CN115785124A - Kras g12d抑制剂及其用途 - Google Patents
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- CN115785124A CN115785124A CN202210062466.9A CN202210062466A CN115785124A CN 115785124 A CN115785124 A CN 115785124A CN 202210062466 A CN202210062466 A CN 202210062466A CN 115785124 A CN115785124 A CN 115785124A
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Abstract
本发明涉及KRAS G12D抑制剂及其用途。具体地,本发明涉及式(I)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,包括其的药物组合物,以及上述化合物或组合物在制备用于治疗、抑制或预防KRAS G12D突变相关疾病的药物中的用途。
Description
技术领域
本发明涉及一种KRAS G12D抑制剂,或其药学上可接受的盐、酯、水合物、溶剂合物或立体异构体,以及其在制备用于治疗、抑制或预防KRAS G12D突变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是患者中最常见的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,KRAS G12C突变蛋白作为一个前沿靶点,已经吸引了很多的研究,但令人遗憾的是,由于突变位点氨基酸残基难以通过化学方式结合,因此涉及KRAS G12D的抑制剂化合物报道的非常少,WO2021041671、WO2021106231虽然公开了一些化合物,然而公开的给药方式是腹腔给药(Intraperitoneal,IP),目前在临床病人治疗给药途径一般采用的是口服(Per oral,PO)和静脉注射(Intravenous,IV)(参见Xiaolun Wang,Shelley Allen等人;Identificationof MRTX1133,a Noncovalent,Potent,and Selective KRASG12D Inhibitor;2021;E),因此寻找更多种类的、活性更高的、治疗效果更好的、可应用与临床上的KRAS G12D抑制剂,对抗肿瘤的研究具有十分重要的意义。
发明内容
本发明主要解决的技术问题是提供效果好的KRAS G12D抑制剂。申请人发现,式A化合物或者其药学上可接受的盐、酯、水合物、溶剂合物或立体异构体,具有良好的抗肿瘤活性:
其中,X2独立地选自氢、取代或未取代的烷基或杂烷基、取代或未取代的酰基(包括饱和或不饱和的脂肪族酰基和芳酰基)、氨基酸残基、取代或为取代的寡肽(二肽、三肽、四肽)残基、磷酰基、膦酰基、胺基膦酰基、磺酰基、硫代酰基、取代或未取代的苄基、取代或未取代的烷氧羰基、取代或未取代的胺基羰基、取代或未取代的巯基硫代羰基、取代或未取代的烷硫基(硫代羰基)、取代或未取代的酯烷基、取代或未取代的苄氧基羰基、糖苷基、糖酸苷基、胆酸类取代基;
A为含有环状结构的有机基团,包括单环、双环、稠环、桥环、螺环、杂环、芳环、芳杂环、脂肪环、以及组合,且该环状结构含有两个或者两个以上的取代基团;
基团A1、A2、A3和A4独立地选自氢或C1到C6的短链烃基,或者A1、A2、A3和A4中的一个或两个基团以及它们所连接的哌嗪环一起形成桥环、稠环或螺环。
在一些实施例中,式(A)所述化合物为式(B)的化合物或者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,X2独立地选自氢、取代或未取代的烷基或杂烷基、取代或未取代的酰基(包括饱和或不饱和的脂肪族酰基和芳酰基)、氨基酸残基、取代或未取代的寡肽(二肽、三肽、四肽)残基、磷酰基、膦酰基、胺基膦酰基、磺酰基、硫代酰基、取代或未取代的苄基、取代或未取代的烷氧羰基、取代或未取代的胺基羰基、取代或未取代的巯基硫代羰基、取代或未取代的烷硫基(硫代羰基)、取代或未取代的酯烷基、取代或未取代的苄氧基羰基、糖苷基、糖酸苷基、胆酸类取代基;
A为含有环状结构的有机基团,包括单环、双环、稠环、桥环、螺环、杂环、芳环、杂芳环、脂肪环、以及组合,且该环状结构含有两个或者两个以上的取代基团。
在一些实施例中,式(B)可以是式(I)的化合物或者其药学上可接受的盐、酯、水合物、溶剂合物或立体异构体,式(I)的化合物具有优异的抗肿瘤活性:
其中,W选自氧(O)、硫(S)或氮(NH);
X1和X2独立地选自氢、取代或未取代的烷基或杂烷基、取代或未取代的酰基(包括饱和或不饱和的脂肪族酰基和芳酰基)、氨基酸残基、取代或未取代的寡肽(二肽、三肽、四肽)残基、磷酰基、膦酰基、胺基膦酰基、磺酰基、硫代酰基、取代或未取代的苄基、取代或未取代的烷氧羰基、取代或未取代的胺基羰基、取代或未取代的巯基硫代羰基、取代或未取代的烷硫基(硫代羰基)、取代或未取代的酯烷基、取代或未取代的苄氧基羰基、糖苷基、糖酸苷基、胆酸类取代基;
X3独立地选自或孤对电子;当X3为孤对电子时,X1和X2不同时为氢;且当X3为时,与X3相连接的N原子形成带有一个正电荷的季铵离子,并与分子内的负离子形成內盐或与另外的酸分子配对成盐,酸分子包括但不限于氢卤酸盐,其中R6a、R6b任意选自氢、C1至C20的烃基或环烃基(可选的,C1至C6的低级烃基或环烃基)、
Y1a、Y1b独立地选自氢、卤素(F、Cl、或Br)、羟基、氨基、胺基、羟甲基、烷氧基、或酰氧基;
Y2独立地选自氢、卤素、羟基、氨基、胺基、羟甲基、烷氧基、酰氧基、或低级烃基;
Y3、Y4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Y3、Y4以及它们所连接的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。
本申请提供的化合物,或者其药物学上可接受的盐、酯、水合物、溶剂合物或立体异构体,可作为KRAS G12D抑制剂,用于治疗KRAS G12D突变相关的疾病,且具有较好的疗效。
进一步地,X1和X2独立地选氢、C1-C20饱和或不饱和烷氧羰基(可选的,C1-C4烷氧羰基)、C1-C20饱和或不饱和烷基酰基(可选的,C1-C6烷基酰基)、C1-C20烷硫基(可选的,C1-C6烷硫基)、
其中R1选自氢、甲基、乙基、丙基、异丙基、C3-C6环烷基,芳香基(例如取代或未取代的苯基,取代或未取代的萘基等);
R2选自氢、C1到C20的饱和或不饱和烷基(可选的,C1到C6的低级脂肪族烃基)、C5-C8芳基烃基、杂环芳烃基、C3-C8碳环或杂环烃基、稠环、萘环、桥环烃基,
R3选自氢、甲基、乙基或丙基,
R4选自氢、C2到C20的烷基、异丙基、异丁基、芳基烃基、碳环或杂环烃基、C2到C20的烷酰氧基;
R5选自2-位取代的乙基,且2-位上取代基包括但不限于氨基、烷氧羰基、烷酰氧基、以及由氨基酸衍生的酰氧基,
R7选自低级烷基或者取代或未取代的芳基,
R8选自取代或未取代C2到C20的饱和或不饱和烷酰基、饱和或不饱和烷氧羰基;
R9选自低级烷基,取代或未取代的苄基、取代或未取代的咪唑-5-甲基、低聚乙二醇基(–[CH2CH2O]nCH3,其中n为0到4的整数)、C2到C20的饱和或不饱和的烷酰基;
R10选自氢、C1-C6的烷氧基、C2到C20的饱和或不饱和的烷酰氧基、取代或未取代C2到C20的饱和或不饱和烷酰基、饱和或不饱和烷氧羰基;
n为0到4的整数。
在一些实施例中,X1为C1-C20饱和或不饱和烷基酰基,吡啶基、苯基、萘基,并且X2为氢。
在一些实施例中,Y1a、Y1b、Y2独立地选自氢,或卤素(F、Cl、或Br,尤其是F)。
在一些实施例中,Y3、Y4独立地选自H、Cl、CF3,或者它们所连接的苯环结构一起形成取代或未被取代的萘环,例如其中R11选自氢、卤素原子(尤其是F)、羟基、取代羟基、以及低级烷基;Y4选自氢、卤素原子、羟基、取代羟基、以及低级烷基。
进一步地,化合物是式(II)和(III)所示化合物:
其中R11选自氢、卤素原子、羟基、取代羟基、以及低级烷基;Y4选自氢、卤素原子、羟基、取代羟基、以及低级烷基。
在一些实施方式中,式(II)中W为氧、R11为氢。在一些实施方式中,式(II)中W为氧、R11为氟。在一些实施方式中,式(III)中W为氧、Y4为氯。在一些实施方式中,式(III)中W为NH、Y4为氢。在一些实施方式中,式(III)中W为NH、Y4为氯。
进一步地,上述任意一个化学结构式中的Y1b和Y2同时为氢。
在一些实施方式中,化合物是式(IV)到(VI)所示的化合物:
在一些实施方式中,化合物为以化合物A1、A2、或A3为基础的衍生物,其中A1、A2、或A3为基础化合物。基础化合物A1到A3的化学结构见表1。所述化合物可以是相应结构所代表的化合物,也可以是其药学上可接受的盐、酯、水合物、溶剂合物或立体异构体。
表1
在一些实施方式中,化合物为如下表2和表2a所示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:
表2
表2a
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、16O、12C、18O、17O、15N和13C等。
上述化合物,具有较好的生物活性,可用于治疗涉及KRAS G12D突变相关的疾病。在一些实施方式中,本申请提供的化合物,可以作为一种前药进入受试者体内,并分解成有效的生物活性成分,从而起到治疗与KRAS G12D有关的疾病的作用。
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。
进一步地,还包括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。也就是说,本发明提供一种适用于口服施用或注射施用的化合物或其药物组合物。
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异构体或水合物或组合物在制备用于治疗、抑制或预防过度增生病症药物中的用途。并且,本发明还提供了一种用于治疗、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KRAS G12D相关的恶性肿瘤或癌症。
进一步地,上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: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:成神经细胞瘤。
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、酯、水合物、溶剂合物或立体异构体、或任意所述的组合物,可用于制备用于治疗、抑制或预防KRAS G12D突变相关的疾病或病症的药物。
本申请提供的化合物,或其药学上可接受的盐或酯或异构体或水合物,具有很好的KRAS G12D抑制效果,可以应用于治疗、抑制或预防KRAS G12D突变相关的疾病或病症的药物的制备。
附图说明
为了更好地理解本发明并更清楚地示出如何实施本发明,现在将通过实施例的方式参考附图进行进一步的说明,所述附图展示了根据本发明的实施例的各个方面和特征,其中:
图1:口服给药时,化合物1、化合物61和化合物A1在等摩尔剂量下给药的药-时曲线,实验动物:ICR小鼠。
图2:口服给药时,化合物4、化合物17、化合物69和化合物A1在等摩尔剂量下给药的药-时曲线,实验动物:ICR小鼠。
图3:静脉注射给药时,化合物32、化合物39、化合物52和化合物A1在等摩尔剂量下给药的药-时曲线,实验动物:ICR小鼠。
图4:静脉注射给药时,本发明的化合物55、化合物56和化合物A1在等摩尔剂量下给药的药-时曲线,实验动物:ICR小鼠。
图5:口服给药时,化合物1、化合物A1和空白对照,小鼠体内肿瘤生长抑制效果对比结果。
图6:腹腔给药化合物52、静脉注射给药化合物52、腹腔给药对照化合物A1和空白对照,小鼠体内肿瘤生长抑制效果对比结果。
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。
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。
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。
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(羧酸酯)所表示的化合物。通常这些化合物可以通过羧酸与醇反应(消去一份子水)得到。
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。
在一些实施例中,如本发明提及烷基、酰基、环烷基、杂环烷基、烷氧基、芳氧基、杂烷氧基、杂芳氧基、芳基、杂芳基基团、氨基酸残基、寡肽(二肽、三肽、四肽)残基、磷酰基、膦酰基、胺基膦酰基、磺酰基、硫代酰基、苄基、烷氧羰基、胺基羰基、巯基硫代羰基、烷硫基、硫代羰基、苄氧基羰基、糖苷基、糖酸苷基时,其是可任选取代的(例如,“取代的”或“未取代的”烷基,“取代的”或“未取代的”杂环基、“取代的”或“未取代的”芳基或“取代的”或“未取代的”杂芳基基团)。
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。
术语“烃基”是只含碳、氢两种原子基团,烃基可以是饱和的,也可以是不饱和的,烷基、烯基和炔基均属于烃基。常见的烃基包括甲基、乙基、丙级、正丁基、异丁基、乙烯基、丙炔基等。
除非对碳数有限定,否则本文中所使用的“低级脂肪族”、“低级烃基”、“低级烷基”、“低级烯基”和“低级炔基”中的“低级”表示该部分具有至少一个(对于烯基和炔基为至少两个)且等于或小于6个碳原子。
术语“环烷基”,“脂环族”,“碳环”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,其中碳环体系具有3至15个碳原子。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯-1-基、环戊烯-2-基、环戊烯-3-基、环己基、环己烯-1-基、环己烯-2-基、环己烯-3环庚基、双环[4,3,0]壬基、降冰片基等。术语环烷基包括未取代的环烷基和取代的环烷基
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。多环系统包括至少一个芳环。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。
