CN107001806A - 用于治疗心肺疾病的鞘氨醇‑1‑磷酸盐受体调节剂 - Google Patents

用于治疗心肺疾病的鞘氨醇‑1‑磷酸盐受体调节剂 Download PDF

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CN107001806A
CN107001806A CN201580059828.7A CN201580059828A CN107001806A CN 107001806 A CN107001806 A CN 107001806A CN 201580059828 A CN201580059828 A CN 201580059828A CN 107001806 A CN107001806 A CN 107001806A
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alkyl
heart
compound
compound according
disease
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CN107001806B (zh
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爱德华·罗伯茨
休·罗斯
玛瑞安吉拉·乌尔巴诺
米格尔·A·格雷罗
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Scripps Research Institute
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

本发明提供了有效作为用于治疗心肺疾病的鞘氨醇‑1‑磷酸盐受体调节剂的化合物，所述心肺疾病诸如，高血压(包括恶性高血压)、绞痛、心肌梗塞、心律失常、充血性心力衰竭、冠心病、动脉粥样硬化、心绞痛、节律障碍、心肌病(包括高血压心肌病)、心力衰竭、心脏骤停、支气管炎、哮喘、慢性阻塞性肺病、囊性纤维化、哮吼、肺气肿、胸膜炎、肺纤维化、肺炎、肺栓塞、肺动脉高压、间皮瘤、心室传导异常、完全心脏阻塞、成人呼吸窘迫综合征、脓毒病综合征、特发性肺纤维化、硬皮病、系统性硬化、腹膜后纤维化、预防瘢痕瘤形成或肝硬化。

Description

用于治疗心肺疾病的鞘氨醇-1-磷酸盐受体调节剂
相关申请的交叉引用
本申请要求于2014年9月29日提交的美国临时申请序列No.62/056,946的优先权，其公开内容通过引用整体并入本文。
政府支持声明
本发明获得美国政府的资助(美国国立卫生研究院批准号MH084512)。因此，美国政府在本发明中可具有一定的权利。
背景技术
提出了鞘氨醇-1-磷酸盐受体(S1PR)亚型3的拮抗作用以具有哮喘、慢性阻塞性肺疾病的治疗用途以及基于受体表达的其他治疗用途以及基因缺失的药理拮抗作用。鉴定了用于鞘磷脂1-磷酸盐(S1P)的5种高亲和力的G-蛋白偶联受体(1)，并且已解决S1PR1的晶体结构(2)。这种受体集合在医学上是重要的，因为非选择性S1PR激动剂芬戈莫德是通过改变淋巴细胞功能治疗复发性多发性硬化症的有效口服疗法。在空间分布、偶联和功能上不同的各种S1P受体亚型可以单独或组合，在动脉介质的胚胎形成、血压调节和心脏功能中起复杂的作用。在男性中FTY720(芬戈莫德)与明显的窦性心动过缓，心脏阻滞和QTc间期延长有关(3，4)。在男性(6)以及啮齿动物(7)中用S1PR1选择性激动剂的窦性心动过缓的阿托品逆转(5)和窦性心动过缓的证明表明窦房结(SA)节段效应和由心室传导的改变引起的事件被明显调节。缺乏S1PR3的小鼠对由S1PR3激动剂产生的各种药理学作用(包括肺和心脏纤维化(8-10)，心律失常(11))具有抗性，并且对例如细胞因子风暴和脓毒病综合征等复杂病理具有抗性。
脓毒病综合征是感染的结果，其特征是不受控制的系统性炎症的状态，在美国每年死亡约20万人(12，13)。据全球估计，认为脓毒病的发病率为每十万人中有140-240例，死亡率高达30％。如果与循环衰竭和器官功能衰竭有关，死亡率保持在50-80％的范围内(14，15)。1979-2000年流行性脓毒病研究估计美国脓毒病护理的年花费为170亿美元(16)，由于医疗费用增加，如今的价钱可能会更高。虽然脓毒病的早期干预和现代支持性护理方法稍微增加脓毒病的总体存活率至37％至30％(17-21)，但仍然存在明显的未满足的医疗需求，需要开发新的治疗策略来对抗这种医疗负担。
尽管采取了改变病原体负担和密集型支持性护理的措施，脓毒病综合征仍具有高发病率，死亡率和显著的成本负担，这反映了用于宿主保护所必需的促炎细胞因子和炎症因子之间的不平衡(22)。最近定义调节系统性炎症的关键因素的特征的工作，已经确定了在动物模型中进行遗传验证的用于治疗干预的新的、化学易处理的靶标。我们最近的工作已表明，钝化不消除宿主反应，细胞因子风暴提供了来自免疫病理学的重要保护，同时免去抗病毒免疫应答(23-25)。在细菌感染中，我们已经通过受体的遗传缺失(26)以及早期选择性中性拮抗剂的使用两者证明了通过树突状细胞(DC)上的S1PR3的S1P信号传导在脓毒病重症模型中加剧了系统性炎症和致命性，即LPS诱导的炎症和盲肠结扎穿刺(CLP)模型。
脓毒症综合征是一项重大的未满足的医疗需求，因为除了抗菌疗法和支持性重症监护之外，没有有效的治疗方案。在这个医疗挑战背后是多种复杂的病理终点，其在终末器官功能衰竭的最终共同途径中结合，并且患者子集的前瞻性识别是一项正在进行的工作。尽管如此，未满足的医疗需求的重要性，加上对共享关键途径的新机制见解，为基于机制的干预提供了新的机会。严重脓毒症的特征病理学症状包括严重炎症、调节异常性凝血、组织微血管水肿、心血管衰竭、肾功能障碍和最终死亡。另外长期的后果是肺纤维化。这些症状主要是由于宿主的免疫系统的过度激活反应于病原体的入侵(27，28)。了解调节宿主免疫过度激活的发生和进展的因素与设计用于脓毒症的新型有效疗法有关。多重系列的证据支持S1PR在控制免疫细胞运输和生理和疾病心血管功能方面的关键作用(29，30)。S1P，来自神经酰胺途径的循环生物活性溶血磷脂(图1)，结合并激活五个紧密相关的G蛋白偶联受体，称为S1PR1-5。有趣的是，具有活性炎症成分(如多发性硬化症(MS)、冠状动脉粥样硬化和狼疮)的人类疾病具有升高的血浆或局部S1P水平(31-34)。在脓毒病的情况下，疾病受试者中甚至存在主要的S1P载体脂蛋白(Apoprotein M)的血浆升高，并且现在是预后不良的危险因素(35，36)。因此，有可能在败血症中改变S1P信号音。自从停止Xigris(37)，脓毒病的内皮成分的预期靶标，并且因为免疫抑制性皮质类固醇疗法由于脓毒病发生肾上腺功能不全而有争议(38，39)，因此只有有限的武库来对抗脓毒病。基于显示S1PR3信号传导有助于促炎症信号，纤维化和不良脓毒病结果的数据，使用体内选择性小分子拮抗剂S1PR3抑制血管平滑肌、冠状动脉平滑肌和支气管平滑肌上的DC，可以有助于改善以支气管收缩、肺纤维化、冠状动脉收缩、树突状细胞的细胞因子扩增，以及弥散性血管内凝血病的产生为特征的多种临床综合征中的治疗结果。
