CN116917293A - 血浆激肽释放酶抑制剂 - Google Patents
血浆激肽释放酶抑制剂 Download PDFInfo
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- CN116917293A CN116917293A CN202180077837.4A CN202180077837A CN116917293A CN 116917293 A CN116917293 A CN 116917293A CN 202180077837 A CN202180077837 A CN 202180077837A CN 116917293 A CN116917293 A CN 116917293A
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- halogen
- hydrogen
- pharmaceutically acceptable
- optionally substituted
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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Abstract
本发明提供了式(I)的化合物和包含一种或多种所述化合物的药物组合物,以及使用所述化合物治疗或预防一种或多种病况的方法,所述病况可以受益于血浆激肽释放酶的抑制,包括遗传性血管性水肿、葡萄膜炎、后葡萄膜炎、湿性年龄相关性黄斑水肿、糖尿病性黄斑水肿、糖尿病性视网膜病变和视网膜静脉闭塞。所述化合物是血浆激肽释放酶的选择性抑制剂。
Description
发明背景
血浆激肽释放酶是胰蛋白酶样丝氨酸蛋白酶的酶原并且存在于血浆中。基因结构与因子XI的基因结构相似。总的来说,血浆激肽释放酶的氨基酸序列与因子XI具有58%的同源性。因子XIIa在内部I389-R390键处的蛋白水解活化产生一条重链(371个氨基酸)和一条轻链(248个氨基酸)。血浆激肽释放酶的活性位点被包含在轻链中。血浆激肽释放酶的轻链与蛋白酶抑制剂(包括α2巨球蛋白和Cl-抑制剂)反应。令人感兴趣的是,在高分子量激肽原(HMWK)存在下,肝素显著加速抗凝血酶III对血浆激肽释放酶的抑制。在血液中,大部分血浆激肽释放酶与HMWK形成复合物进行循环。血浆激肽释放酶裂解HMWK以释放缓激肽。缓激肽释放导致血管渗透性和血管舒张的增加(关于综述,Coleman,R.,“ContactActivation Pathway”,Hemostasis and Thrombosis,第103-122页,LippincottWilliams&Wilkins(2001);Schmaier A.H.,“Contact Activation”,Thrombosis andHemorrhage,第105-128页(1998))。
表现出在C1-酯酶抑制剂上的遗传缺陷的患者患有遗传性血管性水肿(HAE),这是一种终生性疾病,其导致全身(包括手、脚、面部、喉咙、生殖器和胃肠道)的间歇性肿胀。对急性发作引起的水泡的分析已经证实含有高水平的血浆激肽释放酶,并且用基于蛋白的可逆血浆激肽释放酶抑制剂艾卡拉肽(Kalbitor)的治疗已被FDA批准用于治疗HAE的急性发作(Schneider,L等人,J.Allergy Clin.Immunol.,120:第416页(2007))。
此外,在诊断出晚期糖尿病性黄斑水肿(DME)的患者中,血浆激肽释放酶-激肽系统是异常丰富的。最近的出版物已经证实,血浆激肽释放酶会促进在糖尿病性啮齿动物模型中观察到的视网膜血管渗漏和功能障碍(A.Clermont等人,Diabetes,60:1590(2011)),并且用小分子血浆激肽释放酶抑制剂的治疗改善了观察到的视网膜血管渗透性和其它与视网膜血流有关的异常。
本领域中需要开发血浆激肽释放酶抑制剂,其可以用于治疗各种各样的障碍,包括遗传性血管性水肿、糖尿病性黄斑水肿和糖尿病性视网膜病变。
发明概述
本发明涉及式I的化合物:
及其药学上可接受的盐。式I的化合物是血浆激肽释放酶的抑制剂,并因此可以用于治疗、抑制或改善一种或多种可以受益于血浆激肽释放酶的抑制的病况,包括遗传性血管性水肿、葡萄膜炎、后葡萄膜炎、湿性年龄相关性黄斑水肿、糖尿病性黄斑水肿、糖尿病性视网膜病变和视网膜静脉闭塞。本发明的化合物还可以与其它治疗上有效的药剂组合使用,所述药剂包括、但不限于可用于治疗遗传性血管性水肿、葡萄膜炎、后葡萄膜炎、湿性年龄相关性黄斑水肿、糖尿病性黄斑水肿、糖尿病性视网膜病变和视网膜静脉闭塞的其它药物。此外,本发明涉及制备式I的化合物的方法,以及包含式I的化合物及其药学上可接受的盐的药物组合物。
发明详述
本发明涉及式I的化合物或其药学上可接受的盐:
其中X是N或CH;
R1选自氢、卤素、羟基和C1-6烷基;
R2选自氢、卤素、羟基和C1-6烷基;
R3选自氢、卤素、羟基和C1-6烷基,其中所述烷基任选地被1-4个取代基取代,所述取代基独立地选自卤素、氰基和ORx;
R4选自氢、卤素、羟基和C1-6烷基;其中所述烷基任选地被1-4个取代基取代,所述取代基独立地选自卤素、氰基和ORx;
R5是NR9R10或ORx;
每个R6独立地选自氢、卤素、羟基和C1-6烷基,其中所述烷基任选地被1-3个卤素取代;
每个R7选自氢、卤素、羟基和C1-6烷基,其中所述烷基任选地被1-3个卤素取代;
或R6和R7可以与它们所连接的碳原子一起形成3-6元环烷基,所述环烷基任选地被一个或两个卤素取代;
R8选自氢;卤素;羟基;Rx;ORx;苯基;茚满;ORy;可以是单环或二环的杂芳基;杂环基;和可以是单环或二环的C3-6环烷基;其中所述苯基和杂芳基任选地被1-3个取代基取代,所述取代基独立地选自氧代、卤素、Rx、ORx、NR9R10、NR9(C=O)Rx、NR9(C=O)ORx、(C=O)ORx、(C=O)NR9、Ry和ORy;其中所述环烷基和杂环基任选地被1-3个取代基取代,所述取代基独立地选自氧代、卤素、Rx和ORx;
R9是氢或C1-3烷基;
R10是氢或C1-3烷基;
Rx是氢或C1-6烷基,所述C1-6烷基任选地被1-3个选自卤素和羟基的取代基取代,
Ry是苯基、杂环基或C3-6环烷基,其中所述苯基任选地被1-3个卤素取代,所述杂环基任选地被1或2个氧代取代,且所述环烷基任选地被C1-6烷基取代;
n是0-2的整数。
在本发明的一个实施方案中,X是CH。在本发明的另一个实施方案中,X是N。
在本发明的一个实施方案中,R1是卤素。在所述实施方案的一类中,R1是氯。
在本发明的一个实施方案中,R2是卤素。在本发明的一类中,R2是氟。
在本发明的一个实施方案中,R3是氢。在本发明的另一个实施方案中,R3是甲基。
在本发明的一个实施方案中,R4是氢。在本发明的另一个实施方案中,R3是甲基。
在本发明的一个实施方案中,R5是NH2。在本发明的另一个实施方案中,R5是OH。
在本发明的一个实施方案中,R6是氢。
在本发明的一个实施方案中,R7是氢。
在本发明的一个实施方案中,R8是苯基;其中所述苯基任选地被1-3个取代基取代,所述取代基独立地选自卤素、Rx、ORx、NR9R10、NR9(C=O)Rx、NR9(C=O)ORx、(C=O)NR9、(C=O)ORx、Ry和ORy。在所述实施方案的一类中,R8是苯基;其中所述苯基任选地被1-3个取代基取代,所述取代基独立地选自卤素、Rx、ORx、Ry和ORy。
在本发明的一个实施方案中,n是0。在本发明的另一个实施方案中,n是1。在本发明的另一个实施方案中,n是2。
对上述优选类和亚类的提及意在包括特定和优选组的所有组合,除非另外说明。
本发明的具体实施方案包括、但不限于在本文中鉴定为实施例1-133的化合物或其药学上可接受的盐。
在本发明范围内还包括药物组合物,其包含如上所述的式I的化合物和药学上可接受的载体。本发明还考虑涵盖药物组合物,其包含药学上可接受的载体和在本申请中具体公开的任何化合物。本发明的这些和其它方面将从本文包含的教导显而易见。
本发明包括用于治疗其中涉及血浆激肽释放酶活性的疾病或病症的组合物。因此,本发明包括用于治疗哺乳动物中的视力活动受损、糖尿病性视网膜病变、糖尿病性黄斑水肿、视网膜静脉闭塞、遗传性血管性水肿、糖尿病、胰腺炎、脑出血、肾病、心肌病、神经病、炎性肠病、关节炎、炎症、脓毒性休克、低血压、癌症、成人呼吸窘迫综合征、弥散性血管内凝血、心肺旁路手术期间的血液凝固和术后出血(bleeding from postoperative surgery)的组合物,其包含在药学上可接受的载体中的本发明的化合物。本发明的一类包括用于治疗遗传性血管性水肿、葡萄膜炎、后葡萄膜炎、湿性年龄相关性黄斑水肿、糖尿病性黄斑水肿、糖尿病性视网膜病变和视网膜静脉闭塞的组合物。这些组合物可以任选地包括抗炎剂、抗-VEGF剂、免疫抑制剂、抗凝血剂、抗血小板剂和血栓溶解剂。可以将所述组合物添加到血液、血液制品或哺乳动物器官中以实现期望的抑制。
本发明还包括用于预防或治疗哺乳动物中与糖尿病性视网膜病变和糖尿病性黄斑水肿相关的视网膜血管渗透性的组合物,其包含在药学上可接受的载体中的本发明的化合物。这些组合物可以任选地包括抗炎剂、抗-VEGF剂、免疫抑制剂、抗凝血剂、抗血小板剂和血栓溶解剂。
本发明还包括用于治疗眼的炎性病症的组合物,所述炎性病症包括、但不限于葡萄膜炎、后葡萄膜炎、黄斑水肿、急性黄斑变性、湿性年龄相关性黄斑水肿、视网膜脱离、视网膜静脉闭塞、眼肿瘤、真菌感染、病毒感染、多病灶性脉络膜炎、糖尿病性葡萄膜炎、糖尿病性黄斑水肿、糖尿病性视网膜病变、增殖性玻璃体视网膜病变、交感性眼炎、VogtKoyanagi-Harada综合征、组织胞浆菌病和葡萄膜扩散。这些组合物可以任选地包括抗炎剂、抗-VEGF剂、免疫抑制剂、抗凝血剂、抗血小板剂和血栓溶解剂。
本发明还包括治疗后眼疾病的组合物,所述后眼疾病包括、但不限于葡萄膜炎、后葡萄膜炎、湿性年龄相关性黄斑水肿、糖尿病性黄斑水肿、糖尿病性视网膜病变和视网膜静脉闭塞。这些组合物可以任选地包括抗炎剂、抗-VEGF剂、免疫抑制剂、抗凝血剂、抗血小板剂和血栓溶解剂。
应当理解,本发明涉及本文描述的结构式I的化合物、以及结构式I的化合物的药学上可接受的盐、以及当用作游离化合物或它们的药学上可接受的盐的前体或用于其它合成操作中时的非药学上可接受的盐。
