CN112979613B - 2-(1h-吡唑-3-基)吡啶衍生物及其制备方法和用途 - Google Patents
2-(1h-吡唑-3-基)吡啶衍生物及其制备方法和用途 Download PDFInfo
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域，具体涉及一种如式I所示化合物，或其立体异构体、或其盐、或其前药、或其溶剂化物，本发明还涉及其制备方法及其用于制备治疗由组蛋白去甲基化酶JMJD6介导的相关疾病的药物中的用途。
Description
技术领域
本发明属于药物化学领域，具体涉及2-(1H-吡唑-3-基)吡啶衍生物及其制备方法和用途。
背景技术
表观遗传学是一门研究基因核苷酸序列不发生改变的情况下，基因表达可遗传变化的学科。与传统遗传学一样，表观遗传学通过调节生物体内基因转录的过程，进而影响人类生命生长发育有关的基础生理学功能。常见的表观遗传修饰机制主要包括：DNA修饰、组蛋白修饰、RNA修饰、染色质重塑和非编码RNA等。其中组蛋白修饰是目前研究最为广泛的表观遗传修饰机制，根据组蛋白修饰调控因子的不同，可将这些调控因子分为三个大类：写入因子(Writer)、擦除因子(Eraser)、识别因子(Reader)。组蛋白去甲基化酶是一类重要的擦除因子，主要参与调控生物体内组蛋白甲基化平衡。按照作用机制的不同，组蛋白去甲基化酶可以分为两个家族：一类是黄素腺嘌呤二核苷酸(FAD)依赖的赖氨酸特异性去甲基化酶，包括LSD1和LSD2；另一类是含有jumonji结构域(JmjC)的组蛋白去甲基化酶。
JMJD6是一类含有JmjC结构域的组蛋白精氨酸去甲基化酶，它能够催化位于组蛋白H3上的精氨酸残基R2和组蛋白H4上的精氨酸残基R3上的甲基发生去甲基化修饰。近年来的研究表明，JMJD6的错误调控与乳腺癌、非小细胞肺癌(NCSLC)、黑色素瘤、口腔癌、神经胶质瘤、卵巢癌、胰腺癌结肠癌、肝癌等多种人类恶性肿瘤的发生、发展、转移、耐药有着密切关系。例如，JMJD6能够调节神经胶质瘤细胞内部转录暂停—释放过程，从而影响细胞的生存；抑制JMJD6的活性能够有效抑制神经胶质瘤细胞的增殖、转移和侵袭。组蛋白去甲基化酶JMJD6抑制剂可以用于治疗乳腺癌、非小细胞肺癌、黑色素瘤、口腔癌、神经胶质瘤、卵巢癌、胰腺癌、结肠癌、肝癌。
CN108218854A(公开日2018.06.29)公开了苯丙吡喃-2-酮类化合物作为JMJD6抑制剂及用途，其结构如下：
其中，R1为-H、-OCH3、-CH3等，R2为
目前，还没有JMJD6抑制剂药物上市，开发更多的结构新颖的JMJD6抑制剂，以进一步用于制备抗癌药物中的用途，具有广阔的临床前景和意义。
发明内容
本发明的目的在于提供一种结构新颖的2-(1H-吡唑-3-基)吡啶衍生物及其制备方法及其用于制备治疗由组蛋白去甲基化酶JMJD6介导的相关疾病的药物中的用途。
本发明提供一种式Ⅰ所示的化合物，或其立体异构体、或其盐、或其前药、或其溶剂化物，其中：
R1选自-H、卤素、-OH、-NH2、-NO2、-CN、-SO2、取代或未取代的C1-6烷基、取代或未取代的C1-6烷氧基，所述取代基为卤素、-OH、-NH2、-NO2；
R2选自-H、-OR5、-NHR5；
R3选自-H、取代或未取代的C1-6烷基，所述取代基为卤素、-OH、-NH2、-NO2、-CN；
R4选自-H、卤素、-OH、-NH2、-NO2、-CN、-SO2、取代或未取代的C1-6烷基、取代或未取代的芳基、取代或未取代的杂芳基，所述取代基为C1-6烷基、5～7元杂环烷基、C1-6烷氧基；
R5选自-H、取代或未取代的C1-6烷基、3～6元环烷基，所述取代基选自C1-6烷基，C1-6烷氧基，3～6元环烷基、芳基、卤素；
