CN110248944A - 非肽催产素受体激动剂 - Google Patents
非肽催产素受体激动剂 Download PDFInfo
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- CN110248944A CN110248944A CN201780085825.XA CN201780085825A CN110248944A CN 110248944 A CN110248944 A CN 110248944A CN 201780085825 A CN201780085825 A CN 201780085825A CN 110248944 A CN110248944 A CN 110248944A
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- alkyl
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- alkynyl
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- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Abstract
本文公开了根据式I的化合物;药物组合物,其包括、基本上由以下组成或由以下组成:药学上可接受的式I化合物和药学上可接受的载体、稀释剂或赋形剂;式I化合物在制备药物中的用途;以及包括将包含式I化合物的药物组合物施用给患者的方法。所述化合物、组合物、用途和方法是针对治疗以社会行为的根本破坏为特征的神经学疾病、精神疾病和物质使用障碍。
Description
发明领域
本公开涉及化合物、组合物以及用于治疗以社会行为的根本破坏为特征的神经学疾病、精神疾病和物质使用障碍(substance use disorder)的方法。
发明背景
许多精神疾病以社会行为的根本破坏为特征。常见的例子包括自闭症谱系障碍(ASD)和社交焦虑障碍(SAD)。此外,几种疾病具有作为次要症状的社会退缩;例子包括精神分裂症、重度抑郁症(MDD)和物质使用障碍。目前没有直接以社会缺陷为目标的批准药物,以及用于这些疾病的药物治疗(如果有的话)的效果最有限。
全世界数百万人患有某种形式的精神、神经或行为障碍。国立精神卫生研究所(NIMH)的一项推断的研究表明,每年有1000万人患有社交恐怖症,这相当于每小时诊断出1150人。社交功能障碍可显现为多种疾病的主要或次要特征,例如ASD、SAD、MDD、精神分裂症和物质使用障碍。
焦虑症在全世界都很常见,并且是澳大利亚最常见的精神障碍。社交焦虑症(SAD),也称为社交恐怖症,是最常见的焦虑症,而且据了解在其生命中的某个时间影响十分之一的澳大利亚人,并且在任何时候约占总人口的5%。社交焦虑常常伴随诸如抑郁症、精神分裂症和物质使用障碍等其他精神问题,并且经常发生在这些疾病发作前。社会退缩也是儿童神经发育障碍例如自闭的非常突出的特征。
目前有限的针对抗社会行为相关的精神疾病的疗法被批准,精神疾病包括自闭症谱系障碍(ASD)、广泛性焦虑症(GAD)和社交焦虑障碍(SAD)。此外,一些障碍(disorder)具有作为次要症状的社交退缩。这里的例子包括精神分裂症、重度抑郁症(MDD)和物质使用障碍。目前,处方疗法(选择性血清素再摄取抑制剂(SSRI)、血清素和去甲肾上腺素再摄取抑制剂(SNRI)、兴奋剂和抗精神病药)有着充其量有限的效力、起效缓慢、依从性差和大量副作用的概况。这些药物缺乏对这些疾病状态遇到的核心社会缺陷的修改。因此,对患有社交功能障碍的人当前可用的治疗非常有限。
新研究表明,用于治疗这些疾病的有前途的靶点是神经肽催产素(OT)。动物研究显示,OT积极地调节多种社会互动,其包括母性行为(maternal behaviour)、求爱、性行为和点对点互动。人体研究的结果,其中OT通常是鼻内施用,表明OT可以增加信任和合作、改善社会记忆并减少社会恐惧。此外,最近的临床试验表明,对患有自闭症和社交焦虑的人施用OT可以恢复某些方面的社会功能。因此,OT受体具有旨在减轻严重的精神疾病的药物发现的巨大潜力。然而,鼻内OT不太可能是最佳治疗方式。OT是一种无法在初级代谢中存活的环状肽,具有短的生理半衰期并且不容易穿透血脑屏障。
鉴于上述,靶向OT受体具有用于治疗多种社会功能障碍的巨大潜力。虽然已经鉴定了许多靶向OT受体的化合物,但这些化合物具有许多缺点。例如,许多化合物不能选择性地靶向OT受体,因为OT受体与血管加压素1a受体(V1aR)具有高度同源性,这意味着选择性可能极具挑战性。此外,与OT一样,这些化合物中的很多不易穿透血脑屏障;并且很多被代谢分解成有害作用的较小碎片。
在说明书中对任何现有技术的引用并不是承认或暗示该现有技术构成任何管辖区域中的公知常识的一部分,或者该现有技术可以合理地预期被本领域技术人员理解、认为是相关的和/或与其他现有技术结合。
发明概要
本发明涉及式I化合物:
其中,R1、R3、R4、R5或R6各自独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、取代或未取代的芳基(例如,取代或未取代的苯基)、或取代或未取代的杂环基(例如,取代或未取代的吡啶基、吡喃基、或硫代吡喃基(thiopiranyl));
其中R2独立地选自下组:H、F、Br、I、NH2、NO2、OH、ON=O、取代的甲基、取代或未取代的C2-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷氧基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、取代或未取代的芳基(例如,取代或未取代的苯基)、或取代或未取代的杂环基(例如,取代或未取代的吡啶基、吡喃基、或硫代吡喃基);
其中,为取代的芳基或取代的杂环基的各个R1、R2、R3、R4、R5、或R6包括一个或多个选自下组的取代基:F、Cl、Br、I、NH2、N=O、NO2、NHCH3、OH、OCH3、OC≡N、ON=O、SH、SCH3、S(=O)nOH、S(=O)nCH3、SC≡N、COOH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)、或OCHmBr(3-m);
其中,X为选自下组的环状结构:取代或未取代的、稠合或未稠合的芳基;取代或未取代的、稠合或未稠合的杂环基;或者取代或未取代的、稠合或未稠合的环烷基;以及
其中,X1代表一个或多个独立地选自下组的原子或基团:F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、COOH、C1烷基-COOH、COOC1-C2烷基、COOC1-C2烷基芳基、C1烷基-COOC1-C2烷基、C1-C2烷基芳基、OC1-C2烷基芳基、NC1-C2烷基芳基、C1-C2烷基-杂环基、OC1-C2烷基-杂环基、NC1-C2烷基-杂环基;
其中,各个取代的烷基、烯基、炔基、烷基芳基、烷基-杂环基包括一个或多个选自下组的取代基:F、C1、Br、I、≡N、=NH、NH2、N=O、NO2、NHCH3、N=C=O、N=C=S、=O、OH、OCH3、OC≡N、ON=O、=S、SH、SCH3、S(=O)nOH、S(=O)nCH3、SC≡N、苯基、吡啶基、吡喃基、或硫代吡喃基(优选地,所述的苯基、吡啶基、吡喃基、或硫代吡喃基是未取代的);
其中,各个m是选自0、1、或2的整数;以及
各个n是选自0、1、或2的整数。
优选的是,当X1为取代或未取代的C1-C4烷基、或取代或未取代的C2-C4烯基中任何一种时选择取代基从而使得=O和OH两者均未取代在所述烷基或所述烯基的末端碳原子上。
在一个实施例中,R5和R6各自独立地选自:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)、或OCHmBr(3-m);其中,各个m是选自0、1、或2的整数。优选地,R5或R6中的至少一个为H。更优选地,R5和R6为H。
在一种形式中,所述化合物为式IA:
如本文所用,术语“C1-C4烷基”无论单独使用或在化合物术语中,是指具有1至4个碳原子的直链或支链的烃基。适合的烷基包括但不限于:甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基。所述“C1-C4烷基”可任选地被一个或多个取代基所取代。所述取代基可能替代在“C1-C4烷基”碳原子链中的任意一碳原子或多个碳原子上的一个或多个氢原子。
如本文所用,术语“C2-C4烯基”无论单独使用或在化合物术语中,是指具有2至4个碳原子以及包括至少一个碳碳双键的直链或支链的不饱和烃基。适合的烯基包括但不限于:乙烯基、丙烯基、或丁烯基。所述碳碳双键可能在任意两个相邻的碳原子之间。所述“C2-C4烯基”可任选地被一个或多个取代基所取代。所述取代基可能替代在“C2-C4烯基”碳原子链中的任意一碳原子或多个碳原子上的一个或多个氢原子。
如本文所用,术语“C2-C4炔基”无论单独使用或在化合物术语中,是指具有2至4个碳原子以及包括至少一个碳碳三键的直链或支链的不饱和烃基。适合的炔基包括但不限于:乙炔基、丙炔基、或丁炔基。所述碳碳三键可能在任意两个相邻的碳原子之间。所述“C2-C4炔基”可任选地被一个或多个取代基所取代。所述取代基可能替代在“C2-C4炔基”碳原子链中的任意一碳原子或多个碳原子上的一个或多个氢原子。
在一种形式中,所述环状结构‘X’选自下组:稠合或未稠合的芳基;稠合或未稠合的具有一个或多个选自N、O或S(优选地,N)的杂环原子的5元、6元、7元杂环基;或者,5元、6元、7元、8元、9元、10元、11元、12元、13元、14元、15元或16元(优选地,8元、9元、10元、11元或12元)单环烷基、桥接二环烷基或桥接三环烷基(优选地,桥接三环)。桥接环烷基意在覆盖棱烷类(prismanes)和星烷类(asteranes),例如,棱烷、立方烷、篮烷(basketane)等。在本发明的形式中,其中‘X’为稠合的芳基或稠合的杂环基,优选的是,稠合基团包括4个或更少的稠合环(优选地,3个或更少的稠合环,和更优选地2个或更少的稠合环)。稠合环可能是一个或多个芳基、杂环基和/或环烷基环基团的混合物。在本发明的另外的形式中,芳基和/或杂环基是未稠合的。优选的是,所述杂环基为未稠合的5或6元杂环基。更优选地,所述杂环基仅具有单个杂环原子。最优选地,所述杂环基是吡啶基。优选的是,所述环烷基是桥接二环烷基或桥接三环烷基。优选的是,所述环烷基不包括杂环原子。更优选地,所述环烷基是桥接三环烷基,以及最优选地所述桥接三环烷基为金刚烷基(adamantyl)。最优选的是,所述环状结构选自下组:苯基、吡啶基和金刚烷基。
优选的是,所述的化合物不选自下组:
当A1为H;A2为CH3;和A3为CH2CH2COOH、CH=CHCOOH、OCH2CH2CH2COOH、CH2NH2、CH2CH2C(=O)NHCH3、C≡N、NH2或NO2中的任何一种;或者当A1为H;A2为H;和A3为OH;或者当A1为F,A2为H,和A3为CH2NH2。
优选的是,所述取代或未取代的环烷基不是取代的环己烷基团。
优选的是,R1和R4各自独立地选自下组:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。或者,或另外,优选的是,R1和R4是相同的。最优选地,R1和R4均为H。
优选的是,R2独立地选自下组:H、F、Br、I、OH、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。更优选地,R2为H。
优选的是,R3独立地选自下组:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。更优选地,R3选自下组:H、CH3或OCH3。
优选的是,R1、R2、R3或R4中的至少二个为H。更优选地,R1、R2、R3或R4中的至少三个为H。
在一实施方式中,所述取代或未取代的芳基为取代或未取代的苯基,其式为:
其中,各个A1、A2、A3、A4或A5独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基;以及
其中,任选地A1和A2,和/或A2和A3,和/或A3和A4,和/或A4和A5中的一个或多个一起形成稠合的环结构。所述稠合的环结构可能为取代或未取代的芳基、杂环基或环烷基。在该环结构被取代的情况下,优选的是,取代基选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基。
在优选的形式中,(i)当R1、R2、R3、R4、A1、A4和A5各自为H时,A2不为CH3;且A3为CH2CH2COOH、CH=CHCOOH、OCH2CH2CH2COOH、CH2NH2、CH2CH2C(=O)NHCH3、C≡N、NH2或NO2中的任意一种;(ii)当R1、R2、R3、R4、A1、A2和A5各自为H且A3为CH2CH2COOH、CH=CHCOOH、OCH2CH2CH2COOH、CH2NH2、CH2CH2C(=O)NHCH3、C≡N、NH2或NO2中的任意一种时,A4不为CH3;(iii)当R1、R2、R3、R4、A1、A2、A4和A5为H时,A3不为OH;以及(iv)当A1为F,且R1、R2、R3、R4、A2、A4和A5各自为H时,A3不为CH2NH2。
优选的是,各个A1、A2、A3、A4或A5独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C2烷基、取代或未取代的C2烯基、取代或未取代的C2炔基、取代或未取代的OC1-C2烷基、取代或未取代的OC2烯基、取代或未取代的OC2炔基、取代或未取代的NHCl-C2烷基、取代或未取代的NHC2烯基、取代或未取代的NHC2炔基。更优选的是,各个A1、A2、A3、A4或A5独立地选自下组:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。
优选的是,A1、A2、A3、A4或A5中的至少两个为H。更优选地,A1、A2、A3、A4或A5中的至少三个为H。
在一实施方式中,所述取代或未取代的杂环基为取代或未取代的吡啶基,选自下组:
其中,Z是杂环原子,并且其选自下组:N、S或O;以及
存在的每个H1、H2、H3、H4或H5独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基;以及
其中,任选地H1和H2,和/或H2和H3,和/或H3和H4,和/或H4和H5中的一个或多个一起形成稠合的环结构。所述稠合的环结构可能为取代或未取代的芳基、杂环基或环烷基。在该环结构被取代的情况下,优选的是,取代基选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基。
优选的是,Z选自下组:N或O。最优选地,Z为N。
优选的是,存在的各个H1、H2、H3、H4或H5独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C2烷基、取代或未取代的C2烯基、取代或未取代的C2炔基、取代或未取代的OC1-C2烷基、取代或未取代的OC2烯基、取代或未取代的OC2炔基、取代或未取代的NHC1-C2烷基、取代或未取代的NHC2烯基、取代或未取代的NHC2炔基。更优选地,存在的每个H1、H2、H3、H4或H5独立地选自下组:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。
优选的是,存在的各个H1、H2、H3、H4或H5中的至少二个为H。更优选地,存在的各个H1、H2、H3、H4或H5中的至少三个为H。最优选地,存在的各个H1、H2、H3、H4或H5为H。
在一实施方式中,所述取代或未取代的环烷基为金刚烷基环,其式为:
其中,在金刚烷基环上的各个碳原子为未取代的(即包括仅至相邻碳原子和氢的共价键)或者在金刚烷基环上的各个可被取代的碳原子可能被一个或多个选自下组的取代基所取代:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基。
优选的是,在金刚烷基环上的各个可被取代的碳原子可独立地被一个或多个选自下组的取代基所取代:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C2烷基、取代或未取代的C2烯基、取代或未取代的C2炔基、取代或未取代的OC1-C2烷基、取代或未取代的OC2烯基、取代或未取代的OC2炔基、取代或未取代的NHC1-C2烷基、取代或未取代的NHC2烯基、取代或未取代的NHC2炔基。更优选地,在金刚烷基环上的各个可被取代的碳原子可独立地被一个或多个选自下组的取代基所取代:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。
在一实施方式中,所述取代或未取代的环烷基为金刚烷基环,其式为:
其中,各个B1、B2和B3独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基;以及
其中,在金刚烷基环中的各个其他碳原子包括仅至相邻碳环原子和氢的共价键。
优选的是,各个B1、B2和B3独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C2烷基、取代或未取代的C2烯基、取代或未取代的C2炔基、取代或未取代的OC1-C2烷基、取代或未取代的OC2烯基、取代或未取代的OC2炔基、取代或未取代的NHC1-C2烷基、取代或未取代的NHC2烯基、取代或未取代的NHC2炔基。更优选地,各个B1、B2和B3独立地选自下组:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。
优选的是,B1、B2或B3中的至多二个被取代。
在一种形式中,所述环状结构为取代或未取代的芳基。在另一种形式中,所述环状结构为取代或未取代的杂环基。在又一种形式中,所述环状结构为取代或未取代的环烷基。
鉴于以上所述,在本发明的第一方面,提供了一种药物组合物,所述药物组合物包括、基本上由以下组成或由以下组成:药学上可接受的式I化合物(如前定义);以及药学上可接受的载体、稀释剂或赋形剂。
在本发明的第二方面,提供一种方法,包括:将包括式I化合物的药物组合物施用给对象。优选的是,所述药物组合物还包括药学上可接受的载体、稀释剂或赋形剂。
在一实施方式中,所述方法包括以治疗或预防对象的疾病的有效量将药物组合物施用给对象。所述疾病可能是社交功能障碍,例如,社会退缩、攻击性、反社会障碍或对物质成瘾。所述疾病可能是精神疾病,例如,自闭症谱系障碍(autistic spectrum disorder)、社交焦虑症、包括重度抑郁症的抑郁症,或精神分裂症。所述物质可能是,例如,酒精、可卡因、鸦片剂、苯丙胺类、海洛因和尼古丁。
在一实施方式中,所述方法包括将药物组合物施用给患有或正从物质滥用障碍恢复的对象;或者正从物质滥用障碍恢复并寻求维持对物质的持续禁欲的对象。
在第三方面,提供了一种包括式I化合物的药物组合物的用途,用于治疗或预防对象的疾病,和/或维持对象对物质的持续禁欲。
在第四方面,提供了式I化合物用于制造用于治疗疾病的药物的用途,其中所述的疾病选自下组:社交功能障碍,其包括:社会退缩、攻击性、反社会障碍、或对物质成瘾;或者,精神疾病,其包括:社交焦虑症、包括重度抑郁症的抑郁症、或精神分裂症;或者,诸如自闭症谱系障碍的发展障碍。
在本发明的第五方面,提供了式I化合物,其中所述化合物不选自下组:
当A1为H时;A2为CH3;且A3为CH2CH2COOH、CH=CHCOOH、OCH2CH2CH2COOH、CH2NH2、CH2CH2C(=O)NHCH3、C≡N、NH2或NO2中的任何一种;或者当A1为H时;A2为H;且A3为OH;或者当A1为F时,A2为H,和A3为CH2NH2;或者
其中所述取代或未取代的环烷基是取代的环己烷基团的化合物。
通过以下描述,本发明的其他方面和前面段落中所述的其他实施发生将变得显而易见。
附图简要说明
图1:显示用0、1、5和20mg/kg的包括化合物WJ0679的药物组合物进行治疗的小鼠的抱团时间的结果的图。
图2:显示用0、1、5和20mg/kg的包括化合物WJ0679的药物组合物进行治疗的小鼠的积极的社会调查时间的结果的图。
具体实施方式
本发明基于发现式I化合物及其在治疗一系列精神、神经和行为障碍中的用途。特别地,已发现所述式I化合物作为催产素受体(OXTR)的选择性激动剂。
表现出结构上类似于式I化合物的头基的化合物是已知的,例如WAY 267464化合物(见下图)是用于催产素受体的非肽激动剂。
此外,专利公开WO2006/021213和WO03/000692分别公开了后叶加压素(vasopressin)V1A拮抗剂和催产素激动剂,其表现出与WAY 267,464化合物类似的结构,其中公开的许多化合物中包括具有延伸自二氮杂(diazepine)环的4位氮原子的长侧链的吡唑并[1,4]二氮杂头基。然而,与式I化合物相比,这些大化合物表现出许多缺点。例如,虽然这些化合物可以作为OXTR激动剂,但这些化合物也与血管加压素V1a受体(V1aR)结合,其通常作为拮抗剂。其他问题包括这些化合物的生物利用度差,因这些化合物难以穿过血脑屏障,或者这些化合物代谢成没有效果或有有害效果的较小的片段。
