CN107108492A - 细胞坏死抑制剂 - Google Patents

细胞坏死抑制剂 Download PDF

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CN107108492A
CN107108492A CN201580071229.7A CN201580071229A CN107108492A CN 107108492 A CN107108492 A CN 107108492A CN 201580071229 A CN201580071229 A CN 201580071229A CN 107108492 A CN107108492 A CN 107108492A
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compound
unsubstituted
substituted
dimethyl
phenyl
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CN107108492B (zh
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张志远
王晓东
苏亚宁
阮寒英
任艳
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National Institute of Biological Sciences Beijin
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Abstract

本发明提供了抑制细胞坏死和/或人受体相互作用蛋白1激酶(RIP1)的酰胺，包括相应的磺酰胺，及其药学上可接受的盐，氢化物和立体异构体。这些化合物用于药物组合物，以及制备和使用方法，包括用有效量的所述化合物或组合物治疗有需要的人，并检测人的健康或状况的改善结果。

Description

细胞坏死抑制剂
技术领域
肿瘤坏死因子α(TNF-α)诱导的NF-κB活化在免疫***和炎性反应中起核心作用。受体相互作用蛋白1(RIP1)是涉及介导核因子κB(NF-κB)活化、细胞凋亡和细胞坏死的多功能信号转导子。RIP1的激酶活性关键地参与介导细胞程序性坏死，一种不依赖于半胱天冬酶的坏死性细胞死亡通路。Holler et al.Nat mmunol 2000；1:489–495；Degterev etal.Nat Chem Biol 2008；4:313–321.
细胞程序性坏死在多种病理形式的细胞死亡中起作用，包括缺血性脑损伤、神经变性疾病和病毒感染。Dunai,et al.,Dec 2011,Pathol.Oncol.Res.:POR 17(4):791–800.Necrostatin-1(Nec-1),a small molecule inhibitor of RIP1kinase activity,can block necroptosis.Degterev et al.Nat Chem Biol 2005；1:112–119.
相关专利出版物包括：US6756394,US8278344,US2012122889,US2009099242,US2010317701,US2011144169,US20030083386,US20120309795,WO2009023272,WO2010075290,WO2010075561,WO2012125544。
发明内容
本发明提供了细胞坏死和/或人受体相互作用蛋白1激酶(RIP1)的抑制剂，其为如式的酰胺化合物：
其中：
R1是C3-C14环或杂环部分，特别是取代或未取代的，0-3个杂原子C3-C9环烷基，环烯基，环炔基；或取代或未取代的，0-3个杂原子C5-C14芳基；
R2是C3-C14杂环部分，特别是取代或未取代的，1-3个杂原子C3-C9环烷基，环烯基，环炔基；或取代或未取代的，1-3个杂原子C5-C14芳基；且
R3是氢原子，取代或未取代的杂原子，取代或未取代的，0-3个杂原子C1-C9烷基，烯基，炔基；或取代或未取代的，0-3个杂原子C5-C14芳基，
其中每个杂原子独立地是氧，磷，硫或氮；或
该酰胺化合物的相应磺酰胺，或
该化合物或相应的磺酰胺药学上可接受的盐，氢化物或立体异构体；
本发明还提供了所有一般和特别公开的酰胺的相应磺酰胺，如：
其中S可以是双键链接一个或两个氧原子，或其药学上可接受的盐，氢化物或立体异构体，其中R部分如本文所述，或其药学上可接受的盐，氢化物或立体异构体。
本发明提供了包含主题化合物的药物组合物，以及制备和使用主题化合物的方法，包括抑制细胞坏死和/或者人RIP1的方法。组合物可以包含药学上可接受的赋形剂，以有效的单位剂型，和/或者包含另一种不同的用于靶向疾病或病症的治疗剂。在实施方案中，本发明提供了用有效量的主题化合物或药物组合物治疗对其有需要的人的方法，并且任选地检测该人的健康或状况的改善结果。该方法还可任选地包括确定人，特别是诊断和适用的疾病或病症(本文)的前提步骤。
本发明包括本文所述的特定实施方案的所有组合。
本发明的具体实施方案的描述
具体实施方案和实施例的以下描述是通过说明而非限制的方式提供的。本领域技术人员将容易地识别可以改变或修改的各种非关键参数以产生基本相似的结果。本发明提供了极多的实施例。
一方面，本发明提供了下式的细胞坏死和/或人受体相互作用蛋白1激酶(RIP1)的酰胺抑制剂：
其中：
R1是C3-C14环或杂环部分，特别是取代或未取代的，0-3个杂原子C 3-C9环烷基，环烯基，环炔基；或取代或未取代的，0-3个杂原子C5-C14芳基；
R2是C3-C14杂环部分，特别是取代或未取代的，1-3杂原子的C3-C9环烷基，环烯基，环炔基；或取代或未取代的，1-3个杂原子C5-C14芳基；且
R3是氢原子，取代或未取代的杂原子，取代或未取代的，0-3个杂原子C1-C9烷基，烯基，炔基；或者取代或未取代的，0-3个杂原子C5-C14芳基，
其中每个杂原子独立地是氧，磷，硫或氮；或
该酰胺化合物的相应磺酰胺，或
该化合物药学上可接受的盐，氢化物或立体异构体。
在具体实施方案中：
R1是：(a)取代或未取代的苯基；
(b)取代或未取代的2-，3-或4-吡啶；
(c)取代或未取代的萘基或3-氮杂萘基；
(d)取代或未取代的0-3个杂原子环己基，环戊基，如四氢呋喃；或
(e)取代或未取代的0-3个杂原子环戊烯或环戊二烯，如吡咯，唑(例如吡唑，咪唑，***，四唑，戊唑，恶唑，异恶唑，噻唑或异噻唑)，呋喃，间二氧杂环戊烯噻吩，二硫杂环戊烯或硫氧杂环戊烯，优选2-部分，例如2-唑，2-吡咯，2-唑(例如2-吡唑，2-咪唑，2-恶唑，2-异恶唑，2-噻唑或2-异噻唑)，2-呋喃，2-噻吩，2-氧杂环戊二烯，间二氧杂环戊烯或2-硫杂环戊二烯；和/或
R2是具有杂原子的取代或未取代的饱和环：
N，例如氮杂环丙烷，氮杂环丁烷，吡咯烷，哌啶；
N和O，例如氧氮环丙烷，氧氮杂环丁烷，恶唑烷，恶嗪啉；
N和S，例如硫氮环丙烷，氮硫环丁烷，四氢噻唑，硫代吗啉；
N和N，例如二氮环甲烷，二氮杂环丁烷，二氮环戊烷(吡唑烷)，六氢哒嗪；或
R2是具有杂原子的取代或未取代的不饱和环：
N，例如吡咯，二氢吡咯，吡啶，二氢吡啶，四氢吡啶；
N和N/S/O，例如唑，(例如吡唑，咪唑，***，四唑，戊唑，恶唑，异恶唑，噻唑或异噻唑)，嘧啶，恶嗪，噻嗪，三嗪，恶二嗪，噻二嗪；和/或
R3是取代或未取代的，0-3个杂原子C1-C9烷基，烯基或炔基，且在实施方案中，R3是用1,2,3或4个氟原子氟化，例如1-二甲基-2-二氟丙基。
在实施方案中：
R1是取代或未取代的：苯基，环己基，呋喃，噻吩或唑(如噻唑)；和/或
R2是取代或未取代的：氮杂环丙烷，氮杂环丁烷，吡咯烷，哌啶，恶唑烷，恶嗪啉；二氮环戊烷，六氢哒嗪，吡咯，二氢吡咯，二氢吡啶或四氢吡啶；和/或
R3是1-二甲基丙基，1-二甲基丙-2-烯基或1-二甲基丙-2-炔基，每个任选的被1-4个氟原子氟化。
在实施方案中：
R1是取代或未取代的苯基或环己基，和/或
R2是取代或未取代的：氮杂环丁烷，吡咯烷，哌啶，恶唑烷，二氮环戊烷，六氢哒嗪；和/或
R3是1-二甲基丙基；或
该酰胺化合物的相应磺酰胺，或
该化合物或相应的磺酰胺药学上可接受的盐，氢化物或立体异构体。
所有可能的组合都包括在内，仿如每个都被明确地列举，并且杂环包含异构体，例如异-形式。
例如，在实施方案中，化合物具有式I，其中：
R1是未取代的苯基，和/或
R2是未取代的：氮杂环丁烷，吡咯烷，哌啶，恶唑烷，二氮环戊烷，六氢哒嗪；和/或
R3是1-二甲基丙基；或
该酰胺化合物的相应磺酰胺，或
该化合物或相应的磺酰胺药学上可接受的盐，氢化物或立体异构体。
例如，在实施方案中，化合物具有式I，其中：
R1是未取代的苯基，且
R2是未取代的：氮杂环丁烷，吡咯烷，哌啶，恶唑烷，二氮环戊烷，六氢哒嗪；且
R3是1-二甲基丙基；或
该酰胺化合物的相应磺酰胺，或
该化合物或相应的磺酰胺药学上可接受的盐，氢化物或立体异构体。
在实施方案中，主题化合物具有表1的式。
在实施方案中，本发明提供了包含单位剂量的主题化合物和药学上可接受的赋形剂的药物组合物。
在实施方案中，本发明提供了包含主题化合物和药学上可接受的赋形剂，以及一种不同的用于细胞坏死相关疾病或病症的治疗剂的药物组合物。
在实施方案中，本发明提供了治疗细胞坏死相关疾病或病症的方法，包含向有需要的患者施用有效量的主题化合物或组合物。
在实施方案中，本发明提供了治疗方法，其包含诊断细胞坏死相关疾病或病症的前期步骤，或检测细胞坏死相关疾病或病症的改善结果的后续步骤。
适用的疾病或病症为细胞坏死(包括细胞程序性坏死)相关的，以及包括中枢或周围神经***的神经变性疾病，内毒素/败血性休克，末端回肠炎，心肌炎，关节炎，动脉粥样硬化，急性肠炎，缺血性坏死，由肾衰竭或细胞死亡引起的病理，包括视网膜神经元、心肌或免疫细胞死亡，比如化学或放射性诱导的坏死；肝脏疾病，包括药物诱发的肝损伤或毒性、急性肝炎等，胰腺疾病，包括坏死性胰腺炎，心脏、肠系膜、视网膜，肝或脑/大脑缺血性损伤，肾炎，再灌注或器官储存期间的缺血性损伤，头部创伤，包括创伤性脑损伤，中风，败血性休克，冠心病，心肌症，心肌梗塞，股无血管性坏死，镰状细胞病，肌肉消瘦，胃肠疾病，结核病，糖尿病，血管病理改变，肌营养不良症，移植物抗宿主疾病，病毒、细菌和真菌感染，克罗恩氏病，溃疡性结肠炎，哮喘等。
示例性适用的病毒为人免疫缺陷病毒(HIV)，爱泼斯坦-巴尔病毒(EBV)，巨细胞病毒(CMV)5，人疱疹病毒(HHV)，单纯性疱疹病毒(HSV)，人T细胞白血病病毒(HTLV)5，水痘-带状疱疹病毒(VZV)，麻疹病毒，***多瘤空泡病毒(JC和BK)，肝炎病毒，腺病毒，细小病毒，以及人***状瘤病毒。由病毒感染引起的示例性疾病包括但不限于，水痘，巨细胞病毒感染，生殖器疱疹，乙型和丙型肝炎，流行性感冒，以及带状疱疹。
示例性适用的细菌包括但不限于空肠弯曲杆菌，肠杆菌属，屎肠球菌，粪肠球菌，大肠杆菌(如，大肠杆菌O157：H7)，A组链球菌，流感嗜血杆菌，幽门螺杆菌，李斯特菌属，结核分支杆菌，绿脓假单胞菌，肺炎链球菌，沙门氏菌，志贺氏菌，金黄色葡萄球菌，以及表皮葡萄球菌。由细菌感染引起的示例性疾病包括但不限于，炭疽，霍乱，白喉，食源性疾病，麻风病，脑膜炎，消化性溃疡病，肺炎，败血症，破伤风，结核病，伤寒以及***。
示例性适用的神经变性疾病是阿尔兹海默症，亨廷顿病，帕金森氏病，肌萎缩性脊髓侧索硬化症，HIV相关性痴呆，脑缺血，多发性硬化症，路易体病，Menke氏病，威尔逊氏病，克雅氏病以及Fahr疾病。
示例性适用的肌营养不良症或相关疾病是贝克氏肌营养不良症，杜氏肌营养不良症，肌强直性营养不良症，肢带型肌营养不良症，兰迪二式肌营养不良，面肩胛肱型肌营养不良(Steinert氏病)，先天性肌强直症，汤姆森氏病和庞贝氏症。肌肉消瘦可能与癌症，艾滋病，充血性心力衰竭和慢性阻塞性肺病有关，还包括重症监护病人的坏死性肌病。
除非有相反的提示或另有说明，在这些描述和整个说明书中，术语“一个”是指一个或多个，术语“或”指和/或，并且多核苷酸序列被理解为包括相反链以及本文所述的可选择骨架。此外，属类为该属类所有成员的叙述的简称；例如，(C1-C3)烷基的叙述是指所有C1-C3烷基叙述的简写：甲基，乙基和丙基，包括其异构体。
本文所述术语“杂原子”通常是指碳或氢之外的任何原子。优选的杂原子包括氧(O)、磷(P)、硫(S)、氮(N)和卤素，且优选的杂原子官能团为卤代甲酰基、羟基、醛、胺、偶氮、羧基、氰基、硫氰酸盐、羰基、卤素、过氧羟基、亚胺、醛亚胺、异氰化物、异氰酸酯、硝酸盐、腈、亚硝酸盐、硝基、亚硝基、磷酸盐、膦酰基、硫化物、磺酰基、磺基和巯基。
除非另外说明，术语“烷基”本身或作为另一取代基的一部分，是指直链或支链或者环状烃基，或其组合，其为完全饱和的具有指定碳原子数(即C1-C8指1至8个碳)。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、环己基、(环己基)甲基、环丙基甲基，以及如正戊基、正己基、正庚基、正辛基等同系物和异构体。
术语“烯基”本身或作为另一取代基的一部分，是指直链或支链或环状烃基或其组合，其可以是单不饱和或多不饱和的，具有指定的碳原子数(即C2-C8指2至8个碳)和一个或多个双键。烯基的实例包括乙烯基、2-丙烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)及其高级同系物和异构体。
术语“炔基”本身或作为另一取代基的一部分，是指直链或支链烃基或其组合，其可以是单不饱和或多不饱和的，具有指定的碳原子数(即C2-C8指2至8个碳)和一个或多个三键。炔基的实例包括乙炔基、1-和3-丙炔基、3-丁炔基及其高级同系物和异构体。
术语“亚烷基”本身或作为另一取代基的一部分是指衍生自烷基的二价基团，例如以-CH2-CH2-CH2-CH2-实例。通常，烷基(或亚烷基)基团将具有1至24个碳原子，在本发明中优选具有10个或更少碳原子的那些基团。“低级烷基”或“低级亚烷基”为较短链的烷基或亚烷基，通常具有8个或更少的碳原子。
