CN117143175A - 靶向sos1蛋白泛素化调节的化合物及其制备方法和应用 - Google Patents
靶向sos1蛋白泛素化调节的化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于药物化学技术领域,尤其涉及靶向SOS1蛋白泛素化调节的化合物及其制备方法和应用。所述化合物为E3连接酶配体、SOS1蛋白配体,任选还包括连接子结构三部分组成,经体外活性测试证明其对SOS1蛋白具有良好的降解能力。
Description
技术领域
本发明属于药物化学技术领域,尤其涉及靶向SOS1蛋白泛素化调节的双官能团化合物及其制备方法和应用。
背景技术
Ras蛋白(包括H-Ras、N-Ras、K-Ras)属于小GTP酶超家族,是多条细胞信号通路中的重要节点,与细胞的增殖、分化密切相关。Ras蛋白发挥作用取决于其GTP结合状态,即GTP结合的活性状态与GDP结合的非活性状态。这种两种状态受GTP酶活化蛋白(GAPs)和鸟苷酸交换因子(GEFs)调控。通过在两种状态之间转化,Ras在信号通路中发挥“开关”作用,实现信号的转导。Ras蛋白本身具有较弱的GTP酶水解活性,该活性可以被GAPs增强,促进GTP水解为GDP,使Ras蛋白转化为失活状态;GEFs则可催化Ras蛋白释放GDP,从而与细胞内浓度更高的GTP结合,使Ras蛋白转化为失活状态。
Ras蛋白的激活突变是人类癌症中最常见的致癌驱动因素之一,尤其以K-Ras突变为主,约占Ras突变的75%,涉及胰腺癌、结直肠癌、肺腺癌等多种癌症。Ras蛋白发生致癌突变后,GTP水解能力受损,使其稳定在GTP结合的活性形式,引起下游信号通路的持续激活,其最常见的突变位点是12、13、61位氨基酸。尽管Ras蛋白是许多癌症治疗的潜在研究靶点,但是由于Ras蛋白表面相对平滑,缺乏可以结合小分子化合物的口袋,因此被称为“不可成药”靶点。目前选择性靶向KRAS-G12C的共价抑制剂AMG510和MRTX849已进入临床研究阶段,然而迄今为止仍有多种突变型Ras引起的癌症无药可用。
SOS1蛋白是一种作用于Ras蛋白的GEFs,可以促进GDP与GTP的交换激活信号分子Ras。SOS1蛋白具有两个Ras结合位点,分别是与GDP-Ras结合的催化位点和GTP-Ras结合的变构位点(Jeng,H.H.;Taylor,L.J.;Bar-Sagi,D.,Sos-mediated cross-activation ofwild-type Ras by oncogenic Ras is essential for tumorigenesis.Nat Commun2012,3,1168.)。值得注意的是,致癌突变的Ras通过于SOS1蛋白的变构位点结合来促进SOS1介导的野生型Ras的活化。由此可见,SOS1蛋白在Ras信号通路的激活,尤其是致癌Ras引起的信号通路过度激活中发挥十分重要的调控作用。因此通过抑制SOS1的作用达到阻断Ras相关信号通路,从而抑制肿瘤细胞增殖分化可能是治疗Ras驱动癌症的有效策略。目前已经报道的SOS1抑制剂有BAY-293和BI-3406,其中BI-3406系列化合物已经进入临床研究阶段,然而该化合物单独使用时治疗效果未达到预期目标,这可能与该信号通路的负反馈调节及SOS2的代偿作用有关,目前该化合物正在尝试联合用药的治疗策略(Kessler,D.;Gerlach,D.;Kraut,N.;McConnell,D.B.,Targeting Son of Sevenless 1:The pacemakerof KRAS.Curr Opin Chem Biol 2021,62,109-118.)。
蛋白降解靶向嵌合体(PROTAC)技术是近年来新兴的药物研发策略,利用该策略设计出的蛋白靶向降解剂可以在体内发挥类似催化剂作用,通过降解致病蛋白,达到治疗疾病的目的,有着微量高效的特点,有望解决传统小分子抑制剂毒副作用大、容易产生耐药性等不足,并可作用于“不可成药”蛋白靶点,成为药物创新研究的亮点。PROTAC分子通常由三部分组成,分别是E3泛素连接酶配体、靶蛋白配体以及将两者连接的连接结构,PROTAC分子可以在体内将靶蛋白和E3泛素连接酶拉近,形成三元复合物,给靶蛋白打上泛素标签,然后通过泛素-蛋白酶体***(UPS)降解目标蛋白。通过直接调控体内蛋白含量治疗疾病,为创新药物研究提供了广阔的新思路。
综上所述,为解决Ras相关疾病无药可用、治疗效果差的现状,本课题旨在设计合成靶向SOS1蛋白的降解剂,通过减少体内SOS1的含量达到抑制Ras相关信号通路的目的,从而抑制癌症的发展。
发明内容
本发明提供了一种靶向SOS1蛋白泛素化调节的化合物,所述化合物为E3连接酶配体、SOS1蛋白配体组成,或者还包括连接子结构而由三部分组成。本发明经体外活性测试证明所述化合物对SOS1蛋白具有良好的降解能力。
本发明提供了式(I)的化合物、立体异构体或其药学上可接受的盐,其结构如下所示:
其中:X1、X2各自独立地选自N或C;Y选自N、S、O、Si或P;
所述R基团选自:
其中:X选自N或C;W选自S或O;m1、m2各自独立的为0-5的整数;
所述R1选自H;-OH;-NH2;卤素;取代或未取代的直链或支链C1-C3烷基;取代或未取代的直链或支链C1-C3烯基;取代或未取代的直链或支链C1-C3炔基;取代或未取代的直链或支链C1-C3羰基;取代或未取代的C1-C10环烷基;取代或未取代的C1-C10杂环基;取代或未取代的C1-C10芳基或杂芳基;
所述连接基团1选自:不存在;或者取代或未取代的直链或具有支链的C1-C12亚烷基;任选的碳链中含有1-4个选自N、S、O、Si或P的杂原子;
其中:n1、n2、n3各自独立的为0-5的整数;X1、X2、X3、X4各自独立地选自N或C;
所述E3配体选自:
其中:m为0-3的整数;
