CN118126043A - 一种高选择性的plk4抑制剂及制备方法和应用 - Google Patents
一种高选择性的plk4抑制剂及制备方法和应用 Download PDFInfo
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- CN118126043A CN118126043A CN202211540009.2A CN202211540009A CN118126043A CN 118126043 A CN118126043 A CN 118126043A CN 202211540009 A CN202211540009 A CN 202211540009A CN 118126043 A CN118126043 A CN 118126043A
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 150000002431 hydrogen Chemical class 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
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- 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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Abstract
本发明属药物合成领域,涉及一种高选择性的PLK4抑制剂及制备方法和作为PLK4抑制剂中的应用。抑制剂为通式I所示吡唑并嘧啶衍生物,及其几何异构体,对映异构体或其药学上可接受的盐;优选的化合物具有作为蛋白激酶抑制剂,特别是PLK4激酶抑制剂的活性。
Description
技术领域
本发明属药物合成领域,涉及一种高选择性的PLK4抑制剂及制备方法和作为PLK4抑制剂中的应用。
背景技术
恶性肿瘤是目前全世界的主要死亡原因之一。针对恶性肿瘤的化学药物正在经历由早期的非选择性药物到如今拥有特定靶点的小分子药物转变。随着精准医疗概念的提出,靶向肿瘤细胞中异常表达的蛋白激酶,应是未来抗肿瘤领域的主要研究方向。近年来,以控制中心体扩增为途径达到抑制肿瘤细胞增殖目的的治疗手段已成为肿瘤化疗的新兴方案。
Polo样激酶4(PLK4)作为细胞内中心体复制的关键蛋白,在中心体复制和有丝分裂过程中发挥重要功能。已有不少研究表明PLK4过表达会导致中心体扩增而诱发癌症。目前,设计PLK4小分子ATP竞争性抑制剂已成为治疗中心体错误复制诱发的肿瘤的重要手段,且PLK4抑制剂能实现对含有TRIM37基因扩增的肿瘤的精准治疗,这一研究已在乳腺癌、胶质母细胞瘤中得以证实。
Polo样激酶4为Polo样蛋白激酶家族的成员之一,是一种进化上高度保守的丝氨酸/苏氨酸蛋白激酶,其共有5种亚型,即PLK1-5。PLK4主要在分裂活跃组织和细胞中表达,一系列的生物学研究表明,PLK4与细胞周期中中心体复制密切相关,而肿瘤细胞又具有无限增殖的特点。因此,PLK4在肿瘤细胞的增殖,迁移,侵袭,凋亡等多种生物学功能中,发挥着不可替代的作用。大量研究发现,PLK4在人类大部分肿瘤中均存在异常表达,如肝癌、胃癌、肺癌、乳腺癌、黑色素瘤和恶性血液病等。目前,尚未有PLK4抑制剂上市,迄今已报道的PLK4抑制剂仅有两类母核结构。其中一类结构的代表性抑制剂LCR-263对PLK4具有纳摩尔激酶活性且具有高选择性,但其至今未进入临床前研究;另一类结构的代表性抑制剂CFI-400945已进入临床二期研究,但其对TRKA、Aurora A/B缺乏选择性。因此,找到高效、高选择性且具有良好体内性质的新型PLK4抑制剂具有重大科学价值和研究意义。
发明内容
本发明的目的在于提供一种高选择性的PLK4抑制剂及其制备方法和作为PLK4抑制剂中的应用。
为实现上述目的,本发明采用技术方案为:
一种高选择性的PLK4抑制剂,抑制剂为通式I所示吡唑并嘧啶衍生物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,X选自C或N;
Y选自C或N;
Z选自氢、卤素;
R1选自氢、C1-C4烷基;
R2选自氢、C1-C4烷基;
R3选自氢、C1-C4烷基、C3-C6环烷基;
R4选自氢、C1-C6烷基、含最多2个杂原子的C4-C7脂肪环,其中,杂原子为N、O或S;当杂原子为S时,硫原子还可进一步氧化成亚砜或砜;杂原子为N时,氮原子还可进一步被C1-C4烷基或C1-C4烷酰基或C1-C4烷磺酰基取代;
A环选自未取代或被1-3个可相同或不同的Ra取代的芳基;
Ra选自卤素、C1-C4烷基、C1-C6烷氧基。
优选,所述通式I所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,X选自C或N;
Y选自C或N;
Z选自氢、卤素;
R1选自氢;
R2选自氢、甲基;
R3选自氢、甲基、乙基、环丙基;
R4选自氢、甲基、异丙基、含最多2个杂原子的C4-C7脂肪环,其中,杂原子为N、O或S;当杂原子为S时,硫原子还可进一步氧化成亚砜或砜;杂原子为N时,氮原子还可进一步被C1-C4烷基或C1-C4烷酰基或C1-C4烷磺酰基取代;
A环选自含或不含1-3个可相同或不同的Ra取代的苯基,吡啶基,嘧啶基;
Ra选自氟、氯、溴、甲基、甲氧基。
进一步优选,所述通式I所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,X选自C或N;
Y选自C或N;
Z选自氯;
R1选自氢;
R2选自氢、甲基;
R3选自氢、甲基、乙基、环丙基;
R4选自氢、甲基、异丙基、含最多2个杂原子的C4-C7脂肪环,其中,杂原子为N、O或S;当杂原子为S时,硫原子还可进一步氧化成砜;杂原子为N时,氮原子还可进一步被乙酰基、甲磺酰基取代;
A环选自苯基、2-氟苯基、2-氯苯基、2-溴苯基、2,5-二氟苯基、3,5-二氟苯基、3,4,5-三氟苯基、3-甲氧基苯基、3-甲基苯基。
再进一步优选,所述通式I所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,X选自C或N;
Y选自C或N;
Z选自氯;
R1选自氢;
R2选自氢、甲基;
R3选自氢、甲基、乙基、环丙基;
R4选自氢、甲基、异丙基、
A环选自苯基、2-氟苯基、2-氯苯基、2-溴苯基、2,5-二氟苯基、3,5-二氟苯基、3,4,5-三氟苯基、3-甲氧基苯基、3-甲基苯基。
