CN116332903A - 一种具有苯并[b]硒吩结构的二聚化合物及其用途 - Google Patents
一种具有苯并[b]硒吩结构的二聚化合物及其用途 Download PDFInfo
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- CN116332903A CN116332903A CN202310321063.6A CN202310321063A CN116332903A CN 116332903 A CN116332903 A CN 116332903A CN 202310321063 A CN202310321063 A CN 202310321063A CN 116332903 A CN116332903 A CN 116332903A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 154
- BNRDGHFESOHOBF-UHFFFAOYSA-N 1-benzoselenophene Chemical group C1=CC=C2[se]C=CC2=C1 BNRDGHFESOHOBF-UHFFFAOYSA-N 0.000 title description 5
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims description 135
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 150000002431 hydrogen Chemical class 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
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- 239000011737 fluorine Substances 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明公开了一种具有通式(I)所示结构的苯并[b]硒吩结构的二聚化合物或其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药,及其药物组合物。此类化合物对cGAS‑STING通路具有较好的激动活性,可为制备激活cGAS‑STING通路类药物提供依据。同时,本发明化合物对诱导THP1细胞分泌IFNβ具有较好活性,可以用于制备预防和/或治疗STING相关疾病药物,或与免疫检查点抑制剂联用用于制备抗肿瘤药物。
Description
技术领域
本发明属于化学医药技术领域,具体涉及一种具有苯并[b]硒吩结构的二聚化合物及其用途。
背景技术
环鸟苷酸-腺苷酸合酶(cyclic GMP-AMP synthase,cGAS)-干扰素基因刺激蛋白(stimulator of interferon genes,STING)通路是机体固有免疫系统的重要组成部分,在对抗外源性病原体(细菌、病毒等)入侵和消除内源性损伤(死细胞、肿瘤细胞等)方面发挥着重要的作用。胞质中的异常双链DNA(dsDNA)信号能被cGAS识别,由此引发随后一系列的生物级联反应。cGAS结合dsDNA后被激活,能催化GMP和AMP环合生成环鸟苷酸-腺苷酸(cyclic GMP-AMP,cGAMP)。cGAMP作为一种第二信使,与内质网膜蛋白STING识别并结合。随后STING发生构象转变,并进一步移位到高尔基体。在高尔基体上STING蛋白发生寡聚化并招募TBK1,TBK1进一步参与转录因子IRF3和NF-κB的磷酸化。磷酸化的转录因子随后进入细胞核引起下游Ⅰ型干扰素(interferon,IFN)的转录与表达。并由此来增强机体的固有免疫及相关的获得性免疫。
研究表明,激活cGAS-STING通路能促进Ⅰ型IFN和其他细胞因子(如IL6、TNFα、CXCL10等)的表达与分泌,这些因子又进一步促进抗原提呈细胞,如树突状细胞、巨噬细胞等的成熟。抗原提呈细胞对抗原进行交叉提呈,随后募集并激活CD8+T细胞,从而杀伤肿瘤细胞或清除病原体感染。因此,激活cGAS-STING通路能同时启动固有免疫和获得性免疫系统,被认为是治疗肿瘤和感染性疾病的有效手段。
STING作为该通路中的关键蛋白,近年来受到制药界越来越多的关注。到目前为止,国内外多家公司对STING激动剂进行了开发,其中Merck公司的MK-1454目前正处于临床2期试验,与抗PD-1单抗Keytruda联用用于治疗转移性或复发性头颈癌,并且尚有多款产品正在进行临床1期或1/2期试验。这些STING激动剂大多是模拟天然配体cGAMP的环二核苷酸衍生物。此外,一些非环二核苷酸类的STING激动剂也陆续得到公开,包括氨基苯并咪唑类化合物(WO2017175147)、咪唑联哒嗪类化合物(WO2019165032)、苯并噻吩类化合物(WO2019165032)和苯并硒吩类化合物(CN113429387A)等,它们通过激活STING蛋白,用于多种疾病,包括癌症的治疗。
因此,STING激动剂在疾病治疗,特别是在肿瘤免疫疗法的应用中具有重要意义,亟需开发新型的高效STING激动剂来拓宽市场需求。
发明内容
发明目的:本发明的目的在于提供一种如通式I的具有苯并[b]硒吩结构的二聚化合物及其用途。这些化合物对STING蛋白具有很强的亲和力,对cGAS-STING通路具有良好的激动能力,且在抗肿瘤活性上有着优异的效果。
本发明提供了一种如通式I的化合物、其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药:
其中,
L1和L3相同或不同,且各自独立地选自C(R5)2、NR5、O或S;
L2选自C1~C6亚烷基、R6取代的C1~C6亚烷基、C1~C6亚烷基-L4-C1~C6亚烷基、C2~C6亚烯基、C2~C6卤代亚烯基、C2~C6亚炔基、C2~C6卤代亚炔基、C3~C6环烷基或3~6元杂环基;
L4选自O、S、C(O)、C(O)NR5、S(O)、S(O)2、S(O)2NR5、C3~C6环烷基或3~6元杂环基;
X1和X4选自C(O);
X2和X5选自(C(R7)2)p;
X3和X6相同或不同,且各自独立地选自COOR5、C(O)N(R5)2、C(O)NR5OR5、C(O)ON(R5)2、SO2R5、S(O)NR5或C(CF3)2OR5;
A1选自Se、S、O或NH;
R1和R2相同或不同,且各自独立地选自氢、卤素、氰基、硝基、OR5、SR5、N(R5)2、COOR5、C(O)N(R5)2、C1~C6烷基、C1~C6卤代烷基、OR5取代的C1~C6烷基、N(R5)2取代的C1~C6烷基、C2~C6烯基、C2~C6卤代烯基、C2~C6炔基、C2~C6卤代炔基、C3~C6环烷基或3~6元杂环基;
R3和R4相同或不同,且各自独立地选自氢、卤素、氰基、OR5、N(R5)2、C1~C6烷基、C1~C6卤代烷基或C3~C6环烷基;
R5选自氢、C1~C6烷基、C1~C6卤代烷基、C3~C6环烷基、3~6元杂环基或C5~C10芳基;
R6选自氢、卤素、OR5、N(R5)2、C1~C6烷基、C1~C6卤代烷基、C3~C6环烷基或3~6元杂环基;
R7选自氢、卤素、氰基、OR5、N(R5)2、C1~C6烷基、C1~C6卤代烷基、OR5取代的C1~C6烷基或C3~C6环烷基;
任选地,不同碳原子上的2个R7可以与它们之间的碳原子一起形成C3~C6环烷基或3~6元杂环基;
任选地,相同碳原子上的2个R7可以与它们共同连接的碳原子一起形成C3~C6环烷基或3~6元杂环基;
m和n各自独立地选自0、1、2和3;
p选自1、2和3。
本发明的通式I化合物或其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药,优选具有式(I-a)、式(I-b)、式(I-c)或式(I-d)结构的化合物:
其中,L1、L2、L3、X1、X2、X3、X4、X5、X6、A1、R1、R2、R3、R4如通式I中的定义。
在某些优选地实施方式中,
L1和L3相同或不同,且各自独立地选自CH2、NH或O;
L2选自C1~C6亚烷基、R6取代的C1~C6亚烷基、C1~C4亚烷基-L4-C1~C4亚烷基、C2~C4亚烯基、C2~C4卤代亚烯基、C2~C4亚炔基、C2~C4卤代亚炔基、C3~C6环烷基或3~6元杂环基;
L4选自O、S、C(O)、C3~C6环烷基或3~6元杂环基;
X1和X4选自C(O);
X2和X5选自(C(R7)2)p;
X3和X6相同或不同,且各自独立地选自COOR5、C(O)N(R5)2、C(O)NR5OR5或C(O)ON(R5)2;
A1选自Se或S;
R1和R2相同或不同,且各自独立地选自氢、卤素、C1~C3烷基、C1~C3卤代烷基、-O-C1~C3烷基、-O-C1~C3卤代烷基或OH;
R3和R4相同或不同,且各自独立地选自氢、氟、C1~C3烷基;
R5选自氢、C1~C3烷基、C1~C3卤代烷基、C3~C6环烷基、3~6元杂环基或C5~C10芳基;
R6选自氢、氟、OH、NH2、C1~C4烷基、C1~C4卤代烷基、C3~C6环烷基或3~6元杂环基;
R7选自氢、氟、-O-C1~C3烷基、C1~C4烷基、C1~C4卤代烷基、-O-C1~C3烷基取代的C1~C4烷基或C3~C6环烷基;
任选地,不同碳原子上的2个R7可以与它们之间的碳原子一起形成C3~C6环烷基或3~6元杂环基;
任选地,相同碳原子上的2个R7可以与它们共同连接的碳原子一起形成C3~C6环烷基或3~6元杂环基;
p选自1、2和3。
在某些进一步优选地实施方式中,
L2选自C2~C5亚烷基、R6取代的C2~C5亚烷基或C1~C4亚烷基-L4-C1~C4亚烷基;
L4选自O或C(O);
X3和X6相同或不同,且各自独立地选自COOH、COOCH3、COOCH2CH3、C(O)NH2、C(O)NHOH、C(O)NHOCH3或C(O)ONHCH(CH3)2;
R1和R2相同或不同,且各自独立地选自氢、氟、氯、CH3、CH2CH3、OCH3、OCH2CH3、OCH(CH3)2或OCHF2;
R3和R4选自氢;
R6选自氢、氟、CH3、CH2CH3、OH或环丙基;
R7选自氢、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2OCH3或环丙基;
p=2。
在某些进一步优选地实施方式中,
X2和X5选自CHR7CHR7;
X3和X6选自COOH。
在某些进一步优选地实施方式中,
X2和X5选自CH2C(R7)2;
X3和X6选自COOH。
本发明通式I的化合物优选以下化合物:
术语“药学上可接受的盐”是指本发明通式I的化合物与药学上可接受的无毒碱包括有机碱或无机碱所制备出的盐。得自药学上可接受的有机碱的盐,包括伯胺、仲胺和叔胺的盐,取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂,例如甜菜碱、咖啡因、胆碱、N-乙基哌啶、N,N'-二苄基乙二胺、二乙胺、2-二甲基氨基乙醇、精氨酸、乙醇胺、乙二胺、N-乙基吗啉、葡萄糖胺、甲基葡萄糖胺、2-二乙基氨基乙醇、氨基葡萄糖、组氨酸、氨基乙醇、羟钴胺、赖氨酸、吗啉、哌嗪、哌啶、呱咤、多胺树脂、三乙胺、三甲胺、三丙胺、异丙基胺、氨基丁三醇等。得自药学上可接受的无机碱的盐,包括铝盐、铵盐、钙盐、锂盐、镁盐、钾盐、钠盐、锌盐等。
术语“异构体”是指具有相同化学式而有不同的原子排列的化合物。
术语“代谢产物”是指本发明的化合物通过体内代谢产生的药学活性产物。这种产物可以从例如所给药的化合物的氧化、还原、水解、酰胺化、脱酰胺、酯化、脱酯、葡糖醛酸化、酶促裂解等产生。因此,本发明包括本发明的化合物的代谢物,包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
术语“前药”包括其本身可以是具有生物学活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成通式I的一类化合物,或通式I的一个化合物所组成的盐或溶液。所述的前药包括但不限于所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
当化合物具有通式(I-1)所示结构时,合成路线如下:
其中,R1、R2、R7、L2、m和n如上文所定义,R8选自CH3、CH2CH3或C(CH3)3,R9选自CH3或CH2CH3,Y选自Cl,Br或I。化合物18的制备方法与化合物15相同。
在一些更具体的实施例中,R1和R2选自氢、氟、氯、CH3、CH2CH3、OCH3、OCH2CH3、OCH(CH3)2或OCHF2;L2选自C2~C5亚烷基、R6取代的C2~C5亚烷基或C1~C4亚烷基-L4-C1~C4亚烷基;R6选自氢、氟、CH3、CH2CH3、OH或环丙基,L4选自O或C(O);R7选自氢、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2OCH3或环丙基。
通式(I-1)化合物一种具体的制备方法,包括以下步骤:
(1)化合物1与化合物2(溴化苄)经取代反应制得苄基保护的化合物3,反应试剂选自碳酸钾、碳酸钠、氢氧化钠或氢化钠,反应溶剂选自DMF或四氢呋喃;
(2)化合物3与化合物4(二甲基二硒醚)反应制得化合物5,反应试剂选自DTT、巯基乙醇、DBU或碳酸钾中的几种,反应溶剂选自DMF或四氢呋喃;
(3)化合物5与化合物6(2-溴乙酸乙酯)经取代反应得到化合物7,反应溶剂为DMF;
(4)化合物7经分子内缩合反应制得化合物8,反应试剂选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠或氢氧化锂,反应溶剂选自DMF或乙腈;
(5)化合物8经水解得到化合物9,反应试剂选自碳酸钾、氢氧化钠或强氧化锂,反应溶剂选自水、甲醇和四氢呋喃;
(6)化合物9与化合物10(丙二酸单酯钾盐)经缩合反应得到化合物11,反应试剂选自CDI和MgCl2,反应溶剂选自DMF或四氢呋喃;
(7)化合物11与化合物12(卤代酸酯)经取代反应制得化合物13,反应试剂选自碳酸钾、甲醇钠、乙醇钠或氢化钠,反应溶剂选自DMF或四氢呋喃;
(8)化合物13经水解得到化合物14,反应试剂选自碳酸钾、氢氧化钠、氢氧化锂或盐酸,反应溶剂选自醋酸、水或四氢呋喃;
(9)化合物14通过酯保护得到化合物15,反应试剂选自二氯亚砜或草酰氯,反应溶剂选自甲醇、乙醇或二氯甲烷;
(10)化合物15与化合物16(二卤代烷)经取代反应制得化合物17,反应试剂选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化锂、碘化钾或冠醚,反应溶剂选自DMF或四氢呋喃;
(11)化合物17与化合物18二聚化后得到化合物19,反应试剂选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化锂、碘化钾或冠醚,反应溶剂选自DMF或四氢呋喃;
(12)化合物19经水解制得通式(I-1)化合物,反应试剂选自碳酸钾、氢氧化钠或氢氧化锂,反应溶剂选自水、甲醇和四氢呋喃。
当化合物具有通式(I-2)所示结构时,合成路线如下:
其中,R1、R2、L2、m和n如上文所定义,R9选自CH3或CH2CH3,Y选自Cl,Br或I,q选自1、2、3或4。化合物26的制备方法与化合物24相同。
在一些更具体的实施例中,R1和R2选自氢、氟、氯、CH3、CH2CH3、OCH3、OCH2CH3、OCH(CH3)2或OCHF2;L2选自C2~C5亚烷基、R6取代的C2~C5亚烷基或C1~C4亚烷基-L4-C1~C4亚烷基;R6选自氢、氟、CH3、CH2CH3、OH或环丙基;L4选自O或C(O)。
通式(I-2)化合物一种具体的制备方法,包括以下步骤:
(1)由化合物9经脱羧反应得到化合物20,反应试剂为铜粉,反应溶剂为喹啉;
(2)化合物20与化合物21(取代丁二酸酐)经傅-克酰化反应得化合物22,反应试剂选自三氯化铝、氯化锌或四氯化钛,反应溶剂选自二氯甲烷或和四氢呋喃;
(3)化合物22经过脱苄基保护得到化合物23,反应物为氢气,反应试剂选自钯/炭或氢氧化钯/碳,反应溶剂选自四氢呋喃或甲醇;
(4)化合物23经过酯保护得到化合物24,反应试剂选自二氯亚砜或草酰氯,反应溶剂选自甲醇、乙醇或二氯甲烷;
(5)化合物24与化合物16(二卤代烷)经取代反应得到化合物25,反应试剂选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化锂、碘化钾或冠醚,反应溶剂选自DMF或四氢呋喃;
(6)化合物25与化合物26经二聚化得到化合物27,反应试剂选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化锂、碘化钾或冠醚,反应溶剂选自DMF或四氢呋喃。
(7)化合物27经酯水解反应制得通式(I-2)化合物,反应试剂选自碳酸钾、氢氧化钠或氢氧化锂,反应溶剂选自水、甲醇和四氢呋喃。
当化合物具有通式(I-3)所示结构时,合成路线如下:
其中,R1、R2、R7和L2如上文所定义,R8选自CH3、CH2CH3或C(CH3)3,R9选自CH3或CH2CH3,Y选自Cl,Br或I。