Frantz等人在2010年进行了研究来系统地评估V1a、V2和OT受体亚型的代表性配体的亲和力和效果的结构因素(参见Frantz等人“结构的微妙-亲和力和结构-围绕非肽催产素受体激动剂的效果关系(Subtlety of the Structure-Affinity and Structure-Efficacy Relationships around a Nonpeptide Oxytocin Receptor Agonist)”,J.Med.Chem.,2010,53,1546-1562)。
Frantz等人评估的化合物之一为下述化合物:
Frantz等人将该化合物分成仅覆盖吡唑并[1,4]二氮杂头基的“西面部分”,以及覆盖延伸自二氮杂环的4位氮原子的尾基的“东面部分”。之后Frantz等人研究了改变“西面部分”的头基和截断化合物的“东面部分”的效果。有趣的是,Frantz等人证明了截断整个分子的“东面部分”导致该分子作为了OXTR的拮抗剂,或者在某些情况下对OXTR无活性。基于此,Frantz等人得出结论,至少包含脲连接基团的长尾对于OXTR活化是必需的。
令人惊讶的是,本发明人发现式I化合物不仅作为了OXTR激动剂,而且在许多情况下对OXTR具有高选择性,对V1aR具有最小的或无亲和力。式I化合物,其为比较小的分子,也不易受到困扰这些较大分子中的一些的生物利用度和代谢分解的问题的影响。
式I化合物对OXTR起作用,同时避免了与天然配体(即催产素)或WO 2006/021213、WO 03/000692和Frantz等人所讨论的化合物相关的许多隐患。同样地,该化合物避免或减少了对OT的上述问题,并且对于可以通过OXTR激动剂治疗的一系列疾病或障碍具有广泛和有价值的应用。除了治疗疾病状态外,选择性小分子还允许OT受体的分子探针。
鉴于上述,本发明还涉及包含式I化合物的药物组合物。式I化合物以药学有效量被包含,足以对疾病的过程或病况产生所需效果。
适合的剂量水平通常为每千克患者体重每天约0.01至500mg,其可以单剂量或多剂量施用。优选地,所述剂量水平应为每天约0.1至约250mg/kg;更优选地,每天约0.5至约100mg/kg。合适的剂量水平可以是每天约0.01至250mg/kg,每天约0.05至100mg/kg,或每天约0.1至50mg/kg。在这个范围内剂量可以是每天0.05至0.5、0.5至5或5.0到50mg/kg。对于口服给予,组合物优选以片剂的形式提供给待治疗患者,其含有1.0至1000毫克活性成分,特别地,1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0和1000.0毫克活性成分,用于对症调整剂量。所述化合物可以以每天1至4次的方案给予,优选地每天一次或两次。然而,应当理解,用于任何特定患者的剂量的具体剂量水平和频率可能改变并将取决于多种因素包括所用具体化合物的活性、代谢稳定性和化合物的作用时间、年龄、体重、一般健康状况、性别、饮食、给药方式和时间、排泄速率、药物组合、特定疾病状态的严重程度,以及接受治疗的宿主。在组合物中本发明的化合物的量也将取决于所述组合物中的特定化合物。
所述药物组合物可能进一步包括其他治疗活性化合物,其通常用于所公开的障碍或疾病。根据常规药物原理,本领域的普通技术人员可选择联合治疗所用适合的药剂。治疗剂的组合可协同作用以实现本文所公开的各种障碍或疾病的治疗或预防。使用这种方法,可以以较低剂量的每种药物达到治疗效果,从而减少不良副作用的可能性。
本发明的化合物和组合物可被配制用于任何合适的施用途径,包括例如局部(例如,经皮或眼)、口服、口腔、鼻、阴道、直肠或肠胃外施用。如本文所用,术语肠胃外包括皮下、皮内、血管内(例如,静脉内)、肌肉内、脊柱、颅内、鞘内、眼内、眼周、眶内、滑膜内和腹膜内的注射,以及任何类似的注射或输注技术。在特定的实施方式中,优选适于口服使用或肠胃外使用的形式的组合物。适合的口服形式包括:例如片剂、药片(troches)、锭剂(lozenges)、水性或油性悬浮液、可分散的粉末或颗粒、乳液、硬或软胶囊,或糖浆或酏剂。在其他的实施方式之内,本文提供的组合物可被配制为冻干物。
各种剂量单位各自优选地作为离散剂量片剂、胶囊、锭剂、糖衣丸、口香糖(gum)或其他类型的固体制剂提供。胶囊可包封粉末、液体或凝胶。固体制剂可被吞咽,或者可以是可吮吸或可咀嚼的类型(易碎的或类似口香糖的)。本发明考虑了除罩板包装之外的剂量单位固位装置;例如,诸如瓶子、管子、罐子、包裹的包装。所述剂量单位可进一步包括在药物制剂实践中熟知的常规赋形剂,例如粘合剂、胶凝剂、填充剂、压片润滑剂、崩解剂、表面活性剂和着色剂;和可吮吸或可咀嚼的制剂。
意在口服使用的组合物可进一步包括一种或多种组分,例如甜味剂、调味剂、着色剂和/或防腐剂,以提供吸引人的和可口的制剂。片剂含有与适于制造片剂的生理学上可接受的赋形剂混合的活性成分。这种赋形剂包括例如惰性稀释剂如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠,造粒和崩解剂如玉米淀粉或海藻酸,粘合剂如淀粉、明胶或阿拉伯胶,以及润滑剂如硬脂酸镁、硬脂酸或滑石粉。片剂可以是未包衣的,或者片剂可以是通过已知技术包衣,以延缓在胃肠道中的崩解和吸收从而提供较长时期的持续作用。例如,可以采用延时材料如甘油单硬脂酸酯或甘油二硬脂酸酯。
用于口服使用的制剂也可以作为硬明胶胶囊提供,其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合,或者作为软明胶胶囊提供,其中活性成分与水或诸如花生油、液体石蜡或橄榄油的油性介质混合。
水悬浮液含有与适合制造水悬浮液的赋形剂混合的活性成分。这样的赋形剂包括:悬浮剂例如羧甲基纤维素钠、甲基纤维素、羟丙甲纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶,以及分散或湿润剂如天然存在的磷脂(例如卵磷脂)、烯氧化物与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯、环氧乙烷与长链脂肪醇的缩合产物例如十七乙烯基氧基鲸蜡醇、环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物例如聚氧乙烯山梨糖醇单油酸酯、或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物例如聚乙烯基脱水山梨糖醇单油酸酯。水悬浮液还可包括一种或多种防腐剂,例如对羟基苯甲酸乙酯或正丙酯,一种或多种着色剂,一种或多种调味剂,和一种或多种甜味剂,如蔗糖或糖精。
油性悬浮液可通过将活性成分悬浮于植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(例如液体石蜡)中来配制。所述油性悬浮液可包含增稠剂,例如蜂蜡、硬石蜡或十六烷醇。可加入如上述那些甜味剂和/或调味剂以提供可口的口服制剂。可通过添加诸如抗坏血酸的抗氧化剂来保存这种悬浮液。
适用于通过加水制备水性悬浮液的可分散粉末和颗粒提供了与分散或润湿剂、悬浮剂和一种或多种防腐剂混合的活性成分。合适的分散或润湿剂和悬浮剂的例子如上所述。还可有例如甜味剂、调味剂和着色剂的另外的赋形剂。
药物组合物也可以是水包油乳液的形式。油相可以是植物油如橄榄油或花生油,或矿物油如液体石蜡,或其混合物。合适的乳化剂包括天然存在的树胶如阿拉伯树胶或黄蓍胶,天然存在的磷脂例如大豆卵磷脂、衍生自脂肪酸和己糖醇、酐的酯或偏酯如山梨醇单油酸酯,以及衍生自脂肪酸和己糖醇的偏酯与环氧乙烷的缩合产物如聚氧乙烯脱水山梨糖醇单油酸酯。乳液还可包含一种或多种甜味剂和/或调味剂。
糖浆剂和酏剂可以用甜味剂(例如甘油、丙二醇、山梨糖醇或蔗糖)配制。此类制剂还可包括一种或多种缓和剂、防腐剂、调味剂和/或着色剂。
本发明的组合物还可被配制成用于局部(local)或局部的(topical)施用,例如用于局部涂覆至皮肤上。用于局部施用的制剂通常包括与活性剂组合的局部载体,有或没有另外的任选组分。
合适的局部载体和附加组分在本领域中是公知的,并且根据特定的物理形式和递送方式选择载体是显而易见的。局部载体包括:有机溶剂如醇类(例如乙醇、异丙醇或甘油)、诸如丁二醇、异戊二醇或丙二醇的二醇类、诸如羊毛脂的脂族醇,水和有机溶剂的混合物以及有机溶剂(如乙醇和甘油)的混合物,脂质基材料如脂肪酸、酰基甘油包括诸如矿物油的油,和天然或合成的脂肪、磷酸甘油酯、鞘脂类和蜡,蛋白质基材料(如胶原蛋白和明胶),硅酮基材料(非挥发性和挥发性),以及烃基材料如微海绵和聚合物基质。
组合物可进一步包括适用于改善所涂覆的制剂的稳定性或效力的一种或多种组分,例如稳定剂、悬浮剂、乳化剂、粘度调节剂、胶凝剂、防腐剂、抗氧化剂、皮肤渗透促进剂、保湿剂和缓释材料。在马丁代尔(Martindale)-药学大全(The Extra Pharmacopoeia)(医药出版社,伦敦1993)和马丁(Martin)(编),雷明顿的制药科学(Remington’sPharmaceutical Sciences)中描述了这些组分的实例。制剂可包括微胶囊,如羟甲基纤维素或明胶-微胶囊、脂质体、白蛋白微球、微乳液、纳米颗粒或纳米胶囊。
局部制剂可以以各种物理形式制备,包括例如固体、糊剂、乳膏、泡沫、洗剂、凝胶、粉末、含水液体、乳液、喷雾剂和皮肤贴剂。这些形式的物理外观和粘度可以通过配方中存在的乳化剂和粘度调节剂的存在和量来控制。固体通常是坚固且不可倾注流动的并且通常被配制成条或棒,或以颗粒形式。固体可以是不透明的或透明的,并且任选地可以包含溶剂、乳化剂、保湿剂、润肤剂、芳香剂、染料/着色剂、防腐剂和其他增加或增强最终产品效力的活性成分。乳膏和乳液通常彼此相似,主要区别在于它们的粘度。乳液和乳膏都可以是不透明的、半透明的或透明的,并且通常包含乳化剂、溶剂和粘度调节剂,以及保湿剂、润肤剂、芳香剂、染料/着色剂、防腐剂和增加或增强最终产品效力的其他活性成分。凝胶可被制备成具有一系列粘度,从厚或高粘度至薄或低粘度。这些制剂,如乳液和乳膏的那些,也可以包含溶剂、乳化剂、保湿剂、润肤剂、芳香剂、染料/着色剂、防腐剂和增加或增强最终产品效力的其他活性成分。液体比乳霜、乳液或凝胶更薄,并且通常不含乳化剂。液体局部产品通常包含溶剂、乳化剂、保湿剂、润肤剂、芳香剂、染料/着色剂、防腐剂和增加或增强最终产品效力的其他活性成分。
用于局部制剂的乳化剂包括但不限于:离子乳化剂、鲸蜡硬脂醇、非离子乳化剂如聚氧乙烯油醚、PEG-40硬脂酸酯、鲸蜡硬脂醇聚醚(ceteareth)-12、鲸蜡硬脂醇聚醚-20、鲸蜡硬脂醇聚醚-30、鲸蜡硬脂醇聚醚醇、PEG-100硬脂酸酯和硬脂酸甘油酯。合适的粘度调节剂包括但不限于保护胶体或非离子胶,例如羟乙基纤维素、黄原胶、硅酸铝镁、二氧化硅、微晶蜡、蜂蜡、石蜡和十六烷酸鲸蜡醇酯。凝胶组合物可以通过加入胶凝剂如壳聚糖、甲基纤维素、乙基纤维素、聚乙烯醇、聚季铵盐、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、卡波姆或氨化甘草酸酯来形成。合适的表面活性剂包括但不限于非离子、两性、离子和阴离子表面活性剂。例如,在局部制剂中可以使用聚二甲基硅氧烷共聚醇(dimethiconecopolyol)、聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、月桂酰胺DEA、椰油酰胺DEA和椰油酰胺MEA、油基甜菜碱(oleyl betaine)、椰油酰胺丙基磷脂酰PG-二甲基氯化铵(cocamidopropyl phosphatidyl PG-dimonium chloride)和月桂醇聚醚硫酸铵(ammonium laureth sulfate)中的一种或多种。
防腐剂包括但不限于:抗微生物剂例如对羟基苯甲酸甲酯、尼泊金丙酯、山梨酸、苯甲酸和甲醛,以及物理稳定剂和抗氧化剂,例如维生素E、抗坏血酸钠/抗坏血酸和没食子酸丙酯。合适的保湿剂包括但不限于乳酸和其他羟基酸及其盐、甘油、丙二醇和丁二醇。合适的润肤剂包括:羊毛脂醇、羊毛脂、羊毛脂衍生物、胆固醇、凡士林油、新戊酸异硬脂酯和矿物油。合适的芳香剂和着色剂包括但不限于FD&C红色40号和FD&C黄色5号。可包含在局部制剂中的其他合适的另外的成分包括但不限于研磨剂、吸收剂、抗结块剂、消泡剂、抗静电剂、收敛剂(如金缕梅)、醇和草药提取物如洋甘菊提取物、粘合剂/赋形剂、缓冲剂、螯合剂、成膜剂、调节剂、推进剂、遮光剂、pH调节剂和保护剂。
用于局部组合物的递送的典型方式包括使用手指施用、使用物理施用器如布、纸巾、纱布、棒或刷子施用,喷雾包括雾、气雾或泡沫喷雾、滴管施用、喷淋、浸泡和漂洗。也可使用控释载体,并且组合物可被配制成用于透皮施用(例如,作为透皮贴剂)。
药物组合物可被配制成持续释放剂例如胶囊,其在施用后造成了调节剂的缓慢释放。这样的制剂通常可使用熟知的技术制备,并通过例如口服、直肠或皮下植入或通过在所需的目标位置植入来施用。用于这样的制剂的载体是生物相容的,并且也可以是可生物降解的。优选地,该制剂提供了相对恒定水平的调节剂释放。缓释制剂中所包含的调节剂的量取决于例如植入部位、释放的速率和所需时间以及待治疗或预防的病症的性质。
在另一种形式中,本发明涉及治疗对象的方法,该方法包括以药学上可接受形式,将药学有效量的式I化合物施用至所述对象。
如本文所用,“对象”是指动物,例如哺乳动物或鸟类,包括人、猿、马、牛、绵羊、山羊、狗、猫、豚鼠、大鼠、小鼠、鸡等。
本发明人发现式I化合物对一系列神经病症或障碍的治疗特别有用。所述疾病或障碍可能是社交功能障碍,例如,社会退缩、攻击性、反社会障碍或对物质(例如,酒精、可卡因、鸦片剂、苯丙胺类、海洛因和尼古丁)成瘾。所述疾病或障碍可能是精神疾病、社交焦虑症、包括重度抑郁症的抑郁症、健忘、或精神分裂症、或者,诸如自闭症谱系障碍的发展障碍。所述疾病或障碍可能是应激障碍,包括创伤后应激障碍。
如本文所用,术语“治疗的(treating)”和“治疗(treatment)”可包括以下一种或多种:改善对象中疾病的症状、阻断或改善对象中病症或障碍的症状的复发,以及减少对象中病症或障碍的症状的严重性和/或频率。
在另一方面,本发明提供了试剂盒或制品,其包括式I化合物或包括本文所述的式I化合物的药物组合物。
在其他实施方式中,提供了用于本文所述的治疗或预防性应用的试剂盒,所述试剂盒包括:容纳了式I化合物或包含式I化合物的药物组合物的容器;以及具有使用说明的标签或包装插入物。
所述试剂盒或“制品”可包括容器和在所述容器上或与所述容器关联的标签或包装插入物。合适的容器包括例如瓶子、小瓶、注射器、罩板包装等。所述容器可以由诸如玻璃或塑料的多种材料形成如。所述容器容纳式I化合物或组合物,其对治疗疾病有效并且可具有无菌进入口(例如,容器可以是静脉内溶液袋或具有可由皮下注射针刺穿的塞子的小瓶)。标签或包装插入物说明书表明了树枝状聚合物或组合物是用于治疗障碍的。在一实施方式中,所述标签或包装插入物包括使用说明书并表明了所述治疗或预防性组合物可用于治疗本文所述的障碍。
所述试剂盒包括(a)治疗或预防性组合物;和(b)第二容器,其中容纳有第二活性成分(principle)或组分。本发明该实施方式中的试剂盒可进一步包含包装插入物,其表明了组合物和其他活性成分可用于治疗障碍或预防源自本文所述障碍的并发症。或者,或此外,所述试剂盒可进一步包含第二(或第三)容器,其包含药学上可接受的缓冲液,例如抑菌性注射用水(BWFI)、磷酸盐缓冲盐水、林格溶液和葡萄糖溶液。它可进一步包括从商业和用户角度来看所需的其他材料,包括其他缓冲剂、稀释剂、过滤器、针头和注射器。
在某些实施方式中,所述治疗组合物可以以一次性的或可重复使用的装置的形式提供,其包括用于保存式I化合物或包含式I化合物的治疗或预防性药物组合物的容器。在一实施方式中,所述装置是注射器。在装置中,可以以即可使用的状态或以需要混合或添加其他组分的状态提供所述治疗或预防性组合物。
应当理解,在其说明书中所公开和限定的本发明扩展到文本中所提到或显而易见的两个或更多个单独特征的所有可选组合。所有这些不同的组合构成了本发明的各种替代方面。
现在将详细参考本发明的某些实施方式。虽然将结合实施方式描述本发明,但是应该理解,其目的不是将本发明限制于那些实施方式。相反,本发明旨在覆盖所有选择、修改和等同物,其可以包括在由权利要求限定的本发明的范围内。
本领域技术人员将认识到许多类似于或等同于本文所述的方法和材料,这些方法和材料可用于本发明的实践中。本发明决不限于所述的方法和材料。应当理解,在其说明书中所公开和限定的本发明扩展到文本或附图所提到或显而易见的两个或更多个单独特征的所有可选组合。所有这些不同的组合构成了本发明的各种替代方面。
本文提及的所有出版物均通过引用整体并入。
实施例
合成实施例
实施例1:用通式2的苯甲酸使三环1酰胺化的通用过程
方法A:
步骤i:
通过在0℃下用草酰氯(1.0mL,11mmol)随后用DMF(1滴)处理CH2Cl2(10mL)中的母体酸(1.1mmol)来制备酰氯,并在室温下搅拌2小时,随后在氮气流下浓缩,得到通式(2)的酰氯。
步骤ii:
将磁力搅拌下的1(200mg,1mmol)和NEt3(229μL,2mmol)于CH2Cl2(10mL)中的悬浮液通过在0℃下滴加适合的苯甲酰氯(1.1mmol)于CH2Cl2(10mL)中的溶液进行处理。之后将反应混合温热至室温并继续搅拌4h。将得到的溶液用CH2Cl2(25mL)和NaHCO3(25mL的饱和水溶液)稀释,在干燥(MgSO4)前将分离的有机相依次用NaHCO3(25mL的饱和水溶液)和盐水(50mL)洗涤,过滤并在减压下浓缩,从而得到(式1a化合物的)粗油。通过研磨(EtOAc)随后通过重结晶(MeOH/CH2Cl2),或者经由快速色谱法进行纯化,提供所需的酰胺。
方法B:
将冰冷的磁力搅拌下的所需的苯甲酸(1.1mmol)、胺1(200mg,1mmol)和iPr2NEt(348μL,2mmol)于CH2Cl2(20mL)中的溶液通过分批的(500mg,1mmol)进行处理,温热至室温并继续搅拌4h。将反应物料用CH2Cl2(50mL)和水(50mL)稀释,在干燥(MgSO4)前将分离的有机相依次用NaHCO3(25mL饱和水溶液)和盐水(100mL)洗涤,过滤并经由快速柱色谱(二氧化硅,1∶1至1∶0v/v EtOAc/己烷梯度洗脱)纯化,制得作为结晶固体的所需的酰胺。
方法C:
步骤i:
通过在0℃下用草酰氯(1.0mL,11mmol)随后用DMF(1滴)处理CH2Cl2(10mL)中的母体酸(1.1mmol)来制备酰氯,并在室温下搅拌2小时,随后在氮气流下浓缩,得到通式(2)的酰氯。
步骤ii:
将磁力搅拌下的1的二盐酸盐(272mg,1mmol)和碱(3.3mmol)于CH2Cl2(10mL)中的悬浮液通过在0℃下滴加适合的苯甲酰氯(1.1mmol)于CH2Cl2(10mL)的溶液进行处理。所述的碱可以是NEt3、二异丙基乙胺或吡啶。之后将反应混合物温热至室温并继续搅拌4h。将得到的溶液用CH2Cl2(25mL)和NaHCO3(25mL饱和水溶液)稀释,在干燥(MgSO4)前将分离的有机相依次用NaHCO3(25mL饱和水溶液)和盐水(50mL)洗涤,过滤并在减压下浓缩,从而得到(式1a化合物的)粗油。通过研磨(EtOAc)随后通过重结晶(MeOH/CH2Cl2),或者经由快速色谱法进行纯化,提供所需的酰胺。
实施例2:(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(苯基)甲酮[WJ0685]
根据前述的通用过程A,将二氮杂1(150mg,0.75mmol)用苯甲酰氯(174μL,1.5mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的WJ0685(124mg,54%)(Rf=0.23,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):δ8.62(br s,1H,NH),7.27(dd,J=8.1,1.4Hz,1H,3-CH),7.24-7.20(m,1H,6-CH),7.18(s,1H,12-CH),7.19-7.14(m,4H,12/13-4xCH),7.12-7.06(m,1H,2-CH),6.71(dd,J=7.9,1.5Hz,1H,1-CH),6.61(t,J=7.8Hz,1H,14-CH),5.68(d,J=14.5Hz,1H,8-CH2),3.91(d,J=14.4Hz,1H,8-CH2),3.77(s,3H,15-CH3).13C NMR(126MHz,DMSO-d6):δ168.3,139.8,138.9,136.4,135.6,132.3,130.4,129.4,128.2,127.7,127.2,121.1,119.5,100.3,43.1,35.4.IR(金刚石池(diamond cell),纯(neat))νmax:3041,1619,1562,1504,1450,1397,1320,1141,990,827,797,759,727,697,648,598,446cm-1.LRMS(+ESI)m/z:327[(M+Na)+,100%],631[(2M+Na)+,45%].HRMS(+ESI)实测值:(M+Na)+,327.1214.C18H16N4O需求(M+Na)+,327.1216.MP>300℃.HPLC纯度:98.33%,RT:18.01min.