更进一步,所述化合物为:
2-氯-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-苯基苯甲酰胺;
2-氯-N-(2-氟苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2-氯苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2-溴苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(3,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-(3,4,5-三氟苯基)苯甲酰胺;
2-氯-N-(3-甲氧基苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-(间甲苯基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-((1-甲基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
5-((1-(1-乙酰基哌啶-4-基)-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-2-氯-N-(2,5-二氟苯基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(1-(甲磺酰基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-((1-(1,1-二氧代四氢-2H-噻喃-4-基)-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-(1-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)乙基)苯甲酰胺;
5-氯-N-(2,5-二氟苯基)-2-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)异烟酰胺;
2-氯-N-(2,5-二氟苯基)-5-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)烟酰胺;
2-氯-N-(2,5-二氟苯基)-5-(((4-((5-乙基-1H-吡唑-3-基)氨基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-5-((4-((5-环丙基-1H-吡唑-3-基)氨基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-(2,5-二氟苯基)苯甲酰胺。
上面给出的通式I化合物的定义中,汇集所用术语一般定义如下:
卤素:指氟、氯、溴或碘。烷基:直链或支链烷基,例如甲基、乙基、丙基、异丙基、正丁基或叔丁基。环烷基:取代或未取代的环状烷基,例如环丙基、环戊基或环己基;取代基如甲基、卤素等。烷氧基:直链或支链烷基,羟基的氢原子可被这些直链或支链烷基所取代,例如,甲基氧基,乙基氧基,丙基氧基,异丙基氧基等。含1-2个杂原子的脂肪环,如N、O、S的环状烷基,如四氢呋喃基,哌啶基,
上述通式I所示衍生物的制备方法,所述通式I所示衍生物得到制备反应如下:
起始原料1与相应的芳胺缩合得到中间体2,中间体2再与NBS发生自由基反应得到中间体3;中间体4与不同取代基的肼扣环得到中间体5,接着再通过与不同取代基的氨基吡唑取代得到中间体6。中间体3与中间体6再进行取代反应即可得到目标化合物7。根据上述通式方法亦可制备具有类似结构的目标化合物。
进一步的说,以化合物1为起始原料,在高温下与二氯亚砜进行氯代,再与相应的芳胺得到中间体2,高温反应温度为60~100℃,优选80℃反应溶剂可为二甲基亚砜,二氯甲烷,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选N,N-二甲基甲酰胺;中间体2在高温下,与自由基引发剂、NBS反应得到中间体3,反应溶剂可为二氯甲烷、三氯甲烷、四氯甲烷、苯、1,2-二氯甲烷,优选三氯甲烷,反应温度为50~90℃,优选60℃;中间体4在低温碱性条件下,与不同取代基的肼扣环得到中间体5,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选乙醇,反应温度为-78~0℃,优选-78℃,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选三乙胺;中间体5在碱性条件下,经过取代反应得到中间体6,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选N,N-二甲基甲酰胺,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选N,N-二异丙基乙胺,反应温度为40~80℃,优选65℃;中间体6在高温碱性条件下,与中间体3发生取代反应得到中间体7,反应溶剂可为甲醇,乙醇,异丙醇,正丙醇,叔丁醇,仲丁醇,正丁醇,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选异丙醇,反应温度为100~160℃,优选135℃,反应中的碱可为三乙胺,N,N-二异丙基乙胺,碳酸铯,碳酸钾,碳酸钠,碳酸氢钠等,优选三乙胺;
吡唑并嘧啶衍生物的应用,所述通式I所示的化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
所述通式I所示的化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或抗肿瘤药物中的应用。
一种药用组合物,包含通式I所示的化合物及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
所述组合物在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
所述组合物在制备预防或抗肿瘤药物中的应用。
本发明所具有的优点:
本发明着眼于中心体异常引发的肿瘤,设计具有通式I所示结构的化合物,并发现具有此类结构的化合物表现出良好的PLK4抑制活性,同时也表现出了良好的激酶选择性。
本发明通式I所示结构的化合物,不限定于其具体同分异构体,且对PLK4均表现出较好抑制活性,用以治疗PLK4表达异常相关的其它疾病。
