CN113698395A - 转化生长因子受体拮抗剂、其制备方法和应用 - Google Patents
转化生长因子受体拮抗剂、其制备方法和应用 Download PDFInfo
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- CN113698395A CN113698395A CN202010439100.XA CN202010439100A CN113698395A CN 113698395 A CN113698395 A CN 113698395A CN 202010439100 A CN202010439100 A CN 202010439100A CN 113698395 A CN113698395 A CN 113698395A
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- ANUZKYYBDVLEEI-UHFFFAOYSA-N butane;hexane;lithium Chemical compound [Li]CCCC.CCCCCC ANUZKYYBDVLEEI-UHFFFAOYSA-N 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
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- 230000024245 cell differentiation Effects 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
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- 150000002466 imines Chemical class 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
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- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-L malate(2-) Chemical compound [O-]C(=O)C(O)CC([O-])=O BJEPYKJPYRNKOW-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- 230000006510 metastatic growth Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- JZFLATQBIPILFS-UHFFFAOYSA-N methyl 4-bromopyridine-2-carboxylate Chemical compound COC(=O)C1=CC(Br)=CC=N1 JZFLATQBIPILFS-UHFFFAOYSA-N 0.000 description 1
- PKAHQJNJPDVTDP-UHFFFAOYSA-N methyl cyclopropanecarboxylate Chemical compound COC(=O)C1CC1 PKAHQJNJPDVTDP-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
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- 238000010791 quenching Methods 0.000 description 1
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- 239000011541 reaction mixture Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
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- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
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- ZZRPJWCNCLSOLR-UHFFFAOYSA-N trimethyl(prop-2-ynoxy)silane Chemical compound C[Si](C)(C)OCC#C ZZRPJWCNCLSOLR-UHFFFAOYSA-N 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及一种转化生长因子β受体的小分子拮抗剂,制备该小分子拮抗剂的方法,以及所述小分子拮抗剂在制备药物方面的应用。本发明的转化生长因子β受体的小分子拮抗剂具有治疗和/或预防由ALK5介导的多种疾病的用途,具有极大的临床应用潜力。
Description
技术领域
本发明涉及医药化学领域,具体涉及一种转化生长因子β受体的小分子拮抗剂,制备该小分子拮抗剂的方法,以及所述小分子拮抗剂在制备药物方面的应用。
背景技术
转化生长因子-β(transforming growth factorβ,TGF-β)是一种多功能细胞因子,以自分泌、旁分泌和内分泌的方式通过细胞表面复杂的受体信号传导途径参与调节细胞的增殖,分化和凋亡。TGF-β通路由超过33个TGF-β超家族游离配体和13个TGF-β跨膜激酶受体组成。根据下游信号转导所涉及的效应分子的不同,又分为基于Smad的经典途径和非经典途径两类。TGF-β具有至少3种亚型,分别为I型、II型和III型受体。I型和II型受体是跨膜丝氨酸/苏氨酸激酶,二者同时传导信息,III型受体不传递信息,功能主要是将TGF-β传递给II型受体,通过为受体II提供配体而间接地影响信号传导。
研究表明,异常的TGF-β信号和许多种疾病相关,比如癌症、肾纤维化、肝纤维化、肺纤维化、病毒感染、慢性肾炎、急性肾炎、糖尿病肾病、骨质疏松症、关节炎、伤口愈合、溃疡、角膜创伤、心脏瓣膜狭窄、充血性心脏坏死、神经功能损伤、阿尔兹海默综合征、腹膜或皮下粘连、动脉硬化症和肿瘤转移生长等;而TGF-β信号通路中的重要节点TGF-βR1(ALK5)是治疗这些疾病的理想靶点,通过抑制ALK5对其下游信号Smad2或Smad3的磷酸化,阻断或部分阻断TGF-β信号向细胞内的传播,从而纠正异常的TGF-β信号,可以治疗和预防各种ALK5介导的疾病(Nat Rev Drug Discov.2012October,11(10):790-811;Pharmacology&Therapeutics 147(2015)22-31)。
在肿瘤发生过程中,TGF-β通路与肿瘤相关的功能是复杂的。在癌前细胞中抑制肿瘤,而在恶化的癌细胞中促进肿瘤。一方面,在癌变过程中,TGF-β突变不断积累,失去了抑制肿瘤增殖的作用,癌变的细胞不再触发凋亡。另一方面,在特定肿瘤微环境中,如一些消化道癌,TGF-β相关基因表达上调,创造了一种免疫抑制性肿瘤微环境,促进癌细胞的进展和转移。
本发明人意外的发现了一类新的杂环化合物,可作为TGF-β受体拮抗剂,具有治疗和/或预防由ALK5介导的多种疾病的用途。
发明内容
本发明的目的之一是提供一种新的转化生长因子-β的I型受体拮抗剂,具体的,本发明提供式I结构的化合物,其异构体、混合物、溶剂合物、水合物、前药或其药学上可接受的盐:
L1选自O、NH;
L2选自不存在或NH;
R1选自不存在或五元杂芳环,所述五元杂芳环包含1-4个选自N、O或S的杂原子,并且R1不为1-甲基吡唑基;在某些具体的实施方案中,R1为噁唑基,其中,所述噁唑基可选择的被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、硝基、环烷基、酰胺基中的一个或多个基团取代;在某些具体的实施方案中,所述噁唑基为噁唑-2-基,所述噁唑-2-基可选择的被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、硝基、环烷基、酰胺基中的一个或多个基团取代;在某些具体的实施方案中,所述噁唑-2-基被1-羟基-1甲基乙基-1-基取代;
R2选自乙基、叔丁基、四氢吡喃-4-基、四氢呋喃-3-基、环丙基或环丁基;
R3选自环丙基、乙基、异丙基、CHF2、CH2CHF2、CH2CF3;
R4选自F、Cl、H;
X1、X2、X3各自独立的选自CH、N,且X1与X2不同时为N,X2与X3不同时为N;
X4选自N、-CRa,其中,Ra选自H、烷基、烯基、炔基、烷氧基、羟烷基、羟基取代的炔基、羟基取代的烯基、C3-C6环烷基、C3-C6环烯基、C3-C6杂环基;在某些具体的实施方案中,Ra选自H、-C≡CCH2OH、-CH2CH2CH2OH、-CH2CH2CH(CH3)OH、
在某些具体的实施方案中,本发明所述式I化合物具有如下式II的结构:
其中,R1、R2、R3、R4与前述定义相同。
在某些具体的实施方案中,本发明所述式I化合物具有如下式III的结构:
其中,R2、R3、R4及X1均与前述定义相同。
在某些具体的实施方案中,本发明所述式I化合物具有如下式IV的结构:
其中,R2、R3、X4与前述定义相同。
在某些具体的实施方案中,前述R2取代基选自四氢吡喃-4-基;R3取代基选自环丙基。
在某些具体的实施方案中,本发明所述式III化合物中X1为CH;R4为F。
在某些具体的实施方案中,本发明所述式IV化合物中X4为-CRa,其中Ra选自H、烷基、烯基、炔基、烷氧基、羟烷基、羟基取代的炔基、羟基取代的烯基、C3-C6环烷基、C3-C6环烯基、C3-C6杂环基;在某些具体的实施方案中,Ra选自H、-C≡CCH2OH、-CH2CH2CH2OH、-CH2CH2CH(CH3)OH、
在某些具体的实施方案中,本发明所述化合物具有如下所示的化学结构:
本发明的化合物包括其所有异构体(如构象异构体、互变异构体、对映异构体等)、混合物、溶剂合物、水合物、前药或其药学上可接受的盐。
本发明的另一目的是提供一种药物组合物,其包含治疗有效剂量的本发明所述的一种或多种转化生长因子受体拮抗剂,以及药学上可接受的辅料。
本发明的再一目的是提供所述化合物或药物组合物在制备治疗、预防或减少由TGF-β过度表达介导的疾病的药物中的应用。其中,所述TGF-β过度表达介导的疾病包括:癌症、肾纤维化、肝纤维化、肺纤维化、病毒感染、慢性肾炎、急性肾炎、糖尿病肾病、骨质疏松症、关节炎、伤口愈合、溃疡、角膜创伤、心脏瓣膜狭窄、充血性心脏坏死、神经功能损伤、阿尔兹海默综合征、腹膜或皮下粘连、动脉硬化症和肿瘤转移生长等。
