CN114835640A - 成纤维细胞生长因子受体抑制剂、制备方法及应用 - Google Patents
成纤维细胞生长因子受体抑制剂、制备方法及应用 Download PDFInfo
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- CN114835640A CN114835640A CN202210569981.6A CN202210569981A CN114835640A CN 114835640 A CN114835640 A CN 114835640A CN 202210569981 A CN202210569981 A CN 202210569981A CN 114835640 A CN114835640 A CN 114835640A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
本发明公开了成纤维细胞生长因子受体抑制剂、制备方法及应用。一种式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐各取代基的定义如说明书和权利要求书所述。本发明化合物具有FGFR4激酶抑制剂的作用,可以用于制备***疾病的药物,特别是治疗肝细胞癌、乳腺癌、结肠癌、***癌、胰腺癌或横纹肌肉瘤的药物。
Description
技术领域
本发明涉及药物化学领域,具体涉及成纤维细胞生长因子受体抑制剂、制备方法及应用。
背景技术
成纤维细胞生长因子受体4(Fibroblast Growth Factor Receptor 4,FGFR4)是一种受体酪氨酸激酶(Receptor Tyrosine Kinases,RTK),属于FGFR家族的一种亚型。人类FGFR家族包括了FGFR1、FGFR2、FGFR3和FGFR4四种典型的亚型。生理条件下,它们可以与相应的成纤维细胞生长因子(Fibroblast Growth Factors,FGFs)高亲和力地特异性结合,导致相邻两个FGFR分子二聚化并激活,从而介导细胞信号传导,参与胚胎发育、器官形成、血管生成、组织稳态、组织修复和炎症反应等诸多重要的生理过程(Haugsten E M等.Molecular Cancer Research,2010,8(11):1439-1452;Brooks A N等.Clinical CancerResearch,2012,18(7):1855-1862;Turner N等.Nature Reviews Cancer,2010,10(2):116-129)。
在正常生理条件下,FGF19是重要的代谢调节因子;在病理条件下,FGF19可能与多种癌症的发生发展相关。目前认为FGFR4是FGF19唯一显示有特异性的受体,FGF19可以利用β-Klotho作为辅助因子与FGFR4结合并激活下游信号(Goetz R等.Nature ReviewsMolecular Cell Biology,2013,14(3):166-180)。研究发现FGFR4在多种肿瘤中异常激活,其中包括FGFR4在多种人类癌症中如乳腺癌、肝癌、结肠癌、***癌、横纹肌肉瘤的过表达(Levine K M等.Pharmacology&Therapeutics,2020,214:107590);在横纹肌肉瘤中FGFR4激酶结构域发现的N535K和V550E突变(Shern J F等.Cancer Discovery,2014,4(2):216-231;Taylor J G T等.Journal of Clinical Investigation,2009,119(11):3395-3407);FGFR4-G388R与乳腺癌、结直肠癌、***癌、肺癌、软组织肉瘤和头颈部鳞状细胞癌等多种癌症的发生、进展和预后有关(Bange J等.Cancer Research,2002,62(3):840-847;Morimoto Y等.Cancer,2003,98(10):2245-2250);在肝细胞癌中发现FGF19的过表达(Miura S等.BMC Cancer,2012,12:56)。
