CN110066276A - 芳香杂环化合物、其中间体、制备方法、药物组合物和应用 - Google Patents
芳香杂环化合物、其中间体、制备方法、药物组合物和应用 Download PDFInfo
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- CN110066276A CN110066276A CN201810068775.0A CN201810068775A CN110066276A CN 110066276 A CN110066276 A CN 110066276A CN 201810068775 A CN201810068775 A CN 201810068775A CN 110066276 A CN110066276 A CN 110066276A
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- 229910000859 α-Fe Inorganic materials 0.000 description 1
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Abstract
本发明公开了一种芳香杂环化合物、其中间体、制备方法、药物组合物和应用。本发明的芳香杂环化合物是一种新型ALK5抑制剂,用于治疗和/或预防各种ALK5介导的疾病。
Description
技术领域
本发明涉及一种芳香杂环化合物、其中间体、制备方法、药物组合物和应用。
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与活化素(activins)、抑制素(inhibins)、骨形态发生蛋白(bone morphogenetic proteins)和谬氏抑制物质(Mullerian-inhibiting substance)等多种相关蛋白同属于转化生长因子β超家族(TGF-βsuperfamily,TGF-βs)。
TGF-β有3个主要的细胞受体: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。
TGF-β的信号传导通路主要是TGF-β-Smad信号通路,Smad蛋白家族是近年来发现的细胞内信号转导蛋白,已知人体内有8种Smad蛋白分子。无活性的蛋白复合物形式的TGF-β经过激活后,TGF-β在细胞表面与II型受体(TGFβR II)和I型受体(TGFβRI,又称ALK5(activin-like kinase 5))形成一个双二聚体受体复合物,II型受体磷酸化并激活I型受体,接着I型受体磷酸化其连接的Smad蛋白分子(Smad2/3)并释放到胞浆中,与Smad4蛋白形成复合体转移到细胞核内,结合不同的转录因子和转录共激活剂或转录共抑制剂,来调节TGF-β靶基因的转录,产生生物效应。TGF-β-Smad信号通路对细胞的增殖、分化、凋亡、附着、迁移,对细胞外基质的合成、创伤的修复、免疫功能等都有重要的调节作用(Nature 2003,425,577)。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TGFβR I(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.2012 October,11(10):790-811;Pharmacology&Therapeutics 147(2015)22-31)。
现有技术已公开了一些作为ALK5抑制剂的化合物,例如:WO2012002680,WO2009022171,WO2009133070,WO2004048383,WO2004013135,WO2002094833等。
发明人通过研究,发现了一类芳香杂环化合物,可作为ALK5抑制剂,具有治疗和/或预防由ALK5介导的多种疾病的用途。
发明内容
本发明提供了一种芳香杂环化合物、其中间体、制备方法、药物组合物和应用。本发明的芳香杂环化合物是一种新型ALK5抑制剂,用于治疗和/或预防各种ALK5介导的疾病。
本发明提供了一种通式I所示的芳香杂环化合物或其药学上可接受的盐:
其中,
为
环Q中,Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22各自独立地为氢、氘、卤素、磺酸基、取代或未取代的C1-6烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的C3-10环烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-10杂芳基、氰基、-OR61、-SR62、-NRa63Ra64、-C(O)R65、-C(O)OR66、-OC(O)R67、-OC(O)OR68、-C(O)NRa69Ra610、-N(R611)C(O)R612、S(O)R613、-S(O)2R614、-S(O)2NRa615Ra616、-OC(O)NRa617Ra618、-N(R619)C(O)OR620、-N(R621)C(O)NRa622Ra623、-N(R624)S(O)2R625或-OP(O)(OR626)2;R61、R62、Ra63、Ra64、R65、R66、R67、R68、Ra69、Ra610、R611、R612、R613、R614、Ra615、Ra616、Ra617、Ra618、R619、R620、R621、Ra622、Ra623、R624、R625和R626各自独立地为氢、取代或未取代的C1-6烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的C3-10环烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、或取代或未取代的C2-10杂芳基;
Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22中,所述的取代的C1-6烷基、取代的C2-8烯基、取代的C2-8炔基、取代的C3-10环烷基、取代的C2-8杂环烷基、取代的C6-20芳基、取代的C2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个:氘、卤素、C1-6烷基、卤素取代的C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基、C2-10杂芳基、氰基、-OR71、-SR72、-NRa73Ra74、-C(O)R75、-C(O)OR76、-OC(O)R77、-OC(O)OR78、-C(O)NRa79Ra710、-N(R711)C(O)R712、S(O)R713、-S(O)2R714、-S(O)2NRa715Ra716、-OC(O)NRa717Ra718、-N(R719)C(O)OR720、-N(R721)C(O)NRa722Ra723、-N(R724)S(O)2R725或-OP(O)(OR726)2;当取代基为多个时,所述的取代基相同或不同;R71、R72、Ra73、Ra74、R75、R76、R77、R78、Ra79、Ra710、R711、R712、R713、R714、Ra715、Ra716、Ra717、Ra718、R719、R720、R721、Ra722、Ra723、R724、R725和R726各自独立地为C1-6烷基、卤素取代的C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;
R61、R62、Ra63、Ra64、R65、R66、R67、R68、Ra69、Ra610、R611、R612、R613、Ra614、Ra615、Ra616、Ra617、Ra618、R619、R620、R621、Ra622、Ra623、R624、R625和R626中,所述的取代的C1-6烷基、取代的C2-8烯基、取代的C2-8炔基、取代的C3-10环烷基、取代的C2-8杂环烷基、取代的C6-20芳基或取代的C2-10杂芳基中的取代基为下列基团中的一个或多个:氘、卤素、氰基、C1-6烷基、卤素取代的C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基、C2-10杂芳基、-ORc、-SRc1、-NRb1Rb2、-C(O)Rc2、-C(O)ORc3、-OC(O)Rc4、-OC(O)ORc5、-C(O)NRb3Rb4、-N(Rc6)C(O)ORc7、S(O)Rc8、-S(O)2Rc9、-S(O)2NRb5Rb6、-N(Rc10)C(O)Rc11、-N(Rc12)C(O)NRb7Rb8或-N(Rc13)S(O)2Rc14;Rc、Rc1、Rb1、Rb2、Rc2、Rc3、Rc4、Rc5、Rb3、Rb4、Rc6、Rc7、Rc8、Rc9、Rb5、Rb6、Rc10、Rc11、Rc12、Rb7、Rb8、Rc13和Rc14各自独立地为氢、羟基、C1-6烷基、卤素取代的C1-6烷基、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;
