CN111868052B - 苯基吡咯烷酮甲酰肽2受体激动剂 - Google Patents
苯基吡咯烷酮甲酰肽2受体激动剂 Download PDFInfo
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- CN111868052B CN111868052B CN201980017438.1A CN201980017438A CN111868052B CN 111868052 B CN111868052 B CN 111868052B CN 201980017438 A CN201980017438 A CN 201980017438A CN 111868052 B CN111868052 B CN 111868052B
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Classifications
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract
本发明涉及式(II)化合物,其为甲酰肽2(FPR2)受体激动剂和/或甲酰肽1(FPR1)受体激动剂。本发明还提供组合物和使用所述化合物例如治疗动脉粥样硬化、心力衰竭、慢性阻塞性肺病(COPD)和相关疾病的方法。
Description
相关申请的交叉引用
本申请享有2018年3月5日申请的美国临时专利申请第62/638,556号依据35U.S.C.§119(e)的优先权,将该申请全文并入本文中。
技术领域
本发明涉及新颖的吡咯烷酮化合物,其为甲酰肽2(FPR2)受体激动剂和/或甲酰肽1(FPR1)受体激动剂、含有所述化合物的组合物和使用所述化合物例如治疗动脉粥样硬化、心力衰竭、慢性阻塞性肺病(COPD)和相关疾病的方法。
背景技术
甲酰肽受体2(FPR2)属于表达于包括免疫细胞的多个人类组织中且已知在宿主防御和炎症方面至关重要的一小组七跨膜域G蛋白偶联受体。FPR2与FPR1和FPR3共有显著序列同源性(Journal of Autoimmunity 85,2017,64-77)。共同地,这些受体结合多种结构各异的激动剂,包括用作化学引诱剂且活化吞噬细胞的N-甲酰肽和非甲酰肽。内源肽磷脂结合蛋白A1(Annexin A1)及其N端片段为结合人类FPR1和FPR2的配体的实例。属于一类较小促消退介体(SPM)的脂肪酸(诸如类二十烷酸脂氧素A4)也经鉴别为FPR2的激动剂(Ye RD.等人,Pharmacol.Rev.,2009,61,119-61)。
内源性FPR2促消退配体(诸如脂氧素A4和磷脂结合蛋白A1)经报道触发各种各样的细胞质级联,诸如Gi偶联、Ca2+移动和β-抑制蛋白募集。(Int J Mol Sci.2013年4月;14(4):7193-7230)。FPR2调控包括嗜中性粒细胞、巨噬细胞、T细胞和B细胞的先天和后天免疫系统两者。在嗜中性粒细胞中,FPR2配体调节移动、细胞毒性和寿命。在巨噬细胞中,FPR2的激动作用阻止细胞凋亡且增强胞葬作用。(Chandrasekharan JA,Sharma-Walia N,.J.Inflamm.Res.,2015,8,181-92)。FPR2激动作用使炎症开始消退,促成抗纤维化创伤愈合的加快和受伤组织至稳定的恢复(Romano M.等人,Eur.J.Pharmacol.,2015,5,49-63)。
慢性炎症为许多人类疾病的发病机制的途径的部分,且用FPR2激动剂刺激消退途径可同时具有保护和修复作用。缺血-再灌注(I/R)损伤为与高发病率和死亡率相关的若干疾病(诸如心肌梗塞和中风)的共同特征。与心肌细胞死亡和由缺血-再灌注损伤引起的病理性重塑相关的非滋生性创伤愈合引起疤痕形成、纤维化和心脏功能的逐渐丧失。已提出,FPR2调节促进损伤后心肌创伤愈合且减少不良心肌重塑(Kain V.等人,J.Mol.Cell.Cardiol.,2015,84,24-35)。另外,在中枢神经系统中,FPR2促消退激动剂可为治疗包括脑中风(GavinsFN.,Trends Pharmacol.Sci.,2010,31,266-76)和I/R诱导之脊髓损伤(Liu ZQ.等人,Int.J.Clin.Exp.Med.,2015,8,12826-33)的多种临床I/R病况的适用疗法。
除用新颖促消退激动剂靶向FPR2受体在治疗I/R诱导的损伤治疗方面的有利效果以外,这些配体的效用还可应用于其他疾病。在心血管系统中,FPR2受体及其促消退激动剂均被认为促进动脉粥样硬化斑稳定化和愈合(Petri MH.等人,Cardiovasc.Res.,2015,105,65-74;和Fredman G.等人,Sci.Trans.Med.,2015,7(275);275ra20)。还已显示FPR2激动剂在慢性炎性人类疾病的临床前模型中有益,所述疾病包括:传染性疾病、牛皮癣、皮炎、炎性肠综合征、克罗恩病、眼部炎症、败血症、疼痛、代谢疾病/糖尿病、癌症、COPD、哮喘和过敏性疾病、囊性纤维化、急性肺损伤和纤维化、类风湿性关节炎及其他关节疾病、阿尔茨海默病、肾纤维化和器官移植(Romano M.等人,Eur.J.Pharmacol.,2015,5,49-63;Perrett,M.等人,Trends in Pharm.Sci.,2015,36,737-755)。
发明内容
本发明提供可用作FPR2激动剂的新颖吡咯烷酮及其类似物,包括其立体异构体、互变异构体、药学上可接受的盐或溶剂合物。
本发明还提供用于制备本发明化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂合物的方法和中间体。
本发明还提供药物组合物,其包含药学上可接受的载体和至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂合物。
本发明化合物可用于疗法中。
本发明化合物可用于治疗和/或预防与FPR2相关的多种疾病或病症,诸如炎性疾病、心脏病、慢性呼吸道疾病、癌症、败血症、过敏性症状、HIV逆转录病毒感染、循环系统病症、神经炎症、神经病症、疼痛、朊病毒疾病、淀粉样变性和免疫病症。心脏病选自心绞痛、不稳定型心绞痛、心肌梗塞、急性冠状动脉疾病、心脏医源性损伤和心力衰竭,心力衰竭包括(但不限于)急性心力衰竭、慢性缺血性病因心力衰竭和慢性非缺血性病因心力衰竭、收缩性心力衰竭、舒张性心力衰竭、低射血分数心力衰竭(HFREF)和射血分数保留型心力衰竭(HFPEF)。
本发明化合物可单独使用,与本发明的其他化合物组合使用或与一或多种其他试剂组合使用。
本发明的其他特征和优势将自以下实施方式和权利要求书显而易见。
具体实施方式
本发明涵盖式(I)化合物,其为甲酰肽2(FPR2)受体激动剂和/或甲酰肽1(FPR1)受体激动剂、含有所述化合物的组合物和使用所述化合物例如治疗动脉粥样硬化、心力衰竭、慢性阻塞性肺病(COPD)和相关疾病的方法。
本发明的一个方面为一种式(I)化合物:
其中:
Ar1为苯基、吡啶基或哒嗪基且经4位的1个卤素、卤烷基或卤烷氧基取代基和0至2个其他卤素或卤烷基取代基取代;
Ar2为经0至2个选自以下的取代基取代的苯基或吡啶基:氰基、氟、烷基、卤烷基、环烷基、烷氧基和卤烷氧基;
Ar3为苯基或吡啶基且经0至2个选自以下的取代基取代:氰基、卤素、羟基烷基、烷氧基烷基、(R1R2N)烷基、(烷基)2(O)P、(烷基)(O)(NR1)S、烷基SO2和烷基SO2NH;
R1为氢或烷基;且
R2为氢或烷基;或(R1)(R2)N一起为氮杂环丁基、吡咯烷基、哌啶基、哌嗪基或吗啉基,且经0至3个选自氟和烷基的取代基取代;或其药学上可接受的盐。
本发明的另一方面为一种式(I)化合物,其中Ar1为经4位的1个卤素、卤烷基或卤烷氧基取代基和0至2个其他卤素或卤烷基取代基取代的苯基。
本发明的另一方面为一种式(I)化合物,其中Ar2为经0个取代基、1个烷基或环烷基取代基或2个氟取代基取代的苯基。
本发明的另一方面为一种式(I)化合物,其中Ar2为经0个取代基或2个氟取代基取代的苯基。
本发明的另一方面为一种式(I)化合物,其中Ar3为经1至2个选自以下的取代基取代的苯基:氰基、卤素、羟基烷基、烷氧基烷基、(R1R2N)烷基、(烷基)2(O)P、(烷基)(O)(NR1)S、烷基SO2和烷基SO2NH。
本发明的另一方面为一种式(I)化合物,其中R1为氢且R2为氢。
本发明的另一方面为一种式(II)化合物:
或其药学上可接受的盐,其中:
Ar1为经1至2个R1a和1至2个R1b取代的芳基或具有1至3个选自氮、氧和硫的杂原子且经1至2个R1a和1至2个R1b取代的单环杂芳基;
Ar2为经1至4个R2a取代的芳基或具有1至2个氮原子且经1至4个R2a取代的6元杂芳基;
Ar3为经1至4个R3a取代的芳基或具有1至3个选自氮、氧和硫的杂原子且经1至4个R3a取代的单环杂芳基;
R1a为氢或卤素;
R1b为卤素、卤烷基、烷氧基或卤烷氧基;
R2a为氢、氰基、卤素、烷基、羟基烷基、卤烷基、环烷基、烷氧基或卤烷氧基;或者,两个相邻R2a基团与其所连接的碳原子一起形成具有1至4个选自氮、氧和硫的杂原子的杂环;
R3a为氰基、卤素、烷基、烷氧基、羟基烷基、烷氧基烷基、卤烷基、(R1R2N)烷基、R1R2N、烷基C(O)(R2)N烷基、(烷基)2(O)P、(烷氧基)2(O)P、(烷氧基)(烷基)(O)P、(烷基)(O)(NR1)S、烷基SO2或烷基SO2NH;或者,两个相邻R3a基团与其所连接的碳原子一起形成具有1至4个选自氮、氧和硫的杂原子的杂环;
R4a或R4b独立地为氢、烷基、烷氧基、羟基烷基、烷氧基烷基或卤烷氧基;或者,R4a和R4b与它们都连接的碳原子一起形成C3-6环烷基;
R5a或R5b独立地为氢、烷基、羟基烷基、烷氧基烷基或卤烷氧基;
R1为氢或烷基;且
R2为氢或烷基;或R1R2N一起为氮杂环丁基、噁唑基、吡咯烷基、哌啶基、哌嗪基或吗啉基且经0至3个选自卤素、烷基和氧代的取代基取代。
本发明的另一方面为一种式(III)化合物:
或其药学上可接受的盐,其中:
Ar1为经1至2个R1a和1至2个R1b取代的苯基或具有1至3个氮原子且经1个R1a和1至2个R1b取代的6元杂芳基;
Ar3为经1至3个R3a取代的苯基或具有1至3个氮原子且经1至3个R3a取代的5元至6元杂芳基;
R1a为氢或卤素;
R1b为卤素、C1-4卤烷基、C1-4烷氧基或C1-4卤烷氧基;
R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;
R3a为氰基、卤素、C1-4烷基、C1-4羟基烷基、C1-4烷氧基烷基、C1-4卤烷基、(R1R2N)C1-4烷基、R1R2N、C1-4烷基C(O)(R2)NC1-4烷基、(C1-4烷基)2(O)P、(C1-4烷氧基)2(O)P、(C1-4烷氧基)(C1-4烷基)(O)P、C1-4烷基SO2或C1-4烷基SO2NH;
R1R2N一起为噁唑基或吡咯烷基且经0至3个选自卤素、烷基和氧代的取代基取代;
R4a或R4b独立地为氢、C1-4烷基或C1-4羟基烷基;或者,R4a和R4b与它们都连接的碳原子一起形成C3-6环烷基;且
R5a或R5b独立地为氢、C1-4烷基、C1-4羟基烷基或C1-4烷氧基烷基。
本发明的另一方面为一种式(II)或(III)化合物或其药学上可接受的盐,其中:
Ar1为经1至2个R1a和1至2个R1b取代的苯基、经1个R1a和1至2个R1b取代的吡啶基或经1个R1a和1至2个R1b取代的吡嗪基;且
Ar3为经1至3个R3a取代的苯基、经1至3个R3a取代的吡唑基、经1至3个R3a取代的吡啶基或经1至3个R3a取代的嘧啶基。
本发明的另一方面为一种式(IV)化合物:
或其药学上可接受的盐,其中:
Ar1为经1至2个R1a和1至2个R1b取代的苯基、经1个R1a和1至2个R1b取代的吡啶基或经1个R1a和1至2个R1b取代的吡嗪基;
R1a为氢或卤素;
R1b为卤素、C1-4卤烷基、C1-4烷氧基或C1-4卤烷氧基;
R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;
R3a为氰基、卤素、C1-3烷基、C1-3羟基烷基、C1-3烷氧基烷基、C1-3卤烷基、R1R2N、(C1-3烷基)2(O)P、(C1-3烷氧基)2(O)P、(C1-3烷氧基)(C1-3烷基)(O)P、C1-3烷基SO2或C1-3烷基SO2NH;
R4a或R4b独立地为氢、C1-3烷基或C1-3羟基烷基;或者,R4a和R4b与它们都连接的碳原子一起形成C3-6环烷基;且
R5a或R5b独立地为氢、C1-3烷基、C1-3羟基烷基或C1-3烷氧基烷基。
本发明的另一方面为一种式(V)化合物:
或其药学上可接受的盐,其中:
R1a为氢或F;
R1b为卤素、C1-2卤烷基或C1-2烷氧基;
R2a为氢、卤素、C1-3烷基、C1-3卤烷基或C3-6环烷基;
R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH;且
R3a'为卤素。
本发明的另一方面为一种式(V)化合物或其药学上可接受的盐,其中:
R1a为氢或F;
R1b为F、Cl或CF3;
R2a为氢、F、Cl、异丙基、CF3或环丙基;
R3a为(CH3)2(O)P、(CH3CH2)2(O)P、(CH3CH2O)(CH3)(O)P、CH3SO2或CH3SO2NH;且
R3a'为F。
本发明的另一方面为一种式(VI)化合物:
或其药学上可接受的盐,其中:
R1a为氢或卤素;
R1b为卤素、C1-2卤烷基或C1-2烷氧基;
R2a为氢、卤素、C1-3烷基或C3-6环烷基;
R3a为(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
本发明的另一方面为一种式(VII)化合物:
或其药学上可接受的盐,其中:
Ar3为经1至3个R3a取代的吡唑基、经1至3个R3a取代的吡啶基或经1至3个R3a取代的嘧啶基;
R1a为氢或卤素;
R1b为卤素、C1-4卤烷基、C1-4烷氧基或C1-4卤烷氧基;
R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;
R3a为氰基、卤素、C1-4烷基、C1-4羟基烷基、C1-4烷氧基烷基、(R1R2N)C1-4烷基、R1R2N-、(C1-4烷基)2(O)P、(C1-4烷氧基)2(O)P、(C1-4烷氧基)(C1-4烷基)(O)P、C1-4烷基SO2或C1-4烷基SO2NH;
R1为氢或烷基;
R2为氢或烷基;或R1R2N一起为噁唑基或吡咯烷基且经0至3个选自卤素、烷基或氧代的取代基取代;
R4a或R4b独立地为氢、C1-4烷基、C1-4烷氧基、C1-4烷氧基烷基或C1-4卤烷氧基;R4a和R4b与它们都连接的碳原子一起形成C3-6环烷基;且
R5a或R5b独立地为氢、C1-4烷基、C1-4烷氧基、C1-4烷氧基烷基或C1-4卤烷氧基。
本发明的另一方面为一种式(VIII)化合物:
或其药学上可接受的盐,其中:
R1a为氢或卤素;
R1b为卤素、C1-2卤烷基或C1-2烷氧基;
R2a为氢、卤素、C1-3烷基或C3-6环烷基;
R3a为(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH;且
R5a或R5b独立地为氢或C1-2烷基。
本发明的另一方面为一种式(IX)化合物:
或其药学上可接受的盐,其中:
R1a为氢或卤素;
R1b为卤素、C1-2卤烷基或C1-2烷氧基;
R2a为氢、卤素、C1-2卤烷基、C1-3烷基或C3-6环烷基;
Ar3为
