CN116891514A - 一种双官能化合物及其用途 - Google Patents
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- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
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Abstract
本发明涉及一种具有双官能的KRAS G12D调节剂(W‑L‑T)及其应用;其中W表示靶向基团且为KRAS G12D蛋白(靶蛋白)的调节剂,T为E3泛素连接酶的配体基团,L是使靶向基团(W)与配体基团(T)化学连接的双价连接基团。本发明公开的双官能调节剂或化合物以及其组合物,具有降解或抑制靶蛋白的药理活性,可用于治疗、抑制或预防KRAS G12D相关的疾病或病症。
Description
技术领域
本发明涉及一种有W-L-T结构的双官能化合物,或其药学上可接受的盐或酯或水合物或溶剂合物或立体异构体,以及其在制备用于治疗、抑制或预防KRAS G12D相关疾病的药物中的用途。
背景技术
KRAS(Kirsten Rat Sarcoma Viral Oncogene Homolog)基因属于RAS家族,是人类癌症中常见的基因突变之一,其编码的蛋白是一种小GTP酶(small GTPase)。KRAS基因参与了控制基因转录的激酶信号传导路径,从而调节细胞的生长和分化。在细胞内,Kras蛋白在失活和激活状态之间转变,当Kras与鸟嘌呤核苷二磷酸(GDP)结合时,它处于失活状态,当它与鸟嘌呤核苷三磷酸(GTP)结合时,它处于激活状态,并且可以激活下游信号通路。大部分细胞中的Kras处于失活状态,当它被激活后,可以激活的下游信号通路包括MAPK信号通路、PI3K信号通路和Ral-GEFs信号通路。这些信号通路在促进细胞生存、增殖和细胞因子释放方面具有重要作用,从而影响肿瘤发生和发展。
在人类癌症中,KRAS基因突变出现在接近90%的胰腺癌中,约30%至40%的结肠癌中,约17%的子宫内膜癌中,约15%至20%的肺癌中(大多为非小细胞肺癌,Non-SmallCell Lung Cancer,NSCLC)。它也会在胆管癌、宫颈癌、膀胱癌、肝癌和乳腺癌等癌症类型中出现。也就是说,在上述多种癌症中,存在高比例的Kras基因突变。大多数KRAS错义突变发生在12号密码子中,导致甘氨酸变为其他氨基酸。根据存在的特定突变,G12C、G12D和G12R是患者们最常见的Kras突变,如KRAS G12D和KRAS G12V突变,二者在约90%的胰腺癌中均有发现,而KRAS G12D是结肠癌中最常见的Kras突变。
目前关于KRAS G12D的抑制剂已经有了一些报道,如WO2021041671、WO2021106231。但是,以抗癌药物为例,传统上的小分子通过靶向结合来抑制靶蛋白酶活性,诱导癌细胞凋亡,然而肿瘤细胞内的靶蛋白常常会恢复其活性,并通过靶蛋白的过表达或靶蛋白的新突变而获得耐药性。传统小分子抑制剂的缺陷使得小分子药物日渐式微,小分子药物研发亟需引入革命性的新技术。
面对这种现象,研究人员发现了一种新的方法,利用小分子来敲除功能性靶蛋白,而不是单纯的抑制靶蛋白的活性,蛋白质降解靶向嵌合体(Proteolysis TargetingChimera,Protac)是控制这种降解途径的一种方法(参考Angew.Chem.Int.Ed.2016,55,807–810、J.Med.Chem.2018,61,444-452等)。Protac不是传统的酶抑制剂,而是通过诱导选择性细胞内蛋白水解来发挥作用。Protac是由两个活性域和一个连接体组成的异双功能小分子,能够去除特定的不需要的蛋白质。Protac的两个活性域中的一个能与E3泛素连接酶结合,另一个能与降解的目标蛋白质结合。将E3连接酶招募到靶蛋白导致泛素化并随后被蛋白酶体降解靶蛋白。由于Protac只需以高选择性结合其靶蛋白(而不是抑制靶蛋白的酶活性),因此目前有许多努力将以前无效的抑制剂分子重组为下一代药物的Protac。
针对与KRAS G12D突变有关的疾病或病症,能够靶向降解治疗的小分子制剂是十分有意义的。
发明内容
本发明主要解决的技术问题是提供一种能够将E3泛素连接酶聚集到靶蛋白附近进行降解的双官能化合物,其可以用于多种多肽或蛋白质的靶向泛素化调节剂,进而降解或抑制靶向的多肽或蛋白质。本发明公开的双官能化合物,或其药学上可接受的盐、酯或立体异构体,其包含KRAS G12D蛋白的靶向基团W、E3泛素连接酶的配体基团T以及将靶向基团(W)与配体基团(T)进行化学连接的双价连接基团(L),从而使得靶蛋白(KRAS G12D蛋白)能够位于E3泛素连接酶的附近,进而影响或抑制该蛋白质的降解。
本发明所描述的W和T,其数量和位置仅作为示例展示出来,并不用于限制化合物,在实际情况中本领域技术人员可以根据需求调整或变化。
在一些实施方式中,双官能化合物包括靶向基团W和E3泛素连接酶的配体基团T,且W和T分别与双价连接基团L的相应位点共价连接,形成蛋白质降解靶向嵌合体,以下列通式表示:
W-L-T。
在一些实施方式中,双价连接基团L具有L1-L2-L3的结构,双官能化合物包括靶向基团W和E3泛素连接酶的配体基团T,且W和T分别与双价连接基团L1、L2、L3的相应位点共价连接,形成蛋白质降解靶向嵌合体,以下列通式表示:
W-L1-L2-L3-T。
在一些实施方式中,双官能化合物仅包括靶向基团W和E3泛素连接酶的配体基团T,即以W-T的形式展示。
在一些实施方式中,双官能化合物仅包括靶向基团W、双价连接基团L1和E3泛素连接酶的配体基团T,即以W-L1-T的形式展示。
在一些实施方式中,双官能化合物仅包括靶向基团W、双价连接基团L1、L2和E3泛素连接酶的配体基团T,即以W-L1-L2-T的形式展示。
在一些实施方式中,KRAS G12D蛋白的靶向基团W具有选自式(Ia)或式(Ib)所示的结构:
其中X选自氮(N)、碳(CH)、C-F、C-Cl、C-CH3、C-C2H5、或C-C3H7;
R1选自取代或未取代的羟基、氨基或巯基;
R2和R3独立地选自H、卤素、卤代甲基(一卤甲基、二卤甲基、及三卤甲基),或者R2、R3以及它们所连接苯环结构一起形成取代或未被取代的苯并稠环、包括但不限于萘环结构;并且当形成取代的苯并稠环(例如萘环)时,苯并稠环上任选地取代有一个或多个,例如2个或3个独立选自卤素、羟基、氨基、卤代甲基、C1-C2烷基、C2-4炔基的取代基。
所述双价连接基团L具有L1-L2-L3的结构;并且其中L1、L2、L3可同时存在或者存在其中的一者或两者。例如,仅存在L1,或者存在L1和L2,或者存在L1和L3,或者L1、L2、L3同时存在。
进一步地,L1、L2、L3独立的选自具有双连接位点的取代或未取代的烃基、烃氧基、氧基烃基、环烃基、杂环烃基、酰基烃基、烃基酰基、羰基烃基、烃基羰基、酰胺基烃基、烃基酰胺基、芳基、以及寡肽基团中的一种或其中几种的组合而成的双价基团;
其中所述烃基包括饱和烃基、不饱和烃基、芳香族烃基、氧杂烃基、氮杂烃基、硫杂烃基、磷杂烃基以及不同杂原子的混合杂烃基,其中烃基或杂烃基的链长为1到20个原子,并且当其为杂烃基时,所述杂烃基含有1到5个杂原子
在一些实施方式中,其中杂原子化学价根据需要由氢、氧、氮等以相应的键合方式进行满足;
其中所述的杂环烃基中的杂环包括取代或未取代的单环、螺环或稠环等。
在一些实施方式中,L1选自-O-、-NH-;
在一些实施方式中,L1选自式(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)所示的结构:
其中,Y和Z独立地选自氧(O)、氮(NH)、或硫(S);n=0~20(尤其是n=0-5,例如,0、1、2、3、4、5),优选的,n=2;R5和R6独立地选自氢、卤素(例如氟、氯、溴或碘)、羟基、烷氧基、氨基、或胺基;当结构中具有手性中心时,其立体结构独立地选自R-构型、S-构型、或R-和S-构型的混合构型。
在一些实施方式中,Z可为六元氮杂环。
在一些实施方式中,双价连接基团中,L1选自:
其中,n=0~20,优选的n=0~5,更尤其为1~2。
在一些实施方式中,双价连接基团中,L2、L3独立地选自:
其中,L2和L3可不同时存在;
其中,p=0-20(诸如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19),优选的p=0-10;m=0-5;q=0-10,优选的q=0-5。
在一些实施方式中,L1和L3独立地选自-O-、-NH-。
在一些实施方式中,L1、L2和L3中的一个或多个按照本申请展示的结构依次从左往右连接起来。
在一些实施方式中,L1、L2和L3中的一个或多个任意的以本申请展示结构的左端或右端与相邻结构的另一端连接起来。
在一些实施方式中,L2和L3一起形成以下结构:
进一步地,在一些实施方式中,L1、L2和L3一起形成以下结构:
在一些实施方式中,KRAS G12D蛋白的靶向基团W的结构中,左端片段选自以下基团:
在一些具体实施方式中,本发明双官能化合物中的靶向基团W具有下式结构:
在一些实施方式中,所述E3泛素连接酶的配体选自能与VHL(Von Hippel-Lindau)、CRBN(Cereblon)、MDM2、clAP、AhR、Nimbolide、CCW16、KB02或KEAP1结合的配体。
当结构中具有手性中心时,其立体结构独立地选自R-构型、S-构型、或R-和S-构型的混合构型。
进一步地,E3泛素连接酶的配体基团T可以是能与VHL结合的配体,如下所示:
进一步地,E3泛素连接酶的配体基团T可以是能与VHL结合的配体,如下所示:
E3泛素连接酶的配体基团T也可以是能与CRBN结合的配体,如下所示:
其中,O、N可以在苯环上任意位点取代。
进一步地,E3泛素连接酶的配体基团T选自:
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其中,苯环上的取代可以发生在任意位点,当结构中具有手性中心时,其立体结构独立地选自R-构型、S-构型、或R-和S-构型的混合构型。
在一些实施方案中,双官能化合物,包括以下表1、表2所示的化合物或药学上可接受的盐、酯、立体异构体、水合物、溶剂合物。
表1
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表2
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上述化合物具有较好的生物活性,可用于治疗KRAS G12D相关的疾病。
在一些实施方式中,本申请提供的化合物,可以是天然丰度或同位素替代的化合物,同位素可以是1H、D、T、18O、17O、15N和13C等。
本发明还提供一种药物组合物,该药物组合物包括上述任意所述的化合物或其药学上可接受的盐、酯、水合物、溶剂合物、或立体异构体;以及可选的至少一种药学上可接受的赋形剂或载体或稀释剂。
进一步地,药学上可接受的赋形剂包括粘合剂、填充剂、崩解剂、润滑剂和助流剂中的一种或多种。
进一步地,药学上可接受的载体包括乳膏、乳剂、凝胶、脂质体和纳米颗粒中的一种或多种。
进一步地,组合物适用于口服施用或者注射施用。
本申请还提供一种上述任意所述的化合物或其药学上可接受的盐或酯或水合物或溶剂合物或异构体或药物组合物在制备用于治疗、抑制或预防过度增生病症的药物中的用途。本申请还提供了一种治疗、抑制或预防过度增生病症的方法,包括将有效量的上文所述的化合物和/或药物组合物施用至受试者,从而起到治疗相关疾病的效果。
在一些实施方式中,过度增生病症为与KRASG12D相关的恶性肿瘤或癌症。
进一步地,恶性肿瘤或癌症选自:肉瘤(血管肉瘤,纤维肉瘤,横纹肌肉瘤,脂肉瘤),
粘液瘤,横纹肌瘤,纤维瘤,脂肪瘤和畸形瘤;肺:支气管癌(鳞状细胞,未分化小细胞,
未分化大细胞,腺癌),肺泡(支气管)癌,支气管腺瘤,肉瘤,淋巴瘤,软骨瘤,间皮瘤;胃肠:食道(鳞状细胞癌,腺癌,平滑肌瘤,淋巴瘤),胃(癌,淋巴瘤,平滑肌瘤),胰腺(导管腺癌,胰岛素瘤,葡糖单胞菌,胃泌素瘤,类癌肿瘤,舒血管肠肽瘤),小肠(腺癌,淋巴瘤,类癌肿瘤,卡波西氏肉瘤,平滑肌瘤,血管瘤,脂肪瘤,神经纤维瘤,纤维瘤),大肠(腺癌,管状腺瘤,绒毛腺瘤,血肿,平滑肌瘤);泌尿生殖道:肾(腺癌,Wilms肿瘤(肾母细胞瘤),淋巴瘤,白血病),膀胱和尿道(鳞状细胞癌,过渡细胞癌,腺癌),前列腺(腺癌,肉瘤),睾丸(精原细胞瘤,畸形瘤,胚胎癌,畸形癌,绒毛膜癌,肉瘤,间质细胞癌,纤维瘤,纤维腺瘤,腺样瘤,脂肪瘤);肝脏:肝癌(肝细胞癌),胆管癌,肝母细胞瘤,血管肉瘤,肝细胞腺瘤,血管瘤;胆道:胆囊癌,安瓿癌,胆管癌;骨:成骨肉瘤(骨肉瘤),纤维肉瘤,恶性纤维组织细胞瘤,软骨肉瘤,Ewing肉瘤,恶性淋巴瘤(网状细胞肉瘤),多发性骨髓瘤,恶性巨细胞瘤弦状瘤,骨软骨瘤(骨软骨瘤),良性软骨瘤,成软骨细胞瘤,软骨粘液纤维瘤,骨样骨瘤和巨细胞瘤;神经系统:颅骨(骨瘤,血管瘤,肉芽肿,黄瘤,变形性骨炎),脑膜(脑膜瘤,脑膜肉瘤,胶质瘤病),脑(星形细胞瘤,成髓细胞瘤,神经胶质瘤,附睾瘤,生殖细胞瘤(松果体瘤),成胶质细胞瘤多种形式,少突胶质瘤,神经胶质瘤,视网膜母细胞瘤,先天性肿瘤),脊髓神经纤维瘤,脑膜瘤,神经胶质瘤,肉瘤);妇科:子宫(子宫内膜癌(浆液性膀胱癌,粘液性膀胱癌,未分类癌),颗粒鞘细胞瘤,血清间质细胞瘤,发育不良,恶性畸形瘤),外阴(鳞状细胞癌,上皮内癌,腺癌,纤维肉瘤,黑色素瘤),阴道(透明细胞癌,鳞状细胞癌,葡萄膜肉瘤(胚胎横纹肌肉瘤),输卵管(癌);血液学:血液(骨髓性白血病(急性和慢性),急性淋巴细胞白血病,慢性淋巴细胞白血病,骨髓增生性疾病,多发性骨髓瘤,骨髓增生异常综合征),霍奇金氏病,非霍奇金氏淋巴瘤(恶性淋巴瘤);皮肤:恶性黑色素瘤,基底细胞癌,鳞状细胞癌,卡波西肉瘤,摩尔斯发育异常性痣,脂肪瘤,血管瘤,皮肤纤维瘤,瘢痕瘤,银屑病;肾上腺神经母细胞瘤。
在一些实施方式中,恶性肿瘤为非小细胞肺癌、小细胞肺癌、胰腺癌、结直肠癌、胆管癌、宫颈癌、膀胱癌、肝癌或乳腺癌中的一种或多种。
本申请还提供一种试剂盒,该试剂盒包括上述任意所述的化合物或药学上可接受的盐或酯或水合物或溶剂合物或立体异构体、或任意所述的组合物,可制备用于治疗、抑制或预防与KRAS G12D突变相关的疾病的药物。
本申请提供的化合物,或其药学上可接受的盐或酯或水合物或溶剂合物或立体异构体,具有很好的KRAS G12D蛋白的抑制或降解效果,可以应用于治疗、抑制或预防与KRASG12D突变相关的疾病的药物的制备。
具体实施方式
为了对本发明的说明书中所使用的术语提供清楚且一致的理解,在下文中提供一些定义。此外,除了特殊说明,本发明所用的全部技术和科学术语具有同本发明所属领域中普通技术人员通常所理解的相同的含义。
当在权利要求和/或说明书中与术语“包括”结合使用时,词语“一”的使用可以表示“一个”,但它也与“一个或多个”,“至少一个”和“一个或多于一个”的含义已知。类似地,词语“另一个”可以表示至少第二个或者很多个。
如在本说明书和权利要求中所使用的词语“包括”(以及包括的任何形式,诸如“包括”和“包含”),“具有”(以及任何形式的具有,“具有”、“包含”和“含有”)是包括性的和开放式的,并且不排除另外的未列出的要素或处理步骤。术语“约”或“大约”用于表示该值包括在确定该值中所用的仪器和方法带来的误差。
术语“KRAS G12D”是指哺乳动物KRAS蛋白的突变形式,其包含在12号密码子中用天冬氨酸等替代甘氨酸的氨基酸。
本发明公开的双官能团化合物,包括KRAS G12D蛋白的靶向基团W和E3泛素连接酶的配体基团T。除非上下文另有说明,否则术语W和T以其包括性含义使用,例如,术语W包括所有可能靶向识别KRAS G12D蛋白质的部分,其可以是一个独立的能够靶向识别的分子或由分子参与反应生成的基团,也可能是包含靶向识别分子在内的、与其它结构结合的分子或由分子参与反应生成的基团,即W包括所有能够部分用于识别或全部用于靶向识别KRASG12D蛋白质的分子或基团。术语T包括所有可能作为E3泛素连接酶配体使用的部分,其可以是一个独立的能够适配E3泛素连接酶的配体,也可能是包含配体分子或基团在内的、还包含其他结构的分子或基团,即T包括所有能够部分用于或全部用于适配E3泛素连接酶的分子或基团。
本发明公开的L是用于将靶向基团(W)与配体基团(T)进行化学连接的双价连接基团。本发明公开的L,均用于连接W和T,从而起到将W和T组合在一起的作用。在某些实施例中,W与T直接连接,即L可以是不存在的。在大部分情况下L是存在的,本申请提供的L的范围和具体结构并不意于限制,其可以是任何起到连接W和T的结构。
本发明所用术语“药学上可接受的”是指该术语描述的药物、药品、惰性成分等,适合用于与人和低等动物的组织相接触,而没有异常毒性、不相容性、不稳定性、刺激性、过敏反应等,与合理的利益/风险比率相称。
化合物的“药学上可接受的立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。进一步讲,分子中原子或原子团互相连接次序相同,但空间排列不同而引起的异构体称为立体异构体,主要分为两大类:因键长、键角、分子内有双键、有环等原因引起的立体异构体称为构型异构体(configuration stereo-isomer)。一般来讲,构型异构体之间不能或很难互相转换。仅由于单键的旋转而引起的立体异构体称为构象异构体(conformational stereo-isomer),有时也称为旋转异构体(rotamer)。当旋转异构体中的旋转受阻而无法旋转时,则成为“立体异构体”,例如在联苯结构中,当α-和α’-位上存在较大且不同的取代基时,两个苯环之间的单键旋转由于取代基间的阻碍而无法自由旋转,因此产生两个立体异构体。
化合物的“药学上可接受的盐”是指药学上可接受的化合物的盐。理想的化合物的盐(碱性、酸性或带电官能团)可以保留或改善如本发明所定义的母体化合物的生物活性和性质,并且不是生物学上不需要的。药学上可接受的盐可以由含有碱性或酸性片段的母体化合物通过常规化学方法合成。通常,这种盐通过化合物(游离酸或碱)与等化学计量的碱或酸在水中或有机溶剂中或在两者的混合物中反应来制备。盐可以在药剂的最终分离或纯化过程中原位制备,或者将游离酸或碱形式的已纯化的本发明化合物单独的与所期望的相应碱或酸反应并分离由此形成的盐而制备。术语“药学上可接受的盐”还包括含有共价键合至阴离子基团的阳离子基团的两性离子化合物,它们被称作“内盐”。
本发明所用术语“酯”是指可以由通式RCOOR’所表示的基团或片段,通常该基团可以通过羧酸与醇反应(消去一分子水)得到。其中,R诸如为低级烷基或芳基,例如亚甲基、亚乙基、异亚丙基、亚苯基等,但不限于此;R’诸如为低级烷基或芳基,例如甲基、乙基、丙基、异丙基、丁基、苯基等,但不限于此。术语“酯烷基”是指R’为烷基,烷基的一端与酯上的氧直接相连接,另一端与化合物或片段中至少一个碳或杂原子共价键合
术语“取代”或“具有取代基”是指母体化合物或部分具有至少一个取代基团。术语“未取代的”或“不具有取代基”是指母体化合物或部分除了未确定的化合价被氢原子化学饱和外,不具有其他取代基。
除非另外指出,否则“取代的”基团在该基团的一个或多个可取代的位置上具有一个取代基,并且当取代任何给定结构中的多于一个位置时,该取代基在每个位置上是相同或不同的。
如本文所述,“取代基”或“取代基团”是指选自卤素(F、Cl、Br或I)、羟基、巯基、氨基、硝基、羰基、羧基、烷基、烷氧基、烷基氨基、芳基、芳基氧基、芳基氨基、酰基、亚硫酰基、磺酰基、膦酰基或在有机化学中常规使用和接受的其它有机部分。
泛素(ubiquitin,Ub)是由76个氨基酸组成的分子量约8.5kDa的小分子蛋白质,广泛存在于所有真核细胞中,且序列高度保守,从酵母到人仅相差3个氨基酸。泛素化是指泛素在一系列酶的催化作用下共价结合到靶蛋白的过程。泛素化过程通常需要3种泛素化酶的协同作用:E1泛素激活酶、E2泛素结合酶和E3泛素连接酶。常见的E3泛素连接酶包括VHL(Von Hippel-Lindau)、CRBN(Cereblon)、MDM2、clAP、AhR、Nimbolide、CCW16、KB02、KEAP1等。
本发明所用术语“芳基”和“芳香族”是指在共轭单环或多环体系(稠和或非稠和的)中具有“4n+2”个(π)电子,并具有6至14个环原子的芳族基团,其中n是1至3的整数。多环体系包括至少一个芳环。芳基可以直接连接或通过C1-C3烷基(也称为芳基烷基或芳烷基)连接。芳基的实例包括但不限于苯基、苄基、苯乙基、1-苯基乙基、甲苯基、萘基、联苯基、三联苯基、茚基、苯并环辛烯基、苯并环庚烯基、薁基、苊基、芴基、菲基、蒽基等。术语芳基包括未取代的芳基和取代的芳基。芳基通过烃基连接,也称为芳基烃基。
术语“烃基”包括但不限于饱和烃基、不饱和烃基、芳香族烃基、氧杂烃基、氮杂烃基、硫杂烃基、磷杂烃基以及不同杂原子的混合杂烃基,且烃基或杂烃基的链长为1到20个原子,并且当其为杂烃基时、杂烃基含有1到5个杂原子、且其中杂原子化学价根据需要由氢、氧、氮等以相应的键合方式进行满足。
术语“环基”,“脂环族”,“环烃基”和等同表述是指在单环、螺环(共享一个原子)或稠合(共享至少一个键)碳环体系中包含饱和或部分不饱和碳环的基团,其中碳环体系具有3至15个碳原子。术语“环烃基”包括环基与烃基的组合基团。
本发明所用术语“杂环”和等同表述是指在单环、螺环(共享一个原子)或稠合(共享至少一个键)碳环体系中包含饱和或部分不饱和碳环的基团,其具有3个至15个碳原子的基团,包括1至6个杂原子(例如N、O、S、P)或者含杂原子(例如NH、NRx(Rx是烷基、酰基、芳基、杂芳基或环烷基),PO2、SO、SO2等)的基团。杂环烃基可以与C连接或与杂原子连接(例如通过氮原子)。“杂环”或“杂环的”包括杂环烷基和杂芳基。杂环的实例包括但不限于吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噻吩基、苯并恶唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、4αH-咔唑基、咔啉基、苯并二氢吡喃基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、二氢吲哚基、3H-吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基、八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、恶唑烷基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡啶基、吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并恶唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、3,4-三唑基、呫吨基等。术语“杂环”包括未取代的杂环基和取代的杂环基。术语“杂环烃基”是指杂环与烃基的组合基团。
本发明所用术语“酰基”指化合物或片段中至少一个碳或杂原子与-C=O上的碳原子共价键合。本发明所用术语“胺”或“氨基”是指未取代或取代的通式-N-的片段。术语“酰胺基”是指氨基直接与酰基连接的结构-C(=O)N-。术语“酰基烃基”是指酰基与烃基的组合基团,即酰基上的碳原子与烃基相连接。
术语“羰基”是指由碳和氧两种原子通过双键连接而成的-C=O-片段,“羰基”是醛、酮、酸等官能团的组成部分。
术语“酰胺基烃基”或“烃基酰胺基”是指烃基与酰胺基组合连而成的基团。术语“酰基烃基”或“烃基酰基”是指烃基与酰基组合而成的基团。术语“羰基烃基”或“烃基羰基”是指烃基与羰基组合连而成的基团。
本发明所用术语“烷氧基”或“低级烷氧基”是指烷基与氧原子相连的结构。代表性的烷氧基包括具有1至约6个碳原子的基团,例如甲氧基、乙氧基、丙氧基、叔丁氧基等。烷氧基的实例包括但不限于甲氧基、乙氧基、异丙氧基、丙氧基、丁氧基、戊氧基、氟甲氧基、二氟甲氧基、三氟甲氧基、氯甲氧基、二氯甲氧基、三氯甲氧基等。术语“烷氧基”包括未取代或取代的烷氧基,以及全卤代烷氧基等。类似的,术语“烃氧基”或“氧基烃基”是指烃基与氧原子相连的基团或结构。
化合物的“药学上可接受的盐”是指药学上可接受的化合物的盐。理想的化合物的盐(碱性、酸性或带电官能团)可以保留或改善如本发明所定义的母体化合物的生物活性和性质,并且不是生物学上不需要的。药学上可接受的盐可以是Berge等人在"Pharmaceutical Salts",J.Pharm.Sci.66,1-19(1977)所提到的。包括但不限于:
(1)在碱性或带正电荷的官能团上加入酸形成的盐,无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、硝酸、磷酸、碳酸盐等。有机酸包括乙酸、丙酸、乳酸、草酸、乙醇酸、新戊酸、叔丁基乙酸、β-羟基丁酸、戊酸、己酸、环戊烷丙酸、丙酮酸、丙二酸、琥珀酸、苹果酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、环己基氨基磺酸、苯磺酸、磺胺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、3-苯基丙酸、月桂基磺酸、月桂基硫酸、油酸、棕榈酸、硬脂酸、月桂酸、扑酸、泛酸、乳糖酸、藻酸、半乳糖二酸、半乳糖醛酸、葡萄糖酸、葡庚糖酸、谷氨酸、萘甲酸、羟基萘甲酸、水杨酸、抗坏血酸、硬脂酸、粘康酸等。