本发明进一步提供一种通式III化合物的制备方法,如下所示:
含有R2基团的羰基化合物3a可根据实际需求通过商业渠道购买,或使用商购试剂原料并通过本领域常规技术合成得到。通常,含有R2基团的羰基化合物3a可与肼基甲酸叔丁酯经还原胺化生成诸如3b的化合物。此反应可先于醇类溶剂(诸如甲醇、乙醇)中生成亚胺中间体,再使用诸如于醋酸/水中的还原剂(诸如氰基硼氢化钠)完成还原胺化反应。诸如3b的化合物可通过用酸(诸如TFA或稀HCl)处理而经脱保护生成化合物3c。诸如3c的化合物至诸如3d的化合物的环化作用可在醇类溶剂中缩合得到。诸如3d的化合物至诸如3e的化合物的反应可在各种条件(包括取决于L1的原子类型的缩合或金属偶联)下完成。诸如3e的化合物可与3f经金属偶联反应生成通式III化合物(诸如钯)。
本发明进一步提供一种通式IV化合物的制备方法:
化合物4a可购买或合成。通常,化合物4a的NH与OH可被对甲苯磺酰氯双保护,再经弱碱条件下解离生成诸如4b的化合物。诸如4b的化合物可通过用溴苄保护生成化合物4c。诸如4c的化合物在金属试剂的作用下与卤素反应生成化合物4d。诸如4d的化合物的脱保护可在BBr3的作用下完成。诸如4e的化合物与含有R2取代的α-卤代酮在碱的作用下经亲核取代生成诸如4f的化合物。诸如4f的化合物与DMF-DMA经亲核取代生成诸如4g的化合物。诸如4g的化合物的环化作用可与水合肼在弱酸类溶剂中缩合得到。诸如4h的化合物可与含有R3的硼酸化物经金属偶联反应生成诸如4i的化合物。诸如4i的化合物可与含有Ra的炔经金属偶联反应生成诸如4j的化合物。诸如4j的化合物经脱保护得到通式IV化合物。
具体实施方式
术语定义
“烷基”是指直链或含支链的饱和脂族烃基,比如甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基及它们的各种异构体。
“烯基”是指含有指定数目碳原子和至少一个碳碳双键的直链、支链或环状非芳香烃基。
“炔基”是指含有指定数目碳原子和至少一个碳碳三键的直链或支链烃基。
“卤素”是指F、Cl、Br或I;“卤代”是指被选自F、Cl、Br或I的原子所取代。
“羟烷基”是指烷基基团被一个或多个羟基基团所取代,其中烷基基团具有如本发明所述的定义,这样的实例包括,但并不限于羟乙基,2-羟基丙基,羟甲基,1-羟基-1甲基乙基-1-基等。
“环烷基”指饱和或部分不饱和的单环或多环环状烃取代基。例如,“C3-6环烷基”指包括3至6个碳原子的环烷基,典型的C3-6环烷基包括但不限于:环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基等。
“环烯基”是指至少含有一个碳碳双键的环状烃取代基(非芳香族),例如“C3-C6环烯基”是指具有3至6个环原子,且至少含有一个碳碳双键的环状烃基,但不是芳香族。
“烷氧基”是指通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基,“烷氧基”包含以上烷基和环烷基的定义。例如,“C1-4烷氧基”是指通过氧桥链接的具有1至4个碳原子的环状或非环状烷基,典型的C1-4烷氧基包括但不限于:-OMe、-OEt、-O-环烷基等。
“杂环基”是指饱和或部分不饱和的单环或多环状烃取代基,其中一个或多个环原子被选自N、O、S的杂原子取代,其余环原子为碳。例如:“C3-6杂环基”是指包括3至6个环原子的环基,包括但不限于:吡咯烷基、呋喃基、哌啶基、哌嗪基、吗啉基等。
“五元杂芳环”是指含有5个环原子的单杂芳环,其中包含一个或多个杂原子。例如:呋喃、吡咯、噻吩、咪唑、吡唑、三氮唑、四氮唑、恶唑、异噁唑、噻唑等。
“硝基”是指-NO2;
“羟基”是指-OH;
“氰基”是指-CN。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构体、非对应异构体和几何异构体(或构象异构体));例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明所述“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。
本发明所述“水合物”是指本发明化合物与水进行配位形成的配合物。
本发明中所述“药学上可接受的盐”是指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。示例性的酸加成盐包括但不限于:盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、氢氟酸盐、甲酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苦味酸盐、甲磺酸盐、苯甲磺酸盐、苯磺酸盐、天冬氨酸盐、谷氨酸盐等。示例性的碱式盐包括但不限于:碱金属盐、碱土金属盐、有机胺盐等。
本发明中的的缩写均为本领域技术人员已知的,除另有说明外,均代表本领域所通知的含义。
下面通过举例说明本发明的化合物和中间体的合成方法,下述举例仅作为本发明的示例,而不应作为对本发明范围的限制。除特殊说明外,本发明中所涉及的原料和试剂均可通过商业化渠道获得。
本发明中的的缩写均为本领域技术人员已知的,除另有说明外,均代表本领域所通知的含义。例如:DMF是指N,N-二甲基甲酰胺;THF是指四氢呋喃;Me是指甲基。
下面通过举例说明本发明的化合物和中间体的合成方法,下述举例仅作为本发明的示例,而不应作为对本发明范围的限制。除特殊说明外,本发明中所涉及的原料和试剂均可通过商业化渠道获得。
制备例1:2-(4-氨基吡啶-2-基)丙-2-醇的制备
步骤1:2-(4-溴吡啶-2-基)丙-2-醇的制备
室温下,将甲基氯化镁溶液(15mL,3M in THF)加入到已装有温度计和恒压滴液漏斗的干燥的三口瓶中,冰盐浴下将体系温度降至-10℃左右,将4-溴吡啶甲酸甲酯(4.3g)溶于干燥的四氢呋喃(45mL)中缓慢滴入体系中,控制滴加速度使体系温度不超过20℃,滴加完毕,体系恢复至室温,搅拌反应30min,TLC监测反应完全。冰浴下,体系于搅拌下将1M氯化氢水溶液缓慢加入,调节体系pH至7左右(控制体系温度不超过20℃),加水淬灭,乙酸乙酯萃取,有机相用饱和氯化钠溶液反洗一次,无水硫酸钠干燥,浓缩。所得粗品经柱层析纯化得标题化合物3.8g。
MS(ESI)m/z(M+H)+=215.9.
步骤2:2-(4-氨基吡啶-2-基)丙-2-醇的制备
室温下,将2-(4-溴吡啶-2-基)丙-2-醇(645mg),铜粉(134mg),25%氨水(15mL)加入密封罐中,搅拌反应30min后,密封并移至100℃油浴中搅拌过夜,TLC监测反应完全。体系恢复至室温,反应液用硅藻土柱过滤,用乙酸乙酯冲洗至全部产物洗脱出来,滤液浓缩,将残余物溶于乙酸乙酯再用硅藻土柱过滤一次,合并滤液,浓缩,得标题化合物450mg。
MS(ESI)m/z(M+H)+=153.1.
制备例2:2-碘-4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯基-1H-吡咯并[2,3-b]吡啶的制备
步骤1:1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-醇的制备
氩气氛中,将4-羟基-7-氮杂吲哚(1.0g)溶于N,N-二甲基甲酰胺(10mL)中,体系用冰盐浴降温至0℃,缓慢加入氢化钠(0.75g)搅拌30分钟,分批加入对甲苯磺酰氯(3.55g);移去冰盐浴,体系恢复至室温反应2小时,LC-MS显示原料反应完全。体系用乙酸乙酯(50mL)稀释,水(50mL)洗涤一次,饱和氯化钠水溶液(50mL)洗涤一次,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得中间体粗品。中间体粗品用四氢呋喃/甲醇/水的混合溶液(20mL,V/V/V=10/3/3)溶解,加入氢氧化锂(0.54g),室温搅拌反应16小时,LC-MS显示中间体反应完全。体系减压浓缩得粗品,粗品经柱层析纯化得标题化合物1.7g。
MS(ESI)m/z(M+H)+=289.1.
1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.05(d,J=5.5Hz,1H),7.96(d,J=8.4Hz,2H),7.65(d,J=4.0Hz,1H),7.39(d,J=8.2Hz,2H),6.79(d,J=4.1Hz,1H),6.64(d,J=5.5Hz,1H),2.33(s,3H).
步骤2:4-(苄氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶的制备
室温下,将1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-醇(1.45g)溶于N,N-二甲基甲酰胺(20mL)中,依次加入溴化苄(1.03g)、碳酸钾(1.39g),反应16小时,LC-MS显示反应完全。体系用乙酸乙酯(50mL)稀释,水(50mL)洗涤一次,饱和氯化钠溶液(50mL)洗涤一次,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得粗品。粗品经柱层析纯化得标题化合物1.87g。
MS(ESI)m/z(M+H)+=379.1.
1H NMR(400MHz,DMSO-d6)δ8.23(d,J=5.6Hz,1H),7.96(d,J=8.4Hz,2H),7.73(d,J=4.0Hz,1H),7.49–7.45(m,2H),7.44–7.29(m,5H),6.98(d,J=5.7Hz,1H),6.80(d,J=4.0Hz,1H),5.31(s,2H),2.33(s,3H).
步骤3:4-(苄氧基)-2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶的制备
氩气氛中,将4-(苄氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(1.4g)溶于四氢呋喃(40mL)中,体系降温至-70℃,滴加丁基锂的正己烷溶液(2.5mol/mL,1.8mL),控制温度不超过-60℃,于-70℃下保温反应1小时;继续滴加碘(0.94g)的四氢呋喃溶液,滴毕,维持低温搅拌30分钟反应完全。将反应体系缓慢倒入冰水(50mL)中淬灭,乙酸乙酯(100mL)萃取,合并有机相,有机相用10%的亚硫酸氢钠水溶液(50mL)洗涤一次,无水硫酸钠干燥,过滤,滤液减压浓缩得粗品。粗品经柱层析纯化得标题化合物1.3g。
MS(ESI)m/z(M+H)+=505.0.
