CN114933589B - 基于crbn配体诱导fgfr降解的化合物及其制备方法和应用 - Google Patents
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Abstract
本发明公开了一种基于CRBN配体诱导FGFR降解的化合物，包括式(I)所示的化合物或其药学上可接受的盐、水合物：其中，X为 n为3‑11的整数，m为2‑10的整数，h为1‑5的整数。本发明还公开了所述化合物的制备方法和药物组合物，以及所述化合物和药物组合物在在制备预防和/或治疗癌症的药物中的应用。本发明的化合物仅需较少用量即可诱导蛋白降解，这个过程类似于催化反应，并不需要等摩尔量的药物，能减轻对人体的毒副作用。
Description
技术领域
本发明涉及药物化合物合成领域，尤其涉及一种基于CRBN配体诱导FGFR降解的化合物及其制备方法和应用。
背景技术
Cereblon是由人类CRBN基因编码的蛋白，CRBN同源基因是高度保守的，这表明它在生理学中的重要性。Cereblon与损伤DNA结合蛋白1(DDBl)、Cullin-4A(CUL4A)以及Cullin-1调节器(ROCI)组成E3泛素连接酶复合体，该复合体能泛素化一系列蛋白，但具体机制尚不清楚。Cereblon泛素化靶蛋白导致成纤维细胞生长因子8(FGF8)和成纤维细胞生长因10(FGF10)增多，说明泛素化酶复合体对于胚胎肢体生长十分重要。
研究表明，BGJ398是一种有效的选择性FGFR抑制剂，对FGFR1、FGFR2、FGFR3的选择性比FGFR4和VEGFR2高40倍以上。Ⅰ期临床试验中，BGJ398在有FGFR基因畸变的晚期实体瘤患者中显示了很强的抗肿瘤活性、良好的耐受性和安全性，其中最大耐受剂量为125mg·d-1。一项Ⅱ期临床试验评估BGJ398的毒性可以控制，并且对含FGFR2融合的化疗难以治疗的胆管癌具有明显的肿瘤抑制活性。另一项Ⅱ期临床试验评估BGJ398对有FGFR3突变的膀胱尿路上皮癌患者的疗效，受试者每4周给药3周，125mg·d-1，直至出现不可耐受的毒性反应或疾病进展，总缓解率为25.4％，另外38.8％患者疾病稳定。
成纤维细胞生长因子受体(FGFRs)家族是受体酪氨酸激酶(RTK)超家族的一员，包括FGFR1、FGFR2、FGFR3和FGFR4，由4个独立基因编码，具有较高的序列同源性。FGFR能与其天然配体成纤维细胞生长因子(FGF)结合，进行二聚化和自磷酸化，从而激活下游信号转导通路。FGF/FGFR信号通路能调控细胞的增殖、分化和存活，在早期胚胎发育、器官形成、血管生成、组织修复以及代谢调控过程中起重要作用。
研究表明，除了正常生理作用外，FGF和FGFR亦可能作为致癌基因，不仅可驱动肿瘤细胞的增殖，还可介导肿瘤细胞对细胞毒性剂和靶向剂的耐药性。FGFR易通过基因扩增、点突变和染色体易位等形式异常激活。在鳞状非小细胞肺癌、乳腺癌及食道癌中观察到了FGFR1的扩增，在胃癌和乳腺癌中发现了FGFR2的扩增，在膀胱癌、子宫内膜癌和肺鳞状细胞癌中观察到FGFR的激活点突变，在多发性骨髓瘤中观察到易位、FGFR3的扩增和突变。因此，FGFR各亚型的异常可能与肿瘤的发生发展密切相关，FGFR已成为一个极具吸引力的肿瘤治疗靶点，多个FGFR小分子抑制剂正处于临床研究阶段。
研究表明，抑制FGFR往往需要将药物长期维持在较高的浓度，有可能造成严重的副作用，长期使用会导致耐药问题，降低FGFR抑制剂的抗肿瘤效果。并且多靶点FGFR小分子抑制剂由于缺乏选择性，可能存在较多的毒副作用。因此，亟待开发一种抗肿瘤效果优于FGFR抑制剂，并可以降低药物使用剂量，减轻毒副作用的新型FGFR家族内部选择性蛋白降解靶向联合体(PROTACs)。
发明内容
本发明提供了一种基于CRBN配体诱导FGFR降解的化合物及其药物组合物，该化合物或其药物组合物不仅具有优异的FGFR蛋白降解作用和抗癌活性，还能减轻对人体的毒副作用，可用于制备抗肿瘤药物。
本发明的技术方案如下：
一种基于CRBN配体诱导FGFR降解的化合物，包括式(I)所示的化合物或其药学上可接受的盐、水合物：
其中，X为n为3-11的整数，m为2-10的整数，h为1-5的整数。
本发明通过使用连接链将FGFR小分子抑制剂和E3泛素连接酶复合体中Cereblon蛋白配体进行连接，制得一种蛋白降解靶向联合体(PROTACs)双功能小分子，通过对FGFR进行泛素化标记，能够选择性诱导FGFR蛋白降解，具有较好的抗肿瘤活性。