A为CH或N。
进一步地，所述的化合物或其立体异构体、或其盐、或其前药、或其溶剂化物，如式Ⅱ所示，其中：
R1选自-H、卤素、取代或未取代的C1-6烷基，所述取代基为卤素；
R2选自-OR5或-NHR5；
R3选自-H、C1-6烷基；
R4选自-H、取代或未取代的苯环、取代或未取代的吡啶环、取代或未取代的菲环、取代或未取代的苯并呋喃环，所述取代基为C1-6烷基、6元杂环烷基、C1-6烷氧基；
R5选自-H、取代或未取代的C1-6烷基、3～6元环烷基，所述取代基选自3～6元环烷基、芳基、卤素；
A为CH或N。
进一步地，所述的化合物或其立体异构体、或其盐、或其前药、或其溶剂化物，如式Ⅲ所示：
R1选自-H、卤素；
R3选自-H、C1-6烷基；
R4选自-H、取代或未取代的苯环、取代或未取代的吡啶环，所述苯环取代基为C1-6烷基、吗啉基，所述吡啶环取代基为C1-6烷氧基；
R5选自-H、取代或未取代的C1-6烷基、3～6元环烷基，所述取代基选自3～6元环烷基、苯基、卤素。
进一步地，所述的化合物或其立体异构体、或其盐、或其前药、或其溶剂化物，其中：
R1选自-H、-F；
R3选自-H、C1-3烷基；
R4选自-H、取代或未取代的苯环、取代或未取代的吡啶环，所述苯环取代基为甲基、吗啉基，所述吡啶环取代基为甲氧基；
R5选自-H、取代或未取代的C1-6烷基、3～6元环烷基，所述取代基选自3～6元环烷基、苯基、-F。
进一步地，所述化合物或其立体异构体、或其盐、或其前药、或其溶剂化物，其特征在于，其中化合物结构如下：
进一步地，所述的化合物或其立体异构体、或其盐、或其前药、或其溶剂合物，其中盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、醋酸盐、三氟乙酸盐、硫氰酸盐、马来酸盐、羟基马来酸盐、戊二酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、肉桂酸盐、乳酸盐、丙二酸盐、特戊酸盐、琥珀酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、没食子酸盐、葡萄糖酸盐、月桂酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、柠檬酸盐。
进一步地，所述的化合物或其立体异构体、或其盐、或其前药、或其溶剂化物，其特征在于，其合成路线如下：
a、原料1与醇发生酯化反应得中间体1；
b、中间体1与1-(2-四氢吡喃基)-1H-吡唑-5-硼酸频哪酯通过Suzuki-Miyaura偶联反应制备得到中间体2；
c、中间体2脱除保护基得中间体3；
d、中间体3与卤代烃发生亲核反应得化合物A；
e、化合物A溴代制备得中间体4；
f、中间体4与硼酸或硼酸频哪酯通过Suzuki-Miyaura偶联反应制备得到化合物B；
g、中间体3水解制备化合物C；
h、化合物A氨解制备化合物D；
其中，R1、R3、R4、R5、A的定义如前所述。
本发明提供所述化合物或其立体异构体、或其盐、或其前药、或其溶剂合物在制备治疗由组蛋白去甲基化酶JMJD6介导的相关疾病的药物中的用途。
进一步地，所述药物是组蛋白去甲基化酶JMJD6抑制剂；优选地，所述药物是治疗乳腺癌、非小细胞肺癌、黑色素瘤、口腔癌、神经胶质瘤、卵巢癌、胰腺癌、结肠癌、肝癌的药物。
本发明提供一种药物，它是如前所述的化合物或其立体异构体、或其盐、或其前药、或其溶剂合物为活性成分，加上药学上可接受的载体制备而成的制剂。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“取代的”是指基团中一个或多个氢原子被一个或多个非氢原子或基团代替，条件是满足化合价需要，且取代后化合物稳定。
