CN105473576B - 针对心脏病症的嘧啶二酮化合物 - Google Patents
针对心脏病症的嘧啶二酮化合物 Download PDFInfo
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- CN105473576B CN105473576B CN201480046057.3A CN201480046057A CN105473576B CN 105473576 B CN105473576 B CN 105473576B CN 201480046057 A CN201480046057 A CN 201480046057A CN 105473576 B CN105473576 B CN 105473576B
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- compound
- amino
- diketone
- pyrimidine
- phenyl
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- -1 hybar X compound Chemical class 0.000 title claims abstract description 78
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- 238000011282 treatment Methods 0.000 claims abstract description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 67
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 62
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 45
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- 229940079593 drug Drugs 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
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Classifications
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- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Abstract
本申请提供新的嘧啶二酮化合物及其药用盐,其可用于治疗肥厚性心肌病(HCM)和与左心室肥大或舒张期功能障碍相关的病症。本申请描述了所述化合物及其药用盐的合成和表征及治疗HCM和其它形式的心脏病的方法。
Description
对相关申请的交叉引用
本申请根据35U.S.C.§119(e)要求于2013年6月21日提交的美国临时申请61/838,088、于2014年2月13日提交的美国临时申请61/939,655及于2014年4月18日提交的美国临时申请61/981,366的权益,将其各自的全部内容通过引用的方式并入本申请。
关于在联邦资助的研究或开发下作出的发明的权利的声明
不适用
背景技术
遗传性(可遗传的)肥厚性心肌病(HCM)包括一组高外显度(highly penetrant)、单基因性、常染色体显性心肌病。HCM由任一种促成心肌功能单位即肌节的结构蛋白基因中的超过1,000个已知的点突变中的一个或多个引起。发现在一般人群中每500个个体中约1个具有无法由其它已知原因(例如高血压或心瓣膜病)解释的左心室肥大,且一旦排除了其它遗传性(例如溶酶体贮存病)、代谢性或侵润性原因,这些个体中的许多可显示具有HCM。
引起HCM的肌节基因突变是高外显度的,但是在临床严重性和临床过程中存在广泛的变化。一些基因型与较恶性的过程相关,但是在携带相同突变的家族之间甚至在携带相同突变的家族中存在显著的变化。还已经注意到性别差异,其中男性患者与女性患者相比通常受到较严重的影响。尽管许多HCM患者在很长的时间段内仅报告很少的症状或没有症状,但是HCM是一种发病负荷显著累积的进行性疾病。体力不支的症状占主导且可由于运动和其它使心率提高和/或使前负荷降低的活动而加重。对于多种其它病症,症状倾向于随年龄而恶化。目前对于HCM患者来说最普遍的临床负荷为劳累性呼吸困难,其限制了他们的日常生活活动且可使他们变得虚弱。
HCM患者经常在不存在有记载的血液动力学异常如左心室流出道梗阻(带有或不带有二尖瓣返流)的情况下出现症状。患者的劳累性呼吸困难症状可随心房纤颤的发作而快速恶化,而心房纤颤是HCM的一种常见并发症,其可促成使包括中风在内的全身动脉血栓栓塞性疾病的风险得以增加的急性肺水肿。与HCM相关的其它不良事件包括对血容量不足或血容量过多的不耐受及晕厥。与不患有HCM的患者相比,伴发性冠状动脉疾病可引起急性冠状动脉综合征的较高风险。HCM患者中的心脏性猝死(SCD)是不常见的且是难以预测的,但是在年轻成人中是非创伤性死亡的主要原因。ICD植入对于SCD的存活者来说是标准措施且在其他HCM患者风险分析中用于鉴定ICD植入作为一级预防被认为是谨慎的那些患者,尽管这是不精确的。
针对HCM的医学疗法限于对症状进行治疗且不能解决疾病的根本内在原因—破坏正常的肌节功能。目前可用的疗法在缓解症状中的有效性是不定的,但是通常随疾病持续时间的增加而显示出效力的降低。因此,根据经验用β-阻断剂、非二氢吡啶钙通道阻断剂和/或丙吡胺对患者进行治疗。这些药物都没有被标示用于治疗HCM,且基本上没有严格的临床试验证据可用于指导它们的使用。与该不利的情况一起出现的是以下事实:多年来尚未鉴定出针对HCM的新医学疗法。对于具有在血液动力学上显著的流出道梗阻的患者(静息梯度>30mmHg)来说,在适当选择的患者中通常需要外科肌切除术或酒精室间隔消融术以缓解血液动力学梗阻。本申请所提供的新治疗药物和方法解决了对HCM和相关心脏病症的改善治疗的长久需求。
发明内容
在一个方面,本申请提供具有下式的化合物:
或其药用盐。在一些实施方案中,在上式中,R1为选自以下的成员:C1-C8烷基、C3-C8环烷基、C3-C8环烷基-C1-C4烷基、4至7元杂环烷基、苯基、苯基-C1-C4烷基、5至6元杂芳基和5至6元杂芳基-C1-C4烷基,其中每个R1任选取代有1-3个Ra;R2为选自以下的成员:苯基、苯基-C1-C4烷基、5至6元杂芳基和5至6元杂芳基-C1-C4烷基,其中每个R2任选取代有1-5个Rb;R3为选自以下的成员:C1-C4烷基、C3-C4环烷基和4至7元杂环烷基,其中每个R3任选取代有1-3个Rc;R4为H;X为选自以下的成员:H和卤素,且在一些实施方案中,X选自H和F。每个Ra当存在时独立选自卤素、CN、羟基、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、苯基、苯基-C1-C4烷基、苯基-C1-C4烷氧基、苯氧基、-CORa1、-CO2Ra1、-SO2Ra1、-SO2NRa1Ra2和-CONRa1Ra2,其中Ra1和Ra2各自独立选自H、C1-C4烷基和苯基,或任选地,Ra1和Ra2当与氮原子连接时组合形成4至6元环。类似地,每个Rb当存在时独立选自卤素、CN、羟基、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、苯氧基、苯基-C1-C4烷氧基、亚甲二氧基、二氟亚甲二氧基、-CORb1、-CO2Rb1、-SO2Rb1、-SO2NRb1Rb2、CONRb1Rb2、NRb1Rb2、5至6元杂芳基和任选取代有氧代的5至6元杂环基,其中Rb1和Rb2各自独立选自H和C1-C4烷基,或任选地,Rb1和Rb2当与氮原子连接时组合形成4至6元环;且每个Rc当存在时独立选自卤素、羟基和C1-C2烷氧基。
在另一个方面,本申请提供药物组合物,其含有本申请所述化合物或药用盐及药用赋形剂。
在另一个方面,本申请提供对肥厚性心肌病(HCM)或具有与HCM相关的一个或多个病理生理学特征的心脏疾病进行治疗的方法。该方法包括对有此需要的受试者给予有效量的本申请所述化合物或药用盐。
附图说明
图1显示了用于合成本申请所述化合物或药用盐的方案途径(图1A)及用于制备手性胺的途径(图1B)。
具体实施方案
I.概述
已经发现一系列嘧啶二酮化合物及其药用盐可如下在高收缩状态中降低过度收缩性和/或在具有舒张期功能障碍的心脏中促进心脏松弛:在ATP水解后但在与肌动蛋白丝稳固结合且释放磷酸部分前稳定β-心肌肌球蛋白的构象,由此减小可参与肌肉收缩周期的“动力冲程”部分的肌球蛋白分子的比例。因此,所述化合物可在HCM患者中改善心脏弹性、降低动态和/或静态左心室流出梗阻、改善舒张期左心室松弛、降低左心室舒张(充盈)压、降低功能性二尖瓣返流和/或降低左心房和肺毛细血管楔压,这有助于克服令人虚弱的劳累性呼吸困难和/或与经常伴随所述疾病的左心室流出梗阻相关的症状(昏厥或晕厥)。所述化合物还可用于治疗其它心脏病症。
II.定义
本申请使用的术语“烷基”是指直链或支链的饱和的脂族基团,其具有指定数目的碳原子。烷基可包含任何数目的碳,诸如C1-2、C1-3、C1-4、C1-5、C1-6、C1-7、C1-8、C2-3、C2-4、C2-5、C2-6、C3-4、C3-5、C3-6、C4-5、C4-6和C5-6。例如,C1-6烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基等。烷基可指具有至多20个碳原子的烷基,诸如但不限于庚基、辛基、壬基、癸基等。除非另有说明,烷基是未取代的。“取代的烷基”可取代有一个或多个选自以下的部分:卤素、羟基、氨基、烷基氨基、硝基、氰基和烷氧基。
本申请使用的术语“环烷基”是指饱和或部分不饱和的单环、稠合二环或桥接多环结构,其含有3至12个环原子或指定数目的原子。环烷基可包含任何数目的碳,诸如C3-6、C4-6、C5-6、C3-8、C4-8、C5-8和C6-8。饱和的单环环烷基环包括例如环丙基、环丁基、环戊基、环己基和环辛基。饱和的二环和多环环烷基环包括例如降冰片烷、[2.2.2]二环辛烷、十氢萘和金刚烷。环烷基还可以是部分不饱和的,其在环中具有一个或多个双键。部分不饱和的代表性环烷基包括但不限于环丁烯、环戊烯、环己烯、环己而烯(1,3-和1,4-异构体)、环庚烯、环庚二烯、环辛烯、环辛二烯(1,3-、1,4-和1,5-异构体)、降冰片烯和降冰片二烯。除非另有说明,环烷基是未取代的。“取代的环烷基”可取代有一个或多个选自以下的部分:卤素、羟基、氨基、烷基氨基、硝基、氰基和烷氧基。
本申请使用的术语“杂环烷基”是指具有3至12个环成员且具有1至4个选自N、O和S的杂原子的饱和环系。包括但不限于B、Al、Si和P的其它杂原子也可存在于杂环烷基中。杂原子可被氧化以形成诸如但不限于-S(O)-和-S(O)2-的部分。杂环烷基可包含任何数目的环原子,诸如3至6个、4至6个、5至6个或4至7个环成员。任何适当数目的杂原子可包含在杂环烷基中,诸如1、2、3或4个或1至2个、1至3个、1至4个、2至3个、2至4个或3至4个。杂环烷基的实例包括但不限于氮杂环丙烷、氮杂环丁烷、吡咯烷、哌啶、氮杂环庚烷、氮杂环辛烷、奎宁环、吡唑烷、咪唑烷、哌嗪(1,2-、1,3-和1,4-异构体)、氧杂环丙烷、氧杂环丁烷、四氢呋喃、氧杂环己烷(四氢吡喃)、氧杂环庚烷、硫杂环丙烷、硫杂环丁烷、硫杂环戊烷(四氢噻吩)、硫杂环己烷(四氢噻喃)、噁唑烷、异噁唑烷、噻唑烷、异噻唑烷、二氧杂环戊烷、二硫杂环戊烷、吗啉、硫吗啉、二氧杂环己烷或二硫杂环己烷。杂环烷基是未取代的,但是在一些实施方案中可被描述为取代的。“取代的杂环烷基”可取代有一个或多个选自以下的部分:卤素、羟基、氨基、烷基氨基、硝基、氰基和烷氧基。
本申请使用的术语“杂芳基”是指单环或稠合二环或稠合三环的芳族环结构,其含有5至16个环原子,其中所述环原子中的1至5个为杂原子,诸如N、O或S。包括但不限于B、Al、Si和P的其它杂原子也可存在于杂芳基中。杂原子可被氧化以形成诸如但不限于-S(O)-和-S(O)2-的部分。杂芳基可包含任何数目的环原子,诸如5至6个、5至8个、6至8个、5至9个、5至10个、5至11个或5至12个环成员。任何适当数目的杂原子可包含在杂芳基中,诸如1、2、3、4或5个或1至2个、1至3个、1至4个、1至5个、2至3个、2至4个、2至5个、3至4个或3至5个。杂芳基可具有5至8个环成员及1至4个杂原子或具有5至8个环成员及1至3个杂原子或具有5至6个环成员及1至4个杂原子或具有5至6个环成员及1至3个杂原子。杂芳基的实例包括但不限于吡咯、吡啶、咪唑、吡唑、***、四唑、吡嗪、嘧啶、哒嗪、三嗪(1,2,3-、1,2,4-和1,3,5-异构体)、噻吩、呋喃、噻唑、异噻唑、噁唑和异噁唑。杂芳基是未取代的,但是在一些实施方案中可被描述为取代的。“取代的杂芳基”可取代有一个或多个选自以下的部分:卤素、羟基、氨基、烷基氨基、硝基、氰基和烷氧基。
本申请使用的术语“烷氧基”是指以下烷基,其具有将所述烷基连接至连接点的氧原子:即烷基-O-。对于烷基部分,烷氧基可具有任何适当数目的碳原子,诸如C1-6或C1-4。烷氧基包括例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、2-丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基等。烷氧基是未取代的,但是在一些实施方案中可被描述为取代的。“取代的烷氧基”可取代有一个或多个选自以下的部分:卤素、羟基、氨基、烷基氨基、硝基、氰基和烷氧基。
本申请使用的术语“卤代”和“卤素”是指氟、氯、溴和碘。
本申请使用的术语“药用”是指与本申请所述化合物或盐相容及与任何配制所述化合物时使用的其它成分相容的物质。另外,药用物质对于该物质的接受者来说是无毒的。
本申请使用的术语“盐”是指本申请所述化合物的酸盐或碱盐。药用盐可例如由无机酸(盐酸、氢溴酸、磷酸等)、有机酸(乙酸、丙酸、谷氨酸、枸橼酸等)和季铵离子获得。应当理解的是,药用盐是无毒的。关于合适药用盐的其它信息可参见Remington’sPharmaceutical Sciences,17th ed.,Mack Publishing Company,Easton,Pa.,1985,将其通过引用的方式并入本申请。化合物的中性形式可通过使盐与碱或酸接触并以常规方式分离母体化合物而重新获得。
本申请使用的术语“药物组合物”是指包含特定量的本申请所述化合物或药用盐、本申请定义的赋形剂及其它任选成分的产品,及由特定量的特定成分的组合直接或间接获得的任何产品。
本申请使用的术语“赋形剂”是指有助于向受试者给予活性药物的物质。药物赋形剂包括但不限于粘合剂、填充剂、崩解剂、润滑剂、包衣剂、甜味剂、矫味剂和着色剂。本领域技术人员应当认识到其它赋形剂可为有用的。
本申请使用的术语“治疗”是指成功治疗或改善与肥厚性心肌病相关的病理、损伤、病症或症状的任何指标,包括任何客观或主观参数,诸如减轻;缓和;减少症状;使得所述病理、损伤、病症或症状对于患者而言更易于耐受;降低所述病理、损伤、病症或症状的频率或持续时间;或在一些情况下,防止所述病理、损伤、病症或症状的发作。治疗或改善可基于任何客观或主观参数;包括例如体格检查的结果。
III.化合物及其药用盐
在一个方面,本申请提供具有下式的化合物:
或其药用盐。
在上式中,R1为选自以下的成员:C1-C8烷基、C3-C8环烷基、C3-C8环烷基-C1-C4烷基、4至7元杂环烷基、苯基、苯基-C1-C4烷基、5至6元杂芳基和5至6元杂芳基-C1-C4烷基,其中每个R1任选取代有1-3个Ra;R2为选自以下的成员:苯基、苯基-C1-C4烷基、5至6元杂芳基和5至6元杂芳基-C1-C4烷基,其中每个R2任选取代有1-5个Rb;R3为选自以下的成员:C1-C4烷基、C3-C4环烷基和4至7元杂环烷基,其中每个R3任选取代有1-3个Rc;R4为H;X为选自以下的成员:H和卤素,且在所选实施方案中选自H和F。每个Ra当存在时独立选自卤素、CN、羟基、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、苯基、苯基-C1-C4烷基、苯基-C1-C4烷氧基、苯氧基、-CORa1、-CO2Ra1、-SO2Ra1、-SO2NRa1Ra2和-CONRa1Ra2,其中Ra1和Ra2各自独立选自H、C1-C4烷基和苯基,或任选地,Ra1和Ra2当与氮原子连接时组合形成4至6元环。类似地,每个Rb当存在时独立选自卤素、CN、羟基、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、苯氧基、苯基-C1-C4烷氧基、亚甲二氧基、二氟亚甲二氧基、-CORb1、-CO2Rb1、-SO2Rb1、-SO2NRb1Rb2、CONRb1Rb2、NRb1Rb2、5至6元杂芳基和任选取代有氧代的5至6元杂环基,其中Rb1和Rb2各自独立选自H和C1-C4烷基,或任选地,Rb1和Rb2当与氮原子连接时组合形成4至6元环;且每个Rc当存在时独立选自卤素、羟基和C1-C2烷氧基。
在一些实施方案中,R1选自C1-C8烷基、C3-C8环烷基、4至7元杂环烷基、苯基或5至6元杂芳基,其中每个R1任选取代有1-3个Ra。R2为苯基,其任选取代有1-5个Rb。R3选自C1-C4烷基、C3-C4环烷基或4至7元杂环烷基,其中每个R3任选取代有1-2个Rc。R4为H,且X为H或F。在一些实施方案中,每个Ra当存在时独立地为卤素、CN、C1-C4烷基、C1-C4烷氧基、-CORa1、-CO2Ra1、-SO2Ra1、-SO2NRa1Ra2或-CONRa1Ra2,其中Ra1和Ra2各自独立地为H或C1-C4烷基。可选择地,Ra1和Ra2当与氮原子连接时任选组合形成4至6元环。每个Rb当存在时独立地为卤素、CN、C1-C4烷基、C1-C4烷氧基、-CORb1、-CO2Rb1、-SO2Rb1、-SO2NRb1Rb2、CONRb1Rb2、NRb1Rb2、5至6元杂芳基或任选取代有氧代的5至6元杂环基,其中Rb1和Rb2各自独立地为H或C1-C4烷基。可选择地,Rb1和Rb2当与氮原子连接时任选组合形成4至6元环。每个Rc当存在时独立地为卤素或C1-C2烷氧基。
在一些实施方案中,X为H。
在一些实施方案中,R1为C3-C4烷基、C3-C5环烷基或4至6元杂环烷基,其中每个R1任选取代有1-2个Ra。
在一些实施方案中,R1为苯基或5至6元杂芳基,其中每个R1任选取代有1-3个Ra。
在一些实施方案中,R1为C3-C4烷基、C3-C5环烷基或4至6元杂环烷基。
在一些实施方案中,R1为4至6元杂环烷基,其任选取代有1-2个选自以下的Ra:C1-C4烷基、C1-C4烷氧基、-CORa1、-CO2Ra1、-SO2Ra1、-SO2NRa1Ra2和-CONRa1Ra2,其中Ra1和Ra2各自独立地为H或C1-C4烷基。
在一些实施方案中,R1为环丁基、异丙基、异丁基、1-甲氧基丙-2-基、环戊基、环己基、4-四氢吡喃基、1-(甲基磺酰基)哌啶-4-基、1-(甲氧基羰基)哌啶-4-基、4,4-二氟环己基、苯基、吡啶-2-基、吡啶-3-基、异噁唑-3-基、异噁唑-5-基或1-甲基吡唑-3-基。
在一些实施方案中,R2任选取代有1-2个Rb。
在一些实施方案中,R2为苯基、3-甲基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2,5-二氟苯基、3,5-二氟苯基、3-氯苯基、3-甲氧基苯基、3-(3-噁唑烷-2-酮基)苯基、3-(2-甲基咪唑-1-基)苯基、3-(1-吡唑基)苯基或3-(1,2,4-***-1-基)苯基。
在一些实施方案中,R3为C1-C4烷基、C1-C4烷氧基烷基或C3-C4环烷基。
在一些实施方案中,R3为甲基、乙基、丙基、环丙基、环丁基或2-甲氧基甲基。
在一些实施方案中,R3为甲基。
本申请所述化合物或药用盐可具有如上所述的R1、R2、R3、R4、Ra、Ra1、Ra2、Rb、Rb1、Rb2、Rc和X基团的任何组合。针对R2所述的所选实施方案例如可与针对R1所述的任一所选实施方案组合,后者继而可与针对R3所述的任一所选实施方案组合。
在一些实施方案中,例如,R1为C3-C8烷基;R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基。在其它实施方案中,R1为4至7元杂环烷基或5至6元杂芳基,其任选取代有C1-C4烷基、-CO2Ra1、-SO2NRa1Ra2或-SO2Ra1;R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基。在其它实施方案中,R1为C3-C8环烷基或苯基,R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基。
在其它实施方案中,R1为C3-C8烷基;R3为C1-C4烷基;且R2为苯基。在其它实施方案中,R1为4至7元杂环烷基或5至6元杂芳基,其任选取代有C1-C4烷基、-CO2Ra1或-SO2Ra1;R3为C1-C4烷基;且R2为苯基。在其它实施方案中,R1为C3-C8环烷基或苯基;R3为C1-C4烷基;且R2为苯基。
在一些实施方案中,R1为C3-C8烷基;R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基,其取代有1-2个C1-C4烷氧基或卤素。在其它实施方案中,R1为4至7元杂环烷基或5至6元杂芳基,其任选取代有C1-C4烷基、-CO2Ra1或-SO2Ra1;R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基,其取代有1-2个C1-C4烷氧基或卤素。在其它实施方案中,R1为C3-C8环烷基或苯基;R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基,其取代有1-2个C1-C4烷氧基或卤素。