R3a为(C1-2烷基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P或C1-2烷基SO2NH;
R3a'为卤素;
R4a或R4b独立地为氢、C1-2烷基或C1-2羟基烷基;或R4a和R4b与它们都连接的碳原子一起形成C3-6环烷基;且
R5a或R5b独立地为氢、C1-2烷基、C1-2羟基烷基或C1-2烷氧基烷基。
本发明的另一方面为一种式(II)、(III)、(IV)、(VII)或(IX)化合物或其药学上可接受的盐,其中:
R4a为氢;
R4b为氢;
R5a为C1-2烷基、C1-2羟基烷基或C1-2烷氧基烷基;且
R5b为氢。
本发明的另一方面为一种式(II)、(III)、(IV)、(VII)或(IX)化合物或其药学上可接受的盐,其中:
R4a为C1-2烷基;
R4b为C1-2烷基;或R4a和R4b一起形成环丙基;
R5a为氢;且
R5b为氢。
本发明的另一方面为一种化合物,其选自:
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对于式(I)、(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)化合物,包括Ar1、Ar2、Ar3、R1a、R1b、R2a、R3a、R4a、R4b、R5a、R5b、R1、R2的可变取代基的任何实例的范围可与可变取代基的任何其他实例的范围独立地使用。因而,本发明包括不同方面的组合。
在一个非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为各自经1个R1a和1至2个R1b取代的苯基、吡啶基或吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为各自经1至4个R3a取代的苯基、吡唑基、吡啶基或嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的苯基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡唑基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的苯基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的苯基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为各自经1至4个R3a取代的苯基、吡唑基、吡啶基或嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的苯基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡唑基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的苯基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡唑基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在一个非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;或R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为各自经1个R1a和1至2个R1b取代的苯基、吡啶基或吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为各自经1至4个R3a取代的苯基、吡唑基、吡啶基或嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;或R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的苯基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡唑基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的苯基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的苯基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为各自经1至4个R3a取代的苯基、吡唑基、吡啶基或嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的苯基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡唑基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的苯基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡唑基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基,R4b为甲基;R4a为氢,R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a和R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在一个非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为各自经1个R1a和1至2个R1b取代的苯基、吡啶基或吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为各自经1至4个R3a取代的苯基、吡唑基、吡啶基或嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的苯基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡唑基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的苯基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的苯基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为各自经1至4个R3a取代的苯基、吡唑基、吡啶基或嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的苯基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡唑基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的吡啶基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的苯基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡唑基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的吡啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在另一非限制性实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a和R4b全部为氢;R5a为氢,R5b为甲基或羟基甲基;Ar1为经1个R1a和1至2个R1b取代的吡嗪基;R1a为氢或卤素;R1b为卤素、C1-2卤烷基或C1-2烷氧基;Ar2为经1至4个R2a取代的苯基;R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;Ar3为经1至4个R3a取代的嘧啶基;R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
在一个优选实施方案中,对于式(II)、(III)、(IV)、(VII)或(IX)化合物,R4a为甲基;R4b为甲基;R4a为氢;R4b为羟基甲基;或R4a和R4b一起形成环丙基;R5a为氢,R5b为甲基或羟基甲基;R5a为氢;R5b为氢;或R4a、R4b、R5a、R5b全部为氢;Ar1为经1个R1a和1至2个R1b取代的苯基;R1a为氢或F;R1b为F、Cl或CF3;Ar2为经1至2个R2a取代的苯基;R2a为氢、F、Cl、异丙基、CF3CF3、环丙基;Ar3为各自经1至2个R3a取代的苯基或吡啶基;R3a为F、(CH3)2(O)P、(CH3CH2)2(O)P、(CH3CH2O)(CH3)(O)P、CH3SO2或CH3SO2NH。
除非另有规定,否则这些术语具有以下含义。“烷基”意指由1至6个碳构成的直链或支链烷基。“烯基”意指由2至6个碳构成的具有至少一个双键的直链或支链烷基。“炔基”意指由2至6个碳构成的具有至少一个三键的直链或支链烷基。“环烷基”意指由3至7个碳构成的单环环系统。关于烃部分的术语(例如,烷氧基)包括烃部分的直链和支链异构体。“卤素”包括氟、氯、溴和碘。“卤烷基”和“卤烷氧基”包括单卤至全卤的所有卤化异构体。“芳基”意指具有6至12个碳原子的单环或双环芳族烃基,或一个或两个环为芳族基的双环稠环系统。双环稠环系统由苯基与四元至七元芳族或非芳族碳环稠合组成。芳基的代表性实例包括(但不限于)苯基、茚满基、茚基、萘基和四氢萘基。“杂芳基”意指具有1至5个独立地选自氮、氧和硫的杂原子的5元至7元单环或8元至11元双环芳族环系统。在未指定成键连接位置的情况下,键可连接于如本领域从业者所理解的任何适当位置处。取代基的组合和成键模式仅为产生如本领域从业者所理解的稳定化合物的那些。括号或多括号内的术语意欲向本领域技术人员阐明成键关系。举例而言,诸如((R)烷基)的术语意指进一步经取代基R取代的烷基取代基。
本发明包括化合物的所有药学上可接受的盐形式。药学上可接受的盐为相对离子不显著促成化合物的生理学活性或毒性且本身用作药理学等效物的盐。这些盐可根据常见有机技术采用市售试剂制备。一些阴离子盐形式包括乙酸盐、醋硬脂酸盐、苯磺酸盐、溴化物、氯化物、柠檬酸盐、富马酸盐、葡萄糖醛酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、碘化物、乳酸盐、马来酸盐、甲磺酸盐、硝酸盐、双羟萘酸盐、磷酸盐、琥珀酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐和羟萘甲酸盐。一些阳离子盐形式包括铵、铝、苄星青霉素(benzathine)、铋、钙、胆碱、二乙胺、二乙醇胺、锂、镁、葡甲胺、4-苯基环已胺、哌嗪、钾、钠、缓血酸胺和锌。
本发明化合物中的一些以包括以下具有指定碳的结构的立体异构形式存在。本发明包括化合物的所有立体异构形式,包括对映异构体和非对映异构体。制备和分离立体异构体的方法是本领域已知的。本发明包括化合物的所有互变异构形式。本发明包括阻转异构体和旋转异构体。
本发明意欲包括存在于化合物中的原子的所有同位素。同位素包括原子数相同但质量数不同的那些原子。作为一般实例但非限制性地,氢的同位素包括氘和氚。碳同位素包括13C和14C。本发明的同位素标记化合物一般可通过本领域技术人员已知的常规技术或通过类似于本文所描述的方法,使用适当同位素标记试剂代替原本采用的未标记试剂来制备。此类化合物可具有多种潜在用途,例如在确定生物活性时用作标准物和试剂。在稳定同位素的情况下,此类化合物可具有有利改良生物学、药理学或药物动力学特性的潜能。
生物学方法
N-甲酰肽受体(FPR)为在炎症期间促进白细胞应答的化学引诱剂受体家族。FPR属于七跨膜G蛋白偶联受体超家族且与抑制性G蛋白(Gi)连接。已在人体内鉴别到三个家族成员(FPR1、FPR2和FPR3),且其主要以不同分布发现于骨髓细胞中,并且也已在多个器官和组织中有所报道。在激动剂结合后,FPR激活多个生理学途径,诸如细胞内信号传导转导、Ca2+移动和转录。该家族与激活促炎性和促消退下游应答两者的多种多样的配体相互作用,所述配体包括蛋白质、多肽和脂肪酸代谢物。FPR2和FPR1环单磷酸腺苷(cAMP)测定用以测量本发明化合物的活性。
FPR2和FPR1环单磷酸腺苷(cAMP)测定.将毛喉素(FPR2最终浓度5μM,或FPR1最终浓度10μM)和IBMX(最终浓度200μM)的混合物添加至预先布满最终浓度在0.020nM至100μM范围内的含测试化合物的DMSO(最终1%)的384孔Proxiplate(Perkin-Elmer)。将过度表达人类FPR1或人类FPR2受体的中国仓鼠卵巢细胞(CHO)培养于补充有10%合格FBS、250μg/ml吉欧霉素(zeocin)和300μg/ml潮霉素的F-12(哈姆氏;Ham's)培养基(Life Technologies)中。通过添加2,000个人类FPR2细胞每孔或4,000个人类FPR1细胞每孔于补充有0.1%BSA(Perkin-Elmer)的杜氏PBS(Dulbecco's PBS)(含钙和镁)(Technologies)中来引发反应。在室温培育反应混合物30min。根据制造商的说明书使用HTRF HiRange cAMP测定试剂试剂盒(Cisbio)确定胞内cAMP的含量。分开地在所供应裂解缓冲液中制备穴状化合物缀合的抗cAMP和d2荧光标记cAMP的溶液。反应完成时,用等体积的d2-cAMP溶液和抗cAMP溶液裂解细胞。在1h室温培育后,使用400nm激发和590nm和665nm的双重发射下的Envision(Perkin-Elmer)来测量时差式荧光强度。通过绘制665nm发射的荧光强度与590nm发射的强度针对cAMP浓度的比率以1μM至0.1pM的浓度范围下的外部cAMP标准建构校准曲线。随后通过根据cAMP水平对化合物浓度的绘图拟合4参数逻辑斯蒂方程来确定化合物抑制cAMP产生的效力和活性。
在上文所描述的FPR2和FPR1 cAMP测定中测试以下公开的实施例,且发现其具有FPR2和/或FPR1激动活性。下表1列举FPR2和FPR1 cAMP测定中针对以下实施例测量的EC50值。
表1
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药物组合物和使用方法
本发明化合物可给予哺乳动物,优选地人类,用于治疗多种与FPR2受体相关的病况和病症,诸如白塞病(Behcet's disease)、斯维特病(Sweet disease)、系统性红斑狼疮(SLE)、韦格纳肉芽肿病(Wegener's granulomatosis)、病毒感染、糖尿病、截肢、癌症、细菌感染、身体外伤、包括辐射暴露的身体不适、血管收缩、过敏性反应、过敏反应、鼻炎、休克(内毒素休克、出血性休克、创伤性休克、内脏缺血性休克和循环休克)、类风湿性关节炎、痛风、牛皮癣、良性前列腺增生症、心肌缺血、心肌梗塞、心力衰竭、脑损伤、肺病、COPD、COAD、COLD、急性肺损伤、急性呼吸窘迫综合征、慢性支气管炎、肺气肿、哮喘(过敏性哮喘和非过敏性哮喘)、囊性纤维化、肾纤维化、肾病、肾小球疾病、溃疡性结肠炎、IBD、克罗恩病、牙周炎、疼痛、阿尔茨海默病、AIDS、葡萄膜炎青光眼、结膜炎、薛格连综合征、鼻炎、动脉粥样硬化、包括多发性硬化症的神经炎性疾病、中风、败血症等。