以前的研究结果表明，S1PR3缺陷型DC(取自S1PR3敲除)显著增强了使用90％致死剂量(LD90)的LPS给药的小鼠或在多发性脓毒病的盲肠结扎穿刺(CLP)模型之后的小鼠的存活率(26)。最重要的是，该研究指出，用AUY954(一种从血液中隔离B淋巴细胞和T淋巴细胞的选择性S1P1激动剂(40)，并且有用于抑制局部炎症动物模型中的炎症(41))治疗，没有推断出同一研究中的任何保护。另一个使用类似转移方法的报告刚刚显示，DC中的S1PR3缺乏使肾缺血/再灌注研究中的促炎介质显著地钝化，并降低小鼠的肾脏免疫病理(42)。有趣的是，作者进一步暗示将IL-4信号传导作为得益于肾脏缺血/再灌注中的S1PR3缺陷的下游介质。此外，骨髓来源的DC(BMDC)中的S1PR3的siRNA敲除大大减少了transwell DC迁移和迁移到肠系膜淋巴结(43)，这表明S1PR3直接参与DC迁移。总的来说，现有的证据强烈地表明，如用系统S1PR3拮抗剂提出的下调S1PR3 DC信号可能会在脓毒病综合征中开辟新的治疗机会。这些数据强烈表明，S1PR3拮抗剂在脓毒症护理的早期管理期间可能是有价值的，其特征在于具有提高存活潜力的关键治疗窗口(44)(45)。
发明内容
在多种实施方式中，本发明提供一种具有式(I)的化合物，
其中Ar1、Ar2和Ar3各自独立地选自(C6-C10)芳基环系或(5-元至10-元)杂芳基环系，其中Ar1、Ar2或Ar3中的任何芳基环系或杂芳基环系任选地与环烷基或杂环基环稠合；
其中Ar1、Ar2或Ar3中的任何芳基或杂芳基各自任选独立地被至多三个取代基单取代或多取代，所述取代基选自(C1-C4)烷基、(C2-C4)烯基、卤素、卤代(C1-C4)烷基、OH、单羟基(C1-C4)烷基、二羟基(C2-C4)烷基、单羟基(C1-C4)烷氧基、二羟基(C2-C4)烷氧基、(C1-C4)烷氧基、(C2-C6)酰基、(C1-C6)烷氧羰基(CH2)0-2、羧基(CH2)0-2、氧代、氰基、NR2(CH2)0-2、NR2C(＝O)(CH2)0-2、NR2C(＝O)(CH2)0-2O(CH2)0-2、(C1-C4)C(＝O)N(R)、(C1-C4)OC(＝O)N(R)、C＝NOR、(C3-C10)环烷基、(5-元至10-元)杂环基、(C6-C10)芳基、和(5-元至10-元)杂芳基；其中Ar1、Ar2或Ar3中的任何环烷基、杂环基、芳基或杂芳基取代基本身任选被至多三个第二取代基取代，第二取代基选自(C1-C4)烷基、(C2-C4)烯基、卤素、卤代(C1-C4)烷基、OH、单羟基(C1-C4)烷基、二羟基(C2-C4)烷基、单羟基(C1-C4)烷氧基、二羟基(C2-C4)烷氧基、(C1-C4)烷氧基、(C2-C6)酰基、(C1-C6)烷氧基羰基(CH2)0-2、羧基(CH2)0-2、氧代、氰基、NR2(CH2)0-2、NR2C(＝O)(CH2)0-2、NR2C(＝O)(CH2)0-2O(CH2)0-2、(C1-C4)C(＝O)N(R)、(C1-C4)OC(＝O)N(R)以及C＝NOR；
每个R独立地为H、(C1-C4)烷基、羟基(C2-C4)烷基、氰基或((C1-C4)烷基-O)1-2(C1-C4)烷基，或两个R基团连同它们都连接的原子一起可以形成环；
每个R′独立地为H、(C1-C4)烷基、羟基(C2-C4)烷基、(CH2)0-2C(＝O)O(C1-C4)烷基或(C3-C6)环烷基；
X是键、(CH2)1-2、(CH2)0-2N(R)(CH2)0-2、(CH2)0-2O(CH2)0-2、(CH2)0-2N(R)C(＝O)(CH2)0-2、(CH2)0-2C(＝O)N(R)(CH2)0-2、(CH2)0-2N(R)C(＝O)O(CH2)0-2或(CH2)0-2OC(＝O)N(R)(CH2)0-2；
L是键、NR、C(＝O)、SO2、C(＝NR)、C(＝O)CR2、C(＝O)CH(N(R)C(＝O)(C1-C4)烷基，C(＝O)CH(N(R)C(＝O)O(C1-C4)烷基、C(＝O)CH(NR2)，C(＝O)CR(卤素)或是
其中波浪线表示键合点，
或其药学上可接受的盐。
例如，化合物可以具有式(IA)
其中Ar1、Ar2和Ar3各自是独立选择的芳基；X、L、R和R′如本文所定义。
例如，化合物可以具有式(IB)
其中Ar1和Ar2是独立选择的芳基，Ar3是杂芳基；X、L、R和R′如本文所定义。
例如，化合物可以具有式(IC)
其中Ar1为芳基，Ar2和Ar3是独立选择的杂芳基；X、L、R和R′如本文所定义。
例如，化合物可以具有式(ID)
其中Ar1和Ar3是独立选择的芳基，Ar2是杂芳基；X、L、R和R′如本文所定义。
例如，化合物可以具有式(IE)
其中Ar1和Ar3是独立选择的杂芳基，Ar2是芳基；X、L、R和R′如本文所定义。
在多种实施方式中，本发明提供了包含本发明的化合物和药学上可接受的赋形剂的药物组合物。
多种实施方式中，本发明进一步提供了治疗患有心肺疾病的患者的心肺疾病的方法，其包括施用有效量的本发明化合物。例如，该疾病可以是哮喘或慢性阻塞性肺病；或者，该疾病可以包括脓毒病；或其中疾病是冠状动脉粥样硬化。在多种实施方式中，本发明提供一种治疗方法，其中所述疾病包括以支气管收缩、肺纤维化、冠状动脉收缩、树突状细胞的细胞因子扩增或弥散性血管内凝血病的产生为特征的临床综合征。更具体地，本发明提供了治疗患有疾病的患者的疾病的方法，其中所述疾病包括流感感染的炎症，或其中所述疾病是心血管疾病、高血压(包括恶性高血压)、绞痛、心肌梗塞、心律失常、充血性心力衰竭、冠心病、动脉粥样硬化、心绞痛、节律障碍、心肌病(包括高血压心肌病)、心力衰竭、心脏骤停、支气管炎、哮喘、慢性阻塞性肺病、囊性纤维化、哮吼、肺气肿、胸膜炎、肺纤维化、肺炎、肺栓塞、肺动脉高压、间皮瘤、心室传导异常、完全心脏阻塞、成人呼吸窘迫综合征、脓毒病综合征、特发性肺纤维化、硬皮病、系统性硬化、腹膜后纤维化、预防瘢痕瘤形成或肝硬化。
因此，在多种实施方式中，本发明提供医疗用途，其包括使用本发明化合物，例如以药物组合物的形式，用于治疗任何上述列举的医学病症。
具体实施方式
定义
如在说明书和所附权利要求中所使用的，单数形式“一”、“一个”和“所述”包括复数指示物，除非上下文另有明确规定。
如本文所用，术语“约”在提及数值或范围时允许该值或范围的变化程度，例如在所述值或所述限度的10％或5％以内的范围。
术语“疾病”或“病症”或“功能障碍”可互换使用，并且用于指其中鞘氨醇-1-磷酸受体在涉及疾病或病症或症状的生化机制中起作用使得(例如，用有效量或有效浓度的本发明的合成配体)通过作用于鞘氨醇-1-磷酸受体可以实现治疗有益的作用的疾病或病症。“作用于”鞘氨醇-1-磷酸受体或“调节”鞘氨醇-1-磷酸受体可以包括与鞘氨醇-1-磷酸受体结合和/或抑制鞘氨醇-1-磷酸受体的生物活性，和/或在体内变构调节鞘氨醇-1-磷酸受体的生物活性。
当用于描述患有疾病的个体的治疗时，表述“有效量”是指本发明化合物的量或浓度，其有效抑制或以其它方式作用于个体的组织中的鞘氨醇-1-磷酸受体，其中所述鞘氨醇-1-磷酸受体参与病症，其中这种抑制或其它作用进行到足以产生有益治疗作用的程度。
“治疗”或“医治”在本文的含义是指缓解与病症或疾病相关的症状，或抑制这些症状的进一步进展或恶化，或阻止或预防疾病或病症，或治疗疾病或病症。类似地，如本文所用，本发明化合物的“有效量”或“治疗有效量”是指全面或部分地缓解与病症或病情相关的症状，或停止或减缓这些症状的进一步进展或恶化，或阻止疾病或病症，或提供对病症或病情的预防的化合物的量。特别地，“治疗有效量”是指在剂量上并针对有必要的时间段内对实现所需治疗结果有效的量。治疗有效量也是其中本发明化合物的任何毒性或不利影响超过治疗有益效果的量。
要进一步理解，在各种实施方式的描述使用术语“包括”的情况下，本领域技术人员将理解，在一些具体情况下，可以使用“基本上由...组成”或“由...组成”的语言替代地描述实施方式。
