CN113912595B - 一类含有噻唑或噻二唑结构的化合物及其应用 - Google Patents
一类含有噻唑或噻二唑结构的化合物及其应用 Download PDFInfo
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- CN113912595B CN113912595B CN202111188298.XA CN202111188298A CN113912595B CN 113912595 B CN113912595 B CN 113912595B CN 202111188298 A CN202111188298 A CN 202111188298A CN 113912595 B CN113912595 B CN 113912595B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 117
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类含有噻唑或噻二唑结构的化合物及其应用,属于医药技术领域。本发明利用药效团拆分及重组等手段对先导化合物进行结构优化,得到一系列含有噻唑或噻二唑结构的新型骨架的USP8抑制剂,丰富了USP8抑制剂的结构多样性。
Description
技术领域
本发明属于医药技术领域,具体涉及一类含有噻唑或噻二唑结构的化合物及其在制备泛素特异性蛋白酶USP8的抑制剂中的应用。
背景技术
泛素化是一种重要的翻译后修饰过程,通过将泛素转移到底物蛋白上,可以实现对蛋白稳定性和活性的调节,并且泛素化过程还与蛋白的功能定位以及蛋白-蛋白相互作用的正常发挥密切相关(Han J et al.Bioorganic Chemistry,2020,101:103962)。像其他翻译后修饰一样,泛素化是一个可逆的过程。去泛素化酶可以去除底物中的泛素,保护底物不被降解。USP8属于泛素特异性蛋白酶(USPs)家族中的一员,研究表明USP8基因突变或者蛋白的过表达与多种腺癌、胃癌等的发生密切相关。例如对库欣病等垂体腺瘤患者基因测序,发现USP8的体细胞突变导致胞内EGFR去泛素化程度增加,使EGFR在细胞膜上大量积累。而高EGFR水平反过来促使血浆ACTH增加,从而诱导垂体腺瘤的发生(Martin Reinckeet.al.Nat.Genet.2015,47:31-38)。目前治疗非小细胞肺癌的首选药物是受体酪氨酸激酶抑制剂,如吉非替尼和厄洛替尼。但由于EGFR二次突变和/或Met基因扩增,会导致许多患者产生耐药性。而USP8小分子抑制剂通过减少EGFR的表达,抑制了吉非替尼耐药的癌细胞增殖,而对正常细胞无影响(Kim,Y.et.al.Oncogene 2018,37,5387-5402.)。因此,USP8有望成为一种有效的肿瘤治疗靶标,针对其开展化学干预,抑制USP8异常的去泛素化活性,可为肿瘤治疗提供新的途径。
基于已报道的一类含硫脲结构的USP8小分子抑制剂(CN111138358A),为进一步提高化合物抑制活性,并改善其不良理化性质。申请人采用骨架跃迁与药效团拆分及重组等手段,获得了一类含有噻唑或噻二唑结构的新型化合物,丰富了USP8抑制剂的结构多样性。
发明内容
本发明利用药效团拆分及重组等手段对先导化合物进行结构优化,得到一系列含有噻唑或噻二唑结构的新型骨架的USP8抑制剂,并且活性、选择性以及理化性质相较于之前报道的硫脲类结构的USP8抑制剂均有大幅度的提升。
为了实现上述发明目的,本发明采用以下技术方案:
通式(Ⅰ)的化合物或其药学上可接受的盐,
式(Ⅰ)中,
X为C或N,当X为C时,Z为H,A片段为取代芳香环,其中取代基选自氢原子、烷基、烷氧基、三氟甲基、二氟甲基、卤素、氰基、氨基、羟基、羧基、酯基、酰胺、磺酰胺中的一个或多个;当X为N时,A片段不存在,Z选自取代芳香环,其中取代基选自氢原子、烷基、烷氧基、三氟甲基、二氟甲基、卤素、氰基、氨基、羟基、羧基、酯基、酰胺、磺酰胺中的一个或多个;
Y选自 其中n、i各自独立选自0、1或2,m选自1、2或3,n1、n2、m1、m2各自独立选自1、2或3;
R2选自氢原子、烷基、烷氧基、三氟甲基、氰基、硝基、氨基、羟基、卤素或酯基中的一个或多个;
Ar为取代或未取代的芳香环、芳杂环、芳香连环、芳香并环,其中取代基选自氢原子、烷基、烷氧基、三氟甲基、二氟甲基、卤素、氰基、氨基、羟基、羧基、酯基、酰胺、磺酰胺中的一个或多个的一个或多个。
本发明所述的通式(Ⅰ)的化合物的药学上可接受的盐,是指通式(Ⅰ)的化合物与药学上可接受的酸形成的酸加成盐或与药学上可接受的碱形成碱加成盐,所述酸包括:氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸;所述碱加成盐包括:钠盐、钾盐、铵盐、钙盐、铝盐、镁盐或其他金属盐,乙二胺、乙醇胺或其他常见碱加成盐。
通式(Ⅰ)的化合物可通过以下路线合成。
苯基噻唑类化合物的合成:
苯基噻二唑类化合物的合成:
由化合物II-1制备化合物II-2的过程,通过卤素与硫氰酸钾反应生成异硫氰酸酯,溶剂为甲醇或乙醇;由化合物II-2制备化合物II-3的过程,通过异硫氰酸酯合成噻唑环得到,溶剂优选33%氢溴酸乙酸溶液。
由化合物II-4制备化合物II-5的过程,利用2-溴苯乙酮与硫脲反应,溶剂为乙醇;由化合物II-5制备化合物II-6的过程,通过酰胺缩合反应得到,缩合剂优选为HATU,碱为N,N-二异丙基乙胺,溶剂优选N,N-二甲基甲酰胺。由化合物II-3制备化合物II-7的过程,为碱性条件的亲核取代反应,选用碱为碳酸钾,溶剂为丙酮或N,N-二甲基甲酰胺;由II-7制备化合物II-8的过程,同化合物II-6;由化合物II-3制备化合物II-9的过程,通过与芳香卤化物的亲核取代反应得到,选用碱为碳酸钾,溶剂为丙酮或N,N-二甲基甲酰胺;由化合物II-9制备化合物II-10的过程,为脱Boc保护基反应,采用6mol/L盐酸水溶液与1,4-二氧六环的混合体系脱除;由化合物II-10制备化合物II-11的过程,同化合物II-6。化合物II-14、II-17、II-20的制备过程与化合物II-11的过程类似。由化合物II-21制备化合物II-22的过程,为取代苯甲酸与硫代氨基脲的反应,三氯氧磷为催化剂;由化合物II-22制备化合物II-23的过程,同化合物II-6。由化合物II-22制备化合物II-24的过程,为氨基被卤素取代反应,反应试剂溴化铜,亚硝酸异戊酯,溶剂为乙腈;由化合物II-24制备化合物II-25的过程,同化合物I-6;由化合物II-25制备化合物II-26的过程,同化合物II-6。
所述通式(Ⅰ)化合物的药学上可接受的盐可通过与等化学当量或过量酸(无机酸或有机酸)在合适的溶剂或溶剂组合物中反应制得。所述酸包括但不限于氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。所述溶剂包括但不限于甲醇、乙醇、二氯甲烷、丙酮、乙酸乙酯、甲苯或四氢呋喃,或任意几种混合溶剂。
本发明提供了一种药物组合物,其包括药物有效量的活性组分和药学上可接受的辅料;所述活性组分包括通式(Ⅰ)化合物和药学上可接受的盐中的一种或多种。所述药物组合物中,所述辅料包括药学上可接受的载体、稀释剂和/或赋形剂。
根据治疗目的可将药物组合物制成各种类型的给药单位剂型,如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、颗粒剂、胶囊和针剂(溶液或悬浮液)等,优选片剂、胶囊、液体、悬浮液和针剂(溶液或悬浮液)。
本发明所述化合物在临床上的给药方式可采用口服、注射等方式。
一般地,本发明的化合物用于治疗时,人用剂量范围为1-1000mg/天。也可根据剂型的不同和疾病严重程度,使用剂量超出该范围。
本发明还提供了所示通式(Ⅰ)的化合物在制备USP8抑制剂中的应用。
