CN116390913A - 氨基咪唑fpr2激动剂 - Google Patents
氨基咪唑fpr2激动剂 Download PDFInfo
- Publication number
- CN116390913A CN116390913A CN202180069081.9A CN202180069081A CN116390913A CN 116390913 A CN116390913 A CN 116390913A CN 202180069081 A CN202180069081 A CN 202180069081A CN 116390913 A CN116390913 A CN 116390913A
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- Prior art keywords
- alkyl
- hydrogen
- hydroxyalkyl
- halogen
- haloalkyl
- Prior art date
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Classifications
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
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Abstract
本公开文本涉及作为甲酰肽2(FPR2)受体激动剂和/或甲酰肽1(FPR1)受体激动剂的式(I)的化合物。本公开文本还提供了使用所述化合物的组合物和方法,例如其用于治疗动脉粥样硬化、心力衰竭、慢性阻塞性肺病(COPD)和相关疾病。
Description
相关申请的交叉引用
根据35U.S.C.§119(e),本申请有权享有2020年10月9日提交的美国临时专利申请号63/089,730的优先权,将所述美国临时专利申请以其整体并入本文。
背景技术
本发明涉及作为甲酰肽2(FPR2)受体激动剂的新型式(I)的氨基咪唑化合物,还涉及包含它们的组合物,以及使用它们例如用于治疗动脉粥样硬化、心力衰竭、慢性阻塞性肺病(COPD)和相关疾病的方法。
甲酰肽受体2(FPR2)属于七跨膜结构域G蛋白偶联受体的小组,所述G蛋白偶联受体在包括免疫细胞的多种人组织中表达并且已知在宿主防御和炎症中很重要。FPR2与FPR1和FPR3具有显著的序列同源性(Chen K等人,Journal of Autoimmunity 85,2017,64-77)。这些受体共同结合许多结构上多样的激动剂,包括充当化学引诱剂并且激活吞噬细胞的N-甲酰基肽和非甲酰基肽。内源性肽膜联蛋白A1及其N末端片段是结合人FPR1和FPR2的配体的例子。属于一类小型促消退介质(SPM)的脂肪酸(诸如类花生酸脂氧素A4)已经被报道为针对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和膜联蛋白A1)已经被报道为会触发一系列广泛的细胞质级联反应,诸如Gi偶联、Ca2+动员和β-抑制蛋白募集(Cattaneo,F等人,IntJ Mol Sci.2013April;14(4):7193-7230)。FPR2调节先天免疫系统和适应性免疫系统二者,包括嗜中性粒细胞、巨噬细胞、T细胞和B细胞。在嗜中性粒细胞中,FPR2配体调节运动、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并且增强胞葬作用。(Chandrasekharan JA,Sharma-Walia N,.J.Inflamm.Res.,2015,8,181-92)。通过FPR2激动作用消退炎症的启动负责增强抗纤维化伤口愈合和使受伤组织恢复稳态(Romano M.等人,Eur.J.Pharmacol.,2015,5,49-63)。
慢性炎症是许多人类疾病发病机理途径的一部分,并且用FPR2激动剂刺激消退途径可能具有保护作用和修复作用。局部缺血再灌注(I/R)损伤是若干种与高发病率和高死亡率相关的疾病(诸如心肌梗塞和中风)的共同特征。与局部缺血再灌注损伤引起的心肌细胞死亡和病理学重塑相关的非生产性伤口(non-productive wound)愈合会导致疤痕形成、纤维化、和心脏功能的逐步丧失。提出FPR2调节以增强损伤后的心肌伤口愈合并且减少不良的心肌重塑(Kain V.,等人,J.Mol.Cell.Cardiol.,2015,84,24-35)。此外,在中枢神经系统中,FPR2促消退激动剂可能是用于治疗多种临床I/R病症(包括脑中风)(Gavins FN.,Trends Pharmacol.Sci.,2010,31,266-76)和I/R诱导的脊髓损伤(Liu ZQ.等人,Int.J.Clin.Exp.Med.,2015,8,12826-33)的有用的治疗剂。
除了用新型促消退激动剂靶向FPR2受体来治疗I/R诱导的损伤的有益作用外,这些配体的效用也可应用于其他疾病。在心血管系统中,发现FPR2受体及其促消退激动剂均负责致动脉粥样化斑块的稳定和愈合(Petri MH.等人,Cardiovasc.Res.,2015,105,65-74;和Fredman G.等人,Sci.Trans.Med.,2015,7(275);275ra20)。在慢性炎症人类疾病的临床前模型中,FPR2激动剂也已经被显示为有益的,所述慢性炎症人类疾病包括:感染性疾病、银屑病、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、类风湿性关节炎和其他关节疾病、阿尔茨海默病、肾脏纤维化、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
本发明包括作为甲酰肽2(FPR2)受体激动剂的式(I)的化合物,包含它们的组合物,以及使用它们例如用于治疗动脉粥样硬化、心力衰竭、慢性阻塞性肺病(COPD)和相关疾病的方法。
本发明的一个方面是一种式(I)的化合物:
其中
R1是烷基、卤代烷基、羟烷基、烷氧基烷基、(烷氧基羰基)烷基、烷氧基羰基、(NR6R7)羰基、Ar1或(Ar1)烷基;
Ar1是环烷基,芳基,包含碳原子和1-5个选自N、NR5a、O和S的杂原子的杂芳基,包含碳原子和1-5个选自N、NR5a、O和S的杂原子的杂环基,或包含碳原子和1-5个选自N、NR5a、O和S的杂原子的螺杂环基,其各自被1-5个R5取代;
R2是氢、烷基或卤代烷基;
R3是被1个R3a和1-2个R3b取代的苯基或吡啶基;
R3a是卤素、卤代烷基、烷氧基或卤代烷氧基;
R3b是氢、卤素或卤代烷基;
R4是被1-2个R4a取代的苯基或吡啶基;
R4a是卤素、卤代烷基、烷氧基或卤代烷氧基;
R5是氢、羟基、氰基、卤素、烷基、卤代烷基、氨基、卤代烷基氨基、烷氧基烷基、羟烷基、烷氧基、卤代烷氧基、甲酰胺、烷氧基羰基、烷基磺酰基氨基或羟烷基羰基;
R5a是氢、烷基、卤代烷基、烷氧基烷基、羟烷基、氢烷基羰基、甲酰胺、烷基氨基羰基、氨基羰基烷基羰基、烷基磺酰基或烷氧基羰基;
R6和R7独立地是氢,烷基,卤代烷基,羟烷基,环烷基,芳基,包含碳原子和1-4个选自N、NR8a、O和S的杂原子的杂芳基,包含碳原子和1-4个选自N、NR8a、O和S的杂原子的杂环基,芳烷基,或包含碳原子和1-4个选自N、NR8a、O和S的杂原子的杂芳烷基;其中所述环烷基、芳基、杂芳基或杂环基被1-5个R8取代;
或者R6和R7与它们所连接的氮一起形成包含碳原子和0-3个选自N、NR8a、O、S的另外的杂原子的杂环基或杂芳基,其中所述杂芳基或杂环基被1-5个R8取代;
R8是氢、卤素、羟基、羟烷基、烷基、烷氧基或氧代;
R8a是氢、羟烷基或烷基;
或其药学上可接受的盐。
本发明的另一个方面是一种式(I)的化合物,其中
R3是被1个R3a和1-2个R3b取代的苯基;
R3a是相对于咪唑部分在对位的卤素、卤代烷基或烷氧基取代基;
R3b是氢、卤素或卤代烷基;以及
其他变量如式(I)中所定义。
本发明的另一个方面是一种式(I)的化合物,其中
R4是在相对于酰胺部分的对位被1个R4a取代的苯基;
R4a是卤素、烷氧基或卤代烷氧基;以及
其他变量如式(I)中所定义。
本发明的另一个方面是一种式(II)的化合物:
其中
R1是烷基、卤代烷基、羟烷基、烷氧基烷基、(烷氧基羰基)烷基、烷氧基羰基、(NR6R7)羰基、Ar1或(Ar1)烷基;
Ar1是环烷基,芳基,包含碳原子和1-4个选自N、NR5a、O和S的杂原子的杂芳基,包含碳原子和1-4个选自N、NR5a、O和S的杂原子的杂环基,包含碳原子和1-4个选自N、NR5a、O和S的杂原子的螺杂环基,其各自被1-4个R5取代;
R3a是烷氧基;
R3b是氢、卤素或卤代烷基;
R4a是卤素或卤代烷氧基;
R5是氢、羟基、氰基、卤素、烷基、卤代烷基、氨基、卤代烷基氨基、烷氧基烷基、羟烷基、烷氧基、卤代烷氧基、烷氧基羰基或烷基磺酰基氨基;
R5a是氢、烷基、卤代烷基、烷氧基烷基、羟烷基、氢烷基羰基、甲酰胺、烷基氨基羰基、氨基羰基烷基羰基、烷基磺酰基或烷氧基羰基;
R6和R7独立地是氢,烷基,卤代烷基,羟烷基,环烷基,包含碳原子和1-4个选自N、NR8a、O和S的杂原子的杂芳基,芳烷基,或包含碳原子和1-4个选自N、NR8a、O和S的杂原子的杂芳烷基,其中所述环烷基、杂芳基或杂芳烷基被1-4个R8取代;
或者R6和R7与它们所连接的氮一起形成具有0-3个选自N、NR8a、O、S的另外的杂原子的杂环基或杂芳基,其中所述杂环基或杂芳基被1-4个R8取代;
R8是氢、卤素、羟基、羟烷基、烷基、烷氧基或氧代;
R8a是氢、羟烷基或烷基;
或其药学上可接受的盐。
本发明的另一个方面是一种式(II)的化合物,其中
R1是被1-3个R5取代的Ar1;
Ar1是环烷基,芳基,包含碳原子和1-3个选自N、NR5a、O和S的杂原子的杂芳基,包含碳原子和1-3个选自N、NR5a、O和S的杂原子的杂环基,包含碳原子和1-3个选自N、NR5a、O和S的杂原子的螺杂环基,各自被1-3个R5取代;
R3a是烷氧基;
R3b是氢或卤素;
R4a是卤代烷氧基;
R5是氢、羟基、氰基、卤素、烷基、卤代烷基、氨基、卤代烷基氨基、烷氧基烷基、羟烷基、氢烷基羰基、烷氧基、卤代烷氧基、烷氧基羰基或烷基磺酰基氨基;以及
R5a是氢、烷基、卤代烷基、烷氧基烷基、羟烷基、烷基氨基羰基、氨基羰基烷基羰基、烷基磺酰基或烷氧基羰基。
本发明的另一个方面是一种式(II)的化合物,其中
R3a是烷氧基;
R3b是氢或卤素;
R4a是卤代烷氧基;以及
R5是氢、氰基、卤素、烷基、卤代烷基、烷氧基烷基、羟烷基、烷氧基或卤代烷氧基。
本发明的另一个方面是一种式(II)的化合物,其中
R3a是烷氧基;
R3b是氢或卤素;
R4a是卤代烷氧基;
R5是氢、卤素、烷基、卤代烷基、烷氧基烷基、羟烷基、烷基、烷氧羰基或卤代烷氧基。
本发明的另一个方面是一种式(II)的化合物,其中
R3a是烷氧基;
R3b是氢或卤素;
R4a是卤代烷氧基;
R5是氢、烷基或羟烷基;以及
R5a是氢、烷基、氢烷基羰基、烷基氨基羰基、氨基羰基烷基羰基、烷基磺酰基或烷氧基羰基。
本发明的另一个方面是一种式(II)的化合物,其中
R3a是烷氧基;
R3b是氢或卤素;
R4a是卤代烷氧基;
R5是氢、羟基、羟烷基、氨基、卤代烷基氨基或烷基磺酰基氨基。
本发明的另一个方面是一种式(II)的化合物,其中
R1是(Ar1)烷基;
R3a是烷氧基;
R3b是氢或卤素;以及
R4a是卤代烷氧基。
本发明的另一个方面是一种式(II)的化合物,其中
R3a是烷氧基;
R3b是氢或卤素;
R4a是卤代烷氧基;
R5是氢、氰基、卤素、烷基、卤代烷基、烷氧基烷基、羟烷基、烷氧基或卤代烷氧基;以及
R5a是氢或烷基。
本发明的另一个方面是一种式(II)的化合物,其中
R1是烷基或卤代烷基;
R3a是烷氧基;
R3b是氢或卤素;以及
R4a是卤代烷氧基。
本发明的另一个方面是一种式(II)的化合物,其中
R1是烷氧基羰基或(烷氧基羰基)烷基;
R3a是烷氧基;
R3b是氢或卤素;以及
R4a是卤代烷氧基。
本发明的另一个方面是一种式(II)的化合物,其中
R1是(NR6R7)羰基;
R3a是烷氧基;
R3b是氢或卤素;
R4a是卤代烷氧基;
R6和R7独立地是氢,烷基,卤代烷基,羟烷基,环烷基,含有碳原子和1-3个选自N、NR8a、O和S的杂原子的杂芳基,含有碳原子和1-3个选自N、NR8a、O和S的杂原子的杂芳基,或含有碳原子和1-3个选自N、NR8a、O和S的杂原子的杂芳基烷基,其中所述环烷基、杂芳基和杂芳基烷基被1-3个R8取代;
或者R6和R7与它们所连接的氮一起形成
R8是氢、卤素·、羟基、羟烷基、、烷基、烷氧基或氧代;
R8a是氢、羟烷基或烷基。
本发明的另一个方面是一种式(II)的化合物,其中
R1是(NR6R7)羰基;
R3a是烷氧基;
R3b是氢或卤素;
R4a是卤代烷氧基;
R6为氢;
R8是氢、卤素、羟基、羟烷基、烷基或烷氧基。
对于式(I)或(II)的化合物,包括R1、R2、R3、R4和Ar1的可变取代基的任何实例的范围可以与可变取代基的任何其他实例的范围独立使用。这样,本发明包括不同方面的组合。
除非另有说明,这些术语具有下列含义。
“卤素”是指氟、氯、溴和碘。
“羟基”是指-OH。
“氧代”是指=O。
