CN111393414B - 用于治疗扩张性心肌病(dcm)的4-甲基磺酰基取代的哌啶脲化合物 - Google Patents
用于治疗扩张性心肌病(dcm)的4-甲基磺酰基取代的哌啶脲化合物 Download PDFInfo
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- CN111393414B CN111393414B CN202010152637.8A CN202010152637A CN111393414B CN 111393414 B CN111393414 B CN 111393414B CN 202010152637 A CN202010152637 A CN 202010152637A CN 111393414 B CN111393414 B CN 111393414B
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- piperidine
- methyl
- sulfonyl
- mmol
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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Abstract
本发明提供了用于治疗扩张性心肌病(DCM)和与左和/或右心室收缩功能障碍或收缩储备相关的病症的新的4‑甲基砜取代的哌啶脲化合物。本发明描述了化合物的合成和表征,以及用于治疗DCM和其它形式的心脏病的方法。
Description
本发明申请是基于申请日为2016年1月21日,申请号为2016800171267(国际申请号为PCT/US2016/014365),发明名称为“用于治疗扩张性心肌病(DCM)的4-甲基磺酰基取代的哌啶脲化合物”的专利申请的分案申请。
相关申请的交叉引用
本申请要求2015年1月22日提交的美国临时申请62/106,571的优先权权益,其全部内容通过引用并入本文。
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
扩张性心肌病(DCM)包括一组导致左心室扩张和收缩功能障碍(收缩异常)的心肌病症。DCM可以细分为缺血性(归因于冠状动脉疾病)或非缺血性(心肌原发性疾病)。下文中,DCM是指心肌的非缺血性原发性疾病。如果不能发现可鉴定的原因(遗传除外),DCM可以被指定为“特发性”DCM的临床诊断。特发性DCM可以根据是否可以鉴定遗传原因进一步进行分类。超过30个基因(包括肌节基因)的突变扰乱了一组不同的心肌蛋白以引起DCM表型。流行病学数据表明,一般人群的2,500名个体中约1名患有特发性DCM。
引起DCM的肌节基因突变(sarcomere gene mutation)是高度渗透性的,但在临床严重性和临床过程中存在广泛的变异性。一些基因型与更恶性的病程相关,但在携带相同突变的家族之间甚至在家族内存在相当大的变异性。虽然许多DCM患者在长时间内报告最少的症状或无症状,但DCM是一种进行性疾病,具有显著的发病率和死亡率累积负担。DCM的标志是扩张的左心室,形状比平常更圆球形,并且收缩功能降低。可发现患者通常出现心力衰竭症状:呼吸困难、端坐呼吸、运动不耐受、疲劳、腹部不适和食欲不振。体征包括窦性心动过速、奔马律、二尖瓣反流杂音、眩晕、颈静脉扩张、肝肿大、外周水肿和四肢清凉。与许多其它病症一样,症状随年龄增长而恶化。患者行程由于代偿失调性心力衰竭的住院治疗而不时打断,并且突发性心律失常死亡和由于泵故障导致的死亡的风险增加。
诊断取决于患者病史和身体检查。血浆生物标志物诸如B型利钠肽(BNP)或其N-末端前蛋白(NT-proBNP)可以帮助DCM的诊断和管理,特别是将心力衰竭与共患肺部疾病(comorbid pulmonary disease)区分开来。冠状动脉造影可以鉴定心力衰竭是否是由于缺血性病因引起的。心内膜活检可以将DCM与可能需要替代管理策略的疾病进程区分开来,诸如心肌炎、贮积病、结节病或血色素沉着症。
医疗治疗仍然是DCM和心力衰竭患者的支柱。β-阻断剂、ACE抑制剂或ARB,皮质激素受体阻滞剂和环利尿剂继续是治疗心力衰竭症状和降低心血管死亡和心力衰竭住院风险的标准治疗方案。对于左心室射血分数低于30%的患者,植入式心律转复除颤器(ICD)可以减少突发性心律失常死亡。此外,心脏再同步治疗(CRT)已显示可以改善选择患者的无心力衰竭的存活率。尽管有这些干预措施,但心力衰竭的发病率和死亡率仍然很高,并且心力衰竭住院仍然是老年人住院最常见的原因。本发明提供了补救DCM和相关心脏病症的改善治疗的未满足需求的新治疗剂和方法。
发明内容
在一个方面,提供了具有式(I)的化合物:
或其药用盐。
在式(I)中,Ar1为具有至少一个氮原子环成员的5至6元杂芳基;并且任选地被1-3个Ra取代。Ar2为任选地被1-5个Rb取代的5至10元芳基或杂芳基。符号R1和R2各自独立地为选自H、F、C1-C4烷基、氘代C1-C4烷基和卤代C1-C4烷基的成员;或任选地R1和R2可以组合形成C3-C5碳环,其任选地被一个或两个F取代。符号R3表示选自H、F、OH和C1-C4烷基的成员。
Ar1和Ar2各自的取代基如下:每个Ra独立地选自卤素、CN、羟基、C1-C4烷基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、-CORa1、-CO2Ra1、-SO2Ra1、-SO2NRa1Ra2和-CONRa1Ra2,其中每个Ra1和Ra2独立地选自H和C1-C4烷基或任选地,当连接至氮原子时,Ra1和Ra2组合形成4至6元环;或任选地,相邻环成员上的两个Ra取代基组合形成具有0、1或2个选自O、N和S的环成员的5或6元环;和每个Rb独立地选自卤素、CN、羟基、C1-C4烷基、氘代C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、C3-C6环烷基、-NRb1Rb2、-CORb1、-CO2Rb1、-SO2Rb1、-SO2NRb1Rb2、–CONRb1Rb2以及任选地被C1-C4烷基取代的5或6元杂芳基,并且其中每个Rb1和Rb2独立地选自H和C1-C4烷基或任选地,当连接至氮原子时,Rb1和Rb2组合形成4至6元环;或任选地,相邻环成员上的两个Rb取代基组合形成具有0、1或2个选自O、N和S的环成员的5或6元环。
在另一方面,本发明提供药物组合物,其含有如本文所述的化合物或其药用盐和药用赋形剂。
在另一方面,本发明提供治疗扩张性心肌病的方法。所述方法包括向有此需要的受试者给予有效量的如本文所述的化合物或其药用盐。
本发明还包括如下项:
1.具有式(I)的化合物或其药用盐:
其中
Ar1为具有至少一个氮原子环成员的5至6元杂芳基;并且其任选地被1-3个Ra取代;
Ar2为任选地被1-5个Rb取代的5至10元芳基或杂芳基;
R1和R2各自独立地为选自H、F、C1-C4烷基、氘代C1-C4烷基和卤代C1-C4烷基的成员;或任选地R1和R2可以组合形成C3-C5碳环,其任选地被一个或两个F取代;
R3为选自H、F、OH和C1-C4烷基的成员;
每个Ra独立地选自卤素、CN、羟基、C1-C4烷基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、-CORa1、-CO2Ra1、-SO2Ra1、-SO2NRa1Ra2和-CONRa1Ra2,其中每个Ra1和Ra2独立地选自H和C1-C4烷基或任选地,当连接至氮原子时,Ra1和Ra2组合形成4至6元环;或任选地,相邻环成员上的两个Ra取代基组合形成具有0、1或2个选自O、N和S的环成员的5或6元环;和
每个Rb独立地选自卤素、CN、羟基、C1-C4烷基、氘代C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、C3-C6环烷基、-NRb1Rb2、-CORb1、-CO2Rb1、-SO2Rb1、-SO2NRb1Rb2、–CONRb1Rb2以及任选地被C1-C4烷基取代的5或6元杂芳基,并且其中每个Rb1和Rb2独立地选自H和C1-C4烷基或任选地,当连接至氮原子时,Rb1和Rb2组合形成4至6元环;或任选地,相邻环成员上的两个Rb取代基组合形成具有0、1或2个选自O、N和S的环成员的5或6元环。
2.项1的化合物或其药用盐,其中Ar1选自吡啶基、哒嗪基、噁唑基、异噁唑基、1,2,3-噻二唑基、异噻唑基和噻唑基,其各自任选地被1或2个Ra取代。
3.项1的化合物,其中Ar2选自苯基、吡啶基和吡唑基,其各自任选地被1至3个Rb取代。
4.项3的化合物,其中Rb选自卤素、CN、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基和卤代C1-C4烷氧基。
5.项1的化合物,其中R1选自H、F和CH3。
6.项1的化合物,其中R2选自H、F和CH3。
7.项1的化合物,其中R1和R2与各自连接的碳原子一起形成环丙烷环或环丁烷环。
8.项1的化合物,其中R1和R2不相同,并且R1和R2中的至少一个选自F和CH3。
9.项8的化合物,其中带有R1和R2的碳原子具有R构型。
10.项1的化合物,其中R3为H或F。
11.项1的化合物,其中Ar1为4-吡啶基且Ar2为苯基,任选地被1至3个Rb取代。
12.项11的化合物,其中R3为H,并且R1和R2各自为F。
13.项11的化合物,其中R3为H,并且R1和R2各自为CH3。
14.项11的化合物,其中R3为H,R1为CH3,并且R2为F。
15.项14的化合物,其中带有R1和R2的碳原子具有立体化学R构型。
16.项1的化合物,其中Ar1为4-哒嗪基且Ar2为苯基,任选地被1至3个Rb取代。
17.项16的化合物,其中R3为H,并且R1和R2各自为F。
18.项16的化合物,其中R3为H,并且R1和R2各自为CH3。
19.项16的化合物,其中R3为H,R1为CH3,并且R2为F。
20.项19的化合物,其中带有R1和R2的碳原子具有立体化学R构型。
21.项1的化合物,其中Ar1选自1,2,3-噻二唑-5-基、异噻唑-5-基和噻唑-5-基,其各自任选地被一个Ra取代。
22.项21的化合物,其中R3为H,并且R1和R2各自为F。
23.项21的化合物,其中R3为H,并且R1和R2各自为CH3。
24.项21的化合物,其中R3为H,R1为CH3,并且R2为F。
25.项24的化合物,其中带有R1和R2的碳原子具有立体化学R构型。
26.项1的化合物,其选自表2并具有++或+++的活性水平。
27.项1的化合物,其选自
28.项1的化合物,其选自
29.药物组合物,其包含项1-28中任一项的化合物和药用赋形剂。
30.治疗扩张性心肌病(DCM)或具有DCM病理生理学特征的心脏病症诸如具有收缩功能障碍或收缩储备减少的病症的方法,包括向有此需要的受试者给予有效量的项1-28中任一项的化合物。
31.治疗选自收缩功能障碍、舒张功能障碍、HFrEF、HFpEF、慢性心力衰竭和急性心力衰竭的疾病或病症的方法,包括向有此需要的受试者给予有效量的项1-28中任一项的化合物或其药用盐。
32.根据项31的方法,其中所述化合物以用于治疗急性心力衰竭的IV制剂给药。
33.治疗特征在于左心室收缩功能障碍或症状或由于收缩功能障碍引起的运动能力降低的疾病或病症的方法,该方法结合旨在治疗心力衰竭的疗法,该方法包括向有此需要的受试者给予有效量的项1-28中任一项的化合物或其药用盐。
34.治疗扩张性心肌病(DCM)或具有与DCM相关的病理生理学特征的心脏病症的方法,包括向有此需要的受试者给予有效量的项1-28中任一项的化合物或其药用盐,所述方法结合通过下调对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)。
35.项34的方法,其中所述化合物与β-阻断剂组合给药。
附图说明
图1A、1B、1C、1D和1E显示合成本文所述的化合物或药用盐的示意性途径。
具体实施方式
I.概述
已发现一系列4-甲基磺酰基取代的哌啶脲及其药用盐通过增加肌球蛋白的磷酸盐释放而不延长收缩期或缩短舒张期来增加收缩性。因此,所述化合物可以改善DCM患者的收缩功能,帮助他们克服常常与疾病伴随的虚弱的劳累性呼吸困难和疲劳。所述化合物也可用于治疗以心输出量减少为特征的其它心脏病症。
II.定义
本文所用的术语“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”可被一个或多个选自卤素、羟基、氨基、烷基氨基、硝基、氰基和烷氧基的部分取代。
本文所用的术语“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、环己二烯(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”可被一个或多个选自卤素、羟基、氨基、烷基氨基、硝基、氰基和烷氧基的部分取代。
本文所用的术语“杂环烷基”是指具有3至12个环成员及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、二噁烷或二硫杂环己烷。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”可被一个或多个选自卤素、羟基、氨基、烷基氨基、硝基、氰基和烷氧基的部分取代。
除非另有说明,术语“芳基”或“芳族环”是指多不饱和的,通常为芳族的烃基,其可以是单环或共价稠合在一起或共价连接的多环(至多三个环)。芳基的非限制性实例包括苯基、萘基和联苯基。
本文所用的术语“杂芳基”是指单环或稠合二环或三环的芳族环结构,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、三唑、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”可被一个或多个选自卤素、羟基、氨基、烷基氨基、硝基、氰基和烷氧基的部分取代。
本文所用的术语“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”可被一个或多个选自卤素、羟基、氨基、烷基氨基、硝基、氰基和烷氧基的部分取代。
本文所用的术语“卤代”和“卤素”是指氟、氯、溴和碘。
本文所用的术语“药用的”是指与本发明化合物相容以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,药用的物质对于该物质的接受者来说是无毒的。
本文所用的术语“盐”是指本发明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、柠檬酸等)和季铵离子获得。应当理解,药用盐是无毒的。关于合适的药用盐的其它信息可见于Remington's PharmaceuticalSciences,17th ed.,Mack Publishing Company,Easton,Pa.,1985中,其通过引用并入本文。
化合物的中性形式可以通过使盐与碱或酸接触并以常规方式分离母体化合物来再生。化合物的母体形式与某些物理性质中的各种盐形式不同,诸如在极性溶剂中的溶解度,但为了本发明的目的,在其它方面盐与化合物的母体形式等同。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋化合物、非对映异构体、几何异构体、区域异构体和单个异构体(例如,单独的对映异构体)都旨在包括在本发明的范围内。当显示立体化学描述时,它是指其中存在一种异构体并基本上不含其它异构体的化合物。“基本上不含”另一种异构体表示在所示的立体化学中心上的两种异构体的比例至少为70/30,更优选为80/20、90/10或95/5或更多。在一些实施方案中,异构体之一将以至少99%的量存在。
本发明化合物还可以在构成这种化合物的一个或多个原子上含有非天然比例的原子同位素。同位素的非天然比例可以定义为从自然界中发现的量到由所讨论的原子的100%组成的量。例如,化合物可以掺入放射性同位素,诸如氚(3H)、碘-125(125I)或碳-14(14C)或非放射性同位素,诸如氘(2H)或碳-13(13C)。这种同位素变体可以为本申请中其它地方描述的那些提供额外的效用。例如,本发明化合物的同位素变体可以发现额外的效用,包括但不限于作为诊断和/或成像试剂,或作为细胞毒性/放射毒性治疗剂。此外,本发明化合物的同位素变体可以具有改变的药代动力学和药效学特征,其可以有助于增强治疗期间的安全性、耐受性或功效。本发明化合物的所有同位素变体,无论是放射性的还是非放射性的,均旨在包括在本发明的范围内。当具体提到时,诸如氘代C1-C4烷基–该术语是指具有指定数目的碳原子并且氢原子以1至全氘代形式的数目被氘替代的烷基,其中氘替代物大于氘的天然丰度–通常为50%、60%、70%、80%、90%、95%或更多的氘替代物。氘代C1-C4烷基的实例是-CD3、-CH2CD3、-CD2CD3、-CH2CH2CH2D等。
本文所用的术语“药物组合物”是指包含特定量的本发明化合物、如本文所定义的赋形剂及其它任选成分的产品,以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。
本文所用的术语“赋形剂”是指有助于向受试者给予活性剂的物质。可用于本发明的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。本领域技术人员将认识到,其它赋形剂可用于本发明。
本文所用的术语“治疗”是指成功治疗或改善与扩张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;包括例如身体检查的结果。
III.化合物
在一个方面,本文提供具有下式的化合物:
或其药用盐,其中
Ar1为具有至少一个氮原子环成员的5至6元杂芳基;并且其任选地被1-3个Ra取代;
Ar2为任选地被1-5个Rb取代的5至10元芳基或杂芳基;
R1和R2各自独立地为选自H、F、C1-C4烷基、氘代C1-C4烷基和卤代C1-C4烷基的成员;或任选地R1和R2可以组合形成C3-C5碳环,其任选地被一个或两个F取代;
R3为选自H、F、OH和C1-C4烷基的成员;
每个Ra独立地选自卤素、CN、羟基、C1-C4烷基、卤代C1-C4烷基、羟基C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、-CORa1、-CO2Ra1、-SO2Ra1、-SO2NRa1Ra2和-CONRa1Ra2,其中每个Ra1和Ra2独立地选自H和C1-C4烷基或任选地,当连接至氮原子时,Ra1和Ra2组合形成4至6元环;或任选地,相邻环成员上的两个Rb取代基组合形成具有0、1或2个选自O、N和S的环成员的5或6元环;和
每个Rb独立地选自卤素、CN、羟基、C1-C4烷基、氘代C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、C3-C6环烷基、-NRb1Rb2、-CORb1、-CO2Rb1、-SO2Rb1、-SO2NRb1Rb2、–CONRb1Rb2以及任选地被C1-C4烷基取代的5或6元杂芳基,并且其中每个Rb1和Rb2独立地选自H和C1-C4烷基或任选地,当连接至氮原子时,Rb1和Rb2组合形成4至6元环;或任选地,相邻环成员上的两个Rb取代基组合形成具有0、1或2个选自O、N和S的环成员的5或6元环。
在一些实施方案中,提供式I化合物或其药用盐,其中Ar1选自吡啶基、哒嗪基、噁唑基、异噁唑基、吡唑基、1,2,3-噻二唑基、异噻唑基和噻唑基,其各自任选地被1或2个Ra取代。
在其它实施方案中,提供式I化合物或其药用盐,其中Ar2选自苯基、吡啶基和吡唑基,其各自任选地被1至3个Rb取代。在一些这些实施方案中,Rb选自卤素、CN、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基和卤代C1-C4烷氧基。
在其它实施方案中,提供式I化合物或其药用盐,其中R1选自H、F和CH3。
在其它实施方案中,提供式I化合物或其药用盐,其中R2选自H、F和CH3。
在一些实施方案中,提供式I化合物或其药用盐,R1和R2与各自连接的碳原子一起形成环丙烷环或环丁烷环。
在其它实施方案中,提供式I化合物或其药用盐,其中R1和R2各自为F。
在其它实施方案中,提供式I化合物或其药用盐,其中R1≠R2,并且R1或R2中的一个选自F和CH3以形成季手性中心(quaternary chiral center)。
在其它实施方案中,提供式I化合物或其药用盐,其中R1≠R2,并且R1或R2中的一个选自F和CH3以形成具有R构型的季手性中心。
在其它实施方案中,提供式I化合物或其药用盐,其中R3为H或F。
在一些具体实施方案中,提供式I化合物或其药用盐,其中Ar1为4-吡啶基且Ar2为苯基,任选地被1至3个Rb取代。在其它实施方案中,R3为H,并且R1和R2各自为F。在其它实施方案中,R3为H,并且R1和R2各自为CH3。在其它实施方案中,R3为H,R1为CH3,并且R2为F。
在其它具体实施方案中,提供式I化合物或其药用盐,其中Ar1为4-哒嗪基且Ar2为苯基,任选地被1至3个Rb取代。在其它实施方案中,R3为H,并且R1和R2各自为F。在其它实施方案中,R3为H,并且R1和R2各自为CH3。在其它实施方案中,R3为H,R1为CH3,并且R2为F。
在其它具体实施方案中,提供式I化合物或其药用盐,其中Ar1选自噁唑-5-基、异噁唑-3-基、异噁唑-4-基、吡唑-3-基、吡唑-4-基、1,2,3-噻二唑-5-基、异噻唑-5-基和噻唑-5-基,其各自任选地被一个Ra取代。在其它实施方案中,R3为H,并且R1和R2各自为F。在其它实施方案中,R3为H,并且R1和R2各自为CH3。在其它实施方案中,R3为H,R1为CH3,并且R2为F。
在其它所选实施方案中,提供式I化合物或其药用盐,其中R1和R2不相同,并且R1和R2中的至少一个为F或CH3,以在具有R构型的带有R1和R2的碳原子处形成手性中心。
在一些所选实施方案中,提供选自表2并具有++或+++的活性水平的式I化合物或其药用盐。
在一些实施方案中,提供式I化合物或其药用盐,其选自:
本文提供的化合物或其药用盐可以具有上述Ar1、Ar2、R1、R2、R3、Ra、Ra1、Ra2、Rb、Rb1和Rb2组的任何组合。例如,针对R2列举的所选实施方案可以例如与针对R1列举的所选实施方案中的任一个组合,而针对R1列举的所选实施方案又可以与针对R3或Ar1或Ar2列举的所选实施方案中的任一个组合。
式(I)化合物可以通过如图1A、1B和1C中一般概述的方法或实施例中提供的并列于表1中的方法制备。本领域技术人员将认识到,本发明化合物可以使用其它合成方法制备,包括如例如LaRock(Comprehensive Organic Transformations:A Guide toFunctional Group Preparations,Wiley,1999)中所述的转化,作为实施例中提供的转化的替代物。
IV.组合物
在另一方面,本文提供药物组合物,其含有式I化合物或其药用盐和药用赋形剂。所述组合物可用于治疗人和其它受试者的扩张性心肌病。
用于给予本文提供的化合物或其药用盐的药物组合物可以方便地以单位剂量形式呈现,并且可以通过药学和药物递送领域已知的任何方法制备。所有方法包括将活性成分与含有一种或多种辅助成分的载体结合的步骤。通常,药物组合物通过将活性成分与液体载体或细碎固体载体或两者均匀且紧密地结合,然后,如果需要,将产物成形为所需制剂而制备。在药物组合物中,活性剂通常以足以增加心肌收缩力(即改善DCM中的收缩功能障碍)和改善或不恶化舒张期的左心室松弛的量包括在内。这种改善的松弛可以缓解扩张性心肌病和舒张功能障碍的其它病因,诸如具有保留射血分数(HFpEF)的心力衰竭等症状。还可以改善引起冠状动脉血流量损伤的舒张功能障碍的影响,作为心绞痛和缺血性心脏病的辅助剂改善后者(冠状动脉血流量损伤)。它还可以向DCM的有益的左心室重塑和由于缺血性心脏病或由例如心肌梗塞、瓣膜性心脏病或全身高血压引起的慢性体积或压力超负荷引起的左心室功能障碍的其它原因赋予益处。