所述R2、R3、R4和R5各自独立的选自:H;-OH;-NH2;卤素;取代或未取代的直链或支链C1-C6烷基;取代或未取代的直链或支链C1-C6氰基;取代或未取代的直链或支链C1-C6烯基;取代或未取代的直链或支链C1-C6炔基;取代或未取代的直链或支链C1-C6烷氧基;取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺基;取代或未取代的直链或支链C1-C6酯基;取代或未取代的直链或支链C1-C6酰胺基;取代或未取代的直链或支链C1-C6酮基;取代或未取代的C1-C10环烷基;取代或未取代的C1-C10杂环基;取代或未取代的C1-C10芳基或杂芳基。
本发明具体提供了一种化合物、立体异构体、或其盐,其特征在于选自如下化合物:
本发明的一些实施例涉及一种通式Ⅰ所述的化合物或其立体异构体、溶剂化合物、前药、代谢物、药学上可接受的盐或共晶。
本发明也提供所述化合物制备方法。
本发明涉及一种药物组合,包括本发明所述的化合物或其立体异构体、溶剂化合物、前药、代谢物、药学上可接受的盐或共晶,以及药学上可接受的载体。
本发明涉及一种本发明所述的化合物或其立体异构体、溶剂化合物、前药、代谢物、药学上可接受的盐或共晶在用于制备治疗与SOS1活性或表达量相关疾病的药物中的应用。
本发明涉及一种本发明所述的化合物或其立体异构体、溶剂化合物、前药、代谢物、药学上可接受的盐或共晶在用于制备抑制SOS1活性或降低SOS1表达量的药物中的应用。
如上所述的化合物或其立体异构体、溶剂化合物、前药、代谢物、药学上可接受的盐或共晶,可作为SOS1降解剂,可用于预防和/或治疗结肠癌、非小细胞肺癌、胰腺癌、直肠癌、黑色素瘤、多发性骨髓瘤。
术语约定:
“立体异构体”是具有相同化学组成但原子或基团在空间中的排布不同的化合物。其包括“非对映异构体”和“对映异构体”
“非对映异构体”是具有两个或更多手性中心并且其分子不是彼此的镜像的立体异构体。非对映异构体具有不同物理性能,例如:熔点、沸点、谱特性和反应活性。在拆分剂或色谱存在的情况下,使用诸如手性HPLC柱,可以在诸如电泳、结晶的高分辨分析步骤下分离非对映异构体的混合物。
“对映异构体”指代彼此无重叠镜像的一种化合物的两个立体异构体。对映异构体的50:50的混合称为外消旋混合物或外消旋体,其在化学反应或处理过程中可以出现在已经没有立体选择性或立体定向性的情况下。
“烷基”包括支链和直链饱和脂肪族烃基两者,并具有指定数量的碳原子数量,一般1至约12个碳原子。如在本文中使用的术语C1-C6烷基表示具有1至约6个碳原子的烷基。当本文中结合另一基团使用C0-Cn烷基时,以(苯基)C0-C4烷基为例,指定的基团,在这种情况下,苯基是通过单个共价键(C0)直接键合或通过具有指定的碳原子数(在这种情况下,1至约4个碳原子)的烷基链连接。烷基的实例包括但不限于:甲基、乙基、正丙基、异丙基、正丁基、3-甲基丁基、叔丁基、正戊基、和仲戊基。
“烯基”或“烯烃基”指包括一个或多个不饱和的碳-碳键的直链和支链烃链,碳-碳键可以出现在沿着链的任一稳定点。本文中所述的烯基通常具有2至约12个碳原子。优选烯基是低级烯基,那些烯基具有2至约8个碳原子,如:C2-C8、C2-C6、和C2-C4烯基。烯基的实例包括乙烯基、丙烯基、和丁烯基。
“烷氧基”是指具有通过氧桥连接的指定数量的碳原子的如上所定义的烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、3-己氧基、和3-甲基戊氧基。
术语“杂环”表示5-至8-元饱和环、部分不饱和环、或包含选自N、O和S的1至约4个杂原子且剩余的环原子是碳的芳族环,或是7至11元饱和环、部分不饱和环、或芳族杂环***和10至15-元三环***,该***包含选自N、O和S的多环***中的至少1个杂原子并且在多环***中的各环中包含独立地选自N、O和S的至多约4个杂原子。除非另外指明,否则杂环可以连接至它在任何杂原子和碳原子处取代并且产生稳定结构的基团。当指明时,本文中所述的杂环可以在碳或氮原子上被取代,只要得到的化合物是稳定的。可以可选地季铵化杂环中的氮原子。优选杂环基中杂原子的总数不大于4而且优选杂环基中S和O原子的总数不大于2,更优选不大于1。杂环基的实例包括:吡啶基、吲哚基、嘧啶基、哒嗪基(pyridizinyl)、吡嗪基、咪唑基、噁唑基、呋喃基、苯硫基、噻唑基、***基、四唑基、异噁唑基、喹啉基、吡咯基、吡唑基、苯并[b]苯硫基(benz[b]thiophenyl)、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、二氢异吲哚基、5,6,7,8-四氢异喹啉、吡啶基、嘧啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡咯烷基、吗啉基、哌嗪基、哌啶基、和吡咯烷基。
“芳基”或“杂芳基”表示包含选自N、O和S的1至4个、或优选1至3个杂原子并且剩余环原子为碳的稳定的5-或6-元单环或多环。当杂芳基中S和O原子的总数超过1时,这些杂原子不彼此邻近。优选杂芳基中S和O原子的总数不大于2。尤其优选杂芳基中S和O原子的总数不大于1。可以可选地季铵化杂环中的氮原子。当指明时,这些杂芳基还可以用碳或非碳原子或基团取代。这种取代可以包括与可选地包含独立地选自N、O和S的1或2个杂原子的5至7-元饱和的环基的稠合,从而形成例如[1,3]二噁唑并[4,5-c]吡啶基。杂芳基的实例包括但不限于:吡啶基、吲哚基、嘧啶基、哒嗪基、吡嗪基、咪唑基、噁唑基、呋喃基、苯硫基、噻唑基、***基、四唑基、异噁唑基、喹啉基、吡咯基、吡唑基、苯并[b]苯硫基、异喹啉基、喹唑啉基、喹喔啉基、噻吩基、异吲哚基、和5,6,7,8-四氢异喹啉。
“药学上可接受的盐”或“化合物的盐”是所公开的化合物的衍生物,其中,母体化合物通过制备无毒的酸或其碱加成盐。
附图说明
图1为化合物2对SOS1降解的剂量依赖性。
图2为化合物2对SOS1降解的时间依赖性。