在一些实施方案中,R1为C3-C8烷基;R3为C1-C4烷基;且R2为苯基,其取代有1-2个C1-C4烷氧基或卤素。在其它实施方案中,R1为4至7元杂环烷基或5至6元杂芳基,其任选取代有C1-C4烷基、-CO2Ra1或-SO2Ra1;R3为C1-C4烷基;且R2为苯基,其取代有1-2个C1-C4烷氧基或卤素。在其它实施方案中,R1为C3-C8环烷基或苯基;R3为C1-C4烷基;且R2为苯基,其取代有1-2个C1-C4烷氧基或卤素。
在一些实施方案中,R1为C3-C8烷基;R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基,其取代有5至6元杂芳基或任选取代有氧代的5至6元杂环基。在其它实施方案中,R1为4至7元杂环烷基或5至6元杂芳基,其任选取代有C1-C4烷基、-CO2Ra1或-SO2Ra1;R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基,其取代有5至6元杂芳基或任选取代有氧代的5至6元杂环基。在其它实施方案中,R1为C3-C8环烷基或苯基,R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基,其取代有5至6元杂芳基或任选取代有氧代的5至6元杂环基。
在一些实施方案中,R1为C3-C8烷基;R3为C1-C4烷基;且R2为苯基,其取代有5至6元杂芳基或任选取代有氧代的5至6元杂环基。在其它实施方案中,R1为4至7元杂环烷基或5至6元杂芳基,其任选取代有C1-C4烷基、-CO2Ra1或-SO2Ra1;R3为C1-C4烷基;且R2为苯基,其取代有5至6元杂芳基或任选取代有氧代的5至6元杂环基。在其它实施方案中,R1为C3-C8环烷基或苯基;R3为C1-C4烷基;且R2为苯基,其取代有5至6元杂芳基或任选取代有氧代的5至6元杂环基。
在一些实施方案中,R1为C3-C8烷基;R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基,其取代有CN、C1-C4烷基、-CORb1、-CO2Rb1、-SO2Rb1、-SO2NRb1Rb2、CONRb1Rb2或NRb1Rb2。在其它实施方案中,R1为4至7元杂环烷基或5至6元杂芳基,其任选取代有C1-C4烷基、-CO2Ra1或-SO2Ra1;R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基,其取代有CN、C1-C4烷基、-CORb1、-CO2Rb1、-SO2Rb1、CONRb1Rb2或NRb1Rb2。在其它实施方案中,R1为C3-C8环烷基或苯基;R3为C3-C4环烷基或4至7元杂环烷基;且R2为苯基,其取代有CN、C1-C4烷基、-CORb1、-CO2Rb1、-SO2Rb1、CONRb1Rb2或NRb1Rb2。
在一些实施方案中,R1为C3-C8烷基;R3为C1-C4烷基;且R2为苯基,其取代有CN、C1-C4烷基、-CORb1、-CO2Rb1、-SO2Rb1、CONRb1Rb2或NRb1Rb2。在其它实施方案中,R1为4至7元杂环烷基或5至6元杂芳基,其任选取代有C1-C4烷基、-CO2Ra1或-SO2Ra1;R3为C1-C4烷基;且R2为苯基,其取代有CN、C1-C4烷基、-CORb1、-CO2Rb1、-SO2Rb1、CONRb1Rb2或NRb1Rb2。在其它实施方案中,R1为C3-C8环烷基或苯基;R3为C1-C4烷基;且R2为苯基,其取代有CN、C1-C4烷基、-CORb1、-CO2Rb1、-SO2Rb1、CONRb1Rb2、NRb1Rb2或-CONRa1Ra2。
在一些实施方案中,R1为异丙基;R2任选取代有1-2个Rb;且R3为甲基。
在一些实施方案中,R1为4至6元杂环烷基,其任选取代有1-2个选自以下的Ra:C1-C4烷基、C1-C4烷氧基、-CORa1、-CO2Ra1、-SO2Ra1、-SO2NRa1Ra2和-CONRa1Ra2,其中Ra1和Ra2可各自独立地为H或C1-C4烷基;R2任选取代有1-2个Rb;且R3为甲基。
在一些实施方案中,R1为苯基或5至6元杂芳基,其中每个R1任选取代有1-3个Ra;R2任选取代有1-2个Rb;且R3为甲基。
X可为在如上所述的任一实施方案中的H。在其它实施方案中,X可为在如上所述的任一实施方案中的F。另外,具有指定立体化学(指定为R或S,或使用虚线或楔形键指定)的本申请所述化合物将会被本领域技术人员理解为基本上不含其它异构体(例如至少80%、90%、95%直至100%不含其它异构体)。
在一些实施方案中,所述化合物选自:
(S)-3-异丙基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-5-氟-3-异丙基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-5-溴-3-异丙基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-氯苯基)乙基)氨基)-5-氟-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3,5-二氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((环丙基(苯基)甲基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((环丙基(3-甲氧基苯基)甲基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((环丁基(苯基)甲基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-氟苯基)乙基)氨基)-3-(四氢-2H-吡喃-4-基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-甲氧基苯基)乙基)氨基)-3-(四氢-2H-吡喃-4-基)嘧啶-2,4(1H,3H)-二酮;
6-(((S)-1-苯基乙基)氨基)-3-(四氢呋喃-3-基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(1-(甲基磺酰基)哌啶-4-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-4-(2,6-二氧代-4-((1-苯基乙基)氨基)-3,6-二氢嘧啶-1(2H)-基)哌啶-1-羧酸甲酯;
3-((R)-仲丁基)-6-(((S)-1-(3-甲氧基苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-苯基乙基)氨基)-3-(吡啶-3-基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(异噁唑-3-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-(1H-吡唑-1-基)苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(3-甲氧基苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(2-甲氧基苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-苯基丙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-5-甲基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(2-氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-氯苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(4-氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-5-氟-3-异丙基-6-((1-苯基丙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-5-氟-6-((1-(3-氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-5-氟-3-异丙基-6-((1-(3-甲氧基苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(2,5-二氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-溴苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-3-乙基-6-((1-苯基丙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-环丙基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-苯基乙基)氨基)-3-(吡啶-2-基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(1-甲基-1H-吡唑-3-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(异噁唑-5-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-(1H-1,2,4-***-1-基)苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(3-(2-甲基-1H-咪唑-1-基)苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(3-(2-氧代噁唑烷-3-基)苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-环己基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-苯基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-乙基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-甲基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-苯基乙基)氨基)-3-丙基嘧啶-2,4(1H,3H)-二酮;
(S)-3-(3,5-二氟苯基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(间甲苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(4-氟苯基)丙-2-基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(R)-3-异丙基-6-((2,2,2-三氟-1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
3-((R)-1-(苄基氧基)丙-2-基)-6-(((S)-1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
3-((R)-1-羟基丙-2-基)-6-(((S)-1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(3-(三氟甲基)苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-2-(1-((1-异丙基-2,6-二氧代-1,2,3,6-四氢嘧啶-4-基)氨基)乙基)苯甲腈;
(S)-3-苄基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(2,6-二氟苯基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(2,6-二氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(吡啶-4-基)丙-2-基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(4-(苄基氧基)苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(4-羟基苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(R)-6-((2-(苄基氧基)-1-苯基乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-3-(6-甲基吡啶-2-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(2,2-二氟乙基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(苯并[d][1,3]二氧杂环戊烯-5-基)乙基)氨基)-3-(2,2,2-三氟乙基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(邻甲苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-环丁基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(2-(三氟甲基)苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(1-甲基环丙基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-(1H-咪唑-1-基)苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-苯基乙基)氨基)-3-(哒嗪-4-基)嘧啶-2,4(1H,3H)-二酮;
(S)-4-((1-苯基乙基)氨基)-2H-[1,5’-联嘧啶]-2,6(3H)-二酮;
(S)-6-((1-苯基乙基)氨基)-3-(吡嗪-2-基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(吡啶-3-基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(1-甲基-1H-吡唑-4-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-苯基丁基)氨基)嘧啶-2,4(1H,3H)-二酮;
6-(((S)-1-苯基乙基)氨基)-3-((R)-四氢-2H-吡喃-3-基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-环戊基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((2-甲基-1-苯基丙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(4,4-二氟环己基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(戊-3-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(1-苯甲酰基哌啶-4-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((4-苯基丁-2-基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-2-(2,6-二氧代-4-((1-苯基乙基)氨基)-3,6-二氢嘧啶-1(2H)-基)乙酸甲酯
(S)-3-异丙基-6-((1-苯基丙-2-基)氨基)嘧啶-2,4(1H,3H)-二酮;
3-((S)-1-(苄基氧基)丙-2-基)-6-(((S)-1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
3-((S)-1-羟基丙-2-基)-6-(((S)-1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(R)-6-((2-羟基-1-苯基乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
6-(((S)-1-苯基乙基)氨基)-3-((R)-1,1,1-三氟丙-2-基)嘧啶-2,4(1H,3H)-二酮;
6-(((S)-1-苯基乙基)氨基)-3-((S)-1,1,1-三氟丙-2-基)嘧啶-2,4(1H,3H)-二酮;
6-(((S)-1-苯基乙基)氨基)-3-(4,4,4-三氟丁-2-基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-苯基乙基)氨基)-3-(2,2,2-三氟乙基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(叔丁基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(2-甲氧基乙基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
6-(((S)-1-苯基丙基)氨基)-3-((S)-1,1,1-三氟丙-2-基)嘧啶-2,4(1H,3H)-二酮;
3-((R)-1-环丙基乙基)-6-(((S)-1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
3-((S)-1-环丙基乙基)-6-(((S)-1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((环丁基(苯基)甲基)氨基)-3-乙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(苯并[d][1,3]二氧杂环戊烯-5-基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(苯并[d][1,3]二氧杂环戊烯-5-基)乙基)氨基)-3-乙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-苯基丙基)氨基)-3-(2,2,2-三氟乙基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(环丙基甲基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((环丙基(苯基)甲基)氨基)-3-(2,2,2-三氟乙基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((环丁基(苯基)甲基)氨基)-3-(2,2,2-三氟乙基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(1,3-二羟基丙-2-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
6-(((S)-1-(4-氟苯基)丙-2-基)氨基)-3-((S)-1,1,1-三氟丙-2-基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-羟基苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
6-((1-(2-羟基苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-苯基乙基)氨基)-3-(1-(三氟甲基)环丙基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(3,5-二氟苯基)-6-((1-(4-氟苯基)丙-2-基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(2-氯苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-3-异丙基-6-((1-(4-甲氧基苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((环丙基(苯基)甲基)氨基)-3-乙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-氯苯基)乙基)氨基)-3-乙基嘧啶-2,4(1H,3H)-二酮;
(S)-3-乙基-6-((1-(3-(三氟甲基)苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(环丙基甲基)-6-((1-(3-氟苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-(环丙基甲基)-6-((1-(3-(三氟甲基)苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-氯苯基)乙基)氨基)-3-(环丙基甲基)嘧啶-2,4(1H,3H)-二酮;
(S)-5-氯-6-((1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-氟苯基)乙基)氨基)-3-丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3-氯苯基)乙基)氨基)-3-丙基嘧啶-2,4(1H,3H)-二酮;
