CN113614076A - 雌激素受体蛋白降解剂 - Google Patents
雌激素受体蛋白降解剂 Download PDFInfo
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- CN113614076A CN113614076A CN201980093482.0A CN201980093482A CN113614076A CN 113614076 A CN113614076 A CN 113614076A CN 201980093482 A CN201980093482 A CN 201980093482A CN 113614076 A CN113614076 A CN 113614076A
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/13—Amines
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Abstract
本公开提供了由式I表示的化合物:A‑L‑B I,和其盐或溶剂化物,其中A、L和B如说明书中所定义。具有式I的化合物是可用于治疗癌症的雌激素受体降解剂。
Description
技术领域
本公开提供了异双官能的小分子作为雌激素受体(ER)蛋白质降解剂。ER降解剂可用于治疗各种疾病,包括乳腺癌。
背景技术
乳腺癌(BC)是世界范围内女性最常见的恶性肿瘤之一。根据肿瘤受体的状态,乳腺癌可进一步细分为雌激素受体阳性(ER+)、人表皮生长因子受体2(HER2)阳性(HER2+)和三阴性亚型。1ER+乳腺癌发生在大约80%的新诊断的乳腺癌病例中。2作为核受体家族的成员,雌激素受体ERα和ERβ是调节基因表达和介导雌激素生物学效应的转录因子。ERα和ERβ在不同组织中广泛表达,并且ERα被认为是在女性生殖道和乳腺中转导雌激素信号的主要介质。3因此,ERα已被视为多种病理环境中的有希望的治疗靶点,尤其是在癌症和骨质疏松症中,这一点突出表现在他莫昔芬治疗ER+BC和雷洛昔芬预防和治疗绝经后妇女骨质疏松症的临床成功。4,5
尽管通过芳香酶抑制剂抑制雌激素合成和通过选择性雌激素受体调节剂(SERM)抑制ER通路信号传导(图1)已证明在治疗ER+BC方面具有相当大的临床益处,但对这些药物的内在和获得性耐药性的发展给晚期和转移性乳腺癌患者带来了障碍。6,7虽然对芳香化酶抑制剂和SERMs明显存在多种耐药机制,但最近的研究表明,在大多数耐药病例中,肿瘤生长和疾病进展持续依赖ERα信号,ER蛋白仍然是ER+转移性乳腺癌的主要驱动因素。8,9
选择性雌激素受体降解剂(SERD)是靶向ERα进行蛋白酶体依赖性降解的小分子。目前,氟维司群(5,图1)是唯一被批准用于使用标准内分泌疗法治疗绝经后晚期ER+乳腺癌的SERD。10,11氟维司群的临床成功表明ER蛋白的降解对ER+乳腺癌患者是有益的,尤其是那些在标准内分泌治疗后疾病继续进展的患者。由于氟维司群溶解度差且不可口服生物利用,因此临床上通过每月肌肉注射施用。12,13为了解决氟维司群的缺点,已经开发了口服生物可利用的SERD分子,其中一些目前正在进行临床试验评估,作为治疗ER+、转移性BC的新疗法。14-19
传统SERD如氟维司群的可能作用机制是诱导ER蛋白的错误折叠,最终导致蛋白酶体依赖的ERα蛋白降解。20SERD分子通常强有效地诱导ER+乳腺癌细胞中ER蛋白的降解,但它们只能实现ER蛋白的部分降解。21,22因此,可以实现ER更完全降解的新型治疗剂可能比传统的SERD分子更有效地治疗ER+转移性乳腺癌。
蛋白水解靶向嵌合体(PROTAC)概念于2001年首次引入,23其目的是通过劫持细胞E3泛素化连接酶系统来诱导选择性靶蛋白降解。24-28PROTAC是异双官能小分子,含有一个与目标靶蛋白结合的配体,以及针对E3连接酶系统的另一个配体。这两个配体通过化学接头连接在一起。PROTAC策略最近获得了发展,部分原因是一些E3连接酶系统的有效和类似药物的小分子配体的出现,它已经被用于设计一些蛋白质的小分子降解剂。29-43最近,Naito等人报道了几种类似PROTAC的ERα降解剂,它们被命名为特异性和非遗传性IAP依赖性蛋白橡皮擦(Specific and Nongenetic IAP-dependent Protein Erasers,SNIPER)。44,45他们使用ERα拮抗剂和凋亡蛋白抑制剂(IAP)(即E3连接酶)的配体设计了ERαSNIPER分子。然而,虽然SNIPER ER降解剂可有效诱导ER蛋白的部分降解,但它们也会诱导E3连接酶(cIAP1蛋白)的自身泛素化和蛋白酶体降解,这可能会限制其治疗效果。
本领域需要另外的ER降解剂来治疗乳腺癌和其他疾病。
发明内容
在一个方面,本公开提供了由以下式I-V中的任何一个或多个表示的异双官能小分子,及其药学上可接受的盐和溶剂化物,例如水合物,在本文统称为“本公开的化合物”。本公开的化合物是雌激素受体降解剂,因此可用于治疗其中雌激素受体的降解为患者提供治疗益处的疾病或病况。
在另一方面,本公开提供了通过向有此需要的患者(例如人)施用治疗有效量的本公开的化合物来治疗病况或疾病的方法。该疾病或病况可以通过雌激素受体的降解来治疗,例如癌症,例如乳腺癌。
在另一方面,本公开提供了一种在个体中降解雌激素受体的方法,包括向个体施用有效量的至少一种本公开的化合物。
在另一个方面,本公开提供了一种药物组合物,其包含本公开的化合物和赋形剂和/或药学上可接受的载体。
在另一个方面,本公开提供了一种组合物,其包含本公开的化合物和赋形剂和/或药学上可接受的载体,其用于治疗其中雌激素受体的降解提供有益效果的疾病或病况,例如癌症。
在另一个方面,本公开提供一种组合物,其包括:(a)本公开的化合物;(b)第二治疗活性剂;和任选地(c)赋形剂和/或药学上可接受的载体。
在另一个方面,本公开提供了本公开的化合物,其用于治疗目标疾病或病况,例如癌症。
在另一个方面,本公开提供了本公开的化合物用于制备用于治疗感兴趣的疾病或病况(例如癌症)的药物的用途。
在另一个方面,本公开提供了一种试剂盒,其包括本公开的化合物,以及任选地,包含可用于治疗感兴趣的疾病或病况的第二治疗剂的包装的组合物,和包装说明书,所述包装说明书包含用于治疗疾病或病况(例如癌症)的说明。
在另一个方面,本公开提供了制备本公开的化合物的方法。
本公开的另外的实施方案和优点将部分地在下面的描述中阐述,并将从该描述得出,或者可以通过本公开的实践而得知。本公开的实施方案和优点可以通过所附权利要求书中特别指出的元素和组合来实现和获得。应该理解的是,前面的概述和下面的详细描述都只是示例和解释性的,并且并不限制所请求保护的本发明。
附图说明
图1是显示用本公开的化合物和对照化合物处理的MCF-7细胞中ER蛋白的蛋白质印迹分析的图。用不同化合物处理细胞4小时,然后通过蛋白质印迹分析全细胞裂解物,以检查ER蛋白的水平。GADPH蛋白用于加样对照。图下面的数字代表用100的DMSO对照归一化的ERα/GADPH比率。
图2是显示用1nM、10nM和100nM的指定化合物处理的MCF-7细胞中ER蛋白的蛋白质印迹分析的图像。用不同化合物处理MCF-7细胞4小时,并通过蛋白质印迹分析全细胞裂解物,以检查ER蛋白的水平。GADPH蛋白用于加样对照。图下面的数字代表用100的DMSO对照归一化的ERα/GADPH比率。
图3是显示用1nM、10nM和100nM的指定化合物处理的MCF-7细胞中ER蛋白的蛋白质印迹分析的图像。用不同化合物处理MCF-7细胞4小时,并通过蛋白质印迹分析全细胞裂解物,以检查ER蛋白的水平。GADPH蛋白用于加样对照。图下面的数字代表用100的DMSO对照归一化的ERα/GADPH比率。
图4是显示用1nM、10nM和100nM的指定化合物处理的MCF-7细胞中ER蛋白的蛋白质印迹分析的图像。用不同化合物处理MCF-7细胞4小时,并通过蛋白质印迹分析全细胞裂解物,以检查ER蛋白的水平。GADPH蛋白用于加样对照。图下面的数字代表用100的DMSO对照归一化的ERα/GADPH比率。
图5是显示用1nM、10nM和100nM的指定化合物处理的MCF-7细胞中ER蛋白的蛋白质印迹分析的图像。用不同化合物处理MCF-7细胞4小时,并通过蛋白质印迹分析全细胞裂解物,以检查ER蛋白的水平。GADPH蛋白用于加样对照。图下面的数字代表用100的DMSO对照归一化的ERα/GADPH比率。
图6是显示用1nM、10nM和100nM的指定化合物处理的MCF-7细胞中ER蛋白的蛋白质印迹分析的图像。用不同化合物处理MCF-7细胞4小时,并通过蛋白质印迹分析全细胞裂解物,以检查ER蛋白的水平。GADPH蛋白用于加样对照。图下面的数字代表用100的DMSO对照归一化的ERα/GADPH比率。
图7是表示在MCF-7细胞中,在4h,化合物32的ERα降解剂量-反应蛋白质印迹的图像。
图8是表示在T47D细胞中,在4h,化合物32的ERα降解剂量-反应蛋白质印迹的图像。
图9是通过蛋白质印迹法显示在MCF-7细胞中通过化合物32(30nM)和氟维司群(30nM)降解ERα的时间过程的图像。
图10是通过蛋白质印迹法显示在T47D细胞中通过化合物32(30nM)和氟维司群(30nM)降解ERα的时间过程的图像。
图11是通过蛋白质印迹分析显示ERα降解依赖于VHL、ER和蛋白酶体的图像。MCF-7细胞用VHL配体11(1μM)或ER配体雷洛昔芬(1)(1μm)或蛋白酶体抑制剂卡非佐米(1μM)预处理2小时,然后用DMSO或化合物32(30nM)处理4小时。然后通过蛋白质印迹分析全细胞裂解物。
图12是通过蛋白质印迹分析显示ERα降解依赖于VHL、ER和蛋白酶体的图像。MCF-7细胞用VHL配体11(+,0.5μM;++,1μM;+++,5μM;++++,10μM)预处理2小时,然后用DMSO或化合物32(30nM)处理4小时。然后通过蛋白质印迹分析全细胞裂解物。
具体实施方式
I.本公开的化合物
本公开的化合物是异双官能ER受体降解剂。在一个实施方案中,本公开的化合物是由式I表示的化合物:
A-L-BI,
其中:
A是雌激素受体调节剂的自由基,选自由以下组成的组:
R3选自由以下组成的组:C1-C6烷基、C3-C8环烷基和(C3-C8环烷基)C1-C4烷基;
L是接头;且
B是E3连接酶配体的自由基,选自由以下组成的组:
或其药学上可接受的盐或溶剂化物。
在另一个实施方案中,本公开的化合物是由式I表示的化合物,其中A选自由以下组成的组:
或其药学上可接受的盐或溶剂化物。
在另一个实施方案中,本公开的化合物是由式I表示的化合物,其中B选自由以下组成的组:
或其药学上可接受的盐或溶剂化物。
在另一个实施方案中,本公开的化合物是由式II表示的化合物:
其中R3和L的定义与式I相关,或其药学上可接受的盐或溶剂化物。
在另一个实施方案中,本公开的化合物是由式III表示的化合物:
其中L的定义与式I相关,或其药学上可接受的盐或溶剂化物。
在另一个实施方案中,本公开的化合物是由式I-III中的任何一个表示的化合物,其中:
L是-X-L1-Z-;
X选自由以下组成的组:-C≡C-、-O-、-C(=O)N(R1a)-和-N(R3a)-;或者
X不存在;
Z选自由以下组成的组:-C≡C-、-O-、-C(=O)N(R2a)-和-N(R4a)-;或者
Z不存在;
L1选自由以下组成的组:亚烷基、亚杂烷基和-W1-(CH2)m-W2-(CH2)n-
W1不存在;或者
W1选自由以下组成的组:亚苯基、亚杂芳基、亚杂环基和亚环烷基;
W2选自由以下组成的组:亚苯基、亚杂芳基、亚杂环基和亚环烷基;
m是0、1、2、3、4、5、6或7;
n是0、1、2、3、4、5、6、7或8;且
R1a选自由以下组成的组:氢和C1-4烷基;
R2a选自由以下组成的组:氢和C1-4烷基;
R3a选自由以下组成的组:氢和C1-4烷基;且
R4a选自由以下组成的组:氢和C1-4烷基,或其药学上可接受的盐或溶剂化物。
在另一个实施方案中,本公开的化合物是由式I-III中的任何一个表示的化合物,其中L选自由以下组成的组:
或其药学上可接受的盐或溶剂化物。
在另一个实施方案中,本公开的化合物是由式IV表示的化合物:
其中A的定义与式I相关,或其药学上可接受的盐或溶剂化物。
在另一个实施方案中,本公开的化合物是由式V表示的化合物:
其中:
R1选自由以下组成的组:氢和C1-C3烷基;且
R2选自组卤素、氰基、C2-C4炔基、C1-C6烷基和C3-C6环烷基,或其药学上可接受的盐或溶剂化物。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中X是-C≡C-。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中X是-N(H)-。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L是C1-12亚烷基。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L选自由以下组成的组:-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2(CH2)2CH2-、-CH2(CH2)3CH2-、-CH2(CH2)4CH2-、-CH2(CH2)5CH2-和-CH2(CH2)6CH2-。
在另一个实施方案中,本公开的化合物是具有式I的化合物,以及其盐或溶剂化物,其中L是3元至12元亚杂烷基。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L是-A-(CH2)m-W-(CH2)n-且A不存在。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L选自由以下组成的组:
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L是-A-(CH2)m-W-(CH2)n-,A不存在,且W是5元亚杂芳基。在另一个实施方案中,m是0。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中:
L选自由以下组成的组:
Q3选自由以下组成的组:-O-、-S-和-N(R6)-;和
R6选自由以下组成的组:氢和C1-4烷基。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L是-A-(CH2)m-W-(CH2)n-,A不存在,且W是6元亚杂芳基。在另一个实施方案中,m是0。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L选自由以下组成的组:
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L是-A-(CH2)m-W-(CH2)n-,A不存在,且W是亚杂环基。在另一个实施方案中,m是0。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L选自由以下组成的组:
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L选自由以下组成的组:
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L选自由以下组成的组:
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L选自由以下组成的组:
Q3选自由以下组成的组:-O-、-S-和-N(R6)-;且
R6选自由以下组成的组:氢和C1-4烷基。
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L选自由以下组成的组:
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L选自由以下组成的组:
在另一个实施方案中,本公开的化合物是具有式I-III的化合物,以及其盐或溶剂化物,其中L选自由以下组成的组:
本公开的化合物的盐、水合物和溶剂化物也可以在本文所公开的方法中使用。本公开还包括本公开的化合物的所有可能的立体异构体和几何异构体以包括外消旋化合物和光学活性异构体。当期望本公开的化合物为单一对映体时,它可以通过拆分最终产物或通过从异构体纯的起始原料立体定向合成或使用手性助剂来获得,例如,参见Z.Ma etal.,Tetrahedron:Asymmetry,8(6),第883-888页(1997)。拆分最终产物、中间体或起始原料可通过本领域中已知的任何合适的方法来实现。此外,在本公开的化合物可能有互变异构体的情况下,本公开旨在包括化合物的所有互变异构形式。
本公开涵盖本公开化合物及由本公开化合物制备的异双官能靶蛋白降解剂的盐(包括药学上可接受的盐)的制备和用途。如本文所用,药物的“药学上可接受的盐”是指本公开化合物或由本公开化合物制备的异双官能靶蛋白降解剂的盐或两性离子形式。本公开化合物的盐或由本公开化合物制备的异双官能靶蛋白降解剂可在化合物的最终分离和纯化期间制备或单独通过使化合物与具有合适的阳离子的酸反应制得。本公开化合物或由本公开化合物制备的异双官能靶蛋白降解剂的药学上可接受的盐可以是与药学上可接受的酸形成的酸加成盐。可用于形成药学上可接受的盐的酸的实例包括无机酸如硝酸、硼酸、盐酸、氢溴酸、硫酸和磷酸,以及有机酸如草酸、马来酸、琥珀酸和柠檬酸。本公开的化合物的盐的非限制性实例包括,但不限于,盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、2-羟基乙烷磺酸盐、磷酸盐、磷酸氢盐、乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐(hemisulfate)、庚酸盐、己酸盐、甲酸盐、琥珀酸盐、富马酸盐、马来酸盐、抗坏血酸盐、羟乙基磺酸盐、水杨酸盐、甲烷磺酸盐(methanesulfonate)、均三甲苯磺酸盐(mesitylenesulfonate)、亚萘基磺酸盐(naphthylenesulfonate)、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、三氯乙酸、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐、十一烷酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡糖酸盐、甲烷磺酸盐、乙烷二磺酸盐、苯磺酸盐和对甲苯磺酸盐。此外,本公开的化合物中可用的氨基团可以用甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;二甲基、二乙基、二丁基和二戊基硫酸盐;癸基、月桂基、肉豆蔻基和甾醇基氯化物、溴化物和碘化物;和苄基和苯乙基溴化物季铵化。根据上述,本文出现的本公开的化合物的任何指代旨在包括本公开的化合物以及它们的药学上可接受的盐、水合物或溶剂化物的化合物。
本公开涵盖本公开化合物及由本公开化合物制备的异双官能靶蛋白降解剂的溶剂化物的制备和用途。溶剂化物通常不显著改变所述化合物的生理活性或毒性,因此可以用作药理学等同物。如本文所用的术语“溶剂化物”是本公开的化合物与溶剂分子的化合(combination)、物理缔合和/或溶剂化,诸如,例如二溶剂化物、单溶剂化物或半溶剂化物,其中溶剂分子与本公开的化合物的比例分别为约2:1、约1:1或约1:2。该物理缔合涉及不同程度的离子和共价键合,包括氢键键合。在某些情况下,可以分离溶剂化物,例如当一个或多个溶剂分子结合到结晶固体的晶格中时。因此,“溶剂化物”涵盖溶液相和可分离的溶剂化物。本公开化合物及由本公开化合物制备的异双官能靶蛋白降解剂可以作为具有药学上可接受的溶剂如水、甲醇和乙醇的溶剂化形式存在,并且意图是本公开包括本公开化合物的溶剂化和非溶剂化形式。溶剂化物的一种类型是水合物。“水合物”涉及其中溶剂分子是水的溶剂化物的特定亚组(subgroup)。溶剂化物通常可以作为药理学等同物。溶剂化物的制备在本领域中是已知的。参见,例如,M.Caira等人,J.Pharmaceut.Sci.,93(3):601-611(2004),其描述了用乙酸乙酯和用水制备氟康唑的溶剂化物。溶剂化物,半溶剂化物,水合物等的类似制备由E.C.van Tonder等人,AAPS Pharm.Sci.Tech.,5(1):Article 12(2004)和A.L.Bingham等人,Chem.Commun.603-604(2001)描述。制备溶剂化物的典型的非限制性的方法将涉及在高于20℃至约25℃的温度下将本公开的化合物溶解于期望溶剂(有机溶剂、水或其混合物)中,然后以足以形成晶体的速度冷却该溶液,并用已知的方法(例如,过滤)分离晶体。分析技术如红外光谱法可用于确认溶剂化物的晶体中溶剂的存在。
II.本公开的治疗方法
本公开的化合物降解ER蛋白,可用于治疗各种疾病和病况。特别地,本公开的化合物可用于治疗其中降解ER蛋白提供有益效果的疾病或病况的方法,所述疾病或病况例如,癌症和增殖性疾病。本公开的治疗性方法包括向有此需要的个体施用治疗有效量的本公开的化合物。本公开的方法还包括向个体施用除了本公开的化合物之外的第二治疗剂。所述第二治疗剂选自这样的药物,该药物已知可用于治疗使有此需要的个体遭受折磨的疾病或病况,例如,已知可用于治疗特定的癌症的化学治疗剂和/或放射。
本公开提供了作为ER蛋白降解剂的本公开的化合物用于治疗多种疾病和病况,其中ER的降解具有有益效果。本公开的化合物通常对ER的结合亲和力(IC50)小于100μM,例如小于50μM,小于25μM,和小于5μM,小于约1μM,小于约0.5μM,或小于约0.1μM。在一个实施方案中,本公开涉及一种治疗患有疾病或病况的个体的方法,在所述疾病或病况中ER蛋白的降解提供有益效果,所述方法包括向有此需要的个体施用治疗有效量的本公开的化合物。
由于本公开的化合物是ER蛋白的降解剂,因此可以通过采用这些化合物来治疗由ER介导的许多疾病和病况。因此,本公开总体上涉及一种用于治疗在动物(例如,人类)中对ER的降解有反应的病况或病症的方法,所述动物患有或有可能患有所述病况或病症,所述方法包括对动物施用有效量的一种或多种本公开的化合物。
本公开还涉及一种降解有此需要的动物中的ER蛋白的方法,所述方法包括向所述动物施用有效量的至少一种本公开的化合物。
本公开的方法可以通过施用作为净化合物或作为药物组合物的本公开的化合物来完成。本公开的化合物的药物组合物或净化合物的施用可以在感兴趣的疾病或病况发作期间或者之后进行。通常,所述药物组合物是无菌的,并且不含施用时会导致不良反应的毒性、致癌性或致突变化合物。还提供了试剂盒,其包含本公开的化合物和任选地第二治疗剂,所述第二治疗剂可用于治疗其中ER蛋白的降解提供有益效果的疾病和病况,它们单独或一起包装,以及具有使用这些活性剂的说明的说明书。
在一个实施方案中,本公开的化合物与第二治疗剂联合施用,所述第二治疗剂可用于治疗其中ER蛋白的降解提供有益效果的疾病和病况。所述第二治疗剂不同于本公开的化合物。本公开的化合物和第二治疗剂可以同时或依次施用以达到期望效果。此外,本公开的化合物和第二治疗剂可以以单个组合物或两个单独的组合物施用。
以提供所需的治疗效果的量施用第二治疗剂。每种第二治疗剂的有效剂量范围是本领域中已知的,并且在这样已建立的范围内对有此需要的个体施用所述第二治疗剂。
本公开的化合物和第二治疗剂可以作为单个单位剂量一起施用或作为多单位剂量分开施用,其中本公开的化合物在第二治疗剂之前施用,或反之亦然。可以施用一个或多个剂量的本公开的化合物和/或一个或多个剂量的第二治疗剂。因此,本公开的化合物可以与一种或多种第二治疗剂(例如但不限于抗癌剂)联合使用。
可由本公开的方法治疗的疾病和病况包括但不限于癌症和其他增殖性病症。在一个实施方案中,用本公开的化合物或包含本公开的化合物的药物组合物治疗人类患者,其中以足以降低患者中ER蛋白的量施用化合物。
在另一方面,本公开提供了一种治疗受试者中癌症的方法,包括给予治疗有效量的本公开的化合物。虽然不限于特定机制,但在一些实施方案中,本公开的化合物通过降解ER蛋白来治疗癌症。在一个实施方案中,癌症是乳腺癌。
在本公开的方法中,对有此需要的人类施用治疗有效量的、通常按照药学实践配制的本公开的化合物。是否指定这样的治疗取决于个体情况并进行医疗评估(诊断),所述医疗评估(诊断)考虑到所存在的体征、症状和/或机能障碍,发展特定体征、症状和/或机能障碍的风险以及其它因素。
本公开的化合物可以通过任意合适的途径施用,例如通过口服、经颊、吸入、舌下、直肠、阴道、脑池内或鞘内(通过腰椎穿刺)、经尿道、经鼻、经皮(即,透皮)或胃肠外(包括静脉内、肌内、皮下、冠状动脉内、皮内、乳房内、腹膜内、关节内、鞘内、眼球后、肺内注射和/或在特定位点外科手术植入)施用。肠胃外施用可以使用针和注射器或使用高压技术来完成。
药物组合物包括其中本公开的化合物以有效量施用以实现其预期目的的那些。通过个体医生考虑到所诊断的病况或疾病来决定确切的制剂、施用途径和剂量。可以单独地调整剂量和间隔以提供足以维持治疗效果的本公开的化合物的水平。
可通过在细胞培养物或实验动物中的标准药学方法确定本公开的化合物的毒性和治疗功效,例如,用于确定化合物的最大耐受剂量(MTD)(其定义为在动物中不导致毒性的最高剂量)。最大耐受剂量和治疗效果(例如,抑制肿瘤生长)之间的剂量比是治疗指数。该剂量可根据所采用的剂型和所利用的施用途径在此范围内改变。治疗有效量的确定在本领域技术人员的能力范围内,特别是根据本文提供的详细的公开内容。
需要在治疗中使用的本公开的化合物的治疗有效量随待治疗的病况的性质、期望活性的时间长度以及患者的年龄和状况而变化,并且最终由主治医生决定。可以单独地调整剂量和时间间隔以提供足以维持所需的治疗效果的ER蛋白降解剂的血浆水平。所需剂量可方便地以单剂量施用,或以多剂量以适当的时间间隔施用,例如以每天一、二、三、四或更多个亚剂量。常常期望或需要多剂量。例如,本公开的化合物可以以如下频率施用:以四天的时间间隔按每日一剂递送四个剂量(q4d×4);以三天的时间间隔按每日一剂递送四个剂量(q3d×4);以五天的时间间隔每日递送一剂(qd×5);每周一个剂量持续三周(qwk3);五个日剂量(five daily doses),休息两天,再五个日剂量(5/2/5);或者,为适合情况而确定的任何剂量方案。
在本公开的方法中使用的本公开的化合物可以以每剂约0.005至约500mg的量,每剂约0.05至约250mg的量,或每剂约0.5至约100mg的量施用。例如,本公开的化合物可以每剂约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450或500mg的量施用,包括0.005和500mg之间的所有剂量。
