CN106999450A - 免疫调节剂 - Google Patents
免疫调节剂 Download PDFInfo
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- CN106999450A CN106999450A CN201580060328.5A CN201580060328A CN106999450A CN 106999450 A CN106999450 A CN 106999450A CN 201580060328 A CN201580060328 A CN 201580060328A CN 106999450 A CN106999450 A CN 106999450A
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Classifications
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- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
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Abstract
本文描述调节氧化还原酶吲哚胺2,3‑双加氧酶的化合物,及含有所述化合物的组合物。还提供了此类化合物及组合物用于治疗和/或预防由吲哚胺2,3‑双加氧酶介导的一系列不同疾病、病症及病状,包括癌症及免疫相关病症的用途。
Description
相关申请的交叉引用
本申请要求2014年11月5日提交的美国临时申请序列号62/075,678的优先权,该申请的全部内容以引用的方式并入本文中。
发明背景
吲哚胺2,3-双加氧酶(IDO;也称为IDO1)为在免疫调节中起作用的IFN-γ靶基因。IDO为氧化还原酶并且是在色氨酸至N-甲酰基-犬尿氨酸的转化中催化第一及限速步骤的两种酶之一。其作为在若干细胞群体(包括免疫细胞、内皮细胞及成纤维细胞)中发现的41kD单体存在。IDO在物种之间相对非常保守,其中小鼠与人类在氨基酸水平下共享63%序列同一性。衍生自其晶体结构及定位诱变的数据显示底物结合及底物与铁结合的双加氧酶之间的关系均为活性所必需。已经鉴定与IDO共享44%氨基酸序列同源性的IDO的同源物(IDO2),但其功能与IDO在很大程度上不同。(参见例如Serafini,P.等人,Semin.CancerBiol.,16(1):53-65(2006年2月)及Ball,H.J.等人,Gene,396(1):203-213(2007年7月1日))。
IDO在免疫调节中发挥主要作用,且其免疫抑制功能以若干方式显示。重要地,IDO在T细胞水平下调节免疫性,且在IDO与细胞因子产生之间存在联系(nexus)。此外,肿瘤通过上调IDO频繁地操控免疫功能。因此,调节IDO可对多种疾病、病症及病状具有治疗效果。
在IDO与癌症之间存在病理生理学联系。免疫内稳态破坏紧密涉及肿瘤生长及发展,且在肿瘤微环境中产生IDO似乎帮助肿瘤生长及转移。此外,提高的IDO活性水平与多种不同肿瘤相关(Brandacher,G.等人,Clin.Cancer Res.,12(4):1144-1151(2006年2月15日))。
治疗癌症通常需要手术切除,随后是化学疗法及放射疗法。由于肿瘤细胞通过再生原发肿瘤生长及通常更重要地接种远处转移来基本上逃逸的能力,标准治疗方案显示高度变化程度的长期成功。治疗癌症及癌症相关疾病、病症及病状的最近进展包含使用结合免疫疗法与更传统的化学疗法及放射疗法的组合疗法(combination therapy)。在大多数情形下,与传统化学疗法相比,免疫疗法与较少毒性相关,因为其利用患者自身的免疫系统来鉴定及消除肿瘤细胞。
除癌症以外,除其它病状之外,IDO牵涉免疫抑制、慢性感染及自身免疫疾病或病症(例如类风湿性关节炎)。因此,通过抑制IDO活性来抑制色氨酸降解具有极大治疗价值。此外,当T细胞被妊娠、恶性肿瘤或病毒(例如HIV)抑制时,IDO的抑制剂可用于增强T细胞活化。尽管其作用未如此明确定义,IDO抑制剂也可在治疗患有神经或神经精神疾病或病症(例如抑郁)的患者中发现用途。
已经研发IDO的小分子抑制剂以治疗或预防IDO相关疾病。例如,IDO抑制剂1-甲基-DL-色氨酸、对-(3-苯并呋喃基)-DL-丙氨酸、对-[3-苯并(b)噻吩基]-DL-丙氨酸及6-硝基-L-色氨酸已经用于通过改变色氨酸及色氨酸代谢物的局部细胞外浓度来调节T细胞介导的免疫性(WO 99/29310)。具有IDO抑制活性的化合物进一步报导于PCT公开号WO 2004/094409中。
鉴于吲哚胺2,3-双加氧酶在一系列不同疾病、病症及病状中发挥的作用及目前IDO抑制剂的限制(例如功效),需要新的IDO调节剂及与其相关的组合物及方法。
发明概述
本发明涉及调节氧化还原酶吲哚胺2,3-双加氧酶(IDO)的化合物,及包含所述化合物的组合物(例如药物组合物)。此类化合物(包括其合成方法),及组合物在下文详细地描述。
本发明还涉及此类化合物及组合物用于治疗和/或预防一系列不同的由IDO全部或部分介导的疾病、病症及病状的用途。此类疾病、病症及病状在本文中在别处详细地描述。除非另外指示,否则当在本文中描述本发明化合物的用途时,应理解此类化合物可呈组合物(例如药物组合物)形式。
如下文所讨论的,尽管认为本发明化合物通过抑制IDO实现其活性,不需要对化合物的基础作用机制的精确理解来实践本发明。设想化合物可替代地通过抑制色氨酸-2,3-双加氧酶(TDO)活性来实现其活性。还设想化合物可通过抑制IDO及TDO功能两者来实现其活性。尽管本发明化合物一般在本文中称为IDO抑制剂,应理解术语“IDO抑制剂”包涵单独地通过抑制TDO或IDO起作用的化合物,和/或通过抑制IDO及TDO两者起作用的化合物。
在一个方面中,本发明提供由式(I)表示的化合物:
或其药学上可接受的盐、水合物或溶剂化物,其中,
下标n为1或0;
A为-C(O)-、-NH-、-SO2-、-CH2-或-CHR3-;
B为键、-C(O)-、-NH-、-CH2-或-CHR3-;
T为键、-CH2-、-NH-、-O-、-OCH2-、-C(O)CH2-或-CR3R4-;
其中当A为-NH-且B为-C(O)-时,则T不为-C(R3)(R4)-;
D为N或C(R5);
E为N或C(R6);
V为键、-O-或-C(R5a)2;
G为任选取代的芳基、任选取代的杂芳基或任选取代的9-或10-元稠合双环杂芳基;
当R2连接至标识为J1的环顶点时,J1为CH、N或C(R2);
R1及R2独立地为氢、卤素、任选取代的C1-C4卤代烷基、任选取代的C3-C6环烷基、任选取代的3-至6-元环杂烷基、任选取代的苯基、任选取代的杂芳基、任选取代的C1-C4烷基、任选取代的C1-C4烷氧基、CN、SO2NH2、NHSO2CH3、NHSO2CF3、OCF3、SO2CH3、SO2CF3或CONH2,且当R1及R2在苯环的相邻顶点上时,它们可连接在一起形成具有一个或两个独立地选自O、N及S的环顶点的5-或6-元环杂烷基环,其中所述环杂烷基环任选被一个至三个选自氟及C1-C3烷基的成员取代;
R3及R4独立地为氢、任选取代的C1-C6烷基、任选取代的C1-C6卤代烷基、氟、OH、CN、CO2H、C(O)NH2、N(R5a)2、任选取代的-O-C1-C6烷基、-(CR5R5)m-OH、-(CR5R5)m-CO2H、-(CR5R5)m-C(O)NH2、-(CR5R5)m-C(O)NHR5a、-(CR5R5)mN(R5a)2、-NH(CR5R5)mCO2H或-NH(CR5R5)m-C(O)NH2;
各R5独立地为H、F、OH、任选取代的C1-C6烷基或任选取代的-O-C1-C6烷基;
各R5a独立地为H或任选取代的C1-C6烷基;
R6为H、OH、F、任选取代的C1-C6烷基、任选取代的-O-C1-C6烷基或-N(R5a)2;
且各m独立地为1、2或3。
在另一方面中,本发明提供其中式(I)化合物与一种或更多种药学上可接受的赋形剂组合的组合物。
在一些实施方案中,本发明考虑治疗或预防对象(例如人)中的癌症的方法,其包括给予所述对象治疗有效量的至少一种本文所描述的IDO抑制剂。本发明包括治疗或预防对象中的癌症的方法,其通过给予所述对象有效逆转或终止IDO介导的免疫抑制的发展的量的IDO抑制剂。在一些实施方案中,IDO介导的免疫抑制由抗原呈递细胞(APC)介导。
可使用本文所描述的化合物及组合物治疗的癌症的实例包括但不限于:前列腺癌、结肠直肠癌、胰腺癌、子宫颈癌、胃癌、子宫内膜癌、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头部癌、颈部癌、皮肤癌(包括黑素瘤及基底癌)、间皮内膜(mesothelial lining)癌、白血球癌(包括淋巴瘤及白血病)、食道癌、乳癌、肌肉癌、结缔组织癌、肺癌(包括小细胞肺癌及非小细胞癌)、肾上腺癌、甲状腺癌、肾癌或骨癌;胶质母细胞瘤、间皮瘤、肾细胞癌、胃癌、肉瘤、绒膜癌、皮肤基底细胞癌(cutaneous basocellular carcinoma)及睾丸精原细胞瘤。在本发明的一些实施方案中,癌症为黑素瘤、结肠癌、胰腺癌、乳癌、前列腺癌、肺癌、白血病、脑肿瘤、淋巴瘤、肉瘤、卵巢癌、头颈癌、子宫颈癌或卡波西肉瘤(Kaposi's sarcoma)。下文进一步讨论作为用本发明的化合物及组合物治疗的候选物的癌症。
本发明考虑治疗接受骨髓移植或外周血干细胞移植的对象的方法,其通过给予足以增加对肿瘤抗原的延迟型超敏反应、延迟移植后恶性肿瘤的复发时间、增加移植后无复发存活时间和/或增加长期移植后存活率的治疗有效量的IDO抑制剂。
在某些实施方案中,本发明考虑治疗或预防对象(例如人)中的感染性病症(例如病毒感染)的方法,其包括给予所述对象治疗有效量的至少一种IDO抑制剂(例如本发明的新颖抑制剂)。在一些实施方案中,感染性病症为病毒感染(例如慢性病毒感染)、细菌感染或寄生虫感染。在某些实施方案中,病毒感染为人类免疫缺陷病毒或巨细胞病毒。在其它实施方案中,细菌感染为分枝杆菌(Mycobacterium)感染(例如麻风分枝杆菌(Mycobacteriumleprae)或结核分枝杆菌(Mycobacterium tuberculosis))。在还有其它实施方案中,寄生虫感染为杜氏利什曼原虫(Leishmania donovani)、热带利什曼原虫(Leishmaniatropica)、硕大利什曼原虫(Leishmania major)、埃塞俄比亚利什曼原虫(Leishmaniaaethiopica)、墨西哥利什曼原虫(Leishmania mexicana)、恶性疟原虫(Plasmodiumfalciparum)、间日疟原虫(Plasmodium vivax)、卵形疟原虫(Plasmodium ovale)或三日疟原虫(Plasmodium malariae)。在其它实施方案中,感染性病症为真菌感染。
在其它实施方案中,本发明考虑治疗或预防对象(例如人)中的免疫相关疾病、病症或病状的方法,其包括给予所述对象治疗有效量的至少一种IDO抑制剂(例如优选本发明的新颖抑制剂)。下文描述免疫相关疾病、病症及病状的实例。
可通过调节IDO活性全部或部分治疗或预防的其它疾病、病症及病状是本文所描述的IDO抑制剂化合物的候选适应证。
本发明进一步考虑本文所描述的IDO抑制剂与一种或更多种额外药剂的组合的用途。所述一种或更多种额外药剂可具有一些IDO调节活性和/或它们可经由不同作用机制起作用。在一些实施方案中,此类药剂包括放射(例如局部放射疗法或全身放射疗法)和/或非药理学性质的其它治疗模式。当利用组合疗法时,IDO抑制剂及所述一种额外药剂可呈单一组合物或多种组合物的形式,且治疗模式可同时、依序或经由一些其它方案给予。通过举例方式,本发明考虑其中放射期随后为化学治疗期的治疗方案。组合疗法可具有累加或协同效应。下文描述组合疗法的其它益处。
在一些实施方案中,本发明进一步包括本文所描述的IDO抑制剂与骨髓移植、外周血干细胞移植或其它类型的移植疗法的组合的用途。
在特定实施方案中,本发明考虑本文所描述的IDO功能的抑制剂与免疫检查点抑制剂的组合的用途。引起抗原特异性T细胞反应放大的免疫检查点的阻断已显示为人类癌症疗法中的有前景的方法。作为阻断的候选物的免疫检查点(配体及受体)的实例(其中的一些在各种类型的肿瘤细胞中选择性上调)包括PD1(程序性细胞死亡蛋白1)、PDL1(PD1配体)、BTLA(B及T淋巴细胞衰减子)、CTLA4(细胞毒性T-淋巴细胞相关抗原4)、TIM3(T细胞膜蛋白3)、LAG3(淋巴细胞活化基因3)、A2aR(腺苷A2a受体A2aR)及杀伤抑制受体。本文中别处详细地讨论免疫检查点抑制剂及用其的组合疗法。
在其它实施方案中,本发明提供治疗对象中的癌症的方法,其包括给予所述对象治疗有效量的至少一种IDO抑制剂及至少一种化学治疗剂,此类药剂包括但不限于烷基化剂(例如氮芥,诸如苯丁酸氮芥、环磷酰胺、异环磷酰胺(isofamide)、二氯甲基二乙胺、美法仑及尿嘧啶氮芥;氮丙啶,诸如噻替派;甲磺酸酯,诸如白消安(busulfan);核苷类似物(例如吉西他滨);亚硝基脲,诸如卡莫司汀、洛莫司汀及链脲菌素;拓扑异构酶1抑制剂(例如伊立替康);铂络合物,诸如顺铂及卡铂;生物还原性烷基化剂,诸如丝裂霉素、甲基苄肼、达卡巴嗪及六甲蜜胺);DNA链断裂剂(例如博来霉素)、拓扑异构酶II抑制剂(例如安吖啶、放线菌素D、柔红霉素、伊达比星、米托蒽醌、阿霉素、依托泊苷及替尼泊苷);DNA小沟结合剂(例如普卡霉素(plicamydin));抗代谢物(例如叶酸拮抗剂,诸如甲氨蝶呤及三甲曲沙;嘧啶拮抗剂,诸如氟尿嘧啶、氟脱氧尿苷、CB3717、阿扎胞苷、阿糖胞苷及氟尿苷;嘌呤拮抗剂,诸如巯基嘌呤、6-硫鸟嘌呤、氟达拉滨、喷司他丁;天冬酰胺酶(asparginase);及核糖核苷酸还原酶抑制剂,诸如羟基脲);微管蛋白相互作用剂(例如长春新碱、雌氮芥、长春碱、多西他赛(docetaxol)、埃博霉素衍生物及紫杉醇(paclitaxel));激素剂(例如雌激素;结合雌激素;炔雌醇;己烯雌酚;氯烯雌醚(chlortrianisen);双烯雌酚(idenestrol);孕酮,诸如己酸羟孕酮、甲羟孕酮及甲地孕酮;及雄激素,诸如睾酮、丙酸睾酮、氟甲睾酮及甲基睾酮);肾上腺皮质类固醇(例如泼尼松、地塞米松、甲泼尼龙及泼尼松龙);黄体化激素(leutinizinghormone)释放剂或促性腺激素释放激素拮抗剂(例如乙酸亮丙瑞林及乙酸戈舍瑞林);及抗激素抗原(例如他莫昔芬;抗雄激素剂,诸如氟他胺;及抗肾上腺剂,诸如米托坦及氨鲁米特)。本发明还考虑IDO抑制剂与本领域中已知的其它药剂(例如三氧化二砷)及将来研发的其它化学治疗剂的组合的用途。
在涉及治疗癌症的方法的一些实施方案中,给予治疗有效量的IDO抑制剂与至少一种化学治疗剂的组合产生比通过仅给予任一种观察到的癌症存活率高的癌症存活率。在涉及治疗癌症的方法的其它实施方案中,给予治疗有效量的IDO抑制剂与至少一种化学治疗剂的组合引起比通过仅给予一种药剂观察到的肿瘤尺寸或肿瘤生长减少多的肿瘤尺寸减少或肿瘤生长减缓。
在其它实施方案中,本发明考虑治疗或预防对象中的癌症的方法,其包括给予所述对象治疗有效量的至少一种IDO抑制剂及至少一种信号转导抑制剂(STI)。在特定实施方案中,至少一种STI选自bcr/abl激酶抑制剂、表皮生长因子(EGF)受体抑制剂、her-2/neu受体抑制剂及法尼基转移酶抑制剂(FTI)。本文中别处阐述其它候选STI药剂。
本发明还考虑增大对象中肿瘤细胞的排斥反应的方法,其包括给予IDO抑制剂连同至少一种化学治疗剂和/或放射疗法,其中肿瘤细胞的所得排斥反应比通过仅给予IDO抑制剂、化学治疗剂或放射疗法所获得的排斥反应大。
在其它实施方案中,本发明提供治疗对象中的癌症的方法,其包括向所述对象给予治疗有效量的至少一种IDO抑制剂及至少一种除IDO抑制剂外的免疫调节剂。在特定实施方案中,至少一种免疫调节剂选自:CD40L、B7、B7RP1、ant-CD40、抗CD38、抗ICOS、4-IBB配体、树突细胞癌症疫苗、IL2、IL12、ELC/CCL19、SLC/CCL21、MCP-1、IL-4、IL-18、TNF、IL-15、MDC、IFN-α/-β、M-CSF、IL-3、GM-CSF、IL-13及抗IL-10。本文中别处阐述其它候选免疫调节剂。
本发明考虑包括治疗或预防对象(例如人)中的感染性病症(例如病毒感染)的方法的实施方案,所述方法包括给予所述对象治疗有效量的至少一种IDO抑制剂及治疗有效量的抗感染剂。
在本发明的一些实施方案中,额外治疗剂为细胞因子,包括例如粒细胞-巨噬细胞集落刺激因子(GM-CSF)或flt3-配体。本发明也考虑治疗或预防病毒感染(例如慢性病毒感染)的方法,该病毒感染包括但不限于丙型肝炎病毒(HCV)、人类乳头状瘤病毒(HPV)、巨细胞病毒(CMV)、埃巴病毒(Epstein-Barr virus,EBV)、水痘带状疱疹病毒、柯萨奇病毒(coxsackie virus)及人类免疫缺陷病毒(HIV)。下文进一步讨论本文所描述的IDO抑制剂用于治疗(单独或作为组合疗法的组分)感染的用途。
在额外实施方案中,治疗感染性病症经由共同给予疫苗与给予治疗有效量的本发明的IDO抑制剂的组合实现。在一些实施方案中,疫苗为抗病毒疫苗,包括例如抗HIV疫苗。在其它实施方案中,疫苗有效针对结核病或疟疾。在还有其它实施方案中,疫苗为肿瘤疫苗(例如有效针对黑素瘤的疫苗);肿瘤疫苗可包含遗传修饰的肿瘤细胞或遗传修饰的细胞系,包括已经转染以表达粒细胞-巨噬细胞刺激因子(GM-CSF)的遗传修饰的肿瘤细胞或遗传修饰的细胞系。在特定实施方案中,疫苗包括一种或更多种免疫原性肽和/或树突细胞。
在一些实施方案中,本发明考虑使用本文所公开的IDO抑制剂与一种或更多种抗微生物剂的组合的方法。
在涉及通过给予IDO抑制剂及至少一种额外治疗剂治疗感染的某些实施方案中,在给予IDO抑制剂及额外治疗剂两者之后观察到的感染症状与在仅给予任一种之后观察到的相同感染症状相比得到改善。在一些实施方案中,观察到的感染症状可为病毒载量减少、CD4+T细胞计数增加、机会性感染减少、存活时间增加、慢性感染根除或其组合。
附图简述
图1A、1B、1C及1D提供本文所描述的化合物的结构及生物活性。
发明详述
在进一步描述本发明之前,应理解本发明不限于本文所阐述的特定实施方案,且也应理解本文所用的术语仅出于描述特定实施方案的目的,且不意欲为限制性的。
在提供值范围的情况下,应理解除非上下文另外明确指出,否则在那个范围的上限与下限之间的各个中间值(至下限的单位的十分之一)及在那个指定范围内的任何其它指定值或中间值均包涵于本发明内。这些较小范围的上限及下限可独立地包括于较小范围内,且也包涵于本发明中,在所指定范围内受到任何特定排他性限制。在所指定范围包括极限值之一或两者的情况下,排除那些所包括的极限值之一或两者的范围也包括于本发明中。除非另外定义,否则本文所使用的所有技术及科学术语具有与本发明所属领域的普通技术人员通常所理解的相同的含义。
必须注意,除非上下文另外明确说明,否则如本文及随附权利要求书中所用的,单数形式“一(a,an)”及“所述(the)”包括复数指示物。进一步注意,权利要求书可经起草以排除任何任选要素。因此,该陈述意欲与对权利要求要素的叙述结合充当使用诸如“仅仅(solely)”、“仅(only)”及其类似术语的这种排他性术语或使用“否定”限制的前提基础。
本文中讨论的公开物仅仅提供其在本申请的申请日之前的公开内容。另外,所提供公开物的日期可能不同于可能需要独立确认的实际公开日期。
综述
免疫调节异常与宿主免疫系统的肿瘤逃逸紧密相关,引起肿瘤生长及发展。包含化学疗法及放射疗法的传统治疗方法对于患者而言一般难以忍受且由于肿瘤进化以经受住此类治疗而变得较不有效。通过利用患者的自身免疫系统来鉴定及消除肿瘤细胞,免疫疗法具有毒性降低的益处。由于免疫调节酶吲哚胺2,3-双加氧酶的上调包含一种通过肿瘤调控以促进生长的机制,抑制酶活性的药剂(例如小分子化合物)呈现用于预防和/或治疗的有前景的途径。
此外,大量实验数据表明IDO抑制在免疫抑制、肿瘤耐受和/或排斥、慢性感染、HIV感染及自身免疫疾病或病症中的作用。对于患有神经或神经精神疾病或病症(诸如抑郁)的患者,IDO的抑制也可为重要的治疗策略。本文中的化合物、组合物及方法满足对新类别的IDO调节剂的需要。
定义
除非另外指出,否则以下术语意欲具有以下阐述的含义。其它术语在整个说明书别处定义。
除非另外说明,否则术语“烷基”本身或作为另一取代基的一部分,意指具有指定的碳原子数的直链或支链烃基(即C1-8意指一个至八个碳原子)。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基、正庚基、正辛基及其类似烷基。
术语“环烷基”是指具有指出的环原子数(例如C3-6环烷基)且完全饱和或在环顶点之间具有不超过一个双键的烃环。“环烷基”也意指双环及多环烃环,诸如,例如双环[2.2.1]庚烷、双环[2.2.2]辛烷等。
术语“环杂烷基”是指具有指出的环顶点(或成员)数且具有一至五个选自N、O及S的置换一至五个碳顶点的杂原子,且其中氮及硫原子任选被氧化,且氮原子任选被季铵化的环烷基环。环杂烷基可为单环、双环或多环体系。环杂烷基的非限制性实例包括吡咯烷、咪唑烷、吡唑烷、丁内酰胺、戊内酰胺、咪唑啉酮、乙内酰脲、二氧杂环戊烷、邻苯二甲酰亚胺、哌啶、1,4-二噁烷、吗啉、硫代吗啉、硫代吗啉-S-氧化物、硫代吗啉-S,S-氧化物、哌嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氢呋喃、四氢噻吩、奎宁环及其类似物。环杂烷基可经由环碳或杂原子连接至分子的其余部分。
如本文所用,在本文描述的任何化学结构中与单键、双键或叁键相交的波浪线表示单键、双键或叁键与分子的其余部分的连接点。另外,延伸至环(例如苯环)的中心的键意欲表示在任一可用环顶点处的连接。本领域技术人员将理解显示为连接至环的多个取代基将占据提供稳定化合物且另外空间相容的环顶点。对于二价组分,表示意指包括任一方向(正向或反向)。例如,基团“-C(O)NH-”意欲包括在任一方向上的连接:-C(O)NH-或-NHC(O)-,且类似地“-O-CH2CH2-”意欲包括-O-CH2CH2-及-CH2CH2-O-两者。
术语“烷氧基”、“烷氨基”及“烷硫基”(或硫代烷氧基)以其常规含义使用,且指分别经由氧原子、氨基或硫原子连接至分子的其余部分的那些烷基。另外,对于二烷基氨基,烷基部分可相同或不同且也可经组合以形成具有与各自连接的氮原子的3-7元环。因此,表示为二烷基氨基或-NRaRb的基团意欲包括哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基及其类似基团。
除非另外说明,否则术语“卤(halo)”或“卤素(halogen)”本身或作为另一取代基的一部分意指氟、氯、溴或碘原子。另外,诸如“卤代烷基”的术语意欲包括单卤代烷基及多卤代烷基。例如,术语“C1-4卤代烷基”意欲包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基及其类似基团。
除非另外说明,否则术语“芳基”意指多不饱和、通常为芳族的烃基,其可为单环或稠合在一起或共价连接的多个环(高达三个环)。芳基的非限制性实例包括苯基、萘基及联苯(biphenyl)。
术语“杂芳基”是指含有一至五个选自N、O及S的杂原子的芳基(或环),其中氮及硫原子任选被氧化,且氮原子任选被季铵化。杂芳基可经由杂原子连接至分子的其余部分。杂芳基的非限制性实例包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异噁唑基、异苯并呋喃基、异吲哚基、吲嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶(imidazopyridine)、苯并噻唑基(benzothiaxolyl)、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基及其类似基团。杂芳基环的取代基可选自下文描述的可接受取代基。
在一些实施方案中,以上术语(例如“烷基”、“芳基”及“杂芳基”)将任选被取代。以下提供各类基团的所选取代基。
烷基(包括通常称为亚烷基、烯基、炔基及环烷基的那些基团)的任选取代基可为选自以下的各种基团:卤素、-OR′、-NR′R″、-SR′、-SiR′R″R″′、-OC(O)R′、-C(O)R′、-CO2R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R″′、-NR″C(O)2R′、-NH-C(NH2)=NH、-NR′C(NH2)=NH、-NH-C(NH2)=NR′、-S(O)R′、-S(O)2R′、-S(O)2NR′R″、-NR′S(O)2R″、-CN及-NO2,其数目在零至(2m′+1)范围内,其中m′为此类基团中碳原子的总数。R′、R″及R″′各自独立地指氢、未取代的C1-8烷基、未取代的芳基、经1-3个卤素取代的芳基、未取代的C1-8烷基、C1-8烷氧基或C1-8硫代烷氧基或未取代的芳基-C1-4烷基。当R′及R″连接至同一氮原子上时,它们可与氮原子组合以形成3-、4-、5-、6-或7-元环。例如,-NR′R″意欲包括1-吡咯烷基及4-吗啉基。
类似地,芳基及杂芳基的任选取代基不同且一般选自:-卤素、-OR′、-OC(O)R′、-NR′R″、-SR′、-R′、-CN、-NO2、-CO2R′、-CONR′R″、-C(O)R′、-OC(O)NR′R″、-NR″C(O)R′、-NR″C(O)2R′、-NR′-C(O)NR″R″′、-NH-C(NH2)=NH、-NR′C(NH2)=NH、-NH-C(NH2)=NR′、-S(O)R′、-S(O)2R′、-S(O)2NR′R″、-NR′S(O)2R″、-N3、全氟(C1-C4)烷氧基及全氟(C1-C4)烷基,其数目在零至芳环体系上开放价数的总数范围内;且其中R′、R″及R″′独立地选自氢、C1-8烷基、C1-8卤代烷基、C3-6环烷基、C2-8烯基及C2-8炔基。其它合适的取代基包括通过1-4个碳原子的亚烷基系链(tether)连接至环原子的以上芳基取代基中的每一种。
芳基或杂芳基环的相邻原子上的取代基中的两个可任选被式-T-C(O)-(CH2)q-U-的取代基置换,其中T及U独立地为-NH-、-O-、-CH2-或单键,且q为0至2的整数。替代地,芳基或杂芳基环的相邻原子上的取代基中的两个可任选被式-A-(CH2)r-B-的取代基置换,其中A及B独立地为-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-、-S(O)2NR′-或单键,且r为1至3的整数。由此形成的新环的单键之一可任选被双键置换。替代地,芳基或杂芳基环的相邻原子上的取代基中的两个可任选被式-(CH2)s-X-(CH2)t-的取代基置换,其中s及t独立地为0至3的整数,且X为-O-、-NR′-、-S-、-S(O)-、-S(O)2-或-S(O)2NR′-。-NR′-及-S(O)2NR′-中的取代基R′选自氢或未取代的C1-6烷基。
如本文所用,术语“杂原子”意欲包括氧(O)、氮(N)、硫(S)及硅(Si)。
术语“药学上可接受的盐”意欲包括取决于在本文所描述的化合物上发现的特定取代基,用相对无毒的酸或碱制备的活性化合物的盐。当本发明的化合物含有相对酸性官能团时,可通过使此类化合物的中性形式与足够量的所需碱在无溶剂下或在合适的惰性溶剂中接触来获得碱加成盐。自药学上可接受的无机碱衍生的盐的实例包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐及其类似盐。自药学上可接受的有机碱衍生的盐包括伯、仲及叔胺的盐,所述伯、仲及叔胺包括经取代的胺、环状胺、天然存在的胺及其类似物,诸如精氨酸、甜菜碱、咖啡碱、胆碱、N,N'-二苯甲基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺(glucamine)、氨基葡萄糖(glucosamine)、组氨酸、海巴明(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇及其类似物。当本发明的化合物含有相对碱性官能团时,可通过使此类化合物的中性形式与足够量的所需酸在无溶剂下或在合适的惰性溶剂中接触来获得酸加成盐。药学上可接受的酸加成盐的实例包括自无机酸衍生的那些,所述无机酸如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸或亚磷酸及其类似无机酸;以及自相对无毒的有机酸衍生的盐,所述有机酸如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、丁二酸、辛二酸、反丁烯二酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯基磺酸、柠檬酸、酒石酸、甲磺酸及其类似有机酸。还包括氨基酸的盐(诸如精氨酸盐及其类似物),及有机酸(如葡糖醛酸或半乳糖醛酸及其类似酸)的盐(参见例如Berge,S.M.等人,"PharmaceuticalSalts",J.Pharm.Sci.,66:1-19(1977))。本发明的某些特定化合物含有允许化合物转化成碱加成盐或酸加成盐的碱性及酸性官能团两者。
化合物的中性形式可通过使盐与碱或酸接触且以常规方式分离母体化合物而再生。化合物的母体形式与各种盐形式在某些物理性质上不同,诸如在极性溶剂中的溶解性,但出于本发明的目的,在其它方面,盐等效于化合物的母体形式。
除盐形式之外,本发明提供前药形式的化合物。本文所描述的化合物的前药为容易在生理条件下经历化学变化以提供本发明化合物的那些化合物。另外,前药可通过化学或生物化学方法在离体环境中转化成本发明化合物。例如,当前药与合适的酶或化学试剂一起置于经皮贴片储集器中时,其可缓慢转化成本发明化合物。
某些本发明化合物可以未溶剂化形式以及溶剂化形式(包括水合形式)存在。一般而言,溶剂化形式等效于未溶剂化形式,且意欲包涵于本发明范畴内。某些本发明化合物可以多种晶体形式或非晶形式存在。一般而言,所有物理形式均等效用于本发明考虑的用途且意欲在本发明的范畴内。
某些本发明化合物拥有不对称碳原子(光学中心)或双键;外消旋体、非对映异构体、几何异构体、区域异构体(regioisomer)及个别异构体(individual isomer)(例如独立对映异构体(separate enantiomer))都意欲包涵于本发明的范畴内。当显示立体化学描述时,其意指其中异构体之一存在且基本上不含另一异构体的化合物。“基本上不含”另一异构体表明两种异构体的至少80/20比例,更优选90/10或95/5或更高。在一些实施方案中,异构体之一将以至少99%的量存在。
本发明化合物也可在构成此类化合物的原子中的一个或更多个处含有非天然比例的原子同位素。非天然比例的同位素可定义为在自然界中发现的量至由100%所讨论的原子组成的量的范围内。例如,化合物可并入放射性同位素,诸如,例如氚(3H)、碘-125(125I)或碳-14(14C),或非放射性同位素,诸如氘(2H)或碳-13(13C)。此类同位素变体可为在本申请内别处描述的那些提供额外效用。例如,本发明化合物的同位素变体可发现额外效用,包括但不限于作为诊断和/或成像试剂或作为细胞毒性/放射毒性治疗剂。另外,本发明化合物的同位素变体可具有改变的药物动力学及药效学特征,其可有助于治疗期间增强的安全性、耐受性或功效。本发明化合物的所有同位素变体无论是否具有放射性均意欲包涵于本发明的范畴内。
术语“患者”或“对象”可互换使用以指人或非人动物(例如哺乳动物)。
术语“给予/给药(administration,administer)”及其类似术语在其应用于例如对象、细胞、组织、器官或生物流体时是指使例如IDO抑制剂、包含其的药物组合物或诊断剂与对象、细胞、组织、器官或生物流体接触。在细胞的情况下,给予包括使试剂与细胞接触(例如体外或离体)以及使试剂与流体接触,其中流体与细胞接触。
术语“治疗(treat,treating,treatment)”及其类似术语是指在疾病、病症或病状或其症状已经被诊断、观察等之后起始以便暂时或永久地消除、减轻、抑制、缓和或改善折磨对象的疾病、病症或病状的根本病因中的至少一种或与折磨对象的疾病、病症、病状相关的症状中的至少一种的作用过程(诸如给予IDO抑制剂或包含其的药物组合物)。因此,治疗包括抑制(例如阻止疾病、病症或病状或与其相关的临床症状的发展或进一步发展)活动性疾病。
如本文所用的术语“需要治疗”是指由医师或其他照护者作出的对象需要或将受益于治疗的判断。此判断基于在医师或照护者的专门知识范围内的多种因素作出。
术语“预防(prevent,preventing,prevention)”及其类似术语是指一般在对象倾向于患特定疾病、病症或病状的情况下,以暂时或永久地预防、遏制、抑制或减轻对象罹患疾病、病症、病状等的风险(如通过例如临床症状的不存在确定)或延迟其发作的方式起始(例如在疾病、病症、病状或其症状发作之前)的作用过程(诸如给予IDO抑制剂或包含其的药物组合物)。在某些情况下,该术语还指减缓疾病、病症或病状发展或抑制其发展成有害或者另外不希望的状况。
如本文所用的术语“需要预防”是指由医师或其他照护者作出的对象需要或将受益于预防性照护的判断。此判断基于在医师或照护者的专门知识范围内的多种因素作出。
短语“治疗有效量”是指给予对象药剂(单独或作为药物组合物的一部分且呈单一剂量或作为一系列剂量的一部分的),其呈当给予对象时能够对疾病、病症或病状的任何症状、方面或特征具有任何可检测的、积极效果的量。治疗有效量可通过测量相关生理效果确定,且其可结合给药方案及对象病状的诊断分析等调节。通过举例方式,在给予后的特定时间IDO抑制剂(或例如其代谢物)的血清水平的测量值可指示是否已经使用治疗有效量。
短语“呈实现变化的足够量”意指在给予特定疗法之前(例如基线水平)及之后在测量的指示物水平之间存在可检测的差异。指示物包括任何客观参数(例如血清浓度)或主观参数(例如对象的健康感觉)。
术语“小分子”是指具有小于约10kDa,小于约2kDa,或小于约1kDa的分子量的化合物。小分子包括但不限于无机分子、有机分子、含有无机组分的有机分子、包含放射性原子的分子及合成分子。在治疗上,与大分子相比,小分子可更易渗透到细胞,对降解较不敏感,且不大可能引发免疫反应。
如本文所用的术语“IDO抑制剂”、“IDO阻断剂”及与其类似术语是指能够抑制IDO的活性,由此逆转IDO介导的免疫抑制的药剂。IDO抑制剂可为竞争性、非竞争性或不可逆IDO抑制剂。“竞争性IDO抑制剂”为在催化位点可逆地抑制IDO酶活性的化合物;“非竞争性IDO抑制剂”为在非催化位点可逆地抑制IDO酶活性的化合物;且“不可逆IDO抑制剂”为通过与酶形成共价键(或抑制酶功能的其它稳定方式)不可逆地消除IDO酶活性的化合物。多种IDO抑制剂是可商购的(例如5-溴-4-氯-吲哚酚1,3-二乙酸酯及1-甲基-DL-色氨酸(1MT);两者均可购自Sigma-Aldrich,St.Louis,MO)且可用作例如“工具”或“参照”化合物。
术语“配体”是指例如可充当受体的激动剂或拮抗剂的肽、多肽、膜相关或膜结合分子或其复合物。配体包涵天然及合成配体,例如细胞因子、细胞因子变体、类似物、突变蛋白,及衍生自抗体的结合组合物,以及小分子。术语还包涵既不是激动剂也不是拮抗剂,但可结合至受体而不显著影响其生物性质(例如信号传导或黏着)的试剂。此外,术语包括已通过例如化学或重组方法改变为膜结合配体的可溶形式的膜结合配体。配体或受体可为完全细胞内的,即其可存在于胞质溶胶、细胞核或一些其它细胞内区室中。配体与受体的复合物称为“配体-受体复合物”。
术语“抑制剂”及“拮抗剂”或“活化剂”及“激动剂”分别是指例如用于活化例如配体、受体、辅因子、基因、细胞、组织或器官的抑制或活化分子。抑制剂为减少、阻断、防止、延迟活化、灭活、脱敏或下调例如基因、蛋白质、配体、受体或细胞的分子。活化剂为增加、活化、促进、增强活化、敏化或上调例如基因、蛋白质、配体、受体或细胞的分子。抑制剂也可定义为降低、阻断或灭活组成活性的分子。“激动剂”为与靶相互作用以引起或促进靶活化增加的分子。“拮抗剂”为对抗激动剂的作用的分子。拮抗剂防止、降低、抑制或中和激动剂的活性,且拮抗剂也可防止、抑制或减轻靶,例如靶受体的组成活性,甚至在不存在经鉴定激动剂的情况下。
术语“调节(modulate,modulation)”及其类似术语是指分子(例如活化剂或抑制剂)直接或间接增加或减少IDO的功能或活性的能力。调节剂可单独起作用,或其可使用辅因子,例如蛋白质、金属离子或小分子。调节剂的实例包括小分子化合物及其它生物有机分子。小分子化合物的许多库(例如组合库)是可商购的且可充当鉴定调节剂的起点。本领域技术人员能够开发一种或更多种分析(例如生物化学分析或基于细胞的分析),其中此类化合物库可经筛选以便鉴定一种或更多种具有所需性质的化合物;之后,熟练的医药化学家能够通过例如合成及评估其类似物及衍生物来优化此类一种或更多种化合物。合成和/或分子建模研究也可用于鉴定活化剂。
分子的“活性”可描述或指:分子与配体或与受体的结合;催化活性;刺激基因表达或细胞信号传导、分化或成熟的能力;抗原活性;其它分子活性的调节;等等。术语“增殖活性”包括促进例如以下各项、为以下各项所必需或与以下各项专门相关的活性:正常细胞分裂,以及癌症、肿瘤、发育不良、细胞转化、转移及血管生成。
如本文所用,“类似”、“类似活性”、“与...类似的活性”、“类似效果”、“与...类似的效果”及其类似术语为可定量和/或定性观察的相对术语。术语的含义经常取决于使用其的上下文。通过举例方式,均活化受体的两种试剂可自定性观点被视为具有类似效果,但如在技术接受的分析(例如剂量反应分析)或技术接受的动物模型中所测定,如果一种试剂仅能够达到另一试剂的活性的20%,则两种试剂可自定量观点被视为缺乏类似效果。当比较一个结果与另一结果(例如一个结果与参照标准)时,“类似”经常(尽管未必总是)意指一个结果与参照标准偏差小于35%、小于30%、小于25%、小于20%、小于15%、小于10%、小于7%、小于5%、小于4%、小于3%、小于2%或小于1%。在特定实施方案中,如果一个结果与参照标准偏差小于15%、小于10%或小于5%,则其与参照标准类似。通过举例但不限制的方式,活性或效果可指功效、稳定性、溶解性或免疫原性。
“基本上纯的”表明组分占组合物的总含量的大于约50%,且通常总多肽含量的大于约60%。更通常,“基本上纯的”是指其中总组合物的至少75%、至少85%、至少90%或更多为相关组分的组合物。在一些情况下,多肽将占组合物的总含量的大于约90%或大于约95%。
当提及配体/受体、抗体/抗原或其它结合对时,术语“特异性结合”或“选择性结合”表明确定蛋白质及其它生物制剂的异质群体中蛋白质的存在的结合反应。因此,在指定条件下,指定配体结合至特定受体且不以大量结合至样品中所存在的其它蛋白质。所考虑方法的抗体或衍生自抗体的抗原结合位点的结合组合物以任何其它抗体或衍生自其的结合组合物的亲和力的至少两倍大、至少十倍大、至少20倍大或至少100倍大的亲和力结合至其抗原或其变体或突变蛋白。在特定实施方案中,抗体将具有如通过例如斯卡查德分析(Scatchard analysis)(Munsen等人,Analyt.Biochem.,107:220-239(1980))所测定的大于约109升/摩尔的亲和力。
例如细胞、组织、器官或生物体的术语“反应”包括生物化学或生理行为,例如浓度、密度、黏着性或生物区内的迁移、基因表达速率或分化状态的变化,其中该变化与活化、刺激或治疗或与内部机制(诸如遗传编程)相关。在某些情况下,术语“活化”、“刺激”及其类似术语是指如通过内部机制以及通过外部或环境因素调节的细胞活化;而术语“抑制”、“下调”及其类似术语指相反效果。
本文中可互换使用的术语“多肽”、“肽”及“蛋白质”是指任何长度的氨基酸的聚合形式,其可包括遗传编码及非遗传编码的氨基酸、化学或生物化学修饰或衍生的氨基酸及具有经修饰的多肽主链的多肽。术语包括融合蛋白,包括但不限于具有异源氨基酸序列的融合蛋白、具有异源及同源前导序列的融合蛋白,其有或无N-末端甲硫氨酸残基;免疫标记蛋白;及其类似物。
如本文所用的术语“变体”及“同源物”可互换使用以指分别与参考氨基酸或核酸序列类似的氨基酸或DNA序列。该术语包括天然存在的变体及非天然存在的变体。天然存在的变体包括同源物(物种之间分别在氨基酸或核苷酸序列方面不同的多肽及核酸),及等位基因变体(物种内个体之间分别在氨基酸或核苷酸序列方面不同的多肽及核酸)。因此,变体及同源物包括天然存在的DNA序列及由其编码的蛋白质及其同等型,以及蛋白质或基因的剪接变体。该术语还包括在一个或更多个碱基方面与天然存在的DNA序列不同但归因于遗传密码简并仍翻译成与天然存在的蛋白质对应的氨基酸序列的核酸序列。非天然存在的变体及同源物包括分别包含氨基酸或核苷酸序列变化的多肽及核酸,其中序列变化经人工引入(例如突变蛋白);例如变化在实验室中通过人工干预(“人类之手”)产生。因此,非天然存在的变体及同源物也可指与天然存在的序列不同在于一个或更多种保守性取代和/或标记和/或缀合物的那些。
如本文所用的术语“突变蛋白”广泛地指突变重组蛋白。这些蛋白质通常携带单个或多个氨基酸取代且通常衍生自已经受定位诱变或随机诱变的克隆基因或完全合成基因。
术语“DNA”、“核酸”、“核酸分子”、“多核苷酸”及其类似术语可在本文中互换使用以指任何长度的核苷酸的聚合形式(脱氧核糖核苷酸或核糖核苷酸,或其类似物)。多核苷酸的非限制性实例包括线型及环状核酸、信使RNA(mRNA)、互补DNA(cDNA)、重组多核苷酸、载体、探针、引物及其类似物。
吲哚胺2,3-双加氧酶
如先前所提及,IDO为通常在肿瘤细胞中及活化免疫细胞中表达的免疫调节酶。IDO为参与肿瘤免疫逃逸的若干免疫反应检查点中的一种;因此,IDO抑制剂破坏肿瘤逃避身体正常免疫系统的机制。
IDO下调经由色氨酸氧化介导的免疫反应。这引起T细胞活化的抑制及T细胞细胞凋亡的诱导,产生使肿瘤特异性细胞毒性T淋巴细胞功能上灭活或不再能够侵袭对象的癌细胞的环境。因此,旨在通过抑制IDO活性来抑制色氨酸降解的治疗剂为合意的。当T细胞经妊娠、恶性肿瘤或诸如HIV的病毒抑制时,IDO的抑制剂可用于活化T细胞且因此增强T细胞活化。对于患有神经或神经精神疾病或病症(诸如抑郁)的患者,IDO的抑制也可为重要的治疗策略。本文中的化合物、组合物及方法帮助满足目前对IDO调节剂的需要。
IDO的表达通过一系列复杂信号调节,因此涉及多种不同作用机制。例如,IDO可通过DNA甲基转移酶或组蛋白脱乙酰基酶的抑制来诱导。NF-κB信号传导路径还牵涉IDO功能。抑制NF-κB活性阻断IDO表达且产生T细胞相关性及IDO相关性两者稳健性抗肿瘤反应;替代地,NF-κB活化(其可通过诸如干扰素-γR1/-γR2信号传导及toll样受体活化的各种因素来实现)诱导IDO基因表达。
其它机制涉及IDO功能的调节。通过举例方式,反应性氧化物种(ROS)的抑制剂可实现IDO的稳定化;IDO水平可通过抑制或活化IDO下游及上游两者的路径来调节;及干扰素-γ的活化可活化IDO的自分泌诱导。
研究指出IDO路径在许多癌症中具有活性,其既在肿瘤细胞内作为针对T细胞攻击的直接防御,又还在抗原呈递细胞(APC)内在肿瘤-引流淋巴结中引起对肿瘤相关抗原(TAA)的外周耐受。癌症可使用IDO路径来促进表达TAA的可以其它方式被免疫系统识别及攻击的恶性细胞的存活、生长、侵袭及转移。
如本文中所提及,肿瘤组织中通过限速酶IDO的色氨酸分解代谢为IDO抑制剂作为常规化学疗法的治疗替代物或附加物的用途提供机会。然而,某些癌症能够分解代谢色氨酸但很大程度上为IDO阴性。近期研究指出涉及色氨酸分解代谢的色氨酸-2,3-双加氧酶(TDO)的替代酶促路径也在癌症中相关。认为引起在肝脏中调节全身性色氨酸水平的TDO在一些癌症中组成性地表达且也能够抑制抗肿瘤免疫反应(参见例如Platten,M.等人,Cancer Res.,72(21):5435-5440(2012年11月1号))。
IDO在广泛多种人类肿瘤及肿瘤细胞系中以及在宿主APC中表达,其与更糟的临床预后相关。因此,IDO的抑制可改善有IDO介导的免疫抑制的癌症患者的存活率。相比而言,TDO在广泛多种人类肿瘤及肿瘤细胞系中表达,且TDO的表达在晚期人类胶质母细胞瘤中显而易见。表达高水平的IDO或TDO的肿瘤的鉴定可允许更选择性抑制色氨酸调节的免疫抑制路径。替代地,抑制IDO及TDO两者的化合物可提供最大覆盖率以防止肿瘤通过另一色氨酸降解酶的补偿性表达来逃逸。因此,使用双重IDO/TDO抑制剂或IDO-及TDO-特异性抑制剂的组合可证明为在癌症的免疫疗法中用以阻断通过色氨酸代谢介导的免疫抑制的优越的治疗替代方案。
尽管不需要对本发明化合物实现其活性的根本作用机制的精确理解来实践本发明,但认为化合物(或其子集)抑制IDO功能。替代地,化合物(或其子集)可抑制TDO功能。化合物(或其子集)也可对IDO及TDO功能两者具有抑制活性。尽管本发明化合物一般在本文中称为IDO抑制剂,应理解术语“IDO抑制剂”包括单独地经由抑制TDO或IDO起作用的化合物和/或经由抑制IDO及TDO两者起作用的化合物。
鉴定具有合意特征的IDO抑制剂
本发明部分涉及用至少一种具有治疗相关性的性质或特征鉴定IDO抑制剂。候选抑制剂可通过使用例如领域接受的分析或模型鉴定,其实例在本文中描述。
在鉴定之后,可通过使用提供关于抑制剂特征的数据(例如药物动力学参数、测定溶解性或稳定性的方式)的技术进一步评估候选抑制剂。候选抑制剂与参考标准(其可为目前抑制剂的“最佳等级”)的比较是此类候选物的潜在活力的指示。
本发明化合物
如上文所提及,本发明提供由式(I)表示的化合物:
或其药学上可接受的盐、水合物或溶剂化物,其中,
下标n为1或0;
A为-C(O)-、-NH-、-SO2-、-CH2-或-CHR3-;
B为键、-C(O)-、-NH-、-CH2-或-CHR3-;
T为键、-CH2-、-NH-、-O-、-OCH2-、-C(O)CH2-或-CR3R4-;
其中当A为-NH-且B为-C(O)-时,则T不为-C(R3)(R4)-;
D为N或C(R5);
E为N或C(R6);
V为键、-O-或-C(R5a)2;
G为任选取代的芳基、任选取代的杂芳基或任选取代的9-或10-元稠合双环杂芳基;
当R2连接至标识为J1的环顶点时,J1为CH、N或C(R2);
R1及R2独立地为氢、卤素、任选取代的C1-C4卤代烷基、任选取代的C3-C6环烷基、任选取代的3-至6-元环杂烷基、任选取代的苯基、任选取代的杂芳基、任选取代的C1-C4烷基、任选取代的C1-C4烷氧基、CN、SO2NH2、NHSO2CH3、NHSO2CF3、OCF3、SO2CH3、SO2CF3或CONH2,且当R1及R2在苯环的相邻顶点上时,它们可连接在一起形成具有一个或两个独立地选自O、N及S的环顶点的5-或6-元环杂烷基环,其中所述环杂烷基环任选被一个至三个选自氟及C1-C3烷基的成员取代;
R3及R4独立地为氢、任选取代的C1-C6烷基、任选取代的C1-C6卤代烷基、氟、OH、CN、CO2H、C(O)NH2、N(R5a)2、任选取代的-O-C1-C6烷基、-(CR5R5)m-OH、-(CR5R5)m-CO2H、-(CR5R5)m-C(O)NH2、-(CR5R5)m-C(O)NHR5a、-(CR5R5)mN(R5a)2、-NH(CR5R5)mCO2H或-NH(CR5R5)m-C(O)NH2;
各R5独立地为H、F、OH、任选取代的C1-C6烷基或任选取代的-O-C1-C6烷基;
各R5a独立地为H或任选取代的C1-C6烷基;
R6为H、OH、F、任选取代的C1-C6烷基、任选取代的-O-C1-C6烷基或-N(R5a)2;
且各m独立地为1、2或3。
在一些实施方案中,本文提供的化合物具有式(Ia):
在式(Ia)的一些选定实施方案中,提供具有式(Ia1)、(Ia2)或(Ia3)的化合物:
在一些实施方案中,本文提供的化合物具有式(Ib)、(Ic)或(Id):
在一些实施方案中,本文提供的化合物具有式(Ie):
在式(Ie)的一些选定实施方案中,提供具有式(Ie1)的化合物:
在一些实施方案中,本文提供的化合物具有式(If)、(Ig)或(Ih):
在一些实施方案中,本文提供的化合物具有式(Ii)或(Ij):
除非另外提及,否则对于上式(Ia)、(Ia1)、(Ia2)、(Ia3)、(Ib)、(Ic)、(Id)、(Ie)、(Ie1)、(If)、(Ig)、(Ih)、(Ii)及(Ij)中的每一个,下标、字母、J1、R1、R2、R3、R4及R5中的每一个具有参考式(I)提供的含义。
在一组选定实施方案中,提供图1的任一种化合物。
在另一组选定实施方案中,提供具有鉴定为“A”或“B”的活性水平的图1的任一种化合物。
在另一组选定实施方案中,提供具有鉴定为“A”的活性水平的图1的任一种化合物。
合成方法
本发明化合物可由化学文献中已知或可商购的起始物质,通过诸如以下方案中所说明的那些的方法利用有机化学领域的技术人员已知的化学转化来制备。本领域普通技术人员可容易地选择溶剂、温度、压力及其它反应条件。这些方案为说明性的且不意味着限制本领域技术人员可用于制造本文所公开的化合物的可能技术。不同方法对于本领域技术人员而言可能是显而易见的。另外,合成中的多个步骤可以替代顺序或次序进行以得到所需化合物。此外,这些方案中呈离散步骤的反应的表示不排除其以串联形式,通过在相同反应容器中缩短多个步骤或通过在不纯化或表征中间体的情况下进行多个步骤来进行。此外,通过以下方法制备的许多化合物可进一步使用本领域技术人员熟知的常规化学方法改性。所有在本文中引用的文献均以其全文引用的方式并入本文中。
对本文中使用的这些化学转化中许多的参考可在Smith,M.B.等人,March'sAdvanced Organic Chemistry Reactions,Mechanisms,and Structure,第五版,Wiley-Interscience,New York(2001),或关于合成有机化学主题的其它标准文本中找到。某些转化可能需要反应性官能团被保护基掩蔽。为这些基团的引入、移除及对反应条件的相对敏感性提供条件的方便参考为Greene,T.W.等人,Protective Groups in OrganicSynthesis,第三版,Wiley-Interscience,New York(1999)。