实施例3:(3,5-二氟苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮
杂
-5(1H)-基)甲酮[WJ0681]
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自3,5-二氟苯甲酸的酰氯(237mg,1.5mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH/CH2Cl2)纯化,制得淡黄色针状的WJ0681(141mg,41%)(Rf=0.24,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(400MHz,DMSO-d6):δ8.66(br s,1H,NH),7.28(dd,J=8.2,1.4Hz,1H,3-CH),7.19(s,1H,12-CH),7.18-7.09(m,2H,2/6-2xCH),6.90-6.78(m,3H,12/14-3xCH),6.69(td,J=7.6,1.4Hz,1H,1-CH),5.63(d,J=14.5Hz,1H,8-CH2),3.97(d,J=14.5Hz,1H,8-CH2),3.78(s,3H,15-CH3).13C NMR(101MHz,DMSO-d6):δ165.8,161.6(dd,J=12.7Hz),139.9(t,J=8.9Hz),139.6,139.1,135.6,131.5,130.3,128.8,121.3,119.6,110.4(d,J=26.5Hz),104.8(t,J=25.8Hz),99.9,43.2,35.4.19F NMR(376MHz,DMSO-d6):δ-109.50.IR(金刚石池,纯)νmax:3325,1626,1595,1564,1505,1444,1405,1329,1245,1178,1131,991,951,862,845,801,757,726,697,665,630,564,495,448cm-1.LRMS(+ESI)m/z:363[(M+Na)+,100%],703[(2M+Na)+,26%].HRMS(+ESI)实测值:(M+Na)+,363.1024.C18H14F2N4O需求(M+Na)+,363.1028.MP 290-292℃(分解).HPLC纯度:96.65%,RT:19.92min.
实施例4:(3-氟-4-甲基苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二
氮杂
-5(1H)-基)甲酮[WJ0683])
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自3-氟-4-甲基苯甲酸的酰氯(231mg,1.5mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)进行纯化,制得无色立方状WJ0683(137mg,41%)(Rf=0.21,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):δ8.64(br s,1H,NH),7.29(dd,J=8.1,1.4Hz,1H,3-CH),7.17(s,1H,12-CH),7.13(td,J=7.7,1.6Hz,1H,2-CH),7.07(t,J=7.7Hz,1H,14-CH),6.88-6.86(m,2H,13/16-2xCH),6.76(dd,J=7.9,1.6Hz,1H,6-CH),6.66(td,J=7.6,1.4Hz,1H,1-CH),5.66(d,J=14.5Hz,1H,8-CH2),3.92(d,J=14.5Hz,1H,8-CH2),3.77(s,3H,15-CH3),2.12(d,J=1.8Hz,3H,17-CH3).13C NMR(126MHz,DMSO-d6):δ166.8,159.6(d,J=243.3Hz),139.8,138.9,135.9(d,J=7.1Hz),135.6,132.1,130.9(d,J=5.2Hz),130.3,128.5,125.8(d,J=17.0Hz),123.3,121.3,119.6,113.9(d,J=23.8Hz),100.2,43.2,35.4,14.0.19F NMR(471MHz,DMSO-d6):δ-117.72.IR(金刚石池,纯)νmax:3294,1623,1557,1501,1392,1302,1252,989,822,768,730,699,628,568,495,446cm-1.LRMS(+ESI)m/z:359[(M+Na)+,100%],695[(2M+Na)+,21%].HRMS(+ESI)实测值:(M+Na)+,359.1277.C19H17FN4O需求(M+Na)+,359.1279.MP 235-237℃.HPLC纯度:97.99%,RT:19.94min.
实施例5:(1-甲基-4.10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(对甲苯基)甲酮[WJ0653]
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自4-甲基苯甲酸的酰氯(240mg,1.5mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH)纯化,制得白色固体状的WJ0653(95mg,30%)(Rf=0.21,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(400MHz,DMSO-d6):δ8.59(br s,1H,NH),7.39-7.22(m,1H,3-CH),7.16(s,1H,12-CH),7.10(t,J=7.4Hz,1H,2-CH),7.04(d,J=7.8Hz,2H,16-2xCH),6.96(d,J=7.9Hz,2H,17-2xCH),6.69(d,J=7.7Hz,1H,6-CH),6.63(t,J=7.5Hz,1H,1-CH),5.68(d,J=14.5Hz,1H,8-CH2),3.89(d,J=14.5Hz,1H,8-CH2),3.77(s,3H,15-CH3),2.19(s,3H,18-CH3).13C NMR(101MHz,DMSO-d6):δ168.1,139.8,139.1,138.8,135.6,133.4,132.5,130.4,128.2,128.1,127.5,121.2,119.5,100.4,43.1,35.3,20.8.IR(金刚石池,纯)νmax:3313,1617,1557,1501,1389,1293,1251,1140,1023,989,832,767,753,730,707,627,597,490,441cm-1.LRMS(+ESI)m/z:319[(M+H)+,10%]341[(M+Na)+,100%],659[(2M+Na)+,36%].HRMS(+ESI)实测值:(M+Na)+,341.1370.C19H18N4O需求(M+Na)+,341.1373.MP 265℃(分解).HPLC纯度:96.48%,RT:19.04min.
实施例6:(4-氯苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-
5(1H)-基)甲酮[WJ0755]
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自4-氯苯甲酸的酰氯(172mg,1.1mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)进行纯化,制得黄色立方状WJ0755(187mg,55%)(Rf=0.31,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):δ8.62(br s,1H,NH),7.28(dd,J=8.2,1.4Hz,1H,3-CH),7.26-7.20(m,2H,2/12-2xCH),7.20-7.05(m,4H,16/17-4xCH),6.75(dd,J=7.9,1.5Hz,1H,6-CH),6.68-6.58(m,1H,1-CH),5.66(d,J=14.5Hz,1H,8-CH2),3.93(d,J=14.5Hz,1H,8-CH2),3.77(s,3H,15-CH3).13C NMR(126MHz,DMSO-d6):δ167.2,139.7,138.9,135.7,135.3,134.0,131.9,130.4,129.1,128.5,127.8,121.2,119.6,100.3,43.2,35.4.IR(金刚石池,纯)νmax:3319,1623,1560,1504,1453,1408,1296,1245,1137,1088,1015,989,843,827,764,753,700,628,595,553,489cm-1.LRMS(+ESI)m/z:339[(M+H)+,50%]361[(M+Na)+,100%].HRMS(+ESI)实测值:(M+H)+,339.1008.C18H15ClN4O需求(M+H)+,339.1007.MP 243-246℃.HPLC纯度:96.01%,RT:19.95min.
实施例7:(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(4-(三氟甲基)苯基)甲酮[WJ0677]
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自4-三氟甲基苯甲酸的酰氯(285mg,1.5mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得灰白色粉末状的WJ0677(221mg,59%)(Rf=0.27,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):δ8.64(br s,1H,NH),7.54(d,J=8.2Hz,2H,16-2xCH),7.35(d,J=8.0Hz,2H,17-2xCH),7.28(dd,J=8.2,1.4Hz,1H,3-CH),7.20(s,1H,12-CH),7.11(ddd,J=8.3,7.2,1.5Hz,1H,2-CH),6.79(dd,J=7.8,1.5Hz,1H,6-CH),6.62(td,J=7.6,1.4Hz,1H,1-CH),5.67(d,J=14.5Hz,1H,8-CH2),3.97(d,J=14.4Hz,1H,8-CH2),3.78(s,3H,15-CH3).13C NMR(126MHz,DMSO-d6):δ167.1,140.6,139.7,139.0,135.7,131.4,130.5,129.3(q,J=31.9Hz),128.6,127.9,124.7(q,J=3.9Hz),123.4(q,J=273.3Hz),121.1,119.5,100.2,43.2,35.4.19F NMR(471MHz,DMSO-d6):δ-61.33.IR(金刚石池,纯)νmax:3319,1641,1557,1503,1387,1321,1252,1167,1111,1066,1020,992,845,757,732,681,630,610,496,418cm-1.LRMS(+ESI)m/z:395[(M+Na)+,100%],767[(2M+Na)+,24%].HRMS(+ESI)实测值:(M+Na)+,395.1086.C19H15F3N4O需求(M+Na)+,395.1090.MP 204-206℃.HPLC纯度:96.68%,RT:21.21min.
实施例8:3,5-双(苄氧基)苯甲酸
步骤i:
将磁力搅拌下的二羟基苯甲酸(resorcylic acid)(616mg,4.0mmol)和K2CO3(2.76g,20mmol)于DMF(15mL)中的悬浮液用苄基溴(0.96mL,16mmol)进行处理并继续搅拌3h。将反应物用EtOAc(75mL)稀释,用水(3x 50mL)、盐水(100mL)洗涤,并将有机相干燥(MgSO4),过滤和在减压下浓缩。得到的酯立即用于步骤ii中。
步骤ii:
将磁力搅拌下的苄基酯(1.27g,3.0mmol)于MeOH(10mL)中的溶液用NaOH(10mL 2M的水溶液)进行处理,并回流1h。将得到的反应物在减压下浓缩并用醚(50mL)洗涤。将水相酸化至pH 2(HCl,4M水溶液)并用CH2Cl2(2 x 25mL)萃取。将合并的经氯化的层用盐水(100mL)洗涤,干燥(MgSO4),过滤并在减压下浓缩,得到无色晶体3,5-双(苄氧基)苯甲酸(1g,定量)。该化合物的光谱数据在所有方面与先前Fuse S,Otake Y,Mifune Y,Tanaka H:通过单流阿尔登特-埃斯特尔特合成的α-芳基羧酸的简易制备(A Facile Preparation ofalpha-Aryl Carboxylic Acid via One-Flow Arndt-Eistert Synthesis)澳大利亚化学杂志(Aust J Chem)2015,68(11):1657-1661中报道的那些中的相同(其副本通过引用并入本文)。
实施例9:(3,5-双(苄氧基)苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,
4]二氮杂
-5(1H)-基)甲酮
根据前述的通用过程A,将二氮杂1(400mg,2mmol)用衍生自3,5-二苄氧基苯甲酸的酰氯(670mg,2mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的(3,5-双(苄氧基)苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂-5(1H)-基)甲酮(480mg,47%)(Rf=0.37,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(300MHz,DMSO-d6)δ8.63(br s,1H,NH),7.55-7.25(m,11H,Ar-H),7.22-7.06(m,2H,1/3-2xCH),6.82-6.60(m,2H,2/6-2xCH),6.51(t,J=2.3Hz,1H,18-CH),6.39(d,J=2.3Hz,2H,16-2xCH),5.64(d,J=14.6Hz,1H,8-CH2),4.91(q,J=12.0Hz,4H,19-2xCH2),3.91(d,J=14.5Hz,1H,8-CH2),3.77(s,3H,15-CH3).13C NMR(75MHz,DMSO-d6):δ167.6,158.6,139.7,139.0,138.1,136.7,135.6,132.4,130.1,128.4,128.3,127.9,127.6,121.4,119.4,106.4,103.0,100.1,69.3,43.0,35.4.IR(金刚石池,纯)νmax:3317,1642,1638,1543,1513,1387,1322,1251,1166,1119,1061,1020,992,848,753,731,677,628,496,428cm-1.LRMS(+ESI)m/z:517[(M+H)+,100%],1033[(2M+H)+,28%].HRMS(+ESI)实测值:(M+Na)+,539.2053.C32H28N4O3需求(M+Na)+,539.2054.MP 221-224℃.
实施例10:(3,5-二羟基苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二
氮杂
-5(1H)-基)甲酮[WJ0623]
将磁力搅拌下的来自实施例9的产物(270mg,0.5mmol)和Pd/C(27mg,10%w/w)于MeOH(10mL)中的悬浮液放置于氢气氛(1atm)中16h。将所得的混合物通过过滤并将由此留下的固体用MeOH(3×20mL)洗涤。将合并的滤液在减压下浓缩并通过快速柱色谱(二氧化硅,9∶1v/v CH2Cl2/MeOH)纯化并且浓缩相关馏分(Rf=0.11,于1∶9v/v MeOH/CH2Cl2溶液中),制得白色粉末状的WJ0623(116mg,69%)。
1H NMR(300MHz,DMSO-d6):δ9.26(br s,2H,2xOH),8.55(br s,1H,NH),7.27(d,J=8.1Hz,1H,3-CH),7.22-7.03(m,2H,2/12-2xCH),6.71-6.66(m,2H,1/6-2xCH),6.07(s,1H,17-CH),6.05-5.90(m,2H,16-2xCH),5.61(d,J=14.5Hz,1H,8-CH2),3.84(d,J=14.5Hz,1H,8-CH2),3.77(s,3H,15-CH3).13C NMR(75MHz,DMSO-d6):δ168.4,157.6,139.9,138.6,138.2,135.7,132.3,130.1,128.1,121.1,119.5,105.7,103.6,100.5,43.1,35.4.IR(金刚石池,纯)νmax:3293,1626,1567,1503,1446,1396,1295,1250,1169,1145,1004,940,833,803,754,723,696,570,497,447cm-1.LRMS(+ESI)m/z:337[(M+H)+,100%].HRMS(+ESI)实测值:(M+H)+,337.1296.C18H16N4O3需求(M+H)+,337.1295.MP>300℃.HPLC纯度:96.31%,RT:19.48min.
实施例11:(3,5-二甲氧基苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]
二氮杂
-5(1H)-基)甲酮[WJ0629]
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自3,5-二甲氧基苯甲酸的酰氯(273mg,1.5mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的WJ0629(247mg,68%)(Rf=0.32,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(300MHz,DMSO-d6):δ8.64(br s,1H,NH),7.28(d,J=8.1Hz,1H,3-CH),7.23-6.99(m,2H,2/12-2xCH),6.75-6.65(m,2H,1/17-2xCH),6.30-6.24(m,3H,16/6-3xCH),5.65(d,J=14.5Hz,1H,8-CH2),3.91(d,J=14.5Hz,1H,8-CH2),3.77(s,3H,15-CH3),3.59(s,6H,18-2xCH3).13C NMR(75MHz,DMSO-d6):δ167.8,159.6,139.9,139.1,138.1,135.7,132.6,130.1,128.3,121.4,119.5,105.4,101.4,100.2,55.1,43.1,35.4.IR(金刚石池,纯)νmax:3322,1594,1558,1505,1451,1426,1394,1290,1247,1206,1155,1052,986,928,834,765,722,696,630,540,494,441cm-1.LRMS(+ESI)m/z:365[(M+H)+,100%].HRMS(+ESI)实测值:(M+H)+,365.1609.C20H20N4O3需求(M+H)+,365.1608.MP 279-281℃(分解).HPLC纯度:96.37%,RT:18.99min.
实施例12:(3-甲氧基苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮
杂
-5(1H)-基)甲酮[WJ0657]
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自3-甲氧基苯甲酸的酰氯(228mg,1.5mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH)纯化,制得白色蓬松粉末状的WJ0657(112mg,33%)。(Rf=0.28,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):δ8.63(br s,1H,NH),7.28(dd,J=8.2,1.4Hz,1H,3-CH),7.18(s,1H,12-CH),7.15-7.03(m,2H,2/19-2xCH),6.78(dd,J=8.2,2.6Hz,1H,6-CH),6.77-6.71(m,2H,17/18-2xCH),6.71-6.67(m,1H,16-CH),6.64(td,J=7.5,1.4Hz,1H,1-CH),5.67(d,J=14.5Hz,1H,8-CH2),3.91(d,J=14.5Hz,1H,8-CH2),3.78(s,3H,15-CH3),3.60(s,3H,21-CH3).13C NMR(126MHz,DMSO-d6):δ167.9,158.3,139.8,139.0,137.6,135.6,132.4,130.3,128.8,128.3,121.3,119.6,119.5,115.2,112.6,100.3,54.9,43.1,35.4.IR(金刚石池,纯)νmax:3292,1621,1563,1504,1450,1391,1318,1294,1238,1173,1121,1049,984,877,833,800,757,731,694,648,567,498,447cm-1.LRMS(+ESI)m/z:357[(M+Na)+,100%],691[(2M+Na)+,44%].HRMS(+ESI)实测值:(M+Na)+,357.1319.C19H18N4O2需求(M+Na)+,357.1322.MP 267-269℃(分解).HPLC纯度:98.82%,RT:18.51min.