含有本公开的化合物的组合物,或含有其的组合物的剂量可以是约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或约1mg/kg至约50mg/kg。组合物的剂量可以是任何剂量,包括但不限于约1μg/kg。组合物的剂量可以是任何剂量,包括但不限于,约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg/kg、约225μg/kg、约250μg/kg、约275μg/kg、约300μg/kg、约325μg/kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg/kg、约550μg/kg、约575μg/kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg或更多。上述剂量是一般情况的示例,但是存在其中较高或较低剂量有优势的个别情况,并且这些都在本公开的范围之内。在实践中,医生确定最适于个体患者的实际施用方案,其可以随着特定患者的年龄、体重和反应而变化。
本公开的化合物通常与就预期施用途径和标准药物实践而选择的药物载体混合施用。使用一种或多种生理学上可接受的载体以常规方式配制根据本公开使用的药物组合物,所述生理学上可接受的载体包括有利于本公开化合物的加工的赋形剂和/或助剂。
可以例如通过常规的混合、溶解、制粒、制锭(dragee-making)、乳化、包封、包埋或冻干工艺制造这些药物组合物。适当的配方取决于所选择的施用途径。当治疗有效量的本公开的化合物以口服施用时,组合物通常是片剂、胶囊、粉末、溶液或酏剂的形式。当以片剂形式施用时,组合物还可以包含固体载体,如明胶或佐剂。片剂、胶囊和粉末含有约0.01%至约95%,优选约1%至约50%的本公开的化合物。当以液体形式施用时,可以加入液体载体,例如水、石油、或动物或植物来源的油。组合物的液体形式可以进一步含有生理盐水溶液、右旋糖或其它糖类溶液或二醇类。当以液体形式施用时,该组合物含有按重量计约0.1%至约90%,优选约1%至约50%的本公开的化合物。
当通过静脉内、皮肤或皮下注射施用治疗有效量的本公开化合物时,组合物是无热原的、肠胃外可接受的水溶液的形式。适当考虑pH、等渗性、稳定性等的这种肠胃外可接受溶液的制备在本领域的技术范围内。用于静脉内、皮肤或皮下注射的优选的组合物通常包含等渗溶媒。
本公开的化合物可以很容易地与本领域中公知的药学上可接受的载体组合。标准药物载体在Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,PA,第19版,1995中描述。这样的载体使活性剂能够配制成片剂、丸剂、糖衣丸、胶囊、液体、凝胶、糖浆、浆液,悬浮液等,用于由待治疗的患者口服摄取。用于口服使用的药物制剂可以通过将本公开的化合物添加到固体赋形剂中,任选研磨所得的混合物并加工颗粒的混合物,在加入合适的助剂后(如果需要的话),以获得片剂或糖衣丸芯而获得。
合适的赋形剂包括填充剂,例如糖类(例如,乳糖、蔗糖、甘露醇或山梨糖醇)、纤维素制剂、磷酸钙(例如,磷酸三钙或磷酸氢钙),以及粘合剂,例如淀粉糊(使用例如,玉米淀粉、小麦淀粉、大米淀粉或马铃薯淀粉)、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如果需要,可以加入一种或多种崩解剂,例如上述淀粉以及羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或海藻酸或其盐,例如海藻酸钠。还可以添加缓冲剂和pH调节剂以稳定药物组合物。
助剂通常是流动调节剂和润滑剂,例如二氧化硅、滑石、硬脂酸或其盐(例如硬脂酸镁或硬脂酸钙)和聚乙二醇。糖衣丸芯具有耐胃液的合适涂层。为此,可以使用浓缩的糖溶液,其可以任选地包含阿拉伯树胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。为了生产耐胃液的包衣,可以使用合适的纤维素制剂的溶液,例如邻苯二甲酸乙酰纤维素或邻苯二甲酸羟丙基甲基纤维素。可以向片剂或糖衣丸包衣中添加染料或颜料,例如,用于识别或表征活性化合物剂量的组合。
本公开的化合物可被配制成通过注射(例如通过推注(bolus injection)或连续输注)肠胃外施用。用于注射的制剂可以以单位剂量形式存在,例如,在安瓿或多剂量容器中,添加有防腐剂。该组合物可以采取这样的形式,如悬浮液、溶液或在油性或水性溶媒中的乳剂,并且可以包含配制剂如悬浮剂、稳定剂和/或分散剂。
用于肠胃外施用的药物组合物包括水溶性形式的活性剂的水溶液。此外,本公开的化合物的悬浮液可以制备成适当的油性注射悬浮液。合适的亲脂性溶剂或溶媒包括脂肪油或合成脂肪酸酯。水性注射悬浮液可含有增加悬浮液粘度的物质。任选地,悬浮液还可以包含合适的稳定剂或增加化合物的溶解度并允许制备高度浓缩溶液的试剂。可选地,本公开的组合物可以是在使用前用合适的溶媒例如无菌无热原水重构的粉末形式。
本公开的化合物还可以配制在直肠组合物中,诸如栓剂或保留灌肠剂,例如含有常规栓剂基质。除了先前描述的制剂,本公开的化合物还可以配制成储库制剂(depotpreparation)。这样的长效制剂可通过植入(例如,皮下或肌内)或通过肌内注射施用。因此,例如,本公开的化合物可以用合适的聚合材料或疏水材料(例如,作为在可接受的油中的乳剂)或离子交换树脂配制。
特别地,本公开的化合物可以以含赋形剂如淀粉或乳糖的片剂形式,或者以单独或与赋形剂混合的胶囊或胚珠的形式,或以包含调味剂或着色剂的酏剂或悬浮液的形式口服、向颊或舌下施用。这种液体制剂可以用药学上可接受的添加剂,例如悬浮剂来制备。本公开的化合物也可以肠胃外注射,例如,静脉内、肌内、皮下或冠脉内。对于肠胃外施用,本公开的化合物通常以无菌水溶液的形式使用,所述无菌水溶液可以含有其它物质,例如盐或单糖,如甘露糖醇或葡萄糖,以使溶液与血液等渗。
III.定义
本文所用的术语“雌激素受体调节剂”是指作用于雌激素受体的一类药物,包括SERM和SERD。代表性的雌激素受体调节剂包括但不限于:
本文所用的术语“雌激素受体调节剂的自由基”是指母体雌激素受体调节剂缺少原子(例如氢)或原子团(例如-CH3)的化学物质。例如,他莫昔芬(2a)中不存在-CH3提供了以下雌激素受体调节剂的自由基:
氢原子或原子团的缺失使母体雌激素受体调节剂能够与E3泛素连接酶蛋白配体连接,以产生具有如上定义的式I的异双官能化合物。
如本文中的术语“E3连接酶配体”是指结合例如抑制E3泛素连接酶蛋白(包括vonHippel-Lindau蛋白(VHL))的化合物。E3泛素连接酶蛋白的配体是本领域普通技术人员已知的。E3泛素连接酶蛋白的示例性非限制性配体包括基于邻苯二甲酰亚胺的药物,例如沙利度胺或VHL配体,包括但不限于图表1的VHL配体。
图表1
短语“E3连接酶配体的自由基”是指亲本E3连接酶配体缺少原子(例如氢)或原子团(例如-CH3)的化学物质。例如,VHL-a(见上文)缺少-CH3提供了以下E3连接酶配体的自由基:
沙利度胺的氢的缺失提供了以下E3连接酶配体的自由基:
氢原子或原子团的缺失使亲本E3连接酶配体能够与雌激素受体调节剂连接,以产生具有如上定义的式I的异双官能化合物。
本文所用的术语“接头”是指能够将雌激素受体拮抗剂的自由基束缚于E3连接酶配体的自由基的二价化学部分。
本文所用的术语“约”包括所记载的数±10%。因此,“约10”表示9至11。
在本公开中,单独使用或作为另一基团的一部分的术语“卤素”是指-Cl、-F、-Br或-I。
在本公开中,单独使用或作为另一基团的一部分的术语“硝基”是指-NO2。
在本公开中,单独使用或作为另一基团的一部分的术语“氰基”是指-CN。
在本公开中,单独使用或作为另一基团的一部分的术语“羟基”是指-OH。
在本公开中,单独使用或作为另一基团的一部分的术语“烷基”是指含有一到十二个碳原子的未取代的直链或支链脂族烃(即C1-20烷基),或者含有指定的碳原子数的未取代的直链或支链脂族烃,例如,C1烷基如甲基,C2烷基如乙基,C3烷基如丙基或异丙基,C1-3烷基如甲基、乙基、丙基或异丙基等。在一个实施方案中,烷基是C1-10烷基。在另一个实施方案中,烷基是C1-6烷基。在另一个实施方案中,烷基是C1-4烷基。在另一个实施方案中,烷基是直链C1-10烷基。在另一个实施方案中,烷基是支链C3-10烷基。在另一个实施方案中,烷基是直链C1-6烷基。在另一个实施方案中,烷基是支链C3-6烷基。在另一个实施方案中,烷基是直链C1-4烷基。在另一个实施方案中,烷基是支链C3-4烷基。在另一个实施方案中,烷基是直链或支链C3-4烷基。非限制性的示例性C1-10烷基基团包括甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、异丁基、3-戊基、己基、庚基、辛基、壬基和癸基。非限制性示例性C1-4烷基包括甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基和异丁基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“杂烷基”是指含有三至三十个链原子的未取代直链或支链脂族烃(即3元至30元杂烷基)或者含有指定碳原子数的未取代直链或支链脂族烃,其中至少一个-CH2-被至少一个-O-、-N(H)-或-S-取代。所述-O-、-N(H)-或-S-可以独立地位于脂族烃链的任意内部位置,只要每个-O-、-N(H)-或-S-基团被至少两个-CH2-基团分开。在一个实施方案中,一个-CH2-基团被一个-O-基团取代。在另一个实施方案中,两个-CH2-基团被两个-O-基团取代。在另一个实施方案中,三个-CH2-基团被三个-O-基团取代。在另一个实施方案中,四个-CH2-基团被四个-O-基团取代。非限制性示例性杂烷基包括:
-CH2OCH3;
-CH2OCH2CH2CH3;
-CH2CH2CH2OCH3;
-CH2OCH2CH2OCH3;和
-CH2OCH2CH2OCH2CH2OCH。
在本公开中,在本文单独使用或作为另一基团的一部分使用的术语“亚烷基”是指烷基的二价形式。在一个实施方案中,亚烷基是C1-12烷基的二价形式。在一个实施方案中,亚烷基是C1-10烷基的二价形式。在一个实施方案中,亚烷基是C1-8烷基的二价形式。在一个实施方案中,亚烷基是C1-6烷基的二价形式。在另一个实施方案中,亚烷基是C1-4烷基的二价形式。非限制性示例性亚烷基包括:
-CH2-,
-CH2CH2-,
-CH2CH2CH2-,
-CH2(CH2)2CH2-,
-CH(CH2)3CH2-,
-CH2(CH2)4CH2-,
-CH2(CH2)5CH2-,
-CH2CH(CH3)CH2-,和
-CH2C(CH3)2CH2-
在本公开中,在本文单独使用或作为另一基团的一部分使用的术语“亚杂烷基”是指杂烷基的二价形式。在一个实施方案中,亚杂烷基是3元至12元杂烷基的二价形式。在另一个实施方案中,亚杂烷基是3元至10元杂烷基的二价形式。在另一个实施方案中,亚杂烷基是3元至8元杂烷基的二价形式。在另一个实施方案中,亚杂烷基是3元至6元杂烷基的二价形式。在另一个实施方案中,亚杂烷基是3元至4元杂烷基的二价形式。在另一个实施方案中,亚杂烷基是下式的基团:-(CH2)oO-(CH2CH2O)p-(CH2)q-,其中o是2或3;p是0、1、2、3、4、5、6或7;并且q是2或3。在另一个实施方案中,亚杂烷基是下式的基团:-(CH2)rO-(CH2)s-O(CH2)t,其中r是2、3或4;s是3、4或5;并且t是2或3。非限制性示例性亚杂烷基包括:
--CH2OCH2-;
-CH2CH2OCH2CH2-;
-CH2OCH2CH2CH2-;
-CH2CH2OCH2CH2CH2-;
-CH2CH2OCH2CH2OCH2CH2-;和
-CH2CH2OCH2CH2OCH2CH2O-。
在本公开中,单独使用或作为另一基团的一部分使用的术语“任选取代的烷基”是指如上定义的烷基未被取代或被独立地选自以下的一个、两个或三个取代基取代:硝基、卤代烷氧基、芳氧基、芳烷氧基、烷硫基、磺酰氨基、烷基羰基、芳基羰基、烷基磺酰基、芳基磺酰基、羧基、羧烷基和环烷基等。在一个实施方案中,任选取代的烷基被两个取代基取代。在另一个实施方案中,任选取代的烷基被一个取代基取代。非限制性示例性任选取代的烷基包括-CH2CH2NO2、-CH2SO2CH3 CH2CH2CO2H、-CH2CH2SO2CH3、-CH2CH2COPh和-CH2C6H11。
在本公开中,单独使用或作为另一基团的一部分使用的术语“环烷基”是指含有具有3至12个碳原子的1至3个环的饱和和部分不饱和(含有一个或两个双键)环状脂族烃(即C3-12环烷基)或含有具有指定碳原子数的1至3个环的饱和和部分不饱和环状脂族烃。在一个实施方案中,环烷基具有两个环。在一个实施方案中,环烷基具有一个环。在另一个实施方案中,环烷基选自C3-8环烷基。另一个实施方案中,环烷基选自C3-6环烷基。非限制性的示例性的环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片基(norbornyl)、十氢化萘(decalin)、金刚烷基、环己烯基和环戊烯基、环己烯基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“任选取代的环烷基”是指如上定义的环烷基未被取代或被独立地选自以下的一个、两个或三个取代基取代:卤素、硝基、氰基、羟基、氨基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、芳氧基、芳烷氧基、烷硫基、甲酰胺基(carboxamido)、磺酰氨基、烷基羰基、芳基羰基、烷基磺酰基、芳基磺酰基、羧基、羧烷基、烷基、任选取代的环烷基、烯基、炔基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、烷氧基烷基、(氨基)烷基、(甲酰胺基)烷基、巯基烷基和(杂环基)烷基。在一个实施方案中,任选取代的环烷基被两个取代基取代。在另一个实施方案中,任选取代的环烷基被一个取代基取代。
在本公开中,在本文单独使用或作为另一基团的一部分的术语“亚环烷基”是指任选取代的环烷基的二价形式。5元环亚烷基(亚环烷基)的非限制性实例包括:
在本公开中,单独使用或作为另一基团的一部分使用的术语“烯基”是指含有一个、两个或三个碳-碳双键的、如上定义的烷基。在一个实施方案中,烯基选自C2-6烯基。在另一个实施方案中,烯基选自C2-4烯基。非限制性的示例性烯基包括乙烯基、丙烯基、异丙烯基、丁烯基、仲丁烯基、戊烯基和己烯基。
在本公开中,在本文单独使用或作为另一基团的一部分使用的术语“任选取代的烯基”是指如上定义的烯基未被取代或被独立地选自以下的一个、两个或三个取代基取代:卤素、硝基、氰基、羟基、氨基、烷基氨基、二烷基氨基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、芳氧基、芳烷氧基、烷硫基、甲酰胺基、磺酰氨基、烷基羰基、芳基羰基、烷基磺酰基、芳基磺酰基、羧基、羧烷基、烷基、环烷基、烯基、炔基、芳基、杂芳基或杂环基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“炔基”是指含一至三个碳-碳三键的、如上定义的烷基。在一个实施方案中,炔基具有一个碳-碳三键。在一个实施方案中,炔基选自C2-6炔基。在另一个实施方案中,炔基选自C2-4炔基基团。非限制性的示例性的炔基包括乙炔基、丙炔基、丁炔基、2-丁炔基、戊炔基和己炔基。
在本公开中,在本文单独使用或作为另一基团的一部分使用的术语“任选取代的炔基”是指如上定义的炔基未被取代或被独立地选自以下的一个、两个或三个取代基取代:卤素、硝基、氰基、羟基、氨基、烷基氨基、二烷基氨基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、芳氧基、芳烷氧基、烷硫基、甲酰胺基、磺酰氨基、烷基羰基、芳基羰基、烷基磺酰基、芳基磺酰基、羧基、羧烷基、烷基、环烷基、烯基、炔基、芳基、杂芳基或杂环基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“卤代烷基”是指被一个或多个氟、氯、溴和/或碘原子取代的烷基。在一个实施方案中,所述烷基被一个、两个或三个氟和/或氯原子取代。在另一个实施方案中,卤代烷基选自C1-4卤代烷基基团。非限制性的示例性的卤代烷基包括氟甲基、2-氟乙基、二氟甲基、三氟甲基、五氟乙基、1,1-二氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、3,3,3-三氟丙基、4,4,4-三氟丁基和三氯甲基基团。
在本公开中,单独使用或作为另一基团的一部分使用的术语“羟烷基”是指被一个或多个例如一个、两个或三个羟基取代的烷基。在一个实施方案中,羟烷基为单羟基烷基基团,即被一个羟基基团取代的。在另一个实施方案中,羟烷基是二羟基烷基,即,被两个羟基基团取代的,例如,
在另一个实施方案中,羟烷基选自C1-4羟烷基。非限制性的示例性羟烷基包括羟甲基、羟乙基、羟丙基和羟丁基基团,如1-羟乙基、2-羟乙基、1,2-二羟基乙基、2-羟丙基、3-羟丙基、3-羟丁基、4-羟丁基、2-羟基-1-甲基丙基和1,3-二羟基丙-2-基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“烷氧基”是指连接到末端氧原子的任选取代的烷基、任选取代的环烷基、任选取代的烯基或任选取代的炔基。在一个实施方案中,烷氧基选自C1-4烷氧基。在另一个实施方案中,烷氧基选自连接到末端氧原子的C1-4烷基,例如,甲氧基、乙氧基和叔丁氧基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“烷硫基”是指由任选取代的烷基取代的硫原子。在一个实施方案中,烷硫基选自C1-4烷硫基。非限制性的示例性烷硫基包括-SCH3和-SCH2CH3。
在本公开中,单独使用或作为另一基团的一部分使用的术语“烷氧基烷基”是指被烷氧基取代的烷基。非限制性的示例性烷氧基烷基包括甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基、丙氧基甲基、异丙氧基甲基、丙氧基乙基、丙氧基丙基、丁氧基甲基、叔丁氧基甲基、异丁氧基甲基、仲丁氧基甲基和戊氧基甲基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“卤代烷氧基”指的是连接到末端氧原子的卤代烷基。非限制性的示例性卤代烷氧基包括氟甲氧基、二氟甲氧基、三氟甲氧基和2,2,2-三氟乙氧基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“芳基”是指具有6至14个碳原子的单环或双环芳环体系(即,C6-C14芳基)。非限制性的示例性芳基包括苯基(简写为“Ph”)、萘基、菲基、蒽基、茚基、薁基(azulenyl)、联苯基、亚联苯基和芴基。在一个实施方案中,芳基选自苯基或萘基。
在本公开中,在本文单独使用或作为另一基团的一部分使用的术语“任选取代的芳基”是指如上定义的芳基未被取代或被独立地选自以下的一个至五个取代基取代:卤素、硝基、氰基、羟基、氨基、烷基氨基、二烷基氨基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、芳氧基、芳烷氧基、烷硫基、甲酰胺基、磺酰氨基、烷基羰基、芳基羰基、烷基磺酰基、芳基磺酰基、羧基、羧烷基、烷基、任选取代的环烷基、烯基、炔基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、烷氧基烷基、(氨基)烷基、(甲酰胺基)烷基、巯基烷基或(杂环基)烷基。
在一个实施方案中,任选取代的芳基为任选取代的苯基。在一个实施方案中,任选取代的苯基具有四个取代基。在另一个实施方案中,任选取代的苯基具有三个取代基。在另一个实施方案中,任选取代的苯基具有两个取代基。在另一个实施方案中,任选取代的苯基具有一个取代基。非限制性的示例性取代的芳基包括2-甲基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、3-甲基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、4-甲基苯基、4-乙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、2,6-二氟苯基、2,6-二氯苯基、2-甲基-3-甲氧基苯基、2-乙基-3-甲氧基苯基、3,4-二甲氧基苯基、3,5-二氟苯基、3,5-二甲基苯基、3,5-二甲氧基、4-甲基苯基、2-氟-3-氯苯基和3-氯-4-氟苯基。术语任选取代的芳基旨在包括具有稠合的任选取代的环烷基和稠合的任选取代的杂环环的基团。非限制性实例包括:
在本公开中,在本文单独使用或作为另一基团的一部分使用的术语“亚苯基”是指任选取代的苯基的二价形式。非限制性实例包括:
在本公开中,单独使用或作为另一基团的一部分使用的术语“芳氧基”指的是连接到末端氧原子的任选取代的芳基。非限制性的示例性芳氧基是PhO-。
在本公开中,单独使用或作为另一基团的一部分使用的术语“芳烷氧基”是指连接到末端氧原子的芳烷基。非限制性的示例性芳烷氧基是PhCH2O-。
在本公开中,术语“杂芳基”或“杂芳族”是指具有5至14个环原子的单环和双环芳族环体系(即,C5-C14杂芳基),其中所述环之一的至少一个碳原子被独立地选自由氧、氮和硫组成的组的杂原子替换。在一个实施方案中,杂芳基含有1、2、3或4个独立地选自由氧、氮和硫组成的组的杂原子。在一个实施方案中,杂芳基具有三个杂原子。在另一个实施方案中,杂芳基具有两个杂原子。在另一个实施方案中,杂芳基具有一个杂原子。非限制性的示例性杂芳基包括噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基(thianthrenyl)、呋喃基、苯并呋喃基、吡喃基、异苯并呋喃基、苯并噁唑基、色烯基(chromenyl)、呫吨基(xanthenyl)、2H-吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、异喹啉基、喹啉基、酞嗪基、萘啶基(naphthyridinyl)、噌啉基(cinnolinyl)、喹唑啉基、蝶啶基、4aH-咔唑基、咔唑基、β-咔啉基、菲啶基、吖啶基、嘧啶基、菲咯啉(phenanthrolinyl)、吩嗪基(phenazinyl)、噻唑基、异噻唑基、苯酚并噻唑基(phenothiazolyl)、异噁唑基、呋咕基(furazanyl)和吩噁嗪(phenoxazinyl)。在一个实施方案中,所述杂芳基选自噻吩基(例如,噻吩-2-基和噻吩-3-基)、呋喃基(例如,2-呋喃基和3-呋喃基)、吡咯基(例如,1H-吡咯-2-基和1H-吡咯-3-基)、咪唑基(例如,2H-咪唑-2-基和2H-咪唑-4-基)、吡唑基(例如,1H-吡唑-3-基、1H-吡唑-4-基和1H-吡唑-5-基)、吡啶基(例如,吡啶-2-基、吡啶-3-基和吡啶-4-基)、嘧啶基(例如,嘧啶-2-基、嘧啶-4-基和嘧啶-5-基)、噻唑基(例如,噻唑-2-基、噻唑-4-基和噻唑-5-基)、异噻唑基(例如,异噻唑-3-基、异噻唑-4-基和异噻唑-5-基)、噁唑基(例如,噁唑-2-基、噁唑-4-基和噁唑-5-基)、异噁唑基(例如,异噁唑-3-基、异噁唑-4-基和异噁唑-5-基)和吲唑基(例如,1H-吲唑-3-基)。术语“杂芳基”还旨在包括可能的N-氧化物。非限制性的示例性N-氧化物是吡啶基N-氧化物。
在一个实施方案中,杂芳基是5元或6元杂芳基。在一个实施方案中,所述杂芳基是5元杂芳基,即杂芳基为具有5个环原子的单环芳香环体系,其中环的至少一个碳原子被独立地选自氮、氧和硫的杂原子替换。非限制性的示例性5元杂芳基包括噻吩基、呋喃基、吡咯基、噁唑基、吡唑基、咪唑基、噻唑基、异噻唑基和异噁唑基。
在另一个实施方案中,杂芳基是6元杂芳基,例如,杂芳基是具有6个环原子的单环芳环体系,其中环的至少一个碳原子被替换为氮原子。非限制性的示例性6元杂芳基包括吡啶基、吡嗪基、嘧啶基和哒嗪基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“任选取代的杂芳基”是指如上定义的杂芳基未被取代或被独立地选自以下的一个至四个取代基(例如一个或两个取代基)取代:卤素、硝基、氰基、羟基、氨基、烷基氨基、二烷基氨基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、芳氧基、芳烷氧基、烷硫基、甲酰胺基、磺酰氨基、烷基羰基、芳基羰基、烷基磺酰基、芳基磺酰基、羧基、羧烷基、烷基、任选取代的环烷基、烯基、炔基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、烷氧基烷基、(氨基)烷基、(甲酰胺基)烷基、巯基烷基或(杂环基)烷基。在一个实施方案中,任选取代的杂芳基具有一个取代基。任何可用的碳或氮原子均可以被取代。非限制性的示例性任选取代的5元杂芳基包括但不限于
术语任选取代的杂芳基也旨在包括具有稠合的任选取代的环烷基和稠合的任选取代的杂环环的基团。非限制性实例包括:
在本公开中,在本文单独使用或作为另一基团的一部分使用的术语“亚杂芳基”是指任选取代的杂芳基的二价形式。在一个实施方案中,亚杂芳基是5元亚杂芳基。5元亚杂芳基的非限制性实例包括:
在一个实施方案中,亚杂芳基是6元亚杂芳基。6元亚杂芳基的非限制性实例包括:
在本公开中,单独使用或作为另一基团的一部分使用的术语“杂环”或“杂环基”是指饱和的和部分不饱和的(例如,含有一个或两个双键)的环状基团,其含有一个、两个或三个、具有三至十四个环成员(即,3至14元杂环基)的环,其中所述环之一的至少一个碳原子被替换为杂原子。每个杂原子独立地选自由氧、硫(包括亚砜和砜)和/或氮原子组成的组,其可以被氧化或季铵化。术语“杂环基”旨在包括其中环-CH2-被替换为-C(=O)-的基团,例如,环状脲基,如2-咪唑啉酮和环酰胺基团,如β-内酰胺、γ-内酰胺、δ-内酰胺、ε-内酰胺和哌嗪-2-酮。术语“杂环基”还旨在包括具有稠合的任选取代的芳基的基团,例如,二氢吲哚基,苯并二氢吡喃-4-基。在一个实施方案中,杂环基基团选自含有一个环和一个或两个氧和/或氮原子的5-或6-元环状基团。杂环基可通过任意可用的碳或氮原子任选地与分子的其余部分连接。非限制性的示例性杂环基团包括二氧杂环己烷基(dioxanyl)、四氢吡喃基、2-氧代吡咯烷-3-基、哌嗪-2-酮、哌嗪-2,6-二酮、2-咪唑啉酮、哌啶基、吗啉基、哌嗪基、吡咯烷基和二氢吲哚基。