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用BrukerARX-400测定;所用试剂均为分析纯或化学纯。
具体实施例结构如下:
实施例1的制备路线如下所示:
具体合成步骤如下:2-氯-5-甲基-N-苯甲酰胺(2)的合成
将原料1(3.00g,17.65mmol)溶于40mL二氯亚砜中,置于80℃下回流4h。后旋除多余的二氯亚砜,将其用DMF溶解,缓慢滴入苯胺(1.65g,17.65mmol)的DMF溶液中室温反应5h。TLC监测(PE:EA=2:1)原料反应完全,加100mL水,再用乙酸乙酯萃取三次(每次30mL),合并有机层,用饱和食盐水洗、无水硫酸钠干燥后滤除硫酸钠,旋除溶剂,柱层析纯化(PE:EA=4:1),得白色固体,收率77%。
5-(溴甲基)-2-氯-N-苯基苯甲酰胺(3)的合成
将中间体2(2.00g,8.16mmol)溶于40mL三氯甲烷中,置于60℃下加入AIBN(0.82mmol),NBS(1.45g,8.16mmol)。TLC监测(PE:EA=2:1)原料反应完全,旋除溶剂,柱层析纯化(PE:EA=4:1),得白色固体,收率63%。4,6-二氯-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶(5)的合成
将(四氢-2H-吡喃-4-基)肼盐酸盐(1.00g,6.58mmol)溶于15.0mL乙醇中,置于-78℃低温下,再缓慢滴入中间体2(1.38g,6.58mmol)的乙醇溶液15.0mL,再加入三乙胺4.58mL,继续-78℃反应30min,随后移至室温反应1h。TLC监测(PE:EA=4:1)原料反应完全,旋除溶剂,柱层析纯化(PE:EA=10:1),得白色固体,收率85%。
6-氯-N-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(6)的合成
将中间体5(0.50g,1.84mmol)溶于5mL DMF中,再依次5-甲基-1H-吡唑-3-胺(0.18g,1.84mmol)、N,N-二异丙基乙胺(0.425mL,2.40mmol)、碘化钾(0.37g,2.21mmol),后65℃反应1h。TLC检测(DCM:MeOH=15:1),原料反应完全,待反应冷却至室温,加入水50mL,析出白色沉淀,抽滤,得到白色固体,产率88%。
2-氯-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-苯基苯甲酰胺(实施例1)的制备将中间体6(0.08g,0.24mmol)溶于1.5mL异丙醇中,再加入中间体3(0.094g,0.29mmol)、三乙胺0.10mL,后在封管下加热至135℃反应15h。TLC监测(DCM:MeOH=10:1)原料反应完毕,待反应冷却至室温,旋干溶剂,经柱层析(DCM:MeOH=40:1)得白色固体,产率51%。1H NMR(600MHz,DMSO-d6)δ11.94(s,1H),10.41(s,1H),10.12(s,1H),7.97(s,1H),7.66–7.51(m,4H),7.43(t,J=10.2Hz,2H),7.27(t,J=7.8Hz,2H),7.03(t,J=7.3Hz,1H),4.57(t,J=11.4Hz,1H),4.45(s,2H),3.80(s,2H),3.36(t,J=11.3Hz,2H),2.13(s,3H),2.01(d,J=9.3Hz,2H),1.68(d,J=9.6Hz,2H).13CNMR(151MHz,DMSO-d6)δ165.5,161.0,155.2,153.8,140.7,139.3,137.0,131.9,131.6,131.1,130.2,129.7,129.3,129.2(2C),128.2,124.2,119.9(2C),97.4,96.4,66.7(2C),52.6,44.1,32.2(2C),11.7.
实施例2 2-氯-N-(2-氟苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备
参考制备实施例1的方法,将a步骤中苯胺原料等比例替换为2-氟苯胺,即得实施例2.1H NMR(600MHz,CD3OD)δ7.92(t,J=7.7Hz,1H),7.83(s,1H),7.70(s,1H),7.51(d,J=8.3Hz,1H),7.43(d,J=8.3Hz,1H),7.23–7.16(m,3H),6.14(s,1H),4.71(q,J=9.1,6.7Hz,1H),4.64(s,2H),4.03–3.97(m,2H),3.55(t,J=11.9Hz,2H),2.27–2.18(m,5H),1.80(d,J=12.8Hz,2H).13C NMR(151MHz,CD3OD)δ167.1,160.8,155.0,154.9(d,J=241.6Hz),140.1,135.8,135.7,131.5,130.2,129.6,128.8,128.0,126.4,126.3,125.2(d,J=12.1Hz),124.8,124.0,123.8,115.3(d,J=19.8Hz),101.1,96.0,66.8(2C),53.0,43.9,31.5(2C),10.4.
实施例3 2-氯-N-(2-氯苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备参考制备实施例1的方法,将a步骤中苯胺原料等比例替换为2-氯苯胺,即得实施例3.1H NMR(600MHz,DMSO-d6)δ11.99(s,1H),10.16(s,2H),8.05(s,1H),7.65(d,J=6.7Hz,2H),7.60–7.48(m,4H),7.38(t,J=7.4Hz,1H),7.27(t,J=7.3Hz,1H),4.63(t,J=11.2Hz,1H),4.56(s,2H),3.99–3.94(m,2H),3.47(t,J=11.5Hz,2H),2.23(s,3H),2.10(dt,J=11.6,8.3Hz,2H),1.77(d,J=10.9Hz,2H).13C NMR(151MHz,DMSO-d6)δ165.8,161.0,155.3,153.9,148.3,140.8,138.4,136.4,135.9,134.9,132.3,131.1,130.1,129.8,128.8,128.4,128.1,127.9,127.8,97.3,96.4,66.7(2C),52.8,44.1,32.2(2C),11.3.