“羰基”是指-C=O基团。
“烷基”是指由1至7个碳构成的直链或支链烷基,例如甲基、乙基、正丙基、异丙基、w-丁基、异丁基、f-丁基、戊基、己基、庚基等。
“卤代烷基”和“卤代烷氧基”是指卤素取代的烷基或烷氧基。卤代烷基或卤代烷氧基包括单取代的以及多个卤素取代的烷基或烷氧基,直至全卤代的烷基或烷氧基。
“羟烷基”是指至少一个氢原子被羟基取代的烷基。
“烷氧基烷基”是指至少一个氢原子被上述烷氧基取代的烷基。
“烷基磺酰基”是指-SO2烷基,其中烷基如本文所定义。
“烷基磺酰基氨基”是指-NHSO2烷基,其中烷基如本文所定义。
“胺”是指式-NRR'的基团,其中R和R’可以独立地是氢或上述烷基、芳基、芳烷基、环烷基或卤代烷基。
“环烷基”是指包含约3至约10个环碳原子的非芳香族单环或多环体系。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。多环环烷基的非限制性实例包括1-十氢化萘基(1-decalinyl)、降冰片基和金刚烷基。
“芳基”是指具有6至12个碳原子的单环或双环芳族烃基,或者其中一个或两个环为芳环的双环稠合环体系。
“杂芳基”是指具有1-5个独立地选自氮、氧和硫的杂原子的5至7元单环或8至11元双环芳族环体系。在未指定键合附接位置时,键合可在本领域技术人员理解的任何适当位置处附接。
“杂环基”、“杂环”或“杂环的”是指非芳香族单环结构,其中环中的一个或多个原子,即杂原子,是除碳以外的元素。杂原子通常是O、S或N原子。杂环基的实例包括:哌啶、哌嗪、吗啉、吡咯烷、四氢呋喃、氮杂环丁烷、环氧乙烷或氮丙啶等。
“螺杂环基”是指其中至少一个环是杂环的螺环(例如,至少一个环是氮丙啶基、氮杂环丁烷基、呋喃基、吗啉基或哌啶基(piperadinyl))。
取代基和键合方式的组合仅仅为产生本领域技术人员所理解的稳定化合物的那些组合。加括号和多重括号的术语旨在向本领域技术人员阐明键合关系。例如,术语例如((R)烷基)是指进一步被取代基R取代的烷基取代基。
其中R3a在相对于咪唑的对位取代的化合物的一些实例如下所示。
其中R4a相对于酰胺部分在对位被取代的化合物的一些实例如下所示。
本发明包括化合物的所有药学上可接受的盐形式。药学上可接受的盐是其中抗衡离子对所述化合物的生理学活性或毒性没有显著贡献并且因此起药理学等价物作用的盐。这些盐可以使用市售可得的试剂根据常见有机技术制备。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、葡糖醛酸盐、氢溴酸盐、氢氯酸盐、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、甲苯磺酸盐以及昔萘酸盐(xinofoate)。一些阳离子盐形式包括铵、铝、苄星(benzathine)、铋、钙、胆碱、二乙胺、二乙醇胺、锂、镁、葡甲胺、4-苯基环己胺、哌嗪、钾、钠、氨丁三醇和锌。
一些本发明的化合物以立体异构形式存在,包括以下具有所指示的碳的结构。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在本领域是己知的。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。
本发明旨在包括出现在化合物中的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。通过一般举例且没有限制,氢的同位素包括氘和氚。碳的同位素包括11C、13C和14C。本发明的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术,或通过与本文所述那些类似的方法,使用适当同位素标记的试剂代替原本采用的未标记的试剂来制备。此类化合物可具有多种潜在用途,例如作为确定生物活性的标准物和试剂。在稳定同位素的情况下,此类化合物可具有有利地改变生物学、药理学或药代动力学性质的潜力。
生物学方法
N-甲酰肽受体(FPR)是化学引诱剂受体家族,其促进炎症过程中的白细胞反应。FPR属于七跨膜G蛋白偶联受体超家族,并且与抑制性G蛋白(Gi)相关。已经在人类中鉴定出三个家族成员(FPR1、FPR2和FPR3),并且主要以不同的分布存在于骨髓细胞中,并且也已经报道在多个器官和组织中。激动剂结合后,FPR激活多种生理途径,诸如细胞内信号传导转导、Ca2+动员和转录。所述家族与一组多样的配体相互作用,所述配体包括激活促炎症和促消退下游反应的蛋白质、多肽和脂肪酸代谢物。FPR2和FPR1环腺苷一磷酸(cAMP)测定用于测量本专利中化合物的活性。
FPR2和FPR1环腺苷一磷酸(cAMP)测定。将毛喉素(对于FPR2为最终5μM或对于FPR1为最终10μM)和IBMX(最终200μM)的混合物添加到预先用在DMSO中的测试化合物(最终1%)以在0.020nM至100μM范围内的最终浓度点样的384孔Proxiplate(Perkin-Elmer)中。在补充有10%合格FBS、250μg/ml博莱霉素和300μg/ml潮霉素(Life Technologies)的F-12(Ham’s)培养基中培养过表达人FPR1或人FPR2受体的中国仓鼠卵巢细胞(CHO)。通过在补充有0.1% BSA(Perkin-Elmer)的达尔伯克PBS(Dulbecco’s PBS)(含钙和镁)(LifeTechnologies)中添加2,000个人FPR2细胞/孔或4,000个人FPR1细胞/孔来开始反应。将反应混合物在室温孵育30min。根据制造商的说明,使用HTRF HiRange cAMP测定试剂盒(Cisbio)确定细胞内cAMP的水平。分别在提供的裂解缓冲液中制备缀合穴状物的抗cAMP和d2荧光团标记的cAMP的溶液。反应完成后,将细胞用等体积的d2-cAMP溶液和抗cAMP溶液裂解。室温孵育1h后,使用Envision(Perkin-Elmer)在400nm激发下以及在590nm和665nm处的双重发射下测量时间分辨的荧光强度。用浓度在从1μM至0.1pM范围内的外部cAMP标准品通过绘制从665nm发射的荧光强度与从590nm发射的荧光强度比率与cAMP浓度的关系曲线来构建校准曲线。然后通过从cAMP水平与化合物浓度的关系图拟合4参数逻辑斯谛方程来确定化合物抑制cAMP产生的效力和活性。
以下公开的实施例在上述FPR2和FPR1 cAMP测定中进行测试,并且发现具有FPR2和/或FPR1激动剂活性。下表1列出了针对以下实施例测量的在FPR2和FPR1 cAMP测定中的EC50值。
表1
药物组合物和使用方法
本发明的化合物可以施用于哺乳动物(优选人)以治疗与FPR2受体相关的多种病症和障碍,诸如白塞氏病(Behcet’s disease)、斯威特病(Sweet disease)、系统性红斑狼疮(SLE)、韦格纳肉芽肿病、病毒感染、糖尿病、截肢、癌症、细菌感染、身体外伤、物理障碍(包括暴露于辐射)、血管收缩、过敏(anaphylactic)反应、过敏性(allergic)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、银屑病、良性前列腺增生、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、艾滋病、葡萄膜炎并发青光眼、结膜炎、干燥综合征(Sjoegren’ssyndrome)、鼻炎、动脉粥样硬化、神经炎性疾病包括(多发性硬化症)、中风、脓毒症等。
除非另有说明,否则以下术语具有所叙述的含义。术语“受试者”是指可以从用如本领域从业者所理解的FPR2和/或FPR1激动剂的治疗中潜在受益的任何人或其他哺乳动物物种。一些受试者包括具有心血管疾病风险因素的任何年龄的人类。常见风险因素包括年龄、性别、体重、家族史、睡眠呼吸暂停、饮酒或吸烟、缺乏运动性心律不齐、或胰岛素抵抗迹象,诸如黑棘皮病、高血压、血脂异常、或多囊卵巢综合征(PCOS)。术语“患者”意指如由本领域从业者确定的适合于疗法的人。“治疗”(Treating或treatment)包括如本领域从业者所理解的对患者或受试者的治疗。“预防”(Preventing或prevention)包括对患者或受试者的亚临床疾病-状态的预防性治疗(即,预防和/或降低风险),目的在于降低如本领域从业者所理解的临床疾病-状态发生的可能性。基于已知与普通群体相比增加患上临床疾病状态的风险的因素,选择患者进行预防性疗法。“治疗有效量”意指如本领域从业者所理解的有效的化合物的量。
本发明的另一方面是药物组合物,所述药物组合物包含治疗有效量的式(I)-(II)的化合物与药物载体的组合。
本发明的另一方面是药物组合物,所述药物组合物包含治疗有效量的式(I)-(II)的化合物与至少一种其他治疗剂和药物载体的组合。
“药物组合物”意指包含本发明化合物与至少一种另外的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”是指本领域中普遍接受的用于向动物(特别是哺乳动物)递送生物活性剂的介质,包括即佐剂、赋形剂或媒介物,诸如稀释剂、防腐剂、填充剂、流量调节剂、崩解剂、润湿剂、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,取决于施用方式和剂型的性质。
药学上可接受的载体根据本领域普通技术人员认知范围内的许多因素来配制。这些包括但不限于所配制的活性剂的类型和性质;待施用含有所述药剂的组合物的受试者;所述组合物的预期施用途径;以及目标治疗适应症。药学上可接受的载体包括水性和非水性液体介质两者、以及各种固体和半固体剂型。此类载体可以包括除活性剂之外的许多不同的成分和添加剂,此类另外的成分出于本领域普通技术人员熟知的多种原因(例如,活性剂、粘结剂等的稳定化)被包含在配制品中。合适的药学上可接受的载体以及其选择中涉及的因素的描述可在多种可易获得的来源例如像Allen,L.V.,Jr.等人,Remington:TheScience and Practice of Pharmacy(2Volumes),第22版,Pharmaceutical Press(2012)中找到。
特别是当作为单一剂量单位提供时,组合的活性成分之间存在化学相互作用的可能性。出于这种原因,当将本发明的化合物和第二治疗剂以单一剂量单位组合时,将它们配制成使得尽管活性成分以单一剂量单位组合,但是活性成分之间的物理接触是最小化的(也就是说,减少的)。例如,一种活性成分可以是肠溶包衣的。通过对活性成分之一进行肠溶包衣,不仅可以使组合的活性成分之间的接触最小化,而且还可以控制这些组分之一在胃肠道中的释放,使得这些组分之一不在胃中释放,而是在肠道中释放。也可以将活性成分之一用一种材料包衣,所述材料在整个胃肠道中影响持续释放并且还用于使组合的活性成分之间的物理接触最小化。此外,可以将持续释放的组分另外进行肠溶包衣,使得此组分的释放仅在肠道中发生。再另一种方法涉及配制组合产品,其中将一种组分用持续释放和/或肠溶释放聚合物包衣,并且也将另一种组分用聚合物(诸如低粘度级羟丙基甲基纤维素(HPMC))或如本领域中已知的其他适当材料包衣,以进一步将活性组分分开。聚合物包衣用于形成针对与另一种组分相互作用的另外的屏障。
本发明的另一方面是一种用于治疗心脏病的方法,所述方法包括将治疗有效量的式(I)-(II)的化合物施用于患者。
本发明的另一方面是一种用于治疗心脏病的方法,其中所述心脏病选自心绞痛、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。
应当理解,心力衰竭的治疗或预防也可以涉及心血管事件的治疗或预防。如本文所指的治疗或预防可以指治疗或预防与心血管事件相关或由心血管事件引起的某些阴性症状或病症。举例来说,治疗或预防可以涉及减少或预防与心血管事件相关或由心血管事件引起的短轴缩短率、心脏重量、肺重量、肌细胞横截面积、压力超负荷诱导的心脏纤维化、应激诱导的细胞衰老和/或心脏肥大特性或其任何组合的负面变化。可以施用治疗以准备或响应于心血管事件以减轻负面影响。预防可以涉及主动或预防类型的治疗,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,本发明提供了式(I)-(II)的化合物或其药学上可接受的盐在制备用于治疗或预防心力衰竭的药物组合物中的用途,例如,心力衰竭是由以下引起的: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、甲状腺疾病、病毒感染、牙龈炎、药物滥用、酗酒、心包炎、动脉粥样硬化、血管疾病、肥厚型心肌病、扩张型心肌病、心肌梗塞、心房纤维化、左心室收缩功能不全、左心室舒张功能不全、冠状动脉搭桥手术、起搏器植入手术、饥饿、进食障碍、肌营养不良和遗传缺陷。优选地,待治疗的心力衰竭是舒张性心力衰竭、射血分数降低的心力衰竭(HFREF)、射血分数保留的心力衰竭(HFPEF)、急性心力衰竭、和缺血性和非缺血性起源的慢性心力衰竭。
在一个实施方案中,本发明提供了式(I)-(II)的化合物治疗收缩和/或舒张功能不全的用途,其中所述化合物以治疗有效量施用以增加心肌细胞收缩和放松的能力,从而增加右心室和左心室(优选左心室)的充盈和排空。
在另一个实施方案中,本发明提供了式(I)-(II)的化合物治疗心力衰竭的用途,其中所述化合物以治疗有效量施用以增加左心室中的射血分数。