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、水性或油性悬浮液、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,且这种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的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、明胶或阿拉伯胶;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。
水性悬浮液含有活性物质与适于制备水性悬浮液的赋形剂的混合物。这种赋形剂为助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙甲纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和阿拉伯胶;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(heptadecaethyleneoxycetanol))、环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物(诸如聚氧乙烯山梨醇单油酸酯(polyoxyethylene sorbitol monooleate))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醇单油酸酯(polyethylene sorbitan monooleate))。水性悬浮液还可含有一种或多种防腐剂例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诸如蔗糖或糖精。
油性悬浮液可通过将活性成分悬浮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。油性悬浮液可含有增稠剂,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,以提供适口的口服制剂。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悬浮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、助悬剂和一种或多种防腐剂的混合物。合适的分散剂或润湿剂和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。
本文提供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。合适的乳化剂可为天然存在的树胶例如阿拉伯胶或西黄蓍胶,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。这种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悬浮液或油性悬浮液形式。该悬浮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已知技术配制。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悬浮液,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,脂肪酸诸如油酸可用于制备注射剂。
本文提供的化合物或其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:将药物与合适的无刺激性赋形剂混合,所述赋形剂在常温下为固体但在直肠温度下为液体,且因此将会在直肠中融解以释放药物。这种物质包括可可豆脂和聚乙二醇。另外,化合物可经眼部递送通过溶液或软膏剂的方式来给予。另外,目标化合物的经皮递送可通过离子电渗贴片等方式来完成。对于局部使用,可使用含有本文提供的化合物或其药用盐的乳膏剂、软膏剂、胶冻剂、溶液剂或悬浮液等。本文所用的局部应用也意在包括使用口腔洗剂和漱口剂。
本发明化合物还可与作为靶向药物载体的合适聚合物的载体结合。这种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残基的聚氧化乙烯-聚赖氨酸。另外,本文提供的化合物或其药用盐可与可用于实现药物受控释放的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.治疗心脏病症的方法
导致DCM的突变引起肌球蛋白力学中的显著扰动。这些突变根据其在肌球蛋白基因中的位置通过不同的机制发挥其作用。不希望受任何特定理论的束缚,相信本文提供的化合物或其药用盐可以直接结合突变肌节蛋白,并以顺式(通过影响相同的特定功能)或以反式(通过改变补充功能)纠正其异常功能。因此,它们可以通过抵消与这种疾病相关的收缩性过度(hypocontractile)和/或减弱的松弛,为DCM患者提供治疗益处。另外,改善收缩功能的这些化合物可以治疗广泛的病症,其中症状和/或临床结果归因于收缩功能障碍(左侧或右侧心力衰竭)或收缩期储备降低(例如,HFpEF)。
因此,本发明提供了一种治疗扩张性心肌病(DCM)或具有与DCM相关的一种或多种病理生理特征的心脏病症(诸如具有收缩功能障碍或收缩期储备降低的病症)的方法。该方法包括向有此需要的受试者给予有效量的本文提供的化合物。
本发明化合物或其药用盐可改变DCM和其它疾病的天然病史,而不仅仅是缓解症状。赋予DCM患者临床益处的机制可扩展至有或没有可证明的遗传影响的分享类似的病理生理学的其它形式心脏病的患者。例如,通过改善心室收缩对DCM的有效治疗也可以在以收缩功能障碍为特征的更广泛的群体中有效。本发明化合物或其药用盐可以特异性地靶向病症的根本原因或作用于其它下游途径。因此,本发明化合物或其药用盐还可以向患有具有降低的射血分数(HFrEF)、HfpEF、慢性充血性心力衰竭、急性心力衰竭、右侧(或右心室)心力衰竭、心源性休克和心脏手术后的肌力支持的心力衰竭患者赋予益处。本发明化合物或其药用盐可潜在地改善以下患者部分的心脏功能:特发性扩张性心肌病、遗传定义或家族性扩张性心肌病、缺血性或梗死后心肌病、病毒性心肌病或心肌炎、中毒性心肌病(例如蒽环类抗癌治疗后)、代谢性心肌病(与酶替代疗法联合)、舒张性心力衰竭(具有收缩期储备减少)、由于肺动脉高压引起的右心衰竭以及由旁路心血管手术引起的心室功能障碍。本发明化合物或其药用盐还可以促进由于缺血或体积或压力超负荷引起的左心室功能障碍的有益的心室反向重塑,例如心肌梗塞、慢性二尖瓣反流、慢性主动脉瓣狭窄或慢性全身性高血压。通过减少左心室充盈压,所述化合物可改善呼吸困难症状,并降低肺水肿和呼吸衰竭的风险。减少或消除功能性二尖瓣反流和/或降低左心房压力可降低阵发性或永久性心房纤维性颤动的风险,并降低伴随的动脉血栓栓塞并发症风险,包括但不限于脑动脉栓塞性中风。所述化合物或其药用盐可降低与DCM相关的慢性缺血状态的严重程度,从而降低具有可植入式心律转复除颤器(频繁和/或重复ICD放电)和/或需要潜在的毒性抗心律失常药物的患者的突然心脏死亡(SCD)或其等同物的风险。所述化合物或其药用盐在降低或消除具有注意的潜在毒性、药物-药物相互作用和/或副作用的伴随药物的需要方面是有价值的。所述化合物或其药用盐可以减少间质性心肌纤维化和/或减缓进展,停止或逆转左心室僵硬和舒张功能障碍。
根据待治疗的疾病和受试者的状况,本文提供的化合物或其药用盐可以通过口服、肠胃外(例如肌肉内、腹膜内、静脉内、ICV、脑内注射或输注、皮下注射或植入物)、通过植入(例如,当化合物联接到支架装置时)、通过吸入喷雾、鼻、阴道、直肠、舌下或局部给药途径,并且可以单独或一起配制在合适的含有适用于每种给药途径的常规无毒的药用载体、辅料和媒介物的剂量单位制剂中。
在治疗或预防需要改善心室收缩而不损害舒张松弛的病状下,适当的剂量水平通常为约0.001至100mg/kg患者体重/天,可以单剂量或多剂量给药。优选地,剂量水平为约0.01至约25mg/kg/天;更优选约0.05至约10mg/kg/天。合适的剂量水平可以为约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,剂量可以为0.005至0.05、0.05至0.5或0.5至5.0mg/kg/天。对于口服给药,组合物优选以含有1.0至1000毫克活性成分的片剂的形式提供,特别是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,用于待治疗的患者的剂量的症状调整。化合物可以1至4次/天的方案给药,优选每天一次或两次。
然而,应当理解,任何特定患者的具体剂量水平和剂量频率可以变化并且将取决于多种因素,包括所使用的具体化合物的活性、该化合物的代谢稳定性和作用长度、受试者的年龄、体重、遗传特征、一般健康状况、性别和饮食以及给药方式和时间、排泄速率、药物组合以及受治疗的受试者的特定病症的严重程度。
本文提供的化合物和组合物可以与用于治疗、预防、抑制或改善本文提供的化合物和组合物有用的疾病或病症的其它药物组合使用。这种其它药物可以通过与本文提供的化合物或组合物同时或顺序地通过其通常使用的途径和量给药。当本文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,除了本文提供的化合物或组合物外,还含有这种其它药物的药物组合物是优选的。因此,本文提供的药物组合物包括那些除本文提供的化合物或组合物外,还含有一种或多种其它活性成分或治疗剂的药物组合物。合适的其它活性剂包括例如:通过下调心脏的神经激素刺激来阻止心力衰竭进展并试图预防心脏重塑的疗法(例如ACE抑制剂、血管紧张素受体阻断剂(ARB)、β-受体阻滞剂、醛固酮受体拮抗剂或神经内肽酶抑制剂);通过刺激心脏收缩力改善心脏功能的疗法(例如正性变力剂,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);以及降低心脏预负荷的疗法(例如利尿剂,诸如呋塞米)或后负荷的疗法(任何类别的血管扩张剂,包括但不限于钙通道阻滞剂、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)。所述化合物或其药用盐可与β-受体阻滞剂(一种由于负性肌力作用引起的具有已知副作用的药物类别)组合使用,以赋予目标剂量β-受体阻滞剂滴定独特的耐受性。所述化合物或其药用盐可以与用于治疗舒张性心力衰竭的舒张剂(或HFpEF,一种具有舒张功能障碍和收缩储备减少的病症)组合使用。本文提供的化合物与第二活性成分的重量比可以变化并且将取决于每种成分的有效剂量。通常,将使用每种的有效剂量。
VI.实施例
aq:水溶液;BBr3:三溴化硼;BTC:二(三氯甲基)碳酸酯;CH2Cl2:二氯甲烷;CH3CN:乙腈;CH3OH:甲醇;DAST:二乙基氨基三氟化硫;DIAD:偶氮二羧酸二异丙酯;DIEA:二异丙基乙胺;DMF:二甲基甲酰胺;DMSO:二甲基亚砜;dppf:[1,1′-二(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物;DPPA:二苯基磷酰基叠氮化物;equiv.:当量;Et3N:三乙胺;Et2O:乙醚;EtOH:乙醇;h,hr:小时;HATU:(1-[二(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐);HCl:氯化氢;H2O:水;K2CO3:碳酸钾;KHSO4:硫酸氢钾;KNCO:异氰酸钾;LDA:二异丙基氨基锂;mCPBA:间氯过苯甲酸;MgSO4:硫酸镁;mL:毫升;MW:微波(在微波反应器中完成的反应);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;Na2SO3:亚硫酸钠;NBS:N-溴琥珀酰亚胺;NFSI:N-氟二(苯磺酰)亚胺;NH4Cl:氯化铵;NMP:n-甲基吡咯烷酮;pH:-log[H+];POCl3:三氯氧磷;PPTS:对甲苯磺酸吡啶鎓;RP-HPLC:反相高效液相色谱;RT:室温;RTx:保留时间;SFC:超临界流体色谱;TEBAC:三乙基苄基氯化铵;TFA:三氟乙酸;以及THF:四氢呋喃。
实施例1. 4-(((1-异丙基-1H-吡唑-4-基)磺酰基)甲基)-N-(吡啶-4-基)哌啶-1-
甲酰胺的制备.
化合物1.1. 4-((甲苯磺酰基氧基)甲基)哌啶-1-羧酸叔丁酯.
将4-(羟基甲基)哌啶-1-羧酸叔丁酯(50g,232.25mmol,1.00当量)、三乙胺(35.2g,347.86mmol,1.50当量)、4-二甲基氨基吡啶(2.8g,22.92mmol,0.10当量)和4-甲基苯-1-磺酰氯(53g,278.00mmol,1.20当量)在CH2Cl2(500mL)中的溶液在室温在氩气下搅拌过夜。通过过滤除去固体,并减压浓缩滤液。通过硅胶柱(乙酸乙酯/石油醚=1/39v/v))纯化所得残余物,提供78g(91%)的黄色固体。1H-NMR(400MHz,DMSO-d6):δ7.78(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),3.87(m,4H),2.49(m,2H),2.42(s,3H),1.76(m,1H),1.53(m,2H),1.36(s,9H),0.96(m,2H)ppm。
化合物1.2. 4-((脒基硫基)甲基)哌啶-1-羧酸叔丁酯.
将4-((甲苯磺酰基氧基)甲基)哌啶-1-羧酸叔丁酯(1.1,11g,29.77mmol,1.00当量)、硫脲(4.5g,59.13mmol,2.00当量)和碘化钾(2.47g,14.88mmol,0.50当量)在CH3OH(110mL)中的溶液在70℃在氩气下搅拌过夜。将反应混合物冷却至室温并减压浓缩。所得产物(15g,粗物质)不经进一步纯化即用于下一反应。
化合物1.3. 4-(巯基甲基)哌啶-1-羧酸叔丁酯.
将4-((脒基硫基)甲基)哌啶-1-羧酸叔丁酯(1.2,15g,1.00当量,粗物质)和氢氧化钠(2.2g,55.00mmol,1.00当量)在1:2(v/v)CH3OH/H2O(150mL)中的溶液在60℃在氩气下搅拌2h。然后将反应混合物冷却至室温。用HCl(aq)(35%)调节溶液的pH值至7。用EtOAc(3x50mL)萃取所得溶液并合并有机层。用盐水(2x50mL)洗涤有机层。混合物经无水Na2SO4干燥,过滤并减压浓缩。通过硅胶色谱(EtOAc/石油醚=1:8(v/v))纯化所得残余物,提供5.6g(44%)的黄色油状物。1H-NMR(400MHz,CDCl3):δ4.13(m,2H),2.69(m,2H),2.46(m,2H),1.82(m,2H),1.50(s,9H),1.32(m,1H),1.18(m,2H)ppm。
化合物1.4. 4-(((1-异丙基-1H-吡唑-4-基)硫基)甲基)哌啶-1-羧酸叔丁酯.
将4-(巯基甲基)哌啶-1-羧酸叔丁酯(1.3,300mg,1.30mmol,1.00当量)、Xantphos(123mg,0.21mmol,0.20当量)、Pd2(dba)3-CHCl3(144mg,0.10当量)、4-溴-1(丙-2-基)-1H-吡唑(246mg,1.30mmol,1.00当量)和N,N-二异丙基乙胺(195mg,1.51mmol,1.50当量)在1,4-二噁烷(5mL)中的溶液在90℃在氩气下搅拌过夜。将反应混合物冷却至室温并减压浓缩。通过硅胶色谱(EtOAc/石油醚=7:3(v/v))纯化所得残余物,提供400mg(粗物质)的黄色油状物。产物不经进一步纯化直接用于下一步骤。
化合物1.5. 4-(((1-异丙基-1H-吡唑-4-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯.
将4-(((1-异丙基-1H-吡唑-4-基)硫基)甲基)哌啶-1-羧酸叔丁酯(1.4,400mg,1.18mmol,1.00当量)和Oxone(2.17g,3.00当量)在DMF(10mL)中的溶液在室温在氩气下搅拌过夜。通过过滤除去固体,并用EtOAc(25mL)稀释滤液。用H2O(3x15mL)洗涤滤液,经无水Na2SO4干燥,过滤,并减压浓缩,提供200mg(粗物质)的黄色油状物。产物不经进一步纯化直接用于下一步骤。
化合物1.6. 4-(((1-异丙基-1H-吡唑-4-基)磺酰基)甲基)哌啶.
将4-(((1-异丙基-1H-吡唑-4-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(1.5,200mg,0.54mmol,1.00当量)在三氟乙酸/CH2Cl2(1:1(v/v),10mL)中的溶液在室温在氩气下搅拌2h,然后减压浓缩,提供100mg(粗物质)的黄色油状物。该产物不经进一步纯化直接用于下一步骤。
化合物1. 4-(((1-异丙基-1H-吡唑-4-基)磺酰基)甲基)-N-(吡啶-4-基)哌啶-1-甲酰胺.
在0℃在氩气下在搅拌下向吡啶-4-胺(34.7mg,0.368mmol,1.00当量)和BTC(43.7mg,0.40当量)在THF(3mL)中的溶液中滴加N,N-二异丙基乙胺(143mg,1.11mmol,3.00当量)。将所得溶液在0℃搅拌20min,然后在0℃在搅拌下滴加4-(((1-异丙基-1H-吡唑-4-基)磺酰基)甲基)哌啶(1.6,100mg,0.37mmol,1.00当量)在THF(1mL)中的溶液。将所得溶液在0℃搅拌1h,然后通过加入饱和Na2CO3(aq)(10mL)淬灭。用EtOAc(2x20mL)萃取所得溶液,并减压浓缩合并的有机层。通过Prep-HPLC[柱:X Bridge C18,19*150mm,5um;流动相A:水/10mmol/L NH4HCO3,流动相B:ACN;流速:30mL/min;梯度:8min内25%B至65%B;检测器UV,254nm]纯化残余物,提供8.7mg(6%)的白色固体。LC-MS(ES,m/z):392[M+H]+;1H-NMR(400MHz,DMSO-d6):δ8.89(s,1H),8.48(s,1H),8.29(d,J=6.4Hz,2H),7.91(s,1H),7.46(m,2H),4.60(m,1H),4.01(m,2H),3.29(m,2H),2.87(m,2H),2.07(m,1H),1.81(m,2H),1.45(m,6H),1.27(m,2H)ppm。
实施例2.N-(哒嗪-4-基)-4-(1-((4-(三氟甲氧基)苯基)磺酰基)环丙基)哌啶-1-
甲酰胺的制备.
化合物2.1. 4-(((4-(三氟甲氧基)苯基)硫基)甲基)吡啶.
将4-(氯甲基)吡啶(625mg,4.90mmol,1.00当量)、K2CO3(1.35g,9.70mmol,2.00当量)和4-(三氟甲氧基)苯-1-硫醇(950mg,4.89mmol,1.00当量)在DMF(10mL)中的溶液在室温在氩气下搅拌过夜,并通过过滤除去固体。用H2O(30mL)稀释滤液,并用EtOAc(3x20mL)萃取所得溶液。用盐水(2x20mL)洗涤合并的有机层,经无水Na2SO4干燥,过滤并减压浓缩。在硅胶(EtOAc/石油醚)上纯化所得残余物,提供1.3g(93%)的浅黄色油状物。
化合物2.2. 4-(((4-(三氟甲氧基)苯基)磺酰基)甲基)吡啶.
将4-(((4-(三氟甲氧基)苯基)硫基)甲基)吡啶(2.1,800mg,2.80mmol,1.00当量)和mCPBA(1.07g,6.17mmol,2.20当量)在CH2Cl2(20mL)中的溶液在室温在氩气下搅拌2h。然后用饱和Na2CO3(aq)(2x20mL)和盐水(20mL)洗涤溶液。有机层经无水Na2SO4干燥,过滤并减压浓缩。在硅胶(EtOAc/石油醚=1/1(v/v))上纯化所得残余物,提供900mg(96%)的白色固体。MS(ES,m/z):318[M+H]+。
化合物2.3. 4-(1-((4-(三氟甲氧基)苯基)磺酰基)环丙基)吡啶.
将4-((4-(三氟甲氧基)苯基磺酰基)甲基)吡啶(2.2,770mg,2.43mmol,1.00当量)、1-溴-2-氯乙烷(1.47g,10.25mmol,3.00当量)、Cs2CO3(2.37g,7.27mmol,3.00当量)和四丁基溴化铵(157mg,0.49mmol,0.20当量)在DMSO(20mL)中的溶液在室温在氩气下搅拌2h。然后通过加入H2O(30mL)淬灭反应混合物,并用EtOAc(2x30mL)萃取。用盐水(2x20mL)洗涤合并的有机层,经无水Na2SO4干燥,过滤,并减压浓缩。在硅胶(EtOAc/石油醚=2/3(v/v))上纯化所得残余物,提供600mg(72%)的浅黄色固体。MS(ES,m/z):344[M+H]+;1H-NMR(300MHz,CDCl3):δ8.51(d,J=6.0Hz,2H),7.55(d,J=7.6Hz.2H),7.25(d,J=7.6Hz.2H),7.13(d,J=6.0Hz,2H),1.97-2.09(m,2H),1.28-1.34(m,2H)ppm。
化合物2.4. 4-(1-((4-(三氟甲氧基)苯基)磺酰基)环丙基)哌啶.
将4-(1-((4-(三氟甲氧基)苯基)磺酰基)环丙基)吡啶(2.3,400mg,1.17mmol,1.00当量)和PtO2(80mg)在3N HCl/二噁烷(10mL)中的混合物在室温在H2(g)(5atm)气氛下在密封管中搅拌5h。[注意:在用H2(g)吹扫之前用N2(g)吹扫反应瓶]。通过过滤除去固体。减压浓缩滤液,提供400mg(98%)的浅黄色固体。1H-NMR(300MHz,DMSO-d6):δ8.08(d,J=8.1Hz,2H),7.65(d,J=8.1Hz.2H),3.16(m,2H),2.76(m,2H),2.08(m,1H),1.65(m,2H),1.46(m,2H),1.29(m,2H),1.07(m,2H)ppm。
化合物2. N-(哒嗪-4-基)-4-(1-((4-(三氟甲氧基)苯基)磺酰基)环丙基)哌啶-1-甲酰胺.
将4-(1-((4-(三氟甲氧基)苯基)磺酰基)环丙基)哌啶(2.4,58mg,0.17mmol,1.00当量)、哒嗪-4-基氨基甲酸苯酯(5.1,36mg,0.17mmol,1.00当量)和N-乙基-N-异丙基丙-2-胺(65mg,0.50mmol,3.00当量)在DMSO(1mL)中的溶液在70℃在氩气下搅拌2h。冷却至室温后,通过加入H2O(10mL)淬灭反应混合物,并用CH2Cl2(3x20mL)萃取所得混合物。用盐水(2x10mL)洗涤合并的有机层,经无水MgSO4干燥,过滤,并减压浓缩。通过Prep-HPLC[柱:XBridge Prep C18 OBD柱19*150mm 5um 13nm;流动相A:具有10mmol NH4HCO3的水,流动相B:ACN;梯度:10min内25%B至55%B;检测器,UV 254nm]纯化所得残余物,提供32.0mg(41%)的白色固体。MS(ES,m/z):471[M+H]+;1H-NMR(300MHz,DMSO-d6):δ9.23(d,J=1.8Hz,1H),9.08(s,1H),8.85(d,J=6.0Hz,1H),8.08(d,J=8.7Hz,2H),7.72(dd,J=1.8Hz,6.0Hz.1H),7.67(d,J=8.7Hz,1H),4.03-4.14(m,2H),2.73-2.86(m,2H),1.97-2.08(m,1H),1.41-1.52(m,4H),0.92-1.13(m,4H)ppm。
实施例3. 4-(((2-氰基-4-(三氟甲基)苯基)磺酰基)-二氟甲基)-N-(哒嗪-4-基)
哌啶-1-甲酰胺的制备.
化合物3.1.S-硫代乙酸(吡啶-4-基甲基)酯.