(S)-3-丙基-6-((1-(3-(三氟甲基)苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-3-环丁基-6-((1-(4-氟苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(2-羟基苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(3,4-二氟苯基)乙基)氨基)-3-乙基嘧啶-2,4(1H,3H)-二酮;
3-((S)-仲丁基)-6-(((S)-1-(4-氟苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮;
(S)-6-((1-(4-氟苯基)乙基)氨基)-3-丙基嘧啶-2,4(1H,3H)-二酮;和
(S)-3-(6-氟吡啶-2-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮,
或上述任一化合物的药用盐。
在一些实施方案中,所述化合物选自:
或其药用盐。
本申请所述化合物(I)或药用盐可经任何适当的方法制备。化合物可通过例如图1中阐述的途径制备。如在图1A中所示,嘧啶三酮v可通过使脲iii与丙二酸酯iv缩合来合成。该脲iii可通过使胺i与适当的氰酸盐ii反应来制备。将嘧啶三酮用适当的离去基团(Lg)衍生化得到中间体vi。该离去集团可为但不限于卤素,诸如氯或碘。卤代的中间体vi可由嘧啶三酮通过如由Brown所述的方法(The Chemistry of Heterocyclic Compounds,ThePyrimidines,John Wiley&Sons,2009)来制备。中间体vi可通过与胺vii反应而转化为式I的化合物。某些手性胺可由酮或醛ix如在图1B中所示来制备;衍生自酮或醛的亚磺酰基亚胺xii可与Gringard试剂xiii反应得到手性胺vii。本领域技术人员应当认识到本申请所述化合物可通过其它方法,诸如由LaRock所述的方法(Comprehensive OrganicTransformations:A Guide to Functional Group Preparations,Wiley,1999)制备。
IV.组合物
本申请还提供了药物组合物,其含有本申请所述化合物或药用盐及药用赋形剂。所述组合物可用于治疗人类和其它受试者的肥厚性心肌病。
用于给药本申请所述化合物或药用盐的药物组合物可便利地存在于单位剂型中且可通过药学和药物递送领域中已知的任何方法来制备。所有方法包括使活性成分与含有一种或多种辅助成分的载体缔合的步骤。一般地,药物组合物通过如下制备:均匀地且充分地使活性成分与液体载体或精细分散的固体载体或所述两者缔合,且如果需要,则使产物成型为预期制剂。在药物组合物中,通常包含足量的活性成分以对心肌收缩力产生预期效果(即降低HCM中的通常超常的收缩力)且改善处于舒张期的左心室舒张。所述改善的舒张可缓解肥厚性心肌病和舒张期功能障碍的其它病理的症状。其还可改善引起冠状动脉血流受阻的舒张期功能障碍的作用,从而将所述冠状动脉血流受阻改善为心绞痛和缺血性心脏病的辅助因素。其还可给予对于HCM及左心室肥大的其它诱因(由于来自例如心脏瓣膜疾病或***性高血压的慢性容量或压力过度负荷)中有益的左心室重构的益处。
含有活性成分的药物组合物可为适于口服使用的形式,例如片剂、锭剂、糖锭、水性或油性混悬剂、可分散粉末或颗粒、乳剂、硬或软胶囊剂、糖浆剂、醑剂、溶液剂、口腔贴片剂、口服凝胶剂、口香糖、咀嚼片剂、泡腾粉末和泡腾片剂。意在口服使用的组合物可根据制备药物组合物领域中已知的任何方法来制备,且所述组合物可含有一种或多种选自以下的试剂:甜味剂、矫味剂、着色剂、抗氧化剂和防腐剂,以提供药学上美观且适口的制剂。片剂含有活性成分与无毒药用赋形剂的混合物,所述赋形剂适于制备片剂。这些赋形剂可为例如,惰性稀释剂诸如纤维素、二氧化硅、氧化铝、碳酸钙、碳酸钠、葡萄糖、甘露醇、山梨醇、乳糖、磷酸钙或磷酸钠;成颗粒剂和崩解剂例如玉米淀粉或海藻酸;粘合剂例如PVP、纤维素、PEG、淀粉、明胶或***胶;及润滑剂例如硬脂酸镁、硬脂酸或滑石。片剂可为未包衣的,或它们可被肠溶包衣或以其它方式通过已知技术包衣以延缓在胃肠道中的崩解和吸收,从而提供在更长时间内的持续作用。例如,可使用时间延迟物质诸如单硬脂酸甘油酯或二硬脂酸甘油酯。它们还可被包衣以形成用于控制释放的渗透性治疗片剂。
用于口服使用的制剂也可呈硬明胶胶囊的形式,其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合;或呈软明胶胶囊的形式,其中活性成分与水或油性介质例如花生油、液体石蜡或橄榄油混合。另外,乳剂可用非水可混溶性成分诸如油来制备,且用表面活性剂诸如单甘油酯和二甘油酯、PEG酯等稳定。
水性混悬液含有活性物质与适于制备水性混悬液的赋形剂的混合物。所述赋形剂为助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟基-丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和***胶;分散剂或润湿剂可为天然存在的磷脂(例如,卵磷脂)、烯化氧与脂肪酸的缩合产物(例如,聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂肪醇的缩合产物(例如,十七亚乙氧基十六醇(heptadeca ethyleneoxycetanol))、环氧乙烷与衍生自脂肪酸和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(polyoxyethylene sorbitolmonooleate))或环氧乙烷与衍生自脂肪酸和己糖醇脱水物的偏酯的缩合产物(例如,聚乙烯脱水山梨糖醇单油酸酯(polyethylene sorbitan monooleate))。水性混悬剂还可含有一种或多种防腐剂如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂如蔗糖或糖精。
油性混悬剂可通过将活性成分混悬在植物油(例如花生油、橄榄油、麻油或椰子油)或矿物油(诸如液体石蜡)中来配制。油性混悬液可含有增稠剂,例如蜂蜡、固体石蜡或鲸蜡醇。可添加如上阐述的那些甜味剂及矫味剂以得到适口的口服制剂。这些组合物可通过加入抗氧化剂诸如抗坏血酸来保存。
适于通过加入水制备水性混悬液的可分散粉末和颗粒提供了活性成分与分散剂或润湿剂、助悬剂及一种或多种防腐剂的混合物。适当的分散剂或润湿剂及助悬剂已经通过如上提及的那些进行示例说明。也可存在其它的赋形剂,例如甜味剂、矫味剂和着色剂。
本申请描述的药物组合物也可为水包油的乳剂的形式。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,或这些物质的混合物。适当的乳化剂可为天然存在的树胶例如***胶或西黄蓍胶,天然存在的磷脂例如大豆磷脂、卵磷脂,及衍生自脂肪酸和己糖醇脱水物的酯或偏酯例如脱水山梨糖醇单油酸酯,及所述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。所述乳剂也可含有甜味剂和矫味剂。
糖浆剂和醑剂可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖来配制。所述制剂还可含有润湿剂、防腐剂、矫味剂和着色剂。口服溶液剂可与例如,环糊精、PEG和表面活性剂组合制备。
药物组合物可呈无菌注射水性混悬剂或油性混悬液形式。该混悬液可使用上文已提及的合适的分散剂或润湿剂和助悬剂根据本领域已知方法配制。无菌注射制剂还可以是于无毒性的肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或混悬液,如于1,3-丁二醇中的溶液。可使用的可接受媒介物和溶剂包括水、林格溶液(Ringer’s solution)和等张氯化钠溶液。另外,无菌不挥发性油(sterile fixed oil)通常可用作溶剂或助悬介质。出于该目的,可使用任何温和的不挥发性油,包括合成性甘油一酯或甘油二酯。另外,脂肪酸如油酸同样可用于制备注射剂。
本申请所述化合物或药用盐也可以用于直肠给予药物的栓剂形式给予。这些组合物可通过如下制备:使药物与适当的无刺激性赋形剂混合,所述赋形剂在常温为固体而在直肠温度为液体,且因此将会在直肠中融解以释放药物。所述物质包括可可豆脂和聚乙二醇。另外,化合物或药用盐可经眼部递送通过溶液或软膏剂的方式来给予。另外,目标化合物或药用盐的经皮递送可通过离子电渗贴片等来完成。对于局部使用,可使用含有本申请所述化合物或药用盐的乳膏剂、软膏剂、胶冻剂、溶液剂或混悬剂等。本申请使用的局部应用也意在包括使用口腔洗剂和漱口剂。
本申请所述化合物或药用盐还可与作为靶向药物载体的适当聚合物的载体结合。所述聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-苯酚、聚羟乙基天冬酰胺苯酚或取代有棕榈酰基的聚氧化乙烯-聚赖氨酸。另外,本申请所述化合物或药用盐可与可用于实现药物受控释放的一类生物可降解聚合物的载体结合,例如聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯及水凝胶的交联或两亲性嵌段共聚物。聚合物和半渗透性聚合物基质可形成成型物品,诸如阀、支架、管、假体等。
V.心脏病症的治疗方法
导致HCM的突变引起对肌球蛋白力学的显著干扰。这些突变通过取决于它们在肌球蛋白基因的定位的不同机制而发挥其作用。充分研究的HCM突变,即R403Q和R453C位于马达结构域的不同区域且引起不同的力学干扰,其导致提高的力产生的共同结果。不希望被任何特定理论所束缚,认为本申请所述化合物或药用盐可直接结合于突变肌节蛋白,且针对其异常功能可变化为顺式(影响相同的特定功能)或反式(改变互补功能)。因此,它们可对HCM患者提供益处,其通过抵消与该疾病相关的高收缩性和/或舒张受损。
本申请还提供了治疗肥厚性心肌病(HCM)或具有与HCM相关的一个或多个病理生理学特征的心脏疾病的方法。该方法包括向有此需要的受试者给予有效量的本申请所述化合物或药用盐。
本发明的化合物或药用盐可改变HCM和其它疾病的自然病史,而不仅仅是缓解症状。对HCM患者给予临床益处的机制可延用于具有其它形式的心脏疾病的患者,所述其它形式的心脏疾病共同具有相似的病理生理学,且具有或不具有显著的遗传因素的影响。例如,通过改善在舒张期内的心室舒张而进行的HCM的有效治疗,也可有效用于特征在于舒张期功能障碍的更宽范围的群体。本发明化合物或其药用盐可特定地靶标病症的根源或作用于其它下游途径。因此,本发明化合物或其药用盐也可对患有射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛或限制性心肌病的患者给予益处。本发明化合物或其药用盐也可促进由于容量或压力过度负荷造成的左心室肥大的有益心室重构;例如慢性二尖瓣返流、慢性主动脉瓣狭窄或慢性***性高血压;所述化合物或其药用盐联合旨在纠正或减轻容量或压力过度负荷的主要原因的疗法(瓣修复/替换、有效的抗高血压疗法)。通过降低左心室充盈压,化合物可降低肺水肿和呼吸衰竭的风险。降低或消除功能性二尖瓣返流和/或降低左心房压力可降低突发性或持久性心房纤颤的风险,且其降低了动脉血栓栓塞性并发症包括但不限于脑动脉栓塞性中风的伴随性风险。降低或消除动态和/或静态左心室流出道阻塞可减少需要间隔消融治疗(手术或经皮)的可能性及其短期和长期并发症的伴随性风险。该化合物或其药用盐可降低与HCM相关的慢性局部缺血状态的严重性,且由此降低具有可植入的复律器-除颤器(频繁和/或重复的ICD放电)的患者中的心脏性猝死(SCD)或其等同疾病的风险和/或降低对于可能有毒的抗心律不齐药物的需求。该化合物或其药用盐可在降低或消除对于并行药物(具有其伴随的潜在毒性、药物-药物相互作用和/或副作用)的需求方面是有价值的。该化合物或其药用盐可降低间质性心肌纤维化和/或减缓左心室肥大的进展、阻止或逆转左心室肥大。
取决于待治疗的疾病及受试者的状态,本申请所述化合物或药用盐可如下给予:经口服、肠胃外(例如肌内、腹膜内、静脉内、ICV、池内注射或输注、皮下注射或植入)、经植入(例如在该化合物或药用盐连接于支架装置时)、经吸入喷雾、鼻部、***、直肠、舌下或局部途径给药,且可单独或在适于每种给药途径的适当的含有常规无毒的药用载体、辅料和媒介物的剂量单位制剂中一起配制。
在治疗或预防在舒张期内需要改善的心室舒张的病症中,适当的剂量水平将通常为约0.001至100mg/kg患者体重/天,其可以单一剂量或多个剂量给予。在一些实施方案中,剂量水平将为约0.01至约25mg/kg/天;在一些实施方案中为约0.05至约10mg/kg/天。适当的剂量水平可为约0.01至25mg/kg/天、约0.05至10mg/kg/天或约0.1至5mg/kg/天。在该范围内,剂量可为0.005至0.05、0.05至0.5或0.5至5.0mg/kg/天。在一些实施方案中,对于口服给药,在以下片剂形式中提供该组合物:含有1.0至1000毫克的活性成分,具体地1.0、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和1000.0毫克的活性成分,以用于针对症状调整对待治疗的患者所给予的治疗。该化合物或药用盐可在每天1至4次的方案中给予,在一些实施方案中,可在每天一或两次的方案中给予。
然而,应当理解的是,针对任何特定患者的特定剂量水平和给药频率是会变化的且将取决于各种因素,包括所使用的具体化合物或药用盐的活性、该化合物或药用盐的代谢稳定性和作用时长、受试者的年龄、体重、遗传特征、一般健康状况、性别和饮食,及给药方式和时间、***速率、药物组合,及对于正在进行治疗的患者的特定病症的严重性。
本申请提供的化合物和组合物可与其它药物组合使用,所述其它药物用于治疗、预防、抑制或改善使用本申请提供的化合物和组合物有效的疾病或病症。所述其它药物可通过通常用于与本申请提供的化合物或组合物同时或先后使用的途径和量来给予。当本申请提供的化合物或组合物与一种或多种其它药物同时使用时,优选的是含有除本申请提供的化合物或组合物之外的所述其它药物的药物组合物。因此,本申请提供的药物组合物包括那些除了本申请提供的化合物或组合物之外还含有一种或多种其它活性成分或治疗药物的药物组合物。适当的其它活性药物包括例如:通过下调心脏的神经激素刺激来延缓心力衰竭的进展并尝试防止心脏重塑的疗法(例如ACE抑制剂、血管紧张素受体阻断剂(ARB)、β-阻断剂、醛固酮受体拮抗剂或神经内肽酶抑制剂);通过刺激心脏收缩性来改善心脏功能的疗法(例如正性肌力药诸如β-肾上腺素能激动剂多巴酚丁胺或磷酸二酯酶抑制剂米力农);及降低心脏前负荷的疗法(例如利尿剂诸如呋塞米)或降低心脏后负荷的疗法(任何类别的血管舒张剂,包括但不限于钙通道阻断剂、磷酸二酯酶抑制剂、内皮素受体拮抗剂、肾素抑制剂或平滑肌肌球蛋白调节剂)。本申请提供的化合物与第二活性成分的重量比是可变化的且将取决于每种成分的有效剂量。一般来说,将使用每种成分的有效剂量。
VI.实施例
缩写:
aq:水性
BBr3:三溴化硼
CH2Cl2:二氯甲烷
CH3CN:乙腈
CH3OH:甲醇
DIAD:偶氮二羧酸二异丙酯
DIEA:二异丙基乙基胺
DMF:二甲基甲酰胺
DMSO:二甲基亚砜
equiv.:当量
Et3N:三乙胺
Et2O:***
EtOH:乙醇
FeSO4:硫酸亚铁
h:小时
HCl:氯化氢
H2O:水
K2CO3:碳酸钾
KHSO4:硫酸氢钾
KNCO:异氰酸钾
LiBr:溴化锂
MgSO4:硫酸镁
mL:毫升
MW:微波(在微波反应器中完成反应)
NaCl:氯化钠
NaH:氢化钠
NaHCO3:碳酸氢钠
NaOEt:乙醇钠
NaOH:氢氧化钠
NaOMe:甲醇钠
Na2SO4:硫酸钠
NH4Cl:氯化铵
NMP:N-甲基吡咯烷酮
pH:-log[H+]
POCl3:磷酰氯
PPTS:吡啶鎓对甲苯磺酸盐
RP-HPLC:反相高压液相色谱
RT:室温
SEMCl:2-(三甲基甲硅烷基)乙氧基甲基氯
TEBAC:三乙基苄基氯化铵
TFA:三氟乙酸
THF:四氢呋喃
TLC:薄层色谱
实施例1.制备(S)-3-异丙基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮
化合物1.1.异丙基脲。在氩气下在0℃向异丙基胺(15.3g,0.258mol,1.0当量)在CH2Cl2(200mL)中的搅拌溶液中逐滴加入异氰酸三甲基甲硅烷基酯(30g,0.26mol,1.0当量)。使所得的混合物达到环境温度并搅拌过夜。冷却至0℃后,逐滴加入CH3OH(100mL)。将所得的溶液在室温搅拌2小时(h),然后减压浓缩。将粗残留物从CH3OH:Et2O(1:20)中重结晶得到15.4g(58%)标题化合物,其为白色固体。LC/MS:m/z(ES+)103(M+H)+。
化合物1.2.1-异丙基巴比妥酸。向1.1(14.4g,0.14mol,1.00当量)在CH3OH(500mL)中的搅拌溶液中加入丙二酸二甲酯(19.55g,0.148mol,1.05当量)和甲醇钠(18.9g,0.35mol,2.50当量)。将所得的混合物在65℃搅拌过夜。冷却至环境温度且然后冷却至0℃后,使用浓HCl水溶液将pH小心地调节至3。将所得的混合物减压浓缩。将残留物吸收在EtOH(200mL)中并过滤。将滤液减压浓缩并将残留物通过硅胶柱色谱纯化(使用CH2Cl2/CH3OH(20:1)作为洗脱剂)得到16.8g(50%)标题化合物,其为白色固体。LC/MS:m/z(ES+)171(M+H)+。1H-NMR(300MHz,d6-DMSO):δ11.19(s,1H),4.83(m,1H),3.58(s,2H),1.32(d,J=6.0Hz,6H)。
化合物1.3.6-氯-3-异丙基嘧啶-2,4(1H,3H)-二酮。在氩气下向含有化合物1.2(11.4g,66.99mmol,1.00当量)的100mL圆底烧瓶中加入三乙基苄基氯化铵(21.3g,93.51mmol,1.40当量)和POCl3(30mL)。将所得的混合物在50℃搅拌过夜。冷却至室温后,将混合物减压浓缩。将残留物溶于CH2Cl2(150mL)中,随后缓慢加入H2O(100mL)。分离各相并将有机层用H2O(100mL)洗涤,用无水Na2SO4干燥并减压浓缩。将粗残留物通过硅胶柱色谱纯化(使用EtOAc/石油醚(1:1)作为洗脱剂)得到5.12g(40%)标题化合物,其为浅黄色固体。
1H-NMR(300MHz,d6-DMSO):δ12.22(s,1H),5.88(s,1H),4.95(m,1H),1.34(d,J=6.0Hz,6H)。
化合物1.(S)-3-异丙基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮。
向6-氯-3-异丙基嘧啶-2,4(1H,3H)-二酮(1.3,1.0g,5.31mmol)在1,4-二噁烷(20mL)中的溶液中加入(S)-α-甲基苄基胺(Sigma-Aldrich,1.43g,11.7mmol,2.2当量)。将反应混合物在80℃搅拌24h。冷却至环境温度后,将混合物减压浓缩。将残留物吸收在EtOAc(70mL)并用1N HCl水溶液(2×50mL)和盐水(40mL)洗涤。将有机层用无水Na2SO4干燥,然后减压浓缩为原始体积的一半得到析出物。加入己烷(20mL)并将混合物在室温搅拌。将所得的固体通过过滤收集,用己烷(20mL)洗涤并干燥得到1.0g(69%)标题化合物,其为白色固体。LC/MS:m/z(ES+)274(M+H)+。1H-NMR(400MHz,d6-DMSO):δ9.77(s,1H),7.32(m,4H),7.24(m,1H),6.50(d,J=6.8Hz,1H),4.87(m,1H),4.52(m,1H),4.31(d,J=6.8Hz,1H),1.37(m,3H),1.24(m,6H).1H NMR(400MHz,CD3OD)δppm 7.39-7.20(m,5H),5.01(m,1H),4.48(m,1H),1.49(d,J=6.7Hz,3H),1.36(m,6H)。
实施例2.制备(S)-5-氟-3-异丙基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二
酮(2)
向1(80mg,0.293mmol)在乙酸(2.0mL)中的溶液中加入Selectfluor(104mg,0.293mmol,1.0当量)。将混合物在室温搅拌2h。然后将其减压浓缩。将残留物通过硅胶柱色谱纯化(用0-50%EtOAc在己烷中的溶液洗脱)得到6mg(7%)标题化合物,其为白色固体。LC/MS:m/z(ES+)292(M+H)+。1H NMR(400MHz,CD3OD):δppm 7.36-7.24(m,5H),5.04-4.97(m,1H),4.94-4.88(m,1H),1.54(d,J=8.0Hz,3H),1.39(m,6H)。
实施例3.制备(S)-5-溴-3-异丙基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二
酮(3)。
向1(55mg,0.201mmol)在乙酸(1.0mL)中的溶液中加入N-溴琥珀酰亚胺(35mg,0.196mmol)。将混合物在室温搅拌1小时。然后将其减压浓缩。将残留物通过硅胶柱色谱纯化(用0-40%EtOAc在己烷中的溶液洗脱)得到52mg(74%)标题化合物,其为白色固体。LC/MS:m/z(ES+)352,354(M+H,溴谱图)+。1H-NMR(400MHz,CDCl3)δppm 8.96(br s,1H),7.43-7.28(m,5H),5.28(d,J=7.4Hz,1H),5.14(m,1H),4.87(m,1H),1.62(d,J=6.7Hz,3H),1.45-1.39(m,6H)。
实施例4.制备(S)-6-((1-(3-氯苯基)乙基)氨基)-5-氟-3-异丙基嘧啶-2,4(1H,
3H)-二酮
化合物4.1. 5-氟-1-异丙基嘧啶-2,4,6(1H,3H,5H)-三酮。向含有1.1(1.31g,0.013mol,1.00当量)在CH3OH(15mL)中的溶液的100mL圆底烧瓶中加入氟丙二酸二乙酯(2.41g,0.014mol,1.05当量)和甲醇钠(1.74g,0.032mol,2.50当量)。反应烧瓶配备有回流冷凝器并在加热于85℃的油浴中搅拌4h。将反应混合物冷却至0℃并通过小心地加入浓HCl淬灭,通过加入过量的浓HCl调节至pH=2。将反应混合物减压浓缩并将所得的残留物在高真空下干燥18h得到2.65g标题化合物(98%)。1H-NMR(400MHz,CDCl3):δppm 5.53(d,J=24.0Hz,1H),4.91(m,2H),1.46(m,6H)。
