CN116891454A - 小分子抑制剂及制备方法与其在制备抗癌药物中的应用 - Google Patents
小分子抑制剂及制备方法与其在制备抗癌药物中的应用 Download PDFInfo
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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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
- C07D401/14—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 three or more hetero rings
Abstract
本发明属于生物医药技术领域,涉及小分子抑制剂及制备方法与其在制备抗癌药物中的应用。其化学结构式如式(I)所示,本发明提供的小分子抑制剂对β‑catenin/BCL9靶点具有良好的竞争性亲和力,且能够与该靶点紧密结合,竞争性结合破坏β‑catenin/BCL9复合体能力强。其中,部分小分子抑制剂对靶基因Axin表达的抑制效果优异,生物活性更好。
Description
技术领域
本发明属于生物医药技术领域,涉及小分子抑制剂及制备方法与其在制备抗癌药物中的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
结直肠癌(CRC)是世界第三大最常见的癌症,目前,用于结肠癌治疗的靶向药物主要包括抗血管内皮生长因子(VEGF)(贝伐珠单抗、阿柏西普、雷莫西单抗)、抗表皮生长因子受体(EGFR)抗体(西妥昔单抗、帕尼单抗)和多激酶抑制剂(瑞戈非尼)等。传统化疗与这些新靶向药物的应用相结合,显著提高了结直肠癌患者的总生存期。然而,耐药性的快速发展和癌症复发的可能会改变某些药物的有效性。因此,需要设计开发新的可替换的药物,以避免现有药物有效性降低,从而降低临床结直肠癌患者死亡率。
发明内容
为了解决现有技术的不足,目的是提供小分子抑制剂及制备方法与其在制备抗癌药物中的应用,研究表明,本发明提供的小分子抑制剂对β-catenin/BCL9靶点具有良好的竞争性亲和力,且能够与该靶点紧密结合,竞争性结合破坏β-catenin/BCL9复合体能力强。其中,部分小分子抑制剂对靶基因Axin表达的抑制效果优异,生物活性更好。
为了实现上述目的,本发明的技术方案为:
一方面,一种小分子抑制剂,其化学结构式如式(I)所示,
其中,X、Y分别独立的选自C、N,R为
在一些实施例中,X为C时,Y为C或N;Y为C时,X为C或N。进一步地,X为C,Y为C。
在一些实施例中,R为
进一步地,R为/> 更进一步地,R为/>
在一些实施例中,X为C,Y为C,R为研究表明,该条件下的化合物,不仅对β-catenin靶蛋白具有更好的竞争性亲和力,而且对Wnt信号通路的靶基因Axin的抑制效果良好。
另一方面,一种上述小分子抑制剂的制备方法,包括按照如下反应路线进行制备的过程;
其中,X、Y、R如上所述。
在一些实施例中,化合物15-19合成路线如下所示:
具体地,化合物1经过还原胺化反应与环丙胺反应生成化合物3;化合物3与三光气反应生成中间体4;化合物5与化合物6经过威廉姆森醚化反应生成中间体化合物7;化合物9由化合物7和化合物8经过Buchwald偶联反应生成;化合物9与化合物4反应生成化合物11;化合物13由化合物11与化合物12经过Suzuki偶联反应所得;化合物14由化合物13脱去叔丁基所得;目标化合物15~19由化合物14与不同的胺经过酰胺缩合得到。
更为具体地,化合物15~19合成路线中:(a)环丙胺,MeOH,室温,过夜;(b)NaBH4,MeOH,室温,2h,两步,收率80%;(c)三光气,DIPEA,DCM,室温,过夜,收率100%.(d)K2CO3,ACN,80℃,回流,24h,收率90%,(e)Pd2(dba)3,Ruphos,Cs2CO3,Tol,80℃,72h,收率65%;(f)TFA,DCM,室温,2h,收率55%;(g)DIPEA,THF,50℃,过夜,收率60%;(h)K3PO4,Pd(dppf)Cl2,二氧六烷/EtOH/H2O,80℃,48h,收率70%;(i)TFA,DCM,室温,3h,收率100%;(j)HBTU,DIPEA,DCM,室温6h,收率65~75%。
在一些实施例中,化合物20~39合成路线如下所示:
其中,化合物20、22~32化合物结构与R的对应关系,如下表所示。
具体地,化合物20由化合物14和甘氨酸甲酯经过酰胺缩合得到;化合物21由化合物20经过水解反应得到;目标化合物22-32由化合物21与不同的胺衍生物经过酰胺缩合得到。
更为具体地,化合物20~39合成路线中:(a).HATU,DIPEA,THF,室温,过夜,收率100%.(b)LiOH,THF,H2O,室温,5h,收率100%;(c)HATU,DIPEA,THF,室温,过夜,收率85%.(d).TFA,DCM,室温,收率100%
具体地,化合物48~52合成路线如下所示:
其中,化合物48-52化合物结构与R的对应关系,如下表所示。
具体地,化合物40a-b经过还原胺化反应与环丙氨反应生成化合物42a-b;化合物10与化合物42a-b经过CDI缩合生成化合物43a-b;化合物43a-b由化合物42a-b与原料12经过Suzuki偶联反应所得;化合物445a-b由化合物44a-b脱去叔丁基所得;化合物46a-b由化合物45a-b和甘氨酸经过酰胺缩合得到;化合物47a-b由化合物46a-b经过水解反应得到;目标化合物48-52由化合物47a-b与a胺衍生物经过酰胺缩合得到。
更为具体地,化合物48~52合成路线中:(a)环丙胺,MeOH,室温,过夜;(b)NaBH4,MeOH,rt,2h,室温,2h,两步,收率80%;(c)CDI,DIPEA,THF,室温,过夜,收率60%;(d)K3PO4,Pd(dppf)Cl2,二氧六烷/EtOH/H2O,80℃,48h,收率70%;(e)TFA,DCM,rt,3h,收率100%;
(f)HATU,DIPEA,THF,室温,过夜,收率100%.(g)LiOH,THF,H2O,室温,5h,收率100%;
(h)HATU,DIPEA,THF,室温,过夜,收率85%;(i).TFA,DCM,室温,收率100%
第三方面,一种药物组合物,含有上述小分子抑制剂或其药学上可接受的盐。
本发明所述的药学上可接受的盐,包括硫酸盐、盐酸盐、苯磺酸盐、枸橼酸盐等。
第四方面,一种药物制剂,包括活性成分和药学上可接受的辅料,所述活性成分为上述小分子抑制剂或药物组合物。
本发明所述药物制剂的剂型可以为片剂、胶囊、颗粒剂、注射剂等。
本发明所述的药学上可接受的辅料包括赋形剂和/或载体。
本发明所述赋形剂包括但不限于粘合剂、渗透促进剂、崩解剂、增塑剂、防腐剂、螯合剂、增粘剂、湿润剂、填充剂、乳化剂等。
本发明所述载体包括但不限于硬脂酸铝、卵磷脂、甘油、血清蛋白等。
第五方面,一种上述小分子抑制剂、药物组合物或药物制剂在制备β-catenin蛋白靶基因抑制剂药物和/或靶基因Axin抑制剂药物的应用。
第六方面,一种上述小分子抑制剂、药物组合物或药物制剂在制备抗癌药物中的应用。所述抗癌药物用于治疗结直肠癌。
本发明的有益效果为:
研究表明,本发明提供的小分子抑制剂对β-catenin蛋白具有良好的竞争性亲和力,其中,当母核右端引入丙二胺结构时,能够增强竞争性亲和力。为了增加生物活性,在母核右端引入酰胺键来作为骨架衍生的Linker,结果表明,当母核右端引入尤其是/>时,更有利于增强竞争性亲和力。同时,本发明经过对靶基因Axin的表达的抑制情况的实验表明,当母核右端引入尤其是/>时,对Wnt信号通路的靶基因Axin的抑制效果良好。另外,通过分子对接研究表明,本发明提供的化合物26能够与β-catenin蛋白形成更多的氢键相互作用,从而增强其竞争性亲和力。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为本发明实施例中化合物22与ZW4864分子对接模拟结果图(PDB:2GL7),A为ZW4864,B为化合物22。
具体实施方式
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例详细说明本发明的技术方案。
实施例
一、化合物的合成:
N-(4-溴苯甲基)环丙胺(化合物3)的制备:
将4-溴苯甲醛(10g,54mmol,1eq)和环丙胺(18.5g,324mmol,6eq)溶解在100ml甲醇中,并加入250ml三口瓶中,反应装置用氮气保护,在室温下搅拌过夜。然后将温度降至0℃,加入硼氢化钠(4.1g,108mmol,2eq),使温度保持在10℃以下。搅拌反应2h后,加入饱和氯化铵溶液猝灭反应,用TLC板(石油醚:乙酸乙酯=10:1)监测反应。反应基本完成后,真空减压除去溶剂,向残渣中加入水和乙酸乙酯(各100ml×3),萃取三次,合并有机相,用饱和食盐水洗涤三次(100ml×3),无水硫酸钠干燥,抽滤后浓缩滤液,用硅胶柱层析纯化(V(石油醚):V(乙酸乙酯)=20:1为展开剂,2.3L)得到目标化合物3(乳白色油液,9.78g,产率82.21%)。1H NMR(400MHz,DMSO-d6)δ7.47–7.41(m,2H),7.21(dt,J=7.9,1.1Hz,2H),4.12(dt,J=6.2,3.9Hz,1H),3.93(ddt,J=13.9,4.0,1.1Hz,1H),3.86(ddt,J=13.9,3.8,0.9Hz,1H),2.52(dp,J=6.2,4.3Hz,1H),0.65(tddd,J=11.7,5.7,3.2,1.5Hz,4H).MS(ESI)[M+H]+:225.42。
(4-溴苄基)(环丙基)氨基甲酰氯(化合物4)的制备:
将化合物3(2g,1eq)和三光气(1.31g,0.5eq)溶解于40ml的四氢呋喃中,并加入100ml三口瓶中。向反应瓶中加入DIPEA(0.56g,4eq),在室温下搅拌过夜。反应完成后将溶剂旋干后直接得到化合物4(棕色油状固体,2.55g,收率100%)。1H NMR(400MHz,DMSO-d6)δ7.52–7.46(m,2H),7.23(dt,J=8.2,1.0Hz,2H),4.47(dt,J=13.0,0.9Hz,1H),4.38(dt,J=13.0,0.9Hz,1H),3.30(p,J=6.0Hz,1H),0.75–0.56(m,4H).MS(ESI)[M+H]+:287.42。
叔丁基2-(3-溴苯氧基)-2-甲基丙酸酯(化合物7)的制备:
将3-溴苯酚(化合物5,1.0g、4.48mmol,1eq)、叔丁基溴(化合物6,1.55g、8.96mmol,2eq)、碳酸钾(2.47g、17.9mmol,4eq)、硫酸镁(0.54g、4.48mmol,1eq)溶解于50ml乙腈中,并加入100ml三口瓶中。在80℃搅拌回流过夜,用TLC板监测反应(石油醚:
乙酸乙酯=10:1),减压去除溶剂、用水和乙酸乙酯、萃取三次(各100ml×3),合并有机相并用饱和食盐水洗涤(100ml×3),无水硫酸钠干燥、抽滤后浓缩滤液,真空浓缩后用硅胶柱色谱法纯化(V(石油醚):V(乙酸乙酯)=40:1为展开剂,0.7L)获得目标化合物7(无色透明油性液体,1.27g,产率95.62%)。1H NMR(400MHz,DMSO-d6)δ7.30(ddd,J=8.0,2.2,1.3Hz,1H),7.25(dd,J=8.1,7.0Hz,1H),7.07(t,J=2.2Hz,1H),6.88(ddd,J=7.0,2.3,1.4Hz,1H),1.43(s,7H).MS(ESI)[M+H]+:314.65。
(S)-2-(3-(3-((叔丁氧羰基)氨基)哌啶-1-基)苯氧基)-2-甲基丙酸酯的叔丁酯(化合物9)的制备:
将化合物7(3g,41.4mmol,3eq)、化合物8(2g,13.8mmol,1eq)、碳酸铯(13.46g,441.4mmol,3eq)、Pd2(dbu)31.26g,1.4mmol.0.1eq)、Ruphos(1.28g,27.6mmol,0.2eq)溶解于60ml甲苯中,并加入100ml三口瓶中。混合溶剂在80℃,氮气保护下反应过夜。薄层色谱监测后(石油醚:乙酸乙酯=3:1),反应基本完成后,抽滤浓缩滤液并减压去除溶剂,直接用硅胶柱层析纯化(V(石油醚):V(乙酸乙酯)=10:1为展开剂,3.2L),获得目标化合物9(2.28g,乳白色油液,产率77.21%)。
(S)-2-(3-(3-氨基哌啶-1-基)苯氧基)-2-甲基丙酸叔丁酯(化合物10)的制备:
将化合物9(1g,2.23mmol,1eq)、溶于20ml的DCM中,并加入50ml三口瓶中。向反应液中加入3ml的TFA,常温条件下反应3-4h后,薄层色谱监测(石油醚:乙酸乙酯=3:1)。反应基本完成后,将溶剂二氯甲烷旋干,向旋干物中加入100ml的水,用饱和Na2CO3水溶液调pH至3-4后,将水相用二氯甲烷再萃取三遍(100ml×3),再将有机相用饱和NaCl水溶液洗涤三遍(100ml×3),旋干溶剂二氯甲烷后,得到化合物10(0.6g,红棕色油状液体,产率63.72%)。1H NMR(400MHz,DMSO-d6)δ7.15(t,J=7.3Hz,1H),6.65(ddd,J=7.3,2.2,1.1Hz,1H),6.49(ddd,J=7.3,2.3,1.2Hz,1H),6.44(t,J=2.2Hz,1H),3.43–3.27(m,4H),3.03(tdddd,J=7.1,5.7,4.2,2.9,1.5Hz,1H),2.41(t,J=7.0Hz,1H),2.26(t,J=7.0Hz,1H),1.88(ddt,J=11.8,8.8,5.8Hz,1H),1.83–1.64(m,2H),1.61–1.52(m,6H).MS(ESI)[M+H]+:334.26。
(S)-2-(3-(3-(4-溴苄基)-3-环丙基脲)哌啶-1-基)苯氧基)-2-甲基丙酸叔丁酯(化合物13)的制备:
将化合物10(0.87g,1eq)溶解于50ml四氢呋喃中,然后加入化合物4(0.90g,1.2eq)、DIPEA(1.34g,4eq)。并加入100ml三口瓶中,该反应在50℃下搅拌过夜。薄层色谱监测完成后(石油醚:乙酸乙酯=1:1),减压去除溶剂,加入水和DCM(各100ml×3)萃取三遍,用饱和食盐水洗涤三遍(100ml×3)所得有机相,用无水硫酸钠干燥,抽滤浓缩滤液并真空减压浓缩。用硅胶柱层析法(V(石油醚):V(乙酸乙酯)=3:1为展开剂,1L)纯化得到目标化合物11(0.91g,白色固体,收率61.54%)。1H NMR(400MHz,DMSO-d6)δ7.46–7.40(m,2H),7.24(dt,J=8.0,1.0Hz,2H),7.15(t,J=7.3Hz,1H),6.65(ddd,J=7.3,2.2,1.1Hz,1H),6.49(ddd,J=7.3,2.2,1.1Hz,1H),6.44(t,J=2.2Hz,1H),5.89(t,J=5.2Hz,1H),5.57(d,J=9.3Hz,1H),4.31(dq,J=5.2,0.9Hz,2H),3.85–3.76(m,1H),3.49–3.39(m,2H),3.38(ddd,J=12.4,5.9,3.5Hz,1H),3.30(ddd,J=12.4,5.9,3.5Hz,1H),1.93(ddt,J=12.1,8.8,6.1Hz,1H),1.88–1.78(m,1H),1.78–1.68(m,1H),1.68–1.58(m,1H),1.54(s,2H),1.43(s,7H).MS(ESI)[M+H]+:545.30。