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的(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。杂环通过烃基连接,也称为杂环烃基。
术语“稠环”或“稠合环”是指含有稠合环的多环体系。通常,稠环体系包含2或3个环,和/或多达18个环原子。如上所述,环烷基,芳基和杂环基可以形成稠环体系。因此,稠环体系可以是芳族的,部分芳族的或非芳族的并且可以含有杂原子。根据该定义,螺环系统不是稠合多环的,但是本发明的稠合多环系统本身可以具有通过该体系的单个环原子连接到其上的螺环。稠环体系的实例包括但不限于萘基(例如2-萘基)、茚基、菲基、蒽基、芘基、苯并咪唑、苯并噻唑等。
本发明所用术语“酰”是指一分子碳酸脱羟基后留下的-C(=O)Ra的片段,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“胺基”或“氨基”是指未取代或取代的通式-NRbRc的片段。Ra、Rb和Rc各自独立地为取代或未取代的氢、烃基、芳基、环基或杂环基等,或Rb和Rc一起与它们所连接的氮原子形成杂环。术语“酰胺”是指氨基直接与酰基连接的结构-C(=O)NRbRc。术语“酰胺基”指化合物或片段中至少一个碳或杂原子与酰胺基上的碳原子共价键合。
术语“烷酰氧基”是指酰基上的Ra为烷基,氧基的氧原子一端与酰基上的碳原子相连接,另一端与化合物或片段中至少一个碳或杂原子共价键合。
“硫代酰基”是指酰基上的氧原子被硫原子取代后形成的-C(=S)Ra的片段
“脂肪族酰基”是指脂肪族基团与酰基上的碳原子连接的酰基,即Ra是脂肪族。“芳酰基”是指芳基与酰基上的碳原子连接的酰基,即Ra是芳基。
“膦酰”或“磷酰”是指一分子磷酸脱羟基后留下的片段-P(=O)(ORd)Re,“膦酰基”指化合物或片段中至少一个碳或杂原子与膦酰上的磷原子共价键合。Rd为取代或未取代的氢、烃基、芳基、环基或杂环基等,“胺基膦酰基”指胺基与膦酰基相连接,即Re为胺基。
“磺酰”是指一分子磺酸脱羟基后留下的片段,“磺酰基”指化合物或片段中至少一个碳或杂原子与磺酰上的硫原子共价键合。
术语“羰”是指由碳和氧两种原子通过双键连接而成的-C=ORf片段,“羰基”是醛、酮、酸等官能团的组成部分,术语“羰基”指化合物或片段中至少一个碳或杂原子与-C=ORf上的碳原子共价键合,Rf为取代或未取代的氢、烃基、芳基、环基或杂环烷基等。术语“烷氧羰基”是指Rf是烷氧基,即烷氧基上的氧原子与羰基上的碳原子相连接。术语“胺基羰基”是指Rf是胺基,即胺基上的氮原子与羰基上的碳原子相连接。术语“苄氧基羰基”是指苄氧基上的氧原子与羰基上的碳原子相连接。
术语“硫代羰基”是指羰基上的氧原子被硫原子取代后形成的-C(=S)Rf的片段。术语“巯基硫代羰基”是指Rf为巯基,即硫代羰基上的碳原子与巯基上的硫原子相连接。
术语“烷硫基”是指具有巯基连接其上的烷基。合适的烷硫基包括具有1至约20个碳原子,优选1至约15个碳原子的基团。
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。
本发明所称“胆酸类取代基”,是指肝细胞合成的胆汁酸,可以称为初级胆汁酸,包括胆酸、熊去氧胆酸、鹅去氧胆酸、甘氨胆酸、牛磺胆酸、甘氨鹅去氧胆酸、牛磺鹅去氧胆酸,尤其是鹅去氧胆酸取代、熊去氧胆酸取代。
本发明所用术语“基础化合物”或“基础分子”是指具有生物活性的具体化合物或药物分子;除自身可以作为药物分子外,也可以被进一步修饰或衍生化、形成新的化合物,例如前药化合物或衍生化合物。
本发明所用术语“成酯基团”或“酯”是指片段中含有酯官能团-RCOOR’(R’一般为烷基等其他非H基团)的结构。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。本发明所用术语“成盐部分”是指能够与酸性基团,如羧基形成盐的部分,例如但不限于钠、钾、四乙胺、四丁胺等。
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、铁等。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。
如本文所使用的,术语“有效量”是指以单剂量或多剂量施用至受试者后,在受试者中提供所需的治疗、诊断或预后效应的治疗剂(例如化合物)的量或剂量。主治医生或诊断医生通过已知技术并通过观察在类似情况下获得的结果可容易地确定有效量。在确定施用的化合物的有效量或剂量时,考虑许多因素,包括但不限于:受试者的体重、年龄和一般健康状况;涉及的具体疾病;待治疗的疾病或病症的涉及程度或严重程度;受试者个体的回应;施用的特定化合物;施用模式;所施用制剂的生物利用度特征;所选的剂量方案;使用伴随药物;和其他相关考虑。
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)。
在一些实施方式中,“治疗”或“治疗”任何疾病或病症是指缓解了至少一种疾病或病症。在某些实施方式中,治疗”或“治疗”是指缓解至少一种身体参数,其可以是患者可以分辨的或不可分辨的。在某些实施方式中,“治疗”或“治疗”是指身体上(例如,可辨别的症状的稳定)或生理学上(例如,身体参数的稳定)或这两者上来抑制疾病或病症。在某些实施方式中,“治疗”或“治疗”是指在有需要的受试者中改善生活品质或疾病的副作用。“治疗有效量”是指施用至受试者用于治疗或预防疾病的化合物的量足以达到治疗或预防该疾病的效果。“治疗有效量”将依据化合物;疾病及其严重程度;待治疗或预防患有疾病的受试者的年龄、体重等而变化。如本文中所使用的,“治疗有效量”是指化合物物或组合物足以预防、治疗、抑制、降低、缓解或消除疾病,诸如癌症的一种或多种病因、症状或并发症。
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“氨基酸”通常是指同时包含羧酸基团和氨基基团的有机化合物。术语“氨基酸”包括“天然”和“非天然”的氨基酸。另外,术语氨基酸包括O-烷基化的氨基酸或N-烷基化的氨基酸,以及具有含氮、硫或氧的侧链(例如Lys,Cys或Ser)的氨基酸,其中氮、硫或氧原子可以被或不被酰基化或烷基化。氨基酸可以是纯的L-异构体或D-异构体,或者是L-异构体和D-异构体的混合物,包括(但不限于)外消旋混合物。
术语“天然氨基酸”和等同表达是指通常在天然存在的蛋白质中发现的L-氨基酸。天然氨基酸的实例包括但不限于丙氨酸(Ala),半胱氨酸(Cys),天冬氨酸(Asp),谷氨酸(Glu),苯丙氨酸(Phe),甘氨酸(Gly),组氨酸(His),异亮氨酸(Ile),赖氨酸(Lys),亮氨酸(Leu),甲硫氨酸(Met),天冬酰胺(Asn),脯氨酸(Pro),谷氨酰胺(Gln),精氨酸(Arg),丝氨酸(Ser),苏氨酸(Thr),缬氨酸(Val)、色氨酸(Trp),酪氨酸(Tyr),β-丙氨酸(β-Ala)和γ-氨基丁酸(GABA)。
术语“非天然氨基酸”是指天然氨基酸的任何衍生物,包括D-型氨基酸,以及α-和β-氨基酸衍生物。术语“非天然氨基酸”和“不是天然氨基酸”在本文中可互换使用。应注意的是,在本发明中可归类为非天然氨基酸的某些氨基酸(例如羟脯氨酸)也可存在于自然界中的某些生物组织或特定蛋白质中。具有许多不同保护基团、适于固相肽合成中直接应用的氨基酸是可以通过购买得到的。除了二十种最常见的天然氨基酸,根据本发明可使用如下示例性非天然氨基酸和氨基酸衍生物(括号中为常见的缩写):2-氨基己二酸(Aad),3-氨基己二酸(β-Aad),2-氨基丁酸(2-Abu),α,β-脱氢-2-氨基丁酸(8-AU),1-氨基环丙烷-1-羧酸(ACPC),氨基异丁酸(Aib),3-氨基异丁酸(β-Aib),2-氨基-噻唑啉-4-羧酸,5-氨基戊酸(5-Ava),6-氨基己酸(6-Ahx),2-氨基庚酸(Ahe),8-氨基辛酸(8-Aoc),11-氨基十一烷酸(11-Aun),12-氨基十二烷酸(12-Ado),2-氨基苯甲酸(2-Abz),3-氨基苯甲酸(3-Abz),4-氨基苯甲酸(4-Abz),4-氨基-3-羟基-6-甲基庚酸(抑胃酶氨酸,Sta),氨基氧基乙酸(Aoa),2-氨基四氢化萘-2-羧酸(ATC),4-氨基-5-环己基-3-羟基戊酸(ACHPA),对氨基苯丙氨酸(4-NH2-Phe),2-氨基庚二酸(Apm),联苯基丙氨酸(Bip),对溴苯丙氨酸(4-Br-Phe),邻氯苯丙氨酸(2-Cl-Phe),间氯苯丙氨酸(3-Cl-Phe),对氯苯丙氨酸(4-Cl-Phe),间-氯酪氨酸(3-Cl-Tyr),对苯甲酰基苯丙氨酸(Bpa),叔丁基甘氨酸(TLG),环己基丙氨酸(Cha),环己基甘氨酸(Chg),锁链素(Des),2,2-二氨基庚二酸(Dpm),2,3-二氨基丙酸(Dpr),2,4-二氨基丁酸(Dbu),3,4-二氯苯丙氨酸(3,4-Cl2-Phe),3,4-二氟苯丙氨酸(3,4-F2-Phe),3,5-二碘酪氨酸(3,5-I2-Tyr),N-乙基甘氨酸(EtGly),N-乙基天冬酰胺(EtAsn),邻氟苯丙氨酸(2-F-Phe),间氟苯丙氨酸(3-F-Phe),对氟苯丙氨酸(4-F-Phe),间-氟酪氨酸(3-F-Tyr),高丝氨酸(Hse),高苯丙氨酸(Hfe),高酪氨酸(Htyr),羟基赖氨酸(Hyl),异羟基赖氨酸(aHyl),5-羟色氨酸(5-OH-Trp),3-或4-羟基脯氨酸(3-或4-Hyp),对碘苯丙氨酸-异酪氨酸(3-I-Tyr),二氢吲哚-2-羧酸(Idc),异艾杜霉素(Ide),异亮氨酸(α-Ile),异哌啶酸(Inp),N-甲基异亮氨酸(MeLys),间甲基酪氨酸(3-Me-Tyr),N-甲基缬氨酸(MeVal),1-萘基丙氨酸(1-Nal),2-萘基丙氨酸(2-Nal),对硝基苯丙氨酸(4-NO2-Phe),3-硝基酪氨酸(3-NO2-Tyr),正亮氨酸(Nle),正缬氨酸(Nva),鸟氨酸(Orn),邻磷酸酪氨酸(H2PO3-Tyr),八氢吲哚-2-羧酸(Oic),青霉胺(Pen),五氟苯丙氨酸(F5-Phe),苯基甘氨酸(Phg),哌啶酸(Pip),炔丙基甘氨酸(Pra),焦谷氨酸(PGLU),肌氨酸(Sar),四氢异喹啉-3-羧酸(Tic),噻唑烷-4-羧酸(硫代脯氨酸,Th)。
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KRAS G12D抑制剂化合物或组合物来治疗和/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。
通过抑制KRAS G12D活性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KRAS G12D抑制剂化合物和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(例如施用KRAS G12D抑制剂或包含其的药物组合物),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菌剂一起施用以减轻或缓解KRAS G12D突变或与KRAS G12D突变相关的一种或多种症状;或者减缓KRAS G12D突变或与KRAS G12D突变相关的一种或多种症状的发展;或者减轻KRAS G12D突变的严重性或与KRAS G12D突变相关的一种或多种症状的严重性;或者抑制KRAS G12D突变的临床表现;或者抑制KRAS G12D突变的不良症状的表现。
术语“预防”是指以某种方式(例如在疾病、失调、病症或其症状发作之前)开始进行行动(例如施用KRAS G12D抑制剂或包含其的药物组合物),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KRAS G12D突变所致相关疾病的发生。术语“预防”还涵盖通过对易发生KRAS G12D突变的患者或有KRASG12D突变风险的患者给药,根据本发明的化合物或组合物的施用来预防至少一种KRASG12D突变。
如本文所使用的,术语“KRAS G12D突变相关疾病”或“KRAS G12D相关疾病”或其他同义表述意指已知突变的KRAS G12D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突变相关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KRAS G12D抑制剂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KRASG12D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,KRAS G12D抑制剂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(例如KRAS抑制剂)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KRAS G12D抑制剂,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KRAS G12D抑制剂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;其它给药途径包括鼻腔、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KRAS抑制剂。
本发明还提供了包含KRAS G12D抑制剂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KRAS G12D抑制剂(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。KRAS G12D抑制剂可以以即用型(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KRAS G12D抑制剂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KRAS G12D抑制剂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参考附图,并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:
化合物1的合成
4M盐酸二氧六环溶液(50mL)缓慢加入化合物1-1(7g,12.7mmol)的甲醇(30mL)溶液中,混合物室温搅拌2小时后旋干。粗品用碳酸氢钠水溶液调pH到8,甲醇稀释后过滤旋干。残余物再用二氯甲烷溶解,过滤旋干得到粗品1-2(6.0g,收率100%)。