在本公开中,在本文单独使用或作为另一基团的一部分使用的术语“任选取代的杂环基”是指如上定义的杂环基未被取代或被独立地选自以下的一个至四个取代基取代:卤素、硝基、氰基、羟基、氨基、烷基氨基、二烷基氨基、卤代烷基、羟基烷基、烷氧基、卤代烷氧基、芳氧基、芳烷氧基、烷硫基、甲酰胺基、磺酰氨基、烷基羰基、烷氧基羰基、CF3C(=O)-、芳基羰基、烷基磺酰基、芳基磺酰基、羧基、羧烷基、烷基、任选取代的环烷基、烯基、炔基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、烷氧基烷基、(氨基)烷基、(甲酰胺基)烷基、巯基烷基或(杂环基)烷基。取代可以发生在任何可用的碳或氮原子或两者上。非限制性的示例性任选取代的杂环基包括:
在本公开中,单独使用或作为另一基团的一部分使用的术语“氨基”是指-NR10aR10b,其中R10a和R10b各自独立地为氢、烷基、羟烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂环基或任选取代的杂芳基,或者R10a和R10b一起形成3元至8元任选取代的杂环基。非限制性的示例性氨基包括-NH2和-NH2和-N(H)(CH3。
在本公开中,单独使用或作为另一基团的一部分使用的术语“(氨基)烷基”是指被氨基取代的烷基。非限制性的示例性氨基烷基包括-CH2CH2NH2和-CH2CH2N(H)CH3、-CH2CH2N(CH3)2和-CH2N(H)环丙基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“甲酰胺基”是指式-C(=O)NR9aR9b的基团,其中R9a和R9b各自独立为氢、任选取代的烷基、羟烷基、任选取代的环烷基、任选取代的芳基、任选取代的杂环基或任选取代的杂芳基,或者R9a和R9b与它们所连接的氮一起形成3元至8元任选取代的杂环基。在一个实施方案中,R9a和R9b各自独立地为氢或任选取代的烷基。在一个实施方案中,R9a和R9b与它们所连接的氮一起形成3元至8元任选取代的杂环基。非限制性的示例性甲酰胺基基团包括,但不限于-CONH2、-CON(H)CH3、-CON(CH3)2、-CON(H)Ph,
在本公开中,单独使用或作为另一基团的一部分使用的术语“磺酰氨基”是指式-SO2NR8aR8b的基团,其中R8a和R8b各自独立为氢、任选取代的烷基或任选取代的芳基,或者R8a和R8b与它们所连接的氮一起形成3元至8元杂环基。非限制性的示例性磺酰氨基包括-SO2NH2、-SO2N(H)CH3和-SO2N(H)Ph。
在本公开中,单独使用或作为另一基团的一部分使用的术语“烷基羰基”是指被烷基取代的羰基,即-C(=O)-。非限制性的示例性烷基羰基是-COCH3。
在本公开中,单独使用或作为另一基团的一部分使用的术语“芳基羰基”是指被任选取代的芳基取代的羰基,即-C(=O)-。非限制性的示例性芳基羰基是-COPh。
在本公开中,单独使用或作为另一基团的一部分使用的术语“烷氧基羰基”是指被烷氧基取代的羰基,即-C(=O)-。非限制性的示例性烷氧基羰基包括C(=O)OMe、-C(=O)OEt和-C(=O)OtBu。
在本公开中,单独使用或作为另一基团的一部分使用的术语“烷基磺酰基”是指被任何上述任选取代的烷基取代的磺酰基,即,-SO2-。非限制性的示例性烷基磺酰基是-SO2CH3。
在本公开中,单独使用或作为另一基团的一部分使用的术语“芳基磺酰基”是指被任何上述任选取代的芳基取代的磺酰基,即,-SO2-。非限制性的示例性芳基磺酰基是-SO2Ph。
在本公开中,单独使用或作为另一基团的一部分使用的术语“巯基烷基”是指被–SH基团取代的任意上述烷基。
在本公开中,单独使用或作为另一基团的一部分使用的术语“羧基”是指式-COOH的基团。
在本公开中,单独使用或作为另一基团的一部分使用的术语“羧烷基”是指用-COOH取代的任意上述烷基。非限制性的示例性羧烷基是-CH2CO2H。
在本公开中,单独使用或作为另一基团的一部分使用的术语“芳烷基”或“芳基烷基”是指被一个、两个或三个任选取代的芳基取代的烷基。在一个实施方案中,任选取代的芳烷基是被一个任选取代的芳基基团取代的C1-4烷基。在一个实施方案中,任选取代的芳烷基是被一个任选取代的芳基取代的C1或C2烷基。在一个实施方案中,任选取代的芳烷基是被一个任选取代的苯基取代的C1或C2烷基。非限制性的示例性任选取代的芳烷基包括苄基、苯乙基、-CHPh-2、-CH2(4-F-Ph)、-CH2(4-Me-Ph)、-CH2(4-CF3-Ph)和-CH(4-F-Ph)2。
在本公开中,单独使用或作为另一基团的一部分使用的术语“(杂环基)烷基”是指被任选取代的杂环基取代的烷基。在一个实施方案中,(杂环基)烷基是被一个任选取代的杂环基团取代的C1-4烷基。非限制性的示例性(杂环基)烷基包括:
本公开包括通过使一个或多个原子被具有不同原子质量或质量数的原子取代而被同位素标记的(即放射性标记的)任意本公开的化合物。可以掺入本公开的化合物中的同位素的实例包括氢、碳、氮、硫、氧、氟和氯的同位素,例如2H(或氘(D))、3H、11C、13C、14C、15N、18O、17O、35S、18F和36Cl,例如2H、3H和13C。在一个实施方案中,本公开的化合物中的某一位置的一部分原子被取代,即,本公开的化合物在某一位置上富集了具有不同原子质量或质量数的原子。在一个实施方案中,至少约1%的原子被具有不同原子质量或质量数的原子取代。在另一个实施方案中,至少约5%、至少约10%、至少约15%、至少约20%、至少约25%、至少约30%、至少约35%、至少约40%、至少约45%、至少约50%、至少约55%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%或至少约100%的原子被具有不同原子质量或质量数的原子取代。同位素标记的本公开的化合物可通过本领域已知的方法制备。
实施例
实施例1
化合物合成及表征
通用化学方法。
除非另有说明,所有购买的试剂均按原样使用,无需进一步纯化。1HNMR和13C NMR光谱在Bruker Advance 400MHz光谱仪上记录。1H NMR光谱以四甲基硅烷(TMS)的低场百万分之一(ppm)报告。所有13C NMR光谱都以ppm为单位报告,并通过1H去耦获得。在报告的光谱数据中,格式(δ)化学位移(多重性,J值(Hz),积分)与以下缩写一起使用:s=单峰,d=双峰,t=三重峰,q=四重峰,m=多重峰。使用Waters UPLC-质谱仪进行MS分析。最终化合物均通过C18反相制备型HPLC柱纯化,使用溶剂A(0.1%TFA的H2O)和溶剂B(0.1%TFA的MeCN溶液)作为洗脱液。通过UPLC-MS确定所有最终化合物的纯度>95%。
最终化合物的合成在方案3-5中概述。首先,分别如方案1和2所示合成了两个关键的常用中间体53和58。将商业4-乙酰氧基苯甲酸(49)转化为酰氯,在商业6-甲氧基-2-(4-甲氧基苯基)苯并-[b]噻吩进行Friedel-Crafts酰化后,得到化合物50。50在碱性水溶液条件下脱乙酰得到化合物51。将其转化为烷基溴,用过量乙胺取代以提供仲胺(52)。用三溴化硼在52中裂解两个芳基甲氧基醚,得到二羟基中间体53。按照公开的程序,47化合物58的合成开始于商业(S)-1-(4-溴苯基)乙烷-1-胺(54)的叔丁氧羰基保护。随后54与4-甲基噻唑的Suzuki偶联得到化合物55,然后在酸性条件下脱保护,并与市售的(2S,4R)-1-(叔丁氧基羰基)-4-羟基吡咯烷-2-羧酸进行酰胺偶联得到56,在相同条件下脱保护,然后与市售的(S)-1-(叔丁氧基羰基)哌啶-2-羧酸进行酰胺偶联,得到化合物57,酸性脱保护后得到化合物58。
如方案3所示,化合物12的合成开始于使用甲磺酰氯和三甲胺作为碱将商购的2-(2-(2-(丙-2-炔-1-基氧基)甲氧基)甲氧基)乙烷-1-醇(59a)甲磺酸化为化合物60a。在温和的碱性条件下,用化合物53对60a进行亲核取代,得到N-取代的化合物(61a)。化合物61a与先前公开的化合物3-(4-碘-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮50的Sonogashira偶联以高收率得到化合物12。从辛-7-炔-1-醇(59b)开始使用合成化合物12所描述的程序合成化合物13。
如方案4所示,从制备化合物63或65开始研究不同的接头,63或65是可商购的并且可以分别由62或64制备。化合物63或65与化合物53的取代反应提供化合物66,在酸性脱保护后得到酸(67)。化合物67和58的酰胺偶联以高收率提供最终化合物14-21和30-37。
如方案5所示,中间体51用于N-取代基的SAR研究。化合物51首先转化为相应的烷基溴,用过量的伯胺进行亲核攻击,提供化合物68。化合物68与8-溴辛酸叔丁酯(65)的取代反应提供连接体连接的中间体,其经历三溴化硼介导的去甲基化和脱保护得到酸(69)。化合物69和58之间的酰胺偶联以高收率提供最终化合物22-29。使用用于制备化合物15的通用程序合成化合物38-48。
方案1.中间体53的合成a
a试剂和条件:(a)草酰氯,DMF,DCM,0℃-RT,1h;(b)6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩,AlCl3,DCM,0℃-RT,1h;(c)NaOAc,EtOH/H2O,80℃,12h;(d)1,2-二溴乙烷,Cs2CO3,MeCN,回流,12h;(e)EtNH2,DIPEA,DMF,80℃,12h;(f)BBr3,DCM,0℃-RT,1h。
方案2.中间体58的合成a
a试剂和条件:(a)Boc2O,NaHCO3,EtOAc/H2O,2h;(b)4-甲基噻唑,Pd(OAc)2,KOAc,DMA,90℃,12h;(c)4N HCl的二噁烷/MeOH溶液,RT,12h;(d)(2S,4R)-1-(叔丁氧基羰基)-4-羟基吡咯烷-2-羧酸,HATU,DIPEA,DMF,0℃-RT,12h;(e)4N HCl的二噁烷/MeOH溶液,RT,12h;(f)(S)-1-(叔丁氧基羰基)哌啶-2-羧酸,HATU,DIPEA,DMF,0℃-RT,12h;(g)4N HCl的二噁烷/MeOH溶液,RT,12h。
方案3.化合物12和13的合成a
a试剂和条件:(a)MsCl,TEA,DCM,0℃-RT,1h;(b)53,DIPEA,DMF,80℃,12h;(c)3-(4-碘-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮,Pd(PPh3)Cl2,CuI,DMF/TEA,80℃,1h。
方案4.化合物14-21、30-37的合成a
a试剂和条件:(a)TsCl or MsCl,TEA,DCM,0℃-RT,1h;(b)TFAA,tert-BuOH,DCM,0℃-RT,12h;(c)53,DIPEA,DMF,80℃,12h;(d)TFA/DCM,0℃-RT,6h;
(e)58,HATU,DIPEA,DMF,RT,12h。
方案5.化合物22-29的合成a
a试剂和条件:(a)1,2-二溴乙烷,Cs2CO3,MeCN,回流,12h;(b)RNH2,K2CO3,MeCN,80℃;(c)65,K2CO3,DMF,80℃,12h;(d)BBr3,DCM,0℃-RT,1h;(e)58,HATU,DIPEA,DMF,RT,12h。
4-(6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩-3-羰基)苯基乙酸酯(50)
在0℃,在N2下,将草酰氯(9.70mL,120mmol,3.0eq)滴加到4-乙酰氧基苯甲酸(49)(7.206g,40mmol,1.0eq)在无水DCM(80mL)的溶液中。然后添加几滴DMF。将溶液温热至室温并搅拌1小时。浓缩溶液并干燥,得到酰氯,为白色固体。将该中间体溶解在无水DCM(150mL)中,然后加入6-甲氧基-2-(4-甲氧基苯基)-苯并[b]噻吩(8.65g,32mmol,0.8eq),然后在5分钟内分三次加入AlCl3(8.00g,60mmol,1.5eq),伴随大力搅拌,在0℃,在N2下。将混合物温热至室温并搅拌1小时。通过缓慢加入冰-H2O,然后加入1N HCl(aq),淬灭反应。分离各层,并用DCM萃取水层两次。将合并的有机层用无水Na2SO4干燥。过滤和浓缩后,残余物通过硅胶快速柱纯化,用己烷:DCM(100:1-1:100),得到中间体(50),为黄色固体(5.517g,40%收率)。1H NMR(CDCl3,400MHz)δ(ppm)7.81(d,J=8.8Hz,2H),7.61(d,J=8.8Hz,1H),7.32-7.29(m,3H),7.02-6.99(m,3H),6.74(d,J=8.8Hz,2H),3.86(s,3H),3.73(s,3H),2.25(s,3H);13C NMR(CDCl3,100MHz)δ(ppm)193.15,168.63,159.99,157.78,154.38,144.16,140.10,135.03,133.76,131.52,130.48,130.02,125.76,124.16,121.54,114.99,114.13,104.54,55.65,55.28,21.16;C25H21O5S[M+1]+的UPLC-MS(ESI+)计算值:433.11,实测值433.37。
(4-羟基苯基)(6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩-3-基)甲酮(51)
将化合物50(5.517g,12.76mmol,1.0eq)溶解在EtOH(70mL)和H2O(30mL)中。然后,加入NaOAc(5.23g,63.8mmol,5.0eq)。将溶液在90-100℃下搅拌12小时。然后将溶液冷却至室温并浓缩。将残余物在EtOAc和H2O中稀释。分离有机层,水层用EtOAc提取两次。将合并的有机层用无水Na2SO4干燥。过滤和浓缩后,残余物通过硅胶快速柱色谱法纯化,用己烷:EtOAc(5:1-2:1),得到中间体51,为黄色油状物(4.7g,95%收率)。1H NMR(CD3OD,400MHz)δ(ppm)7.64(d,J=9.2Hz,2H),7.43(d,J=8.8Hz,1H),7.30(d,J=2.4Hz,1H),7.24(d,J=8.8Hz,2H),6.89(dd,J=8.8Hz,J=2.4Hz,1H),6.69-6.64(m,4H),3.73(s,3H),3.59(s,3H);13C NMR(CD3OD,100MHz)δ(ppm)193.95,162.85,159.92,157.81,142.33,140.08,133.78,132.55,130.34,129.91,129.06,125.78,123.43,115.04,114.63,113.79,104.34,54.78,54.39;C23H19O4S[M+1]+的UPLC-MS(ESI+)计算值:391.10,实测值391.42。
(4-(2-(乙基氨基)甲氧基)苯基)(6-甲氧基-2-(4-甲氧基苯基)苯并[b]噻吩-3-基)甲酮(52)
将1,2-二溴乙烷(2.0mL,24.0mmol,2.0eq)和Cs2CO3(5.86g,18.0mmol,1.5eq)依次加入到化合物51(4.7g,12.0mmol,1.0eq)在MeCN(200mL)中的溶液中。将溶液加热至回流12小时。将溶液过滤,并将沉淀物用MeCN洗涤。浓缩的残余物无需进一步柱纯化,即可用于下一步。将EtNH2(2.0M的THF溶液)(60mL,120mmol,10.0eq)加入到残余物在DMF中的溶液中。将溶液加热至80℃并搅拌12小时。冷却至室温后,将反应混合物在EtOAc中稀释,饱和盐水洗涤。用EtOAc将水层萃取两次。将合并的有机层干燥并浓缩。残余物通过硅胶快速柱色谱法纯化,用DCM:MeOH(10:1),得到化合物52,为黄色固体(4.43g,80%收率)。1H NMR(CD3OD,400MHz)δ(ppm)7.63(d,J=8.8Hz,2H),7.42(d,J=8.8Hz,1H),7.32(d,J=2.4Hz,1H),7.20(d,J=8.8Hz,2H),6.88(dd,J=8.8Hz,J=2.4Hz,1H),6.71(d,J=8.8Hz,2H),6.64(d,J=8.8Hz,2H),3.93(t,J=4.2Hz,2H),3.75(s,3H),3.59(s,3H),2.83(t,J=5.2Hz,2H),2.59(q,J=7.2Hz,2H),1.06(t,J=7.2Hz,3H);13CNMR(CD3OD,100MHz)δ(ppm)194.88,164.48,161.27,159.20,143.95,141.41,135.02,133.39,131.61,131.48,131.26,127.01,124.76,115.97,115.30,115.10,105.67,68.13,56.10,55.70,49.65,44.52,14.68;C27H28NO4S[M+1]+的UPLC-MS(ESI+)计算值:462.17,实测值462.27。
(4-(2-(乙基氨基)甲氧基)苯基)(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-基)甲酮(53)
在0℃,在N2下,将8.0mL的BBr3溶液(1.0的DCM溶液)(8.0mmol,4.0eq)缓慢加入到52(923mg,2.0mmol,1.0eq)在无水DCM(30mL)中的溶液中。将深红溶液在室温下搅拌2小时,然后滴加MeOH(1.0mL)以淬灭反应。浓缩溶液,将残余物溶于EtOAc(50mL)中,然后加入饱和NaHCO3(50mL)和EtOH(5mL)。将有机层分离,并用无水Na2SO4干燥。过滤后,将溶液浓缩,残余物通过硅胶快速柱色谱法纯化,用DCM:MeOH(10:1-5:1),得到中间体(53),为黄色固体(520mg,60%收率)。1H NMR(CD3OD,400MHz)δ(ppm)7.72(d,J=8.8Hz,2H),7.43(d,J=8.8Hz,1H),7.27(d,J=2.0Hz,1H),7.17(d,J=8.8Hz,2H),6.91(d,J=8.8Hz,2H),6.87(dd,J=8.8Hz,J=2.4Hz,1H),6.61(d,J=8.8Hz,2H),4.27(t,J=4.8Hz,2H),3.42(t,J=4.8Hz,2H),3.14(q,J=7.2Hz,2H),1.33(t,J=7.2Hz,3H);13C NMR(CD3OD,100MHz)δ(ppm)195.41,163.41,159.22,156.80,144.30,141.45,134.21,133.45,132.55,131.42,131.00,125.99,124.68,116.43,116.08,115.39,107.90,64.68,47.41,44.36,11.40;C25H24NO4S[M+1]+的UPLC-MS(ESI+)计算值:434.14,实测值434.11。
叔丁基(2S,4R)-4-羟基-2-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)氨基甲酰基)-吡咯烷-1-羧酸酯(56)
将用报道方法47合成的化合物55溶于4N HCl的二噁烷溶液(25mL,100mmol)和MeOH(25mL)中,并将混合物在环境温度下搅拌12小时。将混合物浓缩,并将残余物在真空下干燥,得到中间体,将其不经进一步纯化用于下一步骤。
在0℃,在N2下,将HATU(14.51g,38.2mmol,1.2eq)加入到如上所述获得的中间体(55)(6.95g,31.8mmol,1.0eq)、(2S,4R)-1-(叔丁氧基羰基)-4-羟基-吡咯烷-2-羧酸(7.36g,31.8mmol,1.0eq)和DIPEA(11.08mL,63.6mmol,2.0eq)在DMF(36ml)中的溶液中。将混合物在环境温度下搅拌12小时,此时,TLC显示反应完成。将反应混合物用H2O(200mL)淬灭,并用EtOAc(150mL×2)萃取。将合并的有机层用盐水(200mL)洗涤,并经Na2SO4干燥。将有机溶液过滤并浓缩,残余物通过硅胶快速柱色谱法纯化,用己烷:EtOAc(100:1-1:100),然后是DCM:MeOH(10:1),得到中间体(56),为白色固体(10.98g,80%收率)。1H NMR(CD3OD,400MHz)δ(ppm)8.84(s,1H),7.43-7.37(m,4H),5.11-5.07(m,1H),4.44-4.37(m,2H),3.60-3.46(m,2H),2.44(s,3H),2.27-2.22(m,1H),1.98-1.91(m,1H),1.50(d,J=7.2Hz,3H),1.46(s,9H);C22H30N3O4S[M+1]+的UPLC-MS(ESI+)计算值:432.20,实测值432.20。
叔丁基((S)-1-((2S,4R)-4-羟基-2-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁烷-2-基)氨基甲酸酯(57)
将如上所述得到的固体(56)溶于4N HCl的二噁烷溶液(25mL,100mmol)和MeOH(25mL)中,并将混合物在环境温度下搅拌12小时。然后将混合物浓缩,并将残余物在真空下干燥,得到中间体,将其不经进一步纯化用于下一步骤。C17H22N3O2S[M+1]+的UPLC-MS(ESI+)计算值:332.14,实测值332.11。在0℃,在N2下,将HATU(1.37g,3.6mmol,1.2eq)加入到该中间体(994mg,3.0mmol,1.0eq)、(S)-2-((叔丁氧基羰基)氨基)-3,3-二甲基丁酸(694mg,3.0mmol,1.0eq)和DIPEA(1.57mL,9.0mmol,3.0eq)在DMF(10ml)中的溶液中。将混合物在环境温度下搅拌12小时,此时,TLC显示反应完成。将反应混合物用H2O(100mL)淬灭,并用EtOAc(75mL×2)萃取。将合并的有机层用盐水(100mL)洗涤,并经Na2SO4干燥。将有机溶液过滤并浓缩。残余物通过硅胶快速柱色谱法纯化,用己烷:EtOAc,然后是DCM:MeOH,得到期望化合物(57),为白色固体(1.31g,80%收率)。1H NMR(CDCl3,400MHz)δ(ppm)8.65(s,1H),7.70(d,J=8.0Hz,1H),7.35-7.31(m,4H),5.29(d,J=9.2Hz,1H),5.06-5.01(m,1H),4.67(t,J=8.0Hz,1H),4.46-4.44(m,1H),4.22-4.19(m,1H),3.91(d,J=17.2Hz,1H),3.61-3.58(m,1H),2.46(s,3H),2.37-2.30(m,1H),2.04-1.99(m,1H),1.44(d,J=7.2Hz,3H),1.35(s,9H),0.96(s,9H);13C NMR(CDCl3,100MHz)δ(ppm)172.22,170.13,156.15,150.56,148.21,143.43,131.74,130.59,129.49,126.46,80.18,69.91,58.86,56.58,48.74,38.60,36.02,35.48,28.34,26.39,22.17,15.95;C28H41N4O5S[M+1]+的UPLC-MS(ESI+)计算值:545.28,实测值545.35。
(2S,4R)-1-((S)-2-氨基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(58)
将如上所述得到的固体材料(57)溶于4N HCl的二噁烷溶液(4mL,16mmol)和MeOH(4.0mL)中,并将混合物在环境温度下搅拌12小时。然后浓缩混合物,将残余物在真空下干燥,得到粗产物,通过反相制备型HPLC纯化,得到纯最终化合物(58),为灰白色固体。C23H33N4O3S[M+1]+的UPLC-MS(ESI+)计算值:445.23,实测值445.44。
(2S,4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(11)
在0℃,在N2下,将HATU(21mg,0.055mmol,1.1eq)加入化合物65(23mg,0.05mmol,1.0eq)、AcOH(4μL,0.06mmol,1.2eq)和DIPEA(26μL,0.15mmol,3.0eq)在DMF(2mL)中的混合物中。将混合物在环境温度下搅拌1小时,然后通过反相制备型HPLC纯化粗混合物,得到标题化合物,为白色固体(19mg,80%收率)。1H NMR(CD3OD,400MHz)δ(ppm)9.02(s,1H),7.47-7.42(m,4H),5.04-4.98(m,1H),4.62-4.55(m,2H),4.43-4.41(m,1H),3.88(d,J=1.08Hz,1H),3.74(dd,J=10.8Hz,J=4.0Hz,1H),2.50(s,3H),2.22-2.16(m,1H),2.00(s,3H),1.98-1.91(m,1H),1.51(d,J=6.8Hz,3H),1.05(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)173.26,173.11,172.28,153.34,148.20,146.01,133.91,131.04,130.51,127.69,127.52,70.97,60.55,59.22,57.97,50.14,38.77,36.41,26.99,22.38,22.29,15.41;C25H35N4O4S[M+1]+的UPLC-MS(ESI+)计算值:487.24,实测值487.43;纯度98.5%(HPLC)。
3-(4-(3-乙基-1-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)-6,9,12-三氧杂-3-氮杂十五烷-14-炔-15-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(12)