术语“烷基”是指饱和碳链，其可以是直链或支链或它们的组合，除非该碳链被另外定义。具有前缀“烷”的其它基团，诸如烷氧基和烷酰基，还可以是直链或支链或它们的组合，除非另外定义碳链。烷基的例子包括(但不限于)甲基、乙基、丙基、异丙基、丁基、仲和叔丁基、戊基、己基、庚基、辛基、壬基。
术语“烷氧基”是指烷基-O-，所述烷基与前述定义相同。
术语C1-6表示1～6个碳原子，C1-3表示1～3个碳原子。
术语“环烷基”是指饱和的单环或二环烃环，单环环烷基的例子包括(但不限于)环丙基、环丁基、环戊基、环己基。所述二环环烷基可为稠合的，包括(但不限于)二环[1.1.0]丁烷、二环[2.1.0]戊烷、二环[2.2.0]己烷、二环[3.1.0]己烷、二环[3.2.0]庚烷及二环[3.3.0]辛烷，还包括桥接二环烷基系统，包括(但不限于)二环[2.2.1]庚烷及二环[1.1.1]戊烷。
术语“3～6元环烷基”是指由3至6个碳原子组成的环烷基。包括环丙基、环丁基、环戊基、环己基。
术语“杂环烷基”是指如上文所定义的环烷基，其中至少一个环碳原子被选自氮、氧或硫的杂原子替代。
术语“5～7元杂环烷基”是指总共5至7个环原子的饱和或部分饱和的环结构移除氢获得的杂环烷基取代基，其中至少一个环原子为选自氧、氮或硫的杂原子。杂环烷基可为具有至多共7元的单环。所述杂环烷基环的实例包括(但不限于)二氢呋喃基、二氢噻吩基、四氢噻吩基、四氢呋喃基、四氢三嗪基、四氢吡唑基、四氢噁嗪基、四氢嘧啶基、咪唑烷基、吡咯烷基、哌啶基、哌嗪基、噁唑烷基、噻唑烷基、吡唑烷基、硫吗啉基、四氢吡喃基、四氢噻嗪基、四氢噻二嗪基、四氢-噁唑基、吗啉基、四氢二嗪基、噁嗪基、氧杂噻嗪基、奎宁环基、四氢喹啉基。
术语“芳基”是指含有5-14个碳原子的单环、二环或三环碳环芳族环或环系，其中所述环中的至少一个是芳族的。芳基的例子包括(但不限于)苯基、萘基和菲基。
术语“杂芳基”是指含有5-14个碳原子且含有至少一个选自N、S(包括SO和SO2)和O的环杂原子的单环、二环或三环或环系，其中所述含有杂原子的环中的至少一个是芳族的。在其中所述环中的一个或多个是饱和的且含有一个或多个N原子的杂芳基环系的情况下，所述N可以呈季胺的形式。杂芳基的例子包括(但不限于)吡咯基、异噁唑基、异噻唑基、吡唑基、吡啶基、噁唑基、噁二唑基、噻二唑基、噻唑基、咪唑基、三唑基、四唑基、呋喃基、三嗪基、噻吩基、嘧啶基、哒嗪基、吡嗪基、苯并异噁唑基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并吡唑基、苯并呋喃基、苯并噻吩基(包括S-氧化物和二氧化物)、苯并三唑基、呋喃并(2,3-b)吡啶基、喹啉基、吲哚基、异喹啉基、喹唑啉基、二苯并呋喃基等。
术语“卤素”包括氟、氯、溴和碘。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
本发明所用的术语“药学上可接受的”是指在在合理的医学判断范围，能适于用来与人类和其他哺乳动物的组织接触，而没有不当毒性、刺激、过敏反应等。
本发明提供了一类新型的2-(1H-吡唑-3-基)吡啶衍生物，并提供了本发明2-(1H-吡唑-3-基)吡啶衍生物的简便、高效、成本低廉的制备方法。本发明的2-(1H-吡唑-3-基)吡啶衍生物对组蛋白去甲基化酶JMJD6具有良好的抑制活性，为本领域中的组蛋白去甲基化酶抑制剂的制备、组蛋白去甲基化酶小分子探针的制备提供了新的有效选择，具有很好的应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