本发明的化合物可以以药学上可接受的盐的形式施用。术语“药学上可接受的盐”是指从药学上可接受的无毒碱或酸(包括无机或有机碱和无机或有机酸)制备的盐。被包括在术语“药学上可接受的盐”中的碱性化合物的盐是指本发明的化合物的无毒盐,其通常通过使游离碱与合适的有机酸或无机酸反应来制备。本发明的碱性化合物的代表性盐包括、但不限于以下的盐:乙酸盐、抗坏血酸盐、己二酸盐、海藻酸盐、天冬氨酸盐(aspirate)、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、右旋樟脑磺酸盐、碳酸盐、氯化物、克拉维酸盐、柠檬酸盐、环戊烷丙酸盐、二乙基乙酸盐、二葡萄糖酸盐、二盐酸盐、十二烷基磺酸盐(dodecylsulfanate)、依地酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐(esylate)、乙磺酸盐(ethanesulfonate)、甲酸盐、富马酸盐、葡庚糖酸盐(gluceptate)、葡萄糖庚酸盐(glucoheptanoate)、葡萄糖酸盐、谷氨酸盐、甘油磷酸盐、羟乙酰氨基苯胂酸盐(glycollylarsanilate)、半硫酸盐、庚酸盐、己酸盐、己基间苯二酚盐、哈胺(hydrabamine)、氢溴酸盐、盐酸盐、2-羟基乙磺酸盐、羟基萘甲酸盐、碘化物、异烟酸盐、异硫代硫酸盐、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、甲磺酸盐、粘酸盐、2-萘磺酸盐、萘磺酸盐、烟酸盐、硝酸盐、N-甲基还原葡糖胺铵盐、油酸盐、草酸盐、扑酸盐(双羟萘酸盐)、棕榈酸盐、泛酸盐、果胶酸盐、过硫酸盐、磷酸盐/二磷酸盐、庚二酸盐、苯基丙酸盐、聚半乳糖醛酸盐、丙酸盐、水杨酸盐、硬脂酸盐、硫酸盐、碱式醋酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、8-氯茶碱盐、硫氰酸盐、甲苯磺酸盐、三乙基碘化物、三氟乙酸盐、十一酸盐(undeconate)、戊酸盐等。此外,在本发明的化合物携带酸性部分的情况下,其合适的药学上可接受的盐包括、但不限于源自无机碱的盐,包括铝、铵、钙、铜、三价铁、二价铁、锂、镁、三价锰、二价锰、钾、钠、锌等。源自药学上可接受的有机无毒碱的盐包括以下物质的盐:伯胺、仲胺和叔胺,环胺,二环己胺和碱性离子交换树脂,诸如精氨酸、甜菜碱、咖啡因、胆碱、N,N-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、哈胺(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。此外,所包括的碱性含氮基团可以被诸如以下试剂季铵化:低级烷基卤化物,诸如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;二烷基硫酸酯如二甲基、二乙基、二丁基和二戊基硫酸酯,长链卤化物,诸如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物;芳烷基卤化物如苄基和苯乙基的溴化物等。
这些盐可以通过已知的方法获得,例如通过将本发明的化合物与等量和含有所需酸、碱等的溶液混合,然后通过过滤盐或蒸馏出溶剂来收集所需盐。本发明的化合物及其盐可以与溶剂(诸如水、乙醇或甘油)形成溶剂化物。根据侧链取代基的类型,本发明的化合物可以同时形成酸加成盐和与碱的盐。
如果式I的化合物在分子中同时含有酸性和碱性基团,除了提到的盐形式外,本发明还包括内盐或内铵盐(betaines)(两性离子)。
本发明包括式I的化合物的所有立体异构形式。除非指明具体的立体化学,否则本发明意在包括这些化合物的所有这样的异构形式。存在于式I的化合物中的不对称中心可以都彼此独立地具有(R)构型或(S)构型。当与手性碳的键在本发明的结构式中被描述为直线时,应当理解,手性碳的(R)和(S)构型和因此各单个对映异构体及其混合物被包括在该式内。当描绘特定构型时,意指该对映异构体((R)或(S),位于该中心)。类似地,当在没有手性碳的手性指定的情况下描述化合物名称时,应当理解,手性碳的(R)和(S)构型以及因此单个对映异构体及其混合物都被包含在该名称中。具体立体异构体或其混合物的产生可以在得到这类立体异构体或混合物的实例中鉴别,但是这决不限制所有立体异构体及其混合物被包括在本发明范围内。
除非指明具体对映异构体或非对映异构体,否则本发明包括所有可能的对映异构体和非对映异构体以及两种或更多种立体异构体以所有比率的混合物,例如对映异构体和/或非对映异构体的混合物。因而,以下形式的对映异构体是本发明的主题:对映异构纯的形式,作为左旋和右旋对映体,外消旋体的形式,和两种对映异构体以所有比率的混合物的形式。在顺/反异构现象的情况下,本发明包括顺式形式和反式形式以及这些形式的所有比率的混合物。如果需要的话,通过用常规方法(例如色谱法或结晶)分离混合物,通过使用立体化学一致的合成起始材料,或通过立体选择性的合成,可以进行单个立体异构体的制备。任选地,可以在分离立体异构体之前进行衍生化。立体异构体混合物的分离可以在式I的化合物的合成期间的中间步骤进行,或者可以在最终的外消旋产物上进行。绝对立体化学可以通过结晶产物或结晶中间体的X-射线晶体学来确定,如果必要的话,所述结晶产物或结晶中间体用含有已知构型的立体中心的试剂衍生化。在本发明的化合物能够互变异构化的情况下,所有单个互变异构体及其混合物都被包括在本发明的范围内。本发明包括所有这样的异构体、以及这样的外消旋体、对映异构体、非对映异构体和互变异构体的盐、溶剂化物(包括水合物)和溶剂化盐及其混合物。
在本发明的化合物中,原子可以表现出它们的天然同位素丰度,或者原子中的一个或多个可以被人工地富集特定同位素,所述同位素具有相同原子序数,但是其原子质量或质量数不同于在自然界中占优势地存在的原子质量或质量数。本发明意在包括具体地和一般地描述的化合物的所有合适的同位素变体。例如,氢(H)的不同同位素形式包括氕(1H)和氘(2H)。氕是在自然界中发现的占优势的氢同位素。氘富集可以提供某些治疗优点,诸如增加体内半衰期或减小剂量需求,或者可以提供可用作生物样品表征的标准品的化合物。通过本领域技术人员众所周知的常规技术,或通过类似于本文一般方法方案和实施例中描述的那些的方法,使用适当的同位素富集的试剂和/或中间体,无需过度实验就可以制备同位素富集的化合物。
当任何变量(例如Rx等)在任何组分中出现超过一次时,它在每次出现时的定义独立于其它每次出现。并且,只有当这样的组合产生稳定的化合物时,才允许取代基和变量的组合。从取代基绘制到环系统中的线代表所示的键可以连接至任何可取代的环原子。如果环系统是二环,则意指该键连接至二环部分的任一个环上的任何合适原子。
应当理解,本领域普通技术人员可以将一个或多个硅(Si)原子掺入本发明的化合物中以替代一个或多个碳原子,以提供化学上稳定的且可以通过本领域已知的技术从容易得到的起始材料容易地合成的化合物。在对比类似的C元素和Si元素键时,碳和硅的共价半径不同,这导致键长和空间排列的差异。与碳相比,这些差异导致含硅化合物的尺寸和形状的细微变化。本领域普通技术人员会理解,尺寸和形状差异可以导致效力、溶解度、脱靶活性的缺乏、包装性能等方面的细微或显著变化。(Diass,J.O.等人,Organometallics(2006)5:1188-1198;Showell,G.A.等人,Bioorganic&Medicinal Chemistry Letters(2006)16:2555-2558)。
应当理解,本领域普通技术人员可以选择本发明的化合物的取代基和取代型式,以提供化学上稳定的且可以通过本领域已知的技术以及下面阐述的那些方法从容易得到的起始材料容易地合成的化合物。如果取代基本身被超过一个基团取代,应当理解,这多个基团可以在同一个碳上或在不同碳上,只要产生稳定的结构即可。短语“任选地(被一个或多个取代基)取代”应当理解为意指,所讨论的基团未被取代或可以被一个或多个取代基取代。
此外,本发明的化合物可以以无定形形式和/或一种或多种结晶形式存在,且因此式I的化合物的所有无定形和结晶形式及其混合物意图被包括在本发明范围内。此外,本发明的一些化合物可以与水(即,水合物)或普通有机溶剂形成溶剂化物。本发明的化合物的这样的溶剂化物和水合物(特别是药学上可接受的溶剂化物和水合物),以及非溶剂化形式和无水形式,同样被包括在本发明的范围内。
并且,在羧酸(-COOH)或醇基存在于本发明的化合物中的情况下,可以采用羧酸衍生物的药学上可接受的酯,诸如甲基、乙基或新戊酰氧基甲基,或醇的酰基衍生物,诸如O-乙酰基、O-新戊酰基、O-苯甲酰基和O-氨酰基。包括本领域已知的用于改变用作持续释放或前药制剂的溶解度或水解特征的那些酯和酰基。
本发明的化合物的任何药学上可接受的前药修饰(其导致在体内转化为在本发明范围内的化合物)也在本发明的范围内。例如,通过可利用的羧酸基团的酯化或通过在化合物中可利用的羟基上形成酯,可以任选地制备酯。类似地,可以制备不稳定的酰胺。可以制备本发明的化合物的药学上可接受的酯或酰胺以作为前药,其可以水解回酸(或-COO-,取决于发生转化的液体或组织的pH)或羟基形式,特别是在体内,并因此被包括在本发明的范围内。药学上可接受的前药修饰的例子包括、但不限于-C1-6烷基酯和被苯基酯取代的-C1-6烷基。
因此,本文描述和要求保护的通用结构式、实施方案和具体化合物中的化合物包括其盐、所有可能的立体异构体和互变异构体、物理形式(例如,无定形和结晶形式)、溶剂化物和水合物形式以及这些形式的任何组合,及其盐、其前药形式及其前药形式的盐,只要这样的形式是可能的,除非另有说明。
除非在本文中指出,否则术语“烷基”和“亚烷基”意图包括具有指定数目的碳原子的支链和直链饱和脂族烃基。在整个说明书中使用烷基的常用缩写,例如甲基可以由包括“Me”或CH3或作为末端基团的延伸键的符号(例如″″)在内的常规缩写表示,乙基可以由“Et”或CH2CH3表示,丙基可以由“Pr”或CH2CH2CH3表示,丁基可以由“Bu”或CH2CH2CH2CH3表示,等。“C1-4烷基”(或“C1-C4烷基”)例如是指具有指定数目的碳原子的直链或支链烷基,包括所有异构体。例如,结构
具有等同的含义。C1-4烷基包括正丁基、异丁基、仲丁基和叔丁基,正丙基和异丙基,乙基和甲基。如果未指定数目,则直链或支链烷基包括1-4个碳原子。
除非指出,否则术语“环烷基”是指具有指定数目的碳原子的单环或二环饱和脂族烃基。例如,“环烷基”包括环丙基、环丁基、环戊基、环己基,诸如此类。
除非指出,否则本文中使用的术语“芳基”代表在每个环中具有至多10个碳原子的稳定单环或二环环系统,其中至少一个环是芳族的。二环芳基环系统包括稠合环系统,其中两个环共享两个原子;和螺环系统,其中两个环共享一个原子。在该定义的范围内的芳基包括、但不限于:苯基、茚、异茚、萘和四氢萘。
除非指出,否则本文中使用的术语“杂芳基”代表在每个环中具有至多10个原子的稳定单环或二环环系统,其中至少一个环是芳族的,并且至少一个环含有1至4个选自O、N和S的杂原子。二环杂芳基环系统包括稠合环系统,其中两个环共享两个原子;和螺环系统,其中两个环共享一个原子。在该定义的范围内的杂芳基包括、但不限于:氮杂吲哚基、苯并咪唑基、苯并异噁唑基、苯并呋喃基、苯并呋咱基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并噁唑基、咔唑基、咔啉基、噌啉基、二氢茚基、呋喃基、吲哚啉基、吲哚基、吲嗪基、吲唑基、异苯并呋喃基、异吲哚基、异喹啉基、异噻唑基、异噁唑基、萘基、萘啶基、噁二唑基、噁唑基、噁唑啉、异噁唑啉、吡喃基、吡嗪基、吡唑基、吡唑并嘧啶基、哒嗪基、吡啶并吡啶基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹喔啉基、四唑基、四唑并吡啶基、噻二唑基、噻唑基、噻吩基、三唑基、二氢苯并咪唑基、二氢苯并呋喃基、二氢苯并噻吩基、二氢苯并噁唑基、二氢吲哚基、二氢喹啉基、二氢苯并二氧杂环己烯基、二氢吡唑并噁嗪基、dihydropyrazolyothiazinedioxidyl、亚甲基二氧基苯、苯并噻唑基、苯并噻吩基、喹啉基、异喹啉基、噁唑基、四氢喹啉、环丁砜基、1,3-苯并二氧杂环戊烯基和3-氧代-3,4二氢-2N-苯并[b][1,4]噻嗪。如果杂芳基含有氮原子,应当理解,其相应的N-氧化物也被包括在该定义中。