在仍另一个实施方案中,本发明提供了式(I)-(II)的化合物治疗心力衰竭的用途,其中所述化合物以治疗有效量施用以减少心脏组织中的纤维化。
本发明的另一方面是一种用于治疗心脏病的方法,其中所述治疗是在心肌梗塞后进行的。
本发明的另一方面是一种用于治疗心脏病的方法,所述方法包括将治疗有效量的式(I)-(II)的化合物与其他治疗剂联合施用于患者。
可以通过任何以下合适的方式施用本发明的化合物:例如口服,诸如片剂、胶囊剂(其中的每一种包括持续释放或定时释放配制品)、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥分散体)、糖浆剂、和乳剂;舌下地;经颊地;肠胃外地,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,作为无菌可注射水性或非水性溶液或悬浮液);鼻内地,包括施用至鼻膜,诸如通过吸入喷雾;局部地,诸如以乳膏或软膏的形式;或直肠地,诸如以栓剂的形式。它们可以单独施用,但是通常将与基于所选择的施用途径和标准药学实践而选择的药物载体一起施用。
当然,本发明的化合物的给药方案将根据已知因素(诸如特定药剂的药效学特征及其施用方式和途径;接受者的物种、年龄、性别、健康、医疗状况和体重;症状的性质和程度;同时治疗的种类;治疗频率;施用途径、患者的肾和肝功能和所希望的效果)而变化。
作为一般指导,当用于所指示的作用时,每种活性成分的每日口服剂量的范围将在约0.01至约5000mg/天之间、优选在约0.1至约1000mg/天之间、并且最优选在约0.1至约250mg/天之间。静脉内地,在恒定速率输注期间,最优选的剂量的范围将为从约0.01至约10mg/kg/分钟。可以将本发明的化合物以单一日剂量施用,或者可以将每日总剂量以每日两次、三次或四次的分剂量施用。
适用于施用的剂型(药物组合物)可以含有从约1毫克至约2000毫克活性成分/剂量单位。在这些药物组合物中,活性成分将通常以基于组合物的总重量按重量计约0.1%-95%的量存在。用于口服施用的典型胶囊含有至少一种本发明的化合物(250mg)、乳糖(75mg)和硬脂酸镁(15mg)。使混合物通过60目筛并且装入1号明胶胶囊中。通过将至少一种本发明的化合物(250mg)无菌放入小瓶中、无菌冷冻干燥和密封来生产典型的可注射制剂。使用时,将小瓶中的内容物与2mL生理盐水混合以产生可注射制剂。
本发明的化合物可以与可用于治疗上述疾病或障碍的其他合适治疗剂组合使用,所述其他合适治疗剂包括:抗动脉粥样硬化药剂、抗血脂异常药剂、抗糖尿病药剂、抗高血糖药剂、抗高胰岛素血症药剂、抗血栓形成药剂、抗视网膜病变药剂、抗神经病药剂、抗肾病药剂、抗局部缺血药剂、抗高血压药剂、抗肥胖症药剂、抗血脂过多药剂、抗高甘油三酯血症药剂、抗高胆固醇血药剂、抗再狭窄药剂、抗胰腺药剂、降血脂药剂、厌食药剂、记忆增强药剂、抗痴呆药剂、认知促进药剂、食欲抑制剂、用于治疗心力衰竭的药剂、用于治疗外周动脉疾病的药剂、用于治疗恶性肿瘤的药剂、以及抗炎症药剂。
本发明的化合物可以与以下至少一种心力衰竭药剂一起使用,所述心力衰竭药剂选自髓袢利尿剂、血管紧张素转化酶(ACE)抑制剂、血管紧张素II受体阻滞剂(ARB)、血管紧张素受体-脑啡肽酶抑制剂(ARNI)、β受体阻滞剂、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。这些药剂包括但不限于呋塞米、布美他尼、托拉塞米、沙库必曲-缬沙坦(sacubitrial-valsartan)、噻嗪类利尿剂、卡托普利、依那普利、赖诺普利、卡维地洛、美托洛尔、比索洛尔、serelaxin、螺旋内酯甾酮、依普利酮、伊伐布雷定、坎地沙坦、依普沙坦、irbestarain、氯沙坦、奥美沙坦、替米沙坦、和缬沙坦。
可以在治疗动脉粥样硬化中将本发明的化合物与以下治疗剂中的至少一种组合使用:抗高脂血药剂、血浆HDL升高药剂、抗高胆固醇药剂、胆固醇生物合成抑制剂(诸如HMGCoA还原酶抑制剂)、LXR激动剂、普罗布考、雷洛昔芬、烟酸、烟酰胺、胆固醇吸收抑制剂、胆汁酸螯合剂(诸如阴离子交换树脂、或季胺(例如,消胆胺或考来替泊))、低密度脂蛋白受体诱导剂、氯贝特、非诺贝特、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、抗糖尿病药剂、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、纤维蛋白原受体拮抗剂、阿司匹林和纤维酸衍生物。
可以在治疗中将本发明的化合物与以下治疗剂中的至少一种组合使用:胆固醇生物合成抑制剂,特别是HMG-CoA还原酶抑制剂。合适的HMG-CoA还原酶抑制剂的例子包括但不限于洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、和罗舒伐他汀。
可以将本发明的化合物与以下抗糖尿病药剂中的至少一种组合使用,取决于所希望的目标疗法。研究表明,通过向治疗方案中添加第二药剂可以进一步改善糖尿病和高脂血症调节。抗糖尿病药剂的例子包括但不限于磺酰脲类药物(诸如氯磺丙脲、甲苯磺丁脲、乙酰苯磺酰环己脲、甲磺吖庚脲、格列本脲(glyburide)、格列齐特、格列本脲(glynase)、格列美脲、和格列吡嗪)、双胍类药物(诸如二甲双胍)、噻唑烷二酮类(诸如环格列酮、吡格列酮、曲格列酮、和罗格列酮)、和相关的胰岛素增敏剂(诸如PPARα、PPARβ和PPARγ的选择性和非选择性激活剂);脱氢表雄酮(也称为DHEA或其缀合的硫酸酯,DHEA-SO4);抗糖皮质激素类;TNFα抑制剂;二肽基肽酶IV(DPP4)抑制剂(诸如西他列汀、沙格列汀)、GLP-1激动剂或类似物(诸如艾塞那肽)、α-葡萄糖苷酶抑制剂(诸如阿卡波糖、米格列醇、和伏格列波糖)、普兰林肽(人类激素胰淀肽的合成类似物)、其他胰岛素促泌剂(诸如瑞格列奈、格列喹酮、和那格列奈)、胰岛素以及用于治疗动脉粥样硬化的上述治疗剂。
可以将本发明的化合物与选自以下的至少一种抗肥胖症药剂组合使用:苯丙醇胺、苯丁胺、安非拉酮、马吲哚、苯氟拉明、右芬氟拉明、非尼拉敏(phentiramine)、β3-肾上腺素能受体激动剂;西布曲明、胃肠脂肪酶抑制剂(诸如奥利司他)和瘦蛋白。用于治疗肥胖症或肥胖症相关的障碍的其他药剂包括神经肽Y、肠抑素、胆囊收缩素、铃蟾肽、胰淀素、组胺H3受体、多巴胺D2受体调节剂、黑素细胞刺激激素、促肾上腺皮质激素释放因子、甘丙肽和γ氨基丁酸(GABA)。
本发明的化合物在涉及FPR2的测试或测定中也可用作标准或参比化合物,例如作为质量标准或对照。可以将此类化合物以商业试剂盒提供,例如用于在涉及FPR2活性的药物研究中使用。例如,可以将本发明的化合物在测定中用作参比,以将其已知活性与具有未知活性的化合物进行比较。这将确保实验者正确地进行测定,并提供比较基础,特别是如果测试化合物是参比化合物的衍生物。当开发新的测定或方案时,可以使用根据本发明的化合物来测试它们的有效性。本发明的化合物也可以用于涉及FPR2的诊断测定。
本发明还涵盖一种制品。如本文所用,所述制品旨在包括但不限于试剂盒和包装。本发明的制品包含:(a)第一容器;(b)位于第一容器内的药物组合物,其中所述组合物包含:第一治疗剂,其包含本发明的化合物或其药学上可接受的盐形式;以及(c)包装说明书,其说明所述药物组合物可以用于治疗血脂异常及其后遗症。在另一个实施方案中,所述包装说明书说明所述药物组合物可以与用于治疗血脂异常及其后遗症的第二治疗剂组合(如先前所定义的)使用。所述制品还可以包含:(d)第二容器,其中组分(a)和(b)位于第二容器内,并且组分(c)位于第二容器内或外。位于第一容器和第二容器内意指相应的容器将物品保持在其边界内。第一容器是用于保持药物组合物的接收容器。此容器可以用于制造、储存、运输和/或单独/批量销售。第一容器旨在涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如,用于乳膏制剂),或用于制造、保持、储存或分配药物产品的任何其他容器。第二容器是用于保持第一容器和任选地包装说明书的容器。第二容器的例子包括但不限于盒(例如,纸板或塑料)、板条箱、纸箱、袋(例如,纸或塑料袋)、小袋和包。所述包装说明书可以通过胶带、胶水、订书钉或其他附接方法物理地附接到第一容器的外侧,或者它可以静置在第二容器内侧而无需与第一容器附接的任何物理装置。可替代地,所述包装说明书位于第二容器的外侧。当位于第二容器外侧时,优选的是,所述包装说明书通过胶带、胶水、订书钉或其他附接方法物理地附接。可替代地,它可以与第二容器外侧相邻或接触,而不是物理附接。所述包装说明书是标签(label)、签条(tag)、标记(marker)等,其列举了与位于第一容器内的药物组合物有关的信息。所列举的信息将通常由管理其中销售制品的地区的管理机构(例如,UnitedStates Food and Drug Administration)来确定。优选地,所述包装说明书具体列举了已被批准药物组合物所针对的适应症。所述包装说明书可以由人可以阅读其中或其上所含信息的任何材料制成。优选地,所述包装说明书是可印刷材料(例如,纸、塑料、硬纸板、箔、背胶纸或塑料等),在其上已形成(例如,印刷或施加)所希望的信息。
化学方法
将如本文所用的缩写定义如下:“1x”表示一次,“2x”表示两次,“3x”表示三次,“℃”表示摄氏度,“aq”表示水性,“Col”表示柱,“eq”表示一个或多个当量,“g”表示克,“mg”表示毫克,“L”表示升,“mL”表示毫升,“μL”表示微升,“N”表示当量浓度,“M”表示摩尔,“nM”表示纳摩尔,“mol”表示摩尔,“mmol”表示毫摩尔,“min”表示分钟,“h”表示小时,“rt”表示室温,“ON”表示过夜,“atm”表示大气压,“psi”表示磅/平方英寸,“conc.”表示浓缩的,“aq”表示“水性”,“sat”或“sat'd”表示饱和的,“MW”表示分子量,“mw”或“μ波”表示微波,“mp”表示熔点,“Wt”表示重量,“MS”或“Mass Spec”表示质谱,“ESI”表示电喷雾电离质谱,“HR”表示高分辨率,“HRMS”表示高分辨率质谱,“LCMS”表示液相色谱质谱,“HPLC”表示高压液相色谱,“RP HPLC”表示反相HPLC,“TLC”或“tlc”表示薄层色谱,“NMR”表示核磁共振光谱,“nOe”表示核欧弗豪塞(Overhauser)效应光谱,“1H”表示质子,“δ”表示德尔塔,“s”代表单峰,“d”表示二重峰,“t”表示三重峰,“q”表示四重峰,“m”表示多重峰,“br”表示宽峰,“Hz”表示赫兹,并且“α”、“β”、“R”、“S”、“E”和“Z”是本领域技术人员熟悉的立体化学名称。
缩写:
AcOH或HOAc 乙酸
ACN 乙腈
ADDP 1,1'-(偶氮二羰基)二哌啶
BOP (苯并三唑-1-基氧基)三(二甲氨基)鏻六氟磷酸盐
CDCl3 氘代氯仿
CD3OD 氘代甲醇
CDI 1,1′-羰基二咪唑
conc 浓缩的
DCM 二氯甲烷
DIEA或DIPEA 二异丙基乙胺
DMF 二甲基甲酰胺
DMSO 二甲亚砜
DMSO-d6 氘代-二甲亚砜
Et3N或TEA 三乙胺
EtOAc 乙酸乙酯
EtOH 乙醇
HATU 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐
HCl 盐酸
HPLC 高效液相色谱法
K2HPO4 磷酸氢钾
LCMS 液相色谱质谱法
MeOH 甲醇
MgSO4 硫酸镁
NMP N-甲基-2-吡咯烷酮
NaCl 氯化钠
Na2CO3 碳酸钠
NaHCO3 碳酸氢钠
NaOH 氢氧化钠
Na2SO4 硫酸钠
NH4Cl 氯化铵
NH4OAc 乙酸铵
Pd(OAc)2 乙酸钯(II)
Pd(PPh3)4 四(三苯基膦)钯(0)
Rt 保留时间
SiO2 二氧化硅
SOCl2 亚硫酰氯
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
可以根据有机合成领域技术人员已知的多种方法制备本发明的化合物。可以使用下面所述的方法以及合成有机化学领域已知的合成方法或者通过本领域技术人员所理解的其变型来合成本发明的化合物。优选的方法包括(但不限于)下面所述的那些方法。在适合所使用的试剂和原料并适合进行转化的溶剂中进行反应。有机合成领域的技术人员可以理解分子上存在的官能度应与提出的转化一致。这有时需要判断以修改合成步骤的顺序或选择一种特定的工艺方案而不是另一种,以获得所需的本发明化合物。
本发明的新型化合物可使用本部分所述的反应和技术制备。而且,在下面所述的合成方法的描述中,应当理解,所有建议的反应条件,包括溶剂的选择、反应气氛、反应温度、实验持续时间和后处理程序,都被选择为该反应的标准条件,这是本领域技术人员应当容易认识到的。对与反应条件相容的取代基的限制对于本领域技术人员来说将是明显的,而且然后必须使用替代方法。
合成
