CN115244043A - 作为trpv1拮抗剂的苯并咪唑酮基肉桂酰胺衍生物和含有其作为活性成分的用于治疗或预防疼痛的药物组合物 - Google Patents
作为trpv1拮抗剂的苯并咪唑酮基肉桂酰胺衍生物和含有其作为活性成分的用于治疗或预防疼痛的药物组合物 Download PDFInfo
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- CN115244043A CN115244043A CN202180018813.1A CN202180018813A CN115244043A CN 115244043 A CN115244043 A CN 115244043A CN 202180018813 A CN202180018813 A CN 202180018813A CN 115244043 A CN115244043 A CN 115244043A
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- Prior art keywords
- imidazol
- benzo
- dihydro
- oxo
- substituted
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Abstract
本发明涉及一种作为TRPV1拮抗剂的苯并咪唑酮基肉桂酰胺衍生物和包含其作为活性成分的用于治疗或预防疼痛的药物组合物。本发明一方面提供的实施例化合物会阻断由辣椒素——一种TRPV1受体激活剂引起的TRPV1激活,但会在约20%至80%的pH下诱发适当的抑制,因此所述化合物具有减轻疼痛并有效降低如体温异常的副作用的效果。
Description
背景技术
发明领域
本发明涉及一种作为TRPV1拮抗剂的苯并咪唑酮基肉桂酰胺衍生物和含有其作为活性成分的用于治疗或预防疼痛的药物组合物。
相关技术的描述
瞬时受体电位香草酸亚型1(TRPV1)是TRP(瞬时受体电位)通道(一种在动物的各种组织中发现的阳离子通道蛋白)的亚族之一,且是一种主要在初级感觉神经元中表达的非选择性阳离子通道。此外,TRPV1作为转导——痛觉通路的第一步(是接受痛觉的过程)中涉及的痛觉感受器和痛觉传感器在痛觉传递中起着重要作用。TRPV1还维持创伤、感染、手术、烧伤和疾病引起的组织损伤后出现的炎症性状态,并参与炎症性温度超敏反应。
换句话说,TRPV1是识别和传递人体中疼痛的“疼痛通路”,并且通过抑制TRPV1功能,其可以选择性阻断不适当的疼痛感觉,同时保持正常的感觉,因此,TRPV1作为开发镇痛药的目标而备受关注。
开发靶向TRPV1的镇痛药的研究主要分为两种机制:激动剂和拮抗剂。对于激动剂,如配体,它们结合受体并递送疼痛,并且在阈值后通过脱敏显示镇痛作用。因此,激动剂具有副作用,例如初期疼痛、灼痛和不适,因此它们仅被开发为透皮镇痛药。相反,TRPV1拮抗剂与配体竞争性地结合至TRPV1受体,并通过TRPV1抑制疼痛传递本身。因此,TRPV1拮抗剂没有副作用,如激动剂诱导的烧灼感和初始疼痛,并且没有强烈的刺激,因此它们可被开发为口服制剂。
具体而言,TRPV1拮抗剂作为开发可应用于神经性疼痛、炎性疼痛和癌症疼痛的新型非阿片类镇痛药物的靶标而受到关注,其由于低效和副作用而需要开发专门的治疗剂。事实上,许多跨国制药公司,包括Abbott和Amgen,已经开发了TRPV1拮抗剂。作为在非临床动物实验中评价低分子TRPV1拮抗剂的功效的结果,证实了显示选择性和强拮抗作用的TRPV1拮抗剂的功效。
然而,据报道,第一代TRPV1拮抗剂ABT-102是一种强TRPV1拮抗剂,已经显示其在啮齿类动物中会增加体温,持续时间超过2天。对于Amgen开发的AMG 517,其作为拮抗剂显示出优异的镇痛效果,但是已知在临床试验中,受试者的体温上升至40.2℃并持续1-5天,导致非常致命的副作用。此外,已经证实一些TRPV1拮抗剂,包括Amgen的AMG7905和AMG8562,即使在没有部分激动作用的情况下也引起体温过低。因此,在TRPV1拮抗剂的开发中,异常体温的解决是一个重要问题。
迄今为止开发的大多数第一代TRPV1拮抗剂升高体温的副作用被认为是由于对TRPV1受体的所有激活剂(辣椒素、热、pH、NADA等)的拮抗作用。特别是,当被摄取时,作为生物碱之一的辣椒素会刺激TRPV1(受体激活通道之一),实际上不会升高温度,但会诱导高烧。
此外,据报道,在TRPV1受体激动剂中阻断100%的pH会引起体温升高,阻断20%或更低会引起高浓度的质子活化,从而导致体温降低。也就是说,在TRPV1拮抗剂的开发中,当阻断由辣椒素和热引起的TRPV1活化时,最重要的任务是通过获得适度抑制pH(20%-80%)的选择性关键策略来克服异常体温现象。
参考现有技术,专利文献1(WO 2011/120604A1)公开了TRPV1拮抗剂化合物和包含其作为活性成分的药物组合物,所述化合物抑制香草素受体TRPV1,从而缓解疼痛并治疗疾病如干眼症。
另一方面,本发明的化合物抑制由辣椒素引起的TRPV1活化,但相对于pH表现出20%-80%的TRPV1抑制活性,因而具有镇痛作用,且没有体温变化的副作用,并在体内具有优异的吸收率。因此,本发明的化合物与上述专利文献1(WO 2011/120604A1)的内容具有下述差异。
首先,在本发明的化合物中,A区是4-氨基-1,3-二氢-2H-苯并[d]咪唑-2-酮衍生物,B区(连接部分)是丙烯酰胺、丙酰胺或环丙烷-1-羧酰胺,C区是苯基、吡啶、吡唑或噻唑。另一方面,在专利文献1(WO 2011/120604A1)中公开的化合物中,A区通常是苯并杂环烯烃,B区是脲或酰胺,并且包括C区的其它取代基是不同的。因此,该化合物具有与本发明化合物整体不同的化学结构。
此外,本发明的化合物阻断由辣椒素和热引起的TRPV1活化,但相对于pH表现出20%-80%的TRPV1抑制活性,因此可制备具有镇痛作用、但不具有异常体温作用并在体内具有优异吸收率的镇痛剂。另一方面,上述专利文献1(WO2011/120604A1)仅在实验例中公开对辣椒素引起的TRPV1活化的抑制作用,但未公开特定pH范围的TRPV1抑制活性、体温变化的副作用和化合物的吸收率。因此,本发明的化合物与专利文献1的化合物在发明有效性方面存在差异。
也就是说,本发明的化合物抑制由辣椒素引起的TRPV1活化,但相对于pH表现出20%-80%的TRPV1抑制活性,因此其具有镇痛作用,没有体温变化的副作用,并具有优异的体内吸收率。因此,本发明人通过证明该化合物可有效用于止痛剂而完成了本发明。
发明内容
本发明的一个目的是提供一种基于苯并咪唑酮的肉桂酰胺衍生化合物,其会阻断由辣椒素(TRPV1受体的激活剂)引起的TRPV1活化,但是会诱导20%至80%的pH的适当抑制,以减轻疼痛并有效降低如异常体温的副作用。
本发明的另一个目的是提供一种用于预防或治疗疼痛的药物组合物,其包含上述化合物作为活性成分。
本发明的另一个目的是提供一种用于预防或改善疼痛的保健功能性食品组合物,其包含上述化合物作为活性成分。
本发明的另一个目的是提供一种治疗疼痛的方法,该方法包括向有需要的受试者施用上述化合物的步骤。
本发明的另一个目的是提供一种用在预防或治疗疼痛的上述化合物。
本发明的另一个目的是提供一种上述化合物在制备用于预防或治疗疼痛的药物中的用途。
为了实现上述目的,在本发明的一方面,本发明提供由本文所述式1表示的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐。
在本发明的另一方面,本发明提供一种用于预防或治疗疼痛的药物组合物,其包含上述化合物作为活性成分。
在本发明的另一方面,本发明提供一种用于预防或改善疼痛的保健功能性食品组合物,其包含上述化合物作为活性成分。
在本发明的另一方面,本发明提供一种治疗疼痛的方法,包括向有需要的受试者施用上述化合物的步骤。
在本发明的另一方面,本发明提供一种用在预防或治疗疼痛的上述化合物。
在本发明的另一方面,本发明提供一种上述化合物在制备用于预防或治疗疼痛的药物中的用途。
有益效果
在本发明一方面中提供的实施例化合物阻断由辣椒素(TRPV1受体激活剂)引起的TRPV1激活,但诱导约20%至80%的pH的适当抑制,因此,所述化合物具有减轻疼痛和有效降低如异常体温的副作用的效果。
具体实施方式
以下,详细描述本发明。
本发明的实施例可以以各种其他形式修改,并且本发明的范围不限于下面描述的实施例。本领域的普通技术人员应当理解,给出本发明的实施例是为了更精确地解释本发明。
此外,除非另有特别说明,在整个说明书中的元素“包括”并不排除其他元素,而是可以包括其它元素。
在本发明的一方面,本发明提供由下式1表示的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐。
[式1]
在上述式1中,
X1和X2独立地为氢,或
通过与它们所连接的碳原子连接形成C=C双键,或
通过与它们所连接的碳原子连接形成3-6元环亚烷基;以及
其中所述取代的5-10元杂芳基和C6-10芳基独立地为被至少一个选自以下的取代基取代的5-10元杂芳基和C6-10芳基:未取代的或被至少一个卤素或羟基取代的C1-12直链或支链烷基、C1-12直链或支链炔基、未取代的或被至少一个C1-5直链或支链烷基取代的C3-10环烷基、未取代的或被至少一个含有至少一个选自N和O的杂原子的C1-5直链或支链烷基取代的5-8元杂环烷基、-NR1R2、-OR3、-SR4、未取代的或被至少一个卤素或C1-5直链或支链烷基取代的C6-10芳基,和含有至少一个选自N、O和S的杂原子的5-8元杂芳基,R1和R2独立地为C1-10直链或支链烷基,
R3为未取代的或被至少一个卤素取代的C1-10直链或支链烷基、C3-10环烷基、或未取代的或被至少一个甲基取代的C3-10环烷基C1-5直链或支链烷基,
R4为未取代的或被至少一个卤素取代的C1-10直链或支链烷基、C3-10环烷基、或未取代的或被至少一个甲基取代的C3-10环烷基C1-5直链或支链烷基。
在另一方面中,
X1和X2独立地为氢,或
通过与它们所连接的碳原子连接形成C=C双键,或
通过与它们所连接的碳原子连接形成3-5元环亚烷基;以及
其中所述取代的5-8元杂芳基和C6-8芳基独立地为被至少一个选自以下取代基取代的5-8元杂芳基和C6-8芳基:未取代的或被至少一个卤素或羟基取代的C1-10直链或支链烷基、C1-10直链或支链炔基、未取代的或被至少一个C1-5直链或支链烷基取代的C3-8环烷基、未取代的或被至少一个含有至少一个选自N和O的杂原子的C1-5直链或支链烷基取代的5-6元杂环烷基、-NR1R2、-OR3、-SR4、未取代的或被至少一个卤素或C1-5直链或支链烷基取代的C6-8芳基和含有至少一个选自N、O和S的杂原子的5-6元杂芳基,R1和R2独立地为C1-8直链或支链烷基,
R3为未取代的或被至少一个卤素取代的C1-8直链或支链烷基、C3-8环烷基、或未取代的或被至少一个甲基取代的C3-8环烷基C1-5直链或支链烷基,
R4为未取代的或被至少一个卤素取代的C1-8直链或支链烷基、C3-8环烷基、或未取代的或被至少一个甲基取代的C3-8环烷基C1-5直链或支链烷基。
在另一方面中,
X1和X2独立地为氢,或
通过与它们所连接的碳原子连接形成C=C双键,或
通过与它们所连接的碳原子连接形成3-4元环亚烷基;以及
其中所述取代的5-6元杂芳基和C6芳基独立地为被至少一个选自以下的取代基取代的5-6元杂芳基和C6芳基:未取代的或被至少一个卤素或羟基取代的C1-7直链或支链烷基、C1-7直链或支链炔基、未取代的或被至少一个C1-5直链或支链烷基取代的C3-6环烷基、未取代的或被至少一个含有至少一个选自N和O的杂原子的C1-5直链或支链烷基取代的5-6元杂环烷基、NR1R2、-OR3、-SR4、未取代的或被至少一个卤素或C1-5直链或支链烷基取代的C6芳基和含有至少一个选自N、O和S的杂原子的5元杂芳基,
R1和R2独立地为C1-5直链或支链烷基,
R3为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基,
R4为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基。
在另一方面中,
X1和X2独立地为氢,或
通过与它们所连接的碳原子连接形成C=C双键,或
通过与它们所连接的碳原子连接而形成环亚环丙基;以及
式1表示的化合物可以是选自以下化合物中的任意一种化合物。
(1)(E)-3-(2-(4-甲基哌啶-1-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(2)(E)-3-(2-(4-乙基哌啶-1-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(3)(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(吡咯烷-1-基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺;
(4)(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(哌啶-1-基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺;
(5)(E)-3-(2-吗啉代-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(6)(E)-3-(2-(二乙基氨基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(7)(E)-3-(2-(二丙基氨基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(8)(E)-3-(2-丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(9)(E)-3-(2-(己氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(10)(E)-3-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(11)(E)-3-(2-环丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(12)(E)-3-(2-(环戊氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(13)(E)-3-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(14)(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(2,2,2-三氟乙氧基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺;
(15)(E)-3-(2-(新戊基氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(16)(E)-3-(2-((2-甲基环丙基)甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(17)(E)-3-(6-(氯二氟甲基)-2-(环丙基甲氧基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(18)(E)-3-(6-环丙基-2-(环丙基甲氧基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(19)(E)-3-(2-(环丙基甲氧基)-6-异丙基吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(20)(E)-3-(2-(环丙基甲氧基)-6-(1-甲基环丙基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(21)(E)-3-(2-(环丙基甲氧基)-6-(二氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(22)(E)-3-(2-(环丙基甲氧基)-6-(1,1-二氟乙基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(23)(E)-3-(6-(叔丁基)-2-(环丙基甲氧基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(24)(E)-3-(2-(环丙基甲氧基)-6-(2-羟基丙-2-基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(25)(E)-3-(2-(环丁基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(26)(E)-3-(2-(环戊基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(27)(E)-3-(2-(异丁硫基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(28)(E)-3-(2-((环丙基甲基)硫基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(29)(E)-3-(2-(环己基硫基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(30)(E)-3-(2-(3-氟苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(31)(E)-3-(2-(3-氯苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(32)(E)-3-(2-(3-异丙基苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(33)(E)-3-(2-(3-氯-4-氟苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(34)(E)-3-(2-(4-氟苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(35)(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(噻吩-2-基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺;
