CN104114541A - 作为甲酰肽样受体-1(fprl-1)受体调节剂的2,5-二氧代咪唑烷-1-基-3-苯基脲衍生物 - Google Patents
作为甲酰肽样受体-1(fprl-1)受体调节剂的2,5-二氧代咪唑烷-1-基-3-苯基脲衍生物 Download PDFInfo
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Classifications
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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
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明涉及式I的新型2,5-二氧代咪唑烷-1-基-3-苯基脲衍生物、它们的制备方法、含有它们的药物组合物和它们作为N-甲酰肽样受体-1(FPRL-1)受体的调节剂的药物的用途。
Description
相关申请
本申请要求于2011年11月10日提交的美国临时申请序列第61/558,080号的权益,其公开内容在此通过引用整体并入本文。
发明领域
本发明涉及新型2,5-二氧代咪唑烷-1-基-3-苯基脲衍生物、它们的制备方法、含有它们的药物组合物和它们作为N-甲酰肽样受体-1(FPRL-1)受体的调节剂的药物的用途。本发明具体涉及治疗与N-甲酰肽样受体-1(FPRL-1)受体调节相关的病症的这些化合物及其药物组合物的用途。
发明背景
N-甲酰肽样受体-1(FPRL-1)受体,也称为N-甲酰肽受体2(FPR2),为在诸如单核细胞和中性粒细胞以及T细胞的炎性细胞中表达的G蛋白偶联的受体并且已经示出在炎症和人类病理学期间在白细胞运输中起着关键作用。FPRL-1为响应于大量外源性和内源性配体的特别混杂的受体,其包括血清淀粉样蛋白A(SAA)、趋化因子变体sCKβ8-1、人类神经保护肽、抗炎性类花生酸脂氧素A4(LXA4)和糖皮质激素调节的蛋白质膜联蛋白A1。FPRL-1在多个***中转导LXA4的抗炎效果,但是它还可介导诸如SAA的肽的促炎信号级联。该能力的受体介导的两个相反作用的结果可能使用不同的受体结构域由不同激动剂(Parmentier,Marc等。Cytokine&Growth FactorReviews17(2006)501-519)。
已经示出由LXA4或其类似物和通过Annexin I蛋白的FPRL-1的活化通过促进炎症的主动消退产生抗炎活性,这涉及多形核中性白细胞(PMN)的抑制和嗜酸细胞的移动并且还刺激单核细胞移动,使来自炎症位点的凋亡细胞能够以非炎性方式清除。此外,已经示出FPRL-1抑制自然杀伤(NK)细胞毒性并促进T细胞的活化,这进一步有助于组织损伤炎性信号的下调。已经示出FPRL-1/LXA4相互作用有益于缺血再灌注,血管生成,皮肤炎症,化疗诱导的脱发,眼部炎症诸如内毒素诱导的葡萄膜炎、角膜伤口愈合、表皮细胞再生等的实验模型。因此FPRL-1表示用于在具有过量炎症应答的疾病中形成新的治疗剂的重要的新型促革命性的(pro-resolutionary)分子靶标。
发明概述
我们现在已经发现了一组新型化合物,其是有效和选择性的FPRL-1调节剂。因此,本文描述的化合物可用于治疗许多种与FPRL-1受体的调节相关的病症。本文中所用的术语“调节剂”包括但不限于:受体激动剂、拮抗剂、反激动剂、反拮抗剂、部分激动剂、部分拮抗剂。
本发明描述了具有FPRL-1受体生物活性的式I化合物。因此,根据本发明的化合物可用于医学,例如用于治疗患有可通过FPRL-1调节得以缓解的疾病和疾患的人。
一方面,本发明提供具有式I的化合物或其几何异构体、对映异构体、非对映异构体、两性离子、水合物、溶剂化物或药学上可接受的盐:
R1为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R2为卤素、任选取代的C1-8烷基、CF3、OR9、C(O)R10、NO2、NR13R14、CN,SR15或SO2R16;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环、或与R5一起形成任选被取代的5或6元环;
R4为氢、任选取代的C1-8烷基、 任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环或与R5一起形成任选被取代的螺单环或多环的、碳环或杂环的、饱和或不饱和的5至10元环;
R5为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环、或与R4一起形成任选被取代的螺单环或多环的碳环或杂环的、饱和或不饱和的5至10元环或与R3一起形成任选被取代的5或6元环;
R6为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R7为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R8为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R10为氢、任选取代的C1-8烷基、O(C1-8烷基)、NR11R12或OH;
R11为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R12为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R13为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R14为氢、任选取代的C6-10芳基、任选取代的C1-8烷基、C(O)(C1-8烷基)或SO2(C1-8烷基);
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R16为OH、O(C1-8烷基)、(C1-8烷基)或NR11R12;
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;
m为1、2、3、4或5;并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、CF3、SR15、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基或任选取代的杂环;
R5为任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基或任选取代的杂环;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、CF3、SR15、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为任选取代的C1-8烷基、任选取代的C6-10芳基、
R5为任选取代的C1-8烷基或任选取代的C3-8环烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;
m为1、2、3、4或5;并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢;
R4为任选取代的C1-8烷基、任选取代的C6-10芳基、
R5为任选取代的C1-8烷基或任选取代的C3-8环烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;
m为1、2、3、4或5;并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、CF3、SR15、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为任选取代的C1-8烷基、
R5为任选取代的C1-8烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;
m为1、2、3、4或5;并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、CF3、SR15、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;R4为
R5为任选取代的C1-8烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;
m为1、2、3、4或5;并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、CF3、SR15、OR9或CN;
R3为氢;
R4为
R5为任选取代的C1-8烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5
m为1、2、3、4或5;并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为任选取代的C1-8烷基;
R5为任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基或任选取代的杂环;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为任选取代的C1-8烷基、
R5为任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基或任选取代的杂环;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5
m为1、2、3、4或5;并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素或氢;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢;
R4为任选取代的C1-8烷基;
R5为任选取代的C1-8烷基;
R6为卤素或氢;
R7为氢;
R8为氢;
R9为任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢、任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3与R5一起形成任选被取代的5或6元环;
R4为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环,
R5与R3一起形成任选被取代的5或6元环;
R6为卤素、氢、任选取代的C1-8烷基;
R7为卤素、氢、任选取代的C1-8烷基;
R8为卤素、氢、任选取代的C1-8烷基;
R9为氢或任选取代的C1-8烷基;并且
R15为氢、任选取代的C1-8烷基或O(C1-8烷基)。
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基或任选取代的杂环;
R4与R5一起形成任选被取代的螺单环或多环的、碳环或杂环的、饱和或不饱和的5至10元环;
R5与R4一起形成任选被取代的螺单环或多环碳环或杂环的、饱和或不饱和的5至10元环;
R6为卤素、氢、任选取代的C1-8烷基;
R7为卤素、氢、任选取代的C1-8烷基;
R8为卤素、氢、任选取代的C1-8烷基;
R9为氢或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为氢、任选取代的C1-8烷基、
R5为任选取代的C1-8烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;
m为1、2、3、4或5;并且
前提条件是式I的所述化合物不为以下结构:
在另一方面,本发明提供具有式I的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为氢、任选取代的C1-8烷基、
R5为任选取代的C1-8烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;
m为1、2、3、4或5;并且
前提条件是式I的所述化合物不为以下结构:
本文中所用的术语“烷基”是指具有直链或支链部分或其组合并且含有1至8个碳原子(除非另外指明)的饱和、单价或二价烃部分。烷基的一个亚甲基(-CH2-)基团可被氧、硫、亚砜、氮、羰基、羧基、磺酰基、硫酸酯、磺酸酯、酰胺、磺酰胺或被二价C3-8环烷基、被二价杂环或被二价芳基基团取代。烷基基团可独立地被卤素原子、羟基基团、C3-8环烷基基团、氨基基团、杂环基团、任选取代的芳基基团、羧酸基团、膦酸基团、膦酸酯基团、磺酸基团、磷酸基团、硝基基团、酰胺基团、酯基团、醚基团、酮基团、磺酰胺基团取代。
本文中所用的术语“环烷基”是指由饱和环状烃衍生的3至8个碳原子的单价或二价基团。环烷基基团可为单环或多环的。环烷基的一个亚甲基(-CH2-)基团可被氧、硫、亚砜、氮、羰基、羧基、磺酰基、硫酸酯、磺酸酯、酰胺、磺酰胺或被二价C3-8环烷基、被二价杂环或被二价芳基基团取代。环烷基可独立地被卤素原子、磺酰基(C1-8烷基)基团、亚砜(C1-8烷基)基团、磺酰胺基团、硝基基团、氰基基团、-OC1-6烷基基团、-SH、-SC1-6烷基基团、-C1-6烷基基团、-C2-6烯基基团、-C2-6炔基基团、酰胺基团、酯基团、醚基团、酮基团、烷基氨基基团、氨基基团、芳基基团、C3-8环烷基基团或羟基基团取代。
