CN116514790A - 一类靶向于stat3的三联芳香杂环哌嗪类小分子有机化合物及其应用 - Google Patents
一类靶向于stat3的三联芳香杂环哌嗪类小分子有机化合物及其应用 Download PDFInfo
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- CN116514790A CN116514790A CN202210082125.8A CN202210082125A CN116514790A CN 116514790 A CN116514790 A CN 116514790A CN 202210082125 A CN202210082125 A CN 202210082125A CN 116514790 A CN116514790 A CN 116514790A
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- oxadiazolyl
- phenyl
- piperazinyl
- trifluoromethyl
- benzyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类靶向于STAT3双磷酸化位点的三联芳香杂环哌嗪类小分子有机化合物,其为式(I‑V)结构所示化合物以及含有(I‑V)化合物的药物组合物、药学上可接受的盐、溶剂化物、代谢产物或前药。本发明还公开了所述三联芳香杂环哌嗪类小分子有机化合物,作为STAT3抑制剂在制备预防和/或治疗STAT3介导或调控的疾病的药物中的应用。
Description
技术领域
本发明涉及生物医药领域,具体涉及一类新型、特异性靶向STAT3的三联芳香杂环哌嗪类小分子有机化合物及其衍生物,以及所述三联芳香杂环哌嗪类类小分子有机化合物或含有该类化合物的药物组合物能够在制备抗肿瘤药物中的应用。
背景技术
信号传导和转录活化因子3(Signal transducers and activators oftranscription 3,STAT3)是STATs家族(STAT1,STAT2,STAT3,STAT4,STAT5a,STAT5a和STAT6)的重要成员之一,主要负责转导胞外信号从而促进细胞的生存和增殖等功能,是多条信号通路发挥功能的关键蛋白。STAT3蛋白结构由六个部分组成,包括N端结构域(NTD),卷曲结构域(CCD),DNA结合结构域(DBD),连接结构域(LD),SH2结构域,以及C端转录区域(CTD),其中高度保守的SH2结构域主要参与受体的招募以及STAT3同源或异元二聚体的形成,是目前开发选择性靶向STAT3抑制剂的热点区域和主要策略之一。
在正常生理功能下,STAT3主要表现为瞬时激活,而在肿瘤等病理条件下STAT3常表现为持续性活化。STAT3活化主要通过经典和非经典两种信号通路。在经典信号通路中,STAT3主要发挥其转录活性功能,在上游信号通路的刺激下,STAT3酪氨酸残基(Tyr705)被非受体酪氨酸激酶如JAK磷酸化,然后与另一个磷酸化的STAT3在SH2结构域相互作用形成二聚体并随后转运进入细胞核中与相应的DNA序列结合从而启动靶基因的转录。此外,以STAT3-Ser727磷酸化介导的活化过程称为STAT3非经典信号途径。在丝氨酸激酶如在MAPK的作用下,STAT3-Ser727发生磷酸化,其一方面能够进一步增强Tyr705介导的转录活性功能从而使STAT3的转录活性最大化,另一方面是进入线粒体影响细胞的代谢过程,包括加强电子传递链(ETC)的活性,增加ATP的产生,影响线粒体通透性过渡孔(mPTP)的开启,加强线粒体DNA(mtDNA)的转录(Cytokine,2016;87:20-5)。过去很长一段时间,STAT3-Tyr705磷酸化介导的STAT3经典活化途径促进肿瘤的发生发展早已被大量的实验结果证明,但近十年来,越来越多的证据表明STAT3-Ser727磷酸化同样影响着肿瘤的发生发展过程,尤其对肿瘤细胞的氧化磷酸化过程的改变(CancerRes.201915;79(20):5272-5287)。此外,Ser727磷酸化还能促进RAS突变依赖的肿瘤细胞发生恶性转化,而这一过程不依赖于Tyr705磷酸化。
近年来,越来越多的研究表明,STAT3 Tyr705和Ser727磷酸化均被发现同时在各种癌症中,如胰腺癌、胃癌、前列腺癌、肝癌、结肠癌以及多种血液瘤中高表达,且通过基因编辑手段条件敲低STAT3显示在体内外能显著抑制多种肿瘤模型的增长,其进一步证明STAT3异常活化能促进肿瘤的发生发展过程(Nat Rev Cancer.201919(2):82-96)。此外,STAT3的异常活化与结肠癌、胃癌等多种肿瘤较差的总体生存率与不良预后存在重要联系。总的来说,目前研究表明STAT3 Tyr705和Ser727磷酸化异常表达在肿瘤进展中均发挥着重要的作用,然而目前针对STAT3双位点磷酸化的抑制剂开发还处在早期阶段,因此,开发高效的STAT3双磷酸化位点抑制剂将能填补市场的空白。
STAT3小分子抑制剂的开发近年来受到广泛关注,然而目前为止大部分STAT3直接抑制剂仍然处于临床前研究,只有少部分进入临床试验中,其中以进展较快的STAT3信号通路抑制剂BBI-608(Napabucasin)为代表,在胃癌、胰腺癌研究中已经进入三期临床实验,且在2016年相继获得FDA在胰腺癌和胃癌中孤儿药资格认证。遗憾的是,最近临床数据显示BBI-608在三期临床试验中由于治疗效果不佳,不得不面临三期临床实验失败的结局(Lancet Gastroenterol Hepatol.2018Apr;3(4):263-270.)。分析其失败原因,首先是其在多种抗肿瘤模型中,BBI-608的体内外的抗肿瘤活性仍需进一步提高;另外,大量文献已经证实BBI-608除STAT3外还有多个作用靶点,且选择性较差,从而具有潜在的治疗毒性。因此,继续开发选择性靶向STAT3的高活性抑制剂具有较大的治疗意义和市场前景。
在开发STAT3抑制剂方面,我们课题组经过多年的努力已经积攒了多年的经验,通过前期大量的投入与发展,发现一类以吲哚环为母核的三芳香杂环磷酸化双功能STAT3小分子抑制剂(CN112300145A),该类抑制剂通过高活性的抑制STAT3的双位点磷酸化从而在多种肿瘤模型中具有较优的抗肿瘤效果,然而该类抑制剂的成药性较差,尤其在理化性质方面需要进一步的提高。通过分析,我们发现其可能原因是由于该类结构分子量偏大,其次是其结构分子刚性较强,限制了与水分子的结合。因此,为了开发成药性更好,理化性质更优的高活性STAT3双磷酸化位点抑制剂,我们利用基于结构的药物设计(SBDD)等技术对STAT3活性口袋进行了系统分析,降低结构骨架的刚性,进一步研究发现了一类分子量更小,溶解性更好的STAT3抑制剂,即本发明所涉及的三联芳香杂环哌嗪类小分子抑制剂,该类抑制剂能在低nM水平同时抑制STAT3 Tyr705和Ser727的磷酸化,从而在体内外达到较好的抗肿瘤效果。为提升该类化合物的溶解性,我们在设计的过程中打破原来以吲哚环为核心结构的分子骨架,有意识的减少其分子量,且在合成了过程中引入吗啉环、羟基、氨基等亲水性结构。经一系列设计和多次结构优化过程后获得一类新型三联芳香杂环哌嗪类化合物,相关实验数据表明,该类新型三联芳香杂环哌嗪类STAT3双磷酸化位点抑制剂对STAT3抑制活性及抗肿瘤活性远远优于阳性化合物BBI-608,且其水溶性较前期开发的双功能STAT3磷酸化抑制剂代表性化合物实施列6(CN112300145A)有了显著性提高。
总的来说,STAT3 Tyr705和Ser727磷酸化表达异常与多种人类疾病,尤其是多种肿瘤的发生发展显著相关,因此开发靶向STAT3双磷酸化位点抑制剂具有较高的临床需求和开发意义。通过不断的研究与发展,在本发明中我们公布了一类抗肿瘤活性较优,理化性质更好的新型三联芳香杂环哌嗪类STAT3双磷酸化位点抑制剂,该类抑制剂对多种与STAT3活化异常的人类疾病具有潜在的治疗意义和市场开发前景。
发明内容
本发明的目的是设计合成一类新型、高效并特异性靶向STAT3的SH2结构域的小分子三联芳香杂环哌嗪类抑制剂,其可以同时抑制STAT3的Tyr705和Ser727位点的磷酸化,具有更好的成药属性。
本发明提供了一类靶向于STAT3双磷酸化位点的三联芳香杂环哌嗪类小分子有机化合物,其包含如式(Ⅰ)所示化合物及其相关类似物或药学上可接受的盐、代谢产物或前药;
其中:
选自5至8元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑、萘环、菲环、喹啉、异喹啉、吲哚、苯并二氮唑、苯并三氮唑、嘌呤;
选自芳香杂环,取自下列中的任意一个:噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑,1,2,4-三氮唑、四氮唑;
选自5元或6元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑;
X独立选自下列基团中的任意一个:-(CH2)n-、
n、m表示0~5;
R1、R2、R3、R4独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C6烷基、C2~C6烯基、C2~C6炔基、C1~C6烷氧基、C1~C6烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基、C5~C10芳香基,5-10元杂芳香基;
任选地,所述C5~C10芳香基,5-10元杂芳香基各自独立地选自下列基团中的任意一个或多个:卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2。
本发明所述式(Ⅰ)中,当R3为时,所述三联芳香杂环哌嗪类小分子有机化合物及其相关类似物或药学上可接受的盐、代谢产物或前药的结构如式(Ⅱ)所示:
其中:
选自5至8元芳香环或芳香杂环,取自下列的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑、萘环、菲环、喹啉、异喹啉、吲哚、苯并二氮唑、苯并三氮唑、嘌呤;
选自芳香杂环,取自下列中的任意一个:噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑、四氮唑;
选自5元或6元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑,1,2,4-三氮唑;
X独立选自下列基团中的任意一个:-(CH2)n-、
n、m表示0~5;
R1、R2、R4独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C6烷基、C2~C6烯基、C2~C6炔基、C1~C6烷氧基、C1~C6烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基、C5~C10芳香基,5-10元杂芳香基;
任选地,所述C5~C10芳香基,5-10元杂芳香基各自独立地选自下列基团中的任意一个或多个:卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2;
R8独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2。
本发明所述式(Ⅱ)中,当为/>时,所述三联芳香杂环哌嗪类小分子有机化合物及其相关类似物或药学上可接受的盐、代谢产物或前药的结构如式(Ⅲ)所示:
其中:
选自5至8元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑、萘环、菲环、喹啉、异喹啉、吲哚、苯并二氮唑、苯并三氮唑、嘌呤;
选自5元或6元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑;
X独立选自下列基团中的任意一个:-(CH2)n-、
n、m表示0~5;
R1、R2、R4独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C6烷基、C2~C6烯基、C2~C6炔基、C1~C6烷氧基、C1~C6烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基、C5~C10芳香基,5-10元杂芳香基;
任选地,所述C5~C10芳香基,5-10元杂芳香基各自独立地选自下列基团中的任意一个或多个:卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2;
R8独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2。
本发明所述式(Ⅲ)中,当为苯环;/>为吡啶环时,所述三联芳香杂环哌嗪类小分子有机化合物及其相关类似物或药学上可接受的盐、代谢产物或前药的结构如(IV)所示:
其中:
X独立选自下列基团中的任意一个:-(CH2)n-、
n、m表示0~5;
R1和R2独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C6烷基、C2~C6烯基、C2~C6炔基、C1~C6烷氧基、C1~C6烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基、C5~C10芳香基,5-10元杂芳香基;
任选地,所述C5~C10芳香基,5-10元杂芳香基各自独立地选自下列基团中的任意一个或多个:卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2;
R8独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2。
本发明所述式(IV)中,当X为羰基时,所述三联芳香杂环哌嗪类小分子有机化合物及其相关类似物或药学上可接受的盐、代谢产物或前药的结构如(V)所示:
其中:
R1和R2独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C6烷基、C2~C6烯基、C2~C6炔基、C1~C6烷氧基、C1~C6烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基C5~C10芳香基,5-10元杂芳香基;
任选地,所述C5~C10芳香基,5-10元杂芳香基各自独立地被一个或多个选自卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2;
R8独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2。
本发明所述靶向于STAT3双磷酸化位点的三联芳香杂环哌嗪类小分子有机化合物包括如下列示之任何一个化合物,或其药学上可接受的盐,代谢产物或前药:
4-甲基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-乙基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-丙基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(三氟甲氧基)苯甲酰基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(三氟甲氧基)苯甲酰基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)乙酮
(E)(3-(4-(三氟甲氧基)苯基)(1-(4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)(1-哌嗪基)丙(2-烯-1-酮
1-(4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)(1-哌嗪基)丙(2-烯(1-酮
(4-(4-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-溴苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-溴(3-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮
(4-(4-溴(2-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮
(4-(4-溴-2,6-二氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮
(4-(3,4-二溴苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)甲酮
(4-(3-氟-4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(3-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(2-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(3-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-甲氧基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-氨基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
叔丁基(4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟碱基](1-哌嗪基)甲基)苯基)氨基甲酸酯
(4-(4-乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
乙酸4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基]烟酰基)(1-哌嗪基)甲基)苯基乙酸酯
(4-(4-(叔丁基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-甲基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(甲基磺酰基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
((4-(4-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
((4-(4-氯苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基](1-哌嗪基)甲基)苄腈
(4-(4-(4-(甲基磺酰基)(1-哌啶基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-((4-四氢-2H-吡喃)氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(4-(5-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(3-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(2-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(4-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(3-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)-2噻吩基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-噻唑基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(4-(4-(三氟甲基)苯基)(2-噁唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(4-(4-(三氟甲基)苯基)(2-噻唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(1-(4-(三氟甲基)苯基)(4-(1,2,3-三唑基)(3-吡啶基)甲酮
(6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮
(6-(3-(-2噻吩基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮
(6-(3-(5-噻唑基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮
(6-(3-(5-噻唑基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮
(6-(3-(4-嘧啶基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮
(6-(3-苯基(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(2-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(3-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(2-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(3-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-氯苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-溴苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(叔丁基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(6-(3-(3-氟-4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮
(6-(3-(2,4-双(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮
(3-甲基-4-(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(R)-(3-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(S)-(3-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(2-甲基-4-(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(S)-(2-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(R)-(2-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮
(1-(4-(2,2,2-三氟乙氧基)苄基)(4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)哌嗪-2-腈
4-(4-(2,2,2-三氟乙氧基)苄基)(1-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)哌嗪-2-腈
(2,6-二甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮
(3,5-二甲基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮
4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)吡啶(3-基)哌嗪甲酰胺
N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(3,3,3-三氟丙基)哌嗪甲酰胺
4-(4-甲氧基苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺
4-(4-(甲基磺酰基)苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺
4-(4-(三氟甲氧基)苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺
4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(4-(三氟甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺
N-(6-(3-(4-甲氧基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺
N-(6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺
N-(6-(3-(4-氯苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺
N-(6-(3-(4-溴苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺
N-(6-(3-(4-硝基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺
N-(6-(3-(3-三氟甲基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺
N-(6-(3-(4-叔丁基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺
4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(6-(三氟甲基)(3-吡啶基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺
N-(6-(3-(3-氯-4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺
在本发明中所使用的术语,“五元或六元芳杂环”是指具有一个或多个选自氮、氧或硫的杂原子的5元至6元的芳香环,非限制性地包括苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑,1,2,4-三氮唑等。
本发明术语“C1~C6烷基”是指具有1至6个碳原子的直链或支链烷烃基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等。
本发明术语“C2~C6烯基”,是指具有2至6个碳原子的至少含一个双键的直链或支链烯烃基、非限制性地包括乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、丁二烯基、戊烯基、戊二烯基、已烯基、已二烯基、已三烯基等。
本发明术语“C2~C6炔基”,是指具有2至6个碳原子的至少含一个三键的直链或支链炔烃基、非限制性地包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、丁二炔基、戊炔基、戊二炔基、已炔基、已二炔基等。
本发明术语“C1~C6烷氧基”,是指具有1至6个碳原子的至少含一个氧原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、乙氧基甲氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、2-戊氧基、3-戊氧基、2-甲基(2-丁氧基、3-甲基(2-丁氧基、3-甲基(1-丁氧基、2-甲基(1-丁氧基、正己氧基等。
本发明术语“C1~C6烷硫基”,是指具有1至6个碳原子的至少含一个硫原子的直链或支链烷硫基,非限制性地包括甲硫基,乙硫基,丙硫基、乙硫基甲硫基、异丙硫基,正丁硫基、异丁硫基、仲丁硫基、叔丁硫基、正戊硫基、2-戊硫基、3-戊硫基、2-甲基(2-丁硫基、3-甲基(2-丁硫基、3-甲基(1-丁硫基、2-甲基(1-丁硫基、正己硫基等。
本发明术语“C3~C6环烷基”,是指具有3至6个碳原子的环烷烃,非限制性地包括环丙基、环丁基、环戊基、环己基等。
本发明术语“C2~C6环烷氧基”,是指具有2至6个碳原子的至少含一个氧原子的环烷氧基,非限制性地包括环氧乙烷基、环氧丙烷基、四氢呋喃基、四氢吡喃基等。
本发明术语“C2~C6含氮环烷基”,是指具有2至6个碳原子的至少含一个氮原子的环烷基,非限制性地包括四氢吡咯基、吗啉基等。
本发明术语“C5~C10芳香基”,是指环上不含杂原子的具有5至10个碳原子的芳香族环基,非限制性地包括苯基、萘基、菲基等。
本发明术语“5-10元杂芳香基”具有一个或多个选自氮、氧或硫的杂原子的5元至10元的芳香环,非限制性地包括吡啶基、嘧啶基、噻唑基、异噻唑基、呋喃基、噻吩基、吡咯基,吲哚基、喹啉基、异喹啉基等。
本发明术语“卤素”是指氟、氯、溴、或碘。
本发明术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、胺、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实施包括无机酸盐,所述无机酸盐包括例如盐酸、氢溴酸、硝酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡萄糖醛酸等有机酸的盐。本发明的某些特定的化合物含有酸性和碱性的官能团,从而可以被转换成任一碱或酸加成盐。
除了盐的形式,本发明所提供的化合物还存在前药形式。本发明所描述的化合物的前药容易在生理条件下发生化学变化从而转化成本发明的化合物。可在体内转化以提供生物活性物质(即式Ⅰ~V所示STAT3的三联芳香杂环哌嗪类类小分子有机化合物)的任何化合物是在本发明的范围和主旨内的前药。例如,含有羧基的化合物可形成生理上可水解的酯,其通过在体内水解已得到式(Ⅰ~V)所示STAT3的三联芳香杂环哌嗪类类小分子有机化合物本身而充当前药。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内,包括顺式和反式异构体、(-)-和(+)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,所有这些异构体以及他们的混合物,均包括在本发明的范围之内。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用同位素标记化合物,比如氘(2H),氚(3H),碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换,无论放射与否,都包括在本发明的范围之内。
本发明术语“赋形剂”通常是指配置有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言,术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型,组合物中一种活性物质的“有效量”是指该组合物中另一种活性物质联用时为了达到预期效果所需的用量。有效量的确定因人而异,取决于受体的年龄和一般情况,也取决于具体的活性物质,个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本发明术语“活性成分”、“治疗剂”,“活性物质”或“活性剂”是指一种化学实体,它可以有效治疗目标紊乱、疾病或病症。
本发明术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即C=O时)意味着两个氢原子被取代。酮取代不会直接发生在芳香基上。
本发明术语“任意被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任意地至多被两个R所取代,并且每种情况下的R都是独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本发明术语“包含”为开放式表达,即包括本发明所指明的内容,但不排除其他方面的内容。
本发明还提供了一种药物组合物,所述药物组合物含有治疗剂量的前述式Ⅰ~V所示的STAT3的三联芳香杂环哌嗪类类小分子有机化合物。
本发明“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,或其他组分例如生理盐水/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
根据本发明的具体实施例,所述药物组合物进一步包括第二药剂。
所述第二药剂用于预防和/或治疗癌症。
根据本发明的具体实施例,所述药物组合物进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。
根据本发明的具体实施例,所述药物组合物呈片剂、可注射流体、胶囊、注射剂,粉针剂,乳膏、凝胶剂、丸剂、粉剂、糖浆、溶液状、透皮贴剂、悬浮液或气雾剂。由此可以显著提高该药物组合物的适用性。并且本发明上述实施例的药物组合物可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒容器中。
本发明所述的药物组合物的各种剂型可按照药学领域的常规制备方法制备。本发明式Ⅰ~V所示STAT3的三联芳香杂环哌嗪类类小分子有机化合物和药物组合物可对哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺或者胃肠道等的途径给药。不管采用何种服用方法,个人的最佳剂量应依据具体的治疗方案而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最合适的剂量。最优选的给药途径为口服或者皮肤给药。
本发明还提出了一类STAT3抑制剂,其包括所述的靶向STAT3的三联芳香杂环哌嗪类类小分子有机化合物及药学上可接受的盐、代谢产物或前药。
根据本发明的具体示例,本发明所述式Ⅰ-V所示STAT3的三联芳香杂环哌嗪类类小分子有机化合物对STAT3有明显的结合作用。
根据本发明的具体示例,本发明所述式Ⅰ-V所示STAT3的三联芳香杂环哌嗪类类小分子有机化合物有较强的选择性靶向STAT3的SH2结合结构域作用。
根据本发明的具体示例,本发明所述式Ⅰ-V所示STAT3的三联芳香杂环哌嗪类类小分子有机化合物对STAT3双酸化位点(Tyr705和Ser727)有明显的抑制作用。
据本发明的具体示例,本发明所述式Ⅰ-V所示STAT3的三联芳香杂环哌嗪类类小分子有机化合物通过抑制STAT3 Ser727磷酸化从而抑制线粒体氧化磷酸化的作用。
根据本发明示例,本发明所述式Ⅰ-V所示STAT3的三联芳香杂环哌嗪类类小分子有机化合物能够对多种癌细胞的增殖、生长、浸润、克隆形成和转移都有明显的抑制作用,对多种癌细胞的凋亡、自噬都有明显的促进作用,可以延长肿瘤患者的生存期。
根据本发明的实施例,第二药剂与式Ⅰ-V所示STAT3的三联芳香杂环哌嗪类类小分子有机化合物的联用,使得所述药物组合物更加有效地用于抑制STAT3,并且用于治疗或者预防癌症、肾纤维化、肺纤维化、类风湿性关节炎、银屑病、红斑狼疮、炎性肺病和炎性肠病等。
本发明所述药物能够有效作为STAT3抑制剂,用于治疗与STAT3和线粒体氧化磷酸化活化有关的疾病,所述疾病包括如消化系统肿瘤食管癌、胃癌、大肠癌、结肠癌、直肠癌、肛门癌;呼吸系统肿瘤喉癌、支气管癌、非小细胞肺癌、小细胞肺癌等;实体瘤肝癌、胰腺癌、星形神经胶质瘤、卵巢癌、前列腺癌等;血液瘤恶性淋巴瘤、非霍奇金氏淋巴瘤、霍奇金氏病、多发性骨髓瘤、浆细胞性肿瘤、急性骨髓性白血病、急性淋巴性白血病、成人T细胞白血病淋巴瘤、慢性骨髓性白血病、慢性淋巴性白血病;上述肿瘤及癌的转移病灶等。根据本发明的实施例,所述药物组合物进一步包括第二药剂,所述第二药剂不同于前面所述化合物并且用于治疗或者预防癌症、肾纤维化、肺纤维化、类风湿性关节炎、银屑病、红斑狼疮、炎性肺病和炎性肠病等。其作为STAT3双磷酸化抑制剂,具有良好的临床应用和医药用途。
本发明进一步提出了一种预防和/或治疗与STAT3双功能磷酸化位点活化有关的疾病的方法,包括向肿瘤患者中施于有效量的如上所述的化合物或药物组合物。
本发明提出了所述式Ⅰ~V所示STAT3的三联芳香杂环哌嗪类类小分子有机化合物的制备方法,所述化合物取自于下列合成方法中的任意一种,其中R1、R2和R3如本发明上述所定义。
其中,合成方法1如下所示:
合成方法2如下所示:
合成方法3如下所示:
合成方法4如下所示:
合成方法5如下所示:
合成方法6如下所示:
合成方法7如下所示:
本发明的有益效果在于:本发明提供的靶向STAT3双磷酸化位点的三联芳香杂环哌嗪类小分子有机化合物或药物组合物可作为STAT3抑制剂,用于预防和/或治疗与STAT3双功能磷酸化位点活化、线粒体氧化磷酸化引起或调控的疾病,具有良好的临床应用和医药用途。
附图说明
图1所示为代表性化合物HP1-034在肿瘤细胞中对STAT3的双磷酸化位点及下游靶基因的抑制作用。
图2所示为代表性化合物HP1-034对胃癌细胞的克隆形成的影响。
图3所示为代表性化合物HP1-034在体内的抗肿瘤作用。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
一、本发明化合物的具体合成
实施例1-1,(4-甲基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-001)的合成。
于100ml圆底烧瓶中称取5-(甲氧羰基)(2-吡啶羧酸(1.0g,5.5mmol),对三氟甲基苯甲酰胺肟(1.4g,6.6mmol),HATU(2.5g,6.6mmol)溶于10ml DMF中,加入N,N-二异丙基乙胺(1.9ml,11.0mmol),常温搅拌2h,加水析出大量固体,抽滤,干燥固体,然后将固体溶于10ml DMF中,加热至120℃,反应2h,后处理后得到中间体6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酸甲酯1.3g,产率70%;然后将中间体6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酸甲酯(1.3g,3.9mmol)溶于32ml CH3OH:H2O=4:1混合溶剂中,加入LiOH.H2O(0.63g,15.6mmol),室温搅拌5h,除去甲醇溶剂,用2M HCl溶液调pH至酸性,抽滤,干燥固体得到中间体6-(3-(4-(三氟甲基)苯基)-5(-1,2,4-噁二唑基)烟酸1.2g,产率90%;称取中间体6-(3-(4-(三氟甲基)苯基)-5(-1,2,4-噁二唑基)烟酸(1.2g,3.6mmol),1-Boc-哌嗪(0.8g,4.3mmol),HATU(1.6g,4.3mmol)溶于DMF溶液中,加入N,N-二异丙基乙胺(1.3ml,7.2mmol),常温搅拌2h,经常规后处理得到中间体4-(6-(3-(4-(三(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)哌嗪(1-甲酸叔丁酯1.6g,产率85%;将中间体4-(6-(3-(4-(三(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)哌嗪(1-甲酸叔丁酯(1.6g,3.1mmol)溶于二氯甲烷溶液中,加入1.4-二氧六环盐酸气31mmol,反应2h,除去二氯甲烷溶剂,得到中间体(1-哌嗪基(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮盐酸盐1.3g,产率95%;称取中间体(1-哌嗪基(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮盐酸盐(100mg,0.2mmol),K2CO3(62mg,0.4mmol)溶于DMF溶液中,加入碘甲烷(39mg,0.3mmol),室温反应2h,加入适量水,用乙酸乙酯萃取三次,无水硫酸钠干燥,柱层析纯化,得到白色产物(4-甲基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-001)75mg,产率90%。1H NMR(500MHz,CDCl3)δ8.90(d,J=1.4Hz,1H),8.37(dd,J=10.5,8.4Hz,3H),8.09–7.97(m,1H),7.79(d,J=8.3Hz,2H),3.86(s,2H),3.47(s,2H),2.55(s,2H),2.41(s,2H),2.35(s,3H).