(方案1:逆向(reverse)酰胺及磺酰胺,环烷基核,直接或O连接的G)
方案1
用诸如氢化钠的碱在诸如THF(方案1)的溶剂中随后用通式结构II的酮处理膦酰基乙酸酯(III)得到三取代烯烃。III(R3不为H)的经取代类似物提供四取代烯烃。此方法及下文描述的额外方法为有机/医药化学领域的技术人员熟悉的转化。下文描述的烯化及转化的替代方法是已知的且将基于本领域技术人员对考虑中的特定基质的适用性由其选择。还原通过在催化剂,通常为钯/碳存在下在H2氛围或更多下搅拌或振荡烯烃在合适的溶剂中的溶液来实现。缩酮基团的水解得到通式结构IV的酮。通常,此通过用诸如HCl的酸的水溶液在诸如THF的共溶剂存在下加热来实现。除显示的环状基于乙二醇的缩酮外,可使用其它环状及非环状缩酮保护基。酮用诸如LiHMDS的碱去质子化且与N-苯基三氟甲磺酰亚胺或类似试剂反应得到通式结构V的三氟甲磺酸酯。这些三氟甲磺酸酯参与与硼酸或酯G-B(OR)2的Suzuki偶联(T.Ishiyama,M.Murata,N.Miyaura,J.Org.Chem.,1995,60,7508-7510)以得到偶联产物。已知关于此反应的许多变体,但一般而言其涉及在诸如DMF的溶剂中在诸如碳酸钾水溶液的碱下加热两种基质及催化剂(诸如(Ph3P)4Pd)。烯烃的还原提供中间体VI(其中V=键且E=CH)。酮IV可通过NaBH4或类似氢化物还原剂还原以得到通式结构VII的醇。这些醇可用诸如氢化钠或KHMDS的碱去质子化,且所得醇盐可与芳基或杂芳基卤化物在SNAr条件下反应,得到额外中间体VI(其中V=O且E=CH)。替代地,反应可通过用DIAD、DEAD或相关偶氮二羧酸酯及三烷基膦或三芳基膦来活化醇VII且与苯酚或相关杂芳基GOH偶联来实现。(Mitsunobu反应)中间体VI(及随后的中间体)可以顺式与反式异构体的混合物形式获得。控制以上反应的立体化学结果的方法对于有机/医药化学领域的技术人员而言是已知的。另外,分离这些异构体的方法是已知的且详细地描述于合成实例中。必要时,可通过中间体VI的烷基化附加基团R4。控制所得不对称中心的绝对立体化学的方法对于本领域技术人员而言是已知的,手性分离方法也是已知的。一般在有机共溶剂(诸如THF)存在下通过用LiOH水溶液或类似碱加热来皂化酯得到羧酸VIII。酸VIII可通常通过用DPPA及三乙胺加热来重排(Curtius及相关重排反应),且中间体异氰酸酯与碱的水溶液反应以得到伯胺IX。这些可与亲电子剂,包括但不限于酰基氯及磺酰氯XVIa反应以得到本发明化合物I。由IX(其中A为CO)制备化合物I的另一方式使用XVIa的羧酸衍生物及肽偶联试剂。关于肽偶联方法的最新综述参见:Ayman El-Faham及Fernando Albericio.Chem.Rev.2011,111,6557-6602。
(方案2:逆向酰胺及磺酰胺,哌啶核,直接或C连接的G)
方案2
哌啶及吡咯烷酯X为已知化合物且可经历SNAr(V=键)及N-烷基化(V=C(R5a)2)反应以得到中间体VI(E=N)。这些中间体可如方案I中所示转化成本发明化合物I。
(方案3:逆向酰胺及磺酰胺,环烷基或哌啶核,直接C、或O连接的G,替代方法)
方案3
方案3说明通过以不同顺序进行方案1的步骤来制备中间体VI的方法。中间体II可转化成如上文所描述的三氟甲磺酸酯且与硼酸或酯G-B(OR)2偶联以得到中间体XI(V=键)。其中V=O的类似物可通过还原酮II及转化成如上文所描述的醚XI制备。缩酮水解得到酮XII。转化成中间体VI通过如上文所描述的烯化及还原实现。其中E=N的中间体XII可由酮XIII,使用SNAr(V=键)或烷基化(V=C(R5a)2)化学反应来制备。
(方案4:截短标准酰胺,环烷基或哌啶核,直接、C、或O连接的G)
方案4
(T=键,B=CO,A=NH)
方案4说明制备额外的本发明化合物的方法。酮XII可通过使用TosMIC(VanLeusen反应)转化成腈。腈的水解得到酸XIV,其可通过用胺在酰胺偶联条件下处理来转化成本发明化合物I。
(方案5:环己胺或4-氨基哌啶的脲及苯乙酸酰胺(phenylaceticamide),直接、C、或O连接的G)
方案5
方案5说明制备额外的本发明化合物的方法。酮XII可通过用氨或铵盐还原胺化转化成伯胺XV。此反应一般使用氰基硼氢化钠在醇溶剂中进行。用异氰酸酯XVIc处理得到脲,其为本发明化合物I。芳基乙酰胺(本发明化合物I)通过使用试剂,诸如Bop及叔胺碱在诸如DMF的溶剂中偶联胺XV与芳基乙酸XVId来获得。
(方案6:在VI至VIII的转化中绝对立体化学的控制)
方案6
方案6说明控制中间体VIII及由其产生的物质的绝对立体化学的方法。酯VI的皂化提供羧酸XVII。用酰基氯(诸如特戊酰氯)处理这些酸提供混合酸酐中间体。在单独容器中,通过用强碱(诸如n-BuLi)处理将已知立体化学及通式结构XVIII的光学纯噁唑烷酮去质子化。这些活性物种经组合以形成酰基噁唑烷酮XIX,其通过诸如NaHMDS的碱去质子化。所得烯醇化物的烷基化以新形成的中心处的立体化学的可预测控制进行以提供物质XX。移除手性助剂得到光学活性羧酸VIII通过用碱性过氧化氢溶液处理来实现。关于此反应的历史及范畴的综述参见:D.A.Evans,M.D.Ennis,D.J.Mathre.J.Am.Chem.Soc.,1982,104(6),第1737-1739页。
(方案7:其中R6=OH的本发明化合物(I)的合成)
方案7
如方案7中所示,通式结构IV的酮可用可通过本领域技术人员熟知的若干方法产生的锂化物(lithiate)G-Li处理,以产生通式结构XXI的叔醇。通式结构XXXI的酯可经由本文已经描述的方法转化成通式结构I的化合物。替代地,酮IV可用有机金属MgBr-V-G(Grignard试剂)处理以得到通式结构XXII的叔醇。
(方案8:其中R5=OH的本发明化合物(I)的合成)
方案8
如方案8中所示,通式结构XII的酮可用其中X=Br的卤代乙酸酯在锌金属存在下处理(Reformatsky反应)以得到通式结构XXIII的叔醇。酯XXIII可通过本文已经描述的方法转化成本发明化合物(I)。
除以上一般方案以外,本文所描述的化合物可通过如以下实施例中提供的代表性方法制备。
增强抑制剂特征的修饰
经常有利且有时必不可少的是改善本文所公开的治疗模式的更多物理性质之一和/或其给予方式。物理性质的改善包括例如提高水溶性、生物利用度、血清半衰期和/或治疗半衰期和/或调节生物活性的方法。
本领域中已知的修饰包括聚乙二醇化、Fc融合及白蛋白融合。尽管一般与大分子试剂(例如多肽)相关,最近已经用特定小分子评估这种修饰。通过举例方式,Chiang,M.等人(J.Am.Chem.Soc.,136(9):3370-3373(2014))描述缀合至免疫球蛋白Fc结构域的腺苷2a受体的小分子激动剂。小分子-Fc缀合物保留有效Fc受体及腺苷2a受体相互作用且与未缀合的小分子相比显示优越的性质。还已描述PEG分子与小分子治疗剂的共价连接(Li,W.等人,Progress in Polymer Science,38:421-444(2013))。
治疗及预防用途
本发明考虑本文所描述的IDO抑制剂在治疗或预防大范围疾病、病症和/或病状和/或其症状中的用途。虽然下文详细地描述特定用途,应理解本发明不限于此。此外,尽管下文阐述一般类别的特定疾病、病症及病状,一些疾病、病症及病状可为多于一个类别的成员,且其它可不为任一所公开类别的成员。
肿瘤学相关病症.根据本发明,IDO抑制剂可用于治疗或预防增生性病状或病症,包括癌症,例如子宫、子宫颈、乳房、前列腺、睾丸、胃肠道(例如食道、口咽、胃、小肠或大肠、结肠或直肠)、肾脏、肾细胞、膀胱、骨骼、骨髓、皮肤、头部或颈部、肝脏、胆囊、心脏、肺、胰腺、唾液腺、肾上腺、甲状腺、大脑(例如胶质瘤)、神经节、中枢神经系统(CNS)及外周神经系统(PNS)的癌症,及造血系统及免疫系统(例如脾或胸腺)的癌症。本发明还提供治疗或预防其它癌症相关疾病、病症或病状的方法,所述疾病、病症或病状包括例如免疫原性肿瘤、非免疫原性肿瘤、休眠肿瘤、病毒诱导的癌症(例如上皮细胞癌、内皮细胞癌、鳞状细胞癌及乳头状瘤病毒)、腺癌、淋巴瘤、癌瘤(carcinomas)、黑素瘤、白血病、骨髓瘤、肉瘤、畸胎癌、化学诱导的癌症、转移及血管生成。本发明考虑例如通过调节T细胞和/或CD8+T细胞的活性调节来降低对肿瘤细胞或癌细胞抗原的耐受性(参见例如Ramirez-Montagut等人,Oncogene,22:3180-3187(2003);及Sawaya等人,New Engl.J.Med.,349:1501-1509(2003))。在特定实施方案中,肿瘤或癌症为结肠癌、卵巢癌、乳癌、黑素瘤、肺癌、胶质母细胞瘤或白血病。术语癌症相关疾病、病症及病状的使用意欲广泛指与癌症直接或间接相关的病状,且包括例如血管生成及癌前病状,诸如发育不良。
在一些实施方案中,本发明提供用IDO抑制剂及至少一种额外治疗或诊断剂治疗增生性病状、癌症、肿瘤或癌前病状的方法,其实例在本文中别处阐述。
免疫及炎性相关病症.如本文所用,诸如“免疫疾病”、“免疫病状”、“免疫病症”、“炎性疾病”、“炎性病状”、“炎性病症”及其类似术语意欲广泛包括任何免疫或炎性相关病状(例如病理学炎症及自身免疫疾病)。此类病状经常不可避免地与其它疾病、病症及病状纠缠在一起。通过举例方式,“免疫病状”可指增生性病状,诸如癌症、肿瘤及血管生成;包括抵抗免疫系统的根除的感染(急性及慢性)、肿瘤及癌症。
可用本发明的化合物及组合物治疗或预防的免疫及炎性相关疾病、病症及病状的非限制性清单包括关节炎(例如类风湿性关节炎)、肾衰竭、狼疮、哮喘、牛皮癣、结肠炎、胰腺炎、过敏、纤维化、外科手术并发症(例如其中炎性细胞因子防止愈合)、贫血及纤维肌痛。可与慢性炎症相关的其它疾病及病症包括阿尔茨海默病(Alzheimer's disease)、充血性心脏衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松、帕金森氏病(Parkinson's disease)、感染、炎性肠病(例如克罗恩氏病(Crohn's disease)及溃疡性结肠炎)、过敏性接触性皮炎及其它湿疹、全身性硬化症、移植及多发性硬化。
在其它免疫相关病症中,考虑抑制IDO功能也可在免疫耐受性及预防子宫内胎儿排斥反应中起作用。
在一些实施方案中,本文所描述的IDO抑制剂可与免疫抑制剂组合以减少免疫效应细胞的数目。
下文更详细地描述IDO抑制剂可特别有效(归因于例如目前疗法的限制)的前述疾病、病症及病状中的一些。
一般特征在于关节的膜内膜(membrane lining)(滑膜)的慢性炎症的类风湿性关节炎(RA)影响大约1%的美国人口(~210万人)。对细胞因子(包括TNF-α及IL-1)在炎性过程中的作用的进一步理解使得能够开发及引入新类别的疾病改善型抗风湿药物(DMARD)。药剂(其中的一些与RA的治疗模式重叠)包括(依那西普)、(英夫利昔单抗)、(阿达木单抗)及(阿那白滞素)。尽管在特定患者群体中这些药剂中的一些减轻症状、抑制结构破坏的发展及改善物理功能,仍需要具有改善的功效、互补作用机制及较少/较不严重不良作用的替代药剂。
牛皮癣,常见免疫介导性慢性皮肤病的群集,影响大于450万美国人,认为其中的150万具有疾病的中度至严重形式。此外,超过10%患有牛皮癣的患者罹患牛皮癣性关节炎,其损害骨骼及关节周围的结缔组织。对牛皮癣的根本生理学的改善的理解导致引入例如靶向引起疾病的炎性性质的T淋巴细胞及细胞因子活性的药剂。此类药剂包括TNF-α抑制剂(也用于类风湿性关节炎(RA)的治疗),包括(依那西普)、(英夫利昔单抗)及(阿达木单抗);及T细胞抑制剂,诸如(阿法赛特(alefacept))及(依法利珠单抗)。尽管这些药剂中的若干种在一些程度上在某些患者群体中有效,但没有任何一种显示有效治疗所有患者。
罹患多发性硬化(MS)(包含多个炎症区域及脑及脊髓中髓鞘结疤的严重衰弱自身免疫疾病)的对象可尤其受本文所描述的IDO抑制剂帮助,因为目前的治疗仅缓解失能的症状或延迟失能的进程。
类似地,对于罹患神经退化性病症(诸如阿尔茨海默病(AD),严重损害患者的思维、记忆及语言过程的大脑病症;及帕金森病(PD),特征在于例如异常运动、僵硬及颤抖的进行性CNS病症)的对象,IDO抑制剂可特别有利。这些病症为进行性及衰弱的,且无可用的治愈性药剂。
病毒相关病症.本发明考虑IDO抑制剂在治疗和/或预防用IDO抑制剂治疗可能有益的任何病毒性疾病、病症或病状中的用途。在特定实施方案中,病毒性病症为慢性病毒性病症。考虑的病毒性疾病、病症及病状的实例包括但不限于乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、人类乳头状瘤病毒(HPV)、HIV、AIDS(包括其表现,诸如恶病质、痴呆及腹泻)、单纯疱疹病毒(HSV)、埃-巴病毒(EBV)、水痘带状疱疹病毒、柯萨奇病毒及巨细胞病毒(CMV)。
细菌及寄生虫相关病症.本发明的实施方案考虑给予对象本文所描述的IDO抑制剂以便治疗细菌感染,例如分枝杆菌感染(例如麻风分枝杆菌或结核分枝杆菌)或由单核细胞增多性李斯特氏菌(Listeria monocytogenes)或刚地弓形虫(Toxplasma gondii)所引起的感染。其它实施方案考虑治疗寄生虫感染,包括但不限于杜氏利什曼原虫、热带利什曼原虫、硕大利什曼原虫、埃塞俄比亚利什曼原虫、墨西哥利什曼原虫、恶性疟原虫、间日疟原虫、卵形疟原虫或三日疟原虫。通常,抗寄生虫疗法预防性地给予(例如在对象行进至具有高频率寄生虫感染的区域之前)。
药物组合物
本发明的IDO抑制剂可呈适用于给予对象的组合物形式。一般而言,此类组合物为包含IDO抑制剂及一种或更多种药学上可接受或生理上可接受的稀释剂、载体或赋形剂的“药物组合物”。在某些实施方案中,IDO抑制剂以治疗上可接受的量存在。药物组合物可用于本发明的方法中;因此,例如药物组合物可离体或体内给予对象以便实践本文所描述的治疗及预防方法及用途。
本发明的药物组合物可经配制以与预期方法或给药途径相容;例示性给药途径在本文中阐述。此外,药物组合物可与其它治疗活性剂或如本文所描述的化合物组合使用以便治疗或预防如由本发明考虑的疾病、病症及病状。
含有活性成分(例如IDO功能的抑制剂)的药物组合物可呈适用于口服使用的形式,例如呈片剂、胶囊、糖锭(troche)、锭剂(lozenge)、水性或油状悬浮液、分散性散剂或颗粒剂、乳剂、硬或软胶囊、或糖浆剂、溶液、微珠或酏剂形式。意欲用于口服使用的药物组合物可根据本领域中已知用于制造药物组合物的任何方法来制备,且此类组合物可含有一种或更多种诸如,例如甜味剂、调味剂、着色剂及防腐剂的试剂以便提供药学上精致且适口的制剂。片剂、胶囊及其类似物含有活性成分与适用于制造片剂的无毒的药学上可接受的赋形剂的掺合物。这些赋形剂可为例如稀释剂,诸如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;粒化剂及崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;及润滑剂,例如硬脂酸镁、硬脂酸或滑石。
适用于口服给予的片剂、胶囊及其类似物可未包覆包衣或通过已知技术包覆包衣以延迟在胃肠道中的崩解及吸收且由此提供持续作用。例如,可采用时间延迟材料,诸如单硬脂酸甘油酯或二硬脂酸甘油酯。它们也可通过本领域中已知的技术包覆包衣以形成用于控制释放的渗透治疗片剂。额外试剂包括可生物降解或生物相容性粒子或聚合物质,诸如聚酯、聚胺酸(polyamine acid)、水凝胶、聚乙烯吡咯烷酮、聚酐、聚乙醇酸、乙烯-乙酸乙烯酯、甲基纤维素、羧甲基纤维素、硫酸鱼精蛋白或丙交酯/乙交酯共聚物、聚丙交酯/乙交酯共聚物或乙烯-乙酸乙烯酯共聚物以便控制给予的组合物的递送。例如,口服试剂可包埋在通过凝聚技术或通过界面聚合、通过分别使用羟甲基纤维素或明胶微胶囊或聚(甲基丙烯酸甲酯)微胶囊制备的微胶囊中或包埋在胶体药物递送系统中。胶体分散系统包括大分子复合物、纳米胶囊、微球、微珠及基于脂质的系统,包括水包油乳液、微胞、混合微胞及脂质体。制备上文所提及的制剂的方法将对于本领域技术人员显而易见。
用于口服使用的制剂也可以硬明胶胶囊形式呈现,其中活性成分与惰性固体稀释剂,例如碳酸钙、磷酸钙、高岭土或微晶纤维素混合;或以软明胶胶囊形式呈现,其中活性成分与水或油介质,例如花生油、液体石蜡或橄榄油混合。
水性悬浮液含有活性物质与适用于其制造的赋形剂的掺合物。此类赋形剂可为悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯-吡咯烷酮、黄蓍胶及阿拉伯胶;分散剂或湿润剂,例如天然存在的磷脂(例如卵磷脂)、或环氧烷与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯)、或环氧乙烷与长链脂族醇的缩合产物(例如对于十七碳亚乙基氧基十六醇(heptadecaethyleneoxycetanol))、或环氧乙烷与衍生自脂肪酸及己糖醇的偏酯的缩合产物(例如聚氧乙烯山梨糖醇单油酸酯)、或环氧乙烷与衍生自脂肪酸及己糖醇酐的偏酯的缩合产物(例如聚乙烯脱水山梨糖醇单油酸酯)。水性悬浮液也可含有一种或更多种防腐剂。
油性悬浮液可通过使活性成分悬浮于植物油(例如花生油、橄榄油、芝麻油或椰子油)中或矿物油(诸如液体石蜡)中来配制。油性悬浮液可含有增稠剂,例如蜂蜡、硬石蜡或十六醇。可添加甜味剂(诸如上述的那些)及调味剂,以提供适口的口服制剂。
适合于通过添加水制备水性悬浮液的分散性散剂及颗粒剂提供活性成分与分散剂或湿润剂、悬浮剂及一种或更多种防腐剂的掺合物。合适的分散剂或湿润剂及悬浮剂在本文中例示。
本发明的药物组合物也可呈水包油乳液形式。油相可为植物油,例如橄榄油或花生油;或矿物油,例如液体石蜡,或这些的混合物。合适的乳化剂可为天然存在的胶,例如阿拉伯胶或黄蓍胶;天然存在的磷脂,例如大豆、卵磷脂;及衍生自脂肪酸的酯或偏酯;己糖醇酐,例如脱水山梨糖醇单油酸酯;及偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。
制剂也可包括载体以使组合物免于快速降解或自身体清除,诸如控制释放制剂,包括植入物、脂质体、水凝胶、前药及微囊封递送系统。例如,可使用时间延迟材料,诸如仅单硬脂酸甘油酯或硬脂酸甘油酯,或其与蜡的组合。
药物组合物通常包含治疗有效量的由本发明考虑的IDO抑制剂及一种或更多种药学上及生理上可接受的配制剂。合适的药学上可接受或生理上可接受的稀释剂、载体或赋形剂包括但不限于抗氧化剂(例如抗坏血酸及硫酸氢钠)、防腐剂(例如苯甲醇、对羟基苯甲酸甲酯、乙基或正丙基对羟基苯甲酸酯)、乳化剂、悬浮剂、分散剂、溶剂、填充剂、膨化剂、清洁剂、缓冲剂、媒剂、稀释剂和/或佐剂。例如,合适的媒剂可为生理盐水溶液或柠檬酸盐缓冲盐水,其可能补充有用于肠胃外给药的药物组合物中常见的其它物质。中性缓冲盐水或与血清白蛋白混合的盐水是另外的例示性媒剂。本领域技术人员将容易识别多种可用于本文中考虑的药物组合物及剂型中的缓冲剂。典型缓冲剂包括但不限于药学上可接受的弱酸、弱碱或其混合物。作为实例,缓冲剂组分可为水溶性物质,诸如磷酸、酒石酸、乳酸、丁二酸、柠檬酸、乙酸、抗坏血酸、天冬氨酸、谷氨酸及其盐。可接受的缓冲剂包括例如Tris缓冲剂、N-(2-羟乙基)哌嗪-N′-(2-乙磺酸)(HEPES)、2-(N-吗啉基)乙磺酸(MES)、2-(N-吗啉基)乙磺酸钠盐(MES)、3-(N-吗啉基)丙磺酸(MOPS)及N-三[羟甲基]甲基-3-氨基丙磺酸(TAPS)。
在已配制药物组合物之后,可将其以溶液、悬浮液、凝胶、乳液、固体或脱水或冻干粉末形式储存于无菌瓶中。此类制剂可以即用形式、需要在使用之前复原的冻干形式、需要在使用之前稀释的液体形式或其它可接受的形式储存。在一些实施方案中,药物组合物提供在一次性容器(例如一次性瓶、安瓿、注射器或自动注射器(类似于例如))中,而多用途容器(例如多用途瓶)提供于其它实施方案中。可使用任何药物递送设备来递送IDO抑制剂,包括植入物(例如可植入泵)及导管系统、缓慢注射泵及装置,这些都为本领域技术人员所熟知。也可利用一般皮下或肌肉内给予的贮库型注射剂来经限定时间段释放本文所公开的多肽。贮库型注射剂通常基于固体或油且一般包含本文所阐述的制剂组分中的至少一种。本领域普通技术人员熟悉贮库型注射剂的可能制剂及用途。
药物组合物可呈无菌可注射水性或油性悬浮液形式。此悬浮液可根据已知技术使用本文中提及的那些合适的分散剂或湿润剂及悬浮剂配制。无菌可注射制剂也可为在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如呈在1,3-丁二醇中的溶液形式。可用的可接受的稀释剂、溶剂及分散介质包括水、林格氏溶液(Ringer'ssolution)、等张氯化钠溶液、EL(BASF,Parsippany,NJ)或磷酸盐缓冲盐水(PBS)、乙醇、多元醇(例如甘油、丙二醇及液体聚乙二醇)及其合适的混合物。此外,无菌不挥发性油通常用作溶剂或悬浮介质。出于此目的,可采用任何温和的不挥发性油,包括合成的单甘油酯或二甘油酯。此外,诸如油酸的脂肪酸在制备可注射剂中发现用途。特定可注射制剂的延长吸收可通过包括延迟吸收的试剂(例如单硬脂酸铝或明胶)实现。
本发明考虑给予呈用于直肠给药的栓剂形式的IDO抑制剂。可通过将药物与合适的无刺激性赋形剂混合来制备栓剂,该赋形剂在常温下为固体但在直肠温度下为液体且因此将在直肠中融化以释放药物。此类物质包括但不限于可可脂及聚乙二醇。
本发明考虑的IDO抑制剂可呈目前已知或将来开发的任何其它合适的药物组合物形式(例如用于经鼻或吸入用途的喷雾剂)。
多肽或其片段在制剂中的浓度可广泛变化(例如按重量计自小于约0.1%,通常在2%下或至少约2%至多达20%至50%或更多)且将通常主要基于流体体积、粘度及基于对象的因素,根据例如所选的特定给药方式来选择。
给药途径
本发明考虑以任何合适方式给予IDO抑制剂及其组合物。合适的给药途径包括口服、肠胃外(例如肌肉内、静脉内、皮下(例如注射或植入)、腹膜内、脑池内、关节内、腹膜内、脑内(脑实质内)及脑室内)、经鼻、阴道、舌下、眼内、直肠、局部(例如经皮)、舌下及吸入。也可利用一般皮下或肌肉内给予的贮库型注射剂来经限定时间段释放本文所公开的IDO抑制剂。
本发明的特定实施方案考虑口服给药。
组合疗法
本发明考虑IDO抑制剂与一种或更多种活性治疗剂(例如化学治疗剂)或其它预防或治疗模式(例如放射)的组合的用途。在这种组合疗法中,各种活性剂经常具有不同、互补作用机制。这种组合疗法可通过允许试剂中的一种或更多种的剂量减少,由此减少或消除与试剂中的一种或更多种相关的不良作用而尤其有利。此外,这种组合疗法可对根本疾病、病症或病状具有协同治疗或预防效果。
如本文所用,“组合”意欲包括可单独给予,例如单独配制用于单独给予(例如如可提供于试剂盒中)的疗法,及可一起在单一制剂(即“共同制剂”)中给予的疗法。
在某些实施方案中,IDO抑制剂依序给予或施用,例如其中一种药剂在一种或更多种其它药剂之前给予。在其它实施方案中,IDO抑制剂同时给予,例如其中两种或更多种药剂在相同时间或大致相同时间给予;该两种或更多种药剂可存在于两个或更多个单独制剂中或组合成单一制剂(即共同制剂)。不论该两种或更多种药剂是否依序或同时给予,出于本发明的目的,认为其应组合给予。
本发明的IDO抑制剂可与至少一种其它(活性)药剂以在情况下合适的任何方式组合使用。在一个实施方案中,将用至少一种活性剂及至少一种本发明的IDO抑制剂的治疗维持一段时间。在另一实施方案中,减少或停止用至少一种活性剂的治疗(例如当对象稳定时),同时将用本发明的IDO抑制剂的治疗维持在恒定给药方案下。在另一实施方案中,减少或停止用至少一种活性剂的治疗(例如当对象稳定时),同时减少用本发明的IDO抑制剂的治疗(例如较低剂量、较低频率给药或较短治疗方案)。在另一实施方案中,减少或停止用至少一种活性剂的治疗(例如当对象稳定时),且增加用本发明的IDO抑制剂的治疗(例如较高剂量、更高频率给药或较长治疗方案)。在另一实施方案中,维持用至少一种活性剂的治疗且减少或停止用本发明的IDO抑制剂的治疗(例如较低剂量、较低频率给药或较短治疗方案)。在另一实施方案中,减少或停止用至少一种活性剂的治疗及用本发明的IDO抑制剂的治疗(例如较低剂量、较低频率给药或较短治疗方案)。
肿瘤学相关病症.本发明提供用IDO抑制剂及至少一种额外治疗剂(诸如放射、免疫调节剂或化学治疗剂)或诊断剂治疗和/或预防增生性病状、癌症、肿瘤或癌前疾病、病症或病状的方法。可在本发明中使用的合适的免疫调节剂包括CD40L、B7及B7RP1;针对刺激受体的活化单克隆抗体(mAb),诸如ant-CD40、抗CD38、抗ICOS及4-IBB配体;树突细胞抗原负载(体外或体内);抗癌疫苗,诸如树突细胞癌疫苗;细胞因子/趋化因子,诸如IL1、IL2、IL12、IL18、ELC/CCL19、SLC/CCL21、MCP-1、IL-4、IL-18、TNF、IL-15、MDC、IFNa/b、M-CSF、IL-3、GM-CSF、IL-13及抗IL-10;细菌脂多糖(LPS);及免疫-刺激寡核苷酸。
化学治疗剂的实例包括但不限于烷基化剂,诸如噻替派及环磷酰胺;磺酸烷基酯,诸如白消安、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,诸如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)及乌瑞替哌(uredopa);乙烯亚胺及甲基三聚氰胺,包括六甲蜜胺、曲他胺(triethylenemelamine)、三亚乙基磷酰胺、三亚乙基硫代磷酰胺及三羟甲基三聚氰胺;氮芥,诸如苯丁酸氮芥、萘氮芥、胆磷酰胺(cholophosphamide)、雌氮芥、异环磷酰胺、二氯甲基二乙胺、二氯甲基二乙胺氧化物盐酸盐、美法仑、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺、尿嘧啶氮芥;亚硝基脲,诸如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀、雷莫司汀;抗生素,诸如阿克拉霉素、放线菌素、安曲霉素、偶氮丝胺酸、博来霉素、放线菌素C、卡奇霉素、卡拉比辛(carabicin)、洋红霉素(caminomycin)、嗜癌霉素、色霉素、放线菌素D、柔红霉素、地托比星、6-重氮-5-氧代-L-正白氨酸、阿霉素、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素、霉酚酸、诺加霉素、橄榄霉素、培洛霉素、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链脲菌素、杀结核菌素、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星;抗代谢物,诸如甲氨蝶呤及5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物,诸如氟达拉滨、6-巯基嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤;嘧啶类似物,诸如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、双脱氧尿苷、脱氧氟尿苷、依诺他滨、氟尿苷、5-FU;雄激素,诸如卡鲁睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷、睾内酯;抗肾上腺剂,诸如氨鲁米特、米托坦、曲洛司坦;叶酸补充剂,诸如亚叶酸;醋葡醛内酯;醛磷酰胺糖苷;氨基乙酰丙酸;安吖啶;比曲比新(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌;依氟鸟氨酸(elformithine);依利醋铵(elliptinium acetate);依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖;氯尼达明;丙脒腙;米托蒽醌;莫哌达醇;二胺硝吖啶;喷司他丁;蛋氨氮芥(phenamet);吡柔比星;鬼臼酸;2-乙基酰肼;甲基苄肼;雷佐生;西佐喃;锗螺胺;细交链孢菌酮酸;三亚胺醌;2,2',2”-三氯三乙胺;尿烷;长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;加西托星(gacytosine);阿拉伯糖苷(Ara-C);环磷酰胺;噻替派;紫杉烷类,例如紫杉醇及多西他赛;苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂及铂配位络合物,诸如顺铂及卡铂;长春碱;依托泊苷(VP-16);异环磷酰胺;丝裂霉素C;米托蒽醌;长春新碱;长春瑞滨;诺维本;诺安托(novantrone);替尼泊苷;道诺霉素;氨基蝶呤;希罗达(xeloda);伊班膦酸盐;CPT11;拓扑异构酶抑制剂;二氟甲基鸟氨酸(DMFO);视黄酸;埃斯波霉素;卡培他滨;及以上中的任一种的药学上可接受的盐、酸或衍生物。
化学治疗剂还包括用来调节或抑制激素对肿瘤的作用的抗激素剂,诸如抗雌激素,包括例如他莫昔芬、雷洛昔芬、芳香酶抑制4(5)-咪唑、4-羟基他莫昔芬、曲沃昔芬、考昔芬(keoxifene)、奥那司酮及托瑞米芬;及抗雄激素,诸如氟他胺、尼鲁米特(nilutamide)、比卡鲁胺、亮丙瑞林及戈舍瑞林;及以上中的任一种的药学上可接受的盐、酸或衍生物。在某些实施方案中,组合疗法包含给予激素或相关激素剂。
化学治疗剂还包括信号转导抑制剂(STI)。术语“信号转导抑制剂”是指选择性抑制信号传导路径中的一个或更多个步骤的药剂。本发明的信号转导抑制剂(STI)包括:(i)bcr/abl激酶抑制剂(例如GLEEVEC);(ii)表皮生长因子(EGF)受体抑制剂,包括激酶抑制剂及抗体;(iii)her-2/neu受体抑制剂(例如HERCEPTIN);(iv)Akt家族激酶或Akt路径的抑制剂(例如雷帕霉素);(v)细胞循环激酶抑制剂(例如夫拉平度(flavopiridol));及(vi)磷脂酰基肌醇激酶抑制剂。
可与IDO抑制剂组合使用的额外治疗模式包括细胞因子或细胞因子拮抗剂(诸如IL-12、IFN)或抗表皮生长因子受体、放射疗法、针对另一肿瘤抗原的单克隆抗体、单克隆抗体与毒素的络合物、T细胞佐剂、骨髓移植或抗原呈递细胞(例如树突细胞疗法)。本文还提供疫苗(例如呈可溶蛋白质形式或呈编码蛋白质的核酸形式)。
心血管疾病.本发明提供用IDO抑制剂及至少一种额外治疗或诊断剂治疗和/或预防某些心血管和/或代谢相关疾病、病症及病状,以及与其相关的病症的方法。
可用于治疗高胆固醇血症(以及动脉粥样硬化)的组合疗法的治疗剂的实例包括他汀类药物(例如CRESTOR、LESCOL、LIPITOR、MEVACOR、PRAVACOL及ZOCOR,其抑制胆固醇的酶促合成;胆汁酸树脂(例如COLESTID、LO-CHOLEST、PREVALITE、QUESTRAN及WELCHOL),其螯合胆固醇且防止其吸收;依泽替米贝(ZETIA),其阻断胆固醇吸收;纤维酸(fibric acid)(例如TRICOR),其减少甘油三酯且可适当地增加HDL;烟酸(例如NIACOR),其适当地降低LDL胆固醇及甘油三酯;和/或前述的组合(例如VYTORIN(依泽替米贝与辛伐他汀)。可为用于与本文所描述的IDO抑制剂组合使用的候选物的替代胆固醇治疗剂包括各种补充剂及草本植物(例如大蒜、普利醇(policosanol)及印度香胶树(guggul))。本发明包括以上中的任一种的药学上可接受的盐、酸或衍生物。
免疫及炎性相关病症.本发明提供用IDO抑制剂及至少一种额外治疗或诊断剂治疗和/或预防免疫和/或炎性相关疾病、病症及病状,以及与其相关的病症的方法。
可用于组合疗法的治疗剂的实例包括但不限于以下:非类固醇抗炎药(NSAID),诸如阿司匹林、布洛芬及其它丙酸衍生物(阿明洛芬、苯恶洛芬、布氯酸、卡洛芬、芬布芬、非诺洛芬、氟洛芬、氟比洛芬、吲哚洛芬、酮洛芬、咪洛芬、萘普生、奥沙普嗪、吡洛芬、普拉洛芬、舒洛芬、噻洛芬酸及硫噁洛芬)、乙酸衍生物(吲哚美辛、阿西美辛(acemetacin)、阿氯芬酸(alclofenac)、环氯茚酸(clidanac)、双氯芬酸(diclofenac)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、芬替酸(fentiazac)、fuirofenac、异丁芬酸(ibufenac)、伊索克酸(isoxepac)、oxpinac、舒林酸、硫平酸、托美汀、齐多美辛及佐美酸)、芬那酸衍生物(氟芬那酸、甲氯芬那酸、甲芬那酸、尼氟酸及托芬那酸)、联苯羧酸衍生物(二氟尼柳及氟苯柳)、昔康(oxicam)(伊索昔康、吡罗昔康、舒多昔康及替诺昔康)、水杨酸盐(乙酰基水杨酸、柳氮磺胺吡啶)及吡唑啉酮(阿扎丙宗、苄哌立隆、非普拉宗、莫非布宗、羟布宗、苯基丁氮酮)。其它组合包括环氧合酶-2(COX-2)抑制剂。
其它用于组合的活性剂包括类固醇,诸如泼尼松龙、泼尼松、甲泼尼龙、倍他米松、地塞米松或氢化可的松。此类组合可尤其有利,因为可通过使需要的类固醇剂量逐渐减少来减少或甚至消除类固醇的一种或更多种不良作用。
可以组合形式用于治疗例如类风湿性关节炎的活性剂的额外实例包括细胞因子抑制抗炎药(CSAID);针对其它人类细胞因子或生长因子的抗体或其它人类细胞因子或生长因子的拮抗剂,所述人类细胞因子或生长因子例如TNF、LT、IL-1β、IL-2、IL-6、IL-7、IL-8、IL-15、IL-16、IL-18、EMAP-II、GM-CSF、FGF或PDGF。
活性剂的特定组合可在不同位置在自身免疫及随后炎性级联反应中干扰,且包括TNF拮抗剂,诸如嵌合、人源化或人TNF抗体、REMICADE、抗TNF抗体片段(例如CDP870)及可溶p55或p75TNF受体、其衍生物、p75TNFRIgG(ENBREL.)或p55TNFR1gG(LENERCEPT)、可溶IL-13受体(sIL-13)以及还有TNFα-转化酶(TACE)抑制剂;类似地,IL-1抑制剂(例如白细胞介素-1-转化酶抑制剂)可有效。其它组合包括白细胞介素11、抗P7及p-选择素糖蛋白配体(PSGL)。可用于与本文所描述的IDO抑制剂组合的药剂的其它实例包括干扰素-β1a(AVONEX)、干扰素-β1b(BETASERON)、考帕松(copaxone)、高压氧、静脉内免疫球蛋白、克拉屈滨及针对其它人类细胞因子或生长因子的抗体或其它人类细胞因子或生长因子的拮抗剂(例如针对CD40配体及CD80的抗体)。
免疫检查点抑制剂.本发明考虑本文所描述的IDO功能的抑制剂与额外免疫检查点抑制剂的组合的用途。
作为所有癌症的特征的极大数目的基因及表观遗传变异提供免疫系统可用以区分肿瘤细胞与其正常对应物的不同组的抗原。在T细胞的情况下,经由T细胞受体(TCR)的抗原识别引起的反应的最终幅度(例如细胞因子产生或增殖的水平)及质量(例如产生的免疫反应的类型,诸如细胞因子产生的模式)通过协同刺激与抑制信号之间的平衡(免疫检查点)调节。在正常生理条件下,免疫检查点对于自身免疫的预防(即自身耐受性的维持)以及还有对于当免疫系统对病原性感染作出反应时使组织免受损伤而言为至关重要的。作为重要免疫耐受机制的肿瘤可异常调节免疫检查点蛋白的表达。
T细胞由于以下而为治疗上操控内源抗肿瘤免疫性的努力的主要焦点:i)其选择性识别所有细胞区室中衍生自蛋白质的肽的能力;ii)其直接识别及杀死抗原表达细胞(通过CD8+效应子T细胞;也称为细胞毒性T淋巴细胞(CTL))的能力;及iii)其通过整合适应性及先天性效应子机制的CD4+辅助T细胞策划不同免疫反应的能力。在临床配置中,引起抗原特异性T细胞反应放大的免疫检查点阻断已显示为人类癌症疗法中的有前景的方法。
T细胞介导的免疫性包括多个依序步骤,其中的每一个通过均衡刺激及抑制信号来调节以便优化反应。虽然免疫反应中几乎所有抑制信号最终调节细胞内信号传导路径,许多经由膜受体起始,其配体为膜结合或可溶的(细胞因子)。虽然调节T细胞活化的协同刺激及抑制受体及配体相对于正常组织而言经常不会在癌症中过度表达,但在组织中调节T细胞效应子功能的抑制配体及受体通常在肿瘤细胞上或在与肿瘤微环境相关的未经转化细胞上过度表达。可溶和膜结合受体-配体免疫检查点的功能可使用激动剂抗体(对于协同刺激路径)或拮抗剂抗体(对于抑制路径)调节。因此,与目前批准用于癌症疗法的大多数抗体相反,阻断免疫检查点的抗体不直接靶向肿瘤细胞,而是靶向淋巴细胞受体或其配体以便增强内源抗肿瘤活性。[参见Pardoll,(2012年4月)Nature Rev.Cancer 12:252-64]。
作为阻断的候选物,其中一些在各种类型的肿瘤细胞中选择性上调的免疫检查点(配体及受体)的实例包括PD1(程序性细胞死亡蛋白1)、PDL1(PD1配体)、BTLA(B及T淋巴细胞衰减子)、CTLA4(细胞毒性T-淋巴细胞相关抗原4)、TIM3(T细胞膜蛋白3)、LAG3(淋巴细胞活化基因3)、A2aR(腺苷A2a受体A2aR)及杀伤抑制受体,其可基于其结构特征分成两种类别:i)杀伤细胞免疫球蛋白样受体(KIR)及ii)C型凝集素受体(II型跨膜受体家族的成员)。其它较不明确定义的免疫检查点已描述于文献中,包括受体(例如2B4(也称为CD244)受体)及配体(例如某些B7家族抑制配体,诸如B7-H3(也称为CD276)及B7-H4(也称为B7-S1、B7x及VCTN1))两者。[参见Pardoll,(2012年4月)Nature Rev.Cancer12:252-64]。
本发明考虑本文所描述的IDO功能的抑制剂与前述免疫检查点受体及配体的抑制剂以及尚未描述的免疫检查点受体及配体的组合的用途。免疫检查点的某些调节剂目前可获得,而其它处于后阶段发展中。举例而言,当其在2011年经批准用于治疗黑素瘤时,完全人源化CTLA4单克隆抗体伊匹单抗(YERVOY;Bristol-Myers Squibb)成为接受美国监管批准的第一种免疫检查点抑制剂。包含CTLA4及抗体(CTLA4-Ig;abatcept(ORENCIA;Bristol-Myers Squibb))的融合蛋白已用于治疗类风湿性关节炎,且其它融合蛋白已显示出在对埃巴病毒敏感的肾移植患者中有效。PD1抗体也可用于治疗癌症,包括例如纳武单抗(nivolumab)(Bristol-Myers Squibb)及帕母单抗(pembroluzimab)(Merck),且也正评估抗PDL1抗体(例如MPDL3280A(Roche))。纳武单抗已经在患有黑素瘤、肺癌及肾癌以及多种其它恶性肿瘤的患者中显示前景。
在本发明的一个方面中,请求保护的IDO抑制剂与免疫-肿瘤学药剂组合,该药剂为T细胞上(i)刺激(包括协同刺激)受体的激动剂或(ii)抑制(包括共抑制)信号的拮抗剂,其均引起抗原特异性T细胞反应放大。某些刺激及抑制分子为免疫球蛋白超家族(IgSF)的成员。结合至协同刺激或共抑制受体的膜结合配体的一个重要家族为B7家族,其包括B7-1、B7-2、B7-H1(PD-L1)、B7-DC(PD-L2)、B7-H2(ICOS-L)、B7-H3、B7-H4、B7-H5(VISTA)及B7-H6。结合至协同刺激或共抑制受体的膜结合配体的另一家族为结合至同源TNF受体家族成员的分子的TNF家族,其包括CD40及CD40L、OX-40、OX-40L、CD70、CD27L、CD30、CD30L、4-1BBL、CD137(4-1BB)、TRAIL/Apo2-L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、TACI、APRIL、BCMA、LTβR、LIGHT、DcR3、HVEM、VEGI/TL1A、TRAMP/DR3、EDAR、EDA1、XEDAR、EDA2、TNFR1、淋巴毒素α/TNFβ、TNFR2、TNFα、LTβR、淋巴毒素α1β2、FAS、FASL、RELT、DR6、TROY、NGFR。
在另一方面中,免疫-肿瘤学药剂为抑制T细胞活化的细胞因子(例如IL-6、IL-10、TGF-β、VEGF及其它免疫抑制细胞因子)或刺激T细胞活化以便刺激免疫反应的细胞因子。
在一个方面中,T细胞反应可通过请求保护的IDO抑制剂与以下中的一种或更多种的组合刺激:(i)抑制T细胞活化的蛋白质的拮抗剂(例如免疫检查点抑制剂),诸如CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM-3、半乳糖凝集素9、CEACAM-1、BTLA、CD69、半乳糖凝集素-1、TIGIT、CD113、GPR56、VISTA、2B4、CD48、GARP、PD1H、LAIR1、TIM-1及TIM-4;和/或(ii)刺激T细胞活化的蛋白质的激动剂,诸如B7-1、B7-2、CD28、4-1BB(CD137)、4-1BBL、ICOS、ICOS-L、OX40、OX40L、GITR、GITRL、CD70、CD27、CD40、DR3和CD2。可与本发明的IDO抑制剂组合用于治疗癌症的其它药剂包括NK细胞上的抑制受体的拮抗剂或NK细胞上的活化受体的激动剂。例如,本文中的化合物可与KIR的拮抗剂,诸如利瑞路单抗(lirilumab)组合。
用于组合疗法的其它药剂包括抑制或耗尽巨噬细胞或单核细胞的药剂,包括但不限于CSF-1R拮抗剂,诸如CSF-1R拮抗剂抗体,包括RG7155(WO11/70024、WO11/107553、WO11/131407、WO13/87699、WO13/119716、WO13/132044)或FPA-008(WO11/140249、WO13169264、WO14/036357)。
在另一方面中,请求保护的IDO抑制剂可与以下中的一种或更多种一起使用:连接阳性协同刺激受体的激动剂、减弱经由抑制受体的信号传导的阻断剂、拮抗剂及一种或更多种全身性增加抗肿瘤T细胞的频率的药剂、克服肿瘤微环境内的不同免疫抑制路径(例如阻断抑制受体接合(例如PD-L1/PD-1相互作用)、耗尽或抑制Treg(例如使用抗CD25单克隆抗体(例如达利珠单抗)或通过离体抗-CD25珠耗尽),或逆转/防止T细胞无反应性或耗尽)的药剂及在肿瘤部位处触发先天性免疫活化和/或炎症的药剂。
在一个方面中,免疫-肿瘤学药剂为CTLA-4拮抗剂,诸如拮抗性CTLA-4抗体。合适的CTLA-4抗体包括例如YERVOY(伊匹单抗)或替西木单抗(tremelimumab)。
在另一方面中,免疫-肿瘤学药剂为PD-1拮抗剂,诸如拮抗性PD-1抗体。合适的PD-1抗体包括例如OPDIVO(纳武单抗)、KEYTRUDA(帕母单抗(pembrolizumab/lambrolizumab)或MEDI-0680(AMP-514;WO2012/145493)。免疫-肿瘤学药剂也可包括皮立珠单抗(pidilizumab,CT-011),尽管已经质疑其对于PD-1结合的特异性。靶向PD-1受体的另一方法为由融合至IgG1的Fc部分的PD-L2(B7-DC)的胞外结构域构成的重组蛋白质,称作AMP-224。
在另一方面中,免疫-肿瘤学药剂为PD-L1拮抗剂,诸如拮抗性PD-L1抗体。合适的PD-L1抗体包括例如MPDL3280A(RG7446;WO2010/077634)、德瓦鲁单抗(durvalumab)(MEDI4736)、BMS-936559(WO2007/005874)及MSB0010718C(WO2013/79174)。
在另一方面中,免疫-肿瘤学药剂为LAG-3拮抗剂,诸如拮抗性LAG-3抗体。合适的LAG3抗体包括例如BMS-986016(WO10/19570、WO14/08218)或IMP-731或IMP-321(WO08/132601、WO09/44273)。
在另一方面中,免疫-肿瘤学药剂为CD137(4-1BB)激动剂,诸如激动性CD137抗体。合适的CD137抗体包括例如优瑞路单抗(urelumab)及PF-05082566(WO12/32433)。
在另一方面中,免疫-肿瘤学药剂为GITR激动剂,诸如激动性GITR抗体。合适的GITR抗体包括例如BMS-986153、BMS-986156、TRX-518(WO06/105021、WO09/009116)及MK-4166(WO11/028683)。
在另一方面中,免疫-肿瘤学药剂为OX40激动剂,诸如激动性OX40抗体。合适的OX40抗体包括例如MEDI-6383或MEDI-6469。
在另一方面中,免疫-肿瘤学药剂为OX40L拮抗剂,诸如拮抗性OX40抗体。合适的OX40L拮抗剂包括例如RG-7888(WO06/029879)。
在另一方面中,免疫-肿瘤学药剂为CD40激动剂,诸如激动性CD40抗体。在另一实施方案中,免疫-肿瘤学药剂为CD40拮抗剂,诸如拮抗性CD40抗体。合适的CD40抗体包括例如鲁卡木单抗(lucatumumab)或达西珠单抗(dacetuzumab)。
在另一方面中,免疫-肿瘤学药剂为CD27激动剂,诸如激动性CD27抗体。合适的CD27抗体包括例如瓦里木单抗(varlilumab)。
在另一方面中,免疫-肿瘤学药剂为MGA271(针对B7H3)(WO11/109400)。
本发明包括以上中任一种的药学上可接受的盐、酸或衍生物。
病毒性疾病.本发明提供用IDO抑制剂及至少一种额外治疗或诊断剂(例如一种或更多种其它抗病毒剂和/或一种或更多种与病毒疗法不相关的药剂)治疗和/或预防病毒性疾病、病症及病状,以及与其相关的病症的方法。
此类组合疗法包括靶向各种病毒生命-周期阶段且具有不同作用机制的抗病毒剂,包括但不限于以下:病毒脱壳的抑制剂(例如金刚烷胺及金刚乙胺);逆转录酶抑制剂(例如阿昔洛韦(acyclovir)、齐多夫定(zidovudine)及拉米夫定(lamivudine));靶向整合酶的药剂;阻断转录因子与病毒DNA的连接的药剂;影响翻译的药剂(例如反义分子)(例如福米韦生(fomivirsen));调节翻译/核酶功能的药剂;蛋白酶抑制剂;病毒装配调节剂(例如利福平(rifampicin));抗逆转录病毒剂,诸如,例如核苷类似物逆转录酶抑制剂(例如叠氮胸苷(AZT)、ddl、ddC、3TC、d4T);非核苷逆转录酶抑制剂(例如依法韦仑(efavirenz)、奈韦拉平(nevirapine));核苷酸类似物逆转录酶抑制剂;及防止病毒粒子释放的药剂(例如扎那米韦(zanamivir)及奥司他韦(oseltamivir))。某些病毒感染(例如HIV)的治疗和/或预防经常需要一组抗病毒剂(“混合物”)。
考虑用于与IDO抑制剂组合使用的其它抗病毒剂包括但不限于以下:阿巴卡韦(abacavir)、阿德福韦(adefovir)、金刚烷胺、安普那韦(amprenavir)、安普利近(ampligen)、阿比朵尔(arbidol)、阿扎那韦(atazanavir)、立普妥(atripla)、boceprevirertet、西多福韦(cidofovir)、双汰芝(combivir)、地瑞那韦(darunavir)、地拉韦啶(delavirdine)、地丹诺辛(didanosine)、二十二烷醇(docosanol)、依度尿苷(edoxudine)、恩曲他滨(emtricitabine)、恩夫韦地(enfuvirtide)、恩替卡韦(entecavir)、泛昔洛韦(famciclovir)、福沙那韦(fosamprenavir)、膦甲酸(foscarnet)、膦乙酸(fosfonet)、更昔洛韦(ganciclovir)、伊巴他滨(ibacitabine)、异丙肌苷(imunovir)、碘苷(idoxuridine)、咪喹莫特(imiquimod)、茚地那韦(indinavir)、肌苷(inosine)、各种干扰素(例如聚乙二醇化干扰素α-2a)、洛匹那韦(lopinavir)、洛韦胺(loviride)、马拉韦罗(maraviroc)、吗啉胍(moroxydine)、甲吲噻腙(methisazone)、奈非那韦(nelfinavir)、多吉美(nexavir)、喷昔洛韦(penciclovir)、帕拉米韦(peramivir)、普可那利(pleconaril)、鬼臼毒素(podophyllotoxin)、雷特格韦(raltegravir)、病毒唑(ribavirin)、利托那韦(ritonavir)、pyramidine、沙奎那韦(saquinavir)、司他夫定(stavudine)、特拉匹韦(telaprevir)、替诺福韦(tenofovir)、替拉那韦(tipranavir)、曲氟尿苷(trifluridine)、三协唯(trizivir)、曲金刚胺(tromantadine)、特鲁瓦达(truvada)、万乃洛韦(valaciclovir)、缬更昔洛韦(valganciclovir)、维克利诺(vicriviroc)、阿糖腺苷(vidarabine)、伟拉咪定(viramidine)及扎西他滨(zalcitabine)。
本发明包括以上中任一项的药学上可接受的盐、酸或衍生物。
寄生虫病症.本发明考虑本文所描述的IDO功能的抑制剂与抗寄生虫剂的组合的用途。此类药剂包括但不限于噻苯咪唑、双羟萘酸噻嘧啶、甲苯达唑、吡喹酮、氯硝柳胺、硫氯酚、奥沙尼喹、美曲膦酯、伊维菌素、阿苯达唑、依氟鸟氨酸、美拉胂醇、喷他脒、苄硝唑、硝呋莫司及硝基咪唑。技术人员了解可发现用于治疗寄生虫病症用途的其它药剂。
本发明包括以上中任一项的药学上可接受的盐、酸或衍生物。
细菌感染.本发明的实施方案考虑本文所描述的IDO抑制剂与可用于治疗或预防细菌病症的药剂的组合的用途。抗细菌剂可以各种方式分类,包括基于作用机制、基于化学结构及基于活性谱。抗细菌剂的实施例包括以下那些:靶向细菌细胞壁的(例如头胞菌素及青霉素)或细胞膜的(例如多黏菌素)或干扰必需细菌酶的(例如磺胺类、利福霉素及喹啉类)。靶向蛋白质合成的大多数抗细菌剂(例如四环素及大环内酯)为抑制细菌的,而诸如氨基糖苷的药剂为杀细菌的。分类抗细菌剂的另一方式基于其靶向特异性;“窄谱”药剂靶向特定类型的细菌(例如革兰氏阳性细菌,诸如链球菌),而“广谱”药剂具有针对较宽范围的细菌的活性。技术人员了解适合于在特定细菌感染中使用的抗细菌剂的类型。
本发明包括上述药剂(及这类药剂的成员)的药学上可接受的盐、酸或衍生物。
剂量
本发明的IDO抑制剂可以取决于例如以下各项的量给予对象:给药目的(例如所需消退程度);给予制剂的对象的年龄、体重、性别及健康和身体状况;给药途径;及疾病、病症、病状或其症状的性质。给药方案还可考虑与给予的药剂相关的任何不良作用的存在、性质及程度。有效剂量及给药方案可容易地从例如安全性及剂量递增试验、体内研究(例如动物模型)及本领域技术人员已知的其它方法确定。