术语“烷氧基”，“烷基氨基”和“烷硫基”(或硫代烷氧基)以其常规含义使用，并且分别指的是通过氧原子、氨基或硫原子与分子剩余部分连接的那些烷基。
除非另外说明，术语“杂烷基”本身或与另一术语组合是指稳定的直链或支链或环状烃基或其组合，由确定数目的碳原子和一至三个选自氧、氮、磷、硅和硫的杂原子组成，其中氮、硫和磷原子可任选地被氧化，且氮杂原子可任选地被季铵化。杂原子氧、氮、磷和硫可置于杂烷基的任何内部位置。杂原子硅可置于杂烷基的任何位置，包括烷基与分子剩余部分连接的位置。实例包括-CH2-CH2-O-CH3,-CH2-CH2-NH-CH3,-CH2-CH2-N(CH3)-CH3,-CH2-S-CH2-CH3,-CH2-CH2,-S(O)-CH3,-CH2-CH2-S(O)2-CH3,-CH＝CH-O-CH3,-Si(CH3)3,-CH2-CH＝N-OCH3,和-CH＝CH-N(CH3)-CH3。最多两个杂原子可以是连续的，例如-CH2-NH-OCH3和-CH2-O-Si(CH3)3。
类似地，术语“杂亚烷基”本身或作为另一取代基的一部分是指衍生自杂烷基的二价基团，例如以-CH2-CH2-S-CH2-CH2-和-CH2-S-CH2-CH2-NH-CH2-为实例。对于杂亚烷基，杂原子也可以占据链末端的任一个或两个(例如亚烷基氧基、亚烷基二氧基、亚烷基氨基、亚烷基二氨基等)。此外，对于亚烷基和杂亚烷基连接基团，没有暗示连接基团的取向。
除非另外说明，术语“环烷基”和“杂环烷基”自身或与其它术语组合，分别表示“烷基”和“杂烷基”的环状形式。相应地，环烷基具有指定的碳原子数(即C3-C8表示3至8个碳)，并且还可以具有一个或两个双键。杂环烷基由指定的碳原子数和选自氧，氮，硅和硫的一至三个杂原子组成，并且其中氮和硫原子可任选地被氧化，且氮杂原子可任选地被季铵化。另外，对于杂环烷基，杂原子可以占据杂环与分子的剩余部分连接的位置。环烷基的实例包括环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环烷基的实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基、3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃-3-基、四氢噻吩-2-基、四氢噻吩-3-基、1-哌嗪基、2-哌嗪基等。
除非另有说明，术语“卤代”和“卤素”本身或作为另一取代基的一部分，是指氟，氯，溴或碘原子。另外，术语例如“卤代烷基”是指包括被一个到(2m'+1)的数目范围内的相同或不同的卤素原子取代的烷基，其中m'是烷基中碳原子的总数。例如，术语“卤代(C1-C4)烷基”是指包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。因此，术语“卤代烷基”包括单卤代烷基(被一个卤素原子取代的烷基)和多卤代烷基(被2至(2m'+1)个卤素原子取代的烷基，其中m'为烷基中碳原子的总数)。除非另外说明，术语“全卤代烷基”是指被(2m'+1)个卤素原子取代的烷基，其中m'是烷基中的碳原子的总数。例如术语“全卤代(C1-C4)烷基”是指包括三氟甲基、五氯乙基、1,1,1-三氟-2-溴-2-氯乙基等。
术语“酰基”是指通过除去酸的羟基部分衍生自有机酸的那些基团。相应地，酰基是指包括如乙酰基、丙酰基、丁酰基、癸酰基、新戊酰基、苯甲酰基等。
除非另外说明，术语“芳基”是指多不饱和的，通常为芳香族的烃取代基，其可以是稠合在一起或共价连接的单环或多环(至多三个环)。芳基的非限制性实例包括苯基、1-萘基、2-萘基、4-联苯基和1,2,3,4-四氢萘。
术语“杂芳基”是指含有0至4个选自氮，氧和硫的杂原子的芳基(或环)，其中氮和硫原子任选地被氧化，且氮杂原子任选地被季铵化。杂芳基可以通过杂原子连接到分子的剩余部分。杂芳基的非限制性实例包括1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。
为简便起见，当与其它术语(例如芳氧基芳基硫氧基芳基烷基)组合使用时，术语“芳基”包括如上定义的芳环和杂芳基环。因此，术语“芳基烷基”是指包括其中芳基连接至烷基的那些基团(例如苄基、苯乙基、吡啶基甲基等)，所述烷基包括其碳原子(例如亚甲基基团)被例如氧原子替代的烷基基团(如苯氧基甲基、2-吡啶基氧基甲基、3-(1-萘氧基)丙基等)。
上述术语(如“烷基”、“杂烷基”、“芳基”和“杂芳基”)中的每一个是指包含所示基团的取代和未取代两种形式。每种类型的基团的优选取代基提供如下。
烷基和杂烷基(以及被称为亚烷基、烯基、杂亚烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基和杂环烯基的那些基团)的取代基可以是选自以下的各种基团：-OR'、＝O、＝NR'、＝N-OR'、-NR'R"、-SR'、卤素、-SiR'R"R'"、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR'-C(O)NR"R'"、-NR'-SO2NR'"、-NR"CO2R'、-NH-C(NH2)＝NH、-NR'C(NH2)＝NH、-NH-C(NH2)＝NR'、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R，-CN和-NO2，数量范围从0至3，那些具有0、1或2个取代基的基团是特别优选的。R'、R"和R'"每个独立地指氢、未取代的(C1-C8)烷基和杂烷基、未取代的芳基、被一至三个卤素取代的芳基、未取代的烷基、烷氧基或硫代烷氧基，或芳基-(C1-C4)烷基基团。当R'和R"连接到相同的氮原子时，它们可以与氮原子组合形成5-，6-或7-元环。例如，-NR'R"是指包括1-吡咯烷基和4-吗啉基。通常，烷基或杂烷基具有0至3个取代基，在本发明中优选具有两个或更少取代基的那些基团。更优选地，烷基或杂烷基将是未取代的或单取代的。最优选地，烷基或杂烷基是未取代的。从上述取代基的讨论中，本领域技术人员将理解术语“烷基”意指包括例如三卤代烷基(例如，-CF3和-CH2CF3)的基团。
烷基和杂烷基的优选取代基选自：-OR'、＝O、-NR'R"、-SR'、卤素、-SiR'R"R'"、-OC(O)R'、-C(O)R'、-CO2R'、-CONR'R"、OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-SO2NR"R'"、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R、-CN和-NO2，其中R'和R"如上面所定义的。进一步优选的取代基选自：-OR'、＝O、-NR'R"、卤素、-OC(O)R'、-CO2R'、-CONR'R"、-OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-SO2NR"R'"、-SO2R'、-SO2NR'R"、-NR"SO2R，-CN和-NO2。
类似地，芳基和杂芳基的取代基是不同的，并且选自：卤素、-OR'、-OC(O)R'、-NR'R"、-SR'、-R'、-CN、-NO2、-CO2R'、-CONR'R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-NR"CO2R'、-NR'-C(O)NR"R'"、-NR'-SO2NR"R'"、-NH-C(NH2)＝NH、-NR'C(NH2)＝NH、-NH-C(NH2)＝NR'、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R、-N3、-CH(Ph)2，全氟(C1-C4)烷氧基和全氟(C1-C4)烷基，数量范围为0至芳族环***上的开放化合价的总数；并且其中R'，R"和R'"独立地选自氢、(C1-C8)烷基和杂烷基、未取代的芳基和杂芳基、(未取代的芳基)-(C1-C4)烷基和(未取代的芳基)氧基-(C1-C4)烷基。当芳基是1,2,3,4-四氢萘时，它可以被取代或未取代的(C3-C7)螺环烷基取代。(C3-C7)螺环烷基可以以本文对“环烷基”所定义的相同方式取代。通常，芳基或杂芳基具有0至3个取代基，在本发明中优选具有两个或更少取代基的那些基团。在本发明的一个实施方案中，芳基或杂芳基是未取代的或单取代的。在另一个实施方案中，芳基或杂芳基将是未取代的。
芳基和杂芳基的优选取代基选自：卤素、-OR'、-OC(O)R'、-NR'R"、-SR'、-R'、-CN、-NO2、-CO2R'、-CONR'R"、-C(O)R'、-OC(O)NR'R"、-NR"C(O)R'、-S(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R、-N3、-CH(Ph)2、全氟(C1-C4)烷氧基和全氟(C1-C4)烷基，其中R'和R"如上所定义。进一步优选的取代基选自：卤素、-OR'、-OC(O)R'、-NR'R"、-R'、-CN、-NO2、-CO2R'、-CONR'R"、-NR"C(O)R'、-SO2R'、-SO2NR'R"、-NR"SO2R，全氟(C1-C4)烷氧基和全氟(C1-C4)烷基。
本文所用的取代基-CO2H包括其生物电子等排置换；参见例如The Practice ofMedicinal Chemistry；Wermuth，C.G.，Ed.；Academic Press:New York,1996；p.203。
芳环或杂芳基环的相邻原子上的两个取代基可任选地被式-T-C(O)-(CH2)q-U-的取代基替代，其中T和U独立地为-NH-、-O-，-CH2-或单键，且q为0-2的整数。或者，芳环或杂芳基环的相邻原子上的两个取代基可任选地被式-A-(CH2)r-B-的取代基替代，其中A和B独立地为-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-，-S(O)2NR'-或单键，且r为1-3的整数。如此形成的新环的单键之一可任选地被双键代替。或者，芳环或杂芳基环的相邻原子上的两个取代基可任选地被式-(CH2)s-X-(CH2)t-的取代基替代，其中s和t独立地为0至3的整数，并且X为-O-、-NR'-、-S-、-S(O)-，-S(O)2-或-S(O)2NR'-。-NR'-和-S(O)2NR'-中的取代基R'选自氢或未取代的(C1-C6)烷基。
本文公开了优选的取代基并在表格、结构，实施例和权利要求中举例说明，并且取代基可以应用于本发明的不同化合物，即任何给定化合物的取代基可以与其它化合物组合使用。
在具体的实施方案中，适用的取代基独立地为取代或未取代的杂原子，取代或未取代的，0-3个杂原子C1-C6烷基，取代或未取代的，0-3个杂原子C2-C6烯基，取代或未取代的，0-3个杂原子C2-C6炔基，或取代或未取代的，0-3个杂原子C6-C14芳基，其中每个杂原子独立地为氧、磷，硫或氮。
在更具体的实施方案中，适用的取代基独立地为醛、醛亚胺、烷酰氧基、烷氧基、烷氧基羰基、烷氧基、烷基、胺、偶氮、卤素、氨基甲酰基、羰基、甲酰氨基、羧基、氰基、酯、卤代、卤代甲酰基、过氧烃基、羟基、亚胺、异氰化物、异氰酸酯、N-叔丁氧羰基、硝酸盐、腈、亚硝酸盐、硝基、亚硝基、磷酸酯、膦酰基、硫化物、磺酰基、磺基、巯基、硫醇、硫氰基，三氟甲基或三氟甲基醚(OCF3)。
术语“药学上可接受的盐”意指包括用相对无毒的酸或碱制备的活性化合物的盐，这取决于在本文所述化合物上发现的具体取代基。当本发明的化合物含有相对酸性的官能团时，碱加成盐可以通过使这种化合物的中性形式与足量的所需碱(要么是纯的要么在合适的惰性溶剂中)接触来获得。药学上可接受的碱加成盐的实例包括钠、钾、钙、铵，有机胺或镁盐，或类似的盐。当本发明的化合物含有相对碱性的官能团时，酸加成盐可以通过将这种化合物的中性形式与足量的所需酸(要么是在纯的要么在合适的惰性溶剂中)接触来获得。药学上可接受的酸加成盐的实例包括那些衍生自无机酸的如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸，氢碘酸或亚磷酸等，和衍生自相对无毒的有机酸如乙酸、丙酸、异丁酸、草酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸，甲磺酸等的盐。还包括氨基酸，例如精氨酸等的盐，以及有机酸，如葡糖醛酸或半乳糖醛酸等的盐。本发明的某些特定化合物同时含有碱性和酸性官能团，其允许化合物转化为碱或酸加成盐。
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成。化合物的母体形式在某些物理特性，例如在极性溶剂中的溶解度方面，不同于各种盐的形式，但是对于本发明的目的而言，这些盐等同于化合物的母体形式。
除了盐形式之外，本发明提供了前药形式的化合物。本文所述的化合物的前药是指在生理条件下经过化学变化以提供本发明化合物的那些化合物。另外，前药可以在体外环境中通过化学或生物化学方法转化为本发明的化合物。例如，当与合适的酶或化学试剂共同置于透皮贴剂储库中时，前药可被缓慢转化为本发明的化合物。前药通常是有用的，因为在一些情况下，它们可能比母体药物更容易施用。例如，它们可能比母体药物更具口服生物利用度。前药在药物组合物中也可能有比母体药物改善的溶解性。本领域已知各种各样的前药衍生物，例如依赖于水解裂解或氧化活化的那些前药。前药的一个非限制性实例是本发明中的一个化合物作为酯(“前药”)给药，但随后代谢水解成羧酸，即活性形式。另外的实例包括本发明化合物的肽基衍生物。
本发明的某些化合物可以非溶剂化形式以及溶剂化形式存在，包括水合物形式。通常，溶剂化形式等同于非溶剂化形式，并且包括在本发明的范围内。本发明的某些化合物可以以多种结晶或无定形形式存在。通常，所有物理形式对于本发明考虑的用途是等效的，并且包含在本发明的范围内。
本发明某些化合物具有不对称碳原子(光学中心)或双键；外消旋体、非对映异构体，几何异构体和单个异构体都旨在包括在本发明的范围内。