在一些更具体的实施例中,R1和R2选自氢、氟、氯、CH3、CH2CH3、OCH3、OCH2CH3、OCH(CH3)2或OCHF2;L2选自C2~C5亚烷基、R6取代的C2~C5亚烷基或C1~C4亚烷基-L4-C1~C4亚烷基;R6选自氢、氟、CH3、CH2CH3、OH或环丙基;L4选自O或C(O)。
通式(I-3)化合物一种具体的制备方法,包括以下步骤:
(1)化合物3与化合物28(巯基乙酸甲酯)经一步的取代和环合反应制得化合
物29,反应试剂选自碳酸钾、碘化亚铜和二乙胺,反应溶剂是DMF;
(2)化合物29经酯水解得到化合物30,反应试剂选自碳酸钾、氢氧化钠或强氧化锂,反应溶剂选自水、甲醇和四氢呋喃;
(3)化合物30与化合物10(丙二酸单酯钾盐)经缩合反应得到化合物31,反应试剂选自CDI和MgCl2,反应溶剂选自DMF或四氢呋喃;
(4)化合物31与化合物12(卤代酸酯)经取代反应得到化合物32,反应试剂选自碳酸钾、甲醇钠、乙醇钠或氢化钠,反应溶剂选自DMF或四氢呋喃;
(5)化合物32经水解得到化合物33,反应试剂可以是碳酸钾、氢氧化钠、氢氧化锂或盐酸,反应溶剂选自醋酸、水或四氢呋喃;
(6)化合物33通过酯基保护得到化合物34,反应试剂选自二氯亚砜或草酰氯,反应溶剂选自甲醇、乙醇或二氯甲烷;
(7)化合物34与化合物16(二卤代烷)经取代反应得到化合物35,反应试剂选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化锂、碘化钾或冠醚,反应溶剂选自DMF或四氢呋喃;
(8)化合物35与化合物18缩合得到化合物36,反应试剂选自碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化锂、碘化钾或冠醚,反应溶剂选自DMF或四氢呋喃;
(9)化合物36水解制得通式(I-3)化合物,反应试剂选自碳酸钾、氢氧化钠或氢氧化锂,反应溶剂选自水、甲醇和四氢呋喃。
本发明还提供了一种药物组合物,其含有一种或多种治疗有效量的本发明所述的通式I化合物或其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药,以及药学上可接受的载体或赋形剂。
在某些优选实施方式中,所述药物组合物为片剂、胶囊、丸剂、散剂、颗粒剂、溶液、混悬液或注射液。给药方式为口服或注射等形式。
常用的药学上可接受的载体或赋形剂包括稳定剂、稀释剂、表面活性剂、润滑剂、抗氧化剂、粘合剂、着色剂、填充剂、乳化剂等。
无菌可注射组合物可按照本领域已知的技术使用适合的分散剂或润湿剂和助悬剂来配制。可以使用的药学上可接受的载体和溶剂包括水、甘露醇、氯化钠溶液等。
局部组合物可被配制成油、洗剂、乳膏剂等。用于组合物的载体包括植物油或矿物油、动物脂肪和高分子量醇等。药学上可接受的载体是活性成分在其中可溶的载体。
可以改变本发明的药物组合物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可以有效实现所需治疗响应、对患者无毒的活性成分的量。所选择的的剂量水平取决于多种因素,包括所用的具体的本发明的化合物或其盐的活性、施用途径、施用时间、所用的具体组合物的排泄速率、治疗的持续时间、与所用的具体组合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、一般健康状况和既往病史以及医学领域中公知的类似因素。
在某些优选实施方式中,所述药物组合物还包含一种或多种第二治疗剂,所述第二治疗剂可以用来预防和/或治疗癌症。
在某些进一步优选地实施方式中,所述第二治疗剂为传统细胞毒类抗肿瘤药物和其它抗肿瘤免疫药物。
本发明还提供了通式I的化合物或其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药,或药物组合物在制备用于疾病治疗药物、制备疫苗佐剂中的用途。所述药物或疫苗佐剂可以用来预防和/或治疗癌症或感染性疾病。
本发明还提供了通式I的化合物或其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药,或药物组合物在制备激活cGAS-STING通路类药物中的用途。所述药物为STING激动剂。
本发明还提供了通式I的化合物或其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药,或药物组合物在制备预防和/或治疗STING相关疾病药物中的用途。
本发明还提供了通式I的化合物或其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药,或药物组合物与免疫检查点抑制剂联用用于制备抗肿瘤药物的用途。所述的免疫检查点抑制剂为PD-1/PD-L1抑制剂、IDO1抑制剂和CTLA-4抑制剂。本发明通式I的化合物或其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药,或药物组合物和免疫检查点抑制剂可同时施用或分别施用。
本发明中,所述的肿瘤包括但不限于肺癌、肝癌、胃癌、乳腺癌、黑色素瘤、结直肠癌、胰腺癌、前列腺癌、鳞状细胞癌、神经胶质瘤和白血病。
有益效果:
本发明制备的通式I的化合物及其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药对cGAS-STING通路具有较好的激动活性,可为制备激活cGAS-STING通路类药物提供依据。同时,本发明化合物对诱导THP1细胞分泌IFNβ具有较好活性。因此,上述化合物可以用于制备预防和/或治疗STING相关疾病药物,+或与免疫检查点抑制剂联用用于制备抗肿瘤药物。
具体实施方式
下面通过具体实施例对本发明技术方案进行详细说明,但是本发明的保护范围不局限于所述实施例。本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。本发明可以采用本领域常用的成盐方法制备成盐的形式,例如:室温下,将化合物溶于盐酸乙醇中进行反应,生成盐酸盐;或者向其中加入苯磺酸进行反应生成苯磺酸盐。
中间体制备例1
步骤1:5-(苄基氧基)-2-溴-4-甲氧基苯甲醛(3a)的制备
将6.93g 2-溴-5-羟基-4-甲氧基苯甲醛(1a,30.0mmol)、8.28g碳酸钾(60.0mmol)和300mL DMF加入到1L反应瓶中,向其中加入6.12g溴化苄(36.0mmol),50℃加热搅拌2h。TLC(石油醚:乙酸乙酯=1:1,v/v)检测原料1a反应完全后,反应液倒入1.5L冰水中。抽滤收集滤饼,滤饼经水洗、干燥后得到产物粗品。向该粗品中加入200mL石油醚并在室温下打浆20min。抽滤,滤饼经石油醚洗涤、干燥后得到化合物3a 9.24g,白色固体,收率96%。1H NMR(300MHz,CDCl3):δ=10.16(s,1H),7.48(s,1H),7.46–7.30(m,5H),7.07(s,1H),5.16(s,2H),3.95(s,3H)ppm。HRMS(ESI+):计算值C15H14BrO3 +(M+H)+,321.0121;实测值321.0125。
步骤2:5-(苄基氧基)-4-甲氧基-2-(甲基硒基)苯甲醛(5a)的制备
将9.63g化合物3a(30.0mmol)、6.16g DTT(二硫苏糖醇,40.0mmol)和100mL DMF加入到500mL反应瓶中,向其中加入3.76g二甲基二硒醚(20.0mmol)和7.60g DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯,50.0mmol)。在氮气保护和室温条件下搅拌24h后,反应液倒入500mL水中,析出沉淀。抽滤,滤饼经水洗后得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=8:1,v/v)纯化后得到化合物5a 5.83g,淡黄色固体,收率87%。1H NMR(300MHz,CDCl3):δ=10.08(s,1H),7.46–7.30(m,6H),6.99(s,1H),5.18(s,2H),3.99(s,3H),2.31(s,3H)ppm。HRMS(ESI+):计算值C16H17O3Se+(M+H)+,337.0337;实测值337.0339。
步骤3:2-((4-(苄基氧基)-2-甲酰基-5-甲氧基苯基)硒基)乙酸乙酯(7a)的制备
将6.70g化合物5a(20.0mmol)和50mL DMF加入到250mL反应瓶中,加入10.02g 2-溴乙酸乙酯(60.0mmol),反应液在150℃下加热搅拌3.5h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,将反应液逐渐冷却到室温。加入250mL水稀释并用80mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩得化合物7a粗品为棕黄色固体。该粗品不经额外纯化直接用于下一步反应。
HRMS(ESI+):计算值C19H21O5Se+(M+H)+,409.0549;实测值409.0546。
步骤4:5-(苄基氧基)-6-甲氧基苯并[b]硒吩-2-甲酸乙酯(8a)的制备
将上一步得到的化合物7a和6.90g K2CO3(50.0mmol)加入到250mL反应瓶中,向其中加入70mL乙腈。反应液在回流状态下搅拌4h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,将反应液逐渐冷却至室温。反应液浓缩后加入300mL水稀释,用80mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=10:1,v/v)纯化得化合物8a 5.91g,淡黄色固体,两步收率76%。1H NMR(300MHz,DMSO-d6):δ=8.24(s,1H),7.74(s,1H),7.68(s,1H),7.50-7.32(m,5H),5.12(s,2H),4.33(q,J=6.9Hz,2H),3.86(s,3H),1.33(t,J=7.0Hz,3H)ppm。HRMS(ESI+):计算值C19H19O4Se+(M+H)+,391.0443;实测值391.0442。
步骤5:5-(苄基氧基)-6-甲氧基苯并[b]硒吩-2-甲酸(9a)的制备
将8.95g化合物8a(23.0mmol)、90mL甲醇和90mL四氢呋喃加入到500mL反应瓶中,加入35mL 2N的氢氧化钠水溶液。反应液在60℃下搅拌1h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,反应溶剂通过减压方式移除,所得残余物用1N HCl调节pH至2~3。抽滤,滤饼经水洗、干燥后得化合物9a 8.22g,米白色固体,收率99%。1H NMR(300MHz,DMSO-d6):δ=8.16(s,1H),7.73(s,1H),7.66(s,1H),7.50–7.32(m,5H),5.12(s,2H),3.85(s,3H)ppm。HRMS(ESI-):计算值C17H13O4Se-(M-H)-,360.9985;实测值360.9988。
步骤6:3-(5-(苄基氧基)-6-甲氧基苯并[b]硒吩-2-基)-3-氧代丙酸甲酯(11a)的制备
将9.03g化合物9a(25.0mmol)、12.15g CDI(N,N'-羰基二咪唑,75.0mmol)和180mLDMF加入到500mL反应瓶中。反应液在室温下搅拌1h,加入7.13g MgCl2(75.0mmol)和11.70g丙二酸单甲酯钾盐(75.0mmol)。室温反应5h,TLC检测(二氯甲烷:甲醇=10:1,v/v)原料反应完全后,将反应液倒入900mL水中。抽滤,滤饼经水洗后得粗品,粗品经硅胶柱层析(石油醚:乙酸乙酯=8:1,v/v)纯化得到化合物11a 8.76g,黄色固体,收率84%。1H NMR(300MHz,CDCl3):δ=8.02(s,1H),7.48–7.31(m,7H),5.21(s,2H),3.98(s,3H),3.97(s,2H),3.76(s,3H)ppm。HRMS(ESI+):计算值C20H19O5Se+(M+H)+,419.0392;实测值419.0390。
中间体制备例2
步骤1:2-(5-(苄基氧基)-6-甲氧基苯并[b]硒吩-2-羰基)丁二酸甲乙酯(13a)的制备
将2.09g化合物11a(5.00mmol)、1.38g K2CO3(10.0mmol)和20mL DMF加入到100mL反应瓶中,加入1.00g 2-溴乙酸乙酯(6.00mmol)。反应液在室温下搅拌4h,TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,反应液中加入100mL水,用40mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩和得化合物13a粗品。该粗品不经过额外纯化直接用于下一步反应。
HRMS(ESI+):计算值C24H25O7Se+(M+H)+,505.0760;实测值505.0759。
步骤2:4-(5-羟基-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸(14a)的制备
将上一步得到的化合物13a和10mL醋酸加入到100mL反应瓶中,缓慢加入10mL浓盐酸。所得反应液在90℃加热下搅拌2h,TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,将反应液自然冷却至室温,加入90mL水并用30mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品通过硅胶柱层析(二氯甲烷:甲醇=30:1,v/v)纯化得化合物14a 0.96g,淡黄色固体,两步收率59%。1H NMR(300MHz,DMSO-d6):δ=12.16(s,1H),9.36(s,1H),8.39(s,1H),7.63(s,1H),7.36(s,1H),3.86(s,3H),3.26(t,J=6.1Hz,2H),2.60(t,J=6.3Hz,2H)ppm。HRMS(ESI-):计算值C13H11O5Se-(M-H)-,326.9777;实测值326.9780。
步骤3:4-(5-羟基-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸乙酯(15a)的制备
将500mg化合物14a(1.53mmol)和15mL无水乙醇加入到100mL反应瓶中,置于冰浴中降温。在0℃下向反应液中缓慢滴入546mg SOCl2(4.59mmol),滴完后逐渐恢复至室温,回流状态下搅拌1h。TLC检测(二氯甲烷:甲醇=10:1,v/v)原料消耗完全后,将反应自然冷却至室温,反应液浓缩后,加水60mL并用15mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=4:1,v/v)纯化得化合物15a 516mg,米白色固体,收率95%。1H NMR(300MHz,CDCl3):δ=8.08(s,1H),7.39(s,1H),7.31(s,1H),4.20(q,J=7.1Hz,2H),3.99(s,3H),3.35(t,J=6.7Hz,2H),2.79(t,J=6.8Hz,2H),1.29(t,J=7.1Hz,3H)ppm。HRMS(ESI+):计算值C15H17O5Se+(M+H)+,357.0236;实测值357.0233。
如下表1所示,中间体15b至15o可以根据上文中间体15a的合成方法,使用与之对应的起始原料和反应物制备得到。
表1中间体15b-15o
中间体制备例3
步骤1:5-(苄基氧基)-6-甲氧基苯并[b]硒吩(20a)的制备
将3.61g化合物9a(10.0mmol)、3.20g铜粉(50.0mmol)和40mL喹啉加入到150mL反应瓶中,所得混合物在170℃条件下搅拌反应2小时。TLC检测(二氯甲烷:甲醇=4:1,v/v)原料反应完全后,待反应液自然冷却至室温,加入115mL 6N HCl,用40mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=4:1,v/v)纯化得化合物20a 2.57g,白色固体,收率81%。1H NMR(300MHz,CDCl3):δ=7.85(d,J=6.0Hz,1H),7.56-7.44(m,3H),7.41-7.27(m,5H),5.20(s,2H),3.97(s,3H)ppm。HRMS(ESI+):计算值C16H15O2Se+,(M+H)+,319.0232;实测值319.0236。
步骤2:2-(5-(苄基氧基)-6-甲氧基苯并[b]硒吩-2-羰基)环丙烷-1-甲酸(22a)的制备