一般而言,给药参数规定剂量小于可对对象不可逆地有毒的量(最大耐受剂量(MTD))且不小于对对象产生可测量效果需要的量。此类量由例如与ADME相关的药物动力学及药效学参数,考虑给药途径及其它因素确定。
有效剂量(ED)为在服用药剂的一部分对象中产生治疗反应或所需效果的药剂的剂量或量。药剂的“中值有效剂量”或ED50为在给予药剂的50%群体中产生治疗反应或所需效果的药剂的剂量或量。尽管ED50常用作药剂效果的合理预期的量度,其不必需为临床医师可考虑所有相关因素认为合适的剂量。因此,在一些情况下,有效量大于计算的ED50,在其它情况下,有效量小于计算的ED50,且在还有其它情况下,有效量与计算的ED50相同。
此外,本发明的IDO抑制剂的有效剂量可为当以一个或更多个剂量给予对象时相对于健康对象产生所需结果的量。例如,对于经历特定病症的对象,有效剂量可为改善该病症的诊断参数、测量值、标记等至少约5%、至少约10%、至少约20%、至少约25%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或大于90%的剂量,其中100%定义为由正常对象展示的诊断参数、测量值、标记等。
对于口服药剂的给予,组合物可以含有1.0毫克至1000毫克活性成分,尤其1.0、3.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0及1000.0毫克活性成分的片剂、胶囊等形式提供。
在某些实施方案中,所需IDO抑制剂的剂量包含于“单位剂型”中。短语“单位剂型”是指物理上离散的单位,各单位含有足以产生所需效果的单独或与一种或更多种额外药剂组合的预定量的IDO抑制剂。将理解单位剂型的参数将取决于特定药剂及待实现的效果。
试剂盒
本发明还考虑包含IDO抑制剂及其药物组合物的试剂盒。试剂盒一般呈如下文所描述的容纳各种组分的实体结构形式,且可用于例如实践上文所描述的方法。
试剂盒可包括本文所公开的IDO抑制剂中的一种或更多种(提供于例如无菌容器中),其可呈适合给予对象的药物组合物形式。IDO抑制剂可以即用形式(例如片剂或胶囊)或以需要例如在给予之前复原或稀释的形式(例如粉末)提供。当IDO抑制剂呈需要经使用者复原或稀释的形式时,试剂盒还可包括与IDO抑制剂一起或与IDO抑制剂分开包装的稀释剂(例如无菌水)、缓冲剂、药学上可接受的赋形剂等。当考虑组合疗法时,试剂盒可分开地含有若干试剂或其可已经在试剂盒中组合。试剂盒的各组分可密封于个别容器内,且所有各种容器可在单个包装内。本发明的试剂盒可经设计用于必需适当地维持其中容纳的组分的情况(例如制冷或冻结)。
试剂盒可含有标签或包装插页,其包括其中组分的鉴定信息及其使用说明(例如给药参数;活性成分的临床药理学,包括作用机制、药物动力学及药效学、不良作用、禁忌等)。标签或插页可包括制造商信息,诸如批号及有效期。标签或包装插页可例如整合至容纳组分的实体结构中,分开地包含于实体结构内,或粘附至试剂盒的组件(例如安瓿、管或瓶)上。
标签或插页可另外包括计算机可读取媒体,诸如磁盘(例如硬盘、卡、内存磁盘);光盘,诸如CD-或DVD-ROM/RAM、DVD、MP3、磁带;或电储存媒体,诸如RAM及ROM,或这些的混合,诸如磁/光储媒体、FLASH媒体或记忆型卡;或并入其中。在一些实施方案中,实际说明书不存在于试剂盒中,但提供从远程源(诸如经由因特网)获得说明书的方式。
实验
提出以下实施例以便向本领域普通技术人员提供如何进行及使用本发明的完整公开及描述,且不意欲限制本发明人视为其发明内容的范围,它们也不意欲表示进行以下实验或其为所有可进行的实验。应理解不一定进行以现在时书写的例示性描述,而是可进行所述描述以产生其中描述的性质的数据等。已努力确保关于所使用的数量(例如量、温度等)的准确性,但应当说明存在一些实验性误差及偏差。
除非另外指示,否则份数为重量份,分子量为重量平均分子量,温度以摄氏度(℃)为单位,且压力为大气压或近大气压。使用标准缩写,包括以下:wt=野生型;bp=碱基对;kb=千碱基;nt=核苷酸;aa=氨基酸;s或sec=秒;min=分钟;h或hr=小时;ng=纳克;μg=微克;mg=毫克;g=克;kg=千克;dl或dL=分升;μl或μL=微升;ml或mL=毫升;l或L=升;μM=微摩尔;mM=毫摩尔;M=摩尔;kDa=千道尔顿;i.m.=肌肉内(地);i.p.=腹膜内(地);SC或SQ=皮下(地);QD=每日;BID=每日两次;QW=每周;QM=每月;HPLC=高效液相层析;BW=体重;U=单位;ns=统计学上不显著;PBS=磷酸盐缓冲盐水;IHC=免疫组织化学;DMEM=Dulbecco的改良的Eagle培养基;EDTA=乙二胺四乙酸。
材料及方法
以下一般材料及方法在指出的情况下使用或可用于以下实施例中:
分子生物学中的标准方法描述于科学文献中(参见例如Sambrook等人,MolecularCloning,第三版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY(2001);及Ausubel等人,Current Protocols in Molecular Biology,第1-4卷,JohnWiley and Sons,Inc.New York,NY(2001),其描述在细菌细胞中克隆及DNA诱变(第1卷)、在哺乳动物细胞及酵母中克隆(第2卷)、糖缀合物及蛋白质表达(第3卷)及生物信息学(第4卷))。
科学文献描述用于蛋白质纯化的方法,包括免疫沉淀、层析、电泳、离心及结晶,以及化学分析、化学修饰、翻译后修饰、融合蛋白产生及蛋白质的糖基化(参见例如Coligan等人,Current Protocols in Protein Science,第1-2卷,John Wiley and Sons,Inc.,NY(2000))。
用于测定例如抗原片段、前导序列、蛋白质折叠、功能结构域、糖基化位点及序列比对的软件套件及数据库是可获得的(参见例如Wisconsin Package(Accelrys,Inc.,San Diego,CA);及(TimeLogic Corp.,Crystal Bay,NV)。
文献充满可充当本文所描述的化合物的评估基础的分析及其它实验技术。
IDO酶分析及犬尿氨酸(KYN)的细胞产生描述于Sarkar,S.A.等人,Diabetes,56:72-79(2007)中。简而言之,除非另外规定,否则所有化学物质可购自Sigma-Aldrich(St.Louis,MO)。1,000个人胰岛的组可在1mL培养基中用细胞因子培养24小时,通过在800xg下离心5分钟且在150μL含有蛋白酶抑制剂混合物的PBS(集合2;Calbiochem,EMDBiosciences,San Diego,CA)中超声波处理来回收。超声波处理物可在10,000x g下离心10分钟,且可通过用相等体积的含有40mmol/L抗坏血酸(中和至pH 7.0)、100μmol/L亚甲基蓝、200μg/mL过氧化氢酶及400μmol/l L-Trp的100mmol/L磷酸钾缓冲液,pH 6.5在37℃下培育40μl样品30分钟来一式三份地分析上清液。分析可通过添加16μL 30%(w/v)三氯乙酸(TCA)终止且进一步在60℃下培育15分钟以将N-甲酰基犬尿氨酸水解成KYN。混合物可随后在12,000rpm下离心15分钟,且KYN可通过在96孔微量滴定板中混合相等体积的上清液与含2%(w/v)艾氏试剂(Ehrlich's reagent)的冰乙酸且使用L-KYN作为标准读取在480nm下的吸光度来定量。胰岛样品中的蛋白质可通过Bio-Rad蛋白质分析在595nm下定量。为了检测胰岛培养上清液中的L-KYN,蛋白质可用5%(w/v)TCA沉淀并在12,000rpm下离心15分钟,且可如上文所描述测定用艾氏试剂进行的上清液中KYN的测定。可如所指出的向培育培养基中添加IL-4(10μg/mL;500-2,000单位/毫升)及1-α-甲基Trp(1-MT;40μmol/L)。此分析也可形成基于细胞的分析的基础,且可经由作为UV/Vis检测之替代方案的LCMS/MS定量。
蛋白质印迹分析.在Miami培养基中在细胞因子存在下培育24小时的1,000-1,200个胰岛的组可经收获且在如上PBS中超声波处理,且50μg蛋白质样品可在10%SDS-PAGE凝胶上进行电泳。用人-IDO质粒(3μg)转染的COS7细胞(0.6×106个细胞/60立方毫米皮氏培养皿)或空载体细胞可分别用作阳性及阴性对照。蛋白质可通过半干法以电泳方式转移至聚偏二氟乙烯膜上且用含5%(w/v)脱脂奶粉的Tris缓冲盐水及0.1%Tween阻断1小时且随后用抗人小鼠IDO抗体(1:500;Chemicon,Temecula,CA)、磷酸化-STAT1αp91及STAT1αp91(1:500;Zymed,San Francisco,CA)培育过夜。在用抗小鼠辣根过氧化酶缀合的二级抗体(Jackson Immunolabs,West Grove,PA)培育1小时之后,免疫反应性蛋白可用ECL蛋白质印迹检测试剂(Amersham BioSciences,Buckinghamshire,U.K.)观测。
IDO的免疫组织化学检测.胰岛可固定在含4%多聚甲醛的PBS(Invitrogen)中1小时,固定在熔融10%猪皮明胶区块(37℃)中,且嵌入最佳切割温度化合物中。对胰岛组织的免疫荧光染色可在7μm用针对胰十二指肠同源盒1(PDX1)及IDO产生的抗体染色的切片进行。抗原修复可在水浴中在含有10mmol/l Tris及1mmol/l EDTA(pH 9.0)的缓冲液中在97℃下进行30分钟。切片可用含5%正常山羊血清的PBS阻断1小时。组织可随后与小鼠单克隆抗人IDO抗体(1:20;Chemicon)及山羊多克隆抗人PDX1抗体(1:2,000;其可自Dr.ChrisWright,School of Medicine,Vanderbilt,TN处请求)在室温下在潮湿腔室中反应过夜。二级抗体抗山羊(用Cy3标记)及抗小鼠(用Cy2标记)可购自Jackson Immunolabs且可以1:200的浓度使用。细胞核可用Hoechst 33258(Molecular Probes,Eugene,OR)染色。图像可通过Intelligent Imaging System软件自配备有Olympus DSU(转盘式共焦)及Hamamatsu ORCAIIER单色CCD摄影机的Olympus 1X81倒置电动显微镜获取。
评估本发明的IDO抑制剂的替代方式描述于WO 2010/0233166中且在下文概述。
生物化学分析.人及小鼠IDO的cDNA克隆已经分离且通过测序检验且为市售的。为了制备用于生物化学研究的IDO,可在大肠杆菌中使用IPTG诱导性pET5a载体系统产生C端His标记的IDO蛋白质且在镍柱上分离。部分纯化蛋白质的产率可通过凝胶电泳检验且浓度通过与蛋白质标准物比较来估计。为了分析IDO酶活性,可按照公开的步骤(参见例如Littlejohn,T.K.等人,Prot.Exp.Purif.,19:22-29(2000))执行用于犬尿氨酸产生的96孔板分光光度法分析。为了筛选IDO抑制活性,化合物可在例如200μM的单一浓度下针对50ngIDO酶以100μL反应体积评估,伴随在例如0、2、20及200μM的增加浓度下添加色氨酸。犬尿氨酸产生可在1小时时测量。
基于细胞的分析.COS-1细胞可用表达IDO cDNA的CMV启动子驱动质粒,使用Lipofectamine 2000(Invitrogen)如制造商所建议瞬时转染。一组伴细胞可用TDO表达质粒瞬时转染。转染后四十八小时,细胞可以6×104个细胞/孔分配成96孔格式。第二天,可洗涤孔且含有20μg/mL色氨酸的新培养基(无酚红)可与抑制剂一起添加。可在5小时时停止反应且移除上清液且如先前针对酶分析所描述以分光光度方式分析犬尿氨酸。为了获得IDO活性的初步确认,化合物可以例如100μM的单一浓度评估。可收集所选化合物的更广泛剂量递增概况。
药效学及药物动力学评估.药效学分析可基于测量犬尿氨酸及色氨酸两者的血清水平,且计算犬尿氨酸/色氨酸比提供独立于基线色氨酸水平的IDO活性的估计值。血清色氨酸及犬尿氨酸水平可通过HPLC分析测定,且血清化合物水平可任选也在相同HPLC运行中测定。
化合物可最初通过用LPS攻击小鼠且随后在血清犬尿氨酸水平平稳时接着给予单次剂量的化合物来评估。因为犬尿氨酸池以在血清中小于10分钟的半衰期快速翻转(turnover),不预期预先存在的犬尿氨酸过度掩盖IDO抑制剂对犬尿氨酸产生的影响。各实验可包括非LPS暴露小鼠(以测定基线犬尿氨酸水平,与另一小鼠比较)及一组仅用媒剂给药的LPS暴露小鼠(以提供IDO活化的阳性对照)。各化合物可最初在小鼠中以在至少100mg/kg范围内的单一高腹膜内单次剂量评估。血液可在规定的时间间隔(例如在化合物给药之后5分钟、15分钟、30分钟、1小时、2小时、4小时、6小时、8小时及24小时,50μL样品)收集用于犬尿氨酸及色氨酸水平的HPLC分析(药效学分析)以及用于化合物的水平(药物动力学分析)。自药物动力学数据,可确定获得的化合物的峰值血清浓度以及估计的清除率。通过比较在各个时间点相对于犬尿氨酸/色氨酸比,化合物在血清中的水平,可粗略地估计体内IDO抑制的有效IC50。可评估展示功效的化合物以确定在峰值浓度下实现100%IDO抑制的最大剂量。
表征或纯化实施例中采用的HPLC/MS及制备型/分析型HPLC方法
使用以下方法进行分析型HPLC/MS:
方法A:使用以下方法的Waters Acquity SDS:2%至98%溶剂B的线性梯度,历时1.7分钟;在220nm下UV观测;柱:BEH C18 2.1mm×50mm;1.7μm粒子(加热至温度50℃);流速:0.8ml/min;流动相A:100%水、0.05%TFA;流动相B:100%乙腈、0.05%TFA。
方法B:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;温度:50℃;梯度:0-100%B,历时3分钟,随后在100%B下保持0.75分钟;流速:1.00mL/min;检测:UV,220nm下。
方法C:Waters SFC-100MS,柱:Chiral OJ-H 25×3cm ID,5μm,流速:100.0mL/min,流动相:80/20 CO2/MeOH,检测器波长:220nm。
方法D:Aurora分析型SFC,柱:Chiral OJ-H 250×4.6mm ID,5μm,流速:2.0mL/min,流动相:80/20 CO2/MeOH。
方法E:Berger制备型SFC,柱:Chiral AS 25×3cm ID,5μm,流速:85.0mL/min,流动相:82/18CO2/MeOH w/0.1%DEA,检测器波长:220nm。
方法F:Aurora分析型SFC,柱:Chiral AS 250×4.6mm ID,5μm,流速:2.0mL/min,流动相:80/20 CO2/MeOH w/0.1%DEA。
方法G:Berger制备型SFC,柱:Chiral AS 25×3cm ID,5μm,流速:85.0mL/min,流动相:86/14CO2/MeOH,检测器波长:220nm。
方法H:Aurora分析型SFC,柱:Chiral AS 250×4.6mm ID,5μm,流速:2.0mL/min,流动相:85/15CO2/MeOH。
方法I:柱:Waters Acquity UPLC BEH C18,2.1×50mm,1.7μm粒子;流动相A:5:95乙腈:水,含0.1%三氟乙酸;流动相B:95:5乙腈:水,含0.1%三氟乙酸;温度:50℃;梯度:0-100%B,历时3分钟,随后在100%B下保持0.75分钟;流速:1.0mL/min;检测:UV,220nm下。
方法J:制备型层析条件:仪器:Berger制备型SFC MGII(LVL-L4021Lab)柱:ChiralIC 25×3cm ID,5μm;流速:85.0mL/min;流动相:74/26CO2/MeOH;检测器波长:220nm。
方法K:制备型层析条件:仪器:Berger制备型SFC MGII(LVL-L4021Lab)柱:ChiralIC 25×3cm ID,5μm;流速:85.0mL/min;流动相:75/25CO2/MeOH保持18分钟,60/40 CO2/MeOH保持11分钟,75/25CO2/MeOH保持3分钟;检测器波长:220nm。
方法L:制备条件:Berger SFC MGII;阶段-1:柱:Chiral OD-H 25×3cm ID,5μm粒子;流动相:82/18CO2/MeOH;检测器波长:220nm;流速:85mL/min。阶段-2:Chiral IF 25×3cm ID,5μm粒子;流动相:80/20CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;阶段-1:柱:Chiral OD-H 250×4.6mm ID,5μm;流动相:80/20CO2/MeOH;流速:2.0mL/min;阶段-2:柱:Chiral IF 250×4.6mm ID,5μm;流动相:80/20 CO2/MeOH;流速:2.0mL/min。Tr与分析条件相对应。
方法M:制备条件:Berger SFC MGII;阶段-1:柱:Chiral OD-H 25×3cm ID,5μm粒子;流动相:80/20 CO2/MeOH;检测器波长:220nm;流速:85mL/min。阶段-2:Chiral IF 25×3cm ID,5μm粒子;流动相:80/20CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;阶段-1:柱:Chiral OD-H 250×4.6mm ID,5μm;流动相:80/20CO2/MeOH;流速:2.0mL/min;阶段-2:柱:Chiral IF 250×4.6mm ID,5μm;流动相:80/20 CO2/MeOH;流速:2.0mL/min。Tr与分析条件相对应。
方法N:制备条件:Berger SFC MGII;柱:125×3cmID,5μm粒子;流动相:80/20 CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:1250×4.6mm ID,5μm;流动相:80/20CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法O:制备条件:Berger SFC MGII;柱:Chiral OJ 25×3cm ID,5μm;流动相:90/10 CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:ChiralOJ 250×4.6mm ID,5μm;流动相:90/10 CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法P:制备条件:Waters SFC-100MS;柱:LUX Cellulose-225×3cm ID,5μm;流动相:75/25CO2/MeOH;检测器波长:220nm;流速:100mL/min。分析条件:Aurora分析型SFC;柱:LUX Cellulose-2 250×4.6mm ID,5μm;流动相:75/25CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法Q:制备条件:Berger SFC MGII;柱:Chiral AD 25×3cm ID,5μm;流动相:80/20 CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:ChiralAD 250×4.6mm ID,5μm;流动相:80/20 CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法R:制备条件:Berger SFC MGII;柱:Chiral AD 25×3cm ID,5μm;流动相:87/13CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:ChiralAD 250×4.6mm ID,5μm;流动相:85/15CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法S:制备条件:Berger SFC MGII;柱:Chiral IF 25×3cm ID,5μm;流动相:75/25CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:ChiralIF 250×4.6mm ID,5μm;流动相:70/30 CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法T:制备条件:Waters SFC100-MS;柱:Chiral IC 25×3cm ID,5μm,结合至R,R25×3cm ID,5μm;流动相:70/30 CO2/MeOH;检测器波长:220nm;流速:100mL/min。分析条件:Aurora分析型SFC;柱:Chiral IC 250×4.6mm ID,5μm,结合至R,R25×3cm ID,5μm;流动相:70/30 CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法U:制备条件:Waters SFC100-MS;柱:Chiral OJ-H 25×3cm ID,5μm;流动相:70/30 CO2/MeOH;检测器波长:220nm;流速:100mL/min。分析条件:Aurora分析型SFC;柱:Chiral OJ-H 250×4.6mm ID,5μm;流动相:70/30 CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法V:制备条件:Berger SFC MGII;柱:Chiral25×3cm ID,5μm;流动相:80/20 CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:Chiral250×4.6mm ID,5μm;流动相:80/20 CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法W:制备条件:Berger SFC MGII;柱:Chiral IC 25×3cm ID,5μm;流动相:85/15CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:ChiralIC 250×4.6mm ID,5μm;流动相:85/15CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法X:制备条件:Berger SFC MGII;柱:Chiral IC 25×3cm ID,5μm;流动相:75/25CO2/MeOH w/0.1%二乙胺;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:Chiral IC 250×4.6mm ID,5μm;流动相:75/25CO2/MeOH w/0.1%二乙胺;流速:2.0mL/min;Tr与分析条件相对应。
方法Y:流动相:80/20 CO2/MeOH/CAN 50/50;流速:2.0mL/min;Tr将:制备条件:Berger SFC MGII;柱:Chiral AD 25×3cm,5μm;流动相:80/20 CO2/MeOH/CAN 50/50;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:Chiral AD 250×4.6mmID,5μm;对应于分析条件。
方法Z:制备条件:Berger SFC MGII;柱:Chiral IC 25×3cm,5μm;流动相:83/17CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:ChiralIC 250×4.6mm ID,5μm;流动相:80/20CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法AA:制备条件:Waters SFC100-MS;柱:Chiral AS-H结合的Chiral OJ-H 25×3cm,5μm;流动相:70/30 CO2/MeOH;检测器波长:220nm;流速:100mL/min。分析条件:分析型SFC;柱:Chiral AS-H,结合至Chiral OJ-H,250×4.6mm ID,5μm;流动相:70/30 CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法AB:使用以下方法的Waters Acquity SDS:2%至98%溶剂B的线性梯度,历时1.6分钟;在220nm下UV观测;柱:BEH C18 2.1mm×50mm;1.7μm粒子(加热至温度50℃);流速:1ml/min;流动相A:100%水、0.05%TFA;流动相B:100%乙腈、0.05%TFA。
方法AC:制备条件:Berger SFC MGII;柱:Chiral AD 25X 3cm ID,5-μm;流动相:90/10 CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:Chiral AD 250X 4.6mm ID,5μm;流动相:90/20 CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法AD:制备条件:Berger SFC MGII;柱:Whelk-O1Kromasil 25X 3cm ID,5-μm粒子;流动相:85/15CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:Whelk-O1Kromasil 250X 4.6mm ID,5μm;流动相:85/15CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
方法AE:制备条件:Berger SFC MGII;柱:Whelk-O1Kromasil 25X 3cm ID,5-μm粒子;流动相:75/25CO2/MeOH;检测器波长:220nm;流速:85mL/min。分析条件:Aurora分析型SFC;柱:Whelk-O1Kromasil 250X 4.6mm ID,5μm;流动相:75/25CO2/MeOH;流速:2.0mL/min;Tr与分析条件相对应。
实施例表征中采用的NMR
使用在400MHz或500MHz下操作的或Bruker变换光谱仪获得1H NMR谱(除非另外说明)。
光谱数据以化学位移(多重性、氢数目、以Hz为单位的偶合常数)形式报导且相对于1H NMR谱的内标(四甲基硅烷=0ppm)或参考残余溶剂峰(CD3SOCD2H为2.49ppm,CD2HOD为3.30ppm,CHD2CN为1.94,CHCl3为7.26ppm,CDHCl2为5.32ppm)以ppm为单位(δ单位)报导。NMR峰的描述中使用的缩写:“a”=表观,“br.s.”=宽单峰。
实施例
一般步骤:
一般步骤A.自酸形成酰胺键。
向羧酸(4.4mmol)在二甲基甲酰胺(DMF,15mL)中的搅拌溶液中添加苯胺(6.6mmol)、二异丙基乙胺(1.53mL,8.8mmol)及1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU)(2.00g,5.28mmol)。在室温下搅拌所得反应混合物3小时,此时添加3M HCl(30mL)及CH2Cl2(30mL)。分离各层,且用CH2Cl2(2×30mL)萃取水层。合并的有机萃取物经无水硫酸钠干燥且在减压下浓缩。通过硅胶层析法纯化所得粗残余物以得到所需产物。
一般步骤B.胺与酰氯之间的反应.
向胺(1.1当量)及NEt3(5.0当量)在CH2Cl2(0.1M)中的溶液中添加酰氯(1.0当量)。在室温下搅拌所得反应混合物15分钟且随后在减压下浓缩。使用硅胶层析法(0%至100%EtOAc/己烷)纯化粗反应混合物以得到所需产物。
顺-4-苯基环己烷-1-甲醛:根据文献步骤(Fox,B.M.等人,J.Med.Chem.,57:3464-3483(2014))制备。使用硅胶层析法(0%至10%EtOAc/己烷)纯化粗混合物以得到作为第一洗脱异构体的所需产物。
顺-(4-苯基环己基)甲醇:在室温下向顺-4-苯基环己烷-1-甲醛(825mg,4.4mmol)在THF(25mL)及MeOH(7mL)中的溶液中历经5分钟逐份添加NaBH4。在室温下搅拌所得混合物45分钟。随后逐滴添加HCl(1M)。用EtOAc(3×)萃取混合物。用盐水洗涤合并的有机层,经Na2SO4干燥且在减压下浓缩。使用硅胶层析法(0%至25%EtOAc/己烷)纯化所得粗混合物以得到所需产物。
顺-(4-(碘甲基)环己基)苯:在0℃下向顺-(4-苯基环己基)甲醇(2g,10.5mmol)、三苯基膦(3.3g,12.6mmol)及咪唑(1.1g,15.8mmol)在CH2Cl2(70mL)中的溶液中添加碘(3.5g,13.7mmol)。使混合物升温至室温且在室温下搅拌2小时。用CH2Cl2稀释混合物且用硫代硫酸钠(2M)洗涤。有机层经无水MgSO4干燥,过滤,且在减压下浓缩。使用硅胶层析法(0%至25%EtOAc/己烷)纯化粗反应混合物以得到呈油状物的所需产物(3g,95%)。
顺-(4-(叠氮基甲基)环己基)苯:向顺-(4-(碘甲基)环己基)苯(2.6g,8.8mmol)在DMF(44mL)中的溶液中添加叠氮化钠(2.8g,43.8mmol)。在室温下搅拌混合物2小时。随后添加更多叠氮化钠(1.14g,17.5mmol)且在室温下搅拌混合物18小时。用Et2O稀释混合物且用水、1M LiCl(2×)及盐水洗涤。有机层经Na2SO4干燥且在减压下浓缩以得到所需产物(1.5g,80%)。
顺-(4-苯基环己基)甲胺:向顺-(4-(叠氮基甲基)环己基)苯(1.5g,7.0mmol)在THF(35mL)中的溶液中添加三苯基膦(2.56g,9.8mmol)。在室温下搅拌混合物30分钟且随后添加水(0.83mL)。在室温下搅拌混合物24小时。将混合物预吸收至硅胶上且使用硅胶层析法[0%至5%(2M NH3/MeOH)/CH2Cl2]纯化以得到呈油状物的所需产物(1.2g,94%)。
实施例1
顺-4-氰基-N-((4-苯基环己基)甲基)苯甲酰胺
用一般步骤B,使用含顺-(4-苯基环己基)甲胺(19mg,0.1mmol)、4-氰基苯甲酰氯(17mg,0.1mmol)及NEt3(51mg,0.5mmol)的CH2Cl2(1mL)制备。使用硅胶层析法(10%至30%EtOAc/己烷)纯化以得到呈白色固体的所需产物。1H NMR(400MHz;CDCl3):δ7.89-7.86(m,2H),7.74-7.71(m,2H),7.32-7.17(m,5H),6.32-6.30(m,1H),3.58(dd,J=7.7,6.0Hz,2H),2.66-2.59(m,1H),2.06-2.00(m,1H),1.80-1.69(m,8H)。m/z 319.3(M+H+)。
实施例2
顺-3-氰基-N-((4-苯基环己基)甲基)苯甲酰胺
用一般步骤B,使用含顺-(4-苯基环己基)甲胺(19mg,0.1mmol)、3-氰基苯甲酰氯(17mg,0.1mmol)及NEt3(51mg,0.5mmol)的CH2Cl2(1mL)制备。使用硅胶层析法(10%至30%EtOAc/己烷)纯化以得到呈白色固体的所需产物。1H NMR(400MHz;CDCl3):δ8.09-8.08(m,1H),8.04(dt,J=7.9,1.5Hz,1H),7.76(dt,J=7.7,1.3Hz,1H),7.56(t,J=7.8Hz,1H),7.32-7.17(m,5H),6.49-6.46(m,1H),3.58(dd,J=7.7,6.0Hz,2H),2.66-2.59(m,1H),2.07-2.01(m,1H),1.80-1.68(m,8H)。m/z 319.2(M+H+)。
实施例3
顺-4-氯-N-((4-苯基环己基)甲基)苯甲酰胺
用一般步骤B,使用含顺-(4-苯基环己基)甲胺(19mg,0.1mmol)、4-氯苯甲酰氯(19mg,0.1mmol)及NEt3(51mg,0.5mmol)的CH2Cl2(1mL)制备。使用硅胶层析法(0%至20%EtOAc/己烷)纯化以得到呈白色固体的所需产物。1H NMR(400MHz;CDCl3):δ7.73-7.69(m,2H),7.41-7.38(m,2H),7.31-7.23(m,4H),7.20-7.16(m,1H),3.55(dd,J=7.7,5.9Hz,2H),2.63-2.59(m,1H),2.04-1.98(m,1H),1.79-1.67(m,8H)。m/z 328.2(M+H+)。
实施例4
顺-3-氯-N-((4-苯基环己基)甲基)苯甲酰胺
用一般步骤B,使用含顺-(4-苯基环己基)甲胺(19mg,0.1mmol)、3-氯苯甲酰氯(19mg,0.1mmol)及NEt3(51mg,0.5mmol)的CH2Cl2(1mL)制备。使用硅胶层析法(0%至20%EtOAc/己烷)纯化以得到呈白色固体的所需产物。1H NMR(400MHz;CDCl3):δ7.76(t,J=1.8Hz,1H),7.64(dt,J=7.7,1.4Hz,1H),7.47-7.44(m,1H),7.38-7.34(m,1H),7.31-7.23(m,4H),7.20-7.16(m,1H),6.30-6.27(m,1H),3.56(dd,J=7.7,6.0Hz,2H),2.64-2.58(m,1H),2.04-1.99(m,1H),1.79-1.66(m,8H)。m/z 328.2(M+H+)。
实施例5
顺-4-氟-N-((4-苯基环己基)甲基)苯甲酰胺
用一般步骤B,使用含顺-(4-苯基环己基)甲胺(16mg,0.1mmol)、4-氟苯甲酰氯(19mg,0.1mmol)及NEt3(51mg,0.5mmol)的CH2Cl2(1mL)制备。使用硅胶层析法(0%至20%EtOAc/己烷)纯化以得到呈白色固体的所需产物。
实施例6
顺-4-氯-N-((4-苯基环己基)甲基)苯磺酰胺
以一般步骤B的方式,使用含顺-(4-苯基环己基)甲胺(38mg,0.2mmol)、4-氯苯磺酰氯(42mg,0.2mmol)及NEt3(101mg,0.5mmol)的CH2Cl2(1mL)制备。使用硅胶层析法(0%至25%EtOAc/己烷)纯化以得到呈白色固体的所需产物。1H NMR(400MHz;CDCl3):δ7.87-7.83(m,2H),7.52-7.48(m,2H),7.31-7.27(m,2H),7.20-7.16(m,3H),5.10(t,J=6.2Hz,1H),3.01(dd,J=7.7,6.3Hz,2H),2.56(dt,J=9.8,5.0Hz,1H),1.87-1.81(m,1H),1.68-1.52(m,8H)。m/z364.1(M+H+)。
实施例7
(4-苯甲基哌啶-1-基)(4-氯苯基)甲酮
向含异氰酸4-氯苯酯(154mg,1.0mmol)的Et2O(5mL)中添加4-苯甲基哌啶(193mg,1.1mmol)。均质反应混合物历经15分钟产生沉淀。冷却反应混合物至0℃且通过过滤收集固体,用额外Et2O(25mL)洗涤,以提供呈白色固体的所需产物。1H NMR(400MHz;CDCl3):δ7.31-7.28(m,4H),7.25-7.21(m,3H),7.16-7.14(m,2H),6.32(s,1H),4.05-4.01(m,2H),2.83(td,J=12.9,2.1Hz,2H),2.57(d,J=6.9Hz,2H),1.77-1.70(m,3H),1.31-1.20(m,2H)。m/z329.2(M+H+)。
实施例8
(4-苯甲基哌啶-1-基)(3-氯苯基)甲酮
向含异氰酸3-氯苯酯(154mg,1.0mmol)的Et2O(5mL)中添加4-苯甲基哌啶(193mg,1.1mmol)。均质反应混合物历经15分钟产生沉淀。冷却反应混合物至0℃且通过过滤收集固体,用额外Et2O(25mL)洗涤,以提供呈白色固体的所需产物。1H NMR(400MHz;CDCl3):δ7.47(t,J=1.2Hz,1H),7.29(q,J=6.4Hz,2H),7.23-7.14(m,5H),7.01-6.96(m,1H),6.33(s,1H),4.05-4.01(m,2H),2.83(td,J=12.9,2.1Hz,2H),2.59-2.52(m,2H),1.78-1.71(m,3H),1.31-1.21(m,2H)。m/z 329.2(M+H+)。
实施例9
顺-N-4-氯-(2-(4-(4-甲氧基苯基)环己基)乙基)苯胺
9A.2-(4-(4-羟苯基)亚环己基)乙酸乙酯
在0℃下历经1小时向NaH(在油中的60%分散体,11.8g,295mmol)在THF(120mL)中的溶液中逐滴添加含膦酰基乙酸三乙酯(46.9mL,236mmol)的THF(250mL)。使混合物升温至室温且在室温下搅拌1小时。在单独烧瓶中,在0℃下向NaH(在油中的60%分散体,8.67g,216mmol)在THF(100mL)中的混合物中小心添加4-(4-羟苯基)环己酮(37.5g,197mmol)在THF(250mL)中的溶液。在室温下搅拌混合物2小时。在0℃下经由套管插入法向膦酸酯混合物中添加环己酮的混合物。使混合物升温至室温且在室温下搅拌2小时。通过小心添加冰及水(1L)淬灭混合物且随后用乙酸乙酯(3×500mL)萃取且合并的有机物随后用盐水(1L)洗涤,经硫酸钠干燥,过滤并浓缩,以97%产率提供呈白色固体的2-(4-(4-羟苯基)亚环己基)乙酸乙酯。
9B.2-(4-(4-羟苯基)环己基)乙酸乙酯
向2-(4-(4-羟苯基)亚环己基)乙酸乙酯(9.74g,35.8mmol)在乙酸乙酯中的溶液中添加Pd/C(0.974g,10wt%)。反应溶液用H2气体的气球充气且在氢气氛围下搅拌过夜持续2天。经由过滤反应混合物,用乙酸乙酯充分洗涤,且在减压下浓缩,以定量产率得到呈白色结晶固体的作为非对映异构体混合物的所需产物。
9C.2-(4-(4-甲氧基苯基)环己基)乙酸乙酯
使实施例9B的产物(20.0g,76.2mmol,1.0当量)的溶液溶解于770mL DMF中。向此溶液中添加6mL(95mmol,1.25当量)碘甲烷,随后添加碳酸铯(43.3g,133mmol,1.75当量)。随后搅拌此混合物16小时直至如通过LCMS所监测的,起始物质耗尽。随后通过冷却至0℃且随后添加1.35L水来淬灭反应。随后用乙酸乙酯(3×500mL)萃取混合物且用盐水(1L)洗涤合并的有机物且经硫酸钠干燥,随后过滤及浓缩。经由柱层析法(5%乙酸乙酯/己烷)纯化粗残余物,以69%产率得到呈澄清油状物的最终化合物。(在10%乙酸乙酯/己烷中Rf=0.5)。
9D.2-(4-(4-甲氧基苯基)环己基)乙酸
向水(8mL)中添加氢氧化锂(1.58g,66.2mmol)。允许浆液在室温下静置30分钟,随后过滤。向实施例9C的产物(2.95g,10.67mmol)在EtOH(9mL)中的溶液中添加滤液。在室温下搅拌浆液2天且用水稀释。过滤混合物且用EtOAc及1M HCl稀释固体。分离各层且有机层经硫酸钠干燥且在减压下浓缩,以提供2-(4-(4-甲氧基苯基)环己基)乙酸。
9E及9F.顺-N-(4-氯苯基)-2-(4-(4-甲氧基苯基)环己基)乙酰胺及反-N-(4-氯苯基)-2-(4-(4-甲氧基苯基)环己基)乙酰胺
用一般步骤A,使用含2-(4-(4-甲氧基苯基)环己基)乙酸(实施例9D的产物,124mg,0.5mmol)、4-氯苯胺(97mg,0.75mmol)、HATU(435mg,0.75mmol)及iPr2NEt(323mg,2.5mmol)的DMF(1.0mL)制备。使用硅胶层析法(0%至25%EtOAc/己烷)纯化得到作为第一洗脱异构体的顺-N-(4-氯苯基)-2-(4-(4-甲氧基苯基)环己基)乙酰胺(实施例9E)(白色固体),及作为第二洗脱异构体的反-N-(4-氯苯基)-2-(4-(4-甲氧基苯基)环己基)乙酰胺(实施例9F)。
顺-N-(4-氯苯基)-2-(4-(4-甲氧基苯基)环己基)乙酰胺:1H NMR(400MHz;CDCl3):δ7.49-7.45(m,2H),7.29-7.26(m,2H),7.17-7.15(m,3H),6.87-6.83(m,2H),3.79(s,3H),2.63-2.55(m,1H),2.45-2.37(m,3H),1.77-1.64(m,8H)。m/z358.2(M+H+)。
实施例9.顺-N-4-氯-(2-(4-(4-甲氧基苯基)环己基)乙基)苯胺
在室温下向顺-N-(4-氯苯基)-2-(4-(4-甲氧基苯基)环己基)乙酰胺(33mg,0.092mmol)在THF(0.5mL)中的溶液中添加硼烷四氢呋喃复合物溶液(0.5mL,0.5mmol,在THF中1M)。在室温下搅拌所得混合物2.5小时,此时添加HCl水溶液(1M)且在室温下搅拌混合物30分钟。观察到气体释放。混合物用饱和Na2CO3碱化且用CH2Cl2(2×)萃取。合并的有机层经无水Na2SO4干燥,过滤,且在减压下浓缩。使用硅胶层析法(0%至10%EtOAc/己烷)纯化所得粗混合物以得到所需产物。1H NMR(400MHz,CDCl3)δ7.19-7.09(m,4H),6.90-6.81(m,2H),6.56(d,J=8.7Hz,2H),3.80(s,3H),3.17-3.07(m,2H),2.55(s,1H),1.85(s,1H),1.80-1.63(m,10H)。m/z 344.2(M+H+)。
实施例10
反-N-4-氯-(2-(4-(4-甲氧基苯基)环己基)乙基)苯胺
使用来自先前实施例的步骤,使用73mg反-N-(4-氯苯基)-2-(4-(4-甲氧基苯基)环己基)乙酰胺制备。使用硅胶层析法(0%至10%EtOAc/己烷)纯化以得到所需产物。1HNMR(400MHz,CDCl3)δ7.17-7.09(m,4H),6.89-6.81(m,2H),6.58-6.51(m,2H),3.80(s,3H),3.18-3.09(m,2H),2.45(t,J=12.3Hz,1H),1.90(d,J=12.3Hz,4H),1.67-1.47(m,4H),1.44(dd,J=17.5,7.8Hz,2H),1.14(dd,J=22.1,12.0Hz,2H)。m/z 344.2(M+H+)。
实施例11
(+/-)顺-3-苯基环戊基(4-氯苯基)氨基甲酸酯
11A.(+/-)-顺-3-苯基环戊-1-醇
如先前所描述(Yamamoto,T.等人,J.Organomet.Chem.,694:1325-1332(2009))制备3-苯基环戊-1-酮。向冷却至0℃的3-苯基环戊-1-酮(1.0g,6.2mmol)在30mL甲醇中的溶液中添加NaBH4(0.27g,7.2mmol)。移除冰浴,且允许反应升温至室温且搅拌3小时。用1MHCl淬灭反应且用EtOAc(30mL)稀释,且分离各层。有机萃取物经无水MgSO4干燥,过滤,且在减压下浓缩。使用硅胶层析法(15%EtOAc/戊烷)纯化~1.6:1顺式:反式醇的所得粗混合物以得到呈无色油状物的所需顺-3-苯基环戊-1-醇(118mg,12%)。1H NMR(400MHz;CDCl3):δ7.16-7.09(m,5H),4.43-4.40(m,1H),3.06-3.00(m,1H),2.70(br s,1H),2.53-2.43(m,1H),2.06-1.63(m,5H)。
实施例11.(+/-)-顺-3-苯基环戊基(4-氯苯基)氨基甲酸酯
向顺-3-苯基环戊-1-醇(150mg,0.95mmol)在CH2CH2中的溶液中添加异氰酸4-氯苯酯(150mg,0.95mmol)。在5分钟之后,在减压下浓缩反应混合物且用乙醚(10mL)磨碎(triturate)。过滤混合物,用乙醚冲洗,得到呈白色固体的所需产物。1H NMR(400MHz;DMSO-d6):δ9.79(br s,1H),7.49(d,J=7.5Hz,2H),7.33-7.14(m,7H),5.09-5.04(m,1H),3.13-3.02(m,1H),2.60-2.48(m,1H),2.08-1.61(m,6H)。
实施例12
顺-(4-苯基环己基)甲基(4-氟苯基)氨基甲酸酯
向顺-(4-苯基环己基)甲醇(200mg,1.05mmol)在乙醚(5mL)中的溶液中添加异氰酸4-氟苯酯(144mg,1.05mmol)。在起始物质耗尽后,浓缩所得溶液,提供白色固体,其在乙醚(3mL)中经磨碎且经过滤以得到呈白色固体的所需产物。1H NMR(400MHz;DMSO-d6):δ9.65(br s,1H),7.48-7.42(m,2H),7.18-7.06(m,7H),4.20(d,J=9.5Hz,2H),2.61-2.51(m,1H),2.07-2.01(m,1H),1.77-1.57(m,8H)。
实施例13
反-1-(4-氟苯基)-3-(4-苯基环己基)脲
在室温下向反-4-苯基环己胺(Combi-Blocks,San Diego,CA)(50mg,0.3mmol)在乙醚中的搅拌溶液中添加异氰酸4-氟苯酯(0.032mL,0.3mmol)。在搅拌30分钟之后,通过真空过滤分离大量白色沉淀,以产生所需产物。1H NMR(400MHz,CDCl3)δ7.35-7.14(m,7H),7.07-6.97(m,2H),6.00(s,1H),4.41-4.30(m,1H),3.83-3.65(m,1H),2.56-2.39(m,1H),2.21-2.10(m,2H),1.99-1.88(m,2H),1.72-1.46(m,2H),1.37-1.07(m,2H)。
实施例14
反-1-(4-氯苯基)-3-(4-苯基环己基)脲
在室温下向反-4-苯基环己胺(50mg,0.3mmol)在乙醚中的搅拌溶液中添加异氰酸4-氯苯酯(44mg,0.3mmol)。在搅拌30分钟之后,通过真空过滤分离大量白色沉淀,以产生所需产物。1H NMR(400MHz,CDCl3)δ7.38-7.12(m,9H),6.05(s,1H),4.39(d,J=7.4Hz,1H),3.88-3.61(m,1H),2.56-2.40(m,1H),2.28-2.12(m,2H),2.00-1.89(m,2H),1.71-1.59(m,2H),1.36-1.16(m,2H)。
实施例15
反-1-(3-氯苯基)-3-(4-苯基环己基)脲
在室温下向反-4-苯基环己胺(50mg,0.3mmol)在乙醚(1.4mL)中的搅拌溶液中添加异氰酸3-氯苯酯(0.035mL,0.3mmol)。在搅拌30分钟之后,通过真空过滤分离大量白色沉淀,且在减压下浓缩,以产生所需产物。1H NMR(400MHz,CDCl3)δ7.42(t,J=2.0Hz,1H),7.34-7.11(m,7H),7.08-7.02(m,1H),6.14(s,1H),4.47(s,1H),3.85-3.62(m,1H),2.61-2.39(m,1H),2.27-2.12(m,2H),2.02-1.89(m,2H),1.74-1.57(m,2H),1.39-1.19(m,2H)。
实施例16
反-2-(3-氯苯基)-N-(4-苯基环己基)乙酰胺
根据一般步骤A,使用反-4-苯基环己胺及3-氯苯基乙酸制备。通过硅胶层析法(0%至50%乙酸乙酯/己烷)纯化,其提供呈白色固体的所需产物。1H NMR(400MHz,CDCl3)δ7.36-7.12(m,9H),5.21(d,J=7.9Hz,1H),3.84(tdt,J=12.0,8.1,4.0Hz,1H),3.53(s,2H),2.51-2.37(m,1H),2.13-1.99(m,2H),1.99-1.85(m,2H),1.67-1.49(m,2H),1.29-1.09(m,2H).m/z 328.2(M+H+)。
实施例17
顺-1-(4-氯苯基)-3-(4-苯基环己基)脲
在室温下向顺-4-苯基环己胺(Li,G.等人,Bioorg.Med.Chem.Lett.,18:1146-1150(2008))(60mg,0.34mmol)在乙醚(1.4mL)中的搅拌溶液中添加异氰酸4-氯苯酯(53mg,0.34mmol)。在搅拌30分钟之后,通过真空过滤分离大量白色沉淀,且在减压下浓缩,以产生所需产物。1H NMR(400MHz,CDCl3)δ7.37-7.09(m,9H),6.28(s,1H),4.88(d,J=7.2Hz,1H),4.17-4.03(m,1H),2.68-2.49(m,1H),1.98-1.87(m,2H),1.87-1.69(m,4H),1.65-1.50(m,2H)。
实施例18
顺-1-(3-氯苯基)-3-(4-苯基环己基)脲
在室温下向顺-4-苯基环己胺(60mg,0.36mmol)在乙醚(1.4mL)中的搅拌溶液中添加异氰酸3-氯苯酯(0.042mL,0.34mmol)。在搅拌30分钟之后,通过真空过滤分离大量白色沉淀,且在减压下浓缩,以产生所需产物。1H NMR(400MHz,CDCl3)δ7.47-7.42(m,1H),7.35-7.14(m,7H),7.04(dt,J=7.5,1.7Hz,1H),6.37(s,1H),4.98(d,J=6.6Hz,1H),4.21-4.02(m,1H),2.68-2.50(m,1H),2.00-1.87(m,2H),1.88-1.67(m,4H),1.67-1.49(m,2H)。
实施例19
顺-2-(4-氯苯基)-N-(4-苯基环己基)乙酰胺
根据一般步骤A,使用顺-4-苯基环己胺及4-氯苯基乙酸(Li,G.等人,Bioorg.Med.Chem.Lett.,18:1146-1150(2008))制备。通过硅胶层析法(0%至50%乙酸乙酯/己烷)纯化,其提供呈白色固体的所需产物。1H NMR(400MHz,CDCl3)δ7.43-7.17(m,7H),7.07(dd,J=7.5,0.8Hz,2H),5.86(s,1H),4.25-4.05(m,1H),3.60(s,2H),2.60-2.46(m,1H),1.89-1.55(m,6H),1.42-1.22(m,2H).m/z328.2(M+H+)。
一般步骤C:酯与苯胺之间的反应.
