CN117050072B - 一种吡唑并吡啶衍生物及其应用 - Google Patents
一种吡唑并吡啶衍生物及其应用 Download PDFInfo
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- CN117050072B CN117050072B CN202210479694.6A CN202210479694A CN117050072B CN 117050072 B CN117050072 B CN 117050072B CN 202210479694 A CN202210479694 A CN 202210479694A CN 117050072 B CN117050072 B CN 117050072B
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- pyrazolo
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- urea
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
本发明属药物合成领域,涉及一类新型吡唑并吡啶衍生物与其类似物,及其制备方法和作为治疗剂特别是作为PLK4抑制剂的用途。如通式(I)的化合物及其几何异构体或其药学上可接受的盐和它们的制备方法。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,涉及一种新型吡唑并吡啶衍生物及其制备方法和作为治疗特别是作为PLK4抑制剂的应用。
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。因此,开发结构新颖且高效的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新型吡唑并吡啶衍生物及其制备方法和作为治疗特别是作为PLK4抑制剂的应用。
为实现上述目的,本发明采用技术方案为:
一种吡唑并吡啶衍生物,衍生物为通式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;通式I所示化合物如下:
其中,A环选自未取代或被1-4个可相同或不同的Ra取代的芳基;
B环选自C3-C7脂肪环、未取代或被1-4个可相同或不同的Ra取代的芳基;
C环选自未取代或被1-4个可相同或不同的Rb取代的芳基;
X选自O或S;
Ra选自卤素、C1-C4烷基、C1-C6卤代烷基、C1-C6烷氧基、胺基;
Rb选自选自C1-C4烷基磺酰基、无取代或被C1-C6烷基取代的氨基磺酰基、含最多2个杂原子的C4-C7脂肪环、被1-2个可相同或不同的Rc取代的亚甲基;
Rc选自含1-2个杂原子的C4-C7脂肪环;
当Rb、Rc选自含1-2个杂原子的C4-C7脂肪环时,杂原子为N、O或S;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烷基取代。
优选,所述衍生物为通式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,A环选自未取代或被1-4个可相同或不同的Ra取代的芳基;
B环选自环丙基、未取代或被1-4个可相同或不同的Ra取代的芳基;
C环选自未取代或被1-4个可相同或不同的Rb取代的芳基;
X选自O或S;
Ra选自氟、氯、溴、甲基、三氟甲基、甲氧基、胺基;
Rb选自甲基磺酰基、氨基磺酰基、含最多2个杂原子的C4-C7脂肪环、被1-2个可相同或不同的Rc取代的亚甲基;
Rc选自含N-甲基哌嗪基、吗啉基;
上述芳基为苯基、吡啶基、嘧啶基,哒嗪基;
当Rb、Rc选自含1-2个杂原子的C4-C7脂肪环时,杂原子为N、O或S;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烷基取代。
进一步优选,所述衍生物为通式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,A环选自苯基、
B环选自苯基、环丙基、对甲基苯基、间氟苯基、间氯苯基、间溴苯基、邻氟苯基、邻氯苯基、邻溴苯基、对氟苯基、对氯苯基、对溴苯基、间三氟甲基苯基、对三氟甲基苯基、间氨基苯基、对氨基苯基、间甲氧基苯基、对甲氧基苯基、2-吡啶基、3-吡啶基、4-吡啶基、3-嘧啶基、3-哒嗪基、4-哒嗪基;
C环选自未取代或被1-4个可相同或不同的Rb取代的芳基;
X选自O;
Rb选自甲磺酰基、氨基磺酰基、哌嗪基、N-甲基哌嗪基、被1-2个可相同或不同的Rc取代的亚甲基;
Rc选自N-甲基哌嗪基、吗啉基。
再进一步优选,所述衍生物为通式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,A环选自苯基、
B环选自苯基、环丙基、对甲基苯基、间氟苯基、间氯苯基、间溴苯基、邻氟苯基、邻氯苯基、邻溴苯基、对氟苯基、对氯苯基、对溴苯基、间三氟甲基苯基、对三氟甲基苯基、间氨基苯基、对氨基苯基、间甲氧基苯基、对甲氧基苯基、2-吡啶基、3-吡啶基、4-吡啶基、3-嘧啶基、3-哒嗪基、4-哒嗪基;
C环选自未取代或被1-4个可相同或不同的Rb取代的苯基;
X选自O;
Rb选自甲磺酰基、氨基磺酰基、哌嗪基、N-甲基哌嗪基、
最优选所述衍生物为:
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-苯基脲;
1-(3-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-苯基脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(3-氟苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(4-氟苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(2-氟苯基)脲;
1-(2-氯苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-氯苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(4-氯苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(2-溴苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-溴苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(4-溴苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(3-(三氟甲基)苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(4-(三氟甲基)苯基)脲;
1-(3-氨基苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(4-氨基苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-甲氧基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(4-甲氧基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(吡啶-2-基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(吡啶-3-基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(吡啶-4-基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(哒嗪-3-基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(哒嗪-4-基)脲;
1-(3-氟-5-(5-(4-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(3-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(3-(哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
3-(3-(3-氟-5-(3-(嘧啶-5-基)脲基)苯基)-1H-吡唑并[3,4-b]吡啶-5-基)苯磺酰胺;