Q3和Q31独立地为S或O;
Q4和Q41独立地为CRq23或N;Rq23与Rq1定义相同;
或者相邻的两个Rqx和与其相连的原子一起形成环状结构;所述的环状结构为取代或未取代的C3-10环烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、或取代或未取代的C2-10杂芳基;所述的环状结构中,所述的取代的C3-10环烷基、取代的C2-8杂环烷基、取代的C6-20芳基或取代的C2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个:氘、卤素、氰基、C1-6烷基、卤素取代的C1-6烷基、C2-8烯基、C2-8炔基、-ORa15、-SRa16、-C(O)ORa17、-CORa18、-C(O)NH2、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;Ra15、Ra16、Ra17和Ra18各自独立地为氢或C1-6烷基;当取代基为多个时,所述的取代基相同或不同;
为
环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、卤素、氰基、硝基、-NRa3Ra4、-ORa5、-SRa6、-C(O)ORa7、-C(O)NRa8Ra9、-CORa10、取代或未取代的C1-6烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的C3-10环烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C4-8环烯基、取代或未取代的C6-20芳基、或取代或未取代的C2-10杂芳基;
Ra4、Ra5、Ra6、Ra7、Ra9和Ra10各自独立地为氢、取代或未取代的C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;
Ra3和Ra8各自独立地为氢、取代或未取代的C1-6烷基、C2-8烯基、C2-8炔基、羟基、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;
R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1中,所述的取代的C1-6烷基、取代的C2-8烯基、取代的C2-8炔基、取代的C3-10环烷基、取代的C2-8杂环烷基、取代的C4-8环烯基、取代的C6-20芳基或取代的C2-10杂芳基中的取代基以及Ra3、Ra4、Ra5、Ra6、Ra7、Ra8、Ra9和Ra10中,所述的取代的C1-6烷基中的取代基各自独立地为下列基团中的一个或多个:氘、卤素、氰基C1-6烷基、卤素取代的C1-6烷基、C2-8烯基、C2-8炔基、-ORa15、-SRa16、-C(O)ORa17、-CORa18、-C(O)NH2、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;Ra15、Ra16、Ra17和Ra18各自独立地为氢或C1-6烷基;当取代基为多个时,所述的取代基相同或不同;
R2为氢、氰基、C1-6烷基、C3-10环烷基、C2-8杂环烷基、-C(O)ORa19或被-ORa20取代的C1-6烷基;Ra19和Ra20各自独立地为C1-6烷基;
为
环B中,R5、R51、R5a、R5a1、R5a2、R5b、R5b1、R5c、R5c1、R5c2、R5d、R5d1、R5d2、R5e、R5e1和R5e2各自独立地为氢、氘或卤素;
R6、R6a、R6b、R6c、R6d和R6e与Rq1定义相同;条件是:R6、R6a、R6b、R6c、R6d和R6e不为氰基;
R7、R8、R9、R10、R11、R12和R13各自独立地为氢、氘或卤素;
或者上述各基团或取代基中,当存在NRXRY时,RX和RY与它们相连的N一起形成取代或未取代的3-8元杂环基;所述的3-8元杂环基中的杂原子选自N、N和O、N和S、或N、O和S;杂原子数为1、2、3或4;所述的取代的3-8元杂环基中的取代基为下列基团中的一个或多个:氘、卤素、氰基、C1-6烷基、C2-8烯基、C2-8炔基、-ORa81、-SRa82、-C(O)ORa83、-CORa84、-C(O)NH2、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;Ra81、Ra82、Ra83和Ra84各自独立地为氢或C1-6烷基;
当Q环为时,不为
本发明中,-NRXRY例如:-NRa3Ra4、-NRa8Ra9、-NRa63Ra64、-NRa69Ra610、-NRa615Ra616、-NRa617Ra618、-NRa622Ra623、-NRa73Ra74、-NRa79Ra710、-NRa715Ra716、-NRa717Ra718、-NRa722Ra723、-NRb1Rb2、-NRb3Rb4、-NRb5Rb6或-NRb7Rb8。
相邻的两个Rqx和与其相连的原子一起形成环状结构,其中,相邻的两个Rqx,例如Rq1和Rq2;Rq2和Rq3;Rq4和Rq5;Rq5和Rq6;Rq7和Rq8;Rq9和Rq10;Rq17和Rq18;Rq18和Rq19;Rq20和Rq21;Rq21和Rq22;当Q4和Q41为CRq23时,相邻的两个Rqx还可为Rq15和Rq23;Rq16和Rq23。
本发明中,术语取代或未取代的C1-6烷基中的C1-6烷基和术语C1-6烷基独立地优选C1-4烷基。所述的C1-4烷基优选甲基、乙基、正丙基、异丙基、正丁基、异丁基、或叔丁基。
本发明中,术语取代或未取代的C2-8烯基中的C2-8烯基和术语C2-8烯基独立地优选C2-4烯基。所述的C2-4烯基优选乙烯基、丙烯基、烯丙基、
本发明中,术语取代或未取代的C2-8炔基中的C2-8炔基和术语C2-8炔基独立地优选C2-4炔基。所述的C2-4炔基优选乙炔基、丙炔基、丁炔基或3-甲基丙炔基。
本发明中,术语取代或未取代的C3-10环烷基中的C3-10环烷基和术语C3-10环烷基独立地优选环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、双环[3.1.1]庚烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.2.2]壬烷基、双环[3.3.1]壬烷基或双环[4.2.1]壬烷基。
本发明中,术语取代或未取代的C2-8杂环烷基中的C2-8杂环烷基和术语C2-8杂环烷基独立地优选氮杂环丁烷基、氮杂环庚烷基、氮丙啶、二氮杂环庚烷基、1,3-二噁烷基、1,3-二氧戊环基、1,3-二硫戊环基、1,3-二噻烷基、咪唑啉基、咪唑烷基、异噻唑烷基、异噻唑基、异噁唑啉基、吗啉基、噁二唑啉基、噁二唑烷基、噁唑啉基、噁唑烷基、哌嗪基、哌啶基、吡喃基、吡唑啉基、吡唑烷基、吡咯啉基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻二唑啉基、噻二唑烷基、噻唑啉基、噻唑烷基、硫代吗啉基、1,1-二氧硫代吗啉基、噻喃基、三噻烷基、2,3-二氢苯并呋喃-2-基、2,3-二氢苯并呋喃-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚-3-基、2,3-二氢苯并噻吩-2-基、十氢喹啉基、十氢异喹啉基、八氢-1H-吲哚基或八氢苯并呋喃基。
本发明中,术语取代或未取代的C4-8环烯基中的C4-8环烯基和术语C4-8环烯基独立地优选环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、降冰片烯基或双环[2.2.2]辛烯基。