(2)当母体化合物中存在酸性质子或者其被金属离子取代时,可以加入碱得到盐。所述金属离子包括碱性金属离子(例如锂、钠、钾),碱土金属离子(镁、钙、钡)或其它金属离子如铝、锌BIAO有机碱包括但不限于N,N'-二苄基乙二胺、乙醇胺、二乙醇胺、三乙醇胺、氨基丁三醇、N-甲基葡萄糖胺、哌嗪、氯普鲁卡因、普鲁卡因、胆碱、赖氨酸等。
药学上可接受的盐可以由含有碱性或酸性片段的母体化合物通过常规化学方法合成。通常,这种盐通过化合物(游离酸或碱)与等化学计量的碱或酸在水中或有机溶剂中或在两者的混合物中反应来制备。盐可以在药剂的最终分离或纯化过程中原位制备,或者将游离酸或碱形式的已纯化的本发明化合物单独的与所期望的相应碱或酸反应并分离由此形成的盐而制备。术语“药学上可接受的盐”还包括含有共价键合至阴离子基团的阳离子基团的两性离子化合物,它们被称作“内盐”。本发明的化合物包括的所有酸,盐,碱和其它离子和非离子形式。例如,如果本发明中化合物为酸,该化合物盐的形式也包含在内。同样,如果本发明中化合物为盐,该化合物酸和/或碱的形式也包含在内。
本发明还提供了药物组合物,在一实施方式中,该药物组合物包括:本发明所披露的化合物或其药学上可接受的盐或酯或异构体或水合物,以及药学上可接受的赋形剂或载体或稀释剂。
具体的,药学上可接受的赋形剂包括粘合剂,填充剂,崩解剂,润滑剂和助流剂中的一种或多种。药学上可接受的载体或稀释剂包括乳膏、乳剂、凝胶、脂质体和纳米颗粒中的一种或多种。
“药物组合物”是指包括如本文所述的化合物,以及取决于给药方式和剂型的要求的至少一种组分,该至少一种组分包括药学上可接受的载体、稀释剂、佐剂、赋形剂或载剂,诸如防腐剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、甜味剂、调味剂、芳香剂、抗菌剂、抗真菌剂、润滑剂和分散剂等。“预防”或“预防”用于表示至少降低获得疾病或病症(或易感性)获得疾病或障碍的可能性(即,使至少一种疾病的临床症状不发展为可能暴露于或易患疾病但尚未经历或显示疾病症状的患者)。
术语“受试者”是指包括哺乳动物和人的动物,尤其是指人。
术语“前药”或其等同表述是指在体外或体内直接或间接转化成活性形式的试剂(例如参见R.B.Silverman,1992,"The Organic Chemistry of Drug Design and DrugAction,"Academic Press,Chap.8;Bundgaard,Hans;Editor.Neth.(1985),"Design ofProdrugs".360pp.Elsevier,Amsterdam;Stella,V.;Borchardt,R.;Hageman,M.;Oliyai,R.;Maag,H.;Tilley,J.(Eds.)(2007),"Prodrugs:Challenges and Rewards,XVIII,1470p.Springer)。前药可用于改变具体药物的生物分布(例如,使药剂通常不会进入蛋白酶反应位点)或药代动力学。已经使用多种基团来修饰化合物以形成前药,例如酯、醚、磷酸酯/盐等。当将前药施用至受试者时,该基团通过酶促或非酶促、还原、氧化或水解地裂解掉,或者以其它方式释放出活性化合物。如本文中所使用的,“前药”包括药学上可接受的盐或酯,或药学上可接受的溶剂化物或螯合物,以及上文的任何结晶形式。
术语“肽”或“寡肽”是指由两个或两个以上氨基酸分子间脱水缩合后以酰胺键相互连接在一起形成的化合物。一般而言,构成肽的氨基酸数目为2(二肽)至20(二十肽)。
术语“残基”是指分子去掉某个基团后的主要部分,例如氨基酸残基(如结构H2NCH2CO-,即甘氨酰基,是由甘氨酸去掉一个羟基后的部分)和肽残基。
在其它实施方式中,本发明提供了用至少一种本发明所提供的双官能化合物或其组合物来抑制、治疗和/或预防免疫相关的疾病、失调和病症,具有炎性成分的疾病,以及与上述相关的失调的方法。
通过分解KRAS G12D突变蛋白可全部或部分治疗或预防的其它疾病、失调和病症,也是本发明提供的双官能化合物和其组合物的候选适应症。
术语“治疗”是指在已经诊断、观察到了疾病、失调或病症或者其症状之后,开始进行行动,以便暂时或永久地消除、减轻、抑制、减缓或改善折磨受试者的疾病、失调或病症的至少一种潜在原因,或者折磨受试者的疾病、失调、病症有关的症状。因此,治疗包括抑制(例如阻止或缓解疾病、失调或病症或与其相关的临床症状的发展或进一步发展)活动性疾病。具体地,如本申请中所使用的术语“治疗”用于具体表示将包括根据本发明的化合物或组合物的治疗物给药至已患有感染的患者。术语“治疗”还涉及将根据本发明的化合物或组合物,可选地与一种或多种抗癌物一起施用以减轻或缓解与KRAS G12D相关的一种或多种症状;或者减缓KRAS G12D相关的一种或多种症状的发展;或者减轻KRAS G12D相关的一种或多种症状的严重性;或者抑制KRAS G12D突变相关的临床表现;或者抑制KRAS G12D突变相关的不良症状的表现。
术语“预防”是指以某种方式(例如在疾病、失调、病症或其症状,从而暂时或永久地预防、抑制、压制或降低受试者患有疾病、失调或病症等的风险(如通过例如缺乏临床症状来确定)或在易患特定疾病、病症或病症的受试者的情况下延迟其发作。在某些情况下,该术语还指减缓疾病、失调或病症的进展或抑制其发展成有害的或其他不希望的状态。具体地,本申请中所使用的术语“预防”用于表示施用根据本发明的化合物或组合物以预防与KRAS G12D相关的疾病的发生。
如本文所使用的,术语“KRAS G12D相关疾病”意指已知KRAS G12D的突变在其中发挥一定作用的任何疾病、病症或其他病理病状。因此,在一些实施例中,本申请涉及治疗或减轻已知KRAS G12D在其中发挥一定作用的一种或多种疾病的严重性。具体地,KRAS G12D相关的疾病为过度增殖性疾病,诸如恶性肿瘤,优选为肺癌诸如非小细胞肺癌、胰腺癌、胆管癌、宫颈癌、膀胱癌、肝癌或乳腺癌等。
在一些实施方式中,本发明进一步提供了本申请所述的双官能化合物和组合物与一种或多种另外的药剂的组合的用途。该一种或多种另外的药剂可具有KRAS G12D调节活性和/或它们可通过不同的作用机制起作用。在一些实施方式中,这样的试剂包含辐射(例如局部放射疗法或全身放射疗法)和/或非药理学性质的其他治疗形式。当使用组合疗法时,双官能化合物和一种另外的药剂可以是单一组合物或多种组合物的形式,并且治疗方式可以同时、依次或通过一些其他方案来施用。举例来说,在一些实施方式中,提供了在辐射阶段之后进行化学治疗阶段的实施方式。联合疗法可以具有叠加效应或协同效应。
含有活性成分的药物组合物可以是适于口服使用的形式,例如片剂、胶囊、锭剂、糖锭、水性或油性混悬剂、可分散的粉剂或颗粒剂、乳剂、硬质或软质胶囊,或糖浆、溶液、微珠或酏剂。用于口服使用的药物组合物可以根据本领域已知用于制造药物组合物的任何方法来制备,并且这样的组合物可以含有一种或多种试剂,例如甜味剂、调味剂、着色剂和防腐剂以提供药学上可接受的制剂。片剂、胶囊等通常含有与适用于制造片剂的无毒的药学上可接受的载体或赋形剂混合的活性成分。这些载体或赋形剂可以是例如稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉,明胶或阿拉伯胶以及润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。
在一些实施方式中,组合物是可注射的制剂。在其它实施方式中,组合物被配制为用于口服施用至受试者。
在一些实施方式中,药物组合物容纳在一次性使用的容器(例如,一次性使用的小瓶、安瓿、注射器或自动注射器),而在其它实施方式中,容纳在多次使用容器(例如,多次使用的小瓶)中。
制剂还可包括载体以保护组合物免于从身体快速降解或消失,诸如控释制剂,包括脂质体、水凝胶和微囊化递送系统。例如,可以使用延时材料,例如单独的甘油单硬脂酸酯或甘油硬脂酸酯,或与蜡组合使用。任何药物递送装置都可用于递送双官能化合物,包括植入物(例如可植入泵)和导管系统,缓慢注射泵和装置。所有这些都是本领域技术人员所熟知的。
药物组合物也可以是无菌注射水性或油性悬浮液的形式。该悬浮液可以根据已知技术使用本申请提到的那些合适的分散剂或润湿剂和悬浮剂来配制。无菌注射制剂还可以是在无毒肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如在1,3-丁二醇中的溶液。可以使用的可接受的稀释剂、溶剂和分散介质包括水、林格氏溶液、等渗氯化钠溶液、Cremophor ELTM(BASF,Parsippany,NJ)或磷酸盐缓冲盐水(PBS)、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇)及其合适的混合物。另外,无菌的固定油通常用作溶剂或悬浮介质。为此目的,可以使用任何温和的固定油,包括合成的甘油一酯或甘油二酯。而且,脂肪酸(如油酸)可用于制备注射剂。可以通过包括延迟吸收的试剂(例如,单硬脂酸铝或明胶)来实现特定的可注射制剂的延长吸收。
本发明提供的双官能化合物和组合物可以以本领域已知的任何适当方式施用于受试者。合适的给药途径包括但不限于口服;肠胃外,例如肌内、静脉内、皮下(例如注射或植入)、腹腔内、脑池内、关节内、脑内(脑实质内和脑室内;鼻腔;阴道;舌下;眼内;直肠;局部(例如透皮);口腔和吸入。一般通过皮下或肌肉内给药的积存注射法也可用于在限定的时间段内释放本申请公开的双官能化合物。
本发明还提供了包含双官能化合物或组合物的试剂盒。试剂盒通常为容纳各种组分的物理结构的形式,并且可用于例如实施本申请提供的方法。例如,试剂盒可以包括本发明公开的一种或多种双官能化合物(例如提供在无菌容器中),其可为适合施用至受试者的药物组合物的形式。双官能化合物可以以即用型(例如片剂或胶囊)形式或以需要例如在施用前重构或稀释(例如粉末)的形式提供。当双官能化合物为需要使用者被重构或稀释的形式时,该试剂盒还可包括与双官能化合物一起包装或者分别包装的稀释剂(例如无菌水)、缓冲液、药学上可接受的赋形剂等。当采用组合疗法时,试剂盒可独立地含有几种治疗剂,或者它们可已经在试剂盒中组合。试剂盒的每个组分可以被封装在单独的容器内,并且所有的各种容器可以在单个包装内。本发明的试剂盒可被设计用于适当地保持容纳在其中的组分所需的条件(例如,冷藏或冷冻)。
为了更好地理解本发明并更清楚地展示出如何实现本发明,现通过示例的方式并结合附图,阐述了根据本发明的实施方式的特征。
实施例
通过参考以下实施例将更容易理解本发明,所述实施例用于说明本发明,而不应被解释为以任何方式限制本发明的范围。
除非另有定义或上下文另有明确规定,本申请使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。应当理解,与本申请所述类似或等同的任何方法和材料可用于本发明的实践或测试。除非另有说明,否则本申请中所使用的材料和仪器均常规商购所得。
制备例:
本发明所公开的化合物,其合成方法可以逐步或模块化进行,方案A公开了部分示例性中间体的合成方法。方案B公开的了示例性化合物的合成步骤,各化合物可参照示例性化合物的合成及化合物自身的设计选择不同的中间体或原料。
中间体a
步骤A:在室温下,将4-羟基哌啶-1-羧酸苄酯(988.82mg,4.20mmol,2eq)和碳酸铯(2.05g,6.3mmol,3eq)添加到化合物a-1(0.9g,2.10mmol,1eq)在DMSO和二氧六环(体积比1:5)的混合溶液中,然后将混合物升温至90℃,搅拌12小时,冷却至室温。添加饱和NH4CI溶液(75mL)和乙酸乙酯(30mL)分离,水相用乙酸乙酯萃取两次(2x 30mL).用饱和食盐水(40mL)洗涤合并的有机相,用无水硫酸钠干燥,过滤,并在真空中浓缩。残余物通过柱层析纯化得到淡黄色固体a-2(760mg,67%收率)。1H NMR(500MHz,CDCl3)δ:8.73(s,1H),7.39-7.30(m,5H),5.33(q,J=4.1Hz,1H),5.15(s,2H),4.48-4.27(m,4H),3.91(s,2H),3.65(s,2H),3.40(ddd,J=13.0,8.5,3.6Hz,2H),2.00(d,J=39.5Hz,4H),1.85(s,2H),1.70(d,J=7.7Hz,2H),1.51(s,9H).m/z(ESI):627[M+H]+.
步骤B:将化合物a-2(1g,1.59mmol,1eq)和磷酸钾(1.01g,4.78mmol,3eq)在四氢呋喃和水(体积比10:3)的混合溶液中置换氮气,然后添加2-[2-氟-6-(甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)-1-萘基]乙炔基三异丙基硅烷(1.14g,2.23mmol,1.4eq)和cataCXium A Pd-G3(174.13mg,239.19μmol,0.15eq),并在80℃、N2下搅拌该混合物4小时,完成后,向混合物中添加乙酸乙酯和水(各60mL),分离有机相,用水(2x 30mL)洗涤,无水硫酸钠干燥,过滤,并在真空中浓缩。残余物用50%乙酸乙酯/石油醚的柱层析纯化,得到黄色固体a-3(1g,产率64%)。m/z(ESI):977.6[M+H]+.
步骤C:在室温下,将化合物a-3(1g,1.02mmol,1eq)和氢氧化钯(50mg,1.02mmol,1eq)溶解在THF(10mL).用氢气球置换气体三次后在室温下反应12小时。反应结束后,硅藻土抽滤反应液,并用甲醇洗涤数次。收集滤液并浓缩,得到黄色固体中间体a(0.8g,90%收率),可直接用于下一步反应。m/z(ESI):843.4[M+H]+.
中间体b的合成
中间体b的合成步骤参照中间体a的步骤,以化合物b-1作为起始原料得到黄色固体(570mg、53%收率)。m/z(ESI):887.0[M+H]+.
中间体c的合成
中间体c的合成步骤参照中间体a的合成步骤,以3-羟基哌啶-1-羧酸苄酯作为起始原料,得到黄色固体中间体c(800mg、90%收率)。m/z(ESI):843.4[M+H]+.
中间体d的合成
中间体d的合成步骤参照中间体f的合成步骤,以N-Cbz脯氨醇作为起始原料,得到黄色固体中间体d(200mg、70%收率)。m/z(ESI):691.6[M+H]+.
中间体e的合成
中间体e的合成步骤参照中间体a的合成步骤,以苯基4-(2-羟乙基)哌嗪-1-甲酸酯作为起始原料,得到黄色固体中间体c(730mg、95%收率)。m/z(ESI):872.5[M+H]+.
中间体f的合成
步骤A:室温下,将中间体b(50mg,52.07μmol,1eq)溶于2mL四氢呋喃中,添加TBAF(27.23mg,104.14μmol,3eq)在室温下搅拌10mL分钟。反应完成后,在真空中浓缩混合物。残余物未经纯化就用于下一步反应。m/z(ESI):865[M+H]+.
步骤B:参照中间体a的步骤C得到淡黄色固体中间体f(65mg,76%收率).m/z(ESI):735[M+H]+.
中间体g的合成
中间体g的合成步骤参照中间体a的合成步骤,以1-Cbz-3-羟甲基吡咯烷作为起始原料,得到黄色固体中间体g(800mg,92%收率)。m/z(ESI):843.3[M+H]+.
中间体h的合成
中间体h的合成步骤参照中间体a的合成步骤,以1-Cbz-3-羟基吡咯烷作为起始原料,得到黄色固体中间体h(150mg,87%收率)。m/z(ESI):830[M+H]+.
中间体i的合成
中间体i的合成步骤参照中间体f的合成步骤,以((3R)-3-((叔丁基二甲基硅氧基)甲基)四氢-1H-吡咯里嗪-7a(5H)-基)甲醇为起始原料得到淡黄色固体中间体i(450mg,89%收率)。m/z(ESI):761.5[M+H]+.
中间体j的合成步骤参考中间体a。
实施例1(化合物24盐的合成过程):
步骤A:将Triton B(1.11g,6.66mmol,0.3eq)和2-烯酸叔丁酯(2.84g,22.19mmol,1eq)加入到化合物1-1(10g,110.96mmol,5eq)的乙腈(15mL)溶液中。将混合物在20℃下搅拌过夜,并在真空下浓缩。通过柱层析(SiO2,石油醚/乙酸乙酯=5:1至1:1)纯化残余物,得到无色油状物1-2(3.5g,72%收率)。1H NMR(500MHz,CDCl3)δ:3.74-3.56(m,4H),3.48(td,J=5.6,1.6Hz,2H),2.48(td,J=6.4,1.6Hz,2H),1.65(qt,J=6.5,3.8Hz,4H),1.44(s,9H).
步骤B:室温下,将碳酸铯(456.45mg,1.40mmol,3eq)添加到化合物a-1(0.2g,466.98μmol,1eq)和化合物1-2(254.84mg,1.17mmol,2.5eq)的二氧六环(5mL)溶液中,然后将反应液温度升高至90℃,搅拌12小时,冷却至室温。将混合物在饱和氯化铵溶液(75mL)和乙酸乙酯(30mL)之间分离,并用乙酸乙酯(2x 30mL)萃取水层。用盐水(40mL)洗涤合并有机相,用无水硫酸钠干燥,过滤,并在真空中浓缩。残余物用10%至60%的乙酸乙酯/石油醚洗脱来通过柱层析纯化,得到淡黄色固体1-3(0.17g,60%收率)。1H NMR(500MHz,CDCl3)δ:8.72(s,1H),4.50-4.42(m,4H),3.70-3.61(m,4H),3.53-3.44(m,2H),2.50-2.43(m,2H),1.98-1.84(m,4H),1.78-1.66(m,6H),1.51(s,9H),1.44(s,9H).m/z(ESI):610.4[M+H]+.
步骤C:将化合物1-3(0.1g,163.90μmol,1eq)和碳酸铯(160.21mg,491.71μmol,3eq)溶于二氧六环和水(3:1)溶液(5mL)中的混合物放入氮气中脱气,然后加入2-[2-氟-6-(甲氧甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)-1-萘基]乙炔基三异丙基硅烷(109.21mg,213.07μmol,1.3eq)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(26.57mg,32.78μmol,0.2eq),并在氮气氛围、100℃下搅拌3小时,反应完成后,向混合物中添加乙酸乙酯(20mL)和水(20mL),分离有机相,用水(10ml x 2)洗涤,并用无水硫酸钠干燥,过滤,并在真空中浓缩。残余物通过硅胶柱层析分离(30%的乙酸乙酯/石油醚),得到黄色固体1-4(60mg,38%收率)。1H NMR(500MHz,CDCl3)δ:9.04(s,1H),7.76(dd,J=9.1,5.6Hz,1H),7.49(d,J=2.6Hz,1H),7.31-7.26(m,3H),5.28(s,2H),4.52-4.32(m,4H),3.65(t,J=6.5Hz,2H),3.52-3.49(m,2H),3.48(s,3H),2.47(t,J=6.5Hz,2H),2.01-1.97(m,4H),1.89(dt,J=12.5,6.7Hz,2H),1.76(dt,J=9.1,6.4Hz,2H),1.50(s,9H),1.43(s,9H),0.85(t,J=7.9Hz,12H).
步骤D:室温下,将化合物1-4(50mg,52.07μmol,1eq)溶于2mL四氢呋喃中,添加TBAF(27.23mg,104.14μmol,3eq)在室温下搅拌10分钟。反应完成后,在真空中浓缩混合物。残余物1-5未经纯化就用于下一步反应。m/z(ESI):804.4[M+H]+.
步骤E:室温下,将化合物1-5(40mg,49.76μmol,1eq)和三氟醋酸(17.02mg,149.27μmol,11.09μL,3eq)在二氯甲烷(2mL)中搅拌30分钟。将混合物减压浓缩,残余物1-6可直接用于下一步反应。m/z(ESI):604.7[M+H]+.
步骤F:冰浴下,将化合物1-6(0.03g,49.70μmol,1eq)溶解于二氯甲烷(2mL)中。在逐滴添加三乙胺(5.03mg,49.70μmol,2eq)后,缓慢逐滴添加Boc2O的二氯甲烷溶液(8.66mg,49.70μmol,1eq).反应液在室温下反应2小时后。TLC和LC-MS显示反应完全,混合物在减压下浓缩。残余物用10%二氯甲烷/甲醇通过硅胶柱纯化,得到黄色油状物1-7(30mg,85%收率)。m/z(ESI):704.5[M+H]+.
步骤G:化合物1-7(0.032g,37.21μmol,1eq)和(2S,4R)-1-(2-氨基-3,3-二甲基丁酰基)-4-羟基-N-[4-(4-甲基噻唑-5-基)苯基]甲基]吡咯烷-2-甲酰胺(17.62mg,40.93μmol,1.1eq)的乙腈(2mL)中添加1-甲基咪唑(10mg,37.21μmol,5eq)和N,N,N',N'-四甲基氯甲脒六氟磷酸盐(37.21μmol,1eq),并在室温下搅拌2小时。反应液直接真空去除溶剂,柱层析得到淡黄色固体(20mg,45%收率).m/z(ESI):1116.9[M+H]+.向上一步得到的化合物(0.02g,15.72μmol,1eq)在乙腈(3mL)中的溶液中缓慢滴加氯化氢的二氧六环溶液(0.1mL,4M),并在室温下搅拌混合物10分钟。反应结束后,在减压下蒸发以除去溶剂,使用制备HPLC(0.1%三氟醋酸/水+乙腈),得到淡黄色三氟醋酸盐固体(4.2mg,25%收率,纯度96.64%)。1H NMR(500MHz,CD3OD)δ:9.04(d,J=4.8Hz,1H),8.88(s,1H),7.88(dd,J=9.4,5.3Hz,2H),7.45(d,J=7.4Hz,3H),7.38(dd,J=8.7,3.8Hz,3H),7.34(t,J=8.8Hz,1H),7.26-7.18(m,1H),4.76(t,J=11.5Hz,4H),4.69-4.65(m,1H),4.54(dtd,J=18.3,13.3,11.7,7.0Hz,5H),4.38-4.25(m,3H),3.91(dd,J=24.1,12.1Hz,3H),3.80(d,J=10.8Hz,1H),3.76-3.66(m,2H),3.61-3.54(m,2H),3.15(dd,J=17.4,8.9Hz,1H),2.62-2.49(m,3H),2.45(d,J=1.7Hz,3H),2.26-2.05(m,6H),1.93(t,J=7.4Hz,2H),1.79(d,J=9.5Hz,2H),1.04-1.02(m,9H).m/z(ESI):1016.8[M+H]+.
实施例2(化合物26盐的合成):
合成步骤参照实施例1,以中间体f为原料,最终得到淡黄色三氟醋酸盐固体(17mg,21%收率,95.06%纯度)。1H NMR(500MHz,CD3OD)δ:9.09(s,1H),8.87(s,1H),7.66(dd,J=9.1,5.8Hz,1H),7.45-7.36(m,4H),7.29(d,J=2.6Hz,1H),7.23(t,J=9.4Hz,1H),7.02(d,J=2.6Hz,1H),4.85-4.76(m,4H),4.59(q,J=6.0Hz,3H),4.55-4.44(m,3H),4.33(d,J=15.5Hz,1H),4.25(d,J=13.0Hz,2H),3.99-3.85(m,4H),3.78(dd,J=10.9,3.9Hz,1H),3.58(q,J=7.1Hz,2H),3.40(t,J=7.9Hz,3H),2.49-2.40(m,7H),2.28(h,J=7.1,5.8Hz,4H),2.21-2.02(m,8H),1.62(dh,J=16.7,6.4,5.7Hz,4H),1.15(t,J=7.0Hz,2H),1.01(s,9H),0.76(t,J=7.4Hz,3H).m/z(ESI):1130.8[M+H]+.
实施例3(化合物27盐的合成):
合成步骤参照实施例1,以中间体f为原料,最终得到淡黄色三氟醋酸盐固体(9.7mg,18%收率,96.87%纯度)。1H NMR(500MHz,CD3OD)δ:9.09(s,1H),9.00(s,1H),7.90-7.87(m,1H),7.48-7.33(m,7H),7.23-7.22(m,1H),4.84-4.81(m,2H),4.62-4.59(m,3H),4.57-4.49(m,3H),4.38-4.35(m,1H),4.29-4.27(m,2H),4.01-3.89(m,2.5H),3.82-3.79(m,1H),3.74-3.60(m,1H),3.53(s,0.5H),3.44-3.40(m,3H),3.35-3.31(m,4H),2.48-2.43(m,5H),2.33-2.29(m,4H),2.24-2.06(m,6H),1.68-1.60(m,4H),1.03(s,9H).m/z(ESI):1126.4[M+H]+.
实施例4(化合物28盐的合成):
步骤A:将化合物b(70mg,78.99μmol,1eq)、6-溴己酸甲酯(19.82mg,94.79μmol,1.2eq)和碘化钾(13.11,1μmol,1eq)溶于10mL乙腈中,添加碳酸钾(32.75mg,236.98μmol,3eq),并在60℃下搅拌混合物12小时。反应完成后,过滤反应液,滤液在真空中浓缩。残余物通过柱层析纯化(10%甲醇/二氯甲烷),得到黄色固体4-1(40mg,49%收率)。m/z(ESI):1015[M+H]+.