(S)-2-(3-(3-(4-(1H-吡唑-4-基)苄基)-3-环丙基脲基)哌啶-1-基)苯氧基)-2-甲基丙酸酯叔丁酯(化合物13)的制备:
将化合物11(0.2g,1eq)、硼酸片哪醇酯(化合物12,0.1g,1.2eq)、Pd(dppf)Cl2(0.021g,0.1eq)、K3PO4(0.177g、3eq)溶解在二氧六环:乙醇:水(16ml,V=5:2:1)中,并加入50ml三口瓶中。混合溶剂在80℃,N2保护下反应过夜。薄层色谱监测后
(石油醚:乙酸乙酯=1:1),抽滤浓缩滤液并减压去除溶剂,用硅胶柱层析直接纯化
(V(石油醚):V(乙酸乙酯)=3:1为展开剂,0.3L),得到目标化合物13(白色粘性固体,0.12g,产率63.85%)。1H NMR(400MHz,DMSO-d6)δ7.88–7.82(m,2H),7.51(dd,J=3.0,2.1Hz,1H),7.37(dt,J=8.9,1.0Hz,2H),7.15(d,J=14.5Hz,0H),6.65(ddd,J=7.3,2.2,1.1Hz,1H),6.61(d,J=2.2Hz,1H),6.49(ddd,J=7.3,2.2,1.1Hz,1H),6.44(t,J=2.2Hz,1H),5.85(t,J=5.1Hz,1H),5.57(d,J=9.3Hz,1H),4.31(dt,J=5.2,1.1Hz,2H),3.85–3.76(m,1H),3.49–3.39(m,2H),3.38(ddd,J=12.4,5.9,3.5Hz,1H),3.30(ddd,J=12.4,5.9,3.5Hz,1H),1.93(ddt,J=12.1,8.8,6.1Hz,1H),1.88–1.78(m,1H),1.78–1.68(m,1H),1.68–1.58(m,1H),1.54(s,2H),1.43(s,6H).MS(ESI)[M+H]+:533.35。
(S)-2-(3-(3-(4-(1H-吡唑-4-基)苄基)-3-环丙基脲)哌啶-1-基)苯氧基)-2-甲基丙酸(化合物14)的制备:
将化合物13(0.45g,1eq)溶解于10ml二氯甲烷中,并加入50ml三口瓶中搅拌,然后取相同体积的10ml三氟乙酸滴加入反应瓶中,在室温下搅拌反应6h。用薄层色谱板监测反应后(石油醚:乙酸乙酯=1:1),浓缩溶剂,真空减压去除三氟乙酸,得到化合物14(白色粘性固体,0.42g,收率100%)。1H NMR(400MHz,DMSO-d6)δ7.88–7.82(m,2H),7.51(dd,J=3.0,2.1Hz,1H),7.37(dt,J=8.9,1.0Hz,2H),7.15(d,J=14.5Hz,0H),6.65(ddd,J=7.3,2.2,1.1Hz,1H),6.61(d,J=2.2Hz,1H),6.49(ddd,J=7.3,2.2,1.1Hz,1H),6.44(t,J=2.2Hz,1H),5.85(t,J=5.1Hz,1H),5.57(d,J=9.3Hz,1H),4.31(dt,J=5.2,1.1Hz,2H),3.85–3.76(m,1H),3.49–3.39(m,2H),3.38(ddd,J=12.4,5.9,3.5Hz,1H),3.30(ddd,J=12.4,5.9,3.5Hz,1H),1.93(ddt,J=12.1,8.8,6.1Hz,1H),1.88–1.68(m,2H),1.68–1.58(m,1H),1.51(s,2H).MS(ESI)[M+H]+:477.50。
化合物15-19的制备:
将化合物14(1.44g,1eq)溶解于二氯甲烷中。加入HBTU(1.37g,2eq),哌嗪
(0.24g,1eq),并加入50ml三口瓶中搅拌,再逐步滴加DIPEA(1.87g,4eq)。室温搅拌反应6h,经薄层色谱板监测反应后(石油醚:乙酸乙酯=1:2)。反应基本完成后加入水、二氯甲烷萃取3次(各100ml×3),然后进行有机相合并、饱和盐水洗涤三遍(100ml×3)、无水硫酸钠干燥、抽滤浓缩滤液并真空减压溶剂、硅胶柱层析纯化(V(石油醚):V(乙酸乙酯)=1:3为展开剂,1.2L),得到目标化合物15(白色粘性固体,1.64g,产率82.76%)。
1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.02(s,2H),7.55(d,J=7.8Hz,2H),7.20(d,J=7.9Hz,2H),7.11(t,J=8.2Hz,1H),6.61(dd,J=8.3,2.3Hz,1H),6.43–6.34(m,1H),6.19(dd,J=8.1,2.3Hz,1H),6.05(d,J=7.8Hz,1H),4.47(d,J=15.4Hz,1H),4.40(d,J=15.4Hz,1H),3.97(s,2H),3.78–3.61(m,3H),3.54(dd,J=12.0,3.7Hz,1H),3.45–3.37(m,1H),2.92–2.68(m,4H),2.34(dq,J=6.7,3.4Hz,1H),1.89–1.79(m,1H),1.72(dq,J=11.8,7.1,6.4Hz,1H),1.55(s,7H),1.42(s,1H),0.75(dt,J=6.9,3.4Hz,2H),0.64(p,J=3.7Hz,2H).MS(ESI)
[M+H]+:585.62。
化合物15:
把上述原料哌嗪替换为乙二胺进行反应,合成、纯化方法参考化合物15,得到目标化合物16为白色固体,收率80.31%。1H NMR(400MHz,Methanol-d4)δ8.50(t,J=5.8Hz,1H),7.95(s,2H),7.58–7.51(m,2H),7.30–7.24(m,2H),7.17(t,J=8.2Hz,1H),6.78(dd,J=7.9,2.3Hz,1H),6.65(t,J=2.3Hz,1H),6.47(dd,J=7.8,2.2Hz,1H),4.56(s,2H),3.98(dt,J=8.1,4.2Hz,1H),3.52(p,J=6.3Hz,3H),3.11–2.96(m,4H),2.44(tt,J=6.7,3.8Hz,1H),1.98–1.85(m,2H),1.80–1.65(m,2H),1.52(d,J=1.8Hz,6H),1.32(s,1H),0.84(dt,J=10.0,3.4Hz,2H),0.79–0.72(m,2H).MS(ESI)[M+H]+:559.67。
化合物16:
把上述原料哌嗪替换为1,3-丙二胺进行反应,合成、纯化方法参考化合物15,得到目标化合物17为白色固体,收率72.88%。1H NMR(400MHz,DMSO-d6)δ12.95(s,1H),8.26(t,J=6.0Hz,1H),7.92(s,2H),7.61–7.52(m,2H),7.19(d,J=8.0Hz,2H),7.09(t,J=8.2Hz,1H),6.62(dd,J=8.3,2.3Hz,1H),6.45(t,J=2.3Hz,1H),6.25(dd,J=8.0,2.2Hz,1H),6.07(d,J=7.8Hz,1H),4.43(q,J=15.4Hz,2H),3.75(t,J=6.7Hz,1H),3.52(dd,J=11.8,3.7Hz,1H),3.39(d,J=12.4Hz,2H),3.17(q,J=6.5Hz,2H),2.89–2.67(m,4H),2.33(dq,J=6.8,3.5Hz,1H),1.86–1.79(m,1H),1.72(p,J=6.9Hz,3H),1.58(t,J=8.5Hz,2H),1.42(s,6H),0.75(dq,J=6.9,3.6Hz,2H),0.64(p,J=3.8Hz,2H).MS(ESI)[M+H]+:573.86。
化合物17:
把上述原料哌嗪替换为吗啉进行反应,合成、纯化方法参考化合物15,得到目标化合物18为白色固体,收率55.41%。1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.02(s,1H),7.55(d,J=7.9Hz,2H),7.19(d,J=7.9Hz,2H),7.09(t,J=8.2Hz,1H),6.59(dd,J=8.3,2.2Hz,1H),6.36(t,J=2.3Hz,1H),6.20(dd,J=8.1,2.3Hz,1H),6.03(d,J=7.9Hz,1H),4.46(d,J=15.4Hz,1H),4.39(d,J=15.3Hz,1H),3.86–3.65(m,3H),3.57–3.39(m,5H),3.19(s,2H),2.82(ddd,J=20.5,12.0,8.8Hz,2H),2.32(dq,J=6.8,3.4Hz,1H),1.83(s,1H),1.77–1.69(m,1H),1.64–1.55(m,2H),1.53(s,6H),1.24(s,1H),0.74(dt,J=6.9,3.5Hz,2H),0.63(p,J=3.6Hz,2H).MS(ESI)[M+H]+:586.84。
化合物18:
把上述原料哌嗪替换为2-羟基乙胺进行反应,合成、纯化方法参考化合物15,得到目标化合物19为白色固体,收率86.15%。1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.95(t,J=5.7Hz,1H),7.55(d,J=7.9Hz,2H),7.19(d,J=8.0Hz,2H),7.07(t,J=8.1Hz,1H),6.62(dd,J=8.3,2.3Hz,1H),6.48(d,J=2.3Hz,1H),6.29(dd,J=8.0,2.2Hz,1H),6.06(d,J=7.8Hz,1H),4.75(s,1H),4.50–4.35(m,2H),3.77(tt,J=8.7,4.5Hz,1H),3.55–3.45(m,2H),3.41(d,J=12.9Hz,3H),3.20(q,J=6.2Hz,2H),2.95–2.74(m,3H),2.68(s,2H),2.33(td,J=6.7,3.4Hz,1H),1.87–1.66(m,2H),1.65–1.46(m,3H),1.40(s,6H),1.23(s,2H),0.74(dq,J=6.6,3.9Hz,2H),0.63(p,J=4.2Hz,2H).MS(ESI)[M+H]+:560.55。
化合物19:
(S)-(2-(3-(3-(4-(1H-吡唑-4-基)苄基)-3-环丙基脲基)哌啶-1-基)苯氧基)-2-甲基丙酰基)甘氨酸甲酯(化合物20)的制备:
将化合物14(0.33g,1eq)溶解于30ml四氢呋喃中。再向其中加入HATU(0.24g,1eq),DIPEA(0.64g,8eq),并加入50ml三口瓶中,搅拌20min后,再向溶剂中加入甘氨酸甲酯(0.09g,1.2eq)。室温搅拌过夜,经薄层色谱板监测反应后(石油醚:乙酸乙酯=1:1),反应完全将溶剂旋干,加入水、DCM萃取3次(100ml×3),然后进行有机相合并、饱和食盐水(100ml×3)洗涤有机相、无水硫酸钠干燥、抽滤浓缩滤液并真空减压浓缩,得到化合物20(粘性棕黄色液体,0.34g,收率94.58%)。1H NMR(400MHz,DMSO-d6)δ7.89–7.82(m,3H),7.51(dd,J=3.0,2.1Hz,1H),7.37(dt,J=8.9,1.0Hz,2H),7.15(d,J=14.6Hz,0H),6.66(ddd,J=7.3,2.2,1.1Hz,1H),6.61(d,J=2.2Hz,1H),6.49(ddd,J=7.3,2.2,1.1Hz,1H),6.44(t,J=2.2Hz,1H),5.85(t,J=5.1Hz,1H),5.57(d,J=9.3Hz,1H),4.31(dt,J=5.2,1.1Hz,2H),3.93(dd,J=5.6,1.7Hz,2H),3.85–3.76(m,1H),3.69(s,2H),3.49–3.39(m,2H),3.38(ddd,J=12.4,5.9,3.5Hz,1H),3.30(ddd,J=12.4,5.9,3.5Hz,1H),1.93(ddt,J=12.1,8.8,6.1Hz,1H),1.88–1.78(m,1H),1.78–1.68(m,1H),1.68–1.58(m,1H),1.47(s,2H).MS(ESI)
[M+H]+:548.92。
(S)-(2-(3-(3-(4-(1H-吡唑-4-基)苄基)-3-环丙基脲基)哌啶-1-基)苯氧基)-2-甲基丙酰基)甘氨酸(化合物21)的制备:
将饱和氢氧化锂(0.15g,2eq)水溶液(2ml)加入到化合物20(1g,1eq)、四氢呋喃(8ml)溶液中,并加入50ml三口瓶中。将混合物在室温下搅拌3h。用薄层色谱法监测反应后(石油醚:乙酸乙酯=1:1),通过减压法去除溶剂。将残渣用50ml的水重新溶解,然后用1mol/L盐酸调节水溶液pH至3~4,然后加入50ml乙酸乙酯萃取一遍。用饱和食盐水(50ml×3)洗涤三遍后得到的有机相,抽滤浓缩滤液并真空减压浓缩除去溶剂,得到化合物21(黄色固体,1.2g,收率100%)。1H NMR(400MHz,DMSO-d6)δ8.09(t,J=5.9Hz,1H),7.88–7.82(m,2H),7.51(dd,J=3.0,2.1Hz,1H),7.37(dt,J=8.9,1.0Hz,2H),7.15(d,J=14.6Hz,0H),6.66(ddd,J=7.3,2.2,1.1Hz,1H),6.61(d,J=2.2Hz,1H),6.49(ddd,J=7.3,2.2,1.1Hz,1H),6.44(t,J=2.2Hz,1H),5.85(t,J=5.1Hz,1H),5.57(d,J=9.3Hz,1H),4.31(dt,J=5.2,1.0Hz,2H),4.00–3.87(m,2H),3.85–3.76(m,1H),3.49–3.39(m,2H),3.38(ddd,J=12.4,5.9,3.5Hz,1H),3.30(ddd,J=12.4,5.9,3.5Hz,1H),1.93(ddt,J=12.1,8.8,6.1Hz,1H),1.88–1.68(m,2H),1.68–1.58(m,1H),1.47(s,2H).MS(ESI)[M+H]+:534.55。
化合物22-32的制备:
将化合物21(0.33g,1eq)溶解于30mlTHF中,并加入50ml三口瓶中。再向其中加入HATU(0.24g,1eq),DIPEA(0.64g,8eq),搅拌20min后,再向溶剂中加入原料S-吡咯烷-3-醇(1.2eq)。室温搅拌过夜,经薄层色谱板监测反应后(石油醚:乙酸乙酯=1:2),反应完全将溶剂旋干,加入水、二氯甲烷萃取3次(各100ml×3),然后进行有机相合并、饱和食盐水(100ml×3)洗涤有机相、无水硫酸钠干燥、抽滤浓缩滤液并真空减压浓缩,得到化合物22(粘性棕黄色液体0.34g,收率94.33%)。1H NMR(400MHz,DMSO-d6)δ8.46(t,J=5.9Hz,1H),7.55(d,J=7.8Hz,2H),7.19(d,J=7.9Hz,2H),7.09(t,J=8.2Hz,1H),6.63(dd,J=8.2,2.3Hz,1H),6.53(t,J=2.3Hz,1H),6.38(dd,J=8.0,2.2Hz,1H),6.03(d,J=7.8Hz,1H),4.43(d,J=11.5Hz,2H),3.86(d,J=5.9Hz,2H),3.76(td,J=7.9,3.7Hz,1H),3.62(s,3H),3.51(dd,J=12.0,3.7Hz,1H),3.38(d,J=13.2Hz,2H),2.85–2.80(m,1H),2.33(tt,J=6.9,3.7Hz,1H),1.82(d,J=11.4Hz,1H),1.79–1.72(m,1H),1.60–1.56(m,1H),1.41(s,6H),1.26(s,1H),0.74(dq,J=6.6,3.5Hz,2H),0.64(p,J=3.9Hz,2H).MS(ESI)[M+H]+:588.96。
化合物22:
把上述原料S-吡咯烷-3-醇替换为化合物(S)-3-(二甲基氨基)吡咯烷进行反应,合成、纯化方法参考化合物22,得到目标产物23为粘性白色液体,收率90.20%。1H NMR(400MHz,DMSO-d6)δ8.07–7.95(m,3H),7.55(d,J=8.2Hz,2H),7.19(d,J=7.9Hz,2H),7.11(t,J=8.2Hz,1H),6.69(d,J=8.4Hz,1H),6.63(s,1H),6.46(d,J=8.1Hz,1H),6.06(d,J=7.8Hz,1H),4.48–4.32(m,3H),4.24(tt,J=4.2,2.6Hz,1H),3.90(dd,J=8.2,5.3Hz,2H),3.85(d,J=5.3Hz,2H),3.49(d,J=4.8Hz,2H),3.36–3.24(m,3H),2.97–2.86(m,2H),2.33(tt,J=6.8,3.8Hz,1H),1.91–1.68(m,4H),1.60(q,J=8.8,7.8Hz,2H),1.41(d,J=1.9Hz,6H),0.74(dq,J=6.6,3.8Hz,2H),0.64(p,J=4.0Hz,2H).MS(ESI)[M+H]+:643.44。
化合物23:
把上述原料S-吡咯烷-3-醇替换为(S)-2-(二甲基氨甲基)吡咯烷进行反应,合成、纯化方法参考化合物22,得到目标产物24为粘性黄白色固体,收率80.24%。1H NMR(400MHz,DMSO-d6)δ8.04–7.96(m,2H),7.58–7.48(m,2H),7.19(d,J=8.0Hz,2H),7.08(t,J=8.2Hz,1H),6.63(dd,J=8.3,2.3Hz,1H),6.55(q,J=2.6Hz,1H),6.40(ddd,J=8.1,4.0,2.1Hz,1H),6.05(d,J=7.8Hz,1H),4.49–4.36(m,2H),3.95–3.81(m,2H),3.76(dq,J=9.4,5.0Hz,1H),3.74–3.47(m,5H),3.41–3.34(m,5H),3.24–3.10(m,2H),3.00(dd,J=11.3,8.1Hz,1H),2.92–2.77(m,2H),2.69(s,1H),2.50–2.38(m,2H),2.32(td,J=6.6,3.4Hz,1H),2.17(d,J=3.3Hz,7H),2.08–1.94(m,2H),1.86–1.69(m,3H),1.57(t,J=9.1Hz,3H),1.41(s,7H),1.24(s,1H),0.73(dd,J=6.9,4.1Hz,2H),0.63(p,J=4.2Hz,2H).MS(ESI)[M+H]+:670.56。
化合物24:
把上述原料S-吡咯烷-3-醇替换为L-脯氨醇进行反应,合成、纯化方法参考化合物22,得到目标产物25为黄白色固体,收率83.42%。1H NMR(400MHz,DMSO-d6)δ8.04(s,3H),7.55(d,J=8.1Hz,2H),7.19(d,J=7.9Hz,3H),6.96–6.73(m,2H),6.58(d,J=8.1Hz,1H),6.17(d,J=7.8Hz,1H),4.43(d,J=2.7Hz,2H),4.33(tt,J=8.5,4.3Hz,1H),4.04–3.85(m,3H),3.55(dd,J=11.8,3.8Hz,1H),3.46(t,J=6.1Hz,3H),3.18(dt,J=11.8,5.7Hz,1H),3.12–2.94(m,3H),2.87(d,J=4.5Hz,3H),2.80(d,J=4.7Hz,3H),2.35(tt,J=6.7,3.7Hz,1H),1.98–1.80(m,6H),1.75–1.55(m,2H),1.44(d,J=1.9Hz,6H),0.76(dt,J=6.5,3.1Hz,2H),0.64(p,J=4.3Hz,2H).MS(ESI)[M+H]+:684.82。
化合物25:
把上述原料S-吡咯烷-3-醇替换为S-2-Boc-氨甲基吡咯烷进行反应,合成、纯化方法参考化合物22,得到中间体33为粘性棕黄色固体,收率94.55%,将化合物33溶于10ml甲醇,再加入2ml 4M盐酸二氧六环溶液,室温搅拌6h,HPLC监测反应完全后,减压浓缩除去溶剂,得白色固体,即化合物26,收率100%。1H NMR(400MHz,DMSO-d6)δ8.02(d,J=9.5Hz,3H),7.83(s,1H),7.55(d,J=8.1Hz,2H),7.19(d,J=8.0Hz,2H),7.12(t,J=8.2Hz,1H),6.71(dd,J=8.3,2.3Hz,1H),6.63(t,J=2.3Hz,1H),6.46(dd,J=8.1,2.1Hz,1H),6.09(d,J=7.7Hz,1H),4.47(d,J=15.4Hz,1H),4.39(d,J=15.4Hz,1H),4.15(dq,J=7.3,4.1,3.6Hz,1H),3.96(dd,J=16.9,5.3Hz,1H),3.89(dd,J=16.9,5.3Hz,1H),3.83–3.76(m,1H),3.55(dd,J=12.0,3.7Hz,1H),3.43(td,J=9.0,7.9,4.1Hz,3H),3.00–2.83(m,4H),2.33(td,J=6.7,3.5Hz,1H),1.97–1.81(m,4H),1.78(dt,J=12.0,5.2Hz,2H),1.60(q,J=10.0,9.5Hz,2H),1.42(d,J=5.0Hz,6H),0.75(dq,J=6.7,4.1Hz,2H),0.64(p,J=4.1Hz,2H).MS(ESI)[M+H]+:656.76。
化合物26:
把上述原料S-吡咯烷-3-醇替换为R-2-Boc-氨甲基吡咯烷进行反应,合成、纯化方法参考化合物26,得到目标产物27为白色固体,收率82.34%。1H NMR(400MHz,DMSO-d6)δ8.03(s,2H),8.03–7.94(m,2H),7.88(s,2H),7.55(d,J=7.9Hz,2H),7.19(d,J=8.0Hz,2H),7.14(td,J=8.2,1.5Hz,1H),6.73(dd,J=8.3,2.2Hz,1H),6.65(dt,J=12.3,2.3Hz,1H),6.49(dt,J=8.1,2.7Hz,1H),6.10(t,J=8.6Hz,1H),4.41(t,J=14.8Hz,2H),4.16(qd,J=6.6,3.1Hz,1H),4.02–3.83(m,2H),3.81(dt,J=8.7,4.6Hz,1H),3.54(dt,J=11.4,4.7Hz,1H),3.44(tdt,J=13.1,8.6,4.1Hz,3H),3.08–2.79(m,4H),2.34(tt,J=6.9,3.8Hz,1H),1.96–1.70(m,6H),1.61(q,J=10.5Hz,2H),1.43(q,J=1.7Hz,6H),0.75(dq,J=6.6,3.9Hz,2H),0.64(p,J=4.1Hz,2H).MS(ESI)[M+H]+:656.69。
化合物27:
把上述原料S-吡咯烷-3-醇替换为S-3-N-Boc-氨甲基吡咯烷盐酸盐进行反应,合成、纯化方法参考化合物26,得到目标产物28为粘性白色固体,收率86.71%。1H NMR(400MHz,DMSO-d6)δ8.04(s,2H),7.99–7.95(m,2H),7.55(d,J=8.0Hz,2H),7.19(d,J=8.0Hz,2H),7.15(dd,J=8.2,4.0Hz,1H),6.80–6.70(m,2H),6.55(d,J=8.1Hz,1H),6.11(dd,J=7.9,2.2Hz,1H),4.46(d,J=15.4Hz,1H),4.39(d,J=15.4Hz,1H),3.90(t,J=5.2Hz,2H),3.88–3.81(m,1H),3.65–3.55(m,2H),3.54(d,J=4.4Hz,1H),3.52–3.42(m,2H),3.25(ddt,J=17.4,7.2,4.8Hz,1H),3.10–2.92(m,3H),2.88(t,J=6.5Hz,2H),2.43–2.26(m,2H),2.08(dq,J=11.4,6.4Hz,1H),1.90–1.55(m,5H),1.43(s,6H),0.74(dd,J=6.9,4.4Hz,2H),0.64(p,J=4.2Hz,2H).MS(ESI)[M+H]+:656.33。
化合物28:
把上述原料S-吡咯烷-3-醇替换为R-3-N-Boc-氨甲基吡咯烷盐酸盐进行反应,合成、纯化方法参考化合物26,得到目标产物29为粘性棕黄色液体,收率88.13%。1H NMR(400MHz,DMSO-d6)δ8.04(s,2H),7.99–7.95(m,2H),7.55(d,J=8.0Hz,2H),7.19(d,J=8.0Hz,2H),7.15(dd,J=8.2,4.0Hz,1H),6.80–6.70(m,2H),6.55(d,J=8.1Hz,1H),6.11(dd,J=7.9,2.2Hz,1H),4.46(d,J=15.4Hz,1H),4.39(d,J=15.4Hz,1H),3.90(t,J=5.2Hz,2H),3.88–3.81(m,1H),3.65–3.55(m,2H),3.54(d,J=4.4Hz,1H),3.52–3.42(m,2H),3.25(ddt,J=17.4,7.2,4.8Hz,1H),3.10–2.92(m,3H),2.88(t,J=6.5Hz,2H),2.43–2.26(m,2H),2.08(dq,J=11.4,6.4Hz,1H),1.90–1.55(m,5H),1.43(s,6H),0.74(dd,J=6.9,4.4Hz,2H),0.64(p,J=4.2Hz,2H).MS(ESI)[M+H]+:656.59。
化合物29:
把上述原料S-吡咯烷-3-醇替换为S-2-BOC-氨基甲基-哌啶进行反应,合成、纯化方法参考化合物26,得到目标产物30为粘性白色液体,收率86.11%。1H NMR(400MHz,DMSO-d6)δ8.01(d,J=12.5Hz,3H),7.87(s,2H),7.55(d,J=7.9Hz,2H),7.19(d,J=7.8Hz,2H),7.15–7.07(m,1H),6.73–6.58(m,2H),6.46(dd,J=8.1,2.2Hz,1H),6.07(d,J=7.8Hz,1H),4.44(s,2H),3.88(d,J=5.4Hz,2H),3.79(s,1H),3.56(ddt,J=16.9,12.4,5.2Hz,3H),3.41(d,J=10.0Hz,2H),3.25(ddd,J=17.3,12.9,7.2Hz,1H),3.05(dd,J=11.8,7.6Hz,1H),2.88(td,J=7.6,3.7Hz,4H),2.33(td,J=6.6,2.9Hz,2H),2.13–2.01(m,1H),1.97(dt,J=12.6,6.2Hz,1H),1.87–1.67(m,3H),1.67–1.53(m,3H),1.42(s,6H),0.74(dd,J=6.9,4.2Hz,2H),0.64(p,J=4.4,4.0Hz,2H).MS(ESI)[M+H]+:656.81。
化合物30:
把上述原料S-吡咯烷-3-醇替换为R-2-BOC-氨基甲基-哌啶进行反应,合成、纯化方法参考化合物26,得到目标产物31为b白色固体,收率80.13%。1H NMR(400MHz,DMSO-d6)δ8.01(d,J=12.5Hz,3H),7.87(s,2H),7.55(d,J=7.9Hz,2H),7.19(d,J=7.8Hz,2H),7.15–7.07(m,1H),6.73–6.58(m,2H),6.46(dd,J=8.1,2.2Hz,1H),6.07(d,J=7.8Hz,1H),4.44(s,2H),3.88(d,J=5.4Hz,2H),3.79(s,1H),3.56(ddt,J=16.9,12.4,5.2Hz,3H),3.41(d,J=10.0Hz,2H),3.25(ddd,J=17.3,12.9,7.2Hz,1H),3.05(dd,J=11.8,7.6Hz,1H),2.88(td,J=7.6,3.7Hz,4H),2.33(td,J=6.6,2.9Hz,2H),2.13–2.01(m,1H),1.97(dt,J=12.6,6.2Hz,1H),1.87–1.67(m,3H),1.67–1.53(m,3H),1.42(s,6H),0.74(dd,J=6.9,4.2Hz,2H),0.64(p,J=4.4,4.0Hz,2H).MS(ESI)[M+H]+:670.67。
化合物31:
把上述原料S-吡咯烷-3-醇替换为2-(2-吡咯烷乙基)氨基甲酸叔丁酯进行反应,合成、纯化方法参考化合物26,得到目标产物32为白色固体,收率80.19%。1H NMR(400MHz,DMSO-d6)δ8.26–8.19(m,2H),7.99(dd,J=3.4,1.7Hz,1H),7.61–7.52(m,2H),7.45–7.37(m,2H),7.16(t,J=7.3Hz,1H),6.78(dddd,J=25.2,7.3,1.9,1.2Hz,2H),6.46(t,J=2.0Hz,1H),4.51–4.35(m,2H),4.01–3.72(m,4H),3.66–3.57(m,2H),3.51(d,J=2.2Hz,1H),3.44–3.19(m,4H),2.93–2.72(m,2H),1.95–1.70(m,11H),1.63(dq,J=13.8,5.6Hz,1H),1.53(s,3H),1.48(s,3H),0.82(dd,J=5.7,5.0Hz,2H),0.64(dd,J=5.7,5.0Hz,2H).MS(ESI)[M+H]+:670.52。