本发明中,术语取代或未取代的C6-20芳基中的C6-20芳基或术语C6-20芳基独立地优选苯基、萘基、蒽基、菲基、薁基、二氢茚-1-基、二氢茚-2-基、二氢茚-3-基、二氢茚-4-基、2,3-二氢吲哚-4-基、2,3-二氢吲哚-5-基、2,3-二氢吲哚-6-基、2,3-二氢吲哚-7-基、茚-1-基、茚-2-基、茚-3-基、茚-4-基、二氢萘-2-基、二氢萘-3-基、二氢萘-4-基、二氢萘-1-基、5,6,7,8-四氢化萘-1-基、5,6,7,8-四氢化萘-2-基、2,3-二氢苯并呋喃-4-基、2,3-二氢苯并呋喃-5-基、2,3-二氢苯并呋喃-6-基、2,3-二氢苯并呋喃-7-基、苯并[d][1,3]间二氧杂环戊烯-4-基、苯并[d][1,3]间二氧杂环戊烯-5-基、2H-苯并呋喃-2-酮-5-基、2H-苯并呋喃-2-酮-6-基、2H-苯并呋喃-2-酮-7-基、2H-苯并呋喃-2-酮-8-基、异吲哚啉-1,3-二酮-4-基、异吲哚啉-1,3-二酮-5-基、茚-1-酮-4-基、茚-1-酮-5-基、茚-1-酮-6-基、茚-1-酮-7-基、2,3-二氢苯并[b][1,4]二噁烷-5-基、2,3-二氢苯并[b][1,4]二噁烷-6-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-5-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-6-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-7-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-8-基、苯并[d]杂氧嗪-2(3H)-酮-5-基、苯并[d]杂氧嗪-2(3H)-酮-6-基、苯并[d]杂氧嗪-2(3H)-酮-7-基、苯并[d]杂氧嗪-2(3H)-酮-8-基、喹唑啉-4(3H)-酮-5-基、喹唑啉-4(3H)-酮-6-基、喹唑啉-4(3H)-酮-7-基、喹唑啉-4(3H)-酮-8-基、喹噁啉-2(1H)-酮-5-基、喹噁啉-2(1H)-酮-6-基、喹噁啉-2(1H)-酮-7-基、喹噁啉-2(1H)-酮-8-基、苯并[d]噻唑-2(3H)-酮-4-基、苯并[d]噻唑-2(3H)-酮-5-基、苯并[d]噻唑-2(3H)-酮-6-基或苯并[d]噻唑-2(3H)-酮-7-基。
本发明中,术语取代或未取代的C2-10杂芳基中的C2-10杂芳基和术语C2-10杂芳基独立地优选呋喃基、咪唑基、异噁唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基、三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁二唑基、苯并噻唑基、噌啉基、5,6-二氢喹啉-2-基、5,6-二氢喹啉-1-基、呋喃并吡啶基、吲唑基、吲哚基、异喹啉基、萘啶基、嘌呤基、喹啉基、5,6,7,8-四氢喹啉-2-基、5,6,7,8-四氢喹啉-3-基、5,6,7,8-四氢喹啉-4-基、5,6,7,8-四氢异喹啉-1-基、噻吩并吡啶基、4,5,6,7-四氢并[c][1,2,5]噁二唑基或6,7-二氢并[c][1,2,5]噁二唑-4(5H)酮基。
在本发明一优选实施方案中,环Q中,Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22各自独立地为氢、氘、卤素、磺酸基、C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基、C2-10杂芳基、氰基、-OR61、-SR62、-NRa63Ra64、-C(O)R65、-C(O)OR66、-OC(O)R67、-OC(O)OR68、-C(O)NRa69Ra610、-N(R611)C(O)R612、S(O)R613、-S(O)2R614、-S(O)2NRa615Ra616、-OC(O)NRa617Ra618、-N(R619)C(O)OR620、-N(R621)C(O)NRa622Ra623、-N(R624)S(O)2R625或-OP(O)(OR626)2;R61、R62、Ra63、Ra64、R65、R66、R67、R68、Ra69、Ra610、R611、R612、R613、R614、Ra615、Ra616、Ra617、Ra618、R619、R620、R621、Ra622、Ra623、R624、R625和R626的定义均同前所述;或者相邻的两个Rqx和与其相连的原子一起形成环状结构;所述的环状结构为取代或未取代的C3-10环烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、或取代或未取代的C2-10杂芳基;所述的取代的C3-10环烷基、取代的C2-8杂环烷基、取代的C6-20芳基、或取代的C2-10杂芳基中的取代基的定义均同前所述。
在本发明一优选实施方案中,环Q中,Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22各自独立地为氢、氘、卤素或C1-6烷基。
在本发明一优选实施方案中,环Q中,Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22为氢或C1-6烷基。
在本发明一优选实施方案中,环Q为 Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22的定义同前所述,其中,优选地,Rq5、Rq6和与其相连的原子一起形成C6-20芳基,例如苯基。
在本发明一优选实施方案中,环Q为 Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22的定义同前所述。
在本发明一优选实施方案中,环Q为 进一步优选为
在本发明一优选实施方案中,环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、卤素、氰基、硝基、-NRa3Ra4、-ORa5、-SRa6、-C(O)ORa7、-C(O)NRa8Ra9、-CORa10、取代或未取代的C1-6烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、或取代或未取代的C2-10杂芳基;其中,Ra3、Ra4、Ra5、Ra6、Ra7、Ra8、Ra9和Ra10的定义均同前所述;所述的取代的C1-6烷基、取代的C2-8杂环烷基、取代的C6-20芳基和取代的C2-10杂芳基中的取代基的定义均同前所述。
在本发明一优选实施方案中,环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、卤素、-ORa5、-SRa6、-C(O)NRa8Ra9、或取代或未取代的C1-6烷基;其中,Ra5、Ra6、Ra8和Ra9的定义均同前所述;所述的取代的C1-6烷基中的取代基同前所述。
在本发明一优选实施方案中,环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、卤素、-ORa5、或取代或未取代的C1-6烷基;其中,Ra5优选氢或C1-6烷基,所述的取代的C1-6烷基中的取代基优选下列取代基中的一个或多个:氘或卤素。
在本发明一优选实施方案中,环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、C1-6烷基或卤素取代的C1-6烷基,所述的卤素的个数为一个或多个(例如1-6个,再如1-3个)。
在本发明一优选实施方案中,环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、卤素、三氟甲基、二氟甲基、氘代甲基、甲基或甲氧基。
在本发明一优选实施方案中,环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、三氟甲基或甲基。
在本发明一优选实施方案中,R2为氢、C1-6烷基或C3-10环烷基。
在本发明一优选实施方案中,为R3、R31、R32、R33、R3b、R3b1、R3e、R3e1和R2的定义均同前所述。
在本发明一优选实施方案中,为
在本发明一优选实施方案中,环B中,R5、R51、R5a、R5a1、R5a2、R5b、R5b1、R5c、R5c1、R5c2、R5d、R5d1、R5d2、R5e、R5e1和R5e2各自独立地为氢。
在本发明一优选实施方案中,环B中,R7、R8、R9、R10、R11、R12和R13各自独立地为氢。
在本发明一优选实施方案中,环B中,R6、R6a、R6b、R6c、R6d和R6e各自独立地为氢、卤素、取代或未取代的C1-6烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-10杂芳基、-OR61、-SR62、-NRa63Ra64、-C(O)R65、-C(O)OR66、-OC(O)R67、-OC(O)OR68、-C(O)NRa69Ra610、-N(R611)C(O)R612、S(O)R613、-S(O)2R614、-S(O)2NRa615Ra616、-OC(O)NRa617Ra618、-N(R619)C(O)OR620、-N(R621)C(O)NRa622Ra623、-N(R624)S(O)2R625或-OP(O)(OR626)2;R61、R62、Ra63、Ra64、R65、R66、R67、R68、Ra69、Ra610、R611、R612、R613、R614、Ra615、Ra616、Ra617、Ra618、R619、R620、R621、Ra622、Ra623、R624、R625和R626的定义均同前所述;所述的取代的C1-6烷基、取代的C2-8杂环烷基、取代的C6-20芳基或取代的C2-10杂芳基中取代基的定义均同前所述。