本发明还提供通式(Ⅰ)所示化合物在用于治疗USP8介导的免疫抑制相关疾病中的应用。
本发明所述的USP8介导的免疫抑制相关疾病包括癌症、神经变性疾病、血液系统疾病、内分泌系统疾病。其中癌症优选但不局限于非小细胞肺癌、肝癌、胃癌、胆管癌、乳腺癌、胰腺癌、宫颈癌、垂体瘤、多发性骨髓瘤、白血病、黑色素瘤、胶质瘤;神经系统变性疾病优选但不局限于帕金森症、阿尔兹海默症;血液系统疾病优选但不局限于范可尼贫血;内分泌系统疾病优选但不局限于库欣病。
除非另外说明,在说明书和权利要求中使用的以下术语具有下面讨论的含义:
术语“芳香环”指含有1-12个碳原子的单环或稠合多环或联苯基团,具有完全的共轭π电子系统。芳香环的非限制性实例有苯基、萘基和联苯,芳香环可以是取代的或未取代的。
术语“芳杂环”指含有1-6个原子的单环体系,体系含有一个、两个、三个或四个选自N、O或S的环杂原子,其余环原子是C,并具有完全的共轭π电子系统。未取代的芳杂环非限制性实例包括吡咯、呋喃、噻吩、咪唑、噁唑、噻唑、噻二唑、吡唑、吡啶、嘧啶、四唑和三嗪。芳杂环可以是取代的或未取代的。
术语“烷基”表示1-20个碳原子的饱和的脂烃基,包括直链和支链基团。烷基可以是取代的或未取代的。当是取代的烷基时,该取代基优选是一或多个。
术语“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
术语“三氟甲基”表示-CF3基团。
术语“硝基”表示-NO2基团。
术语“氨基”表示-NH2基团。
术语“氰基”表示-CN基团。
术语“羧基”表示-COOH基团。
术语“羟基”表示-OH基团。
术语“酯基”表示-COOCH3等甲酸酯基团。
术语“卤素”表示氟、氯、溴或碘。优选为氟、氯、溴。
具体实施方式
为了进一步阐释本发明,下面给出一系列实施例,这些实施例完全是例证性的,它们仅用来对本发明具体描述,不应当理解为对本发明的限制。
实施例1
4-苯基噻唑-2-胺(II-2)
将化合物II-1(2g,10.05mmol),硫脲(0.84g,11.16mmol),乙醇(20ml)加入到三颈瓶中,反应液澄清,加热回流3h,TLC监测反应完全,待反应结束后,将反应液减压蒸除溶剂,乙醇加水重结晶得黄色固体1.6g,收率90%。
4-三氟甲基-2-(萘-1-磺酰胺基)苯甲酸(I-2)
将化合物I-3(0.36g,1.76mmol),萘-1-磺酰氯(0.4g,1.76mmol),氢氧化钠(84mg,2.1mmol),水(10ml)加入到三颈瓶中,室温下快速搅拌3h,逐渐有大量白色固体析出。反应液抽滤,用1mol/L盐酸洗涤滤饼,烘干,得白色固体0.5g,收率72%。1H NMR(300MHz,DMSO-d6):δ=8.78-8.75(d,1H,J=8.4Hz,Ar-H),8.25-8.23(d,1H,J=7.4Hz,Ar-H),8.14-8.11(d,1H,J=8.4Hz,Ar-H),8.03-8.01(d,1H,J=7.6Hz,Ar-H),7.96-7.93(d,1H,J=8.2Hz,Ar-H),7.66-7.56(m,4H,Ar-H)ppm.HRMS(ESI),[M+H]+calculated for C18H12F3NO4S396.0512,found 396.0548。
N-(4-苯基噻唑-2-基)-4-三氟甲基-2-(萘-1-磺酰氨基)苯甲酰胺(L01)
将化合物I-2(0.2g,1.14mmol),HATU(0.53g,1.37mmol),N,N-二异丙基乙胺(0.46g,3.42mmol),N,N-二甲基甲酰胺(2mL)加入到三颈瓶中,氮气保护条件下0℃搅拌30min,加入苯并[d]噻唑-2-胺(171mg,1.14mmol),氮气保护下70℃反应6h,待反应结束后,反应液冷却至室温,缓慢加入到5mL的1mol/L盐酸中,逐渐析出淡黄色固体。抽滤,滤饼烘干后,经硅胶柱层析纯化得淡黄色固体0.4g,收率85%。1H NMR(300MHz,DMSO-d6):δ=8.40-8.37(dd,1H,J1=7.3Hz,J2=1.3Hz,Ar-H),8.22(s,1H,Ar-H),8.18-8.14(m,4H,Ar-H),7.97-7.95(d,1H,J=8.2Hz,Ar-H),7.86-7.82(m,1H,Ar-H),7.57-7.55(m,1H,Ar-H),7.52-7.47(m,4H,Ar-H),7.40-7.33(m,3H,Ar-H)ppm.HRMS(ESI),[M+H]+calculated forC27H18F3N3O3S2 554.0815,found 554.0815。
实施例2
N-(4-苯基噻唑-2-基)-4-甲氧基-2-(噻吩-2-磺酰氨基)苯甲酰胺(L04)
用噻吩-2-磺酰氯代替萘-1-磺酰氯之外,以与化合物L01相同的方法合成得到淡黄色固体0.1g,收率60%。1H NMR(300MHz,DMSO-d6):δ=8.13-8.10(d,1H,J=8.7Hz,Ar-H),7.99-7.97(t,3H,J1=5.1Hz,J2=1.4Hz,Ar-H),7.77(s,1H,Ar-H),7.71-7.70(d,1H,J=3.7Hz,Ar-H),7.53-7.46(m,2H,Ar-H),7.40-7.35(t,1H,J1=6.9Hz,J2=6.5Hz,Ar-H),7.16-7.13(t,1H,J1=4.5Hz,J2=4.2Hz,Ar-H),7.06(s,1H,Ar-H),6.88-6.86(d,1H,J=8.6Hz,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C21H17N3O4S3 470.0308,found470.0373。
实施例3
N-(4-苯基噻唑-2-基)-4-甲氧基-2-((2-(三氟甲基)苯基)磺酰氨基)苯甲酰胺(L06)
用2-(三氟甲基)苯磺酰氯(0.5g,2.04mmol)代替萘-1-磺酰氯之外,以与化合物L01相同的方法合成得到淡黄色固体0.2g,收率70%。1H NMR(300MHz,DMSO-d6):δ=8.26-8.24(d,1H,J=7.0Hz,Ar-H),8.13-8.10(d,1H,J=8.9Hz,Ar-H),8.02-7.87(m,5H,Ar-H),7.76(s,1H,Ar-H),7.50-7.45(t,1H,J1=7.7Hz,J2=7.3Hz,Ar-H),7.39-7.34(m,1H,Ar-H),6.95-6.94(d,1H,J=2.3Hz,Ar-H),6.83-6.80(m,1H,Ar-H),3.80(s,3H,OCH3)ppm.HRMS(ESI),[M-H]-calculated for C24H18F3N3O4S2 532.0618,found 532.0614。
实施例4
4-溴-2-(吡啶-3-磺酰氨基)苯甲酸(II-4)
将化合物II-3(0.3g,1.39mmol)),吡啶-3-磺酰氯(0.25g,1.39mmol),氢氧化钠(67mg,1.67mmol),水(15ml)加入到三颈瓶中,逐渐有橙黄色固体析出。待反应结束后,抽滤,滤饼用甲醇打浆后抽滤,得淡黄色固体纯品0.3g,收率61%。1H NMR(300MHz,DMSO-d6):δ=9.02(s.1H,Ar-H),8.88-8.87(d,1H,J=3.7Hz,Ar-H),8.27-8.25(d,1H,J=5.6Hz,Ar-H),7.87-7.84(d,1H,J=8.5Hz,Ar-H),7.70-7.65(m,2H,Ar-H),7.44-7.41(d,1H,J=8.6Hz,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C12H9BrN2O4S 354.9393,found354.9390。
N-(4-苯基噻唑-2-基)-4-溴-2-(吡啶-3-磺酰氨基)苯甲酰胺(L07)