本文中所用的术语“环烯基”是指由具有一个或多个双键的饱和环烷基衍生的3至8个碳原子的单价或或二价基团。环烯基基团可为单环或多环的。环烯基的一个亚甲基(-CH2-)基团可被二价C3-8环烷基、被二价杂环或被二价芳基基团取代。环烯基基团可独立地被卤素原子、磺酰基基团、亚砜基团、硝基基团、氰基基团、-OC1-6烷基基团、-SC1-6烷基基团、-C1-6烷基基团、-C2-6烯基基团、-C2-6炔基基团、酮基团、烷基氨基基团、酰胺基团、酯基团、醚基团、氨基基团、芳基基团、磺酰胺基团、C3-8环烷基基团或羟基基团取代。
本文中所用的术语“卤素”是指氯、溴、氟、碘的原子。
本文中所用的术语“烯基”是指由具有至少一个双键的饱和烷基衍生的具有2至6个碳原子的单价或二价烃基。C2-6烯基可以呈E或Z构型。烯基基团可被如以上定义的烷基基团或被卤素原子取代。
本文中所用的术语“炔基”是指由具有至少一个三键的饱和烷基衍生的具有2至6个碳原子的单价或二价烃基。炔基基团可被如以上定义的烷基基团或被卤素原子取代。
本文中所用的术语“杂环”是指3至10元环,其可为芳族或非芳族的、饱和或非饱和的,含有中断碳环结构的至少一个选自氧、氮、硫的杂原子或其至少两个的组合。杂环可被C=O中断;S和N杂原子可被氧化。杂环可为单环或多环的。杂环部分可被卤素原子、磺酰基基团、亚砜基团、磺酰胺基团、硝基基团、氰基基团、-OC1-6烷基基团、-SC1-6烷基基团、-C1-6烷基基团、-C2-6烯基基团、-C2-6炔基基团、酮基团、烷基氨基基团、氨基基团、芳基基团、酰胺基团、酯基团、醚基团、C3-8环烷基基团或羟基基团取代。
本文中所用的术语“芳基”是指由由含有6至10个碳原子的环组成的芳族烃通过去除一个氢而衍生的有机部分。芳基可为单环或多环的。一个或多个氢原子可独立地被卤素原子、磺酰基(C1-6烷基)基团、亚砜(C1-6烷基)基团、磺酰胺基团、羧酸基团、C1-6烷基羧化物(酯)基团、酰胺基团、硝基基团、氰基基团、-OC1-6烷基基团、-SH、-SC1-6烷基基团、-C1-6烷基基团、-C2-6烯基基团、-C2-6炔基基团、醚基团、酮基团、醛基团、磺酰胺基团、烷基氨基基团、酯基团、氨基基团、芳基基团、C3-8环烷基基团或羟基基团取代。
本文中所用的术语“羟基”表示式“–OH”的基团。
本文中所用的术语“羰基”表示式“-C(O)-”的基团。
本文中所用的术语“醛”表示式“-C(O)H”的基团。
本文中所用的术语“酮”表示式“-C(O)Rx”的基团,其中Rx为如上定义的烷基、芳基、环烷基、环烯基、杂环。
本文中所用的术语“醚”表示式-(O)Rx的基团,其中Rx为如上定义的烷基、芳基、环烷基、环烯基、杂环。
本文中所用的术语“胺”表示式“-NRxRy“的基团,其中Rx为如上定义的烷基、芳基、环烷基、环烯基、杂环并且Ry为如以上定义的烷基、芳基、环烷基、杂环。
本文中所用的术语“羧基”表示式“-C(O)O-”的基团。
本文中所用的术语“磺酰基”表示式“-SO2 -”的基团。
本文中所用的术语“硫酸酯”表示式“-O-S(O)2-O-”的基团。
本文中所用的术语“磺酸酯”表示式“-S(O)2-O-”的基团。
本文中所用的术语“羧酸”表示式“-C(O)OH”的基团。
本文中所用的术语“酯”表示式“-C(O)ORx”的基团,其中Rx为如上定义的烷基、芳基、环烷基、环烯基、杂环。
本文中所用的术语“硝基”表示式“–NO2“的基团。
本文中所用的术语“氰基”表示式“-CN”基团。
本文中所用的术语“酰胺”表示式“-C(O)NRxRy”的基团,其中Rx和Ry可独立地为如上定义的氢、烷基、芳基、环烷基、环烯基、杂环。
本文中所用的术语“sulfonamide”表示式“-S(O)2NRxRy”的基团,其中Rx和Ry可独立地为如上定义的氢、烷基、芳基、环烷基、环烯基、杂环。
本文中所用的术语“亚砜”表示式“-S(O)-”的基团。
本文中所用的术语“膦酸”表示式“-P(O)(OH)2”的基团。
本文中所用的术语“膦酸酯”表示式“-P(O)(OH)(OC1-8烷基)”或“-P(O)(OC1-8烷基)(OC1-8烷基)”的基团。
本文中所用的术语“磷酸”表示式“-OP(O)(OH)2”基团。
本文中所用的术语“磺酸”表示式“-S(O)2OH“的基团。
本文中所用的式“H”表示氢原子。
本文中所用的式“O”表示氧原子。
本文中所用的式“N”表示氮原子。
本文中所用的式“S”表示硫原子。
通常R1为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16。优选的R1为卤素或氢。更优选的R1为氢或氟。
通常R2为卤素、任选取代的C1-8烷基、OR9、C(O)R10、CF3、NO2、NR13R14、CN、SR15或SO2R16。优选的R2为卤素、任选取代的C1-8烷基、OR9、CN或SR15。更优选的R2为氯、溴、甲氧基、CF3、甲基、乙基、氰基、硫甲基。
通常R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环、或与R5一起形成任选被取代的5或6元环。优选的R3为氢或与R5一起形成任选被取代的5或6元环。更优选的R3为氢或与R5一起形成任选被取代的6元环。
通常R4为氢、任选取代的C1-8烷基、 任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环或与R5一起形成任选被取代的螺单环或多环的、碳环或杂环的、饱和或不饱和的5至10元环。优选的R4为任选取代的C1-8烷基、任选取代的C3-8环烷基或与R5一起形成任选被取代的螺单环或多环的、碳环或杂环的、饱和或不饱和的5至10元环。
更优选的R4为甲基、异丙基、乙基、环丙基、异丁基、 或与R5一起形成螺单环或多环的、碳环的、饱和或不饱和的5至10元环。最优选的R4为甲基、异丙基、乙基、环丙基、异丁基、 或与R5一起形成螺环戊基或环己基单环饱和的碳环或螺多环部分不饱和的8或10元环诸如2,3-二氢-1H-茚或1,2,3,4-四氢萘(1,2,3,4-tetrahydronaphtalene)。
通常R5为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环、或与R4一起形成任选被取代的螺单环或多环的碳环或杂环的、饱和或不饱和的5至10元环或与R3一起形成任选被取代的5或6元环。优选的R5为任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的杂环或与R4一起形成任选被取代的螺单环或多环碳环或杂环的、饱和或未饱和的5至10元环或与R3一起形成任选被取代的5或6元环。
更优选的R5为甲基、乙基、异丙基、异丁基、用任选取代的苯基取代的乙基、用任选取代的呋喃取代的乙基、用任选取代的噻吩取代的乙基、任选取代的吲哚、环丙基或与R4一起形成螺环戊基或环己基单环饱和碳环或螺多环部分不饱和的8或10元环诸如2,3-二氢-1H-茚或1,2,3,4-四氢萘或形成任选被取代的6元环。
通常R6为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16。优选的R6为卤素或氢。更优选的R6为氟或氢。
通常R7为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16。优选的R7为氢。
通常R8为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16。优选的R8为氢。
通常R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基。优选的R9为任选取代的C1-8烷基。更优选的R9为甲基。
通常R10为氢、任选取代的C1-8烷基、O(C1-8烷基)、NR11R12或OH。
通常R11为氢、任选取代的C6-10芳基或任选取代的C1-8烷基。
通常R12为氢、任选取代的C6-10芳基或任选取代的C1-8烷基。
通常R13为氢、任选取代的C6-10芳基或任选取代的C1-8烷基。
通常R14为氢、任选取代的C6-10芳基、任选取代的C1-8烷基、C(O)(C1-8烷基)或SO2(C1-8烷基)。
通常R15为氢、任选取代的C1-8烷基或O(C1-8烷基)。
通常R16为羟基、O(C1-8烷基)、(C1-8烷基)或NR11R12。
通常R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基。
优选的R17为氢、甲基、乙基、叔丁基。
通常R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基。
优选的R18为氢、甲基、乙基、叔丁基-(CH2)n-(COOC1-8烷基)、-(CH2)n-OH、-(CH2)n-P(O)(OC1-8烷基)2、-(CH2)n-P(O)(OH)(OC1-8烷基)、-(CH2)n-(COOH)、-(CH2)n-(CONH(C1-8烷基))、-(CH2)n-(CONH2)、-(CH2)n-(CON(C1-8烷基)(C1-8烷基))、-(CH2)n-(SO3H)、-(C(C1-8烷基)(C1-8烷基))n(COO C1-8烷基)、-(C(C1-8烷基)(C1-8烷基))n(OH)、-(C(C1-8烷基)(C1-8烷基))n P(O)(OC1-8烷基)2、-(C(C1-8烷基)(C1-8烷基))nP(O)(OH)(OC1-8烷基)、-(C(C1-8烷基)(C1-8烷基))n(COOH)、-(C(C1-8烷基)(C1-8烷基))n(CONH(C1-8烷基))、-(C(C1-8烷基)(C1-8烷基))n(CONH2)、-(C(C1-8烷基)(C1-8烷基))n(CON(C1-8烷基)(C1-8烷基))、-(C(C1-8烷基)(C1-8烷基))n-(SO3H)、-(CH(C1-8烷基))n(COO C1-8烷基)、-(CH(C1-8烷基))n(OH)、-(CH(C1-8烷基))n P(O)(OC1-8烷基)2、-(CH(C1-8烷基))n P(O)(OH)(OC1-8烷基)、-(CH(C1-8烷基))n(COOH)、-(CH(C1-8烷基))n(CONH(C1-8烷基))、-(CH(C1-8烷基))n(CONH2)、-(CH(C1-8烷基))n(CON(C1-8烷基)(C1-8烷基))、-(CH(C1-8烷基))n-(SO3H)。
更优选的R18为氢、-(CH2)2(OH)、-(CH2)(COOtBu)、-(CH2)(CONH2)、-(C(CH3)2)(COOH)、-(C(CH3)2)(COOtBu)、-(CH2)P(O)(OiPr)2、-(CH2)P(O)(OEt)2、-(CH2)P(O)(OH)(OEt)、-(CH2)2(COOtBu)、-(CH2)2(CONH2)、-(C(CH3)2)(CH2)(COOH)、-(C(CH3)2)(CH2)(COOtBu)、-(CH2)2P(O)(OiPr)2、-(CH2)2P(O)(OEt)2、或(CH2)2P(O)(OH)(OEt)。
通常R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基。
优选的R19为氢、甲基、乙基、叔丁基、-(CH2)n-(COOC1-8烷基)、-(CH2)n-OH、-(CH2)n-P(O)(OC1-8烷基)2、-(CH2)n-P(O)(OH)(OC1-8烷基)、-(CH2)n-(COOH)、-(CH2)n-(CONH(C1-8烷基))、-(CH2)n-(CONH2)、-(CH2)n-(CON(C1-8烷基)(C1-8烷基))、-(CH2)n-(SO3H)、-(C(C1-8烷基)(C1-8烷基))n(COO C1-8烷基)、-(C(C1-8烷基)(C1-8烷基))n(OH)、-(C(C1-8烷基)(C1-8烷基))n P(O)(OC1-8烷基)2、-(C(C1-8烷基)(C1-8烷基))nP(O)(OH)(OC1-8烷基)、-(C(C1-8烷基)(C1-8烷基))n(COOH)、-(C(C1-8烷基)(C1-8烷基))n(CONH(C1-8烷基))、-(C(C1-8烷基)(C1-8烷基))n(CONH2)、-(C(C1-8烷基)(C1-8烷基))n(CON(C1-8烷基)(C1-8烷基))、-(C(C1-8烷基)(C1-8烷基))n-(SO3H)、-(CH(C1-8烷基))n(COO C1-8烷基)、-(CH(C1-8烷基))n(OH)、-(CH(C1-8烷基))n P(O)(OC1-8烷基)2、-(CH(C1-8烷基))n P(O)(OH)(OC1-8烷基)、-(CH(C1-8烷基))n(COOH)、-(CH(C1-8烷基))n(CONH(C1-8烷基))、-(CH(C1-8烷基))n(CONH2)、-(CH(C1-8烷基))n(CON(C1-8烷基)(C1-8烷基))、-(CH(C1-8烷基))n-(SO3H)。
优选的R19为氢、甲基、乙基、叔丁基。
通常R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基。优选的R20为氢、甲基、乙基、叔丁基。
通常R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基。优选的R21为氢、甲基、乙基、叔丁基。