1-(3-氟-5-(5-(4-(吗啉甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(3-(吗啉甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-环丙基-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(4-溴苯基)-3-(3-氟-5-(5-(4-(吗啉甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(对甲苯基)脲。
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。卤代烷基:直链或支链烷基,在这些烷基上的氢原子可部分或全部被卤原子所取代,例如,氯甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基等。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,哌嗪基等。
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:
以5-溴-1H-吡唑并[3,4-b]吡啶为起始原料,高温条件下与N-碘代丁二酰亚胺(NIS)发生碘代反应得到中间体2,中间体2在低温碱性条件下,与SEMCl得到中间体3。紧接着发生Suziki偶联反应得到中间体4,中间体4再进行一步Suziki反应得到中间体5,随后与相应的异氰酸酯反应得到中间体6,最后在酸性条件下脱除SEM保护基得到终产物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。
上述制备过程流程中R2为C环,A环以未取代或被至少1个Ra的苯基,R3为B环。
进一步的说,以5-溴-1H-吡唑并[3,4-b]吡啶为起始原料,高温条件下与NIS发生碘代反应得到中间体2,高温反应温度为60~100℃,优选80℃,反应溶剂可为乙腈,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;中间体2在低温碱性条件下,与SEMCl得到中间体3,反应溶剂可为乙腈,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,反应温度为-78~0℃,优选0℃,反应中的碱可为氢化钠,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,优选氢化钠;中间体3发生Suziki偶联反应得到中间体4,反应温度为80~150℃,优选80℃,反应溶剂可为二甲基亚砜,甲苯,N,N-二甲基甲酰胺,N-甲基吡咯烷酮,1,4-二氧六环,四氢呋喃,1,4-二氧六环:水=4:1等,优选1,4-二氧六环:水=4:1,催化剂可为乙酸钯,Pd(dba)2,四三苯基磷钯,PdCl2(dppf)2等,优选乙酸钯,配体可为三苯基磷,Xphos,Xtanphos,BINAP等,优选Xphos,碱可为乙酸钾,碳酸钾,碳酸钠,碳酸氢钠,氢化钠,叔丁醇钾,叔丁醇钠,碳酸铯,甲醇钠,乙醇钠,磷酸钾等,优选磷酸钾;中间体4再进行一步Suziki反应得到中间体5,反应温度为80~120℃,优选90℃,反应溶剂可为二甲基亚砜,甲苯,N,N-二甲基甲酰胺,N-甲基吡咯烷酮,1,4-二氧六环,四氢呋喃,1,4-二氧六环:水=4:1等,优选1,4-二氧六环:水=4:1,催化剂可为乙酸钯,Pd(dba)2,四三苯基磷钯,PdCl2(dppf)2等,优选PdCl2(dppf)2,碱可为乙酸钾,碳酸钾,碳酸钠,碳酸氢钠,氢化钠,叔丁醇钾,叔丁醇钠,碳酸铯,甲醇钠,乙醇钠等,优选碳酸钠;中间体5与相应的异氰酸酯反应得到中间体6,反应溶剂可为乙腈,甲苯,二氯甲烷,二甲基亚砜,四氢呋喃,1,4-二氧六环,N,N-二甲基甲酰胺,优选四氢呋喃;中间体6最后在酸性条件下脱除SEM保护基得到终产物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,乙酸乙酯,优选乙酸乙酯,反应温度为0~70℃,优选25℃,反应中的酸可为氯化氢的乙酸乙酯饱和溶液,氯化氢的乙醇溶液,氯化氢的1,4-二氧六环溶液,氯化氢的甲醇溶液,氯化氢的水溶液,对甲苯磺酸,苯磺酸等,优选氯化氢的乙酸乙酯饱和溶液。
吡唑并吡啶衍生物的应用,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:
本发明的抑制剂为典型的二型激酶抑制剂,填充了PLK4靶点二型抑制剂的空白,具有重大科研意义与价值。
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较好的PLK4抑制活性,用以治疗PLK4表达异常相关的其它疾病。
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-600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:5-溴-3-碘-1H-吡唑并[3,4-b]吡啶(2)的合成
向50mL干燥的反应瓶加入化合物1(2.00g,10.09mmol),再加入干燥的N,N-二甲基甲酰胺20mL,最后加入NIS(2.50g,11.10mmol)并80℃反应8h。TLC监测(PE:EA=4:1)原料反应完全,待反应冷却至室温,将反应液加入200mL水中,有黄色固体析出,抽滤得棕黄色固体,产率95%。
5-溴-3-碘-1-((2-(三甲硅基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶(3)的合成
将化合物2(3.27g,10.19mmol)溶于30mL N,N-二甲基甲酰胺中,置于0℃下,再缓慢分批加入氢化钠(0.49g,20.18mmol),反应30min,随后再加入SEMCl并移至室温反应10h。TLC监测(PE:EA=4:1)原料反应完全,将反应液加入300mL水中,有淡黄色固体析出,抽滤得淡黄色固体,产率92%。
3-(5-溴-1-((2-(三甲硅基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-3-基)-5-氟苯胺(4)的合成
将中间体3(0.20g,0.44mmol),3-氟-5-氨基苯硼酸(0.10g,0.44mmol),磷酸钾(0.23g,0.88mmol),醋酸钯(0.01g,0.04mmol)和Xphos(0.04g,0.09mmol)分别加入1,4-二氧六环和水(8mL:2mL)的混合溶剂中,80℃反应8h。TLC监测(PE:EA=1:1)原料反应完全,待反应冷却至室温,减压浓缩,经柱层析分离得淡黄色固体,产率67%。
3-氟-5-(5-(3-(甲磺酰基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-3-基)苯胺(5)的合成
将中间体4(0.10g,0.23mmol),3-甲磺酰基苯硼酸(0.07g,0.23mmol),四三苯基膦钯(0.03g,0.03mmol)和碳酸钠(0.05g,0.46mmol)分别加入1,4-二氧六环和水(8mL:2mL)的混合溶剂中,90℃反应6h。TLC监测(DCM:MeOH=20:1)原料反应完全,待反应冷却至室温,减压浓缩,经柱层析分离得白色固体,产率74%。
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-苯基脲(6)的合成
将中间体5(0.12g,0.23mmol),异氰酸苯酯(0.04g,0.23mmol),三乙胺0.12mL在0℃条件下加入干燥的四氢呋喃溶液中,后室温反应4h。TLC监测(DCM:MeOH=20:1)原料反应完全,减压浓缩,经柱层析分离得白色固体,产率65%。
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-苯基脲(实施例1)的制备
将中间体6(0.05g,0.10mmol),溶于1mL氯化氢的乙酸乙酯饱和溶液,室温搅拌4h。TLC监测(DCM:MeOH=10:1)反应完全,减压过滤,用乙酸乙酯洗涤滤饼三次,烘干即可,得浅绿色固体,收率91%。1H NMR(600MHz,DMSO-d6)δ14.13(s,1H),9.16(s,1H),9.01(d,J=2.1Hz,1H),8.87(t,J=4.4Hz,2H),8.36(d,J=1.7Hz,1H),8.25(d,J=7.8Hz,1H),8.00(d,J=8.4Hz,1H),7.97(s,1H),7.84(t,J=7.8Hz,1H),7.54(t,J=10.3Hz,2H),7.50(dd,J=8.5,1.0Hz,2H),7.34–7.30(m,2H),7.02(t,J=7.3Hz,1H),3.35(s,3H).HRMS(ESI,m/z)calcd for C26H20FN5O3S[M+Na]+,524.1169;found524.1229.
