CN116903581A - Shp2/hdac双靶点抑制剂及其制备方法和应用 - Google Patents
Shp2/hdac双靶点抑制剂及其制备方法和应用 Download PDFInfo
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- CN116903581A CN116903581A CN202310157573.4A CN202310157573A CN116903581A CN 116903581 A CN116903581 A CN 116903581A CN 202310157573 A CN202310157573 A CN 202310157573A CN 116903581 A CN116903581 A CN 116903581A
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- amino
- methylpiperidin
- dichlorophenyl
- pyrazin
- shp2
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Abstract
本发明公开了结构如下的SHP2/HDAC双靶点抑制剂及其制备方法和用途。本发明化合物不仅表现出良好的SHP2和HDAC酶抑制活性,而且对实体肿瘤和血液肿瘤均有较好的抗增殖活性,能够明显的抑制肿瘤生长,本发明还提供所述的SHP2/HDAC双靶点抑制剂在制备与SHP2/HDAC双靶点以及RAS信号通路过度激活有关的肿瘤疾病药物中的用途。
Description
技术领域
本发明涉及一种SHP2/HDAC双靶点抑制剂及其制备方法、药物组合物与医药用途,属于医药技术领域。
背景技术
由PTPN11基因编码的非受体蛋白酪氨酸磷酸酶SHP2是重要致癌因子。SHP2通过自身的N端SH2结构域与PTP结构域的相互作用保持自抑制构象,限制底物进入催化位点。当双磷酸酪氨酸肽(例如IRS-1)与SH2结构域结合时,SH2和PTP结构域之间的相互作用被破坏,从而暴露了PTP催化结构域,增加了SHP2的去磷酸化酶催化活性。SHP2在许多癌症相关的信号通路中发挥作用,例如RAS-RAF-ERK,PI3K-AKT,JAK-STAT,NF-κB和mTOR。SHP2激活突变发生在多种类型癌症中,例如,青少年粒单核细胞白血病、B细胞急性淋巴细胞白血病、急性髓系白血病、乳腺癌、肺癌、肝癌、结肠癌、神经母细胞瘤和黑色素瘤等。因此,SHP2是一个很有前景的癌症治疗靶点。迄今为止,已有多个SHP2抑制剂在进行临床试验。
组蛋白去乙酰化酶是重要的表观遗传调节因子,通过调节组蛋白和非组蛋白等多种底物的去乙酰化,在染色体的结构修饰和基因表达调控中发挥着关键作用。目前已发现HDAC有4大类18个亚型,其中I类HDACs与癌症的发生发展关系最为密切。HDACs在不同类型的癌症中都过度表达,近年来已成为重要的抗癌治疗靶点。迄今为止,已有五种HDAC抑制剂获批用于临床治疗血液系统恶性肿瘤,例如皮肤T细胞淋巴瘤(CTCL)、外周T细胞淋巴瘤和多发性骨髓瘤。
RAS-ERK通路是癌症中的一个主要信号级联反应。作为致癌基因,高活性的SHP2能够完全激活RAS-ERK通路,促进癌细胞的存活和过度增殖。已有研究证明SHP2抑制剂和ERK信号通路抑制的联合用药,不仅能够增强抗肿瘤效果,而且能够有效克服ERK信号通路抑制剂的耐药性。另一方面,有研究发现HDAC抑制剂与RAS抑制剂联用也能够协同抑制ERK信号通路激活,发挥更强的抗肿瘤作用。这提示我们,与单一靶点抑制剂相比,SHP2抑制剂和HDAC抑制剂联合使用可能会具有更强的抗肿瘤活性。我们使用了MV4-11细胞,研究了SHP2抑制剂(SHP099)和HDAC抑制剂(SAHA)的联合用药,结果显示联合用药比单一疗法具有更好的抗增殖活性(SHP099,IC50=1.75μM;SAHA,IC50=0.50μM;SHP099+SAHA,IC50=0.24μM)。基于以上研究基础,本发明设计、合成一系列SHP2/HDAC双靶点抑制剂以期能够获得更强的抗肿瘤分子,并对该类双靶点的应用进行深入研究。
发明内容
本发明目的是提供一种SHP2/HDAC双靶点抑制剂;本发明的另一个目的是提供SHP2/HDAC双靶点抑制剂的制备方法和用途。
技术方案:
一、SHP2/HDAC双靶点抑制剂
本发明提供一种SHP2/HDAC双靶点抑制剂或药学上可接受的盐,具有式Ⅰ所示的结构:
通式I中,R1、R2各自独立的选自氢、氟、氯、溴;
A为呋喃、噻吩、吡咯、噻唑、咪唑、噁唑、噻唑、异噁唑、异噻唑、吡啶、吡嗪、嘧啶、哒嗪、吡喃、哌嗪、吲哚、喹啉、蝶啶、吖啶、苯并咪唑、异喹啉、吡嗪并吡唑、吡嗪并咪唑;
R3为氢原子或羰基;
X为0至10个碳原子的饱和直链烃基、芳基或以下连接基团之一:
n=0,1,2,3,4,5,6,7,8,9,10;
R4为羟基或2-氨基苯基;
R5为氢原子或以下结构:
R6为氢原子或羰基;
Y为0至10个碳原子的饱和直链烃基、苯基或以下连接基团之一:
n=0,1,2,3,4,5,6,7,8,9,10;
R7为羟基或2-氨基苯基。上述通式I化合物,优选为如下之一:
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-羟基丙二酰胺(8a)
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N4-羟基琥珀酰胺(8b)
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N5-羟基戊二酰胺(8c)
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N6-羟基己二胺(8d)
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N7-羟基庚二酰胺(8e)
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N8-羟基辛二酰胺(8f)
5-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-N-羟基戊酰胺(8g)
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-羟基间苯二甲酰胺(8h)
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N4-羟基对苯二甲酰胺(8i)
N1-(2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-2-氧代乙基)-N4-羟基对苯二甲酰胺(8j)
(E)-N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(4-(3-(羟基氨基))-3-oxoprop-1-烯-1-基)苄基)丙二酰胺(8k)
(E)-N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(3-(3-(羟基氨基))-3-oxoprop-1-烯-1-基)苄基)丙二酰胺(8l)
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(4-(羟基氨基甲酰基)苄基)丙二酰胺(8m)
(E)-3-(4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)苯基)-N-羟基丙烯酰胺(8n)
3-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-羟基苯甲酰胺(8o)
4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-羟基苯甲酰胺(8p)
(E)-3-(4-(2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)乙酰氨基)苯基)-N-羟基丙烯酰胺(8q)
(E)-3-(4-((2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)乙酰氨基)甲基)苯基)-N-羟基丙烯酰胺(8r)
(E)-4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-(4-(3-(羟基氨基)-3-氧代丙基-1-烯-1-基)苯基)苯甲酰胺(8s)
(E)-4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-(4-(3-(羟基氨基)-3-oxoprop-1-烯-1-基)苄基)苯甲酰胺(8t)
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(2-氨基苯基)丙二酰胺(8u)
4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-(2-氨基苯基)苯甲酰胺(8v)
本发明的通式I所示化合物可以通过公知的方法制成药学上可接受的盐,该盐是指式I所示化合物与酸或碱混合制成的盐;