(36)(E)-3-(2-(呋喃-2-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(37)(E)-3-(2-(噁唑-2-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(38)(E)-3-(2-(噁唑-5-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(39)(E)-3-(2-(3,3-二甲基-1-丁炔-1-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(40)(E)-3-(2-(3,3-二甲基丁基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(41)(E)-3-(2-环戊基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(42)(E)-3-(2-异丁氧基-4-(三氟甲基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(43)(E)-3-(2-(环丙基甲氧基)-4-(三氟甲基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(44)(E)-3-(2-(环丙基甲氧基)-4-(2-羟基丙-2-基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(45)(E)-3-(4-(叔丁基)-2-(环丙基甲氧基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(46)(E)-3-(4-环丙基-2-(环丙基甲氧基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(47)(E)-3-(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(48)(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(1-(间甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)丙烯酰胺;
(49)(E)-3-(1-(3-氯-4-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(50)(E)-3-(1-(3-异丙基苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(51)(E)-3-(1-(3-氯苯基)-3-异丙基-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(52)(E)-3-(1-(3-氯苯基)-3-(1-甲基环丙基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(53)(E)-3-(3-(叔丁基)-1-(3-氯苯基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(54)(E)-3-(4-(3-氯苯基)-2-(三氟甲基)噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(55)(E)-3-(4-(3-氯苯基)-2-异丙基噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(56)(E)-3-(4-(3-氯苯基)-2-环丙基噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(57)(E)-3-(4-(3-氯苯基)-2-(1-甲基环丙基)噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(58)(E)-3-(2-(叔丁基)-4-(3-氯苯基)噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(59)3-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙酰胺;
(60)3-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙亚胺;
(61)2-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(62)2-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(63)2-(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(64)2-(1-(3-氯苯基)-3-(1,1-二氟乙基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(65)2-(1-(3-氯苯基)-3-异丙基-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(66)2-(1-(3-氯苯基)-3-环丙基-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(67)2-(1-(3-氯苯基)-3-(1-甲基环丙基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;以及
(68)2-(3-(叔丁基)-1-(3-氯苯基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺。
在另一方面中,
其中所述取代的5-6元杂芳基是被两个选自以下的取代基取代的5-6元杂芳基:未取代的或被至少一个卤素或羟基取代的C1-7直链或支链烷基、C1-7直链或支链炔基、未取代的或被至少一个C1-5直链或支链烷基取代的C3-6环烷基、未取代的或被至少一个含有至少一个选自N和O的杂原子的C1-5直链或支链烷基取代的5-6元杂环烷基、NR1R2、-OR3、-SR4、未取代的或被至少一个卤素或C1-5直链或支链烷基取代的C6芳基和含有至少一个选自N、O和S的杂原子的5元杂芳基,
R1和R2独立地为C1-5直链或支链烷基,
R3为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基,
R4为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基。
在另一方面中,
其中取代吡啶是被两个选自以下的取代基取代的吡啶:未取代的或被至少一个卤素或羟基取代的C1-7直链或支链烷基、C1-7直链或支链炔基、未取代的或被至少一个C1-5直链或支链烷基取代的C3-6环烷基、未取代的或被至少一个含有至少一个选自N和O的杂原子的C1-5直链或支链烷基取代的5-6元杂环烷基、NR1R2、-OR3、-SR4、未取代的或被至少一个卤素或C1-5直链或支链烷基取代的C6芳基和含有至少一个选自N、O和S的杂原子的5元杂芳基,
R1和R2独立地为C1-5直链或支链烷基,
R3为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基,
R4为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基。
本发明的式1表示的化合物可以以药学上可接受的盐的形式使用,其中所述盐优选为由药学上可接受的游离酸形成的酸加成盐。本文中的酸加成盐可以从无机酸,例如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸和亚磷酸;无毒有机酸,例如脂族单/二羧酸、苯基取代的链烷酸、羟基链烷酸、烷二酸、芳族酸和脂族/芳族磺酸;或有机酸,如三氟乙酸、苯甲酸、柠檬酸、乳酸、马来酸、葡糖酸、甲磺酸、4-甲苯磺酸、酒石酸和富马酸获得。药学上无毒的盐例如为硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、氟化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、卡巴酸盐、富马酸盐、苹果酸盐、丁炔-1,4-二酸盐、己烷-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、羟基丁酸盐、乙醇酸盐、苹果酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐。
根据本发明的酸加成盐可通过本领域技术人员已知的常规方法制备。例如,将式1所示的衍生物溶解在有机溶剂如甲醇、乙醇、丙酮、二氯甲烷和乙腈中,向其中加入有机酸或无机酸以诱导沉淀。然后,过滤沉淀并干燥,得到盐。或者将溶剂和过量的酸减压蒸馏,干燥,得到盐。或者将沉淀物在有机溶剂中结晶,即得。
通过使用碱可制备药学上可接受的金属盐。通过以下方法获得碱金属或碱土金属盐:将化合物溶于过量的碱金属氢氧化物或碱土金属氢氧化物溶液中;过滤不溶性复合盐;蒸发剩余溶液并干燥。此时,金属盐优选以药学上合适的钠、钾或钙盐形式制备。相应的盐是通过碱金属或碱土金属盐与适当的银盐(例如硝酸银)反应来制备。
此外,本发明不仅包括由式1表示的化合物,还包括其药学上可接受的盐,以及可能由其产生的溶剂化物、光学异构体或水合物。
术语“水合物”是指含有通过非共价分子间力结合的化学计量或非化学计量量的水的本发明的化合物或其盐。本发明的式1表示的化合物的水合物可以含有通过非共价分子间力结合的化学计量或非化学计量量的水。水合物可以含有1当量或更多的水,优选1-5当量的水。水合物可以通过从水或含水溶剂中结晶式1表示的化合物、其异构体或其药学上可接受的盐来制备。
术语“溶剂化物”是指含有通过非共价分子间力结合的化学计量或非化学计量量的溶剂的本发明的化合物或其盐。因此,优选的溶剂包括挥发性的、无毒的和/或适于给人施用的溶剂。
术语“异构体”是指具有相同化学式或分子式,但结构或空间上不同的本发明化合物或其盐。此种异构体包括结构异构体如互变异构体、具有不对称碳中心的R或S异构体、立体异构体如几何异构体(反式、顺式)和光学异构体(对映体)。所有这些异构体及其混合物也包括在本发明的范围内。
在本发明的另一方面,本发明提供一种用于预防或治疗疼痛的药物组合物,其包含式1所示的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。此时,该化合物可通过抑制TRPV1(瞬时受体电位香草酸亚型1)受体激活剂而表现出对疼痛的预防或治疗活性。优选地,该化合物通过抑制辣椒素——TRPV1(瞬时受体电位香草酸亚型1)受体激活剂来预防或治疗疼痛,并将pH抑制在20%至80%范围内,以减少如体温异常的副作用。
本发明的式1表示的化合物或其药学上可接受的盐可以口服或肠胃外给药,并且可以以药物制剂的一般形式使用。也就是说,该化合物或其药学上可接受的盐可以通过与常用的稀释剂或赋形剂如填料、填充剂、粘合剂、润湿剂、崩解剂和表面活性剂混合来制备用于口服或肠胃外给药。用于口服给药的固体制剂是片剂、丸剂、粉剂、颗粒剂和胶囊剂。这些固体制剂通过将一种或多种化合物与一种或多种合适的赋形剂如淀粉、碳酸钙、蔗糖或乳糖、明胶等混合来制备。除了简单的赋形剂之外,可以使用润滑剂,例如硬脂酸镁、滑石等。口服给药的液体制剂是混悬剂、溶液剂、乳剂和糖浆剂,并且上述制剂除了通常使用的简单稀释剂如水和液体石蜡外,还可以含有各种赋形剂如润湿剂、甜味剂、芳香剂和防腐剂。用于肠胃外给药的制剂是无菌水溶液、水不溶性赋形剂、悬浮液和乳液。除了活性化合物之外,水不溶性赋形剂和混悬剂可以含有丙二醇、聚乙二醇、植物油如橄榄油、可注射的酯如油酸乙酯等。
包含式1所示化合物或其药学上可接受的盐作为活性成分的药物组合物可以通过肠胃外给药,肠胃外给药包括皮下注射、静脉内注射、肌肉内注射或胸内注射。
此时,为了制备式1所示的化合物或其药学上可接受的盐作为用于肠胃外给药的制剂,将式1所示的化合物或其药学上可接受的盐与稳定剂或缓冲剂在水中混合以制备溶液或悬浮液,然后将其配制为安瓿或小瓶。本文的组合物可以是无菌的,并且另外含有防腐剂、稳定剂、可湿性粉剂或乳化剂、用于调节渗透压的盐和/或缓冲剂以及其他治疗上有用的材料,并且组合物可以通过常规混合、制粒或包衣方法配制。
用于口服给药的制剂的例子有片剂、丸剂、硬/软胶囊、溶液、悬浮液、乳剂、糖浆、颗粒、酏剂和锭剂等。除了活性成分之外,这些制剂还可以包括稀释剂(例如,乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸)和润滑剂(例如,二氧化硅、滑石、硬脂酸盐及其镁盐或钙盐和/或聚乙二醇)。片剂可以包括粘合剂,例如硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮,并且如果必要,还可以包括崩解剂,例如淀粉、琼脂糖、褐藻酸或其钠盐或共沸混合物和/或吸收剂、着色剂、香料和甜味剂。
在本发明的另一方面中,本发明提供一种用于治疗或缓解疼痛的镇痛组合物,其含有式1所示的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。此时,该化合物可通过抑制TRPV1(瞬时受体电位香草酸亚型1)受体激活剂而表现出治疗或缓解疼痛的活性。优选地,该化合物通过抑制辣椒素——TRPV1(瞬时受体电位香草酸亚型1)受体激活剂来治疗或缓解疼痛,并将pH抑制在20%至80%的范围内,以减少如体温异常的副作用。
在本发明的另一方面,本发明提供一种用于预防或缓解疼痛的保健功能性食品组合物,其含有式1所示的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。此时,该化合物可通过抑制TRPV1(瞬时受体电位香草酸亚型1)受体激活剂而表现出对疼痛的预防或改善活性。优选地,该化合物通过抑制辣椒素——TRPV1(瞬时受体电位香草酸亚型1)受体激活剂来预防或改善疼痛,并将pH抑制在20%至80%的范围内以减少如异常体温的副作用。
根据本发明的式1表示的化合物可以用作食品添加剂。在这种情况下,该化合物可以直接添加,或者按照常规方法与其他食品成分混合添加。活性成分的混合比例可以根据使用目的(预防或改善)进行调节。通常,保健食品中所述化合物的量可以以基于食品总重量的0.1至90重量份的量添加。然而,如果健康和卫生或调节健康状况需要长期给药,则含量可以低于上述含量,但是由于已经证明该化合物非常安全,因此也可以接受更高的含量。
此外,与其他饮料一样,本发明的保健功能性饮料组合物除了式1所示的化合物外,还可另外包括各种调味剂或天然碳水化合物等。上述天然碳水化合物可以是单糖(如葡萄糖和果糖)、二糖(如麦芽糖和蔗糖)、多糖(如糊精和环糊精)和糖醇(如木糖醇、山梨糖醇和赤藓糖醇)中的一种。此外,天然甜味剂(甜菜碱、甜菊提取物,例如莱鲍迪甙A、甘草甜素等)和合成甜味剂(糖精、阿斯巴甜等)可以作为甜味剂。天然碳水化合物的含量优选为100g本发明的组合物中1-20g,更优选为5-12g。
除上述成分外,根据本发明的式1表示的化合物可以包括各种营养素、维生素、矿物质(电解质)、香料(包括天然香料和合成香料)、着色剂和填充剂(奶酪、巧克力等)、果胶酸及其盐、褐藻酸及其盐、有机酸、保护性胶体增粘剂、pH调节剂、稳定剂、防腐剂、甘油、醇、用于添加到苏打中的碳酸盐等。本发明的式1表示的化合物还可以包括可添加到天然果汁、水果饮料和蔬菜饮料中的果肉。
在本发明的另一方面,本发明提供一种用于预防或治疗疼痛的药物试剂盒,其包括第一组分和第二组分,所述第一组分含有式1所示的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分;所述第二组分含有镇痛剂作为活性成分。
此时,镇痛剂可以不受限制地使用,只要它是已知的镇痛剂。镇痛剂可以是抗炎镇痛剂(NSAID,如COX抑制剂)或阿片类镇痛药。镇痛剂的一些实例可以是对乙酰氨基酚、阿司匹林、布洛芬、酮洛芬、美洛昔康、双氯芬酸钾、依托多酸、舒林酸、吲哚美辛、塞来昔布、伐地昔布、罗非昔布、塞来昔布、氢可酮、羟吗啡酮、丁丙诺啡、芬太尼、氢吗啡酮、曲马多等,或其组合。
在本发明的另一方面,本发明提供一种治疗疼痛的方法,包括向有需要的受试者施用上述化合物的步骤。在本发明的另一方面,本发明提供用在预防或治疗疼痛中的上述化合物。在本发明的另一方面,本发明提供上述化合物在制备用于预防或治疗疼痛的药物中的用途。
本发明的一方面中提供的实施例化合物阻断由辣椒素——TRPV1受体激活剂引起的TRPV1激活,但诱发约20%至80%的pH的适当抑制,因此所述化合物具有减轻疼痛和有效降低副作用如异常体温的作用。这些由下文描述的实施例和实验例直接支持。
以下,将通过实施例和实验例对本发明进行详细说明。
然而,以下实施例和实验例仅用于说明本发明,本发明的内容并不限于此。
合成
1.化合物的合成
1-1.A区的合成
[反应式1]A-区(4-氨基-1,3-二氢-2H-苯并[d]咪唑-2-酮衍生物)的合成
1-1-1.4-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮的合成