实施例2
1-(3-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-苯基脲的制备
参考制备实施例1的方法,将c步骤中3-氟-5-氨基苯硼酸原料等比例替换为3-氨基苯硼酸,即得实施例2.1H NMR(600MHz,DMSO-d6)δ9.43(s,1H),9.19(s,1H),9.00(d,J=2.0Hz,1H),8.85(d,J=2.1Hz,1H),8.36(t,J=1.6Hz,1H),8.30(t,J=1.6Hz,1H),8.25(d,J=7.9Hz,1H),8.00–7.97(m,1H),7.82(t,J=7.8Hz,1H),7.74(d,J=7.6Hz,1H),7.54(dd,J=8.1,1.1Hz,1H),7.50(d,J=7.6Hz,2H),7.47(t,J=7.8Hz,1H),7.30(t,J=7.9Hz,2H),6.98(t,J=7.3Hz,1H),3.35(s,3H).HRMS(ESI,m/z)calcd for C26H21N5O3S[M+Na]+,506.1263;found 506.1315.
实施例3
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(3-氟苯基)脲(实施例3)的制备:
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为3-氟异氰酸苯酯,即得实施例3.1H NMR(600MHz,DMSO-d6)δ14.27(s,1H),9.37(s,1H),9.27(s,1H),9.14(d,J=2.0Hz,1H),8.99(d,J=2.0Hz,1H),8.49(t,J=1.7Hz,1H),8.37(d,J=8.1Hz,1H),8.12(d,J=8.1Hz,1H),8.09(s,1H),7.95(d,J=7.8Hz,1H),7.68(dd,J=11.3,1.6Hz,2H),7.47(d,J=7.0Hz,1H),7.32(d,J=9.5Hz,1H),6.97–6.94(m,1H),6.83–6.79(m,1H),3.50(s,3H).HRMS(ESI,m/z)calcd forC26H19F2N5O3S[M+Na]+,542.1075;found 542.1127.
实施例4
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(4-氟苯基)脲(实施例4)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为4-氟异氰酸苯酯,即得实施例4.1H NMR(600MHz,DMSO-d6)δ14.11(s,1H),9.57(d,J=4.6Hz,1H),9.18(s,1H),8.99(d,J=2.1Hz,1H),8.85(d,J=2.1Hz,1H),8.35(t,J=1.6Hz,1H),8.25(d,J=7.8Hz,1H),8.00–7.96(m,2H),7.81(t,J=7.8Hz,1H),7.52(tt,J=6.8,2.4Hz,4H),7.16–7.11(m,2H),3.34(s,3H).HRMS(ESI,m/z)calcdfor C26H19F2N5O3S[M+Na]+,542.1075;found 542.1134.
实施例5
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(2-氟苯基)脲(实施例5)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为2-氟异氰酸苯酯,即得实施例5.1H NMR(600MHz,DMSO-d6)δ14.12(s,1H),9.87(s,1H),8.99(d,J=2.1Hz,1H),8.86(d,J=2.0Hz,1H),8.76(s,1H),8.35(s,1H),8.25(d,J=7.8Hz,1H),8.14(dd,J=8.9,7.5Hz,1H),7.97(d,J=9.2Hz,2H),7.81(t,J=7.8Hz,1H),7.56–7.53(m,2H),7.26(d,J=8.2Hz,1H),7.17(t,J=7.6Hz,1H),7.04(d,J=7.3Hz,1H),3.28(s,3H).HRMS(ESI,m/z)calcd for C26H19F2N5O3S[M-H]-,518.1099;found518.1071.
实施例6
1-(2-氯苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例6)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为2-氯异氰酸苯酯,即得实施例6.1H NMR(600MHz,DMSO-d6)δ14.12(s,1H),9.84(s,1H),8.99(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.41(s,1H),8.35(s,1H),8.23(d,J=7.9Hz,1H),8.17(d,J=8.2Hz,1H),7.99–7.93(m,2H),7.81(t,J=7.8Hz,1H),7.58–7.52(m,2H),7.48(d,J=8.0Hz,1H),7.33(t,J=7.8Hz,1H),7.07(t,J=6.9Hz,1H),3.33(s,3H).HRMS(ESI,m/z)calcd for C26H19ClFN5O3S[M+Na]+,558.0779;found558.0816.