向100mL干燥的反应瓶中加入0.71g 3-氧杂二环[3.1.0]己烷-2,4-二酮(21a,6.31mmol)、1.26g无水三氯化铝(9.46mmol)和30mL无水二氯甲烷,置于冰浴下搅拌1h。冰浴下加入1.00g化合物20a(3.15mmol),加完后,转移至室温继续搅拌12h。加入150mL饱和氯化铵溶液,用40mL二氯甲烷萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(二氯甲烷:甲醇=30:1,v/v)纯化得化合物22a0.27g,黄色固体,收率20%。1H NMR(300MHz,CDCl3):δ=7.98(s,1H),7.52–7.31(m,7H),5.22(s,2H),3.96(s,3H),3.22(q,J=8.2Hz,1H),2.46(q,J=8.1Hz,1H),2.20-2.09(m,1H),1.58-1.48(m,1H)ppm。HRMS(ESI-):计算值C21H17O5Se-,(M-H)-,429.0247;实测值429.0248。
步骤3:2-(5-羟基-6-甲氧基苯并[b]硒吩-2-羰基)环丙烷-1-甲酸(23a)的制备
将0.27g化合物22a(0.63mmol)、27mg Pd/C和20mL甲醇加入到100mL反应瓶中,用氢气置换反应瓶中的空气三次,室温条件下搅拌10h。TLC检测(二氯甲烷:甲醇=10:1,v/v)原料反应完全后,通过硅藻土抽滤,滤液浓缩、干燥后得化合物23a 205mg,淡黄色固体,收率96%。1H NMR(300MHz,DMSO-d6):δ=12.12(s,1H),9.28(s,1H),8.16(s,1H),7.57(s,1H),7.31(s,1H),3.86(s,3H),3.20(q,J=8.2Hz,1H),2.41(q,J=8.1Hz,1H),2.19-2.10(m,1H),1.61-1.50(m,1H)ppm。HRMS(ESI-):计算值C14H11O5Se-,(M-H)-,338.9777;实测值338.9773。
步骤4:2-(5-羟基-6-甲氧基苯并[b]硒吩-2-羰基)环丙烷-1-甲酸乙酯(24a)的制备
将205mg化合物23a(0.60mmol)和6mL无水乙醇加入到50mL反应瓶中,置于冰浴中降温。在0℃下向反应液中缓慢滴入216mg SOCl2(1.81mmol),滴完后逐渐恢复至室温,回流状态下搅拌1h。TLC检测(二氯甲烷:甲醇=10:1,v/v)原料消耗完全后,将反应自然冷却至室温,反应液浓缩后,加水40mL并用15mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=4:1,v/v)纯化得化合物24a 213mg,淡黄色固体,收率96%。1H NMR(300MHz,CDCl3):δ=8.10(s,1H),7.37(s,1H),7.32(s,1H),4.19(q,J=7.2Hz,2H),3.97(s,3H),3.24(q,J=8.1Hz,1H),2.33(q,J=8.0Hz,1H),2.16-2.05(m,1H),1.55-1.44(m,1H),1.30(t,J=7.0Hz,3H)ppm。HRMS(ESI-):计算值C16H17O5Se+,(M+H)+,369.0236;实测值369.0233。
如下表2所示,中间体24b和24c可以根据上文中间体24a的合成方法,使用与之对应的反应物制备得到。
表2中间体24b-24c
中间体制备例4
步骤1:5-(苄基氧基)-6-甲氧基苯并[b]噻吩-2-甲酸甲酯(29a)的制备
将6.42g化合物3a(20.0mmol)、8.28g K2CO3(60.0mmol)和70mL DMF加入到250mL反应瓶中,加入3.18g巯基乙酸甲酯(30.0mmol)、0.38g碘化亚铜(2mmol)和0.15g二乙胺(2mmol)。反应混合物在60℃加热条件下反应8h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全,待反应液冷却至室温后,倒入350mL水中。抽滤,滤饼经水洗、干燥后得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=8:1,v/v)纯化得化合物29a 5.58g,淡黄色固体,收率85%。1H NMR(300MHz,CDCl3):δ=7.86(s,1H),7.48-7.33(m,5H),7.27(s,2H),5.20(s,2H),3.98(s,3H),3.91(s,3H)ppm。HRMS(ESI+):计算值C18H17O4S+,(M+H)+,329.0842;实测值329.0845。
步骤2:5-(苄基氧基)-6-甲氧基苯并[b]噻吩-2-甲酸(30a)的制备
将5.58g化合物29a(17.0mmol)、70mL甲醇和70mL四氢呋喃加入到250mL反应瓶中,加入25mL 2N NaOH水溶液。反应液在60℃下搅拌1h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,减压蒸除反应溶剂,所得残留物用1N HCl调节pH至2~3。抽滤,滤饼经水洗、干燥后得化合物30a 5.28g,米白色固体,收率99%。
1H NMR(300MHz,DMSO-d6):δ=13.12(s,1H),7.88(s,1H),7.56(s,1H),7.54(s,1H),7.48-7.26(m,5H),5.10(s,2H),3.84(s,3H)ppm。HRMS(ESI-):计算值C17H13O4S-,(M-H)-,313.0540;实测值313.0541。
步骤3:3-(5-(苄基氧基)-6-甲氧基苯并[b]噻吩-2-基)-3-氧代丙酸甲酯(31a)的制备
将4.71g化合物30a(15.0mmol)、7.29g CDI(45.0mmol)和100mL DMF加入到500mL反应瓶中。所得反应液在室温下搅拌1h,加入4.28g MgCl2(45.0mmol)和7.02g丙二酸单甲酯钾盐(45.0mmol)。室温反应5h,TLC检测(二氯甲烷:甲醇=10:1,v/v)原料反应完全后,将反应液倒入500mL水中。抽滤,滤饼经水洗后得粗品,粗品经硅胶柱层析(石油醚:乙酸乙酯=8:1,v/v)纯化得到化合物31a 4.27g,黄色固体,收率77%。1H NMR(300MHz,CDCl3):δ=7.87(s,1H),7.50-7.34(m,5H),7.28(s,2H),5.19(s,2H),3.98(s,3H),3.95(s,2H),3.71(s,3H)ppm。HRMS(ESI+):计算值C20H19O5S+(M+H)+,371.0948;实测值371.0947。
步骤4:2-(5-(苄基氧基)-6-甲氧基苯并[b]噻吩-2-羰基)丁二酸甲乙酯(32a)的制备
将1.85g化合物31a(5.0mmol)、1.38g K2CO3(10.0mmol)和20mL DMF加入到100mL反应瓶中,加入1.00g 2-溴乙酸乙酯(6.0mmol)。反应液在室温下搅拌4h,TLC(石油醚:乙酸乙酯=4:1,v/v)检测原料反应完全后,反应液中加入100mL水,用40mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩和得化合物32a粗品。该粗品不经过额外纯化直接用于下一步反应。
HRMS(ESI+):计算值C24H25O7S+(M+H)+,457.1316;实测值457.1318。
步骤5:4-(5-羟基-6-甲氧基苯并[b]噻吩-2-基)4-氧代丁酸(33a)的制备
将上一步制备得到的化合物32a和10mL醋酸加入到100mL反应瓶中,缓慢加入10mL浓盐酸,所得反应液在90℃下搅拌反应2h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,将反应液逐渐冷却至室温,加入100mL水并用30mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品通过硅胶柱层析(二氯甲烷:甲醇=30:1,v/v)纯化得化合物33a 0.94g,淡黄色固体,两步收率67%。1H NMR(300MHz,DMSO-d6):δ=12.14(s,1H),9.33(s,1H),8.12(s,1H),7.48(s,1H),7.25(s,1H),3.83(s,3H),3.18(t,J=6.1Hz,2H),2.53(t,J=6.1Hz,2H)ppm。HRMS(ESI-):计算值C13H11O5S-(M-H)-,279.0333;实测值279.0335。
步骤6:4-(5-羟基-6-甲氧基苯并[b]噻吩-2-基)4-氧代丁酸乙酯(34a)的制备
将0.94g化合物33a(3.36mmol)和30mL无水乙醇加入到100mL反应瓶中,置于冰浴中降温。在0℃下缓慢滴入1.20g SOCl2(10.07mmol),滴完后将反应移至室温。待其恢复至室温后,在回流状态下继续搅拌2h。TLC检测(二氯甲烷:甲醇=10:1,v/v)原料反应完全后,反应液自然冷却至室温,减压蒸除溶剂,加入80mL水并用20mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品通过硅胶柱层析(石油醚:乙酸乙酯=4:1,v/v)纯化得化合物34a 0.95g,淡黄色固体,收率92%。1H NMR(300MHz,CDCl3):δ=7.92(s,1H),7.27(s,2H),4.17(q,J=7.3Hz,2H),3.97(s,3H),3.16(t,J=6.0Hz,2H),2.51(t,J=6.1Hz,2H),1.29(t,J=6.9Hz,3H)ppm。HRMS(ESI+):计算值C15H17O5S+(M+H)+,309.0791;实测值309.0791。
如下表3所示,中间体34b至34f可以根据上文中间体34a的合成方法,使用与之对应的起始原料和反应物制备得到。
表3中间体34b-34f
实施例1 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸二乙酯)(C48)的制备
步骤1:4-(5-(3-溴丙基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸乙酯(17a)的制备
将258mg化合物15a(0.73mmol)、201mg K2CO3(1.45mmol)和7mL DMF加入到100mL反应瓶中,加入1.47g 1,3-二溴丙烷(7.27mmol),反应液在45℃加热下搅拌2h。TLC检测(石油醚:乙酸乙酯=1:1,v/v)原料反应完全后,加入50mL水稀释,用12mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=4:1)纯化得化合物17a 263mg,淡黄色固体,收率76%。1H NMR(300MHz,CDCl3):δ=8.11(s,1H),7.34(s,1H),7.33(s,1H),4.23–4.13(m,4H),3.95(s,3H),3.69(t,J=6.3Hz,2H),3.35(t,J=6.8Hz,2H),2.80(t,J=6.7Hz,2H),2.46–2.38(m,2H),1.29(t,J=7.1Hz,3H)ppm。HRMS(ESI+):计算值C18H22BrO5Se+(M+H)+,476.9810;实测值476.9814。
步骤2:4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸二乙酯)(C48)的制备
将250mg化合物17a(0.53mmol)、186mg化合物15a(0.53mmol)、217mg K2CO3(1.58mmol)、9mg KI(0.05mmol)、14mg 18-冠醚-6(0.05mmol)和6mL DMF一起加入到50mL反应瓶中,所得反应液在50℃下搅拌8h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,加水50mL,用12mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=2:1,v/v)纯化得化合物C48 347mg,黄色固体,收率88%。
1H NMR(300MHz,DMSO-d6):δ=8.40(s,2H),7.72(s,2H),7.59(s,2H),4.23(t,J=5.6Hz,4H),4.09(q,J=7.1Hz,4H),3.85(s,6H),3.31(t,J=5.8Hz,4H),2.68(t,J=6.2Hz,4H),2.33–2.27(m,2H),1.20(t,J=7.1Hz,6H)ppm。
13C NMR(75MHz,DMSO-d6):δ=191.17,170.83,148.93,146.29,143.08,136.28,135.60,133.25,110.76,109.04,66.01,59.90,56.14,32.98,29.18,28.68,15.52ppm。
HRMS(ESI+):计算值C33H37O10Se2 +(M+H)+,753.0712;实测值753.0715。
实施例2 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C1)的制备
将150mg化合物19a(0.20mmol)、2mL甲醇和2mL四氢呋喃加入到50mL反应瓶中,加入0.6mL 2N氢氧化钠水溶液,反应液在55℃加热下搅拌1h。TLC检测(石油醚:乙酸乙酯=2:1,v/v)原料反应完全后,反应液浓缩,所得残余物用1N HCl调节pH至2~3,用15mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(二氯甲烷:甲醇=30:1,v/v)纯化得化合物C1 98mg,黄色固体,收率71%。1HNMR(300MHz,DMSO-d6):δ=12.19(s,2H),8.40(s,2H),7.71(s,2H),7.59(s,2H),4.23(t,J=5.9Hz,4H),3.85(s,6H),3.27(t,J=5.9Hz,4H),2.61(t,J=6.2Hz,4H),2.31–2.27(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.04,174.20,150.99,147.94,145.12,137.39,135.52,134.61,110.74,108.60,65.63,56.34,33.01,29.08,28.50ppm。HRMS(ESI-):计算值C29H27O10Se2 -(M-H)-,694.9940;实测值694.9943。
实施例3 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(2-甲基-4-氧代丁酸)(C2)的制备
参照实施例1和2所述的制备方法,将两分子中间体15b通过1,3-二溴丙烷连接制备得到化合物C2。
1H NMR(300MHz,DMSO-d6):δ=12.17(s,2H),8.39(s,2H),7.71(s,2H),7.57(s,2H),4.23(t,J=5.9Hz,4H),3.85(s,6H),3.42-3.36(m,2H),3.09-3.02(m,2H),2.94-2.85(m,2H),2.30(t,J=5.9Hz,2H),1.19(d,J=7.1Hz,6H)ppm。
13C NMR(75MHz,DMSO-d6):δ=193.37,176.59,150.58,147.48,144.85,137.01,135.05,134.25,110.37,108.17,65.21,55.88,40.87,34.83,28.63,17.05ppm。
HRMS(ESI–):计算值C31H31O10Se2 -,(M-H)-,723.0253;实测值723.0249。
实施例4 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(2-乙基-4-氧代丁酸)(C3)的制备
参照实施例1和2所述的制备方法,将两分子中间体15c通过1,3-二溴丙烷连接制备得到化合物C3。
1H NMR(300MHz,DMSO-d6):δ=12.19(s,2H),8.42(s,2H),7.70(s,2H),7.59(s,2H),4.23(t,J=5.9Hz,4H),3.85(s,6H),3.38(dd,J1=17.4Hz,J2=9.6Hz,2H),3.11(dd,J1=17.4Hz,J2=4.4Hz,2H),2.92-3.83(m,2H),2.30(t,J=5.7Hz,2H),1.62(p,J=6.6Hz,4H),0.95(t,J=7.4Hz,6H)ppm。
13C NMR(75MHz,DMSO-d6):δ=193.83,176.15,150.73,147.65,144.99,137.21,135.26,134.57,110.48,108.28,65.33,56.07,41.68,28.75,24.78,11.52ppm。
HRMS(ESI–):计算值C33H35O10Se2 -,(M-H)-,751.0566;实测值751.0569。
实施例5 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(2-异丙基-4-氧代丁酸)(C4)的制备
参照实施例1和2所述的制备方法,将两分子中间体15d通过1,3-二溴丙烷连接制备得到化合物C4。