化合物4.2. 6-氯-5-氟-3-异丙基嘧啶-2,4(1H,3H)-二酮。向含有4.1(2.65g,0.014mmol,1.00当量)的配备有回流冷凝器的100mL圆底烧瓶中加入三乙基苄基氯化铵(4.50g,0.019mmol,1.40当量)和POCl3(25mL)。将反应混合物在50℃搅拌4h,然后冷却至室温。将混合物减压浓缩并将所得的残留物溶于CH2Cl2(50mL)中。缓慢加入水(50mL)并分离各层。将有机层第二次用H2O(100mL)洗涤,用无水MgSO4干燥并减压浓缩。将所得的残留物通过快速色谱纯化(硅胶,30%EtOAc在己烷中的溶液)得到2.67g(93%)标题化合物,其为白色固体。1H-NMR(400MHz,CDCl3):δppm 5.19-5.05(m,2H),1.48(d,J=7.04Hz,6H)。
化合物4.(S)-6-((1-(3-氯苯基)乙基)氨基)-5-氟-3-异丙基嘧啶-2,4(1H,3H)-二酮。
向在厚壁压力容器中的4.2(150mg,0.70mmol,1当量)在DMF(2mL)中的溶液中加入(S)-3-氯-α-甲基苄基胺(150mg,0.70mmol,1.0当量)和质子海绵(190mg,0.90mol,1.25当量)。将压力容器密封并将反应混合物在防爆屏蔽后加热至95℃且保持3h。将反应混合物冷却至室温并减压浓缩。将所得的残留物通过制备性RP-HPLC纯化(使用配备有PhenomenexGemini-NX C18柱的Shimadzu Prominence LC-20AP***,用10-90%CH3CN/H2O(均含有0.1%TFA)洗脱,30min,20mL/min)。将含有纯化合物的馏分合并并冻干得到30mg(13%)标题化合物,其为白色固体。LC/MS:m/z(ES+)326(M+H)+。
1H-NMR(400MHz,CDCl3)δppm 9.47(br s,1H),7.35-7.27(m,3H),7.22-7.16(m,1H),5.12(m,1H),4.89(m,1H),4.69(d,J=5.9Hz,1H),1.59(d,J=6.7Hz,3H),1.43(m,6H)。
实施例5.制备(S)-6-((1-(3,5-二氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,
3H)-二酮。
化合物5.1.((R,E)-N-(3,5-二氟亚苄基)-2-甲基丙-2-亚磺酰胺。向3,5-二氟苯甲醛(1.00g,7.04mmol,1.00当量)在CH2Cl2(20mL)中的溶液中加入吡啶鎓对甲苯磺酸盐(0.089g,0.35mmol,0.05当量)、(R)-(+)-2-甲基丙-2-亚磺酰胺(0.852g,7.03mmol,1.00当量)和MgSO4(4.2g,35.00mmol,5.00当量)。将所得的混合物在室温搅拌过夜。将反应混合物过滤并减压浓缩。将所得的残留物通过快速色谱纯化(硅胶,20%EtOAc在石油醚中的溶液)得到500mg(29%)标题化合物,其为黄色油状物。
化合物5.2.(R)-N-((S)-1-(3,5-二氟苯基)乙基)-2-甲基丙-2-亚磺酰胺。在氩气下在-48℃将甲基溴化镁(5.17mL,3M,2.00当量)逐滴加到5.1(1.9g,7.75mmol,1.00当量)在CH2Cl2(50mL)中的溶液中。将反应混合物温热至室温并搅拌过夜。将反应混合物小心地用饱和NH4Cl水溶液(20mL)淬灭。分离各层并将水层进一步用CH2Cl2(3×50mL)萃取。将合并的有机层用无水MgSO4干燥并减压浓缩得到1.3g(64%)标题化合物,其为黄色油状物。1HNMR(300MHz,CDCl3):δppm 6.92-6.81(m,2H),6.75-6.65(m,1H),4.65-4.55,(m,1H),3.46-3.42(m,1H),1.53-1.44(m,3H),1.26-1.22(m,9H)。
化合物5.3.(S)-1-(3,5-二氟苯基)乙-1-胺盐酸盐。向5.2(1.3g,4.97mmol,1.00当量)在CH3OH(10mL)中的溶液中加入4N HCl在1,4-二噁烷中的溶液(2.67mL,2.00当量)。将反应混合物在室温搅拌0.5h,然后减压浓缩。将所得的残留物溶于CH3OH(3mL)中并加入Et2O(300mL)。将所得的析出物通过过滤分离得到0.80g(83%)标题化合物。1H NMR(300MHz,D2O):δppm 6.98-6.83(m,3H),4.45-4.38(m,1H),1.51-1.48(d,J=6.9Hz,3H)。
化合物5.(S)-6-((1-(3,5-二氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮。
将化合物5.3(50mg,0.32mmol,1.00当量)溶于1N NaOH(10mL)中并将所得的混合物在25℃搅拌。1h后,将混合物用EtOAc(5×10mL)萃取。将合并的有机层用无水Na2SO4干燥,过滤并减压浓缩。合并所得的残留物和化合物1.3(35.6mg,0.19mmol,0.60当量)。将混合物在100℃搅拌18h,然后冷却至室温并减压浓缩。将所得的残留物通过制备性RP-HPLC纯化得到28mg(29%)标题化合物,其为灰白色固体。LC/MS:m/z(ES+)310(M+H)+。1H-NMR(300MHz,DMSO-d6):δppm 9.83(s,1H),7.06-7.12(m,3H),6.54(d,J=6.6Hz,1H),4.91-4.82(m,1H),4.54-4.46(m,1H),4.30(m,1H),1.34(d,J=6.6Hz,3H),1.22(d,J=6.9Hz,6H)。
实施例6.制备(S)-6-((环丙基(苯基)甲基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二
酮。
化合物6.1.(R,E)-N-亚苄基-2-甲基丙-2-亚磺酰胺。标题化合物以与5.1相同的方式制备,除了使用苯甲醛(5.0g,47.12mmol,1.00当量)代替3,5-二氟苯甲醛,得到2.8g(28%)标题化合物。1H NMR(300MHz,d6-DMSO):δppm 8.62(s,1H),7.89-7.87(m,2H),7.55-7.49(m,3H),1.31(s,9H)。
化合物6.2.(S)-N-((S)-环丙基(苯基)甲基)-2-甲基丙-2-亚磺酰胺。标题化合物使用与用于制备5.2的操作相似的操作制备,除了使用6.1(1.0g,4.78mmol,1.00当量)和环丙基溴化镁(9.6mL,1M,2.00当量)代替5.1和甲基溴化镁,得到0.5g(35%)标题化合物,其为黄色油状物。1H NMR(300MHz,DMSO-d6):δppm 7.36-7.23(m,5H),3.67-3.51(m,2H),1.31(m,10H),0.85-0.15(m,4H)。
化合物6.3.(S)-环丙基(苯基)甲胺盐酸盐。标题化合物使用与用于制备5.3的操作相似的操作制备,除了使用6.2(500mg,1.69mmol,1.00当量)代替5.2,得到220mg(88%)标题化合物,其为黄色油状物。1H NMR(300MHz,d6-DMSO):δppm 7.37-7.31(m,5H),3.53(d,J=10.0Hz,1H),1.37-1.25(m,1H),0.75-0.55(m,1H),0.53-0.31(m,2H),0.25-0.15(m,1H)。
化合物6.(S)-6-((环丙基(苯基)甲基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮。
标题化合物使用与用于制备5的操作相似的操作制备,除了使用6.3(200mg,1.36mmol,1.00当量)代替5.3并使用1,4-二噁烷作为溶剂。减压浓缩后,使用手性HPLC(Phenomenex Lux 5μCellulose-4,2.12*25,5μm柱)进行纯化(使用EtOH:己烷的等度混合物(1:4)作为洗脱剂)得到22mg(5%)标题化合物,其为白色固体。LC/MS:m/z(ES+)300(M+H)+。1H-NMR(300MHz,DMSO-d6)δppm 9.82(s,1H),7.39-7.25(m,5H),7.25-7.32(m,1H),6.72(m,1H),4.90(m,1H),4.22(s,1H),3.78(m,1H),1.27(m,6H),1.57(m,1H),0.60(m,1H),0.56-0.32(m,2H)。
实施例7.制备(S)-6-((环丙基(3-甲氧基苯基)甲基)氨基)-3-异丙基嘧啶-2,4
(1H,3H)-二酮。
将6-氯-3-异丙基嘧啶-2,4(1H,3H)-二酮(1.3,50mg,0.265mmol)、(S)-环丙基-(3-甲氧基苯基)甲基胺(Sigma-Aldrich,104mg,0.587mmol)和质子海绵(85mg,0.397mmol)在NMP(0.5mL)中的溶液在130℃搅拌2h。冷却至室温后,将混合物通过制备性RP-HPLC纯化(配备有Phenomenex Gemini-NX C18柱的Shimadzu Prominence LC-20AP***,用20-90%CH3CN在H2O中的溶液(均含有0.1%TFA)洗脱)。将含有纯化合物的馏分合并并冻干得到10mg(11%)标题化合物,其为白色固体。LC/MS:m/z(ES+)330(M+H)+。1H-NMR(400MHz,CD3OD):δppm 7.26(t,J=7.8Hz,H),6.92-6.79(m,3H),5.00(m,1H),3.79(s,3H),3.74(d,J=8.6Hz,1H),1.36(d,J=7.0Hz,6H),1.23-1.13(m,1H),0.68-0.60(m,1H),0.58-0.50(m,1H),0.50-0.42(m,1H),0.41-0.34(m,1H)。
实施例8.制备(S)-6-((环丁基(苯基)甲基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二
酮。
化合物8.1.(S,E)-N-(环丁基亚甲基)-2-甲基丙-2-亚磺酰胺。向环丁烷甲醛(1.0g,11.89mmol,1.00当量)在CH2Cl2(10mL)中的溶液中加入吡啶鎓对甲苯磺酸盐(0.143g,0.57mmol,0.05当量)、(S)-(-)-2-甲基丙-2-亚磺酰胺(1.22g,10.07mmol,0.85当量)和硫酸镁(7.14g,59.32mmol,5.00当量)。将所得的混合物在室温搅拌过夜。将反应混合物过滤并减压浓缩。将所得的残留物通过快速色谱纯化(硅胶,30%EtOAc在石油醚中的溶液)得到2.0g(90%)标题化合物,其为白色固体。1H NMR(400MHz,CDCl3)δppm 8.08(d,J=10.8Hz,1H),3.36-3.32(m,1H),2.25-2.16(m,4H),2.03-1.90(m,2H),1.15(s,9H)。
化合物8.2.(S)-N-((S)-环丁基(苯基)甲基)-2-甲基丙-2-亚磺酰胺。将苯基溴化镁(3M在Et2O中,15.3mL,2.00当量)逐滴加到8.1(4.3g,22.96mmol,1.00当量)在THF(40mL)中的溶液中。将反应混合物在65℃加热3h。然后将其冷却至室温并小心地用饱和NH4Cl水溶液(30mL)淬灭。将所得的混合物用EtOAc(3×30mL)萃取并将合并的有机层用无水Na2SO4干燥并减压浓缩得到5.8g(95%)标题化合物,其为白色固体。1H-NMR(300MHz,CDCl3)δ7.30-7.21(m,5H),4.23(d,J=9.6Hz,1H),2.73-2.68(m,1H),1.95-1.60(m,6H),1.14(s,9H)。
化合物8.3.(S)-环丁基(苯基)甲胺盐酸盐。标题化合物使用与用于制备5.3的操作相似的操作制备,除了使用8.2(5.8g,0.022mol,1.00当量)代替5.2,得到3.20g(91%)标题化合物,其为白色固体。1H NMR(300MHz,D2O):δppm 7.36-7.28(m,5H),4.18(m,1H),2.87-2.73(m,1H),2.11-2.01(m,1H),1.90-1.69(m,5H)。
化合物8.(S)-6-((环丁基(苯基)甲基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮。将化合物8.3(0.200g,1.24mmol,1.00当量)溶于1N NaOH(10mL)中并在25℃搅拌1h。将反应混合物用EtOAc(5×10mL)萃取。将合并的有机层用无水Na2SO4干燥,过滤并减压浓缩。将所得的残留物溶于NMP中并与1.3和质子海绵混合并如就制备7所述那样加热。分离标题化合物(35mg,9%),其为白色固体。LC/MS:m/z(ES+)314(M+H)+。1H NMR(300MHz,CD3OD):δppm7.38-7.26(m,5H),5.08-4.97(m,1H),4.25(d,J=6.9Hz,1H),2.68-2.58(m,1H),2.19-2.13(m,1H),1.98-1.83(m,5H),1.36(d,J=6.9Hz,6H)。
实施例9.制备(S)-6-((1-苯基乙基)氨基)-3-(四氢-2H-吡喃-4-基)嘧啶-2,4
(1H,3H)-二酮。
化合物9.1. 1-(四氢-2H-吡喃-4-基)脲。将四氢-2H-吡喃-4-胺(5.0g,49.4mmol,1.0当量)和异氰酸钾(4.0g,49.5mmol,1.0当量)的混合物在H2O(50mL)中回流过夜。将反应混合物冷却至室温并加入过量的NaCl以有助于饱和水层。将析出物通过过滤分离得到所需产物(1.28g,8.88mmol)。将水层用EtOAc(3×15mL)洗涤,然后浓缩并与甲苯(3×100mL)共沸。将所得的固体混悬在1:4CH3OH:EtOAc(100mL)中并过滤总计四次。将合并的有机层减压浓缩并与分离的析出物合并得到5.01g(70%)标题化合物。LC/MS:m/z(ES+)145(M+H)+。1H-NMR(400MHz,DMSO-d6):δ6.14(d,J=7.5Hz,1H),5.47(s,2H),3.85(dt,J=11.6,3.6Hz,2H),3.65-3.52(m,1H),3.38(td,J=11.4,2.2Hz,2H),1.80-1.72(m,2H),1.42-1.27(m,2H)。
化合物9.2. 1-(四氢-2H-吡喃-4-基)嘧啶-2,4,6(1H,3H,5H)-三酮。将化合物9.1(2.8g,19.4mmol)溶于EtOH(30mL)中并加入丙二酸二乙酯(2.45mL,21.4mmol,1.1当量)和NaOEt(7.55mL,23.3mmol,1.2当量)。将反应混合物在85℃搅拌过夜,然后冷却至室温。将反应混合物用H2O(5mL)稀释并加入过量的KHSO4以饱和水层。将反应混合物用EtOAc(3×15mL)萃取。将合并的有机层用无水MgSO4干燥,过滤并减压浓缩。将所得的残留物通过快速色谱纯化(硅胶,0-25%CH3OH在CH2Cl2中的溶液)得到1.57g含有标题化合物的混合物,其无需进一步纯化即使用。LC/MS:m/z(ES-)211(M-H)-。
化合物9.3. 6-氯-3-(四氢-2H-吡喃-4-基)嘧啶-2,4(1H,3H)-二酮。向9.2(1.57g,7.4mmol,1当量)在CH3CN(15mL)中的溶液中加入POCl3(0.551mL,5.9mmol,0.8当量)。将反应混合物在80℃搅拌过夜。再加入POCl3(0.4当量)并将反应混合物在80℃搅拌3h。在80℃搅拌3h和5h后,再加入POCl3(0.4当量)。然后将反应混合物在90℃搅拌1h。将反应混合物冷却至室温,浓缩,用Et2O(15mL)涡旋并弃去。将所得的残留物用Et2O(15mL)淋洗并弃去直到弃去的Et2O是澄清的。将所得的残留物小心地混悬在CH3OH(10mL)中并过滤。将滤液浓缩得到原料和标题化合物的混合物(~85%纯,1.6g)。LC/MS:m/z(ES-)229(M-H)-。
化合物9.(S)-6-((1-苯基乙基)氨基)-3-(四氢-2H-吡喃-4-基)嘧啶-2,4(1H,3H)-二酮。将9.3(0.15g,0.65mmol,1当量)和(S)-(-)-α-甲基苄基胺(470mg,3.88mmol,6.0当量)的混合物在90℃搅拌过夜。将反应混合物冷却至室温并将所得的残留物通过制备性RP-HPLC纯化(0-40%CH3CN在H2O中的溶液,30min),随后在制备性TLC板(2000μm)上进行第二次纯化(7%CH3OH在CH2Cl2中的溶液)得到23mg(11%)标题化合物。LC/MS:m/z(ES+)316(M+H)+。1H NMR(400MHz,DMSO-d6):δppm 10.23(s,1H),7.40-7.32(m,4H),7.31-7.17(m,1H),6.93(s,1H),4.84-4.71(m,1H),4.56-4.43(m,1H),4.35(s,1H),3.93-3.78(m,2H),3.28(t,J=12.1Hz,2H),2.63-2.39(m,2H),1.40(d,J=6.7Hz,3H),1.35-1.16(m,2H)。
实施例10.制备(S)-6-((1-(3-甲氧基苯基)乙基)氨基)-3-(四氢-2H-吡喃-4-基)
嘧啶-2,4(1H,3H)-二酮(10)。
向9.3(0.58g,0.25mmol)在2-丙醇和H2O的混合物(4:1,1mL)中的溶液中加入(S)-1-(3-甲氧基苯基)-乙基胺(0.113g,0.75mmol,3.0当量)。将反应混合物加热至120℃且保持2h。冷却后,将反应混合物减压浓缩,溶于CH3OH中并过滤。将滤液通过制备性RP-HPLC纯化(20-100%CH3CN在H2O中的溶液,40min,25mL/min)得到18mg(21%)标题化合物,其为灰白色固体。LC/MS:m/z(ES+)346(M+H)+。1H NMR(400MHz,丙酮-d6)δ8.90(s,1H),7.15(dd,J=8.3,8.1Hz,1H),6.88(s,1H),6.86(d,J=8.3Hz,1H),6.68(d,J=8.1Hz,1H),6.15(s,1H),4.74(m,1H),4.48(m,1H),4.35(s,1H),3.82(m,2H),3.68(s,3H),3.2(m,2H),2.55(m,2H)1.44(d,J=6.6Hz,3H),1.15(m,2H)。
实施例11.制备6-(((S)-1-苯基乙基)氨基)-3-(四氢呋喃-3-基)嘧啶-2,4(1H,
3H)-二酮。
化合物11.1. 6-氯-1-((2-(三甲基甲硅烷基)乙氧基)甲基)嘧啶-2,4(1H,3H)-二酮。在0℃向6-氯-尿嘧啶(3.0g,20.47mmol,1当量)和LiBr(1.78g,20.5mmol,1.0当量)在NMP(70mL)中的混合物中加入NaH(60%分散在矿物油中,0.82g,20.5mmol,1.0当量)。将反应混合物在0℃搅拌10min并经由加料漏斗缓慢加入2-(三甲基甲硅烷基)乙氧基甲基氯(3.75g,22.5mmol,1.1当量)。将反应混合物在室温搅拌过夜,然后用EtOAc(150mL)稀释。将混合物用饱和NH4Cl水溶液(50mL)、饱和NaHCO3水溶液(50mL)和盐水(50mL)洗涤。将有机层用无水Na2SO4干燥并减压浓缩得到3.2g(57%)标题化合物,其为白色固体。LC/MS:m/z(ES+)299(M+Na)+。1H NMR(400MHz,CDCl3):δppm 9.00-8.80(br-s,1H),5.95(s,1H),5.45(s,2H)),3.63(t,J=7.0Hz,2H),1.48(t,J=7.0Hz,2H),0.01(s,9H)。
化合物11.2. 6-氯-3-(四氢呋喃-3-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)嘧啶-2,4(1H,3H)-二酮。在0℃向11.1(277mg,1.0mmol,1当量)、3-羟基四氢呋喃(106mg,1.2mmol,1.2当量)和三苯基膦(320mg,1.2mmol,1.2当量)在THF(7.5mL)中的溶液中逐滴加入偶氮二羧酸二异丙酯(0.240g,1.2mmol,1.2当量)。将反应混合物在室温搅拌30分钟。将反应混合物减压浓缩并将所得的残留物通过制备性RP-HPLC纯化(含有0.1%甲酸缓冲剂的20-100%CH3CN在H2O中的溶液,40min,25mL/min)得到102mg(29%)标题化合物。LC/MS:m/z(ES+)347(M+H)+。1H NMR(400MHz,CDCl3)δ5.92(s,1H),5.58(m,1H),5.41(s,2H),4.20(m,1H),4.00-3.85(m,3H),3.65(t,J=7.0Hz,2H),2.35-2.20(m,1H),2.20-2.08(m,1H),0.95(t,2H),0.01(s,9H);13C NMR(CDCl3)δ160.7,150.7,145.6,102.0,74.8,68.7,67.9,67.5,51.9,28.7,18.0,0.0。
化合物11.3. 6-氯-3-(四氢呋喃-3-基)嘧啶-2,4(1H,3H)-二酮。将化合物11.2(0.50g,1.4mmol,1.0当量)溶于三氟乙酸(1mL)中。将反应混合物在室温搅拌30分钟,然后减压浓缩。将所得的残留物通过制备性RP-HPLC纯化(10%CH3CN在H2O中的溶液,40min,25mL/min)得到300mg(96%)标题化合物,其为白色固体。LC/MS:m/z(ES+)217(M+H)+。1H NMR(400MHz,DMSO-d6):δppm 5.90(s,1H),5.35(m,1H),4.00(m,1H),3.85-3.68(m,3H),2.20(m,1H),2.01(m,1H)。