用化合物II-4(0.3g,0.84mmol)代替中间体I-2之外,以与化合物L01相同的方法合成得到淡黄色固体0.12g,收率72%。1H NMR(300MHz,DMSO-d6):δ=8.94-8.80(m,2H,Ar-H),8.28-8.16(m,1H,Ar-H),8.00-7.97(d,1H,J=8.4Hz,Ar-H),7.88-7.76(m,2H,Ar-H),7.70-7.59(m,1H,Ar-H),7.53-7.39(m,4H,Ar-H)ppm.HRMS(ESI),[M-H]-calculated forC21H15BrN4O3S2 512.9696,found 512.9690。
实施例5
N-(4-苯基噻唑-2-基)-4-甲氧基-2-((4-溴苯基)磺酰氨基)苯甲酰胺(L09)
用4-溴苯磺酰氯(0.3g,1.17mmol)代替噻吩-2-磺酰氯之外,以与化合物L01相同的方法合成得到浅灰色固体0.13g,收率75%。1H NMR(300MHz,DMSO-d6):δ=8.05-7.97(m,3H,Ar-H),7.77-7.75(d,5H,J=4.1Hz,Ar-H),7.51-7.46(t,2H,J1=7.2Hz,J2=7.8Hz,Ar-H),7.52-7.47(t,2H,J1=7.7Hz,J2=7.2Hz,Ar-H),7.40-7.37(d,1H,J=7.3Hz,Ar-H),6.92-6.91(d,1H,J=2.5Hz,Ar-H),6.88-6.84(dd,1H,J1=8.9Hz,J2=2.5Hz Ar-H),3.82(s,3H,OCH3)ppm.HRMS(ESI),[M-H]-calculated for C23H18BrN3O4S2 541.9849,found541.9839。
实施例6
N-(4-苯基噻唑-2-基)-4-甲氧基-2-((4-(4-甲基吡啶-3-基)苯基)磺酰胺基)苯甲酰胺(L10)
将化合物L09(0.2g,0.36mmol),4-甲基吡啶-3-硼酸频那醇酯(0.15g,0.72mmol),碳酸钾(0.1g,0.72mmol),四三苯基膦钯(20mg,0.018mmol),1,4-二氧六环(2ml),水(1ml)加入到三颈瓶中,反应需氮气保护,70-80℃反应过夜,TLC监测原料L09反应完全。反应液抽滤,滤液用二氯甲烷萃取,将有机层用无水硫酸钠除水,减压蒸除溶剂。柱层析纯化得米黄色固体0.15g,收率75%。1H NMR(300MHz,DMSO-d6):δ=8.49-8.47(d,1H,J=5.1Hz,Ar-H),8.40(s,1H,Ar-H),8.09-8.06(d,1H,J=8.9Hz,Ar-H),7.98-7.89(m,4H,Ar-H),7.76(s,1H,Ar-H),7.69-7.58(m,6H,Ar-H),7.51-7.46(t,2H,J1=7.6Hz,J2=7.3Hz,Ar-H),7.38(s,1H,Ar-H),7.01-7.00(d,1H,J=2.4Hz,Ar-H),3.84(s,3H,OCH3),2.2(s,3H,CH3-Ar)ppm.HRMS(ESI),[M-H]-calculated for C29H24N4O4S2 555.1166,found 555.1428。
实施例7
2-(吡啶-3-磺酰氨基)-4-(三氟甲基)苯甲酸(II-6)
用吡啶-3-磺酰氯(0.43g,2.44mmol)代替萘-1磺酰氯之外,以与化合物I-2相同的方法合成得到浅灰色固体0.6g,收率82%。1H NMR(300MHz,DMSO-d6):δ=8.97(s,1H,Ar-H),8.85(s,1H,Ar-H),8.21-8.10(m,2H,Ar-H),7.71-7.55(m,3H,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C13H9F3N2O4S 345.0162,found 345.0149。
5-苯基-1,3,4-噻二唑-2-胺(II-8)
将苯甲酸(0.43g,2.44mmol),硫代氨基脲(1.8g,19.67mmol),三氯氧磷(20ml)加入到三颈瓶中,75℃反应5小时,TLC监测反应完全。待反应液冷却至室温,在冰浴的条件下向反应液中缓慢滴加1mol/L盐酸溶液淬灭三氯氧磷。后用乙酸乙酯萃取,将有机层用无水硫酸钠除水,减压蒸出溶剂。柱层析纯化得白色固体1.9g,收率88%。1H NMR(300MHz,DMSO-d6):δ=7.83-7.81(t,2H,J1=3.7Hz,J2=3.5Hz,Ar-H),7.57-7.55(t,3H,J1=2.9Hz,J2=2.4Hz,Ar-H)ppm.HRMS(ESI),[M+H]+calculated for C8H7N3S178.0434,found 178.0419。
N-(5-苯基-1,3,4-噻二唑-2-基)-4-三氟甲基-2-(吡啶-3-磺酰氨基)苯甲酰胺(L12)
用中间体II-8(0.1g,0.578mmol)代替中间体II-2之外,以与化合物L01相同的方法合成得到淡黄色固体0.1g,收率65%。1H NMR(300MHz,DMSO-d6):δ=8.86(s,1H,Ar-H),8.78-8.77(d,1H,J=4.6Hz,Ar-H),8.12-8.10(d,1H,J=7.9Hz,Ar-H),8.01-8.00(m,3H,Ar-H),7.67-7.51(m,6H,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C21H14F3N5O3S2504.0417,found 504.0362。
实施例8
N-(5-苯基-1,3,4-噻二唑-2-基)-4-溴-2-(吡啶-3-磺酰氨基)苯甲酰胺(L14)
用中间体II-8(0.17g,0.95mmol)代替中间体II-2之外,以与化合物L01相同的方法合成得到米白色固体0.60g,收率90%。1H NMR(300MHz,DMSO-d6):δ=8.92(s,1H,Ar-H),8.82-8.80(d,1H,J=4.8Hz,Ar-H),8.18-8.15(m,1H,Ar-H),8.05-8.02(m,1H,Ar-H),7.86-7.82(m,1H,Ar-H),7.64-7.59(m,4H,Ar-H),7.52-7.48(m,2H,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C20H14BrN5O3S2 513.9648,found 513.9640。
实施例9
N-(5-苯基-1,3,4-噻二唑-2-基)-4-三氟甲基-2-([1,1'-联苯]-4-磺酰氨基)苯甲酰胺(L17)
用中间体II-8(0.1g,0.59mmol)代替中间体II-2之外,以与化合物L01相同的方法合成得到灰色固体0.15g,收率72%。1H NMR(300MHz,DMSO-d6):δ=8.11-8.08(m,2H,Ar-H),7.92-7.91(m,4H,Ar-H),7.73-7.67(m,7H,Ar-H),7.55-7.54(m,4H,Ar-H)ppm.HRMS(ESI),[M-H]-calculated for C28H19F3N4O3S2 579.0778,found 579.0776。
实施例10
2-溴-5-苯基-1,3,4-噻二唑(II-9)
将溴化铜(0.87g,3.90mmol),亚硝酸异戊酯(0.45g,3.90mmol),乙腈(30ml)加入到三颈瓶中,室温搅拌15min后,加入化合物II-8(0.3g,1.70mmol),继续室温搅拌2h。待反应结束后,减压蒸除溶剂,加入乙酸乙酯稀释后,用1mol/L盐酸水洗(10mlx3),将有机层用无水硫酸钠除水,减压蒸除溶剂,得黄色固体0.3g,收率81%。1H NMR(300MHz,DMSO-d6):δ=7.83-7.81(t,2H,J1=3.7Hz,J2=3.5Hz,Ar-H),7.57-7.55(t,3H,J1=2.9Hz,J2=2.4Hz,Ar-H)ppm.HRMS(ESI),[M+H]+calculated for C8H5BrN2S240.9430,found 240.9442。