发明内容
本发明利用计算机辅助药物设计手段,设计了一系列全新结构的成纤维细胞生长因子受体抑制剂。
本发明的另一目的是提供该成纤维细胞生长因子受体抑制剂的制备方法。
本发明的又一目的是提供该成纤维细胞生长因子受体抑制剂的应用。
本发明的目的可通过以下技术方案实现:
一种式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐,
其中:
A为C6-8芳基,5至8元杂芳基,C3-8环烷基,3至8元杂环烷基或C3-8环烯基;
B为苯基或杂芳基;
X选自-O-、-NH-或无中的一种;
Y选自-NHCONH-、-NHCO或-CONH-中的一种;
L是指能与亲核试剂形成共价键的部分,选自有以下结构的基团:
R1、R2和R3各自独立的选自氢、卤素、任选取代的C1-4烷基或任选取代的杂环基烷基;
R4和R5选自氢、卤素、氰基、巯基、羟基、氨基、酰胺基、酯基、酰胺基、磺酰基、亚磺酰基、任选取代的C1-6烷基或任选取代的C1-6烷氧基;
R6选自氯原子、氰基或选自以下结构的基团:
R7选自氢、羟基、氰基、任选取代的C1-4烷基或任选取代的杂环基烷基;
m为1或2;n为0,1,2,3或4;p为0,1,2,3或4
作为本发明的一种优选,所述的式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐,
其中:
A为吡啶环;
B选自苯基、吡啶基或吡嗪基;
X为-O-或无中的一种;
Y为-NHCONH-;
R4选自氢、C1-3的烷基、C1-3的烷氧基,卤素;
R5为三氟甲基;
R6选自氯原子、4-甲基哌嗪基-1-亚甲基、4-乙基哌嗪基-1亚甲基、吗啉-1-亚甲基、吡咯-1-亚甲基;
n为1或2。
作为本发明的进一步优选,所述的式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐,
其中:
A为吡啶环;
B选自苯基、吡啶基或吡嗪基;
X为-O-或无中的一种;
Y为-NHCONH-;
L选自丙烯酰胺基、氯乙酰胺基、丁烯酰胺基、丁炔酰胺基、2-氟丙烯酰胺基或丙酰胺基;
R4选自氢、甲基、氟、氯、甲氧基;
R5为三氟甲基;
R6选自4-甲基哌嗪基-1-亚甲基、4-乙基哌嗪基-1亚甲基;
n为1。
作为本发明的更进一步优选,所述的式(Ⅰ)化合物选自以下任意一种:
本发明所述的式(Ⅰ)的化合物的制备方法,反应路线选自以下任意一条:
路线一:
首先原料a与BTC在吡啶的催化下反应生成异氰酸苯酯,后加入市售原料或实验室制备的中间体b,经过缩合反应得到芳基脲中间体c,同时原料d在Pd(dppf)Cl2的催化下与联硼酸频那醇酯进行Miyaura硼化反应得到苯硼酸频那醇酯中间体e,进一步的中间体c和中间体e在Pd(PPh3)4的催化下进行Suzuki偶联反应得到中间体f;最后中间体f与相应的羧酸和酰氯缩合得到通式化合物(Ⅰa)。
路线二:
首先原料g和原料h在碱性条件下亲核取代生成中间体i,中间体i与BTC在吡啶的催化下反应生成异氰酸苯酯,后加入市售原料或实验室制备原料b,经过缩合反应得到芳基脲中间体j;中间体j的硝基通过钯碳和氢气还原为氨基中间体k;最后中间体k与相应的羧酸和酰氯缩合得到通式化合物(Ⅰb)。
对映异构体和非对映异构体混合物的方法是本领域技术人员所熟悉的。本发明包括任何具有FGFR4激酶抑制活性、分离的消旋或光学活性形式的式(Ⅰ)。
一种药物组合物,包含所述的式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐和药学上可接受的受体、辅料或稀释剂。
本发明所述的式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐在制备治疗与FGFR4异常激活有关的疾病的药物中的应用。
作为本发明的一种优选,所述的与FGFR4异常激活有关的疾病选自肝细胞癌、乳腺癌、结直肠癌、***癌、胰腺癌、横纹肌肉瘤、肺癌、软组织肉瘤、头颈部鳞状细胞癌或***。
服用方式:
本发明化合物可单独或在药用组合物中与药学上可接受的受体、辅料或稀释剂组合给予哺乳动物,优选人;可口服或皮下、肌注、腹膜内、静脉、直肠及局部、眼睛、肺部、鼻腔、胃肠外给予化合物。
药物代谢及前药:
本发明所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本发明所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。
本发明所述的式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐在制备成纤维细胞生长因子受体抑制剂中的应用。
本发明的有益效果是:本发明设计具有式(Ⅰ)结构特征的小分子化合物,该类化合物可以有效抑制成纤维细胞生长因子受体4的活性,对FGFR4介导的肝癌细胞系具有显著的抗增殖活性。
下文通过实施例与制备进一步解释并列举本发明化合物及相应制备方法。应了解,尽管具体实施例中给出了典型或优选的反应条件(如反应温度、时间、反应物的摩尔比、反应溶剂以及压力等),但是本领域技术人员也可以使用其他反应条件。最佳反应条件可随所用的特定梵音第五或溶剂而发生改变,但所述条件可由所属领域的技术人员通过常规化而确定。
下述实施例化合物的结构通过核磁共振(NMR)和/或质谱(MS)来表征。使用BrukerAV-300型(300MHz)核磁共振仪,将化合物溶于适当的氘代试剂中,环境温度下以TMS为内标进行1H-NMR分析。NMR化学位移(δ)以ppm为单位,并使用以下简称:s,单峰;d,双峰;t,三重峰;q,四重峰;m,多重峰;brs,宽单峰。MS通过Water Q-TOF Micros TM质谱仪测定。
反应的起始原料、中间体以及实施例化合物可以通过沉淀、过滤、重结晶、蒸发、蒸馏以及色谱法(如柱层析法、TLC分析纯化等)等常规技术分离与纯化。
现结合实施例,对本发明进一步做描述。但需要理解,本发明不限于这些实施例,以下实施例只是提供实践本发明的方法,并不一定任何方式限制本发明的范畴。
具体实施方式
实施例1、合成N-(5-(3-甲基-4-(3-(4-(4-甲基哌嗪-1-亚甲基)-3-(三氟甲基)苯
基)脲基)苯基)吡啶-2-基)丙烯酰胺(W-1)
步骤1、制备中间体4-硝基-2-三氟甲基溴苄
将原料2-甲基-5-硝基三氟甲苯(3.20g,15.6mmol)溶于1,2-二氯乙烷(40mL)中,室温搅拌下加入N-溴代丁二酰亚胺(3.04g,17.1mmol)和偶氮二异丁腈(256mg,1.56mmol),随后升温至80℃反应。TLC监测反应完成后,加水(100mL)稀释反应液,二氯甲烷(100mL×3)萃取,有机相用饱和氯化钠水溶液(100mL)洗涤,无水硫酸钠干燥,减压浓缩,柱层析纯化(洗脱剂PE:EA=400:1~50:1),得到淡黄色液体(3.32g,产率75.8%)。
1H NMR(300MHz,Chloroform-d)δ(ppm):8.54(d,J=2.3Hz,1H),8.42(dd,J=8.6,2.4Hz,1H),7.84(d,J=8.6Hz,1H),4.67(s,2H).
步骤2、制备中间体4-(4-甲基哌嗪-1-亚甲基)-3-三氟甲基-1-硝基苯
将4-硝基-2-三氟甲基溴苄(3.29g,11.7mmol)溶于二氯甲烷(50mL)中,室温搅拌下加入无水碳酸钾(1.62g,11.7mmol)。随后在冰浴下,将N-甲基哌嗪(2.6mL,23.4mmol)的二氯甲烷溶液(5mL)溶液逐滴加入反应液中,滴毕升至室温搅拌反应。TLC监测反应完成后,加水(100mL)稀释反应液,二氯甲烷溶液(100mL×3)萃取,有机相用饱和氯化钠水溶液(100mL)洗涤,无水硫酸钠干燥,减压浓缩,柱层析纯化(以DCM:MeOH=80:1,1%TEA洗脱),得到淡黄色液体(3.23g,产率89.8%)。
1H NMR(300MHz,Chloroform-d)δ(ppm):8.51(d,J=2.3Hz,1H),8.38(dd,J=8.6,2.4Hz,1H),8.11(d,J=8.6Hz,1H),3.75(s,2H),2.54(s,8H),2.32(s,3H).