“化学上可行的”是指其中普遍理解的有机结构规则不被破坏的键合配置或化合物；例如在某些情况下将包含的权利要求的定义内的结构，例如，本质上不存在的五价碳原子，将被理解为不在权利要求范围内。在本文中在其所有实施方式中公开的结构旨在仅包括“化学上可行的”结构，并且任何所陈述的不具有化学可行性的结构，例如以可变原子或基团表示的结构，不旨在被本文公开或主张权利。
当取代基被指定为具有特定同一性的一个或多个原子时，“或键”时，构型是指当取代基为“或键”时，紧邻指定的取代基的基团以化学上可行的键合构型彼此直接连接。
意图是所有单个对映异构体、非对映异构体和外消旋形式的结构，除非具体指出特定的立体化学或异构形式。在几种情况下，尽管在特定要求保护的化合物中描述了单独的立体异构体，但立体化学指定并不意味着替代的异构体形式是较不优选的、不期望的或不要求保护的。用于本发明的化合物可以包含在任何或所有的不对称原子上的富集或拆分的光学异构体，如根据描述是明显的，以任何浓度的富集度。外消旋和非对映异构体混合物以及单独的光学异构体都可以被分离或合成，以便基本上不含其对映异构体或非对映体配偶体，并且这些都在本发明的范围内。
如本文所用，术语“稳定化合物”和“稳定结构”意在表示足够稳健以便能够从反应混合物中分离至有用的纯度，并配制成有效的治疗剂的化合物。本文仅考虑稳定的化合物。
当叙述基团时，其中该基团可以在结构内以多于一个的取向存在，导致多于一个的分子结构，例如，甲酰胺基C(＝O)NR，应理解该基团可以以任何可能的取向存在，例如X-C(＝O)N(R)-Y或X-N(R)C(＝O)-Y，除非上下文清楚地限制了分子结构中的基团的取向。
经取代的环基团，例如经取代的环烷基、芳基、杂环基和杂芳基也包括环和稠合环系，其中与氢原子的键被与碳原子的键或与如上定义的取代基的键取代。因此，经取代的环烷基、芳基、杂环基和杂芳基也可以被烷基、烯基和炔基取代，或用上面列出的取代基或本领域普通技术人员已知的其它取代基取代。
本文使用的术语“环系”是指包含一个、两个、三个或更多个环的部分，其可以被非环基团或其它环系取代，或被非环基团和其它环系取代，所述部分可是完全饱和的，部分不饱和的，完全不饱和的或芳族的，并且当环系包含多于一个环时，该环可以是稠合的、桥连的或螺环的。
环系可以被如上所述的取代基单取代或独立地多取代。“螺环”是指其中两个环在单个四面体碳原子上稠合的结构类，如本领域中公知的。
对于包含一个或多个取代基的本文所述的任何基团，当然应理解，这些基团不包含在空间上不实用和/或合成上不可行的任何取代或取代模式。此外，该公开主题的化合物包括由这些化合物取代产生的所有立体化学异构体。
当基团(例如烷基、烯基、炔基、环烷基、芳基等)中的碳原子数被指定为范围时，意指表示碳原子数的各个单独的整数。例如，(C1-C4)烷基的叙述表示烷基可以是甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基或叔丁基中的任何一种。应当理解，碳原子数的说明必须是整数。
当指定环中的原子数，例如3-元至9-元环烷基或杂环基时，环烷基环或杂环基环可包括3、4、5、6、7、8或9个原子中的任何一个。环烷基环是碳环；除了能够形成两个或更多个键的碳，例如氮、氧、硫等之外，杂环基环还可以包括任何元素的原子。环中的原子数应理解为必须是整数。
烷基包括具有1至约20个碳原子，通常为1至12个碳原子，或在一些实施方式中为1至8个碳原子的直链和支链碳基团。直链烷基的实例包括具有1至8个碳原子的那些直链烷基，例如甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基。支链烷基的实例包括但不限于异丙基、异丁基、仲丁基、叔丁基、新戊基、异戊基和2，2-二甲基丙基。如本文所用，术语“烷基”包括正烷基、异烷基和非卤代烷基以及其它支链形式的烷基。代表性的经取代的烷基可以被上述任何取代基(例如氨基、羟基、氰基、羧基、硝基、硫、烷氧基和卤素基团)取代一次或多次。示例性的烷基包括但不限于具有1-6个碳原子，1-4个碳原子或1-3个碳原子的直链或支链烃，这里分别称为C1-6烷基、C1-4烷基和C1-3烷基。示例性的烷基包括但不限于甲基、乙基、丙基、异丙基、2-甲基-1-丁基、3-甲基-2-丁基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2，2-二甲基-1-丁基、3，3-二甲基-1-丁基、2-乙基-1-丁基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基等。
环烷基是含有一个或多个碳环的基团，包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。在一些实施方式中，环烷基可以具有3至约8-12个环成员，而在其它实施方式中，环碳原子数为从3个至4个、5个、6个或7个。环烷基还包括多环环烷基，例如但不限于，降冰片基、金刚烷基、莰烯基、异莰烯基、和蒈烯基(carenyl group)、以及稠合环，例如但不限于十氢化萘基等。环烷基还包括被如上定义的直链或支链烷基取代的环。
除了在两个碳原子之间存在至少一个双键之外，烯基包括如上定义的直链和支链和环烷基。因此，烯基具有2个至约20个碳原子，通常2个至12个碳原子，或在一些实施方式中为2个至8个碳原子。实例包括但不限于乙烯基、-CH＝CH(CH3)、-CH＝C(CH3)2、-C(CH3)＝CH2、-C(CH3)＝CH(CH3)、-C(CH2CH2)＝CH2、环己烯基、环戊烯基、环己二烯基、丁二烯基、戊二烯基和己二烯基等。示例性烯基包括但不限于分别具有2-6个或3-4个碳原子的直链或支链基团，本文称为C2-6烯基和C3-4烯基。示例性烯基包括但不限于乙烯基、烯丙基、丁烯基、戊烯基等。
芳基是在环中不含杂原子的环状芳族烃。本领域众所周知的芳族化合物是含有4n+2π电子的多不饱和环系，其中n为整数。因此，芳基包括但不限于苯基、薁基、庚烯基、联苯基、茚基、芴基、菲基、三苯基、芘基、并四苯基(naphthacenyl)、草屈基(chrysenyl)、联苯烯基、蒽基和萘基。在一些实施方式中，芳基在基团的环部分含有约6个至约14个碳。芳基可以是未取代的或取代的，如上所定义。代表性经取代的芳基可以被单取代或取代多于一次，例如但不限于2-取代、3-取代、4-取代、5-取代或6-取代的苯基或2-8取代的萘基，其可以被碳或如上面列出的那些非碳基团取代。
也称为芳基烷基的芳烷基是如上定义的烷基，其中烷基的氢或碳键被如上定义的与芳基的键代替。代表性的芳烷基包括苄基和苯基乙基以及稠合(环烷基芳基)烷基，例如4-乙基-茚满基。芳烯基是如上所定义的烯基，其中烷基的氢或碳键被如上定义的与芳基的键所代替。
杂环基基团或术语“杂环基”包括含有3个或更多个环成员的芳族和非芳族环化合物，其中一个或多个环原子是杂原子，例如但不限于N、O和S。因此，杂环基可以是环杂烷基或杂芳基，或多环，其任何组合。在一些实施方式中，杂环基包括3个至约20个环成员，而其它这样的基团具有3个至约15个环成员。被称为C2-杂环基的杂环基基团可以是具有两个碳原子和三个杂原子的5-环，具有两个碳原子和四个杂原子的6-环等等。同样，C4-杂环基可以是具有一个杂原子的5-环，具有两个杂原子的6-环等等。碳原子数加上杂原子数等于环原子总数。环(例如3-元至10-元杂环基)的大小也可以由环中的原子总数表示，计算碳和非碳环原子两者。杂环基环还可以包括一个或多个双键。杂芳基环是杂环基的实例。术语“杂环基”包括稠环种类，稠环种类包括稠合芳族基团和稠合非芳族基团。例如，二氧杂环己基(dioxolanyl)环和苯并二氧杂环己基环系(亚甲二氧基苯基环系)均为本文含义内的杂环基。该术语还包括多环，例如含有一个或多个杂原子的二环和三环系，例如但不限于奎宁环基(quinuclidyl)。