图3为化合物2对NCI-H358的增殖抑制作用。
具体实施方式
下面通过具体实施例对本发明做进一步阐述,以更好理解本发明,但并不构成对本发明的限制。
本发明的化合物或其药学上可接受的盐的制备方法,其中一种合成路线包括以下步骤如下所示:
合成路线I
合成路线II
以下结合具体实施例,对本发明化合物制备及性能进行进一步说明。
实施例1、化合物1的制备
化合物1分子式:(2S,4R)-1-((S)-2-(4-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)丁胺基)-3,3-二甲基丁酰)-4-羟基-N-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
合成过程参照路线I,具体合成步骤如下:
将S-1-1(2.26g,9.7mmol;1.0eq.)溶解于20mL四氢呋喃中。然后在室温下添加(R)-2-甲基丙烷-2-亚砜酰胺(1.8g,14.5mmol;1.5eq.)和Ti(OEt)4(5.5g,24.3mmol;2.5eq.)。在80℃搅拌过夜后,将反应混合物冷却至室温,并用冰水淬灭,用乙酸乙酯萃取,合并有机相,无水Na2SO4干燥,减压去除溶剂,得到粗产物。粗产物通过快速色谱柱纯化,得到淡黄色固体S-1-2,收率:75%。
将S-3-2(2.45g,7.3mmol;1.0eq.)溶于四氢呋喃(50mL)和水(1mL)的混合溶液中,在-78℃下缓慢加入NaBH4(497mg,13.1mmol;1.8eq.),然后在室温下搅拌3h。用冰水淬灭反应,用乙酸乙酯萃取,合并有机相,无水Na2SO4干燥。反应生成的非对映体混合物,经快速色谱分离,获得白色固体S-1-3,收率:87%。
向S-1-3(2.0g,6.0mmol)中加入4M HCl的1,4-二氧六环溶液10mL,在室温下搅拌1h。减压除去溶剂,得到中间体S-1-4。收率:95%。
向S-2-1(14.4g,50.0mmol;1.0eq.)的乙腈溶液(100mL)中加入甲烷磺酸(38.0g,400.0mmol;8.0eq.)。反应混合物在100℃下搅拌过夜。经UPLC-MS检测反应完毕后,将混合物冷却至室温。向反应混合物中滴加NaHCO3水溶液,调节pH至碱性,静置片刻后有沉淀产生,抽滤,冻干后得到粗产品S-2-2。收率:91%。
向S-2-2(12.7g,43.0mmol;1.0eq.)的二氯甲烷(100mL)悬浮液中加入2,4,6-三异丙基苯磺酰氯(15.6g,51.6mmol;1.2eq.)、DMAP(524mg,4.3mmol;0.1eq.)和Et3N(12.9g,127.8mmol;3.0eq.)。反应混合物在室温下搅拌12h。用二氯甲烷稀释溶剂,加入NaHCO3水溶液,并用DCM萃取。合并的有机层用无水Na2SO4干燥,过滤,并在真空中去除溶剂。粗产物通过快速色谱柱纯化,得到所需产物S-2-3,收率:60%。
将S-2-3(8.4g,15.0mmol;1.0eq.)和S-2-4(4.1g,15.0mmol;1.0eq.)溶解在50mL异丙醇中,95℃下搅拌过夜。在UPLC-MS证明起始材料完全转化后,将混合物冷却至室温。在真空中去除溶剂。粗产物通过快速色谱柱纯化,得到中间体S-2-4,收率:91%。
将S-2-4溶于10mL甲醇,加入Pd/C,在氢气氛围中室温搅拌过夜,经UPLC-MS检测反应完毕后,使用硅藻土过滤除去Pd/C,在减压条件下蒸干溶剂,利用快速色谱柱纯化,得到S-2-5,收率:74%。
将S-2-5(500mg,1.27mmol;1.0eq.)溶于10mL乙腈,加入K2CO3(440mg,3.19mmol;2.5eq.)和4-溴代丁酸甲酯(274mg,1.52mmol;1.2eq.),在70℃条件下搅拌过夜,经UPLC-MS检测反应完毕后,在减压条件下蒸干溶剂,加入乙酸乙酯和水稀释,分离有机层,用盐水洗涤,并用无水Na2SO4干燥,利用快速色谱柱纯化,得到S-2-6,收率:57%。
将S-2-6(400mg,0.813mmol;1.0eq.)溶于3mL四氢呋喃,加入事先溶于1mL水的氢氧化锂(78mg,3.25mmol;4.0eq.),在室温下搅拌2h。反应完成后用乙酸调节反应液pH至4-6,用水和乙酸乙酯萃取,分离有机相,用无水Na2SO4干燥,溶液在真空下被除去。得到中间体S-2-7,收率:95%。
将V-1-1(100mg,0.215mmol;1.0eq.)、S-2-7(52mg,0.215mmol;1.0eq.)、HATU(122mg,0.322mmol;1.5eq.)和DIPEA(111mg,0.858mmol;4eq.)溶于3mL N,N-二甲基甲酰胺,室温下搅拌6h,UPLC-MS检测反应完毕后,用水和乙酸乙酯稀释反应混合物。分离有机层,用盐水洗涤,并用无水Na2SO4干燥。溶液在真空下被除去。然后通过prep-HPLC纯化得到实施例1,收率:69%。1H NMR(400MHz,DMSO-d6)δ9.65(d,J=8.0Hz,1H),8.95(s,1H),8.55(t,J=6.1Hz,1H),8.01(d,J=9.3Hz,1H),7.93(s,1H),7.36(q,J=8.3Hz,4H),7.06(s,1H),6.82(d,J=4.4Hz,2H),6.71(s,1H),5.66(q,J=7.2Hz,2H),5.11(s,1H),4.53(d,J=9.3Hz,1H),4.39(dt,J=15.2,7.3Hz,2H),4.32(s,1H),4.19(d,J=5.5Hz,1H),4.15(d,J=5.2Hz,1H),4.13–4.04(m,2H),3.94(s,3H),3.64(d,J=30.0Hz,2H),2.54(s,3H),2.40(s,3H),2.29(s,1H),1.97(d,J=19.6Hz,4H),1.92–1.81(m,1H),1.59(d,J=7.0Hz,3H),0.88(s,9H)。