N-(2-(4-(5-苯基-1,3,4-噻二唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L19)
以与化合物L01相同的方法合成得到淡黄色固体0.22g,收率79%。1H NMR(300MHz,DMSO-d6):δ=8.97-8.96(d,1H,J=2.3Hz,Ar-H),8.93-8.91(dd,1H,J1=4.8Hz,J2=1.5Hz,Ar-H),8.24-8.20(m,1H,Ar-H),7.90-7.87(m,2H,Ar-H),7.75-7.69(m,3H,Ar-H),7.57-7.56(m,3H,Ar-H),7.45(s,1H,Ar-H),3.83-3.75(m,4H,NCH 2CH2N),3.64-3.59(m,2H,NCH2CH2 N),3.41-3.37(m,2H,NCH2CH2 N)ppm.HRMS(ESI),[M+H]+calculated forC25H21F3N6O3S2575.1142,found 575.1145。
实施例11
N-(2-(4-(5-苯基-1,3,4-噻二唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)-[1,1'-联苯]-4-磺酰胺(L20)
以与化合物L01相同的方法合成得到淡黄色固体0.18g,收率53%。1H NMR(300MHz,DMSO-d6):δ=9.87(s,1H,NH),7.95-7.94(d,4H,J=2.8Hz,Ar-H),7.87-7.84(dd,2H,J1=7.9Hz,J2=2.3Hz,Ar-H),7.79-7.76(d,2H,J=7.2Hz,Ar-H),7.61-7.55(m,3H,Ar-H),7.53-7.50(d,2H,J=7.7Hz,Ar-H),7.47-7.44(m,1H,Ar-H),7.39-7.36(d,1H,J=8.5Hz,Ar-H),6.91-6.88(dd,1H,J1=8.6Hz,J2=2.4Hz,Ar-H),6.84-6.83(d,1H,J=2.4Hz,Ar-H),3.78(s,3H,OCH3),3.61-3.40(m,8H,NCH 2CH 2N)ppm。
实施例12
2-溴苯基噻唑(II-13)
将II-11(2.0g,10.05mmol),硫氰酸钾(1.08g,11.05mmol),无水乙醇(20ml)加入到三颈瓶中,加热至回流反应2h。待反应结束后,趁热过滤掉生成的溴化钾,将滤液减压蒸除溶剂,得乳白色晶体1.9g,将其溶于乙酸(20ml)中,向反应液中缓慢滴加20ml 33%氢溴酸乙酸溶液,滴加完毕升温至回流,TLC监测反应情况。待反应结束后,将反应液冷却至室温,析出大量淡黄色固体,抽滤,将滤饼用饱和碳酸氢钠溶液洗涤(5mlx3),将其烘干,得淡黄色固体1g,收率60%。1H NMR(300MHz,DMSO-d6):δ=8.19(s,1H,Ar-H),7.95-7.92(m,2H,Ar-H),7.52-7.43(m,2H,Ar-H)ppm。
1-(4-苯基噻唑-2-基)哌啶-4-胺(II-15)
将化合物II-14(2.5g),1,4-二氧六环(15ml),6mol/L盐酸(15ml)加入到圆底烧瓶中,40℃反应1h。待反应结束后,用饱和碳酸氢钠溶液将反应液PH调至中性或弱碱性,加二氯甲烷萃取。将有机层减压蒸除溶剂,得白色固体2g,收率86%。1H NMR(300MHz,DMSO-d6):δ=7.90-7.87(m,2H,Ar-H),7.44-7.39(t,2H,J1=7.7Hz,J2=7.2Hz,Ar-H),7.33-7.31(m,2H,Ar-H),4.05-4.01(m,2H),3.60(s,1H),3.20-3.13(m,2H),2.07-2.03(m,2H),1.68-1.63(m,2H)ppm.HRMS(ESI),[M+H]+calculated for C14H17N3S260.1216,found 260.1227。
N-(1-(4-苯基噻唑-2-基)哌啶-4-基)-2-(吡啶-3-磺酰氨基)-4-(三氟甲基)苯甲酰胺(L21)
将中间体II-6(0.2g,0.58mmol),N,N-二甲基甲酰胺(2ml)加入到三颈瓶中,0℃下氮气保护加入HATU(0.27g,0.70mmol),N,N-二异丙基乙胺(0.23g,1.74mmol)搅拌30min后,加入化合物II-15(0.15g,0.58mmol),室温反应5h,TLC监测反应情况。待反应结束后,将反应液倒入5V体积1mol/L盐酸中,有淡黄色固体析出,抽滤,将滤饼烘干经柱层析纯化得米黄色固体0.14g,收率75%。1H NMR(300MHz,DMSO-d6):δ=8.82-8.76(m,2H,Ar-H),7.86-7.83(m,3H,Ar-H),7.66-7.61(m,4H,Ar-H),7.38-7.26(m,4H,Ar-H),3.99-3.95(m,2H),3.60(s,1H),3.20-3.15(m,2H),2.91-2.88(m,2H),1.99-1.86(m,2H)ppm.HRMS(ESI),[M+H]+calculated for C27H24F3N5O3S2 588.1346,found 588.1341。
实施例13
N-(2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L23)
以与化合物L01相同的方法合成得到乳白色固体0.11g,收率74%。1H NMR(300MHz,DMSO-d6):δ=8.91-8.89(t,1H,J1=2.5Hz,J2=2.3Hz,Ar-H),8.86-8.85(d,1H,J=3.5Hz,Ar-H),8.18-8.07(m,2H,Ar-H),7.90-7.88(d,1H,J=7.1Hz,Ar-H),7.68-7.66(m,3H,Ar-H),7.42-7.35(m,4H,Ar-H),3.56-3.54(m,4H,NCH 2CH2N),3.10-3.06(m,4H,NCH 2CH2N)ppm。HRMS(ESI),[M+H]+calculated for C26H22F3N5O3S2 574.1189,found574.1195。
实施例14
N-(2-(4-(4-(对甲苯基)噻唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L24)
以与化合物L01相同的方法合成得到白色固体0.18g,收率80%。1H NMR(300MHz,DMSO-d6):δ=10.54(s,1H,NH),8.91-8.90(d,1H,J=2.1Hz,Ar-H),8.86-8.84(dd,1H,J1=4.8Hz,J2=1.4Hz,Ar-H),8.18-8.14(m,1H,Ar-H),7.79-7.77(d,2H,J=8.1Hz,Ar-H),7.68-7.63(m,3H,Ar-H),7.40(s,1H,Ar-H),7.28(s,1H,Ar-H),7.24-7.21(d,2H,J=8.0Hz,Ar-H),3.76-3.51(m,8H,NCH 2CH 2N),2.34(s,3H,CH3Ar)ppm.HRMS(ESI),[M+H]+calculatedfor C27H24F3N5O3S2588.1346,found 588.1364。
实施例15
N-(2-(4-(4-(3,4-二甲苯基)噻唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L26)