除非另有指定,否则以下术语具有所陈述的含义。如本领域技术人员所理解,术语“受试者”是指可能受益于使用FPR2和/或FPR1激动剂的治疗的任何人类或其他哺乳动物物种。一些受试者包括任何年龄的具有心血管疾病风险因素的人类。常见风险因素包括年龄、性别、体重、家族病史、睡眠呼吸暂停、使用酒精或烟草、身体活动不足心律不整或胰岛素抵抗的症状诸如黑色棘皮症、高血压、血脂异常或多囊性卵巢综合征(PCOS)。术语“患者”意指适合于如由本领域技术人员所判定的疗法的人。如本领域技术人员所理解,“治疗”(treating或treatment)涵盖患者或受试者的治疗。如本领域技术人员所理解,“预防”(preventing或prevention)涵盖预防性治疗(亦即防治和/或风险降低)患者或受试者的亚临床疾病病状,旨在降低出现临床疾病病状的机率。基于已知相较于一般群体增加罹患临床疾病病状的风险的因素而选择进行预防性疗法的患者。如本领域技术人员所理解,“治疗有效量”意指有效的化合物的量。
本发明的另一方面为药物组合物,其包含治疗有效量的式(I)至(IX)化合物与药用载体的组合。
本发明的另一方面为药物组合物,其包含治疗有效量的式(I)至(IX)化合物与至少一种其他治疗剂和药用载体的组合。
“药物组合物”意指包含本发明化合物与至少一种其他药学上可接受的载体的组合的组合物。“药学上可接受的载体”是指本领域一般接受用于向动物(尤其哺乳动物)递送生物活性剂的介质,取决于给药模式的性质和剂型,包括(即)佐剂、赋形剂或媒介物,诸如稀释剂、防腐剂、填充剂、流动调节剂、崩解剂、湿润剂、乳化剂、悬浮剂、甜味剂、调味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂。
药学上可接受的载体根据本领域普通技术人员范围内的多个因素调配。这些因素包括(但不限于):所调配的活性剂的类型和性质;给予含该试剂的组合物的受试者;组合物的预期给药途径;以及所靶向的治疗适应症。药学上可接受的载体包括水性和非水性液体介质,以及各种固体和半固体剂型。除活性剂以外,此类载体还可包括多种不同成分和添加剂,此类其他成分出于本领域普通技术人员熟知的多种原因(例如使活性剂、粘合剂等稳定)而包括于调配物中。对于适合的药学上可接受的载体及其选择所设计的因素的描述见于多种容易获得的来源,诸如Allen,L.V.,Jr.等人,Remington:The Science andPractice of Pharmacy(2卷),第22版,Pharmaceutical Press(2012)。
尤其当以单个剂量单元形式提供时,组合的活性成分之间可能存在化学相互作用。因此,当本发明化合物和第二治疗剂在单个剂量单元中组合时,其经调配使得尽管活性成分在单个剂量单元中组合,但活性成分之间的物理接触降至最低(即降低)。举例而言,一种活性成分可包覆肠溶包衣。通过对活性成分中的一种包覆肠溶包衣,不仅可使组合的活性成分之间的接触降至最低,而且可控制这些组分中的一种在胃肠道中的释放,使得这些组分中的一种不在胃中释放,而是在肠中释放。活性成分中的一种还可包覆有影响在整个胃肠道中持续释放的物质,且也用以使组合的活性成分之间的物理接触降至最低。此外,持久释放的组分可另外包覆肠溶包衣,使得该组分的释放仅在肠道中发生。另一方法将涉及组合产物的调配,其中一种组分包覆有持续和/或肠释放聚合物,且另一组分还包覆有诸如低粘度级别的羟丙基甲基纤维素(HPMC)的聚合物或本领域已知的其他适当物质,以进一步分离活性组分。聚合物包衣用以形成与另一组分的相互作用的其他屏障。
本发明的另一方面为一种用于治疗心脏病的方法,其包括向患者给予治疗有效量的式(I)化合物。
本发明的另一方面为一种用于治疗心脏病的方法,其中心脏病选自:心绞痛、不稳定型心绞痛、心肌梗塞、心力衰竭、急性冠状动脉疾病、急性心力衰竭、慢性心力衰竭和心脏医源性损伤。
应理解,心力衰竭的治疗或预防可同样包含心血管事件的治疗或预防。如本文中所提及的治疗或预防可指与心血管事件相关或由于心血管事件引起的某些负性症状或病况的治疗或预防。举例而言,治疗或预防可包含减少或预防与心血管事件相关或由于心血管事件引起的缩短分数、心脏重量、肺重量、肌细胞横截面积、压力超负荷诱发的心脏纤维化、应激诱发的细胞老化和/或心脏肥大特性或其任何组合的负向改变。可在预防心血管事件时或响应于心血管事件施予治疗以减轻负面影响。预防可包含前瞻性或预防性类型的治疗,以预防心血管事件或减少心血管事件的负面影响的发生。
在一个实施方案中,本发明提供一种式(I)至(IX)化合物或其药学上可接受的盐的用途,其用于制备治疗或预防心力衰竭的药物组合物,举例而言,心力衰竭是由高血压、缺血性心脏病、非缺血性心脏病、暴露于心脏毒性化合物、心肌炎、川崎病、I型和II型糖尿病、甲状腺病、病毒感染、齿龈炎、药物滥用、酒精滥用、心包炎、动脉粥样硬化、血管疾病、肥厚性心肌症、扩张型心肌症、心肌梗塞、心房纤维化、左心室收缩功能障碍、左心室舒张功能障碍、冠状动脉旁路手术、起搏器植入手术、饥饿、进食障碍、肌肉萎缩症和遗传缺陷引起。优选地,待治疗的心力衰竭为舒张性心力衰竭、低射血分数心力衰竭(HFREF)、射血分数保留型心力衰竭(HFPEF)、急性心力衰竭以及慢性缺血性病因心力衰竭和慢性非缺血性病因心力衰竭。
在一个实施方案中,本发明提供一种式(I)至(IX)化合物治疗收缩和/或舒张功能障碍的用途,其中以治疗有效量给予化合物以增强心脏肌肉细胞收缩与放松的能力,由此增加右心室和左心室两者(优选地左心室)的填充和排空。
在另一实施方案中,本发明提供一种式(I)至(IX)化合物治疗心力衰竭的用途,其中以治疗有效量给予化合物,以增加左心室的射血分数。
在再一实施方案中,本发明提供一种式(I)至(IX)化合物治疗心力衰竭的用途,其中以治疗有效量给予化合物,以减少心脏组织的纤维化。
本发明的另一方面为一种用于治疗心脏病的方法,其中治疗是在心肌梗塞之后。
本发明的另一方面为一种用于治疗皮肤疾病的方法,所述皮肤疾病包括(但不限于)玫瑰痤疮、猛暴性玫瑰痤疮、晒伤、牛皮癣、更年期相关潮热、与潮热相关的潮红和发红、与潮热相关的红斑、由睾丸切除术特应性皮炎引起的潮热、由于昆虫叮咬引起的发红和瘙痒、光老化、脂溢性皮炎、痤疮、过敏性皮炎、面部毛细管扩张(先前存在的较小血管的扩张)、血管异常增生(angioectasias)、鼻瘤(rhinophyma)(伴随滤泡扩张的鼻部肥大)、痤疮样皮疹(可渗液或结痂)、灼痛或刺痛感、皮肤红斑、伴随皮肤血管扩张的皮肤高活性、莱耳综合征(Lyell's syndrome)、史蒂芬斯-强森综合征(Stevens-Johnson syndrome)、与痔疮相关的局部瘙痒和不适、痔疮、轻微多形性红斑、严重多形性红斑、结节性红斑、眼部浮肿、荨麻疹、搔痒症、紫癜、静脉曲张、接触性皮炎、特应性皮炎、钱币状皮炎(nummulardermatitis)、全身性剥脱性皮炎、郁滞性皮炎、慢性单纯性苔癣、口周皮炎、须部假性毛囊炎、环状肉芽肿、光化性角化症、基底细胞癌、鳞状细胞癌、湿疹、真皮创伤愈合、肥厚性瘢痕、瘢痕瘤、烧伤、玫瑰痤疮、特应性皮炎、痤疮、牛皮癣、脂溢性皮炎、光化性角化症、基底细胞癌、鳞状细胞癌、黑素瘤、病毒性疣、光老化、光损伤、黑斑、炎症后色素沉着过多、其他色素沉着病症和秃发症(瘢痕性和非瘢痕性形式)。除已通过证实加速创伤愈合的活性而例示的以外,预期下文化合物对许多不同类型的皮肤病具有治疗效果。
本发明的另一方面为一种用于治疗心脏病的方法,其包括连同其他治疗剂向患者给予治疗有效量的式(I)化合物。
本发明化合物可通过任何适合的手段给药,例如经口,诸如片剂、胶囊(其各自包括持续释放或定时释放调配物)、丸剂、散剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥分散液)、糖浆和乳液;舌下;经颊;肠胃外,诸如通过皮下、静脉内、肌肉内或胸骨内注射,或输注技术(例如作为无菌可注射水溶液或非水溶液或悬浮液);经鼻,包括向鼻膜给药,诸如通过吸入喷雾;表面,诸如以乳霜或软膏形式;或经直肠,诸如以栓剂形式。其可单独给药,但通常将与基于所选给药途径和标准药学实践选择的药用载体一起投与。
本发明化合物的给药方案当然将取决于已知因素而变化,诸如特定药剂的药效学特征及其给药模式和途径;接受者的物种、年龄、性别、健康状况、医学条件和体重;症状的性质和程度;同时发生的治疗的种类;治疗频率;给药途径;患者的肾功能和肝功能;以及期望作用。
借助于一般指导,各活性成分在用于指定作用时的每日口服剂量将在每天约0.01至约5000mg之间,优选每天约0.1至约1000mg之间,且最优选每天约0.1至约250mg之间的范围内。静脉内给药时,在恒定速率输注期间,最优选剂量将在每分钟约0.01至约10mg/kg的范围内。本发明化合物可以单次日剂量给药,或每日总剂量可按每日两次、三次或四次分次剂量给药。
适合于给药的剂型(药物组合物)可含有每剂量单位约1毫克至约2000毫克的活性成分。在这些药物组合物中,活性成分通常将以按该组合物的总重量计约0.1-95重量%的量存在。用于经口给药的典型胶囊含有至少一种本发明化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。混合物通过60目筛且装入l号明胶胶囊中。通过将至少一种本发明化合物(250mg)以无菌方式放入小瓶中、以无菌方式冷冻干燥和密封来制造典型可注射制剂。对于使用,将小瓶的内含物与2mL生理盐水混合产生可注射制剂。
本发明化合物可与适用于治疗前述疾病或病症的其他适合治疗剂组合使用,所述治疗剂包括:抗动脉粥样硬化剂、抗脂质异常剂、抗糖尿病剂、抗高血糖剂、抗高胰岛素血症剂、抗血栓剂、抗视网膜病变剂、抗神经病变剂、抗肾病剂、抗缺血剂、抗高血压剂、抗肥胖剂、抗高血脂剂、抗高甘油三酯血症剂、抗高胆固醇血症剂、抗再狭窄剂、抗胰腺病剂、降脂剂、厌食剂、记忆增强剂、抗痴呆剂、认知促进剂、食欲抑制剂、心力衰竭治疗剂、外周动脉疾病治疗剂、恶性肿瘤治疗剂和抗炎剂。
本发明化合物可与至少一种以下心力衰竭药物一起使用,所述心力衰竭药物选自袢利尿剂、血管紧张素转化酶(ACE)抑制剂、血管紧张素II受体阻断剂(ARB)、血管紧张素受体-脑啡肽酶抑制剂(ARNI)、β阻断剂、盐皮质激素受体拮抗剂、硝酰基供体、RXFP1激动剂、APJ激动剂和强心剂。这些药物包括(但不限于)呋塞米(furosemide)、布美他尼(bumetanide)、托拉塞米(torsemide)、沙库巴曲-缬沙坦(sacubitrial-valsartan)、噻嗪类利尿剂、卡托普利(captopril)、依那普利(enalapril)、赖诺普利(lisinopril)、卡维地洛(carvedilol)、美托洛尔(metopolol)、比绍洛尔(bisoprolol)、塞雷拉辛(serelaxin)、螺内酯(spironolactone)、依普利酮(eplerenone)、伊伐布雷定(ivabradine)、坎地沙坦(candesartan)、依普罗沙坦(eprosartan)、厄贝沙坦(irbestarain)、洛沙坦(losartan)、奥美沙坦(olmesartan)、替米沙坦(telmisartan)和缬沙坦(valsartan)。
本发明化合物可与至少一种以下治疗剂组合用于治疗动脉粥样硬化:抗高血脂剂、血浆HDL升高剂、抗高胆固醇血症剂、胆固醇生物合成抑制剂(诸如HMG CoA还原酶抑制剂)、LXR激动剂、普罗布可(probucol)、雷诺昔酚(raloxifene)、烟酸、烟酰胺、胆固醇吸收抑制剂、胆酸螯合剂(诸如阴离子交换树脂或季胺(例如,消胆胺或考来替泼(colestipol)))、低密度脂蛋白受体诱导剂、氯贝特(clofibrate)、非诺贝特(fenofibrate)、苯扎贝特(benzofibrate)、环丙贝特(cipofibrate)、吉非罗齐(gemfibrizol)、维生素B6、维生素B12、抗氧化维生素、β-阻断剂、抗糖尿病剂、血管紧张素II拮抗剂、血管紧张素转化酶抑制剂、血小板凝集抑制剂、血纤维蛋白原受体拮抗剂、阿司匹林和纤维酸衍生物。
本发明化合物可与至少一种以下治疗剂组合用于治疗:胆固醇生物合成抑制剂,尤其HMG-CoA还原酶抑制剂。适合HMG-CoA还原酶抑制剂的实例包括(但不限于)洛伐他汀(lovastatin)、辛伐他汀(simvastatin)、普伐他汀(pravastatin)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)和瑞舒伐他汀(rosuvastatin)。
本发明化合物可取决于所需目标疗法而与至少一种以下抗糖尿病剂组合使用。研究表明,糖尿病和高脂质血症调节可通过将第二药剂添加至治疗方案中而进一步改进。抗糖尿病剂的实例包括(但不限于)磺酰脲类(诸如氯磺丙脲、甲苯磺丁脲、乙酰苯磺酰环己脲、甲磺氮脲(tolazamide)、格列本脲(glyburide)、格列齐特(gliclazide)、格列农(glynase)、格列美脲(glimepiride)和格列吡嗪(glipizide));双胍类(诸如二甲双胍);噻唑烷二酮(诸如环格列酮(ciglitazone)、吡格列酮(pioglitazone)、曲格列酮(troglitazone)和罗格列酮(rosiglitazone))和相关胰岛素敏化剂,诸如PPARα、PPARβ和PPARγ的选择性和非选择性活化剂;脱氢表雄酮(也称作DHEA或其缀合的硫酸酯DHEA-SO4);抗糖皮质激素;TNFα抑制剂;二肽基肽酶IV(DPP4)抑制剂(诸如西他列汀(sitagliptin)、沙格列汀(saxagliptin));GLP-1激动剂或类似物(诸如艾塞那肽(exenatide));α葡糖苷酶抑制剂(诸如阿卡波糖(acarbose)、米格列醇(miglitol)和伏格列波糖(voglibose));普兰林肽(pramlintide)(人类激素胰淀素的合成类似物);其他胰岛素促泌素(诸如瑞格列奈(repaglinide)、格列喹酮(gliquidone)和那格列奈(nateglinide));胰岛素;以及以上所论述用于治疗动脉粥样硬化的治疗剂。
本发明化合物可与至少一种以下抗肥胖剂组合使用,所述抗肥胖剂选自苯丙醇胺、苯丁胺、安非拉酮(diethylpropion)、马吲哚(mazindol)、氟苯丙胺(fenfluramine)、右芬氟拉明(dexfenfluramine)、菲尼拉明(phentiramine)、β3-肾上腺素受体激动剂、西布曲明(sibutramine)、肠胃脂肪酶抑制剂(诸如奥利司他(orlistat))和瘦蛋白。用于治疗肥胖或肥胖相关病症的其他药剂包括神经肽Y、肠抑素、胆囊收缩素、铃蟾素、胰淀素、组胺H3受体、多巴胺D2受体调节剂、黑色素细胞刺激激素、促肾上腺皮质激素释放因子、甘丙肽和γ氨基丁酸(GABA)。
本发明化合物还可用作涉及FPR2的测试或测定中的标准或参考化合物,例如作为质量标准或对照。此类化合物可在市售试剂盒中提供,例如用于涉及FPR2活性的药物研究中。举例而言,本发明化合物可在测定中用作参考物以将其已知活性与具有未知活性的化合物相比较。这将确保实验者正确进行测定且提供比较基础,当测试化合物为参考化合物的衍生物时尤其如此。当研发新的测定或方案时,本发明化合物可用于测试其有效性。本发明化合物还可用于涉及FPR2的诊断测定中。