实施例7
1-(3-氯苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例7)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为3-氯异氰酸苯酯,即得实施例7.1H NMR(600MHz,CDCl3)δ8.87(d,J=2.1Hz,1H),8.58(d,J=2.1Hz,1H),8.26(t,J=1.7Hz,1H),8.07(s,1H),8.03–8.00(m,2H),7.77(t,J=7.8Hz,1H),7.71(d,J=1.4Hz,1H),7.68(s,1H),7.52(qd,J=4.1,2.1Hz,2H),7.43–7.40(m,1H),7.28(dd,J=2.0,0.8Hz,1H),7.21(t,J=8.0Hz,1H),7.02(ddd,J=7.9,2.0,0.9Hz,1H),3.19(s,3H).HRMS(ESI,m/z)calcd for C26H19ClFN5O3S[M+Na]+,558.0779;found 558.0829.
实施例8
1-(4-氯苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例8)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为4-氯异氰酸苯酯,即得实施例8.1H NMR(600MHz,DMSO-d6)δ14.10(s,1H),9.26(s,1H),9.07(s,1H),8.99(d,J=2.1Hz,1H),8.84(d,J=2.0Hz,1H),8.34(s,1H),8.23(d,J=7.4Hz,1H),8.00–7.96(m,2H),7.82(t,J=7.8Hz,1H),7.54–7.50(m,4H),7.34(d,J=8.9Hz,2H),3.33(s,3H).HRMS(ESI,m/z)calcd for C26H19ClFN5O3S[M+Na]+,558.0779;found 558.0840.
实施例9
1-(2-溴苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例9)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为2-溴异氰酸苯酯,即得实施例9.1H NMR(600MHz,DMSO-d6)δ14.11(s,1H),9.38(s,1H),9.20(s,1H),8.99(d,J=2.1Hz,1H),8.85(d,J=2.1Hz,1H),8.35(s,1H),8.23(d,J=8.0Hz,1H),7.98(d,J=7.9Hz,1H),7.95(s,1H),7.85(t,J=1.9Hz,1H),7.82(t,J=7.8Hz,1H),7.55–7.53(m,2H),7.38–7.36(m,1H),7.26(t,J=8.0Hz,1H),7.18(dd,J=7.9,1.0Hz,1H),3.34(s,3H).HRMS(ESI,m/z)calcd for C26H19BrFN5O3S[M+Na]+,602.0274;found 602.0319.
实施例10
1-(3-溴苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例10)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为3-溴异氰酸苯酯,即得实施例10.1H NMR(600MHz,DMSO-d6)δ14.12(s,1H),9.99(s,1H),8.99(d,J=2.1Hz,1H),8.86(d,J=2.1Hz,1H),8.35(t,J=1.7Hz,1H),8.26(s,1H),8.24(d,J=7.9Hz,1H),8.07(dd,J=8.2,1.5Hz,1H),7.97(dd,J=6.9,5.9Hz,2H),7.82(d,J=7.8Hz,1H),7.64(dd,J=8.0,1.4Hz,1H),7.57–7.53(m,2H),7.37(dd,J=11.3,4.2Hz,1H),7.03–7.00(m,1H),3.33(s,3H).HRMS(ESI,m/z)calcd forC26H19BrFN5O3S[M+Na]+,602.0274;found 602.0310.
实施例11
1-(4-溴苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例11)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为4-溴异氰酸苯酯,即得实施例11.1H NMR(600MHz,DMSO-d6)δ14.11(s,1H),9.16(s,1H),9.01(d,J=15.0Hz,2H),8.84(s,1H),8.35(s,1H),8.22(d,J=7.6Hz,1H),7.99–7.96(m,2H),7.82(t,J=7.7Hz,1H),7.54–7.51(m,2H),7.47(s,4H),3.33(s,3H).HRMS(ESI,m/z)calcd for C26H19BrFN5O3S[M+Na]+,602.02737;found 602.02753.
实施例12
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(3-(三氟甲基)苯基)脲(实施例12)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为3-三氟甲基异氰酸苯酯,即得实施例12.1H NMR(600MHz,DMSO-d6)δ14.11(s,1H),9.27(d,J=10.4Hz,2H),8.99(d,J=2.1Hz,1H),8.84(d,J=2.0Hz,1H),8.35(t,J=1.7Hz,1H),8.22(d,J=8.4Hz,1H),7.98(dd,J=21.5,13.1Hz,3H),7.81(t,J=7.8Hz,1H),7.65(d,J=8.3Hz,1H),7.55(ddd,J=7.2,6.5,4.9Hz,3H),7.34(d,J=7.7Hz,1H),3.33(s,3H).HRMS(ESI,m/z)calcd for C27H19F4N5O3S[M-H]-,568.1067;found 568.1072.
实施例13
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(4-(三氟甲基)苯基)脲(实施例13)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为4-三氟甲基异氰酸苯酯,即得实施例13.1H NMR(600MHz,DMSO-d6)δ14.12(s,1H),9.30(s,1H),9.26(s,1H),8.99(d,J=2.0Hz,1H),8.85(d,J=1.9Hz,1H),8.35(s,1H),8.23(d,J=7.9Hz,1H),7.98(s,2H),7.83(d,J=7.8Hz,1H),7.70(d,J=8.7Hz,2H),7.65(d,J=8.8Hz,2H),7.55(s,2H),3.33(s,3H).HRMS(ESI,m/z)calcd forC27H19F4N5O3S[M-H]-,568.1067;found 568.1083.
