CN101704810A - 钾通道功能的环烷基抑制剂 - Google Patents
钾通道功能的环烷基抑制剂 Download PDFInfo
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- CN101704810A CN101704810A CN200910175525A CN200910175525A CN101704810A CN 101704810 A CN101704810 A CN 101704810A CN 200910175525 A CN200910175525 A CN 200910175525A CN 200910175525 A CN200910175525 A CN 200910175525A CN 101704810 A CN101704810 A CN 101704810A
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- alkyl
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- aryl
- heteroaryl
- heterocyclic radical
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
本发明涉及钾通道功能的环烷基抑制剂,提供用作钾通道功能抑制剂(特别是电压门控K+通道的Kv1亚家族的抑制剂,尤其是连接超快激活延迟整流的K+电流IKur的Kv1.5抑制剂)的新的环烷基化合物,使用此类化合物预防和治疗心律失常和IKur-相关的疾病的方法,及含有此类化合物的药用组合物。
Description
本申请是国际申请日为2003年1月31日、国际申请号为PCT/US03/03170、发明名称为“钾通道功能的环烷基抑制剂”的国际申请进入中国的中国专利申请的分案申请,该中国专利申请的申请号为03807570.9,发明名称为“钾通道功能的环烷基抑制剂”。
技术领域
本发明提供用作钾通道功能抑制剂(尤其是电压门控K+通道的Kv1亚家族的抑制剂,更特别是连接超快激活延迟整流的K+电流IKur的Kv1.5抑制剂)的环烷基化合物以及含有此类化合物的药用组合物。本发明还提供使用此类化合物治疗心律失常、IKur-相关的疾病和由离子通道功能介导的其它疾病的方法。
背景技术
在大约五十年以前,当Hodgkin和Huxley发现钾离子在兴奋乌贼的巨大轴突的电流中起作用时,人们首次认识到了钾离子通道的重要性。然而,由于缺少选择性的、高亲和性的钾通道配体,在该领域的研究受到了阻碍。但是,重组DNA技术及单细胞和全细胞的电压箝技术的出现已经改变了该领域的缓慢进度。实际上,已经克隆出了表现出功能性的、药理学的和组织分布特性的钾通道。这些克隆的钾通道在鉴定治疗各种不同疾病状态的候选化合物的试验中是有用的靶点。钾通道已经成为迄今发现的离子通道中最多变化的一类。它们调控许多细胞活动,如肌肉收缩、神经-内分泌分泌、动作电位的频率和持续时间、电解质的动态平衡和静息膜电位。
钾通道在真核细胞和原核细胞中表达,并且是控制电的和非电的细胞功能的元素。已经按照它们的生物物理学和药理学的特性将钾通道分类。已经基于氨基酸序列和功能特性将这些通道的亚类命名。其中突出的是电压依赖性钾通道,例如电压门控性钾通道(如Kv1、Kv2、Kv3、Kv4)。在这些亚类中已经根据其推定的功能、药理学及在细胞和组织中的分布的特性分出亚型(Chandy and Gutman,″Voltage-gatedpotassium channel genes″in Handbook of Receptors andChannels-Ligand and Voltage-gated Ion Channels,ed.R.A.North,1995;Doupnik等,Curr.Opin.Neurobiol.5:268,1995)。例如,基于通道的分子序列,将钾通道Kv1类进一步细分,如Kv1.1、Kv1.2、Kv1.3、Kv1.4、Kv1.5、Kv1.6和Kv1.7。功能性电压门控性K+通道可以以多聚体结构存在,该结构由相同的或不同的亚单位联合而形成。人们认为这种现象说明了K+通道的广泛多样性。然而,在大多数情况下,仍不清楚天然K+通道的亚单位组成和特定通道所扮演的生理学角色。
通过Kv1.3抑制作用而引起的膜的去极化已经被证明是防止T细胞增值的一个有效方法,因此适用于许多自身免疫疾病。人类T淋巴细胞质膜中的K+通道的抑制已被认定是通过调节细胞内Ca++的动态平衡而在诱导免疫抑制应答中发挥作用,已发现这对T细胞的活化有重要意义。
Kv1.3电压门控性钾通道见于神经细胞、血细胞、破骨细胞和T淋巴细胞。Chandy和Cahalan实验室提出一种假设,即阻断Kv1.3通道可诱导免疫抑制应答(immunosuppressant response)。(Chandy等,J.Exp.Med.160,369,1984;Decoursey等,Nature,307,465,1984)。然而,他们的研究中所用的K+通道阻断剂是非选择性的。直到将玛格(斑蝎)毒素(margatoxin)肽(一种在蝎子毒液中发现的肽)用于研究,才有了验证该假设的Kv1.3通道特异性的抑制剂。尽管有实验室(Price等,Proc.Natl,Acad,Sci.USA,86,10171,1989)表明卡律毒素可阻断人类T细胞的Kv1.3通道,但随后又表明卡律毒素可抑制人类T淋巴细胞的四种不同的K+通道(Kv1.3和三种各自不同的小传导性Ca++活化的K+通道),从而限制了该毒素作为Kv1.3生理学功能的探针的应用(Leonard等,Proc.Natl,Acad.Sci,USA,89,10094,1992)。另一方面,玛格(斑蝎)毒素在T细胞中只阻断Kv1.3,且在体外和体内模型中均有免疫抑制剂活性。(Lin等,J.exp.Med,177,637,1993)。然而,该化合物的强毒性限制了它的治疗效用。最近报道了一类化合物,它们可能是上述药物的一类有吸引力的替代物,例如参见美国专利号5,670,504、5,631,282、5,696,156、5,679,705和5,696,156。论及先前药物的一些活性/毒性问题时,这些化合物倾向于有大的分子量且一般通过天然产物合成处理而制备,其分离烦琐且费时。
已证实免疫调节异常存在于多种自身免疫和慢性炎症疾病中,包括系统性红斑狼疮、慢性类风湿性关节炎、I型和II型糖尿病、炎症性肠疾病、胆汁性肝硬化、葡萄膜炎、多发性硬化以及其他疾病如Crohn氏病、溃疡性结肠炎、大疱性类疱疮、结节病、银屑病、鱼鳞病、Graves眼病和哮喘。
虽然这些疾病各自的基本发病机理可能很不相同,但它们均出现各种自身抗体和自身反应性淋巴细胞。这种自身反应性部分原因可能是由于掌控正常免疫系统运作的自身稳态控制的一种缺失。同样地,在骨髓或器官移植之后,宿主淋巴细胞识别出异体组织抗原,然后开始产生抗体而导致移植排斥
自身免疫或排斥过程的一种最终结果是由炎症细胞或它们释放的介质所导致的组织破坏。抗炎药如非甾体抗炎药(NSAID′s)主要通过阻断这些炎症介质的作用和分泌而发挥作用,但对于该疾病的免疫基础毫无改变。另一方面,细胞毒药物(如环磷酰胺)以将正常的和自身免疫反应都切断的这样一种非特异性的方式发挥作用。实际上,以这类非特异性免疫抑制剂治疗的病人更容易死于感染而非死于他们的自身免疫疾病。
环胞菌素A(CsA)于1983年被美国FDA批准应用,是当前防止被移植器官的排斥反应的最主要的药物。在1993年,FK-506(普乐可复)被美国FDA批准应用于防止肝移植的排斥反应。CsA和FK-506通过抑制人体的免疫系统而阻止它动员其巨大的天然防护药剂库来排斥移植的异体蛋白而发挥作用。在1994年,CsA被美国FDA批准应用于治疗严重的银屑病,并已经被欧洲管理机构批准应用于治疗异位性皮炎。虽然它们在对抗移植排斥中有效,但已知CsA和FK-506可导致严重的不良的副作用,包括肾毒性、神经毒性和胃肠不适。因此,仍需要发展一种选择性的没有这些副作用的免疫抑制剂。钾通道抑制剂有望成为该问题的解决方案。
心房颤动(AF)和心房扑动是临床实践中最常见的心律失常,并且随着人口的老龄化其患病率倾向于升高.目前,每年有超过一百万美国人患AF,占所有确诊的心脏病病例的5%以上,并且在美国每年导致80,000例以上的中风发生.虽然AF是一种很少致命的心律失常,但它仍然造成实际的病态,并且可导致发生充血性心力衰竭或血栓栓塞等并发症.目前应用的第I类和第III类抗心律失常药可减少AF的复发率,但是由于多种潜在的副作用(包括心室的致心律失常作用)而使应用有限.由于目前的治疗方法不充分且有许多副作用,因此明显需要发展新的治疗方法.
第III类抗心律失常药是一类可导致选择性延长动作电位时程同时无明显的心脏抑制作用的药物。本类中可用的药物数目很有限。例如已经证实索他洛尔和胺碘酮具有有趣的第III类抗心律失常药物特性(Singh B.N.,Vaughan Williams E.M.″A Third Class of Anti-ArrhythmicAction:Effects On Atrial And Ventricular Intracellular Potentials AndOther Pharmacological Actions On Cardiac Muscle,of MJ 1999 and AH3747″Br.J.Pharmacol 1970;39:675-689和Singh B.N.,VaughanWilliams E.M,″The Effect of Amiodarone,A New Anti-Anginal Drug,On Cardiac Muscle″,Br J.Pharmacol 1970;39:657-667),但这些并非选择性的第III类抗心律失常药。索他洛尔还具有第II类抗心律失常药的作用,共可导致心脏抑制作用因而对于某些易感病人是禁忌的。由于胺碘酮具有多种电生理学的作用,它同样也不是选择性的第III类抗心律失常药,且因副作用而严格受限(Nademanee,K.″The AmiodaroneOdessey″.J.Am.Coll.Cardiol.1992;20:1063-1065)。人们希望这类药物能有效地预防心室纤维性颤动。根据定义,认为选择性的第III类抗心律失常药不会象第I类抗心律失常药一样,在抑制动作电位的传导的同时导致心肌抑制或引发心律失常。
第III类抗心律失常药通过延长心脏动作电位时程而增加心肌的不应性。理论上来说,可以通过增强内向电流(例如Na+或Ca2+电流;下文中分别表示为INa和ICa)或减少外向的复极钾(K+)电流而延长心脏动作电位(时程)。在动作电位平台期,延迟整流(IK)K+电流是整个复极过程中主要的外向电流,然而短暂的外向(Ito)和内向整流(IKI)K+电流分别负责复极的快速起始期和终上期。细胞的电生理学研究已经证明IK包括两种药理学上和反应动力学上截然不同的K+电流亚型,Ikr(快速激活及失活)和Iks(缓慢激活及失活)(Sanguinetti和Jurkiewicz,TwoComponents Of Cardiac Delayed Rectifier K+ Current:DifferentialSensitivity To Block By ClassIII Antiarrhythmic Agents,J Gen Physiol1990,96:195-215)。当前研制的第III类抗心律失常药包括d-索他洛尔、多非利特(UK-68,798)、阿莫兰特(H234/09)、E-4031和甲磺酰胺-N-[1′-6-氰基-1,2,3,4-四氢-2-萘基]-3,4-二氢-4-羟基螺[2H-1-苯并吡喃-2,4′-哌啶-6-基]一氯化物主要是(如果非专一性的话)阻断Ikr。虽然胺碘酮是一种Iks的阻断剂(Balser J.R.Bennett,P.B.,Hondeghem,L.M.和Roden,D.M.″Suppression Of Time-Dependent Outward Current InGuinea Pig Ventricular Myocytes:Actions Of Quinidine AndAmiodarone.Circ.Res.1991,69:519-529),但它也阻断INa和ICa,影响甲状腺功能,也被当作一种非特异性的肾上腺素阻断剂,并且可作为磷脂酶抑制剂发挥作用(Nademanee,K.″The Amiodarone Odessey″.J.Am.Coll.Cardiol.1992;20:1063-1065)。因此其治疗心律失常的方法并不明确。大多数已知的正在研究的第III类抗心律失常药主要是阻断Ikr。
已经证实折返激动作用(折返)是人类室上性心律失常潜在的主要机制。折返激动作用要求在慢传导速度和足够短的不应期之间存在临界平衡,以使得多重折返环路的形成与维持同时共存并维持AF。通过延长动作电位时程(APD)而增加心肌的不应性可以预防和/或终止折返性心律失常。目前研究中的大多数选择性的第III类抗心律失常药,如d-索他洛尔和多非利特,主要是(如非专一地)阻断Ikr,这是在人类心房和心室中均被发现的Ik快速激活成分。
由于这些Ikr阻断剂在心房和心室中均能延长APD和增加不应性,同时本身不影响传导,因此理论上它们代表了治疗心律失常(如AF)的潜在的有用药物。这些药物有一种在慢心率时增加致心律失常的风险性的倾向。例如,应用这些化合物时已经观察到了尖端扭转性室速(Roden,D.M.″Current Status of Class III Antiarrhythmic Drug Therapy″,Am J.Cardiol,1993;72:44B-49B)。这种在慢心率时逾常的影响已经被称为“反向的频率依赖性”,它与非频率依赖的和频率依赖的作用形成对照(Hondeghem,L.M.″Development of Class III AntiarrhythmicAgents″.J.Cadiovasc.Cardiol.20(Supp1.2):S17-S22)。
延时整流的缓慢激活成分(Iks)潜在地克服了一些与室性心律失常相关的Ikr阻断剂的局限性。然而由于其缓慢激活的动力学特性,Iks在心房复极中的作用可能因为心房相对短的APD而受到限制。因此,尽管Iks阻断剂可能在室性心律失常的情况下提供明显的益处,但人们认为它们影响SVT(室上性心律失常)的能力是极小的。
人们相信超快激活的延时整流K+电流(Ikur)代表了克隆的钾通道指定的Kv1.5的天然的配对物,虽然它存在于人类心房,但它似乎不存在于人类心室。此外,由于其快速的激活和有限的缓慢失活,人们认为Ikur能明显地促成人类心房的复极。因此,一种特异的Ikur阻断剂,即一种拮抗Kv1.5的化合物,将通过在人类心房中延迟复极以延长不应性同时不导致心室复极的延迟,后者是以目前的第III类抗心律失常药治疗时观察到的除极后产生心律失常和获得性长QT综合征的原因,从而克服其他化合物的缺点。
在完整的人体心房心肌细胞中,已经鉴别出一种超快激活的延迟整流K+电流Ikur(也被称为持续性外向电流)、Isus或Iso,并且当其由人类心脏中分离出并在人类(HEK-293)细胞系中稳定表达时(Wang等,1993,Circ Res 73:1061-1076;Fedida等,1993,Circ Res 73:210-216;Snyders等,1993,J Gen Physiol 101:513-543),该电流的特性和动力学与人类K+通道克隆(hKv1.5,HK2)表达的完全一致,且其最早克隆于大鼠之脑中(Swanson等,10,Neuron 4:929-939)。尽管现在市场中提供各种抗心律失常药物,但人们仍未获得那些既有满意的效力又有高的安全范围的药物。例如,根据Vaughan-Williams之分类表(″Classification Of Antiarrhythmic Drugs:In:Cardiac Arrhythmias,edited by:E.Sandoe,E.Flensted-Jensen,K.Olesen;Sweden,Astra,Sodertalje,第449-472页,1981),可引起动作电位最大上升速率(max)的选择性抑制的第I类抗心律失常药对于心室纤维性颤动的预防是不足够的。另外,关于安全性,它们还存在问题,即,它们可导致心肌收缩的抑制,并且由于抑制脉冲性传导而具有诱导心律失常的趋势。β-肾上腺素受体阻滞剂和钙拮抗剂分别属于第II类和第IV类,由于其效果或者局限于某一种特定类型的心律失常,或由于其在某些心血管病患者中具有心脏抑制特性而成为禁忌,而使它们各有缺点。然而,其安全性高于第I类抗心律失常药。
发明内容
本发明提供下式I的环烷基化合物,包括其对映体、非对映体及其盐,
它们用作钾通道功能的抑制剂(尤其是电压门控K+通道的Kv1亚家族的抑制剂,更特别是连接超快激活延迟整流的K+电流IKur的Kv1.5的抑制剂),用于治疗诸如心律失常的疾病和IKur-相关的疾病,其中虚线表示任选的双键,前提是当存在双键时,R1a不存在;
m和p独立为0、1、2或3;
R1为
-SO2R8c,-CO2H,-OC(O)CCl3,-C(O)R8c,-CO2R8c,-C(=S)R8c,-NR6R7,-OC(O)NR6R7、-N3、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、卤代基、全氟烷基、氰基、硝基、羟基、任选取代的烷氧基、任选取代的芳氧基、任选取代的杂芳氧基、任选取代的烷基、任选取代的链烯基或任选取代的炔基;
R1a为H或Rx;
或R1和R1a一起形成氧代基;
或R1和R1a与它们连接的碳原子结合在一起形成任选取代的螺-稠合的杂环基;
或R1和R1a结合在一起形成基团
R2为杂芳基、(杂芳基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、烷基、链烯基或环烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1、T2或T3;
J为一个键,任选由一个或多个基团T1a、T2a或T3a独立取代的C1-4亚烷基或任选由一个或多个基团T1a、T2a或T3a独立取代的C1-4亚链烯基;
R3为
R4为烷基、卤代烷基、链烯基、环烷基、杂环基、芳基或杂芳基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:
T1b、T2b或T3b;
R4a为R4或OR4;
R5为-NR6aR7a,或杂芳基、(杂芳基)烷基、芳基、(芳基)烷基、烷基、环烷基、(环烷基)烷基、杂环基、(杂环基)烷基、烷基、链烯基或炔基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1c、T2c或T3c;
R6、R6a、R7、R7a、R8、R8a、R8a1、R8a2、R8a3、R8a4、R8a5和R9独立为H、烷基、羟基、烷氧基、芳氧基、杂环基氧基、杂芳氧基、(羟基)烷基、(烷氧基)烷基、(芳氧基)烷基、(杂环基氧基)烷基、(杂芳氧基)烷基、(氰基)烷基、(链烯基)烷基、(炔基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、-C(O)R12,-CO2R12,-C(O)-NR12R13或-NR12R13,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6和R7,或R6a和R7a与它们连接的氮原子一起可以结合形成饱和的或不饱和的4-8元环(或者环烷基或者杂环基),所述环任选由一个或多个以下的基团独立取代:T1d、T2d或T3d;
或R6或R7之一可以与R8、R8a或R9之一结合形成饱和的或不饱和的5-8元环(或者环烷基或者杂环基),所述环任选由一个或多个以下的基团独立取代:T1d、T2d或T3d;
或R6a或R7a之一可以与R8a1结合形成饱和的或不饱和的5-8元环(或者环烷基或者杂环基),所述环任选由一个或多个以下的基团独立取代:T1d、T2d或T3d;
R8b独立为H、烷基、芳基、氰基、硝基、酰基或-SO2(烷基);
R8c独立为H、烷基、环烷基、链烯基、炔基、芳基、芳基烷基、环杂烷基、杂芳基、氨基或烷氧基;
R8d为R4、COR4、CO2R4、SO2R4、CONR6R7或SO2-NR6R7;
R10、R10a、R11和R11a独立为H、烷基、芳基、(芳基)烷基、烷氧基、(烷氧基)烷基、卤代基、羟基、(羟基)烷基、氨基、酰氨基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、磺酰氨基、环烷基、(环烷基)烷基或氰基,其中任何一个基团可以在可利用的原子上(当化合价允许时)任选由一个或多个以下的基团独立地取代:T1e、T2e或T3e;
或R10和R10a,或R11和R11a可以结合形成氧代基;
或R10a可以与R11a结合形成一个键;
或R10可以与R9结合形成饱和的或不饱和的环;
R12和R13独立为H、烷基、羟基、烷氧基、芳氧基、杂环基氧基、杂芳氧基、(羟基)烷基、(烷氧基)烷基、(芳氧基)烷基、(杂环基氧基)烷基、(杂芳氧基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1f、T2f或T3f;
或R12和R13与它们连接的氮原子一起可以结合形成饱和的或不饱和的环(或者环烷基或者杂环基),所述环可以任选由一个或多个以下的基团独立地取代:T1f、T2f或T3f;
W为=NR8a2、=N-CO2R8a2、=N-COR8a2、=N-CN或=N-SO2R8a2;
X为
Z、Z1和Z2独立为=O、=S、=NR8a4或=N-CN;
R14独立为
其中q为1、2或3;
RY为连接于任何可利用的环碳原子的任选的氧代取代基;
X1为O、S、NR8a5或CH2;和
X2为NR8a5或CH2;
RX为一个或多个连接于任何可利用的环碳原子的任选的取代基,所述取代基独立选自T1g、T2g或T3g;
T1-1g、T2-2g和T3-3g各自独立为
(1)氢或T6,其中T6为
(i)烷基、(羟基)烷基、(烷氧基)烷基、链烯基、炔基、环烷基、(环烷基)烷基、环烯基、(环烯基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基或(杂芳基)烷基;
(ii)基团(i),所述基团本身被一个或多个相同或不同的基团(i)取代;或
(iii)基团(i)或(ii),所述基团被一个或多个(优选1-3个)选自T1-1g、T2-2g和T3-3g定义的以下基团(2)-(13)独立地取代,
(2)-OH或-OT6,
(3)-SH或-ST6,
(4)-C(O)tH、-C(O)tT6或-O-C(O)T6,其中t为1或2;
(5)-SO3H、-S(O)tT6或S(O)tN(T9)T6,
(6)卤代基,
(7)氰基,
(8)硝基,
(9)-T4-NT7T8,
(10)-T4-N(T9)-T5-NT7T8,
(11)-T4-N(T10)-T5-T6,
(12)-T4-N(T10)-T5-H,
(13)氧代基,
T4和T5各自独立为
(1)单键,
(2)-T11-S(O)t-T12-,
(3)-T11-C(O)-T12-,
(4)-T11-C(S)-T12-,
(5)-T11-O-T12-,
(6)-T11-S-T12-,
(7)-T11-O-C(O)-T12-,
(8)-T11-C(O)-O-T12-,
(9)-T11-C(=NT9a)-T12-或
(10)-T11-C(O)-C(O)-T12-,
T7、T8、T9、T9a和T10
(1)各自独立为氢或在T6的定义中提供的基团,或
(2)T7和T8可以一起为亚烷基或亚链烯基,与它们连接的原子一起形成饱和的或不饱和的3-至8-元环,所述环为未取代的或由在T1-1g、T2-2g和T3-3g的定义中所列的一个或多个基团取代,或
(3)T7或T8与T9一起,可以为亚烷基或亚链烯基,与它们连接的氮原子一起形成饱和的或不饱和的3-至8-元环,所述环为未取代的或由在T1-1g、T2-2g和T3-3g的定义中所列的一个或多个基团取代,或
(4)T7和T8或T9和T10与它们连接的氮原子一起可以结合形成基团-N=CT13T14,其中T13和T14各自独立为H或在T6的定义中提供的基团;和
T11和T12各自独立为
(1)单键,
(2)亚烷基,
(3)亚链烯基,或
(4)亚炔基。
本发明提供用一种或多种式I化合物、其对映体、非对映体或其药学上可接受的盐预防和治疗心律失常和IKur-相关的疾病的新方法。具体地说,本发明提供选择性预防和治疗室上性心律失常的新方法。
式I范围内的优选化合物包括式Ia、Ib和Ic的化合物:
式I范围内的优选化合物包括这样的一些化合物及其盐,其中一个或多个,
以及特别是全部R1、R1a、R2、J和R3选自以下的定义;
R1为氢、羟基、-NR6R7、-O-C(O)-NR6R7、-O-C(O)-R4、-N(R8)-SO2-NR6R7、-N(R8)-C(Z)-N(R8a)-SO2-R4、-N(R8)-C(Z)-N(R8a)-SO2-OH、-SO2-R8c、-N(R8)-C(W)-NR6R7或基团
R1a为H,或R1a和R1结合形成氧代基或任选取代的螺-稠合的杂环基;
R2为任选取代的烷基、任选取代的链烯基、任选取代的芳基(尤其是苯基或萘基)、任选取代的(芳基)烷基(尤其是苄基)或任选取代的杂芳基(尤其是噻吩基、苯并噻吩基、吡啶基或异噁唑基);
J为一个键、任选取代的C1-4亚烷基(尤其是亚甲基)或任选取代的C1-4亚链烯基(尤其是亚乙烯基);
R3为-R5、-OR5、-C(Z1)-R5、-C(Z1)-O-R5、-O-C(Z1)-R5、-N(R8a1)-C(Z1)-R5、-N(R8a1)-C(Z1)-O-R5或-N(R8a1)-SO2-R5;
R5为任选取代的芳基、任选取代的(芳基)烷基、任选取代的杂芳基、任选取代的(杂芳基)烷基、任选取代的杂环基、任选取代的(杂环基)烷基、任选取代的环烷基、任选取代的(环烷基)烷基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、-NR6aR7a或基团,