适宜的酸加成盐是由形成无毒盐的酸形成。具有代表性的酸加成盐包括但不限于乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、碳酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、碳酸盐、柠檬酸盐、二葡糖酸盐(digluconate)、甘油磷酸盐、半硫酸盐(hemisulfate)、庚酸盐、己酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、葡萄糖醛酸盐、谷氨酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(isethionate)、乳酸盐、马来酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、烟酸盐(nicotinate)、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐(picrate)、三甲基乙酸盐(pivalate)、丙酸盐、蔗糖盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、对甲苯磺酸盐、三氟乙酸盐及十一酸盐。二、SHP2/HDAC双靶点抑制剂的制备方法
SHP2/HDAC双靶点抑制剂制备方法,化合物1和化合物2发生Suzuki偶联反应得到中间体3,然后氨基被Boc保护基团保护,得到中间体4;4与(4-甲基哌啶-4-基)氨基甲酸叔丁酯发生亲核取代反应得到中间体5,随后脱除Boc保护基得到中间体6;6与不同碳长的单酸甲酯或含芳基的羧酸中间体在HATU条件下缩合并在羟胺的甲醇溶液中氨解得到目标化合物8a-8f,8h-8m;6与含溴的不同中间体发生亲核取代反应并在羟胺的甲醇溶液中氨解得到目标化合物8g,8n-8t;6与邻苯二胺在HATU条件下缩合得到目标化合物8u和8v;
反应路线一如下:
反应试剂和反应条件:(a)DPPF二氯化钯,K3PO4,1,4-二氧六环/水,90℃,12h;(b)碳酸酐二叔丁酯,DMAP,二氯甲烷,室温,8小时;(c)(4-甲基哌啶-4-基)氨基甲酸叔丁酯,DIPEA,DMF,85℃,8小时;(d)4M HCl/EtOAc,室温,8小时;(e)HATU、DIPEA、DMF、室温、8小时;(f)羟胺的甲醇溶液,室温,6小时;
反应路线二如下:
反应试剂和反应条件:(a)HATU,DIPEA,DMF,室温,8小时;(b)K2CO3,DMF,室温或80℃,8小时;(c)羟胺的甲醇溶液,室温,6小时;
反应路线三如下:
反应试剂和反应条件:(a)HATU,DIPEA,DMF,室温,8小时;(b)4M氢氧化钠/水,50℃,1小时。
三、SHP2/HDAC双靶点抑制剂的应用
一种药物组合物,其含有治疗有效量的一种或多种所述的SHP2/HDAC双靶点抑制剂,及药用辅料或载体。
所述的SHP2/HDAC双靶点抑制剂在制备SHP2抑制剂中的用途。
所述的SHP2/HDAC双靶点抑制剂在制备组蛋白去乙酰化酶抑制剂中的用途。
所述的SHP2/HDAC双靶点抑制剂在制备与SHP2/HDAC双靶点以及RAS信号通路过度激活有关的肿瘤疾病药物中的用途。
所述肿瘤为肺癌、肝癌、非小细胞肺癌、皮肤癌、胰腺癌、卵巢癌、乳腺癌、膀胱癌、淋巴瘤、食管癌、胃肠道癌、鼻咽癌、白血病、脑胶质瘤、前列腺癌、骨髓瘤、KRAS突变的肿瘤。
有益效果
本发明化合物不仅表现出良好的SHP2和HDAC酶抑制活性,在细胞内能够抑制SHP2和HDAC活性,下调ERK磷酸化水平,而且具有一定广谱的体外抗肿瘤活性,能够明显的延缓肿瘤生长,可以应用于SHP2和HDAC介导的ERK信号通路异常病理学特征的肿瘤疾病。该类化合物作为首次报道的基于SHP2和HDAC的双靶点抗肿瘤药物,具有进一步的开发和研究价值。
附图说明
图1是化合物8r和8t对人急性单核细胞白血病细胞MV4-11体内抗肿瘤活性结果图,其中,A:荷瘤小鼠肿瘤体积;B:荷瘤小鼠体重变化;C:荷瘤小鼠肿瘤质量;D:荷瘤小鼠肿瘤体积生长曲线。
具体实施方式
本发明所用试剂、原料或中间体均市售可得或可按文献方法制备。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。下面结合实施例对本发明做进一步的说明,但不限于此。
实施例1:中间体6的制备
6-氯-3-(2,3-二氯苯基)吡嗪-2-胺(3)
将2,3-二氯苯基硼酸(1g,5.24mmol)、2-氨基-3-溴-6-氯吡嗪(1.092g,5.24mmol)、PdCl2(dppf)(383mg,0.524mmol)、K3PO4(3.333g,51.72mmol)溶于20mL 1,4-二氧六环/水溶液在氮气保护下90℃搅拌12小时。冷却至室温后,将反应混合物通过硅藻土过滤,并加入20mL水,然后用EtOAc萃取三次,合并有机层,饱和食盐水洗,无水硫酸镁干燥,减压除去溶剂,粗品经柱层析纯化(PE/EA=100:1-20:1),得到黄色固体1.2g,收率:90%。1HNMR(400MHz,Chloroform-d)δ8.02(s,1H),7.60(dd,J=7.8,1.7Hz,1H),7.37(t,J=7.7Hz,1H),7.32(dd,J=7.6,1.7Hz,1H),4.66(s,2H).
叔丁基(叔丁氧基羰基)(6-氯-3-(2,3-二氯苯基)吡嗪-2-基)氨基甲酸酯(4)
将化合物3(100mg,0.364mmol)、(Boc)2O(199mg,0.91mmol)和DMAP(5mg,0.036mmol)溶于DCM(5mL)中并在室温搅拌8小时。将反应混合物用1M HCl洗涤并用盐水洗涤,无水硫酸镁干燥并将粗产物通过柱层析(PE/EA=100:1-30:1)纯化,得到黄色固体107mg,产率:62%。1H NMR(400MHz,Chloroform-d)δ8.67(s,1H),7.56(dd,J=7.9,1.6Hz,1H),7.34(dd,J=7.7,1.6Hz,1H),7.28(d,J=7.8Hz,1H),1.37(s,18H).
叔丁基(叔丁氧基羰基)(6-(4-((叔丁氧基羰基)氨基)-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)吡嗪-2-基)氨基甲酸酯(5)
将化合物4(193mg,0.406mmol)、(4-甲基哌啶-4-基)氨基甲酸叔丁酯(105mg,0.487mmol)、DIPEA(0.1mL,0.61mmol)溶于DMF(2mL)中在85℃下搅拌8小时。将反应混合物用EtOAc稀释并用水和盐水溶液洗涤。有机层用无水硫酸镁干燥,过滤,浓缩,得到粗品为油状物。粗品经柱层析纯化(PE/EA=100:1-5:1),得到黄色油状物288mg,产率:90%。1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.67(dd,J=8.0,1.3Hz,1H),7.42(t,J=7.9Hz,1H),7.29(dd,J=7.7,1.3Hz,1H),6.67(s,1H),3.98–3.85(m,2H),3.33(d,J=10.5Hz,2H),2.15(d,J=12.5Hz,2H),1.53–1.44(m,2H),1.40(s,9H),1.28(s,18H).
6-(4-氨基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)吡嗪-2-胺盐酸盐(6)
将化合物5(288mg,0.44mmol)在4M HCl/EtOAc(20mL)中的溶液在室温搅拌8小时。过滤得到黄色固体(40mg),产率:21%。1H NMR(400MHz,DMSO-d6)δ7.61(d,J=7.9Hz,1H),7.48(s,1H),7.38(t,J=7.8Hz,1H),7.30(d,J=7.1Hz,1H),5.58(s,2H),3.72–3.60(m,2H),3.51–3.45(m,2H),1.48–1.35(m,4H),1.09(s,3H).13C NMR(101MHz,DMSO)δ153.90,153.22,133.48,132.73,132.59,132.07,131.83,129.15,118.29,110.50,56.45,52.36,34.55,22.85,19.03.HRMS(ESI+)m/z,calcd for C16H19Cl2N5([M+H]+)352.1090,found:352.1053.
实施例2:中间体7a-7f,7h-7m的制备
3-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-3-氧代丙酸甲酯(7a)
将6(158mg,0.406mmol)、3-甲氧基-3-氧代丙酸(0.05mL,0.447mmol)、HATU(155mg,0.406mmol)、DIPEA(0.28mL,1.627mmol)溶解在DMF(5mL)中并在室温下搅拌8小时。然后,将反应混合物用EtOAc稀释并用水和盐水溶液洗涤。有机层用无水硫酸镁干燥,过滤,浓缩,得到粗品。粗品通过柱层析(DCM/MeOH=100:1-50:1)纯化,得到白色固体106mg,产率:60%。1H NMR(400MHz,Chloroform-d)δ7.62(s,1H),7.50(dd,J=7.6,1.9Hz,1H),7.32(dd,J=7.6,1.9Hz,1H),7.30(d,J=7.7Hz,1H),7.17(s,1H),4.23(s,2H),3.97–3.94(m,2H),3.76(s,3H),3.31(s,2H),3.28–3.21(m,2H),2.25–2.21(m,2H),1.74–1.67(m,2H),1.48(s,3H).