实施例13:(2-甲氧基苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮
杂
-5(1H)-基)甲酮[WJ0659]
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自2-甲氧基苯甲酸的酰氯(228mg,1.5mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH)纯化,制得白色粉末状的WJ0659(144mg,43%)。(Rf=0.22,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(400MHz,DMSO-d6):δ8.54(br s,1H,NH),7.26-7.08(m,4H,2/3/4/12-3xCH),6.99(t,J=8.0Hz,1H,1-CH),6.74(br s,3H,16/18/19-3xCH),6.60-6.38(m,1H,17-CH),5.57(d,J=14.4Hz,1H,8-CH2),3.88(d,J=14.4Hz,1H,8-CH2),3.77(s,3H,15-CH3),3.57(s,3H,21-CH3).13C NMR(101MHz,DMSO-d6):δ166.9,154.8,139.9,138.8,135.6,130.7,129.9,129.5,127.9,126.5,120.3,119.7,119.0,111.4,110.7,100.6,55.0,42.5,35.3.IR(金刚石池,纯)νmax:3287,1626,1561,1506,1495,1459,1400,1321,1247,1110,1022,828,754,739,733,642,600cm-1.LRMS(+ESI)m/z:357[(M+Na)+,100%],691[(2M+Na)+,24%].HRMS(+ESI)实测值:(M+Na)+,357.1318.C19H18N4O2需求(M+Na)+,357.1322.MP281-282℃(分解).HPLC纯度:98.53%,RT:17.68min.
实施例14:(4-甲氧基苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮
杂
-5(1H)-基)甲酮[WJ0661]
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自4-甲氧基苯甲酸的酰氯(228mg,1.5mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH)纯化,制得白色针状的WJ0661(212mg,63%)。(Rf=0.19,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):δ8.58(br s,1H,NH),7.29(dd,J=8.2,1.3Hz,1H,3-CH),7.23-7.00(m,4H,1/2/6/12-4xCH),6.85-6.53(m,4H,16/18-4xCH),5.68(d,J=14.6Hz,1H,8-CH2),3.88(d,J=14.6Hz,1H,8-CH2),3.76(s,3H,15-CH3),3.68(s,3H,21-CH3).13C NMR(126MHz,DMSO-d6):δ167.7,160.0,139.9,138.7,135.6,132.7,130.3,129.5,128.2,128.1,121.3,119.6,112.9,100.5,55.1,43.2,35.3.IR(金刚石池,纯)νmax:3285,1619,1561,1503,1444,1390,1299,1254,1178,1143,1117,1022,987,850,828,792,756,731,643,607,494,441cm-1.LRMS(+ESI)m/z:357[(M+Na)+,100%],691[(2M+Na)+,27%].HRMS(+ESI)实测值:(M+Na)+,357.1319.C19H18N4O2需求(M+Na)+,357.1322.MP296-298℃(分解).HPLC纯度:97.47%,RT:18.89min.
实施例15:(3-氟苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮[WJ0679]
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自3-氟苯甲酸的酰氯(210mg,1.5mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的WJ0679(221mg,69%)(Rf=0.25,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):8.64(br s,1H,NH),7.27(dd,J=8.2,1.4Hz,1H,3-CH),7.25-7.20(m,1H,20-CH),7.19(s,1H,12-CH),7.12(ddd,J=8.2,7.3,1.6Hz,1H,16-CH),7.07(td,J=8.4,2.3Hz,1H,2-CH),6.97(dt,J=7.7,1.2Hz,1H,17-CH),6.93(ddd,J=9.5,2.7,1.4Hz,1H,18-CH),6.79(dd,J=7.8,1.5Hz,1H,6-CH),6.65(td,J=7.6,1.4Hz,1H,1-CH),5.65(d,J=14.5Hz,1H,8-CH2),3.94(d,J=14.4Hz,1H,8-CH2),3.77(s,3H,15-CH3).13CNMR(126MHz,DMSO-d6):δ166.9,161.2(d,J=244.4Hz),139.8,139.0,138.7(d,J=7.4Hz),135.7,131.9,130.4,129.9(d,J=7.9Hz),128.5,123.3,121.3,119.6,116.3(d,J=20.7Hz),114.1(d,J=22.9Hz),100.1,43.2,35.4.19F NMR(471MHz,DMSO-d6):δ-113.2.IR(金刚石池,纯)νmax:3319,1624,1564,1504,1453,1404,1300,1246,1177,992,873,837,818,796,758,730,691,630,562,498,451,419cm-1.LRMS(+ESI)m/z:345[(M+Na)+,100%],667[(2M+Na)+,46%].HRMS(+ESI)实测值:(M+Na)+,345.1119.C18H14FN4O需求(M+Na)+,345.1122.MP 286-288℃(分解).HPLC纯度:98.21%,RT:18.94min.
实施例16:(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(间甲苯基)甲酮[WJ0823]
根据前述的通用过程A,将二氮杂1(100mg,0.5mmol)用衍生自3-甲基苯甲酸的酰氯(82mg,0.6mmol)进行处理,随后经由研磨(EtOAc)和柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得白色结晶固体状的WJ0823(87mg,55%)(Rf=0.22,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(400MHz,DMSO-d6):δ8.61(br s,1H,NH),7.34-7.21(m,1H,3-CH),7.17(s,1H,12-CH),7.10(t,J=7.6Hz,1H,2-CH),7.01-6.91(m,3H,16/18/19-3xCH),6.87(d,J=7.3Hz,1H,17-CH),6.70(d,J=7.3Hz,1H,6-CH),6.62(t,J=7.5Hz,1H,1-CH),5.67(d,J=14.5Hz,1H,8-CH2),3.90(d,J=14.5Hz,1H,8-CH2),3.77(s,3H,15-CH3),2.16(s,3H,21-CH3).13C NMR(101MHz,DMSO-d6):δ168.3,139.8,138.9,136.9,136.3,135.6,132.4,130.3,130.0,128.2,128.0,127.4,124.3,121.1,119.4,100.3,43.0,35.3,20.8.IR(金刚石池,纯)νmax:3325,1621,1561,1558,1506,1444,1408,1321,1247,1178,1131,985,951,862,845,801,808,756,649,607,492,441cm-1.LRMS(+ESI)m/z:341[(M+Na)+,100%]HRMS(+ESI)实测值:(M+H)+,319.1555.C19H18N4O需求(M+H)+,319.1553.MP 254-256℃.HPLC纯度:96.31%,RT:19.48min.
实施例17:(3,4-二甲苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮
杂
-5(1H)-基)甲酮[WJ05103]
根据前述的通用过程A,将二氮杂1(150mg,0.75mmol)用衍生自3,4-二甲基苯甲酸的酰氯(125mg,0.82mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的WJ05103(121mg,49%)(Rf=0.21,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):8.60(s,1H,NH),7.31-7.24(m,1H,3-CH),7.16(s,1H,12-CH),7.10(t,J=7.3Hz,1H,2-CH),7.03(s,1H,16-CH),6.86(d,J=7.8Hz,1H,6-CH),6.77(d,J=7.7Hz,1H,17-CH),6.69(d,J=7.7Hz,1H,18-CH),6.63(t,J=7.5Hz,1H,1-CH),5.67(d,J=14.5Hz,1H,8-CH2),3.88(d,J=14.5Hz,1H,8-CH2),3.77(s,3H,15-CH3),2.10(s,3H,20-CH3),2.07(s,3H,21-CH3).13C NMR(126MHz,DMSO-d6):δ168.2,139.9,138.9,137.9,135.6,135.6,133.7,132.7,130.3,128.9,128.5,128.1,124.9,121.3,119.5,100.4,43.1,35.4,19.2,19.2.IR(金刚石池,纯)νmax:3281,1618,1557,1499,1440,1413,1378,1314,1253,1172,990,834,811,768,754,727,696,629,610,563,489,445cm-1.LRMS(+ESI)m/z:333[(M+H)+,51%],665[(2M+H)+,100%].HRMS(+ESI)实测值:(M+Na)+,333.1707.C20H20N4O需求(M+H)+,333.1710.MP 254-256℃(分解).HPLC纯度:97.86%,RT:19.89min.
实施例18:(3,4-二氯苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮
杂
-5(1H)-基)甲酮[WJ0824]
根据前述的通用过程A,将二氮杂1(100mg,0.5mmol)用衍生自3,4-二氯苯甲酸的酰氯(100mg,0.52mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得黄色粉末状的WJ0824(139mg,75%)(Rf=0.20,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):8.67(s,1H,NH),7.45(d,J=8.4Hz,1H,18-CH),7.35(d,J=2.0Hz,1H,16-CH),7.30(dd,J=8.2,1.4Hz,1H,3-CH),7.19(s,1H,12-CH),7.15(td,J=8.3,7.8,1.6Hz,1H,2-CH),7.08(dd,J=8.3,2.0Hz,1H,17-CH),6.83(dd,J=7.9,1.5Hz,1H,6-CH),6.69(ddd,J=8.2,7.3,1.3Hz,1H,1-CH),5.64(d,J=14.5Hz,1H,8-CH2),3.95(d,J=14.4Hz,1H,8-CH2),3.77(s,3H,15-CH3).13C NMR(126MHz,DMSO-d6):δ165.9,139.7,139.0,136.9,135.7,132.0,131.5,130.6,130.4,130.0,129.3,128.7,127.4,121.3,119.6,100.0,43.3,35.4.IR(金刚石池,纯)νmax:3260,1637,1557,1504,1387,1367,1296,1242,1122,1031,999,835,751,719,612,552,526,435cm-1.LRMS(-ESI)m/z:371/373[(M-H),100/68%].HRMS(+ESI)实测值:(M+H)+,373.0620/375.0589.C18H14Cl2N4O需求(M+H)+,373.0617/375.0588.MP 263-264℃(分解).HPLC纯度:99.84%,RT:22.87min.
实施例19:((3r,5r,7r)-金刚烷-1-基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-
e][1,4]二氮杂
-5(1H)-基)甲酮[WJ0687]
根据前述的通用过程B,将二氮杂1(150mg,0.75mmo1)用衍生自金刚烷羧酸的酰氯(270mg,1.5mmol)进行处理,随后经由研磨(EtOAc)之后自MeOH中重结晶纯化,制得白色针状的WJ0687(201mg,78%)(Rf=0.28,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(400MHz,DMSO-d6):8.42(s,1H,NH),7.36-7.27(m,2H,3/2-2xCH),7.26-7.19(m,1H,6-CH),7.05(s,1H,12-CH),7.03-6.95(m,1H,1-CH),5.44(d,J=14.3Hz,1H,8-CH2),3.69(s,3H,15-CH3),3.60(d,J=14.3Hz,1H,8-CH2),1.83-1.66(m,6H,22-3xCH2),1.58-1.43(m,6H,17-3xCH2),1.52-1.37(m,3H,16-3xCH).13C NMR(101MHz,DMSO-d6):δ175.1,140.5,139.2,135.8,133.2,130.9,128.9,121.4,120.2,100.6,46.3,43.0,39.3,35.9,35.2,27.8.IR(金刚石池,纯)νmax:3276,2901,1614,1555,1499,1435,1376,1276,1248,1175,988,837,759,725,646,590,500,445cm-1.LRMS(+ESI)m/z:363[(M+H)+,11%],385[(M+Na)+,100%].HRMS(+ESI)实测值:(M+Na)+,385.1995.C22H26N4O需求(M+Na)+,385.1999.MP 283-285℃.HPLC纯度:99.47%,RT:21.90min.
实施例20:((1r,3s,5R,7S)-3-氟代金刚烷-1-基)(1-甲基-4,10-二氢苯并[b]吡
唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮[WJ0807F]
根据前述的通用过程A,将二氮杂1(150mg,0.75mmol)用衍生自3-氟代金刚烷羧酸的酰氯(149mg,0.75mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得白色晶状粉末状的WJ0807F(148mg,52%)(Rf=0.41,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):8.46(br s,1H,NH),7.40-7.29(m,2H,3/2-2xCH),7.28-7.21(m,1H,6-CH),7.06(s,1H,12-CH),7.02(ddd,J=7.7,6.3,2.4Hz,1H,1-CH),5.44(d,J=14.3Hz,1H,8-CH2),3.70(s,3H,15-CH3),3.64(d,J=14.3Hz,1H,8-CH2),2.05(d,J=12.3Hz,2H),1.80(dd,J=11.6,6.0Hz,1H),1.71(d,J=12.9Hz,1H),1.61(d,J=14.1Hz,3H),1.53(d,J=10.7Hz,2H),1.40(dd,J=28.7,12.8Hz,4H),1.23(d,J=12.6Hz,1H).13CNMR(126MHz,DMSO-d6):δ173.3,140.5,139.1,135.9,132.7,130.8,129.2,121.5,120.2,100.5,92.4(d,J=182.2Hz),47.2(d,J=9.7Hz),46.4,44.0(d,J=19.3Hz,2CH2),41.2(d,J=17.2Hz,2CH2),37.7,37.1,35.2,34.1,30.4(d,J=10.0Hz).19F NMR(471MHz,DMSO-d6):δ-113.2.IR(金刚石池,纯)νmax:3276,2912,1613,1593,1555,1450,1389,1278,1249,1156,1020,987,929,836,763,724,695,645,591,536,444cm-1.LRMS(+ESI)m/z:381[(M+H)+,100%],403[(M+Na)+,50%].HRMS(+ESI)实测值:(M+H)+,381.2086.C22H25FN4O需求(M+H)+,381.2085.MP 266-268℃(分解).HPLC纯度:95.38%,RT:20.52min.
实施例21:((1r,3R,5S,7r)-3,5-二氟代金刚烷-1-基)(1-甲基-4,10-二氢苯并
[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮[WJ0807diF]
根据前述的通用过程A,将二氮杂1(150mg,0.75mmol)用衍生自二氟代金刚烷羧酸的酰氯(162mg,0.75mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得白色针状的WJ0807diF(207mg,69%)(Rf=0.39,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):8.51(br s,1H,NH),7.41-7.31(m,2H,3/2-2xCH),7.29(dd,J=7.9,1.4Hz,1H,6-CH),7.07(s,1H,12-CH),7.04(ddd,J=7.8,6.6,2.1Hz,1H,1-CH),5.45(d,J=14.3Hz,1H,8-CH2),3.80-3.59(m,4H,15-CH3/8-CH2),2.00-1.71(m,5H),1.60(d,J=25.0Hz,4H),1.48(s,3H),1.33(d,J=13.1Hz,1H).13C NMR(126MHz,DMSO-d6):δ171.6,140.6,139.0,135.9,132.2,130.8,129.4,121.7,121.7,120.3,100.3,93.1(dd,J=186.1,13.8Hz),47.9(d,J=10.1Hz),46.6(t,J=9.4Hz),42.9(d,J=17.1Hz,2CH2),42.6-42.2(m,2CH2),36.9,36.1,35.3,29.9(t,J=10.7Hz).19F NMR(471MHz,DMSO-d6):-104.46(dd,J=1790.7,230.2Hz,2F).IR(金刚石池,纯)νmax:3301,2944,1735,1611,1554,1498,1444,1375,1328,1308,1277,1245,1175,1122,1042,1018,987,951,867,831,804,755,723,693,639,544,460,417cm-1.LRMS(+ESI)m/z:399[(M+H)+,20%],421[(M+Na)+,100%].HRMS(+ESI)实测值:(M+H)+,399.1991.C22H24F2N4O需求(M+H)+,399.1991.MP 262-264℃(分解).HPLC纯度:96.14%,RT:19.24min.
实施例22:(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(吡啶-2-基)甲酮[WJ0759]
根据前述的通用过程A,将二氮杂1(100mg,0.5mmol)用衍生自吡啶甲酸的酰氯(74mg,0.6mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH)纯化,制得棕色结晶固体WJ0759(90mg,59%)(Rf=0.58,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):δ8.58(br s,1H,NH),8.25(dt,J=4.8,1.4Hz,1H,16-CH),7.67(td,J=7.7,1.7Hz,1H,2-CH),7.33(dd,J=7.9,1.1Hz,1H,3-CH),7.25-7.15(m,3H,12/17/16-3xCH),7.04(ddd,J=8.4,7.3,1.6Hz,1H,18-CH),6.69(dd,J=7.9,1.6Hz,1H,6-CH),6.54(td,J=7.6,1.4Hz,1H,1-CH),5.65(d,J=14.4Hz,1H,8-CH2),3.95(d,J=14.4Hz,1H,8-CH2),3.76(s,3H,15-CH3).13C NMR(126MHz,DMSO-d6):δ166.8,154.4,148.2,139.8,138.7,136.3,135.6,131.3,130.1,127.9,123.8,122.4,120.4,119.4,100.0,42.9,35.3.IR(金刚石池,纯)νmax:3275,1620,1561,1504,1441,1397,1320,1244,1152,1050,989,848,826,811,752,741,691,658,631,614,595,488,446cm-1.LRMS(+ESI)m/z:328[(M+Na)+,100%],633[(2M+Na)+,60%].HRMS(+ESI)实测值:(M+H)+,306.1351.C17H15N5O需求(M+H)+,306.1349.MP269-271℃(分解).HPLC纯度:96.78%,RT:15.07min.
实施例23:(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(吡啶-3-基)甲酮[WJ0753]]
根据前述的通用过程A,将二氮杂1(200mg,1mmol)用衍生自尼克酸的酰氯(148mg,1.2mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH)纯化,制得白色粉末状的WJ0753(140mg,46%)。(Rf=0.60,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):δ8.65(br s,1H,NH),8.40(dd,J=4.9,1.7Hz,1H,17-CH),8.27(dd,J=2.3,0.9Hz,1H,6-CH),7.54(dt,J=7.9,1.9Hz,1H,19-CH),7.29(dd,J=8.2,1.4Hz,1H,3-CH),7.23(ddd,J=7.9,4.9,0.9Hz,1H,18-CH),7.19(s,1H,12-CH),7.13(ddd,J=8.3,7.2,1.6Hz,1H,2-CH),6.82(dd,J=7.9,1.6Hz,1H,6-CH),6.71-6.56(m,1H,1-CH),5.67(d,J=14.5Hz,1H,8-CH2),3.97(d,J=14.4Hz,1H,8-CH2),3.78(s,3H,15-CH3).13C NMR(126MHz,DMSO-d6):δ166.2,150.0,147.6,139.7,139.2,135.6,134.8,132.3,131.6,130.6,128.6,122.9,121.2,119.6,100.1,43.2,35.4.IR(金刚石池,纯)νmax:3315,1623,1563,1503,1449,1408,1300,1246,1148,1024,993,946,827,756,742,707,691,630,557,494,448cm-1.LRMS(+ESI)m/z:301[(M+H)+,60%],328[(M+Na)+,100%].HRMS(+ESI)实测值:(M+H)+,306.1350.C17H15N5O需求(M+H)+,306.1349.MP 247-249℃(分解).HPLC纯度:98.10%,RT:14.09min.
实施例24:(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(吡啶-4-基)甲酮[WJ0757]
根据前述的通用过程A,将二氮杂1(100mg,0.5mmol)用衍生自异烟酸的酰氯(74mg,0.6mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH)纯化,制得黄色结晶固体WJ0757(80mg,52%)。(Rf=0.51,于1∶9∶90v/v/v 28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):δ8.65(br s,1H,NH),8.46-8.33(m,2H,17-2xCH),7.27(dd,J=8.2,1.4Hz,1H,3-CH),7.20(s,1H,12-CH),7.12(ddd,J=8.4,7.4,1.6Hz,1H,2-CH),7.10-7.06(m,2H,16-2xCH),6.83(dd,J=7.9,1.5Hz,1H,6-CH),6.64(td,J=7.6,1.4Hz,1H,6-CH),5.63(d,J=14.5Hz,1H,8-CH2),3.97(d,J=14.4Hz,1H,8-CH2),3.78(s,3H,15-CH3).13C NMR(126MHz,DMSO-d6):δ166.4,149.3,144.0,139.6,139.1,135.7,131.0,130.5,128.8,121.1,121.1,119.5,100.0,43.1,35.4.IR(金刚石池,纯)νmax:3328,1626,1561,1503,1450,1408,1299,1244,1146,989,948,826,758,741,685,648,633,602,544,494,449cm-1.LRMS(+ESI)m/z:328[(M+Na)+,100%],633[(2M+Na)+,60%].HRMS(+ESI)实测值:(M+H)+,306.1350.C17H15N5O需求(M+H)+,306.1349.MP 267-269℃(分解).HPLC纯度:99.00%,RT:13.40min.