本发明的化合物还可以在构成这种化合物的一个或多个原子处含有非天然比例的原子同位素。例如，化合物可以用放射性同位素放射性标记，例如氚(3H)，碘-125(125I)或碳-14(14C)。本发明化合物的所有同位素变体，无论是否是放射性的，都旨在包括在本发明的范围内。
术语“治疗有效量”是指将在一定程度上引起组织、***、动物或人的生物或医学反应的题述化合物的量，这正是研究者、兽医、医生或其他临床医生所寻求的，例如当施用时，足以预防所治疗的病症或障碍的一种或多种症状的发展或在一定程度上减轻所治疗的病症或障碍的一种或多种症状。治疗有效量会根据化合物、疾病及其严重程度，以及待治疗的哺乳动物的年龄、体重等的不同而变化。
本发明还提供了包含题述化合物和药学上可接受的赋形剂的药物组合物，特别是包含单位剂量的题述化合物的组合物，尤其是该组合物与描述组合物用于治疗适用疾病或病症(本文中)的说明书共包装。
施用的组合物可以是散装液体溶液或悬浮液或散装粉末的形式。然而，更普遍地，组合物以单位剂型呈现以促进精确给药。术语“单位剂型”是指适合作为人类受试者和其它哺乳动物的单位剂量的物理上不连续的单位，每个单位含有计算产生所需治疗效果的预定量的活性物质，并与合适的药物辅料结合。典型的单位剂型包括液体组合物的预先填充的、预先测量的安瓿或注射器，或在固体组合物的情况下的丸剂、片剂、胶囊、锭剂等。在这样的组合物中，化合物通常是次要组分(约从0.1％至50％重量，或优选地约为从1％至40％重量)，其余是各种载体和加工助剂，有助于形成所需剂量。
合适的赋形剂或载体和用于制备可施用组合物的方法是本领域技术人员已知或显而易见的，并且在诸如Remington's Pharmaceutical Science，Mack Publishing Co，NJ(1991)的出版物中有更详细地描述。此外，该化合物与本文所述的或本领域已知的其它治疗剂、特别是其它抗坏死剂，联合用药时可有利地使用。因此，组合物可以单独、联合或组合施用于单一剂量单位。
施用量取决于化合物剂型，施用途径等，并且通常在常规试验中凭经验确定，并且根据靶标、宿主和施用途径等将必然发生变化。通常，根据具体应用，单位剂量制剂中活性化合物的量可以从约1，3，10或30到约30，100，300或1000mg变化或调节。在一个具体实施方案中，单位剂型包装在适于顺序使用的多包装中，例如泡罩包装，包括至少6，9或12个单位剂型的片材。所用的实际剂量可以根据患者的需要和所治疗的病症的严重程度而变化。对于特定情况的适当剂量的确定在本领域的技术范围内。通常，用小于化合物最佳剂量的较小剂量开始治疗。此后，剂量增加少量，直到达到在这种情况下的最佳效果。为了方便起见，如果需要，总日剂量可以分开并在当天内分批给药。
化合物可以通过多种方法施用，包括但不限于胃肠外、体表、口服或局部施用，例如通过气雾剂或经皮，用于预防和/或治疗性处理。此外，根据熟练临床医生的知识，治疗方案(例如，给药的剂量和次数)可以视所观察到的给予的治疗剂对患者的作用及所观察到的疾病与所施用的治疗剂的反应而变化。
在用于治疗患者的治疗有效方案的过程中，可以以治疗有效剂量和总量施用本发明的治疗剂。对于更有效的化合物，每千克患者的微克(μg)量可能是足够的，例如在约1，10或100ug/kg至约0.01，0.1，1，10或100mg/kg的患者体重范围内，尽管最佳剂量是化合物特定的，并且通常每种化合物是根据经验确定的。
一般来说，临床试验中的常规实验将确定最佳治疗效果的具体范围，对于每种治疗剂，每种给药方案，并且对特定患者的给药也将根据患者状况和对初始剂量的反应被调整到有效和安全的范围内。然而，最终给药方案将根据主治临床医生的判断，考虑诸如年龄、病人的状况和大小以及化合物效力、所治疗疾病的严重性等因素来调整。例如，化合物的剂量方案可以是以两至四个(优选两个)分开的剂量口服给药，从10毫克至2000毫克/天，优选的是10至1000毫克/天，更优选的是50至600毫克/天。还可以使用间歇治疗(例如，三周内一周或四周内三周)。
应理解，本文所述的实施例和实施方案仅用于说明目的，并且鉴于本领域技术人员会联想到其各种修改或变化，且包括在本申请的精神和范围以及所附权利要求的范围内。本文引用的所有出版物、专利和专利申请(包括其中的引用)在此以其全文并入作为参考用于所有目的。
实施例
表1.化合物列表
2.化合物的制备
化合物1：2,2-二甲基-1-(2-苯基氮杂环丙烷-1-基)丁-1-酮的制备
将2-苯基氮丙啶(35mg，0.294mmol)和三乙胺(59.4mg，0.588mmol)溶于1.5mL无水CH2Cl2中。在氮气下，于0℃下将1ml CH2Cl2中的2,2-二甲基丁酰氯(43.3mg，0.323mmol)缓慢加入到溶液中。将混合物在室温下搅拌2小时，用CH2Cl2和水稀释。有机层用饱和NaHCO3和盐水洗涤，用Na2SO4干燥并浓缩。残余物通过色谱法纯化，得到化合物1(20mg，31％)，为无色油状物。
1HNMR(CDCl3,400MHz):δ7.36-7.44(m,5H),5.90(dd,1H,J＝9.2,4.0Hz),3.44(dd,1H,J＝13.6,9.2Hz),3.26(dd,1H,J＝4.0,13.6Hz),1.61(qd,2H,J＝7.6,2.4Hz),1.21(s,3H),1.19(s,3H),0.74(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C14H19NO,218.1；测得值218.3.
化合物2：2,2-二甲基-1-(2-苯基氮杂环丁烷-1-基)丁-1-酮的制备
根据化合物1概述的步骤，由2-苯基氮杂环丁烷(50mg)和2,2-二甲基丁酰氯(55mg)制备标题化合物2，产率为77％。1HNMR(CDCl3,400MHz):δ7.31-7.36(m,4H),7.23-7.28(m,1H),5.35-5.39(m,1H),4.34-4.46(m,2H),2.66-2.74(m,1H),2.07-2.14(m,1H),1.59(q,2H,J＝7.6Hz),1.14(s,6H),0.89(t,3H,J＝7.6
Hz).LC-MS(ESI)[M+H]+计算值C15H21NO,232.2；测得值,232.4
化合物3：(S)-2,2-二甲基-1-(2-苯基氮杂环丁烷-1-基)丁-1-酮的制备
根据化合物1概述的步骤，从(S)-2-苯基氮杂环丁烷(50mg)和2,2-二甲基丁酰氯(55mg)制备标题化合物3，产率为77％。1HNMR(CDCl3,400MHz):δ7.32-7.37(m,4H),7.22-7.24(m,1H),5.37(dd,1H,J＝8.8,6.4Hz),4.26-4.45(m,2H),2.66-2.75(m,1H),2.07-2.15(m,1H),1.58(q,2H,J＝7.6Hz),1.15(s,6H),0.87(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C15H21NO,232.2；测得值,232.4.
化合物4：2,2-二甲基-1-(2-苯基吡咯烷-1-基)丁-1-酮的制备
根据化合物1概述的步骤，从2-苯基吡咯烷(50mg)和2,2-二甲基丁酰氯(55mg)制备标题化合物4，产率为46％。1HNMR(CDCl3,400MHz):δ7.28-7.30(m,1H),7.15-7.20(m,3H),5.25(m,1H),3.82(t,2H,J＝6.4Hz),2.17-2.26(m,1H),1.78-2.01(m,3H),1.59-1.67(m,2H),1.23(s,6H),0.85(t,3H,J＝7.2Hz).
LC-MS(ESI)[M+H]+计算值C16H23NO,246.2；测得值246.4.
化合物5：1-(2-环己基吡咯烷-1-基)-2,2-二甲基丁-1-酮的制备
根据化合物1概述的步骤，由2-环己基吡咯烷(70mg)和2,2-二甲基丁酰氯(73mg)制备标题化合物5，产率为46％。1HNMR(CDCl3,400MHz):δ4.13-4.18(m,1H),3.74-3.80(m,1H),3.27-3.33(m,1H),1.87-2.00(m,5H),1.65-1.82(m,6H),1.53-1.60(m,2H),1.22(s,6H),0.92-1.18(m,4H),0.87(t,3H,J＝7.6Hz).
LC-MS(ESI)[M+H]+计算值C16H29NO,252.2；测得值252.4.
化合物6：2,2-二甲基-1-(2-苯基恶唑烷-3-基)丁-1-酮的制备
根据化合物1概述的步骤，由2-苯基恶唑烷(80mg)和2,2-二甲基丁酰氯(108mg)制备标题化合物6，产率为46％。1HNMR(CDCl3,400MHz):δ7.87-7.90(m,2H),7.61-7.66(m,1H),7.52-7.56(m,2H),6.14(brs,1H),3.72(t,2H,J＝4.8Hz),3.43(dd,2H,J＝10.0,5.6Hz),1.55(q,2H,J＝7.6Hz),1.16(s,6H),0.85(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C15H21NO2,248.2；测得值,248.4.
化合物7：(S)-2,2-二甲基-1-(4-苯基恶唑烷-3-基)丁-1-酮的制备
根据化合物1概述的步骤，从(S)-4-苯基恶唑烷(57mg)和2,2-二甲基丁酰氯(102mg)制备标题化合物7，产率为46％。1HNMR(CDCl3,400MHz):δ7.30-7.34(m,2H),7.23-7.26(m,3H),5.29(dd,2H,J＝10.4,4.4Hz),5.21(dd,1H,J＝6.4,4.4Hz),4.23(dd,1H,J＝8.8,6.4Hz),3.88(dd,1H,J＝8.8,4.4Hz),1.53-1.59(m,2H),1.17(s,3Hz),1.16(s,3H),0.81(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C15H21NO2,248.2；测得值,248.4.
化合物8：(R)-2,2-二甲基-1-(4-苯基恶唑烷-3-基)丁-1-酮的制备
根据化合物1概述的步骤，从(R)-4-苯基恶唑烷(80mg)和2,2-二甲基丁酰氯(86mg)制备标题化合物8，产率为46％。1HNMR(CDCl3,400MHz):7.40-7.42(m,2H),7.30-7.33(m,3H),5.29(dd,2H,J＝4.4,10.4Hz),5.21(dd,1H,J＝4.0,6.4Hz),4.23(dd,1H,J＝8.4,6.4Hz),3.87(dd,1H J＝4.0,8.4Hz),1.53-1.60(m,2H),1.15(s,3H),1.17(s,3H),0.811(t,3H,J＝7.2Hz).LC-MS(ESI)[M+H]+计算值C15H21NO2,248.2；测得值248.4.
化合物9：1-(2-(3-氟苯基)吡咯烷-1-基)-2,2-二甲基丁-1-酮的制备
根据化合物1概述的步骤，从2-(3-氟苯基)吡咯烷(95mg)和2,2-二甲基丁酰氯(93mg)制备标题化合物9，产率66％。1HNMR(CDCl3,400MHz):δ7.21-7.25(m,1H),6.80-6.94(m,3H),5.22(m,1H),3.82(t,2H,J＝6.8Hz),2.17-2.26(m,1H),1.87-2.01(m,2H),1.70-1.78(m,1H),1.59-1.69(m,2H),1.24(s,3H),1.21(s,3H),0.86(t,3H,J＝7.2Hz).LC-MS(ESI)[M+H]+计算值C16H22FNO,264.2；测得值,264.4.
化合物10：2,2-二甲基-1-(2-(2,3,5-三氟苯基)吡咯烷-1-基)丁-1-酮的制备
根据化合物1概述的步骤，从2-(2,3,5-三氟苯基)吡咯烷(50mg)和2,2-二甲基丁酰氯(34mg)制备标题化合物10，产率66％。1HNMR(CDCl3,400MHz):δ6.66-6.71(m,1H),6.44-6.46(m,1H),5.43-5.46(m,1H),3.79-3.86(m,2H),2.21-2.26(m,1H),1.90-1.98(m,2H),1.69-1.77(m,1H),1.61-1.68(m,2H),1.26(s,3H),1.23(s,3H),0.89(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C16H20F3NO,300.1；测得值,300.4.
化合物11:2,2-二甲基-1-(2-苯基哌啶-1-基)丁-1-酮的制备
根据化合物1概述的步骤，从2-苯基哌啶(50mg)和2,2-二甲基丁酰氯(50mg)制备标题化合物11，产率53％。1HNMR(CDCl3,400MHz):δ7.32-7.36(m,2H),7.22-7.24(m,3H),5.98(m,1H),4.09(m,1H),2.90(m,1H),2.42(d,1H,J＝14Hz),1.83-1.91(m,1H),1.65-1.71(m,4H),1.51-1.61(m,2H),1.32(s,3H),1.29(s,3H),0.98(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C17H25NO,260.2；测得值260.4.
化合物12：2,2-二甲基-1-(3-苯基吗啉)丁-1-酮的制备
根据化合物1概述的步骤，由3-苯基吗啉(25mg)和2,2-二甲基丁酰氯(23mg)制备标题化合物12，产率为20％。1HNMR(CDCl3,400MHz):δ7.47-7.52(m,2H),7.32-7.36(m,2H),7.25-7.28(m,1H),5.54-5.76(m,1H),4.50(d,1H,J＝12.0Hz),3.83-3.91(m,3H),3.56-3.62(td,1H,J＝2.4,12.0Hz),3.27-3.31(m,1H),1.59(q,2H,J＝7.6Hz),1.26(s,6H),0.90(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C16H23NO2,262.2；测得值,262.4.