以与化合物L01相同的方法合成得到白色固体0.21g,收率74%。1H NMR(300MHz,DMSO-d6):δ=8.96-8.92(m,2H,Ar-H),8.25-8.23(d,1H,J=7.5Hz,Ar-H),7.73-7.62(m,5H,Ar-H),7.43(s,1H,Ar-H),7.29(s,1H,Ar-H),7.23-7.20(d,1H,J=7.8Hz,Ar-H),3.79-3.38(m,8H,NCH 2CH 2N),2.31(s,3H,CH3Ar),2.29(s,3H,CH3Ar)ppm.HRMS(ESI),[M+H]+calculated for C28H26 F3N5O3S2 601.1429,found 602.1510。
实施例16
N-(2-(4-(4-(4-(三氟甲基)苯基)噻唑-2-基)哌嗪-1-羰基)-5-(三氟甲基)苯基)吡啶-3-磺酰胺(L27)
以与化合物L01相同的方法合成得到白色固体0.14g,收率71%。1H NMR(300MHz,DMSO-d6):δ=10.56(s,1H,NH),8.92-8.91(d,1H,J=2.1Hz,Ar-H),8.87-8.85(m,1H,Ar-H),8.18-8.09(m,3H,Ar-H),7.80-7.78(d,2H,J=8.3Hz,Ar-H),7.69-7.63(m,3H,Ar-H),7.61(s,1H,Ar-H),7.39(s,1H,Ar-H),3.77-3.60(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C27H21 F6N5O3S2 642.1063,found 642.1076。
实施例17
N-(5-硝基-2-(4-(4-(4-(三氟甲基)苯基)噻唑-2-基)哌嗪-1-羰基)苯基)吡啶-3-磺酰胺(L29)
利用类似化合物L01的方法合成得到米白色固体,收率72%。1H NMR(300MHz,DMSO-d6):δ=8.96(s,1H,Ar-H),8.86-8.85(d,1H,J=4.7Hz,Ar-H),8.21-8.18(dd,1H,J1=8.0Hz,J2=1.7Hz,Ar-H),8.12-8.09(m,3H,Ar-H),8.02-8.01(d,1H,J=1.9Hz,Ar-H),7.79-7.77(d,2H,J=7.9Hz,Ar-H),7.69-7.64(m,2H,Ar-H),7.60(s,1H,Ar-H),3.77(s,2H,NCH 2CH2N),3.67(s,2H,NCH 2CH2N),3.32(s,2H,NCH2CH 2N),3.19(s,2H,NCH2CH 2N)ppm.HRMS(ESI),[M-H]-calculated for C26H21F3N6O5S2 617.0894,found 617.0862。
实施例18
N-(5-氨基-2-(4-(4-(4-(三氟甲基)苯基)噻唑-2-基)哌嗪-1-羰基)苯基)吡啶-3-磺酰胺(L30)
将化合物L29(0.15g,0.24mmol),10%钯碳(30mg),四氢呋喃(10ml)加入圆底烧瓶中,向反应体系中通入氢气,室温下反应6h,TLC监测反应完全。待反应结束后,过滤掉钯碳,将滤液减压蒸除溶剂,得白色固体0.10g,收率90%。1H NMR(300MHz,DMSO-d6):δ=9.86(s,1H,NH),8.91(s,1H,Ar-H),8.83-8.81(m,1H,Ar-H),8.17-8.09(m,3H,Ar-H),7.80-7.77(d,2H,J=8.2Hz,Ar-H),7.67-7.62(m,1H,Ar-H),7.60(s,1H,Ar-H),7.18-7.15(d,1H,J=8.4Hz,Ar-H),7.04-7.02(d,1H,J=8.4Hz,Ar-H),6.74-6.62(m,1H,Ar-H),6.40-6.37(d,1H,J=8.4Hz,Ar-H),3.56-3.52(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated forC26H23F3N6O3S2 589.1298,found 589.1164。
实施例19
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N-(5-甲氧基-2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L31)
以与化合物L01相同的方法合成得到米白色固体0.17g,收率74%。1H NMR(300MHz,DMSO-d6):δ=9.94(s,1H,NH),7.98-7.97(dd,1H,J1=5.0Hz,J2=1.4Hz,Ar-H),7.91-7.88(m,2H,Ar-H),7.62-7.60(dd,1H,J1=3.8Hz,J2=1.4Hz,Ar-H),7.42-7.40(m,1H,Ar-H),7.36-7.33(m,3H,Ar-H),7.20-7.18(m,1H,Ar-H),6.89-6.85(dd,1H,J1=8.6Hz,J2=2.5Hz,Ar-H),6.74-6.73(d,1H,J=2.5Hz,Ar-H),3.74(s,1H,OCH3),3.56-3.40(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C25H24N4O4S3 541.1033,found541.1032。
实施例20
N-(5-甲氧基-2-(4-(4-(4-甲氧基)苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L33)
以与化合物L01相同的方法合成得到淡黄色固体90mg,收率58%。1H NMR(300MHz,DMSO-d6):δ=9.94(s,1H,NH),7.99-7.97(d,1H,J=4.6Hz,Ar-H),7.83-7.81(d,2H,J=8.6Hz,Ar-H),7.62-7.61(d,1H,J=3.0Hz,Ar-H),7.36-7.34(d,1H,J=8.5Hz,Ar-H),7.21-7.19(m,2H,Ar-H),7.01-6.98(d,2H,J=8.8Hz,Ar-H),6.89-6.86(d,1H,J=8.4Hz,Ar-H),6.74(s,1H,Ar-H),3.81(s,3H,OCH3),3.75(s,3H,OCH3),3.57(d,4H,NCH 2CH2N),2.92(s,2H,NCH2CH 2N),2.72(s,2H,NCH2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C26H26N4O5S3571.1138,found 571.1152。
实施例21
N-(5-甲氧基-2-(4-(4-(4-硝基苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L35)
以与化合物L01相同的方法合成得到淡黄色固体0.4g,收率70%。1H NMR(300MHz,DMSO-d6):δ=9.92(s,1H,NH),8.31-8.28(d,2H,J=8.7Hz,Ar-H),8.17-8.14(d,2H,J=8.7Hz,Ar-H),7.98-7.97(d,1H,J=4.6Hz,Ar-H),7.74(s,1H,Ar-H),7.61-7.60(d,1H,J=3.4Hz,Ar-H),7.36-7.33(d,1H,J=8.6Hz,Ar-H),7.20-7.17(t,1H,J1=4.3Hz,J2=4.2Hz,Ar-H),6.88-6.85(d,1H,J=6.7Hz,Ar-H),6.74-6.73(d,1H,J=1.9Hz,Ar-H),3.74(s,3H,OCH3),3.60-3.43(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C25H23N5O6S3586.0883,found586.0821。