1H NMR(300MHz,DMSO-d6):δ=12.20(s,2H),8.45(s,2H),7.71(s,2H),7.60(s,2H),4.22(t,J=6.0Hz,4H),3.84(s,6H),3.43-3.37(m,2H),3.10-3.01(m,2H),2.94-2.86(m,2H),2.31(t,J=5.8Hz,2H),2.20-2.15(m,2H),1.14(d,J=7.1Hz,6H),1.06(d,J=7.0Hz,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.54,175.98,150.11,147.53,145.19,137.40,135.51,134.23,109.94,108.24,65.14,56.36,45.83,40.77,32.64,30.31,20.89,20.06ppm。HRMS(ESI–):计算值C35H39O10Se2 -,(M-H)-,779.0879;实测值779.0881。
实施例6 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(2-环丙基-4-氧代丁酸)(C5)的制备
参照实施例1和2所述的制备方法,将两分子中间体15e通过1,3-二溴丙烷连接制备得到化合物C5。1H NMR(300MHz,DMSO-d6):δ=12.20(s,2H),8.42(s,2H),7.69(s,2H),7.62(s,2H),4.21(t,J=5.9Hz,4H),3.83(s,6H),3.41-3.35(m,2H),3.12-3.03(m,2H),2.95-2.85(m,2H),2.29(t,J=6.0Hz,2H),2.32-2.20(m,2H),1.66-1.55(m,4H),1.47-1.39(m,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=192.88,176.17,150.34,148.10,145.25,137.82,136.03,134.56,110.02,107.61,65.34,57.29,46.28,39.75,28.94,12.89,7.80,7.12ppm。HRMS(ESI–):计算值C35H35O10Se2 -,(M-H)-,775.0566;实测值775.0567。
实施例7 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(2-丁基-4-氧代丁酸)(C6)的制备
参照实施例1和2所述的制备方法,将两分子中间体15f通过1,3-二溴丙烷连接制备得到化合物C6。
1H NMR(300MHz,DMSO-d6):δ=12.19(s,2H),8.43(s,2H),7.71(s,2H),7.61(s,2H),4.20(t,J=5.9Hz,4H),3.85(s,6H),3.39-3.33(m,2H),3.11-3.02(m,2H),2.91-2.85(m,2H),2.30(t,J=5.9Hz,2H),1.63-1.58(m,4H),1.35-1.27(m,8H),1.00-0.93(m,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=195.01,177.22,150.58,146.97,145.35,137.28,135.49,134.20,111.83,108.95,65.47,56.81,42.66,41.07,30.36,28.57,26.10,20.53,13.69ppm。HRMS(ESI–):计算值C37H43O10Se2 -,(M-H)-,807.1192;实测值807.1191。
实施例8 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(2-甲氧甲基-4-氧代丁酸)(C7)的制备
参照实施例1和2所述的制备方法,将两分子中间体15g通过1,3-二溴丙烷连接制备得到化合物C7。
1H NMR(300MHz,DMSO-d6):δ=12.21(s,2H),8.43(s,2H),7.71(s,2H),7.63(s,2H),4.23(t,J=5.8Hz,4H),3.83(s,6H),3.62(d,J=6.3Hz,4H),3.42-3.36(m,2H),3.21(s,6H),3.11-3.04(m,2H),2.93-2.81(m,2H),2.30(t,J=5.9Hz,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.27,174.86,151.29,148.54,145.06,137.00,136.11,134.84,110.57,108.16,73.91,64.97,59.05,56.13,42.75,39.30,29.44ppm。HRMS(ESI–):计算值C33H35O12Se2 -,(M-H)-,783.0464;实测值783.0464。
实施例9 2,2'-(5,5'-(丙烷-1,3-二基双(氧基)双(6-甲氧基苯并[b]硒吩-5,2-二基-2-羰基))双(环丙烷-1-甲酸)(C8)的制备
参照实施例1和2所述的制备方法,将两分子中间体24a通过1,3-二溴丙烷连接制备得到化合物C8。
1H NMR(300MHz,DMSO-d6):δ=12.20(s,2H),8.42(s,2H),7.70(s,2H),7.62(s,2H),4.20(t,J=5.8Hz,4H),3.84(s,6H),3.50-3.41(m,2H),2.30(t,J=6.0Hz,2H),2.25-2.17(m,2H),1.77-1.55(m,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.51,173.70,150.68,147.93,144.37,137.55,135.42,134.27,111.58,108.73,64.32,56.59,33.71,30.49,21.30,14.82ppm。HRMS(ESI–):计算值C31H27O10Se2 -,(M-H)-,718.9940;实测值718.9937。
实施例10 2,2'-(5,5'-(丙烷-1,3-二基双(氧基)双(6-甲氧基苯并[b]硒吩-5,2-二基-2-羰基))双(环丁烷-1-甲酸)(C9)的制备
参照实施例1和2所述的制备方法,将两分子中间体24b通过1,3-二溴丙烷连接制备得到化合物C9。
1H NMR(300MHz,DMSO-d6):δ=12.19(s,2H),8.38(s,2H),7.69(s,2H),7.58(s,2H),4.23(t,J=5.9Hz,4H),3.84(s,6H),3.23-3.06(m,4H),2.29(t,J=6.0Hz,2H),2.19-2.01(m,8H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.03,174.16,151.22,147.95,144.66,137.26,135.30,134.53,110.12,108.74,64.43,56.23,50.16,44.61,29.83,25.37,24.62ppm。HRMS(ESI–):计算值C33H31O10Se2 -,(M-H)-,747.0253;实测值747.0251。
实施例11 2,2'-(5,5'-(丙烷-1,3-二基双(氧基)双(6-甲氧基苯并[b]硒吩-5,2-二基-2-羰基))双(环己烷-1-甲酸)(C10)的制备
参照实施例1和2所述的制备方法,将两分子中间体24c通过1,3-二溴丙烷连接制备得到化合物C10。
1H NMR(300MHz,DMSO-d6):δ=12.19(s,2H),8.40(s,2H),7.70(s,2H),7.58(s,2H),4.22(t,J=5.9Hz,4H),3.83(s,6H),2.79-2.67(m,4H),2.30(t,J=6.0Hz,2H),1.81-1.63(m,16H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.29,174.54,150.75,147.67,145.00,137.73,136.17,134.99,109.84,108.31,63.15,56.34,51.96,48.30,29.66,27.49,25.82,25.17,24.67ppm。HRMS(ESI–):cacld for C37H39O10Se2 -,(M-H)-,803.0879;found803.0876。
实施例12 4,4'-((丙烷-1,3-二基双(氧基))双(5-甲氧基苯并[b]硒吩-6,2-二基))双(4-氧代丁酸)(C11)的制备
参照实施例1和2所述的制备方法,将两分子中间体15h通过1,3-二溴丙烷连接制备得到化合物C11。1H NMR(300MHz,DMSO-d6):δ=12.18(s,2H),8.42(s,2H),7.76(s,2H),7.53(s,2H),4.26(t,J=6.0Hz,4H),3.83(s,6H),3.27(t,J=6.0Hz,4H),2.61(t,J=6.2Hz,4H),2.31-2.27(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.55,173.67,149.44,148.47,144.73,136.64,135.17,134.12,109.16,108.95,65.16,55.66,32.55,28.49,28.06ppm。HRMS(ESI-):计算值C29H27O10Se2 -(M-H)-,694.9940;实测值694.9942。
实施例13 4,4'-((丙烷-1,3-二基双(氧基))双(5-甲氧基苯并[b]硒吩-6,2-二基))双(2-甲基-4-氧代丁酸)(C12)的制备
参照实施例1和2所述的制备方法,将两分子中间体15i通过1,3-二溴丙烷连接制备得到化合物C12。
1H NMR(300MHz,DMSO-d6):δ=12.16(s,2H),8.41(s,2H),7.75(s,2H),7.51(s,2H),4.25(d,J=5.7Hz,4H),3.82(s,6H),3.42–3.36(m,2H),3.10(d,J1=17.1Hz,J2=5.1Hz,2H),2.91–2.84(m,2H),2.30(t,J=5.9Hz,2H),1.19(d,J=7.2Hz,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.86,177.04,149.93,148.93,145.40,137.19,135.63,134.73,109.62,109.41,65.61,56.12,41.33,35.29,28.94,17.50ppm。HRMS(ESI–):计算值C31H31O10Se2 -,(M-H)-,723.0253;实测值723.0254。
实施例14 4,4'-((丙烷-1,3-二基双(氧基))双(5-甲氧基苯并[b]硒吩-6,2-二基))双(2-乙基-4-氧代丁酸)(C13)的制备
参照实施例1和2所述的制备方法,将两分子中间体15j通过1,3-二溴丙烷连接制备得到化合物C13。
1H NMR(300MHz,DMSO-d6):δ=12.18(s,2H),8.44(s,2H),7.75(s,2H),7.52(s,2H),4.26(t,J=5.4Hz,4H),3.82(s,6H),3.42-3.36(m,2H),3.11-3.03(m,2H),2.82-2.73(m,2H),2.31(t,J=5.7Hz,2H),1.69-.54(m,4H),0.95(t,J=7.4Hz,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.58,175.93,149.47,148.48,144.94,136.75,135.19,134.36,109.16,108.96,65.15,55.66,41.58,28.49,24.60,11.33ppm。HRMS(ESI–):计算值C33H35O10Se2 -,(M-H)-,751.0566;实测值751.0566。
实施例15 4-(5-(3-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-2-甲基-4-氧代丁酸(C14)的制备
参照实施例1和2所述的制备方法,将一分子中间体15a和一分子中间体15b通过1,3-二溴丙烷连接制备得到化合物C14。1H NMR(300MHz,DMSO-d6):δ=12.17(s,2H),8.39(s,2H),7.69(s,2H),7.59(s,2H),4.23(t,J=5.8Hz,4H),3.85(s,6H),3.40-3.32(m,2H),3.18-3.06(m,2H),2.77-2.60(m,3H),2.29(t,J=5.9Hz,2H),1.19(d,J=7.2Hz,3H)ppm。13CNMR(75MHz,DMSO-d6):δ=193.65,193.49,176.72,173.81,150.65,150.61,147.57,144.94,144.74,137.10,137.00,135.15,134.39,134.24,110.37,108.24,65.26,55.97,40.95,32.63,28.70,28.13,17.16ppm。HRMS(ESI–):计算值C30H29O10Se2 -,(M-H)-,709.0097;实测值709.0098。
实施例16 4-(5-(3-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酸(C15)的制备
参照实施例1和2所述的制备方法,将一分子中间体15a和一分子中间体15c通过1,3-二溴丙烷连接制备得到化合物C15。1H NMR(300MHz,DMSO-d6):δ=12.18(s,2H),8.41(s,2H),7.71(s,2H),7.57(s 2H),4.22(t,J=6.0Hz,4H),3.83(s,6H),3.46-3.37(m,2H),3.17-3.08(m,2H),2.67-2.57(m,3H),2.27(t,J=5.9Hz,2H),1.65-1.54(m,2H),0.94(t,J=7.5Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ=195.27,194.59,174.63,173.39,150.84,150.42,146.90,145.00,144.83,137.23,137.16,135.18,134.76,134.50,110.92,108.97,65.21,55.66,43.63,42.75,39.24,30.10,28.79,25.18,12.86ppm。HRMS(ESI–):计算值C31H31O10Se2 -,(M-H)-,723.0253;实测值723.0257。
实施例17 2-(5-(3-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-羰基)环丁烷-1-甲酸(C16)的制备
参照实施例1和2所述的制备方法,将一分子中间体15a和一分子中间体24b通过1,3-二溴丙烷连接制备得到化合物C16。1H NMR(300MHz,DMSO-d6):δ=12.20(s,2H),8.44(s,2H),7.69(s,2H),7.55(s 2H),4.24(t,J=6.0Hz,4H),3.84(s,6H),3.45-3.32(m,1H),3.19-3.08(m,1H),3.07-3.03(m,2H),2.63-2.56(m,2H),2.33(t,J=6.0Hz,2H),2.21-2.02(m,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.06,193.03,175.19,174.20,150.41,150.28,145.99,145.15,144.61,138.34,137.94,135.83,134.49,134.14,111.07,107.89,65.65,56.78,52.94,44.48,37.61,30.45,29.88,24.95,22.17ppm。HRMS(ESI–):计算值C31H29O10Se2 -,(M-H)-,721.0097;实测值721.0099。
实施例18 2-(5-(3-((2-(3-羧基戊酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-羰基)环丁烷-1-甲酸(C17)的制备
参照实施例1和2所述的制备方法,将一分子中间体15c和一分子中间体24b通过1,3-二溴丙烷连接制备得到化合物C17。
1H NMR(300MHz,DMSO-d6):δ=12.17(s,2H),8.45(s,2H),7.71(s,2H),7.57(s2H),4.20(t,J=6.0Hz,4H),3.83(s,6H),3.46-3.35(m,1H),3.12-3.04(m,1H),3.09-3.03(m,2H),2.69-2.60(m,1H),2.31(t,J=6.1Hz,2H),2.20-2.00(m,4H),1.65-1.54(m,2H),0.95(t,J=7.3Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.21,193.85,175.36,174.61,150.68,150.02,145.72,145.05,144.17,138.19,137.63,135.84,134.90,134.57,111.49,107.41,65.39,56.27,50.52,43.92,42.47,41.71,30.94,24.72,23.00,11.95ppm。HRMS(ESI–):计算值C33H33O10Se2 -,(M-H)-,749.0410;实测值749.0412。