将3-硝基苯-1,2-二胺(1当量)溶解在乙腈中,在0℃下向其中滴加三光气(1.2当量)3-5分钟,然后在室温下搅拌30分钟,优选1小时。通过在0℃下缓慢滴加水稀释反应混合物,当不再产生气体并开始形成深黄-绿色固体时,将反应混合物在室温下搅拌30分钟,优选1小时。然后,将所产生的黄绿色固体过滤并用水洗涤,得到目标产物4-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮。(收率:80-89%)
1-1-2.4-氨基-1,3-二氢-2H-苯并[d]咪唑-2-酮的合成
将上述反应中得到的4-硝基-1,3-二氢-2H-苯并[d]咪唑-2-酮(l当量)用还原剂(诸如溶于低级醇如甲醇中的10%钯-活性炭(Pd-C))氢化,过滤,并将滤液减压干燥。通过填充有硅胶的快速柱层析纯化反应物,使用二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,得到目标化合物4-氨基-1,3-二氢-2H-苯并[d]咪唑-2-酮。(收率80-85%)
1-2.C区的合成
[反应式2]吡啶C-区的合成
1-2-1.R2-吡啶/苯基的合成
[方法1A]NR/OR
将吡啶或苯基(其中R1为CF3或C(CH3)3,Y为CN或Br,Z为OH、Cl、F或SH)作为原料,溶于THF或DMF中,在0℃下向其中加入DBU(2当量)、NaH(2当量)或K2CO3(2当量),然后搅拌5至10分钟。将相应的NR、OR、卤代烷基和SR(2当量)溶于THF或DMF中,并加入到搅拌的混合物中,然后在室温下搅拌16小时。通过加水终止反应,并将反应物用乙酸乙酯或二氯甲烷萃取。将得到的有机层用盐水洗涤,用硫酸镁干燥,然后真空浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,得到目标化合物。(收率:85%-92%)
[方法1B]C-C
将原料2-氯-6-(三氟甲基)烟腈(2-氯-6-(三氟甲基)烟腈)(1当量)溶于甲苯中,搅拌,向其中加入溶于水中的Na2CO3(24当量),然后搅拌5-10分钟。然后,加入Pd(PPh3)4(0.2当量)。在混合物回流30分钟或3小时后,将反应器温度降低至室温。将相应的硼酸(2当量)溶于甲苯或1,4-二噁烷中并向其中滴加,将混合物回流并搅拌15小时。反应完成后,将反应器的温度降低至室温,并将反应物用硅藻土衬垫过滤器过滤并减压浓缩。将得到的混合物溶解在乙酸乙酯中,用盐水和水洗涤,用硫酸镁干燥,并真空浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,得到目标化合物。(产率:72%-85%)
[方法1C]C-C
将原料2-氯-6-(三氟甲基)烟腈(2-氯-6-(三氟甲基)烟腈)(1当量)溶于甲苯中并搅拌,向其中加入相应的炔烃(2当量)、Pd(PPh3)4(0.2当量)、碘化铜(I)(0.2当量)和TEA(2当量),将混合物回流并搅拌15小时。反应完成后,将反应器的温度降低至室温,并将反应物用硅藻土衬垫过滤器过滤并减压浓缩。将得到的混合物溶于EtOAc,用盐水和水洗涤,用硫酸镁干燥,真空浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯和己烷的混合溶剂作为洗脱溶剂,得到目标化合物。(产率:65%-73%)
1-2-2.吡啶/苯甲醛的合成
将上述反应中得到的吡啶/苄腈(1当量)溶解在甲苯中,并充入氮气,在-78℃下向其中缓慢滴加DIBAL-H(甲苯中1M,2当量),然后在相同温度下搅拌2小时。通过加入NH4Cl水溶液终止反应,用EtOAc萃取有机物质。将所得混合物用盐水和水洗涤,用硫酸镁干燥,并真空浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯和己烷的混合溶剂作为洗脱溶剂,得到目标化合物。(收率61%-75%)
1-2-3.E-甲基/乙酸乙酯的合成
[方法2A]
将上述反应中得到的醛(1当量)溶解在甲苯中,向其中加入(三苯基膦烯)乙酸甲酯或(三苯基膦烯)乙酸乙酯(2当量),然后在室温下搅拌24小时。反应完成后,减压浓缩除去甲苯,获得的残留物通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯和己烷的混合溶剂作为洗脱溶剂,得到目标化合物。(收率:50%-65%)
[方法2B](E)-3-(2-(环丙基甲氧基)-6-(2-羟基丙-2-基)吡啶-3-基)丙烯酸甲酯的合成
在Y中含有溴的2-(5-溴-6-(环丙基甲氧基)吡啶-2-基)丙-2-醇的情况下,将2-(5-溴-6-(环丙基甲氧基)吡啶-2-基)丙-2-醇(1当量)溶解在无水DMF中,向其中加入丙烯酸甲酯(4当量)、P(o-tol)3(0.3当量)和三乙胺(10当量),然后用惰性气体(氮气和氩气)鼓泡至少5分钟。将反应混合物在室温下搅拌10至30分钟。向其中加入Pd(OAc)2(3mol%),然后用惰性气体(氮气和氩气)鼓泡5-10分钟。然后,将反应混合物在100℃下搅拌24小时。反应完成后,将反应器的温度降低至室温。用EtOAc稀释反应物,用水和盐水洗涤,用硫酸镁干燥,并真空浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯和己烷的混合溶剂作为洗脱溶剂,得到目标化合物。(收率:65%)
1-2-4.三氟甲基吡啶环丙烷-1-羧酸酯的合成
将三甲基碘化亚砜(2当量)溶解在DMSO中,在0℃下向其中加入NaH(2当量),然后在室温下搅拌1-2小时,优选直到形成澄清混合物。将上述反应中得到的原料吡啶丙烯酸酯(1当量)溶解在少量DMSO中,向其中缓慢滴加,并将混合物在室温下搅拌2-4小时。通过加水终止反应,并用乙酸乙酯萃取有机物质。将反应混合物用水和盐水洗涤,将得到的滤液用硫酸镁干燥并真空浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,得到目标化合物。(收率:80%-90%)
1-2-5.吡啶/苯基丙烯酸和环丙烷羧酸的合成
将上述反应中得到的吡啶或丙烯酸苯酯或吡啶环丙烷羧酸酯(1当量)溶解在THF中,加入LiOH·H2O(2-3当量)和相同量的水,然后在室温下搅拌2-5小时。反应完成后,在0℃加入1N HCl调节反应物的pH至2-3,用EtOAc萃取有机物质,用水和盐水洗涤,所得滤液经硫酸镁干燥并真空浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,得到目标化合物。(产率:85%-98%)
1-3.C区原料的合成
[反应式3]
1-3-1. 2,2-二氟丙酸酐的合成方法
在-10℃、搅拌下将2,2-二氟丙酸(1当量)溶于二氯甲烷,向其中滴入草酰氯(oxanyl chloride)(1.2当量),在室温下搅拌4小时。然后,以粗制状态用作下一步反应的原料。
1-3-2. 4-乙氧基二氟丁烯酮的合成方法
将原料上述反应中得到的2,2-二氟丙酸酐或市售的2,2-二氟乙酸酐和2-氯-2,2-二氟乙酸酐(1当量)溶于氯仿中,将反应器的温度降至0℃,然后搅拌。向反应混合物中加入乙基乙烯基醚(1.3当量)和吡啶(1.3当量),然后在室温下搅拌4小时。加入1N HCl终止反应,用二氯甲烷萃取有机物质,用水和盐水洗涤,并在30℃减压浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯和己烷的混合溶剂作为洗脱溶剂,得到目标化合物。(收率89-95%)
1-3-3. 2-羟基烟腈的合成
将2-氰基乙酰胺(1当量)溶解在乙醇中,向其中滴加NaOEt 21%的乙醇溶液(1.5当量),然后在室温下搅拌10-20分钟。在将反应器的温度降低至0℃后,将在上述反应中获得的原料(1当量)逐滴加入反应混合物中。升高反应器温度,将反应混合物在回流条件下反应5小时。反应完成后,将反应器温度降至室温,用4N HCl酸化反应物,用EtOAc萃取,用水和盐水洗涤。将所得混合物用硫酸镁干燥并真空浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯和己烷的混合溶剂作为洗脱溶剂,得到目标化合物。(收率:60%-75%)
1-3-4. 2-氯烟腈的合成
将上述反应中得到的原料(1当量)溶解在苯基磷酰二氯中,并在密封管中在170℃下搅拌3小时。反应完成后,将反应器温度降至室温,用EtOAc或醚萃取反应物,并用水和盐水洗涤。将所得混合物用硫酸镁干燥并真空浓缩。将得到的残余物通过填充有硅胶的快速柱层析纯化,得到目标化合物。(收率71%-82%)
[反应式4]
1-4-1.(Z)-3-环丙基-3-氧代丙-1-烯-1-醇酯的合成
在反应容器中加入NaH(1当量),通入氮气,加入甲苯和乙醇,搅拌。向混合物中加入溶解在甲苯中的环丙基甲基酮(1当量)和甲酸乙酯(1当量),然后在室温下反应15小时。反应完成后,将过量的甲苯加入反应物中,过滤并减压浓缩,得到目标产物。(产率:81%)
1-4-2. 6-环丙基-2-羟基烟腈的合成
将在上述反应中获得的(Z)-3-环丙基-3-氧代丙-1-烯-1-醇酯(1当量)溶解于1,4-二噁烷中,向其中加入2-氰基乙酰胺(1当量),然后回流反应21小时。反应完成后,将反应器的温度降低至室温,并过滤反应物。向所得滤液中加入AcOH,然后搅拌10-30分钟。然后,将反应混合物用EtOAc萃取,用水和盐水洗涤,将得到的混合物用硫酸镁干燥,真空浓缩,得到目标产物。(收率:60%-70%)
1-4-3. 2-氯-6-环丙基烟腈的合成
将上述反应中得到的6-环丙基-2-羟基烟腈(1当量)溶解在苯基磷酸二氯中,并在密封管中170℃下搅拌3小时。反应完成后,将反应器温度降至室温,用EtOAc或醚萃取反应物,并用水和盐水洗涤。将所得混合物用硫酸镁干燥并真空浓缩。将得到的残余物通过填充有硅胶的快速柱层析纯化,得到目标化合物。(收率71%-82%)
[反应式5]
1-5-1.二甲基氨基丙烯/丁烯-1-酮的合成
在密封试管中,将原料3-甲基丁烷-2-酮或1-(1-甲基环丙基)乙烷-1-酮或3,3-二甲基丁烷-2-酮溶解在过量的二甲基甲酰胺二甲基缩醛中,并在110℃下搅拌5小时。反应完成后,将反应器温度降至室温,并将有机层用二氯甲烷萃取,并用水和盐水洗涤。将所得混合物用硫酸镁干燥,并在30℃下减压浓缩。将得到的残余物通过填充有硅胶的快速柱层析纯化,得到目标化合物。(收率:20%-50%)
1-5-2. 2-羟基烟腈的合成
将上述反应中得到的原料(1当量)和氰化物乙酰胺(cyanide acetamide)(1.3当量)加入AcOH和哌啶(1:1.3)的混合物中,然后回流搅拌24小时。反应完成后,将反应器温度降至室温,用4N HCl酸化反应物,用EtOAc萃取,用水和盐水洗涤。将所得的混合物用硫酸镁干燥并真空浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯和己烷的混合溶剂作为洗脱溶剂,得到目标化合物。(收率:60%-75%)
1-5-3.氯烟腈的合成
将上述反应中得到的原料(1当量)溶于二氯磷酸苯酯中,在密封管中170℃下搅拌3小时。反应完成后,将反应器温度降至室温,用EtOAc或醚萃取反应物,并用水和盐水洗涤。将所得混合物用硫酸镁干燥并真空浓缩。将得到的残余物通过填充有硅胶的快速柱层析纯化,得到目标化合物。(收率71%-82%)
[反应式6]
1-6-1. 5-溴-2-(甲氧基羰基)吡啶-1-氧化物的合成
将原料5-溴吡啶甲酸甲酯(1.0当量)溶于二氯甲烷中,向其中加入m-CPBA(2.0当量),回流条件下搅拌20小时。将反应器的温度冷却至室温,并通过加入Na2SO3水溶液(饱和Na2SO3)终止反应。用二氯甲烷萃取有机物质,并用水和盐水洗涤。将所得混合物用硫酸镁干燥并真空浓缩。将得到的残余物通过填充有硅胶的快速柱层析纯化,得到目标化合物。(产率:76%-85%)
1-6-2. 5-溴-6-氯吡啶甲酸甲酯的合成
在0℃下将过量的POCl3添加到上述反应中得到的5-溴-2-(甲氧基羰基)吡啶1-氧化物)(1当量)中,并将混合物在95℃下搅拌1小时。通过加入水终止反应。用EtOAc萃取有机物质,用水和盐水洗涤。将所得混合物用硫酸镁干燥并真空浓缩。将得到的残余物通过填充有硅胶的快速柱层析纯化,得到目标化合物。(产率:68%-90%)
1-6-3. 2-(5-溴-6-氯吡啶-2-基)丙-2-醇的合成
将上述反应中得到的5-溴-6-氯吡啶甲酸甲酯(1当量)溶于THF中,在0℃下,在充氮反应器中向其中滴加3M CH3MgBr的乙醚溶液(4.0当量),然后在室温下搅拌1小时。通过加入NH4Cl水溶液终止反应。有机层用EtOAc萃取,用水和盐水洗涤。将所得混合物经硫酸镁干燥并真空浓缩,得到目标化合物。(收率:70%-85%)
[反应式7]
1-7-1. 2-巯基-6-(三氟甲基)烟腈的合成
将原料2-氯-6-(三氟甲基)烟腈(1当量)溶解在叔丁醇中,向其中加入Na2S(1当量),然后在微波中于150℃搅拌20分钟。通过加入1N HCl终止反应。有机层用EtOAc萃取,用水和盐水洗涤。将所得混合物用硫酸镁干燥并真空浓缩。将得到的残余物通过填充有硅胶的快速柱层析纯化,得到目标化合物。(收率:60%-65%)
[反应式8]4-环丙基-2-氟苯腈的合成
1-8-1. 4-环丙基-2-氟苯腈的合成
将原料4-溴-2-氟苄腈(1当量)溶解在甲苯中,搅拌,向其中加入溶解在水中的Na2CO3(24当量),然后搅拌5~10分钟。然后,向反应混合物中加入Pd(PPh3)4(0.2当量)。在回流条件下搅拌混合物2小时后,将反应器温度降低至室温,向其中滴加溶解在1,4-二氧杂环己烷(1,4-二恶烷)中的相应硼酸(2当量),随后在回流条件下搅拌15小时。反应完成后,将反应器的温度降低至室温,并将反应物用硅藻土衬垫过滤器过滤并减压浓缩。将得到的混合物溶解在乙酸乙酯中,用盐水和水洗涤,用硫酸镁干燥,并真空浓缩。将得到的残渣通过填充有硅胶的快速柱层析纯化,使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,得到目标化合物。(收率:85%)
[反应式9]吡唑C-区的合成
1-9-1.NR吡唑-5-羧酸酯的合成
将反应式10~11中合成的原料1H-吡唑-5-甲酸酯(1当量)溶于二氯甲烷中,搅拌,向其中加入适当的酸(2当量)、Cu(OAc)2(1.5当量)和吡啶(2当量),然后在室温下反应24小时。反应完成后,用硅藻土衬垫过滤器过滤反应物,并在减压下浓缩滤液。使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,将残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(收率:80%-90%)
1-9-2. 1H-吡唑基甲醇的合成方法
在反应容器中将LAH(2当量)溶解在THF中,并充入氮气,在0℃下向其中滴加溶解在THF中的上述反应中获得的原料(1当量),随后在室温下搅拌30分钟至1小时。反应完成后,将反应器的温度降低至0℃,并通过缓慢加入NaHCO3水溶液终止反应。用硅藻土衬垫过滤器过滤反应物,并在减压下浓缩滤液。使用二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,将残渣通过填充硅胶的快速柱层析进行纯化,得到目标化合物。(产率:90%-98%)
1-9-3. 1H-吡唑丙烯酸酯的合成
将上述反应得到的原料(1当量)溶解在甲苯中,向其中加入MnO2(1当量),然后在室温下搅拌30分钟至1小时。向混合物中加入(三苯基亚正膦基)乙酸甲酯(3.5当量),然后在回流条件下反应24小时。反应完成后,用硅藻土衬垫过滤器过滤反应物。用EtOAc萃取有机物质,用盐水和水洗涤,将滤液用硫酸镁干燥,并真空浓缩。使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(收率:75%-90%)
1-9-4. 1H-吡唑基环丙烷-1-羧酸酯的合成
将三甲基碘化亚砜(2当量)溶解在DMSO中,在0℃下向其中加入NaH(2当量),然后在室温下搅拌1-2小时,优选直到形成澄清的混合物。将上述反应中得到的原料1H-吡唑基丙烯酸酯(1当量)溶解在少量DMSO中,缓慢滴加至混合物中,然后在室温下搅拌2至4小时。通过加入水终止反应,并用乙酸乙酯萃取有机物质。将混合物用水和盐水洗涤,将得到的滤液用硫酸镁干燥并真空浓缩。使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(收率:80%-90%)
1-9-5.羧酸的合成
将上述反应中得到的丙烯酸酯或环羧酸酯(1当量)溶解在THF中,向其中加入LiOH·H2O(2-3当量)和相同量的水,然后在室温下搅拌2-5小时。反应完成后,在0℃加入1NHCl将反应物的pH调节至2-3。用乙酸乙酯萃取有机物质,用水和盐水洗涤,所得滤液经硫酸镁干燥并真空浓缩。使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(产率:85%-98%)
[反应式10]1H-吡唑-5-羧酸酯的合成
[方法A]
1-10-1. 3-(三氟甲基)-1H-吡唑-5-甲酸甲酯的合成
将原料丙酸甲酯(1当量)溶于二氯甲烷中,向其中缓慢滴加溶于水的NaNO2(3当量),然后搅拌10-20分钟。将反应器温度降低至0℃,并将3,3,3-三氟苯胺(3当量)滴加至反应混合物中,随后在0℃搅拌1至2小时。将反应混合物在室温下搅拌30分钟,通过加入水终止反应。用二氯甲烷萃取有机物质,用水和盐水洗涤,将得到的滤液用硫酸镁干燥并真空浓缩。使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(产率:65%-88%)
[方法B]
1-10-2. 1H-吡唑-5-羧酸酯的合成
将甲基-1-甲基环丙基酮、异丙基甲基酮或频哪酮(1当量)加入在0℃下将t-BuOK(1.5当量)溶于THF的混合物中,向其中滴加溶解在THF中的草酸二乙酯(1当量),然后在室温下搅拌15小时。向混合物中加入AcOH(0.15ml/mmol),向其中滴加一水合肼(1.1当量),然后在回流条件下搅拌3小时。反应完成后,将反应物减压浓缩,向所得固体中加入水,然后搅拌3至6小时。将得到的固体减压过滤并干燥,得到目标产物。(收率:80%-91%)
[反应式11]噻唑C-区的合成