本文中使用的术语“杂环”或“杂环基”意指在每个环中具有至多10个原子的稳定非芳族单环或二环环系统,除非另外指出,否则含有1-4个选自O、N、S、SO或SO2的杂原子。二环杂环系统包括稠合环系统,其中两个环共享两个原子;和螺环系统,其中两个环共享一个原子。因此,“杂环基”包括、但不限于以下:氮杂螺壬基、氮杂螺辛基、氮杂环丁基、二氧杂环己烷基、氧杂二氮杂螺癸烯基、氧杂螺辛基、噁唑烷酮基、哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、四氢呋喃基、四氢吡喃基、二氢哌啶基、四氢噻吩基等。如果杂环含有氮,应当理解,其相应的N-氧化物也被包括在该定义中。
除非指出,否则术语“卤素”或“卤代”是指氟、氯、溴或碘。
(Fluka)硅藻土是硅藻土,且可以被称作“celite”。
除非在本文中指出,否则含有取代基变量诸如下面的变量“R”(其被描绘为不连接至任何一个特定二环环碳原子)的结构:
代表这样的结构:其中所述变量可以任选地连接至任何二环环碳原子。例如,上述结构中所示的变量R可以连接至6个二环环碳原子i、ii、iii、iv、v或vi中的任何一个。
除非在本文中指出,否则二环环系统包括稠合环系统,其中两个环共享两个原子;和螺环系统,其中两个环共享一个原子。
本发明还涉及药物,其含有至少一种式I的化合物和/或式I的化合物的药学上可接受的盐和/或任选的式I的化合物的立体异构形式或式I的化合物的立体异构形式的药学上可接受的盐,以及药学上合适的和药学上可接受的媒介物、添加剂和/或其它活性物质和助剂。
本文所用的术语“患者”用于指示哺乳动物诸如灵长类动物、人类、绵羊、马、牛、猪、狗、猫、大鼠和小鼠。
通过口服、吸入、直肠或透皮施用或通过皮下、关节内、腹膜内或静脉内注射,可以施用根据本发明的药物。口服施用是优选的。可以用式I的化合物涂覆支架和与体内血液接触的其它表面。
本发明还涉及用于生产药物的方法,其包括使用药学上合适的和药学上可接受的载体以及任选的其它合适的活性物质、添加剂或助剂将至少一种式I的化合物制成合适的施用形式。
合适的固体或盖仑制剂形式是例如颗粒剂、粉剂、包衣片剂、片剂、(微)胶囊剂、栓剂、糖浆剂、果汁、混悬液、乳剂、滴剂或可注射溶液以及具有活性物质的延长释放的制剂,在其制备中使用常规赋形剂诸如媒介物、崩解剂、粘合剂、包衣剂、膨胀剂、助流剂或润滑剂、调味剂、甜味剂和增溶剂。可以提及的经常使用的助剂是碳酸镁、二氧化钛、乳糖、甘露醇和其它糖、滑石粉、乳糖、明胶、淀粉、纤维素及其衍生物、动物油和植物油诸如鳕鱼肝油、向日葵油、花生油或芝麻油、聚乙二醇和溶剂,诸如、例如无菌水和一元醇或多元醇诸如甘油。
根据多种因素来选择利用血浆激肽释放酶抑制剂的剂量方案,所述因素包括患者的类型、种族、年龄、重量、性别和医疗状况;要治疗的病症的严重程度;施用途径;患者的肾和肝功能;和所采用的特定化合物或其盐。普通技术医师或兽医可以容易地确定和开出预防、对抗或阻止病症进展所需的药物的有效量。
当用于指定效果时,血浆激肽释放酶抑制剂的口服剂量范围为约0.01mg/千克体重/天(mg/kg/天)至约30mg/kg/天,优选0.025-7.5mg/kg/天,更优选0.1-2.5mg/kg/天,且最优选0.1-0.5mg/kg/天(除非另有说明,活性成分的量是基于游离碱)。例如,80kg患者将接受约0.8mg/天至2.4g/天,优选2-600mg/天,更优选8-200mg/天,且最优选8-40mg/kg/天。因此,用于每天施用一次的适当制备的药物含有0.8mg至2.4g,优选2mg至600mg,更优选8mg至200mg,且最优选8mg至40mg,例如,8mg、10mg、20mg和40mg。有利地,可以以每天两次、三次或四次的分份剂量施用血浆激肽释放酶抑制剂。对于每天施用两次,适当制备的药物含有0.4mg至4g,优选1mg至300mg,更优选4mg至100mg,且最优选4mg至20mg,例如,4mg、5mg、10mg和20mg。
在静脉内,患者接受足以递送0.025-7.5mg/kg/天、优选0.1-2.5mg/kg/天和更优选0.1-0.5mg/kg/天的量的活性成分。这样的量可以以许多合适的方式施用,例如在一个延长的时间段内或每天数次施用大体积的低浓度的活性成分,在一个短时间段内施用小体积的高浓度的活性成分,例如每天一次。通常,可以制备常规静脉内制剂,其含有浓度在约0.01-1.0mg/mL的活性成分,例如0.1mg/mL、0.3mg/mL和0.6mg/mL,并且每天以0.01mL/kg患者重量至10.0mL/kg患者重量的量施用,例如0.1mL/kg、0.2mL/kg、0.5mL/kg。在一个实施例中,一名每天两次接受8mL具有0.5mg/mL浓度的活性成分的静脉内制剂的80kg患者每天接受8mg活性成分。葡糖醛酸、L-乳酸、乙酸、柠檬酸或任何在静脉内施用可接受的pH范围内具有合理缓冲能力的药学上可接受的酸/共轭碱可以用作缓冲剂。取决于要施用的药物的溶解度,本领域普通技术人员容易做出适当缓冲剂和制剂的pH的选择。
式I的化合物可以作为单一疗法施用和与其它治疗剂组合施用,所述其它治疗剂包括、但不限于抗炎剂、抗-VEGF剂、免疫抑制剂、抗凝血剂、抗血小板剂和血栓溶解剂。
“抗炎剂”是当以治疗上有效的水平施用时直接地或间接地有效减轻炎症的任何药剂。“抗炎剂”包括、但不限于甾体类抗炎剂和糖皮质激素。合适的抗炎剂包括、但不限于可的松、地塞米松、氢化可的松、甲泼尼龙、泼尼松龙、泼尼松和曲安西龙。
“抗-VEGF剂”是直接地或间接地有效抑制VEGF(血管内皮生长因子)活性的任何药剂。合适的抗-VEGF剂包括、但不限于贝伐珠单抗、雷珠单抗和阿柏西普。
“免疫抑制剂”是直接地或间接地有效抑制或降低身体免疫系统的强度的任何药剂。合适的免疫抑制剂包括、但不限于皮质类固醇(例如、泼尼松、布地奈德、泼尼松龙)、janus激酶抑制剂(例如托法替尼)、钙调磷酸酶抑制剂(例如环孢素、他克莫司)、mTOR抑制剂(例如西罗莫司、依维莫司)、IMDH抑制剂(例如硫唑嘌呤、来氟米特、麦考酚酯)、生物制品(例如阿巴西普、阿达木单抗、阿那白滞素、赛妥珠单抗、依那西普、戈利木单抗、英夫利昔单抗、依奇珠单抗、那他珠单抗、利妥昔单抗、苏金单抗、托珠单抗、乌司奴单抗、维多珠单抗)和单克隆抗体(例如巴利昔单抗、达克珠单抗)。
合适的抗凝血剂包括、但不限于因子XIa抑制剂、凝血酶抑制剂、凝血酶受体拮抗剂、因子VIIa抑制剂、因子Xa抑制剂、因子IXa抑制剂、因子XIIa抑制剂、腺苷二磷酸抗血小板剂(例如,P2Y12拮抗剂)、纤维蛋白原受体拮抗剂(例如以治疗或预防不稳定型心绞痛或预防血管成形术以后的再阻塞和再狭窄)、其它抗凝血剂诸如阿司匹林和血栓溶解剂诸如纤溶酶原激活物或链激酶,以在各种血管病变的治疗中实现协同效应。这样的抗凝血剂包括例如阿哌沙班、达比加群、坎格雷洛、替格瑞洛、沃拉帕沙、氯吡格雷、依度沙班、米泊美生、普拉格雷、利伐沙班和塞莫肝素。例如,患有冠状动脉疾病的患者和接受血管成形术手术的患者将受益于纤维蛋白原受体拮抗剂和凝血酶抑制剂的共同施用。
在某些实施方案中,本文描述的抗炎剂、抗-VEGF剂、免疫抑制剂、抗凝血剂、抗血小板剂和血栓溶解剂以本领域报道的它们的常规剂量范围和方案使用,包括例如在以下文献中描述的剂量:Physicians′Desk Reference的各版本,诸如第70版(2016)和更早的版本。在其它实施方案中,本文描述的抗炎剂、抗-VEGF剂、免疫抑制剂、抗凝血剂、抗血小板剂和血栓溶解剂以低于其常规剂量范围的剂量使用。
可替换地或另外地,一种或多种另外的药理学活性剂可以与本发明的化合物组合施用。所述另外的活性剂(或多种活性剂)意指在体内具有活性的药物活性剂(或多种活性剂),包括在施用后转化为药学活性形式的前药,其不同于本发明的化合物,并且当这样的形式在商业上销售或在其它方面化学上可能时,还包括所述另外的活性剂的游离酸、游离碱和药学上可接受的盐。通常,任何合适的一种或多种另外的活性剂(包括、但不限于抗高血压剂、另外的利尿剂、抗动脉粥样硬化剂诸如调节脂质的化合物、抗糖尿病剂和/或抗肥胖剂)可以在单一剂量制剂中与本发明的化合物一起以任何组合使用(固定剂量药物组合),或者可以在一种或多种单独的剂量制剂中施用给患者,这允许同时或依次施用活性剂(单独的活性剂的共同施用)。可以使用的另外的活性剂的例子包括、但不限于血管紧张素转换酶抑制剂(例如,阿拉普利、贝那普利、卡托普利、西罗普利、西拉普利、地拉普利、依那普利、依那普利拉、福辛普利、咪达普利、赖诺普利、莫维普利、培哚普利、喹那普利、雷米普利、螺普利、替莫普利或群多普利);血管紧张素II受体拮抗剂,也被称作血管紧张素受体阻滞剂或ARB,其可以呈游离碱、游离酸、盐或前药形式,诸如阿齐沙坦,例如,美阿沙坦钾坎地沙坦,例如,坎地沙坦酯/>依普罗沙坦,例如,甲磺酸依普罗沙坦/>厄贝沙坦/>氯沙坦,例如,氯沙坦钾奥美沙坦,例如,奥美沙坦酯/>替米沙坦缬沙坦/>和与噻嗪样利尿剂诸如氢氯噻嗪(例如,DIOVAN/>ATACAND/>)等)组合使用的这些药物中的任一种;保钾利尿剂诸如盐酸阿米洛利、螺内酯、依普利酮、氨苯蝶啶,每种与或不与HCTZ一起;中性内肽酶抑制剂(例如,塞奥芬(thiorphan)和膦酰二肽);醛固酮拮抗剂;醛固酮合酶抑制剂;肾素抑制剂;enalkrein;RO 42-5892;A 65317;CP 80794;ES 1005;ES 8891;SQ 34017;阿利吉仑(2(S),4(S),5(S),7(S)-N-(2-氨基甲酰基-2-甲基丙基)-5-氨基-4-羟基-2,7-二异丙基-8-[4-甲氧基-3-(3-甲氧基丙氧基)-苯基]-辛酰胺半富马酸盐)SPP600,SPP630和SPP635);内皮素受体拮抗剂;血管扩张剂(例如硝普盐);钙通道阻滞剂(例如,氨氯地平、硝苯地平、维拉帕米、地尔硫卓、非洛地平、戈洛帕米、尼鲁地平、尼莫地平、尼卡地平);钾通道活化剂(例如,尼可地尔、吡那地尔、色满卡林、米诺地尔、阿普卡林、氯普唑仑);交感神经阻滞药;β-肾上腺素能阻断药(例如,醋丁洛尔、阿替洛尔、倍他洛尔、比索洛尔、卡维地洛、美托洛尔、酒石酸美托洛尔、纳多洛尔、普萘洛尔、索他洛尔、噻吗洛尔);α肾上腺素能阻断药(例如,多沙唑嗪、哌唑嗪或α甲基多巴);中枢α肾上腺素能激动剂;周围血管扩张剂(例如肼屈嗪);降脂剂,例如,HMG-CoA还原酶抑制剂诸如辛伐他汀和洛伐他汀(它们以内酯前药形式作为/>知/>销售并在施用后作为抑制剂起作用),和二羟基开环酸HMG-CoA还原酶抑制剂的药学上可接受的盐诸如阿托伐他汀(特别是以/>销售的钙盐)、瑞舒伐他汀(特别是以/>销售的钙盐)、普伐他汀(特别是以销售的钠盐)和氟伐他汀(特别是以/>销售的钠盐);胆固醇吸收抑制剂诸如依折麦布/>和与任何其它降脂剂诸如上面指出的HMG-CoA还原酶抑制剂和特别是与辛伐他汀/>或与阿托伐他汀钙组合的依折麦布;立即释放或控释形式的烟碱酸,和特别是与DP拮抗剂诸如拉罗匹仑和/或与HMG-CoA还原酶抑制剂组合的烟碱酸;烟碱酸受体激动剂诸如阿昔莫司和阿昔呋喃,以及烟碱酸受体部分激动剂;代谢改变剂,包括胰岛素敏化剂和用于治疗糖尿病的有关化合物诸如双胍类(例如,二甲双胍)、氯茴苯酸类(例如,瑞格列奈、那格列奈)、磺酰脲类(例如,氯磺丙脲、格列美脲、格列吡嗪、格列本脲、妥拉磺脲、甲苯磺丁脲)、也被称作格列酮类的噻唑烷二酮类(例如,吡格列酮、罗格列酮)、α葡萄糖苷酶抑制剂(例如,阿卡波糖、米格列醇)、二肽基肽酶抑制剂、(例如,西格列汀/>阿格列汀、维格列汀、沙格列汀、利拉利汀、度格列汀、吉格列汀)、麦角生物碱(例如,溴隐亭)、组合药物诸如/>(西格列汀和二甲双胍)和可注射的糖尿病药物诸如艾塞那肽和乙酸普兰林肽;葡萄糖摄取抑制剂,诸如钠-葡萄糖转运蛋白(SGLT)抑制剂和它的各种异形体,诸如SGLT-1、SGLT-2(例如,ASP-1941、TS-071、BI-10773、托格列净、LX-4211、卡格列净、达格列净、埃格列净、依格列净、瑞格列净和索格列净)和SGLT-3;或与对于预防或治疗上述疾病有益的其它药物,包括、但不限于二氮嗪;且包括游离酸、游离碱和药学上可接受的盐形式、前药形式,例如,在化学上可能的情况下,以上药剂的前药的酯和盐。提供上述药物的商标名称来举例说明活性剂的销售形式;这样的药物可以以单独的剂型使用以与本发明的化合物同时或依次施用,或者其中的一种或多种活性剂可以用于包括本发明的化合物的固定剂量药物组合中。