步骤4:2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-醇的制备
室温下,将4-(苄氧基)-2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(595mg)溶于二氯甲烷(10mL)中,缓慢滴加三溴化硼(887mg)的二氯甲烷溶液,搅拌反应16小时,LC-MS显示反应完全。体系用二氯甲烷(30mL)稀释,饱和碳酸氢钠水溶液(50mL)洗涤一次,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品380mg,粗品直接用于下一步反应。
MS(ESI)m/z(M+H)+=414.9.
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.00(d,J=5.5Hz,1H),7.90(d,J=8.3Hz,2H),7.40(d,J=8.0Hz,2H),7.15(s,1H),6.60(d,J=5.6Hz,1H),2.32(s,3H).
步骤5:2-((2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-1-(四氢-2H-吡喃-4-基)乙-1-酮的制备
将2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-醇(380mg)溶于N,N-二甲基甲酰胺(3mL)中,依次加入2-溴-1-(四氢-2H-吡喃-4-基)乙-1-酮(286mg)、碳酸钾(254mg),室温反应4小时,LC-MS显示原料反应完全。将体系用乙酸乙酯(50mL)稀释,水(50mL)洗涤一次,饱和氯化钠溶液(50mL)洗涤一次,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得粗品。粗品用柱层析纯化得标题化合物396mg。
MS(ESI)m/z(M+H)+=541.0.
1H NMR(400MHz,DMSO-d6)δ8.13(d,J=5.7Hz,1H),7.92(d,J=8.4Hz,2H),7.42(d,J=8.1Hz,2H),7.14(s,1H),6.68(d,J=5.8Hz,1H),5.22(s,2H),3.91–3.81(m,2H),3.39–3.30(m,2H),2.89–2.79(m,1H),2.34(s,3H),1.83–1.70(m,2H),1.58–1.42(m,2H).
步骤6:3-(二甲基氨基)-2-((2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-1-(四氢-2H-吡喃-4-基)丙-2-烯-1-酮的制备
室温下,将2-((2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-1-(四氢-2H-吡喃-4-基)乙-1-酮(530mg)溶于N,N-二甲基甲酰胺二甲基缩醛(5mL)中,体系升温至100℃,反应2小时,LC-MS显示反应完全。反应体系降温至室温,减压浓缩得粗品,直接用于下一步反应。
MS(ESI)m/z(M+H)+=596.1.
步骤7:2-碘-4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯基磺酰基-1H-吡咯并[2,3-b]吡啶的制备
室温下,将3-(二甲基氨基)-2-((2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)-1-(四氢-2H-吡喃-4-基)丙-2-烯-1-酮粗品(上一步反应按摩尔收率100%计)溶于乙酸(3mL)中,滴加水合肼(147mg),体系搅拌反应过夜,LC-MS显示反应完全。体系直接浓缩至干,乙酸乙酯(20mL)溶解,饱和碳酸氢钠水溶液(20mL)洗涤一次,有机相用无水硫酸钠(5g)干燥,过滤,滤液减压浓缩得粗品。粗品经柱层析纯化得标题化合物320mg。
MS(ESI)m/z(M+H)+=565.0.
实施例1:2-(4-((4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)氧基)吡啶-2-基)氨基)吡啶-2-基)丙-2-醇的制备
合成步骤如下所示:
步骤1:2-(四氢-2H-吡喃-4-基)肼-1-羧酸叔丁酯的制备
氮气氛中,将四氢-4H-吡喃-4-酮(5g),肼甲酸叔丁酯(7.3g)溶于甲醇(120mL)中,室温搅拌过夜,LC-MS监测反应完全。体系浓缩除去溶剂,加入水和冰醋酸(70mL/35mL),室温搅拌30min,体系由浑浊变澄清,继续分多次加入氰基硼氢化钠(3.15g),搅拌反应2h,LC-MS监测反应完全。冰浴下,将体系用1M氢氧化钠溶液调节pH至6~7,二氯甲烷萃取,合并有机相,无水硫酸钠干燥,过滤,浓缩,所得粗品经柱层析纯化,得标题化合物10.6g。
MS(ESI)m/z(M+H)+=159.0.(叔丁基断掉的碎片峰)
步骤2:(四氢-2H-吡喃-4-基)肼盐酸盐的制备
室温下,将2-(四氢-2H-吡喃-4-基)肼-1-羧酸叔丁酯(10.6g)溶于甲醇(100mL)中,缓慢滴加到盐酸1,4-二氧六环溶液中(25mL,4M),搅拌反应过夜,LC-MS监测反应完全。体系直接浓缩,得标题化合物9.1g。
MS(ESI)m/z(M+H)+=117.1.
步骤3:3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-醇的制备
室温下,将(四氢-2H-吡喃-4-基)肼盐酸盐(3.74g),3-环丙基-3-氧代丙酸乙酯(3.12g)加入到乙醇(100mL)中,体系升温至75℃,回流反应4h,TLC监测反应完全。体系冷却至室温,浓缩除去溶剂,所得粗品经柱层析纯化,得标题化合物2.3g。
MS(ESI)m/z(M+H)+=209.1.
步骤4:2-氯-4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)氧基)吡啶的制备
氮气氛中,将3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-醇(2.3g)加入到干燥的N,N-二甲基甲酰胺(30mL)中,冰浴下,分多次加入氢化钠(484mg,60%含量),低温搅拌20min,继续加入2-氯-4-氟吡啶(1.6g),体系升温至90℃,搅拌反应4h,TLC监测原料反应完毕。体系冷却至室温,加水淬灭,乙酸乙酯萃取,有机相用水反洗两次,无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化,得标题化合物1g。
MS(ESI)m/z(M+H)+=320.1.
步骤5:2-(4-((4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)氧基)吡啶-2-基)氨基)吡啶-2-基)丙-2-醇的制备
氮气氛中,将2-氯-4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)氧基)吡啶(100mg),2-(4-氨基吡啶-2-基)丙-2-醇(64mg),苯酚钠(60mg)加入1,4-二氧六环(5mL)中混合,继续加入三(二亚苄基丙酮)二钯(15mg),4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(19mg),再氮气置换2min,体系移至100℃搅拌反应4h,TLC监测反应完全。体系冷却至室温,硅藻土过滤,滤液浓缩,残余物经柱层析纯化得粗品120mg,粗品再经反相制备柱分离,得标题化合物56mg。
MS(ESI)m/z(M+H)+=436.2.
1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.23-8.21(dd,J=6.1,1.4Hz,2H),7.79–7.64(m,2H),6.70–6.68(dd,J=5.8,2.3Hz,1H),6.48(d,J=2.3Hz,1H),5.76(s,1H),5.11(s,1H),4.23–4.15(tt,J=11.4,4.2Hz,1H),3.99–3.88(m,2H),3.41–3.38(dd,J=12.1,2.0Hz,2H),2.04–1.95(m,2H),1.90–1.84(m,1H),1.74–1.69(m,2H),1.41(s,6H),0.90–0.85(m,2H),0.69–0.65(m,2H).
本领域技术人员可根据本领域一般知识,采用适宜的商品化试剂为原料,并参照上述实施例1的方法,制备得到以下示例性化合物,所述化合物的结构以及表征数据见下表:
实施例5:4-(1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡唑并[3,4-b]吡啶的制备
步骤1:1-(4-甲氧基苄基)-1H-吡唑-5-胺的制备
将丙烯腈(5.0g)溶于四氢呋喃(50mL)中,冰浴下,加入水合肼(4.95g),体系恢复至室温搅拌反应1h,继续加入对甲氧基苯甲醛(13.5g),搅拌反应1h;体系浓缩以除去四氢呋喃,加入丁醇(20mL)稀释,继续加入由丁醇(100mL)和钠(2.26g)配置好的丁醇钠溶液于80℃下搅拌反应3小时,TLC显示原料反应完全。体系加水(100mL)淬灭,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化,得标题化合物4.0g。
MS(ESI)m/z(M+H)+=204.1.
步骤2:2-((((1-(4-甲氧基苄基)-1H-吡唑-5-基)氨基)亚甲基)丙二酸二乙酯的制备
室温下,将1-(4-甲氧基苄基)-1H-吡唑-5-胺(2.5g)溶于1,4-二氧六环(40mL)中,加入2-(乙氧基亚甲基)丙二酸二乙酯(2.82g),体系升温至125℃,搅拌反应3h,TLC显示原料反应完全。体系加水(50mL)淬灭,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化得标题化合物2.96g。
MS(ESI)m/z(M+H)+=374.2.
步骤3:4-羟基-1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯的制备
室温下,将2-((((1-(4-甲氧基苄基)-1H-吡唑-5-基)氨基)亚甲基)丙二酸二乙酯(3.32g)溶于二苯醚(12mL)中,于250℃下微波反应3h,LCMS显示反应完全。体系加入石油醚(15mL),有固体析出,过滤,固体用石油醚洗涤两次,固体干燥,得标题化合物1.6g。
MS(ESI)m/z(M+H)+=328.1.
步骤4:4-羟基-1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-5-羧酸的制备
室温下,将4-羟基-1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-5-羧酸乙酯(1.6g)混悬于乙醇(10mL)中,体系升温至75℃,加入10%氢氧化钠溶液(10mL),搅拌反应1h,LCMS显示反应完全。体系用氯化氢溶液调节pH至1-2,有固体析出,过滤,固体用水洗涤两次,干燥得标题化合物2.3g。
MS(ESI)m/z(M+H)+=300.1.