在本发明一优选实施方案中,环B中,R6、R6a、R6b、R6c、R6d和R6e各自独立地为氢、卤素、取代或未取代的C1-6烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-10杂芳基、-OR61、-SR62、-NRa63Ra64、-C(O)R65、-C(O)OR66、-OC(O)R67、-OC(O)OR68、-C(O)NRa69Ra610、-N(R611)C(O)R612、S(O)R613、-S(O)2R614、-S(O)2NRa615Ra616、-OC(O)NRa617Ra618、-N(R619)C(O)OR620、-N(R621)C(O)NRa622Ra623、-N(R624)S(O)2R625或-OP(O)(OR626)2;R61、R62、Ra63、Ra64、R65、R66、R67、R68、Ra69、Ra610、R611、R612、R613、R614、Ra615、Ra616、Ra617、Ra618、R619、R620、R621、Ra622、Ra623、R624、R625和R626的定义均同前所述;所述的取代的C1-6烷基、取代的C2-8杂环烷基、取代的C6-20芳基或取代的C2-10杂芳基中取代基的定义均同前所述。
在本发明一优选实施方案中,环B中,R6、R6a、R6b、R6c、R6d和R6e各自独立地为氢、卤素、取代或未取代的C1-6烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-10杂芳基、-OR61、-SR62、-C(O)R65、-C(O)OR66或-C(O)NRa69Ra610;R61、R62、R65、R66、Ra69和Ra610的定义均同前所述;所述的取代的C1-6烷基、取代的C2-8杂环烷基、取代的C6-20芳基或取代的C2-10杂芳基中的取代基的定义均同前所述。
在本发明一优选实施方案中,环B中,R6、R6a、R6b、R6c、R6d和R6e各自独立地为氢、卤素、-C(O)OR66或-C(O)NRa69Ra610;R66、Ra69和Ra610的定义均同前所述;优选地,R66为氢或C1-6烷基;Ra69和Ra610独立地为氢或C1-6烷基;优选地,Ra69和Ra610为氢,或其中一个为氢,另外一个为C1-6烷基。
在本发明一优选实施方案中,环B中,R6、R6a、R6b、R6c、R6d和R6e各自独立地为氢、卤素(例如Br)、
在本发明一优选实施方案中,为R5a、R5a1、R5a2、R6a和R8的定义均同前所述。
在本发明一优选实施方案中,为
在本发明一优选实施方案中,
环Q中,Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22各自独立地为氢、氘、卤素或C1-6烷基;
环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、卤素、-ORa5、或取代或未取代的C1-6烷基;其中,Ra5优选氢或C1-6烷基;所述的取代的C1-6烷基中的取代基优选下列取代基中的一个或多个:氘或卤素;R2为氢、C1-6烷基或C3-10环烷基;
和环B中,R5、R51、R5a、R5a1、R5a2、R5b、R5b1、R5c、R5c1、R5c2、R5d、R5d1、R5d2、R5e、R5e1、R5e2、R7、R8、R9、R10、R11、R12和R13为氢;R6、R6a、R6b、R6c、R6d和R6e各自独立地为氢、卤素、取代或未取代的C1-6烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-10杂芳基、-OR61、-SR62、-C(O)R65、-C(O)OR66或-C(O)NRa69Ra610;R61、R62、R65、R66、Ra69和Ra610的定义均同前所述;所述的取代的C1-6烷基、取代的C2-8杂环烷基、取代的C6-20芳基或取代的C2-10杂芳基中的取代基的定义均同前所述。
在本发明一优选实施方案中,
环Q中,Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22为氢或C1-6烷基;
环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、C1-6烷基或卤素取代的C1-6烷基;所述的卤素的个数为一个或多个(例如1-6个,再如1-3个);R2为氢、C1-6烷基或C3-10环烷基;
和环B中,R5、R51、R5a、R5a1、R5a2、R5b、R5b1、R5c、R5c1、R5c2、R5d、R5d1、R5d2、R5e、R5e1、R5e2、R7、R8、R9、R10、R11、R12和R13为氢;R6、R6a、R6b、R6c、R6d和R6e各自独立地为氢、卤素、-C(O)OR66或-C(O)NRa69Ra610;R66、Ra69和Ra610的定义均同前所述;优选地,R66为氢或C1-6烷基;Ra69和Ra610独立地为氢或C1-6烷基。
在本发明一优选实施方案中,
环Q为 Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22的定义同前所述;
为R3、R31、R32、R33、R3b、R3b1、R3e、R3e1和R2的定义均同前所述;
和为R5a、R5a1、R5a2、R6a和R8的定义均同前所述。
在本发明一优选实施方案中,
环Q为
为
和为
本发明中,所述的通式I所示的芳香杂环化合物优选下列任一化合物:
本发明的所述的通式I所示的芳香杂环化合物和/或其药学可接受的盐都可以用商业上可获得的原料,通过已知的方法合成得到。
本发明还提供了一种所述的通式I所示的芳香杂环化合物的制备方法,其包括下列步骤:将化合物I-A与化合物I-B进行偶联反应得到通式I所示的芳香杂环化合物;
其中,Xa和Xb其中一个为H,另一个为卤素,例如Cl、Br或I;该情况下,Xa优选为咪唑环中两个氮原子之间的碳原子上的氢;
或者,Xa和Xb其中一个为有机锡试剂如三正丁基锡试剂或者有机硼试剂如硼酸,频哪醇硼酯等,另一个为卤素,例如Cl、Br或I;
或者Xa和Xb其中一个为-OPG1,PG1为对甲苯磺酰基、甲磺酰基等基团;另一个为有机锡试剂如三正丁基锡试剂或者有机硼试剂如硼酸,频哪醇硼酯等;
环C1和环C2一个为环A,另一个为环B;环A、环B和环Q的定义同前所述。
当环Q为时,其还可采用下列方法制备得到,所述的方法包括下列步骤:将化合物III-1进行环合反应,得到通式III所示的芳香杂环化合物;
环C1和环C2一个为环A,另一个为环B;环A和环B的定义同前所述。
当环Q为时,其还可采用下列方法制备得到,所述的方法包括下列步骤:将化合物VI-1进行环合反应,得到通式VI所示的芳香杂环化合物;
环C1和环C2一个为环A,另一个为环B;环A和环B的定义同前所述。
当环Q为其还可采用下列方法制备得到,所述的方法包括下列步骤:将化合物V-1进行环合反应,得到通式V所示的芳香杂环化合物;
环C1和环C2一个为环A,另一个为环B;环A和环B的定义同前所述。
其中,部分化合物可以通过路线1的方法合成。其包括下列步骤:将通N-boc吡咯-2-硼酸与化合物I-4进行偶联反应得到化合物I-3,化合物I-3脱除boc保护基得到化合物I-1,化合物I-1与化合物I-2进行偶联反应得到通式I所示的芳香杂环化合物。
合成路线1:
其中,X1、X2为Cl、Br或I。环C1为环A时,环C2为环B;或者环C1为环B时,环C2为环A。环A和环B的定义均同前所述。
例如:
另一些化合物可以通过路线2的方法合成。其包括下列步骤:化合物咪唑与化合物I-4在铜试剂作用下生成化合物II-1,化合物II-1再与化合物I-2在钯试剂催化下通过偶联反应获得化合物II。
合成路线2:
其中,X1、X2为Cl、Br或I。环C1为环A时,环C2为环B;或者环C1为环B时,环C2为环A。环A和环B的定义均同前所述。
例如:
另一些化合物通过路线3的方法合成。其包括下列步骤:化合物III-2与化合物III-3在酸的作用下通过缩合反应生成化合物III-1,化合物III-1与对甲基苯磺酰甲基异腈反应获得化合物III。
合成路线3:
