8.49(dd,J＝4.7,1.7Hz,1H),7.88(s,1H),7.71(d,J＝7.3,1.5Hz,1H),7.52(d,J＝7.6Hz,2H),7.40–7.28(m,3H),7.28–7.19(m,1H),5.54–5.36(m,1H),2.38(s,3H),1.64(d,J＝7.0Hz,3H).
实施例3、N-(1-(2-氟苯基)乙基)-8-(2-甲基吡啶-3-基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺的合成
步骤1、化合物3-2的合成
按照实施例1中步骤2的合成方法，将步骤2中的1-(2-氟苯基)氨基环丙烷替换为1-(2-氟苯基)乙胺，合成方法相同，得到化合物8-溴-N-[1-(2-氟苯基)乙基]-[1,2,4]三唑[4,3-c]嘧啶-5-胺LC-MC：m/z 337[M+H]+
步骤2、化合物3的合成
按照实施例1中步骤3的合成方法，将步骤3中的8-溴-N-[1-(2-氟苯基)环丙基]-[1,2,4]三唑[4,3-c]嘧啶-5-胺替换为8-溴-N-[1-(2-氟苯基)乙基]-[1,2,4]三唑[4,3-c]嘧啶-5-胺，合成方法相同，得到化合物N-(1-(2-氟苯基)乙基)-8-(2-甲基吡啶-3-基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺LC-MC：m/z 349[M+H]+
1H NMR(400MHz,Methanol-d4)δ8.47(dd,J＝5.0,1.7Hz,1H),8.40(s,1H),7.85(s,1H),7.77(dd,J＝7.7,1.7Hz,1H),7.52(td,J＝7.7,1.8Hz,1H),7.36(dd,J＝7.7,4.9Hz,1H),7.32–7.24(m,1H),7.17–7.06(m,2H),5.76(d,J＝7.0Hz,1H),2.42(s,3H),1.71(d,J＝7.0Hz,3H).实施例4和5、(R)-N-(1-(2-甲氧基苯基)乙基)-8-(2-甲基嘧啶-3-基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺和(S)-N-(1-(2-甲氧基苯基)乙基)-8-(2-甲基吡啶-3-基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺的合成
步骤1、化合物4-2的合成
按照实施例1中步骤2的合成方法，将步骤2中的1-(2-氟苯基)氨基环丙烷替换为1-(2-甲氧基苯基)乙胺，合成方法相同，得到化合物8-溴-N-[1-(2-甲氧基苯基)乙基]-[1,2,4]三唑[4,3-c]嘧啶-5-胺LC-MC：m/z 349[M+H]+
步骤2、化合物4和5的合成
按照实施例1中步骤3的合成方法，将步骤3中的8-溴-N-[1-(2-氟苯基)环丙基]-[1,2,4]三唑[4,3-c]嘧啶-5-胺替换为8-溴-N-[1-(2-甲氧基苯基)乙基]-[1,2,4]三唑[4,3-c]嘧啶-5-胺，合成方法相同，得到化合物(R)-N-(1-(2-甲氧基苯基)乙基)-8-(2-甲基嘧啶-3-基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺和(S)-N-(1-(2-甲氧基苯基)乙基)-8-(2-甲基吡啶-3-基)-[1,2,4]三唑[4,3-c]嘧啶-5-胺LC-MC：m/z 361[M+H]+
化合物4：1H NMR(400MHz,Methanol-d4)δ9.58(s,1H),8.75(dd,J＝5.9,1.6Hz,1H),8.56(dd,J＝8.0,1.5Hz,1H),7.97(dd,J＝7.9,5.8Hz,1H),7.77(s,1H),7.40(dd,J＝7.6,1.7Hz,1H),7.25(td,J＝7.9,1.7Hz,1H),7.00(dd,J＝8.2,1.0Hz,1H),6.92(td,J＝7.5,1.1Hz,1H),5.78(q,J＝6.9Hz,1H),3.89(s,3H),2.70(s,3H),1.66(d,J＝7.0Hz,3H).
化合物5：1H NMR(400MHz,Methanol-d4)δ8.77(s,1H),8.55(d,J＝7.5Hz,1H),8.45(s,1H),8.03(s,1H),7.97(s,1H),7.37(d,J＝7.6Hz,1H),7.26(t,J＝7.9Hz,1H),7.03(d,J＝8.3Hz,1H),6.92(t,J＝7.4Hz,1H),5.77(t,J＝7.0Hz,1H),3.94(s,3H),2.69(s,3H),1.66(d,J＝6.9Hz,3H).