二、本发明化合物对STAT3依赖的荧光素酶报告基因(Luciferase reporter)的抑制活性和对肿瘤细胞ATP产生的抑制活性以及抗肿瘤增殖活性评价。
1.技术方法:
(1)荧光素酶报告基因检测
在HEK293T中进行STAT3荧光素酶报告基因检测。将HEK293T铺于10cm皿,在80-90%密度时,共转STAT3荧光素酶报告质粒与Renilla质粒至24h。消化细胞,以合适密度铺于96孔板,过夜培养后,在除对照孔以外的孔中,加入IL-6(20ng/mL)及不同浓度本发明实施例制备的化合物,孵育4-8h后,裂解细胞,收集裂解液并加入STAT3荧光素酶报告基因luciferase底物,检测荧光,确定本发明实施例制备的化合物的抑制活性。
(2)肿瘤细胞ATP生成的检测
ATP检测根据ATP需提供能量以催化萤火虫萤光素酶转变为萤光素,从而当体系中萤光素酶和萤光素均足量时,在一定的浓度范围内萤光的产生和ATP的浓度成正比,用于检测ATP含量。将细胞以适量密度铺于6孔板,过夜培养,第二天加入密度梯度的本发明实施例制备的化合物,处理22-24h,使用碧云天ATP检测试剂盒中裂解液裂解细胞,混匀充分裂解细胞,离心后,取上清进行检测。检测时,以ATP浓度0、0.1、1和10μM制备标准曲线。先将100μL的ATP检测液加入检测板,静置5min,以消耗本底ATP,之后加入标准浓度蛋白和不同浓度样品蛋白,在酶标仪进行ATP含量检测。
(3)MTS方法检测肿瘤细胞增殖
MTS实验是通过比色法测定活细胞数量,以确认细胞增殖的方法。MTS可被活细胞内线粒体内的琥珀酸脱氢酶还原,成橙黄色的有高度水溶性的甲瓒染料,在490nm处测量的吸光值(甲瓒含量)与活细胞的数量呈正比,从而反映细胞活力情况。运用此实验评价本发明实施例制备的化合物对胰腺癌、胃癌、肝癌细胞增殖的影响,从而判断其对细胞增殖的抑制率。细胞以6000-20000个/孔的密度,均匀铺于96孔板,过夜培养,根据本发明实施例制备的化合物以浓度梯度加入96孔板中,保持对照组加入同样体积的培养基,药物处理72后,进行MTS检测。GraphPad7 Prism软件用于不同化合物的IC50计算。
本发明化合物HP1-001至HP1-087对STAT3依赖的Luciferase抑制活性用IC50(半数抑制浓度)来表示;本发明化合物HP1-001至HP1-087对肿瘤细胞ATP生成的抑制活性用IC50(半数抑制浓度)来表示;本发明化合物HP1-001至HP1-087对胃癌、肺癌、胰腺癌、弥漫性大B细胞淋巴瘤的抗增殖活性用IC50(半数抑制浓度)来表示,上述测试结果见于表1。
表1.本发明化合物HP1-001至HP1-087体外对STAT3分子水平的抑制活性及体外抗肿瘤细胞增殖活性测试结果
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2、结论
2.1实验结果如表1所示,在STAT3依赖的Luciferase筛选体系中,本发明化合物HP1-001至HP1-087能在不同程度抑制其荧光素酶报告基因的表达,其中,大部分化合物能以低nM的活性抑制STAT3依赖的荧光素酶报告基因(Luciferase),表明该类化合物能靶向STAT3抑制其STAT3 Tyr705的磷酸化,从而抑制STAT3的转录功能;如IC50低于100nM抑制活性的HP1-004、HP1-006、HP1-008、HP1-010、HP1-012、HP1-018、HP1-019、HP1-021、HP1-023、HP1-028、HP1-032、HP1-036、HP1-039、HP1-040、HP1-047、HP1-057、HP1-058、HP1-064、HP1-079等化合物;IC50低于50nM的HP1-009、HP1-011、HP1-013、HP1-014、HP1-016、HP1-017、HP1-020、HP1-027、HP1-033、HP1-051、HP1-072、HP1-074等化合物;IC50低于10nM的HP1-005,HP1-026、HP1-031、HP1-034、HP1-042、HP1-054、HP1-061、HP1-070、HP1-073、HP1-077、HP1-086等化合物。
2.2表1显示本发明化合物HP1-001至HP1-087能在不同程度抑制肿瘤细胞ATP的生成,该实验用于表示化合物对STAT3-Ser727磷酸化的抑制活性,同Luciferase抑制活性类似,HP1-009、HP1-011、HP1-013、HP1-014、HP1-016、HP1-017、HP1-020、HP1-027、HP1-033、HP1-051、HP1-072、HP1-074等化合物以低于50nM的抑制活性,HP1-005,HP1-026、HP1-031、HP1-034、HP1-042、HP1-054、HP1-061、HP1-070、HP1-073、HP1-077、HP1-086等化合物以低于50nM的抑制活性抑制癌细胞MKN45中ATP的产生,表明该类化合物也能抑制STAT3 Ser727的磷酸化,从而抑制其介导的线粒体氧化磷酸化;此外,本发明大部分化合物对STAT3依赖的荧光素酶的抑制活性和对肿瘤细胞的ATP抑制活性具有一致性,表明本发明化合物能同时抑制STAT3 Tyr705和STAT3 Ser727的磷酸化。
2.3表1还展示了本发明化合物HP1-001至HP1-087对不同种类型肿瘤如消化系统肿瘤胃癌,呼吸系统肿瘤肺癌,实体瘤胰腺癌,血液瘤弥漫性大B细胞淋巴瘤的抑制活性,从结果可以发现,绝大部分化合物如HP1-005、HP1-009、HP1-013、HP1-016、HP1-017、HP1-018、HP1-020、HP1-026、HP1-031、HP1-033、HP1-034、HP1-035、HP1-044、HP1-049、HP1-051、HP1-054、HP1-059、HP1-061、HP1-070、HP1-073、HP1-074、HP1-077、HP1-081、HP1-086等以低于20nM的活性在不同类型的肿瘤细胞中都表现出优异的抗肿瘤细胞增殖效果,说明本发明化合物对不同类型肿瘤具有良好的抗增殖作用。
三、本发明部分化合物在不同pH下的动力学溶解度和热力学溶解度
1、技术方法:
(1)热力学溶解度的测量
a.将样品粉末(约2mg本发明实施例制备的化合物)分别加入EP管中。
b.分别在上述EP管中加入450μLpH 2,pH 7.4,pH 9的缓冲液,得到过饱和悬浮液。
c.将该悬浮液在摇床上旋转至少2分钟。
d.将样品在恒温孵育仪器上以800rpm的转速振荡24小时。
e.离心样品20分钟(eg.12000rpm)。
f.用0.45μm滤器过滤上清液,通过HPLC检测,用标准曲线计算浓度。
(2)动力学溶解度的测量
a.称取样品粉末(约1mg本发明实施例制备的化合物)溶于DMSO中,配成10mM的溶液,然后取10μL该溶液分别加入EP管中。
b.分别在上述EP管中加入450μLpH 2,pH 7.4,pH 9的缓冲液,得到过饱和悬浮液。
c.将该悬浮液在摇床上旋转至少2分钟。
d.在恒温孵育仪器上以800rpm的转速振荡EP管24小时。
e.离心样品20分钟(eg.12000rpm)。
f.用0.45μm滤器过滤上清液,通过HPLC检测,用标准曲线计算浓度。
表2.不同pH下代表性化合物的动力学溶解度和热力学溶解度
2、结论
为了快速评价本发明实施例制备的化合物的水溶性,本发明选取了部分在分子和细胞水平抑制活性均较好的化合物作为代表性化合物测量其热力学和动力学溶解度。结果显示,相比于本发明前期开发的同类产品中的代表性化合物(CN112300145A)(其溶解度在不同pH下的溶解度均小于<1.56),相比之下,本发明实施例制备的化合物的水溶性得到很大改善,包括代表性化合物HP1-018、HP1-022、HP1-033、HP1-034、HP1-035、HP1-051、HP1-058、HP1-061、HP1-072、HP1-074、HP1-084、HP1-086无论在动力学溶解度,还是热力学溶解度,其在酸性、中性及碱性条件下水溶性较同类产品中的代表性化合物(CN112300145A)明显提高。
四、本发明表性化合物在肿瘤细胞中对抑制STAT3 Tyr705和Ser727磷酸化及下游靶基因的表达。
1、技术方法:
(1)免疫印迹(Western Blot)
不同细胞经浓度梯度代表性本发明实施例制备的化合物(如HP1-018、HP1-022、HP1-033、HP1-034、HP1-035、HP1-051、HP1-058、HP1-061等)处理22-24h后,PBS清洗,加入含磷酸酶抑制剂、蛋白酶抑制剂的蛋白裂解液,冰上裂解30min,期间充分涡旋,裂解完全。将细胞裂解液进行离心、BCA定量。用10%的聚丙烯酰胺凝胶(SDS-PAGE)进行电泳以分离蛋白质样品,经转膜,封闭后,分别用STAT3及p-STAT3(p-STAT3 Tyr705、p-STAT3 Ser727)、关键下游蛋白(c-Myc和Cyclin D1)和GAPDH进行一抗4℃孵育,孵育时间10-14h。第二天,用相同来源的二抗孵育,最后用Odyssey扫膜仪检测不同化合物处理下相关蛋白的表达水平。
2、结论
实验结果如图1所示,图1A为本发明代表性化合物HP1-034在三株胃癌细胞的中抑制STAT3双磷酸化及其下游靶基因的表达,结果显示HP1-034能在40nM以下完全抑制三株胃癌细胞内p-STAT3 Tyr705和p-STAT3 Ser727及下游靶基因c-Myc和Cyclin D1的表达;图1B为HP1-034在mRNA水平对STAT3下游靶基因的抑制情况,结果显示HP1-034在40nM以下以浓度依赖的方式抑制下游靶基因的mRNA表达。这一结果更直观的表明该类抑制剂能同时抑制STAT3 Tyr705和Ser727的磷酸化。
另外,通过类似实验,结果发现本发明化合物HP1-009、HP1-011、HP1-013、HP1-014、HP1-016、HP1-017、HP1-020、HP1-027、HP1-033、HP1-005,HP1-026、HP1-031、HP1-034、HP1-042、HP1-054、HP1-061、HP1-070、HP1-073、HP1-077、HP1-086都可以以浓度依赖性抑制p-STAT3 Tyr705和p-STAT3 Ser727及下游靶基因c-Myc和Cyclin D1的表达。
五、本发明化合物对胃癌细胞的克隆形成的影响。
1、技术方法
(1)克隆形成
不同胃癌细胞以6000/孔铺于6孔板,待细胞贴壁后,按照浓度梯度,进行药物处理,孵育5-7天后,用4%多聚甲醛固定细胞20min,之后用0.2%的结晶紫进行染色30min。染色完成后,漂洗、晾干,最后拍照。
2、结论
代表性实验结果如图2所示,图2A为本发明化合物HP1-033对三株胃癌细胞克隆形成的抑制情况,统计图如图2C,结果显示HP1-033在20nM就能显著抑制三株胃癌细胞的克隆形成,相比正处于三期临床的STAT3抑制剂的BBI608(图2B、2D),其抑制活性具有显著性提高,该结果进一步证明该类化合物在体外对肿瘤细胞具有较好的抗增殖作用。
另外,通过类似实验,结果发现本发明化合物HP1-009、HP1-011、HP1-013、HP1-014、HP1-018、HP1-022、HP1-033、HP1-035、HP1-051、HP1-058、HP1-061、HP1-072、HP1-074、HP1-084和HP1-086在体外同样对肿瘤细胞的克隆形成具有较好的抑制作用。
六,本发明化合物在小鼠荷瘤实验中的抗肿瘤作用评估。
1、技术方法:
(1)裸鼠皮下荷瘤实验
将MKN45细胞消化后,用含50%基质胶的PBS重悬细胞。在6-8周,雄性裸鼠外侧皮下注射肿瘤细胞,细胞量为500W/只。待1周左右细胞成瘤后,将小鼠进行分组(CoNtrol、BBI608-50 mg/kg、本发明化合物HP1-034-25mg/kg和本发明化合物HP1-034 mg/kg),并根据小鼠分组进行药物处理。化合物使用0.5%甲基纤维素(MC)进行配置,给药方式为灌胃口服。其中,Control对照组小鼠100μL/天0.5%MC,BBI608组小鼠50mg/kg/天,HP1-034低剂量组小鼠25mg/kg/天,HP1-034高剂量组小鼠50mg/kg/天,每3-4天测量肿瘤的体积,按照公式体积=长×宽2×0.52,计算肿瘤体积,同时测量肿瘤重量,观测化合物安全性。在肿瘤体积到达2000mm3左右,处死小鼠并剥离肿瘤,进行肿瘤拍照并称重。
(2)肿瘤组织WB实验
将剥离的肿瘤分成特定大小用于WB检测。每组选取3个肿瘤块,加入蛋白裂解液,并使用组织碾磨仪破碎细胞,细胞裂解后经离心、BCA定量以及煮沸变性后,用10%的聚丙烯酰胺凝胶(SDS-PAGE)进行电泳以分离蛋白质样品,经转膜,封闭后,分别用STAT3及p-STAT3(p-Tyr705、p-Ser727)、关键下游(c-Myc和Cyclin D1)和GAPDH进行一抗4℃孵育,孵育时间10-14h。第二天,用相同来源的二抗孵育,最后用Odyssey扫膜仪检测不同化合物处理下相关蛋白的表达水平。
2、结论
实验结果如图3所示,在MKN45异种模型中,HP1-035显著抑制肿瘤生长,与阳性化合物BBI608有显著性优势(图3A和3C),且对小鼠体重无明显影响,显示化合物较低的毒性(图3B);另外,通过肿瘤组织WB实验发现HP1-034能显著抑制小鼠体内STAT3双位点的磷酸化及其下游基因的表达(图3D)。综上所述,HP1-034可以靶向STAT3抑制小鼠模型中胃癌肿瘤的生长。
另外,通过类似实验,结果发现HP1-005,HP1-026、HP1-031、HP1-034、HP1-042、HP1-054、HP1-061、HP1-070、HP1-073、HP1-077、HP1-086通过显著抑制小鼠体内STAT3双位点的磷酸化及其下游基因的表达从而抑制肿瘤增殖。
七,本发明代表性化合物的制备实施例
实施例7-1,(4-乙基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-002)的合成。
称取中间体(1-哌嗪基(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮盐酸盐(100mg,0.2mmol),K2CO3(62mg,0.4mmol)溶于DMF溶液中,加入溴乙烷(32mg,0.3mmol),室温反应3h,加入适量水,用乙酸乙酯萃取三次,无水硫酸钠干燥,柱层析纯化,得到白色产物((4-乙基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-002)64mg,产率75%。1H NMR(500MHz,CDCl3)δ8.93(d,J=1.7Hz,1H),8.44–8.36(m,3H),8.05(dd,J=8.0,2.0Hz,1H),7.82(d,J=8.3Hz,2H),3.89(s,2H),3.51(s,2H),2.61(s,2H),2.55–2.43(m,4H),1.14(t,J=7.2Hz,3H).
实施例7-2,(4-丙基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-003)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成溴丙烷,得到白色产物(4-丙基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(3)71g,产率78%。1H NMR(500MHz,DMSO)δ8.89(d,J=1.4Hz,1H),8.43(d,J=8.0Hz,1H),8.35(d,J=8.1Hz,2H),8.17(dd,J=8.0,2.1Hz,1H),8.02(d,J=8.3Hz,2H),3.68(s,2H),3.36(s,2H),2.47(s,2H),2.40–2.34(m,2H),2.32–2.25(m,2H),1.51–1.41(m,2H),0.87(t,J=7.4Hz,3H).
实施例7-3,1-(4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)(1-哌嗪基)丙(2-烯(1-酮(HP1-004)的合成。
称取中间体(1-哌嗪基(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮盐酸盐(100mg,0.2mmol)溶于二氯甲烷溶液中,加入丙烯酰氯(20mg,0.22mmol),冰浴下加入Et3N(30mg,0.3mmol),反应1h,加入适量水淬灭,用乙酸乙酯萃取三次,无水硫酸钠干燥,柱层析纯化,得到白色产物(1-(4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)(1-哌嗪基)丙(2-烯(1-酮(HP1-004)73mg,产率81%。1H NMR(500MHz,CDCl3)δ8.94(d,J=1.2Hz,1H),8.44(d,J=8.0Hz,1H),8.39(d,J=8.1Hz,2H),8.08(dd,J=8.0,2.1Hz,1H),7.82(d,J=8.2Hz,2H),6.60(s,1H),6.39(d,J=16.7Hz,1H),5.81(d,J=10.6Hz,1H),3.75(s,4H),3.54(s,4H).
实施例7-4,(4-(4-(三氟甲氧基)苯甲酰基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-005)的合成。
称取中间体(1-哌嗪基(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮盐酸盐(100mg,0.2mmol),对三氟甲氧基苯甲酸(49mg,0.24mmol),HATU(91mg,0.24mmol)溶于DMF溶液中,加入N,N-二异丙基乙胺(103mg,0.4mmol),常温搅拌2h,加入适量水,用乙酸乙酯萃取三次,无水硫酸钠干燥有机相,柱层析纯化得到白色产物(4-(4-(三氟甲氧基)苯甲酰基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-005)100mg,产率85%。1H NMR(500MHz,CDCl3)δ8.81(s,1H),8.32(d,J=8.0Hz,1H),8.30(d,J=8.1Hz,2H),8.07(dd,J=8.0,2.0Hz,1H),7.82(d,J=8.3Hz,2H),7.36(s,2H),7.52(d,J=7.8Hz,2H),3.80(s,4H),3.75–3.58(m,2H),3.49(s,2H).
实施例7-5,(4-(4-(三氟甲氧基)苯甲酰基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)乙酮(HP1-006)的合成。
采用与(HP1-005)相同的合成方法,将对三氟甲氧基苯甲酸换成对三氟甲氧基苯乙酸,得到白色产物(4-(4-(三氟甲氧基)苯甲酰基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)乙酮(HP1-006)99mg,产率82%。
1H NMR(500MHz,CDCl3)δ8.91(s,1H),8.42(d,J=8.0Hz,1H),8.38(d,J=8.1Hz,2H),8.04(dd,J=8.0,2.0Hz,1H),7.82(d,J=8.3Hz,2H),7.30(s,2H),7.22(d,J=7.8Hz,2H),3.80(s,4H),3.75–3.58(m,4H),3.49(s,2H).