杂环基可以是未取代的，或可以如上所述被取代。杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、噻吩基、苯并噻吩基、苯并呋喃基、二氢苯并呋喃基、吲哚基、二氢吲哚基、氮杂吲哚基、吲唑啉基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑基吡啶基、thianaphthalenyl、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、喹喔啉基和喹唑啉基。代表性的经取代的杂环基可以是单取代或取代多于一次，例如但不限于哌啶基或喹啉基，它们是2-取代、3-取代、4-取代、5-取代或6-取代的或被诸如上面列出的基团二取代的。
杂芳基是含有5个或更多个环成员的芳族环化合物，环成员中的一个或多个是杂原子，例如但不限于N、O和S；例如，杂芳基环可以具有5个至约8-12个环成员。杂芳基是具有芳香族电子结构的多种杂环基，其是含有4n+2π电子的多不饱和环系，其中n为整数。指定为C2-杂芳基的杂芳基可以为具有两个碳原子和三个杂原子的5-环(即5元环)，具有两个碳原子和四个杂原子的6-环(即，6元环)等等。同样，C4-杂芳基可以是具有一个杂原子的5-环，具有两个杂原子的6-环，等等。碳原子数加上杂原子数的总和等于环原子的总数。杂芳基包括但不限于诸如吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、吡啶基、嘧啶基、噻吩基、苯并噻吩基、苯并呋喃基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑基吡啶基、thianaphthalenyl、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、喹喔啉基和喹唑啉基。杂芳基可以是未取代的，或者可以被如上所述的取代基取代。代表性的经取代的杂芳基可以用例如上列出的那些独立选择的基团取代一次或多次。
芳基和杂芳基的额外的实例包括但不限于苯基，联苯基，茚基，萘基(1-萘基、2-萘基)，N-羟基四唑基，N-羟基三唑基，N-羟基咪唑基，蒽基(1-蒽基、2-蒽基、3-蒽基)，噻吩基(2-噻吩基、3-噻吩基)，呋喃基(2-呋喃基、3-呋喃基)，吲哚基，噁二唑基，异噁唑基，喹唑啉基，芴基，呫吨基(xanthenyl)，异茚满基，二苯甲基，吖啶基，噻唑基，吡咯基(2-吡咯基)，吡唑基(3-吡唑基)，咪唑基(1-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)，三唑基(1，2，3-三唑-1-基、1，2，3-三唑-2-基、1，2，3-三唑-4-基、1，2，4-三唑-3-基)，噁唑基(2-噁唑基、4-噁唑基、5-噁唑基)，噻唑基(2-噻唑基、4-噻唑基、5-噻唑基)，吡啶基(2-吡啶基、3-吡啶基、4-吡啶基)，嘧啶基(2-嘧啶基、4-嘧啶基、5-嘧啶基、6-嘧啶基)，吡嗪基，哒嗪基(3-哒嗪基、4-哒嗪基、5-哒嗪基)，喹啉基(2-喹啉基、3-喹啉基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基、8-喹啉基)，异喹啉基(1-异喹啉基、3-异喹啉基、4-异喹啉基、5-异喹啉基、6-异喹啉基、7-异喹啉基、8-异喹啉基)，苯并[b]呋喃基(2-苯并[b]呋喃基、3-苯并[b]呋喃基、4-苯并[b]呋喃基、5-苯并[b]呋喃基、6-苯并[b]呋喃基、7-苯并[b]呋喃基)，2，3-二氢-苯并[b]呋喃基(2-(2，3-二氢-苯并[b]呋喃基))，3-(2，3-二氢-苯并[b]呋喃基)，4-(2，3-二氢-苯并[b]呋喃基)，5-(2，3-二氢-苯并[b]呋喃基)，6-(2，3-二氢-苯并[b]呋喃基)，7-(2，3-二氢-苯并[b]呋喃基)，苯并[b]噻吩基(2-苯并[b]噻吩基、3-苯并[b]噻吩基、4-苯并[b]噻吩基、5-苯并[b]噻吩基、6-苯并[b]噻吩基、7-苯并[b]噻吩基)，2，3-二氢-苯并[b]噻吩基，(2-(2，3-二氢-苯并[b]噻吩基，3-(2，3-二氢-苯并[b]噻吩基)，4-(2，3-二氢-苯并[b]噻吩基)，5-(2，3-二氢-苯并[b]噻吩基)，6-(2，3-二氢-苯并[b]噻吩基)，7-(2，3-二氢-苯并[b]噻吩基)，吲哚基(1-吲哚基、2-吲哚基、3-吲哚基、4-吲哚基、5-吲哚基、6-吲哚基、7-吲哚基)，吲唑基(1-吲唑基、3-吲唑基、4-吲唑基、5-吲唑基、6-吲唑基、7-吲唑基)，苯并咪唑基(1-苯并咪唑基、2-苯并咪唑基、4-苯并咪唑基、5-苯并咪唑基、6-苯并咪唑基、7-苯并咪唑基、8-苯并咪唑基)，苯并噁唑基(1-苯并噁唑基、2-苯并噁唑基)，苯并噻唑基(1-苯并噻唑基、2-苯并噻唑基、4-苯并噻唑基、5-苯并噻唑基、6-苯并噻唑基、7-苯并噻唑基)，咔唑基(1-咔唑基、2-咔唑基、3-咔唑基、4-咔唑基)，5H-二苯并[b，f]氮杂(5H-二苯并[b，f]吖庚因-1-基、5H-二苯并[b，f]吖庚因-2-基、5H-二苯并[b，f]吖庚因-3-基、5H-二苯并[b，f]吖庚因-4-基、5H-二苯并[b，f]吖庚因-5-基)，10，11-二氢-5H-二苯并[b，f]吖庚因(10，11-二氢-5H-二苯并[b，f]吖庚因-1-基、10，11-二氢-5H-二苯并[b，f]吖庚因-2-基、10，11-二氢-5H-二苯并[b，f]吖庚因-3-基、10，11-二氢-5H-二苯并[b，f]吖庚因-4-基、10，11-二氢-5H-二苯并[b，f]氮杂-5-基)等。
包含氮的任何杂环基或杂芳基可以是N-氧化物或N-甲氧(metho)盐或其它N-季铵化盐；当存在阳离子N-季铵化盐时，可以理解，存在阴离子抗衡离子用于电荷平衡。包含硫的任何杂环基或杂芳基可以是亚砜或砜或S-甲氧盐或其它S-烷基化盐；当存在阳离子S-烷基化盐时，应理解存在阴离子抗衡离子用于电荷平衡。
术语“烷氧基(alkoxy)”或“烷氧基(alkoxyl)”是指与烷基(包括环烷基)连接的氧原子，如上所定义。直链烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、正丁氧基、正戊氧基、正己氧基等。支链烷氧基的实例包括但不限于异丙氧基、仲丁氧基、叔丁氧基、异戊氧基、异己氧基等。示例性的烷氧基包括但不限于具有1-6个或2-6个碳原子的烷氧基，本文分别称为C1-6烷氧基，和C2-6烷氧基。示例性的烷氧基包括但不限于甲氧基、乙氧基、异丙氧基等。
烷氧基可以包括与氧原子键合的1个至约12-20个碳原子，并且还可以包括双键或三键，并且还可以包括杂原子。例如，烯丙氧基是本文含义内的烷氧基。甲氧基乙氧基也是本文含义中的烷氧基，如在结构的两个相邻原子被取代的情况下亚甲二氧基也是本文含义中的烷氧基。
除非另有说明，术语“卤代”或“卤素”或“卤化物”它们自身或作为另一取代基的一部分是指氟、氯、溴或碘原子，优选氟、氯或溴。