化合物13：1–((2S,4S)-4-羟基-2-苯基吡咯烷-1-基)-2,2-二甲基丁-1-酮的制备
将(2S,4S)-4–((叔丁基二甲基甲硅烷基)氧基)2-苯基吡咯烷(185mg)和三甲胺(0.18ml)溶于2mL无水二氯甲烷中。将混合物冷却至0℃，加入2,2-二甲基丁酰氯(134mg)，然后温热至室温并搅拌16小时。混合物用二氯甲烷和水稀释。水层用二氯甲烷萃取。合并有机层并浓缩。残余物通过柱色谱纯化，得到1–((S,4S)-4–((叔丁基二甲基甲硅烷基)氧基)-2-苯基吡咯烷-1-基)-2,2-二甲基丁-1-酮(130mg，52％)。1H-NMR(CDCl3):7.11-7.29(M,5H),5.10-5.20(m,1H),4.31-4.37(m,1H),4.12(dd,J＝6.0,10.4Hz),3.62(dd,J＝6.4,10.4Hz),2.46-2.52(m,1H),1.80-1.84(m,1H),1.57-1.72(m,2H),1.24(s,3H),1.22(s,3H),0.84-0.87(m,12H),0.09(s,3H),0.01(s,3H).
将上述中间体(50mg)溶于THF(4ml)中，加入TBAF(42mg)。将混合物在室温下搅拌16小时，用二氯甲烷和水稀释。水层用二氯甲烷萃取，合并有机层并浓缩。残余物通过柱色谱纯化，得到化合物13(20mg，57％)，为白色固体。1H-NMR(CDCl3):δ7.28-7.32(m,2H),7.17-7.24(m,3H),5.24-5.32(m,1H),4.45-4.51(m,1H),4.15(dd,1H,J＝5.6,11.2Hz),3.76(dd,1H,J＝4.4,11.2Hz),2.50-2.57(m,1H),1.90-1.95(m,1H),1.60-1.69(m,2H),1.25(s,3H),1.21(s,3H),0.86(t,3H,J＝7.6Hz).MS(ES)[M+H]+计算值C16H23NO2,262.2；测得值,262.2.
化合物14：1-(3,3-二氟-2-苯基氮杂环丁烷-1-基)-2,2-二甲基丁-1-酮的制备
根据化合物1概述的步骤，由3,3-二氟-2-苯基氮杂环丁烷(25mg)和2,2-二甲基丁酰氯(40mg)制备标题化合物14，产率为46％。1H NMR(CDCl3,400MHz):δ7.34-7.42(m,3H),7.27-7.29(m,2H),5.60-5.66(m,1H),4.54-4.69(m,2H),1.60(q,2H,J＝7.6Hz),1.17(s,3Hz),1.15(s,3Hz),0.89(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C15H19F2NO,268.1；测得值,268.1.
化合物15：1-((2S,4R)-4-羟基-2-苯基吡咯烷-1-基)-2,2-二甲基丁-1-酮的制备
向化合物(30mg)的无水DCM(4ml)溶液中加入4-甲苯磺酰氯(27mg)，将混合物在室温下搅拌16h，用水(2mL)淬灭。水层用DCM(15mL×3)萃取，合并有机层，用盐水洗涤，用Na2SO4干燥并蒸发至干。残余物通过色谱法纯化，得到白色固体状的(3S，5S)-1-(2,2-二甲基丁酰基)-5-苯基吡咯烷-3-基4-甲基苯磺酸酯(38.1mg，80％)。1H NMR:(CDCl3,400M Hz):δ7.55(d,2H,J＝8.0Hz),7.20-7.26(m,3H),7.08-7.18(m,3H),5.18-5.21(m,1H),5.06-5.11(m,1H),4.13-4.18(m,1H),3.90-3.94(m,1H),2.42(s,3H),2.40-2.47(m,1H),1.95-1.99(m,1H)1.51-1.60(m,2H),1.14(s,3H),1.16(s,3H),0.79(t,3H,J＝7.6Hz).将上述中间体溶于无水DMSO(2mL)中，加入乙酸钠三水合物(12mg)。将混合物在120℃下搅拌60小时，加入4ml水。水层用DCM(15mL×3)萃取，有机层合并，用盐水洗涤，蒸发至干。残余物通过柱色谱纯化，得到(3R，5S)-1-(2,2-二甲基丁酰基)-5-苯基吡咯烷-3-基乙酸酯(13mg，47％)。1H NMR:(CDCl3,400M Hz):δ7.27-7.31(m,2H),7.16-7.22(m,3H),5.27-5.32(m,2H),5.12(d,2H,J＝12.0Hz),3.91(dd,1H,J＝4.0,12.0Hz),2.42-2.49(m,1H),2.06(s,3H),1.52-1.61(m,2H),1.22(s,3H),1.19(s,3H),0.84(t,3H,J＝7.6Hz).
将上述中间体(13mg)溶于THF(1mL)中，加入MeOH(0.2mL)和0.01mL 1NNaOH。将混合物在0℃下搅拌1小时，并用1N HCl中和。水层用DCM萃取，合并有机层并蒸发至干。残余物通过制备高效色谱纯化，得到标题化合物15(4mg，36％)。1H NMR:(CDCl3,400M Hz):δ7.27-7.36(m,2H),7.13-7.21(m,3H),5.32(t,1H,J＝7.6Hz),4.53-4.57(m,1H),3.88-3.96(m,2H),2.27-2.34(m,1H),1.94-2.02(m,1H),1.64-1.75(m,2H),1.23(s,3H),1.21(s,3H),0.86(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C16H23NO2,262.2；测得值,262.2
化合物16：1-(3-羟基-2-苯基氮杂环丁烷-1-基)-2,2-二甲基丁-1-酮的制备
向2-苯基氮杂环丁烷-3-醇(27mg)的THF(2ml)和水(2ml)溶液中加入饱和NaHCO3水溶液(0.5ml)。将混合物在室温下搅拌30分钟，并冷却至0℃，向混合物中加入2,2-二甲基丁酰氯(37mg)并搅拌过夜。混合物用DCM萃取，合并的有机层用水洗涤并浓缩。粗产物通过制备高效液相色谱纯化，得到化合物16(5mg，12％)，为白色固体。1H NMR:(CDCl3,400M Hz):δ7.29-7.44(m,5H),5.62-5.64(m,1H),4.73-4.78(m,1H),4.63-4.69(m,1H),4.11-4.24(m,1H),1.60(q,2H,J＝7.6Hz),1.20(s,6H),0.89(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C15H21NO2,248.2,测得值,248.4
化合物17：2,2-二甲基-1-(2-苯基哌嗪-1-基)丁-1-酮的制备
将4-(2,2-二甲基丁酰基)-3-苯基哌嗪-1-甲酸叔丁酯(0.8g)溶于3ml EtOAc中，然后加入4N HCl的EtOAc(10ml)溶液。将混合物在室温下搅拌3小时。除去溶剂后，残余物用石油醚洗涤，得到化合物150的(0.45g，68％)，为盐酸盐。1HNMR(CD3OD,400MHz):δ7.43-7.47(m,2H),7.29-7.36(m,3H),5.93-5.99(m,1H),4.54(d,1H,J＝14.8Hz),4.14(d,1H,J＝13.6Hz),3.41-3.48(m,2H),3.26-3.29(m,1H),3.13-3.21(m,1H),1.69-1.79(m,2H),1.32(s,3H),1.29(s,3H),0.96(t,3H,J＝7.2Hz).LC-MS(ESI)[M+H]+计算值C16H24N2O,261.2；测得值,261.4.
化合物18：1-(4-乙酰基-2-苯基哌嗪-1-基)-2,2-二甲基丁-1-酮的制备
根据化合物1概述的步骤，由化合物17(20mg)和乙酰氯(6.4mg)，制备标题化合物18，收率为52％。1HNMR(CDCl3,400MHz):δ1H-NMR(CDCl3)δ7.27-7.35(m,5H),5.75-5.77(m,1H),4.27-4.30(m,1H),4.11-4.21(m,2H),3.58-3.64(m,2H),3.23-3.30(m,1H),2.03(s,3H),1.61-1.66(m,2H),1.29(s,3H),1.28(s,3H),0.95(t,3H,J＝8.0Hz).LC-MS(ESI)[M+H]+计算值C18H26N2O2,303.2；测得值,303.4.
化合物19：4-(2,2-二甲基丁酰基)-3-苯基哌嗪-1-甲酸叔丁酯的制备
根据化合物1概述的步骤，由3-苯基哌嗪-1-甲酸叔丁酯(500mg)和2,2-二甲基丁酰氯(282mg)制备标题化合物19，产率为90％。1HNMR(CDCl3,400MHz):δ7.31-7.34(m,4H),7.22-7.25(m,1H),5.76-5.86(m,1H),4.55-4.70(m,1H),3.75-4.15(m,2H),2.80-3.30(m,3H),1.68(q,2H,J＝7.6Hz),1.47(s,9H),1.30(s,3H),1.29(s,3H),0.95(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C21H32N2O3,361.2；测得值361.4.
化合物20：2,2-二甲基-1-(5-苯基-4,5-二氢-1H-吡唑-1-基)丁-1-酮的制备
根据化合物1概述的步骤，由5-苯基-4,5-二氢-1H-吡唑(60mg)和2,2-二甲基丁酰氯(56mg)制备标题化合物20，收率为46％。1HNMR(CDCl3,400MHz):δ7.27-7.32(m,2H),7.20-7.24(m,1H),7.14-7.17(m,2H),6.90(t,1H,J＝1.6Hz),5.38(dd,1H,J＝12.0,4.8Hz),3.30(ddd,1H,J＝18.0,12.0,1.6Hz),2.68(ddd,1H,J＝18.0,4.8,1.6Hz),1.83(qd,2H,J＝7.6,3.2Hz),1.27(s,3H,),1.25(s,3H,)0.78(t,3H,J＝7.2Hz).LC-MS(ESI)[M+H]+计算值C15H20N2O,245.2；测得值,245.2。
化合物21：2,2-二甲基-1-(5-苯基吡唑烷-1-基)丁-1-酮的制备
在0℃下，在氮气下向化合物20(40mg)的无水四氢呋喃(5ml)溶液中逐滴加入三乙基硼氢化锂(1M的四氢呋喃)溶液。将混合物在0℃下搅拌2小时，用2M氢氧化钠(2ml)淬灭。将溶剂蒸发至干，残余物用二氯甲烷萃取。萃取液用2M氢氧化钠溶液洗涤并浓缩。残余物通过柱色谱法纯化，得到化合物21(23mg，56％)。1H NMR(CDCl3,400M Hz):δ7.27-7.35(m,4H),7.22-7.26(m,1H),5.39-5.43(m,1H),3.34-3.38(m,1H),2.71-2.77(m,1H),2.01-2.10(m,1H),1.72-1.80(m,1H),1.50-1.55(m,2H),1.22(s,3Hz),1.24(s,3Hz),0.84(t,3H,J＝7.2Hz).LC-MS(ESI)[M+H]+计算值C15H22N2O,247.1；测得值,247.1.
化合物22：2,2-二甲基-1-(2-甲基-5-苯基吡唑烷-1-基)丁-1-酮的制备
化合物21(10mg)，碳酸铯(26.5mg)和碘甲烷(11.5mg)在N，N-二甲基甲酰胺(1ml)中置于Biotage Initiator微波合成仪中，其被编程加热到110℃，搅拌90min。然后将混合物真空浓缩。残余物通过硅胶快速色谱法纯化，得到化合物156(4mg，38％)。1HNMR(CDCl3,400M Hz):δ7.25-7.32(m,4H),7.18-7.22(m,1H),5.38(t,1H,J＝8.8Hz),2.94-3.05(m,2H),2.58-2.65(m,1H),2.56(s,3H),2.32-2.38(m,1H),1.76-1.89(m,2H),1.30(s,3H),1.28(s,3H),0.92(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C16H24N2O,261.2；测得值261.2.
化合物23：(R)-3-(2,2-二甲基丁酰基)-4-苯基恶唑烷-2-酮的制备
在0℃和氮气下将n-BuLi(2.4M，在THF中，0.214mL，0.51mmol)缓慢加入到(R)-4-苯基恶唑烷-2-酮(80mg，0.49mmol)的2mL THF溶液中，在0℃下搅拌50分钟。然后在0℃下将2,2-二甲基丁酰氯(78.9mg，0.59mmol)缓慢加入溶液中。将混合物在室温下搅拌3.5小时，用饱和NH4Cl水溶液淬灭。水层用EtOAc(5mL×3)萃取。合并的有机层用水和盐水洗涤，用Na2SO4干燥，过滤并浓缩。残余物在-20℃下用石油醚结晶，得到31mg化合物23，为白色固体(产率＝24.2％)。1H NMR(CDCl3,400MHz):δ(ppm)7.29-7.40(m,5H),5.48(dd,1H,J＝4.8,8.4Hz),4.67(t,1H,J＝8.4Hz),4.23(dd,1H,J＝4.8,8.4Hz),1.77-1.95(m,2H),1.31(s,3H),1.29(s,3H),0.70(t,3H,J＝7.2Hz).LC-MS(ESI)[M+H]+计算值C15H19NO3,262.1；测得值262.2.
化合物24：(S)-1-(2,2-二甲基丁酰基)-4-苯基氮杂环丁烷-2-酮的制备
将(S)-4-苯基氮杂环丁-2-酮(60mg，0.41mmol)和三乙胺(189.5mg，1.9mmol)溶于2mL无水二氯甲烷中。将混合物冷却至0℃，加入2,2-二甲基丁酰氯(60.1mg，0.448mmol)，然后温热至室温并搅拌16小时。混合物用水稀释，水层用二氯甲烷萃取。萃取液用盐水洗涤，用Na2SO4干燥，过滤并浓缩。残余物通过柱色谱法(乙酸乙酯/石油醚＝1/5)纯化，得到无色油状化合物24(50mg，50％).1H NMR(CDCl3,400M Hz):δ(ppm)7.34-7.38(m,2H),7.29-7.33(m,3H),4.94(dd,1H,J＝3.2Hz,J＝6.8Hz),3.38(dd,1H,J＝6.8Hz,J＝16.4Hz),2.84(dd,1H,J＝3.2Hz,J＝16.4Hz),1.84(q,2H,J＝7.6Hz),1.26(s,6H),0.80(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C15H19NO2,246.1；测得值246.2。
化合物25：4-(3-叠氮基苯基)-1-(2,2-二甲基丁酰基)氮杂环丁烷-2-酮的制备
在0℃，将1-叠氮基-3-乙烯基苯(200mg)的无水甲苯(3ml)溶液滴加到搅拌着的氯代磺酰基异氰酸酯(119ul)的无水甲苯(3ml)溶液中。将混合物在室温下搅拌8小时，然后静置过夜。将溶液滴加到剧烈搅拌的亚硫酸钠(87mg)和碳酸钠(73mg)的水(1ml)溶液中。分离层，水层用甲苯萃取。将合并的有机层用Na2SO4干燥，过滤并浓缩，残余物用***洗涤，得到4-(3-叠氮基苯基)氮杂环丁-2-酮(100mg)。1H NMR(CDCl3,400MHz):7.36(t,J＝7.76Hz,1H),7.11-7.17(m,1H),6.18-7.01(m,2H),4.72(dd,J＝2.4,5.2Hz,1H),3.43-3.49(m,1H),2.84-2.88(m,1H).