优选的，n为5-11的整数；m为2-8的整数；h为1-4的整数。优选的化合物具有较好的诱导FGFR降解作用和抗肿瘤活性。
最优选的，n为5、7、9或11；m为2、5或8；h为1-4的整数。优选的化合物具有更好的诱导FGFR降解作用和抗肿瘤活性。
本发明所述的化合物还包括式(I)所示的化合物的立体异构体。本发明化合物的所有立体异构体，包括但不限于非对映异构体、对映异构体和阻转异构体以及他们的混合物(如外消旋物)，均包括在本发明的范围内。
本发明所述的化合物还包括式(I)所示的化合物的互变异构体。属于“互变异构体”或“互变异构形式”是指经由低能垒相互转化的不同能量的结构异构体。
本发明所述的化合物还包括式(I)所示的化合物的衍生物的前药，式(I)所示的化合物的衍生物自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明所述的化合物还包括式(I)所示的化合物的药学上可接受的盐包括与下列酸形成的加成盐：盐酸、氢嗅酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、茶二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸或苯甲酸；以及盐酸、氢嗅酸、硫酸、柠檬酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、三氟乙酸、马来酸、苯磺酸或琉珀酸的酸成盐。
本发明还提供了式(I)所示的化合物的制备方法，包括如下步骤：
(1)将式(VII)所示的化合物与式(Ⅱ)所示的化合物溶于有机溶剂，反应得到式(Ⅲ)所示的化合物；
(2)将取代苯胺和固体三光气反应；在加入式(Ⅲ)所示的化合物进行反应，得到式(IV)所示的化合物；
(3)将式(IV)所示的化合物脱除Boc保护，得到式(V)所示的化合物；
(4)将式(Ⅵ)所示的化合物、式(V)所示的化合物、缩合剂溶于有机溶剂进行反应，得到式(I)所示的化合物；
其中，X为n为3-11的整数，m为2-10的整数，h为1-5的整数。
上述步骤的反应式如下所示：
其中，X为n为3-11的整数，m为2-10的整数，h为1-5的整数；
其中：(a)异丙醇、N,N-二异丙基乙胺、室温搅拌；(b)正丁醇、N,N-二异丙基乙胺、甲胺、120℃；(c)2,6-二氯-3,5-二甲氧基苯胺、三光气、四氢呋喃、N,N-二异丙基乙胺、甲苯、冰浴、80℃；(d)二氯甲烷、三氟乙酸；(e)HATU、N,N-二异丙基乙胺、N,N-二甲基甲酰胺。
本发明还提供了一种药物组合物，包括式(I)所示的化合物或其药学上可接受的盐、水合物；还包括药学上可接受的赋形剂。
在所述的药物组合物中，式(I)所示的化合物或其药学上可接受的盐、水合物作为活性成份，与药学上可接受的赋形剂混合制成药物组合物。所述的赋形剂为用于药学领域的稀释剂、辅助剂或载体。
在药物组合物中加入药学上可接受的辅料制成的临床上可接受的剂型。所述剂型为注射剂、片剂或胶囊剂。
本发明还提供了一种药物组合物，包括式(I)所示的化合物或其药学上可接受的盐、水合物，和不同的抗肿瘤药剂。本发明所述的化合物或其药学上可接受的盐、水合物可作为抗肿瘤药剂单独使用，还可以与不同的抗肿瘤药剂联合使用，用于治疗或预防肿瘤。
本发明还提供了式(I)所示的化合物或其药学上可接受的盐、水合物在制备预防和/或治疗癌症的药物中的应用。
本发明还提供了所述的药物组合物在制备预防和/或治疗癌症的药物中的应用。
所述的癌症为多发性骨髓瘤、胃癌、肺癌、乳腺癌、食管癌、结肠癌、髓母细胞瘤、急性粒细胞白血病、慢性白血病、前列腺癌、肝细胞瘤、肾细胞瘤、宫颈癌、皮肤癌、卵巢癌、结肠癌、神经胶质瘤、甲状腺癌或胰腺癌。
与现有技术相比，本发明的有益效果为：
(1)本发明式(I)所示的双功能小分子可以对FGFR进行泛素化标记，仅需较少用量即可诱导蛋白降解，这个过程类似于催化反应，并不需要等摩尔量的药物，能减轻对人体的毒副作用；
(2)本发明体外抗肿瘤活性测试及体外FGFR2、3蛋白降解活性测试表明，式(I)所示的双功能小分子表现出了优异的FGFR2、3蛋白降解作用和抗癌活性，其抗癌效果优于FGFR抑制剂BGJ398，可用于预防或/和治疗多种癌症，在医药领域具有巨大的应用前景。
附图说明
图1为实施例1、4、6和7制得的化合物以及化合物BGJ398对FGFR的降解效果图，其中(a)为BGJ398，(b)为ML-1，(c)为ML-4，(d)为ML-6，(e)为ML-7。
具体实施方式