粗品1-2(3g,1eq,6.65mmol)加入到化合物1-3(4.09g,1.2eq,7.98mmol)的二氧六环(50mL)中,再加入碳酸铯(6.5g,3eq,19.96mmol)的水(20mL)溶液,最后加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(810mg,0.15eq,1mmol)。混合物氮气置换三次后,在氮气氛围中加热至100度,并在此温度下搅拌2小时。反应液降温后,加入水和二氯甲烷稀释。分出有机相,有机相水洗、盐水洗、干燥后过滤旋干。残余物通过柱层析纯化(MeOH/DCM(0.1%TEA)=0%~5%)得到化合物1-4(4g,收率75.06%)。
1M浓度TBAF四氢呋喃溶液(25mL,5eq,25mmol)加入到化合物1-4(4g,1eq,5mmol)的四氢呋喃(40mL)溶液中。反应液室温下搅拌1小时后真空浓缩。残余物通过柱层析纯化(MeOH/DCM(0.1%TEA)=0%~6%)得到化合物1-5(1.9g,收率59.02%)。
三乙胺(16.99g,1.2eq,167.87mmol)加入到对硝基苯酚(21.41g,1.1eq,153.88mmol)的二氯甲烷(96.23mL)溶液中,然后在0度下缓慢加入化合物1-a(20g,1eq,139.89mmol)。混合物升至室温并搅拌1小时后,用水洗,盐水洗,无水硫酸钠干燥后,过滤旋干。残余物通过柱层析纯化(PE/EA=0%~6%)得到化合物1-b(17.5g,收率50.93%)。
化合物1-b(10g,1eq,40.71mmol)溶解到丙酮(100mL)中,然后加入碘化钠(24.41g,4eq,162.86mmol)。混合物氮气置换后,加热到50度并在温度下搅拌30小时。混合物过滤,滤液旋干。残余物通过柱层析纯化(PE/EA=0%~3%)得到化合物1-c(8.3g,收率60.48%)。
正丁酸(20g,1eq,227.00mmol)溶解到乙腈(200mL)和水(100mL)的混合溶剂中,加入氧化银(31.56g,0.6eq,136mmol)。混合物室温下避光反应16小时后,过滤。滤液旋干得到丁酸银(11g,收率24.85%)。
丁酸银(2.53g,1.15eq,12.96mmol)加入到化合物1-c(3.8g,1eq,11.27mmol)的甲苯(38mL)溶液中。反应液加热至50度,并在此温度下搅拌过夜。反应液降至室温后过滤,滤液旋得到固体。此固体通过柱层析纯化(PE/EA=0%~3%)得到化合物1-d(1.59g,收率47.51%)。
化合物1-d(1.58g,1.8eq,5.3mmol)加入到化合物1-5(1.9g,1eq,2.95mmol)的二氯甲烷(19mL)溶液中,然后加入三乙胺(745.56mg,2.5eq,7.37mmol)和DMAP(72.01mg,0.2eq,0.589mmol)。混合物于40度搅拌1小时,然后旋干。残余物通过柱层析纯化(MeOH/DCM=0%~3%)得到化合物1-6(1.56g,收率65.93%)。
化合物1-6(1.56g,1eq,1.94mmol)溶解到二氯甲烷(100mL)和甲醇(0.5mL)的混合溶剂中,然后缓慢加入4M的盐酸二氧六环溶液(6mL)。反应液室温搅拌15分钟后40度快速旋干。残余物加入二氯甲烷溶解,用三乙胺调节pH至碱性,然后旋干。残余物再次加入二氯溶解,用水洗两到三次,盐水洗,无水硫酸钠干燥后过滤。滤液旋干得到粗品1。粗品通过柱层析纯化(MeOH/DCM=0%~5%)得到化合物1(1.2g,收率80.07%)。1H NMR(500MHz,CD3OD)δppm 0.96-1.05(m,3H),1.57(s,3H),1.69(s,2H),1.84-2.13(m,7H),2.18-2.48(m,5H),3.06-3.18(m,1H),3.38-3.50(m,3H),3.70-3.88(m,2H),4.19-4.34(m,2H),4.29-4.45(m,2H),4.46-4.56(m,2H),5.33(s,0.5H),5.44(s,0.5H),6.84-6.95(m,1H),7.24(s,1H),7.32-7.42(m,2H),7.87-7.94(m,1H),9.06(s,1H).m/z(ESI+):759.3.
化合物2的合成
化合物2的合成方法参考化合物1,用异戊酸作为原料。1H NMR(500MHz,CD3OD)δppm9.14(s,1H),7.92(dd,J=9.0,6.0Hz,1H),7.41(d,J=2.5Hz,1H),7.38(t,J=9.0Hz,1H),7.25(d,J=2.5Hz,1H),6.87(q,J=5.5Hz,1H),5.61(d,J=52Hz,1H),4.82-4.62(m,4H),4.54(s,2H),4.12-3.72(m,5H),3.56-3.46(m,1H),3.38(d,J=9.2Hz,1H),2.82-2.55(m,3H),2.52-2.44(m,1H),2.43-2.34(m,2H),2.27-2.16(m,1H),2.14-1.96(m,2H),1.87(d,J=7.9Hz,2H),1.58(d,J=4.3Hz,3H),1.21(s,6H).m/z(ESI+):759.6.
化合物3的合成
化合物3的合成方法参考化合物1,用乙酸作为原料。1H NMR(500MHz,CD3OD)δppm9.14(s,1H),7.91(dd,J=9.0,6.0Hz,1H),7.41(d,J=2.5Hz,1H),7.37(t,J=9.0Hz,1H),7.25(d,J=2.5Hz,1H),6.87(q,J=5.0Hz,1H),5.61(d,J=51.0Hz,1H),4.84-4.64(m,4H),4.53(s,2H),4.11-3.71(m,5H),3.57-3.47(m,1H),3.38(d,J=9.1Hz,1H),2.81-2.57(m,2H),2.52-2.43(m,1H),2.43-2.34(m,2H),2.27-1.98(m,6H),1.86(d,J=8.0Hz,2H),1.57(s,3H).m/z(ESI+):731.57.
化合物4的合成
化合物3(50mg,0.068mmol,1eq)溶于二氯甲烷(5mL)中,加入异戊酸(6.99mg,0.068mmol,1eq),DCC(14.12mg,0.068mmol,1eq)和DMAP(8.36mg,0.068mmol,1eq)。混合物在室温下搅拌1小时后,旋干。残余物通过柱层析纯化(MeOH/DCM=0%~3%)得到化合物4(36.1mg,收率64.3%)。1H NMR(500MHz,CD3OD)δppm 9.08(s,1H),8.13(dd,J=9.0,6.0Hz,1H),7.91(d,J=2.5Hz,1H),7.51(t,J=9.0Hz,1H),7.47(s,1H),6.86(d,J=5.5Hz,1H),5.38(d,J=53.5Hz,1H),4.82-4.62(m,2H),4.57-4.46(m,2H),4.46-4.30(m,2H),3.94-3.70(m,2H),3.57-3.38(m,3H),3.16-3.09(m,1H),2.57(d,J=7.0Hz,2H),2.49-2.18(m,4H),2.13-1.93(m,8H),1.93-1.80(m,2H),1.56(s,3H),1.11(d,J=6.5Hz,6H).m/z(ESI+):815.5.
化合物5的合成
化合物5的合成方法参考化合物1,用特戊酸作为原料。1H NMR(500MHz,CD3OD)δppm9.05(s,1H),7.89(dd,J=9.0,5.5Hz,1H),7.38(d,J=2.0Hz,2H),7.35(t,J=9.0Hz,1H),7.24(s,1H),6.85(q,J=5.0Hz,1H),5.37(d,J=53.5Hz,1H),4.80-4.63(m,2H),4.58-4.44(m,2H),4.42-4.28(m,2H),3.93-3.64(m,2H),3.50-3.36(m,2H),3.32-3.26(m,1H),3.16-3.05(m,1H),2.47-2.15(m,3H),2.13-1.82(m,7H),1.57(s,3H),1.24(d,J=6.5Hz,9H).m/z,(ESI+):773.3.
化合物6的合成
化合物6的合成方法参考化合物1,用2-丙基戊酸作为原料。1H NMR(500MHz,DMSO-d6)δppm 10.19(s,1H),9.04(s,1H),8.00(m,1H),7.62-7.36(m,2H),7.19(s,1H),6.81(q,J=5.0Hz,1H),5.30(d,J=53.5Hz,1H),4.49(m,4H),4.17-3.95(m,3H),3.81-3.40(m,2H),3.07(m,3H),2.85(m,1H),2.08(m,3H),1.92-1.76(m,6H),1.50(m,5H),1.41(m,2H),1.26(m,5H),1.07(m,1H),0.90(m,6H).(ESI+):815.3.
化合物7的合成
化合物7的合成方法参考化合物4,用特戊酸及化合物1为原料。1H NMR(500MHz,CD3OD)δppm 0.93-1.01(m,3H),1.40(s,9H),1.49-1.58(m,3H),1.60-1.72(m,2H),1.80-2.07(m,7H),2.10-2.40(m,5H),2.99-3.08(m,1H),3.14-3.28(m,3H),3.43-3.52(m,1H),3.73-3.85(m,1H),4.21-4.36(m,2H),4.42-4.52(m,2H),4.59-4.75(m,2H),5.26(s,0.5H),5.37(s,0.5H),6.81-6.90(m,1H),7.41(s,1H),7.46-7.53(m,1H),7.87(s,1H),8.06-8.13(m,1H),9.04(s,1H).m/z(ESI+):843.4.
化合物8的合成
化合物8的合成方法参考化合物1,用3-环戊基丙酸作为原料。1H NMR(500MHz,CD3OD)δppm 9.06(s,1H),7.89(dd,J=9.0,5.5Hz,1H),7.38(d,J=2.5Hz,1H),7.36(t,J=9.0Hz,1H),7.24(s,1H),6.88(d,J=5.5Hz,1H),5.37(d,J=54.0Hz,1H),4.80-4.60(m,2H),4.51(s,2H),4.44-4.27(m,2H),3.92-3.68(m,2H),3.50-3.37(m,2H),3.17-3.04(m,1H),2.48-2.24(m,4H),2.24-2.16(m,1H),2.13-2.00(m,4H),2.00-1.76(m,6H),1.74-1.48(m,9H),1.20-1.08(m,2H).m/z(ESI+):813.3.
化合物9的合成
化合物9的合成方法参考化合物1,用环戊基乙酸作为原料。1H NMR(500MHz,CD3OD)δppm 9.06(s,1H),7.89(dd,J=9.0,5.5Hz,1H),7.42-7.31(m,2H),7.23(s,1H),6.88(d,J=5.0Hz,1H),5.39(d,J=53.5Hz,1H),4.8-4.63(m,2H),4.56-4.46(m,2H),4.45-4.31(m,2H),3.90-3.70(m,2H),3.51-3.37(m,3H),3.19-3.08(m,1H),2.52-2.18(m,6H),2.15-1.94(m,5H),1.93-1.81(m,4H),1.76-1.49(m,7H),1.29-1.18(m,2H).m/z(ESI+):799.3.
化合物10的合成
化合物10的合成方法参考化合物1,用异戊酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.94-1.03(m,6H),1.48-1.58(m,3H),1.81-2.06(m,7H),2.06-2.39(m,6H),2.99-3.08(m,1H),3.20-3.29(m,2H),3.34-3.40(m,1H),3.64-3.84(m,2H),4.21-4.36(m,2H),4.43-4.53(m,2H),4.60-4.76(m,3H),5.27(s,0.5H),5.38(s,0.5H),6.82-6.91(m,1H),7.21(d,J=2.0Hz,1H),7.29-7.39(m,2H),7.83-7.90(m,1H),9.02(s,1H).m/z(ESI+):773.4.
化合物11的合成
化合物11的合成方法参考化合物1,用正己酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.84-0.97(m,3H),1.31-1.41(m,4H),1.45-1.58(m,3H),1.58-1.69(m,2H),1.80-2.11(m,7H),2.13-2.43(m,5H),3.02-3.13(m,1H),3.23-3.29(m,1H),3.34-3.43(m,2H),3.63-3.85(m,2H),4.25-4.40(m,2H),4.43-4.52(m,2H),4.60-4.75(m,2H),5.29(s,0.5H),5.39(s,0.5H),6.82-6.89(m,1H),7.20(s,1H),7.28-7.39(m,2H),7.83-7.91(m,1H),9.02(s,1H).m/z(ESI+):787.3.
化合物12的合成
化合物12的合成方法参考化合物1,用金刚烷乙酸作为原料。1H NMR(500MHz,CD3OD)δppm 1.53(s,3H),1.66-1.73(m,12H),1.87-2.35(m,15H),3.02(s,1H),3.17-3.36(m,4H),3.70-3.78(m,2H),4.22-4.32(m,2H),4.48(s,2H),4.67(s,2H),5.25-5.36(m,1H),6.86(s,1H),7.20(s,1H),7.30-7.35(m,2H),7.84-7.87(m,1H),9.00(s,1H).m/z(ESI+):866.4.
化合物13的合成
化合物13的合成方法参考化合物1,用2-甲基丁酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.93(s,3H),1.15(s,3H),1.29(s,1H),1.54-1.67(m,6H),1.86-2.40(m,12H),3.07-3.39(m,2H),3.72-3.78(m,2H),4.26-4.37(m,2H),4.47(s,2H),4.67(s,2H),5.28-5.39(m,1H),6.86(s,1H),7.20(s,1H),7.31-7.35(m,2H),7.85-7.88(m,1H),9.02(s,1H).m/z(ESI+):773.3.