将上述中间体(30mg)和三乙胺(27uL)溶于二氯甲烷(4mL)中。将混合物冷却至0℃，加入2,2-二甲基丁酰氯(26mg)。将混合物温热至室温并搅拌2小时，并用水稀释。水层用二氯甲烷萃取。将合并的有机层用水和盐水洗涤，用Na2SO4干燥并浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/石油醚＝1/4)纯化，得到所需产物25(35mg，48％)，为白色固体。.1H NMR(CDCl3,400M Hz):δ7.33-7.37(m,1H),7.06-7.09(m,1H),6.93-6.99(m,2H),4.92(dd,1H,J＝3.2,6.4Hz),3.39(dd,1H,J＝6.4,16.4Hz),2.81(dd,1H,J＝3.2,16.4Hz),1.846(qd,2H,J＝1.2,7.6Hz),1.27(s,3H),1.26(s,3H),0.82(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C15H18N4O2,287.1；测得值,287.2.
化合物26：4-(3-溴苯基)-1-(2,2-二甲基丁酰基)氮杂环丁烷-2-酮的制备
根据化合物25概述的步骤，由4-(3-溴苯基)氮杂环丁烷-2-酮(200mg)和2,2-二甲基丁酰氯(147mg)，制备标题化合物26，收率为51％。1H NMR(CDCl3,400M Hz):δ7.41-7.47(m,2H),7.23-7.24(m,2H),4.89(dd,1H,J＝3.6,6.4Hz),3.39(dd,1H,J＝6.4,16.4Hz),2.81(dd,1H,J＝3.6,16.4Hz),1.84(q,2H,J＝7.2Hz),1.26(s,6H),0.82(t,3H,J＝7.2Hz).LC-MS(ESI)[M+H]+计算值C15H18BrNO2,324.1；测得值324.2,326.2.
化合物172：1-(2,2-二甲基丁酰基)-4-(3-乙炔基苯基)氮杂环丁烷-2-酮的制备
向化合物26(165mg)和三苯基膦(13mg)的无水三乙胺(4ml)溶液中加入乙炔基三甲基硅烷(87ul)和乙酸钯(6mg)。将混合物加热回流4小时，冷却至室温并过滤。将滤液真空浓缩至稠油状物，通过柱色谱法(乙酸乙酯/石油＝1/10)纯化，得到1-(2,2-二甲基丁酰基)-4-(3-((三甲基甲硅烷基)乙炔基)苯基)氮杂环丁烷-2-酮(140mg，80％)，为黄色固体。1H NMR(CDCl3,400M Hz):7.38-7.42(m,2H),7.22-7.31(m,2H),4.90(dd,J＝3.2,6.8Hz,1H),3.37(dd,J＝6.8,16.4Hz,1H),2.82(dd,J＝3.2,16.4Hz,1H),1.95-1.73(m,2H),1.26(s,6H),0.81(t,J＝7.6Hz,3H),0.24(s,9H).
将上述中间体(60mg)溶于四氢呋喃(3ml)中，然后在0℃下将四丁基氟化铵(51mg)加入到该溶液中。将混合物在0℃下搅拌3小时。反应完成后，加入水(3ml)，用CH2Cl2萃取。将合并的有机层用水和盐水洗涤，用Na2SO4干燥并浓缩。残余物通过硅胶柱色谱纯化，得到化合物27(11mg，23％)。1H NMR(CDCl3,400M Hz):δ7.42-7.44(m,2H),7.28-7.34(m,2H),4.91(dd,1H,J＝3.2,6.4Hz),3.39(dd,1H,J＝6.4,16.4Hz),3.08(s,1H),2.82(dd,1H,J＝3.2,16.4Hz),1.84(q,2H,J＝7.2Hz),1.26(s,6H),0.81(t,3H,J＝7.2Hz).MS(ES)[M+H]+计算值C17H19NO2,270.1；测得值,270.3.
化合物28：1-(2,2-二甲基丁酰基)-4-(3-硝基苯基)氮杂环丁-2-酮的制备
根据化合物25概述的步骤，由4-(3-硝基苯基)氮杂环丁烷-2-酮(10mg)(根据化合物170概述的步骤，由1-硝基-3-乙烯基苯(200mg)和氯磺酰基异氰酸酯(116ul)制备得到)和2,2-二甲基丁酰氯(179mg)，制备标题化合物28，收率为25％。1H NMR(CDCl3,400M Hz):δ8.18-8.20(m,2H),7.64-7.66(m,1H),7.55-7.59(m,1H),5.04(q,1H,J＝3.6,6.4Hz),3.48(dd,1H,J＝6.4,16.4Hz),2.87(dd,1H,J＝3.6,16.4Hz),1.82-1.89(m,2H),1.27(s,6H),0.82(t,3H,J＝7.6Hz).MS(ES)[M+H]+计算值C15H18N2O4,290；测得值,291.
化合物29：1-(2,2-二甲基丁酰基)-5-苯基吡咯烷-2-酮的制备
根据化合物1概述的步骤，由5-苯基吡咯烷-2-酮(50mg)和2,2-二甲基丁酰氯(50mg)，制备标题化合物29，收率为38％。1HNMR(CDCl3,400MHz):δ7.27-7.35(m,2H),7.20-7.25(m,3H),5.379(dd,1H,J＝4.4Hz,J＝8.0Hz),2.70-2.79(m,1H),2.42-2.60(m,2H),1.87-2.00(m,2H),1.64-1.73(m,1H),1.30(s,3H),1.24(s,3H),0.68(t,3H,J＝7.6Hz).MS(ES)[M+H]+计算值C16H21NO2,260.2；测得值,260.3.
化合物30：(R)-3-(2,2-二甲基丁酰基)-4-苯基-1-(丙-2-炔-1-基)咪唑烷-2-酮的制备
根据化合物53概述的步骤，由((R)-2-((叔丁氧基羰基)氨基)-2-苯基乙酸和丙-2-炔-1-胺制备(R)-(2-氧代-1-苯基-2-(丙-2-炔-1-基氨基)乙基)氨基甲酸叔丁酯。1HNMR(CDCl3,400M Hz):δ7.32-7.36(m,5H),6.03(brs,1H),5.73(brs,1H),5.15(brs,1H),3.93-4.12(m,2H),2.20(t,J＝2.8Hz),1.41(s,9H)。
将上述化合物(500mg)溶于CH2Cl2(8ml)中，加入TFA(2ml)。将混合物搅拌4小时并浓缩。标准处理后，将得到的粗产物：(R)-2-氨基-2-苯基-N-(丙-2-炔-1-基)乙酰胺(240mg)加入到氢化铝锂(194mg)在THF(5ml)中的溶液中，并搅拌1小时，然后将混合物回流2小时，依次加入0.2ml水，0.2ml 15％NaOH和0.2ml水，过滤并蒸发。所得黄色液体(130mg)不经进一步纯化用于下一步骤。
将上述化合物：(R)-1-苯基-N2-(丙-2-炔-1-基)乙烷-1,2-二胺(130mg)和三乙胺(0.5ml)溶于无水THF(30ml)中，在0℃下加入光气(118mg)，搅拌过夜。混合物用二氯甲烷和水稀释。水层用二氯甲烷萃取。将合并的有机层用水和盐水洗涤，干燥(Na2SO4)并真空浓缩。残余物通过柱色谱纯化，得到150mg(R)-4-苯基-1-(丙-2-炔-1-基)咪唑烷-2-酮。
将上述中间体(150mg)和三乙胺(0.16ml)溶于无水二氯甲烷(2ml)中。将混合物冷却至0℃，加入2,2-二甲基丁酰氯(120mg)，然后温热至室温并搅拌16小时。混合物用二氯甲烷和水稀释。水层用二氯甲烷萃取。合并有机层并浓缩。残余物通过柱色谱纯化，得到化合物30(50mg，总产率10％)，为无色油状物。1H NMR(CDCl3,400M Hz):δ7.27-7.35(m,5H),5.37(dd,1H,J＝3.6,9.2Hz),4.12-4.13(m,2H),3.91(t,1H,J＝9.2Hz),3.32(dd,1H,J＝3.6,9.2Hz),2.27(t,1H,J＝2.4Hz),1.89(dq,2H,J＝1.6,7.6Hz),1.28(s,3H),1.29(s,3H),0.70(t,3H,J＝7.6Hz).MS(ES)[M+H]+计算值C18H22N2O2,299.2；测得值,299.3.
化合物31:(R)-3-(2,2-二甲基丁酰基)-1-甲基-4-苯基咪唑烷-2-酮的制备
根据化合物1概述的步骤，由(R)-3-(2,2-二甲基丁酰基)-1-甲基-4-苯基咪唑烷-2-酮(50mg)和2,2-二甲基丁酰氯(45mg)，制备标题化合物31。1H NMR(CDCl3,400M Hz):δ7.31-7.35(m,2H),7.24-7.30(m,3H),5.33(dd,1H,J＝4.0,9.2Hz),3.813(t,1H,J＝9.2Hz),3.20(dd,1H,J＝4.0,9.2Hz),2.900(s,3H),1.92(m,2H),1.31(s,3H),1.29(s,3H),0.73(t,3H,J＝7.2Hz).MS(ES)[M+H]+计算值C16H22N2O2,275.2；测得值275.4.
化合物32：1-(2,2-二甲基丁酰)-3,3-二氟-4-苯基氮杂环丁-2-酮的制备
根据化合物1概述的步骤，由3,3-二氟-4-苯基氮杂环丁烷-2-酮(30mg)和2,2-二甲基丁酰氯(44mg)制备标题化合物32，收率为60％。1H NMR(CDCl3,400M Hz):δ7.39-7.43(m,3H),7.24-7.27(m,2H),5.35(dd,1H,J＝3.2,10.4Hz),1.79-1.92(m,2H),1.32(s,3H),1.30(s,3H),0.86(t,3H,J＝7.6Hz).MS(ES)[M+H]+计算值C15H17F2NO2,282.1；测得值,282.3.
化合物33：2-(2,2-二甲基丁酸)-1-苯基吡唑烷-3-酮的制备
根据化合物1概述的步骤，由苯基吡唑烷-3-酮(50mg)和2,2-甲基丁酰氯(50mg)制备标题化合物33，产率为25％。1HNMR(CDCl3,400MHz):δ7.19-7.35(m,2H),6.97-7.07(m,2H),6.85(t,1H,J＝8.0Hz),3.916(t,2H,J＝8.0Hz),3.14(t,2H,J＝8.0Hz),1.69(q,2H,J＝7.6Hz),1.28(s,6H),0.93(t,3H,J＝7.6Hz).MS(ES)[M+H]+计算值C15H20N2O2,261.2；测得值,261.3.
化合物34：1-(2,2-二甲基丁酸)-5-苯基吡唑烷-3-酮的制备
在0℃和氮气下，向5-苯基吡唑烷-3-酮(65mg)和三乙胺(0.066ml)的无水四氢呋喃(4ml)溶液中缓慢加入2,2-二甲基丁酰氯(0.06ml)。然后将混合物温热至室温并搅拌2小时。混合物用水稀释，水层用二氯甲烷萃取。将合并的有机层用盐水洗涤，干燥(Na2SO4)并浓缩。残余物通过柱色谱法(乙酸乙酯/石油醚＝1/3)纯化，得到1,1'-(3-氧代-5-苯基吡唑烷-1,2-二基)双(2,2-二甲基丁烷-1-酮)(50mg，34％)，为白色固体。
将上述中间体(10mg)溶于四氢呋喃(1ml)中，加入1M氢氧化钠(0.05ml)。将混合物搅拌2小时，用二氯甲烷和水稀释。水层用二氯甲烷萃取。将合并的有机物用盐水洗涤，用Na2SO4干燥并浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/石油醚＝1/2)纯化，得到化合物34(5.1mg，69％)，为白色固体。1H NMR(CDCl3,400M Hz):δ7.28-7.40(m,5H),5.82(d,1H,J＝9.6Hz),3.34(dd,1H,J＝9.6,16.4Hz),2.60(d,1H,J＝16.4Hz),1.57(q,2H,J＝7.6Hz),1.17(s,3H),1.14(s,3H),0.81(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C15H20N2O2,261.2；测得值,261.3.
化合物35：(2-(3-氟苯基)吡咯烷-1-基)(1-(三氟甲基)环戊基)甲酮的制备
2-(3-氟苯基)吡咯烷(9mg)，其根据文献报道的步骤制备，和1-(三氟甲基)环戊烷甲酸(10mg)溶于无水DMF(1ml)中。向该溶液中加入2-(7-氮杂-1H-苯并***-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(31mg)和N，N-二异丙基乙胺(14mg)。将混合物在室温下搅拌16小时。在减压下除去溶剂，残余物通过柱色谱纯化，得到所需产物35(8mg，44.2％)。1H NMR:(CDCl3,400M Hz):δ7.24-7.28(m,1H),6.87-6.92(m,2H),6.79-6.82(m,1H),5.16-5.19(m,1H),3.90-3.96(m,1H),3.73-3.79(m,1H),2.46-2.50(m,1H),2.28-2.36(m,2H),2.09-2.19(m,2H),1.95-2.06(m,1H),1.83-1.93(m,1H),1.64-1.78(m,5H).LC-MS(ESI)[M+H]+计算值C17H19F4NO,330.1；测得值330.3。
化合物36：(2-(3-氯苯基)吡咯烷-1-基)(1-(三氟甲基)环丁基)甲酮的制备
根据化合物35概述的步骤，由1-(三氟甲基)环丁烷甲酸(20mg)和2-(3-氟苯基)吡咯烷(19.6mg)制备标题化合物36，产率32％。1H NMR:(CDCl3,400MHz):δ7.23-7.29(m,1H),6.81-6.95(m,3H),5.13-5.16(m,1H),3.58-3.70(m,2H),2.71-2.82(m,1H),2.59-2.67(m,1H),2.41-2.56(m,2H),2.31-2.39(m,1H),2.08-2.18(m,1H),1.95－2.05(m,1H),1.76-1.92(m,3H).LC-MS(ESI)[M+H]+计算值C16H17F4NO,316.1；测得值316.3.