式(I)的化合物(其中R1、R2、R3和R4定义如下)可通过以下方案和工作实施例中描述的示例性方法以及本领域技术人员使用的相关公开文献程序制备。用于这些反应的示例性试剂和程序出现在下文和工作实施例中。以下方法中的保护和脱保护可通过本领域公知的程序进行(参见,例如,Wuts,P.G.M.等人,Protecting Groups in Organic Synthesis,第4版,Wiley(2007))。有机合成和官能团转化的一般方法见:Trost,B.M.等人编辑,Comprehensive Organic Synthesis:Selectivity,Strategy&Efficiency in ModernOrganic Chemistry,Pergamon Press,纽约,NY(1991);Smith,M.B.等人,March'sAdvanced Organic Chemistry:Reactions,Mechanisms,and Structure.第6版,Wiley&Sons,纽约,NY(2007);Katritzky,A.R.等人编辑,Comprehensive Organic FunctionalGroups Transformations II,第2版,Elsevier Science Inc.,Tarrytown,NY(2004);Larock,R.C.,Comprehensive Organic Transformations,VCH Publishers,Inc.,纽约,NY(1999),以及其中的参考文献。
其中R3为取代苯基的本发明氨基咪唑化合物可使用方案1中所述的一般路线制备。
方案1
在无机碱如碳酸氢钠存在下,在合适的溶剂如DMF中用苯胺置换经取代的α-溴代酮G1a,并且随后在溶剂如MeOH或NMP中与过量的氰胺缩合,可得到G1b。在叔胺碱(例如TEA、DIEA)存在下,与由例如HATU或BOP活化的芳基羧酸偶联可提供经取代的氨基咪唑G1c。
实验
除了在另有说明的情况下,在示例性实施例中使用以下方法。中间体和最终产物的纯化通过正相或反相色谱法进行。除非另有指示,否则使用预填充的SiO2柱用己烷和EtOAc或DCM和MeOH的梯度洗脱进行正相色谱法。
实施例的反相制备型HPLC使用Waters XBridge C18柱(19x 200mm,5-μm颗粒)用UV和LCMS检测使用含有0.1% TFA或10mM NH4OAc的流动相A(95%水,5% ACN)和流动相B(5%水,95% ACN)的可变梯度进行。
方法A:0至100% B的线性梯度经3min,在100% B下的保持时间为0.75min;
在220nm处的UV可视化
柱:Waters BEH C18 2.1x 50mm
流速:1.0mL/min
溶剂A:10mM NH4OAc、95%水、5% ACN
溶剂B:10mM NH4OAc、5%水、95% ACN
方法B:0至100% B的线性梯度经3min,在100% B下的保持时间为0.75min;
在220nm处的UV可视化
柱:Waters BEH C18 2.1x 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C:2至98% B的线性梯度经1min,在100% B下的保持时间为0.50min;
在220nm处的UV可视化
柱:Waters BEH C18 2.1x 50mm
流速:0.8mL/min
溶剂A:含有0.05% TFA的水
溶剂B:含有0.05% TFA的ACN
使用在300MHz、400MHz或500MHz频率下运行的Bruker光谱仪获得1H NMR光谱。光谱数据以以下格式报告:化学位移(多重性、偶合常数和氢数)。化学位移在四甲基硅烷内标物的低场以ppm指定(δ单位,四甲基硅烷=0ppm)和/或参考溶剂峰,所述溶剂峰在1H NMR光谱中出现在对于(CD3)2SO的2.50ppm处、对于CD3OD的3.31ppm处、对于CD3CN的1.94处和对于CDCl3的7.26ppm处。
实施例1:N-[1-(2,6-二氟-4-甲氧基苯基)-4-苯基-1H-咪唑-2-基]-4-(二氟甲氧基)苯甲酰胺
中间体1:1-(2,6-二氟-4-甲氧基苯基)-4-苯基-1H-咪唑-2-胺
在室温向2,6-二氟-4-甲氧基苯胺在DMF(3.8mL)中的搅拌溶液中添加碳酸氢钠(71mg,0.85mmol),接着添加2-溴-1-苯基乙酮(180mg,0.88mmol)。将所得溶液在室温搅拌16小时。向所得中间体中添加氰胺(264mg,6.28mmol)。将所得溶液在95℃加热16小时。通过反相HPLC纯化粗材料,得到中间体1(25mg,0.084mmol,13%产率)。MS(ESI)m/z:302.3(M+H)+。1H NMR(500MHz,DMSO-d6)δ7.65(br d,J=7.6Hz,2H),7.31(t,J=7.6Hz,2H),7.23-7.10(m,2H),6.96(br d,J=9.8Hz,2H),5.60(s,2H),3.84(s,3H)。
实施例1:N-[1-(2,6-二氟-4-甲氧基苯基)-4-苯基-1H-咪唑-2-基]-4-(二氟甲氧基)苯甲酰胺
向4-(二氟甲氧基)苯甲酸(79mg,0.42mmol)在DMF(0.25ml)中的搅拌溶液中添加BOP(190mg,0.42mmol),接着添加DIEA(0.15mL,0.84mmol)。将所得溶液在室温搅拌15分钟。向所得混合物中添加中间体1(25mg,0.084mmol)在DMF(0.25mL)中的溶液,并将反应在50℃加热16小时。通过反相HPLC纯化粗材料,得到实施例1(18mg,0.038mmol,45%产率)。MS(ESI)m/z:472.2(M+H)+。
按照对于实施例1所描述的制备表2中的以下实施例。
表2
实施例44:1-(2,6-二氟-4-甲氧基苯基)-2-[4-(二氟甲氧基)苯甲酰胺基]-N-[(1H-吡唑-3-基)甲基]-1H-咪唑-4-甲酰胺
中间体2:1-(2,6-二氟-4-甲氧基苯基)-2-(4-(二氟甲氧基)苯甲酰胺基)-1H-咪唑-4-甲酸
向化合物38(130mg,0.27mmol)在THF(1mL)和MeOH(0.25mL)中的搅拌溶液中添加1N NaOH溶液(2.7mL,2.7mmol)。将所得混合物在室温搅拌2小时。通过使用1N HCl将反应调节至pH=1,并用EtOAc萃取混合物(3x)。将合并的提取物干燥(Na2SO4),过滤并在减压下蒸发,得到中间体2,其不经进一步纯化而使用。
实施例44:1-(2,6-二氟-4-甲氧基苯基)-2-[4-(二氟甲氧基)苯甲酰胺基]-N-[(1H-吡唑-3-基)甲基]-1H-咪唑-4-甲酰胺
向中间体2(10mg,0.023mmol)在DMF(0.40ml)中的搅拌溶液中添加BOP(15mg,0.034mmol),接着添加DIEA(0.020mL,0.11mmol)。将所得溶液在室温搅拌15分钟。向所得混合物中添加(1H-吡唑-3-基)甲胺(4mg,0.046mmol),并在室温将反应物搅拌16小时。通过反相HPLC纯化粗材料,得到标题化合物(5mg,0.009mmol,40%产率)。MS(ESI)m/z:519.1(M+H)+。1H NMR(500MHz,DMSO-d6)δ8.33(s,1H),7.94(s,1H),7.86(br d,J=8.5Hz,2H),7.58(brs,1H),7.34(t,J=73.6Hz,1H),7.26(br d,J=8.5Hz,2H),6.94(br d,J=10.4Hz,2H),6.17(s,1H),4.46(br d,J=5.8Hz,2H),3.79(s,3H)按照对于实施例44所描述的制备表3中的以下实施例。
表3
实施例63:N-[1-(2,6-二氟-4-甲氧基苯基)-4-(哌啶-4-基)-1H-咪唑-2-基]-4-(二氟甲氧基)苯甲酰胺
中间体3:4-(1-(2,6-二氟-4-甲氧基苯基)-2-(4-二氟甲氧基)苯甲酰胺基)-1H-咪唑-4-基)哌啶-1-甲酸叔丁酯
向中间体3(按照对于实施例1所描述的制备)(29mg,0.50mmol)在DCM(0.5mL)中的溶液中添加TFA(0.5mL)。将所得混合物在室温搅拌16小时。通过反相HPLC纯化材料,得到实施例63(14mg,0.29mmol,57%产率)。MS(ESI)m/z:479.2(M+H)+。1H NMR(500MHz,DMSO-d6)δ7.89(br d,J=8.5Hz,2H),7.29(t,J=73.9Hz,1H),7.19(br d,J=8.5Hz,2H),7.00(s,1H),6.95(br d,J=10.1Hz,2H),3.82(s,3H),3.30-3.24(m,1H),3.20-3.14(m,1H),3.09(br d,J=11.9Hz,2H),2.79-2.65(m,3H),2.56(br s,4H),2.52(br s,6H),1.97(br d,J=11.6Hz,2H),1.83(s,3H),1.54(br d,J=10.4Hz,2H),1.01(d,J=6.4Hz,2H)。
实施例64:按照对于实施例63所描述的制备4-(二氟甲氧基)-N-[1-(4-甲氧基苯基)-4-(哌啶-3-基)-1H-咪唑-2-基]苯甲酰胺。
通过反相HPLC纯化材料,得到实施例64(21.3mg,0.05mmol,87%产率)。MS(ESI)m/z:443.1(M+H)+。1H NMR(500MHz,DMSO-d6)δ7.95(br d,J=7.3Hz,2H),7.46(br s,2H),7.31(t,J=73.8Hz,1H),7.22(br d,J=8.2Hz,2H),7.17(br s,1H),7.15(br s,1H),7.02(brd,J=8.2Hz,2H),3.77(s,3H),3.30(br s,1H),3.05(br d,J=8.9Hz,1H),2.84(br s,1H),2.78-2.63(m,2H),2.07-2.01(m,1H),1.74(br s,1H),1.58(br s,2H)。
实施例65:N-[1-(2,6-二氟-4-甲氧基苯基)-4-[1-(乙磺酰基)哌啶-4-基]-1H-咪唑-2-基]-4-(二氟甲氧基)苯甲酰胺
向化合物63(10mg,0.021mmol)在DCM(0.4ml)中的溶液中添加乙磺酰氯(16mg,0.12mmol),然后添加DIEA(0.027mL,0.16mmol)。将所得溶液在室温搅拌过夜。通过反相HPLC纯化粗材料,得到实施例65(2mg,0.003mmol,13%产率)。MS(ESI)m/z:571.2(M+H)+。1HNMR(500MHz,DMSO-d6)δ7.89(br s,2H),7.30(s,2H),7.20(s,2H),7.10(s,1H),3.81(br s,1H),3.68(br d,J=11.9Hz,2H),3.08(q,J=7.3Hz,2H),3.00(s,1H),2.97-2.89(m,3H),2.55(s,6H),2.51(br s,8H),2.10-2.05(m,2H),1.80(br d,J=6.4Hz,1H),1.24(t,J=7.3Hz,4H),1.18(s,1H)。
实施例66:4-[1-(2,6-二氟-4-甲氧基苯基)-2-[4-(二氟甲氧基)苯甲酰胺基]-1H-咪唑-4-基]-N-乙基哌啶-1-甲酰胺
向化合物63(10mg,0.021mmol)在DCM(0.4mL)中的溶液中添加异氰酸乙酯(13mg,0.13mmol),然后添加DIEA(0.027mL,0.16mmol)。将所得溶液在室温搅拌过夜。通过反相HPLC纯化粗材料,得到实施例66(3.0mg,0.004mmol,15%产率)。MS(ESI)m/z:550.22(M+H)+。1H NMR(500MHz,DMSO-d6)δ7.90(br d,J=7.7Hz,2H),7.39(s,1H),7.24(s,1H),7.17(brd,J=8.0Hz,2H),7.09(s,1H),6.98-6.89(m,3H),4.01(br d,J=13.2Hz,2H),3.89(s,1H),3.83(br s,2H),3.11-3.03(m,2H),2.94(q,J=7.3Hz,1H),2.78(br t,J=11.9Hz,2H),1.98-1.91(m,2H),1.50-1.39(m,2H),1.19(t,J=7.3Hz,1H),1.03(t,J=7.1Hz,3H)。
实施例67:N-{4-[1-(3-氨基甲酰基丙酰基)哌啶-4-基]-1-(2,6-二氟-4-甲氧基苯基)-1H-咪唑-2-基}-4-(二氟甲氧基)苯甲酰胺
向4-氨基-4-氧代丁酸(5mg,0.042mmol)在DMF(0.2mL)中的溶液中添加BOP(12mg,0.026mmol),然后添加DIEA(0.018mL,0.11mmol)。将所得溶液在室温搅拌10分钟。向该混合物中添加实施例63(10mg,0.021mmol)在DMF(0.2mL)中的溶液。将反应在室温搅拌过夜。通过反相HPLC纯化粗材料,得到实施例67(1mg,0.002mmol,9%产率)。MS(ESI)m/z:578.14(M+H)+。1H NMR(500MHz,DMSO-d6)δ7.90(br d,J=8.5Hz,2H),7.45(s,1H),7.29(br d,J=13.4Hz,1H),7.19(br d,J=8.5Hz,2H),7.16(s,1H),7.02(s,1H),6.96(br d,J=10.4Hz,2H),6.71(br s,1H),4.44(br d,J=13.1Hz,1H),3.96(br d,J=13.1Hz,1H),3.82(s,3H),3.12(br t,J=12.7Hz,1H),2.92-2.83(m,1H),2.67(br t,J=12.5Hz,1H),2.36-2.28(m,2H),2.04(br d,J=13.1Hz,1H),1.97(br d,J=11.9Hz,1H),1.90(s,2H),1.58-1.48(m,1H),1.45-1.35(m,1H)。