实施例1 2-溴-4-甲酸乙酯吡啶(中间体1a)的制备
在50mL圆底烧瓶中加入2-溴-4-吡啶羧酸(404mg，2mmol)，乙醇15mL和2～3滴浓H2SO4后加热回流反应过夜。待反应完毕，冷却至室温，减压蒸馏除去溶剂，残留物用DCM溶解，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩得无色油液307mg，产率67％。
1H NMR(400MHz,Chloroform-d)δ8.52(dd,J＝5.0,0.8Hz,1H),8.04(dd,J＝1.4,0.8Hz,1H),7.81(dd,J＝5.0,1.4Hz,1H),4.43(q,J＝7.2Hz,2H),1.42(t,J＝7.1Hz,3H).ESI-ms(m/z)：230.0[M+H]+。
按照中间体1a类似的制备条件，以相应的羧酸为原料，以相应的醇作为溶剂，可以制备得到中间体1b-r。结构如下：
表1中间体1b-r的结构
实施例2 2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)异烟酸乙酯(中间体2a)的制备
在50mL双颈烧瓶中加入2-溴-4-甲酸乙酯吡啶(1a,230mg，1mmol)，1-(2-四氢吡喃基)-1H-吡唑-5-硼酸频哪酯(278mg，1mmol)，K3PO4(424mg，2mmol)和PdCl2dppf·DCM(82mg，0.1mmol)后加入1，4-二氧六环/水(4：1)混合溶剂15mL，将反应体系抽真空，用氩气置换三次后，加热至85℃在氩气气氛下回流反应5h。反应完毕后，冷却至室温，用硅藻土抽滤，滤液减压蒸馏除去溶剂，残留物中加入50mL水，用乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩拌样，采用柱层析法纯化，洗脱液选用PE:EA＝3：1，得无色油液2a,262mg，产率87％。
1H NMR(400MHz,DMSO-d6)δ8.90(d,J＝4.2Hz,1H),8.15(s,1H),7.85(s,1H),7.62(s,1H),6.89(s,1H),6.05(d,J＝8.8Hz,1H),4.40(d,J＝6.8Hz,2H),3.89(d,J＝10.2Hz,1H),3.55(s,1H),2.39(d,J＝11.8Hz,1H),2.05–1.82(m,2H),1.59(d,J＝47.3Hz,3H),1.36(t,J＝6.7Hz,3H).ESI-ms(m/z)：302.1[M+H]+。
按照中间体2a类似的制备条件，以相应的羧酸酯和1-(2-四氢吡喃基)-1H-吡唑-5-硼酸频哪酯为原料，以K3PO4或K2CO3或Cs2CO3作碱，以1，4-二氧六环/水(4：1)作为溶剂，80～100℃加热回流反应，可以制备得到中间体2b-r。中间体结构如下：
表2中间体2b-r的结构
实施例3 2-(1H-吡唑-3-基)异烟酸乙酯(中间体3a)的制备
在50mL圆底烧瓶中加入2-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-5-基)异烟酸乙酯(2a,301mg，1mmol)，3mL二氯甲烷和3mL无水乙醇，搅拌下滴加4M HCl的1，4-二氧六环溶液1mL，加毕置于常温反应过夜，待反应完毕，减压蒸馏除去溶剂，残留物中加入DCM30mL，用饱和碳酸钠水溶液洗涤，有机相用无水硫酸钠干燥，过滤，滤液浓缩得白色固体3a,109mg，产率50％。
1H NMR(400MHz,DMSO-d6)δ13.18(s,1H),8.78(d,J＝4.6Hz,1H),8.41(s,1H),7.87(s,1H),7.73(d,J＝4.1Hz,1H),6.89(s,1H),4.40(q,J＝7.1Hz,2H),1.37(t,J＝7.1Hz,3H).ESI-ms(m/z):218.1[M+H]+。