实施例19 4-(6-(3-((2-(3-羧基丙酰基)-5-甲氧基苯并[b]硒吩-6-基)氧基)丙氧基)-5-甲氧基苯并[b]噻吩-2-基)-4-氧代丁酸(C18)的制备
参照实施例1和2所述的制备方法,将一分子中间体15h和一分子中间体34d通过1,3-二溴丙烷连接制备得到化合物C18。1H NMR(300MHz,DMSO-d6):δ=12.19(s,1H),12.13(s,1H),8.41(s,1H),7.95(s,1H),7.54(s,1H),7.32(s,1H),7.21(s,1H),7.06(s,1H),4.23(t,J=6.1Hz,4H),3.84(s,6H),3.41(t,J=6.1Hz,2H),3.11(t,J=6.0Hz,2H),2.75(t,J=5.9Hz,2H),2.61(t,J=6.1Hz,2H),2.35-2.20(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=195.31,194.81,174.73,151.29,151.38,148.03,147.59,144.94,140.69,137.42,136.39,135.26,134.07,133.43,130.28,109.47,108.74,108.33,104.60,68.88,56.36,37.86,36.92,30.51,29.93,29.01ppm。HRMS(ESI–):计算值C29H27O10SSe-,(M-H)-,647.0496;实测值647.0499。
实施例20 4-(6-(3-((2-(3-羧基丁酰基)-5-甲氧基苯并[b]硒吩-6-基)氧基)丙氧基)-5-甲氧基苯并[b]噻吩-2-基)-2-甲基-4-氧代丁酸(C19)的制备
参照实施例1和2所述的制备方法,将一分子中间体15i和一分子中间体34e通过1,3-二溴丙烷连接制备得到化合物C19。1H NMR(300MHz,DMSO-d6):δ=12.20(s,1H),12.11(s,1H),8.44(s,1H),7.98(s,1H),7.55(s,1H),7.32(s,1H),7.22(s,1H),7.03(s,1H),4.22(t,J=6.1Hz,4H),3.83(s,6H),3.40-3.35(m,2H),3.09-3.05(m,2H),2.78-2.65(m,2H),2.35-2.21(m,2H),1.18(dd,J1=10.5Hz,J2=4.7Hz,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=195.44,194.83,174.47,151.36,151.11,148.63,147.17,144.84,140.81,137.72,136.10,135.55,134.53,133.14,130.19,109.31,108.74,108.26,104.35,68.61,56.70,45.90,43.02,37.84,35.23,29.95,17.62,17.31ppm。HRMS(ESI–):计算值C31H31O10SSe-,(M-H)-,675.0809;实测值675.0811。
实施例21 4-(6-(3-((2-(3-羧基戊酰基)-5-甲氧基苯并[b]硒吩-6-基)氧基)丙氧基)-5-甲氧基苯并[b]噻吩-2-基)-2-乙基-4-氧代丁酸(C20)的制备
参照实施例1和2所述的制备方法,将一分子中间体15j和一分子中间体34f通过1,3-二溴丙烷连接制备得到化合物C20。1H NMR(300MHz,DMSO-d6):δ=12.18(s,1H),12.13(s,1H),8.42(s,1H),7.97(s,1H),7.55(s,1H),7.33(s,1H),7.21(s,1H),7.02(s,1H),4.20(t,J=5.9Hz,4H),3.84(s,6H),3.43-3.35(m,2H),3.12-3.06(m,2H),2.77-2.60(m,2H),2.37-2.19(m,2H),1.65-1.57(m,4H),0.96(dt,J1=10.7Hz,J2=2.9Hz,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=195.27,194.77,174.04,151.86,151.32,148.47,147.74,144.06,140.90,137.21,136.69,135.55,134.62,133.34,130.24,109.03,108.73,108.11,104.33,68.14,56.67,43.08,42.64,41.31,40.09,30.39,24.57,24.06,11.77,11.34ppm。HRMS(ESI–):计算值C33H35O10SSe-,(M-H)-,703.1122;实测值703.1120。
实施例22 4-(5-(3-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]噻吩-2-基)-4-氧代丁酸(C21)的制备
参照实施例1和2所述的制备方法,将一分子中间体15a和一分子中间体34a通过1,3-二溴丙烷连接制备得到化合物C21。1H NMR(300MHz,DMSO-d6):δ=12.23(s,1H),12.11(s,1H),8.45(s,1H),7.91(s,1H),7.40(s,1H),7.29(s,1H),7.21(s,1H),7.09(s,1H),4.21(t,J=6.2Hz,4H),3.85(s,6H),3.42(t,J=6.1Hz,2H),3.10(t,J=6.0Hz,2H),2.77(t,J=5.9Hz,2H),2.62(t,J=6.1Hz,2H),2.32-2.23(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.82,194.63,174.47,151.69,151.14,148.01,147.21,144.41,140.86,137.91,136.19,135.71,134.16,133.39,130.77,110.17,109.97,108.28,104.25,68.40,56.33,37.72,36.51,30.20,29.60,29.18ppm。HRMS(ESI–):计算值C29H27O10SSe-,(M-H)-,647.0496;实测值647.0495。
实施例23 4-(5-(3-((2-(3-羧基丁酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]噻吩-2-基)-2-甲基-4-氧代丁酸(C22)的制备
参照实施例1和2所述的制备方法,将一分子中间体15b和一分子中间体34b通过1,3-二溴丙烷连接制备得到化合物C22。1H NMR(300MHz,DMSO-d6):δ=12.23(s,1H),12.11(s,1H),8.45(s,1H),7.91(s,1H),7.40(s,1H),7.29(s,1H),7.21(s,1H),7.09(s,1H),4.21(t,J=6.1Hz,4H),3.85(s,6H),3.46-3.39(m,2H),3.11-3.04(m,2H),2.77-2.65(m,2H),2.33-2.20(m,2H),1.19(dd,J1=10.7Hz,J2=4.8Hz,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.84,194.10,174.26,151.31,151.09,148.67,147.65,144.64,140.50,137.93,136.55,135.24,134.60,133.44,130.37,110.79,109.32,108.47,104.29,68.03,56.71,45.51,43.95,37.69,35.31,29.88,17.90,17,74ppm。HRMS(ESI–):计算值C31H31O10SSe-,(M-H)-,675.0809;实测值675.0810。
实施例24 4-(5-(3-((2-(3-羧基戊酰基)-6-甲氧基苯并[b]硒吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]噻吩-2-基)-2-乙基-4-氧代丁酸(C23)的制备
参照实施例1和2所述的制备方法,将一分子中间体15c和一分子中间体34c通过1,3-二溴丙烷连接制备得到化合物C23。1H NMR(300MHz,DMSO-d6):δ=12.22(s,1H),12.12(s,1H),8.41(s,1H),7.92(s,1H),7.39(s,1H),7.28(s,1H),7.20(s,1H),7.06(s,1H),4.22(t,J=6.0Hz,4H),3.85(s,6H),3.43-3.36(m,2H),3.11-3.06(m,2H),2.75-2.60(m,2H),2.37-2.20(m,2H),1.67-1.57(m,4H),0.96(dt,J1=10.3Hz,J2=3.3Hz,6H)ppm。
13C NMR(75MHz,DMSO-d6):δ=194.94,194.29,175.15,151.70,150.86,148.65,147.19,145.62,140.35,137.61,136.63,135.00,134.22,133.05,131.78,110.06,109.14,108.39,104.45,68.75,56.74,43.11,42.23,41.79,40.06,30.55,24.89,24.56,11.49,11.22ppm。HRMS(ESI–):计算值C33H35O10SSe-,(M-H)-,703.1122;实测值703.1119。
实施例25 4-(5-(3-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]噻吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-2-甲基-4-氧代丁酸(C24)的制备
参照实施例1和2所述的制备方法,将一分子中间体15b和一分子中间体34a通过1,3-二溴丙烷连接制备得到化合物C24。1H NMR(300MHz,DMSO-d6):δ=12.19(s,1H),12.13(s,1H),8.44(s,1H),7.95(s,1H),7.54(s,1H),7.32(s,1H),7.21(s,1H),7.06(s,1H),4.23(t,J=6.1Hz,4H),3.84(s,6H),3.47(t,J=6.3Hz,2H),3.45-3.37(m,1H),3.12-3.07(m,1H),2.75-2.66(m,3H),2.32-2.23(m,2H),1.19(d,J=6.9Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.51,194.23,175.85,151.57,150.20,148.98,147.39,145.29,140.63,137.96,136.86,135.42,134.79,133.83,131.40,110.11,109.22,108.05,104.60,68.92,56.02,45.75,36.53,36.18,30.50,29.96,18.30ppm。HRMS(ESI–):计算值C30H29O10SSe-,(M-H)-,661.0652;实测值661.0651。
实施例26 4-(5-(3-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]噻吩-5-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-2-乙基-4-氧代丁酸(C25)的制备
参照实施例1和2所述的制备方法,将一分子中间体15c和一分子中间体34a通过1,3-二溴丙烷连接制备得到化合物C25。1H NMR(300MHz,DMSO-d6):δ=12.19(s,1H),12.13(s,1H),8.43(s,1H),7.95(s,1H),7.54(s,1H),7.32(s,1H),7.21(s,1H),7.06(s,1H),4.23(t,J=6.1Hz,4H),3.84(s,6H),3.49(t,J=6.3Hz,2H),3.49-3.40(m,1H),3.17-3.13(m,1H),2.77-2.61(m,3H),2.37-2.19(m,2H),1.65-1.56(m,2H),0.94(t,J=7.3Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.86,194.34,175.47,151.72,150.58,148.71,147.20,145.68,141.06,137.45,136.90,135.02,134.60,134.09,131.77,109.27,109.15,108.08,104.05,68.64,56.10,43.87,41.48,39.00,30.80,30.28,25.99,12.54ppm。HRMS(ESI–):计算值C31H31O10SSe-,(M-H)-,675.0809;实测值675.0805。
实施例27 4-(5-(3-((2-(3-羧基丙酰基)-5-甲氧基苯并[b]硒吩-6-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸(C26)的制备
参照实施例1和2所述的制备方法,将一分子中间体15a和一分子中间体15h通过1,3-二溴丙烷连接制备得到化合物C26。1H NMR(300MHz,DMSO-d6):δ=12.24(s,1H),12.19(s,1H),8.42(s,1H),8.39(s,1H),7.76(s,1H),7.71(s,1H),7.58(s,1H),7.53(s,1H),4.27(dt,J1=14.7Hz,J2=5.1Hz,4H),3.84(s,3H),3.82(s,3H),3.27(t,J=6.5Hz,4H),2.61(t,J=6.1Hz,4H),2.30-2.26(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.67,173.99,150.49,149.46,148.48,147.45,144.82,144.73,136.93,136.67,135.19,135.06,134.16,110.24,109.13,108.94,108.16,65.22,65.07,55.90,55.67,32.66,32.33,28.57,28.27ppm。HRMS(ESI–):计算值C29H27O10Se2 -,(M-H)-,694.9940;实测值694.9937。实施例284-(5-(3-((2-(3-羧基丙酰基)-5-甲氧基苯并[b]硒吩-6-基)氧基)丙氧基)-6-甲氧基苯并[b]噻吩-2-基)-4-氧代丁酸(C27)的制备
参照实施例1和2所述的制备方法,将一分子中间体15h和一分子中间体34a通过1,3-二溴丙烷连接制备得到化合物C27。1H NMR(300MHz,DMSO-d6):δ=12.19(s,1H),12.10(s,1H),8.40(s,1H),7.97(s,1H),7.40(s,1H),7.30(s,1H),7.22(s,1H),7.06(s,1H),4.22-4.16(m,2H),3.86(s,3H),3.84(s,3H),3.44(t,J=5.9Hz,2H),3.11(t,J=6.0Hz,2H),2.72(t,J=5.8Hz,2H),2.61(t,J=5.9Hz,2H),2.31-2.26(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=195.22,194.48,178.51,153.04,152.64,148.06,147.79,145.95,141.59,137.06,136.44,135.84,134.55,133.54,132.64,110.98,109.73,108.37,104.05,68.40,68.02,56.64,56.37,37.62,36.74,30.59,29.81,29.29ppm。HRMS(ESI–):计算值C29H27O10SSe-,(M-H)-,647.0496;实测值647.0499。
实施例29 4-(5-(3-((2-(3-羧基丙酰基)-5-甲氧基苯并[b]噻吩-6-基)氧基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸(C28)的制备