在0℃,将甲磺酰氯(0.35mL,4.5mmol,1.5eq)和Et3N(0.84mL,6.0mmol,2.0eq)依次加入到商品化合物2-(2-(2-(丙-2-炔-1-基氧基)甲氧基)甲氧基)乙烷-1-醇(59a)(565mg,3.0mmol,1.0eq)在DCM(10mL)中的溶液中。将混合物温热至室温并搅拌1小时。浓缩后,残余物通过硅胶快速柱色谱法纯化,用己烷:EtOAc(2:1-1:2),得到标题化合物(60a),为无色油状物(710mg,89%收率)。1H NMR(CDCl3,400MHz)δ(ppm)4.21-4.18(m,2H),4.01(d,J=2.4Hz,2H),3.61-3.58(m,2H),3.51-3.46(m,8H),2.92(s,3H),2.41(t,J=2.4Hz,1H);13C NMR(CDCl3,100MHz)δ(ppm)79.71,74.91,70.33,70.25,70.09,69.51,68.90,68.77,58.09,37.43。
将DIPEA(0.09mL,0.5mmol,5.0eq)加入到化合物53(44mg,0.1mmol,1.0eq)和60a(40mg,0.15mmol,1.5eq)在DMF(3.0mL)中的溶液中。将溶液在100℃下搅拌12小时。冷却至室温后,残余物通过反相制备型HPLC纯化,得到标题化合物(61a),为白色固体(30mg,50%收率)。C34H38NO7S[M+1]+的UPLC-MS(ESI+)计算值:604.24,实测值604.30。
将3-(4-碘-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(19mg,0.05mmol,1.0eq)加入到化合物在DMF(2.0mL)中的溶液中。伴随超声处理,用N2吹扫并再填充溶液,然后依次加入Pd(PPh3)2Cl2(3.5mg,0.005mmol,0.1eq)、CuI(2.0mg,0.01mmol,0.2eq)和Me3N(2.0mL)。将溶液用N2吹扫并重新填充。将溶液在80℃下搅拌1小时,然后冷却至室温。加入EtOAc和H2O,水层用EtOAc萃取两次。将合并的有机层用无水Na2SO4干燥。过滤和浓缩后,残余物通过反相制备型HPLC纯化,得到标题化合物(12),为黄色固体(18mg,43%收率)。1H NMR(CD3OD,400MHz)δ(ppm)7.76-7.71(m,3H),7.58(d,J=7.6Hz,1H),7.46-7.40(m,2H),7.25(d,J=2.0Hz,1H),7.16(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),6.85(dd,J=8.8Hz,J=2.0Hz,1H),6.60(d,J=8.8Hz,2H),5.12(dd,J=13.2Hz,J=5.2Hz,1H),4.42-4.34(m,6H),3.81-3.78(m,2H),3.70-3.59(m,10H),3.43(t,J=4.8Hz,2H),3.35(q,J=7.6Hz,2H),2.90-2.81(m,1H),2.74-2.68(m,1H),2.37-2.30(m,1H),2.11-2.05(m,1H),1.32(t,J=7.6Hz,3H);13CNMR(CD3OD,100MHz)δ(ppm)195.30,174.53,172.14,170.68,163.12,159.25,156.85,145.48,144.12,141.47,135.99,134.20,133.51,133.10,132.62,131.44,130.98,129.77,126.01,124.75,124.71,119.34,116.50,116.12,115.49,107.94,91.94,82.61,71.34,71.24,70.43,65.49,63.61,59.69,54.01,53.58,53.13,51.37,32.30,24.02,9.07;C47H48N3O10S[M+1]+的UPLC-MS(ESI+)计算值:846.31,实测值846.52;纯度99.1%(HPLC)。
3-(4-(8-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)-苯氧基)乙基)氨基)辛-1-炔-1-基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(13)
使用类似于化合物12的三步程序从59b制备该化合物。1H NMR(CD3OD,400MHz)δ(ppm)7.73-7.71(m,3H),7.56(d,J=7.2Hz,1H),7.47-7.42(m,2H),7.26(d,J=2.0Hz,1H),7.16(d,J=8.4Hz,2H),6.91-6.86(m,3H),6.60(d,J=8.8Hz,2H),5.16(dd,J=13.6Hz,J=5.2Hz,1H),4.50(d,J=17.2Hz,1H),4.44(d,J=17.2Hz,1H),4.35(t,J=4.4Hz,2H),3.58(t,J=4.4Hz,2H),3.32-3.30(m,2H),3.21(q,J=7.6Hz,2H),2.93-2.84(m,1H),2.77-2.73(m,1H),2.50-2.44(m,3H),2.17-2.12(m,1H),1.79-1.72(m,2H),1.68-1.61(m,2H),1.58-1.51(m,2H),1.47-1.42(m,2H),1.33(t,J=7.2Hz,3H);13C NMR(CD3OD,100MHz)δ(ppm)195.28,174.58,172.22,170.98,163.03,159.27,156.87,145.24,144.38,141.48,135.77,134.20,133.51,132.92,132.75,131.47,130.99,129.62,126.02,124.72,123.74,120.90,116.46,116.12,115.38,107.92,97.08,77.41,63.59,54.42,53.66,52.53,50.31,32.33,29.39,27.05,24.68,24.08,19.94,9.10;C46H46N3O7S[M+1]+的UPLC-MS(ESI+)计算值:784.31,实测值784.27;纯度98.9%(HPLC)。
如方案4中所述,制备ER PROTAC的通用程序
路线A:由化合物32(ERD-308)举例说明。
(2S,4R)-1-((S)-2-(2-((5-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)戊基)氧基)乙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(32,ERD-308)
将NaOH(4.0g,100.0mmol,10.0eq)和四丁基氯化铵(2.78g,10.0mmol,1.0eq)依次加入到5-(苄基氧基)戊烷-1-醇(1.94g,10.0mmol,1.0eq)和2-溴乙酸叔丁酯(3.90g,20.0mmol,2.0eq)在H2O(20mL)和DCM(20mL)中的溶液中。将溶液在室温下搅拌过夜,直至TLC显示反应完成。将混合物在DCM(100mL)和H2O(100mL)之间分配,收集有机层,用盐水(100mL)洗涤,用无水Na2SO4干燥,并在减压下浓缩,得到残余物,通过硅胶快速柱色谱法纯化,用己烷:EtOAc(10:1-5:1),得到叔丁基2-((5-(苄基氧基)戊基)-氧基)乙酸酯,为无色油状物(987mg,32%收率)。
在H2气氛下,将叔丁基2-((5-(苄基氧基)戊基)氧基)乙酸酯(770mg,2.5mmol,1.0eq)和10wt%钯/碳(100mg)在MeOH(20mL)中的混合物在室温下搅拌过夜。当TLC显示反应完成时,将溶液通过硅藻土过滤并用MeOH洗涤。将合并的滤液减压浓缩。残余物通过硅胶快速柱色谱法纯化,用己烷:EtOAc(2:1-1:1),得到叔丁基2-((5-羟基戊基)氧基)乙酸酯(62),为无色油状物(671mg,95%收率)。1H NMR(CDCl3,400MHz)δ(ppm)3.58(s,2H),3.21(t,J=6.8Hz,2H),3.15(t,J=6.8Hz,2H),1.31-1.14(m,4H),1.12-1.05(m,12H);13CNMR(CDCl3,100MHz)δ(ppm)169.51,80.94,71.18,68.20,61.54,31.96,28.97,27.67,21.95。
在0℃,将4-甲苯磺酰基氯(879mg,4.6mmol,1.5eq)和Et3N(0.86mL,6.14mmol,2.0eq)依次加入到叔丁基2-((5-羟基戊基)氧基)乙酸酯(62)在DCM(10mL)中的溶液中。将混合物温热至室温并搅拌1小时。浓缩后,残余物通过硅胶快速柱色谱法纯化,用己烷:EtOAc(5:1-2:1),得到中间体叔丁基2-((5-(甲苯磺酰氧基)戊基)氧基)乙酸酯(63),为无色油状物(1.02g,89%收率)。1H NMR(CDCl3,400MHz)δ(ppm)7.75(d,J=8.0Hz,2H),7.32(d,J=8.0Hz,2H),3.99(t,J=6.4Hz,2H),3.88(s,2H),3.43(t,J=6.4Hz,2H),2.42(s,3H),1.68-1.61(m,2H),1.57-1.50(m,2H),1.44(s,9H),1.42-1.36(m,2H);13CNMR(CDCl3,100MHz)δ(ppm)169.76,144.75,133.16,129.89,127.92,81.54,71.19,70.55,68.76,28.99,28.65,28.15,22.07,21.67;C18H28NaO6S[M+23]+的UPLC-MS(ESI+)计算值:395.15,实测值395.36。
将DIPEA(0.18mL,1.0mmol,5.0eq)加入到化合物53(87mg,0.2mmol,1.0eq)和叔丁基2-((5-(甲苯磺酰氧基)戊基)氧基)乙酸酯63(223mg,0.6mmol,3.0eq)在DMF(3.0mL)中的溶液中。将溶液在80℃下搅拌12小时。冷却至室温后,用EtOAc和H2O稀释溶液。将有机层分离,并用无水Na2SO4干燥。过滤和浓缩后,残余物通过硅胶快速柱色谱法纯化,用DCM:MeOH(10:1),得到中间体(66),为无色油状物(114mg,90%收率)。1H NMR(CDCl3,400MHz)δ(ppm)7.65(d,J=8.8Hz,2H),7.42(d,J=7.2Hz,1H),7.19(s,1H),7.08(d,J=8.0Hz,2H),6.81(d,J=9.2Hz,1H),6.59-6.54(m,4H),3.99-3.95(m,2H),3.92(s,2H),3.48-3.40(m,4H),2.86-2.82(m,2H),2.64(q,J=6.8Hz,2H),2.55-2.51(m,2H),1.59-1.52(m,2H),1.44(s,9H),1.31-1.25(m,2H),1.01(t,J=6.8Hz,3H);13C NMR(CDCl3,100MHz)δ(ppm)194.16,170.28,162.73,157.39,154.83,143.60,140.09,133.37,132.59,130.47,129.90,125.01,124.06,116.02,115.57,114.20,107.67,82.05,71.67,68.75,53.54,53.32,51.72,47.86,29.78,29.38,28.18,24.01,10.64;C36H44NO7S[M+23]+的UPLC-MS(ESI+)计算值:634.28,实测值634.18。
在0℃下,将三氟乙酸(5.0mL)加入到中间体66(114mg,0.18mmol)在DCM(10mL)中的溶液中。将溶液在室温下搅拌6小时。浓缩后,残余物通过反相制备型HPLC纯化,得到标题化合物(67),为淡黄色固体(81mg,78%收率)。C32H36NO7S[M+23]+的UPLC-MS(ESI+)计算值:578.22,实测值578.06。
将HATU(53mg,0.14mmol,1.0eq)加入到中间体67(81mg,0.14mmol,1.0eq)、化合物58(67mg,0.15mmol,1.1eq)和DIPEA(0.12mL,0.70mmol,5.0eq)在DMF(2mL)中的溶液中。将混合物在室温下搅拌1小时,然后通过反相制备型HPLC纯化,得到标题化合物32(ERD-308),为黄色固体(56mg,40%收率)。1H NMR(CD3OD,400MHz)δ(ppm)8.86(s,1H),7.74(d,J=9.2Hz,2H),7.43-7.35(m,5H),7.26(d,J=2.0Hz,1H),7.18(d,J=8.4Hz,2H),6.91-6.85(m,3H),6.62(d,J=8.4Hz,2H),4.98-4.95(m,1H),4.89(s,2H),4.69-4.64(m,1H),4.59-4.53(m,1H),4.45-4.41(m,1H),4.31(t,J=4.8Hz,2H),4.02-3.92(m,2H),3.84(d,J=11.2Hz,1H),3.74(dd,J=10.8Hz,J=3.6Hz,1H),3.56(t,J=6.8Hz,2H),3.45(t,J=4.8Hz,2H),3.11-3.07(m,2H),2.47(s,3H),2.22-2.19(m,1H),1.98-1.92(m,1H),1.76-1.66(m,4H),1.57-1.46(m,5H),1.02(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.36,173.13,173.05,171.91,171.80,163.11,159.29,156.87,152.90,149.01,145.60,144.31,141.47,134.22,133.55,132.72,131.45,131.02,130.49,127.61,127.38,126.00,124.72,116.50,116.13,115.45,107.93,72.40,70.90,70.73,69.08,63.61,60.68,58.14,54.33,52.59,50.26,38.90,37.80,37.13,29.90,26.93,24.56,24.40,22.43,15.79,9.18;C55H66N5O9S2[M+1]+的UPLC-MS(ESI+)计算值:1004.43,实测值1004.11;纯度97.4%(HPLC)。
路线B:由化合物15(ERD-148)举例说明。
(2S,4R)-1-((S)-2-(8-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(15,ERD-148)
在0℃,将三氟乙酸酐(3.80mL,27.34mmol,2.0eq)加入到商业8-溴辛酸(64,3.05g,13.67mmol,1.0eq)在50mL DCM中溶液中。将溶液在室温下搅拌2小时。然后加入叔丁醇(3.92mL,41.01mmol,3.0eq)并将溶液在室温下搅拌12小时。然后加入饱和NaHCO3水溶液,分离有机层并用无水Na2SO4干燥。过滤和浓缩后,残余物通过硅胶快速柱色谱法纯化,用己烷:EtOAc(20:1-5:1),得到8-溴辛酸叔丁酯(65),为无色油状物(2.48g,65%收率)。1HNMR(CDCl3,400MHz)δ(ppm)3.34(t,J=6.8Hz,2H),2.14(t,J=7.6Hz,2H),1.83-1.75(m,2H),1.54-1.49(m,2H),1.40-1.36(m,11H),1.29-1.25(m,4H);13C NMR(CDCl3,100MHz)δ(ppm)173.08,79.88,35.47,33.81,32.73,28.86,28.44,28.12,27.99,24.95;
使用类似于化合物32的方法制备化合物15(ERD-148),其中中间体65代替化合物63作为原料。1H NMR(CD3OD,400MHz)δ(ppm)9.09(s,1H),7.75(d,J=8.8Hz,2H),7.47-7.41(m,5H),7.27(d,J=2.4Hz,1H),7.19-7.15(m,2H),6.92(d,J=8.8Hz,2H),6.87(dd,J=8.8Hz,J=2.4Hz,1H),6.63-6.59(m,2H),5.02-4.90(m,1H),4.64-4.54(m,2H),4.43-4.41(m,1H),4.35(t,J=4.4Hz,2H),3.88(d,J=11.2Hz,1H),3.74(dd,J=11.2Hz,J=4.0Hz,1H),3.60(t,J=4.8Hz,2H),3.31-3.17(m,4H),2.50(s,3H),2.32-2.17(m,3H),1.98-1.91(m,1H),1.75-1.65(m,2H),1.65-1.55(m,2H),1.50(d,J=6.8Hz,3H),1.43-1.29(m,9H),1.03(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)193.96,174.53,171.84,170.93,161.69,157.88,155.47,152.13,144.63,142.99,140.09,132.82,132.14,131.39,130.07,129.62,129.12,126.33,124.64,123.31,115.08,114.74,114.01,106.51,69.57,62.17,59.21,57.61,56.61,53.15,51.19,48.85,48.76,37.41,35.10,28.54,28.41,25.93,25.65,25.33,23.31,20.96,13.89,7.67;C56H68N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:1002.45,实测值1002.51;纯度97.5%(HPLC)。
(2S,4R)-1-((S)-17-(叔丁基)-3-乙基-1-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)-15-氧代-6,9,12-三氧杂-3,16-二氮杂十八烷-18-酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(14)
该化合物使用与用于化合物32的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.87(s,1H),7.72(d,J=8.8Hz,2H),7.44-7.39(m,5H),7.26(d,J=2.0Hz,1H),7.19(d,J=8.4Hz,2H),6.89-6.85(m,3H),6.63(d,J=8.4Hz,2H),5.02-4.96(m,1H),4.64-4.54(m,2H),4.43-4.41(m,1H),4.20(t,J=5.2Hz,2H),3.85(d,J=11.2Hz,1H),3.75-3.64(m,5H),3.60-3.55(m,8H),3.20-2.93(m,6H),2.54-2.46(m,5H),2.20-2.17(m,1H),1.98-1.92(m,1H),1.49(d,J=7.2Hz,3H),1.67(t,J=7.2Hz,3H),1.02(s,9H);C57H70N5O11S2[M+1]+的UPLC-MS(ESI+)计算值:1064.45,实测值1064.74;纯度96.4%(HPLC)。
(2S,4R)-1-((S)-2-(4-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)丁酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(16)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.87(s,1H),7.73(d,J=8.8Hz,2H),7.45-7.39(m,5H),7.26(d,J=2.0Hz,1H),7.18(d,J=8.8Hz,1H),6.90(d,J=8.8Hz,2H),6.86(dd,J=8.8Hz,J=2.4Hz,1H),6.62(d,J=8.8Hz,2H),5.00-4.95(m,1H),4.56-4.50(m,2H),4.38-4.36(m,1H),4.26(t,J=4.8Hz,2H),3.83(d,J=11.2Hz,1H),3.66(dd,J=10.8Hz,J=4.0Hz,1H),3.06-2.99(m,4H),2.47(s,3H),2.43(t,J=6.4Hz,2H),2.20-2.15(m,1H),1.97-1.89(m,3H),1.49(d,J=6.8Hz,3H),1.23(t,J=7.2Hz,3H),1.00(s,9H);C52H60N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:946.39,实测值946.41;纯度97.4%(HPLC);
(2S,4R)-1-((S)-2-(5-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)戊酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(17)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.87(s,1H),7.76-7.73(m,1H),7.45-7.38(m,5H),7.27(d,J=2.0Hz,1H),7.20-7.14(m,2H),6.94-6.92(m,2H),6.89-6.85(m,1H),6.62-6.59(m,2H),5.01-4.97(m,1H),4.59-4.52(m,2H),4.43-4.41(m,1H),4.36(t,J=4.8Hz,2H),3.86(d,J=11.2Hz,1H),3.72(dd,J=10.8Hz,J=4.0Hz,1H),3.59(t,J=4.8Hz,2H),3.31-3.21(m,4H),2.47(s,3H),2.37(t,J=6.8Hz,2H),2.21-2.16(m,1H),1.98-1.91(m,1H),1.79-1.68(m,4H),1.48(d,J=7.2Hz,3H),1.34(t,J=7.2Hz,3H),1.04(s,9H);C53H62N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:960.40,实测值960.84;纯度96.9%(HPLC)。
(2S,4R)-1-((S)-2-(6-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)己酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(18)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.87(s,1H),7.73(d,J=9.2Hz,2H),7.44-7.38(m,5H),7.26(d,J=2.4Hz,1H),7.16(d,J=8.8Hz,2H),6.90(d,J=9.2Hz,2H),6.87(dd,J=8.8Hz,J=2.0Hz,1H),6.61(d,J=8.8Hz,2H),5.03-4.96(m,1H),4.61-4.54(m,2H),4.41-4.39(m,1H),4.35(t,J=4.8Hz,2H),3.87-3.84(m,1H),3.73-3.71(m,1H),3.58(t,J=4.4Hz,2H),3.31-3.17(m,4H),2.47(s,3H),2.37-2.26(m,2H),2.21-2.16(m,1H),1.97-1.91(m,1H),1.77-1.62(m,4H),1.49(d,J=7.2Hz,3H),1.45-1.30(m,5H),1.02(s,9H);C54H64N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:974.42,实测值974.63;纯度99.6%(HPLC)。
(2S,4R)-1-((S)-2-(7-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)庚酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(19)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.86(s,1H),7.71(d,J=8.8Hz,2H),7.44-7.38(m,5H),7.26(d,J=2.0Hz,1H),7.17(d,J=8.8Hz,2H),6.89-6.80(m,3H),6.62(d,J=8.8Hz,2H),5.02-4.97(m,1H),4.63-4.55(m,2H),4.43-4.41(m,1H),4.24(t,J=4.8Hz,2H),3.87(d,J=10.8Hz,1H),3.74(dd,J=10.8Hz,J=4.0Hz,1H),3.32-3.30(m,2H),3.04-2.90(m,4H),2.47(s,3H),2.34-2.16(m,3H),1.98-1.91(m,1H),1.63-1.60(m,4H),1.49(d,J=7.2Hz,3H),1.37-1.35(m,4H),1.25-1.18(m,3H),1.01(s,9H);C55H66N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:988.44,实测值988.60;纯度96.2%(HPLC)。
(2S,4R)-1-((S)-2-(9-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)壬酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(20)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.87(s,1H),7.75-7.70(m,2H),7.44-7.39(m,5H),7.26(d,J=2.4Hz,1H),7.18-7.15(m,2H),6.90(d,J=8.8Hz,2H),6.87(dd,J=8.8Hz,J=2.4Hz,1H),6.61(d,J=8.8Hz,2H),5.04-4.88(m,1H),4.64-4.55(m,2H),4.45-4.40(m,1H),4.35(t,J=4.8Hz,2H),3.89-3.86(m,1H),3.74(dd,J=10.8Hz,J=4.0Hz,1H),3.58(t,J=4.8Hz,2H),3.31-3.28(m,2H),3.21-3.15(m,2H),2.47(s,3H),2.31-2.17(m,3H),1.98-1.92(m,1H),1.75-1.55(m,4H),1.50(d,J=7.2Hz,3H),1.36-1.31(m,11H),1.03(s,9H);C57H70N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:1016.47,实测值1016.53;纯度95.7%(HPLC)。