4-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-4-氧代丁酸甲酯(7b)
7b以与7a相同的方式合成,产率:70%。1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),7.50(dd,J=7.6,1.9Hz,1H),7.33(dd,J=7.6,1.9Hz,1H),7.29(d,J=7.7Hz,1H),5.55(s,1H),4.23(s,2H),3.88(dt,J=13.4,4.4Hz,2H),3.68(s,3H),3.28(ddd,J=13.5,10.6,3.0Hz,2H),2.67(t,J=6.6Hz,2H),2.46(t,J=6.6Hz,2H),2.18(d,J=13.8Hz,2H),1.70(td,J=10.3,5.3Hz,2H),1.45(s,3H).
5-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-5-氧代戊酸甲酯(7c)
7c以与7a相同的方式合成,产率:60%。1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),7.50(dd,J=7.6,1.9Hz,1H),7.33(dd,J=7.6,1.9Hz,1H),7.29(d,J=7.6Hz,1H),5.41(s,1H),4.25(s,2H),3.86(dt,J=13.3,4.4Hz,2H),3.67(s,3H),3.30(ddd,J=13.3,10.4,3.0Hz,2H),2.40(t,J=7.1Hz,2H),2.21(dt,J=19.4,10.5Hz,4H),1.97(q,J=7.2Hz,2H),1.71(ddd,J=14.0,10.3,4.1Hz,2H),1.46(s,3H).
6-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-6-氧代己酸甲酯(7d)
7d以与7a相同的方式合成,产率:69%。1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),7.50(dd,J=7.6,2.0Hz,1H),7.34–7.31(m,1H),7.31–7.27(m,1H),5.39(s,1H),4.26(s,2H),3.86(dt,J=13.8,4.7Hz,2H),3.67(s,3H),3.30(ddd,J=13.5,10.3,3.2Hz,2H),2.38–2.33(m,2H),2.23–2.15(m,4H),1.75–1.70(m,2H),1.67(t,J=3.6Hz,4H),1.46(s,3H).
7-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-7-氧代庚酸甲酯(7e)
7e以与7a相同的方式合成,产率:43%。1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),7.50(dd,J=7.6,1.9Hz,1H),7.33(dd,J=7.6,1.9Hz,1H),7.29(d,J=7.6Hz,1H),5.20(s,1H),4.23(s,2H),3.85(dt,J=13.4,4.4Hz,2H),3.66(s,3H),3.36–3.24(m,2H),2.32(t,J=7.4Hz,2H),2.17(q,J=7.3Hz,4H),1.78–1.70(m,2H),1.69–1.63(m,4H),1.46(s,3H),1.38(q,J=8.1Hz,2H).
8-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-8-氧代辛酸甲酯(7f)
7f以与7a相同的方式合成,产率:56%。1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),7.50(dd,J=7.6,1.9Hz,1H),7.33(dd,J=7.6,1.9Hz,1H),7.30(d,J=7.6Hz,1H),5.20(s,1H),4.23(s,2H),3.86(dt,J=13.3,4.3Hz,2H),3.66(s,3H),3.34–3.25(m,2H),2.31(t,J=7.5Hz,2H),2.17(q,J=9.8,7.8Hz,4H),1.72(td,J=10.1,5.2Hz,2H),1.63(s,4H),1.46(s,3H),1.35(dt,J=7.2,3.8Hz,4H).
3-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基甲酰基)苯甲酸甲酯(7h)
7h以与7a相同的方式合成,产率:74%。1H NMR(400MHz,Chloroform-d)δ8.34(s,1H),8.16(d,J=7.8Hz,1H),8.01(d,J=7.8Hz,1H),7.63(s,1H),7.54(t,J=7.8Hz,1H),7.50(dd,J=7.7,1.8Hz,1H),7.33(dd,J=7.7,1.8Hz,1H),7.29(d,J=7.7Hz,1H),5.98(s,1H),4.25(s,2H),3.95(s,3H),3.91(dt,J=13.4,4.5Hz,2H),3.44–3.38(ddd,J=13.9,10.1,4.0Hz,2H),2.36–2.33(m,2H),1.86(ddd,J=13.9,10.1,4.0Hz,2H),1.60(s,3H).
4-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基甲酰基)苯甲酸甲酯(7i)
7i以与7a相同的方式合成,产率:74%。1H NMR(400MHz,Chloroform-d)δ8.10(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,2H),7.63(s,1H),7.50(dd,J=7.6,2.0Hz,1H),7.33(dd,J=7.6,2.0Hz,1H),7.30(d,J=7.6Hz,1H),5.94(s,1H),4.25(s,2H),3.95(s,3H),3.91(dd,J=11.3,6.7Hz,2H),3.43–3.37(m,2H),2.40–2.30(m,3H),1.86(ddd,J=14.1,10.1,4.2Hz,2H),1.60(s,3H).
4-((2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-2-氧代乙基)氨基甲酰基)苯甲酸甲酯(7j)
7j以与7a相同的方式合成,产率:56%。1H NMR(400MHz,Chloroform-d)δ8.09(d,J=8.2Hz,2H),7.88(d,J=8.3Hz,2H),7.66(t,J=5.0Hz,1H),7.57(s,1H),7.49(dd,J=7.6,2.0Hz,1H),7.32(dd,J=7.7,2.0Hz,1H),7.27(t,J=7.6Hz,1H),6.85(s,1H),4.28(s,2H),4.18(d,J=4.9Hz,2H),3.94(s,3H),3.92–3.82(m,2H),3.27(ddd,J=13.6,10.6,3.0Hz,2H),2.23(dt,J=13.6,3.6Hz,2H),1.69(ddd,J=14.2,10.6,4.2Hz,2H),1.48(s,3H).
甲基(E)-3-(4-((3-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-3-氧代丙酰胺基)甲基)苯基)丙烯酸酯(7k)
7k以与7a相同的方式合成,产率:50%。1H NMR(400MHz,Chloroform-d)δ7.65(d,J=16.1Hz,1H),7.60(s,1H),7.51–7.46(m,3H),7.36–7.29(m,2H),7.26(s,2H),7.02(d,J=6.5Hz,1H),6.96(s,1H),6.41(d,J=16.0Hz,1H),4.47(d,J=5.9Hz,2H),4.26(s,2H),3.93–3.87(m,2H),3.79(s,3H),3.27–3.21(m,2H),3.20(s,2H),2.20(d,J=13.6Hz,2H),1.69(ddd,J=14.2,10.6,4.0Hz,2H),1.45(s,3H).
甲基(E)-3-(3-((3-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-3-氧代丙酰胺基)甲基)苯基)丙烯酸酯(7l)
7l以与7a相同的方式合成,产率:58%。1H NMR(400MHz,Chloroform-d)δ7.66(d,J=16.0Hz,1H),7.59(s,1H),7.50(dd,J=7.7,1.9Hz,1H),7.41(d,J=9.1Hz,2H),7.35–7.27(m,4H),7.04(t,J=5.9Hz,1H),6.93(s,1H),6.43(d,J=16.0Hz,1H),4.46(d,J=5.9Hz,2H),4.25(s,2H),3.89(dt,J=13.6,4.5Hz,2H),3.80(s,3H),3.30–3.20(m,2H),3.20(s,2H),2.20–2.16(m,2H),1.68(ddd,J=14.2,10.5,4.2Hz,2H),1.45(s,3H).
4-((3-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-3-氧代丙酰胺基)甲基)苯甲酸甲酯(7m)
7m以与7a相同的方式合成,产率:41%。1H NMR(400MHz,Chloroform-d)δ7.99(d,J=8.2Hz,2H),7.59(s,1H),7.49(dd,J=7.7,1.8Hz,1H),7.34–7.28(m,5H),6.99(s,1H),4.50(d,J=5.9Hz,2H),4.28(s,2H),3.90(s,3H),3.87(t,J=4.3Hz,2H),3.28–3.22(m,2H),3.21(s,2H),2.20–2.16(m,2H),1.73–1.66(m,2H),1.44(s,3H).