实施例4 2-氯-N-(2-溴苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备参考制备实施例1的方法,将a步骤中苯胺原料等比例替换为2-溴苯胺,即得实施例4.1H NMR(600MHz,CD3OD)δ7.84–7.73(m,3H),7.64(d,J=7.9Hz,1H),7.53(d,J=7.8Hz,1H),7.47(d,J=8.2Hz,1H),7.40(t,J=7.6Hz,1H),7.18(t,J=7.5Hz,1H),6.14(s,1H),4.74–4.66(m,3H),4.03(d,J=8.2Hz,2H),3.56(t,J=11.8Hz,2H),2.29–2.20(m,5H),1.81(d,J=12.3Hz,2H).13C NMR(101MHz,CD3OD)δ163.7,160.5,160.1,157.3,141.4,140.1,136.7,136.4,135.5,133.7,132.6,131.6,130.8,129.7,128.8,128.2,127.7,127.5,120.0,92.7,89.8,66.8(2C),53.1,43.9,31.6(2C),11.4.
实施例5 2-氯-N-(2,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备参考制备实施例1的方法,将a步骤中苯胺原料等比例替换为2,5-二氟苯胺,即得实施例5.1H NMR(600MHz,CD3OD)δ7.92(s,1H),7.84(s,1H),7.70(s,1H),7.54(d,J=8.0Hz,1H),7.46(d,J=8.3Hz,1H),7.19(td,J=9.7,4.8Hz,1H),6.93(ddd,J=11.7,8.4,3.2Hz,1H),6.12(s,1H),4.75–4.71(m,1H),4.66(s,2H),4.03(d,J=8.2Hz,2H),3.57(t,J=11.4Hz,2H),2.28–2.22(m,5H),1.82(d,J=10.9Hz,2H).13C NMR(151MHz,CD3OD)δ166.9,159.6,158.3(d,J=240.9Hz),154.6,151.4,150.3(d,J=243.9Hz),139.8,139.7,135.7,135.6,131.8,130.4,129.6,128.9,128.0,126.6(dd,J=15.2,10.1Hz),115.9(dd,J=22.5,9.9Hz),111.6(dd,J=24.6,7.4Hz),110.5(d,J=28.8Hz),95.7(2C),66.7(2C),53.2,43.9,31.5(2C),10.2.
实施例6 2-氯-N-(3,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备参考制备实施例1的方法,将a步骤中苯胺原料等比例替换为3,5-二氟苯胺,即得实施例6.1H NMR(600MHz,CD3OD)δ7.79(s,1H),7.66(s,1H),7.53(d,J=8.2Hz,1H),7.44(d,J=8.3Hz,1H),7.34–7.31(m,2H),6.73–6.69(m,1H),6.15(s,1H),4.71(dd,J=10.0,5.8Hz,1H),4.64(s,2H),4.02(d,J=8.5Hz,2H),3.56(t,J=11.4Hz,2H),2.27–2.21(m,5H),1.80(d,J=11.2Hz,2H).13C NMR(151MHz,CD3OD)δ166.9,163.26(d,J=244.5Hz,2C),160.2,154.9,141.0,140.9,140.8,140.0,135.9,131.6,130.4,129.5,128.6,127.8,124.9,102.5(d,J=30.2Hz,2C),98.8(t,J=26.2Hz),95.9,95.7,66.8(2C),53.1,43.9,31.5(2C),10.4.
实施例7 2-氯-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-(3,4,5-三氟苯基)苯甲酰胺的制备参考制备实施例1的方法,将a步骤中苯胺原料等比例替换为3,4,5-三氟苯胺,即得实施例7.1H NMR(600MHz,DMSO-d6)δ12.02(s,1H),10.87(s,1H),10.20(s,1H),8.04(s,1H),7.61–7.56(m,4H),7.52(d,J=7.8Hz,1H),4.65–4.60(m,1H),4.53(s,2H),3.91(s,2H),3.45(t,J=11.5Hz,2H),2.20(s,3H),2.09(dt,J=11.9,8.0Hz,2H),1.75(d,J=10.1Hz,2H).13C NMR(151MHz,DMSO-d6)δ166.0,160.9,155.2,153.8,150.57(ddd,J=244.5,10.0,5.4Hz,2C),141.0,136.2,135.5(td,J=11.2,2.4Hz),135.4(ddd,J=245.8,31.6,15.9Hz),134.7,132.3,131.6,130.1,129.9,128.9,128.1,104.2(d,J=25.2Hz,2C),96.4(2C),66.7(2C),52.7,44.1,32.2(2C),11.3.
实施例8 2-氯-N-(3-甲氧基苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备参考制备实施例1的方法,将a步骤中苯胺原料等比例替换为3-甲氧基苯胺,即得实施例8.1H NMR(600MHz,DMSO-d6)δ12.05(s,1H),10.47(s,1H),10.34(s,1H),8.06(s,1H),7.88–7.65(m,2H),7.53–7.48(m,2H),7.39(s,1H),7.24(d,J=4.8Hz,2H),6.69(dd,J=6.9,4.3Hz,1H),4.64(t,J=11.4Hz,1H),4.53(s,2H),3.87(s,2H),3.73(s,3H),3.44(t,J=11.7Hz,2H),2.21(s,3H),2.07(d,J=9.5Hz,2H),1.76(d,J=10.0Hz,2H).13C NMR(151MHz,DMSO-d6)δ165.5,160.7,159.9,154.9,147.7,141.2,140.5,139.7,138.4,137.0,132.4,130.0,129.7,129.2,128.4,128.2,112.2,109.6,105.7,97.0,96.2,66.6(2C),55.4,52.6,44.1,32.2(2C),11.7.