在0℃在氩气下向4-(氯甲基)吡啶盐酸盐(9g,54.87mmol,1.00当量)和K2CO3(7.6g,54.99mmol,1.50当量)在DMF(50mL)中的混合物中分几批加入硫代乙酸钾(9.38g,82.13mmol,1.00当量)。将所得混合物在50℃在油浴中搅拌1h。冷却至室温后,通过加入冰水(500mL)淬灭反应混合物。用EtOAc(3x300mL)萃取所得溶液。用盐水(2x500mL)洗涤合并的有机层,经无水Na2SO4干燥,过滤,并减压浓缩,提供9g(98%)的棕色液体。MS(ES,m/z):168[M+H]+。
化合物3.2. 4-(((2-溴-4-(三氟甲基)苯基)硫基)甲基)吡啶.
将S-硫代乙酸(吡啶-4-基甲基)酯(3.1,4.75g,28.40mmol,1.20当量)、Pd2(dba)3-CHCl3(2.94g,2.84mmonl,0.10当量)、碳酸钾(9.8g,70.91mmol,2.50当量)、2-溴-1-碘-4-(三氟甲基)苯(8.3g,23.65mmol,1.00当量)和Xantphos(3.29g,5.69mmol,0.20当量)在1,4-二噁烷(50mL)中的混合物在85℃在油浴中在密封管中搅拌10min。随后在85℃滴加MeOH(9.1g,284.02mmol,10.00当量)。将所得混合物在85℃在油浴中搅拌2h。冷却至室温后,通过过滤除去固体,并减压浓缩滤液。通过硅胶色谱(EtOAc/石油醚=1/1(v/v))纯化所得残余物,提供6g(73%)的棕色油状物。MS(ES,m/z):349[M+H]+,388[M+H+CH3CN]+。
化合物3.3. 4-(((2-溴-4-(三氟甲基)苯基)磺酰基)甲基)吡啶.
将4-(((2-溴-4-(三氟甲基)苯基)硫基)甲基)吡啶(3.2,4.6g,13.21mmol,1.00当量)和Oxone(20.35g,33.02mmol,2.5当量)在甲醇/水(1:1,50mL)中的溶液在室温搅拌过夜。用水(800mL)溶解混合物,并用K2CO3(aq.)调节溶液的pH值至9-10。通过过滤收集固体,提供5g(100%)的黄色固体。1H-NMR(400MHz,DMSO-d6,ppm):δ8.53(d,J=6.0Hz,2H),8.40(m,1H),7.97(m,2H),7.24-7.25(d,J=6.0Hz,2H),5.03(s,2H)。
化合物3.4. 4-(((2-溴-4-(三氟甲基)苯基)磺酰基)二氟甲基)吡啶.
在-10℃在氩气下向4-(((2-溴-4-(三氟甲基)苯基)磺酰基)甲基)吡啶(3.3,2.45g,6.44mmol,1.00当量)在THF(40mL)中的溶液中滴加t-BuOK(1M于THF中,19.4mL,19.32mmol,3当量)。将所得溶液在-10℃搅拌30min。随后在-10℃在搅拌下滴加THF(5mL)中的N-氟二(苯磺酰)亚胺(5.1g,16.17mmol,2.50当量)。将所得溶液在-10℃搅拌1小时。然后通过加入NH4Cl(sat.)(50mL)淬灭反应混合物。用EtOAc(3x50mL)萃取所得混合物并合并有机层。在真空下浓缩溶液。通过Flash-Prep-HPLC[柱,C18;流动相,在35min内CH3CN:H2O=0:100提高至CH3CN:H2O=100:0;检测器,UV 254nm]纯化所得残余物,提供1g(37%)的黄色固体。MS(ES,m/z):[M+H+CH3CN]+458。
化合物3.5. 4-(((2-溴-4-(三氟甲基)苯基)磺酰基)二氟甲基)哌啶.
向压力罐反应器中的4-(((2-溴-4-(三氟甲基)苯基)磺酰基)二氟甲基)-吡啶(3.4,500mg,1.20mmol,1.00当量)和PtO2(200mg,40%)的混合物中加入HOAc(6mL)和三氟乙酸(6mL)。用H2(g)(20atm)吹扫反应混合物,并将溶液在60℃在油浴中搅拌2天。[注意:在用H2(g)吹扫之前用N2(g)吹扫反应瓶]。通过过滤除去固体。加入第二等份的PtO2(200mg,40%),并将所得溶液在60℃在油浴中再搅拌2天。通过过滤除去固体并减压浓缩滤液,提供500mg(粗物质)的棕色固体。该产物不经进一步纯化直接用于下一步骤。
化合物3.6. 4-(((2-溴-4-(三氟甲基)苯基)磺酰基)二氟甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺.
将4-(((2-溴-4-(三氟甲基)苯基)磺酰基)二氟甲基)-哌啶(3.5,0.5g,1.15mmol,1.00当量)、DIEA(1.5g,5.75mmol,5.00当量)和哒嗪-4-基氨基甲酸苯酯(5.1,0.5g,2.30mmol,2.00当量)在DMSO(10mL)中的溶液在70℃在油浴中在氩气下搅拌3h。直接通过Flash-Prep-HPLC[柱,C18;流动相,在35min内CH3CN:H2O=0:100提高至CH3CN:H2O=100:0;检测器,UV254nm]纯化混合物,提供240mg(36%)的棕色固体。MS(ES,m/z):[M+H]+543,[M+H+CH3CN]+584。
化合物3. 4-(((2-氰基-4-(三氟甲基)苯基)磺酰基)二氟甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺.
将4-(((2-溴-4-(三氟甲基)苯基)磺酰基)二氟甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺(3.6,190mg,0.35mmol,1.00当量)、CuCN(125mg,1.4mmol,4.00当量)、dppf(156mg,0.28mmol,0.80当量)和Pd2(dba)3CHCl3(145mg,0.14mmol,0.40当量)在1,4-二噁烷(10mL)中的混合物在100℃在油浴中在氩气下搅拌1小时。冷却至室温后,用H2O(40mL)稀释所得混合物,并用EtOAc(2x50mL)萃取。用FeSO4(sat.)(30mL)洗涤合并的有机层,并经无水硫酸镁干燥。在真空下浓缩溶液,并通过Prep-HPLC[柱,SUNFIRE,19*150mm,5um;流动相,流动相A:水/10mM NH4HCO3,流动相B:CH3CN;流速:20mL/min;梯度:8min内25-75%B;检测器,254nm]纯化所得残余物,提供53.1mg(31%)的浅黄色固体。MS(ES,m/z):[M+H]+490,[M+Na]+512;1H-NMR(400MHz,DMSO-d6,ppm):δ9.28(m,2H),8.88(m,2H),8.45(m,2H),7.75(d,J=3.2Hz,1H),4.26(m,2H),2.93-3.04(m,3H),2.05(m,2H),1.51-1.60(m,2H)。19F-NMR(400MHz,DMSO-d6,ppm):62.107,104.437。
实施例4. 4-(((2-(二氟甲基)苯基)磺酰基)二氟甲基)-N-(哒嗪-4-基)哌啶-1-
甲酰胺的制备.
化合物4.1. 1-溴-2-(二氟甲基)苯.
在0℃在氩气下在搅拌下向2-溴苯甲醛(10.0g,54.05mmol,1.00当量)在CH2Cl2(100mL)中的溶液中滴加DAST(17.4g,107.95mmol,2.00当量)。将所得溶液在室温搅拌3h。然后通过缓慢且小心地加入NaHCO3(sat.)(200mL)淬灭反应混合物。用CH2Cl2(3x100mL)萃取所得混合物,并用盐水(150mL)洗涤合并的有机层,经无水硫酸钠干燥,过滤,并减压浓缩。通过硅胶色谱(EtOAc/石油醚(1:40))纯化所得残余物,提供9.0g(80%)的无色油状物。1H-NMR(CDCl3,400MHz,ppm):δ7.68(m,1H),7.61(m,1H),7.42(m,1H),7.33(m,1H),6.79-7.05(t,J=52Hz,1H)。19F-NMR(CDCl3,400MHz,ppm):δ114.63。
化合物4.2. 4-(((2-(二氟甲基)苯基)硫基)甲基)哌啶-1-羧酸叔丁酯.
将1-溴-2-(二氟甲基)苯(4.1,3.0g,14.49mmol,1.00当量)、Pd2(dba)3-CHCl3(750mg,0.82mmol,0.05当量)、碳酸钾(6.04g,43.70mmol,3.00当量)、Xantphos(838mg,1.45mmol,0.10当量)和4-[(乙酰基硫基)甲基]哌啶-1-羧酸叔丁酯(3.96g,14.48mmol,1.00当量)在1,4-二噁烷(80mL)中的混合物在80℃在油浴中在氩气下搅拌10min。随后在80℃滴加甲醇(4.6g,143.57mmol,10.00当量)。将所得溶液在80℃在油浴中搅拌1h。将反应混合物冷却至室温,然后减压浓缩。通过硅胶色谱(EtOAc/石油醚(1:10))纯化所得残余物,提供3.0g(58%)的无色油状物。1H-NMR(400MHz,CDCl3,ppm):δ7.65(m,1H),7.35-7.48(m,3H),6.97-7.24(t,J=52Hz,1H),4.10(m,2H),2.83(m,2H),2.66(m,2H),1.57(m,2H),1.45(s,9H),1.16-1.27(m,3H)。
化合物4.3. 4-(((2-(二氟甲基)苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯.
在0℃向4-(((2-(二氟甲基)苯基)硫基)甲基)哌啶-1-羧酸叔丁酯(4.2,2.0g,5.60mmol,1.00当量)在CH2Cl2(40mL)中的溶液中分几批加入mCPBA(4.8g,27.82mmol,4.00当量)。将所得溶液在室温搅拌2h。然后通过加入NaHCO3(sat.)(150mL)淬灭反应混合物。用CH2Cl2(3x100mL)萃取所得溶液。用H2O(2x100mL)和盐水(150mL)洗涤合并的有机层,经无水硫酸钠干燥并减压浓缩。通过硅胶色谱(EtOAc/石油醚(1:10))纯化所得残余物,提供800mg(37%)的无色油状物。1H-NMR(400MHz,CDCl3,ppm):δ8.09(m,1H),7.92(m,1H),7.79(m,1H),7.71(m,1H),7.49-7.70(t,J=44Hz,1H),4.07(m,2H),3.10(m,2H),2.74(m,2H),2.23(m,1H),1.87(m,2H),1.47(s,9H),1.26(m,2H)。
化合物4.4. 4-(((2-(二氟甲基)苯基)磺酰基)二氟甲基)哌啶-1-羧酸叔丁酯.
在-78℃在氩气下在搅拌下向4-(((2-(二氟甲基)苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(4.3,800mg,2.05mmol,1.00当量)和NFSI(3.2g,5.00当量)在THF(20mL)中的混合物中滴加NaHMDS的溶液(2.0M于THF中,8mL,8.00当量)。将所得溶液在-78℃搅拌1小时,然后通过加入NH4Cl(sat.)(100mL)淬灭反应混合物。用EtOAc(3x100mL)萃取所得溶液,并用H2O(2x100mL)、盐水(150mL)洗涤合并的有机层,经无水硫酸钠干燥并减压浓缩。通过硅胶色谱(EtOAc/石油醚=1/3(v/v))纯化所得残余物,提供600mg(69%)的无色油状物。1H-NMR(400MHz,CDCl3):δ8.006(m,2H),7.90(m,1H),7.74(m,1H),7.26-7.48(t,J=44Hz,1H),4.26(m,2H),2.76(m,3H),2.07(m,2H),1.61(m,2H),1.47(s,9H)ppm。19F-NMR(376MHz,CDCl3):δ-106.80,-109.33ppm。
化合物4.5. 4-(((2-(二氟甲基)苯基)磺酰基)二氟甲基)哌啶三氟乙酸盐.
将4-(((2-(二氟甲基)苯基)磺酰基)二氟甲基)哌啶-1-羧酸叔丁酯(4.4,600mg,1.41mmol,1.00当量)和三氟乙酸(4mL)在CH2Cl2(4mL)中的溶液在室温在氩气下搅拌1小时。减压浓缩所得混合物,提供600mg的粗棕色油状物。该产物不经进一步纯化直接用于下一步骤。MS(ES,m/z):325[M+H]+,367[M+CH3CN+H]+。
化合物4. 4-(((2-(二氟甲基)苯基)磺酰基)二氟甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺.
将4-(((2-(二氟甲基)苯基)磺酰基)二氟甲基)哌啶三氟乙酸盐(4.5,460mg,1.05mmol,1.00当量)、DIEA(731mg,5.66mmol,4.00当量)和哒嗪-4-基氨基甲酸苯酯(5.1,609mg,2.83mmol,2.00当量)在DMSO(5mL)中的混合物在80℃在油浴中在氩气下搅拌1小时。将反应混合物冷却至室温,并直接通过Flash-Prep-HPLC[柱,C18;流动相,在35min内CH3CN:H2O=0:100(v/v)升至CH3CN:H2O=100:0(v/v);检测器,UV 254nm]纯化,提供350mg(75%)的灰白色固体。LC-MS(ES,m/z):447[M+H]+,488[M+CH3CN+H]+;1H-NMR(400MHz,CD3OD):δ9.24(m,1H),8.87(m,1H),8.02-8.14(m,3H),7.88(m,2H),7.37-7.64(t,J=56Hz,1H),4.34(m,2H),2.91-3.13(m,3H),2.18(m,2H),1.74(m,2H)ppm。
实施例5. 4-(二氟((3-氟苯基)磺酰基)甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺的
制备.
化合物5.1.哒嗪-4-基氨基甲酸苯酯.
在0℃向4-氨基哒嗪(1.00g,10.51mmol)在THF(10mL)和乙腈(10mL)的1:1混合物中的悬浮液中加入吡啶(1.03mL,12.62mmol),随后经10分钟的时间段滴加氯甲酸苯酯(1.58mL,12.62mmol)。将反应混合物搅拌2h同时温热至室温。通过过滤分离沉淀物并在高真空下干燥1h,提供呈灰白色粉末状的所需产物(0.923g,41%)。LC-MS(ES,m/z):216[M+H]+;1H-NMR(400MHz,CDCl3):δ11.00(br.s.,1H),9.25(d,J=1.96Hz,1H),9.03(d,J=5.87Hz,1H),7.76(dd,J=5.87,2.74Hz,1H),7.38-7.51(m,2H),7.19-7.35(m,3H)ppm。
化合物5.2. 4-(((3-氟苯基)-l3-硫基)甲基)哌啶-1-羧酸叔丁酯.
向4-(溴甲基)哌啶-1-羧酸叔丁酯(10.0g,35.94mmol)在DMF(100mL)中的溶液中加入碳酸钾(7.45g,53.90mmol),随后加入3-氟硫代苯酚(3.20mL,37.87mmol)。将反应混合物在室温搅拌24h。用H2O稀释反应混合物,并用EtOAc萃取。用H2O、饱和NaCl洗涤有机层,经Na2SO4干燥,过滤并浓缩。获得呈透明油状的所需产物(11.8g)并不经纯化即使用。LC-MS(ES,m/z):324[M-H]-。
化合物5.3. 4-(((3-氟苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯.
向4-(((3-氟苯基)-l3-硫基)甲基)哌啶-1-羧酸叔丁酯(5.2,11.8g)在DMF(110mL)中的溶液中加入Oxone(66.4g,107.9mmol)。将反应混合物在室温搅拌18h。用H2O稀释反应混合物,并萃取到EtOAc中。用0.5N NaOH、饱和NaCl洗涤有机层,用Na2SO4干燥,过滤并浓缩。通过快速色谱(20%-40%EtOAc/己烷)纯化所得残余物,提供呈白色固体状的所需产物(7.48g,56%,经两步)。LC-MS(ES,m/z):302[M-56+H]+;1H-NMR(400MHz,CDCl3):δ7.72(d,J=7.83Hz,1H),7.54-7.65(m,2H),7.37(td,J=8.22,2.74Hz,1H),3.97-4.20(m,2H),3.02(d,J=6.26Hz,2H),2.74(m,2H),2.13-2.26(m,1H),1.89–1.86(m,2H),1.44(s,9H),1.19-1.33(m,2H)ppm。
化合物5.4. 4-(二氟((3-氟苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯.
在-78℃在氮气下向4-(((3-氟苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(5.3,1.00g,2.80mmol)和N-氟二(苯磺酰)亚胺(3.50g,11.1mmol)在无水THF(50mL)中的溶液中滴加LDA(2.0M于THF中,3.5mL,3.50mmol))。将反应混合物在-78℃搅拌25分钟。滴加第二等份的LDA(2.0M于THF中,2.0mL,2.00mmol),并将反应混合物在-78℃搅拌40分钟。缓慢加入NaHMDS(1.0M于THF中,7.0mL,7.00mmol),并将反应混合物在-78℃搅拌1.5h。将己烷(150mL)加入到反应混合物中,并通过过滤除去沉淀物。用饱和NaHCO3、饱和NaCl洗涤滤液,用Na2SO4干燥,过滤并浓缩。通过快速色谱(0–20%EtOAc/己烷)纯化所得残余物,提供呈白色固体状的所需产物(0.6g,54%)。LC-MS(ES,m/z):338[M-56+H]+;1H-NMR(400MHz,CDCl3):δ7.77(d,J=7.83Hz,1H),7.65-7.70(m,1H),7.62(m,1H),7.46(m,1H),4.25(br.s.,2H),2.60-2.87(m,3H),2.07(d,J=13.30Hz,2H),1.55-1.67(m,2H),1.46(s,9H)ppm。
化合物5.5. 4-(二氟((3-氟苯基)磺酰基)甲基)哌啶.
向4-(二氟((3-氟苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(5.4,8.0g,20.35mmol)在二噁烷(30mL)中的溶液中加入4N HCl/二噁烷(30mL)。将反应混合物在室温搅拌1h,然后浓缩。将所得残余物溶于EtOH(30mL)中,并加入150mL 5%NaHCO3水溶液。将破碎的固体在室温搅拌30分钟。过滤固体,用水洗涤并干燥,提供呈白色固体状的所需产物(4.68g),其不经进一步纯化即使用。LC-MS(ES,m/z):294[M+H]+。
化合物5. 4-(二氟((3-氟苯基)磺酰基)甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺.
在密封管中向4-(二氟((3-氟苯基)磺酰基)甲基)哌啶(5.5,4.68g,15.95mmol)和1-苯基-3-(哒嗪-4-基)脲(3.50g,16.27mmol)在乙腈(50mL)中的溶液中加入三乙胺(31.9mmol,3.22g)。将反应混合物在60℃在防爆屏蔽后加热2h。通过快速色谱(0-7%(v/v)MeOH/DCM)纯化所得残余物,提供呈白色固体状的所需产物(6.2g)。LC-MS(ES,m/z):415[M+H]+;1H NMR(400MHz,CD3OD):δ9.23(dd,J=2.7,0.8Hz,1H),8.80-8.94(m,1H),7.82-7.96(m,2H),7.70-7.80(m,2H),7.58-7.68(m,1H),4.32(d,J=14.1Hz,2H),3.03(t,J=12.3Hz,2H),2.83-2.97(m,1H),2.16(d,J=12.9Hz,2H),1.63-1.78(m,2H)ppm。
实施例6. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
的制备.
化合物6.1. 4-(1-((3-氟苯基)磺酰基)乙基)哌啶-1-羧酸叔丁酯.
在-78℃向4-(((3-氟苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(5.3,0.10g,0.279mmol)在无水THF(1mL)中的溶液中加入LDA(2.0M于THF中,0.168mL,0.336mmol)。将反应混合物在-78℃在氮气下搅拌15分钟,然后加入碘甲烷(0.017mL,0.279mmol)。使反应混合物搅拌18h同时温热至室温。用H2O稀释反应混合物并萃取到EtOAc中。用Na2SO4干燥有机层,过滤并浓缩。通过快速色谱(20%EtOAc/己烷)纯化所得残余物,提供呈无色油状的所需产物(0.103g,98%)。LC-MS(ES,m/z):316[M-56+H]+;1H-NMR(400MHz,CDCl3):δ7.66-7.71(m,1H),7.53-7.62(m,2H),7.33-7.40(m,2H),3.98-4.33(m,2H),3.00–2.94(m,1H),2.63-2.80(m,2H),2.44–2.37(m,1H),1.96–1.92(m,1H),1.45(s,9H),1.23-1.42(m,2H),1.20(d,J=7.04Hz,3H)ppm。
化合物6.2. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶-1-羧酸叔丁酯.
在-78℃向4-(1-((3-氟苯基)磺酰基)乙基)哌啶-1-羧酸叔丁酯(6.1,0.103g,0.277mmol)在无水THF(1mL)中的溶液中加入LDA(2.0M于THF中,0.173mL,0.346mmol)。将反应混合物在-78℃搅拌15分钟,然后加入N-氟二(苯磺酰)亚胺(0.087g,0.277mmol)。将反应混合物在-78℃搅拌2h。加入第二等份的LDA(2.0M于THF中,0.173mL,0.346mmol)和N-氟二(苯磺酰)亚胺(0.087g,0.277mmol),并将反应混合物在-78℃再搅拌30分钟。用H2O稀释反应混合物,温热至室温,并萃取到EtOAc中。用Na2SO4干燥有机层,过滤并浓缩。通过快速色谱(20%EtOAc/己烷)纯化所得残余物,提供呈无色油状的所需产物(0.028g,26%)。LC-MS(ES,m/z):334[M-56+H]+;1H-NMR(400MHz,CDCl3):δ7.74–7.72(m,1H),7.54-7.67(m,2H),7.42(ddt,J=8.27,6.99,1.37,1.37Hz,1H),4.30–4.15(m,2H),2.77–2.64(m,3H),2.40-2.53(m,1H),2.21–2.17(m,1H),1.81–1.78(m,2H),1.48-1.58(m,3H),1.46(s,9H)ppm。
化合物6.3. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶.
向4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶-1-羧酸叔丁酯(6.2,0.046g,0.119mmol)在CH2Cl2(1mL)中的溶液中加入TFA(0.20mL)。将反应混合物在室温搅拌18h,然后浓缩。将所得残余物溶于EtOH(1mL)中并加入MP-碳酸盐(0.376g,1.19mmol)。将反应混合物在室温搅拌30分钟。通过过滤除去固体并浓缩滤液,提供呈无色油状的所需产物(0.026g,75%),其不经进一步纯化即使用。LC-MS(ES,m/z):290[M+H]+。
化合物6.3a.(R)-4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶和化合物6.3b.(S)-4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶.