实施例14
1-(3-氨基苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例14)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为3-氨基异氰酸苯酯,即得实施例14.1HNMR(600MHz,DMSO-d6)δ14.13(s,1H),10.06(s,3H),9.78(s,1H),9.00(d,J=2.1Hz,1H),8.85(d,J=2.1Hz,1H),8.35(t,J=1.7Hz,1H),8.27(d,J=8.2Hz,1H),7.98–7.94(m,2H),7.83–7.80(m,1H),7.70(s,1H),7.59–7.57(m,1H),7.55–7.53(m,1H),7.42–7.38(m,2H),6.98(dd,J=6.6,2.1Hz,1H),3.35(s,3H).HRMS(ESI,m/z)calcd for C26H21FN6O3S[M+Na]+,539.1278;found539.1345.
实施例15
1-(4-氨基苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例15)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为4-氨基异氰酸苯酯,即得实施例15.1H NMR(600MHz,DMSO-d6)δ14.11(s,1H),10.01(s,3H),9.75(s,1H),9.46(s,1H),9.00(d,J=2.0Hz,1H),8.85(d,J=2.0Hz,1H),8.35(s,1H),8.26(d,J=7.8Hz,1H),7.98(d,J=7.7Hz,2H),7.81(t,J=7.8Hz,1H),7.60(d,J=8.9Hz,2H),7.52(d,J=11.2Hz,2H),7.31(d,J=7.6Hz,2H),3.34(s,3H).HRMS(ESI,m/z)calcd for C26H21FN6O3S[M-H]-,515.1302;found 515.1315.
实施例16
1-(3-甲氧基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例16)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为3-甲氧基异氰酸苯酯,即得实施例16.1H NMR(600MHz,DMSO-d6)δ14.11(s,1H),9.52(s,1H),9.11(s,1H),9.00(d,J=2.0Hz,1H),8.86(d,J=1.9Hz,1H),8.35(s,1H),8.25(d,J=7.7Hz,1H),8.00–7.93(m,2H),7.82(t,J=7.8Hz,1H),7.53(t,J=11.1Hz,2H),7.20(dd,J=11.4,4.9Hz,2H),6.97(d,J=8.2Hz,1H),6.57(dd,J=8.3,2.0Hz,1H),3.74(s,3H),3.34(s,3H).HRMS(ESI,m/z)calcd for C27H22FN5O4S[M+Na]+,554.1275;found 554.1307.
实施例17
1-(4-甲氧基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例17)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为4-甲氧基异氰酸苯酯,即得实施例17.1HNMR(600MHz,DMSO-d6)δ14.10(s,1H),9.02–8.98(m,2H),8.84(d,J=1.1Hz,1H),8.63(s,1H),8.34(s,1H),8.22(d,J=7.8Hz,1H),7.98(d,J=7.8Hz,1H),7.93(s,1H),7.82(t,J=7.8Hz,1H),7.51(dd,J=17.3,10.5Hz,2H),7.38(d,J=8.9Hz,2H),6.89(d,J=8.9Hz,2H),3.73(s,3H),3.33(s,3H).HRMS(ESI,m/z)calcd for C27H22FN5O4S[M+Na]+,554.1275;found554.1292.
实施例18
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(吡啶-2-基)脲(实施例18)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为2-异氰酸酯吡啶,即得实施例18.1H NMR(600MHz,DMSO-d6)δ14.12(s,1H),10.86–10.81(m,1H),9.60(s,1H),8.99(d,J=2.1Hz,1H),8.87(d,J=2.1Hz,1H),8.37(t,J=1.7Hz,1H),8.34–8.32(m,1H),8.23(d,J=7.8Hz,1H),8.04(s,1H),7.98(d,J=7.8Hz,1H),7.80(dd,J=15.0,7.9Hz,2H),7.60(dd,J=10.3,1.5Hz,2H),7.55(d,J=8.4Hz,1H),7.06(d,J=5.1Hz,1H),3.34(s,3H).HRMS(ESI,m/z)calcd for C25H19FN6O3S[M-H]-,501.1145;found 501.1159.
实施例19
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(吡啶-3-基)脲(实施例19)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为3-异氰酸酯吡啶,即得实施例19.1H NMR(600MHz,DMSO-d6)δ14.14(s,1H),10.33(s,1H),10.16(s,1H),9.11(s,1H),9.00(d,J=2.1Hz,1H),8.87(d,J=2.0Hz,1H),8.53(d,J=5.4Hz,1H),8.41(d,J=8.5Hz,1H),8.36(t,J=1.6Hz,1H),8.25(d,J=7.9Hz,1H),8.04(s,1H),7.96(d,J=7.7Hz,2H),7.82(t,J=7.8Hz,1H),7.62–7.59(m,1H),7.55(dt,J=11.2,2.1Hz,1H),3.35(s,3H).HRMS(ESI,m/z)calcd for C25H19FN6O3S[M+Na]+,525.1121;found 525.1168.
实施例20
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(吡啶-4-基)脲(实施例20)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为4-异氰酸酯吡啶,即得实施例20.1H NMR(600MHz,DMSO-d6)δ14.69(s,1H),14.16(s,1H),11.24(s,1H),10.46(s,1H),9.01(d,J=2.0Hz,1H),8.86(d,J=2.1Hz,1H),8.62(d,J=7.1Hz,2H),8.36(t,J=1.6Hz,1H),8.26(d,J=7.8Hz,1H),8.08(s,1H),7.97(dd,J=12.4,7.5Hz,3H),7.82(t,J=7.8Hz,1H),7.66(d,J=8.9Hz,1H),7.53(dt,J=11.0,2.1Hz,1H),3.35(s,3H).HRMS(ESI,m/z)calcd for C25H19FN6O3S[M+H]+,503.1301;found 503.1360.