与其它合适药剂组合的本发明的血浆激肽释放酶抑制剂的典型剂量可以与没有共同施用另外的药剂而施用的血浆激肽释放酶抑制剂的那些剂量相同,或者可以显著低于没有共同施用另外的药剂而施用的血浆激肽释放酶抑制剂的那些剂量,取决于患者的治疗需要。
将化合物以治疗有效量施用给哺乳动物。“治疗有效量”是指这样的本发明的化合物的量:其当单独地或与另外的治疗剂组合施用给哺乳动物时,有效治疗(即,预防、抑制或改善)疾病状况或治疗宿主中疾病的进展。
本发明的化合物优选地以治疗有效量单独施用给哺乳动物。但是,本发明的化合物也可以如下所述以治疗有效量与另外的治疗剂组合施用给哺乳动物。当组合施用时,化合物的组合优选地、但不一定是协同组合。当组合施用时化合物的作用(在本申请中,对期望靶标的抑制)大于当作为单一药剂分别施用时每种化合物的累加作用,则发生协同作用,例如如Chou和Talalay,Adv.Enzyme Regul.1984,22,27-55所描述。一般而言,在化合物的次优浓度下最清楚地证明协同作用。与单个组分相比,协同作用可以是降低的细胞毒性、增加的抗凝血作用或所述组合的一些其它有益作用。
“组合施用”或“组合疗法”是指,将本发明的化合物和一种或多种另外的治疗剂并行地施用给正在治疗的哺乳动物。当组合施用时,每种组分可以同时施用或在不同时间点以任何顺序依次施用。因此,每种组分可以单独施用,但在时间上足够接近,从而提供期望的治疗效果。每种组分的施用不需要通过相同的施用途径;例如,一种组分可以口服施用,另一种组分可以递送进眼的玻璃体中。
本发明在范围上不受限于实施例中公开的具体实施方案,所述实施方案旨在举例说明本发明的几个方面,并且在功能上等同的任何实施方案均在本发明的范围内。实际上,除了本文所示和描述的那些之外,本发明的各种修改对于相关领域的技术人员来说将变得显而易见,并且意图落入所附权利要求的范围内。
一般方法
使用常规技术或根据以下一般合成方案中概述的方法,可以制备本发明的化合物。本领域技术人员可以改变显示的程序和试剂以得到相似的中间体和/或最终化合物。
在VARIAN或Bruker NMR Systems(400、500或600MHz)上测量NMR谱。以从四甲基硅烷(TMS)的ppm低场和高场报告化学位移,并参考内部TMS或溶剂共振(1H NMR:δ7.27(对于CDCl3),δ2.50(对于(CD3)(CHD2)SO,和13C NMR:δ77.02(对于CDCl3),δ39.51(对于(CD3)2SO))。以赫兹(Hz)为单位表示耦合常数(J),且将自旋多重性表示为s(单峰)、d(双峰)、dd(双二重峰)、t(三重峰)、m(多重峰)和br(宽峰)。在Waters Thar 80SFC或Berger MG II制备型SFC系统上进行手性拆分。在SHIMADAZU LC-MS-2020、SHIMADAZU LC-MS-2010或Agilent 1100系列LC-MS、Agilent Prime-1260或Waters Acquity LC-MS仪器上,使用C18柱,采用在含有0.02至0.1%TFA的水中的MeCN梯度,记录LC-MS数据。紫外检测在220和/或254nm,并将ESI电离用于MS检测。
当使用手性柱通过色谱法实现手性拆分时,在表中列出了用于SFC手性拆分的手性柱。使用的一些手性柱是CHIRALPAK AD、CHIRALCEL OJ、CHIRALPAK AS、CHIRALPAK AY、CHIRALPAK IA、CHIRALPAK AD-H和CHIRALPAK AS-H。此后,这些手性柱将由两个或三个字母缩写来表示。按照惯例,来自手性拆分的快速洗脱的异构体总是列在该表中的首位,紧接着是同一拆分的较慢洗脱的异构体。如果分离出超过2种异构体,它们将总是按它们的洗脱顺序列在表中,诸如峰1,然后是峰2、峰3,诸如此类。在结构中在手性中心附近的*符号表示,该手性中心通过手性拆分进行拆分,其立体化学构型没有明确确定。
并且,TLC是薄层色谱法;UV是紫外;W是瓦特;重量%是重量百分比;x g是重力的倍数;αD是在589nm偏振光的比旋光度;℃是摄氏度;%w/v是前一种试剂的重量相对于后一种试剂的体积的百分比;Hz是赫兹;cpm是每分钟计数;δH是化学位移;d是双峰;dd是双二重峰;MHz是兆赫;MS是质谱,且通过ES-MS得到的质谱在本文中可以表示为“LC-MS”;m/z是质荷比;n是正;N是当量浓度;nm是纳米;nM是纳摩尔浓度。
为了本说明书的目的,以下缩写具有指出的含义:[Mes-Acr-Me]+是9-间三甲基苯基-10-甲基吖啶鎓四氟硼酸盐;X-PHOS Pd G2是氯(2-二环己基膦基-2′,4′,6′-三异丙基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)。
Ac 乙酰基
ACN 乙腈
AcOH 乙酸
aq. 水性的
Boc或BOC 叔丁氧基羰基
br 宽峰
Bu或nBu (正)丁基
Bz 苯甲酰基
℃ 摄氏度
calcd. 计算的
δ 化学位移
d 双峰
DAST (二乙基氨基)三氟化硫
DBU 1,8-二氮杂双环[5.4.0]十一碳-7-烯
DCM 二氯甲烷
dd 双二重峰
DIEA,DIPEA N,N-二异丙基乙胺或Hünig氏碱
DMF 二甲基甲酰胺
DMSO 二甲亚砜
DPPA 叠氮磷酸二苯酯
dqd 四双重峰的双重峰
DTT 二硫苏糖醇
EDC 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺
EDTA 乙二胺四乙酸
当量 当量
ESI 电喷雾电离
Et 乙基
Et2O 乙醚
EtOH 乙醇
EtOAc 乙酸乙酯
g 克
GST 谷胱甘肽S-转移酶
h 小时
HATU N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)
脲鎓六氟磷酸盐
HPLC 高效液相色谱法
Hz 赫兹
IPA 异丙醇
iPr 异丙基
J 耦合常数
LC 液相色谱法
LCMS 液相色谱-质谱法
LED 发光二极管
m 多重峰
M 摩尔浓度
Me 甲基
MeOH 甲醇
mg 毫克
MHz 兆赫
min 分钟
μL 微升
mL 毫升
mM 毫摩尔浓度
mmol 毫摩尔
MS 质谱法
MTBE 甲基叔丁基醚
N 氮取代的
nm 纳米
nM 纳摩尔浓度
NMP 1-甲基吡咯烷酮
NMR 核磁共振光谱法
OAc 乙酸酯
Ph 苯基
Pr 丙基
q 四重峰
rac 外消旋混合物
RT或rt 室温(环境温度,约25℃)
s 单峰
satd. 饱和的
SFC 超临界流体色谱法
t 三重峰
T3P 丙烷膦酸酐
TBAF 叔丁基氟化铵
TBS或TBDMS 叔丁基二甲基甲硅烷基
TBSCl 叔丁基二甲基氯硅烷
tBu 叔丁基
tBuOH 叔丁醇
TCFH 四甲基氯甲脒六氟磷酸盐
TEA 三乙胺(Et3N)
tert 叔
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱法
TMS 三甲基甲硅烷基
TMSCl 三甲基氯硅烷
Tris 三(羟甲基)氨基甲烷
Ts 甲苯磺酰基(甲苯基)
tt 三三重峰
X-phos或X-PHOS 2-二环己基膦基-2′,4′,6′-三异丙基联苯
一般方法
所用的起始材料得自商业来源或在其它实施例中制备,除非另外指出。用于制备本发明的化合物的方法由以下方案示例。除非另有说明,否则所用的所有起始材料都是商购可得的。
手性分离方法
使用手性SFC分离化合物的非对映异构或对映异构混合物的一般制备条件如下:
一般方案
方案A.
方案A示例了从Boc-保护的苯胺A1和酮诸如A2制备被取代的螺氨基甲酸酯诸如A6的合成顺序。在路易斯酸(例如LaCl3)存在下发生苯胺A1的定向锂化和向杂环酮A2的添加。叔醇经历在氨基甲酸酯上的原位环化以产生螺氨基甲酸酯衍生物诸如A3,可以对其进行手性分离,优选地使用超临界流体色谱法(SFC)以提供对映异构体A4和A5。任一种对映异构体(例如A4)的脱保护产生仲胺A6。
方案B.
方案B示例了从羰基衍生物诸如B1制备烷基肼诸如B4的合成顺序。羰基B1与苯甲酰肼的缩合产生中间体B2,将其还原为受保护的肼B3。在酸性条件下的脱保护产生烷基肼B4。
方案C.
方案C示例了从羰基衍生物诸如C1制备CF3乙基肼衍生物诸如C4的合成顺序。羰基C1与苯甲酰肼的缩合产生中间体C2。用TMSCF3向C2添加CF3,提供CF3-乙基中间体C3,将其在酸性条件下脱保护以产生肼衍生物C4。
方案D.
方案D示例了从烷基卤诸如D1合成烷基肼衍生物诸如D2。用烷基卤D1对肼的烷基化提供了烷基肼D2。
方案E.
方案E示例了从羧酸衍生物诸如E1制备烷基肼衍生物诸如E3的合成顺序。羧酸E1的光氧化还原脱羧酰肼化提供了受保护的肼中间体E2。脱保护产生烷基肼衍生物E3。
方案F.
方案F示例了从烷基羧酸衍生物诸如F1制备烷基肼衍生物诸如F4的合成顺序。烷基羧酸F1的Curtius重排产生受保护的胺F2。F2的氧化提供了N-亚硝基中间体F3,将其还原和脱保护以产生烷基肼衍生物F4。
方案G.
方案G示例了从芳基溴化物诸如G1合成芳基肼诸如G2。通过在合适的碱存在下钯催化的芳基溴化物诸如G1与肼的交叉偶联反应来制备芳基肼G2。
方案H.
方案H示例了从肼衍生物诸如H2和氰基烷氧基丙烯酸酯H1制备氨基吡唑衍生物诸如H4的合成顺序。被取代的肼H2与氰基乙氧基丙烯酸酯H1的缩合提供酯氨基吡唑衍生物诸如H3。H3的皂化产生羧酸H4。
方案I.
方案I示例了从肼衍生物诸如I2和烷氧基亚甲基丙二酸酯I1制备羟基吡唑衍生物诸如I4的合成顺序。被取代的肼I2与丙二酸酯I1的缩合提供酯羟基吡唑衍生物诸如I3。I3的皂化产生羧酸I4。
方案J.
方案J示例了从未被取代的氨基吡唑衍生物诸如J1制备N-取代的氨基吡唑衍生物诸如J4的合成顺序。氨基吡唑J1的烷基化提供了N-取代的氨基吡唑J3。J3的皂化提供了N-取代的氨基吡唑的羧酸J4。
方案K.