实施例25:(2-溴苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮[WJ0822]
根据前述的通用过程A,将二氮杂1(90mg,0.45mmol)用衍生自2-溴苯甲酸的酰氯(90mg,0.45mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH)纯化,制得白色结晶固体WJ0822(97mg,56%)。(Rf=0.59于EtOAc中)。
1H NMR(400MHz,DMSO-d6):δ8.59(br s,1H,NH),7.50-7.44(m,2H,16/17-CH),7.23-7.17(m,2H,12/3-2xCH),7.18-7.10(m,2H,18/19-2xCH),7.05(ddd,J=8.4,7.3,1.6Hz,1H,2-CH),6.94(dd,J=7.9,1.5Hz,1H,6-CH),6.65-6.57(m,1H,1-CH),5.57(d,J=14.4Hz,1H,8-CH2),3.98(d,J=14.4Hz,1H,8-CH2),3.76(s,3H,15-CH3).13C NMR(101MHz,DMSO-d6):δ166.6,140.0,139.6,138.9,138.3,135.7,132.3,130.1,128.6,127.8,126.9,120.7,120.1,119.5,119.1,100.2,42.9,35.4.IR(金刚石池,纯)νmax:3307,1625,1557,1502,1390,1302,1145,1049,1028,982,826,784,756,739,689,633,597,492,445cm-1.LRMS(-ESI)m/z:381/383[(M-H)-,90/100%].HRMS(+ESI)实测值:(M+H)+,383.0502/385.0481.C18H15BrN4O需求(M+H)+,383.0502/385.0482.MP 244-246℃.HPLC纯度:97.02%,RT:19.23min.
实施例26:(3-溴苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮[WJ0821]
根据前述的通用过程A,将二氮杂1(90mg,0.45mmol)用衍生自3-溴苯甲酸的酰氯(90mg,0.45mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH)纯化,制得白色粉末状的WJ0821(100mg,58%)。(Rf=0.64于EtOAc中)。
1H NMR(400MHz,DMSO-d6):δ8.66(br s,1H,NH),7.43(dt,J=6.7,2.3Hz,1H,16-CH),7.36-7.25(m,2H,18/19-2xCH),7.18(s,1H,12-CH),7.17-7.06(m,3H,2/3/17-3xCH),6.79(dd,J=7.9,1.6Hz,1H,6-CH),6.70-6.63(m,1H,1-CH),5.65(d,J=14.6Hz,1H,8-CH2),3.94(d,J=14.5Hz,1H,8-CH2),3.77(s,3H,15-CH3).13C NMR(101MHz,DMSO-d6):δ166.6,139.7,139.0,138.6,135.7,132.2,131.7,130.4,129.9,129.9,128.5,126.1,121.3,120.9,119.5,100.1,43.2,35.4.IR(金刚石池,纯)νmax:3317,1623,1562,1504,1450,1403,1297,1247,1144,990,829,796,761,716,696,631,555,496,448cm-1.LRMS(-ESI)m/z:381/383[(M-H)-,98/100%].HRMS(+ESI)实测值:(M+H)+,383.0502/385.0482.C18H15BrN4O需求(M+H)+,383.0502/385.0482.MP218-220℃.HPLC纯度:96.58%,RT:21.25min.
实施例27:(4-溴苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮[WJ0820]
根据前述的通用过程A,将二氮杂1(90mg,0.45mmol)用衍生自4-溴苯甲酸的酰氯(90mg,0.45mmol)进行处理,随后经由研磨(EtOAc)和重结晶(MeOH)纯化,制得白色粉末状的WJ0820(119mg,69%)。(Rf=0.75于EtOAc中)。
1H NMR(400MHz,DMSO-d6):δ8.62(s,1H,NH),7.42-7.33(m,2H,16-2xCH),7.28(dd,J=8.1,1.4Hz,1H,3-CH),7.18(s,1H,12-CH),7.16-7.10(m,1H,2-CH),7.10-7.02(m,2H,17-2xCH),6.75(dd,J=7.8,1.6Hz,1H,6-CH),6.65(td,J=7.5,1.4Hz,1H,1-CH),5.66(d,J=14.5Hz,1H,8-CH2),3.92(d,J=14.5Hz,1H,8-CH2),3.77(s,3H,15-CH3).13C NMR(101MHz,DMSO-d6):δ167.3,139.7,138.9,135.6,135.6,131.8,130.7,130.4,129.3,128.4,122.8,121.2,119.6,100.2,43.2,35.4.IR(金刚石池,纯)νmax:3322,1624,1558,1504,1453,1403,1297,1246,1136,1069,1012,989,828,763,750,695,629,594,548,495,449,423cm-1.LRMS(-ESI)m/z:381/383[(M-H)-,94/100%].HRMS(+ESI)实测值:(M+H)+,383.0505/385.0482.C18H15BrN4O需求(M+H)+,383.0502/385.0482.MP 249-251℃.HPLC纯度:96.11%,RT:20.26min.
实施例28:1-甲基-5-((4-甲基-2-硝基苯基)氨基)-1H-吡唑-4-甲醛(3)
将磁力搅拌下的5-氯-1-甲基-1H-吡唑-4-甲醛(250mg,1.7mmol)和2-硝基-4-甲基苯胺(789g,5.2mmol)于DMF(20mL)中的溶液用粉末状的KOH(194mg,3.5mmol)进行处理,之后在100℃下加热18h。将所得的混合物冷却并用NH4Cl(250mL饱和水溶液)稀释并用EtOAc(3×100mL)萃取。在干燥(MgSO4)之前将合并的有机相用盐水(100mL)洗涤,过滤并在减压下浓缩,从而得到橙色晶状固体。使用特利丹(Teledyne)ISCORf+系统使该残余物经中压液相色谱(MPLC)(二氧化硅,80%己烷/EtOAc 40分钟,随后50%己烷/EtOAc梯度洗脱)并浓缩相关馏分(Rf=0.41,于1∶1v/v EtOAc/己烷溶液中),得到橙色结晶固体1-甲基-5-((4-甲基-2-硝基苯基)氨基)-1H-吡唑-4-甲醛(290mg,66%)。该化合物的光谱数据在所有方面与那些先前报道的相同。
1H NMR(300MHz,氯仿-d):δ9.62(s,1H,10-CH),9.18(s,1H,NH),7.98(d,J=1.4Hz,1H,3-CH),7.91(s,1H,13-CH)7.22(dd,J=8.6,1.3Hz,1H,1-CH),6.47(d,J=8.6Hz,1H,6-CH),3.65(s,3H,14-CH3),2.28(s,3H,15-CH3).13C NMR(75MHz,氯仿-d):δ193.3,141.0,140.6,138.0,137.2,134.7,130.4,126.2,116.4,116.0,35.8,20.2.
实施例29:1,7-二甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
(4)
将1-甲基-5-((4-甲基-2-硝基苯基)氨基)-1H-吡唑-4-甲醛(260mg,1.0mmol)和Pd/C(20mg,10%w/w)于MeOH(100mL)中的悬浮液在室温下在氢氛围(1atm)中磁力搅拌16h。将所得的混合物通过过滤并将由此留下的固体用甲醇(3×20mL)洗涤。将合并的滤液在减压下浓缩并自CH2Cl2/MeOH中重结晶,从而得到黄色针状的,7-二甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-e][1,4]二氮杂(200mg,93%),其立即用于后续步骤中。
实施例30:(1,7-二甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5
(1H)-基)(苯基)甲酮[WJ07117Me]
根据前述的通用过程A,将1,7-二甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-e][1,4]二氮杂(200mg,0.93mmol)用苯甲酰氯(174μL,1.5mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得灰白色粉末状的WJ07117Me(177mg,60%)(Rf=0.21,于1∶9∶90v/v/v28%氨水/MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):8.48(s,1H,NH),7.32-7.20(m,1H,6-CH),7.20-7.10(m,6H,16/17/18/12-6xCH),6.97-6.86(m,1H,1-CH),6.54(d,J=1.7Hz,1H,3-CH),5.66(d,J=14.5Hz,1H,8-CH2),3.89(d,J=14.5Hz,1H,8-CH2),3.75(s,3H,14-CH3),1.94(s,3H,15-CH3).13C NMR(126MHz,DMSO-d6):δ168.2,140.0,136.5,135.6,132.2,130.5,130.1,129.3,128.7,127.7,127.6,127.2,119.4,99.9,43.1,35.3,19.6.IR(金刚石池,纯)νmax:3267,1613,1553,1510,1401,1314,1247,1138,986,823,796,759,724,703,652,569,488,462,432cm-1.LRMS(+ESI)m/z:341[(M+Na)+,100%].HRMS(+ESI)实测值:(M+H)+,319.1554.C19H18N4O需求(M+H)+,319.1553.MP 235-238℃.HPLC纯度:96.44%,RT:18.85min.
实施例31:5-((4-甲氧基-2-硝基苯基)氨基)-1-甲基-1H-吡唑-4-甲醛(5)
将磁力搅拌下的5-氯-1-甲基-1H-吡唑-4-甲醛(250mg,1.7mmol)和2-硝基-4-甲氧基苯胺(872g,5.2mmol)于DMF(20mL)中的溶液用粉末状的KOH(194mg,3.5mmol)进行处理,之后在100℃下加热18h。将所得的混合物冷却并用NH4Cl(250mL饱和水溶液)稀释并用EtOAc(3×100mL)萃取。在干燥(MgSO4)之前将合并的有机相用盐水(100mL)洗涤,过滤并在减压下浓缩,从而得到橙色晶状固体。使用特利丹ISCORf+系统使该残余物经中压液相色谱(MPLC)(二氧化硅,80%己烷/EtOAc 40分钟,随后50%己烷/EtOAc梯度洗脱)并浓缩相关馏分(Rf=0.22,于1∶1v/v EtOAc/己烷溶液中),得到棕色结晶固体标题吡唑(5)(274mg,58%)。该化合物的光谱数据在所有方面与那些先前报道的相同。
1H NMR(300MHz,氯仿-d):δ9.72(s,1H,10-CH),9.13(s,1H,NH),7.94(s,1H,13-CH),7.66(d,J=2.4Hz,1H,3-CH)7.11(dd,J=9.2,2.3Hz,1H,1-CH),6.57(d,J=9.2Hz,1H,6-CH),3.82(s,3H,14-CH3),3.68(s,3H,15-CH3).13C NMR(75MHz,氯仿-d):δ193.3,153.0,141.0,140.9,135.2,134.2,125.1,118.2,115.4,108.0,55.8,35.9.
实施例32:7-甲氧基-1-甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
将5-((4-甲氧基-2-硝基苯基)氨基)-1-甲基-1H-吡唑-4-甲醛(276mg,1.0mmol)和Pd/C(30mg,10%w/w)于MeOH(100mL)中的悬浮液在室温下在氢氛围(1atm)中磁力搅拌16h。将所得的混合物通过过滤并将由此留下的固体用甲醇(3×20mL)洗涤。将合并的滤液在减压下浓缩并自CH2Cl2/MeOH中重结晶,得到粉色结晶固体7-甲氧基-1-甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-e][1,4]二氮杂(200mg,87%),其立即用于后续步骤中。
实施例33:(7-甲氧基-1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-
5(1H)-基)(苯基)甲酮[WJ07117MeO]
根据前述的通用过程A,将7-甲氧基-1-甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-e][1,4]二氮杂(200mg,0.87mmol)用苯甲酰氯(174μL,1.5mmol)进行处理,随后经由快速柱色谱(二氧化硅,0.25∶2.25∶97.5至0.5∶4.5∶95v/v/v 28%氨水/MeOH/CH2Cl2梯度洗脱)纯化,制得WJ07117MeO(221mg,76%)
1H NMR(400MHz,DMSO-d6):8.37(br s,1H,NH),7.28-7.24(m,1H,6-CH),灰白色粉末(Rf=0.24,于1∶9∶90v/v/v28%氨水/MeOH/CH2Cl2溶液中).7.20-7.17(m,5H,17/18/19-5xCH),7.16(s,1H,12-CH),6.72(dd,J=8.9,2.9Hz,1H,1-CH),6.37(d,J=2.9Hz,1H,3-CH),5.67(d,J=14.5Hz,1H,8-CH2),3.92(d,J=14.5Hz,1H,8-CH2),3.75(s,3H,15-CH3),3.43(s,3H,16-CH3).13C NMR(101MHz,DMSO-d6):δ168.3,153.6,140.2,136.5,135.6,133.3,132.5,129.4,127.6,127.1,120.5,115.1,114.6,99.5,55.2,42.9,35.2.IR(金刚石池,纯)νmax:3329,1614,1566,1509,1450,1402,1289,1208,1173,1139,1030,986,835,810,759,726,696,652,566,475cm-1.LRMS(+ESI)m/z:357[(M+Na)+,100%].HRMS(+ESI)实测值:(M+H)+,335.1504.C19H18N4O2需求(M+H)+,335.1503.MP 248-250℃.HPLC纯度:98.29%,RT:17.69min.
实施例34:(4-(苄氧基)苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二
氮杂
-5(1H)-基)甲酮(BzE)
根据前述的通用过程A,将二氮杂1(1.9g,9.5mmol)用衍生自环己烷羧酸的酰氯(2.6g,11.4mmol)进行处理,随后通过快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B041(3.5g,90%)(Rf=0.72于EtOAc中)。
1H NMR(300MHz,DMSO-d6):δ8.57(s,1H),7.47-7.24(m,6H),7.20-6.98(m,4H),6.78(d,J=8.3Hz,2H),6.68(d,J=9.4Hz,2H),5.68(d,J=14.6Hz,1H),5.02(s,2H),3.88(d,J=14.6Hz,1H),3.76(s,3H).13C NMR(75MHz,DMSO-d6):δ167.63,159.10,139.83,138.70,136.55,135.52,132.69,130.29,129.44,128.45,128.34,128.05,127.87,127.80,121.23,119.57,113.70,100.41,69.21,43.15,35.28.IR(金刚石池,纯)νmax:3323,2939,2878,1620,1561,1504,1451,1397,1297,1225,1170,1038,832,764,728,695,629cm-1.LRMS(+ESI)m/z:433[(M+Na)+,100%],m/z:411[(M+H)+,20%].MP:207-209℃.HPLC纯度:99.24%,RT:22.82min.
实施例35:(4-羟基苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮(TAR-B049)
将磁力搅拌下的来自TAR-B048的产物(1.0g,2.44mmol)和Pd/C(270mg,10%w/w)于MeOH/THF(100mL,1∶1v/v)中的悬浮液放置于氢气氛(1atm)中16h。将所得的混合物通过过滤并将由此留下的固体用MeOH(3×50mL)洗涤。将合并的滤液在减压下浓缩并通过快速柱色谱(二氧化硅,9∶1v/v CH2Cl2/MeOH)纯化并且浓缩相关馏分(Rf=0.42EtOAc),制得白色粉末状的TAR-B049(773mg,99%)。
1H NMR(300MHz,DMSO-d6):δ9.85(s,1H),8.59(s,1H),7.30(d,J=8.2Hz,1H),7.12(d,J=6.4Hz,2H),6.99(d,J=8.2Hz,2H),6.66(d,J=4.6Hz,2H),6.51(d,J=8.2Hz,2H),5.66(d,J=14.8Hz,1H),3.86(d,J=14.9Hz,1H),3.76(s,3H).13C NMR(75MHz,DMSO-d6):δ168.03,158.65,139.93,138.69,135.53,132.97,130.30,129.63,127.91,126.46,121.19,119.58,114.29,100.51,35.34,25.48.IR(金刚石池,纯)νmax:3305,2953,1621,1563,1503,1449,1395,1243,1142,1005,825,754,731cm-1.LRMS(+ESI)m/z:343[(M+Na)+,100%],m/z:321[(M+H)+,27%].MP:>300℃.
实施例36:环己基(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5
(1H)-基)甲酮(CA6)
根据前述的通用过程C,将二氮杂1二盐酸盐(150mg,0.75mmol)用衍生自环己烷羧酸的酰氯(115mg,0.61mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B041(214mg,92%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.37(s,1H),7.38-7.28(m,2H),7.21(d,J=7.9Hz,1H),7.07(s,1H),7.00(ddd,J=8.2,5.7,2.9Hz,1H),5.39(d,J=14.4Hz,1H),3.73(s,1H),3.68(s,4H),2.18-2.03(m,1H),1.66(t,J=16.1Hz,2H),1.58-1.43(m,1H),1.41-1.22(m,2H),1.16-0.85(m,3H),0.73(q,J=12.8Hz,1H).13C NMR(75MHz,DMSO-d6):δ173.88,139.72,139.25,135.62,131.55,129.81,128.68,121.57,120.13,100.44,54.82,42.60,40.45,35.13,29.05,28.65,25.20,24.92.IR(金刚石池,纯)νmax:3297,1650,1555,1501,1409,1355,1287,1245,1170,1118,989,832,762,696cm-1.LRMS(+ESI)m/z:369[(M+Na)+,100%].MP:238-240℃.HPLC纯度:95.78%,RT:20.47min.
实施例37:环戊基(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5
(1H)-基)甲酮(CA5)
根据前述的通用过程C,将二氮杂1二盐酸盐(140mg,0.51mmol)用衍生自环戊烷羧酸的酰氯(70mg,0.61mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B091(139mg,92%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,氯仿-d):δ7.37-7.30(m,1H),7.25(d,J=6.3Hz,2H),7.10(t,J=7.5Hz,2H),6.34(s,1H),5.72(d,J=14.5Hz,1H),3.90(d,J=14.5Hz,1H),3.79(s,3H),2.65(p,J=7.9Hz,1H),2.07-1.89(m,2H),1.86-1.54(m,4H),1.52-1.23(m,2H).13C NMR(75MHz,氯仿-d):δ176.09,139.44,139.07,136.56,132.35,130.60,129.05,122.66,119.81,101.76,43.24,42.06,34.85,30.80,26.37,26.32.IR(金刚石池,纯)νmax:3279,2939,2865,1627,1557,1503,1395,1300,1249,1173,988,830,757,641cm-1.LRMS(+ESI)m/z:319[(M+Na)+,100%],m/z:297[(M+H)+,8%].MP:>300℃.HPLC纯度:99.11%,RT:18.69min.
实施例38:环丙基(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5
(1H)-基)甲酮(CA3)
根据前述的通用过程C,将二氮杂1二盐酸盐(286mg,1.05mmol)用衍生自环丙烷羧酸的酰氯(108mg,1.25mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B093(239mg,85%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,氯仿-d):7.34-7.22(m,2H),7.19(s,1H),7.10-6.91(m,2H),5.97(s,1H),5.69(d,J=14.6Hz,1H),3.86(d,J=14.6Hz,1H),3.73(s,3H),1.32(ddd,J=9.3,6.3,4.0Hz,1H),1.13-0.89(m,2H),0.72-0.62(m,1H),0.61-0.45(m,1H).13C NMR(75MHz,氯仿-d):δ172.95,139.21,139.01,136.41,131.95,130.95,128.96,122.47,119.82,101.72,43.09,34.82,12.50,8.92,8.53cm-1.LRMS(+ESI)m/z:291[(M+Na)+,100%].MP:207-209℃.HPLC纯度:95.25%,RT:16.47min.