步骤5:1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-4-醇的制备
室温下,将4-羟基-1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-5-羧酸(1.0g)混悬于二苯醚(10mL)中,体系升温至180℃微波反应1.5h,TLC显示原料反应完全。体系加水(10mL)淬灭,乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化,得标题化合物447mg。
MS(ESI)m/z(M+H)+=256.1.
步骤6:2-(1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-4-基)氧基)-1-(四氢-2H-吡喃-4-基)乙-1-酮的制备
室温下,将1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-4-醇(447mg)溶于干燥的N,N-二甲基甲酰胺(10mL)中,依次加入2-溴-1-(四氢-2H-吡喃-4-基)乙-1-酮(722mg),碳酸铯(1.14g)混匀,体系升温至90℃,搅拌反应2h,TLC显示原料消耗完毕。体系加水(20mL)淬灭,乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化,得标题化合物1.0g。
MS(ESI)m/z(M+H)+=382.2.
步骤7:1-(4-甲氧基苄基)-4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡唑并[3,4-b]吡啶的制备
1)(E)-3-(二甲基氨基)-2-((1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-4-基)氧基)-1-(四氢-2H-吡喃-4-基)丙-2-烯-1-酮的制备
室温下,将2-(1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-4-基)氧基)-1-(四氢-2H-吡喃-4-基)乙-1-酮(600mg)溶于1,1-二甲氧基-N,N-二甲基甲胺(4mL)中,体系升温至100℃,搅拌反应2h,TLC显示原料消耗完毕。体系加水(6mL)淬灭,乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,得标题化合物472mg。
MS(ESI)m/z(M+H)+=437.2.
2)1-(4-甲氧基苄基)-4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡唑并[3,4-b]吡啶的制备
室温下,将(E)-3-(二甲基氨基)-2-((1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-4-基)氧基)-1-(四氢-2H-吡喃-4-基)丙-2-烯-1-酮(472mg)溶于乙酸(4mL)中,冰浴下,加入水合肼(168mg),恢复至室温,搅拌反应8h,TLC显示原料消耗完毕。将体系倒入冰水中(20mL),乙酸乙酯萃取,有机相分别用水(30mL)、饱和碳酸氢钠溶液(30mL)、饱和氯化钠溶液(30mL)洗涤,合并有机相,无水硫酸钠干燥,浓缩,得标题化合物489mg。
MS(ESI)m/z(M+H)+=406.2.
步骤8:4-(1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶的制备
室温下,将醋酸铜(199mg)、联吡啶(85mg)溶于1,2-二氯乙烷(5mL)中,体系升温至75℃,搅拌反应25分钟;体系冷却至室温,依次加入1-(4-甲氧基苄基)-4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡唑并[3,4-b]吡啶(200mg)的1,2-二氯乙烷溶液、碳酸钠(105mg)、环丙基硼酸(85mg),体系升温至75℃,搅拌反应2h(反应需要氧气参与),TLC显示原料消耗完毕。体系加水(8mL)淬灭,乙酸乙酯萃取,无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化,得标题化合物122mg。
MS(ESI)m/z(M+H)+=446.2.
步骤9:4-(1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡唑并[3,4-b]吡啶的制备
室温下,将4-(1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶(52mg)溶于三氟乙酸(4mL)中,体系升温至70℃,搅拌反应1h,TLC显示原料消耗完毕。体系浓缩以除去三氟乙酸,用氯仿带酸2次,所得粗品经反相制备得标题化合物36mg。
MS(ESI)m/z(M+H)+=326.2.
1H NMR(400MHz,Methanol-d4)δ8.37(d,J=5.6Hz,1H),7.88(s,1H),7.78(s,1H),6.62(d,J=5.5Hz,1H),3.92(ddd,J=11.6,4.4,2.0Hz,2H),3.68(tt,J=7.3,3.8Hz,1H),3.41(td,J=11.8,2.3Hz,2H),2.85(tt,J=11.7,4.0Hz,1H),2.01–1.79(m,2H),1.74(ddt,J=13.0,4.3,2.2Hz,2H),1.26–0.85(m,4H).
实施例6:4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶的制备
步骤1:1-(四氢-2H-吡喃-4-基)-2-((1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)乙-1-酮的制备
室温下,将1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-醇(200mg)溶于N,N-二甲基甲酰胺(5mL)中,依次加入2-溴-1-(四氢-2H-吡喃-4-基)乙-1-酮(215mg),碳酸铯(451mg),体系升温至90℃,搅拌反应1.5h,TLC显示原料消耗完毕。体系加水(5mL)淬灭,乙酸乙酯萃取3次,饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化,得标题化合物450mg。
MS(ESI)m/z(M+H)+=415.1.
步骤2:4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶的制备1)(E)-3-(二甲基氨基)-1-(四氢-2H-吡喃-4-基)-2-((1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)丙-2-烯-1-酮的制备
室温下,将1-(四氢-2H-吡喃-4-基)-2-((1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)乙-1-酮(450mg)溶于1,1-二甲氧基-N,N-二甲基甲胺(4mL)中,体系升温至100℃,搅拌反应2h,LCMS显示反应完全。体系浓缩以除去1,1-二甲氧基-N,N-二甲基甲胺,加水淬灭(5mL),乙酸乙酯萃取2次,无水硫酸钠干燥,减压浓缩得标题化合物380mg。
MS(ESI)m/z(M+H)+=456.2.
2)4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶的制备
室温下,将(E)-3-(二甲基氨基)-1-(四氢-2H-吡喃-4-基)-2-((1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)氧基)丙-2-烯-1-酮(380mg)溶于乙酸(4mL)中,冰浴下,加入水合肼(146mg),体系恢复至室温,搅拌反应8h,LCMS显示反应完全。将体系倒入冰水中(20mL),乙酸乙酯萃取3次,分别用水(30mL)、饱和碳酸氢钠溶液(30mL)、饱和氯化钠溶液(30mL)洗涤,收集有机相,无水硫酸钠干燥,浓缩,得标题化合物303mg。
MS(ESI)m/z(M+H)+=439.1.
步骤3:4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶的制备
室温下,将醋酸铜(92mg)与联吡啶(79mg)溶于1,2-二氯乙烷(5mL)中,体系升温至75℃,搅拌反应25分钟;体系冷却至室温,依次加入4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(200mg)的1,2-二氯乙烷溶液、碳酸钠(97mg)、环丙基硼酸(79mg),继续于75℃下反应2h(反应需要氧气参与),TLC显示原料消耗完毕。体系加水(8mL)淬灭,乙酸乙酯萃取3次,无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化,得标题化合物160mg。
MS(ESI)m/z(M+H)+=479.2.
步骤4:4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶的制备
室温下,称取4-((1-环丙基-3-)四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(57mg)溶于四氢呋喃(2mL)中,加入氢氧化锂(2mol/L,5mL)于120℃微波反应1.5h,TLC显示原料消耗完毕。体系加水(10mL)淬灭,用氯化氢溶液调节pH至6-7,乙酸乙酯萃取2次,有机相用无水硫酸钠干燥,浓缩,所得粗品经反相制备得标题化合物6mg。
MS(ESI)m/z(M+H)+=325.0.
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.02(d,J=5.5Hz,1H),7.83(s,1H),7.40–7.24(m,1H),6.37(d,J=5.5Hz,1H),6.34–6.25(m,1H),3.75(dt,J=11.3,3.4Hz,2H),3.64(tt,J=7.4,3.8Hz,1H),3.27–3.15(m,2H),2.68(ddd,J=15.5,8.9,6.9Hz,1H),1.76–1.51(m,4H),1.14–0.80(m,4H).
实施例7:2-(4-((4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)胺基)吡啶-2-基)氨基)吡啶-2-基)丙-2-醇的制备
步骤1:3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-胺的制备
室温下,将(四氢-2H-吡喃-4-基)肼盐酸盐(1.87g)、3-环丙基-3-氧代丙腈(1.60g)加入乙醇(40mL)中,回流反应3.5h,TLC监测反应完全。体系冷却至室温,浓缩除去大部分溶剂,加入乙酸乙酯和水,体系用碳酸钠水溶液调节pH约至10,分液,水相用乙酸乙酯萃取两次,合并有机相,饱和氯化钠溶液反洗一次,无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化,得标题化合物1.51g。
MS(ESI)m/z(M+H)+=208.1.
步骤2:2-氯-4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)氨基)吡啶的制备
氮气氛中,将3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-胺(230mg)、2-氯-4-碘吡啶(591mg)、三(二亚苄基丙酮)二钯(75mg)、4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(48mg)、碳酸铯(1.62g)加入1,4-二氧六环(6mL)中,体系升温至90℃搅拌反应3h,TLC监测反应完全。体系冷却至室温,加入水和乙酸乙酯,分液,水相用乙酸乙酯萃取两次,合并有机相,用水洗涤两次,有机相用无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化,得标题化合物390mg。
MS(ESI)m/z(M+H)+=319.1.