本发明还涵盖一种制品。如本文所用,制品意欲包括(但不限于)试剂盒和包装。本发明制品包含:(a)第一容器;(b)位于该第一容器内的药物组合物,其中该组合物包含第一治疗剂,该第一治疗剂包含本发明化合物或其药学上可接受的盐形式;以及(c)药品说明书,其陈述该药物组合物可用于治疗血脂异常及其后遗症。在另一实施方案中,药品说明书陈述该药物组合物可与第二治疗剂组合(如上文所定义)用于治疗血脂异常及其后遗症。制品可进一步包含:(d)第二容器,其中组分(a)和(b)位于第二容器中,且组分(c)位于第二容器内或外。位于第一和第二容器内意指各容器分别将物品容纳于其边界内。第一容器为用于容纳药物组合物的盛器。该容器可用于制造、储存、运送和/或个别/整体出售。第一容器意欲涵盖瓶子、罐、小瓶、烧瓶、注射器、试管(例如用于乳膏制剂)或用以制备、容纳、储存或分配药物产品的任何其他容器。第二容器为用于容纳第一容器和任选存在的药品说明书的容器。第二容器的实例包括(但不限于)盒(例如卡纸板或塑料)、板条箱、纸盒、袋(例如纸袋或塑料袋)、小袋和大袋。药品说明书可经由胶带、胶、U形钉或另一附着方法物理附着于第一容器的外部,或其可留在第二容器内部而不借助于任何物理方式附着于第一容器。或者,药品说明书位于第二容器外部上。当位于第二容器的外部上时,药品说明书优选经由胶带、胶、U形钉或另一附着方法以物理方式附着。替代地,其可与第二容器外部相邻或接触但不物理附着。药品说明书为叙述与第一容器内的药物组合物有关的信息的标记、标签、标记物等。所叙述信息通常将由控管出售制品的地区的监管机构(例如美国食品与药物管理局(the United States Food and Drug Administration))决定。优选地,药品说明书具体叙述药物组合物已审批通过的适应症。药品说明书可由任何材料制成,个人可从上面读取其中或其上所含的信息。优选地,药品说明书为上面已形成(例如印刷或涂覆)所需信息的可印刷材料(例如纸、塑料、卡纸板、箔、粘着剂-背衬纸或塑料等)。
化学方法
如本文所用的缩写定义如下:“1×”:一次;“2×”:两次;“3×”:三次;“℃”:摄氏度;“aq”:水溶液;“Col”:柱;“eq”:当量;“g”:克;“mg”:毫克;“L”:升;“mL”:毫升;“μL”:微升;“N”:当量浓度;“M”:摩尔浓度;“nM”:纳摩尔浓度;“mol”:摩尔;“mmol”:毫摩尔;“min”:分钟;“h”:小时;“rt”:室温;“RT”:保留时间;“ON”:过夜;“atm”:大气压;“psi”:磅/平方英寸;“conc.”:浓缩物;“aq”:“水溶液”;“sat”或“sat'd”:饱和;“MW”:分子量;“mw”或“μwave”:微波;“mp”:熔点;“Wt”:重量;“MS”或“Mass Spec”:质谱;“ESI”:电喷雾电离质谱;“HR”:高分辨率;“HRMS”:高分辨率质谱;“LCMS”:液相色谱质谱;“HPLC”:高压液相色谱;“RPHPLC”:反相HPLC;“TLC”或“tlc”:薄层色谱;“NMR”:核磁共振频谱;“nOe”:核欧佛豪瑟效应频谱;“1H”:质子;“δ”:德尔塔;“s”:单峰;“d”:二重峰;“t”:三重峰;“q”:四重峰;“m”:多重峰;“br”:宽峰;“Hz”:赫兹;且“α”、“β”、“R”、“S”、“E”和“Z”为本领域技术人员熟悉的立体化学标示。
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本发明化合物可通过本领域已知的各种方法制备,包括以下方案和具体实施方案部分中的方法。合成方案中所示的结构编号和变量编号与权利要求书或说明书其余部分的结构或变量编号不同,且不应混淆。方案中的变量仅欲说明如何制备本发明的一些化合物。
本发明不限于前述说明性实施例,且所述实施例应在所有方面被视为说明性的而非限定性的,因此意欲涵盖权利要求书的等效意义和范围内出现的所有变化。
本领域中的任何合成路线的规划的考虑因素在于用于保护本发明所描述的化合物中存在的反应性官能团的保护基的选择。向经培训的从业者描述多种替代方式的权威性说明为Greene,T.W.等人,Protecting Groups in Organic Synthesis,第4版,Wiley(2007))。
可通过以下一或多种合成方案来制备具有通式(I)的化合物:其中A、B、C、Rx、Ry和Rz分别如上文以Ar1、Ar2和Ar3、(R2a)1-4、(R3a)1-4和(R1a)1-2、(R1b)1-2的形式所定义。
可通过方案1中所示的通用路线以经适当保护的3-氨基吡咯烷-2-酮1a(其中PG为保护基,诸如Boc或Cbz)为起始物质来制备本发明的1-芳基吡咯烷酮化合物,其中环A、B和C为经取代苯环。1a可通过本领域技术人员已知的方法制备。在诸如碳酸钾或碳酸铯的碱和诸如N,N'-二甲基亚乙基二胺或Xanthphos的适合配体存在下,1a与经取代的碘苯或溴苯1b或其他适合卤代芳基或杂芳基化合物于诸如丁醇或二噁烷或甲苯的适合溶剂中进行铜或Pd催化偶联,可得到1-苯基吡咯烷酮1c。用于该转化的其他方法取决于环B的性质包括使用本领域技术人员已知的针对这些类型的偶联的方法的Ullmann、Goldberg和Buchwald铜催化酰胺化或Buchwald Pd催化酰胺化的其他变型(参见例如Yin和Buchwald OrganicLett.2000,2,1101;Klapers等人.JACS,2001,123,7727;Klapars等人JACS,2002,124,7421;Yin和Buchwald JACS.2002,124,6043;Kiyomor、Madoux和Buchwald,Tet.Lett.,1999,40,2657)。随后使1c与经适合取代的苯基硼酸1d或类似硼酸酯或三氟硼酸酯试剂进行钯催化偶联可提供联芳基化合物1e。自1e去除Boc或Cbz保护基,之后缩合所得游离胺与经适合取代的异氰酸苯酯1g或苯基氨基甲酸酯1h可提供脲1f。适合异氰酸酯或4-硝基苯基氨基甲酸酯为市售的或可通过本领域技术人员已知的方法容易地自对应苯胺获得。替代地,脲1f可如下获得:用氯甲酸4-硝基苯酯处理脱除保护基的3-氨基吡咯烷酮中间体以形成氨基甲酸酯,之后与经适当取代的苯胺1j缩合。本领域技术人员还将认识到,本发明的其他化合物(其中环A、B或C为杂芳基环;诸如吡啶、嘧啶、噻唑等)还可使用方案1中所概述的方法通过用适当杂芳基碘化物或溴化物取代1b、杂芳基硼酸或硼酸酯取代1d和杂芳基胺、异氰酸酯或对硝基苯基氨基甲酸酯取代1e来制备。使用手性HPLC或SFC分离外消旋化合物以提供单一对映异构体。
方案1
替代地,如方案2中所描述,本发明化合物可通过以下操作由中间体1c制备:首先将胺脱除保护基和使用上文针对1e至1f的转化所描述的条件形成与环A的脲键以提供化合物2a。化合物2a随后可在如方案1中针对1c至1e的转化所示的Pd催化条件下与适当硼酸或硼酸酯偶联。可使用手性HPLC或SFC分离外消旋化合物以提供单一对映异构体。
方案2
另外,如方案3中所示,本发明化合物可通过以下操作由中间体2a制备:根据Suzuki和Miyaura的方法使用铱/Pd催化的C-H硼基化转化成硼酸酯3a,之后使用钯或铜催化方法使所得硼酸频哪醇酯物质与芳基或杂芳基卤化物偶联以提供化合物1f。可使用手性HPLC或SFC分离外消旋化合物以提供单一对映异构体。
方案3
替代地,如方案4中所描述,本发明化合物可通过溴胺4a得到中间体4b来制备。随后在诸如含磷酸钾的乙腈的碱性条件下与2,4-二溴-丁酰基氯化物进行酰胺偶联,之后进行氨水介导的环闭合,可得到内酰胺1c。中间体1c可使用方案1至3中所示的反应转化成最终产物。可使用手性HPLC或SFC分离外消旋化合物以提供单一对映异构体。
方案4
如方案5中所描述,具有经取代的内酰胺的本发明化合物可由中间体5a制备。在诸如碳酸钾或碳酸铯的碱和诸如N,N'-二甲基亚乙基二胺或Xanthphos的适合配体存在下,5a与经取代的碘苯或溴苯1b或其他适合卤素芳基或杂芳基化合物于诸如丁醇或二噁烷或甲苯的适合溶剂中进行铜或Pd催化偶联,可得到1-苯基吡咯烷酮5b。用于该转化的其他方法取决于环B的性质包括使用本领域技术人员已知的针对这些类型的偶联的方法的Ullmann和Buchwald铜催化酰胺化或Buchwald Pd催化酰胺化的其他变型。随后制备内酰胺烯醇化锂并用诸如2,4,6-三异丙基苯磺酰基叠氮化物(trisyl azide)的叠氮化物处理,可得到中间体5c(参见例如J.Org.Chem.2003,68,7219-7233)。将叠氮化物还原成胺,之后保护胺,可得到中间体5d。先前方案中描述的化学方法可用以将该中间体转化成本申请所要求保护的化合物。可使用手性HPLC或SFC分离外消旋化合物以提供单一对映异构体。
方案5
本发明化合物还可使用方案6中所示的路线合成。中间体1c的钯催化硼基化产生中间体6a。适合的经取代芳基卤化物(诸如6b)的钯介导的偶联可得到联芳基内酰胺1e。先前方案中描述的化学方法可用以将该中间体转化成本申请所要求保护的化合物。可使用手性HPLC或SFC分离外消旋化合物以提供单一对映异构体。
方案6
本发明的其他特征在例示性实施方案的以下描述中将变得显而易知,所述例示性实施方案为了说明本发明而给出且不意欲对其进行限制。
除了另外标记之处以外,在例示性实施例中使用以下方法。通过正相或反相色谱进行中间体和最终产物的纯化。除非另有指示,否则使用预填充的SiO2滤筒用己烷和乙酸乙酯或DCM和MeOH的梯度洗脱来进行正相色谱。使用C18柱,通过UV 220nm或制备型LCMS检测,用以下梯度洗脱来进行反相制备型HPLC:溶剂A(90%水、10%甲醇、0.1%TFA)和溶剂B(10%水、90%甲醇、0.1%TFA)的梯度;或溶剂A(95%水、5%Acn、0.1%TFA)和溶剂B(5%水、95%ACN、0.1%TFA)的梯度;或溶剂A(95%水、2%Acn、0.1%HCOOH)和溶剂B(98%Acn、2%水、0.1%HCOOH)的梯度;或溶剂A(95%水、5%Acn、10mM NH4OAc)和溶剂B(98%ACN、2%水、10mM NH4OAc)的梯度;或溶剂A(98%水、2%Acn、0.1%NH4OH)和溶剂B(98%Acn、2%水、0.1%NH4OH)的梯度。
实施例的表征中采用的LC/MS方法。在与WatersZQ质谱仪偶联的Waters Acquity系统上进行反相分析性HPLC/MS。/>
方法A:经3min 0-100%B的线性梯度,在100%B下的保持时间为0.75min;
UV观测:220nm
柱:Waters BEH C18 2.1×50mm
流速:1.0mL/min
溶剂A:0.1%TFA、95%水、5%Acn
溶剂B:0.1%TFA、5%水、95%Acn
方法B:经3min 0-100%B的线性梯度,在100%B下的保持时间为0.75min;
UV观测:220nm
柱:Waters BEH C18 2.1×50mm
流速:1.0mL/min
溶剂A:10mM乙酸铵、95%水、5%Acn
溶剂B:10mM乙酸铵、5%水、95%Acn
分析性HPLC:实施例的表征中采用的方法
方法C:Ascentis Express C18,2.1×50mm,2.7μm颗粒;溶剂A:95%水、5%Acn,0.05%TFA;溶剂B:95%Acn,5%水,0.1%TFA;温度:50℃;梯度:经3分钟0-100%B,随后在100%B下保持1分钟;流量:1.1mL/min。
方法D:Ascentis Express C18,2.1×50mm,2.7μm颗粒;溶剂A:95%水、5%Acn+10mM乙酸铵;溶剂B:95%乙腈、5%水+10mM乙酸铵;温度:50℃;梯度:经3分钟0-100%B,随后在100%B下保持1分钟;流量:1.1mL/min。
方法E:柱Kinetex C18,75×3mm,2.6μm颗粒;溶剂A:98%水、2%Acn+10mM乙酸铵;溶剂B:98%Acn、2%水+10mM乙酸铵;温度:25℃;梯度:经4分钟20-100%B,随后在100%B下保持0.6分钟;流量:1.0mL/min;随后,梯度:经0.4分钟100-20%B;流量:1.5mL/min,UV220nm。
SFC和手性纯度方法
方法I:Chiralpak AD-H,250×4.6mm,5.0μm颗粒;CO2%:60%,Co溶剂%:40%{0.2%DEA/IPA:Acn(1:1)},总流量:4.0g/min,背压:100巴,温度:25℃,UV:218nm。
方法II:Chiralpak OD-H,250×4.6mm,5.0μm颗粒;CO2%:60%,Co溶剂%:40%{0.2%DEA/IPA:Acn(1:1)},总流量:4.0g/min,背压:104巴,温度:24.9℃,UV:287nm。
方法III:Chiralpak OJ-H,250×4.6mm,5.0μm颗粒;CO2%:60%,Co溶剂%:30%(0.3%DEA/甲醇),总流量:4.0g/min,背压:101巴,温度:23.6℃,UV:272nm。
方法IV:Chiralpak AS-H,250×4.6mm,5.0μm颗粒;CO2%:60%,Co溶剂%:40%(0.3%DEA/甲醇),总流量:4.0g/min,背压:102巴,温度:25.4℃,UV:272nm。
方法V:Chiralcel OJ-H,250×4.6mm,5.0μm颗粒;CO2%:60%,Co溶剂%:40%(0.2%DEA/甲醇),总流量:4.0g/min,背压:102巴,温度:24.6℃,UV:272nm。
方法VI:Luxcellulose-2,250×4.6mm,5.0μm颗粒;CO2%:60%,Co溶剂%:35%(0.2%DEA/甲醇),总流量:3.0g/min,背压:101巴,温度:23.6℃,UV:260nm。
方法VII:Chiralcel AS-H,250×4.6mm,5.0μm颗粒;CO2%:60%,Co溶剂%:40%(0.2%DEA/甲醇),总流量:4.0g/min,背压:101巴,温度:24.4℃,UV:270nm。
方法VIII:Chiralpak IC,250×4.6mm,5.0μm颗粒;CO2%:60%,Co溶剂%:40%(0.2%DEA/甲醇),总流量:4.0g/min,背压:101巴,温度:24.4℃,UV:270nm。
方法IX:柱:chiralpak IF(250×4.6mm),5微米,流动相:0.2%DEA/乙醇,流量:1.0ml/min。
方法X:柱:LUX AMYLOSE 2(250×4.6mm),5微米,流动相:含0.2%DEA的正己烷:乙醇:5:95,流量:1.0ml/min。
方法XI:柱:CHIRALCEL OD-H(250×4.6mm),5微米,流动相:含0.2%DEA的正己烷:乙醇:70:30,流量:1.0ml/min。
方法XII:柱:CHIRAL PAK ID(250×4.6mm),5微米,流动相:0.1%DEA/甲醇,流量:1.0ml/min。
实施例的表征中采用的NMR。使用在如下频率下操作的Bruker或傅立叶变换光谱仪获得1H NMR谱图:1H NMR:400MHz(Bruker或/>)或500MHz(Bruker或/>)。13C NMR:100MHz(Bruker或/>)。谱图数据以如下格式报道:化学位移(多重性、偶合常数和氢的数目)。化学位移以四甲基硅烷内部标准物的ppm低场(δ单位,四甲基硅烷=0ppm)说明和/或参考溶剂峰,在1H NMR谱图中,CD2HSOCD3的溶剂峰出现在2.49ppm处,CD2HOD的溶剂峰出现在3.30ppm处,CD3CN的溶剂峰出现在1.94ppm处且CHCl3的溶剂峰出现在7.24ppm处,且在13C NMR谱图中,CD3SOCD3的溶剂峰出现在39.7ppm处,CD3OD的溶剂峰出现在49.0ppm处且CDCl3的溶剂峰出现在77.0ppm处。所有13C NMR谱图经质子去耦。
中间体1:3-氨基吡咯烷-2-酮