“卤代烷基”基团包括单卤代烷基，其中所有卤素原子可以相同或不同的聚卤代烷基，和全卤代烷基，其中所有氢原子被相同或不同的卤素原子(例如氟和/或氯原子)取代。卤代烷基的实例包括三氟甲基、1，1-二氯乙基、1，2-二氯乙基、1，3-二溴-3，3-二氟丙基、全氟丁基等。
本文中使用的术语“酰基”基团是指含有羰基部分的基团，其中基团通过羰基碳原子键合。羰基碳原子也与另一个碳原子键合，该另一个碳原子可以是烷基、芳基、芳烷基环烷基、环烷基烷基、杂环基、杂环基烷基、杂芳基、杂芳基烷基等的一部分。在羰基碳原子键合到氢原子的特殊情况下，该基团是“甲酰基”基团，也是本文所定义的作为术语的酰基基团的实例。酰基可以包括与羰基键合的0至约12-20个额外的碳原子。酰基可以包括本文含义中的双键或三键。丙烯酰基是含双键的酰基的实例。酰基也可以包括本文含义内的杂原子。烟酰基(吡啶基-3-羰基)基团是本文含义内的酰基的实例。其它实例包括乙酰基、苯甲酰基、苯乙酰基、吡啶基乙酰基、肉桂酰基和丙烯酰基等。当含有与羰基碳原子键合的碳原子的基团含有卤素时，该基团被称为“卤代酰基”基团。实例是三氟乙酰基。
术语“胺”包括具有例如式N(基团)3的伯、仲和叔胺，其中每个基团可以独立地为H或非-H，例如烷基、芳基等。胺包括但不限于R-NH2，其中R是碳基部分，例如烷基胺、芳基胺、烷基芳基胺；R2NH，其中每个R独立地选自的碳基部分，例如二烷基胺、二芳基胺、芳烷基胺、杂环基胺等；和R3N，其中每个R独立地选自的碳基部分，例如三烷基胺、二烷基芳基胺、烷基二芳基胺、三芳基胺等。本文所用的术语“胺”还包括带正电荷(阳离子)的形式，例如胺盐和季铵化胺。
“氨基”是-NH2、-NHR、-NR2或-NR3 +形式的取代基，其中每个R是独立选择的碳基基团和各自的质子化形式，除了不能被质子化的-NR3 +以外。因此，任何被氨基取代的化合物都可以视为胺。本文含义中的“氨基”可以是伯、仲、叔或季氨基。“烷基氨基”基团包括单烷基氨基、二烷基氨基和三烷基氨基(三烷基铵)基团。
“铵”离子包括未取代的铵离子NH4 +，但除非另有说明，它还包括胺的任何质子化或季铵化形式。因此，在本文的含义中，三甲基盐酸铵和四甲基氯化铵都是铵离子和胺。
术语“酰胺”(或“酰氨基”)分别包括C-酰胺基和N-酰胺基，即分别为-C(O)NR2和-NRC(O)R基团。因此，酰胺基团包括但不限于伯羧酰胺基团(-C(O)NH2)和甲酰胺基(-NHC(O)H))。“甲酰氨基”基团是式C(O)NR2的基团，其中R可以是H、烷基、芳基等。
使用本领域众所周知的化学基团的标准缩写；例如Me＝甲基、Et＝乙基、i-Pr＝异丙基、Bu＝丁基、t-Bu＝叔丁基、Ph＝苯基、Bn＝苄基、Ac＝乙酰基、Bz＝苯甲酰基等。
本领域众所周知的“盐”包括与平衡离子组合的以离子形式存在的有机化合物，例如羧酸，磺酸或胺。例如，以其阴离子形式存在的酸可以与例如金属阳离子(例如钠、钾等)之类的阳离子；与铵盐(如NH4 +)，或各种胺的阳离子，包括四烷基铵盐(如四甲基铵)，或其它阳离子(如三甲基锍等)形成盐。“药学上可接受的”或“药理学上可接受的”盐是由已经被批准用于人类消耗并通常是无毒的离子形成的盐，例如氯化物盐或钠盐。“两性离子”是例如可以在分子中形成的内盐，该分子具有至少两个可离子化基团，一个形成阴离子，另一个形成阳离子，用于彼此平衡。例如，氨基酸(如甘氨酸)可以两性离子形式存在。“两性离子”是本文含义内的盐。本发明的化合物可以采用盐的形式。术语“盐”包括作为本发明化合物的游离酸或游离碱的加成盐。盐可以是“药学上可接受的盐”。术语“药学上可接受的盐”是指具有毒性特征的在可用于药物应用的范围内的盐。然而药学上不可接受的盐可具有诸如高结晶度之类的性质，其在本发明的实践中具有实用性，例如在本发明化合物的合成、纯化或配制过程中的实用性。
“药学上或药理学上可接受的”包括在适当时施用于动物或人类时不产生不利的，过敏的或其他不良反应的分子实体和组合物。对于人类施用，制剂应满足FDA Office ofBiologics标准要求的无菌性、致热原性和一般安全性以及纯度标准。
合适的药学上可接受的酸加成盐可以由无机酸或有机酸制备。无机酸的实例包括盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。合适的有机酸可以选自脂族、脂环族、芳族、芳脂族、杂环、羧酸和磺酸类的有机酸、其实例包括甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡萄糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸(anthranilic)、4-羟基苯甲酸、苯乙酸、扁桃酸、扑酸(帕莫酸(pamoic))、甲磺酸、乙磺酸、苯磺酸、泛酸、三氟甲磺酸、2-羟基乙磺酸、对甲苯磺酸、对氨基苯磺酸(sulfanilic)、环己基氨基磺酸、硬脂酸、海藻酸、β-羟基丁酸、水杨酸、粘酸(galactaric)和半乳糖醛酸。药学上不可接受的酸加成盐的实例包括例如高氯酸盐和四氟硼酸盐。
如果必须为整数的变量的值(例如烷基中的碳原子数或环上的取代基的数量)被描述为范围，例如0-4，这意味着该值可以是0和4之间的包括0和4的任何整数，即0、1、2、3或4。
在多种实施方式中，例如用于本发明方法的化合物或成组的化合物，可以是上述实施方式的任何组合和/或子组合中的任何一种。
在多种实施方式中，提供了任何实施例中所示的化合物，或示例性化合物之中的化合物。条款可适用于任何公开的类别或实施方式，其中上述公开的其它实施方式或种类中的任何一个或多个可以从这些类别或实施方式中排除。
本文所述的化合物可以基于本文包含的教导和本领域已知的合成方法以多种方式制备。在下面描述的合成方法的描述中，应当理解，可以选择包括溶剂、反应气氛、反应温度、实验的持续时间和后处理程序的所有提出的反应条件作为该反应的条件标准，除非另有说明。有机合成领域的技术人员可以理解，存在于分子各部分上的官能度应与提出的试剂和反应物相容。与反应条件不相容的取代基对于本领域技术人员来说是显而易见的，因此指出了替代方法。这些实施例的起始材料是可商购的或通过标准方法从已知材料容易地制备。所有可商购的化学品均得自Aldrich、Alfa Aesare、Wako、Acros、Fisher、Fluka、Maybridge等，并且在不经进一步纯化的情况下使用，除非另有说明。例如，通过使它们通过活性氧化铝柱获得干溶剂。
本发明还包括本发明的分离的化合物。表述“分离的化合物”是指本发明化合物或本发明化合物的混合物的制剂，其中分离的化合物已经与在一种或多种化合物的合成中使用的试剂分离，和/或与在一种或多种化合物的合成中形成的副产物分离。
“分离”并不意味着制剂在技术上是纯的(均匀的)，而是其纯到足够以可以在治疗上使用的形式复合。优选地，“分离的化合物”是指本发明化合物或本发明化合物的混合物的制剂，其含有占总重量的至少10重量％的量的本发明的命名化合物或化合物的混合物。优选地，制剂含有占总重量的至少50重量％的命名化合物或化合物混合物；更优选占总重量的至少80重量％；最优选为制剂总重量的至少90重量％，至少95重量％或至少98重量％。
本发明的化合物和中间体可以从其反应混合物中分离，并通过标准技术纯化，标准技术如过滤、液-液萃取、固相萃取、蒸馏、重结晶或色谱法，包括快速柱色谱法或HPLC。
互变异构