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实施例和制备例的范围并不以任何方式限制本发明的范围。本发明的原料可以从商业途径获得或通过本领域已知的方法制备。
化合物的结构通过核磁共振(1H-NMR)和高分辨质谱(HRMS)来确定，NMR测定是用ACF-400BRUK型核磁共振仪，测定溶剂为氘代氯仿(CDC13)或氘代二甲亚砜(DMSO-D6)。柱层析采用200-300目硅胶。
其中，X为n为3-11的整数，m为2-10的整数，h为1-5的整数。
化合物(Ⅴ)的制备方法如下：
(1)将4,6-二氯嘧啶(Ⅶ)(1.50g，11mmol)加入到100mL单口瓶并完全溶解于30mL异丙醇(i-PrOH)中，加入3倍当量的N,N-二异丙基乙胺(DIPEA)(5.3mL，30mmol)于室温下搅拌下滴加10mL i-PrOH溶解的1-Boc-4-(4-氨基苯基)哌嗪(Ⅱ)(2.77g，10mmol)。将反应置于40℃下反应过夜。将反应液过滤，适量乙醇洗固体产物，得到灰白色固体。
(2)将上一步所得灰白色固体(1.92g，5mmol)加入到35mL耐压管中，加入15mL溶剂正丁醇，加入N，N-二异丙基乙胺(2.8mL，15mmol)，加入5mL甲胺的乙醇溶液。密闭于120℃温度下反应过夜。于65℃水浴加热真空下旋干溶剂正丁醇，得到当量的白色固体(Ⅲ)。
(3)将取代苯胺(444mg，2mmol)和固体三光气(296.7mg，1mmol)加入到100mL单口瓶中，加入20mL无水THF溶解，溶液超声溶解至澄清后置-10℃搅拌下缓慢滴加三乙胺(1.1mL，8mmol)。加完后移至室温反应，待反应30min后加热至80℃回流反应1h。旋干溶剂THF，真空下抽干残余少量溶剂，得到淡黄色固体备用。
(4)将化合物(Ⅲ)(768mg，2mmol)加入到步骤(3)的100mL圆底烧瓶中，加入30mL甲苯溶解，加入有机碱DIPEA(1.5mL，8mmol)，于80℃下反应过夜。旋干溶剂甲苯，加入DCM(二氯甲烷)与H2O萃取(DCM 50mL×3/20mL H2O)，合并有机项，无水硫酸钠干燥。过柱分离，使用展开剂极性梯度DCM:MeOH＝100:1-80:1-50:1。使用石油醚/丙酮体系进行重结晶。过夜，析出白色固体(Ⅳ)。
(5)将化合物(Ⅳ)加入25mL圆底烧瓶中，加入5mLDCM完全溶解，于室温搅拌下加入5mL的三氟乙酸，加完后室温条件下反应2h。真空旋干溶剂，加入适量四氢呋喃溶解，在冰浴条件下滴加饱和碳酸氢钠水溶液，加至一定程度有白色固体析出，加到没有固体继续析出时停止滴加，在冰浴条件下继续搅拌0.5h待固体完全析出。将反应经过漏斗抽滤，适量水洗去残留的NaHCO3，将漏斗置于真空干燥除水或者烘箱除水，得到白色固体(Ⅴ)。
(6)将化合物(Ⅵ)、HATU(2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、DIPEA、加入溶剂DMF(N,N-二甲基甲酰胺)中，室温搅拌15min，加入化合物(Ⅴ)，室温搅拌30min反应结束，向反应瓶中加入50mL水，用二氯甲烷(20mL×3)萃取，合并有机相，用饱和食盐水(100mL×3)洗涤有机相，旋干有机相，硅胶色谱柱分离纯化得到化合物(I)。
实施例1：
制备：2-(4-(4-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)苯基)哌嗪-1-基)-N-(2-(2-(2,6-二氧哌啶-3-基)-1，3-二氧异吲哚啉-4-基)氨基)乙基)乙酰胺(ML-1)
制备方法：将2-(4-(4-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)苯基)哌嗪-1-基)乙酸酸30mg加入1.5mLDMF中，加入HATU 29mg，N,N-二异丙基乙胺45μL，室温下搅拌15min，加入4-((2-氨基乙基)氨基)-2-(2,6-二氧代哌啶-3-基)异二氢吲哚-1,3-二酮16mg，室温下搅拌30min。加入50mL水，并用二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(50mL×3)洗涤有机相，无水硫酸钠干燥，真空浓缩有机相得到产物ML-1。