在室温向六甲基二硅氮烷(11mL,523mmol)于CH3CN(100mL)中的搅拌溶液中添加DL-2,4-二氨基丁酸二盐酸盐(10g,52mmol)于Acn(100mL)中的溶液。将所得反应混合物加热至回流保持40h。随后,将粗反应混合物倒入冰冷MeOH(400mL)中,在室温搅拌30min且减压蒸发。将所得固体溶解于CH2Cl2(700mL)中,且通过真空过滤移除不溶残余物。随后,减压浓缩滤液,得到呈黄色固体的3-氨基吡咯烷-2-酮(4.1g,41mmol,78%产率)。1H NMR(400MHz,DMSO-d6):δ7.59(br.s.,2H),3.23-3.10(m,1H),3.09-3.03(m,2H),2.23-2.22(m,1H),1.70-1.57(m,1H)。
中间体2:(2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
在室温于氩气氛围中向3-氨基吡咯烷-2-酮(4.0g,40mmol)于甲醇-三乙胺(130mL,9:1)中的经搅拌溶液中添加Boc-酸酐(9.6mL,41mmol)。在室温搅拌反应混合物过夜,之后加热至回流保持两小时。随后,将反应混合物冷却至室温且减压浓缩。将醚(50mL)添加至粗残余物中,且经由布氏漏斗过滤固体,得到呈棕色固体的中间体2(4.0g,20mmol,50%产率)。1H NMR(400MHz,DMSO-d6):δ7.69(br.s.,1H),6.99(d,J=8.0Hz,1H),4.06-3.96(m,1H),3.19-3.10(m,2H),2.29-2.19(m,1H),1.89-1.76(m,1H),1.35(s,9H)。
中间体3:(1-(4-溴-2,3-二氟苯基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
向中间体2(1.0g,5.0mmol)于1,4-二噁烷(10mL)中的经搅拌溶液中添加1,4-二溴-2,3-二氟苯(1.6g,6.0mmol)和Cs2CO3(3.3g,10mmol)。用氮气吹扫反应混合物5min且向其中装入Xantphos(0.29g,0.50mmol)和Pd2(dba)3(0.23g,0.25mmol)。将反应混合物再次用氮气吹扫3min且在120℃加热16h。将反应混合物冷却,经硅藻土垫过滤,且减压浓缩滤液。使用柱色谱(石油醚-EtOAc)纯化粗产物,得到呈棕色固体的中间体3(1.1g,2.8mmol,47%产率)。MS(ESI)m/z:391.2(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.61-7.59(m,1H),7.35-7.28(m,2H),4.39-4.28(m,1H),3.82-3.64(m,2H),2.42-2.31(m,1H),2.10-1.97(m,1H),1.40(s,9H)。
中间体4:(1-(2,3-二氟-2'-(甲基磺酰氨基)-[1,1'-联苯]-4-基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
在室温向中间体3(1.1g,2.1mmol)于1.4-二噁烷-水(11mL,10:1)的溶液中添加(2-(甲基磺酰氨基)苯基)硼酸(0.45g,2.1mmol)和磷酸三钾(0.74g,4.2mmol)。用氮气吹扫反应混合物5min且向其中装入PdCl2(dppf)-CH2Cl2(0.17g,0.21mmol)。将反应混合物再次用氮气吹扫3min且在80℃加热16h。将反应混合物冷却并经硅藻土垫过滤,且减压浓缩滤液。经由柱色谱(石油醚-EtOAc)纯化粗产物,得到呈棕色固体的中间体4(0.44g,0.91mmol,43%产率)。MS(ESI)m/z:482.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),7.53-7.44(m,2H),7.38-7.29(m,4H),7.24-7.17(m,1H),4.36-4.31(m,1H),3.86-3.69(m,2H),2.90(s,3H),2.41-2.37(m,1H),2.10-2.02(m,1H),1.41(s,9H)。
中间体5:N-(4'-(3-氨基-2-氧代吡咯烷-1-基)-2',3'-二氟-[1,1'-联苯]-2-基)甲磺酰胺盐酸盐
向中间体4(440mg,0.91mmol)于1,4-二噁烷(1mL)中的冰冷溶液中添加4N HCl/1,4-二噁烷(4.6mL,1mmol),且在室温搅拌反应混合物2h。减压蒸发溶剂。用二乙醚(20mL×2)湿磨胶状固体并干燥,得到呈棕色固体的中间体5(350mg,0.84mmol,92%产率)。
MS(ESI)m/z:418.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.71(br.s.,3H),7.55-7.47(m,2H),7.45-7.24(m,4H),4.33-4.25(m,1H),3.97-3.85(m,2H),2.89(s,3H),2.64-2.54(m,1H),2.30-2.17(m,1H)。
中间体6:(R)-(2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
在0℃将1-丙烷膦酸酐(50%于EtOAc中,210mL,340mmol)添加至Boc-D-2,4-二氨基丁酸(50g,230mmol)和TEA(96mL,690mmol)于DCM(1500mL)中的溶液中。在氮气下在室温搅拌反应混合物过夜。真空浓缩反应混合物,且通过柱色谱(MeOH/DCM)纯化粗产物。用EtOAc/石油醚使产物重结晶,获得呈白色固体的中间体6(32g,70mmol,70%产率)。MS(ESI)m/z:201.2(M+H)+。1H NMR(400MHz,DMSO-d6)δ=7.69(s,1H),6.99(br.d.,J=9.0Hz,1H),4.01(q,J=9.0Hz,1H),3.17-3.09(m,2H),2.28-2.19(m,1H),1.90-1.75(m,1H),1.39(s,9H)。
中间体7:(R)-(1-(2,3-二氟-4-溴苯基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
将中间体6(20g,100mmol)、2,3-二氟-1,4-二溴苯(14g,110mmol)、磷酸三钾(32g,150mmol)和碘化亚铜(7.6g,40mmol)于1,4-二噁烷(250mL)的反应混合物用氮气吹扫5min。添加N,N'-二甲基亚乙基二胺(5.5mL,50mmol),且将反应混合物在压力管中于65℃加热12h。将反应混合物用EtOAc稀释,经硅藻土过滤,且减压浓缩。将粗产物通过柱色谱(35%EtOAc/石油醚)纯化且重结晶(EtOAc/石油醚),获得呈白色固体的中间体7(18g,39mmol,39%产率)。MS(ESI)m/z:439.0(M+H)+。1H NMR(400MHz,CDCl3)δ=7.54(ddd,J=8.5,6.3,2.3Hz,1H),7.09(ddd,J=8.5,6.3,2.3Hz,1H),5.16(br.s.,1H),4.41-4.30(m,1H),3.87(m,1H),3.79-3.69(m,1H),2.85-2.73(m,1H),2.17-2.05(m,1H),1.48(m,9H)。
中间体8:(2-溴苯基)二甲基膦氧化物
在压力管中,用氩气使1-溴-2-碘苯(2.3mL,18mmol)、磷酸三钾(5.6g,27mmol)和Xantphos(0.61g,1.1mmol)于DMF(40mL)中的反应混合物脱气3min。添加二甲基膦氧化物(1.7g,21mmol)和PdOAc2(0.20g,0.88mmol)。用氩气使混合物脱气且在110℃加热16h。将反应混合物冷却至室温,经硅藻土过滤且减压浓缩。通过柱色谱(CHCl3/MeOH)纯化粗产物,得到中间体8(2.1g,9.0mmol,51%产率)。MS(ESI)m/z:233.0(M+H)+。1H NMR(300MHz,DMSO-d6)δ=7.97(ddd,J=11.9,7.8,2.0Hz,1H),7.76(ddd,J=7.8,3.9,1.2Hz,1H),7.65-7.44(m,2H),1.83(d,J=13.5Hz,6H)。
中间体9:(R)-(1-(2'-(二甲基磷酰基)-2,3-二氟-[1,1'-联苯]-4-基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
用氩气吹扫中间体7(15g,38mmol)、中间体8(11g,46mmol)、bispin(24g,96mmol)和K3PO4(24g,115mmol)于1,4-二噁烷(250mL)中的反应混合物5min。添加PdCl2(dppf)-CH2Cl2加合物(3.1g,3.8mmol),且再次用氩气吹扫混合物,随后在105℃于压力管中搅拌24h。将反应混合物用EtOAc稀释,经硅藻土过滤,且减压浓缩。通过柱色谱(5%MeOH/CHCl3)纯化粗产物,得到中间体9(9.0g,19mmol,51%产率)。MS(ESI)m/z:465.4(M+H)+。1H NMR(400MHz,DMSO-d6)δ=7.92(ddd,J=12.8,7.6,1.3Hz,1H),7.70-7.49(m,2H),7.41-7.23(m,4H),4.54-4.23(m,1H),3.87-3.70(m,2H),2.44-2.37(m,1H),2.21-2.00(m,1H),1.51(br.d.,J=13.1Hz,6H),1.42(s,9H)。
中间体10:(R)-3-氨基-1-(2'-(二甲基磷酰基)-2,3-二氟-[1,1'-联苯]-4-基)吡咯烷-2-酮盐酸盐
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在室温将HCl(4M于1,4-二噁烷中,200mL,800mmol)添加至中间体9(34g,73mmol)于1,4-二噁烷(500mL)中的经搅拌溶液中。将反应混合物搅拌3h且减压浓缩,得到中间体10(28g,70mmol,95%产率),其不经进一步纯化即用于下一合成步骤。MS(ESI)m/z:365.2(M+H)+。1H NMR(400MHz,DMSO-d6)δ=8.62(br.s.,3H),7.95-7.81(m,1H),7.68-7.57(m,2H),7.39-7.32(m,2H),7.31-7.24(m,1H),4.33-4.19(m,1H),3.94-3.84(m,2H),2.61-2.53(m,1H),2.25-2.15(m,1H),1.53(d,J=13.1Hz,6H)。
中间体11:(4-氯-2-氟苯基)氨基甲酸苯酯
在0℃将氯甲酸苯酯(20mL,160mmol)缓慢添加至4-氯-2-氟苯胺(19mL,170mmol)和吡啶(35mL,430mmol)于DCM(250mL)中的溶液中。使反应混合物逐渐升温至室温且搅拌12h。用水淬灭反应混合物。用DCM(3×200mL)萃取混合物。将合并的有机层用0.5N HCl和10%碳酸氢钠洗涤,经硫酸钠干燥且真空浓缩。将固体于石油醚(100mL)中搅拌15min,过滤并干燥,得到中间体11(36g,40mmol,78%产率)。1H NMR(300MHz,氯仿-d)δ=10.22-9.99(m,1H),7.73(br.t.,J=8.7Hz,1H),7.52(dd,J=10.7,2.1Hz,1H),7.47-7.38(m,2H),7.34-7.18(m,4H)。
中间体12:(2-氟-4-(三氟甲基)苯基)氨基甲酸苯酯
在0℃将氯甲酸苯酯(4.5mL,36mmol)缓慢添加至2-氟-4-(三氟甲基)苯胺(8.0g,45mmol)和吡啶(9.0mL,110mmol)于DCM(80mL)中的溶液中。使反应混合物逐渐升温至室温且搅拌3h。用水淬灭反应混合物,且用DCM(3×200mL)萃取混合物。将合并的有机层用0.5NHCl和10%碳酸氢钠洗涤,经硫酸钠干燥且真空浓缩。将固体于石油醚(100mL)中搅拌15min,过滤并干燥,得到中间体11(9.0g,30mmol,67%产率)。MS(ESI)m/z:317.2(M+NH4)+。1H NMR(300MHz,氯仿-d)δ=10.43(s,1H),8.04(br.t.,J=8.1Hz,1H),7.75(br.d.,J=10.9Hz,1H),7.60(br.d.,J=8.6Hz,1H),7.52-7.38(m,2H),7.36-7.21(m,3H)。
中间体13:(R)-1-(1-(4-溴-2,3-二氟苯基)-2-氧代吡咯烷-3-基)-3-(2-氟-4-(三氟甲基)苯基)脲
在0℃将HCl(4M于二噁烷中,32mL,130mmol)逐滴添加至中间体7(10g,26mmol)于DCE(300mL)中的溶液中。将反应混合物在室温搅拌2h,且减压浓缩。将粗中间体溶解于1,4-二噁烷(300mL)中且冷却至0℃。经10min的时段逐滴添加DIEA(22mL,130mmol),添加中间体12(6.9g,23mmol),且在室温搅拌混合物12h。经硅藻土过滤反应混合物,且用EtOAc洗涤过滤塞。滤液经硫酸钠干燥且减压浓缩。通过柱色谱(2%MeOH:DCM)纯化粗产物,得到中间体13(12g,24mmol,95%产率)。MS(ESI)m/z:496.0(M+H)+。
中间体14:(R)-1-(1-(2,3-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)苯基)-2-氧代吡咯烷-3-基)-3-(2-氟-4-(三氟甲基)苯基)脲
用氩气使中间体13(12g,24mmol)和bispin(18g,73mmol)于1,4-二噁烷(120mL)中的溶液脱气5min。添加PdCl2(dppf)-CH2Cl2(4.0g,4.8mmol),且将反应混合物缓慢加热至110℃并搅拌16h。经硅藻土过滤混合物,且用EtOAc洗涤硅藻土塞。滤液经硫酸钠干燥且减压浓缩,得到中间体14(13g,24mmol,99%产率)。MS(ESI)m/z:544.2(M+H)+。
中间体15:(3-溴吡啶-2-基)二甲基膦氧化物
向3-溴-2-碘吡啶(5.0g,18mmol)于DMF(5mL)中的经搅拌溶液中添加二甲基膦氧化物(1.7g,21mmol)和K3PO4(4.1g,19mmol)。用氮气吹扫反应混合物5min且向其中装入Xantphos(1.0g,1.8mmol)和Pd(OAc)2(0.20g,0.88mmol)。再次用氮气吹扫反应混合物3min且在100℃加热9小时。反应混合物经硅藻土过滤且减压浓缩。通过柱色谱(5%MeOH-CHCl3)纯化粗物质,得到呈棕色液体的中间体15(2.7g,12mmol,66%产率)。MS(ESI)m/z:234.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ=8.72(d,J=4.8Hz,1H),8.23-8.20(m,1H),7.53-7.49(m,1H),1.66(d,J=13.6Hz,6H)。
中间体16:(2-溴-6-氟苯基)二甲基膦氧化物
向1-溴-3-氟-2-碘苯(2.0g,6.7mmol)于1,4-二噁烷(15mL)中的经搅拌溶液中添加二甲基膦氧化物(0.62g,8.0mmol)和K3PO4(1.6g,7.3mmol)。用氮气吹扫反应混合物5min且向其中装入Xantphos(0.39g,0.67mmol)和Pd2(dba)3(0.30g,0.33mmol)。再次用氮气吹扫反应混合物3min且在100℃加热9h。反应混合物经硅藻土过滤且减压浓缩。通过柱色谱(0至100%EtOAc-己烷,接着3%MeOH-CHCl3)纯化粗物质,得到呈黄色固体的中间体16(0.33g,1.3mmol,20%产率)。MS(ESI)m/z:250.9[M+H]+。1H NMR(400MHz,DMSO-d6)δ=7.63(d,J=8.0Hz,1H),7.52(td,J=8.0,6.0Hz,1H),7.43-7.28(m,1H),1.87(d,J=16.6Hz,3H),1.86(d,J=16.6Hz,3H)。