(2S,4R)-1-((S)-2-(10-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)癸酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(21)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.86(s,1H),7.72(d,J=8.8Hz,2H),7.43-7.36(m,5H),7.26(d,J=2.0Hz,1H),7.17(d,J=8.8Hz,2H),6.89-6.84(m,3H),6.61(d,J=8.8Hz,2H),5.02-4.97(m,1H),4.64-4.55(m,2H),4.43-4.41(m,1H),4.27(t,J=4.8Hz,2H),3.88(d,J=11.2Hz,1H),3.74(dd,J=11.2Hz,J=4.0Hz,1H),3.39(t,J=4.4Hz,2H),3.15-3.09(m,2H),3.03-2.98(m,2H),2.46(s,3H),2.33-2.17(m,3H),1.98-1.92(m,1H),1.69-1.50(m,4H),1.49(d,J=7.2Hz,3H),1.33-1.23(m,13H),1.03(s,9H);C58H72N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:1030.48,实测值1030.46;纯度96.4%(HPLC)。
(2S,4R)-4-羟基-1-((S)-2-(8-((2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)(甲基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(22)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.95(s,1H),7.74(d,J=9.2Hz,2H),7.45-7.42(m,5H),7.27(d,J=2.0Hz,1H),7.17(d,J=8.4Hz,2H),6.92(d,J=8.8Hz,2H),6.87(dd,J=8.8Hz,J=2.4Hz,1H),6.61(d,J=8.8Hz,2H),5.02-4.97(m,1H),4.64-4.54(m,2H),4.42-4.37(m,3H),3.87(d,J=11.2Hz,1H),3.74(dd,J=11.2Hz,J=4.4Hz,1H),3.66-3.48(m,2H),3.23-3.13(m,2H),2.93(s,3H),2.48(s,3H),2.34-2.17(m,3H),1.98-1.91(m,1H),1.80-1.70(m,2H),1.63-1.55(m,2H),1.50(d,J=7.2Hz,3H),1.45-1.35(m,6H),1.03(s,9H);C55H66N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:988.44,实测值988.54;纯度95.0%(HPLC)。
(2S,4R)-4-羟基-1-((S)-2-(8-((2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)(异丙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(23)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.86(s,1H),7.72(d,J=8.8Hz,2H),7.43-7.38(m,5H),7.26(d,J=2.0Hz,1H),7.17(d,J=8.8Hz,2H),6.88-6.84(m,3H),6.62(d,J=8.8Hz,2H),5.02-4.97(m,1H),4.63-4.55(m,2H),4.43-4.41(m,1H),4.16(t,J=5.2Hz,2H),3.87(d,J=11.2Hz,1H),3.74(dd,J=10.8Hz,J=4.0Hz,1H),3.37-3.35(m,1H),2.86-2.82(m,2H),2.46(s,3H),2.31-2.16(m,3H),1.98-1.92(m,1H),1.59-1.56(m,4H),1.49(d,J=6.8Hz,3H),1.33-1.27(m,10H),1.18(d,J=6.8Hz,6H),1.03(s,9H);C57H70N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:1016.47,实测值1016.55;纯度96.0%(HPLC)。
(2S,4R)-1-((S)-2-(8-(叔丁基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(ERD-107-WMA,24)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.97(s,1H),7.76(d,J=8.8Hz,2H),7.47-7.40(m,5H),7.26(d,J=2.4Hz,1H),7.18(d,J=8.8Hz,2H),6.92-6.86(m,3H),6.62-6.60(m,2H),5.03-4.97(m,1H),4.62(s,1H),4.59-4.55(m,1H),4.45-4.41(m,1H),4.32(t,J=4.4Hz,2H),3.91-3.83(m,2H),3.74(dd,J=11.2Hz,J=4.0Hz,1H),3.49-3.38(m,2H),3.14-3.10(m,1H),2.48(s,3H),2.33-2.17(m,3H),1.99-1.92(m,1H),1.83-1.73(m,1H),1.70-1.55(m,4H),1.51-1.47(m,3H),1.47-1.45(m,9H),1.39-1.29(m,6H),1.03(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.34,175.92,173.23,172.33,163.09,159.30,156.89,153.17,148.54,145.80,144.45,141.51,134.22,133.59,132.77,131.50,131.25,130.98,130.51,127.67,127.45,126.04,124.72,116.47,116.15,115.30,107.91,70.97,67.43,65.32,60.63,59.02,58.00,53.38,51.70,50.16,49.71,38.82,36.50,29.99,29.86,27.63,27.53,27.06,26.76,24.94,22.37,15.57;C58H72N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:1030.48,实测值1030.52。
(2S,4R)-1-((S)-2-(8-(环丙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(25)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)9.04(s,1H),7.73(d,J=9.2Hz,2H),7.46-7.41(m,5H),7.26(d,J=2.0Hz,1H),7.16(d,J=8.8Hz,2H),6.91-6.86(m,3H),6.61(d,J=8.8Hz,2H),5.03-4.97(m,1H),4.64-4.61(m,1H),4.57(t,J=8.4Hz,1H),4.42-4.29(m,3H),3.87(d,J=11.2Hz,1H),3.76-3.65(m,3H),3.32-3.30(m,1H),2.89-2.84(m,1H),2.49(s,3H),2.33-2.17(m,3H),1.99-1.92(m,1H),1.85-1.75(m,2H),1.63-1.55(m,2H),1.50(d,J=7.2Hz,3H),1.45-1.35(m,6H),1.03(s,9H),1.00-0.90(m,4H);13CNMR(CD3OD,100MHz)δ(ppm)195.30,175.92,173.23,172.33,162.98,159.26,156.84,153.43,145.96,144.57,141.46,134.21,133.53,132.77,131.50,131.02,130.49,127.70,126.01,124.75,116.45,116.14,115.38,107.92,70.95,63.22,60.61,59.01,57.98,57.85,55.33,50.14,38.78,38.54,36.47,29.94,29.81,27.42,27.04,26.72,24.72,22.34,15.31;C57H68N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:1014.45,实测值1014.61;纯度96.1%(HPLC)。
(2S,4R)-1-((S)-2-(8-(环丁基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(26)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)9.04(s,1H),7.74(d,J=8.8Hz,2H),7.44-7.42(m,5H),7.26(d,J=2.4Hz,1H),7.17(d,J=8.8Hz,2H),6.91-6.85(m,3H),6.62(d,J=8.8Hz,2H),5.03-4.97(m,1H),4.64-4.55(m,2H),4.45-4.41(m,1H),4.32-4.29(m,2H),3.91-3.86(m,2H),3.74(dd,J=11.2Hz,J=4.0Hz,1H),3.49(t,J=4.8Hz,2H),3.09(t,J=8.8Hz,2H),2.48(s,3H),2.35-2.15(m,7H),1.99-1.92(m,1H),1.87-1.55(m,6H),1.50(d,J=7.2Hz,3H),1.40-1.30(m,6H),1.03(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.32,175.91,173.22,172.33,163.01,159.27,156.85,153.42,145.95,144.39,141.46,134.22,133.54,132.73,131.45,131.01,130.49,127.70,125.99,124.73,116.49,116.15,115.37,107.94,70.95,63.46,60.60,59.61,59.01,57.98,52.11,50.49,50.14,38.78,36.49,36.47,29.94,29.79,27.40,27.05,26.71,24.30,22.35,15.33,14.18;C58H70N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:1028.47,实测值1029.18;纯度97.7%(HPLC)。
(2S,4R)-1-((S)-2-(8-(环戊基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(27)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.93(s,1H),7.75(d,J=8.8Hz,2H),7.45-7.41(m,5H),7.26(d,J=2.4Hz,1H),7.18(d,J=8.8Hz,2H),6.92-6.85(m,3H),6.61(d,J=8.8Hz,2H),5.02-4.98(m,1H),4.64-4.55(m,2H),4.43-4.41(m,1H),4.37-4.33(m,2H),3.89-3.73(m,3H),3.65-3.55(m,2H),3.22(t,J=8.4Hz,2H),2.48(s,3H),2.30-2.15(m,5H),2.03-1.94(m,1H),1.84-1.57(m,10H),1.50(d,J=7.2Hz,3H),1.45-1.30(m,6H),1.03(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.34,175.89,173.21,172.34,163.06,159.29,156.87,153.06,148.67,145.73,144.37,141.49,134.22,133.55,132.78,131.46,131.32,131.01,130.49,127.65,127.42,126.03,124.71,116.48,116.14,115.36,107.92,70.96,67.31,63.94,60.62,59.00,57.99,54.01,52.09,38.80,36.50,29.97,29.84,29.20,29.14,27.39,27.05,26.72,24.85,24.81,24.66,22.34,15.61;C59H72N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:1042.48,实测值1042.39;纯度>99.5%(HPLC)。
(2S,4R)-1-((S)-2-(8-(环己基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(28,ERD-045-WMA)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.87(s,1H),7.75(d,J=8.8Hz,2H),7.45-7.39(m,5H),7.26(d,J=2.0Hz,1H),7.18(d,J=8.4Hz,2H),6.91-6.84(m,3H),6.62-6.60(m,2H),5.02-4.97(m,1H),4.64-4.54(m,2H),4.45-4.41(m,1H),4.32(t,J=4.4Hz,2H),3.89-3.85(m,1H),3.74(dd,J=11.2Hz,J=4.0Hz,1H),3.59-3.45(m,2H),3.18-3.08(m,2H),2.47(s,3H),2.34-2.16(m,3H),2.03-1.90(m,5H),1.74-1.31(m,20H),1.03(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.37,175.94,173.22,172.33,163.29,159.29,156.87,152.87,149.07,145.61,144.35,141.49,134.23,133.56,133.34,131.53,131.47,131.03,130.50,127.62,127.41,126.04,116.47,116.13,115.36,107.91,70.96,60.62,59.01,58.00,53.41,51.06,50.15,49.28,38.81,37.63,36.50,30.00,29.89,27.58,27.05,26.20,26.19,26.18,26.17,26.15,26.14,22.36,15.79;C60H74N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:1056.50,实测值1056.54。
(2S,4R)-1-((S)-2-(8-((环丁基甲基)(2-(4-(6-羟基-2-(4-羟基苯基)苯并-[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(29)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.98(s,1H),7.73(d,J=8.8Hz,2H),7.44-7.36(m,5H),7.26(d,J=2.0Hz,1H),7.17(d,J=8.4Hz,2H),6.90-6.85(m,3H),6.61(d,J=8.4Hz,2H),5.02-4.97(m,1H),4.64-4.55(m,2H),4.45-4.41(m,1H),4.33(t,J=4.4Hz,2H),3.87(d,J=11.2Hz,1H),3.74(dd,J=11.2Hz,J=4.0Hz,1H),3.54-3.52(m,2H),3.28-3.25(m,2H),3.16-3.11(m,2H),2.80-2.73(m,1H),2.48(s,3H),2.32-2.14(m,5H),2.04-1.84(m,5H),1.75-1.65(m,2H),1.65-1.55(m,2H),1.49(d,J=7.2Hz,3H),1.42-1.30(m,6H),1.03(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.33,175.89,173.20,172.32,163.05,159.27,156.84,153.25,148.24,145.84,144.30,141.45,134.22,133.52,132.72,131.43,131.07,131.01,130.48,127.67,125.97,124.72,116.50,116.14,115.39,107.95,70.94,63.50,60.60,60.11,59.00,57.98,55.21,51.06,50.13,38.78,36.48,31.78,29.94,29.81,28.20,28.09,27.35,27.05,26.71,24.52,22.34,19.42,15.46;C59H72N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:1042.48,实测值1042.82;纯度>99.5%(HPLC)。
(2S,4R)-1-((S)-14-(叔丁基)-3-乙基-1-(4-(6-羟基-2-(4-羟基苯基)苯并[b]-噻吩-3-羰基)苯氧基)-12-氧代-6,9-二氧杂-3,13-二氮杂十五烷-15-酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(30)
该化合物使用与用于化合物32的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.86(s,1H),7.74(d,J=8.8Hz,2H),7.44-7.37(m,5H),7.27(d,J=2.4Hz,1H),7.18(d,J=8.8Hz,2H),6.93(d,J=8.8Hz,2H),6.87(dd,J=8.8Hz,J=2.4Hz,1H),6.62(d,J=8.4Hz,2H),5.02-4.95(m,1H),4.57-4.53(m,2H),4.40-4.37(m,3H),3.85-3.80(m,3H),3.73-3.58(m,9H),3.45(t,J=8.8Hz,2H),3.37(q,J=7.2Hz,2H),2.55-2.44(m,5H),2.22-2.17(m,1H),1.97-1.91(m,1H),1.48(d,J=7.2Hz,3H),1.35(t,J=7.2Hz,3H),1.01(s,9H);C55H66N5O10S2[M+1]+的UPLC-MS(ESI+)计算值:1020.43,实测值1020.77;纯度97.2%(HPLC)。
(2S,4R)-1-((S)-2-(叔丁基)-12-乙基-14-(4-(6-羟基-2-(4-羟基苯基)苯并[b]-噻吩-3-羰基)苯氧基)-4-氧代-6,9-二氧杂-3,12-二氮杂十四烷酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(31)
该化合物使用与用于化合物32的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)9.11(s,1H),7.73(d,J=8.4Hz,2H),7.44-7.37(m,5H),7.26(d,J=2.0Hz,1H),7.17(d,J=8.8Hz,2H),6.92-6.84(m,3H),6.61(d,J=8.4Hz,2H),4.97-4.91(m,1H),4.71-4.68(m,1H),4.57-4.54(m,1H),4.41-4.38(m,3H),4.02-3.40(m,16H),2.48(s,3H),2.36-2.20(m,1H),1.95-1.89(m,1H),1.45(d,J=7.2Hz,2H),1.37(t,J=7.6Hz,3H),1.01(s,9H);C54H64N5O10S2[M+1]+的UPLC-MS(ESI+)计算值:1006.41,实测值1006.66;纯度95.1%(HPLC)。
(2S,4R)-1-((S)-2-(4-(4-(2-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)乙基)哌啶-1-基)丁酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(33)
该化合物使用与用于化合物32的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.95(s,1H),7.74(d,J=8.8Hz,2H),7.45-7.40(m,5H),7.27(d,J=2.4Hz,1H),7.17(d,J=8.4Hz,2H),6.93(d,J=9.2Hz,2H),6.87(dd,J=8.8Hz,J=2.4Hz,1H),6.60(d,J=8.4Hz,2H),5.03-4.90(m,1H),4.59-4.53(m,2H),4.43-4.41(m,1H),4.37(t,J=4.8Hz,2H),3.90(d,J=10.8Hz,1H),3.74(dd,J=10.8Hz,J=4.0Hz,1H),3.61-3.56(m,4H),3.35-3.27(m,4H),3.10(t,J=6.8Hz,2H),2.94-2.86(m,2H),2.51(t,J=6.4Hz,2H),2.48(s,3H),2.22-2.17(m,1H),2.01-1.95(m,5H),1.78-1.68(m,3H),1.59-1.57(m,2H),1.50(d,J=7.2Hz,3H),1.34(t,J=7.6Hz,3H),1.06(s,9H);C59H73N6O8S2[M+1]+的UPLC-MS(ESI+)计算值:1057.49,实测值1057.90;纯度99.1%(HPLC)。
(2S,4R)-1-((S)-2-(4-(4-(2-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)乙基)哌嗪-1-基)丁酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(34)
该化合物使用与用于化合物32的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.94(s,1H),7.75(d,J=8.8Hz,2H),7.45-7.40(m,5H),7.27(d,J=2.4Hz,1H),7.18(d,J=8.4Hz,2H),6.93(d,J=9.2Hz,2H),6.87(dd,J=8.8Hz,J=2.4Hz,1H),6.61(d,J=8.4Hz,2H),5.03-4.99(m,1H),4.58-4.54(m,2H),4.44-4.39(m,3H),3.90(d,J=10.8Hz,1H),3.76-3.70(m,3H),3.51-3.48(m,2H),3.42-3.37(m,2H),3.14-3.12(m,2H),2.85(t,J=6.4Hz,2H),2.53(t,J=6.4Hz,2H),2.48(s,3H),2.23-2.18(m,1H),2.01-1.92(m,3H),1.50(d,J=6.8Hz,3H),1.36(t,J=7.2Hz,3H),1.06(s,9H);C58H72N7O8S2[M+1]+的UPLC-MS(ESI+)计算值:1058.49,实测值1058.72;纯度99.3%(HPLC)。
(2S,4R)-1-((S)-2-(3-(4-(5-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)戊-1-炔-1-基)-1H-吡唑-1-基)丙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(35)
该化合物使用与用于化合物32的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)9.13(s,1H),7.69(d,J=8.8Hz,2H),7.62(s,1H),7.46-7.41(m,6H),7.27(d,J=2.0Hz,1H),7.17(d,J=8.4Hz,2H),6.90-6.86(m,3H),6.61(d,J=8.8Hz,2H),5.01-4.96(m,1H),4.59-4.55(m,2H),4.42-4.26(m,5H),3.86(d,J=10.8Hz,1H),3.72(dd,J=10.8Hz,J=4.0Hz,1H),3.62-3.57(m,2H),3.41-3.30(m,4H),2.92-2.85(m,1H),2.75-2.70(m,1H),2.54(t,J=6.8Hz,2H),2.50(s,3H),2.22-2.17(m,1H),2.01-1.91(m,3H),1.50(d,J=6.8Hz,3H),1.36(t,J=7.2Hz,3H),0.95(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.31,173.25,172.24,172.10,163.01,159.26,156.86,153.68,146.13,144.43,142.84,141.47,134.21,133.48,132.76,131.49,131.00,130.51,127.74,126.02,124.77,116.48,116.15,115.42,107.92,104.32,88.60,74.07,70.96,63.58,60.60,59.18,57.88,53.41,52.83,50.53,50.45,38.77,36.74,36.42,26.98,23.92,22.36,17.27,15.15,9.16;C59H66N7O8S2[M+1]+的UPLC-MS(ESI+)计算值:1064.44,实测值1064.89;纯度95.1%(HPLC)。