按照中间体3a类似的制备条件，可以制备得到中间体3b-r。中间体结构如下：
表3中间体3b-r的结构
实施例4 2-(1-甲基-1H-吡唑-3-基)异烟酸乙酯(化合物4a)的制备
在50mL圆底烧瓶中加入2-(1H-吡唑-3-基)异烟酸乙酯(3a,217mg，1mmol)，用5mLDMF溶解，再加入碳酸铯(652mg，2mmol)，常温搅拌下加入CH3I(93μL，1.5mmol)，加毕继续常温反应5h，采用薄层色谱(TLC)监测反应完毕后，过滤，滤液减压蒸馏除去溶剂后用乙酸乙酯溶解拌样，采用柱层析纯化，洗脱液选用PE:EA＝2:1，得白色固体4a,173mg，产率75％。
1H NMR(400MHz,DMSO-d6)δ8.77(d,J＝5.0Hz,1H),8.33(s,1H),7.81(d,J＝1.9Hz,1H),7.72(d,J＝5.0Hz,1H),6.85(d,J＝2.0Hz,1H),4.39(q,J＝7.1Hz,2H),3.95(s,3H),1.36(t,J＝7.1Hz,3H).ESI-ms(m/z):232.1[M+H]+。
按照化合物4a类似的制备条件，以碘甲烷，2-碘代丙烷或碘乙烷为亲核取代试剂，K2CO3或Cs2CO3为碱，THF或DMF为溶剂，25～60℃反应5～12h，可以制备得到化合物4b-u。表征数据如下：
表4化合物4b-u的结构、1H NMR和ESI-ms
实施例5化合物5a-b的制备
注：3a：R3＝H，4a:R3＝CH3；5a：R3＝CH3，5b:R3＝H
在50mL圆底烧瓶中加入2-(1-甲基-1H-吡唑-3-基)异烟酸乙酯(4a,45mg，0.19mmol)，用甲醇5mL溶解，加入NaOH(10mg in 1mL H2O，0.25mmol)后置于常温反应过夜，待反应完毕，减压蒸馏除去溶剂，残余物加水溶解，用柠檬酸水溶液调pH至3～4，析出白色固体，过滤，滤饼用水洗涤滤干后转移至烧瓶中，加EtOH，减压蒸馏除去溶剂，得白色固体即化合物5a，18mg，产率46％。
1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),8.73(d,J＝4.9Hz,1H),8.33(s,1H),7.80(d,J＝1.8Hz,1H),7.69(d,J＝3.8Hz,1H),6.84(d,J＝1.9Hz,1H),3.94(s,3H).ESI-ms(m/z):204.1[M+H]+。
按照化合物5a类似的制备条件，以3a为原料，可以制备得到化合物5b。表征数据如下：
表5化合物5b的结构、1H NMR和ESI-ms
实施例6N-乙基-2-(1-甲基-1H-吡唑-3-基)-4-吡啶甲酰胺(化合物6a)的制备
将2-(1-甲基-1H-吡唑-3-基)异烟酸乙酯(4a,53mg，0.23mmol)加入到15mL封管中，用3mL EtOH溶解，加入2mL乙胺后置于80℃反应2h，待反应完毕，减压蒸馏除去溶剂，残留物用DCM/H2O萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩的灰色固体6a,40mg，产率75％。
1H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.67(d,J＝5.0Hz,1H),8.27(s,1H),7.80(d,J＝2.1Hz,1H),7.63(dd,J＝5.1,1.5Hz,1H),6.83(d,J＝2.2Hz,1H),3.94(s,3H),3.32(d,J＝8.0Hz,2H),1.15(t,J＝7.2Hz,3H).ESI-ms(m/z):231.1[M+H]+。