实施例39:(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(4-甲基环己基)甲酮(TAR-C41)
根据前述的通用过程C,将二氮杂1二盐酸盐(240mg,0.88mmol)用衍生自4-甲基环己烷-1-羧酸的酰氯(125mg,0.88mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-C041(263mg,92%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,氯仿-d):δ7.29(d,J=6.0Hz,2H),7.19(d,J=7.6Hz,1H),7.14-7.03(m,2H),6.34(s,1H),5.65(d,J=14.6Hz,1H),3.84(d,J=14.6Hz,1H),3.79(s,3H),2.37-2.23(m,1H),1.96-1.76(m,1H),1.66(m,1H),1.62-1.43(m,3H),1.42-1.26(m,2H),1.19(ddd,J=14.0,9.3,4.9Hz,2H),0.92(d,J=7.0Hz,3H).13C NMR(75MHz,氯仿-d):δ175.86,139.30,139.26,136.42,132.16,130.14,129.05,122.57,120.06,101.79,43.10,40.16,34.89,30.96,30.73,27.87,24.74,24.51,18.60.IR(金刚石池,纯)νmax:3280,2922,1634,1556,1500,1449,1406,1306,1246,1173,988,838,759,692cm-1.LRMS(+ESI)m/z:347[(M+Na)+,100%].MP:234-239℃.HPLC纯度:97.42%,RT:21.87min.
实施例40:(4-(己氧基)苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二
氮杂
-5(1H)-基)甲酮(TAR-B085)
根据前述的通用过程C,将二氮杂1二盐酸盐(132mg,0.49mmol)用衍生自4-(己氧基)苯甲酸的酰氯(108mg,0.49mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B085(168mg,85%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.57(s,1H),7.29(d,J=8.1Hz,1H),7.11(dd,J=15.2,8.3Hz,4H),6.68(d,J=7.5Hz,4H),5.76-5.58(m,1H),3.98-3.82(m,3H),3.76(s,3H),1.62(q,J=6.8Hz,2H),1.45-1.21(m,6H),0.96-0.73(m,3H).13C NMR(75MHz,DMSO-d6):δ167.71,159.46,139.85,138.68,135.54,132.71,130.31,129.47,128.04,121.20,119.56,113.33,100.45,73.51,67.42,43.14,35.31,30.94,28.50,25.09,22.01,13.87.IR(金刚石池,纯)νmax3275,2937,2856,1609,1557,1502,1450,1395,1299,1252,1173,1145,1069,1044,988,830,755,731,641cm-1.LRMS(+ESI)m/z:427[(M+Na)+,100%].MP:204-206℃.HPLC纯度:98.23%,RT:25.95min.
实施例41:4-(1-甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5-
羰基)苯甲酸(TAR-C076)
根据前述的通用过程A,将二氮杂1(2.0g,10.0mmol)用衍生自4-(甲氧基羰基)苯甲酸的酰氯(1.98g,11.0mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-C076(3.08g,85%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.65(s,1H),7.73(d,J=8.0Hz,2H),7.27(d,J=7.9Hz,3H),7.20(s,1H),7.10(t,J=7.6Hz,1H),6.76(d,J=7.8Hz,1H),6.60(t,J=7.5Hz,1H),5.67(d,J=14.6Hz,1H),3.96(d,J=14.6Hz,1H),3.89(s,3H),3.80(s,3H).LRMS(-ESI)m/z:385[(M+Na)+,100%].MP:>300℃.纯度:95.80%,RT:19.07min.
实施例42:4-(1-甲基-1,4,5,10-四氢苯并[b]吡唑[3,4-e][1,4]二氮杂
-5-羰
基)苯甲酸(TAR-C077)
将MeOH/H2O(55mL,1∶1v/v)中的来自TAR-B048的产物(2.0g,5.50mmol)和LiOH.H2O(461mg,11.0mmol)磁力搅拌16h。将所得的混合物浓缩至一半体积并用CH2Cl2洗涤。将水层用2M HCl酸化至pH 4。过滤收集沉淀,制得白色粉末状的TAR-C077(1.32g,69%)。(Rf=0.05,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.90(s,1H),7.63(d,J=7.9Hz,2H),7.41(dd,J=8.2,1.4Hz,1H),7.16(s,1H),7.06(dd,J=8.5,6.7Hz,3H),6.69-6.64(m,1H),6.58(t,J=7.5Hz,1H),5.67(d,J=14.5Hz,1H),3.90(d,J=14.5Hz,1H),3.81(s,3H),未观察到COOH信号.13C NMR(75MHz,DMSO-d6):δ168.84,168.45,140.94,139.97,138.98,136.60,135.61,132.26,130.31,128.19,128.04,126.27,120.96,119.60,100.33,43.05,35.59.IR(金刚石池,纯)νmax:3310,1608,1579,1555,1503,1386,1294,1255,858,742cm-1.LRMS(-ESI)m/z:347[(M-H)-,100%].MP:>300℃.HPLC纯度:98.74%,RT:16.55min.
实施例43:(2-氟苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮(TAR-B075)
根据前述的通用过程C,将二氮杂1二盐酸盐(244mg,0.90mmol)用衍生自2-氟苯甲酸的酰氯(126mg,0.90mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B075(264mg,91%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.61(s,1H),7.31-6.94(m,7H),6.80(dd,J=7.9,1.5Hz,1H),6.59(td,J=7.5,1.4Hz,1H),5.61(d,J=14.5Hz,1H),3.96(d,J=14.5Hz,1H),3.76(s,3H).13C NMR(75MHz,DMSO-d6):δ164.46,157.62(d,J=246.4Hz),139.70,139.04,135.65,130.94(d,J=8.1Hz),130.47,129.75,128.45,128.20(d,J=3.7Hz),125.11(d,J=17.5Hz),123.91(d,J=3.4Hz),120.53,119.49,115.24(d,J=21.1Hz),100.08,42.87,35.35.19F NMR(282MHz,DMSO-d6)δ-115.23(dt,J=11.4,6.3Hz).IR(金刚石池,纯)νmax:3295,1627,1560,1504,1397,1318,1223,989,830,785,756,732,640cm-1.LRMS(+ESI)m/z:345[(M+Na)+,100%].MP:287-290℃.HPLC纯度:99.37%,RT:18.71min.
实施例44:(4-氟苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮(TAR-B076)
根据前述的通用过程C,将二氮杂1二盐酸盐(244mg,0.90mmol)用衍生自4-氟苯甲酸的酰氯(126mg,0.90mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B076(264mg,91%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):8.67(s,1H),7.31(d,J=8.1Hz,1H),7.19(m,3H),7.12(t,J=7.7Hz,1H),7.00(t,J=8.7Hz,2H),6.73(d,J=7.8Hz,1H),6.64(t,J=7.5Hz,1H),5.67(d,J=14.5Hz,1H),3.92(d,J=14.5Hz,1H),3.78(s,3H).13C NMR(75MHz,DMSO-d6):δ168.27,162.26(d,J=247.4Hz),139.88,138.81,135.52,132.80,132.12,130.40,129.80(d,J=8.6Hz),128.32,121.20,119.60,114.67(d,J=21.8Hz),100.39,43.15,35.37.19FNMR(282MHz,DMSO-d6)δ-110.97(td,J=8.8,4.5Hz).IR(金刚石池,纯)νmax:3281,1624,1558,1503,1390,1318,1233,1164,1140,990,854,828,755,730cm-1.LRMS(+ESI)m/z:345[(M+Na)+,100%].MP:290-293℃.HPLC纯度:99.51%,RT:19.14min.
实施例45:(2-氟-5-(三氟甲基)苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e]
[1,4]二氮杂
-5(1H)-基)甲酮(TAR-B077)
根据前述的通用过程C,将二氮杂1二盐酸盐(235mg,0.86mmol)用衍生自2-氟-5-(三氟甲基)苯甲酸的酰氯(180mg,0.86mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B077(295mg,81%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(500MHz,DMSO-d6):8.66(s,1H),7.72-7.57(m,2H),7.29(t,J=8.9Hz,1H),7.25(dd,J=8.2,1.4Hz,1H),7.21(s,1H),7.10(ddd,J=8.2,7.2,1.5Hz,1H),6.90(d,J=1.5Hz,1H),6.62(td,J=7.6,1.4Hz,1H),5.63(d,J=14.4Hz,1H),4.02(d,J=14.5Hz,1H),3.77(s,3H).13C NMR(125MHz,DMSO-d6):δ162.94,159.56(d,J=253.3Hz),129.91,129.79,128.79,128.43(m),126.17(m),126.59,126.00(d,J=19.1Hz),124.98(dq,J=32.6,3.2Hz),124.43,122.26,120.57,120.10,119.45,116.73(d,J=22.9Hz),99.89,43.02,35.39.19F NMR(282MHz,DMSO-d6)δ-60.75(s,3H),-109.21(m,1H).IR(金刚石池,纯)νmax:3324,1627,1566,1504,1437,1396,1324,1298,1267,1174,1146,1116,1071,988,902,825,781,755,664cm-1.LRMS(+ESI)m/z:413[(M+Na)+,100%],391[(M+H)+,10%].MP:257-259℃.HPLC纯度:99.91%,RT:21.65min.
实施例46:(2-氟吡啶-3-基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二
氮杂
-5(1H)-基)甲酮(TAR-B078)
根据前述的通用过程C,将二氮杂1二盐酸盐(362mg,1.33mmol)用衍生自2-氟烟酸的酰氯(188mg,1.33mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B078(348mg,81%)(Rf=0.30,于1∶9v/vMeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):8.60(s,1H),8.14-7.97(m,1H),7.78(ddd,J=9.3,7.3,2.0Hz,1H),7.28-7.17(m,3H),7.15-7.01(m,1H),6.86(dd,J=7.9,1.5Hz,1H),6.62(td,J=7.6,1.4Hz,1H),5.61(d,J=14.5Hz,1H),4.00(d,J=14.5Hz,1H),3.76(s,3H).13C NMR(75MHz,DMSO-d6):δ163.12,157.67(d,J=236.4Hz),148.05(d,J=14.5Hz),139.75(d,J=3.6Hz),139.62,139.20,135.64,129.88,128.74,121.54(d,J=4.3Hz),120.57,120.15,119.65(d,J=33.6Hz),119.63,119.63,99.90,43.02,35.30.19F NMR(282MHz,DMSO-d6)δ-69.04(d,J=9.0Hz).IR(金刚石池,纯)νmax:3328,1630,1567,1504,1433,1412,1301,1245,815,772,751,620cm-1.LRMS(+ESI)m/z:446[(M+Na)+,100%],324[(M+H)+,10%].MP:268-271℃.HPLC纯度:99.58%,RT:16.73min.
实施例47:(2-氟-5-甲氧基苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,
4]二氮杂
-5(1H)-基)甲酮(TAR-B080)
根据前述的通用过程C,将二氮杂1二盐酸盐(160mg,0.59mmol)用衍生自2-氟-5-甲氧基苯甲酸的酰氯(100mg,0.59mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B080(208mg,92%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):8.59(s,1H),7.22(dd,J=8.2,1.4Hz,1H),7.18(s,1H),7.08(ddd,J=8.2,7.2,1.6Hz,1H),6.93(t,J=9.0Hz,1H),6.84(dd,J=7.9,1.5Hz,1H),6.77(ddd,J=9.1,4.2,3.2Hz,1H),6.69-6.59(m,2H),5.60(d,J=14.5Hz,1H),3.96(d,J=14.5Hz,1H),3.75(s,3H),3.62(s,3H).13C NMR(75MHz,DMSO-d6):δ164.15,154.65,152.00(d,J=239.2Hz),139.44(d,J=39.2Hz),135.66,130.66,129.73,128.55,125.39(d,J=19.4Hz),120.71,119.46,116.16(d,J=6.5Hz),115.95(d,J=8.6Hz),112.55,99.99,55.51,42.85,35.35.19F NMR(282MHz,DMSO-d6)δ-126.31(m).IR(金刚石池,纯)νmax:3305,1632,1561,1501,1446,1420,1392,1317,1277,1251,1208,1102,1037,985,870,825,781,752,728,698,628cm-1.LRMS(+ESI)m/z:375[(M+Na)+,100%].MP:250-253℃.HPLC纯度:99.62%,RT:19.29min.
实施例48:(2-(2-氟乙氧基)苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,
4]二氮杂
-5(1H)-基)甲酮(TAR-B086)
根据前述的通用过程C,将二氮杂1二盐酸盐(272mg,1.0mmol)用衍生自2-(2-氟乙氧基)苯甲酸的酰氯(184mg,1.0mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B086(341mg,93%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):8.61(s,1H),7.27(dd,J=8.1,1.4Hz,1H),7.18(s,1H),7.15-7.00(m,2H),6.86-6.78(m,1H),6.78-6.71(m,3H),6.64(td,J=7.6,1.4Hz,1H),5.67(d,J=14.5Hz,1H),4.72(dt,J=5.0,2.5Hz,1H),4.60(dt,J=5.0,2.5Hz,1H),4.24-3.95(m,2H),3.92(d,J=14.5Hz,1H),3.78(s,3H).13C NMR(100MHz,DMSO-d6):δ167.85,157.30,139.80,138.96,137.76,135.63,132.34,130.29,128.90,128.26,121.25,119.86,119.49,115.79,113.23,100.21,81.97(d,J=166.8Hz),66.97(d,J=19.1Hz),43.09,35.37.19FNMR(282MHz,DMSO-d6)δ-221.58(m).IR(金刚石池,纯)νmax:3328,1621,1605,1556,1505,1444,1395,1297,1249,1173,1144,1069,1050,991,923,880,832,761,732,634cm-1.LRMS(+ESI)m/z:389[(M+Na)+,100%].MP:207-208℃.HPLC纯度:95.27%,RT:18.29min.
实施例49:(3-(2-氟乙氧基)苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,
4]二氮杂
-5(1H)-基)甲酮(TAR-B087)
根据前述的通用过程C,将二氮杂1二盐酸盐(272mg,1.0mmol)用衍生自3-(2-氟乙氧基)苯甲酸的酰氯(184mg,1.0mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B087(333mg,91%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):8.61(s,1H),7.27(dd,J=8.1,1.4Hz,1H),7.18(s,1H),7.14-7.04(m,2H),6.86-6.79(m,1H),6.78-6.70(m,3H),6.64(td,J=7.6,1.4Hz,1H),5.67(d,J=14.5Hz,1H),4.72(dt,J=5.0,2.5Hz,1H),4.60(dt,J=5.0,2.5Hz,1H),4.25-3.94(m,2H),3.92(d,J=14.5Hz,1H),3.78(s,3H).13C NMR(100MHz,DMSO-d6):δ167.85,157.30,139.80,138.96,137.76,135.63,132.34,130.29,128.90,128.26,121.25,119.86,119.49,115.79,113.23,100.21,81.97(d,J=166.8Hz),66.97(d,J=19.1Hz),43.09,35.37.19FNMR(282MHz,DMSO-d6)δ-222.05(tt,J=47.8,30.1Hz).IR(金刚石池,纯)νmax:3320,1619,1559,1505,1436,1395,1299,1241,1052,990,945,881,832,815,761,693,629cm-1.LRMS(+ESI)m/z:389[(M+Na)+,100%].MP:207-208℃.HPLC纯度:99.19%,RT:19.28min.
实施例50:(4-(2-氟乙氧基)苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,
4]二氮杂
-5(1H)-基)甲酮(TAR-B088)
根据前述的通用过程C,将二氮杂1二盐酸盐(272mg,1.0mmol)用衍生自4-(2-氟乙氧基)苯甲酸的酰氯(184mg,1.0mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TAR-B088(341mg,93%)(Rf=0.30,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):8.58(s,1H),7.30(dd,J=8.1,1.3Hz,1H),7.21-7.01(m,4H),6.71(dd,J=19.4,9.6Hz,4H),5.73-5.54(m,1H),4.76(t,J=3.8Hz,1H),4.66-4.54(m,1H),4.17(dt,J=30.0,3.8Hz,2H),3.89(d,J=14.6Hz,1H),3.77(s,3H)).13C NMR(100MHz,DMSO-d6):δ167.64,158.85,139.83,138.71,135.52,132.63,130.30,129.44,128.65,128.04,121.19,119.56,113.42,100.42,81.93(d,J=166.7Hz),66.94(d,J=18.9Hz),43.15,35.27.19F NMR(282MHz,DMSO-d6)δ-222.27(tt,J=47.8,30.0Hz).IR(金刚石池,纯)νmax:3306,1605,1555,1503,1388,1296,1247,1174,1048,990,921,878,836,759,732,633cm-1.LRMS(+ESI)m/z:389[(M+Na)+,100%].MP:193-195℃.HPLC纯度:99.36%,RT:18.92min.
实施例51:立方烷-1-基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮(QB)
根据前述的通用过程C,将二氮杂1二盐酸盐(154mg,0.56mmol)用衍生自立方烷-1-羧酸的酰氯(100mg,0.67mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的QB(146mg,78%)(Rf=0.50,于1∶9v/vMeOH/CH2Cl2中)。
1H NMR(300MHz,氯仿-d):δ7.25-7.16(m,3H),7.02-6.91(m,2H),5.84(s,1H),5.66(d,J=15Hz,1H),4.29(s,1H),4.03(s,1H),3.83(s,3H),3.74(s,3H),3.61(s,3H).IR(金刚石池,纯)νmax:3277,2986,1607,1556,1504,1407,1303,1217,1165,986,843,761,692,581,498,445cm-1.LRMS(+ESI)m/z:353[(M+Na)+,100%].MP:194-203℃.HPLC纯度:95.87%,RT:18.60min.
实施例52:环庚基(4,10-二氢苯并[b]吡唑并[2,3-e][1,4]二氮杂
-5(1H)-基)
甲酮(CA7)
根据前述的通用过程C,将二氮杂1二盐酸盐(152mg,0.59mmol)用衍生自环庚烷羧酸的酰氯(100mg,0.70mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的CA7(121mg,67%)(Rf=0.50,于1∶9v/vMeOH/CH2Cl2中)。
1H NMR(300MHz,氯仿-d):δ7.28-7.26(m,1H),7.25-7.24(m,2H),7.19-6.99(m,2H),5,98(s,1H),5.62(d,J=15Hz,1H),3.81(d,J=15Hz,1H),3.72(s,3H),2.35-2.31(m,1H),1.81-1.67(m,4H),1.57-1.23(m,8H).13C NMR(75MHz,氯仿-d):δ176.89,139.21,136.60,132.40,130.59,129.12,122.86,119.78,42.84,42.37,34.80,31.54,31.22,28.24,26.84,26.70.IR(金刚石池,纯)νmax:3287,2917,2852,1632,1609,1556,1499,1432,1398,1306,1281,1228,1163,988,819,754,718,645,582,447cm-1.LRMS(+ESI)m/z:347[(M+Na)+,100%].MP:198-205℃.HPLC纯度:95.87%,RT:20.61min.
实施例53:4-(1-甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5-
羰基)双环[2.2.2]辛烷-1-羧酸甲酯(BcO-MC)
根据前述的通用过程C,将二氮杂1二盐酸盐(107mg,0.39mmol)用衍生自4-(甲氧基羰基)双环[2.2.2]辛烷-1-羧酸的酰氯(100mg,0.47mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的BcO-MC(59mg,70%)(Rf=0.50,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.43(s,1H),7.32-7.28(m,2H),7.22-7.20(m,1H),7.05-6.98(m,2H),5.43(d,J=12Hz,1H),3.69(s,3H),3.63(d,J=12Hz,1H),3.50(s,3H),1.69-1.62(m,3H),1.50-1.36(m,9H).13C NMR(75MHz,DMSO-d6):δ176.90,174.52,140.37139.13,135.81,132.96,130.98,128.90,121.60,120.18,100.53,51.42,46.17,40.82,38.69,37.75,35.20,27.50,27.44.IR(金刚石池,纯)νmax:3274,2947,2872,1726,1614,1594,1553,1501,1386,1280,1252,1080,1017,768,593cm-1.LRMS(+ESI)m/z:417[(M+Na)+,100%].MP:198-211℃.HPLC纯度:98.64%,RT:18.61min.