按照对于实施例67所描述的制备实施例68和69(表3)。
实施例70:N-(1-(2,6-二氟-4-甲氧基苯基)-4-异丙基-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
中间体4:1-(2,6-二氟-4-甲氧基苯基)胍
向N,N’-二-叔丁氧羰基-1H-吡唑-1-甲脒(780mg,2.5mmol)在氯仿(5mL)中的溶液中添加2,6-二氟-4-甲氧基苯胺(400mg,2.5mol),并将混合物在55℃搅拌16小时。添加另外的N,N’-二-叔丁氧羰基-1H-吡唑-1-甲脒(200mg)并继续加热另外24小时。将混合物冷却至室温,然后通过硅胶色谱法纯化,用2至20%的EtOAc/己烷洗脱,得到呈白色固体的[(2,6-二氟-4-甲氧基苯基)羰基亚氨基]双氨基甲酸二叔丁酯(370mg,产率37%)。
然后将白色固体用在二噁烷中的4N HCl(2.3mL,9.1mmol)处理,并将混合物老化48小时。蒸发混合物,然后从ACN、接着乙醚中共蒸发,得到呈白色固体的1-(2,6-二氟-4-甲氧基苯基)胍,HCl(230mg,100%产率)。MS(ESI)m/z:202.1(M+H)+。1H NMR(500MHz,DMSO-d6)δ9.29(br s,1H),7.57(br s,4H),6.92(d,J=9.6Hz,2H),3.81(s,3H)。
中间体5:1-(2,6-二氟-4-甲氧基苯基)-4-异丙基-1H-咪唑-2-胺:
向中间体4(24mg,0.10mmol)和碳酸钾(42mg,0.30mmol)在EtOH(0.33mL)中的混合物中添加1-溴-3-甲基丁-2-酮(12μl,0.10mmol),并将混合物加热回流10分钟。将混合物冷却至室温,并且在真空下除去溶剂。将残余物通过硅胶色谱法纯化,用0.5至15% MeOH/DCM洗脱,得到呈白色固体的标题化合物(15mg,0.06mmol,56%产率)。MS(ESI)m/z:268.1(M+H)+。1H NMR(500MHz,氯仿-d)δ6.69-6.55(m,2H),6.27(s,1H),4.31(br s,2H),3.85(s,3H),2.79(spt,J=6.7Hz,1H),1.25(d,J=6.9Hz,6H)。
实施例70:N-(1-(2,6-二氟-4-甲氧基苯基)-4-异丙基-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺)
向中间体5(15mg,0.06mmol)和4-(二氟甲氧基)苯甲酸(16mg,0.084mmol)在DMF(0.5mL)中的溶液中添加DIPEA(0.035mL,0.20mmol),然后添加HATU(38mg,0.10mmol),并且搅拌混合物16h。将混合物用70% EtOAc/己烷稀释,用饱和NH4Cl、1.5M K2HPO4洗涤,然后干燥(Na2SO4),过滤并浓缩。将残余物通过硅胶色谱法纯化,用5%至40% EtOAc/己烷洗脱,接着进行反相HPLC,得到标题化合物(10mg,0.022mmol,40%产率)。MS(ESI)m/z:438.2(M+H)+。1H NMR(500MHz,DMSO-d6)δ7.91(br d,J=8.5Hz,2H),7.30(t,J=73.6Hz,1H),7.20(brd,J=8.2Hz,2H),7.05(s,1H),6.98(br d,J=10.1Hz,2H),3.84(s,3H),2.95(dt,J=13.8,6.7Hz,1H),1.25(d,J=7.0Hz,6H)
按照对于实施例70所描述的制备实施例71和72(表3)。
实施例73:N-(1-(2,6-二氟-4-甲氧基苯基)-4-((5-甲基-1,3,4-噁二唑-2-基)甲基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
向化合物72(按照对于实施例70所描述的制备)(30mg,0.062mmol)在DCM(0.6mL)中的溶液中添加肼(0.020mL,0.62mmol),并将混合物搅拌16小时。将混合物从DCM中蒸发两次并置于真空下,得到呈白色固体的N-(1-(2,6-二氟-4-甲氧基苯基)-4-(2-肼基-2-氧代乙基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺(29mg,0.062mmol,99%产率)。向固体(14mg,0.030mmol)和乙酸(2.1μl,0.036mmol)在二噁烷(0.25mL)中的溶液中添加1-丙膦酸环酐(50%于EtOAc中)(0.045mL,0.075mmol),并在70℃加热反应1.5h。添加另外的1-丙烷膦酸环酸酐(50%于EtOAc中)(0.045mL,0.075mmol),并将反应在105℃加热1.5小时。使反应冷却至室温,在氮气流下蒸发,然后过滤。通过反相HPLC纯化粗材料,得到标题化合物(4mg,7.4μmol,25%产率)。MS(ESI)m/z:492.12(M+H)+。1H NMR(500MHz,DMSO-d6)δ7.82(brd,J=7.6Hz,2H),7.31(t,J=72.9Hz,1H),7.23(br d,J=7.3Hz,2H),7.16(s,1H),6.88(brd,J=11.0Hz,2H),4.16(br s,2H),3.76(s,3H),2.48(s,3H)。
实施例74:N-(1-(2,6-二氟-4-甲氧基苯基)-4-(3-羟基环丁基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺。
中间体6:1-(3-(苄氧基)环丁基)-2-溴乙-1-酮
向1-(3-(苄氧基)环丁基)乙-1-酮(430mg,2.1mmol)在EtOH(5.3mL)中的0℃搅拌溶液中逐滴添加溴(110μl,2.1mmol)在EtOH(1mL)中的溶液。将混合物在0℃搅拌2小时,温热至室温并搅拌16小时。将混合物倒入饱和NaHCO3溶液中并用DCM萃取。将合并的有机萃取物用盐水洗涤,用Na2SO4干燥并在减压下浓缩。将残余物通过硅胶快速色谱纯化,用0至100% EtOAc/己烷洗脱,得到呈顺式和反式异构体的混合物的中间体6(280mg,1.0mmol,47%产率),该中间体直接用于下一步。
中间体7:4-(3-(苄氧基)环丁基)-1-(2,6-二氟-4-甲氧基苯基)-1H-咪唑-2-胺
向中间体4(210mg,0.77mmol)和碳酸钾(320mg,2.30mmol)在EtOH(2.6mL)中的混合物中添加中间体6(280mg,1.0mmol),并且将混合物在80℃搅拌2.5小时。将混合物冷却至室温,用DCM稀释并过滤。将滤液在减压下浓缩,并且将残余物通过硅胶快速色谱法纯化,用0至20% MeOH/DCM洗脱,得到中间体7(270mg,0.7mmol,91%产率)。LCMS(方法B)Rt=0.77min,(M+H)+=386.1。
中间体8:N-(4-(3-(苄氧基)环丁基)-1-(2,6-二氟-4-甲氧基苯基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
向中间体7(270mg,0.7mmol)和4-(二氟甲氧基)苯甲酸(160mg,0.84mmol)在DMF(2mL)中的溶液中添加DIPEA(0.37mL,2.1mmol),然后添加HATU(400mg,1.05mmol),并将混合物在80℃搅拌3天。将混合物用EtOAc稀释,用水、1N HCl和盐水洗涤,用硫酸钠干燥,过滤并且减压浓缩。将残余物通过硅胶快速色谱法纯化,用0至100%EtOAc/己烷洗脱,得到呈顺式和反式异构体混合物的中间体8(185mg,0.33mmol,47%产率)。LCMS(方法B)Rt=0.93min,(M+H)+=556.0。
实施例74:N-(1-(2,6-二氟-4-甲氧基苯基)-4-(3-羟基环丁基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
向中间体8(180mg,0.33mmol)在EtOH(5mL)中的溶液中添加10%Pd-C(35mg,0.033mmol)。将反应在室温在氢气气氛下搅拌过夜。将混合物通过硅藻土垫过滤并且在减压下浓缩。通过反相HPLC纯化材料,得到标题化合物(7.7mg,0.016mmol,5%产率)。MS(ESI)m/z:466.1(M+H)+。1H NMR(500MHz,DMSO-d6)δ8.00-7.81(m,2H),7.09(br s,5H),6.95-6.82(m,1H),4.51-4.32(m,1H),4.31-4.20(m,1H),3.94-3.86(m,3H),2.45-2.28(m,2H),2.29-2.14(m,2H)。
实施例75:N-(1-(2,6-二氟-4-甲氧基苯基)-4-(2-氮杂螺[3.3]庚-6-基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
中间体9:6-乙酰基-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
在氩气气氛下向N,O-二甲基羟基胺盐酸盐(200mg,2.1mmol)和2-(叔丁氧基羰基)-2-氮杂螺[3.3]庚烷-6-甲酸(250mg,1.04mmol)和TEA(0.7mL,5.18mmol)在DCM(10mL)中的0℃搅拌溶液中逐滴添加T3P(50%于EtOAc中,1.2mL,2.1mmol)。使反应混合物在室温搅拌3小时。将混合物用EtOAc稀释,用水、1N HCl溶液和盐水洗涤,用硫酸钠干燥并且浓缩。将粗产物通过硅胶柱色谱法纯化,用0-100% EtAOc/己烷洗脱,然后用甲基溴化镁(3M于THF中)(1.1mL,3.2mmol)处理,得到标题化合物(227mg,0.95mmol,90%产率)。
中间体10:6-(2-氨基-1-(2,6-二氟-4-甲氧基苯基)-1H-咪唑-4-基)-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯
向中间体4(210mg,0.77mmol)和碳酸钾(212mg,1.532mmol)在ACN(7.6mL)中的混合物中添加中间体9(220mg,0.92mmol)和四溴化碳(300mg,0.92mmmol)。将混合物在70℃加热过夜。将混合物用DCM稀释并且通过硅藻土过滤。将滤液在减压下浓缩,并且将残余物通过反相制备型HPLC纯化,得到中间体10(67mg,0.16mmol,21%产率)。MS(ESI)m/z:421.1(M+H)+。
实施例75:N-(1-(2,6-二氟-4-甲氧基苯基)-4-(2-氮杂螺[3.3]庚-6-基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
向中间体10(67mg,0.16mmol)和4-(二氟甲氧基)苯甲酸(45mg,0.24mmol)在DMF(2mL)中的溶液中添加DIPEA(0.083mL,0.47mmol),然后添加HATU(91mg,0.24mmol),并且将混合物在80℃搅拌6小时。将反应混合物在减压下浓缩。将粗残余物用50% TFA/DCM(1.0mL)处理30分钟。将混合物减压浓缩,并且将残余物通过反相HPLC纯化,得到标题化合物(18mg,0.036mmol,23%产率)。MS(ESI)m/z:491.2(M+H)+。1H NMR(500MHz,甲醇-d4)δ7.88(br d,J=8.7Hz,2H),7.23-7.15(m,2H),7.04-6.72(m,4H),3.85(s,3H),3.51-3.41(m,1H),2.79-2.70(m,2H),2.58-2.50(m,2H),1.50-1.26(m,4H)。
实施例76:N-(1-(2,6-二氟-4-甲氧基苯基)-4-(4-羟基环己基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
中间体11:N-(1-(2,6-二氟-4-甲氧基苯基)-4-(1,4-二氧杂螺[4.5]癸-8-基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
按照实施例74中所述,从中间体4和1-(1,4-二氧杂螺[4.5]癸-8-基)乙-1-酮制备中间体11来获得中间体11(390mg,0.72mmol,63%产率)。LCMS(方法A,Rt=0.83min),MS(ESI)m/z:536.0(M+H)+。1H NMR(500MHz,DMSO-d6)δ8.04-7.79(m,2H),7.38-6.82(m,6H),3.97-3.70(m,7H),2.82-2.66(m,1H),1.79-1.44(m,8H)。
中间体12:N-(1-(2,6-二氟-4-甲氧基苯基)-4-(4-氧代环己基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