化合物11. 6-(((S)-1-苯基乙基)氨基)-3-(四氢呋喃-3-基)嘧啶-2,4(1H,3H)-二酮。
标题化合物使用与用于制备9的操作相似的操作制备,除了使用11.3(22mg,0.10mmol,1.00当量)代替9.3,得到15mg(50%)标题化合物,其为白色固体。LC/MS:m/z(ES+)302(M+H)+。1H NMR(400MHz,CDCl3):δppm 10.50(1H),7.50-7.20(m,5H),5.90(m,1H),5.60(m,1H),4.78(m,1H),4.45(s,1H),4.20(m,1H),4.05-3.90(m,2H),3.90-3.80(m,1H),2.45-2.10(m,2H),1.55(d,J=6.7Hz,3H)。
实施例12.制备(S)-3-(1-(甲基磺酰基)哌啶-4-基)-6-(1-苯基乙基氨基)嘧啶-
2,4(1H,3H)-二酮。
化合物12.1. 4-(3-苯甲酰基脲基)哌啶-1-羧酸叔丁酯。在0℃向异氰酸苯甲酰基酯(4.8g,32.6mmol)在CH2Cl2(180mL)中的溶液中加入4-氨基-1-N-boc-哌啶(6.0g,30mmol)。将反应混合物在室温搅拌4h并浓缩。将残留物用Et2O(100mL)处理。将析出物过滤并用Et2O洗涤得到5.70g(55%)标题化合物,其为白色固体。LC/MS:m/z(ES+)337(M+H)+。
化合物12.2. 4-脲基哌啶-1-羧酸叔丁酯。向12.1(5.60g,16.1mmol)在CH3OH(70mL)和H2O(70mL)中的混合物中分批加入氢氧化钠(11.6g,290mmol)。将反应混合物在室温搅拌过夜,然后回流1h。将混合物冷却至室温并减压浓缩除去CH3OH。将析出物过滤,用H2O洗涤并干燥得到3.2g(82%)标题化合物,其为白色固体。LC/MS:m/z(ES+)266(M+Na)+。
化合物12.3. 4-(2,4,6-三氧代-四氢嘧啶-1(2H)-基)哌啶-1-羧酸叔丁酯。向12.2(3.63g,14.9mmol)、丙二酸二乙酯(2.6mL,16.5mmol,1.1当量)和无水乙醇(60mL)的混合物中加入NaOEt(21%在EtOH中,6.6mL,17.7mmol,1.2当量)。将混合物回流14h并浓缩。将残留物吸收在H2O(15mL)中并用EtOAc(2×30mL)洗涤。分离水层并用浓HCl调节至pH=5。将析出物过滤,用H2O洗涤并干燥得到3.70g(80%)标题化合物,其为灰白色固体。LC/MS:m/z(ES+)334(M+Na)+。
化合物12.4. 6-氯-3-(哌啶-4-基)嘧啶-2,4(1H,3H)-二酮。向12.3(2.55g,8.19mmol)和POCl3(10mL,100.65mmol)的混合物中逐滴加入H2O(0.41mL,22.78mmol)。将混合物在120℃搅拌30min,然后浓缩。将残留物小心地吸收在冰水(20g)中。向混合物中分批加入K2CO3(~8.0g)直到pH为~7。将析出物过滤,用H2O(20mL)和EtOAc(50mL)洗涤。将所得的物质干燥得到1.45g(77%)标题化合物,其为灰白色固体。LC/MS:m/z(ES+)230(M+H)+。
化合物12.5. 6-氯-3-(1-(甲基磺酰基)哌啶-4-基)嘧啶-2,4(1H,3H)-二酮。向12.4(380mg,1.65mmol,1.0当量)和CH2Cl2(8mL)的混合物中加入Et3N(0.70mL,4.95mmol,3当量)和甲磺酰氯(0.23mL,2.5mmol,1.5当量)。将混合物在室温搅拌2h,然后用H2O(3mL)淬灭得到析出物。将析出物过滤并用CH2Cl2(3×3mL)洗涤。将滤液浓缩至~1.5mL。过滤第二批析出物,随后用H2O(2×1mL)和CH2Cl2(3×2mL)洗涤。合并析出物得到320mg(63%)标题化合物,其为灰白色固体。LC/MS:m/z(ES+)308(M+H)+。
化合物12.(S)-3-(1-(甲基磺酰基)哌啶-4-基)-6-(1-苯基乙基氨基)嘧啶-2,4(1H,3H)-二酮。将12.5(20mg,0.065mmol)和(S)-α-甲基苄基胺(180mg,1.5mmol,23当量)的混合物在125℃搅拌1h。将混合物减压浓缩,溶于CH3OH中并过滤。将滤液使用制备性RP-HPLC纯化(历时40min用线性梯度20%至100%CH3CN在H2O中的溶液(0.1%甲酸缓冲剂)洗脱)得到16mg(63%)标题化合物,其为灰白色固体。LC/MS:m/z(ES+)393(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.40(br s,1H),7.35-7.25(m,4H),7.15(m,1H),6.55(s,1H),4.58(m,1H),4.42(m,1H),4.30(s,1H),3.52(m,2H),2.79(s,3H),2.70-2.62(m,2H),2.50-2.48(m,2H),1.48-1.38(m,2H),1.32(d,J=6.8Hz,3H)。
实施例13.制备(S)-4-(2,6-二氧代-4-(1-苯基乙基氨基)-2,3-二氢嘧啶-1(6H)-
基)哌啶-1-羧酸甲酯。
化合物13.1. 4-(4-氯-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)哌啶-1-羧酸甲酯。向12.4(115mg,0.5mmol,1.0当量)和CH2Cl2(2mL)的混合物中先后加入Et3N(0.14mL,1.5mmol,3.0当量)和氯甲酸甲酯(95mg,1.0mmol,2.0当量)。将混合物在室温搅拌1h,用CH2Cl2(8mL)稀释,用饱和NaHCO3水溶液(1mL)、H2O(1mL)和盐水(1mL)洗涤,用无水Na2SO4干燥并浓缩得到105mg(73%)灰白色固体。LC/MS:m/z(ES+)288(M+H)+。
化合物13.(S)-4-(2,6-二氧代-4-(1-苯基乙基氨基)-2,3-二氢嘧啶-1(6H)-基)哌啶-1-羧酸甲酯。将13.1(58mg,0.20mmol)和(S)-α-甲基苄基胺(240mg,1.5mmol)的混合物在120℃搅拌0.5h。标题化合物使用与用于制备9的操作相似的操作制备,得到40mg(63%)标题化合物,其为灰白色固体。LC/MS:m/z(ES+)373(M+H)+。1H-NMR(400MHz,CDCl3):δppm 9.85(s,1H),7.29-7.15(m,5H),5.75(br s,1),4.80(m,1H),4.60(s,1H),4.35(m,1H),4.20-4.00(m,2H),3.58(s,3H),2.80-2.70(m,2H),2.46(m,2H),1.50(m,2H),1.38(d,J=6.7Hz,3H)。
实施例14.制备3-(R)-仲丁基-6-((S)-1-(3-甲氧基苯基)乙基氨基)嘧啶-2,4
(1H,3H)-二酮。
化合物14.1.(R)-1-仲丁基脲。将异氰酸苯甲酰基酯(5.36g,36.5mmol,1.05当量)溶于CH2Cl2(20mL)中并在冰浴中冷却至0℃。在搅拌下小心地加入(R)-丁-2-胺(2.54g,34.7mmol,1当量)在CH2Cl2(10mL)中的溶液。将混合物在室温搅拌3h。反应完成后,将混合物浓缩。将残留物混悬在Et2O(20mL)中并过滤。将固体吸收在CH3OH和H2O的1:1混合物(200mL)中,随后加入NaOH(6.9g,174mmol,5当量)。将反应混合物在室温搅拌过夜。将CH3OH从溶液中蒸发并收集所得的析出物(1.66g,39%)。LC/MS:m/z(ES+)117(M+H)+。
化合物14.2.(R)-1-仲丁基嘧啶-2,4,6(1H,3H,5H)-三酮。将化合物14.1(1.66g,14.3mmol,1.0当量)溶于EtOH(10mL)中并加入丙二酸二乙酯(1.8mL,15.7mmol,1.1当量)和NaOEt(5.6mL,17.1mmol,1.2当量)。将反应混合物在80℃搅拌2h,然后冷却至室温。加入水(20mL),然后将EtOH通过蒸发除去。加入KHSO4(过量)以饱和水层,然后将其用EtOAc萃取。将合并的有机层用无水MgSO4干燥并浓缩得到1.6g(61%)标题化合物,其作为粗残留物无需进一步纯化即使用。LC/MS:m/z(ES-)183(M-H)-。
化合物14.3.(R)-3-仲丁基-6-氯嘧啶-2,4(1H,3H)-二酮。将14.2(1.6g,8.7mmol,1当量)和POCl3(648μL,7.0mmol,0.8当量)在CH3CN(10mL)中的混合物在90℃搅拌2h。再加入POCl3(0.8当量)并在90℃搅拌3h。将反应混合物冷却至室温,小心地用CH3OH(10mL)淬灭,搅拌30分钟并用正相HPLC纯化(先后使用0-25%CH3OH/CH2Cl2和CH3OH冲洗)。产物和原料共同洗脱。将混合物浓缩,将残留物吸收在CH3CN(10mL)中并加入POCl3(648μL)。将反应混合物在90℃搅拌3h,然后冷却至室温。将反应混合物小心地用CH3OH(10mL)淬灭并搅拌30分钟。将反应混合物通过正相HPLC纯化(使用前述条件),浓缩并真空干燥得到450mg(32%)标题化合物,其为灰白色固体。LC/MS:m/z(ES-)201(M-H)-。
化合物14.3-(R)-仲丁基-6-((S)-1-(3-甲氧基苯基)乙基氨基)嘧啶-2,4(1H,3H)-二酮。将14.3(150mg,0.74mmol,1.0当量)在无水(S)-1-(3-甲氧基苯基)乙胺(400μL)中的混合物在90℃搅拌过夜。将反应混合物使用制备性RP-HPLC在Agilent***上纯化(历时45min使用梯度0-40%CH3CN在H2O中的溶液)得到13mg(6%)标题化合物,其为灰白色固体。LC/MS:m/z(ES+)318(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.79(s,1H),7.28(t,J=8.1Hz,1H),6.94-6.88(m,2H),6.84(dd,J=8.2,1.7Hz,1H),6.51(d,J=6.4Hz,1H),4.72-4.59(m,1H),4.47(m,1H),4.35(s,1H),3.76(s,3H),1.98-1.84(m,1H),1.61(m,1H),1.39(d,J=6.7Hz,3H),1.25(d,J=6.9Hz,3H),0.70(t,J=7.4Hz,3H)。
实施例15.制备(S)-6-(1-苯基乙基氨基)-3-(吡啶-3-基)嘧啶-2,4(1H,3H)-二
酮。
化合物15.1. 1-(吡啶-3-基)脲。将异氰酸苯甲酰基酯(3.28g,22.3mmol,1.05当量)吸收在CH2Cl2(30mL)中并冷却至-10℃。在搅拌下分批加入吡啶-3-胺(2g,21.2mmol,1当量)。将混合物在室温搅拌3h。反应完成后,将其浓缩,然后吸收在CH3OH和H2O的1:1混合物(100mL)中,随后加入NaOH(4.25g,106.3mmol,5当量)。将反应混合物在室温搅拌过夜,浓缩至干,然后与甲苯共沸三次。将10%CH3OH在EtOAc中的混合物(100mL)加到固体中并搅拌10分钟,随后过滤。将固体混悬并再过滤两次。将合并的滤液再过滤一次以除去任何固体,使其通过滤器并浓缩。将残留物用EtOAc(5mL)研磨并真空干燥得到3.5g粗物质(灰白色固体),其无需进一步纯化即使用。LC/MS:m/z(ES+)138(M+H)+。
化合物15.2. 1-(吡啶-3-基)嘧啶-2,4,6(1H,3H,5H)-三酮。将化合物15.1(3.0g,21.8mmol,1.0当量)吸收在EtOH(20mL)中,随后加入丙二酸二乙酯(2.75mL,24.1mmol,1.1当量)和NaOEt(8.5mL,26.3mmol,1.2当量)。将反应混合物在85℃搅拌过夜,然后冷却至室温。缓慢加入水(100mL),随后小心地加入碳酸氢钠(8g)。将所得的混合物用EtOAc洗涤三次。将水层浓缩至50mL并加入CH3OH(150mL)。将析出物通过过滤除去并将滤液浓缩。将所得的残留物通过快速色谱纯化(硅胶,0-25%CH3OH/CH2Cl2)得到1.70g(38%)标题化合物,其为浅黄色固体。LC/MS:m/z(ES+)206(M+H)+。
化合物15.3. 6-氯-3-(吡啶-3-基)嘧啶-2,4(1H,3H)-二酮。将15.2(700mg,3.41mmol,1.0当量)和POCl3(255μL,2.7mmol,0.8当量)在CH3CN(10mL)中的混合物在90℃搅拌2h。再加入POCl3(0.8当量)并在90℃继续搅拌2h。再加入POCl3(1.6当量),随后小心地加入H2O(150μl,2.5当量)。将反应混合物在90℃搅拌过夜。冷却至室温后,将混合物过滤并将固体小心地用CH3OH(1mL)洗涤。将乙酸乙酯(20mL)加到滤液中并将所得的析出物通过过滤收集并真空干燥得到230mg(30%)标题化合物,其为浅黄色固体。LC/MS:m/z(ES+)224(M+H)+。
化合物15.(S)-6-(1-苯基乙基氨基)-3-(吡啶-3-基)嘧啶-2,4(1H,3H)-二酮。将15.3(100mg,0.45mmol,1当量)在无水(S)-(-)-α-甲基苄基胺(500μL)中的混合物在100℃搅拌过夜。冷却后,将反应混合物使用制备性RP-HPLC在Agilent***上纯化(历时45min使用梯度0-40%CH3CN在H2O中的溶液),随后在制备性TLC板(2000μm)上进行第二次纯化(使用7%CH3OH/CH2Cl2)得到39.5mg(28%)标题化合物。LC/MS:m/z(ES+)309(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 11.15(s,1H),8.49(dd,J=4.8,1.4Hz,1H),8.34(d,J=2.4Hz,1H),7.65-7.58(m,1H),7.44(dd,J=8.1,4.8Hz,1H),7.37(m,5H),7.26(m,1H),4.61-4.53(m,1H),4.48(s,1H),1.39(d,J=6.8Hz,3H)。
实施例16.制备(S)-3-(异噁唑-3-基)-6-(1-苯基乙基氨基)嘧啶-2,4(1H,3H)-二
酮(16)。
标题化合物使用与用于制备化合物15的操作相似的操作制备,除了使用异噁唑-3-胺代替吡啶-3-胺。LC/MS:m/z(ES+)299(M+H)+。
1H-NMR(400MHz,DMSO-d6):δppm 8.96(s,1H),7.38(d,J=3.9Hz,4H),7.28(dd,J=8.4,4.3Hz,2H),7.10(s,1H),6.63(s,1H),4.74-4.52(m,1H),4.48(s,1H),1.44(d,J=6.6Hz,3H)。
实施例17.制备(S)-6-((1-(3-(1H-吡唑-1-基)苯基)乙基)氨基)-3-异丙基嘧啶-
2,4(1H,3H)-二酮(17)。
标题化合物通过35与1H-吡唑在碘化亚铜、碳酸铯和反式-N,N’-二甲基环己烷-1,2-二胺存在下的Ullman偶联(P.E.Fanta.“The Ullmann Synthesis of Biaryls”.Synthesis,1974,9-21)来制备。LC/MS:m/z(ES+)340(M+H)+。1H-NMR(400MHz,CD3OD):δppm8.26(s,1H),7.70(m,2H),7.66(m,1H),7.51(m,1H),7.34(m,1H),6.55(s,1H),5.05(m,1H),4.62(m,1H),1.58(d,J=6.8Hz,3H),1.37(m,6H)。
实施例18.制备其它嘧啶二酮化合物。
表1中的化合物根据如上所述的实施例制备。
表1.化合物和分析数据
实施例48.制备(S)-6-((1-苯基乙基)氨基)-3-丙基嘧啶-2,4(1H,3H)-二酮。
化合物48.1. 1-丙基脲。在0℃向正丙基胺(2.15g,36.5mmol,1.00当量)在CH2Cl2(35mL)中的搅拌溶液中逐滴加入异氰酸三甲基甲硅烷基酯(4.94g(85%纯度),36.5mmol,1.00当量)。将反应混合物在室温搅拌72h,然后冷却至0℃。将冰冷的混合物通过逐滴加入CH3OH(10mL)淬灭并减压浓缩。将所得的固体混悬在Et2O(30mL)中并过滤。将固体进一步用Et2O(30mL)洗涤并干燥得到2.0g(38%)标题化合物,其为白色固体。
化合物48.2. 1-丙基嘧啶-2,4,6(1H,3H,5H)-三酮。向48.1(600mg,5.88mmol,1.00当量)在CH3OH(1mL)中的溶液中加入丙二酸二乙酯(960mg,6.0mmol,1.02当量)和甲醇钠(1mL,25wt%NaOCH3在CH3OH中的溶液)。将反应混合物在微波反应器中在130℃加热1h。将混合物冷却并将混合物用浓HCl小心地调节至pH=3。除去挥发物并加入H2O(10mL)。固体析出并过滤。将其进一步用额外的H2O(10mL)洗涤并干燥得到560mg(56%)标题化合物,其为白色固体。
化合物48.3. 6-氯-3-丙基嘧啶-2,4(1H,3H)-二酮。将化合物48.2(560mg,3.30mmol)和POCl3(2mL)加到厚壁压力容器中,随后将其密封。将所得的溶液在防爆屏蔽后加热至70℃并搅拌50分钟。将反应混合物冷却并减压浓缩。向所得的残留物中加入CH2Cl2(30mL),然后将其减压除去。再进行一次加入和蒸发CH2Cl2(30mL),然后将所得的残留物用CH2Cl2(50mL)稀释。向有机层中小心地加入饱和NaHCO3水溶液(50mL)。分离各层并将有机层进一步用H2O(30mL)和盐水(30mL)洗涤。将有机层浓缩并通过快速色谱纯化(硅胶,使用10%EtOAc在CH2Cl2中的溶液)得到160mg(26%)标题化合物,其为白色固体。
化合物48.(S)-6-((1-苯基乙基)氨基)-3-丙基嘧啶-2,4(1H,3H)-二酮。向48.3(160mg,0.85mmol,1.0当量)在1,4-二噁烷(1.5mL)中的溶液中加入Et3N(200μL)和(S)-α-甲基苄基胺(235mg,1.94mmol,2.3当量)。将混合物在微波反应器中在130℃加热2h。将混合物冷却并浓缩。将所得的残留物用H2O:CH3CN的8:3混合物处理,这导致析出。将固体过滤并先后用H2O(10mL)和EtOAc(10mL)洗涤。将固体干燥得到67mg(29%)标题化合物,其为白色固体。LC/MS:m/z(ES+)274(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.92(br s,1H),7.36-7.22(m,5H),6.54(d,J=7.0Hz,1H),4.50(quin,J=6.7Hz,1H),4.35(s,1H),3.54(dd,J=8.0,6.9Hz,2H),1.42-1.36(m,5H),0.76(t,J=7.6Hz,3H)。
实施例49.制备(S)-3-(3,5-二氟苯基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,
3H)-二酮。
化合物49.1. 1-(3,5-二氟苯基)脲。在氩气下在室温向3,5-二氟苯胺(4.0g,31mmol,1.00当量)在CH2Cl2(50mL)中的搅拌溶液中逐滴加入异氰酸三甲基甲硅烷基酯(3.56g,30.90mmol,1.00当量)。将反应混合物搅拌过夜并通过逐滴加入CH3OH(50mL)淬灭。将反应混合物减压浓缩并将所得的残留物通过快速色谱纯化(硅胶,用CHCl3/CH3OH(10:1至7:1)洗脱)得到2.0g(38%)标题化合物,其为白色固体。1H-NMR(400MHz,DMSO-d6):δppm8.96(s,1H),7.16-7.10(m,2H),6.72-6.66(m,1H),6.07(br s,2H)。
化合物49.2. 1-(3,5-二氟苯基)嘧啶-2,4,6(1H,3H,5H)-三酮。向49.1(1.6g,0.0093mol,1.1当量)在CH3OH(20mL)中的搅拌溶液中加入丙二酸二乙酯(1.4g,0.0087mol,1.0当量)和甲醇钠(1.25g,0.0231mol,2.7当量)。将所得的混合物在65℃搅拌过夜。冷却至环境温度后,使用1N HCl水溶液将pH小心地调节至5。将所得的溶液用EtOAc(3×50mL)萃取。合并有机层并减压浓缩。将残留物用CH3OH(50mL)洗涤并将所得的固体通过过滤分离得到700mg(31%)标题化合物,其为白色固体。1H-NMR(400MHz,DMSO-d6):δppm 11.66(s,1H),7.43-7.35(m,1H),7.11-7.08(m,2H),3.77(s,2H)。
化合物49.3. 6-氯-3-(3,5-二氟苯基)嘧啶-2,4(1H,3H)-二酮。在氩气下向含有49.2(740mg,3.08mmol,1.00当量)的25mL圆底烧瓶中加入三乙基苄基氯化铵(840mg,1.20当量)和POCl3(3mL)。将所得的溶液在50℃搅拌4h。将反应混合物冷却并通过小心地加入水/冰(20mL)淬灭。将溶液的pH用2N氢氧化钠调节至5。将所得的溶液用EtOAc(2×10mL)萃取并合并有机层。将有机层用盐水(10mL)洗涤,用无水MgSO4干燥,过滤并减压浓缩。这得到500mg(粗的)标题化合物,其为白色固体。1H-NMR(400MHz,DMSO-d6):δppm 12.60(br,1H),7.38-7.32(m,1H),7.21-7.16(m,2H),6.05(s,1H)。
化合物49.(S)-3-(3,5-二氟苯基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮。向49.3(200mg,0.77mmol)中加入(S)-α-甲基苄基胺(1.5mL)。将所得的溶液在120℃搅拌2h。将反应混合物用DMF(3mL)稀释并将粗产物(100mg)通过使用以下条件的制备性RP-HPLC纯化:XBridge Prep C18OBD柱,5μm,19*150mm;流动相:含有0.05%TFA的H2O和CH3CN(40.0%至90.0%CH3CN,10min)。这得到21.6mg(8%)标题化合物,其为白色固体。LC/MS:m/z(ES+)344(M+H)+。1H-NMR(300MHz,DMSO-d6):δppm 10.25(br s,1H),7.38-7.35(m,4H),7.28-7.21(m,2H),7.03-6.98(m,2H),6.76(d,J=6.9Hz,1H),4.59(quin,J=6.7Hz,1H),4.50(d,J=2.0Hz,1H),1.42(d,J=6.7Hz,3H)。