产物ML-1的核磁共振表征如下：1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),11.07(s,1H),9.42(s,1H),8.33(s,1H),7.58–7.47(m,1H),7.36(d,J＝8.4Hz,3H),7.16(d,J＝8.7Hz,1H),6.97(dd,J＝16.0,7.0Hz,1H),6.84(s,3H),6.67(t,J＝6.0Hz,1H),6.35(s,1H),5.00(dd,J＝12.9,5.4Hz,1H),3.88(s,8H),3.32(d,J＝61.6Hz,6H),3.12–2.72(m,7H),2.52(td,J＝18.5,18.0,9.1Hz,6H).HRMS m/z:calcd for C41H43Cl2N11O8[M+H]+887.3,found 888.34。
实施例2：
制备2-(4-(4-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)苯基)哌嗪-1-基)-N-(8-(2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚-4-基)氨基)辛基)乙酰胺(ML-2)
制备方法：将2-(4-(4-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)苯基)哌嗪-1-基)乙酸酸30mg加入1.5mLDMF中，加入HATU 29mg，N，N-二异丙基乙胺45μL，室温下搅拌15min，加入4-((8-氨基辛基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚啉-1,3-二酮20.4mg，室温下搅拌30min。加入50mL水，并用二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(50mL×3)洗涤有机相，无水硫酸钠干燥，真空浓缩有机相得到产物ML-2。
产物的核磁共振表征如下：1H NMR(400MHz,Chloroform-d)δ12.61(s,1H),9.45(s,1H),8.36(s,1H),7.59(s,1H),7.48(t,1H),7.24–7.14(m,3H),7.07(d,J＝7.1Hz,1H),6.94(d,2H),6.86(d,J＝8.6Hz,1H),6.52(s,1H),6.22(t,J＝5.6Hz,1H),6.10(s,1H),4.91(dd,J＝12.0,5.4Hz,1H),3.91(s,6H),3.34–3.17(m,8H),3.08(s,2H),2.92–2.63(m,7H),1.63(q,J＝7.1Hz,2H),1.58–1.48(m,2H),1.44–1.20(m,12H).HRMS m/z:calcd forC47H55Cl2N11O8[M+H]+971.4,found 972.72。
实施例3：
制备3-(2,6-二氯-3,5-二甲氧基苯基)-1-(6-((4-(4-(12-((2-(2,6-二氧代哌啶-3-基)-1,3)-二氧代异吲哚啉-4-基)氨基)十二烷基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)-1-甲基脲(ML-3)
制备方法：将12-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)十二酸27mg加入1.5mLDMF中，加入HATU 32mg，N,N-二异丙基乙胺51μL，室温下搅拌15min，加入3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基-1-(6-((4-(哌嗪-1-基)苯基)氨基)嘧啶-4-基)尿素30mg，室温下搅拌30min。加入50mL水，并用二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(50mL×3)洗涤有机相，无水硫酸钠干燥，真空浓缩有机相得到产物ML-3。
产物的核磁共振表征如下：1H NMR(400MHz,Chloroform-d)δ12.54(s,1H),9.51(s,1H),8.37(s,1H),7.52–7.39(m,1H),7.24(d,J＝8.1Hz,2H),7.05(dd,J＝15.7,7.1Hz,1H),7.00–6.94(m,3H),6.85(dd,J＝16.2,8.5Hz,1H),6.51(s,1H),6.28–6.18(m,1H),6.11(s,1H),4.91(dd,J＝12.1,5.3Hz,1H),3.91(s,6H),3.80(t,J＝5.3Hz,2H),3.65(t,J＝5.1Hz,2H),3.30(s,3H),3.29–3.09(m,6H),3.02–2.64(m,3H),2.37(t,J＝7.6Hz,2H),1.70–1.57(m,5H),1.43–1.15(m,14H).HRMS m/z:calcd for C49H58Cl2N10O8[M+H]+984.4,found 1007.4。