其中,环C1为环A时,环C2为环B;或者环C1为环B时,环C2为环A。环A和环B的定义均同前所述。
例如:
还有一些化合物通过路线4的方法合成。其包括下列步骤:化合物IV-5先转化为化合物IV-3,化合物IV-3在强碱作用下与化合物IV-4缩合得到化合物IV-2,化合物IV-2再进一步转化为化合物IV-1,进而转化得到化合物IV。
合成路线4:
其中,环C2为环B;或者环C1为环B时,环C2为环A。环A和环B的定义均同前所述。
例如:
化合物IV还可以进一步转化为化合物V,按照如下合成路线5。其包括下列步骤:化合物IV氢解转化为化合物V-1,化合物V-1进一步转化为化合物V。
合成路线5:
其中,环C1为环A时,环C2为环B;或者环C1为环B时,环C2为环A。环A和环B的定义均同前所述。
例如:
还有一些化合物通过路线6的方法合成。其包括下列步骤:化合物VI-3与化合物VI-4在钯试剂作用下偶联得到化合物VI-1,化合物VI-1进一步在钯试剂作用下与化合物VI-2偶联转化为化合物VI。
合成路线6:
其中,X1,X2为Cl、Br或I。环C1为环A时,环C2为环B;或者环C1为环B时,环C2为环A。环A和环B的定义均同前所述。Y1和Y2独立地为有机锡试剂如三正丁基锡试剂或者有机硼试剂如硼酸,频哪醇硼酯等。
例如:
还有一些化合物通过路线7的方法合成。其包括下列步骤:化合物VII-3与化合物VI-4在钯试剂作用下偶联得到化合物VII-2,化合物VII-2进一步转化为化合物VII-1,化合物VII-1在钯试剂作用下与化合物VI-2偶联转化为化合物VII。
合成路线7:
其中,X为Cl、Br或I。环C1为环A时,环C2为环B;或者环C1为环B时,环C2为环A。环A和环B的定义均同前所述。Y1,Y2为有机锡试剂如三正丁基锡试剂或者有机硼试剂如硼酸,频哪醇硼酯等。Alk为C1-6烷基。PG1为对甲苯磺酰基、甲磺酰基等基团。
例如:
本发明中所述各条反应路线中涉及的化学反应所采用的条件和步骤均可参照本领域常规的此类反应的条件和步骤进行,具体可参照文献:R.Larock,ComprehensiveOrganic Transformations,VCH Publishers(1989);T.W.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd ED.,John Wiley and Sons(1999);L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,JohnWiley and Sons(1994);L.Paquette,ed.,Encyclopedia of Reagents for OrganicSynthesis,John Wiley and Sons(1995)及其后续的版本。本申请在此引用上述文献全文。此外,上述方法所得的化合物还可以参照上述文献的相关方法,进一步通过对外周位置进行修饰而获得本发明的其它目标化合物。
按照上述方法制备得到的至少一种芳香杂环化合物或其药学上可接受的盐可以通过柱层析、高效液相色谱、结晶或其它适当的条件进行纯化。所述柱层析、高效液相色谱和结晶等纯化方法的条件和步骤均可按照本领域常规的条件和步骤选择。
本发明还提供了一种用于制备所述的通式I所示的芳香杂环化合物的中间体化合物,其为下列任一化合物:
本文所述的化合物,包括但不限于,它们的光学异构体、外消旋体,及其他混合物。在这些情况下,单一对映体或非对映体,例如具有光学活性的结构,可通过不对称合成或由外消旋混合物或非对映体混合物拆分得到。对于消旋混合物或非对映体混合物的拆分,可以用传统的方法分离,例如使用拆分试剂结晶;也可以用色谱法分离。例如手性高效液相色谱(HPLC)柱。另外,这类化合物包含Z-和E-型(或顺-和反-式)的含C=C双键化合物。本文所述化合物存在各种互变异构体,术语“化合物”包括该化合物的所有互变异构形式。这里化合物也包括其不同的晶体形式,包含多晶和包合物。同样,术语“盐”也包括了该化合物的所有异构体。消旋体、其他混合物、Z-和E-型、互变异构体和晶体形式。
本发明还提供了所述的通式I所示的芳香杂环化合物或其药学上可接受的盐在制备ALK5抑制剂或者制备用于治疗和/或预防ALK5介导的疾病的药物中的应用。
所述的“ALK5介导的疾病”包括但不限于:癌症、器官纤维化、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中的一种或多种,优选癌症和/或器官纤维化。所述的癌症包括但不限于结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头或颈癌、骨癌、皮肤癌、直肠癌、肝癌、结肠癌、食道癌、胃癌、胰腺癌、甲状腺癌、膀胱癌、淋巴瘤、白血病和黑色素瘤。所述的器官纤维化包括但不限于肾纤维化、肝纤维化和肺纤维化。
本发明还提供了一种药物组合物,其包含预防和/或治疗有效剂量的所述的通式I所示的含氮芳香杂环化合物和其药学上可接受的盐中的一种或多种,以及药学上可接受的载体。
本发明中,所述的“预防和/或治疗有效剂量”表示(i)预防和/或治疗本申请所述的具体疾病或病症的本发明化合物的量,(ii)削弱、改善或消除本申请所述的具体疾病或病症的一种或多种症状的本发明化合物的量,或(iii)预防或延迟本申请所述的具体疾病或病症的一种或多种症状的发作的本发明化合物的量。治疗人类患者的剂量可为0.0001mg/kg-50mg/kg,最通常为0.001mg/kg-10mg/kg体重,例如0.01mg/kg-1mg/kg范围内。这样的剂量可给予例如每日1-5次。
根据治疗目的,可将药物组合物制成各种类型的给药单位剂型,如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等,优选片剂、丸剂、颗粒剂和胶囊等。
为了使片剂形式的药物组合物成形,可使用本领域任何已知并广泛使用的赋形剂。例如,载体,如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等;粘合剂,如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液,羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等;崩解剂,如干淀粉、藻酸钠、琼脂粉和海带粉,碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等;崩解抑制剂,如白糖、甘油三硬脂酸酯、椰子油和氢化油;吸附促进剂,如季胺碱和十二烷基硫酸钠等;润湿剂,如甘油、淀粉等;吸附剂,如淀粉、乳糖、高岭土、膨润土和胶体硅酸等;以及润滑剂,如纯净的滑石,硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形,可使用本领域任何已知的并广泛使用的赋形剂,例如,载体,如乳糖,淀粉,椰子油,硬化植物油,高岭土和滑石粉等;粘合剂,如阿拉伯树胶粉,黄蓍胶粉,明胶和乙醇等;崩解剂,如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形,可使用本领域任何已知并广泛使用的赋性剂,例如,聚乙二醇,椰子油,高级醇,高级醇的酯,明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物,可将溶液或悬浮液消毒后(最好加入适量的氯化钠,葡萄糖或甘油等),制成与血液等渗压的针剂。在制备针剂时,也可使用本领域内任何常用的载体。例如,水,乙醇,丙二醇,乙氧基化的异硬脂醇,聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外,还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明中,所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状,选择各种剂型的制剂给药。例如,片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药;针剂可以单独给药,或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射;栓剂为给药到直肠。
除非另有说明,在本发明说明书和权利要求书中出现的以下术语具有下述含义:
本发明所使用的术语前面和/或后面可以加单破折号,“-”,或双破折号,“=”,表明被命名取代基及其母体部分之间键的键序;单破折号表示单键,双破折号表示双键或螺环取代基情况下的一对单键。在没有单破折号或双破折号时,可以认为在取代基及其母体部分之间形成单键;此外,取代基是被“从左到右”阅读,除非另有指示。例如,C1-6烷氧基羰基氧基和-OC(O)C1-6烷基表示相同的功能;同样,芳基烷基,芳基烷基-,和-烷基芳基表示相同的功能。