1-11-1. 3-(3-氯苯基)-3-氧代丙酸甲酯的合成
通过在充满氮气的反应容器中搅拌,将NaH(3当量)溶解在THF中。将反应器温度降至0℃,缓慢滴加原料1-(3-氯苯基)乙-1-酮(1当量)和碳酸二甲酯(3当量),然后在室温下搅拌10至30分钟。将反应器温度升高至50℃,并将反应物搅拌15小时。在0℃下加入1N HCl终止反应。将有机物质用乙酸乙酯萃取,用水和盐水洗涤,将得到的滤液用硫酸镁干燥并真空浓缩。使用乙酸乙酯和己烷的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(产率:65%-88%)
1-11-2. 2-氯-3-(3-氯苯基)-3-氧代丙酸甲酯的合成
将上述反应中得到的3-(3-氯苯基)-3-氧代丙酸甲酯(1当量)溶于氯仿中,然后向反应器中充满氮气,在0℃下向其中滴加磺酰氯(1.1当量),然后在回流条件下搅拌15小时。反应完成后,将反应混合物减压浓缩。使用乙酸乙酯和己烷的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(产率:75%-88%)
1-11-3.R-羧酰胺的合成
在充满氮气的反应容器中,将1-甲基环丙烷-1-羧酸或新戊酸(1当量)溶解在甲苯中,在0℃下向其中滴加亚硫酰氯(1.1当量),然后在室温下搅拌5小时。在零下温度下向其中缓慢滴加过量的NH4OH水溶液,然后在室温下搅拌15小时。通过加入水终止反应。用EtOAc萃取有机物质,用水和盐水洗涤,将得到的滤液用硫酸镁干燥并真空浓缩,得到目标化合物。(收率71%-89%)
1-11-4.R-硫代酰胺的合成
使用在上述反应中得到的1-甲基环丙烷-1-甲酰胺和新戊酰胺,或者市售的异丁酰胺和2,2,2-三氟乙酰胺作为原料,将它们溶解在THF或甲苯中,向其中加入劳森试剂(Lawesson’s reagent)(0.6当量),然后在室温下搅拌15-30分钟。然后,将反应混合物在回流条件下搅拌2小时,优选4小时。反应完成后,将反应混合物减压浓缩。使用二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(收率:45%-68%)
1-11-5.噻唑-5-羧酸酯的合成方法
将上述反应中得到的2-氯-3-(3-氯苯基)-3-氧代丙酸甲酯(1当量)溶解在MeOH或i-PrOH:n-BuOH(1:1)的混合溶液中,向其中滴加溶解在相同溶剂中的1-11-4中得到的硫代甲酰胺(1.32当量),然后在室温下搅拌10-30分钟。然后,将反应混合物在回流条件下搅拌15小时。通过加水终止反应。用乙酸乙酯萃取有机物质。用乙酸乙酯萃取有机物质,用水和盐水洗涤,将得到的滤液用硫酸镁干燥并真空浓缩。使用乙酸乙酯和己烷的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(产率:65%-88%)
1-11-6.R-(3-氯苯基)噻唑-5-基甲醇的合成
在反应容器中将LAH(2当量)溶解在THF中,并充入氮气,在0℃下向其中滴加上述反应中获得的溶解在THF中的原料噻唑-5-羧酸酯(1当量),随后在室温下搅拌30分钟至1小时。将反应器的温度降低至0℃,并通过缓慢加入NaHCO3水溶液终止反应。用硅藻土衬垫过滤器过滤反应物,并在减压下浓缩所得滤液。使用二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(产率:90%-98%)
1-11-7.R-(3-氯苯基)噻唑-5-基)丙烯酸甲酯的合成
将1-11-6中得到的原料(1当量)溶解在甲苯中,向其中加入MnO2(1当量),然后在室温下搅拌30分钟至1小时。将(三苯基亚正膦基)乙酸甲酯)或(三苯基亚正膦基)乙酸乙酯)(3.5当量)加入混合物中,然后在回流条件下搅拌24小时。反应完成后,用硅藻土衬垫过滤器过滤反应物,并用乙酸乙酯萃取有机物质,用水和盐水洗涤。将得到的滤液用硫酸镁干燥,并真空浓缩。使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(收率:75%-90%)
1-11-8.(E)-R-(3-氯苯基)噻唑基-丙烯酸的合成
将在11-7中得到的丙烯酸酯(1当量)溶解在THF中,向其中加入LiOH·H2O(2-3当量)和相同量的水,然后在室温下搅拌2-5小时。反应完成后,在0℃加入1N HCl以将反应物的pH调节至2-3。用EtOAc萃取有机物质,用水和盐水洗涤,所得滤液经硫酸镁干燥并真空浓缩。使用乙酸乙酯、己烷或二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,将得到的残渣通过填充有硅胶的快速柱层析纯化,得到目标化合物。(产率:85%-98%)
1-3.B区的合成
[反应式12]EDC偶联
1-12-1.EDC偶联
将上述反应中得到的丙烯酸或环丙烷-1-羧酸溶解在DMA中,向其中加入EDC·HCl(1.5当量)和DMAP(1.5当量),然后在室温下搅拌10-20分钟。在加入反应式1A和1B中获得的4-氨基-苯并[d]咪唑-2-酮(4-氨基-苯并[d]咪唑-2-酮)衍生物(2当量)后,将该混合物在室温下搅拌3小时,优选5小时。通过加入水终止反应。有机层用乙酸乙酯或二氯甲烷萃取,并减压浓缩。将得到的残渣通过柱色谱法纯化,得到目标化合物。(收率:60-88%)
[反应式13]
1-13-1. 6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙酰胺(6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙酰胺)的合成
将1-12-1中获得的(E)-3-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺((E)-3-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺)或(E)-3-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺((E)-3-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺)(1当量)用溶于低级醇如甲醇中的还原剂如10%钯-活性炭(Pd-c)氢化,用硅藻土衬垫过滤,并在减压下干燥滤液。使用二氯甲烷和甲醇的混合溶剂作为洗脱溶剂,通过填充有硅胶的快速柱层析纯化反应物,得到目标化合物。(产率:90%-98%)
实施例1至68的化合物通过反应式1至13合成,各实施例化合物的NMR数据如下。
代表性地,<实施例1>的化合物通过使用[反应式2]中的R1为CF3、X为N、R2为甲基哌啶的化合物作为[反应式12]中的起始原料,并与A-区反应来制备。
<实施例1>(E)-3-(2-(4-甲基哌啶-1-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率72%;1H NMR(500MHz,DMSO)δ10.72(s,1H),10.15(s,1H),9.96(s,1H),8.05(d,J=7.65Hz,1H).7.70(m,1H),7.59(d,J=10.20Hz,1H),7.42(d,J=7.75Hz,1H),7.24(d,J=8.05Hz,1H),6.93(t,J=7.90Hz,1H),6.86(d,J=15.70Hz,1H),6.78(d,J=7.70Hz,1H),4.20(m,1H),3.63(d,J=12.55Hz,2H),2.86(t,J=12.15Hz,2H),1.96(m,1H),1.72(d,J=11.45Hz,2H),1.58(m,1H),1.31-1.26(m,2H),1.25(s,4H),0.95(d,J=6.45Hz,3H);Mass(FAB)m/z 446[M+H]+
<实施例2>(E)-3-(2-(4-乙基哌啶-1-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率88%;1H-NMR(400MHz,DMSO)δ10.69(s,1H),10.09(s,1H),9.88(s,1H),8.01(d,J=7.6Hz,1H),7.51(d,J=15.6Hz,1H),7.39(d,J=8.0Hz,1H),7.20(d,J=8.4Hz,1H),6.89(t,J=8.0Hz,1H),6.81(d,J=15.6Hz,1H),6.74(d,J=7.2Hz,1H),3.62(d,J=14.2Hz,2H),2.81(t,J=11.6Hz,2H),1.74(d,J=10.4Hz,2H),1.27-1.19(m,4H),1.15-1.13(t,J=7.6Hz,1H),0.84(m,3H);Mass(FAB)m/z 460[M+H]+
<实施例3>(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(吡咯烷-1-基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺
白色固体,收率65%;1H-NMR(400MHz,DMSO)δ10.67(s,1H),10.08(s,1H),9.08(s,1H),7.83(d,J=7.2Hz,1H),7.78(d,J=15.6Hz,1H),7.20(d,J=8.0Hz,1H),7.11(d,J=8.0Hz,1H),6.88(t,J=8.0Hz,1H),6.72(d,J=7.6Hz,1H),6.50(d,J=15.2Hz,1H),3.49(m,4H),1.85(m,4H);Mass(FAB)m/z 418[M+H]+
<实施例4>(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(哌啶-1-基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺
黄色固体,收率61%;1H NMR(300MHz,DMSO)δ10.73(s,1H),10.14(s,1H),9.92(s,1H),8.06(d,J=7.71Hz,1H),7.56(d,J=15.39Hz,1H),7.44(d,J=7.68Hz,1H),7.23(d,J=7.89Hz,1H),6.95-6.84(m,2H),6.77(d,J=7.86Hz,1H),3.24(m,4H),1.66(m,8H);Mass(ESI)m/z 432[M+H]+
<实施例5>(E)-3-(2-吗啉基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率82%;1H NMR(300MHz,CD3OD)δ8.06(d,J=7.9Hz,1H),7.84(d,J=15.8Hz,1H),7.38(d,J=7.9Hz,1H),7.05(s,1H),7.04(d,J=2.4Hz,1H),6.93-6.87(m,2H),3.86(m,4H),3.33(m,4H);Mass(ESI)m/z 434[M+H]+
<实施例6>(E)-3-(2-(二乙基氨基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率80%;1H NMR(500MHz,DMSO)δ10.72(s,1H),10.12(s,1H),9.90(s,1H),7.99(d,J=7.60Hz,1H),7.59(d,J=15.55Hz,1H),7.33(d,J=7.75Hz,1H),7.25(d,J=8.10Hz,1H),6.92(t,J=7.95Hz,1H),6.78(d,J=11.76Hz,1H),6.76(s,1H),2.94(m,4H)1.14(t,J=6.90Hz,6H);Mass(FAB)m/z 420[M+H]+
<实施例7>(E)-3-(2-(二丙基氨基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率82%;1H NM(500MHz,DMSO)δ10.72(s,1H),10.10(s,1H),9.91(s,1H),7.97(d,J=7.60Hz,1H),7.59(d,J=15.55Hz,1H),7.31(d,J=7.70Hz,1H),7.25(d,J=8.10Hz,1H),6.93(t,J=7.90Hz,1H),6.75-6.78(dd,J=3.35Hz,7.95Hz,2H),3.28(t,J=7.50Hz,4H),1.60(q,J=7.25Hz,4H),0.81(t,J=7.35Hz,6H);Mass(FAB)m/z 448[M+H]+
<实施例8>(E)-3-(2-丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率63%;1H-NMR(300MHz,DMSO)δ10.71(s,1H),10.15(s,1H),9.95(s,1H),8.24(d,J=7.5Hz,1H),7.71(d,J=15.8Hz,1H),7.57(d,J=7.9Hz,1H),7.20(d,J=8.2Hz,1H),7.05(d,J=15.8Hz,1H),6.93(t,J=7.5Hz,1H),6.78(d,J=7.7Hz,1H),4.44(t,J=6.6Hz,2H),1.81(m,2H),1.46(m,2H),0.96(t,J=7.32Hz,3H);Mass(FAB)m/z 421[M+H]+
<实施例9>(E)-3-(2-(己氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率73%;1H NMR(300MHz,DMSO)δ10.71(s,1H),10.15(s,1H),9.95(s,1H),8.24(d,J=7.71Hz,1H),7.70(d,J=15.75Hz,1H),7.56(d,J=7.68Hz,1H),7.21(d,J=8.25Hz,1H),7.05(d,J=15.75Hz,1H),6.93(t,1H),6.77(d,J=7.89Hz,1H),4.43(t,J=6.57Hz,2H),1.82(m,2H),1.43-1.23(m,7H),0.88-0.86(m,3H);Mass(FAB)m/z 449[M+H]+
<实施例10>(E)-3-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率73%;1H NMR(300MHz,DMSO)δ10.72(s,1H),10.16(s,1H),7.95(s,1H),8.25(d,J=7.71Hz,1H),7.74(d,J=15.75Hz,1H),7.57(d,J=7.69Hz,1H),7.19(d,J=7.71Hz,1H),7.04(d,J=15.72Hz,1H),6.93(t,J=8.04Hz,1H),6.78(d,J=7.68Hz,1H),4.21(d,J=6.78Hz,1H),2.17(p,J=6.57Hz,1H),1.02(d,J=6.78Hz,6H);Mass(ESI)m/z421[M+H]+
<实施例11>(E)-3-(2-环丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率82%;1H-NMR(300MHz,DMSO)δ10.71(s,1H),10.14(s,1H),9.98(s,1H),8.23(d,J=7.7Hz,1H),7.68(d,J=15.6Hz,1H),7.56(d,J=7.5Hz,1H),7.18(d,J=7.9Hz,1H),7.09(d,J=7.5Hz,1H),6.93(t,J=7.9Hz,1H),6.78(d,J=7.9Hz,1H),5.26(m,1H),2.50(m,2H),2.22(m,2H),1.78(m,2H);Mass(ESI)m/z 419[M+H]+
<实施例12>(E)-3-(2-(环戊氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率62%;1H-NMR(400MHz,DMSO-D6)δ10.66(s,1H),10.09(s,1H),9.90(s,1H),8.18(d,J=7.8Hz,1H),7.63(d,J=16.1Hz,1H),7.50(d,J=7.4Hz,1H),7.13(d,J=8.3Hz,1H),6.99(d,J=16.1Hz,1H),6.89(t,J=7.8Hz,1H),6.74(d,J=7.8Hz,1H),5.45(s,1H),2.01(t,J=6.4Hz,3H),1.92(s,2H),1.69-1.79(m,4H),1.59(d,J=8.3Hz,3H);Mass(ESI)m/z 433[M+H]+
<实施例13>(E)-3-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
浅黄色固体,产率82%;1H NMR(600MHz,DMSO)δ10.70(s,1H),10.14(s,1H),9.95(s,1H),8.24(d,J=7.80Hz,1H),7.73(d,J=16.02Hz,1H),7.57(d,J=7.38Hz,1H),7.20(d,J=8.28Hz,1H),7.07(d,J=16.02Hz,1H),6.93(t,J=8.28Hz,1H),6.77(d,J=7.80Hz,1H),4.29(d,J=6.84Hz,2H),1.35(m,1H),0.60(q,J=6.42Hz,2H),0.42(q,J=5.04Hz,2H);Mass(ESI)m/z 419[M+H]+
<实施例14>(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(2,2,2-三氟乙氧基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺
浅黄色固体,收率62%;1H-NMR(400MHz,DMSO)δ10.68(s,1H),10.14(s,1H),9.98(s.1H),8.33(d,J=7.2Hz,1H),7.69(m,2H),7.14(d,J=7.6Hz,1H),6.96(d,J=15.6Hz,1H),6.89(t,J=8.0Hz,1H),6.74(d,J=8.8Hz,1H),5.11(q,J=8.8Hz,2H);Mass(FAB)m/z447[M+H]+