方案K示例了从螺氨基甲酸酯哌啶衍生物诸如K1和羧酸衍生物诸如K2制备螺氨基甲酸酯吡唑或三唑衍生物诸如K1。使用肽偶联剂诸如TCFH、EDC、HATU或T3P使羧酸K2与螺氨基甲酸酯K1偶联,提供酰胺K3。
方案L.
方案L示例了从螺氨基甲酸酯哌啶衍生物诸如L1制备螺氨基甲酸酯氨基吡唑衍生物诸如L5的合成顺序。螺氨基甲酸酯L1与氰基乙酸的偶联提供中间体L2,其经历缩合以产生氰基丙烯酸酯衍生物诸如L3。在碱性或酸性条件下L3与各种肼L4的缩合提供了氨基吡唑诸如L5。
中间体A2-1
3-环丙基-5-氧代哌啶-1-甲酸叔丁酯
在N2气氛下在-78℃将环丙基溴化镁(30.0mL,15.2mmol,0.5M在THF中)加入CuI(1.45g,7.61mmol)在THF(20mL)中的悬浮液中。使得到的混合物温热至0℃并搅拌另外1h以产生有机铜酸盐试剂。然后将溶液冷却至-78℃,随后加入3-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(1.0g,5.1mmol)的THF溶液(5mL)和TMSCl(1.30mL,10.1mmol)。将反应混合物在-78℃搅拌1h,然后用MeOH淬灭。将混合物用EtOAc和饱和NH4Cl水溶液稀释,并分离各层。将有机层经MgSO4干燥,过滤并在减压下浓缩。将粗残余物通过硅胶色谱法纯化以提供标题化合物。1H NMR(600MHz,CDCl3)δ4.12-3.74(m,3H),3.18(br s,1H),2.66(dd,J=16.3,4.6Hz,1H),2.33(dd,J=16.1,10.5Hz,1H),1.49(s,9H),1.32-1.24(m,1H),0.63(tt,J=8.7,4.7Hz,1H),0.55(dd,J=12.9,5.3Hz,2H),0.25(s,1H),0.18-0.11(m,1H)。
中间体A2-2
3-(二氟甲基)-5-氧代哌啶-1-甲酸叔丁酯
在室温向3-氧代-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(1.1g,5.6mmol)和二氟甲烷亚磺酸锌(2.5g,8.4mmol)在三氟甲苯(22mL)和H2O(9mL)中的溶液中逐滴加入叔丁基过氧化氢(1.70mL,12.6mmol,70%wt/v在H2O中)。将反应混合物加热至35℃并搅拌12h。然后,将烧瓶冷却至室温,用H2O和DCM稀释并将各层分离。将合并的有机层经MgSO4干燥,过滤并在减压下浓缩。将粗残余物通过硅胶色谱法(EtOAc:己烷)纯化以提供标题化合物。1H NMR(600MHz,CDCl3)δ5.80(t,J=55.5Hz,1H),4.12-3.72(m,3H),3.50(br s,1H),2.63(dd,J=15.7,5.3Hz,1H),2.59-2.53(m,1H),2.50(dd,J=15.6,8.7Hz,1H),1.47(s,9H)。
中间体A2-3
3-氧代-5-(三氟甲基)哌啶-1-甲酸叔丁酯
在室温向3-羟基-5-(三氟甲基)哌啶-1-甲酸叔丁酯(8.0g,29.7mmol)在DCM(50mL)中的溶液中加入NaHCO3(7.5g,89mmol)和戴斯-马丁氧化剂(15.1g,35.7mmol)。将反应混合物在室温搅拌1h。然后,将反应用H2O淬灭并用DCM稀释。将各层分离并将水相用DCM萃取。将合并的有机层经MgSO4干燥,过滤并在减压下浓缩。将粗残余物通过硅胶色谱法(EtOAc:己烷)纯化以提供标题化合物。1H NMR(600MHz,CDCl3)δ4.32-3.77(m,3H),3.72-3.20(m,1H),2.83(d,J=6.9Hz,1H),2.73(dd,J=16.7,6.1Hz,1H),2.57(dd,J=16.6,9.4Hz,1H),1.47(s,9H)。
中间体A6-1
6-氯-5-氟-5′,5′-二甲基螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-2(1H)-酮
步骤1:6-氯-5-氟-5′,5′-二甲基-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′- 哌啶]-1′-甲酸叔丁酯:在N2气氛下将THF(55mL)加入含有(4-氯-3-氟苯基)氨基甲酸叔丁酯(2.21g,9.0mmol)的圆底烧瓶中,并将溶液冷却至-78℃。向搅拌溶液中,历时40分钟加入nBuLi(11.2mL,27.9mmol,2.5M在己烷中)。将反应混合物在-78℃搅拌另外45分钟,在此时,在-78℃历时40分钟将LaCl3·2LiCl溶液(22.5mL,13.5mmol,0.6M在THF中)和3,3-二甲基-5-氧代哌啶-1-甲酸叔丁酯(3.10g,13.5mmol)加入反应混合物中。使反应混合物温热至室温并搅拌16h。将KOtBu(5.3mL,9.0mmol,1.7M在THF中)加入反应混合物中,并将溶液加热至60℃保持另外3h。将反应冷却至室温,用1M HCl淬灭并用EtOAc稀释。将各层分离并将水相用EtOAc萃取。将合并的有机层经MgSO4干燥,过滤并在减压下浓缩。将粗残余物通过硅胶色谱法(EtOAc:己烷)纯化以提供标题化合物。LCMS[M+Na]+=421.1(计算值421.1)。
步骤2:6-氯-5-氟-5′,5′-二甲基螺[苯并[d][13]噁嗪-4,3′-哌啶]-2(1H)-酮:将HCl(25.0mL,100mmol,4M在二氧杂环己烷中)加入含有6-氯-5-氟-5′,5′-二甲基-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-甲酸叔丁酯(7.98g,20.0mmol)在1,4-二氧杂环己烷(30mL)中的悬浮液的圆底烧瓶中。将反应混合物加热至90℃并剧烈搅拌12h。将反应冷却至室温,并浓缩以产生粗制的标题化合物,将其不经进一步纯化地用于下一步。LCMS[M+H]+=299.1(计算值299.1)。
表A.使用适当的起始材料使用与关于中间体A6-1描述的程序类似的程序制备下列化合物.
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中间体A6-15
(rac)-(4R或S,5′R或S)-6-氯-5-氟-5′-羟基-2-氧代-1,2-二氢螺[苯并[d][1,3]
噁嗪-4,3′-哌啶]-1′-甲酸叔丁酯
步骤1:3-((叔丁基二甲基甲硅烷基)氧基)-5-氧代哌啶-1-甲酸叔丁酯:将含有3-羟基-5-氧代哌啶-1-甲酸叔丁酯(22.4g,104mmol)在DMF(224mL)中的溶液的烧瓶冷却至0℃。加入咪唑(21.2g,312mmol)和TBSCl(18.8g,125mmol),并将反应混合物温热至室温并搅拌16h。将反应用H2O淬灭,并用MTBE萃取。将各层分离,并将合并的有机层用盐水洗涤。将有机层经Na2SO4干燥,过滤并浓缩以提供粗残余物,将其通过硅胶色谱法(EtOAc:石油醚)纯化以提供标题化合物。LCMS[M-55]+=274.3(计算值274.2)。
步骤2:(rac)-(4R或S,5′R或S)-5′-((叔丁基二甲基甲硅烷基)氧基)-6-氯-5-氟- 2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-甲酸叔丁酯和(rac)-(4S或R,5′S 或R)-5′-((叔丁基二甲基甲硅烷基)氧基)-6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3] 噁嗪-4,3′-哌啶]-1′-甲酸叔丁酯:将THF(188mL)加入含有(4-氯-3-氟苯基)氨基甲酸叔丁酯(12.5g,50.9mmol)的圆底烧瓶中,并将混合物冷却至-78℃。历时1h加入nBuLi(63.1mL,158mmol,2.5M在己烷中),随后在-78℃历时5min逐滴加入LaCl3·2LiCl溶液(x 102mL,61.1mmol,0.6M在THF中)和3-((叔丁基二甲基甲硅烷基)氧基)-5-氧代哌啶-1-甲酸叔丁酯(20.1g,61.1mmol)。将反应混合物在-78℃搅拌1h,并温热至室温另外12h。将反应用饱和NH4Cl水溶液淬灭,倒入含有冰的烧瓶中并搅拌15min。将混合物用EtOAc稀释,将各层分离并将合并的有机层经MgSO4干燥,过滤并浓缩以提供粗残余物,将其通过硅胶色谱法(EtOAc:石油醚)纯化以提供为非对映异构体混合物的标题化合物。通过制备型反相HPLC(ACN/水+10mM NH4HCO3)分离非对映异构体。得到标题化合物的较快洗脱的非对映异构体:LCMS[M+Na]+=523.3(计算值523.2)。得到标题化合物的较慢洗脱的非对映异构体:LCMS[M+Na]+=523.3(计算值523.2)。
步骤3:(rac)-(4R或S,5′R或S)-6-氯-5-氟-5′-羟基螺[苯并[d][1,3]噁嗪-4,3′- 哌啶]-2(1H)-酮:将含有在THF(20mL)中的(rac)-(4S或R,5′S或R)-5′-((叔丁基二甲基甲硅烷基)氧基)-6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-甲酸叔丁酯(来自前一步的较慢洗脱的峰,1.0g,2.0mmol)的烧瓶冷却至0℃。加入TBAF(6.0mL,6.0mmol),并将反应混合物温热至40℃保持12h。将反应用冰水淬灭并搅拌15min。将混合物用EtOAc稀释,将各层分离,并将合并的有机层用盐水洗涤。将有机层经MgSO4干燥,过滤并在减压下浓缩以提供粗产物,将其不经进一步纯化地继续使用。将HCl(0.9mL,3.5mmol,4M在二氧杂环己烷中)加入含有粗产物(34mg,0.090mmol)在1,4-二氧杂环己烷(0.8mL)中的悬浮液的管形瓶中。将反应混合物在室温剧烈搅拌12h并浓缩以产生粗制的标题化合物。将粗产物不经进一步纯化用于下一步。LCMS[M+H]+=287.0(计算值287.1)。
中间体A6-16
(rac)-(4R或S,5′R或S)-6-氯-5,5′-二氟螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-2
(1H)-酮
步骤1:(rac)-(4R或S,5′R或S)-6-氯-5,5′-二氟-2-氧代-1,2-二氢螺[苯并[d] [1,3]噁嗪-4,3′-哌啶]-1′-甲酸叔丁酯:将含有在THF(20mL)中的(rac)-(4S或R,5′S或R)-5′-((叔丁基二甲基甲硅烷基)氧基)-6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-甲酸叔丁酯(来自中间体A6-15的步骤1的较慢洗脱的峰,1.0g,2.0mmol)的烧瓶冷却至0℃。将TBAF(6.0mL,6.0mmol,1M THF溶液)加入烧瓶中,并将反应混合物温热至40℃保持12h。将反应用冰水淬灭并搅拌15min。将混合物用EtOAc稀释,将各层分离并将合并的有机层用盐水洗涤。将有机层经MgSO4干燥,过滤并在减压下浓缩以提供粗产物,将其不经进一步纯化地继续使用。在N2气氛下将在DCM(5mL)中的粗制的乙醇(100mg,0.260mmol)冷却至-78℃。逐滴加入在DCM(2mL)中的DAST(625mg,0.390mmol),并将反应混合物在-78℃搅拌1h。将反应混合物通过硅胶色谱法(EtOAc:DCM)直接纯化以提供标题化合物。LCMS[M+H]+=411.3(计算值411.1)。
步骤2:(rac)-(4R或S,5′R或S)-6-氯-5,5′-二氟螺[苯并[d][1,3]噁嗪-4,3′-哌 啶]-2(1H)-酮:将HCl(0.6mL,2.3mmol,4M在二氧杂环己烷中)加入含有在1,4-二氧杂环己烷(0.6mL)中的(rac)-(4R或S,5′R或S)-6-氯-5,5′-二氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-甲酸叔丁酯(45mg,0.12mmol)的管形瓶中,并将反应混合物在室温搅拌3h。在减压下除去溶剂以产生粗产物,将其不经进一步纯化地用于下一步。LCMS[M+H]+=289.1(计算值289.1)。