化合物32:
化合物48-52的制备:
合成、纯化方法参考化合物22;将合成过程中的化合物11替换为化合物43a,目标化合物48为白色固体,收率54.67%。1H NMR(400MHz,DMSO-d6)δ8.51(dd,J=1.6,0.7Hz,1H),8.38(d,J=1.8Hz,1H),8.22(t,J=4.9Hz,1H),8.08(dd,J=3.8,1.8Hz,1H),7.77–7.68(m,2H),7.16(t,J=7.3Hz,1H),6.82(ddd,J=7.3,2.3,1.2Hz,1H),6.75(ddd,J=7.3,2.2,1.2Hz,1H),6.46(t,J=2.2Hz,1H),6.16(d,J=9.1Hz,1H),4.45(d,J=14.7Hz,1H),4.42–4.29(m,3H),3.93–3.78(m,3H),3.66–3.43(m,5H),3.43–3.35(m,1H),3.35–3.19(m,3H),2.06–1.96(m,1H),1.93–1.70(m,5H),1.53(s,3H),1.48(s,3H),0.82(dd,J=5.7,5.0Hz,2H),0.64(dd,J=5.7,5.0Hz,2H).MS(ESI)[M+H]+:644.52。
化合物48:
合成、纯化方法参考化合物26;将化合物11替换为化合物43b,目标化合物49为白色固体,收率81.22%。1H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.2Hz,1H),8.35(d,J=1.8Hz,1H),8.22(t,J=5.3Hz,1H),8.04(dd,J=3.4,1.7Hz,1H),7.96(dd,J=8.3,2.3Hz,1H),7.39(d,J=8.2Hz,1H),7.16(t,J=7.3Hz,1H),6.82(ddd,J=7.3,2.0,1.2Hz,1H),6.75(ddd,J=7.3,1.9,1.2Hz,1H),6.46(t,J=1.9Hz,1H),6.16(d,J=9.2Hz,1H),4.66–4.51(m,2H),3.95–3.82(m,3H),3.77(dd,J=15.8,5.3Hz,1H),3.68–3.59(m,2H),3.51(d,J=2.2Hz,1H),3.44–3.28(m,4H),2.93–2.70(m,3H),2.64(q,J=6.7Hz,1H),2.00–1.65(m,8H),1.53(s,3H),1.48(s,3H),0.82(dd,J=5.6,5.0Hz,2H),0.64(dd,J=5.6,5.0Hz,2H).MS(ESI)[M+H]+:657.52。
化合物49:
合成、纯化方法参考化合物26;将化合物11替换为化合物43a,目标化合物50为白色固体,收率32.41%。1H NMR(400MHz,DMSO-d6)δ8.51(dd,J=1.8,0.8Hz,1H),8.38(d,J=1.8Hz,1H),8.22(t,J=5.3Hz,1H),8.08(dd,J=3.8,1.8Hz,1H),7.77–7.68(m,2H),7.16(t,J=7.3Hz,1H),6.82(ddd,J=7.3,2.0,1.2Hz,1H),6.75(ddd,J=7.3,1.9,1.2Hz,1H),6.46(t,J=1.9Hz,1H),6.16(d,J=9.1Hz,1H),4.45(d,J=14.7Hz,1H),4.34(d,J=14.8Hz,1H),3.95–3.82(m,3H),3.77(dd,J=15.8,5.3Hz,1H),3.68–3.59(m,2H),3.51(d,J=2.2Hz,1H),3.44–3.28(m,3H),3.24(p,J=5.7Hz,1H),2.93–2.70(m,3H),2.64(q,J=6.7Hz,1H),2.00–1.65(m,8H),1.53(s,3H),1.48(s,3H),0.82(dd,J=5.7,5.0Hz,2H),0.64(dd,J=5.7,5.0Hz,2H).MS(ESI)[M+H]+:657.52。
化合物50:
合成、纯化方法参考化合物26;将化合物11替换为化合物43b,目标化合物51为白色固体,收率54.31%。1H NMR(400MHz,DMSO-d6)δ8.59(d,J=2.2Hz,1H),8.35(d,J=1.8Hz,1H),8.22(t,J=5.3Hz,1H),8.04(dd,J=3.4,1.7Hz,1H),7.96(dd,J=8.3,2.3Hz,1H),7.39(d,J=8.2Hz,1H),7.16(t,J=7.3Hz,1H),6.82(ddd,J=7.3,2.0,1.2Hz,1H),6.75(ddd,J=7.3,1.9,1.2Hz,1H),6.46(t,J=1.9Hz,1H),6.16(d,J=9.2Hz,1H),4.66–4.51(m,2H),3.94–3.85(m,2H),3.84(s,1H),3.77(dd,J=15.8,5.3Hz,1H),3.67–3.58(m,2H),3.51(d,J=2.2Hz,1H),3.44–3.28(m,4H),2.93–2.70(m,3H),2.64(q,J=6.7Hz,1H),1.98–1.69(m,8H),1.53(s,3H),1.48(s,3H),0.82(dd,J=5.6,5.0Hz,2H),0.64(dd,J=5.6,5.0Hz,2H).MS(ESI)[M+H]+:657.87。
化合物51:
合成、纯化方法参考化合物26;将化合物11替换为化合物43a,目标化合物52为白色固体,收率87.99%。1H NMR(400MHz,DMSO-d6)δ8.51(dd,J=1.8,0.8Hz,1H),8.38(d,J=1.8Hz,1H),8.22(t,J=5.3Hz,1H),8.08(dd,J=3.8,1.8Hz,1H),7.77–7.68(m,2H),7.16(t,J=7.3Hz,1H),6.82(ddd,J=7.3,2.0,1.2Hz,1H),6.75(ddd,J=7.3,1.9,1.2Hz,1H),6.46(t,J=1.9Hz,1H),6.16(d,J=9.1Hz,1H),4.45(d,J=14.7Hz,1H),4.34(d,J=14.8Hz,1H),3.94–3.82(m,3H),3.77(dd,J=15.8,5.3Hz,1H),3.67–3.58(m,2H),3.51(d,J=2.2Hz,1H),3.44–3.28(m,3H),3.24(p,J=5.7Hz,1H),2.93–2.70(m,3H),2.64(q,J=6.7Hz,1H),1.98–1.69(m,8H),1.53(s,3H),1.48(s,3H),0.82(dd,J=5.7,5.0Hz,2H),0.64(dd,J=5.7,5.0Hz,2H).MS(ESI)[M+H]+:657.65。
化合物52:
化合物43a的合成和纯化方法参考化合物3的制备过程,将化合物3的制备过程中的化合物1替换2-溴-5-醛基吡啶,制备成化合物43a。
化合物43b的合成和纯化方法参考化合物3的制备过程,将化合物3的制备过程中的化合物1替换为5-溴-2-吡啶甲醛,制备成化合物43b。
二、药理检测实验:
荧光偏振实验:
调配荧光偏振(FP)缓冲液,缓冲液成分为25mM HEPES,100mM NaCl,0.01%TritonX-100,0.1% BSA,并在黑色底部不透明96孔板中每孔加入180μl缓冲液和20nM BCL9-FAM示踪剂。实验开始时,向孔中分别加入1μMβ-catenin蛋白和不同浓度的化合物,其浓度梯度为0.625、1.25、2.5、5和10μM,每种浓度条件下实验3个复孔。代表100%抑制的阳性对照孔只含有示踪剂,而0%抑制的阴性对照孔则含有示踪剂和β-catenin蛋白。使用排枪将所有孔轻轻吹打混匀,在室温条件下与水平摇床上震荡2h,使得化合物与β-catenin蛋白充分接触,并与BCL9-FAM示踪剂竞争性结合β-catenin蛋白。震荡结束后,立即使用酶标仪对428nm-528nm区间进行荧光偏振分析。对结果数据使用Graphpad软件进行分析,绘制不同化合物的浓度梯度-竞争性抑制曲线,从而筛选亲和力优秀,竞争性结合破坏β-catenin/BCL9复合体能力强的化合物。
实时荧光定量PCR分析:
用不同浓度的ZW4864和化合物处理HCT116和CT26细胞24h,药物处理完成后弃孔内上清,向每孔中加入500μL Trizol(Accurate Biology,A3A2199)。吹打混匀后,在室温下裂解10分钟,并将孔内混合物转移至1.5mL EP管中。每管中加入100μL氯仿,充分混匀后静置分层,随后12000rpm,4℃离心10分钟。用200μL枪头小心吸取上层液体转移至新1.5mL EP管中。向新管中加入等量异丙醇,充分混匀后2000rpm,4℃离心10分钟。小心去除上清,并用500μL75%乙醇清洗沉淀。12000rpm,4℃离心10分钟,小心吸去乙醇后,待沉淀晾干后加入20μLDEPC水溶解RNA沉淀,并用酶标仪测量RNA浓度。吸取从细胞中分离总RNA(500ng),用Evo-mmlv反转录预混剂逆转录为cDNA。然后用Green预混Pro Taq(AccurateBiology,AG11706,AG11701)和StepOne-Plus实时PCR系统(Applied Biosystems)对cDNA进行稀释和定量。
体外生物学评价结果:
竞争性亲和力检测:
本实施例使用全长β-catenin和BCL9 HD2多肽建立竞争荧光偏振(FP)分析方法来评价脲结构小分子抑制剂对β-catenin/BCL9PPI的抑制活性。该方法可以直接反应抑制剂对于靶蛋白β-catenin的竞争性亲和力。
化合物15~20、22~32、48~52的竞争性亲和力检测结果如表1~3所示。
表1化合物17~21的竞争性亲和力
其中,化合物22~32的通式如下:
表2化合物25~36的竞争性亲和力
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其中,化合物48~52的通式如下:
表3化合物58~62的竞争性亲和力
其中,化合物48~52的通式如下:
本实施例基于化合物15~20的母核结构,在母核右端引入哌嗪结构、酰胺乙二胺、酰胺丙二胺、酰胺吗啉、酰胺乙醇和酰胺乙酸结构分别获得了化合物15~20,在这6个化合物的比较中,化合物16的FP结果较好,FP IC50达到了2.217μM,说明丙二胺的结构的引入可能会在化合物的亲和力增强上带来帮助。
考虑到酰胺键对生物活性的帮助,本实施例在基于上述母核结构的右端引入酰胺键来作为骨架衍生的Linker,在末端的羧酸基团上,将其接入吡咯间位羟基,亚甲基羟基结构,合成出化合物22和25,其中化合物22的竞争性亲和力比化合物16提高了快一倍,显示出良好的竞争性亲和力,其FP IC50为1.633μM。而化合物20和22在与靶点的亲和力上都没有提高。相反,化合物27靶点亲和力相较于22降低了四倍多。本实施例又在22的基础上,将间位羟基做改变,替换为邻位和间位亚甲基伯胺结构,并合成其反转异构体,得到化合物26-29,发现与靶点的竞争性结合并没有明显的提高。后面我们又将修饰基团上的伯胺去甲基化,并去掉亚甲基结构,合成了化合物24,结果其在靶点的竞争性结合上表现良好。本实施例又借鉴化合物16的设计思路,在吡咯环上替换其类似结构基团,设计出化合物32,发现其亲和力有所提升,FP IC50为1.954μM。本实施例又将吡咯环结构改成吡啶,保留亚甲基伯胺结构,发现其对生物活性的提高帮助不大。
氮原子的引入可能会成功的提高化合物靶点的竞争性结合力,所以在化合物22的基础上,本实施例在母核的另一端与吡唑环相连的苯环上引入氮原子,合成了化合物48,但发现化合物靶点的竞争性结合力比化合物22降低了3倍。在保留亚甲基伯胺的基础上做了相同尝试,合成出了化合物49-52,发现化合物50的竞争性亲和力有明显的提高。
对靶基因Axin抑制活性检测:
基于竞争荧光偏振法检测后,选择了8个具有代表性化合物对其进行了逆转录和实时荧光定量PCR实验,进一步探索化合物对靶基因Axin的表达的抑制情况。结果如表4所示。
表4八个化合物qPCR靶基因Axin表达
由表4的结果表明,化合物22在qPCR实验中的IC50值达到了纳摩尔级别,为0.746μM,说明其对Wnt信号通路的靶基因Axin的抑制效果良好。而其他在竞争荧光偏振法实验中表现良好的化合物,都没有显示出很好的对靶基因Axin的抑制作用。
ZW4864和化合物22分子对接研究对比
本实施例选取β-catenin/BCL9蛋白的共晶结构(PDB:2GL7)定义结合位点,选取ZW4864A和基于FP与qPCR实验中生物活性最好的化合物22,探索二者与β-catenin靶蛋白结合模式的异同,从而验证其竞争性亲和力的提高。结果如图1所示。
化合物ZW4864右端的酰胺哌嗪环与β-catenin蛋白的D-145和K-181形成氢键,吡唑环上的氨基与E-155形成氢键相互作用(图1A),化合物22与β-catenin蛋白的残基D-145和K-181形成氢键相互作用(图1B)。该分子对接结果表明相较于ZW4864,化合物22更好的占据了靶蛋白的疏水口袋,这也侧面说明了其竞争性亲和力提高的原因。
ZW4864的化学结构式为:
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种小分子抑制剂,其特征是,其化学结构式如式(I)所示,
其中,X、Y分别独立的选自C、N,R为
2.如权利要求1所述的小分子抑制剂,其特征是,X为C时,Y为C或N;Y为C时,X为C或N;优选地,X为C,Y为C。
3.如权利要求1所述的小分子抑制剂,其特征是,R为 优选地,R为进一步地优选地,R为/>
4.如权利要求1所述的小分子抑制剂,其特征是,X为C,Y为C,R为
5.一种权利要求1所述的小分子抑制剂的制备方法,其特征是,包括按照如下反应路线进行制备的过程;
其中,X、Y、R如权利要求1所述。
6.一种药物组合物,其特征是,含有权利要求1~4任一所述的小分子抑制剂或其药学上可接受的盐。
7.一种药物制剂,包括活性成分和药学上可接受的辅料,其特征是,所述活性成分为权利要求1~4任一所述的小分子抑制剂或权利要求6所述的药物组合物。
8.如权利要求7所述的药物制剂,其特征是,所述的药学上可接受的辅料包括赋形剂和/或载体。
9.一种权利要求1~4任一所述的小分子抑制剂、权利要求6所述的药物组合物或权利要求7或8所述的药物制剂在制备β-catenin蛋白靶基因抑制剂药物和/或靶基因Axin抑制剂药物的应用。
10.一种权利要求1~4任一所述的小分子抑制剂、权利要求6所述的药物组合物或权利要求7或8所述的药物制剂在制备治疗结直肠癌的药物中的应用。
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