中间体17:二乙基膦氧化物
在室温向2M溴化乙基镁(330mL,650mmol)于THF中的经搅拌溶液中添加膦酸二乙酯(30g,220mmol),且再搅拌混合物2小时。随后,添加K2CO3(90g,650mmol)于水(120mL)中的冷溶液,且经硅藻土垫过滤反应混合物。将滤液减压浓缩并与甲苯(20mL×3)共沸。将粗物质用DCM(100mL)稀释,经棉床过滤且减压浓缩,得到呈微黄色液体的中间体17(12g,110mmol,52%产率)。MS(ESI)m/z:107.2[M+H]+。
中间体18:(2-溴苯基)二乙基膦氧化物
向1-溴-2-碘苯(10g,35.3mmol)于DMF(50mL)中的经搅拌溶液中添加二乙基膦氧化物(4.5g,42mmol)和K3PO4(15g,71mmol)。用氮气吹扫反应混合物5min且向其中装入Xantphos(1.0g,1.8mmol)和乙酸钯(II)(0.40g,1.8mmol)。将反应混合物再次用氮气吹扫3min,加热至100℃且搅拌16h。将反应混合物冷却,经硅藻土垫过滤,且减压浓缩滤液。通过柱色谱(MeOH-EtOAc)纯化粗产物,得到呈微黄色液体的中间体18(3.2g,12mmol,35%产率)。MS(ESI)m/z:263.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ=8.05-7.94(m,1H),7.79-7.68(m,2H),7.64-7.48(m,1H),2.26-2.03(m,4H),0.93(td,J=17.4,7.7Hz,6H)。
中间体19:(2-溴苯基)膦酸二甲酯
向三氟甲烷磺酸2-溴苯基酯(2.0g,6.6mmol)于甲苯(100mL)中的经搅拌溶液中添加膦酸二甲酯(1.1g,9.8mmol)和DIEA(1.7mL,9.8mmol)。用氮气吹扫反应混合物5min且向其中装入1,3-双(二苯膦基)丙烷(0.14g,0.33mmol)和乙酸钯(II)(0.04g,0.17mmol)。将反应混合物再次用氮气吹扫3min且在110℃加热16h。将反应混合物冷却并经硅藻土垫过滤,且减压浓缩滤液。通过快速色谱(5至10%MeOH/氯仿)纯化产物,得到呈无色液体的中间体19(1.2g,3.6mmol,55%产率)。MS(ESI)m/z:267.1[M+H]+。1H NMR(400MHz,CDCl3)δ=8.02-8.00(m,1H)7.70-7.69(m,1H)7.43-7.41(m,2H)3.83-3.73(m,6H)。
中间体20:(2-溴苯基)(甲基)亚膦酸乙酯
向1-溴-2-碘苯(1.0g,3.5mmol)于DMF(5mL)中的经搅拌溶液中添加甲基亚膦酸二乙酯(0.58g,4.2mmol)和K3PO4(2.3g,11mmol)。用氮气吹扫反应混合物5min且向其中装入Xantphos(0.21g,0.35mmol)和乙酸钯(II)(0.040g,0.18mmol)。将反应混合物再次用氮气吹扫3min且在110℃加热16h。将反应混合物冷却,经硅藻土垫过滤,且减压浓缩滤液。通过快速色谱(石油醚-EtOAc)纯化粗产物,得到呈棕色液体的中间体20(0.35g,1.3mmol,38%产率)。MS(ESI)m/z:263.1[M+H]+。1H NMR(400MHz,CDCl3)δ=8.18-8.13(m,1H)7.67-7.65(m,1H)7.64-7.38(m,2H)4.07-4.03(m,1H)3.85-3.80(m,1H)1.86(d,J=15.0Hz,3H),1.32(t,J=7.2Hz,3H)。
中间体21:4-溴-3-环丙基-2-氟苯胺
在室温于氩气氛围下向3-环丙基-2-氟苯胺(0.85g,5.6mmol)于DMF(11mL)中的冰冷溶液中添加NBS(1.0g,5.6mmol)。经3h使反应混合物逐渐升温至室温且用Na2S2O3水溶液(10mL)淬灭。用EtOAc(30mL×2)萃取两相混合物。将合并的有机层用盐水(15mL×2)洗涤,经Na2SO4干燥,减压浓缩且经由快速柱色谱(25%EtOAc-石油醚)纯化,得到呈橙色液体的中间体21(1.2g,5.0mmol,89%产率)。1H NMR(400MHz,CDCl3)δ=7.11(d,J=8.5Hz,1H),6.51(t,J=8.8Hz,1H),3.67(br s,2H),1.80(tt,J=8.6,5.7Hz,1H),1.07-0.82(m,4H)。
中间体22:(1-(4-溴-3-环丙基-2-氟苯基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
在0℃于氮气下向中间体21(1.1g,4.8mmol)于Acn(10mL)中的经搅拌溶液中添加K3PO4(1.0g,4.8mmol)。将所得混合物用2,4-二溴丁酰氯(0.60mL,4.5mmol)处理且搅拌2h。随后,添加K2CO3(2.0g,14mmol),且搅拌混合物16h。经硅藻土垫过滤固体,且用Acn(15mL×2)洗涤该垫。部分蒸发滤液,添加氨(水溶液,10mL,460mmol),且在40℃搅拌混合物16h。将混合物用EtOAc(20mL×3)萃取且用盐水(20mL)洗涤。经合并的有机物经Na2SO4干燥且蒸发,得到粗产物3-氨基-1-(4-溴-3-环丙基-2-氟苯基)吡咯烷-2-酮(1.0g,3.2mmol,67%产率),其不经进一步纯化即用于下一步骤中。
在室温于氩气氛围中向3-氨基-1-(4-溴-3-环丙基-2-氟苯基)吡咯烷-2-酮于DCM(15mL)中的经搅拌溶液中添加TEA(0.98mL,7.0mmol)和(Boc)2O(0.90mL,3.9mmol)。在室温搅拌反应混合物6小时。随后,用饱和NH4Cl水溶液(20mL)淬灭反应混合物且用EtOAc(20mL×3)萃取。将合并的有机层用盐水(20mL)洗涤,经Na2SO4干燥,减压浓缩且经由快速色谱(20%EtOAc-石油醚)纯化,得到呈微黄色胶状固体的中间体22(1.0g,2.4mmol,69%产率)。MS(ESI)m/z:413.1[M+H]+。1H NMR(400MHz,CDCl3)δ=7.38(dd,J=8.5,1.5Hz,1H),7.14-7.09(m,1H),5.18(br.s.,1H),4.37-4.33(m,1H),3.86-3.74(m,1H),3.69-3.62(m,1H),2.79-2.75(m,1H),2.15-2.01(m,1H),1.80(tt,J=8.6,5.7Hz,1H),1.48(s,9H),1.14-1.01(m,2H),0.91-0.84(m,2H)。
中间体23:(1-(2-环丙基-2'-(二甲基磷酰基)-3-氟-[1,1'-联苯]-4-基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
在室温向中间体22(0.50g,1.2mmol)于1,4-二噁烷(10mL)中的溶液中添加(2-溴苯基)二甲基膦氧化物(0.42g,1.8mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(0.92g,3.6mmol)和K2CO3(0.42g,3.0mmol)。用氮气吹扫反应混合物5min,随后向其中装入PdCl2(dppf).DCM(0.090g,0.12mmol)。将反应混合物再次用氮气吹扫3min且在100℃加热16h。将反应混合物冷却并经硅藻土垫过滤,且减压浓缩滤液。通过快速色谱(MeOH-CHCl3)纯化粗中间体,得到呈橙色固体的中间体23(0.30g,0.62mmol,51%产率)。MS(ESI)m/z:487.1[M+H]+。1H NMR(400MHz,CDCl3)δ=8.25-8.10(m,1H),7.62-7.48(m,2H),7.33-7.21(m,2H),7.07-6.95(m,1H),5.26-5.10(m,1H),4.48-4.27(m,1H),3.93-3.79(m,1H),3.79-3.67(m,1H),2.88-2.74(m,1H),2.20-2.01(m,1H),1.54-1.37(m,16H),1.04-0.85(m,2H),0.73-0.68(m,2H)。
中间体24:3-氨基-1-(2-环丙基-2'-(二甲基磷酰基)-3-氟-[1,1'-联苯]-4-基)吡咯烷-2-酮盐酸盐
在室温于氩气氛围中向中间体23(0.33g,0.68mmol)于1,4-二噁烷(1mL)中的冰冷溶液中添加4M HCl/1,4-二噁烷(3.0mL,12mmol),且在室温搅拌混合物2h。减压蒸发溶剂,获得胶状固体。将粗产物用石油醚(10mL×2)湿磨并干燥,得到呈棕色胶状固体的中间体24(0.26mg,0.67mmol,99%产率)。MS(ESI)m/z:387.1[M+H]+。
中间体25:(1-(4-溴-3-氟-2-(三氟甲基)苯基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
在0℃于氮气下向4-溴-2-氟-3-(三氟甲基)苯胺(0.70g,2.7mmol)于Acn(10mL)中的经搅拌溶液中添加K3PO4(0.58g,2.7mmol)。将所得混合物用2,4-二溴丁酰氯(0.29mL,2.2mmol)处理且搅拌2h。随后,添加K2CO3(1.1g,8.1mmol),且搅拌反应混合物16h。经硅藻土垫过滤混合物,且用Acn(15mL×2)洗涤该垫。部分蒸发滤液且添加氨(水溶液)(10mL,462mmol)。在40℃搅拌混合物16h,随后用EtOAc(20mL×3)萃取。将经合并的有机物用盐水(20mL)洗涤,经Na2SO4干燥且蒸发,得到粗产物3-氨基-1-(4-溴-2-氟-3-(三氟甲基)苯基)吡咯烷-2-酮(0.88g,2.6mmol,95%产率),其不经任何进一步纯化即用于下一步骤中。
在室温于氩气氛围中向粗产物3-氨基-1-(4-溴-3-氟-2-(三氟甲基)苯基)吡咯烷-2-酮于DCM(15mL)中的经搅拌溶液中添加TEA(3.7mL,26mmol)和(Boc)2O(3.4mL,15mmol)。在室温搅拌反应混合物6小时,随后用饱和NH4Cl水溶液(20mL)淬灭且用EtOAc(20mL×3)萃取。将合并的有机层用盐水(20mL)洗涤,经Na2SO4干燥,减压浓缩且经由柱色谱(30%EtOAc-石油醚)纯化,得到呈微黄色胶状固体的中间体25(4.8g,11mmol,82%产率)。MS(ESI)m/z:442.8[M+H]+。1H NMR(300MHz,CDCl3)δ=7.82(t,J=7.8Hz,1H),7.02(br.d.,J=8.7Hz,1H),5.23-5.05(m,1H),4.43-4.23(m,1H),3.80-3.53(m,2H),2.89-2.68(m,1H),2.21-2.03(m,1H),1.47(s,9H)。
中间体26:(1-(2'-(二甲基磷酰基)-2-氟-3-(三氟甲基)-[1,1'-联苯]-4-基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
在室温向中间体25(0.60g,1.4mmol)于1,4-二噁烷(10mL)中的溶液中添加(2-溴苯基)二甲基膦氧化物(0.41mg,1.8mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(0.52g,2.0mmol)和K2CO3(0.56mg,4.1mmol)。用氮气吹扫反应混合物5min,随后向其中装入PdCl2(dppf).DCM(56mg,0.070mmol)。将反应混合物再次用氮气吹扫3min且在100℃加热16h。将反应混合物冷却,经硅藻土垫过滤,且减压浓缩滤液。通过柱色谱(EtOAc/石油醚)纯化粗产物,得到呈橙色固体的中间体26(0.30g,0.58mmol,43%产率)。MS(ESI)m/z:515.1
中间体27:3-氨基-1-(2'-(二甲基磷酰基)-2-氟-3-(三氟甲基)-[1,1'-联苯]-4-基)吡咯烷-2-酮盐酸盐
在室温于氩气氛围中向中间体26(0.30g,0.58mmol)于1,4-二噁烷(5mL)中的冰冷溶液中添加4M HCl/1,4-二噁烷(5mL)且在室温搅拌2h。减压蒸发溶剂。将固体用石油醚(10mL×2)湿磨且干燥,得到呈棕色胶状固体的中间体27(0.20g,0.48mmol,83%产率)。MS(ESI)m/z:415.1[M+H]+。
中间体28:(S)-1-(4-溴-2,3-二氟苯基)-5-(羟基甲基)吡咯烷-2-酮
在室温向(S)-5-(羟基甲基)吡咯烷-2-酮(1.0g,8.7mmol)于1,4-二噁烷(15mL)中的溶液中添加1,4-二溴-2,3-二氟苯(2.4g,8.7mmol)、K3PO4(3.7g,17mmol)和N,N'-二甲基亚乙基二胺(0.15g,1.7mmol)。用氮气吹扫反应混合物5min,随后向其中装入碘化铜(I)(0.17g,0.87mmol)。将反应混合物再次用氮气吹扫3min且在95℃加热12h。将反应混合物冷却,经硅藻土垫过滤,且减压浓缩滤液。通过柱色谱(3%MeOH-CHCl3)纯化粗化合物,得到呈微黄色固体的中间体28(0.80g,2.6mmol,30%产率)。MS(ESI)m/z:305.9[M+H]+。1H NMR(400MHz,DMSO-d6)δ=7.59(ddd,J=8.8,7.0,2.3Hz,1H),7.24(ddd,J=9.0,7.0,2.0Hz,1H),4.80(t,J=5.0Hz,1H),4.20-4.04(m,1H),3.37(dd,J=5.0,4.0Hz,2H),2.56-2.45(m,1H),2.43-2.35(m,1H),2.25-2.18(m,1H),2.07-1.95(m,1H)。
中间体29:(S)-1-(4-溴-2,3-二氟苯基)-5-(((叔丁基二甲基硅烷基)氧基)甲基)吡咯烷-2-酮
在室温于氩气氛围中向中间体28(0.80g,2.6mmol)于DCM(10mL)中的经搅拌溶液中添加TEA(0.55mL,3.9mmol)和叔丁基二甲基氯硅烷(0.43g,2.9mmol)。在室温搅拌反应混合物16h。将反应混合物用饱和NH4Cl水溶液(20mL)淬灭且用DCM(20mL×2)萃取。将合并的有机层用盐水(20mL)洗涤,经Na2SO4干燥,减压浓缩。经由柱色谱(15%EtOAc-石油醚)纯化粗产物,得到呈白色固体的中间体29(0.85g,2.0mmol,77%产率)。MS(ESI)m/z:420.2[M+H]+。1H NMR(400MHz,CDCl3)δ=7.35(m,1H),7.15-7.05(m,1H),4.24-4.17(m,1H),3.62-3.49(m,2H),2.69-2.63(m,1H),2.54-2.50(m,1H),2.41-2.26(m,1H),2.14-2.03(m,1H),0.84(s,9H),-0.02(s,3H),-0.05(s,3H)。
中间体30:(3R,5S)-3-叠氮基-1-(4-溴-2,3-二氟苯基-5-(((叔丁基二甲基硅烷基)氧基)甲基)吡咯烷-2-酮