中间体A6-17
(4R和S,6′S)-6-氯-5-氟-6′-甲基螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-2(1H)-酮
步骤1:(4R和S,6′S)-6-氯-5-氟-6′-甲基-2-氧代-1,2-二氢螺[苯并[d][1,3]噁 嗪-4,3′-哌啶]-1′-甲酸苄酯:将THF(15mL)加入(4-氯-3-氟苯基)氨基甲酸叔丁酯(600mg,2.44mmol)中并冷却至-78℃。历时40min加入nBuLi(3.0mL,7.57mmol,2.5M在己烷中),并将得到的混合物在-78℃搅拌另外45min。在-78℃历时40min加入LaCl3·2LiCl溶液(6.1mL,3.66mmol,0.6M在THF中)和(S)-2-甲基-5-氧代哌啶-1-甲酸苄酯(900mg,3.66mmol),并将反应混合物温热至室温并搅拌16h。加入KOtBu(1.40mL,2.44mmol,1.7M在THF中),并将反应加热至60℃保持另外3h。将反应冷却至室温,用1M HCl淬灭并用EtOAc稀释。将各层分离并将水层用EtOAc萃取。将合并的有机层经MgSO4干燥,过滤并浓缩以提供粗残余物,将其通过硅胶色谱法(EtOAc:己烷)纯化以提供为非对映异构体混合物的标题化合物。LCMS[M+H]+=419.0(计算值419.1)。
步骤2:(4R和S,6′S)-6-氯-5-氟-6′-甲基螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-2 (1H)-酮:将HBr(3.9mL,71.6mmol,33重量%在AcOH中)加入含有(4R和S,6′S)-6-氯-5-氟-6′-甲基-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-甲酸苄酯(600mg,1.43mmol)的管形瓶中。将反应混合物加热至80℃保持12h。将反应冷却至室温,并浓缩以产生粗制的标题化合物,将其不经进一步纯化地用于下一步。LCMS[M+H]+=285.1(计算值285.1)。
中间体B4-1
rac-(1,1,1-三氟丁烷-2-基)肼
步骤1:N′-(1,1,1-三氟丁烷-2-亚基)苯甲酰肼:向1,1,1-三氟丁烷-2-酮(1.39g,11.0mmol)在甲苯(10mL)中的溶液中加入苯甲酰肼(1.50g,11.0mmol),并将反应混合物加热至110℃保持18h。将反应冷却至室温,倒入水中,然后过滤。将固体用水洗涤并进一步干燥以产生期望的粗制的标题化合物。LCMS[M+H]+=245.4(计算值245.1)。
步骤2:N′-(1,1,1-三氟丁烷-2-基)苯甲酰肼:将N′-(1,1,1-三氟丁烷-2-亚基)苯甲酰肼(500mg,2.05mmol)在THF(6mL)中的溶液冷却至0℃并逐滴加入BH3 THF(4.09mL,4.09mmol,1.0M THF溶液)。使反应温热至室温并搅拌14h。将反应重新冷却至0℃并用MeOH淬灭。在减压下除去溶剂并加入二氯甲烷。将浆料过滤以除去不溶物,并将有机层用饱和NH4Cl水溶液洗涤,经MgSO4干燥,过滤并浓缩以提供标题化合物。LCMS[M+H]+=246.7(计算值247.1)。
步骤3:(1,1,1-三氟丁烷-2-基)肼:向N′-(1,1,1-三氟丁烷-2-基)苯甲酰肼(274mg,1.11mmol)在MeOH(3mL)中的溶液中加入氯化氢(1.48mL,17.8mmol,37%水溶液),并将得到的混合物加热至80℃保持16h。将反应冷却至室温,并在减压下浓缩。加入EtOAc,并将沉淀物过滤,并用EtOAc洗涤以提供标题化合物。1H NMR(400MHz,CD3OD)δ3.34-3.49(m,1H),1.80(dqd,J=14.7,7.5,4.4Hz,1H),1.46-1.65(m,1H),0.97-1.27(m,3H)。
表B.使用适当的起始材料使用与在中间体B4-1中描述的那些类似的程序制备下列化合物.
中间体C4-1
(2,2,2-三氟-1-(1-氟环丙基)乙基)肼
步骤1:N′-((1-氟环丙基)亚甲基)苯甲酰肼:将1-氟环丙烷-1-甲醛(176mg,2.0mmol)加入苯甲酰肼(272mg,2.0mmol)在甲苯(4mL)中的溶液中,并将反应混合物加热至60℃保持1h。将反应冷却至室温,并浓缩以提供粗产物,将其不经任何纯化地用于下一步。LCMS[M+H]+=207.1(计算值207.1)。
步骤2:N′-(2,2,2-三氟-1-(1-氟环丙基)乙基)苯甲酰肼:将烯丙基三甲基硅烷(0.48mL,3.0mmol)和BF3·Et2O(0.37mL,3.0mmol)依次加入N′-((1-氟环丙基)亚甲基)苯甲酰肼(412mg,2.0mmol)在1,2-二氯乙烷(4.0mL)中的悬浮液中,并将混合物回流加热5min。将溶剂在真空下蒸发,并将得到的残余物溶解在DMF(4mL)中。加入TMSCF3(0.60mL,4.0mmol)和NaOAc(660mg,8.0mmol),并将混合物加热至55℃保持3h。将反应冷却至室温并用饱和Na2CO3水溶液淬灭,并搅拌另外5min。将混合物用H2O稀释,并用EtOAc萃取。将合并的有机层经MgSO4干燥,过滤,并浓缩以提供粗残余物,将其通过硅胶色谱法(EtOAc:己烷)纯化以提供标题化合物。LCMS[M+H]+=277.1(计算值277.1)。
步骤3:(2,2,2-三氟-1-(1-氟环丙基)乙基)肼:向N′-(2,2,2-三氟-1-(1-氟环丙基)乙基)苯甲酰肼(140mg,0.51mmol)在MeOH(0.75mL)中的溶液中加入HCl(0.7mL,8.1mmol,37%水溶液),并将得到的混合物加热至80℃保持16h。将反应冷却至室温,并浓缩以提供粗产物,将其与甲苯一起共沸以提供标题化合物,将其不经纯化继续使用。LCMS[M+H]+=173.1(计算值173.1)。
表C.使用适当的起始材料使用与在中间体C4-1中描述的那些类似的程序制备下列化合物.
中间体D2-1
((1-氟环丙基)甲基)肼
将肼(0.33mL,0.33mmol,1.0M THF溶液)加入含有在EtOH(0.3mL)中的1-(溴甲基)-1-氟环丙烷(50mg,0.33mmol)的管形瓶中,并将得到的混合物加热至70℃保持16h。将反应冷却至室温,并浓缩以提供粗产物,将其与甲苯一起共沸以提供标题化合物,将其不经纯化继续使用。LCMS[M+H]+=105.1(计算值105.1)。
表D.使用适当的起始材料使用与在中间体D2-1中描述的那些类似的程序制备下列化合物.
中间体E3-1
(1-(4-氟苯基)环丙基)肼
步骤1:1-(1-(4-氟苯基)环丙基)肼-1,2-二甲酸二叔丁酯:将乙腈(20mL)加入含有1-(4-氟苯基)环丙烷-1-甲酸(360mg,2.0mmol)和[Mes-Acr-Me]+光催化剂(16mg,0.04mmol)的管形瓶中。将溶液用N2脱气5min。脱气以后,快速连续加入DBU(0.06mL,0.4mmol)和偶氮二甲酸二叔丁酯(576mg,2.5mmol)。将管形瓶放在450nm蓝色LED(Merck光反应器)前面并搅拌12h。在减压下除去溶剂,并将粗制混合物通过硅胶色谱法(EtOAc:己烷)纯化以提供标题化合物。LCMS[M-155]+=211.1(计算值211.2)。
步骤2:(1-(4-氟苯基)环丙基)肼:将HCl(6.6mL,26.2mmol,4.0M二氧杂环己烷溶液)加入含有1-(1-(4-氟苯基)环丙基)肼-1,2-二甲酸二叔丁酯(640mg,1.75mmol)的管形瓶中,并将反应混合物在室温搅拌16h。在减压下除去溶剂,并将混合物与甲苯一起共沸以提供标题化合物,将其不经纯化继续使用。LCMS[M+H]+=167.0(计算值167.1)。
表E.使用适当的起始材料使用与在中间体E3-1中描述的那些类似的程序制备下列化合物.
中间体F4-1
(1-(三氟甲基)环丙基)肼
步骤1:(1-(三氟甲基)环丙基)氨基甲酸叔丁酯:向1-(三氟甲基)环丙烷甲酸(5.00g,32.4mmol)在tBuOH(5mL)中的溶液中加入TEA(5.00mL,35.7mmol)和二苯基膦叠氮化物(diphenylphosphinyl azide)(11.8g,48.7mmol),并将得到的混合物在室温搅拌0.5h,并加热至100℃保持15h。将反应用EtOAc稀释,并用5%柠檬酸、饱和NaHCO3水溶液和盐水洗涤。将有机层经Na2SO4干燥,过滤并浓缩以提供粗产物,将其通过硅胶色谱法(EtOAc:石油醚)纯化以产生标题化合物。1H NMR(400MHz,CDCl3)δ4.99-5.12(m,1H),1.45(s,9H),1.26(br s,2H),1.11(br s,2H)。
步骤2:亚硝基(1-(三氟甲基)环丙基)氨基甲酸叔丁酯:在-30℃将四氟硼酸亚硝(78mg,0.67mmol)分成小份加入(1-(三氟甲基)环丙基)氨基甲酸叔丁酯(100mg,0.440mmol)在吡啶(0.2mL)和乙腈(2mL)中的溶液中。将溶液在-30℃搅拌30min,然后温热至0℃保持2h。将反应在减压下浓缩以产生粗产物,将其通过制备型TLC(EtOAc:石油醚)纯化以提供标题化合物。1H NMR(400MHz,CDCl3)δ1.69(s,9H),1.57-1.62(m,4H)。
步骤3:(1-(三氟甲基)环丙基)肼:将在MeOH(2mL)中的亚硝基(1-(三氟甲基)环丙基)氨基甲酸叔丁酯(100mg,0.390mmol)在-78℃搅拌30min。在-78℃加入HCl(0.32mL,3.9mmol,37%水溶液)和锌(257mg,3.93mmol),并将得到的混合物搅拌2h。将反应温热至室温,过滤并浓缩以提供标题化合物,将其不经纯化继续使用。LCMS[M+H]+=141.0(计算值141.1)。
中间体G2-1
(2-(二氟甲氧基)苯基)肼
将THF(1ml)加入NaOtBu(129mg,1.35mmol)和X-PHOS Pd G2(10.6mg,0.0130mmol)的混合物中。加入1-溴-2-(二氟甲氧基)苯(300mg,1.35mmol),并将混合物在室温搅拌10min。一次性加入肼(42μL,1.3mmol),将管形瓶加热至90℃(预热浴)并搅拌12h。将反应冷却至室温,用MeOH稀释并过滤。将滤液浓缩至干燥,并将粗制混合物通过反相制备型-HPLC(C18固定相,ACN/水+0.1%TFA)纯化以提供标题化合物。LCMS[M+H]+=175.0(计算值175.1)。
表G.使用适当的起始材料使用与在中间体G2-1中描述的那些类似的程序制备下列化合物.
中间体H4-1
5-氨基-1-((四氢-2H-吡喃-4-基)甲基)-1H-吡唑-4-甲酸
步骤1:5-氨基-1-((四氢-2H-吡喃-4-基)甲基)-1H-吡唑-4-甲酸乙酯:在0℃将氢化钠(30.9mg,1.29mmol)加入5-氨基-1H-吡唑-4-甲酸乙酯(100mg,0.650mmol)在ACN(1mL)中的搅拌溶液中。1h以后,加入4-(溴甲基)四氢-2H-吡喃(173mg,0.970mmol),并将得到的混合物加热至80℃保持12h。将反应冷却至室温并用饱和NH4Cl水溶液淬灭。将水相用EtOAc萃取,并将合并的有机层经Na2SO4干燥,过滤并在减压下浓缩。将粗产物通过制备型反相HPLC(C18固定相,ACN/水+0.04%NH4OH)纯化以提供标题化合物。LCMS[M+H]+=254.2无水(计算值254.1)。
步骤2:5-氨基-1-((四氢-2H-吡喃-4-基)甲基)-1H-吡唑-4-甲酸:向5-氨基-1-((四氢-2H-吡喃-4-基)甲基)-1H-吡唑-4-甲酸乙酯(100mg,0.400mmol)在EtOH(1mL)和H2O(0.2mL)中的溶液中加入LiOH·H2O(20mg,0.47mmol),并将得到的混合物加热至60℃保持12h。将混合物浓缩以产生粗产物,将其不经任何纯化地用在下一步中。LCMS[M+H]+=226.0(计算值226.1)。
表H.使用适当的起始材料使用与在中间体H4-1中描述的那些类似的程序制备下列化合物.