将中间体11(390mg,0.73mmol)和TFA(3mL)的混合物在室温搅拌3天。将反应混合物在减压下浓缩,得到中间体12(310mg,0.64mmol,87%产率)。LCMS(方法A,Rt=0.80min),MS(ESI)m/z:492.0(M+H)+。
实施例76:N-(1-(2,6-二氟-4-甲氧基苯基)-4-(4-羟基环己基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
在室温向中间体12(40mg,0.081mmol)在MeOH(2mL)中的溶液中添加NaBH4(5mg,0.13mmol)。将反应在室温搅拌2小时。将反应混合物通过硅藻土过滤,并且将滤液在减压下浓缩。将残余物通过反相HPLC纯化,得到实施例76(6mg,0.011mmol,14%产率)。MS(ESI)m/z:494.03(M+H)+。1H NMR(500MHz,DMSO-d6)δ7.90(br d,J=8.6Hz,2H),7.39-7.03(m,3H),6.95-6.84(m,3H),3.83(s,3H),3.71-3.59(m,1H),2.71-2.64(m,1H),1.85-1.76(m,2H),1.74-1.63(m,4H),1.62-1.52(m,2H)。
实施例77:N-(1-(2,6-二氟-4-甲氧基苯基)-4-((6-氟-1H-咪唑并[4,5-b]吡啶-2-基)甲基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
中间体13:2-(1-(2,6-二氟-4-甲氧基苯基)-2-(4-(二氟甲氧基)苯甲酰胺基)-1H-咪唑-4-基)-2-甲基丙酸甲酯
按照对于实施例74所描述的制备中间体13。
中间体14:2-(1-(2,6-二氟-4-甲氧基苯基)-2-(4-(二氟甲氧基)苯甲酰胺基)-1H-咪唑-4-基)-2-甲基丙酸,钠盐
向中间体13(210mg,0.42mmol)在THF/MeOH(3:1,4mL)中的搅拌溶液中添加1NNaOH(0.85mL,0.85mmol)。将混合物在室温搅拌3天。将混合物浓缩并且直接用于下一步。
中间体15:N-(4-(2-((2-氨基-5-氟吡啶-3-基)氨基)-2-氧代乙基)-1-(2,6-二氟-4-甲氧基苯基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
将中间体14(47mg,0.1mmol)、5-氟吡啶-2,3-二胺(16mg,0.13mmol)、HATU(49mg,0.13mmol)和DIPEA(0.052mL,0.30mmol)在ACN(2mL)中的混合物在室温搅拌过夜。将粗材料用DCM稀释,用盐水洗涤,干燥并且浓缩。将残余物通过快速色谱法纯化,用0至100% EtOAc洗脱,得到中间体14(12mg,0.021mmol,22%产率)。
实施例77:N-(1-(2,6-二氟-4-甲氧基苯基)-4-((6-氟-1H-咪唑并[4,5-b]吡啶-2-基)甲基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
将中间体15(12mg,0.021mmol)和AcOH(1mL)的混合物在95℃加热3小时。将混合物冷却至室温,用DMF稀释,并且通过反相HPLC纯化,得到标题化合物(3mg,0.005mmol,5%产率)。MS(ESI)m/z:545.2(M+H)+。1H NMR(500MHz,CD3OD)δ8.23(br s,1H),7.84(br d,J=7.8Hz,2H),7.70(br d,J=8.5Hz,1H),7.33-6.63(m,6H),4.31(s,2H),3.82(s,3H)。
按照实施例75中所述的制备实施例78-81(表3)。
实施例82:N-(1-(2,6-二氟-4-甲氧基苯基)-4-(3-((2,2,2-三氟乙基)氨基)环丁基)-1H-咪唑-2-基)-4-(二氟甲氧基)苯甲酰胺
向实施例81(20mg,0.040mmol)在THF(0.4mL)和TEA(56μl,0.40mmol)中的溶液中添加三氟甲烷磺酸2,2,2-三氟乙基酯(23mg,0.10mmol)。将所得溶液在室温搅拌4小时。将反应混合物用DMF稀释并且通过反相HPLC纯化,得到实施例82(16mg,0.028mmol,70%产率)。MS(ESI)m/z:547.3(M+H)+。1H NMR(500MHz,CD3OD)δ8.05-7.76(m,2H),7.21-7.08(m,2H),7.05-6.63(m,4H),4.24-4.03(m,1H),3.88-3.81(m,3H),3.52-3.43(m,1H),2.91(s,3H),2.63-2.54(m,2H),2.49(br s,2H)。
实施例83:按照实施例82中所描述的制备N-[1-(2,6-D二氟-4-甲氧基苯基)-4-(3-甲基磺酰氨基环丁基)-1H-咪唑-2-基]-4-(二氟甲氧基)苯甲酰胺(表3)。
根据上述程序合成表4中的以下实施例。
表4
表中实施例的NMR数据:
实施例2:1H NMR(500MHz,DMSO-d6)δ7.95-7.87(m,3H),7.81(br d,J=7.2Hz,2H),7.39(br d,J=7.4Hz,4H),7.32(t,J=73.4Hz,1H),7.29-7.20(m,3H),7.00(br d,J=8.1Hz,2H),3.74(br s,3H)。
实施例3:1H NMR(500MHz,DMSO-d6)δ7.89(s,1H),7.84(br d,J=8.0Hz,2H),7.39-7.34(m,2H),7.33-7.27(m,2H),7.24(br d,J=8.2Hz,2H),6.90(br d,J=10.4Hz,2H),6.82(br d,J=7.2Hz,1H),3.70-3.67(m,6H)
实施例4:1H NMR(500MHz,DMSO-d6)δ7.88-7.78(m,5H),7.27(t,J=73.5Hz,1H),7.25-7.19(m,4H),6.89(br d,J=10.4Hz,2H),3.77(s,3H)。
实施例5:1H NMR(500MHz,DMSO-d6)δ10.91(br s,1H),7.91-7.81(m,3H),7.77(s,1H),7.62(br d,J=8.3Hz,1H),7.41(br d,J=8.3Hz,1H),7.30(t,J=73.5Hz,1H),7.24(br d,J=8.3Hz,2H),6.90(br d,J=10.3Hz,2H),3.75(br s,3H),2.35(s,3H)。
实施例6:1H NMR(500MHz,DMSO-d6)δ8.07(br s,1H),8.00(br d,J=8.0Hz,2H),7.85(br d,J=8.2Hz,2H),7.75(br d,J=8.0Hz,2H),7.30(t,J=73.5Hz,1H),7.24(br d,J=8.5Hz,2H),6.92(br d,J=10.4Hz,2H),3.76(s,3H)。
实施例7:1H NMR(500MHz,DMSO-d6)δ7.92-7.78(m,5H),7.36–7.06(m,1H),7.30(t,J=73.5Hz,1H),7.22(br dd,J=16.1,8.3Hz,4H),6.90(br d,J=10.2Hz,2H),3.76(br s,3H)。
实施例8:1H NMR(500MHz,DMSO-d6)δ7.82(br d,J=7.5Hz,2H),7.68(br d,J=7.1Hz,2H),7.49-7.39(m,2H),7.32-7.11(m,4H),6.93(br d,J=9.9Hz,2H),3.76(br s,3H),2.21(br s,3H)。
实施例9:1H NMR(500MHz,DMSO-d6)δ8.32(s,1H),8.01(br s,1H),7.97-7.82(m,6H),7.58-7.40(m,2H),7.31(t,J=73.4Hz,1H),7.25(br d,J=8.2Hz,2H),6.93(br d,J=10.1Hz,2H),3.77(br s,3H)。
实施例10:1H NMR(500MHz,DMSO-d6)δ7.95(s,1H),7.83(br d,J=8.1Hz,2H),7.63(br d,J=7.7Hz,1H),7.56(br d,J=10.3Hz,1H),7.47-7.39(m,1H),7.27(t,J=73.2Hz,1H),7.23(br d,J=8.4Hz,2H),7.07(br t,J=7.4Hz,1H),6.89(br d,J=10.4Hz,2H),3.77(s,3H)。
实施例11:1H NMR(500MHz,DMSO-d6)δ7.89(br s,1H),7.81(br dd,J=14.7,8.4Hz,4H),7.48-7.40(m,2H),7.27(t,J=73.5Hz,1H),7.23(br d,J=8.3Hz,2H),6.89(brd,J=10.3Hz,2H),3.77(br s,3H)。
实施例12:1H NMR(500MHz,DMSO-d6)δ7.99(br s,1H),7.87-7.80(m,3H),7.75(brd,J=7.4Hz,1H),7.43(br t,J=7.7Hz,1H),7.34-7.09(m,4H),6.91(br d,J=10.4Hz,2H),3.76(br s,3H)。
实施例13:1H NMR(500MHz,DMSO-d6)δ7.82(br d,J=7.7Hz,2H),7.71(br d,J=8.0Hz,2H),7.48(br d,J=8.0Hz,2H),7.29(t,J=73.2Hz,1H),7.22(br d,J=8.1Hz,2H),6.93(br d,J=9.9Hz,2H),3.76(br s,3H),2.21(br s,3H)。
实施例14:1H NMR(500MHz,DMSO-d6)δ7.87(br d,J=7.6Hz,2H),7.75-7.71(m,4H),7.33(t,J=73.6Hz,1H),7.25(br d,J=7.9Hz,2H),6.98(br d,J=8.2Hz,2H),6.92(br d,J=9.8Hz,2H),3.78(s,6H)。
实施例15:1H NMR(500MHz,DMSO-d6)δ7.91-7.78(m,3H),7.69(br d,J=7.7Hz,2H),7.33(t,J=73.3Hz,1H),7.23(br dd,J=18.6,8.0Hz,4H),6.92(br d,J=10.3Hz,2H),3.77(s,3H),2.31(s,3H)。
实施例16:1H NMR(500MHz,DMSO-d6)δ8.10(br s,1H),7.97(br d,J=7.9Hz,2H),7.83(br d,J=7.3Hz,4H),7.28(t,J=73.5Hz,1H),7.23(br d,J=6.4Hz,2H),6.91(br d,J=10.4Hz,2H),3.76(br s,3H)。
实施例17:1H NMR(500MHz,DMSO-d6)δ8.19(s,1H),8.13(br d,J=8.2Hz,1H),8.06(s,1H),7.85(br d,J=8.5Hz,2H),7.70(br d,J=7.6Hz,1H),7.65-7.59(m,1H),7.30(t,J=73.6Hz,1H),7.24(br d,J=8.5Hz,2H),6.92(br d,J=10.1Hz,2H),3.77(s,3H)。
实施例18:1H NMR(500MHz,DMSO-d6)δ8.02(br s,2H),7.85(br d,J=7.4Hz,2H),7.77(br d,J=6.6Hz,1H),7.65(br d,J=7.9Hz,1H),7.30(t,J=73.5Hz,1H),7.23(br d,J=6.7Hz,2H),6.92(br d,J=10.1Hz,2H),3.76(br s,3H)。
实施例19:1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),7.90(br d,J=7.0Hz,2H),7.75(s,1H),7.68(br s,1H),7.55(br d,J=7.6Hz,1H),7.43-7.42(m,1H),7.38(br d,J=7.6Hz,1H),7.35(t,J=73.4Hz,1H),7.27(br d,J=7.6Hz,2H),7.00(br d,J=8.2Hz,2H),6.77(br d,J=8.2Hz,1H),4.54(br t,J=8.2Hz,2H),3.75(br s,3H),3.20(br t,J=8.2Hz,2H)。
实施例20:1H NMR(500MHz,DMSO-d6)δ8.38(d,J=5.2Hz,1H),8.34(s,1H),7.90(brd,J=8.5Hz,2H),7.84(s,1H),7.78(br d,J=4.6Hz,1H),7.41(br d,J=8.5Hz,2H),7.34(t,J=73.4Hz,1H),7.27(br d,J=8.5Hz,2H),7.02(br d,J=8.5Hz,2H),3.75(s,3H)。