实施例7-6,(E)(3-(4-(三氟甲氧基)苯基)(1-(4-(6-(3-(4-(三氟甲基)苯基)5-(-1,2,4-噁二唑基)烟酰基)(1-哌嗪基)丙(2-烯-1-酮(HP1-007)的合成。
采用与(HP1-005)相同的合成方法,将对三氟甲氧基苯甲酸换成对三氟甲氧基肉桂酸,得到白色产物(E)(3-(4-(三氟甲氧基)苯基)(1-(4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)(1-哌嗪)丙(2-烯-1-酮(HP1-007)109mg,产率89%。1H NMR(500MHz,CDCl3)δ8.96(d,J=1.4Hz,1H),8.44(d,J=8.0Hz,1H),8.39(d,J=8.2Hz,2H),8.09(dd,J=8.0,2.0Hz,1H),7.83(d,J=8.3Hz,2H),7.74(d,J=15.4Hz,1H),7.59(d,J=8.0Hz,2H),7.26(d,J=8.2Hz,2H),6.88(s,1H),4.04–3.71(m,6H),3.58(s,2H).
实施例7-7,(4-(4-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-008)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对三氟甲氧基苄溴,得到白色产物(4-(4-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-008)91mg,产率78.5%。1H NMR(500MHz,CDCl3)δ8.89(d,J=2.0Hz,1H),8.40–8.32(m,3H),8.02(dd,J=8.0,2.0Hz,1H),7.79(d,J=8.4Hz,2H),7.35(d,J=8.5Hz,2H),7.18(d,J=8.2Hz,2H),3.85(s,2H),3.56(s,2H),3.46(s,2H),2.58(s,2H),2.44(s,2H).
实施例7-8,(4-(4-溴苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-009)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对溴基苄溴,得到白色产物(4-(4-溴苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-009)98mg,产率85.5%。1H NMR(500MHz,CDCl3)δ8.91(s,1H),8.43–8.35(m,3H),8.04(dd,J=8.0,1.9Hz,1H),7.82(d,J=8.0Hz,2H),7.54–7.45(m,2H),7.23(d,J=7.4Hz,2H),3.86(s,2H),3.54(s,2H),3.48(s,2H),2.59(s,2H),2.45(s,2H).
实施例7-9,(4-(4-溴(3-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮(HP1-010)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成4-溴(3-氟基苄溴,得到白色产物(4-(4-溴(3-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮(HP1-010)70mg,产率60%。1H NMR(500MHz,DMSO)δ8.88(d,J=1.6Hz,1H),8.41(d,J=8.0Hz,1H),8.34(d,J=8.2Hz,2H),8.16(dd,J=8.0,2.0Hz,1H),8.01(d,J=8.3Hz,2H),7.70–7.61(m,1H),7.33(d,J=8.5Hz,1H),7.14(d,J=6.9Hz,1H),3.69(s,2H),3.54(s,2H),3.38(s,2H),3.32(s,2H),2.40(s,2H).
实施例7-10,(4-(4-溴(2-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮(HP1-011)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成4-溴(2-氟基苄溴,得到白色产物4-(4-溴(2-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮(HP1-011)81mg,产率81%。1H NMR(500MHz,DMSO)δ8.89(d,J=1.3Hz,1H),8.45–8.39(m,1H),8.35(d,J=8.1Hz,2H),8.17(dd,J=8.0,2.1Hz,1H),8.02(d,J=8.3Hz,2H),7.57–7.50(m,1H),7.44–7.37(m,2H),3.68(s,2H),3.57(s,2H),3.37(s,2H),2.42(s,4H).
实施例7-11,(4-(4-溴-2,6-二氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-012)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成4-溴-2,6-二氟基苄溴,得到白色产物4-(4-溴-2,6-二氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮(HP1-012)63mg,产率52%。1H NMR(500MHz,DMSO)δ8.88(d,J=1.3Hz,1H),8.41(d,J=8.1Hz,1H),8.35(d,J=8.1Hz,2H),8.16(dd,J=8.0,2.0Hz,1H),8.02(d,J=8.3Hz,2H),7.50(d,J=6.8Hz,2H),3.66(s,1H),3.62(s,2H),3.32(s,4H),2.42(s,3H).
实施例7-12,(4-(3,4-二溴苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-013)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成3,4-二溴基苄溴,得到白色产物(4-(3,4-二溴苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)甲酮(13)118mg,产率91%。1H NMR(500MHz,DMSO)δ8.88(d,J=1.3Hz,1H),8.41(d,J=8.1Hz,1H),8.35(d,J=8.1Hz,2H),8.16(dd,J=8.0,2.0Hz,1H),8.02(d,J=8.3Hz,2H),7.50(d,J=6.8Hz,2H),3.66(s,2H),3.62(s,2H),3.32(s,4H),2.42(s,2H).
实施例7-13,(4-(3-氟-4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-014)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成4-(3-氟-4-(2,2,2-三氟乙氧基苄溴,得到白色产物4-(3-氟-4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-014)96mg,产率70%。1HNMR(500MHz,CDCl3)δ8.91(d,J=2.0Hz,1H),8.43–8.34(m,3H),8.04(dd,J=8.0,2.0Hz,1H),7.82(d,J=8.3Hz,2H),7.22–7.13(m,1H),7.07–6.98(m,2H),4.43(q,J=8.2Hz,2H),3.87(s,2H),3.53(s,2H),3.49(s,2H),2.59(s,2H),2.45(s,2H).
实施例7-14,(4-(3-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-015)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成4-(3-(三氟甲氧基)基苄溴,得到白色产物(4-(3-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-015)96mg,产率83%。1H NMR(500MHz,CDCl3)δ8.89(d,J=1.3Hz,1H),8.41–8.33(m,3H),8.02(dd,J=8.0,2.1Hz,1H),7.79(d,J=8.3Hz,2H),7.35(t,J=7.9Hz,1H),7.26–7.22(m,2H),7.13(d,J=8.2Hz,1H),3.86(s,2H),3.58(s,2H),3.47(s,2H),2.59(s,2H),2.45(s,2H).
实施例7-15,(4-(2-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-016)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成4-(2-(三氟甲氧基)基苄溴,得到白色产物(4-(2-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-016)83mg,产率72%。1H NMR(500MHz,CDCl3)δ8.89(d,J=1.4Hz,1H),8.42–8.29(m,3H),8.02(dd,J=8.0,2.0Hz,1H),7.79(d,J=8.2Hz,2H),7.51(d,J=6.1Hz,1H),7.38–7.27(m,3H),3.84(s,2H),3.64(s,2H),3.46(s,2H),2.61(s,2H),2.48(s,2H).
实施例7-16,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-017)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成4-(4-(2,2,2-三氟乙氧基)苄溴,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-017)108mg,产率92%。1H NMR(500MHz,DMSO)δ8.88(d,J=1.3Hz,1H),8.41(d,J=8.0Hz,1H),8.33(d,J=8.0Hz,2H),8.16(dd,J=8.0,2.0Hz,1H),8.00(d,J=7.6Hz,2H),7.28(d,J=8.4Hz,2H),7.02(d,J=8.5Hz,2H),4.74(q,J=8.9Hz,2H),3.68(s,2H),3.48(s,2H),3.38(s,2H),2.46(s,2H),2.38(s,2H).
实施例7-17,(4-(3-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-018)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成4-(3-(2,2,2-三氟乙氧基)苄溴,得到白色产物(4-(3-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-018)94mg,产率79.5%。1H NMR(500MHz,CDCl3)δ8.92(d,J=1.4Hz,1H),8.44–8.35(m,3H),8.04(dd,J=8.0,2.1Hz,1H),7.82(d,J=8.3Hz,2H),7.31(d,J=7.9Hz,1H),7.06–6.97(m,2H),6.87(dd,J=8.1,2.4Hz,1H),4.38(q,J=8.1Hz,2H),3.87(s,2H),3.57(s,2H),3.49(s,2H),2.61(s,2H),2.47(s,2H).
实施例7-18,(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-019)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成4-(2-(2,2,2-三氟乙氧基)苄溴,得到白色产物(4-(3-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-019)77mg,产率65%。1H NMR(500MHz,CDCl3)δ8.91(d,J=1.9Hz,1H),8.39(dd,J=8.0,5.6Hz,3H),8.04(dd,J=8.0,2.1Hz,1H),7.82(d,J=8.3Hz,2H),7.38(d,J=7.3Hz,1H),7.33–7.30(m,1H),7.08(dd,J=7.4Hz,1H),6.88(d,J=8.2Hz,1H),4.40(q,J=8.1Hz,2H),3.86(s,2H),3.68(s,2H),3.47(s,2H),2.66(s,2H),2.52(s,2H).
实施例7-19,(4-(4-甲氧基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-020)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对甲氧基苄溴,得到白色产物(4-(4-甲氧基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-020)90mg,产率86%。1H NMR(500MHz,CDCl3)δ8.91(d,J=2.0Hz,1H),8.41–8.36(m,3H),8.04(dd,J=8.0,1.9Hz,1H),7.82(d,J=8.4Hz,2H),7.25(d,J=8.5Hz,2H),6.89(d,J=8.5Hz,2H),3.88–3.80(m,5H),3.53(s,2H),3.47(s,2H),2.59(s,2H),2.45(s,2H).
实施例7-20、叔丁基(4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟碱基](1-哌嗪基)甲基)苯基)氨基甲酸酯(HP1-021)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对4-(叔丁氧基羰基氨基)苄溴,得到白色产物叔丁基(4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟碱基](1-哌嗪基)甲基)苯基)氨基甲酸酯(HP1-021)89mg,产率73.2%。1H NMR(500MHz,CDCl3)δ8.91(d,J=1.8Hz,1H),8.41–8.36(m,3H),8.04(dd,J=8.0,2.1Hz,1H),7.82(d,J=8.3Hz,2H),7.35(d,J=8.2Hz,2H),7.25(d,J=8.4Hz,2H),6.50(s,1H),3.85(s,2H),3.53(s,2H),3.46(s,2H),2.59(s,2H),2.44(s,2H),1.54(s,9H).
实施例7-21,(4-(4-氨基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-022)的合成。
将产物叔丁基(4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟碱基](1-哌嗪基)甲基)苯基)氨基甲酸酯脱去保护基团后得到黄色产物4-(4-氨基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-022)43mg,产率58%。1H NMR(500MHz,DMSO)δ8.88(d,J=1.3Hz,1H),8.42(d,J=8.0Hz,1H),8.35(d,J=8.1Hz,2H),8.16(dd,J=8.0,2.1Hz,1H),8.02(d,J=8.3Hz,2H),6.94(d,J=8.2Hz,2H),6.51(d,J=8.3Hz,2H),4.97(s,2H),3.67(s,2H),3.34(s,4H),2.43(s,2H),2.34(s,2H).
实施例7-22,(4-(4-乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-023)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对乙氧基苄溴,得到白色产物(4-(4-乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-023)81mg,产率75%。1H NMR(500MHz,CDCl3)δ8.84(d,J=1.7Hz,1H),8.42–8.35(m,3H),8.04(dd,J=8.0,2.1Hz,1H),7.82(d,J=8.3Hz,2H),7.52(d,J=7.9Hz,2H),7.27(d,J=7.9Hz,2H),3.86(s,2H),3.45(s,2H),3.34(s,4H),2.60(s,2H),2.46(s,2H),2.37(s,3H).
实施例7-23,乙酸4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)(1-哌嗪基)甲基)苯基乙酸酯(HP1-024)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成4-溴甲基苯基乙酸酯,得到白色产物(乙酸4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)(1-哌嗪基)甲基)苯基乙酸酯(HP1-024)67mg,产率61%。1H NMR(500MHz,CDCl3)δ8.92(dd,J=2.0,0.7Hz,1H),8.42–8.36(m,3H),8.04(dd,J=8.0,2.1Hz,1H),7.82(d,J=8.2Hz,2H),7.35(d,J=8.5Hz,2H),7.07(d,J=8.5Hz,2H),3.87(s,2H),3.57(s,2H),3.48(s,2H),2.61(s,2H),2.46(s,2H),2.32(s,3H).
实施例7-24,(4-(4-甲基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-025)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对甲基苄溴,得到白色产物(4-(4-甲基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-025)96mg,产率95%。1HNMR(500MHz,CDCl3)δ8.91(d,J=1.7Hz,1H),8.42–8.35(m,3H),8.04(dd,J=8.0,2.1Hz,1H),7.82(d,J=8.3Hz,2H),7.22(d,J=7.9Hz,2H),7.17(d,J=7.9Hz,2H),3.86(s,2H),3.55(s,2H),3.47(s,2H),2.60(s,2H),2.46(s,2H),2.37(s,3H).
实施例7-25,(4-(4-(叔丁基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)吡啶(3-基)甲酮(HP1-026)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对叔丁基苄溴,得到白色产物(4-(4-(叔丁基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)吡啶(3-基)甲酮(HP1-026)98mg,产率90%。1H NMR(500MHz,CDCl3)δ8.89(d,J=2.0Hz,1H),8.38–8.34(m,3H),8.01(dd,J=8.0,1.5Hz,1H),7.79(d,J=8.3Hz,2H),7.35(d,J=8.1Hz,2H),7.24(d,J=8.1Hz,2H),3.84(s,2H),3.54(s,2H),3.45(s,2H),2.58(s,2H),2.44(s,2H),1.32(s,9H).
实施例7-26,(4-(4-(甲基磺酰基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-027)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对甲基磺酰基苄溴,得到白色产物((4-(4-(甲基磺酰基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-027)87mg,产率76.3%。1H NMR(500MHz,CDCl3)δ8.92(d,J=1.7Hz,1H),8.43–8.35(m,3H),8.05(dd,J=8.0,2.1Hz,1H),7.94(d,J=8.3Hz,2H),7.82(d,J=8.3Hz,2H),7.58(d,J=8.3Hz,2H),3.88(s,2H),3.68(s,2H),3.51(s,2H),3.09(s,3H),2.62(s,2H),2.49(s,2H).
实施例7-27,((4-(4-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-028)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对氟苄溴,得到白色产物((4-(4-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-028)91mg,产率89%。1HNMR(500MHz,CDCl3)δ8.91(d,J=1.3Hz,1H),8.41–8.35(m,3H),8.04(dd,J=8.0,2.1Hz,1H),7.81(d,J=8.2Hz,2H),7.31(dd,J=8.5,5.5Hz,2H),7.07–7.01(m,2H),3.86(s,2H),3.55(s,2H),3.47(s,2H),2.59(s,2H),2.45(s,2H).
实施例7-28,((4-(4-氯苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-029)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对氯苄溴,得到白色产物((4-(4-氯苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-029)93mg,产率89.5%。11H NMR(500MHz,CDCl3)δ8.91(d,J=1.4Hz,1H),8.43–8.35(m,3H),8.04(dd,J=8.0,2.1Hz,1H),7.82(d,J=8.3Hz,2H),7.34–7.31(m,2H),7.29(s,1H),7.27(s,1H),3.86(s,2H),3.55(s,2H),3.48(s,2H),2.59(s,2H),2.45(s,2H).
实施例7-29,((4-(4-溴苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-030)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对溴苄溴,得到白色产物((4-(4-氯苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-030)97mg,产率85%。1H NMR(500MHz,CDCl3)δ8.91(s,1H),8.43–8.35(m,3H),8.04(dd,J=8.0,1.9Hz,1H),7.82(d,J=8.0Hz,2H),7.54–7.45(m,2H),7.23(d,J=7.4Hz,2H),3.86(s,2H),3.54(s,2H),3.48(s,2H),2.59(s,2H),2.45(s,2H).