实施例21
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲(实施例21)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为5-异氰酸酯嘧啶,即得实施例21.1H NMR(600MHz,DMSO-d6)δ14.18(s,1H),10.24(s,1H),9.89(s,1H),9.00(d,J=2.0Hz,1H),8.96(s,2H),8.88–8.86(m,2H),8.36(s,1H),8.27(d,J=7.8Hz,1H),8.00(s,1H),7.97(d,J=7.8Hz,1H),7.81(t,J=7.8Hz,1H),7.56(dd,J=10.4,1.2Hz,2H),3.36(s,3H).HRMS(ESI,m/z)calcd forC24H18FN7O3S[M+Na]+,526.1074;found 526.1095.
实施例22
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(哒嗪-3-基)脲(实施例22)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为3-异氰酸酯哒嗪,即得实施例22.1H NMR(600MHz,DMSO-d6)δ14.16(s,1H),10.42(s,1H),10.04(s,1H),9.00(d,J=1.9Hz,1H),8.94(d,J=4.0Hz,1H),8.87(d,J=1.9Hz,1H),8.36(s,1H),8.25(d,J=7.5Hz,1H),8.21(d,J=9.0Hz,1H),8.04(s,1H),7.98(d,J=7.8Hz,1H),7.82(t,J=7.8Hz,1H),7.73(dd,J=9.0,4.6Hz,1H),7.61(d,J=9.9Hz,1H),7.55(d,J=11.0Hz,1H),3.35(s,3H).HRMS(ESI,m/z)calcd for C24H18FN7O3S[M+Na]+,526.1074;found 526.1078./>
实施例23
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(哒嗪-4-基)脲(实施例23)的制备
参考制备实施例1的方法,将e步骤中异氰酸苯酯原料等比例替换为4-异氰酸酯哒嗪,即得实施例23.1H NMR(600MHz,DMSO-d6)δ14.19(s,1H),11.74(s,1H),10.80(s,1H),9.30(d,J=6.8Hz,2H),9.01(d,J=2.0Hz,1H),8.88(d,J=2.0Hz,1H),8.40(d,J=4.4Hz,1H),8.36(s,1H),8.27(d,J=7.8Hz,1H),8.10(s,1H),7.97(d,J=7.9Hz,1H),7.81(t,J=7.8Hz,1H),7.68(d,J=9.3Hz,1H),7.57–7.51(m,1H),3.36(s,3H).HRMS(ESI,m/z)calcd for C24H18FN7O3S[M+Na]+,526.1074;found526.1103.
实施例24
1-(3-氟-5-(5-(4-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲(实施例24)的制备
参考制备实施例21的方法,将d步骤中3-甲磺酰基苯硼酸原料等比例替换为4-甲磺酰基苯硼酸,即得实施例24.1H NMR(600MHz,DMSO-d6)δ14.13(s,1H),10.02(d,J=21.5Hz,1H),9.69(d,J=18.3Hz,1H),9.00(d,J=2.1Hz,1H),8.95(s,2H),8.89(d,J=2.1Hz,1H),8.85(s,1H),8.20(d,J=8.4Hz,2H),8.05(d,J=8.4Hz,2H),8.01(s,1H),7.57(d,J=1.9Hz,1H),7.55(s,1H),3.29(s,3H).HRMS(ESI,m/z)calcd for C24H18FN7O3S[M+Na]+,526.1074;found 526.1101.
实施例25
1-(3-氟-5-(5-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲(实施例25)的制备
参考制备实施例21的方法,将d步骤中3-甲磺酰基苯硼酸原料等比例替换为4-(4-甲基-1-哌嗪基)苯硼酸频哪醇酯,即得实施例25.1H NMR(600MHz,DMSO-d6)δ13.99(s,1H),10.14(s,1H),9.81(s,1H),8.96(s,2H),8.90(d,J=1.5Hz,1H),8.84(s,1H),8.71(d,J=1.5Hz,1H),8.07(s,1H),7.82(d,J=8.6Hz,2H),7.50(d,J=10.5Hz,2H),7.15(d,J=8.6Hz,2H),3.57(s,4H),3.34(s,4H),2.77(s,3H).HRMS(ESI,m/z)calcd for C28H26FN9O[M+Na]+,546.2142;found 546.2186.
实施例26
1-(3-氟-5-(5-(3-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲(实施例26)的制备
参考制备实施例21的方法,将d步骤中3-甲磺酰基苯硼酸原料等比例替换为3-(4-甲基哌嗪-1-基)苯硼酸,即得实施例26.1H NMR(600MHz,DMSO-d6)δ14.05(s,1H),10.55(s,1H),10.00(s,1H),9.67(s,1H),8.95(s,2H),8.92(d,J=2.0Hz,1H),8.85(s,1H),8.72(d,J=2.1Hz,1H),8.03(s,1H),7.55–7.49(m,2H),7.42(t,J=7.9Hz,2H),7.34(d,J=8.1Hz,1H),7.07(dd,J=8.1,2.1Hz,1H),4.03(d,J=10.5Hz,2H),3.51(d,J=9.8Hz,2H),3.22–3.14(m,4H),2.84(d,J=4.7Hz,3H).HRMS(ESI,m/z)calcd for C28H26FN9O[M+Na]+,546.2142;found 546.2188.