实施例2、化合物2的制备
化合物2的分子式:(2S,4R)-1-((S)-2-(5-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)戊胺基)-3,3-二甲基丁酰)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
参照合成路线I,具体合成步骤是将实施例1中的4-溴代丁酸甲酯替换为5-溴代戊酸甲酯,其余与实施例1相同。总收率:1.3%。1H NMR(400MHz,DMSO-d6)δ9.64(d,J=7.9Hz,1H),8.95(s,1H),8.56(t,J=6.2Hz,1H),8.03–7.77(m,2H),7.36(q,J=8.4Hz,4H),7.06(s,1H),6.84(d,J=8.7Hz,2H),6.72(d,J=1.9Hz,1H),5.68(p,J=7.1Hz,2H),5.10(s,1H),4.52(d,J=9.3Hz,1H),4.40(dt,J=12.7,7.2Hz,2H),4.31(s,1H),4.19(d,J=5.4Hz,1H),4.15(d,J=5.4Hz,1H),4.09(d,J=8.4Hz,2H),3.93(s,3H),3.62(d,J=10.7Hz,2H),2.54(s,3H),2.40(s,3H),2.33(d,J=6.5Hz,1H),2.20(dt,J=14.1,7.0Hz,1H),1.99(q,J=10.9,9.8Hz,1H),1.86(ddd,J=12.9,8.8,4.5Hz,1H),1.76(d,J=6.6Hz,2H),1.71–1.61(m,2H),1.59(d,J=7.0Hz,3H),0.90(s,9H).
实施例3、化合物3的制备
化合物3的分子式:(2S,4R)-1-((S)-2-(6-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)己胺基)-3,3-二甲基丁酰)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
参照合成路线I,具体合成步骤是将实施例1中的4-溴代丁酸甲酯替换为6-溴代己酸甲酯,其余与实施例1相同。总收率:1.9%。1H NMR(400MHz,DMSO-d6)δ9.63(d,J=7.9Hz,1H),8.95(s,1H),8.56(t,J=6.1Hz,1H),7.96–7.85(m,2H),7.41–7.31(m,4H),7.08(s,1H),6.83(d,J=7.0Hz,2H),6.71(s,1H),5.67(p,J=7.2Hz,1H),4.51(d,J=9.3Hz,1H),4.44–4.35(m,2H),4.31(s,1H),4.17(dd,J=15.9,5.5Hz,1H),4.11–4.04(m,2H),3.92(s,3H),3.65–3.58(m,2H),2.54(s,3H),2.40(s,3H),2.33–2.23(m,1H),2.19–2.08(m,1H),2.04–1.75(m,4H),1.59(d,J=7.0Hz,3H),1.56–1.49(m,1H),1.45–1.36(m,2H),0.89(s,9H)。
实施例4、化合物4的制备
化合物4的分子式:(2S,4R)-1-((S)-2-(7-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)庚胺基)-3,3-二甲基丁酰)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
参照合成路线I,具体合成步骤是将实施例1中的4-溴代丁酸甲酯替换为7-溴代庚酸甲酯,其余与实施例1相同。总收率:2.1%。1H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.56(t,J=6.1Hz,1H),7.91–7.84(m,2H),7.43–7.31(m,4H),7.08(s,1H),6.85–6.80(m,2H),6.70(s,1H),5.65(p,J=7.5Hz,1H),4.51(d,J=9.4Hz,1H),4.45–4.35(m,2H),4.31(s,1H),4.17(dd,J=16.0,5.4Hz,1H),4.09–4.04(m,2H),3.91(s,3H),2.51(s,3H),2.40(s,3H),2.31–2.20(m,1H),2.15–1.82(m,3H),1.80–1.71(m,2H),1.57(d,J=7.0Hz,3H),1.46–1.38(m,3H),1.33–1.27(m,2H),0.89(s,9H)。
实施例5、化合物5的制备
化合物5的分子式:(2S,4R)-1-((S)-2-(8-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)辛胺基)-3,3-二甲基丁酰)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
参照合成路线I,具体合成步骤是将实施例1中的4-溴代丁酸甲酯替换为8-溴代辛酸甲酯,其余与实施例1相同。总收率:2.7%。1H NMR(400MHz,DMSO-d6)δ9.62(d,J=8.1Hz,1H),8.95(s,1H),8.55(t,J=6.1Hz,1H),7.92(s,1H),7.85(d,J=9.4Hz,1H),7.36(q,J=8.3Hz,4H),7.04(s,1H),6.83(d,J=8.0Hz,2H),6.71(s,1H),5.68(t,J=7.3Hz,2H),5.10(s,1H),4.51(d,J=9.4Hz,1H),4.39(dt,J=16.2,7.2Hz,2H),4.31(s,1H),4.19(d,J=5.3Hz,1H),4.15(d,J=5.2Hz,1H),4.08(d,J=3.1Hz,2H),3.92(s,3H),3.61(d,J=7.1Hz,2H),2.54(s,3H),2.40(s,3H),2.09(dd,J=13.8,6.8Hz,1H),1.96(q,J=6.9,6.1Hz,2H),1.91–1.82(m,1H),1.76(d,J=7.6Hz,2H),1.59(d,J=7.0Hz,3H),1.42(q,J=7.0Hz,4H),1.36–1.22(m,4H),0.89(s,9H)。