在0℃下向苯胺(2.0当量)在THF(0.25M)中的溶液中添加iPrMgCl(2.0当量,在THF中2M)的溶液。使所得溶液升温至室温且搅拌5分钟,此时逐滴添加酯(1.0当量)。在室温下搅拌所得反应混合物8小时且倒入水中。添加EtOAc,且分离各层。用EtOAc(3×)萃取水层。合并的有机萃取物经无水MgSO4干燥,过滤,且在减压下浓缩。使用硅胶层析法(0%至100%EtOAc/己烷)纯化粗反应混合物以得到所需产物。
实施例20
顺-4-苯甲基-N-(4-氯苯基)环己烷-1-甲酰胺
使用一般步骤C,使用可通过WO2005080317A2中显示的方法制备的4-苯甲基环己烷-1-甲酸乙酯(250mg,1.0mmol)及4-氯苯胺(191mg,1.5mmol)制备。使用硅胶层析法(0%至50%EtOAc/己烷)纯化得到所需产物。1H NMR(400MHz;CDCl3):δ7.49(d,J=8.8Hz,2H),7.28(d,J=8.7Hz,2H),7.23-7.10(m,5H),2.62(d,J=7.7Hz,2H),2.48-2.37(m,1H),2.04-1.93(m,2H),1.88-1.82(m,2H),1.74-1.43(m,4H),1.10-0.93(m,1H);m/z 328.1(M+H+)。
实施例21
反-4-苯甲基-N-(4-氯苯基)环己烷-1-甲酰胺
自先前实施例中的柱子进一步洗脱得到作为第二洗脱异构体的所需产物。1H NMR(400MHz;CDCl3):δ7.46(d,J=8.8Hz,2H),7.31-7.26(m,3H),7.26-7.24(m,1H),7.22-7.11(m,4H),2.52(d,J=7.1Hz,2H),2.20-2.10(m,1H),1.97(d,J=11.4Hz,2H),1.86-1.73(m,2H),1.57-1.45(m,3H),1.38-1.24(m,2H);m/z 328.1(M+H+)。
实施例22
顺-4-苯甲基-N-(4-氰基苯基)环己烷-1-甲酰胺
使用一般步骤C,使用4-苯甲基环己烷-1-甲酸乙酯(250mg,1.0mmol)及4-氨基苯甲腈(177mg,1.5mmol)制备。使用硅胶层析法(0%至50%EtOAc/己烷)纯化得到所需产物。1H NMR(400MHz;CDCl3):δ7.73-7.63(m,2H),7.63-7.55(m,2H),7.51(s,1H),7.32-7.24(m,2H),7.23-7.10(m,3H),2.61(d,J=7.6Hz,2H),2.49-2.45(m,1H),2.04-1.91(m,1H),1.89-1.77(m,1H),1.74-1.46(m,7H);m/z 319.2(M+H+)。
实施例23
反-4-苯甲基-N-(4-氰基苯基)环己烷-1-甲酰胺
自先前实施例中的柱子进一步洗脱得到作为第二洗脱异构体的所需产物。1H NMR(400MHz;CDCl3):δ7.73-7.63(m,2H),7.63-7.55(m,2H),7.46(s,1H),7.32-7.24(m,2H),7.23-7.10(m,3H),2.52(d,J=7.1Hz,2H),2.21(tt,J=12.1,3.4Hz,1H),2.04-1.91(m,2H),1.89-1.77(m,2H),1.74-1.46(m,3H),1.03(qd,J=13.2,3.5Hz,2H);m/z 319.2(M+H+)。
实施例24
顺-4-苯甲基-N-(4-氟苯基)环己烷-1-甲酰胺
使用一般步骤C,使用4-苯甲基环己烷-1-甲酸乙酯(250mg,1.0mmol)及4-氟苯胺(0.15mL,1.5mmol)制备。使用硅胶层析法(0%至50%EtOAc/己烷)纯化得到所需产物。1HNMR(400MHz;CDCl3):δ7.48(ddd,J=10.5,6.9,4.8Hz,2H),7.34-7.11(m,5H),7.09-6.94(m,3H),2.62(d,J=7.6Hz,2H),2.48-2.36(m,1H),2.04-1.92(m,2H),1.88-1.76(m,1H),1.74-1.40(m,5H),1.12-0.94(m,1H);m/z 312.2(M+H+)。
实施例25
反-4-苯甲基-N-(4-氟苯基)环己烷-1-甲酰胺
自先前实施例中的柱子进一步洗脱得到作为第二洗脱异构体的所需产物。1H NMR(400MHz;CDCl3):δ7.46(dd,J=9.0,4.8Hz,2H),7.33-7.11(m,5H),7.10-6.95(m,3H),2.52(d,J=7.0Hz,2H),2.20-2.11(m,1H),1.97(d,J=10.4Hz,2H),1.84(d,J=13.0Hz,2H),1.61-1.44(m,3H),1.00(dd,J=29.4,10.9Hz,2H);m/z 312.2(M+H+)。
实施例26
顺-4-苯甲基-N-(4-甲氧基苯基)环己烷-1-甲酰胺
使用一般步骤C,使用4-苯甲基环己烷-1-甲酸乙酯(250mg,1.0mmol)及4-甲氧基苯胺(185mg,1.5mmol)制备。使用硅胶层析法(0%至50%EtOAc/己烷)纯化得到所需产物。1H NMR(400MHz;CDCl3):δ7.46-7.38(m,2H),7.33-7.23(m,2H),7.22-7.09(m,4H),6.92-6.80(m,2H),3.79(s,3H),2.62(d,J=7.6Hz,2H),2.48-2.35(m,1H),2.05-1.95(m,2H),1.86-1.75(m,1H),1.70-1.63(m,2H),1.65-1.48(m,4H);m/z 324.2(M+H+)。
实施例27
反-4-苯甲基-N-(4-甲氧基苯基)环己烷-1-甲酰胺
自先前实施例中的柱子进一步洗脱得到作为第二洗脱异构体的所需产物。1H NMR(400MHz;CDCl3):δ7.40(d,J=9.0Hz,2H),7.29(d,J=7.0Hz,2H),7.23-7.09(m,3H),7.01(s,1H),6.84(d,J=8.9Hz,2H),3.78(s,3H),2.52(d,J=6.9Hz,2H),2.15(tt,J=12.2,3.5Hz,1H),1.98(d,J=11.2Hz,2H),1.83(d,J=13.6Hz,2H),1.55-1.49(m,3H),1.04(qd,J=13.3,3.3Hz,2H);m/z 324.2(M+H+)。
实施例29
N-苯甲基-2-(4-(4-甲氧基苯基)环己基)乙酰胺
在室温下向2-(4-(4-甲氧基苯基)环己基)乙酸(9D的产物,152mg,0.61mmol)在CH2Cl2(1.2mL)中的溶液中添加乙二酰氯(63μL,0.73mmol)及一滴DMF。观察到气体释放且混合物颜色变成黄色。在室温下搅拌混合物1小时且随后在减压下浓缩。使残余物溶解于CH2Cl2(1.2mL)中且在室温下添加苯甲胺(67μL,0.61mmol)及三乙胺(85μL,0.61mmol)。形成白色沉淀且添加更多三乙胺(170μL,1.22mmol)及CH2Cl2(1.2mL)。在室温下搅拌均质混合物3小时。在减压下浓缩混合物。使残余物溶解于EtOAc中且用饱和NaHCO3及盐水洗涤。有机层经硫酸钠干燥且在减压下浓缩。使用硅胶层析法(35%EtOAc/己烷)纯化残余物以得到异构体的混合物。残余物自庚烷/IPA重结晶以得到呈白色固体的作为反式:顺式异构体的2:1混合物的所需产物。m/z 338.3(M+H+)。
实施例30
顺-N-苯甲基-2-(4-(4-甲氧基苯基)环己基)乙酰胺
在减压下浓缩来自先前实施例的母液得到所需产物。1H NMR(400MHz,CDCl3)δ7.45-7.23(m,5H),7.20-7.07(m,2H),6.92-6.71(m,2H),5.80(s,1H),4.46(d,J=5.7Hz,2H),3.79(s,3H),2.66-2.48(m,1H),2.38-2.28(m,3H),1.79-1.58(m,8H);m/z 338.2(M+H+)。
实施例31
N-(4-氯苯基)-4-苯氧基哌啶-1-甲酰胺
31A.N-(4-氯苯基)-4-氧代哌啶-1-甲酰胺
使哌啶-4-酮盐酸盐(1.37g,10.1mmol)溶解于CH2Cl2中,用1M NaOH(60mL)洗涤,经无水MgSO4干燥,过滤,且在减压下浓缩,以提供呈澄清无色油状物的游离碱。用CH2Cl2(6mL)稀释哌啶-4-酮,且冷却溶液至0℃。向溶液中添加异氰酸4-氯苯酯(1.59g,10.1mmol),且立即移除冰浴。在3小时之后,用盐水(10mL)及1M NaOH(2mL)稀释反应混合物且用CH2Cl2(2×30mL)萃取。合并的有机层经无水MgSO4干燥,过滤,且在减压下浓缩得到呈白色固体的所需中间体。1H NMR(400MHz;CDCl3):8.80(s,1H),7.50(d,J=9.0Hz,2H),7.27(d,J=8.8Hz,2H),3.72(t,J=6.2Hz,4H),2.38(t,J=6.2Hz,4H);m/z253.1(M+H+)。
31B.N-(4-氯苯基)-4-羟基哌啶-1-甲酰胺
在室温下向N-(4-氯苯基)-4-氧代哌啶-1-甲酰胺(401mg,1.58mmol)在甲醇(20mL)中的溶液中添加NaBH4(89mg,2.36mmol)。允许反应搅拌14小时,随后添加1M HCl(20mL)。用CH2Cl2(60mL)萃取溶液,经无水MgSO4干燥,过滤,且在减压下浓缩以得到呈油状物的所需产物。1H NMR(400MHz;CDCl3):8.57(s,1H),7.46(d,J=9.0Hz,2H),7.24(d,J=9.0Hz,2H),4.70(d,J=4.3Hz,1H),3.79(td,J=4.3,13.6Hz,2H),3.68-3.58(m,1H),3.02(ddd,J=3.2,10.0,13.3Hz,2H),1.75-1.67(m,2H),1.34-1.21(m,2H)。
实施例31.N-(4-氯苯基)-4-苯氧基哌啶-1-甲酰胺
在室温下向N-(4-氯苯基)-4-羟基哌啶-1-甲酰胺(100mg,0.39mmol)及PPh3(430mg,1.6mmol)在THF(2mL)中的溶液中添加偶氮二甲酸二乙酯(DEAD)(0.068mL,0.43mmol)及苯酚(41mg,0.43mmol)。允许溶液在室温下搅拌16小时,随后在减压下浓缩。使用硅胶层析法(30%EtOAc/己烷)纯化粗残余物,以得到呈澄清无色膜的所需产物。1H NMR(400MHz;CDCl3):δ7.34-7.22(m,6H),6.99-6.90(m,3H),6.48(br s,1H),4.59-4.54(m,1H),3.75-3.67(m,2H),3.52-3.46(m,2H),2.4-1.97(m,2H),1.94-1.86(m,2H);m/z 331.2(M+H+)。
实施例32
N-(4-氯苯基)-4-苯氧基环己烷-1-甲酰胺
32A.N-(4-氯苯基)-4-羟基环己烷-1-甲酰胺
向100mL圆底烧瓶中添加4-羟基环己烷-1-甲酸(2.0g,14mmol)、4-氯苯胺(1.8g,14mmol)及1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU)(6.3g,17mmol),随后添加DMF(46mL)及二异丙基乙胺(2.5mL,28mmol)。在氩气下搅拌溶液16小时。用EtOAc(60mL)稀释反应溶液,用1N NaOH(50mL)洗涤,经无水MgSO4干燥,过滤,且在减压下浓缩。使用硅胶层析法(0%至100%EtOAc/己烷)纯化粗残余物以得到呈白色固体的所需产物。m/z 254.2(M+H+)。
实施例32.N-(4-氯苯基)-4-苯氧基环己烷-1-甲酰胺
向50mL圆底烧瓶中添加N-(4-氯苯基)-4-羟基环己烷-1-甲酰胺(1.6g,6.3mmol)、聚合物键合型PPh3(3.0mmol/g PPh3,8.4g,25mmol)及苯酚(0.894g,9.5mmol)。抽空烧瓶且用氩气回填。向烧瓶中添加THF(30mL),且冷却混合物至0℃。通过注射器逐滴添加DEAD(1.49mL,9.5mmol),且移除冰浴。允许混合物升温至室温且搅拌16小时。用EtOAc(50mL)稀释反应混合物,经由1:1:硅胶垫过滤,且在减压下浓缩。使用硅胶层析法(0%至18%,随后18%至30%EtOAc/己烷)纯化粗残余物以得到呈白色固体的所需产物。1H NMR(400MHz;CDCl3):δ7.48(d,J=8.7Hz,2H),7.32-7.27(m,4H),7.15(br s,1H),6.99-6.84(m,3H),4.34-4.14(m,1H),2.36-2.19(m,3H),2.08(d,J=11.7Hz,2H),1.81-1.68(m,2H),1.55-1.43(m,2H);m/z 330.2(M+H+)。
实施例33
2-(4-氯苯基)-N-((反)-4-(4-甲氧基苯基)环己基)乙酰胺
33A.甲磺酸顺-4-(4-甲氧基苯基)环己酯
在0℃下向顺-4-(4-甲氧基苯基)-环己醇(Chem.Commun.,48:9376(2012))(366mg,1.77mmol)及三乙胺(0.49mL,3.55mmol)在四氢呋喃(9mL)中的溶液中添加甲磺酰氯(0.21mL,2.66mmol)。搅拌混合物1.5小时,随后用水淬灭,用EtOAc稀释,随后依次用稀HCl、饱和碳酸氢钠水溶液及盐水洗涤。有机相经硫酸钠干燥,随后在减压下浓缩,随后使用硅胶层析法(20%至50%EtOAc/己烷)纯化所得残余物以得到呈白色固体的甲磺酸顺-4-(4-甲氧基苯基)环己酯。
33B.(反)-4-(4-甲氧基苯基)环己-1-胺
向甲磺酸顺-4-(4-甲氧基苯基)环己酯(430mg,1.51mmol)在DMF(7.5mL)中的混合物中添加叠氮化钠(108mg,1.66mmol)。随后在70℃下加热混合物4小时。冷却混合物至室温,用水淬灭,随后用EtOAc稀释。用水随后盐水洗涤有机相若干次,随后在减压下浓缩至~10mL。向此混合物中添加湿润10%Pd/C(70mg,10%w/w)且将反应容器放置在氢气氛围、室温下16小时。过滤混合物且在减压下浓缩滤液以得到残余物,其使用硅胶层析法(10%至20%甲醇/二氯甲烷)纯化以提供呈灰白色固体的所需产物,(反)-4-(4-甲氧基苯基)环己-1-胺。
实施例33.2-(4-氯苯基)-N-((反)-4-(4-甲氧基苯基)环己基)乙酰胺
在室温下搅拌含有在DMF(6mL)中的4-氯苯基乙酸(109mg,0.64mmol)及1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(266mg,0.70mmol)的溶液10分钟,随后添加(反)-4-(4-甲氧基苯基)环己-1-胺(131mg,0.64mmol)。在搅拌20分钟之后,添加N,N-二异丙基乙胺(0.33mL,1.92mmol),且再搅拌混合物1小时。随后将烧瓶内含物倒入盐水(30mL)中且过滤。在减压下浓缩滤液以得到残余物,其使用硅胶层析法(5%MeOH/CH2Cl2)纯化以产生呈白色固体的所需2-(4-氯苯基)-N-((反)-4-(4-甲氧基苯基)环己基)乙酰胺。1H NMR(400MHz;CDCl3):δ7.33(d,J=8.4Hz.2H),7.21(d,J=8.1Hz,2H),7.09(d,J=8.7Hz,2H),6.83(d,J=9Hz,2H),5.18(d,J=8.4Hz,1H),3.85-3.78(m,4H),3.52(s,2H),2.43-2.34(m,1H),2.05-2.00(m,2H),1.90-1.85(m,2H),1.51-1.04(m,4H)ppm.m/z 358.2(M+H)+。
实施例34
4-氟-N-(1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-基)苯胺,HCl
34A.2-(4-(4-羟苯基)亚环己基)乙酸乙酯
向经烘箱干燥的烧瓶(烧瓶#1)中添加NaH(在油中的60%分散体,11.8g,295mmol)及120mL THF,随后冷却混合物至0℃。历经1小时向此混合物中逐滴添加膦酰基乙酸三乙酯(46.9mL,236mmol)在250mL THF中的混合物。在添加完成之后,在室温下搅拌混合物1小时。
历经45分钟向含有NaH(在油中的60%分散体,8.67g,216mmol)在100mL THF中的0℃混合物的单独烧瓶(烧瓶#2)中小心添加37.47g(196.9mmol)4-(4-羟苯基)环己酮在250mL THF中的溶液。在添加完成之后,在室温下搅拌混合物2小时直至混合物变为澄清溶液。一旦此溶液澄清,冷却烧瓶#1至0℃且经由套管插入法添加烧瓶#2的内含物。在此添加完成之后,使混合物升温至室温且搅拌2小时。随后通过小心添加冰及水(1L)淬灭混合物且随后用EtOAc(3×500mL)萃取。随后用盐水(1L)洗涤合并的有机层,经硫酸钠干燥,过滤,且在减压下浓缩,以97%产率提供呈白色固体的2-(4-(4-羟苯基)亚环己基)乙酸乙酯。
34B.2-(4-(4-羟苯基)环己基)乙酸乙酯
向2-(4-(4-羟苯基)亚环己基)乙酸乙酯(9.74g,35.8mmol)在EtOAc中的溶液中添加Pd/C(0.974g,10wt%)。溶液用H2(g)的气球充气且在氢气氛围下搅拌2天。随后经由垫过滤混合物,该垫用EtOAc彻底冲洗。随后在减压下浓缩合并的滤液,以定量产率得到呈白色结晶固体的作为非对映异构体混合物的2-(4-(4-羟苯基)环己基)乙酸乙酯。
34C.2-(4-(4-甲氧基苯基)环己基)乙酸乙酯
向2-(4-(4-羟苯基)环己基)乙酸乙酯(34B,34.1g,130mmol)在DMF(300mL)中的溶液中添加Cs2CO3(65.0g,200mmol),随后添加碘甲烷(21.3g,150mmol)。在室温下搅拌所得悬浮液16小时。在减压下浓缩混合物且使残余物在EtOAc(150ml)与水(200mL)之间分配。分离各层且用EtOAc(3×150mL)萃取水层。将这些合并的有机萃取物与最初有机层组合且经无水MgSO4干燥,过滤,且在减压下浓缩。使用硅胶层析法(0%至30%EtOAc/己烷)纯化残余物以得到呈澄清油状物的2-(4-(4-甲氧基苯基)环己基)乙酸乙酯。
34D.2-(4-(4-甲氧基苯基)环己基)乙-1-醇
使2-(4-(4-甲氧基苯基)环己基)乙酸乙酯(34C,1.45g,5.25mmol)溶解于THF(26mL)中且冷却至0℃。随后逐份添加LiAlH4(596mg,15.7mmol),且历经2小时使混合物升温至室温。用水随后2N HCl水溶液淬灭混合物,随后用EtOAc萃取。用盐水洗涤合并的有机相,经硫酸钠干燥,且在减压下浓缩以提供2-(4-(4-甲氧基苯基)环己基)乙-1-醇(1.17g,95%)。
34E.2-(4-(4-甲氧基苯基)环己基)乙醛
在0℃下向2-(4-(4-甲氧基苯基)环己基)乙-1-醇(34D,1.17g,5.00mmol)在二氯甲烷(50mL)中的混合物中添加碳酸氢钠(1.26g,15.0mmol),随后添加戴斯-马丁(Dess-Martin)高碘烷(3.19g,7.5mmol)。在室温下搅拌所得混合物16小时,随后用二氯甲烷稀释,随后用水洗涤。在减压下浓缩有机层以得到残余物,其吸附至硅胶上且使用硅胶层析法(20%EtOAc/己烷)纯化以提供呈无色油状物的2-(4-(4-甲氧基苯基)环己基)乙醛(609mg,52%)。
34F.1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-醇
在0℃下用TBAF在THF(15.72mL,15.72mmol)中的1M溶液处理2-(4-(4-甲氧基苯基)环己基)乙醛(34E,609mg,2.62mmol)及TMS-CF3(0.58mL,3.93mmol)在THF(6mL)中的溶液。允许混合物升温至室温持续16小时,随后历经30分钟用2N HCl水溶液(3mL)淬灭。使混合物在EtOAc与水之间分配且分离各层。用盐水洗涤有机层,经硫酸钠干燥且在减压下浓缩,得到残余物,其使用硅胶层析法(15%EtOAc/己烷)纯化以提供呈无色油状物的1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-醇(565mg,71%)。
34G.1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-酮
在0℃下向1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-醇(34F,565mg,1.89mmol)在CH2Cl2(19mL)中的溶液中添加碳酸氢钠(476mg,5.67),随后添加戴斯-马丁高碘烷(1.04g,2.46mmol)。在室温下搅拌混合物16小时,随后用CH2Cl2稀释且用水洗涤。在减压下浓缩混合物且使用硅胶层析法(10%EtOAc/己烷)纯化残余物以得到呈无色油状物的1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-酮(356mg,63%),其在静置后结晶。
34H.N-(4-氯苯基)-1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-亚胺及(Z)-4-氯-N-(3,3,3-三氟-1-(4-(4-甲氧基苯基)环己基)丙-1-烯-2-基)苯胺
利用迪安-斯达克分水器(Dean-Stark trap)将溶解于甲苯(5mL)中的1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-酮(34G,178mg,0.59mmol)、4-氟苯胺(0.14mL,1.19mmol)及p-TsOH(5mg,0.03mmol)的混合物加热至回流持续16小时。在减压下浓缩混合物以得到残余物,其通过在中性氧化铝上的柱层析法(7%EtOAc/己烷)来纯化以得到呈粘稠无色油状物的亚胺N-(4-氯苯基)-1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-亚胺与(Z)-4-氯-N-(3,3,3-三氟-1-(4-(4-甲氧基苯基)环己基)丙-1-烯-2-基)苯胺的混合物。
实施例34.4-氟-N-(1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-基)苯胺
在室温下向34H的产物(N-(4-氯苯基)-1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-亚胺及(Z)-4-氯-N-(3,3,3-三氟-1-(4-(4-甲氧基苯基)环己基)丙-1-烯-2-基)苯胺)(34H,160mg,0.41mmol)在MeOH(10mL)中的混合物中添加硼氢化钠(46mg,1.2mmol)。在室温下搅拌所得混合物1.5小时,随后用饱和氯化铵水溶液淬灭,随后用二氯甲烷萃取。合并的有机相经硫酸钠干燥且在减压下浓缩。通过制备型HPLC(Varian ProStar,其使用Hamilton C18PRP-1柱(15×250mm),流速为20mL/min,流动相A:0.5%甲酸/水;流动相B:0.5%甲酸/乙腈;在30分钟期间0%至100%B梯度洗脱)纯化所得残余物以得到残余物。用含2M HCl的乙醚稀释残余物且在减压下浓缩以得到作为顺式/反式异构体的外消旋混合物的所需化合物的HCl盐。1H NMR(300MHz;CDCl3):δ7.16-7.08(m,2H),6.95-6.81(m,4H),6.65-6.59(m,2H),3.93-3.85(m,1H),3.85-3.71(m,3H),3.41(d,J=9.0Hz,1H),2.55-2.50(m,1H),2.41(tt,J=12.3,3.0Hz,1H),2.17-2.08(m,1H),1.99-1.00(m,9H)ppm。m/z396.15(M+H)+。
实施例35
4-氯-N-(1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-基)苯胺盐酸盐
利用用于提供4-氟-N-(1,1,1-三氟-3-(4-(4-甲氧基苯基)环己基)丙-2-基)苯胺的步骤,用4-氯苯胺代替4-氟苯胺制备。MS(ES):m/z=412.10[M+H]+。tR=2.94分钟(方法M)。
实施例36
2-(4-氰基苯基)-N-((反)-4-苯基环己基)乙酰胺
以一般步骤A的方式,使用反-4-苯基-环己胺(PCT公开号WO 2001/092204)(138mg,0.79mmol)、2-(4-氰基苯基)乙酸(138mg,0.86mmol)、1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(360mg,0.95mmol)及DMF(4mL)制得以下化合物。通过制备型TLC(33%EtOAc/己烷)随后制备型HPLC(Varian ProStar,其使用Hamilton C18PRP-1柱(15×250mm),流速为20mL/min,流动相A:0.5%甲酸/水;流动相B:0.5%甲酸/乙腈;在30分钟期间0%至100%B梯度洗脱)纯化残余物以得到所需产物。1HNMR(300MHz;CDCl3):δ7.64(dd,J=8.4,1.8Hz,2H),7.40(dd,J=8.4,1.8Hz,2H),7.32-7.24(m,2H),7.21-7.16(m,3H),5.31(d,J=7.5Hz,1H),3.89-3.79(m,1H),3.60(s,2H),2.45(tt,J=16.0,3.6Hz,1H),2.10-1.90(m,4H),1.66-1.56(m,2H),1.30-1.16(m,2H)ppm.m/z 319(M+H)+。
实施例37
2-(4-氯苯基)-N-((反)-4-苯基环己基)丙酰胺
以一般步骤A的方式,使用反-4-苯基-环己胺(PCT公开号WO 2001/092204)(138mg,0.79mmol)、2-(4-氯苯基)丙酸(158mg,0.86mmol)、1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(360mg,0.95mmol)及DMF(4mL)制得以下化合物。通过制备型TLC(33%EtOAc/己烷)纯化残余物以得到残余物。通过制备型HPLC(Varian ProStar,其使用Hamilton C18PRP-1柱(15×250mm),流速为20mL/min,流动相A:0.5%甲酸/水;流动相B:0.5%甲酸/乙腈;在30分钟期间0%至100%B梯度洗脱)进一步纯化残余物以得到作为外消旋混合物的所需产物。1H NMR(300MHz;CDCl3):δ7.34-7.14(m,9H),5.16(d,J=7.8Hz,1H),3.86-3.75(m,1H),3.48(q,J=7.2Hz,1H),2.42(tt,J=12.3,3.3Hz,1H),2.09-1.84(m,4H),1.68-1.52(m,2H),1.49(d,J=7.2Hz,3H),1.26-1.06(m,2H)ppm.m/z 342(M+H)+。
实施例38
2-(4-氯苯基)-N-((反)-4-(喹啉-4-基)环己基)乙酰胺
38A.4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)喹啉
将三氟甲磺酸1,4-二氧杂螺[4.5]癸-7-烯-8-基酯(Bioorg.Med.Chem.Lett.,24:5377(2014))(6.9g,23.9mmol)放置于500mL圆底烧瓶中,随后放置喹诺酮-4-硼酸(4.55g,26.3mmol)、Pd(PPh3)4(1.39g,1.2mmol,5mol%)、KBr(2.85g,23.94mmol)及碳酸钠(6.34g,59.85mmol)。抽空烧瓶且用N2回填三次,随后向固体中添加脱气二噁烷(100mL)及水(10mL)且搅拌混合物且在N2氛围下加热至90℃。在16小时之后,冷却混合物至室温,且添加SiO2。在减压下浓缩混合物且通过硅胶柱层析法(0%至100%EtOAc/己烷)纯化残余物以得到4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)喹啉(3.2g,50%)。
38B.4-(1,4-二氧杂螺[4.5]癸-8-基)喹诺酮
4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)喹诺酮(3.2g,12.0mmol)、NaHCO3(500mg,6.0mmol)及MeOH(70mL)的混合物用N2(g)净化,随后向混合物中添加20wt%Pd/C(干燥活化,10wt%)。使H2(g)鼓泡通过溶液直至起始物质完全消失。混合物用N2(g)净化,经由过滤,且在减压下浓缩滤液。通过急骤层析法纯化残余物以得到4-(1,4-二氧杂螺[4.5]癸-8-基)喹诺酮(2.9g,90%)。
38C.4-(喹啉-4-基)环己-1-酮
向4-(1,4-二氧杂螺[4.5]癸-8-基)喹诺酮(3.0g,11mmol)在丙酮(30mL)中的混合物中添加3M HCl水溶液(30mL)。在室温下搅拌混合物24小时之后,其在减压下浓缩且添加NaHCO3(饱和水溶液)以将pH调节为8.0以上。随后用EtOAc萃取混合物。合并的有机层经Na2SO4干燥,且在减压下浓缩以提供呈黄色油状物的4-(喹啉-4-基)环己-1-酮(2.3g,90%),其在静置后固化。
38D.4-(喹啉-4-基)环己-1-胺
所需胺经由用乙酸铵及氰基硼氢化钠将4-(喹啉-4-基)环己-1-酮还原胺化以得到4-(喹啉-4-基)环己-1-胺来制得。
38E.2-(4-氯苯基)-N-((反)-4-(喹啉-4-基)环己基)乙酰胺
使用一般步骤A,其使用4-(喹啉-4-基)环己-1-胺及2-(4-氯苯基)乙酸。使用制备型HPLC(Varian ProStar,其使用Hamilton C18PRP-1柱(15×250mm),流速为20mL/min,流动相A:0.5%甲酸/水;流动相B:0.5%甲酸/乙腈;在30分钟期间0%至100%B梯度洗脱)纯化残余物以得到呈白色粉末的所需化合物。1H NMR(400MHz;CD3OD):δ8.77-8.74(m,1H),8.26-8.21(m,1H),8.05-8.01(m,1H),7.79-7.73(m,1H),7.68-7.63(m,1H),7.49-7.45(m,1H),7.34-7.27(m,4H),3.82-3.77(m,1H),3.50-3.42(m,3H),2.13-2.03(m,4H),1.82-1.70(m,2H),1.65-1.60(m,2H)ppm。m/z 379(M+H)+。
实施例40
N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-3-甲基苯磺酰胺
制备物40A:
在N2下在-78℃下向1,4-二氧杂螺[4.5]癸-8-酮(300g,1920.86mmol,1.0当量)及苯基三氟甲磺酰亚胺(823.47g,2305.03mmol,1.2当量)在MTBE(7.5L)中的搅拌溶液中历经70分钟添加含2.0M NaHMDS的THF(1152.2mL,2305.03mmol,1.2当量),且再搅拌混合物60分钟。使反应混合物升温至室温且搅拌过夜直至TLC显示起始物质完全耗尽。用KHSO4水溶液(100ml)淬灭混合物,过滤以移除固体且完全浓缩滤液。向残余物中添加3L MTBE,随后用5%NaOH(1.5L×3)洗涤。浓缩有机相,获得567g粗制备物40A(淡黄色油状物,产率102%)。粗产物可不经进一步纯化而直接用于下一步骤中。
制备物40A:1H NMR(400MHz,CDCl3):δ(ppm)5.65(t,J=4.0Hz,1H),3.98(d,J=1.5Hz,4H),2.53(s,2H),2.40(s,2H),1.90(t,J=6.6Hz,2H)。
制备物40B:
加热粗制备物40A(600g,2.08mol,1当量)、B2Pin2(687.1g,2.71mol,1.3当量)、KOAc(613g,6.24mol,3当量)、NaBr(86g,0.833mol,0.4当量)及Pd(dppf)Cl2(76g,0.1mol,0.05当量)在二噁烷(6.5L)中的混合物至回流过夜。一旦反应完成,浓缩混合物且通过FCC(2%→10%→20%EtOAc/PE)纯化以得到制备物40B(369g,66%)。
制备物40B:LC-MS:267.1(M+1)+,1H NMR(400MHz,CDCl3)δ 6.46(s,1H),3.98(s,4H),2.37-2.35(m,4H),1.74-1.60(t,2H),1.24(s,12H)。
制备物40C:
加热制备物40B(368g,1.38mol,1.3当量)、4-氯-6-氟喹啉(195g,1.07mol,1当量)、K2CO3(445g,3.22mol,3当量)及Pd(PPh3)4(25g,22mmol,0.02当量)在二噁烷-水(3L,4:1)中的混合物至回流过夜。随后浓缩溶液且用EtOAc萃取。通过FCC(38%EtOAc/石油醚)纯化得到制备物40C(236g,77%)。
制备物40C:LC-MS:286.1(M+1)+,1H NMR(400MHz,CDCl3)δ8.80-8.29(d,1H),8.11-8.07(q,1H),7.63-7.61(q,1H),7.47-7.46(q,1H),7.26-7.22(m,1H),5.75-5.74(m,1H),4.08-4.05(m,4H),2.63-2.59(m,2H),2.59-2.53(m,2H),2.0-1.97(m,2H)。
制备物40D:
在55℃下向含制备物40C(125g,0.44mol)的IPA(2L)中添加10%Pd/C且在H2氛围下搅拌混合物过夜。过滤混合物且浓缩以得到粗制备物40D(130g),其直接用于下一步骤中。
制备物40E:
在45℃下用含4N HCl(300mL)的丙酮(1200mL)处理制备物40D(100g,0.348mol)过夜。通过TLC监测混合物。然后在真空中浓缩溶液。用6N NaOH将残余物调节为pH 9,并使混合物在乙酸乙酯与水之间分配。用盐水洗涤有机层,经无水Na2SO4干燥,过滤且浓缩,得到淡黄色固体,其随后通过硅胶柱,使用己烷及乙酸乙酯(20%乙酸乙酯至70%乙酸乙酯)纯化以得到呈白色固体的制备物40E,(47g+20g混合物,产率>55%)。制备物40E:LC-MS:244.0(M+1)+,1H NMR(400MHz,CDCl3)δ8.84(d,J=4.6Hz,1H),8.16(dd,J=9.3,5.7Hz,1H),7.72(dd,J=10.3,2.8Hz,1H),7.52(ddd,J=9.2,7.8,2.7Hz,1H),7.29(d,J=4.6Hz,1H),3.69(ddd,J=12.1,9.0,3.3Hz,1H),2.77-2.54(m,4H),2.37(ddd,J=13.4,5.9,3.0Hz,2H),2.04(qd,J=12.6,5.3Hz,2H)。
制备物40F:
使制备物40E(57.8g,237.8mmol)溶解于EtOH(240mL)中且冷却至0℃。逐份添加NaBH4(9.94g,261.6mmol),维持温度在0-10℃范围内(放热反应)。搅拌所得悬浮液20分钟。反应混合物的等分试样的LC/MS指示酮耗尽(m/z(M+H)+=244)。在0℃下通过历经15分钟缓慢添加丙酮(58mL)来淬灭反应(放热)。将反应(reaction)缓慢倒在500mL饱和氯化铵水溶液及500g冰上。用EtOAc(3×300mL)萃取所得水溶液且用饱和氯化铵水溶液(250mL)及饱和氯化钠水溶液(250mL)洗涤合并的有机级分。有机部分经无水硫酸钠干燥且在减压下浓缩。添加足够二氧化硅以吸附油状物且用含10%MeOH的CH2Cl2稀释。使用类似数量的二氧化硅作为二氧化硅塞以纯化物质。二氧化硅塞用含10%MeOH的CH2Cl2洗涤直至通过TLC(7:3EtOAc/己烷,Rf=0.4)不再能检测UV活性物质。浓缩滤液,随后悬浮于500mL甲苯中且再次浓缩。分离呈黄色固体的粗制备物40F(58.2g),其不经进一步纯化而用于随后步骤中。
制备物40G:
向制备物40F(58.2g,237.8mmol)中添加MeCN(125mL)及吡啶(38.7mL,480mmol)且使用冰/水浴冷却反应混合物至5℃。在5℃下逐滴添加甲磺酰氯(26.0mL,336mmol)(放热反应),在5℃下搅拌反应混合物1小时且随后达到室温且再搅拌16小时,在此时间期间形成白色沉淀。通过添加饱和氯化铵水溶液(200mL)淬灭非均质混合物且用CH2Cl2(3×300mL)萃取。合并的有机级分经无水硫酸钠干燥且在减压下浓缩。通过共沸从甲苯(3×300mL)移除过量吡啶。使粗物质如下从H2O/MeOH重结晶:添加1mL/mmol H2O且在油浴中加热浆液至120℃。添加MeOH直至固体进入溶液(~0.5L)中。在冷却之后通过过滤收集白色晶体以得到制备物40G(58.6g,>20:1dr,76%,经两个步骤)。m/z(M+H)+=324.1。1H-NMR(400MHz;CDCl3):δ8.82(dd,J=4.6,0.2Hz,1H),8.15-8.11(m,1H),7.64-7.61(m,1H),7.52-7.46(m,1H),7.25(s,1H),4.78(tt,J=10.9,5.2Hz,1H),3.24-3.16(m,1H),3.07(d,J=1.0Hz,3H),2.42-2.38(m,2H),2.16-2.12(m,2H),1.93-1.66(m,4H)。
制备物40H:
向NaH(6.0g,在油中的60%悬浮液,150mmol)在1,2-二甲氧基乙烷(100mL)中的在Ar下在水-冰浴中冷却的搅拌悬浮液中逐滴添加丙二酸二叔丁酯(33.5mL,150mmol)。在搅拌10分钟之后,添加制备物40G(16.2g,50mmol)且在85℃下加热反应20小时。此后,添加乙酸(100mL),反应烧瓶装备有蒸馏头且温度升高至130℃。在大气压下蒸馏出1,2-二甲氧基乙烷直至馏出物为酸性(~100mL)。移除蒸馏头,连接回流冷凝器,添加水(20mL)且在130℃下加热反应12小时。在减压下浓缩反应且倒在200g冰及100mL饱和NaOAc水溶液上。通过过滤分离呈白色固体的制备物40H且通过用甲苯在迪恩-斯达克设备中回流来进一步干燥(11.0g,76%)。m/z(M+H)+=288.2。1H-NMR(400MHz;DMSO-d6):δ12.05(bs,1H),8.79(d,J=4.5Hz,1H),8.06(dd,J=9.2,5.8Hz,1H),7.94(dd,J=11.0,2.8Hz,1H),7.66-7.61(m,1H),7.50(d,J=4.6Hz,1H),2.41(d,J=7.6Hz,2H),2.28-2.23(m,1H),1.87-1.78(m,2H),1.73-1.64(m,6H)。
制备物40I:
向制备物40H(1.4g,4.8mmol)在THF(15mL)中的溶液中添加NEt3(1.3mL,9.6mmol)。冷却反应混合物至0℃且逐滴添加三甲基乙酰氯(0.713mL,5.8mmol)且在0℃下搅拌所得溶液30分钟。在单独烧瓶中,用含1M LiHMDS溶液的THF(逐滴添加6.24mL,6.24mmol)处理0℃下的含(R)-4-苯基噁唑烷-2-酮(3,1.01g,6.24mmol)的THF(45mL)且在0℃下搅拌。经由套管向第一烧瓶中添加锂化物。允许反应混合物升温至室温且搅拌3小时。LC/MS指示起始羧酸的完全耗尽及所需酰亚胺的形成。将反应混合物倒在饱和氯化铵水溶液(50mL)上且分离各层。用EtOAc(3×50mL)萃取水层。合并的有机萃取物经无水硫酸钠干燥且使用EtOAc/己烷0至100%梯度在二氧化硅上层析,以83%产率得到呈白色泡沫的制备物40I。m/z(M+H)+=433.3。1H-NMR(400MHz;CDCl3):δ8.80(d,J=4.5Hz,1H),8.11(dd,J=9.1,5.7Hz,1H),7.63(dd,J=10.5,2.5Hz,1H),7.48-7.43(m,1H),7.40-7.30(m,6H),5.47-5.44(m,1H),4.71(t,J=8.9Hz,1H),4.31-4.28(m,1H),3.20-3.11(m,3H),2.49-2.46(m,1H),1.82-1.67(m,6H)。
制备物40J:
冷却制备物40I(21.6g,50mmol)在无水THF(200mL)中的溶液至-40℃(使用乙腈/干冰浴,出现一些沉淀)且历经5分钟添加在THF中的2M NaHMDS溶液(30mL,60mmol)(观察到温度升高5-8℃)。搅拌所得黄色反应混合物10分钟,其变为均质,且历经2分钟逐滴添加MeI(10.6g,75mmol)(观察到温度升高10℃)。在-40℃下搅拌反应混合物1小时且LC/MS指示起始物质的完全耗尽及所需甲基酰亚胺的形成。用饱和氯化铵水溶液(400mL)快速稀释反应混合物且搅拌两相混合物15分钟。添加iPrOAc(100mL),分离各层,且用iPrOAc(3×50mL)萃取水层。合并的有机萃取物经无水硫酸镁干燥,过滤,且浓缩。所得残余物通过以下重结晶:溶解于400mL热丙酮中且添加H2O直至形成乳白色溶液,随后通过加热(~3:1丙酮/H2O)再溶解。获得呈白色针状物的制备物40J(15.04g,2批,68%)。m/z(M+H)+=447.3。1H-NMR(400MHz;CDCl3):δ8.81(d,J=4.6Hz,1H),8.10(dd,J=9.2,5.7Hz,1H),7.65(dd,J=10.6,2.7Hz,1H),7.47-7.42(m,1H),7.41-7.29(m,6H),5.47(dd,J=8.8,3.8Hz,1H),4.69(t,J=8.9Hz,1H),4.38-4.30(m,1H),4.26(dd,J=8.9,3.9Hz,1H),3.26-3.21(m,1H),2.18-2.15(m,1H),1.93-1.64(m,8H),1.09(d,J=6.9Hz,3H)。
制备物40K:
在0℃下向制备物40J(82.0g,183.6mmol)在THF(610mL)中的溶液中添加H2O2(35wt%,82mL)及LiOH(7.04g,293.8mmol)在H2O(189mL)中的水溶液。允许所得反应混合物缓慢升温至室温且搅拌过夜。冷却反应至0℃且添加饱和亚硫酸氢钠水溶液(250mL)。在搅拌30分钟之后,在减压下移除THF。添加乙酸(34mL),随后添加EtOAc(300mL)。分离各层,且用EtOAc(3×500mL)萃取水层。合并的有机萃取物经无水Na2SO4干燥,过滤,且在减压下浓缩。使棕色粗反应混合物悬浮于MeCN(400mL)中且在剧烈搅拌下使悬浮液达到回流。在冷却至室温之后,通过过滤收集固体,用额外MeCN洗涤。获得呈白色固体的制备物40K(45.4g,82%)。m/z(M+H)+=302.2。1H-NMR(400MHz;DMSO-d6):δ12.10(s,1H),8.79(d,J=4.5Hz,1H),8.07(dd,J=9.2,5.9Hz,1H),7.97-7.94(m,1H),7.67-7.62(m,1H),7.49(d,J=4.5Hz,1H),3.41-3.36(m,1H),2.73-2.65(m,1H),1.83-1.61(m,9H),1.08(d,J=6.8Hz,3H)。手性HPLC,>99%对映异构体过量(ChiralPak IC-3,3μM,4.6×250mm,15分钟等度70%庚烷30%i-PrOH,在230nm检测下),在0.75mL/min的流速下,所需对映异构体的停留时间为8.6分钟,非所需对映异构体在9.5分钟洗脱。
制备物40L:
使制备物40K(2g,6.64mmol)溶解于甲苯(22.12ml)中且添加叠氮磷酸二苯酯(2.009g,7.30mmol)及三乙胺(1.110ml,7.96mmol)。密封瓶且加热至70℃。在2小时之后,冷却反应至室温且在减压下浓缩。使粗残余物溶解于40mL THF及40mL水中且添加氢氧化锂(1.589g,66.4mmol)。在室温下搅拌反应1小时。反应用1N HCl酸化(形成白色沉淀)且用EtOAc萃取。水性部分随后用1N NaOH碱化(形成沉淀)且用EtOAc萃取5次。在真空中浓缩碱性萃取物以得到40L(1.68g,6.17mmol,93%产率)。C17H21FN2的LC-MS分析计算值272.17,实验值[M+H]273.1Tr=0.50分钟(方法A)。1H NMR(400Mhz,氯仿-d)δ:8.80(d,J=4.6Hz,1H),8.11(dd,J=9.3,5.7Hz,1H),7.67(dd,J=10.6,2.8Hz,1H),7.46(ddd,J=9.2,8.0,2.8Hz,1H),7.32(d,J=4.5Hz,1H),3.27-3.37(m,1H),3.13(dq,J=9.3,6.3Hz,1H),2.01-2.10(m,1H),1.67-1.92(m,6H),1.37-1.55(m,4H),1.15(d,J=6.4Hz,3H)。
实施例40.N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-3-甲基苯磺酰胺
使制备物40L(20mg,0.073mmol)溶解于DCM(0.2mL)中且添加至含有苯基磺酰氯(26mg,0.147mmol)及DCM(0.2mL)的瓶中,随后直接添加DIPEA(64.1μl,0.367mmol)。在室温下搅拌反应过夜。在过夜之后,在真空中浓缩反应,溶解于2mL DMF中,过滤,且经由HPLC纯化以得到实施例40(12.2mg,0.28mmol,39%)。C24H27FN2O2S的LC-MS分析计算值426.18,实验值[M+H]427.3Tr=2.065分钟(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.82(d,J=4.5Hz,1H),8.08(dd,J=9.2,5.8Hz,1H),7.90(dd,J=10.9,2.5Hz,1H),7.60-7.72(m,3H),7.50(d,J=8.5Hz,1H),7.45(t,J=7.7Hz,1H),7.38(d,J=7.6Hz,1H),7.32(d,J=4.5Hz,1H),3.29(t,J=10.5Hz,1H),2.35(s,3H),1.64-1.83(m,3H),1.41-1.64(m,4H),1.23-1.41(m,2H),0.92(d,J=6.4Hz,3H)。
实施例41至46
实施例41至46由制备物40L,按照用于实施例40的步骤使用相应的磺酰氯制备。
实施例47
4-氯-N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)苯甲酰胺
使制备物40L(4mg,0.015mmol)溶解于DMF(147μl)中且添加HOBT(2.92mg,0.019mmol)、EDC(3.66mg,0.019mmol)、4-氯苯甲酸(4.60mg,0.029mmol)及TEA(10.23μl,0.073mmol)且在室温下搅拌反应过夜。随后用1.8mL DMF稀释反应且经由制备型HPLC纯化以得到实施例47(2.3mg,0.006mmol,38%)。C24H24ClFN2的LC-MS分析计算值410.16,实验值[M+H]411.0Tr=2.057分钟(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.82(d,J=4.5Hz,1H),8.36(d,J=8.8Hz,1H),8.08(dd,J=9.2,5.8Hz,1H),7.95(dd,J=11.0,2.7Hz,1H),7.86(d,J=8.6Hz,2H),7.65(td,J=8.7,2.7Hz,1H),7.52(d,J=8.5Hz,2H),7.47(d,J=4.5Hz,1H),4.42(d,J=6.6Hz,1H),1.74-1.91(m,6H),1.56-1.73(m,4H),1.18(d,J=6.5Hz,3H)。
实施例48至69
实施例48至69由制备物40L,按照用于实施例47的步骤使用相应的苯甲酸制备。
实施例70
N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-[1,1′-联苯]-4-甲酰胺