步骤B:在室温下,向4-1(40mg,39.44μmol,1eq)加入1ml的H2O和1ml四氢呋喃,及氢氧化锂(4.72mg,197.18μmol,5eq),然后将混合物升高至50℃并搅拌1h。反应结束后,真空浓缩大部分溶剂后,加入10%柠檬酸调节pH,然后用乙酸乙酯萃取,收集有机层,饱和氯化钠溶液洗涤后用无水硫酸钠干燥,真空浓缩有机相,得到黄色固体4-2(35mg,88%收率)。m/z(ESI):1000[M+H]+.
剩余合成步骤参照实施例1,最终得到淡黄色三氟醋酸盐固体(10mg,22%收率,92.23%纯度)。1H NMR(500MHz,CD3OD)δ:9.09(s,1H),8.97(s,1H),7.90-7.87(m,1H),7.48-7.41(m,4H),7.39-7.33(m,2H),7.23-7.23(m,1H),4.87-4.82(m,2H),4.64-4.60(m,3H),4.57-4.50(m,3H),4.38-4.35(m,1H),4.29-4.27(m,2H),4.01-3.90(m,3H),3.82-3.79(m,1H),3.57-3.36(m,7H),3.26-3.22(m,2H),3.16-3.13(m,2H),2.48(s,3H),2.32-2.21(m,5H),2.15-2.07(m,5H),1.77-1.64(m,4.5H),1.42-1.37(m,2.5H),1.04(s,9H).m/z(ESI):1113.5[M+H]+.
实施例5(化合物29盐的合成):
合成步骤参照实施例4,以7-溴庚酸甲酯为原料,最终得到淡黄色三氟醋酸盐固体(20.9mg,45%收率,96.82%纯度)。1H NMR(500MHz,CD3OD)δ:9.09(s,1H),8.97(s,1H),7.90-7.87(m,1H),7.46-7.41(m,4H),7.39-7.33(m,2H),7.23-7.23(m,1H),4.84(t,J=15Hz,2H),4.64-4.62(m,3H),4.57-4.50(m,3H),4.38-4.35(m,1H),4.29-4.27(m,2H),4.01-3.90(m,3H),3.82-3.79(m,1H),3.59-3.40(m,7H),3.27-3.24(m,2H),3.16-3.13(m,2H),2.48(s,3H),2.30-2.20(m,5H),2.15-2.08(m,5H),1.73-1.68(m,2H),1.63-1.60(m,2H),1.38(brs,4H),1.03(s,9H).m/z(ESI):1127.5[M+H]+.
实施例6(化合物30盐的合成):
合成步骤参照实施例4,以4-溴丁酸甲酯为原料,最终得到淡黄色三氟醋酸盐固体(21.1mg,42%收率,95.84%纯度)。1H NMR(500MHz,CD3OD)δ:9.09(s,1H),8.95(s,1H),7.90-7.87(m,1H),7.46-7.45(m,2H),7.41-7.32(m,4H),7.23-7.22(m,1H),4.86-4.83(m,3H),4.63(t,J=5Hz,2H),4.56-4.52(m,3H),4.48-4.47(m,1H),4.34-4.27(m,3H),4.00-3.93(m,3H),3.78-3.76(m,1H),3.50-3.41(m,6H),3.17-3.12(m,3H),2.58-2.58(m,2H),2.49-2.46(m,3H),2.27-2.23(m,3H),2.15(brs,4H),2.10-2.04(m,1H),1.99-1.98(m,2H),1.06(s,9H).m/z(ESI):1085.5[M+H]+.
实施例7(化合物31盐的合成):
合成步骤参照实施例4,以8-溴辛酸甲酯为原料,最终得到淡黄色三氟醋酸盐固体(14.3mg,25%收率,95.03%纯度)。1H NMR(500MHz,CD3OD)δ:9.06(s,1H),8.92(s,1H),7.90-7.87(m,1H),7.48-7.41(m,4H),7.38-7.33(m,2H),7.22-7.21(m,1H),4.83(m,2H),4.64-4.50(m,6H),4.38-4.35(m,1H),4.28-4.26(m,2H),3.98-3.90(m,3H),3.82-3.79(m,1H),3.46-3.35(m,7H),3.08-3.05(m,2H),3.02-2.99(m,2H),2.47(s,3H),2.31-2.04(m,10H),1.71-1.58(m,4H),1.36(brs,6H),1.03(s,9H).m/z(ESI):1141.5[M+H]+.
实施例8(化合物32盐的合成):
合成步骤参照实施例4,通过中间体e最终得到淡黄色三氟醋酸盐固体(33.1mg,51%收率,98.34%纯度)。1H NMR(500MHz,CD3OD)δ:9.09(s,1H),8.96(s,1H),7.91-7.83(m,2H),7.48-7.33(m,6H),7.23-7.22(m,1H),4.89-4.78(m,3H),4.67-4.63(m,2H),4.57-4.50(m,3H),4.38-4.35(m,1H),4.29-4.26(m,2H),4.01-3.98(m,1H),3.91-3.88(m,2H),3.82-3.79(m,1H),3.46(s,1H),3.45-3.37(m,2H),3.25-3.09(m,5H),2.48(s,3H),2.32-2.05(m,9H),1.68-1.59(m,4H),1.36(brs,6H),1.03(s,9H).m/z(ESI):1126.4[M+H]+.
实施例9(化合物33盐的合成):
合成步骤参照实施例4,最终得到白色三氟醋酸盐固体(4.5mg,12%收率,91.42%纯度)。1H NMR(500MHz,DMSO-d6)δ:11.65(s,1H),10.92(s,1H),9.94-9.92(m,1H),9.80(s,1H),9.63(s,1H),9.12(s,1H),8.00-7.98(m,1H),7.96-7.67(m,1H),7.49-7.41(m,3H),7.23(s,1H),7.06-7.05(m,1H),4.52-4.50(m,1H),4.51-4.50(m,5H),4.36-4.34(m,2H),4.20-4.19(m,2H),4.00-3.99(m,6H),3.30(s,2H),3.32-3.18(m,2H),3.07-2.99(m,2.5H),2.90-2.87(m,0.5H),2.64-2.58(m,2H),2.36-2.35(m,1H),2.30-2.27(m,2H),2.18-2.15(m,3H),2.07-1.94(m,7H),1.23-1.16(m,5H).m/z(ESI):952.7[M+H]+.
实施例10(化合物34盐的合成):
合成步骤参照实施例2,以中间体d为原料最终得到白色三氟醋酸盐固体(18mg,16%收率,97.04%纯度)。1H NMR(500MHz,CD3OD)δ:8.93(s,1H),8.90(s,1H),7.72-7.69(m,1H),7.47-7.41(m,4H),7.35(s,1H),7.29(t,J=10Hz,1H),7.1-7.10(m,1H),4.87-4.69(m,4H),4.64-4.47(m,6H),4.38-4.23(m,4H),4.09-3.73(m,8H),2.62-2.55(m,1H),2.47(s,3H),2.43-2.38(m,2H),2.20-2.09(m,8H),1.68-1.59(m,4H),1.32-1.30(m,1H),1.04(s,9H),0.86(t,J=5Hz,3H).m/z(ESI):1087.8[M+H]+.
实施例11(化合物35盐的合成):
合成步骤参照实施例2,以中间体d为原料最终得到白色三氟醋酸盐固体(16.5mg,14%收率,96.66%纯度)。1H NMR(500MHz,CD3OD)δ:8.92-8.91(m,2H),7.171(t,J=5Hz,1H),7.47-7.40(m,4H),7.35(brs,1H),7.28(t,J=10Hz,1H),7.16-7.11(m,1H),4.68-4.62(m,5H),4.36-4.26(m,3H),3.95-7.79(m,5H),2.60(brs,1H),2.47(s,3H),2.37(t,J=5Hz,1H),2.24-2.16(m,10H),1.66-1.52(m,5H),1.33-1.30(m,14H),1.02(s,9H),0.86(brs,3H).m/z(ESI):1129.9[M+H]+.
实施例12(化合物36盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(8.6mg,11%收率,95.06%纯度)。1H NMR(500MHz,CD3OD)δ:9.09(s,1H),8.94(s,1H),7.89-7.86(m,1H),7.37-7.35(m,2H),7.34-7.32(m,4H),7.22(s,1H),5.49(s,2H),4.81-4.79(m,2H),4.65(s,1H),4.56-4.52(m,3H),4.37-4.29(m,3H),4.12-3.92(m,4H),3.82-3.80(m,1H),3.39(s,1H),2.47(s,3H),2.21-2.02(m,8H),1.35-1.29(m,9H),1.07(s,9H).m/z(ESI):1129.9[M+H]+.
实施例13(化合物37盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(38.8mg,45%收率,96.21%纯度)。1H NMR(500MHz,CD3OD)δ:9.08(s,1H),8.90(s,1H),7.90-7.87(m,1H),7.45-7.36(m,2H),7.34-7.32(m,5H),7.21(s,1H),4.88-4.78(m,2H),4.57-4.51(m,4H),4.35-4.28(m,3H),3.96-3.94(m,3H),3.81-3.79(m,1H),3.59-3.51(m,2H),3.37(s,1H),3.24-3.17(m,3H),2.58-2.53(m,2H),2.46(s,3H),2.42-2.36(m,2H),2.28-2.21(m,2H),2.16-2.04(m,8H),1.07(s,9H).m/z(ESI):1041.6[M+H]+.
实施例14(化合物38盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(45.9mg,53%收率,96.67%纯度)。1H NMR(500MHz,CD3OD)δ:9.06(s,1H),8.90(s,1H),7.86(dd,J=9.2,5.7Hz,1H),7.45-7.28(m,7H),7.19(d,J=2.5Hz,1H),5.47(s,1H),4.77(t,J=13.6Hz,2H),4.62(t,J=4.2Hz,1H),4.57-4.44(m,3H),4.38-4.23(m,3H),3.99-3.92(m,2H),3.89(d,J=11.7Hz,1H),3.78(dd,J=11.0,3.9Hz,1H),3.60(dd,J=79.0,12.6Hz,2H),3.37(s,2H),3.17(dt,J=38.8,14.4Hz,3H),2.50(d,J=14.2Hz,1H),2.45(s,3H),2.39-2.25(m,4H),2.23-2.03(m,9H),1.75(s,2H),1.62(s,2H),1.39(s,4H),1.01(s,9H).m/z(ESI):1127.5[M+H]+.
实施例15(化合物39盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(27.8mg,36%收率,97.18%纯度)。1H NMR(500MHz,CD3OD)δ:9.07(s,1H),8.93(s,1H),7.86(dd,J=9.2,5.7Hz,1H),7.47-7.29(m,7H),7.19(d,J=2.6Hz,1H),5.47(s,2H),4.79(d,J=16.1Hz,3H),4.62(s,1H),4.56-4.46(m,3H),4.37-4.23(m,3H),3.99-3.85(m,3H),3.81-3.75(m,1H),3.60(dd,J=78.4,13.1Hz,2H),3.34(d,J=21.4Hz,2H),3.19-3.09(m,3H),2.50(d,J=14.3Hz,1H),2.45(s,3H),2.39-1.95(m,12H),1.75(s,2H),1.60(d,J=10.2Hz,2H),1.38(s,6H),1.01(s,9H).m/z(ESI):1127.5[M+H]+.
实施例16(化合物40盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(22.9mg,30%收率,95.25%纯度)。1H NMR(500MHz,CD3OD)δ:9.08-9.07(m,1H),8.91(s,1H),7.90-7.84(m,1H),7.47-7.46(m,2H),7.42-7.40(m,2H),7.38-7.32(m,2H),7.21(s,1H),5.60-5.43(m,1H),4.86-4.80(m,2H),4.65-4.63(m,1H),4.57-4.50(m,3H),4.37-4.34(m,1H),4.28(brs,2H),3.99-3.89(m,3H),3.82-3.80(m,1H),3.39(s,1H),3.19-3.11(m,7H),2.48(s,3H),2.29-2.08(m,10H),1.77(brs,2H),1.71-1.65(m,5H),1.61(brs,2H),1.46-1.39(m,10H),1.03(s,9H).m/z(ESI):1111.3[M+H]+.
实施例17(化合物41盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(43.6mg,52%收率,98.23%纯度)。1H NMR(500MHz,CD3OD)δ:9.08-9.07(m,1H),8.91(s,1H),7.90-7.87(m,1H),7.82-7.80(d,J=10Hz,1H),7.47-7.46(m,2H),7.44-7.40(m,2H),7.37-7.32(m,2H),7.21(s,1H),4.83-4.79(m,2H),4.65-4.63(m,1H),4.57-4.50(m,3H),4.37-4.34(m,1H),4.28(brs,2H),3.98-3.94(m,3H),3.82-3.80(m,1H),3.71-3.69(m,1H),3.56-3.53(m,1H),3.38(s,1H),3.35(s,1H),3.25-3.16(m,3H),2.54-2.52(m,1H),2.48(s,3H),2.39-2.36(m,1H),2.29-2.00(m,10H),1.77(brs,2H),1.61(brs,2H),1.39-1.35(m,10H),1.03(s,9H).m/z(ESI):1125.7[M+H]+.
实施例18(化合物42盐的合成):
合成步骤参照实施例4,以实施例17为原料通过加氢还原最终得到淡黄色三氟醋酸盐固体(1.1mg,12%收率,95.54%纯度)。m/z(ESI):1129.6[M+H]+.
实施例19(化合物43盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(31.2mg,45%收率,97.48%纯度)。1H NMR(500MHz,CD3OD)δ:9.10(s,1H),8.97(s,1H),7.90-7.87(m,1H),7.48-7.46(m,2H),7.45-7.43(m,2H),7.38-7.33(m,2H),7.22(s,1H),5.60-5.34(m,1H),4.86-4.80(m,2H),4.64(s,1H),4.59-4.50(m,3H),4.37-4.33(m,1H),4.29(brs,2H),4.01-3.89(m,3H),3.82-3.79(m,1H),3.72-3.62(m,1H),3.56-3.53(m,1H),3.41(s,1H),3.37-3.34(m,1H),3.20-3.11(m,3H),2.48(s,3H),2.39-2.04(m,12H),1.77(brs,2H),1.70-1.66(m,1H),1.60(brs,2H),1.43-1.33(m,14H),1.03(s,9H).m/z(ESI):1139.3[M+H]+.
实施例20(化合物44盐的合成):
合成步骤参照实施例4,以实施例19为原料通过加氢还原最终得到淡黄色三氟醋酸盐固体(7.1mg,50%收率,98.79%纯度)。1H NMR(500MHz,CD3OD)δ:9.12-9.11(m,1H),8.91(s,1H),7.71-7.68(dd,J1=5Hz,J2=10Hz,1H),7.47-7.41(m,4H),7.32-7.32(m,1H),7.27(t,J=10Hz,1H),7.04-7.03(m,1H),5.60(brs,0.6H),5.45-5.43(m,0.4H),4.87-4.76(m,3H),4.65-4.64(m,1H),4.57-4.50(m,3H),4.37-4.34(m,1H),4.29-4.26(m,2H),4.00-3.89(m,3H),3.82-3.79(m,1H),3.72-3.69(m,1H),3.56-3.54(m,1H),3.38-3.35(m,2H),3.26-3.121(m,3H),2.48(s,3H),2.41-2.36(m,1H),2.33-2.08(m,10H),1.77(brs,2H),1.60(brs,2H),1.40-1.30(m,14H),1.03(s,9H),0.81-0.78(m,3H).m/z(ESI):1143.5[M+H]+.
实施例21(化合物45盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(30mg,35%收率,99.32%纯度)。1H NMR(500MHz,CD3OD)δ:9.12-9.07(m,1H),8.95(s,1H),8.62-8.60(m,1H),7.90-7.85(m,2H),7.46-7.41(m,4H),7.38-7.33(m,2H),7.21-7.21(m,1H),5.60(s,0.7H),5.45-5.41(m,0.3H),5.01-4.99(m,2H),4.86-4.79(m,2H),4.64-4.62(m,1H),4.57-4.54(m,1H),4.43(s,1H),4.28(s,2H),3.99-3.94(m,2H),3.88-3.86(m,1H),3.76-3.69(m,2H),3.56-3.54(m,1.5H),3.40-3.35(m,2H),3.25-3.16(m,3.5H),2.54-2.52(m,1H),2.48(s,3H),2.39-2.21(m,10H),2.04-1.91(m,2H),1.77(brs,2H),1.61-1.56(m,2H),1.50(d,J=5Hz,3H),1.39-1.33(m,14H),1.04(s,9H).m/z(ESI):1153.7[M+H]+.
实施例22(化合物46盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(13mg,26%收率,99.09%纯度)。1H NMR(500MHz,CD3OD)δ:9.08-9.07(m,1H),8.92(s,1H),7.90-7.85(m,2H),7.48-7.45(m,2H),7.43-7.40(m,2H),7.38-7.33(m,2H),7.21-7.20(m,1H),5.60(s,0.7H),5.50-5.40(m,0.3H),4.86-4.77(m,2H),4.65-4.63(m,1H),4.57-4.50(m,3H),4.38-4.34(m,1H),4.28(brs,2H),3.98-3.89(m,3H),3.82-3.79(m,1H),3.72-3.69(m,1H),3.56-3.53(m,1.6H),3.45-3.44(m,0.4H),3.39(s,2H),3.25-3.16(m,3H),2.55-2.52(m,1H),2.48(s,3H),2.40-2.26(m,3H),2.25-2.20(m,3H),2.11-1.99(m,2H),1.77(brs,2H),1.60(brs,2H),1.39-1.32(m,18H),1.03(s,9H).m/z(ESI):1153.7[M+H]+.
实施例23(化合物47盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(8.1mg,21%收率,98.48%纯度)。1H NMR(500MHz,CD3OD)δ:9.08-9.07(m,1H),8.92(s,1H),7.90-7.78(m,2H),7.48-7.41(m,4H),7.38-7.33(m,2H),7.21-7.20(m,1H),5.60(s,0.6H),5.45-5.41(m,0.4H),4.87-4.77(m,2H),4.64-4.63(m,1H),4.57-4.50(m,3H),4.37-4.34(m,1H),4.28(brs,2H),3.98-3.89(m,3H),3.82-3.79(m,1H),3.72-3.69(m,0.8H),3.63-3.62(m,0.2H),3.56-3.53(m,1H),3.39-3.35(m,2H),3.25-3.13(m,3H),2.55-2.52(m,0.7H),2.48(s,3H),2.40-2.36(m,1.3H),2.33-2.20(m,4H),2.10-1.99(m,3H),1.77(brs,2H),1.60(brs,2H),1.39-1.30(m,20H),1.03(s,9H).m/z(ESI):1181.5[M+H]+.
实施例24(化合物48盐的合成):
合成步骤参照实施例4,以中间体c为原料最终得到淡黄色三氟醋酸盐固体(30.7mg,45%收率,96.63%纯度)。1H NMR(500MHz,CD3OD)δ:9.10-8.95(m,1H),8.86(s,1H),7.79(dd,J=9.4,5.9Hz,1H),7.33(q,J=8.2Hz,4H),7.29-7.22(m,2H),7.12(d,J=3.2Hz,1H),4.79-4.66(m,2H),4.55-4.42(m,2H),4.33(s,1H),4.18(s,2H),3.96-3.74(m,4H),3.64(d,J=10.9Hz,1H),3.55-3.41(m,1H),3.38-3.24(m,2H),3.16-2.87(m,3H),2.39(s,3H),2.23-1.97(m,10H),1.90-1.79(m,2H),1.64(s,2H),1.47(d,J=7.7Hz,2H),1.40(d,J=7.4Hz,3H),1.33-1.13(m,14H),0.93(s,9H).m/z(ESI):1153.8[M+H]+.
实施例25(化合物49盐的合成):
合成步骤参照实施例4,以中间体c为原料最终得到淡黄色三氟醋酸盐固体(17.4mg,30%收率,92.10%纯度)。1H NMR(500MHz,CD3OD)δ:9.04(s,1H),7.91-7.76(m,1H),7.59(d,J=8.5Hz,1H),7.42-7.23(m,3H),7.17(s,1H),7.01(d,J=8.5Hz,1H),5.66(s,1H),4.82-4.70(m,2H),4.66(d,J=13.2Hz,1H),4.30(t,J=7.4Hz,1H),4.23(s,2H),4.05(d,J=7.7Hz,1H),3.95(s,3H),3.92-3.76(m,2H),3.55-3.48(m,1H),3.34(d,J=13.8Hz,1H),3.22-2.89(m,6H),2.70(d,J=11.6Hz,3H),2.46-2.32(m,3H),2.25(dd,J=13.4,6.0Hz,2H),2.16-2.02(m,4H),1.89(d,J=15.6Hz,4H),1.75-1.51(m,7H),1.38-1.24(m,12H).m/z(ESI):1035.3[M+H]+.
实施例26(化合物50盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(7.2mg,20%收率,97.24%纯度)。1H NMR(500MHz,CD3OD)δ:9.08-9.07(m,1H),7.89-7.86(m,1H),7.66-7.64(m,1H),7.37-7.32(m,3H),7.21-7.20(m,1H),7.09-7.07(m,1H),5.62-5.44(m,1H),4.82-4.71(m,3H),4.37-4.34(m,1H),4.28(brs,2H),4.14-4.11(m,1H),4.00(s,3H),3.98-3.90(m,2H),3.69-3.67(m,1H),3.54-3.52(m,1H),3.38-3.36(m,1H),3.28-3.20(m,4H),3.03-2.96(m,1H),2.79-2.72(m,3H),2.54-2.29(m,6H),2.22-2.11(m,5H),2.04-1.94(m,3H),1.78-1.62(m,6H),1.40(brs,10H).m/z(ESI):1021.3[M+H]+.
实施例27(化合物51盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(30mg,45%收率,98.40%纯度)。1H NMR(500MHz,CD3OD)δ:9.09-9.08(m,1H),8.94(s,1H),8.00(t.J=5Hz,1H),7.89-7.86(m,1H),7.42-7.40(m,2H),7.37-7.30(m,4H),7.22(s,1H),5.58-5.42(m,1H),4.86-4.76(m,2H),4.68-4.64(m,1H),4.59-4.56(m,1H),4.49-4.46(m,2H),4.38-4.33(m,1H),4.28(brs,2H),4.01-3.93(m,2H),3.90-3.86(m,1H),3.82-3.80(m,2H),3.72-3.71(m,2H),3.64-3.62(m,3H),3.40-3.35(m,2H),3.24-3.17(m,1H),2.57-2.55(m,2H),2.50-2.48(m,1H),2.46-2.45(m,3H),2.34-2.23(m,3H),2.18-2.06(m,7H),2.04(s,2H),1.06(s,9H).m/z(ESI):1085.5[M+H]+.
实施例28(化合物52盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(31.3mg,40%收率,96.95%纯度)。1H NMR(500MHz,CD3OD)δ:9.09(s,1H),8.97(s,1H),7.92-7.86(m,1H),7.45-7.43(m,2H),7.39-7.37(m,3H),7.35-7.31(m,1H),7.23-7.22(m,1H),5.58-5.41(m,1H),4.86-4.80(m,3H),4.68-4.65(m,1H),4.57-4.53(m,1H),4.49-4.47(m,2H),4.41-4.36(m,1H),4.28(brs,2H),4.01-3.96(m,2H),3.93-3.88(m,1H),3.81-3.78(m,1H),3.70(brs,2H),3.57-3.52(m,3H),3.41(s,1H),3.38-3.35(m,0.5H),3.26-3.18(m,2.5H),2.58-2.49(m,3H),2.48-2.45(m,3H),2.37-2.34(m,1H),2.25-2.04(m,8H),1.90-1.82(m,2H),1.70-1.65(m,2H),1.03-1.01(m,9H).m/z(ESI):1099.5[M+H]+.
实施例29(化合物53盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(13.4mg,25%收率,95.35%纯度)。1H NMR(500MHz,CD3OD)δ:9.08(s,1H),8.92(s,1H),7.88-7.71(m,2H),7.44-7.31(m,7H),7.21(s,1H),5.56-5.44(m,1H),4.83-4.76(m,3H),4.60-4.57(m,1H),4.47-4.38(m,3H),4.27(brs,2H),4.13-4.06(m,2H),3.96-3.85(m,4H),3.80-3.74(m,6H),3.65-3.58(m,2H),3.46-3.37(m,3H),2.46-2.42(m,3H),2.29-2.26(m,3H),2.15-2.04(m,6H),1.53(s,1H),1.05(s,9H).m/z(ESI):1101.3[M+H]+.
实施例30(化合物54盐的合成):
合成步骤参照实施例4,以中间体a为原料最终得到淡黄色三氟醋酸盐固体(8.7mg,16%收率,88.13%纯度)。1H NMR(500MHz,CD3OD)δ:9.10-9.08(m,1H),8.96(s,1H),7.88(s,1H),7.64-7.63(m,1H),7.45-7.32(m,7H),7.22(s,1H),5.57-5.35(m,1H),4.86-4.79(m,3H),4.69-4.66(m,1H),4.54-4.47(m,3H),4.42-4.38(m,1H),4.28(brs,2H),4.06-4.04(m,2H),3.97-3.78(m,7H),3.72-3.68(m,9H),3.41(brs,3H),2.47(s,3H),2.33-2.04(m,10H),1.03(s,9H).m/z(ESI):1145.3[M+H]+.
实施例31(化合物55盐的合成):
合成步骤参照实施例4,以中间体h为原料最终得到淡黄色三氟醋酸盐固体(8.7mg,15%收率,98.09%纯度)。1H NMR(500MHz,CD3OD)δ:9.09(s,1H),8.90(s,1H),8.58-8.57(m,0.5H),7.90-7.81(m,1.5H),7.45-7.40(m,4H),7.38-7.33(m,2H),7.21-7.20(m,1H),5.89-5.82(m,1H),5.02-4.99(m,1H),4.82-4.79(m,3H),4.63-4.62(m,1H),4.57-4.54(m,1H),4.43(s,1H),4.28(brs,2H),4.01-3.86(m,4H),3.76-3.74(m,1H),3.55-3.52(m,1H),3.38-3.35(m,1H),3.26-3.25(m,2H),2.48(s,3H),2.31-2.10(m,7H),1.99-1.92(m,1H),1.75(brs,2H),1.62-1.56(m,2H),1.50(d,J=5Hz,3H),1.39-1.33(m,14H),1.03(s,9H).m/z(ESI):1139.5[M+H]+.