步骤3:2-(4-((4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)胺基)吡啶-2-基)氨基)吡啶-2-基)丙-2-醇的制备
氮气氛中,将2-氯-4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)氨基)吡啶(112mg)、2-(4-氨基吡啶-2-基)丙-2-醇(64mg)、苯酚钠(65mg)、三(二亚苄基丙酮)二钯(16mg)、4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(21mg)加入1,4-二氧六环(8mL)中,体系升温至100℃搅拌反应过夜,TLC监测反应剩余少量原料。体系冷却至室温,硅藻土过滤,滤液浓缩,浓缩物经柱层析纯化得粗品100mg。粗品经反相制备柱分离,得标题化合物33mg。
MS(ESI)m/z(M+H)+=435.2.
1H NMR(600MHz,DMSO-d6)δ9.20(s,1H),8.33(s,1H),8.14(d,J=5.8Hz,1H),7.91(d,J=5.8Hz,1H),7.70–7.64(m,2H),6.32(dd,J=5.7,2.0Hz,1H),6.16(d,J=1.9Hz,1H),5.81(s,1H),5.06(s,1H),4.25–4.17(m,1H),3.92(dd,J=10.8,4.4Hz,2H),3.36(td,J=12.1,2.1Hz,2H),2.01(qd,J=12.7,4.7Hz,2H),1.86(tt,J=8.4,5.1Hz,1H),1.69(ddd,J=12.7,4.4,2.0Hz,2H),1.39(s,6H),0.88–0.82(m,2H),0.68–0.62(m,2H).
实施例8:2-(4-((4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-基)氨基)吡啶-2-基)氨基)吡啶-2-基)丙-2-醇的制备
步骤1:甲基-环丙烷氨基甲酸酯盐酸盐(环丙烷羧酰亚胺酸乙酯盐酸盐)的制备
冰浴下,将盐酸二氧六环溶液(22ml,4M)置于单口瓶中,将环丙基腈(2.72g)的甲醇(3.6mL)溶液缓慢滴加到反应体系中,滴毕,低温搅拌反应3.0h,移除冰浴,体系恢复至室温,搅拌反应过夜。体系析出大量固体,浓缩至干后加入甲叔醚打浆,抽滤,固体用甲叔醚洗涤。收集固体,浓缩至干,得标题化合物5.1g。
MS(ESI)m/z(M+H)+=100.1.
步骤2:甲基(Z)-N-氰基环丙烷氨基甲酸甲酯的制备
室温下,将甲基-环丙烷氨基甲酸酯盐酸盐(1.35g)和氰胺(0.42g)溶于甲醇(6mL)中,体系升温至90℃,搅拌反应1.5h。体系析出固体,将体系置于冰浴下搅拌,加入四氢呋喃(6mL),抽滤,四氢呋喃洗涤一次,滤液浓缩,浓缩物用二氯甲烷溶解,再次抽滤,二氯甲烷洗涤固体,滤液浓缩得到标题化合物1.20g。
MS(ESI)m/z(M+H)+=125.1.
步骤3:3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-胺的制备
室温下,将甲基(Z)-N-氰基环丙烷氨基甲酸甲酯(1.24g)和(四氢-2H-吡喃-4-基)肼盐酸盐(1.52g)溶于乙醇(20mL)中,体系升温至80℃,搅拌反应4.5h。体系浓缩除去大部分溶剂,加入乙酸乙酯和水,用碳酸钠水溶液调节pH=10,乙酸乙酯萃取三次,合并有机相,饱和氯化钠溶液反洗,有机相用无水硫酸钠干燥,浓缩,所得粗品经柱层析纯化,得标题化合物0.1g。
MS(ESI)m/z(M+H)+=209.1.
步骤4:2-氯-N-(3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-基)吡啶-4-胺的制备
氮气氛中,将3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-胺(100mg)、2-氯-4-碘吡啶(180mg)、醋酸钯(6mg)、4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(30mg)、碳酸铯(490g)加入1,4-二氧六环(4mL)中混匀,体系于100℃下搅拌反应4.5h。体系冷却至室温,加水淬灭,乙酸乙酯萃取,合并有机相,水反洗两次,无水硫酸钠干燥,有机相浓缩后经prep-TLC纯化,得标题化合物40mg。
MS(ESI)m/z(M+H)+=320.1.
步骤5:2-(4-((4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-基)氨基)吡啶-2-基)氨基)吡啶-2-基)丙-2-醇的制备
氮气氛中,将2-氯-N-(3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-基)吡啶-4-胺(40mg)、2-(4-氨基吡啶-2-基)丙-2-醇(30mg)、苯酚钠(25mg)、三(二亚苄基丙酮)二钯(12mg)、4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(8mg)加入1,4-二氧六环(4mL)中混匀,体系于100℃下搅拌反应过夜,TLC监测反应剩余少量原料。体系冷却至室温,硅藻土过滤,滤液浓缩后经prep-TLC纯化,得粗品15mg。粗品经反相制备柱分离,得标题化合物2.2mg。
MS(ESI)m/z(M+H)+=436.2.
1H NMR(600MHz,DMSO-d6)δ9.31(s,1H),9.17(s,1H),8.18(d,J=5.5Hz,1H),8.02(d,J=5.8Hz,1H),7.73-7.67(m,2H),7.11(d,J=1.9Hz,1H),6.86(dd,J=5.8,2.0Hz,1H),5.10(s,1H),4.48(td,J=11.1,5.4Hz,1H),3.97(dd,J=11.2,4.3Hz,2H),3.43(td,J=11.9,2.0Hz,2H),2.04-1.93(m,2H),1.91(tt,J=8.3,5.6Hz,1H),1.78(d,J=13.4Hz,2H),1.41(s,6H),1.24(d,J=4.0Hz,4H).
实施例9:2-(4-((3-氟-4-((1-(四氢-2H-吡喃-4-基)-3-(2,2,2-三氟乙基)-1H-吡唑-5-基)氧基)吡啶-2-基)氨基)吡啶-2-基)丙-2-醇的制备
步骤1:2,2-二甲基-5-(3,3,3-三氟丙酰基)-1,3-二氧六环-4,6-二酮的制备
室温下,将三氟丙酸(1.92g)溶于四氢呋喃(15mL)中,分批加入羰基二咪唑(3.16g),有气体放出,加毕,搅拌反应6小时;继续加入三乙胺(1.52g)和米氏酸(2.16g),室温下搅拌反应15小时。向体系盐酸水溶液(1.0M),乙酸乙酯萃取,合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,得粗品2.68g。
MS(ESI)m/z(M+H)+=255.0.
步骤2:5,5,5-三氟-3-氧戊酸乙酯的制备
将上述粗品2,2-二甲基-5-(3,3,3-三氟丙酰基)-1,3-二氧六环-4,6-二酮(2.68g)溶于甲苯(60mL)和乙醇(20mL)中,体系升温至85℃,搅拌反应10小时。体系冷却至室温,浓缩除去溶剂,经柱层析纯化得标题化合物0.54g。
MS(ESI)m/z(M+H)+=199.1.
步骤3:1-(四氢-2H-吡喃-4-基)-3-(2,2,2-三氟乙基)-1H-吡唑-5-醇的制备
室温下,将(四氢-2H-吡喃-4-基)肼盐酸盐(0.56g)、5,5,5-三氟-3-氧戊酸乙酯(0.53g)溶于乙醇(15mL)中,升温回流反应3.5h,TLC监测反应完全。体系冷却至室温,浓缩除去溶剂,经柱层析纯化,得标题化合物0.24g。
MS(ESI)m/z(M+H)+=251.9.
步骤4:2-氯-3-氟-4-((3-(2,2,2-三氟乙基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)氨基)吡啶的制备
氮气氛中,将1-(四氢-2H-吡喃-4-基)-3-(2,2,2-三氟乙基)-1H-吡唑-5-醇(240mg)溶于二甲基亚砜(5mL)中,加入叔丁醇钾(129mg),室温下搅拌反应0.5小时;向体系中加入2,4-二氯-5-氟吡啶(318mg),氮气置换后室温搅拌1小时,体系升温至70℃继续反应1.5小时。体系冷却至室温,加水淬灭,乙酸乙酯萃取,有机相用饱和氯化钠水溶液洗涤三次,浓缩,所得粗品经柱层析纯化,得标题化合物0.1g。
MS(ESI)m/z(M+H)+=380.1.
步骤5:2-(4-((3-氟-4-((1-(四氢-2H-吡喃-4-基)-3-(2,2,2-三氟乙基)-1H-吡唑-5-基)氧基)吡啶-2-基)氨基)吡啶-2-基)丙-2-醇的制备
室温下,将2-氯-3-氟-4-((3-(2,2,2-三氟乙基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑-5-基)氨基)吡啶(40mg)、2-(4-氨基吡啶-2-基)丙-2-醇(28mg)、苯酚钠(26mg)、三(二亚苄基丙酮)二钯(6mg)、4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(8mg)加入1,4-二氧六环(2.5mL)中混匀,氮气保护,体系升温至100℃,搅拌反应过夜,TLC监测反应原料反应完全。体系冷却至室温,硅藻土过滤,滤液浓缩,浓缩物经柱层析纯化得粗品50mg。粗品经反相制备柱分离,得标题化合物28mg。
MS(ESI)m/z(M+H)+=496.2.