通常n为1、2、3、4或5。优选的n为1、2或3。最优选的n为1或2。
通常m为1、2、3、4或5。优选的m为1、2或3。最优选的m为1或2。
本发明的化合物为:
1-(4-溴苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-氯苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-甲氧基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-乙基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-氰基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-甲基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-甲基硫基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.4]壬-3-基)脲;
1-(4-溴-2-氟苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.4]壬-3-基)脲;
1-(4-溴苯基)-3-(4,4-二甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(2,5-二氧代-1′,3′-二氢螺[咪唑烷-4,2′-茚]-1-基)脲;
1-(4-溴苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.5]癸-3-基)脲;
1-(4-溴-2-氟苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.5]癸-3-基)脲;
1-(4-氯-2-氟苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-氯-3-氟苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(2,4-二氧代-1,3-二氮杂螺[4,5]癸-3-基)-3-(4-甲氧基苯基)脲;
(S)-1-(4-溴苯基)-3-(1,3-二氧代-10,10a-二氢咪唑并[1,5-b]异喹啉-2(1H,3H,5H)-基)脲;
(S)-1-(4-溴-2-氟苯基)-3-(1,3-二氧代-10,10a-二氢咪唑并[1,5-b]异喹啉-2(1H,3H,5H)-基)脲;
1-(4-溴-2-氟苯基)-3-(2,5-二氧代-1′,3′-二氢螺[咪唑烷-4,2′-茚]-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-(苯氧基甲基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(2,5-二氧代-3’,4’-二氢-1’H-螺[咪唑烷-4.2’萘-1-基)脲;
1-(4-溴-2-氟苯基)-3-(2,5-二氧代-3’,4’-二氢-1’H-螺[咪唑烷-4.2’萘-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-(苯氧基甲基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-乙基-2,5-二氧代-4-(苯乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-乙基-2,5-二氧代-4-(苯乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-异丁基-2,5-二氧代-4-苯乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-异丁基-2,5-二氧代-4-苯乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(4-氯苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-氯苯乙基)-4-甲基-2,5-二氧代-咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-呋喃-2-基)乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-呋喃-2-基)乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(4-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(4-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-(2-噻吩-2-基)乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-(2-噻吩-2-基)乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-4-(2-(5-甲基呋喃-2-基)乙基)-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-氟-4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-氟-4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-异丙基-4-(2-((4-甲氧基苄基)氧基)乙基)-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(3-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-(2-(吡啶-4-基)乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-(吡啶-4-基)乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-异丙基-4-(((4-甲氧基苄基)氧基)甲基)-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-异丙基-4-(((4-甲氧基苄基)氧基)甲基)-2,5-二氧代咪唑烷-1-基)脲;
4-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(2-(1-(3-(4-溴-2-氟苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(1-(3-(4-溴-2-氟苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸乙酯;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸乙酯;
1-(4-溴苯基)-3-[4-(1H-吲哚-3-基甲基)-4-甲基-2,5-二氧代咪唑烷-1-基]脲;
1-(4-溴-2-氟苯基)-3-[4-(5-乙基-1H-吲哚-2-基)-4-甲基-2,5-二氧代咪唑烷-1-基]脲;
1-(4-溴苯基)-3-(4,4-二环丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-[2,5-二氧代-4,4-二(丙-2-基)咪唑烷-1-基]脲;
乙基-3-[1-{[(4-溴苯基)氨甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]丙酸酯;
1-(4-溴苯基)-3-(4,4-二甲基-2,5-二氧代-3-苯基咪唑烷-1-基)脲;
(-)-1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
(+)-1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
(+)-1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
(-)-1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(羟甲基)-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-羟乙基)-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-羟甲基)-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
4-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸;
2-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸;
2-(2-(1-(3-(4-溴苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸;
2-(2-(1-(3-(4-溴-2-氟苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸;
2-(1-(3-(4-溴-2-氟苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸;
3-[1-{[(4-溴苯基)氨甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]丙酸;
3-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)丙酸;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)-N-(2-羟乙基)乙酰胺;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)乙酸叔丁酯;
((2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)甲基)膦酸二乙酯;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)-N,N-双(2-羟乙基)乙酰胺;
((2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)甲基)膦酸二异丙酯;
((2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)甲基)膦酸氢乙酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)2-甲基丙酸叔丁酯;
3-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)丙酸叔丁酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)乙酸;
3-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)丙酸;
2-(1-(3-(4-溴-2-氟苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)-N-(2-羟乙基)乙酰胺;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)2-甲基丙酸;
N-(2-氨基-2-氧代乙基)-2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰胺。
一些式I化合物及一些它们的中间体在其结构中具有至少一个不对称中心。此不对称中心可以R或S构型存在,所述R和S标记的使用与Pure Appli.Chem.(1976),45,11-13中所述的规则一致。
术语“药学上可接受的盐”是指指保持上文确定的化合物的所需生物活性并表现出最小的或不表现出非期望的毒理效应的盐或复合物。根据本发明的“药学上可接受的盐”包括式I化合物能够形成的具有治疗活性的无毒碱式或酸式盐形式。
作为碱以其游离形式存在的式I化合物的酸加成盐形式可通过用合适的酸处理游离碱而获得,诸如无机酸,例如盐酸、氢溴酸、硫酸、磷酸、硝酸等;或有机酸,例如乙酸、羟基乙酸、丙酸、乳酸、丙酮酸、丙二酸、延胡索酸、马来酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、扑酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、甲酸等(Handbook of Pharmaceutical Salts,P.Heinrich Stahal&CamilleG.Wermuth(编辑),Verlag Helvetica Chemica Acta-Zürich,2002,329-345)。