实施例32(化合物56盐的合成):
合成步骤参照实施例4,以中间体g为原料最终得到淡黄色三氟醋酸盐固体(38.8mg,45%收率,95.47%纯度)。1H NMR(500MHz,CD3OD)δ:9.08(s,1H),8.91(s,1H),8.58-8.57(m,1H),7.90-7.81(m,2H),7.45-7.41(m,4H),7.38-7.32(m,2H),7.22(brs,1H),5.01-4.99(m,2H),4.87-4.84(m,3H),4.63-4.50(m,4H),4.43(s,1H),4.29-4.27(m,2H),4.01-3.81(m,4H),3.76-3.73(m,2H),3.37-3.35(m,2H),3.26-3.08(m,4H),2.48(s,3H),2.28-1.93(m,10H),1.74(brs,2H),1.59-1.56(m,2H),1.50(d,J=10Hz,3H),1.38-1.31(m,14H),1.03(s,9H).m/z(ESI):1153.6[M+H]+.
实施例33(化合物57盐的合成):
合成步骤参照实施例4,以中间体g为原料最终得到淡黄色三氟醋酸盐固体(22mg,25%收率,89.11%纯度)。1H NMR(500MHz,CD3OD)δ:10.90(s,1H),9.83-9.36(m,1H),9.13(s,2H),8.00-7.97(m,1H),7.62-7.60(m,1H),7.49-7.41(m,3H),7.18-7.17(m,1H),7.03-7.01(m,1H),4.66-4.31(m,6H),4.21(brs,2H),4.01-3.94(m,5H),3.86-3.47(m,10H),3.14-3.09(m,3H),2.93-2.88(m,2H),2.67-2.54(m,4H),2.36-2.13(m,3H),1.96(brs,4H),1.87-1.78(m,1.5H),1.64-1.47(m,5.5H),1.27(brs,12H).m/z(ESI):1036.7[M+H]+.
实施例34(化合物58的合成):
步骤A:将中间体i(50mg,65.71μmol,1eq)溶于无水四氢呋喃(3mL)中,向反应液中添加三乙胺(6.65mg,65.71μmol,1eq)和(4-硝基苯基)碳酰氯(19.87mg,98.57μmol,1.5eq).将混合物在35℃下搅拌16小时。LC-MS检测反应结束后,真空蒸发溶剂,残余物34-1可直接用于下一步反应,无须纯化。m/z(ESI):761.5[M+H]+.
步骤B:将34-1(60mg,63.83μmol,1eq)的无水四氢呋喃(3mL)溶液中添加三乙胺和(2S,4R)-1-[(2S)-2-[3-(2-氨基乙氧基)乙氧基]丙胺基]-3,3-二甲基丁酰基]-4-羟基-N-[(1S)-1-[4-(4-甲基噻唑-5-基)苯基]乙基]吡咯烷-2-甲酰胺盐酸盐(81.73mg,127.66μmol,2.0eq).将混合物在25℃下搅拌2小时。反应结束后真空浓缩反应液,通过硅胶柱(DCM/MeOH=201/,V/V)纯化得到34-2(30mg,33.80%产率)。m/z(ESI):1390.7[M+H]+.
步骤C:将34-2(30mg,21.57μmol,1eq)溶于3mL无水二氯甲烷中,加入4M盐酸乙酸乙酯溶液(7.87mg,215.73μmol,10eq),反应液室温下搅拌反应10分钟后,真空浓缩反应液,残余物通过制备HPLC(0.05%NH3.H2O/MeCN)得到白色固体(3.8mg,13.75%产率,97.32%纯度).。1H NMR(500MHz,CD3OD)δ:9.07(s,1H),8.87(s,1H),7.69-7.66(m,1H),7.43-7.38(m,4H),7.31-7.30(m,1H),7.26-7.23(m,1H),7.06-7.05(m,1H),5.01-4.97(m,1H),4.64-4.55(m,4H),4.42-4.38(m,2H),4.30-4.29(m,3H),3.87-3.85(m,1H),3.75-3.58(m,12H),3.54-3.52(m,2H),3.35(s,1H),3.01(brs,1H),2.90(brs,1H),2.59-2.54(m,1H),2.49-2.45(m,5H),2.26-2.17(m,3H),2.06-2.02(m,1H),1.96-1.73(m,10H),1.57-1.49(m,3H),1.32-1.29(m,3H),1.03(s,9H),0.81-0.77(m,3H).m/z(ESI):1246.4[M+H]+.
实施例35(化合物59的盐的合成):
合成步骤参照实施例4,最后得到目标产物(10.8mg,33.17%收率,纯度96.67%)。1HNMR(500MHz,Methanol-d6)δ1.31-1.34(m,2H),1.85-1.93(m,4H),2.06-2.14(m,4H),2.65-2.75(m,14H),3.40(s,1H),3.51-3.55(m,4H),3.76-3.78(m,7H),4.54-4.58(m,2H),4.61-4.69(m,3H),5.11(dd,J=12.5,5.4Hz,1H),7.24(d,J=2.1Hz,1H),7.25-7.29(m,1H),7.34(d,J=8.9Hz,1H),7.38-7.41(m,2H),7.72(d,J=8.5Hz,1H),7.89(dd,J=9.0,5.8Hz,1H),9.03(s,1H).m/z(ESI):968.29[M+H]+..
实施例36(化合物60的合成):
合成步骤参照实施例4,最后得到目标产物(28.8mg,33.98%收率,纯度93.67%)。1HNMR(500MHz,DMSO)δ1.66(s,6H),1.92-1.93(m,3H),2.00-2.07(m,1H),2.33-2.49(m,12H),2.54-2.62(m,2H),3.21(s,4H),3.57-3.67(m,7H),3.95(s,1H),4.33(d,J=12.0Hz,1H),4.41(s,3H),4.47(d,J=12.5Hz,1H),5.09(dd,J=12.5,5.0Hz,1H),7.19(s,1H),7.25(d,J=8.0Hz,1H),7.36(s,1H),7.41(s,1H),7.48(t,J=9.0Hz,1H),7.69(d,J=8.5Hz,1H),7.99(dd,J=8.5,6.0Hz,1H),9.04(s,1H),11.08(s,1H).m/z(ESI):968.3[M+H]+..
实施例37(化合物61的合成):
合成步骤参照实施例4,最后得到目标产物(16.6mg,17.98%收率,纯度94.35%)。1HNMR(500MHz,Methanol-d4)δ2.11(s,4H),2.15-2.28(m,4H),2.30-2.38(m,1H),2.41-2.51(m,1H),2.72-2.86(m,2H),3.01-3.10(m,1H),3.13-3.25(m,3H),3.41(s,1H),3.49(t,J=13.1Hz,1H),3.80(d,J=6.8Hz,3H),3.86-3.99(m,3H),4.06-4.14(m,1H),4.19(s,2H),4.33-4.46(m,2H),4.70-4.84(m,3H),6.98(d,J=8.6Hz,1H),7.11-7.19(m,1H),7.19-7.24(m,2H),7.34(d,J=10.8,2.6Hz,1H),7.56(d,J=8.4Hz,1H),7.70-7.82(m,1H),9.10(s,1H).m/z(ESI):968.4[M+H]+..
实施例38(化合物62的合成):
参照实施例4,最后得到目标产物(21.5mg,16.38%收率,纯度95.09%)。1H NMR(500MHz,DMSO-d6)δ1.66(s,6H),1.92-1.93(m,3H),2.00-2.07(m,1H),2.33-2.49(m,12H),2.54-2.62(m,2H),3.21(s,4H),3.57-3.67(m,7H),3.95(s,1H),4.33(d,J=12.0Hz,1H),4.41(s,3H),4.47(d,J=12.5Hz,1H),5.09(dd,J=12.5,5.0Hz,1H),7.19(s,1H),7.25(d,J=8.0Hz,1H),7.36(s,1H),7.41(s,1H),7.48(t,J 34-=9.0Hz,1H),7.69(d,J=8.5Hz,1H),7.99(dd,J=8.5,6.0Hz,1H),9.04(s,1H),11.08(s,1H).m/z(ESI):968.4[M+H]+..
实施例39(化合物63盐的合成):
参照实施例4,最终得到淡黄色三氟醋酸盐固体(7.6mg,收率30.09%,纯度96.67%)。1H NMR(500MHz,Methanol-d4)δ:1.06(s,9H),1.37-1.30(m,6H),2.04-1.96(m,2H),2.15-2.12(m,6H),2.28-2.25(m,3H),2.47(s,3H),3.06-2.99(m,3H),3.38(s,2H),3.61-3.51(m,10H),3.78-3.76(m,1H),3.85-3.82(m,1H),3.98-3.91(m,2H),4.29-4.27(m,2H),4.45(brs,1H),4.64-4.55(m,4H),4.74-4.73(m,1H),4.83-4.81(m,4H),7.21-7.20(m,1H),7.38-7.33(m,2H),7.50-7.45(m,4H),7.90-7.87(m,1H),8.91(s,1H),9.07(s,1H).m/z(ESI):1268.7[M+H]+.
实施例40(化合物64盐的合成):
参照实施例4,最终得到淡黄色三氟醋酸盐固体(24.1mg,收率41.14%,纯度98.48%)。1H NMR(500MHz,Methanol-d4)δ1.05(s,9H),1.35-1.26(m,4H),1.98-1.93(m,1H),2.22-2.1(m,5H),2.32-2.30(m,2H),2.49(s,3H),3.00-2.91(m,1H),3.26-3.10(m,1H),3.42-3.41(m,3H),3.67-3.56(m,1H),3.78-3.75(m,,1H),3.85-3.82(m,1H),4.02-3.94(m,2H),4.29-4.27(m,2H),4.45(brs,1H),4.61-4.54(m,3H),4.74-4.72(m,1H),4.84-4.79(m,2H),5.43-5.32(m,1H),7.23-7.22(m,1H),7.38-7.32(m,2H),7.51-7.42(m,5H),7.90-7.87(m,1H),8.96(s,1H),9.10(s,1H).m/z(ESI):1142.5[M+H]+.
实施例41(化合物65盐的合成):
参照实施例4,最终得到淡黄色三氟醋酸盐固体(24.1mg,收率41.14%,纯度98.48%)。1H NMR(500MHz,Methanol-d4)δ1.05(s,9H),1.35-1.26(m,4H),1.98-1.93(m,1H),2.22-2.1(m,5H),2.32-2.30(m,2H),2.49(s,3H),3.00-2.91(m,1H),3.26-3.10(m,1H),3.42-3.41(m,3H),3.67-3.56(m,1H),3.78-3.75(m,,1H),3.85-3.82(m,1H),4.02-3.94(m,2H),4.29-4.27(m,2H),4.45(brs,1H),4.61-4.54(m,3H),4.74-4.72(m,1H),4.84-4.79(m,2H),5.43-5.32(m,1H),7.23-7.22(m,1H),7.38-7.32(m,2H),7.51-7.42(m,5H),7.90-7.87(m,1H),8.96(s,1H),9.10(s,1H).m/z(ESI):1142.5[M+H]+.
实施例42(化合物66的合成):
参照实施例4,最终得到白色固体(2.1mg,收率10.75%,纯度96.01%)。1H NMR(500MHz,Methanol-d4)δ1.03(s,9H),1.50-4.49(m,3H),2.04-1.56(m,16H),2.20-2.15(m,3H),2.33-2.24(m,2H),2.50-2.47(m,4H),2.88-2.84(m,1H),3.00-2.94(m,1H),3.15-3.10(m,2H),3.57-3.52(m,1H),3.76-3.65(m,5H),3.88-3.86(m,1H),4.30-4.27(m,3H),4.42-4.36(m,2H),4.63-4.54(m,5H),5.01-4.97(m,1H),7.06-7.05(m,1H),7.26-7.22(m,1H),7.30-7.29(m,1H),7.43-7.38(m,4H),7.68-7.65(m,1H),8.87(s,1H),9.06(s,1H).m/z(ESI):1186.5[M+H]+.
实施例43(化合物67的合成):
参照实施例4,最终得到白色固体(10.1mg,收率21.75%,纯度96.01%)。1H NMR(500MHz,Methanol-d4)δ1.03(s,9H),1.50-4.49(m,3H),2.04-1.56(m,16H),2.20-2.15(m,3H),2.33-2.24(m,2H),2.50-2.47(m,4H),2.88-2.84(m,1H),3.00-2.94(m,1H),3.15-3.10(m,2H),3.57-3.52(m,1H),3.76-3.65(m,5H),3.88-3.86(m,1H),4.30-4.27(m,3H),4.42-4.36(m,2H),4.63-4.54(m,5H),5.01-4.97(m,1H),7.06-7.05(m,1H),7.26-7.22(m,1H),7.30-7.29(m,1H),7.43-7.38(m,4H),7.68-7.65(m,1H),8.87(s,1H),9.06(s,1H).m/z(ESI):1186.5[M+H]+.
实施例44(化合物68的合成):
参照实施例4,最终得到白色固体(6.1mg,收率13.38%,纯度98.16%)。1H NMR(500MHz,Methanol-d4)δ0.81-0.78(m,3H),1.03(s,9H),1.33-1.30(m,8H),1.51-1.47(m,5H),2.04-1.56(m,16H),2.31-2.15(m,5H),2.51-2.47(m,4H),2.83-2.81(m,1H),2.94-2.91(m,1H),3.11-3.08(m,2H),3.49-3.45(m,1H),3.65(brs,2H),3.75-3.72(m,3H),3.89-3.86(m,1H),4.27-4.25(m,3H),4.36-4.34(m,1H),4.42(brs,1H),4.62-4.55(m,5H),5.02-4.98(m,1H),7.06-7.05(m,1H),7.26-7.22(m,1H),7.30-7.29(m,1H),7.44-7.40(m,4H),7.68-7.65(m,1H),8.87(s,1H),9.06(s,1H).m/z(ESI):1128.5[M+H]+.
实施例45(化合物69盐的合成):
参照实施例1,最终得到淡黄色三氟醋酸盐固体(17.2mg,45%收率,纯度95.70%)。1H NMR(500MHz,Methanol-d4)δ:9.08(s,1H),7.88(dd,J=9.2,5.7Hz,1H),7.66(d,J=8.4Hz,1H),7.44-7.28(m,3H),7.21(d,J=2.5Hz,1H),7.09(d,J=8.5Hz,1H),4.85-4.77(m,3H),4.71(d,J=13.3Hz,1H),4.47-4.23(m,5H),4.00(s,3H),3.96(d,J=14.0Hz,2H),3.89-3.43(m,4H),3.37(s,1H),3.03(t,J=12.4Hz,1H),2.88(t,J=12.8Hz,1H),2.83-2.66(m,2H),2.59-2.26(m,6H),2.23-2.09(m,5H),2.01(d,J=13.3Hz,2H),1.91-1.67(m,2H).m/z(ESI):909.5[M+H]+.
实施例46(化合物70盐的合成):
步骤A:中间体a(100mg,118.61μmol,1eq)的混合物,在室温下,将4-甲酰哌啶-1-羧酸苄基酯(35.20mg,142.33μmol,1.2eq)和三乙酰氧基硼氢化钠(30.17mg)在DCE(5mL)中搅拌过夜。用1N氢氧化钠水溶液和1N氯化氢水溶液洗涤原油,用硫酸镁干燥,蒸发溶剂,用10%甲醇/DCM制备TLC纯化残渣,得到少量黄色固体46-1(100mg,产率78%)。m/z(ESI):1074.5[M+H]+.
步骤B:反应瓶中加入46-1(100mg,93.08μmol,1eq)和钯(50mg,93.08μmol,1-MeOH)溶液室温。用氢气球置换气体三次,然后在室温下反应12小时。硅藻土用于抽滤,并用甲醇洗涤数次。收集滤液并浓缩,得到黄色固体(0.08g,产率92%),可直接用于下一步反应。m/z(ESI):940.5[M+H]+.
剩余过程参照实施例1得到淡黄色三氟醋酸盐固体(13.4mg,25%收率,纯度95.42%)。1H NMR(500MHz,Methanol-d4)δ:9.08(s,1H),8.92(s,1H),7.88(dd,J=9.2,5.7Hz,2H),7.47(d,J=4.1Hz,4H),7.39-7.31(m,2H),7.21(d,J=2.5Hz,1H),5.36(q,J=6.6Hz,1H),4.80(d,J=12.4Hz,2H),4.73(d,J=9.2Hz,1H),4.56(t,J=8.4Hz,2H),4.47(d,J=28.7Hz,3H),4.28(s,2H),4.07(s,1H),4.01-3.90(m,2H),3.86-3.74(m,2H),3.73-3.48(m,2H),3.37(s,2H),3.24-2.95(m,6H),2.63(q,J=13.9Hz,1H),2.49(s,3H),2.39-2.07(m,11H),1.96(ddd,J=13.4,9.4,4.4Hz,1H),1.81(d,J=14.1Hz,3H),1.31(dd,J=17.7,8.0Hz,4H),1.05(s,9H).m/z(ESI):1196.5[M+H]+.
实施例47(化合物71盐的合成):
参照实施例46得到淡黄色三氟醋酸盐固体(28.2mg,70%收率,纯度97.71%)。1HNMR(500MHz,Methanol-d4)δ:9.04(s,1H),8.88(s,1H),7.84(dd,J=9.2,5.7Hz,1H),7.48-7.39(m,4H),7.38-7.25(m,2H),7.17(d,J=2.5Hz,1H),4.83-4.66(m,3H),4.57-4.48(m,1H),4.41(s,1H),4.27(d,J=26.2Hz,4H),3.92(s,2H),3.82-3.68(m,2H),3.66-3.49(m,8H),3.37(d,J=28.9Hz,6H),3.15-2.96(m,2H),2.44(s,3H),2.38-2.23(m,3H),2.12(dq,J=23.6,12.0,11.6Hz,6H),2.01-1.86(m,1H),1.38-1.18(m,4H),1.01(s,9H).m/z(ESI):909.5[M+H]+.
实施例48(化合物72盐的合成):
合成步骤参照实施例4,最终得到淡黄色三氟醋酸盐固体(10.2mg,收率11.14%,纯度94.62%)。1H NMR(500MHz,Methanol-d4)δ9.08(s,1H),7.91-7.84(m,1H),7.66(d,J=8.3Hz,1H),7.40-7.30(m,3H),7.22(s,1H),7.09(d,J=8.3Hz,1H),4.81(m,3H),4.72(d,J=12.5Hz,1H),4.62(m,2H),4.36(dd,J=9.1,5.0Hz,1H),4.28(m,2H),4.21(m,1H),4.00(s,3H),3.99-3.90(m,2H),3.74(m,2H),3.38(s,2H),3.27(m,1H),3.12(m,3H),3.03(m,1H),2.82-2.68(m,3H),2.46(m,1H),2.32(m,3H),2.13(m,4H),2.10-1.95(m,6H),1.72(m,2H).m/z(ESI):937.5[M+H]+.
实施例49(化合物73盐的合成):
合成过程参照实施例46得到淡黄色三氟醋酸盐固体(22.4mg,62%收率,纯度98.93%)。1H NMR(500MHz,Methanol-d4)δ:9.05(s,1H),8.89(s,1H),7.84(dd,J=9.2,5.7Hz,1H),7.44(t,J=4.4Hz,4H),7.40-7.25(m,2H),7.17(s,1H),4.82-4.60(m,4H),4.56-4.31(m,4H),4.29-4.06(m,4H),3.91(t,J=13.0Hz,2H),3.85-3.65(m,2H),3.57-3.31(m,4H),2.92-2.62(m,2H),2.44(d,J=2.1Hz,3H),2.39-2.22(m,3H),2.21-2.03(m,7H),2.00-1.84(m,1H),1.28(dd,J=33.9,13.6Hz,5H),1.03(s,9H).m/z(ESI):1196.5[M+H]+.
实施例50(化合物74盐的合成):
步骤A:将中间体b(200mg,225.69μmol,1eq)加入到乙腈(5mL)中,随后加入DBU(171.80mg,1.13mmol,168.43μL,5eq),之后加入丙烯酸乙酯(27.11mg,270.83μmol,1.2eq),在20℃下搅拌过夜。将混合物加入水(10mL)和乙酸乙酯(10mL),分离后用乙酸乙酯(10mL*2)萃取,合并有机相并用柱层析(10%MeOH/DCM)纯化得到黄色油状物50-1(140mg,62%收率)。m/z(ESI):987[M+H]+.
步骤B:室温下,将氢氧化锂(17mg,709.75umol,5eq.)加入到50-1(4mL)和水(2mL)溶液里。然后将反应升温至50℃。搅拌1小时。冷却至室温,将甲醇在真空下除去,用10wt%柠檬酸调到中性,加水(10mL)和乙酸乙酯(10mL),再用乙酸乙酯(10mL*2)萃取,硫酸钠干燥,在真空下浓缩汁黄色固体50-2(110mg,114.80umol,80.87%收率)。m/z(ESI):959[M+H]+.
步骤C:将50-2(110mg,114.80umol,1.eq.)和3-(1-甲基-6-(哌啶-4-基)-1H-吲唑-3-基)哌啶-2,6-二酮(44.9mg,1387.7umol,1.2eq.)加入到DMF(5mL)里,然后先加入DIEA(59.35mg,4eq.),再加入HATU(47.6mg,126.28umol。室温搅拌0.5小时。用饱和氯化铵(5mL)淬灭,用乙酸乙酯(10mL*2)萃取,再用盐水(10mL*2)洗.浓缩后用硅胶柱以10%MeOH/DCM过柱得到50-3(105mg,82.9umol,72.21%收率)。m/z(ESI):1267[M+H]+.
步骤D:室温下将50-3(105mg,82.9umol,1eq.)加入到四氢呋喃(2mL)溶液里,再加入四丁基氟化铵(1mL).室温搅拌1小时。用饱和氯化铵(5mL)淬灭,乙酸乙酯(10mL)萃取,水(10mL)洗,硫酸钠干燥后在真空下浓缩干得到50-4(70mg,63.05umol,76.05收率)。未经纯化进行下一步反应。m/z(ESI):1111[M+H]+.
步骤E:将50-4(70mg,63.05umol,1eq.)加入到DCM(2mL)里,再加入HCl(1mL),室温搅拌10分钟。将混合物真空下浓缩干,用prep-HPLC(0.1%三氟乙酸水+乙腈)制备后冻干得到淡黄色三氟乙酸盐固体(15mg,16.7%收率,纯度95.02%)。1H NMR(500MHz,Methanol-d4)δ1.74(dd,J=44.7,11.2Hz,3H),1.97(t,J=13.1Hz,3H),2.09-2.20(m,5H),2.22(d,J=7.8Hz,3H),2.31(dd,J=13.3,5.9Hz,1H),2.45(dd,J=9.2,4.9Hz,1H),2.77(q,J=16.5,14.3Hz,4H),2.89(s,3H),3.13(s,3H),3.40(s,2H),3.94(dd,J=21.9,14.0Hz,3H),4.00(s,4H),4.06(d,J=13.6Hz,1H),4.28(d,J=10.7Hz,2H),4.36(dd,J=9.3,5.1Hz,1H),4.62(q,J=6.3Hz,2H),4.71(d,J=13.2Hz,1H),4.82(d,J=14.1Hz,3H),7.08(d,J=8.5Hz,1H),7.22(d,J=2.6Hz,1H),7.35(td,J=10.3,9.7,5.1Hz,3H),7.65(d,J=8.4Hz,1H),7.88(d,J=8.8Hz,1H),9.07(s,1H).m/z(ESI):967[M+H]+.
实施例51(化合物75盐的合成):
步骤A:将51-1(300mg,919.14μmol,1eq)和4-氧哌啶-1-羧酸叔丁酯(219.76mg,1.10mmol,1.2eq)溶解在四氢呋喃(1.5mL)和甲醇(6mL)的混合溶剂中,再用吸管滴入2滴醋酸到反应液中,将混合物在55℃下搅拌反应1小时,然后向反应液中加入氰基硼氢化钠(173.28mg,2.76mmol,3eq),混合物继续在55℃下搅拌反应过夜。LC-MS监测原料反应完毕,先浓缩掉大部分溶剂,残留物加入50mL水,用二氯甲烷:甲醇=10:1(3x 15mL)萃取水层,用盐水(40mL)洗涤合并有机相,用硫酸钠干燥,过滤,并在真空中浓缩。残渣通过柱层析纯化,用0-10%的二氯甲烷/甲醇洗脱,得到目标产品51-2(155mg,33.1%收率)。m/z(ESI):510.37[M+H]+.
步骤B:将51-2(150mg,294.33μmol,1eq)溶解在二氯甲烷(2mL)和甲醇(2mL)的混合溶剂中,加入盐酸二氧六环溶液(4M,1.03mL,14eq),反应液室温搅拌3小时。LC-MS监测原料反应完毕,反应液直接浓缩得白色固体51-3(130mg,99%收率)。m/z(ESI):410.70[M+H]+.
步骤C:将中间体b(100mg,129.39μmol,1eq),51-3(69.25mg,155.27μmol,1.2eq)和N,N,N',N'-四甲基氯甲脒六氟磷酸盐(54.35mg,194.09μmol,1.5eq)溶于DMF溶液(4mL)中,然后加入N-甲基咪唑(53.05mg,646.97μmol,5eq),混合物室温搅拌3小时。LC-MS监测反应液有少量产物生成且有一个很大的杂质。混合物是浑浊状态,加入DIEA(0.5mL),溶液变澄清,然后室温搅拌过夜。次日LC-MS监测原料反应完毕,加入饱和氯化铵溶液中和反应液,然后用二氯甲烷:甲醇:氨甲醇=100:10:1(3x 15mL)萃取,用盐水(40mL)洗涤合并有机相,用硫酸钠干燥,过滤,并在真空中浓缩。残渣通过柱层析纯化,用0-20%的二氯甲烷/甲醇洗脱,得到目标产品51-4(25mg,14.1%收率).。m/z(ESI):1164.81[M+H]+.