实施例9 2-氯-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-(间甲苯基)苯甲酰胺的制备参考制备实施例1的方法,将a步骤中苯胺原料等比例替换为3-甲基苯胺,即得实施例9.1H NMR(600MHz,DMSO-d6)δ12.05(s,1H),10.41–10.27(m,2H),8.07(s,1H),7.64(s,2H),7.55–7.49(m,3H),7.45(d,J=7.5Hz,1H),7.21(t,J=7.4Hz,1H),6.92(d,J=6.9Hz,1H),4.64(s,1H),4.52(s,2H),3.87(s,2H),3.44(s,2H),2.29(s,3H),2.20(s,3H),2.08(d,J=9.6Hz,2H),1.76(s,2H).13C NMR(151MHz,DMSO-d6)δ165.5,160.9,155.1,153.7,143.7,140.6,139.3,138.4,137.1,136.2,132.4,131.1,129.9,129.3,128.9,128.2,124.9,120.4,117.1,96.9,96.3,66.7(2C),52.6,44.0,32.2(2C),21.7,11.3.
实施例10 2-氯-N-(2,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备参考制备实施例5的方法,将c步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为水合肼,即得实施例10.1H NMR(600MHz,DMSO-d6)δ10.55(s,1H),10.21(s,1H),8.05(s,1H),7.77(s,1H),7.56(s,1H),7.48(d,J=5.8Hz,2H),7.36–7.32(m,1H),7.10–7.05(m,1H),4.57(s,2H),2.21(s,3H).13C NMR(151MHz,DMSO-d6)δ166.0,161.3,158.8,158.0(d,J=239.9Hz),153.7,150.8(d,J=242.6Hz),140.7,136.2,133.3,131.1,130.5,130.2,130.0,128.3,127.9,127.16(dd,J=13.8,11.8Hz),117.2(dd,J=22.2,9.8Hz),112.6(dd,J=24.5,7.5Hz),111.6(d,J=27.3Hz),95.8,85.8,43.7,11.4.
实施例11 2-氯-N-(2,5-二氟苯基)-5-((1-甲基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备参考制备实施例5的方法,将c步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为甲基肼硫酸盐,即得实施例11.1H NMR(600MHz,DMSO-d6)δ11.99(s,1H),10.54(s,1H),10.14(s,1H),8.03(s,1H),7.76(s,1H),7.61(s,1H),7.55(s,1H),7.50(s,2H),7.34(dd,J=14.0,9.3Hz,1H),7.08(d,J=8.0Hz,1H),4.58(s,2H),3.72(s,3H),2.20(s,3H).13C NMR(151MHz,DMSO-d6)δ166.1,161.4,158.0(d,J=239.0Hz),155.9,153.9,150.8(d,J=243.6Hz),148.3,140.8,138.4,136.1,132.3,130.9,129.8,128.8,128.3,127.1(dd,J=14.2,11.6Hz),117.2(dd,J=22.2,9.7Hz),112.6(dd,J=24.0,7.5Hz),111.7(d,J=27.9Hz),97.5,96.1,43.9,33.3,11.2.
实施例12 2-氯-N-(2,5-二氟苯基)-5-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备参考制备实施例5的方法,将c步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为异丙基肼盐酸盐,即得实施例12.1H NMR(600MHz,DMSO-d6)δ11.98(s,1H),10.53(s,1H),10.08(s,1H),8.03(s,1H),7.76(s,1H),7.63(s,1H),7.49(s,3H),7.34(dd,J=14.3,9.3Hz,1H),7.07(t,J=8.2Hz,1H),4.82–4.76(m,1H),4.55(s,2H),2.20(s,3H),1.37(d,J=6.3Hz,6H).13C NMR(151MHz,DMSO-d6)δ166.0,161.1,158.0(d,J=239.1Hz),154.9,150.8(d,J=242.5Hz),148.4,140.7,138.3,136.1,135.8,132.2,131.0,129.7,128.9,128.3,127.1(dd,J=13.9,11.9Hz),117.2(dd,J=22.2,9.7Hz),112.5(dd,J=24.1,7.0Hz),111.6(d,J=28.5Hz),97.6,96.4,47.8,43.9,22.1(2C),11.2.
实施例13 5-((1-(1-乙酰基哌啶-4-基)-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-2-氯-N-(2,5-二氟苯基)苯甲酰胺的制备参考制备实施例5的方法,将c步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为1-(4-肼基哌啶-1-基)乙酮二盐酸盐,即得实施例13.1H NMR(600MHz,CD3OD)δ7.92(s,1H),7.83(s,1H),7.70(s,1H),7.52(d,J=8.0Hz,1H),7.45(d,J=8.3Hz,1H),7.21–7.17(m,1H),6.93(t,J=8.3Hz,1H),6.15(s,1H),4.78–4.73(m,1H),4.65–4.60(m,2H),4.00(d,J=12.3Hz,1H),3.30–3.20(m,2H),2.82(t,J=11.9Hz,1H),2.26(s,3H),2.12–2.03(m,5H),1.97–1.90(m,2H).13C NMR(101MHz,CD3OD)δ170.1,166.9,164.9,158.3(d,J=240.1Hz),155.1,153.4,150.3(d,J=242.7Hz),142.7,140.0,137.4,135.5,131.7,131.6,130.4,129.5,128.8,128.1(dd,J=18.4,9.0Hz),115.9(dd,J=22.5,9.6Hz),111.5(dd,J=24.4,8.2Hz),110.5(d,J=27.5Hz),96.3,95.9,53.5,45.3,43.9,40.6,31.0,30.2,19.8,10.4.