化合物37：金刚烷-1-基(2-(3-氟苯基)吡咯烷-1-基)甲酮的制备
根据化合物1概述的步骤，从2-(3-氟苯基)吡咯烷(60mg)和金刚烷-1-碳酰氯(81mg)制备标题化合物37，产率为46％。1HNMR(CDCl3,400MHz):δ7.21-7.26(m,1H),6.78-6.92(m,3H),5.25(m,1H),3.91(m,2H),2.17-2.26(m,1H),1.89-1.20(m,10H),1.71-1.76(m,8H).LC-MS(ESI)[M+H]+计算值C21H26FNO,328.2；测得值,328.4.
化合物38：(S)-1-(2,2-二甲基丁-3-烯酰基)-4-苯基氮杂环丁-2-酮的制备
根据化合物1的概述的步骤，由(S)-4-苯基氮杂环丁烷-2-酮(100mg)和2,2-二甲基丁-3-烯酰氯(107mg)，制备标题化合物38，产率为34％。1H NMR(CDCl3,400M Hz):δ7.27-7.39(m,5H),6.26(dd,1H,J＝10.8,17.2Hz),5.18(dd,1H,J＝0.8,10.8Hz),5.12(d,1H,J＝0.8,17.2Hz),4.94(dd,1H,J＝3.6,6.4Hz),3.39(dd,1H,J＝6.4,16.4Hz),2.82(dd,1H,J＝3.6,16.4Hz),1.41(s,3H),1.39(s,3H).LC-MS(ESI)[M+H]+计算值C15H17NO2,244.1；测得值,244.3。
化合物39：(R)-3-乙酰基-4-苯基恶唑烷-2-酮的制备
根据化合物1概述的步骤，从(R)-4-苯基恶唑烷-2-酮(80mg)和乙酰氯(46mg)制备标题化合物39，收率60％。1H NMR(CDCl3,400M Hz):δ7.29-7.41(m,5H),5.425(dd,1H,J＝3.6,8.8Hz),4.69(t,1H,J＝8.8Hz),4.29(dd,1H,J＝3.6,8.8Hz),1.53(s,3H).LC-MS(ESI)[M+H]+计算值C11H11NO3,206.1；测得值,206.2.
化合物40：(S)-1-(3-氯丙烯酰基)-4-苯基氮杂环丁-2-酮的制备
将(S)-4-苯基氮杂环丁烷-2-酮(40mg，0.272mmol)和DIEA(35.1mg，0.272mmol)在0.5mL CH2Cl2中的溶液缓慢加入到3-氯丙烯酰氯(37.1mg，0.299mmoL)和DIEA(38.6mg，0.299mmoL)在1.5mL CH2Cl2中的溶液中。将混合物在室温下搅拌16小时。除去溶剂后，得到的棕色残余物通过制备薄板层析纯化，得到0.4mg化合物40，为棕色油状物(收率＝0.6％)。1H NMR:(CDCl3,400M Hz)δ7.31-7.40(m,5H),7.14(d,1H,J＝8.0Hz),6.83(d,1H,J＝8.0Hz),5.11(dd,1H,J＝3.6,6.4Hz),3.53(dd,1H,J＝6.4,16.4Hz),3.03(dd,1H,J＝3.6,16.4Hz).LC-MS(ESI)[M+H]+计算值C12H10ClNO2,236.0；测得值,236.2.
化合物41：(4S)-1-(叔丁基亚磺酰基)-4-苯基氮杂环丁-2-酮的制备
在0℃下向(S)-4-苯基氮杂环丁烷-2-酮(50mg)和三乙胺(0.1mL)的无水THF(2mL)溶液中缓慢加入2-甲基丙烷-2-亚磺酰氯(50ul)氮。将混合物温热至室温并搅拌2小时。混合物用二氯甲烷和水稀释。水层用二氯甲烷萃取，合并的有机层用盐水洗涤，干燥(Na2SO4)并浓缩。残余物通过硅胶柱色谱法(乙酸乙酯/石油醚＝1/5)纯化，得到化合物167(20mg，24％)，为白色固体。1H NMR(CDCl3,400M Hz):δ7.33-7.46(m,5H),5.12(dd,1H,J＝3.6,6.8Hz),3.60(dd,1H,J＝16.0,6.8Hz),3.21(dd,1H,J＝16.0,3.6Hz),0.98(s,9H).LC-MS(ESI)[M+H]+计算值C13H17NO2S,252.1；测得值252.2.
化合物42：(S)-1-(异丙基磺酰基)-4-苯基氮杂环丁-2-酮的制备
根据化合物23概述的步骤，从(S)-4-苯基氮杂环丁烷-2-酮(50mg)和丙烷-2-磺酰氯(58mg)制备标题化合物42，产率为34％。1H NMR(CDCl3,400MHz):δ7.37-7.46(m,5H),5.20(dd,1H,J＝3.2,6.4Hz),3.61(dd,1H,J＝6.4,16.0Hz),3.17(dd,1H,J＝3.2,16.0Hz),2.93-3.00(m,1H),1.29(d,3H,J＝3.2Hz),1.27(d,3H,J＝3.2Hz).LC-MS(ESI)[M+H]+计算值C12H15NO3S,254.1；测得值254.2.
化合物43：(S)-1-(乙基磺酰基)-4-苯基氮杂环丁-2-酮的制备
根据化合物23概述的步骤，从(S)-4-苯基氮杂环丁烷-2-酮(50mg)和乙磺酰氯(52.5mg)制备标题化合物43，产率33％。1H NMR(CDCl3,400MHz):7.37-7.45(m,5H),5.19(dd,1H,J＝3.6,6.4Hz),3.61(dd,1H,J＝6.4,16.4Hz),3.16(dd,1H,J＝3.6,16.4Hz),2.80(q,2H,J＝7.2Hz),1.31(t,3H,J＝7.2Hz).LC-MS(ESI)[M+H]+计算值C11H13NO3S,240.1；测得值240.2
化合物44：4-(3-叠氮基苯基)-1-(2,2-二甲基丁-3-炔酰基)氮杂环丁-2-酮的制备
根据化合物24概述的步骤，从4-(3-叠氮基苯基)氮杂环丁烷-2-酮(50mg)(根据化合物25概述的步骤制备得到)和2,2-二甲基丁-3-炔酰氯(1.3g)，制备化合物44，产率为1.3％。1H NMR(CDCl3,400M Hz):δ7.34-7.38(m,1H),7.09-7.11(m,1H),6.97-7.00(m,2H),4.98(dd,1H,J＝3.2,6.8Hz),3.48(dd,1H,J＝6.8,16.4Hz),2.88(dd,1H,J＝3.2,16.4Hz),2.35(s,1H),1.59(s,3H),1.57(s,3H).MS(ES)[M+H]+计算值C15H14N4O2,283.1；测得值,283.3.
化合物45：(S)-1-(叔丁基磺酰基)-4-苯基氮杂环丁-2-酮的制备
向化合物41(9mg)的二氯甲烷(4ml)溶液中加入m-CPBA(12.3mg)。将混合物在室温下搅拌16小时，并用水稀释。水层用二氯甲烷萃取，合并的有机层用盐水洗涤，干燥(Na2SO4)并浓缩。通过制备薄板层析(乙酸乙酯/石油醚＝1/3)纯化残余物，得到化合物45(5mg，52％)，为白色固体。1H NMR(CDCl3,400M Hz):δ7.34-7.47(m,5H),5.24(dd,1H,J＝3.6,6.4Hz),3.61(dd,1H,J＝6.4,16.4Hz),3.238(dd,1H,J＝3.6,16.4Hz),1.20(s,9H).LC-MS(ESI)[M+H]+计算值C13H17NO3S,268.1；测得值268.2.
化合物46：
(S)-2,2-二甲基-1-(2-苯基氮杂环丁烷-1-基)丁-3-炔-1-酮的制备
根据化合物35概述的步骤，由(S)-2-苯基氮杂环丁烷(50mg)和2,2-二甲基丁-3-炔酸(69mg)制备化合物46，收率13％。1HNMR(CDCl3,400MHz):δ7.34-7.37(m,5H),5.35-5.39(dd,1H,J＝6.0,8.4Hz),4.56-4.66(m,2H),2.70-2.79(m,1H),2.40(s,1H),2.11-2.19(m,1H),1.47(s,3H),1.45(s,3H).MS(ES)[M+H]+计算值C15H17NO,228.1；测得值,228.1.
化合物47：(S)-1-(金刚烷-2-羰基)-4-苯基氮杂环丁-2-酮的制备
根据化合物24概述的步骤，由(S)-4-苯基氮杂环丁烷-2-酮(50mg)和金刚烷-2-碳酰氯(81mg)制备标题化合物47，产率为32％。1H NMR(CDCl3,400M Hz):δ7.27-7.38(m,5H),4.94(dd,1H,J＝3.2,6.8Hz),3.37(dd,1H,J＝6.8,16.4Hz),2.79(dd,1H,J＝3.2,16.4Hz),1.93-2.10(m,10H),1.72-1.79(m,5H).LC-MS(ESI)[M+H]+计算值C20H23NO2,310.2；测得值,310.3.
化合物48：(S)-1-乙基-4-苯基氮杂环丁-2-酮:的制备
(S)-4-苯基氮杂环丁-2-酮(15mg)溶解在2mL无水THF中，并在0℃和氮气下分批加入NaH(5mg，60％在原料油中)。在0℃下搅拌30分钟后，加入碘乙烷(17.5mg)。将混合物在室温下搅拌16小时，用1mL水淬灭并用EtOAc萃取。萃取液用盐水洗涤，用Na2SO4干燥，过滤并浓缩。残余物通过硅胶柱色谱纯化，得到2.6mg白色固体的化合物48，产率为14.6％。1H NMR:(CDCl3,400MHz):δ7.31-7.41(m,5H),4.56(dd,1H,J＝2.4,5.2Hz),3.43-3.52(m,1H),3.34(dd,1H,J＝5.2Hz,J＝14.4Hz),2.90-2.99(m,1H),2.81(dd,1H,J＝2.4Hz,14.4Hz),1.07(t,3H,J＝7.2Hz).[M+H]+计算值C11H13NO,176.1；测得值176.2.
化合物49：(S)-4-苯基-1-(丙-2-炔基)氮杂环丁烷-2-酮的制备
在0℃下,将(S)-4-苯基氮杂环丁烷-2-酮(30mg，0.204mmol)和3-碘丙-1-炔(26.8mg，0.227mmol)在2mL THF中的溶液滴加到KOH(13.7mg，0.245mmol)和四丁基溴化铵(26.8mg，0.227mmol)在2mL THF中的混合物中。将混合物在室温下搅拌16小时。过滤后，将滤液蒸发至干，通过制备薄层色谱板(乙酸乙酯/石油醚＝1/4)纯化棕色残余物，得到30mg淡黄色固体的化合物49(产率＝79.6％)。1H NMR(CDCl3,400M Hz):δ7.28-7.38(m,5H),6.70(t,1H,J＝6.4Hz),5.20(dd,1H,J＝6.4,10.8Hz),4.98(dd,1H,J＝6.4,10.8Hz),4.69(dd,1H,J＝2.8,5.6Hz),3.46(dd,1H,J＝5.6,14.8Hz),2.884(dd,1H,J＝2.8,14.8Hz).LC-MS(ESI)[M+H]+计算值C12H11NO,186.1；测得值186.2.
化合物50：(S)-1-(环丙基甲基)-4-苯基氮杂环丁-2-酮的制备
根据化合物48概述的步骤，从(S)-4-苯基氮杂环丁烷-2-酮(15mg)，(溴甲基)环丙烷(15mg)和NaH(4.5mg，60％在原料油中)，制备标题化合物50，产率为9.7％。1H NMR:(CDCl3,400M Hz):δ7.31-7.40(m,5H),4.67(dd,1H,J＝2.4,5.2Hz),3.43(dd,1H,J＝6.4,14.4Hz),3.38(dd,1H,J＝5.2,14.8Hz),2.82(dd,1H,J＝2.4,14.8Hz),2.57(dd,1H,J＝7.6,14.4Hz),0.82-0.88(m,1H),0.36-0.46(m,2H),0.01-0.07(m,2H).LC-MS(ESI)[M+H]+calcdforC13H15NO,202.1；测得值,202.2.
化合物51：(R)-3-乙基-4-苯基恶唑烷-2-酮的制备
在氮气下，将(R)-4-苯基恶唑烷-2-酮(50mg，0.31mmol)溶于2mL无水THF中，在0℃下分批加入NaH(15mg，0.38mmol，60％在原料油中)。在0℃下搅拌30分钟后，加入碘乙烷(57.4mg，0.37mmol)。将混合物在室温下搅拌16小时，用1mL水淬灭并用EtOAc萃取。萃取液用盐水洗涤，用Na2SO4干燥，过滤并浓缩。残余物通过硅胶柱色谱纯化，得到12mg化合物51，为白色固体，收率为20.5％。1H NMR:(CDCl3,400M Hz)δ7.38-7.44(m,3H),7.30-7.32(m,2H),4.80(dd,1H,J＝7.2,8.8Hz),4.61(t,1H,J＝8.8Hz),4.10(dd,1H,J＝7.2,8.8Hz),3.47-3.56(m,1H),2.80-2.89(m,1H),1.05(t,3H,J＝7.2Hz).MS(ES)[M+H]+计算值C11H13NO2,192.1；测得值192.2.