以下用试验例的方式说明本发明的有益效果：
试验例、生物活性实验
多梳抑制复合物PRC2广泛参与肿瘤的发生与恶化，其抑制剂发现是目前表观遗传抗肿瘤药物研究中的热点。EED和EZH2是PRC2的核心成分之一，EED具有结合(H3K27me3)小肽作用，结合H3K27me3后，将PRC2定位在染色质上，并充当支架功能，提供一个EZH2可催化的结构，从而刺激PRC2的甲基转移酶活性，使得H3K27ME3标记在染色质上传播。由于PRC2的催化活性依赖于EZH2与EED的蛋白-蛋白相互作用，靶向EED的小分子抑制剂可能抑制PRC2的致癌活性。因此，寻找抑制EED的化合物为抑制PRC2活性提供了新方法。本发明公开了化合物可以作为EED靶点抑制剂，并对EED和/或PRC2作用机理相关的疾病有治疗作用。
本发明公开化合物的生物学功能在生化水平的测试中得到了证明。在生化测试中，本发明公开的化合物能够与和EED蛋白结合的H3K27Me3多肽有强的竞争结合作用。
试验例1：通过TR-FRET方法评价化合物在阻断EED与H3K27me3结合的效果
首先配置不同浓度梯度的化合物溶液。取DMSO溶解到浓度为2～50mM测试化合物和40mM参考化合物EED226(Cayman,22031)和A-395(Sigma,SML 1923-5MG)将化合物用100％DMSO进行2倍或3倍稀释，配制成200×DMSO溶液，共9个剂量点。取2μL 200×稀释好的化合物到98μL反应缓冲液(25mM Hepes,0.01％BSA,0.5mM DTT,1mM EDTA,pH 8.0)中混匀。取5μL不同浓度梯度的化合物至384检测板(Corning,3574)中，每个浓度梯度设置2个平行重复。
其次进行结合阻断反应。用上述反应缓冲液稀释Flag-EED(BPS,50280)蛋白至40nM，以及生物素标记的多肽片段H3K27(1-50)me3-biotin peptide(Cisbio定制)至400nM。底物序列为ARTKQTARKSTGGKAPRKQLATKAARK(me3)SAPATGGVKKPHRYRPGTVALRE-K(Biotin)。分别转移5μL浓度为400nM多肽片段以及5μL的40nM蛋白至含有化合物的检测孔内，薄膜封住检测板，25℃孵育30min。
最后使用TR-FRET方法检测。分别准备LANCE Eu-W1024 anti-FLAG(供体)(PerkinElmer,AD0273)和Streptavidin-XL665(受体)(PerkinElmer,AL108C)溶液至上述反应缓冲液中，再向各检测孔中加入5μL上述受体和供体，终浓度依次为2nM和50nM。锡箔遮封住检测板，将检测板在25℃，避光孵育60min。使用Tecan Spark 20M读数(用320nm波长为激发光，在665nm和620nm波长值为发射光读荧光信号值)。计算荧光信号比值：665/620*1000为最终的酶活性信号值，根据阳性对照(最大信号对照)和阴性对照(最小信号对照)获得的读数TR-FRET信号进行标准化，以给出不同浓度化合物的抑制率。再通过GraphPadPrism 6以log(inhibitor)vs.response–Variable slope模式拟合计算得出化合物对酶活性抑制的IC50。拟合方程为：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))，其中Y代表已知的百分剩余酶活性，X代表Log后的已知化合物的浓度。
按照上述方法对实施例制备的化合物进行EED抑制活性检测，试验结果见表1，其中测定各化合物的IC50按照说明分类：
“+”表示IC50测定值小于等于100μM大于1μM；
“++”表示IC50测定值小于等于1μM；
表1、本发明化合物对EED的抑制活性
| 实施例化合物 | EED IC50 |
| 1 | ++ |
| 2 | ++ |
| 3 | ++ |
| 4 | ++ |
| 5 | ++ |
Claims (7)
1.式I所示的化合物、或其药学上可接受的盐：
其中，
A环选自
每个RA1分别独立选自C1～6烷基；
R1选自氢；
R2、R3分别独立选自氢、C1～6烷基；且R2、R3不同时为氢；
或者，R2、R3相连形成3～6元环烷基；
R4、R5分别独立选自氢、C1～6烷基；
R6选自氢、卤素、氰基、硝基、C1～6烷基、卤素取代的C1～6烷基、-OR62；
R62选自C1～6烷基。
2.根据权利要求1所述的化合物、或其药学上可接受的盐，其特征在于：
每个RA1分别独立选自C1～4烷基；
R1选自氢；
R2、R3分别独立选自氢、C1～4烷基；且R2、R3不同时为氢；
或者，R2、R3相连形成环丙烷；
R4、R5分别独立选自氢、C1～4烷基；
R6选自氢、卤素、-OR62；
R62分别独立选自C1～4烷基。
3.根据权利要求1～2任一项所述的化合物、或其药学上可接受的盐，其特征在于：所述化合物具体为：
4.权利要求1～3任一项所述的化合物、或其药学上可接受的盐在制备药物中的用途。
5.权利要求1～3任一项所述的化合物、或其药学上可接受的盐在制备治疗与EED蛋白和/或PRC2蛋白复合物相关疾病的药物中的用途。
6.根据权利要求5所述的用途，其特征在于：所述与EED和/或PRC2蛋白复合物活性相关的疾病为肿瘤、癌症、癌前期综合征相关的疾病中的一种或几种。
7.一种药物组合物，其特征在于：以权利要求1～3任一项所述的化合物、或其药学上可接受的盐，加上药学上可接受的辅料制备而成的制剂。
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