R6、R6a、R7和R7a独立为H、任选取代的芳基、任选取代的杂芳基、任选取代的环烷基、任选取代的杂环基、任选取代的(芳基)烷基、任选取代的(杂芳基)烷基、任选取代的(杂环基)烷基、任选取代的烷基或COR12;
或R6和R7或R6a和R7a与它们连接的氮原子结合在一起形成任选取代的、饱和或不饱和的5-8元环;和
R4、R8、R8a1、R8c、R9、R10、R10a、R11、R11a、RX、X、X1、Z1和W如上所定义。
式I范围内的更优选的化合物包括那些,其中一个或多个以及特别是全部R1、R1a、R2、J和R3均选自以下的定义的化合物及其盐:
R1为氢、羟基、-O-C(O)-NR6R7、-O-C(O)-R4、-N(R8)-SO2-NR6R7、-SO2-R8c、-N(R8)-C(W)-NR6R7、-N(R8)-C(Z)-N(R8a)-SO2-R4、-N(R8)-C(Z)-N(R8a)-SO2-OH或基团
R1a为H;
R2为苯基、萘基、噻吩基、苯并噻吩基、烷基或链烯基,其中任何一个基团可以按如上所述被任选取代;
J为一个键、亚甲基或亚乙基;
R3为-R5、-C(Z1)-R5、-O-C(Z1)-R5或-N(R8a1)-C(Z1)-R5;
R5为任选取代的烷基、任选取代的环烷基、任选取代的杂芳基任选取代的芳基或-NR6aR7a;
R6、R6a、R7和R7a独立为H、任选取代的芳基、任选取代的杂芳基、任选取代的环烷基、任选取代的杂环基、任选取代的(芳基)烷基、任选取代的(杂芳基)烷基、任选取代的(杂环基)烷基、任选取代的烷基或COR12;
或R6和R7或R6a和R7a与它们连接的氮原子结合在一起形成任选取代的、饱和或不饱和的5-8元环;和
R4、R8、R8a1、R8c、R9、R10、R10a、R11、R11a、X、Z1和W如上所定义。
式I范围内的最优选的化合物包括其中一个或多个以及特别是全部R1、R1a、R2、J和R3选自以下的定义的化合物及其盐:
R1为
(a)氢或羟基;
(b)-O-C(O)-NR6R7、-N(R8)-SO2-NR6R7或-N(R8)-C(W)-NR6R7
其中
R6和R7独立为
(i)H,或
(ii)烷基、环烷基、链烯基、炔基、芳基、杂芳基、杂环基、烷氧基、(芳基)烷基、(环烷基)烷基、(杂芳基)烷基、(杂环基)烷基、(烷氧基)烷基或NR12R13,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,
或R6和R7结合形成由选自以下的一个或多个基团任选取代的杂环基环:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;和
R8为
(i)H;或
(ii)烷基、环烷基、芳基、杂芳基、杂环基、(环烷基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,
(c)-O-C(O)-R4、-N(R8)-C(Z)-N(R8a)-SO2-R4或-N(R8)-C(Z)-N(R8a)-SO2-OH
其中R4为
(i)H或
(ii)烷基、环烷基、链烯基、炔基、芳基、杂芳基、杂环基、烷氧基、(芳基)烷基、(环烷基)烷基、(杂芳基)烷基、(杂环基)烷基、(烷氧基)烷基或NR12R13,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;和
R8和R8a独立为
(i)H;或
(ii)烷基、环烷基、芳基、杂芳基、杂环基、(环烷基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;
或(d)或基团
R1a为H;
R2为苯基、(苯基)烷基、萘基、噻吩基苯并噻吩基、烷基或链烯基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;
J为一个键,亚甲基或亚乙基;
R3为
(a)-R5或其中R5为杂芳基、杂环基或-NR6aR7a,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:
OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;
(b)-C(Z1)-R5或-O-C(Z1)-R5,
其中
R5为芳基、(芳基)烷基、杂芳基、(杂芳基)烷基)或-NR6aR7a;
和
R6a和R7a独立为
(i)H;或
(ii)烷基、环烷基、芳基、(芳基)烷基、杂芳基(杂芳基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;或
(c)-N(R8a1)-C(Z1)-R5或-N(R8a1)-SO2-R5
其中
R5为芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、烷基、链烯基、炔基、环烷基、(烷氧基)烷基或(环烷氧基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;和
R8a1为
(i)H;或
(ii)烷基、环烷基、芳基、杂芳基、杂环基、(环烷基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,
R5为任选取代的烷基、任选取代的环烷基、任选取代的杂芳基、任选取代的芳基或-NR6aR7a;
R6、R6a、R7和R7a独立为H、任选取代的芳基、任选取代的杂芳基、任选取代的环烷基、任选取代的杂环基、任选取代的(芳基)烷基、任选取代的(杂芳基)烷基、任选取代的(杂环基)烷基、任选取代的烷基或COR12;或
R6和R7或R6a和R7a与它们连接的氮原子结合在一起形成任选取代的、饱和或不饱和的5-8元环;和
R4、R8、R8a1、R8c、R9、R10、R10a、R11、R11a、X、Z1和W如上所定义。
发明详述
本发明说明书所用术语的定义如下。除非另外指明,对本文的基团或术语提供的初始定义应用于本说明书全文的基团或术语(单个或作为另一个基团的一部分)。
术语″烷(alk)”或”烷基″指具有1-12个碳原子,优选1-8个碳原子的直链或支链烃基,如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、戊基、己基、庚基、辛基等。低级烷基,即1-6个碳原子的烷基,通常为最优选。术语″取代的烷基″指由在T1-1g,T2-2g和T3-3g的定义中所列的一个或多个基团取代的烷基,所述基团优选选自氰基,卤代基,氧代基,羟基,-OT6,-C(O)tT6,-OC(O)T6,-T4-NT7T8,-T4-N(T9)-T5-T6,-S(O)tT6或-S(O)tN(T9)T6。
术语″链烯基″指具有2-12个碳原子,优选2-4个碳原子,并且具有至少一个碳-碳双键(顺式或反式)的直链或支链烃基,如乙烯基。术语″取代的链烯基″指由在T1-1g,T2-2g和T3-3g的定义中所列的一个或多个基团取代的链烯基,所述基团优选选自氰基,卤代基,氧代基,羟基,-OT6,-C(O)tT6,-OC(O)T6,-T4-NT7T8,-T4-N(T9)-T5-T6,-S(O)tT6或-S(O)tN(T9)T6。
术语″炔基″指具有2-12个碳原子,优选2-4个碳原子,并且具有至少一个碳-碳三键的直链或支链烃基,如乙炔基。术语″取代的炔基″指由在T1-1g,T2-2g和T3-3g的定义中所列的一个或多个基团取代的炔基,所述基团优选选自氰基,卤代基,氧代基,羟基,-OT6,-C(O)tT6,-OC(O)T6,-T4-NT7T8,-T4-N(T9)-T5-T6,-S(O)tT6或-S(O)tN(T9)T6。
术语″亚烷基″指由单键连接的1-4个碳原子的直链桥(如,-(CH2)X-,其中x为1-5),其可以为由在T1-1g,T2-2g和T3-3g的定义中所列的一个或多个基团取代,所述基团优选选自氰基,卤代基,氧代基,羟基,-OT6,-C(O)tT6,-OC(O)T6,-T4-NT7T8,-T4-N(T9)-T5-T6,-S(O)tT6或-S(O)tN(T9)T6。
术语″亚链烯基″指由单键连接的具有一个或二个双键的2-5个碳原子的直链桥,其可以为由在T1-1g,T2-2g和T3-3g的定义中所列的一个或多个基团取代,所述基团优选选自氰基,卤代基,氧代基,羟基,-OT6,-C(O)tT6,-OC(O)T6,-T4-NT7T8,-T4-N(T9)-T5-T6,-S(O)tT6或-S(O)tN(T9)T6。示例性的亚链烯基为-CH=CH-CH=CH-,-CH2-CH=CH-,-CH2-CH=CH-CH2-,-C(CH3)2CH=CH-和-CH(C2H5)-CH=CH-。
术语″亚炔基″指由单键连接的具有一个三键的2-5个碳原子的直链桥,其可以为由在T1-1g,T2-2g和T3-3g的定义中所列的一个或多个基团取代,所述基团优选选自氰基,卤代基,氧代基,羟基,-OT6,-C(O)tT6,-OC(O)T6,-T4-NT7T8,-T4-N(T9)-T5-T6,-S(O)tT6或-S(O)tN(T9)T6。示例性的亚炔基为-C≡C-,-CH2-C≡C-,-CH(CH3)-C≡C-和-C≡C-CH(C2H5)CH2-。
术语″芳(ar)”或”芳基″指芳族碳环(即烃)一-、二-或三环,其优选具有6-14个碳原子,如苯基、萘基和联苯基,以及稠合于环烷基、环烯基、杂环基或杂芳基环的此类环。实例包括:
术语″取代的芳基″指由在T1-1g,T2-2g和T3-3g的定义中所列的一个或多个基团取代的芳基,所述基团优选选自氰基,卤代基,氧代基,羟基,-OT6,-C(O)tT6,-OC(O)T6,-T4-NT7T8,-T4-N(T9)-T5-T6,-S(O)tT6或-S(O)tN(T9)T6。
术语″环烷基″指含有1-3个环的饱和和部分不饱和的(含有1或2个双键)环烃基,包括单环烷基,二环烷基和三环烷基,所述环烃基含有总共3-20个成环碳原子,优选3-7个成环碳原子,并且所述环可以稠合于1或2个芳环或杂环基环,其包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、环己烯基(hexenyl)
等。术语″取代的环烷基″指由在T1-1g,T2-2g和T3-3g的定义中所列的一个或多个基团取代的环烷基,所述基团优选选自氰基,卤代基,氧代基,羟基,-OT6,-C(O)tT6,-OC(O)T6,-T4-NT7T8,-T4-N(T9)-T5-T6,-S(O)tT6或-S(O)tN(T9)T6。
术语″卤素″和″卤代基″指氟、氯、溴和碘。
术语″杂环″、″杂环的″、″杂环基团”或”杂环基″指完全饱和的或部分或不饱和的环状基团(例如,3-13元单环、7-17元二环或10-20元三环环系,优选含有总共3-10个环原子),所述环系在至少一个含碳原子环上含有至少一个杂原子。含有杂原子的所述杂环基的每一个环可以含有1、2、3或4个选自氮原子、氧原子和/或硫原子的杂原子,其中所述氮和硫杂原子可以任选被氧化,所述氮杂原子可以任选被取代或季铵化。所述杂环基可以连接在所述环或环系的任何杂原子或碳原子上。多环杂环的各环可以为稠合的,桥接的和/或通过一个或多个螺接连接。示例性的杂环基包括
术语″取代的杂环″、″取代的杂环的″、″取代的杂环基团″和″取代的杂环基″指由在T1-1g,T2-2g和T3-3g的定义中所列的一个或多个基团取代的杂环、杂环的和杂环基,所述基团优选选自氰基,卤代基,氧代基,羟基,-OT6,-C(O)tT6、-OC(O)T6,-T4-NT7T8,-T4-N(T9)-T5-T6,-S(O)tT6或-S(O)tN(T9)T6。
本文单独或作为另一个基团的一部分所用的术语″杂芳基″指含有1-4个氮原子和/或1或2个氧或硫原子的5-、6-或7-元芳环,前提是所述环含有至少1个碳原子和不超过4个杂原子。所述杂芳基环通过可利用的碳或氮原子连接。稠合于环烷基、芳基、环杂烷基或另一个杂芳基环的此类环也包括在杂芳基环的定义的范围内。在杂芳基环上的1、2或3个可利用的碳或氮原子可以任选由在T1,T2和T3的定义中所列的各取代基取代。在杂芳基环上的氮或硫原子也可以被氧化。杂芳基环的实例包括
在整个说明书中,可以选择其基团和取代基,以提供稳定的部分和化合物。
式I化合物形成的盐也包括在本发明范围内。除非另外指明,在此涉及的式I化合物,应理解为包括其盐。在此所用的术语″盐″,指与无机酸和碱和/或有机酸和碱所成的酸式盐和/或碱式盐。此外,当式I化合物同时含有碱性部分和酸性部分时,可以形成两性离子(内盐),它们也包括在本文所用的术语″盐″中。优选药学上可接受的(即,非毒性的、生理学上可接受的)盐,虽然其它的盐可以用于制备过程所采用的例如分离或纯化步骤中。式I化合物的盐可以,例如,通过使式(I)化合物与一定量(例如等当量)的酸或碱在介质(如所述盐能沉淀于其中的介质或在水性介质中)中反应,随后冷冻干燥而形成。
含有碱性部分的式I化合物可以与各种有机酸和无机酸形成盐.示例性的酸加成盐包括乙酸盐(如与乙酸或三卤代乙酸(例如,三氟乙酸)形成的那些盐)、己二酸盐、藻酸盐、抗坏血酸盐、门冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、延胡索酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐(hemisulfates)、庚酸盐、己酸盐、盐酸盐(与盐酸形成的盐)、氢溴酸盐(与溴化氢形成的盐)、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐(与马来酸形成的盐)、甲磺酸盐(与甲磺酸形成的盐)、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酯酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的盐)、磺酸盐(如在此提及的那些盐)、酒石酸盐、硫氰酸盐、甲苯磺酸盐(如对甲苯磺酸盐)、十一烷酸盐等.
含有酸性部分的式I化合物可以与各种有机碱和无机碱形成盐。示例性的碱性盐包括铵盐、碱金属盐(如钠、锂和钾盐);碱土金属盐(如钙和镁盐);与有机碱(例如,有机胺)形成的盐,如苄星青霉素G、二环己基胺、hydrabamines(由N,N-双(脱氢枞酸基)乙二胺)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺(glucamides)、叔丁基胺所形成的盐以及与氨基酸(如精氨酸、赖氨酸等)所形成的盐。
含碱性氮的基团可以被试剂季铵化,所述试剂有如低级烷基卤化物(例如,甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物)、二烷基硫酸酯(例如,硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯)、长链卤化物(如,癸基、十二烷基、十四烷基和十八烷酰基的氯化物、溴化物和碘化物)、芳烷基卤化物(例如,苄基溴和苯乙基溴)等。
本文还设计了本发明化合物的药物前体和溶剂合物。在此所用的术语″药物前体″指这样的一种化合物,当它给予患者后,通过代谢和化学过程的化学转变,可得到式(I)化合物和/或其盐和/或溶剂合物。式(I)化合物的溶剂合物优选水合物。
就式(I)化合物及其盐可以以它们的互变异构形式存在来讲,本文构思的所有此类互变异构形式均作为本发明的一部分。
本发明化合物的所有立体异构体,例如由于在各种R和Z取代基上的不对称碳原子而可以存在的立体异构体,包括对映体形式(其甚至可以在没有不对称碳原子时存在)和非对映异构体形式,均包括在本发明范围内。本发明化合物的各单一立体异构体可以例如基本游离于其它异构体,或者可以例如作为外消旋体的混合物或与所有其它的异构体的混合物,或与其它选择的立体异构体的混合物。本发明的手性中心可以具有如IUPAC 1974推荐(Recommendations)的命名法所定义的S或R构型。
术语″包括″、″如″、″例如″等意指示例性的实施方案,但并不限制本发明的范围。
流程
式I化合物可以采用下面概述的步骤的顺序制备。具体地说,式I化合物,其中R1为-O-CO-NR6R7,R2为芳基、取代的芳基或杂芳基且-J-R3为-CH2-NH-CO-R5,可以采用流程1制备。
流程1
对乙腈2进行双迈克尔加成(Bis Michael addition),随后经狄克曼缩合作用,得到中间体环己基β-酮基酯4。经Krapcho脱羧为酮,接着经酮保护,然后将腈6还原生成伯胺7。随后将所述胺酰化、去保护,然后将生成的酮9还原。可以分离顺式和反式醇,然后用于得到终产物酯和氨基甲酸酯。
式I化合物,其中R1为-NR8-C(NCN)-NR6R7,R2为芳基、取代的芳基或杂芳基且-J-R3为-CH2-NH-CO-R5,可以采用流程2制备。
流程2
保护可市售获得的化合物1的酮部分,接着用LAH还原腈,得到胺3。将该胺酰化,使缩酮部分去保护,得到酮4。经还原性胺化,得到胺5。通过置换二苯基氰基脲的苯氧基,可以制备式6化合物。在醇溶剂中,将6和胺温热至60-75℃,得到化合物7。
或者,式I化合物,其中R1为-NR8-C(NCN)-NR6R7,R2为芳基、取代的芳基或杂芳基且-J-R3为-CH2-NH-CO-R5,可以采用流程3制备。
流程3
通过本领域技术人员熟知的方法,由可市售获得的试剂可以容易地制备用于本制备方法的化合物1。取代的环己基氰基胍(如化合物3)的制备可以采用流程2中所述的方法进行。水解TFA保护的基团,然后酰化胺4,可以得到式5化合物。
式I化合物,其中R1为-NH-SO2-NR6R7,R2为芳基、取代的芳基或杂芳基且-J-R3为-CH2-NH-CO-R5,可以采用流程4制备。
流程4
按照文献(Dewynter,G等,Tetrahedron,1996,52,14217-14224)描述的方法,可以将胺1转化为相应的磺酰基噁唑烷。在65-75℃的温度下,在醇溶剂(如乙醇和异丙醇)中,通过噁唑烷2与胺的置换反应,可以制备式3化合物。
式I化合物,其中R1为-NH-C(=NCO2R8)-NR6R7,R2为芳基、取代的芳基或杂芳基且-J-R3为-CH2-NH-CO-R5,可以采用流程5制备。
流程5
用异硫代氰基甲酸酯处理胺1,可以得到硫脲2,在EDCI的存在下,通过与胺偶合,可由2得到式3化合物。
式I化合物,其中R1为乙内酰脲杂环,R2为芳基、取代的芳基或杂芳基且-J-R3为-CH2-NH-CO-R5,可以采用流程6制备。
流程6
用光气处理胺1可以获得异氰酸酯2。在65-75℃下,在醇溶剂(如乙醇或异丙醇)中,用取代的氨基酯处理异氰酸酯2,可以获得式3化合物。
或者,根据流程7,在合适的溶剂(如二氯甲烷或THF)中,用取代的异氰基乙酸酯处理胺1,接着在酸性条件下闭环,可以获得式3化合物。
流程7
式I化合物,其中R1为咪唑烷-2-酮杂环,R2为芳基、取代的芳基或杂芳基且-J-R3为-CH2-NH-CO-R5,可以采用流程8制备。
流程8
用取代的乙二胺2使酮1还原性胺化,可以得到环己胺3。在溶剂(如THF或二氯甲烷)中,用羰基二咪唑4处理,可以将胺3转化为相应的式5的环脲。
式I化合物,其中R1为咪唑烷-2-亚基氨腈杂环,R2为芳基、取代的芳基或杂芳基且-J-R3为-CH2-NH-CO-R5,可以采用流程9制备。
流程9
在65-75℃温度下,在醇溶剂(如乙醇或异丙醇)中,用氰基亚胺酸二苯酯(dipheny carbonidate)2处理得自流程7的相同的中间体1,可以制备式3化合物。
式I化合物,其中-J-R3为-CH2-NH-R6,其中R6为芳基或杂芳基,可以采用流程10制备。
流程10
在钯催化剂如Pd2(dba)3的存在下,可使中间体1与取代的芳基或杂芳基化合物(其中X为Cl、Br、I、OTf或类似的离去基团)反应,得到化合物2。
式I化合物,其中-J-R3为-CONR6R7,可以采用流程11制备。
流程11
采用文献中已知的各种标准的偶合方法,可以使羧酸1与胺HNR6R7反应,得到式2的酰胺化合物。在溶剂(如二氯甲烷或乙腈)中,通过转化为酰氯或酰氟而活化所述羧酸,接着在碱(如三乙胺或吡啶)的存在下与胺反应,这是特别有用的偶合方法。
式I化合物,其中R1为-O-CO-NR6R7且-J-R3为杂环(例如噁二唑),可以采用流程12制备.
流程12
在有机溶剂(如正丙醇)中,可以使腈1与羟胺反应,得到甲脒(carboxamidine)2。采用标准的偶合方法,用各种羧酸、酰氯或酰氟可以酰化甲脒2,然后使得到的中间体经加热环合,得到1,2,4-噁二唑3。使1,2,4-噁二唑3的缩酮基团去保护,接着在有机溶剂(如四氢呋喃)中,用还原剂如硼氢化钠还原酮,得到羟基化合物4。通过首先使该羟基衍生物与氯代甲酸4-硝基苯酯反应,得到碳酸酯中间体,然后使其与胺反应,形成氨基甲酸酯,可以使羟基化合物4转化为氨基甲酸酯5。
采用流程13可以制备式I化合物,其中R1为-O-CO-NR6R7且-J-R3为杂环,例如四唑。
流程13
在升高的温度下,可以使腈1与叠氮化钠在有机溶剂(如N,N-二甲基甲酰胺)中反应,形成四唑2.通过在碱(如碳酸钾)的存在下,在有机溶剂(如乙腈)中,用烷基卤处理,可以使四唑2烷基化.使烷基化的四唑3的缩酮基团去保护,接着在有机溶剂(如四氢呋喃)中,通过用还原剂如硼氢化钠还原所述酮,得到羟基化合物4.通过首先使该羟基衍生物与氯代甲酸4-硝基苯基酯反应,得到碳酸酯中间体,然后使其与胺反应形成氨基甲酸酯,可以将羟基化合物4转化为氨基甲酸酯5.
采用流程14可以制备式I化合物,其中-J-R3为杂环,例如3H-喹唑啉-4-酮。
流程14
采用文献中已知的各种标准的偶合方法,可以使羧酸1与邻氨基苯甲酸反应,得到酰胺化合物2。在升高的温度下,在碱性条件下,在有机溶剂(如乙醇)中,环合化合物2,得到式3化合物。
采用流程15可以制备式I化合物,其中-J-R3为杂环,例如苯并噁唑。
流程15
采用文献中已知的各种标准的偶合方法,可以使羧酸1与2-氨基酚衍生物反应,得到酰胺化合物2。在升高的温度下,在酸性条件下,在有机溶剂(如对-二甲苯)中,环合化合物2,得到式3化合物。
采用流程16可以制备式I化合物,其中-J-R3为杂环,例如苯并咪唑。
流程16
采用文献中已知的各种标准的偶合方法,可以使羧酸1与邻-苯二胺衍生物反应,得到酰胺化合物2。在升高的温度下,在酸性条件下,在溶剂(如乙酸)中,环合化合物2,得到式3化合物。
采用流程17可以制备式I化合物,其中-J-R3为-CO-NR6aR7a且R1为-O-CO-NR6R7。
流程17
在升高的温度下,在溶剂如乙二醇中,通过用碱如氢氧化钠处理,可以使腈1转化为羧酸2。采用文献中已知的各种标准的偶合方法,可以使羧酸2与胺HNR6aR7a反应,得到酰胺化合物3。使酰胺3的缩酮基团去保护,接着在有机溶剂如四氢呋喃中,用还原剂如硼氢化钠还原酮,得到羟基化合物4。通过首先使该羟基衍生物4与氯代甲酸4-硝基苯基酯反应,得到碳酸酯中间体,然后使其与HNR6R7反应,形成氨基甲酸酯,可以将羟基化合物4转化为式5的氨基甲酸酯。
采用流程18可以制备式I化合物,其中-J-R3为-CO-NR6aR7a且R1为-NR8-CO-R4。
流程18
采用文献中已知的各种标准的偶合方法,可以使羧酸1与胺HNR6aR7a反应,得到酰胺化合物2。通过使酰胺2的缩酮基团去保护,接着通过首先用胺H2NR8处理所述酮,形成亚胺中间体,接着在有机溶剂如甲醇中,用还原剂如氰基硼氢化钠还原所述亚胺,使所述酮还原性胺化,得到氨基化合物3。采用各种标准偶合方法,可以使氨基化合物3与羧酸R4CO2H反应,得到化合物4。
采用流程19可以制备式I化合物,其中-J-R3为-CONR6aR7a且R1为-NR8-C(NCN)-NR6R7。
流程19
在升高的温度下,在溶剂如乙腈中,可以使胺1与氰基亚胺酸二苯酯(diphenylcyanocarbonimidate)反应,得到中间体2,它可以与胺HNR6R7进一步反应,得到化合物3。
式I化合物,其中-J-R3为(氨基)甲基,可以采用如在实施例323或以下流程20和21中所述方法制备。
流程20
流程21
如在以下实施例中所述,本发明范围内的其它化合物可以由上述方法获得的化合物,通过经化学合成的常用方法,将取代基转化为其它官能团而制备获得。
含有手性中心的式I化合物可以通过非-外消旋合成以非-外消旋形式获得或通过本领域技术人员熟知的方法经拆分获得。为非-外消旋的化合物在实施例中被称作″手性″。
在下述实施例中,保护反应性官能团如羟基、氨基、硫代基或羧基(这些基团在最终产物中是需要的),以避免它们参与不必要的反应可能是必须的。引入和除去保护基团是本领域技术人员熟知的,例如参见(Green,T.W.在″Protective Groups in Organic Synthesis(有机合成中的保护基团)″,John Wiley和Sons,1991中所述)。
效用
本发明范围内的化合物能抑制电压门控性K+通道的Kv1亚科,因此可用于治疗和/或预防以下各种疾病:心律失常,包括室上性心律失常、房性心律失常、心房扑动、心房纤维性颤动,心肌缺血的并发症,以及用作心率控制药;心绞痛,包括Prinzmetal氏症、血管痉挛症和变异症的缓解;胃肠疾病包括反流性食管炎、功能性消化不良、动力障碍(包括便秘和腹泻)以及肠激惹综合征;血管和内脏平滑肌的疾病,包括哮喘、慢性阻塞性肺疾病、成人呼吸窘迫综合征、周围血管疾病(包括间歇性跛行)、静脉功能不全、阳痿、脑血管和冠状动脉痉挛以及Raynaud氏病;炎症性和免疫性疾病,包括炎症性肠病、类风湿性关节炎、移植排斥、哮喘、慢性阻塞性肺疾病、囊性纤维化和动脉粥样硬化;细胞增殖性疾病包括再狭窄以及癌症(包括白血病);听觉系统疾病;视觉系统疾病,包括黄斑变性和白内障;糖尿病,包括糖尿病视网膜病、糖尿病肾病和糖尿病神经病;肌肉疾病,包括肌强直和萎缩;周围神经病变;认知障碍;偏头痛;记忆丧失,包括阿尔茨海默氏病和痴呆;中枢神经系统引起的运动机能障碍,包括帕金森氏病和共济失调;癫痫;以及其他离子通道引起的疾病.