实施例21:1H NMR(500MHz,DMSO-d6)δ10.64(s,1H),8.13-7.99(m,1H),7.91(br d,J=8.5Hz,2H),7.68(d,J=3.4Hz,1H),7.41(br d,J=8.9Hz,1H),7.36(t,J=73.6Hz,1H),7.33(br s,1H),7.32(br s,1H),7.28(br d,J=8.5Hz,2H),7.17(br t,J=7.6Hz,1H),7.01(br d,J=8.5Hz,2H),3.75(s,3H)。
实施例22:1H NMR(500MHz,DMSO-d6)δ8.34(s,1H),8.05-7.97(m,2H),7.97-7.91(m,2H),7.85(br d,J=7.9Hz,1H),7.76(br d,J=5.2Hz,1H),7.58-7.40(m,3H),7.36-7.12(m,3H),7.14(s,1H),7.07-7.00(m,2H),3.77(s,3H)。
实施例23:1H NMR(500MHz,DMSO-d6)δ8.22(s,1H),8.10(d,J=7.6Hz,1H),7.96(brd,J=7.9Hz,1H),7.91(br d,J=8.5Hz,2H),7.54-7.39(m,5H),7.34(t,J=73.6Hz,1H),7.28(br d,J=8.5Hz,2H),7.02(br d,J=8.5Hz,2H),3.75(s,3H)。
实施例24:1H NMR(500MHz,DMSO-d6)δ7.96(s,1H),7.90(br d,J=8.5Hz,2H),7.83(d,J=3.1Hz,1H),7.64(d,J=3.1Hz,1H),7.42(br d,J=8.5Hz,2H),7.35(t,J=73.6Hz,1H),7.28(br d,J=8.2Hz,2H),7.01(br d,J=8.9Hz,2H),3.75(s,3H)。
实施例25:1H NMR(500MHz,DMSO-d6)δ10.64(s,1H),8.05(br t,J=6.7Hz,1H),7.91(br d,J=8.2Hz,2H),7.69(br d,J=3.1Hz,1H),7.42(br d,J=8.9Hz,2H),7.35(t,J=73.5Hz,1H),7.28(br d,J=7.9Hz,5H),7.01(br d,J=8.9Hz,2H),3.75(s,3H)。
实施例26:1H NMR(500MHz,DMSO-d6)δ7.97(s,1H),7.90(br d,J=8.5Hz,2H),7.71(d,J=1.5Hz,1H),7.60(d,J=8.9Hz,1H),7.43(br d,J=8.5Hz,2H),7.34(t,J=73.6Hz,1H),7.32-7.25(m,3H),7.07(s,1H),7.02(br d,J=8.5Hz,2H),3.75(s,3H)。
实施例27:1H NMR(500MHz,DMSO-d6)δ8.13-7.85(m,3H),7.65(br s,1H),7.31-6.99(m,6H),3.85(s,3H),2.72-2.61(m,1H),2.00(br s,2H),1.77(br s,2H),1.69(br d,J=11.3Hz,1H),1.36(br t,J=9.6Hz,4H),1.23(br s,1H)。
实施例29:1H NMR(500MHz,DMSO-d6)δ8.21(s,1H),7.89(br d,J=8.5Hz,2H),7.41(br d,J=8.5Hz,2H),7.33(t,J=73.6Hz,1H),7.27(br d,J=8.5Hz,2H),7.02(br d,J=8.5Hz,3H),4.39(q,J=6.9Hz,2H),3.75(s,3H),1.33(t,J=7.2Hz,3H)。
实施例30:1H NMR(500MHz,DMSO-d6)δ10.67(s,1H),8.10(s,1H),7.88(br d,J=8.5Hz,2H),7.39(br d,J=8.9Hz,2H),7.35(t,J=73.6Hz,1H),7.27(br d,J=8.5Hz,2H),7.00(br d,J=8.9Hz,2H),4.26(q,J=7.0Hz,2H),3.74(s,3H),1.29(t,J=7.0Hz,3H)。
实施例32:1H NMR(500MHz,DMSO-d6)δ8.05(br d,J=11.1Hz,1H),7.88(br d,J=4.5Hz,1H),7.74-7.61(m,1H),7.49-6.91(m,7H),3.90-3.67(m,3H),1.33-1.23(m,9H)。
实施例33:1H NMR(500MHz,DMSO-d6)δ10.82(s,1H),8.05(br t,J=6.9Hz,1H),7.87(br d,J=8.6Hz,2H),7.65(br d,J=3.3Hz,1H),7.36-7.20(m,5H),7.29(t,J=73.6Hz,1H),6.89(br d,J=10.1Hz,2H),3.79(s,3H)。
实施例34:1H NMR(500MHz,DMSO-d6)δ8.39(d,J=5.2Hz,1H),8.24(s,1H),7.86(brd,J=8.7Hz,2H),7.82(s,1H),7.76(d,J=5.1Hz,1H),7.28(t,J=73.5Hz,1H),7.24(d,J=8.6Hz,2H),6.91(br d,J=10.0Hz,2H),3.79(s,3H)。
实施例36:1H NMR(500MHz,DMSO-d6)δ7.92-7.84(m,3H),7.82-7.74(m,1H),7.65(br s,1H),7.50-7.41(m,1H),7.29(t,J=73.5Hz,1H),7.25(br d,J=8.6Hz,2H),6.91(brd,J=10.1Hz,2H),3.80(s,3H)。
实施例37:1H NMR(500MHz,DMSO-d6)δ7.96-7.78(m,2H),7.24-7.10(m,3H),7.10-6.99(m,2H),6.87(br s,1H),3.92-3.70(m,3H),2.04-1.77(m,1H),0.82(br s,2H),0.69(br s,2H)。
实施例38:1H NMR(500MHz,DMSO-d6)δ8.04(s,1H),7.84(d,J=8.7Hz,2H),7.26(t,J=73.6Hz,1H),7.22(br d,J=8.6Hz,2H),6.88(br d,J=10.2Hz,2H),4.28(q,J=7.1Hz,2H),3.79(s,3H),1.30(t,J=7.1Hz,3H)。
实施例39:1H NMR(500MHz,DMSO-d6)δ8.03-7.80(m,2H),7.36(br s,1H),7.27-7.06(m,3H),7.04-6.80(m,3H),3.89(br d,J=4.5Hz,3H),2.61(br s,2H),1.22(t,J=7.5Hz,3H)。
实施例40:1H NMR(500MHz,DMSO-d6)δ7.98(s,1H),7.85(br d,J=8.2Hz,3H),7.66(br s,1H),7.31(t,J=73.5Hz,1H),7.25(br d,J=8.5Hz,2H),6.92(br d,J=10.1Hz,2H),3.77(s,3H)。
实施例42:1H NMR(500MHz,DMSO-d6)δ8.11(s,1H),7.88(br d,J=8.7Hz,2H),7.40(br d,J=8.8Hz,2H),7.31(t,J=73.5Hz,1H),7.26(br d,J=8.7Hz,2H),7.01(br d,J=8.9Hz,2H),3.76(s,3H)。
实施例43:1H NMR(500MHz,DMSO-d6)δ8.13(s,1H),7.87(br d,J=8.5Hz,2H),7.39(d,J=8.9Hz,2H),7.34(t,J=73.4Hz,1H),7.27(br d,J=8.5Hz,2H),7.01(d,J=8.9Hz,2H),3.74(s,3H)。
实施例45:1H NMR(500MHz,DMSO-d6)δ7.89(br d,J=7.9Hz,2H),7.82(s,1H),7.39(br d,J=8.9Hz,2H),7.35(t,J=73.4Hz,1H),7.26(br d,J=8.5Hz,2H),7.01(s,2H),3.89(s,1H),3.74(s,3H),3.17(s,1H),2.89(s,1H),2.73(br d,J=6.4Hz,5H)。
实施例46:1H NMR(500MHz,DMSO-d6)δ8.11(br s,1H),7.89(br d,J=8.2Hz,2H),7.85(s,1H),7.39(br d,J=8.5Hz,2H),7.35(t,J=73.4Hz,1H),7.27(br d,J=8.5Hz,2H),7.01(br d,J=8.9Hz,2H),3.75(s,3H),3.46(br t,J=6.1Hz,1H),1.65(br t,J=6.4Hz,2H)。三个烷基质子被DMSO溶剂峰遮蔽。
实施例47:1H NMR(500MHz,DMSO-d6)δ8.79(br s,1H),8.54(s,1H),8.44(br d,J=4.3Hz,1H),7.92(s,1H),7.83(br d,J=8.5Hz,2H),7.73(br d,J=7.6Hz,1H),7.35(dd,J=7.3,4.9Hz,1H),7.31(t,J=73.5Hz,1H),7.24(br d,J=8.5Hz,2H),6.92(br d,J=10.1Hz,2H),4.46(br d,J=6.1Hz,2H),3.77(s,3H)。
实施例49:1H NMR(500MHz,DMSO-d6)δ7.87(s,1H),7.83(br d,J=8.2Hz,2H),7.67(br d,J=7.3Hz,1H),7.32(t,J=73.4Hz,1H),7.24(br d,J=8.2Hz,2H),6.91(br d,J=10.1Hz,2H),3.89(s,1H),3.77(s,3H),3.74-3.68(m,1H),1.86-1.76(m,4H),1.47-1.36(m,2H),1.29-1.20(m,2H)。
实施例50:1H NMR(500MHz,DMSO-d6)δ7.90-7.82(m,3H),7.32(t,J=73.4Hz,1H),7.24(br d,J=8.2Hz,2H),6.90(br d,J=10.4Hz,2H),4.18(br s,1H),3.89(s,1H),3.76(s,3H),3.66-3.54(m,1H),3.45(s,1H),3.16(s,1H),2.91(br d,J=7.0Hz,2H),1.97-1.82(m,4H)。
实施例51:1H NMR(500MHz,DMSO-d6)δ7.86-7.80(m,4H),7.31(t,J=73.6Hz,1H),7.24(br d,J=8.2Hz,2H),6.90(br d,J=10.4Hz,2H),3.76(s,3H),3.46(br s,1H),3.16(br s,1H),2.91(q,J=7.0Hz,1H),1.90(br d,J=4.6Hz,1H),1.73(br s,1H),1.41(br s,2H),1.27-1.21(m,1H),1.15(t,J=7.3Hz,2H)。
实施例52:1H NMR(500MHz,DMSO-d6)δ7.86-7.81(m,3H),7.32(t,J=73.4Hz,1H),7.24(br d,J=8.5Hz,2H),6.90(br d,J=10.4Hz,2H),4.12-3.92(m,1H),3.76(s,3H),3.49-3.42(m,1H),3.16(br d,J=4.3Hz,1H),2.95-2.87(m,1H),1.79(br d,J=9.2Hz,2H),1.36(br d,J=8.5Hz,2H),1.15(t,J=7.2Hz,1H)。
实施例53:1H NMR(500MHz,DMSO-d6)δ7.94-7.88(m,2H),7.84(br d,J=8.2Hz,2H),7.33(t,J=73.6Hz,1H),7.25(br d,J=8.5Hz,2H),6.93(br d,J=10.4Hz,2H),4.78(br t,J=5.2Hz,1H),3.77(s,3H),3.50(q,J=5.8Hz,1H),3.34(br d,J=8.9Hz,1H),3.17(d,J=5.2Hz,1H),2.92(q,J=7.2Hz,1H)。
实施例54:1H NMR(500MHz,DMSO-d6)δ7.91(s,1H),7.84(br d,J=8.2Hz,2H),7.33(t,J=73.4Hz,1H),7.24(br d,J=8.2Hz,2H),6.91(br d,J=10.1Hz,2H),3.77(s,3H),3.64(br s,2H),3.43-3.34(m,1H),3.17(br d,J=4.6Hz,1H),2.97-2.87(m,1H)。未观察到四个烷基质子(水抑制)。
实施例55:1H NMR(500MHz,DMSO-d6)δ7.99(s,1H),7.84(br d,J=8.2Hz,2H),7.33(t,J=73.6Hz,1H),7.25(br d,J=8.5Hz,2H),6.92(br d,J=10.4Hz,2H),3.77(s,3H),3.48-3.40(m,1H),3.16(s,1H),2.92(br d,J=6.1Hz,1H),2.74-2.62(m,3H)。四个烷基质子被DMSO溶剂峰遮蔽。