化合物52：(R)-4-苯基-3-(丙-2-炔-1-基)恶唑烷-2-酮的制备
根据化合物51概述的步骤，从(R)-4-苯基恶唑烷-2-酮(80mg)和3-溴丙-1-炔(116mg)制备标题化合物52，产率为46％。1HNMR(CDCl3,400MHz):δ7.37-7.46(m,3H),7.32-7.35(m,2H),4.96(t,1H,J＝8.4Hz),4.67(t,1H,J＝8.4Hz),4.41(dd,1H,J＝2.4,17.6Hz),4.16(dd,1H,J＝8.4,8.4Hz),3.39(dd,1H,J＝2.4,17.6Hz),2.25(t,1H,J＝2.4Hz).LC-MS(ESI)[M+H]+计算值C12H11NO2,202.1；测得值,202.2.
化合物53和54：
根据方案1中概述的步骤制备化合物53和54
方案1:试剂和条件:(a)Na/THF,-78℃(b)NaH,2,2-二甲基丁酰氯(对于53)或2,2-二甲基丁-3-烯酰氯(对于54),THF。.
化合物56和57：
根据方案2中概述的步骤制备化合物56和57
方案2:试剂和条件:(a)Pd/C,H2(b)NaH,2,2-二甲基丁酰氯(对于56)或2,2-二甲基丁-3-烯酰氯(化合物57),THF。
化合物55和58：
根据方案3中概述的步骤制备化合物55和58
方案3:试剂和条件:(a)NaH,2,2-二甲基丁酰氯(对于55)或2,2-二甲基丁-3-烯酰氯(对于58),THF。
化合物59-68：
根据方案4概述的步骤制备化合物59-68
方案4:试剂和条件:(a)LiAlH4,THF,回流(b)Et3N,2,2-二甲基丁酰氯(对59-61,65,67)或2,2-二甲基丁-3-烯酰氯(62-64,66,68)THF。
化合物69：
根据方案5概述的步骤制备化合物69
方案5:试剂和条件:(a)Et3N,2,2-二甲基丁-3-烯酰氯,THF。
化合物70：
根据方案6的步骤制备化合物70
方案6:试剂和条件:(a)LiAlH4,THF,回流(b)Et3N,2-甲基丁烷-2-磺酰氯,THF。
化合物72和73：
根据方案7的步骤制备化合物72和73
方案7:试剂和条件:(a)TFA/DCM(b)Et3N,2,2-二甲基丁酰氯(对72)，2,2-二甲基丁-3-烯酰氯(73)THF。
化合物74和75：
根据方案8的步骤制备化合物74和75
方案8:试剂和条件:(a)K2CO3,苯硫酚,DMF(b)Et3N,2,2-二甲基丁酰氯(对74)，2,2-二甲基丁-3-烯酰氯(对75)，THF。
化合物76和77：
根据方案9的方法制备化合物76和77
方案9:试剂和条件:(a)Et3N,2,2-二甲基丁酰氯(对76)或2,2-二甲基丁-3-烯酰氯(对77)，THF。
化合物78：2,2-二甲基-1-(2-苯基-1H-吡咯-1-基)丁-1-酮的制备
在氩气氛下向NaH(30mg，0.7mmol)在无水THF(3ml)中的搅拌悬浮液中加入2-苯基-1H-吡咯(50mg)的无水THF(1ml)溶液。在室温下搅拌5分钟后，停止释放氢气，加入2,2,2-二甲基丁酰氯(56mg)。将反应混合物在室温下搅拌1小时。将反应混合物倒入饱和NH4Cl水溶液中，用二氯甲烷萃取(3x10ml)。将合并的有机层用Na2SO4干燥并蒸发，得到所需产物(30mg，36％)。1HNMR(CDCl3,400MHz):δ7.45-7.47(m,2H),7.34-7.39(m,2H),7.18-7.23(m,1H),6.85-6.88(d,1H,J＝8.0Hz),6.51-6.54(m,1H),6.29-6.32(d,1H,J＝8.0Hz),1.39(q,2H,J＝7.6Hz),0.97(s,6H),0.86(t,3H,J＝7.6Hz).LC-MS(ESI)[M+H]+计算值C16H19NO,242.1；测得值,242.4.
化合物S1：1-((2R，3S)-3-羟基-2-苯基吡咯烷-1-基)-2,2-二甲基丁-1-酮(S1)的制备
根据先前描述的方法(US2009/0012120A1)(35mg)制备(2R，3S)-2-苯基-1-甲苯磺酰基吡咯烷-3-醇，并将苯酚(31mg)加入到4mL HBr(48％，w/w)。将混合物在100℃下搅拌12小时，然后冷却至室温，用***(2mL)萃取，弃去***层。将水溶液冷冻干燥，得到(2R，3S)-2-苯基吡咯烷-3-醇(30mg)，无需进一步纯化。
将上述溶解在2mL THF/H2O(1:1)中的氨基醇(30mg)和0.45mL饱和NaHCO3水溶液。将溶液冷却至0℃，加入2,2-二甲基丁酰氯(16mg)，将混合物在室温下搅拌12小时。混合物用EtOAc萃取，合并的有机层用盐水洗涤，干燥(Na2SO4)并真空浓缩。通过制备高效液相色谱进行纯化，得到化合物S1(15mg，两步收率52％)，为无色油状物。1H NMR(400MHz,CDCl3)δ7.30(t,J＝7.3Hz,2H),7.22(t,J＝7.0Hz,1H),7.12(d,J＝7.4Hz,2H),5.33(brs,1H),4.19(brs,1H),4.05-3.94(m,2H),2.05(brs,1H),1.91(brs,1H),1.73–1.60(m,2H),1.25(s,3H),1.20(s,3H),0.88(t,J＝6.8Hz,3H).LC-MS(ESI)[M+H]+计算值C16H24NO2,262.18；测得值,262.44.
化合物S2：1-((2R，3R)-3-羟基-2-苯基吡咯烷-1-基)-2,2-二甲基丁-1-酮的制备
向化合物S1(30mg)的无水DCM(4mL)溶液中加入4-甲苯磺酰氯(27mg)，将混合物在室温下搅拌16h，用水(2mL)淬灭。水层用DCM(15mL×3)萃取，合并有机层，用盐水洗涤，用Na2SO4干燥并蒸发至干。残余物通过柱色谱纯化，得到(2R，3S)-1-(2,2-二甲基丁酰基)-2-苯基吡咯烷-3-基-4-甲基苯磺酸酯(36mg，75％)。LC-MS(ESI)[M+H]+计算值C23H30NO4S，416.19；测得值，416.52。
将上述中间体溶于无水DMSO(2mL)中，并加入乙酸钠三水合物(12mg)。将混合物在100℃下搅拌60小时，加入4mL水。水层用DCM(15mL×3)萃取，合并有机层，用盐水洗涤，用Na2SO4干燥并蒸发至干。将残余物不经进一步纯化用于下一步骤。将上述中间体(15mg)溶于THF(1mL)和MeOH(0.2mL)中，加入0.01mL 1N NaOH。将混合物在0℃下搅拌1小时，并用1NHCl中和。水层用DCM萃取，合并有机层并蒸发至干。残余物通过制备薄板层析纯化，得到标题化合物S2(5mg，三步总产率17％)。1H NMR(400MHz,CDCl3)δ7.33(t,J＝7.2Hz,2H),7.27-7.24(m,1H),7.15(d,J＝7.8Hz,2H),5.18(d,J＝4.5Hz,1H),3.93(brs,2H),2.08(brs,1H),1.71(brs,1H),1.62-1.53(m,2H),1.19(s,6H),0.85(t,J＝6.8Hz,3H).LC-MS(ESI)[M+H]+计算值C16H24NO2,262.18；测得值,262.44.
化合物S3：(R)-1-(2,2-二甲基丁酰基)-2-苯基吡咯烷-3-酮的制备
在0℃，向化合物S2(6mg)和4AMS(10mg)的DCM(2mL)混合物中加入PCC(15mg)。将混合物在室温下搅拌1小时，然后通过Al2O3过滤。将滤液真空浓缩。所得残余物通过制备薄板层析纯化，得到所需产物S3(4mg，67％)。1HNMR(400MHz,CDCl3)δ7.38–7.21(m,5H),4.50–4.41(m,1H),4.07-3.98(m,1H),2.75–2.62(m,2H),1.72–1.59(m,2H),1.22(d,J＝15.1Hz,6H),0.85(t,J＝7.3Hz,3H).LC-MS(ESI)[M+H]+计算值C16H22NO2,260.16；测得值,262.30.
化合物S4和S5合成路线:
化合物S4：1-((2R，3R)-3-羟基-2-苯基氮杂环丁烷-1-基)-2,2-二甲基丁-1-酮的制备
根据先前描述的方法(Tetrahedron 2008,64,9928-9936)制备的(R)-2-苯基-1-甲苯磺酰基氮杂环丁-3-酮(和NaBH 4(75.5mg)在甲醇(15mL)中室温下搅拌3小时后。通过加入固体柠檬酸使反应混合物淬灭，直到pH达到5至6.向反应混合物中加入硅胶，蒸出溶剂。残余物通过硅胶柱色谱法(EtOAc:己烷，1:3)纯化，得到所需产物，两种异构体a和b，其绝对构型通过1H-1H核超越效应(NOE)证实。产物a：1-((2R，3R)-3-羟基-2-苯基氮杂环丁烷-1-基)-2,2-二甲基丁-1-酮，1HNMR(400MHz，CDCl 3)δ7.72(d，J＝8.3Hz，2H)，7.44-7.31(m，7H)，5.11(d，J＝6.7Hz，1H)，4.37(td，J＝6.7,2.8Hz，1H)，4.05(dd，J＝1H)，3.74(ddd，J＝9.5,2.8,1.1Hz，1H)，2.45(s，3H)。产物b：1-((2R,3S)-3-羟基-2-苯基氮杂环丁烷-1-基)-2,2-二甲基丁-1-酮，1H NMR(400MHz，CDCl 3)δ7.66(d，J＝8.2Hz，2H)，7.41-7.28(m，7H)，4.50(d，J＝5.7Hz，1H)，4.24(dd，J＝12.5,6.4Hz，1H)，4.02(t，J＝1H)，3.52-3.45(m，1H)，2.44(s，3H)。
将1-((2R，3R)-3-羟基-2-苯基氮杂环丁烷-1-基)-2,2-二甲基丁-1-酮(50mg)和三乙胺(33.2mg)溶于2mL DCM，并在0℃下加入34mg对甲苯磺酰氯。将混合物在室温下搅拌12小时，然后真空浓缩。残余物通过硅胶柱色谱纯化(EtOAc:己烷，1:5)，得到(2R，3R)-3-((叔丁基二甲基甲硅烷基)氧基)-2-苯基-1-甲苯磺酰氮丙啶(63mg，92％)。1H NMR(400MHz,cdcl3)δ7.68(d,J＝8.3Hz,2H),7.38–7.26(m,7H),4.99(d,J＝6.6Hz,1H),4.38(td,J＝6.5,2.7Hz,1H),4.04(dd,J＝8.9,6.4Hz,1H),3.69(ddd,J＝8.9,2.7,1.0Hz,1H),2.43(s,3H),0.63(s,9H),-0.19(s,3H),-0.42(s,3H).
在-78℃下，向(2R，3R)-3-((叔丁基二甲基甲硅烷基)氧基)-2-苯基-1-甲苯基氮杂环丁烷(30mg)在绝对1,2-二甲氧基乙烷(6mL)中的溶液中滴加萘钠(0.67M，1.2mL)。将反应混合物搅拌90分钟，用水稀释，用氯仿萃取。将合并的有机层用饱和食盐水洗涤，浓缩，得到粗品(2R，3R)-3-((叔丁基二甲基甲硅烷基)氧基)-2-苯基氮杂环丁烷(45mg)，将其溶于甲醇(4mL)，加入浓盐酸(0.2mL)。将混合物搅拌2小时，加入饱和NaHCO 3溶液直到pH达到8。将混合物真空浓缩，残余物用DCM和水稀释，水层用DCM萃取，合并的有机层用饱和食盐水洗涤并浓缩，得到粗产物(2R，3R)-2-苯基氮杂环丁-3-醇(32mg)，其不经进一步纯化用于下一步骤。
向(2R，3R)-2-苯基氮杂环丁烷-3-醇(32mg)在THF(2mL)和H 2O(2mL)中的溶液中加入饱和NaHCO 3(0.5mL)溶液。将混合物冷却至0℃，加入2,2-二甲基丁酰氯(29mg)，并在室温下搅拌过夜。混合物用DCM萃取，合并的有机层用水洗涤并浓缩。将粗产物通过制备高效液相色谱纯化，得到化合物S4(6.8mg,三步总收率36％).1H NMR(400MHz,CDCl3)δ7.39–7.22(m,5H),5.12(d,J＝3.4Hz,1H),4.62–4.53(m,1H),4.31(dd,J＝10.3,3.9Hz,1H),4.14(dd,J＝9.4,4.5Hz,1H),1.56-1.52(m,2H),1.16(d,J＝2.4Hz,6H),0.88(t,J＝7.5Hz,3H).LC-MS(ESI)[M+H]+计算值C15H22NO2,248.16,测得值,248.25
化合物S5：1-((2R，3S)-3-羟基-2-苯基氮杂环丁烷-1-基)-2,2-二甲基丁-1-酮的制备
根据化合物S4概述的步骤，从1-((2R，3S)-3-羟基-2-苯基氮杂环丁烷-1-基)-2,2-二甲基丁-1-酮，制备化合物S5。1H NMR(400MHz,CDCl3)δ7.43–7.22(m,5H),4.76-4.71(m,1H),4.65–4.58(m,1H),4.16-4.09(m,1H),3.72–3.65(m,1H),1.54-1.52(m,2H),1.23(s,6H),0.86(t,J＝6.8Hz,3H).LC-MS(ESI)[M+H]+计算值C15H22NO2,248.16,测得值,248.25.
化合物S6：(S)-1-(乙基磺酰基)-2-苯基氮杂环丁烷的制备
(S)-2-苯基氮杂环丁烷(35mg，0.263mmol)和三乙胺(53.2mg，0.526mmol)溶于2mL无水CH2Cl2中。在氮气和0℃下将乙磺酰氯(40.4mg，0.316mmol)缓慢加入到该溶液中。将混合物在室温下搅拌2小时，用CH2Cl2和水稀释。有机层用饱和NaHCO3溶液，盐水洗涤，用Na2SO4干燥并浓缩。残余物通过色谱法纯化，得到化合物S6(20mg，33％)，为浅黄色油状物。1H NMR(400MHz,CDCl3)δ7.40–7.27(m,5H),5.01(dd,J＝9.0,5.5Hz,1H),3.32(dd,J＝13.2,6.4Hz,2H),3.08–3.02(m,2H),2.32(m,2H),1.37(t,J＝7.4Hz,3H).LC-MS(ESI)[M+H]+计算值C11H16NO2S,226.09；测得值,226.21.