本发明化合物作为电压门控性K+通道的Kv1亚科的抑制剂,可用于治疗以下多种疾病,包括由器官或组织移植引起的抵抗、骨髓移植导致的移植物抗宿主疾病、类风湿性关节炎、系统性红斑狼疮、桥本氏甲状腺炎、多发性硬化、重症肌无力、I型糖尿病葡萄膜炎、青少年发病的或初发型糖尿病、后部葡萄膜炎、变态反应性脑脊髓炎、肾小球性肾炎、致病性微生物导致的感染性疾病、炎症性和高增殖性皮肤病、银屑病、异位性皮炎、接触性皮炎、湿疹样皮炎、脂溢性皮炎、扁平苔癣、天疱疮、大疱性类疱疮、大疱性表皮松解症、荨麻疹、血管性水肿、血管炎、红斑、影响皮肤的嗜酸粒细胞增多症、红斑狼疮、痤疮、斑秃、角膜结膜炎、春季结膜炎、Behcet氏病相关性葡萄膜炎、角膜炎、疱疹角膜炎、圆锥角膜、角膜上皮营养不良、角膜白斑、眼天疱疮、Mooren氏溃疡性巩膜炎、Graves′眼病、Vogt-Koyanagi-Harada综合征、结节病、花粉过敏、可逆性阻塞性气道疾病、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、尘埃性哮喘、慢性或顽固性哮喘、晚期哮喘和呼吸道高反应、支气管炎、胃溃疡、缺血性疾病和血栓形成导致的血管损害、缺血性肠病、炎症性肠病、坏死性小肠结肠炎、与热烧伤和白三烯B4-介导的疾病相关的肠损害,Coeliaz病、直肠炎、嗜酸细胞性胃肠炎、肥大细胞增多症、Crohn氏病、溃疡性结肠炎、偏头痛、鼻粘膜炎、湿疹、间质性肾炎、Good-pasture氏综合征、溶血-尿毒症综合征、糖尿病肾病、多发性肌炎、Guillain-Barre综合征、Meniere氏病、多发性神经炎、单神经炎、神经根病、甲状腺功能亢进症、Basedow氏病、纯红细胞再生障碍、再生障碍性贫血、再生不良性贫血、原发性血小板减少性紫癜、自身免疫性溶血性贫血、粒细胞缺乏症、恶性贫血、巨幼细胞性贫血、红细胞发生不能、骨质疏松症、结节病、肺纤维化、原发性间质性肺炎、皮肌炎、寻常性白斑病、寻常性鱼鳞病、光过敏症(photoallergic sensitivity)、皮肤T细胞淋巴瘤、动脉硬化、动脉粥样硬化、主动脉炎综合征、结节性多动脉炎、非炎性心肌病、硬皮病、Wegener氏肉芽肿、Sjogren氏综合征、肥胖病、嗜酸粒细胞性筋膜炎、齿龈、牙周组织、齿槽骨、牙骨质损害、肾小球肾炎、可通过防止头发脱落或提供头发萌发和/或促进头发产生和头发生长治疗的男性型秃头或老年性秃头、肌营养不良;脓皮病和Sezary氏综合征、Addison氏病、器官保存、移植或缺血性疾病导致的缺血-再灌注损伤、内毒素休克、伪膜性结肠炎、药物或辐射导致的结肠炎、缺血性急性肾功能不全、慢性肾功能不全、肺-氧或药物导致的毒素病、肺癌、肺气肿、白内障、铁质沉着病、色素性视网膜炎(retinitis,pigentosa)、老年性黄斑变性、玻璃体疤痕化(vitrealscarring)、角膜碱烧伤、多形性红斑皮炎、线状IgA大疱性皮炎(linearIgA ballous dermatitis)和水泥皮炎(cement dermatitis)、齿龈炎、牙周炎、败血症、胰腺炎、环境污染导致的疾病、老化、癌变(carcinogenis)、癌转移和低气压病、组胺和白三烯-C4释放引起的疾病、Behcet氏病、自身免疫性肝炎、原发性胆汁性肝硬化、硬化性胆管炎、肝部分切除术、急性肝坏死、毒素、病毒性肝炎、休克或恶质病导致的肝坏死、乙型病毒性肝炎、非甲/非乙型肝炎、肝硬化、酒精性肝硬化、肝衰竭、爆发性肝衰竭、迟发性肝衰竭、“慢性肝炎中急性”肝衰竭(″acute-on-chronic″liver failure)、化学疗法作用的augention(augentionof chemotherapeutic effect)、巨细胞病毒感染、人类巨细胞病毒(HCMV)感染、AIDS、癌症、老年痴呆、创伤以及慢性细菌感染。
本发明的化合物为抗心律失常药,其用于预防和治疗(包括部分缓解或治愈)心律失常。作为Kv1.5抑制剂的本发明范围内的化合物特别用于选择性地预防和治疗室上心律失常,如心房纤维性颤动和心房扑动。″选择性预防和治疗室上心律失常″意指预防或治疗室上心律失常,其中延长心房的有效不应期与延长心室的有效不应期的比率大于1∶1。该比率优选大于4∶1,更优选大于10∶1,并且最好获得心房有效不应期的延长,而无明显的可检测出的心室有效不应期的延长。
此外,本发明范围内的化合物阻断IKur,因而可以用于预防和治疗所有的IKur-相关疾病。″IKur-相关疾病″为可以通过给予IKur阻断剂而预防、部分缓解或治愈的疾病。已知Kv1.5基因在胃组织、肠/结肠组织、肺动脉和胰β细胞中表达。因此,给予IKur阻断剂可对以下疾病提供有用的治疗:如:回流性食管炎、功能性消化不良、便秘、哮喘和糖尿病。此外,已知Kv1.5在垂体前叶表达。因此,给予IKur阻断剂可以刺激生长激素分泌。另外,IKur抑制剂可用于细胞增殖性疾病(如白血病)和自身免疫性疾病(如类风湿性关节炎和移植排斥反应)。
因此,本发明提供用于预防或治疗一种或多种上述疾病的方法,该方法包括给予有此需要的患者有效量的至少一种式I化合物。在本发明方法中,可将诸如下述的那些其它治疗剂与本发明化合物一起使用。在本发明的方法中,可将这样的其它治疗剂在本发明化合物给药之前、给药的同时或给药之后给予。
本发明也提供药用组合物,其包含有效量的能够预防或治疗一种或多种上述疾病的至少一种式I化合物或其盐和药学上可接受的媒介物或稀释剂。本发明的组合物可含有如下所述的其它治疗剂,并可以例如根据药物制剂领域熟知的那些技术,通过使用常规的固体或液体媒介物或稀释剂,以及适合于所需给药方式的类型的药用添加剂(例如,赋形剂、粘合剂、防腐剂、稳定剂、调味剂等)来配制。
式I化合物可以通过任何合适的方法给予,例如,口服(如以片剂、胶囊、颗粒剂或散剂的形式);舌下;颊下;胃肠外(如经皮下、静脉内、肌内或胸骨内注射,或者输注(例如,无菌注射水溶液或非水溶液或悬浮液))给药;鼻腔给药,如经吸入的喷雾剂给药;局部给药,如以霜剂或软膏剂的形式给药;直肠给药,如以栓剂的形式给予;以含有非毒性的、药学上可接受的媒介物或稀释剂的剂量单位制剂形式给予。本发明化合物可以,例如,以适合于立即释放或延缓释放的形式给药。立即释放或延缓释放可以通过采用含有本发明化合物的合适的药用组合物来实现,或者特别是在延缓释放的情况下,采用诸如皮下植入物或渗透泵的装置来实现。在其中给予式I化合物以预防或治疗心律失常的情况下,可以给予所述化合物以实现化学转化为正常的窦性心律,或可以任选与心电转化(electrical cardioconversion)联合使用。
用于口服给予的示例性组合物包括混悬剂,它可含有,例如,用于增大体积的微晶纤维素、作为悬浮剂的海藻酸或藻酸钠、作为粘度增强剂的甲基纤维素和诸如本领域已知的那些甜味剂或矫味剂;即释片剂,它可含有,例如,微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和/或乳糖和/或其它诸如本领域已知的那些赋形剂、粘合剂、填充剂、崩解剂、稀释剂和润滑剂.式I化合物也可以经舌下和/或颊下给予通过口腔传递.模制片、压片或冻干片为可以采用的示例性形式.示例性的组合物包括将本发明化合物与速溶稀释剂(如甘露糖醇、乳糖、蔗糖和/或环糊精)一起配制的那些组合物.这类制剂也可包括高分子量的赋形剂,如纤维素或聚乙二醇(PEG).这样的制剂也可包括有助于粘膜粘附的赋形剂,如羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)、马来酸酐共聚物(如,Gantrez)以及控制释放的试剂,如聚丙烯酸共聚物(例如、Carbopol 934)。也可以加入润滑剂、助流剂、矫味剂、着色剂和稳定剂,以便于制备和使用。
用于鼻内气溶胶或吸入给药的示例性组合物包括在盐水中的溶液剂,其可含有,例如,苄醇或其它合适的防腐剂、增加生物利用度的吸收促进剂,和/或其它如本领域已知的那些助溶剂或分散剂。
用于胃肠外给药的示例性组合物包括注射液或悬浮液,它们可含有,例如,合适的非毒性的、胃肠外可接受的稀释剂或溶剂,如甘露糖醇、1,3-丁二醇、水、林格氏溶液、等渗的氯化钠溶液或其它合适的分散剂或润湿剂和助悬剂,包括合成的甘油一酯或甘油二酯,以及脂肪酸(包括油酸)。
用于直肠给药的示例性组合物包括栓剂,其可含有,例如,合适的非刺激性赋形剂,如可可脂、合成的甘油酯或聚乙二醇,它们在常温下为固体,而在直肠腔内被液化和/或溶解,以释放出药物。
用于局部给药的示例性组合物包括局部用载体,如Plastibase(用聚乙烯凝胶化的矿物油)。
本发明化合物的有效量可由本领域普通技术人员确定,它包括对成人患者的每日约0.001-100mg/kg体重的活性化合物的示例性剂量,该剂量可以以单次剂量或以各分开的剂量形式(如每日1-4次)给予。应该理解,对任何具体的患者来说,用药的特定剂量水平和次数是可以变化的并取决于多种因素,所述因素包括所用的特定化合物的活性、该化合物的代谢稳定性和作用时间的长短、患者的人种、年龄、体重、一般健康状况、性别和饮食习惯、给药方式和时间、排泄速率、联合用药情况以及具体疾病的严重程度。优选治疗患者包括患有任何上述疾病的动物,最优选哺乳动物类,如人及驯养的动物,如狗、猫、马等。
本发明化合物可单独应用或互相联合应用和/或与其他用于治疗上述疾病或其他疾病的合适的治疗药物联合应用,包括:其他抗心律失常药如第I类抗心律失常药(例如普罗帕酮)、第II类抗心律失常药(例如卡维地洛和普萘洛尔)、第III类抗心律失常药(例如索他洛尔、多非利特、胺碘酮、阿齐利特和伊布利特)、第IV类抗心律失常药(例如地尔硫和维拉帕米)、5-羟色胺(5-HT)拮抗剂(例如舒兰色罗、serraline和tropsetron)以及决奈达隆;钙通道阻断剂(L型和T型),如地尔硫,维拉帕米、硝苯地平、氨氯地平和mybefradil;环氧化酶抑制剂(即COX-1和/或COX-2抑制剂),如阿司匹林、吲哚美辛、布洛芬、匹罗昔康、萘普生、西乐葆、万络和非甾体类抗炎药(NSAIDs);抗血小板药如GPIIb/IIIa阻断剂(例如阿昔单抗、eptifibatide和替罗非班)、P2Y12拮抗剂(例如氯吡格雷、噻氯匹定和CS-747)、血栓素受体拮抗剂(例如伊非曲班)、阿司匹林和与或不与阿司匹林联用的PDE-III抑制剂(例如双嘧达莫);利尿剂,如氯噻嗪、氢氯噻嗪、氟甲甲噻、氢氟噻嗪、苄氟噻嗪、甲氯噻嗪(methylchlorothiazide)、三氯噻嗪、泊利噻嗪、苄噻嗪、依他尼酸tricrynafen(ethacrynic acid tricrynafen)、氯噻酮、呋塞米、musolimine、布美他尼、氨苯喋啶、阿米洛利和螺内酯;抗高血压药,如α肾上腺素能阻断剂、β肾上腺素能阻断剂、钙通道阻断剂、利尿剂、肾素抑制剂、血管紧张素转化酶(ACE)抑制剂(例如卡托普利、佐芬普利、福辛普利、依那普利、ceranopril、西拉普利、地拉普利、喷托普利、喹那普利、雷米普利、赖诺普利)、血管紧张素II(AlI)拮抗剂(例如依奥沙坦、厄贝沙坦、缬沙坦)、内皮素(ET)拮抗剂(例如西他生坦、atrsentan和美国专利号5,612,359和6,043,265公布的化合物)、内皮素/血管紧张素II(ET/AII)双重拮抗剂(例如WO 00/01389公布的化合物)、中性肽链内切酶(NEP)抑制剂、血管肽酶抑制剂(中性肽链内切酶-血管紧张素转化酶双重抑制剂)(例如奥马曲拉和gemopatrilat)、硝酸盐以及这些抗高血压药物的组合;抗血栓/溶血栓药,如组织纤溶酶原激活剂(tPA)、重组tPA、替奈普酶(TNK)、拉诺替普酶(nPA)、VIIa因子抑制剂、Xa因子抑制剂、凝血酶抑制剂(例如水蛭素和阿加曲班)、纤溶酶原激活物抑制剂-1(PAI-1)抑制剂(即组织纤溶酶原激活物抑制剂的灭活剂)、α-2抗纤溶酶抑制剂、链激酶、尿激酶、尿激酶原、茴酰化纤溶酶原链激酶激活剂复合物以及动物或唾液腺纤溶酶原激活剂;抗凝血剂,如华法林和肝素(包括未分级和低分子量肝素,如依诺肝素和达肝素钠);HMG-CoA还原酶抑制剂,如普伐他汀、洛伐他汀、阿托伐他汀、辛伐他汀、NK-104(也称作伊伐他汀或尼伐他汀(nisvastatin)或nisbastatin)和ZD-4522(也称作罗苏伐他汀或atavastatin或visastatin);其他降胆固醇/脂药,如角鲨烯合成酶抑制剂、贝特类以及胆汁酸鳌合剂(例如消胆胺);抗增殖药,如环胞菌素A、泰素、FK 506和多柔比星;抗肿瘤药,如泰素、多柔比星、埃博霉素(Epothilones)、顺铂、卡铂;抗糖尿病药,如双胍类(如二甲双胍)、葡萄糖苷酶抑制剂(例如阿卡波糖)、胰岛素、美格列奈类(例如瑞格列奈)、磺酰脲(例如格列美脲、格列苯脲和格列吡嗪)、双胍/格列苯脲合剂(即glucovance)、噻唑烷二酮类(例如曲格列酮、罗格列酮和吡格列酮)、PPAR-γ激动剂、aP2抑制剂以及DP4抑制剂;拟甲状腺剂(包括甲状腺素受体拮抗剂)(例如促甲状腺素、polythyroid、KB-130015和决奈达隆);盐皮质激素受体拮抗剂,如螺内酯、依普利酮;生长激素促释放素;抗骨质疏松药(例如阿仑膦酸和雷洛昔芬);激素替代治疗药物,如雌激素(包括倍美力中的轭合雌激素)以及雌二醇;抗抑郁药,如奈法唑酮和舍曲林;抗焦虑药,如地西泮、劳拉西泮、丁螺环酮和双羟萘酸羟嗪;口服避孕药;抗溃疡和胃食管反流病药,如法莫替丁、雷尼替丁和奥美拉唑;减肥药,如奥利司他;强心甙类,包括洋地黄和毒毛花甙G;磷酸二酯酶抑制剂,包括磷酸二酯酶III(PDE III)抑制剂(例如西洛他唑)和磷酸二酯酶V(PDE V)抑制剂(例如西地那非);蛋白酪氨酸激酶抑制剂;类固醇类抗炎药,如泼尼松和地塞米松;以及其他抗炎药,如依那西普。
当与本发明化合物联合使用时,可以例如以在Physicians′DeskReference(RDR)中说明的那些量或由本领域普通技术人员采用别的方式确定的量,使用上面的其它治疗剂。
测定作为IKur抑制剂的化合物的活性程度的测定法为本领域所熟知,并参考文献诸如J.Gen.Physiol.Apr;101(4):513-43和Br.J.Pharmacol.1995年5月;115(2):267-74中描述。
测定作为Kv1亚家族的其它成员的抑制剂的化合物的活性程度的测定法也为本领域所熟知。例如,Kv1.1、Kv1.2和Kv1.3的抑制作用可以采用Grissmer S等在Mol Pharmacol 1994年6月;45(6):1227-34中描述的方法测量。Kv1.4的抑制作用可以采用Petersen KR和Nerbonne JM在Pflugres Arch 1999年2月;437(3):381-92中描述的方法测量。Kv1.6的抑制作用可以采用Bowlby MR,和Levitan IB,在JNeurophysiol 1995年6月;73(6):2221-9中描述的方法测量。而Kv1.7的抑制作用可以采用Kalman K等在J Biol Chem 1998年3月6日;273(10):5851-7中描述的方法测量.
在如上文描述的Kv1测定法中,本发明范围内的化合物显示出活性。
本说明书中引用的所有文献全文通过引用结合到本文中。
下面的实施例和制备法描述了制备和使用本发明的方式和方法,这些实施例和制备法是为说明之用,而不作任何限制。应该理解,可以有其它落入由说明书所附的权利要求书所限定的本发明的精神和范围内的实施方案。
具体实施方式
实施例1
顺式和反式-N-(4-羟基-1-噻吩-2-基-环己基甲基)-2-甲氧基-苯甲酰胺
合成:
化合物2:于室温下,将三硝基甲苯B(Triton B)(0.19mL,40%甲醇溶液(重量比),0.42mmol)加入到2-噻吩乙腈(500mg,4.06mmol)的乙腈(27ml)溶液中.在氮气下,将反应混合物加热至95℃,缓慢加入丙烯酸甲酯(3.6ml,40mmol)(剧烈放热).5小时后,使反应混合物冷却,用50ml乙醚稀释.将该溶液转移至分液漏斗中,用HCl(1N,2x20ml)和饱和NaCl(1x20ml)顺次洗涤.经无水硫酸钠干燥有机部分,倾析并浓缩,得到1.10g(92%粗产率)的2,为深棕色油状物:1H NMR(CDCl3)2.2ppm,2H,多重峰;2.3ppm,2H,多重峰;2.4ppm,2H,多重峰;3.65ppm,6H,单峰;6.97ppm,1H,dd,J=3.6和6.2Hz;7.13ppm,1H,dd,J=1.2和3.6Hz;7.32ppm,1H,dd,J=1.2和5.1Hz。
化合物3:使化合物2(1.10g,3.72mmol)溶于无水二甲基乙二醇(20ml)中。将氢化钠(60%在矿物油中的悬浮液,360mg,11.2mmol)缓慢加入到该溶液中,在氮气下,将生成的棕色淤浆加热至95℃4.5小时,然后使之冷却过夜(12小时)。小心地将淤浆倾入15ml水中,用100ml乙醚稀释。将有机部分用HCl(3.7N,2x20ml)洗涤,经无水硫酸钠干燥,倾析并浓缩,得到棕色油状物。该粗品油状物经硅胶快速层析纯化,用3∶1己烷∶乙酸乙酯洗脱,得到298mg(31%分离率)3,为浅棕色油状物。HPLC Rt 3.10分钟,纯度100%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%水溶液,0.2%磷酸)的梯度,于220nm处UV检测。LCMS Rt 1.61分钟,[M+Na]286.10YMC S5柱4.6x30mm,2分钟的0至100%MeOH(90%在水中,0.1%TFA)的梯度,于220nm处UV检测。1H NMR(CDCl3)2.2ppm,2H,多重峰;2.4ppm,2H,多重峰;2.7ppm,2H,多重峰;2.75ppm,1H,d,J=13.6Hz;3.15ppm,1H,d,J=15.0Hz;7.00ppm,1H,dd,J=3.6和5.1Hz;7.18ppm,1H,dd,J=1.2和3.6Hz;7.29ppm,1H,dd,J=1.2和5.2Hz;12.2ppm,1H,单峰。
化合物4:向β-酮酯3(298mg,1.13mmol)的DMSO(8mL,含有0.5mL水)溶液中加入氯化钠(420mg,7.24mmol)。将反应混合物加热至150℃5小时,然后使之冷却至室温。将该溶液用1∶1乙醚∶乙酸乙酯(50ml)稀释,转移至分液漏斗中,用10%氯化锂(3x20ml)洗涤。经无水硫酸钠干燥有机部分,倾析并浓缩,得到4,为浅棕色粉末,其纯度足以用于下一步骤,(184mg,80%收率)。HPLC Rt 2.36分钟,纯度97%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%水溶液,0.2%磷酸)的梯度,于220nm处UV检测。1H NMR(CDCl3)2.3ppm,2H,多重峰;2.6ppm,4H,多重峰;2.9ppm,2H,多重峰;7.00ppm,1H,dd,J=3.6和6.2Hz;7.20ppm,1H,dd,J=1.2和3.6Hz;7.32ppm,1H,dd,J=1.2和5.1Hz。
化合物5:使溶于甲苯(2ml)和乙二醇(0.54ml,9.6mmol)中,加入甲苯磺酸(9mg,0.05mmol)。将该溶液加热至回流,用Dean-Stark共沸14小时除去水。将冷却的反应混合物用乙醚(100ml)稀释,然后用水(3x20ml)洗涤。经无水硫酸钠干燥有机部分,倾析并浓缩,得到5,为浅棕色油状物,(323mg,粗品定量收率)。HPLC Rt 2.90分钟,纯度83.0%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%在水中,0.2%磷酸)的梯度,于220nm处UV检测。1H NMR(CDCl3)1.9ppm,2H,多重峰;2.0ppm,2H,多重峰;2.1ppm,2H,多重峰;2.2ppm,2H,多重峰;4.00ppm,4H,多重峰;6.98ppm,1H,dd,J=1.2和3.6Hz;7.14ppm,1H,dd,J=1.2和5.1Hz;7.27ppm,1H,dd,J=1.2和5.1Hz。
化合物6:于室温下,将氢化锂铝(1.0M的THF溶液,1.35ml,1.35mmol)溶液加入到5的THF(5ml)溶液中。在氮气下,将得到的淤浆加热至回流3小时,然后冷却至0℃。滴加入1N NaOH(0.3ml),剧烈搅拌10分钟后,加入无水硫酸钠。通过玻璃滤器(glass frit)过滤淤浆,用THF洗涤滤器,然后浓缩滤液得到151mg(66%收率)的6,为无色油状物。HPLC Rt 1.47分钟,纯度98%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%水溶液,0.2%磷酸)的梯度,于220nm处UV检测。1H NMR(CDCl3)1.7ppm,4H,多重峰;1.8ppm,2H,多重峰;2.1ppm,2H,多重峰;2.7ppm,2H,多重峰;3.92,4H,多重峰;6.86,1H,dd,J=0.9和3.5Hz;6.97,1H,dd,J=3.5和5.0Hz;7.21,1H,dd,J=0.9和5.0Hz。
化合物7:于室温下,将邻-甲氧苯甲酰氯(107mg,0.597mmol)加入到胺6的二氯甲烷(2ml)和TEA(63mg,0.63mmol)的溶液中。将得到的淡黄色溶液搅拌1小时,然后直接填入硅胶层析柱中。用1∶1己烷∶乙酸乙酯洗脱该柱,得到195mg(85%收率)酰胺7,为无色油状物。HPLCRt 3.34分钟,纯度97%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%水溶液,0.2%磷酸)的梯度,于220nm处UV检测。LCMSRt 1.73分钟,[M+1]388.13YMC S5柱4.6x30mm,2分钟的0至100%MeOH(90%水溶液,0.1%TFA)的梯度,于220nm处UV检测。1HNMR(CDCl3)1.7ppm,4H,多重峰;2.0ppm,2H,多重峰;2.2ppm,2H,多重峰;3.68ppm,2H,d,J=6.0Hz;3.73,3H,s;4.1ppm,4H,多重峰;6.89ppm,1H,d,J=8.3Hz;6.95ppm,1H,dd,J=0.9和3.5Hz;7.01ppm,1H,dd,J=3.5和5.1Hz;7.06ppm,1H,dd,J=7.4和8.0Hz;7.27ppm,1H,dd,J=0.8和4.9Hz;7.40ppm,1H,dd,J=1.1和1.7Hz;7.8ppm,1H,br s;8.19ppm,1H,dd,J=1.8和7.8Hz。
化合物8:使7(195mg,0.504mmol)溶于THF(4ml)中,加入2N HCl(1ml)。将得到的溶液加热至40℃3小时,使之冷却,用乙醚(50ml)稀释,用饱和碳酸氢钠(3x20ml)洗涤。经无水硫酸钠干燥有机部分,倾析并浓缩,得到200mg(粗品定量收率)的9,为无色油状物。HPLC Rt3.00分钟,纯度92%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%水溶液,0.2%磷酸)的梯度,于220nm处UV检测。LCMSRt 1.55分钟,[M+1]333.08YMC S5柱4.6x30mm,2分钟的0至100%MeOH(90%水溶液,0.1%TFA)的梯度,于220nm处UV检测。1H NMR(CDCl3)2.2ppm,2H,多重峰;2.5ppm,6H,多重峰;3.75,3H,s;3.79ppm,1H,d,J=6.2Hz;6.92ppm,1H,d,J=8.3Hz;7.03ppm,1H,dd,J=0.9和3.5Hz;7.08ppm,2H,多重峰;7.35ppm,1H,dd,J=0.8和5.1Hz;7.43ppm,1H,ddd,J=1.8,7.5和8.5Hz;7.9ppm,1H,br t;8.20ppm,1H,dd,J=1.8和7.8Hz。
化合物9和10:向粗品酮8(200mg粗品,0.504mmol)的THF溶液中(4ml)加入硼氢化钠(44mg,1.5mmol)。于室温、氮气下,将该反应混合物搅拌14小时,然后用二氯甲烷(100ml)稀释该淤浆。将该淤浆转移至分液漏斗中,将有机部分用1N HCl(2x20ml)洗涤,经无水硫酸钠干燥,倾析并浓缩,得到9和10的混合物,为无色油状物。经制备性薄层层析(25x25cm,1mm板,于254nm处UV检测)分离异构体,用2∶1二氯甲烷∶MTBE作为洗脱液。分离较小极性的成分为化合物9(43mg):HPLC Rt 3.16分钟,纯度95%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%水溶液,0.2%磷酸)的梯度,于220nm处UV检测。LCMS Rt 1.64分钟,[M+1]346.10YMC S5柱4.6x30mm,2分钟的0至100%MeOH(90%水溶液,0.1%TFA)的梯度,于220nm处UV检测。1H NMR(MeOD)1.3ppm,2H,多重峰;1.5ppm,2H,多重峰;2.1ppm,2H,br d;3.37ppm,2H,s;3.5ppm,1H,多重峰;3.64ppm,3H,s;6.8ppm,4H,多重峰;7.22ppm,1H,dd,J=0.7和5.4Hz;7.32ppm,1H,dd,J=1.8和8.7Hz;7.78ppm,1H,dd,J=1.7和7.8Hz;8.0ppm,1H,br s。分离较大极性的成分为化合物10(47mg):HPLC Rt 2.95分钟,纯度94%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%水溶液,0.2%磷酸)的梯度,于220nm处UV检测。LCMS Rt 1.52分钟,[M+1]346.13YMC S5柱4.6x30mm,2分钟的0至100%MeOH(90%水溶液,0.1%TFA)的梯度,于220nm处UV检测。1H NMR(MeOD)1.6ppm,4H,多重峰;1.8ppm,2H,多重峰;2.0ppm,2H,多重峰;3.62ppm,1H,d,J=5.9Hz;3.63,1H,br多重峰;3.64ppm,3H,s;6.9ppm,4H,多重峰;7.26ppm,1H,dd,J=0.6和4.6Hz;7.36ppm,1H,dd,J=1.8和8.7Hz;7.87ppm,1H,dd,J=1.8和7.8Hz;8.0ppm,1H,br t。
实施例2-12
实施例2-12采用在实施例1中描述的方法制备。
实施例13
反式-乙基-氨基甲酸4-[(2-甲氧基-苯甲酰基氨基)-甲基]-4-噻吩-2-基-环己基酯
合成:
化合物1 1的合成描述于实施例1中。
化合物2:于室温下,将氯代甲酸4-硝基苯酯(45mg,0.22mmol)加入到醇1(43mg,0.12mmol)的含有三乙胺(约38mg)的二氯甲烷(10ml)溶液中。将得到的黄色溶液搅拌72小时,然后,经硅胶层析直接纯化,用2∶1己烷∶乙酸乙酯洗脱,得到32mg(52%收率)的2,为无色油状物。HPLC Rt 3.91分钟,纯度84%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%水溶液,0.2%磷酸)的梯度,于220nm处UV检测。1H NMR(CDCl3)1.8ppm,4H,多重峰;2.1ppm,2H,多重峰;2.3ppm,2H,多重峰;3.69ppm,1H,d,J=6.0Hz;3.75ppm,3H,s;4.8ppm,1H,多重峰;6.9ppm,3H,多重峰;7.05ppm,2H,多重峰;7.32ppm,1H,d,J=8.0Hz;7.45ppm,1H,dd,J=1.8和8.7Hz;7.9ppm,1H,br t;8.15ppm,1H,d,J=8.0Hz;8.20ppm,1H,dd,J=1.8和7.8Hz。
化合物3:于室温下,将乙胺溶液(0.8ml,2.0M的THF溶液)加入到2(32mg,0.062mmol)的二氯甲烷(3ml)溶液中。1小时后,将黄色溶液直接装入制备性薄层层析板(25x25cm,1mm,于254nm处UV检测器)中。用1∶1己烷∶乙酸乙酯洗脱该板,得到11mg(43%收率)的3,为无色玻璃状物。HPLC Rt 3.37分钟,纯度96%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%水溶液,0.2%磷酸)的梯度,于220nm处UV检测。LCMS Rt 1.71分钟,[M+1]417.14YMC S5柱4.6x30mm,2分钟的0至100%MeOH(90%水溶液,0.1%TFA)的梯度,于220nm处UV检测。1H NMR(CDCl3)1.09ppm,3H,t,J=7.1Hz;1.6ppm,2H,多重峰;1.8ppm,2H,多重峰;2.0ppm,2H,多重峰;2.2ppm,2H,多重峰;3.18ppm,2H,多重峰;3.65ppm,2H,d,J=6.0Hz;3.74ppm,3H,s;4.72ppm,1H,br s;4.48ppm,1H,br s;6.90ppm,1H,d,J=8.2Hz;6.95ppm,1H,d,J=3.0Hz;7.15ppm,2H,多重峰;7.28ppm,1H,d,J=5.0Hz;7.45ppm,1H,dd,J=1.8和8.8Hz;7.8ppm,1H,br s;8.20ppm,1H,d,J=2.2和7.7Hz。
实施例14-27
实施例14-27采用实施例13中描述的方法制备。
实施例28
乙酸4[(2-甲氧基-苯甲酰基氨基)-甲基]-4-噻吩-3-基-环己基酯
合成:
化合物1:1的合成描述于实施例1中。