实施例22
N-(5-甲氧基-2-(4-(4-(4-氨基苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L36)
将化合物L35硝基还原得到L36,合成方法与化合物L30类似,收率84%。1H NMR(300MHz,DMSO-d6):δ=7.98-7.96(t,1H,J1=J2=3.8Hz,Ar-H),7.61-7.60(m,1H,Ar-H),7.57(s,1H,Ar-H),7.55(s,1H,Ar-H),7.35-7.33(d,1H,J=8.5Hz,Ar-H),7.20-7.17(t,1H,J1=4.8Hz,J2=3.8Hz,Ar-H),6.92(s,1H,Ar-H),6.88-6.85(dd,1H,J1=8.6,J2=2.4Hz,Ar-H),6.76-6.75(d,1H,J=2.3Hz,Ar-H),6.60-6.57(d,2H,J=8.5Hz,Ar-H),3.75(s,3H,OCH3),3.70-3.53(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C25H23N5O4S3556.1142,found 556.1224。
实施例23
N-(5-甲氧基-2-(4-(4-(4-氰基苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L38)
以与化合物L01相同的方法合成得到淡黄色固体0.14g,收率70%。1H NMR(300MHz,DMSO-d6):δ=9.93(s,1H,NH),8.09-8.06(d,2H,J=7.9Hz,Ar-H),7.98-7.96(d,1H,J=4.1Hz,Ar-H),7.90-7.87(d,2H,J=8.4Hz,Ar-H),7.66-7.55(m,2H,Ar-H),7.35-7.32(d,1H,J=8.9Hz,Ar-H),7.19(s 1H,Ar-H),6.88-6.85(d,1H,J=8.3Hz,Ar-H),6.73(s,1H,Ar-H),3.74(s,3H,OCH3),3.70-3.50(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C26H23N5O4S3566.0985,found 566.0979。
实施例24
2-((5-氯噻吩)-2-磺酰氨基)-4-甲氧基苯甲酸(II-19)
以与中间体I-2相同的方法合成得到淡黄色固体2.7g,收率79%。1H NMR(300MHz,DMSO-d6):δ=11.50(s,1H,NH),7.94-7.91(d,1H,J=8.9Hz,Ar-H),7.65-7.64(d,1H,J=4.1Hz,Ar-H),7.26-7.25(d,1H,J=4.1Hz,Ar-H),7.07-7.06(d,1H,J=2.4Hz,Ar-H),6.82-6.78(dd,1H,J1=8.9,J2=2.5Hz,Ar-H),3.44(s,3H,OCH3)ppm.HRMS(ESI),[M-H]-calculated for C12H10ClNO5S2 345.9616,found 345.9599。
5-氯-N-(5-甲氧基-2-(4-(4-(间甲苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L39)
以与化合物L01相同的方法合成得到淡黄色固体0.14g,收率70%。1H NMR(300MHz,DMSO-d6):δ=10.14(s,1H,NH),7.71-7.66(t,1H,J1=7.8,J2=7.1Hz,Ar-H),7.50-7.49(d,1H,J=3.9Hz,Ar-H),7.37-7.26(m,4H,Ar-H),7.15-7.12(d,1H,J=7.5Hz,Ar-H),6.92-6.89(d,1H,J=8.2Hz,Ar-H),6.75(s,1H,Ar-H),3.76(s,3H,OCH3),3.62-3.57(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C26H25ClN4O4S3 589.0799,found589.0802。
实施例25
5-氯-N-(5-甲氧基-2-(4-(4-(4-氯苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L40)
以与化合物L40相同的方法合成得到淡黄色固体0.18g,收率74%。1H NMR(300MHz,DMSO-d6):δ=9.54(s,1H,NH),7.97-7.94(d,2H,J=7.9Hz,Ar-H),7.53-7.48(m,4H,Ar-H),7.32-7.25(m,2H,Ar-H),7.18-7.17(d,1H,J=3.3Hz,Ar-H),6.91-6.89(d,1H,J=6.9Hz,Ar-H),3.93(s,3H,OCH3),3.79-3.75(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C25H22Cl2N4O4S3 609.0253,found 609.0275。
实施例26
5-氯-N-(5-甲氧基-2-(4-(4-(4-(三氟甲基)苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L41)
以与化合物L01相同的方法合成得到淡黄色固体0.17g,收率72%。1H NMR(300MHz,DMSO-d6):δ=10.13(s,1H,NH),8.12-8.09(d,2H,J=8.2Hz,Ar-H),7.80-7.77(d,2H,J=8.5Hz,Ar-H),7.60(s,1H,Ar-H),7.51-7.49(d,1H,J=4.1Hz,Ar-H),7.38-7.35(d,1H,J=8.6Hz,Ar-H),7.28-7.26(d,1H,J=4.1Hz,Ar-H),6.93-6.89(dd,1H,J1=8.6,J2=2.5Hz,Ar-H),6.76-6.75(d,1H,J=2.4Hz,Ar-H),3.77(s,3H,OCH3),3.59-3.55(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C26H22ClF3N4O4S3 643.0517,found643.0429。
实施例27
5-氯-N-(5-甲氧基-2-(4-(4-(4-羟基苯基)噻唑-2-基)哌嗪-1-羰基)苯基)噻吩-2-磺酰胺(L42)
以与化合物L01相同的方法合成得到淡黄色固体0.12g,收率65%。1H NMR(300MHz,DMSO-d6):δ=9.57(s,1H,OH),7.72-7.69(d,2H,J=8.6Hz,Ar-H),7.50-7.49(d,1H,J=4.1Hz,Ar-H),7.36-7.34(d,1H,J=8.6Hz,Ar-H),7.27-7.26(d,1H,J=4.1Hz,Ar-H),7.07(s,1H,Ar-H),6.91-6.88(d,1H,J=6.5Hz,Ar-H),6.81-6.76(m,3H,Ar-H),3.77(s,3H,OCH3),3.64-3.54(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated forC25H23ClN4O5S3 591.0592,found591.0512。
实施例28
4-溴-N-(5-甲氧基-2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)苯基)苯磺酰胺(II-18)