实施例7-30,4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基](1-哌嗪基)甲基)苄腈(HP1-031)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成对腈基苄溴,得到白色产物4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基](1-哌嗪基)甲基)苄腈(31)87mg,产率84%。1H NMR(500MHz,CDCl3)δ8.89(d,J=1.4Hz,1H),8.39–8.36(m,2H),8.35(s,1H),8.03(dd,J=8.0,2.1Hz,1H),7.79(d,J=8.3Hz,2H),7.63(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H),3.85(s,2H),3.62(s,2H),3.48(s,2H),2.58(s,2H),2.45(s,2H).
实施例7-31,(4-(4-(4-(甲基磺酰基)(1-哌啶基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-032)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成(4-(甲基磺酰基)(1-哌啶基)苄溴,得到白色产物(4-(4-(4-(甲基磺酰基)(1-哌啶基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-032)75mg,产率58%。1HNMR(500MHz,CDCl3)δ8.91(d,J=1.0Hz,1H),8.44–8.34(m,2H),8.04(dd,J=8.0,1.3Hz,1H),7.82(d,J=8.3Hz,2H),7.75–7.71(m,1H),7.57–7.54(m,1H),7.23(d,J=8.3Hz,1H),6.92(d,J=8.4Hz,2H),4.30–4.19(m,2H),3.87(d,J=12.7Hz,4H),3.51(s,2H),3.47(s,2H),3.06–2.96(m,1H),2.89(s,3H),2.80(t,J=11.5Hz,2H),2.59(s,2H),2.45(s,2H),2.32–2.21(m,2H).
实施例7-32,(4-(4-((4-四氢-2H-吡喃)氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-033)的合成。
采用与(HP1-002)相同的合成方法,将溴乙烷换成(4-(甲基磺酰基)(1-哌啶基)苄溴,得到白色产物(4-(4-((4-四氢-2H-吡喃)氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-033)97mg,产率82.5%。1HNMR(500MHz,CDCl3)δ8.91(d,J=1.9Hz,1H),8.44–8.33(m,3H),8.04(dd,J=8.0,2.1Hz,1H),7.82(d,J=8.4Hz,2H),7.24(d,J=8.5Hz,2H),6.90(d,J=8.6Hz,2H),4.50(dt,J=11.8,3.8Hz,1H),4.05–3.97(m,2H),3.86(s,2H),3.63–3.56(m,2H),3.52(s,2H),3.47(s,2H),2.59(s,2H),2.45(s,2H),2.09–2.00(m,2H),1.86–1.76(m,2H).
实施例7-33,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(4-(5-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮(HP1-034)的合成。
于100ml圆底烧瓶中称取对苯二甲酸单甲酯(0.3g,1.7mmol),对三氟甲基苯甲酰胺肟(0.5g,2.0mmol),HATU(0.76g,2.0mmol)溶于5ml DMF中,加入N,N-二异丙基乙胺(0.6ml,11.0mmol),常温搅拌2h,加水析出大量固体,抽滤,干燥固体,然后将固体溶于5mlDMF中,加热至120℃,反应2h,常规后处理后得到中间体6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯甲酸甲酯0.41g,产率70%;然后将中间体6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯甲酸甲酯(0.41g,1.2mmol)溶于16ml CH3OH:H2O=4:1混合溶剂中,加入LiOH.H2O(197mg,4.8mmol),室温搅拌5h,除去甲醇溶剂,用2M HCl溶液调pH至酸性,抽滤,干燥固体得到中间体6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯甲酸0.36g,产率90%;称取中间体6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯甲酸(100mg,0.3mmol),1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐(111mg,0.36mmol),HATU(136mg,0.36mmol)溶于DMF溶液中,加入N,N-二异丙基乙胺(154mg,0.6mmol),常温搅拌2h,经常规后处理得到中间体(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(4-(5-(4-(三氟甲基)苯基)(3-(1,2,4-噁二唑基)苯基)甲酮(HP1-034)150mg,产率85%。1H NMR(500MHz,CDCl3)δ8.31(s,1H),8.30(s,1H),8.28(d,J=1.6Hz,1H),8.26(d,J=1.6Hz,1H),7.79(d,J=8.3Hz,2H),7.62–7.58(m,2H),7.28(s,1H),7.26(s,1H),6.93–6.87(m,2H),4.34(q,J=8.1Hz,2H),3.82(s,2H),3.51(s,2H),3.42(s,2H),2.54(s,2H),2.39(s,2H).
实施例7-34,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(3-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮(HP1-035)的合成。
采用与(HP1-034)相同的合成方法,将对苯二甲酸单甲酯替换为间苯二甲酸单甲酯,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(3-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮(HP1-035)92mg,最后一步产率为52%。1HNMR(500MHz,DMSO)δ8.33(d,J=8.0Hz,2H),8.28(s,1H),8.16(s,1H),8.00(d,J=8.1Hz,2H),7.75(d,J=4.3Hz,2H),7.27(d,J=8.2Hz,2H),7.01(d,J=8.3Hz,2H),4.73(dd,J=17.6,8.8Hz,2H),3.66(s,2H),3.47(s,2H),2.69(s,2H),2.44(s,2H),2.36(s,2H).
实施例7-35,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(2-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮(HP1-036)的合成。
采用与(HP1-034)相同的合成方法,将对苯二甲酸单甲酯替换为邻苯二甲酸单甲酯,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(2-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮(HP1-036)70mg,最后一步产率为40%。1HNMR(500MHz,DMSO)δ8.28(d,J=7.9Hz,2H),8.21(d,J=7.7Hz,1H),8.03(d,J=8.0Hz,2H),7.83–7.76(m,1H),7.74–7.67(m,1H),7.52(d,J=7.7Hz,1H),7.21(d,J=8.2Hz,2H),6.97(d,J=8.2Hz,2H),4.71(q,J=17.7,8.8Hz,2H),3.69(s,2H),3.40(s,2H),3.16(s,2H),2.45(s,2H),2.23(s,2H).
实施例7-36,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮(HP1-037)的合成。
采用与(HP1-034)相同的合成方法,将对苯二甲酸单甲酯替换为6-(甲氧羰基)烟酸,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮(37)141mg,最后一步产率为80%。1H NMR(500MHz,CDCl3)δ9.43(d,J=1.5Hz,1H),8.61(dd,J=8.1,2.1Hz,1H),8.34(d,J=8.2Hz,2H),7.89(d,J=8.2Hz,1H),7.83(d,J=8.3Hz,2H),7.31(d,J=8.6Hz,2H),6.93(d,J=8.6Hz,2H),4.42–4.32(m,2H),3.87(s,2H),3.67–3.56(m,2H),3.54(s,2H),2.63–2.56(m,2H),2.53–2.44(m,2H).
实施例7-37,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(4-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮(HP1-038)的合成。
采用与(HP1-034)相同的合成方法,将对苯二甲酸单甲酯替换为2-(甲氧基羰基)异烟酸,得到白色产物4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(4-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮(HP1-038)115mg,最后一步产率为65%。1HNMR(500MHz,CDCl3)δ8.86(dd,J=5.1,0.7Hz,1H),8.48(s,1H),8.33(d,J=8.1Hz,2H),8.12(dd,J=5.0,1.5Hz,1H),7.83(d,J=8.2Hz,2H),7.34(s,2H),6.94(d,J=8.4Hz,2H),4.37(q,J=8.1Hz,2H),3.91(s,2H),3.70(s,2H),3.58(s,2H),2.59(d,J=49.4Hz,4H).
实施例7-38,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮(HP1-039)的合成。
采用与(HP1-034)相同的合成方法,将对苯二甲酸单甲酯替换为2,6-吡啶二羧酸单甲酯,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮(HP1-039)62mg,最后一步产率为35%。1H NMR(500MHz,CDCl3)δ8.40(d,J=7.8Hz,1H),8.35(d,J=8.1Hz,2H),8.09(dd,J=7.8Hz,1H),7.98(d,J=7.8Hz,1H),7.82(d,J=8.3Hz,2H),7.32(d,J=8.4Hz,2H),6.94(d,J=8.4Hz,2H),4.37(q,J=8.2Hz,2H),3.89(s,2H),3.83–3.75(m,2H),3.56(s,2H),2.65–2.59(m,2H),2.59–2.54(m,2H).
实施例7-39,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(3-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮(HP1-040)的合成。
采用与(HP1-034)相同的合成方法,将对苯二甲酸单甲酯替换为2,6-吡啶二羧酸单甲酯,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(3-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮(HP1-040)53mg,最后一步产率为30%。1H NMR(500MHz,CDCl3)δ8.90(dd,J=4.7,1.6Hz,1H),8.31(d,J=8.1Hz,2H),7.83(dd,J=7.8,1.6Hz,1H),7.79(d,J=8.2Hz,2H),7.61(dd,J=7.8,4.7Hz,1H),7.21(d,J=8.6Hz,2H),6.87(d,J=8.6Hz,2H),4.32(q,J=8.1Hz,2H),3.89(s,2H),3.45(s,2H),3.29–3.20(m,2H),2.60(s,2H),2.31(s,2H).
实施例7-40,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)-2噻吩基)甲酮(HP1-041)的合成。
采用与(HP1-034)相同的合成方法,将对苯二甲酸单甲酯替换为5-羧酸(2-噻吩甲酸甲酯,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)-2噻吩基)甲酮(HP1-041)100mg,最后一步产率为56%。1H NMR(500MHz,CDCl3)δ8.31(s,1H),8.29(s,1H),7.90(d,J=3.9Hz,1H),7.81(s,1H),7.79(s,1H),7.37(d,J=3.9Hz,1H),7.31(s,1H),7.29(s,1H),6.95(s,1H),6.93(s,1H),4.37(q,J=8.1Hz,2H),3.78(s,4H),3.54(s,2H),2.53(s,4H).
实施例7-41,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-噻唑基)甲酮(HP1-042)的合成。
采用与(HP1-034)相同的合成方法,将对苯二甲酸单甲酯替换为2-(甲氧基羰基)噻唑(5-羧酸,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-噻唑基)甲酮(HP1-042)82mg,最后一步产率为46%。1H NMR(500MHz,CDCl3)δ8.54(s,1H),8.33(d,J=8.1Hz,2H),7.81(d,J=8.3Hz,2H),7.32(d,J=8.6Hz,2H),6.95(d,J=8.6Hz,2H),4.55(s,2H),4.38(q,J=8.1Hz,2H),3.91–3.83(m,2H),3.55(s,2H),2.67–2.56(m,4H).
实施例7-42,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(4-(4-(三氟甲基)苯基)(2-噁唑基)(3-吡啶基)甲酮(HP1-043)的合成。
称取5-(甲氧羰基)-2-吡啶羧酸(181mg,1.0mmol),2-氨基-4-三氟甲基苯乙酮(243mg,1.2mmol),HATU(456mg,1.2mmol)溶于5ml DMF中,加入N,N-二异丙基乙胺(0.4ml,2mmol),常温搅拌2h,加水析出大量固体,抽滤,干燥固体,柱层析纯化后得到中间体6-((2-氧代(2-(4-(三氟甲基)苯基)乙基)氨基甲酰基)烟酸甲酯292mg产率80%;然后将中间体6-((2-氧代(2-(4-(三氟甲基)苯基)乙基)氨基甲酰基)烟酸甲酯溶于三氯氧磷中,加热到110℃反应2h,将反应降至室温后加入冰水淬灭反应,用乙酸乙酯萃取3次,干燥纯化后得到中间体6-(4-(三氟甲基)苯基)(2-噁唑基)烟酸甲酯222mg,产率80%;将上一步产物和LiOH.H2O溶于甲醇水的混合溶剂中,室温搅拌5h,除去甲醇溶剂,用2M HCl溶液调pH至酸性,抽滤,干燥固体得到中间体181mg,0.5mmol),1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐(372mg,0.6mmol)HATU(228mg,0.6mmol)溶于5ml DMF中,加入N,N-二异丙基乙胺(0.2ml,1.2mmol),常温搅拌2h,加水析出大量固体,抽滤,干燥后柱层析纯化后得到产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(4-(4-(三氟甲基)苯基)(2-噁唑基)(3-吡啶基)甲酮(HP1-043)244mg,产率83%。1H NMR(500MHz,CDCl3)δ8.82(d,J=1.5Hz,1H),8.27(d,J=8.1Hz,1H),7.95(dd,J=8.1,1.9Hz,2H),7.93(s,1H),7.74(d,J=8.3Hz,2H),7.68(s,1H),7.30(s,2H),6.93(d,J=8.6Hz,2H),4.37(q,J=8.1Hz,2H),3.85(s,2H),3.54(s,2H),3.49(s,2H),2.58(s,2H),2.44(s,2H).
实施例7-43,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(4-(4-(三氟甲基)苯基)(2-噻唑基)(3-吡啶基)甲酮(HP1-044)的合成。
称取6-氰基烟酸甲酯(162mg,1.0mmol)溶于无水乙醇溶液中,然后加入P2S5(244mg,1.1mmol)室温搅拌30分钟,然后加热至回流反应2h,除去乙醇溶剂,萃取干燥得到中间体6-氨基甲硫酰基烟酸甲酯156mg,产率80%;将中间体6-氨基甲硫酰基烟酸甲酯(156mg,0.8mmol),2-溴(1-(4-(三氟甲基)苯基)乙(1-酮(256mg,0.96mmol)溶于无水乙醇溶剂中,加热至回流反应3h,得到中间体6-(4-(4-(4-(三氟甲基)苯基)(2-噻唑基)烟酸甲酯151mg,产率52%;将6-(4-(4-(4-(三氟甲基)苯基)(2-噻唑基)烟酸甲酯(151mg,0.4mmol),LiOH.H2O(65mg,1,6mmol)溶于甲醇水的混合溶剂中,室温搅拌5h,除去甲醇溶剂,用2M HCl溶液调pH至酸性,抽滤,干燥固体得到中间体6-(4-(4-(4-(三氟甲基)苯基)(2-噻唑基)烟酸119mg,产率85%;将中间体6-(4-(4-(4-(三氟甲基)苯基)(2-噻唑基)烟酸(119mg,0.34mmol),1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐(126mg,0.4mmol)HATU(155mg,0.4mmol)溶于5ml DMF中,加入N,N-二异丙基乙胺(0.1ml,0.6mmol),常温搅拌2h,加水析出大量固体,抽滤,干燥后柱层析纯化后得到产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(4-(4-(三氟甲基)苯基)(2-噻唑基)(3-吡啶基)甲酮(HP1-044)186mg,产率77%。
实施例7-44,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(1-(4-(三氟甲基)苯基)-1H-1,2,3-三唑-4-基)(3-吡啶基)甲酮(HP1-045)的合成。
称取对三氟甲基苯胺(161mg,1.0mmol),溶于5ml 5M HCl溶液中,冰浴下滴加NaNO2(161mg,1.0mmol)水溶液,冰浴下反应1小时后,再向混合物中滴加NaN3(130mg,2.0mmol)的水溶液,继续冰浴下反应1h,加入冰水淬灭反应,用无水硫酸钠干燥后出去乙酸乙酯溶剂得到中间体1-叠氮基-4-(三氟甲基)苯160mg,产率86%;然后将中体体1-叠氮基-4-(三氟甲基)苯(160mg,0.86mmol),6-乙炔基烟酸甲酯(207mg,1.3mmol)溶于叔丁醇和水2:1的混合溶剂中,再加入0.1mmol的GuSO4和0.1mmol的L-抗坏血酸钠,室温下过夜反应得到中间体6-(1-(4-(三氟甲基)苯基)-4-(1,2,3-三唑)烟酸甲酯180mg,产率60%;将6-(1-(4-(三氟甲基)苯基)-4-(1,2,3-三唑)烟酸甲酯(180mg,0.5mmol),LiOH.H2O(82mg,2。0mmol)溶于甲醇水的混合溶剂中,室温搅拌5h,除去甲醇溶剂,用2M HCl溶液调pH至酸性,抽滤,干燥固体得到中间体6-(1-(4-(三氟甲基)苯基)-4-(1,2,3-三唑)烟酸248mg,产率89%;最后将中间体6-(1-(4-(三氟甲基)苯基)-4-(1,2,3-三唑烟酸(248mg,0.45mmol),1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐(167mg,0.54mmol),HATU(205mg,0.54mmol)溶于5ml DMF中,加入N,N-二异丙基乙胺(0.15ml,0.9mmol),常温搅拌2h,加水析出大量固体,抽滤,干燥后柱层析纯化后得到产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(4-(4-(三氟甲基)苯基)(2-噻唑基)(3-吡啶基)甲酮(HP1-045)215mg,产率77%。1H NMR(500MHz,CDCl3)δ8.71(s,1H),8.70(d,J=1.4Hz,1H),8.33(d,J=8.1Hz,1H),8.01(d,J=8.4Hz,2H),7.90(dd,J=8.1,2.1Hz,1H),7.87(d,J=8.6Hz,2H),7.30(s,2H),6.94(s,1H),6.92(s,1H),4.41–4.34(m,2H),3.84(s,2H),3.54(s,2H),3.01(d,J=6.8Hz,2H),2.61(s,2H),2.45(s,2H).