以其酸形式存在的式I化合物的碱加成盐形式可以通过用合适的碱处理酸而获得,诸如无机碱,例如氢氧化钠、氢氧化镁、氢氧化钾、氢氧化钙、氨等;或有机碱例如L-精氨酸、乙醇胺、甜菜碱、苄星(benzathine)、吗啉等。(Handbook of Pharmaceutical Salts,P.HeinrichStahal&Camille G.Wermuth(编辑),Verlag Helvetica Chemica Acta-Zürich,2002,329-345)。
式I化合物及其盐可以呈溶剂化物形式,溶剂化物包括在本发明的范围内。这种溶剂化物包括例如水合物、醇化物等。
至于本发明提及一种化合物或多种化合物,旨在涵盖该化合物的每一种可能的同分异构形式及其混合物,除非具体提及的是特定的同分异构形式。
根据本发明的化合物可以不同的多晶型物存在。虽然未在上式中明确指明,但是此类形式旨在包括在本发明的范围内。
本发明的化合物被指明用于治疗或预防有可能有涉及N-甲酰肽样受体-1受体的成分的病状。
在另一个实施方案中,提供了在药学上可接受的载体中包含至少一种本发明化合物的药物组合物。
在本发明进一步的实施方案中,提供了治疗与N-甲酰肽样受体-1受体的调节相关的病症的方法。
这种方法可例如通过向有此需要的受试者施用含有治疗有效量的至少一种本发明化合物的药物组合物来实施。
N-甲酰肽样受体-1受体调节剂的治疗效用是眼部炎症性疾病,包括但不限于湿性及干性年龄相关性黄斑变性(ARMD)、葡萄膜炎、干眼病、角膜炎、变应性眼病和影响眼睛后部的疾患,诸如黄斑病变和视网膜变性(包括非渗出性年龄相关黄斑变性、渗出性年龄相关黄斑变性、脉络膜新生血管形成、糖尿病性视网膜病变(增生性的)、早产儿视网膜病(ROP)、急性黄斑视神经视网膜病变、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿和糖尿病性黄斑水肿;传染性角膜炎、葡萄膜炎、疱疹性角膜炎、角膜血管生成、***生成、葡萄膜炎、视网膜炎和脉络膜炎,诸如急性多灶性鳞状色素上皮病变、贝切特氏病、鸟枪弹样视网膜脉络膜病变、感染性(梅毒、莱姆病、结核病、弓形体病)、中间葡萄膜炎(睫状体平坦部炎(pars planitis))、多灶性脉络膜炎、多发性消散白点综合征(mewds)、眼部结节病、后巩膜炎、匐行状脉络膜炎、视网膜下纤维化和葡萄膜炎综合征、Vogt-Koyanagi-Harada综合征和血管疾病/渗出性疾病诸如视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、囊样黄斑水肿、弥散性血管内凝血病变、视网膜分支静脉阻塞、高血压性眼底改变、眼部缺血综合征、视网膜动脉血管瘤、柯氏症(Coat's disease)、旁中心凹毛细管扩张、半侧视网膜静脉阻塞、视***静脉炎、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉疾病(CAD)、磨砂分支血管炎、镰状红细胞性视网膜病变和其它血红蛋白病、血管样条纹症、家族性渗出性玻璃体视网膜病变和视网膜静脉周围炎;创伤性/外科疾患诸如交感性眼炎、葡萄膜炎视网膜疾病、视网膜脱离、创伤、激光引起的疾患、由光动力学疗法、光凝固、手术中的灌注不足引起的疾患、放射性视网膜病变和骨髓移植视网膜病变;增生性病症诸如增生性玻璃体视网膜病变和视网膜前膜、和增生性糖尿病性视网膜病变;感染性病症,例如眼组织胞浆菌病、眼弓蛔虫病、推测的假组织胞浆菌病综合征(POHS)、眼内炎、弓形体病、与HIV感染有关的视网膜疾病、与HIV感染相关的脉络膜病、与HIV感染相关的葡萄膜炎性病变、病毒性视网膜炎、急性视网膜坏死、进行性外部视网膜坏死、真菌视网膜疾病、眼梅毒、眼结核、弥漫性单侧亚急性视神经视网膜炎和蝇蛆病;遗传病症诸如色素性视网膜炎、与视网膜营养不良相关的全身性疾病、先天性静止性夜盲症、锥营养不良、斯特格氏病(Stargardt's disease)和眼底黄色斑点症、贝斯特氏病、视网膜色素上皮的图形营养不良、X-连锁视网膜劈裂、Sorsby眼底营养不良、良性同心性黄斑病变、Bietti结晶样营养不良,和弹性假黄色瘤;视网膜撕裂/裂孔如视网膜脱离、黄斑裂孔和巨大视网膜撕裂;肿瘤诸如与肿瘤有关的视网膜疾病、视网膜色素上皮细胞先天性肥大、后部葡萄膜黑色素瘤、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜和视网膜色素上皮细胞的联合错构瘤、视网膜母细胞瘤、眼底血管增生性肿瘤、视网膜星形细胞瘤、和眼内淋巴肿瘤;以及影响眼睛后部的各种其它疾病,诸如点状内层脉络膜病变、急性多灶性鳞状色素上皮病变、近视视网膜变性和急性视网膜色素上皮炎、全身性炎性疾病,诸如中风、冠状动脉疾病、阻塞性气道疾病、HIV-介导的逆转录病毒感染,心血管病症包括冠状动脉疾病、神经炎症、神经学病症、疼痛和免疫病症、哮喘、***反应性疾病、炎症、***性红斑狼疮、银屑病,CNS病症诸如阿尔茨海默病、关节炎、败血病、炎性肠病、恶病质、心绞痛、手术后角膜炎症、眼睑炎、MGD、皮肤伤口愈合、烧伤、酒渣鼻、特应性皮炎、痤疮、银屑病、脂溢性皮炎、光线性角化病、病毒性疣、光老化风湿性关节炎和相关的炎症病症、脱发、青光眼、静脉分支闭塞、贝斯特氏卵黄状黄斑变性(Best’s vitelliform macular degenartion)、色素性视网膜炎、增生性玻璃体视网膜病变(PVR)和RPE任一光感受器的任何其它退行性疾病(Perretti,Mauro等.Pharmacology&Therapeutics127(2010)175-188.)。
这些化合物可用于治疗患有一系列可通过N-甲酰肽样受体-1受体调节得以缓解的疾患和疾病的哺乳动物,包括人,所述疾患和疾病包括但不限于眼部炎性疾病的治疗:湿性及干性年龄相关性黄斑变性(ARMD)、葡萄膜炎、干眼病、角膜炎、变应性眼病和影响眼睛后部的疾患,诸如黄斑病变和视网膜变性(包括非渗出性年龄相关黄斑变性、渗出性年龄相关黄斑变性、脉络膜新生血管形成、糖尿病性视网膜病变(增生性的)、早产儿视网膜病(ROP)、急性黄斑视神经视网膜病变、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿和糖尿病性黄斑水肿;传染性角膜炎、葡萄膜炎、疱疹性角膜炎、角膜血管生成、***生成、葡萄膜炎、视网膜炎和脉络膜炎,诸如急性多灶性鳞状色素上皮病变、贝切特氏病、鸟枪弹样视网膜脉络膜病变、感染性(梅毒、莱姆病、结核病、弓形体病)、中间葡萄膜炎(睫状体平坦部炎)、多灶性脉络膜炎、多发性消散白点综合征、眼部结节病、后巩膜炎、匐行状脉络膜炎、视网膜下纤维化和葡萄膜炎综合征、Vogt-Koyanagi-Harada综合征和血管疾病/渗出性疾病诸如视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、囊样黄斑水肿、弥散性血管内凝血病变、视网膜分支静脉阻塞、高血压性眼底改变、眼部缺血综合征、视网膜动脉血管瘤、柯氏症、旁中心凹毛细管扩张、半侧视网膜静脉阻塞、视***静脉炎、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉疾病(CAD)、磨砂分支血管炎、镰状红细胞性视网膜病变和其它血红蛋白病、血管样条纹症、家族性渗出性玻璃体视网膜病变和视网膜静脉周围炎;创伤性/外科疾患诸如交感性眼炎、葡萄膜炎视网膜疾病、视网膜脱离、创伤、激光引起的疾患、由光动力学疗法、光凝固、手术中的灌注不足引起的疾患、放射性视网膜病变和骨髓移植视网膜病变;增生性病症诸如增生性玻璃体视网膜病变和视网膜前膜、和增生性糖尿病性视网膜病变;感染性病症,例如眼组织胞浆菌病、眼弓蛔虫病、推测的假组织胞浆菌病综合征(POHS)、眼内炎、弓形体病、与HIV感染有关的视网膜疾病、与HIV感染相关的脉络膜病、与HIV感染相关的葡萄膜炎性病变、病毒性视网膜炎、急性视网膜坏死、进行性外部视网膜坏死、真菌视网膜疾病、眼梅毒、眼结核、弥漫性单侧亚急性视神经视网膜炎和蝇蛆病;遗传病症诸如色素性视网膜炎、与视网膜营养不良相关的全身性疾病、先天性静止性夜盲症、锥营养不良、斯特格氏病和眼底黄色斑点症、贝斯特氏病、视网膜色素上皮的图形营养不良、X-连锁视网膜劈裂、Sorsby眼底营养不良、良性同心性黄斑病变、Bietti结晶样营养不良,和弹性假黄色瘤;视网膜撕裂/裂孔如视网膜脱离、黄斑裂孔和巨大视网膜撕裂;肿瘤诸如与肿瘤有关的视网膜疾病、视网膜色素上皮细胞先天性肥大、后部葡萄膜黑色素瘤、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜和视网膜色素上皮细胞的联合错构瘤、视网膜母细胞瘤、眼底血管增生性肿瘤、视网膜星形细胞瘤、和眼内淋巴肿瘤;以及影响眼睛后部的各种其它疾病,诸如点状内层脉络膜病变、急性多灶性鳞状色素上皮病变、近视视网膜变性和急性视网膜色素上皮炎、全身性炎性疾病,诸如中风、冠状动脉疾病、阻塞性气道疾病、HIV-介导的逆转录病毒感染,心血管病症包括冠状动脉疾病、神经炎症、神经学病症、疼痛和免疫病症、哮喘、***反应性疾病、炎症、***性红斑狼疮、银屑病,CNS病症诸如阿尔茨海默病、关节炎、败血病、炎性肠病、恶病质、心绞痛、手术后角膜炎症、眼睑炎、MGD、皮肤伤口愈合、烧伤、酒渣鼻、特应性皮炎、痤疮、银屑病、脂溢性皮炎、光线性角化病、病毒性疣、光老化风湿性关节炎和相关的炎症病症、脱发、青光眼、静脉分支闭塞、贝斯特氏卵黄状黄斑变性、色素性视网膜炎、增生性玻璃体视网膜病变(PVR)和RPE任一光感受器的任何其它退行性疾病。
在本发明的又一个实施方案中,提供了用于治疗与FPRL-1受体的调节相关的病症的方法。这种方法可以例如通过向有此需要的受试者施用治疗有效量的至少一种本发明化合物或其任意组合、或其药学上可接受的盐、水合物、溶剂化物、晶型和单独的同分异构体、对映异构体和非对映异构体来实施。
本发明涉及式I化合物或其药学上可接受的盐用于制造治疗以下眼部炎症疾病的药剂的用途包括但不限于:葡萄膜炎、干眼病、角膜炎、变应性眼病和影响眼睛后部的疾患,诸如黄斑病变和视网膜变性(包括非渗出性年龄相关黄斑变性、渗出性年龄相关黄斑变性、脉络膜新生血管形成、糖尿病性视网膜病变、急性黄斑视神经视网膜病变、中心性浆液性脉络膜视网膜病变、囊样黄斑水肿和糖尿病性黄斑水肿;传染性角膜炎、葡萄膜炎、疱疹性角膜炎、角膜血管生成、***生成、葡萄膜炎、视网膜炎和脉络膜炎,诸如急性多灶性鳞状色素上皮病变、贝切特氏病、鸟枪弹样视网膜脉络膜病变、感染性(梅毒、莱姆病、结核病、弓形体病)、中间葡萄膜炎(睫状体平坦部炎)、多灶性脉络膜炎、多发性消散白点综合征、眼部结节病、后巩膜炎、匐行状脉络膜炎、视网膜下纤维化和葡萄膜炎综合征、Vogt-Koyanagi-Harada综合征和血管疾病/渗出性疾病诸如视网膜动脉阻塞性疾病、视网膜中央静脉阻塞、弥散性血管内凝血病变、视网膜分支静脉阻塞、高血压性眼底改变、眼部缺血综合征、视网膜动脉血管瘤、柯氏症、旁中心凹毛细管扩张、半侧视网膜静脉阻塞、视***静脉炎、视网膜中央动脉阻塞、视网膜分支动脉阻塞、颈动脉疾病(CAD)、磨砂分支血管炎、镰状红细胞性视网膜病变和其它血红蛋白病、血管样条纹症、家族性渗出性玻璃体视网膜病变和视网膜静脉周围炎;创伤性/外科疾患诸如交感性眼炎、葡萄膜炎视网膜疾病、视网膜脱离、创伤、激光引起的疾患、由光动力学疗法、光凝固、手术中的灌注不足引起的疾患、放射性视网膜病变和骨髓移植视网膜病变;增生性病症诸如增生性玻璃体视网膜病变和视网膜前膜、和增生性糖尿病性视网膜病变;感染性病症,例如眼组织胞浆菌病、眼弓蛔虫病、推测的假组织胞浆菌病综合征(POHS)、眼内炎、弓形体病、与HIV感染有关的视网膜疾病、与HIV感染相关的脉络膜病、与HIV感染相关的葡萄膜炎性病变、病毒性视网膜炎、急性视网膜坏死、进行性外部视网膜坏死、真菌视网膜疾病、眼梅毒、眼结核、弥漫性单侧亚急性视神经视网膜炎和蝇蛆病;遗传病症诸如色素性视网膜炎、与视网膜营养不良相关的全身性疾病、先天性静止性夜盲症、锥营养不良、斯特格氏病和眼底黄色斑点症、贝斯特氏病、视网膜色素上皮的图形营养不良、X-连锁视网膜劈裂、Sorsby眼底营养不良、良性同心性黄斑病变、Bietti结晶样营养不良,和弹性假黄色瘤;视网膜撕裂/裂孔如视网膜脱离、黄斑裂孔和巨大视网膜撕裂;肿瘤诸如与肿瘤有关的视网膜疾病、视网膜色素上皮细胞先天性肥大、后部葡萄膜黑色素瘤、脉络膜血管瘤、脉络膜骨瘤、脉络膜转移、视网膜和视网膜色素上皮细胞的联合错构瘤、视网膜母细胞瘤、眼底血管增生性肿瘤、视网膜星形细胞瘤、和眼内淋巴肿瘤;以及影响眼睛后部的各种其它疾病,诸如点状内层脉络膜病变、急性多灶性鳞状色素上皮病变、近视视网膜变性和急性视网膜色素上皮炎、全身性炎性疾病,诸如中风、冠状动脉疾病、阻塞性气道疾病、HIV-介导的逆转录病毒感染,心血管病症包括冠状动脉疾病、神经炎症、神经学病症、疼痛和免疫病症、哮喘、***反应性疾病、炎症、***性红斑狼疮、银屑病,CNS病症诸如阿尔茨海默病、关节炎、败血病、炎性肠病、恶病质、心绞痛、手术后角膜炎症、眼睑炎、MGD、皮肤伤口愈合、烧伤、酒渣鼻、特应性皮炎、痤疮、银屑病、脂溢性皮炎、光线性角化病、病毒性疣、光老化风湿性关节炎和相关的炎症病症、脱发、青光眼、静脉分支闭塞、贝斯特氏卵黄状黄斑变性、色素性视网膜炎、增生性玻璃体视网膜病变(PVR)和RPE任一光感受器的任何其它退行性疾病。