中间体I4-1
5-氨基-1-(1-(三氟甲基)环丙基)-1H-吡唑-4-甲酸
步骤1:5-氨基-1-(1-(三氟甲基)环丙基)-1H-吡唑-4-甲酸乙酯:将(1-(三氟甲基)环丙基)肼(50mg,0.36mmol)、2-氰基-3-乙氧基丙烯酸甲酯(56mg,0.36mmol)和DIEA(0.31mL,1.8mmol)在EtOH(1mL)中的溶液加热至80℃保持12h。将反应冷却至室温,并在减压下浓缩以产生粗产物,将其通过制备型TLC(EtOAc:石油醚)纯化以提供标题化合物。LCMS[M+H]+=264.1(计算值264.1)。
步骤2:5-氨基-1-(1-(三氟甲基)环丙基)-1H-吡唑-4-甲酸:向5-氨基-1-(1-(三氟甲基)环丙基)-1H-吡唑-4-甲酸乙酯(50mg,0.20mmol)在MeOH(2mL)和H2O(0.5mL)中的溶液中加入LiOH·H2O(42.1mg,1.0mmol)。将得到的混合物加热至70℃保持5h。将反应冷却至室温,浓缩,用1M HCl酸化至pH 2,并用EtOAc萃取。将合并的有机层经Na2SO4干燥,过滤,并在减压下浓缩以产生粗产物,将其不经进一步纯化地继续使用。LCMS[M+H]+=235.9(计算值236.1)。
中间体I4-2
按照与上面关于中间体I4-1描述的那些类似的程序制备中间体I4-2。LCMS[M+H]+=210.1(计算值210.0)。
中间体L3-1
(R,E/Z)-2-(6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-
1′-羰基)-3-乙氧基丙烯腈
步骤1:3-(6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′- 基)-3-氧代丙腈:将DIEA(7.06mL,40.4mmol)加入6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-鎓氯化物(4.14g,13.5mmol)和2-氰基乙酸(1.26g,14.8mmol)在EtOAc(41mL)和DMF(6.2mL)中的溶液中。加入1-丙基膦酸酐(1-Propanephonicanhydride)(9.60ml,16.2mmol),并将得到的混合物在室温搅拌过夜。将反应用H2O淬灭,并用EtOAc萃取。将合并的有机层用盐水洗涤,经MgSO4干燥并浓缩以提供粗残余物,将其通过硅胶色谱法(((3:1)EtOH:EtOAc):己烷)纯化以提供标题化合物。LCMS[M+H]+=337.9(计算值338.1)。
步骤2:(R,E/Z)-2-(6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌 啶]-1′-羰基)-3-乙氧基丙烯腈:将ZnCl2(无水,303mg,2.21mmol)加入在原甲酸三乙酯(18.5mL,111mmol)和NMP(0.8mL)中的3-(6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-基)-3-氧代丙腈(2.50g,7.40mmol)中,并将反应混合物加热至130℃保持4h。将反应冷却至室温,用饱和NaHCO3水溶液淬灭,并用EtOAc萃取。将合并的有机层经MgSO4干燥,过滤,并浓缩以提供粗残余物,将其通过硅胶色谱法(EtOAc:己烷)纯化以提供标题化合物。LCMS[M+H]+=394.0(计算值394.1)。
中间体L3-2
(R)-2-(6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-羰
基)-3-羟基丙烯腈
将THF(15mL)加入(R)-3-(6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-基)-3-氧代丙腈(1.82g,4.43mmol)和甲酸甲酯(3.99g,66.5mmol)的混合物中。将反应混合物声处理以溶解固体,随后逐滴加入KOtBu溶液(14.2mL,14.2mmol,1M在THF中),并将得到的混合物在室温搅拌12h。将反应用H2O稀释,用1M HCl中和至pH 6,并用EtOAc萃取。将合并的有机层经MgSO4干燥,过滤并浓缩以提供粗制的标题化合物,将其不经任何纯化地用于下一步。LCMS[M+H]+=366.4(计算值366.1)。
实施例1
(R)-1′-(5-氨基-1-(2,2,2-三氟乙基)-1H-吡唑-4-羰基)-6-氯-5-氟螺[苯并[d]
[1,3]噁嗪-4,3′-哌啶]-2(1H)-酮
将(R,E/Z)-2-(6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-羰基)-3-乙氧基丙烯腈(0.25mL,0.10mmol,在EtOH中的0.4M储备溶液)加入含有(2,2,2-三氟乙基)肼(17mg,0.15mmol)的管形瓶中。将TEA(42μL,0.30mmol)加入管形瓶中,并将混合物加热至70℃保持12h。将反应冷却至室温,并通过制备型反相HPLC(C18固定相,ACN/水+0.05%TFA)直接纯化以提供标题化合物.:1H NMR(500MHz,CD3OD)δ7.55(s,1H),7.43(t,J=8.1Hz,1H),6.74(d,J=8.6Hz,1H),4.76-4.66(m,3H),4.46(d,J=13.3Hz,1H),3.53(s,1H),3.24-3.16(m,1H),2.52(t,J=11.5Hz,1H),2.30(d,J=13.6Hz,1H),2.17(q,J=10.4Hz,1H),1.73(d,J=12.7Hz,1H)。LCMS[M+H]+=462.3(计算值462.1)。
实施例2
(R)-1′-(5-氨基-1-(2,2,2-三氟乙基)-1H-吡唑-4-羰基)-6-氯-5-氟-5′,5′-二
甲基螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-2(1H)-酮
给3mL管形瓶装入在DMF(0.2mL)中的(R)-6-氯-5-氟-5′,5′-二甲基螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-2(1H)-酮(67mg,0.20mmol)和5-氨基-1-(2,2,2-三氟乙基)-1H-吡唑-4-甲酸(84mg,0.40mmol)。向该混合物中,加入TEA(0.14mL,1.0mmol),随后加入T3P(0.18μL,0.6mmol,50%w/v在DMF中),并将得到的混合物在室温搅拌2h。将反应混合物通过制备型反相HPLC(C18固定相,ACN/水+0.05%HCO2H)直接纯化以提供标题化合物。1H NMR(500MHz,CD3OD)δ7.62(s,1H),7.44-7.40(m,1H),6.74(dd,J=8.7,1.1Hz,1H),4.79-4.70(m,3H),4.27(d,J=12.9Hz,1H),3.73(s,1H),2.97(d,J=12.4Hz,1H),2.17-2.03(m,2H),1.24(s,3H),1.03(s,3H)。LCMS[M+H]+=490.4(计算值490.1)。
实施例3和4
(R)-1′-(5-氨基-1-((R)-1,1,1-三氟丁烷-2-基)-1H-吡唑-4-羰基)-6-氯-5-氟
螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-2(1H)-酮和(R)-1′-(5-氨基-1-((S)-1,1,1-三氟丁
烷-2-基)-1H-吡唑-4-羰基)-6-氯-5-氟螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-2(1H)-酮
将(R)-2-(6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-羰基)-3-羟基丙烯腈(0.25mL,0.01mmol,在AcOH中的0.4M储备溶液)加入含有R-和S-(1,1,1-三氟丁烷-2-基)肼(31mg,0.15mmol)的管形瓶中,并将得到的混合物加热至80℃保持12h。将粗制混合物通过制备型反相HPLC(C18固定相,ACN/水+0.05%TFA)直接纯化以提供标题化合物的非对映异构体的混合物。将标题化合物通过制备型手性SFC用方法A拆分。得到标题化合物的较快洗脱的异构体(实施例3):1H NMR(400MHz,CD3OD)δ7.57(s,1H),7.41(dd,J=8.6,7.8Hz,1H),6.72(dd,J=8.7,1.3Hz,1H),4.74-4.81(m,1H),4.68(br d,J=13.4Hz,1H),4.45(br d,J=12.2Hz,1H),3.43-3.58(m,1H),3.05-3.25(m,1H),2.42-2.58(m,1H),2.24-2.34(m,2H),2.11-2.22(m,1H),1.95-2.07(m,1H),1.72(dt,J=11.3,2.2Hz,1H),0.82(t,J=7.3Hz,3H)。LCMS[M+H]+=490.1(计算值490.1)。得到标题化合物的较慢洗脱的异构体(实施例4)。1H NMR(400MHz,CD3OD)δ7.57(s,1H),7.41(dd,J=8.7,7.7Hz,1H),6.73(dd,J=8.7,1.3Hz,1H),4.76-4.80(m,1H),4.68(br d,J=14.9Hz,1H),4.46(br d,J=11.5Hz,1H),3.41-3.62(m,1H),3.02-3.25(m,1H),2.45-2.60(m,1H),2.22-2.36(m,2H),2.10-2.22(m,1H),2.00(dqd,J=14.1,7.3,3.9Hz,1H),1.65-1.77(m,1H),0.80-0.88(m,3H)。LCMS[M+H]+=490.2(计算值490.1)。
表1.按照与关于实施例1-4描述的程序类似的程序,使用适当的起始材料制备下列化合物.