在-78℃向中间体29(1.0g,2.4mmol)于THF(20mL)中的经搅拌溶液中添加二异丙基氨基锂(1.8mL,3.6mmol)且持续搅拌30min。随后,将2,4,6-三异丙基苯磺酰叠氮(1.0g,3.3mmol)于THF(5mL)中的溶液插管导入混合物中,且搅拌混合物4h。随后,将反应混合物用饱和NaHCO3水溶液(2mL)淬灭且逐渐升温至室温。将反应混合物用EtOAc(40mL)稀释,用H2O(10mL×2)和盐水(20mL)洗涤,经Na2SO4干燥,且减压浓缩。通过柱色谱(15%EtOAc-石油醚,40g柱)纯化粗残余物,得到呈橙色固体的中间体30(0.85g,1.8mmol,77%产率)。MS(ESI)m/z:461.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ=7.65(ddd,J=9.0,7.0,2.0Hz,1H),7.36-7.28(m,1H),4.72-4.64(m,1H),4.33-4.24(m,1H),3.63-3.52(m,2H),2.48-2.28(m,1H),2.14(dt,J=13.3,8.7Hz,1H),0.91-0.66(m,9H),-0.06(s,3H),-0.08(s,3H)。
中间体31:((3R,5S)-1-(4-溴-2,3-二氟苯基)-5-(((叔丁基二甲基硅烷基)氧基)甲基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
向中间体30(0.85g,1.8mmol)于THF(8mL)中的经搅拌溶液中添加三苯基膦(0.73g,2.8mmol)和H2O(0.8mL)。将反应混合物在室温搅拌3h且在65℃加热6h。减压蒸发溶剂且不经进一步纯化即用于下一步骤。在室温于氩气氛围中向粗产物(5S)-3-氨基-1-(4-溴-2,3-二氟苯基)-5-(((叔丁基二甲基硅烷基)氧基)甲基)吡咯烷-2-酮于DCM(5mL)中的经搅拌溶液中添加Boc-酸酐(0.84mL,3.6mmol)和TEA(0.75mL,5.4mmol)。在室温搅拌反应混合物2h。随后,将反应混合物用饱和NH4Cl水溶液(15mL)淬灭且用CHCl3(20mL×2)萃取。将合并的有机层用盐水(15mL)洗涤,经Na2SO4干燥,减压浓缩。经由柱色谱(15%EtOAc-石油醚)纯化粗产物,得到呈白色固体的中间体31(0.80g,1.5mmol,83%产率)。MS(ESI)m/z:535.2[M+H]+。1H NMR(400MHz,CDCl3)δ=7.41-7.32(m,1H),7.15-7.01(m,1H),5.02-5.22(m,1H),4.73-4.61(m,1H),4.52-4.43(m,1H),4.21-4.10(m,1H),3.61-3.52(m,1H),2.63-2.51(m,1H),2.35-2.31(m,1H),1.43(s,9H),0.84(s,9H),-0.06(s,3H),-0.08(s,3H)。
中间体32:((3R,5S)-5-(((叔丁基二甲基硅烷基)氧基)甲基)-1-(2'-(二甲基磷酰基)-2,3-二氟-[1,1'-联苯]-4-基)-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
向中间体31(0.80g,1.49mmol)于1,4-二噁烷(10mL)中的经搅拌溶液中添加(2-溴苯基)二甲基膦氧化物(0.52g,2.2mmol)、双(频哪醇合)二硼(1.1g,4.5mmol)和K2CO3(0.42mg,3.0mmol)。用氩气吹扫反应混合物5min且向其中装入PdCl2(dppf)-CH2Cl2加合物(0.13mg,0.15mmol)。再次用氮气吹扫反应混合物3min且在100℃加热12h。将反应混合物冷却,经硅藻土垫过滤,且减压浓缩滤液。通过柱色谱(MeOH/CHCl3)纯化粗产物,得到呈棕色固体的中间体32(0.40g,0.66mmol,44%产率)。MS(ESI)m/z:609.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ=8.01-7.97(m,1H),7.85-7.81(m,1H),7.80-7.64(m,2H),7.59-7.27(m,3H),4.66-4.56(m,1H),4.42-4.33(m,1H),3.76-3.55(m,2H),2.46-2.28(m,2H),1.54-1.39(m,15H),0.84(s,9H),0.06(s,3H),-0.08(s,3H)。
中间体33:(3R,5S)-3-氨基-1-(2'-(二甲基磷酰基)-2,3-二氟-[1,1'-联苯]-4-基)-5-(羟基甲基)吡咯烷-2-酮盐酸盐
在室温于氩气氛围中向中间体32(0.40g,0.66mmol)于1,4-二噁烷(1mL)中的冰冷溶液中添加4M HCl/1,4-二噁烷(2.5mL,10mmol)且在室温搅拌两小时。减压蒸发溶剂,且将胶状固体用EtOAc(10ml×2)进一步湿磨并干燥,得到呈棕色固体的中间体33(0.22g,0.56mmol,85%产率)。MS(ESI)m/z:395.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ=7.97-7.88(m,1H),7.82-7.72(m,1H),7.69-7.47(m,2H),7.43-7.25(m,2H),4.35-4.29(m,2H),4.11-3.86(m,4H),3.55-3.34(m,2H),2.48-2.27(m,2H),1.52(br d,J=13.1Hz,6H)。
中间体34:1-(4-溴-2,3-二氟苯基)-5-甲基吡咯烷-2-酮
在室温向外消旋5-甲基吡咯烷-2-酮(1.0g,10mmol)于1,4-二噁烷(10mL)中的溶液中添加1,4-二溴-2,3-二氟苯(3.3g,12mmol)、K3PO4(4.3g,20mmol)和N,N'-二甲基亚乙基二胺(0.18g,2.0mmol)。用氮气吹扫反应混合物5min,随后向其中装入碘化铜(I)(0.19g,1.0mmol)。将反应混合物再次用氮气吹扫3min且在80℃加热6h。将反应混合物冷却,经硅藻土垫过滤,且减压浓缩滤液。通过柱色谱(石油醚-EtOAc)纯化粗产物,得到呈棕色液体的中间体34(0.90g,3.1mmol,31%产率)。MS(ESI)m/z:291.0[M+H]+。1H NMR(400MHz,CDCl3)δ=7.38-7.01(m,1H),6.99-6.96(m,1H),4.24-4.20(m,1H),2.62-2.51(m,2H),2.50-2.38(m,1H),1.81-1.76(m,1H),1.17(d,J=6.4Hz,3H)。
中间体35:3-叠氮基-1-(4-溴-2,3-二氟苯基)-5-甲基吡咯烷-2-酮
在-78℃向中间体34(0.20g,0.69mmol)于THF(3mL)中的经搅拌溶液中添加二异丙基氨基锂(0.69mL,1.4mmol)且持续搅拌40min。随后,将2,4,6-三异丙基苯磺酰叠氮(0.26g,0.83mmol)于THF(2mL)中的溶液插管导入混合物中,且搅拌混合物4h。随后将混合物用饱和NH4Cl水溶液(10mL)淬灭,逐渐升温至室温且用EtOAc(20mL×2)萃取。将合并的有机层用盐水(15mL)洗涤,经Na2SO4干燥,且减压浓缩。通过柱色谱(12%EtOAc-石油醚)纯化粗残余物,得到呈橙色固体的中间体35(0.10g,0.21mmol,31%产率)。MS(ESI)m/z:331.1[M+H]+。1H NMR(400MHz,CDCl3)δ=7.40-7.36(m,1H),7.04-6.98(m,1H),4.36-4.31(m,1H),4.26-4.21(m,1H),2.32-2.26(m,1H),2.14-2.043(m,1H),1.16(d,J=6.4Hz,3H)。
中间体36:(1-(4-溴-2,3-二氟苯基)-5-甲基-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
向3-叠氮基-1-(4-溴-2,3-二氟苯基)-5-甲基吡咯烷-2-酮(1.5g,4.5mmol)于THF(21mL)中的经搅拌溶液中添加三苯基膦(2.4g,9.1mmol)和水(3mL)。将反应混合物在室温搅拌30min且加热至65℃,保持6h。减压蒸发溶剂且粗产物不经进一步纯化即用于下一步骤。
在室温于氩气氛围中向粗产物3-氨基-1-(4-溴-2,3-二氟苯基)-5-甲基吡咯烷-2-酮于DCM(20mL)中的经搅拌溶液中添加TEA(0.82mL,5.9mmol)和Boc-酸酐(1.4mL,5.9mmol)。在室温搅拌反应混合物2h。随后,将反应混合物用饱和NH4Cl水溶液(25mL)淬灭且用CHCl3(30mL×2)萃取。将合并的有机层用盐水(25mL)洗涤,经Na2SO4干燥,且减压浓缩。经由柱色谱(50%EtOAc-石油醚)纯化粗产物,得到呈棕色固体的中间体36(1.3g,3.2mmol,82%产率)。MS(ESI)m/z:405.2[M+H]+。1H NMR(400MHz,CDCl3)δ=7.39-7.26(m,1H),7.0-6.99(m,1H),5.29-5.07(m,1H),4.58-4.31(m,1H),4.30-4.13(m,1H),2.51-2.04(m,1H),1.81-1.76(m,1H),1.45(s,9H),1.30-1.15(m,3H)。(非对映异构体混合物)
中间体37:(1-(2'-(二甲基磷酰基)-2,3-二氟-[1,1'-联苯]-4-基)-5-甲基-2-氧代吡咯烷-3-基)氨基甲酸叔丁酯
向中间体36(1.0g,2.5mmol)于1,4-二噁烷(15mL)中的经搅拌溶液中添加(2-溴苯基)二甲基膦氧化物(0.58g,2.5mmol)、双(频哪醇合)二硼(1.9g,7.4mmol)和K2CO3(1.0g,7.4mmol)。用氮气吹扫反应混合物5min且向其中装入PdCl2(dppf).CH2Cl2加合物(0.20g,0.25mmol)。将反应混合物再次用氮气吹扫3min且在110℃加热15h。将混合物冷却,经硅藻土垫过滤,且减压浓缩滤液。通过快速色谱(MeOH/CDCl3)纯化粗化合物,得到呈棕色固体的中间体37(0.70g,1.5mmol,59%产率)。MS(ESI)m/z:479.2[M+H]+。1H NMR(400MHz,CDCl3)δ=7.78-7.73(m,1H),7.62-7.51(m,3H),7.37-7.28(m,1H),7.23-7.18(m,1H),5.31-5.11(m,1H),4.59-4.24(m,2H),2.58-2.32(m,1H),1.77-1.74(m,3H),1.65-1.49(m,13H),1.30-1.23(m,3H)。(非对映异构体混合物)
中间体38:3-氨基-1-(2'-(二甲基磷酰基)-2,3-二氟-[1,1'-联苯]-4-基)-5-甲基吡咯烷-2-酮盐酸盐
于氩气氛围中向中间体37(0.70g,1.5mmol)于1,4-二噁烷(5mL)中的冰冷溶液中添加4M HCl(7.3mL,29mmol)/1,4-二噁烷且在室温搅拌2h。减压蒸发溶剂,得到呈棕色液体的中间体38(0.50g,1.2mmol,82%产率)。MS(ESI)m/z:379.2[M+H]+。1H NMR(400MHz,CDCl3)δ=7.78-7.73(m,1H),7.62-7.51(m,3H),7.37-7.28(m,1H),7.23-7.18(m,1H),5.38-4.98(m,3H),4.59-4.42(m,2H),2.58-2.29(m,1H),1.71-1.63(m,3H),1.55-1.49(m,4H),1.30-1.23(m,3H)。
实施例1:(R)-N-(4'-(3-(3-(4-氯苯基)脲基)-2-氧代吡咯烷-1-基)-2',3'-二氟-[1,1'-联苯]-2-基)甲磺酰胺
在室温于氮气下向中间体5(50mg,0.12mmol)于DCE(2mL)中的经搅拌溶液中依序添加DIPEA(0.084mL,0.48mmol)和1-氯-4-异氰酸酯基苯(22.0mg,0.144mmol)。在室温搅拌所得反应混合物4h。将反应混合物用水淬灭且用EtOAc萃取。将有机层用冰冷水、盐水洗涤,经Na2SO4干燥且减压浓缩。通过反相色谱、接着手性HPLC纯化粗化合物,得到实施例1(16mg,0.028mmol,24%)。RT=1.732min,94.2%,(方法C);MS(ESI)m/z:535.1[M+H]+;1H NMR(400MHz,DMSO-d6):δ9.17(s,1H),8.87(s,1H),7.96(s,1H),7.58-7.29(m,10H),4.64-4.48(m,1H),3.96-3.82(m,1H),3.81-3.66(m,1H),2.74(s,3H),2.59-2.55(m,1H),2.20-2.07(m,1H)。
实施例25:(R)-1-(4-氯-2-氟苯基)-3-(1-(2'-(二甲基磷酰基)-2,3-二氟-[1,1'-联苯]-4-基)-2-氧代吡咯烷-3-基)脲
在0℃将DIEA(61mL,350mmol)缓慢添加至中间体10(28g,70mmol)于DCE(560mL)中的溶液中。搅拌2min后,添加中间体11(17g,63mmol),且将反应混合物缓慢加热至50℃并搅拌12h。减压浓缩反应混合物,且经由柱色谱(5%MeOH/DCM)纯化粗产物。通过制备型HPLC纯化产物,用水洗涤且干燥,获得呈白色固体的实施例25(29g,54mmol,78%产率)。
实施例57:(R)-1-(1-(2'-(二甲基磷酰基)-2,3-二氟-[1,1'-联苯]-4-基)-2-氧代吡咯烷-3-基)-3-(2-氟-4-(三氟甲基)苯基)脲
在0℃将DIEA(5.5mL,6.2mmol)缓慢添加至中间体10(2.5g,6.2mmol)于DCE(70mL)中的溶液中。搅拌2min后,添加中间体12(1.7g,5.6mmol),且将反应混合物缓慢加热至50℃并搅拌8h。减压浓缩反应混合物,且经由柱色谱(6.5%MeOH/DCM)纯化粗产物。通过制备型HPLC纯化产物,用水洗涤且干燥,获得呈白色固体的实施例57(2.2g,3.9mmol,62%产率)。
实施例73:(R)-1-(1-(4-(2-(二甲基磷酰基)吡啶-3-基)-2,3-二氟苯基)-2-氧代吡咯烷-3-基)-3-(2-氟-4-(三氟甲基)苯基)脲
向中间体14(13g,24mmol)和中间体15(5.6g,24mmol)于1,4二噁烷(260mL)和水(26mL)中的溶液中添加磷酸钾(10g,48mmol)和PdCl2(dppf)-CH2Cl2(2.0g,2.4mmol)。将反应混合物搅拌30min,缓慢升温至110℃且搅拌12h。经硅藻土过滤混合物,且用EtOAc洗涤硅藻土塞。滤液经硫酸钠干燥且减压浓缩。经由柱色谱(2%MeOH/DCM)纯化粗化合物,得到实施例73(9.1g,16mmol,66%产率)。
实施例89:(R)-1-(1-(2-环丙基-2'-(二甲基磷酰基)-3-氟-[1,1'-联苯]-4-基)-2-氧代吡咯烷-3-基)-3-(2-氟-4-(三氟甲基)苯基)脲
在室温于氩气氛围中向中间体24(0.13g,0.34mmol)于DMF(2mL)中的冰冷悬浮液中添加DIEA(0.18mL,1.0mmol)和中间体12(0.12g,0.41mmol)。随后,在50℃加热所得溶液2小时。减压浓缩反应混合物,且通过反相色谱、接着手性HPLC纯化粗产物,得到实施例89(0.07g,0.12mmol,33%产率)。
实施例91:(R)-1-(4-氯-2-氟苯基)-3-(1-(2'-(二甲基磷酰基)-2-氟-3-(三氟甲基)-[1,1'-联苯]-4-基)-2-氧代吡咯烷-3-基)脲
在室温于氩气氛围中向中间体27(0.080g,0.18mmol)于DCE(2mL)中的冰冷悬浮液中添加DIEA(0.06mL,0.36mmol)和中间体11(0.060g,0.21mmol)。随后,在50℃加热所得溶液2h。减压浓缩反应混合物,且通过反相色谱、接着手性HPLC纯化粗产物,得到呈白色固体的实施例91(0.060g,0.11mmol,60%产率)。