实施例6、化合物6的制备
化合物6的分子式:(2S,4R)-1-((S)-2-(9-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)壬胺基)-3,3-二甲基丁酰)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
参照合成路线I,具体合成步骤是将实施例1中的4-溴代丁酸甲酯替换为9-溴代壬酸甲酯,其余与实施例1相同。总收率:2.1%。1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.95(s,1H),8.55(t,J=6.1Hz,1H),7.91(s,1H),7.85(d,J=9.3Hz,1H),7.42–7.31(m,4H),7.03(s,1H),6.86–6.79(m,2H),6.71(s,1H),5.74–5.65(m,1H),4.51(d,J=9.3Hz,1H),4.45–4.34(m,2H),4.31(s,1H),4.17(dd,J=16.0,5.4Hz,1H),4.08(s,2H),3.92(s,3H),3.65–3.57(m,2H),2.54(s,3H),2.40(s,3H),2.28–2.18(m,1H),2.12–2.01(m,1H),2.00–1.84(m,2H),1.81–1.73(m,2H),1.59(d,J=7.0Hz,3H),1.52–1.36(m,5H),1.35–1.25(m,4H),0.89(s,9H)。
实施例7、化合物7的制备
化合物7的分子式:(2S,4R)-1-((S)-2-(10-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-7-甲氧基-2-甲基喹唑啉-6-基)氧基)癸胺基)-3,3-二甲基丁酰)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
参照合成路线I,具体合成步骤将实施例1中的4-溴代丁酸甲酯替换为10-溴代癸酸甲酯,其余与实施例1相同。总收率:3.6%。1H NMR(400MHz,DMSO-d6)δ9.64(d,J=7.7Hz,1H),8.95(s,1H),8.56(t,J=6.1Hz,1H),7.92(s,1H),7.84(d,J=9.4Hz,1H),7.36(q,J=8.4Hz,4H),7.08(s,1H),6.95–6.78(m,2H),6.72(s,1H),5.68(t,J=7.3Hz,2H),5.10(s,1H),4.51(d,J=9.4Hz,1H),4.39(dt,J=12.7,7.2Hz,2H),4.33–4.26(m,1H),4.19(d,J=5.5Hz,1H),4.15(d,J=5.4Hz,1H),4.08(td,J=6.4,3.4Hz,2H),3.92(s,3H),3.75–3.53(m,2H),2.54(s,3H),2.40(s,3H),2.23(dt,J=14.8,7.7Hz,1H),2.15–1.94(m,2H),1.86(ddd,J=12.9,8.7,4.5Hz,1H),1.77(t,J=7.4Hz,2H),1.59(d,J=7.0Hz,3H),1.43(dd,J=15.1,7.7Hz,4H),1.30(s,2H),1.28–1.13(m,6H),0.89(s,9H)。
实施例8、化合物8的制备
化合物8的分子式:(2S,4R)-4-羟基-1-((S)-2-(5-(4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-))((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)-3,6-二氢吡啶-1(2H)-基)-5-氧代戊酰胺基)-3,3-二甲基丁酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
参照合成路线II,具体合成步骤如下:
将S-3-1(2g,9.7mmol;1.0eq.)溶解于20mL四氢呋喃中。然后在室温下添加(R)-2-甲基丙烷-2-亚砜酰胺(1.8g,14.5mmol;1.5eq.)和Ti(OEt)4(5.5g,24.3mmol;2.5eq.)。在80℃搅拌过夜后,将反应混合物冷却至室温,并用冰水淬灭,用乙酸乙酯萃取,合并有机相,无水Na2SO4干燥,减压去除溶剂,得到粗产物。粗产物通过快速色谱柱纯化,得到淡黄色固体S-3-2,收率:79%。
将S-3-2(2.4g,7.77mmol;1.0eq.)溶于四氢呋喃(50mL)和水(1mL)的混合溶液中,在-78℃下缓慢加入NaBH4(531mg,14.0mmol;1.8eq.),然后在室温下搅拌3h。用冰水淬灭反应,用乙酸乙酯萃取,合并有机相,无水Na2SO4干燥。反应生成的非对映体混合物,经快速色谱分离,获得白色固体S-3-3,收率:85%。
向S-3-3(2.0g,6.6mmol)中加入4M HCl的1,4-二氧六环溶液9mL,在室温下搅拌1h。减压除去溶剂,得到中间体S-3-4。收率:96%。1H NMR(400MHz,DMSO-d6)δ8.72(s,3H),7.67(d,J=1.5Hz,1H),7.31(d,J=1.5Hz,1H),4.64(q,1H),1.54(d,J=6.8Hz,3H).