以与化合物L31类似的方法制备得到浅灰色固体。1H NMR(300MHz,DMSO-d6):δ=9.93(s,1H,OH),7.92-7.89(d,2H,J=7.3Hz,Ar-H),7.86-7.84(d,2H,J=8.6Hz,Ar-H),7.75-7.73(d,2H,J=8.6Hz,Ar-H),7.46-7.41(t,2H,J1=7.8,J2=7.3Hz,Ar-H),7.37-7.31(m,3H,Ar-H),6.88-6.84(dd,1H,J1=8.6,J2=2.5Hz,Ar-H),6.67-6.66(d,1H,J=2.4Hz,Ar-H),3.74(s,3H,OCH3),3.56-3.40(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculatedfor C27H25BrN4O4S2 613.0574,found 613.0588。
3'-氨基-N-(5-甲氧基-2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)苯基)-[1,1'-联苯]-4-磺酰胺(L43)
将中间体II-18(0.2g,0.33mmol)以及3-氨基苯硼酸频那醇酯(0.14g,0.65mmol)以与化合物L10相同的方法合成得到浅灰色固体0.12g,收率77%。1H NMR(300MHz,DMSO-d6):δ=7.90-7.85(t,4H,J1=8.6Hz,J2=7.6Hz,Ar-H),7.79-7.76(d,2H,J=8.6Hz,Ar-H),7.45-7.40(t,2H,J1=7.7Hz,J2=7.3Hz,Ar-H),7.36-7.31(m,3H,Ar-H),7.15-7.10(t,1H,J1=7.9Hz,J2=7.8Hz,Ar-H),6.90(s,1H,Ar-H),6.85-6.81(m,2H,Ar-H),6.71-6.64(d,1H,J=2.3Hz,Ar-H),6.67-6.64(d,1H,J=8.2Hz,Ar-H),3.71(s,3H,OCH3),3.70-3.50(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C33H31N5O4S2 626.1890,found626.1777。
实施例29
3'-羟基-N-(5-甲氧基-2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)苯基)-[1,1'-联苯]-4-磺酰胺(L44)
以与化合物L10相同的方法合成得到米白色固体0.11g,收率55%。1H NMR(300MHz,DMSO-d6):δ=9.85(s,1H,NH),9.68(s,1H,OH),7.90-7.82(m,6H,Ar-H),7.45-7.40(t,2H,J1=7.7Hz,J2=7.2Hz,Ar-H),7.34-7.25(m,4H,Ar-H),7.14-7.08(t,2H,J1=8.9,J2=7.9Hz,Ar-H),6.86-6.81(m,2H,Ar-H),6.72-6.71(d,1H,J=2.4Hz,Ar-H),3.71(s,3H,OCH3),3.63-3.38(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated forC33H30N4O5S2 627.1731,found 627.1698。
实施例30
4'-(N-(5-甲氧基-2-(4-(4-苯基噻唑-2-基)哌嗪-1-羰基)苯基)氨磺酰基)-[1,1'-联苯]-3-羧酸(L47)
以与化合物L10相同的方法合成得到米白色固体0.12g,收率60%。收率84%。1HNMR(300MHz,DMSO-d6):δ=9.89(s,1H,NH),8.25(s,1H,Ar-H),8.02-7.86(m,8H,Ar-H),7.64-7.59(t,1H,J1=7.8Hz,J2=7.7Hz,Ar-H),7.45-7.40(t,2H,J1=7.7Hz,J2=7.2Hz,Ar-H),7.34-7.30(m,3H,Ar-H),6.85-6.82(dd,1H,J1=8.6Hz,J2=2.4Hz,Ar-H),6.75-6.74(d,1H,J=2.3Hz,Ar-H),3.72(s,3H,OCH3),3.60-3.38(m,8H,NCH 2CH 2N)ppm.HRMS(ESI),[M+H]+calculated for C34H30N4O6S2 655.1680,found 655.1686。
实施例31
N-(5-甲氧基-2-(3-((4-(4-(三氟甲基)苯基)噻唑-2-基)氨基)吡咯烷-1-羰基)苯基)噻吩-2-磺酰胺(L49)
与化合物L01的制备类似,得到浅灰色固体,收率71%。1H NMR(300MHz,Acetone-d6):δ=8.14(s,2H,Ar-H),7.96-7.76(m.3H,Ar-H),7.56-7.54(d,2H,J=8.6Hz,Ar-H),7.29-7.27(d,2H,J=6.6Hz,Ar-H),7.23-7.21(d,1H,J=5.6Hz,Ar-H),6.81(s,1H,Ar-H),3.90(s,3H,OCH3),3.61-3.58(m,2H,NCH(CH2)CH 2N),2.87-2.85(m,2H,NCHCH2CH 2N),2.84-2.80(m,1H,NCH(CH2)CH2N),2.08-2.05(m,2H,NCH(CH2)CH 2CH2N)ppm.HRMS(ESI),[M+H]+calculated for C26H23F3N4O4S3 609.0907,found 609.0880。
实施例32
N-(5-甲氧基-2-(5-(4-(对甲苯基)噻唑-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)苯基)噻吩-2-磺酰胺(L50)
以与化合物L01相同的方法合成得到浅灰色固体,收率76%。1H NMR(300MHz,Acetone-d6):δ=8.04-8.03(d,2H,J=2.5Hz,Ar-H),7.81-7.61(m,3H,Ar-H),7.58-7.52(m,1H,Ar-H),7.34-7.25(m,3H,Ar-H),7.1-7.03(m,1H,Ar-H),6.86-6.79(m,3H,Ar-H),4.91-4.84(m,2H,CHCH 2NCO),3.77(s,3H,OCH3),3.74-3.70(m,2H,NCH 2CHN),3.59(s,1H,NCH(CH2)CH2),3.37(s,1H,NCH(CH2)CH2),2.40(s,3H,CH3Ar),2.22-2.21(m,2H,CHCH 2CH)ppm.HRMS(ESI),[M+H]+calculated for C27H26N4O4S3 567.1189,found 567.1253.
实施例33
N-(5-甲氧基-2-(5-(4-(4-(三氟甲基)苯基)噻唑-2-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羰基)苯基)噻吩-2-磺酰胺(L51)
以与化合物L01类似的方法合成得到浅灰色固体,收率70%。1H NMR(300MHz,Acetone-d6):δ=8.15-8.12(d,2H,J=8.0Hz,Ar-H),7.84-7.81(d,2H,J=8.3Hz,Ar-H),7.58-7.46(m,4H,Ar-H),7.21(s,1H,Ar-H),6.97(s,1H,Ar-H),6.77(s,1H,Ar-H),3.94-3.90(m,3H,CHCH 2NCO),3.87(s,3H,OCH3),3.52(s,1H,NCH(CH2)CH2),2.98-2.82(m,2H,NCH 2),2.32-2.30(m,2H,CHCH 2CH)ppm.HRMS(ESI),[M+H]+calculated forC27H23F3N4O4S3621.0907,found 621.0964.