实施例54:双环[2.2.2]辛-1-基(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]
二氮杂
-5(1H)-基)甲酮(BcO)
根据前述的通用过程C,将二氮杂1二盐酸盐(176mg,0.65mmol)用衍生自双环[2.2.2]辛烷-1-羧酸的酰氯(100mg,0.65mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的BcO(142mg,65%)(Rf=0.50,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ7.30(m,1H),7.19(m),7.08(d,J=7.6Hz,2H),6.40(s,1H),5.66(d,J=14.6Hz,1H),3.79(br s,4H),1.82-1.23(m,12H),1.00-0.76(m,1H).IR(金刚石池,纯)νmax:2940,2921,2863,1685,1409,1292,1270,957,910,891,748,653,542cm- 1.LRMS(+ESI)m/z:359[(M+Na)+,100%].HPLC纯度:96.87%,RT:21.77min.
实施例55:(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(萘-2-基)甲酮(TRGA-81)
根据前述的通用过程C,将二氮杂1二盐酸盐(132mg,0.48mmol)用衍生自2-萘甲酸的酰氯(100mg,0.58mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TRGA-81(139mg,81%)(Rf=0.50,于1∶9v/vMeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.57(s,1H),7.84(d,J=6Hz,1H),7.79(d,J=18Hz,1H),7.73-7.46(m,3H),7.25-7.09(m,4H),6.95-6.89(m,1H),6.72(d,J=9Hz,1H),6.42-6.37(m,1H),5.77(d,J=15Hz,1H),4.03(d,J=15Hz,1H),3.81(s,3H).13C NMR(75MHz,DMSO-d6):δ168.21,139.73,138.62,135.80,134.54,132.62,129.67,129.60,128.56,128.27,128.22,128.01,126.52,126.07,124.99,124.43,123.81,120.54,119.42,100.49,43.01,35.38.IR(金刚石池,纯)νmax:3300,1617,1504,1404,1377,1318,833,796,780,748,725,447cm-1.LRMS(+ESI)m/z:377[(M+Na)+,100%].MP:228-243℃.HPLC纯度:98.03%,RT:19.10min.
实施例56:(1-甲基-4,10-二氧苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(萘-1-基)甲酮(TRGA-89)
根据前述的通用过程C,将二氮杂1二盐酸盐(132mg,0.48mmol)用衍生自1-萘甲酸的酰氯(100mg,0.58mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TRGA-89(141mg,82%)(Rf=0.50,于1∶9v/vMeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.72(s,1H),7.83(d,J=15Hz,3H),7.67(d,J=9Hz,1H),7.51-7.20(m,5H),7.09-7.04(m,1H),6.77(d,J=9Hz,1H),6.57-6.52(m,1H),5.99(d,J=15Hz,1H),4.03(d,J=15Hz,1H),3.85(s,3H).13C NMR(75MHz,DMSO-d6):δ168.18,139.87,138.99,135.67,133.91,132.88,132.26,131.88,130.47,128.24,128.24,127.45,127.45,127.06,126.94,126.49,124.34,121.13,119.57,100.35,43.21,35.41.IR(金刚石池,纯)νmax:3312,1610,1565,1505,1402,1298,12.48,1035,820,762,728,701,477,449cm-1.LRMS(+ESI)m/z:377[(M+Na)+,100%].MP:231-233℃.HPLC纯度:98.85%,RT:20.51min.
实施例57:苯并[d][1,3]二氧杂环戊烯-5-基(1-甲基-4,10-二氢苯并[b]吡唑并
[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮(TRGA-95)
根据前述的通用过程C,将二氮杂1二盐酸盐(137mg,0.50mmol)用衍生自苯并[d][1,3]二氧杂环戊烯-5-羧酸的酰氯(100mg,0.60mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TRGA-95(158mg,75%)(Rf=0.50,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.59(s,1H),7.29(d,J=9Hz,2H),7.15(d,J=9Hz,2H),6.71(br s,4H),5.96(s,2H),5.66(d,J=15Hz,1H),3.89(d,J=15Hz,1H),3.76(s,3H).13C NMR(75MHz,DMSO-d6):δ167.46,148.06,146.52,139.84,138.72,135.56,132.67,130.19,129.97,128.18,122.16,121.35,119.61,107.88,107.45,101.31,100.31,43.21,35.32.LRMS(+ESI)m/z:371[(M+Na)+,100%].HPLC纯度:99.53%,RT:17.19min.
实施例58:(4-乙基苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)甲酮(TRGA-99)
根据前述的通用过程C,将二氮杂1二盐酸盐(152mg,0.55mmol)用衍生自4-乙基苯甲酸的酰氯(100mg,0.66mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TRGA-99(134mg,73%)(Rf=0.50,于1∶9v/vMeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.59(s,1H),7.28(d,J=9Hz,1H),7.16-6.98(m,6H),6.72-6.63(m,2H),5.68(d,J=15Hz,1H),3.89(d,J=15Hz,1H),3.77(s,3H),2.50(q,J=6Hz,2H),1.08(t,J=6Hz,3H).13C NMR(75MHz,DMSO-d6):δ168.10,145.23,139.84,138.81,135.60,133.65,132.53,130.37,128.15,127.56,126.95,121.18,119.54,100.36,43.14,35.33,27.78,15.07.IR(金刚石池,纯)νmax:2971,1618,1561,1500,1388,1315,1244,1139,1051,1018,983,827,757,726,629,594,489,462cm-1.LRMS(+ESI)m/z:355[(M+Na)+,100%].HPLC纯度:99.87%,RT:19.63min.
实施例59:(4-异丙基苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮
杂
-5(1H)-基)甲酮(TRGA-101)
根据前述的通用过程C,将二氮杂1二盐酸盐(139mg,0.51mmol)用衍生自4-异丙基苯甲酸的酰氯(100mg,0.61mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TRGA-101(129mg,73%)(Rf=0.50,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.59(s,1H),7.30-7.01(m,7H),6.73-6.61(m,2H),5.68(d,J=12Hz,1H),3.89(d,J=12Hz,1H),3.77(s,3H),2.78(sep,J=6Hz,1H),1.10(d,J=6Hz,6H).13C NMR(75MHz,DMSO-d6):δ167.98,152.92,139.84,138.80,135.60,133.71,132.48,130.38,128.17,127.65,125.50,121.15,119.55,100.38,43.17,35.33,33.05,23.60.IR(金刚石池,纯)νmax:3283,2958,1601,1556,1502,1392,1317,834,753,730cm- 1.LRMS(+ESI)m/z:369[(M+Na)+,100%].HPLC纯度:95.03%,RT:20.64min.
实施例60:(4-(叔丁基)苯基)(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二
氮杂
-5(1H)-基)甲酮(TRGA-105)
根据前述的通用过程C,将二氮杂1二盐酸盐(139mg,0.56mmol)用衍生自4-(叔丁基)苯甲酸的酰氯(100mg,0.56mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TRGA-105(158mg,78%)(Rf=0.50,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,DMSO-d6):δ8.59(s,1H),7.31-7.27(m,1H),7.19-7.08(m,6H),6.74-6.64(m,2H),5.68(d,J=15Hz,1H),3.89(d,J=15Hz,1H),3.77(s,3H),1.17(s,9H).13C NMR(75MHz,DMSO-d6):δ167.96,152.16,139.88,138.80,135.64,133.33,130.39,129.17,128.22,127.50,124.36,121.18,119.59,100.47,43.27,35.35,34.39,30.87.IR(金刚石池,纯)νmax:3313,1607,1556,1504,1392,1294,1143,994,827,762,749,727,708,627,601,500,448cm-1.LRMS(+ESI)m/z:383[(M+Na)+,100%].HPLC纯度:99.78%,RT:21.51min.
实施例61:(1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-基)
(2,2,3,3-四甲基环丙基)甲酮(TRGA-111)
根据前述的通用过程C,将二氮杂1二盐酸盐(160mg,0.59mmol)用衍生自2,2,3,3-四甲基环丙烷-1-羧酸的酰氯(100mg,0.70mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶99至1∶9v/MeOH/CH2Cl2梯度洗脱)纯化,制得白色粉末状的TRGA-111(129mg,68%)(Rf=0.50,于1∶9v/v MeOH/CH2Cl2中)。
1H NMR(300MHz,氯仿-d):δ7.26-7.18(m,2H),7.12-7.09(m,1H),7.04-6.95(m,2H),5.95(s,1H),5.66(d,J=15Hz,1H),3.80(d,J=15Hz,1H),3.73(s,3H),1.67(s,1H),1.23(s,3H),1.19(s,3H),0.94(s,3H),0.81(s,3H).13C NMR(75MHz,氯仿-d):δ171.24,139.07,138.66,136.55,132.43,131.40,128.72,122.33,119.43,102.29,42.45,36.69,34.78,28.48,28.26,23.81,22.82,17.63,17.22.IR(金刚石池,纯)νmax:3309,2930,1623,1557,1500,1427,1393,1315,1245,986,936,833,760,723,584cm-1.LRMS(+ESI)m/z:347[(M+Na)+,100%].HPLC纯度:98.82%,RT:20.46min.
实施例62:5-(3,4-二甲基苯基)-1-甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-e]
[1,4]二氮杂
(WJ05105)
将搅拌下的二氮杂1(150mg,0.75mmol)和3,4二甲基苯甲醛(100mg,0.75mmol)于CH2Cl2(10mL)中的溶液在1小时内分批用三乙酰氧基硼氢化钠(795mg,3.75mmol)处理并继续搅拌12h。将得到的悬浮液用CH2Cl2(25mL)稀释并且随后用NaHCO3(25mL饱和水溶液)、盐水(50mL)洗涤,干燥(MgSO4),过滤并在减压下浓缩。将得到的油通过快速柱色谱(二氧化硅,2.5∶97.5v/v CH2Cl2/MeOH)纯化并且浓缩相关馏分(Rf=0.28,于2.5∶97.5v/v MeOH/CH2Cl2溶液中),制得白色粉末状的标题化合物(211mg,88%)。
1H NMR(500MHz,DMSO-d6):8.11(br s,1H,NH),7.16(dd,J=8.0,1.5Hz,1H,3-CH),7.09-7.01(m,3H,16/17/18-3xCH),7.01-6.94(m,2H,1/2-2xCH),6.88(s,1H,12-CH),6.79(ddd,J=7.9,7.2,1.5Hz,1H,6-CH),4.01(s,2H,10-CH2),3.76(s,2H,8-CH2),3.72(s,3H,15-CH3),2.20-2.15(m,6H,19/20-2xCH3).13C NMR(126MHz,DMSO-d6):δ141.2,140.4,139.1,136.5,135.7(1),135.7(0),134.5,129.5,129.2,125.9,125.6,124.3,120.9,119.4,100.4,57.4,48.5,35.1,19.4,19.0.IR(金刚石池,纯)νmax:3269,1603,1554,1503,1431,1393,1363,1332,1294,1252,1132,1020,990,856,837,819,762,714,664,640,596,556,476,443cm-1.LRMS(+ESI)m/z:319[(M+H)+,100%].HRMS(+ESI)实测值:(M+H)+,319.1915.C20H22N4需求(M+H)+,319.1917.MP171-173℃.HPLC纯度:97.08%,RT:17.48min.
实施例63:5-(3,5-二甲氧基苯基)-1-甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-
e][1,4]二氮杂
(WJ0625)
将搅拌下的二氮杂1(150mg,0.75mmol)和3,5-二甲氧基苯甲醛(125mg,0.75mmol)于CH2Cl2(10mL)中的溶液在1小时内分批用三乙酰氧基硼氢化钠(795mg,3.75mmol)处理并继续搅拌12h。将得到的悬浮液用CH2Cl2(25mL)稀释并且随后用NaHCO3(25mL饱和水溶液)、盐水(50mL)洗涤,干燥(MgSO4),过滤并在减压下浓缩随后经由快速柱色谱(二氧化硅,2.5∶97.5v/v MeOH/CH2Cl2)纯化,制得白色泡沫状的标题化合物(148mg,56%)(Rf=0.1,于2.5:97.5v/v MeOH/CH2Cl2溶液中)。
1H NMR(500MHz,DMSO-d6):8.14(br s,1H,NH),7.17(dd,J=8.1,1.5Hz,1H,3-CH),7.06(dd,J=8.0,1.5Hz,1H,6-CH),6.97(ddd,J=7.9,7.2,1.5Hz,1H,2-CH),6.92(s,1H,12-CH),6.80(ddd,J=7.9,7.2,1.5Hz,1H,1-CH),6.46(d,J=2.3Hz,2H,15-2xCH),6.33(t,J=2.3Hz,1H,14-CH),4.07(s,2H,10-CH2),3.79(s,2H,8-CH2),3.73(s,3H,15-CH3),3.67(s,6H,16-2xCH3).13C NMR(126MHz,DMSO-d6):δ160.3,141.8,141.1,140.5,139.0,135.7,125.6,124.3,121.0,119.4,105.9,100.5,98.5,57.6,55.0,49.0,35.1.IR(金刚石池,纯)νmax:3309,1626,1560,1504,1429,1392,1317,1247,1146,1029,990,827,757,741,690,636,597,493,447cm-1.LRMS(+ESI)m/z:351[(M+H)+,100%].HRMS(+ESI)实测值:(M+Na)+,373.1636.C20H22N4O2需求(M+Na)+,373.1635.MP 210-212℃.HPLC纯度:95.61%,RT:16.93min.
实施例64:5-((1-甲基-4,10-二氢苯并[b]吡唑并[3,4-e][1,4]二氮杂
-5(1H)-
基)苯-1,3-二醇(WJ0627)
将搅拌下的二氮杂1(150mg,0.75mmol)和间苯二酚(104mg,0.75mmol)于CH2Cl2(10mL)中的溶液在1小时内分批用三乙酰氧基硼氢化钠(795mg,3.75mmol)处理并继续搅拌12h。将得到的悬浮液用CH2Cl2(25mL)稀释并且随后用NaHCO3(25mL饱和水溶液)、盐水(50mL)洗涤,干燥(MgSO4),过滤并在减压下浓缩随后经由快速柱色谱(二氧化硅,2.5∶97.5v/v MeOH/CH2Cl2)纯化,制得白色晶体粉末标题化合物(111mg,46%)(Rf=0.04,于2.5:97.5v/v MeOH/CH2Cl2溶液中)。
1H NMR(400MHz,DMSO-d6):9.09(br d,J=2.2Hz,2H,2OH),8.08(br s,1H,NH),7.16(dd,J=8.0,1.5Hz,1H,3-CH),7.05(dd,J=8.0,1.5Hz,1H,6-CH),6.95(td,J=7.6,1.5Hz,1H,2-CH),6.90(s,1H,12-CH),6.81(td,J=7.5,1.5Hz,1H,1-CH),6.20(d,J=2.1Hz,2H,16-2xCH),6.05(t,J=2.2Hz,1H,18-CH),3.93(s,2H,10-CH2),3.76(s,2H,8-CH2),3.72(s,3H,15-CH3).13C NMR(101MHz,DMSO-d6):δ158.2,141.5,141.4,140.5,138.8,135.7,125.0,124.1,121.1,119.5,106.2,101.2,100.4,57.9,48.8,35.1.IR(金刚石池,纯)νmax:3334,1586,1553,1499,1440,1386,1297,1213,1157,1002,956,833,762,744,688,619,559,529,439cm-1.LRMS(+ESI)m/z:323[(M+H)+,100%].HRMS(+ESI)实测值:(M+H)+,323.1503.C18H18N4O2需求(M+H)+,323.1503.MP 236-238℃.HPLC纯度:95.51%,RT:13.01min.
实施例65:5-((4-氯苯基)磺酰基)-1-甲基-1,4,5,10-四氢苯并[b]吡唑并[3,4-
e][1,4]二氮杂
(WJ0633)
根据前述的通用过程A(步骤ii),将二氮杂1(200mg,1mmol)用4-氯磺酰基氯(253mg,1.2mmol)进行处理,随后经由快速柱色谱(二氧化硅,1∶3至1∶1v/v EtOAc:己烷梯度洗脱)纯化,制得白色晶状固体标题化合物(120mg,32%)(Rf=0.26,于1∶1v/v EtOAc/己烷溶液中)。
1H NMR(500MHz,DMSO-d6):8.01(s,1H,NH),7.36(d,J=8.6Hz,2H,16-2xCH),7.29-7.22(m,2H,2/6-2xCH),7.10(dd,J=8.6,1.5Hz,1H,3-CH),7.05(s,1H,12-CH),7.02(d,J=8.7Hz,2H,17-2xCH),6.94-6.87(m,1H,1-CH),4.97(br s,1H,8-CH2),4.35(br s,1H,8-CH2),3.27(s,3H,15-CH3).13C NMR(126MHz,DMSO-d6):δ139.4,138.9,138.0,137.2,135.6,133.4,129.5,128.8,128.1,126.2,120.2,119.5,100.0,47.8,34.6.IR(金刚石池,纯)νmax:3251,1563,1507,1338,1162,1088,1041,997,899,847,823,762,737,701,681,616,582,567,541,474cm-1.LRMS(+APCI)m/z:375[(M+H)+,100%],377[(M+H)+,48%].HRMS(+ESI)实测值:(M+H)+,375.0677/377.0647.C17H15ClN4O2S需求(M+H)+,375.0677/377.0647.MP 206-208℃.HPLC纯度:95.43%,RT:20.79min.
实施例66:1-甲基-5-((4-(三氟甲基)苯基)磺酰基)-1,4,5,10-四氢苯并[b]吡唑
并[3,4-e][1,4]二氮杂
(WJ0639)
根据前述的通用过程A(步骤ii),将二氮杂1(200mg,1mmol)用4-三氟甲基磺酰基氯(294mg,1.2mmol)进行处理,随后经由快速柱色谱(二氧化硅,1.5∶98.5v/v MeOH/CH2Cl2)纯化,制得黄色晶状固体状的标题化合物(210mg,51%)(Rf=0.42,于1.5:98.5v/vMeOH/CH2Cl2溶液中)。
1H NMR(400MHz,DMSO-d6):7.99(s,1H,NH),7.67(d,J=8.3Hz,2H,17-2xCH),7.35-7.21(m,4H,2/6/16-4xCH),7.11(dd,J=8.6,1.4Hz,1H,3-CH),7.06(s,1H,12-CH),6.93(td,J=7.6,1.4Hz,1H,1-CH),5.00(br s,1H,8-CH2),4.38(s,1H,8-CH2),3.16(s,3H,15-CH3).13C NMR(101MHz,DMSO-d6):δ143.1,139.3,138.7,135.6,133.4,131.9(q,J=32.1Hz),129.6,127.9,126.1,125.1(q,J=4.0Hz),123.5(q,J=272.9Hz),120.3,119.6,100.1,47.8,34.3.19F NMR(376MHz,DMSO-d6):δ-61.4.IR(金刚石池,纯)νmax:3543,3195,1620,1563,1508,1319,1163,1090,1058,998,900,840,785,763,710,680,609,563,540,426cm-1.LRMS(+APCI)m/z:409[(M+H)+,100%].HRMS(+ESI)实测值:(M+H)+,409.0941.C18H15F3N4O2S需求(M+H)+,409.0941.MP 203-205℃.HPLC纯度:95.82%,RT:21.26min.