按照化合物6a类似的制备条件，可以制备得到化合物6b。表征数据如下：
表6化合物6b的结构、1H NMR和ESI-ms
实施例7 2-(1-甲基-4-苯基-1H-吡唑-3-基)异烟酸乙酯(化合物7a)的制备
第一步：2-(4-溴-1-甲基-1H-吡唑-3-基)异烟酸乙酯的制备
在50mL圆底烧瓶中加入2-(1-甲基-1H-吡唑-3-基)异烟酸乙酯(4a,230mg，1mmol)，用DMF溶解后加入N-溴代丁二酰亚胺(NBS，267mg，1.5mmol)，置于50℃反应1h，TLC检测反应完毕，加入Na2S2O3水溶液搅至棕色褪去，用EA萃取，有机相用brine洗涤，无水硫酸钠干燥，过滤，滤液拌样，采用柱层析法纯化，洗脱液选用PE:EA＝1：1，得白色固体280mg，产率90％。
1H NMR(400MHz,DMSO-d6)δ8.84(d,J＝5.0Hz,1H),8.30(s,1H),8.09(s,1H),7.78(dd,J＝5.0,1.6Hz,1H),4.39(q,J＝7.1Hz,2H),3.94(s,3H),1.36(t,J＝7.1Hz,3H).ESI-ms(m/z):310.0[M+H]+
第二步：2-(1-甲基-4-苯基-1H-吡唑-3-基)异烟酸乙酯(化合物7a)的制备
在50mL双颈烧瓶中加入2-(4-溴-1-甲基-1H-吡唑-3-基)异烟酸乙酯(140mg，0.45mmol)，苯硼酸(60mg，0.49mmol)，K2CO3(125mg，0.9mmol)和PdCl2dppf·DCM(37mg，0.045mmol)后加入1，4-二氧六环/水(4：1)混合溶剂15mL，将反应体系抽真空，用氩气置换三次后，加热至85℃在氩气气氛下回流反应过夜。反应完毕后，冷却至室温，用硅藻土抽滤，滤液减压蒸馏除去溶剂，残留物中加入50mL水，用乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩拌样，采用柱层析法纯化，洗脱液选用PE:EA＝1：1，得类白色固体7a,20mg，产率15％。
1H NMR(400MHz,DMSO-d6)δ8.64(d,J＝5.1Hz,1H),8.15(s,1H),7.99(s,1H),7.72(dd,J＝5.2,1.7Hz,1H),7.40–7.19(m,5H),4.37(q,J＝7.1Hz,2H),3.96(s,3H),1.34(t,J＝7.1Hz,3H).ESI-ms(m/z):308.1[M+H]+
按照化合物7a类似的制备条件，以相应的硼酸或硼酸酯和2-(4-溴-1-甲基-1H-吡唑-3-基)异烟酸乙酯为原料，以K2CO3或K3PO4作碱，以1，4-二氧六环/水(4：1)作为溶剂，80～100℃加热回流反应，可以制备得到化合物7b-g。表征数据如下：
表7化合物7b-g的结构、1H NMR和ESI-ms
实施例8化合物对组蛋白去甲基化酶的体外活性
实验目的：检测本发明化合物在体外对组蛋白去甲基化酶的抑制活性，使用Succinate-GloTM JmjC Demethylase/Hydroxylase Assay(Promega)试剂盒测试化合物对组蛋白去甲基化酶JMJD6的体外抑制活性。
实验原理：在组蛋白去甲基化过程中，辅因子α-酮戊二酸被还原为琥珀酸。若组蛋白去甲基化酶活性被抑制，α-酮戊二酸则不会被还原。因此，通过测定琥珀酸的浓度即可间接反映组蛋白去甲基化酶的活性。