在任何给定病例中要施用的化合物的实际量将由医生考虑相关的情况予以确定,诸如考虑病状的严重程度、患者的年龄及体重、患者的一般身体状况、病因和施用途径。
将以任何可接受的形式给患者口服施用所述化合物,诸如片剂、液体、胶囊、粉末等,或者其它途径可能是可取的或必要的,特别是如果患者出现恶心的情况。此类其它途径可以毫无例外地包括透皮、肠胃外、皮下、鼻内、通过植入支架、鞘内、玻璃体内、眼局部、眼后部、肌内、静脉内和直肠内递送模式。另外,可对制剂进行设计以在给定时间段内延迟活性化合物的释放,或仔细地控制在治疗过程期间于给定时间释放的药物量。
在本发明的另一个实施方案中,提供了在药学上可接受的载体中包括至少一种本发明化合物的药物组合物。短语“药学上可接受的”意指载体、稀释剂或赋形剂必须与制剂中的其它成分相容并且对其受者无害。
本发明的药物组合物可以固体、溶液、乳液、分散体、贴剂、胶束、脂质体等形式使用,其中所得到的组合物包含作为活性成分与适用于肠内或肠胃外应用的有机或无机载体或赋形剂配混的一种或多种本发明化合物。本发明化合物可例如与通常无毒、药学上可接受的用于片剂、丸剂、胶囊剂、栓剂、溶液、乳剂、混悬剂和任何其他适用形式的载体组合。可用的载体包括葡萄糖、乳糖、***胶、明胶、甘露醇、淀粉糊、三硅酸镁、滑石、玉米淀粉、角蛋白、胶体二氧化硅、马铃薯淀粉、脲、中等链长甘油三酯、葡聚糖和其它适合于以固体、半固体或液体形式在制造制剂中使用的载体。此外,可以使用助剂、稳定剂、增稠剂和着色剂以及芳香剂。本发明化合物以足以对进程或病情产生所需效果的量包括在药物组合物中。
含有本发明化合物的药物组合物可以呈适合口服使用的形式,例如作为片剂、锭剂、糖锭剂、水性或油性混悬液、分散性粉末或颗粒、乳液、硬或软胶囊、或糖浆剂或酏剂。意图用于口服使用的组合物可根据本领域已知的用于制造药物组合物的任何方法制备,并且此类组合物可含有选自由以下组成的组的一种或多种试剂:甜味剂,诸如蔗糖、乳糖或糖精;调味剂,诸如薄荷油、冬青油或桂樱油;着色剂和防腐剂,以便提供药学上美观和可口的制剂。含有与无毒药学上可接受的赋形剂配混的本发明化合物的片剂也通过已知的方法制造。所用的赋形剂可以例如为:(1)惰性稀释剂,诸如碳酸钙、乳糖、磷酸钙或磷酸钠;(2)制粒剂和崩解剂,诸如玉米淀粉、马铃薯淀粉或藻酸;(3)粘合剂,诸如黄蓍胶、玉米淀粉、明胶或***树胶;以及(4)润滑剂,诸如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的,或者它们可以通过已知技术包衣以延缓在胃肠道中的崩解和吸收,并从而在更长的时间内提供持久的作用。例如,可以使用延时材料,诸如单硬脂酸甘油酯或二硬脂酸甘油酯。
在一些情况下,口服使用的制剂可以为硬明胶胶囊形式,其中将本发明化合物与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合。它们也可以呈软明胶胶囊形式,其中将本发明化合物与水或油性介质例如花生油、液体石蜡或橄榄油混合。
药物组合物可以呈无菌注射用混悬剂形式。该混悬剂可根据已知的方法使用合适的分散剂或润湿剂和助悬剂配制。无菌注射用制剂也可以为无毒、肠胃外可接受的稀释剂或溶剂中的无菌注射用溶液或混悬剂,例如作为1,3-丁二醇中的溶液。通常将无菌、固定油用作溶剂或助悬介质。为此,可以采用任何温和的固定油,包括合成的单或二甘油酯、脂肪酸(包括油酸)、天然存在的植物油(如芝麻油、椰子油、花生油、棉籽油等)或合成的脂肪媒介物(如油酸乙酯)等等。缓冲剂、防腐剂、抗氧化剂等可按需要掺入。
本发明化合物可以用于药物直肠施用的栓剂形式施用。这些组合物可通过将本发明化合物与合适的非刺激性赋形剂混合来制备,所述赋形剂诸如可可油、合成的聚乙二醇甘油酯,它们在常温下为固体,但在直肠腔内则液化和/或溶解以释放药物。
因为个别受试者可能呈现症状严重程度的广泛变化并且每种药物有其独特的治疗特点,所以对每一受试者使用的精确施用模式和用量由待医师酌处。
本文所述的化合物和药物组合物适合作为包括人在内的哺乳动物的药剂,用于治疗疾病和或缓解对通过激动剂或N-甲酰肽样受体-1(FPRL-1)受体的功能性拮抗剂治疗有反应的病状。因此,在本发明进一步的实施方案中,提供了治疗与N-甲酰肽样受体-1(FPRL-1)受体的调节相关的病症的方法。这种方法可以例如通过向有此需要的受试者施用含有治疗有效量的至少一种本发明化合物的药物组合物来实施。如本文所用,术语“治疗有效量”意指研究人员、兽医、医生或其他临床医生所寻求的将引起有此需要的受试者出现生物学或医学反应的药物组合物的量。在一些实施方案中,有此需要的受试者是哺乳动物。在一些实施方案中,所述哺乳动物是人。
本发明还涉及用于制备式I化合物的工艺。可采用与合成有机化学领域技术人员所理解的常规方法相似地制备根据本发明的式I化合物。下面提出的合成方案1阐明了如何制备根据本发明的化合物。
方案1
本发明范围内的化合物可以如方案1中描述制备。通常,3-氨基-2,4-咪唑烷二酮可与含苯基异氰酸酯的甲苯在100℃下反应以提供式I化合物。在此阶段,本领域技术人员将认识到属于本发明的范围内的许多另外的化合物可通过进行各种普通的化学反应制备。某些特定化学转化的详细内容提供于实施例。
本领域技术人员将能够按常规方式修改和/或改动以下方案以合成由式I所涵盖的本发明的任何化合物。
本发明的详细描述
要理解的是,前文一般性描述和下文详细描述均仅仅为示例性和阐释性的,而不限制受权利要求书保护的本发明。如本文所用,除非另外具体指明,否则单数的使用包括复数。
对本领域技术人员将显而易见的是,一些本发明化合物可含有一个或多个不对称中心,使得所述化合物可以对映异构体形式以及以非对映异构体形式存在。除非另外具体指明,否则本发明的范围包括所有对映异构体、非对映体和外消旋混合物。一些本发明化合物可与药学上可接受的酸或碱形成盐,并且本文所述的化合物的此类药学上可接受的盐也在本发明的范围内。
本发明包括所有药学上可接受的同位素富集的化合物。任何本发明化合物可含有富集的或不同于天然比例的一种或多种同位素原子,如氘2H(或D)代替氢1H(或H),或者使用富含13C的材料代替12C等。类似的取代可用于N、O和S。同位素的使用可有助于本发明的分析以及治疗方面。例如,氘的使用可通过改变本发明化合物的代谢(率)来增加体内半衰期。这些化合物可根据通过使用富含同位素的试剂所述的制备方法来制备。
以下实施例仅用于示例目的,并不旨在也不应将其解释为以任何方式限制本发明。本领域技术人员将会意识到,可以在不超出本发明的精神或范围的情况下对以下实施例进行变动和修改。
对本领域技术人员显而易见的是,可以通过按常规方式分离其混合物来获得单独的同分异构形式。例如,在非对映异构体的情况下可以采用色谱分离。
用ACD第12.5版生成化合物名称;用软件生成实施例中使用的一些中间体及试剂的名称,所述软件诸如Chem Bio Draw Ultra12.0版、ACD12.5版本或MDL ISIS Draw2.5SP1中的Auto Nom2000。
通常,化合物的表征使用在300或600MHz Varian上记录并在室温下获得的NMR谱进行。参考内部TMS或参考溶剂信号以ppm给出化学位移。旋光度记录在Perkin Elmer Polarimeter341上,20℃处589nm,Na/Hal灯。
所有未描述其合成的试剂、溶剂、催化剂均购自化学品供应商,诸如Sigma Aldrich、Fluka、Bio-Blocks、Combi-blocks、TCI、VWR、Lancaster、Oakwood、Trans World Chemical、Alfa、Fisher、Maybridge、Frontier、Matrix、Ukrorgsynth、Toronto、Ryan Scientific、SiliCycle、Anaspec、Syn Chem、Chem-Impex、MIC-scientific,Ltd;然而一些已知的中间体则根据已公布的程序来制备。
除另指出外,一般通过柱色谱法(Auto-column)在带有二氧化硅柱的Teledyne-ISCO CombiFlash上纯化本发明的化合物。
外消旋化合物的对映异构体通过手性固定相高压液相色谱法分离。
在实施例中使用以下缩写:
Et3N 三乙胺
THF 四氢呋喃
h 小时
DEA 二乙醇胺
CF3CO2H 三氟乙酸
MgSO4 硫酸镁
CH2Cl2 二氯甲烷
EtOAc 乙酸乙酯
NaHCO3 碳酸氢钠
CDCl3 氘化氯仿
MeOH 甲醇
CD3OD 氘化甲醇
HCl 盐酸
(NH4)2CO3 碳酸铵
KCN ***
K2CO3 碳酸钾
DMSO 二甲基磺酰胺
Pd(OAc)2 醋酸钯
DDQ 2,3-二氯-5,6-二氰基苯并醌
RT 室温
i-PrMgCl-THF 异丙基氯化镁于四氢呋喃中
EtOH 乙醇
DMF 二甲基甲酰胺
NH3 铵
KOH 氢氧化钾
DMAP 4-二甲基氨基吡啶
LiOH 氢氧化锂
ClCO2Et 氯甲酸乙酯
以下合成方法例示可如何制备根据本发明的化合物。本领域技术人员将能够按常规方式修改和/或改动以下方案以合成由式I所涵盖的任何本发明的化合物。
实施例1
中间体1
(2,5-二氧代-1’,3’-二氢螺[咪唑烷-4,2’-茚]-1-基)氨基甲酸叔丁酯
向二-1H-咪唑-1-基-甲酮CAS 530-62-1(486mg,3mmol)在二噁烷(10mL)的溶液中加入1,1-二甲基乙基酯肼羧酸,CAS 870-46-2(330mg,2.5mmol)在二噁烷(10mL)的溶液并在环境温度下搅拌90min。然后,将2-氨基-2,3-二氢-1H-茚-2-羧酸甲酯,CAS 199330-64-8(570mg,2.5mmol)以固体形式加入至反应,随后立即加入Et3N(505mg,5mmol)。然后将反应物加热至65℃保持4h。将反应混合物浓缩至约15mL,并在环境温度下静置。中间体1以白色固体分离并通过过滤收集。
1HNMR(CDCl3):δ1.50(s,9H),3.16(br d,J=15Hz,2H),3.69(d,J=15Hz,2H),7.23(br s,4H).
实施例2
中间体2
1-氨基-1′,3′-二氢螺[咪唑烷-4,2′-茚]-1-基)-2,5-二酮
向冷的(-78℃)中间体1(300mg,0.94mmol)加入CF3CO2H(3mL)。然后移除冷却浴并将搅拌的反应混合物在环境温度升温。在30min之后,去除所有的CF3CO2H并将粗混合物通过NaHCO3水溶液淬灭直至碱性。将混合物用CH2Cl2(2x30mL)提取。将有机层合并,用MgSO4干燥,过滤并将溶剂在减压下去除。分离出中间体2。
1HNMR(CD3OD):δ3.10(d,J=16.2Hz,2H),3.51(d,J=16.2Hz,2H),7.19–7.25(m,4H).
实施例3
中间体3
1-((4-甲氧基苄基)氧基)-4-甲基戊-3-酮
向1-羟基-4-甲基戊-3-酮CAS 132350-33-5(580mg,5mmol)在CH2Cl2(8mL)的冷的溶液(0℃)加入樟脑磺酸(58mg)然后加入4-甲氧基苄基-2,2,2-三氯乙酰亚胺酯CAS 89238-99-3(1.42g,5mmol)在CH2Cl2(8mL)的溶液并在室温搅拌16h。将反应物通过加入NaHCO3(10mL)水溶液淬灭,用CH2Cl2(30mL)萃取。将有机层干燥(MgSO4)并将溶剂在减压下去除。将粗产物通过硅胶色谱法使用含EtOAc的己烷作为洗脱液纯化。中间体3分离为无色油状物。
1HNMR(CDCl3):δ1.10(d,J=6.9Hz,6H),2.50–2.67(m,1H),2.74(t,J=6.6Hz,2H),3.71(t,J=6.6Hz,2H),3.80(s,3H),4.44(s,2H),6.84–6.89(m,2H),7.21–7.27(m,2H
实施例4
中间体4
1-((4-甲氧基苄基)氧基)-3-甲基丁-2-酮
向N-甲氧基-2-((4-甲氧基苄基)氧基)-N-甲基乙酰胺CAS191731-32-5(856mg,3.6mmol)在THF(10mL)的冷的(-78℃)溶液加入i-PrMgCl-THF溶液。然后将反应物升温至室温,并搅拌2h,将反应混合物倒入冷的2N HCl并用EtOAc萃取,将有机层干燥(MgSO4)并将溶剂在减压下回收。将粗混合物通过硅胶色谱法使用含EtOAc的己烷纯化。中间体4分离为无色油状物。
1HNMR(CDCl3):δ1.08(d,J=6.7Hz,6H),2.70–2.91(m,1H),3.80(s,3H),4.10(s,2H),4.52(s,2H),6.88(d,J=8.8Hz,2H),7.28(d,J=8.8Hz,2H).
实施例5
中间体5
5-异丙基-5-(2-((4-甲氧基苄基)氧基)乙基)咪唑烷-2,4-二酮
将中间体3 1.82g,10mmol)、(NH4)2CO3(4.24g,40mmol)、KCN(2.5g,37.5mmol)和EtOH(20mL)的混合物加热至60℃保持15h。将粗混合物通过短硅藻土柱过滤。然后将溶剂在减压下去除并将中间体5分离为固体。
1HNMR(CDCl3):δ0.94(d,J=4.2Hz,3H),0.96(d,J=4.2Hz,3H),1.90–2.21(m,3H),3.41–3.60(m,2H),3.78(s,3H),4.34(d,J=8.4Hz,1H),4.38(d,J=8.4Hz,1H),6.80–6.90(m,2H),7.20–7.27(m,2H).