向S-4-1(12.3g,47.4mmol;1.0eq.)的乙腈溶液(100mL)中加入甲烷磺酸(36.8g,379.2mmol;8.0eq.)。反应混合物在100℃下搅拌过夜。经UPLC-MS检测反应完毕后,将混合物冷却至室温。向反应混合物中滴加NaHCO3水溶液,调节pH至碱性,静置片刻后有沉淀产生,抽滤,冻干后得到粗产品S-4-2。收率:90%。
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向S-4-2(11.46g,42.6mmol;1.0eq.)的二氯甲烷(100mL)悬浮液中加入2,4,6-三异丙基苯磺酰氯(15.4g,51.1mmol;1.2eq.)、DMAP(524mg,4.3mmol;0.1eq.)和Et3N(12.9g,127.8mmol;3.0eq.)。反应混合物在室温下搅拌12h。用二氯甲烷稀释溶剂,加入NaHCO3水溶液,并用DCM萃取。合并的有机层用无水Na2SO4干燥,过滤,并在真空中去除溶剂。粗产物通过快速色谱柱纯化,得到所需产物S-4-3,收率:67%。
将S-4-3(7.7g,14.4mmol;1.0eq.)和S-3-4(3.5g,14.4mmol;1.0eq.)溶解在50mL异丙醇中,95℃下搅拌过夜。在UPLC-MS证明起始材料完全转化后,将混合物冷却至室温。在真空中去除溶剂。粗产物通过快速色谱柱纯化,得到中间体S-4-4,收率:91%。
将S-4-4(2.64g,5.87mmol;1.0eq.)、(2-(羟甲基)苯基)硼酸(981mg,6.45mmol;1.1eq.)、Pd(PPh3)4(678mg,0.587mmol;0.1eq.)和Cs2CO3(5739mg,17.6mmol;3.0eq.)溶于四氢呋喃和水的混合溶液中,充氩气保护,在70℃条件下搅拌过夜。TLC检测反应完毕后,将反应液冷却至室温,并用乙酸乙酯和水萃取。混合有机层用盐水清洗,并用无水Na2SO4干燥,在减压下除去溶剂。粗产物通过快速色谱柱纯化,得到所需化合物S-4-5,收率:76%。
向S-4-5(533mg,1.1mmol;1.0eq.)的二氯甲烷(10mL)溶液中缓慢加入戴斯-马丁氧化剂(1462mg,3.45mmol;3.0eq.)。室温下搅拌5h,TLC检测反应完成。向反应混合物中加入Na2S2O4和NaHCO3的水溶液,并在室温下再搅拌30min。用乙酸乙酯萃取溶液,用盐水洗涤。合并的有机层用无水Na2SO4干燥,并在真空中浓缩。粗产物通过快速色谱柱进一步纯化,得到化合物S-5-1,收率:59%。
将S-5-1(1000mg,2.07mmol;1.0eq.)和甲胺(64mg,2.07mmol;1.0eq.)溶于1,2-二氯乙烷(20mL),室温下搅拌1h后缓慢加入NaBH(OAc)3(877mg,4.14mmol;2.0eq.),继续室温搅拌过夜,UPLC-MS检测反应完毕后,用水稀释反应混合物,用二氯甲烷萃取,并用无水Na2SO4干燥,在真空中除去溶剂。粗产物通过快速色谱柱纯化,得到的产物溶于10mL乙醇,缓慢加入Boc酸酐(243mg,1.10mmol;1.2eq.),室温条件下搅拌3h,TLC检测反应完毕后,在加压条件下除去反应溶剂,通过快速色谱柱纯化,得到目标化合物S-5-2,收率:42%。
将S-5-2(500mg,0.787mmol;1eq.)、(1-(叔丁氧羰基)-1,2,3,6-四氢吡啶-4-基)硼酸(197mg,0.866mmol;1.1eq.)、Pd(PPh3)4(9mg,0.079mmol;0.1eq.)和Cs2CO3(770mg,2.36mmol;3.0eq.)溶于四氢呋喃和水的混合溶液中,充氩气保护,在70℃条件下搅拌过夜。TLC检测反应完毕后,将反应液冷却至室温,并用乙酸乙酯和水萃取。混合有机层用盐水清洗,并用无水Na2SO4干燥,在减压下除去溶剂。粗产物通过快速色谱柱纯化,得到所需化合物S-5-3,收率:72%。
将V-1-1(150mg,0.348mmol;1.0eq.)、戊二酸单甲酯(56mg,0.348mmol;1.0eq.)、HATU(159mg,0.418mmol;1.2eq.)和DIPEA(270mg,2.09mmol;6.0eq.)溶于5mL N,N-二甲基甲酰胺,室温下搅拌6h,UPLC-MS检测反应完毕后,用水和乙酸乙酯稀释反应混合物。分离有机层,用盐水洗涤,并用无水Na2SO4干燥。溶液在真空下被除去。通过快速色谱柱纯化得到的中间体溶于四氢呋喃,加入事先溶于水的氢氧化锂,在室温下搅拌2h。反应完成后用乙酸调节反应液pH至4-6,用水和乙酸乙酯萃取,合并有机相用无水Na2SO4干燥,溶液在真空下被除去。得到中间体V-1-3。两步收率:58%。
将V-1-3(30mg,0.050mmol;1.0eq.)、S-5-3(27mg,0.05mmol;1.0eq)、HATU(29mg,0.075mmol;1.5eq.)和DIPEA(39mg,0.075mmol;6.0eq.)溶于3mL N,N-二甲基甲酰胺,室温下搅拌6h,UPLC-MS检测反应完毕后,用水和乙酸乙酯稀释反应混合物。分离有机层,用盐水洗涤,并用无水Na2SO4干燥。溶液在真空下被除去。然后通过快速色谱柱纯化得到粗产品。将所得粗产品溶于二氯甲烷,加入4M HCl的1,4-二氧六环溶液5mL,在室温下搅拌1h。减压除去溶剂,粗产物经prep-HPLC纯化后得到实施例8。两步收率:43%。1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.77(s,1H),8.56(t,J=6.0Hz,1H),8.11(s,1H),7.94–7.87(m,1H),7.65–7.55(m,1H),7.45–7.30(m,9H),7.17(s,1H),7.05(s,1H),6.01–5.91(m,1H),5.85(d,J=6.4Hz,1H),5.14(s,1H),4.51(d,J=9.2Hz,1H),4.43–4.35(m,2H),4.32(s,1H),4.17(dd,J=15.9,5.4Hz,1H),4.11(s,2H),4.07(s,2H),3.84(s,3H),3.83–3.79(m,1H),3.63(s,3H),3.58–3.54(m,3H),2.46(s,3H),2.40(s,3H),2.36–2.09(m,6H),2.05–1.71(m,4H),1.69(d,J=7.0Hz,3H),0.91(s,9H)。
实施例9、化合物9的制备