使用Prep-SFC(柱:Phenomenex3u Celloluse-2,4.6*100mm,3um;流动相A:CO2,流动相B:4.0min内EtOH(0.1%DEA)梯度10%至50%,在50%保持2.0min;流速:150mL/min;220nm)分离4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶的对映异构体(6.3,1.89g),提供RT1=2.16min(6.3a,0.938g,98%)的白色固体和RT2-=2.75min(6.3b,0.948g,98%)的白色固体。
化合物6. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)-N-(哒嗪-4-基)哌啶-1-甲酰胺三氟乙酸盐.
向4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶(6.3,0.026g,0.089mmol)在DMSO(1mL)中的溶液中加入哒嗪-4-基氨基甲酸苯酯(5.1,0.028g,0.132mmol),随后加入DIEA(0.055mL,0.309mmol)。将反应混合物置于预热的80℃油浴中并搅拌2h。将反应混合物冷却至室温,并用EtOAc和H2O稀释。分离两层。用Na2SO4干燥有机层,过滤并浓缩。使用反相高效液相色谱(0-90%(v/v)CH3CN/H2O(二者均含有0.1%TFA))纯化所得残余物,提供呈白色固体状的所需产物(0.015g,42%)。LC-MS-(ES,m/z):411[M+H]+;1H-NMR(400MHz,CDCl3):δ10.55(s,1H),9.60(d,J=1.96Hz,1H),8.77(d,J=7.04Hz,1H),8.67(dd,J=6.85,2.15Hz,1H),7.74(d,J=7.43Hz,1H),7.56-7.67(m,2H),7.43(td,J=8.12,2.15Hz,1H),4.49(t,J=12.91Hz,2H),2.96(br.s.,2H),2.55-2.68(m,1H),2.33(d,J=12.91Hz,1H),1.96(d,J=13.30Hz,1H),1.42-1.59(m,5H)ppm。
实施例7. 4-(2-((3-氟苯基)磺酰基)丙-2-基)-N-(哒嗪-4-基)哌啶-1-甲酰胺的
制备.
化合物7.1. 4-(2-((3-氟苯基)磺酰基)丙-2-基)哌啶-1-羧酸叔丁酯
以与化合物6.1类似的方式制备化合物7.1,不同之处在于用二(三甲基甲硅烷基)酰胺钠代替LDA和使用3.5当量的碘甲烷,提供呈白色固体状的所需产物(1.8g,83%),其不经纯化即用于下一反应。
化合物7.2. 4-(2-((3-氟苯基)磺酰基)丙-2-基)哌啶.
以与化合物5.5类似的方式制备化合物7.2,提供所需产物,其不经纯化即用于下一反应。
化合物7. 4-(2-((3-氟苯基)磺酰基)丙-2-基)-N-(哒嗪-4-基)哌啶-1-甲酰胺.
以与化合物5类似的方式制备化合物7,提供呈白色固体状的所需产物(0.56g,72%)。LC-MS(ES,m/z):407[M+H]+;1H-NMR(400MHz,DMSO-d6,ppm):δ9.28(s,1H),9.17(s,1H),8.88(d,J=6.0Hz,1H),7.78-7.66(m,5H),4.23-4.20(m,2H),2.83-2.77(m,2H),2.08-1.94(m,3H),1.40-1.37(m,2H),1.19(s,6H)ppm。
实施例8. 4-(1-氟-1-((4-(三氟甲基)苯基)磺酰基)乙基)-N-(异噁唑-3-基)哌
啶-1-甲酰胺的制备
化合物8.1. 4-(三氟甲基)苯亚磺酸钠
向4-(三氟甲基)苯磺酰氯(0.424g,1.73mmol)在H2O(2.5mL)中的溶液中加入NaHCO3(0.291g,3.46mmol)和Na2SO3(0.437g,3.46mmol)。将反应混合物置于预热的80℃油浴中并搅拌3h。将反应混合物冷却至室温并减压浓缩。将所得残余物悬浮于EtOH(5mL)中并通过过滤除去固体。减压浓缩滤液,提供呈白色固体状的所需产物(0.40g,99%),其不经进一步纯化即使用。LC-MS(ES,m/z):232[M+H]+。
化合物8.2. 4-(((4-(三氟甲基)苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯.
向4-(((4-(三氟甲基)苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(8.1,0.40g,1.79mmol)在DMF(10mL)中的溶液中加入K2CO3(0.495g,3.58mmol)和4-(溴甲基)哌啶-1-羧酸叔丁酯(0.499g,1.79mmol)。将反应混合物置于预热的80℃油浴中并搅拌3h。然后将反应混合物搅拌过夜同时冷却至室温。通过过滤除去固体。用EtOAc(15mL)和H2O(10mL)稀释滤液并分离两层。用Na2SO4干燥有机层,过滤并浓缩。通过快速色谱(20%EtOAc/己烷)纯化所得残余物,提供呈无色油状的所需产物(0.21g,73%)。LC-MS(ES,m/z):222[M-56+H]+;1H-NMR(400MHz,CDCl3):δ8.09(d,J=8.07Hz,2H),7.88(d,J=8.19Hz,2H),4.10(d,J=13.69Hz,2H),3.05(d,J=6.36Hz,2H),2.77(t,J=12.72Hz,2H),2.24(br.s.,1H),1.92(d,J=12.23Hz,2H),1.47(s,9H),1.22-1.38(m,2H)ppm。
化合物8.3. 4-(氟((4-(三氟甲基)苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
在-78℃向4-(((4-(三氟甲基)苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(8.2,0.207g,0.508mmol)在THF(3mL)中的溶液中加入LDA(2.0M于THF中,0.279mL,0.559mmol)。将反应混合物搅拌25分钟,然后加入NFSI(0.241g,0.762mmol)。将反应混合物在-78℃搅拌4h,然后用EtOAc(5mL)稀释并温热至室温。用H2O(5mL)稀释反应混合物并分离两层。用Na2SO4干燥有机层,过滤,然后浓缩。通过快速色谱(20%EtOAc/己烷)纯化所得残余物,提供呈无色油状的所需产物(0.16g,21%),其直接用于下一反应。LC-MS(ES,m/z):370[M-56+H]+。
化合物8.4. 4-(1-氟-1-((4-(三氟甲基)苯基)磺酰基)乙基)哌啶-1-羧酸叔丁酯
在-78℃向4-(((4-(三氟甲基)苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(8.3,0.160g,0.377mmol)在THF(3mL)中的溶液中加入LDA(2.0M于THF中,0.235mL,0.471mmol)。将反应混合物搅拌20分钟,然后加入碘甲烷(0.094g,0.659mmol)。用EtOAc(6mL)和H2O(2mL)稀释反应混合物并温热至室温。分离两层并用Na2SO4干燥有机层,过滤,然后浓缩。通过快速色谱(20%(v/v)EtOAc/己烷)纯化所得残余物,提供呈无色油状的所需产物(0.09g,55%),其直接用于下一反应。LC-MS(ES,m/z):384[M-56+H]+。
化合物8.5. 4-(1-氟-1-((4-(三氟甲基)苯基)磺酰基)乙基)哌啶
以与化合物6.3类似的方式制备化合物8.5,提供所需产物,其不经纯化即用于下一反应。
化合物8. 4-(1-氟-1-((4-(三氟甲基)苯基)磺酰基)乙基)-N-(异噁唑-3-基)哌啶-1-甲酰胺
以与化合物6类似的方式制备化合物8,提供呈白色固体状的所需产物(0.010g,33%)。LC-MS(ES,m/z):450.1[M+H]+;1H NMR(400MHz,CDCl3):δ8.41(s,1H),8.16(s,1H),8.00(d,J=7.95Hz,2H),7.80(d,J=8.19Hz,2H),6.92(s,1H),4.16-4.30(m,2H),2.83-2.95(m,2H),2.51-2.61(m,1H),2.25(d,J=13.00Hz,1H),1.86(d,J=12.96Hz,1H),1.35-1.54(m,5H)ppm。
实施例9. 4-(1-氟-1-((6-甲氧基吡啶-3-基)磺酰基)乙基)-N-(哒嗪-4-基)哌
啶-1-甲酰胺的制备
化合物9.1. 4-(((6-甲氧基吡啶-3-基)硫基)甲基)哌啶-1-羧酸叔丁酯
以与化合物4.2类似的方式制备化合物9.1,提供呈黄色固体状的所需产物(1.78g,48%)。1H NMR(400MHz,CDCl3)δ8.17–8.23(dd,J=2.4,0.7Hz,1H),7.59–7.67(dd,J=8.6,2.5Hz,1H),6.68–6.75(dd,J=8.6,0.7Hz,1H),4.05–4.15(m,2H),3.94(s,3H),2.59–2.75(m,4H),1.76–1.87(m,2H),1.50–1.64(m,1H),1.42–1.48(s,9H),1.06–1.21(m,2H)ppm。
化合物9.2. 4-(((6-甲氧基吡啶-3-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
以与化合物4.3类似的方式制备化合物9.2,提供呈白色固体状的所需产物(0.20g,81%)。1H NMR(400MHz,CDCl3)δppm 8.63–8.70(d,J=2.5Hz,1H),7.91–8.04(dd,J=8.8,2.6Hz,1H),6.79–6.89(d,J=8.8Hz,1H),3.97–4.11(m,5H),2.94–3.02(d,J=6.3Hz,2H),2.63–2.79(m,2H),2.08–2.22(m,1H),1.72–1.91(m,2H),1.41(s,9H),1.15–1.34(m,2H)ppm。
化合物9.3. 4-(氟((6-甲氧基吡啶-3-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
在-78℃向4-[(6-甲氧基吡啶-3-磺酰基)甲基]哌啶-1-羧酸叔丁酯(9.2,1.00g,2.70mmol)在THF(10mL)中的溶液中滴加NaHMDS(2.0M于THF中,1.4mL,0.700mmol),随后滴加NFSI(840mg,2.66mmol)在THF(5mL)中的溶液。将所得溶液搅拌2h同时温热至室温。用己烷(100mL)稀释所得溶液,并通过过滤除去固体。用饱和NaCl(50mL)洗涤滤液,经无水Na2SO4干燥,并浓缩。通过硅胶色谱(EtOAc/石油醚(1:10-1:5(v/v)))纯化所得残余物,提供呈灰白色固体状的所需产物(0.75g,72%)。LC-MS(ES,m/z):288.9[M-56+H]+。
化合物9.4. 4-(1-氟-1-((6-甲氧基吡啶-3-基)磺酰基)乙基)哌啶-1-羧酸叔丁酯
在-78℃向4-[氟(6-甲氧基吡啶-3-磺酰基)甲基]哌啶-1-羧酸叔丁酯(9.3,0.700g,1.80mmol)在THF(15mL)中的溶液中加入NaHMDS(2.0M于THF中,1mL,2.00mmol),随后滴加碘甲烷(0.282g,1.98mmol)。将所得溶液搅拌2h同时温热至室温。然后通过加入饱和NH4Cl(aq)(40mL)淬灭反应混合物。用EtOAc(3x10mL)萃取所得溶液,并用饱和NaCl(50mL)洗涤合并的有机层,经Na2SO4干燥,过滤并浓缩。通过硅胶柱使用(EtOAc/石油醚(1:10-1:5(v/v)))纯化所得残余物,提供呈黄色油状的所需产物(0.600g,83%)。1H NMR(300MHz,DMSO-d6)δ8.64(d,J=2.7Hz,1H),8.10(dd,J=8.7,1.5Hz,1H),7.10(d,J=8.7Hz,1H),4.03(m,2H),3.99(s,3H),2.71(s,1H),2.32(m,1H),2.02(m,1H),1.62(m,1H),1.52(d,J=22.8Hz,1H),1.40(s,9H),1.24-1.39(m,5H)ppm。
化合物9.5. 5-(1-氟-1-(哌啶-4-基)乙磺酰基)-2-甲氧基吡啶盐酸盐
向4-[1-氟-1-(6-甲氧基吡啶-3-磺酰基)乙基]哌啶-1-羧酸叔丁酯(9.4,0.600g,1.49mmol)在1,4-二噁烷(5mL)中的溶液中滴加1,4-二噁烷(5mL)中的4N HCl。将所得溶液在室温搅拌1h,然后浓缩。所得残余物(0.500g,粗物质)不经纯化直接用于下一反应。LC-MS(ES,m/z):302.7[M+H]+。
化合物9. 4-(1-氟-1-((6-甲氧基吡啶-3-基)磺酰基)乙基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
向5-(1-氟-1-(哌啶-4-基)乙磺酰基)-2-甲氧基吡啶盐酸盐(9.5,0.300g,粗物质)在DMSO(7mL)中的溶液中加入三乙胺(0.400g,3.95mmol)和N-(哒嗪-4-基)氨基甲酸苯酯(0.312mg,1.45mmol)。将反应混合物在70℃搅拌1h。将反应混合物冷却至室温,然后通过加入H2O(20mL)淬灭。用EtOAc(3x10mL)萃取所得溶液,并用饱和NaCl(50mL)洗涤合并的有机层,经Na2SO4干燥,过滤并浓缩。通过Prep-HPLC(柱:X Bridge RP,19*150mm,5μm;流动相A:H2O/10mM NH4HCO3,流动相B:ACN;流速:20mL/min;梯度:10min内24%B酯33%B;254nm)纯化所得残余物,提供呈白色固体状的所需产物(0.216g,39%)。LC-MS(ES,m/z):424.1[M+H]+;1H-NMR(300MHz,CD3OD):δ9.24(d,J=2.7Hz,1H),8.86(d,J=6.0Hz,1H),8.65(d,J=2.4Hz,1H),8.09(d,J=8.7Hz,1H),7.86(dd,J=2.7,6.0Hz,1H),7.02(d,J=9.0Hz,1H),4.40-4.25(m,2H),4.05(s,3H),2.96(t,J=13.2Hz,2H),2.68-2.48(m,1H),2.27(d,J=12.9Hz,1H),1.89(d,J=12.9Hz,1H),1.65-1.45(m,2H),1.58(d,J=22.5Hz,3H)ppm。
实施例10. 1-(4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶-1-基)-2-(哒嗪-4-
基)乙-1-酮的制备
化合物10. 1-(4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶-1-基)-2-(哒嗪-4-基)乙-1-酮
向4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶(6.3,0.025g,0.086mmol)和2-(哒嗪-4-基)乙酸钠(0.014g,0.086mmol)在DMF(1mL)中的溶液中加入三乙胺(0.024mL,0.172mmol)和HATU(0.039g,0.103mmol)。将反应混合物在室温搅拌18h,并用EtOAc(5mL)和H2O(2mL)稀释反应混合物。分离两层,并用Na2SO4干燥有机层,过滤并浓缩。使用反相高效液相色谱(0-90%CH3CN/H2O(二者均含有0.1%TFA))纯化所得残余物,提供呈白色固体状的所需产物(0.015g,42%)。LC-MS(ES,m/z):410[M+H]+;1H-NMR(400MHz,CDCl3):δ9.28(m,2H),7.73(t,J=6.04Hz,1H),7.66(d,J=7.83Hz,1H),7.60(m,3H),7.41-7.32(m,1H),4.73-4.61(m,1H),4.00-3.86(m,1H),3.80(s,2H),3.04(m,1H),2.39-2.15(m,2H),1.79(m,1H),1.52-1.27(m,5H)ppm。
实施例11. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)-N-(异噁唑-5-基)哌啶-1-甲
酰胺的制备
化合物11. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)-N-(异噁唑-5-基)哌啶-1-甲酰胺
在0℃向4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶(6.3,0.050g,0.172mmol)在THF(1mL)中的溶液中加入DIEA(0.184mL,1.03mmol),随后加入三光气(0.017g,0.057mmol)。将反应混合物搅拌15分钟,然后加入异噁唑-5-胺(0.014g,0.172mmol)。将反应混合物在室温搅拌过夜,然后用EtOAc(5mL)稀释并用H2O(2mL)淬灭。分离两相,并浓缩有机层。使用反相高效液相色谱(0-90%CH3CN/H2O(二者均含有0.1%TFA))纯化所得残余物,提供呈白色固体状的所需产物(0.015g,42%)。LC-MS(ES,m/z):400[M+H]+;1H NMR(400MHz,CDCl3):δ8.06(d,J=1.8Hz,1H),7.70-7.62(m,1H),7.60-7.48(m,2H),7.30(m,2H),6.14(m,1H),4.18-4.00(m,2H),2.99-2.83(m,2H),2.62-2.49(m,1H),2.30(m,1H),1.94(m,1H),1.51-1.33(m,5H)ppm。
实施例12. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)-N-(6-甲基哒嗪-4-基)哌啶-
1-甲酰胺的制备
化合物12. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)-N-(6-甲基哒嗪-4-基)哌啶-1-甲酰胺
向6-甲基哒嗪-4-羧酸(0.060g,0.345mmol)和三乙胺(0.058mL,0.414mmol)在DMF(1mL)中的溶液中加入DPPA(0.082mL,0.372mmol)。将反应混合物置于预热的90℃油浴中并搅拌10分钟。缓慢加入4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶(6.3,0.025g,0.086mmol)在DMF(1mL)中的溶液。将反应混合物搅拌3.5h同时冷却至室温。用EtOAc(5mL)和H2O(2mL)稀释反应混合物并分离两层。浓缩有机层,并使用反相高效液相色谱(0-90%CH3CN/H2O(二者均含有0.1%TFA))纯化所得残余物,提供呈白色固体状的所需产物(0.047g,4%)。LC-MS(ES,m/z):425[M+H]+;1H NMR(400MHz,CDCl3):δ10.58(br s,1H),9.44(m,1H),8.53(m,1H),7.76(d,J=8.19Hz,1H),7.65(s,1H),7.45(dt,J=1.83,8.19Hz,1H),7.15(m,1H),4.57-4.38(m,2H),2.94-2.78(m,2H),2.71(s,3H),2.43(m,1H),2.37(m,1H),1.96-1.84(m,1H),1.58-1.37(m,5H)ppm。
实施例13. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)-N-(1-甲基-1H-吡唑-4-基)哌
啶-1-甲酰胺的制备
化合物13.1. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)-N-(1H-吡唑-4-基)哌啶-1-甲酰胺
将4-(4-(1-氟-1-((3-氟苯基)磺酰基)乙基)哌啶-1-甲酰氨基)-1H-吡唑-1-羧酸叔丁酯(0.093g,0.185mmol)的溶液溶于DCM(2mL)中,并缓慢加入三氟乙酸(0.20mL,2.61mmol)。将反应混合物在室温搅拌过夜。浓缩反应混合物,并使用反相高效液相色谱(0-90%(v/v)CH3CN/H2O(二者均含有0.1%TFA))纯化所得残余物,提供呈白色固体状的所需产物(0.032g,70%)。LC-MS(ES,m/z):499.1[M+H]+;1H NMR(400MHz,CDCl3):δ8.31(s,1H),7.78(m,1H),7.71(s,1H),7.69(m,2H),7.49(m,1H),6.33(br s,1H),4.29-4.06(m,2H),3.05-2.88(m,2H),2.54(m,1H),2.27(m,1H),2.02(m,1H),1.72-1.40(m,14H)ppm。
化合物13. 4-(1-氟-1-((3-氟苯基)磺酰基)乙基)-N-(1-甲基-1H-吡唑-4-基)哌啶-1-甲酰胺
向4-(1-氟-1-((3-氟苯基)磺酰基)乙基)-N-(1H-吡唑-4-基)哌啶-1-甲酰胺(13.1,0.030g,0.075mmol)和K2CO3(0.026g,0.188mmol)在DMF(1mL)中的溶液中加入碘甲烷(0.005mL,0.090mmol)。将反应混合物置于预热的60℃油浴中并搅拌18h。将反应混合物冷却至室温并过滤。浓缩滤液,使用反相高效液相色谱(0-90%(v/v)CH3CN/H2O(二者均含有0.1%TFA))纯化所得残余物,提供呈白色固体状的所需产物(0.032g,70%)。LC-MS(ES,m/z):399.1[M+H]+;1H NMR(400MHz,CDCl3):δ7.88(br s,2H),7.68(d,J=7.70Hz,1H),7.62-7.51(m,2H),7.49-7.32(m,2H),4.28-4.02(m,2H),2.95(m,2H),2.59(m,2H),2.20(d,J=11.86Hz,1H),1.85(d,J=12.35Hz,1H),1.54-1.31(m,5H)ppm。
实施例14. 4-(1-((6-(二氟甲氧基)吡啶-3-基)磺酰基)-1-氟乙基)-N-(哒嗪-4-
基)哌啶-1-甲酰胺的制备
化合物14.1. 4-(((6-羟基吡啶-3-基)硫基)甲基)哌啶-1-羧酸叔丁酯
以与化合物4.2类似的方式制备化合物14.1,提供呈黄色固体状的所需产物(4.00g,72%)。1H NMR(400MHz,CDCl3)δ7.50–7.65(m,3H),6.62–6.70(m,1H),6.53–6.60(d,J=10.4Hz,1H),2.60–2.73(m,4H),1.76–1.84(m,2H),1.50–1.63(m,1H),1.41–1.46(s,9H),1.22–1.32(m,3H),1.06–1.20(m,2H)ppm。
化合物14.2. 4-(((6-羟基吡啶-3-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
向4-[[(6-羟基吡啶-3-基)硫基]甲基]哌啶-1-羧酸叔丁酯(14.1,4.00g,12.33mmol)和氯化钌(III)(0.80g,3.85mmol)在THF/H2O(1:1(v/v),60mL)中的溶液中滴加NaIO4(12.0g,49.3mmol)在水(5mL)中的溶液。将所得溶液在室温搅拌1h。然后通过加入H2O(30mL)淬灭反应混合物,并用EtOAc(3x20mL)萃取,经无水Na2SO4干燥,过滤并浓缩。通过硅胶柱使用(EtOAc/石油醚(100:1))纯化所得残余物,提供呈白色固体状的所需产物(2.40g,55%)。1H NMR(400MHz,DMSO-d6):δ12.35(s,1H),7.89–7.95(d,J=2.8Hz,1H),7.67–7.75(m,1H),6.41–6.48(d,J=9.7Hz,1H),3.78–3.86(d,J=13.3Hz,2H),3.23–3.28(d,J=6.3Hz,4H),2.73(s,1H),1.91–2.02(m,1H),1.70–1.78(m,2H),1.34–1.39(s,9H),1.07–1.20(m,2H)ppm。