实施例50.制备(S)-3-异丙基-6-((1-(间甲苯基)乙基)氨基)嘧啶-2,4(1H,3H)- 二酮。
化合物50.1.(R,E)-2-甲基-N-(1-(间甲苯基)亚乙基)丙-2-亚磺酰胺。向1-(3-甲基苯基)乙酮(1.61g,12.0mmol,1.00当量)和(R)-(+)-2-甲基丙-2-亚磺酰胺(1.94g,14mmol,1.33当量)在THF(50mL)中的搅拌溶液中逐滴加入Ti(OEt)4(3.19g,14mmol,1.17当量)。将反应混合物在60℃搅拌16h,冷却至室温并用饱和NaHCO3水溶液(50mL)淬灭。分离各层并将水层进一步用EtOAc(2×100mL)萃取。将合并的有机层浓缩并将所得的残留物通过快速色谱纯化(硅胶,用0-5%CH3OH在CH2Cl2中的溶液洗脱)得到1.51g(53%)标题化合物,其为白色固体。LC/MS:m/z(ES+)238(M+H)+。
化合物50.2.(R)-2-甲基-N-((S)-1-(间甲苯基)乙基)丙-2-亚磺酰胺。在78℃在氮气气氛下向50.1(1.51g,6.37mmol)在THF(30mL)中的溶液中加入L-selectride(逐滴,10mL,1.0M在THF中,10mmol)。将反应混合物温热至0℃,搅拌1h并小心地用饱和NH4Cl水溶液(30mL)淬灭。分离各层并将水层进一步用EtOAc(2×50mL)萃取。将合并的有机层浓缩并将所得的残留物通过快速色谱纯化(硅胶,用0-5%CH3OH在CH2Cl2中的溶液洗脱)得到0.85g(56%)标题化合物。LC/MS:m/z(ES+)240(M+H)+。
化合物50.3.(S)-1-(间甲苯基)乙-1-胺盐酸盐。向无水EtOH(10mL)中加入AcCl(1.5mL,逐滴)。将混合物搅拌10分钟,然后加到50.2(0.85g,3.56mmol)在EtOH(3mL)中的溶液。将反应混合物在环境温度搅拌2h并浓缩。将所得的固体混悬在Et2O中并过滤。将固体再用Et2O洗涤并干燥得到402mg(66%)标题化合物,其为白色固体。LC/MS:m/z(ES+)136(M+H)+。
化合物50.4.(S)-1-(间甲苯基)乙-1-胺。向50.3(205mg,1.20mmol)在CH2Cl2(10mL)中的搅拌溶液中加入MP-碳酸盐(1.0g,3.18mmol/g)。将反应混合物在室温搅拌1h,然后过滤。将固体珠子再用10mL CH2Cl2洗涤并将合并的滤液浓缩得到标题化合物,其无需任何纯化即使用。
化合物50.(S)-3-异丙基-6-((1-(间甲苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮。在0.5至2.0mL微波管中向50.4(推定~1.2mmol,来自前述反应,2.0当量)中加入化合物1.3(110mg,0.59mmol,1.0当量)。将微波管密封并在防爆屏蔽后在120℃加热2.5h。冷却(至~60℃)后,将NMP(2.5mL)加到反应混合物中。将混合物用超声波处理并加热(至~60℃)直到固体完全溶解。将所得的溶液冷却至40℃并加入H2O/CH3CN的3:1混合物(5mL)。固体析出并通过过滤收集。随后将浅米色固体用H2O洗涤并干燥得到97mg(57%)标题化合物,其为白色固体。LC/MS:m/z(ES+)288(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.73(br s,1H),7.22(t,J=8.0Hz,1H),7.12-7.04(m,3H),6.45(d,J=8.0Hz,1H),4.90-4.86(m,1H),4.42(q,J=6.7Hz,1H),4.31(d,J=2.4Hz,1H),2.29(s,3H),1.36(d,J=6.7Hz,3H),1.27-1.23(m,6H)。
实施例51.制备(S)-6-((1-(4-氟苯基)丙-2-基)氨基)-3-异丙基嘧啶-2,4(1H, 3H)-二酮。
化合物51.1. 2-(4-氟苯基)-N-甲氧基-N-甲基乙酰胺。向2-(4-氟苯基)乙酸(15g,97.32mmol,1.00当量)在CH2Cl2(300mL)中的搅拌溶液中加入甲氧基(甲基)胺盐酸盐(11.1g,113.79mmol,1.20当量)、4-二甲基氨基吡啶(12g,98.22mmol,1.00当量)、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(28.2g,147.10mmol,1.50当量)和DIEA(37.5g,290.14mmol,3.00当量)。将所得的溶液在室温搅拌16h,然后用EtOAc(150mL)稀释。将有机层用1N HCl水溶液(2×150mL)和盐水(2×150mL)洗涤。然后将其用无水Na2SO4干燥并减压浓缩。将粗残留物通过快速色谱纯化(硅胶,用EtOAc/石油醚(1:3)洗脱)。这得到18g(88%)标题化合物,其为黄色油状物。1H-NMR(400MHz,CDCl3):δppm 7.29-7.25(m,2H),7.03-6.99(m,2H),3.75(s,2H),3.65(s,3H),3.21(s,3H)。
化合物51.2. 2-(4-氟苯基)乙醛。在氩气下在-10℃向51.1(3g,15.21mmol,1.00当量)在THF(60mL)中的搅拌溶液中分批加入LiAlH4(1.15g,30.30mmol,2.00当量)(小心…放热反应)。将所得的溶液在室温搅拌1h,然后冷却至-10℃。然后将反应混合物通过小心地加入饱和NH4Cl水溶液(50mL)淬灭。将所得的固体过滤并将滤液用EtOAc(3×50mL)萃取。合并有机层,用盐水(50mL)洗涤,用无水Na2SO4干燥并减压浓缩得到2.5g(粗的)标题化合物,其为黄色油状物。
化合物51.3.(S)-1-(4-氟苯基)丙-2-胺盐酸盐。标题化合物根据就制备5.3所述的方法合成,使用51.2代替3,5-二氟苯甲醛。LC/MS:m/z(ES+)154(M+H)+。
化合物51.4.(S)-1-(4-氟苯基)丙-2-胺。向1N NaOH水溶液(5mL)中加入51.3(300mg,1.59mmol)。将所得的混合物在25℃搅拌一小时。将所得的溶液用EtOAc(2×10mL)萃取。将有机层用无水硫酸钠干燥并减压浓缩得到160mg(65%)标题化合物。LC/MS:m/z(ES+)154(M+H)+。
化合物51.(S)-6-((1-(4-氟苯基)丙-2-基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮。向51.4(160mg,1.04mmol,2.00当量)在NMP(0.5mL)中的搅拌溶液中加入1.3(99mg,0.52mmol,1.00当量)和质子海绵(168mg,0.78mmol,1.50当量)。将所得的溶液在100℃在油浴中搅拌5h。将反应混合物减压浓缩。将残留物(100mg)通过制备性RP-HPLC纯化得到30mg(19%)标题化合物,其为灰色固体。LC/MS:m/z(ES+)306(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.81(br s,1H),7.27(dd,J=8.8,5.6Hz,2H),7.17-7.12(m,2H),5.89(d,J=7.6Hz,1H),5.00-4.92(m,1H),4.58(s,1H),3.69-3.65(m,1H),2.74(d,J=6.4Hz,2H),1.31(d,J=6.8Hz,6H),1.08(d,J=6.4Hz,3H)。
实施例52.制备(R)-3-异丙基-6-((2,2,2-三氟-1-苯基乙基)氨基)嘧啶-2,4(1H,
3H)-二酮(52)。
向0.2-0.5mL微波小瓶中加入1.3(85mg,0.45mmol)和(R)-2,2,2-三氟-1-苯基乙-1-胺(200μL,过量)。将反应混合物密封并在180℃在微波反应器中加热40分钟。将反应混合物冷却至环境温度,然后加入NMP(1mL)以完全溶解固体。随后加入H2O/CH3CN的2:1混合物(6mL),这导致析出。将固体通过过滤分离,用H2O洗涤并干燥得到50mg(34%)标题化合物,其为白色固体。LC/MS:m/z(ES+)328(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.79(br s,1H),7.50-7.40(m,5H),5.66-5.56(m,2H),4.92-4.87(m,2H),1.28-1.25(m,6H)。
实施例53.制备3-((R)-1-(苄基氧基)丙-2-基)-6-(((S)-1-苯基乙基)氨基)嘧 啶-2,4(1H,3H)-二酮。
化合物53.1.(R)-1-(1-羟基丙-2-基)脲。在氮气下在0℃向(R)-(-)-2-氨基-1-丙醇(0.65g,8.68mmol,1当量)在CH2Cl2(10mL)中的搅拌溶液中逐滴加入异氰酸三甲基甲硅烷基酯(1.00g,8.68mmol,1.0当量)。将反应混合物搅拌过夜同时缓慢温热至室温。冷却至0℃后,逐滴加入CH3OH(10mL)。将所得的溶液在室温搅拌2h,然后减压浓缩得到标题化合物(1.02g,99%),其为白色固体。
化合物53.2.(R)-1-(1-(苄基氧基)丙-2-基)脲。在0℃向氢化钠(0.52g,13.2mmol,1.5当量)在THF(10mL)中的混悬液中加入53.1(1.02g,8.67mmol,1当量)。将反应混合物在0℃在氮气下搅拌20分钟,然后加入苄基溴(1.03mL,8.67mmol,1当量)。将反应混合物搅拌过夜同时缓慢温热至室温。将反应混合物用H2O(3mL)淬灭并萃取到EtOAc(15mL)中,用无水Na2SO4干燥,过滤并浓缩。将所得的残留物通过快速色谱纯化(10%CH3OH在CH2Cl2中的溶液)得到510mg(28%)标题化合物。LC/MS:m/z(ES+)209(M+H)+。
1H-NMR(400MHz,CDCl3):δppm 7.42-7.27(m,5H),4.79(d,J=6.7Hz,1H),4.52(d,J=2.7Hz,2H),3.91(s,1H),3.51(dd,J=9.4,3.9Hz,1H),3.40(dd,J=9.2,5.3Hz,1H),1.19(d,J=7.0Hz,3H)。
化合物53.3.(R)-1-(1-(苄基氧基)丙-2-基)嘧啶-2,4,6(1H,3H,5H)-三酮。向含有53.2(0.51g,2.42mmol,1当量)在CH3OH(10mL)中的溶液的微波小瓶中先后加入丙二酸二乙酯(2.55g,2.55mmol,1.05当量)和甲醇钠(25%wt在CH3OH中的溶液,1.31g,6.06mmol,2.5当量)。将小瓶盖好并将反应混合物在微波反应器中在150℃加热15分钟。冷却至室温后,将反应混合物用H2O(2mL)淬灭并将pH用浓HCl调节至3。将反应混合物转移到圆底烧瓶中并减压浓缩。将所得的残留物通过快速色谱纯化(5%CH3OH在CH2Cl2中的溶液)得到0.62g(92%)标题化合物,其为白色固体。LC/MS:m/z(ES+)277(M+H)+。1H-NMR(400MHz,CDCl3):δppm 7.99(s,1H),7.38-7.22(m,5H),5.16-5.11(m,1H),4.52(d,J=12.0Hz,1H),4.45(d,J=12.0Hz,1H),4.02(t,J=9.8Hz,1H),3.56(q,J=1.57Hz,2H),1.37(d,J=7.00Hz,3H)。
化合物53.4.(R)-3-(1-(苄基氧基)丙-2-基)-6-氯嘧啶-2,4(1H,3H)-二酮。向含有53.3(0.25g,0.91mmol,1当量)的微波小瓶中加入三乙基苄基氯化铵(0.28g,1.26mmol,1.4当量)和POCl3(1mL)。将小瓶盖好并将反应混合物在微波反应器中在130℃加热1分钟。将反应混合物转移到圆底烧瓶中并减压浓缩。将所得的残留物溶于CH2Cl2(5mL)中并小心地加入水(2mL)。将混合物搅拌10分钟。分离各层并将有机层用Na2SO4干燥,过滤并减压浓缩。将所得的残留物通过快速色谱纯化(硅胶,5%CH3OH在CH2Cl2中的溶液)得到150mg(55%)标题化合物。LC/MS:m/z(ES+)295(M+H)+。1H-NMR(400MHz,CDCl3):δppm 10.27(s,1H),7.36-7.20(m,5H),5.32-5.21(m,2H),4.57(d,J=12.0Hz,1H),4.48(d,J=12.0Hz,1H),4.10(dd,J=10.0,9.2Hz,1H),1.40(d,J=7.0Hz,3H)。
化合物53.3-((R)-1-(苄基氧基)丙-2-基)-6-(((S)-1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮。向含有(S)-α-甲基苄基胺(1.5mL)的微波小瓶中加入53.4(0.12g,0.42mmol)。将小瓶盖好并将反应混合物在微波反应器中在150℃加热10分钟。冷却后,将反应混合物通过硅胶塞过滤(10%CH3OH在CH2Cl2中的溶液)并将滤液减压浓缩。将所得的残留物溶于CH2Cl2(10mL)中并用10%HCl(5mL)洗涤。将有机层用无水Na2SO4干燥,过滤并浓缩得到150mg(94%)标题化合物。LC/MS:m/z(ES+)380(M+H)+。1H-NMR(400MHz,CDCl3):δppm 9.96(br s 1H),7.35-7.24(m,10H),4.70(br s,1H),4.53-4.41(m,4H),4.03-3.99(m,1H),3.65-3.61(m,1H),1.49(d,J=6.7Hz,3H),1.37(d,J=7.0Hz,3H)。
实施例54.制备3-((R)-1-羟基丙-2-基)-6-(((S)-1-苯基乙基)氨基)嘧啶-2,4 (1H,3H)-二酮(54)。
向53(0.10g,0.26mmol,1当量)在EtOH(2mL)中的溶液中加入钯/炭(10wt%载量(干基),基质活性炭,湿载体,Degussa型,0.025g)。将反应烧瓶用氮气净化,然后配备氢气气囊。将反应混合物抽空,然后用氢气填充。重复三次该抽空/净化操作并将反应混合物在室温搅拌4h。用氮气净化后,将反应混合物过滤并将滤液减压浓缩。将所得的残留物混悬在CH3CN(2mL)中并将析出物通过过滤分离。将析出物溶于CH2Cl2:CH3OH(1:1,2mL)中并通过.2μM PTFE 25mm滤器过滤并减压浓缩得到27mg(35%)标题化合物。LC/MS:m/z(ES+)290(M+H)+。1H-NMR(400MHz,CDCl3):δppm 9.67(s,1H),7.35-7.24(m,5H),5.64(d,J=5.5Hz,1H),5.08-5.04(m,1H),4.66(s,1H),4.42-4.35(m,1H),4.24(s,1H),4.04-3.91(m,1H),3.78-3.68(m,1H),1.50(d,J=6.70Hz,3H),1.35(d,J=7.00Hz,3H)。
实施例55.制备(S)-3-异丙基-6-((1-(3-(三氟甲基)苯基)乙基)氨基)嘧啶-2,4 (1H,3H)-二酮。
化合物55.1.(S)-1-(3-(三氟甲基)苯基)乙-1-胺盐酸盐。标题化合物根据就制备5.3所述的方法合成,使用3-(三氟甲基)苯甲醛代替3,5-二氟苯甲醛。
化合物55.(S)-3-异丙基-6-((1-(3-(三氟甲基)苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮。在惰性氩气气氛下向55.1(59.8mg,0.27mmol,1.00当量)在DMSO(1.5mL)中的搅拌溶液中加入Et3N(0.2mL)和1.3(50mg,0.27mmol,1.00当量)。将所得的溶液在120℃在油浴中搅拌6h。冷却后,将混合物减压浓缩并将所得的残留物(75mg)通过制备性RP-HPLC纯化得到6.5mg(7%)标题化合物,其为白色固体。LC/MS:m/z(ES+)342(M+H)+。1H-NMR(300MHz,DMSO-d6):δppm 7.78(s,1H),7.74-7.60(m,3H),7.20(br,1H),6.02(br,1H),4.96(dt,J=10.1,5.1Hz,1H),4.67-4.64(m,1H),4.36(s,1H),1.44(d,J=6.8Hz,3H),1.31-1.28(m,6H)。
实施例56.制备(S)-3-异丙基-6-((1-(2-氰基苯基)乙基)氨基)嘧啶-2,4(1H,
3H)-二酮(56)。
中间体56.1使用与用于制备化合物35的操作相似的操作制备,使用1.3和(S)-1-(2-溴苯基)乙-1-胺盐酸盐(由相应的2-溴苯甲醛使用就实施例6.3所述的方法合成)。向56.1(40mg,0.11mmol,1.00当量)在DMF(2mL)中的搅拌溶液中加入Zn(CN)2(20mg,0.17mmol,1.50当量)和四(三苯基膦)钯(131mg,0.11mmol,0.20当量)。小心:含有氰化物的反应。将所得的溶液在氩气气氛下在100℃在油浴中搅拌2h。冷却后,将反应混合物用饱和FeSO4水溶液(5mL)淬灭。将所得的混合物用EtOAc(20mL)稀释并用饱和FeSO4水溶液(2×20mL)洗涤。将有机层用无水Na2SO4干燥,过滤并减压浓缩。将粗产物(5mg)通过使用以下条件的手性制备性HPLC纯化:柱:Phenomenex Lux-25μCellulose-2,30*150mm;流动相:己烷和EtOH(保持50.0%EtOH,35min),得到2.1mg(6%)标题化合物。LC/MS:m/z(ES+)299(M+H)+。1H-NMR(300MHz,CD3CN):δppm 8.59(br s,1H),7.73(d,J=8.4Hz,1H),7.61-7.56(m,1H),7.48-7.45(m,2H),5.09-4.94(m,3H),1.46(d,J=6.6Hz,3H),1.34-1.26(m,6H)。
实施例57.制备(S)-3-苄基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮。
化合物57.1.氯化3-乙氧基-3-氧代-1-(1-乙氧基)丙-1-亚胺鎓。向氰基乙酸乙酯(5.0g,44mmol)在无水Et2O(5mL)中的搅拌溶液中加入无水EtOH(3mL)。将反应混合物冷却至0℃并用HCl气体鼓泡10分钟。将反应混合物温热至室温并搅拌16h。将形成的白色析出物过滤并用Et2O(40mL)洗涤并干燥得到(6.99g)标题化合物,其为白色固体。LC/MS:m/z(ES+)160(M+H)+。
化合物57.2.(S,E/Z)-3-氨基-3-((1-苯基乙基)氨基)丙烯酸乙酯。向57.1(585mg,3.0mmol)在EtOH(15mL)中的搅拌溶液中加入DIEA(0.8mL)和(S)-α-甲基苄基胺(290mg,2.4mmol)。将反应混合物搅拌16h并浓缩。将粗物质通过快速色谱纯化(硅胶,用CH3OH在CH2Cl2中的溶液(0至10%)洗脱)得到0.57g(98%)标题化合物,其为澄清油状物。NMR分析表明产物为E/Z异构体的混合物。LC/MS:m/z(ES+)235(M+H)+。
化合物57.3.(S,Z)-3-(3-苄基脲基)-3-((1-苯基乙基)氨基)丙烯酸乙酯。平行进行两次反应,然后合并,这是因为其均形成产物(通过HPLC确定)。在第一次反应中,将异氰酸苄基酯(150μL,1.2mmol)加到57.2(143mg,0.61mmol)在CH3CN(1mL)中的搅拌溶液中。10min后,加入DIEA(300μL)。将反应混合物再搅拌10min并用H2O(12mL)淬灭。固体析出并通过过滤除去。在第二次反应中,将异氰酸苄基酯(150μL,1.2mmol)加到57.2(143mg,0.61mmol)和DIEA(300μL)在CH3CN(1mL)中的搅拌溶液中。10min后,将反应混合物用H2O(10mL)淬灭。将所得的混合物用EtOAc(40mL)稀释并分离各层。向有机层中加入来自第一次反应的滤液。分离各层并将有机层浓缩得到标题化合物,其无需进一步纯化即使用。
化合物57.(S)-3-苄基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮。进行两次反应,然后合并,这是因为其均形成产物(通过HPLC确定)。第一次反应使用1/3粗的57.3在CH3OH(1mL)中的溶液。将其在微波反应器中在120℃加热10min。将剩余的2/3粗的57.3在CH3OH(2mL)中的溶液在微波反应器中在120℃加热20min。冷却至环境温度后,合并反应混合物并将CH3OH减压除去。将含有0.1%TFA的CH3CN/H2O的50/50混合物(5mL)加到所得的残留物中。固体析出并过滤。将所得的棕色固体用EtOAc洗涤得到7mg标题化合物,其为白色固体。LC/MS:m/z(ES+)322(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 10.05(br s,1H),7.35-7.31(m,4H),7.26-7.16(m,6H),6.61(d,J=7.0Hz,1H),4.79(s,2H),4.52(quin,J=6.8Hz,1H),4.42(d,J=2.3Hz,1H),1.39(d,J=6.7Hz,3H)。
实施例58.制备(S)-3-(2,6-二氟苯基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,
3H)-二酮(58)。