化合物9的分子式:(2S,4R)-4-羟基-1-((S)-2-(3-(4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-))((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)-3,6-二氢吡啶-1(2H)-基)-3-氧代丙酰胺基)-3,3-二甲基丁酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
参照合成路线II,具体合成步骤是将实施例8中的戊二酸单甲酯替换为丙二酸单甲酯,其余与实施例8相同,总收率:2.1%。1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.25(s,1H),8.11(d,J=12.8Hz,1H),8.00(t,J=9.1Hz,1H),7.68(d,J=9.1Hz,1H),7.55–7.48(m,2H),7.40–7.28(m,8H),7.24(d,J=1.5Hz,1H),6.24(tt,J=6.3,1.0Hz,1H),5.38(tq,J=6.7,3.2Hz,1H),5.09(dq,J=9.1,6.8Hz,1H),4.61(d,J=12.8Hz,1H),4.44–4.31(m,4H),4.13(d,J=7.3Hz,1H),4.11–3.98(m,2H),3.86(s,3H),3.70(ddt,J=6.1,2.1,1.0Hz,2H),3.68–3.61(m,3H),3.49(dd,J=12.3,7.0Hz,1H),3.24(d,J=12.5Hz,1H),3.18(d,J=12.3Hz,1H),3.14–3.05(m,1H),3.03(ddt,J=7.2,6.1,1.0Hz,1H),2.52(s,3H),2.48(d,J=3.1Hz,3H),2.37(s,3H),2.19–2.04(m,2H),1.78(d,J=6.8Hz,3H),0.97(s,9H)。
实施例10、化合物10的制备
化合物10的分子式:(2S,4R)-4-羟基-1-((S)-2-(4-(4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-))((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)-3,6-二氢吡啶-1(2H)-基)-4-氧代丁酰胺基)-3,3-二甲基丁酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
参照合成路线II,具体合成步骤是将实施例8中的戊二酸单甲酯替换为丁二酸单甲酯,其余与实施例8相同。总收率:2.5%。1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.25(s,1H),8.07–7.95(m,2H),7.68(d,J=9.1Hz,1H),7.55–7.48(m,2H),7.40–7.28(m,8H),7.24(d,J=1.5Hz,1H),6.24(tt,J=6.3,1.0Hz,1H),5.38(tq,J=6.6,3.2Hz,1H),5.09(dq,J=9.1,6.8Hz,1H),4.59(d,J=12.5Hz,1H),4.42–4.34(m,4H),4.34–4.24(m,1H),4.11–4.00(m,2H),3.98(dt,J=6.3,1.0Hz,1H),3.86(s,3H),3.73(dt,J=6.3,1.0Hz,1H),3.68–3.53(m,3H),3.47(dd,J=12.4,7.0Hz,1H),3.02(tdq,J=7.0,5.9,1.0Hz,2H),2.63–2.54(m,2H),2.52(s,3H),2.50–2.39(m,5H),2.37(s,3H),2.20(dt,J=12.3,6.9Hz,1H),2.06(dt,J=12.4,7.0Hz,1H),1.78(d,J=6.8Hz,3H),0.97(s,9H)。
实施例11、化合物11的制备
化合物11的分子式:(2S,4R)-4-羟基-1-((S)-2-(6-(4-(7-甲氧基-2-甲基-4-(((R)-1-(4-(2-))((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)-3,6-二氢吡啶-1(2H)-基)-6-氧代己酰胺基)-3,3-二甲基丁酰基)-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺。
参照合成路线II,具体合成步骤是将实施例8中的戊二酸单甲酯替换为己二酸单甲酯,其余与实施例8相同。总收率:2.3%。1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.57(t,J=6.1Hz,1H),8.37(d,J=8.2Hz,1H),8.18(s,1H),8.05(d,J=2.6Hz,1H),7.87(d,J=9.3Hz,1H),7.56–7.50(m,1H),7.42–7.28(m,9H),7.20(s,1H),7.00(s,1H),5.96–5.87(m,1H),5.83(d,J=10.5Hz,1H),4.51(d,J=9.4Hz,1H),4.43–4.35(m,2H),4.31(s,1H),4.17(dd,J=15.9,5.4Hz,1H),4.08(d,J=21.5Hz,2H),3.83(d,J=5.9Hz,6H),3.63–3.59(m,5H),2.40(d,J=1.7Hz,6H),2.33(s,3H),2.31–2.21(m,2H),2.17–2.06(m,1H),2.03–1.92(m,1H),1.90–1.81(m,1H),1.66(d,J=6.9Hz,3H),1.52–1.43(m,4H),1.16–1.10(m,1H),0.89(s,9H)。
实施例12:本发明化合物对PANC-1和K562细胞中SOS1表达量降低作用的评价
将人胰腺癌细胞PANC-1或人慢性髓原白血病细胞K562在含有10% PBS和2.5%马血清的DMEM高糖培养基(以下记作评价培养基)中以达到3×105/孔的量接种于6孔微孔培养板(Corning),培养过夜。在该培养物中添加含有实施例化合物的评价培养基中,使得实施例化合物的终浓度达到0.1、1和10μmol/L,培养24小时。24小时培养后,除去培养基,使用PBS清洗细胞之后,添加含有1% Protease Inhibitor Cocktail的RIPA裂解液,经裂解、离心后获得总蛋白提取液,通过BCA法检测提取液中的蛋白浓度;采用SDS-PAGE进行蛋白电泳,之后200mA恒流电转120min将蛋白转印到PVDF(MilliporeSigma IPVH00010)膜上;将PVDF膜置于含有5%的脱脂奶中,室温封闭1h;分别使用Anti-SOS1抗体[12409](CST)进行免疫反应;洗膜后滴加ECL发光液,曝光。使用软件Image J对条带进行灰度分析。每个样品同时检测GAPDH蛋白条带作为内参。根据蛋白条带灰度计算实施例化合物SOS1蛋白降解率,NA代表未测。