参照实施例1和2所述的制备方法,将一分子中间体15a和一分子中间体34d通过1,3-二溴丙烷连接制备得到化合物C28。1H NMR(300MHz,DMSO-d6):δ=12.24(s,1H),12.13(s,1H),8.42(s,1H),7.96(s,1H),7.41(s,1H),7.30(s,1H),7.21(s,1H),7.07(s,1H),4.22-4.17(m,2H),3.85(s,3H),3.84(s,3H),3.47(t,J=5.9Hz,2H),3.10(t,J=6.0Hz,2H),2.78(t,J=5.8Hz,2H),2.65(t,J=5.9Hz,2H),2.32-2.24(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=195.68,194.41,178.38,153.83,152.96,148.84,147.06,145.63,141.16,137.55,136.59,135.81,134.09,133.12,132.37,110.81,109.07,108.27,104.75,68.45,68.08,56.69,56.25,37.00,36.03,30.73,29.91,29.13ppm。HRMS(ESI–):计算值C29H27O10SSe-,(M-H)-,647.0496;实测值647.0498。
实施例30 4,4'-((乙烷-1,2-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C29)的制备
参照实施例1和2所述的制备方法,将两分子中间体15a通过1,2-二溴乙烷连接制备得到化合物C29。1H NMR(300MHz,DMSO-d6):δ=12.19(s,2H),8.41(s,2H),7.73(s,2H),7.64(s,2H),4.41(s,4H),3.86(s,6H),3.28(t,J=6.0Hz,4H),2.62(t,J=6.0Hz,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.71,173.85,150.47,147.39,144.85,137.19,135.12,134.24,110.45,108.31,67.23,55.91,32.64,28.15ppm。HRMS(ESI–):计算值C28H25O10Se2 -,(M-H)-,680.9784;实测值680.9781。
实施例31 4,4'-((丁烷-1,4-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C30)的制备
参照实施例1和2所述的制备方法,将两分子中间体15a通过1,4-二溴丁烷连接制备得到化合物C30。
1H NMR(300MHz,DMSO-d6):δ=12.20(s,2H),8.41(s,2H),7.72(s,2H),7.57(s,2H),4.12(t,J=5.9Hz,4H),3.84(s,6H),3.26(t,J=5.9Hz,4H),2.61(t,J=6.1Hz,4H),1.96(t,J=5.3Hz,4H)ppm.13C NMR(75MHz,DMSO-d6):δ=193.68,173.83,150.62,147.69,144.70,136.81,135.15,134.26,110.11,108.15,68.15,55.95,32.64,28.17,25.56ppm.HRMS(ESI–):计算值C30H29O10Se2 -,(M-H)-,709.0097;实测值709.0095。
实施例32 4,4'-((戊烷-1,5-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C31)的制备
参照实施例1和2所述的制备方法,将两分子中间体15a通过1,5-二溴戊烷连接制备得到化合物C31。
1H NMR(300MHz,DMSO-d6):δ=12.20(s,2H),8.42(s,2H),7.73(s,2H),7.57(s,2H),4.12(t,J=5.9Hz,4H),3.84(s,6H),3.30(t,J=6.0Hz,4H),2.64(t,J=6.1Hz,4H),1.75-1.56(m,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.03,173.16,150.39,147.96,144.27,136.49,135.76,134.10,110.91,108.89,68.14,55.50,38.52,29.47,29.18,23.23ppm。HRMS(ESI–):计算值C31H31O10Se2 -,(M-H)-,723.0253;实测值723.0251。
实施例33 4,4'-(((氧基双(乙烷-2,1-二基))双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C32)的制备
参照实施例1和2所述的制备方法,将两分子中间体15a通过2,2'-二溴二乙醚连接制备得到化合物C32。
1H NMR(300MHz,DMSO-d6):δ=12.20(s,2H),8.43(s,2H),7.70(s,2H),7.58(s,2H),4.17(t,J=5.9Hz,4H),3.84(s,6H),3.79(t,J=6.4Hz,4H),3.29(t,J=6.0Hz,4H),2.62(t,J=6.1Hz,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.33,173.56,150.94,147.68,144.83,136.19,135.06,134.54,110.42,108.32,71.60,68.56,55.57,37.40,29.17ppm。HRMS(ESI–):计算值C30H29O11Se2 -,(M-H)-,725.0046;实测值725.0044。
实施例34 4,4'-(((2-甲基丙烷-1,3-二基)双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C33)的制备
参照实施例1和2所述的制备方法,将两分子中间体15a通过1,3-二溴-2-甲基丙烷连接制备得到化合物C33。1H NMR(300MHz,DMSO-d6):δ=12.19(s,2H),8.39(s,2H),7.71(s,2H),7.65(s,2H),4.61(brs,2H),4.39(brs,2H),3.82(s,6H),3.25(t,J=6.3Hz,4H),2.59(t,J=6.4Hz,4H),2.28–2.26(m,1H),1.23(s,3H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.66,173.82,150.74,147.66,144.90,137.52,135.12,134.08,111.44,108.44,67.12,56.09,43.12,32.66,28.12,25.23ppm。HRMS(ESI–):计算值C30H29O10Se2 -,(M-H)-,709.0097;实测值709.0096。
实施例35 4,4'-(((环丙烷-1,1-二基)双(亚甲基))双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C34)的制备
参照实施例1和2所述的制备方法,将两分子中间体15a通过1,1-双(溴甲基)环丙烷连接制备得到化合物C34。1H NMR(300MHz,DMSO-d6):δ=12.24(s,2H),8.30(s,2H),7.68(s,2H),7.53(s,2H),4.04(s,4H),3.82(s,6H),3.25(t,J=6.2Hz,4H),2.60(t,J=6.1Hz,4H),0.75(s,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.63,173.84,150.67,147.82,144.73,137.02,135.09,134.10,110.71,108.21,72.01,55.98,38.76,32.63,28.11,15.48ppm。HRMS(ESI–):计算值C31H29O10Se2 -,(M-H)-,721.0097;实测值721.0096。
实施例36 4,4'-(((2,2-二甲基丙烷-1,3-二基)双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C35)的制备
参照实施例1和2所述的制备方法,将两分子中间体15a通过1,3-二溴-2,2-二甲基丙烷连接制备得到化合物C35。1H NMR(300MHz,DMSO-d6):δ=12.23(s,2H),8.40(s,2H),7.71(s,2H),7.52(s,2H),3.97(s,4H),3.83(s,6H),3.17(t,J=6.1Hz,4H),2.58(t,J=6.1Hz,4H),1.10(s,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.18,173.65,149.96,147.52,143.25,137.05,135.11,134.41,110.29,108.19,75.34,56.27,38.62,37.39,29.55,23.22ppm。HRMS(ESI–):计算值C31H31O10Se2 -,(M-H)-,723.0253;实测值723.0250。
实施例37 4,4'-((丁烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C36)的制备
参照实施例1和2所述的制备方法,将两分子中间体15a通过1,3-二溴丁烷连接制备得到化合物C36。1H NMR(300MHz,DMSO-d6):δ=12.21(s,2H),8.42(s,2H),7.71(s,1H),7.69(s,1H),7.52(s,2H),4.48-4.36(m,1H),4.14-3.98(m,2H),3.83(s,6H),3.12(t,J=6.0Hz,4H),2.61(t,J=6.1Hz,4H),2.14-1.99(m,2H),1.47(d,J=6.9Hz,3H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.56,173.03,149.12,147.89,143.46,137.28,135.12,134.99,110.74,108.89,75.79,67.85,56.81,37.95,35.86,29.57,20.26ppm。HRMS(ESI–):计算值C30H29O10Se2 -,(M-H)-,709.0097;实测值709.0099。
实施例38 4,4'-(((2-氧代丙烷-1,3-二基)双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C37)的制备
参照实施例1和2所述的制备方法,将两分子中间体15a通过1,3-二溴丙酮连接制备得到化合物C37。1H NMR(300MHz,DMSO-d6):δ=12.25(s,2H),8.37(s,2H),7.73(s,2H),7.55(s,2H),4.98(s,4H),3.83(s,6H),3.15(t,J=5.9Hz,4H),2.60(t,J=6.0Hz,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=200.14,194.03,173.48,149.20,147.30,143.86,137.33,135.35,133.48,109.92,108.46,71.09,56.86,37.37,29.19ppm。HRMS(ESI–):计算值C29H25O11Se2 -,(M-H)-,708.9733;实测值708.9730。
实施例39 4,4'-(((2-羟基丙烷-1,3-二基)双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C38)的制备
将100mg化合物C37(0.14mmol)、6mL四氢呋喃和3mL水加入到100mL反应瓶中,分四次加入21mg硼氢化钠(0.56mmol)。反应混合物在室温下搅拌30min。TLC(二氯甲烷:甲醇=10:1,v/v)检测原料反应完全,加入40mL 2N HCl,用15mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩得粗品。粗品经硅胶柱层析(二氯甲烷:甲醇=30:1,v/v)纯化得化合物C38 89mg,淡黄色固体,收率89%。1H NMR(300MHz,DMSO-d6):δ=12.24(s,2H),8.41(s,2H),7.68(s,2H),7.52(s,2H),4.72(s,1H),4.16-4.09(m,5H),3.84(s,6H),3.09(t,J=6.0Hz,4H),2.59(t,J=5.8Hz,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.94,173.71,149.61,147.54,143.03,137.22,135.31,133.82,109.67,108.06,71.45,69.07,56.59,37.08,29.41ppm。HRMS(ESI–):计算值C29H27O11Se2 -,(M-H)-,710.9889;实测值710.9892。
实施例40 4,4'-((丙烷-1,3-二基双(氧基))双(苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C39)的制备
参照实施例1和2所述的制备方法,将两分子中间体15k通过1,3-二溴丙烷连接制备得到化合物C39。1H NMR(300MHz,DMSO-d6):δ=12.19(s,2H),8.39(s,2H),7.70(s,2H),7.53(d,J=7.4Hz,2H),7.34(dd,J1=7.2Hz,J2=3.6Hz,2H),4.22(t,J=5.8Hz,4H),3.15(t,J=6.0Hz,4H),2.59(t,J=5.9Hz,4H),2.30(t,J=6.0Hz,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.09,173.99,147.72,143.81,137.83,135.27,133.16,109.91,108.73,107.05,68.68,37.17,29.82,29.40ppm。HRMS(ESI–):计算值C27H23O8Se2 -,(M-H)-,634.9729;实测值634.9730。
实施例41 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C40)的制备
参照实施例1和2所述的制备方法,将两分子中间体15l通过1,3-二溴丙烷连接制备得到化合物C40。
1H NMR(300MHz,DMSO-d6):δ=12.17(s,2H),8.41(s,2H),7.70(s,2H),7.53(s,2H),4.17(t,J=5.8Hz,4H),3.15(t,J=6.2Hz,4H),2.62(t,J=6.2Hz,4H),2.28(t,J=6.1Hz,2H),2.12(s,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=195.04,172.50,147.63,144.87,137.49,135.16,133.01,130.67,109.79,107.67,67.47,37.56,30.31,29.69,16.59ppm。HRMS(ESI–):计算值C29H27O8Se2 -,(M-H)-,663.0042;实测值663.0046。
实施例42 4,4'-((丙烷-1,3-二基双(氧基))双(6-(二氟甲氧基)苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C41)的制备
参照实施例1和2所述的制备方法,将两分子中间体15m通过1,3-二溴丙烷连接制备得到化合物C41。1H NMR(300MHz,DMSO-d6):δ=12.24(s,2H),8.40(s,2H),7.69(s,2H),7.52(s,2H),6.65(t,J=68.2Hz,2H),4.23(t,J=6.4Hz,4H),3.17(t,J=6.1Hz,4H),2.60(t,J=6.0Hz,4H),2.31(t,J=6.1Hz,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.80,172.76,168.31,147.12,144.35,137.53,135.48,133.22,128.89,110.26,108.48,67.23,37.98,30.07,29.56ppm。HRMS(ESI–):计算值C29H23F4O10Se2 -,(M-H)-,766.9563;实测值766.9561。
实施例43 4,4'-(丁烷-1,4-二基双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C42)的制备