在本发明中，应当理解的是，式(I)化合物或其盐可能表现出互变异构现象，其中两种化合物能够通过在两个原子之间交换氢原子而易于相互转化，该氢原子与该两个原子中的任何一个形成共价键。由于互变异构化合物彼此之间存在移动平衡，因此它们可被认为是相同化合物的不同异构形式。应当理解，本说明书中的式图可以仅代表可能的互变异构形式之一。然而，还应当理解，本发明包括任何互变异构形式，而不仅限于在式图中使用的任何一种互变异构形式。本说明书中的式图可以仅表示可能的互变异构形式之一，并且应当理解，该说明书包括所描绘的化合物的所有可能的互变异构形式，而不仅仅是在本文中以图形方式方便示出的那些形式。例如，互变异构可以由如波浪线所指示的吡唑基显示。虽然两个取代基都称为4-吡唑基，但是显而易见的是，不同的氮原子在每个结构中都带有氢原子。
这种互变异构体也可以用取代的吡唑(如3-甲基吡唑、5-甲基吡唑或3，5-二甲基吡唑等)发生。互变异构的另一个例子是酰胺亚胺(环状时，内酰胺-内酰胺)互变异构体，例如在与环氮原子相邻处携带环氧原子的杂环化合物中可见。例如，平衡：
是互变异构现象的示例。因此，本文描述的作为一种互变异构体的结构意图也包括另一种互变异构体。
光学异构体
应当理解，当本发明的化合物含有一个或多个手性中心时，化合物可以以单个和基本上纯的对映异构体或非对映异构体形式或外消旋混合物存在，也可以分离为单个和基本上纯的对映异构体或非对映异构体形式或外消旋混合物。因此，本发明包括本发明化合物的任何可能的对映异构体、非对映异构体、外消旋体或其混合物。
本发明的化合物或在本发明的实践方法中使用的化合物可以含有一个或多个手性中心，因此以立体异构体的形式存在。当本文使用时，术语“立体异构体”由所有对映异构体或非对映异构体组成。根据立体碳原子周围的取代基的构型，这些化合物可以用符号“(+)”、“(-)”、“R”或“S”表示，但本领域技术人员应认识到，结构可以隐含地表示手性中心。本发明包括这些化合物的各种立体异构体及其混合物。对映异构体或非对映异构体的混合物在命名中可以称为“(±)”，但技术人员将认识到结构可以隐含地表示手性中心。
本公开的化合物可以含有一个或多个双键，并且因此以由碳-碳双键周围的取代基排列而产生的几何异构体存在。符号表示可以是本文所述的单键、双键或三键的键。碳-碳双键周围的取代基被指定为“Z”或“E”构型，其中根据IUPAC标准使用术语“Z”和“E”。除非另有说明，否则描述双键的结构包括“E”和“Z”异构体两者。碳-碳双键周围的取代基替代地称为“顺式”或“反式”，其中“顺式”表示双键的同一侧上的取代基，“反式”表示双键的相对侧上的取代基。
本发明的化合物或在本发明的实践方法中使用的化合物可以含有碳环或杂环，因此作为由环周围的取代基排列而产生的几何异构体存在。碳环或杂环周围的取代基的排列被指定为“Z”或“E”构型，其中根据IUPAC标准使用术语“Z”和“E”。除非另有说明，描述碳环或杂环的结构包括“Z”和“E”异构体。碳环或杂环周围的取代基也可以称为“顺式”或“反式”，其中术语“顺式”表示环平面同一侧上的取代基，术语“反式”表示环平面的相对侧上的取代基。其中取代基位于环平面的相同侧和相对侧上的化合物的混合物称为“顺式/反式”。
预期化合物的各个对映异构体和非对映异构体可以由包含不对称或立体中心的商售原料合成制备，或通过制备外消旋混合物然后通过本领域普通技术人员熟知的拆分方法来制备。这些拆分方法的实例是(1)将对映异构体的混合物连接到手性助剂上，通过重结晶或色谱分离得到的非对映异构体混合物，并从辅助剂中释放出光学纯的产物，(2)使用光学活性拆分剂形成盐，(3)在手性液相色谱柱上直接分离光学对映异构体的混合物，或(4)使用立体选择性化学或酶试剂的动力学拆分。外消旋混合物也可以通过众所周知的方法(例如手性-相液相色谱法或在手性溶剂中结晶该化合物)拆分成它们的组分对映异构体。立体选择性合成，其中单个反应物在新立体中心的形成期间或在预先存在的立体中心的转化期间形成不等的立体异构体混合物的化学或酶反应是本领域公知的。立体选择性合成包括对映和非对映选择性转化，并且可能涉及使用手性助剂。例如，参见Carreira andKvaerno，Classics in Stereoselective Synthesis，Wiley-VCH：Weinheim，2009。
由手性中心的存在引起的异构体包括成对被称为“对映异构体”的不可重叠的异构体。纯化合物的单个对映异构体是光学活性的，即它们能够使平面偏振光的平面旋转。根据Cahn-Ingold-Prelog系统指定单个对映异构体。取代基的优先级基于原子量排序，如由系统方法确定的，较高的原子量具有较高的优先级排序。一旦确定了四分基团的优先级排序，则分子被定向成使得最低排名基团被指向远离观察者。然后，如果其他基团的下降排序顺时针进行，则分子被指定为具有(R)绝对构型，并且如果其他基团的下降排序逆时针进行，则将该分子指定为具有(S)绝对构型。在下面的方案的例子中，Cahn-Ingold-Prelog排序是A＞B＞C＞D。最低排序的原子，D被定向远离观察者。实线楔形物表示键合的原子从纸张的平面向观察者突出，虚线楔形物指示键合的原子从纸张的平面外的观察者突出离开，即“纸张”由原子A、C和针对如下所示(R)构型的手性碳原子定义。
携带上面显示的A-D原子的碳原子被称为“手性”碳原子，分子中这种碳原子的位置称为“手性中心”。本发明的化合物可以含有多于一个手性中心，并且以相同的方式描述每个手性中心处的构型。
使用实线楔形物和虚线楔形物描述手性结构有各种惯例。例如，对于上述(R)构型，以下两种描述是等效的：
本发明意在包括非对映异构体以及它们的外消旋和拆分的、非对映体和对映体纯的形式及其盐。非对映异构体对可以通过已知的分离技术来拆分，分离技术包括正相和反相色谱法和结晶。
“分离的光学异构体”或“分离的对映异构体”是指已经从相同式的相应光学异构体基本上纯化的化合物。优选地，分离的异构体的对映体纯度为至少约80重量％，更优选为至少90重量％，甚至更优选为至少98重量％，最优选至少约99重量％。“对映体纯度”是指化合物的光学异构体的对映异构体混合物中占优势的对映异构体的百分比。纯的单个对映体的对映体纯度为100％。
分离的光学异构体可以通过公知的手性分离技术从外消旋混合物中纯化。根据一种这样的方法，使用合适的手性柱，例如 家族柱(DaicelChemical Industries，Ltd.，日本东京)系列的成员，通过HPLC将本发明化合物或其手性中间体的外消旋混合物分离成99重量％的纯光学异构体。所述柱按照制造商的说明进行操作。
获得单独且基本上纯的光学异构体的另一种公知的方法是经典拆分，其中含有离子化官能团(如质子化胺或羧酸酯基团)的手性外消旋化合物与相反电离的手性非芳族添加剂形成非对映体盐。然后可以通过标准物理手段(例如差异溶解度)分离得到的非对映异构体盐形式，然后可以通过标准化学方法将手性非芳族添加剂去除或与替代的反离子交换，或者替代地非对映体盐形式可以保留为盐以用作治疗剂或治疗剂的前体。
本发明的一个实施方式的另一方面提供本发明化合物单独或与另一种药物组合的组合物。如本文所述，本发明的化合物包括立体异构体、互变异构体、溶剂合物、前药、药学上可接受的盐及其混合物。含有本发明化合物的组合物可以通过常规技术制备，例如如Remington：The Science and Practice of Pharmacy，19th Ed.，1995或其更新版本中所述，其通过引用并入本文。组合物可以以常规形式出现，例如以胶囊、片剂、气溶胶、溶液、悬浮液或局部应用形式出现。
本发明的化合物可以施用于哺乳动物，特别是需要这种治疗、预防、消除、缓解或改善病情的人。这样的哺乳动物还包括动物，即包括家畜(例如，家庭宠物，农场动物)，也包括非家畜(例如，野生动物)。