步骤D:将51-4(25mg,17.18μmol,1eq)溶解在二氯甲烷(2mL)中,加入盐酸二氧六环溶液(4M,0.5mL),反应液室温搅拌30分钟。LC-MS监测原料反应完毕且有目标产物生成,反应液直接浓缩去除溶剂,残留物溶解在二氯甲烷中,加入三乙胺调至弱碱性,再浓缩去除溶剂,残留物使用制备HPLC(0.1%三氟醋酸/水+乙腈),得到淡黄色三氟醋酸盐固体(13.5mg,49.4%收率,纯度92.80%).1H NMR(500MHz,Methanol-d4)δ1.68-1.71(m,1H),1.83-1.85(m,1H),2.01-2.12(m,4H),2.14-2.18(m,6H),2.24-2.27(m,4H),2.32-2.36(m,4H),2.47-2.51(m,1H),2.72-2.81(m,3H),3.11-3.13(m,4H),3.27-3.29(m,3H),3.40-3.42(m,3H),3.55-3.64(m,1H),3.72-3.77(m,4H),3.96-4.01(m,1H),4.05(s,3H),4.31-4.32(m,3H),4.40(dd,J=9.2,5.1Hz,1H),4.63-4.67(m,2H),4.78(d,J=12.6Hz,1H),4.86(d,J=13.9Hz,2H),7.13(d,J=8.4Hz,1H),7.25(s,1H),7.36-7.41(m,3H),7.73(d,J=8.4Hz,1H),7.91(dd,J=8.5,5.8Hz,1H),9.11(s,1H).m/z(ESI):1020.7[M+H]+.
实施例52(化合物76盐的合成):
合成步骤参照实施例1,最终得到淡黄色三氟乙酸盐固体(15.5mg,收率25.69%,纯度95.19%)。1H NMR(500MHz,Methanol-d4)δ1.04(s,9H),1.37-1.28(m,5H),1.45-1.42(m,6H),1.57(brs,2H),1.70-1.65(m,1H),1.88-1.78(m,4H),2.04-1.99(m,1H),2.24-2.11(m,8H),2.38-2.35(m,1H),2.49(s,3H),3.24-3.12(m,4H),3.39-3.34(m,2H),3.55-3.53(m,1H),3.71-3.64(m,1H),3.80-3.78(m,1H),3.87-3.85(m,1H),3.99-3.91(m,2H),4.08(t,J=5Hz,2H),4.28(brs,2H),4.50-4.37(m,3H),4.65-4.61(m,1H),4.83-4.74(m,5H),5.59-5.34(m,1H),7.01-6.99(m,2H),7.22(s,1H),7.38-7.33(m,2H),7.49-7.47(m,1H),7.54-7.53(m,1H),7.90-7.87(m,1H),8.92(s,1H),9.08-9.07(m,1H).m/z(ESI):1213.6[M+H]+.
实施例53(化合物77盐的合成):
合成步骤参照实施例1,最终得到淡黄色三氟乙酸盐固体(16.9mg,收率28.92%,纯度38.06%)。1H NMR(500MHz,Methanol-d4)δ1.04(s,9H),1.40-1.27(m,16H),1.55-1.53(m,2H),1.86-1.77(m,4H),2.04-2.00(m,1H),2.27-2.10(m,8H),2.39-2.36(m,1H),2.49(s,3H),3.25-3.13(m,3H),3.39-3.34(m,2H),3.56-3.53(m,1H),3.71-3.64(m,1H),3.87-3.78(m,2H),3.99-3.91(m,2H),4.07(t,J=5Hz,2h),4.28(brs,2H),4.51-4.37(m,3H),4.65-4.62(m,1H),4.86-4.74(m,4H),5.60-5.41(m,1H),7.01-6.98(m,2H),7.22-7.21(m,1H),7.38-7.33(m,2H),7.49-7.47(m,1H),7.55-7.52(m,1H),7.90-7.87(m,1H),8.93(s,1H),9.08-9.07(m,1H)..m/z(ESI):1213.6[M+H]+.
实施例54(化合物78盐的合成):
合成步骤参照实施例1,最终得到得到黄色固体(22.2mg,收率37.52%,纯度96.58%)。1H NMR(500MHz,Methanol-d4)δ1.03(s,9H),1.38-1.28(m,18H),1.54-1.50(m,2H),1.86-1.77(m,4H),2.04-1.93(m,1H),2.27-2.10(m,7H),2.38-2.35(m,1H),2.50(s,3H),3.19-3.15(m,2H),3.24-3.23(m,4H),3.39-3.34(m,2H),3.56-3.53(m,1H),3.71-3.64(m,1H),3.87-3.78(m,2H),4.00-3.92(m,2H),4.07-4.05(m,2H),4.28(brs,2H),4.51-4.37(m,3H),4.65-4.62(m,1H),4.85-4.74(m,4H),5.59-5.39(m,1H),7.01-6.98(m,2H),7.21(brs,1H),7.38-7.32(m,2H),7.49-7.47(m,1H),7.55-7.53(m,1H),7.90-7.87(m,1H),8.92-8.91(m,1H),9.08-9.07(m,1H).m/z(ESI):1241.7[M+H]+.
实施例55(化合物80盐的合成):
合成步骤参照实施例1,最终得到淡黄色三氟乙酸盐固体(7.7mg,收率6.59%,纯度98.67%)。1H NMR(500MHz,Methanol-d4)δ0.81-0.78(m,3H),1.04(s,9H),1.40-1.34(m,12H),1.51-1.45(m,3H),1.64-1.56(m,2H),1.77(brs,2H),2.04-1.92(m,2H),2.32-2.14(m,10H),2.42-2.37(m,1H),2.56-2.48(m,4H),3.26-3.16(m,3H),3.38-3.36(m,1H),3.56-3.54(m,1H),3.76-3.70(m,2H),4.01-3.86(m,3H),4.29-4.26(m,2H),4.43(brs,1H),4.58-4.54(m,1H),4.64-4.62(m,1H),4.83-4.78(m,2H),5.02-4.99(m,1H),5.60-5.42(m,1H),7.04(s,1H),7.29-7.25(m,1H),7.32-7.29(m,1H),7.45-7.41(m,3H),7.71-7.68(m,1H),7.83-7.81(m,1H),8.92-8.90(m,1H),9.12-9.11(m,1H).m/z(ESI):1157.8[M+H]+.
实施例56(化合物82盐的合成):
合成步骤参照实施例51,最终得到黄色固体。纯度90.28A%。1H NMR(500MHz,Methanol-d4)δ1.19-1.46(m,3H),1.72(t,J=28.2Hz,4H),1.98-2.27(m,12H),2.29-2.61(m,7H),2.61-3.20(m,6H),3.21-3.53(m,29H),3.52-3.93(m,6H),4.02(s,3H),4.23-4.45(m,4H),7.10(d,J=8.4Hz,1H),7.21(s,1H),7.30-7.50(m,3H),7.56-8.02(m,2H),9.08(s,1H).MS:1333.87[M+H]+.
实施例57(化合物83盐的合成):
合成步骤参照实施例4,以中间体h为原料,最终经过制备得到(2S,4R)-1-((S)-2-(10-((S)-3-((4-((1R,5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基)吡咯烷-1-基)癸酰胺)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-甲基-4-噻唑-5-苯基)苯基甲酰胺三氟醋酸盐(黄色固体,49mg,纯度96.8%,收率48.28%)。1H NMR(500MHz,Methanol-d4)δ1.03(d,J=2.6Hz,9H),1.34(s,8H),1.39(s,3H),1.44(dd,J=15.0,7.5Hz,2H),1.50(d,J=7.0Hz,3H),1.58(dd,J=14.0,7.3Hz,2H),1.68(dd,J=10.1,6.1Hz,2H),1.75(s,2H),1.88-2.00(m,1H),2.11(d,J=10.7Hz,2H),2.16(d,J=11.0Hz,2H),2.28(tt,J=15.2,7.3Hz,2H),2.48(s,3H),3.11-3.15(m,2H),3.26(d,J=8.9Hz,2H),3.38(d,J=11.8Hz,1H),3.54(d,J=14.1Hz,1H),3.75(dd,J=10.9,3.9Hz,1H),3.87(d,J=11.2Hz,2H),3.98(d,J=11.2Hz,2H),4.28(s,2H),4.43(s,1H),4.56(t,J=8.2Hz,1H),4.58-4.68(m,1H),4.81(d,J=14.6Hz,2H),5.00(t,J=6.8Hz,1H),7.21(t,J=2.4Hz,1H),7.33(d,J=8.9Hz,1H),7.40-7.46(m,5H),7.88(dd,J=9.1,5.7Hz,1H),8.91(d,J=9.6Hz,1H),9.09(s,1H).m/z(ESI):1225.6[M+H]+.
实施例58(化合物84盐的合成):
合成步骤参照实施例4,以中间体h为原料,最终经过制备得到(2S,4R)-1-((S)-2-(12-((S)-3-((4-((1R,5S)-3,8-二氮杂环[3.2.1]辛烷-3-基)-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶[4,3-d]嘧啶-2-基)氧基吡咯烷-1-基)十二烷基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-4-4-4-4-甲基-5-噻唑-2-乙基吡咯烷基)甲酰胺三氟醋酸盐(黄色固体,10mg,纯度98.8%,收率21.43%)。1H NMR(500MHz,Methanol-d4)δ1.04(s,10H),1.32(s,16H),1.50(d,J=7.0Hz,4H),1.55-1.65(m,3H),1.76(s,2H),1.95(ddd,J=13.2,8.9,4.5Hz,1H),2.11(d,J=10.8Hz,2H),2.20-2.34(m,3H),2.48(s,3H),3.25(s,1H),3.38(d,J=11.6Hz,2H),3.54(d,J=14.1Hz,1H),3.75(dd,J=11.3,3.9Hz,1H),3.87(d,J=11.3Hz,2H),3.93-4.04(m,3H),4.28(d,J=8.4Hz,2H),4.43(s,1H),4.56(t,J=8.4Hz,1H),4.63(d,J=6.3Hz,1H),4.81(d,J=12.4Hz,2H),4.97-5.07(m,2H),7.21(s,1H),7.33(d,J=9.0Hz,1H),7.35-7.39(m,2H),7.43(q,J=8.2Hz,5H),7.88(dd,J=9.2,5.7Hz,1H),8.92(d,J=8.0Hz,1H),9.09(s,1H).m/z(ESI):1153.7[M+H]+.
实施例59(化合物85盐的合成):
合成步骤参考实施例51,最终得到目标化合物(58.8mg,38.99μmol,98.24%纯度)。1H NMR(500MHz,Methanol-d4)δ1.03(s,9H),1.31-1.34(m,7H),1.37-1.46(m,6H),1.47-1.54(m,3H),1.55-1.62(m,2H),1.66-1.71(m,2H),1.75(s,2H),2.08-2.33(m,7H),2.48(s,3H),3.09-3.16(m,2H),3.35-3.41(m,2H),3.49-3.59(m,1H),3.71-3.78(m,1H),3.84-4.03(m,4H),4.24-4.34(m,2H),4.41-4.46(m,1H),4.52-4.59(m,1H),4.61-4.68(m,1H),4.96-5.05(m,1H),7.20-7.23(m,1H),7.32-7.39(m,2H),7.40-7.46(m,4H),7.81(d,J=9.0Hz,1H),8.56(d,J=7.4Hz,1H),9.09(s,1H).m/z(ESI+):1139.6[M+H]+.
实施例60(化合物86盐的合成):
合成步骤参考实施例4,最终得到目标化合物(26.0mg,17.29μmol,98.49%纯度)。1HNMR(500MHz,Methanol-d4)δ1.07(s,9H),1.33-1.39(m,7H),1.41-1.50(m,6H),1.54(d,J=7.0Hz,3H),1.58-1.66(m,2H),1.68-1.75(m,2H),1.76-1.86(m,2H),2.11-2.35(m,7H),2.51(s,3H),3.10-3.22(m,2H),3.25-3.31(m,2H),3.38-3.43(m,1H),3.54-3.63(m,1H),3.74-3.81(m,1H),3.88-4.07(m,4H),4.27-4.33(m,2H),4.47(s,1H),4.57-4.62(m,1H),4.64-4.69(m,1H),4.78-4.84(m,3H),5.01-5.09(m,1H),7.25(s,1H),7.35-7.43(m,2H),7.44-7.53(m,4H),7.92(dd,J=9.1,5.7Hz,1H),8.95(s,1H),9.13(s,1H).m/z(ESI+):1139.6[M+H]+.
实施例61(化合物87盐的合成):
合成步骤参照实施例4,以中间体h为原料最终得到淡黄色三氟醋酸盐固体(31.5mg,19%收率,纯度94.07%)。1H NMR(500MHz,Methanol-d6)δ1.04(s,2H),1.07(s,9H),1.35-1.42(m,18H),1.54(d,J=6.9Hz,3H),1.57-1.65(m,2H),1.79(s,2H),1.97-2.01(m,1H),2.13-2.15(d,J=9.9Hz,2H),2.21-2.32(m,5H),2.52(s,3H),3.29(s,1H),3.40(d,J=11.8Hz,1H),3.56-3.65(m,1H),3.77-3.79(m,1H),3.91(d,J=11.1Hz,2H),3.99-4.05(m,2H),4.32(s,2H),4.47(s,1H),4.60(t,J=8.3Hz,1H),4.66(s,1H),5.03-5.04(m,1H),7.25(s,1H),7.37(t,J=9.0Hz,1H),7.41(s,1H),7.44-7.50(m,4H),7.88-7.94(m,1H),8.96(s,1H),9.13(s,1H);m/z(ESI):1153.5[M+H]+.
实施例62(化合物88盐的合成):
合成步骤参照实施例4,以中间体h为原料最终得到淡黄色三氟醋酸盐固体(22mg,15.5%收率,纯度97.94%)。1H NMR(500MHz,Methanol-d6)δ1.06(s,9H),1.37-1.46(m,12H),1.53(d,J=6.9Hz,3H),1.68-1.78(m,6H),2.13-2.29(m,6H),2.50(s,3H),3.14-3.18(m,6H),3.28(s,1H),3.39(d,J=12.2Hz,1H),3.51-3.67(m,1H),3.90(d,J=10.9Hz,1H),3.98-4.04(m,2H),4.31(s,2H),4.46(s,1H),4.59(t,J=8.2Hz,1H),4.65(d,J=5.8Hz,1H),5.01-5.04(m,1H),7.24(s,1H),7.36(t,J=8.9Hz,1H),7.40(s,1H),7.43-7.47(m,4H),7.88-7.93(m,1H),8.94(s,1H),9.12(s,1H);m/z(ESI):1125.5[M+H]+.
实施例63(化合物90盐的合成):
合成步骤参照实施例4,最终得到淡黄色三氟乙酸盐固体(61.2mg,收率50.4%,纯度94.41%)。1H NMR(500MHz,Methanol-d4)δ1.00-1.06(m,9H),1.26-1.38(m,12H),1.50(d,J=5.0Hz,3H),1.55-1.65(m,4H),1.92-2.00(m,1H),2.07-2.40(m,10H),2.42-2.55(m,4H),3.08-3.24(m,4H),3.34-3.38(m,1H),3.72-3.78(m,1H),3.84-3.90(m,1H),3.93-4.08(m,3H),4.10-4.20(m,1H),4.25-4.32(m,2H),4.40-4.51(m,2H),4.56(d,J=10.0Hz,1H),4.60-4.65(m,1H),4.74-4.83(m,3H),4.92-5.03(m,2H),7.20-7.24(m,1H),7.32-7.39(m,2H),7.39-7.46(m,4H),7.85-7.91(m,1H),8.92(s,1H),9.08-9.15(m,1H).m/z(ESI):1210.6[M+H]+.
实施例64(化合物91盐的合成):
合成步骤参考实施例4,最终得到黄色固体(9.2mg,收率12.56%,纯度97.11%)。1H NMR(400MHz,Methanol-d4)δ1.04(s,9H),1.31-1.38(m,4H),1.45-1.55(m,3H),1.55-1.68(m,5H),1.76-1.98(m,6H),2.12-2.21(m,4H),2.23-2.32(m,3H),2.44-2.50(m,4H),2.51(s,3H),2.93-3.02(m,1H),3.34-3.43(m,2H),3.64-3.77(m,5H),3.84-3.92(m,1H),4.31-4.40(m,1H),4.40-4.53(m,3H),4.54-4.66(m,9H),4.96-5.07(m,1H),7.17-7.24(m,1H),7.27-7.36(m,2H),7.40-7.46(m,4H),7.85(dd,J=9.2,5.7Hz,1H),8.87(s,1H),9.01(s,1H).m/z(ESI):1154.7[M+H]+.
实施例65(化合物92盐的合成):
合成过程参考实施例51,经制备得到黄色固体(12.1mg,纯度95.04%,收率9.00%)。1H NMR(500MHz,Methanol-d4)δ0.88-0.95(m,2H),0.99-1.09(m,2H),1.27-1.34(m,1H),2.09-2.23(m,8H),2.29-2.37(m,1H),2.42-2.52(m,1H),2.66(s,4H),2.72-2.83(m,2H),3.03-3.13(m,2H),3.23(dt,J=13.0,5.3Hz,2H),3.32-3.53(m,4H),3.73-3.87(m,3H),3.89-4.01(m,2H),4.02(s,3H),4.29(d,J=13.1Hz,2H),4.34-4.40(m,2H),4.44(d,J=11.7Hz,1H),4.61(d,J=11.7Hz,1H),4.80(s,2H),7.11(d,J=8.5Hz,1H),7.22(d,J=2.6Hz,1H),7.36(dd,J=20.2,11.5Hz,3H),7.71(d,J=8.4Hz,1H),7.86(d,J=7.2Hz,1H),9.09(s,1H).m/z(ESI):978.5[M+H]+.
实施例66(化合物93盐的合成):
合成过程参考实施例4,经制备得到黄色固体产物(7.6mg,纯度98.94%,收率9.42%)。1H NMR(500MHz,Methanol-d4)δ1.02(s,9H),1.29(brs,14H),1.42-1.48(m,2H),1.50(d,J=7.0Hz,3H),1.54-1.61(m,5H),1.92-2.00(m,1H),2.05-2.31(m,2H),2.33-2.45(m,2H),2.48(s,3H),3.06(t,J=7.4Hz,2H),3.34(s,1H),3.39-3.47(m,1H),3.55-3.64(m,1H),3.72-3.79(m,1H),3.85-3.90(m,1H),3.91-4.05(m,2H),4.18-4.25(m,1H),4.26-4.31(m,2H),4.33-4.40(m,1H),4.41-4.49(m,2H),4.56(t,J=8.4Hz,1H),4.60-4.69(m,2H),4.71-4.77(m,1H),4.97-5.04(m,1H),7.22(s,1H),7.32-7.39(m,2H),7.43(q,J=8.1Hz,4H),7.78(d,J=8.7Hz,0.5H),7.89(dd,J=9.3,5.7Hz,1H),8.54(d,J=7.5Hz,0.5H),8.93(s,1H),9.12(s,1H).m/z(ESI):1266.7[M+H]+.
实施例67(化合物94盐的合成):
合成步骤参考实施例51,最终经制备冻干得到黄色固体(17.5mg,纯度90.59%,收率33.36%)。1H NMR(500MHz,Methanol-d4)δ1.35(d,J=16.2Hz,5H),1.64(t,J=7.1Hz,1H),1.76(d,J=15.4Hz,1H),1.86(s,1H),1.96-2.11(m,3H),2.21(d,J=19.9Hz,5H),2.36(dt,J=13.5,6.3Hz,2H),2.50(dq,J=13.3,5.9,3.7Hz,2H),2.79(dt,J=14.7,5.8Hz,2H),2.90(t,J=12.7Hz,1H),3.06(s,2H),3.40(s,1H),3.48(d,J=1.6Hz,1H),3.86(d,J=13.7Hz,2H),4.02(d,J=8.1Hz,4H),4.32(d,J=10.1Hz,2H),4.36-4.43(m,1H),4.53(dd,J=33.1,11.9Hz,2H),4.62-4.76(m,3H),7.03-7.15(m,1H),7.25(d,J=3.0Hz,1H),7.33-7.44(m,3H),7.69(d,J=9.1Hz,1H),7.91(s,1H),9.12(s,1H).m/z(ESI):909.5[M+H]+.
实施例68(化合物95盐的合成):
合成步骤参考实施例51,最终得到目标化合物(4mg,纯度91.81%,收率8.5%)。1HNMR(500MHz,Methanol-d4)δ1.32(d,J=4.4Hz,4H),1.73(tt,J=12.7,7.0Hz,2H),1.96(d,J=12.8Hz,2H),2.06(d,J=6.2Hz,1H),2.16-2.21(m,3H),2.34(dd,J=13.6,6.2Hz,1H),2.48(ddd,J=22.6,11.1,5.6Hz,3H),2.74-2.82(m,2H),2.99(t,J=13.2Hz,3H),3.19(s,3H),3.40(d,J=16.9Hz,1H),4.02(s,3H),4.22(d,J=13.0Hz,3H),4.32(d,J=9.4Hz,2H),4.38(dd,J=9.2,5.2Hz,1H),4.46(s,1H),5.00(d,J=12.4Hz,2H),7.10(d,J=8.5Hz,1H),7.25(d,J=2.6Hz,1H),7.34-7.44(m,3H),7.68(d,J=8.5Hz,1H),7.91(dd,J=9.2,5.7Hz,1H),9.15(d,J=2.6Hz,1H).m/z(ESI):924.5[M+H]+.
实施例69(化合物96盐的合成):
合成步骤参考实施例4,最终得到目标产品(6mg,纯度89.0%,收率9.1%)。1H NMR(500MHz,Methanol-d4)δ1.25-1.39(m,7H),1.43(s,2H),1.66-1.80(m,2H),1.94(s,2H),2.12(d,J=9.7Hz,4H),2.30(dd,J=13.8,6.4Hz,1H),2.37-2.50(m,3H),2.69-2.78(m,2H),2.98(d,J=10.3Hz,2H),3.15(d,J=12.1Hz,3H),3.37(d,J=13.9Hz,2H),3.48(d,J=30.9Hz,1H),3.94(d,J=15.0Hz,2H),3.97-4.00(m,4H),4.16(d,J=31.8Hz,2H),4.26(s,2H),4.34(dd,J=8.2,4.5Hz,1H),4.51(s,1H),4.94(d,J=10.7Hz,2H),7.06(d,J=8.6Hz,1H),7.21(d,J=2.6Hz,1H),7.33(t,J=9.4Hz,3H),7.63(d,J=8.4Hz,1H),7.85(dd,J=9.0,5.9Hz,1H),9.10(d,J=4.1Hz,1H).m/z(ESI):992.6[M+H]+.
实施例70(化合物97盐的合成):
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合成过程参考实施例4,经制备得到黄色固体(23.2mg,纯度94.83%,收率25.29%)。1H NMR(500MHz,Methanol-d4)δ1.38-1.46(m,1H),1.62-1.85(m,9H),1.99-2.07(m,1H),2.17-2.26(m,1H),2.27-2.35(m,1H),2.40-2.50(m,1H),2.66-3.07(m,8H),3.20-3.27(m,1H),3.33-3.37(m,2H),3.51-3.75(m,5H),3.98(s,3H),4.24-4.43(m,7H),4.54-4.66(m,2H),7.06(d,J=8.7Hz,1H),7.20(s,1H),7.24-7.40(m,3H),7.62(d,J=8.6Hz,1H),7.76-7.89(m,1H),8.99(s,1H).m/z(ESI):965.4[M+H]+.
实施例71(化合物98盐的合成):
合成过程参考实施例4,经制备得到黄色固体产物(4mg,纯度95.71%,收率3.35%)。1H NMR(500MHz,Methanol-d4)δ1.03(s,9H),1.31-1.29(m,14H),1.42-1.47(m,2H),1.48-1.53(m,3H),1.54-1.62(m,2H),1.92-2.00(m,1H),2.06-2.26(m,14H),2.32-2.44(m,2H),2.48(s,3H),3.06(t,J=7.4Hz,2H),3.39-3.47(m,1H),3.54-3.63(m,1H),3.72-3.78(m,1H),3.84-3.90(m,1H),3.92-4.07(m,2H),4.18-4.39(m,5H),4.40-4.51(m,2H),4.56(t,J=8.2Hz,1H),4.60-4.69(m,2H),4.70-4.76(m,1H),4.95-5.05(m,1H),7.22(s,1H),7.31-7.39(m,2H),7.43(q,J=8.0Hz,4H),7.77(d,J=8.9Hz,0.5H),7.88(t,J=7.5Hz,1H),8.52(d,J=7.2Hz,0.5H),8.92(s,1H),9.12(s,1H).m/z(ESI):1252.6[M+H]+.
实施例72(化合物99盐的合成):
合成步骤参考实施例80,经制备得到黄色固体产物(16.6mg,纯度97.81%,收率22.58%)。1H NMR(500MHz,Methanol-d4)δ2.11(s,4H),2.15-2.28(m,4H),2.30-2.38(m,1H),2.41-2.51(m,1H),2.72-2.86(m,2H),3.01-3.10(m,1H),3.13-3.25(m,3H),3.41(s,1H),3.49(t,J=13.1Hz,1H),3.80(d,J=6.8Hz,3H),3.86-3.99(m,3H),4.06-4.14(m,1H),4.19(s,2H),4.33-4.46(m,2H),4.70-4.84(m,3H),6.98(d,J=8.6Hz,1H),7.11-7.19(m,1H),7.19-7.24(m,2H),7.34(d,J=10.8,2.6Hz,1H),7.56(d,J=8.4Hz,1H),7.70-7.82(m,1H),9.10(s,1H).m/z(ESI):852.5[M+H]+.
实施例73(化合物100盐的合成):
合成步骤参考实施例80,经制备得到黄色固体(15mg,纯度94.35%,收率31.8%)。1HNMR(500MHz,Methanol-d4)δ1.29(d,J=4.4Hz,3H),1.63-1.82(m,2H),1.99(t,J=12.4Hz,2H),2.14(d,J=30.3Hz,8H),2.26-2.36(m,1H),2.46(d,J=8.8Hz,1H),2.77(tt,J=14.4,8.5Hz,4H),2.96-3.06(m,1H),3.06-3.19(m,3H),3.26(s,1H),3.36(d,J=14.7Hz,3H),3.95(d,J=13.2Hz,2H),3.99(s,3H),4.18(s,1H),4.20(s,1H),4.27-4.40(m,3H),4.53(dd,J=36.1,17.6Hz,2H),4.71(d,J=13.3Hz,1H),4.81(s,1H),7.08(d,J=8.5Hz,1H),7.21(d,J=2.5Hz,1H),7.28-7.39(m,3H),7.65(d,J=8.4Hz,1H),7.85(dd,J=9.2,5.7Hz,1H),9.10(s,1H).m/z(ESI):964.6[M+H]+.