步骤3、制备中间体4-(4-甲基哌嗪-1-亚甲基)-3-三氟甲基苯胺
将4-(4-甲基哌嗪-1-亚甲基)-3-三氟甲基-1-硝基苯(3.03g,10mmol)溶于甲醇(40mL)中,室温搅拌下加入10%钯碳(300mg)和85%水合肼(4.9mL,100mmol),随后升温至65℃反应。TLC监测反应完成后,反应液用硅藻土抽滤,滤液减压浓缩后,加水(100mL)稀释反应液,二氯甲烷(100mL×3)萃取,有机相用饱和氯化钠水溶液(100mL)洗涤,无水硫酸钠干燥,减压蒸除溶剂后干燥,得到淡黄色固体(2.14g,产率78.5%)。
1H NMR(300MHz,Chloroform-d)δ(ppm):7.47(d,J=8.3Hz,1H),6.92(d,J=2.5Hz,1H),6.79(dd,J=8.2,2.4Hz,1H),3.76(s,2H),3.53(s,2H),2.46(s,8H),2.29(s,3H).
步骤4、制备中间体1-(4-溴-2-甲基苯基)-3-(4-(4-甲基哌嗪-1-亚甲基)-3-(三
氟甲基)苯基)脲
在氮气保护条件下,将三光气(302mg,1.02mmol)溶于无水四氢呋喃(10mL)中。-5℃下,将含有吡啶(943μL,18mmol)和2-甲基-4-溴苯胺(558mg,3mmol)的四氢呋喃(3mL)溶液缓慢滴加到反应体系中,滴毕升至室温反应30分钟。随后滴加化合物4-(4-甲基哌嗪-1-亚甲基)-3-三氟甲基苯胺(727mg,2.7mmol)的四氢呋喃(2mL)溶液,于室温继续反应。TLC监测反应完成后,抽滤,滤饼用四氢呋喃洗涤三次后干燥。得到粉色固体(1.11g,产率84.8%)。
1H NMR(300MHz,DMSO-d6)δ(ppm):9.51(s,1H),8.14(s,1H),7.97(s,1H),7.82(d,J=8.7Hz,1H),7.63(d,J=8.6Hz,1H),7.56(d,J=8.4Hz,1H),7.40(s,1H),7.32(d,J=8.7Hz,1H),3.53(s,2H),2.39(s,8H),2.25(s,3H),2.20(s,3H).
步骤5、制备中间体2-氨基吡啶-5-硼酸频哪醇酯
将2-氨基-5-溴吡啶(2.60g,15mmol)、联硼酸频那醇酯(4.57g,18mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(548mg,0.75mmol)和醋酸钾(4.42g,45mmol)依次投入干燥的二颈瓶中,加入无水二氧六环(30mL)后,置换氮气三次,升温至100℃搅拌反应。TLC监测反应完成后,硅藻土抽滤,滤液减压旋干,石油醚打浆,抽滤后干燥,得到浅褐色固体(3.25g,产率98.5%)。
步骤6、制备中间体1-(4-(6-氨基吡啶-3-基)-2-甲基苯基)-3-(4-(4-甲基哌嗪-
1-亚甲基)-3-(三氟甲基)苯基)脲
将2-氨基吡啶-5-硼酸频哪醇酯(660mg,3mmol)、1-(4-溴-2-甲基苯基)-3-(4-(4-甲基哌嗪-1-亚甲基)-3-(三氟甲基)苯基)脲(970mg,2mmol)(970mg,2mmol)、四(三苯基膦)钯(115mg,0.01mmol)和碳酸铯(1.30g,4mmol)依次投入史林克管中,加入甲苯/乙醇/水(9/6/3mL)后,置换氮气三次,升温至100℃搅拌反应。TLC监测反应完成后,硅藻土抽滤,减压浓缩,柱层析纯化(洗脱剂DCM:MeOH=100:1~40:1,1%TEA),得到浅黄色固体(511mg,产率51.3%)。
1H NMR(300MHz,DMSO-d6)δ(ppm):9.32(s,1H),8.22(d,J=2.5Hz,1H),8.01(s,1H),7.98(d,J=2.1Hz,1H),7.83(d,J=8.4Hz,1H),7.69–7.64(m,1H),7.61(s,1H),7.59–7.54(m,1H),7.41(d,J=2.2Hz,1H),7.35(dd,J=8.4,2.3Hz,1H),6.51(d,J=8.6Hz,1H),5.99(s,2H),3.53(s,2H),2.38(s,8H),2.29(s,3H),2.18(s,3H).