标题化合物根据如在实施例50中所述的略微修改的操作合成。在此将1,4-二噁烷用作溶剂并将反应混合物在110℃加热16h。将所得的混合物冷却并减压浓缩。将粗物质通过制备性RP-HPLC纯化得到19mg标题化合物,其为白色固体。LC/MS:m/z(ES+)344(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 10.44(br s,1H),7.52-7.42(m,2H),7.39-7.36(m,3H),7.34-7.16(m,3H),6.91(br s,1H),4.65-4.56(m,1H),4.52(s,1H),1.43(d,J=6.7Hz,3H)。
实施例59.制备(S)-6-((1-(2,6-二氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,
3H)-二酮。
化合物59.1.2,6-二氟苯甲醛。标题化合物根据就制备51.2所述的方法合成。在此使用商购的2,6-二氟苯甲酸代替2-(4-氟苯基)乙酸。
化合物59.2.(S)-1-(2,6-二氟苯基)乙-1-胺盐酸盐。标题化合物根据就制备5.3所述的方法合成。在此使用59.1代替3,5-二氟苯甲醛。
化合物59.(S)-6-((1-(2,6-二氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮。59.1与1.3的反应以与在实施例51中所述的操作相似的方式进行。在此将反应混合物在130℃加热5h。通过手性HPLC对反应混合物进行的分析显示出非微小量的对映异构体。使用制备性手性HPLC对对映异构体进行分离,其使用EtOH:己烷的等度混合物(1:4)作为洗脱剂和Phenomenex Lux-25μCellulose-2,30*150mm柱(40min运行)。LC/MS:m/z(ES+)310(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.80(br s,1H),7.45-7.41(m,1H),7.18-7.14(m,2H),6.52(d,J=8.0Hz,1H),4.94-4.88(m,1H),4.79(quint,J=7.6Hz,1H),4.41(s,1H),1.56(d,J=6.8Hz,3H),1.30-1.26(m,6H)。
实施例60.制备(R)-6-((1-(2,6-二氟苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,
3H)-二酮(60R)。
标题化合物作为在实施例59中进行的化学反应的副产物产生。将其通过制备性手性HPLC分离,其使用EtOH:己烷的等度混合物(1:4)作为洗脱剂和Phenomenex Lux-25μCellulose-2,30*150mm柱(40min运行)。LC/MS:m/z(ES+)310(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.98-9.61(br,1H),7.45-7.41(m,1H),7.18-7.14(m,2H),6.52(d,J=8.0Hz,1H),4.94-4.88(m,1H),4.79(quint,J=7.6Hz,1H),4.41(s,1H),1.56(d,J=6.8Hz,3H),1.30-1.26(m,6H)。
实施例61.制备(S)-3-异丙基-6-((1-(吡啶-4-基)丙-2-基)氨基)嘧啶-2,4(1H, 3H)-二酮。
化合物61.1.N-甲氧基-N-甲基-2-(吡啶-4-基)乙酰胺。标题化合物根据就制备51.1所述的方法合成。在此使用商购的4-吡啶乙酸代替2-(4-氟苯基)乙酸。
化合物61.2. 1-(吡啶-4-基)丙-2-酮。向用惰性氩气气氛净化并保持的250mL 3颈圆底烧瓶中加入THF(70mL)和N-甲氧基-N-甲基-2-(吡啶-4-基)乙酰胺(7.0g,0.039mol,1.0当量)。将混合物冷却至0℃并逐滴加入CH3MgBr(3M在THF中的溶液,65mL,5.0当量)。将所得的溶液温热至环境温度并搅拌16h。将反应混合物冷却至0℃并通过加入饱和NH4Cl(水溶液,100mL)淬灭。将所得的溶液用EtOAc(3×200mL)萃取。合并有机层,用无水Na2SO4干燥并减压浓缩。将粗物质通过快速色谱纯化(硅胶,CH2Cl2/CH3OH(20:1))得到2.7g(51%)标题化合物,其为黄色油状物。1H-NMR(400MHz,CDCl3):δppm 8.58(m,2H),7.17(d,J=0.4Hz,2H),3.75(s,2H),2.24(s,3H)。
化合物61.3.(R)-2-甲基-N-((S)-1-(吡啶-4-基)丙-2-基)丙-2-亚磺酰胺。标题化合物根据在实施例50中所述的操作制备,使用61.2代替1-(3-甲基苯基)乙酮。在此使用L-selectride进行的还原反应导致标题化合物(61.3)(20%对映异构体过量)的分离。
化合物61.4.(S)-1-(吡啶-4-基)丙-2-胺。标题化合物使用在实施例5中所述的两步操作制备。首先通过用HCl在1,4-二噁烷中的溶液处理将磺酰胺61.3转化为盐酸盐(参见针对化合物5.3的操作)。随后将盐酸盐转化为游离碱(参见针对化合物5的操作)得到标题化合物(~20%ee)。
化合物61.(S)-3-异丙基-6-((1-(吡啶-4-基)丙-2-基)氨基)嘧啶-2,4(1H,3H)-二酮。标题化合物根据就51所述的操作制备。在此将反应混合物在100℃搅拌1h。将反应混合物减压浓缩并将残留物(100mg)通过制备性HPLC纯化得到13.1mg标题化合物,其为对映异构体的混合物。将对映异构体(13.1mg)通过手性制备性HPLC分离,其使用Chiralpak IC,2*25cm,5μm柱且使用EtOH:己烷的等度混合物(1:3)作为洗脱剂(20min运行)。这得到8.2mg(8%)标题化合物,其为浅黄色固体。LC/MS:m/z(ES+)289(M+H)+。
1H-NMR(300MHz,CD3OD):δppm 8.41(d,J=5.7Hz,2H),7.29(d,J=6.0Hz,2H),5.06-4.96(m,1H),4.68(s,1H),3.82-3.75(m,1H),2.87-2.83(m,2H),1.36(d,J=7.2Hz,6H),1.12(d,J=7.2Hz,3H)。
实施例62.制备(S)-6-((1-(4-(苄基氧基)苯基)乙基)氨基)-3-异丙基嘧啶-2,4 (1H,3H)-二酮。
化合物62.1.(S)-2-(1-(4-(甲氧基)苯基)乙基)异二氢吲哚-1,3-二酮。在2-5mL微波小瓶中向邻苯二甲酰亚胺(1.3g,0.0088mol)中加入(S)-1-(4-甲氧基苯基)乙-1-胺(2.20mL,0.015mol)和K2CO3(1.2g,0.0087mol)。将反应混合物盖好并在160℃加热2分钟。将所得的粗固体混悬在n-BuOH中并过滤。将滤液放置一边。将固体用H2O洗涤并将滤液弃去。将固体用CH2Cl2洗涤并将所得的滤液用H2O分配。合并有机层(n-BuOH和CH2Cl2层)并浓缩。将粗残留物通过硅胶柱色谱纯化(使用CH2Cl2作为洗脱剂)得到1.6g(64%)标题化合物。LC/MS:m/z(ES+)282(M+H)+。
化合物62.2.(S)-2-(1-(4-羟基苯基)乙基)异二氢吲哚-1,3-二酮。在0℃向62.1(640mg,2.28mmol)在CH2Cl2(8mL)中的搅拌溶液中加入BBr3(1.0M在CH2Cl2中的溶液,3mL,逐滴)。历时30分钟将反应混合物温热至室温。剩余显著量的原料,因此将反应混合物再次冷却至0℃。再加入BBr3(2mL,1.0M在CH2Cl2中的溶液)并历时30分钟将反应混合物温热至室温。将反应混合物倒在5%NaHCO3(水溶液)/冰上。分离各层并将水层进一步用CH2Cl2萃取。将合并的有机层用盐水洗涤,用无水Na2SO4干燥并浓缩得到500mg(82%)标题化合物,其为白色固体。LC/MS:m/z(ES+)268(M+H)+。
化合物62.3.(S)-2-(1-(4-(苄基氧基)苯基)乙基)异二氢吲哚-1,3-二酮。向62.2(500mg,1.87mmol)在DMF(10mL)中的搅拌溶液中加入K2CO3(560mg,4.05mmol,2.17当量)和苄基溴(0.30mL,420mg,2.45mmol,1.3当量)。将反应混合物在120℃搅拌5h。将反应混合物冷却并过滤。加入水(20mL)并使用EtOAc(60mL)萃取产物。将有机层先后用H2O、10%Na2CO3(水溶液)、H2O和盐水(2×)洗涤。将有机层用无水MgSO4干燥并浓缩。将粗残留物通过快速色谱纯化(硅胶,用CH2Cl2洗脱)得到480mg(72%)标题化合物。LC/MS:m/z(ES+)358(M+H)+。
化合物62.4.(S)-1-(4-(苄基氧基)苯基)乙-1-胺。向62.3(480mg,1.34mmol)在EtOH/H2O的70/30混合物(20mL)中的搅拌溶液中加入N2H4 .H2O(1.5mL)。将反应混合物搅拌16h并浓缩。将所得的物质在EtOAc和5%Na2CO3(水溶液)之间分配。分离各层并将EtOAc层用盐水洗涤并浓缩得到280mg(92%)标题化合物,其无需进一步纯化即使用。LC/MS:m/z(ES+)228(M+H)+。
化合物62.(S)-6-((1-(4-(苄基氧基)苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮。向0.5-2.0mL微波小瓶中加入1,4-二噁烷(1mL)、62.4(280mg,1.23mmol)、1.3(250mg,1.33mmol)和DIEA(400μL)。将反应混合物盖好,在135℃在微波反应器中加热1.5h,冷却,然后浓缩。将粗反应混合物用50/50CH3CN/H2O(0.1%TFA)处理,这导致析出。将固体通过过滤分离并干燥得到45mg(10%)白色固体。LC/MS:m/z(ES+)380(M+H)+。
1H-NMR(400MHz,DMSO-d6):δppm 9.73(br,1H),7.43-7.29(m,5H),7.23(d,J=14.5Hz,2H),6.97(d,J=14.5Hz,2H),6.42(d,J=7.0Hz,1H),5.06(s,2H),4.93-4.85(m,1H),4.42(quin,J=6.8Hz,1H),4.32(d,J=1.6Hz,1H),1.35(d,J=6.7Hz,3H)、(m,1H)1.27-1.23(m,6H)。
实施例63.制备(S)-6-((1-(4-羟基苯基)乙基)氨基)-3-异丙基嘧啶-2,4(1H,
3H)-二酮(63)。
向62(43mg,0.11mmol)在CH3OH(20mL)中的搅拌溶液中加入钯/炭(50mg,10wt%载量(干基),基质活性炭,湿载体,Degussa型)。将容器先后用氮气和氢气净化。将反应混合物在氢气气氛下搅拌2h。用氮气净化***后,将混合物通过硅藻土过滤并浓缩。将所得的固体溶于8mL CH3CN中,然后加入20mL H2O(0.1%TFA)。将溶液冷冻并冻干得到29mg(90%)标题化合物,其为白色固体。LC/MS:m/z(ES+)290(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.70(br,1H),9.32(s,1H),7.10(d,J=8.6Hz,2H),6.71(d,J=8.6Hz,2H),6.36(d,J=7.0Hz,1H),4.92-4.85(m,1H),4.37-4.33(m,2H),1.33(d,J=6.7Hz,3H),1.27-1.23(m,6H)。
实施例64.制备(R)-6-((2-(苄基氧基)-1-苯基乙基)氨基)-3-异丙基嘧啶-2,4
(1H,3H)-二酮。
化合物64.1.(R)-2-(2-羟基-1-苯基乙基)异二氢吲哚-1,3-二酮。向2.0-5.0mL微波小瓶中加入(R)-2-氨基-2-苯基乙-1-醇(1.53g,0.0112mol)和邻苯二甲酸酐(1.65g,0.0112mol)。将反应混合物盖好并在微波反应器中加热至150℃且保持2分钟。将混合物冷却并用CH3CN(2mL)稀释,重新盖好并在微波反应器中在140℃第二次加热20分钟。减压除去挥发物并将所得的固体混悬在EtOAc(50mL)中。将有机层用5%NaHCO3(水溶液)、H2O和盐水洗涤,用无水MgSO4干燥并浓缩。将粗残留物通过快速色谱纯化(硅胶,用CH3OH在CH2Cl2中的溶液(0至5%)洗脱)得到2.81g(94%)标题化合物。LC/MS:m/z(ES+)268(M+H)+。
化合物64.2.(R)-2-(2-(苄基氧基)-1-苯基乙基)异二氢吲哚-1,3-二酮。标题化合物以与就62.3所述的操作相似的方式制备。然而,在该情况下,使用NaH(60%在矿物油中的分散液,1.2当量)代替K2CO3。具体地,在0℃加入NaH并在室温搅拌45分钟。将反应混合物冷却回到0℃,然后加入苄基溴(1.2当量)。进行如就62.3所述的后处理操作,随后通过快速色谱纯化(硅胶,用CH2Cl2洗脱)得到标题化合物(59%收率)。LC/MS:m/z(ES+)358(M+H)+。
1H-NMR(400MHz,CDCl3):δppm 7.84-7.79(m,2H),7.72-7.67(m,2H),7.52-7.48(m,2H),7.37-7.20(m,8H),5.62(dd,J=10.2,5.9Hz,1H),4.63(t,J=10.2Hz,1H),4.58(s,2H),4.06-4.01(m,1H)。
化合物64.3.(R)-2-(苄基氧基)-1-苯基乙-1-胺。标题化合物以与就62.4所述的操作相似的方式制备。LC/MS:m/z(ES+)228(M+H)+。1H-NMR(400MHz,CDCl3):δppm 7.40-7.24(m,10H),4.56(d,J=2.0Hz,2H),4.25(dd,J=8.8,3.7Hz,1H),3.65-3.60(m,1H),3.49-3.44(m,1H)。
化合物64.(R)-6-((2-(苄基氧基)-1-苯基乙基)氨基)-3-异丙基嘧啶-2,4(1H,3H)-二酮。标题化合物以与就62所述的操作相似的方式制备。在此将反应混合物在140℃加热1h。冷却后,将粗反应混合物用50/50CH3CN/H2O(0.1%TFA)处理,这导致析出。LC/MS:m/z(ES+)380(M+H)+。
1H-NMR(400MHz,DMSO-d6):δppm 10.01(br,1H),7.36-7.26(m,10H),6.62(d,J=6.7Hz,1H),4.93-4.83(m,1H),4.67-4.62(m,1H),4.50(dd,J=12.0,2.0Hz,2H),4.30(s,1H),3.68-3.64(m,1H),3.60-3.55(m,1H)1.27-1.23(m,6H)。
实施例65.制备(S)-3-(6-甲基吡啶-2-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,
3H)-二酮。
化合物65.1. 1-(6-甲基吡啶-2-基)脲。向用惰性氩气气氛净化并保持的25mL圆底烧瓶中加入脲(1.48g,24.64mmol,1.00当量)和6-甲基吡啶-2-胺(3g,27.74mmol,1.00当量)。将所得的混合物在145℃搅拌2h。冷却后,将粗产物(4g)纯化,使用CombiFlash柱,C18硅胶;使用历时40min CH3CN:H2O=0:100至CH3CN:H2O=50:50的流动相。这分离到1.2g(32%)标题化合物,其为白色固体。1H-NMR(400MHz,DMSO-d6):δppm 9.07(s,1H),7.56-7.52(m,1H),7.18-7.14(m,1H),6.80-6.75(m,1H),2.36(s,3H)。
化合物65.2. 1-(6-甲基吡啶-2-基)嘧啶-2,4,6(1H,3H,5H)-三酮。标题化合物以与就1.2所述的操作相似的方式制备。在此在65℃搅拌过夜后,将反应混合物减压浓缩并将粗产物从CH3OH:Et2O(1:50)中析出。将固体通过过滤收集并溶于CH3OH(50mL)中。将溶液的pH值用离子交换树脂(Dowex 50WX8-100,5g)调节至7。将固体过滤并将滤液减压浓缩得到0.5g(29%)标题化合物,其为白色固体。1H-NMR(400MHz,DMSO-d6):δppm 9.27(br s,1H),7.69(t,J=7.6Hz,1H),7.17(d,J=7.6Hz,1H),6.93(d,J=7.6Hz,1H),3.18(s,2H),2.44(s,3H)。
化合物65.3. 6-氯-3-(6-甲基吡啶-2-基)嘧啶-2,4(1H,3H)-二酮。在0℃向65.2(500mg,2.28mmol,1.00当量)在POCl3(5mL)中的搅拌溶液中加入一滴(~20μL)H2O。将所得的溶液温热至室温,搅拌30min,加热至70℃并搅拌2h。冷却后,将所得的混合物减压浓缩。将所得的残留物小心地溶于10mL冰水中。将pH用离子交换树脂(活化的201×4(711)强碱性苯乙烯离子交换树脂,20g)调节至7并将固体过滤。将滤液减压浓缩得到0.2g(37%)标题化合物,其为黄色固体。
化合物65.(S)-3-(6-甲基吡啶-2-基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮。向用惰性氩气气氛净化并保持的10mL圆底烧瓶中加入(S)-α-甲基苄基胺(0.5mL)和65.3(200mg,0.84mmol,1.00当量)。将所得的溶液在110℃搅拌3h。冷却后,将所得的混合物真空浓缩。将残留物(100mg)通过使用以下条件的制备性RP-HPLC纯化:柱:XBridge PrepC18OBD柱,5μm,19*150mm;流动相:含有0.05%NH4(HCO3)的H2O和CH3CN(15%至80%CH3CN,8min)。这得到28.8mg(11%)标题化合物,其为白色固体。LC/MS:m/z(ES+)323(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 7.76(t,J=7.6Hz,1H),7.39-7.22(m,7H),7.05(d,J=7.6Hz,1H),6.82(br,1H),4.63-4.59(m,1H),4.46(s,1H),2.43(s,3H),1.44(d,J=6.4Hz,3H)。
实施例66.制备(S)-3-(2,2-二氟乙基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,
3H)-二酮。
化合物66.1. 6-氯-3-(2,2-二氟乙基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)嘧啶-2,4(1H,3H)-二酮。在0℃向11.1(130mg,0.47mmol)和Et3N(0.2mL)在CH2Cl2(2mL)中的搅拌溶液中加入三氟甲磺酸2,2-二氟乙基酯(0.10mL)。将反应混合物温热至室温并搅拌30分钟。将混合物浓缩得到呈粗混合物形式的标题化合物。
化合物66.2. 6-氯-3-(2,2-二氟乙基)嘧啶-2,4(1H,3H)-二酮。将粗65.1溶于CH2Cl2/TFA(1:1,4mL)中并搅拌3h并浓缩。将所得的物质用5%NaHCO3(水溶液)处理直到pH为7。将乙酸乙酯加到混合物中并分离各层。将水层浓缩。将所得的固体混悬在CH3CN(15mL)中并通过过滤除去。将滤液浓缩得到52mg标题化合物。
化合物66.(S)-3-(2,2-二氟乙基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮。向66.2(52mg,0.25mmol)在1,4-二噁烷(1.5mL)中的溶液中加入Et3N(100μL)和(S)-α-甲基苄基胺(188mg,1.55mmol)。将反应混合物在微波反应器中在100℃加热32分钟,冷却至室温,然后浓缩。将所得的残留物溶于含有2滴TFA(~40μL)的2:3CH3CN/H2O(10mL)中。将混合物通过制备性RP-HPLC纯化得到8mg(11%)标题化合物,其为白色固体。LC/MS:m/z(ES+)296(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 10.20(br s,1H),7.37-7.32(m,4H),7.26-7.23(m,1H),6.71(d,J=7.0Hz,1H),6.07(tt,J=56.0,4.5Hz,1H),4.54(quin,J=6.8Hz,1H),4.43(d,J=2.3Hz,1H),4.02(td,J=14.3,4.7Hz,2H),1.40(d,J=6.7Hz,3H)。
实施例67.制备(S)-6-((1-(苯并[d][1,3]二氧杂环戊烯-5-基)乙基)氨基)-3-
(2,2,2-三氟乙基)嘧啶-2,4(1H,3H)-二酮。
化合物67.1. 2H-1,3-苯并二氧杂环戊烯-5-甲醛。向3,4-二羟基苯甲醛(10g,72.40mmol,1.00当量)在DMF(150mL)中的搅拌溶液中加入碳酸铯(35.4g,108.31mmol,1.50当量)和二溴甲烷(18.7g,107.57mmol,1.50当量)。将所得的溶液在110℃搅拌2h。将溶液冷却至室温并将固体通过过滤除去。将滤液用H2O(300mL)稀释。将所得的溶液用EtOAc(2×300mL)萃取。合并有机层,用硫酸钠干燥并减压浓缩。将粗残留物通过硅胶柱色谱纯化(用EtOAc/石油醚(1:9)洗脱)得到8g(74%)标题化合物,其为黄色固体。1H-NMR(300MHz,CDCl3):δppm 9.81(s,1H),7.41(d,J=8.1Hz,1H),7.34(s,1H),6.93(d,J=8.1Hz,1H),6.08(s,2H)。
化合物67.2.(S)-1-(苯并[d][1,3]二氧杂环戊烯-5-基)乙-1-胺盐酸盐。标题化合物根据就制备5.3所述的方法合成。在此使用67.1代替3,5-二氟苯甲醛。LC/MS:m/z(ES+)166(M+H)+。