化合物14.3. 4-(((6-(二氟甲氧基)吡啶-3-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
向4-(((6-羟基吡啶-3-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(14.2,1.00g,2.81mmol)和K2CO3(0.590g,5.57mmol)在CH3CN(20mL)中的溶液中加入2,2-二氟-2-(氟磺酰基)乙酸(0.550g,3.09mmol)。将所得溶液在室温搅拌2h。然后通过加入H2O(50mL)淬灭反应混合物,并用EtOAc(3x30mL)萃取。用盐水(50mL)洗涤合并的有机层,经Na2SO4干燥,过滤并浓缩。通过硅胶柱使用(EtOAc/石油醚(1:10–1:3(v/v)))纯化所得残余物,提供呈白色固体状的所需产物(1.00g,88%)。1H NMR(300MHz,CDCl3):δ8.74(d,J=2.4,1H),8.21(dd,J=2.4Hz,8.7Hz,1H),7.31-7.78(t,J=71.7Hz,1H),7.08(d,J=8.4Hz,1H),4.08(d,J=13.5Hz,2H),3.04(d,J=6.3Hz,2H),2.72-2.81(m,2H),2.22(m,1H),1.92(d,J=12.9Hz,2H),1.46(s,9H),1.24-1.37(m,2H)ppm。
化合物14.4. 4-(((6-(二氟甲氧基)吡啶-3-基)磺酰基)氟甲基)哌啶-1-羧酸叔丁酯
以与化合物9.3类似的方式制备化合物14.4,提供呈黄色油状的所需产物(0.20g,34%)。1H NMR(300MHz,CDCl3)δ8.74(d,J=2.4,1H),8.22(m,1H),7.31-7.80(t,J=71.7Hz,1H),7.15(d,J=8.4Hz,1H),4.77-4.95(dd,J=6.0,18.0Hz,1H),4.19(m,2H),2.79(m,2H),2.40-2.60(m,1H),2.00(m,1H),1.50-1.60(m,3H),1.47(s,9H)ppm。
化合物14.5. 4-(1-((6-(二氟甲氧基)吡啶-3-基)磺酰基)-1-氟乙基)哌啶-1-羧酸叔丁酯
以与化合物9.4类似的方式制备化合物14.5,提供呈黄色油状的所需产物(0.100g,48%)。1H NMR(300MHz,CDCl3)δ8.70(d,J=2.4,1H),8.20(m,1H),7.37-7.73(t,J=71.6Hz,1H),7.08(d,J=8.4Hz,1H),4.24(m,2H),2.69-2.77(m,2H),2.43-2.59(m,1H),2.18(m,1H),1.81(d,J=12.0Hz,1H),1.55(d,J=22Hz,3H),1.50(s,9H),1.31-1.40(m,2H)ppm。
化合物14.6. 2-(二氟甲氧基)-5-((1-氟-1-(哌啶-4-基)乙基)磺酰基)吡啶
以与化合物4.5类似的方式制备化合物14.6,提供呈黄色油状的所需产物(0.300g)。所需产物不经纯化直接用于下一反应。LC-MS(ES,m/z):339.0[M+H]+。
化合物14. 4-(1-((6-(二氟甲氧基)吡啶-3-基)磺酰基)-1-氟乙基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
以与化合物9类似的方式制备化合物14,提供呈白色固体状的所需产物(0.116g,29%)。LC-MS(ES,m/z):460.1[M+H]+;1H NMR(400MHz,DMSO-d6):δ9.28(d,J=2.0Hz,1H),9.21(s,1H),8.88(d,J=6.0Hz,1H),8.77(d,J=2.4Hz,1H),8.37(dd,J=8.4,1.6Hz,1H),7.83(t,J=71.6Hz,1H),7.77(d,J=2.4Hz,1H),7.41(d,J=8.8Hz,1H),4.23–4.31(m,2H),2.89(m,2H),2.47(m,1H),2.10(m,1H),1.73(m,1H),1.57(d,J=22.8Hz,3H),1.40(m,2H)ppm。
实施例15. 4-(1-((3-氯-1-甲基-1H-吡唑-5-基)磺酰基)-1-氟乙基)-N-(哒嗪-
4-基)哌啶-1-甲酰胺的制备
化合物15.1. 4-((甲苯磺酰基氧基)甲基)哌啶-1-羧酸苄酯
以与化合物1.1类似的方式制备化合物15.1,提供呈白色固体状的所需产物(13.0g,80%)。LC-MS(ES,m/z):404.2[M+H]+;1H NMR(300MHz,CDCl3):δ7.78(d,J=8.4Hz,2H),7.38-7.78(m,7H),5.10(s,2H),4.20-4.15(m,2H),3.85(d,J=6.3Hz,2H),2.77-2.69(m,2H),2.41(s,3H),1.89-1.79(m,1H),1.69-1.64(m,2H),1.19-1.15(m,2H)ppm。
化合物15.2. 4-((脒基硫基)甲基)哌啶-1-羧酸苄酯
以与化合物3.1类似的方式制备化合物15.2,提供呈棕色油状的所需产物(25.0g)。该物质不经进一步纯化即用于下一反应。LC-MS(ES,m/z):308.1[M+H]+。
化合物15.3. 4-(((3-氨基-1-甲基-1H-吡唑-5-基)硫基)甲基)哌啶-1-羧酸苄酯
以与化合物4.2类似的方式制备化合物15.3,提供呈黄色油状的所需产物(8.3g,59%)。1H NMR(400MHz,CDCl3)δ7.29-7.39(m,5H),5.65(s,1H),5.12(s,2H),4.05-4.19(m,2H),3.71(s,3H),2.66-2.79(m,2H),2.64(m,2H),1.73-1.85(m,2H),1.60-1.72(m,1H),1.10-1.35(m,2H)ppm。
化合物15.4. 4-(((3-氯-1-甲基-1H-吡唑-5-基)硫基)甲基)哌啶-1-羧酸苄酯
在0℃向4-(((3-氨基-1-甲基-1H-吡唑-5-基)硫基)甲基)哌啶-1-羧酸苄酯(1.9g,5.27mmol)在浓HCl(9.5mL)和AcOH(57mL)中的溶液中滴加硝酸钠(0.551g,7.99mmol)在H2O(9.5mL)中的溶液。将所得溶液在0℃搅拌30分钟。将温度升高至80℃,并滴加氯化亚铜(I)(2.09g,21.1mmol)在浓HCl(9.5mL)和AcOH(19mL)中的溶液。将所得溶液再搅拌10min同时温度保持在70℃。用EtOAc(100mL)萃取所得溶液并合并有机层。用盐水(50mL)洗涤所得溶液,经无水Na2SO4干燥,过滤,然后浓缩。通过硅胶柱使用(EtOAc/石油醚(1:2(v/v)))纯化所得残余物,提供呈白色固体状的所需产物(0.700g,35%)。1H NMR(300MHz,CDCl3):δ7.29-7.39(m,5H),6.19(s,1H),5.12(s,2H),4.23-4.19(m,2H),3.83(s,3H),2.68-2.80(m,3H),1.69-1.85(m,2H),1.60(m,1H),1.22(m,2H)ppm。
化合物15.5. 4-(((3-氯-1-甲基-1H-吡唑-5-基)磺酰基)甲基)哌啶-1-羧酸苄酯
以与化合物5.3类似的方式制备化合物15.5,提供呈黄色油状的所需产物(8.3g,59%)。1H NMR(400MHz,CDCl3):δ7.26-7.39(m,5H),6.14(s,1H),5.12(s,2H),4.17-4.28(m,2H),4.09(s,3H),3.09(m,2H),2.84(m,2H),2.19-2.29(m,1H),1.91(m,2H),1.27-1.40(m,2H)ppm。
化合物15.6. 4-(1-((3-氯-1-甲基-1H-吡唑-5-基)磺酰基)-1-氟乙基)哌啶-1-羧酸苄酯
在-78℃向4-[(3-氯-1-甲基-1H-吡唑-5-磺酰基)甲基]哌啶-1-羧酸苄酯(15.5,2.9g,7.04mmol)在THF(120mL)中的溶液中滴加t-BuOK(7mL,7.04mmol,1M于THF中),随后滴加NFSI(1.33g,4.22mmol)在THF(20mL)中的溶液。将所得溶液在-78℃搅拌1h,然后再滴加t-BuOK(21.1mL,21.12mmol,1M于THF中)。将所得溶液在-78℃搅拌30min,然后滴加碘甲烷(3.00g,21.14mmol)。将所得溶液在-78℃再搅拌30min,然后通过加入正己烷(50mL)淬灭。将反应混合物温热至室温,通过过滤除去固体,并浓缩滤液。通过prep-HPLC(在50min内ACN/H2O 10:90(v/v)升至ACN/H2O80:20(v/v);检测器,UV 254nm)纯化所得残余物,提供呈白色固体状的产物(1.5g,83%)。1H NMR(400MHz,CDCl3):δ7.35(m,5H),6.80(s,1H),5.13(s,2H),4.09-4.33(m,2H),4.07(s,3H),2.56-2.82(m,2H),2.52(m,1H),2.12(m,1H),1.84(m,1H),1.59(d,J=24.0Hz,3H),1.40(m,2H)ppm。
化合物15.7. 4-(1-((3-氯-1-甲基-1H-吡唑-5-基)磺酰基)-1-氟乙基)哌啶盐酸盐
向4-[1-(3-氯-1-甲基-1H-吡唑-5-磺酰基)-1-氟乙基]哌啶-1-羧酸苄酯(15.6,1.00g,2.25mmol,1.00)在甲醇(5mL)中的溶液中加入浓HCl(15mL)。将所得溶液在70℃在油浴中搅拌3h,然后浓缩。用甲醇(2mL)沉淀所得残余物。通过从乙醚中重结晶纯化粗产物,提供呈白色固体状的所需产物(0.429g,55%)。LC-MS(ES,m/z):310.1[M+H]+;1H NMR(400MHz,CD3OD):δ7.05(s,1H),4.09(s,3H),3.50(m,2H),3.03-3.13(m,2H),2.64-2.73(m,1H),2.35(m,1H),2.10(m,2H),1.70-1.85(m,2H),1.65(d,J=24.0Hz,3H)ppm;19F NMR(376MHz,CD3OD):δ-146.30ppm。
化合物15. 4-(1-((3-氯-1-甲基-1H-吡唑-5-基)磺酰基)-1-氟乙基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
以与化合物6类似的方式制备化合物15,提供呈灰白色固体状的所需产物(0.012g,8%)。LC-MS(ES,m/z):430.1[M+H]+;1H NMR(300MHz,CD3OD):δ9.20(m,1H),8.84(d,J=8.0Hz,1H),7.83(m,1H),6.99(s,1H),4.33(m,2H),4.03(s,3H),2.99(m,2H),2.56(m,1H),2.17(m,1H),1.90(m,1H),1.66-1.42(m,5H)ppm;19F NMR(376MHz,CD3OD):δ-77.12,-145.34ppm。
实施例16. 4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰基)乙基)-
N-(异噁唑-3-基)哌啶-1-甲酰胺的制备
化合物16.1. 4-溴-1-甲基-3-(三氟甲基)-1H-吡唑
将1-甲基-3-(三氟甲基)-1H-吡唑(10.0g,66.62mmol)和NBS(16.2g,66.62mmol)在DMF(100mL)中的溶液置于用氩气吹扫并用氩气惰性气氛保持的10-mL密封管中。将所得溶液在50℃在油浴中搅拌过夜。然后通过加入冰水(1L)淬灭反应混合物。用乙醚(3x200mL)萃取所得溶液,合并有机层并经无水Na2SO4干燥,过滤,然后浓缩,提供呈黄色油状的所需产物(12.0g,粗物质),其不经进一步纯化直接使用。1H NMR(400MHz,CDCl3):δ7.46(s,1H),3.94(s,3H)ppm。
化合物16.2. 4-(((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)硫基)甲基)哌啶-1-羧酸叔丁酯
以与化合物4.2类似的方式制备化合物16.2,提供呈黄色固体状的所需产物(0.200g,粗物质)。所需产物不经进一步纯化即用于下一反应。LC-MS(ES,m/z):279.9[M+H-Boc]+。
化合物16.3. 4-(((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
以与化合物14.2类似的方式制备化合物16.3,提供呈黄色固体状的所需产物(0.200g,15%)。所需产物不经进一步纯化即用于下一反应。1H NMR(400MHz,CDCl3):δ7.96(s,1H),4.07(m,2H),4.02(s,3H),3.14(d,J=6.4Hz,2H),2.74(m,1H),2.22(m,2H),1.90(m,2H),1.46(s,9H),1.25-1.35(m,2H)ppm。
化合物16.4. 4-(氟((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
在-78℃向4-[[1-甲基-3-(三氟甲基)-1H-吡唑-4-磺酰基]甲基]哌啶-1-羧酸叔丁酯(16.3,0.450mg,1.09mmol)在THF(20mL)中的溶液中滴加t-BuOK溶液(11mL,1.0M于THF中,5.54mmol)。将所得溶液搅拌0.5h,然后加入NFSI(2.42g,7.63mmol)在THF(2mL)中的溶液。将所得溶液在-78℃再搅拌1h,然后通过加入冰水(50mL)淬灭。用EtOAc(3x50mL)萃取所得混合物,并合并有机层,然后经Na2SO4干燥并浓缩。通过prep-HPLC(在50min内ACN/H2O 0:100(v/v)升至ACN/H2O 100:0(v/v);检测器,UV 254nm)纯化所得残余物,提供呈白色固体状的产物(0.200g,43%)。1H NMR(400MHz,CDCl3):δ7.99(s,1H),4.87-5.00(m,1H),4.18(d,J=13.2Hz,2H),4.03(s,3H),2.71-2.82(m,2H),2.42–2.54(m,1H),1.93-2.01(m,2H),1.40-1.60(m,11H)ppm。
化合物16.5. 4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰基)乙基)哌啶-1-羧酸叔丁酯
在-78℃向4-[氟[1-甲基-3-(三氟甲基)-1H-吡唑-4-磺酰基]甲基]哌啶-1-羧酸叔丁酯(16.4,0.060g,0.14mmol)在THF(3mL)中的溶液中加入t-BuOK溶液(0.45mL,1.0M于THF中,0.56mmol)。将反应混合物在-78℃搅拌0.5h,然后滴加碘甲烷(0.052g,0.37mmol)。将反应混合物在-78℃再搅拌4小时,然后通过加入冰水(30mL)淬灭。用EtOAc(3x30mL)萃取所得溶液。合并的有机层经Na2SO4干燥,过滤并浓缩,提供呈固体状的所需产物(0.040g,粗物质),其不经进一步纯化即用于下一反应。LC-MS(ES,m/z):344[M+H-Boc]+。
化合物16.6. 4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰基)乙基)哌啶盐酸盐
以与化合物9.5类似的方式制备化合物16.4,提供呈白色的所需产物(0.104g,93%)。LC-MS(ES,m/z):343.9[M+H]+;1H NMR(400MHz,D2O):δ8.39(s,1H),3.93(s,3H),3.38-3.50(m,2H),2.88-3.02(m,2H),2.53(m,1H),2.21(d,J=14.5Hz,1H),2.01(dt,J=14.4,3.0Hz,1H),1.58-1.77(m,4H),1.55(s,2H)ppm。
化合物16. 4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰基)乙基)-N-(异噁唑-3-基)哌啶-1-甲酰胺
以与化合物9类似的方式制备化合物16,提供呈白色固体状的所需产物(0.09g,22%)。LC-MS(ES,m/z):454.1[M+H]+;1H NMR(400MHz,CD3OD):δ8.39(d,J=1.5Hz,2H),6.68(d,J=1.8Hz,1H),4.00-4.30(m,2H),3.98(s,3H),2.84-2.93(m,2H),2.48-2.58(m,1H),2.18(d,J=1.5Hz,1H),1.84(d,J=12.6Hz,1H),1.33-1.61(m,5H)ppm;19F NMR(376MHz,CD3OD):δ-61.149,-61.182,-144.269,-144.300ppm。
实施例17. 4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-5-基)磺酰基)-1-氟乙基)-
N-(哒嗪-4-基)哌啶-1-甲酰胺的制备
化合物17.1. 3-(二氟甲基)-1-甲基-1H-吡唑
在0℃向1-甲基-1H-吡唑-3-甲醛(4.00g,36.33mmol)在CH2Cl2(50mL)中的溶液中滴加DAST(23.4g,145.17mmol,4.00当量)。将反应混合物在室温搅拌过夜,然后通过加入饱和NaHCO3(100mL)淬灭,并用CH2Cl2(3x200mL)萃取。合并的有机层经无水MgSO4干燥,过滤并浓缩,提供呈油状的所需产物(4.8g,粗物质),其不经进一步纯化即用于下一反应。1H NMR(400MHz,CDCl3):δ7.32-7.37(m,1H),6.44-6.45(t,1H),6.80(m,1H),3.90(s,3H)ppm。
化合物17.2. 3-(二氟甲基)-5-碘-1-甲基-1H-吡唑
在-78℃向3-(二氟甲基)-1-甲基-1H-吡唑(17.1,4.8g,36.33mmol)在THF(50mL)中的溶液中滴加n-BuLi(20.0mL,2.5M于正己烷中)。将所得溶液在-78℃搅拌30min,然后滴加I2(13.8g,54.49mmol)在THF(50mL)中的溶液。将反应混合物在-78℃搅拌2h,然后通过加入NH4Cl(sat.)(100mL)淬灭。用Et2O(2x200mL)萃取所得溶液,并用饱和Na2S2O3(aq.)(2x100mL)洗涤合并的有机层,经无水MgSO4干燥,过滤并浓缩,提供所需产物(9.0g,粗物质),其不经进一步纯化即用于下一反应。1H NMR(400MHz,CDCl3):δ6.51-6.78(m,2H),3.97(s,3H)ppm。
化合物17.3. 4-(((3-(二氟甲基)-1-甲基-1H-吡唑-5-基)硫基)甲基)哌啶-1-羧酸叔丁酯
以与化合物4.2类似的方式制备化合物17.3,提供呈深红色油状的所需产物(0.370g,38%)。所需产物不经进一步纯化即用于下一反应。1H NMR(400MHz,CDCl3):δ6.44-6.74(m,2H),4.08-4.17(m,2H),3.83-3.96(m,3H),2.62-2.76(m,4H),1.82(d,J=13.2Hz,2H),1.60(m,2H),1.46(s,8H),1.09-1.28(m,2H)ppm。
化合物17.4. 4-(((3-(二氟甲基)-1-甲基-1H-吡唑-5-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
以与化合物14.2类似的方式制备化合物17.4,提供呈深红色油状的所需产物(0.200g,68%)。所需产物不经进一步纯化即用于下一反应。1H NMR(400MHz,CDCl3):δ7.05(s,1H),6.67(t,J=54.7Hz,1H),4.17(m,5H),3.11(d,J=6.4Hz,2H),2.68-2.84(m,2H),2.24(m,1H),1.90(d,J=13.5Hz,2H),1.45(s,9H),1.22-1.41(m,2H)ppm。
化合物17.5. 4-(((3-(二氟甲基)-1-甲基-1H-吡唑-5-基)磺酰基)氟甲基)哌啶-1-羧酸叔丁酯
以与化合物16.4类似的方式制备化合物17.5,提供呈黄色油状的所需产物(0.900g,29%)。1H NMR(400MHz,CDCl3):δ7.11(s,1H),6.68(t,J=54.7Hz,1H),5.03(d,J=6.4Hz,0.5H),4.87(d,J=6.4Hz,0.5H),4.16(s,5H),2.86–2.69(m,2H),2.45(s,1H),2.04–1.91(m,2H),1.59–1.50(m,2H),1.46(s,9H)ppm。
化合物17.6. 4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-5-基)磺酰基)-1-氟乙基)哌啶-1-羧酸叔丁酯
以与化合物16.5类似的方式制备化合物17.6,提供呈透明油状的所需产物(0.900g,29%)。1H NMR(400MHz,CDCl3):δ7.11(s,1H),6.70(t,J=54.7Hz,1H),4.25(m,2H),4.14(s,3H),2.74(m,2H),2.51(m,1H),2.13(d,J=12.2Hz,1H),1.81(m,1H),1.53-1.65(m,4H),1.47(s,9H)ppm。
化合物17.7. 4-[1-[3-(二氟甲基)-1-甲基-1H-吡唑-5-磺酰基]1-氟乙基]哌啶三氟乙酸盐
以与化合物4.5类似的方式制备化合物17.7,提供呈白色固体状的所需产物(0.496g,69%)。所需产物不经进一步纯化即用于下一反应。LC-MS(ES,m/z):326.1[M+H]+,367.1[M+H+CH3CN]+;1H NMR(300MHz,CD3OD):δ7.24(s,1H),6.80(t,J=54.5Hz,1H),4.11(s,3H),3.47(m,2H),3.05(m,2H),2.69(m,1H),2.28-2.40(m,1H),2.09(m,1H),1.57-1.87(m,5H)ppm。
化合物17. 4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-5-基)磺酰基)-1-氟乙基)-N-(哒嗪-4-基)哌啶-1-甲酰胺氟乙基]哌啶三氟乙酸盐
以与化合物9类似的方式制备化合物17,提供呈白色固体状的所需产物(0.068g,60%)。LC-MS(ES,m/z):447.0[M+H]+;1H NMR(300MHz,CD3OD):δ9.20(d,J=2.1Hz,1H),8.84(d,J=6.0Hz,1H),7.84–7.81(m,1H),7.21(s,1H),6.79(t,J=54.3Hz,1H),4.34–4.26(m,2H),4.11(s,3H),3.03–2.94(m,2H),2.64–2.53(m,1H),2.19–2.15(m,1H),1.90–1.86(m,1H),1.65–1.48(m,5H)ppm。
实施例18.(R)-4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)磺酰基)乙
基)-N-(异噁唑-3-基)哌啶-1-甲酰胺的制备
化合物18.1. 1-甲基-3-(三氟甲基)-1H-吡唑
向(3E)-4-乙氧基-1,1,1-三氟丁-3-烯-2-酮(29.0g,172.50mmol)在甲醇(300mL)中的溶液中分批加入甲基肼硫酸盐(39.8g,276.10mmol),随后分批加入三乙胺(18.0g,177.88mmol)。将所得溶液在40℃搅拌过夜。然后将所得混合物冷却至室温并在真空下浓缩。然后通过加入冰水(200mL)淬灭反应混合物并用Et2O(3x200mL)萃取。用盐水(2x200mL)洗涤合并的有机层,经无水MgSO4干燥,过滤并浓缩,提供呈浅棕色油状的所需产物(29.0g,粗物质),其直接用于下一反应。LC-MS(ES,m/z):151.0[M+H]+,192.0[M+H+CH3CN]+;1H NMR(300MHz,CDCl3):δ7.37(m,1H),6.48(d,J=2.2Hz,1H),3.94(s,3H)ppm。