(2S,4R)-1-((S)-2-(2-(4-(4-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)丁-1-炔-1-基)-1H-吡唑-1-基)乙酰胺基)-3,3-二甲基-丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(36)
该化合物使用与用于化合物32的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.87(s,1H),7.74-7.70(m,3H),7.52(s,1H),7.44-7.41(m,5H),7.26(d,J=2.0Hz,1H),7.18(d,J=8.4Hz,2H),6.88-6.85(m,3H),6.63(d,J=8.8Hz,2H),5.01-4.98(m,1H),4.62-4.52(m,2H),4.42-4.39(m,3H),3.82(d,J=11.2Hz,1H),3.76-3.64(m,3H),3.50-3.39(m,6H),2.96(t,J=7.2Hz,2H),2.47(s,3H),2.26-2.15(m,1H),1.96-1.90(m,1H),1.49(d,J=7.2Hz,3H),1.38(t,J=7.2Hz,3H),1.02(s,9H);C57H62N7O8S2[M+1]+的UPLC-MS(ESI+)计算值:1036.41,实测值1035.92;纯度98.8%(HPLC)。
(2S,4R)-1-((S)-2-(2-(4-(4-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)丁基)-1H-吡唑-1-基)乙酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(37)
该化合物使用与用于化合物32的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)9.23(s,1H),7.70(d,J=8.8Hz,2H),7.49(s,1H),7.44-7.37(m,6H),7.25(d,J=2.4Hz,1H),7.14(d,J=8.8Hz,2H),6.87-6.83(m,3H),6.59(d,J=8.4Hz,2H),4.99-4.83(m,3H),4.61-4.52(m,2H),4.40-4.37(m,1H),4.30(t,J=4.4Hz,2H),3.81(d,J=11.2Hz,1H),3.69(dd,J=11.2Hz,J=4.0Hz,1H),3.54(d,J=4.0Hz,2H),3.28-3.16(m,4H),2.54-2.46(m,5H),2.22-2.17(m,1H),1.96-1.89(m,1H),1.73-1.60(m,4H),1.47(d,J=7.2Hz,3H),1.30(t,J=7.2Hz,3H),1.00(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.28,173.08,171.67,169.31,163.05,159.21,156.78,153.34,147.93,145.88,144.26,141.40,140.79,134.19,133.92,133.49,132.59,131.61,131.41,130.96,130.89,130.45,127.65,125.90,124.74,122.64,116.52,116.16,115.42,108.00,70.90,63.51,60.56,59.13,57.96,54.70,54.16,52.44,50.14,38.80,36.70,28.55,26.93,26.82,24.24,24.05,22.38,15.39,9.07;C57H66N7O8S2[M+1]+的UPLC-MS(ESI+)计算值:1040.44,实测值1040.17;纯度98.7%(HPLC)。
(2S,4R)-1-((S)-2-(8-(乙基(2-(4-((Z)-1-(4-羟基苯基)-2-苯基丁-1-烯-1-基)-苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(38)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.98(s,1H),7.47-7.36(m,4H),7.13-7.01(m,7H),6.84-6.75(m,3H),6.66-6.60(m,2H),5.03-4.98(m,1H),4.64-4.62(m,1H),4.56(t,J=8.4Hz,1H),4.45-4.41(m,1H),4.22-4.18(m,2H),3.89-3.86(m,1H),3.74(dd,J=11.2Hz,J=4.0Hz,1H),3.55-3.52(m,2H),3.21-3.15(m,2H),2.52-2.45(m,5H),2.32-2.17(m,3H),1.99-1.92(m,1H),1.78-1.56(m,5H),1.52-1.49(m,3H),1.45-1.30(m,9H),1.04(s,9H),0.91(t,J=7.2Hz,3H);13C NMR(CD3OD,100MHz)δ(ppm)175.90,173.22,172.31,157.41,156.91,153.20,145.85,144.03,142.58,139.49,138.76,136.07,133.23,131.55,130.91,130.51,128.88,127.67,127.04,115.92,114.46,70.96,63.11,60.60,58.99,58.00,54.48,52.76,50.15,38.82,37.64,36.51,33.74,29.95,29.93,29.86,29.81,27.36,27.05,26.73,24.71,22.37,15.54,13.86,9.04;C57H74N5O6S[M+1]+的UPLC-MS(ESI+)计算值:956.54,实测值956.51。
(2S,4R)-1-((S)-2-(8-((2-(4-(1,2-Di苯基丁-1-烯-1-基)苯氧基)乙基)(乙基)氨基)-辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(39)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)9.08(s,1H),7.47-7.42(m,4H),7.36-7.32(m,1H),7.28-7.22(m,0.5H),7.21-7.07(m,7H),7.03-6.95(m,2.5H),6.86-6.82(m,2H),6.66-6.64(m,1H),5.03-4.98(m,1H),4.64-4.62(m,1H),4.57(t,J=8.4Hz,1H),4.43-4.41(m,1H),4.38(t,J=4.8Hz,1H),4.21(t,J=4.8Hz,1H),3.88(d,J=10.8Hz,1H),3.74(dd,J=10.8Hz,J=4.0Hz,1H),3.64(t,J=4.8Hz,1H),3.53(t,J=4.8Hz,1H),3.38-3.34(m,1H),3.31-3.17(m,3H),2.49-2.42(m,5H),2.30-2.19(m,3H),1.99-1.95(m,1H),1.70-1.56(m,4H),1.50(d,J=7.2Hz,3H),1.40-1.30(m,9H),1.04(s,9H),0.94-0.88(m,3H);C57H74N5O5S[M+1]+的UPLC-MS(ESI+)计算值:940.54,实测值940.82;纯度97.0%(HPLC)。
(2S,4R)-1-((S)-2-(8-(乙基(2-(4-((5-羟基-2-(4-羟基苯基)-3-甲基-1H-indol-1-基)甲基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(40)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)9.08(s,1H),7.45-7.40(m,4H),7.12(d,J=8.4Hz,2H),6.99(d,J=8.8Hz,1H),6.91(d,J=2.4Hz,1H),6.84-6.75(m,6H),6.63(dd,J=8.8Hz,J=2.4Hz,1H),5.11(s,2H),5.02-4.97(m,1H),4.64-4.62(m,1H),4.56(t,J=8.4Hz,1H),4.43-4.41(m,1H),4.24(t,J=4.8Hz,1H),3.87(d,J=11.2Hz,1H),3.73(dd,J=11.2Hz,J=4.0Hz,1H),3.54(t,J=4.8Hz,1H),2.49(s,3H),2.31-2.15(m,6H),1.98-1.92(m,1H),1.73-1.65(m,2H),1.59-1.55(m,2H),1.50(d,J=7.2Hz,3H),1.40-1.29(m,9H),1.03(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)175.91,173.21,172.33,158.52,157.92,153.66,151.65,146.06,139.86,133.87,133.08,132.79,131.04,130.50,128.68,127.72,124.47,116.23,115.54,112.17,111.59,108.66,103.92,70.94,63.27,60.60,59.00,57.98,54.43,52.72,50.15,47.58,38.78,36.47,29.90,29.80,29.76,27.04,24.69,22.35,15.21,9.62,9.05;C57H73N6O7S[M+1]+的UPLC-MS(ESI+)计算值:985.53,实测值985.82;纯度>99.5%(HPLC)。
(2S,4R)-1-((S)-2-(8-(乙基(2-(4-((1R,2S)-6-羟基-2-苯基-1,2,3,4-四氢萘-1-基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(41)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.94(s,1H),7.46-7.35(m,4H),7.13-7.09(m,3H),6.83-6.80(m,2H),6.68-6.61(m,4H),6.52(dd,J=8.4Hz,J=4.0Hz 1H),6.38(d,J=8.4Hz,2H),5.03-4.98(m,1H),4.64-4.54(m,2H),4.43-4.41(m,1H),4.25-4.20(m,3H),3.89-3.86(m,1H),3.75(dd,J=11.2Hz,J=4.0Hz,1H),3.56-3.53(m,2H),3.37-3.35(m,1H),3.23-3.16(m,2H),3.06-2.99(m,2H),2.49(s,3H),2.34-2.14(m,4H),1.99-1.92(m,1H),1.79-1.50(m,8H),1.38-1.29(m,9H),1.03(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)175.89,173.23,172.31,157.05,156.64,153.10,148.68,145.79,138.82,137.76,132.43,132.06,131.33,130.51,129.21,128.72,127.66,127.66,127.44,126.97,126.63,115.50,114.68,113.98,70.96,63.16,61.04,60.61,58.98,58.01,54.48,52.81,52.24,51.57,50.15,46.73,38.82,36.52,36.49,30.97,29.97,28.83,27.38,27.05,26.74,25.59,24.73,24.44,23.24,22.37,15.62,9.06;C57H74N5O6S[M+1]+的UPLC-MS(ESI+)计算值:956.54,实测值956.48。
(2S,4R)-1-((S)-2-(8-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(42)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)8.86(s,1H),7.74(d,J=9.2Hz,2H),7.46-7.39(m,5H),7.27(d,J=2.4Hz,1H),7.18(d,J=8.8Hz,2H),6.91(d,J=8.8Hz,2H),6.87(dd,J=8.8Hz,J=2.0Hz,1H),6.61(d,J=8.8Hz,2H),4.64(d,J=8.8Hz,1H),4.58-4.49(m,3H),4.38-4.33(m,3H),3.90(d,J=11.2Hz,1H),3.80(dd,J=10.8Hz,J=4.0Hz,1H),3.59(t,J=4.8Hz,2H),3.21-3.17(m,2H),2.46(s,3H),2.32-2.19(m,3H),2.11-2.03(m,1H),1.73-1.71(m,2H),1.62-1.59(m,2H),1.38-1.29(m,9H),1.02(s,9H);C55H66N5O8S2[M+1]+的UPLC-MS(ESI+)计算值:988.44,实测值988.98;纯度97.8%(HPLC)。
(2S,4R)-N-((S)-1-(4-氯苯基)乙基)-1-((S)-2-(8-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基吡咯烷-2-甲酰胺(43)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)7.75(d,J=8.8Hz,2H),7.44(d,J=8.8Hz,1H),7.32-7.27(m,5H),7.21-7.15(m,2H),6.95-6.86(m,3H),6.65-6.60(m,2H),4.95-4.87(m,1H),4.63-4.61(m,1H),4.53(t,J=8.4Hz,2H),3.87-3.84(m,1H),3.73(dd,J=11.2Hz,J=4.0Hz,1H),3.64-3.54(m,3H),3.26-3.16(m,3H),3.07-2.96(m,1H),2.33-2.13(m,3H),1.95-1.88(m,1H),1.78-1.58(m,5H),1.51(d,J=7.2Hz,2H),1.41-1.29(m,11H),1.02(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.37,175.91,173.18,172.29,163.09,159.28,156.88,144.38,144.13,141.49,134.22,133.71,133.53,132.77,131.65,131.47,131.02,129.56,128.70,128.70,128.47,126.04,124.71,116.59,124.71,116.59,116.47,116.13,115.41,107.91,70.94,63.57,60.57,58.99,57.98,54.55,52.59,50.24,49.82,38.78,36.49,34.62,29.95,29.81,27.33,27.03,26.73,25.75,24.71,22.28,9.06;C52H64ClN4O8S[M+1]+的UPLC-MS(ESI+)计算值:939.41,实测值939.45。
(2S,4R)-N-((S)-1-(4-氯苯基)乙基)-1-((S)-2-(8-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基吡咯烷-2-甲酰胺(44)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)7.75(d,J=8.8Hz,2H),7.68(d,J=8.8Hz,2H),7.49-7.40(m,3H),7.27(d,J=2.4Hz,1H),7.18(d,J=8.8Hz,2H),6.94-6.86(m,3H),6.64-6.60(m,2H),5.01-4.96(m,1H),4.63-4.61(m,1H),4.47-4.38(m,1H),4.35(t,J=4.8Hz,2H),3.88-3.85(m,1H),3.72(dd,J=11.2Hz,J=4.0Hz,1H),3.60-3.58(m,2H),3.23-3.17(m,2H),2.32-2.16(m,3H),1.94-1.87(m,1H),1.73-1.60(m,5H),1.54-1.46(m,3H),1.38-1.29(m,10H),1.02(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.36,175.91,173.38,172.30,163.09,159.28,156.88,151.22,144.39,141.49,134.22,131.47,131.02,128.06,127.85,126.04,124.71,119.67,116.48,116.13,115.40,111.78,107.91,70.95,63.56,60.51,58.99,57.99,54.54,52.58,50.33,50.22,38.81,36.49,29.96,29.82,27.34,27.02,26.73,24.72,22.09,9.06;C53H64N5O8S[M+1]+的UPLC-MS(ESI+)计算值:930.45,实测值930.48。
(2S,4R)-1-((S)-2-(8-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-N-((S)-1-(4-乙炔基苯基)乙基)-4-羟基吡咯烷-2-甲酰胺(45)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)7.75(d,J=8.8Hz,2H),7.46-7.38(m,3H),7.29-7.22(m,3H),7.19-7.15(m,2H),6.93-6.86(m,3H),6.61(d,J=8.8Hz,2H),4.97-4.92(m,1H),4.63-4.61(m,1H),4.54(t,J=8.4Hz,2H),4.42-4.39(m,1H),4.36(t,J=4.8Hz,2H),3.88-3.85(m,1H),3.75-3.71(m,2H),3.63-3.58(m,3H),3.44(s,1H),3.26-3.17(m,3H),2.33-2.14(m,4H),1.95-1.89(m,1H),1.80-1.65(m,3H),1.67-1.54(m,3H),1.46-1.30(m,10H),1.02(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.38,175.91,173.20,172.29,163.10,161.00,159.28,156.88,155.70,146.12,144.39,141.49,134.22,133.53,133.18,132.77,131.47,131.02,130.05,129.93,127.14,126.04,124.71,122.43,116.47,116.12,115.41,107.90,84.19,78.50,70.95,64.27,60.58,59.62,58.99,57.98,55.93,55.83,55.65,54.56,53.65,52.59,50.17,36.49,29.94,29.81,27.03,26.73,24.71,22.23,18.70,17.26,13.17,9.07;C53H64N5O8S[M+1]+的UPLC-MS(ESI+)计算值:929.45,实测值929.49。
(2S,4R)-N-((S)-1-(4-环丙基苯基)乙基)-1-((S)-2-(8-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基吡咯烷-2-甲酰胺(46)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)7.76(d,J=8.8Hz,2H),7.45(d,J=8.8Hz,1H),7.27(d,J=2.0Hz,2H),7.20-7.10(m,4H),7.02-6.98(m,2H),6.94-6.86(m,3H),6.63-6.59(m,2H),4.95-4.91(m,1H),4.63-4.61(m,1H),4.54(t,J=8.4Hz,1H),4.43-4.39(m,1H),4.36-4.34(m,2H),3.87-3.85(m,1H),3.75-3.71(m,1H),3.63-3.58(m,2H),3.23-3.17(m,2H),2.31-2.23(m,2H),2.18-2.11(m,1H),1.96-1.83(m,2H),1.72-1.59(m,4H),1.51-1.28(m,12H),1.02(s,9H),1.00-0.90(m,2H),0.64-0.60(m,2H);13CNMR(CD3OD,100MHz)δ(ppm)195.36,175.88,172.98,172.30,163.07,159.29,156.90,144.39,144.17,142.11,141.50,134.22,133.54,131.48,131.02,126.95,126.72,126.06,124.70,116.47,116.13,115.40,107.90,70.94,63.55,60.64,58.98,57.98,55.90,54.57,53.58,52.62,51.85,51.29,38.76,36.51,29.93,29.83,27.36,27.04,26.72,24.72,15.77,9.51,9.06;C55H69N4O8S[M+1]+的UPLC-MS(ESI+)计算值:945.48,实测值945.51。
(2S,4R)-1-((S)-2-(8-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-异丙基苯基)乙基)吡咯烷-2-甲酰胺(47)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)7.75(d,J=8.8Hz,2H),7.44(d,J=8.8Hz,2H),7.27(d,J=2.0Hz,1H),7.22-7.15(m,6H),6.93-6.86(m,3H),6.63-6.59(m,2H),4.96-4.91(m,1H),4.62(d,J=8.8Hz,1H),4.53(d,J=8.4Hz,1H),4.43-4.36(m,1H),4.35-4.29(m,2H),3.87-3.84(m,1H),3.75-3.71(m,1H),3.60-3.53(m,2H),3.24-3.15(m,2H),2.89-2.81(m,1H),2.34-2.21(m,2H),2.18-2.12(m,1H),1.98-1.91(m,1H),1.73-1.70(m,2H),1.63-1.58(m,2H),1.52-1.29(m,12H),1.22(d,J=7.2Hz,6H),1.02(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)195.35,175.89,173.00,172.30,163.08,159.29,156.88,148.92,144.37,142.57,141.49,134.22,133.53,132.79,131.47,131.01,127.50,126.76,126.03,124.71,116.13,115.40,107.91,70.94,63.55,60.63,58.98,57.98,54.53,52.57,50.20,50.10,38.76,36.51,35.06,29.94,29.81,27.34,27.04,26.72,24.70,24.45,22.49,9.06;C55H71N4O8S[M+1]+的UPLC-MS(ESI+)计算值:947.50,实测值947.53。
(2S,4R)-N-((S)-1-(4-(叔丁基)苯基)乙基)-1-((S)-2-(8-(乙基(2-(4-(6-羟基-2-(4-羟基苯基)苯并[b]噻吩-3-羰基)苯氧基)乙基)氨基)辛酰胺基)-3,3-二甲基丁酰基)-4-羟基吡咯烷-2-甲酰胺(48)
该化合物使用与用于化合物15的程序类似的程序制备。1H NMR(CD3OD,400MHz)δ(ppm)7.75(d,J=8.8Hz,2H),7.45(d,J=8.8Hz,1H),7.34(d,J=8.4Hz,2H),7.27(d,J=2.0Hz,1H),7.22-7.16(m,4H),6.93-6.86(m,3H),6.63-6.59(m,2H),4.95-4.91(m,1H),4.65-4.60(m,1H),4.53(t,J=8.4Hz,1H),4.42-4.40(m,1H),4.35(t,J=4.4Hz,2H),3.87-3.84(m,1H),3.75-3.71(m,1H),3.60-3.56(m,2H),3.25-3.16(m,2H),2.34-2.14(m,3H),1.98-1.91(m,1H),1.74-1.71(m,2H),1.64-1.55(m,2H),1.45-1.32(m,1H),1.29(s,9H),1.02(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)193.36,173.88,171.01,170.31,161.08,157.29,154.88,149.06,142.37,140.13,139.49,132.22,131.53,130.80,129.47,129.02,124.71,124.48,124.39,124.04,122.70,114.47,114.13,113.40,105.91,68.95,61.56,58.64,56.98,55.98,52.54,50.58,48.21,48.02,36.77,34.51,33.26,29.78,27.94,27.81,25.34,25.04,24.72,22.70,20.45,7.06;C56H73N4O8S[M+1]+的UPLC-MS(ESI+)计算值:961.51,实测值961.55。