化合物2:于室温下,将乙酰氯(6mg,0.08mmol)加入到醇1(14mg,0.040mmol)的含有TEA(约8mg)的二氯甲烷(10ml)溶液中。将得到的黄色溶液搅拌16小时,然后经制备性HLPC直接纯化:YMC ODS S520x100mm柱,30-100%MeOH(90%水溶液,0.1%TFA)梯度8分钟,流速20mL/分钟,于220nm处UV检测。酯2在保留时间8.6分钟洗脱,分离出无色油状物(6.6mg,收率43%)。HPLC Rt 3.42分钟,纯度100%,YMC S5柱4.6x50mm,4分钟的0至100%MeOH(90%水溶液,0.2%磷酸)的梯度,于220nm处UV检测。LCMS Rt 1.78分钟,[M+1]388.13YMC S5柱4.6x30mm,2分钟的0至100%MeOH(90%水溶液,0.1%TFA),于220nm处UV检测。1H NMR(CDCl3)1.7ppm,2H,多重峰;1.8ppm,2H,多重峰;1.9ppm,4H,多重峰;2.06ppm,3H,s;3.71ppm,3H,s;3.71ppm,2H,d,J=8.0Hz;5.3ppm,1H,七重峰;6.90ppm,1H,d,J=8.3Hz;7.06ppm,1H,t;7.1ppm,2H,多重峰;7.4ppm,2H,多重峰;7.74ppm,1H,br t;8.19ppm,1H,dd,J=1.8Hz和7.8Hz。
实施例29-30
实施例29-30采用实施例28中描述的方法合成。
实施例31
顺式-2-甲氧基-N-[4-(N-甲基-N’-氰基胍基)-1-苯基-环己基甲基]-苯甲酰胺
合成:
化合物1:化合物1由市售获得。
化合物2:向4-苯基-4-氰基-环己烷-1-酮1(10g,50mmol)的200ml甲苯溶液中分别一次性加入对甲苯磺酸一水合物(2.5g,13.1mmol)和乙二醇(20ml,360mmol)。将得到的溶液在回流下搅拌5小时。真空浓缩反应混合物,得到油状残留物。然后用EtOAc(200ml)稀释,用碳酸氢钠水溶液(50mlx2)和盐水(50mlx1)洗涤。经硫酸镁干燥有机层,真空浓缩,得到油状物(12.9g,>95%),其无须任何进一步的纯化而用于下面的反应。
化合物3:向腈2(12.9g)的100ml THF溶液中滴加入60ml 1MLAH/THF,将生成的溶液在回流下搅拌2小时。
使反应混合物冷却至0℃,小心地用水猝灭。将反应混合物用EtOAc(500ml)稀释,用饱和氢氧化锂-氯化钠(50mlx3)洗涤。经硫酸镁干燥有机层,真空浓缩,得到油状物(13.6g,>95%),其无须进一步纯化而用于下面的反应。
化合物4:于0℃,向胺3(5.9g,24mmol)和三乙胺(6.0ml,43mmol)的100ml二氯甲烷溶液中滴加入甲氧苯甲酰氯(4.5ml,30.4mmol),将生成的溶液搅拌2小时。真空浓缩反应混合物,得到白色固体残留物,使其分配于EtOAc(200ml)和碳酸氢钠水溶液(50ml)之间。经硫酸镁干燥有机层,真空浓缩,得到油状物,将其稀释于50ml THF和50ml2N HCl水溶液中。于25℃,将得到的溶液搅拌12小时。将反应混合物用EtOAc(200ml)稀释。分离有机层,用盐水(50mlx2)洗涤,经硫酸镁干燥。浓缩有机层,得到油状残留物,将其经柱层析纯化(50%乙酸乙酯/己烷),得到6.8g(20.2mmol,84%两步)所需产物。
化合物5:向酮4(13g,38.6mmol)的100ml MeOH溶液中加入乙酸铵(23.2g,300mmol)和NaBH(OAc)3(12.2g,57.8mmol),于25℃将得到的混合物搅拌12小时。真空浓缩反应混合物,得到固体残留物,使其分配于EtOAc(200ml)和1N NaOH水溶液(30mlx 2)之间。经硫酸镁干燥有机层。浓缩有机溶液,得到油状残留物,将其经柱层析(10%NH3-MeOH/二氯甲烷),得到10.8g所需产物,为两种非对映异构体的1∶1混合物。
化合物6和7:使胺5(3.6g,10.7mmol)溶于乙腈(100ml)中。滴加入溶于30ml乙腈中的二碳酸二叔丁基酯(3.5g,16mmol)溶液。于25℃搅拌该混合物2小时。真空浓缩反应混合物,得到油状残留物,将其经柱层析(50%Hex/EtOAc),得到boc-保护的胺的2.1g反式-异构体(保留时间:2.43分钟)和1.9g顺式-异构体(保留时间:2.67分钟)。使每种胺溶于40ml 25%TFA/二氯甲烷中,于25℃搅拌2小时。真空浓缩,得到油状残留物,使其溶于乙酸乙酯(各150ml)中,用1N NaOH水溶液(100mlx2)洗涤。经硫酸镁干燥有机层,真空浓缩,得到油状物,其对应于单一非对映异构体的胺。
化合物9:向胺6的顺式-异构体(700mg,2.07mmol)的40ml 2-丙醇溶液中加入氰基亚胺酸二苯酯(0.48g,2.07mmol),将该反应混合物回流搅拌4小时。真空浓缩,得到油状物,其无需任何进一步的纯化而用于以下的反应。
化合物10:向9(100mg,0.21mmol)的2ml 2-丙醇溶液中加入2mlMeNH2(2N的THF溶液)。于75℃,于密封管中搅拌该混合物2小时。使该反应混合物冷却至室温,真空浓缩,得到油状残留物,将其经制备性HPLC纯化(YMC S5ODS 30x 250mm反相柱;30分钟的70∶30A∶B至100%B的梯度,其中溶剂A=90∶10∶0.1水∶MeOH∶TFA,溶剂B=90∶10∶0.1MeOH∶水∶TFA),得到53.4mg(0.13mmol,62%)所需产物,经冷冻干燥后为白色固体(MeOH/水)。[M+H]=420。
实施例32-52
实施例32-52采用实施例31中描述的方法合成。
实施例53
反式-2-甲氧基-N-[4-(N-甲基-N′-氰基胍基)-1-苯基-环己基甲基]-苯甲酰胺
合成:
化合物1:化合物1按实施例31中所述合成。
化合物2:向反式-胺1(300mg,1.26mmol)的20ml 2-丙醇溶液中加入氰基亚胺酸二苯酯(0.24g,1.26mmol),将得到的混合物在回流下搅拌4小时。真空浓缩反应混合物,得到油状物,其无须任何进一步的纯化而用于下一步反应。
化合物3:向中间体2(100mg,0.21mmol)的2ml 2-丙醇溶液中加入2ml甲胺(2N的THF溶液)。于75℃,在密封管中搅拌该混合物2小时。冷却反应混合物,真空浓缩,得到油状残留物,将其经制备性HPLC纯化(按实施例1所述),得到49.3mg(0.12mmol,57%)所需产物,经冷冻干燥后为白色固体(MeOH/水)。[M+H]=420。
实施例54-61实施例54-61采用实施例53中描述的方法合成。
实施例62和63:
反式和顺式-N-[4-(N,N’-二乙基-氰基胍基)-1-苯基-1-环己基甲基]-2-甲氧基-苯甲酰胺
化合物1:1的合成描述于实施例31中。
化合物2:向酮1(0.34g,1mmol)的35ml二氯甲烷溶液中加入EtNH2(1ml 2M的THF溶液,2mmol)、NaBH(OAc)3(0.42g,2mmol)和数滴AcOH(催化量)。于25℃,将得到的溶液搅拌3小时。真空浓缩反应混合物,得到油状残留物,将其稀释于250ml AcOH中,用1N NaOH水溶液(20mlx2)洗涤。经硫酸钠干燥有机层,真空浓缩,得到2,为油状物(0.35g,>95%),其无须进一步纯化而用于下面的反应。化合物3:于70℃,将氰基亚胺酸二苯酯(2.4g,10mmol)和EtNH2(5ml2M在MeOH中的溶液,10mmol)的10ml 2-丙醇溶液在密封管中搅拌4小时。真空浓缩反应混合物,得到白色固体,将其经柱层析纯化(30%乙酸乙酯/己烷),得到1.6g(85%)所需产物3,为白色固体。
化合物4:于70℃,将化合物2(110mg,0.3mmol)和化合物3(74mg,0.39mmol)的5ml 2-丙醇溶液搅拌12小时。浓缩反应混合物,经制备性-HPLC纯化(描述于实施例31的合成中),得到顺式和反式非对映异构体。获得反式化合物(保留时间:3.19分钟)(23mg)和顺式化合物(保留时间:3036分钟)(14mg),均为无色油状物。质谱[M+H]+ 462。
实施例64:
反式-2-甲氧基-N-[4-(N-乙基-N’-亚磺酰脲基(sulfenylureido))-1-苯基-环己基甲基]-苯甲酰胺
合成:
化合物1:1的合成描述于实施例31中。
化合物2:使氯代磺酰基异氰酸酯(0.37ml,4.1mmmol)溶于40ml二氯甲烷中并冷却至0℃。缓慢加入氯代乙醇(0.27ml,4.1mmol),于0℃,将反应混合物搅拌另外1.5小时。将胺1(1.4g,4.1mmol)和三乙胺(1.3ml,12.4mmol)的50ml二氯甲烷溶液缓慢加入到该反应混合物中,以使反应温度不超过5℃。使反应混合物温热至25℃并搅拌过夜。将反应物通过滴加2N HCl猝灭用NaCl饱和。分离有机层,将水层用二氯甲烷(100ml x 3)提取。经硫酸镁干燥合并的有机层,真空浓缩,得到2,为白色固体(2.0g),其无须进一步纯化而用于下面的反应。
化合物3:于65℃,将2(90mg,0.18mmol)、EtNH2(0.4mmol,0.2ml2M的MeOH溶液)和三乙胺(0.1ml)在2ml乙腈中的溶液搅拌2小时。将反应混合物经制备性HPLC纯化(描述于实施例31的合成中),得到12.1mg的3,为无色油状物。质谱[M+H]+=446。
实施例65-72
实施例65-72采用实施例64中描述的方法合成。
实施例73:
顺式-2-甲氧基-N-{4-[N-(4-甲氧苯甲酰基)-N′-亚磺酰脲基]-1-苯基-环己基甲基}-苯甲酰胺
合成:
化合物1:1的合成描述于实施例31中。
化合物2:使氯代磺酰基异氰酸酯(0.22ml,2.5mmol)溶于2ml二氯甲烷中并冷却至0℃。缓慢加入氯代乙醇(0.16ml,0.25mmol),于0℃将反应混合物搅拌另外1.5小时。将顺式-胺1(0.85g,2.5mmol)和三乙胺(0.8ml,7.6mmol)的30ml二氯甲烷溶液缓慢加入到反应混合物中。使该溶液温热至25℃并搅拌过夜。通过滴加2N HCl猝灭反应物,用NaCl饱和。分离有机层,将水层用二氯甲烷(60mlx3)提取。经硫酸镁干燥合并的有机层,真空浓缩,,得到白色固体,将其经柱层析纯化(50%Hex/EtOAc),得到1.1g(2.2mmol,87%)的2,为白色固体。
化合物3:于65℃,将2(17mg,0.035mmol)和对-甲氧基苯胺(10mg,0.08mmol)的1ml乙腈溶液搅拌2小时。反应混合物经制备性HPLC纯化(描述于实施例31的合成中),得到3.2mg的3,为无色油状物。质谱[M+H]+ 524。
实施例74-147
实施例74-147采用实施例73中描述的方法合成。
实施例148:
顺式-N-[4-(N′-乙基-胍基)-1-苯基-环己基甲基]-2-甲氧基-苯甲酰胺
合成:
化合物1:化合物1的合成描述于实施例31中。
化合物2:向胺1(0.35g,1.0mmol)在10ml二氯甲烷和5ml碳酸氢钠水溶液中的溶液中一次性加入硫光气(0.3ml,4.0mmol).于25℃将该反应混合物搅拌2小时.然后分离有机层,真空浓缩,得到油状物(0.34g,89%).使油状物溶于10ml 7N NH3/MeOH中,于25℃搅拌12小时。真空浓缩反应混合物,得到2,为油状物,其无须进一步纯化而用于下一步反应。
化合物3:向2的10ml乙腈溶液中加入MeI(0.5ml),在25℃下,将生成的溶液搅拌12小时。真空浓缩反应混合物,得到白色固体,使其分配于EtOAc(50ml)和盐水(20ml)之间。经硫酸镁干燥有机层,真空浓缩,得到350mg(>95%)3,为油状物,其无须进一步纯化而用于下面的反应。
化合物4:向3(0.17g,0.45mmol)的10ml二氯甲烷溶液中加入三乙胺(0.2ml)和乙酰氯(0.2ml,2.8mmol),于0℃,将生成的溶液搅拌1小时。将反应混合物用EtOAc(50ml)稀释,用盐水(10ml x 2)洗涤。经硫酸镁干燥有机层,真空浓缩,得到4,为深色油状物,其无须进一步纯化而用于下面的反应。
化合物5:于70℃将4(35mg,0.077mmol)和乙胺(1mmol,0.5ml 2MNH3的THF溶液)的1ml 2-丙醇溶液在密封管中搅拌12小时。然后使反应混合物经制备性HPLC纯化(描述于实施例31的合成中),得到17.9mg(40%)所需产物5,为无色油状物。质谱[M+H]+=409。
实施例149-152
实施例149-152采用在实施例148中描述的方法合成。
实施例153
顺式-2,4-二甲氧基-N-[4-(N-甲基-N’-氰基胍基)-1-苯基-环己基甲基]-苯甲酰胺
合成:
化合物11的合成描述于实施例31中。
化合物2:向胺1(1.0g,4.0mmol)和三乙胺(0.67ml,4.8mmol)的10ml二氯甲烷溶液中滴加入三氟乙酸酐(1.0ml,4.8mmol),于-78℃搅拌生成的溶液2小时。真空浓缩反应混合物,得到油状残留物,使其分配于EtOAc(100ml)和盐水(20mlx2)之间。经硫酸镁干燥有机层,真空浓缩,得到所需产物2(1.3g,0.38mmol,>95%),为无色油状物。该产物无须进一步纯化而用于下一步反应。
化合物3:使中间体2(1.3g)溶于THF(50ml)中。向该溶液中加入30ml 2N HCl,于25℃,将生成的溶液搅拌12小时。HPLC分析显示起始原料完全消失并形成新的产物。将反应混合物用EtOAc(100ml)稀释,然后用碳酸氢钠水溶液(30mlx2)洗涤。经硫酸镁干燥有机层,真空浓缩,得到1.2g(>95%)的3,为油状物。
化合物4:向酮3(1.2g,4mmol)的MeOH(60ml)溶液中加入乙酸铵(2.5g,31mmol),接着一次性加入NaBH(OAc)3(1.4g,5.2mmol)。于25℃,将得到的溶液搅拌3小时。浓缩反应混合物,使生成的固体再溶解于乙酸乙酯(100ml)中,用NaOH水溶液(1M,30mlx2)洗涤。经硫酸镁干燥有机层,真空浓缩,得到油状物,为所需胺4的顺式和反式非对映异构体的1∶1混合物。
化合物5:向胺4(0.30g,l mmol)的2-丙醇(2ml)溶液中加入氰基亚胺酸二苯酯(240mg,1mmol),于70℃搅拌生成的溶液3小时。HPLC分析指示反应完成。使反应混合物冷却至25℃,然后移入密封管中。向该密封管中加入2ml 2M MeNH2(4mmol)。于70℃,将得到的溶液搅拌另外5小时。将该反应化合物浓缩至2ml溶液,经制备性HPLC纯化(描述于实施例31的合成中),得到化合物5的顺式-异构体(保留时间:2.90分钟)(70mg)和反式-异构体(保留时间:2.65分钟)(60mg)。
化合物6:使中间体5的顺式异构体(1.1g,2.9mmol)溶于40ml含有7%碳酸钾水溶液的MeOH-H2O的1∶1混合物中,于25℃,将生成的溶液搅拌3小时。HPLC分析指示反应完成。真空浓缩反应混合物,得到白色固体,使其分配于EtOAc(100ml)和盐水(20mlx2)之间。将含水层用乙酸乙酯(50ml)提取。经硫酸镁干燥有机层,真空浓缩,得到0.81g(>95%)的6,为油状物,其无须任何进一步的纯化而用于下面的反应。
化合物7:向胺6(40mg,0.014mmol)的2ml二氯甲烷溶液中顺次加入2,4-二甲氧基苯甲酸(38mg,0.021mmol)、EDCI(60mg,0.031mmol)和二异丙基乙胺(57μL,0.031mmol).于35℃搅拌该混合物30小时.反应混合物经制备性HPLC纯化(描述于实施例31的合成中),得到6.7mg所需产物7,为无色油状物.质谱[M+H]+=450。
实施例154-170
实施例154-170采用实施例153中描述的方法合成。
实施例171:
2-甲氧基-N-[4-(N-乙基-N′-乙氧基羰基-胍基)-1-苯基-环己基甲基]-苯甲酰胺。
合成:
化合物1:1的合成描述于实施例31中。
化合物2:于0℃,向胺1(顺式和反式异构体的混合物,0.34g,1.0mmol)的15ml二氯甲烷溶液中加入0.12ml异硫氰基甲酸乙酯(0.12ml,1.0mmol)。于0℃,搅拌该混合物0.5小时,于25℃搅拌3小时。将反应混合物用100ml二氯甲烷稀释,用1N HCl(20ml)和盐水(20ml)洗涤。有机溶液经硫酸镁干燥,真空浓缩,得到0.43g(95%)所需产物2,为无色油状物,其无须进一步纯化而用于下面的反应。
化合物3:向中间体2(50mg,0.11mmol)的5ml二氯甲烷溶液中顺次加入乙胺(0.1ml 2N的THF溶液,0.2mmol)、EDCI(42mg,0.22mmol)和二异丙基乙胺(0.02ml,0.11mmol)。于25℃,搅拌反应混合物12小时。该反应混合物经制备性HPLC纯化(描述于实施例31的合成中),得到22.2mg(42%)所需产物3(顺式-和反式-异构体的1∶1混合物),为无色油状物。质谱[M+H]+=481。
实施例172-178
实施例172-178采用实施例171中描述的方法合成。
实施例179:
顺式-N-[4-(2,5-二氧代-咪唑啉-1-基)-1-苯基-环己基甲基]-2-甲氧基-苯甲酰胺
合成:
化合物1:化合物1的合成描述于实施例31中。
化合物2:向顺式-胺(50mg,0.15mmol)的5ml二氯甲烷溶液中一次性加入乙酸基异氰酸乙酯(30mg,0.16mmol),于25℃搅拌反应混合物5小时。然后真空浓缩反应混合物,得到油状残留物,使其溶于1mlEtOH-3N HCl水溶液(1∶1混合物)中。于45℃搅拌该混合物12小时。反应混合物经制备性HPLC纯化,得到23.4mg(37%)所需产物2,为白色固体。质谱[M+H]+=422。
实施例180:
顺式-N-[4-(2,5-二氧代-4-(S)-异丙基-咪唑啉-1-基)-1-苯基-环己基甲基]-2-甲氧基-苯甲酰胺。
合成:
化合物1:1的合成描述于实施例31中。
化合物2:按在实施例179中所述相同的方法,用顺式-胺1(50mg,0.15mmol)和(S)-(-)-2-异氰酸基(isocyanato)-3-甲基丁酸甲酯(35mg,0.23mmol)作为起始原料进行该反应,得到16.7mg(0.036mmol,24%)所需产物,为白色固体。质谱[M+H]+=464。
实施例181:
反式-N-[4-(2,5-二氧代-咪唑啉-1-基)-1-苯基-环己基甲基]-2-甲氧基-苯甲酰胺。
合成:
化合物1:1的合成描述于实施例31中。
化合物2:按在实施例179中所述相同的方法,用反式-胺(50mg,0.15mmol)、醋酸基异氰酸乙酯(30mg,0.16mmol))作为起始原料进行该反应,得到6.4mg(0.015mmol,10%)所需产物,为白色固体。质谱[M+H]+=422。
实施例182:
反式-N-[4-(2,5-二氧代-4-(S)-异丙基-咪唑啉-1-基)-1-苯基-环己基甲基]-2-甲氧基-苯甲酰胺
合成:
化合物1:1的合成描述于实施例31中。
化合物2:按在实施例180中所述相同的方法,用反式-胺(50mg,0.15mmol)和(S)-(-)-2-异氰酰基-3-甲基丁酸甲酯(35mg,0.23mmol)作为起始原料进行该反应,得到23.4mg(0.051mmol,33%)所需产物,为白色固体。质谱[M+H]+=464。
实施例183:
顺式-N-[4-(2,5-二氧代-4-(S)-四氢-吡咯并[1,2-C]咪唑-2-基)-1-苯基-环己基甲基]-2-甲氧基-苯甲酰胺。
合成:
化合物1:1的合成描述于实施例31中。
化合物2:向顺式-胺1(200mg,0.59mmol)的10ml二氯甲烷溶液中加入10ml碳酸氢钠水溶液。向该多相溶液中滴加入1ml光气(20%的甲苯溶液),于25℃,将得到的混合物搅拌5小时。分离有机层。将含水层用二氯甲烷(20ml)提取。经硫酸镁干燥合并的有机层,真空浓缩,得到油状物,经鉴定为所需产物2,其无须进一步纯化而用于下一步反应。
化合物3:向异氰酸酯2(1/10的2,由前一步骤制备)的1ml 2-丙醇溶液中加入0.1ml三乙胺和L-脯氨酸甲酯.HCl(100mg,0.61mmol),于25℃,将生成的溶液搅拌12小时。使该反应混合物与1ml 3N HCl水溶液混合,于70℃,将生成的溶液搅拌12小时。使其冷却至25℃,经制备性HPLC纯化(描述于实施例31的合成中),得到14.6mg(53%)所需产物3,为无色油状物。质谱[M+H]+=462。
实施例184-192
实施例184-192采用实施例183中描述的方法合成。
实施例193:
顺式-和反式-N-(2,4-二氧代-1-苯基-1,3-二氮杂-螺[4,5]癸-8-基甲基)-2-甲氧基-苯甲酰胺
合成:
化合物1:1的合成描述于实施例31中。
化合物2和3:向酮(0.48g,1.42mmol)在20ml 50%EtOH水溶液中的溶液中分别一次性加入KCN(0.11g,1.70mmol)和(NH4)2CO3(0.68g,7.10mmol),于55℃,搅拌生成的溶液12小时。真空浓缩该混合物,得到含水的溶液,用乙酸乙酯(100mlx3)提取。经硫酸镁干燥有机层,真空浓缩,得到无色油状物。使该油状物溶于二氯甲烷中,即有白色固体沉淀出来。该白色固体(230mg)由1∶1比例的两种非对映异构构成。真空浓缩母液,得到油状物,将其经制备性HPLC纯化(描述于实施例31的合成中),得到16.1mg的一种异构体(保留时间:2.82分钟)。使该白色固体溶于30ml热EtOH中,于25℃搅拌5天,得到55.7mg另一种异构体的白色固体沉淀。两种化合物的质谱[M+H]+=408。
实施例194:
顺式-2-甲氧基-N-[4-(2-氧代-咪唑烷-1-基)-1-苯基-环己基甲基]-苯甲酰胺
合成:
化合物1:化合物1的合成描述于实施例31中。
化合物2和3:向酮1(0.5g,1.5mmol)的10ml二氯乙烷溶液中分别一次性加入N-乙酰基乙二胺(0.34ml,3.0mmol)和NaBH(OAc)3(0.64g,3.0mmol),于25℃搅拌生成的溶液12小时。用二氯甲烷(50ml)稀释,用1N的NaOH水溶液洗涤。分离有机层,真空浓缩,得到油状残留物。使残留物溶于20ml二氯甲烷中,于25℃与1.0g(4.5mmol)二碳酸二叔丁基酯一起搅拌1小时。真空浓缩反应混合物,得到油状残留物,将其经制备性HPLC纯化(描述于实施例31的合成中),得到顺式-2(保留时间:2.42分钟)和反式-3(保留时间:2.57分钟)两种异构体。化合物4:使化合物2溶于20ml 3N HCl水溶液中,于25℃搅拌12小时。使反应物冷却至0℃,用20%NaOH水溶液碱化,用二氯甲烷(50ml x 3)提取。有机层经硫酸镁干燥,真空浓缩,得到157mg的4。
化合物5:使顺式-胺4(100mg,0.26mmol)溶于5ml二氯甲烷中,于25℃与羰基二咪唑(100mg,0.61mmol)一起搅拌12小时。浓缩反应混合物,经制备性HPLC纯化(描述于实施例31的合成中),得到14.6mg所需产物,为白色固体。质谱[M+H]+=408。
实施例195:
反式-2-甲氧基-N-[4-(2-氧代-咪唑烷-1-基)-1-苯基-环己基甲基]-苯甲酰胺
合成:
化合物1:化合物1的合成描述于实施例31中。
化合物2和3:化合物2和3的合成描述于实施例194中。
化合物4:使化合物3溶于20ml 3N HCl水溶液中,于25℃搅拌12小时。使反应物冷却至0℃,用20%NaOH水溶液碱化,用二氯甲烷(50ml x 3)提取。经硫酸镁干燥有机层,真空浓缩,得到135mg的4。
化合物5:使反式-胺4(100mg,0.26mmol)溶于5ml二氯甲烷中,于25℃与羰基二咪唑(100mg,0.61mmol)一起搅拌12小时。浓缩反应混合物,经制备性HPLC纯化(描述于实施例31的合成中),得到15.8mg所需产物,为白色固体。质谱[M+H]+=408。
实施例196:
顺式-N-[4-(2-氰基亚氨基-咪唑啉-1-基)-1-苯基-环己基甲基]-2-甲氧基-苯甲酰胺
合成:
化合物1:1的合成描述于实施例194中。
化合物2;于70℃,将顺式-胺(75mg,0.20mmol)和氰基亚胺酸二苯酯(75mg,0.32mmol)的3ml 2-丙醇溶液搅拌4小时。反应混合物经制备性HPLC纯化(描述于实施例31中),得到32.0mg(37%)所需产物2,为无色油状物。质谱[M+H]+=432。
实施例197:
反式-N-[4-(2-氰基亚氨基-咪唑啉-1-基)-1-苯基-环己基甲基]-2-甲氧基-苯甲酰胺
合成:
化合物1:1的合成描述于实施例194中。
化合物2:按实施例196中所述相同的方法,用75mg(0.20mmol)所述反式-胺和氰基亚胺酸二苯酯(75mg,0.32mmol)作为起始原料进行该反应,得到47.6mg(0.11mmol,55%)所需产物2,为白色固体.质谱[M+H]+=432。
实施例198:
1-苯基-环己烷甲酸苄基酰胺
合成:
化合物1:化合物1由市售获得。
化合物2:使1-苯基-环己烷甲酸1(0.010g;0.049mmol)在二氯甲烷(1ml)中的悬浮液冷却至0℃,用三乙胺(0.010mL;0.072mmol)处理,接着用六氟磷酸四甲基氟代甲脒鎓(formamidinium)(0.014g;0.053mmol)。温热至室温(大约1小时)后,除去溶剂,残留物用于随后的反应。
化合物3:使化合物2溶于乙腈(1ml)中。加入PS-DIEA(聚苯乙烯-二异丙基乙胺树脂;0.2g),将生成的悬浮液用苄基胺(0.006mg;0.056mmol)处理,于室温下震摇。12小时后,加入PS-TsCI(聚苯乙烯-甲苯磺酰基氯,高填充树脂;0.2g),再将反应混合物震摇另外12小时。搅拌反应混合物并浓缩,得到0.011g(79%)化合物3。LCMS m/z=294.4(M+H)+
实施例199-289
实施例199-289采用实施例198中描述的方法合成。在某些情况下,采用反相HPLC进一步纯化。
实施例290
1-(4-氟-苯基)-环己烷羧酸[2-(4-氯代-苯基)-乙基]-(1-甲基-1H-咪唑-2-基甲基)-酰胺
合成:
化合物1:化合物1由市售获得。
化合物2:用1-甲基-1H-咪唑-2-甲醛(1.80g;16.3mmol)处理2-(4-氯代苯基)乙胺(2.25mL;16.1mmol)和硫酸钠(10.0g;70.4mmol)在甲醇(20ml)中的悬浮液,并加热至40℃。24小时后,使反应混合物冷却至0℃,用硼氢化钠(0.73g;19.3mmol)处理,使缓慢温热至室温。3小时后,除去溶剂,使粗品残留物分配于乙酸乙酯和饱和碳酸氢钠水溶液之间。分离有机层,用饱和氯化钠水溶液洗涤,干燥(硫酸镁)并浓缩。使油状残留物溶于四氢呋喃中,用1N HCl的乙醚(35ml)溶液处理。即刻形成白色沉淀,收集得到5g(96%)[2-(4-氯代-苯基)-乙基]-(1-甲基-1H-咪唑-2-基甲基)-胺.2HCl。LCMS m/z=250.7(M+H)+
化合物3:用草酰氯(0.042mL;0.48mmol)和1滴N,N-二甲基甲酰胺处理1-(4-氟-苯基)-环己烷甲酸(0.106mg;0.48mmol)在二氯甲烷(10ml)中的悬浮液.于室温下,搅拌反应混合物15分钟,此时加入三乙胺(0.28mL;2.0mmol)和[2-(4-氯代-苯基)-乙基]-(1-甲基-1H-咪唑-2-基甲基)-胺·2HCl(0.16g;0.50mmol).再搅拌30分钟后,除去溶剂,将残留物用反相HPLC纯化,得到0.114g(52%)3,为白色固体.LCMS m/z=455.0(M+H)+。
实施例291:
1-(4-氯代-苯基)-环己烷甲酸[2-(4-氯代-苯基)乙基]-(1-甲基-1H-咪唑-2-基甲基)-酰胺。
合成:
采用在实施例290中描述的方法制备标题化合物。
LCMS m/z=471.5(M+H)+。
实施例292:
1-(4-氟-苯基)-环己烷甲酸苄基-(1-甲基-1H-咪唑-2-基甲基)-酰胺。
采用在实施例290中描述的方法制备标题化合物。
LCMS m/z=406.5(M+H)+
实施例293
乙基-氨基甲酸4-[5-(3-甲氧基-苄基)-[1,2,4]噁二唑-3-基]-4-苯基-环己基酯。
合成:
化合物1:化合物1的合成描述于实施例31中。
化合物2:于98℃,将化合物1(5.8g;23.8mmol)、盐酸羟胺(4.21g;60.6mmol)和甲醇钠(3.27g;60.6mmol)在正丙醇(100ml)中的溶液加热过夜。减压浓缩反应混合物,用EtOAc(100ml)稀释,用水洗涤,经无水硫酸钠干燥。经快速层析(1∶1;己烷∶乙酸乙酯)纯化,得到2(4.6g;71%),为白色固体。LCMS m/z=277.1(M+H)+
化合物3:向化合物2(0.100g,0.36mmol)的2-甲氧基乙醚(5ml)溶液中加入碳酸钾(0.72mmol),接着加入3-甲氧基苯基乙酰氯(0.067g,0.36mmol)。将反应混合物于室温下搅拌30分钟,然后于120℃加热3小时。冷却至室温后,用水稀释反应混合物,用乙酸乙酯提取,经无水硫酸钠干燥。经硅胶柱层析纯化(7∶3己烷∶乙酸乙酯),得到3(0.085g;58%),为油状物。
1H NMR(CDCl3,300MHz):δ(ppm)1.65-1.80(4H,m),2.25-2.40(2H,m),2.60-2.70(2H,m),3.74(3H,s),3.94(4H,s),4.14(2H,s),6.75-6.90(3H,m),7.15-7.45(6H,m);LCMS m/z=407.2(M+H)+.