1H NMR(400MHz,DMSO-d6)δ9.50(d,J=1.6Hz,1H),8.27(d,J=5.6Hz,1H),8.08(d,J=5.6Hz,1H),7.98(d,J=2.2Hz,1H),7.70(dd,J=5.6,2.2Hz,1H),6.72(t,J=5.5Hz,1H),6.02(s,1H),5.13(s,1H),4.46(tt,J=11.5,4.3Hz,1H),3.94(dd,J=11.5,4.2Hz,2H),3.61(q,J=11.4Hz,2H),3.46(td,J=12.0,2.0Hz,2H),2.03(qd,J=12.4,4.6Hz,2H),1.88–1.79(m,2H),1.43(s,6H).
本领域技术人员可根据本领域一般知识,采用适宜的商品化试剂为原料,并参照上述实施例9的方法,制备得到实施例10的化合物,所述化合物的结构以及表征数据见下表:
实施例11:2-(4-((4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-基)氧基)吡啶-2-基)氨基)吡啶-2-基)丙-2-醇的制备
步骤1:环丙烷碳酰肼的制备
室温下,将环丙烷甲酸甲酯(10g)、一水合肼(6.5g)加入乙醇(100mL)中混匀,升温回流反应4h,TLC监测反应完全。体系冷却至室温,0℃保存30分钟有固体析出,抽滤,得标题化合物2.3g。
MS(ESI)m/z(M+H)+=101.1
步骤2:N'-(四氢-2H-吡喃-4-基)环丙烷甲酰肼的制备
室温下,将环丙烷碳酰肼(2.3g)、四氢-4H-吡喃-4-酮(2.3g)加入甲醇(60mL)中,搅拌反应20小时,TLC监测反应完毕。体系直接浓缩,得3.74g固体。将上述固体加入水(30mL)和醋酸(60mL)中,搅拌反应30分钟,分批加入氰基硼氢化钠(1.45g),继续反应2h,TLC监测反应完全。体系用氢氧化钠溶液(2M)调pH至8-9,二氯甲烷萃取3次,有机相用无水硫酸钠干燥,浓缩,经柱层析纯化得标题化合物1.95g。
MS(ESI)m/z(M+H)+=185.1.
步骤3:2-(环丙烷羰基)-1-(四氢-2H-吡喃-4-基)肼-1-羧酰胺的制备
室温下,将N'-(四氢-2H-吡喃-4-基)环丙烷甲酰肼(500mg)溶于四氢呋喃(5mL)中,加入异氰酸根合三甲基硅烷(610mg),搅拌反应48小时,TLC监测反应完全。体系浓缩,经柱层析纯化得粗品800mg,直接用于下一步。
MS(ESI)m/z(M+H)+=228.2.
步骤4:3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-醇的制备
氮气氛中,将2-(环丙烷羰基)-1-(四氢-2H-吡喃-4-基)肼-1-羧酰胺(500mg)溶于甲苯(5mL)中,加入一水对甲基苯磺酸(832mg),体系升温至110℃,搅拌反应4h,LCMS监测原料反应完毕。体系冷却至室温,浓缩,经柱层析纯化得标题化合物105mg。
MS(ESI)m/z(M+H)+=210.1.
步骤5:2-氯-4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-基)氧基)吡啶的制备
氮气氛中,将3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-醇(100mg)溶于N,N-二甲基甲酰胺(5mL)中,在冰浴下,加入碳酸钾(130mg),维持低温搅拌20min,继续加入2-氯-4-氟吡啶(70mg),体系升温至60℃,搅拌反应过夜,TLC监测原料反应完毕。体系冷却至室温,加水淬灭,乙酸乙酯萃取,有机相用水洗两次,无水硫酸钠干燥,浓缩后经prep-TLC制备纯化,得标题化合物105mg。
MS(ESI)m/z(M+H)+=321.2.
步骤6:2-(4-((4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-基)氧基)吡啶-2-基)氨基)吡啶-2-基)丙-2-醇的制备
氮气氛中,将2-氯-4-((3-环丙基-1-(四氢-2H-吡喃-4-基)-1H-1,2,4-三唑-5-基)氧基)吡啶(100mg)、2-(4-氨基吡啶-2-基)丙-2-醇(32mg)、苯酚钠(32mg)、加入1,4-二氧六环(3mL)混匀,加入三(二亚苄基丙酮)二钯(7mg)、4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(8.8mg),氮气置换2min,体系升温至100℃,搅拌反应3h,TLC监测反应完全。体系冷却至室温,硅藻土过滤,滤液浓缩,经prep-TLC纯化得粗品78mg。粗品经反相制备柱分离,得标题化合物36mg。
MS(ESI)m/z(M+H)+=437.2.
1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),8.41(d,J=5.5Hz,1H),8.30–8.23(m,1H),7.80–7.74(m,2H),7.16–7.07(m,2H),5.15(s,1H),4.23(tt,J=11.4,4.3Hz,1H),3.94(dd,J=10.9,4.4Hz,2H),3.45(td,J=11.9,2.1Hz,2H),1.97–1.69(m,5H),1.43(s,6H),1.01–0.90(m,4H).
实施例12:3-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶-2-基)丙-2-炔-1-醇的制备
步骤1:4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶的制备
室温下,将2,2'-联吡啶(97mg)溶于1,2-二氯乙烷(10mL)中,搅拌下加入醋酸铜(113mg),体系升温至75℃,搅拌反应30分钟;将反应体系降温至10℃,依次加入2-碘-4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(320mg)、环丙基苯硼酸(98mg)、碳酸钠(120mg),体系再次升温至75℃,空气气氛下保温反应16小时,LCMS显示反应完全。体系降温至室温,过滤,滤液减压浓缩得粗品。所得粗品经柱层析纯化,得标题化合物242mg。
MS(ESI)m/z(M+H)+=605.1.
步骤2:3-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-2-基)丙-2-炔-1-醇的制备
氩气氛中,将4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(128mg)溶于四氢呋喃(5mL)中,依次加入三甲基(丙-2-炔-1-基氧基)硅烷(156mg)、碘化亚铜(4mg)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(15mg)、N,N-二异丙基乙胺(129mg),体系升温至90℃,搅拌反应过夜,LCMS显示反应完全。体系降温至室温,硅藻土过滤,滤液减压浓缩得粗品。粗品经prep-TLC纯化得标题化合物60mg。
MS(ESI)m/z(M+H)+=533.1.
1H NMR(400MHz,DMSO-d6)δ8.28(d,J=5.6Hz,1H),7.97(d,J=8.4Hz,2H),7.88(s,1H),7.42(d,J=8.2Hz,2H),7.04(s,1H),6.67(d,J=5.7Hz,1H),5.55(t,J=6.1Hz,1H),4.44(d,J=6.0Hz,2H),3.82–3.55(m,3H),3.29–3.07(m,2H),2.74–2.59(m,1H),2.34(s,3H),1.66–1.54(m,4H),1.07–0.88(m,4H).
步骤3:3-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶-2-基)丙-2-炔-1-醇的制备
室温下,将3-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-2-基)丙-2-炔-1-醇(60mg)溶于甲醇/水的混合溶液(5mL,V/V=20/1)中,加入碳酸钾(77mg),体系升温至100℃,保温反应3小时,LCMS显示反应完全。体系降温至室温,硅藻土过滤,滤液减压浓缩得粗品(50mg)。取粗品(30mg)用prep-HPLC纯化得标题化合物15.28mg。
MS(ESI)m/z(M+H)+=379.2.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),8.11(d,J=5.5Hz,1H),7.89(s,1H),6.57(s,1H),6.43(d,J=5.5Hz,1H),5.46(s,1H),4.36(s,2H),3.88–3.61(m,3H),3.31–3.21(m,2H),2.81–2.64(m,1H),1.75–1.57(m,4H),1.09–0.88(m,4H).
实施例13:3-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶-2-基)丙-1-醇的制备
室温下,将实施例12中的3-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶-2-基)丙-2-炔-1-醇粗品(20mg)溶于甲醇(3mL)中,加入5%的湿钯碳(10mg),体系用氢气置换三次,搅拌反应4小时,LCMS显示反应完全。体系用硅藻土过滤,滤液减压浓缩得粗品。所得粗品经prep-HPLC纯化得标题化合物4.8mg。
MS(ESI)m/z(M+H)+=383.2.
1H NMR(400MHz,Methanol-d4)δ7.95(d,J=5.7Hz,1H),7.67(s,1H),6.47(d,J=5.6Hz,1H),6.14(s,1H),3.95–3.88(m,2H),3.68–3.61(m,3H),3.40(td,J=11.8,2.2Hz,2H),2.90–2.79(m,3H),2.01–1.81(m,4H),1.78–1.70(m,2H),1.15–1.02(m,4H).
实施例14:(S)-4-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶-2-基)丁-2-醇的制备
步骤1:(S)-4-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-2-基)丁-3-炔-2-醇的制备
氩气氛中,将4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-2-碘-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(121mg)溶于四氢呋喃(5mL)中,依次加入(S)-丁-3-炔-2-醇(28mg)、碘化亚铜(4mg)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(15mg)、N,N-二异丙基乙胺(129mg),体系升温至90℃,保温反应过夜,LCMS显示反应完全。体系降温至室温,硅藻土过滤,滤液减压浓缩得粗品。粗品经prep-HPLC纯化得标题化合物58mg。
MS(ESI)m/z(M+H)+=547.2.