实施例7-45,(6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-046)的合成。
称取5-(甲氧羰基)(2-吡啶羧酸(181mg,1.0mmol),对氟苯甲酰胺肟(184mg,1.2mmol),HATU(456mg,1.2mmol)溶于5ml DMF中,加入N,N-二异丙基乙胺(0.35ml,2mmol),常温搅拌2h,加水析出大量固体,抽滤,干燥固体,然后将固体溶于5ml DMF中,加热至120℃,反应2h,后处理后得到中间体6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)烟酸甲酯228mg,产率76.5%;然后将中间体6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)烟酸甲酯(228mg,0.76mmol)溶于12ml CH3OH:H2O=4:1混合溶剂中,加入LiOH.H2O(124mg,3.0mmol),室温搅拌5h,除去甲醇溶剂,用2M HCl溶液调pH至酸性,抽滤,干燥固体得到中间体6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)烟酸184mg,产率85%;最后称取中间体6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)烟酸(184mg,0.65mmol),1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐(241mg,0.78mmol),HATU(296mg,0.78mmol)溶于DMF溶液中,加入N,N-二异丙基乙胺(0.25ml,1.3mmol),常温搅拌2h,经常规后处理得到白色产物6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-046),239mg,产率68%。1H NMR(500MHz,CDCl3)δ8.91–8.89(m,1H),8.37(d,J=8.0Hz,1H),8.28–8.22(m,2H),8.03(dd,J=8.0,2.1Hz,1H),7.30(s,1H),7.28–7.20(m,3H),6.96–6.91(m,2H),4.37(q,J=8.1Hz,2H),3.86(s,2H),3.54(s,2H),3.47(s,2H),2.58(s,2H),2.44(s,2H).
实施例7-46,(6-(3-(-2噻吩基)(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-047)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为噻吩(2-胺肟,得到白色产物(6-(3-(-2噻吩基)(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-047)103mg,最后一步产率为65%。1H NMR(500MHz,DMSO)δ8.87(s,1H),8.37(d,J=8.1Hz,1H),8.14(dd,J=8.0,2.1Hz,1H),7.96(d,J=5.0Hz,1H),7.93(d,J=3.7Hz,1H),7.28(d,J=8.6Hz,2H),7.06–7.00(m,3H),4.74(q,J=8.9,2.9Hz,2H),3.52–3.48(m,2H),3.36(s,2H),3.25(s,2H),2.46(s,2H),2.37(s,2H).
实施例7-47,(6-(3-(5-噻唑基)(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-048)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为噻唑(5-胺肟,得到白色产物(6-(3-(5-噻唑基)(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-048)114mg,最后一步产率为72%。1H NMR(500MHz,DMSO)δ8.89(s,1H),8.41(d,J=8.0Hz,1H),8.22(dd,J=10.2,3.1Hz,2H),8.16(d,J=7.6Hz,1H),7.28(d,J=8.3Hz,2H),7.02(d,J=8.2Hz,2H),4.74(q,J=17.8,8.9Hz,2H),3.49(s,2H),3.37(s,2H),2.64(s,2H),2.48–2.44(m,2H),2.37(s,2H)
实施例7-48,(6-(3-(4-嘧啶基)(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-049)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为嘧啶(5-胺肟,得到白色产物(6-(3-(4-嘧啶基)(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-049)122mg,最后一步产率为78%。1H NMR(500MHz,DMSO)δ9.10(s,1H),9.09(s,1H),8.89–8.88(m,1H),8.42(d,J=8.0Hz,1H),8.16(dd,J=8.0,2.1Hz,1H),7.79–7.76(m,1H),7.28(d,J=8.7Hz,2H),7.02(d,J=8.7Hz,2H),4.74(q,J=8.9Hz,2H),3.68(s,2H),3.49(s,2H),3.38(s,2H),2.46(s,2H),2.37(d,J=1.9Hz,2H).
实施例7-49,(6-(3-苯基(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-050)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为苯甲酰胺肟,得到白色产物(6-(3-苯基(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-050)92mg,最后一步产率为59%。1HNMR(500MHz,DMSO)δ8.88(dd,J=2.1,0.8Hz,1H),8.40(dd,J=8.0,0.8Hz,1H),8.17–8.12(m,3H),7.67–7.61(m,3H),7.28(d,J=8.7Hz,2H),7.02(d,J=8.7Hz,2H),4.74(q,J=8.9Hz,2H),3.68(s,2H),3.49(s,2H),3.37(s,2H),2.46(s,2H),2.37(s,2H).
实施例7-50,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(2-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-051)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为邻三氟甲基苯甲酰胺肟,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(2-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-051)131mg,最后一步产率为74%。1H NMR(500MHz,CDCl3)δ8.89(d,J=1.6Hz,1H),8.37(d,J=8.0Hz,1H),8.01(dd,J=8.0,2.1Hz,1H),7.96–7.88(m,2H),7.79–7.68(m,2H),7.30(s,1H),7.28(s,1H),6.99–6.90(m,2H),4.37(q,J=8.1Hz,2H),3.85(s,2H),3.54(s,2H),3.47(s,2H),2.58(s,2H),2.44(s,2H).
实施例7-51,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(3-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-052)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为间三氟甲基苯甲酰胺肟,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(3-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-052)135mg,最后一步产率为76%。1H NMR(500MHz,DMSO)δ8.89(s,1H),8.47–8.42(m,2H),8.38(s,1H),8.16(d,J=8.1Hz,1H),8.06(d,J=7.7Hz,1H),7.92–7.89(m,1H),7.28(d,J=8.6Hz,2H),7.02(d,J=8.4Hz,2H),4.74(q,J=17.7,8.8Hz,2H),3.68(s,2H),3.49(s,2H),3.37(s,2H),2.37(s,4H).
实施例7-52,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(2-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-053)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为邻氟苯甲酰胺肟,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(2-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-053)115mg,最后一步产率为71%。1H NMR(500MHz,CDCl3)δ8.91(d,J=1.8Hz,1H),8.40(d,J=8.0Hz,1H),8.28–8.22(m,1H),8.03(dd,J=8.0,2.0Hz,1H),7.60–7.53(m,1H),7.39–7.29(m,4H),6.97–6.91(m,2H),4.37(q,J=8.1Hz,2H),3.86(s,2H),3.65–3.40(m,4H),2.68–2.36(m,4H).
实施例7-53,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(3-氟苯基(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-054)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为间氟苯甲酰胺肟,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(3-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-054)97mg,最后一步产率为60%。1HNMR(500MHz,CDCl3)δ8.90(d,J=1.5Hz,1H),8.39(d,J=8.0Hz,1H),8.09–8.01(m,2H),7.96(dd,J=9.0,1.9Hz,1H),7.58–7.49(m,1H),7.37(d,J=8.7Hz,2H),7.00–6.88(m,2H),4.37(q,J=8.1Hz,2H),3.86(s,3H),3.60–3.42(m,4H),2.66–2.36(m,4H).
实施例7-54,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-氯苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-055)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为对氯苯甲酰胺肟,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-氯苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-055)144mg,最后一步产率为86%。1H NMR(500MHz,DMSO)δ8.88(s,1H),8.40(d,J=8.0Hz,1H),8.20–8.12(m,3H),7.71(d,J=8.5Hz,2H),7.28(d,J=8.2Hz,2H),7.02(d,J=8.3Hz,2H),4.74(q,J=17.6,8.7Hz,2H),3.68(s,2H),3.49(s,2H),3.37(s,2H),2.47(s,2H),2.37(s,2H).
实施例7-55,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-溴苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-056)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为对溴苯甲酰胺肟,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-氯苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-056)81mg,最后一步产率为45%。1HNMR(500MHz,CDCl3)δ8.90(d,J=1.6Hz,1H),8.38(d,J=8.0Hz,1H),8.13(d,J=2.2Hz,1H),8.11(d,J=1.9Hz,1H),8.03(dd,J=8.0,2.1Hz,1H),7.70(d,J=1.8Hz,1H),7.68(d,J=1.8Hz,1H),7.38(d,J=8.6Hz,2H),6.95(d,J=8.5Hz,2H),4.37(q,J=8.1Hz,2H),3.86(s,2H),3.64–3.40(m,4H),2.59(s,2H),2.45(s,2H).
实施例7-56,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-057)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为对甲基苯甲酰胺肟,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-057)140mg,最后一步产率为87%。1HNMR(500MHz,DMSO)δ8.87(d,J=1.4Hz,1H),8.39(d,J=8.0Hz,1H),8.16–8.14(m,1H),8.03(s,1H),8.01(s,1H),7.45(s,1H),7.43(s,1H),7.29(s,1H),7.27(s,1H),7.03(s,1H),7.01(s,1H),4.74(q,J=8.9Hz,2H),3.68(s,2H),3.49(s,2H),3.37(s,2H),2.46(s,2H),2.42(s,3H),2.37(s,2H).
实施例7-57,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-058)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为对三氟甲氧基苯甲酰胺肟,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-058)118mg,最后一步产率为65%。1H NMR(500MHz,DMSO)δ8.88(d,J=1.4Hz,1H),8.41(d,J=8.0Hz,1H),8.28–8.25(m,2H),8.16(dd,J=8.0,2.1Hz,1H),7.64(d,J=8.1Hz,2H),7.28(d,J=8.5Hz,2H),7.02(d,J=8.6Hz,2H),4.74(q,J=8.9Hz,2H),3.68(s,2H),3.49(s,2H),3.37(s,2H),2.46(s,2H),2.37(s,2H).
实施例7-58,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-059)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为对三氟甲氧基苯甲酰胺肟,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-059)114mg,最后一步产率为74%。1HNMR(500MHz,DMSO)δ8.87(s,1H),8.39(d,J=8.0Hz,1H),8.14(dd,J=8.1,2.0Hz,1H),8.10–8.04(m,2H),7.28(d,J=8.6Hz,2H),7.17(d,J=8.9Hz,2H),7.02(d,J=8.5Hz,2H),4.74(q,J=17.9,8.9Hz,2H),3.87(s,3H),3.68(s,2H),3.49(s,2H),3.37(s,2H),2.46(s,2H),2.37(s,2H).
实施例7-59,(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(叔丁基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-060)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为对三氟甲氧基苯甲酰胺肟,得到白色产物(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(叔丁基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-060)142mg,最后一步产率为82%。1H NMR(500MHz,CDCl3)δ8.91–8.89(m,1H),8.95–8.85(m,1H),8.38(d,J=8.0Hz,1H),8.17(d,J=8.1Hz,2H),8.06–7.99(m,1H),7.56(d,J=8.2Hz,2H),7.30(s,1H),6.93(d,J=8.3Hz,2H),4.37(q,J=8.2Hz,2H),3.85(s,2H),3.54(s,2H),3.47(s,2H),2.58(s,2H),2.44(s,2H),1.40(s,9H).
实施例7-60,(6-(3-(3-氟-4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-061)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为3-氟-4-三氟甲基苯甲酰胺肟,得到白色产物(6-(3-(3-氟-4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-061)78mg,最后一步产率为43%。1HNMR(500MHz,DMSO)δ8.89(d,J=1.3Hz,1H),8.43(d,J=8.0Hz,1H),8.20–8.16(m,3H),8.11–8.07(m,1H),7.28(d,J=8.7Hz,2H),7.03(s,1H),7.01(s,1H),4.74(q,J=17.8,8.8Hz,2H),3.68(s,2H),3.49(s,2H),3.37(s,2H),2.46(s,2H),2.37(s,2H).
实施例7-61,(6-(3-(2,4-双(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-062)的合成。
采用与(HP1-046)相同的合成方法,将对氟苯甲酰胺肟替换为(6-(3-(2,4-双(三氟甲基)苯基)(5-(1,2,4-噁二唑基(3-吡啶基)(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮(HP1-062)98mg,最后一步产率为50%。1H NMR(500MHz,DMSO)δ8.89(s,1H),8.41–8.36(m,2H),8.36(s,1H),8.27(d,J=8.5Hz,1H),8.16(d,J=8.4Hz,1H),7.28(d,J=8.1Hz,2H),7.02(d,J=8.1Hz,2H),4.74(q,J=18.1,9.1Hz,2H),3.68(s,2H),3.49(s,2H),3.36(s,2H),2.37(s,4H).
实施例7-62,(3-甲基-4-(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-063)的合成。
称取6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酸(120mg,0.36mmol),2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐(139mg,0.43mmol),HATU(164mg,0.43mmol)溶于DMF溶液中,加入N,N-二异丙基乙胺(0.2ml,0.72mmol),常温搅拌2h,经常规后处理得到白色产物(3-甲基-4-(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-063)182mg,产率84%。1HNMR(500MHz,DMSO)δ8.88(s,1H),8.46–8.39(m,1H),8.35(d,J=7.3Hz,2H),8.16(d,J=8.1Hz,1H),8.02(d,J=7.8Hz,2H),7.28(s,2H),7.02(s,2H),4.73(q,J=16.1,7.6Hz,2H),4.04–3.95(m,1H),3.87(s,2H),3.31–3.21(m,2H),3.14(s,2H),2.16(s,2H),1.20(d,J=37.6Hz,3H).
实施例7-63,(R)-(3-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-064)的合成。
采用与(HP1-063)相同的合成方法,将2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为(R)(2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐,得到白色产物(R)-(3-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-064)163mg,产率75%。1HNMR(500MHz,DMSO)δ8.88(d,J=1.9Hz,1H),8.42(t,J=9.2Hz,1H),8.35(d,J=7.9Hz,2H),8.16(dd,J=8.0,2.1Hz,1H),8.02(d,J=7.9Hz,2H),7.27(d,J=7.1Hz,2H),7.04–6.99(m,2H),4.73(q,J=16.4,8.1Hz,2H),3.49–3.35(m,1H),3.30–3.20(m,2H),3.17–3.05(m,2H),2.73–2.52(m,2H),2.21–2.10(m,2H),1.27–1.14(m,3H).
实施例7-64,(S)-(3-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-065)的合成。
采用与(HP1-063)相同的合成方法,将2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为(S)(2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐,得到白色产物(S)-(3-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-065)165mg,产率76%。1HNMR(500MHz,DMSO)δ8.88(d,J=1.2Hz,1H),8.44–8.33(m,3H),8.16(dd,J=8.0,2.1Hz,1H),8.02(d,J=7.8Hz,2H),7.28(s,2H),7.04–6.99(m,2H),4.73(q,2H),4.02–3.87(m,2H),3.46–3.36(m,1H),3.32–3.19(m,2H),2.73–2.54(m,2H),2.32–2.01(m,2H),1.24–1.16(m,3H).