实施例3:中间体7g,7n-7t,7v的制备
5-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)戊酸甲酯(7g)
将化合物6(89mg,0.23mmol)、5-溴戊酸甲酯(54mg,0.27mmol)和K2CO3(95mg,0.69mmol)溶于3mL DMF并在80℃下搅拌8小时。反应完后,将反应混合物倒入水中并用EtOAc萃取。合并的EtOAc用饱和食盐水洗涤并用无水硫酸镁干燥。减压蒸馏将得到的粗品通过柱层析(DCM/MeOH=100:1-30:1)纯化,得到白色固体50mg,产率:47%。1H NMR(400MHz,DMSO-d6)δ7.62(dd,J=8.0,1.3Hz,1H),7.48(s,1H),7.39(t,J=7.8Hz,1H),7.31(dd,J=8.0,1.3Hz,1H),5.59(s,2H),3.58(s,3H),3.55(s,3H),3.39(s,2H),2.55–2.52(m,2H),2.32(t,J=7.4Hz,2H),1.60(dt,J=15.5,7.5Hz,4H),1.42(dq,J=14.1,6.3Hz,4H),1.10(s,3H).
甲基(E)-3-(4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)苯基)丙烯酸酯(7n)
将化合物6(136mg,0.35mmol)、(E)-3-(4-(溴甲基)苯基)丙烯酸甲酯(99mg,0.388mmol)和K2CO3(146mg,1.05mmol)溶于3mLDMF中并在室温下搅拌。将反应混合物倒入水中并用EtOAc萃取。合并的EtOAc用饱和食盐水洗涤并用无水硫酸镁干燥。减压蒸馏将得到的粗品通过柱层析(DCM/MeOH=100:1-50:1)纯化得到黄色固体117mg,收率:63%。1HNMR(400MHz,Chloroform-d)δ7.69(d,J=16.0Hz,1H),7.62(s,1H),7.49(d,J=8.2Hz,3H),7.41(d,J=8.1Hz,2H),7.33(dd,J=7.6,1.7Hz,1H),7.29(d,J=7.7Hz,1H),6.42(d,J=16.0Hz,1H),4.20(s,2H),3.80(s,3H),3.77(s,2H),3.73(dd,J=11.5,6.5Hz,2H),3.64–3.56(m,2H),1.76–1.69(m,2H),1.67–1.61(m,2H),1.25(s,3H).
3-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)苯甲酸甲酯(7o)
7o以与7n相同的方式合成,产率:71%。1H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.92(d,J=7.8Hz,1H),7.62(s,1H),7.60(d,J=7.7Hz,1H),7.49(dd,J=7.8,1.4Hz,1H),7.40(t,J=7.7Hz,1H),7.33(dd,J=7.8,1.4Hz,1H),7.29(d,J=7.7Hz,1H),4.20(s,2H),3.92(s,3H),3.80(s,2H),3.76–3.70(m,2H),3.65–3.58(m,2H),1.76–1.70(m,2H),1.68–1.62(m,2H),1.26(s,3H).
4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)苯甲酸甲酯(7p)
7p以与7n相同的方式合成,产率:42%。1H NMR(400MHz,Chloroform-d)δ7.99(d,J=8.1Hz,2H),7.62(s,1H),7.49(dd,J=7.9,1.6Hz,1H),7.46(d,J=8.1Hz,2H),7.33(dd,J=7.6,1.5Hz,1H),7.29(d,J=7.7Hz,1H),4.20(s,2H),3.91(s,3H),3.81(s,2H),3.78–3.69(m,2H),3.63–3.57(m,2H),1.76–1.61(m,4H),1.26(s,3H).
甲基(E)-3-(4-(2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)乙酰氨基)苯基)丙烯酸酯(7q)
7q以与7g相同的方式合成,产率:62%。1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),7.72–7.66(s,4H),7.65–7.56(m,2H),7.50(s,1H),7.39(t,J=7.8Hz,1H),7.31(dd,J=7.6,1.2Hz,1H),6.54(d,J=16.0Hz,1H),5.60(s,2H),3.71(s,3H),3.62–3.55(m,4H),3.32(s,2H),2.36(s,1H),1.66–1.57(m,2H),1.53–1.47(m,2H),1.10(s,3H).
甲基(E)-3-(4-((2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)乙酰氨基)甲基)苯基)丙烯酸酯(7r)
7r以与7g相同的方式合成,产率:53%。7r was synthesized in the same wayas 7g,yield:53%.1H NMR(400MHz,DMSO-d6)δ8.40(t,J=6.1Hz,1H),7.67–7.63(m,3H),7.62–7.61(m,1H),7.48(s,1H),7.38(t,J=7.8Hz,1H),7.32–7.30(m,3H),6.61(d,J=16.1Hz,1H),5.59(s,2H),4.35(d,J=6.1Hz,2H),3.71(s,3H),3.61–3.51(m,4H),3.16(s,2H),2.21(s,1H),1.59–1.56(m,2H),1.52–1.39(m,2H),1.05(s,3H).
甲基(E)-3-(4-(4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)苯甲酰胺基)苯基)丙烯酸酯(7s)
7s以与7n相同的方式合成,产率:75%。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),7.92(d,J=8.1Hz,2H),7.87(d,J=8.6Hz,2H),7.72(d,J=8.6Hz,2H),7.66–7.60(m,2H),7.56(d,J=8.1Hz,2H),7.50(s,1H),7.39(t,J=7.8Hz,1H),7.31(d,J=6.6Hz,1H),6.57(d,J=16.0Hz,1H),5.60(s,2H),3.72(s,3H),3.67–3.64(m,2H),3.56–3.51(m,2H),1.99(s,1H),1.70–1.66(m,2H),1.52–1.47(m,2H),1.17(s,3H).
甲基(E)-3-(4-((4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)苯甲酰氨基)甲基)苯基)丙烯酸酯(7t)
7t以与7n相同的方式合成,产率:54%。1H NMR(400MHz,DMSO-d6)δ9.02(t,J=5.9Hz,1H),7.84(d,J=8.1Hz,2H),7.72–7.65(m,3H),7.62(d,J=6.4Hz,1H),7.54–7.46(m,3H),7.44–7.27(m,4H),6.61(d,J=16.0Hz,1H),5.59(s,2H),4.49(d,J=5.7Hz,2H),3.74(s,2H),3.72(s,3H),3.67–3.63(m,2H),3.56–3.48(m,2H),1.90(s,1H),1.68–1.65(m,2H),1.51–1.46(m,2H),1.16(s,3H).
4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)苯甲酸(7v)
将6(233mg,0.6mmol)、4-(溴甲基)苯甲酸甲酯(151mg,0.66mmol)和K2CO3(249mg,1.8mmol)溶于3mL DMF中在室温下8小时。然后,将反应混合物倒入水中并用EtOAc萃取。合并的EtOAc用饱和食盐水洗涤并经无水硫酸镁干燥,过滤并浓缩,得到固体,然后,溶解在10mL混合溶剂(4M NaOH/EtOH=1:1)中,在50℃下搅拌1小时,除去有机溶剂。残余水溶液用1M HCl酸化至pH值5-6并产生黄色沉淀。过滤得到黄色固体100mg,不经纯化直接用于下一步反应,收率:34%。1H NMR(400MHz,DMSO-d6)δ9.35(s,1H),7.99(d,J=8.0Hz,2H),7.75(d,J=7.5Hz,2H),7.63(d,J=8.0Hz,1H),7.57(s,1H),7.40(t,J=7.8Hz,1H),7.30(d,J=7.6Hz,1H),5.70(s,2H),4.31–4.28(m,2H),4.24(s,2H),3.13–2.99(m,2H),2.07–1.95(s,4H),1.58(s,3H).
实施例4:目标化合物8a-8v的制备
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-羟基丙二酰胺(8a)
将KOH(11.2g,200mmol)和NH2OH-HCl(9.2g,132.4mmol)分别溶解在28mL和48mL无水MeOH中,得到溶液A和溶液B。然后将溶液A在0°下滴加到溶液B中C并搅拌30分钟。然后,滤出沉淀物(KCl),得到NH2OK溶液。将化合物7a(106mg,0.23mmol)溶解在NH2OK溶液(5mL)中并在室温搅拌6小时。反应完成后,真空蒸发溶剂。将残余物用1M HCl酸化至pH 7,过滤沉淀并干燥以获得粗产物。粗产物通过柱层析(DCM/MeOH=100:1-20:1)纯化,得到黄色固体60mg,产率:57%,mp 158-160℃。1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.88(s,1H),7.77(s,1H),7.61(d,J=8.0Hz,1H),7.50(s,1H),7.39(t,J=7.8Hz,1H),7.30(d,J=7.5Hz,1H),5.60(s,2H),3.88–3.85(m,2H),3.21–3.16(m,2H),2.91(s,2H),2.15–2.11(m,2H),1.50–1.45(m,2H),1.32(s,3H).13C NMR(101MHz,DMSO)δ166.82,153.61,151.11,139.87,132.49,132.00,131.10,130.17,128.69,125.25,117.12,51.62,41.93,40.53,35.16,26.32.HRMS(ESI-)m/z,calcd for C19H22Cl2N6O3([M-H]-)451.1058,found:451.1062.