化合物4:用2N HCl(0.4ml)处理化合物3(80mg,0.20mmol)的四氢呋喃(1.25ml)溶液,于40℃加热6小时。加入饱和碳酸氢钠水溶液。将水相用乙酸乙酯提取,有机相经无水硫酸钠干燥。经硅胶柱层析纯化(7∶3己烷∶乙酸乙酯),得到4(40mg;60%),为油状物。LCMSm/z=363.2(M+H)+。
化合物5:于0℃,用硼氢化钠(250mg,6.62mmol)处理4(1.2g,3.31mmol)的四氢呋喃(20ml)溶液。从0℃至室温搅拌过夜,将反应混合物用饱和碳酸钠水溶液猝灭,用乙酸乙酯提取。将有机层用饱和氯化钠水溶液洗涤,经无水硫酸钠干燥。经硅胶柱层析纯化(7∶3己烷∶乙酸乙酯),得到5(1.12g,93%)。LCMS m/z=365.5(M+H)+。
化合物6:
1H NMR(CDCl3,300MHz):δ(ppm)1.11(3H,t,J=7.1Hz),1.50-1.70(2H,m),1.90-2.18(4H,bd,J=9.7Hz),2.88(2H,bd,J=13.6Hz),3.10-3.25(2H,m),3.74(3H,s),4.14(2H,s),4.60-4.80(2H,m),6.70-6.90(3H,m),7.08-7.40(6H,m).LCMS m/z=436.2(M+H)+.
实施例294-322
采用于实施例293中描述的方法合成实施例294-322。在某些情况下,采用反相HPLC进一步纯化。
乙基-氨基甲酸4-(异喹啉-1-基氨基甲基)-4-苯基-环己基酯
合成:
化合物1:化合物1的合成描述于实施例31中。
化合物2:由市售获得。
化合物3:将化合物1(2.0g,8.09mmol)、2(1.1g,6.75mmol)、叔丁醇钠(908mg,9.75mmol)、乙酸钯(75.7mg,0.34mmol)和2-(二-叔丁基膦酰基)联苯基(100.7mg,0.3374mmol)在甲苯(20ml)中的混合物于110℃加热20小时。通过CELITE滤除不溶性物质,减压除去溶剂,残留物经硅胶快速层析纯化,用40%乙酸乙酯-己烷洗脱,得到标题化合物(1.5g,50%收率),为黄色油状物。
化合物4:使二氧戊环3(1.5g)溶于THF中,用2N HCl稀释,然后搅拌过夜.将该溶液加入到乙酸乙酯和饱和碳酸氢钠的混合物中.将所述有机溶液用另外2份碳酸氢盐溶液洗涤,接着用盐水洗涤.经硫酸钠干燥该溶液,减压除去溶剂,得到1.25g(94%)化合物4,为橙色糖浆状物,无须进一步纯化而使用.
化合物5和6:将硼氢化钠(215mg,5.82mmol)加入到酮4(1.25g,3.79mmol)的THF(10ml)溶液中,将该混合物搅拌过夜。使反应物分配于乙酸乙酯和稀HCl之间。将含水层用饱和碳酸氢钠碱化。将产物提取到乙酸乙酯中,将其经硫酸钠干燥,减压除去溶剂。通过硅胶快速层析,用乙酸乙酯作为洗脱液,得到5(异构体A,469mg)和6(异构体B,170mg)。
化合物7:将樟脑磺酸(160.1mg,0.689mmol)加入到5(114mg,0.344mmol)在二氯甲烷(10ml)中的搅拌溶液中。5分钟后,加入异氰酸乙基酯(32.7μl,0.414mmol),继续搅拌2小时。用氨的甲醇制溶液猝灭反应物,减压除去溶剂,残留物通过硅胶快速层析,用60%乙酸乙酯-己烷洗脱,然后用5%甲醇-二氯甲烷洗脱,得到10.2mg标题化合物,[M+H]404。
实施例324
乙基-氨基甲酸4-(异喹啉-1-基氨基甲基)-4-苯基-环己基酯
合成:
化合物1:化合物1的合成描述于实施例323中。
化合物2:以类似于实施例323中描述的反应,使化合物1(76.3mg,0.230mmol)、樟脑磺酸(106.8mg,0.460mmol)和异氰酸乙基酯(21.8μl,0.276mmol)在二氯甲烷(10ml)中反应,得到16.3mg化合物2,[M+H]403。
实施例325
异喹啉-1-基-(1-苯基-环己基甲基)-胺
合成:
化合物1:化合物1由市售获得。
化合物2:用草酰氯(0.23mL;2.64mmol)和1滴N,N-二甲基甲酰胺处理1-苯基-1-环己烷甲酸(0.484g;2.37mmol)在二氯甲烷(30ml)中的悬浮液。于室温下,将反应混合物搅拌30分钟,此时加入三乙胺(1mL;7.2mmol)和1-氨基异喹啉(0.36g;2.50mmol)。搅拌另外15分钟后,将反应混合物用水和饱和氯化钠水溶液洗涤,干燥(硫酸镁)并浓缩。粗残留物经硅胶柱层析纯化,用3∶1∶1己烷∶乙酸乙酯∶二氯甲烷作为洗脱液,得到0.605g 1-苯基-环己烷甲酸异喹啉-1-基酰胺,为白色泡沫物。LCMS m/z=331.2(M+H)+
化合物3:将1-苯基-环己烷甲酸异喹啉-1-基酰胺(0.117g;0.35mmol)的四氢呋喃(10ml)溶液冷却至0℃,然后用氢化锂铝(0.040g;1.05mmol)处理。使反应混合物缓慢温热至室温。于室温下18小时后,加入另外氢化锂铝(0.04g;1.05mmol),于40℃将该反应混合物加热2小时。将反应混合物再冷却到0℃,通过滴加入水小心地猝灭。蒸发除去四氢呋喃,将粗品残留物用乙酸乙酯和饱和碳酸氢钠水溶液稀释。分离有机层,用饱和氯化钠水溶液洗涤,干燥(硫酸镁),过滤并浓缩。经硅胶柱层析,用7∶3己烷∶乙酸乙酯作为洗脱液,得到0.042g异喹啉-1-基-(1-苯基-环己基甲基)-胺,为黄色油状物。
LCMSm/z=317.2(M+H)+;1H NMR(CDCl3,300MHz)δ(ppm)7.96(1H,d,J=6.0Hz),7.54-7.26(9H,m),6.61(1H,d,J=6.0Hz),4.80(1H,宽S),3.76(2H,d,J=5.4hz),2.26-2.20(2H,m),1.84-1.77(2H,m),1.66-1.61(2H,m),1.55-1.43(4H,m);13C NMR(CDCl3,75MHz)155.4,144.9,141.4,137.1,129.5,128.9(两个碳),127.1,127.0(两个碳),126.4,125.8,121.0,118.1,11.5,52.2,42.6,34.3(两个碳),26.6,22.2(两个碳).
实施例326-329
实施例326-329采用于实施例325中描述的方法合成。
实施例330
(1-苯基-环己基甲基)-喹唑啉-4-基-胺
合成:
化合物1:化合物1由市售获得。
化合物2:使1-苯基-环己烷甲腈(11.0g;59mmol)的四氢呋喃(100ml)溶液冷却至0℃,在0.5小时内分数批用氢化锂铝(11g,289mmol)处理。当氢化锂铝加入完毕时,移去冷浴,于室温下搅拌反应混合物12小时。再使反应混合物冷却至0℃,通过滴加2N NaOH(约20ml)小心地猝灭,用乙醚稀释,通过硅藻土柱过滤,干燥(硫酸镁)。获得C-(1-苯基-环己基)-甲胺,为无色油状物,无须进一步纯化而使用。LCMSm/z 190.2(M+H)+
化合物3:于室温下,用三乙胺(0.3mL;2.2mmol)和2,4-二氯-喹唑啉(0.32g;1.62mmol)处理C-(1-苯基-环己基)-甲胺(0.28g;1.48mmol)的四氢呋喃(10ml)溶液。于室温下搅拌该化合物12小时,此时通过旋转蒸发除去溶剂。使粗残留物分配于乙酸乙酯和10%HCl水溶液之间。分离有机层,用饱和氯化钠水溶液洗涤,干燥(硫酸镁),过滤并浓缩。从二氯甲烷中重结晶产物,得到(2-氯代-喹唑啉-4-基)-(1-苯基-环己基甲基)-胺,为白色固体。LCMS m/z=352.2(M+H)+
化合物4:用10%披钯碳(200mg)处理(2-氯代-喹唑啉-4-基)-(1-苯基-环己基甲基)-胺(0.065g;0.18mmol)的无水甲醇(2ml)溶液,然后置于氢气氛下(45psi)。于室温下震摇反应混合物3小时。将反应混合物通过硅藻土过滤并蒸发。粗残留物经硅胶柱层析纯化,用9∶1乙酸乙酯∶己烷作为洗脱液,得到0.052g(1-苯基-环己基甲基)-喹唑啉-4-基-胺,为白色泡沫物。LCMS m/z=318.2(M+H)+
实施例331
N2-乙基-N4-(1-苯基-环己基甲基)-喹唑啉-2,4-二胺
合成:
化合物1:化合物1如上所述制备。
化合物2:用1ml 2M乙胺的四氢呋喃溶液处理(2-氯-喹唑啉-4-基)-(1-苯基-环己基甲基)-胺(0.052g;0.15mmol)。密封反应容器,于60℃将该反应混合物加热24小时。真空下除去挥发性成分,粗残留物直接经制备性HPLC纯化,得到0.020g N2-乙基-N4-(1-苯基-环己基甲基)-喹唑啉-2,4-二胺,为白色固体。LCMS m/z=361.2(M+H)+
实施例332
合成:
化合物1:化合物1由市售获得。
化合物2:用3小时,向回流的2-氟苯基乙腈(5ml,41mmol)的100ml乙腈溶液中滴加入在100ml乙腈中的丙烯酸甲酯(36ml,400mmol)。回流下,将得到的溶液搅拌另外6小时。真空浓缩反应混合物,得到油状残留物,将其经柱层析纯化(40%乙酸乙酯/己烷),得到化合物2(11.2g,89%),为无色油状物。
化合物3:向化合物2的200ml DCM溶液中一次性加入NaH(2.5g,108mmol),将生成的溶液在回流下搅拌12小时。使反应混合物冷却至-78℃,通过加入冰猝灭。用EtOAc(150ml)稀释该混合物,过滤出有机层。浓缩有机层,得到油状物(8.8g,89%),经NMR分析,其与所需产物一致,其可无须进一步纯化而用于下面的反应。
化合物4:使化合物3溶于80ml DMSO和4ml水中。于140℃搅拌该混合物15小时。冷却反应混合物,用EtOAc(400ml)稀释,用10%氯化锂水溶液(30mlx3)洗涤。将含水层用乙酸乙酯(50mlx2)提取。经硫酸镁干燥合并的有机层,真空浓缩,得到油状残留物,将其经柱层析纯化(25-50%乙酸乙酯/己烷),得到所需产物(5.5g,65%)。化合物5:化合物5的合成按照在实施例31的合成中完全相同的反应程序进行,其中将实施例31中的化合物1由本实施例中的化合物4代替。[M+H]=438。
实施例333-334
实施例333-334采用于实施例332中描述的方法合成。
合成:
化合物1:化合物1由市售获得。
化合物2:化合物2按照在实施例333的合成中描述的完全相同的方法制备,其中3-氟苯基乙腈代替实施例335的合成中的2-氟苯基乙腈。化合物3:化合物3按照在实施例31的合成中描述的顺序制备,其中使用4-(3-氟苯基)-4-氰基环己酮2代替实施例31中的化合物1。[M+H]=438。
实施例336-341
采用于实施例335中描述的方法合成。
合成:
化合物1:化合物1由市售获得。
化合物2:化合物2按照在实施例332的合成中描述的完全相同的方法制备,其中4-氟苯基乙腈代替2-氟苯基乙腈。
化合物3:化合物3按照在实施例31的合成中描述的顺序制备,其中化合物2用于代替实施例31中的化合物1。[M+H]=438。
实施例343-348
实施例343-348采用在实施例342中描述的方法合成。
实施例349
合成:
化合物1:1的合成描述于实施例31中。
化合物2:2的合成描述于实施例73中。
化合物3:于65℃,将2(20mg,0.041mmol)、4-(氨基甲基)吡啶(10mg,0.10mmol)的1ml乙腈溶液搅拌2小时。反应混合物经制备性HPLC纯化(描述于实施例31的合成中),得到11.2mg的3,为无色油状物。质谱[M+H]=509。
实施例350-396
实施例350-396采用在实施例349中描述的方法合成。
实施例397
化合物1:化合物1由市售获得。
化合物2:化合物2按照在实施例332的合成中描述的完全相同的方法制备,其中2-甲氧基苯基乙腈代替在实施例332的合成中的2-氟苯基乙腈。
化合物3:化合物3按照在实施例31的合成中描述的顺序制备,其中4-(2-甲氧基苯基)-4-氰基环己酮2被用于代替在实施例31中的化合物1。[M+H]=450。
实施例398-404
实施例398-404采用在实施例397中描述的方法合成。
实施例405
合成:
化合物1:1的合成描述于实施例388中。
化合物2:2的合成按照实施例73中描述的相同方法进行。
化合物3:于65℃,将2(40mg,0.083mmol)、4-(氨基甲基)吡啶(20mg,0.20mmol)在1ml乙腈中的溶液搅拌2小时。反应混合物经制备性HPLC纯化(描述于实施例31的合成中),得到8.9mg的3,为无色油状物。质谱[M+H]=539。
实施例406-410
实施例406-410采用实施例405中描述的方法合成。
实施例411和412
实施例411,和实施例412
合成:
化合物1:化合物1的合成描述于实施例31中。
化合物2:向一个用于微波反应器的特别设计的小瓶中一次性加入化合物1(0.57g,2.3mmol)、Pd2(dba)3(42mg,0.046mmol)、BINAP(79mg,0.13mmol)和t-BuONa(0.38g,2.3mmol)。将该反应小瓶置于真空下以除去空气。然后向该混合物中加入22ml脱气的THF,盖上反应小瓶。将反应混合物置于微波反应器中,于180℃加热20分钟。冷却反应混合物,经柱层析(20-50%乙酸乙酯/己烷),得到0.62g(72%)所需产物,为油状固体。
化合物3:使化合物2(3.0g,8.0mmol)溶于THF(60ml)和HCl水溶液(10ml)中,于35℃,将生成的溶液搅拌4小时.从反应混合物中蒸发THF,将剩余的水溶液用乙酸乙酯(100mlx2)提取.经硫酸镁干燥有机层,真空浓缩,得到油状物(2.4g,>95%),经鉴定其为所需产物(两种异构体的1∶1混合物),其无须任何进一步的纯化而用于下面的反应(>95%纯度).
化合物4:向化合物3(1.2g,3.6mmol)的50ml MeOH溶液中一次性加入NH4OAc(2.2g,27mmol)和NaBH(OAc)3(0.98g,4.6mmol),于室温下,将生成的溶液搅拌12小时。真空浓缩反应混合物,得到油状残留物,使其分配于EtOAc(200ml)和盐水(50ml)之间。将含水层用乙酸乙酯(50mlx2)进一步提取。合并的有机溶液经硫酸镁干燥,真空浓缩,得到油状物(1.2g,>95%),经鉴定其为所需产物,其无须进一步纯化而用于以下反应(>90%纯度)。
化合物5和6:化合物4的合成按照在实施例31的合成中的完全相同的方法进行,采用化合物4(0.13g,0.39mmol)、氰基亚胺酸二苯酯(94mg,0.39mmol)和5ml 2N MeNH2的MeOH溶液,得到20.9mg化合物5和12.3mg化合物6。
实施例413-418
实施例413-418采用实施例411中描述的方法合成。
实施例419
合成:
化合物1:化合物1的合成描述于实施例153中。
化合物2:化合物2按程序库(library)合成的部分方法制备。通用方法如下:向化合物1(8.3mg,0.03mmol)的1ml 1,2-二氯乙烷溶液中一次性加入3-(三氟甲基)苯甲酰氯(20μL,0.14mmol)和20mg聚合物-结合的胺(PL-MPH树脂,Polymer Laboratories),将得到混合物搅拌12小时。向反应混合物中加入聚合物-结合的树脂PL-EDA(50mg,PolymerLaboratories),将得到混合物再搅拌5小时。然后过滤反应混合物,超速真空(speed-vac)浓缩,得到8.0mg(0.020mmol,67%)所需产物,为无色油状物。[M+H]=458。
实施例420-449
实施例420-449采用实施例419中描述的方法合成。
合成:
化合物1:化合物1的合成描述于实施例153中。
化合物2:化合物2按程序库合成的部分方法制备。通用方法如下:向所述酸(10mg,0.06mmol)的1ml DCM和0.3ml DMF溶液中加入EDCI(11.5mg,0.06mmol)和HOAt(8.2mg,0.06mmol)。向该溶液中加入在1.2ml DCE-DMF(2∶1)中的化合物1(11mg,0.04mmol)。于25℃,将该反应混合物搅拌12小时。反应混合物经制备性-HPLC纯化(见实施例31),然后经快速真空浓缩,得到10.8mg(0.021mmol,41%)所需产物,为无色油状物。
实施例451-562
实施例451-562采用实施例450中描述的方法合成。
实施例563
合成:
化合物1:化合物1的合成描述于实施例31中。
化合物2:向6-甲氧基水杨酸(4.2g,25mmol)的DCM(15ml)和DMF(5ml)溶液中一次性分别加入EDCI(3.8g,1.325mmol)和HOAt(33.4g,25mmol),将生成的溶液搅拌0.5小时。将混合物滴加到化合物1(4.7g,19mmol)的15ml DCM溶液中。于25℃,将得到的溶液搅拌12小时。真空蒸发反应混合物,得到油状残留物,将其经柱层析纯化(20-50%乙酸乙酯/己烷),得到化合物2(5.8g,77%),为无色油状物。
化合物3:使化合物2(5.8g,14.6mmol)溶于THF(80ml)和2NHCl-MeOH(40ml)中。于50℃搅拌该混合物5小时。然后将反应混合物倾入到乙酸乙酯(300ml)中,分离有机层。将含水层用乙酸乙酯(50ml x 2)提取。将合并的有机层用碳酸氢钠水溶液洗涤,经硫酸钠干燥,真空浓缩,得到所需产物(4.0g,80%),其为纯品(>95%),且无须任何进一步的纯化而用于随后的反应。
化合物4:使化合物3(4.0g,11.3mmol)溶于MeOH(100ml)中,于-78℃与硼氢化钠(0.50g,13mmol)一起搅拌3小时。HPLC分析显示反应完成。真空浓缩该混合物,得到白色固体混合物,使其分配于EtOAc(200ml)和盐水(50ml)之间。经硫酸钠干燥有机层,真空浓缩,得到醇(4.0g,>95%),为油状物。使醇溶于30ml DCM中,于0℃加入吡啶(10ml)和甲酰氯(1.1ml,13.6mmol)。于25℃搅拌生成的溶液12小时。通过加入水猝灭反应物。将含水层用DCM(20mLx2)进一步提取。将合并的有机溶液用1N HCl水溶液(30mlx 2)洗涤,经硫酸钠干燥。浓缩该有机溶液,得到所需产物(5.2g,85%纯度),为油状物,其无须任何进一步的纯化而用于随后的反应。
化合物5:使得自上面的化合物4溶于20ml DMF中,加入NaN3(1.2g,15mmol)。于80℃搅拌混合物12小时。真空浓缩反应混合物,以除去DMF,然后分配于乙酸乙酯(100ml)和盐水(30ml)之间。将含水层用乙酸乙酯(50mlx2)提取。合并的有机溶液经CombiFlash纯化(0-20%乙酸乙酯/己烷),得到所需产物(2.0g,5.3mmol,53%两步),为顺式-和反式-异构体(4∶1比例)的混合物。
化合物6:使化合物5溶于30ml MeOH中,加入催化量的10%Pd/C。将该混合物置于氢气下,于25℃搅拌2小时。使反应混合物通过加有硅藻土的漏斗过滤。真空浓缩滤液,得到所需产物(1.4g,75%),为无色油状物。
化合物7:向化合物6(0.36g,1mmol)的10ml异丙醇溶液中加入氰基亚胺酸二苯酯(0.24g,1mmol),于60℃搅拌生成的溶液5小时。然后真空浓缩反应混合物,得到油状残留物,使其溶于10mlMeNH2-MeOH溶液中,于80℃在密封管中搅拌5小时。浓缩反应混合物,经CombiFlash(20-100%乙酸乙酯/己烷)纯化,得到所需产物(0.34g,78%)。[M+H]=436。
实施例564-571
实施例564-571采用实施例563中描述的方法合成。
实施例572和实施例573
实施例572,和实施例573
合成:
化合物1:化合物1的合成描述于实施例554中。
化合物2:于0℃,向氯代磺酰基异氰酸酯(22μl,0.25mmol)的1mlDCM溶液中加入氯代乙醇(17μl,0.25mmol)。然后于25℃将该反应物搅拌另外4小时。将该反应混合物再次冷却至0℃,加入在2ml DCM中的90mg(0.25mmol)化合物1。于25℃,将该反应混合物搅拌另外12小时。然后用10ml DCM稀释反应混合物,用1N HCl水溶液洗涤。有机溶液经硫酸钠干燥,真空浓缩,得到130mg所需产物,其无须任何进一步的纯化而用于下面的反应。
化合物3和4:将化合物2(30mg,0.07mmol)和4-(氨基甲基)吡啶(16ml,0.14mmol)稀释于1ml乙腈中,于60℃搅拌12小时。反应混合物经制备性HPLC纯化(见实施例31),得到12.7mg实施例572和3.3mg实施例573。
实施例574-579
实施例574-579采用实施例572中所述的方法合成。
实施例580
合成:
化合物1:化合物1的合成描述于实施例31中。
化合物2:向化合物1(0.20g,0.60mmol)和三乙胺(0.5ml)的5ml DCM溶液中一次性加入三光气(0.20g,0.67mmol),于25℃搅拌生成的溶液1小时。真空浓缩反应混合物,得到油状残留物,将其经柱层析纯化(50%乙酸乙酯/己烷),得到213mg(0.58g,>95%)所需产物,为油状物。
化合物3:向化合物2(20mg,0.055mmol)和苯磺酰胺(20mg,0.13mmol)的2ml丙酮溶液中一次性加入0.2ml 1N NaOH水溶液,于25℃搅拌生成的溶液1小时。通过加入0.2ml HCl水溶液中和该溶液,经制备性HPLC(见实施例31)纯化,经快速真空浓缩后,得到10.1mg(0.019mmol,30%)所需产物,为白色固体。[M+H]=522
实施例581-590
实施例581-590采用在实施例580中描述的方法合成。
实施例591
合成:
化合物1:化合物1的合成描述于实施例31中。
化合物2:向化合物1(338mg,1.0mmol)的10ml乙醇溶液中一次性加入N-氰基二硫代亚氨基碳酸二甲酯(147mg,1.0mmol),于70℃搅拌生成的溶液2小时。HPLC和LC-MS分析显示反应完成。真空浓缩反应混合物,得到油状物,其无须任何进一步的纯化而用于下面的反应。
化合物3:使化合物2(40mg,0.09mmol)、NaOH(3.7μg,0.09mmol)和4-氯代苯磺酰胺(34mg,0.18mmol)溶于1ml二氧六环中。于230℃,在微波反应器中,将生成的溶液搅拌15分钟。然后使反应混合物冷却,经制备性HPLC纯化(见实施例31),浓缩洗脱液后,得到6.2mg,(0.011mmol,11%)所需产物,为浅灰色固体。[M+H]=581。
实施例592和593
实施例592-593采用在实施例591中描述的方法合成。
实施例594
合成:
化合物1:化合物1由市售获得。
化合物2:向化合物1(4.6ml,40mmol)在100ml无水THF中的溶液中滴加入MeLi(2N的THF溶液,40mmol),于-78℃搅拌生成的溶液1小时。用30分钟向该溶液中滴加入在50ml THF中的溴代亚甲基环氧丙烷(bromoepihydrin)(3.4ml,40mmol),于-78℃再将搅拌反应混合物1小时。将MeMgBr(3M的THF溶液,40mmol)加入到反应混合物中。于室温下搅拌反应混合物另外12小时。然后用EtOAc(250ml)稀释反应混合物,用盐水(50ml x 3)洗涤。经硫酸镁干燥有机层,真空浓缩,得到油状残留物,将其经CombiFlash(0至100%乙酸乙酯/己烷)纯化,得到5.6g(29mmol,73%)所需产物,为顺式和反式异构体(4∶1)的混合物。
化合物3:于70℃,向化合物2(1.6g,9.0mmol)的30ml THF溶液中加入LAH(1.0M的THF溶液,10mmol),将生成的溶液搅拌4小时。通过加入几片冰猝灭反应物,通过硅藻土过滤该混合物。浓缩滤液,得到油状物(1.5g,>95%),其无须任何进一步的纯化而用于随后的反应。
化合物4:向化合物3(1.5g,9.0mmol)的50ml THF和三乙胺(2.0ml)溶液中滴加入甲氧基苯甲酰氯(1.3ml,9.0mmol),于25℃搅拌生成的溶液1小时。然后用EtOAc(100ml)稀释反应混合物,用盐水洗涤。有机溶液经硫酸镁干燥,真空浓缩,得到油状物,经鉴定其为双-酰化产物。使该产物溶于30%THF水溶液(20ml)中,将LiOH(300mg)加入其中。于70℃搅拌得到的混合物12小时。将该混合物用EtOAc(50ml)稀释,用盐水(30ml)洗涤。浓缩有机层,经硫酸镁干燥后,得到油状残留物,将其经CombiFlash纯化,得到1.5g,(4.5mmol,50%两步)所需产物,为无色油状物。
化合物5:使化合物4溶于10ml DCM和2ml吡啶中.向该溶液中加入甲磺酰氯(1ml,13mmol),于25℃搅拌生成的溶液2小时.用EtOAc(200ml)稀释该反应混合物,用盐水(30mlx2)洗涤.经硫酸镁干燥有机层,真空浓缩,得到油状物,其无须任何进一步的纯化而用于随后的反应.