中间体6至10是以与用于中间体5的描述于实施例5的方法类似的方式制备。使用的原料和结果列表于以下表1中。
表1
实施例6
中间体12
3-氨基-5-乙基-5-异丙基咪唑烷-2,4-二酮
在150℃将5-乙基-5-(1-甲基乙基)-2,4-咪唑烷二酮CAS98492-91-2(2.47g,14.53mmol)和肼水合物(10mL)的混合物在密封管中加热保持5天。将粗混合物通过硅胶快速色谱法使用MeOH:CH2Cl2,(1:19)纯化。中间体12分离为白色固体。
1HNMR(CD3OD):δ0.78–0.92(m,6H),0.95(d,J=6.00Hz,3H),1.78(q,J=7.33Hz,2H),1.96–2.06(m,1H).
中间体13至19是以与用于中间体12的描述于实施例6的方法类似的方式制备。使用的原料和结果列表于以下表2中。
表2
实施例7
中间体20
3-氨基-5-(4-氯苯乙基)-5-甲基咪唑烷-2,4-二酮
将4-(4-氯苯基)丁-2-酮CAS3506-75-0(1.82g,10mmol)、(NH4)2CO3(4.24g,40mmol)、KCN(2.5g,37.5mmol)和EtOH(20mL)的混合物加热至60℃保持15h。将粗混合物通过短硅藻土柱过滤。然后将溶剂在减压下去除。
中间体5-(4-氯苯乙基)-5-甲基咪唑烷-2,4-二酮分离为棕色固体。将5-(4-氯苯乙基)-5-甲基咪唑烷-2,4-二酮(400mg,1.9mmol)和肼水合物(4mL)的混合物在密封管中加热至100℃保持5h。将该混合物通过硅胶色谱法使用含MeOH的CH2Cl2作为洗脱液纯化,中间体20分离为白色固体。
1HNMR(CD3OD):δ1.40(s,3H),1.82–1.95(m,1H),2.01–2.10(m,1H),2.40–2.46(m,1H),2.58–2.66(m,1H),7.14(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,2H).
中间体21至31是以与用于中间体20的描述于实施例7的方法类似的方式制备。使用的原料和结果列表于以下表3中。
表3
实施例8
中间体32
3-氨基-5-异丙基-5-(2-((4-甲氧基苄基)氧基)乙基)咪唑烷-2,4-二酮
将中间体5(320mg,1.05mmol)、K2CO3、DMF(3mL)、THF(3mL)的混合物加热至70℃并一次性加入O-(2,4-二硝基苯基)羟胺CAS17508-17-7(224mg,1.55mmol)。以15分钟间隔分四次加入O-(2,4-二硝基苯基)羟胺CAS17508-17-7(每次112mg)和K2CO3(120mg)。将混合物冷却至室温,用EtOAc(70mL)萃取,用K2CO3水溶液洗涤,干燥(MgSO4)并去除溶剂。将粗的中间体通过硅胶色谱法使用含EtOAc的己烷作为洗脱液纯化,分离到中间体32。
1HNMR(CD3OD):δ0.86(d,J=4.2Hz,3H),0.95(d,J=4.2Hz,3H),1.94–2.00(m,2H),2.18–2.22(m,1H),3.45–3.50(m,2H),3.77(s,3H),4.26(d,J=10.8Hz,1H),4.34(d,J=10.8Hz,1H),6.82–6.90(m,2H),7.20–7.24(m,2H).
中间体33至39是以与用于中间体32的描述于实施例8的方法类似的方式制备。使用的原料和结果列表于以下表4中。
表4
实施例9
中间体41
甲基-4(2-(1-氨基-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸
将中间体33(460mg,1.5mmol)、膦、1,1'-(1,3-丙二基)双[1,1-二环己基-、四氟硼酸铑(1-)CAS1002345-50-7(40mg,0.08mmol)、Pd(OAc)2(9mg)、K2CO3(600mg,4.5mmol)、分子筛DMSO(6mL)用一氧化碳鼓泡然后将MeOH(250mg)加入至反应物,将反应物用橡胶隔片覆盖,并将一氧化碳填充的气囊***至所述隔片中。将反应物加热至75℃保持16h并通过在减压下去除溶剂处理,经粗品通过硅胶柱色谱法使用5% 7N NH3-MeOH和95%CH2Cl2纯化。中间体41分离为白色固体。
1HNMR(CD3OD):δ1.41(s,3H),1.90–1.97(m,1H),2.07–2.14(m,1H),2.52–2.54(m,1H),2.66–2.71(m,1H),3.88(s,3H),7.27(d,J=8.4Hz,2H),7.91(dd,J=8.4,1.8Hz,2H).
中间体42和43是以与用于中间体41的描述于实施例9的方法类似的方式制备。使用的原料和结果列表于以下表5中。
表5
实施例10
化合物1
1-(4-溴苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲
将3-氨基-5,5-二乙基咪唑烷-2,4-二酮CAS 1007-61-0(70mg,0.4mmol)、4-溴苯基异氰酸酯CAS 2493-02-9(80mg,0.4mmol)在甲苯(5mL)的混合物在100℃下加热8h。在将反应物冷却至环境温度时,化合物1分离为白色固体,所述化合物1通过过滤收集并在高真空下干燥。
1HNMR(CD3OD):δ0.95(br s,6H),1.65–1.75(m,2H),1.81–1.91(m,2H),7.36(d,J=6.00Hz,2H),7.40(d,J=6.00Hz,2H).
化合物2至68是以与用于化合物1的描述于实施例10的方法类似的方式制备。使用的原料和结果列表于以下表6中。
表6.
实施例11
化合物70
(-)-1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲
化合物71
(+)-1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲
外消旋化合物9通过手性固相高压液相色谱法:制备柱(IC,2×15cm)和流动相(超临界流体)20%甲醇(0.1%DEA)/CO2,100bar;70mL/min,UV220nm分离成单独的对映异构体化合物70和化合物71。
(-)对映异构体,峰1,RT0.86min–化合物70
[α]D=-16.52°,MeOH,c=0.0115g/mL
(+)对映异构体,峰2,RT1.09min–化合物71
[α]D=+16.69°,MeOH,c=0.0115g/Ml
实施例12
化合物72
(+)-1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲
化合物73
(-)-1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲
外消旋化合物18通过手性固相高压液相色谱法:制备柱(IA,2×15cm)和流动相(超临界流体)50%甲醇(0.1%DEA)/CO2,100bar;70mL/min,UV254nm分离成单独的对映异构体化合物72和化合物73。
(+)对映异构体,峰1,RT2.22min–化合物72
[α]D=+15.9°,MeOH,c=0.9364g/mL
(-)对映异构体,峰2,RT4.82min–化合物73
[α]D=-15.4°,MeOH,c=0.9182g/mL
实施例13
化合物74
1-(4-溴苯基)-3-(4-(羟甲基)-4-异丙基-2,5-二氧代咪唑烷-1-基)脲
向化合物56(100mg,0.2mmol)在CH2Cl2(5mL)的冷的(0℃)溶液中加入DDQ、CAS84-58-2(100mg,0.4mmol)并搅拌90min。向反应物中加入饱和硫代硫酸钠(2mL)并搅拌30min。将溶剂在减压下去除并通过硅胶色谱法使用含MeOH的CH2Cl2纯化。产物获得为白色固体。
1HNMR(CD3OD):δ0.98(d,J=7.0Hz,6H),2.06–2.20(m,1H),3.75–3.90(m,2H),7.31–7.41(m,4H).
化合物75和76是以与用于化合物74的描述于实施例13的方法类似的方式制备。使用的原料和结果列表于以下表7中。
表7
实施例14
化合物77
4-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲
酸
向化合物58(30mg,0.06mmol)在二噁烷(2mL)的溶液加入KOH-H2O(0.5M溶液,1mL)并在室温下搅拌90min。将溶剂在减压下去除,然后将反应物冷却(0℃)并用10%HCl酸化至pH2。将粗产物通过硅胶色谱法使用含MeOH的CH2Cl2纯化。化合物77分离为白色固体。
1HNMR(CD3OD):δ1.50(s,3H),1.92–2.03(m,1H),2.11–2.21(m,1H),2.62–2.85(m,2H),7.32(d,J=7.8Hz,2H),7.35–7.45(m,4H),7.92–7.97(m,2H).
化合物78至83是以与用于化合物77的描述于实施例14的方法类似的方式制备。使用的原料和结果列表于以下表8中。
表8
实施例15
化合物84
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)-N-(2-羟乙
基)乙酰胺
向化合物81(50mg,0.12mmol)在CH2Cl2(5mL)的溶液加入乙醇胺(15mg,0.24mmol)、丙基丙酸酐(0.1mL,50%wt/wt在EtOAc中)、Et3N(61mg,0.6mmol)、DMAP(4mg)并在室温搅拌18h。将溶剂在旋转蒸发仪上去除并将粗反应物通过制备型薄层色谱法纯化。化合物84分离为白色固体。
1H NMR(CD3OD)0.90–1.08(m,6H),1.97–2.09(m,1H),2.92(d,J=9.4Hz,2H),3.52–3.66(m,4H),7.31–7.47(m,2H),7.56(br.s,2H).
化合物85至91是以与用于化合物84的描述于实施例15的方法类似的方式制备。使用的原料和结果列表于以下表9中。
表9
实施例16
化合物92
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨
基)乙酸
向化合物85(131mg,0.23mmol)中加入甲酸(3mL)并在室温搅拌1h。将溶剂在室温下于真空中去除。化合物92分离为白色固体。
1H NMR(CD3OD)δ0.94(d,J=6.5Hz,3H),1.03(d,J=6.9Hz,3H),2.03(m,1H),3.00(d,J=6.2Hz,2H),3.90(d,J=4.4Hz,2H),7.37(d,J=8.9Hz,2H),7.47–7.60(m,2H).
化合物93至96是以与用于化合物92的描述于实施例16的方法类似的方式制备。使用的原料和结果列表于以下表10。
表10
实施例17
化合物96
N-(2-氨基-2-氧代乙基)-2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代
咪唑烷-4-基)乙酰胺
向化合物92(180mg,0.38mmol)在THF(5mL)的冷的(-31℃)浑浊的混合物中加入Et3N(118mg,1.18mmol)。在5min之后,加入ClCO2Et(66mg,0.61mmol)并搅拌20min。将NH3气鼓泡通过反应混合物。然后将反应物逐渐升温至室温。将粗反应物通过硅胶色谱法用含10%MeOH的CH2Cl2洗脱来纯化。然后将产物用10%HCl洗涤以去除产物中的碱性杂质。化合物96分离为白色固体。
1H NMR(甲醇-d4)δ0.95(d,J=6.6Hz,3H),1.03(d,J=6.9Hz,3H),1.94–2.12(m,1H),2.88–3.14(m,2H),3.84(d,J=11.0Hz,2H),7.33–7.47(m,2H),7.49–7.63(m,2H).