<实施例15>(E)-3-(2-(新戊基氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率52%;1H-NMR(400MHz,DMSO)δ10.68(s,1H),10.13(s,1H),9.91(s.1H),8.22(d,J=7.6Hz,1H),7.74(d,J=16.0Hz,1H),7.75(d,J=0.80Hz,1H),7.15(d,J=8.4Hz,1H),6.95(d,J=8.4Hz,1H),6.88(t,J=8.4Hz,1H),6.73(d,J=7.6Hz,1H),4.60(s,2H),1.02(s,9H);Mass(FAB)m/z 435[M+H]+
<实施例16>(E)-3-(2-((2-甲基环丙基)甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率63%;1H-NMR(400MHz,DMSO)δ10.69(s,1H),10.15(s,1H),9.94(s,1H),8.20(d,J=7.6Hz,1H),7.72-7.66(m,1H),7.52(d,J=8.0Hz,1H),7.16(d,J=7.6Hz,1H),7.03(d,J=16.0Hz,1H),6.89(t,J=8.0Hz,1H),6.74(d,J=7.2Hz,1H),4.32-4.18(m,2H),0.99(d,J=6.0Hz,3H),0.81-0.80(m,2H),0.54(m,1H),0.32(m,1H);Mass(FAB)m/z433[M+H]+
<实施例17>(E)-3-(6-(氯二氟甲基)-2-(环丙基甲氧基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率71%;1H NMR(400MHz,DMSO)δ10.67(s,1H),10.23(s,1H),10.02(s,1H),8.20(d,J=8.0Hz,1H),7.68(d,J=16.0Hz,1H),7.46(d,J=7.6Hz,1H),7.19(d,J=8.0Hz,1H),7.05(d,J=16.0Hz,1H),6.88(t,J=8.4Hz,1H),6.73(d,J=7.6Hz,1H),4.26(d,J=7.2Hz,2H),1.33(m,1H),0.55(d,J=8.0Hz,2H),0.38(d,J=5.2Hz,2H);Mass(ESI)m/z 435[M+H]+
<实施例18>(E)-3-(6-环丙基-2-(环丙基甲氧基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率82%;1H NMR(400MHz,DMSO)δ10.66(s,1H),10.09(s,1H),9.75(s,1H),7.80(d,J=7.8Hz,1H),7.64(d,J=16.0Hz,1H),7.19(t,J=8.0Hz,1H),6.96(d,J=7.8Hz,1H),6.79-6.90(m,2H),6.71(d,J=7.3Hz,1H),4.14(d,J=6.9Hz,2H),1.99-2.05(m,1H),0.93(d,J=6.4Hz,4H),0.81(t,J=6.9Hz,1H),0.53(d,J=6.9Hz,2H),0.31(d,J=4.6Hz,2H);Mass(FAB)m/z 391[M+H]+
<实施例19>(E)-3-(2-(环丙基甲氧基)-6-异丙基吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率52%;1H NMR(400MHz,DMSO)δ10.67(s,1H),10.10(s,1H),9.77(s,1H),7.87(d,J=7.6Hz,1H),7.67(d,J=16.0Hz,1H),7.20(d,J=8.0Hz,1H),6.92-6.83(m,3H),6.72(d,J=7.2Hz,1H),4.23(d,J=6.8Hz,2H),2.94-2.87(m,1H),1.36-1.27(m,1H),1.19(d,J=6.8Hz,6H),0.56-0.51(m,2H),0.35-0.33(m,2H);Mass(FAB)m/z 393[M+H]+
<实施例20>(E)-3-(2-(环丙基甲氧基)-6-(1-甲基环丙基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率61%;1H NMR(400MHz,DMSO)δ10.65(s,1H),10.23(s,1H),9.87(s,1H),7.86(d,J=8.4Hz,1H),7.65(d,J=16.0Hz,1H),7.23(d,J=8.0Hz,1H),6.98(d,J=8.0Hz,1H),6.89-6.84(m,2H),6.70(d,J=8.0Hz,1H),4.13(d,J=6.8Hz,2H),1.42(s,3H),1.27-1.25(m,1H),1.18-1.17(m,2H),0.81-0.78(m,2H),0.55-0.52(m,2H),0.32-0.31(m,2H);Mass(FAB)m/z 405[M+H]+
<实施例21>(E)-3-(2-(环丙基甲氧基)-6-(二氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率70%;1H NMR(DMSO,400MHz)δ10.68(s,1H),10.21(s,1H),9.97(s,1H),8.14(d,J=7.2Hz,1H),7.69(d,J=16.0Hz,1H),7.32(d,J=7.2Hz,1H),7.18(d,J=8.0Hz,1H),7.02-6.72(m,4H),4.23(d,J=6.8Hz,2H),1.33-1.28(m,1H),0.57-0.53(m,2H),0.38-0.34(m,2H);Mass(FAB)m/z 401[M+H]+
<实施例22>(E)-3-(2-(环丙基甲氧基)-6-(1,1-二氟乙基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率59%;1H NMR(DMSO,400MHz)δ10.67(s,1H),10.20(s,1H),9.97(s,1H),8.12(d,J=8.0Hz,1H),7.69(d,J=16.0Hz,1H),7.32(d,J=7.6Hz,1H),7.19(d,J=8.4Hz,1H),6.99(d,J=16.0Hz,1H),6.89(t,J=8.0Hz,1H),6.73(d,J=7.6Hz,1H),4.25(d,J=6.8Hz,2H),1.95(t,J=18.8Hz,3H),1.35-1.30(m,1H),0.58-0.53(m,2H),0.38-0.35(m,2H);Mass(FAB)m/z 415[M+H]+
<实施例23>(E)-3-(6-(叔丁基)-2-(环丙基甲氧基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率59%;1H NMR(DMSO,400MHz)δ10.66(s,1H),10.17(s,1H),9.84(s,1H),7.88(d,J=8.0Hz,1H),7.66(d,J=15.6Hz,1H),7.21(d,J=8.0Hz,1H),7.02(d,J=7.6Hz,1H),6.89-6.85(m,2H),6.71(d,J=8.0Hz,1H),4.23(d,J=6.8Hz,2H),1.36-1.30(m,1H),1.26(s,9H),0.56-0.51(m,2H),0.35-0.33(m,2H);Mass(FAB)m/z 407[M+H]+
<实施例24>(E)-3-(2-(环丙基甲氧基)-6-(2-羟基丙烷-2-基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率63%;1H NMR(DMSO,400MHz)δ10.65(s,1H),10.33(s,1H),9.98(s,1H),7.95(d,J=7.6Hz,1H),7.68(d,J=16.0Hz,1H),7.25(d,J=7.6Hz,1H),6.93-6.86(m,2H),6.71(d,J=7.6Hz),5.12(s,1H),4.22(d,J=7.2Hz,2H),1.39(s,6H),1.34-1.27(m,1H),0.56-0.51(m,2H),0.36-0.32(m,2H);Mass(FAB)m/z 409[M+H]+
<实施例25>(E)-3-(2-(环丁基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率83%;1H NMR(300MHz,DMSO)δ10.72(s,1H),10.10(s,1H),9.91(s,1H),7.97(d,J=7.60Hz,1H),7.69(d,J=15.36Hz,1H),7.55(d,J=7.68Hz,1H),7.15(d,J=7.95Hz,1H),7.01(d,J=15.93Hz,1H),6.92(m,1H),6.78(d,J=7.95Hz,1H),4.40(d,J=6.96Hz,2H),2.01(m,2H),1.89(m,3H),1.21(m,2H);Mass(FAB)m/z 433[M+H]+
<实施例26>(E)-3-(2-(环戊基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率63%;1H NMR(300MHz,DMSO)δ10.72(s,1H),10.16(s,1H),9.94(s,1H),8.24(d,J=7.71Hz,1H),7.72(d,J=15.75Hz,1H),7.57(d,J=7.68Hz,1H),7.19(d,J=7.89Hz,1H),7.04(d,J=15.75Hz,1H),6.93(t,J=7.86Hz,1H),6.78(d,J=7.71Hz,1H),4.31(d,J=7.14Hz,2H),2.46(m,1H),1.80(m,2H),1.61(m,4H),1.37(m,2H);Mass(FAB)m/z447[M+H]+
<实施例27>(E)-3-(2-(异丁基硫基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率55%;1H NMR(400MHz,DMSO)δ10.73(s,1H),10.22(s,1H),10.08(s,1H),8.15(d,J=8.43Hz,1H),7.22(d,J=8.43Hz,1H),7.73(d,J=16.11Hz,1H),7.71(m,1H),6.96(d,J=15.93Hz,1H),6.92(d,J=7.89Hz,1H),6.78(d,J=7.86Hz,1H),3.17(d,J=6.24Hz,2H),1.94(m,1H),1.00(d,J=6.42Hz,6H);Mass(FAB)m/z 437[M+H]+
<实施例28>(E)-3-(2-((环丙基甲基)硫基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率55%;1H NMR(400MHz,DMSO)δ10.67(s,1H),10.11(s,1H),9.98(s,1H),8.14(d,J=7.88Hz,1H),7.70(d,J=7.88Hz,1H),7.72(d,J=15.56Hz,1H),7.22(d,J=8.12Hz,1H),6.94(d,J=8.24Hz,1H),6.62(d,J=7.64Hz,1H),6.78(d,J=7.68Hz,1H),6.93(d,J=15.88Hz,1H),3.21(d,J=7.20Hz,2H),1.16(m,1H),0.55(m,2H),0.3469(m,2H);Mass(FAB)m/z 435[M+H]+
<实施例29>(E)-3-(2-(环己基硫基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率59%;1H NMR(400MHz,DMSO)δ10.72(s,1H),10.19(s,1H),10.04(s,1H),8.14(d,J=8.07Hz,1H),7.70(d,J=8.04Hz,1H),7.67(d,J=15.36Hz,1H),7.22(d,J=8.07Hz,1H),6.94(d,J=7.32Hz,1H),6.93(d,J=15.75Hz,1H),6.78(d,J=7.68Hz,1H),3.91(m,1H),2.03(m,2H),1.72(m,2H),1.51(m,6H);Mass(FAB)m/z 463[M+H]+
<实施例30>(E)-3-(2-(3-氟苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率75%;1H NMR(400MHz,DMSO)δ10.72(s,1H),10.13(s,1H),9.99(s,1H),8.45(d,J=8.43Hz,1H),8.07(d,J=8.58Hz,1H),7.55(m,2H),7.43(m,3H),7.20(d,J=8.25Hz,1H),6.93(m,2H),6.76(d,J=7.86Hz,1H);Mass(FAB)m/z 443[M+H]+
<实施例31>(E)-3-(2-(3-氯苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率62%;1H NMR(300MHz,DMSO)δ10.72(s,1H),10.11(s,1H),9.98(s,1H),8.45(d,J=8.2Hz,1H),8.07(d,J=8.3Hz,1H),7.51-7.65(m,5H),7.20(d,J=8.3Hz,1H),6.89-6.98(m,2),6.71(d,J=7.50Hz,1H);Mass(ESI)m/z 459[M+H]+
<实施例32>(E)-3-(2-(3-异丙基苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率82%;1H NMR(300MHz,DMSO)δ10.71(s,1H),10.05(s,1H),9.95(s,1H),8.42(d,J=7.7Hz,1H),8.02(d,J=8.1Hz,1H),7.59(d,J=15.8Hz,1H),7.39-7.51(m,4H),7.20(d,J=8.4Hz,1H),6.89-6.97(m,2H),6.76(d,J=7.7Hz,1H),2.98(m,1H),1.24(d,J=6.8Hz,6H);Mass(FAB)m/z467[M+H]+
<实施例33>(E)-3-(2-(3-氯-4-氟苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率82%;1H NMR(300MHz,DMSO)δ10.72(s,1H),10.10(s,1H),9.98(s,1H),8.44(d,J=6.1Hz,1H),8.07(d,J=8.2Hz,1H),7.81(dd,J=1.8,7.1Hz,1H),7.59-7.66(m,2H),7.53(d,J=15.4Hz,1H),7.21(d,J=8.3Hz,1H),.6.89-6.97(m,2H),6.77(d,J=7.50Hz,1H);Mass(FAB)m/z 477[M+H]+
<实施例34>(E)-3-(2-(4-氟苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率69%;1H NMR(400MHz,DMSO)δ10.71(s,1H),10.13(s,1H),10.00(s,1H),8.41(d,J=8.07Hz,1H),8.01(d,J=8.25Hz,1H),7.63(m,2H),7.53(d,J=15.54Hz,1H),7.39(m,2H),7.20(d,J=8.22Hz,1H),6.93(m,2H),6.75(d,J=7.68Hz,1H);Mass(FAB)m/z 443[M+H]+
<实施例35>(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(噻吩-2-基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺
黄色固体,收率71%;1H NMR(400MHz,DMSO)δ10.70(s,1H),10.14(s,1H),10.01(s,1H),8.27(d,J=7.8Hz,1H),7.83-7.91(m,3H),7.48-7.48(m,1H),7.25(dd,J=5.3,3.9Hz,1H),7.17(d,J=8.3Hz,1H),6.85-6.92(m,2H),6.75(d,J=7.8Hz,1H);Mass(FAB)m/z 431[M+H]+
<实施例36>(E)-3-(2-(呋喃-2-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
浅棕色固体,收率61%;1H NMR(400MHz,DMSO)δ10.69(s,1H),10.12(s,1H),9.97(s,1H),8.29(d,J=8.0Hz,1H),8.00-8.07(m,2H),7.89(d,J=8.2Hz,1H),7.19(d,J=8.2Hz,1H),7.08(d,J=3.7Hz,1H),6.83-6.92(m,2H),6.73-6.76(m,2H);Mass(FAB)m/z415[M+H]+
<实施例37>(E)-3-(2-(恶唑-2-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
浅棕色固体,收率58%;1H NMR(300MHz,DMSO)δ10.69(s,1H),10.12(s,1H),9.97(s,1H),8.29(d,J=8.0Hz,1H),7.75(d,J=8.2Hz,1H),7.60(d,J=8.2Hz,1H),7.15(m,2H),6.83-6.92(m,2H),6.73-6.76(m,2H);Mass(FAB)m/z 416[M+H]+
<实施例38>(E)-3-(2-(恶唑-5-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