化合物6:使化合物5和NaN3(1.3g,8.9mmol)溶于10ml DMF中,于120℃搅拌该混合物5小时。将反应混合物用EtOAc(100ml)稀释,用盐水(20mlx3)洗涤。有机溶液经硫酸钠干燥,真空浓缩,得到油状物,其经CombiFlash(0-30%乙酸乙酯/己烷)纯化,得到1.1g叠氮化物。使该叠氮化物溶于20ml MeOH中,向该溶液中加入催化量的10%Pd-C。在氢气下搅拌反应混合物2小时。将反应混合物通过漏斗(Whatman,0.45μm NYL)过滤,真空浓缩,得到所需产物(1.1g,79%,从化合物4计),为无色油状物。
化合物7:向化合物6(180mg,0.58mmol)的5ml异丙醇溶液中加入氰基亚胺酸二苯酯(150mg,0.64mmol),于80℃搅拌生成的溶液2小时。然后真空浓缩反应混合物,得到油状残留物。使其溶于5ml 2NMeNH2的甲醇溶液,于80℃,在密封管中搅拌5小时。通过HPLC监测反应的进行。真空浓缩反应混合物,得到油状残留物,将其经CombiFlash(0-100%乙酸乙酯/己烷)纯化,得到0.12g(0.29mmol,50%)所需产物,为顺式和反式异构体的混合物。[M+H]=410。
实施例595-597
实施例595-597采用在实施例594中描述的方法合成。
顺式-N-{4-[N′-氰基-N″-乙基-N-(2-甲氧基-乙基)-胍基]-1-苯基-环己基甲基}-2-甲氧基-苯甲酰胺
合成:
化合物1:1的合成如前所述。
化合物2和3:向1(185mg,0.55mmol)的1,2-二氯乙烷(2ml)溶液中加入2-甲氧基乙胺(0.048mL,0.55mmol),接着加入三乙酰氧基硼氢化钠(163mg,0.77mmol)和乙酸(0.031ml,0.55mmol),然后搅拌该反应物1.5小时。通过加入1NNaOH(2ml)猝灭反应物,然后用Et2O(3x4ml)提取。将合并的有机提取物用盐水(2ml)洗涤,干燥(硫酸镁)、过滤、真空浓缩。残留物经硅胶层析,用1∶1∶98-1∶5∶94NH4OH/MeOH/CHCl3梯度洗脱,,得到2(80mg,37%收率,HPLC Rt1.50分钟,采用Phenomenex 30x 4.65u柱,2分钟梯度,采用5mL/分钟的流速。0至100%溶剂B。溶剂A=10/90/0.1%MeOH/水/TFA。溶剂B=90/10/0.1%。M+H=397.3)和3(66mg,30%收率,HPLC Rt 1.43分钟,采用Phenomenex 30x 4.65u柱,2分钟梯度,采用5mL/分钟的流速。0至100%溶剂B。溶剂A=10/90/0.1%MeOH/水/TFA。溶剂B=90/10/0.1%。M+H=397.3),为白色固体。
化合物4:向胺2的顺式-异构体(15mg,0.038mmol)的2-丙醇(1ml)溶液中加入1-氰基-3-乙基-2-苯基-异脲(36mg,0.19mmol),然后在75℃油浴中,将该反应混合物加热5天。在氮气流下除去溶剂,然后将残留物经制备性TLC纯化,用5∶20∶75MeOH/EtOAc/己烷洗脱,得到4(9.5mg,51%收率,HPLC Rt 1.88分钟,使用Phenomenex 30x 4.65u柱,2分钟梯度,使用5mL/分钟的流速。0至100%溶剂B。溶剂A=10/90/0.1%MeOH/水/TFA。溶剂B=90/10/0.1%。M+H=492.3),为白色固体。
实施例600-604
实施例600-604采用在实施例599中描述的方法制备。
实施例605
反式-N-{4-[N′-氰基-N″-乙基-N-(2-甲氧基-乙基)-胍基]-1-苯基-环己基甲基}-2-甲氧基-苯甲酰胺
合成:
化合物3:化合物3的合成描述于实施例599中。
化合物5:向胺3的反式-异构体(15mg,0.038mmol)的2-丙醇(1ml)溶液中加入1-氰基-3-乙基-2-苯基-异脲(36mg,0.19mmol),然后在75℃油浴中,将该反应混合物加热5天。在氮气流下除去溶剂,然后残留物经制备型TLC纯化,用5∶20∶75MeOH/EtOAc/己烷洗脱,得到5(10.8mg,58%收率,HPLC Rt 1.77分钟,使用Phenomenex 30x 4.65u柱,2分钟梯度,使用5mL/分钟的流速。0至100%溶剂B。溶剂A=10/90/0.1%MeOH/水/TFA。溶剂B=90/10/0.1%。M+H=492.3),为白色固体。
实施例606-609
实施例606-609采用在实施例605中描述的方法制备。
实施例610
顺式-2-甲氧基-N-{4-[(2-甲氧基-乙基)-(吗啉-4-磺酰基)-氨基]-1-苯基-环己基甲基}-苯甲酰胺
合成:
化合物2:化合物2的合成描述于实施例599中。
化合物6:向胺2的顺式-异构体(15mg,0.038mmol)的二甲基甲酰胺(0.5ml)溶液中加入三乙胺(0.007mL,0.05mmol),接着加入吗啉-4-磺酰氯(8.4mg,0.045mmol)和催化量的DMAP。将该反应物搅拌5天,然后用50%乙酸乙酯/己烷(4ml)稀释,用w/0.1N HCl(2ml)和盐水(2ml)洗涤。干燥(硫酸钠)有机相,过滤,真空浓缩。残留物经制备型TLC纯化,用3∶25∶72MeOH/己烷/EtOAc洗脱,得到6(7.8mg,38%收率,HPLC Rt 2.30分钟,使用Phenomenex 30x 4.65u柱,2分钟梯度,及1分钟保留时间,使用5mL/分钟的流速。0至100%溶剂B。溶剂A=10/90/0.1%MeOH/水/TFA。溶剂B=90/10/0.1%。M+H=546.1),为白色固体。
实施例611-615
实施例611-615采用在实施例610中描述的方法制备。
实施例616
反式-2-甲氧基-N-{4-[(2-甲氧基-乙基)-(吗啉-4-磺酰基)-氨基]-1-苯基-环己基甲基}-苯甲酰胺
化合物3:化合物3的合成描述于实施例599中。
化合物7:向胺3的反式-异构体(15mg,0.038mmol)的二甲基甲酰胺(0.5ml)溶液中加入三乙胺(0.007ml,0.05mmol),接着加入吗啉-4-磺酰氯(8.4mg,0.045mmol)和催化量的DMAP。将该反应物搅拌5天,然后用50%乙酸乙酯/己烷(4ml)稀释,用w/0.1N HCl(2ml)和盐水(2ml)洗涤。干燥(硫酸钠)有机相,过滤,真空浓缩。残留物经制备型TLC纯化,用3∶25∶72MeOH/己烷/EtOAc洗脱,得到7(3.8mg,18%收率,HPLC Rt 2.20分钟,使用Phenomenex 30x 4.65u柱,2分钟梯度,及1分钟的保留时间,使用5mL/分钟的流速。0至100%溶剂B。溶剂A=10/90/0.1%MeOH/水/TFA。溶剂B=90/10/0.1%。M+H=546.1),为白色固体。
实施例617-621
采用在实施例616中描述的方法制备实施例617-621。
N-(1-苄基-环己基甲基)-2-甲氧基-苯甲酰胺
合成:
化合物1:化合物1由市售获得。
化合物2:在氩气下,将环己烷甲腈(6.14g;56.2mmol)的四氢呋喃(40ml)溶液冷却至-78℃,用2M的二异丙基氨化锂在THF/正-庚烷(36mL;72mmol)中的溶液处理。移去冷浴,于室温下,将该反应混合物搅拌10分钟。再使反应混合物冷却至-78℃,用苄基溴(9.8g;57.3mmol)的四氢呋喃(10ml)溶液处理,使缓慢温热至室温过夜。浓缩反应混合物,使残留物分配于乙醚和10%盐酸水溶液之间。分离有机层,用饱和氯化钠水溶液洗涤,干燥(无水硫酸钠),过滤并浓缩。经硅胶柱层析,用9∶1己烷∶乙酸乙酯作为洗脱液,得到11g化合物2,为澄清油状物。质谱[M+H]+=200。
化合物3:将化合物2(3.8g;19.1mmol)的四氢呋喃(40ml)溶液冷却至0℃,分批用氢化锂铝(3.8g;100.1mmol)处理.使反应混合物缓慢温热至室温过夜.将反应混合物用2N氢氧化钠(约2ml)小心地猝灭,通过硅藻土柱过滤,用乙酸乙酯作为洗脱液,干燥(无水硫酸钠),过滤并浓缩,得到3.8g化合物3,为澄清油状物,其无须进一步纯化而用于下一步骤.质谱[M+H]+=204。
标题化合物:于室温下,将化合物3(0.38g;1.8mmol)的四氢呋喃(20ml)溶液用三乙胺(0.2mL;1.4mmol)处理,接着用邻-甲氧基苯甲酰氯(0.34g;2.0mmol)处理。搅拌反应物48小时,然后减压除去溶剂。使残留物分配于乙酸乙酯和10%盐酸水溶液之间。分离有机层,用饱和氯化钠水溶液洗涤,干燥(无水硫酸钠),过滤并浓缩。经硅胶柱层析,用8∶1己烷∶乙酸乙酯作为洗脱液,得到0.46g N-(1-苄基-环己基甲基)-2-甲氧基-苯甲酰胺,为澄清油状物。质谱[M+H]+=338。
实施例623-647
可以采用在实施例622中描述的方法制备实施例623-647。
实施例648
2-甲氧基-N-(1-苯基-环己基甲基)-烟酰胺
化合物1:按实施例330中所述制备化合物1。
标题化合物:用草酰氯(0.14mL;1.6mmol)和2滴N,N-二甲基甲酰胺处理2-甲氧基烟酸(0.23g;1.5mmol)在二氯甲烷(15ml)中的悬浮液。于室温下搅拌反应混合物30分钟,此时加入三乙胺(0.3mL;2.2mmol)和化合物1(0.315g;1.66mmol)。搅拌另外15分钟后,将反应混合物用水和饱和氯化钠水溶液洗涤,干燥(硫酸镁)并浓缩。粗残留物经硅胶柱层析纯化,用7∶3己烷∶乙酸乙酯作为洗脱液,得到0.37g 2-甲氧基-N-(1-苯基-环己基甲基)-烟酰胺,为白色固体。质谱[M+H]+=325。
实施例649
合成:
化合物1:按实施例330中所述制备化合物1。
化合物2:用N-氰基亚胺酸二苯酯(2.2g;9.2mmol)处理化合物1(1.2g;6.3mmol)的无水乙腈(30ml)溶液,于80℃加热4小时。使反应混合物置于室温下过夜。通过过滤收集形成的白色沉淀,用己烷洗涤,得到1.0g化合物2,为白色固体。质谱[M+H]+=334。
标题化合物:用2M乙胺的THF溶液(0.5mL;1mmol)处理化合物2(0.027g;0.08mmol),于60℃在用螺丝盖扭紧的小瓶中加热过夜.蒸发除去溶剂和过量的乙胺,粗产物经制备型反相液相层析纯化,得到0.008g标题化合物,为白色固体.质谱[M+H]+285。
实施例650-660
采用在实施例649中描述的方法制备实施例650-660。
实施例661
5-苄基-3-(1-苯基-环己基甲基)-咪唑烷-2,4-二酮
合成:
化合物1:按实施例330中所述制备化合物1。
标题化合物:用2-异氰酸基-3-苯基丙酸乙酯(0.325g;0.38mmol)处理化合物1(0.255g;1.35mmol)的无水二氯甲烷(8ml)溶液,于室温下搅拌过夜。通过蒸发除去溶剂,使残留物溶于乙醇(1ml)、6N盐酸(0.5ml)和水(0.5ml)中,将反应混合物加热至50℃。于50℃3小时后,加入另外的6N盐酸(1ml),于65℃,将该反应混合物加热过夜。浓缩反应混合物,粗产物经硅胶柱层析直接纯化,用1∶1乙酸乙酯∶己烷作为洗脱液,得到0.053g 5-苄基-3-(1-苯基-环己基甲基)-咪唑烷-2,4-二酮,为白色固体。质谱[M+H]+=363。
实施例662
1-异丙烯基-环己烷甲酸(3-苯基-丙基)-酰胺
合成:
化合物1:化合物1由市售获得。
化合物2:于0℃,向二异丙基胺(4.2ml)在THF(30ml)中的溶液中加入在己烷(1.6M,19ml)中的n-BuLi。搅拌30分钟后,使反应混合物冷却至-78℃,然后滴加入在THF(10ml)中的环己烷甲腈(1.09g,10mmol)。2小时后,加入丙酮(1.16g,20mmol)。在-78℃至室温下,将该反应混合物搅拌过夜,用Et2O(100ml)稀释,用1N HCl、水、盐水洗涤,经无水硫酸钠干燥。经快速层析(1∶1,己烷-Et2O)纯化,得到1-(1-羟基-1-甲基-乙基)-环己烷甲腈(1.27g,76%),为无色油状物。
1H NMR(CDCl3,300MHz)δ(ppm)0.86-1.91(8H,m),1.35(6H,s),2.01(2H,d,J=12.8Hz),3.65(1H,t,J=6.4Hz).质谱[M+H]+=168.1.
化合物3:将化合物2(530mg,3.17mmol)和磷酰氯(11.7g,76.1mmol)在CHCl3(12ml)中回流加热18小时,然后冷却至室温。缓慢加入水(75ml)。将含水层用CH2Cl2(2x)提取,将合并的提取物经无水硫酸钠干燥。经快速层析(2∶1,己烷-CH2Cl2)纯化,得到1-异丙烯基-环己烷甲腈(1.27g,76%),为无色油状物。
1H NMR(CDCl3,300MHz)δ(ppm)1.16-2.17(13H,m),4.96(1H,s),5.11(1H,s).质谱[M+H]+=150.1.
化合物4:于185℃,将化合物3(280mg,1.87mmol)和KOH(460mg,8.20mmol)在乙二醇(3.7ml)中加热18小时,然后冷却至室温。将反应混合物用水稀释,然后用Et2O(2x)提取。将水相用6N HCl酸化,然后用CH2Cl2(3x)提取,经无水硫酸钠干燥,得到1-异丙烯基-环己烷甲酸(234mg,74%),为亮白色固体。
1H NMR(CDCl3,300MHz)δ(ppm)1.16-1.65(9H,m),1.79(3H,s),2.16-2.20(2H,m),4.99(2H,s).质谱[M+H]+=169.1.
标题化合物:采用在实施例74中描述的方法,使化合物4与3-苯基丙基胺反应,得到1-异丙烯基-环己烷甲酸(3-苯基-丙基)-酰胺。质谱[M+H]+=286.1。
实施例663-665
采用在实施例662中描述的方法制备实施例663-665。
实施例666
1-异丙基-环己烷甲酸(3-苯基-丙基)-酰胺
合成:
化合物1:可以按实施例662中所述制备化合物1。
标题化合物:在氢气下,将化合物1(33mg,0.12mmol)和10%披钯碳(30mg)在EtOH(1ml)中搅拌18小时。将反应混合物经硅藻土过滤,浓缩得到1-异丙基-环己烷甲酸(3-苯基-丙基)-酰胺(33mg,100%),为无色油状物。
1H NMR(CDCl3,300MHz)δ(ppm)0.86(6H,d,J=6.8Hz),1.00-1.40(5H,m),1.50-1.65(4H,m),1.80-1.90(4H,m),2.67(2H,t,J=7.5Hz),3.33-3.48(2H,m),5.59(1H,s),7.17-7.31(5H,m).质谱[M+H]+=288.
实施例667-668
实施例667-668采用实施例666中描述的方法制备。
实施例669
N-(1-异丙烯基-环己基甲基)-2-甲氧基-苯甲酰胺
合成:
化合物1:可以按实施例662中所述制备化合物1。
化合物2:向冷却至0℃的在THF(3ml)中的化合物1(100mg,0.67mmol)中加入LAH(102mg,2.68mmol)。从0℃至室温,将该反应混合物搅拌过夜,然后用水(0.1ml)、15%NaOH(0.1ml)、水(0.3ml)猝灭,然后过滤,经无水硫酸钠干燥,得到(1-异丙烯基-环己基)-甲胺(63mg,61%),为无色油状物。
1H NMR(CDCl3,300MHz)δ(ppm)1.05-1.80(15H,m),2.46(2H,s),4.76(1H,s),5.07(1H,s).质谱[M+H]+=154.
标题化合物:采用在实施例1中描述的方法,使化合物2与邻-甲氧基苯甲酰氯反应,得到N-(1-异丙烯基-环己基甲基)-2-甲氧基-苯甲酰胺。质谱[M+H]+=288。
实施例670:实施例670采用实施例669中描述的方法制备。
实施例671
N-(1-异丙基-环己基甲基)-2-甲氧基-苯甲酰胺
合成:
化合物1:化合物1按实施例669中所述制备。
标题化合物:采用实施例669中所述的方法制备标题化合物。质谱[M+H]+=290。
实施例672
2-甲基-3-(1-苯基-环己基甲基)-3H-咪唑并[4,5-b]吡啶
合成:
化合物1:化合物1可以按实施例330中所述制备。
化合物2:用N,N-二异丙基乙胺(1mL;5.73mmol)和2-溴-3-硝基-吡啶(1.18g;5.81mmol)处理化合物1(1.21g;6.39mmol)的无水四氢呋喃(30ml)溶液。于60℃将反应混合物加热21小时。减压除去溶剂,将残留物用乙酸乙酯和10%盐酸水溶液处理。分离有机层,用饱和氯化钠水溶液洗涤,干燥(无水硫酸钠),过滤并浓缩。通过从最少量的乙酸乙酯中重结晶纯化产物,得到1.3g(3-硝基-吡啶-2-基)-(1-苯基-环己基甲基)-胺,为浅褐色固体。质谱[M+H]+=312。
化合物3:在氩气下,将化合物2(0.96g;3.1mmol)的四氢呋喃(25ml)和甲醇(10ml)溶液冷却至0℃.加入硼氢化钠(0.62g;16.4mmol)和氯化镍(II)(0.06g;0.46mmol),移去冷浴.于室温下,搅拌反应混合物1小时,此时TLC分析指示无起始原料剩余.用2N NaOH(5ml)猝灭反应物,减压除去挥发性成分。将残留物用乙酸乙酯和1N NaOH处理。分离有机层,用饱和氯化钠水溶液洗涤,干燥(无水硫酸钠),过滤并浓缩。通过从最少量的乙酸乙酯和数滴甲醇中重结晶纯化产物,得到0.47g(N2-(1-苯基-环己基甲基)-吡啶-2,3-二胺,为白色固体。质谱[M+H]+=282。
标题化合物:将化合物3(0.087g;0.31mmol)、乙酸(1ml)和EEDQ(0.094g;0.38mmol)混合,然后在氩气下,于120℃加热4小时。使该反应混合物冷却至室温,用乙腈和水稀释,经制备型反相液相层析纯化,得到0.01g的2-甲基-3-(1-苯基-环己基甲基)-3H-咪唑并[4,5-b]吡啶,为白色固体。质谱[M+H]+=306。
实施例673
3-(1-苯基-环己基甲基)-1,3-二氢-咪唑并[4,5-b]吡啶-2-酮合成:
化合物1:化合物1按实施例672中所述制备。
标题化合物:用三乙胺(0.05mL;0.36mmol)和双光气(0.041mL;0.34mmol)处理化合物1(0.095g;0.34mmol)的二氯甲烷(2ml)溶液,于室温下搅拌2小时。将额外的二氯甲烷和5%盐酸水溶液加入到反应混合物中。分离有机层,用饱和氯化钠水溶液洗涤并浓缩。使残留物溶于乙腈/水混合液中,冷冻干燥该混合物,得到0.04g的3-(1-苯基-环己基甲基)-1,3-二氢-咪唑并[4,5-b]吡啶-2-酮,为白色固体。质谱[M+H]+=308
{2-[(1-苯基-环己基甲基)-氨基]-吡啶-3-基}-甲醇
合成:
化合物1:化合物1可以按实施例330中所述制备。
化合物2:可以采用描述于实施例672中的方法,用2-氯代烟酸乙酯代替2-溴-3-硝基-吡啶,制备化合物2。通过硅胶柱层析,用8∶2己烷∶乙酸乙酯作为洗脱液,分离出无色油状产物。质谱[M+H]+=339。
标题化合物:在氩气下,将化合物2(0.15g;0.43mmol)的四氢呋喃(6ml)溶液冷却至0℃。以每份10mg加入氢化锂铝(0.073g;19.2mmol)。加入完毕后,移去冷浴,于室温下搅拌反应混合物0.5小时。用水(1ml)猝灭反应物,减压浓缩反应混合物。将残留物用乙酸乙酯和饱和碳酸氢钠水溶液处理。分离有机层,用饱和氯化钠水溶液洗涤,干燥(无水硫酸钠),过滤并浓缩。经硅胶柱层析,用1∶1己烷∶乙酸乙酯作为洗脱液,得到0.06g{2-[(1-苯基-环己基甲基)-氨基]-吡啶-3-基}-甲醇,为白色泡沫物。质谱[M+H]+=297。
实施例675
N-(4-甲基-吡啶-2-基)-3-苯基-N-(1-苯基-环己基甲基)-丙酰胺
合成:
化合物1:化合物1由市售获得。
化合物2:可以采用描述于实施例325中的方法,用4-甲基-吡啶-2-基胺代替异喹啉-1-基胺,制备化合物2.通过从最少量的乙酸乙酯、数滴甲醇和数滴己烷中重结晶纯化产物,得到化合物2,为棕色粉末.质谱[M+H]+=295。
化合物3:化合物3可以采用描述于实施例325中的方法制备。分离出无色油状物的产物。质谱[M+H]+=281。
标题化合物:用聚苯乙烯-二异丙基乙胺(PS-DIEA)(200mg)和氢化肉桂酰氯(0.05g;0.3mmol)处理化合物3(0.035g;0.13mmol)的乙腈(2ml)溶液。将反应物震摇6小时。反应混合物经制备型反相液相层析直接纯化,得到0.02g N-(4-甲基-吡啶-2-基)-3-苯基-N-(1-苯基-环己基甲基)-丙酰胺,为白色固体。质谱[M+H]+=413。
实施例676-680
实施例675-680采用描述于实施例675中的方法制备。
实施例681
3-苯基-N-(1-苯基-环己基甲基)-N-嘧啶-2-基-丙酰胺
合成:
化合物1:化合物1可以按实施例330中所述制备
化合物2:化合物2可以采用描述于实施例672中的方法制备。质谱[M+H]+=268。
化合物3:用三乙胺(0.1mL;0.72mmol)和氢化肉桂酰氯(0.08g;0.47mmol)处理化合物2(0.1g;0.37mmol)的四氢呋喃(2ml)溶液。于室温下搅拌反应混合物48小时。通过蒸发除去溶剂,残留物经制备型反相液相层析直接纯化,得到0.018g的3-苯基-N-(1-苯基-环己基甲基)-N-嘧啶-2-基-丙酰胺,为白色固体。质谱[M+H]+=400。
实施例682
2-甲氧基-N-[2-(1-苯基-环己基)-乙基]-苯甲酰胺
合成:
化合物1:化合物1由市售获得。
化合物2:向冷却至0℃的LAH(3.8g,0.1mol)悬浮液中缓慢加入1-苯基-环己烷甲酸(10.2g,50.0mmol).于0℃至室温,搅拌过夜后,将反应混合物用水(3.8ml)、15%NaOH(3.8ml)、水(11.4ml)猝灭,过滤.将所述盐用Et2O洗涤,合并的有机相经无水硫酸钠干燥,得到(1-苯基-环己基)-甲醇(8.48g,89%),为白色固体。
1H NMR(CDCl3,300MHz)δ(ppm)1.30-1.70(9H,m),2.15-2.36(2H,m),3.51(2H,s),7.20-7.27(1H,m),7.34-7.41(4H,m).质谱[M+H]+=191.1.
化合物3:向在CH2Cl2(50ml)中的化合物2(5.0g,26.3mmol)中加入13.4g(31.6mmol)Dess-Martin periodinane。2小时后,加入硫代硫酸钠(58g),接着加入饱和碳酸氢钠水溶液(200ml)。搅拌1小时后,用EtOAc稀释反应混合物,然后用水、盐水洗涤,经无水硫酸钠干燥。经快速层析(3∶1,己烷-EtOAc)纯化,得到1-苯基-环己烷甲醛(4.47g,90%),为无色油状物。质谱[M+H]+=189.1。
化合物4:于0℃,向在PhCH3(130ml)中的化合物3(4.47g,23.7mmol)中加入36ml氰化二乙基铝(1.0M/PhCH3)。于0℃搅拌3小时后,用饱和Rochelle氏盐猝灭反应混合物,于室温下搅拌2小时。将含水层用CH2Cl2(2x)提取,合并的提取物经无水硫酸钠干燥。羟基-(1-苯基-环己基)-乙腈可无须纯化而使用。质谱[M+H]+=216.1。
化合物5:向在二氯甲烷(80ml)中的化合物4(23.7mmol)中加入5.07g(28.4mmol)的1,1’-硫代羰基二咪唑,接着加入DMAP(0.579g,4.74mmol)。搅拌过夜后,用水洗涤反应混合物,经无水硫酸钠干燥。经快速层析(3∶1,己烷-EtOAc)纯化,得到咪唑-1-硫代甲酸O-[氰基-(1-苯基-环己基)-甲基]酯(6.27g,81%),为黄色糖浆状物。质谱[M+H]+=326.1。
化合物6:将化合物5(6.27g,19.3mmol)、Bu3SnH(16.8g,57.8mmol)和AIBN(0.63g,3.85mmol)在PhCH3(100ml)中回流加热1小时,然后浓缩。经快速层析(己烷,然后4∶1己烷-EtOAc)纯化,得到(1-苯基-环己基)-乙腈(3.84g,100%),为无色油状物。
1HNMR(CDCl3,300MHz)δ(ppm)1.20-1.80(8H,m),2.25-2.49(2H,m),2.49(2H,s),7.35-7.46(5H,m).质谱[M+H]+=210.1.