实施例70:N-((R)-1-((顺)-4-(6-氟喹啉-4-基)环己基)乙基)-[1,1′-联苯]-4-甲酰胺
使制备物40L(50mg,0.184mmol)溶解于DMF(1836μl)中且添加HOBT(36.5mg,0.239mmol)、EDC(45.8mg,0.239mmol)、[1,1'-联苯]-4-甲酸(54.6mg,0.275mmol)及TEA(128μl,0.918mmol)且在室温下搅拌反应3小时。用EtOAc稀释反应且用5:1水/饱和NaHCO3水溶液洗涤。合并的有机萃取物经硫酸钠干燥,过滤且在真空中浓缩。经由硅胶急骤柱层析法纯化粗残余物以得到实施例70(63mg,0.132mmol,72.0%产率)。C30H29FN2O的LC-MS分析计算值452.23,实验值[M+H]453.3Tr=2.297分钟(方法B)。1H NMR(400MHz,氯仿-d)δ:8.82(d,J=4.5Hz,1H),8.13(dd,J=9.2,5.7Hz,1H),7.85(d,J=8.6Hz,2H),7.64-7.70(m,3H),7.58-7.64(m,J=7.0Hz,2H),7.36-7.50(m,5H),5.91(d,J=9.2Hz,1H),4.58-4.70(m,1H),3.30(tt,J=10.6,3.6Hz,1H),1.96-2.15(m,3H),1.80(br.s.,6H),1.33(d,J=6.6Hz,3H)。
实施例71
4-氯-N-(1-((反)-4-(喹啉-4-基氧基)环己基)丙基)苯甲酰胺
中间体71A.2-(1,4-二氧杂螺[4.5]癸-8-亚基)乙酸乙酯(Ethyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate)
在0℃下向氢化钠(3.84g,96mmol)在THF(64.0ml)中的悬浮液中添加膦酰基乙酸三乙酯(21.79ml,109mmol)。在室温下搅拌反应30分钟。30分钟后,再冷却反应至0℃且添加1,4-二氧杂螺[4.5]癸-8-酮(10g,64.0mmol)在5mL THF中的溶液。随后在室温下搅拌反应30分钟,随后用水淬灭。用DCM萃取混合物三次。合并的有机萃取物经硫酸钠干燥,过滤,且在真空中浓缩。经由硅胶层析法纯化粗残余物以得到中间体71A(13.88g,61.3mmol,96%产率)。TLC:产物以紫色斑点形式在茴香醛中染色(Rf=0.75,在1:1己烷/EtOAc中)。1H NMR(400MHz,氯仿-d)δ:5.65(s,1H),4.13(q,J=7.2Hz,2H),3.92-3.99(m,4H),2.94-3.02(m,2H),2.31-2.40(m,2H),1.71-1.79(m,4H),1.26(t,J=7.2Hz,3H)。
中间体71B.2-(1,4-二氧杂螺[4.5]癸-8-基)乙酸乙酯
使中间体71A(13.88g,61.3mmol)溶解于EtOAc(61.3ml)中且在氮气氛围下添加至含有湿的10%钯/碳(1.306g,12.27mmol)(54%w/w水)的帕尔氢化瓶中。用氮气净化反应瓶且回填三次,且随后用氢气重复。在用氢气填充瓶至50psi之后,将瓶放置于帕尔振荡器中且振荡。在4小时之后,经加压过滤反应且在真空中浓缩以得到中间体71B(13.78g,60.4mmol,98%产率)。C12H20O4的LC-MS分析计算值228.14,实验值[M+H]229.1Tr=0.83分钟(方法A)。1H NMR(400MHz,氯仿-d)δ:4.11(q,J=7.2Hz,2H),3.88-3.95(m,4H),2.21(d,J=7.0Hz,2H),1.83(dqd,J=11.0,7.5,3.5Hz,1H),1.68-1.78(m,4H),1.50-1.61(m,2H),1.27-1.35(m,2H),1.24(t,J=7.2Hz,3H)。
中间体71C.2-(1,4-二氧杂螺[4.5]癸-8-基)丁酸乙酯
使二异丙胺(2.347ml,16.63mmol)溶解于干燥THF(15.99ml)中(在N2氛围下)且冷却至-78℃。在-78℃下历经~5分钟添加n-BuLi(6.14ml,15.35mmol)(在己烷中2.5M)。在搅拌45分钟之后,使反应升温至室温保持10分钟且回到-78℃。随后,添加1,3-二甲基四氢嘧啶-2(1H)-酮(1.541ml,12.79mmol),随后添加中间体71B(2.92g,12.79mmol)在THF(15.99ml)中的溶液(逐滴,历经~5分钟)。在1小时之后,历经~5分钟逐滴添加碘乙烷(1.125ml,14.07mmol)(纯)。在-78℃下再搅拌反应2小时,随后缓慢升温至室温。随后在室温下搅拌反应过夜。反应通过倒入1:1水/盐水中且用EtOAc萃取来淬灭。合并的有机物用盐水洗涤,经硫酸钠干燥,过滤且在真空中浓缩。经由硅胶柱层析法纯化粗残余物以得到中间体71C(2.27g,8.86mmol,69%产率)。TLC:产物以紫色斑点形式在茴香醛中染色(Rf=0.80,在1:1己烷/EtOAc中)。1H NMR(400MHz,氯仿-d)δ:4.14(q,J=7.5Hz,2H),3.88-3.95(m,4H),2.09(td,J=8.4,5.6Hz,1H),1.69-1.83(m,4H),1.45-1.64(m,6H),1.33-1.42(m,1H),1.25(t,J=7.1Hz,3H),0.86(t,J=7.5Hz,3H)。
中间体71D.2-(4-氧代环己基)丁酸乙酯
使中间体71C(2.00g,7.80mmol)溶解于THF(39.0ml)中且添加盐酸,1M(39.0ml)。在室温下搅拌反应2小时。在真空中浓缩反应,用水稀释且用EtOAc萃取。合并的有机萃取物经硫酸钠干燥,过滤且在真空中浓缩。在硅胶柱层析上纯化粗物质以得到中间体71D(1.47g,6.92mmol,89%产率)。TLC:产物在茴香醛中染色成微粉红色(Rf=0.65,在1:1己烷/EtOAc中)。1H NMR(400MHz,氯仿-d)δ:4.15(q,J=7.1Hz,2H),2.25-2.42(m,4H),2.18(ddd,J=9.3,7.8,5.2Hz,1H),2.10(ddt,J=13.1,6.2,3.3Hz,1H),1.90-2.03(m,2H),1.56-1.70(m,2H),1.38-1.56(m,2H),1.25(t,J=7.2Hz,3H),0.89(t,J=7.4Hz,3H)。
中间体71E.2-((反)-4-羟基环己基)丁酸乙酯
使中间体71D(1.47g,6.92mmol)溶解于EtOH(13.85ml)中且冷却至0℃。添加NaBH4(0.314g,8.31mmol)且随后允许反应在0℃下搅拌1小时。反应用饱和NH4Cl水溶液淬灭且用EtOAc萃取。合并的有机萃取物经硫酸钠干燥,过滤,且在真空中浓缩。经由硅胶柱层析法纯化粗物质以得到中间体71E(1.22g,5.69mmol,82%产率)以及顺式-异构体(138mg,0.644mmol,9.30%产率)。1H NMR(400MHz,氯仿-d)δ:4.14(q,J=7.1Hz,2H),3.53(t,J=10.5Hz,1H),1.92-2.08(m,2H),1.80-1.89(m,1H),1.63-1.70(m,1H),1.52-1.62(m,4H),1.37-1.52(m,2H),1.26(t,J=7.2Hz,3H),0.95-1.17(m,2H),0.87(t,J=7.4Hz,3H)。
中间体71F.2-((反)-4-(喹啉-4-基氧基)环己基)丁酸乙酯
使中间体71E(100mg,0.467mmol)溶解于DMSO(933μl)中且在室温下逐份缓慢添加NaH(22.40mg,0.933mmol)。在1小时之后,添加4-溴喹啉(117mg,0.560mmol)且加热反应至80℃。在16小时之后,反应用氯化铵淬灭且用EtOAc萃取。合并的有机萃取物经硫酸钠干燥,过滤,在真空中浓缩。经由硅胶柱层析法纯化粗残余物以得到中间体71F(89mg,0.261mmol,55.9%产率)。C21H27NO3的LC-MS分析计算值341.20,实验值[M+H]342.3Tr=0.84分钟(方法A)。
中间体71G.2-((反)-4-(喹啉-4-基氧基)环己基)丁酸
使中间体71F(89mg,0.261mmol)溶解于THF(1043μl)、水(1043μl)及MeOH(521μl)中。添加氢氧化锂(62.4mg,2.61mmol)且在60℃下搅拌反应24小时。在真空中浓缩反应,用水稀释,用添加的乙酸酸化(形成沉淀),且用EtOAc萃取。合并的有机萃取物经硫酸钠干燥,过滤且在真空中浓缩以得到中间体71G(74mg,0.236mmol,91%产率)。C19H23NO3的LC-MS分析计算值313.17,实验值[M+H]314.2Tr=0.69分钟(方法A)。
中间体71H.1-((反)-4-(喹啉-4-基氧基)环己基)丙-1-胺
在瓶中使中间体71G(190mg,0.606mmol)溶解于甲苯(2021μl)中且添加叠氮磷酸二苯酯(184mg,0.667mmol)及TEA(101μl,0.728mmol)。密封瓶且加热至80℃。在2小时之后,冷却反应至室温且在减压下浓缩。使粗残余物溶解于1mL THF及1mL水中且添加LiOH(145mg,6.06mmol)。在室温下搅拌反应1小时。反应用1N HCl酸化(形成白色沉淀)且用EtOAc萃取以移除DPPA相关杂质。随后,反应用1N NaOH碱化(再次形成沉淀)且用EtOAc(×5)萃取。在真空中浓缩碱性萃取物以得到中间体71H(35mg,0.123mmol,20.30%产率)。C18H24N2O的LC-MS分析计算值284.19,实验值[M+H]285.2Tr=0.55分钟(方法A)。
实例71.4-氯-N-(1-((反)-4-(喹啉-4-基氧基)环己基)丙基)苯甲酰胺
使中间体71H(35mg,0.123mmol)溶解于DMF(1231μl)中且添加HOBT(24.50mg,0.160mmol)、EDC(30.7mg,0.160mmol)、4-氯苯甲酸(38.5mg,0.246mmol)及TEA(86μl,0.615mmol)且在室温下搅拌反应。在2小时之后,反应用DMF稀释,过滤且经由制备型HPLC纯化以得到实施例71(24.6mg,0.058,46.8%产率)。C25H27ClN2O2的LC-MS分析计算值422.18,实验值[M+H]423.3Tr=0.82分钟(方法A)。1H NMR(500MHz,DMSO-d6)δ:8.67(d,J=5.2Hz,1H),8.15(d,J=9.0Hz,1H),8.11(d,J=8.2Hz,1H),7.87-7.94(m,3H),7.72(t,J=7.6Hz,1H),7.49-7.58(m,3H),7.10(d,J=5.2Hz,1H),4.62(t,J=10.2Hz,1H),3.74-3.85(m,J=8.9Hz,1H),2.21(d,J=10.1Hz,2H),1.86(t,J=14.3Hz,2H),1.39-1.71(m,5H),1.28(q,J=12.3Hz,2H),0.85(t,J=7.2Hz,3H)。
对映异构体1及对映异构体2
对映异构体1:实施例71
4-氯-N-(1-((反)-4-(喹啉-4-基氧基)环己基)丙基)苯甲酰胺(纯手性的,立体化学未知)
对映异构体2:实施例71
4-氯-N-(1-((反)-4-(喹啉-4-基氧基)环己基)丙基)苯甲酰胺(纯手性的,立体化学未知)
实施例71对映异构体1及对映异构体2:外消旋体样品的手性分离(方法C)得到对映异构体1Tr=5.195分钟(方法D)及对映异构体2Tr=8.226分钟(方法D),绝对立体化学未测定。
对映异构体1:MS(ES):m/z=423.3[M+H]+。Tr=2.126分钟(方法A)。1H NMR(500MHz,DMSO-d6)δ:8.78(d,J=5.1Hz,1H),8.14-8.22(m,2H),7.97(d,J=8.2Hz,1H),7.89(d,J=8.2Hz,2H),7.82(t,J=7.6Hz,1H),7.62(t,J=7.5Hz,1H),7.54(d,J=8.3Hz,2H),7.25(d,J=5.6Hz,1H),4.65-4.75(m,1H),3.75-3.84(m,J=8.8Hz,1H),2.22(d,J=10.4Hz,2H),1.81-1.92(m,2H),1.43-1.70(m,5H),1.28(q,J=12.2Hz,2H),0.85(t,J=7.2Hz,3H)。
对映异构体2:MS(ES):m/z=423.3[M+H]+。Tr=2.126分钟(方法A)。1H NMR(500MHz,DMSO-d6)δ:8.67(d,J=5.0Hz,1H),8.16(d,J=9.0Hz,1H),8.11(d,J=8.2Hz,1H),7.85-7.94(m,3H),7.72(t,J=7.3Hz,1H),7.54(d,J=8.2Hz,3H),7.09(d,J=5.2Hz,1H),4.61(t,J=10.1Hz,1H),3.75-3.83(m,J=8.5Hz,1H),2.21(d,J=10.2Hz,2H),1.85(t,J=14.0Hz,2H),1.39-1.69(m,5H),1.22-1.33(m,2H),0.85(t,J=7.1Hz,3H)。
实施例72
4-氯-N-(1-((反)-4-((8-(三氟甲基)喹啉-4-基)氧基)环己基)丙基)苯甲酰胺
实施例72由中间体71E及概述用于制得71F、71G、71H及实施例71的类似步骤制备,不同之处在于在部分F中使用4-氯-8-(三氟甲基)喹啉。C26H26ClF3N2O2的LC-MS分析计算值490.16,实验值[M+H]491.2Tr=0.99分钟(方法A)。1H NMR(500MHz,DMSO-d6)δ:8.80(d,J=5.0Hz,1H),8.40(d,J=8.2Hz,1H),8.17(d,J=8.9Hz,1H),8.14(d,J=7.2Hz,1H),7.88(d,J=8.2Hz,2H),7.65(t,J=7.8Hz,1H),7.53(d,J=8.2Hz,2H),7.24(d,J=5.1Hz,1H),4.66(t,J=10.0Hz,1H),3.74-3.84(m,J=6.6Hz,1H),2.21(d,J=10.2Hz,2H),1.85(t,J=13.5Hz,2H),1.40-1.71(m,5H),1.27(q,J=12.1Hz,2H),0.84(t,J=7.0Hz,3H)。
实施例73和实施例74
(反)-N-(4-氯苯甲基)-4-(6-氟喹啉-4-基)环己烷甲酰胺
(顺)-N-(4-氯苯甲基)-4-(6-氟喹啉-4-基)环己烷甲酰胺
(纯手性,绝对及相对立体化学未指定)
中间体73A.三氟甲磺酸1,4-二氧杂螺[4.5]癸-7-烯-8-基酯
在氮气氛围下在-78℃下向1,4-二氧杂螺[4.5]癸-8-酮(300g,1920.86mmol,1.0当量)和N-苯基三氟甲磺酰亚胺(823.47g,2305.03mmol,1.2当量)在MTBE(7.5L)中的搅拌溶液中历经70分钟添加含2.0M NaHMDS的THF(1152.2mL,2305.03mmol,1.2当量),且再搅拌混合物60分钟。使反应混合物升温至室温且搅拌过夜直至TLC显示起始物质完全耗尽。用KHSO4水溶液(100ml)淬灭混合物,过滤以移除固体且完全浓缩滤液。向残余物中添加3LMTBE,随后用5%NaOH(1.5L×3)洗涤。浓缩有机相,获得中间体34A(567g,淡黄色油状物,产率102%产率)。TLC Rf:0.7(PE/EtOAc=10/1,KMnO4).1H NMR(400MHz,CDCl3):δ(ppm)5.65(t,J=4.0Hz,1H),3.98(d,J=1.5Hz,4H),2.53(s,2H),
2.40(s,2H),1.90(t,J=6.6Hz,2H)。
中间体73B.4,4,5,5-四甲基-2-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)-1,3,2-二氧硼戊环
将中间体73A(600g,2.08mol,1当量)、B2Pin2(687.1g,2.71mol,1.3当量)、KOAc(613g,6.24mol,3当量)、NaBr(86g 0.833mol,0.4当量)和Pd(dppf)Cl2(76g,0.1mol,0.05当量)在二噁烷(6.5L)中的混合物加热至回流过夜。一旦反应完成,浓缩混合物并通过硅胶柱层析法纯化以得到中间体73B(369g,66%产率)。C14H23BO4的LC-MS分析计算值266.17,实验值[M+H]267.1。1H NMR(400MHz,CDCl3)δ6.46(s,1H),3.98(s,4H),2.37-2.35(m,4H),1.74-1.60(t,2H),1.24(s,12H)。
中间体73C.6-氟-4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)喹啉
将中间体73B(368g,1.38mol,1.3当量)、4-氯-6-氟喹啉(195g,1.07mol,1当量)、K2CO3(445g,3.22mol,3当量)和Pd(PPh3)4(25g,22mmol,0.02当量)在二噁烷-水(3L,4:1)中的混合物加热至回流过夜。浓缩溶液并用EtOAc萃取。粗残余物经由硅胶柱层析法纯化以得到中间体73C(236g,77%产率)。C17H16FNO2的LC-MS分析计算值285.12,实验值[M+H]286.1。1H NMR(400MHz,CDCl3)δ8.80-8.29(d,1H),8.11-8.07(q,1H),7.63-7.61(q,1H),7.47-7.46(q,1H),7.26-7.22(m,1H),5.75-5.74(m,1H),4.08-4.05(m,4H),2.63-2.59(m,2H),2.59-2.53(m,2H),2.0-1.97(m,2H)。
中间体73D.6-氟-4-(1,4-二氧杂螺[4.5]癸-8-基)喹啉
向55℃下含中间体73C(125g,0.44mol)的IPA(2L)中添加10%Pd/C并将混合物在H2氛围下搅拌过夜。过滤混合物并浓缩以得到粗中间体73D(128g,100%产率),其直接用于下一步骤。C17H18FNO2的LC-MS分析计算值287.13,实验值[M+H]288.2,rt=0.62min(方法A)。
中间体73E.4-(6-氟喹啉-4-基)环己酮
在45℃下用含4N HCl(300mL)的丙酮(1200mL)处理中间体73D(100g,0.348mol)过夜。然后在真空中浓缩溶液。用6N NaOH将残余物调节至pH 9。使混合物在乙酸乙酯和水之间分配。有机层用盐水洗涤,经无水Na2SO4干燥,过滤并浓缩以得到淡黄色固体,其然后通过硅胶柱层析法纯化以得到呈白色固体的中间体73E(67g,55%产率)。C15H4FNO的LC-MS分析计算值243.11,实验值[M+H]244.0。1H NMR(400MHz,CDCl3)δ8.84(d,J=4.6Hz,1H),8.16(dd,J=9.3,5.7Hz,1H),7.72(dd,J=10.3,2.8Hz,1H),7.52(ddd,J=9.2,7.8,2.7Hz,1H),7.29(d,J=4.6Hz,1H),3.69(ddd,J=12.1,9.0,3.3Hz,1H),2.77-2.54(m,4H),2.37(ddd,J=13.4,5.9,3.0Hz,2H),2.04(qd,J=12.6,5.3Hz,2H)。
中间体73F.4-(6-氟喹啉-4-基)环己烷甲腈
向中间体73E(500mg,2.055mmol)和1-((异氰基甲基)磺酰基)-4-甲基苯(522mg,2.67mmol)在DMSO(10.100ml)和甲醇(0.202ml)中的溶液中添加2-甲基丙-2-醇钾(554mg,4.93mmol)。在添加完成后,在室温下搅拌反应混合物。1小时之后,用乙醚(30mL)稀释反应并用水(20ml)洗涤。有机层经无水MgSO4干燥,在减压下浓缩。经由硅胶柱层析法纯化粗物质以得到作为顺式和反式异构体(~2:1比例)的混合物的中间体73F(280mg,1.101mmol,53.6%产率)。C16H15FN2的LC-MS分析计算值254.12,实验值[M+H]255.1,rt=0.60(第一洗脱非对映异构体)和0.62min(第二洗脱非对映异构体)(方法A)。
中间体73G.4-(6-氟喹啉-4-基)环己烷甲酸
使中间体73F(280mg,1.101mmol)溶解于甲醇(5505μl)和盐酸,37%(5505μl)中。在70℃下加热反应。48小时之后,将反应缓慢添加至100mL水中并用碳酸氢钠(饱和水溶液)碱化。水相用EtOAc萃取。合并的有机物经硫酸钠干燥,过滤并在真空中浓缩以得到粗4-(6-氟喹啉-4-基)环己烷甲酸甲酯。使此粗物质溶解于THF(4260μl)、水(4260μl)、MeOH(2130μl)中并添加氢氧化锂(255mg,10.65mmol)。在室温下搅拌反应1小时。然后浓缩反应,用1NHCl酸化并用EtOAc萃取。合并的有机物经硫酸钠干燥,过滤并在真空中浓缩以得到粗残余物。经由硅胶柱层析法纯化此粗残余物以得到中间体73G(顺式和反式的混合物)(63mg,0.231mmol,21.64%产率)。C16H16FNO2的LC-MS分析计算值273.1,实验值[M+H]274.1,rt=0.55(方法A)。
实施例73和实施例74.N-(4-氯苯甲基)-4-(6-氟喹啉-4-基)环己烷甲酰胺(顺式和反式异构体的混合物)
使中间体73G(15mg,0.055mmol)溶解于亚硫酰氯(40.1μl,0.549mmol)中并且添加DMF(2.125μl,0.027mmol)。在室温下搅拌反应1小时。之后,在真空中浓缩反应,溶解于甲苯中,再次浓缩并放在高真空下。15分钟之后,使粗酰氯溶解于ACN(274μl)中并添加至0℃下(4-氯苯基)甲胺(15.54mg,0.110mmol)在ACN(274μl)和TEA(38.2μl,0.274mmol)中的溶液中。然后允许反应升温至室温。1小时之后,用水稀释反应并用EtOAc萃取。有机物经硫酸钠干燥,过滤并在真空中浓缩。使粗残余物溶解于DMF中,过滤并经由制备型HPLC纯化以得到两种非对映异构体。
第一洗脱非对映异构体,实施例73(4.9mg,0.012mmol,22%产率)。C23H22ClFN2O的LC-MS分析计算值396.14,实验值[M+H]397.0,rt=1.891(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.80(d,J=4.4Hz,1H),8.40(t,J=5.7Hz,1H),8.08(dd,J=9.0,5.9Hz,1H),7.99(d,J=9.8Hz,1H),7.66(t,J=8.6Hz,1H),7.45(d,J=4.3Hz,1H),7.37(d,J=8.2Hz,2H),7.26(d,J=8.1Hz,2H),4.26(d,J=5.8Hz,2H),3.33(t,J=11.9Hz,1H),2.32(t,J=11.9Hz,1H),1.92(t,J=11.2Hz,4H),1.71-1.83(m,2H),1.56(q,J=12.3Hz,2H)。
第二洗脱对映异构体,实施例74(3.6mg,0.009mmol,17%产率)C23H22ClFN2O的LC-MS分析计算值396.14,实验值[M+H]397.0,rt=1.940(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.78(d,J=4.3Hz,1H),8.37(t,J=5.5Hz,1H),8.07(dd,J=8.9,6.0Hz,1H),7.95(d,J=10.8Hz,1H),7.65(t,J=8.6Hz,1H),7.36(d,J=8.0Hz,2H),7.23-7.31(m,3H),4.27(d,J=5.7Hz,2H),3.33(br.s.,1H),2.61(br.s.,1H),2.01-2.13(m,2H),1.74-1.85(m,4H),1.65-1.74(m,2H)。
实施例75及实施例76
(反)-N-(4-氯苯基)-4-(6-氟喹啉-4-基)环己烷甲酰胺
(顺)-N-(4-氯苯基)-4-(6-氟喹啉-4-基)环己烷甲酰胺
(纯手性,绝对及相对立体化学未指定)
实施例75及实施例76由中间体73G,利用用于制得实施例73及实施例74的步骤制成。
第一洗脱非对映异构体:(7.1mg,0.018mmol,34%产率)C22H20ClFN2O的LC-MS分析计算值382.13,实验值[M+H]383.2,rt=2.011(方法B)。1H NMR(500MHz,DMSO-d6)δ:10.00(s,1H),8.78(d,J=4.4Hz,1H),8.07(dd,J=9.1,5.8Hz,1H),7.96(d,J=8.8Hz,1H),7.59-7.68(m,3H),7.39(d,J=4.4Hz,1H),7.33(d,J=8.8Hz,2H),3.37(br.s.,1H),2.78(br.s.,1H),2.09(d,J=12.1Hz,2H),1.81-2.00(m,4H),1.75(d,J=11.4Hz,2H)。
第二洗脱非对映异构体:(8.4mg,0.021mmol,39%产率)C22H20ClFN2O的LC-MS分析计算值382.13,实验值[M+H]383.0,rt=1.988(方法B)。1H NMR(500MHz,DMSO-d6)δ:10.09(s,1H),8.81(d,J=4.4Hz,1H),8.08(dd,J=9.0,5.9Hz,1H),8.01(d,J=8.9Hz,1H),7.61-7.71(m,3H),7.46(d,J=4.4Hz,1H),7.34(d,J=8.7Hz,2H),3.36(t,J=11.9Hz,1H),2.41-2.48(m,1H)(埋在DMSO下的三重峰),1.97(d,J=9.7Hz,4H),1.76-1.88(m,2H),1.54-1.65(m,2H)。
实施例77a
(±)-4-氯-N-(1-((顺)-4-(吡啶-4-基氧基)环己基)丙基)苯甲酰胺
中间体77A.2-((顺)-4-(吡啶-4-基氧基)环己基)丁酸乙酯
使中间体71E(100mg,0.467mmol)溶解于THF(1867μl)中且添加吡啶-4-醇(98mg,1.027mmol)及三苯基膦(269mg,1.027mmol)。溶液在冰浴中冷却至0℃。添加偶氮二甲酸二异丙酯(200μl,1.027mmol)且一旦完成添加后允许在室温下搅拌反应。在室温下搅拌16小时。在真空中浓缩反应且经由硅胶柱层析法纯化以得到中间体77A(89mg,0.205mmol,43.9%产率)。C17H25NO3的LC-MS分析计算值291.18,实验值[M+H]292.3Tr=0.84分钟(方法A)。1H NMR(400MHz,氯仿-d)δ:8.34-8.42(m,2H),6.71-6.79(m,2H),4.57-4.64(m,1H),4.15(q,J=7.1Hz,2H),2.14(ddd,J=9.8,7.9,4.6Hz,1H),1.97-2.07(m,2H),1.38-1.69(m,9H),1.24-1.29(m,3H),0.88(t,J=7.4Hz,3H)。
中间体77B.2-((顺)-4-(吡啶-4-基氧基)环己基)丁酸
使中间体77A(89mg,0.305mmol)溶解于THF(244μl)、水(244μl)及MeOH(122μl)中。添加氢氧化锂(73.1mg,3.05mmol)且在60℃下搅拌反应16小时。再次添加氢氧化锂(73.1mg,3.05mmol)且在60℃下再搅拌反应24小时。在真空中浓缩反应,用水稀释且用EtOAc萃取。水层随后用AcOH处理且用EtOAc萃取。LCMS显示产物保留在水层中。用7:3氯仿:丙醇再次萃取。LCMS显示产物成功地从水层被萃取。合并的有机层经硫酸钠干燥,过滤,且在真空中浓缩以得到中间体77B(73mg,0.277mmol,91%产率)。物质未进一步纯化。C15H21NO3的LC-MS分析计算值263.15,实验值[M+H]264.2Tr=0.58分钟(方法A)。
中间体77C.1-((顺)-4-(吡啶-4-基氧基)环己基)丙-1-胺
使中间体77B(35mg,0.133mmol)溶解于甲苯(443μl)中且添加叠氮磷酸二苯酯(40.2mg,0.146mmol)及TEA(22.23μl,0.159mmol)。密封反应瓶(在达至温度时用针排气)且加热至80℃。在2小时之后,冷却反应至室温且在减压下浓缩。使粗残余物溶解于1mL THF及1mL水中,添加LiOH(31.8mg,1.329mmol)。在室温下搅拌反应过夜。反应用1N HCl酸化且用EtOAc萃取(丢弃萃取物)。水性部分随后用1N NaOH碱化且用EtOAc(×2)萃取。合并的碱性有机萃取物经硫酸钠干燥,过滤且在真空中浓缩以得到中间体77C(25mg,0.107mmol,80%产率)。C14H22N2O的LC-MS分析计算值234.17,实验值[M+H]235.1Tr=0.43分钟(方法A)。
实施例77a.(±)-4-氯-N-(1-((顺)-4-(吡啶-4-基氧基)环己基)丙基)苯甲酰胺
使中间体77C(25mg,0.107mmol)溶解于DMF(1067μl)中且添加HOBT(21.24mg,0.139mmol)、EDC(26.6mg,0.139mmol)、4-氯苯甲酸(33.4mg,0.213mmol)及TEA(74.3μl,0.533mmol)且在室温下搅拌反应。在2小时之后,用DMF稀释反应以使总体积达2mL,过滤,且经由制备型HPLC纯化以得到实施例77a(23.2mg,0.062mmol,58%产率)。C21H25ClN2O2的LC-MS分析计算值372.16,实验值[M+H]373.3Tr=0.73分钟(方法A)。1H NMR(500MHz,DMSO-d6)δ:8.30(d,J=5.6Hz,2H),8.17(d,J=9.1Hz,1H),7.81(d,J=8.3Hz,2H),7.51(d,J=8.3Hz,2H),6.91(d,J=5.6Hz,2H),4.69(br.s.,1H),1.88(d,J=12.0Hz,2H),1.25-1.68(m,9H),0.81(t,J=7.2Hz,3H)。
实例77b及c
4-氯-N-((R)-1-((顺)-4-(吡啶-4-基氧基)环己基)丙基)苯甲酰胺
4-氯-N-((S)-1-((顺)-4-(吡啶-4-基氧基)环己基)丙基)苯甲酰胺
(纯手性,绝对及相对立体化学未指定)
实施例77b及实施例77c:外消旋实施例77a的手性分离(方法E)得到实施例77b Tr=3.391分钟(方法F)及实施例77c Tr=3.851分钟(方法F),绝对立体化学未测定。
实施例77b:MS(ES):m/z=373.3[M+H]+。Tr=1.783分钟(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.34(d,J=4.9Hz,2H),8.12(d,J=9.0Hz,1H),7.84(d,J=8.3Hz,2H),7.53(d,J=8.3Hz,2H),6.94(d,J=5.5Hz,2H),4.71(br.s.,1H),1.89(br.s.,2H),1.27-1.69(m,10H),0.83(t,J=7.2Hz,3H)。
实施例77c:MS(ES):m/z=373.3[M+H]+。Tr=1.793分钟(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.34(d,J=3.6Hz,2H),8.12(d,J=9.0Hz,1H),7.84(d,J=8.3Hz,2H),7.53(d,J=8.4Hz,2H),6.95(d,J=5.4Hz,2H),4.72(br.s.,1H),1.86-1.94(m,J=5.0Hz,2H),1.29-1.68(m,10H),0.83(t,J=7.2Hz,3H)。
实施例78
(±)-4-氯-N-(1-((顺)-4-((6-(三氟甲基)喹啉-4-基)氧基)环己基)丙基)苯甲酰胺
实施例78由中间体71E,按照用于制得中间体77A、77B、77C及实施例77a的相同步骤,使用4-羟基-6-三氟甲基喹啉而非77A的合成中的吡啶-4-醇来合成。C26H26ClF3N2O2的LC-MS分析计算值490.16,实验值[M+H]491.2Tr=0.86分钟(方法A)。1H NMR(500MHz,DMSO-d6)δ:8.81(d,J=5.2Hz,1H),8.36(s,1H),8.16(d,J=9.0Hz,1H),8.12(d,J=8.8Hz,1H),7.96(d,J=8.2Hz,1H),7.81(d,J=8.3Hz,2H),7.45(d,J=8.4Hz,2H),7.15(d,J=5.3Hz,1H),4.98(br.s.,1H),2.07(t,J=15.6Hz,2H),1.37-1.74(m,9H),0.82(t,J=7.2Hz,3H)。
实施例79a
(±)-4-氯-N-(1-((顺)-4-((2-(三氟甲基)喹啉-4-基)氧基)环己基)丙基)苯甲酰胺
实施例79a由中间体71E,按照用于制得中间体77A、77B、77C及实施例77a的相同步骤,使用4-羟基-2-三氟甲基喹啉而非77A的合成中的吡啶-4-醇来合成。C26H26ClF3N2O2的LC-MS分析计算值490.16,实验值[M+H]491.2Tr=1.13分钟(方法A)。1H NMR(500MHz,DMSO-d6)δ:8.17(d,J=8.3Hz,1H),8.14(d,J=9.1Hz,1H),8.05(d,J=8.4Hz,1H),7.81-7.91(m,3H),7.50-7.58(m,3H),7.39(s,1H),5.18(br.s.,1H),2.07(t,J=13.9Hz,2H),1.40-1.74(m,9H),0.85(t,J=7.2Hz,3H)。
实施例79b及c
4-氯-N-((R)-1-((顺)-4-(2-(三氟甲基)喹啉-4-基氧基)环己基)丙基)苯甲酰胺及
4-氯-N-((S)-1-((顺)-4-(2-(三氟甲基)喹啉-4-基氧基)环己基)丙基)苯甲酰胺(纯手性,绝对及相对立体化学未指定)
实施例79b及实施例79c:外消旋实施例79a的手性分离(方法G)得到实施例79b Tr=3.998分钟(方法H)及实施例79c Tr=5.009分钟(方法H),绝对立体化学未测定。
实施例79b:MS(ES):m/z=491.3[M+H]+。Tr=2.438分钟(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.11-8.20(m,2H),8.05(d,J=8.3Hz,1H),7.81-7.89(m,J=7.0Hz,3H),7.49-7.57(m,3H),7.37(s,1H),5.16(br.s.,1H),3.83(br.s.,1H),2.06(t,J=13.4Hz,2H),1.56-1.76(m,6H),1.39-1.56(m,3H),0.84(t,J=6.9Hz,3H)。
实施例79c:MS(ES):m/z=491.3[M+H]+。Tr=2.438分钟(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.16(t,J=8.8Hz,2H),8.04(d,J=8.5Hz,1H),7.85(m,3H),7.49-7.56(m,3H),7.37(s,1H),5.15(br.s.,1H),3.83(br.s.,1H),2.00-2.11(m,2H),1.56-1.73(m,6H),1.40-1.55(m,3H),0.84(t,J=7.2Hz,3H)。
实施例80
4-氯-N-(1-(顺-4-(喹啉-4-基氧基)环己基)丙基)苯甲酰胺
实施例80由中间体71E,按照用于制得中间体77A、77B、77C及实施例77的相同步骤,使用4-羟基喹啉而非77A的合成中的吡啶-4-醇来合成。C25H27ClN2O2的LC-MS分析计算值422.18,实验值[M+H]423.2Tr=0.78分钟(方法A)。1H NMR(500MHz,DMSO-d6)δ:8.66(d,J=5.0Hz,1H),8.14(d,J=9.0Hz,1H),8.08(d,J=8.1Hz,1H),7.90(d,J=8.3Hz,1H),7.85(d,J=8.2Hz,2H),7.70(t,J=7.4Hz,1H),7.52(d,J=8.2Hz,2H),7.36(t,J=7.5Hz,1H),7.00(d,J=5.1Hz,1H),4.95(br.s.,1H),2.06(t,J=13.9Hz,2H),1.38-1.71(m,9H),0.84(t,J=7.0Hz,3H)。
实施例81
4-氯-N-((1-(6-氟喹啉-4-基)-4-羟基哌啶-4-基)甲基)苯甲酰胺
81A.4-((4-氯苯甲酰氨基)甲基)-4-羟基哌啶-1-甲酸叔丁酯
用三乙胺(0.454mL,3.26mmol)随后BOP(0.576g,1.303mmol)处理4-(氨甲基)-4-羟基哌啶-1-甲酸叔丁酯(0.25g,1.086mmol)及4-氯苯甲酸(0.204g,1.303mmol)在DMF(2mL)中的溶液。搅拌反应2小时,随后用稀HOAc水溶液淬灭。此导致形成沉淀,因此过滤混合物且用水冲洗。其随后悬浮于稀碳酸氢钠水溶液中,经超声波处理,随后过滤,用水冲洗,且风干以得到呈无色固体的4-((4-氯苯甲酰氨基)甲基)-4-羟基哌啶-1-甲酸叔丁酯(0.38g,90%产率),mp172-173℃。MS(ES):m/z=369[M+H]+。tR=0.93分钟(方法A)。
81B.4-氯-N-((4-羟基哌啶-4-基)甲基)苯甲酰胺,HCl
用4-((4-氯苯甲酰氨基)甲基)-4-羟基哌啶-1-甲酸叔丁酯(0.35g,0.949mmol)处理HCl(3.56ml,14.23mmol)在二噁烷中的溶液。最初,物质在其添加时溶解,但最终形成胶状物。搅拌此15分钟,随后添加~3mL二氯甲烷且继续搅拌2小时。在此时间期间,产物呈现精细分散的悬浮液的形式。在减压下浓缩得到呈白色粉末的4-氯-N-((4-羟基哌啶-4-基)甲基)苯甲酰胺,HCl(0.29g,定量产率)。MS(ES):m/z=269[M+H]+。tR=0.55分钟(方法A)。
实施例81.4-氯-N-((1-(6-氟喹啉-4-基)-4-羟基哌啶-4-基)甲基)苯甲酰胺
用DIEA(0.286mL,1.638mmol)处理4-氯-6-氟喹啉(0.119g,0.655mmol)及4-氯-N-((4-羟基哌啶-4-基)甲基)苯甲酰胺,HCl(0.2g,0.655mmol)在NMP(1mL)中的悬浮液且加热至135℃持续5小时。在约45分钟之后,反应变得均质。冷却反应至~80℃且用~3mL 5%HOAc水溶液处理,导致形成沉淀。短暂搅拌此,过滤,用水冲洗若干次且用10%EtOAc-己烷冲洗一次,且风干以得到呈灰白色固体的4-氯-N-((1-(6-氟喹啉-4-基)-4-羟基哌啶-4-基)甲基)苯甲酰胺(0.21g,74%产率),mp 91-94℃。MS(ES):m/z=414[M+H]+。tR=0.68分钟(方法A)。1H NMR(400MHz,DMSO-d6)δ8.67(d,1H,J=4.9Hz),8.46(t,1H,J=6.1Hz),7.99-8.04(m,1H),7.94(d,2H,J=8.7Hz),7.55-7.63(m,4H),7.05(d,1H,J=5.0Hz),4.71(s,1H),3.42(d,2H,J=6.1Hz),3.24-3.31(m,积分被水峰遮蔽),3.10-3.18(m,2H),1.85-1.94(m,2H),1.67-1.72(m,2H)。
实施例84
N-([1,1′-联苯]-4-基)-4-(6-氟喹啉-4-基)哌嗪-1-甲酰胺
84A.4-(6-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯
在可密封瓶中向4-氯-6-氟喹啉(500.0mg,2.8mmol)在NMP(5mL)中的均质混合物中添加1-Boc-哌嗪(750.0mg,4.0mmol),随后添加DIPEA(2mL,11.6mmol)。在添加完成之后,将瓶加盖且在120℃下搅拌混合物。在15小时之后,冷却反应至室温随后在水与Et2O之间分配。分离各层且水层用Et2O再萃取两次,随后用EtOAc萃取一次。组合这些有机萃取物与最初有机层且用盐水洗涤,干燥(Na2SO4),过滤且在真空中浓缩以得到呈油状物的粗产物。通过Isco层析法纯化得到呈固体的4-(6-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯(719.3mg;77%产率)。MS(ES):m/z=332[M+H]+。tR=0.70分钟(方法A)。1H NMR(400MHz,DMSO-d6)δ8.70(d,J=4.9Hz,1H),8.04(dd,J=9.2,5.6Hz,1H),7.76-7.58(m,2H),7.07(d,J=5.0Hz,1H),3.71-3.54(m,4H),3.14-3.01(m,4H),1.44(s,9H)。
84B.6-氟-4-(哌嗪-1-基)喹啉
在室温下在氮气下向4-(6-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯(700.0mg,2.1mmol)在无水二噁烷(4mL)中的均质混合物中添加HCl(在二噁烷中4N,10mL,40.0mmol)。在6小时之后,形成沉淀,其通过真空过滤分离,用无水二噁烷冲洗且在真空下干燥以得到呈HCl盐的标题化合物(508.0mg,79%产率),其不经进一步纯化而使用。MS(ES):m/z=232[M+H]+。tR=0.38分钟(方法A)。84N-([1,1′-联苯]-4-基)-4-(6-氟喹啉-4-基)哌嗪-1-甲酰胺
在室温下向6-氟-4-(哌嗪-1-基)喹啉的HCl盐(84B,25.0mg,0.09mmol)在无水DMF(1mL)中的非均质混合物中添加DIPEA(0.05mL,0.29mmol),随后添加4-异氰酸基-1,1′-联苯(23.0mg,0.12mmol)。搅拌所得混合物96小时,随后用DMF稀释,通过注射器式过滤器,随后经由制备型HPLC/MS纯化以得到标题化合物(12.9mg;21%产率)。MS(ES):m/z=427[M+H]+。tR=1.55分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ8.69(d,J=6.5Hz,1H),8.07(dd,J=9.2,5.1Hz,1H),7.99-7.96(m,1H),7.93-7.90(m,1H),7.63(d,J=7.7Hz,2H),7.58-7.57(m,4H),7.44-7.41(m,2H),7.33-7.26(m,2H),7.20(d,J=6.6Hz,1H),3.87-3.81(m,4H),3.81-3.73(m,4H)。
实施例86
N-((1-(6-氟喹啉-4-基)哌啶-4-基)甲基)-4-甲基苯甲酰胺
86A.((1-(6-氟喹啉-4-基)哌啶-4-基)甲基)氨基甲酸叔丁酯
在可密封瓶中向4-氯-6-氟喹啉(220.0mg,1.2mmol)在无水NMP(4mL)中的均质混合物中添加(哌啶-4-基甲基)氨基甲酸叔丁酯(350.0mg,1.6mmol),随后添加DIPEA(0.8mL,4.6mmol)。密封瓶且在60℃下搅拌混合物2小时,随后在90℃下搅拌17小时,随后在120℃下搅拌24小时。在冷却至室温之后,通过Isco硅胶层析法纯化反应混合物以得到呈灰白色固体的((1-(6-氟喹啉-4-基)哌啶-4-基)甲基)氨基甲酸叔丁酯(323.7mg;74%产率)。MS(ES):m/z=360[M+H]+。tR=0.71分钟(方法A)。1H NMR(400MHz,DMSO-d6)δ8.66(d,J=5.0Hz,1H),8.01(dd,J=9.1,5.7Hz,1H),7.66-7.51(m,2H),7.01(d,J=4.9Hz,1H),6.93(t,J=5.7Hz,1H),3.48(d,J=12.2Hz,2H),2.94(t,J=6.3Hz,2H),2.76(t,J=11.2Hz,2H),1.80(d,J=11.1Hz,2H),1.67-1.55(m,1H),1.51-1.42(m,2H),1.40(s,9H)。
86B.(1-(6-氟喹啉-4-基)哌啶-4-基)甲胺
在氮气氛围下向((1-(6-氟喹啉-4-基)哌啶-4-基)甲基)氨基甲酸叔丁酯(308.1mg,0.9mmol)在DCM(10mL)中的均质混合物中添加TFA(1.2mL,15.6mmol)。在环境温度下搅拌所得混合物45分钟,随后在真空中浓缩以得到呈金色油状物的标题化合物的TFA盐,其不经进一步纯化而使用。MS(ES):m/z=260[M+H]+。tR=0.43分钟(方法A)。
实施例86.N-((1-(6-氟喹啉-4-基)哌啶-4-基)甲基)-4-甲基苯甲酰胺
在氮气氛围下向(1-(6-氟喹啉-4-基)哌啶-4-基)甲胺的TFA盐(86B,41.8mg,0.09mmol)、4-甲基苯甲酸(14.0mg,0.1mmol)及DIPEA(0.06mL,0.3mmol)在无水THF(1mL)、二噁烷(0.5mL)及DMF(0.5mL)中的均质混合物中添加PyBOP(44.6mg,0.09mmol)。在环境温度下搅拌15小时之后,混合物用DMSO稀释,通过注射器式过滤器,随后经由制备型HPLC/MS纯化以得到标题化合物(21.1mg;65%产率)。MS(ES):m/z=378[M+H]+。tR=1.25分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ8.63-8.53(m,2H),7.97(dd,J=8.9,5.7Hz,1H),7.70(d,J=7.9Hz,2H),7.63-7.51(m,2H),7.25(d,J=7.8Hz,2H),7.00(d,J=4.8Hz,1H),3.47(d,J=11.4Hz,2H),2.76(t,J=11.6Hz,2H),~2.53(m,积分,准确化学位移范围被溶剂峰遮蔽),2.31(s,3H),1.87-1.73(m,3H),1.55-1.41(m,2H)。
实施例87
3,4-二氯-N-((1-(6-氟喹啉-4-基)哌啶-4-基)甲基)苯甲酰胺
在氮气氛围下向(1-(6-氟喹啉-4-基)哌啶-4-基)甲胺的TFA盐(86B,41.8mg,0.09mmol)在无水THF(1mL)及二噁烷(0.5mL)中的非均质混合物中添加DIPEA(0.06mL,0.3mmol),随后添加3,4-二氯苯甲酰氯(18.9mg,0.09mmol)。在环境温度下搅拌16小时之后,混合物用DMF稀释,经由注射器式过滤器过滤,随后经由制备型HPLC/MS纯化以得到标题化合物(23.1mg;62%产率)。MS(ES):m/z=432[M+H]+。tR=1.51分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ8.83-8.76(m,1H),8.63(d,J=4.8Hz,1H),8.07(s,1H),7.99(dd,J=8.8,5.7Hz,1H),7.82(d,J=8.2Hz,1H),7.73(d,J=8.4Hz,1H),7.64-7.54(m,2H),7.01(d,J=4.8Hz,1H),3.71-3.44(m,2H),3.34-3.21(m,2H),2.76(t,J=11.7Hz,2H),1.88-1.75(m,3H),1.56-1.45(m,2H)。
实施例88至90
(1-(6-氟喹啉-4-基)哌啶-4-基)甲胺的TFA盐与合适酰基氯在针对实施例87所描述的条件下的反应(以下方案1)得到显示于以下表1中的本发明化合物。
方案1
表1
实施例91
1-(1-(6-氟喹啉-4-基)哌啶-4-基)-3-(对甲苯基)脲
91A.(1-(6-氟喹啉-4-基)哌啶-4-基)氨基甲酸叔丁酯
在可密封瓶中向4-氯-6-氟喹啉(200.0mg,1.1mmol)在无水NMP(5mL)中的均质混合物中添加4-Boc-氨基哌啶(309.0mg,1.5mmol),随后添加DIPEA(0.8mL,4.6mmol)。密封瓶且在120℃下搅拌混合物15小时。在冷却至室温之后,使反应混合物在EtOAc与水之间分配。分离各层且用EtOAc再萃取水层两次。合并有机萃取物,用盐水洗涤,干燥(Na2SO4),过滤且在真空中浓缩以得到粗产物,基于定量产率,其不经进一步纯化而使用。MS(ES):m/z=346[M+H]+。tR=0.70分钟(方法A)。