化合物在PANC-1和K562细胞中诱导SOS1降解的结果如表1所示。
表1
在所有实施例化合物中,实施例2化合物表现出最好的SOS1降解效果,在测定浓度下对PANC-1和K562细胞中SOS1的降解率均接近90%。我们选择化合物2在上述两种细胞中进行了SOS1降解活性随时间和剂量的依赖关系研究,如图1中A和B所示,化合物2在两种细胞系中对SOS1的降解呈明显的剂量依赖性,DC50分别为129.8nM和43.1nM(图1是C和D)。图2中A和B为化合物2对SOS1降解的时间依赖性关系,在以1μmol/L的剂量给药24h后,化合物2对SOS1的降解率可以达到70%以上(图2中C和D)。
实施例13:化合物2对NCI-H358细胞3D增殖抑制活性
将NCI-H358细胞接种在96孔Nunclon Sphera Plates中,并与连续稀释的化合物2和抑制剂BI3406分别孵育9天。按照制造商的说明,使用CellTiter-Glo 3D CellViability Assay测定细胞活力。IC50值即半数抑制浓度,通过非线性回归(曲线拟合)使用Graphpad Prism中的可变斜率(四个参数)确定。
细胞增殖抑制结果如图3所示,其中显示化合物2表现出对NCI-H358细胞的增殖抑制活性,在3.0μmol/L时抑制率达到50%,抑制剂BI3406作为阳性对照,其抑制活性略差于化合物2。
以上描述是本发明的一般性描述。根据情况或实际需要,可进行形式的变化和等值的替代,虽然本文采用特定的术语,但这些术语意在描述,而不是为了限制的目的。本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围之内。
Claims (10)
1.一种降解SOS1蛋白的化合物,其具有式I所示的结构,
其中:X1、X2各自独立地选自N或C;Y选自N、S、O、Si或P;
所述R基团选自:
其中:X选自N或C;W选自S或O;m1、m2各自独立的为0-5的整数;
所述R1选自H;-OH;-NH2;卤素;取代或未取代的直链或支链C1-C3烷基;取代或未取代的直链或支链C1-C3烯基;取代或未取代的直链或支链C1-C3炔基;取代或未取代的直链或支链C1-C3羰基;取代或未取代的C1-C10环烷基;取代或未取代的C1-C10杂环基;取代或未取代的C1-C10芳基或杂芳基;
所述连接基团1选自:不存在;或者取代或未取代的直链或具有支链的C1-C12亚烷基;任选的碳链中含有1-4个选自N、S、O、Si或P的杂原子;
其中:n1、n2、n3各自独立的为0-5的整数;X1、X2、X3、X4各自独立地选自N或C;
所述E3配体选自:
其中:m为0-3的整数;
所述R2、R3、R4和R5各自独立的选自:H;-OH;-NH2;卤素;取代或未取代的直链或支链C1-C6烷基;取代或未取代的直链或支链C1-C6氰基;取代或未取代的直链或支链C1-C6烯基;取代或未取代的直链或支链C1-C6炔基;取代或未取代的直链或支链C1-C6烷氧基;取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺基;取代或未取代的直链或支链C1-C6酯基;取代或未取代的直链或支链C1-C6酰胺基;取代或未取代的直链或支链C1-C6酮基;取代或未取代的C1-C10环烷基;取代或未取代的C1-C10杂环基;取代或未取代的C1-C10芳基或杂芳基。
2.如权利要求1所述的化合物,其特征在于,所述化合物具有下述结构式:
其中:X1、X2各自独立地选自N或C;Y选自N或O;
m1为0-5的整数,m2为0-4的整数;
所述R1选自H;-OH;-NH2;卤素;取代或未取代的直链或支链C1-C3烷基;取代或未取代的直链或支链C1-C3烯基;取代或未取代的直链或支链C1-C3炔基;取代或未取代的直链或支链C1-C3羰基;取代或未取代的C1-C10环烷基;取代或未取代的C1-C10杂环基;取代或未取代的C1-C10芳基或杂芳基;
R2、R3、R4和R5各自独立的选自:H;-OH;-NH2;卤素;取代或未取代的直链或支链C1-C6烷基;取代或未取代的直链或支链C1-C6氰基;取代或未取代的直链或支链C1-C6烯基;取代或未取代的直链或支链C1-C6炔基;取代或未取代的直链或支链C1-C6烷氧基;取代或未取代的直链或支链C1-C6仲胺基、叔胺基或季胺基;取代或未取代的直链或支链C1-C6酯基;取代或未取代的直链或支链C1-C6酰胺基;取代或未取代的直链或支链C1-C6酮基;取代或未取代的C1-C10环烷基;取代或未取代的C1-C10杂环基;取代或未取代的C1-C10芳基或杂芳基。
所述连接基团选自:不存在;或者取代或未取代的直链或具有支链的C1-C12亚烷基;任选的碳链中含有1-4个选自N、S、O、Si或P的杂原子;
其中:n1、n2、n3各自独立的为0-5的整数;X1、X2、X3、X4各自独立地选自N或C。
3.如权利要求2所述的化合物,其特征在于,所述化合物具有下述结构式:
4.如权利要求1或2或3所述的化合物的立体异构体、溶剂化合物、前药、代谢物、药学上可接受的盐或共晶。
5.含有如权利要求1或2或3所述的化合物,或其立体异构体、溶剂化合物、前药、代谢物、药学上可接受的盐或共晶的药物组合物。
6.如权利要求5所述的药物组合物,还包括药学上可接受的载体。
7.如权利要求1或2或3所述的化合物,或其立体异构体、溶剂化合物、前药、代谢物、药学上可接受的盐或共晶在制备用于治疗或预防与SOS1活性或表达量相关疾病的药物中的应用。
8.如权利要求7所述的应用,其特征在于,所述的化合物或其立体异构体、溶剂化合物、前药、代谢物、药学上可接受的盐或共晶作为SOS1降解剂发挥作用。
9.如权利要求8所述的应用,其特征在于,其用于预防或治疗结肠癌、非小细胞肺癌、胰腺癌、直肠癌、黑色素瘤或多发性骨髓瘤。
10.如权利要求1或2或3所述化合物的制备方法,其特征在于,按下述合成路线I或II之一得到所述化合物:
合成路线I
合成路线II
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