实施例7-65,(2-甲基-4-(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-066)的合成。
采用与(HP1-063)相同的合成方法,将2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为3-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐,得到白色产物(2-甲基-4-(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-066)65mg,产率76%。1H NMR(500MHz,DMSO)δ8.88(s,1H),8.42(d,J=8.0Hz,1H),8.35(d,J=8.2Hz,2H),8.16(d,J=7.8Hz,1H),8.02(d,J=8.3Hz,2H),7.29(d,J=8.6Hz,2H),7.03(d,J=8.6Hz,2H),4.74(q,J=17.8,9.0Hz,2H),3.53–3.49(m,1H),3.41(d,J=13.3Hz,2H),2.64(s,2H),2.18–2.14(m,2H),2.07–2.01(m,2H),1.31(d,J=2.5Hz,3H).
实施例7-66,(S)-(2-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-067)的合成。
采用与(HP1-063)相同的合成方法,将2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为(S)(3-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐,得到白色产物(S)-(2-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-067)154mg,产率71%。1H NMR(500MHz,CDCl3)δ8.89(s,1H),8.45–8.34(m,3H),8.02(d,J=8.0Hz,1H),7.82(d,J=8.2Hz,2H),7.30(d,J=8.4Hz,2H),6.93(d,J=8.4Hz,2H),4.37(q,J=8.1Hz,2H),3.60–3.39(m,3H),2.70(s,2H),2.19(d,J=50.1Hz,2H),1.42(s,3H),1.29(s,2H).
实施例7-67,(R)-(2-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-068)的合成。
采用与(HP1-063)相同的合成方法,将2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为(R)(3-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐,得到白色产物(R)-(2-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮(HP1-068)151mg,产率69%。1H NMR(500MHz,CDCl3)δ8.89(s,1H),8.41–8.36(m,3H),8.02(d,J=6.6Hz,1H),7.82(d,J=8.2Hz,2H),7.30(d,J=8.5Hz,2H),6.93(d,J=8.4Hz,2H),4.37(q,J=8.1Hz,2H),3.59–3.40(m,3H),2.70(s,2H),2.27–2.12(m,2H),1.43(s,3H),1.29(s,2H).
实施例7-68,(1-(4-(2,2,2-三氟乙氧基)苄基)-4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)哌嗪-2-腈(HP1-069)的合成。
采用与(HP1-063)相同的合成方法,将2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪(2-甲腈盐酸盐,得到白色产物(1-(4-(2,2,2-三氟乙氧基)苄基)-4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)哌嗪-2-腈(HP1-069)128mg,产率58%。1H NMR(500MHz,CDCl3)δ8.91(d,J=25.4Hz,1H),8.48(d,J=7.9Hz,3H),7.83(d,J=8.1Hz,2H),7.43(d,J=26.3Hz,2H),7.65(d,J=7.4Hz,1H),6.95(d,J=7.9Hz,2H),4.67(q,J=8.1Hz,2H),4.29(s,1H),3.64(d,J=12.7Hz,2H),3.67–3.44(m,2H),3.24–3.06(m,2H),2.43–2.29(m,2H).
实施例7-69,4-(4-(2,2,2-三氟乙氧基)苄基)(1-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)哌嗪-2-腈(HP1-070)的合成。
采用与(HP1-063)相同的合成方法,将2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪(2-甲腈盐酸盐,得到白色产物4-(4-(2,2,2-三氟乙氧基)苄基)(1-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)哌嗪-2-腈(HP1-070)119mg,产率54%。1H NMR(500MHz,CDCl3)δ9.00(d,J=25.4Hz,1H),8.38(d,J=7.9Hz,3H),7.81(d,J=8.1Hz,2H),7.33(d,J=26.3Hz,2H),7.25(d,J=7.4Hz,1H),6.95(d,J=7.9Hz,2H),4.37(q,J=8.1Hz,2H),4.19(s,1H),3.65(d,J=12.7Hz,2H),3.58–3.44(m,2H),3.24–3.06(m,2H),2.41–2.29(m,2H).
实施例7-70,(2,6-二甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮(HP1-071)的合成。
采用与(HP1-063)相同的合成方法,将2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为3,5-二甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐,得到白色产物(2,6-二甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮(HP1-071)102mg,产率46%。1HNMR(500MHz,CDCl3)δ8.88(s,1H),8.40–8.37(m,3H),7.99(d,J=8.0Hz,1H),7.82(s,1H),7.81(s,1H),7.34(s,1H),7.32(s,1H),6.94(s,1H),6.93(s,1H),4.37(q,J=16.3,8.2Hz,2H),3.51(s,2H),2.70(s,2H),2.28–2.24(m,2H),1.45(s,6H),1.28(s,2H).
实施例7-71,(3,5-二甲基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮(HP1-072)的合成。
采用与(HP1-063)相同的合成方法,将2-甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为2,6-二甲基(1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐,得到白色产物(3,5-二甲基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮(HP1-072)86mg,产率为39%。1H NMR(500MHz,CDCl3)δ8.90(d,J=0.9Hz,1H),8.42–8.36(m,3H),8.07–8.03(m,1H),7.82(d,J=8.2Hz,2H),7.33(d,J=8.5Hz,2H),6.92(d,J=8.4Hz,2H),4.37(q,J=8.1Hz,2H),3.84(d,J=3.7Hz,2H),3.48(d,J=12.6Hz,1H),3.12–2.90(m,2H),2.81(dd,J=29.6,17.7Hz,2H),2.61(s,1H),1.20(d,J=4.9Hz,3H),1.00(d,J=5.2Hz,3H).
实施例7-72,4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)吡啶(3-基)哌嗪甲酰胺(HP1-073)的合成。
称取5-Boc-氨基(2-吡啶羧酸(238mg,1.0mmol),对三氟甲基苯甲酰胺肟(244mg,1.2mmol),HATU(456mg,1.2mmol)溶于5mlDMF中,加入N,N-二异丙基乙胺(0.35ml,2.0mmol),常温搅拌2h,加水析出大量固体,抽滤,干燥固体,然后将固体溶于5ml DMF中,加热至120℃,反应2h,后处理后得到中间体(6-(3-(4-(三(三氟甲基)苯基))(5-(1,2,4-噁二唑基)(3-吡啶基)氨基甲酸叔丁酯263mg,产率65%;将中间体(6-(3-(4-(三(三氟甲基)苯基))(5-(1,2,4-噁二唑基)(3-吡啶基)氨基甲酸叔丁酯(263mg,0.65mmol),溶于DCM溶液中,加入盐酸二氧六环溶液,室温反应4h,除去二氯甲烷溶剂,加适量水,用2M碳酸钠水溶液调pH至7.5左右,乙酸乙酯萃取并用无水硫酸钠干燥后得到中间体6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)吡啶(3-胺170mg,产率85%;将中间6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)吡啶(3-胺(170mg,0.56mmol),吡啶(53mg,0.67mmol))溶于无水乙腈中,冰浴下滴加氯甲酸苯酯(97mg,0.62mmol),冰浴下反应1h,加水淬灭反应,用乙酸乙酯萃取,无水硫酸钠干燥后除去溶剂,然后加入无水DMSO溶解,加入中间体1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐(173mg,0.56mmol),三乙胺(0.15ml,1.1mmol),室温反应1h,经常规后处理后得到白色产物4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)吡啶(3-基)哌嗪-1-甲酰胺(HP1-073)190mg,产率为56%。1H NMR(500MHz,CDCl3)δ8.63(d,J=2.4Hz,1H),8.41–8.37(m,2H),8.36(s,1H),8.27(d,J=8.7Hz,1H),7.82–7.77(m,2H),7.33–7.29(m,2H),6.97–6.92(m,2H),6.78(s,1H),4.38(q,J=8.1Hz,2H),3.63–3.56(m,4H),3.54(s,2H),2.58–2.49(m,4H).
实施例7-73,N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)4-(3,3,3-三氟丙基)哌嗪甲酰胺(HP1-074)的合成。
采用与(HP1-073)相同的合成方法,将中间体1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为1-(3,3,3-三氟丙基)哌嗪盐酸盐,得到白色产物N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)-4-(3,3,3-三氟丙基)哌嗪甲酰胺(HP1-074)198mg,最后一步产率为69%。1H NMR(500MHz,CDCl3)δ8.66(d,J=2.6Hz,1H),8.39(dd,J=8.8,2.6Hz,2H),8.36(s,1H),8.28(d,J=8.7Hz,1H),7.80(s,1H),7.79(s,1H),6.82(s,1H),3.59(s,4H),1.61(s,8H).
实施例7-74,4-(4-甲氧基苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺(HP1-075)的合成。
采用与(HP1-073)相同的合成方法,将中间体1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为1-(4-(2,2,2-三氟甲氧基)苄基)哌嗪盐酸盐,得到白色产物4-(4-甲氧基苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺(HP1-075)183mg,最后一步产率为61%。1H NMR(500MHz,CDCl3)δ8.63(d,J=2.4Hz,1H),8.39(dd,J=8.8,2.7Hz,2H),8.36(s,1H),8.27(d,J=8.7Hz,1H),7.80(s,1H),7.79(s,1H),7.27(s,1H),7.26(s,1H),6.91(s,1H),6.89(s,1H),6.73(s,1H),3.84(s,3H),3.61–3.57(m,4H),3.53(s,2H),2.56–2.51(m,4H).
实施例7-75,4-(4-(甲基磺酰基)苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺(HP1-076)的合成。
采用与(HP1-073)相同的合成方法,将中间体1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为1-(4-(甲基磺酰基)苄基)哌嗪盐酸盐,得到白色产物4-(4-甲氧基苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪-1-甲酰胺(HP1-076)198mg,最后一步产率为69%。1H NMR(500MHz,CDCl3)δ8.65(d,J=2.5Hz,1H),8.39(dd,J=8.7,2.5Hz,2H),8.36(s,1H),8.27(d,J=8.7Hz,1H),7.95(d,J=8.3Hz,2H),7.80(d,J=8.3Hz,2H),7.60(d,J=8.3Hz,2H),6.79(s,1H),3.68(s,2H),3.64–3.59(m,4H),3.10(s,3H),2.62–2.53(m,4H).
实施例7-76,4-(4-(三氟甲氧基)苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺(HP1-077)的合成。
采用与(HP1-073)相同的合成方法,将中间体1-(4-(2,2,2-三氟乙氧基)苄基)哌嗪盐酸盐替换为1-(4-(三氟甲氧基)苄基)哌嗪盐酸盐,得到白色产物4-(4-甲氧基苄基)-N-(6-(3-(4-(三氟甲基)苯基(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪-1-甲酰胺(HP1-077)197mg,最后一步产率为54%。1H NMR(500MHz,CDCl3)δ8.64(d,J=2.5Hz,1H),8.41–8.37(m,2H),8.36(s,1H),8.27(d,J=8.7Hz,1H),7.79(d,J=8.3Hz,2H),7.39(d,J=8.5Hz,2H),7.21(d,J=8.0Hz,2H),6.82(s,1H),3.63–3.59(m,4H),3.58(s,2H),2.58–2.51(m,4H).
实施例7-77,4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(4-(三氟甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪-1-甲酰胺(HP1-078)的合成。
采用与(HP1-073)相同的合成方法,将中间体对三氟甲基苯甲酰胺肟替换为对三氟甲氧基苯甲酰胺肟,得到白色产物4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(4-(三氟甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪-1-甲酰胺(HP1-078)197mg,最后一步产率为54%。1H NMR(500MHz,CDCl3)δ8.62(d,J=2.5Hz,1H),8.38(dd,J=8.7,2.6Hz,1H),8.29(d,J=2.1Hz,1H),8.28–8.24(m,2H),7.39–7.35(m,2H),7.32–7.29(m,2H),6.97–6.92(m,2H),6.77(s,1H),4.38(q,J=8.1Hz,2H),3.62–3.57(m,4H),3.54(s,2H),2.57–2.50(m,4H).
实施例7-78,N-(6-(3-(4-甲氧基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-079)的合成。
采用与(73)相同的合成方法,将中间体对三氟甲基苯甲酰胺肟替换为对甲氧基苯甲酰胺肟,得到白色产物N-(6-(3-(4-甲氧基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-079)197mg,最后一步产率为54%。1H NMR(500MHz,CDCl3)δ8.61(d,J=2.6Hz,1H),8.38–8.34(m,1H),8.27–8.23(m,1H),8.20–8.15(m,2H),7.33–7.29(m,2H),7.06–7.01(m,2H),6.94(d,J=8.6Hz,2H),6.72(s,1H),4.38(q,J=8.1Hz,2H),3.90(s,3H),3.60–3.57(m,4H),3.54(s,2H),2.56–2.51(m,4H).
实施例7-79,N-(6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-080)的合成。
采用与(HP1-073)相同的合成方法,将中间体对三氟甲基苯甲酰胺肟替换为对氟苯甲酰胺肟,得到白色产物N-(6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-080)161mg,最后一步产率为52%。1H NMR(500MHz,CDCl3)δ8.62(d,J=2.5Hz,1H),8.38(dd,J=8.7,2.6Hz,1H),8.26–8.22(m,3H),7.73(dd,J=5.7,3.3Hz,1H),7.55(dd,J=5.7,3.3Hz,1H),7.24–7.19(m,2H),6.94(d,J=8.6Hz,2H),6.75(s,1H),4.38(q,J=8.1Hz,2H),3.62–3.56(m,4H),3.54(s,2H),2.57–2.49(m,4H).
实施例7-80,N-(6-(3-(4-氯苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-081)的合成。
采用与(HP1-073)相同的合成方法,将中间体对三氟甲基苯甲酰胺肟替换为对氯苯甲酰胺肟,得到白色产物N-(6-(3-(4-氯苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-081)192mg,最后一步产率为60%。1HNMR(500MHz,DMSO)δ9.24(s,1H),8.90(s,1H),8.23(d,J=3.2Hz,2H),8.11(d,J=8.5Hz,2H),7.69(d,J=8.5Hz,2H),7.29(d,J=8.4Hz,2H),7.03(d,J=8.5Hz,2H),4.75(q,J=8.9Hz,2H),3.51(s,4H),3.48(s,2H),2.40(s,4H)
实施例7-81,N-(6-(3-(4-溴苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-082)的合成。
采用与(HP1-073)相同的合成方法,将中间体对三氟甲基苯甲酰胺肟替换为对溴苯甲酰胺肟,得到白色产物N-(6-(3-(4-溴苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-082)145mg,最后一步产率为42%。1HNMR(500MHz,DMSO)δ9.24(s,1H),8.90(s,1H),8.26–8.21(m,2H),8.04(d,J=8.5Hz,2H),7.83(d,J=8.5Hz,2H),7.29(d,J=8.6Hz,2H),7.03(d,J=8.6Hz,2H),4.75(q,J=8.9Hz,2H),3.54–3.49(m,4H),3.48(s,2H),2.42–2.38(m,4H).