实施例4：
制备3-(2,6-二氯-3,5-二甲氧基苯基)-1-(6-((4-(4-(8-((2-(2,6-二氧哌啶-3-基)-1,3)-二氧代异吲哚啉-4-基)氨基)辛酰基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)-1-甲基脲(ML-4)
制备方法：将8-((2-(2,6-二氧哌啶-3-基)-1,3-二氧异吲哚啉-4-基)氨基)辛酸23mg加入1.5mLDMF中，加入HATU 32mg，N，N-二异丙基乙胺51μL，室温下搅拌15min，加入3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基-1-(6-((4-(哌嗪-1-基)苯基)氨基)嘧啶-4-基)尿素30mg，室温下搅拌30min。加入50mL水，并用二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(50mL×3)洗涤有机相，无水硫酸钠干燥，真空浓缩有机相得到产物ML-4。
产物的核磁共振表征如下：1H NMR(400MHz,Chloroform-d)δ12.58(s,1H),9.43(s,1H),8.37(s,1H),7.70(s,1H),7.47(t,J＝7.8Hz,1H),7.23(d,J＝8.5Hz,2H),7.06(d,J＝7.1Hz,1H),6.95(d,J＝8.4Hz,2H),6.86(d,J＝8.5Hz,1H),6.50(s,1H),6.21(t,J＝5.6Hz,1H),6.11(s,1H),4.90(dd,J＝11.9,5.4Hz,1H),3.90(s,6H),3.85–3.70(m,2H),3.63(t,J＝5.1Hz,2H),3.29(s,3H),3.29–3.08(m,6H),2.91–2.65(m,3H),2.37(t,J＝7.6Hz,2H),1.71–1.59(m,5H),1.45–1.33(m,6H).HRMS m/z:calcd for C45H50Cl2N10O8[M+H]+928.3,found 929.46。
实施例5：
制备:3-(2,6-二氯-3,5-二甲氧基苯基)-1-(6-((4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3)-二氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)苯基)氨基)嘧啶-4-基)-1-甲基脲(ML-5)
制备方法：将6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酸22mg加入1.5mLDMF中，加入HATU 32mg，N，N-二异丙基乙胺51μL，室温下搅拌15min，加入3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基-1-(6-((4-(哌嗪-1-基)苯基)氨基)嘧啶-4-基)尿素30mg，室温下搅拌30min。加入50mL水，并用二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(50mL×3)洗涤有机相，无水硫酸钠干燥，真空浓缩有机相得到产物ML-5。
产物的核磁共振表征如下：1H NMR(400MHz,Chloroform-d)δ12.54(s,1H),9.22(s,1H),8.37(s,1H),7.68(s,1H),7.47(t,J＝7.8Hz,1H),7.24(d,J＝7.8Hz,2H),7.07(d,J＝7.1Hz,1H),6.96(d,J＝8.4Hz,2H),6.87(d,J＝8.5Hz,1H),6.50(s,1H),6.22(t,J＝5.6Hz,1H),6.11(s,1H),4.90(dd,J＝11.9,5.4Hz,1H),3.90(s,6H),3.83–3.76(m,2H),3.64(t,J＝5.1Hz,2H),3.32–3.23(m,5H),3.17(s,4H),2.91–2.65(m,4H),2.39(t,J＝7.4Hz,2H),1.71(h,J＝6.9Hz,4H),1.49(q,J＝8.2Hz,2H).HRMS m/z:calcd forC43H46Cl2N10O8[M+H]+900.3,found 901.33。