91B.1-(6-氟喹啉-4-基)哌啶-4-胺
在氮气氛围下向(1-(6-氟喹啉-4-基)哌啶-4-基)氨基甲酸叔丁酯(380.0mg,1.1mmol)在二噁烷(2mL)中的均质混合物中添加含4M HCl的二噁烷(2mL,8.0mmol)。在环境温度下搅拌所得混合物6小时,在此时间期间形成沉淀。真空过滤得到呈浅黄色固体的标题化合物的HCl盐(358mg,100%产率),其不经进一步纯化而使用。MS(ES):m/z=246[M+H]+。tR=0.42分钟(方法A)。
实施例91.1-(1-(6-氟喹啉-4-基)哌啶-4-基)-3-(对甲苯基)脲
在室温下向1-(6-氟喹啉-4-基)哌啶-4-胺的HCl盐(91B,30.0mg,0.09mmol)在无水THF(1mL)中的非均质混合物中添加DIPEA(0.05mL,0.29mmol),随后添加1-异氰酸基-4-甲基苯(15.1mg,0.11mmol)。搅拌所得混合物88小时,随后用DMSO稀释,通过注射器式过滤器,随后经由制备型HPLC/MS纯化以得到标题化合物(21.7mg;60%产率)。MS(ES):m/z=379[M+H]+。tR=1.30分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ8.67(d,J=2.5Hz,1H),8.29(s,1H),8.11-7.96(m,1H),7.70-7.57(m,2H),7.27(d,J=7.3Hz,2H),7.12-6.97(m,3H),6.23(d,J=7.2Hz,1H),3.79-3.68(m,1H),3.53-3.37(m,2H),3.05-2.90(m,2H),2.21(s,3H),2.11-1.98(m,2H),1.81-1.65(m,2H)。
实施例92
1-(4-氯-2-氟苯基)-3-(1-(6-氟喹啉-4-基)哌啶-4-基)脲
实施例92(19.3mg;49%产率)按照与实施例91的合成类似的步骤制备,不同之处在于使用4-氯-2-氟-1-异氰酸基苯(19.4mg,0.11mmol)代替1-异氰酸基-4-甲基苯。MS(ES):m/z=417[M+H]+。Tr=1.42分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ8.67(d,J=4.8Hz,1H),8.39(s,1H),8.16(t,J=8.9Hz,1H),8.02(dd,J=9.9,5.6Hz,1H),7.68-7.56(m,2H),7.39(d,J=11.2Hz,1H),7.17(d,J=8.8Hz,1H),7.06(d,J=4.7Hz,1H),6.84(d,J=7.3Hz,1H),3.82-3.70(m,1H),3.50-3.37(m,2H),2.98(t,J=10.8Hz,2H),2.12-2.01(m,2H),1.78-1.65(m,2H)。
实施例93
1-(4-氟苯基)-3-(1-(6-氟喹啉-4-基)哌啶-4-基)脲
实施例93(21.8mg;61%产率)按照与实施例91的合成类似的步骤制备,不同之处在于使用1-氟-4-异氰酸基苯(15.5mg,0.11mmol)代替1-异氰酸基-4-甲基苯。MS(ES):m/z=383[M+H]+。Tr=1.18分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ8.57(d,J=6.1Hz,1H),8.44(s,1H),8.00(dd,J=9.2,5.2Hz,1H),7.84-7.71(m,2H),7.35(dd,J=8.4,4.9Hz,2H),7.15(d,J=6.3Hz,1H),7.05(t,J=8.7Hz,2H),6.31(d,J=7.5Hz,1H),3.86-3.85(m,3H),3.35(t,J=11.1Hz,2H),2.07-2.00(m,2H),1.74-1.61(m,2H)。
实施例97
反-N-(4-甲氧基苯甲基)-4-苯基环己胺
用(4-甲氧基苯基)甲胺(1.575g,11.48mmol)及高氯酸镁(0.128g,0.574mmol)处理反-4-苯基环己酮(2g,11.48mmol)在DCM(30mL)中的悬浮液。在室温下搅拌16小时之后,添加Na2SO4且在室温下继续搅拌1小时。过滤混合物,用MeOH洗涤且浓缩母液,产生黄色粘稠油状物。使油状物溶解于MeOH(10mL)中,且逐份用NaBH4(0.651g,17.22mmol)处理,随后在室温下搅拌30分钟直至完成反应。用水(75ml)淬灭反应且用EtOAc(3×)萃取。干燥合并的有机萃取物,过滤,且浓缩。黄色残余物在ISCO二氧化硅柱(40g)上纯化,在20分钟内用(DCM:10%MeOH/DCM,含有2.5%NH4OH=0%-70%)洗脱,产生(1r,4r)-N-(4-甲氧基苯甲基)-4-苯基环己胺(870mg,2.94mmol,25%)。1H NMR(500MHz,氯仿-d)δ7.32-7.22(m,3H),7.22-7.10(m,4H),6.92-6.77(m,2H),3.84-3.70(m,5H),2.60-2.46(m,2H),2.15-2.02(m,2H),1.97-1.82(m,2H),1.49(qd,J=12.9,3.0Hz,2H),1.36-1.15(m,2H)MS:C20H25NO的分析计算值295.194,实验值[M+H]296.1LC:tr=1.4分钟(方法I)
实施例119
1-(4-氯苯基)-3-(反-4-(6-氟喹啉-4-基)环己基)脲
119A.反-4-(6-氟喹啉-4-基)环己胺
在微波瓶中向4-(6-氟喹啉-4-基)环己酮(350mg,1.439mmol)在EtOH(6mL)中的溶液中添加乙酸铵(1663mg,21.58mmol)。用氰基硼氢化钠(108mg,1.726mmol)处理所得悬浮液。将反应加盖且在130℃下微波处理5分钟。冷却反应至室温且用MeOH稀释且通过制备型HPLC(Luna 5μ,30×100mm)(40mL/min流速,梯度为0%B-100%B,历时12分钟)纯化。在100%B下保持2分钟。(A:含0.1%TFA的水/MeOH(90:10),B:含0.1%TFA的水/MeOH(10:90),在254nm下监测)。合并含有产物的级分且浓缩以得到反-4-(6-氟喹啉-4-基)环己胺(310mg,0.624mmol,43.4%产率)。1H NMR(400MHz,DMSO-d6)δ8.88(d,J=4.6Hz,1H),8.19-8.05(m,2H),7.92(br.s.,3H),7.73(td,J=8.7,2.8Hz,1H),7.53(d,J=4.6Hz,1H),3.36(br.s.,1H),3.22-3.02(m,1H),2.09(br.s.,2H),1.96(br.s.,2H),1.77-1.52(m,4H)MS:C15H17FN2的分析计算值244.138,实验值[M+H]245.1LC:tr=0.42分钟(方法A)。
实施例119.1-(4-氯苯基)-3-(反-4-(6-氟喹啉-4-基)环己基)脲
在室温下向反-4-(6-氟喹啉-4-基)环己胺(20mg,0.042mmol)在THF(0.5mL)中的溶液中添加1-氯-4-异氰酸基苯(9.76mg,0.064mmol)。在室温下搅拌反应3h。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:30-70%B,历时22分钟,随后在100%B下保持5分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥。产物的产量为11.4mg(0.029mmol,67%)。1H NMR(400MHz,DMSO-d6)δ8.82(d,J=4.5Hz,1H),8.50(s,1H),8.10(dd,J=9.3,5.9Hz,1H),8.03(dd,J=11.1,2.8Hz,1H),7.68(td,J=8.7,2.8Hz,1H),7.50(d,J=4.5Hz,1H),7.46-7.35(m,2H),7.33-7.19(m,2H),6.19(d,J=7.7Hz,1H),3.70-3.52(m,1H),3.42-3.34(m,1H),2.04(d,J=9.3Hz,2H),1.92(d,J=12.1Hz,2H),1.79-1.63(m,2H),1.61-1.45(m,2H)MS:C22H21ClFN3O的分析计算值397.136,实验值[M+H]398.2LC:tr=1.39分钟(方法I)。
这些化合物按照实施例119中的步骤使用相应的异氰酸酯获得。
实施例125
1-(4-氯苯基)-3-(顺-4-(6-氟喹啉-4-基)环己基)脲
125A.顺-4-(6-氟喹啉-4-基)环己胺
向在微波瓶中的4-(6-氟喹啉-4-基)环己酮(350mg,1.439mmol)在EtOH(6mL)中的溶液中添加乙酸铵(1663mg,21.58mmol)。向所得悬浮液中添加氰基硼氢化钠(108mg,1.726mmol)。将反应加盖且在130℃下微波处理5分钟。冷却反应至室温且用MeOH稀释且通过制备型HPLC(Luna 5μ,30×100mm)(40mL/min流速,梯度为0%B-100%B,历时12分钟,在100%B下保持2分钟)纯化。(A:含0.1%TFA的水/MeOH(90:10),B:含0.1%TFA的水/MeOH(10:90),在254nm下监测)。合并含有产物的级分且浓缩以得到顺-4-(6-氟喹啉-4-基)环己胺(100mg,0.201mmol,14%产率)。1H NMR(400MHz,DMSO-d6)δ8.94(d,J=4.6Hz,1H),8.19-8.03(m,2H),7.94(br.s.,1H),7.74(td,J=8.7,2.8Hz,1H),7.60(d,J=4.8Hz,1H),3.59(br.s.,1H),3.49(t,J=11.0Hz,1H),2.10-1.82(m,6H),1.75(d,J=10.8Hz,2H)MS:C15H17FN2的分析计算值244.138,实验值[M+H]245.1LC:tr=0.45分钟(方法A)。
实施例125.1-(4-氯苯基)-3-(顺-4-(6-氟喹啉-4-基)环己基)脲
在室温下向顺-4-(6-氟喹啉-4-基)环己胺(25mg,0.053mmol)在THF(0.5mL)中的溶液中添加1-氯-4-异氰酸基苯(16.27mg,0.106mmol)。在室温下搅拌反应2小时。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:30-70%B,历时22分钟,随后在100%B下保持5分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥。产物的产量为14.7mg(0.034mmol,64%)。1H NMR(500MHz,DMSO-d6)δ8.95(d,J=4.5Hz,1H),8.56(s,1H),8.21-8.08(m,2H),7.78(t,J=8.5Hz,1H),7.63(d,J=4.4Hz,1H),7.43(d,J=8.3Hz,2H),7.27(d,J=7.4Hz,2H),6.69(d,J=7.4Hz,1H),4.01(br.s.,1H),3.59(d,J=9.4Hz,1H),1.96-1.78(m,4H),1.76(br.s.,4H)MS:C22H21ClFN3O的分析计算值397.136,实验值[M+H]398.2LC:tr=1.44分钟(方法I)。
实施例130
反-N-苯甲基-4-(6-氟喹啉-4-基)环己胺
在室温下向4-(6-氟喹啉-4-基)环己酮(100mg,0.411mmol)及苯甲基胺(66mg,0.617mmol)在CH2Cl2(2mL)中的溶液中添加乙酸(0.024mL,0.411mmol),随后添加三乙酰氧基硼氢化钠(131mg,0.617mmol)。在室温下搅拌反应4小时。随后其用MeOH稀释且用制备型HPLC(Phen Luna 5u 30×100mm)(40mL/min流速,梯度为0%B-100%B,历时12分钟,在100%B下保持2分钟)纯化。(A:含0.1%TFA的水/MeOH(90:10),B:含0.1%TFA的水/MeOH(10:90),在254nm下监测)。蒸发含有产物的级分得到(1r,4r)-N-苯甲基-4-(6-氟喹啉-4-基)环己胺(150mg)。此物质的等分试样(15mg)在以下条件下进一步纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:10-50%B,历时18分钟,随后在100%B下保持5分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥。产物的产量为3.1mg,
1H NMR(500MHz,DMSO-d6)δ8.78(br d,J=4.2Hz,1H),8.08(br dd,J=8.8,6.0Hz,1H),7.96(br d,J=10.6Hz,1H),7.72-7.62(m,1H),7.43(br d,J=7.0Hz,3H),7.37(br t,J=7.3Hz,2H),7.34-7.25(m,1H),3.94(s,1H),3.74-3.63(m,1H),3.29(br s,1H),2.78(brs,1H),2.14(br s,2H),1.99-1.84(m,3H),1.55(br s,4H)。MS:C22H23FN2的分析计算值334.185,实验值[M+H]335.1LC:tr=0.78分钟(方法I)。
实施例131
顺-N-苯甲基-4-(6-氟喹啉-4-基)环己胺
实施例131按照实施例130中的步骤,使用相应的顺-4-(6-氟喹啉-4-基)环己酮及苯甲基胺获得。1H NMR(500MHz,DMSO-d6)δ8.84(d,J=3.8Hz,1H),8.14-8.04(m,1H),8.00(d,J=10.8Hz,1H),7.67(t,J=8.7Hz,1H),7.55-7.46(m,3H),7.41(t,J=7.2Hz,2H),7.35(d,J=7.2Hz,1H),4.01(br.s.,2H),3.41(br.s.,1H),3.17(br.s.,1H),2.09-1.99(m,2H),1.99-1.80(m,4H),1.67(d,J=12.0Hz,2H)。MS:C22H23FN2的分析计算值334.185,实验值[M+H]335.2LC:tr=0.90分钟(方法I)。
实施例139
2-(4-(((反-4-(6-氟喹啉-4-基)环己基)氨基)甲基)苯基)乙酸
实施例139按照实施例130中的步骤,使用相应的反-4-(6-氟喹啉-4-基)环己酮及2-(4-(氨甲基)苯基)乙酸盐酸盐获得。1H NMR(500MHz,DMSO-d6)δ8.91(br.s.,2H),8.83(d,J=3.9Hz,1H),8.20-8.08(m,1H),8.03(d,J=10.7Hz,1H),7.71(t,J=8.3Hz,1H),7.48(d,J=7.9Hz,3H),7.35(d,J=7.3Hz,2H),4.21(br.s.,2H),3.60(d,J=19.4Hz,2H),3.41-3.28(m,1H),3.21(br.s.,1H),2.28(d,J=10.6Hz,2H),2.01(d,J=11.3Hz,2H),1.81-1.59(m,4H)MS:C24H25FN2O2的分析计算值392.190,实验值[M+H]393.1LC:tr=0.72分钟(方法I)。
实施例140
2-(4-(((顺-4-(6-氟喹啉-4-基)环己基)氨基)甲基)苯基)乙酸
实施例140按照实施例130中的步骤,使用相应的顺-4-(6-氟喹啉-4-基)环己酮及2-(4-(氨甲基)苯基)乙酸盐酸盐获得。1H NMR(500MHz,DMSO-d6)δ8.81(d,J=4.2Hz,1H),8.16-8.03(m,1H),7.98(d,J=9.6Hz,1H),7.73-7.60(m,1H),7.51(d,J=4.3Hz,1H),7.42-7.29(m,J=7.6Hz,2H),7.26-7.08(m,J=7.5Hz,2H),3.81(br.s.,1H),3.64(br.s.,1H),3.49(s,1H),3.34(br.s.,1H),3.16(s,1H),2.99(br.s.,1H),2.01-1.87(m,4H),1.83-1.68(m,2H),1.61(d,J=11.9Hz,2H)。MS:C24H25FN2O2的分析计算值392.190,实验值[M+H]393.2LC:tr=0.79分钟(方法I)。
实施例144
2-(4-氯苯基)-N-(反-4-(6-氟喹啉-4-基)环己基)乙酰胺
在室温下向反-4-(6-氟喹啉-4-基)环己胺(20mg,0.042mmol)(中间体119A)在THF(0.5mL)中的溶液中添加2-(4-氯苯基)乙酰氯(16.02mg,0.085mmol),随后添加三乙胺(0.024mL,0.169mmol)。在室温下搅拌反应3小时。经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:50-100%B,历时20分钟,随后在100%B下保持5分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥。产物的产量为11.5mg(0.029mmol,68%)。1H NMR(500MHz,DMSO-d6)δ8.76(d,J=4.5Hz,1H),8.25(d,J=7.7Hz,1H),8.07(dd,J=9.1,5.8Hz,1H),7.93(d,J=8.8Hz,1H),7.71-7.58(m,1H),7.46(d,J=4.4Hz,1H),7.36-7.30(m,J=8.2Hz,2H),7.29-7.13(m,J=8.2Hz,2H),3.94-3.81(m,2H),3.61(d,J=7.3Hz,1H),3.25(t,J=11.2Hz,1H),1.88(t,J=13.7Hz,4H),1.66-1.43(m,4H)MS:C23H22ClFN2O的分析计算值396.140,实验值[M+H]397.0LC:tr=1.37分钟(方法I)。
这些化合物按照实施例144中的步骤,使用相应的胺及酰基氯获得。
实施例157a、b、c、d、e
4-氯-N-(1-(4-(2-甲基吡啶-4-基)环己基)乙基)苯甲酰胺
4-氯-N-((S)-1-(顺-4-(2-甲基吡啶-4-基)环己基)乙基)苯甲酰胺
4-氯-N-((R)-1-(顺-4-(2-甲基吡啶-4-基)环己基)乙基)苯甲酰胺
4-氯-N-((S)-1-(反-4-(2-甲基吡啶-4-基)环己基)乙基)苯甲酰胺
4-氯-N-((R)-1-(反-4-(2-甲基吡啶-4-基)环己基)乙基)苯甲酰胺
157A.2-(1,4-二氧杂螺[4.5]癸-8-亚基)丙酸乙酯
向NaH(0.307g,7.68mmol)在THF(8mL)中的在0℃下冷却的悬浮液中缓慢添加2-(二乙氧基磷酰基)丙酸乙酯(1.830g,7.68mmol)。在30分钟之后,添加1,4-二氧杂螺[4.5]癸-8-酮(1g,6.40mmol)。在0℃下搅拌所得混合物2小时,随后升温至室温过夜。用水淬灭混合物且在真空中移除THF。使残余物溶解于EtOAc中,用水及盐水洗涤。溶液经Na2SO4干燥,过滤且浓缩。通过ISCO(EtOAc/己烷0-30%)纯化粗物质。浓缩含有产物的级分,产生2-(1,4-二氧杂螺[4.5]癸-8-亚基)丙酸乙酯(1.2g,78%产率),淡黄色油状物。1H NMR(400MHz,氯仿-d)δ4.19(q,J=7.1Hz,2H),4.03-3.89(m,4H),2.68-2.53(m,2H),2.46-2.28(m,2H),1.89(s,3H),1.78-1.66(m,4H),1.30(t,J=7.1Hz,3H)。
157B.2-(1,4-二氧杂螺[4.5]癸-8-基)丙酸乙酯
在45psi下在帕尔振荡器中氢化2-(1,4-二氧杂螺[4.5]癸-8-亚基)丙酸乙酯(500mg,2.081mmol)及10%钯/碳(25mg,0.024mmol)在EtOAc(5mL)中的悬浮液6小时。过滤催化剂且浓缩滤液,产生呈浅色油状物的2-(4-(3-甲基吡啶-4-基)环己基)丙酸乙酯(450mg,89%产率)。1H NMR(400MHz,氯仿-d)δ4.12(dtt,J=10.7,7.1,3.6Hz,2H),3.98-3.81(m,4H),2.35-2.17(m,1H),1.83-1.68(m,3H),1.66-1.45(m,4H),1.43-1.28(m,2H),1.27-1.22(m,3H),1.14-1.07(m,3H)。
157C.2-(4-氧代环己基)丙酸乙酯
向2-(1,4-二氧杂螺[4.5]癸-8-基)丙酸乙酯(450mg,1.857mmol)在THF(5mL)中的溶液中添加1M氯化氢(水溶液)(0.929mL,3.71mmol)。在50℃下加热混合物,持续6小时。浓缩反应混合物。使残余物溶解于EtOAc中,用水(2×)及盐水洗涤。溶液经Na2SO4干燥且浓缩。用ISCO(EtOAc/己烷0-30%)纯化粗物质。浓缩含有产物的级分,产生呈澄清油状物的2-(4-氧代环己基)丙酸乙酯(290mg,79%产率)。1H NMR(400MHz,氯仿-d)δ4.22-4.06(m,2H),2.46-2.30(m,5H),2.13-1.91(m,3H),1.56-1.42(m,2H),1.31-1.24(m,3H),1.18(d,J=7.1Hz,3H)。
157D.2-(4-(((三氟甲基)磺酰基)氧基)环己-3-烯-1-基)丙酸乙酯
使2-(4-氧代环己基)丙酸乙酯(200mg,1.01mmol)及2,6-二叔丁基-4-甲基吡啶(238mg,1.16mmol)溶解于干燥DCM(10ml)中。向反应混合物中逐滴添加三氟甲磺酸酐(0.186mL,1.11mmol)且搅拌2小时。过滤悬浮液且用DCM稀释滤液,用1N HCl(2×)、饱和碳酸氢钠溶液、水及盐水洗涤。溶液经Na2SO4干燥且浓缩,产生呈棕色油状物的2-(4-(((三氟甲基)磺酰基)氧基)环己-3-烯-1-基)丙酸乙酯(320mg,96%产率)。1H NMR(400MHz,氯仿-d)δ5.73(t,J=6.1Hz,1H),4.28-4.05(m,2H),2.52-2.17(m,4H),2.08-1.79(m,3H),1.49(dt,J=11.1,6.6Hz,1H),1.31-1.20(m,3H),1.19-1.04(m,3H)。
157E.2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)环己-3-烯-1-基)丙酸乙酯
向2-(4-(((三氟甲基)磺酰基)氧基)环己-3-烯-1-基)丙酸乙酯(300mg,0.908mmol)在DMSO(5mL)中的溶液中添加4,4,4',4',5,5,5',5'-八甲基-2,2'-双(1,3,2-二氧硼戊环)(230mg,0.908mmol)及乙酸钾(267mg,2.72mmol)。在混合物用N2脱气10分钟之后,添加PdCl2(dppf)(19.9mg,0.027mmol)。在80℃下加热混合物过夜。使混合物在EtOAc与水之间分配。浓缩有机相且通过ISCO硅胶柱纯化。浓缩含有产物的级分,产生呈棕色油状物的2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)环己-3-烯-1-基)丙酸乙酯(168mg,60%产率)。1H NMR(400MHz,氯仿-d)δ6.66-6.40(m,1H),4.31-4.00(m,2H),2.34-2.26(m,1H),2.25-2.19(m,1H),2.19-2.04(m,2H),1.95-1.75(m,3H),1.73-1.60(m,1H),1.29-1.24(m,15H),1.13(dd,J=11.6,7.0Hz,3H)。
157F.2-(4-(2-甲基吡啶-4-基)环己-3-烯-1-基)丙酸乙酯
向2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)环己-3-烯-1-基)丙酸乙酯(120mg,0.389mmol)在二噁烷(3mL)中的溶液中添加4-溴-2-甲基吡啶(67.0mg,0.389mmol)、水(1mL)及Na2CO3(165mg,1.557mmol)。混合物用N2脱气10分钟。随后添加Pd(Ph3P)4(22.49mg,0.019mmol)。加热混合物至100℃持续16小时。经冷却的混合物用EtOAc稀释,用水及盐水洗涤。溶液经Na2SO4干燥,过滤且蒸发。通过ISCO硅胶层析法(0-50%EtOAc/己烷)纯化粗物质。浓缩含有产物的级分,产生呈黄色油状物的2-(4-(2-甲基吡啶-4-基)环己-3-烯-1-基)丙酸乙酯(100mg,0.366mmol,94%产率)。1H NMR(400MHz,氯仿-d)δ8.61-8.11(m,1H),7.09-6.68(m,2H),4.15(qdd,J=7.1,3.3,1.8Hz,2H),2.71-2.57(m,1H),2.53(d,J=5.3Hz,3H),2.47-2.35(m,0.5H),2.29(t,J=7.1Hz,0.5H),1.98-1.75(m,3H),1.67-1.38(m,4H),1.32-1.22(m,4H),1.21-1.09(m,4H)。
157G.2-(4-(2-甲基吡啶-4-基)环己基)丙酸乙酯
使2-(4-(2-甲基吡啶-4-基)环己-3-烯-1-基)丙酸乙酯(100mg,0.366mmol)溶解于MeOH(5mL)中。添加甲酸铵(115mg,1.829mmol)及钯/碳(10%)(10.51mg,0.099mmol)。容器配备有回流冷凝器,抽空且用N2冲洗三次。随后加热反应至回流。在一小时之后,冷却反应且过滤。在真空中浓缩滤液。使残余物溶解于EtOAc中,用碳酸氢钠溶液、水及盐水洗涤。溶液经Na2SO4干燥,过滤且浓缩。粗产物直接用于下一步骤中。
157H.2-(4-(2-甲基吡啶-4-基)环己基)丙酸
向2-(4-(2-甲基吡啶-4-基)环己基)丙酸乙酯(320mg,1.162mmol)在THF(2mL)、MeOH(2mL)及水中的混合物中添加LiOH(278mg,11.62mmol)。在70℃下加热混合物持续4小时。LC-MS指示反应完成。冷却混合物至室温,用1N HCl中和直至pH~4,且用EtOAc萃取3次。合并的有机相用水及盐水洗涤。溶液经Na2SO4干燥且浓缩。1H NMR(400MHz,氯仿-d)δ8.41(d,J=5.3Hz,1H),7.09-6.94(m,2H),2.75-2.59(m,1H),2.54(d,J=3.5Hz,3H),2.44(br.s.,1H),2.35(t,J=7.0Hz,1H),1.98-1.82(m,3H),1.77-1.61(m,4H),1.56-1.39(m,1H),1.20(d,J=6.7Hz,3H);MS:C15H21NO2的分析计算值247.16,实验值[M+H]248.08LC:tr=0.55分钟。
157I.1-(4-(2-甲基吡啶-4-基)环己基)乙胺
使2-(4-(2-甲基吡啶-4-基)环己基)丙酸(240mg,0.970mmol)(157B)溶解在甲苯(5ml)中且添加叠氮磷酸二苯酯(0.230mL,1.067mmol)及三乙胺(0.162mL,1.164mmol)。密封瓶且加热至70℃。在约2小时之后,冷却反应至室温且在减压下浓缩。使粗残余物溶解于40mL THF及40mL水中且添加氢氧化锂(1.589g,66.4mmol)。在室温下搅拌反应。1小时之后的LCMS显示异氰酸酯耗尽。反应用1N HCl酸化(形成白色沉淀)且用EtOAc萃取以移除DPPA相关杂质。溶液用1N NaOH变为碱性(再次形成沉淀)且用EtOAc(×5)萃取。在真空中浓缩碱性萃取物以得到呈黄色油状物的1-(4-(2-甲基吡啶-4-基)环己基)乙胺(140mg,0.641mmol,66.1%产率)。1H NMR(400MHz,氯仿-d)δ8.65-8.17(m,1H),7.08-6.86(m,2H),2.97(dd,J=8.6,6.4Hz,0.5H),2.79-2.62(m,1H),2.52(d,J=2.8Hz,3H),2.48-2.33(m,0.5H),2.03-1.90(m,2H),1.90-1.68(m,4H),1.50-1.11(m,3H),1.08(dd,J=6.4,2.8Hz,3H)。MS:C14H22N2的分析计算值218.18,实验值[M+H]219.2LC:tr=0.43分钟。
实施例157a.4-氯-N-(1-(4-(2-甲基吡啶-4-基)环己基)乙基)苯甲酰胺
向1-(4-(2-甲基吡啶-4-基)环己基)乙胺(100mg,0.458mmol)(157I)在THF(2mL)中的溶液中添加4-氯苯甲酸(108mg,0.687mmol)、HOBT(140mg,0.916mmol)、EDC(176mg,0.916mmol)及TEA(0.192mL,1.374mmol)。在室温下搅拌混合物过夜。过滤反应混合物且经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水,含0.1%三氟乙酸;流动相B:95:5乙腈:水,含0.1%三氟乙酸;梯度:25-100%B,历时20分钟,随后在100%B下保持4分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥,产生4-氯-N-(1-(4-(2-甲基吡啶-4-基)环己基)乙基)苯甲酰胺(136.8mg,84%产率)。1H NMR(500MHz,DMSO-d6)δ8.52-8.20(m,2H),7.84(dd,J=10.6,8.7Hz,2H),7.52(dd,J=8.4,2.4Hz,2H),7.27-6.85(m,2H),4.24(br.s.,0.5H),3.87(d,J=7.4Hz,0.5H),3.62-3.37(m,1H),2.42(d,J=9.1Hz,3H),1.94-1.31(m,8H),1.20-1.02(m,4H)。
实施例157b、c、d、e.4-氯-N-(1-(4-(2-甲基吡啶-4-基)环己基)乙基)苯甲酰胺(纯手性,绝对及相对立体化学未测定)
经由手性分离进一步纯化物质。拆分大约140mg样品。经由制备型SFC在以下条件下纯化该物质:柱:Chiral AD 25×3cm ID,5μm粒子;流动相:70/30 CO2/MeOH;检测器波长:220nm;流速:85mL/min。在MeOH中收集级分(“峰-1”tr=10.117,“峰-2”tr=11.355,“峰-3”tr=14.873及“峰-4”tr=18.312;分析条件:柱:Chiral AD 250×4.6mm ID,5μm粒子;流动相:70/30CO2/MeOH,流速:2.0mL/min)。
157b第一洗脱异构体:1H NMR(500MHz,DMSO-d6)δ8.44-8.18(m,2H),7.84(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,2H),7.24-6.96(m,2H),4.26(d,J=6.9Hz,1H),2.60(br.s.,1H),2.43(s,3H),1.84-1.36(m,9H),1.14(d,J=6.5Hz,3H)。MS:C21H25ClN2O的分析计算值356.17,实验值[M+H]357.0LC:tr=1.826(方法A)。
157c第二洗脱异构体:1H NMR(500MHz,DMSO-d6)δ8.48-8.19(m,2H),7.81(d,J=8.3Hz,2H),7.50(d,J=8.3Hz,2H),7.27-6.82(m,2H),4.24(d,J=6.9Hz,1H),2.60(br.s.,1H),2.42(s,3H),1.83-1.37(m,9H),1.13(d,J=6.4Hz,3H)。MS:C21H25ClN2O的分析计算值356.17,实验值[M+H]356.9LC:tr=1.864(方法A)。
157d第三洗脱异构体:1H NMR(500MHz,DMSO-d6)δ8.28(d,J=5.6Hz,2H),7.86(d,J=8.4Hz,2H),7.52(d,J=8.4Hz,2H),7.23-6.87(m,2H),3.87(d,J=6.4Hz,1H),2.40(s,4H),1.96-1.71(m,4H),1.58-1.28(m,3H),1.21-0.99(m,5H)。MS:C21H25ClN2O的分析计算值356.17,实验值[M+H]356.9LC:tr=1.857(方法A)。
157e第四洗脱异构体:1H NMR(500MHz,DMSO-d6)δ8.28(d,J=4.9Hz,2H),7.86(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,2H),7.24-6.84(m,2H),4.06-3.74(m,1H),2.46-2.28(m,4H),1.95-1.71(m,4H),1.61-1.29(m,3H),1.21-1.02(m,5H)MS:C21H25ClN2O的分析计算值356.17,实验值[M+H]356.8LC:tr=1.857(方法A)。
以下化合物使用实施例157中的步骤获得。
实施例163
5-乙氧基-N-((R)-1-(顺-4-(6-氟喹啉-4-基)环己基)乙基)吡啶酰胺
163A.5-乙氧基吡啶甲酸甲酯
向5-羟基吡啶甲酸甲酯(0.1g,0.653mmol)在DMF(2mL)中的溶液中添加EtI(0.06mL,0.72mmol)及K2CO3(0.135g,0.980mmol)。在室温下搅拌反应混合物2小时。用饱和NaHCO3溶液及乙酸乙酯稀释反应混合物。分离有机层且在真空中浓缩以得到中间体163A(白色固体,0.09g,0.497mmol,76%产率)。C9H11NO3的LC-MS分析计算值181.07,实验值[M+H]182.1,Tr=0.66分钟(方法A)。1H NMR(400MHz,甲醇-d4)δ:8.29(d,J=2.6Hz,1H),8.11(dd,J=8.6,0.4Hz,1H),7.48(dd,J=8.7,3.0Hz,1H),4.20(q,J=7.0Hz,2H),3.94(s,3H),1.45(t,J=6.9Hz,3H)。
163B.5-乙氧基吡啶甲酸
向5-乙氧基吡啶甲酸甲酯(0.09g,0.497mmol)在THF(1mL)及MeOH(1mL)中的溶液中添加氢氧化锂溶液(1.49mL,2.98mmol)。在室温下搅拌反应混合物3小时。用1N HCl溶液及乙酸乙酯稀释反应混合物。分离有机层且经MgSO4干燥。在真空中浓缩滤液以得到中间体163B(白色固体,0.06g,0.359mmol,72.3%产率)。C8H9NO3的LC-MS分析计算值167.06,实验值[M+H]168.1,Tr=0.49分钟(方法A)。1H NMR(400MHz,DMSO-d6)δ:12.75(br.s.,1H),8.35(d,J=2.6Hz,1H),8.01(d,J=8.6Hz,1H),7.48(dd,J=8.8,2.9Hz,1H),4.19(q,J=6.9Hz,2H),1.37(t,J=6.9Hz,3H)。
实施例163.5-乙氧基-N-((R)-1-(顺-4-(6-氟喹啉-4-基)环己基)乙基)吡啶酰胺
向5-乙氧基吡啶甲酸(14.36mg,0.086mmol)在DMF(1mL)中的溶液中添加HATU(33mg,0.086mmol)。在室温下搅拌反应混合物5分钟,随后添加(R)-1-(顺-4-(6-氟喹啉-4-基)环己基)乙胺(18mg,0.066mmol)中间体40L及N-甲基吗啉(0.032mL,0.264mmol)。在室温下搅拌所得混合物2小时。在真空中浓缩反应混合物且使残余物溶解于MeOH中,过滤,且经由制备型HPLC纯化以得到实施例163(16mg,0.038mmol,57%产率)。C25H28FN3O2的LC-MS分析计算值421.22,实验值[M+H]422.3。Tr=1.63分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ:8.81(d,J=4.4Hz,1H),8.36(d,J=9.6Hz,1H),8.26(d,J=2.4Hz,1H),8.07(dd,J=9.1,5.8Hz,1H),7.99-7.85(m,2H),7.73-7.59(m,1H),7.55-7.39(m,2H),4.39(d,J=6.6Hz,1H),4.14(q,J=6.9Hz,2H),3.71-3.52(m,1H),1.94-1.52(m,9H),1.34(t,J=6.9Hz,3H),1.19(d,J=6.4Hz,3H)。
实施例164a、b、c、d
4-氯-N-((R)-1-(顺-4-(6-氟喹啉-4-基)环己基)丙基)苯甲酰胺
4-氯-N-((S)-1-(顺-4-(6-氟喹啉-4-基)环己基)丙基)苯甲酰胺
4-氯-N-((R)-1-(反-4-(6-氟喹啉-4-基)环己基)丙基)苯甲酰胺
4-氯-N-((S)-1-(反-4-(6-氟喹啉-4-基)环己基)丙基)苯甲酰胺
(纯手性,绝对及相对立体化学未测定)
164A.2-(1,4-二氧杂螺[4.5]癸-8-亚基)乙酸乙酯
在0℃下在氮气下向含有氢化钠(46.1g,1153mmol)的烧瓶中添加THF(1200mL)。随后逐滴添加膦酰基乙酸三乙酯(258g,1153mmol)。在0℃下搅拌反应混合物30分钟。随后添加1,4-二氧杂螺[4.5]癸-8-酮(150g,960mmol)且在0℃下搅拌2小时。使反应混合物升温至室温且搅拌16小时。用水(500ml)淬灭反应且在真空中浓缩混合物。用乙酸乙酯(3×1000mL)萃取残余物。用水(500ml)及盐水(500ml)依次洗涤合并的有机层。滤液经硫酸钠干燥且在真空中浓缩。经由急骤柱层析法,用0-30%乙酸乙酯/石油醚洗脱来纯化粗物质以得到中间体164A(淡黄色油状物,135g,597mmol,62.1%产率)。C12H18O4的LC-MS分析计算值226.12,实验值[M+H]。1H NMR(400MHz,氯仿-d)δ:5.66(s,1H),4.14(q,J=7.2Hz,2H),4.02-3.82(m,4H),3.24-2.86(m,2H),2.63-2.27(m,2H),1.98-1.68(m,4H),1.27(t,J=7.2Hz,3H)。
164B.2-(1,4-二氧杂螺[4.5]癸-8-基)乙酸乙酯
使2-(1,4-二氧杂螺[4.5]癸-8-亚基)乙酸乙酯(13.88g,61.3mmol)溶解于EtOAc(61.3ml)中且在氮气氛围下添加至含有10%钯/碳(1.306g,12.27mmol)(54%w/w水)的帕尔氢化瓶中。反应瓶用氮气净化,随后用氢气净化。在用氢气填充瓶至50psi之后,将瓶放置于帕尔振荡器中且振荡。在4小时之后,经加压过滤反应混合物且在真空中浓缩以得到中间体164B 2-(1,4-二氧杂螺[4.5]癸-8-基)乙酸乙酯(无色油状物,13.78g,60.4mmol,98%产率)。C12H20O4的LC-MS分析计算值228.14,实验值[M+H]229.1。Tr=0.83分钟(方法A)。1H NMR(400MHz,氯仿-d)δ:4.31-4.08(m,2H),4.00-3.86(m,4H),2.22(d,J=7.0Hz,2H),1.91-1.79(m,1H),1.78-1.70(m,4H),1.63-1.50(m,2H),1.37-1.14(m,5H)。
164C.2-(4-氧代环己基)乙酸乙酯
在10升反应器中放入含2-(1,4-二氧杂螺[4.5]癸-8-基)乙酸乙酯(67.5g,296mmol)的丙酮(5000mL)。向反应混合物中添加1M HCl溶液(1183mL,1183mmol)且在回流下加热所得混合物2小时。浓缩反应混合物以移除丙酮。用乙酸乙酯(3×1000mL)萃取残余物。用水及盐水洗涤合并的有机层。经硫酸钠干燥有机层且在真空中浓缩。经由急骤柱层析法,用0-20%乙酸乙酯/石油醚洗脱来纯化粗物质以得到中间体164C(淡黄色液体,40g,217mmol,73.4%产率)。C10H16O3的GC-MS分析计算值184.11,实验值[M]184。Tr=10.03分钟(方法J)。
164D.2-(4-(三氟甲基磺酰氧基)环己-3-烯基)乙酸乙酯
在氮气下向2升4颈烧瓶中装入含2,6-二叔丁基-4-甲基吡啶(84g,407mmol)的二氯甲烷(500mL)。逐滴添加Tf2O(55.0mL,326mmol)。随后缓慢添加2-(4-氧代环己基)乙酸乙酯(50g,271mmol)在二氯甲烷(500mL)中的溶液。完成添加后,在室温下搅拌反应混合物过夜。用1000mL二氯甲烷稀释反应混合物且用水及碳酸钠溶液及随后水洗涤。有机层经硫酸钠干燥且在真空中浓缩。经由急骤柱层析法,用0-10%乙酸乙酯/石油醚洗脱来纯化粗物质以得到中间体164D(淡黄色油状物,65g,206mmol,76%产率)。C11H15F3O5S的GC-MS分析计算值316.06,实验值[M]317。Tr=10.16分钟(方法J)。
164E.2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)环己-3-烯基)乙酸乙酯
在氮气下在2升4颈烧瓶中放入含2-(4-(((三氟甲基)磺酰基)氧基)环己-3-烯-1-基)乙酸乙酯(120g,379mmol)、BISPIN(106g,417mmol)及乙酸钾(112g,1138mmol)的1,4-二噁烷(1200mL)。氮气在反应混合物内净化10分钟。随后添加1,1′-双(二苯基膦基)二茂铁-二氯化钯二氯甲烷络合物(15.49g,18.97mmol)。在80℃下加热反应混合物16小时。浓缩反应混合物。使残余物在乙酸乙酯与水之间分配,经由床过滤。分离有机层且用乙酸乙酯(3×)萃取水层。用水、盐水洗涤合并的有机层,且经硫酸钠干燥且在真空中浓缩。经由急骤柱层析法,用0-10%乙酸乙酯/石油醚洗脱来纯化粗物质以得到中间体164E(淡黄色油状物,56g,190mmol,50.2%产率)。C16H27BO4的GC-MS分析计算值294.20,实验值[M]295.3。Tr=1.10分钟(方法A)。1H NMR(400MHz,氯仿-d)δ:6.52(dd,J=4.1,1.9Hz,1H),4.14(q,J=7.1Hz,2H),2.62-1.97(m,6H),1.94-1.68(m,2H),1.33-1.21(m,16H)。
164F.2-(4-(6-氟喹啉-4-基)环己-3-烯-1-基)乙酸乙酯
使2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)环己-3-烯-1-基)乙酸乙酯(中间体164E)(5g,17.00mmol)溶解于二噁烷(28.3ml)及水(7.08ml)中。添加4-氯-6-氟喹啉(2.57g,14.15mmol),随后添加K2CO3(5.87g,42.5mmol)。混合物用氮气鼓泡5分钟,随后添加Pd(Ph3P)4(0.327g,0.283mmol)。在添加之后,将反应抽空且用N2回填三次且随后密封(密封瓶用封口膜封口)且加热至100℃持续16小时。在真空中浓缩反应且经由硅胶急骤柱层析法直接纯化以得到中间体164F(4.22g,13.47mmol,95%产率)。C19H20FNO2的LC-MS分析计算值313.15,实验值[M+H]314.1Tr=0.75分钟(方法A)。
164G.2-(4-(6-氟喹啉-4-基)环己基)乙酸乙酯
使中间体164F(4.22g,13.47mmol)溶解于MeOH(67.3ml)中且添加甲酸铵(4.25g,67.3mmol)。容器配备有回流冷凝器且抽空且用氮气冲洗3次。随后添加钯/碳(0.143g,1.347mmol)(湿润,Degussa型)且加热反应至回流持续1小时。冷却反应,在真空中浓缩,且用DCM稀释。过滤出固体且浓缩滤液以得到作为顺式与反式非对映异构体的混合物的粗中间体164G(4.20g,13.32mmol,99%产率)。C19H22FNO2的LC-MS分析计算值315.16,实验值[M+H]316.2Tr=0.76分钟(方法A)。
164H.2-(4-(6-氟喹啉-4-基)环己基)丁酸乙酯
在-78℃下向含有THF(6mL)的烧瓶中添加二异丙氨基锂(在THF中的2.0M溶液)(3.17mL,6.34mmol),随后在-78℃下逐滴添加1,3-二甲基四氢嘧啶-2(1H)-酮(0.573mL,4.76mmol)及2-(4-(6-氟喹啉-4-基)环己基)乙酸乙酯(1.0g,3.17mmol)在THF(10mL)中的溶液。所得混合物变成棕色溶液且在-78℃下搅拌1小时,随后缓慢添加碘乙烷(0.51mL,6.34mmol)。随后在冰浴温度下搅拌反应混合物1小时,升温至室温过夜。通过倒入水中来淬灭反应且用EtOAc萃取。用盐水洗涤合并的有机层,用MgSO4干燥,过滤且在真空中浓缩。使残余物溶解于DCM中且通过硅胶急骤层析法,用0-20%乙酸乙酯/己烷洗脱来纯化以得到中间体164H(油状物,0.81g,2.359mmol,74.4%产率)。C21H26FNO2的LC-MS分析计算值343.19,实验值[M+H]344.3。Tr=0.87-0.88分钟(方法A)。1H NMR(400MHz,氯仿-d)δ:8.88-8.77(m,1H),8.18-8.06(m,1H),7.66(dd,J=10.6,2.6Hz,1H),7.47(ddd,J=9.2,8.0,2.9Hz,1H),7.36(d,J=4.6Hz,1H),4.25-4.15(m,2H),3.34-3.09(m,1H),2.70-2.16(m,1H),2.13-1.49(m,13H),1.36-1.24(m,3H),1.00-0.90(m,3H)。
164I.2-(4-(6-氟喹啉-4-基)环己基)丁酸
向2-(4-(6-氟喹啉-4-基)环己基)丁酸乙酯(0.81g,2.359mmol)在THF(4mL)及MeOH(7mL)中的溶液中缓慢添加2.0M LiOH溶液(7.1mL,14.2mmol)。在室温下搅拌反应混合物过夜。次日,向反应中添加更多LiOH溶液(7.1mL,14.2mmol)且在70℃下加热所得混合物28小时。冷却反应混合物且添加乙酸乙酯。分离水层且向水层中添加1N HCl溶液以将pH调节至5-6。所得混合物用水及CHCl3:2-丙醇(2:1)稀释。分离有机层且经MgSO4干燥。在真空中浓缩滤液以得到作为顺式与反式(3:2)异构体的混合物的中间体164I(0.64g,2.029mmol,86%产率)。C19H22FNO2的LC-MS分析计算值315.16,实验值[M+H]316.3。Tr=0.72分钟(方法A)。1H NMR(400MHz,氯仿-d)δ:8.83(d,J=4.4Hz,1H),8.30-8.03(m,1H),7.67(dd,J=10.6,2.4Hz,1H),7.48(ddd,J=9.2,7.9,2.6Hz,1H),7.38(d,J=4.6Hz,1H),7.32-7.27(m,1H),3.37-3.07(m,1H),2.77-2.21(m,1H),2.11-1.30(m,11H),1.07-1.00(m,3H)。
164J.1-(4-(6-氟喹啉-4-基)环己基)丙-1-胺
向2-(4-(6-氟喹啉-4-基)环己基)丁酸(0.31g,0.983mmol)在甲苯(8mL)中的悬浮液中添加叠氮磷酸二苯酯(0.245mL,1.13mmol)及三乙胺(0.15mL,1.28mmol)。在添加TEA之后反应混合物变成澄清溶液。密封瓶且加热至70℃持续2.5小时。在减压下浓缩反应混合物。向残余物中添加THF(10mL)及2.0M氢氧化锂溶液(4.91mL,9.83mmol)且在室温下搅拌所得混合物1小时。反应混合物用1N HCl酸化(形成白色沉淀)且用EtOAc萃取以移除DPPA相关杂质。随后水层用1N NaOH碱化(再次形成沉淀)且用EtOAc萃取四次。合并碱性萃取物,经MgSO4干燥且在真空中浓缩滤液以得到作为顺式及反式的混合物的无色油状物,在高真空下干燥过夜以得到中间体164J(油状物,0.245g,0.855mmol,87%产率)。C18H23FN2的LC-MS分析计算值286.19,实验值[M+H]287.3。Tr=0.54分钟,0.55分钟(方法A)。1H NMR(400MHz,氯仿-d)δ:8.81(d,J=4.6Hz,1H),8.12(dd,J=9.1,5.8Hz,1H),7.67(dd,J=10.6,2.6Hz,1H),7.47(ddd,J=9.2,8.0,2.9Hz,1H),7.37-7.28(m,1H),3.41-3.09(m,1H),2.97-2.50(m,1H),2.19-1.23(m,11H),1.06-0.93(m,3H)。