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N4-羟基琥珀酰胺(8b)
8b以与8a相同的方式合成,产率:38%。mp 238-240℃.1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),7.87(s,1H),7.61(d,J=7.5Hz,1H),7.49(s,1H),7.41–7.34(m,1H),7.30(d,J=7.6Hz,1H),5.59(s,2H),3.85–3.82(m,2H),3.29–3.08(m,2H),2.37–2.32(m,2H),2.30–1.88(m,4H),1.57–1.38(m,2H),1.29(s,3H).13C NMR(101MHz,DMSO)δ171.70,169.00,153.60,151.10,139.87,132.49,132.00,131.09,130.16,128.69,125.16,117.10,51.28,35.23,31.99,28.48,26.38.HRMS(ESI-)m/z,calcd for C20H24Cl2N6O3([M-H]-)465.1214,found:465.1210.
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N5-羟基戊二酰胺(8c)
8c以与8a相同的方式合成,产率:45%。mp 214-216℃.1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.70(s,1H),7.62(dd,J=8.0,1.6Hz,1H),7.50(s,1H),7.45–7.35(m,2H),7.30(dd,J=7.7,1.6Hz,1H),5.63(s,2H),3.88–3.82(m,2H),3.25–3.11(m,2H),2.19–2.06(m,4H),1.95(t,J=7.5Hz,2H),1.70(p,J=7.5Hz,2H),1.45(ddd,J=14.1,10.5,4.1Hz,2H),1.30(s,3H).13C NMR(101MHz,DMSO)δ172.35,169.16,153.56,151.10,139.87,132.50,132.00,131.09,130.15,128.68,125.18,117.08,51.28,36.06,35.31,32.24,26.36,22.24.HRMS(ESI-)m/z,calcd for C21H26Cl2N6O3([M-H]-)479.1371,found:479.1361.
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N6-羟基己二胺(8d)
8d以与8a相同的方式合成,产率:40%。mp 144-146℃.1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.67(s,1H),7.62(dd,J=7.9,1.6Hz,1H),7.51(s,1H),7.43–7.36(m,2H),7.31(dd,J=7.7,1.6Hz,1H),5.62(s,2H),3.85(dt,J=13.7,4.5Hz,2H),3.18(ddd,J=13.5,10.5,3.0Hz,2H),2.19–2.07(m,4H),1.97–1.94(m,2H),1.52–1.43(m,6H),1.31(s,3H).13C NMR(101MHz,DMSO)δ172.64,169.48,153.53,151.10,139.87,132.51,132.00,131.09,130.15,128.68,125.17,117.08,51.27,36.46,35.25,32.66,26.34,25.70,25.34.HRMS(ESI-)m/z,calcd for C22H28Cl2N6O3([M-H]-)493.1527,found:493.1510.
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N7-羟基庚二酰胺(8e)
8e以与8a相同的方式合成,产率:43%。mp 124-126℃.1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.69(s,1H),7.61(d,J=7.8Hz,1H),7.50(s,1H),7.39(t,J=7.8Hz,1H),7.34(s,1H),7.30(d,J=7.0Hz,1H),5.58(s,2H),3.85–3.82(m,2H),3.18(t,J=10.8Hz,2H),2.19–2.04(m,4H),1.93(t,J=7.2Hz,2H),1.56–1.41(m,6H),1.30(s,3H),1.26–1.20(m,2H).13CNMR(101MHz,DMSO)δ172.74,169.42,153.54,151.10,139.88,132.49,132.00,131.09,130.15,128.69,125.17,117.07,51.24,36.53,35.25,32.61,28.76,26.34,25.71,25.41.HRMS(ESI-)m/z,calcd for C23H30Cl2N6O3([M-H]-)507.1683,found:507.1682.
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N8-羟基辛二酰胺(8f)
8f以与8a相同的方式合成,产率:34%。mp 146-148℃.1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),8.63(s,1H),7.61(d,J=7.9Hz,1H),7.50(s,1H),7.39(t,J=7.8Hz,1H),7.34(s,1H),7.30(d,J=6.8Hz,1H),5.58(s,2H),3.85–3.82(m,2H),3.18(t,J=10.9Hz,2H),2.17–2.13(m,2H),2.08(t,J=7.3Hz,2H),1.92(t,J=7.2Hz,2H),1.48–1.47(m,6H),1.30(s,3H),1.24–1.17(s,4H).13C NMR(101MHz,DMSO)δ172.81,169.49,153.55,151.10,139.87,132.49,131.99,131.09,130.16,128.69,125.18,117.07,51.23,36.64,35.24,32.71,28.90,26.37,25.91,25.57.HRMS(ESI-)m/z,calcd for C24H32Cl2N6O3([M-H]-)521.1840,found:521.1825.
5-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-N-羟基戊酰胺(8g)
8g以与8a相同的方式合成,产率:53%。mp 156-158℃.1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),7.61(d,J=7.9Hz,1H),7.47(s,1H),7.38(t,J=7.8Hz,1H),7.30(d,J=7.5Hz,1H),5.57(s,2H),3.63–3.60(m,2H),3.48–3.43(m,2H),2.45(t,J=6.6Hz,2H),1.94(t,J=7.3Hz,2H),1.57–1.54(m,4H),1.43–1.34(m,4H),1.06(s,3H).13C NMR(101MHz,DMSO)δ169.46,153.66,151.08,139.93,132.51,132.01,131.09,130.11,128.66,124.88,117.11,50.21,40.83,40.69,36.49,32.79,30.68,25.67,23.75.HRMS(ESI+)m/z,calcdfor C21H28Cl2N6O2([M+H]+)467.1723,found:467.1718.
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-羟基间苯二甲酰胺(8h)
8h以与8a相同的方式合成,产率:45%。mp 210-212℃.1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.23(s,1H),7.96–7.80(m,3H),7.61(dd,J=8.0,1.6Hz,1H),7.53(s,1H),7.45(t,J=7.6Hz,1H),7.39(t,J=7.8Hz,1H),7.31(dd,J=7.6,1.6Hz,1H),5.61(s,2H),3.93–3.87(m,2H),3.31–3.26(m,2H),2.42–2.39(m,2H),1.64–1.53(m,2H),1.44(s,3H).13CNMR(101MHz,DMSO)δ167.22,163.62,153.64,151.12,139.88,136.36,132.50,132.00,131.10,130.16,129.39,128.70,128.45,126.10,125.23,117.15,52.29,52.11,40.84,35.22,26.19.HRMS(ESI-)m/z,calcd for C24H24Cl2N6O3([M-H]-)513.1214,found:513.1208.
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N4-羟基对苯二甲酰胺(8i)
8i以与8a相同的方式合成,产率:55%。mp 190-192℃.1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.90–7.81(m,5H),7.62(dd,J=8.0,1.6Hz,1H),7.53(s,1H),7.40(t,J=7.8Hz,1H),7.31(dd,J=7.6,1.6Hz,1H),5.62(s,2H),3.93–3.87(m,2H),3.31–3.24(m,2H),2.41–2.37(m,2H),1.64–1.55(m,2H),1.44(s,3H).13C NMR(101MHz,DMSO)δ166.86,153.63,151.12,139.88,132.50,132.00,131.09,130.16,128.70,127.88,126.94,125.25,117.14,52.33,52.18,40.82,35.20,26.17.HRMS(ESI-)m/z,calcd for C24H24Cl2N6O3([M-H]-)513.1214,found:513.1203.