步骤2:(S)-4-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶-2-基)丁-3-炔-2-醇
室温下,将(S)-4-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-2-基)丁-3-炔-2-醇(58mg)溶于甲醇/水的混合溶液(V/V=20/1,5mL)中,加入碳酸钾(69mg),体系升温至100℃,保温反应3小时,LCMS显示反应完全。体系降温至室温,硅藻土过滤,滤液直接用于下一步反应。
MS(ESI)m/z(M+H)+=393.2.
步骤3:(S)-4-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶-2-基)丁-2-醇的制备
氢气氛中,向上述滤液中加入5%的湿钯碳(10mg),室温搅拌反应4小时,LCMS显示反应完全。体系用硅藻土过滤,滤液减压浓缩得粗品。所得粗品经prep-HPLC纯化,得标题化合物8.15mg。
MS(ESI)m/z(M+H)+=397.2.
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),7.94(d,J=5.5Hz,1H),7.82(s,1H),6.35(d,J=5.5Hz,1H),6.01(s,1H),4.53(s,1H),3.84–3.74(m,2H),3.70–3.58(m,2H),3.31–3.22(m,2H),2.83–2.63(m,3H),1.77–1.60(m,6H),1.10(d,J=6.1Hz,3H),1.06–0.89(m,4H).
本领域技术人员可根据本领域一般知识,采用适宜的商品化试剂为原料,并参照上述实施例14的方法,制备得到实施例15的化合物,所述化合物的结构以及表征数据见下表:
实施例16:2-(2-((4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)吡啶-2-基)氨基)恶唑-5-基)丙-2-醇的制备
步骤1:2-((2-溴吡啶-4-)氧基)-1-(四氢-2H-吡喃-4-基)乙-1-酮的制备
室温下,将2-溴-4-羟基吡啶(870mg)溶于N,N-二甲基甲酰胺(10mL)中,搅拌下依次加入2-溴-1-(四氢-2H-吡喃-4-基)乙-1-酮(1.55g)、碳酸钾(1.38g),反应2小时,LCMS显示反应完全。体系用乙酸乙酯(50mL)稀释,水(50mL)洗涤一次,饱和氯化钠水溶液(50mL)洗涤一次,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得粗品。粗品经柱层析纯化,得标题化合物1.12g。
MS(ESI)m/z(M+H)+=300.0.
步骤2:(Z)-2-((2-溴吡啶-4-基)氧基)-3-(二甲基氨基)-1-(四氢-2H-吡喃-4-基)丙-2-烯-1-酮的制备
室温下,将2-((2-溴吡啶-4-基)氧基)-1-(四氢-2H-吡喃-4-基)乙-1-酮(530mg)溶于N,N-二甲基甲酰胺二甲基缩醛(5mL)中,体系升温至100℃,保温反应1小时,LCMS显示反应完全。体系降温至室温,减压浓缩得粗品,直接用于下一步反应。
MS(ESI)m/z(M+H)+=355.1.
步骤3:2-溴-4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)吡啶的制备
室温下,将(Z)-2-((2-溴吡啶-4-基)氧基)-3-(二甲基氨基)-1-(四氢-2H-吡喃-4-基)丙-2-烯-1-酮粗品(上一步反应按摩尔收率100%计)溶于乙酸(3mL)中,搅拌下滴加水合肼(270mg),滴毕,搅拌反应16小时,LCMS显示反应完全。将反应体系浓缩干,乙酸乙酯(20mL)溶解,饱和碳酸氢钠水溶液(20mL)洗涤一次,收取有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得粗品。粗品经柱层析纯化,得标题化合物540mg。
MS(ESI)m/z(M+H)+=324.1.
步骤4:2-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)吡啶的制备
室温下,将2,2'-联吡啶(286mg)溶于1,2-二氯乙烷(10mL)中,加入醋酸铜(333mg),体系升温至75℃保温反应30分钟,再将体系降温至10℃,依次加入2-溴-4-((3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)吡啶(540mg)、环丙基苯硼酸(286mg)、碳酸钠(353mg),体系再次升温至75℃,空气中保温反应16小时,LCMS显示反应完全。体系降温至室温,过滤,滤液减压浓缩得粗品。粗品经柱层析纯化,得标题化合物200mg。
MS(ESI)m/z(M+H)+=364.1.
步骤5:2-((4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)吡啶-2-基)氨基)恶唑-5-羧酸乙酯的制备
氩气氛中,将2-溴-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)吡啶(182mg)溶于叔丁醇(5mL)中,依次加入2-氨基恶唑-5-羧酸乙酯(156mg)、二环己基[3,6-二甲氧基-2',4',6'-三异丙基[1,1'-联苯]-2-基]膦(144mg)、[2-(二环己基磷)-3,6-甲氧基-2',4',6'-三异丙基-1,1'-联苯][2-(2-氨基乙基)苯]氯化钯(199mg)、碳酸钾(138mg),氩气置换,体系升温至100℃,保温反应16小时,LCMS显示反应完全。体系降温至室温,硅藻土过滤,滤液减压浓缩得粗品。粗品经prep-TLC纯化,得标题化合物100mg。
MS(ESI)m/z(M+H)+=440.1.
步骤6:2-(2-((4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)吡啶-2-基)氨基)恶唑-5-基)丙-2-醇的制备
氩气氛中,将2-((4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)吡啶-2-基)氨基)恶唑-5-羧酸乙酯(90mg)溶于四氢呋喃(5mL)中,冰浴下,缓慢滴加甲基溴化镁的四氢呋喃溶液(0.34mL,3.0M),滴毕,体系恢复至室温搅拌反应2小时,LCMS显示反应完全。体系用饱和氯化铵水溶液(1mL)淬灭,加水(10mL)稀释,乙酸乙酯(10mL)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩得粗品。粗品经制备液相色谱仪纯化得标题化合物15mg。
MS(ESI)m/z(M+H)+=426.2.
1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.09(d,J=5.8Hz,1H),7.83(s,1H),7.65(s,1H),6.68(s,1H),6.51(dd,J=5.8,2.3Hz,1H),5.17(s,1H),3.81(dt,J=11.3,3.3Hz,2H),3.69–3.62(m,1H),3.33–3.25(m,2H),2.81–2.62(m,1H),1.71–1.58(m,4H),1.41(s,6H),1.07–0.89(m,4H).
实施例17:3-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶-2-基)环戊-3-烯-1-醇的制备
步骤1:叔丁基(环戊-3-烯-1-基氧基)二苯基硅烷的制备
室温下,将3-环戊烯-1-醇(841mg)溶于二氯甲烷(20mL)中,依次加入叔丁基二苯基氯硅烷(3.03g)、咪唑(1.36g),搅拌反应过夜,TLC显示反应完全。反应体系用二氯甲烷(20mL)稀释,水(50mL)洗涤一次,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,经柱层析纯化得标题化合物3.01g。
1H NMR(400MHz,Methanol-d4)δ7.69–7.59(m,4H),7.45–7.32(m,6H),5.60(s,2H),4.58–4.50(m,1H),2.47–2.24(m,3H),1.03(s,9H).
步骤2:叔丁基((3,4-二溴环戊基)氧基)二苯基硅烷的制备
室温下,将叔丁基(环戊-3-烯-1-基氧基)二苯基硅烷(1.86g)溶于四氯化碳(20mL)中,滴加溴素(2.76g),搅拌反应8小时,TLC显示反应完全。将反应体系缓慢倒入10%的亚硫酸氢钠水溶液(50mL)中,搅拌30分钟,二氯甲烷(50mL)萃取,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩得粗品2.9g,直接用于下一步反应。
步骤3:叔丁基((3-溴环戊-3-烯-1-基)氧基)二苯基硅烷的制备
氩气氛中,将叔丁基((3,4-二溴环戊基)氧基)二苯基硅烷粗品(2.9g)溶于干燥的四氢呋喃(40mL)中,冰盐浴下,体系降温至-10℃,滴加叔丁醇钾(1.94g)的四氢呋喃悬浊液,滴毕,控制温度在-10~0℃反应2小时,TLC显示反应完全。将体系缓慢倒入冰水(100ml)中,用乙酸乙酯(50mL)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,经柱层析纯化得标题化合物930mg。
1H NMR(400MHz,DMSO-d6)δ7.63–7.55(m,4H),7.49–7.38(m,6H),5.87(q,J=2.2Hz,1H),4.58–4.48(m,1H),2.74–2.64(m,1H),2.50–2.44(m,2H),2.33–2.22(m,1H),0.99(s,9H).
步骤4:叔丁基二苯基((3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)环戊-3-烯-1-基)氧基)硅烷的制备
氩气氛中,将叔丁基((3-溴环戊-3-烯-1-基)氧基)二苯基硅烷(860mg)溶于干燥的1,4-二氧六环(10mL)中,依次加入联硼酸频那醇酯(1.63g)、醋酸钾(631mg)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(157mg),体系升温至100℃,保温反应2小时,LCMS显示反应完全。反应体系降温至室温,硅藻土过滤,滤液减压浓缩得粗品。粗品经prep-TLC纯化,得标题化合物610mg。
1H NMR(400MHz,Chloroform-d)δ7.69–7.63(m,4H),7.45–7.32(m,6H),6.47–6.37(m,1H),4.61–4.50(m,1H),2.70–2.42(m,4H),1.26(s,12H),1.04(s,9H).