化合物7:向在0℃冷却的在THF中(10ml)的化合物6(500mg,2.51mmol)中缓慢加入382mg(10.04mmol)LAH。于0℃至室温搅拌过夜后,使反应混合物冷却至0℃,然后用水(0.38ml)、15%NaOH(0.38ml)、水(1.14ml)猝灭,过滤。用Et2O洗涤所述盐,合并的有机相经无水硫酸钠干燥,得到2-(1-苯基-环己基)-乙胺(510mg,100%),为无色油状物。质谱[M+H]+=204.2
标题化合物:2-甲氧基-N-[2-(1-苯基-环己基)-乙基]-苯甲酰胺可以采用实施例1中所述方法制备。质谱[M+H]+=338。
实施例683
实施例683采用描述于实施例682中的方法制备
实施例684
N-(2-甲氧基-苯基)-2-(1-苯基-环己基)-乙酰胺
合成:
化合物1:化合物1按实施例682中所述制备。
化合物2:于170℃,将化合物1(3.58g,17.96mmol)和KOH(4.42g,78.77mmol)在乙二醇(35ml)中加热48小时,然后冷却至室温。将反应混合物用水稀释,然后用Et2O(2x)提取。将水相用6N HCl酸化,然后用Et2O(3x)提取,经无水硫酸钠干燥,得到(1-苯基-环己基)-乙酸(3.43mg,88%),为褐色固体。质谱[M+H]+=219.1。
标题化合物:向在二氯甲烷(1ml)中的化合物2(50mg,0.23mmol)中加入24μL(0.27mmol)草酰氯,接着加入1滴DMF。1小时后,加入邻-甲氧基苯胺(28mg,0.23mmol),接着加入三乙胺(97μL,0.27mmol)。搅拌3小时后,用EtOAc稀释反应混合物,用1N HCl、1NNaOH、水、盐水洗涤,经无水硫酸钠干燥。经快速层析(9∶1,己烷-EtOAc)纯化,得到N-(2-甲氧基-苯基)-2-(1-苯基-环己基)-乙酰胺(37mg,50%),为白色固体。质谱[M+H]+=324。
实施例685
2-(1-苯基-环己基甲基)-1H-苯并咪唑
合成:
化合物1:化合物1按实施例684中所述制备。
化合物2:向化合物1(100mg,0.046mmol)的二氯甲烷(2ml)溶液中加入48μL(0.54mmol)草酰氯,接着加入1滴DMF。1.5小时后,将得到的酰氯加入到1,2-苯二胺(28mg,0.23mmol)溶液中,加入三乙胺(190μL,0.1.38mmol)。搅拌1小时后,用EtOAc稀释反应混合物,用1N HCl、1N NaOH、水、盐水洗涤,经无水硫酸钠干燥。N-(2-氨基-苯基)-2-(1-苯基-环己基)-乙酰胺无须纯化而用于下一步骤。
标题化合物:于100℃,将化合物2(0.46mmol)在冰醋酸(2ml)中加热2小时,然后冷却至室温。浓缩反应混合物,残留物经快速层析(1∶1,己烷-EtOAc)纯化,得到2-(1-苯基-环己基甲基)-1H-苯并咪唑(73mg,54%),为白色固体。质谱[M+H]+=291。
实施例686-687
实施例686-687采用描述于实施例685中的方法制备
实施例688
2-(1-苯基-环己基甲基)-3H-喹唑啉-4-酮
合成:
化合物1:化合物1按实施例684中所述制备。
化合物2:向在二氯甲烷(1ml)中的化合物2(75mg,0.0.34mmol)中加入36μL(0.0.41mmol)草酰氯,接着加入1滴DMF。1小时后,加入邻氨基苯甲酰胺(anthranilamide)(46mg,0.0.34mmol),接着加入三乙胺(150μL,1.02mmol)。搅拌过夜后,用EtOAc稀释反应混合物,用1NHCl、1N NaOH、水、盐水洗涤,经无水硫酸钠干燥。经快速层析(1∶1,己烷-EtOAc)纯化,得到2-[2-(1-苯基-环己基)-乙酰基氨基]-苯甲酰胺(78mg,68%),为白色固体。质谱[M+H]+=337.2。
标题化合物:于80℃,将所述酰胺(73mg,0.217mmol)在EtOH(1ml)和2N NaOH(1ml)中加热1小时。浓缩反应混合物,用二氯甲烷(3x)提取,然后经无水硫酸钠干燥。经快速层析(1∶1,己烷-EtOAc)纯化,得到2-(1-苯基-环己基甲基)-3H-喹唑啉-4-酮(66mg,96%),为白色固体。质谱[M+H]+=319.2。
实施例689
1-(1-苯基-环己基甲氧基)-异喹啉
合成:
化合物1:化合物1采用描述于实施例682中的方法制备。
标题化合物:在氩气下,将化合物1(0.23g;1.23mmol)的四氢呋喃(10ml)溶液冷却至0℃.以每份5-10mg缓慢加入氢化钠(0.080g;3.3mmol).加入完毕后,于0℃搅拌反应混合物0.25小时,加入1-氯代异喹啉(0.32g;2.0mmol).使反应混合物缓慢温热至室温过夜.加入另外的氢化钠(0.080g;3.3mmol),于60℃将该反应混合物加热7小时.通过蒸发除去溶剂,残留物经硅胶柱层析纯化,用8∶2己烷∶乙酸乙酯作为洗脱液,得到0.02g 1-(1-苯基-环己基甲氧基)-异喹啉。质谱[M+H]+=318。
实施例690-694
实施例690-694采用描述于实施例325中的方法制备
Claims (17)
1.一种式I化合物
其对映体、非对映体、溶剂合物或其盐,其中
m和p独立为0、1、2或3,条件是当m为1时,p不为2;
R1为
-N(R8)R14、-N(R8)C(O)R14、-SO2R8c、-CO2H、-C(O)R8c、-NR6R7、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、卤代基、全氟烷基、氰基、硝基、羟基、任选取代的烷氧基、任选取代的芳氧基、任选取代的杂芳氧基、任选取代的烷基、任选取代的链烯基或任选取代的炔基;
R1a为H、烷基、(羟基)烷基、(烷氧基)烷基、链烯基、炔基、环烷基、(环烷基)烷基、环烯基、(环烯基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基或(杂芳基)烷基;
或R1和R1a一起形成氧代基;
或R1和R1a与它们连接的碳原子结合在一起形成任选取代的螺-稠合的杂环基;
或R1和R1a结合在一起形成基团
R2为杂芳基、(杂芳基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、烷基、链烯基或环烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1、T2或T3;
J为键或任选由一个或多个基团T1a、T2a或T3a独立地取代的C1-4亚烷基;
R3为
R4为烷基、卤代烷基、链烯基、环烷基、杂环基、芳基或杂芳基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:
T1b、T2b或T3b;
R4a为R4或OR4;
R5为-NR6aR7a,或杂芳基、(杂芳基)烷基、芳基、(芳基)烷基、烷基、环烷基、(环烷基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1c、T2c或T3c;
R6、R6a、R7、R7a、R8、R8a、R8a1、R8a2、R8a3、R8a4、R8a5和R9独立为H、烷基、羟基、烷氧基、芳氧基、杂环基氧基、杂芳氧基、(羟基)烷基、(烷氧基)烷基、(芳氧基)烷基、(杂环基氧基)烷基、(杂芳氧基)烷基、(氰基)烷基、(链烯基)烷基、(炔基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、-C(O)R12、-CO2R12或-C(O)-NR12R13,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6和R7,或R6a和R7a与它们连接的氮原子一起可以结合形成饱和的或不饱和的4-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6或R7之一可以与R8、R8a或R9之一结合形成饱和的或不饱和的5-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6a或R7a之一可以与R8a1结合形成饱和的或不饱和的5-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
R8b独立为H、烷基、芳基、氰基、硝基、酰基或-SO2(烷基);
R8c独立为烷基、环烷基、链烯基、炔基、芳基、芳基烷基、环杂烷基、杂芳基、氨基或烷氧基;
R8d为R4、COR4、CO2R4、SO2R4、CONR6R7或SO2-NR6R7;
R10R10a、R11和R11a独立为H、烷基、芳基、(芳基)烷基、烷氧基、(烷氧基)烷基、卤代基、羟基、(羟基)烷基、氨基、酰氨基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、亚磺酰氨基、环烷基、(环烷基)烷基或氰基,其中任何一个基团可以在可利用的原子上任选由一个或多个以下的基团独立地取代:T1e、T2e或T3e;
或R10和R10a,或R11和R11a可以结合形成氧代基;
或R10a可以与R11a结合形成键;
或R10可以与R9结合形成饱和或不饱和环;
R12和R13独立为H、烷基、羟基、烷氧基、芳氧基、杂环基氧基、杂芳氧基、(羟基)烷基、(烷氧基)烷基、(芳氧基)烷基、(杂环基氧基)烷基、(杂芳氧基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1f、T2f或T3f;
或R12和R13与它们连接的氮原子一起可以结合形成饱和的或不饱和的环,所述环可以任选由一个或多个以下的基团独立地取代:T1f、T2f或T3f;
W为=NR8a2、=N-CO2R8a2、=N-COR8a2、=N-CN或=N-SO2R8a2;
X为
Z、Z1和Z2独立为=O、=S、=NR8a4或=N-CN;
R14独立为
其中q为1、2或3;
RY为连接于任何可利用的环碳原子的任选的氧代取代基;
X1为O、S、NR8a5或CH2;和
X2为NR8a5或CH2;
RX为一个或多个连接于任何可利用的环碳原子的任选的取代基,所述取代基独立选自T1g、T2g或T3g;
T1-1g、T2-2g和T3-3g各自独立为
(1)氢或T6,其中T6为
(i)烷基、(羟基)烷基、(烷氧基)烷基、链烯基、炔基、环烷基、(环烷基)烷基、环烯基、(环烯基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基或(杂芳基)烷基;
(ii)(i)中的基团,所述基团本身被一个或多个相同或不同的(i)中的基团取代;或
(iii)(i)或(ii)中的基团,所述基团被一个或多个(优选1-3个)选自以下T1-1g、T2-2g和T3-3g定义的(2)-(13)中的基团独立地取代,
(2)-OH或-OT6,
(3)-SH或-ST6,
(4)-C(O)tH、-C(O)tT6或-O-C(O)T6,其中t为1或2;
(5)-SO3H、-S(O)tT6或S(O)tN(T9)T6,
(6)卤代基,
(7)氰基,
(8)硝基,
(9)-T4-NT7T8,
(10)-T4-N(T9)-T5-NT7T8,
(11)-T4-N(T10)-T5-T6,
(12)-T4-N(T10)-T5-H,
(13)氧代基,
T4和T5各自独立为
(1)单键,
(2)-T11-S(O)t-T12-,
(3)-T11-C(O)-T12-,
(4)-T11-C(S)-T12-,
(5)-T11-O-T12-,
(6)-T11-S-T12-,
(7)-T11-O-C(O)-T12-,
(8)-T11-C(O)-O-T12
(9)-T11-C(=NT9a)-T12-或
(10)-T11-C(O)-C(O)-T12-
T7、T8、T9、T9a和T10
(1)各自独立为氢或在T6的定义中规定的基团,或
(2)T7和T8可以一起为亚烷基或亚链烯基,与它们连接的原子一起形成饱和的或不饱和的3-至8-元环,所述环为未取代的或由在T1-1g、T2-2g和T3-3g的定义中所列的一个或多个基团取代,
或
(3)T7或T8与T9一起,可以为亚烷基或亚链烯基,与它们连接的氮原子一起形成饱和的或不饱和的3-至8-元环,所述环为未取代的或由在T1-1g、T2-2g和T3-3g的定义中所列的一个或多个基团取代,或
(4)T7和T8或T9和T10与它们连接的氮原子一起可以结合形成基团-N=CT13T14,其中T13和T14各自独立为H或在T6的定义中规定的基团;
T11和T12各自独立为
(1)单键,
(2)亚烷基,
(3)亚链烯基,或
(4)亚炔基;
前提是
(i)当以下条件(a)和(b)都满足时,R2不是
(b)R1为H、卤代基、羟基、氰基、硝基、芳基、烷氧基、芳氧基、杂芳氧基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、-OC(=O)CCl3、-SO2(烷基)、-SO2(芳基)、-SO2(芳基烷基)、-CO2H、-C(=O)(烷基)、-CO2(烷基)、-C(=O)NR6*R7*、-NR6*R7*、-OC(=O)NR6*R7*、-N3、-N(R8)C(O)NR6*R7*、-OC(=O)OR4-OC(=O)R4或-N(H)S(O2)R4,或R1和R1a结合形成氧代基;或R1和R1a与它们连接的碳原子一起结合形成螺稠合的杂环基,或R1和R1a结合在一起形成基团
其中
R6*和R7*各自独立为H、芳基、-C(O)芳基、-CO2芳基、烷基、-C(O)烷基、-CO2烷基、-S(O)u烷基、-C(O)S(O)u烷基、-S(O)u芳基、-C(O)S(O)u芳基或杂环基;
R5a为
R8a为H或烷基;和
u为0、1、2或3;
(ii)当以下条件(c)和(d)都满足时,R2不是噻吩基:
(c)-J-R3为-NR6bR7b其中R6b和R7b独立为H、烷基、环烷基,或
R6b和R7b结合形成含有至少一个双键的含氮环状基团;和
(d)R1为烷基、环烷基、链烯基、炔基、烷氧基、氨基或氰基;
(iii)所述化合物不是下式的化合物
其中
R1c为-OC(O)NHR7c或-OC(O)R4b;
R2a为烷基或苯基;
R3a为
R4b为烷基;
R5b为-NHR7d或由1-3个独立选自卤代基、烷基或烷氧基的基团取代的苄基;
R7c为H、烷基、苯基或苄基;
R7d为由1-3个独立选自卤代基、烷基或烷氧基的基团取代的苯基;
RXa为羟基、-OC(O)NHR7c或-OC(O)R4b;
RXb和RXc独立为H或烷基;
n*为1-4;
n**为0-3;
(iv)当以下条件(e)和(f)都满足时,R2不是苯基:
(e)R1为烷基、烷氧基或苯基;和
(f)-J-R3为N-芳基取代的哌嗪基;
(v)当以下条件(g)和(h)都满足时,R1不是羟基、烷氧基、芳氧基、烷基或芳基,或当以下条件(g)和(h)都满足时,R1和R1a不形成=CH2:
(g)R2为烷基、芳基或芳基烷基;和
(h)-J-R3为-NR6eR7e或-(CHR20)-R5c
其中
R5c为任选取代的苯基;
R6e为氢、羟基或烷氧基;
R7e为任选取代的苯基;和
R20为氢、羟基或烷氧基;
(vi)当以下条件(j)和(k)都满足时,R2不是任选取代的苯基或吡啶基:
(j)R1a为H、羟基、烷基或(羟基)烷基,和R1为H、羟基、
-(CH2)n*-NR6fR7f、-(CH2)n*-CO2R8e、环烷基、杂环基或杂芳基;或R1a和R1结合形成氧代基、-O(CH2)m*O-或=CHCO2R8e
其中
n*为0-2;
m*为1或2;
R6f和R7f独立为H、烷基、链烯基、(羟基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基、(杂芳基)烷基、CHO、-C(O)-烷基、-C(O)-环烷基、-C(O)-(环烷基)烷基、-C(O)-芳基、-C(O)-(芳基)烷基、-C(O)-杂环基、-C(O)-(杂环基)烷基、-C(O)-烷基-NR8eR8f、-C(O)-NR8eR8f、-CO2-烷基、-烷基-CO2-烷基、-CO2-环烷基、-CO2-(环烷基)烷基、-CO2-芳基、-CO2-(芳基)烷基、-CO2-杂环基、-CO2-(杂环基)烷基、-CO2-NR8eR8f、-CO2-烷基-NR8eR8f、-NR8eCOR8f、-烷基-NR8eCOR8f、-NR8eCO2R8f、-烷基-NR8eCO2R8f、-C(O)N(R8e)(芳基)、-烷基-C(O)N(R8e)(芳基)、-C(O)N(R8e)(杂环基)、-烷基-C(O)N(R8e)(杂环基);
或R6f和R7f与它们连接的氮原子一起结合形成任选取代的杂环基环,所述杂环基环选自:
R8e和R8f独立为H、烷基、环烷基、(氟)烷基或-CH2CO2-烷基;
R8g为H、烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基、(杂芳基)烷基、CHO、-C(O)-烷基、-C(O)-环烷基、-C(O)-(环烷基)烷基、-C(O)-芳基、
-C(O)-(芳基)烷基、-C(O)-杂环基、-C(O)-(杂环基)烷基、-CO2-烷基、-CO2-环烷基、-CO2-(环烷基)烷基、-CO2-芳基、-CO2-(芳基)烷基、-CO2-杂环基、-CO2-(杂环基)烷基、-CO2-NR6fR7f或-CO2-(烷基)-NR6fR7f;
(k)-J-R3为以下的基团:
-C(O)-NR8a1-(CR15R16)-R5*,-(CR15R16)-NR8a1-C(O)-R5*,-(CR15R16)-NR8a1-(CR17R18)-R5*,-C(O)O-(CR15R16)-R5*,-(CR15R16)-OC(O)-R5*,-(CR15R16)-O-(CR17R18)-R5*,-C(R15)=C(R16)-R5*,-(CR15R16)-C(R17)=C(R18)-R5*,-(CR15R16)-C(R17R18)-(CR19R20)-R5*,-C(O)-(CR15R16)-(CR17R18)-R5*,-(CR15R16)-C(O)-(CR17R18)-R5*,-(CR15R16)-(CR17R18)-C(O)-R5*,-N(R8a1)-C(O)-(CR15R16)-R5*,-N(R8a1)-(CR15R16)-(CR17R18)-R5*,-N(R8a1)-C(O)-C(O)-R5*,-OC(O)-(CR15R16)-R5*,或-O-(CR15R16)-(CR17R18)-R5*,
其中
R5*为
其中
T1c*为羟基、烷基、氟代烷基、链烯基、环烷基、(环烷基)烷基、烷氧基、氟代烷氧基、(烷氧基)烷基、(烷氧基)烷氧基、(氟代烷氧基)烷基、链烯基氧基、环烷基氧基、(环烷基)烷氧基、苯氧基、氰基、卤代基、-NT7T8其中T7和T8如上所定义、-SH、-ST6其中T6如上定义、-S(O)tT6其中t如上定义、-C(O)tH、-C(O)tT6或-C(O)-NT7T8;
T2c*为H、卤素、烷基或烷氧基;
或当T1c*与T2c*相邻时,它们可以结合形成由烷基、氟代烷基、=O或=S任选取代的5或6-元杂环基或杂芳基环;
T3c*为H、卤素、烷基、氟代烷基、烷氧基、氟代烷氧基、环烷基、(环烷基)烷基、氰基、杂芳基、-NT7T8、-SH、-ST6、-S(O)tT6、-C(O)tH、-C(O)tT6或-C(O)-NT7T8,或由氰基、CO2H、CO2T6或-C(O)-NT7T8取代的烷基;
和
R15、R16、R17、R18、R19和R20独立为H、羟基、烷基、链烯基、(羟基)烷基、(烷氧基)烷基、-(CH2)n*-NR6fR7f、-CHO、-C(O)烷基或-CO2烷基;
或R15和R16一起形成-CH2CH2-;
或R17和R18一起形成-CH2CH2-;
或R19和R20一起形成-CH2CH2-。
4.一种权利要求1的化合物,其中
R1为
(a)-N(R8)-SO2-NR6R7或-N(R8)-C(W)-NR6R7
其中
R6和R7独立为
(i)H,或
(ii)烷基、环烷基、链烯基、炔基、芳基、杂芳基、杂环基、烷氧基、(芳基)烷基、(环烷基)烷基、(杂芳基)烷基、(杂环基)烷基或(烷氧基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,
或R6和R7结合形成由选自以下的一个或多个基团任选取代的杂环基环:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;
和
R8为
(i)H;或
(ii)烷基、环烷基、芳基、杂芳基、杂环基、(环烷基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,
(b)-N(R8)-C(Z)-N(R8a)-SO2-OH
其中
R4为
(i)H或
(ii)烷基、环烷基、链烯基、炔基、芳基、杂芳基、杂环基、烷氧基、(芳基)烷基、(环烷基)烷基、(杂芳基)烷基、(杂环基)烷基或(烷氧基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;和
R8和R8a独立为
(i)H;或
(ii)烷基、环烷基、芳基、杂芳基、杂环基、(环烷基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;或
(c)或基团
R1a为H;
R2为苯基、(苯基)烷基、萘基、噻吩基苯并噻吩基、烷基或链烯基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;
J为键、亚甲基或亚乙基;
R3为
(a)-R5,其中R5为杂芳基、杂环基或-NR6aR7a,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;
(b)-C(Z1)-R5或-O-C(Z1)-R5,
其中
R5为芳基、(芳基)烷基、杂芳基、(杂芳基)烷基或-NR6aR7a;和
R6a和R7a独立为
(i)H;或
(ii)烷基、环烷基、芳基、(芳基)烷基、杂芳基(杂芳基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;或
(c)-N(R8a1)-C(Z1)-R5或-N(R8a1)-SO2-R5
其中
R5为芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、烷基、环烷基、(烷氧基)烷基或(环烷氧基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;
和
R8a1为
(i)H;或
(ii)烷基、环烷基、芳基、杂芳基、杂环基、(环烷基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、
卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,
R5为任选取代的烷基、任选取代的环烷基、任选取代的杂芳基、任选取代的芳基或-NR6aR7a;
R6、R6a、R7和R7a独立为H,任选取代的芳基、任选取代的杂芳基、任选取代的环烷基、任选取代的杂环基、任选取代的(芳基)烷基、任选取代的(杂芳基)烷基、任选取代的(杂环基)烷基、任选取代的烷基或COR12;
或R6和R7,或R6a和R7a与它们连接的氮原子结合在一起形成任选取代的、饱和或不饱和的5-8元环。
5.一种权利要求1的化合物,其中
R1为
(a)氢或羟基;
(b)-O-C(O)-NR6R7、-N(R8)-SO2-NR6R7或-N(R8)-C(W)-NR6R7
其中
R6和R7独立为
(i)H或
(ii)烷基、环烷基、链烯基、炔基、芳基、杂芳基、杂环基、烷氧基、(芳基)烷基、(环烷基)烷基、(杂芳基)烷基、(杂环基)烷基或(烷氧基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,或R6和R7结合形成由选自以下的一个或多个基团任选取代的杂环基环:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;和
R8为
(i)H;或
(ii)烷基、环烷基、芳基、杂芳基、杂环基、(环烷基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,或
(c)基团
R1a为H;
R2为苯基、(苯基)烷基、萘基、噻吩基苯并噻吩基、烷基或链烯基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;
J为键、亚甲基或亚乙基;
R3为
(a)-R5,其中R5为杂芳基、杂环基,其中任一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;
(b)-C(Z1)-R5或-O-C(Z1)-R5,
其中
Z1为=NR8a4或=N-CN;
R5为芳基、(芳基)烷基、杂芳基、(杂芳基)烷基)或-NR6aR7a;和
R6a和R7a独立为
(i)H;或
(ii)烷基、环烷基、芳基、(芳基)烷基、杂芳基(杂芳基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;或
(c)-N(R8a1)-C(Z1)-R5或-N(R8a1)-SO2-R5
其中
Z1为=NR8a4或=N-CN;
R5为芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、烷基、环烷基、(烷氧基)烷基或(环烷氧基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基;和
R8a1为
(i)H;或
(ii)烷基、环烷基、芳基、杂芳基、杂环基、(环烷基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,其中任何一个基团可以任选由选自以下的一个或多个基团独立地取代:OH、SH、OT6、ST6、C(O)tT6、NT7T8、氰基、卤代基、氧代基、烷基、卤代烷基、芳基、杂芳基、杂环基、(OH)烷基、(SH)烷基、(OT6)烷基、(ST6)烷基、(C(O)tT6)烷基、(NT7T8)烷基、(氰基)烷基、(芳基)烷基、(杂芳基)烷基或(杂环基)烷基,
R5为任选取代的烷基、任选取代的环烷基、任选取代的杂芳基、任选取代的芳基或-NR6aR7a;
R6、R6a、R7和R7a独立为H、任选取代的芳基、任选取代的杂芳基、任选取代的环烷基、任选取代的杂环基、任选取代的(芳基)烷基、任选取代的(杂芳基)烷基、任选取代的(杂环基)烷基、任选取代的烷基或COR12;
或R6和R7或R6a和R7a与它们连接的氮原子结合在一起形成任选取代的、饱和或不饱和的5-8元环。
6.一种药用组合物,它包含至少一种权利要求1的化合物及其合适的媒介物或载体。
7.一种权利要求6的药用组合物,它还包含至少一种选自以下的另外的治疗剂:抗心律失常药、钙通道阻断剂、抗血小板药、抗高血压药、抗血栓形成药/抗溶解血栓药、抗凝血剂、HMG-CoA还原酶抑制剂、抗糖尿病药、拟甲状腺剂、盐皮质激素受体拮抗剂或强心甙类。
8.权利要求7的药用组合物,其中
(b)抗血小板药选自氟吡格雷、伊非曲班和阿司匹林;
(c)抗高血压药选自β肾上腺素能阻断剂、ACE抑制剂、AII拮抗剂、ET拮抗剂、ET/AII双重拮抗剂和血管肽酶抑制剂;
(d)抗血栓形成药/抗溶解血栓药选自tPA、重组tPA、TNK、nPA、VIIa因子抑制剂、Xa因子抑制剂和凝血酶抑制剂;
(e)抗凝血剂选自华法林和肝素;
(f)HMG-CoA还原酶抑制剂选自普伐他汀、洛伐他汀、阿托伐他汀、辛伐他汀、NK-104和ZD-4522;
(g)抗糖尿病药选自双胍类和双胍/格列苯脲组合剂;
(h)盐皮质激素受体拮抗剂选自螺内酯和依普利酮;和
(i)强心苷类选自洋地黄和毒毛花苷G。
9.权利要求8的药用组合物,其中
(a)ACE抑制剂选自卡托普利、佐芬普利、福辛普利、依那普利、ceranopril、西拉普利、地拉普利、喷托普利、喹那普利、雷米普利和赖诺普利;和
(b)血管肽酶抑制剂选自奥马曲拉和gemopatrilat。
10.式I的化合物、其对映体、非对映体、溶剂合物或其盐在制备用于治疗IKur-相关的疾病的药物中的用途
其中
m和p独立为0、1、2或3,条件是当m为1时,p不为2;
R1为
-N(R8)R14、-N(R8)C(O)R14、-SO2R8c、-CO2H、-C(O)R8c、-NR6R7、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、卤代基、全氟烷基、氰基、硝基、羟基、任选取代的烷氧基、任选取代的芳氧基、任选取代的杂芳氧基、任选取代的烷基、任选取代的链烯基或任选取代的炔基;
R1a为H、烷基、(羟基)烷基、(烷氧基)烷基、链烯基、炔基、环烷基、(环烷基)烷基、环烯基、(环烯基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基或(杂芳基)烷基;
或R1和R1a一起形成氧代基;
或R1和R1a与它们连接的碳原子结合在一起形成任选取代的螺-稠合的杂环基;
或R1和R1a结合在一起形成基团
R2为杂芳基、(杂芳基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、烷基、链烯基或环烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1、T2或T3;
J为键或任选由一个或多个基团T1a、T2a或T3a独立地取代的C1-4亚烷基;
R3为
R4为烷基、卤代烷基、链烯基、环烷基、杂环基、芳基或杂芳基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:
T1b、T2b或T3b;
R4a为R4或OR4;
R5为-NR6aR7a,或杂芳基、(杂芳基)烷基、芳基、(芳基)烷基、烷基、环烷基、(环烷基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1c、T2c或T3c;