化合物14的合成
化合物14的合成方法参考化合物1,用环己基甲酸作为原料。1H NMR(500MHz,CD3OD)δppm 9.06(s,1H),7.90(dd,J=9.0,5.5Hz,1H),7.42-7.33(m,2H),7.24(s,1H),6.86(q,J=5.0Hz,1H),5.37(d,J=53.5Hz,1H),4.82-4.60(m,2H),4.57-4.45(m,2H),4.43-4.29(m,2H),3.90-3.67(m,2H),3.46-3.37(m,2H),3.17-3.06(m,1H),2.50-2.15(m,4H),2.15-1.84(m,9H),1.83-1.74(m,2H),1.74-1.62(m,1H),1.61-1.53(m,3H),1.53-1.43(m,2H),1.42-1.24(m,5H).m/z(ESI+):799.3.
化合物15的合成
化合物15的合成方法参考化合物1,用正辛酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.81-0.95(m,3H),1.27-1.36(m,8H),1.49-1.68(m,5H),1.80-2.55(m,12H),3.12-3.21(m,1H),3.34-3.50(m,3H),3.68-3.87(m,2H),4.32-4.53(m,4H),4.60-4.78(m,2H),5.34(s,0.5H),5.45(s,0.5H),6.80-6.90(m,1H),7.20(s,1H),7.29-7.39(m,2H),7.83-7.91(m,1H),9.04(s,1H).m/z(ESI+):815.3.
化合物16的合成
化合物16的合成方法参考化合物1,用2,2-二甲基丁酸作为原料。1H NMR(500MHz,CD3OD)δppm 9.05(s,1H),7.94-7.85(m,1H),7.44-7.30(m,2H),7.23(s,1H),6.87-6.88(m,1H),5.31-5.41(m,1H),4.71(s,2H),4.50(m,2H),4.41-4.26(m,2H),3.81(m,2H),3.41(s,1H),3.30(m,2H),3.09(s,1H),2.19-2.39(m,3H),2.13-1.84(m,7H),1.57-1.62(m,5H),1.31-1.33(m,1H),1.21(s,6H),0.91(s,3H).(ESI+):787.4.
化合物17的合成
化合物17的合成方法参考化合物1,用3,3-二甲基丁酸作为原料。1H NMR(500MHz,CD3OD)δppm 1.06(s,9H),1.54(s,3H),1.86-2.34(m,13H),3.03-3.04(m,1H),3.22-3.38(m,3H),3.75-3.78(m,2H),4.23-4.33(m,2H),4.48(s,2H),4.70(s,2H),5.26-5.37(m,1H),6.86(s,1H),7.20(s,1H),7.31-7.35(m,2H),7.85-7.88(m,1H),9.01(s,1H).(ESI+):755.4.
化合物18的合成
化合物18的合成方法参考化合物1,用2-乙基已酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.87-1.02(m,6H),1.28-1.31(m,4H),1.47-1.68(m,7H),1.82-2.42(m,11H),2.99-3.09(m,1H),3.23-3.28(m,1H),3.35-3.47(m,3H),3.68-3.86(m,1H),4.22-4.37(m,2H),4.42-4.53(m,2H),4.62-4.76(m,2H),5.27(s,0.5H),5.38(s,0.5H),6.82-6.94(m,1H),7.21(s,1H),7.28-7.39(m,2H),7.82-7.91(m,1H),9.02(s,1H).m/z(ESI+):815.4.
化合物19的合成
化合物19的合成方法参考化合物1,用丙酸作为原料。1H NMR(500MHz,CD3OD)δppm1.07-1.18(m,3H),1.49-1.59(m,3H),1.80-2.46(m,12H),2.98-3.09(m,1H),3.21-3.27(m,2H),3.36-3.47(m,3H),3.74-3.87(m,1H),4.19-4.37(m,2H),4.42-4.54(m,2H),4.59-4.74(m,1H),5.27(s,0.5H),5.37(s,0.5H),6.81-6.90(m,1H),7.21(s,1H),7.29-7.40(m,2H),7.82-7.93(m,1H),9.02(s,1H).m/z(ESI+):745.3.
化合物20的合成
化合物20的合成方法参考化合物1,用2-丁基已酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.85(s,6H),1.25(s,8H),1.48-1.55(m,7H),1.88-1.90(m,7H),2.12(s,1H),2.20-2.42(m,3H),3.03(s,1H),3.34(s,3H),3.65-3.74(m,2H),4.26-4.62(m,7H),5.24-5.35(m,1H),6.83(s,1H),7.15(s,1H),7.27-7.29(m,2H),7.80(s,1H),8.97(s,1H).m/z(ESI+):843.4.
化合物21的合成
化合物21的合成方法参考化合物1,用戊酸作为原料。1H NMR(500MHz,CD3OD)δppm0.95-0.98(t,J=7.5Hz,3H),1.32-1.42(m,3H),1.57-1.64(m,5H),1.86-1.87(m,2H),2.06-2.19(m,3H),2.39-2.48(m,6H),2.59-2.74(m,2H),3.39-3.51(m,2H),3.82-4.09(m,5H),4.33(s,2H),4.73-4.78(m,4H),5.56-5.66(m,1H),6.88-6.89(m,1H),7.25(s,1H),7.36-7.41(m,2H),7.90-7.93(m,1H),9.14(s,1H).m/z(ESI+):773.3.
化合物22的合成
化合物22的合成方法参考化合物1,用烟酸作为原料。1H NMR(500MHz,CD3OD)δppm1.71(s,3H),1.87-2.34(m,11H),3.04-3.30(m,3H),3.81(s,2H),4.27-4.32(m,2H),4.50-4.65(m,5H),5.27-5.38(m,1H),7.14(s,1H),7.20(s,1H),7.33-7.35(m,2H),7.60(s,1H),7.86(s,1H),8.44(s,1H),8.78(s,1H),9.02(s,1H),9.16(s,1H).m/z(ESI+):794.3.
化合物23的合成
化合物23的合成方法参考化合物1,用1-萘甲酸作为原料。1H NMR(500MHz,CD3OD)δppm 1.73(s,3H),1.82-2.22(m,11H),3.00(s,1H),3.18-3.22(m,3H),3.78-3.80(m,2H),4.22-4.26(m,2H),4.49-4.62(m,4H),5.22-5.33(m,1H),7.20(m,2H),7.27-7.29(m,2H),7.53-7.55(m,3H),7.82-7.93(m,2H),8.10-8.23(m,2H),8.85-9.00(m,2H).m/z(ESI+):843.3.
化合物24的合成
化合物24的合成方法参考化合物1,用苯甲酸作为原料。1H NMR(500MHz,CD3OD)δppm 9.04(d,J=15.5Hz,1H),8.08(s,2H),7.89(dd,J=9.0,5.5Hz,1H),7.67(s,1H),7.53(t,J=7.5Hz,2H),7.41-7.32(m,2H),7.23(s,1H),7.14(d,J=5.5Hz,1H),5.36(d,J=53.5Hz,1H),4.84-4.61(m,2H),4.60-4.47(m,2H),4.42-4.25(m,2H),3.93-3.71(m,2H),3.40(d,J=8.5Hz,1H),3.31-3.25(m,1H),3.15-3.03(m,1H),2.48-2.14(m,4H),2.13-2.01(m,4H),2.00-1.79(m,3H),1.79-1.65(m,3H).m/z,(ESI+):793.3.
化合物25的合成
化合物25的合成方法参考化合物1,用2-丁基辛酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.94(s,6H),1.33(s,12H),1.57(t,J=14.0Hz,7H),1.90(s,3H),2.03(s,3H),2.13-2.34(m,3H),2.36-2.38(m,2H),3.06(s,1H),3.24-3.27(m,3H),3.39(m,1H),3.74-3.82(m,2H),4.24-4.37(m,2H),4.50(s,2H),4.70(s,2H),5.34(d,J=53.5Hz,1H),6.91(s,1H),7.23(s,1H),7.34-7.35(m,2H),7.86-7.93(m,1H),9.04(s,1H).m/z,(ESI+):871.4.
化合物26的盐的合成
4M的盐酸二氧六环(3mL)溶液缓慢加入到化合物1-3(1.2g,2.34mmol,1eq)的二氯甲烷(10mL)溶液中。混合物在室温下搅拌1小时后真空浓缩,残余物通过柱层析纯化(EA/PE=0%~15%)得到化合物26-1(1.02g,收率93.27%)。
化合物1-1(1g,1.81mmol,1eq)加入到化合物26-1(1.02g,2.18mmol,1.2eq)的二氧六环(25mL)溶液中,然后加入碳酸铯(1.77g,5.44mmol,1eq)的水溶液,最后加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(294.21mg,0.36mmol,0.2eq)。混合物氮气置换三次后,在氮气氛围中加热至100度,并在此温度下搅拌2小时。反应液降温后,加入水和乙酸乙酯稀释。分出有机相,有机相水洗、盐水洗、干燥后过滤旋干。残余物通过柱层析纯化(MeOH/DCM=0%~4%)得到化合物26-2(759mg,收率48.8%)。
1M的TBAF四氢呋喃(4.43mL)溶液加入到化合物26-2(759mg,0.88mmol,1eq)的四氢呋喃(7.6mL)溶液中。反应液在室温下搅拌1.5小时后真空浓缩,残余物通过柱层析纯化(MeOH/DCM=0%~10%)得到化合物26-3(639mg,收率100%)。
癸酸(7.67mg,0.044mmol,1eq)加入到化合物26-3(31.2mg,0.044mmol,1eq)的二氯甲烷(2.99mL)溶液中,然后再加入DMAP(0.54mg,0.004mmol,0.1eq)和DCC(9.19mg,0.044mmol,1eq)。反应液在室温下搅拌1.5小时后真空浓缩,残余物通过柱层析纯化(MeOH/DCM=0%~4%)得到化合物26-4(29mg,收率76.18%)。
三氟乙酸(1mL)加入到化合物26-4(29mg,0.033mmol,1eq)的二氯甲烷(1mL)溶液中。反应液在室温下搅拌5分钟后真空浓缩,残余物通过反相制备色谱得到化合物26的盐(12.2mg,收率32.32%)。1H NMR 500MHz,CD3OD)δppm 9.16(s,1H),8.14(dd,J=9.0,5.5Hz,1H),7.92(s,1H),7.52(t,J=9.0Hz,1H),7.48(s,1H),5.61(d,J=51.5Hz,1H),4.75(s,2H),4.31(d,J=10.0Hz,2H),4.15-3.82(m,5H),3.49(dd,J=18.4,9.0Hz,2H),2.83-2.56(m,4H),2.53-2.43(m,1H),2.43-2.32(m,2H),2.17(dd,J=33.0,9.0Hz,5H),1.84-1.75(m,2H),1.57-1.27(m,14H),0.91(t,J=6.5Hz,3H).m/z,(ESI+):755.7.
化合物27的盐的合成
化合物27的盐的合成方法参考化合物26,用异戊酸作为原料。1H NMR(500MHz,CD3OD)δppm 1.08(d,J=5.0Hz,7H),2.03-2.47(m,10H),2.55-2.74(m,2H),2.57-2.75(m,2H),3.44-3.50(m,2H),3.85-4.05(m,5H),4.28(d,J=10.0Hz,2H),4.72-4.74(m,2H),5.53-5.63(m,1H),7.44(s,1H),7.50(d,J=10.0Hz,1H),7.90(s,1H),8.12(q,J=10.0Hz,1H),9.13(s,1H).m/z,(ESI+):785.5.
化合物28的盐的合成化合物28的盐的合成方法参考化合物26,用特戊酸作为原料。1H NMR(500MHz,CD3OD)δ9.16(s,1H),8.15(dd,J=9.0,5.5Hz,1H),7.92(d,J=2.0Hz,1H),7.53(t,J=9.0Hz,1H),7.44(s,1H),5.61(d,J=51.5Hz,1H),4.81-4.71(m,2H),4.32(s,2H),4.12-3.87(m,5H),3.59-3.44(m,2H),2.87-2.61(m,2H),2.55-2.44(m,1H),2.43-2.34(m,2H),2.28-2.10(m,5H),1.43(s,9H).m/z,(ESI+):685.6.
化合物29的盐的合成
化合物29的盐的合成方法参考化合物26,用十二烷酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.53-0.94(m,3H),1.28-1.48(m,16H),1.71-1.82(m,2H),2.01-2.24(m,5H),2.29-2.50(m,3H),2.56-2.77(m,4H),3.42-3.52(m,2H),3.81-4.07(m,5H),4.23-4.34(m,2H),4.66-4.77(m,2H),4.86(s,1H),5.53(s,0.5H),5.63(s,0.5H),7.46(s,1H),7.50(d,J=9.0Hz,1H),7.91(d,J=2.0Hz,1H),8.08-8.17(m,1H),9.13(s,1H).m/z(ESI+):783.4.
化合物30的盐的合成
化合物30的盐的合成方法参考化合物26,用环戊基丙酸作为原料。1H NMR(500MHz,CD3OD)δppm 9.16(s,1H),8.14(dd,J=9.0,5.5Hz,1H),7.93(d,J=2.2Hz,1H),7.53(t,J=9.0Hz,1H),7.49(s,1H),5.61(d,J=51.5Hz,1H),4.90(d,J=13.0Hz,1H),4.75(s,2H),4.38-4.27(m,2H),4.12-3.87(m,5H),3.55-3.45(m,2H),2.82-2.58(m,4H),2.55-2.32(m,3H),2.31-2.07(m,5H),1.99-1.78(m,5H),1.77-1.54(m,4H),1.28-1.17(m,2H).m/z(ESI+):725.4.