化合物18.2. 5-碘-1-甲基-3-(三氟甲基)-1H-吡唑
在-78℃向1-甲基-3-(三氟甲基)-1H-吡唑(18.1,3.7g,24.65mmol)在THF(40mL)中的溶液中滴加n-BuLi(2.5M于正己烷中,11.2mL,27.11mmol)。将所得溶液在-78℃搅拌10min,然后滴加I2溶液(10.0g,39.44mmol)在THF(10mL)中的溶液。将反应混合物在-78℃搅拌30分钟,然后通过加入饱和NH4Cl(aq)(100mL)淬灭并用Et2O(3x200mL)萃取。用饱和Na2S2O3(aq)(2x100mL)和盐水(2x50mL)洗涤合并的有机层,经无水MgSO4干燥,过滤并浓缩,提供呈黄色固体状的所需产物(8.0g,粗物质),其直接用于下一反应。LC-MS(ES,m/z):276.8[M+H]+,317.8[M+H+CH3CN]+;1H NMR(300MHz,CDCl3):δ6.67(s,1H),3.96(s,3H)ppm。
化合物18.3. 4-(((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)硫基)甲基)哌啶-1-羧酸叔丁酯
以与化合物4.2类似的方式制备化合物18.3,提供呈深红色油状的所需产物(2.20g,85%)。所需产物不经进一步纯化即用于下一反应。1H NMR(300MHz,CDCl3):δ6.53(s,1H),4.13(d,J=13.1Hz,2H),3.94(s,3H),2.60-2.78(m,4H),1.82(d,J=13.5Hz,2H),1.53-1.70(m,1H),1.46(s,9H),1.07-1.29(m,2H)ppm。
化合物18.4. 4-(((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
以与化合物14.2类似的方式制备化合物18.4,提供呈深红色油状的所需产物(3.5g,92%)。所需产物不经进一步纯化即用于下一反应。1H NMR(400MHz,CD3OD):δ7.09(s,1H),4.20(s,3H),4.12(m,2H),3.12(d,J=6.4Hz,2H),2.71-2.83(m,2H),2.27(m,1H),1.90(d,J=12.9Hz,2H),1.45(s,9H),1.30(m,2H)ppm。
化合物18.5. 4-(氟((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
以与化合物16.4类似的方式制备化合物18.5,提供呈黄色油状的所需产物(0.100g,27%)。1H NMR(400MHz,CDCl3):δ7.15(s,1H),4.97(dd,J=48.0,6.5Hz,1H),4.21(m,5H),2.71-2.82(m,2H),2.48(m,1H),1.97(t,J=12.8Hz,2H),1.48(m,2H),1.46(s,9H)ppm。
化合物18.6. 4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)磺酰基)乙基)哌啶-1-羧酸叔丁酯
以与化合物16.5类似的方式制备化合物18.6,提供呈透明油状的所需产物(10.0g,86%)。1H NMR(400MHz,CDCl3):δ7.12(s,1H),4.25(d,J=15.2Hz,2H),4.15(s,3H),2.70(tt,J=12.9,2.6Hz,2H),2.48(m,1H),2.08(d,J=13.2Hz,1H),1.79(d,J=13.3Hz,1H),1.58(d,J=22.4Hz,3H),1.44(s,9H),1.19-1,40(m,2H)ppm。
化合物18.6a.(R)-4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)磺酰基)乙基)哌啶-1-羧酸叔丁酯和化合物18.6b.(S)-4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)磺酰基)乙基)哌啶-1-羧酸叔丁酯
使用Prep-SFC(柱:Phenomenex Lux 5u Cellulose-4250*50mm;流动相A:CO2:80,流动相B:MeOH:20;流速:150mL/min;220nm)分离4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)磺酰基)乙基)哌啶-1-羧酸叔丁酯(18.6,3.3g)的对映异构体,提供RT1=3.04min(18.6a,1.3g,78%)的白色固体和RT2=3.59min(18.6b,1.3g,78%)的白色固体。
化合物18.7.(R)-4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)磺酰基)乙基)哌啶盐酸盐
向4-[(1R)-1-氟-1-[1-甲基-3-(三氟甲基)-1H-吡唑-5-磺酰基]乙基]哌啶-1-羧酸叔丁酯(18.6a,1.3g,2.93mmol)在CH2Cl2(10mL)中的溶液中加入CH3OH(10mL)中的4NHCl。将所得溶液在室温搅拌1h,然后浓缩。将所得残余物溶于CH3OH(5mL)中并通过加入Et2O(8mL)沉淀,提供呈白色固体状的所需产物(1.03g,92%)。LC-MS(ES,m/z):344.0[M+H]+,385.0[M+H+CH3CN]+;1H NMR(400MHz,CD3OD):δ7.42(s,1H),4.16(s,3H),3.46(d,J=8.9Hz,2H),3.06(dt,J=14.0,10.5Hz,2H),2.62-2.79(m,1H),2.34(d,J=14.6Hz,1H),2.09(d,J=14.5Hz,1H),1.77(t,J=12.8Hz,2H),1.66(d,J=22.9Hz,3H)ppm。
化合物18.(R)-4-(1-氟-1-((1-甲基-3-(三氟甲基)-1H-吡唑-5-基)磺酰基)乙基)-N-(异噁唑-3-基)哌啶-1-甲酰胺
以与化合物9类似的方式制备化合物18,提供呈白色固体状的所需产物(0.09g,22%)。LC-MS(ES,m/z):454.1[M+H]+;1H NMR(400MHz,CD3CN):δ8.36(s,1H),8.01-8.16(m,1H),8.09(br.s.,1H),7.39(s,1H),6.85(s,1H),4.17(s,5H),2.82-3.00(m,2H),2.45-2.61(m,1H),2.05-2.17(m,1H),1.76-1.90(m,1H),1.59-1.72(m,3H),1.41-1.58(m,2H)ppm。
实施例19. 4-(1-((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)-N-(异噁
唑-3-基)哌啶-1-甲酰胺的制备
化合物19.1. 3-氯-1-甲基-1H-吡唑
在0℃向1-甲基-1H-吡唑-3-胺(5.0g,51.48mmol)在浓HCl(aq)(50mL)中的溶液中加入NaNO2(3.56g,51.59mmol)。将所得溶液在0℃搅拌30min,然后加入到CuCl(5.1g,51.48mmol)在浓HCl(aq)(50mL)中的溶液中。将反应混合物在80℃搅拌过夜,然后通过加入H2O(100mL)淬灭。用EtOAc(50mL)萃取所得溶液,用盐水(3x50mL)洗涤,经无水MgSO4干燥,过滤并浓缩。通过快速色谱(CH2Cl2/石油醚=1:1(v/v))纯化所得残余物,提供呈固体状的所需产物(1.9g,32%)。1H NMR(400MHz,CD3OD):δ7.57(d,J=2.3Hz,1H),6.22(d,J=2.3Hz,1H),3.85(s,3H)ppm。
化合物19.2. 3-氯-1-甲基-1H-吡唑-4-磺酰氯
将3-氯-1-甲基-1H-吡唑(19.1,3.0g,25.74mmol)加入到氯磺酸(20mL)中,并将反应混合物在100℃搅拌过夜。然后通过加入水/冰(200mL)淬灭反应混合物,用EtOAc(3x200mL)萃取,用盐水(3x200mL)洗涤,经MgSO4干燥,过滤并浓缩。通过快速色谱(10%(v/v)CH3OH/CH2Cl2)纯化所得残余物,提供呈白色固体状的所需产物(4.2g,76%)。1H NMR(400MHz,CDCl3):δ12.48(d,J=6.1Hz,1H),7.90(d,J=3.0Hz,3H)ppm。
化合物19.3. 4-(((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)甲基)吡啶
在50℃向NaHCO3(5.86g,69.75mmol)和Na2SO3(5.86g,69.75mmol)在H2O(7.5mL)中的溶液中加入3-氯-1-甲基-1H-吡唑-4-磺酰氯(19.2,5.0g,23.25mmol)在二噁烷(2.5mL)中的溶液。将反应混合物在50℃搅拌1.5h,然后浓缩。然后将所得残余物加入到4-(溴甲基)吡啶氢溴酸盐(4.94g,19.53mmol)在DMF(100mL)中的溶液中。将所得溶液在室温搅拌15min,然后加热至50℃且保持2h。然后通过加入H2O(200mL)淬灭反应混合物,用EtOAc(3x100mL)萃取,用盐水(100mL)洗涤,经NaSO4干燥,过滤并浓缩,提供呈白色固体状的所需产物(3.7g,粗物质),其不经纯化直接用于下一反应。LC-MS(ES,m/z):271.9[M+H]+,312.9[M+CH3CN]+;1H NMR(400MHz,DMSO-d6):δ8.56(m,2H),8.31(s,1H),7.24(m,2H),4.72(s,2H),3.84(s,3H)ppm。
化合物19.4. 4-(((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)氟甲基)吡啶
在-78℃向4-[(3-氯-1-甲基-1H-吡唑-4-磺酰基)甲基]吡啶(19.3,200mg,0.74mmol)在THF(5mL)中的溶液中加入t-BuOK(0.44mL,0.44mmol,1M于THF中)和NFSI(127mg,0.41mmol)。将反应混合物在-78℃搅拌2h,然后通过加入H2O(20mL)淬灭。用EtOAc(3x20mL)萃取所得溶液,用盐水(3x20mL)洗涤,经无水MgSO4干燥,过滤并浓缩,提供呈白色固体状的所需产物(0.100g,47%)。LC-MS(ES,m/z):290.0[M+H]+,331.2[M+CH3CN]+。
化合物19.5. 4-(1-((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)吡啶
在-78℃向4-[(3-氯-1-甲基-1H-吡唑-4-磺酰基)(氟甲基)吡啶(19.4,0.100g,0.35mmol)在THF(5mL)中的溶液中加入t-BuOK(0.42mL,0.42mmol,1M于THF中)和碘甲烷(0.58g,0.41mmol)。将反应混合物在-78℃搅拌2h,然后通过加入H2O(20mL)淬灭。用EtOAc(3x20mL)萃取所得溶液,用盐水(3x20mL)洗涤,经无水MgSO4干燥,过滤并浓缩。通过硅胶柱色谱(EtOAc/石油醚=4:1(v/v))纯化所得残余物,提供呈白色固体状的所需产物(0.80g,76%)。LC-MS(ES,m/z):303.9[M+H]+;1H NMR(400MHz,CD3OD):δ8.70–8.59(m,2H),8.15(s,1H),7.59–7.48(m,2H),3.89(s,3H),2.14(d,J=22.8Hz,3H)ppm。
化合物19.6. 4-(1-((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶
向含有4-(1-((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)吡啶(0.150g,0.49mmol)在二噁烷(3mL)中的4N HCl中的溶液的压力釜式反应器中加入PtO2(0.75g,0.245mmol)。吹扫系统,然后用H2(g)(5atm)气氛保持,并在35℃搅拌2h。然后将反应混合物冷却至室温,抽真空并用N2(g)吹扫。通过过滤除去固体并浓缩反应混合物,提供呈黄色固体状的所需产物(0.120g,粗物质)。该物质直接用于下一反应。LC-MS(ES,m/z):310.0[M+H]+,351.1[M+CH3CN]+。
化合物19. 4-(1-((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)-N-(异噁唑-3-基)哌啶-1-甲酰胺
以与化合物9类似的方式制备化合物19,提供呈白色固体状的所需产物(0.011g,7%)。LC-MS(ES,m/z):420.2[M+H]+,465.3[M+Na+CH3CN]+;1H NMR(400MHz,CD3OD):δ8.45(d,J=1.8Hz,1H),8.30(s,1H),6.76(d,J=1.8Hz,1H),4.30(t,J=16.4Hz,2H),3.95(s,3H),2.93(m,2H),2.52(m,1H),2.25(d,J=13.4Hz,1H),1.88(d,J=13.0Hz,1H),1.66(d,J=23.0Hz,3H),1.52(m,2H)ppm。
实施例20.(R)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙
基)-N-(异噁唑-3-基)哌啶-1-甲酰胺的制备
化合物20.1. 4-溴-1-甲基-1H-吡唑-3-甲醛
向1-甲基-1H-吡唑-3-甲醛(150g,1.36mol)在DMF(1000mL)中的溶液中加入NBS(240g,1.35mol)。将所得溶液在50℃搅拌2h,然后通过加入冰水(2000mL)淬灭。将反应混合物用冰/盐浴冷却至-10℃,并通过过滤收集固体,提供呈白色固体状的所需产物(200g,78%)。1H NMR(300MHz,CDCl3):δ9.90(d,J=0.7Hz,1H),7.46(s,1H),3.96(s,3H)ppm。
化合物20.2. 4-(((3-甲酰基-1-甲基-1H-吡唑-4-基)硫基)甲基)哌啶-1-羧酸叔丁酯
向4-溴-1-甲基-1H-吡唑-3-甲醛(20.1,20g,105.81mmol)在1,4-二噁烷(300mL)中的溶液中加入Pd2(dba)3.CHCl3(5.4g,5.22mmol)、K2CO3(36g,260.47mmol)、Xantphos(6.1g,10.54mmol)、KI(1.7g,10.58mmol)和4-[(乙酰基硫基)甲基]哌啶-1-羧酸叔丁酯(34g,124.36mmol)。将反应混合物加热至80℃,并滴加MeOH(40g,1.25mol)。将反应混合物在85℃搅拌12h。将反应混合物用冰水浴冷却至室温,并通过过滤除去固体。浓缩滤液,并通过快速柱色谱(EtOAc/石油醚=1/2(v/v))纯化所得残余物,提供呈黄色固体状的所需产物(24g,60%)。1H NMR(400MHz,CDCl3):δ10.02(d,J=0.8Hz,1H),7.35(s,1H),4.11(m,2H),4.00(s,3H),2.77(d,J=6.9Hz,2H),2.68(t,J=12.9Hz,2H),1.89–1.79(m,2H),1.70–1.58(m,1H),1.47(s,9H),1.32–1.11(m,2H)ppm。
化合物20.3. 4-(((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)硫基)甲基)哌啶-1-羧酸叔丁酯
在0℃向4-(((3-甲酰基-1-甲基-1H-吡唑-4-基)硫基)甲基)哌啶-1-羧酸叔丁酯(20.2,50g,147.30mmol)在二氯甲烷(500mL)中的溶液中滴加DAST(95g,589.37mmol)。将反应混合物在30℃搅拌过夜。将温度降至0℃,并用饱和NaHCO3(aq)淬灭反应混合物。用EtOAc(3x1000mL)萃取所得溶液。用盐水(500mL)洗涤合并的有机层,经无水Na2SO4干燥,过滤并浓缩。通过快速色谱(EtOAc/石油醚=1/5(v/v))纯化所得残余物,提供呈黄色固体状的所需产物(35g,66%)。1H NMR(300MHz,CD3OD):δ7.73(s,1H),6.74(t,J=53.9Hz,1H),4.07–3.95(m,2H),3.87(d,J=1.1Hz,3H),2.66(d,J=12.6Hz,2H),2.58(d,J=6.9Hz,2H),1.81(d,J=13.0Hz,2H),1.54(m,1H),1.41(s,9H),1.07(m,2H)ppm。
化合物20.4. 4-(((5-氯-3-(二氟甲基)-1-甲基-1H-吡唑-4-基)硫基)甲基)哌啶-1-羧酸叔丁酯
在-78℃向4-(((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)硫基)甲基)哌啶-1-羧酸叔丁酯(20.3,30g,83.00mmol)在THF(400mL)中的溶液中滴加n-BuLi溶液(50mL,124.5mmol,2.5M于正己烷中)。将反应混合物搅拌20分钟,然后滴加全氯乙烷(23.6g,99.72mmol)在THF(30mL)中的溶液。将反应混合物在-78℃搅拌30min,然后通过加入饱和NH4Cl(aq)(100mL)淬灭。用EtOAc(3x500mL)萃取所得溶液,用盐水(300mL)洗涤,经无水Na2SO4干燥,过滤,然后浓缩,提供呈白色固体状的所需产物(30g,粗物质),其不经进一步纯化即用于下一反应。1H NMR(400MHz,CDCl3):δ6.68(t,J=53.8Hz,1H),4.16–4.04(m,2H),3.90(t,J=0.9Hz,3H),2.71–2.56(m,4H),1.91–1.75(m,2H),1.45(m,10H),1.19–1.04(m,2H)ppm。
化合物20.5. 4-(((5-氯-3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
以与化合物14.2类似的方式制备化合物20.5,提供呈白色固体状的所需产物(28g,86%)。1H NMR(400MHz,CDCl3):δ7.03(t,J=53.8Hz,1H),4.12–4.03(m,2H),3.96(s,3H),3.10(d,J=6.3Hz,2H),2.74(m,2H),1.90(m,2H),1.44(s,9H),1.36–1.18(m,3H)ppm。
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化合物20.6. 4-(((5-氯-3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)氟甲基)哌啶-1-羧酸叔丁酯
在-78℃向4-(((5-氯-3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(20.5,25g,58.43mmol)在THF(300mL)中的溶液中滴加LDA(43mL,87.64mmol,2.0M于THF中),随后滴加NFSI(22g,58.43mmol)在THF(100mL)中的溶液。将反应混合物在-78℃搅拌30min,然后通过加入饱和NH4Cl(aq)(500mL)淬灭。用EtOAc(3x500mL)萃取反应混合物,用盐水(500mL)洗涤,经无水Na2SO4干燥,过滤,并浓缩。通过快速色谱(EtOAc/石油醚=1/4(v/v))纯化所得残余物,提供呈白色固体状的所需产物(18g,69%)。1H NMR(300MHz,CD3OD):δ6.96(t,J=53.2Hz,1H),5.27(d,J=6.4Hz,1H),5.11(d,J=6.4Hz,1H),4.16–4.02(m,2H),3.94(s,3H),2.80(s,2H),2.42(m,1H),1.92(m,2H),1.43(s,9H),0.95–0.74(m,2H)ppm。
化合物20.7. 4-(1-((5-氯-3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶-1-羧酸叔丁酯
在-78℃向4-(((5-氯-3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)氟甲基)哌啶-1-羧酸叔丁酯(20.6,15.6g,34.99mmol)在THF(250mL)中的溶液中滴加t-BuOK溶液(70mL,69.98mmol,1.0M于THF中)。将反应混合物搅拌5分钟,然后滴加碘甲烷(7.4g,52.14mmol)。将反应混合物在-78℃搅拌15min,然后通过加入饱和NH4Cl(aq)(500mL)淬灭。用EtOAc(3x500mL)萃取所得溶液,用盐水(300mL)洗涤,经无水Na2SO4干燥,过滤,然后浓缩,提供呈白色固体状的所需产物(15g,粗物质),其不经纯化直接用于下一步骤。
化合物20.8. 4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶-1-羧酸叔丁酯
在-78℃向4-(1-((5-氯-3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶-1-羧酸叔丁酯(20.7,25g,54.36mmol)在THF(400mL)中的溶液中滴加n-BuLi(28mL,70.66mmol,2.5M于己烷中)。将反应混合物在-78℃搅拌30min,然后通过加入冰水(200mL)淬灭。用EtOAc(3x500mL)萃取所得混合物,用盐水(300mL)洗涤,经无水Na2SO4干燥,过滤,然后浓缩。通过Flash-Prep-HPLC(柱,C18硅胶;流动相,在60min内ACN:H2O=20:80(v/v)升至ACN:H2O=95:5(v/v);检测器,UV 254nm)纯化所得残余物,提供呈白色固体状的所需产物(15g,65%)。1H NMR(300MHz,CDCl3):δ7.85(s,1H),6.95(t,J=53.3Hz,1H),4.18(m,2H),4.01(s,3H),2.79–2.59(m,2H),2.43(m,1H),2.16–2.05(m,1H),1.77(m,1H),1.53(d,J=22.2Hz,3H),1.43(s,9H),1.32(m,2H)ppm。
化合物20.8a.(R)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶-1-羧酸叔丁酯和化合物20.8b.(S)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶-1-羧酸叔丁酯
使用Prep-SFC(柱:Phenomenex Lux Cellulose-4(5*25cm,5μm);流动相A:CO2:70,流动相B:EtOH:30;流速:150mL/min;220nm)分离4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶-1-羧酸叔丁酯(20.8,63.6g)的对映异构体,提供RT1=1.448min(20.8a,24.0g,91%,[α]=-26.9(C=0.37g/100mL,T=23.6℃,MeOH))的白色固体和RT2=1.744min(20.8b,24.0g,91%,[α]=+23.4(C=0.33g/100mL,T=24.6℃,MeOH))的白色固体。
化合物20.9.(R)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶盐酸盐
以与化合物18.7类似的方式制备化合物20.9,提供呈白色固体状的所需产物(15.0g,85%)。LC-MS(ES,m/z):326.0[M+H]+;1H NMR(300MHz,CD3OD):δ8.29(s,1H),6.92(t,J=53.1Hz,1H),4.01(s,3H),3.19–3.07(m,2H),2.62–2.52(m,1H),2.41–2.38(m,1H),2.10–2.03(m,1H),1.76–1.73(m,1H),1.56–1.38(m,5H)ppm。
化合物20.10.异噁唑-3-基氨基甲酸苯酯