步骤7、制备N-(5-(3-甲基-4-(3-(4-(4-甲基哌嗪-1-亚甲基)-3-(三氟甲基)苯
基)脲基)苯基)吡啶-2-基)丙烯酰胺(W-1)
将1-(4-(6-氨基吡啶-3-基)-2-甲基苯基)-3-(4-(4-甲基哌嗪-1-亚甲基)-3-(三氟甲基)苯基)脲(99.7mg,0.2mmol)溶于无水二氯甲烷(3mL)中,室温搅拌下加入三乙胺(83μL,0.6mmol)。随后在冰浴下,缓慢滴加丙烯酰氯(20μL,0.25mmol)的二氯甲烷(1mL)溶液,滴毕升至室温搅拌过夜。TLC检测反应完成后,加入水(20mL)淬灭反应,二氯甲烷(20mL×3)萃取,有机相用饱和氯化铵水溶液(20mL)洗涤,无水硫酸钠干燥,减压浓缩,柱层析纯化(DCM:MeOH=60:1,1%TEA溶液洗脱)。二氯甲烷和正己烷混合溶剂打浆,抽滤后干燥,得到白色固体(46.7mg,产率42.3%)。
1H NMR(300MHz,DMSO-d6)δ(ppm):10.82(s,1H),9.43(s,1H),8.66(d,J=2.4Hz,1H),8.26(d,J=8.6Hz,1H),8.10(d,J=8.5Hz,2H),7.98(d,J=8.8Hz,2H),7.64(d,J=8.6Hz,1H),7.59(s,2H),7.53(d,J=9.7Hz,1H),6.64(dd,J=17.0,10.1Hz,1H),6.33(d,J=17.1Hz,1H),5.84–5.77(m,1H),3.53(s,2H),2.38(s,8H),2.33(s,3H),2.17(s,3H).
HRMS(ESI)m/z calcd for C29H31F3N6O2[M+H]+,553.2533;found,553.2531.
实施例2、合成N-(5-(3-甲基-4-(3-(4-(4-甲基哌嗪-1-亚甲基)-3-(三氟甲基)苯
基)脲基)苯氧基)吡啶-2-基)丙烯酰胺(W-23)
步骤1、制备中间体2-甲基-4-((6-硝基吡啶-3-基)氧基)苯胺
在氮气保护条件下,将原料3-甲基-4-氨基苯酚(1.60g,13mmol)溶于无水N,N-二甲基甲酰胺(20mL)中,加入碳酸铯(9.45g,29mmol),室温下搅拌30分钟。随后将2-硝基-5-氯吡啶(2.30g,14.5mmol)的DMF(5mL)溶液缓慢滴加至反应液中,滴毕升温至90℃反应。TLC监测反应完成后,加入水(50mL)稀释,乙酸乙酯(50mL×3)萃取,饱和氯化钠水溶液(50mL×2)洗涤,并用无水硫酸钠干燥,减压浓缩,柱层析纯化(洗脱剂PE:EA=8:1),得到黄色固体(1.71g,产率53.7%)。
1H NMR(300MHz,Chloroform-d)δ(ppm):8.28(d,J=2.9Hz,1H),8.19(d,J=8.9Hz,1H),7.33(dd,J=9.0,2.9Hz,1H),6.84–6.77(m,2H),6.71(d,J=8.3Hz,1H),3.67(s,2H),2.19(s,3H).