化合物31的盐的合成化合物31的盐的合成方法参考化合物26,用十六烷酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.87-0.91(m,3H),1.28-1.50(m,24H),1.72-1.82(m,2H),1.96-2.20(m,6H),2.20-2.52(m,3H),2.53-2.63(m,1H),2.63-2.72(m,2H),3.43-3.51(m,3H),3.74-4.01(m,4H),4.15-4.26(m,2H),4.58-4.71(m,2H),4.79-4.85(m,2H),5.49(s,0.5H),5.60(s,0.5H),7.42-7.56(m,2H),7.91(s,1H),8.07-8.20(m,1H),9.12(s,1H).m/z(ESI+):839.6.
化合物32的盐的合成化合物32的盐的合成方法参考化合物26,用2-己基癸酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.87(t,J=5.0Hz,6H),1.28-1.46(m,22H),1.64-1.66(m,2H),75-1.81(m,2H),2.10-2.16(m,5H),2.35-2.44(m,3H),2.57-2.75(m,3H),3.45=3.50(m,2H),3.86-4.02(m,5H),4.27-4.29(m,2H),4.72(s,2H),5.53-5.63(m,1H),7.38(s,1H),7.51(t,J=10.0Hz,1H),7.87-7.88(m,1H),8.12-8.15(m,1H),9.14(s,1H).m/z(ESI+):839.5.
化合物33的盐的合成
化合物33的盐的合成方法参考化合物26,用异丁酸作为原料。1H NMR(500MHz,CD3OD)δppm 1.36(s,3H),1.38(s,3H),2.13-2.21(m,5H),2.35-2.50(m,3H),2.60-2.78(m,2H),2.91-2.97(m,1H),3.47-3.53(m,2H),3.90-4.06(m,2H)4.31(s,2H),4.74-4.75(d,J=5.0Hz,2H),4.88-4.91(m,2H),5.56-5.67(m,1H),7.47(s,1H),7.51-7.55(m,1H),7.93(s,1H),8.14-8.16(m,1H),9.17(s,1H).m/z(ESI+):671.3.
化合物34的盐的合成
化合物34盐的合成方法参考化合物26,用熊去氧胆酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.73(s,3H),0.97(s,3H),1.04(d,J=5.5Hz,3H),1.14-1.39(m,9H),1.40-1.67(m,12H),1.77-2.26(m,12H),2.29-2.49(m,3H),2.54-2.79(m,4H),3.41-3.55(m,4H),3.83-4.08(m,5H),4.23-4.33(m,2H),4.64-4.76(m,2H),5.53(s,0.5H),5.64(s,0.5H),7.42-7.55(m,2H),7.90(s,1H),8.07-8.15(m,1H),9.13(s,1H).m/z(ESI+):975.5.
化合物35的合成
化合物35的合成方法参考化合物26,用花生四烯酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.89-0.92(t,J=7.5Hz,3H),1.31-1.37(m,10H),1.85-1.91(m,2H),2.04-2.08(m,2H),2.13-2.50(m,10H),2.75-2.91(m,9H),3.48-3.52(m,2H),3.89-4.08(m,6H),4.31-4.33(m,2H),4.75(s,4H),5.29-5.48(m,8H),5.57-5.67(m,1H)7.50-7.55(m,2H)7.94(s,1H),8.12-8.15(m,1H),9.16(s,1H).m/z(ESI+):887.5.
化合物36的盐的合成
化合物36的盐的合成方法参考化合物26,用2-甲基丁酸作为原料。1H NMR(500MHz,CD3OD)δ1.06(t,J=7.5Hz,3H),1.32(d,J=7.0Hz,3H),1.63-1.75(m,1H),1.81-1.88(m,1H),2.10-2.18(m,5H),2.31-2.39(m,2H),2.45(s,1H),2.56-2.79(m,3H),3.45-3.51(m,2H),3.85-4.08(m,5H),4.29(d,J=10.0Hz,2H),4.68-4.76(m,2H),4.86(s,2H),5.53(s,1H),5.64(s,1H),7.43(s,1H),7.51(t,J=9.0Hz,1H),7.91(d,J=2.0Hz,1H),8.13(dd,J=9.0,5.5Hz,1H),9.14(s,1H).m/z(ESI+):685.3.
化合物37的合成
化合物37的合成方法参考化合物26,用十四烷酸作为原料。1H NMR(500MHz,CD3OD)δ9.16(s,1H),8.13-8.14(m,1H),7.93(s,1H),7.49-7.55(m,2H),5.56-5.61(m,1H),4.91(m,2H),4.75(s,2H),4.31(s,2H),4.09-3.86(m,4H),3.48-3.50(d,2H),2.60-2.75(m,4H),2.37-2.47(m,3H),2.07-2.19(m,5H),1.78-1.79(m,2H),1.31-1.48(m,21H),0.90-0.93(m,3H).(ESI+):811.5.
化合物38的盐的合成
化合物38的盐的合成方法参考化合物26,用2-丙基戊酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.99(t,J=5.0Hz,6H),1.45-1.79(m,8H),2.11-2.76(m,11H),3.48-3.49(m,2H),3.86-4.05(m,5H),4.26-4.29(m,2H),4.72(s,2H),4.84-4.93(m,2H),5.54-5.64(m,1H),7.38(s,1H),7.51(t,J=10.0Hz,1H),7.88-7.89(m,1H),8.13-8.16(m,1H),9.13(s,1H).(ESI+):727.3.
化合物39的盐的合成
化合物39的合成方法参考化合物26,用壬酸作为原料。1H NMR(500MHz,CD3OD)δppm0.91-0.93(m,3H),1.35-1.47(m,12H),1.61-1.64(m,2H),1.76-1.81(m,2H),2.13-2.23(m,4H),2.29-2.49(m,4H),2.68-2.7(m,2H),3.49-3.50(m,2H),3.89-4.07(m,4H),4.30-4.32(m,2H),4.75(s,2H),5.56-5.67(m,1H),7.49(s,1H),7.51-7.55(t,J=18.0Hz,1H),7.91-7.94(d,J=2.0Hz,1H),8.13-8.16(m,1H),9.16(s,1H).m/z(ESI+):741.3.
化合物40的盐的合成
化合物40的盐的合成方法参考化合物26,用油酸作为原料。1H NMR(500MHz,CD3OD)δppm 9.16(s,1H),8.15-8.16(m,1H),7.94(s,1H),7.49-7.55(m,2H),5.56-5.66(m,1H),5.37(s,2H),4.89-4.95(m,1H),4.72-4.78m,2H),4.32(s,2H),3.82-4.06(m,4H),3.48-3.52(m,2H),2.81-2.55(m,4H),2.31-2.47(m,3H),2.01-2.19(m,8H),1.78-1.81(m,2H),1.63(s,1H),1.31-1.48(m,22H),0.91-0.93(m,3H).(ESI+):865.4.
化合物41的盐的合成
化合物41的盐的合成方法参考化合物26,用2-丁基辛酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.88-0.96(m,6H),1.29-1.42(m,13H),1.65-1.78(m,4H),2.09-2.15(m,5H),2.35-2.76(m,5H),3.46-3.48(m,2H),3.86-4.02(m,5H),4.26-4.29(m,2H),4.72(s,2H),4.85-4.94(m,2H),5.53-5.64(m,1H),7.38(s,1H),7.51(t,J=10.0Hz,1H),7.88(s,1H),8.13-8.15(m,1H),9.14(s,1H).(ESI+):783.4.
化合物42的盐的合成
化合物42的盐的合成方法参考化合物26,用2-丁基己酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.95(t,J=5.0Hz,6H),1.39-1.42(s,8H),1.65-1.66(m,2H),1.79(t,J=5.0Hz,2H),2.10-2.15(m,5H),2.35-2.45(m,3H),2.57-2.75(m,3H),3.46-3.50(m,2H),3.90-4.04(m,5H),4.27-4.29(m,2H),4.69-4.75(m,2H),4.85-4.93(m,2H),5.53-5.64(m,1H),7.38(s,1H),7.51(t,J=10.0Hz,1H),7.88-7.89(m,1H),8.13-8.16(m,1H),9.14(s,1H).(ESI+):755.4.
化合物43的盐的合成
化合物43的盐的合成方法参考化合物26,用辛酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.91(t,J=6.5Hz,3H),1.32-1.48(m,8H),1.71-1.82(m,2H),2.08-2.22(m,5H),2.28-2.50(m,3H),2.55-2.78(m,4H),3.46(d,J=8.0Hz,2H),3.86-4.02(m,5H),4.29(s,2H),4.72(s,2H),4.87(d,J=12.5Hz,2H),5.58(d,J=51.7Hz,1H),7.49(dd,J=20.0,11.1Hz,2H),7.91(d,J=2.0Hz,1H),8.12(dd,J=9.0,5.5Hz,1H),9.13(s,1H).(ESI+):727.4.
化合物44的盐的合成
化合物44的盐的合成方法参考化合物26,用金刚烷乙酸作为原料。1H NMR(500MHz,CD3OD)δppm 1.66-1.84(m,15H),2.09-2.15(m,5H),2.34-2.36(m,2H),2.39(s,2H),2.44-2.45(m,1H),2.59-2.72(m,2H),3.45-3.49(m,2H),3.85-4.04(m,5H),4.26-4.29(m,2H),4.72(s,2H),4.84-4.93(m,2H),5.53-5.63(m,1H),7.43(s,1H),7.50(t,J=10.0Hz,1H),7.88-7.89(m,1H),8.12-8.14(m,1H),9.13(s,1H).(ESI+):777.3.
化合物45的盐的合成
化合物45的盐的合成方法参考化合物26,用烟酸作为原料。1H NMR(500MHz,CD3OD)δppm 2.10-2.22(m,5H),2.33-2.35(m,2H),2.45-2.47(m,1H),2.56-2.77(m,2H),3.46-3.51(m,2H),3.85-4.03(m,5H),4.27-4.29(m,2H),4.72-4.75(m,2H),4.87-4.88(m,2H),5.54-5.64(m,1H),7.52-7.55(m,1H),7.69(s,1H),7.73-7.76(m,1H),8.12-8.18(m,2H),8.69-8.70(m,1H),8.89(s,1H),9.15(s,1H),9.38(s,1H).(ESI+):706.2.
化合物46的盐的合成
化合物46的盐的合成方法参考化合物26,用3,3-二甲基丁酸作为原料。1H NMR(500MHz,CD3OD)δppm 9.16(s,1H),8.15-8.18(m,1H),7.94(s,1H),7.54(t,J=8.5Hz,1H),7.46(s,1H),5.56-5.66(m,1H),4.75(m,2H),4.31(d,J=11.0Hz,2H),4.10-3.88(m,6H),3.49-3.50(m,2H),2.63-2.78(m,2H),2.58(s,2H),2.48(m,1H),2.35-2.41(m,2H),2.28-2.08(m,6H),1.19(s,9H).(ESI+):699.3.
化合物47的盐的合成
化合物47的盐的合成方法参考化合物26,用1-萘甲酸作为原料。1H NMR(500MHz,CD3OD)δppm 2.10-2.15(m,5H),2.35-2.45(m,3H),2.57-2.75(m,2H),3.49-3.51(m,2H),3.86-4.02(m,5H),4.27-4.30(m,2H),4.69-4.73(m,2H),4.89-4.93(m,2H),5.54-5.64(m,1H),7.53-7.56(m,1H),7.60-7.70(m,4H),8.02(d,J=5.0Hz,1H),8.14-8.24(m,3H),8.58(d,J=5.0Hz,1H),8.99(d,J=5Hz,1H),9.16(s,1H).(ESI+):755.3.
化合物48的合成
吡啶(109.7mg,1.39mmol,0.1eq)加入到化合物48-1(1g,13.87mmol,1eq)的四氯化碳(10mL)溶液中,氮气保护下冷却到零下20度到零下10度,缓慢加入三聚光气(2.36g,6.93mmol,0.5eq)。混合物缓慢生物至室温,然后加热至40度,并在此温度下搅拌1小时。反应液冷却至室温,然后过滤。滤液旋干得到化合物48-2(1.5g,收率63.24%)。
三乙胺(1.07g,10.52mmol,1.2eq)加入到对硝基苯酚(1.34g,9.65mmol,1.1eq)的四氢呋喃(20mL)溶液中,然后加入化合物48-2(1.5g,8.77mmol,1eq)。反应液在室温下搅拌1.5小时后,加入二氯甲烷和水。分出的有机相用水洗,盐水洗后,然后用无水硫酸钠干燥过滤。滤液选干后的残余物通过柱层析纯化(DCM)得到化合物48-3(2.2g,收率91.66%)。
化合物48-3(2.2g,8.04mmol,1eq)溶解到丙酮(20mL)中,然后加入碘化钠(3.01g,20.1mmol,2.5eq)。混合物加热至50度并在此温度下搅拌15小时。反应液冷却至室温,然后过滤。滤液选干后的残余物通过柱层析纯化(DCM)得到化合物48-4(1.6g,收率60%)。
化合物48-4(0.5g,0.82mmol,1eq)溶于甲苯(10mL)中,加入丁酸银(240.3mg,1.23mmol,1.5eq)。混合物升温至50度并再次温度下搅拌15小时。反应液冷却至室温后过滤,滤液真空浓缩。残余物通过柱层析纯化(DCM)得到化合物48-5(120mg,收率44.89%)。
化合物48-5(60.55mg,0.18mmol,3eq)加入到化合物1-5(40mg,0.062mmol,1eq)的二氯甲烷(3mL)溶液中,然后加入DMAP(1.52mg,0.012mmol,0.2eq)和三乙胺(18.84mmol,0.18mmol,3eq)。混合物加热至40度并在此温度下搅拌1.5小时。反应液冷却后真空浓缩,残余物通过柱层析纯化(MeOH/DCM=0%~4%)得到化合物48-6(40mg,收率77.59%)。
化合物48-6(40mg,0.048mmol,1eq)溶解到二氯甲烷(5mL)中,然后加入4M的盐酸二氧六环溶液(0.5mL)。反应液在室温下搅拌15分钟然后真空浓缩。残余物用三乙胺碱化,然后通过柱层析纯化(MeOH/DCM=0%~6%)得到化合物48(16.8mg,收率43.5%)。1H NMR(500MHz,CD3OD)δppm 9.12(s,1H),7.96-7.88(m,1H),7.40(d,J=2.5Hz,1H),7.37(t,J=9.0Hz,1H),7.24(s,1H),6.83(s,1H),5.58(d,J=50.5Hz,1H),4.75-4.59(m,2H),4.57-4.47(m,2H),4.02-3.76(m,4H),3.50-3.38(m,4H),2.77-2.51(m,2H),2.49-2.28(m,5H),2.25-1.98(m,3H),1.94-1.80(m,4H),1.76-1.60(m,2H),1.60-1.45(m,2H),1.42-1.26(m,4H),1.11-0.96(m,6H).m/z,(ESI+):787.3.