实施例6：
制备:2-(4-(4-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)苯基)哌嗪-1-基)-N-(2-(2-(2,6-二氧哌啶-3-基)-1，3-二氧异吲哚啉-4-基)氨基)乙氧基)乙基)乙酰胺(ML-6)
制备方法：将2-(4-(4-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)苯基)哌嗪-1-基)乙酸酸30mg加入1.5mLDMF中，加入HATU 29mg，N，N-二异丙基乙胺45μL，室温下搅拌15min，加入4-((2-(2-氨基乙氧基)乙基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚-1,3-二酮18.3mg，室温下搅拌30min。加入50mL水，并用二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(50mL×3)洗涤有机相，无水硫酸钠干燥，真空浓缩有机相得到产物ML-6。
产物的核磁共振表征如下：1H NMR(400MHz,Chloroform-d)δ12.59(s,1H),9.28(s,1H),8.36(s,1H),7.47(t,J＝7.8Hz,2H),7.31(s,1H),7.18(d,J＝8.4Hz,2H),7.08(d,J＝7.1Hz,1H),6.88(d,J＝8.4Hz,3H),6.51(s,1H),6.47(t,J＝5.6Hz,1H),6.09(s,1H),4.89(dd,J＝11.4,5.6Hz,1H),3.91(s,6H),3.71(t,J＝5.3Hz,2H),3.61(t,J＝5.1Hz,2H),3.57–3.50(m,2H),3.48–3.35(m,2H),3.29(s,3H),3.19(d,J＝15.9Hz,7H),2.98–2.58(m,7H).HRMS m/z:calcd for C43H47Cl2N11O9[M+H]+931.3,found 932.39。
实施例7：
制备:2-(4-(4-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)苯基)哌嗪-1-基)-N-(2-(2-(2,6-二氧哌啶-3-基)-1，3-二氧异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙基)乙酰胺(ML-7)
制备方法：将2-(4-(4-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)苯基)哌嗪-1-基)乙酸酸30mg加入1.5mLDMF中，加入HATU 29mg，N,N-二异丙基乙胺45μL，室温下搅拌15min，加入4-((2-(2-氨基乙氧基)乙氧基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮20.6mg，室温下搅拌30min。加入50mL水，并用二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(50mL×3)洗涤有机相，无水硫酸钠干燥，真空浓缩有机相得到产物ML-7。
产物的核磁共振表征如下：1H NMR(400MHz,Chloroform-d)δ12.61(s,1H),9.88(s,1H),8.36(s,1H),7.64(s,1H),7.46(dd,J＝14.7,7.0Hz,2H),7.19(d,J＝8.4Hz,2H),7.08(d,J＝7.1Hz,1H),6.91(d,J＝8.3Hz,2H),6.86(d,J＝8.5Hz,1H),6.51(s,1H),6.42(t,J＝5.6Hz,1H),6.10(s,1H),4.92(dd,1H),3.91(s,6H),3.81–3.63(m,6H),3.61(t,J＝5.1Hz,2H),3.51(q,J＝5.4Hz,2H),3.41(q,J＝5.7Hz,2H),3.29(s,3H),3.27–3.10(m,6H),2.93–2.58(m,8H).HRMS m/z:calcd for C45H51Cl2N11O10[M+H]+975.3,found976.32。