N1-(2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-2-氧代乙基)-N4-羟基对苯二甲酰胺(8j)
8j以与8a相同的方式合成,产率:51%。mp 184-186℃.1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.80(s,1H),8.66(s,1H),7.98–7.90(m,2H),7.87–7.79(m,2H),7.67–7.54(m,2H),7.51(s,1H),7.40(t,J=7.8Hz,1H),7.32(dd,J=7.6,1.7Hz,1H),5.62(s,2H),3.98–3.80(m,4H),3.27–3.16(m,2H),2.19–2.16(m,2H),1.54–1.44(m,2H),1.34(s,3H).13C NMR(101MHz,DMSO)δ169.00,166.93,166.34,153.60,151.11,139.87,132.50,132.00,131.10,130.16,129.43,128.70,127.76,127.19,127.01,125.23,117.13,51.57,51.37,43.53,35.25,26.44.HRMS(ESI-)m/z,calcd for C26H27Cl2N7O4([M-H]-)570.1429,found:570.1409.
(E)-N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(4-(3-(羟基氨基))-3-oxoprop-1-烯-1-基)苄基)丙二酰胺(8k)
8k以与8a相同的方式合成,产率:60%。mp 176-178℃.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.49(s,1H),7.70(s,1H),7.61(d,J=7.9Hz,1H),7.51(s,1H),7.47(d,J=7.4Hz,2H),7.39(t,J=7.8Hz,1H),7.37–7.17(m,4H),6.45(d,J=15.9Hz,1H),5.60(s,2H),4.30(d,J=5.6Hz,2H),3.89–3.85(m,2H),3.25–3.17(m,2H),3.14(s,2H),2.16–2.13(m,2H),1.51–1.46(m,2H),1.33(s,3H).13C NMR(101MHz,DMSO)δ167.78,167.11,153.61,151.11,141.01,139.86,134.12,132.49,132.00,131.10,130.17,128.70,128.17,127.78,125.25,119.40,117.11,51.63,44.75,42.45,40.54,35.17,26.34.HRMS(ESI-)m/z,calcdfor C29H31Cl2N7O4([M-H]-)610.1742,found:610.1738.
(E)-N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(3-(3-(羟基氨基))-3-oxoprop-1-烯-1-基)苄基)丙二酰胺(8l)
8l以与8a相同的方式合成,产率:64%。mp 190-192℃.1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.50(s,1H),7.69(s,1H),7.61(d,J=7.9Hz,1H),7.50(s,1H),7.46–7.34(m,3H),7.34–7.11(m,4H),6.48(d,J=15.5Hz,1H),5.59(s,2H),4.30(d,J=5.2Hz,2H),3.88–3.85(m,2H),3.20–3.18(m,2H),3.14(s,2H),2.15–2.12(m,2H),1.48(t,J=10.2Hz,2H),1.32(s,3H).13C NMR(101MHz,DMSO)δ167.80,167.09,153.60,151.11,140.40,139.87,132.49,132.00,131.10,130.16,129.33,128.69,128.42,126.54,126.31,125.22,117.11,51.62,44.79,42.54,40.53,35.18,26.36.HRMS(ESI-)m/z,calcd for C29H31Cl2N7O4([M-H]-)610.1742,found:610.1735.
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(4-(羟基氨基甲酰基)苄基)丙二酰胺(8m)
8m以与8a相同的方式合成,产率:46%。mp 180-182℃.1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.59(s,1H),7.77(d,J=7.1Hz,1H),7.71(d,J=8.0Hz,2H),7.63–7.59(m,1H),7.50(s,1H),7.39(t,J=7.8Hz,1H),7.34–7.27(m,3H),5.60(s,2H),4.32(d,J=5.7Hz,2H),3.89–3.85(m,2H),3.23–3.20(m,2H),3.16(s,2H),2.17–2.13(m,2H),1.48(t,J=10.1Hz,2H),1.33(s,3H).13C NMR(101MHz,DMSO)δ167.83,167.14,164.13,153.61,151.11,139.86,132.49,132.00,131.10,130.17,128.70,127.38,127.17,125.23,117.12,51.65,44.81,42.38,35.16,26.35.HRMS(ESI-)m/z,calcd for C27H29Cl2N7O4([M-H]-)584.1585,found:584.1580.
(E)-3-(4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)苯基)-N-羟基丙烯酰胺(8n)
8n以与8a相同的方式合成,产率:42%。mp 166-168℃.1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.00(s,1H),7.60(dd,J=7.6,1.3Hz,1H),7.56–7.46(m,3H),7.45–7.35(m,4H),7.31(dd,J=7.6,1.3Hz,1H),6.43(d,J=15.8Hz,1H),5.56(s,2H),3.70(s,2H),3.67–3.64(m,2H),3.54–3.50(m,2H),1.68–1.65(m,2H),1.51–1.45(m,2H),1.16(s,3H).13C NMR(101MHz,DMSO)δ163.18,153.66,151.10,144.14,139.93,133.59,132.49,132.00,131.11,130.12,129.06,128.68,127.67,124.93,118.88,117.09,50.93,45.32,40.68,36.39,25.75.HRMS(ESI-)m/z,calcd for C26H28Cl2N6O2([M-H]-)525.1578,found:525.1571.
3-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-羟基苯甲酰胺(8o)
8o以与8a相同的方式合成,产率:42%。mp 152-154℃.1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.00(s,1H),7.79(s,1H),7.61(dd,J=7.6,1.4Hz,1H),7.58(s,1H),7.53(d,J=7.6Hz,1H),7.49(s,1H),7.41–7.35(m,2H),7.31(dd,J=7.6,1.4Hz,1H),5.57(s,2H),3.72(s,2H),3.66–3.63(m,2H),3.60–3.49(m,2H),1.69–1.66(m,2H),1.52–1.47(m,2H),1.18(s,3H).13C NMR(101MHz,DMSO)δ164.76,153.65,151.10,142.61,139.93,133.09,132.49,132.01,131.39,131.11,130.12,128.68,128.49,127.23,125.37,124.94,117.08,51.05,45.42,36.36,25.63.HRMS(ESI-)m/z,calcd for C24H26Cl2N6O2([M-H]-)499.1422,found:499.1417.
4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-羟基苯甲酰胺(8p)
8p以与8a相同的方式合成,产率:48%。mp 156-158℃.1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.97(s,1H),7.89–7.69(m,2H),7.61(dd,J=8.0,1.6Hz,1H),7.49(s,1H),7.46(d,J=8.1Hz,2H),7.39(t,J=7.8Hz,1H),7.31(dd,J=7.7,1.6Hz,1H),5.56(s,2H),3.73(d,J=6.0Hz,2H),3.67–3.62(m,2H),3.55–3.49(m,2H),1.68–1.65(m,2H),1.52–1.45(m,2H),1.16(s,3H).13C NMR(101MHz,DMSO)δ164.58,153.65,151.10,145.80,139.93,132.50,132.01,131.40,131.11,130.12,129.55,128.68,128.41,128.18,127.11,124.95,117.09,51.05,45.24,40.68,36.35,25.64.HRMS(ESI-)m/z,calcd for C24H26Cl2N6O2([M-H]-)499.1422,found:499.1417.
(E)-3-(4-(2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)乙酰氨基)苯基)-N-羟基丙烯酰胺(8q)
8q以与8a相同的方式合成,产率:50%。mp 176-178℃.1H NMR(400MHz,DMSO-d6)δ10.08(s,1H),7.69(d,J=8.6Hz,2H),7.62(d,J=8.4Hz,3H),7.51–7.47(m,2H),7.39(t,J=7.8Hz,1H),7.31(d,J=7.4Hz,1H),6.44(d,J=16.0Hz,1H),5.60(s,2H),3.59–3.57(s,4H),1.68–1.58(m,2H),1.54–1.47(m,2H),1.10(s,3H).13C NMR(101MHz,DMSO)δ171.59,168.98,153.64,153.57,151.09,139.93,132.50,132.01,131.10,130.12,128.67,128.57,125.03,124.96,119.70,117.09,50.88,50.57,46.03,43.39,36.31,25.38.HRMS(ESI+)m/z,calcd for C27H29Cl2N7O3([M+H]+)570.1781,found:570.1691.