化合物49的合成
化合物49的合成方法参考化合物48,用异丁醛作为原料。11H NMR(500MHz,CD3OD)δppm 9.04(s,1H),7.89(dd,J=9.0,5.5Hz,1H),7.45-7.31(m,2H),7.23(s,1H),6.65(d,J=4.3Hz,1H),5.34(d,J=54.0Hz,1H),4.79-4.62(m,2H),4.59-4.46(m,2H),4.38-4.22(m,2H),3.92-3.60(m,2H),3.40(d,J=8.0Hz,1H),3.32-3.18(m,3H),3.09-2.98(m,1H),2.48-2.09(m,4H),2.09-1.99(m,4H),1.98-1.83(m,3H),1.77-1.60(m,2H),1.16-0.96(m,9H).m/z,(ESI+):787.4.
化合物50的合成
化合物50的合成方法参考化合物48,用异丁醛作为原料。1H NMR(500MHz,CD3OD)δppm 0.97(t,J=5.0Hz,3H),1.21-1.69(m,6H),1.66-1.72(m,3H),1.80-2.01(m,12H),2.13-2.37(m,5H),3.02-3.03(m,1H),3.22-3.38(m,3H),3.78(s,2H),4.23-4.33(m,2H),4.47(s,2H),4.69(s,2H),5.26-5.37(m,1H),6.61-6.61(m,1H),7.21(s,1H),7.31-7.35(s,2H),7.85-7.88(m,1H),9.02(s,1H).m/z,(ESI+):827.4.
化合物51的盐的合成
DMF(13.3mg,0.18mmol,0.0008eq)加入到化合物51-1(5.8g,22.6mmol,1eq)的二氯亚砜(50mL)溶液中。反应液加热至85度并在此温度下搅拌3小时后,冷却至室温。反应液浓缩得到酰氯粗品。
二羟基丙酮(1.04g,11.56mmol,1eq)溶于二氯甲烷(30mL)中,加入吡啶(1.87g,23.7mmol,2.05eq),最后缓慢加入酰氯粗品。反应液室温下搅拌过夜后,加入水和二氯甲烷。分出有机相,用无水硫酸钠干燥后过滤。滤液真空浓缩,残余物通过柱层析纯化(EA/PE=0%~25%)得到化合物51-2(2.32g,收率35.41%)。
化合物51-2(2.22g,3.92mmol,1eq)分散到四氢呋喃(22mL)和水(15mL)的混合溶液中,然后冷却至0度。然后加入硼氢化钠(222mg,5.87mol,1.5eq),反应液在0度搅拌2分钟。保持内温0度下用0.5N的盐酸水溶液调节pH至7,然后加入二氯甲烷萃取。分出的有机相用无水硫酸钠干燥后过滤。滤液真空浓缩,获得的残余物通过柱层析纯化(EA/PE=0%~10%)得到化合物51-3(1.02g,收率45.78%)。
三乙胺(80mg,0.79mmol,1.5eq)加入到化合物51-3(300mg,0.53mmol,1eq)的二氯甲烷(3mL)溶液中,随后加入DMAP(6.44mg,0.05mmol,0.1eq),最后加入氯甲酸对硝基苯酯(127mg,0.63mmol,1.2eq)。反应液在室温下搅拌5小时,真空出去溶剂。残余物通过柱层析纯化(EA/PE=0%~10%)得到化合物51-4(123mg,收率31.78%)。
三乙胺(8.66mg,0.085mmol,1.5eq)加入到化合物26-3(40mg,0.057mmol,1eq)的二氯甲烷(4mL)溶液中,随后加入DMAP(0.7mg,0.005mmol,0.1eq),最后加入化合物51-4(50.28mg,0.068mmol,1.2eq)。反应液在室温下搅拌3小时后旋干。残余物通过柱层析纯化(MeOH/DCM=0%~4%)得到化合物51-5粗品(73mg,收率100%)。
三氟乙酸(3mL)加入到化合物51-5(73mg,0.056mmol,1eq)的二氯甲烷(3mL)溶液中。反应液室温下搅拌10分钟后真空浓缩,残余物通过薄板层析纯化得到化合物51的盐(15.6mg,收率16.48%)。1H NMR(500MHz,CD3OD)δppm 0.87-0.91(m,6H),1.20-1.31(m,48H),1.58-1.66(m,4H),1.96-2.24(m,5H),2.24-2.51(m,7H),2.51-2.74(m,2H),3.82-4.03(m,5H),4.16-4.46(m,4H),4.49-4.59(m,2H),4.63-4.75(m,2H),5.21(s,1H),5.51(s,0.5H),5.62(s,0.5H),7.48-7.55(m,1H),7.58(s,1H),8.02(s,1H),8.11-8.17(m,1H),9.14(s,1H).m/z(ESI+):1196.0.
化合物52的盐的合成
化合物52的盐的合成方法参考化合物51,用壬酸作为原料。1H NMR(500MHz,CD3OD)δppm 9.18(s,1H),8.17(dd,J=9.0,5.5Hz,1H),8.06(d,J=2.0Hz,1H),7.61(s,1H),7.56(t,J=9.0Hz,1H),5.62(d,J=51.5Hz,1H),5.29-5.21(m,1H),4.75(s,2H),4.57(d,J=10.0Hz,2H),4.40-4.28(m,4H),4.14-3.81(m,5H),3.61-3.45(m,2H),2.84-2.57(m,2H),2.55-2.44(m,1H),2.40(t,J=6.6Hz,6H),2.32-2.12(m,5H),1.74-1.61(m,4H),1.44-1.18(m,20H),0.87(t,J=6.0Hz,6H).m/z(ESI+):999.5.
化合物53的盐的合成
化合物53的盐的合成方法参考化合物51,用十二烷酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.86(t,J=5.0Hz,6H),1.23-1.36(m,32H),1.59-1.62(m,5H),2.08-2.15(m,6H),2.35-2.43(m,8H),2.54-2.75(m,1H),3.45-3.48(m,2H),3.81-4.03(m,5H),4.27-4.30(m,4H),4.52-4.55(m,2H),4.69(s,2H),5.21(s,1H),5.52-5.62(m,1H),7.51(t,J=5.0Hz,1H),7.58(s,1H),8.01(s,1H),8.11-8.14(m,1H),9.13(s,1H).m/z(ESI+):1083.7.
化合物54的盐的合成
化合物54的盐的合成方法参考化合物51,用油酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.89(t,J=5.0Hz,6H),1.21-1.27(m,40H),1.60-1.62(m,5H),1.97-2.16(m,13H),2.36-2.73(m,10H),3.46-3.47(m,2H),3.86-4.05(m,5H),4.23-4.44(m,4H),4.53-55(m,2H),4.72(s,2H),5.20-5.41(m,5H),5.53-5.64(m,1H),7.52(t,J=5.0Hz,1H),7.58(s,1H),8.02(s,1H),8.11-8.14(m,1H),9.14(s,1H).m/z(ESI+):1248.5.
化合物55的盐的合成
化合物55的盐的合成方法参考化合物51,用丁酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.91-0.95(m,6H),1.61-1.66(m,4H),2.10-2.18(m,5H),2.31-2.73(m,10H),3.46-3.50(m,2H),3.85-4.06(m,5H),4.24-4.30(m,4H),4.38-4.42(m,1H),4.51-4.56(m,2H),4.72(s,2H),5.21-5.64(m,2H),7.52(t,J=5.0Hz,1H),7.57(s,1H),8.01-8.02(m,1H),8.12-8.15(m,1H),9.14(s,1H).m/z(ESI+):859.4.
化合物56的盐的合成
化合物56的盐的合成方法参考化合物51,用癸酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.84(t,J=5.0Hz,6H),1.24-1.31(m,24H),1.59-1.62(m,4H),2.10-2.76(m,14H),3.47-3.48(m,2H),3.86-4.06(m,5H),4.28-4.30(m,4H),4.53-55(m,2H),4.72(s,2H),4.86-4.90(m,2H),5.21(s,1H),5.54-5.64(m,1H),7.52(t,J=5.0Hz,1H),7.58(s,1H),8.02(s,1H),8.12-8.15(m,1H),9.14(s,1H).m/z(ESI+):1027.5.
化合物57的盐的合成
化合物57的盐的合成方法参考化合物51,用十一烷酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.85(t,J=5.0Hz,6H),1.21-1.29(m,28H),1.59-1.62(m,4H),2.10-2.18(m,6H),2.35-2.47(m,8H),2.57-2.76(m,2H),3.46-3.48(m,2H),3.86-4.06(m,5H),4.28-4.29(m,4H),4.52-4.55(m,2H),4.72(s,2H),5.21(s,1H),5.53-5.64(m,1H),7.52(t,J=10.0Hz,1H),7.58(s,1H),8.02(s,1H),8.12-8.15(m,1H),9.14(s,1H).m/z(ESI+):1055.5.
化合物58的盐的合成
化合物58的盐的合成方法参考化合物51,用十四烷酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.88(t,J=7.0Hz,6H),1.21-1.29(m,40H),1.55-1.66(m,4H),2.09-2.16(m,5H),2.28-2.48(m,7H),2.61-2.66(m,2H),3.47(d,J=9.0Hz,2H),3.84-3.99(m,5H),4.21-4.34(m,4H),4.50-4.57(m,2H),4.71(s,4H),5.21(s,1H),5.53(s,1H),5.63(s,1H),7.52(t,J=9.0Hz,1H),7.58(s,1H),8.02(d,J=2.0Hz,1H),8.13(dd,J=9.0,6.0Hz,1H),9.14(s,1H).m/z(ESI+):1139.7.
化合物59的盐的合成
化合物59的盐的合成方法参考化合物51,用十六烷酸作为原料。1H NMR(500MHz,MeOD)δppm 0.89(t,J=7.0Hz,6H),1.21-1.30(m,44H),1.60-1.61(m,4H),2.00-2.21(m,5H),2.35-2.38(m7H),2.49-2.72(m,2H),3.46(d,J=9.0Hz,2H),3.88-3.97(m,3H),4.25-4.29(m,2H),4.53-4.68(m,10H),5.21(s,1H),5.56(d,J=51.5Hz,1H),7.52(t,J=9.0Hz,1H),7.58(s,1H),8.02(s,1H),8.15(d,J=5.5Hz,1H),9.14(s,1H).m/z(ESI+):1167.7.
化合物60的盐的合成
化合物60的盐的合成方法参考化合物51,用十三烷酸作为原料。1H NMR(500MHz,CD3OD)δppm 0.87(t,J=5.0Hz,6H),1.21-1.30(m,36H),1.58-1.62(m,4H),2.10-2.16(m,5H),2.35-2.47(m,7H),2.57-2.76(m,2H),3.47-3.49(m,2H),3.86-4.06(m,5H),4.27-4.29(m,4H),4.52-4.55(m,2H),4.72(s,2H),4.85-4.92(m,2H),5.21(s,1H),5.54-5.64(m,1H),7.52(t,J=10.0Hz,1H),7.58(s,1H),8.02(s,1H),8.12-8.15(m,1H),9.14(s,1H).m/z(ESI+):1111.7.