实施例8：
制备:2-(4-(4-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)苯基)哌嗪-1-基)-N-(2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)乙基)乙酰胺(ML-8)
制备方法：将2-(4-(4-((6-(3-(2,6-二氯-3,5-二甲氧基苯基)-1-甲基脲基)嘧啶-4-基)氨基)苯基)哌嗪-1-基)乙酸酸30mg加入1.5mLDMF中，加入HATU 29mg，N,N-二异丙基乙胺45μL，室温下搅拌15min，加入4-((2-(2-(2-氨基乙氧基)乙氧基)乙基)氨基)-2-(2,6-二氧哌啶-3-基)异吲哚啉-1,3-二酮23mg，室温下搅拌30min。加入50mL水，并用二氯甲烷(20mL×3)萃取，合并有机相，饱和食盐水(50mL×3)洗涤有机相，无水硫酸钠干燥，真空浓缩有机相得到产物ML-8。
产物的核磁共振表征如下：1H NMR(400MHz,Chloroform-d)δ12.61(s,1H),9.96(s,1H),8.37(d,J＝4.4Hz,1H),7.76–7.37(m,3H),7.21(d,J＝8.8Hz,2H),7.09(d,J＝7.1Hz,1H),6.94(d,J＝8.5Hz,2H),6.88(d,J＝8.6Hz,1H),6.52(s,1H),6.43(t,J＝5.4Hz,1H),6.10(s,1H),4.92(dd,J＝11.5,5.5Hz,1H),3.92(s,6H),3.74–3.53(m,13H),3.54–3.38(m,4H),3.36–3.11(m,10H),3.03–2.58(m,6H).HRMS m/z:calcd for C47H55Cl2N11O11[M+H]+1019.3,found 1020.31。
FGFR蛋白降解活性测试
将药物与FGFR高表达细胞KatoIII进行孵育6小时。随后用预冷的PBS洗涤2次，PMSF与PIPA裂解液以1:100的比例混合，冰上裂解细胞10min，4℃，12000r/min*20min离心，取上清，即细胞总蛋白，用BCA法定量检测蛋白量，用5微升蛋白上样缓冲液稀释蛋白后100℃变性5分钟。蛋白在SDS-PAGE电泳分离，转膜，封闭2小时，一抗4℃孵育过夜。TBST洗膜，二抗1:1000孵育2小时后显影，结果如图1所示。
图1为实施例1、4、6和7制得的化合物以及化合物BGJ398对FGFR的降解效果图，由图1可知，本发明实施例1、4、6和7制得的化合物ML-1、ML-4、ML-6、ML-7均具有较好的FGFR降解效果，而现有化合物BGJ398没有降解能力。
另外，实施例2-3、5、8制得的化合物对FGFR的降解效果与实施例1、4、6和7制得的化合物的效果相似。
以上所述的实施例对本发明的技术方案和有益效果进行了详细说明，应理解的是以上所述仅为本发明的具体实施例，并不用于限制本发明，凡在本发明的原则范围内所做的任何修改、补充和等同替换等，均应包含在本发明的保护范围之内。
Claims (7)
1.一种基于CRBN配体诱导FGFR降解的化合物，其特征在于，包括式(I)所示的化合物或其药学上可接受的盐：
其中，X为n为5、7或11；m为2或8；h为1或2。
2.一种药物组合物，其特征在于，包括如权利要求1所述的式(I)所示的化合物或其药学上可接受的盐；还包括药学上可接受的赋形剂。
3.一种药物组合物，其特征在于，包括如权利要求1所述的式(I)所示的化合物或其药学上可接受的盐，和不同的抗肿瘤药剂。
4.一种如权利要求1所述的化合物在或其药学上可接受的盐在制备预防和/或治疗癌症的药物中的应用。
5.根据权利要求4所述的应用，其特征在于，所述的癌症为多发性骨髓瘤、胃癌、肺癌、乳腺癌、食管癌、结肠癌、髓母细胞瘤、急性粒细胞白血病、慢性白血病、前列腺癌、肝细胞瘤、肾细胞瘤、宫颈癌、皮肤癌、卵巢癌、神经胶质瘤、甲状腺癌或胰腺癌。
6.一种如权利要求2或3所述的药物组合物在制备预防和/或治疗癌症的药物中的应用。
7.根据权利要求6所述的应用，其特征在于，所述的癌症为多发性骨髓瘤、胃癌、肺癌、乳腺癌、食管癌、结肠癌、髓母细胞瘤、急性粒细胞白血病、慢性白血病、前列腺癌、肝细胞瘤、肾细胞瘤、宫颈癌、皮肤癌、卵巢癌、神经胶质瘤、甲状腺癌或胰腺癌。
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