生物学数据
根据式1的化合物的生物活性列于以下表11。稳定表达FPRL1的HEK-Gα 16和CHO-Gα 16细胞培养在(F12、10%FBS、1%PSA、400μg/ml遗传霉素和50μg/ml潮霉素中)以及将稳定表达FPR1的HEK-Gqi5细胞培养在(DMEM高葡萄糖、10%FBS、1%PSA、400μg/ml遗传霉素和50μg/ml潮霉素中)。通常,在实验前一天,将18,000个细胞/孔置于384-孔透明底部聚-d-赖氨酸涂布的板中。第二天,将筛选化合物诱导的钙活性在FLIPRTetra上测定。在384-孔微板中使用EP3和MultiPROBE自动液体处理***制备药板。在0.61至10,000nM的浓度范围内测试化合物。结果表示为EC50(nM)和功效值。
表11
Claims (14)
1.一种由式I表示的化合物,其对映异构体、非对映异构体、水合物、溶剂化物或其药学上可接受的盐:
R1为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R2为卤素、任选取代的C1-8烷基、CF3、OR9、C(O)R10、NO2、NR13R14、CN,SR15或SO2R16;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环、或与R5一起形成任选被取代的5或6元环;
R4为氢、任选取代的C1-8烷基、 任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环、或与R5一起形成任选被取代的螺单环或多环的、碳环或杂环的、饱和或不饱和的5至10元环;
R5为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环、或与R4一起形成任选被取代的螺单环或多环的碳环或杂环的、饱和或不饱和的5至10元环或与R3一起形成任选被取代的5或6元环;
R6为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R7为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R8为卤素、氢、任选取代的C1-8烷基、OR9、C(O)R10、NO2、NR13R14、CN、SR15或SO2R16;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R10为氢、任选取代的C1-8烷基、O(C1-8烷基)、NR11R12或OH;
R11为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R12为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R13为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R14为氢、任选取代的C6-10芳基、任选取代的C1-8烷基、C(O)(C1-8烷基)或SO2(C1-8烷基);
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R16为OH、O(C1-8烷基)、(C1-8烷基)或NR11R12;
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;
m为1、2、3、4或5;并且
前提条件是式I的所述化合物不为以下结构:
2.根据权利要求1所述的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、CF3、SR15、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基或任选取代的杂环;
R5为任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基或任选取代的杂环;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;并且
R15为氢、任选取代的C1-8烷基或O(C1-8烷基)。
3.根据权利要求1所述的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、CF3、SR15、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为任选取代的C1-8烷基、任选取代的C6-10芳基、
R5为任选取代的C1-8烷基或任选取代的C3-8环烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;并且
m为1、2、3、4或5。
4.根据权利要求1所述的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢;
R4为任选取代的C1-8烷基、任选取代的C6-10芳基、
R5为任选取代的C1-8烷基或任选取代的C3-8环烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;并且
m为1、2、3、4或5。
5.根据权利要求1所述的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、CF3、SR15、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为任选取代的C1-8烷基、
R5为任选取代的C1-8烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;并且
m为1、2、3、4或5。
6.根据权利要求1所述的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、CF3、SR15、OR9或CN;
R3为氢;
R4为
R5为任选取代的C1-8烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1、2、3、4或5;并且
m为1、2、3、4或5。
7.根据权利要求1所述的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基或任选取代的C3-8环烯基;
R4为任选取代的C1-8烷基;
R5为任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基或任选取代的杂环;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;并且
R15为氢、任选取代的C1-8烷基或O(C1-8烷基)。
8.根据权利要求1所述的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢;
R4为 R5为任选取代的C1-8烷基;
R6为卤素、氢或任选取代的C1-8烷基;
R7为卤素、氢或任选取代的C1-8烷基;
R8为卤素、氢或任选取代的C1-8烷基;
R9为氢、C(O)(C1-8烷基)或任选取代的C1-8烷基;
R15为氢、任选取代的C1-8烷基或O(C1-8烷基);
R17为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R18为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R19为氢、C(O)(C1-8烷基)、任选取代的C6-10芳基或任选取代的C1-8烷基;
R20为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
R21为氢、任选取代的C6-10芳基或任选取代的C1-8烷基;
n为1或2;并且
m为1或2。
9.根据权利要求1所述的化合物,其中:
R1为卤素、氢或任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基或任选取代的杂环;
R4与R5一起形成任选被取代的螺单环或多环的、碳环或杂环的、饱和或不饱和的5至10元环;
R5与R4一起形成任选被取代的螺单环或多环碳环或杂环的、饱和或不饱和的5至10元环;
R6为卤素、氢、任选取代的C1-8烷基;
R7为卤素、氢、任选取代的C1-8烷基;
R8为卤素、氢、任选取代的C1-8烷基;
R9为氢或任选取代的C1-8烷基;并且
R15为氢、任选取代的C1-8烷基或O(C1-8烷基)。
10.根据权利要求1所述的化合物,其中:
R1为卤素、氢、任选取代的C1-8烷基;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3与R5一起形成任选被取代的5或6元环;
R4为氢、任选取代的C1-8烷基、任选取代的C3-8环烷基、任选取代的C3-8环烯基、任选取代的C6-10芳基、任选取代的杂环,
R5与R3一起形成任选被取代的5或6元环;
R6为卤素、氢、任选取代的C1-8烷基;
R7为卤素、氢、任选取代的C1-8烷基;
R8为卤素、氢、任选取代的C1-8烷基;
R9为氢或任选取代的C1-8烷基;并且
R15为氢、任选取代的C1-8烷基或O(C1-8烷基)。
11.根据权利要求1所述的化合物,其中:
R1为卤素或氢;
R2为卤素、任选取代的C1-8烷基、SR15、CF3、OR9或CN;
R3为氢;
R4为任选取代的C1-8烷基;
R5为任选取代的C1-8烷基;
R6为卤素或氢;
R7为氢;
R8为氢;
R9为任选取代的C1-8烷基;并且
R15为氢、任选取代的C1-8烷基或O(C1-8烷基)。
12.根据权利要求1所述的化合物,其选自:
1-(4-溴苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-氯苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-甲氧基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-乙基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-氰基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-甲基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-甲基硫基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.4]壬-3-基)脲;
1-(4-溴-2-氟苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.4]壬-3-基)脲;
1-(4-溴苯基)-3-(4,4-二甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(2,5-二氧代-1′,3′-二氢螺[咪唑烷-4,2′-茚]-1-基)脲;
1-(4-溴苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.5]癸-3-基)脲;
1-(4-溴-2-氟苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.5]癸-3-基)脲;
1-(4-氯-2-氟苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-氯-3-氟苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(2,4-二氧代-1,3-二氮杂螺[4,5]癸-3-基)-3-(4-甲氧基苯基)脲;
(S)-1-(4-溴苯基)-3-(1,3-二氧代-10,10a-二氢咪唑并[1,5-b]异喹啉-2(1H,3H,5H)-基)脲;
(S)-1-(4-溴-2-氟苯基)-3-(1,3-二氧代-10,10a-二氢咪唑并[1,5-b]异喹啉-2(1H,3H,5H)-基)脲;
1-(4-溴-2-氟苯基)-3-(2,5-二氧代-1′,3′-二氢螺[咪唑烷-4,2′-茚]-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-(苯氧基甲基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(2,5-二氧代-3’,4’-二氢-1’H-螺[咪唑烷-4.2’萘-1-基)脲;
1-(4-溴-2-氟苯基)-3-(2,5-二氧代-3’,4’-二氢-1’H-螺[咪唑烷-4.2’萘-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-(苯氧基甲基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-乙基-2,5-二氧代-4-(苯乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-乙基-2,5-二氧代-4-(苯乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-异丁基-2,5-二氧代-4-苯乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-异丁基-2,5-二氧代-4-苯乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(4-氯苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-氯苯乙基)-4-甲基-2,5-二氧代-咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-呋喃-2-基)乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-呋喃-2-基)乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(4-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(4-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-(2-噻吩-2-基)乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-(2-噻吩-2-基)乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-4-(2-(5-甲基呋喃-2-基)乙基)-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-氟-4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-氟-4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-异丙基-4-(2-((4-甲氧基苄基)氧基)乙基)-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(3-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-(2-(吡啶-4-基)乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-(吡啶-4-基)乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-异丙基-4-(((4-甲氧基苄基)氧基)甲基)-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-异丙基-4-(((4-甲氧基苄基)氧基)甲基)-2,5-二氧代咪唑烷-1-基)脲;
4-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(2-(1-(3-(4-溴-2-氟苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(1-(3-(4-溴-2-氟苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸乙酯;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸乙酯;
1-(4-溴苯基)-3-[4-(1H-吲哚-3-基甲基)-4-甲基-2,5-二氧代咪唑烷-1-基]脲;
1-(4-溴-2-氟苯基)-3-[4-(5-乙基-1H-吲哚-2-基)-4-甲基-2,5-二氧代咪唑烷-1-基]脲;
1-(4-溴苯基)-3-(4,4-二环丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-[2,5-二氧代-4,4-二(丙-2-基)咪唑烷-1-基]脲;
乙基-3-[1-{[(4-溴苯基)氨甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]丙酸酯;
1-(4-溴苯基)-3-(4,4-二甲基-2,5-二氧代-3-苯基咪唑烷-1-基)脲;
(-)-1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
(+)-1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
(+)-1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
(-)-1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(羟甲基)-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-羟乙基)-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-羟甲基)-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
4-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸;
2-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸;
2-(2-(1-(3-(4-溴苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸;
2-(2-(1-(3-(4-溴-2-氟苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸;
2-(1-(3-(4-溴-2-氟苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸;
3-[1-{[(4-溴苯基)氨甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]丙酸;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)-N-(2-羟乙基)乙酰胺;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)乙酸叔丁酯;
((2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)甲基)膦酸二乙酯;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)-N,N-双(2-羟乙基)乙酰胺;
((2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)甲基)膦酸二异丙酯;
((2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)甲基)膦酸氢乙酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)2-甲基丙酸叔丁酯;
3-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)丙酸叔丁酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)乙酸;
3-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)丙酸;
2-(1-(3-(4-溴-2-氟苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)-N-(2-羟乙基)乙酰胺;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)2-甲基丙酸;和
N-(2-氨基-2-氧代乙基)-2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰胺。
13.一种药物组合物,其包含根据权利要求1所述的作为活性成分的治疗有效量的化合物和药学上可接受的佐剂、稀释剂或载体。
14.根据权利要求13所述的药物组合物,其中所述化合物选自:
1-(4-溴苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-氯苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-甲氧基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-乙基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-氰基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-甲基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-甲基硫基苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.4]壬-3-基)脲;
1-(4-溴-2-氟苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.4]壬-3-基)脲;
1-(4-溴苯基)-3-(4,4-二甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(2,5-二氧代-1′,3′-二氢螺[咪唑烷-4,2′-茚]-1-基)脲;
1-(4-溴苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.5]癸-3-基)脲;
1-(4-溴-2-氟苯基)-3-(2,4-二氧代-1,3-二氮杂螺[4.5]癸-3-基)脲;
1-(4-氯-2-氟苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-氯-3-氟苯基)-3-(4,4-二乙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(2,4-二氧代-1,3-二氮杂螺[4,5]癸-3-基)-3-(4-甲氧基苯基)脲;
(S)-1-(4-溴苯基)-3-(1,3-二氧代-10,10a-二氢咪唑并[1,5-b]异喹啉-2(1H,3H,5H)-基)脲;
(S)-1-(4-溴-2-氟苯基)-3-(1,3-二氧代-10,10a-二氢咪唑并[1,5-b]异喹啉-2(1H,3H,5H)-基)脲;
1-(4-溴-2-氟苯基)-3-(2,5-二氧代-1′,3′-二氢螺[咪唑烷-4,2′-茚]-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-(苯氧基甲基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(2,5-二氧代-3’,4’-二氢-1’H-螺[咪唑烷-4.2’萘-1-基)脲;