本发明的化合物在宽剂量范围内是有效的。例如，在成年人的治疗中，可以每天使用约0.05mg至约5000mg，优选约1mg至约2000mg，更优选约2mg至约2000mg的剂量。典型剂量为每天约10mg至约1000mg。在为患者选择方案时，通常需要以较高的剂量开始，并且当病症受到控制时减少剂量。确切的剂量将取决于化合物的活性、给药方式、所需治疗、给药形式、待治疗对象和待治疗对象的体重，以及负责的医生或兽医的偏好和经验。
通常，本发明的化合物以单位剂量形式分配，每单位剂量包括约0.05mg至约1000mg活性成分以及药学上可接受的载体。
通常，适合于口服、鼻腔、肺部或经皮给药的剂量形式包括约125μg至约1250mg，优选约250μg至约500mg，更优选约2.5mg至约250mg的混合有药学上可接受的载体或稀释剂的化合物。
剂量形式可以每天或每天多于一次(如每天两次或三次)给药。替代地，如果处方医师认为是可取的，则剂量形式可以比每天更低频繁地给药，例如每隔一天或每周一次。
评估
评价本文所公开和要求保护的任何化合物对鞘氨醇-1-磷酸受体的抑制作用的有效性，以及在使用上面描述的方法或科学文献中找到的各种细胞测定法是在普通技术的范围中。因此，普通技术人员可以在不经过不必要的实验的情况下制备和评估任何要求保护的化合物。
任何发现是鞘氨醇-1-磷酸受体的有效抑制剂的化合物同样可以在动物模型和人类临床研究中使用研究者的技能和经验进行测试，以指导剂量和治疗方案的选择。
在多种实施方式中，化合物是下面表1、2或3所示的化合物。这些化合物可以通过本文公开的合成方法与有机合成领域的普通技术人员的知识结合，包括使用适当选择的前体、中间体、试剂和反应机理来制备。
虽然已经针对本领域技术人员充分详细描述和示例了本发明，但是在不脱离权利要求书的精神和范围的情况下，各种替代方案、修改和改进对于本领域技术人员将是显而易见的。
本文中引用的所有专利和出版物通过引用并入本文，只要如同每个单独的出版物被具体和单独地指示为通过引用整体并入。
已经使用的术语和表述被用作描述而不是限制的术语，并且不意图在这些术语和表述的使用中排除所示出和描述的特征或其部分的任何等同物，而是认识到在所要求保护的本发明的范围内各种修改是可能的。因此，应当理解，尽管通过优选实施方式和可选特征具体公开了本发明，但是本领域技术人员可以采用本文公开的构思的修改和变化，并且将这些修改和变化视为在本发明的由所附权利要求限定的范围内。
描述
虽然出版的工具化合物提供了有价值的构思验证，但是作为氨基磷酸酯的鞘脂类似物通常不具有必要的动力学和稳定性以获得最佳的有用性。我们最近的出版物记录了将S1PR1与S1PR3绑定口袋分开的关键方面(7，46)。虽然S1PR1调节剂的系统“免疫抑制”作用理论上将可用于抑制局部环境中的炎症，例如EAE中CNS的炎症或流感感染引起的肺炎(25，47)，S1PR1激动剂可能由于心动过缓(6，7)和其增加肺微血管通透性的潜力(48)(49)而导致脓毒症的风险。因此，用缺乏S1P1亲和力的选择性S1PR3拮抗剂抑制脓毒病中的系统性炎症是合乎期望的。
最近，(Jo等人，2012和其中的参考文献)，我们基于我们发表的非常相似的S1PR1亚型的X射线结构描述了S1PR3的模型(2)。使用定点诱变、配体竞争结合、功能测定和分子模拟的组合，我们证明了内源性泛-S1P受体激动剂，S1P如预期的那样结合到正构位点(orthosteric site)(50)，该新S1PR3选择性激动剂CYM-5541结合到变构位点，因此是变构激动剂，并且S1PR3选择性拮抗剂，SPM-242竞争结合到正构和变构位点两者，这认为是“bitopic”的。SPM-242和CYM-5541的S1PR3选择性被推断来自与S1P受体家族的较不保守的(非-正构的)区域的结合。在我们寻求类似药物的S1PR3拮抗剂时，我们选择使用变构激动剂CYM-5541作为起点。我们假设通过将其他“药物友好型”官能团(-OH、-NR2等)连接到相对较低分子量的CYM-5541支架上，我们应该能够挑选受体上的辅助结合基团(例如与肽骨架或附近侧链(如Asn-95、Ser-99、Gln-281、Glu-115和Arg-114)键合的氢)，得到具有增强的溶解度特征的新的bitopic配位体。
表1：本发明的具体化合物
Boc＝叔丁氧羰基
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实施例
呈现了选择性地改变鞘氨醇-1-磷酸受体(S1P-R)的作用并因此具有治疗心血管和/或肺系统疾病或病症的潜力的化合物。这些疾病/病症包括但不限于：心血管疾病、高血压(包括恶性高血压)、绞痛、心肌梗塞、心律失常、充血性心力衰竭、冠心病、动脉粥样硬化、心绞痛、节律障碍、心肌病(包括高血压心肌病)、心力衰竭、心脏骤停、支气管炎、哮喘、慢性阻塞性肺病、囊性纤维化、哮吼(croup)、肺气肿、胸膜炎、肺纤维化、肺炎、肺栓塞、肺动脉高压、间皮瘤、心室传导异常、完全心脏阻塞、成人呼吸窘迫综合征、脓毒病综合征、特发性肺纤维化、硬皮病、系统性硬化、腹膜后纤维化、预防瘢痕瘤形成、肝硬化。
下面的本发明的化合物已经显示表现出作为一种或多种已知的鞘氨醇-1-磷酸受体的拮抗剂/激动剂的活性，其具有IC50/EC50值低于10微摩尔。下面的表2和3给出了代表性的例子。
表2
表3：
Boc＝叔丁氧羰基
Ph＝苯基
Rac＝外消旋体；所示的所有的化合物包括所有立体异构体，除非另有说明。
异构体1，异构体2；表明结构的分离异构体，但没有绝对的构型。
总体合成方案：
试剂和条件：i)I(1.2当量)，II(1当量)，Ti(OEt)4，70℃，30分钟；ii)III(1当量)，IV(3当量)，-78℃，2小时；iii)HCl(2当量)，MeOH，室温，30分钟；iv)VI(1当量)，羧酸衍生物(1.2当量)，EDCI(1.2当量)，HOBt(1.2当量)，DIPEA(1.2当量)，CH2Cl2，室温，2小时。
将密封管中的I、II和Ti(OEt)4的混合物在70℃下加热30分钟。将混合物溶于EtOAc中并用盐水洗涤。将有机相用无水Na2SO4干燥并减压浓缩。产物III不经进一步纯化使用。在-78℃向III在THF的溶液中缓慢加入芳基溴化镁IV，将反应物搅拌2小时。混合物用饱和氯化铵溶液淬灭，产物用EtOAc萃取。将有机相用无水Na2SO4干燥并真空浓缩，然后通过使用己烷/EtOAc的柱色谱法(CC)纯化产物V。向V在MeOH中的溶液中加入4M HCl的二噁烷溶液，将反应物在室温(rt)下搅拌30分钟。将混合物减压浓缩，产物VI不经进一步纯化即可使用。将VI、适当的羧酸、EDCI、HOBt和DIPEA在二氯甲烷中的溶液在室温下搅拌2小时。将混合物减压浓缩，产物VII通过HPLC纯化。
试剂和条件：i)VI(1当量)，VIII(1.1当量)或X(1.1当量)，DIPEA(2当量)，EtOH，MW，130℃，30分钟。
将合适的芳基氯(VIII或X)、VI和DIPEA在EtOH中的混合物在130℃下用微波照射加热30分钟，得到通过HPLC纯化的相应产物(IX或XI)。
试剂和条件：i)XII(1当量)，XIII(1当量)，HCO2H(Cat.)，EtOH，60℃，过夜；ii)XIV(1当量)，XV(1当量)，THF，0℃至室温下，搅拌过夜
将XII、XIII和催化量的甲酸在EtOH中的混合物在60℃下加热过夜。将粗产物浓缩并通过使用己烷/EtOAc的CC纯化。在0℃向XIV在THF溶液中滴加XV在Et2O中的溶液；将反应混合物在室温下搅拌过夜。混合物用饱和氯化铵溶液淬灭，产物用EtOAc萃取。将有机相用无水Na2SO4干燥并减压浓缩。通过使用己烷/EtOAc的CC或HPLC纯化产物XVI。