实施例67:1-甲基-5-甲苯磺酰基-1,4,5,10-四氢苯并[b]吡唑并[3,4-e][1,4]二
氮杂
(WJ0641)
根据前述的通用过程A(步骤ii),将二氮杂1(200mg,1mmol)用4-甲磺酰基氯(228mg,1.2mmol)进行处理,随后经由快速柱色谱(二氧化硅,1.5∶98.5v/v MeOH/CH2Cl2)纯化,制得白色结晶固体标题化合物(291mg,82%)(Rf=0.48,1.5∶98.5v/v MeOH/CH2Cl2溶液中)。
1H NMR(300MHz,DMSO-d6):7.92(br s,1H,NH),7.22(td,J=7.3,1.5Hz,2H,17-2xCH),7.12-7.00(m,4H,16/6/2-4xCH),6.97-6.76(m,3H,1/3/12-3xCH),4.86(br s,1H,8-CH2),4.40(br s,1H,8-CH2),3.22(s,3H,15-CH3),2.33(s,3H,18-CH3).13C NMR(75MHz,DMSO-d6):δ142.4,139.7,139.0,136.3,135.4,133.4,129.2,128.4,127.0,126.4,120.0,119.3,100.2,47.7,34.6,20.9.IR(金刚石池,纯)νmax:3550,3160,1622,1591,1563,1509,1444,1333,1290,1163,1088,1041,996,898,844,814,754,737,702,683,659,572,555,534,500,483cm-1.LRMS(+APCI)m/z:354[(M+H)+,100%].HRMS(+ESI)实测值:(M+Na)+,377.1042.C18H18N4O2S需求(M+Na)+,377.1043.MP 184-186℃.HPLC纯度:97.72%,RT:20.01min.
测试式I化合物的选择性的实施例
下述实施例阐释了一些式I化合物对OXTR相比V1aR的选择性。
表达OTR和V1aR的认胚胎肾(HEK)细胞的产生
如Jorgensen等人2016所报道的那样(其全部公开通过引用并入)建立了使用Flp-InTM T-RExTM系统(生命技术公司(Life Technologies),卡尔斯巴德,CA,USA)转染以稳定表达未标记的hOTR和V1aR的人胚胎肾细胞(HEK-293)。随后将细胞保持在含有潮霉素(80μg/ml)、青霉素(100U/ml)、链霉素(0.1mg/ml)和灭瘟素S盐酸盐(blasticidine Shydrochloride)(15μg/ml)的10%DMEM中。
膜制备
为了诱导受体表达,将细胞与四环素(2μg/mL)一起孵育48小时。使用具有5mMEDTA的PBS(pH 7.4)从培养瓶中分离表达OTR和V1aR的HEK293细胞。将收获的细胞以1200g离心5分钟,并在使用Ultra-Turrax匀浆器(IKA,威明顿市,NC,USA)均质化之前重悬于匀浆缓冲液(50mM HEPES,5mM EDTA,5mM MgCl2;pH 7.4)中。将匀浆在48,000g、4℃下经30分钟离心三次,将膜沉淀重悬于50mM三(羟甲基)氨基甲烷盐酸盐(Tris HCl)、5mM MgCl2(pH7.4)中。根据制造商的方案(伯乐Bio-Rad,赫拉克勒斯(Hercules),CA,USA)使用了二喹啉甲酸分析以测量最终蛋白质浓度。将膜储存于-80℃下直至用于竞争放射性配体结合研究。
竞争放射性配体结合
将膜(50μg/孔)与[酪氨酰-2,6-3H]-催产素(10nM)或[苯丙氨酰基-3,4,5-3H]-血管加压素(8-L-精氨酸)(2nM;珀金埃尔默(Perkin Elmer),沃尔瑟姆,MS,USA)和对数间隔浓度的竞争化合物(1nM-10μM)在反应缓冲液(50mM三氨基甲烷盐酸盐,5mM MgCl2,pH7.4)中一起孵育。将反应在4℃下孵育90分钟以达到平衡,并通过玻璃纤维滤器(沃特曼(Whatman)GF/A 1.6μM;密理博(Millipore),达姆施塔特,德国)快速过滤来终止,并用冰冷的反应缓冲液洗涤。将滤膜干燥,然后与Microscint 0(珀金埃尔默)一起温育30分钟,之后用Microbeta2 2450酶标仪(珀金埃尔默)检测放射性。在1μM冷催产素或血管加压素(西格玛奥德里奇(Sigma Aldrich))存在下测定非特异性结合,并从总结合值中减去以计算特异性结合值。在化合物存在下的特异性结合表示为在载体对照存在下特异性结合的百分比。使用平方和F检验来比较单位点、双位点和S形与可变希尔斜率(hill slope)结合模型的拟合优度,并使用Graphpad Prism(Graphpad软件,拉荷亚,CA,USA)计算Ki。
IP1累积试验
将表达OTR或V1aR的HEK-293细胞以每孔8.75x103个细胞的密度接种到包被了聚-L-赖氨酸(100μg/ml)的384孔板上。将细胞在四环素(2μg/mL)中孵育48小时以诱导受体表达。根据制造商的方案,使用HTRF IP-One试剂盒(CisBio国际,贝德福德,MA,USA)指示由偶联至OTR和V1aR的Gq蛋白的激活诱导的细胞内IP1水平。对于激动剂评估,在经1小时加入Ab穴合物(Ab-Cryptate)和IP1-d2之前,将细胞与对数间隔浓度的化合物(1nM-100μM)一起孵育1小时。将每孔的内容物转移到白壁代用板(white-walled proxy plate)(珀金埃尔默)中并使用Pherastar微孔板酶标仪(BMG实验技术(Labtech),凯里,NC,USA)读取荧光。对于拮抗剂评估,将细胞以~EC70浓度与化合物(1nM-100μM)或载体对照混合的的OT(30nM)或AVP(25nM)孵育1小时。化合物和OT或AVP存在时的IP1水平表示为在载体对照存在下OT或AVP观察到的水平的百分比。在药物或载体中孵育5分钟后确定OT和AVP的浓度响应曲线,并使用GraphPad PRISM将数据拟合成式为y=Min+(Max-Min)/(1+10^((logEC50-X)*n))的4-参数逻辑方程,其中X是药物浓度,n是希尔(Hill)斜率。数据代表至少3次独立实验(每次重复一次)的平均值±s.d.。
分析了以下化合物以确定对于OXTR相比V1aR的选择性,其结果总结在下表1中:
实施例测试WJ0679对小鼠社会互动的影响(N=64)
物种:小鼠(Mus musculus)
品种:BALB/c
性别:雄性
年龄:测试时6-7周
载体:88%等渗盐水,10%DMSO,2%吐温80
化合物:WJ0629
剂量:0、1、5、20mg/kg
施用途径:腹腔(i.p.)注射
将小鼠置于(40×40×40cm)场地在重量和治疗配对的不熟悉小鼠中进行10分钟的测试,在接受其腹腔注射后30分钟开始。感兴趣的变量是小鼠彼此密切身体接触所花费的时间以及每只小鼠参与积极的社会调查(嗅探另一只老鼠)所花费的时间。
图1显示了所有剂量的WJ0679都显著增加了密切身体接触所花费的时间,其效果在较低剂量(1和5mg/kg)下最显著。
图2显示了1和20mg/kg剂量的WJ0679显著增加了积极的社会调查。
Claims (29)
1.一种药物组合物,所述药物组合物包括、基本上由以下组成、或由以下组成:药学上可接受的式I化合物以及药学上可接受的载体、稀释剂或赋形剂:
其中,R1、R3、R4、R5或R6各自独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、取代或未取代的芳基,或者取代或未取代的杂环基;
其中R2独立地选自下组:H、F、Br、I、NH2、NO2、OH、ON=O、取代的甲基、取代或未取代的C2-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、取代或未取代的芳基,或者取代或未取代的杂环基;
其中,为取代的芳基或取代的杂芳基的各个R1、R2、R3、R4、R5、或R6包括一个或多个选自下组的取代基:F、Cl、Br、I、NH2、N=O、NO2、NHCH3、OH、OCH3、OC≡N、ON=O、SH、SCH3、S(=O)nOH、S(=O)nCH3、SC≡N、COOH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)、或OCHmBr(3-m);
其中,X为选自下组的环状结构:取代或未取代的、稠合或未稠合的芳基;取代或未取代的、稠合或未稠合的杂环基;或者取代或未取代的、稠合或未稠合的环烷基;以及
其中,X1代表一个或多个独立地选自下组的原子或基团:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、COOH、C1烷基-COOH、COOC1-C2烷基、COOC1-C2烷基芳基、C1烷基-COOC1-C2烷基、C1-C2烷基芳基、OC1-C2烷基芳基、NC1-C2烷基芳基、C1-C2烷基-杂环基、OC1-C2烷基-杂环基、NC1-C2烷基-杂环基;
其中,各个取代的烷基、烯基、炔基、烷基芳基或烷基-杂环基包括一个或多个选自下组的取代基:F、Cl、Br、I、≡N、=NH、NH2、N=O、NO2、NHCH3、N=C=O、N=C=S、=O、OH、OCH3、OC≡N、ON=O、=S、SH、SCH3、S(=O)nOH、S(=O)nCH3和SC≡N;
其中,各个m是选自0、1或2的整数;以及
各个n是选自0、1或2的整数。
2.如权利要求1所述的药物组合物,其特征在于,所述环状结构选自下组:稠合或未稠合的芳基;稠合或未稠合的具有一个或多个选自N、O或S的杂环原子的5元、6元、7元杂环基;或者,5元、6元、7元、8元、9元、10元、11元、12元、13元、14元、15元或16元单环烷基、桥接二环烷基或桥接三环烷基。
3.如权利要求1或2所述的药物组合物,其特征在于,所述芳基为未稠合的芳基,所述杂环基为未稠合的仅具有单个杂环原子的杂环基,以及所述环烷基是桥接二环烷基或三环烷基。
4.如前述权利要求中的任何一项所述的药物组合物,其特征在于,所述环状结构选自下组:苯基、吡啶基和金刚烷基。
5.如前述权利要求中的任何一项所述的药物组合物,其特征在于,R1、R3、R4、R5和R6各自独立地选自下组:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。
6.如前述权利要求中的任何一项所述的药物组合物,其特征在于,R2独立地选自下组:H、F、Br、I、OH、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。
7.如前述权利要求中的任何一项所述的药物组合物,其特征在于,所述取代或未取代的芳基为取代或未取代的苯基,其式为:
其中,各个A1、A2、A3、A4或A5独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基;以及
其中,任选地A1和A2,和/或A2和A3,和/或A3和A4,和/或A4和A5中的一个或多个一起形成稠合的环结构。
8.如权利要求7所述的药物组合物,其特征在于,A1、A2、A3、A4或A5各自独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C2烷基、取代或未取代的C2烯基、取代或未取代的C2炔基、取代或未取代的OC1-C2烷基、取代或未取代的OC2烯基、取代或未取代的OC2炔基、取代或未取代的NHC1-C2烷基、取代或未取代的NHC2烯基、取代或未取代的NHC2炔基。
9.如权利要求8所述的药物组合物,其特征在于,A1、A2、A3、A4或A5各自独立地选自下组:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。
10.如前述权利要求中的任何一项所述的药物组合物,其特征在于,所述取代或未取代的杂环基为选自下组的取代或未取代的吡啶基:
其中:
Z是杂环原子,并且其选自下组:N、S或O;以及
存在的每个H1、H2、H3、H4或H5独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基;以及
其中,任选地H1和H2,和/或H2和H3,和/或H3和H4,和/或H4和H5中的一个或多个一起形成稠合的环结构。
11.如权利要求10所述的药物组合物,其特征在于,Z为N。
12.如权利要求10或11所述的药物组合物,其特征在于,存在的每个H1、H2、H3、H4或H5独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C2烷基、取代或未取代的C2烯基、取代或未取代的C2炔基、取代或未取代的OC1-C2烷基、取代或未取代的OC2烯基、取代或未取代的OC2炔基、取代或未取代的NHC1-C2烷基、取代或未取代的NHC2烯基、取代或未取代的NHC2炔基。
13.如权利要求12所述的药物组合物,其特征在于,存在的每个H1、H2、H3、H4或H5独立地选自下组:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。
14.如前述权利要求中的任何一项所述的药物组合物,其特征在于,所述取代或未取代的环烷基为取代或未取代的金刚烷基环,其式为:
其中,在金刚烷基环上的各个碳原子为未取代的,仅具有至相邻碳原子和氢的共价键;或者在金刚烷基环上的能被取代的各个碳原子被一个或多个选自下组的取代基所取代:F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基。
15.如权利要求14所述的药物组合物,其特征在于,在金刚烷基环上的能取代的各个碳原子独立地被一个或多个选自下组的取代基所取代:F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C2烷基、取代或未取代的C2烯基、取代或未取代的C2炔基、取代或未取代的OC1-C2烷基、取代或未取代的OC2烯基、取代或未取代的OC2炔基、取代或未取代的NHC1-C2烷基、取代或未取代的NHC2烯基、取代或未取代的NHC2炔基。
16.如权利要求16所述的药物组合物,其特征在于,在金刚烷基环上的能取代的各个碳原子独立地被一个或多个选自下组的取代基所取代:F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。
17.如权利要求1至13中任一项所述的药物组合物,其特征在于,所述取代或未取代的环烷基为取代或未取代的金刚烷基环,其式为:
其中,各个B1、B2和B3独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基。
18.如权利要求17所述的药物组合物,其特征在于,B1、B2和B3各自独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C2烷基、取代或未取代的C2烯基、取代或未取代的C2炔基、取代或未取代的OC1-C2烷基、取代或未取代的OC2烯基、取代或未取代的OC2炔基、取代或未取代的NHC1-C2烷基、取代或未取代的NHC2烯基、取代或未取代的NHC2炔基。
19.如权利要求18所述的药物组合物,其特征在于,B1、B2和B3各自独立地选自下组:H、F、Cl、Br、I、OH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)或OCHmBr(3-m)。
20.如权利要求1所述的药物组合物,其特征在于,所述化合物选自下组:
21.一种方法,包括:
将如权利要求1至20中任一项所述的药物组合物施用给对象。
22.如权利要求21所述的方法,其特征在于,所述方法包括:以有效治疗或预防对象的疾病的量,将药学上可接受的组合物施用给所述对象。
23.如权利要求22所述的方法,其特征在于,所述疾病选自下组:
社交功能障碍,其包括:社会退缩、攻击性、反社会障碍或对物质成瘾;
精神疾病,其包括:自闭症谱系障碍、社交焦虑症、包括重度抑郁症的抑郁症,或精神分裂症。
24.如权利要求23所述的方法,其特征在于,所述物质选自下组:酒精、可卡因、鸦片剂、苯丙胺类、海洛因和尼古丁。
25.如权利要求22所述的方法,其特征在于,所述方法包括:将所述药物组合物施用给:
患有物质滥用障碍或正从物质滥用障碍恢复的对象;或者
正从物质滥用障碍恢复并寻求维持对物质的持续禁欲的对象。
26.如权利要求1至20中任一所述的药物组合物用于治疗或预防对象的疾病,和/或维持对象对物质的持续禁欲的用途。
27.一种式I化合物用于制造用于治疗疾病的药物的用途,其特征在于,所述疾病选自下组:社交功能障碍,其包括:社会退缩、攻击性、反社会障碍或对物质成瘾;或者,精神疾病,其包括:自闭症谱系障碍、社交焦虑症、包括重度抑郁症在内的抑郁症、或精神分裂症;
其中,R1、R3、R4、R5或R6各自独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、取代或未取代的芳基,或者取代或未取代的杂环基;
其中R2独立地选自下组:H、F、Br、I、NH2、NO2、OH、ON=O、取代的甲基、取代或未取代的C2-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、取代或未取代的芳基,或者取代或未取代的杂环基;
其中,为取代的芳基或取代的杂芳基的各个R1、R2、R3、R4、R5、或R6包括一个或多个选自下组的取代基:F、Cl、Br、I、NH2、N=O、NO2、NHCH3、OH、OCH3、OC≡N、ON=O、SH、SCH3、S(=O)nOH、S(=O)nCH3、SC≡N、COOH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)、或OCHmBr(3-m);
其中,X为选自下组的环状结构:取代或未取代的、稠合或未稠合的芳基;取代或未取代的、稠合或未稠合的杂环基;或者取代或未取代的、稠合或未稠合的环烷基;以及
其中,各个X1代表一个或多个独立地选自下组的原子或基团:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、COOH、C1烷基-COOH、COOC1-C2烷基、COOC1-C2烷基芳基、C1烷基-COOC1-C2烷基、C1-C2烷基芳基、OC1-C2烷基芳基、NC1-C2烷基芳基、C1-C2烷基-杂环基、OC1-C2烷基-杂环基、NC1-C2烷基-杂环基;
其中,各个取代的烷基、烯基、炔基、烷基芳基、烷基-杂环基包括一个或多个选自下组的取代基:F、Cl、Br、I、≡N、=NH、NH2、N=O、NO2、NHCH3、N=C=O、N=C=S、=O、OH、OCH3、OC≡N、ON=O、=S、SH、SCH3、S(=O)nOH、S(=O)nCH3和SC≡N;
其中,各个m是选自0、1或2的整数;以及
各个n是选自0、1或2的整数。
28.一种式I化合物
其中,R1、R3、R4、R5或R6各自独立地选自下组:H、F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、取代或未取代的芳基,或者取代或未取代的杂环基;
其中R2独立地选自下组:H、F、Br、I、NH2、NO2、OH、ON=O、取代的甲基、取代或未取代的C2-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、取代或未取代的芳基,或者取代或未取代的杂环基;
其中,为取代的芳基或取代的杂芳基的各个R1、R2、R3、R4、R5、或R6包括一个或多个选自下组的取代基:F、Cl、Br、I、NH2、N=O、NO2、NHCH3、OH、OCH3、OC≡N、ON=O、SH、SCH3、S(=O)nOH、S(=O)nCH3、SC≡N、COOH、CH3、CHmF(3-m)、CHmCl(3-m)、CHmBr(3-m)、OCH3、OCHmF(3-m)、OCHmCl(3-m)、或OCHmBr(3-m);
其中,X为选自下组的环状结构:取代或未取代的、稠合或未稠合的芳基;取代或未取代的、稠合或未稠合的杂环基;或者取代或未取代的、稠合或未稠合的环烷基;以及
其中,各个X1代表一个或多个独立地选自下组的原子或基团:F、Cl、Br、I、NH2、NO2、OH、ON=O、取代或未取代的C1-C4烷基、取代或未取代的C2-C4烯基、取代或未取代的C2-C4炔基、取代或未取代的OC1-C4烷基、取代或未取代的OC2-C4烯基、取代或未取代的OC2-C4炔基、取代或未取代的NHC1-C4烷基、取代或未取代的NHC2-C4烯基、取代或未取代的NHC2-C4炔基、COOH、C1烷基-COOH、COOC1-C2烷基、COOC1-C2烷基芳基、C1烷基-COOC1-C2烷基、C1-C2烷基芳基、OC1-C2烷基芳基、NC1-C2烷基芳基、C1-C2烷基-杂环基、OC1-C2烷基-杂环基、NC1-C2烷基-杂环基;
其中,各个取代的烷基、烯基、或炔基包括一个或多个选自下组的取代基:F、Cl、Br、I、≡N、=NH、NH2、N=O、NO2、NHCH3、N=C=O、N=C=S、=O、OH、OCH3、OC≡N、ON=O、=S、SH、SCH3、S(=O)nOH、S(=O)nCH3和SC≡N;
其中,各个m是选自0、1或2的整数;以及
各个n是选自0、1或2的整数;以及
其中所述的化合物不选自下组:
当A1为H时;A2为CH3;且A3为CH2CH2COOH、CH=CHCOOH、OCH2CH2CH2COOH、CH2NH2、CH2CH2C(=O)NHCH3、C≡N、NH2或NO2中的任何一种;或者当A1为H时;A2为H;且A3为OH;或者当A1为F时,A2为H,和A3为CH2NH2;或者
一种化合物,其中所述取代或未取代的环烷基为取代的环己烷基团。
29.一种化合物,选自下组:
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