在-20℃经15min向3-氨基-异噁唑(25g,0.297mmol)和吡啶(29.0mL,0.356mmol)在乙腈(600mL)中的溶液中滴加氯甲酸苯酯(39.1mL,0.312mmol)。将反应混合物逐渐升温至rt并在rt下搅拌过夜。随后,浓缩反应混合物并将残余物加入到冰水(500mL)中。过滤悬浮液,用水洗涤固体并真空干燥,得到呈白色固体状的所需产物(58.76g,97%收率)。
化合物20.(R)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)-N-(异噁唑-3-基)哌啶-1-甲酰胺
在65℃经5分钟向(R)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶(20.9,20.0g,61.46mmol)在乙腈(246mL,0.5M)中的溶液中分批加入N-(异噁唑-3-基)氨基甲酸苯酯(13.18g,64.54mmol)。在65℃搅拌过夜后,浓缩反应混合物,并通过硅胶柱色谱(ISCO CombiFlash,330g柱,CAT#69-2203-330)使用MeOH/DCM=0%至2%(v/v)作为洗脱剂纯化残余物,得到呈白色固体状的所需产物(25.6g,96%收率)。LC-MS-(ES,m/z):436.0[M+H]+;1H NMR(400MHz,CDCl3):δ8.23(s,1H),8.11(s,1H),7.89(s,1H),6.98(t,J=53.1Hz,1H),6.98(s,1H),4.32–4.25(m,2H),4.04(s,3H),2.99–2.90(m,2H),2.62–2.54(m,1H),2.27–2.24(m,1H),1.94–1.91(m,1H),1.53–1.47(m,5H)ppm;19F NMR(376MHz,CDCl3):δ-114.3至-117.1(m,2F),-144.8(s,1F)ppm。
实施例21.(S)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙
基)-N-(异噁唑-3-基)哌啶-1-甲酰胺的制备
化合物21.1.(S)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶盐酸盐
以与化合物18.7类似的方式制备化合物21.1,提供呈白色固体状的所需产物(15.0g,85%)。LC-MS(ES,m/z):326.0[M+H]+;1H NMR(300MHz,CD3OD):δ8.29(s,1H),6.92(t,J=53.1Hz,1H),4.01(s,3H),3.19–3.07(m,2H),2.62–2.52(m,1H),2.41–2.38(m,1H),2.10–2.03(m,1H),1.76–1.73(m,1H),1.56–1.38(m,5H)ppm。
化合物21.(S)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)-N-(异噁唑-3-基)哌啶-1-甲酰胺
向(S)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶(21.1,0.20g,0.553mmol)在乙腈(2mL)中的溶液中加入N-(异噁唑-3-基)氨基甲酸苯酯(0.118g,0.580mmol),随后加入三甲胺(0.167g,1.65mmol)。在65℃搅拌过夜后,浓缩反应混合物,并通过反相高效液相色谱(0-90%CH3CN/H2O(二者均含有0.1%TFA))纯化残余物,提供呈白色固体状的所需产物(0.162g,67%)。LC-MS(ES,m/z):436.0[M+H]+;1H NMR(400MHz,CDCl3):δ8.60(s,1H),8.22(s,1H),7.89(s,1H),6.99(t,J=52.0Hz,1H),6.99(s,1H),4.37–4.25(m,2H),4.04(s,3H),2.99–2.90(m,2H),2.62–2.54(m,1H),2.27–2.24(m,1H),1.94–1.91(m,1H),1.53–1.47(m,5H)ppm;19F NMR(376MHz,CDCl3):δ-114.3至-117.1(m,2F),-144.8(s,1F)ppm。
实施例22. 4-(二氟(咪唑并[1,2-a]吡啶-8-基磺酰基)甲基)-N-(哒嗪-4-基)哌
啶-1-甲酰胺的制备
化合物22.1 4-(((2-氯吡啶-3-基)硫基)甲基)哌啶-1-羧酸叔丁酯
以与化合物4.2类似的方式制备化合物22.1,提供呈黄色固体状的所需产物(1.99g,55%)。1H NMR(300MHz,DMSO-d6):δ8.16-8.18(dd,J=4.4,1.6Hz,1H),7.827.85(dd,J=8.0,1.6Hz,1H),7.39-7.42(dd,J=8.0,4.8Hz,1H),3.92-3.95(d,J=12.0Hz,2H),2.99-3.00(d,J=6.8Hz,2H),2.70(m,2H),1.79-1.82(d,J=12.8Hz,2H),1.68-1.75(m,1H),1.39(s,9H),1.10-1.14(m,2H)ppm。
化合物22.2 4-(((2-氯吡啶-3-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
以与化合物4.3类似的方式制备化合物22.2,提供呈黄色固体状的所需产物(0.72g,53%)。1H NMR(400MHz,DMSO-d6):δ8.74-8.76(dd,J=4.8,1.6Hz,1H),8.44-8.46(dd,J=8.0,2.0Hz,1H),7.73-7.76(dd,J=7.6,4.8Hz,1H),3.84-3.87(d,J=8.4Hz,2H),3.56-3.57(d,J=6.4Hz,2H),2.65(m,2H),2.07(m,1H),1.72-1.75(d,J=12.0Hz,2H),1.38(s,9H),1.17-1.26(m,2H)ppm。
化合物22.3. 4-(((2-氯吡啶-3-基)磺酰基)二氟甲基)哌啶-1-羧酸叔丁酯
以与化合物4.4类似的方式制备化合物22.3,提供呈黄色固体状的所需产物(0.36g,66%)。1H NMR(400MHz,CDCl3):δ8.70-8.71(dd,J=4.8,2.0Hz,1H),8.41-8.43(dd,J=8.0,2.0Hz,1H),7.51-7.54(dd,J=7.6,4.8,4.8Hz,1H),4.27(s,2H),2.74-2.77(m,3H),2.06-2.09(d,J=13.6Hz,2H),1.60-1.64(m,2H),1.47(s,9H)ppm。
化合物22.4. 4-(((2-氨基吡啶-3-基)磺酰基)二氟甲基)哌啶-1-羧酸叔丁酯
向4-(((2-氯吡啶-3-基)磺酰基)二氟甲基)哌啶-1-羧酸叔丁酯(22.3,0.360g,0.88mmol)在EtOH(2mL)中的溶液中加入EtOH(10mL)中的饱和NH3。将所得溶液在室温搅拌2h,然后浓缩。通过快速色谱(EtOAc/石油醚=1/1(v/v))纯化所得残余物,提供呈浅黄色固体状的所需产物(0.100g,29%)。1H NMR(400MHz,CDCl3):δ8.31-8.33(d,J=3.6Hz,1H),7.94-7.96(d,J=7.8Hz,1H),6.76-6.80(dd,J=7.5,4.8Hz,1H),6.15(s,2H),4.22-4.25(d,J=8.7Hz,2H),2.62-2.78(m,3H),2.04-2.08(d,J=12.9Hz,2H),1.61-1.66(m,2H),1.46(s,9H)ppm。
化合物22.5. 4-(二氟(咪唑并[1,2-a]吡啶-8-基磺酰基)甲基)-哌啶-1-羧酸叔丁酯
向4-(((2-氨基吡啶-3-基)磺酰基)二氟甲基)-哌啶-1-羧酸叔丁酯(22.4,0.100g,0.26mmol)在EtOH(1.2mL)和H2O(1.4mL)中的溶液中加入NaOAc(0.526g,2.52当量)、2-氯-1,1-二甲氧基乙烷(0.59g,0.47mmol)和6NHCl(0.1mL)。将所得溶液在75℃搅拌过夜。在真空下除去EtOH,并用EtOAc(3x5mL)萃取所得溶液。用盐水(2x5mL)洗涤合并的有机层,经无水Na2SO4干燥,过滤并浓缩。通过快速柱色谱(EtOAc/石油醚=1/1(v/v))纯化所得残余物,提供呈浅黄色固体状的所需产物(0.75g,71%)。LC-MS(ES,m/z):316[M+H]+。
化合物22.6. 8-((二氟(哌啶-4-基)甲基)磺酰基)咪唑并[1,2-a]吡啶盐酸盐
以与化合物9.5类似的方式制备化合物22.6,提供呈黄色固体状的所需产物(0.51g,粗物质)。LC-MS(ES,m/z):316[M+H]+。
化合物22. 4-(二氟(咪唑并[1,2-a]吡啶-8-基磺酰基)甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
以与化合物9类似的方式制备化合物22,提供呈黄色固体状的所需产物(0.33g,47%)。LC-MS(ES,m/z):437[M+H]+;1H NMR(300MHz,DMSO-d6):δ9.25-9.26(m,1H),9.23(s,1H),9.04-9.06(dd,J=6.9,1.2Hz,1H),8.84-8.86(dd,J=6.0,0.6Hz,1H),8.22-8.23(d,J=1.5Hz,1H),8.03-8.05(dd,J=7.2,0.9Hz,1H),7.77-7.78(d,J=1.5Hz,1H),7.73-7.76(dd,J=6.0,2.8Hz,1H),7.18-7.20(t,J=7.0Hz,1H),4.22-4.27(d,J=14.1Hz,2H),2.89-2.97(t,J=12.8Hz,3H),2.08-2.10(d,J=5.4Hz,2H),1.48-1.54(m,2H)ppm。
实施例23. 4-(((1,3-二甲基-1H-吡唑-5-基)磺酰基)二氟甲基)-N-(哒嗪-4-基)
哌啶-1-甲酰胺的制备
化合物23.1. 2,5-二甲基-2,4-二氢-3H-吡唑-3-酮
在0℃向甲基肼硫酸盐(5.47g,37.95mmol)在甲苯(100mL)中的溶液中滴加三乙胺(30.7g,303.39mmol)。将所得溶液在0℃搅拌30min,然后滴加3-氧代丁酸乙酯(5g,38.42mmol),随后分批加入硫酸镁(9.12g,2.00当量)。使所得溶液在室温在搅拌下再反应2天。通过过滤除去固体并浓缩滤液。通过快速柱色谱(6%(v/v)CH3OH/CH2Cl2)纯化所得残余物,提供呈黄色固体状的所需产物(8g,粗物质)。1H NMR(300MHz,CDCl3):δ3.28(s,3H),3.19(s,2H),2.10(s,3H)ppm。
化合物23.2.三氟甲磺酸1,3-二甲基-4,5-二氢-1H-吡唑-5-基酯
在0℃向2,5-二甲基-2,4-二氢-3H-吡唑-3-酮(23.1,2g,17.84mmol)在二氯甲烷(20mL)中的溶液中滴加2,6-二甲基吡啶(2.86g,26.76mmol),随后滴加三氟甲磺酸酐(6.54g,23.18mmol)。将所得溶液在室温搅拌2h,然后通过加入H2O(20mL)淬灭。用二氯甲烷(2x25mL)萃取所得溶液,合并的有机层经无水MgSO4干燥,过滤并浓缩。通过快速色谱(9%(v/v)EtOAc/石油醚)纯化所得残余物,提供呈黄色油状的所需产物(0.750g,17%)。1H NMR(300MHz,CDCl3):δ5.93(s,1H),3.75(s,3H),2.24(s,3H)ppm。
化合物23.3. 4-(((1,3-二甲基-1H-吡唑-5-基)硫基)甲基)哌啶-1-羧酸叔丁酯
向三氟甲磺酸1,3-二甲基-4,5-二氢-1H-吡唑-5-基酯(23.2,1.9g,7.78mmol)在1,4-二噁烷(50mL)中的溶液中加入4-(巯基甲基)哌啶-1-羧酸叔丁酯(1.3,1.8g,7.78mmol)、碳酸钾(2.69g,19.46mmol)、Xantphos(0.450g,0.78mmol)和Pd2(dba)3(0.403g,0.44mmol)。将所得溶液在100℃搅拌4h。将反应混合物冷却至室温,通过过滤除去固体,并浓缩滤液。通过快速色谱(22%EtOAc/石油醚)纯化所得残余物,提供呈黄色油状的所需产物(1.95g,77%)。1H NMR(300MHz,CDCl3):δ6.08(s,1H),4.13-4.09(m,2H),3.84(s,3H),2.71-2.63(m,4H),2.25(s,3H),1.82(d,J=12.9Hz,2H),1.60-1.50(m,1H),1.45(s,9H),1.23-1.12(m,2H)ppm。
化合物23.4. 4-(((1,3-二甲基-1H-吡唑-5-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
以与化合物14.2类似的方式制备化合物23.4,提供呈黄色油状的所需产物(1.60g,7%)。LC-MS(ES,m/z):437[M+H]+;1H NMR(300MHz,DMSO-d6):δ6.61(s,1H),4.16-4.06(m,5H),3.07(d,J=6.3Hz,2H),2.79-2.70(m,2H),2.28(s,3H),2.19-2.10(m,1H),1.87(d,J=13.5Hz,2H),1.45(s,9H),1.31-1.24(m,2H)ppm。
化合物23.5. 4-(((1,3-二甲基-1H-吡唑-5-基)磺酰基)二氟甲基)-哌啶-1-羧酸叔丁酯
以与化合物4.4类似的方式制备化合物23.5,提供呈黄色固体状的所需产物(0.66g,粗物质),其不经纯化直接用于下一反应。1H NMR(400MHz,CDCl3):δ6.77(s,1H),422-4.27(d,J=13.2Hz,3H),4.06(s,3H),2.67-2.79(m,3H),2.31(s,3H),2.03-2.07(d,J=12.9Hz,2H),1.57-1.67(m,2H),1.46(s,9H),1.28(m,2H)ppm。
化合物23.6. 4-(((1,3-二甲基-1H-吡唑-5-基)磺酰基)二氟甲基)哌啶盐酸盐
以与化合物9.5类似的方式制备化合物23.6,提供呈黄色固体状的所需产物(0.51g,粗物质)。LC-MS(ES,m/z):294[M+H]+。
化合物23. 4-(((1,3-二甲基-1H-吡唑-5-基)磺酰基)二氟甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
以与化合物9类似的方式制备化合物23,提供呈黄色固体状的所需产物(0.33g,47%)。LC-MS(ES,m/z):415[M+H]+;1H NMR(300MHz,DMSO-d6):δ9.27-9.23(m,2H),8.88(m,1H),7.45(m,1H),7.03(s,1H)。4.24(d,J=13.2Hz,2H),4.00(s,3H),3.02-2.88(m,3H),2.25(s,3H),2.01(d,J=12.0Hz,2H),1.59-1.46(m,2H)ppm。
实施例24. 4-(((3-环丙基-1-甲基-1H-吡唑-5-基)磺酰基)二氟甲基)-N-(哒嗪-
4-基)哌啶-1-甲酰胺的制备
化合物24.1. 3-环丙基-1-甲基-1H-吡唑-5-醇
以与化合物23.1类似的方式制备化合物24.1,提供呈黄色固体状的所需产物(1.60g,45%)。LC-MS(ES,m/z):139[M+H]+;1H NMR(300MHz,DMSO-d6):δ10.61(s,1H),5.02(s,1H),3.58(s,3H),1.62-1.73(m,1H),0.72-0.81(m,2H),0.53-0.67(m,2H)ppm。
化合物24.2. 3-环丙基-1-甲基-1H-吡唑-5-硫醇
向3-环丙基-1-甲基-1H-吡唑-5-醇(1.6g,11.58mmol)在甲苯(30mL)中的溶液中加入Lawesson试剂(4.68g,11.58mmol)。将所得溶液在60℃搅拌过夜,冷却至室温,然后浓缩。通过快速色谱(氯仿/甲醇=20/1(v/v))纯化所得残余物,提供呈黄色油状的所需产物(1.1g,62%)。LC-MS(ES,m/z):155[M+H]+。
化合物24.3. 4-(((3-环丙基-1-甲基-1H-吡唑-5-基)硫基)甲基)-哌啶-1-羧酸叔丁酯
向3-环丙基-1-甲基-1H-吡唑-5-硫醇(24.2,1.1g,7.13mmol)在DMF(20mL)中的溶液中加入4-((甲苯磺酰基氧基)甲基)哌啶-1-羧酸叔丁酯(1.1,2.63g,7.12mmol)和Cs2CO3(4.6g,14.12mmol)。将反应混合物在室温搅拌3h,然后通过加入H2O(100mL)淬灭,并用EtOAc(3x30mL)萃取。合并的有机层经无水Na2SO4干燥,过滤并浓缩,提供呈黄色油状的所需产物(1.5g,60%)。LC-MS(ES,m/z):352[M+H]+。
化合物24.4. 4-(((3-环丙基-1-甲基-1H-吡唑-5-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
以与化合物14.2类似的方式制备化合物24.4,提供呈黄色油状的所需产物(1.60g,7%)。LC-MS(ES,m/z):406[M+Na]+;1H NMR(300MHz,DMSO-d6):δ6.66(s,1H),3.96(s,3H),3.83-3.87(d,J=18.6Hz,2H),3.40-3.42(d,J=6.3Hz,2H),2.74(s,1H),1.99-2.03(m,1H),1.87-1.93(m,1H),1.72-1.75(d,J=11.1Hz,2H),1.38(s,9H),1.15-1.25(m,2H),0.80-0.90(m,2H),0.65-0.70(m,2H)ppm。
化合物24.5. 4-(((3-环丙基-1-甲基-1H-吡唑-5-基)磺酰基)二氟甲基)哌啶-1-羧酸叔丁酯
以与化合物4.4类似的方式制备化合物24.5,提供呈黄色固体状的所需产物(0.70g,64%)。LC-MS(ES,m/z):406[M-CH3+H]+。
化合物24.6. 4-(((3-环丙基-1-甲基-1H-吡唑-5-基)磺酰基)二氟甲基)-哌啶盐酸盐
以与化合物9.5类似的方式制备化合物24.6,提供呈红色固体状的所需产物(0.40g,粗物质)。LC-MS(ES,m/z):320[M+H]+。
化合物24. 4-(((3-环丙基-1-甲基-1H-吡唑-5-基)磺酰基)二氟甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
以与化合物9类似的方式制备化合物24,提供呈黄色固体状的所需产物(0.33g,47%)。LC-MS(ES,m/z):441[M+H]+;1H NMR(300MHz,CDCl3):δ9.13-9.14(d,J=2.4Hz,1H),8.88-8.90(d,J=6.3Hz,1H),8.63(s,1H),8.02-8.05(m,1H),6.66(s,1H),4.39-4.43(d,J=13.5Hz,2H),4.03(s,3H),2.92-3.00(m,2H),2.71-2.79(m,1H),2.12-2.16(d,J=2.4Hz,2H),1.88-1.96(m,1H),1.66-1.76(m,2H),0.99(m,2H),0.98(m,2H)ppm。
实施例25. 4-(二氟((2-(羟基甲基)苯基)磺酰基)甲基)-N-(哒嗪-4-基)哌啶-1-
甲酰胺的制备
化合物25.1. 4-(二氟((2-甲酰基苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯
在-78℃向4-[[(2-溴苯)磺酰基]二氟甲基]哌啶-1-羧酸叔丁酯(600mg,1.32mmol)在THF(15mL)中的溶液中滴加n-BuLi(0.52mL,2.5M于正己烷中,2.64mmol)。将反应混合物在-78℃搅拌30分钟,然后加入DMF(0.300g,4.10mmol)。将所得溶液在搅拌下再反应5min同时温度保持在-78℃。然后通过加入NH4Cl(sat.)(2mL)淬灭反应混合物。用EtOAc(3x100mL)萃取所得溶液,合并有机层,经无水硫酸钠干燥,并在真空下浓缩,提供呈黄色油状的所需产物(0.600g,粗物质),其不经进一步纯化即使用。LC-MS(ES,m/z):425.9[M+H]+。
化合物25.2. 2-((二氟(1-(2,2,2-三氟乙酰基)-1l4-哌啶-4-基)甲基)磺酰基)苯甲醛
以与化合物4.5类似的方式制备化合物25.2,提供呈黄色固体状的所需产物(0.40g,粗物质),其不经进一步纯化直接使用。LC-MS(ES,m/z):304[M+H]+。
化合物25.3. 4-(二氟((2-甲酰基苯基)磺酰基)甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
以与化合物4类似的方式制备化合物25.2,提供呈黄色固体状的所需产物(0.150g,27%)。LC-MS(ES,m/z):425[M+H]+;1H NMR(300MHz,DMSO-d6):δ10.57(s,1H),9.33–9.15(m,2H),8.87(m,1H),8.17–7.88(m,4H),7.81–7.69(m,1H),4.24(d,J=13.2Hz,2H),3.01(m,3H),2.00(d,J=19.3Hz,2H),1.54(m,2H)ppm。
化合物25. 4-(二氟((2-(羟基甲基)苯基)磺酰基)甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
在0℃向4-(二氟((2-甲酰基苯基)磺酰基)甲基)-N-(哒嗪-4-基)哌啶-1-甲酰胺(25.3,0.150g,0.35mmol)在甲醇(10.0g,312.09mmol)中的溶液中加入NaBH4(0.017g,0.45mmol)。将所得溶液在室温搅拌1h。然后通过加入NH4Cl(sat.)(20mL)淬灭反应混合物。用EtOAc(3x50mL)萃取所得溶液并合并有机层,经无水硫酸钠干燥并浓缩。通过Prep-HPLC(柱:X Bridge C18,19*250mm,10um;流动相A:水/10mM NH4HCO3,流动相B:ACN;流速:30mL/min;梯度:6min内15-60%B;254nm)纯化所得残余物,提供呈白色固体状的所需产物(0.0356g,24%)。LC-MS(ES,m/z):427[M+H]+;1H NMR(300MHz,CD3OD):δ9.22-9.26(m,2H),8.87-8.89(m,1H),7.89-7.99(m,3H),7.73-7.75(m,1H),6.60-6.64(m,1H),5.56-5.58(t,J=5.6Hz,1H),4.90-4.92(d,J=5.6Hz,2H),4.22-4.25(m,2H),2.88-2.97(m,3H),2.00-2.07(m,2H),1.46-1.57(m,2H)ppm。
实施例26.N-(异噁唑-3-基)-4-(2-((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰
基)丙-2-基)哌啶-1-甲酰胺
化合物26.1. 4-(2-((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰基)丙-2-基)哌啶-1-羧酸叔丁酯
在-78℃向4-(((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(16.3,1.0g,2.43mmol)在THF(20mL)中的溶液中滴加t-BuOK溶液(1N于THF中,7.2mL,7.29mmol)。将所得溶液在-78℃搅拌20min,然后滴加MeI(858mg,6.07mmol)在THF(2mL)中的溶液。使所得溶液在液氮浴中在搅拌下再反应1h同时温度保持在-60℃。然后通过加入NH4Cl(sat.)(50mL)淬灭反应混合物。用EtOAc(3x100mL)萃取所得溶液,用盐水(2x100mL)洗涤,经无水硫酸钠干燥,过滤并浓缩。通过Flash-Prep-HPLC((IntelFlash-1):柱,C18硅胶;流动相,在35min内CH3CN:H2O=20:80(v/v)升至CH3CN:H2O=95:5(v/v);检测器,UV 254nm)纯化所得残余物,提供呈白色固体状的所需产物(0.150g,14%)。LC-MS(ES,m/z):462.1[M+H]+。