化合物61的合成
60%的氢化钠(116mg,2.9mmol,1.2eq)加入到无水四氢呋喃(10mL)中,氮气保护下冷却至0度。然后加入化合物61-1(300mg,2.42mmol,1eq),当反应液中的气泡消失后,升至室温搅拌30分钟,然后在冷却至0度。缓慢滴加特戊酰氯(320mg,2.66mmol,1.1eq),反应液在0度下搅拌30分钟后升至室温,然后在室温下搅拌2小时。用10mL饱和碳酸氢钠水溶液淬灭反应,再加入水和乙酸乙酯。分出的有机相用盐水洗,然后用无水硫酸钠干燥后过滤。滤液旋干得到残余物,残余物通过柱层析纯化(EA/Hexane=0%~40%)得到化合物61-2(381mg,收率75.7%)。
三乙胺(58.31mg,0.57mmol,1.2eq)加入到化合物61-2(100mg,0.48mmol,1eq)的二氯甲烷(2mL)溶液中,然后再加入氯甲酸对硝基苯酯(106.5mg,0.53mmol,1.1eq)。反应液在室温搅拌6小时,然后浓缩。残余物通过柱层析纯化(EA/Hexane=0%~10%)得到无色油状化合物61-3(124mg,收率69.17%)。
三乙胺(9.42mg,0.093mmol,1.5eq)加入到化合物1-5(40mg,0.062mmol,1eq)的二氯甲烷(4mL)溶液中,然后加入DMAP(0.758mg,0.006mmol,0.1eq)和化合物61-3(27.8mg,0.074mmol,1.2eq)。反应液加热至40度,并在此温度下搅拌3小时。反应液冷却后浓缩,残余物通过柱层析纯化(MeOH/DCM=0%~4%)得到化合物61-4粗品(79mg,收率100%)。
4M的盐酸二氧六环溶液(1mL)加入到化合物61-4(79mg,0.089mmol,1eq)的二氯甲烷(10mL)溶液中。反应液在室温下搅拌2分钟后真空浓缩,残余物通过制备色谱纯化得到化合物61(20.7mg,收率27.24%)。1H NMR(500MHz,CD3OD)δppm 1.35(s,9H),1.79-1.94(m,3H),1.95-2.05(m,4H),2.10-2.37(m,3H),2.97-3.05(m,1H),3.14-3.29(m,3H),3.34-3.38(m,1H),3.76(s,2H),4.19-4.34(m,2H),4.50(s,2H),4.66(s,2H),5.19-5.28(m,2.5H),5.36(s,0.5H),7.08(d,J=8.5Hz,2H),7.20(s,1H),7.28-7.38(m,2H),7.48(d,J=8.5Hz,2H),7.82-7.91(m,1H),9.01(s,1H).m/z(ESI+):835.4.
化合物62的合成
化合物62的合成方法参考化合物61,用丁酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 1.03(t,J=5.0Hz,3H),1.73-1.79(m,2H),1.83-1.92(m,4H),1.96-2.00(m,5H),2.12-2.36(m,3H),2.56(t,J=10.0Hz,2H),2.99-3.02(m,1H),3.17-3.24(m,3H),3.75(s,2H),4.22-4.32(m,2H),4.50-4.65(m,4H),5.22(s,2H),5.25-5.36(m,1H),7.11(d,J=10Hz,2H),7.20(s,1H),7.30-7.35(m,2H),7.47(d,J=5.0Hz,2H),7.84-7.87(m,1H),9.00(s,1H).m/z(ESI+):821.6.
化合物63的合成
化合物63的合成方法参考化合物61,用乙酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 1.85-2.01(m,8H),2.15-2.23(m,2H),2.27(s,3H),3.02-3.03(m,5H),3.76(s,1H),4.26-4.32(m,1H),4.51-4.59(m,7H),5.22(s,2H),5.26-5.37(m,2H),7.12-7.13(d,J=5.0Hz,2H),7.20(s,1H),7.31-7.35(m,2H),7.47-7.48(m,2H),7.86(s,1H),9.01(s,1H).m/z(ESI+):793.59.
化合物64的合成
化合物64的合成方法参考化合物61,用癸酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 0.90(t,J=10.0Hz,3H),1.31-1.42(m,14H),1.69-2.00(m,9H),2.12-2.33(m,3H),2.57(t,J=5.0Hz,2H),3.01-3.03(m,1H),3.20-3.24(m,2H),3.33(t,J=10.0Hz,1H),3.75(s,2H),4.22-4.32(m,2H),4.50-4.65(m,4H),5.22(s,2H),5.25-5.36(m,1H),7.10(d,J=5.0Hz,2H),7.20(s,1H),7.32(d,J=10.0Hz,1H),7.35(s,1H),7.47(d,J=5.0Hz,2H),7.85(q,J=5Hz,1H),9.00(s,1H).m/z(ESI+):905.7.
化合物65的合成
化合物65的合成方法参考化合物61,用异戊酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 1.05(d,J=5.0Hz,7H),1.82(d,J=10.0Hz,2H),2.02(s,2H),2.16-2.21(m,2H),2.32-2.35(m,2H),2.45(m,J=5.0Hz,2H),2.55-2.74(m,2H),3.44-3.50(m,1H),3.75-4.05(m,5H),4.52(s,2H),4.62-4.71(m,4H),5.23(s,2H),5.52-5.62(m,1H),7.10(d,J=5.0Hz,2H),7.21(s,1H),7.34(d,J=10.0Hz,1H),7.37(s,1H),7.48(d,J=10.0Hz,2H),7.88(q,J=5.0Hz,1H),9.09(s,1H).m/z(ESI+):835.7.
化合物66的合成
化合物66的合成方法参考化合物61,用2-丙基戊酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 0.97(t,J=10.0Hz,6H),1.41-1.46(m,4H),1.53-1.58(m,2H),1.68-1.75(m,2H),1.82-1.89(m,3H),1.99-2.35(m,7H),2.63(t,J=5.0Hz,1H),3.17-3.36(m,4H),3.75(s,2H),4.22-4.31(m,2H),4.49-4.64(m,4H),5.22(s,2H),5.25-5.36(m,1H),7.07(d,J=10.0Hz,2H),7.20(s,1H),7.30-7.34(m,2H),7.48(d,J=10.0Hz,2H),7.83-7.86(m,1H),9.00(s,1H).m/z(ESI+):877.5.
化合物67的合成
化合物67的合成方法参考化合物61,用戊酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 0.97(t,J=5.0Hz,3H),1.42-1.48(m,2H),1.67-1.70(m,2H),1.83-1.99(m,7H),2.11-2.22(m,3H),2.58(t,J=5.0Hz,2H),2.99-3.02(m,1H),3.19-3.36(m,4H),3.75(s,2H),4.21-4.28(m,2H),4.49-4.63(m,4H),5.22(s,2H),5.25-5.35(m,1H),7.10(d,J=10.0Hz,2H),7.20(s,1H),7.30-7.35(m,2H),7.47(d,J=10.0Hz,2H),7.84-7.86(m,1H),9.00(s,1H).m/z(ESI+):835.4.
化合物68的合成
化合物68的合成方法参考化合物61,用环戊基乙酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 1.25-1.29(m,2H),1.60-1.70(m,4H),1.82-2.03(m,9H),2.11-2.35(m,4H),2.57(d,J=5.0Hz,2H),2.99-3.02(m,1H),3.20-3.36(m,4H),3.74(s,2H),4.21-4.31(m,2H),4.49-4.64(m,4H),5.22(s,2H),5.24-5.35(m,1H),7.10(d,J=10.0Hz,2H),7.20(s,1H),7.30-7.34(m,2H),7.47(d,J=10.0Hz,2H),7.84-7.87(m,1H),8.99(s,1H).m/z(ESI+):861.5.
化合物69的合成
化合物69的合成方法参考化合物61,用环戊基丙酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 1.17-1.18(m,2H),1.58-1.76(m,6H),1.84-2.00(m,10H),2.14-2.36(m,3H),2.59(t,J=5.0Hz,2H),3.01-3.02(m,1H),3.17-3.36(m,4H),3.75(s,2H),4.22-4.32(m,2H),4.50-4.66(m,4H),5.22(s,2H),5.25-5.36(m,1H),7.11(d,J=10.0Hz,2H),7.20(s,1H),7.31-7.35(m,2H),7.48(d,J=10.0Hz,2H),7.85-7.88(m,1H),9.00(s,1H).m/z(ESI+):875.5.
化合物70的合成
化合物70的合成方法参考化合物61,用2-己基癸酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 0.89(t,J=5.0Hz,6H),1.32-1.39(m,20H),1.58-1.60(m,2H),1.70-1.73(m,2H),1.82-1.89(m,3H),1.99-2.32(m,7H),2.58-2.60(m,1H),3.01-3.02(m,1H),3.19-3.35(m,4H),3.75(s,2H),4.22-4.31(m,2H),4.49-4.64(m,4H),5.23-5.36(m,3H),7.06(d,J=5.0Hz,2H),7.20(s,1H),7.30-7.34(m,2H),7.49(d,J=5.0Hz,2H),7.84-7.87(m,1H),9.00(s,1H).m/z(ESI+):989.5.
化合物71的合成
化合物71的合成方法参考化合物61,用十二烷酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 0.87-0.93(m,3H),1.28-1.44(m,16H),1.67-1.76(m,2H),1.81-2.05(m,7H),2.11-2.37(m,3H),2.54-2.60(m,2H),2.98-3.06(m,1H),3.13-3.29(m,3H),3.35(d,J=8.5Hz,1H),3.75(s,2H),4.19-4.34(m,2H),4.44-4.54(m,2H),4.58-4.73(m,2H),5.22(s,2H),5.26(s,0.5H),5.37(s,1H),7.10(d,J=8.5Hz,2H),7.20(s,1H),7.28-7.37(m,2H),7.48(d,J=8.5Hz,2H),7.83-7.89(m,1H),9.00(s,1H).m/z(ESI+):933.5
化合物72的合成
化合物72的合成方法参考化合物61,用十六烷酰氯作为原料。1H NMR(500MHz,CD3OD)δppm 0.85-0.93(m,3H),1.28-1.44(m,24H),1.66-1.77(m,2H),1.81-2.06(m,7H),2.11-2.40(m,3H),2.58(t,J=7.5Hz,2H),3.00-3.09(m,1H),3.13-3.29(m,3H),3.36(d,J=8.5Hz,1H),3.70-3.82(m,2H),4.20-4.37(m,2H),4.45-4.55(m,2H),4.58-4.73(m,2H),5.18-5.29(m,2.5H),5.38(s,0.5H),7.11(d,J=8.5Hz,2H),7.20(s,1H),7.29-7.38(m,2H),7.48(d,J=8.5Hz,2H),7.84-7.90(m,1H),9.01(s,1H).m/z(ESI+):989.5
化合物73的合成
化合物73的合成方法参考化合物61,用十四烷酰氯作为原料。1H NMR(500MHz,DMSO-d6)δppm 10.18(s,1H),9.05(s,1H),7.99-7.81(m,1H),7.48-7.50(m,3H),7.42(s,1H),7.19(s,1H),7.14-7.16(m,2H),5.27-5.38(m,1H),5.19(s,1H),4.60-4.61(m,1H),4.45(s,3H),4.20-3.89(m,2H),3.78-3.63(m,2H),3.14(m,3H),2.89(s,1H),2.57-2.60(m,2H),2.12(m,3H),1.80-1.89(m,7H),1.63-1.64(m,2H),1.32(s,2H),1.29(s,20H),0.85-0.87(m,3H).(ESI+):961.5.
化合物74的合成
三乙胺(10.41mg,0.102mmol,1.5eq)加入化合物69(60mg,0.068mmol,1eq)的二氯甲烷(6mL)溶液中,然后加入DMAP(0.84mg,0.007mmol,0.1eq)和特戊酰氯(9.92mg,0.082mmol,1.2eq)。反应液在室温下搅拌1.5小时,然后加入二氯甲烷和水。分出的有机相用水洗,盐水洗,无水硫酸钠干燥后过滤。滤液旋干,残余物用柱层析纯化(MeOH/DCM=0%~4%)得到化合物74(44mg,收率65.5%)。1H NMR(500MHz,CD3OD)δppm 9.05(s,1H),8.11(dd,J=9.0,5.5Hz,1H),7.89(d,J=2.5Hz,1H),7.55-7.47(m,3H),7.45(s,1H),7.13(d,J=8.5Hz,2H),5.37(d,J=53.5Hz,1H),5.25(s,2H),4.84-4.58(m,2H),4.58-4.45(m,2H),4.43-4.26(m,2H),3.86-3.70(m,2H),3.50(d,J=8.0Hz,1H),3.17-3.03(m,1H),2.62(t,J=7.6Hz,2H),2.43-2.15(m,3H),2.15-1.81(m,10H),1.81-1.54(m,6H),1.46-1.40(m,9H),1.19(d,J=11.0Hz,2H).m/z,(ESI+):959.3.
化合物75的合成
化合物75的合成方法参考化合物74,用化合物61作为原料。1H NMR(500MHz,CD3OD)δppm 9.07(s,1H),8.12(dd,J=9.1,5.7Hz,1H),7.89(d,J=2.2Hz,1H),7.55-7.48(m,3H),7.45(s,1H),7.11(d,J=8.4Hz,2H),5.42(d,J=52.9Hz,1H),5.25(s,2H),4.78-4.61(m,2H),4.58-4.36(m,4H),3.88-3.69(m,2H),3.64-3.41(m,4H),3.26-3.14(m,1H),2.56-2.22(m,3H),2.20-2.09(m,2H),2.09-1.95(m,3H),1.93-1.78(m,2H),1.42(s,9H),1.38(s,9H).m/z(ESI+):919.48.
化合物76的合成
化合物76的合成方法参考化合物74,用化合物1作为原料,所用中间体参考化合物51-4的合成。1H NMR(500MHz,CD3OD)δppm 0.80-0.88(m,6H),0.93-1.01(m,3H),1.20-1.36(m,20H),1.50-1.70(m,9H),1.82-2.08(m,7H),2.09-2.40(m,9H),2.99-3.07(m,1H),3.15-3.27(m,3H),3.51(d,J=7.0Hz,1H),3.68-3.84(m,2H),4.18-4.35(m,4H),4.43-4.56(m,4H),4.59-4.76(m,2H),5.16-5.28(m,1.5H),5.37(s,0.5H),6.81-6.90(m,1H),7.47-7.58(m,2H),8.00(s,1H),8.09-8.15(m,1H),9.05(s,1H).m/z(ESI+):1157.6.