步骤2、制备中间体1-(2-甲基-4-((6-硝基吡啶-3-基)氧基)苯基)-3-(4-(4-甲基
哌嗪-1-亚甲基)-3-(三氟甲基)苯基)脲
在氮气保护下,将三光气(164mg,0.55mmol)溶于无水四氢呋喃(5mL)中。冰浴下,将含有吡啶(785μL,9.72mmol)、2-甲基-4-((6-硝基吡啶-3-基)氧基)苯胺(412mg,1.62mmol)的四氢呋喃(2mL)溶液缓慢滴加到反应体系中,滴毕升至室温反应30分钟。随后滴加4-(4-甲基哌嗪-1-亚甲基)-3-三氟甲基苯胺(398mg,1.46mmol)的四氢呋喃(2mL)溶液,于室温继续反应。TLC监测反应完成后,直接减压浓缩,柱层析纯化(洗脱剂DCM:MeOH=100:1,1%TEA),得到黄色固体(625mg,产率78.7%)。
步骤3、制备中间体1-(4-((6-氨基吡啶-3-基)氧基)-2-甲基苯基)-3-(4-(4-甲基
哌嗪-1-亚甲基)-3-(三氟甲基)苯基)脲
将1-(2-甲基-4-((6-硝基吡啶-3-基)氧基)苯基)-3-(4-(4-甲基哌嗪-1-亚甲基)-3-(三氟甲基)苯基)脲(1.50g,2.76mmol)溶解在乙醇:水(10:5mL)中,室温搅拌下加入铁粉(1.21g,22mmol)、氯化铵(1.47g,27.6mmol),随后升温至85℃反应。TLC检测反应完成后,反应液用硅藻土抽滤,滤液减压旋干后,加入水(30mL)稀释,二氯甲烷(50mL×3)萃取,有机相用无水硫酸钠干燥,减压蒸除溶剂后干燥,得到白色固体(1.26g,产率88.7%)。
步骤4、制备N-(5-(3-甲基-4-(3-(4-(4-甲基哌嗪-1-亚甲基)-3-(三氟甲基)苯
基)脲基)苯氧基)吡啶-2-基)丙烯酰胺(W-23)
将1-(4-((6-氨基吡啶-3-基)氧基)-2-甲基苯基)-3-(4-(4-甲基哌嗪-1-亚甲基)-3-(三氟甲基)苯基)脲(98mg,0.2mmol)溶于无水二氯甲烷中,室温搅拌下加入三乙胺(83.4ul,0.6mmol),随后在冰浴下,缓慢滴加丙烯酰氯(25ul,0.25mmol)的二氯甲烷溶液,滴毕升至室温搅拌过夜。TLC检测反应完成后,加入水(20mL)淬灭反应,二氯甲烷(20mL×3)萃取,有机相用饱和氯化铵水溶液(20mL)洗涤,无水硫酸钠干燥,减压浓缩,柱层析纯化(DCM:MeOH=60:1,1%TEA溶液洗脱)。二氯甲烷和正己烷混合溶剂打浆,抽滤后干燥,得到白色固体(41.6mg,产率38.5%)。
1H NMR(300MHz,DMSO-d6)δ(ppm):10.77(s,1H),9.39(s,1H),8.22(d,J=9.0Hz,1H),8.12(d,J=2.9Hz,1H),8.08(s,1H),7.97(d,J=2.2Hz,1H),7.73(d,J=8.8Hz,1H),7.62(d,J=8.6Hz,1H),7.56(dd,J=8.6,2.2Hz,1H),7.50(dd,J=9.0,3.0Hz,1H),6.94(d,J=2.9Hz,1H),6.87(dd,J=8.7,2.9Hz,1H),6.60(dd,J=17.0,10.1Hz,1H),6.30(dd,J=17.0,2.1Hz,1H),5.78(dd,J=10.2,2.0Hz,1H),3.53(s,2H),2.41(s,8H),2.23(d,J=2.9Hz,6H).
HRMS(ESI)m/z calcd for C29H31F3N6O3[M+H]+,569.2482;found,569.2494.