实施例34
2-(4-(4-(三氟甲基)苯基)噻唑-2-基)-2,7-二氮杂螺[3.5]壬烷-7-羧酸叔丁酯(II-23)
将原料II-20(0.3g,0.97mmol),2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(0.38g,1.45mmol),N,N-二甲基甲酰胺(3ml),碳酸钾(0.4g,2.9mmol),110℃反应过夜,待反应结束后,将反应液冷却至室温,将其倒入5倍体积水中,用二氯甲烷萃取(8ml x 3),将有机层合并,减压蒸除溶剂,经柱层析纯化得到淡黄色固体0.23g,收率71%。1H NMR(300MHz,DMSO-d6):δ=8.09-8.06(d,2H,J=8.1Hz,Ar-H),7.78-7.76(d,2H,J=8.3Hz,Ar-H),7.53(s,1H,Ar-H),3.85(s,4H,CH2(CH 2)2NCO),3.36-3.34(m,4H,NCH2CCH2),1.77-1.73(t,4H,J1=5.4Hz,J2=5.2Hz,CCH2CH2)ppm.HRMS(ESI),[M+H]+calculated forC22H26F3N3O2S454.1771,found 454.1886。
N-(5-甲氧基-2-(2-(4-(4-(三氟甲基)苯基)噻唑-2-基)-2,7-二氮杂螺[3.5]壬烷-7-羰基)苯基)噻吩-2-磺酰胺(L53)
将化合物II-23脱Boc保护后,得到化合物II-24,用II-24(0.2g,0.56mmol)代替II-17之外,以与化合物L01相同的方法合成得到淡黄色固体0.10g,收率68%。1H NMR(300MHz,Acetone-d6):δ=8.20-8.17(d,2H,J=8.0Hz,Ar-H),8.02-8.00(d,1H,J=5.0Hz,Ar-H),7.87-7.84(d,2H,J=8.2Hz,Ar-H),7.63-7.62(d,1H,J=3.2Hz,Ar-H),7.56-7.53(d,1H,J=8.6Hz,Ar-H),7.36-7.33(d,1H,J=5.6Hz,Ar-H),7.28-7.22(m,2H,Ar-H),6.85-6.81(dd,1H,J1=8.3Hz,J2=2.1Hz,Ar-H)4.37(s,4H,CH2(CH 2)2NCO),3.90(s,3H,OCH3),3.52(s,4H,NCH 2CCH2),1.98(s,4H,CCH 2CH2)ppm.HRMS(ESI),[M+H]+calculated forC29H27F3N4O4S3 649.1220,found649.1228。
实施例35
N-(5-(三氟甲基)-2-(2-(4-(4-(三氟甲基)苯基)噻唑-2-基)-2,7-二氮杂螺[3.5]壬烷-7-羰基)苯基)吡啶-3-磺酰胺(L54)
以与化合物L53相同的方法合成得到淡黄色固体,收率61%。1H NMR(300MHz,Acetone-d6):δ=9.08-9.07(d,1H,J=1.5Hz,Ar-H),8.94-8.87(dd,1H,J1=8.3Hz,J2=4.6Hz,Ar-H),8.31-8.28(d,2H,J=8.2Hz,Ar-H),8.09-8.03(t,2H,J1=9.9Hz,J2=8.2Hz,Ar-H),7.92(s,1H,Ar-H),7.86-7.83(d,1H,J=8.2Hz,Ar-H),7.76-7.72(m,2H,Ar-H),7.64-7.60(m,2H,Ar-H),4.25-4.08(m,4H,CH2(CH 2)2NCO),3.76-3.71(m,4H,NCH 2CCH2),1.54-1.52(s,4H,CCH 2CH2)ppm.HRMS(ESI),[M+H]+calculated for C30H25F6N5O3S2682.1376,found 682.1388。
实施例36
4-甲氧基-2-(噻吩-2-磺酰氨基)-N-(1-(4-(4-(三氟甲基)苯基)噻唑-2-基)吡咯烷-3-基)苯甲酰胺(L55)
以与化合物L53相同的方法制备得到淡黄色固体,收率69%。1H NMR(300MHz,Acetone-d6):δ=8.32(s,2H,Ar-H),7.88-7.72(m.2H,Ar-H),7.66-7.58(d,3H,J=8.6Hz,Ar-H),7.30-7.26(d,2H,J=6.7Hz,Ar-H),7.25-7.23(d,1H,J=5.9Hz,Ar-H),6.79-6.77(m,1H,Ar-H),3.91(s,3H,OCH3),3.69-3.66(m,1H,NHCH(CH2)CH2),3.11-2.90(m,2H,NCH 2CH(CH2)NH),2.84-2.71(m,2H,NCH 2CH2CHNH),1.96-1.73(m,2H,NCH2CH 2CHNH)ppm.HRMS(ESI),[M+H]+calculated for C26H23F3N4O4S3 609.0907,found 609.0980。
实施例37
USP8小分子抑制剂酶活测试方法以及USP7、USP2选择性测试方法
本实施例利用底物Ubiquitin-Rho-110建立了靶向USP8的高通量筛选体系。使用DMSO将底物粉末溶解到浓度200μM。然后配置筛选所用实验缓冲液,成分包括50mM Tris-HCl,pH 7.5,1mM EDTA,100mM NaCl和0.05%(w/v)CHAPS。将USP8蛋白、USP2蛋白和USP7蛋白用实验缓冲液分别稀释到1nM、2nM、1nM,分别取2.5μL加入到384孔板中。接着加入2.5μL化合物稀释缓冲液。之后,再分别加入5μL 200nM底物,室温孵育。设置Envision酶标仪激发波长为480nM,发射波长为580nM,40分钟后读取反应产物荧光强度,利用Graphpad Prism5.0软件拟合求得IC50。结果如表1所示。
表1本发明部分化合物对USP8的抑制活性IC50
注:“++++”表示IC50<5μM,“+++”表示IC50<20μM,“+++”表示IC50<50μM,“+”表示IC50>50μM。
实施例38
细胞存活实验测定化合物对MCF-7细胞系增殖抑制作用。
本实施例选择MCF-7细胞株,选择多个重点化合物处理细胞,进行细胞增殖抑制的检测。细胞均以3×104mL-1的密度培养于96孔透明板中,用化合物或相同体积的DMSO处理细胞,处理3天后,利用CellTiter-Glo试剂,用Envision多孔微型板检测仪测定各个孔的荧光强度,指示细胞活力。半增殖抑制浓度GI50值经GraphPad Prism 5.0软件拟合求得。结果见表2所示。
表2本发明部分化合物对MCF-7的增殖抑制活性GI50
Compound | GI50(μM) |
L01 | 23.11 |
L02 | 7.15 |
L03 | 16.20 |
L05 | 22.12 |
L06 | 9.16 |
L09 | 5.91 |
L11 | 10.46 |
L12 | 28.47 |
L14 | 31.54 |
L15 | 5.45 |
L16 | 25.55 |
L31 | 23.47 |
L33 | 15.19 |
L38 | 30.20 |
由上表可知,本发明的化合物在MCF-7细胞上表现出了较好的增殖抑制效果。
Claims (7)
1.通式(Ⅰ)的化合物或其药学上可接受的盐,
式(Ⅰ)中,
X为C或N,当X为C时,Z为H,A片段为取代苯环,取代基选自氢原子、甲基、甲氧基、三氟甲基、卤素、氰基、氨基、羟基、羧基、酰胺、磺酰胺、硝基中的一个或多个;当X为N时,A片段不存在,Z为苯环;
Y选自 其中n、i各自独立选自0、1或2,m选自1、2或3,n1、n2、m1、m2各自独立选自1、2或3;
R2选自氢原子、甲基、甲氧基、三氟甲基、氰基、硝基、氨基、羟基、卤素的一个或多个;
Ar为取代或未取代的吡啶环、噻吩环、苯环、联苯或萘环,取代基选自氢原子、甲基、羟基、羧基、氨基、酯基、卤素、氰基中的一个或多个。
2.根据权利要求1所述通式(Ⅰ)的化合物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐是指通式(Ⅰ)的化合物与药学上可接受的酸形成的酸加成盐或与药学上可接受的碱形成碱加成盐,所述酸选自氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸;所述碱加成盐选自钠盐、钾盐、铵盐、钙盐、铝盐、镁盐、乙二胺盐或乙醇胺盐。
3.根据权利要求1所述通式(Ⅰ)的化合物或其药学上可接受的盐,其特征在于,所述化合物选自以下化合物式中的一个:
4.一种药物组合物,包括药物有效量的活性组分和药学上可接受的辅料,其特征在于,所述活性组分包括权利要求1所述的通式(Ⅰ)的化合物或其药学上可接受的盐中的一种或多种。
5.权利要求1所述通式(Ⅰ)的化合物或其药学上可接受的盐在制备USP8抑制剂中的应用。
6.权利要求1所述通式(Ⅰ)的化合物或其药学上可接受的盐在制备USP8介导的相关疾病的治疗药物中的应用。
7.根据权利要求6所述的应用,其特征在于,所述USP8介导的相关疾病包括癌症、神经变性疾病、血液系统疾病、内分泌系统疾病。
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