步骤5:2-(4-((叔丁基二苯基甲硅烷基)氧基)环戊-1-烯-1-基)-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶的制备
氩气氛中,将叔丁基二苯基((3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)环戊-3-烯-1-基)氧基)硅烷(32mg)溶于1,4-二氧六环和水的混合溶剂(1mL,V/V=10/1)中,依次加入4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-2-溴-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(40mg)、碳酸铯(47mg)、四三苯基膦钯(8mg),体系升温至110℃,保温反应2小时,TLC显示反应完全。反应体系降温至室温,硅藻土过滤,滤液减压浓缩得粗品。粗品经prep-TLC纯化,得标题化合物20mg。
MS(ESI)m/z(M+H)+=799.3.
步骤5:3-(4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1H-吡咯并[2,3-b]吡啶-2-基)环戊-3-烯-1-醇的制备
室温下,将2-(4-((叔丁基二苯基甲硅烷基)氧基)环戊-1-烯-1-基)-4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-1-甲苯磺酰基-1H-吡咯并[2,3-b]吡啶(20mg)溶于四氢呋喃(0.5mL)中,加入四丁基氟化铵的四氢呋喃溶液(1.0mL,1.0M),搅拌反应2小时,TLC显示反应完全。反应体系减压浓缩,浓缩物经prep-TLC纯化得中间体。将中间体溶于甲醇和水的混合溶剂(1.0mL,V/V=10/1)中,加入碳酸钾(17mg),体系升温至90℃反应1小时,TLC显示反应完全。体系降至室温,硅藻土过滤,滤液减压浓缩得粗品。粗品经prep-HPLC纯化,得标题化合物4.7mg。
MS(ESI)m/z(M+H)+=407.2.
1H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.02(d,J=5.5Hz,1H),7.86(s,1H),6.37(d,J=5.5Hz,1H),6.34–6.31(m,1H),6.18(s,1H),4.82(s,1H),4.49–4.43(m,1H),3.82–3.75(m,2H),3.72–3.63(m,1H),3.31–3.22(m,2H),2.92–2.81(m,1H),2.80–2.66(m,2H),2.56–2.52(m,1H),2.42–2.30(m,1H),1.73–1.60(m,4H),1.08–0.89(m,4H).
对照化合物1:4-((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-N-(1-甲基-1H-吡唑-5-基)吡啶-2-胺
MS(ESI)m/z(M+H)+=381.2.
1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),7.98(d,J=5.8Hz,1H),7.85(s,1H),7.28(d,J=1.9Hz,1H),6.45(dd,J=5.8,2.3Hz,1H),6.23(d,J=2.3Hz,1H),6.19(d,J=2.0Hz,1H),3.87–3.79(m,2H),3.68–3.62(m,1H),3.62(s,3H),3.33–3.27(m,2H),2.77–2.65(m,1H),1.67–1.60(m,4H),1.05–0.90(m,4H).
对照化合物2:4-(((1-环丙基-3-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)氧基)-N-(1-甲基-1H-吡唑-4-基)吡啶-2-胺
MS(ESI)m/z(M+H)+=381.2.
1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.96(d,J=5.9Hz,1H),7.87(d,J=0.8Hz,1H),7.83(s,1H),7.32(d,J=0.8Hz,1H),6.31(dd,J=5.8,2.2Hz,1H),6.05(d,J=2.2Hz,1H),3.85–3.79(m,2H),3.77(s,3H),3.68–3.60(m,1H),3.33–3.26(m,2H),2.74–2.65(m,1H),1.71–1.58(m,4H),1.07–0.89(m,4H).
生物活性验证
1.1实验目的
利用ADP-Glo的方法,在ALK5(TGFβR1)激酶上进行受试化合物的筛选,起始浓度为1μM,3倍稀释,10个浓度,单孔或复孔检测。
1.2实验材料
1.2.1试剂及耗材
试剂名称 | 供货商 | 货号 | 批号 |
ALK5(TGFβR1) | Carna Biosciences,Inc. | 09-141 | 10CBS-0450L |
ADP-Glo Kit | Promega Corporation | V9102 | 0000319847 |
384-well white plate | PerkinElmer | 6008280 | 8310-17411 |
1.2.2仪器
离心机(生产厂家:Eppendorf,型号:5430)
酶标仪(生产厂家:PerkinElmer,型号:Envision)
分液器(生产厂家:Labcyte,型号:Echo 550)
1.3实验方法
1.3.1化合物配置
化合物溶解在100%DMSO中,配制成10mM储存液,氮气柜避光储存。
1.3.2激酶反应过程
(1)配制1×Kinase buffer。
(2)化合物浓度梯度的配制:取受试化合物浓度为100μM的100%DMSO溶液,按3倍梯度稀释成10个浓度,每个浓度分别用分液器Echo 550转移50nL到384孔板的化合物孔(受试化合物的测试浓度为1μM起始);阴性对照孔和阳性对照孔中分别加50nL的DMSO。
(3)用1×Kinase buffer配制2倍终浓度的激酶溶液。
(4)在化合物孔和阳性对照孔分别加2.5μL的2倍终浓度的激酶溶液;在阴性对照孔中加2.5μL的1×Kinasebuffer。
(5)1000rpm离心30秒,振荡混匀后室温孵育10分钟。
(6)用1×Kinase buffer配制2倍终浓度的ATP溶液。
(7)加入2.5μL的2倍终浓度的ATP溶液,起始反应。
(8)将384孔板1000rpm离心30秒,振荡混匀后室温孵育120分钟。
(9)加入5μL ADP-Glo Reagent,1000rpm离心30秒,振荡混匀后室温孵育120分钟。
(10)加入10μL Kinase Detection Reagent,1000rpm离心30秒,振荡混匀后室温孵育30分钟。
(11)用Envision酶标仪读数。
1.3.3数据分析
其中:RLU:样品的化学发光值;Mean(NC):阴性对照孔均值;Mean(PC):阳性对照孔比值均值。
拟合量效曲线
以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。
计算公式是Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
1.4实验结果
本发明化合物对ALK5激酶抑制活性通过上述试验方法验证,并计算IC50值。在某些实施例中,本发明中的化合物对ALK5激酶活性的IC50值小于1000nM。在某些实施例中,本发明中的化合物对ALK5激酶活性的IC50值小于200nM。在某些实施例中,本发明中的化合物对ALK5激酶活性的IC50值小于100nM。在某些实施例中,本发明中的化合物对ALK5激酶活性的IC50值小于10nM。在某些实施例中,本发明中的化合物对ALK5激酶活性的IC50值在小于1nM。
本发明中部分化合物活性例举如下表1,其中“+”代表化合物IC50值≤10nm,“++”代表化合物IC50值在10nm~100nm之间,“+++”代表化合物IC50值在100nm~1000nm之间,“++++”代表化合物IC50值在1μm~10μm之间,“NA”代表未检测。
表1本发明化合物对ALK5激酶抑制活性
实施例编号 | ALK5 IC<sub>50</sub>(nM) |
1 | ++ |
2 | +++ |
3 | +++ |
4 | NA |
5 | ++++ |
6 | ++ |
7 | NA |
8 | NA |
9 | ++++ |
10 | >10000 |
11 | NA |
12 | ++ |
13 | +++ |
14 | ++ |
15 | ++ |
16 | + |
17 | + |
对照化合物1 | ++ |
对照化合物2 | ++ |
Claims (10)
1.式I结构的化合物,其异构体、混合物、溶剂合物、水合物、前药或其药学上可接受的盐:
其中:环A选自
L1选自O、NH;
L2选自不存在或NH;
R1选自不存在或五元杂芳环,所述五元杂芳环包含1-4个选自N、O或S的杂原子,并且R1不为1-甲基吡唑基;优选地,R1为噁唑基,其中,所述噁唑基可选择的被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、硝基、环烷基、酰胺基中的一个或多个基团取代;优选地,所述噁唑基为噁唑-2-基,所述噁唑-2-基可选择的被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、硝基、环烷基、酰胺基中的一个或多个基团取代;优选地,所述噁唑-2-基被1-羟基-1甲基乙基-1-基取代;
R2选自乙基、叔丁基、四氢吡喃-4-基、四氢呋喃-3-基、环丙基或环丁基;
R3选自环丙基、乙基、异丙基、CHF2、CH2CHF2、CH2CF3;
R4选自F、Cl、H;
X1、X2、X3各自独立的选自CH、N,且X1与X2不同时为N,X2与X3不同时为N;
5.根据权利要求1-4中任意一项所述的化合物,其中R2取代基选自四氢吡喃-4-基;R3取代基选自环丙基。
6.根据权利要求3或5所述的化合物,其中X1为CH;R4为F。
9.一种药物组合物,其包含一种或多种治疗有效剂量的权利要求1-8中任意一项所述的化合物,以及药学上可接受的辅料。
10.权利要求1-9中任意一项所述化合物或药物组合物在制备治疗、预防或减少由TGF-β过度表达介导的疾病的药物中的应用;其中,所述TGF-β过度表达介导的疾病包括:癌症、肾纤维化、肝纤维化、肺纤维化、病毒感染、慢性肾炎、急性肾炎、糖尿病肾病、骨质疏松症、关节炎、伤口愈合、溃疡、角膜创伤、心脏瓣膜狭窄、充血性心脏坏死、神经功能损伤、阿尔兹海默综合征、腹膜或皮下粘连、动脉硬化症和肿瘤转移生长等。
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