(E)-3-(4-((2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)乙酰氨基)甲基)苯基)-N-羟基丙烯酰胺(8r)
8r以与8a相同的方式合成,产率:62%。mp 164-166℃.1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.37(t,J=6.0Hz,1H),7.61(d,J=7.9Hz,1H),7.47(d,J=10.9Hz,2H),7.38(t,J=7.8Hz,1H),7.34–7.09(m,4H),6.43(d,J=16.0Hz,1H),5.59(s,2H),4.32(d,J=5.4Hz,2H),3.61–3.51(m,4H),3.15(s,2H),2.20(s,1H),1.58–1.55(m,2H),1.49–1.38(m,2H),1.05(s,3H).13C NMR(101MHz,DMSO)δ172.62,162.68,153.63,151.09,139.92,137.34,132.50,132.00,131.10,130.13,128.68,128.15,127.70,124.95,119.54,117.10,50.69,45.31,42.18,36.32,25.39.HRMS(ESI+)m/z,calcd for C28H31Cl2N7O3([M+H]+)584.1938,found:584.1914.
(E)-4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-(4-(3-(羟基氨基)-3-氧代丙基-1-烯-1-基)苯基)苯甲酰胺(8s)
8s以与8a相同的方式合成,产率:58%。mp 178-180℃.1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),7.92(d,J=7.9Hz,2H),7.84(d,J=8.3Hz,2H),7.61(d,J=7.9Hz,1H),7.55(d,J=7.7Hz,4H),7.50(s,1H),7.43–7.35(m,2H),7.31(d,J=7.5Hz,2H),6.40(d,J=15.6Hz,1H),5.59(s,2H),3.77(s,2H),3.68–3.64(m,2H),3.53(t,J=9.7Hz,2H),1.99(s,1H),1.70–1.66(m,2H),1.52–1.47(m,2H),1.17(s,3H).13C NMR(101MHz,DMSO)δ166.02,163.32,153.68,151.10,146.95,140.84,139.94,133.25,132.52,132.02,131.11,130.58,130.13,128.67,128.43,128.35,128.02,124.95,120.80,118.11,117.12,50.88,45.34,40.72,36.50,25.88.HRMS(ESI+)m/z,calcd for C33H33Cl2N7O3([M+H]+)646.2094,found:646.2042.
(E)-4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-(4-(3-(羟基氨基)-3-oxoprop-1-烯-1-基)苄基)苯甲酰胺(8t)
8t以与8a相同的方式合成,产率:64%。mp 166-168℃.1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.08–8.94(m,1H),7.85(d,J=8.0Hz,2H),7.61(d,J=7.9Hz,1H),7.54–7.43(m,5H),7.43–7.36(m,2H),7.34(d,J=8.0Hz,2H),7.30(d,J=7.6Hz,1H),6.44(d,J=16.0Hz,1H),5.59(s,2H),4.49(d,J=5.5Hz,2H),3.76(s,2H),3.67–3.51(m,4H),1.69–1.66(m,1H),1.52–1.50(m,2H),1.18(s,3H).13C NMR(101MHz,DMSO)δ166.66,163.21,153.64,151.11,141.76,139.93,138.43,133.89,132.96,132.53,132.02,131.10,130.13,128.68,128.45,128.22,127.94,127.58,124.98,119.14,117.12,51.31,45.23,42.89,40.71,36.29,25.41.HRMS(ESI+)m/z,calcd for C34H35Cl2N7O3([M+H]+)660.2251,found:660.2198.
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(2-氨基苯基)丙二酰胺(8u)
8u以与7a相同的方式合成,产率:40%。mp 228-230℃.1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),7.75(s,1H),7.67–7.58(m,1H),7.51(s,1H),7.39(t,J=7.8Hz,1H),7.35–7.26(m,1H),7.10(d,J=7.7Hz,1H),6.91(t,J=7.1Hz,1H),6.70(d,J=7.5Hz,1H),6.51(t,J=7.6Hz,1H),5.60(s,2H),4.93(s,2H),3.89–3.86(m,2H),3.28(s,2H),3.24–3.19(m,2H),2.17–2.14(m,2H),1.53–1.48(m,2H),1.35(s,3H).13C NMR(101MHz,DMSO)δ167.42,166.70,153.61,151.11,143.06,139.89,132.51,132.02,131.09,130.16,128.68,126.77,126.37,125.29,123.29,117.17,116.39,115.92,51.76,45.12,40.59,35.22,26.32.HRMS(ESI-)m/z,calcd for C25H27Cl2N7O2([M-H]-)526.1531,found:526.1526.
4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-(2-氨基苯基)苯甲酰胺(8v)
8v以与7a相同的方式合成,产率:31%。mp 166-168℃.1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),7.94(d,J=7.9Hz,2H),7.61(dd,J=7.9,1.4Hz,1H),7.58–7.45(m,3H),7.39(t,J=7.8Hz,1H),7.31(dd,J=7.6,1.4Hz,1H),7.17(d,J=7.6Hz,1H),7.01–6.94(m,1H),6.78(d,J=7.9Hz,1H),6.60(t,J=7.5Hz,1H),5.58(s,2H),4.87(s,2H),3.80(s,2H),3.67–3.54(m,3H),1.71–1.68(m,2H),1.52(s,2H),1.20(s,3H).13C NMR(101MHz,DMSO)δ165.70,153.64,151.11,143.55,139.93,133.33,132.53,132.02,131.10,130.14,128.68,128.40,128.08,127.11,126.89,125.02,123.97,117.15,116.82,116.69,55.36,45.24,40.74,36.28,25.40.HRMS(ESI-)m/z,calcd for C30H31Cl2N7O([M-H]-)574.1894,found:574.1891.
实施例5:本发明中目标化合物对HDACs抑制活性
1.材料:
HDACs酶(HeLa细胞核提取物);Boc-Lys(Ac)-AMC底物;胰酶;EDTA;TrichostatinA(TSA,0.3mM,溶于二甲基亚砜);96孔全黑酶标板;甘油;超纯水
2.方法:
Buffer的配制:
配方为15mM Tris-HCl(pH=8.0),250μM EDTA,250mM NaCl,10%甘油。
Trypsin溶液的配制:
配方为10mg/mL胰酶,Buffer,2μM TSA。
底物溶液的配制:
用DMSO溶解底物配制成30mM的储备液,然后用buffer稀释至300μM,使得
DMSO的含量为1%左右。
酶液的稀释:
用buffer将酶液按1:80的比例稀释。
化合物溶液的配制:
用buffer将化合物(待测化合物和阳性对照药SAHA)稀释成5×终浓度
100%和空白的配制与测定:
50μL HDAC buffer与10μL酶液混合,5分钟后加入40μL底物在37℃下反应0.5小时,然后加入100μL Trypsin solution终止上述反应,并在37℃下反应20分钟后在(390nm/460nm)测定荧光强度,即得100%吸收;60μL buffer加入40μL底物后在37℃下反应0.5小时加入100μL Trypsin溶液,并在37℃下反应20分钟后在(390nm/460nm)测定荧光强度,即得空白吸收。
化合物抑制HDACs活性的测定:
50μL含有药物的buffer与10μL酶液混合预先孵育5分钟,加入40μL底物后在37℃下反应0.5小时,然后再加入100μL Trypsin溶液终止上述反应,并在37℃下反应20分钟后,在(390nm/460nm)测定荧光强度,利用GraphPad Prism软件和公式计算抑制率和IC50值。
(表1)
表1.目标化合物的HDACs抑制活性
a IC50值表示为两次独立测定的平均值±标准偏差。
实施例6:本发明中目标化合物对SHP2抑制活性
1.材料:
SHP2WT全长蛋白;DiFMUP;黑色酶标板;pIRS-1肽;HEPES;NaCl;KCl;EDTA;
Tween20;DTT。
2.方法:
Buffer的配制:
配方为60mM HEPES(pH 7.5),75mM NaCl,75mM KCl,1mM EDTA,0.05% Tween20,