1-(4-溴-2-氟苯基)-3-(2,5-二氧代-3’,4’-二氢-1’H-螺[咪唑烷-4.2’萘-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-(苯氧基甲基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-乙基-2,5-二氧代-4-(苯乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-乙基-2,5-二氧代-4-(苯乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-异丁基-2,5-二氧代-4-苯乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-异丁基-2,5-二氧代-4-苯乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(4-氯苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-氯苯乙基)-4-甲基-2,5-二氧代-咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-呋喃-2-基)乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-呋喃-2-基)乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(4-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(4-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-氟苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-(2-噻吩-2-基)乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-(2-噻吩-2-基)乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-4-(2-(5-甲基呋喃-2-基)乙基)-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-氟-4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-氟-4-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-异丙基-4-(2-((4-甲氧基苄基)氧基)乙基)-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(3-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(3-羟基苯乙基)-4-甲基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-(2-(吡啶-4-基)乙基)咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-甲基-2,5-二氧代-4-(吡啶-4-基)乙基)咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-异丙基-4-(((4-甲氧基苄基)氧基)甲基)-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-异丙基-4-(((4-甲氧基苄基)氧基)甲基)-2,5-二氧代咪唑烷-1-基)脲;
4-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(2-(1-(3-(4-溴-2-氟苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(1-(3-(4-溴-2-氟苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸乙酯;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸乙酯;
1-(4-溴苯基)-3-[4-(1H-吲哚-3-基甲基)-4-甲基-2,5-二氧代咪唑烷-1-基]脲;
1-(4-溴-2-氟苯基)-3-[4-(5-乙基-1H-吲哚-2-基)-4-甲基-2,5-二氧代咪唑烷-1-基]脲;
1-(4-溴苯基)-3-(4,4-二环丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-[2,5-二氧代-4,4-二(丙-2-基)咪唑烷-1-基]脲;
乙基-3-[1-{[(4-溴苯基)氨甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]丙酸酯;
1-(4-溴苯基)-3-(4,4-二甲基-2,5-二氧代-3-苯基咪唑烷-1-基)脲;
(-)-1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
(+)-1-(4-溴苯基)-3-(4-甲基-2,5-二氧代-4-苯乙基咪唑烷-1-基)脲;
(+)-1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
(-)-1-(4-溴苯基)-3-(4-乙基-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(羟甲基)-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴苯基)-3-(4-(2-羟乙基)-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
1-(4-溴-2-氟苯基)-3-(4-(2-羟甲基)-4-异丙基-2,5-二氧代咪唑烷-1-基)脲;
4-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸;
2-(2-(1-(3-(4-溴苯基)脲基)-4-甲基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸;
2-(2-(1-(3-(4-溴苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸;
2-(2-(1-(3-(4-溴-2-氟苯基)脲基)-4-乙基-2,5-二氧代咪唑烷-4-基)乙基)苯甲酸甲酯;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸;
2-(1-(3-(4-溴-2-氟苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酸;
3-[1-{[(4-溴苯基)氨甲酰基]氨基}-2,5-二氧代-4-(丙-2-基)咪唑烷-4-基]丙酸;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)-N-(2-羟乙基)乙酰胺;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)乙酸叔丁酯;
((2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)甲基)膦酸二乙酯;
2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)-N,N-双(2-羟乙基)乙酰胺;
((2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)甲基)膦酸二异丙酯;
((2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)甲基)膦酸氢乙酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)2-甲基丙酸叔丁酯;
3-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)丙酸叔丁酯;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)乙酸;
3-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)丙酸;
2-(1-(3-(4-溴-2-氟苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)-N-(2-羟乙基)乙酰胺;
2-(2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰氨基)2-甲基丙酸;和
N-(2-氨基-2-氧代乙基)-2-(1-(3-(4-溴苯基)脲基)-4-异丙基-2,5-二氧代咪唑烷-4-基)乙酰胺。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107849049A (zh) * | 2015-05-27 | 2018-03-27 | 杏林制药株式会社 | 脲衍生物或其药用盐 |
CN111868052A (zh) * | 2018-03-05 | 2020-10-30 | 百时美施贵宝公司 | 苯基吡咯烷酮甲酰肽2受体激动剂 |
CN114805334A (zh) * | 2022-05-24 | 2022-07-29 | 深圳大学 | 一种QC和GSK-3β多靶向抑制剂及其制备方法与应用 |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2012329098B2 (en) | 2011-10-26 | 2017-08-03 | Allergan, Inc. | Amide derivatives of N-urea substituted amino acids as formyl peptide receptor like-1 (FPRL-1) receptor modulators |
US8492556B2 (en) * | 2011-11-10 | 2013-07-23 | Allergan, Inc. | 2,5-Dioxoimidazolidin-1-yl-3-phenylurea derivatives as formyl peptide receptor like-1 (FPRL-1) receptor modulators |
BR112015021392B1 (pt) | 2013-03-06 | 2021-11-16 | Allergan, Inc | Uso de agonistas do receptor de peptídeo formil 2 para tratar doenças dermatológicas |
AU2014225992B2 (en) * | 2013-03-06 | 2018-03-22 | Allergan, Inc. | Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases |
AR097279A1 (es) | 2013-08-09 | 2016-03-02 | Actelion Pharmaceuticals Ltd | Derivados de benzimidazolil-metil urea como agonistas del receptor de alx |
US9926264B2 (en) | 2013-11-21 | 2018-03-27 | Allergan, Inc. | Phenylcarbamate derivatives as formyl peptide receptor modulators |
SG11201604296QA (en) * | 2013-11-28 | 2016-07-28 | Kyorin Seiyaku Kk | Urea derivative or pharmacologically acceptable salt thereof |
WO2015116574A1 (en) * | 2014-01-29 | 2015-08-06 | Allergan, Inc. | Urea hydantoin derivatives as formyl peptide modulators |
US9920013B2 (en) * | 2014-01-29 | 2018-03-20 | Allergan, Inc. | 2,5-dioxoimidazolidin-1-yl-3-urea derivatives as formyl peptide modulators |
CN106458921B (zh) | 2014-05-21 | 2020-03-24 | 阿勒根公司 | 作为甲酰肽受体调节剂的咪唑衍生物 |
EP3229807A4 (en) | 2014-12-11 | 2018-10-17 | President and Fellows of Harvard College | Inhibitors of cellular necrosis and related methods |
EP3303284B1 (en) | 2015-05-27 | 2020-04-08 | Kyorin Pharmaceutical Co., Ltd. | Urea derivative or pharmacologically acceptable salt thereof |
JP2020015664A (ja) * | 2016-11-21 | 2020-01-30 | 宇部興産株式会社 | 含窒素多環式ヘテロ環誘導体 |
EP3634958B1 (en) * | 2017-06-09 | 2021-07-21 | Bristol-Myers Squibb Company | Cyclopropyl urea formyl peptide 2 receptor and formyl peptide 1 receptor agonists |
KR102217512B1 (ko) * | 2020-07-07 | 2021-02-19 | 한화시스템 주식회사 | 배터리 관리 시스템을 통한 회수 요청 또는 자동 복귀를 수행하는 무인 잠수정 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003006425A2 (en) * | 2001-07-10 | 2003-01-23 | 4Sc Ag | Novel compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
CN1706833A (zh) * | 2004-06-04 | 2005-12-14 | 中国科学院上海药物研究所 | 一类甲酰肽样受体-1调节剂、其制备方法和用途 |
CN1894580A (zh) * | 2003-11-07 | 2007-01-10 | 阿卡蒂亚药品公司 | 脂氧素受体fprl1作为一种用于鉴定能有效治疗疼痛和炎症化合物的工具 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2001253538B2 (en) * | 2000-05-31 | 2004-03-04 | Tanabe Seiyaku Co., Ltd. | Inhibitors of alpha l beta 2 mediated cell adhesion |
SE0100903D0 (sv) * | 2001-03-15 | 2001-03-15 | Astrazeneca Ab | Compounds |
FR2850652B1 (fr) * | 2003-01-31 | 2008-05-30 | Aventis Pharma Sa | Nouveaux derives d'uree cyclique, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases |
WO2005087236A1 (en) * | 2004-03-11 | 2005-09-22 | Glaxo Group Limited | Novel m3 muscarinic acetylcholine receptor antagonists |
CA2652307A1 (en) * | 2006-04-10 | 2007-10-18 | Painceptor Pharma Corporation | Compositions and methods for modulating gated ion channels |
JP2011503182A (ja) * | 2007-11-15 | 2011-01-27 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 使用方法 |
US8541577B2 (en) * | 2011-11-10 | 2013-09-24 | Allergan, Inc. | Aryl urea derivatives as N-formyl peptide receptors like-1 (FPRL-1) receptor modulators |
US8492556B2 (en) * | 2011-11-10 | 2013-07-23 | Allergan, Inc. | 2,5-Dioxoimidazolidin-1-yl-3-phenylurea derivatives as formyl peptide receptor like-1 (FPRL-1) receptor modulators |
EP2814815A1 (en) * | 2012-02-16 | 2014-12-24 | Allergan, Inc. | Imidazolidine-2,4-dione derivatives as n-formyl peptide receptor 2 modulators |
-
2012
- 2012-11-09 US US13/673,800 patent/US8492556B2/en active Active
- 2012-11-10 ES ES16177209T patent/ES2733826T3/es active Active
- 2012-11-10 EP EP16177209.0A patent/EP3103797B1/en active Active
- 2012-11-10 DK DK16177209.0T patent/DK3103797T3/da active
- 2012-11-10 JP JP2014541358A patent/JP6078075B2/ja active Active
- 2012-11-10 RU RU2014122753A patent/RU2645673C2/ru active
- 2012-11-10 TR TR2019/09663T patent/TR201909663T4/tr unknown
- 2012-11-10 KR KR1020147015539A patent/KR102271500B1/ko active IP Right Grant
- 2012-11-10 AU AU2012335039A patent/AU2012335039C1/en active Active
- 2012-11-10 BR BR112014011316A patent/BR112014011316A2/pt not_active Application Discontinuation
- 2012-11-10 WO PCT/US2012/064571 patent/WO2013071203A1/en active Application Filing
- 2012-11-10 EP EP12791050.3A patent/EP2776403B1/en active Active
- 2012-11-10 CN CN201280060036.8A patent/CN104114541A/zh active Pending
- 2012-11-10 CA CA2855390A patent/CA2855390C/en active Active
-
2017
- 2017-01-13 JP JP2017004062A patent/JP6392382B2/ja active Active
- 2017-11-16 AU AU2017261559A patent/AU2017261559C1/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003006425A2 (en) * | 2001-07-10 | 2003-01-23 | 4Sc Ag | Novel compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
CN1894580A (zh) * | 2003-11-07 | 2007-01-10 | 阿卡蒂亚药品公司 | 脂氧素受体fprl1作为一种用于鉴定能有效治疗疼痛和炎症化合物的工具 |
CN1706833A (zh) * | 2004-06-04 | 2005-12-14 | 中国科学院上海药物研究所 | 一类甲酰肽样受体-1调节剂、其制备方法和用途 |
Non-Patent Citations (2)
Title |
---|
AGOSTINO CILIBRIZZI,等: "6-Methyl-2,4-disubstituted pyridazin-3-(2H)-ones: a novel class of small-molecule agonists for formyl peptide receptors", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
ROLAND W. BÜRLI,等: "Potent hFPRL1 (ALXR) agonists as potential anti-inflammatory agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107849049A (zh) * | 2015-05-27 | 2018-03-27 | 杏林制药株式会社 | 脲衍生物或其药用盐 |
CN107849049B (zh) * | 2015-05-27 | 2021-03-16 | 杏林制药株式会社 | 脲衍生物或其药用盐 |
CN113185452A (zh) * | 2015-05-27 | 2021-07-30 | 杏林制药株式会社 | 脲衍生物或其药用盐 |
CN111868052A (zh) * | 2018-03-05 | 2020-10-30 | 百时美施贵宝公司 | 苯基吡咯烷酮甲酰肽2受体激动剂 |
CN111868052B (zh) * | 2018-03-05 | 2024-03-08 | 百时美施贵宝公司 | 苯基吡咯烷酮甲酰肽2受体激动剂 |
CN114805334A (zh) * | 2022-05-24 | 2022-07-29 | 深圳大学 | 一种QC和GSK-3β多靶向抑制剂及其制备方法与应用 |
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RU2014122753A (ru) | 2015-12-20 |
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