实施例74(化合物101的合成):
合成步骤参考实施例80,经制备得到黄色固体(31.8mg,纯度97.29%,收率32.11%)。1H NMR(500MHz,Methanol-d4)δ1.61(s,1H),1.70-1.80(m,4H),1.84-1.96(m,8H),2.06-2.16(m,3H),2.28-2.47(m,4H),2.57-2.68(m,2H),2.74-2.81(m,2H),2.93-3.05(m,4H),3.34(s,3H),3.37-3.44(m,3H),3.49-3.59(m,2H),3.61-3.77(m,5H),3.94-4.10(m,3H),4.37(s,1H),4.49-4.70(m,2H),5.53(s,1H),7.06(s,1H),7.16-7.41(m,4H),7.64(s,1H),7.82(s,1H),9.00(s,1H).m/z(ESI):1018.7[M+H]+..
实施例75(化合物102盐的合成):
合成步骤参考实施例80,最终得到目标化合物(9.6mg,5.55μmol,96.25%纯度)。1H NMR(500MHz,Methanol-d4)δ1.03-1.12(m,9H),1.29-1.51(m,14H),1.99(m,5H),2.16(m,5H),2.31(m,2H),2.49(s,3H),3.05(m,4H),3.36(m,2H),3.51(m,8H),3.67-3.85(m,4H),3.95(m,2H),4.28(d,J=10.1Hz,2H),4.45(s,1H),4.60(m,3H),4.72-4.82(m,4H),5.36(m,1H),7.21(d,J=2.5Hz,1H),7.32-7.39(m,2H),7.47(m,4H),7.89(m,1H),8.90(s,1H),9.08(s,1H).m/z(ESI+):1321.8[M+H]+.
实施例76(化合物103盐的合成):
合成步骤参照实施例4,最终得到淡黄色三氟乙酸盐固体(4mg,收率10.4%,纯度98.01%)。1H NMR(500MHz,Methanol-d4)δ1.00-1.06(m,9H),1.26-1.38(m,12H),1.50(d,J=5.0Hz,3H),1.55-1.65(m,4H),1.92-2.00(m,1H),2.07-2.40(m,10H),2.42-2.55(m,4H),3.08-3.24(m,4H),3.34-3.38(m,1H),3.72-3.78(m,1H),3.84-3.90(m,1H),3.93-4.08(m,3H),4.10-4.20(m,1H),4.25-4.32(m,2H),4.40-4.51(m,2H),4.56(d,J=10.0Hz,1H),4.60-4.65(m,1H),4.74-4.83(m,3H),4.92-5.03(m,2H),7.20-7.24(m,1H),7.32-7.39(m,2H),7.39-7.46(m,4H),7.85-7.91(m,1H),8.92(s,1H),9.08-9.15(m,1H).m/z(ESI):1210.6[M+H]+.
实施例77(化合物104盐的合成):
合成步骤参照实施例4,最终得到淡黄色三氟乙酸盐固体(7.5mg,收率13.4%,纯度96.71%)。1H NMR(500MHz,Methanol-d4)δ1.00-1.06(m,9H),1.26-1.38(m,12H),1.50(d,J=5.0Hz,3H),1.55-1.65(m,4H),1.92-2.00(m,1H),2.07-2.40(m,10H),2.42-2.55(m,4H),3.08-3.24(m,4H),3.34-3.38(m,1H),3.72-3.78(m,1H),3.84-3.90(m,1H),3.93-4.08(m,3H),4.10-4.20(m,1H),4.25-4.32(m,2H),4.40-4.51(m,2H),4.56(d,J=10.0Hz,1H),4.60-4.65(m,1H),4.74-4.83(m,3H),4.92-5.03(m,2H),7.20-7.24(m,1H),7.32-7.39(m,2H),7.39-7.46(m,4H),7.85-7.91(m,1H),8.92(s,1H),9.08-9.15(m,1H).m/z(ESI):1210.6[M+H]+.
实施例78(化合物105盐的合成):
合成步骤参考实施例4,最终得到目标化合物(10.5mg,6.07μmol,20.07%产率,96.24%纯度)。1H NMR(500MHz,Methanol-d4)δ1.05(m,9H),1.28-1.42(m,16H),1.56(s,2H),1.75(m,2H),1.96(m,1H),2.16(m,5H),2.36(m,2H),2.47(m,3H),3.00-3.06(m,2H),3.11-3.26(m,3H),3.38(m,2H),3.44-3.65(m,9H),3.75-3.84(m,2H),3.98(m,3H),4.29(m,2H),4.45(s,1H),4.56(m,1H),4.71-4.84(m,4H),5.38(m,1H),7.22(m,1H),7.32-7.39(m,2H),7.48(m,4H),7.88(dd,J=9.1,5.6Hz,1H),8.90(s,1H),9.09(s,1H).m/z(ESI+):1323.7[M+H]+.
实施例79(化合物106盐的合成):
合成步骤参考实施例4,最终得到目标化合物(11.1mg,5.52μmol,14.40%产率,93.36%)。1H NMR(500MHz,Methanol-d4)δ0.69-0.74(m,2H),0.82-0.94(m,2H),1.05(m,9H),1.21-1.37(m,18H),1.50-1.59(m,2H),1.63-1.72(m,2H),1.92-2.01(m,1H),2.17(m,5H),2.35(m,2H),2.47(m,3H),2.82(m,1H),2.98-3.13(m,5H),3.35(m,2H),3.38-3.66(m,13H),3.76-3.92(m,2H),4.01(,1H),4.22-4.34(m,2H),4.37-4.47(m,2H),4.53-4.61(m,2H),4.72-4.85(m,4H),5.39(m,1H),7.23(s,1H),7.31-7.39(m,2H),7.44-7.49(m,4H),7.89(dd,J=9.2,5.7Hz,1H),8.91(s,1H),9.07(s,1H).m/z(ESI+):1421.1[M+H]+.
实施例80(化合物107盐的合成):
步骤A:将哌啶-4-羧酸甲酯(200mg,1.40mmol,1eq)和中间体j(889.02mg,1.47mmol,1.05eq),无水碳酸钾(580.48mg,4.20mmol,3eq)溶解在无水DMF(10mL)中。将混合物在50℃下搅拌反应2小时。TLC监测原料反应完毕,反应液用饱和氯化铵溶液(40mL)中和,加水(20mL),并用乙酸乙酯(2x 30mL)萃取水层。用饱和食盐水(60mL)洗涤合并有机相,用硫酸钠干燥,过滤,并在真空中浓缩。残留物通过柱层析(SiO2,二氯甲烷/甲醇=100:0至95:5)分离纯化,得到目标产物80-1(650mg,75%收率)。
步骤B:将80-1(650mg,1.05mmol,1eq)和磷酸钾(667.72mg,3.15mmol,3eq)溶于二氧六环(15mL)和水(5mL)混合溶液中,混合物放入空气中脱气,然后加入((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)萘-1-基)乙炔基)三异丙基硅烷(645.71mg,1.26mmol,1.2eq)和甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(152.86mg,209.97μmol,0.2eq),并在氮气氛围下100℃搅拌3小时,反应完成后,向混合物中添加乙酸乙酯(40mL),分离有机相,用饱和食盐水(40mL)洗涤,并用无水硫酸钠干燥,过滤,并在真空中浓缩。残渣通过硅胶柱层析(SiO2,二氯甲烷/甲醇=100:0至97:3)纯化残余物,得到黄色固体80-2(870mg,85%收率)。
步骤C:80-2(200.00mg,0.21mmol,1.0eq)溶解在甲醇(6mL)和水(1mL)的混合溶液中,室温下加入氢氧化锂(49.42mg,2.06mmol,10eq).将混合物在50℃下搅拌反应2小时。TLC监测原料反应完毕,先将混合物浓缩除去大部分溶剂,然后冰浴下用1N HCl水溶液调溶液的PH至5左右,并用乙酸乙酯(2x 20mL)萃取水层。用盐水(40mL)洗涤合并有机相,用硫酸钠干燥,过滤,并在真空中浓缩。通过制备硅胶板(SiO2,二氯甲烷/甲醇=10:1)分离纯化残余物,得到目标产物80-3(170mg,86%收率)。
步骤D:80-3(170.00mg,0.18mmol,1.0eq)和3-(3-氟-4-(哌嗪-1-基)苯基)氨基)哌啶-2,6-二酮(65.42mg,0.21mmol,1.2eq)溶解在无水DMF(4mL)中,再加入HATU(101.51mg,0.27mmol,1.5eq)和N,N-二异丙基乙胺(115.00mg,0.89mmol,154.99μL,5eq).将混合物在室温下搅拌反应10分钟。LC-MS监测原料反应完毕,反应液用饱和氯化铵溶液(20mL)中和,加水(20mL),并用乙酸乙酯(2x 20mL)萃取水层。用饱和食盐水(40mL)洗涤合并有机相,用硫酸钠干燥,过滤,并在真空中浓缩。通过制备硅胶板(SiO2,二氯甲烷/甲醇=10:1)分离纯化残余物,得到目标产物80-4(90mg,40%收率).m/z(ESI):1244.62
[M+H]+。
步骤E:室温下,将80-4(90mg,72.37μmol,1eq)溶于四氢呋喃(2mL)中,添加TBAF(1M,361.87μL,361.87μmol,5eq),反应液在室温下搅拌2小时。LC-MS监测原料反应完毕,反应液用饱和氯化铵溶液(20mL)中和,加水(20mL),并用乙酸乙酯(2x 20mL)萃取水层。用饱和食盐水(40mL)洗涤合并有机相,用硫酸钠干燥,过滤,并在真空中浓缩。通过制备硅胶板(SiO2,二氯甲烷/甲醇=10:1)分离纯化残余物,得到目标产物80-5(65mg,82.6%收率).m/z(ESI):1087.97[M+H]+。
步骤F:80-5(65mg,59.79μmol,1eq)溶解在二氯甲烷(3mL)中,加入盐酸乙酸乙酯溶液(4M,0.6mL),反应液室温搅拌10分钟。LC-MS监测原料反应完毕且有目标产物生成,反应液直接浓缩去除溶剂,残留物使用制备HPLC(0.1%三氟醋酸/水+乙腈),得到淡黄色三氟醋酸盐固体(30mg,35.7%收率,纯度91.43%)。1H NMR(500MHz,Methanol-d6)δ0.91-0.94(m,2H),1.03(s,2H),1.97-1.98(m,1H),2.13-2.19(m,9H),2.32(d,J=12.7Hz,1H),2.73-2.87(m,2H),3.01-3.16(m,7H),3.29-3.34(m,1H),3.37-3.40(m,2H),3.79(s,4H),4.00(t,J=14.2Hz,4H),4.29-4.35(m,3H),4.48-4.63(m,2H),4.80-4.84(m,1H),6.55(d,J=8.3Hz,1H),6.60(d,J=14.4Hz,1H),6.95-6.97(m,1H),7.25(s,1H),7.36(t,J=8.9Hz,1H),7.40(s,1H),7.88-7.94(m,1H),9.13(s,1H).m/z(ESI):943.78[M+H]+。
实施例81(化合物108的合成):
合成步骤参考实施例80,最终得到淡黄色固体(35mg,62.58%收率,纯度96.35%)。1H NMR(500MHz,Methanol-d6)δ0.54(s,2H),0.76(s,2H),1.82-1.97(m,5H),2.30-2.36(m,1H),2.48-2.54(m,4H),2.65(s,5H),2.96(s,4H),3.28(s,2H),3.38(s,1H),3.61-3.65(m,2H),3.71-3.78(m,4H),4.49(s,2H),4.64(s,8H),6.48(d,J=8.7Hz,1H),6.55(d,J=14.5Hz,1H),6.85(t,J=9.0Hz,1H),7.24(s,1H),7.33-7.38(m,2H),7.89(dd,J=8.9,5.9Hz,1H),9.03(s,1H).m/z(ESI):958.6[M+H]+.
实施例82(化合物109的合成):
合成步骤参考实施例80,最终得到目标化合物(2.3mg,纯度96.66%,收率6.42%)。1H NMR(500MHz,Methanol-d4)δ0.60(s,2H),0.79(s,2H),0.90(t,J=6.9Hz,1H),1.03(t,J=7.4Hz,1H),1.36-1.45(m,3H),1.58-1.73(m,2H),1.80(d,J=13.0Hz,2H),1.87-2.06(m,6H),2.27-2.35(m,1H),2.49(s,2H),2.60(t,J=11.7Hz,2H),2.69(t,J=4.3Hz,1H),2.73(t,J=4.2Hz,1H),2.76-2.85(m,4H),3.15-3.27(m,2H),3.39(s,1H),3.78(d,J=13.1Hz,2H),3.86(s,2H),4.23(dd,J=11.8,4.8Hz,1H),4.35-4.43(m,1H),4.47-4.54(m,1H),4.58-4.73(m,3H),6.45-6.58(m,2H),6.90(t,J=9.2Hz,1H),7.21(s,1H),7.28-7.40(m,2H),7.87(dd,J=9.1,5.8Hz,1H),9.03(s,1H).m/z(ESI):929.4[M+H]+.
实施例83(化合物110的合成):
合成步骤参考实施例80,最终得到目标化合物(5.1mg,5.30μmol,10.07%产率,93.56%纯度)。1H NMR(500MHz,Methanol-d4)δ9.10(s,1H),7.89(d,J=8.1Hz,1H),7.43-7.29(m,2H),7.22(s,1H),7.02(d,J=9.7Hz,1H),6.62-6.49(m,2H),4.62(d,J=12.1Hz,1H),4.45(d,J=12.2Hz,1H),4.28(d,J=10.6Hz,3H),3.95(dd,J=23.8,14.3Hz,2H),3.72(dd,J=44.8,11.6Hz,3H),3.43(d,J=16.9Hz,3H),3.17(s,2H),3.04(s,4H),2.80(d,J=13.8Hz,1H),2.72(d,J=18.0Hz,1H),2.29(s,1H),2.17(d,J=17.7Hz,4H),2.03(s,4H),1.89(s,2H),1.78(s,2H),1.61(s,3H),1.02(d,J=13.3Hz,3H),0.89(d,J=14.5Hz,3H).m/z(ESI+):900.4[M+H]+.
实施例84(化合物111的合成):
合成步骤参考实施例80,经制备得到黄色固体(10.5mg,纯度96.23%,收率11.45%)。1H NMR(500MHz,Methanol-d4)δ0.51(s,2H),0.72(s,2H),0.90(t,J=6.8Hz,1H),1.03(t,J=7.4Hz,1H),1.30(s,3H),1.42(d,J=7.5Hz,1H),1.52(s,1H),1.66(s,4H),1.74(t,J=9.5Hz,4H),1.79-1.91(m,6H),1.91-1.98(m,3H),2.03(d,J=8.1Hz,4H),2.09-2.15(m,2H),2.31(dd,J=13.5,6.2Hz,1H),2.38-2.55(m,3H),2.69-2.79(m,3H),3.20-3.27(m,1H),3.38(s,2H),3.54(s,2H),3.70(dd,J=26.6,11.0Hz,4H),4.01(s,3H),4.35(dd,J=9.2,5.1Hz,1H),4.42(s,2H),4.60(s,3H),7.10(d,J=8.5Hz,1H),7.23(d,J=2.6Hz,1H),7.31(d,J=8.9Hz,1H),7.35(dd,J=5.8,3.2Hz,2H),7.65(d,J=8.4Hz,1H),7.86(dd,J=9.1,5.6Hz,1H),9.00(s,1H).m/z(ESI):1087.8[M+H]+.
实施例85(化合物112的合成):
合成过程参考实施例80,经制备得到黄色固体产物(15.7mg,纯度96.38%,收率21.71%)。1H NMR(500MHz,Methanol-d4)δ0.52(s,2H),0.72(s,2H),1.03(t,J=7.4Hz,2H),1.41-1.44(m,1H),1.56-1.60(m,2H),1.63-1.68(m,4H),1.78-1.90(m,7H),1.91-1.97(m,2H),1.99-2.06(m,2H),2.27-2.34(m,1H),2.39-2.49(m,4H),2.67-2.78(m,4H),3.05(d,J=11.0Hz,2H),3.21-3.26(m,2H),3.36(s,1H),3.64-3.75(m,4H),4.01(s,3H),4.32-4.40(m,2H),4.43-4.48(m,1H),4.56(d,J=12.7Hz,1H),4.64(d,J=12.6Hz,1H),7.08(d,J=8.5Hz,1H),7.21(d,J=2.6Hz,1H),7.28-7.38(m,3H),7.64(d,J=8.5Hz,1H),7.85(dd,J=9.2,5.7Hz,1H),9.00(s,1H).m/z(ESI):975.8[M+H]+.
实施例86(化合物113的合成):
合成过程参考实施例80,经制备得到黄色固体产物(11.6mg,纯度95.92%,收率32.11%)。1H NMR(500MHz,Methanol-d4)δ0.52(s,2H),0.73(s,2H),1.03(t,J=7.4Hz,2H),1.42(q,J=7.5Hz,1H),1.57-1.70(m,3H),1.77-1.92(m,10H),1.97(t,J=11.7Hz,2H),2.27-2.34(m,1H),2.36-2.48(m,5H),2.66-2.82(m,3H),3.04-3.11(m,2H),3.19-3.25(m,2H),3.38(s,1H),3.70(dd,J=22.9,10.6Hz,4H),4.01(s,3H),4.32-4.41(m,2H),4.48-4.52(m,1H),4.55-4.60(m,1H),4.62-4.69(m,1H),7.06(d,J=8.5Hz,1H),7.21(d,J=2.6Hz,1H),7.26-7.35(m,3H),7.63(d,J=8.5Hz,1H),7.83(dd,J=9.2,5.7Hz,1H),9.00(s,1H).m/z(ESI):935.7[M+H]+.
实施例87(化合物114的合成):
合成过程参考实施例80,经制备得到黄色固体产物(10.5mg,纯度86.57%,收率17.31%)。1H NMR(500MHz,Methanol-d4)δ1.30(s,5H),1.59(d,J=13.2Hz,2H),1.65(s,3H),1.73(s,1H),1.84(s,2H),1.88-1.90(m,2H),1.95(d,J=4.4Hz,2H),2.03(d,J=6.5Hz,2H),2.14(s,2H),2.22(d,J=9.2Hz,2H),2.30(dd,J=11.4,6.6Hz,2H),2.53(d,J=11.0Hz,2H),2.68-2.74(m,1H),2.85(s,4H),3.25(d,J=9.2Hz,2H),3.51(s,2H),3.58(s,2H),3.70-3.77(m,4H),4.28(dd,J=11.9,4.8Hz,1H),4.60(s,6H),5.20(d,J=14.8Hz,2H),6.43-6.55(m,2H),7.03(t,J=8.6Hz,1H),7.21(d,J=2.5Hz,1H),7.29-7.39(m,2H),7.86(dd,J=9.1,5.7Hz,1H),9.01(s,1H).m/z(ESI):1011.8[M+H]+.
实施例88(化合物115的合成):
合成过程参考实施例80,经制备得到黄色固体产物(10mg,纯度87.3%,收率33.45%)。1H NMR(500MHz,Methanol-d4)δ0.51(s,2H),0.72(s,2H),0.90(s,2H),1.30(s,4H),1.56-1.65(m,2H),1.87(s,2H),2.00-2.04(m,2H),2.20(d,J=7.1Hz,3H),2.45(q,J=12.7Hz,5H),2.74(d,J=16.8Hz,3H),2.81-2.88(m,2H),2.96(t,J=12.5Hz,2H),3.37(s,1H),3.68(s,1H),3.69-3.76(m,2H),4.00(d,J=12.9Hz,2H),4.37(d,J=10.9Hz,1H),4.49(d,J=10.9Hz,1H),4.59(s,2H),4.65(d,J=12.4Hz,1H),5.03-5.09(m,1H),7.16-7.23(m,2H),7.28-7.37(m,3H),7.65(d,J=8.6Hz,1H),7.85(dd,J=9.1,5.7Hz,1H),9.00(s,1H).m/z(ESI):966.6[M+H]+.
实施例89(化合物116的合成):
合成过程参考实施例80,经制备得到黄色固体产物(27mg,纯度82%,收率31.69%)。1H NMR(500MHz,DMSO-d6)δ0.41(s,2H),0.65(s,2H),0.85(t,J=6.7Hz,2H),0.93(t,J=7.3Hz,1H),1.23(s,4H),1.35(s,2H),1.45(s,1H),1.65(s,3H),1.96-2.03(m,4H),2.34(d,J=17.2Hz,4H),2.43(s,1H),2.62(d,J=17.9Hz,2H),2.85-2.92(m,1H),3.19(s,2H),3.41(s,4H),3.53(s,3H),3.92(s,1H),4.29(s,2H),4.47(d,J=12.1Hz,1H),7.16(d,J=2.5Hz,1H),7.23(d,J=9.0Hz,1H),7.31-7.40(m,2H),7.45(t,J=9.0Hz,1H),7.67(d,J=8.4Hz,1H),7.96(dd,J=9.2,6.1Hz,1H),9.02(s,1H).m/z(ESI):994.6[M+H]+.
实施例90(化合物117的合成):
合成过程参考实施例80,经制备得到黄色固体产物(20mg,纯度85%,收率24.78%)。1H NMR(500MHz,DMSO-d6)δ0.45(s,2H),0.68(d,J=4.1Hz,2H),1.23(s,2H),1.65(d,J=10.4Hz,4H),2.00(dd,J=11.8,6.5Hz,2H),2.38(d,J=3.5Hz,2H),2.56(d,J=4.7Hz,5H),2.88(ddd,J=17.8,14.2,5.4Hz,2H),3.41(d,J=5.3Hz,4H),3.54(d,J=11.6Hz,3H),3.62(d,J=11.9Hz,1H),3.92(s,1H),4.25-4.33(m,3H),4.47(d,J=12.0Hz,1H),7.14(d,J=2.5Hz,1H),7.22(d,J=9.2Hz,1H),7.29-7.38(m,2H),7.44(t,J=9.0Hz,1H),7.66(d,J=8.5Hz,1H),7.95(dd,J=9.3,5.9Hz,1H),9.02(s,1H).m/z(ESI):868.6[M+H]+.
实施例91(化合物118的合成):
合成过程参考实施例80,经制备得到黄色固体(4.9mg,纯度90.13%,收率7.2%)。1HNMR(500MHz,Methanol-d4)δ0.45-0.54(m,2H),0.66-0.75(m,2H),1.60-1.72(m,2H),1.74-1.98(m,6H),2.02-2.22(m,3H),2.26-2.56(m,10H),2.66-2.78(m,4H),2.97(t,J=12.5Hz,1H),3.04-3.22(m,2H),3.38(s,1H),3.62-3.69(m,3H),3.73(d,J=12.6Hz,1H),4.00(s,3H),4.30-4.39(m,2H),4.52(t,J=11.4Hz,2H),4.65(d,J=12.9Hz,2H),7.07(d,J=8.5Hz,1H),7.21(s,1H),7.32(dd,J=18.3,4.6Hz,3H),7.64(d,J=8.4Hz,1H),7.79-7.89(m,1H),8.99(s,1H).m/z(ESI):1018.7[M+H]+.
实施例92(化合物120的合成):
合成过程参考实施例4和实施例80,经制备得到黄色固体产物(16mg,纯度90.67%,收率27.85%)。1H NMR(500MHz,Methanol-d4)δ1.90(d,J=30.9Hz,6H),2.26-2.38(m,3H),2.51(s,3H),2.59(s,2H),2.73-2.82(m,3H),3.10(d,J=11.0Hz,2H),3.64(d,J=7.0Hz,4H),3.78(s,2H),4.03(s,3H),4.15(s,2H),4.30-4.40(m,3H),4.46-4.54(m,2H),4.62(s,6H),7.12(d,J=8.5Hz,1H),7.22(d,J=2.5Hz,1H),7.36(dd,J=11.9,9.1Hz,3H),7.66(d,J=8.4Hz,1H),7.88(dd,J=9.1,5.7Hz,1H),8.80(s,1H).m/z(ESI):950.7[M+H]+.
实施例93(化合物124盐的合成):
化合物的合成过程参考实施例80的合成步骤,最后得到三氟醋酸盐(38mg,51.99%收率)。1H NMR(500MHz,Methanol-d4)δ0.94-0.99(m,2H),1.01-1.04(m,2H),1.98(qd,J=12.4,4.7Hz,1H),2.14-2.16(m,4H),2.29-2.37(m,1H),2.72-2.80(m,1H),2.80-2.89(m,1H),3.25(s,2H),3.37-3.46(m,4H),3.51(dd,J=13.6,4.2Hz,1H),3.90(d,J=9.5Hz,1H),4.00(dd,J=28.0,14.0Hz,3H),4.26-4.31(m,3H),4.52(d,J=12.0Hz,1H),4.62(d,J=12.0Hz,1H),4.83-4.90(m,4H),6.47(d,J=8.6Hz,1H),6.57(d,J=14.3Hz,1H),6.87(t,J=9.1Hz,1H),7.26(s,1H),7.36(t,J=8.9Hz,1H),7.42(s,1H),7.92(dd,J=8.9,5.8Hz,1H),9.14(s,1H).m/z(ESI):832.5[M+H]+.
实施例94(化合物125盐的合成):
合成步骤参考实施例80,得到淡黄色固体(26mg,35.79%收率,纯度98.46%)。1HNMR(500MHz,Methanol-d6)δ0.84-0.95(m,2H),1.09-1.12(m,2H),2.00-2.30(m,14H),2.79-2.89(m,2H),3.21(d,J=10.8Hz,1H),3.27(d,J=9.5Hz,1H),3.39-3.43(m,1H),3.50-3.70(m,5H),3.90(s,1H),4.04(d,J=9.3Hz,2H),4.09-4.20(m,1H),4.24-4.41(m,4H),4.65-4.68(m,1H),5.07(d,J=10.4Hz,1H),6.51-6.59(m,1H),6.59-6.68(m,1H),7.25(s,1H),7.34(dd,J=21.9,8.6Hz,2H),7.40(d,J=1.6Hz,1H),7.89(dd,J=8.5,6.0Hz,1H),9.10(s,1H).m/z(ESI):886.7[M+H]+.
实施例95(化合物126盐的合成):
合成步骤参考实施例80,得到淡黄色固体(45mg,61.96%收率,纯度95.18%)。1HNMR(500MHz,Methanol-d6)δ0.94(s,2H),1.05-1.06(m,2H),2.15-2.25(m,5H),2.33-2.35(m,1H),2.75(d,J=16.1Hz,1H),2.82-2.92(m,1H),3.38(d,J=13.7Hz,2H),3.43(s,1H),3.51(d,J=13.6Hz,2H),3.57(s,5H),3.75-3.86(m,7H),3.95(d,J=14.0Hz,1H),4.03(d,J=13.7Hz,1H),4.31(d,J=12.5Hz,2H),4.45(s,2H),4.47(d,J=12.0Hz,1H),4.63(d,J=11.6Hz,1H),4.82-4.90(m,4H),7.25(s,1H),7.37(t,J=8.9Hz,1H),7.41(s,1H),7.53(d,J=8.5Hz,1H),7.91(dd,J=8.7,6.1Hz,1H),8.03(d,J=8.6Hz,1H),8.42(s,1H),9.12(s,1H).m/z(ESI):969.7[M+H]+.