步骤1:4-(5-(4-((叔丁基二甲基硅基)氧基)丁基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸乙酯(38)的制备
干燥的50mL反应瓶中加入128mg I2(0.5mmol),0.98g锌粉(15.0mmol)和10mL无水四氢呋喃,用N2置换瓶中空气三次。所得混合物在室温下反应直至碘的红色褪去。加入2.68g(4-溴丁氧基)叔丁基二甲基硅烷(10.0mmol),反应液在80℃加热下搅拌3h。待反应液降至室温后,得到化合物(4-((叔丁基二甲基甲硅烷基)氧基)丁基)溴化锌(化合物37)的四氢呋喃溶液,并立即直接用于下一步反应。
将2.09g化合物15n(5.0mmol)、0.20g C-Phos Pd G3([(2-二环己基膦基-2',6'-双(N,N-二甲基氨)-1,1'-联苯)-2-(2'-氨基-1,1'-联苯)]甲磺酸钯(II),0.25mmol)和20mL无水四氢呋喃加入到100mL反应瓶中,N2置换瓶中空气三次。用注射器缓慢加入新制备的(4-((叔丁基二甲基甲硅烷基)氧基)丁基)溴化锌(化合物37)的四氢呋喃溶液(1M,10mL,10mmol)。所得反应混合物在室温下搅拌18h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)反应完全后,加水100mL并用20mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=10:1,v/v)纯化得化合物38 1.24g,黄色固体,收率47%。
1H NMR(300MHz,CDCl3):δ=8.05(s,1H),7.96(s,1H),7.30(s,1H),4.22(q,J=7.2Hz,2H),3.96(s,3H),3.68(t,J=7.0Hz,2H),3.17(t,J=6.9Hz,2H),2.67(t,J=6.8Hz,2H),2.59(t,J=6.9Hz,2H),1.72-1.55(m,4H),1.27(t,J=7.4Hz,3H),0.84(s,9H),0.02(s,6H)ppm。HRMS(ESI+):计算值C25H39O5SeSi+,(M+H)+,527.1726;实测值527.1730。
步骤2:4-(5-(4-羟基丁基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸乙酯(39)的制备
将1.24g化合物38(2.35mmol)和5mL甲醇加入到50mL反应瓶中,加入5mL水和5mL醋酸。所得反应混合物在室温下搅拌18h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,加入40mL水并用15mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=8:1,v/v)纯化得化合物39 0.88g,黄色固体,收率91%。
1H NMR(300MHz,CDCl3):δ=8.07(s,1H),7.96(s,1H),7.31(s,1H),4.20(q,J=7.0Hz,2H),4.06(t,J=6.8Hz,2H),3.97(s,3H),3.21(t,J=6.9Hz,2H),2.72-2.62(m,4H),1.75-1.66(m,4H),1.25(t,J=7.0Hz,3H)ppm。HRMS(ESI+):计算值C19H25O5Se+,(M+H)+,413.0862;实测值413.0864。
步骤3:4-(5-(4-溴丁基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸乙酯(40)的制备
将0.88g化合物39(2.14mmol)、1.12g三苯基膦(4.28mmol)和10mL四氢呋喃加入到50mL反应瓶中,并置于冰浴中降温。在0℃下加入0.57g NBS(N-溴代琥珀酰亚胺,3.21mmol),加完后,继续在0℃下搅拌1h。TLC检测(石油醚:乙酸乙酯=1:1,v/v)原料反应完全后,加入50mL水并用15mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=10:1,v/v)纯化得化合物40 0.86g,黄色固体,收率85%。
1H NMR(300MHz,CDCl3):δ=8.05(s,1H),7.95(s,1H),7.26(s,1H),4.17(q,J=7.0Hz,2H),3.97(s,3H),3.48(t,J=7.5Hz,2H),3.21(t,J=6.9Hz,2H),2.70-2.63(m,4H),1.96-1.86(m,2H),1.82-1.77(m,2H),1.25(t,J=7.2Hz,3H)ppm。HRMS(ESI+):计算值C19H24BrO4Se+,(M+H)+,475.0018;实测值475.0017。
步骤4:4-(6-甲氧基-5-(4-(4,4,5,5-四甲基-1,3,2,-二氧杂硼烷-2-基)丁基)苯并[b]硒吩-2-基)-4-氧代丁酸乙酯(42)的制备
将0.86g化合物40(1.82mmol)、0.69g联硼酸频那醇酯(2.73mmol)、35mg碘化亚铜(0.18mmol)、62mg三苯基膦(0.24mmol)、0.29g叔丁醇锂(3.64mmol)和8mL DMF加入50mL反应瓶中,N2置换瓶中空气五次。所得反应混合物在室温下搅拌反应18h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,加入40mL乙酸乙酯稀释反应液,通过硅藻土抽滤,滤液浓缩,所得残留物通过硅胶柱层析(石油醚:乙酸乙酯=10:1,v/v)纯化得化合物42 0.69g,黄色固体,收率73%。
1H NMR(300MHz,CDCl3):δ=8.07(s,1H),7.95(s,1H),7.24(s,1H),4.21(q,J=7.3Hz,2H),3.96(s,3H),3.19(t,J=6.9Hz,2H),2.70(t,J=6.7Hz,2H),2.61(t,J=7.1Hz,2H),1.67-1.56(m,4H),1.39(t,J=5.6Hz,2H)1.22(t,J=7.5Hz,3H),1.21(s,12H)ppm。HRMS(ESI+):计算值C25H36BO6Se+,(M+H)+,523.1765;实测值523.1766。
步骤5:4,4'-(丁烷-1,4-二基双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸二乙酯)(43)的制备
将100mg化合物42(0.19mmol)、119mg化合物15n(0.29mmol)、31mg PdCl2(dppf)-CH2Cl2(1,1-双(二苯基膦)二茂铁二氯化钯二氯甲烷络合物,0.038mmol)、248mg碳酸铯(0.76mmol)、4mL 1,4-二氧六环和1mL水加入到50mL反应瓶中,所得混合物在100℃下反应18h。TLC检测(石油醚:乙酸乙酯=2:1,v/v)原料反应完全,待反应液冷却到室温后,抽滤,滤液浓缩,所得残留物通过硅胶柱层析(石油醚:乙酸乙酯=6:1,v/v)纯化得化合物4389mg,黄色固体,收率64%。
1H NMR(300MHz,CDCl3):δ=8.07(s,2H),7.97(s,2H),7.28(s,2H),4.20(q,J=7.6Hz,4H),3.96(s,6H),3.20(t,J=6.3Hz,4H),2.78-2.70(m,4H),2.63(t,J=5.6Hz,4H),1.76-1.69(m,4H),1.20(t,J=7.2Hz,6H)ppm。HRMS(ESI+):计算值C34H39O8Se2 +,(M+H)+,735.0970;实测值735.0967。
步骤6:4,4'-(丁烷-1,4-二基双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C42)的制备
将89mg化合物43(0.12mmol)、1mL甲醇和1mL四氢呋喃加入到25mL反应瓶中,加入400μL 2N NaOH水溶液,所得反应混合物在55℃下搅拌1h。TLC检测(石油醚:乙酸乙酯=4:1,v/v)原料反应完全后,反应液浓缩,所得残余物用1N HCl调节pH至2~3,再用10mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩得粗品。粗品经硅胶柱层析(二氯甲烷:甲醇=30:1,v/v)纯化得化合物C42 59mg,淡黄色固体,收率73%。
1H NMR(300MHz,DMSO-d6):δ=12.24(s,2H),8.41(s,2H),8.37(s,2H),7.56(s,2H),3.86(s,6H),3.15(t,J=6.3Hz,4H),2.71-2.67(m,4H),2.60(t,J=6.1Hz,4H),1.71-1.66(m,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.20,173.11,149.49,143.05,137.39,135.45,133.94,111.93,109.13,108.41,56.47,37.18,30.21,29.99,29.72ppm。HRMS(ESI–):计算值C30H29O8Se2 -,(M-H)-,677.0198;实测值677.0195。
实施例44 4,4'-(丙烷-1,3-二基双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C43)的制备
参照实施例43所述制备方法,将(4-溴丁氧基)叔丁基二甲基硅烷替换为(3-溴丙氧基)叔丁基二甲基硅烷,以相同的合成方法制备得到化合物C43。
1H NMR(300MHz,DMSO-d6):δ=12.24(s,2H),8.40(s,2H),8.37(s,2H),7.53(s,2H),3.85(s,6H),3.20(t,J=5.9Hz,4H),2.71(t,J=7.0Hz,4H),2.61(t,J=6.1Hz,4H),2.30(t,J=5.8Hz,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.02,173.64,149.55,143.94,137.06,135.60,133.12,112.83,109.94,107.14,56.86,37.83,29.61,29.39,28.33ppm。HRMS(ESI–):计算值C29H27O8Se2 -,(M-H)-,663.0042;实测值663.0038。
实施例45 4,4'-(戊烷-1,5-二基双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸)(C44)的制备
参照实施例43所述制备方法,将(4-溴丁氧基)叔丁基二甲基硅烷替换为(5-溴戊氧基)叔丁基二甲基硅烷为反应物,以相同的合成方法制备得到化合物C44。1H NMR(300MHz,DMSO-d6):δ=12.23(s,2H),8.43(s,2H),8.36(s,2H),7.52(s,2H),3.86(s,6H),3.17(t,J=5.9Hz,4H),2.68(t,J=7.1Hz,4H),2.61(t,J=6.0Hz,4H),1.69-1.60(m,4H),1.45-1.36(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=193.74,173.12,149.89,143.22,137.28,134.14,133.33,111.50,110.06,108.09,56.91,37.62,30.95,29.80,29.03,28.17ppm。HRMS(ESI–):计算值C31H31O8Se2 -,(M-H)-,691.0355;实测值691.0353。
实施例46 4-(5-(4-(2-(4-乙氧基-4-氧代丁酰基)-6-甲氧基苯并[b]硒吩-5-基)丁氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸(C45)的制备
步骤1:4-(5-(4-(2-(4-乙氧基4-氧代丁酰基)-6-甲氧基苯并[b]硒吩-5-基)丁氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸乙酯(44)的制备
将100mg化合物15n(0.28mmol)、89mg化合物40(0.19mmol)、116mg K2CO3(0.84mmol)、5mg KI(0.028mmol)、7mg 18-冠醚-6(0.028mmol)和4mL DMF一起加入到25mL反应瓶中,所得反应液在50℃下搅拌8h。TLC检测(石油醚:乙酸乙酯=1:1,v/v)原料反应完全后,加水20mL,用8mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=2:1,v/v)纯化得化合物44 115mg,黄色固体,收率81%。
1H NMR(300MHz,CDCl3):δ=8.07(s,1H),8.05(s,1H),7.97(s,1H),7.34(s,1H),7.28(s,1H),7.26(s,1H),4.11-4.03(m,2H),3.96(s,3H),3.94(s,3H),3.15(t,J=6.1Hz,4H),2.73(t,J=6.5Hz,2H),2.58(t,J=5.8Hz,4H),1.83-1.71(m,4H),1.20(t,J=7.3Hz,6H)ppm。HRMS(ESI+):计算值C34H39O9Se2 +,(M+H)+,751.0919;实测值751.0920。
步骤2:4-(5-(4-(2-(4-乙氧基-4-氧代丁酰基)-6-甲氧基苯并[b]硒吩-5-基)丁氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸(C45)的制备
将115mg化合物44(0.15mmol)、1.5mL甲醇和1.5mL四氢呋喃加入到25mL反应瓶中,加入500μL 2N NaOH水溶液,所得反应混合物在55℃下搅拌1h。TLC检测(石油醚:乙酸乙酯=2:1,v/v)原料反应完全后,反应液浓缩,所得残余物用1N HCl调节pH至2~3,用10mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩得粗品。粗品经硅胶柱层析(二氯甲烷:甲醇=30:1,v/v)纯化得化合物C45 69mg,淡黄色固体,收率66%。1H NMR(300MHz,DMSO-d6):δ=12.25(s,2H),8.43(s,1H),8.40(s,1H),8.38(s,1H),7.71(s,1H),7.62(s,1H),7.60(s,1H),4.10(t,J=5.5Hz,2H),3.84(s,3H),3.83(s,3H),3.18(t,J=5.9Hz,4H),2.72(t,J=7.0Hz,2H),2.59(t,J=6.0Hz,4H),1.82-1.70(m,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.75,176.84,158.91,149.17,147.52,141.56,138.71,138.24,133.14,131.79,131.22,126.55,126.16,112.25,110.07,108.09,69.22,56.16,55.70,37.89,30.08,29.46,29.07,26.20ppm。HRMS(ESI–):计算值C30H29O9Se2 -,(M-H)-,693.0147;实测值693.0144。
实施例47 4-(5-(4-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]硒吩-5-基)氨基)丁基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸(C46)的制备
参照实施例46所述制备方法,以化合物15o替换化合物15n为反应物,以相同的合成方法制备得到化合物C46。1H NMR(300MHz,DMSO-d6):δ=12.25(s,2H),8.44(s,1H),8.42(s,1H),8.39(s,1H),7.73(s,1H),7.61(s,1H),7.60(s,1H),6.98(t,J=8.3Hz,1H),3.84(s,3H),3.83(s,3H),3.34-3.27(m,2H),3.17(t,J=6.2Hz,4H),2.70(t,J=7.0Hz,2H),2.60(t,J=6.0Hz,4H),1.68-1.61(m,4H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.80,176.60,158.89,149.36,147.59,141.35,138.31,138.11,133.17,131.81,131.16,126.56,126.36,112.76,110.92,108.35,56.14,55.47,43.76,37.61,30.53,29.75,29.69,26.37ppm。HRMS(ESI–):计算值C30H30NO8Se2 -,(M-H)-,692.0307;实测值692.0309。