实验方法：在384孔板中，加入2.5μL一定浓度的小分子溶液和2.5μL JMJD6蛋白溶液，JMJD6蛋白溶液浓度为2.2mg/mL，室温孵育10min后加入5μL靶蛋白底物(Luc7like2蛋白267-274位氨基酸多肽)溶液。将反应体系中的各组分混合均匀，室温反应8h。随后加入Succinate-GloTMJmjC Demethylase/Hydroxylase Assay试剂盒中的试剂I(由Succinate-GloTM缓冲液、乙酰乙酰辅酶A与Succinate-GloTM溶液按比例混合)。室温孵育1h后，加入试剂盒中的试剂II(由ATP检测缓冲液与ATP检测底物按比例混合)。在室温下孵育10min，使用多功能酶标仪检测吸光度。
抑制率(％)＝(对照组-药品处理组)/(对照组-空白对照)*100％
最后用Graphpad Prism软件拟合得出半数抑制浓度(IC50)。
通过以上实验方法，测试了本发明化合物对组蛋白去甲基化酶JMJD6的体外抑制活性。
表8给出了本发明部分化合物对组蛋白去甲基化酶JMJD6的体外抑制活性。
表8受试化合物对组蛋白去甲基化酶JMJD6的抑制活性
本发明化合物表现出组蛋白去甲基化酶JMJD6的抑制活性。其中化合物3b、4a、4b、4c、4d、4f、4g、4h、4i、4j、4k、4l、4t、4u、5a、5b的活性优良，可以作为组蛋白去甲基化酶JMJD6抑制剂，可进一步制备抗癌药物。
综上所述，本发明提供了一类结构新颖的2-(1H-吡唑-3-基)吡啶衍生物，并提供了本发明2-(1H-吡唑-3-基)吡啶衍生物的简便、高效、成本低廉的制备方法。本发明的2-(1H-吡唑-3-基)吡啶衍生物对组蛋白去甲基化酶JMJD6具有良好的抑制活性，为本领域中的组蛋白去甲基化酶抑制剂的制备、组蛋白去甲基化酶小分子探针的制备提供了新的有效选择，为进一步制备抗癌药物提供了基础，具有很好的应用前景。
Claims (7)
1.式Ⅰ所示的化合物，或其立体异构体、或其盐，其特征在于，其中：
式I
R1选自-H、-F；
R3选自-H、C1-3烷基；
R4选自-H、取代或未取代的苯环、取代或未取代的吡啶环，所述苯环取代基为甲基、吗啉基，所述吡啶环取代基为甲氧基；
R5选自3~6元环烷基、取代或未取代的C1-6烷基，所述取代基选自3~6元环烷基、苯基、-F；
且式I化合物不为：
2.根据权利要求1所述化合物或其立体异构体、或其盐，其特征在于，所述化合物结构如下：
3.根据权利要求1或2所述的化合物或其立体异构体、或其盐，其特征在于：其中盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、醋酸盐、三氟乙酸盐、硫氰酸盐、马来酸盐、羟基马来酸盐、戊二酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、肉桂酸盐、乳酸盐、丙二酸盐、特戊酸盐、琥珀酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、没食子酸盐、葡萄糖酸盐、月桂酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、柠檬酸盐。
4.权利要求1或2所述化合物或其立体异构体、或其盐在制备治疗由组蛋白去甲基化酶JMJD6介导的相关疾病的药物中的用途。
5.根据权利要求4所述的用途，其特征在于：所述药物是组蛋白去甲基化酶JMJD6抑制剂。
6.如权利要求5所述的用途，其特征在于，所述药物是治疗乳腺癌、非小细胞肺癌、黑色素瘤、口腔癌、神经胶质瘤、卵巢癌、胰腺癌、结肠癌、肝癌的药物。
7.一种药物，其特征在于：它是以权利要求1或2所述的化合物或其立体异构体、或其盐为活性成分，加上药学上可接受的载体制备而成的制剂。
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