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表2.按照与关于实施例3和4描述的程序类似的程序,使用适当的起始材料制备下列化合物。使用在表中指定的手性SFC方法分离非对映异构体产物。对于那些非对映异构体对,快速洗脱的异构体列在第一位。
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实施例132
(R)-6-氯-5-氟-1′-(1-(4-氟苄基)-5-羟基-1H-吡唑-4-羰基)螺[苯并[d][1,3]
噁嗪-4,3′-哌啶]-2(1H)-酮
步骤1:1-(4-氟苄基)-5-羟基-1H-吡唑-4-甲酸乙酯:向(4-氟苄基)肼盐酸盐(650mg,3.68mmol)和2-(乙氧基亚甲基)丙二酸二乙酯(875mg,4.05mmol)在H2O(3mL)中的溶液中加入K2CO3(1.27g,9.20mmol),并将得到的混合物加热至100℃保持3h。将反应冷却至室温,并将混合物用EtOAc洗涤。将水相用1M HCl酸化至pH 2,并用EtOAc萃取。将有机层经Na2SO4干燥,过滤,并在减压下浓缩以产生粗制的标题化合物,将其不经进一步纯化地继续使用。LCMS[M+H]+=265.0(计算值265.1)。
步骤2:1-(4-氟苄基)-5-羟基-1H-吡唑-4-甲酸:向1-(4-氟苄基)-5-羟基-1H-吡唑-4-甲酸乙酯(25mg,0.095mmol)在EtOH(1mL)和H2O(0.2mL)中的溶液中加入NaOH(38mg,0.95mmol),并将得到的混合物加热至90℃保持4h。将反应冷却至室温,并浓缩以提供粗残余物,将其用1M HCl酸化至pH 2,并用EtOAc萃取。将有机层经Na2SO4-干燥,过滤,并在减压下浓缩以产生粗制的标题化合物,将其不经进一步纯化地继续使用。LCMS[M+H]+=237.0(计算值237.1)。
步骤3:(R)-6-氯-5-氟-1′-(1-(4-氟苄基)-5-羟基-1H-吡唑-4-羰基)螺[苯并[d] [1,3]噁嗪-4.3′-哌啶]-2(1H)-酮:向1-(4-氟苄基)-5-羟基-1H-吡唑-4-甲酸(20mg,0.085mmol)和(R)-6-氯-5-氟螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-2(1H)-酮(31mg,0.085mmol)在ACN(2mL)中的溶液中加入TCFH(26mg,0.093mmol)和1-甲基咪唑(21mg,0.25mmol),并将得到的混合物在室温搅拌12h。将反应浓缩以提供粗残余物,将其通过制备型反相HPLC(C18固定相,ACN/水+0.1%TFA)纯化以提供标题化合物的非对映异构体的混合物。1H NMR(500MHz,CD3OD)δ7.91(br s,1H),7.46(t,J=8.2Hz,1H),7.32(br s,2H),7.09(br t,J=8.5Hz,2H),6.76(br d,J=8.4Hz,1H),5.13(br s,2H),4.36(s,2H),3.19(br s,2H),2.52(br s,1H),2.31(br d,J=13.7Hz,1H),2.17(br d,J=13.1Hz,1H),1.75(br d,J=14.5Hz,1H)。LCMS[M+H]+=489.1(计算值489.1)。
实施例133
(R)-1′-(5-氨基-1-苄基-1H-1,2,3-三唑-4-羰基)-6-氯-5-氟螺[苯并[d][1,3]
噁嗪-4,3′-哌啶]-2(1H)-酮
给4mL管形瓶装入在DMF(5mL)中的(R)-6-氯-5-氟-2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,3′-哌啶]-1′-鎓2,2,2-三氟乙酸盐(50mg,0.13mmol)和5-氨基-1-苄基-1H-1,2,3-三唑-4-甲酸(28mg,0.13mmol)。向该混合物中,加入DIEA(23μL,0.13mmol),随后一次性加入HATU(49mg,0.13mmol),并使得到的混合物在室温搅拌2h。将反应混合物通过制备型反相HPLC(C18固定相,ACN/水+0.05%TFA)直接纯化以提供标题化合物。1H NMR(500MHz,CD3OD)δ7.91(br s,1H),7.46(t,J=8.2Hz,1H),7.32(br s,2H),7.09(brt,J=8.5Hz,2H),6.76(br d,J=8.4Hz,1H),5.13(br s,2H),4.36(s,2H),3.19(br s,2H),2.52(br s,1H),2.31(br d,J=13.7Hz,1H),2.17(br d,J=13.1Hz,1H),1.75(br d,J=14.5Hz,1H)。LCMS[M+H]+=489.1(计算值489.1)。
因子XIa测定
使用有关的纯化的丝氨酸蛋白酶和适当的合成底物,可以确定本发明的化合物作为凝血因子XIa的抑制剂的有效性。在不存在和存在本发明的化合物的情况下,测量有关的丝氨酸蛋白酶对生色或荧光底物的水解速率。在室温或在37℃进行测定。底物的水解导致氨基三氟甲基香豆素(AFC)的释放,通过在405nm激发下测量在510nm的发射的增加,通过荧光光谱法对其进行监测。在抑制剂存在下荧光变化率的降低指示酶抑制。这样的方法是本领域技术人员已知的。将该测定的结果表示为半数最大抑制浓度(IC50)或抑制常数Ki。
将化合物与人(0.04nM)因子XIa一起在含有150mM氯化钠、5mM氯化钙、0.1%PEG8000的pH 7.4的50mM HEPES缓冲液中在25℃预温育30分钟。通过添加底物甘氨酸-脯氨酸-精氨酸-7-酰氨基-4-三氟甲基香豆素(GPR-AFC)并在25℃温育60分钟以后在400/505nm测量荧光来确定因子XIa酶活性。从数据计算每个数据点的抑制百分比,并使用log(抑制剂)相对于应答的四参数方程进行分析以确定半数最大抑制浓度(IC50)。使用Cheng-Prusoff方程将IC50转化成平衡抑制常数(Ki)。
该测定显示的活性指示,本发明的化合物可以在治疗上用于在遭受不稳定型心绞痛、急性冠状动脉综合征、顽固性心绞痛、心肌梗塞、短暂缺血发作、心房颤动、中风诸如血栓性中风或栓塞性中风、静脉血栓形成、冠状动脉和脑动脉血栓形成、脑和肺栓塞、动脉粥样硬化、深静脉血栓形成、弥散性血管内凝血和再通血管的再阻塞或再狭窄的患者中治疗或预防各种心血管和/或脑血管血栓栓塞性病症。
血浆激肽释放酶测定
使用有关的纯化的丝氨酸蛋白酶和适当的合成底物,可以确定本发明的化合物作为血浆激肽释放酶的抑制剂的有效性。在不存在和存在本发明的化合物的情况下,测量有关的丝氨酸蛋白酶对生色或荧光底物的水解速率。在室温或在37℃进行测定。底物的水解导致氨基三氟甲基香豆素(AFC)的释放,通过在405nm激发下测量在510nm的发射的增加,通过荧光光谱法对其进行监测。在抑制剂存在下荧光变化率的降低指示酶抑制。这样的方法是本领域技术人员已知的。将该测定的结果表示为半数最大抑制浓度(IC50)或抑制常数Ki。
在含有150mM NaCl、5mM CaCl2和0.1%PEG 8000(聚乙二醇;Fisher Scientific)的pH 7.4的50mM HEPES缓冲液中进行血浆激肽释放酶测定。使用终浓度为0.5nM的纯化的人血浆激肽释放酶(Enzyme Research Laboratories)和浓度为100mM的合成底物乙酰基-K-P-R-AFC(Sigma#C6608)进行测定。
通过在含有酶或用抑制剂平衡的酶的溶液中将底物储备溶液稀释至少十倍至终浓度≤0.2Km来进行活性测定。在对照实验中确定实现酶和抑制剂之间的平衡所需的时间。在线性进展曲线条件下进行反应,并在405Ex/510Em nm测量荧光增加。将值转换为对照反应的抑制百分比(减去100%抑制值以后)。从四参数逻辑曲线拟合的拐点确定IC50。使用Cheng Prusoff方程Ki=IC50/(1+([S]/Km))计算Ki。
该测定显示的活性指示,本发明的化合物可以在治疗上用于在遭受不稳定型心绞痛、急性冠状动脉综合征、顽固性心绞痛、心肌梗塞、短暂缺血发作、心房颤动、中风诸如血栓性中风或栓塞性中风、静脉血栓形成、冠状动脉和脑动脉血栓形成、脑和肺栓塞、动脉粥样硬化、深静脉血栓形成、弥散性血管内凝血、再通血管的再阻塞或再狭窄、遗传性血管性水肿、葡萄膜炎、后葡萄膜炎、湿性年龄相关性黄斑水肿、糖尿病性黄斑水肿、糖尿病性视网膜病变和视网膜静脉闭塞的患者中治疗或预防各种眼科、心血管和/或脑血管血栓栓塞性病症。
所选化合物的血浆激肽释放酶IC50(nM)和FXIa IC50(nM)如下:
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Claims (18)
1.下式的化合物或其药学上可接受的盐:
其中X是N或CH;
R1选自氢、卤素、羟基和C1-6烷基;
R2选自氢、卤素、羟基和C1-6烷基;
R3选自氢、卤素、羟基和C1-6烷基,其中所述烷基任选地被1-4个取代基取代,所述取代基独立地选自卤素、氰基和ORx;
R4选自氢、卤素、羟基和C1-6烷基;其中所述烷基任选地被1-4个取代基取代,所述取代基独立地选自卤素、氰基和ORx;
R5是NR9R10或ORx;
每个R6独立地选自氢、卤素、羟基和C1-6烷基,其中所述烷基任选地被1-3个卤素取代;
每个R7选自氢、卤素、羟基和C1-6烷基,其中所述烷基任选地被1-3个卤素取代;
或R6和R7可以与它们所连接的碳原子一起形成3-6元环烷基,所述环烷基任选地被一个或两个卤素取代;
R8选自氢;卤素;羟基;Rx;ORx;苯基;茚满;ORy;可以是单环或二环的杂芳基;杂环基;和可以是单环或二环的C3-6环烷基;其中所述苯基和杂芳基任选地被1-3个取代基取代,所述取代基独立地选自氧代、卤素、Rx、ORx、NR9R10、NR9(C=O)Rx、NR9(C=O)ORx、(C=O)ORx、(C=O)NR9、Ry和ORy;其中所述环烷基和杂环基任选地被1-3个取代基取代,所述取代基独立地选自氧代、卤素、Rx和ORx;
R9是氢或C1-3烷基;
R10是氢或C1-3烷基;
Rx是氢或C1-6烷基,所述C1-6烷基任选地被1-3个选自卤素和羟基的取代基取代,
Ry是苯基、杂环基或C3-6环烷基,其中所述苯基任选地被1-3个卤素取代,所述杂环基任选地被1或2个氧代取代,且所述环烷基任选地被C1-6烷基取代;
n是0-2的整数。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中R1是卤素;R2是卤素。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐,其中R3是氢或甲基;R4是氢或甲基。
4.根据权利要求1-3中的任一项所述的化合物或其药学上可接受的盐,其中R5是NH2。
5.根据权利要求1-4中的任一项所述的化合物或其药学上可接受的盐,其中n是0或1。
6.根据权利要求1-5中的任一项所述的化合物或其药学上可接受的盐,其中R8是苯基;其中所述苯基任选地被1-3个取代基取代,所述取代基独立地选自卤素、Rx、ORx、NR9R10、NR9(C=O)Rx、NR9(C=O)ORx、(C=O)NR9、(C=O)ORx、Ry和ORy。
7.根据权利要求1-6中的任一项所述的化合物或其药学上可接受的盐,其中R8是苯基;其中所述苯基任选地被1-3个取代基取代,所述取代基独立地选自卤素、Rx、ORx、Ry和ORy。
8.根据权利要求1-7中的任一项所述的化合物或其药学上可接受的盐,其中n是1;R6是氢;R7是氢。
9.根据权利要求1所述的化合物或其药学上可接受的盐,所述化合物选自化合物1-133中的任一种。
10.药物组合物,其包含根据权利要求1-9中的任一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
11.用于在哺乳动物中治疗视力活动受损、糖尿病性视网膜病变、糖尿病性黄斑水肿、视网膜静脉闭塞、遗传性血管性水肿、糖尿病、胰腺炎、脑出血、肾病、心肌病、神经病、炎性肠病、关节炎、炎症、脓毒性休克、低血压、癌症、成人呼吸窘迫综合征、弥散性血管内凝血、心肺旁路手术期间的血液凝固或术后出血的方法,所述方法包括向有此需要的哺乳动物施用根据权利要求10所述的组合物。
12.用于在哺乳动物中治疗葡萄膜炎、后葡萄膜炎、湿性年龄相关性黄斑水肿、糖尿病性黄斑水肿、糖尿病性视网膜病变或视网膜静脉闭塞的方法,所述方法包括向有此需要的哺乳动物施用根据权利要求10所述的组合物。
13.在哺乳动物中治疗糖尿病性视网膜病变或糖尿病性黄斑水肿的方法,所述方法包括向有此需要的哺乳动物施用根据权利要求10所述的组合物。
14.在哺乳动物中治疗视网膜静脉闭塞的方法,所述方法包括向有此需要的哺乳动物施用根据权利要求10所述的组合物。
15.根据权利要求1-9中的任一项所述的化合物或其药学上可接受的盐,其用于制备药物,所述药物用于在有此需要的哺乳动物中治疗葡萄膜炎、后葡萄膜炎、湿性年龄相关性黄斑水肿、糖尿病性黄斑水肿、糖尿病性视网膜病变或视网膜静脉闭塞。
16.根据权利要求1-9中的任一项所述的化合物或其药学上可接受的盐,其用于治疗。
17.根据权利要求10所述的组合物,所述组合物进一步包含选自以下的另一种药剂:抗炎剂、抗-VEGF剂、免疫抑制剂、抗凝血剂、抗血小板剂和血栓溶解剂。
18.根据权利要求11所述的方法,进一步包含选自以下的另一种药剂:抗炎剂、抗-VEGF剂、免疫抑制剂、抗凝血剂、抗血小板剂和血栓溶解剂。
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KR20080087817A (ko) * | 2005-12-14 | 2008-10-01 | 브리스톨-마이어스 스큅 컴퍼니 | 인자 xia 억제제로서 아릴프로피온아미드,아릴아크릴아미드, 아릴프로핀아미드 또는 아릴메틸우레아유사체 |
EP3134408B1 (en) * | 2014-04-22 | 2020-08-12 | Merck Sharp & Dohme Corp. | FACTOR XIa INHIBITORS |
EP3371162B1 (en) * | 2015-10-29 | 2022-01-26 | Merck Sharp & Dohme Corp. | Macrocyclic spirocarbamate derivatives as factor xia inhibitors, pharmaceutically acceptable compositions and their use |
-
2021
- 2021-11-18 JP JP2023529952A patent/JP2023551150A/ja active Pending
- 2021-11-18 KR KR1020237019976A patent/KR20230110544A/ko unknown
- 2021-11-18 MX MX2023005855A patent/MX2023005855A/es unknown
- 2021-11-18 CA CA3198550A patent/CA3198550A1/en active Pending
- 2021-11-18 EP EP21895603.5A patent/EP4247372A1/en active Pending
- 2021-11-18 AU AU2021383762A patent/AU2021383762A1/en active Pending
- 2021-11-18 WO PCT/US2021/059930 patent/WO2022109161A1/en active Application Filing
- 2021-11-18 CN CN202180077837.4A patent/CN116917293A/zh active Pending
- 2021-11-18 US US18/252,261 patent/US20240025917A1/en active Pending
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WO2022109161A1 (en) | 2022-05-27 |
JP2023551150A (ja) | 2023-12-07 |
CA3198550A1 (en) | 2022-05-27 |
US20240025917A1 (en) | 2024-01-25 |
AU2021383762A1 (en) | 2023-06-15 |
EP4247372A1 (en) | 2023-09-27 |
KR20230110544A (ko) | 2023-07-24 |
MX2023005855A (es) | 2023-06-05 |
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