本发明术语“烷基”指包括1~6个碳原子的支链和直链的饱和脂族烃基,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。本发明中确定了碳数范围的“Cx1-y1”烷基(x1和y1为整数),如“C1-6烷基”,除碳数范围与本段中“烷基”的碳数定义范围不同外,其余定义均相同。当“烷基”基团作为两个其它类之间的连接基团时,它也可以是直链或支链,例子包括但不限于-CH2-,-CH2CH2-,-CH2CH2CHC(CH3)-,-CH2CH2(CH2CH3)CH2-。
本发明术语“环烷基”指单环或双环环烷基。单环环烷基是含3至10个碳原子的环烃基基团,这些基团可以饱和或不饱和,但不是芳族。在某些实施方式中,环烷基基团完全饱和。双环环烷基是桥接的单环环烷基或稠合的双环环烷基。桥接的单环环烷基中含有单环环烷基环,其中单环环烷基环的两个非相邻碳原子被一至三个额外碳原子之间的亚烷基桥连接(即,-(CH2)w-形式的桥接基团,其中w是1、2或3)。稠合双环环烷基包含稠合到苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基的单环环烷基环。桥连或稠合的双环环烷基,通过单环环烷基环内含有的任何碳原子连接到母体分子部分。环烷基可以任选地被作为独立氧代基或硫基的一个或两个基团取代。
本发明中术语“环烯基”指单环或双环环烯基。单环环烯基是含3至8个碳原子的环烃基基团,这些基团不饱和(即,含有至少一个环形碳-碳双键)但不是芳族。双环环烯基环是桥连的单环环或稠合的双环环。桥接的单环环中含有单环环烯基环,其中单环环的两个非相邻碳原子被一至三个额外碳原子之间的亚烷基桥连接(即,-(CH2)w-形式的桥接基团,其中w是1、2或3)。稠合双环环烯基环系统包含稠合到苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基的单环环烯基环。桥连或稠合的双环环烯基,通过单环环烯基环内含有的任何碳原子连接到母体分子部分。环烯基基团可以任选地被作为独立氧代基或硫基的一个或两个基团取代。
本发明中,术语“烷氧基”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。由此,“烷氧基”包含以上烷基和环烷基的定义。
本发明中,术语“烷硫基”指通过硫桥连接的具有所述碳原子数目的环状或者非环状烷基。由此,“烷硫基”包含以上烷基和环烷基的定义。
本发明中,术语“烯基”指含有指定数目碳原子和至少一个碳碳双键的直链、支链或者环状非芳香烃基。优选存在一个碳碳双键,并且可以存在高达四个非芳香碳碳双键。由此,“C2-8烯基”是指具有2-8个碳原子的烯基。烯基的直链、支链或者环部分可以含有双键,并且如果表明为取代烯基,那么可以被取代。
本发明中,术语“炔基”指含有指定数目碳原子和至少一个碳碳三键的直链、支链或者环状烃基。其中可以存在高达三个碳碳三键。由此,“C2-8炔基”是指具有2-8个碳原子的炔基。“C2-6炔基”是指具有2-6个碳原子的炔基。
本发明中,术语“芳基”是指单环芳基或芳族双环体系中含有至少一个苯环或只含有碳原子的双环体系。双环芳基可以是稠合到单环环烷基、单环环烯基或单环杂环的苯基。双环芳基通过双环体系的苯基部分所含的任何碳原子或带有萘基或薁基的任何碳原子附到母体分子上。双环芳基的稠合单环环烷基或单环杂环基部分可以任选地被一个或两个氧代基和/或硫基基团取代。在某些实施例中,双环芳基是稠合到5元或6元单环环烷基、5元或6元单环环烯基或5元或6元单环杂环基的(i)萘基或(ii)苯基环,其中稠合的环烷基、环烯基和杂环基可以任选地被作为独立氧代基或硫基的一个或两个基团取代。
本发明中,术语“氰基”指-CN基团。
本发明中,术语“羧基”指-COOH基团。
本发明中,术语“磺酸基”指-SOOOH基团。
本发明中,术语“卤素”指氟、氯、溴或碘。
本发明中,术语“杂芳基”指含有至少一个杂芳环的单环杂芳基或双环体系。单环杂芳基可以是一个5元或6元环。5元环由两个双键和一个、两个、三个或四个氮原子以及一个氧原子或硫原子组成。6元环由三个双键和一个、两个、三个或四个氮原子组成。5元或6元杂芳基通过杂芳基内含有的任意碳原子或氮原子连接到母体分子上。双环杂芳基由稠合到苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基的单环杂芳基组成。稠合的双环杂芳基的环烷基或杂环基部分可以任选地被作为独立氧代基或硫基的一个或两个基团取代。当双环杂芳基含有稠合的环烷基、环烯基或杂环基环时,则双环杂芳基通过双环体系的单环杂芳基部分含有的任何碳原子或氮原子连接到母体分子上。当双环杂芳基是稠合到苯环或单环杂芳基的单环杂芳基时,双环杂芳基通过双环体系内任何碳原子或氮原子连接到母体分子上。在某些实施例中,稠合双环杂芳基是稠合到苯基环、5元或6元单环环烷基、5元或6元单环环烯基、5元或6元单环杂环基或5元或6元单环杂芳基的5元或6元单环杂芳环,其中稠合的环烷基、环烯基和杂环基可以任选地被作为独立氧代基或硫基的一个或两个基团取代。
本发明中,术语“杂环基”或“杂环”指单环杂环或双环杂环。该单环杂环是3、4、5、6或7元环,含有至少一个选自O、N和S的杂原子,其中该环为饱和或不饱和,但不是芳族。单环杂环通过单环杂环内含有的任何碳原子或氮原子连接到母体分子上。双环杂环是稠合到苯基、单环环烷基、单环环烯基、单环杂环基或单环杂芳基的单环杂环。双环杂环通过双环体系的单环杂环部分内含有的任何碳原子或氮原子连接到母体分子上。在某些实施例中,双环杂环基是稠合到苯环、5元或6元单环环烷基、5元或6元单环环烯基、5元或6元单环杂环基或5元或6元单环杂芳基的5元或6元单环杂环基环,其特征在于双环杂环基可以任选地被作为独立氧代基或硫基的一个或两个基团取代。
本发明中,术语“羟基”指一个-OH基团。
本发明中,术语“硝基”指一个-NO2基团。
关于任一基团包含一个或多个取代基,本领域一般技术人员均可理解,但不包括不切实际的高位阻、合成上不可行的和/或内在不稳定的取代基。
本发明中,所用的术语“药学上可接受的盐”指药学上可接受的与酸或与碱形成的盐和溶剂化物。这类药学上可接受的盐包括但不限于与无机酸形成的盐,如盐酸盐、磷酸盐、二磷酸盐、氢溴酸盐、硫酸盐、亚磺酸盐、硝酸盐、及其类似盐;也包括与有机酸形成的盐,如苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、醋酸盐、乳酸盐、磺酸盐、对甲苯磺酸盐、2-羟基乙基磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和链烷酸盐如醋酸盐,HOOC-(CH2)n-COOH其中n为0-4的盐,及其类似盐。类似地,药学上可接受的阳离子包括但不限于钠、钾、钙、铝、锂和铵。本领域的成熟技术人员可识别各种可能用来制备无毒的药学上可接受的盐的合成方法。
本发明中,所述的“溶剂化物”如“水合物”,是由溶剂和化合物互相作用形成。术语“化合物”,应该包括了化合物的溶剂化物(包括化合物的水合物)。同样,“盐”也包括了盐的溶剂化物(如盐的水合物)。合适的溶剂化物是药学上可接受的,例如水合物,它包括了单水合物和半水合物。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明中,所述的室温指环境温度,为10℃-35℃。
本发明的积极进步效果在于:本发明的芳香杂环取代烯烃化合物是一种ALK5抑制剂,可用于制备治疗癌症、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疾病的药物。
具体实施方式
本发明所用的试剂和原料(除了中间体)均为商业渠道获得。本发明中所述的室温指环境温度,为10℃-35℃。过夜是指8-15小时。回流是常压下溶剂回流温度。
以下为实施例中使用到的缩写列表:
化合物1的合成路线
化合物1-e的合成
化合物1-e根据WO2015/157093方法合成。
化合物1-d的合成
将1-e(500mg,2.07mmol)溶于二氯甲烷(10mL)中。在冰浴下,向溶液中慢慢加入草酰氯(1mL)和一滴DMF。反应物升至室温反应60分钟。反应物减压浓缩,加入二氯甲烷(5mL)稀释。在冰浴下,将该溶液慢慢滴加到氨水(5mL)中,反应混合物在0℃下反应10分钟,再升至室温搅拌过夜。分液,水层用二氯甲烷萃取,合并有机相分别用水,食盐水洗涤,无水硫酸钠干燥,浓缩得到化合物1-d(300mg,60%)为白色固体。LC-MS(ESI):m/z=239.9[M+H]+.