实施例164.4-氯-N-(1-(4-(6-氟喹啉-4-基)环己基)丙基)苯甲酰胺
向4-氯苯甲酸(42.6mg,0.272mmol)在DMF(2mL)中的溶液中添加HATU(104mg,0.272mmol)。在室温下搅拌反应混合物10分钟,随后添加含1-(4-(6-氟喹啉-4-基)环己基)丙-1-胺(60mg,0.210mmol)(中间体164J)的THF(0.5mL)及N-甲基吗啉(0.10mL,0.838mmol)。在室温下搅拌所得混合物2小时。在真空中浓缩反应混合物且使残余物溶解于MeOH中,过滤,且经由制备型HPLC纯化以得到含有四种异构体的混合物。通过制备型SFC(方法C)进一步分离异构体以得到:
第一洗脱实施例164a(15mg,0.035mmol,16.7%产率)。C25H26ClFN2O的LC-MS分析计算值424.17,实验值[M+H]424.9,Tr=1.57分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ:8.82(d,J=3.9Hz,1H),8.19(d,J=9.1Hz,1H),8.12-8.03(m,1H),7.94(d,J=10.3Hz,1H),7.86(d,J=8.0Hz,2H),7.65(t,J=7.9Hz,1H),7.52(d,J=8.0Hz,2H),7.46(d,J=3.5Hz,1H),4.27(d,J=8.0Hz,1H),3.37(br.s.,1H),1.92-1.54(m,10H),1.40(d,J=6.2Hz,1H),0.86(t,J=6.9Hz,3H)。
第二洗脱实施例164b(8.6mg,0.020mmol,9.6%产率)。C25H26ClFN2O的LC-MS分析计算值424.17,实验值[M+H]424.9,Tr=1.55分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ:8.78(d,J=4.5Hz,1H),8.17(d,J=9.0Hz,1H),8.07(dd,J=9.0,5.8Hz,1H),7.97(d,J=9.0Hz,1H),7.90(d,J=8.3Hz,2H),7.71-7.59(m,1H),7.54(d,J=8.3Hz,2H),7.43(d,J=4.4Hz,1H),3.80(br.s.,1H),3.27(t,J=11.3Hz,1H),1.97-1.81(m,4H),1.74-1.29(m,7H),0.86(t,J=7.2Hz,3H)。
第三洗脱实施例164c(6.5mg,0.015mmol,6.9%产率)。C25H26ClFN2O的LC-MS分析计算值424.17,实验值[M+H]425.0,Tr=1.55分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ:8.78(d,J=4.4Hz,1H),8.17(d,J=9.1Hz,1H),8.07(dd,J=8.9,5.8Hz,1H),7.97(d,J=8.9Hz,1H),7.90(d,J=8.3Hz,2H),7.71-7.60(m,1H),7.54(d,J=8.3Hz,2H),7.43(d,J=4.3Hz,1H),3.81(br.s.,1H),3.36-3.21(m,1H),1.90(d,J=12.5Hz,4H),1.73-1.28(m,7H),0.86(t,J=7.1Hz,3H)。
第四洗脱实施例164d(13.9mg,0.032mmol,15.5%产率)。C25H26ClFN2O的LC-MS分析计算值424.17,实验值[M+H]425.1,Tr=1.58分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ:8.82(d,J=4.3Hz,1H),8.19(d,J=9.1Hz,1H),8.08(dd,J=9.0,5.9Hz,1H),7.95(d,J=9.5Hz,1H),7.87(d,J=8.3Hz,2H),7.65(t,J=7.4Hz,1H),7.53(d,J=8.3Hz,2H),7.46(d,J=4.3Hz,1H),4.28(d,J=7.8Hz,1H),3.37(br.s.,1H),1.92-1.53(m,10H),1.39(dt,J=14.7,7.6Hz,1H),0.87(t,J=7.1Hz,3H)。
实施例165a、b、c、d
4-氰基-N-((R)-1-(顺-4-(6-氟喹啉-4-基)环己基)丙基)苯甲酰胺
4-氰基-N-((S)-1-(顺-4-(6-氟喹啉-4-基)环己基)丙基)苯甲酰胺
4-氰基-N-((R)-1-(反-4-(6-氟喹啉-4-基)环己基)丙基)苯甲酰胺
4-氰基-N-((S)-1-(反-4-(6-氟喹啉-4-基)环己基)丙基)苯甲酰胺
(纯手性,绝对及相对立体化学未测定)
实施例165.4-氰基-N-(1-(4-(6-氟喹啉-4-基)环己基)丙基)苯甲酰胺
向4-氰基苯甲酸(33.4mg,0.227mmol)在DMF(2mL)中的溶液中添加HATU(86mg,0.227mmol)。在室温下搅拌反应混合物10分钟,随后添加含1-(4-(6-氟喹啉-4-基)环己基)丙-1-胺(50mg,0.175mmol)(中间体164J)的THF(0.5mL)及N-甲基吗啉(0.10mL,0.838mmol)。在室温下搅拌所得混合物2小时。在真空中浓缩反应混合物且使残余物溶解于MeOH中,过滤,且经由制备型HPLC纯化得到含有四种异构体的混合物。通过制备型SFC(方法K)进一步分离异构体以得到:
第一洗脱实施例165a(10.7mg,0.025mmol,14.6%产率)。C26H26FN3O的LC-MS分析计算值415.21,实验值[M+H]416.2,Tr=1.40分钟(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.82(d,J=4.4Hz,1H),8.37(d,J=9.1Hz,1H),8.08(dd,J=9.0,5.8Hz,1H),8.02-7.87(m,5H),7.69-7.58(m,1H),7.46(d,J=4.4Hz,1H),4.29(d,J=8.2Hz,1H),3.53-3.42(m,1H),1.96-1.56(m,10H),1.50-1.31(m,1H),0.88(t,J=7.2Hz,3H)。
第二洗脱实施例165b(5.7mg,0.014mmol,7.8%产率)。C26H26FN3O的LC-MS分析计算值415.21,实验值[M+H]416.0,Tr=1.51分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ:8.78(d,J=4.5Hz,1H),8.34(d,J=9.0Hz,1H),8.13-7.99(m,3H),7.99-7.86(m,3H),7.74-7.57(m,1H),7.43(d,J=4.4Hz,1H),3.81(br.s.,1H),3.27(t,J=11.4Hz,1H),2.00-1.81(m,4H),1.76-1.30(m,7H),0.87(t,J=7.2Hz,3H)。
第三洗脱实施例165c(5.5mg,0.013mmol,7.5%产率)。C26H26FN3O的LC-MS分析计算值415.21,实验值[M+H]416.0,Tr=1.51分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ:8.79(d,J=4.5Hz,1H),8.34(d,J=8.9Hz,1H),8.13-8.00(m,3H),7.99-7.86(m,3H),7.72-7.55(m,1H),7.43(d,J=4.5Hz,1H),3.82(d,J=9.0Hz,1H),3.28(t,J=11.7Hz,1H),1.99-1.80(m,4H),1.75-1.29(m,7H),0.87(t,J=7.2Hz,3H)。
第四洗脱实施例165d(12mg,0.029mmol,16.4%产率)。C26H26FN3O的LC-MS分析计算值415.21,实验值[M+H]416.0,Tr=1.52分钟(方法I)。1H NMR(500MHz,DMSO-d6)δ:8.81(d,J=4.4Hz,1H),8.38(d,J=9.1Hz,1H),8.08(dd,J=9.1,5.8Hz,1H),8.01-7.88(m,5H),7.70-7.60(m,1H),7.47(d,J=4.4Hz,1H),4.28(d,J=8.4Hz,1H),3.49-3.28(m,1H),1.96-1.56(m,10H),1.48-1.31(m,1H),0.87(t,J=7.2Hz,3H)。
实施例176至196
实施例176至196由中间体40L,按照用于实施例164的步骤使用相应的酸制备。
实施例197
4-氯-N-(1-(4-(吡唑并[1,5-a]嘧啶-7-基)环己基)乙基)苯甲酰胺,
4-氯-N-((R)-1-(顺-4-(吡唑并[1,5-a]嘧啶-7-基)环己基)乙基)苯甲酰胺,
4-氯-N-((S)-1-(顺-4-(吡唑并[1,5-a]嘧啶-7-基)环己基)乙基)苯甲酰胺,
4-氯-N-((R)-1-(反-4-(吡唑并[1,5-a]嘧啶-7-基)环己基)乙基)苯甲酰胺,
4-氯-N-((S)-1-(反-4-(吡唑并[1,5-a]嘧啶-7-基)环己基)乙基)苯甲酰胺
绝对和相对立体化学未知,任意指定
197A.2-(1,4-二氧杂螺[4.5]癸-8-亚基)丙酸乙酯
向NaH(0.307g,7.68mmol)在THF(8mL)中的在0℃冷却的悬浮液中缓慢添加2-(二乙氧基磷酰基)丙酸乙酯(1.830g,7.68mmol)。在30分钟之后,添加1,4-二氧杂螺[4.5]癸-8-酮(1g,6.40mmol)。在0℃下搅拌所得混合物2小时,随后升温至室温过夜。用水淬灭混合物且在减压下移除THF。使残余物溶解于EtOAc中,用水、盐水洗涤,经Na2SO4干燥并浓缩。通过ISCO(EtOAc/Hex 0-30%)纯化粗物质。浓缩含有产物的级分,产生中间体197A(1.2g,78%产率),淡黄色油状物。1H NMR(400MHz,氯仿-d)δ4.19(q,J=7.1Hz,2H),4.03-3.89(m,4H),2.68-2.53(m,2H),2.46-2.28(m,2H),1.89(s,3H),1.78-1.66(m,4H),1.30(t,J=7.1Hz,3H)。
197B.2-(1,4-二氧杂螺[4.5]癸-8-基)丙酸乙酯
在45psi下在帕尔振荡器中氢化中间体143A(500mg,2.081mmol)(1A)及10%钯/碳(25mg,0.024mmol)在EtOAc(5mL)中的悬浮液6小时。过滤催化剂且浓缩滤液,产生呈浅色油状物的中间体197B(450mg,89%产率)。1H NMR(400MHz,氯仿-d)δ4.12(dtt,J=10.7,7.1,3.6Hz,2H),3.98-3.81(m,4H),2.35-2.17(m,1H),1.83-1.68(m,3H),1.66-1.45(m,4H),1.43-1.28(m,2H),1.27-1.22(m,3H),1.14-1.07(m,3H)。
197C.2-(4-氧代环己基)丙酸乙酯
向2-(1,4-二氧杂螺[4.5]癸-8-基)丙酸乙酯(450mg,1.857mmol)(1B)在THF(5mL)中的溶液中添加1M氯化氢(水溶液)(0.929mL,3.71mmol)。将混合物加热至50℃持续6小时。浓缩反应混合物。使残余物溶解于EtOAc中,用水(2X)、盐水洗涤,经Na2SO4干燥并浓缩。用ISCO(EtOAc/Hex 0-30%)纯化粗物质。浓缩含有产物的级分,产生呈澄清油状物的中间体197C(290mg,79%产率)。1H NMR(400MHz,氯仿-d)δ4.22-4.06(m,2H),2.46-2.30(m,5H),2.13-1.91(m,3H),1.56-1.42(m,2H),1.31-1.24(m,3H),1.18(d,J=7.1Hz,3H)。
197D.2-(4-(((三氟甲基)磺酰基)氧基)环己-3-烯-1-基)丙酸乙酯
使中间体143C(200mg,1.01mmol)(1C)和2,6-二叔丁基-4-甲基吡啶(238mg,1.16mmol)溶解于干燥DCM(10ml)中。向反应混合物中逐滴添加三氟甲磺酸酐(0.186mL,1.11mmol)且搅拌2小时。过滤悬浮液且用DCM稀释滤液,用1N HCl(2X)、饱和碳酸氢钠溶液、水、盐水洗涤并经Na2SO4干燥且浓缩,产生呈棕色油状物的中间体197D(320mg,96%产率)。1H NMR(400MHz,氯仿-d)δ5.73(t,J=6.1Hz,1H),4.28-4.05(m,2H),2.52-2.17(m,4H),2.08-1.79(m,3H),1.49(dt,J=11.1,6.6Hz,1H),1.31-1.20(m,3H),1.19-1.04(m,3H)。
197E.2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)环己-3-烯-1-基)丙酸乙酯
向中间体143D(300mg,0.908mmol)(1D)在DMSO(5mL)中的溶液中添加4,4,4',4',5,5,5',5'-八甲基-2,2'-双(1,3,2-二氧硼戊环)(230mg,0.908mmol)及乙酸钾(267mg,2.72mmol)。在混合物用N2脱气10分钟之后,添加PdCl2(dppf)(19.9mg,0.027mmol)。加热混合物至80℃过夜。使混合物在EtOAc与水之间分配。浓缩有机相且通过ISCO纯化。浓缩含有产物的级分,产生呈棕色油状物的中间体197E(168mg,60%产率)。1H NMR(400MHz,氯仿-d)δ6.66-6.40(m,1H),4.31-4.00(m,2H),2.34-2.26(m,1H),2.25-2.19(m,1H),2.19-2.04(m,2H),1.95-1.75(m,3H),1.73-1.60(m,1H),1.29-1.24(m,15H),1.13(dd,J=11.6,7.0Hz,3H)。
197F.2-(4-(吡唑并[1,5-a]嘧啶-7-基)环己-3-烯-1-基)丙酸乙酯
将7-氯吡唑并[1,5-a]嘧啶(0.193g,1.260mmol)、中间体143E(0.400g,1.298mmol)、Na2CO3(0.534g,5.04mmol)和Pd(Ph3P)4(0.073g,0.063mmol)在二噁烷(11.67ml)和水(3.89ml)中的混合物在100℃下加热过夜。反应用水淬灭并用EtOAc稀释。分离各层。水相用EtOAc(3X)萃取。合并有机物,经Na2SO4干燥,过滤并浓缩以得到棕色残余物。通过硅胶层析法,使用ISCO机(40g柱,40mL/min,0-70%EtOAc/己烷,历时16min,tr=10.5min)纯化粗物质得到呈黄色残余物的197F(0.224g,0.748mmol,59.4%产率)。ESI MS(M+H)+=300.2.HPLC峰tr=0.95分钟。HPLC条件:方法A。
197G.2-(4-(吡唑并[1,5-a]嘧啶-7-基)环己基)丙酸乙酯
向143F(0.224g,0.748mmol)在MeOH(3.74ml)中的溶液中添加甲酸铵(0.236g,3.74mmol),然后添加Pd/C(0.021g,0.202mmol)。将反应在70℃下加热1h。经过滤反应并用CH2Cl2洗涤滤饼。浓缩滤液。使粗物质溶解于EtOAc中并用饱和N aHCO3水溶液(1X)洗涤。有机相经Na2SO4干燥,过滤并浓缩以得到呈黄色残余物的197G(220mg,98%)。ESI MS(M+H)+=302.2。HPLC峰tr=0.94分钟。HPLC条件:方法A。
197H.2-(4-(吡唑并[1,5-a]嘧啶-7-基)环己基)丙酸
向197G(0.1112g,0.369mmol)在THF(1.318ml)及MeOH(0.527ml)中的溶液中添加氢氧化锂(3.69ml,3.69mmol)。在70℃下加热反应2.5小时,随后使其冷却至室温。用1N HCl将反应调节至pH 7,随后用EtOAc稀释。分离各层。用EtOAc(5×)萃取水相。合并有机相,经Na2SO4干燥,过滤,且浓缩以得到呈黄色残余物的197H(82.7mg,82%)。ESI MS(M+H)+=274.1。HPLC峰tr=0.73分钟。HPLC条件:方法A。
197I.1-(4-(吡唑并[1,5-a]嘧啶-7-基)环己基)乙胺
在反应瓶中使197H(0.0823g,0.301mmol)溶解于甲苯(1.004ml)中且添加叠氮磷酸二苯酯(0.071ml,0.331mmol)及三乙胺(0.050ml,0.361mmol)。密封瓶且加热至80℃。在约2小时之后,冷却反应至室温。使粗残余物溶解于1mL THF中且添加1mL水及氢氧化锂(0.072g,3.01mmol)。在室温下搅拌反应。反应用1N HCl酸化至pH=1且用EtOAc萃取以移除DPPA相关杂质。丢弃有机层。水层随后用1N NaOH碱化至pH=12且用EtOAc(3×)萃取。合并的有机相经硫酸钠干燥,过滤,且在真空中浓缩得到呈橙色残余物的197I(46.5mg,0.190mmol,63.2%产率)。ESI MS(M+H)+=245.2。HPLC峰tr=0.52分钟。HPLC条件:方法A。
实例197a.(+/-)-顺-及反-4-氯-N-(1-(4-(吡唑并[1,5-a]嘧啶-7-基)环己基)乙基)苯甲酰胺
在室温下向197I(46.5mg,0.190mmol)在THF(1359μl)中的溶液中添加4-氯苯甲酸(89mg,0.571mmol),随后添加1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(109mg,0.571mmol)、4-羟基苯并三唑(77mg,0.571mmol)及惠宁氏碱(Hunig's base)(133μl,0.761mmol)。在室温下搅拌反应16小时。浓缩反应,随后经由制备型LC/MS在以下条件下纯化:柱:XBridge C18,19×200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:20-70%B,历时20分钟,随后在100%B下保持5分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥以得到作为4种异构体的混合物的标题化合物(22.5mg,30%)。ESI MS(M+H)+=383.0。HPLC峰tr=1.714分钟。纯度=98%。HPLC条件:方法B。
通过以下方法拆分约20.6mg的实施例197a。经由制备型SFC在以下条件下纯化异构体混合物:柱:Chiral AD,25x 3cm ID,5μm粒子;流动相A:70/30 CO2/MeOH;检测器波长:220nm;流速:85mL/min。在MeOH中收集级分(“峰-1”tr=7.485,“峰-2”tr=9.868,“峰-3”tr=11.635,“峰-4”tr=16.651;分析条件:柱:Chiral AD,250x 4.6mm ID,5μm粒子;流动相A:70/30 CO2/MeOH;流速:2.0mL/min)。各级分的立体异构纯度估计大于99%,基于制备型SFC色谱图。经由制备型LC/MS进一步纯化各非对映异构体或对映异构体。
实施例197b,第一洗脱异构体:经由制备型LC/MS在以下条件下纯化粗物质:柱:
XBridge C18,19x 200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:20-70%B,历时20分钟,然后在100%B下保持5分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥,得到异构体1(5.0mg,6.6%)。ESI MS(M+H)+=383.3.HPLC峰tr=1.764分钟。纯度=96%.HPLC条件:B。绝对立体化学未测定。
实施例197c,第二洗脱异构体:经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19x 200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:20-70%B,经历20分钟,然后在100%B下保持5分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥。经由制备型LC/MS在以下条件下进一步纯化该物质:柱:XBridge C18,19x 200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:35-65%B,经历25分钟,然后在65%B下保持2分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥,得到异构体2(5.2mg,7.0%)。ESI MS(M+H)+=383.1.HPLC峰tr=1.726分钟。纯度=98%。HPLC条件:B。绝对立体化学未测定。
实施例197d,第三洗脱异构体:经由制备型LC/MS在以下条件下纯化粗物质:柱:
XBridge C18,19x 200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:20-70%B,历时20分钟,然后在100%B下保持5分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥,得到异构体3(4.7mg,6.3%)。ESI MS(M+H)+=383.2。HPLC峰tr=1.848分钟。纯度=97%。
HPLC条件:B。绝对立体化学未测定。
实施例197e,第四洗脱异构体:经由制备型LC/MS在以下条件下纯化粗物质:柱:XBridge C18,19x 200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:20-70%B,经历20分钟,然后在100%B下保持5分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥,得到异构体4(4.5mg,5.9%)。ESI MS(M+H)+=383.2。HPLC峰tr=1.806分钟。纯度=96%。HPLC条件:B。绝对立体化学未测定。
实施例198
4-氯-N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)丁-3-烯-1-基)苯甲酰胺
198A.(R)-3-((R)-2-((1s,4S)-4-(6-氟喹啉-4-基)环己基)戊-4-烯酰基)-4-苯基噁唑烷-2-酮
在-40℃下向制备物40I(50mg,0.116mmol)在THF(2mL)中的溶液中逐滴添加NaHMDS(1M,在THF中)(0.139mL,0.139mmol)。在-40℃至-30℃下搅拌混合物15min。然后逐滴添加含3-溴丙-1-烯(28.0mg,0.231mmol)的THF(0.5mL)。在-20℃下搅拌反应16h。通过将反应倒入饱和NH4Cl溶液中使反应在-20℃下淬灭。水相用EtOAc萃取。有机物用盐水洗涤,经MgSO4干燥,过滤并浓缩,得到粗物质。该粗物质中加入MeOH并过滤,以移除固体。用制备型HPLC(Phen Luna 5u 30x 100mm),40mL/min流速,梯度为20%B-100%B,历时10分钟,在100%B下保持5min(A:含0.1%TFA的水/MeOH(90:10),B:含0.1%TFA的水/MeOH(10:90),在254nm下监测来纯化滤液。合并包含产物的级分(tr=9.428min)。浓缩之后,获得呈白色固体的(R)-3-((R)-2-((1s,4S)-4-(6-氟喹啉-4-基)环己基)戊-4-烯酰基)-4-苯基噁唑烷-2-酮(25mg,0.052mmol,44.8%产率)。1H NMR(400MHz,氯仿-d)δ9.12(d,J=5.5Hz,1H),8.64(dd,J=9.3,5.0Hz,1H),8.01-7.89(m,2H),7.89-7.75(m,1H),7.47-7.31(m,5H),5.62-5.45(m,2H),4.84-4.76(m,1H),4.76-4.68(m,1H),4.68-4.52(m,1H),4.36(dd,J=9.0,3.9Hz,1H),3.55-3.33(m,1H),2.49-2.35(m,1H),2.33-2.21(m,2H),2.12-1.97(m,2H),1.93-1.65(m,6H)LC-MS:M+H=473.3(tr=0.90min)(方法A)。
198B:(R)-2-((1s,4S)-4-(6-氟喹啉-4-基)环己基)戊-4-烯酸
在0℃下向制备物198A(250mg,0.529mmol)在THF(2mL)中的溶液中添加含2.0MLiOH的H2O(0.476mL,0.952mmol),然后添加30%H2O2(0.360mL,3.17mmol)。在0℃下搅拌反应10min。然后使其升温至室温并在室温下搅拌持续16h。通过添加饱和Na2SO3在0℃下小心地使反应淬灭。用1N HCl将pH调节至5~6并用EtOAc萃取混合物。合并的有机物经MgSO4干燥,过滤并浓缩。粗物质用制备型HPLC(9次注入)(Phen Luna 5u 30x 100mm),40mL/min流速,梯度为20%B-100%B,历时10分钟,在100%B下保持5分钟(A:含0.1%TFA的水/MeOH(90:10),B:含0.1%TFA的水/MeOH(10:90),在254nm下监测来纯化。获得呈白色固体的1B(78mg,0.236mmol,44.6%产率)。1H NMR(400MHz,氯仿-d)δ9.22(br.s.,1H),8.63(dd,J=9.0,5.0Hz,1H),7.98-7.75(m,4H),5.85(dd,J=16.9,9.7Hz,1H),5.25-5.03(m,2H),3.50(br.s.,1H),2.89-2.75(m,1H),2.54-2.32(m,2H),2.16(d,J=10.1Hz,1H),2.06(d,J=13.2Hz,1H),2.01-1.71(m,6H)LC-MS:M+H=328(tr=0.69min)(方法A)。
198C:(R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)丁-3-烯-1-胺
使制备物198B(55mg,0.168mmol)溶解于甲苯(1mL)中并添加叠氮磷酸二苯酯(0.040mL,0.185mmol)和三乙胺(0.028mL,0.202mmol)。密封瓶且加热至70℃。在约3h之后,添加叠氮磷酸二苯酯(0.040mL,0.185mmol)和三乙胺(0.028mL,0.202mmol)。再加热反应3h。将反应冷却至室温并在减压下浓缩。使粗残余物溶解于THF(0.2mL)和2M LiOH(0.840mL,1.680mmol)中。在室温下搅拌反应持续16h。LCMS显示异氰酸酯耗尽。希望的M+1新峰在室温下=0.56min。用1N HCl酸化反应(白色沉淀物形成)至pH1并用EtOAc萃取以移除DPPA相关杂质。该物质用制备型HPLC(Phen Luna 5u 30x 100mm),40mL/min流速,梯度为0%B-100%B,经历10分钟,在100%B下保持5min(A:含0.1%TFA的水/MeOH(90:10),B:含0.1%TFA的水/MeOH(10:90),在254nm下监控来纯化。获得制备物198C(30mg,0.040mmol,23.77%产率)。LC-MS:M+H=299.2(TR=0.56min)(方法A)。
实施例198:4-氯-N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)丁-3-烯-1-基)苯甲酰胺
在室温下向制备物198C(15mg,0.029mmol)在THF(0.5mL)中的溶液中添加惠宁氏碱(0.015mL,0.086mmol),然后添加4-氯苯甲酰氯(9.98mg,0.057mmol)。在室温下搅拌反应2h。经由制备型LC/MS在以下条件下纯化该粗物质:柱:XBridge C18,19x 200mm,5μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:50-100%B,历时20分钟,然后在100%B下保持10分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥。产物1的产率为3.8mg(8.70umol,30.5%)。
1H NMR(500MHz,DMSO-d6)δ8.82(d,J=4.4Hz,1H),8.27(d,J=9.0Hz,1H),8.09(dd,J=9.0,5.9Hz,1H),7.95(d,J=10.9Hz,1H),7.84(d,J=8.3Hz,2H),7.66(t,J=7.5Hz,1H),7.57-7.43(m,3H),5.90-5.73(m,1H),5.07(d,J=17.2Hz,1H),4.98(d,J=10.1Hz,1H),4.42(d,J=8.9Hz,1H),3.39(br.s.,1H),2.26-2.13(m,1H),1.94-1.71(m,7H),1.68(br.s.,1H),1.62(d,J=11.1Hz,1H)LC-MS:M+H=437.3tr=2.23min(方法B)。
实施例199
N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)丁-3-烯-1-基)-[1,1’-联苯]-4-甲酰胺
实施例199按照实施例198中的步骤使用198C和[1,1’-联苯]-4-碳酰氯获得。1HNMR(500MHz,DMSO-d6)δ8.83(d,J=4.5Hz,1H),8.25(d,J=9.2Hz,1H),8.09(dd,J=9.1,5.8Hz,1H),8.01-7.84(m,3H),7.80-7.61(m,5H),7.54-7.45(m,3H),7.45-7.27(m,1H),5.90-5.79(m,1H),5.10(d,J=17.4Hz,1H),5.00(d,J=9.8Hz,1H),4.46(d,J=7.9Hz,1H),3.40(br.s.,1H),2.31-2.16(m,1H),2.01-1.78(m,6H),1.75(br.s.,2H),1.69(br.s.,1H),1.63(d,J=12.2Hz,1H)LC-MS:M+H=470.3tr=2.41min(方法B)。
实施例200和实施例201
(手性)N-1-((1s,4S)-4-(喹啉-3-基)环己基)丙基)-[1,1’-联苯]-4-甲酰胺
200A:2-(4-(喹啉-3-基)环己-3-烯-1-基)乙酸乙酯
将2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)环己-3-烯-1-基)乙酸乙酯(5.26g,17.88mmol)溶解于二噁烷(40mL)及水(10.00mL)中。添加3-溴喹啉(3.1g,14.90mmol),然后添加碳酸钾(6.18g,44.7mmol)。混合物用N2鼓泡5分钟,随后添加四(三苯基膦)钯(0)(0.344g,0.298mmol)。在添加之后,将反应抽空且用N2回填三次且随后密封并加热至100℃持续16小时。反应用EtOAc和水稀释。分离有机物并用盐水洗涤,经MgSO4干燥,过滤并在真空中浓缩,且经由ISCO(120g柱,85mL/min,0-30%EtOAc/己烷)直接纯化以得到制备物200A(4.47g,14.38mmol,96%产率)。1H NMR(400MHz,氯仿-d)δ9.05(d,J=2.3Hz,1H),8.09(d,J=8.4Hz,1H),8.02(d,J=2.2Hz,1H),7.86-7.76(m,1H),7.67(ddd,J=8.4,6.9,1.5Hz,1H),7.58-7.45(m,1H),6.38-6.18(m,1H),4.20(q,J=7.1Hz,2H),2.67-2.56(m,2H),2.55-2.43(m,1H),2.42-2.35(m,2H),2.30-2.18(m,1H),2.12-1.92(m,2H),1.57(ddt,J=12.8,10.8,7.9Hz,1H),1.36-1.27(m,3H)LC-MS:M+H=296.2tr=0.74min(方法A)。
200B:2-(4-(喹啉-3-基)环己基)乙酸乙酯
使制备物200A(3.5g,11.85mmol)溶解于MeOH(70mL)中并添加甲酸铵(3.74g,59.2mmol)。容器配备有回流冷凝器且腾空且用N2冲洗3次。随后添加10%Pd/C(1.256g,1.185mmol)且在70℃下加热反应。1小时后的LCMS显示还原完成。冷却反应,过滤出固体且浓缩滤液以得到粗物质。该粗物质用ISCO 120g,85mL/min.0-50%EtOAc/己烷纯化。制备物200B(0.71g,2.308mmol,19.48%产率)用10%EtOAc/己烷洗脱。LC-MS:M+H=302.2tr=0.81min(方法A)。
200C:2-(4-(喹啉-3-基)环己基)丁酸乙酯
在0℃下向制备物200B(920mg,3.09mmol)在THF(10mL)中的溶液中逐滴添加含1MNaHMDS的THF(7.73mL,7.73mmol)。在0℃下搅拌混合物30min。然后逐滴添加碘乙烷(0.3mL,3.75mmol)。在0℃下搅拌所得混合物45min。[溶液的颜色没有改变许多]。逐滴添加碘乙烷(0.4mL,5.00mmol)并在0℃下搅拌反应[溶液的颜色变得稍微更深]。1h之后,添加碘乙烷(0.15mL,1.875mmol)并在室温下搅拌反应2h。LC-MS显示所需产物形成但仍有起始物质留下。将反应倒入饱和NH4Cl溶液中。添加EtOAc并分离有机物,并用盐水洗涤,经MgSO4干燥,过滤并浓缩,得到粗物质。该粗物质用ISCO 80g柱,60mL/min.0-30%EtOAc/己烷,历时40min纯化。所需产物用25%EtOAc/己烷洗脱。合并级分5-11。浓缩后,获得呈澄清液体的制备物200C(386mg,1.174mmol,38.0%产率)。LC-MS;M+H=326.2(TR=0.81,0.82min)(方法A)。
200D:2-(4-(喹啉-3-基)环己基)丁酸
在室温下向制备物200C(385mg,1.183mmol)在THF(1mL)及MeOH(5mL)中的溶液中添加2M LiOH(5.91mL,11.83mmol)和1M NaOH(2.366mL,2.366mmol)。在60℃下搅拌反应持续48h。LC-MS仍显示一点起始物质和甲酯。冷却至室温。用浓HCl将混合物调节至pH 5。用EtOAc萃取水层。分离有机物并用盐水洗涤,经MgSO4干燥,过滤并浓缩,得到呈白色固体的制备物200D(400mg,1.076mmol,91%产率)。LC-MS:M+H=298.2(tr=0.67min)(方法A)。
200E:1-(4-(喹啉-3-基)环己基)丙-1-胺
使制备物200D(200mg,0.673mmol)溶解于甲苯(2mL)中并添加叠氮磷酸二苯酯(0.290mL,1.345mmol)和三乙胺(0.187mL,1.345mmol)。密封瓶且加热至70℃,持续16h。将反应冷却至室温并在减压下浓缩。使粗残余物溶解于THF(2mL)及2M LiOH(2.354mL,4.71mmol)中。在室温下搅拌反应,持续3天。LCMS显示异氰酸酯耗尽。希望的M+1新峰在室温下=0.50min。用1N HCl将反应酸化至pH1并用EtOAc萃取以移除DPPA相关杂质。然后用2MLiOH将水层调节至pH 10。用EtOAc(3x)萃取。合并的有机物用盐水洗涤,经MgSO4干燥,过滤并浓缩,得到呈澄清液体的制备物200E(110mg,0.398mmol,59.1%产率)。LC-MS:M+H=269.2(tr=0.50min)(方法A)。
实施例200a和实施例200b:N-(1-((1r,4r)-4-(喹啉-3-基)环己基)丙基)-[1,1’-联苯]-4-甲酰胺和N-(1-((1r,4r)-4-(喹啉-3-基)环己基)丙基)-[1,1’-联苯]-4-甲酰胺(相对和绝对立体化学未确定,任意指定)
在室温下向1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(102mg,0.533mmol)在DMF(4mL)中的溶液中添加[1,1'-联苯]-4-甲酸(162mg,0.820mmol)、1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(102mg,0.533mmol)、1-羟基苯并三唑(82mg,0.533mmol)和三乙胺(0.171mL,1.230mmol)。在室温下搅拌反应持续16h。用EtOAc和水稀释反应。分离有机物并用盐水洗涤,经MgSO4干燥,过滤并浓缩至干。粗物质用ISCO 40g柱,40mL/min,0-70%EtOAc/己烷,历时40min纯化。用60%EtOAc/己烷洗脱3F(90mg,0.197mmol,48%)。
实施例200a 1H NMR(400MHz,氯仿-d)δ8.86(d,J=2.2Hz,1H),8.15-8.01(m,2H),7.89-7.77(m,3H),7.74-7.58(m,5H),7.58-7.47(m,3H),7.47-7.34(m,1H),5.81(d,J=9.8Hz,1H),4.56-4.27(m,1H),2.96(br.s.,1H),2.26-2.09(m,1H),2.01-1.78(m,8H),1.77-1.64(m,1H),1.52-1.36(m,1H),1.08-0.96(m,3H)LC-MS:M+H=449.3(tr=0.88min)(方法A)。
实施例200b(65mg,0.142mmol,35%)用70%EtOAc/己烷洗脱。1H NMR(400MHz,氯仿-d)δ8.83(d,J=2.3Hz,1H),8.09(d,J=8.4Hz,1H),7.96-7.85(m,3H),7.79(d,J=8.3Hz,1H),7.73-7.61(m,5H),7.58-7.47(m,3H),7.45-7.31(m,1H),5.92(d,J=9.5Hz,1H),4.21-4.01(m,1H),2.82-2.55(m,1H),2.18-1.95(m,4H),1.83(ddd,J=14.0,7.4,4.5Hz,1H),1.75-1.47(m,4H),1.47-1.32(m,2H),1.05(t,J=7.4Hz,3H)LC-MS:M+H=449.3(tr=0.88min)(方法A)。
实施例200c和200d:N-((R)-1-((1s,4S)-4-(喹啉-3-基)环己基)丙基)-[1,1'-联苯]-4-甲酰胺和N-((S)-1-((1s,4R)-4-(喹啉-3-基)环己基)丙基)-[1,1'-联苯]-4-甲酰胺(绝对和相对立体化学未确定,任意指定)
外消旋体实施例200a经由制备型SFC在以下条件下纯化:柱:Chiral AD-H 25x3cm ID,5μm粒子;流动相A:50/50 CO2/MeOH;检测器波长:220nm;流速:85mL/min。级分(“峰-1”tr=10.78min(实施例200c)和“峰-2”tr=23.917min(实施例200d);
1H NMR(400MHz,氯仿-d)δ8.86(d,J=2.2Hz,1H),8.15-8.01(m,2H),7.89-7.77(m,3H),7.74-7.58(m,5H),7.58-7.47(m,3H),7.47-7.34(m,1H),5.81(d,J=9.8Hz,1H),4.56-4.27(m,1H),2.96(br.s.,1H),2.26-2.09(m,1H),2.01-1.78(m,8H),1.77-1.64(m,1H),1.52-1.36(m,1H),1.08-0.96(m,3H)LC-MS:M+H=449.3(tr=0.88min)(方法A)。
实施例201和202
N-((R)-1-((1r,4R)-4-(喹啉-3-基)环己基)丙基)-[1,1'-联苯]-4-甲酰胺和N-((S)-1-((1r,4S)-4-(喹啉-3-基)环己基)丙基)-[1,1'-联苯]-4-甲酰胺(绝对和相对立体化学未确定,任意指定)
经由制备型SFC在以下条件下纯化外消旋体实施例200b:柱:Chiral IC-H 25x3cm ID,5μm粒子;流动相A:50/50 CO2/MeOH;检测器波长:220nm;流速:85mL/min。级分(“峰-1”tr=10.811min(实施例201)和“峰-2”tr=10.842min(实施例202);
1H NMR(400MHz,氯仿-d)δ8.83(d,J=2.3Hz,1H),8.09(d,J=8.4Hz,1H),7.96-7.85(m,3H),7.79(d,J=8.3Hz,1H),7.73-7.61(m,5H),7.58-7.47(m,3H),7.45-7.31(m,1H),5.92(d,J=9.5Hz,1H),4.21-4.01(m,1H),2.82-2.55(m,1H),2.18-1.95(m,4H),1.83(ddd,J=14.0,7.4,4.5Hz,1H),1.75-1.47(m,4H),1.47-1.32(m,2H),1.05(t,J=7.4Hz,3H)LC-MS:M+H=449.2(tr=0.86min)(方法A)。
实施例203
4-氯-N-((R)-1-(顺-4-(喹啉-3-基)环己基)丙基)苯甲酰胺
4-氯-N-((S)-1-(顺-4-(喹啉-3-基)环己基)丙基)苯甲酰胺
4-氯-N-((R)-1-(反-4-(喹啉-3-基)环己基)丙基)苯甲酰胺
4-氯-N-((S)-1-(反-4-(喹啉-3-基)环己基)丙基)苯甲酰胺
绝对和相对立体化学未知
实施例203a-d按照实施例200和201中的步骤使用200E和4-氯苯甲酰氯获得。经由制备型SFC在以下条件下纯化外消旋体:柱:Chiral IC-H 25x 3cm ID,5μm粒子;流动相A:65/35CO2/MeOH;检测器波长:220nm;流速:85mL/min。级分(“峰-1”tr=5.98min(实施例203a)和“峰-2”tr=6.29min(实施例203b);(“峰-3”tr=8.0min(实施例203c)和“峰-4”tr=9.0min(实施例203d);
实施例203a和203b 1H NMR(400MHz,氯仿-d)δ8.86(d,J=2.2Hz,1H),8.16-8.00(m,2H),7.80(d,J=8.2Hz,1H),7.73-7.63(m,3H),7.59-7.46(m,1H),7.45-7.35(m,2H),5.71(d,J=10.0Hz,1H),4.49-4.23(m,1H),3.06-2.83(m,1H),2.24-2.05(m,1H),2.00-1.83(m,5H),1.83-1.73(m,3H),1.73-1.63(m,1H),1.51-1.35(m,1H),1.00(t,J=7.4Hz,3H)LC-MS:M+H=407.2(tr=0.81min)(方法A)。
实施例203c和203d 1H NMR(400MHz,氯仿-d)δ8.86(d,J=2.2Hz,1H),8.16-8.00(m,2H),7.80(d,J=8.2Hz,1H),7.73-7.63(m,3H),7.59-7.46(m,1H),7.45-7.35(m,2H),5.71(d,J=10.0Hz,1H),4.49-4.23(m,1H),3.06-2.83(m,1H),2.24-2.05(m,1H),2.00-1.83(m,5H),1.83-1.73(m,3H),1.73-1.63(m,1H),1.51-1.35(m,1H),1.00(t,J=7.4Hz,3H)LC-MS:M+H=407.2(tr=0.81min)(方法A)。
实施例207
rac-4-氯-N-(1-((反)-4-((3-氯-2-甲基吡啶-4-基)氧基)环己基)乙基)苯甲酰胺
207A.rac-2-((反)-4-((3-氯-2-甲基吡啶-4-基)氧基)环己基)丙酸乙酯
将rac-2-((反)-4-羟基环己基)丙酸乙酯(1.001g,5mmol)在THF(4mL)中的溶液冷却至0℃并用六甲基二硅氮烷钾盐(5.50mL,5.50mmol)处理,历时1min。搅拌反应10分钟,然后用3,4-二氯-2-甲基吡啶(0.851g,5.25mmol)处理。在0℃下搅拌反应40分钟,然后用氯化铵水溶液淬灭。一起搅拌各相1小时,然后用1:1EtOAc-己烷萃取,将有机萃取物干燥并汽提以提供油状物。制备型HPLC提供呈金色油状物的rac-2-((反)-4-((3-氯-2-甲基吡啶-4-基)氧基)环己基)丙酸乙酯(0.47g,29%产率)。MS(ES):m/z=326[M+H]+。tR=0.78min(方法A)。
207B.rac-2-((反)-4-((3-氯-2-甲基吡啶-4-基)氧基)环己基)丙酸
用含氢氧化锂(0.154g,6.45mmol)的水(4mL)处理制备物207A(0.42g,1.289mmol)在THF(4mL)中的溶液。添加甲醇,~4mL以得到单一相,且在50℃下搅拌反应1小时。然后将反应冷却并在室温下搅拌。在氮气流下移除大部分溶剂并用水将反应稀释至~6ml。将该混浊悬浮液过滤并用HOAc水溶液将滤液溶液pH调节至~5.5。将所得沉淀过滤,用水清洗并风干以得到呈白色固体的rac-2-((反)-4-((3-氯-2-甲基吡啶-4-基)氧基)环己基)丙酸(0.16g,42%产率)。MS(ES):m/z=298[M+H]+。tR=0.63min(方法A)。
207C.rac-1-((反)-4-((3-氯-2-甲基吡啶-4-基)氧基)环己基)乙胺
用三乙胺(0.158ml,1.135mmol)然后叠氮磷酸二苯酯(0.244g,1.004mmol)处理制备物207B(0.26g,0.873mmol)在甲苯(4.37ml)中的溶液。将溶液升温至70℃(许多鼓泡)。在30分钟之后,冷却溶液并汽提。使残余物再溶解于THF(5mL)中并添加至氢氧化锂(0.836g,34.9mmol)在20mL水和8mL THF的溶液中。在室温下搅拌此混合物30min,其然后用乙醚稀释并用1M HCl水溶液洗涤两次。将合并的水相排入饱和碳酸钠水溶液(最终pH~12),且此混合物先后用EtOAc和3:1氯仿-IPA萃取。合并这两次有机萃取物,干燥并汽提以得到油状物rac-1-((反)-4-((3-氯-2-甲基吡啶-4-基)氧基)环己基)乙胺(0.18g,77%产率)。MS(ES):m/z=269[M+H]+。tR=0.47min(方法A)。
实施例207:rac-4-氯-N-(1-((反)-4-((3-氯-2-甲基吡啶-4-基)氧基)环己基)乙基)苯甲酰胺
用三乙胺(0.016mL,0.112mmol)然后BOP(0.021g,0.048mmol)处理制备物207C(0.01g,0.037mmol)和4-氯苯甲酸(6.99mg,0.045mmol)在DMF(0.25mL)中的溶液。在室温下搅拌反应2小时,然后用一滴水淬灭并用DMF稀释至2mL。然后通过制备型HPLC纯化此溶液。合适级分的浓缩提供0.0088g(50%)的标题化合物。MS(ES):m/z=407[M+H]+。tR=2.05min(方法B)。
实施例208-210:在针对207C转化成实施例207所述的条件下胺207C(前面实施例中制备)与合适苯甲酸的Bop偶联(方案9,下面)提供下表1中所示的本发明的化合物。(所有个体(entry)是在环己基处具有反式相对立体化学的外消旋体。)
方案9
表1
表2.