浅棕色固体,收率51%;1H NMR(400MHz,DMSO)δ10.69(s,1H),10.12(s,1H),9.97(s,1H),8.29(s,1H),7.75(d,J=8.2Hz,1H),7.60(d,J=8.2Hz,1H),7.09(m,2H),6.83-6.92(m,2H),6.73-6.76(m,2H);Mass(FAB)m/z 416[M+H]+
<实施例39>(E)-3-(2-(3,3-二甲基-1-丁炔-1-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率67%;1H-NMR(400MHz,DMSO)δ10.70(s,1H),10.16(s,1H),9.99(s,1H),8.35(d,J=8.0Hz,1H),7.95(d,J=16.0Hz,1H),7.16(d,J=8.0Hz,1H),7.02(d,J=16.0Hz,1H),6.89(t,J=8.0Hz,1H),6.75(d,J=8.0Hz,1H),1.35(s,9H);Mass(FAB)m/z429[M+H]+
<实施例40>(E)-3-(2-(3,3-二甲基丁基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率82%;1H-NMR(400MHz,DMSO)δ10.70(s,1H),10.14(s,1H),9.97(s,1H),8.20(d,J=8.0Hz,1H),7.80(m,2H),7.19(d,J=8.0Hz,1H),6.87-6.91(m,2H),6.72(d,J=8.0Hz,1H),2.88(m,2H),1.47(m,2H);Mass(FAB)m/z 433[M+H]+
<实施例41>(E)-3-(2-环戊基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率82%;1H-NMR(400MHz,DMSO)δ10.69(s,1H),10.13(s,1H),9.95(s,1H),8.14(d,J=8.0Hz,1H),7.87(d,J=15.6Hz,1H),7.76(d,J=8.0Hz,1H),7.16(d,J=7.6Hz,1H),6.89(t,J=7.6Hz,1H),6.80-6.73(m,2H),3.62-3.54(m,1H),1.95(m,2H),1.85-1.76(m,4H),1.65(m,2H);Mass(FAB)m/z 417[M+H]+
<实施例42>(E)-3-(2-异丁氧基-4-(三氟甲基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率71%;1H NMR(300MHz,DMSO)δ10.69(s,1H),10.10(s,1H),9.85(s,1H),7.89(d,J=15.2Hz,1H),7.80(d,J=7.9Hz,1H),7.36(m,2H),7.20(d,J=8.2Hz,1H),6.88-6.93(m,2H),6.75(d,J=7.7Hz,1H),3.95(d,J=6.2Hz,2H),1.97-2.12(m,1H),1.02(d,J=6.6Hz,6H);Mass(ESI)m/z 420[M+H]+
<实施例43>(E)-3-(2-(环丙基甲氧基)-4-(三氟甲基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率65%;1H NMR(300MHz,DMSO)δ10.70(s,1H),10.12(s,1H),9.88,(s,1H),7.89(d,J=15.8Hz,1H),7.81(d,J=7.7Hz,1H),7.34-7.38(m,2H),7.22(d,J=8.8Hz,1H),6.90-6.96(m,2H),6.76(d,J=7.7Hz,1H),4.03(d,J=7.1Hz,2H),1.31-1.16(m,1H),0.62(m,2H),0.38(m,2H);Mass(FAB)m/z 418[M+H]+
<实施例44>(E)-3-(2-(环丙基甲氧基)-4-(2-羟基丙烷-2-基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率60%;1H NMR(400MHz,DMSO)δ10.66(s,1H),10.07(s,1H),9.70(s,1H),7.85(d,J=15.6Hz,1H),7.50(d,J=7.8Hz,1H),7.22(d,J=8.2Hz,1H),6.99-7.01(m,2H),6.88(t,J=8.0Hz,1H),6.70-6.75(m,2H),3.91(d,J=6.9Hz,2H),1.24(s,6H),0.57(t,J=6.2Hz,2H),0.34(t,J=5.0Hz,2H);Mass(FAB)m/z 408[M+H]+
<实施例45>(E)-3-(4-(叔丁基)-2-(环丙基甲氧基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率70%;1H NMR(400MHz,DMSO)δ10.66(s,1H),10.07(s,1H),9.70(s,1H),7.85(d,J=15.6Hz,1H),7.50(d,J=7.8Hz,1H),7.22(d,J=8.2Hz,1H),6.99-7.01(m,2H),6.88(t,J=8.0Hz,1H),6.70-6.76(m,2H),3.92(d,J=6.9Hz,2H),1.25(s,10H),0.57(t,J=6.2Hz,2H),0.34(t,J=5.0Hz,2H);Mass(FAB)m/z 406[M+H]+
<实施例46>(E)-3-(4-环丙基-2-(环丙基甲氧基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率82%;1H-NMR(400MHz,DMSO)δ10.66(s,1H),10.05(s,1H),9.66(s,1H),7.82(d,J=15.6Hz,1H),7.43(d,J=7.8Hz,1H),7.21(d,J=7.8Hz,1H),6.87(t,J=8.0Hz,1H),6.66-6.72(m,4H),3.88(d,J=6.9Hz,2H),1.87-1.95(m,1H),1.25(m,1H),0.95(t,J=6.4Hz,2H),0.71(d,J=4.6Hz,2H),0.57(d,J=7.8Hz,2H),0.32(d,J=4.6Hz,2H);Mass(FAB)m/z 390[M+H]+
<实施例47>(E)-3-(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
白色固体,收率82%;1H NMR(300MHz,DMSO)δ10.73(s,1H),10.14(s,1H),10.02(s,1H),7.78(m,1H),7.67(m,2H),7.60(m,1H),7.50(s,1H),7.26(d,J=15.54Hz,1H),7.15(d,J=7.86Hz,1H),6.91(t,J=8.04Hz,1H),6.88(d,J=15.6Hz,1H),6.76(d,J=7.68Hz,1H);Mass(FAB)m/z 448[M+H]+
<实施例48>(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(1-(间甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)丙烯酰胺
白色固体,收率60%;1H NMR(300MHz,DMSO)δ10.69(s,1H),10.11(s,1H),9.99,(s,1H),7.42-7.55(m,4H),7.35(d,J=7.9Hz,1H),7.26(d,J=15.7Hz,1H),7.15(d,J=7.9Hz,1H),6.86-6.93(m,2H),6.76(d,J=7.7Hz,1H),2.42(s,3H);Mass(FAB)m/z 428[M+H]+
<实施例49>(E)-3-(1-(3-氯-4-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
淡黄色固体,收率73%;1H NMR(300MHz,DMSO)δ10.70(s,1H),10.10(s,1H),9.99,(s,1H),7.99(dd,J=6.78,2.55Hz,1H),7.69-7.74(m,2H),7.48(s,1H),7.24(d,J=15.8Hz,1H),7.15(d,J=8.1Hz,1H),6.92(d,J=8.0Hz,1H),6.85(d,J=16.3Hz,1H),6.76(d,J=7.9Hz,1H);Mass(FAB)m/z 466[M+H]+
<实施例50>(E)-3-(1-(3-异丙基苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
淡黄色固体,收率66%;1H NMR(300MHz,DMSO)δ10.70(s,1H),10.09(s,1H),9.98(s,1H),7.58-7.44(m,4H),7.37(m,1H),7.28(d,J=15.75Hz,1H),7.15(d,J=8.25Hz,1H),6.93-6.80(m,2H),6.76(d,J=7.5Hz,1H),3.02(m,1H),1.26(s,3H),1.24(s,3H);Mass(FAB)m/z 456[M+H]+
<实施例51>(E)-3-(1-(3-氯苯基)-3-异丙基-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率46%;1H NMR(300MHz,DMSO)δ10.70(s,1H),10.10(s,1H),9.90(s,1H),7.59(m,3H),7.46(m,1H),7.31(d,J=15.39Hz,1H),7.19(m,1H),6.90(m,1H),6.81(m,3H),3.0(m,1H),1.28(d,J=6.96Hz,4H);Mass(FAB)m/z 422[M+H]+
<实施例52>(E)-3-(1-(3-氯苯基)-3-(1-甲基环丙基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率87%;1H NMR(300MHz,DMSO)δ10.70(s,1H),10.10(s,1H),9.90(s,1H),7.61-7.58(m,3H),7.44(m,1H),7.28(d,J=15.39Hz,1H),7.20(d,J=8.25Hz,1H),6.90(m,1H),6.78-6.71(m,3H),1.45(s,3H),1.23(s,1H),0.99(m,2H),0.80(m,2H);Mass(FAB)m/z 434[M+H]+
<实施例53>(E)-3-(3-(叔丁基)-1-(3-氯苯基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
黄色固体,收率88%;1H NMR(300MHz,DMSO-D6)δ10.73(s,1H),10.09(s,1H),9.87,(s,1H),7.57-7.64(m,3H),7.44-7.47(m,1H),7.32(d,J=15.4Hz,1H),7.20(d,J=8.0Hz,1H),6.86-6.93(m,2H),6.74-6.79(m,2H),1.33(s,9H);Mass(FAB)m/z 436[M+H]+
<实施例54>(E)-3-(4-(3-氯苯基)-2-(三氟甲基)噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
浅棕色固体,收率77%;1H-NMR(400MHz,DMSO)δ10.70(s,1H),10.08(s,1H),10.02(s,1H),7.66(d,J=10.8Hz,1H),7.59(m,4H),7.12(d,J=8.0Hz,1H),6.88(t,J=8.4Hz,1H),6.80(d,J=15.6Hz,1H),6.74(d,J=8.0Hz,1H);Mass(FAB)m/z 465[M+H]+
<实施例55>(E)-3-(4-(3-氯苯基)-2-异丙基噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
浅黄色固体,产率78%;1H NMR(400MHz,DMSO)δ10.69(s,1H),10.05(s,1H),9.85(s,1H),7.63(d,J=15.2Hz,1H),7.63(s,1H),7.56-7.52(m,3H),7.17(d,J=8.4Hz,1H),6.88(t,J=8.0Hz,1H),6.73(d,J=7.6Hz,1H),6.56(d,J=15.6Hz,1H),3.35(m,1H),1.37(d,J=6.8Hz,6H);Mass(FAB)m/z 439[M+H]+
<实施例56>(E)-3-(4-(3-氯苯基)-2-环丙基噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
浅黄色固体,产率78%;1H NMR(400MHz,DMSO)δ10.69(s,1H),10.05(s,1H),9.84(s,1H),7.61(s,1H),7.60(d,J=15.6Hz,1H),7.56-7.53(m,3H),7.17(d,J=8.0Hz,1H),6.88(t,J=8.4Hz,1H),6.73(d,J=7.2Hz,1H),6.50(d,J=15.6Hz,1H),1.21(m,3H),1.10(m,2H);Mass(FAB)m/z 437[M+H]+
<实施例57>(E)-3-(4-(3-氯苯基)-2-(1-甲基环丙基)噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
浅棕色固体,收率66%;1H NMR(400MHz,DMSO)δ10.68(s,1H),10.03(s,1H),9.81(s,1H),7.59(m,1H),7.58(d,J=15.2Hz,1H),7.54-7.49(m,3H),7.15(d,J=8.4Hz,1H),6.86(t,J=8.0Hz,1H),6.71(d,J=7.2Hz,1H),6.51(d,J=15.2Hz,1H),1.55(s,3H),1.31(m,2H),1.08(m,2H);Mass(FAB)m/z 451[M+H]+
<实施例58>(E)-3-(2-(叔丁基)-4-(3-氯苯基)噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺
浅棕色固体,收率66%;1H NMR(400MHz,DMSO)δ10.66(s,1H),10.01(s,1H),9.82(s,1H),7.67(d,J=15.2Hz,1H),7.66(m,1H),7.58(m,3H),7.21(d,J=8.12Hz,1H),6.91(t,J=7.96Hz,1H),6.75(d,J=7.72Hz,1H),6.60(d,J=15.2Hz,1H),1.46(s,9H);Mass(FAB)m/z 453[M+H]+
<实施例59>3-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙酰胺
浅黄色固体,产率86%;1H NMR(500MHz,CDCl3)δ9.14(s,1H),8.16(s,1H),7.58(d,J=7.35Hz,1H),7.27(s,1H),7.16(d,J=7.40Hz,1H),6.93(t,J=7.90Hz,1H),6.81(d,J=7.75Hz,1H),6.58(d,J=8.05Hz,1H),4.16(d,J=6.45Hz,2H),3.05(t,J=7.25Hz,2H),2.74(t,J=7.25Hz,2H),2.11(p,J=6.70Hz,1H),1.03(d,J=6.65Hz,6H);Mass(FAB)m/z423[M+H]+
<实施例60>3-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙酰胺
白色固体,收率77%;1H NMR(300MHz,DMSO)δ10.66(s,1H),10.08(s,1H),9.53(s,1H),7.80(d,J=7.50Hz,1H),7.41(d,J=6.00Hz,1H),7.07(d,J=8.25Hz,1H),6.87(t,J=7.86Hz,1H),6.72(d,J=7.86Hz,1H),4.20(d,J=6.96Hz,2H),2.96(t,J=7.14Hz.2H),2.70(t,J=7.50Hz,2H),1.28(m,1H),0.55(q,J=5.70Hz,2H),0.40(q,J=5.70Hz,2H);Mass(FAB)m/z 421[M+H]+
<实施例61>2-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺
浅黄色固体,产率72%;1H NMR(500MHz,CDCl3)δ9.14(s,1H),8.16(s,1H),7.58(d,J=7.35Hz,1H),7.27(s,1H),7.16(d,J=7.40Hz,1H),6.93(t,J=7.90Hz,1H),6.81(d,J=7.75Hz,1H),6.58(d,J=8.05Hz,1H),4.16(d,J=6.45Hz,2H),3.11(s,1H),2.89(s,1H),2.11(p,J=6.70Hz,1H),1.23(m,2H),1.03(d,J=6.65Hz,6H),0.89(m,1H);Mass(FAB)m/z435[M+H]+
<实施例62>2-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺
白色固体,收率65%;1H NMR(300MHz,DMSO)δ10.66(s,1H),10.08(s,1H),9.53(s,1H),7.80(d,J=7.50Hz,1H),7.41(d,J=6.00Hz,1H),7.07(d,J=8.25Hz,1H),6.87(t,J=7.86Hz,1H),6.72(d,J=7.86Hz,1H),4.20(d,J=6.96Hz,2H),2.96(t,J=7.14Hz.2H),2.70(t,J=7.50Hz,2H),1.28(m,3H),0.80(m,1H),0.55(q,J=5.70Hz,2H),0.40(q,J=5.70Hz,2H);Mass(FAB)m/z 433[M+H]+