5mM DTT。
化合物抑制SHP2WT活性的测定:
在黑色孔板中加入0.5nM SHP2WT,1μM双酪氨酸磷酸化肽和不同浓度的化合物,室温孵育30分钟。然后加入10μM DiFMUP共同孵育30分钟(缓冲液:60mM HEPES pH 7.2,75mMNaCl,75mM KCl,1mM EDTA,0.05%吐温-20和5mM DTT)。最后,加入5μL的50μM bpV(Phen)(Sigma,#SML0889)溶液以淬灭反应。用多功能读数仪读取450nm(λex=350)处的荧光光强度,IC50值用GraphPad Prism软件计算。(表2)
表2目标化合物的SHP2抑制活性
a IC50值表示为两次独立测定的平均值±标准偏差。
实施例7:本发明中目标化合物抗增殖活性实验
1.材料:
BxPC-3(人胰腺癌细胞),SW 1990(人胰腺癌细胞),AsPC-1(人胰腺癌细胞),MV4-11(人急性单核细胞白血病细胞),KYSE520(人食管鳞癌细胞)四株细胞,10%胎牛血清(美国Hyclone公司),2.5g·L-1胰蛋白酶(美国Gibco公司),CCK-8,改良型RPMI1640培养基,DMEM培养基(美国Hyclone公司),阳性对照药HDAC抑制剂SAHA,阳性对照药SHP2抑制剂(SHP099),96孔板。
2.方法:
常规培养细胞,收集对数生长的细胞进行实验;用含胎牛血清10%的RPMI1640或DMEM培养基将对数生长期实体瘤细胞稀释至4×103个·mL-1(血液瘤细胞稀释至1×104个·mL-1)后接种于96孔板中(每孔加100μL),不加细胞的作为空白孔,之后放于恒温孵育箱(37℃,5%二氧化碳)中培养8小时;加入用培养基配制的目标化合物溶液和阳性药溶液,不加药的作为100%孔,于恒温孵育箱(37℃,5%二氧化碳)中培养72小时后加入20μL CCK-8,三小时后用酶标仪于450nm波长处测定每孔的吸光度值,计算抑制率和IC50值。(表3)
表3.选定化合物对肿瘤细胞的抗增殖活性
a IC50值表示为两次独立测定的平均值±标准偏差。
实施例8:本发明化合物对人急性单核细胞白血病细胞治疗效果研究
1.材料:
细胞系:人急性单核细胞白血病细胞(MV4-11)。
实验动物:六周龄BALB/c雌性裸鼠。
2.方法:
将约2×107个MV4-11细胞重悬于50μL无血清高糖培养基和50μL基质胶中,并皮下植入BALB/c裸鼠右侧腋窝区域。当肿瘤体积达到约100mm3时,开始口服给药,连续20天。治疗组剂量为40mg/kg/d,对照组给予等量生理盐水。在治疗期间每天测量肿瘤大小和小鼠体重。肿瘤体积计算公式:V(mm3)=长(mm)×宽2(mm)/2;肿瘤生长抑制值(TGI)计算公式:TGI=(1-治疗组肿瘤平均重量/对照组肿瘤平均重量)×100%。
3.实验结果:
结果如图1所示,目标化合物8r和8t的肿瘤抑制率分别为44%和64%,抑瘤效果明显优于阳性对照药,其中8t效果最好,也优于阳性对照药的组合。
Claims (8)
1.一种SHP2/HDAC双靶点抑制剂,是具有通式I结构的化合物,以及其立体异构体、药学上可接受的盐:
通式I中,
R1、R2各自独立的选自氢、氟、氯、溴;
A为呋喃、噻吩、吡咯、噻唑、咪唑、噁唑、噻唑、异噁唑、异噻唑、吡啶、吡嗪、嘧啶、哒嗪、吡喃、哌嗪、吲哚、喹啉、蝶啶、吖啶、苯并咪唑、异喹啉、吡嗪并吡唑、吡嗪并咪唑;
R3为氢原子或羰基;
X为0至10个碳原子的饱和直链烃基、芳基或以下连接基团之一:
n=0,1,2,3,4,5,6,7,8,9,10;
R4为羟基或2-氨基苯基;
R5为氢原子或以下结构:
R6为氢原子或羰基;
Y为0至10个碳原子的饱和直链烃基、苯基或以下连接基团之一:
n=0,1,2,3,4,5,6,7,8,9,10;
R7为羟基或2-氨基苯基。
2.如权利要求1所述的SHP2/HDAC双靶点抑制剂,其特征在于,为下列之一:
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-羟基丙二酰胺(8a),
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N4-羟基琥珀酰胺(8b),
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N5-羟基戊二酰胺(8c),
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N6-羟基己二胺(8d),
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N7-羟基庚二酰胺(8e),
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N8-羟基辛二酰胺(8f),
5-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-N-羟基戊酰胺(8g),
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-羟基间苯二甲酰胺(8h),
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N4-羟基对苯二甲酰胺(8i),
N1-(2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)-2-氧代乙基)-N4-羟基对苯二甲酰胺(8j),
(E)-N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(4-(3-(羟基氨基))-3-氧代丙基-1-烯-1-基)苄基)丙二酰胺(8k),
(E)-N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(3-(3-(羟基氨基))-3-氧代丙基-1-烯-1-基)苄基)丙二酰胺(8l),
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(4-(羟基氨基甲酰基)苄基)丙二酰胺(8m),
(E)-3-(4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)苯基)-N-羟基丙烯酰胺(8n),
3-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-羟基苯甲酰胺(8o),
4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-羟基苯甲酰胺(8p),
(E)-3-(4-(2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)乙酰氨基)苯基)-N-羟基丙烯酰胺(8q),
(E)-3-(4-((2-((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)乙酰氨基)甲基)苯基)-N-羟基丙烯酰胺(8r),
(E)-4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-(4-(3-(羟基氨基)-3-氧代丙基-1-烯-1-基)苯基)苯甲酰胺(8s),
(E)-4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-(4-(3-(羟基氨基)-3-氧代丙基-1-烯-1-基)苄基)苯甲酰胺(8t),
N1-(1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)-N3-(2-氨基苯基)丙二酰胺(8u),和
4-(((1-(6-氨基-5-(2,3-二氯苯基)吡嗪-2-基)-4-甲基哌啶-4-基)氨基)甲基)-N-(2-氨基苯基)苯甲酰胺(8v)。
3.如权利要求1所述的一种SHP2/HDAC双靶点抑制剂的制备方法,包括步骤:
化合物1和化合物2发生Suzuki偶联反应得到中间体3,然后氨基被Boc保护基团保护,得到中间体4;4与(4-甲基哌啶-4-基)氨基甲酸叔丁酯发生亲核取代反应得到中间体5,随后脱除Boc保护基得到中间体6;6与不同碳长的单酸甲酯或含芳基的羧酸中间体在HATU条件下缩合并在羟胺的甲醇溶液中氨解得到目标化合物8a-8f,8h-8m;6与含溴的不同中间体发生亲核取代反应并在羟胺的甲醇溶液中氨解得到目标化合物8g,8n-8t;6与邻苯二胺在HATU条件下缩合得到目标化合物8u和8v;
合成路线1:
反应试剂和反应条件:(a)DPPF二氯化钯,K3PO4,1,4-二氧六环/水,90℃,12h;(b)碳酸酐二叔丁酯,DMAP,二氯甲烷,室温,8小时;(c)(4-甲基哌啶-4-基)氨基甲酸叔丁酯,DIPEA,DMF,85℃,8小时;(d)4M HCl/EtOAc,室温,8小时;(e)HATU、DIPEA、DMF、室温、8小时;(f)羟胺的甲醇溶液,室温,6小时;
合成路线2:
反应试剂和反应条件:(a)HATU,DIPEA,DMF,室温,8小时;(b)K2CO3,DMF,室温或80℃,8小时;(c)羟胺的甲醇溶液,室温,6小时;
合成路线3:
反应试剂和反应条件:(a)HATU,DIPEA,DMF,室温,8小时;(b)4M氢氧化钠/水,50℃,1小时。
4.一种药物组合物,其含有治疗有效量的一种或多种如权利要求1或2所述的SHP2/HDAC双靶点抑制剂,其立体异构体或其药学上可接受的盐及药用辅料或载体。
5.权利要求1或2所述的SHP2/HDAC双靶点抑制剂在制备SHP2抑制剂中的用途。
6.权利要求1或2所述的SHP2/HDAC双靶点抑制剂在制备组蛋白去乙酰化酶抑制剂中的用途。
7.权利要求1或2所述的SHP2/HDAC双靶点抑制剂在制备治疗与上述靶点以及RAS信号通路过度激活有关的肿瘤疾病药物中的用途。
8.根据权利要求7所述的用途,所述肿瘤为肺癌、肝癌、非小细胞肺癌、皮肤癌、胰腺癌、卵巢癌、乳腺癌、膀胱癌、淋巴瘤、食管癌、胃肠道癌、鼻咽癌、白血病、脑胶质瘤、前列腺癌、骨髓瘤、KRAS突变的肿瘤。
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