实施例211–225按照实施例157中的步骤使用相应的吡啶基卤化物制备(绝对和相对立体化学未知)
实施例226
4-氯-N-((1-(6-氟喹啉-4-基)-4-甲基哌啶-4-基)甲基)苯甲酰胺
226A.4-((4-氯苯甲酰氨基)甲基)-4-甲基哌啶-1-甲酸叔丁酯
在氮气氛围下向4-(氨甲基)-4-甲基哌啶-1-甲酸叔丁酯(53.0mg,0.23mmol)在无水DCM(2mL)中的均质混合物中添加DIPEA(0.17mL,0.97mmol),然后添加4-氯苯甲酰氯(0.05mL,0.390mmol)。在室温下搅拌所得混合物持续4小时,然后使之在DCM和水之间分配。分离各层并用DCM再萃取水层两次。合并这些有机萃取物与初始有机层且在真空中浓缩以得到呈琥珀色残余物的标题化合物,其不经过纯化而用于下一步骤。MS(ES):m/z=367[M+H]+。tR=1.00min(方法A)。
226B.4-氯-N-((4-甲基哌啶-4-基)甲基)苯甲酰胺
在氮气氛围下向4-((4-氯苯甲酰氨基)甲基)-4-甲基哌啶-1-甲酸叔丁酯(226A,0.23mmol)在无水二噁烷(3mL)中的均质混合物中添加HCl(4N,在二噁烷中,0.5mL,2.0mmol)。在室温下搅拌所得混合物45小时,然后使之在水和EtOAc之间分配。分离各层并用EtOAc再一次萃取水层。合并有机层并用水洗涤,且将该水层添加至初始的水层中。将合并的水层冻干以得到呈棕色残余物的标题化合物的HCl盐,其不经过进一步纯化而使用。MS(ES):m/z=267[M+H]+。tR=0.59min(方法A)。
实施例226:4-氯-N-((1-(6-氟喹啉-4-基)-4-甲基哌啶-4-基)甲基)苯甲酰胺
向装有4-氯-6-氟喹啉(15.0mg,0.08mmol)的可密封烧瓶中添加4-氯-N-((4-甲基哌啶-4-基)甲基)苯甲酰胺的HCl盐(226B,23.4mg,0.09mmol)和DIPEA(0.07mL,0.40mmol)在无水NMP(1mL)中的均质混合物。密封瓶并在120℃下搅拌混合物。在65小时之后,使反应混合物冷却至室温,用DMF稀释,通过注射器式过滤器,然后经由制备型HPLC/MS纯化以得到标题化合物(19.4mg;57%产率)。MS(ES):m/z=412[M+H]+。tR=1.91min(方法B)。1H NMR(500MHz,DMSO-d6)δ8.63-8.53(m,2H),8.00(dd,J=9.1,5.3Hz,1H),7.85(d,J=8.4Hz,2H),7.81-7.71(m,2H),7.52(d,J=8.3Hz,2H),7.10(d,J=6.3Hz,1H),3.71-3.60(m,1H),3.55-3.43(m,1H),3.31(d,J=6.1Hz,2H),2.95-2.85(m,1H),2.56-2.54(m,1H),1.79-1.68(m,2H),1.58-1.49(m,2H),1.04(s,3H)。
实施例227
4-氯-N-((4-甲基-1-(2-(三氟甲基)吡啶-4-基)哌啶-4-基)甲基)苯甲酰胺
实施例227(13.9mg;41%产率)按照与用于实施例226的合成的步骤类似的步骤制备,所不同的是在最后步骤中使用4-氯-2-(三氟甲基)吡啶代替4-氯-6-氟喹啉。MS(ES):m/z=412[M+H]+。tR=1.96min(方法B)。1H NMR(500MHz,DMSO-d6)δ8.57-8.48(m,1H),8.19(d,J=5.9Hz,1H),7.78(d,J=8.3Hz,2H),7.49(d,J=8.4Hz,2H),7.13(s,1H),7.01-6.91(m,1H),3.74-3.54(m,2H),3.34-3.24(m,2H),3.21(d,J=6.2Hz,2H),1.55-1.43(m,2H),1.39-1.30(m,2H),0.96(s,3H)。
实施例228
N-((4-甲基-1-(2-(三氟甲基)吡啶-4-基)哌啶-4-基)甲基)-[1,1'-联苯]-4-甲酰胺
实施例228(15.6mg;44%产率)按照与用于实施例227的合成的步骤类似的步骤制备,所不同的是在初始步骤中使用[1,1'-联苯]-4-碳酰氯代替4-氯苯甲酰氯。MS(ES):m/z=454[M+H]+.tR=2.12min(方法B)。1H NMR(500MHz,DMSO-d6)δ8.49(t,J=6.1Hz,1H),8.21(d,J=6.0Hz,1H),7.90(d,J=8.2Hz,2H),7.79-7.65(m,4H),7.48(t,J=7.5Hz,2H),7.44-7.36(m,1H),7.16(s,1H),7.04-6.94(m,1H),3.69-3.53(m,2H),3.31(t,J=9.8Hz,2H),3.25(d,J=6.1Hz,2H),1.59-1.48(m,2H),1.41-1.32(m,2H),0.99(s,3H)。
实施例229
(+/-)-4-氯-N-(1-((1r,4r)-4-((2-(三氟甲基)吡啶-4-基)氧基)环己基)乙基)苯甲酰胺
制备物229A.2-((1r,4r)-4-((2-(三氟甲基)吡啶-4-基)氧基)环己基)丙酸乙酯
向2-((1r,4r)-4-羟基环己基)丙酸乙酯(0.1294g,0.646mmol)在DMF(1.077ml)中的溶液中添加NaH(0.043g,1.077mmol)。在30min之后,添加4-溴-2-(三氟甲基)吡啶(0.071ml,0.538mmol)。在80℃下加热反应过夜。反应用饱和NH4Cl水溶液淬灭并用EtOAc稀释。分离各层。水相用EtOAc(2X)萃取。合并的有机相用水洗涤,经Na2SO4干燥,过滤并浓缩以得到棕色残余物。通过硅胶层析法使用ISCO机器(40g柱,40mL/min,0-30%EtOAc/己烷,历时14min,tr=9.5min)纯化粗物质得到作为无色残余物的标题化合物(0.0646g,0.187mmol,34.7%产率)。ESI MS(M+H)+=346.2。HPLC峰tr=1.09分钟。HPLC条件:A。制备物229B.2-((1r,4r)-4-((2-(三氟甲基)吡啶-4-基)氧基)环己基)丙酸
向制备物229A(0.0437g,0.127mmol)在THF(0.452ml)和MeOH(0.181ml)中的溶液中添加氢氧化锂(1.265ml,1.265mmol)。在70℃下加热反应2小时,然后允许其冷却至室温。用1N HCl将反应调节至pH 7,然后用EtOAc稀释。分离各层。水相用EtOAc(3X)萃取。合并有机相,经Na2SO4干燥,过滤并浓缩以得到呈无色残余物的标题化合物(18.2mg,45%产率)。ESI MS(M+H)+=318.1。HPLC峰tr=0.89分钟。HPLC条件:A。
制备物229C.1-((1r,4r)-4-((2-(三氟甲基)吡啶-4-基)氧基)环己基)乙胺
使制备物229B(18.2mg,0.057mmol)溶解于甲苯(191μl)中并添加叠氮磷酸二苯酯(13.59μl,0.063mmol)和三乙胺(9.59μl,0.069mmol)。密封瓶且加热至80℃。在约2小时之后,将反应冷却至室温。另外加热反应2小时,然后允许其冷却至室温。向该反应添加1mLTHF和1mL水及氢氧化锂(13.74mg,0.574mmol)。在室温下搅拌反应过夜。用1N HCl(~5.5mL)将反应酸化至pH=1并用EtOAc萃取以移除DPPA相关杂质。然后用1N NaOH将水相碱化至pH=12并用EtOAc(3X)萃取。有机萃取物经硫酸钠干燥,过滤并在真空中浓缩以得到呈黄色残余物的标题化合物(3.8mg,0.013mmol,22.98%产率)。
实施例229:(+/-)-4-氯-N-(1-((1r,4r)-4-((2-(三氟甲基)吡啶-4-基)氧基)环己基)乙基)苯甲酰胺
在室温下向制备物229C(3.8mg,0.013mmol)在THF(132μl)中的溶液中添加惠宁氏碱(6.91μl,0.040mmol),然后添加4-氯苯甲酰氯(3.38μl,0.026mmol)。在室温下搅拌反应2小时。经由制备型LC/MS在以下条件下纯化该粗物质:柱:XBridge C18,19x 150mm,5-μm粒子;流动相A:5:95乙腈:水,含10mM乙酸铵;流动相B:95:5乙腈:水,含10mM乙酸铵;梯度:25-100%B,历时20分钟,然后在100%B下保持5分钟;流速:20mL/min。合并含有所需产物的级分且经由离心蒸发干燥以得到标题化合物(2.5mg,44%)。ESI MS(M+H)+=427.2。HPLC峰tr=2.101分钟。纯度=100%。HPLC条件:B。
实施例230
N-(1-((1s,4s)-4-(6-(三氟甲基)喹啉-4-基)环己基)丙基)联苯-4-甲酰胺
230A.2-(4-(6-(三氟甲基)喹啉-4-基)环己-3-烯基)乙酸乙酯
向4-氯-6-(三氟甲基)喹啉(2.05g,8.85mmol)、2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)环己-3-烯-1-基)乙酸乙酯(3.12g,10.62mmol)在1,4-二噁烷(35mL)中的溶液中添加碳酸钾(3.67g,26.6mmol)和水(7mL)。反应混合物用氮气流净化3分钟,然后添加Pd(Ph3P)4(0.409g,0.354mmol)。在100℃下在氮气流下加热所得混合物过夜。使反应混合物冷却下来并用乙酸乙酯和饱和NaHCO3溶液稀释。分离有机层并用饱和NaHCO3溶液洗涤,且经MgSO4干燥。在真空中浓缩滤液并经由硅胶急骤柱层析法用0-50%乙酸乙酯/己烷洗脱来纯化残余物以得到中间体230A(油状物,3.0g,8.26mmol,93%产率)。C20H20F3NO2的LC-MS分析计算值363.14,实验值[M+H]364.5.Tr=0.97min(方法A)。1H NMR(400MHz,氯仿-d)δ:8.95(d,J=4.5Hz,1H),8.31(s,1H),8.22(d,J=8.8Hz,1H),7.87(dd,J=8.8,2.0Hz,1H),7.29(d,J=4.5Hz,1H),5.86(dd,J=2.8,1.7Hz,1H),4.20(q,J=7.2Hz,2H),2.65-2.24(m,5H),2.15-1.96(m,2H),1.73-1.54(m,2H),1.36-1.29(m,3H)。
230B.2-(4-(6-(三氟甲基)喹啉-4-基)环己基)乙酸乙酯
2-(4-(6-(三氟甲基)喹啉-4-基)环己-3-烯-1-基)乙酸乙酯(3.0g,8.26mmol)、甲酸铵(2.08g,33.0mmol)在MeOH(50mL)中的反应混合物用氮气流净化3min,然后添加Pd-C(0.88g,0.41mmol)。在85℃下加热所得混合物2小时。使反应混合物冷却下来。经由垫过滤反应混合物并用MeOH洗涤滤饼。在真空中浓缩滤液。残余物用乙酸乙酯萃取并用饱和NaHCO3溶液、盐水依次洗涤。有机层经MgSO4干燥并在真空中浓缩滤液以得到作为作为顺式和反式非对映异构体的混合物的中间体230B(油状物,2.6g,7.12mmol,86%产率)。C20H22F3NO2的LC-MS分析计算值365.16,实验值[M+H]366.2。Tr=0.94min(方法A)。1H NMR(400MHz,氯仿-d)δ:9.05-8.85(m,1H),8.36(s,1H),8.24(d,J=8.8Hz,1H),7.88(dd,J=8.9,1.7Hz,1H),7.51-7.33(m,1H),4.29-4.03(m,2H),3.51-3.23(m,1H),2.61-2.29(m,2H),2.12-1.35(m,9H),1.32-1.21(m,3H)。230C 2-((1s,4s)-4-(6-(三氟甲基)喹啉-4-基)环己基)丁酸乙酯
在-78℃下向含有THF(15mL)的烧瓶中添加二异丙氨基锂(在THF中的2.0M溶液)(7.65mL,15.30mmol),然后在-78℃下逐滴添加1,3-二甲基四氢嘧啶-2(1H)-酮(1.29mL,10.67mmol)及2-(4-(6-(三氟甲基)喹啉-4-基)环己基)乙酸乙酯(2.6g,7.12mmol)在THF(10mL)中的溶液。所得混合物变成深棕色溶液且在-78℃下搅拌1小时,随后缓慢添加碘乙烷(1.14mL,14.23mmol)。将反应混合物升温至室温并搅拌3小时。反应通过倒入水中来淬灭并用EtOAc萃取。合并的有机物用盐水洗涤,用MgSO4干燥,过滤并在真空中浓缩滤液。经由硅胶急骤柱层析法,用0-20%乙酸乙酯/己烷洗脱来纯化萃取物,得到较少量异构体和较大量顺式异构体的中间体230C(油状物,1.1g,2.77mmol,39%产率)。C22H26F3NO2的LC-MS分析计算值393.19,实验值[M+H]394.3。Tr=0.97min(方法A)。1H NMR(400MHz,氯仿-d)δ:8.97(d,J=4.6Hz,1H),8.37(s,1H),8.24(d,J=8.8Hz,1H),7.88(dd,J=8.8,2.0Hz,1H),7.46(d,J=4.6Hz,1H),4.20(q,J=7.2Hz,2H),3.57-3.32(m,1H),2.64(td,J=10.8,4.0Hz,1H),2.14-1.58(m,11H),1.29(t,J=7.2Hz,3H),0.95(t,J=7.4Hz,3H)。
230D.2-((1s,4s)-4-(6-(三氟甲基)喹啉-4-基)环己基)丁酸
向2-((1s,4s)-4-(6-(三氟甲基)喹啉-4-基)环己基)丁酸乙酯(1.1g,2.80mmol)在THF(20mL)及MeOH(8mL)中的反应混合物中添加氢氧化锂溶液(2.0M溶液)(13.98mL,28.0mmol)。在65℃下加热所得混合物过周末。冷却反应混合物并用水稀释。向混合物中添加1N HCl溶液以将pH调节至约5。在pH 5-6下析出(crash out)白色固体。所得混合物用乙酸乙酯萃取两次。分离有机层并用盐水洗涤,经MgSO4干燥。在真空中浓缩滤液以得到作为外消旋体的中间体230D(黄色固体,0.93g,2.55mmol,91%产率)。C20H22F3NO2的LC-MS分析计算值365.16,实验值[M+H]366.3。Tr=0.81min(方法A)。1H NMR(400MHz,DMSO-d6)δ:12.10(br.s.,1H),8.99(d,J=4.6Hz,1H),8.57(s,1H),8.23(d,J=8.8Hz,1H),8.00(dd,J=8.7,1.9Hz,1H),7.65(d,J=4.6Hz,1H),3.61(d,J=10.3Hz,1H),1.96-1.54(m,11H),1.49-1.29(m,1H),0.90(t,J=7.4Hz,3H)。
230E 1-((1s,4s)-4-(6-(三氟甲基)喹啉-4-基)环己基)丙-1-胺
向2-((1s,4s)-4-(6-(三氟甲基)喹啉-4-基)环己基)丁酸(0.58g,1.587mmol)在甲苯(15mL)中的悬浮液中添加叠氮磷酸二苯酯(0.40mL,1.83mmol)及三乙胺(0.24mL,2.06mmol)。在添加TEA之后反应混合物变成澄清溶液。将反应混合物加热至70℃持续2h。将反应冷却至室温。在减压下浓缩反应混合物。向残余物中添加THF(15mL)及2.0M氢氧化锂溶液(7.94mL,15.87mmol)并在室温下搅拌所得混合物4小时。反应混合物用1N HCl酸化(形成白色沉淀)且用EtOAc萃取以移除DPPA相关杂质。随后水层用1N NaOH碱化(再次形成沉淀)且用EtOAc萃取四次。合并有机萃取物,经MgSO4干燥并在真空中浓缩滤液以得到淡黄色油状物,在高真空下干燥过夜以得到中间体230E(油状物,0.47g,1.397mmol,88%产率)。C19H23F3N2的LC-MS分析计算值336.18,实验值[M+H]337.2.Tr=0.68min(方法A)。1H NMR(400MHz,氯仿-d)δ:8.95(d,J=4.6Hz,1H),8.38(s,1H),8.24(d,J=8.8Hz,1H),7.88(dd,J=8.8,1.8Hz,1H),7.45(d,J=4.6Hz,1H),3.57-3.44(m,1H),2.90(td,J=8.5,3.0Hz,1H),2.22-1.20(m,13H),1.01(d,J=15.0Hz,3H)。
实施例230N-(1-((1s,4s)-4-(6-(三氟甲基)喹啉-4-基)环己基)丙基)联苯-4-甲酰胺
向[1,1'-联苯]-4-甲酸(21.2mg,0.107mmol)在DMF(1.5mL)中的溶液中添加HATU(44mg,0.116mmol)。在室温下搅拌反应混合物10min,然后添加1-((1s,4s)-4-(6-(三氟甲基)喹啉-4-基)环己基)丙-1-胺(30mg,0.089mmol)在THF(0.8mL)和DIPEA(0.03mL,0.178mmol)中的溶液。在室温下搅拌反应混合物2h并在真空中浓缩。使残余物溶解于MeOH,过滤并经由制备型HPLC纯化以得到外消旋实施例230(33mg,0.063mmol,71%产率)。C32H31F3N2O的LC-MS分析计算值516.24,实验值[M+H]517.0.Tr=2.02min(方法B)。1H NMR(500MHz,DMSO-d6)δ:9.01(d,J=4.5Hz,1H),8.55(s,1H),8.30-8.21(m,1H),8.17(d,J=9.3Hz,1H),8.03-7.91(m,3H),7.79-7.67(m,4H),7.61(d,J=4.5Hz,1H),7.48(t,J=7.4Hz,2H),7.43-7.37(m,1H),4.33(d,J=8.7Hz,1H),4.02-3.49(m,1H),1.99-1.33(m,11H),0.90(t,J=7.0Hz,3H)。
实施例231a-e
(绝对和相对立体化学未知)
4-氯-N-(1-(4-(6-(二氟甲基)吡啶-2-基)环己基)丙基)苯甲酰胺
231A.2-(4-(6-(二氟甲基)吡啶-2-基)环己-3-烯基)乙酸乙酯
向2-溴-6-(二氟甲基)吡啶(1.55g,7.45mmol)、2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)环己-3-烯-1-基)乙酸乙酯(2.52g,8.57mmol)在1,4-二噁烷(20mL)中的反应混合物中添加K2CO3(7.45mL,22.36mmol)溶液且所得混合物用氮气流净化3min,然后添加Pd(Ph3P)4(0.431g,0.373mmol)且反应混合物用氮气流净化,然后在110℃下在氮气下加热持续20h。反应混合物用盐水和乙酸乙酯稀释。分离有机层,经MgSO4干燥。在真空中浓缩滤液且残余物经由硅胶急骤柱层析法用0-20%乙酸乙酯/己烷洗脱来纯化,得到中间体231A(油状物,2.2g,7.45mmol,99%产率)。C16H19F2NO2的LC-MS分析计算值295.14,实验值[M+H]296.2.Tr=1.10min(方法A)。1H NMR(400MHz,甲醇-d4)δ:7.92-7.80(m,1H),7.60(dd,J=8.0,0.8Hz,1H),7.47(d,J=7.7Hz,1H),6.71(dd,J=3.1,2.0Hz,1H),6.65-6.44(m,1H),4.20-4.08(m,2H),2.79-2.65(m,1H),2.56-2.39(m,2H),2.36(d,J=7.0Hz,2H),2.20-1.92(m,3H),1.48(dtd,J=13.0,10.6,5.5Hz,1H),1.30-1.22(m,3H)。
231B.2-(4-(6-(二氟甲基)吡啶-2-基)环己基)乙酸乙酯
粗2-(4-(6-(二氟甲基)吡啶-2-基)环己-3-烯-1-基)乙酸乙酯(2.1g,7.11mmol)、甲酸铵(1.794g,28.4mmol)在MeOH(40mL)中的反应混合物用氮气流净化3min,然后添加5%Pd-C(0.757g,0.356mmol)。在85℃下加热所得混合物2h。使反应混合物冷却下来。过滤反应混合物并用MeOH洗涤滤饼。在真空中浓缩滤液。残余物用乙酸乙酯萃取并用饱和NaHCO3溶液、盐水依次洗涤。有机层经MgSO4干燥并在真空中浓缩滤液以得到作为顺式和反式非对映异构体的混合物的中间体231B(油状物,1.8g,6.05mmol,85%产率)。
C16H21F2NO2的LC-MS分析计算值297.15,实验值298.2[M+H]。Tr=1.09min(方法A)。1H NMR(400MHz,氯仿-d)δ:7.75(t,J=7.8Hz,1H),7.55-7.42(m,1H),7.34-7.23(m,1H),6.98(dd,J=14.0,7.8Hz,1H),6.80-6.42(m,1H),4.33-4.04(m,2H),2.91-2.59(m,1H),2.55-2.36(m,2H),2.34-2.20(m,1H),2.07-1.52(m,8H),1.32-1.23(m,3H)。
231C 2-(4-(6-(二氟甲基)吡啶-2-基)环己基)丁酸乙酯
在-78℃下向含有THF(8mL)的烧瓶中添加二异丙氨基锂(在THF中的2.0M溶液)(3.70mL,7.40mmol),随后在-78℃下逐滴添加1,3-二甲基四氢嘧啶-2(1H)-酮(0.81mL,6.73mmol)及2-(4-(6-(二氟甲基)吡啶-2-基)环己基)乙酸乙酯(1.0g,3.36mmol)在THF(10mL)中的溶液。所得混合物变成棕色溶液且在-78℃下搅拌1小时,随后缓慢添加碘乙烷(0.54mL,6.73mmol)。然后在-78℃下搅拌反应混合物0.5h,升温至室温保持20h。在冰浴温度下向反应混合物添加更多二异丙氨基锂(在THF中的2.0M溶液)(3.70mL,7.40mmol)(1.8mL)。在冰浴温度下搅拌反应混合物2小时。反应通过倒入水中来淬灭且用EtOAc萃取。合并的有机物用盐水洗涤,经硫酸钠干燥,过滤并在真空中浓缩。经由硅胶急骤柱层析法用0-16%乙酸乙酯/己烷洗脱来纯化萃取物,得到中间体231C(油状物,0.365g,1.122mmol,33%产率)。C18H25F2NO2的LC-MS分析计算值325.18,实验值[M+H]326.3。Tr=1.12min(方法A)。1H NMR(400MHz,氯仿-d)δ:7.82-7.69(m,1H),7.45(d,J=7.5Hz,1H),7.32(d,J=7.9Hz,0.5H),7.26-7.21(m,0.5H),6.84-6.33(m,1H),4.17(qd,J=7.1,5.9Hz,2H),2.90(dt,J=8.8,4.4Hz,0.5H),2.70(tt,J=12.2,3.4Hz,0.5H),2.53-2.36(m,0.5H),2.18-2.09(m,0.5H),2.06-1.73(m,5H),1.71-1.57(m,4H),1.55-1.44(m,1H),1.27(dt,J=12.8,7.2Hz,4H),0.90(t,J=7.4Hz,3H)。
231D.2-(4-(6-(二氟甲基)吡啶-2-基)环己基)丁酸
在室温下向2-(4-(6-(二氟甲基)吡啶-2-基)环己基)丁酸乙酯(0.4g,1.229mmol)在THF(6mL)及MeOH(3mL)中的反应混合物中添加LiOH溶液(6.15mL,18.44mmol)。然后在60℃下加热反应混合物过夜。向反应混合物添加更多THF(4mL)和LiOH溶液(6.15mL,18.44mmol)并在60℃下再加热反应混合物持续3天。向反应混合物中添加2N HCl溶液以将pH调节至约5-6且所得混合物用乙酸乙酯萃取两次。分离有机层并经MgSO4干燥。在真空中浓缩滤液以得到中间体231D(黄色固体,0.37g,1.22mmol,99%产率)。C16H21F2NO2的LC-MS分析计算值297.15,实验值[M+H]298.3,Tr=0.96min(方法A)。
1H NMR(400MHz,甲醇-d4)δ:7.86(td,J=7.8,1.5Hz,1H),7.50-7.37(m,2H),6.86-6.47(m,1H),2.99-2.84(m,0.5H),2.72(tt,J=12.2,3.4Hz,0.5H),2.53-2.37(m,0.5H),2.15-1.42(m,10.5H),1.36-1.12(m,1H),0.94(td,J=7.4,2.9Hz,3H)。231E.1-(4-(6-(二氟甲基)吡啶-2-基)环己基)丙-1-胺
向2-(4-(6-(二氟甲基)吡啶-2-基)环己基)丁酸(0.32g,1.076mmol)在甲苯(8mL)中的悬浮液中添加叠氮磷酸二苯酯(0.27mL,1.24mmol)和三乙胺(0.17mL,1.40mmol)。在添加TEA之后密封瓶中的反应混合物变成澄清溶液。将反应混合物加热至70℃持续2.5h。在减压下浓缩反应混合物。向残余物中添加THF(10mL)和2.0M氢氧化锂溶液(5.4mL,10.76mmol)并在室温下搅拌所得混合物1h。反应混合物用1N HCl酸化(形成白色沉淀)并用EtOAc萃取以移除DPPA相关杂质。随后水层用1N NaOH碱化(再次形成沉淀)且用EtOAc萃取3次。合并碱性萃取物,经MgSO4干燥并在真空中浓缩滤液以得到无色油状物,在高真空下干燥过夜以得到中间体231E(油状物,95mg,0.35mmol,33%产率)。C15H22F2N2的LC-MS分析计算值268.17,实验值[M+H]269.5.Tr=0.71min(方法A)。
1H NMR(400MHz,甲醇-d4)δ:7.84(td,J=7.8,2.2Hz,1H),7.54-7.34(m,2H),6.82-6.39(m,1H),2.98(dt,J=7.6,3.5Hz,0.5H),2.80-2.64(m,1H),2.49(dt,J=8.1,4.7Hz,0.5H),2.21-1.17(m,11H),0.96(q,J=7.4Hz,3H)。
实施例231,四种异构体,4-氯-N-(1-(4-(6-(二氟甲基)吡啶-2-基)环己基)丙基)苯甲酰胺
向4-氯苯甲酸(30.1mg,0.192mmol)在DMF(1mL)中的溶液中添加HATU(79mg,0.208mmol)。在室温下搅拌反应混合物3min,然后添加中间体231C(43mg,0.160mmol)在THF(1mL)和DIPEA(0.1mL,0.50mmol)中的溶液。在室温下搅拌反应混合物1h并在真空中浓缩。使残余物溶解于MeOH,过滤并经由制备型HPLC纯化以得到非对映异构体的混合物实施例231a。
通过制备型SFC(方法R)进一步分离异构体以得到第一洗脱物实施例231b(11.3mg,0.027mmol,16.8%产率)。C22H25ClF2N2O的LC-MS分析计算值406.16,实验值[M+H]406.9.Tr=2.15min(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.11(d,J=9.1Hz,1H),7.90(t,J=7.8Hz,1H),7.82(d,J=8.3Hz,2H),7.57-7.41(m,4H),7.02-6.68(m,1H),4.02(d,J=9.6Hz,1H),2.86(br.s.,1H),2.02-1.82(m,2H),1.77-1.26(m,9H),0.82(t,J=7.2Hz,3H)。
第二洗脱物实施例231c(10.5mg,0.025mmol,15.8%产率)。C22H25ClF2N2O的LC-MS分析计算值406.16,实验值[M+H]407.2.Tr=2.28min(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.09(d,J=9.1Hz,1H),7.92(t,J=7.8Hz,1H),7.84(d,J=8.4Hz,2H),7.59-7.38(m,4H),7.04-6.73(m,1H),4.03(d,J=8.1Hz,1H),2.88(br.s.,1H),2.06-1.24(m,11H),0.83(t,J=7.2Hz,3H)。
第三洗脱物实施例231d(8mg,0.019mmol,12.0%产率)。C22H25ClF2N2O的LC-MS分析计算值406.16,实验值[M+H]407.0.Tr=2.12min(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.15(d,J=9.1Hz,1H),7.95-7.77(m,3H),7.52(d,J=8.3Hz,2H),7.49-7.35(m,2H),7.05-6.59(m,1H),3.75(d,J=9.1Hz,1H),2.79-2.58(m,1H),1.97-1.77(m,4H),1.71-1.36(m,5H),1.17(br.s.,2H),0.84(t,J=7.2Hz,3H)。
第四洗脱物实施例231E(8.9mg,0.021mmol,13.4%产率)。C22H25ClF2N2O的LC-MS分析计算值406.16,实验值[M+H]406.9.Tr=2.12min(方法B)。1H NMR(500MHz,DMSO-d6)δ:8.15(d,J=9.0Hz,1H),7.96-7.80(m,3H),7.53(d,J=8.3Hz,2H),7.48(d,J=7.6Hz,1H),7.43(d,J=7.7Hz,1H),6.99-6.72(m,1H),3.75(d,J=9.1Hz,1H),2.78-2.58(m,1H),1.99-1.77(m,4H),1.70-1.38(m,5H),1.17(br.s.,2H),0.84(t,J=7.2Hz,3H)。
实施例232
N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-4-(5-甲基-1,3,4-噁二唑-2-基)苯甲酰胺
232A.4-溴-N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)苯甲酰胺
向4-溴苯甲酸(354mg,1.762mmol)在DMF(6mL)中的溶液中添加HATU(670mg,1.762mmol)。在室温下搅拌反应混合物5分钟,然后添加(R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙胺(400mg,1.469mmol)在THF(3mL)和DIPEA(0.77mL,4.41mmol)中的溶液。在室温下搅拌反应混合物3小时。反应混合物用乙酸乙酯和饱和NaHCO3溶液稀释。分离有机层并用盐水洗涤,经MgSO4干燥。在真空中浓缩滤液且经由硅胶急骤柱层析法用0-70%乙酸乙酯/己烷洗脱来纯化残余物,得到中间体232A(白色固体,0.55g,1.208mmol,82%产率)。C24H24BrFN2O的LC-MS分析计算值454.1,实验值[M+H]455.1,457.1。Tr=0.85min(方法A)。1HNMR(400MHz,氯仿-d)δ:8.82(d,J=4.5Hz,1H),8.12(dd,J=9.3,5.7Hz,1H),7.73-7.63(m,3H),7.62-7.56(m,2H),7.47(ddd,J=9.2,8.0,2.8Hz,1H),7.42(d,J=4.5Hz,1H),5.85(d,J=9.3Hz,1H),4.61(tq,J=9.7,6.5Hz,1H),3.45-3.17(m,1H),2.15-1.68(m,9H),1.32(d,J=6.6Hz,3H)。
232B.N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯甲酰胺
向4-溴-N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)苯甲酰胺(0.55g,1.208mmol)在1,4-二噁烷(20mL)中的溶液中添加乙酸钾(0.356g,3.62mmol)和双(频哪醇合)二硼(0.368g,1.449mmol)。反应混合物用氮气流净化3分钟,然后添加PdCl2(dppf)(0.088g,0.121mmol。在90℃下加热反应混合物过夜。使反应混合物冷却下来并用饱和NaHCO3溶液和乙酸乙酯稀释。分离有机层并用盐水洗涤,经MgSO4干燥。在真空中浓缩滤液以得到作为硼酸酯和酸混合物的粗中间体232B(黑色固体,0.6g,1.208mmol,99%产率)。C30H36BFN2O3的LC-MS分析计算值502.28,实验值[M+H]503.5。Tr=0.87min(方法A)。
实施例232:N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-4-(5-甲基-1,3,4-噁二唑-2-基)苯甲酰胺
向2-溴-5-甲基-1,3,4-噁二唑(15.57mg,0.096mmol)和粗N-((R)-1-((1s,4S)-4-(6-氟喹啉-4-基)环己基)乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯甲酰胺(40mg,0.080mmol)在二噁烷(2mL)中的反应混合物中添加Na2CO3(2.0M溶液)(0.12mL,0.24mmol)。反应混合物用氮气流净化2分钟,然后添加PdCl2(dppf)(5.8mg,0.0080mmol)。在90℃下加热密封管中的所得混合物持续16h。反应混合物用乙酸乙酯和饱和NaHCO3溶液稀释。分离有机层并在真空中浓缩。使残余物溶解于DMF,过滤并经由制备型HPLC纯化以得到实施例232(17mg,0.037mmol,46.1%产率)。C27H27FN4O2的LC-MS分析计算值458.21,实验值[M+H]458.9.Tr=1.23min(方法I)。1H NMR(500MHz,DMSO-d6)δ:8.83(d,J=4.5Hz,1H),8.47(d,J=8.8Hz,1H),8.14-8.00(m,5H),7.97(d,J=8.8Hz,1H),7.66(t,J=7.4Hz,1H),7.48(d,J=4.3Hz,1H),4.46(br.s.,1H),3.38(br.s.,1H),2.59(s,3H),1.96-1.54(m,9H),1.22(d,J=6.4Hz,3H)。
实施例233-253
实施例233-253由中间体40L按照用于实施例47的步骤使用相应的酸或者按照用于实施例231的步骤制备。
实施例254-256
实施例254-256由中间体230E按照用于实施例230的步骤使用相应的酸制备。
实施例257-263
实施例257-263由中间体164J,按照用于实施例164的步骤使用相应的酸制备。
生物实施例
在基于海拉细胞(HeLa cell)的吲哚胺2,3-双加氧酶(IDO)分析中评估抑制剂活性。
海拉(CCL-2)细胞获自且在补充有4.5g/L葡萄糖、4.5g/L L-谷氨酰胺及4.5g/L丙酮酸钠(#10-013-CV,Corning)、2mM L-丙氨酰基-L-谷氨酰胺二肽(#35050-061,Gibco)、100U/mL青霉素、100μg/mL链霉素(#SV30010,HyClone)及10%胎牛血清(#SH30071.03HyClone)的Dulbecco的改良的Eagle培养基中培养。细胞维持在湿润的培育箱中37℃下5%CO2中。
如下根据犬尿氨酸产生来评估IDO活性:海拉细胞以5,000个细胞/孔的密度接种于96孔培养板中且允许其平衡过夜。在24小时之后,抽吸培养基且用含有最终浓度为25ng/mL的IFNγ(#285-IF/CF,R&D Systems)的培养基替换。将各测试化合物的连续稀释以200μL培养基的总体积添加至细胞中。再培育48小时之后,将170μL上清液自各孔转移至新96孔板。将12.1μL的6.1N三氯乙酸(#T0699,Sigma-Aldrich)添加至各孔中且混合,随后在65℃下培育20分钟以将吲哚胺2,3-双加氧酶的产物N-甲酰基犬尿氨酸水解成犬尿氨酸。随后使反应混合物在500xg下离心10分钟以使沉淀物沉淀。将100μL上清液自各孔转移至新96孔板。将100μl含2%(w/v)对二甲氨基苯甲醛(#15647-7,Sigma-Aldrich)的乙酸(#A6283,Sigma-Aldrich)添加至各孔中,混合且在室温下培育20分钟。通过测量在480nm下的吸光度及相对于L-犬尿氨酸(#K8625,Sigma-Aldrich)标准曲线,使用M2e微板读取器(Molecular Devices)校准来测定犬尿氨酸浓度。测定在各抑制剂浓度下的活性百分比且使用非线性回归评估IC50值。
本文所描述的化合物的活性提供于图1中,其中效能(potency)水平如下提供:(效能:IDO IC50:A<0.1μM;B<1μM;C<10μM)。
生物活性的评估
针对IDO活性抑制测试例示性化合物。下文提供实验步骤及结果。
通过电穿孔使用含有人IDO1cDNA(NM 002164.2)的基于pCDNA的哺乳动物表达载体转染HEK293细胞。它们在含有1mg/ml G418的培养基(具有10%FBS的DMEM)中培养两周。选择稳定表达人IDO1蛋白的HEK293细胞的克隆且延伸用于IDO抑制分析。
将人IDO1/HEK293细胞以10,000个细胞/50μL/孔用含有10%FBS的RPMI/无酚红培养基在384孔黑壁透明底组织培养板(Matrix Technologies LLC)中接种,随后使用ECHO液体处理系统将100nL某浓度的化合物添加至各孔中。在具有5%CO2的37℃培育箱中培育细胞20小时。
通过添加三氯乙酸(Sigma-Aldrich)至0.2%的最终浓度来停止化合物处理。在50℃下进一步培育细胞板30分钟。在新透明底384孔板中混合相等体积的上清液(20μL)及含0.2%(w/v)艾氏试剂(4-二甲氨基苯甲醛,Sigma-Aldrich)的冰乙酸。随后在室温下培育此板30分钟。在Envision板读取器上测量490nm下的吸光度。
使用呈百分之百抑制的500nM参考标准处理的计数及呈百分之零抑制的无化合物但DMSO处理的计数计算化合物IC50值。
本文中描述的化合物的活性提供于图1中,其中效能水平如下提供:(效能:IDOIC50:A<0.05μM;B<0.25μM;C<2μM)。
IDO分析的结果显示于下表中。
HEK人IDO-1
本发明的特定实施方案描述于本文中,包括本发明人已知的进行本发明的最佳模式。在阅读前述内容后,所公开的实施方案的描述、变体可对于本领域中工作的个体变得显而易见,且预期本领域技术人员可按需要采用此类变体。因此,意欲本发明不同于本文所具体描述的来实施,且本发明包括如由适用法律准许的附录权利要求中所述的主题的所有修改及等效物。此外,除非本文另外指示或另外明显与上下文矛盾,否则本发明涵盖上述要素在其所有可能变体中的任何组合。
本说明书中所引用的所有出版物、专利申请、编录号及其它参考文献都以引用的方式并入本文中,如同各单独出版物或专利申请具体地且个别地指示以引用的方式并入一般。
Claims (34)
1.一种具有式(I)的化合物:
(I)
或其药学上可接受的盐、水合物或溶剂化物,其中
下标n为1或0;
A为-C(O)-、-NH-、-SO2-、-CH2-或-CHR3-;
B为键、-C(O)-、-NH-、-CH2-或-CHR3-;
T为键、-CH2-、-NH-、-O-、-OCH2-、-C(O)CH2-或-CR3R4-;
其中当A为-NH-且B为-C(O)-时,则T不为-C(R3)(R4)-;
D为N或C(R5);
E为N或C(R6);
V为键、-O-或-C(R5a)2;
G为任选取代的芳基、任选取代的杂芳基或任选取代的9-或10-元稠合双环杂芳基;
当R2连接至标识为J1的环顶点时,J1为CH、N或C(R2);
R1及R2独立地为氢、卤素、任选取代的C1-C4卤代烷基、任选取代的C3-C6环烷基、任选取代的3-至6-元环杂烷基、任选取代的苯基、任选取代的杂芳基、任选取代的C1-C4烷基、任选取代的C1-C4烷氧基、CN、SO2NH2、NHSO2CH3、NHSO2CF3、OCF3、SO2CH3、SO2CF3或CONH2,且当R1及R2在苯环的相邻顶点上时,它们可连接在一起形成具有一个或两个独立地选自O、N及S的环顶点的5-或6-元环杂烷基环,其中所述环杂烷基环任选被一个至三个选自氟及C1-C3烷基的成员取代;
R3及R4独立地为氢、任选取代的C1-C6烷基、任选取代的C1-C6卤代烷基、氟、OH、CN、CO2H、C(O)NH2、N(R5a)2、任选取代的-O-C1-C6烷基、-(CR5R5)m-OH、-(CR5R5)m-CO2H、-(CR5R5)m-C(O)NH2、-(CR5R5)m-C(O)NHR5a、-(CR5R5)mN(R5a)2、-NH(CR5R5)mCO2H或-NH(CR5R5)m-C(O)NH2;
各R5独立地为H、F、OH、任选取代的C1-C6烷基或任选取代的-O-C1-C6烷基;
各R5a独立地为H或任选取代的C1-C6烷基;
R6为H、OH、F、任选取代的C1-C6烷基、任选取代的-O-C1-C6烷基或-N(R5a)2;
且各m独立地为1、2或3。
2.权利要求1的化合物,其具有下式:
(Ia)。
3.权利要求2的化合物,其具有下式:
(Ia1)。
4.权利要求3的化合物,其具有下式:
(Ia2)。
5.权利要求4的化合物,其具有下式:
。
6.权利要求4的化合物,其具有下式:
。
7.权利要求4的化合物,其具有下式:
。
8.权利要求4的化合物,其具有下式:
。
9.权利要求4的化合物,其具有下式:
(Ia3)。
10.权利要求9的化合物,其具有下式:
。
11.权利要求9的化合物,其具有下式:
。
12.权利要求9的化合物,其具有下式:
。
13.权利要求9的化合物,其具有下式:
。
14.权利要求1的化合物,其具有下式:
(Ib)。
15.权利要求1的化合物,其具有下式:
(Ic)。
16.权利要求1的化合物,其具有下式:
(Id)。
17.权利要求1的化合物,其具有下式:
(Ie)。
18.权利要求17的化合物,其具有下式:
(Ie1)。
19.权利要求1的化合物,其具有下式:
(If)。
20.权利要求1的化合物,其具有下式:
(Ig)。
21.权利要求1的化合物,其具有下式:
(Ih)。
22.权利要求1的化合物,其具有下式:
(Ii)。
23.一种化合物,其如实施例中所提供。
24.权利要求1的化合物,其具有下式:
(Ij)。
25.一种药物组合物,其包含权利要求1的化合物及药学上可接受的赋形剂。
26.一种治疗至少部分由IDO介导的疾病、病症或病状的方法,所述方法包括给予需要其的对象有效量的权利要求1的化合物。
27.权利要求26的方法,其中所述疾病、病症或病状为癌症。
28.权利要求27的方法,其中所述癌症为前列腺癌、结肠癌、直肠癌、胰腺癌、子宫颈癌、胃癌、子宫内膜癌、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头部癌、颈部癌、皮肤癌(包括黑素瘤及基底癌)、间皮内膜癌、白血球癌(包括淋巴瘤及白血病)、食道癌、乳癌、肌肉癌、结缔组织癌、肺癌(包括小细胞肺癌及非小细胞癌)、肾上腺癌、甲状腺癌、肾癌或骨癌;或为胶质母细胞瘤、间皮瘤、肾细胞癌、胃癌、肉瘤(包括卡波西肉瘤)、绒膜癌、皮肤基底细胞癌或睾丸精原细胞瘤。
29.权利要求27的方法,其中所述癌症选自黑素瘤、结肠癌、胰腺癌、乳癌、前列腺癌、肺癌、白血病、脑肿瘤、淋巴瘤、卵巢癌及卡波西肉瘤。
30.一种组合,其包含权利要求1的化合物及至少一种额外治疗剂。
31.权利要求30的组合,其中所述至少一种额外治疗剂为化学治疗剂、免疫和/或炎症调节剂、抗高胆固醇血症剂或抗感染剂。
32.权利要求30的组合,其中所述至少一种额外治疗剂为免疫检查点抑制剂。
33.一种治疗对象中的癌症的方法,所述方法包括给予所述对象有效量的权利要求1的化合物及免疫检查点抑制剂。
34.权利要求32的组合或权利要求33的方法,其中所述免疫检查点抑制剂选自伊匹单抗、纳武单抗及帕母单抗。
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