实施例27
1-(3-氟-5-(5-(3-(哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲(实施例27)的制备
参考制备实施例21的方法,将d步骤中3-甲磺酰基苯硼酸原料等比例替换为3-[4-(叔丁氧基羰基)哌嗪-1-基]苯硼酸频那醇酯,即得实施例27.1H NMR(400MHz,DMSO-d6)δ14.04(s,1H),9.95(s,1H),9.63(s,1H),9.03(s,2H),8.95(s,2H),8.91(d,J=2.0Hz,1H),8.85(s,1H),8.72(d,J=2.0Hz,1H),8.03(s,1H),7.52(tt,J=3.6,2.3Hz,2H),7.44–7.40(m,2H),7.34(d,J=7.9Hz,1H),7.07(dd,J=8.2,2.1Hz,1H),3.53–3.50(m,4H),3.26(s,4H),3.07(qd,J=7.3,4.9Hz,1H).HRMS(ESI,m/z)calcdfor C28H26FN9O[M+Na]+,532.1986;found 532.2008.
实施例28
3-(3-(3-氟-5-(3-(嘧啶-5-基)脲基)苯基)-1H-吡唑并[3,4-b]吡啶-5-基)苯磺酰胺(实施例28)的制备
参考制备实施例21的方法,将d步骤中3-甲磺酰基苯硼酸原料等比例替换为3-硼苯磺酰胺,即得实施例28.1H NMR(600MHz,DMSO-d6)δ14.16(s,1H),9.79(s,1H),9.45(s,1H),8.95(s,2H),8.93(d,J=2.0Hz,1H),8.85(s,1H),8.81(d,J=2.0Hz,1H),8.27(s,1H),8.12(d,J=7.8Hz,1H),7.98(s,1H),7.87(d,J=7.9Hz,1H),7.73(t,J=7.8Hz,1H),7.59–7.54(m,2H),7.47(s,2H).HRMS(ESI,m/z)calcdfor C23H17FN8O3S[M+Na]+,527.1026;found 527.1043.
实施例29
1-(3-氟-5-(5-(4-(吗啉甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲(实施例29)的制备
参考制备实施例21的方法,将d步骤中3-甲磺酰基苯硼酸原料等比例替换为4-(4-吗啉甲基)苯硼酸频哪酯,即得实施例29.1HNMR(600MHz,DMSO-d6)δ14.11(s,1H),11.53(s,1H),10.18(s,1H),9.86(s,1H),8.96(s,1H),8.95–8.94(m,1H),8.86–8.85(m,1H),8.81–8.80(m,1H),8.01(d,J=7.8Hz,2H),7.79(s,1H),7.58–7.52(m,2H),4.41(s,2H),3.95(s,2H),3.84(d,J=11.4Hz,2H),3.27(d,J=12.1Hz,2H),3.15–3.10(m,2H).HRMS(ESI,m/z)calcd for C28H25FN8O2[M+H]+,525.2163;found 525.2194.
实施例30
1-(3-氟-5-(5-(3-(吗啉甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲(实施例30)的制备
参考制备实施例21的方法,将d步骤中3-甲磺酰基苯硼酸原料等比例替换为4-[3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苄基]吗啉,即得实施例30.1H NMR(600MHz,DMSO-d6)δ14.12(s,1H),11.46(s,1H),10.46(s,1H),9.80(s,1H),9.05(d,J=1.8Hz,1H),8.97(s,2H),8.91(d,J=1.8Hz,1H),8.88(s,1H),8.32(s,1H),8.04–8.01(m,2H),7.63(dd,J=14.4,8.6Hz,3H),7.53(d,J=9.4Hz,1H),4.53(d,J=5.1Hz,2H),3.97(d,J=9.9Hz,2H),3.90(t,J=11.6Hz,2H),3.33(d,J=12.0Hz,2H),3.24–3.19(m,2H).HRMS(ESI,m/z)calcd for C28H25FN8O2[M+H]+,525.2163;found525.2196.
实施例31
1-(3-氟-5-(5-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲(实施例31)的制备
参考制备实施例21的方法,将d步骤中3-甲磺酰基苯硼酸原料等比例替换为4-(4-甲基-1-哌嗪甲基)苯硼酸频哪酯,即得实施例31.1H NMR(600MHz,DMSO-d6)δ14.04(s,1H),11.97(s,1H),10.23(s,1H),9.93(s,1H),8.97(s,3H),8.88(s,1H),8.81(d,J=1.8Hz,1H),8.03–8.00(m,3H),7.84(d,J=8.1Hz,2H),7.54(dd,J=16.2,10.4Hz,2H),4.51(s,2H),3.67(s,4H),3.55–3.43(m,4H),2.81(s,3H).HRMS(ESI,m/z)calcd for C29H28FN9O[M+H]+,538.2479;found 538.2510.
实施例32
1-环丙基-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例32)的制备
参考制备实施例21的方法,将e步骤中异氰酸苯酯原料等比例替换为异氰酸酯基环丙烷,即得实施例32.1H NMR(400MHz,DMSO-d6)δ9.24(d,J=2.9Hz,1H),8.40(t,J=2.8Hz,1H),8.37(d,J=2.9Hz,1H),8.14(s,1H),8.03(ddd,J=13.4,4.4,3.1Hz,1H),7.93–7.85(m,2H),7.72(dt,J=15.9,3.0Hz,1H),7.39(t,J=2.9Hz,1H),7.17(dt,J=15.9,2.9Hz,1H),5.13(s,1H),3.32(s,3H),2.75(p,J=17.9Hz,1H),0.88–0.74(m,2H),0.65–0.47(m,2H).HRMS(ESI,m/z)calcd for C23H20FN5O3S[M+Na]+,488.1169;found 488.1182.