化合物1-c的合成
将1-d(100mg,0.42mmol)溶于二氧六环(10mL)中。在冰浴下,向溶液中加入吡啶(0.34mL,4.2mmol),搅拌5分钟后慢慢滴加三氟乙酸酐(0.29mL,2.08mmol)。反应物升至室温搅拌5小时。反应结束后,加入水淬灭,再减压浓缩除去有机溶剂。混合物溶于乙酸乙酯,分别经水和饱和食盐水洗涤,无水硫酸钠干燥,浓缩得到化合物1-c(80mg,86%)为白色固体。LC-MS(ESI):m/z=221.9[M+H]+.
化合物1-b的合成
将1-Boc-吡咯-2-硼酸(1.11g,5.27mmol),2-溴-6-甲基吡啶(0.5mL,4.39mmol),Pd(dppf)Cl2(359mg,0.44mmol),碳酸钠(1.16g,10.99mmol),1,4-二氧六环(10mL)和水(2mL)加入反应瓶中。反应液用N2置换,于85℃反应过夜。反应结束后,反应液用乙酸乙酯稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干。粗品经硅胶柱层析分离(PE:EA=3:1)得到化合物1-b(600mg,53%)为白色固体。LC-MS(ESI):m/z=259.1[M+H]+.
化合物1-a的合成
将1-b(600mg,2.36mmol)溶于二氯甲烷(10mL)和三氟乙酸(10mL),室温搅拌过夜。反应结束后,减压浓缩除去有机溶剂,加入饱和碳酸氢钠水溶液(10mL)和DCM(10mL),分液。水层用二氯甲烷萃取,合并有机层,用无水硫酸钠干燥,过滤,浓缩得到1-a(300mg,81%)为棕色固体。LC-MS(ESI):m/z=159.2[M+H]+.
化合物1的合成
往反应瓶中加入化合物1-a(40mg,0.25mmol),1-c(56mg,0.25mmol),铁酸铜(6mg,0.025mmol),叔丁醇钾(57mg,0.51mmol)和无水DMF(10mL)。反应液用N2置换,在150℃下搅拌过夜。反应结束后,用乙酸乙酯稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干。粗品经prep-HPLC纯化得到化合物1(30mg,40%)为白色固体。LC-MS(ESI):m/z=318.1[M+H]+;1H NMR(500MHz,MeOD):δ9.55(d,J=2.0Hz,1H),8.34(s,1H),7.64(d,J=10.0Hz,1H),7.60(t,J=8.0Hz,1H),7.36(dd,J=9.5,2.0Hz,1H),7.28(d,J=7.5Hz,1H),7.14(dd,J=2.0,1.0Hz,1H),7.01(d,J=8Hz,1H),6.78(dd,J=3.5,1.5Hz,1H),6.43(dd,J=4,3Hz,1H),2.21(s,3H).
化合物2的合成路线
化合物2-b的合成
将1-Boc-吡咯-2-硼酸(329mg,1.56mmol),SM-1(350mg,1.3mmol),Pd(dppf)Cl2(106mg,0.13mmol),碳酸钠(345mg,3.25mmol),1,4-二氧六环(10mL)和水(2mL)加入反应瓶中。反应液用N2置换,于85℃反应过夜。反应结束后,反应液用乙酸乙酯稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干。粗品经硅胶柱层析分离(PE:EA=5:1)得到产物2-b(450mg,95%)为白色固体。LC-MS(ESI):m/z=356.0[M+H]+.
化合物2-a的合成
将2-b(450mg,1.27mmol)溶于二氯甲烷(10mL)和三氟乙酸(10mL),室温搅拌过夜。反应结束后,减压浓缩除去有机溶剂,加入饱和碳酸氢钠水溶液(10mL)和DCM(10mL),分液。水层用二氯甲烷萃取,合并有机层,用无水硫酸钠干燥,过滤,浓缩得到2-a(300mg,92%)为棕色固体。LC-MS(ESI):m/z=256.1[M+H]+.
化合物2的合成
往反应瓶中加入化合物2-a(100mg,0.39mmol),6-溴-2-甲基吡啶(67mg,0.39mmol),三(二亚苄基丙酮)二钯(36mg,0.039mmol),1,1'-联萘-2,2'-双二苯膦(49mg,0.078mmol),叔丁醇钠(75mg,0.78mmol)和甲苯(10mL)。反应液用N2置换,在120℃下搅拌过夜。反应液用乙酸乙酯稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干。粗品经硅胶柱层析分离(PE:EA=1:1)得到产物2(20mg,15%)为棕色油状物。LC-MS(ESI):m/z=347.0[M+H]+.
化合物3的合成路线
化合物3的合成
将2(20mg,0.057mmol)溶于甲醇(2mL)和THF(2mL),加入氢氧化钠水溶液(2M,2mL),室温搅拌过夜。反应结束后,减压浓缩除去有机溶剂,加入水(10mL)和DCM(10mL),分液,弃去有机层。将水层冷却至0℃,用2M盐酸中和至pH为5-6。用二氯甲烷萃取,有机层水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干得到3(15mg,82%)。LC-MS(ESI):m/z=319.0[M+H]+.