实施例14 2-氯-N-(2,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨
基)-1-(1-(甲磺酰基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备
参考制备实施例5的方法,将c步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为4-肼基-1-(甲磺酰基)哌啶,即得实施例14.1H NMR(600MHz,CD3OD)δ7.93–7.90(m,1H),7.79(s,1H),7.70(s,1H),7.53(d,J=7.9Hz,1H),7.46(d,J=8.3Hz,1H),7.19(td,J=9.7,4.9Hz,1H),6.95–6.91(m,1H),6.17(s,1H),4.62–4.56(m,3H),3.81(d,J=11.3Hz,2H),2.95(td,J=12.2,10.3Hz,2H),2.85(s,3H),2.31–2.25(m,5H),1.96(d,J=11.5Hz,2H).13C NMR(151MHz,CD3OD)δ167.0,164.2,161.0,158.3(d,J=240.0Hz),155.2,154.5,150.3(d,J=241.4Hz),140.2,140.0,135.5,131.6,130.5,129.5,128.7,128.1,126.6(dd,J=12.7,11.8Hz),115.9(dd,J=22.5,9.6Hz),111.5(dd,J=24.2,6.9Hz),110.5(d,J=29.0Hz),96.1(2C),53.3,45.1(2C),44.9,43.9,30.3(2C),10.4.
实施例15 2-氯-N-(2,5-二氟苯基)-5-((1-(1,1-二氧代四氢-2H-噻喃-4-
基)-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备
参考制备实施例5的方法,将c步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为(1,1-二氧硫代-4-基)肼盐酸盐,即得实施例15.1H NMR(600MHz,DMSO-d6)δ12.02(s,1H),10.54(s,1H),10.15(s,1H),8.09(s,1H),7.78(s,1H),7.69(s,1H),7.61(s,1H),7.49(d,J=7.8Hz,1H),7.34(td,J=9.6,5.1Hz,1H),7.08(t,J=8.4Hz,1H),4.84(s,1H),4.53(s,2H),3.44(t,J=11.5Hz,2H),3.22–3.14(m,2H),2.62–2.55(m,2H),2.22–2.16(m,5H).13C NMR(151MHz,DMSO-d6)δ166.1,164.2,161.0,158.0(d,J=239.7Hz),155.3,153.9,150.8(d,J=242.3Hz),140.7,138.4,136.2,132.8,131.5,129.7,129.2,128.3,127.1(dd,J=13.9,11.8Hz),117.2(dd,J=22.2,9.7Hz),112.6(dd,J=24.3,7.4Hz),111.5(d,J=28.2Hz),97.4,96.4,51.4,49.4(2C),44.0,29.5(2C),11.2.
实施例16 2-氯-N-(2,5-二氟苯基)-5-(1-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)乙基)苯甲酰胺的制备参考制备实施例12的方法,将a步骤中原料1等比例替换为2-氯-5-乙基苯甲酸,即得实施例16.1H NMR(600MHz,DMSO-d6)δ12.00(s,1H),10.54(s,1H),10.14(s,1H),7.98(s,1H),7.77(s,1H),7.68(s,1H),7.58(s,1H),7.48(d,J=8.2Hz,2H),7.34(dd,J=14.2,9.4Hz,1H),7.08(d,J=7.9Hz,1H),5.17(s,1H),4.78(s,1H),2.22(s,3H),1.51–1.31(m,9H).13C NMR(151MHz,DMSO-d6)δ166.1,160.1,158.0(d,J=238.9Hz),154.8,153.8,150.8(d,J=242.6Hz),145.8,138.6,136.1,131.8,129.9,129.6,128.2,127.7,127.2(dd,J=14.0,11.9Hz),117.2(dd,J=22.2,9.7Hz),112.6(dd,J=24.0,7.1Hz),111.6(d,J=27.8Hz),97.4,96.2,49.6,48.0,24.1,22.0,11.7.
实施例17 5-氯-N-(2,5-二氟苯基)-2-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)异烟酰胺的制备参考制备实施例12的方法,将a步骤中原料1等比例替换为5-氯-2-甲基异烟酸,即得实施例17.1H NMR(600MHz,DMSO-d6)δ12.00(s,1H),10.68(s,1H),9.12(s,1H),8.35(s,1H),8.07(s,2H),7.82–7.80(m,1H),7.50(s,1H),7.35–7.31(m,1H),7.10–7.04(m,1H),4.80(s,1H),4.52(s,2H),2.20(s,3H),1.35(d,J=6.6Hz,6H).
实施例18 2-氯-N-(2,5-二氟苯基)-5-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)烟酰胺的制备参考制备实施例12的方法,将a步骤中原料1等比例替换为2-氯-5-甲基烟酸,即得实施例18.1H NMR(600MHz,DMSO-d6)δ12.01(s,1H),10.72(s,1H),10.11(s,1H),8.55(s,1H),8.07(s,2H),7.84–7.81(m,1H),7.52(s,1H),7.37–7.33(m,1H),7.11–7.06(m,1H),4.81(s,1H),4.55(s,2H),2.21(s,3H),1.37(d,J=6.6Hz,6H).