实施例33
1-(4-溴苯基)-3-(3-氟-5-(5-(4-(吗啉甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲(实施例33)的制备
参考制备实施例11的方法,将d步骤中3-甲磺酰基苯硼酸原料等比例替换为4-(4-吗啉甲基)苯硼酸频哪酯,即得实施例33.1H NMR(600MHz,DMSO-d6)δ14.08(s,1H),10.95(s,1H),9.71(s,1H),9.40(s,1H),8.96(d,J=2.0Hz,1H),8.79(d,J=2.0Hz,1H),8.02(d,J=8.2Hz,2H),7.95(s,1H),7.75(d,J=8.2Hz,2H),7.54(d,J=11.4Hz,1H),7.48(t,J=7.2Hz,4H),4.42(d,J=5.1Hz,2H),3.96(d,J=11.1Hz,2H),3.77(t,J=11.8Hz,2H),3.28(d,J=11.8Hz,2H),3.13(d,J=12.2Hz,2H).HRMS(ESI,m/z)calcd for C30H26BrFN6O2[M+Na]+,623.1182;found 623.1198.
实施例34
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(对甲苯基)脲(实施例34)的制备
参考制备实施例21的方法,将e步骤中异氰酸苯酯原料等比例替换为4-异氰酸酯基甲苯,即得实施例34.1H NMR(600MHz,DMSO-d6)δ14.11(s,1H),9.24(s,1H),8.44(s,1H),8.39(s,1H),8.37(s,1H),8.21(s,1H),8.03(s,1H),7.88(d,J=20.0Hz,2H),7.72(s,1H),7.39(s,1H),7.22(s,2H),7.17(s,1H),6.96(s,2H),3.32(s,3H),2.32(s,3H).HRMS(ESI,m/z)calcd for C27H22FN5O3S[M+Na]+,538.1325;found538.1340.
实施例35:本发明部分产物的体外酶抑制活性研究
实验材料:
TecanF500酶标仪。
LanthaEu Kinase Binding Assay试剂盒(包含Kinase Tracer 236、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615纳米带通为10纳米光栅的滤镜完成的。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DeltaF(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0.003μM。
表1实施例化合物IC50值
实施例 | IC50(μM) | 实施例 | IC50(μM) |
实施例1 | 2.473 | 实施例2 | 10.701 |
实施例3 | 0.387 | 实施例4 | 0.561 |
实施例5 | 2.725 | 实施例6 | 2.946 |
实施例7 | 0.325 | 实施例8 | 0.597 |
实施例9 | 0.748 | 实施例10 | 0.719 |
实施例11 | 4.461 | 实施例12 | 0.365 |
实施例13 | 1.283 | 实施例14 | 0.288 |
实施例15 | 1.848 | 实施例16 | 0.396 |
实施例17 | 0.638 | 实施例18 | 0.862 |
实施例19 | 0.094 | 实施例20 | 0.328 |
实施例21 | 0.041 | 实施例22 | 0.253 |
实施例23 | 0.217 | 实施例24 | 0.102 |
实施例25 | 0.277 | 实施例26 | 0.107 |
实施例27 | 0.064 | 实施例28 | 0.074 |
实施例29 | 0.035 | 实施例30 | 0.066 |
实施例31 | 0.018 | 实施例32 | 0.985 |
实施例33 | 0.142 | 实施例34 | 0.411 |
Claims (6)
1.一种吡唑并吡啶衍生物,其特征在于:所述衍生物为:
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-苯基脲;
1-(3-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-苯基脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(3-氟苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(4-氟苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(2-氟苯基)脲;
1-(2-氯苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-氯苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(4-氯苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(2-溴苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-溴苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(4-溴苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(3-(三氟甲基)苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(4-(三氟甲基)苯基)脲;
1-(3-氨基苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲 ;
1-(4-氨基苯基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-甲氧基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(4-甲氧基)-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(吡啶-2-基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(吡啶-3-基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(吡啶-4-基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(哒嗪-3-基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(哒嗪-4-基)脲;
1-(3-氟-5-(5-(4-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(3-(4-甲基哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(3-(哌嗪-1-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
3-(3-(3-氟-5-(3-(嘧啶-5-基)脲基)苯基)-1H-吡唑并[3,4-b]吡啶-5-基)苯磺酰胺;
1-(3-氟-5-(5-(4-(吗啉甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(3-(吗啉甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-(3-氟-5-(5-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(嘧啶-5-基)脲;
1-环丙基-3-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(4-溴苯基)-3-(3-氟-5-(5-(4-(吗啉甲基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)脲;
1-(3-氟-5-(5-(3-(甲磺酰基)苯基)-1H-吡唑并[3,4-b]吡啶-3-基)苯基)-3-(对甲苯基)脲。
2.按权利要求1所述吡唑并吡啶衍生物的应用,其特征在于:所述衍生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。
3.按权利要求1所述吡唑并吡啶衍生物的应用,其特征在于:所述衍生物在制备预防或抗肿瘤药物中的应用。
4.一种药用组合物,其特征在于:包含权利要求1所示衍生物作为活性成分以及药学上可接受的赋形剂。
5.按权利要求4所述药用组合物的应用,其特征在于: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。
6.按权利要求4所述药用组合物的应用,其特征在于:所述组合物在制备预防或抗肿瘤药物中的应用。
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CN108558876A (zh) * | 2018-05-28 | 2018-09-21 | 中南大学 | 吡唑[3,4-b]并吡啶类衍生物及其制备方法和应用 |
CN108774224A (zh) * | 2018-04-23 | 2018-11-09 | 浙江大学 | 吡唑并[3,4-b]吡啶类化合物及其制备方法和应用 |
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CN108774224A (zh) * | 2018-04-23 | 2018-11-09 | 浙江大学 | 吡唑并[3,4-b]吡啶类化合物及其制备方法和应用 |
CN108558876A (zh) * | 2018-05-28 | 2018-09-21 | 中南大学 | 吡唑[3,4-b]并吡啶类衍生物及其制备方法和应用 |
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