实施例48 4-(5-(3-((2-(3-羧基丙酰基)-6-甲氧基苯并[b]硒吩-5-基)氨基)丙氧基)-6-甲氧基苯并[b]硒吩-2-基)-4-氧代丁酸(C47)的制备
参照实施例1和2所述的制备方法,将一分子中间体15a和一分子中间体15o通过1,3-二溴丙烷连接制备得到化合物C47。
1H NMR(300MHz,DMSO-d6):δ=12.21(s,2H),8.43(s,1H),8.42(s,1H),7.69(s,1H),7.67(s,1H),7.62(s,1H),7.60(s,1H),6.95(t,J=8.0Hz,1H),4.11(t,J=5.7Hz,2H),3.85(s,3H),3.83(s,3H),3.39-3.25(m,2H),3.19(t,J=6.1Hz,4H),2.58(t,J=6.0Hz,4H),2.05-2.00(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.97,176.32,158.88,149.79,147.80,141.92,138.64,138.35,133.13,131.29,131.07,127.27,126.91,112.63,110.21,108.48,67.58,56.05,55.22,43.34,37.89,29.70,28.74ppm。HRMS(ESI–):计算值C29H28NO9Se2 -,(M-H)-,694.0100;实测值694.0098。
实施例49 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酸-1,1,1-三氟-2-丙醇酯)(C49)的制备
将100mg化合物C1(0.14mmol)、66mg 1,1,1-三氟-2-丙醇(0.58mmol)、89mg DCC(N,N'-二环己基碳二亚胺,0.43mmol)、3.5mg DMAP(4-二甲氨基吡啶,0.029mmol)和3mL二氯甲烷加入到25mL反应瓶中,所得混合物在室温下搅拌8h。TLC检测(二氯甲烷:甲醇=10:1,v/v)原料反应完全后,加入9mL二氯甲烷稀释,抽滤,滤液浓缩。向所得残余物中加入6mL乙酸乙酯并置于冰浴中放置10min,抽滤,滤液浓缩后通过硅胶柱层析(石油醚:乙酸乙酯=2:1,v/v)纯化得化合物C49 80mg,淡黄色固体,收率63%。
1H NMR(300MHz,DMSO-d6):δ=8.43(s,2H),7.69(s,2H),7.56(s,2H),5.16-5.05(m,2H),4.32-4.14(m,4H),3.85(s,6H),3.14-3.06(m,4H),2.62-2.52(m,4H),2.38–2.16(m,2H),1.40(d,J=7.8Hz,6H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.36,171.25,150.23,147.46,145.84,137.02,135.03,134.21,110.80,108.28,70.53,67.46,56.57,37.50,30.35,30.12,16.99ppm。HRMS(ESI+):计算值C35H35F6O10Se2 +,(M+H)+,889.0459;实测值889.0462。
实施例50 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(4-氧代丁酰胺)(C50)的制备
将100mg化合物C1(0.14mmol)、44mg N-甲基吗啉(0.43mmol)和3mL四氢呋喃加入到25mL反应瓶中,并于冰浴下滴加59mg氯甲酸异丁酯(0.43mmol),滴加完毕后,转移至室温下搅拌1h。再次在冰浴下滴加0.1mL氨水,所得反应液在室温下搅拌4h。TLC检测(二氯甲烷:甲醇=10:1,v/v)原料反应完全后,加入15mL水并用10mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后,将所得残余物通过硅胶柱层析(石油醚:乙酸乙酯=1:1,v/v)纯化得到化合物C50 74mg,黄色固体,收率74%。1H NMR(300MHz,DMSO-d6):δ=8.42(s,2H),7.70(s,2H),7.56(s,2H),4.22(t,J=5.8Hz,4H),3.84(s,6H),3.13(t,J=6.1Hz,4H),2.42(t,J=6.3Hz,4H),2.32–2.22(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=194.90,175.41,150.35,147.10,145.47,137.64,135.91,134.35,109.92,108.75,67.36,56.81,37.66,33.98,30.13ppm。HRMS(ESI+):计算值C29H31N2O8Se2 +,(M+H)+,695.0405;实测值695.0405。
实施例51 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(N-羟基-4-氧代丁酰胺)(C51)的制备
将100mg化合物C1(0.14mmol)、164mg HATU(O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯,0.43mmol)、130mg N,N-二异丙基乙胺(1.01mmol)和3mL DMF加入到25mL反应瓶中,所得混合物在室温下搅拌30min。随后加入40mg盐酸羟胺(0.58mmol),室温下继续搅拌4h。TLC检测(二氯甲烷:甲醇=10:1,v/v)原料反应完全后,向反应液中加入15mL水,用10mL乙酸乙酯萃取三次。合并有机相,经水洗、饱和食盐水洗、无水硫酸钠干燥、抽滤、浓缩后得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯=1:1,v/v)纯化得化合物C5149mg,淡黄色固体,收率47%。
1H NMR(300MHz,DMSO-d6):δ=8.45(s,2H),7.70(s,2H),7.57(s,2H),4.22(t,J=5.9Hz,4H),3.83(s,6H),3.10(t,J=6.0Hz,4H),2.38(t,J=6.2Hz,4H),2.31–2.22(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=195.18,172.93,150.44,147.97,145.86,137.00,135.01,134.96,109.65,108.64,67.51,56.28,37.79,30.86,30.03ppm。HRMS(ESI+):计算值C29H31N2O10Se2 +,(M+H)+,727.0304;实测值727.0308。
实施例52 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(N-甲氧基-4-氧代丁酰胺)(C52)的制备
参照实施例51所述的制备方法,将原料盐酸羟胺替换为甲氧基胺盐酸盐,以相同的合成方法制备得到化合物C52。1H NMR(300MHz,DMSO-d6):δ=11.08(s,2H),8.47(s,2H),7.71(s,2H),7.55(s,2H),4.23(t,J=5.9Hz,4H),3.82(s,6H),3.57(s,6H),3.11(t,J=6.0Hz,4H),2.35(t,J=6.2Hz,4H),2.33–2.24(m,2H)ppm。13C NMR(75MHz,DMSO-d6):δ=197.20,174.68,152.02,147.66,144.79,138.69,136.91,133.50,109.43,107.28,67.77,56.21,59.34,38.07,31.72,28.54ppm。HRMS(ESI+):计算值C31H35N2O10Se2 +,(M+H)+,755.0617;实测值755.0622。
实施例53 4,4'-((丙烷-1,3-二基双(氧基))双(6-甲氧基苯并[b]硒吩-5,2-二基))双(1-((异丙基氨基)氧基)丁烷-1,4-二酮)(C53)的制备
参照实施例51所述的制备方法,将原料盐酸羟胺替换为N-异丙基羟胺盐酸盐,以相同的合成方法制备得到化合物C53。1H NMR(300MHz,DMSO-d6):δ=8.41(s,2H),7.71(s,2H),7.59(s,2H),4.22(t,J=6.1Hz,4H),3.85(s,6H),3.15(m,2H),3.09(t,J=6.3Hz,4H),2.45(t,J=6.1Hz,4H),2.30–2.23(m,2H),0.99(d,J=6.3Hz,12H)ppm。
13C NMR(75MHz,DMSO-d6):δ=199.07,173.56,150.17,148.82,138.71,137.65,134.53,132.18,111.30,108.69,67.34,56.18,51.99,37.26,30.30ppm。HRMS(ESI+):计算值C35H43N2O10Se2 +,(M+H)+,811.1243;实测值811.1248。
实施例54基于THP1-Lucia、RAW-Lucia荧光素酶报告基因实验
将THP1-dualTM(Invivogen:thpd-nfis)细胞或RAW-LuciaTM(Invivogen:rawl-isg)细胞使用培养基稀释并吸取180μL细胞悬液接种于96孔板,使得每孔含有1×105个细胞。随后将待测化合物20μL加入到96孔板中(化合物终浓度为10μM,每孔终体积为200μL)并于37℃下孵育24h。随后吸取10μL上清液至新的96孔白板中,并加入50μL QUANT-Luc试剂(Invivogene:rep-qlc1,rep-qlc2)。充分混匀后立刻使用酶标仪进行测定。实验设置3个复孔。空白孔为细胞培养介质,阴性孔中加入二甲基亚砜DMSO。测试结果以激动倍数(fold)表示,通过(测试孔-空白孔)/(阴性孔-空白孔)计算得到。
测试结果如下表4所示,以2',3'-cGAMP作为阳性对照,2',3'-cGAMP是STING蛋白的内源性配体,是公认的高活性STING激动剂。其中***表示激动倍数在20倍以上,**表示激动倍数在10~20倍,*表示激动倍数在1~10倍。
表4本发明化合物荧光素酶报告基因实验激动活性
化合物作用于细胞后,引起荧光素酶表达量相对于阴性对照的倍数,可以反映化合物对cGAS-STING通路的激活能力。从表4可以看出,本发明化合物在荧光素酶报告基因实验中激活cGAS-STING通路的相对激动倍数在1~20倍及以上,因此具有较好的cGAS-STING通路激动活性,可为制备激活cGAS-STING通路类药物提供依据。
实施例55基于THP1细胞的干扰素β诱导实验
分泌细胞因子IFNβ通过酶联免疫实验(ELISA)测定。将THP1细胞接种于96孔板中(RPMI 1640培养基不含血清),使每孔细胞数量为5~7×105个。待测化合物配制成10mMDMSO储存液,并用培养基稀释至目标浓度加入到含有细胞的96孔板中(使化合物终浓度为20μM,每孔终体积为200μL),并在37℃,5% CO2环境中孵育3.5h。随后收集细胞于4℃,1000rpm离心20分钟,收集上清液进行ELISA测定。实验设置3个复孔。
结果如下表5所示,以2',3'-cGAMP作为阳性对照,测试结果以相对于20μM浓度的2',3'-cGAMP的活性百分比表示。
表5本发明化合物对THP1细胞中IFNβ诱导分泌
由表5可见,本发明代表化合物对诱导THP1细胞分泌IFNβ具有较好活性,可为制备预防和/或治疗STING相关疾病药物,或与免疫检查点抑制剂联用用于制备抗肿瘤药物提供依据。如上所述,尽管参照特定的优选实施例已经表示和表述了本发明,但其不得解释为对本发明自身的限制。在不脱离所附权利要求定义的本发明的精神和范围前提下,可对其在形式上和细节上作出各种变化。
Claims (10)
1.一种通式I的化合物或其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药:
其中,
L1和L3相同或不同,且各自独立地选自C(R5)2、NR5、O或S;
L2选自C1~C6亚烷基、R6取代的C1~C6亚烷基、C1~C6亚烷基-L4-C1~C6亚烷基、C2~C6亚烯基、C2~C6卤代亚烯基、C2~C6亚炔基、C2~C6卤代亚炔基、C3~C6环烷基或3~6元杂环基;
L4选自O、S、C(O)、C(O)NR5、S(O)、S(O)2、S(O)2NR5、C3~C6环烷基或3~6元杂环基;
X1和X4选自C(O);
X2和X5选自(C(R7)2)p;
X3和X6相同或不同,且各自独立地选自COOR5、C(O)N(R5)2、C(O)NR5OR5、C(O)ON(R5)2、SO2R5、S(O)NR5或C(CF3)2OR5;
A1选自Se、S、O或NH;
R1和R2相同或不同,且各自独立地选自氢、卤素、氰基、硝基、OR5、SR5、N(R5)2、COOR5、C(O)N(R5)2、C1~C6烷基、C1~C6卤代烷基、OR5取代的C1~C6烷基、N(R5)2取代的C1~C6烷基、C2~C6烯基、C2~C6卤代烯基、C2~C6炔基、C2~C6卤代炔基、C3~C6环烷基或3~6元杂环基;
R3和R4相同或不同,且各自独立地选自氢、卤素、氰基、OR5、N(R5)2、C1~C6烷基、C1~C6卤代烷基或C3~C6环烷基;
R5选自氢、C1~C6烷基、C1~C6卤代烷基、C3~C6环烷基、3~6元杂环基或C5~C10芳基;
R6选自氢、卤素、OR5、N(R5)2、C1~C6烷基、C1~C6卤代烷基、C3~C6环烷基或3~6元杂环基;
R7选自氢、卤素、氰基、OR5、N(R5)2、C1~C6烷基、C1~C6卤代烷基、OR5取代的C1~C6烷基或C3~C6环烷基;
任选地,不同碳原子上的2个R7可以与它们之间的碳原子一起形成C3~C6环烷基或3~6元杂环基;
任选地,相同碳原子上的2个R7可以与它们共同连接的碳原子一起形成C3~C6环烷基或3~6元杂环基;
m和n各自独立地选自0、1、2和3;
p选自1、2和3。
3.根据权利要求2所述的化合物,其特征在于:
L1和L3相同或不同,且各自独立地选自CH2、NH或O;
L2选自C1~C6亚烷基、R6取代的C1~C6亚烷基、C1~C4亚烷基-L4-C1~C4亚烷基、C2~C4亚烯基、C2~C4卤代亚烯基、C2~C4亚炔基、C2~C4卤代亚炔基、C3~C6环烷基或3~6元杂环基;
L4选自O、S、C(O)、C3~C6环烷基或3~6元杂环基;
X1和X4选自C(O);
X2和X5选自(C(R7)2)p;
X3和X6相同或不同,且各自独立地选自COOR5、C(O)N(R5)2、C(O)NR5OR5或C(O)ON(R5)2;
A1选自Se或S;
R1和R2相同或不同,且各自独立地选自氢、卤素、C1~C3烷基、C1~C3卤代烷基、-O-C1~C3烷基、-O-C1~C3卤代烷基或OH;
R3和R4相同或不同,且各自独立地选自氢、氟或C1~C3烷基;
R5选自氢、C1~C3烷基、C1~C3卤代烷基、C3~C6环烷基、3~6元杂环基或C5~C10芳基;
R6选自氢、氟、OH、NH2、C1~C4烷基、C1~C4卤代烷基、C3~C6环烷基或3~6元杂环基;
R7选自氢、氟、-O-C1~C3烷基、C1~C4烷基、C1~C4卤代烷基、-O-C1~C3烷基取代的C1~C4烷基或C3~C6环烷基;
任选地,不同碳原子上的2个R7可以与它们之间的碳原子一起形成C3~C6环烷基或3~6元杂环基;
任选地,相同碳原子上的2个R7可以与它们共同连接的碳原子一起形成C3~C6环烷基或3~6元杂环基;
p选自1、2和3。
4.根据权利要求3所述的化合物,其特征在于:
L2选自C2~C5亚烷基、R6取代的C2~C5亚烷基或C1~C4亚烷基-L4-C1~C4亚烷基;
L4选自O或C(O);
X3和X6相同或不同,且各自独立地选自COOH、COOCH3、COOCH2CH3、C(O)NH2、C(O)NHOH、C(O)NHOCH3或C(O)ONHCH(CH3)2;
R1和R2相同或不同,且各自独立地选自氢、氟、氯、CH3、CH2CH3、OCH3、OCH2CH3、OCH(CH3)2或OCHF2;
R3和R4选自氢;
R6选自氢、氟、CH3、CH2CH3、OH或环丙基;
R7选自氢、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、CH2OCH3或环丙基;
p=2。
5.根据权利要求4所述的化合物,其特征在于:
X2和X5选自CHR7CHR7;
X3和X6选自COOH。
6.根据权利要求4所述的化合物,其特征在于:
X2和X5选自CH2C(R7)2;
X3和X6选自COOH。
8.一种药物组合物,其特征在于:包括权利要求1-7任一项所述的化合物或其药学上可接受的盐、异构体、代谢产物、溶剂合物或前药以及药学上可接受的载体或赋形剂。
9.根据权利要求1-7任一项所述的化合物在制备激活cGAS-STING通路类药物中的用途。
10.根据权利要求1-7任一项所述的化合物在制备预防和/或治疗STING相关疾病药物中的用途。
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