实施例7-82,N-(6-(3-(4-硝基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-083)的合成。
采用与(HP1-073)相同的合成方法,将中间体对三氟甲基苯甲酰胺肟替换为对硝基苯甲酰胺肟,得到白色产物N-(6-(3-(4-硝基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-083)173mg,最后一步产率为53%。1HNMR(500MHz,DMSO)δ9.25(s,1H),8.91(d,J=2.3Hz,1H),8.46(d,J=8.8Hz,2H),8.37(d,J=8.9Hz,2H),8.28–8.23(m,2H),7.29(d,J=8.5Hz,2H),7.03(d,J=8.5Hz,2H),4.75(q,J=8.9Hz,2H),3.52(s,4H),3.49(s,2H),2.44–2.36(m,4H)。
实施例7-83,N-(6-(3-(3-三氟甲基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(84)的合成。
采用与(HP1-073)相同的合成方法,将中间体对三氟甲基苯甲酰胺肟替换为间三氟甲基苯甲酰胺肟,得到白色产物N-(6-(3-(3-三氟甲基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-084)193mg,最后一步产率为57%。1H NMR(500MHz,DMSO)δ9.24(s,1H),8.91(d,J=2.4Hz,1H),8.40(d,J=7.8Hz,1H),8.34(s,1H),8.28(d,J=8.7Hz,1H),8.23(dd,J=8.7,2.5Hz,1H),8.03(d,J=7.9Hz,1H),7.88(t,J=7.8Hz,1H),7.29(d,J=8.6Hz,2H),7.03(d,J=8.6Hz,2H),4.75(q,J=8.9Hz,2H),3.53–3.50(m,4H),3.48(s,2H),2.42–2.38(m,4H)。
实施例7-84,N-(6-(3-(4-叔丁基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-085)的合成。
采用与(HP1-073)相同的合成方法,将中间体对三氟甲基苯甲酰胺肟替换为4-叔丁基苯甲酰胺肟,得到白色产物N-(6-(3-(4-叔丁基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-085)196mg,最后一步产率为59%。1H NMR(500MHz,DMSO)δ9.23(s,1H),8.90(d,J=1.4Hz,1H),8.24–8.22(m,2H),8.03(d,J=8.4Hz,2H),7.64(d,J=8.5Hz,2H),7.29(d,J=8.6Hz,2H),7.03(d,J=8.6Hz,2H),4.75(q,J=8.9Hz,2H),3.51(s,4H),3.49(s,2H),2.42–2.39(m,4H),1.34(s,9H)
实施例7-85,4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(6-(三氟甲基)(3-吡啶基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪-1-甲酰胺(HP1-086)的合成。
采用与(HP1-073)相同的合成方法,将中间体对三氟甲基苯甲酰胺肟替换为N-羟基-6-(三氟甲基)烟酰胺,得到白色产物4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(6-(三氟甲基)(3-吡啶基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪-1-甲酰胺(HP1-086)129mg,最后一步产率为38%。1H NMR(500MHz,DMSO)δ9.24(s,1H),8.90(s,1H),8.23(d,J=2.8Hz,1H),8.04(d,J=8.5Hz,2H),7.83(d,J=8.5Hz,2H),7.29(d,J=8.6Hz,2H),7.03(d,J=8.6Hz,2H),4.75(q,J=8.9Hz,2H),3.53–3.48(m,6H),2.42–2.38(m,4H)
实施例7-86,N-(6-(3-(3-氯-4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪(1-羧酰胺(HP1-087)的合成。
采用与(HP1-073)相同的合成方法,将中间体对三氟甲基苯甲酰胺肟替换为3-氯-4-三氟甲酰胺肟,得到白色产物N-(6-(3-(4-叔丁基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪-1-甲酰胺(HP1-087)162mg,最后一步产率为45%。1H NMR(500MHz,DMSO)δ9.25(s,1H),8.90(d,J=2.3Hz,1H),8.31(s,1H),8.28–8.21(m,3H),8.11(d,J=8.3Hz,1H),7.29(d,J=8.5Hz,2H),7.03(d,J=8.6Hz,2H),4.75(q,J=8.9Hz,2H),3.55–3.49(m,4H),3.48(s,2H),2.42–2.38(m,4H).
本发明的保护内容不局限于以上实施例。在不背离本发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (15)
1.一类靶向于STAT3双磷酸化位点的三联芳香杂环哌嗪类小分子有机化合物,其特征在于,其包含如式(Ⅰ)所示化合物及其相关类似物或药学上可接受的盐、代谢产物或前药;
其中:
选自5至8元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑、萘环、菲环、喹啉、异喹啉、吲哚、苯并二氮唑、苯并三氮唑、嘌呤;
选自芳香杂环,取自下列中的任意一个:噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑、四氮唑;
选自5元或6元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑;
X独立选自下列基团中的任意一个:-(CH2)n-、
n、m表示0~5;
R1、R2、R3、R4独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C6烷基、C2~C6烯基、C2~C6炔基、C1~C6烷氧基、C1~C6烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基、C5~C10芳香基,5-10元杂芳香基;
任选地,所述C5~C10芳香基,5-10元杂芳香基各自独立地选自下列基团中的任意一个或多个:卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2。
2.根据权利要求1所述的靶向于STAT3双磷酸化位点的三联芳香杂环哌嗪类小分子有机化合物及其相关类似物或药学上可接受的盐、代谢产物或前药,其特征在于,当R3为时,其结构如(Ⅱ)所示:
其中:
选自5至8元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑、萘环、菲环、喹啉、异喹啉、吲哚、苯并二氮唑、苯并三氮唑、嘌呤;
选自芳香杂环,取自下列中的任意一个:噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑、四氮唑;
选自5元或6元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑;
X独立选自下列基团中的任意一个:-(CH2)n-、
n、m表示0~5;
R1、R2和R4独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C6烷基、C2~C6烯基、C2~C6炔基、C1~C6烷氧基、C1~C6烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基、C5~C10芳香基,5-10元杂芳香基;
任选地,所述C5~C10芳香基,5-10元杂芳香基各自独立地选自下列基团中的任意一个或多个:卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2;
R8独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2。
3.根据权利要求2所述的靶向于STAT3双磷酸化位点的三联芳香杂环哌嗪类小分子有机化合物及其相关类似物或药学上可接受的盐、代谢产物或前药,其特征在于,当为时,其结构如(Ⅲ)所示:
其中:
选自5至8元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑、萘环、菲环、喹啉、异喹啉、吲哚、苯并二氮唑、苯并三氮唑、嘌呤;
选自5元或6元芳香环或芳香杂环,取自下列中的任意一个:苯环、吡啶、哒嗪、嘧啶、吡嗪、噻吩、噻唑、异噻唑、吡咯、吡唑、咪唑、噁唑、噁二唑、1,2,3-三氮唑、1,2,4-三氮唑;
X独立选自下列基团中的任意一个:-(CH2)n-、
n、m表示0~5;
R1、R2和R4独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C6烷基、C2~C6烯基、C2~C6炔基、C1~C6烷氧基、C1~C6烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基、C5~C10芳香基,5-10元杂芳香基;
任选地,所述C5~C10芳香基,5-10元杂芳香基各自独立地选自下列基团中的任意一个或多个:卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2;
R8独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2。
4.根据权利要求3所述的靶向于STAT3双磷酸化位点的三联芳香杂环哌嗪类小分子有机化合物及其相关类似物或药学上可接受的盐、代谢产物或前药,其特征在于,当为苯环;/>为吡啶环时,其结构如(IV)所示:
其中:
X独立选自下列基团中的任意一个:-(CH2)n-、
n、m表示0~5;
R1和R2独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C6烷基、C2~C6烯基、C2~C6炔基、C1~C6烷氧基、C1~C6烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基、C5~C10芳香基,5-10元杂芳香基;
任选地,所述C5~C10芳香基,5-10元杂芳香基各自独立地选自下列基团中的任意一个或多个:卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2;
R8独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2。
5.根据权利要求4所述的靶向于STAT3双磷酸化位点的三联芳香杂环哌嗪类小分子有机化合物及其相关类似物或药学上可接受的盐、代谢产物或前药,其特征在于,当X为羰基时,其结构如(V)所示:
其中:
R1和R2独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C6烷基、C2~C6烯基、C2~C6炔基、C1~C6烷氧基、C1~C6烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基C5~C10芳香基,5-10元杂芳香基;
任选地,所述C5~C10芳香基,5-10元杂芳香基各自独立地选自下列基团中的任意一个或多个:卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2;
R8独立表示下列基团中的任意一个或多个:氢、卤素、羟基、氰基、氨基、硝基、-S(O)pR5、-C(O)R5、-C(O)OR5、-OC(O)R5、-NR6R7、-C(O)NR7、C1~C4烷基、C2~C4烯基、C2~C4炔基、C1~C4烷氧基、C1~C4烷硫基、C3~C6环烷基、C2~C6环烷氧基、C2~C6环烷硫基、C2~C6含氮环烷基取代基取代;其中R5、R6、R7各自独立地选自氢或C1~C4烷基,p为0、1或2。
6.根据权利要求1-5之任一项所述的靶向于STAT3双磷酸化位点的三联芳香杂环哌嗪类小分子有机化合物及其相关类似物或药学上可接受的盐、代谢产物或前药,其特征在于,包括:
(4-甲基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-乙基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-丙基(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(三氟甲氧基)苯甲酰基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(三氟甲氧基)苯甲酰基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)乙酮;
(E)(3-(4-(三氟甲氧基)苯基)(1-(4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)(1-哌嗪基)丙(2-烯-1-酮;
1-(4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)(1-哌嗪基)丙(2-烯(1-酮;
(4-(4-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-溴苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-溴(3-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮;
(4-(4-溴(2-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮;
(4-(4-溴-2,6-二氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基甲酮
(4-(3,4-二溴苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)甲酮;
(4-(3-氟-4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(3-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(2-(三氟甲氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(3-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-甲氧基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-氨基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
叔丁基(4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟碱基](1-哌嗪基)甲基)苯基)氨基甲酸酯;
(4-(4-乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
乙酸4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基]烟酰基)(1-哌嗪基)甲基)苯基乙酸酯;
(4-(4-(叔丁基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)吡啶(3-基)甲酮;
(4-(4-甲基苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(甲基磺酰基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
((4-(4-氟苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
((4-(4-氯苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
4-((4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基](1-哌嗪基)甲基)苄腈;
(4-(4-(4-(甲基磺酰基)(1-哌啶基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(4-(四氢-2H-吡喃)氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(4-(5-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(3-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(2-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)苯基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)2-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(4-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)2-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(3-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)-2噻吩基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(5-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(2-噻唑基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(4-(4-(三氟甲基)苯基)(2-噁唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(4-(4-(三氟甲基)苯基)(2-噻唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(1-(4-(三氟甲基)苯基)(4-(1,2,3-三唑基)(3-吡啶基)甲酮;
(6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮;
(6-(3-(-2噻吩基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮;
(6-(3-(5-噻唑基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮;
(6-(3-(5-噻唑基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮;
(6-(3-(4-嘧啶基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮;
(6-(3-苯基(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(2-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(3-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(2-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(3-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-氯苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-溴苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(叔丁基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(6-(3-(3-氟-4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮;
(6-(3-(2,4-双(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)甲酮;
(3-甲基-4-(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(R)-(3-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(S)-(3-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)-1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(2-甲基-4-(4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(S)-(2-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(R)-(2-甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(1-(4-(2,2,2-三氟乙氧基)苄基)-4-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)哌嗪-2-腈;
4-(4-(2,2,2-三氟乙氧基)苄基)(1-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)烟酰基)哌嗪-2-腈;
(2,6-二甲基-4-(4-(2-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
(3,5-二甲基-4-(4-(2,2,2-三氟乙氧基)苄基)(1-哌嗪基)(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)甲酮;
4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)吡啶(3-基)哌嗪甲酰胺;
N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(3,3,3-三氟丙基)哌嗪甲酰胺;
4-(4-甲氧基苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺;
4-(4-(甲基磺酰基)苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺;
4-(4-(三氟甲氧基)苄基)-N-(6-(3-(4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺;
4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(4-(三氟甲氧基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺;
N-(6-(3-(4-甲氧基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺;
N-(6-(3-(4-氟苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺;
N-(6-(3-(4-氯苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺;
N-(6-(3-(4-溴苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺;
N-(6-(3-(4-硝基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺;
N-(6-(3-(3-三氟甲基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺;
N-(6-(3-(4-叔丁基苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺;
4-(4-(2,2,2-三氟乙氧基)苄基)-N-(6-(3-(6-(三氟甲基)(3-吡啶基)(5-(1,2,4-噁二唑基)(3-吡啶基)哌嗪甲酰胺;
N-(6-(3-(3-氯-4-(三氟甲基)苯基)(5-(1,2,4-噁二唑基)(3-吡啶基-4-(4-(2,2,2-三氟乙氧基)苄基)哌嗪甲酰胺。
7.一种药物组合物,其特征在于,所述药物组合物含有如权利要求1-5之任一项所述的靶向于STAT3的三联芳香杂环哌嗪类类小分子有机化合物或其类似物或药学上可接受的盐,以及药学上可接受的载体。
8.根据权利要求7所述的药物组合物,其特征在于,所述药物组合物进一步包括第二药剂;和/或,所述药物组合物进一步包括赋形剂、稀释剂、辅剂、媒介物或其组合。
9.一类STAT3抑制剂,其特征在于,其包括根据权利要求1-5之任一项所述的靶向STAT3的三联芳香杂环哌嗪类类小分子有机化合物及药学上可接受的盐、代谢产物或前药,或如权利要求7所述的药物组合物。
10.根据权利要求1-5之任一项所述的一类靶向STAT3的三联芳香杂环哌嗪类类小分子有机化合物及药学上可接受的盐、代谢产物或前药、或根据权利要求7所述的药物组合物在制备STAT3抑制剂中的应用。
11.根据权利要求1-5之任一项所述的靶向STAT3的三联芳香杂环哌嗪类类小分子有机化合物及药学上可接受的盐、代谢产物或前药、或根据权利要求7所述的药物组合物在制备抑制STAT3的磷酸化,抑制STAT3的转录活性和线粒体的氧化磷酸化的抑制剂中的应用。
12.根据权利要求1-5之任一项所述的一类靶向STAT3的三联芳香杂环哌嗪类类小分子有机化合物及药学上可接受的盐、代谢产物或前药、或根据权利要求7所述的药物组合物在制备预防和/或治疗与STAT3和线粒体氧化磷酸化活化有关的疾病的药物中的应用。
13.根据权利要求12所述的应用,其特征在于,所述的靶向STAT3的三联芳香杂环哌嗪类类小分子有机化合物及药学上可接受的盐、代谢产物或前药、或药物组合物用于抑制癌细胞的增殖、生长、迁移、浸润、克隆形成和转移,促进癌细胞的凋亡,促进肿瘤细胞的自噬,和/或延长肿瘤患者的生存期。
14.根据权利要求12所述的应用,其特征在于,所述疾病包括消化系统肿瘤食管癌、胃癌、大肠癌、结肠癌、直肠癌、肛门癌;呼吸系统肿瘤喉癌、支气管癌、非小细胞肺癌、小细胞肺癌;实体瘤肝癌、胰腺癌、星形神经胶质瘤、卵巢癌、前列腺癌;血液瘤恶性淋巴瘤、非霍奇金氏淋巴瘤、霍奇金氏病、多发性骨髓瘤、浆细胞性肿瘤、急性骨髓性白血病、急性淋巴性白血病、成人T细胞白血病淋巴瘤、慢性骨髓性白血病、慢性淋巴性白血病;上述肿瘤及癌的转移病灶。
15.一种预防和/或治疗与STAT3磷酸化异常有关的疾病的方法,其特征在于,向有需要的个体中施于有效量的如权利要求1-5之任一项所述的化合物或如权利要求7所述的药物组合物。
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