实施例19 2-氯-N-(2,5-二氟苯基)-5-(((4-((5-乙基-1H-吡唑-3-基)氨基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺的制备参考制备实施例12的方法,将d步骤中原料5-甲基-1H-吡唑-3-胺等比例替换为5-乙基-1H-吡唑-3-胺,即得实施例19.1H NMR(600MHz,DMSO-d6)δ12.05(s,1H),10.54(s,1H),10.22(s,1H),8.04(s,1H),7.77(s,1H),7.64(s,1H),7.50(t,J=9.6Hz,3H),7.36–7.32(m,1H),7.07(t,J=8.4Hz,1H),4.81(dt,J=13.2,6.6Hz,1H),4.57(s,2H),2.67–2.57(m,2H),1.38(d,J=6.6Hz,6H),1.22(t,J=7.6Hz,3H).13C NMR(151MHz,DMSO-d6)δ166.0,161.1,158.0(d,J=238.6Hz),154.9,153.8,150.8(d,J=242.5Hz),145.3,140.6,136.1,132.7,132.1,131.1,129.8,128.9,128.4,127.2(dd,J=14.3,11.6Hz),117.2(dd,J=22.3,9.9Hz),112.5(dd,J=24.1,7.4Hz),111.6(d,J=27.9Hz),96.4,95.9,47.8,44.0,22.3,22.1(2C),11.7.
实施例20 2-氯-5-((4-((5-环丙基-1H-吡唑-3-基)氨基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-(2,5-二氟苯基)苯甲酰胺的制备参考制备实施例12的方法,将d步骤中原料5-甲基-1H-吡唑-3-胺等比例替换为5-环丙基-1H-吡唑-3-胺,即得实施例20.1H NMR(600MHz,DMSO-d6δ12.07(s,1H),10.54(s,1H),10.20(s,1H),8.03(s,1H),7.77(s,1H),7.65(s,1H),7.50(d,J=7.4Hz,3H),7.37–7.32(m,1H),7.08(t,J=8.4Hz,1H),6.50(s,1H),4.81(dt,J=13.1,6.4Hz,1H),4.58(s,2H),1.99–1.92(m,1H),1.38(d,J=6.6Hz,6H),1.01–0.92(m,4H).13C NMR(151MHz,DMSO-d6)δ164.9,156.9(d,J=239.8Hz),156.2,152.8,152.2,149.7(d,J=243.2Hz),146.2,139.6,135.1,131.7,131.0,130.1,128.7,127.8,127.4,126.1(dd,J=14.1,11.8Hz),116.1(dd,J=22.4,9.9Hz),111.5(dd,J=24.1,7.6Hz),110.5(d,J=28.1Hz),95.3,93.7,46.7,42.8,21.2(2C),7.1(2C),6.2.
实施例21:本发明部分产物的体外酶抑制活性研究
实验材料:
Tecan F500酶标仪。
Eu Kinase Binding Assay试剂盒(包含Kinase Tracer236、Eu-Anti-GST Antibody、激酶缓冲溶液(1X Kinase Buffer A)),384浅孔板,重组人PLK4蛋白(aa 1-836,含一个GST tag)。/>
重组人PLK4蛋白激酶浓度50ng/μL(Thermo Scientific:PV6395),蒸馏水,DMSO。
实验方法:
首先将上述实施例制备化合物样品用DMSO配成20mM的溶液,之后根据测试需要,再用激酶缓冲溶液(1X Kinase Buffer A))稀释成200μM、40μM、10μM、1.6μM、0.32μM、0.064μM、0.0128μM、0.00256μM、0.000512、0.0001024μM;后向384孔板加入化合物样品(4μL),再加入将8μL含重组人PLK4激酶(浓度为50ng/μL)和Eu-Anti-GST Antibody的激酶缓冲溶液、4μL含Tracer 236的激酶缓冲溶液,后在室温下孵育60分钟,读板。
结果评定方法:通过添加Eu标记抗体检测激酶“示踪剂”结合。示踪剂和抗体与激酶的结合导致高度的FRET,反之使用激酶抑制因子代替示踪剂会造成FRET丢失。铕供体由一个带30nm光栅的340nm激发滤镜激发,使用中心在665纳米处、带通为10纳米的滤光片,以检测转移至Alexa Fluor 647示踪剂的能量。然后这一信号被替代为铕的峰值激发,这是使用一个615nm,10nm光栅的滤镜完成的。使用665纳米信号除以615纳米信号来计算“发射比”。所以每一个孔板反应的HTRF信号(665/615)比值被计算。结果被表征为Delta F(DF%):
计算抑制率(%activity):在不加化合物样品的情况下,激酶活性的DF%被定义为100%。当加入化合物样品后,激酶活性率:
计算IC50:在加入化合物的情况下,激酶活性的DF%被绘制成Y-轴,化合物的浓度对数值被绘制成X-轴。IC50值是通过数据拟合成S-型计量反应曲线获得。实验采用centrinone作为阳性对照,测试centrinone的IC50值为3.0nM。
表1部分实施例化合物得IC50值
实施例 | IC50(nM) | 实施例 | IC50(nM) |
实施例1 | 5.4 | 实施例2 | 9.3 |
实施例3 | 19.5 | 实施例5 | 0.91 |
实施例6 | 3.7 | 实施例8 | 9.7 |
实施例9 | 51.4 | 实施例10 | 0.32 |
实施例11 | 1.24 | 实施例12 | 2.57 |
实施例13 | 0.31 | 实施例14 | 0.99 |
实施例15 | 0.41 | 实施例16 | 8.6 |
实施例17 | 18.2 | 实施例18 | 32.8 |
实施例19 | 19.9 |
由表1可知,表中化合物对PLK4均表现出强效的抑制活性。其中化合物5、10、11、12、13、14、15的抑制活性优于阳性化合物。进一步选择化合物12进行激酶选择性试验。
实施例22:本发明实施例12的激酶选择性
表2实施例12在0.5μM浓度下的激酶选择性
由表2可见,化合物12在0.5μM浓度下,对以上68个激酶的抑制率均低于50%。这表明化合物12具有一定的体外激酶选择性。
Claims (9)
1.一种高选择性的PLK4抑制剂,其特征在于:抑制剂为通式I所示吡唑并嘧啶衍生物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,X选自C或N;
Y选自C或N;
Z选自氢、卤素;
R1选自氢、C1-C4烷基;
R2选自氢、C1-C4烷基;