化合物67.(S)-6-((1-(苯并[d][1,3]二氧杂环戊烯-5-基)乙基)氨基)-3-(2,2,2-三氟乙基)嘧啶-2,4(1H,3H)-二酮。标题化合物根据在实施例59中所述的方法合成。在此使用67.2代替(S)-1-(2,6-二氟苯基)乙-1-胺盐酸盐并使用6-氯-3-(2,2,2-三氟乙基)嘧啶-2,4(1H,3H)-二酮(根据在实施例1中所述的方法合成)代替1.3。LC/MS:m/z(ES+)358(M+H)+。1H-NMR(300MHz,DMSO-d6):δppm 10.27(br s,1H),6.94(d,J=1.2Hz,1H),6.89-6.82(m,3H),6.72(d,J=6.9Hz,1H),5.99(s,2H),4.48-4.40(m,4H),1.38(d,J=6.9Hz,3H)。
实施例68.制备(S)-3-异丙基-6-((1-(邻甲苯基)乙基)氨基)嘧啶-2,4(1H,3H)- 二酮(68)。
向(1S)-1-(2-甲基苯基)乙-1-胺(310mg,2.29mmol,1.50当量)在NMP(1mL)中的搅拌溶液中加入质子海绵(491.4mg,2.30mmol,1.50当量)和1.3(288mg,1.53mmol,1.00当量)。将所得的溶液在130℃在油浴中搅拌1h,冷却至室温,然后用DMSO(2mL)稀释。将固体过滤并将滤液通过使用以下条件的快速制备性HPLC纯化:柱:X Bridge C18,19*150mm,5μm;流动相A:H2O/0.05%TFA,流动相B:CH3CN;流速:20mL/min;梯度:历时10min 30%B至70%B。这得到50mg粗产物,随后将其通过使用以下条件的手性制备性HPLC分离:柱:ChiralpakIC,2*25cm,5μm;流动相:己烷和乙醇(9:1,15min)。这得到35.6mg(8%)标题化合物,其为白色固体。LC/MS:m/z(ES+)288(M+H)+。
1H-NMR(300MHz,DMSO-d6):δppm 9.76(br s,1H),7.28(d,J=7.2Hz,1H)7.24-7.14(m,3H),6.48(d,J=6.3Hz,1H),4.95-4.86(m,1H),4.60(quin,J=6.9Hz,1H),4.19(s,1H),2.34(s,3H),1.37(d,J=6.6Hz,3H),1.27(d,J=6.9Hz,6H)。
实施例69.制备(S)-3-环丁基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮。
化合物69.1. 1-环丁基脲。在0℃向环丁胺(40g,562.42mmol,1.00当量)在CH2Cl2(400mL)中的搅拌溶液中分批加入异氰酸三甲基甲硅烷基酯(64.70g,561.60mmol,1.00当量)。将所得的溶液在室温搅拌过夜并通过加入CH3OH(80mL)淬灭。将所得的混合物在室温搅拌1h,然后减压浓缩。将残留物用Et2O(2×100mL)洗涤并过滤得到53g(83%)标题化合物,其为白色固体。1H-NMR(300MHz,DMSO-d6):δppm 6.17(d,J=9.0Hz,1H),5.33(s,2H),3.99-3.91(m,1H),2.16-2.07(m,2H),1.81-1.68(m,2H),1.61-1.45(m,2H)。
化合物69.2. 1-环丁基嘧啶-2,4,6(1H,3H,5H)-三酮。向甲醇钠(62.43g,1.156mol,2.40当量)在CH3OH(500mL)中的搅拌溶液中加入丙二酸二甲酯(76.42g,0.578mol,1.20当量)和69.1(55g,0.48mol,1.00当量)。将所得的溶液加热至65℃并搅拌过夜.将反应混合物冷却并通过加入H2O(100mL)淬灭。将溶液的pH用浓HCl调节至1。将所得的混合物减压浓缩。将残留物通过硅胶柱色谱纯化(使用CH2Cl2/CH3OH(20:1)作为洗脱剂)得到60g(68%)标题化合物,其为白色固体。1H-NMR(400MHz,DMSO-d6):δppm 11.20(s,1H),4.95-4.86(m,1H),3.56(s,2H),2.72-2.62(m,2H),2.16-2.09(m,2H),1.78-1.60(m,2H)。
化合物69.3. 6-氯-3-环丁基嘧啶-2,4(1H,3H)-二酮。向69.2(80g,0.44mol,1.00当量)和三乙基苄基氯化铵(140.2g,0.615mol,1.40当量)中加入POCl3(300mL)。将反应混合物在65℃搅拌1h,然后减压浓缩。将反应混合物通过小心地加入1L水/冰淬灭,然后将溶液的pH值用2N NaOH(水溶液)调节至1。将固体过滤,用CH3OH(300mL)和Et2O(2×300mL)洗涤并干燥。这得到78g(89%)标题化合物,其为浅黄色固体。1H-NMR(300MHz,DMSO-d6):δppm12.23(s,1H),5.82(s,1H),5.13-5.01(m,1H),2.87-2.73(m,2H),2.13-2.03(m,2H),1.80-1.56(m,2H)。
化合物69.(S)-3-环丁基-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮。向用惰性氩气气氛净化并保持的500mL圆底烧瓶中加入69.3(78g,388.79mmol,1.00当量)和(S)-α-甲基苄基胺(150mL,2.00当量)。将反应混合物在120℃搅拌3h。将反应混合物冷却至室温,用CH3OH(1L)稀释并进一步冷却至0℃。将所得的固体过滤,用Et2O(2×300mL)洗涤并真空干燥得到57.25g(52%)标题化合物,其为白色固体。LC/MS:m/z(ES+)286(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.94(br s,1H),7.40-7.32(m,4H),7.30-7.26(m,1H),6.40(brs,1H),5.19-5.10(m,1H),4.56-4.49(m,1H),4.35(s,1H),2.91-2.81(m,2H),2.02-1.95(m,2H),1.76-1.58(m,2H),1.42(d,J=6.8Hz,3H)。
实施例70.制备(S)-3-异丙基-6-((1-(2-(三氟甲基)苯基)乙基)氨基)嘧啶-2,4 (1H,3H)-二酮。
化合物70.1.(R,E)-2-甲基-N-(2-(三氟甲基)亚苄基)丙-2-亚磺酰胺。向用惰性氩气气氛净化并保持的100mL圆底烧瓶中加入CH2Cl2(50mL)、2-(三氟甲基)苯甲醛(2.01g,11.54mmol,1.00当量)、(R)-(+)-2-甲基丙-2-亚磺酰胺(1.68g,13.86mmol,1.20当量)、吡啶鎓对甲苯磺酸盐(0.145g,0.05当量)和硫酸镁(6.93g,5.00当量)。将所得的溶液在40℃搅拌48h。将混合物冷却至室温并将固体过滤。将滤液减压浓缩并将所得的残留物通过快速色谱纯化(硅胶,用EtOAc/石油醚(1:20)洗脱)。这得到0.96g(30%)标题化合物,其为浅黄色固体。LC/MS:m/z(ES+)278(M+H)+。1H-NMR(300MHz,DMSO-d6):δppm 8.82-8.80(m,1H),8.24(d,J=7.2Hz,1H),7.95-7.80(m,3H),1.22(s,9H)。
化合物70.2.(R)-2-甲基-N-((1S)-1-(2-(三氟甲基)苯基)-乙基)丙-2-亚磺酰胺。在-50℃向70.1(578mg,2.08mmol,1.00当量)在THF(20mL)中的搅拌溶液中逐滴加入3M甲基溴化镁在Et2O中的溶液(1.4mL,4.20mmol,2.0当量)。将所得的溶液在-50℃搅拌2.5h并在室温再搅拌10h。将反应混合物通过加入饱和NH4Cl水溶液(10mL)淬灭,然后减压浓缩。将所得的残留物用H2O(50mL)处理并用CH2Cl2(2×50mL)萃取。合并有机层,用Na2SO4干燥并减压浓缩。这得到700mg(60%de)标题化合物,其为黄色固体。LC/MS:m/z(ES+)294(M+H)+。1H-NMR(300MHz,DMSO-d6):δppm 7.77-7.74(m,1H),7.67-7.60(m,2H),7.43-7.38(m,1H),5.53(d,J=4.5Hz,1H),4.70-4.60(m,1H),1.42(d,J=6.6Hz,3H),1.02(s,9H)。
化合物70.3.(S)-1-(2-(三氟甲基)苯基)乙-1-胺盐酸盐。向70.2(700mg,2.39mmol,1.00当量)在CH3OH(4mL)中的搅拌溶液中逐滴加入4N HCl在1,4-二噁烷(2mL)中的溶液。将所得的溶液在室温搅拌1h,然后减压浓缩。通过加入Et2O(5mL)使固体析出。将固体过滤并干燥得到标题化合物,其为白色固体(0.32g,60%)。
化合物70.4.(S)-1-(2-(三氟甲基)苯基)乙-1-胺。向50mL圆底烧瓶中加入70.3(320mg,1.43mmol,1.00当量)和氢氧化钠(80mg,2.00mmol,1.40当量)在H2O(20mL)中的溶液。将所得的溶液在室温搅拌1h,然后用EtOAc(20mL)萃取。合并有机层并减压浓缩。这得到190mg(70%)标题化合物,其为浅黄色油状物。
化合物70.(S)-3-异丙基-6-((1-(2-(三氟甲基)苯基)乙基)氨基)嘧啶-2,4(1H,3H)-二酮。向用惰性氩气气氛净化并保持的10mL圆底烧瓶中加入NMP(2mL)、70.4(160mg,0.85mmol,1.00当量)、1.3(160mg,0.85mmol,1.00当量)和质子海绵(273mg,1.28mmol,1.5当量)。将所得的溶液在130℃搅拌4h。将粗产物(200mg)通过使用以下条件的手性制备性HPLC纯化:柱:Phenomenex Lux-25μCellulose-2,30*150mm;流动相:己烷-HPLC和乙醇-HPLC(保持20%乙醇-HPLC,14min);检测器:UV 254/220nm。得到160mg粗产物。将得到的物质(60mg)进一步通过使用以下条件的手性制备性HPLC纯化:Phenomenex Lux-25μCellulose-230*150mm;流动相和梯度:己烷:EtOH=80:20;保留时间(峰2)(min):11.106。这得到30mg标题化合物,其为白色固体。LC/MS:m/z(ES+)342(M+H)+。1H-NMR(400MHz,DMSO-d6):δppm 9.84(br,1H),7.78-7.68(m,3H),7.56-7.52(m,1H),6.75(br s,1H),4.93-4.86(m,1H),4.68-4.63(m,1H),4.13(s,1H),1.46(d,J=6.8Hz,3H),1.25(d,J=7.2Hz,6H)。
实施例71.制备(S)-3-(1-甲基环丙基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H, 3H)-二酮。
化合物71.1. 1-(1-甲基环丙基)脲。向1-甲基环丙烷-1-胺盐酸盐(429mg,3.99mmol,1.00当量)和三乙胺(268mg,2.65mmol,1.00当量)在CH2Cl2(6mL)中的搅拌溶液中加入异氰酸三甲基甲硅烷基酯(366mg,3.18mmol,1.20当量)。将所得的混合物在室温搅拌过夜并通过在0℃逐滴加入CH3OH(2mL)淬灭。将所得的溶液温热至室温并再搅拌1h。将所得的混合物减压浓缩。使粗产物从CH3OH:Et2O(1:40)中析出得到300mg(66%)标题化合物,其为白色固体。
化合物71.2. 1-(1-甲基环丙基)嘧啶-2,4,6(1H,3H,5H)-三酮。向71.1(320mg,2.80mmol,1.0当量)在CH3OH(2mL)中的搅拌溶液中加入甲醇钠(390mg,7.2mmol,2.5当量)和丙二酸二甲酯(380mg,2.88mmol,1.0当量)。将所得的溶液在65℃搅拌过夜。冷却后,将反应混合物通过加入H2O(100mL)淬灭。将溶液的pH用浓HCl调节至2并将所得的混合物减压浓缩。将粗残留物通过硅胶柱色谱纯化(用EtOAc/石油醚(1:3)作为洗脱剂)。这得到100mg(20%)标题化合物,其为白色固体。1H-NMR(300MHz,CDCl3):δppm 8.04(br,1H),3.61(s,2H),1.41(s,3H),1.00-,0.86(m,4H)。
化合物71.3. 6-氯-3-(1-甲基环丙基)嘧啶-2,4(1H,3H)-二酮。向71.2(100mg,0.55mmol,1.00当量)和三乙基苄基氯化铵(180mg,0.79mmol,1.00当量)中加入POCl3(2mL)。将所得的溶液在50℃搅拌3h,然后减压浓缩。将残留物小心地通过加入10mL水/冰淬灭并用EtOAc(2×30mL)萃取。合并有机层并减压浓缩。将粗残留物通过硅胶柱色谱纯化(用CH2Cl2/CH3OH(10:1)作为洗脱剂)得到40mg(36%)标题化合物,其为黄色固体。
化合物71.(S)-3-(1-甲基环丙基)-6-((1-苯基乙基)氨基)嘧啶-2,4(1H,3H)-二酮。向71.3(40mg,0.20mmol,1.00当量)中加入(S)-α-甲基苄基胺(0.5mL)。将反应混合物在130℃搅拌2h,然后减压浓缩。将所得的残留物通过使用以下条件的制备性RP-HPLC纯化:柱:X Bridge C18,19*150mm,5μm;流动相A:H2O/0.05%TFA,流动相B:CH3CN;流速:20mL/min;梯度:历时10min 30%B至70%B。这得到15.1mg(27%)标题化合物,其为白色固体。LC/MS:m/z(ES+)286(M+H)+。1H-NMR(300MHz,CD3CN):δppm 8.41(br,1H),7.42-7.29(m,5H),5.79(br,1H),4.48-4.44(m,1H),4.30(s,1H),1.47(d,J=6.9Hz,3H),1.27(s,3H),0.87-0.77(m,4H)。
实施例72.制备其它嘧啶二酮化合物。
表1B中的化合物根据如上所述的实施例制备(示例性方法提供在“参考实施例编号”中)。
实施例73.肌球蛋白抑制测定
使用将ADP(二磷酸腺苷)从心脏肌球蛋白中的释放与由丙酮酸激酶和乳酸脱氢酶(PK/LDH)构成的酶偶联***结合起来的生物化学测定且监测NADH的吸光度降低作为时间的函数(在340nm)评估小分子药物抑制牛心脏肌球蛋白的酶活性的能力。PK通过将PEP(磷酸烯醇丙酮酸)转化为丙酮酸而将ADP转化为ATP(三磷酸腺苷)。然后LDH通过将NADH(烟酰胺腺嘌呤二核苷酸)转化为NAD(氧化的烟酰胺腺嘌呤二核苷酸)而将丙酮酸转化为乳酸。心脏肌球蛋白的来源为呈去肌膜的肌原纤维形式的牛心脏。在测试小分子药物前评估牛肌原纤维的钙应答且选择实现肌原纤维***的50%(pCa50)或75%(pCa75)活化的钙浓度作为用于评估小分子药物的抑制活性的最终条件。所有酶活性在pH为6.8的含有12mM PIPES(哌嗪-N,N’-二(2-乙磺酸)和2mM氯化镁的缓冲溶液(PM12缓冲剂)中测量。最终测定条件为1mg/mL牛心脏肌原纤维、0.4mM PK/LDH、50μM ATP、0.1mg/mL BSA(牛血清白蛋白)、10ppm消泡剂、1mM DTT、0.5mM NADH、1.5mM PEP及实现肌原纤维的50%或75%活化所需要的预期游离钙浓度。
在DMSO中对化合物进行连续稀释以能够在100μL的体积中在DMSO的固定浓度为2%(v/v)的情况下实现化合物的最终预期浓度。典型地,将2μL连续稀释液加到96孔板中以实现8或12点剂量响应。加入含有牛心脏肌原纤维、PK/LDH和钙溶液(实现预期活化)的50μL溶液后,通过加入含有ATP、PEP和NADH的50μL溶液开始酶促反应。反应进程在环境温度使用澄明的半面积板在Molecular Devices M5e读板器中监测。将读板器设置为在340nm以动力学模式读取吸光度15分钟。将数据记录为吸光度应答对时间的斜率。将吸光度应答作为时间的函数的斜率归一化为含有DMSO的板上的斜率。然后将该归一化的比值作为小分子药物浓度的函数作图且使用GraphPad Prism将数据拟合成四参数拟合。该曲线的中点为IC50且为当抑制总应答的50%时的浓度。在最高测试浓度不能实现50%抑制的任何药物被报道为IC50大于所测试的最高浓度(即IC50>25μM)。
表2.所选化合物的肌球蛋白抑制活性a
a+++相应于IC50值低于1μM的。++相应于IC50值为1至15μM。+相应于IC50值高于15μM。
如上所述评估针对兔骨骼肌肌原纤维的选择性,除了肌球蛋白的来源为来自兔的呈肌原纤维形式的快速骨骼肌肌球蛋白。还如上所述确定了针对兔骨骼肌肌原纤维的剂量响应。
实施例74.针对活性的立体化学优选
如上所述测试配对的立体异构体抑制肌球蛋白活性的能力。结果汇总于表3中。在所有情况下,(R)立体异构体的活性都显著低于(S)立体异构体。
表3.(S)和(R)立体异构体的相对活性a
a使用0.5μM肌球蛋白进行测定,因此低于1.0μM的IC50值是近似的。
实施例75.心肌细胞收缩性测定
成年大鼠心室心肌细胞的收缩性通过边缘检测使用IonOptix收缩性***确定。将心肌细胞在Tyrode缓冲液(137mM NaCl,3.7mM KCL,0.5mMMgCl2,1.5mM CaCl2,4mM HEPES,11mM葡萄糖)中的等分液置于灌注室(Series 20 RC-27NE;Warner Instruments)中,允许附着在盖玻片上,然后用37℃Tyrode缓冲液灌注。以1Hz和10V刺激心肌细胞。仅将具有清晰的纹理、在起搏前是静息的、细胞长度为120-180微米、基线缩短分数等于细胞长度的3-8%且收缩速度大于100微米/秒的心肌细胞用于收缩性实验。为了确定对化合物的应答,首先用Tyrodes缓冲液灌注心肌细胞60秒,随后用化合物灌注5分钟且用Tyrodes缓冲液清洗140秒。使用IonOptix软件连续记录数据。使用Ionwizard软件(IonOptix)分析收缩性数据。对于每个细胞,对10-20个收缩性瞬时状态进行平均且对基线(无化合物)条件与用化合物处理的条件进行比较。通过对缩短分数(FS)的效果测量化合物,其中缩短分数为细胞在收缩时的最大长度除以基线细胞长度且相对于就未处理的细胞而言的100%而归一化的比值。
表4.所选化合物对心肌细胞收缩的抑制a
ID | 在0.3μM的活性 | 在1.0μM的活性 |
1 | ++ | +++ |
2 | ++ | +++ |
12 | n.d. | ++ |
19 | n.d. | + |
27 | ++ | n.d. |
67 | n.d. | +++ |
a+表示缩短分数抑制值小于33%。++表示缩短分数抑制值为33%至66%。+++表示缩短分数抑制值大于66%。
实施例76.在大鼠中的急性药效学效果
以对体内靶标接合的度量形式测试代表性化合物在大鼠中调节心脏收缩性的能力。缩短分数即对收缩性的度量如下确定:标记左心室的直径在收缩期/收缩(LVESd)结束时相对于舒张期/舒张(LVEDd)的变化且将该变化表示为以下比值:FS=(LVEDd-LVESd)/LVEDd。将饲喂的雄性Sprague-Dawley大鼠用异氟烷轻微麻醉且在胸骨旁位置使用经胸壁超声心动图(TTE)测量基线缩短分数。该测量后,使动物恢复并通过经口管饲接受单剂量的化合物(4mg/kg)。在给药后3小时,在轻微麻醉下采集第二次和第三次超声心动图以确定药物对收缩性的效果。效果在表5中以基线缩短分数的减少百分数形式给出。
表5.所选化合物在大鼠中对收缩性的抑制a
ID | 在给药后3小时缩短分数的减少% |
1 | +++ |
45 | + |
48 | +++ |
49 | +++ |
69 | + |
70 | ++ |
71 | +++ |
a+表示缩短分数的相对变化小于15%。++表示缩短分数的相对变化在15-30%之间。+++表示缩短分数的相对变化大于30%。
尽管本发明已经通过示例说明及实施例的方式进行了详细的描述以达到清楚理解的目的,但是本领域技术人员将认识到的是,可在所附权利要求书的范围内进行某些改变和修饰。另外,本申请提供的每份参考文献以其完整形式通过引用的方式并入本申请,就如同每份参考文献各自通过引用的方式并入本申请。当在本申请和本申请提供的参考文献之间存在争议时,以本申请为准。
Claims (17)
1.具有下式的化合物或其药用盐:
其中
R1为C3-C4烷基;
R2为苯基,其任选取代有1-5个Rb;
R3为选自以下的成员:C1-C4烷基和C3-C4环烷基,且任选取代有1个Rc;
R4为H;
X为H;
每个Rb独立选自卤素、CN、C1-C4烷基和C1-C4烷氧基;且
Rc为C1-C2烷氧基,且其中所述化合物在带有R3的碳原子处基本上不含其它异构体。
2.权利要求1的化合物或其药用盐,其中R1选自异丙基和仲丁基。
3.权利要求1的化合物或其药用盐,其中R2任选取代有1-2个Rb。
4.权利要求1的化合物或其药用盐,其中R2选自苯基、3-甲基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2,5-二氟苯基、3,5-二氟苯基、3-氯苯基和3-甲氧基苯基。
5.权利要求1的化合物或其药用盐,其中R3选自C1-C4烷基、C1-C4烷氧基烷基和C3-C4环烷基。
6.权利要求1的化合物或其药用盐,其中R3选自甲基、乙基、丙基、环丙基、环丁基和2-甲氧基甲基。
7.权利要求1的化合物或其药用盐,其中R3为甲基。
8.权利要求1的化合物或其药用盐,其中R1为异丙基;R2为任选取代有1-2个Rb的苯基;且R3为甲基。
9.一种药物组合物,其包含权利要求1-8中任一项的化合物或其药用盐及药用赋形剂。
10.权利要求1的化合物或其药用盐,所述化合物选自:
11.具有下式的化合物或其药用盐:
12.一种药物组合物,其包含具有下式的化合物或其药用盐及药用赋形剂:
13.权利要求1-8或10-11中任一项的化合物或其药用盐在制备用于治疗肥厚性心肌病的药物中的用途。
14.具有下式的化合物或其药用盐在制备用于治疗肥厚性心肌病的药物中的用途:
15.权利要求14的用途,其中所述治疗降低受试者中的左心室流出梗阻。
16.权利要求1-8或10-11中任一项的化合物或其药用盐在制备用于治疗疾病或病症的药物中的用途,所述疾病或病症选自射血分数保留的舒张性心力衰竭、缺血性心脏病、心绞痛和限制性心肌病。
17.权利要求16的用途,其中所述疾病或病症为射血分数保留的舒张性心力衰竭。
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