R6、R6a、R7、R7a、R8、R8a、R8a1、R8a2、R8a3、R8a4、R8a5和R9独立为H、烷基、羟基、烷氧基、芳氧基、杂环基氧基、杂芳氧基、(羟基)烷基、(烷氧基)烷基、(芳氧基)烷基、(杂环基氧基)烷基、(杂芳氧基)烷基、(氰基)烷基、(链烯基)烷基、(炔基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、-C(O)R12、-CO2R12或-C(O)-NR12R13,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6和R7,或R6a和R7a与它们连接的氮原子一起可以结合形成饱和的或不饱和的4-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6或R7之一可以与R8、R8a或R9之一结合形成饱和的或不饱和的5-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6a或R7a之一可以与R8a1结合形成饱和的或不饱和的5-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
R8b独立为H、烷基、芳基、氰基、硝基、酰基或-SO2(烷基);
R8c独立为烷基、环烷基、链烯基、炔基、芳基、芳基烷基、环杂烷基、杂芳基、氨基或烷氧基;
R8d为R4、COR4、CO2R4、SO2R4、CONR6R7或SO2-NR6R7;
R10R10a、R11和R11a独立为H、烷基、芳基、(芳基)烷基、烷氧基、(烷氧基)烷基、卤代基、羟基、(羟基)烷基、氨基、酰氨基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、亚磺酰氨基、环烷基、(环烷基)烷基或氰基,其中任何一个基团可以在可利用的原子上任选由一个或多个以下的基团独立地取代:T1e、T2e或T3e;
或R10和R10a,或R11和R11a可以结合形成氧代基;
或R10a可以与R11a结合形成一个键;
或R10可以与R9结合形成饱和的或不饱和的环;
R12和R13独立为H、烷基、羟基、烷氧基、芳氧基、杂环基氧基、杂芳氧基、(羟基)烷基、(烷氧基)烷基、(芳氧基)烷基、(杂环基氧基)烷基、(杂芳氧基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1f、T2f或T3f;
或R12和R13与它们连接的氮原子一起可以结合形成饱和的或不饱和的环,所述环可以任选由一个或多个以下的基团独立地取代:T1f、T2f或T3f;
W为=NR8a2、=N-CO2R8a2、=N-COR8a2、=N-CN或=N-SO2R8a2;
X为
Z、Z1和Z2独立为=O、=S、=NR8a4或=N-CN;
R14独立为
其中q为1、2或3;
RY为连接于任何可利用的环碳原子的任选的氧代取代基;
X1为O、S、NR8a5或CH2;和
X2为NR8a5或CH2;
RX为一个或多个连接于任何可利用的环碳原子的任选的取代基,所述取代基独立选自T1g、T2g或T3g;
T1-1g、T2-2g和T3-3g各自独立为
(1)氢或T6,其中T6为
(i)烷基、(羟基)烷基、(烷氧基)烷基、链烯基、炔基、环烷基、(环烷基)烷基、环烯基、(环烯基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基或(杂芳基)烷基;
(ii)(i)中的基团,所述基团本身被一个或多个相同或不同的(i)中的基团取代;或
(iii)(i)或(ii)中的基团,所述基团被一个或多个(优选1-3个)选自T1-1g、T2-2g和T3-3g定义的以下的(2)-(13)中的基团独立地取代,
(2)-OH或-OT6,
(3)-SH或-ST6,
(4)-C(O)tH、-C(O)tT6或-O-C(O)T6,其中t为1或2;
(5)-SO3H、-S(O)tT6或S(O)tN(T9)T6,
(6)卤代基,
(7)氰基,
(8)硝基,
(9)-T4-NT7T8,
(10)-T4-N(T9)-T5-NT7T8,
(11)-T4-N(T10)-T5-T6,
(12)-T4-N(T10)-T5-H,
(13)氧代基,
T4和T5各自独立为
(1)单键,
(2)-T11-S(O)t-T12-,
(3)-T11-C(O)-T12-,
(4)-T11-C(S)-T12-,
(5)-T11-O-T12-,
(6)-T11-S-T12-,
(7)-T11-O-C(O)-T12-,
(8)-T11-C(O)-O-T12-,
(9)-T11-C(=NT9a)-T12-或
(10)-T11-C(O)-C(O)-T12-
T7、T8、T9、T9a和T10
(1)各自独立为氢或在T6的定义中规定的基团,或
(2)T7和T8可以一起为亚烷基或亚链烯基,与它们连接的原子一起形成饱和的或不饱和的3-至8-元环,所述环为未取代的或由在T1-1g、T2-2g和T3-3g的定义中所列的一个或多个基团取代,
或
(3)T7或T8与T9一起可以为亚烷基或亚链烯基,与它们连接的氮原子一起形成饱和的或不饱和的3-至8-元环,所述环为未取代的或由在T1-1g、T2-2g和T3-3g的定义中所列的一个或多个基团取代,或
(4)T7和T8或T9和T10与它们连接的氮原子一起可以结合形成基团-N=CT13T14,其中T13和T14各自独立为H或在T6的定义中规定的基团;
T11和T12各自独立为
(1)单键,
(2)亚烷基,
(3)亚链烯基,或
(4)亚炔基;
前提是
当以下条件(a)和(b)都满足时,R2不是
(b)R1为H、卤代基、羟基、氰基、硝基、芳基、烷氧基、芳氧基、杂芳氧基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、-OC(=O)CCl3、-SO2(烷基)、-SO2(芳基)、-SO2(芳基烷基)、-CO2H、-C(=O)(烷基)、-CO2(烷基)、-C(=O)NR6*R7*、-NR6*R7*、-OC(=O)NR6*R7*、-N3、-N(R8)C(O)NR6*R7*、-OC(=O)OR4-OC(=O)R4或-N(H)S(O2)R4,或R1和R1a结合形成氧代基;或R1和R1a与它们连接的碳原子一起结合形成螺稠合的杂环基,或R1和R1a结合在一起形成基团
其中
R6*和R7*各自独立为H、芳基、-C(O)芳基、-CO2芳基、
烷基、-C(O)烷基、-CO2烷基、-S(O)u烷基、-C(O)S(O)u
烷基、-S(O)u芳基、-C(O)S(O)u芳基或杂环基;
R5a为
R8a为H或烷基;和
u为0、1、2或3。
11.权利要求10的用途,其中所述IKur-相关疾病为心律失常、胃肠道疾病或炎性疾病或免疫性疾病。
12.权利要求11的用途,其中所述心律失常为室上心律失常。
13.权利要求12的用途,其中所述室上心律失常为心房纤维性颤动或心房扑动。
14.权利要求11的用途,其中所述胃肠道疾病为反流性食管炎或运动障碍。
15.权利要求11的用途,其中所述炎性疾病为慢性阻塞性肺病。
16.式I的化合物、其对映体、非对映体、溶剂合物或其盐在制备用于治疗糖尿病、认知障碍或癫痫症的药物中的用途
其中
m和p独立为0、1、2或3,条件是当m为1时,p不为2;
R1为
-N(R8)R14、-N(R8)C(O)R14、-SO2R8c、-CO2H、-C(O)R8c、-NR6R7、
任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、卤代基、全氟烷基、氰基、硝基、羟基、任选取代的烷氧基、任选取代的芳氧基、任选取代的杂芳氧基、任选取代的烷基、任选取代的链烯基或任选取代的炔基;
R1a为H、烷基、(羟基)烷基、(烷氧基)烷基、链烯基、炔基、环烷基、(环烷基)烷基、环烯基、(环烯基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基或(杂芳基)烷基;
或R1和R1a一起形成氧代基;
或R1和R1a与它们连接的碳原子结合在一起形成任选取代的螺-稠合的杂环基;
或R1和R1a结合在一起形成基团
R2为杂芳基、(杂芳基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、烷基、链烯基或环烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1、T2或T3;
J为键或任选由一个或多个基团T1a、T2a或T3a独立地取代的C1-4亚烷基;
R3为
R4为烷基、卤代烷基、链烯基、环烷基、杂环基、芳基或杂芳基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:
T1b、T2b或T3b;
R4a为R4或OR4;
R5为-NR6aR7a,或杂芳基、(杂芳基)烷基、芳基、(芳基)烷基、烷基、环烷基、(环烷基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1c、T2c或T3c;
R6、R6a、R7、R7a、R8、R8a、R8a1、R8a2、R8a3、R8a4、R8a5和R9独立为H、烷基、羟基、烷氧基、芳氧基、杂环基氧基、杂芳氧基、(羟基)烷基、(烷氧基)烷基、(芳氧基)烷基、(杂环基氧基)烷基、(杂芳氧基)烷基、(氰基)烷基、(链烯基)烷基、(炔基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、-C(O)R12、-CO2R12或-C(O)-NR12R13,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6和R7,或R6a和R7a与它们连接的氮原子一起可以结合形成饱和的或不饱和的4-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6或R7之一可以与R8、R8a或R9之一结合形成饱和的或不饱和的5-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6a或R7a之一可以与R8a1结合形成饱和的或不饱和的5-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
R8b独立为H、烷基、芳基、氰基、硝基、酰基或-SO2(烷基);
R8c独立为烷基、环烷基、链烯基、炔基、芳基、芳基烷基、环杂烷基、杂芳基、氨基或烷氧基;
R8d为R4、COR4、CO2R4、SO2R4、CONR6R7或SO2-NR6R7;
R10R10a、R11和R11a独立为H、烷基、芳基、(芳基)烷基、烷氧基、(烷氧基)烷基、卤代基、羟基、(羟基)烷基、氨基、酰氨基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、亚磺酰氨基、环烷基、(环烷基)烷基或氰基,其中任何一个基团可以在可利用的原子上任选由一个或多个以下的基团独立地取代:T1e、T2e或T3e;
或R10和R10a,或R11和R11a可以结合形成氧代基;
或R10a可以与R11a结合形成键;
或R10可以与R9结合形成饱和的或不饱和的环;
R12和R13独立为H、烷基、羟基、烷氧基、芳氧基、杂环基氧基、杂芳氧基、(羟基)烷基、(烷氧基)烷基、(芳氧基)烷基、(杂环基氧基)烷基、(杂芳氧基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1f、T2f或T3f;
或R12和R13与它们连接的氮原子一起可以结合形成饱和的或不饱和的环,所述环可以任选由一个或多个以下的基团独立地取代:T1f、T2f或T3f;
W为=NR8a2、=N-CO2R8a2、=N-COR8a2、=N-CN或=N-SO2R8a2;
X为
Z、Z1和Z2独立为=O、=S、=NR8a4或=N-CN;
R14独立为
其中q为1、2或3;
RY为连接于任何可利用的环碳原子的任选的氧代取代基;
X1为O、S、NR8a5或CH2;和
X2为NR8a5或CH2;
RX为一个或多个连接于任何可利用的环碳原子的任选的取代基,所述取代基独立选自T1g、T2g或T3g;
T1-1g、T2-2g和T3-3g各自独立为
(1)氢或T6,其中T6为
(i)烷基、(羟基)烷基、(烷氧基)烷基、链烯基、炔基、环烷基、(环烷基)烷基、环烯基、(环烯基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基或(杂芳基)烷基;
(ii)(i)中的基团,所述基团本身被一个或多个相同或不同的(i)中的基团取代;或
(iii)(i)或(ii)中的基团,所述基团被一个或多个(优选1-3个)选自T1-1g、T2-2g和T3-3g定义的以下的(2)-(13)中的基团独立地取代,
(2)-OH或-OT6,
(3)-SH或-ST6,
(4)-C(O)tH、-C(O)tT6或-O-C(O)T6,其中t为1或2;
(5)-SO3H、-S(O)tT6或S(O)tN(T9)T6,
(6)卤代基,
(7)氰基,
(8)硝基,
(9)-T4-NT7T8,
(10)-T4-N(T9)-T5-NT7T8,
(11)-T4-N(T10)-T5-T6,
(12)-T4-N(T10)-T5-H,
(13)氧代基,
T4和T5各自独立为
(1)单键,
(2)-T11-S(O)t-T12-,
(3)-T11-C(O)-T12-,
(4)-T11-C(S)-T12-,
(5)-T11-O-T12-,
(6)-T11-S-T12-,
(7)-T11-O-C(O)-T12-,
(8)-T11-C(O)-O-T12-,
(9)-T11-C(=NT9a)-T12-或
(10)-T11-C(O)-C(O)-T12-
T7、T8、T9、T9a和T10
(1)各自独立为氢或在T6的定义中规定的基团,或
(2)T7和T8可以一起为亚烷基或亚链烯基,与它们连接的原子一起形成饱和的或不饱和的3-至8-元环,所述环为未取代的或由在T1-1g、T2-2g和T3-3g的定义中所列的一个或多个基团取代,
或
(3)T7或T8与T9一起可以为亚烷基或亚链烯基,与它们连接的氮原子一起形成饱和的或不饱和的3-至8-元环,所述环为未取代的或由在T1-1g、T2-2g和T3-3g的定义中所列的一个或多个基团取代,或
(4)T7和T8或T9和T10与它们连接的氮原子一起可以结合形成基团-N=CT13T14,其中T13和T14各自独立为H或在T6的定义中规定的基团;
T11和T12各自独立为
(1)单键,
(2)亚烷基,
(3)亚链烯基,或
(4)亚炔基;
前提是
(b)R1为H、卤代基、羟基、氰基、硝基、芳基、烷氧基、芳氧基、杂芳氧基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、-OC(=O)CCl3、-SO2(烷基)、-SO2(芳基)、-SO2(芳基烷基)、-CO2H、-C(=O)(烷基)、-CO2(烷基)、-C(=O)NR6*R7*、-NR6*R7*、-OC(=O)NR6*R7*、-N3、-N(R8)C(O)NR6*R7*、-OC(=O)OR4-OC(=O)R4或-N(H)S(O2)R4,或R1和R1a结合形成氧代基;或R1和R1a与它们连接的碳原子一起结合形成螺稠合的杂环基,或R1和R1a结合在一起形成基团
其中
R6*和R7*各自独立为H、芳基、-C(O)芳基、-CO2芳基、烷基、-C(O)烷基、-CO2烷基、-S(O)u烷基、-C(O)S(O)u烷基、-S(O)u芳基、-C(O)S(O)u芳基或杂环基;
R5a为
R8a为H或烷基;和
u为0、1、2或3。
17.一种式I化合物
其对映体、非对映体或其盐,其中
m和p独立为0、1、2或3,条件是当m为1时,p不为2;
R1为
-N(R8)R14、-N(R8)C(O)R14、-SO2R8c、-CO2H、-C(O)R8c、-NR6R7、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、卤代基、全氟烷基、氰基、硝基、羟基、任选取代的烷氧基、任选取代的芳氧基、任选取代的杂芳氧基、任选取代的烷基、任选取代的链烯基或任选取代的炔基;
R1a为H、烷基、(羟基)烷基、(烷氧基)烷基、链烯基、炔基、环烷基、(环烷基)烷基、环烯基、(环烯基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基或(杂芳基)烷基;
或R1和R1a一起形成氧代基;
或R1和R1a与它们连接的碳原子结合在一起形成任选取代的螺-稠合的杂环基;
或R1和R1a结合在一起形成基团
R2为杂芳基、(杂芳基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、烷基或环烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1、T2或T3;
J为键或任选由一个或多个基团T1a、T2a或T3a独立地取代的C1-4亚烷基;
R3为
R4为烷基、卤代烷基、链烯基、环烷基、杂环基、芳基或杂芳基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:
T1b、T2b或T3b;
R4a为R4或OR4;
R5为-NR6aR7a,或杂芳基、(杂芳基)烷基、芳基、(芳基)烷基、烷基、环烷基、(环烷基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1c、T2c或T3c;
R6、R6a、R7、R7a、R8、R8a、R8a1、R8a2、R8a3、R8a4、R8a5和R9独立为H、烷基、羟基、烷氧基、芳氧基、杂环基氧基、杂芳氧基、(羟基)烷基、(烷氧基)烷基、(芳氧基)烷基、(杂环基氧基)烷基、(杂芳氧基)烷基、(氰基)烷基、(链烯基)烷基、(炔基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、-C(O)R12、-CO2R12或-C(O)-NR12R13,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6和R7,或R6a和R7a与它们连接的氮原子一起可以结合形成饱和的或不饱和的4-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6或R7之一可以与R8、R8a或R9之一结合形成饱和的或不饱和的5-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
或R6a或R7a之一可以与R8a1结合形成饱和的或不饱和的5-8元环,所述环任选由一个或多个以下的基团独立地取代:T1d、T2d或T3d;
R8b独立为H、烷基、芳基、氰基、硝基、酰基或-SO2(烷基);
R8c独立为烷基、环烷基、链烯基、炔基、芳基、芳基烷基、环杂烷基、杂芳基、氨基或烷氧基;
R8d为R4、COR4、CO2R4、SO2R4、CONR6R7或SO2-NR6R7;
R10R10a、R11和R11a独立为H、烷基、芳基、(芳基)烷基、烷氧基、(烷氧基)烷基、卤代基、羟基、(羟基)烷基、氨基、酰氨基、杂芳基、(杂芳基)烷基、杂环基、(杂环基)烷基、亚磺酰氨基、环烷基、(环烷基)烷基、氰基或氧代基,其中任何一个基团可以在可利用的原子上任选由一个或多个以下的基团独立地取代:T1e、T2e或T3e;
或R10a可以与R11a结合形成一个键;
或R10可以与R9结合形成饱和的或不饱和的环;
R12和R13独立为H、烷基、羟基、烷氧基、芳氧基、杂环基氧基、杂芳氧基、(羟基)烷基、(烷氧基)烷基、(芳氧基)烷基、(杂环基氧基)烷基、(杂芳氧基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂芳基、(杂芳基)烷基、杂环基或(杂环基)烷基,其中任何一个基团可以任选由一个或多个以下的基团独立地取代:T1f、T2f或T3f;
或R12和R13与它们连接的氮原子一起可以结合形成饱和的或不饱和的环,所述环可以任选由一个或多个以下的基团独立地取代:T1f、T2f或T3f;
W为=NR8a2、=N-CO2R8a2、=N-COR8a2、=N-CN或=N-SO2R8a2;
X为
Z、Z1和Z2独立为=O、=S、=NR8a4或=N-CN;
R14独立为
其中q为1、2或3;
RY为连接于任何可利用的环碳原子的任选的氧代取代基;
X1为O、S、NR8a5或CH2;和
X2为NR8a5或CH2;
RX为一个或多个连接于任何可利用的环碳原子的任选的取代基,所述取代基独立选自T1g、T2g或T3g;
T1-1g、T2-2g和T3-3g各自独立为
(1)氢或T6,其中T6为
(i)烷基、(羟基)烷基、(烷氧基)烷基、链烯基、炔基、环烷基、(环烷基)烷基、环烯基、(环烯基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基或(杂芳基)烷基;
(ii)(i)中的基团,所述基团本身被一个或多个相同或不同的(i)中的基团取代;或
(iii)(i)或(ii)中的基团,所述基团被一个或多个(优选1-3个)选自T1-1g、T2-2g和T3-3g定义的以下的(2)-(13)中的基团独立地取代,
(2)-OH或-OT6,
(3)-SH或-ST6,
(4)-C(O)tH、-C(O)tT6或-O-C(O)T6,其中t为1或2;
(5)-SO3H、-S(O)tT6或S(O)tN(T9)T6,
(6)卤代基,
(7)氰基,
(8)硝基,
(9)-T4-NT7T8,
(1O)-T4-N(T9)-T5-NT7T8,
(11)-T4-N(T10)-T5-T6,
(12)-T4-N(T10)-T5-H,
(13)氧代基,
T4和T5各自独立为
(1)单键,
(2)-T11-S(O)t-T12-,
(3)-T11-C(O)-T12-,
(4)-T11-C(S)-T12-,
(5)-T11-O-T12-,
(6)-T11-S-T12-,
(7)-T11-O-C(O)-T12-,
(8)-T11-C(O)-O-T12-,
(9)-T11-C(=NT9a)-T12-或
(10)-T11-C(O)-C(O)-T12-
T7、T8、T9、T9a和T10
(1)各自独立为氢或在T6的定义中规定的基团,或
(2)T7和T8可以一起为亚烷基或亚链烯基,与它们连接的原子一起形成饱和的或不饱和的3-至8-元环,所述环为未取代的或由在T1-1g、T2-2g和T3-3g的定义中所列的一个或多个基团取代,或
(3)T7或T8与T9一起可以为亚烷基或亚链烯基,与它们连接的氮原子一起形成饱和的或不饱和的3-至8-元环,所述环为未取代的或由在T1-1g、T2-2g和T3-3g的定义中所列的一个或多个基团取代,或
(4)T7和T8或T9和T10与它们连接的氮原子一起可以结合形成基团-N=CT13T14,其中T13和T14各自独立为H或在T6的定义中规定的基团;
T11和T12各自独立为
(1)单键,
(2)亚烷基,
(3)亚链烯基,或
(4)亚炔基;
前提是
(i)当以下条件(a)和(b)都满足时,R2不是
(b)R1为H、卤代基、羟基、氰基、硝基、芳基、烷氧基、芳氧基、杂芳氧基、任选取代的烷基、任选取代的链烯基、任选取代的炔基、-OC(=O)CCl3、-SO2(烷基)、-SO2(芳基)、-SO2(芳基烷基)、-CO2H、-C(=O)(烷基)、-CO2(烷基)、-C(=O)NR6*R7*、-NR6*R7*、-OC(=O)NR6*R7*、-N3、-N(R8)C(O)NR6*R7*、-OC(=O)OR4、-OC(=O)R4或-N(H)S(O2)R4,或R1和R1a结合形成氧代基;或R1和R1a与它们连接的碳原子一起结合形成螺稠合的杂环基,或R1和R1a结合在一起形成基团
其中
R6*和R7*各自独立为H、芳基、-C(O)芳基、-CO2芳基、烷基、-C(O)烷基、-CO2烷基、-S(O)u烷基、-C(O)S(O)u烷基、-S(O)u芳基、-C(O)S(O)u芳基或杂环基;
R5a为
R8a为H或烷基;和
u为0、1、2或3;
(ii)当以下条件(c)和(d)都满足时,R2不是噻吩基:
(c)-J-R3为-NR6bR7b,其中R6b和R7b独立为H、烷基、环烷基,或R6b和R7b结合形成含有至少一个双键的含氮环状基团;和
(d)R1为烷基、环烷基、链烯基、炔基、烷氧基、氨基或氰基;
(iii)所述化合物不是下式的化合物
其中
R1c为-OC(O)NHR7c或-OC(O)R4b;
R2a为烷基或苯基;
R3a为
R4b为烷基;
R5b为-NHR7d或由1-3个独立选自卤代基、烷基或烷氧基的基团取代的苄基;
R7c为H、烷基、苯基或苄基;
R7d为由1-3个独立选自卤代基、烷基或烷氧基的基团取代的苯基;
RXa为羟基、-OC(O)NHR7c或-OC(O)R4b;
RXb和RXc独立为H或烷基;
n*为1-4;
n**为0-3;
(iv)当以下条件(e)和(f)都满足时,R2不是苯基:
(e)R1为烷基、烷氧基或苯基;和
(f)-J-R3为N-芳基取代的哌嗪基;
(v)当以下条件(g)和(h)都满足时,R1不是羟基、烷氧基、芳氧基、烷基或芳基,或当以下条件(g)和(h)都满足时,R1和R1a不形成=CH2:
(g)R2为烷基、芳基或芳基烷基;和
(h)-J-R3为-NR6eR7e或-(CHR20)-R5c
其中
R5c为任选取代的苯基;
R6e为氢、羟基或烷氧基;
R7e为任选取代的苯基;和
R20为氢、羟基或烷氧基;
(vi)当以下条件(j)和(k)都满足时,R2不是任选取代的苯基或吡啶基:
(j)R1a为H、羟基、烷基或(羟基)烷基,和R1为H、羟基、
-(CH2)n*-NR6fR7f、-(CH2)n*-CO2R8e、环烷基、杂环基或杂芳基;
或R1a和R1结合形成氧代基、-O(CH2)m*O-或=CHCO2R8e
其中
n*为0-2;
m*为1或2;
R6f和R7f独立为H、烷基、链烯基、(羟基)烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基、(杂芳基)烷基、CHO、-C(O)-烷基、-C(O)-环烷基、-C(O)-(环烷基)烷基、-C(O)-芳基、-C(O)-(芳基)烷基、-C(O)-杂环基、-C(O)-(杂环基)烷基、-C(O)-烷基-NR8eR8f、-C(O)-NR8eR8f、-CO2-烷基、-烷基-CO2-烷基、-CO2-环烷基、-CO2-(环烷基)烷基、-CO2-芳基、-CO2-(芳基)烷基、-CO2-杂环基、-CO2-(杂环基)烷基、-CO2-NR8eR8f、-CO2-烷基-NR8eR8f、-NR8eCOR8f、-烷基-NR8eCOR8f、-NR8eCO2R8f、-烷基-NR8eCO2R8f、-C(O)N(R8e)(芳基)、-烷基-C(O)N(R8e)(芳基)、-C(O)N(R8e)(杂环基)、-烷基-C(O)N(R8e)(杂环基);
或R6f和R7f与它们连接的氮原子一起结合形成任选取代的杂环基环,所述杂环基环选自:
R8e和R8f独立为H、烷基、环烷基、(氟)烷基或-CH2CO2-烷基;
R8g为H、烷基、环烷基、(环烷基)烷基、芳基、(芳基)烷基、杂环基、(杂环基)烷基、杂芳基、(杂芳基)烷基、CHO、-C(O)-烷基、-C(O)-环烷基、-C(O)-(环烷基)烷基、-C(O)-芳基、-C(O)-(芳基)烷基、-C(O)-杂环基、-C(O)-(杂环基)烷基、-CO2-烷基、-CO2-环烷基、-CO2-(环烷基)烷基、-CO2-芳基、-CO2-(芳基)烷基、-CO2-杂环基、-CO2(杂环基)烷基、-CO2-NR6fR7f或-CO2-(烷基)-NR6fR7f;
(k)-J-R3为以下的基团:
-C(O)-NR8a1-(CR15R16)-R5*,-(CR15R16)-NR8a1-C(O)-R5*,-(CR15R16)-NR8a1-(CR17R18)-R5*,-C(O)O-(CR15R16)-R5*,-(CR15R16)-OC(O)-R5*,-(CR15R16)-O-(CR17R18)-R5*,-C(R15)=C(R16)-R5*,-(CR15R16)-C(R17)=C(R18)-R5*,-(CR15R16)-C(R17R18)-(CR19R20)-R5*,-C(O)-(CR15R16)-(CR17R18)-R5*,-(CR15R16)-C(O)-(CR17R18)-R5*,-(CR15R16)-(CR17R18)-C(O)-R5*,-N(R8a1)-C(O)-(CR15R16)-R5*,-N(R8a1)-(CR15R16)-(CR17R18)-R5*,-N(R8a1)-C(O)-C(O)-R5*,-OC(O)-(CR15R16)-R5*,或-O-(CR15R16)-(CR17R18)-R5*,
其中
R5*为
其中
T1c*为羟基、烷基、氟代烷基、链烯基、环烷基、(环烷基)烷基、烷氧基、氟代烷氧基、(烷氧基)烷基、(烷氧基)烷氧基、(氟代烷氧基)烷基、链烯基氧基、环烷基氧基、(环烷基)烷氧基、苯氧基、氰基、卤代基、-NT7T8其中T7和T8如上所定义、-SH、-ST6其中T6如上定义、-S(O)tT6其中t如上定义、-C(O)tH、-C(O)tT6或-C(O)-NT7T8;
T2c*为H、卤素、烷基或烷氧基;
或当T1c*与T2c*相邻时,它们可以结合形成由烷基、氟代烷基、=O或=S任选取代的5或6-元杂环基或杂芳基环
T3c*为H、卤素、烷基、氟代烷基、烷氧基、氟代烷氧基、环烷基、(环烷基)烷基、氰基、杂芳基、-NT7T8、-SH、-ST6、-S(O)tT6、-C(O)tH、-C(O)tT6或-C(O)-NT7T8,或由氰基、CO2H、CO2T6或-C(O)-NT7T8取代的烷基;
和
R15、R16、R17、R18、R19和R20独立为H、羟基、烷基、链烯基、(羟基)烷基、(烷氧基)烷基、-(CH2)n*-NR6fR7f、-CHO、-C(O)烷基或-CO2烷基;
或R15和R16一起形成-CH2CH2-;
或R17和R18一起形成-CH2CH2-;
或R19和R20一起形成-CH2CH2-。
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CN105175278A (zh) * | 2015-09-17 | 2015-12-23 | 上海大学 | 7-肟醚酰胺脱氢枞酸化合物及其合成方法 |
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