实施例96(化合物127盐的合成):
合成步骤参考实施例80,得到淡黄色固体(24mg,33.75%收率,纯度90.62%)。1HNMR(500MHz,Methanol-d6)δ0.87-0.97(m,2H),1.00-1.03(m,2H),1.58(s,2H),1.84(s,4H),2.02(d,J=14.8Hz,2H),2.13-2.22(m,5H),2.69-2.83(m,2H),2.84-2.95(m,1H),3.20(t,J=12.9Hz,2H),3.27(d,J=13.7Hz,1H),3.38-3.51(m,7H),3.71(d,J=12.7Hz,1H),3.80(d,J=11.9Hz,1H),3.96(d,J=14.0Hz,1H),4.05(d,J=13.9Hz,1H),4.31(d,J=12.9Hz,2H),4.51(d,J=11.8Hz,1H),4.62(d,J=12.0Hz,1H),4.82(s,2H),5.10(dd,J=12.6,5.4Hz,1H),7.19(d,J=8.5Hz,1H),7.27(s,1H),7.32(s,1H),7.36(d,J=8.9Hz,1H),7.43(s,1H),7.69(d,J=8.5Hz,1H),7.92(dd,J=8.9,5.8Hz,1H),9.13(s,1H).m/z(ESI):936.6[M+H]+.
实施例97(化合物122的合成):
合成步骤参考实施例80,得到白色固体。1H NMR(500MHz,DMSO-d6)δ0.44(s,2H),0.66(s,2H),1.46(s,9H),1.68-1.80(m,6H),1.85(s,2H),2.08-2.19(m,3H),2.30-2.39(m,5H),2.45(s,2H),2.57-2.69(m,3H),2.91(d,J=10.0Hz,2H),3.14(s,2H),3.41-3.44(m,4H),3.52-3.69(m,5H),3.94(s,3H),3.98(s,1H),4.27-4.34(m,5H),4.56(d,J=10.0Hz,1H),5.36(s,2H),7.01(d,J=5.0Hz,1H),7.36(s,1H),7.39(s,1H),7.54(t,J=10.0Hz,1H),7.59(d,J=10.0Hz,1H),7.73(s,1H),8.09(dd,J=10.0,5.0Hz,1H),9.08(s,1H),10.88(s,1H).m/z(ESI):1122.9[M+H]+.
实施例98(化合物128的合成):
合成步骤参考实施例80,得到白色固体。1H NMR(500MHz,DMSO-d6)δ0.42(s,2H),0.65(s,2H),1.55-1.64(m,4H),1.67-1.80(m,4H),2.10-2.17(m,2H),2.31-2.37(m,5H),2.40-2.48(m,4H),2.57-2.67(m,4H),2.91(d,J=10.0Hz,2H),3.14(s,2H),3.50-3.61(m,6H),3.95(s,3H),4.29-4.34(m,3H),4.34-4.41(m,2H),6.32(s,2H),6.46(s,1H),6.87(s,1H),7.02(d,J=5.0Hz,1H),7.40(s,1H),7.59(d,J=5.0Hz,1H),9.02(s,1H),10.88(s,1H).m/z(ESI):987.7[M+H]+.
实施例99(化合物129的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,DMSO-d6)δ0.39(s,2H),0.59-0.66(m,2H),1.20-1.25(m,3H),1.30-1.37(m,1H),1.53(s,4H),1.65(s,3H),1.69-1.83(m,6H),1.86-1.94(m,2H),2.12-2.19(m,1H),2.20-2.28(m,3H),2.31-2.38(m,2H),2.55-2.69(m,4H),2.92-3.01(m,5H),3.51-3.55(m,6H),3.61-3.66(m,2H),3.92-3.97(m,5H),4.22-4.34(m,4H),4.38-4.51(m,2H),7.02(d,J=10.0Hz,1H),7.18(s,1H),7.37(s,1H),7.40-7.48(m,2H),7.58(d,J=5.0Hz,1H),7.95(dd,J=10.0,5.0Hz,1H),9.01(s,1H).m/z(ESI):1046.9[M+H]+.
实施例100(化合物133的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.52(s,2H),0.72(s,2H),1.21-1.27(m,2H),1.31-1.34(m,2H),1.38-1.46(m,1H),1.58-1.68(m,2H),1.74-1.80(m,3H),1.86-1.89(m,4H),1.95-2.03(m,2H),2.06-2.13(m,2H),2.24(d,J=5.0Hz,2H),2.31-2.37(m,1H),2.40-2.53(m,3H),2.66-2.81(m,3H),3.01-3.07(m,2H),3.08-3.15(m,2H),3.21-3.26(m,1H),3.37(s,1H),3.64-3.75(m,4H),4.00(s,3H),4.32-4.41(m,2H),4.44-4.48(m,1H),4.57(d,J=10.0Hz,1H),4.64(d,J=15.0Hz,1H),7.08(d,J=10.0Hz,1H),7.21(s,1H),7.28-7.35(m,3H),7.84(dd,J=10.0,5.0Hz,1H),9.00(s,1H).m/z(ESI):949.8[M+H]+.
实施例101(化合物134盐的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.93-0.94(m,4H),2.12-2.19(m,5H),2.33-2.38(m,2H),2.76(d,J=16.9Hz,1H),2.86-2.91(m,1H),3.48-3.68(m,14H),3.94(s,1H),4.07(s,1H),4.22(s,2H),4.31(d,J=18.3Hz,4H),4.63(s,4H),7.25-7.38(m,5H),7.87-8.34(m,2H),9.12(s,1H).m/z(ESI):912.7[M+H]+.
实施例102(化合物135的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.59(s,2H),0.79(s,2H),1.32(s,4H),1.65-1.66(m,1H),1.84(d,J=13.9Hz,4H),1.89(s,2H),2.15-2.16(m,2H),2.27(d,J=6.5Hz,2H),2.63(s,7H),2.71-2.76(m,2H),2.86-2.92(m,1H),3.23-3.24(m,2H),3.37(s,1H),3.40(s,1H),3.70(s,2H),3.75(d,J=13.0Hz,2H),4.41(d,J=11.1Hz,1H),4.50(d,J=11.1Hz,1H),4.60(d,J=12.6Hz,1H),4.67(d,J=12.2Hz,2H),5.13(dd,J=12.4,5.3Hz,1H),7.24(s,1H),7.30-7.36(m,2H),7.37(s,1H),7.40(d,J=7.1Hz,1H),7.69(t,J=7.8Hz,1H),7.88(dd,J=8.8,5.7Hz,1H),9.04(s,1H).m/z(ESI):965.7[M+H]+.
实施例103(化合物136的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.52(d,J=4.8Hz,2H),0.72(d,J=4.2Hz,2H),1.23(d,J=11.3Hz,2H),1.29(s,4H),1.63(d,J=36.9Hz,2H),1.73-1.89(m,6H),1.98(t,J=11.9Hz,2H),2.22(d,J=7.2Hz,2H),2.30(ddd,J=12.1,5.8,3.0Hz,1H),2.46(q,J=12.7Hz,2H),2.56(t,J=5.0Hz,4H),2.71(ddd,J=17.8,4.9,2.6Hz,1H),2.83(ddd,J=18.5,13.5,5.5Hz,1H),3.10(t,J=10.7Hz,2H),3.37(d,J=7.1Hz,5H),3.70(dd,J=25.7,11.0Hz,4H),4.38(d,J=11.0Hz,1H),4.46(d,J=11.0Hz,1H),4.57(d,J=12.5Hz,1H),4.64(d,J=12.6Hz,1H),4.77-4.81(m,1H),7.21(d,J=2.5Hz,1H),7.29-7.37(m,3H),7.85(dd,J=9.1,5.7Hz,1H),7.92(d,J=8.8Hz,1H),8.29(d,J=2.8Hz,1H),9.00(s,1H).m/z(ESI):940.7[M+H]+.
实施例104(化合物137盐的合成):
合成步骤参考实施例4,得到白色固体。1H NMR(500MHz,CD3OD)δppm 9.11-8.98(m,1H),7.87-7.75(m,1H),7.64-7.51(m,1H),7.37-7.17(m,4H),7.05-6.90(m,1H),4.81-4.60(m,2H),4.41-4.13(m,5H),4.00-3.87(m,5H),3.60-3.43(m,2H),3.25-3.00(m,4H),2.97-2.29(m,12H),2.15(d,J=18.0Hz,4H),1.95-1.53(m,4H),1.32(s,2H),1.10(d,J=9.7Hz,5H),0.88-0.67(m,4H).+03.00m/z(ESI):1007.8[M+H]+.
实施例105(化合物138的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.49(s,2H),0.69(s,2H),1.31-1.35(m,1H),1.71-1.88(m,8H),2.08-2.21(m,2H),2.27-2.37(m,1H),2.40-2.52(m,2H),2.53-2.61(m,3H),2.64-2.69(m,1H),2.71-2.84(m,4H),2.87-3.03(m,3H),3.09-3.25(m,2H),3.37(s,1H),3.41-3.48(m,1H),3.59-3.69(m,6H),3.72-3.78(m,1H),3.97(d,J=10.0Hz,3H),4.27-4.39(m,2H),4.46-4.61(m,3H),7.00(d,J=8.3Hz,1H),7.22(d,J=2.6Hz,1H),7.24-7.34(m,3H),7.82(d,J=5.0Hz,1H),8.95(d,J=15.0Hz,1H).m/z(ESI):1004.8[M+H]+.
实施例106(化合物139的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.49(m,2H),0.68-0.82(m,2H),1.03(td,J=7.4,2.6Hz,4H),1.30-1.32(m,2H),1.42(m,2H),1.66(m,2H),1.78-1.94(m,6H),2.07(m,1H),2.16-2.26(m,1H),2.32(m,1H),2.46(m,2H),2.58-2.68(m,2H),2.69-2.82(m,3H),2.99-3.12(m,2H),3.19-3.27(m,3H),3.73(m,3H),4.00(m,3H),4.23(m,1H),4.35(m,1H),4.61(m,4H),4.68-4.82(m,2H),4.86(m,2H),7.06(m,1H),7.16-7.36(m,4H),7.61(m,1H),7.83(m,1H),8.99(m,1H).m/z(ESI):971.7[M+H]+.
实施例107(化合物140的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.61(s,2H),0.79(s,2H),1.03(t,J=7.5Hz,1H),1.30(m,4H),1.37-1.46(m,4H),1.61-1.68(m,2H),1.73-1.76(m,2H),1.80–1.83(m,3H),1.86-1.95(m,3H),2.29-2.39(m,2H),2.52(m,2H),2.65-2.75(m,2H),2.78-2.84(m,1H),3.22(m,2H),3.71(m,3H),4.23(dd,J=11.8,4.7Hz,1H),4.36(m,1H),4.58(m,6H),6.41-6.64(m,2H),6.89(m,1H),7.21(m,1H),7.28-7.38(m,2H),7.85(dd,J=9.1,5.8Hz,1H),9.02(s,1H).m/z(ESI):914.7[M+H]+.
实施例108(化合物141的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,DMSO-d6)δ0.40(s,2H),0.64(s,2H),0.84(d,J=7.3Hz,1H),1.06(d,J=12.4Hz,2H),1.23(s,6H),1.49(d,J=16.0Hz,2H),1.69(s,3H),1.84(s,2H),1.93-2.08(m,2H),2.14(d,J=7.1Hz,2H),2.29(dd,J=13.7,6.6Hz,2H),2.59-2.67(m,1H),2.82-3.02(m,4H),3.21(d,J=5.6Hz,3H),3.57-3.68(m,4H),3.94(d,J=2.5Hz,1H),4.22-4.31(m,3H),4.50(d,J=12.3Hz,1H),5.10(d,J=8.6Hz,1H),7.17(d,J=2.9Hz,1H),7.39(d,J=2.9Hz,1H),7.41-7.49(m,2H),7.72(dd,J=11.4,2.6Hz,1H),7.97(t,J=7.5Hz,1H),9.03(s,1H),10.17(s,1H),11.11(s,1H).m/z(ESI):984.7[M+H]+.
实施例109(化合物142的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.54(s,2H),0.76(s,2H),0.94(m,1H),1.06(m,1H),1.37(m,3H),1.58-1.72(m,3H),1.78-1.96(m,6H),1.98-2.09(m,3H),2.47(s,2H),2.70-2.84(m,4H),2.95-3.01(m,4H),3.22(m,2H),3.67-3.78(m,4H),4.37-4.54(m,2H),6.22-6.47(m,1H),6.50-6.67(m,1H),6.90(m,1H),7.24(m,1H),7.32-7.47(m,2H),7.88(dd,J=9.1,5.7Hz,1H),9.03(s,1H).m/z(ESI):915.7[M+H]+.
实施例110(化合物143的合成):
合成步骤参考实施例4,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.83(dd,J=7.0,1.6Hz,3H),0.87-0.93(m,2H),0.95(dd,J=6.7,2.6Hz,6H),1.06(m,2H),1.43(m,4H),1.60(m,4H),1.70(m,4H),1.79-2.00(m,4H),2.11(d,J=12.4Hz,2H),2.24(m,1H),2.35-2.46(m,1H),2.55(m,2H),2.65(m,1H),2.83-2.91(m,2H),3.27(m,3H),3.40(s,1H),3.73(m,4H),3.90(m,1H),4.06(m,1H),4.59(d,J=12.6Hz,1H),4.67(d,J=12.6Hz,1H),5.45-5.71(m,1H),7.23(m,1H),7.32-7.41(m,2H),7.87(dd,J=9.1,5.6Hz,1H),9.03(s,1H).m/z(ESI):810.8[M+H]+.
实施例111(化合物144盐的合成):
合成步骤参考实施例80,得到白色固体。1H NMR(500MHz,CD3OD)δppm 9.09(s,1H),7.72(s,1H),7.64(s,1H),7.49-7.06(m,4H),7.05-6.78(m,1H),4.85-4.43(m,2H),4.43-4.11(m,4H),4.10-3.78(m,4H),3.73-3.38(m,6H),3.24-3.08(m,1H),3.01-2.67(m,2H),2.54-2.42(m,1H),2.40-1.94(m,7H),1.67-1.55(m,1H),1.41-1.11(m,11H),1.05-0.80(m,4H).m/z(ESI):921.7[M+H]+.
实施例112(化合物145的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,CD3OD)δppm 9.00(s,1H),8.27(s,1H),8.00-7.79(m,2H),7.43-7.27(m,3H),7.18(s,1H),4.79-4.62(m,2H),4.60-4.50(m,1H),4.48-4.37(m,1H),4.18-3.93(m,2H),3.82(s,2H),3.69-3.42(m,1H),3.36(s,4H),2.87-2.69(m,5H),2.62-2.45(m,2H),2.40-2.10(m,2H),2.06-1.89(m,4H),1.62(s,1H),0.90(s,1H),0.76(s,2H),0.56(s,2H).m/z(ESI):843.7[M+H]+.
实施例113(化合物146盐的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.90-0.97(m,2H),1.03-1.07(m,2H),1.32(s,4H),1.81(s,2H),2.15-2.20(m,11H),2.53(dt,J=13.1,8.8Hz,1H),2.81-2.85(m,1H),2.90-3.00(m,1H),3.09-3.15(m,6H),3.26(d,J=12.1Hz,1H),3.47(d,J=13.3Hz,1H),3.52(s,1H),3.75(s,2H),3.92-3.97(m,2H),4.06-4.08(m,2H),4.32(d,J=14.2Hz,2H),4.41-4.48(m,1H),4.49-4.57(m,2H),4.65(d,J=11.3Hz,1H),5.18(dd,J=13.2,4.9Hz,1H),7.27(s,1H),7.34-7.43(m,2H),7.48(d,J=7.3Hz,1H),7.54(s,1H),7.81(d,J=7.8Hz,1H),7.87-7.96(m,1H),9.12(s,1H).m/z(ESI):950.8[M+H]+.
实施例114(化合物147的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.77(s,2H),0.93(s,2H),1.32(s,2H),1.54-1.70(m,4H),1.81-2.10(m,10H),2.36-2.41(m,3H),2.45-2.53(m,1H),2.74-2.84(m,5H),2.95-3.05(m,3H),3.15-3.26(m,1H),3.42(s,1H),3.55-3.65(m,2H),3.77(s,4H),4.00-4.10(m,4H),4.38-4.42(m,1H),4.43-4.56(m,2H),7.05(d,J=8.3Hz,1H),7.23(s,1H),7.32(s,2H),7.66(d,J=8.1Hz,1H),7.80-7.85(m,1H),8.56(s,1H),9.07(s,1H).m/z(ESI):977.8[M+H]+.
实施例115(化合物148的合成):
合成步骤参考实施例110,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.76-0.80(m,3H),0.87-0.92(m,6H),1.03(t,J=5.0Hz,3H),1.38-1.45(m,2H),1.59-1.69(m,4H),1.76-1.82(m,1H),1.84-1.91(m,2H),2.03-2.11(m,2H),2.15-2.22(m,1H),2.39-2.46(m,1H),2.67-2.73(m,1H),2.75-2.80(m,2H),2.87-2.96(m,2H),3.15-3.27(m,4H),3.37(s,1H),3.41-3.47(m,2H),3.51-3.58(m,2H),3.60-3.69(m,4H),3.83-3.91(m,1H),4.00-4.09(m,1H),5.55(s,1H),7.20(s,1H),7.29-7.37(m,2H),7.86(dd,J=10.0,5.0Hz,1H),9.01(s,1H).m/z(ESI):812.7[M+H]+.
实施例116(化合物149的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.83(s,2H),0.97(s,2H),1.32(s,1H),1.69-1.75(m,5H),1.86-2.21(m,11H),2.32-2.38(m,1H),2.48-2.53(m,1H),2.75-2.91(m,6H),3.03(s,2H),3.13(d,J=15.0Hz,1H),3.47(s,1H),3.52(d,J=10.5Hz,2H),3.70-3.74(m,2H),3.86(t,J=12.0Hz,2H),3.96(s,2H),4.06(s,3H),4.40(dd,J=8.7,4.9Hz,1H),4.47(d,J=11.7Hz,1H),4.56(d,J=11.6Hz,1H),4.70-4.74(m,2H),7.11(d,J=8.3Hz,1H),7.25(s,1H),7.34-7.37(m,2H),7.40(s,1H),7.73(d,J=8.3Hz,1H),7.84-7.91(m,1H),9.10(s,1H).m/z(ESI):963.8[M+H]+.
实施例117(化合物150盐的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,CD3OD)δ9.05(s,1H),8.46(s,1H),7.87(dd,J=9.2,5.7Hz,1H),7.37-7.29(m,2H),7.20(d,J=2.7Hz,1H),6.90(t,J=9.0Hz,1H),6.58-6.42(m,2H),4.71-4.52(m,3H),4.35(d,J=11.8Hz,1H),4.23(dd,J=11.8,4.8Hz,1H),3.97-3.71(m,4H),3.46-3.35(m,2H),3.21-2.88(m,8H),2.86-2.65(m,3H),2.65-2.47(m,3H),2.38-2.23(m,1H),2.19-2.00(m,2H),1.99-1.81(m,9H),1.80-1.67(m,2H),1.36-1.23(m,2H),0.93(s,2H),0.79(s,2H).m/z(ESI):955.6[M+H]+.
实施例118(化合物151的合成):
合成步骤参考实施例80,得到灰色固体。1H NMR(500MHz,Methanol-d4)δ0.91(d,J=6.2Hz,2H),1.02(d,J=10.3Hz,2H),1.29(d,J=4.3Hz,9H),1.37(dd,J=6.7,4.2Hz,3H),1.61(d,J=6.9Hz,1H),2.03(d,J=6.3Hz,4H),2.17(dd,J=16.2,8.4Hz,6H),2.35(t,J=7.4Hz,1H),2.47-2.53(m,1H),2.79(d,J=17.6Hz,1H),2.92-2.96(m,2H),3.19-3.25(m,2H),3.41-3.45(m,2H),3.53-3.59(m,1H),3.73(dd,J=11.9,7.0Hz,2H),3.89(d,J=17.0Hz,2H),4.01(s,1H),4.29(d,J=13.9Hz,2H),4.52(d,J=11.2Hz,2H),4.78-4.85(m,2H),5.17(dd,J=13.2,5.4Hz,1H),7.22(d,J=2.6Hz,1H),7.34-7.39(m,2H),7.65(d,J=8.1Hz,1H),7.70(s,1H),7.81(t,J=7.7Hz,1H),7.89(dd,J=9.2,5.5Hz,1H),9.08(s,1H).m/z(ESI):975.46[M+H]+.
实施例119(化合物152盐的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,DMSO-d6)δ0.41(s,2H),0.64(s,2H),1.23(s,6H),1.39-1.58(m,6H),1.73(s,4H),1.88(d,J=9.3Hz,2H),1.95-2.08(m,2H),2.24-2.42(m,9H),2.56-2.73(m,3H),2.87(t,J=8.7Hz,2H),3.93(s,2H),4.21-4.37(m,3H),4.52(d,J=12.5Hz,1H),5.10(dd,J=12.9,5.5Hz,1H),7.17(s,1H),7.36-7.52(m,3H),7.72(d,J=11.4Hz,1H),7.97(dd,J=9.1,6.0Hz,1H),8.22(s,2H),9.04(s,1H),11.12(s,1H).m/z(ESI):1008.43[M+H]+.
实施例120(化合物153盐的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.83-1.11(m,4H),1.90-1.99(m,1H),2.02-2.22(m,8H),2.27(m,2H),2.48-2.60(m,1H),2.72(m,2H),2.81-2.95(m,1H),2.97-3.11(m,2H),3.14-3.28(m,4H),3.42(m,2H),3.57(m,2H),3.71-3.79(m,1H),3.81-4.05(m,6H),4.29(d,J=14.6Hz,2H),4.42-4.68(m,2H),4.76-4.86(m,4H),5.10-5.22(m,1H),7.23(s,1H),7.32-7.44(m,3H),7.51(d,J=7.2Hz,1H),7.76(m,1H),7.89(m,1H),9.09(s,1H).m/z(ESI):991.8[M+H]+.
实施例121(化合物154盐的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.89(m,2H),1.02(m,2H),1.96(m,1H),2.02-2.25(m,9H),2.27(d,J=8.8Hz,2H),2.54(m,1H),2.66-2.80(m,2H),2.88(m,1H),3.04(m,2H),3.23(m,4H),3.40(m,4H),3.72-4.04(m,4H),4.29(m,2H),4.45(m,1H),4.56(m,1H),4.74-4.87(m,6H),5.10(dd,J=12.6,5.4Hz,1H),7.23(m,1H),7.32-7.43(m,3H),7.47(s,1H),7.76(d,J=8.5Hz,1H),7.89(m,1H),9.09(s,1H).m/z(ESI):991.8[M+H]+.
实施例122(化合物155盐的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.83-1.06(m,4H),1.97-2.23(m,9H),2.34(m,2H),2.49(m,2H),2.71-2.88(m,2H),2.98-3.26(m,4H),3.46(m,4H),3.58-3.69(m,2H),3.77(m,2H),3.87-4.08(m,7H),4.29(m,5H),4.37-4.42(m,2H),4.56(m,1H),4.84(m,2H),7.11(m,1H),7.19-7.46(m,4H),7.71(m,1H),7.84(s,1H),9.08(s,1H).m/z(ESI):992.9[M+H]+.
实施例123(化合物156盐的合成):
合成步骤参考实施例80,得到白色固体。1H NMR(500MHz,Methanol-d4)δ0.74-0.83(m,5H),0.88-0.95(m,2H),1.57-1.73(m,4H),1.88-2.23(m,16H),2.27-2.36(m,3H),2.43-2.52(m,2H),2.69-2.82(m,5H),2.93-3.13(m,4H),3.44-3.55(m,5H),3.55-3.69(m,4H),3.79-3.91(m,2H),3.94-4.04(m,5H),4.36(dd,J=10.0,5.0Hz,1H),4.42-4.52(m,2H),4.67-4.79(m,2H),7.06(s,1H),7.11(d,J=10.0Hz,1H),7.26(d,J=10.0Hz,1H),7.32(s,1H),7.39(s,1H),7.66-7.73(m,2H),8.52(s,1H),9.10(s,1H).m/z(ESI):1090.8[M+H]+.
实施例124(化合物157盐的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.89(m,2H),1.01(m,2H),2.00-2.27(m,14H),2.52(m,2H),2.75-2.86(m,1H),2.89-3.10(m,6H),3.23(m,1H),3.40(m,2H),3.58(m,2H),3.73(m,2H),3.82-4.07(m,3H),4.29(d,J=13.7Hz,2H),4.42-4.66(m,4H),4.75-4.87(m,4H),5.20(m,1H),7.23(d,J=2.6Hz,1H),7.31-7.41(m,2H),7.56(m,2H),7.70-7.76(m,1H),7.87(m,1H),9.08(s,1H).m/z(ESI):976.6[M+H]+.
实施例125(化合物158盐的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.93(m,2H),1.05(m,2H),1.40(m,J=6.8,4.3Hz,4H),1.96-2.36(m,13H),2.62(m,1H),2.82-2.94(m,2H),2.97-3.15(m,4H),3.22-3.32(m,2H),3.44(d,J=24.6Hz,2H),3.73(m,4H),3.91(m,1H),4.00(m,2H),4.32(m,2H),4.54(m,2H),4.85(m,2H),5.47(m,1H),7.12(m,1H),7.25(s,1H),7.32-7.38(m,1H),7.41-7.53(m,1H),7.88(m,2H),8.16(m,1H),8.31-8.51(m,1H),9.11(s,1H).m/z(ESI):1012.6[M+H]+.
实施例126(化合物159盐的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.89(s,2H),1.01(s,2H),1.29-1.36(m,2H),2.17(m,4H),2.25-2.29(m,4H),2.33(m,1H),2.47(m,1H),2.69-2.89(m,3H),3.10(m,2H),3.34-3.41(m,2H),3.96(m,2H),3.98(s,3H),4.05(m,1H),4.29(m,2H),4.36(dd,J=9.3,5.1Hz,1H),4.47-4.60(m,2H),4.81(m,2H),7.10-7.16(m,1H),7.22(m,1H),7.29(m,1H),7.36(mz,1H),7.67(m,1H),7.81-7.89(m,1H),8.02(s,1H),9.09(s,1H).m/z(ESI):895.5[M+H]+.