实施例56:1H NMR(500MHz,DMSO-d6)δ8.69(br s,1H),8.47(s,2H),7.94(s,1H),7.84(br d,J=8.5Hz,2H),7.33(t,J=73.6Hz,1H),7.25(br d,J=8.5Hz,2H),6.93(br d,J=10.1Hz,2H),4.57(br d,J=5.8Hz,2H),3.77(s,3H),2.47(s,3H)。
实施例57:1H NMR(500MHz,DMSO-d6)δ7.84(br d,J=10.4Hz,3H),7.27(t,J=73.6Hz,1H),7.23(br d,J=7.8Hz,2H),6.89(br d,J=6.4Hz,2H),4.33(br d,J=19.5Hz,1H),3.91(br s,1H),3.79(br s,3H),3.63-3.52(m,1H),3.50-3.38(m,1H),2.98(s,1H),2.02-1.76(m,3H)。
实施例58:1H NMR(500MHz,DMSO-d6)δ8.09(br s,1H),7.97(s,1H),7.85(br d,J=8.5Hz,2H),7.33(t,J=73.6Hz,1H),7.24(br d,J=8.5Hz,2H),6.92(br d,J=10.1Hz,2H),3.77(s,3H),1.90(s,1H),1.23(s,1H)。烷基质子被DMSO峰和水抑制遮蔽。
实施例59:1H NMR(500MHz,DMSO-d6)δ7.92-7.83(m,3H),7.34(t,J=73.2Hz,1H),7.24(br d,J=7.9Hz,2H),6.92(br d,J=9.2Hz,2H),4.13-4.05(m,1H),3.78(br s,3H),3.65-3.55(m,1H),3.51-3.39(m,1H),2.38(br dd,J=12.1,7.5Hz,1H),2.33-2.22(m,1H),1.99(br d,J=7.3Hz,1H),1.94-1.86(m,1H),1.71(br s,1H),1.66-1.55(m,1H),1.23(s,1H)。
实施例60:1H NMR(500MHz,DMSO-d6)δ8.08(br s,1H),7.87(s,1H),7.83(br d,J=8.2Hz,2H),7.32(t,J=73.5Hz,1H)7.24(br d,J=8.2Hz,2H),6.91(br d,J=10.4Hz,2H),4.58(t,J=5.2Hz,1H),3.77(s,3H),3.31(q,J=6.7Hz,1H),3.16(d,J=5.2Hz,1H),1.66(五重峰,J=6.5Hz,3H)。
实施例61:1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.85(br d,J=8.5Hz,2H),7.34(t,J=73.6Hz,1H),7.25(d,J=8.5Hz,2H),6.93(br d,J=10.1Hz,2H),3.78(s,3H),2.85-2.78(m,4H)。四个质子被DMSO溶剂峰遮蔽。
实施例64:1H NMR(500MHz,DMSO-d6)δ7.95(br d,J=7.3Hz,2H),7.46(br s,2H),7.31(t,J=73.8Hz,1H),7.22(br d,J=8.2Hz,2H),7.17(br s,1H),7.15(br s,1H),7.02(br d,J=8.2Hz,2H),3.77(s,3H),3.30(br s,1H),3.05(br d,J=8.9Hz,1H),2.84(br s,1H),2.78-2.63(m,2H),2.07-2.01(m,1H),1.74(br s,1H),1.58(br s,2H)。
实施例68:1H NMR(500MHz,DMSO-d6)δ7.97-7.81(m,2H),7.35-6.80(m,7H),4.53(br t,J=5.5Hz,1H),4.45(br d,J=3.1Hz,1H),3.97(br d,J=11.6Hz,1H),3.91-3.74(m,3H),3.65(q,J=6.4Hz,2H),3.19-3.08(m,1H),2.99-2.90(m,1H),2.80(br s,1H),2.67(br d,J=19.8Hz,1H),2.08(s,1H),2.06-1.94(m,2H),1.92(s,1H),1.52(br s,1H),1.41(br d,J=10.7Hz,1H),1.24(s,1H)。
实施例69:1H NMR(500MHz,DMSO-d6)δ7.87-7.81(m,3H),7.34(t,J=73.5Hz,1H),7.24(br d,J=8.5Hz,2H),6.91(br d,J=10.4Hz,2H),5.16-5.03(m,1H),4.50(br d,J=5.5Hz,1H),3.90(s,1H),3.77(s,3H),3.31-3.24(m,1H),3.17(d,J=4.9Hz,1H),1.91(s,1H),1.78-1.63(m,4H),1.11(br s,2H)。
实施例71:1H NMR(500MHz,DMSO-d6)δ8.00-7.76(m,2H),7.38–7.27(m,4H),7.29-6.78(m,8H),4.03-3.72(m,5H)。
实施例72:1H NMR(500MHz,CDCl3)δ8.10(br d,J=8.3Hz,2H),7.06(br d,J=8.3Hz,2H),6.66(s,1H),6.64(s,2H),6.54(t,J=73.7Hz,1H),4.25(q,J=7.0Hz,2H),3.87(s,3H),3.65(s,2H),1.32(t,J=7.2Hz,3H)。
实施例78:1H NMR(500MHz,DMSO-d6)δ8.40(br s,1H),8.03-7.74(m,4H),7.38(brd,J=7.6Hz,1H),7.30-7.07(m,4H),6.92-6.62(m,2H),3.83(br s,2H),3.73(br s,3H)。
实施例79:1H NMR(500MHz,DMSO-d6)δ7.91-7.86(m,2H),7.31(s,1H),7.24-7.17(m,3H),6.98-6.92(m,2H),3.98-3.84(m,4H),3.81(s,3H),3.29-3.21(m,1H)。
实施例80:1H NMR(500MHz,CD3OD)δ8.01-7.80(m,3H),7.31-7.20(m,3H),7.13-6.61(m,4H),3.87(s,3H)。
实施例81:1H NMR(500MHz,DMSO-d6)δ7.96-7.73(m,2H),7.41-7.08(m,3H),7.07-7.03(m,1H),6.91(br d,J=10.3Hz,2H),3.82(s,3H),3.70(br s,1H),3.41-2.92(m,1H),2.67-2.59(m,2H),2.36-2.26(m,2H)。
实施例83:1H NMR(500MHz,CD3OD)δ8.05-7.76(m,2H),7.21-7.08(m,2H),7.05-6.63(m,4H),4.24-4.03(m,1H),3.88-3.81(m,3H),3.52-3.43(m,1H),2.91(s,3H),2.63
-2.54(m,2H),2.49(br s,2H)。
对于本领域技术人员来说应清楚的是,本公开文本并不限于前述说明性实施例,并且其可以在不背离本公开文本的基本属性的情况下体现为其他具体形式。因此,希望所述实施例在所有方面都被视为说明性的而非限制性的,参考所附的权利要求而不是前述实施例,并且因此落入权利要求的等同内容的含义和范围内的所有变化均旨在包含在其中。
Claims (18)
1.一种式(I)的化合物或其药学上可接受的盐:
其中
R1是烷基、卤代烷基、羟烷基、烷氧基烷基、(烷氧基羰基)烷基、烷氧基羰基、(NR6R7)羰基、Ar1或(Ar1)烷基;
Ar1是环烷基,芳基,包含碳原子和1-5个选自N、NR5a、O和S的杂原子的杂芳基,包含碳原子和1-5个选自N、NR5a、O和S的杂原子的杂环基,或包含碳原子和1-5个选自N、NR5a、O和S的杂原子的螺杂环基,其各自被1-5个R5取代;
R2是氢、烷基或卤代烷基;
R3是被1个R3a和1-2个R3b取代的苯基或吡啶基;
R3a是卤素、卤代烷基、烷氧基或卤代烷氧基;
R3b是氢、卤素或卤代烷基;
R4是被1-2个R4a取代的苯基或吡啶基;
R4a是卤素、卤代烷基、烷氧基或卤代烷氧基;
R5是氢、羟基、氰基、卤素、烷基、卤代烷基、氨基、卤代烷基氨基、烷氧基烷基、羟烷基、烷氧基、卤代烷氧基、甲酰胺、烷氧基羰基、烷基磺酰基氨基或羟烷基羰基;
R5a是氢、烷基、卤代烷基、烷氧基烷基、羟烷基、羟基烷基羰基、甲酰胺、烷基氨基羰基、氨基羰基烷基羰基、烷基磺酰基或烷氧基羰基;
R6和R7独立地是氢,烷基,卤代烷基,羟烷基,环烷基,芳基,包含碳原子和1-4个选自N、NR8a、O和S的杂原子的杂芳基,包含碳原子和1-4个选自N、NR8a、O和S的杂原子的杂环基,芳烷基,或包含碳原子和1-4个选自N、NR8a、O和S的杂原子的杂芳烷基;其中所述环烷基、芳基、杂芳基或杂环基被1-5个R8取代;
或者R6和R7与它们所连接的氮一起形成包含碳原子和0-3个选自N、NR8a、O、S的另外的杂原子的杂环基或杂芳基,其中所述杂芳基或杂环基被1-5个R8取代;
R8是氢、卤素、羟基、羟烷基、烷基、烷氧基或氧代;
R8a是氢、羟烷基或烷基。
2.根据权利要求1所述的化合物,其中
R3是被1个R3a和1-2个R3b取代的苯基;
R3a是相对于咪唑部分在对位的卤素、卤代烷基或烷氧基取代基;以及
R3b是氢、卤素或卤代烷基。
3.根据权利要求1所述的化合物,其中
R4是在相对于酰胺部分的对位被1个R4a取代的苯基;以及
R4a是卤素、烷氧基或卤代烷氧基。
4.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(II):
其中
R1是烷基、卤代烷基、羟烷基、烷氧基烷基、(烷氧基羰基)烷基、烷氧基羰基、(NR6R7)羰基、Ar1或(Ar1)烷基;
Ar1是环烷基,芳基,包含碳原子和1-4个选自N、NR5a、O和S的杂原子的杂芳基,包含碳原子和1-4个选自N、NR5a、O和S的杂原子的杂环基,包含碳原子和1-4个选自N、NR5a、O和S的杂原子的螺杂环基,其各自被1-4个R5取代;
R3a是烷氧基;
R3b是氢、卤素或卤代烷基;
R4a是卤素或卤代烷氧基;
R5是氢、羟基、氰基、卤素、烷基、卤代烷基、氨基、卤代烷基氨基、烷氧基烷基、羟烷基、烷氧基、卤代烷氧基、烷氧基羰基或烷基磺酰基氨基;
R5a是氢、烷基、卤代烷基、烷氧基烷基、羟烷基、氢烷基羰基、甲酰胺、烷基氨基羰基、氨基羰基烷基羰基、烷基磺酰基或烷氧基羰基;
R6和R7独立地是氢,烷基,卤代烷基,羟烷基,环烷基,包含碳原子和1-4个选自N、NR8a、O和S的杂原子的杂芳基,芳烷基,或包含碳原子和1-4个选自N、NR8a、O和S的杂原子的杂芳烷基,其中所述环烷基、杂芳基或杂芳烷基被1-4个R8取代;
或者R6和R7与它们所连接的氮一起形成具有0-3个选自N、NR8a、O、S的另外的杂原子的杂环基或杂芳基,其中所述杂环基或杂芳基被1-4个R8取代;
R8是氢、卤素、羟基、羟烷基、烷基、烷氧基或氧代;
R8a是氢、羟烷基或烷基。
5.根据权利要求4所述的化合物,其中
R1是被1-3个R5取代的Ar1;
Ar1是环烷基,芳基,包含碳原子和1-3个选自N、NR5a、O和S的杂原子的杂芳基,包含碳原子和1-3个选自N、NR5a、O和S的杂原子的杂环基,包含碳原子和1-3个选自N、NR5a、O和S的杂原子的螺杂环基,其各自被1-3个R5取代;
R3a是烷氧基;
R3b是氢或卤素;
R4a是卤代烷氧基;
R5是氢、羟基、氰基、卤素、烷基、卤代烷基、氨基、卤代烷基氨基、烷氧基烷基、羟烷基、烷氧基、卤代烷氧基、烷氧基羰基或烷基磺酰基氨基;以及
R5a是氢、烷基、卤代烷基、烷氧基烷基、羟烷基、氢烷基羰基、烷基氨基羰基、氨基羰基烷基羰基、烷基磺酰基或烷氧基羰基。
10.根据权利要求4所述的化合物,其中
R1是(Ar1)烷基;
R3a是烷氧基;
R3b是氢或卤素;以及
R4a是卤代烷氧基。
12.根据权利要求4所述的化合物,其中
R1是烷基或卤代烷基;
R3a是烷氧基;
R3b是氢或卤素;以及
R4a是卤代烷氧基。
13.根据权利要求4所述的化合物,其中
R1是烷氧基羰基或(烷氧基羰基)烷基;
R3a是烷氧基;
R3b是氢或卤素;以及
R4a是卤代烷氧基。
16.一种药物组合物,所述组合物包含根据权利要求1所述的化合物或其药学上可接受的盐以及药学上可接受的载体、稀释剂或赋形剂。
17.一种用于治疗心脏病的方法,所述方法包括向有需要的患者施用治疗有效量的根据权利要求16所述的药物组合物。
18.根据权利要求17所述的方法,其中所述心脏病选自心绞痛、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。
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