实例及其结构表征信息总结与表1所示:
合成方法如实施例1或实施例2:
表1、实施例及其结构表征信息:
生物测试
1、体外激酶活性测试
将所有化合物完全溶解在DMSO中,制备成浓度为10mM的母液。然后,稀释至所需最高浓度的50倍。在96孔板中加入100μL稀释液,同时在两个空孔中加入100μL DMSO,作为无化合物对照和无酶对照,并将板标记为源板。将10μL的化合物从源板转移到新的96孔板上作为中间板,中间板每孔加入90μL 1x激酶碱基缓冲液,振荡混匀10分钟。从中间板的每个孔中取5μL液体转移到384孔板上,一式两份。用1x激酶碱基缓冲液配制2.5x终浓度的激酶溶液,在1x激酶碱基缓冲液中加入FAM标记肽和ATP配置成2.5x多肽溶液。在384孔检测板每孔加入10μL 2.5x激酶溶液,室温孵育10分钟,然后在每孔加入10μL 2.5x多肽溶液,在28℃下孵育一段时间,加入30μL终止缓冲液停止激酶反应。用酶标仪读取转化率。数据分析:抑制率(%)=(max-conversion)/(max-min)*100
其中,conversion是化合物的转化率读数;max是阳性对照孔,代表无化合物孔的转化率读数;min是阴性对照孔,代表无酶孔的转化率读数。结果如表2所示。
表2、化合物在1μM测试浓度下对FGFR4激酶的抑制率
以上数据表明,本发明化合物对FGFR4具有显著的抑制作用,值得进一步研究。
2、体外肿瘤细胞抗增殖实验
首先将细胞消化、计数,配制成密度为4.5×104个/mL的细胞悬液,在96孔细胞培养板中每孔加入100μL细胞悬液,然后将96孔细胞培养板置于37℃,5%CO2培养箱中培养24小时。用培养基稀释药物至所需浓度,向每孔加入100μL相应的含药培养基,同时设立阴性对照组,将96孔细胞培养板置于37℃,5%CO2培养箱中继续培养72小时。然后,向每孔加入10μL CCK-8,在培养箱继续培养2~3小时。摇床10分钟轻轻地混匀,去除96孔板中气泡;在酶标仪(BioTek)上测定450nm波长下每孔的吸光度,计算抑制率。抑制率(%)=(阴性对照组OD值-实验组OD值)/阴性对照组OD值*100%。,结果如表3所示。
表3、化合物体外肿瘤细胞抗增殖活性结果:
以上数据表明,本发明化合物对肝细胞癌株Hep3B,HuH7具有显著抑制作用。
Claims (9)
1.一种式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐,
其中:
A为C6-8芳基,5至8元杂芳基,C3-8环烷基,3至8元杂环烷基或C3-8环烯基;
B为苯基或杂芳基;
X选自-O-、-NH-或无中的一种;
Y选自-NHCONH-、-NHCO或-CONH-中的一种;
L是指能与亲核试剂形成共价键的部分,选自有以下结构的基团:
R1、R2和R3各自独立的选自氢、卤素、任选取代的C1-4烷基或任选取代的杂环基烷基;
R4和R5选自氢、卤素、氰基、巯基、羟基、氨基、酰胺基、酯基、酰胺基、磺酰基、亚磺酰基、任选取代的C1-6烷基或任选取代的C1-6烷氧基;
R6选自氯原子、氰基或选自以下结构的基团:
R7选自氢、羟基、氰基、任选取代的C1-4烷基或任选取代的杂环基烷基;
m为1或2;n为0,1,2,3或4;p为0,1,2,3或4。
3.如权利要求2所述的式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐,其特征在于:
A为吡啶环;
B选自苯基、吡啶基或吡嗪基;
X为-O-或无中的一种;
Y为-NHCONH-;
L选自丙烯酰胺基、氯乙酰胺基、丁烯酰胺基、丁炔酰胺基、2-氟丙烯酰胺基或丙酰胺基;
R4选自氢、甲基、氟、氯、甲氧基;
R5为三氟甲基;
R6选自4-甲基哌嗪基-1-亚甲基、4-乙基哌嗪基-1亚甲基;
n为1。
6.一种药物组合物,其特征在于包含权利要求1所述的式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐和药用辅料。
7.权利要求1所述的式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐在制备治疗与FGFR4异常激活有关的疾病的药物中的应用。
8.根据权利要求7所述的应用,其特征在于所述的与FGFR4异常激活有关的疾病选自肝细胞癌、乳腺癌、结直肠癌、***癌、胰腺癌、横纹肌肉瘤、肺癌、软组织肉瘤、头颈部鳞状细胞癌或***。
9.权利要求1所述的式(Ⅰ)化合物,其立体异构体,互变异构体或药学上可接受的盐在制备成纤维细胞生长因子受体抑制剂中的应用。
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