实施例2
生物测定
细胞培养。人乳腺癌细胞系MCF-7(HTB-22TM)和T47D(HTB-133TM)购自弗吉尼亚州马纳萨斯美国典型培养物保藏中心(ATCC),并在含有10%胎牛血清、1单位/ml的青霉素和1μg/ml的链霉素的Dulbecco's Modified Eagle's培养基(DMEM)中培养维持。如所述,在实验中使用购买后具有3-8代的细胞。
蛋白质印迹分析。蛋白质印迹分析基本上按照之前的描述进行(Hu等,2015,PMID:26358219)。将用指定化合物处理的细胞在含有蛋白酶抑制剂混合物(Roche Diagnostics,曼海姆,德国)的放射免疫沉淀分析蛋白裂解和提取缓冲液(25mmol/L Tris.HCl,pH 7.6,150mmol/L NaCl,1%Nonidet P-40,1%脱氧胆酸钠和0.1%十二烷基硫酸钠)中裂解。通过BCA分析(Fisher Scientific,Pittsburgh,PA)测定蛋白质浓度后,将等量的总蛋白质通过10%SDS-聚丙烯酰胺凝胶进行电泳。如所述,将分离的蛋白质条带转移到PVDF膜(GEHealthcare Life Sciences,马尔堡,马萨诸塞州)上,并针对不同的抗体进行印迹。人雌激素受体α抗体(AB16460)购自马萨诸塞州剑桥市Abcam公司。用来自密苏里州圣路易斯的Sigma-Aldrich Corporation的辣根过氧化物酶偶联的抗甘油醛-3-磷酸脱氢酶抗体(G9295)对膜进行重印迹。如biochemlabsolutions.com中所述,使用GelQuant.NET软件扫描印迹并量化条带强度。目标蛋白的相对平均强度在标准化为来自单个重复的3-磷酸甘油醛脱氢酶条带的强度后表示。
细胞生长测定。将细胞以1500个/孔接种在96孔板中过夜。接种后一天,用指定剂量的化合物处理它们。在化合物处理后4天,按照制造商(CaymanChemical,安娜堡,密歇根州)的说明,通过比色WST-8测定评估细胞的生长。
分子建模。雷洛昔芬的N,N-二乙氨基类似物在与ER的复合物中的结合姿态是使用MOE程序用与雷洛昔芬共结晶的结构(PDB:1ERR)49建模的。如果原子缺失,则基于MOE中的amber10库重建残基,并使用“质子化3D”模块添加质子,考虑设置pH值为7,温度为300K,盐浓度为0.1mol/L。然后使用雷洛昔芬进行对接模拟,以定义与保留的结晶H2O分子的结合位点。配体由“三角匹配器”放置,并通过London dG评分进行评估。然后应用DGVI/WSA dG评分进行姿态排名,并选择排名最高的姿态。本文中出现的数字是使用万维网pymol.org上提供的PyMOL程序准备的。
VHL-ElonginBC复合物的克隆和纯化。VHL的DNA序列(编码残基54-213)通过PCR构建,并使用不依赖连接的克隆插入His-TEV表达载体58。Elongin B(编码残基1-118)和Elongin C(编码残基1-96)的DNA序列通过PCR构建,并使用Gibson组装插入pCDFDuet 1。59BL21(DE3)细胞同时用两种质粒转化并生长在37℃的Terrific Brothe中,直到OD600为1.2。细胞在24℃下用0.4mM IPTG诱导过夜。将沉淀的细胞冻融,然后重新悬浮在20mM TrisHCl pH7.0、200mM NaCl和0.1%β-巯基乙醇(bME)中,其中包含蛋白酶抑制剂。细胞悬液通过超声裂解并通过离心去除碎片。上清液在4℃下与Ni-NTA(Qiagen)一起孵育1小时,Ni-NTA(Qiagen)在20mM Tris-HCl pH 7.0、200mM NaCl和10mM咪唑中预洗。蛋白质复合物在20mM Tris-HCl pH 7.0、200mM NaCl和300mM咪唑中洗脱,透析到20mM Tris-HCl pH7.0、150mM NaCl和0.01%bME中,并与TEV蛋白酶在4℃下孵育过夜。将蛋白质样品重新加入Ni-NTA柱以去除His标签。将含有VHL复合物的流通液稀释至75mM NaCl并上样到HiTrap Q柱(GE Healthcare)。样品用盐梯度(0.075–1M NaCl)洗脱、浓缩并在Superdex S75柱(GEHealthcare)上进一步纯化,该柱用20mM Bis-Tris 7.0、150mM NaCl和1mM DTT预平衡。将样品等分并储存在-80℃。
VHL配体对VHL的结合亲和力。使用VHL-ElonginBC复合物和荧光标记探针(SI)建立了荧光偏振(FP)竞争性测定。在竞争性结合实验中确定VHL配体的IC50和Ki值。将在DMSO中的5μL化合物和95μL的预孵育的蛋白质/示踪剂复合物溶液的混合物加入测定板中,将所述测定板在室温下轻轻摇动孵育60分钟。VHL-ElonginBC复合物和荧光探针的最终浓度均为5nM。在每个测定板中均包括了仅含有蛋白质/探针复合物的阴性对照(相当于0%抑制)和仅含有游离探针的阳性对照(相当于100%抑制)。在Microfluor 1 96孔黑色圆底板(Thermo Scientific,Waltham,MA)中,使用Infinite M-1000平板阅读器(Tecan U.S.,Research Triangle Park,NC)在激发波长为485nm和发射波长为530nm的条件下测量FP值,单位为毫米极化单位(mP)。通过竞争曲线的非线性回归拟合确定IC50值。基于竞争性测定中探针的KD值以及蛋白质和探针的浓度,通过非线性回归拟合直接获得竞争性抑制剂的Ki值。所有FP竞争实验在三个独立实验中一式两份进行。
实施例3
生物试验结果
评估了本公开的代表性化合物在MCF-7ER+乳腺癌细胞系中诱导ER降解的能力,氟维司群用作对照。
化合物12-15的蛋白质印迹数据如图1所示。评估了接头长度从3到9个原子的本公开的代表性化合物在1nM、10nM和100nM的浓度下诱导MCF-7细胞中ER降解的能力,其中包含了化合物15、氟维司群(5)、RAD1901(9)和雷洛昔芬(1)作为对照。蛋白质印记数据如图2所示。具有包含6-9个碳原子的接头的化合物15、18、19、20和21在低至1nM的浓度下在诱导ER降解方面出人意料地有效。
评估了具有不同R3基团的本公开的代表性化合物在1nM、10nM和100nM的浓度下诱导MCF-7细胞中ER降解的能力,其中包含了化合物15、氟维司群(5)、RAD1901(9)和雷洛昔芬(1)作为对照。蛋白质印记数据如图3所示。
评估了具有不同接头的本公开的代表性化合物在1nM、10nM和100nM的浓度下诱导MCF-7细胞中ER降解的能力,其中包含了化合物15、氟维司群(5)、RAD1901(9)和雷洛昔芬(1)作为对照。蛋白质印记数据如图4所示。
评估了具有不同雌激素受体的本公开的代表性化合物在1nM、10nM和100nM的浓度下诱导MCF-7细胞中ER降解的能力,其中包含了化合物15、氟维司群(5)、RAD1901(9)和雷洛昔芬(1)作为对照。蛋白质印记数据如图5所示。
评估了具有不同E3连接酶配体的本公开的代表性化合物,见表1,在1nM、10nM和100nM的浓度下诱导MCF-7细胞中ER降解的能力,其中包含了化合物15、氟维司群(5)、RAD1901(9)和雷洛昔芬(1)作为对照。蛋白质印记数据如图6所示。
使用VHL的荧光偏振(FP)测定来确定VHL配体11和43a-48a的结合亲和力,其中包括先前报道的VHL配体(VH032)54作为对照。这些结果列于表1。
表1
测试了化合物32在宽浓度范围内的ER降解,以确定其在MCF-7细胞中的DC50(实现50%蛋白质降解的浓度)。参见图7。蛋白质印迹数据的量化显示化合物32在处理4小时的MCF-7细胞中达到0.17nM的DC50值。基于在低至5nM的浓度下的量化,化合物32实现了>95%的最大ER降解。
还评估了化合物32在T47D ER+乳腺癌细胞系中诱导ER降解的能力。如图8所示,化合物32的DC50值为0.43nM,在5nM时最大降解>95%。1μM的化合物32在T47D细胞中也表现出引人注目的作用。
检测了化合物32在MCF-7细胞中诱导ER降解的动力学。如图9所示,在30nM的浓度下,化合物32在1小时处理后降低了>80%的ER蛋白水平,在3小时时间点实现了基本上完全的ER降解,表明快速动力学。相比之下,氟维司群在1h时对ER水平的降低只有适度的影响,在处理24小时后达到最大约90%的ER降解。在T47D细胞中获得的32和氟维司群的动力学数据与在MCF-7细胞中观察到的相似,见图10。
研究了32诱导ER降解的作用机制。通过添加1μM雷洛昔芬或1μM蛋白酶体抑制剂卡非佐米,30nM浓度的化合物32诱导的ER降解被显著降低,但单独使用雷洛昔芬或卡非佐米对ER蛋白水平没有影响。参见图11。有趣的是,1μM的VHL配体(11)仅略微地阻断30nM的化合物32的降解(图11)。为了进一步证实降解是VHL依赖性的,进行了VHL配体11的剂量反应实验。如图12所示,化合物32的降解被5μM或10μM的11完全阻断。
使用WST-8细胞增殖试验评估了化合物32抑制MCF-7细胞中细胞增殖的能力,其中包括雷洛昔芬和氟维司群作为对照(数据未显示)。化合物32在MCF-7细胞中达到0.77nM的IC50值和57.5%的最大抑制(Imax)。氟维司群的Imax值为43.8%。雷洛昔芬的Imax值为34.0%。RAD1901是先前报道的SERD分子18,其Imax值为25.7%。化合物32在三阴性乳腺癌细胞MDA-MB-231和原代人乳腺上皮细胞中未表现出细胞增殖抑制作用。
为了直观地评估细胞效应,使用结晶紫染色实验测试了10nM、100nM和300nM的化合物32,以雷洛昔芬和氟维司群作为对照(数据未显示)。与WST-8细胞增殖试验一致,在所有三种测试浓度下,用化合物32处理MCF-7细胞比雷洛昔芬或氟维司群更显著降低细胞增殖。
使用定量逆转录聚合酶链反应(qRT-PCR)分析评估了化合物32抑制pGR和GREB1的mRNA水平的能力,pGR和GREB1是MCF-7细胞中的两个ER调节基因(数据未显示)。两种基因的表达都被化合物32强烈抑制。10nM和100nM的化合物32在抑制pGR和GREB1表达方面均比氟维司群稍微更有效。10nM和100nM的化合物32在抑制pGR和GREB1的表达方面均比雷洛昔芬更有效。
实施例4
VHL配体表征
(2S,4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(11):1H NMR(CD3OD,400MHz)δ(ppm)9.02(s,1H),7.47-7.42(m,4H),5.04-4.98(m,1H),4.62-4.55(m,2H),4.43-4.41(m,1H),3.88(d,J=10.8Hz,1H),3.74(dd,J=10.8Hz,J=4.0Hz,1H),2.50(s,3H),2.22-2.16(m,1H),2.00(s,3H),1.98-1.91(m,1H),1.51(d,J=6.8Hz,3H),1.05(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)173.26,173.11,172.28,153.34,148.20,146.01,133.91,131.04,130.51,127.69,127.52,70.97,60.55,59.22,57.97,50.14,38.77,36.41,26.99,22.38,22.29,15.41;C25H35N4O4S[M+1]+的UPLC-MS(ESI+)计算值:487.24,实测值487.43。
(2S,4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(VH032):1H NMR(CD3OD,400MHz)δ(ppm)9.59(s,1H),7.53-7.45(m,4H),4.61-4.51(m,4H),4.38(d,J=15.6Hz,1H),3.92(d,J=10.8Hz,1H),3.80(dd,J=10.8Hz,J=4.0Hz,1H),2.54(s,3H),2.26-2.21(m,1H),2.12-2.05(m,1H),2.00(s,3H),1.03(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)174.50,173.12,172.31,155.25,152.15,141.76,130.38,129.89,129.24,122.18,71.06,60.80,59.21,57.97,43.61,38.89,36.42,26.95,22.31,13.84;C24H33N4O4S[M+1]+的UPLC-MS(ESI+)计算值:473.22,实测值473.07。
(2S,4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-N-((S)-1-(4-氯苯基)乙基)-4-羟基吡咯烷-2-甲酰胺(43a):1H NMR(CD3OD,400MHz)δ(ppm)7.30-7.28(m,4H),4.94(q,J=6.8Hz,1H),4.61(s,1H),4.56-4.51(m,1H),4.43-4.41(m,1H),3.86(d,J=11.2Hz,1H),3.73(dd,J=11.2Hz,J=4.0Hz,1H),2.19-2.13(m,1H),2.00(s,3H),1.95-1.88(m,1H),1.45(d,J=6.8Hz,3H),1.04(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)173.18,172.19,144.17,133.69,129.54,128.68,70.94,60.52,59.26,57.94,38.73,36.41,26.98,22.28,22.23;C21H31ClN3O4[M+1]+的UPLC-MS(ESI+)计算值:424.20,实测值424.30。
(2S,4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-N-((S)-1-(4-乙炔基苯基)乙基)-4-羟基吡咯烷-2-甲酰胺(44a):1H NMR(CD3OD,400MHz)δ(ppm)7.41(d,J=8.4Hz,2H),7.29(d,J=8.4Hz,2H),4.96(q,J=6.8Hz,1H),4.61(s,1H),4.56-4.52(m,1H),4.44-4.41(m,1H),3.87(d,J=10.8Hz,1H),3.73(dd,J=10.8Hz,J=4.0Hz,1H),3.43(s,1H),2.20-2.13(m,1H),2.00(s,3H),1.98-1.88(m,1H),1.46(d,J=6.8Hz,3H),1.04(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)173.20,173.18,172.20,146.14,133.17,127.13,122.41,84.20,78.45,70.95,60.52,59.25,57.94,38.74,36.41,26.98,22.23;C23H32N3O4[M+1]+的UPLC-MS(ESI+)计算值:414.24,实测值414.30。
(2S,4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-N-((S)-1-(4-氰基苯基)乙基)-4-羟基吡咯烷-2-甲酰胺(45a):1H NMR(CD3OD,400MHz)δ(ppm)7.68(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),4.99(q,J=7.2Hz,1H),4.60(s,1H),4.55(t,J=8.4Hz,1H),4.44-4.41(m,1H),3.87(d,J=10.8Hz,1H),3.73(dd,J=10.8Hz,J=4.0Hz,1H),2.21-2.15(m,1H),2.00(s,3H),1.94-1.87(m,1H),1.48(d,J=7.2Hz,3H),1.03(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)173.40,173.12,172.26,151.27,135.50,128.06,119.68,111.76,70.95,60.46,59.23,57.96,38.76,36.39,26.97,26.94,22.27,22.11;C22H31N4O4[M+1]+的UPLC-MS(ESI+)计算值:415.23,实测值415.40。
(2S,4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-N-((S)-1-(4-环丙基苯基)乙基)-4-羟基吡咯烷-2-甲酰胺(46a):1H NMR(CD3OD,400MHz)δ(ppm)7.17(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H),4.92-4.89(m,1H),4.61(s,1H),4.53(t,J=8.4Hz,1H),4.42-4.41(m,1H),3.86(d,J=10.8Hz,1H),3.73(dd,J=10.8Hz,J=4.0Hz,1H),2.17-2.11(m,1H),2.00(s,3H),1.97-1.83(m,2H),1.44(d,J=7.2Hz,3H),1.04(s,9H),0.94-0.90(m,2H),0.64-0.61(m,2H);13C NMR(CD3OD,100MHz)δ(ppm)173.15,172.96,172.19,144.10,142.13,126.93,126.70,70.93,60.54,59.22,57.92,50.00,38.68,36.41,26.98,22.40,22.25,15.77,9.46;C24H36N3O4[M+1]+的UPLC-MS(ESI+)计算值:430.27,实测值430.49。
(2S,4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-异丙基苯基)乙基)吡咯烷-2-甲酰胺(47a):1H NMR(CD3OD,400MHz)δ(ppm)7.23-7.16(m,4H),4.95-4.91(m,1H),4.61(s,1H),4.54(t,J=8.4Hz,1H),4.43-4.41(m,1H),3.86(d,J=11.2Hz,1H),3.74(dd,J=11.2Hz,J=4.0Hz,1H),2.88-2.85(m,1H),2.18-2.12(m,1H),2.01-1.91(m,4H),1.45(d,J=6.8Hz,3H),1.22(d,J=6.8Hz,6H),1.04(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)173.09,173.03,172.27,148.90,142.63,127.49,127.00,70.96,60.57,59.19,57.93,50.00,38.71,36.42,35.06,26.99,24.44,22.48,22.29;C24H38N3O4[M+1]+的UPLC-MS(ESI+)计算值:432.29,实测值432.44。
(2S,4R)-1-((S)-2-乙酰胺基-3,3-二甲基丁酰基)-N-((S)-1-(4-(叔丁基)苯基)乙基)-4-羟基吡咯烷-2-甲酰胺(48a):1H NMR(CD3OD,400MHz)δ(ppm)7.35(d,J=8.0Hz,2H),7.22(d,J=8.0Hz,2H),4.93(q,J=7.2Hz,1H),4.61(s,1H),4.55(t,J=8.4Hz,1H),4.43-4.41(m,1H),3.87(d,J=11.2Hz,1H),3.74(dd,J=11.2Hz,J=4.0Hz,1H),2.19-2.13(m,1H),2.01-1.92(m,4H),1.45(d,J=7.2Hz,3H),1.29(s,9H),1.04(s,9H);13C NMR(CD3OD,100MHz)δ(ppm)173.09,173.02,172.25,151.02,142.17,126.71,126.37,70.95,60.56,59.19,57.93,50.00,38.71,36.42,35.24,31.78,26.99,22.46,22.29;C25H40N3O4[M+1]+的UPLC-MS(ESI+)计算值:446.30,实测值446.40。
REFERENCES
(1)Tong,C.W.S.;Wu,M.;Cho,W.C.S.;To,K.K.W.Recent advances in thetreatment of breast cancer.Front.Oncol.2018,8.
(2)Anderson,W.F.;Katki,H.A.;Rosenberg,P.S.Incidence of breast cancerin the United States:current and future trends.J.Natl.Cancer Inst.2011,103,1397-1402.
(3)Nilsson,S.;Koehler,K.F.;Gustafsson,J.A.Development of subtype-selective oestrogen receptor-based therapeutics.Nat.Rev.Drug Discovery 2011,10,778-792.
(4)Jordan,V.C.Tamoxifen:a most unlikely pioneeringmedicine.Nat.Rev.Drug Discovery 2003,2,205-213.
(5)Das,S.;Crockett,J.C.Osteoporosis-a current view of pharmacologicalprevention and treatment.Drug Des.Devel.Ther.2013,7,435-448.
(6)De Marchi,T.;Foekens,J.A.;Umar,A.;Martens,J.W.Endocrine therapyresistance in estrogen receptor(ER)-positive breast cancer.Drug DiscoveryToday 2016,21,1181-1188.
(7)AlFakeeh,A.;Brezden-Masley,C.Overcoming endocrine resistance inhormone receptor-positive breast cancer.Curr.Oncol.2018,25,S18-S27.
(8)Martin,L.A.;Ribas,R.;Simigdala,N.;Schuster,E.;Pancholi,S.;Tenev,T.;Gellert,P.;Buluwela,L.;Harrod,A.;Thornhill,A.;Nikitorowicz-Buniak,J.;Bhamra,A.;Turgeon,M.O.;Poulogiannis,G.;Gao,Q.;Martins,V.;Hills,M.;Garcia-Murillas,I.;Fribbens,C.;Patani,N.;Li,Z.;Sikora,M.J.;Turner,N.;Zwart,W.;Oesterreich,S.;Carroll,J.;Ali,S.;Dowsett,M.Discovery of naturally occurringESR1 mutations in breast cancer cell lines modelling endocrineresistance.Nat.Commun.2017,8,1865.
(9)Nardone,A.;De Angelis,C.;Trivedi,M.V.;Osborne,C.K.;Schiff,R.Thechanging role of ER in endocrine resistance.Breast 2015,24,S60-S66.
(10)Robertson,J.F.;Harrison,M.Fulvestrant:pharmacokinetics andpharmacology.Br.J.Cancer 2004,90,S7-S10.
(11)Osborne,C.K.;Wakeling,A.;Nicholson,R.I.Fulvestrant:an oestrogenreceptor antagonist with a novel mechanism of action.Br.J.Cancer 2004,90,S2-S6.
(12)Howell,A.;Sapunar,F.Fulvestrant revisited:efficacy and safety ofthe 500-mg dose.Clin.Breast Cancer 2011,11,204-210.
(13)Robertson,J.F.;Lindemann,J.;Garnett,S.;Anderson,E.;Nicholson,R.I.;Kuter,I.;Gee,J.M.A good drug made better:the fulvestrant dose-responsestory.Clin.Breast Cancer 2014,14,381-389.
(14)McDonnell,D.P.;Wardell,S.E.;Norris,J.D.Oral selective estrogenreceptor downregulators(SERDs),a breakthrough endocrine therapy for breastcancer.J.Med.Chem.2015,58,4883-4887.
(15)Abdel-Magid,A.F.Selective estrogen receptor degraders(SERDs):apromising treatment to overcome resistance to endocrine therapy in ERα-positive breast cancer.ACS Med.Chem.Lett.2017,8,1129-1131.