<实施例63>2-(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺
白色固体,收率78%;1H NMR(400MHz,DMSO)δ10.67(s,1H),9.95(s,1H),9.85(s,1H),7.75(s,1H),7.66-7.64(t,J=5.88Hz,1H),7.57(s,2H),7.07(d,J=6.52Hz,1H),6.90(d,1H),6.87(s,1H),6.74(d,J=6.16Hz,1H),2.35(m,1H),2.18(m,1H),1.53(t,J=5.92Hz,2H),1.23(s,2H),0.80(m,1H);Mass(FAB)m/z 462[M+H]+
<实施例64>2-(1-(3-氯苯基)-3-(1,1-二氟乙基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺
黄色固体,收率65%;1H NMR(300MHz,DMSO)δ10.67(s,1H),9.95(s,1H),9.87(s,1H),7.63(s,1H),7.56(m,1H),7.46(t,J=8.22Hz,1H),7.41(s,1H),7.10(d,J=7.89Hz,1H),6.88(t,J=7.68Hz,1H),6.73(d,J=8.07Hz,1H),6.05(s,1H),1.23(m,1H),0.91(m,1H),0.67(m,3H);Mass(FAB)m/z 458[M+H]+
<实施例65>2-(1-(3-氯苯基)-3-异丙基-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺
浅棕色固体,收率60%;1H NMR(300MHz,DMSO)δ10.67(s,1H),9.98(s,1H),9.89(s,1H),7.64(s,1H),7.59(d,J=7.68Hz,1H),7.48(t,J=8.25Hz,1H),7.42(m,1H),7.16(d,J=8.04Hz,1H),6.88(t,J=7.53Hz,1H),6.72(d,J=7.62Hz,1H),6.21(s,1H),2.30(m,1H),2.19(m,1H),1.74(s,2H),1.51(m,1H),1.23(d,J=6.78Hz,6H);Mass(FAB)m/z 436[M+H]+
<实施例66>2-(1-(3-氯苯基)-3-环丙基-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺
黄色固体,收率82%;1H NMR(300MHz,DMSO)δ10.67(s,1H),9.98(s,1H),9.89(s,1H),7.64(s,1H),7.57(m,2H),7.49(t,J=8.25Hz,2H),7.42(m,2H),7.10(d,J=7.86Hz,1H),6.88(t,J=7.68Hz,1H),6.73(d,J=7.68Hz,1H),6.05(s,1H),2.32(m,1H),2.08(m,1H),1.95(m,2H),1.51(m,1H),0.89(m,2H),0.67(m,2H);Mass(FAB)m/z 434[M+H]+
<实施例67>2-(1-(3-氯苯基)-3-(1-甲基环丙基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺
黄色固体,收率73%;1H NMR(300MHz,DMSO)δ10.68(s,1H),9.96(s,1H),9.87(s,1H),7.64(s,1H),7.57(m,1H),7.49(t,J=8.25Hz,1H),7.42(m,1H),7.10(d,J=7.86Hz,1H),6.88(t,J=7.68Hz,1H),6.73(d,J=7.68Hz,1H),6.12(s,1H),1.40(s,3H),0.91(s,2H),0.74(s,2H);Mass(FAB)m/z 448[M+H]+
<实施例68>2-(3-(叔丁基)-1-(3-氯苯基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺
黄色固体,收率82%;1H NMR(400MHz,DMSO)δ10.67(s,1H),9.93(s,1H),9.85(s,1H),7.64(s,1H),7.60(d,J=6.92Hz,1H),7.51(t,J=8.00Hz,1H),7.44(d,J=6.92Hz,1H),7.11(d,J=8.08Hz,1H),6.89(t,J=7.96Hz,1H),6.74(d,J=7.76Hz,1H),6.22(s,1H),2.32(m,1H),2.13(m,1H),1.53(m,1H),1.42(m,1H),1.27(s,9H);Mass(FAB)m/z 450[M+H]+
实施例1-68中制备的化合物的化学式总结并示于下表1中。
[表1]
<对比例1>1-(2-氧代-1,3-二氢苯并咪唑-4-基)-3-[[2-吡咯烷-1-基-6-(三氟甲基)-3-吡啶基]甲基]脲的制备
制备韩国专利公开号10-2013-0065636(WO 2011/120604A1)中公开的实施例39的化合物作为对比例1的化合物。
<对比例2>1-[[2-异丙氧基-6-(三氟甲基)-3-吡啶基]甲基]-3-(2-氧代-1,3-二氢苯并咪唑-4-基)脲的制备
制备韩国专利公开号10-2013-0065634(WO 2011/120604 A1)中公开的实施例68的化合物作为对比例2的化合物。
<对比例3>1-(2-氧代-1,3-二氢苯并咪唑-4-基)-3-[[2-(1-哌啶基)-6-(三氟甲基)-3-吡啶基]甲基]脲的制备
制备韩国专利公开号10-2013-0065634(WO 2011/120604 A1)中公开的实施例71的化合物作为对比例3的化合物。
<实验例1>对TRPV1(瞬时受体电位香草酸亚型1)受体激活剂的拮抗作用(体外)的评价
如上所述,已经报道迄今为止开发的第一代TRPV1拮抗剂增加体温的的副作用是由于对所有TRPV1受体激活剂(辣椒素、热、pH、NADA)的拮抗作用。特别是,已经报道,在TRPV1受体激活剂中阻断100%的pH会导致体温过度升高,阻断20%或更低会导致高浓度下的质子活化,从而导致体温过度降低。也就是说,在TRPV1拮抗剂的开发中,当阻断由辣椒素和热引起的TRPV1活化时,但会诱导约20%至80%的pH的适当抑制,这可能导致不仅减轻疼痛而且减少副作用如异常体温的效果。
在下文中,评估本发明一方面中提供的实施例化合物是否能阻断辣椒素引起的TRPV1活化,但诱导约20%-80%的pH的适当抑制,从而减轻疼痛并降低副作用如异常体温。
研究了对辣椒素和pH,hTRPV1受体激活剂的拮抗作用,并将目标设定为IC50(CAP)<15nM(功效),pH=6(非体温过高)时80%的抑制。这是因为在我们自己的实验中,对照临床药物Mavatrep的IC50(CAP)被研究为13.8nM,当pH拮抗作用低于80%抑制时,认为是非体温过高。
Ca2+内流测定
PrecisIONTM hTRPV1-HEK重组细胞(CYL3063)购自Millipore,用作人TRPV1(hTRPV1)拮抗剂测定的细胞。DME/F-12(HyClone)(10%FBS,1%NEAA,1%青霉素链霉素)用作培养基,Fluo4-NW(分子探针,F-36206)用作ELISA试剂盒。在37℃和5%CO2条件下培养上述细胞后,将细胞以5×104细胞/孔的密度接种于96孔板中,然后培养16小时。然后,移除培养基,并向每孔加入100μL染色溶液,接着,在37℃、5%CO2条件下培养30分钟。然后,将细胞在室温下驯化15分钟,向各孔中加入测试物质(本发明的实施例化合物和比较例化合物),然后在室温下培养15分钟。将辣椒素(Sigma,M2028)稀释至10nM浓度后,将其添加到平板的各孔中,并测量荧光(ex485/em535)。在上述实验中,使用BCTC作为代表性TRPV1拮抗剂来评估药物的功效。
人pH抑制活性的评价
PrecisIONTM hTRPV1-HEK重组细胞(CYL3063)购自Millipore并使用。在37℃和5%CO2条件下培养上述细胞后,将细胞以5×104细胞/孔的密度接种于96孔板中,随后培养16小时。然后,移除培养基,在各孔中加入100μL染色溶液,在37℃和5%CO2条件下培养30分钟。30分钟后,移除所有现有的染色溶液,并用100μL HBSS代替。然后,将细胞在室温下驯化15分钟,向各孔加入测试物质(本发明的实施例化合物和比较例化合物),然后在室温下培养15分钟。然后,用MES将最终pH调至6.0,并测量荧光(ex485/em535)。在pH试验中,使用BCTC作为TRPV1拮抗剂来评估药物的功效。
<实验例1>的体外测试结果与<实验例2>的体内测试结果合并,如下表2所示。
<实验例2>生物利用度(BA)的评价
功效、ADME和毒性性质对于新的药物候选物是重要的,作为药代动力学性质,它们应当具有高于一定水平的血液浓度分布,基于此,检查PK-PD相关性是否良好非常重要。使用从实验动物如大鼠或小鼠获得的新候选药物的PK参数,可以通过异速缩放或PK-PD预测来预测人类的血液浓度和药物功效。为此,重要的是测量Cl和Vss,其会确定剂量和给药间隔,以在口服给药期间获得PK参数,如Cmax、t1/2和AUCall。另外,可以获得与候选物质的代谢酶、转运体和组织分布相关的基本信息,并且可以估计不适当的物理性质。通过这种分析获得的信息可以为获得最佳候选物提供重要的决策标准,并有助于更有效药物的分子设计和开发。
测试方法
实验中使用SD大鼠(Coatec,Hana贸易有限公司,7-8周龄,雄性,n=4,250-300g)。将大鼠在小型动物饲养室(实验动物中心)中饲养,温度为22±2℃,相对湿度为50±5%,光照时间为12小时(08:00~20:00),光照强度为150~300lux。在整个试验期间自由进食,并且自由饮用RO水。在口服测试物质(本发明的实施例化合物和比较例化合物)之前,将大鼠禁食16小时。
本发明的实施例化合物和比较例化合物的剂量在静脉给药时为5mg/kg,在口服给药时为10mg/kg。对于静脉内给药,施用溶解有10%DMSO、10%Cremophor EL和80%PEG400的澄清溶液。对于口服给药,施用10%DMSO和10%Cremophor EL溶于80%DDW中的溶液或悬浮液。
在静脉给药或口服给药后,在5分钟、15分钟、30分钟、1小时、2小时、4小时、6小时和8小时收集血液,并通过LC-MS/MS测量血浆中测试物质(本发明的实施例化合物和比较例化合物)的浓度。
在将80μl乙腈(包括内标)加入20μl血浆后,在4℃下通过涡旋以15,000rpm离心5分钟。通过LC-MS/MS分析离心后获得的上清液。对于HPLC,使用Nexera XR系统(岛津,日本),对于质谱仪,使用TSQ vantage三重四级杆(triple quadruple)(赛默公司,美国)。
①HPLC条件
②质谱条件
PK参数使用Phoenix WinNonlin 6.4版本(Pharsight,USA)程序,采用非房室分析模型计算。
通过梯形法则从测得的血浆浓度计算高达8小时的AUC(血浆浓度-时间曲线下的面积),口服吸收率(F%)根据静脉给药相同剂量时与AUC的比值计算。AUC在血浆水平上升阶段使用线性梯形法则计算,在血浆水平下降阶段使用对数梯形法则计算。
结果如下表2所示。
[表2]
*NT=未测试
如表2所示,本发明一方面提供的实施例化合物阻断由辣椒素引起的TRPV1活化,但诱导约20%-80%的pH的适当抑制,因此该化合物具有减轻疼痛和降低副作用如体温异常的作用。此外,证实本发明的化合物具有高的PK值,因此实施例化合物容易被人体吸收,因此也保持了热中性。
另一方面,对比例1-3的化合物阻断由辣椒素引起的TRPV1活化,但会抑制pH低于或高于所需,即在20%-80%的适当范围之外。此外,证实对比例的化合物具有低的PK值,因此,该化合物不容易被人体吸收,因而存在难以将它们用作实际的镇痛剂的问题。
<制造例1>粉末的制备
式1所示的衍生物2g
乳糖1g
通过混合所有上述组分制备粉末,将其填充在密封包装中。
<制造例2>片剂的制备
通过常规制备片剂的方法混合所有上述组分来制备片剂。
<制造例3>胶囊的制备
通过混合所有上述组分制备胶囊,根据制备胶囊的常规方法将其填充到明胶胶囊中。
<制造例4>注射液的制备
根据制备注射溶液的常规方法以所示的量通过包含所有上述组分来制备注射溶液。
<制造例5>保健功能性食品的制备
根据优选的混合比例混合适于保健功能性食品的维生素和矿物质,但是组成比例可以任意调整。在根据制备保健功能性食品的常规方法混合上述组分后,制备颗粒,并根据常规方法将颗粒用于制备保健功能性食品。
<制造例6>健康饮料的调制
根据制备健康饮料的常规方法混合上述组分。将混合物在85℃下加热1小时,同时搅拌,然后过滤。将滤液装入灭菌容器中,将其密封并再次灭菌,储存在冰箱中直到它们用于制备健康饮料组合物。
根据优选的混合比例混合适于受欢迎的饮料的成分,但是组成比例可以根据地区和种族偏好,例如需求类别、需求国家和使用目的等来调整。
工业实用性
本发明的一方面中提供的实施例化合物阻断由辣椒素和热引起的TRPV1活化,但相对于pH表现出20%-80%的TRPV2抑制活性,因此其不仅可以改善疼痛,而且可以有效降低副作用,如异常体温效应。
Claims (15)
1.一种下式1表示的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐:
[式1]
在上述式1中,
X1和X2独立地为氢,或
通过与它们所连接的碳原子连接形成C=C双键,或
通过与它们所连接的碳原子连接形成3-6元环亚烷基;以及
其中所述取代的5-10元杂芳基和C6-10芳基独立地为被至少一个选自以下的取代基取代的5-10元杂芳基和C6-10芳基:未取代的或被至少一个卤素或羟基取代的C1-12直链或支链烷基、C1-12直链或支链炔基、未取代的或被至少一个C1-5直链或支链烷基取代的C3-10环烷基、未取代的或被至少一个含有至少一个选自N和O的杂原子的C1-5直链或支链烷基取代的5-8元杂环烷基、-NR1R2、-OR3、-SR4、未取代的或被至少一个卤素或C1-5直链或支链烷基取代的C6-10芳基,以及含有至少一个选自N、O和S的杂原子的5-8元杂芳基,
R1和R2独立地为C1-10直链或支链烷基,
R3为未取代的或被至少一个卤素取代的C1-10直链或支链烷基、C3-10环烷基、或未取代的或被至少一个甲基取代的C3-10环烷基C1-5直链或支链烷基,
R4为未取代的或被至少一个卤素取代的C1-10直链或支链烷基、C3-10环烷基、或未取代的或被至少一个甲基取代的C3-10环烷基C1-5直链或支链烷基。
2.根据权利要求1所述的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中:
X1和X2独立地为氢,或
通过与它们所连接的碳原子连接形成C=C双键,或
通过与它们所连接的碳原子连接形成3-5元环亚烷基;以及
其中所述取代的5-8元杂芳基和C6-8芳基独立地为被至少一个选自以下的取代基取代的5-8元杂芳基和C6-8芳基:未取代的或被至少一个卤素或羟基取代的C1-10直链或支链烷基、C1-10直链或支链炔基、未取代的或被至少一个C1-5直链或支链烷基取代的C3-8环烷基、未取代的或被至少一个含有至少一个选自N和O的杂原子的C1-5直链或支链烷基取代的5-6元杂环烷基、-NR1R2、-OR3、-SR4、未取代的或被至少一个卤素或C1-5直链或支链烷基取代的C6-8芳基、以及含有至少一个选自N、O和S的杂原子的5-6元杂芳基,
R1和R2独立地为C1-8直链或支链烷基,
R3为未取代的或被至少一个卤素取代的C1-8直链或支链烷基、C3-8环烷基、或未取代的或被至少一个甲基取代的C3-8环烷基C1-5直链或支链烷基,
R4为未取代的或被至少一个卤素取代的C1-8直链或支链烷基、C3-8环烷基、或未取代的或被至少一个甲基取代的C3-8环烷基C1-5直链或支链烷基。
3.根据权利要求1所述的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中:
X1和X2独立地为氢,或
通过与它们所连接的碳原子连接形成C=C双键,或
通过与它们所连接的碳原子连接形成3-4元环亚烷基;以及
其中所述取代的5-6元杂芳基和C6芳基独立地为被至少一个选自以下的取代基取代的5-6元杂芳基和C6芳基:未取代的或被至少一个卤素或羟基取代的C1-7直链或支链烷基、C1-7直链或支链炔基、未取代的或被至少一个C1-5直链或支链烷基取代的C3-6环烷基、未取代的或被至少一个含有至少一个选自N和O的杂原子的C1-5直链或支链烷基取代的5-6元杂环烷基、NR1R2、-OR3、-SR4、未取代的或被至少一个卤素或C1-5直链或支链烷基取代的C6芳基、和含有至少一个选自N、O和S的杂原子的5元杂芳基,
R1和R2独立地为C1-5直链或支链烷基,
R3为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基,
R4为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基。
5.根据权利要求1所述的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中所述由式1表示的化合物选自以下化合物:
(1)(E)-3-(2-(4-甲基哌啶-1-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(2)(E)-3-(2-(4-乙基哌啶-1-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(3)(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(吡咯烷-1-基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺;