R3选自氢、C1-C4烷基、C3-C6环烷基;
R4选自氢、C1-C6烷基、含最多2个杂原子的C4-C7脂肪环,其中,杂原子为N、O或S;当杂原子为S时,硫原子还可进一步氧化成亚砜或砜;杂原子为N时,氮原子还可进一步被C1-C4烷基或C1-C4烷酰基或C1-C4烷磺酰基取代;
A环选自未取代或被1-3个可相同或不同的Ra取代的芳基;
Ra选自卤素、C1-C4烷基、C1-C6烷氧基。
2.按权利要求1所述的高选择性的PLK4抑制剂,其特征在于:所述通式I所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,X选自C或N;
Y选自C或N;
Z选自氢、卤素;
R1选自氢;
R2选自氢、甲基;
R3选自氢、甲基、乙基、环丙基;
R4选自氢、甲基、异丙基、含最多2个杂原子的C4-C7脂肪环,其中,杂原子为N、O或S;当杂原子为S时,硫原子还可进一步氧化成亚砜或砜;杂原子为N时,氮原子还可进一步被C1-C4烷基或C1-C4烷酰基或C1-C4烷磺酰基取代;
A环选自含或不含1-3个可相同或不同的Ra取代的苯基,吡啶基,嘧啶基;
Ra选自氟、氯、溴、甲基、甲氧基。
3.按权利要求2所述的高选择性的PLK4抑制剂,其特征在于:所述通式I所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,X选自C或N;
Y选自C或N;
Z选自氯;
R1选自氢;
R2选自氢、甲基;
R3选自氢、甲基、乙基、环丙基;
R4选自氢、甲基、异丙基、含最多2个杂原子的C4-C7脂肪环,其中,杂原子为N、O或S;当杂原子为S时,硫原子还可进一步氧化成砜;杂原子为N时,氮原子还可进一步被乙酰基、甲磺酰基取代;
A环选自苯基、2-氟苯基、2-氯苯基、2-溴苯基、2,5-二氟苯基、3,5-二氟苯基、3,4,5-三氟苯基、3-甲氧基苯基、3-甲基苯基。
4.按权利要求3所述的高选择性的PLK4抑制剂,其特征在于:所述通式I所示的化合物,及其几何异构体,对映异构体或其药学上可接受的盐;
其中,X选自C或N;
Y选自C或N;
Z选自氯;
R1选自氢;
R2选自氢、甲基;
R3选自氢、甲基、乙基、环丙基;
R4选自氢、甲基、异丙基、
A环选自苯基、2-氟苯基、2-氯苯基、2-溴苯基、2,5-二氟苯基、3,5-二氟苯基、3,4,5-三氟苯基、3-甲氧基苯基、3-甲基苯基。
5.按权利要求4所述的高选择性的PLK4抑制剂,其特征在于:所述衍生物为:
2-氯-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-苯基苯甲酰胺;
2-氯-N-(2-氟苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2-氯苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2-溴苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(3,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-(3,4,5-三氟苯基)苯甲酰胺;
2-氯-N-(3-甲氧基苯基)-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-5-((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-(间甲苯基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-((1-甲基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
5-((1-(1-乙酰基哌啶-4-基)-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并
[3,4-d]嘧啶-6-基)氨基)甲基)-2-氯-N-(2,5-二氟苯基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-(((4-((5-甲基-1H-吡唑-3-基)氨基)-1-(1-(甲磺酰基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-((1-(1,1-二氧代四氢-2H-噻喃-4-基)-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-N-(2,5-二氟苯基)-5-(1-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)乙基)苯甲酰胺;
5-氯-N-(2,5-二氟苯基)-2-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)异烟酰胺;
2-氯-N-(2,5-二氟苯基)-5-((1-异丙基-4-((5-甲基-1H-吡唑-3-基)氨基)-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)烟酰胺;
2-氯-N-(2,5-二氟苯基)-5-(((4-((5-乙基-1H-吡唑-3-基)氨基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)苯甲酰胺;
2-氯-5-((4-((5-环丙基-1H-吡唑-3-基)氨基)-1-异丙基-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)甲基)-N-(2,5-二氟苯基)苯甲酰胺。
6.一种药用组合物,其特征在于:包含权利要求1至6中任何一项的通式I所示的化合物及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
7.按权利要求1或6所述的应用,其特征在于:所述通式I所示的化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,或权利要求6所述药用组合物在制备PLK4抑制剂中的应用。
8.按权利要求1或6所述的应用,其特征在于:所述通式I所示的化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,或权利要求6所述药用组合物在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
9.按权利要求1或6所述的应用,其特征在于:所述通式I所示的化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,或权利要求6所述药用组合物在制备预防或抗肿瘤药物中的应用。
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