(16)Weir,H.M.;Bradbury,R.H.;Lawson,M.;Rabow,A.A.;Buttar,D.;Callis,R.J.;Curwen,J.O.;de Almeida,C.;Ballard,P.;Hulse,M.;Donald,C.S.;Feron,L.J.;Karoutchi,G.;MacFaul,P.;Moss,T.;Norman,R.A.;Pearson,S.E.;Tonge,M.;Davies,G.;Walker,G.E.;Wilson,Z.;Rowlinson,R.;Powell,S.;Sadler,C.;Richmond,G.;Ladd,B.;Pazolli,E.;Mazzola,A.M.;D'Cruz,C.;De Savi,C.AZD9496:an oral estrogen receptorinhibitor that blocks the growth of ER-positive and ESR1-mutant breast tumorsin preclinical models.Cancer Res.2016,76,3307-3318.
(17)Joseph,J.D.;Darimont,B.;Zhou,W.;Arrazate,A.;Young,A.;Ingalla,E.;Walter,K.;Blake,R.A.;Nonomiya,J.;Guan,Z.;Kategaya,L.;Govek,S.P.;Lai,A.G.;Kahraman,M.;Brigham,D.;Sensintaffar,J.;Lu,N.;Shao,G.;Qian,J.;Grillot,K.;Moon,M.;Prudente,R.;Bischoff,E.;Lee,K.J.;Bonnefous,C.;Douglas,K.L.;Julien,J.D.;Nagasawa,J.Y.;Aparicio,A.;Kaufman,J.;Haley,B.;Giltnane,J.M.;Wertz,I.E.;Lackner,M.R.;Nannini,M.A.;Sampath,D.;Schwarz,L.;Manning,H.C.;Tantawy,M.N.;Arteaga,C.L.;Heyman,R.A.;Rix,P.J.;Friedman,L.;Smith,N.D.;Metcalfe,C.;Hager,J.H.The selective estrogen receptor downregulator GDC-0810 is efficacious indiverse models of ER+breast cancer.eLife 2016,5,e15828.
(18)Bihani,T.;Patel,H.K.;Arlt,H.;Tao,N.;Jiang,H.;Brown,J.L.;Purandare,D.M.;Hattersley,G.;Garner,F.Elacestrant(RAD1901),a selectiveestrogen receptor degrader(SERD),has antitumor activity in multiple ER+breastcancer patient-derived xenograft models.Clin.Cancer Res.2017,23,4793-4804.
(19)Tria,G.S.;Abrams,T.;Baird,J.;Burks,H.E.;Firestone,B.;Gaither,L.A.;Hamann,L.G.;He,G.;Kirby,C.A.;Kim,S.;Lombardo,F.;Macchi,K.J.;McDonnell,D.P.;Mishina,Y.;Norris,J.D.;Nunez,J.;Springer,C.;Sun,Y.;Thomsen,N.M.;Wang,C.;Wang,J.;Yu,B.;Tiong-Yip,C.L.;Peukert,S.Discoveryof LSZ102,a potent,orallybioavailable selective estrogen receptor degrader(SERD)for the treatment ofestrogen receptor positive breast cancer.J.Med.Chem.2018,61,2837-2864.
(20)Carlson,R.W.The history and mechanism of action offulvestrant.Clin.Breast Cancer 2005,6,S5-S8.
(21)Marsaud,V.;Gougelet,A.;Maillard,S.;Renoir,J.M.Variousphosphorylation pathways,depending on agonist and antagonist binding toendogenous estrogen receptorα(ERα),differentially affect ERαextractability,proteasome-mediated stability,and transcriptional activity in human breastcancer cells.Mol.Endocrinol.2003,17,2013-2027.
(22)Wittmann,B.M.;Sherk,A.;McDonnell,D.P.Definition of functionallyimportant mechanistic differences among selective estrogen receptor down-regulators.Cancer Res.2007,67,9549-9560.
(23)Sakamoto,K.M.;Kim,K.B.;Kumagai,A.;Mercurio,F.;Crews,C.M.;Deshaies,R.J.Protacs:chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.Proc.Natl.Acad.Sci.U.S.A.2001,98,8554-8559.
(24)Toure,M.;Crews,C.M.Small-molecule PROTACS:new approaches toprotein degradation.Angew.Chem.,Int.Ed.2016,55,1966-1973.
(25)Lai,A.C.;Crews,C.M.Induced protein degradation:an emerging drugdiscovery paradigm.Nat.Rev.Drug Discovery 2017,16,101-114.
(26)Burslem,G.M.;Crews,C.M.Small-molecule modulation of proteinhomeostasis.Chem.Rev.2017,117,11269-11301.
(27)Cromm,P.M.;Crews,C.M.Targeted protein degradation:from chemicalbiology to drug discovery.Cell Chem.Biol.2017,24,1181-1190.
(28)Ottis,P.;Crews,C.M.Proteolysis-targeting chimeras:induced proteindegradation as a therapeutic strategy.ACS Chem.Biol.2017,12,892-898.
(29)Rodriguez-Gonzalez,A.;Cyrus,K.;Salcius,M.;Kim,K.;Crews,C.M.;Deshaies,R.J.;Sakamoto,K.M.Targeting steroid hormone receptors forubiquitination and degradation in breast and prostate cancer.Oncogene 2008,27,7201-7211.
(30)Jiang,Y.;Deng,Q.;Zhao,H.;Xie,M.;Chen,L.;Yin,F.;Qin,X.;Zheng,W.;Zhao,Y.;Li,Z.Development of stabilized peptide-based PROTACs against estrogenreceptorα.ACS Chem.Biol.2018,13,628-635.
(31)Winter,G.E.B.,D.L.;Paulk,J.;Roberts,J.M.;Souza,A.;;Dhe-Paganon,S.B.,J.E.Phthalimide conjugation as a strategy for in vivo target proteindegradation.Science 2015,348,1376-1381.
(32)Lu,J.;Qian,Y.;Altieri,M.;Dong,H.;Wang,J.;Raina,K.;Hines,J.;Winkler,J.D.;Crew,A.P.;Coleman,K.;Crews,C.M.Hijacking the E3 ubiquitin ligasecereblon to efficiently target BRD4.Chem.Biol.2015,22,755-763.
(33)Bondeson,D.P.;Mares,A.;Smith,I.E.;Ko,E.;Campos,S.;Miah,A.H.;Mulholland,K.E.;Routly,N.;Buckley,D.L.;Gustafson,J.L.;Zinn,N.;Grandi,P.;Shimamura,S.;Bergamini,G.;Faelth-Savitski,M.;Bantscheff,M.;Cox,C.;Gordon,D.A.;Willard,R.R.;Flanagan,J.J.;Casillas,L.N.;Votta,B.J.;den Besten,W.;Famm,K.;Kruidenier,L.;Carter,P.S.;Harling,J.D.;Churcher,I.;Crews,C.M.Catalytic invivo protein knockdown by small-molecule PROTACs.Nat.Chem.Biol.2015,11,611-617.
(34)Lai,A.C.;Toure,M.;Hellerschmied,D.;Salami,J.;Jaime-Figueroa,S.;Ko,E.;Hines,J.;Crews,C.M.Modular PROTAC design for the degradation ofoncogenic BCR-ABL.Angew.Chem.,Int.Ed.2016,55,807-810.
(35)Robb,C.M.;Contreras,J.I.;Kour,S.;Taylor,M.A.;Abid,M.;Sonawane,Y.A.;Zahid,M.;Murry,D.J.;Natarajan,A.;Rana,S.Chemically induced degradationof CDK9 by a proteolysis targeting chimera(PROTAC).Chem.Commun.2017,53,7577-7580.
(36)Zhang,C.;Han,X.R.;Yang,X.;Jiang,B.;Liu,J.;Xiong,Y.;Jin,J.Proteolysis targeting chimeras(PROTACs)of anaplastic lymphoma kinase(ALK).Eur.J.Med.Chem.2018,151,304-314.
(37)Lu,M.;Liu,T.;Jiao,Q.;Ji,J.;Tao,M.;Liu,Y.;You,Q.;Jiang,Z.Discoveryof a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway.Eur.J.Med.Chem.2018,146,251-259.
(38)Burslem,G.M.;Smith,B.E.;Lai,A.C.;Jaime-Figueroa,S.;McQuaid,D.C.;Bondeson,D.P.;Toure,M.;Dong,H.;Qian,Y.;Wang,J.;Crew,A.P.;Hines,J.;Crews,C.M.The advantages of targeted protein degradation over inhibition:an RTKcase study.Cell Chem.Biol.2018,25,67-77.
(39)Schiedel,M.;Herp,D.;Hammelmann,S.;Swyter,S.;Lehotzky,A.;Robaa,D.;Olah,J.;Ovadi,J.;Sippl,W.;Jung,M.Chemically induced degradation of sirtuin 2(sirt2)by a proteolysis targeting chimera(PROTAC)based on sirtuin rearrangingligands(SirReals).J.Med.Chem.2018,61,482-491.
(40)Shibata,N.;Nagai,K.;Morita,Y.;Ujikawa,O.;Ohoka,N.;Hattori,T.;Koyama,R.;Sano,O.;Imaeda,Y.;Nara,H.;Cho,N.;Naito,M.Development of proteindegradation inducers of androgen receptor by conjugation of androgen receptorligands and inhibitor of apoptosis protein ligands.J.Med.Chem.2018,61,543-575.
(41)Crew,A.P.;Raina,K.;Dong,H.;Qian,Y.;Wang,J.;Vigil,D.;Serebrenik,Y.V.;Hamman,B.D.;Morgan,A.;Ferraro,C.;Siu,K.;Neklesa,T.K.;Winkler,J.D.;Coleman,K.G.;Crews,C.M.Identification and characterization of von Hippel-Lindau-recruiting proteolysis targeting chimeras(PROTACs)of TANK-bindingkinase 1.J.Med.Chem.2018,61,583-598.
(42)Sun,Y.;Zhao,X.;Ding,N.;Gao,H.;Wu,Y.;Yang,Y.;Zhao,M.;Hwang,J.;Song,Y.;Liu,W.;Rao,Y.PROTAC-induced BTK degradation as a novel therapy formutated BTK C481S induced ibrutinib-resistant B-cell malignancies.CellRes.2018,28,779-781.
(43)Yang,K.;Song,Y.;Xie,H.;Wu,H.;Wu,Y.T.;Leisten,E.D.;Tang,W.Development of the first small molecule histone deacetylase 6(HDAC6)degraders.Bioorg.Med.Chem.Lett.2018,28,2493-2497.
(44)Ohoka,N.;Okuhira,K.;Ito,M.;Nagai,K.;Shibata,N.;Hattori,T.;Ujikawa,O.;Shimokawa,K.;Sano,O.;Koyama,R.;Fujita,H.;Teratani,M.;Matsumoto,H.;Imaeda,Y.;Nara,H.;Cho,N.;Naito,M.In vivo knockdown of pathogenic proteins viaspecific and nongenetic inhibitor of apoptosis protein(IAP)-dependent proteinerasers(SNIPERs).J.Biol.Chem.2017,292,4556-4570.
(45)Ohoka,N.;Morita,Y.;Nagai,K.;Shimokawa,K.;Ujikawa,O.;Fujimori,I.;Ito,M.;Hayase,Y.;Okuhira,K.;Shibata,N.;Hattori,T.;Sameshima,T.;Sano,O.;Koyama,R.;Imaeda,Y.;Nara,H.;Cho,N.;Naito,M.Derivatization of inhibitor ofapoptosis protein(IAP)ligands yields improved inducers of estrogen receptorαdegradation.J.Biol.Chem.2018,293,6776-6790.
(46)Ottis,P.;Toure,M.;Cromm,P.M.;Ko,E.;Gustafson,J.L.;Crews,C.M.Assessing different E3 ligases for small molecule induced proteinubiquitination and degradation.ACS Chem.Biol.2017,12,2570-2578.
(47)Kanak Rainaa,J.L.,Yimin Qiana,Martha Altieria,Deborah Gordona,AnnMarie K.Rossia,Jing Wanga,Xin Chena,Hanqing Donga,Kam Siua,James D.Winklera,Andrew P.Crewa,Craig M.Crews and Kevin G.Colemana.PROTAC-induced BET proteindegradation as a therapy for castration-resistant prostate cancer.Proc.Natl.Acad.Sci.U.S.A.2016,113,7124-7129.
(48)Zhou,B.;Hu,J.;Xu,F.;Chen,Z.;Bai,L.;Fernandez-Salas,E.;Lin,M.;Liu,L.;Yang,C.Y.;Zhao,Y.;McEachern,D.;Przybranowski,S.;Wen,B.;Sun,D.;Wang,S.Discovery of a small-molecule degrader of bromodomain and extra-terminal(BET)proteins with picomolar cellular potencies and capable of achievingtumor regression.J.Med.Chem.2018,61,462-481.
(49)Andrzej M.Brzozowski,A.C.W.P.,Zbigniew Dauter,Roderick E.Hubbard,Tomas Bonn,Owe Engstro,Lars O¨hman,Geoffrey L.Greene,Jan-A°ke Gustafsson,MatsCarlquist.Molecular basis of agonism and antagonism in the oestrogenreceptor.Nature 1997,389,753-758.
(50)Qin,C.;Hu,Y.;Zhou,B.;Fernandez-Salas,E.;Yang,C.Y.;Liu,L.;McEachern,D.;Przybranowski,S.;Wang,M.;Stuckey,J.;Meagher,J.;Bai,L.;Chen,Z.;Lin,M.;Yang,J.;Ziazadeh,D.N.;Xu,F.;Hu,J.;Xiang,W.;Huang,L.;Li,S.;Wen,B.;Sun,D.;Wang,S.Discovery of QCA570 as an exceptionally potent and efficaciousproteolysis targeting chimera(PROTAC)degrader of the bromodomain and extra-terminal(BET)proteins capable of inducing complete and durable tumorregression.J.Med.Chem.2018,61,6685-6704.
(51)Bai,L.;Zhou,B.;Yang,C.Y.;Ji,J.;McEachern,D.;Przybranowski,S.;Jiang,H.;Hu,J.;Xu,F.;Zhao,Y.;Liu,L.;Fernandez-Salas,E.;Xu,J.;Dou,Y.;Wen,B.;Sun,D.;Meagher,J.;Stuckey,J.;Hayes,D.F.;Li,S.;Ellis,M.J.;Wang,S.Targeteddegradation of BET proteins in triple-negative breast cancer.Cancer Res.2017,77,2476-2487.
(52)Buckley,D.L.;Van Molle,I.;Gareiss,P.C.;Tae,H.S.;Michel,J.;Noblin,D.J.;Jorgensen,W.L.;Ciulli,A.;Crews,C.M.Targeting the von Hippel-LindauE3ubiquitin ligase using small molecules to disrupt the VHL/HIF-1αinteraction.J.Am.Chem.Soc.2012,134,4465-4468.
(53)Buckley,D.L.;Gustafson,J.L.;Van Molle,I.;Roth,A.G.;Tae,H.S.;Gareiss,P.C.;Jorgensen,W.L.;Ciulli,A.;Crews,C.M.Small-molecule inhibitors ofthe interaction between the E3 ligase VHL and HIF-1α.Angew.Chem.,Int.Ed.2012,51,11463-11467.
(54)Galdeano,C.;Gadd,M.S.;Soares,P.;Scaffidi,S.;Van Molle,I.;Birced,I.;Hewitt,S.;Dias,D.M.;Ciulli,A.Structure-guided design and optimization ofsmall molecules targeting the protein-protein interaction between the vonHippel-Lindau (VHL)E3 ubiquitin ligase and the hypoxia inducible factor(HIF)αsubunit with in vitro nanomolar affinities.J.Med.Chem.2014,57,8657-8663.
(55)Soares,P.;Gadd,M.S.;Frost,J.;Galdeano,C.;Ellis,L.;Epemolu,O.;Rocha,S.;Read,K.D.;Ciulli,A.Group-based optimization of potent and cell-active inhibitors of the von Hippel-Lindau(VHL)E3 ubiquitin ligase:structure-activity relationships leading to the chemical probe(2S,4R)-1-((S)-2-(1-cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(VH298).J.Med.Chem.2018,61,599-618.
(56)Gadd,M.S.;Testa,A.;Lucas,X.;Chan,K.H.;Chen,W.;Lamont,D.J.;Zengerle,M.;Ciulli,A.Structural basis of PROTAC cooperative recognition forselective protein degradation.Nat.Chem.Biol.2017,13,514-521.
(57)Long,M.J.;Poganik,J.R.;Aye,Y.On-demand targeting:investigatingbiology with proximity-directed chemistry.J.Am.Chem.Soc.2016,138,3610-3622.
(58)Stols,L.;Gu,M.;Dieckman,L.;Raffen,R.;Collart,F.R.;Donnelly,M.I.Anew vector for high-throughput,ligation-independent cloning encoding atobacco etch virus protease cleavage site.Protein Expr.Purif.2002,25,8-15.
(59)Benoit,R.M.;Ostermeier,C.;Geiser,M.;Li,J.S.;Widmer,H.;Auer,M.Seamless insert-plasmid assembly at high efficiency and low cost.PLoS One2016,11,e0153158.
应理解,前述实施方案和示例不旨在在任何方面限制本公开的范围,并且本文提出的权利要求旨在涵盖所有实施方案和示例,无论其是否在本文中明确呈现。
本文引用的所有专利和出版物均通过引用整体并入。
Claims (14)
6.根据权利要求1至5中任一项所述的化合物,其中
L是-X-L1-Z-;
X选自由以下组成的组:-C≡C-、-O-、-C(=O)N(R1a)-和-N(R3a)-;或者
X不存在;
Z选自由以下组成的组:-C≡C-、-O-、-C(=O)N(R2a)-和-N(R4a)-;或者
Z不存在;
L1选自由以下组成的组:亚烷基、亚杂烷基和-W1-(CH2)m-W2-(CH2)n-
W1不存在;或者
W1选自由以下组成的组:亚苯基、亚杂芳基、亚杂环基和亚环烷基;
W2选自由以下组成的组:亚苯基、亚杂芳基、亚杂环基和亚环烷基;
m是0、1、2、3、4、5、6、或7;
n是0、1、2、3、4、5、6、7或8;且
R1a选自由以下组成的组:氢和C1-4烷基;
R2a选自由以下组成的组:氢和C1-4烷基;
R3a选自由以下组成的组:氢和C1-4烷基;且
R4a选自由以下组成的组:氢和C1-4烷基,
或其药学上可接受的盐或溶剂化物。
10.一种药物组合物,其包含权利要求1至9中任一项所述的化合物,或其药学上可接受的盐或溶剂化物,以及药学上可接受的赋形剂。
11.一种治疗有此需要的患者癌症的方法,所述方法包括向受试者施用药学有效量的权利要求1-12中任一项的化合物,或其药学上可接受的盐或溶剂化物。
12.根据权利要求11所述的方法,其中所述癌症是乳腺癌。
13.根据权利要求11或12所述的方法,其中所述化合物与第二抗癌剂组合施用。
14.根据权利要求13所述的方法,其中所述第二抗癌剂选自由以下组成的组:阿贝西利、紫杉醇、ado-曲妥珠单抗emtansine、飞尼妥、阿那曲唑、帕米膦酸二钠、依西美坦、卡培他滨、多西他赛、盐酸多柔比星、盐酸表柔比星、甲磺酸艾日布林、依西美坦、氟尿嘧啶、托瑞米芬、氟维司群、来曲唑、盐酸吉西他滨、醋酸戈舍瑞林、曲妥珠单抗、帕博西尼、伊沙匹隆、瑞博西尼、拉帕替尼二甲苯磺酸盐、奥拉帕尼、醋酸甲地孕酮、甲氨蝶呤、马来酸来那替尼、帕博西尼、帕米膦酸二钠、帕妥珠单抗、他莫昔芬柠檬酸盐、泰索帝、噻替派、托瑞米芬、曲妥珠单抗和硫酸长春碱。
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WO2024054625A2 (en) * | 2022-09-08 | 2024-03-14 | Nikang Therapeutics, Inc. | Bifunctional compounds for degrading kras g12d via ubiquitin proteasome pathway |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015000868A1 (en) * | 2013-07-03 | 2015-01-08 | Glaxosmithkline Intellectual Property Development Limited | Novel compounds |
CN105452244A (zh) * | 2013-07-03 | 2016-03-30 | 葛兰素史克知识产权开发有限公司 | 作为雌激素受体抑制剂的苯并噻吩衍生物 |
WO2018053354A1 (en) * | 2016-09-15 | 2018-03-22 | Arvinas, Inc. | Indole derivatives as estrogen receptor degraders |
US20180155322A1 (en) * | 2016-12-01 | 2018-06-07 | Arvinas, Inc. | Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders |
CN108495618A (zh) * | 2016-07-12 | 2018-09-04 | 冰洲石生物科技公司 | 新的化合物及其用途 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2019251151B2 (en) * | 2018-04-09 | 2022-07-07 | Shanghaitech University | Target protein degradation compounds, their anti-tumor use, their intermediates and use of intermediates |
-
2019
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- 2019-12-19 KR KR1020217022980A patent/KR20210136973A/ko unknown
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015000868A1 (en) * | 2013-07-03 | 2015-01-08 | Glaxosmithkline Intellectual Property Development Limited | Novel compounds |
CN105452244A (zh) * | 2013-07-03 | 2016-03-30 | 葛兰素史克知识产权开发有限公司 | 作为雌激素受体抑制剂的苯并噻吩衍生物 |
CN108495618A (zh) * | 2016-07-12 | 2018-09-04 | 冰洲石生物科技公司 | 新的化合物及其用途 |
WO2018053354A1 (en) * | 2016-09-15 | 2018-03-22 | Arvinas, Inc. | Indole derivatives as estrogen receptor degraders |
US20180155322A1 (en) * | 2016-12-01 | 2018-06-07 | Arvinas, Inc. | Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders |
Non-Patent Citations (1)
Title |
---|
HU, JIANTAO等: "Discovery of ERD-308 as a highly potent proteolysis targeting chimera (PROTAC) degrader of estrogen receptor (ER)", JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, no. 3, 18 January 2019 (2019-01-18), pages 1420 - 1442, XP055672912, DOI: 10.1021/acs.jmedchem.8b01572 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115475164A (zh) * | 2022-08-22 | 2022-12-16 | 西安交通大学 | 一种可降解PDGFR-β的蛋白降解靶向嵌合体及其制备方法和应用 |
CN115475164B (zh) * | 2022-08-22 | 2024-06-04 | 西安交通大学 | 一种可降解PDGFR-β的蛋白降解靶向嵌合体及其制备方法和应用 |
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