实施例109:1-(4-氯-2-氟苯基)-3-(1-(2'-(二甲基磷酰基)-2,3-二氟-[1,1'-联苯]-4-基)-5-甲基-2-氧代吡咯烷-3-基)脲
在室温于氩气氛围中向中间体38(0.20g,0.48mmol)于DCE(10mL)中的冰冷悬浮液中添加DIEA(0.34mL,1.9mmol)和中间体11(73mg,0.25mmol)。随后,在50℃加热所得溶液3h。减压浓缩反应混合物,且通过反相色谱、接着手性HPLC纯化粗产物,得到呈白色固体的实施例109(0.02g,0.04mmol,8.3%产率)。
实施例112:1-(4-氯-2-氟苯基)-3-((3R,5S)-1-(2'-(二甲基磷酰基)-2,3-二氟-[1,1'-联苯]-4-基)-5-(羟基甲基)-2-氧代吡咯烷-3-基)脲
在室温于氩气氛围中向中间体22(0.11g,0.28mmol)于DMF(2mL)中的冰冷悬浮液中添加DIEA(0.15mL,0.84mmol)和中间体11(0.11g,0.42mmol)。随后,在50℃加热所得溶液3h。减压浓缩反应混合物,且通过反相色谱、接着手性HPLC纯化粗产物,得到实施例112(0.05g,0.08mmol,29%产率)。
表1中的以下实施例通过使用与上文在实施例1、25、57、73、89、91、109和112中所示相同的操作制备。
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本领域技术人员显而易知的是,本发明不限于前述说明性实施例,且其可以其他不背离本发明基本属性的具体形式实施。因此,需要从各方面将实施例视为说明性而非限制性的,参考随附权利要求书而非前述实施例,且在权利要求书等效意义或范围内出现的所有变化意欲涵盖于本发明中。
Claims (55)
1.一种式(II)化合物或其药学上可接受的盐:
其中:
Ar1为经1至2个R1a和1至2个R1b取代的苯基或具有1至3个选自氮、氧和硫的杂原子且经1至2个R1a和1至2个R1b取代的5元至7元单环杂芳基;
Ar2为经1至4个R2a取代的苯基;
Ar3为经1至4个R3a取代的苯基或具有1至3个选自氮、氧和硫的杂原子且经1至4个R3a取代的5元至7元单环杂芳基;
R1a为氢或卤素;
R1b为卤素、卤烷基、烷氧基或卤烷氧基;
R2a为氢、氰基、卤素、烷基、羟基烷基、卤烷基、环烷基、烷氧基或卤烷氧基;
R3a为氰基、卤素、烷基、烷氧基、羟基烷基、烷氧基烷基、卤烷基、(R1R2N)烷基、R1R2N、烷基C(O)(R2)N烷基、(烷基)2(O)P、(烷氧基)2(O)P、(烷氧基)(烷基)(O)P、(烷基)(O)(NR1)S、烷基SO2或烷基SO2NH;
R4a或R4b独立地为氢、烷基、烷氧基、羟基烷基、烷氧基烷基或卤烷氧基;或者,R4a和R4b与它们都连接的碳原子一起形成C3-6环烷基;
R5a或R5b独立地为氢、烷基、羟基烷基、烷氧基烷基或卤烷氧基;
R1为氢或烷基;且
R2为氢或烷基;或R1R2N一起为氮杂环丁基、噁唑基、吡咯烷基、哌啶基、哌嗪基或吗啉基,且经0至3个选自卤素、烷基和氧代的取代基取代;
“烷基”意指由1至6个碳构成的直链或支链烷基;
“环烷基”意指由3至7个碳构成的单环环系统。
2.根据权利要求1所述的化合物或其药学上可接受的盐,所述化合物具有式(III):
其中:
Ar1为经1至2个R1a和1至2个R1b取代的苯基或具有1至3个氮原子且经1个R1a和1至2个R1b取代的6元杂芳基;
Ar3为经1至3个R3a取代的苯基或具有1至3个氮原子且经1至3个R3a取代的5元至6元杂芳基;
R1a为氢或卤素;
R1b为卤素、C1-4卤烷基、C1-4烷氧基或C1-4卤烷氧基;
R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;
R3a为氰基、卤素、C1-4烷基、C1-4羟基烷基、C1-4烷氧基烷基、C1-4卤烷基、(R1R2N)C1-4烷基、R1R2N、C1-4烷基C(O)(R2)NC1-4烷基、(C1-4烷基)2(O)P、(C1-4烷氧基)2(O)P、(C1-4烷氧基)(C1-4烷基)(O)P、C1-4烷基SO2或C1-4烷基SO2NH;
R1R2N一起为噁唑基或吡咯烷基且经0至3个选自卤素、烷基和氧代的取代基取代;
R4a或R4b独立地为氢、C1-4烷基或C1-4羟基烷基;或者,R4a和R4b与它们都连接的碳原子一起形成C3-6环烷基;且
R5a或R5b独立地为氢、C1-4烷基、C1-4羟基烷基或C1-4烷氧基烷基。
3.根据权利要求2所述的化合物或其药学上可接受的盐,其中:
Ar1为经1至2个R1a和1至2个R1b取代的苯基、经1个R1a和1至2个R1b取代的吡啶基或经1个R1a和1至2个R1b取代的吡嗪基;且
Ar3为经1至3个R3a取代的苯基、经1至3个R3a取代的吡唑基、经1至3个R3a取代的吡啶基或经1至3个R3a取代的嘧啶基。
4.根据权利要求2或3所述的化合物或其药学上可接受的盐,所述化合物具有式(IV):
其中:
Ar1为经1至2个R1a和1至2个R1b取代的苯基、经1个R1a和1至2个R1b取代的吡啶基或经1个R1a和1至2个R1b取代的吡嗪基;
R1a为氢或卤素;
R1b为卤素、C1-4卤烷基、C1-4烷氧基或C1-4卤烷氧基;
R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;
R3a为氰基、卤素、C1-3烷基、C1-3羟基烷基、C1-3烷氧基烷基、C1-3卤烷基、R1R2N、(C1-3烷基)2(O)P、(C1-3烷氧基)2(O)P、(C1-3烷氧基)(C1-3烷基)(O)P、C1-3烷基SO2或C1-3烷基SO2NH;
R4a或R4b独立地为氢、C1-3烷基或C1-3羟基烷基;或者,R4a和R4b与它们都连接的碳原子一起形成C3-6环烷基;且
R5a或R5b独立地为氢、C1-3烷基、C1-3羟基烷基或C1-3烷氧基烷基。
5.根据权利要求4所述的化合物或其药学上可接受的盐,所述化合物具有式(V):
其中:
R1a为氢或F;
R1b为卤素、C1-2卤烷基或C1-2烷氧基;
R2a为氢、卤素、C1-3烷基、C1-3卤烷基或C3-6环烷基;
R3a为卤素、羟基烷基、烷氧基烷基、(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH;且
R3a'为卤素。
6.根据权利要求5所述的化合物或其药学上可接受的盐,其中:
R1a为氢或F;
R1b为F、Cl或CF3;
R2a为氢、F、Cl、异丙基、CF3或环丙基;
R3a为(CH3)2(O)P、(CH3CH2)2(O)P、(CH3CH2O)(CH3)(O)P、CH3SO2或CH3SO2NH;且
R3a'为F。
7.根据权利要求4所述的化合物或其药学上可接受的盐,所述化合物具有式(VI):
其中:
R1a为氢或卤素;
R1b为卤素、C1-2卤烷基或C1-2烷氧基;
R2a为氢、卤素、C1-3烷基或C3-6环烷基;
R3a为(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH。
8.根据权利要求2或3所述的化合物或其药学上可接受的盐,所述化合物具有式(VII):
其中:
Ar3为经1至3个R3a取代的吡唑基、经1至3个R3a取代的吡啶基或经1至3个R3a取代的嘧啶基;
R1a为氢或卤素;
R1b为卤素、C1-4卤烷基、C1-4烷氧基或C1-4卤烷氧基;
R2a为氢、卤素、C1-4烷基、C1-4羟基烷基、C1-4卤烷基、C3-6环烷基、C1-4烷氧基或C1-4卤烷氧基;
R3a为氰基、卤素、C1-4烷基、C1-4羟基烷基、C1-4烷氧基烷基、(R1R2N)C1-4烷基、R1R2N-、(C1-4烷基)2(O)P、(C1-4烷氧基)2(O)P、(C1-4烷氧基)(C1-4烷基)(O)P、C1-4烷基SO2或C1-4烷基SO2NH;
R1为氢或烷基;
R2为氢或烷基;或R1R2N一起为噁唑基或吡咯烷基且经0至3个选自卤素、烷基或氧代的取代基取代;
R4a或R4b独立地为氢、C1-4烷基、C1-4烷氧基、C1-4烷氧基烷基或C1-4卤烷氧基;R4a和R4b与它们都连接的碳原子一起形成C3-6环烷基;且
R5a或R5b独立地为氢、C1-4烷基、C1-4烷氧基、C1-4烷氧基烷基或C1-4卤烷氧基。
9.根据权利要求8所述的化合物或其药学上可接受的盐,所述化合物具有式(VIII):
其中:
R1a为氢或卤素;
R1b为卤素、C1-2卤烷基或C1-2烷氧基;
R2a为氢、卤素、C1-3烷基或C3-6环烷基;
R3a为(C1-2烷基)2(O)P、(C1-2烷氧基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P、C1-2烷基SO2或C1-2烷基SO2NH;且
R5a或R5b独立地为氢或C1-2烷基。
10.根据权利要求1所述的化合物或其药学上可接受的盐,所述化合物具有式(IX):
其中:
R1a为氢或卤素;
R1b为卤素、C1-2卤烷基或C1-2烷氧基;
R2a为氢、卤素、C1-2卤烷基、C1-3烷基或C3-6环烷基;
Ar3为
R3a为(C1-2烷基)2(O)P、(C1-2烷氧基)(C1-2烷基)(O)P或C1-2烷基SO2NH;
R3a'为卤素;
R4a或R4b独立地为氢、C1-2烷基或C1-2羟基烷基;或R4a和R4b与它们都连接的碳原子一起形成C3-6环烷基;且
R5a或R5b独立地为氢、C1-2烷基、C1-2羟基烷基或C1-2烷氧基烷基。
11.根据权利要求4所述的化合物或其药学上可接受的盐,其中:
R4a为氢;
R4b为氢;
R5a为C1-2烷基、C1-2羟基烷基或C1-2烷氧基烷基;且
R5b为氢。
12.根据权利要求4所述的化合物或其药学上可接受的盐,其中:
R4a为C1-2烷基;
R4b为C1-2烷基;
R5a为氢;且
R5b为氢。
13.一种式(I)化合物或其药学上可接受的盐:
其中:
Ar1为苯基、吡啶基或哒嗪基且经4位的1个卤素、卤烷基或卤烷氧基取代基和0至2个其他卤素或卤烷基取代基取代;
Ar2为苯基且经0至2个选自以下的取代基取代:氰基、氟、烷基、卤烷基、环烷基、烷氧基和卤烷氧基;
Ar3为苯基或吡啶基且经0至2个选自以下的取代基取代:氰基、卤素、羟基烷基、烷氧基烷基、(R1R2N)烷基、(烷基)2(O)P、(烷基)(O)(NR1)S、烷基SO2和烷基SO2NH;
R1为氢或烷基;且
R2为氢或烷基;
或(R1)(R2)N一起为氮杂环丁基、吡咯烷基、哌啶基、哌嗪基或吗啉基且经0至3个选自卤素和烷基的取代基取代;
“烷基”意指由1至6个碳构成的直链或支链烷基;
“环烷基”意指由3至7个碳构成的单环环系统。
14.根据权利要求13所述的化合物或其药学上可接受的盐,其中Ar1为经4位的1个卤素、卤烷基或卤烷氧基取代基和0至2个其他卤素或卤烷基取代基取代的苯基。
15.根据权利要求13所述的化合物或其药学上可接受的盐,其中Ar2为经0个取代基、1个烷基或环烷基取代基或1至2个氟取代基取代的苯基。
16.根据权利要求13所述的化合物或其药学上可接受的盐,其中Ar3为经1至2个选自以下的取代基取代的苯基:氰基、卤素、羟基烷基、烷氧基烷基、(R1R2N)烷基、(烷基)2(O)P、(烷基)(O)(NR1)S、烷基SO2和烷基SO2NH。
17.根据权利要求13所述的化合物或其药学上可接受的盐,其中R1为氢且R2为氢。
18.根据权利要求13所述的化合物或其药学上可接受的盐,所述化合物选自:
19.一种化合物或其药学上可接受的盐,所述化合物选自:
/>
20.一种组合物,其包含根据权利要求1至19中任一项所述的化合物或其药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
21.根据权利要求1至19中任一项所述的化合物或其药学上可接受的盐或根据权利要求20所述的组合物,其用于疗法中。
22.根据权利要求1至19中任一项所述的化合物或其药学上可接受的盐在制备用于治疗心脏病的药物中的用途。
23.根据权利要求22所述的用途,其中所述心脏病选自心绞痛和心力衰竭。
24.根据权利要求22所述的用途,其中所述心脏病选自不稳定型心绞痛、心肌梗塞、急性冠状动脉疾病、急性心力衰竭、慢性心力衰竭和心脏医源性损伤。
25.根据权利要求23所述的用途,其中所述心力衰竭选自充血性心力衰竭、收缩性心力衰竭、舒张性心力衰竭、低射血分数心力衰竭(HFREF)、射血分数保留型心力衰竭(HFPEF)、急性心力衰竭、慢性缺血性病因心力衰竭和慢性非缺血性病因心力衰竭。
26.一种化合物,其为
27.一种化合物的药学上可接受的盐,所述化合物为
28.一种组合物,其包含根据权利要求26所述的化合物和药学上可接受的载体、稀释剂或赋形剂。
29.一种组合物,其包含根据权利要求27所述的药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
30.根据权利要求26所述的化合物在制备用于治疗心力衰竭的药物中的用途。
31.根据权利要求27所述的药学上可接受的盐在制备用于治疗心力衰竭的药物中的用途。
32.一种化合物,其为
/>
33.一种化合物的药学上可接受的盐,所述化合物为
34.一种组合物,其包含根据权利要求32所述的化合物和药学上可接受的载体、稀释剂或赋形剂。
35.一种组合物,其包含根据权利要求33所述的药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
36.根据权利要求32所述的化合物在制备用于治疗心力衰竭的药物中的用途。
37.根据权利要求33所述的药学上可接受的盐在制备用于治疗心力衰竭的药物中的用途。
38.一种化合物,其为
39.一种化合物的药学上可接受的盐,所述化合物为
40.一种组合物,其包含根据权利要求38所述的化合物和药学上可接受的载体、稀释剂或赋形剂。
41.一种组合物,其包含根据权利要求39所述的药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
42.根据权利要求38所述的化合物在制备用于治疗心力衰竭的药物中的用途。
43.根据权利要求39所述的药学上可接受的盐在制备用于治疗心力衰竭的药物中的用途。
44.一种化合物,其为
45.一种化合物的药学上可接受的盐,所述化合物为
46.一种组合物,其包含根据权利要求44所述的化合物和药学上可接受的载体、稀释剂或赋形剂。
47.一种组合物,其包含根据权利要求45所述的药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
48.根据权利要求44所述的化合物在制备用于治疗心力衰竭的药物中的用途。
49.根据权利要求45所述的药学上可接受的盐在制备用于治疗心力衰竭的药物中的用途。
50.一种化合物,其为
/>
51.一种化合物的药学上可接受的盐,所述化合物为
52.一种组合物,其包含根据权利要求50所述的化合物和药学上可接受的载体、稀释剂或赋形剂。
53.一种组合物,其包含根据权利要求51所述的药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂。
54.根据权利要求50所述的化合物在制备用于治疗心力衰竭的药物中的用途。
55.根据权利要求51所述的药学上可接受的盐在制备用于治疗心力衰竭的药物中的用途。
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