化合物77的合成
化合物77的合成方法参考化合物76,用化合物3作为原料.1H NMR(500MHz,CD3OD)δppm 9.07(s,1H),8.12(dd,J=9.1,5.4Hz,1H),8.01(s,1H),7.59(d,J=2.3Hz,1H),7.52(t,J=8.8Hz,1H),6.92-6.81(m,1H),5.34(d,J=54.4Hz,1H),5.27-5.22(m,1H),4.79-4.59(m,2H),4.58-4.42(m,4H),4.39-4.23(m,4H),3.94-3.65(m,2H),3.52(d,J=5.9Hz,1H),3.33-3.17(m,3H),3.11-2.99(m,1H),2.42-2.33(m,4H),2.32-2.14(m,3H),2.14-1.98(m,7H),1.97-1.81(m,3H),1.69-1.52(m,7H),1.34-1.19(m,20H),0.86(t,J=5.2Hz,6H).m/z(ESI+):1129.4.
其它化合物的合成方法与上文中所示的合成相似,并且通过核磁和质谱进行鉴定。所得到的核磁和质谱数据参见表3。
表3
生物学测定
实验例1.药代动力学实验
实验动物采用ICR小鼠共96只,雄性,体重30-34g,随机分为32组(进行口服给药和静脉给药),每组3只。口服给药后0.167、0.5、1、2、4、6、8、24h收集血样,静注给药后0.083、0.25、0.5、1、2、4、6、8h收集血样。被测试化合物于5%DMSO、5%Solutol和90%的20%SBE-β-CD溶媒中配制成实验用溶液。将动物禁食12小时后,以静注3mg/kg和口服10mg/kg化合物A1当量尾静脉静注给药或口服给药。于给药后,在预设时间点采血(约50μL/只),定量吸取20μL全血至预先加入200μL含内标乙腈的EP管中,在4℃下以12000rpm离心5min后收集上清液,低温保存。取上清液进行LC-MS/MS分析,检测血浆中相应药物、代谢物的含量。
表4至表5中示出了不同化合物口服或静脉注射给药后AUC(平均血药浓度-时间曲线下面积)数据。
图1至图4中示出了给予不同化合物后A1的药-时曲线。
表4化合物A1和本发明的化合物以等摩尔剂量口服给予ICR小鼠后的平均血药浓度-时间曲线下面积
由表4可见,口服给予化合物A1、1、4、6、7、8、9、10、11、17、61和77时,血浆中A1的AUC大大高于口服给予与A1(对照化合物)时血浆中A1的AUC;其中,口服给予化合物10后,血浆中A1的AUC增加到口服给予A1时的8.5倍以上,极大地提高了A1的口服生物可利用度。相反,化合物52和71则略微影响了A1的口服生物可利用度。
表5化合物A1和本发明的化合物以等摩尔剂量静脉注射给予ICR小鼠后的平均血药浓度-时间曲线下面积
由表5可见,静脉注射化合物32、33、36、39、52、55、56、71和77的血浆AUC高于对照化合物A1,其中化合物36表现出近4倍的优势。
图1示出了口服给药时,本发明的化合物1、化合物61对比阳性对照A1测得的药-时曲线。
图2示出了口服给药时,本发明的化合物4、化合物17、化合物69对比阳性对照A1测得的药-时曲线。
图3示出了静脉注射给药时,本发明的化合物32、化合物39、化合物52对比阳性对照A1测得的药-时曲线。
图4示出了静脉注射给药时,本发明的化合物55、化合物56对比阳性对照A1测得的药-时曲线。
实验例2.AsPC-1小鼠药效模型肿瘤增殖抑制实验
(1)口服给药处理后小鼠体内肿瘤生长抑制作用的研究
将AsPC-1人转移胰腺癌细胞5x106悬于0.1mL PBS中,植入6-8周龄Balb/C6-8裸鼠后第11天,将13只动物随机分配至溶媒对照组(4只)、化合物A1给药组(4只)和化合物1给药组(5只)。用100mg/kg化合物A1和126mg/kg化合物1每天两次口服口服给药。化合物给药方式和剂量见表6。每周两次通过游标卡尺测量肿瘤长、短径,计算肿瘤体积(TV=(长径x短径x短径)/2)。肿瘤生长的抑制情况通过肿瘤(体积)抑制率TGI来评价。TGI=[1-(Vt-V0(实验组))/(Vt-V0(溶媒对照组))]x100%。
相对于溶媒对照组,126mg/kg化合物1口服给药16天后,肿瘤生长受到显著抑制(P=0.0146,TGI为53.95%)。100mg/kg化合物A1口服给药12后,相对溶媒对照对于肿瘤生长无抑制作用,TGI仅为9.07%。相对于100mg/kg化合物A1给药组,126mg/kg化合物1给药后对于肿瘤生长的抑制作用也有显著差异,P=0.003。结果显示,两种处理方式对于受试动物的体重均无影响。
表6化合物给药方式和剂量
TGI=[1-(Vt-V0(实验组))/(Vt-V0(溶媒对照组))]x100%
图5中示出了口服给药化合物1、阳性对照化合物A1和空白对照后,小鼠体内肿瘤生长抑制效果对比结果。
(2)非口服给药处理后小鼠体内肿瘤生长抑制作用的研究
将AsPC-1人转移胰腺癌细胞5x106悬于0.1mL PBS中,植入6-8周龄Balb/C6-8裸鼠后第11天,将24只动物随机分配至溶媒对照组(5只)、化合物A1腹腔给药组(5只)、化合物A1尾静脉给药组(3只)、化合物52腹腔给药组(5只)和化合物52尾静脉给药组(6只)。所有给药组均使用等摩尔剂量(化合物A1,6mg/kg)给药,每天一次给药,连续给药27天。化合物给药方式和剂量见表7。每周两次通过游标卡尺测量肿瘤长、短径,计算肿瘤体积(TV=(长径x短径x短径)/2)。肿瘤生长的抑制情况通过肿瘤(体积)抑制率TGI来评价。
TGI=[1-(Vt-V0(实验组))/(Vt-V0(溶媒对照组))]*100%。
相对于溶媒对照组,所有给药组的药物处理都能对肿瘤生长有一定的抑制作用,6mg/kg化合物A1腹腔给药27天后,肿瘤生长抑制率TGI为37.27%,P=0.018。
13.44mg/kg化合物52腹腔给药27天后,肿瘤生长抑制率TGI为36.12%,P=0.0047。
13.44mg/kg化合物52尾静脉给药27天后,肿瘤生长抑制率TGI为47.22%,P=0.027。结果表明,实验中所有受试动物的体重在整个实验中均保持稳定。
表7:化合物给药方式和剂量
注*:动物死亡
TGI=[1-(Vt-V0(实验组))/(Vt-V0(溶媒对照组))]x100%
图6中示出了腹腔给药化合物52、静脉注射给药化合物52、腹腔给药阳性对照化合物A1、静脉注射给药对照化合物A1和空白对照后,小鼠体内肿瘤生长抑制效果对比结果。本申请公开的化合物,具有较好的KRAS G12D的抑制效果。因此,此类化合物可用于制备用于治疗、抑制或预防与KRAS G12D突变相关的疾病的药物。
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 (21)
1.式A化合物或者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,X2独立地选自氢、取代或未取代的烷基或杂烷基、取代或未取代的酰基(包括饱和或不饱和的脂肪族酰基和芳酰基)、氨基酸残基、取代或未取代的寡肽(二肽、三肽、四肽)残基、磷酰基、膦酰基、胺基膦酰基、磺酰基、硫代酰基、取代或未取代的苄基、取代或未取代的烷氧羰基、取代或未取代的胺基羰基、取代或未取代的巯基硫代羰基、取代或未取代的烷硫基(硫代羰基)、取代或未取代的酯烷基、取代或未取代的苄氧基羰基、糖苷基、糖酸苷基、胆酸类取代基;
A为含有环状结构的有机基团,包括单环、双环、稠环、桥环、螺环、杂环、芳环、芳杂环、脂肪环以及它们的组合,且该环状结构含有两个或者两个以上的取代基团;
基团A1、A2、A3和A4独立地选自氢或C1到C6的短链烃基,或者A1、A2、A3和A4中的一个或两个基团以及它们所连接的哌嗪环一起形成桥环、稠环或螺环。
2.根据权利要求1所述的化合物,其中式(A)所述化合物为式(B)化合物或者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,X2独立地选自氢、取代或未取代的烷基或杂烷基、取代或未取代的酰基(包括饱和或不饱和的脂肪族酰基和芳酰基)、氨基酸残基、取代或未取代的寡肽(二肽、三肽、四肽)残基、磷酰基、膦酰基、胺基膦酰基、磺酰基、硫代酰基、取代或未取代的苄基、取代或未取代的烷氧羰基、取代或未取代的胺基羰基、取代或未取代的巯基硫代羰基、取代或未取代的烷硫基(硫代羰基)、取代或未取代的酯烷基、取代或未取代的苄氧基羰基、糖苷基、糖酸苷基、胆酸类取代基;
A为含有环状结构的有机基团,包括单环、双环、稠环、桥环、螺环、杂环、芳环、芳杂环、脂肪环以及它们的组合,且该环状结构含有两个或者两个以上的取代基团。
3.根据权利要求1或2所述的化合物,其中,所述化合物为式(I)所示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:
其中,
W选自氧(O)、硫(S)或氮(NH);
X1和X2独立地选自氢、取代或未取代的烷基或杂烷基、取代或未取代的酰基(包括饱和或不饱和脂肪族酰基,和芳酰基)、氨基酸残基、取代或未取代的寡肽(二肽、三肽、四肽)残基、磷酰基、膦酰基、胺基膦酰基、磺酰基、硫代酰基、取代或未取代的苄基、取代或未取代的烷氧羰基、取代或未取代的胺基羰基、取代或未取代的巯基硫代羰基、取代或未取代的烷硫基、取代或未取代的酯烷基、硫代羰基、取代或未取代的苄氧基羰基、糖苷基、糖酸苷基、胆酸类取代基;
X3独立地选自或孤对电子;其中,当X3为孤对电子时,X1和X2不同时为氢;当X3为时,与X3相连接的N原子形成带有一个正电荷的季铵离子,并与分子内的负离子形成内盐或与另外的酸分子配对成盐,酸分子包括但不限于氢卤酸盐,其中R6a、R6b任意选自氢、C1至C20的烃基或C3至C20环烃基、
Y1a、Y1b独立地选自氢、卤素(F、Cl、或Br)、羟基、氨基、胺基、羟甲基、烷氧基、或酰氧基;
Y2独立地选自氢、卤素、羟基、氨基、胺基、羟甲基、烷氧基、酰氧基、或低级烃基;
Y3、Y4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Y3、Y4以及它们所连接的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R1选自氢、甲基、乙基、丙基或异丙基、C3-C6环烷基、芳香基;
R2选自氢、C1到C20的饱和或不饱和烷基、芳基烃基、芳基、杂环芳烃基、C3-C8碳环或杂环烃基、稠环、萘环、桥环烃基;
R3选自氢、甲基、乙基或丙基;
R4选自氢、C2到C20的烷基、异丙基、异丁基、芳基烃基、碳环或杂环烃基、C2到C20的烷酰氧基;
R5选自2-位取代的乙基,且2-位上取代基包括但不限于氨基、烷氧羰基、烷酰氧基、以及由氨基酸衍生的酰氧基;
R7选自低级烷基或者取代或未取代的芳基;
R8选自取代或未取代C2到C20的饱和或不饱和烷酰基、饱和或不饱和烷氧羰基;
R9选自低级烷基,取代或未取代的苄基、取代或未取代的咪唑-5-甲基、低聚乙二醇基(–[CH2CH2O]nCH3,其中n为0到4的整数)、C2到C20的饱和或不饱和的烷酰基;
R10选自氢、C1-C6的烷氧基、C2到C20的饱和或不饱和的烷酰氧基、取代或未取代C2到C20的饱和或不饱和烷酰基、饱和或不饱和烷氧羰基。
6.根据权利要求4所述的化合物,其中,式(II)中W为氧,且R11为氢或氟。
7.根据权利要求6所述的化合物,其中,式(III)中W为氧,且Y4为氯。
8.根据权利要求4所述的化合物,其中,式(III)中W为NH,且Y4为氢或氯。
9.根据权利要求4至7中任一项所述的化合物,其中,Y1b和Y2同时为氢。
12.一种药物组合物,所述组合物包括权利要求1至11中任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。
13.根据权利要求12所述的药物组合物,其中,还包括至少一种药学上可接受的赋形剂或载体或稀释剂。
14.根据权利要求13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。
15.根据权利要求13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。
16.根据权利要求12至15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。
17.权利要求1至11中任一项所述的化合物或其药学上可接受的盐或酯或异构体或水合物或权利要求12至16中任一项所述的药物组合物在制备用于治疗、预防或抑制过度增生病症的药物中的用途。
18.根据权利要求17所述的用途,其中,所述过度增生病症为与KRAS G12D突变相关的恶性肿瘤或癌症。
19.根据权利要求18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: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:成神经细胞瘤。
20.根据权利要求19所述的用途,其特征在于,所述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。
21.试剂盒在制备用于治疗、抑制或预防涉及KRAS G12D突变相关的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11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、或者根据权利要求12至16中任一项所述的组合物。
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