试剂和条件：i)XVII(1当量)，XVIII(1.2当量)，EDCI(1.2当量)，HOBt(1.2当量)，二噁烷，MW，110℃，30分钟；ii)XIX(1当量)，TFA(20当量)，CH2Cl2，室温，20分钟；iii)羧酸衍生物(1.2当量)，EDCI(1.2当量)，HOBt(1.2当量)，DIPEA(1.2当量)，CH2Cl2，室温，2小时。
在微波小瓶中，在室温下用HOBt和EDCI处理搅拌的XVII在二噁烷中的溶液。将反应物搅拌10分钟，然后加入XVIII。将反应物在室温下再搅拌30分钟，然后在微波照射下加热至110℃持续30分钟。向反应液中加入盐水，并用EtOAc(3×)萃取产物。将有机相用无水Na2SO4干燥并减压浓缩。通过使用己烷/EtOAc的CC纯化产物XIX。将XIX在二氯甲烷中的溶液用TFA在室温下搅拌20分钟。将混合物减压浓缩，产物不经进一步纯化使用。将TFA盐、适当的羧酸、EDCI、HOBt和DIPEA在二氯甲烷中的溶液在室温下搅拌2小时。将混合物减压浓缩，产物XX通过HPLC纯化。

Claims (27)

1.一种具有式(I)的化合物
其中Ar1、Ar2和Ar3各自独立地选自(C6-C10)芳基环系或(5-元至10-元)杂芳基环系，其中Ar1、Ar2或Ar3中的任何芳基环系或杂芳基环系任选地与环烷基或杂环基环稠合；
其中Ar1、Ar2或Ar3中的任何芳基或杂芳基各自任选独立地被至多三个取代基单取代或多取代，所述取代基选自(C1-C4)烷基、(C2-C4)烯基、卤素、卤代(C1-C4)烷基、OH、单羟基(C1-C4)烷基、二羟基(C2-C4)烷基、单羟基(C1-C4)烷氧基、二羟基(C2-C4)烷氧基、(C1-C4)烷氧基、(C2-C6)酰基、(C1-C6)烷氧羰基(CH2)0-2、羧基(CH2)0-2、氧代、氰基、NR2(CH2)0-2、NR2C(＝O)(CH2)0-2、NR2C(＝O)(CH2)0-2O(CH2)0-2、(C1-C4)C(＝O)N(R)、(C1-C4)OC(＝O)N(R)、C＝NOR、(C3-C10)环烷基、(5-元至10-元)杂环基、(C6-C10)芳基、和(5-元至10-元)杂芳基；其中Ar1、Ar2或Ar3中的任何环烷基、杂环基、芳基或杂芳基取代基本身任选被至多三个第二取代基取代，所述第二取代基选自(C1-C4)烷基、(C2-C4)烯基、卤素、卤代(C1-C4)烷基、OH、单羟基(C1-C4)烷基、二羟基(C2-C4)烷基、单羟基(C1-C4)烷氧基、二羟基(C2-C4)烷氧基、(C1-C4)烷氧基、(C2-C6)酰基、(C1-C6)烷氧基羰基(CH2)0-2、羧基(CH2)0-2、氧代、氰基、NR2(CH2)0-2、NR2C(＝O)(CH2)0-2、NR2C(＝O)(CH2)0-2O(CH2)0-2、(C1-C4)C(＝O)N(R)、(C1-C4)OC(＝O)N(R)以及C＝NOR；
每个R独立地为H、(C1-C4)烷基、羟基(C2-C4)烷基、氰基或((C1-C4)烷基-O)1-2(C1-C4)烷基，或两个R基团连同它们都连接的原子一起能形成环；
每个R'独立地为H、(C1-C4)烷基、羟基(C2-C4)烷基、(CH2)0-2C(＝O)O(C1-C4)烷基或(C3-C6)环烷基；
X是键、(CH2)1-2、(CH2)0-2N(R)(CH2)0-2、(CH2)0-2O(CH2)0-2、(CH2)0-2N(R)C(＝O)(CH2)0-2、(CH2)0-2C(＝O)N(R)(CH2)0-2、(CH2)0-2N(R)C(＝O)O(CH2)0-2或(CH2)0-2OC(＝O)N(R)(CH2)0-2；
L是键、NR、C(＝O)、SO2、C(＝NR)、C(＝O)CR2、C(＝O)CH(N(R)C(＝O)(C1-C4)烷基、C(＝O)CH(N(R)C(＝O)O(C1-C4)烷基、C(＝O)CH(NR2)、C(＝O)CR(卤素)或是
或其中波浪线表示键合点，
或其药学上可接受的盐。
2.一种具有式(IA)的根据权利要求1所述的化合物，
其中Ar1、Ar2和Ar3各自是独立选择的芳基；X、L、R和R'如权利要求1所定义。
3.根据权利要求2所述的化合物，其中X是NR且L是键或C(＝O)。
4.根据权利要求2所述的化合物，其中Ar1、Ar2和Ar3各自为苯基。
5.一种具有式(IB)的根据权利要求1所述的化合物，
其中Ar1和Ar 2是独立选择的芳基，Ar3是杂芳基；X、L、R和R'如权利要求1所定义。
6.根据权利要求5所述的化合物，其中X是NR，L是键或是C(＝O)。
7.根据权利要求5所述的化合物，其中Ar3是吡啶基或喹啉基。
8.根据权利要求5所述的化合物，其中Ar1和Ar3是苯基。
9.一种具有式(IC)的根据权利要求1所述的化合物，
其中Ar1为芳基，Ar2和Ar3为独立选择的杂芳基；X、L、R和R'如权利要求1所定义。
10.根据权利要求9所述的化合物，其中X是NR，L是键或C(＝O)。
11.根据权利要求9所述的化合物，其中Ar1是苯基，Ar2是吡啶基或喹啉基，Ar3是吡啶基或喹啉基，或其任何组合。
12.一种具有式(ID)的根据权利要求1所述的化合物
其中Ar1和Ar3是独立选择的芳基，Ar2是杂芳基；X、L、R和R'如权利要求1所定义。
13.根据权利要求12所述的化合物，其中X是NR，L是键或是C(＝O)。
14.根据权利要求12所述的化合物，其中Ar1和Ar3是苯基，Ar2是吡啶基或喹啉基，或其任何组合。
15.一种具有式(IE)的根据权利要求1所述的化合物，
其中Ar1和Ar3是独立选择的杂芳基，Ar2是芳基；X、L、R和R'如权利要求1所定义。
16.根据权利要求15所述的化合物，其中X是NR，L是键或是C(＝O)。
17.根据权利要求15所述的化合物，其中Ar2是苯基，Ar1是吡啶基或喹啉基，Ar3是吡啶基或喹啉基，或其任何组合。
18.一种药物组合物，其包含权利要求1所述的化合物和药学上可接受的赋形剂。
19.一种治疗患有心肺疾病的患者的心肺疾病的方法，其包括施用有效量的权利要求1所述的化合物。
20.一种治疗患有心肺疾病的患者的心肺疾病的方法，其包括向所述患者施用有效量的来自表1的化合物。
21.一种治疗患有心肺疾病的患者的心肺疾病的方法，其包括向所述患者施用有效量的来自表2或3的化合物。
22.根据权利要求19所述的方法，其中所述疾病是哮喘或慢性阻塞性肺病。
23.根据权利要求19所述的方法，其中所述疾病包括脓毒病。
24.根据权利要求19所述的方法，其中所述疾病是冠状动脉粥样硬化。
25.根据权利要求19所述的方法，其中所述疾病包括以支气管收缩、肺纤维化、冠状动脉收缩、树突状细胞的细胞因子扩增或弥散性血管内凝血病的产生为特征的临床综合征。
26.根据权利要求19所述的方法，其中所述疾病包括流感感染的炎症。
27.根据权利要求19所述的方法，其中所述疾病是心血管疾病、高血压(包括恶性高血压)、绞痛、心肌梗塞、心律失常、充血性心力衰竭、冠心病、动脉粥样硬化、心绞痛、节律障碍、心肌病(包括高血压心肌病)、心力衰竭、心脏骤停、支气管炎、哮喘、慢性阻塞性肺病、囊性纤维化、哮吼、肺气肿、胸膜炎、肺纤维化、肺炎、肺栓塞、肺动脉高压、间皮瘤、心室传导异常、完全心脏阻塞、成人呼吸窘迫综合征、脓毒病综合征、特发性肺纤维化、硬皮病、系统性硬化、腹膜后纤维化、预防瘢痕瘤形成或肝硬化。
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