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化合物26.2. 4-(2-((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰基)丙-2-基)哌啶
以与化合物4.5类似的方式制备化合物26.2,提供呈黄色固体状的所需产物(0.25g,粗物质),其不经进一步纯化直接使用。LC-MS(ES,m/z):340.0[M+H]+。
化合物26.N-(异噁唑-3-基)-4-(2-((1-甲基-3-(三氟甲基)-1H-吡唑-4-基)磺酰基)丙-2-基)哌啶-1-甲酰胺
以与化合物9类似的方式制备化合物26,提供呈黄色固体状的所需产物(0.024g,13%)。LC-MS(ES,m/z):448.0[M+H]+;1H NMR(300MHz,CD3OD):δ8.40(s,1H),8.33(s,1H),6.70(s,1H),4.21(d,J=13.8Hz,2H),3.99(s,3H),2.90-2.81(m,2H),2.22-2.03(m,3H),1.49-1.44(m,2H),1.27(s,6H)ppm。
实施例27. 4-(2-((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)丙-2-基)-N-(异噁唑-
3-基)哌啶-1-甲酰胺的制备
化合物27.1. 4-(2-((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)丙-2-基)吡啶
在0℃向4-[(3-氯-1-甲基-1H-吡唑-4-磺酰基)甲基]吡啶(680mg,2.50mmol)在DMF(10mL)中的溶液中加入氢化钠(200mg,8.33mmol),随后加入MeI(713mg,5.00mmol)。将所得溶液在0℃在冰/盐浴中搅拌2h。然后通过加入水(20mL)淬灭反应混合物。用EtOAc(3x20mL)萃取所得溶液,用盐水(3x20mL)洗涤,经无水硫酸镁干燥,过滤并浓缩。通过快速色谱(二氯甲烷/甲醇(20:1))纯化所得残余物,提供呈黄色固体状的所需产物(0.650g,87%)。LC-MS(ES,m/z):299.9[M+H]+;1H NMR(300MHz,DMSO-d6):δ8.60–8.53(m,2H),8.25(s,1H),7.47-7.40(m,2H),3.84(s,3H),1.73(s,6H)ppm。
化合物27.2. 4-(2-((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)丙-2-基)哌啶
向4-(2-((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)丙-2-基)吡啶(27.1,0.200g,0.67mmol)在1,4-二噁烷(3mL)中的4N HCl中的溶液中加入PtO2(0.80g,0.27mmol)。然后将H2(g)引入混合物中,并保持5atm的压力同时将反应混合物在35℃搅拌48h。将反应混合物冷却至室温并过滤。浓缩滤液,并通过Prep-HPLC(柱:XBridge Prep C18 OBD柱,5um,19*150m;流动相A:H2O(10mmol/L NH4HCO3),流动相B:ACN;流速:20mL/min;梯度:8min内20%B至40%B;检测器,UV 254nm)纯化所得残余物,提供呈白色固体状的所需产物(0.20g,10%)。LC-MS(ES,m/z):306.0[M+H]+。
化合物27. 4-(2-((3-氯-1-甲基-1H-吡唑-4-基)磺酰基)丙-2-基)-N-(异噁唑-3-基)哌啶-1-甲酰胺
以与化合物9类似的方式制备化合物27,提供呈黄色固体状的所需产物(0.038g,16%)。LC-MS(ES,m/z):416.1[M+H]+;1H NMR(400MHz,CD3OD):δ8.45(d,J=1.8Hz,1H),8.23(s,1H),6.76(d,J=1.8Hz,1H),4.26(m,2H),3.94(s,3H),2.97–2.85(m,2H),2.15(m,3H),1.55–1.39(m,2H),1.33(s,6H)ppm。
实施例28. 4-(3,3-二氟-1-((3-氟苯基)磺酰基)环丁基)-N-(哒嗪-4-基)哌啶-
1-甲酰胺的制备
化合物28.1. 4-(1-((3-氟苯基)磺酰基)-3-羟基环丁基)哌啶-1-羧酸叔丁酯
在10℃向4-(((3-氟苯基)磺酰基)甲基)哌啶-1-羧酸叔丁酯(5.3,2.0g,5.60mmol)在THF(100mL)中的溶液中滴加n-BuLi(2.5M,6.7mL,16.8mmol)。将所得溶液在-10℃搅拌30min,然后滴加2-(氯甲基)氧杂环丙烷(1.04g,11.24mmol)。将反应混合物搅拌过夜同时温热至室温,然后通过加入水(30mL)淬灭。用EtOAc(2x50mL)萃取所得溶液,经无水硫酸钠干燥,过滤并浓缩。通过Prep-HPLC((IntelFlash-1):柱,C18硅胶;流动相A:具有10mmol NH4HCO3的水,流动相B:ACN;流速:50mL/min;梯度:40min内0%B至100%B;检测器,UV 254nm)纯化所得残余物,提供呈黄色固体状的所需产物(1.1g,47%)。LC-MS(ES,m/z):414.1[M+H]+。
化合物28.2. 4-(1-((3-氟苯基)磺酰基)-3-氧代环丁基)哌啶-1-羧酸叔丁酯
向4-(1-((3-氟苯基)磺酰基)-3-羟基环丁基)哌啶-1-羧酸叔丁酯(28.1,1.1g,2.66mmol)在EtOAc(40mL)中的溶液中加入IBX(1.49g,5.32mmol)。将所得溶液在75℃搅拌过夜。将反应混合物冷却至室温,并通过过滤除去固体。用盐水(2x30mL)洗涤滤液,经无水硫酸钠干燥,过滤并浓缩,提供呈黄色油状的所需产物(1.0g,粗物质),其不经进一步纯化直接使用。LC-MS(ES,m/z):397.0[M-CH3+H]+。
化合物28.3. 4-(3,3-二氟-1-((3-氟苯基)磺酰基)环丁基)-哌啶-1-羧酸叔丁酯
向4-(1-((3-氟苯基)磺酰基)-3-氧代环丁基)哌啶-1-羧酸叔丁酯(0.300g,0.73mmol)在二氯甲烷(10mL)中的溶液中加入DAST(1.17g,7.26mmol)。将所得溶液在室温搅拌3天。然后通过加入水(10mL)淬灭反应混合物,并通过加入碳酸氢钠将溶液的pH调节至7。用DCM(2x20mL)萃取所得溶液,经无水硫酸镁干燥,过滤并浓缩。通过制备型薄层色谱(石油醚/乙酸乙酯=1/1(v/v))纯化所得残余物,提供呈黄色固体状的所需产物(0.150g,47%)。1H NMR(400MHz,DMSO-d6):δ7.72-7.86(m,4H),3.92-4.02(m,2H),3.22-3.32(m,4H),3.08-3.15(m,2H),1.75-1.79(m,3H),1.36(s,9H),1.18-1.20(m,2H)ppm。
化合物28.4. 4-(3,3-二氟-1-((3-氟苯基)磺酰基)环丁基)哌啶
以与化合物9.5类似的方式制备化合物28.4,提供呈红色固体状的所需产物(0.140g,粗物质)。LC-MS(ES,m/z):334[M+H]+。
化合物28. 4-(3,3-二氟-1-((3-氟苯基)磺酰基)环丁基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
以与化合物4类似的方式制备化合物28,提供呈白色固体状的所需产物(0.027g,14%)。LC-MS(ES,m/z):455[M+H]+;1H NMR(300MHz,DMSO-d6):δ9.18(d,J=0.9Hz,1H),8.83(dd,J1=0.9Hz,J2=6.0Hz,1H),7.84-7.66(m,4H),7.57-7.54(m,1H),4.22(d,J=13.8Hz,2H),3.33-3.23(m,2H),3.04-2.94(m,2H),2.81-2.73(m,2H),2.00-1.92(m,3H),1.47-1.42(m,2H)ppm。
实施例29. 4-((S)-1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙
基)-N-(2-((S)-1-羟基乙基)吡啶-4-基)哌啶-1-甲酰胺的制备
实施例29.1.(2-氰基吡啶-4-基)氨基甲酸叔丁酯
向4-溴吡啶-2-甲腈(20g,109.29mmol)在1,4-二噁烷(300mL)中的溶液中加入Pd(OAc)2(2.98g,13.27mmol)、XPhos(18.9g,39.34)、Cs2CO3(50.3g,154.38mmol)。将所得溶液在100℃搅拌1h。将反应冷却至室温,并通过过滤除去固体。浓缩滤液,并通过快速柱色谱(EtOAc/石油醚=1/3(v/v))纯化所得残余物,提供呈黄色固体状的所需产物(23g,95%)。LC-MS(ES,m/z):220[M+H]+。1H NMR(300MHz,CDCl3):δ8.49(d,J=5.6Hz,1H),7.87(d,J=2.2Hz,1H),7.43(dd,J=5.6,2.2Hz,1H),6.90(s,1H),1.54(s,9H)ppm。
实施例29.2.(2-乙酰基吡啶-4-基)氨基甲酸叔丁酯
在0℃向(2-氰基吡啶-4-基)氨基甲酸叔丁酯(29.1,23.0g,104.91mmol)在THF(200mL)中的溶液中滴加MeMgBr溶液(1M于THF中,125.4mmol,125.4mL)。将所得溶液搅拌1h,然后通过加入冰水(1000mL)淬灭。用EtOAc(3x500mL)萃取所得溶液并合并有机层,用盐水(2x200mL)洗涤,经无水硫酸钠干燥并浓缩。通过快速柱色谱(EtOAc/石油醚=1/4(v/v))纯化所得残余物,提供呈白色固体状的所需产物(21g,85%)。LC-MS(ES,m/z):237[M+H]+。1HNMR(300MHz,CDCl3):δ8.49(d,J=5.4Hz,1H),7.81–7.71(m,2H),6.89(s,1H),2.68(s,3H),1.51(s,9H)ppm。
实施例29.3. 1-(4-氨基吡啶-2-基)乙-1-酮
向N-(2-乙酰基吡啶-4-基)氨基甲酸叔丁酯(29.2,2.3g,9.73mmol)在二氯甲烷(5mL)中的溶液中加入三氟乙酸(15g,132.70mmol)。将所得溶液在室温搅拌过夜,然后浓缩。从乙醚中沉淀粗产物并通过过滤收集固体,提供呈白色固体状的所需产物(2.0g,82%)。1H NMR(300MHz,DMSO-d6):δ13.33(s,1H),8.28(s,2H),8.08(d,J=6.8Hz,1H),7.44(d,J=2.4Hz,1H),6.86(dd,J=6.8,2.4Hz,1H),2.46(m,3H)ppm。
实施例29.4.(2-乙酰基吡啶-4-基)氨基甲酸苯酯
在0℃向1-(4-氨基吡啶-2-基)乙-1-酮(29.3,5g,36.72mmol)在ACN/THF(1:1(v/v),50mL)和吡啶(4.74g,59.92mmol)中的溶液中滴加氯甲酸苯酯(4.68g,29.89mmol)。将所得溶液在室温搅拌2h。在真空下浓缩所得混合物,并用乙醚(2x30mL)洗涤,提供呈黄色固体状的所需产物(9g,粗物质),其不经进一步纯化直接使用。LC-MS(ES,m/z):257[M+H]+。
实施例29.5.(S)-N-(2-乙酰基吡啶-4-基)-4-(1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)哌啶-1-甲酰胺
以与化合物4类似的方式制备化合物29.5,提供呈白色固体状的所需产物(0.28g,37%)。LC-MS(ES,m/z):488[M+H]+;1H NMR(300MHz,DMSO-d6):δ9.15(s,1H),8.62(s,1H),8.42(d,J=5.6Hz,1H),8.05(d,J=2.1Hz,1H),7.73(dd,J=5.7,2.2Hz,1H),6.92(d,J=53.0Hz,1H),4.20(d,J=12.6Hz,2H),3.96(s,3H),2.81(m,2H),2.56(s,3H),2.46(m,1H),1.99(d,J=13.2Hz,1H),1.69(d,J=12.5Hz,1H),1.53(d,J=22.8Hz,3H),1.42–1.30(m,2H)ppm。
实施例29. 4-((S)-1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)-N-(2-((S)-1-羟基乙基)吡啶-4-基)哌啶-1-甲酰胺
在0℃向4-((S)-1-((3-(二氟甲基)-1-甲基-1H-吡唑-4-基)磺酰基)-1-氟乙基)-N-(2-((S)-1-羟基乙基)吡啶-4-基)哌啶-1-甲酰胺(29.5,0.120g,0.25mmol)在THF(2mL)中的溶液中滴加(R)-Me-CBS(0.074mL,0.75mmol),随后滴加BH3-THF(0.37mL,0.375mmol)。将所得溶液在0℃在水/冰浴中搅拌1h,然后通过加入甲醇(2mL)淬灭。浓缩反应混合物,并通过Prep-HPLC((IntelFlash-1):柱,C18硅胶;流动相,在30min内CH3CN:H2O=5:95升至CH3CN:H2O=95:5;检测器,UV 254nm)纯化所得残余物,提供呈外消旋体形式的所需产物。通过Prep-SFC((Prep SFC100):柱,CHIRALPAK-AD-H-SL002,20*250mm;流动相A:CO2:50,流动相B:IPA:50;流速:40mL/min;220nm;RT1=4.68min;RT2=5.98min)纯化外消旋体(50mg),提供呈白色固体状的所需产物(0.029,24%)。LC-MS(ES,m/z):490.2[M+H]+;1H NMR(300MHz,CD3OD):δ8.33(s,1H),8.18(d,J=5.8Hz,1H),7.59(d,J=2.1Hz,1H),7.38(dd,J=5.8,2.2Hz,1H),6.94(t,J=53.1Hz,1H),4.76(m,1H),4.27(m,2H),4.00(s,3H),3.00–2.80(m,2H),2.51(s,1H),2.18(d,J=13.2Hz,1H),1.84(d,J=13.3Hz,1H),1.65–1.36(m,8H)ppm。
实施例30. 4-氟-4-(2-((3-氟苯基)磺酰基)丙-2-基)-N-(哒嗪-4-基)哌啶-1-甲
酰胺的制备
实施例30.1.二((3-氟苯基)硫基)甲烷
向3-氟苯-1-硫醇(2g,15.60mmol)和碳酸钾(3.23g,23.37mmol)在DMF(10mL)中的溶液中加入CH2Br2(1.5g,8.58mmol)。将所得溶液在70℃搅拌过夜,冷却至室温,然后浓缩。通过快速柱色谱(EtOAc/石油醚=1/10(v/v))纯化所得残余物,提供呈固体状的所需产物(2.1g,50%)。1H NMR(300MHz,CD3OD):δ7.30-7.40(m,4H),7.21-7.23(m,2H),7.04-7.09(m,2H),4.82(s,2H)ppm。
实施例30.2.二((3-氟苯基)磺酰基)甲烷
向二((3-氟苯基)磺酰基)甲烷(30.1,0.200g,0.75mmol)在THF/H2O(1:1(v/v),10mL)中的溶液中加入NaIO4(1.6g,7.5mmol)和RuCl3(0.15g,0.075mmol)。将所得溶液在室温搅拌1h,然后通过加入水(20mL)淬灭。用EtOAc(3x20mL)萃取所得溶液,用盐水(3x20mL)洗涤,经无水硫酸镁干燥,过滤并浓缩,提供呈黄色固体状的所需产物(0.180g,73%),其不经进一步纯化即使用。1H NMR(400MHz,DMSO-d6):δ7.63-7.76(m,8H),6.13(s,2H)ppm。
实施例30.3. 3,3'-(丙烷-2,2-二基二磺酰基)二(氟苯)
向二((3-氟苯基)磺酰基)甲烷(30.2,2.0g,6.02mmol)在DMSO(15mL)中的溶液中加入氢化钠(0.600g,15.00mmol),随后经30分钟加入MeI(2.55g,17.96mmol)。将所得溶液在室温搅拌2h,然后通过加入水(80mL)淬灭。用EtOAc(3x30mL)萃取所得溶液,用盐水(2x30mL)洗涤,经无水硫酸钠干燥,过滤并浓缩。通过快速柱色谱(EtOAc/石油醚=1/1(v/v))纯化所得残余物,提供呈白色固体状的所需产物(1.8g,83%)。1H NMR(400MHz,DMSO-d6):δ7.72-7.88(m,8H),1.65(s,6H)ppm。
实施例30.4. 4-(2-((3-氟苯基)磺酰基)丙-2-基)-4-羟基哌啶-1-羧酸叔丁酯
向3,3’-(丙烷-2,2-二基二磺酰基)二(氟苯)(30.3,1.0g,2.77mmol)和4-氧代哌啶-1-羧酸叔丁酯(1.6g,8.03mmol)在THF(5mL)中的溶液中加入SmI2(83mL,8.31mmol)。将所得溶液在室温搅拌1h,然后通过加入饱和NH4Cl(400mL)和水(10mL)淬灭。用EtOAc(3x150mL)萃取所得溶液,用盐水(2x100mL)洗涤,经无水硫酸钠干燥,过滤并浓缩。通过快速色谱(EtOAc/石油醚=1/3(v/v))纯化所得残余物,提供呈白色固体状的所需产物(0.830g,75%)。1H NMR(400MHz,DMSO-d6):δ7.57-7.70(m,4H),4.97(m,1H),3.77-3.79(d,J=10.8,2H),2.95-2.97(m,2H),1.76-1.97(m,4H),1.41(s,9H),1.22(s,6H)ppm。
实施例30.5. 4-氟-4-(2-((3-氟苯基)磺酰基)丙-2-基)哌啶-1-羧酸叔丁酯
在-30℃向4-氟-4-(2-((3-氟苯基)磺酰基)丙-2-基)哌啶-1-羧酸叔丁酯(30.4,0.040g,0.10mmol)在DCM(3mL)中的溶液中加入DAST(0.024g,0.15mmol)。将所得溶液搅拌过夜同时升温至0℃。然后通过加入水(10mL)淬灭反应混合物,用EtOAc(3x10mL)萃取,用盐水(2x10mL)洗涤,经无水硫酸钠干燥,过滤并浓缩。通过快速柱色谱(乙酸乙酯/石油醚=1/3(v/v))纯化所得残余物,提供呈白色固体状的所需产物(0.025g)。LC-MS(ES,m/z):389[M-CH3+H]+。
实施例30.6. 4-氟-4-(2-((3-氟苯基)磺酰基)丙-2-基)哌啶盐酸盐
以与化合物9.5类似的方式制备化合物30.6,提供呈白色固体状的所需产物(0.350g,粗物质),其不经进一步纯化直接使用。LC-MS(ES,m/z):304[M+H]+。
实施例30. 4-氟-4-(2-((3-氟苯基)磺酰基)丙-2-基)-N-(哒嗪-4-基)哌啶-1-甲酰胺
以与化合物4类似的方式制备化合物30,提供呈白色固体状的所需产物(0.070g,14%)。LC-MS(ES,m/z):425[M+H]+;1H NMR(300MHz,DMSO-d6):δ9.26-9.28(m,2H),8.87-8.89(d,J=6.0Hz,1H),7.62-7.77(m,5H),4.10-4.15(d,J=14.8Hz,2H),2.96-3.32(m,2H),2.22-2.52(m,2H),1.359(s,6H)ppm。
表1中的化合物根据如上所述的实施例制备。
表1.本发明的代表性化合物和分析数据
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实施例8.肌球蛋白活化测定
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)构成的酶偶联系统结合起来的生物化学测定,并监测作为时间的函数的NADH的吸光度降低(在340nm),来评估小分子药物活化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(skinned)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响应性,并选择实现肌原纤维系统的50%(pCa50或pCa=~6)或<5%(pCa=10)活化的钙浓度作为用于评估小分子药物的活化活性的最终条件。所有酶活性在pH 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、50uM ATP、0.1mg/mLBSA(牛血清白蛋白)、10ppm消泡剂、2mM BME、0.5mM NADH、1.5mM PEP以及实现肌原纤维的50%或<5%活化所需要的所需游离钙浓度。
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3.3%(v/v)的情况下实现化合物的最终所需浓度。典型地,将1μL连续稀释液加入到384孔板中以实现10点剂量响应。加入含有牛心脏肌原纤维、PK/LDH和钙溶液(其实现所需活化)的14μL溶液后,通过加入含有ATP、PEP和NADH的15μL溶液开始酶促反应。反应进程在环境温度使用透明底板在PerkinElmer Envision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响应对时间的斜率。将吸光度响应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浓度的函数作图并使用EXCEL XLfit将数据拟合成四参数拟合。总响应增加20%或50%的浓度报告为AC20或AC50。在最高测试浓度不能实现相应百分比活化的任何试剂报告为AC20或AC50大于最高测试浓度(即AC50>50uM)。
表2.所选化合物的肌球蛋白活化a
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a+++表示肌球蛋白活化值AC20<2μM;++表示肌球蛋白活化值AC20为2μM-5μM;+表示肌球蛋白活化值AC20>5μM。
如上所述评估针对兔骨骼肌原纤维的选择性,不同之处在于肌球蛋白的来源为来自兔以肌原纤维形式的快速骨骼肌球蛋白。还如上所述确定针对兔骨骼肌原纤维的剂量响应。
实施例9.心肌细胞收缩性测定.
成年大鼠心室肌细胞的收缩性通过边缘检测使用IonOptix收缩性系统确定。将肌细胞在Tyrode缓冲液(137mM NaCl,3.7mM KCl,0.5mMmgCl2,1.5mM CaCl2,4mM HEPES,11mM葡萄糖)中的等分试样置于灌注室(系列20RC-27NE;Warner Instruments)中,允许附着在盖玻片上,然后灌注37℃Tyrode缓冲液。以1Hz和10V刺激肌细胞。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、基线分数缩短等于细胞长度的3-8%且收缩速度大于100微米/秒的肌细胞用于收缩性实验。为了确定对化合物的响应,首先用Tyrodes缓冲液灌注肌细胞60秒,随后用化合物灌注5分钟并用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并对基线(无化合物)条件与用化合物处理的条件进行比较。化合物活性通过对分数缩短(FS)的影响来测量,其中分数缩短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3.所选化合物对心肌细胞收缩的活化a
a+表示相对于基线,分数缩短活化<20%。++表示相对于基线,分数缩短活化值为20%至50%。+++表示相对于基线,分数缩短活化值大于50%。
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 (5)
1.一种化合物或其盐,所述化合物选自:
2.根据权利要求1所述的化合物或其盐,所述化合物为
3.根据权利要求1所述的化合物或其盐,所述化合物为
4.根据权利要求1所述的化合物或其盐,所述化合物为
5.根据权利要求1所述的化合物或其盐,所述化合物为
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