(4)(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(哌啶-1-基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺;
(5)(E)-3-(2-吗啉代-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(6)(E)-3-(2-(二乙基氨基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(7)(E)-3-(2-(二丙基氨基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(8)(E)-3-(2-丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(9)(E)-3-(2-(己氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(10)(E)-3-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(11)(E)-3-(2-环丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(12)(E)-3-(2-(环戊氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(13)(E)-3-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(14)(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(2,2,2-三氟乙氧基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺;
(15)(E)-3-(2-(新戊基氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(16)(E)-3-(2-((2-甲基环丙基)甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(17)(E)-3-(6-(氯二氟甲基)-2-(环丙基甲氧基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(18)(E)-3-(6-环丙基-2-(环丙基甲氧基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(19)(E)-3-(2-(环丙基甲氧基)-6-异丙基吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(20)(E)-3-(2-(环丙基甲氧基)-6-(1-甲基环丙基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(21)(E)-3-(2-(环丙基甲氧基)-6-(二氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(22)(E)-3-(2-(环丙基甲氧基)-6-(1,1-二氟乙基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(23)(E)-3-(6-(叔丁基)-2-(环丙基甲氧基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(24)(E)-3-(2-(环丙基甲氧基)-6-(2-羟基丙-2-基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(25)(E)-3-(2-(环丁基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(26)(E)-3-(2-(环戊基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(27)(E)-3-(2-(异丁硫基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(28)(E)-3-(2-((环丙基甲基)硫基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(29)(E)-3-(2-(环己基硫基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(30)(E)-3-(2-(3-氟苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(31)(E)-3-(2-(3-氯苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(32)(E)-3-(2-(3-异丙基苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(33)(E)-3-(2-(3-氯-4-氟苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(34)(E)-3-(2-(4-氟苯基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(35)(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(2-(噻吩-2-基)-6-(三氟甲基)吡啶-3-基)丙烯酰胺;
(36)(E)-3-(2-(呋喃-2-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(37)(E)-3-(2-(噁唑-2-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(38)(E)-3-(2-(噁唑-5-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(39)(E)-3-(2-(3,3-二甲基-1-丁炔-1-基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(40)(E)-3-(2-(3,3-二甲基丁基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(41)(E)-3-(2-环戊基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(42)(E)-3-(2-异丁氧基-4-(三氟甲基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(43)(E)-3-(2-(环丙基甲氧基)-4-(三氟甲基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(44)(E)-3-(2-(环丙基甲氧基)-4-(2-羟基丙-2-基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(45)(E)-3-(4-(叔丁基)-2-(环丙基甲氧基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(46)(E)-3-(4-环丙基-2-(环丙基甲氧基)苯基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(47)(E)-3-(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(48)(E)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)-3-(1-(间甲苯基)-3-(三氟甲基)-1H-吡唑-5-基)丙烯酰胺;
(49)(E)-3-(1-(3-氯-4-氟苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(50)(E)-3-(1-(3-异丙基苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(51)(E)-3-(1-(3-氯苯基)-3-异丙基-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(52)(E)-3-(1-(3-氯苯基)-3-(1-甲基环丙基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(53)(E)-3-(3-(叔丁基)-1-(3-氯苯基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(54)(E)-3-(4-(3-氯苯基)-2-(三氟甲基)噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(55)(E)-3-(4-(3-氯苯基)-2-异丙基噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(56)(E)-3-(4-(3-氯苯基)-2-环丙基噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(57)(E)-3-(4-(3-氯苯基)-2-(1-甲基环丙基)噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(58)(E)-3-(2-(叔丁基)-4-(3-氯苯基)噻唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙烯酰胺;
(59)3-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙酰胺;
(60)3-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)丙亚胺;
(61)2-(2-异丁氧基-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(62)2-(2-(环丙基甲氧基)-6-(三氟甲基)吡啶-3-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(63)2-(1-(3-氯苯基)-3-(三氟甲基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(64)2-(1-(3-氯苯基)-3-(1,1-二氟乙基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(65)2-(1-(3-氯苯基)-3-异丙基-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(66)2-(1-(3-氯苯基)-3-环丙基-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;
(67)2-(1-(3-氯苯基)-3-(1-甲基环丙基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺;以及
(68)2-(3-(叔丁基)-1-(3-氯苯基)-1H-吡唑-5-基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)环丙烷-1-甲酰胺。
6.根据权利要求1所述的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中:
其中所述取代的5-6元杂芳基是被两个选自以下的取代基取代的5-6元杂芳基:未取代的或被至少一个卤素或羟基取代的C1-7直链或支链烷基、C1-7直链或支链炔基、未取代的或被至少一个C1-5直链或支链烷基取代的C3-6环烷基、未取代的或被至少一个含有至少一个选自N和O的杂原子的C1-5直链或支链烷基取代的5-6元杂环烷基、NR1R2、-OR3、-SR4、未取代的或被至少一个卤素或C1-5直链或支链烷基取代的C6芳基以及含有至少一个选自N、O和S的杂原子的5元杂芳基,
R1和R2独立地为C1-5直链或支链烷基,
R3为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基,
R4为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基。
7.根据权利要求1所述的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中:
其中所述取代吡啶是被两个选自以下的取代基取代的吡啶:未取代的或被至少一个卤素或羟基取代的C1-7直链或支链烷基、C1-7直链或支链炔基、未取代的或被至少一个C1-5直链或支链烷基取代的C3-6环烷基、未取代的或被至少一个含有至少一个选自N和O的杂原子的C1-5直链或支链烷基取代的5-6元杂环烷基、NR1R2、-OR3、-SR4、未取代的或被至少一个卤素或C1-5直链或支链烷基取代的C6芳基以及含有至少一个选自N、O和S的杂原子的5元杂芳基,
R1和R2独立地为C1-5直链或支链烷基,
R3为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基,
R4为未取代的或被至少一个卤素取代的C1-7直链或支链烷基、C3-6环烷基、或未取代的或被至少一个甲基取代的C3-6环烷基C1-5直链或支链烷基。
8.一种用于预防或治疗疼痛的药物组合物,其含有权利要求1所述的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
9.根据权利要求8所述的用于预防或治疗疼痛的药物组合物,其中所述化合物通过抑制TRPV1(瞬时受体电位香草酸亚型1)受体激活剂显示对疼痛的预防或治疗活性。
10.根据权利要求9所述的用于预防或治疗疼痛的药物组合物,其中所述化合物通过抑制辣椒素、TRPV1(瞬时受体电位香草酸亚型1)受体激活剂来预防或治疗疼痛,并且将pH抑制在20%至80%范围内以减少如体温异常的副作用。
11.一种用于治疗或缓解疼痛的镇痛组合物,其含有权利要求1所述的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
12.一种用于预防或改善疼痛的保健功能性食品组合物,其含有权利要求1所述的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
13.根据权利要求12所述的用于预防或改善疼痛的保健功能性食品组合物,其中所述化合物通过抑制TRPV1(瞬时受体电位香草酸亚型1)受体激活剂显示预防或改善疼痛的活性。
14.根据权利要求13所述的用于预防或改善疼痛的保健功能性食品组合物,其中所述化合物通过抑制辣椒素、TRPV1(瞬时受体电位香草酸亚型1)受体激活剂来预防或改善疼痛,并且将pH抑制在20%至80%范围内以减少如体温异常的副作用。
15.一种用于预防或治疗疼痛的药物试剂盒,其包含第一组分和第二组分,所述第一组分包含权利要求1所述的化合物、其立体异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分;所述第二组分含有镇痛剂作为活性成分。
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KR10-2020-0048788 | 2020-04-22 | ||
KR1020200048788A KR102334947B1 (ko) | 2020-04-22 | 2020-04-22 | Trpv1 길항제로서 벤즈이미다졸론계 시남아마이드 유도체 및 이를 유효성분으로 함유하는 통증의 치료 또는 예방용 약학적 조성물 |
PCT/KR2021/002963 WO2021215656A1 (ko) | 2020-04-22 | 2021-03-10 | Trpv1 길항제로서 벤즈이미다졸론계 시남아마이드 유도체 및 이를 유효성분으로 함유하는 통증의 치료 또는 예방용 약학적 조성물 |
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- 2021-03-10 WO PCT/KR2021/002963 patent/WO2021215656A1/ko active Application Filing
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JP7477912B2 (ja) | 2024-05-02 |
JP2023516618A (ja) | 2023-04-20 |
AU2021258843A1 (en) | 2022-09-15 |
KR102334947B1 (ko) | 2021-12-06 |
AU2021258843B2 (en) | 2023-07-20 |
MX2022010369A (es) | 2022-09-21 |
ZA202209481B (en) | 2023-05-31 |
CA3173067A1 (en) | 2021-10-28 |
BR112022017035A2 (pt) | 2022-11-16 |
EP4095133A1 (en) | 2022-11-30 |
EP4095133A4 (en) | 2023-06-14 |
US20230147428A1 (en) | 2023-05-11 |
KR20210130886A (ko) | 2021-11-02 |
WO2021215656A1 (ko) | 2021-10-28 |
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