实施例127(化合物160的合成):
合成步骤参考实施例80,得到白色固体。1H NMR(500MHz,Methanol-d4)δ0.53(s,2H),0.73(s,2H),0.81(d,J=5.0Hz,3H),1.56-1.70(m,6H),1.76-2.06(m,12H),2.16-2.24(m,1H),2.26-2.37(m,2H),2.39-2.56(m,6H),2.69-2.82(m,4H),3.07(d,J=10.0Hz,2H),3.63-3.76(m,4H),4.01(s,3H),4.31-4.47(m,3H),4.55-4.70(m,3H),7.04-7.11(m,2H),7.25(d,J=10.0Hz,1H),7.30(d,J=5.0Hz,1H),7.35(s,1H),7.60-7.71(m,2H),9.05(s,1H).m/z(ESI):979.8[M+H]+.
实施例128(化合物161的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.49-0.59(m,2H),0.70-0.77(m,2H),1.62-1.74(m,6H),1.78-1.91(m,4H),2.03-2.10(m,2H),2.13-2.19(m,1H),2.35(d,J=10.0Hz,1H),2.45-2.52(m,4H),2.59-2.70(m,2H),2.76-2.85(m,2H),2.87-2.95(m,2H),3.21-3.27(m,6H),3.38(s,1H),3.46(s,3H),3.53-3.57(m,1H),3.64-3.75(m,4H),4.33-4.40(m,1H),4.43-4.49(m,1H),4.54-4.60(m,1H),4.61-4.69(m,1H),5.30-5.39(m,1H),5.70(s,1H),6.85-6.91(m,1H),7.01-7.09(m,2H),7.19-7.23(m,1H),7.27-7.36(m,2H),7.85(dd,J=10.0,5.0Hz,1H),9.00(s,1H).m/z(ESI):989.7[M+H]+.
实施例129(化合物162的合成):
合成步骤参考实施例80,得到白色固体。1H NMR(500MHz,CD3OD)δppm 9.08(s,1H),7.88(dd,J=8.8,5.8Hz,1H),7.44-7.30(m,3H),7.26-7.09(m,4H),4.88-4.76(m,2H),4.51(dt,J=25.0,12.1Hz,2H),4.29(d,J=13.7Hz,2H),4.05-3.98(m,1H),3.96-3.83(m,3H),3.79-3.67(m,2H),3.60-3.51(m,2H),3.46-3.37(m,2H),3.27-3.15(m,1H),3.13-2.84(m,5H),2.77-2.48(m,3H),2.32-1.90(m,17H),1.05-0.95(m,2H),0.95-0.86(m,2H).m/z(ESI):921.7[M+H]+.
实施例130(化合物163的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.90(s,2H),1.00(s,2H),1.29(d,J=5.2Hz,9H),1.61(d,J=7.6Hz,2H),1.81(d,J=12.9Hz,1H),2.03(d,J=5.6Hz,3H),2.19(t,J=7.6Hz,2H),2.38-2.50(m,1H),2.73(t,J=6.5Hz,2H),3.04(d,J=31.5Hz,1H),3.37-3.41(m,2H),3.67-3.81(m,2H),3.94(dd,J=25.3,14.0Hz,2H),4.10(q,J=7.2Hz,1H),4.26(s,2H),4.34-4.45(m,2H),4.63(d,J=12.2Hz,1H),4.82(d,J=13.8Hz,2H),5.34(t,J=5.0Hz,1H),6.34(d,J=7.3Hz,1H),6.97(t,J=7.7Hz,1H),7.03(d,J=8.1Hz,1H),7.23(d,J=8.0Hz,2H),7.35(dt,J=11.8,5.7Hz,2H),7.79-7.90(m,1H),9.09(s,1H).m/z(ESI):892.40[M+H]+.
实施例131(化合物164的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.90(s,2H),0.96-1.03(m,2H),1.29(d,J=4.2Hz,6H),1.60(t,J=7.3Hz,2H),2.02-2.06(m,5H),2.17(d,J=9.4Hz,4H),2.27(d,J=8.8Hz,2H),2.54(s,1H),2.80(dd,J=15.1,4.2Hz,2H),2.90-2.95(m,3H),2.99-3.13(m,2H),3.35(s,1H),3.43(s,3H),3.52-3.61(m,2H),3.73(q,J=9.2,8.5Hz,2H),3.85(d,J=12.9Hz,1H),3.93(d,J=14.2Hz,1H),4.01(d,J=13.9Hz,1H),4.29(d,J=13.7Hz,2H),4.46(t,J=10.9Hz,1H),4.55(t,J=10.7Hz,1H),5.29-5.38(m,3H),7.03(d,J=8.3Hz,1H),7.08(d,J=7.1Hz,2H),7.22(d,J=2.5Hz,1H),7.32-7.38(m,2H),7.87(dd,J=9.2,5.7Hz,1H),9.07(s,1H).m/z(ESI):990.47[M+H]+.
实施例132(化合物165的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.87-0.92(m,2H),0.99(s,2H),1.28-1.36(m,6H),1.71(s,2H),2.03(s,1H),2.11(s,3H),2.28(dd,J=12.9,6.1Hz,1H),2.42(d,J=8.4Hz,1H),2.75(dt,J=9.2,5.7Hz,2H),3.00(q,J=11.6Hz,2H),3.10(d,J=6.6Hz,2H),3.18(dd,J=14.6,7.9Hz,1H),3.41(d,J=15.2Hz,2H),3.84(s,3H),3.99(d,J=13.6Hz,2H),4.16(s,2H),4.26(dd,J=9.7,4.8Hz,2H),4.46(d,J=11.6Hz,1H),4.58(d,J=12.4Hz,1H),4.77(d,J=14.2Hz,2H),6.34(s,1H),6.58(d,J=8.9Hz,1H),7.22(d,J=2.4Hz,1H),7.26(d,J=8.8Hz,1H),7.34(t,J=3.0Hz,1H),7.37(dd,J=8.7,4.3Hz,1H),7.79(dt,J=9.3,5.0Hz,1H),9.07(s,1H).m/z(ESI):880.40[M+H]+..
实施例133(化合物166盐的合成):
合成步骤参考实施例80,得到白色固体。1H NMR(500MHz,CD3OD)δppm 9.08(s,1H),8.13(t,J=7.6Hz,1H),8.00(d,J=8.1Hz,1H),7.88(dd,J=8.7,5.9Hz,1H),7.45(dd,J=27.3,8.0Hz,1H),7.39-7.18(m,4H),4.80(d,J=15.2Hz,2H),4.48(tt,J=17.1,10.2Hz,2H),4.29(d,J=13.5Hz,2H),4.20-3.49(m,10H),3.48-3.36(m,2H),3.26-2.89(m,6H),2.76-2.40(m,3H),2.40-1.90(m,16H),1.05-0.95(m,2H),0.92-0.88(m,2H).m/z(ESI):921.6[M+H]+.
实施例134(化合物167的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.89(m,2H),1.00(m,2H),1.80-2.07(m,5H),2.13(m,5H),2.32(m,2H),2.43(m,1H),2.57(m,1H),2.69-2.83(m,2H),2.98(m,1H),3.09(m,1H),3.16-3.27(m,1H),3.35-3.46(m,2H),3.75(m,1H),3.80-3.97(m,5H),4.02(m,2H),4.27(s,3H),4.40-4.66(m,2H),4.81(m,2H),6.41(d,J=22.6Hz,1H),6.65(d,J=8.6Hz,1H),7.20-7.40(m,3H),7.48(m,1H),7.74-7.85(m,1H),9.09(s,1H).m/z(ESI):907.7[M+H]+.
实施例135(化合物168的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,CD3OD)δppm 9.08(s,1H),8.42(d,J=8.1Hz,1H),8.12(d,J=6.8Hz,1H),7.91-7.80(m,2H),7.40(d,J=7.2Hz,1H),7.37-7.28(m,2H),7.23(s,1H),7.08(d,J=7.3Hz,1H),5.48-5.39(m,1H),4.79(d,J=14.6Hz,1H),4.62(d,J=11.8Hz,1H),4.44(d,J=11.8Hz,1H),4.31(d,J=16.4Hz,2H),4.05(t,J=13.2Hz,2H),3.93(t,J=12.9Hz,2H),3.85-3.40(m,6H),3.28-2.93(m,6H),2.85(dd,J=19.6,9.7Hz,2H),2.39-1.99(m,11H),1.83(d,J=12.2Hz,2H),1.36(dd,J=21.3,15.2Hz,3H),1.01(d,J=9.4Hz,2H),0.96-0.86(m,2H).m/z(ESI):986.7[M+H]+.
实施例136(化合物169盐的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.89(m,4H),2.00-2.21(m,8H),2.31(m,1H),2.46(m,1H),2.58-2.82(m,5H),2.86-2.95(m,3H),3.00-3.05(m,1H),3.34-3.40(m,2H),3.44-3.58(m,3H),3.65(m,1H),3.94(m,1H),4.01(s,3H),4.24-4.40(m,6H),4.45-4.63(m,2H),4.78-4.90(m,4H),7.07(d,J=8.5Hz,1H),7.24(s,1H),7.29-7.43(m,3H),7.69(d,J=8.4Hz,1H),7.88(m,1H),9.10(s,1H).m/z(ESI):947.6[M+H]+.
实施例137(化合物170盐的合成):
合成步骤参考实施例80,得到浅黄色固体。1H NMR(500MHz,Methanol-d4)δ0.89(m,2H),1.02(m,2H),1.86-2.33(m,16H),2.54(m,1H),2.67-2.81(m,2H),2.84-3.27(m,7H),3.36-3.50(m,2H),3.60(m,2H),3.70-3.79(m,2H),3.90(m,2H),4.03(m,1H),4.29(d,J=15.3Hz,2H),4.45(t,J=11.3Hz,1H),4.57(t,J=10.8Hz,1H),4.75-4.90(m,2H),5.15(dd,J=12.7,5.4Hz,1H),7.23(d,J=2.5Hz,1H),7.30-7.39(m,2H),7.76(d,J=7.7Hz,1H),7.81(s,1H),7.88(d,J=7.7Hz,2H),9.10(s,1H).m/z(ESI):990.5[M+H]+.
实施例138(化合物171的合成):
合成步骤参考实施例80,得到黄色固体。1H NMR(500MHz,Methanol-d4)δ0.54(s,2H),0.74(s,2H),1.57-1.62(m,2H),1.63-1.72(m,4H),1.79-1.93(m,8H),1.93-2.01(m,2H),2.02-2.09(m,2H),2.13-2.20(m,1H),2.40-2.54(m,4H),2.71-2.83(m,3H),2.85-2.95(m,1H),3.07(d,J=10.0Hz,2H),3.40(s,1H),3.66-3.84(m,5H),4.34-4.41(m,1H),4.44-4.50(m,1H),4.60(d,J=15.0Hz,1H),4.67(d,J=15.0Hz,1H),5.16(dd,J=15.0,10.0Hz,1H),7.23(s,1H),7.30-7.39(m,2H),7.74-7.83(m,3H),7.85-7.92(m,1H),9.02(s,1H).m/z(ESI):990.7[M+H]+.
生物学测定
实验一:蛋白降解实验
取对数生长期的Aspc-1(Cobioer,CBP60546)细胞株,按照1E6/孔接种于6孔细胞培养板(Corning,3516),并将该培养板放置于37℃,5%二氧化碳的培养箱过夜孵育。第二天将待测化合物用DMSO(Sigma,RNBF5902)配置成10mM的储备液,再用完全培养基稀释为不同浓度的工作液,加入相对应的孔板中,放置于37℃,5%二氧化碳的培养箱继续培养。化合物处理24h后,取出细胞培养板,用预冷的PBS(Gibco,14190250)清洗细胞两次,再按40μl/孔加入含蛋白酶抑制剂(InvitrogenTM,AM2696)的RIPA裂解液。用细胞刮刀将贴壁细胞刮下来,并将细胞裂解液转移至1.5ml离心管,放置于冰上裂解30min。裂解结束后,在4℃,14000rpm条件下离心10min,将上清转移到新的1.5ml离心管,置于冰上,用BCA蛋白检测试剂盒(Thermo Fisher,23225)测蛋白浓度。取40μl细胞裂解液与10μl 5X SDS(Beyotime,P0015L)上样缓冲液混匀后,95℃水浴10min使蛋白变性。将变性后的蛋白样品按30μl/孔加入4-20% Bis-Tris gel(金斯瑞,M00656)对应的孔中,先将电压调至80V跑30min,再调至120V跑40min,直至条带跑至合适的位置。电泳结束,用iBlot2(Life Technologies,IB21001)在20V,7min的条件下进行转膜。转膜结束,用5%的脱脂奶粉室温封闭2h,再用TBST(Thermo Scientific,28360)缓冲液漂洗三次,每次10min。5%的脱脂奶粉按合适的比例稀释一抗,配置一抗工作液,4℃过夜孵育。一抗孵育结束,用TBST缓冲液在室温洗膜三次,每次10min,同时用5%的脱脂奶粉配置二抗工作液,室温孵育二抗1h。再用TBST洗膜三次后,加ECL显色液,用Biorad Chemi Doc凝胶成像仪成像,并用Image Lab分析条带灰度值。蛋白降解率按照下列公式计算:RAS蛋白表达率=(RAS-化合物/GAPDH)/(RAS-DMSO/GAPDH)
降解率(%)=(1-RAS蛋白表达率)*100
表3出了不同化合物在1μM浓度时,在Aspc-1细胞株上的Ras蛋白降解率,其中“-”表示本发明化合物Ras蛋白降解率低于或等于10%,“+”表示本发明化合物Ras蛋白降解率大于10%且小于或等于30%,“++”表示的本发明化合物Ras蛋白降解率为31%和60%之间,“+++”表示的本发明化合物Ras蛋白降解率大于61%。
表3.1μM浓度时Ras蛋白降解率
表4出了不同化合物在0.1μM浓度时,在Aspc-1细胞株上的Ras蛋白降解率,其中“-”表示本发明化合物Ras蛋白降解率低于或等于10%,“+”表示本发明化合物Ras蛋白降解率大于10%且小于或等于30%,“++”表示的本发明化合物Ras蛋白降解率为31%和60%之间,“+++”表示的本发明化合物Ras蛋白降解率大于61%。
表4.1μM浓度时Ras蛋白降解率
表5示出了不同化合物在50nM浓度时,在Aspc-1细胞株上的Ras蛋白降解率,其中“-”表示本发明化合物Ras蛋白降解率低于或等于10%,“+”表示本发明化合物Ras蛋白降解率大于10%且小于或等于30%,“++”表示的本发明化合物Ras蛋白降解率为31%和60%之间,“+++”表示的本发明化合物Ras蛋白降解率大于61%。
表5.50nM浓度时Ras蛋白降解率
表6公开了不同化合物对Aspc-1细胞中的G12D的降解活性,其中“++++”表示本发明化合物的DC50小于或等于10nM,“+++”表示化合物DC50大于10nM,且小于或等于50nM,“++”表示化合物IC50大于50nM且小于或等于100μM,“+”表示化合物IC50大于100nM且小于或等于200nM。
表6不同化合物在Aspc-1细胞中的降解活性
Compd ID | DC50(nM) | Compd ID | DC50(nM) |
33 | +++ | 43 | ++ |
45 | +++ | 55 | ++ |
56 | +++ | 57 | ++++ |
75 | ++++ | 82 | ++++ |
83 | + | 92 | ++++ |
93 | ++ | 99 | +++ |
110 | ++++ | 111 | ++++ |
112 | ++++ | 113 | ++++ |
114 | ++++ | 115 | +++ |
118 | ++++ | 129 | ++++ |
133 | ++++ | 135 | ++++ |
146 | ++++ | 149 | ++++ |
150 | ++++ | 151 | ++++ |
154 | ++++ | 155 | +++ |
156 | ++++ | 157 | - |
158 | ++++ | 160 | ++++ |
164 | ++++ |
实验二:细胞增殖实验
取对数生长期的Aspc-1(Cobioer,CBP60546)细胞株,将细胞密度调整为4.2E4/ml,按照95μl/孔接种于96孔细胞培养板(Corning,3599),则每孔细胞数为4E3,后将板子放置于37℃,5%的二氧化碳培养箱过夜孵育。第二天将待测化合物用DMSO(Sigma,RNBF5902)配置成10mM的储备液,梯度稀释后再用完全培养基配制为不同浓度的工作液,加入相对应的孔板中,放置于37℃,5%的二氧化碳培养箱继续培养。72h后取出细胞培养板,按照50μl/孔加入Cell Titer Glo(Promega,G7573),室温孵育10min后,酶标仪检测Luminescence,用GraphPad 7.0按照四参数方程拟合抑制曲线。
表7示出了不同化合物在Aspc-1细胞株中的抑制作用,其中“++++”表示本发明化合物的IC50小于或等于100nM,“+++”表示化合物IC50大于100nM,且小于或等于1μM,“++”表示化合物IC50大于1μM且小于或等于5μM,“+”表示化合物IC50大于5μM且小于或等于10μM。
表7.不同化合物在Aspc-1细胞株中的抑制作用
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尽管参照本发明的实施例详细描述了本发明,但提供这些实施例是为了说明而不是限制本发明。根据本发明原理能够得到的其它实施例均属于本发明权利要求所界定的范畴。
Claims (19)
1.一种具有W-L-T结构的双官能化合物,或其药学上可接受的盐、酯、水合物、溶剂合物或立体异构体,其中:
W是KRAS G12D蛋白的靶向基团;
T是E3泛素连接酶的配体基团;
L是使靶向基团(W)与配体基团(T)化学连接的双价连接基团。
2.根据权利要求1所述的双官能化合物,其中,KRAS G12D蛋白的靶向基团W具有式(Ia)或式(Ib)所示的结构:
其中,X选自氮(N)、碳(CH)、C–F、C–Cl、C–CH3、C–C2H5、或C–C3H7;
R1选自取代或未取代的羟基、氨基或巯基;
R2和R3独立地选自H、卤素、卤代甲基(一卤甲基、二卤甲基、及三卤甲基),或者R2、R3以及它们所连接苯环结构一起形成取代或未被取代的苯并稠环,包括但不限于萘环结构,其中当形成取代的苯并稠环时,苯并稠环上任选地取代有一个或多个,例如2个或3个独立选自卤素、羟基、氨基、卤代甲基、C1-C2烷基、C2-4炔基的取代基。
3.根据权利要求1所述的双官能化合物,其中,所述双价连接基团L具有L1-L2-L3的结构,其中L1、L2、L3可同时存在或者存在其中的一者或两者;并且
L1、L2、L3独立的选自具有双连接位点的取代或未取代的烃基、烃氧基、氧基烃基、环烃基、杂环烃基、酰基烃基、烃基酰基、羰基烃基、烃基羰基、酰胺基烃基、烃基酰胺基、芳基、以及寡肽基团中的一种或其中几种的组合而成的双价基团;
其中所述烃基包括饱和烃基、不饱和烃基、芳香族烃基、氧杂烃基、氮杂烃基、硫杂烃基、磷杂烃基以及不同杂原子的混合杂烃基,其中烃基或杂烃基的链长为1到20个原子,并且当其为杂烃基时,所述杂烃基含有1到5个杂原子;
其中所述杂环烃基中的杂环包括取代或未取代的单环、螺环或稠环等。
4.根据权利要求3所述的双官能化合物,其中,L1选自氧、氮或式(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)、(IIh)、(IIi)、(IIj)、(IIk)所示的结构:
其中,Y和Z独立地选自氧(O)、氮(NH)、或硫(S);
n=0~20;
R5和R6独立地选自氢、卤素、羟基、烷氧基、氨基、或胺基;
当结构中具有手性中心时,其立体结构独立地选自R-构型、S-构型、或R-和S-构型的混合构型。
5.根据权利要求3所述的双官能化合物,其中,L1选自:
其中,n=0~20,尤其为0~5,更尤其为1~2。
6.根据权利要求3所述的双官能化合物,其中,L2、L3独立地选自:
或者不存在;
其中,L2和L3可不同时存在;
其中,p=0-20,优选的p=0-10;m=0-5;q=0-10,优选的q=0-5。
7.根据权利要求2所述的双官能化合物,其中,在KRAS G12D蛋白的靶向基团W的结构中,片段选自:/>
8.根据权利要求1所述的双官能化合物,其中,所述E3泛素连接酶的配体选自能与VHL(Von Hippel-Lindau)、CRBN(Cereblon)、MDM2、clAP、AhR、Nimbolide、CCW16、KB02或KEAP1结合的配体。
9.根据权利要求1至6中任意一项所述的双官能化合物,其中,E3泛素连接酶的配体基团T选自:
其中,苯环上的取代可以发生在任意可取代的位点。
10.选自说明书表1中的化合物141至171的双官能化合物或其药学上可接受的盐、酯、水合物、溶剂合物或立体异构体。
11.一种药物组合物,包括:至少一种权利要求1至10中任意一项所述的化合物或其药学上可接受的盐、酯、水合物、溶剂合物或立体异构体;以及可选的至少一种药学上可接受的赋形剂或载体或稀释剂。
12.根据权利要求11所述的药物组合物,其中,所述药学上可接受的赋形剂包括粘合剂、填充剂、崩解剂、润滑剂和助流剂中的一种或多种。
13.根据权利要求11所述的药物组合物,其中,所述药学上可接受的载体包括乳膏、乳剂、凝胶、脂质体和纳米颗粒中的一种或多种。
14.根据权利要求11至13中任一项所述的药物组合物,其特征在于,所述组合物适用于口服施用或者注射施用。
15.权利要求1至10中任一项所述的化合物或其药学上可接受的盐或酯或水合物或溶剂合物或立体异构体或者权利要求11至14中任一项所述的药物组合物在制备用于治疗、抑制或预防过度增生病症的药物中的用途。
16.根据权利要求15所述的用途,其中,所述过度增生病症为KRAS G12D相关的恶性肿瘤或癌症。
17.根据权利要求16所述的用途,其中,所述恶性肿瘤或癌症选自:
肉瘤(血管肉瘤,纤维肉瘤,横纹肌肉瘤,脂肉瘤),粘液瘤,横纹肌瘤,纤维瘤,脂肪瘤和畸形瘤;
肺部肿瘤或癌症:支气管癌(鳞状细胞癌,未分化小细胞癌,未分化大细胞癌,腺癌),肺泡(支气管)癌,支气管腺瘤,肉瘤,淋巴瘤,软骨瘤,间皮瘤;
胃肠部肿瘤或癌症:食道(鳞状细胞癌,腺癌,平滑肌瘤,淋巴瘤),胃(癌,淋巴瘤,平滑肌瘤),胰腺(导管腺癌,胰岛素瘤,葡糖单胞菌,胃泌素瘤,类癌肿瘤,舒血管肠肽瘤),小肠(腺癌,淋巴瘤,类癌肿瘤,卡波西氏肉瘤,平滑肌瘤,血管瘤,脂肪瘤,神经纤维瘤,纤维瘤),大肠(腺癌,管状腺瘤,绒毛腺瘤,血肿,平滑肌瘤);
泌尿生殖道肿瘤或癌症:肾(腺癌,Wilms肿瘤(肾母细胞瘤),淋巴瘤),膀胱和尿道(鳞状细胞癌,过渡细胞癌,腺癌),前列腺(腺癌,肉瘤),睾丸(精原细胞瘤,畸形瘤,胚胎癌,畸形癌,绒毛膜癌,肉瘤,间质细胞癌,纤维瘤,纤维腺瘤,腺样瘤,脂肪瘤);
肝脏:肝癌(肝细胞癌),胆管癌,肝母细胞瘤,血管肉瘤,肝细胞腺瘤,血管瘤;
胆道肿瘤或癌症:胆囊癌,安瓿癌,胆管癌;
骨肿瘤或癌症:成骨肉瘤(骨肉瘤),纤维肉瘤,恶性纤维组织细胞瘤,软骨肉瘤,Ewing肉瘤,恶性淋巴瘤(网状细胞肉瘤),多发性骨髓瘤,恶性巨细胞瘤弦状瘤,骨软骨瘤(骨软骨瘤),良性软骨瘤,成软骨细胞瘤,软骨粘液纤维瘤,骨样骨瘤和巨细胞瘤;
神经系统肿瘤或癌症:颅骨(骨瘤,血管瘤,肉芽肿,黄瘤,变形性骨炎),脑膜(脑膜瘤,脑膜肉瘤,胶质瘤病),脑(星形细胞瘤,成髓细胞瘤,神经胶质瘤,附睾瘤,生殖细胞瘤(松果体瘤),成胶质细胞瘤,少突胶质瘤,神经胶质瘤,视网膜母细胞瘤,先天性肿瘤),脊髓神经纤维瘤,脑膜瘤,神经胶质瘤,肉瘤);
妇科肿瘤或癌症:子宫(子宫内膜癌(浆液性膀胱癌,粘液性膀胱癌,未分类癌),颗粒鞘细胞瘤,血清间质细胞瘤,发育不良,恶性畸形瘤),外阴(鳞状细胞癌,上皮内癌,腺癌,纤维肉瘤,黑色素瘤),阴道(透明细胞癌,鳞状细胞癌,葡萄膜肉瘤(胚胎横纹肌肉瘤);
血液科肿瘤或癌症:白血病(急性骨髓性白血病,慢性骨髓性白血病,急性淋巴细胞白血病,慢性淋巴细胞白血病,骨髓增生性疾病,多发性骨髓瘤,骨髓增生异常综合征),霍奇金氏病,非霍奇金氏淋巴瘤;
皮肤科肿瘤或癌症:恶性黑色素瘤,基底细胞癌,鳞状细胞癌,卡波西肉瘤,摩尔斯发育异常性痣,脂肪瘤,血管瘤,皮肤纤维瘤,瘢痕瘤,银屑病;
肾上腺肿瘤或癌症:成神经细胞瘤。
18.根据权利要求16所述的用途,其中,所述恶性肿瘤或癌症选自非小细胞肺癌、小细胞肺癌、胰腺癌、结直肠癌、胆管癌、宫颈癌、膀胱癌、肝癌或乳腺癌中的一种或多种。
19.试剂盒在制备用于治疗、抑制或预防与KRAS G12D相关疾病的药物中的用途,其中,所述试剂盒包括根据权利要求1至10中任一项所述的化合物或药学上可接受的盐、酯、水合物、溶剂合物或立体异构体,或者权利要求11至14中任一项所述的药物组合物。
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