化合物S7:(2S)-1-(叔丁基亚磺酰基)-2-苯基氮杂环丁烷的制备
根据化合物S6概述的步骤，由(S)-2-苯基氮杂环丁烷(55mg)和2-甲基丙烷-2-亚磺酰氯(69.4mg)制备化合物S7，收率为47％。1H NMR(400MHz,CDCl3)δ7.47(d,J＝8.0Hz,2H),7.37–7.31(m,2H),7.28–7.23(m,1H),5.43–5.33(t,J＝8.0Hz,1H),3.98(dd,J＝17.4,8.0Hz,1H),3.89–3.79(m,1H),2.74-2.65(m,1H),2.37–2.20(m,1H),0.90(s,9H).LC-MS(ESI)[M+H]+计算值C13H20NOS,238.13；测得值,238.28.
化合物S8：(S)-1-(叔丁基磺酰基)-2-苯基氮杂环丁烷的制备
在0℃向化合物S7(11mg)的DCM(4mL)溶液中加入m-CPBA(75％，w/w，16mg)。将混合物在室温下搅拌12小时，真空浓缩。残余物通过制备薄板层析纯化纯化，得到化合物S8。1HNMR(400MHz,CDCl3)δ7.49(d,J＝8.0Hz,2H),7.39–7.33(m,2H),7.30–7.25(m,1H),5.45–5.35(m,1H),4.00(dd,J＝17.4,8.0Hz,1H),3.91–3.81(m,1H),2.76-2.68(m,1H),2.39–2.22(m,1H),0.92(s,9H).
化合物S9：(S)-1-(叔丁基磺酰基)-2-苯基氮杂环丁烷的制备
将2,2-二甲基-3-氧代丁酸苄酯(400mg)，双(2-甲氧基乙基)氨基三氟化硫(5mL)和一滴乙醇的混合物在50℃下搅拌12小时。将混合物冷却至0℃，加入冷水。将混合物加入饱和NaHCO3溶液直至pH达到8，用DCM萃取。合并的有机层用盐水洗涤，干燥(Na2SO4)并真空浓缩。通过色谱法纯化3,3-二氟-2,2-二甲基丁酸苄酯(206mg，47％)。1H NMR(400MHz,CDCl3)δ7.38–7.30(m,5H),5.15(s,2H),1.63(t,J＝19.2Hz,3H),1.34(t,J＝0.9Hz,6H).
向搅拌的3,3-二氟-2,2-二甲基丁酸苄酯(206mg)的甲醇(5mL)溶液中加入Pd/C(10％，20.6mg)，所得混合物在室温下氮化12h。将混合物通过硅藻土垫过滤，滤饼用甲醇洗涤。减压蒸发滤液，得到白色固体的3,3-二氟-2,2-二甲基丁酸(105mg，81％)，不经进一步纯化用于下一步骤。1H NMR(400MHz,CDCl3)δ1.73(t,J＝18Hz,3H),1.38(s,3H).
向(S)-2-苯基氮杂环丁烷(70mg)和3,3-二氟-2,2-二甲基丁酸(40mg)在无水DMF(1mL)中的溶液中加入2-(7-氮杂-1H苯并***-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(150mg)和DIEA(0.14mL)。将混合物在室温下搅拌12小时并真空浓缩。残余物用CH2Cl2和水稀释。水层用CH2Cl2萃取。有机层用饱和食盐水洗涤，用Na2SO4干燥并浓缩。残余物通过制备薄板层析纯化，得到化合物S9(35mg,50％).1H NMR(400MHz,CDCl3)δ7.38–7.22(m,5H),5.39-5.31(m,1H),4.59–4.45(m,2H),2.73-2.65(m,1H),2.16-2.06(m,1H),1.59(t,J＝19.5Hz,3H),1.32(s,6H).LC-MS(ESI)[M+H]+计算值C15H20F2NO,268.15；测得值,268.19.
化合物S10：3,3-二氟-2,2-二甲基-1-(2-苯基吡咯烷-1-基)丁-1-酮的制备
根据化合物S9概述的步骤，从2-苯基吡咯烷(48mg)和3,3-二氟-2,2-二甲基丁酸(50mg)制备化合物S10，产率为65％。1H NMR(400MHz,CDCl3)δ7.29-7.09(m,5H),5.30–5.13(m,1H),3.95(m,2H),2.25-2.16(m,1H),2.09–1.68(m,3H),1.54(t,J＝19.5Hz,3H),1.39(s,6H).LC-MS(ESI)[M+H]+计算值C16H22F2NO,282.17；测得值,282.36.
化合物S11：2,2-二甲基-1-(2-苯基吡咯烷-1-基)丙-1-酮的制备
根据化合物S6概述的步骤，由2-苯基吡咯烷(51mg)和新戊酰氯(50mg)制备化合物S11，产率为74％。1H NMR(400MHz,CDCl3)δ7.29-7.25(m,2H),7.12-7.10(m,3H),5.31–5.16(m,1H),3.88–3.74(m,2H),2.26-2.17(m,1H),1.88-1.77(m,3H),1.24(s,9H).LC-MS(ESI)[M+H]+计算值C15H22NO,232.17；测得值,232.20.
化合物S12：(S)-2,2-二甲基-1-(2-苯基氮杂环丁烷-1-基)丙-1-酮的制备
根据化合物S6概述的步骤，由(S)-2-苯基氮杂环丁烷(10mg)和新戊酰氯(13.5mg)制备化合物S12，收率为44％。1H NMR(400MHz,CDCl3)δ7.37–7.31(m,2H),7.28-7.25(m,3H),5.14–5.05(m,1H),4.08–3.98(m,2H),2.20-2.08(m,2H),1.20(s,9H).LC-MS(ESI)[M+H]+计算值C14H20NO,218.15；测得值,218.20.
化合物S13：
根据方案S1概述的步骤制备化合物S13
方案S1:试剂和条件：(a)Na/THF,-78℃(b)3,3-二氟-2,2-二甲基丁酸,EDCI,DIEA,DMF,室温。
化合物S14
根据方案S2概述的步骤制备化合物S14
方案S2:试剂和条件:(a)Pd/C,H2(b)3,3-二氟-2,2-二甲基丁酰氯,NaH,THF.
化合物S15：
根据方案S3概述的步骤制备化合物S15
方案S3:试剂和条件:(a)3,3-二氟-2,2-二甲基丁酰氯,NaH,THF.
化合物S16
根据方案S4概述的步骤制备化合物S16
方案S4:试剂和条件:(a)TFA/DCM(b)3,3-二氟-2,2-二甲基丁酰氯,Et3N,DCM.
化合物S17：
根据方案S5概述的步骤制备化合物S17
方案S5:试剂和条件:(a)K2CO3,苯硫酚,DMF(b)3,3-二氟-2,2-二甲基丁酰氯,Et3N,DCM.
3.RIPK1的激酶测定
材料：具有N端GST-标签(目录编号#R07-34G)的重组全长RIPK1蛋白购自SignalChem。ADP-GloTM激酶测定试剂盒(目录编号#V9102)来自Promega。MBP蛋白(目录编号#M2295)和其它所有化学品均来自Sigma。384孔测试板(目录编号#3674，白板，不透明)购自Corning。
激酶活性测定和数据分析：RIPK1激酶测定在白色384孔板中进行。测试缓冲液含有25mM HEPES(pH7.2)，20mM氯化镁，12.5mM氯化锰，5mMEGTA，2mMEDTA，12.5mMβ-甘油磷酸和2mMDTT。RIPK1首先和化合物或是DMSO对照孵育15分钟，之后加入ATP/MBP的底物混合物以引发反应。RIPK1的终浓度为161nM，ATP终浓度为50μM，MBP为20μM。室温反应90分钟后，按ADP-GloTM激酶测定试剂盒(Promega)的技术手册加入ADP-Glo试剂和检测溶液，在PerkinElmer Enspire上测量发光。数据使用Graphpad Prim(GraphPad软件；www.graphpad.com)进行分析。使用具有S形剂量反应的非线性回归模型拟合曲线。
结果：hRIPK1激酶测定的pIC50和我们的细胞坏死测定的pEC50相关。示例性数据如下所示：
4.细胞坏死测定
方法：
HT-29细胞在McCoy’s 5A培养基(Invitrogen)中培养。第一天，HT-29细胞以每孔2500-3500个细胞的密度覆盖在96孔分析板中。第二天，通过加入20ng/ml TNF-α(T)，100nMSmac模拟物(S)，和20μM z-VAD(Z)诱导细胞坏死。同时，将来自约20万个化合物的化学文库的10mM化合物输送至每孔中。处理24小时后，通过使用CellTiter-Glo发光细胞活力测定试剂盒测量ATP水平来测定细胞活性。根据制造商的说明进行CellTiter-Glo测定(Promega)，化学发光使用PerkinElmer Enspire多模式读数器记录。将存活的细胞归一化为用DMSO处理的那些细胞。Nec-1作为筛选坏死抑制剂的阳性对照。数据表示为重复的平均值±标准偏差。
通过如上所述测量ATP水平来测定HT-29细胞中化合物#9和其衍生化合物对坏死的剂量依赖型的抑制。化合物坏死的活性数据如下：

Claims (10)

1.一种酰胺化合物，其为细胞坏死和/或人受体相互作用蛋白1激酶(RIP1)抑制剂，其式为：
其中：
R1是C3-C14环或杂环部分，特别是取代或未取代的，0-3个杂原子C3-C9环烷基，环烯基，环炔基；或取代或未取代的，0-3个杂原子C5-C14芳基；
R2是C3-C14杂环部分，特别是取代或未取代的，1-3个杂原子的C3-C9环烷基，环烯基，环炔基；或取代或未取代的，1-3个杂原子C5-C14芳基；且
R3是氢原子，取代或未取代的杂原子，取代或未取代的，0-3个杂原子C1-C9烷基，烯基，炔基；或者取代或未取代的，0-3个杂原子C5-C14芳基，
其中每个杂原子独立地是氧，磷，硫或氮；或
该酰胺化合物的相应磺酰胺，或
该化合物药学上可接受的盐，氢化物或立体异构体。
2.权利要求1的化合物，其中：
R1是：(a)取代或未取代的苯基；
(b)取代或未取代的2-，3-或4-吡啶；
(c)取代或未取代的萘基或3-氮杂萘基；
(d)取代或未取代的0-3个杂原子环己基，环戊基，如四氢呋喃；或
(e)取代或未取代的0-3个杂原子环戊烯或环戊二烯，例如吡咯，唑(例如吡唑，咪唑，***，四唑，戊唑，恶唑，异恶唑，噻唑或异噻唑)，呋喃，间二氧杂环戊烯噻吩，二硫杂环戊烯或氧硫杂环戊烯，优选2-部分，例如2-唑，2-吡咯，2-唑(例如2-吡唑，2-咪唑，2-恶唑，2-异恶唑，2-噻唑或2-异噻唑)，2-呋喃，2-噻吩，2-氧杂环戊二烯，间二氧杂环戊烯或2-硫杂环戊二烯；和/或
R2是具有杂原子的取代或未取代的饱和环：
N，例如氮杂环丙烷，氮杂环丁烷，吡咯烷，哌啶；
N和O，例如氧氮环丙烷，氧氮杂环丁烷，恶唑烷，恶嗪啉；
N和S，例如硫氮环丙烷，氮硫环丁烷，四氢噻唑，硫代吗啉；
N和N，例如二氮环甲烷，二氮杂环丁烷，二氮环戊烷(吡唑烷)，六氢哒嗪；或
R2是具有杂原子的取代或未取代的不饱和环：
N，例如吡咯，二氢吡咯，吡啶，二氢吡啶，四氢吡啶；
N和N/S/O，例如唑(例如，吡唑，咪唑，***，四唑，戊唑，恶唑，异恶唑，噻唑或异噻唑)，嘧啶，恶嗪，噻嗪，三嗪，恶二嗪，噻二嗪；和/或
R3是取代或未取代的，0-3个杂原子C1-C9烷基，烯基或炔基。
3.权利要求1的化合物,其中：
R1是取代或未取代的：苯基，环己基，呋喃，噻吩或唑(如噻唑)和/或
R2是取代或未取代的：氮杂环丙烷，氮杂环丁烷，吡咯烷，哌啶，恶唑烷，恶嗪啉；二氮环戊烷，六氢哒嗪，吡咯，二氢吡咯，二氢吡啶或四氢吡啶；和/或
R3是1-二甲基丙基，1-二甲基丙-2-烯基或1-二甲基丙-2-炔基。
4.权利要求1的化合物,其中：
R1是取代或未取代的苯基或环己基，和/或
R2是取代或未取代的：氮杂环丁烷，吡咯烷，哌啶，恶唑烷，二氮环戊烷，六氢哒嗪；和/或
R3是1-二甲基丙基；或
该酰胺化合物的相应磺酰胺，或
该化合物或相应的磺酰胺药学上可接受的盐，氢化物或立体异构体。
5.权利要求1的化合物,其中：
R1是未取代的苯基，和/或
R2是未取代的：氮杂环丁烷，吡咯烷，哌啶，恶唑烷，二氮环戊烷，六氢哒嗪；和/或
R3是1-二甲基丙基；或
该酰胺化合物的相应磺酰胺，或
该化合物或相应的磺酰胺药学上可接受的盐，氢化物或立体异构体。
6.权利要求1的化合物，其具有表1的式。
7.一种药物组合物，其包含单位剂量的权利要求1的化合物以及药学上可接受的赋形剂。
8.一种药物组合物，其包含单位剂量的权利要求1的化合物和药学上可接受的赋形剂，以及一种不同的用于细胞坏死相关疾病或病症的治疗剂。
9.一种治疗坏死相关疾病或病症的方法，包括向有需要的患者施用有效剂量的权利要求1的化合物或权利要求7或8的组合物。
10.权利要求9所述的方法，其进一步包含诊断细胞坏死相关疾病或病症的前期步骤，或检测细胞坏死相关疾病或病症的改善结果的后续步骤。
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