化合物4和5的合成路线
化合物4和5的合成
将3(15mg,0.047mmol)溶于二氯甲烷(10mL)中。在冰浴下,向溶液中慢慢加入草酰氯(1mL)和一滴DMF。反应物升至室温反应60分钟。反应物减压浓缩,加入二氯甲烷(5mL)稀释。在冰浴下,将该溶液慢慢滴加到氨水(5mL)中,反应混合物在0℃下反应10分钟,再升至室温搅拌过夜。分液,水层用二氯甲烷萃取,合并有机相分别用水,食盐水洗涤,无水硫酸钠干燥,浓缩得到粗品。粗产品经高效液相制备色谱得到白色固体4(2mg,13%)和5(2mg,12%)。
化合物4:LC-MS(ESI):m/z=318.1[M+H]+;1H NMR(500MHz,MeOD):δ9.53(s,1H),8.40(s,1H),7.72(t,J=7.5Hz,1H),7.63(s,1H),7.39(s,1H),7.34(dd,J=3,1.5Hz,1H),7.23(d,J=7.5Hz,1H),7.03(d,J=7.5Hz,1H),6.61(dd,J=3.5,1.5Hz,1H),6.44(t,J=3Hz,1H),2.45(s,3H).
化合物5:LC-MS(ESI):m/z=346.0[M+H]+;1H NMR(500MHz,MeOD):δ8.98(s,1H),8.06(s,1H),7.69(t,J=7.5Hz,1H),7.50(d,J=9.5Hz,1H),7.33(dd,J=2.5,1.5Hz,1H),7.22(d,J=7.5Hz,1H),7.14(dd,J=9.0,1.5Hz,1H),6.99(d,J=8.0Hz,1H),6.56(dd,J=3.5,2Hz,1H),6.41(t,J=3.5Hz,1H),3.27(s,6H),2.47(s,3H).
化合物6的合成路线
化合物6-a的合成
往反应瓶中加入化合物咪唑(531mg,7.8mmol),SM-1(2g,7.43mmol),碘化亚铜(141mg,0.74mmol),碳酸钾(2g,14.86mmol),L-脯氨酸(171.1mg,1.48mmol)和无水二甲亚砜(10mL)。反应液用N2置换,在120℃下搅拌过夜。反应液用乙酸乙酯稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干。粗品经硅胶柱层析分离(PE:EA=1:1)得到产物6-a(0.5g,26%)为茶色固体。LC-MS(ESI):m/z=257.2[M+H]+.
化合物6的合成
往反应瓶中加入化合物6-a(400mg,1.56mmol),2-溴-6-甲基吡啶(537mg,3.12mmol),氟化铯(474mg,3.12mmol),醋酸钯(35mg,0.156mmol),三苯基砷(96mg,0.312mmol)和DMF(10mL)。反应液用N2置换,在140℃下搅拌过夜。反应结束后反应液用乙酸乙酯稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干得到粗品。粗产品经高效液相制备色谱得到化合物6(30mg,5.5%)为白色固体。LC-MS(ESI):m/z=348.1[M+H]+.
化合物7的合成路线
化合物7的合成
将6(30mg,0.086mmol)加入到甲醇(2mL)和THF(2mL),加入氢氧化钠水溶液(2M,2mL),室温搅拌过夜。反应结束后,减压浓缩除去有机溶剂,加入水(10mL)和DCM(30mL),分液,弃去有机层。将水层冷却至0℃,用2M盐酸中和至pH为6-7。过滤出微黄色沉淀物,干燥得到化合物7(20mg,72%)。LC-MS(ESI):m/z=320.0[M+H]+.
化合物8的合成路线
化合物8的合成
将7(20mg,0.063mmol)溶于二氯甲烷(10mL)中。在冰浴下,向溶液中慢慢加入草酰氯(1mL)和一滴DMF。反应物升至室温反应60分钟。反应物减压浓缩,加入二氯甲烷(5mL)稀释。在冰浴下,将该溶液慢慢滴加到氨水(5mL)中,反应混合物在0℃下反应10分钟,再升至室温搅拌过夜。分液,水层用二氯甲烷萃取,合并有机相分别用水和食盐水洗涤,无水硫酸钠干燥,浓缩得到粗品。粗产品经高效液相制备色谱得到化合物8(5mg,25%)为白色固体。LC-MS(ESI):m/z=319.1[M+H]+;1H NMR(500MHz,MeOD):δ9.65(s,1H),8.38(s,1H),7.72-7.81(m,3H),7.55(s,1H),7.52(d,J=9.5Hz,1H),7.32(s,1H),7.17(d,J=7.5Hz,1H),2.12(s,3H).
化合物9的合成路线
化合物9-c的合成
往反应瓶中加入化合物1-c(1.2g,5.4mmol),二苯甲酮亚胺(1.47g,8.1mmol),叔丁醇钠(1.04g,10.81mmol),Pd2(dba)3(247.4mg,0.27mmol),1,1'-联萘-2,2'-双二苯膦(336mg,0.54mmol)和甲苯(40mL)。反应液用N2置换,在100℃下搅拌一小时。反应结束后反应液用乙酸乙酯稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干得到黑色油状物。加入稀盐酸(2M,10mL),搅拌半小时,用碳酸氢钠固体中和至pH>7,用二氯甲烷萃取,有机相干燥,浓缩,所得粗产品经硅胶柱层析得到固体9-c(0.5g,59%)。LC-MS(ESI):m/z=159.1[M+H]+.
化合物9-b的合成
往反应瓶中加入化合物6-甲基-2-吡啶甲醛(200mg,1.26mmol),9-c(200mg,1.26mmol),甲醇(10mL)和几滴甲酸。反应液在室温下搅拌过夜。反应结束后浓缩,所得固体用乙酸乙酯洗涤,干燥得到产物9-b(0.2g,61%)为固体。LC-MS(ESI):m/z=262.1[M+H]+.
化合物9的合成
往反应瓶中加入化合物9-b(50mg,0.19mmol),对甲基苯磺酰甲基异腈(56mg,0.287mmol),碳酸钾(56mg,0.4mmol),DMF(4.6mL)和乙二醇二甲醚(3.75mL)。反应液用N2置换,在100℃下搅拌2小时。结束后,浓缩,所得油状物重新溶解在二甲亚砜(2mL)中。在冰浴下,往该溶液中滴加入30%过氧化氢(24.9mg,0.73mmol)。混合物升至室温,搅拌过夜。反应结束后,过滤,滤液经高效液相制备色谱得到白色固体9(15mg,26%)。LC-MS(ESI):m/z=319.0[M+H]+;1H NMR(400MHz,MeOD):δ9.70(s,1H),8.38(s,1H),8.09(s,1H),7.73(d,J=9.2,1H),7.70(t,J=8.0Hz,1H),7.62(s,1H),7.46(dd,J=9.6,2.0Hz,1H),7.43(d,J=7.6Hz,1H),7.11(t,J=8.0Hz,1H),2.21(s,3H).
化合物10的合成路线
化合物10-c的合成
室温下,将浓盐酸(2.0mL)加入到6-三氟甲基吡啶-2-甲酸(1.91g,10.0mmol)的甲醇(20mL)溶液中,80℃搅拌过夜。反应结束后,将溶剂旋干,残留物溶于乙酸乙酯(100mL)溶液中,饱和的碳酸氢钠溶液洗(50mL),氯化钠洗(50mL),无水硫酸钠干燥,过滤,浓缩得到10-c(1.89g,92%)为白色固体。LC-MS(ESI):m/z=206.1[M+H]+.
化合物10-b的合成
将10-c(800mg,3.9mmol)的四氢呋喃(10mL)溶液冷却至-78℃,搅拌10分钟后,将DIBAL-H(5.8mL,5.8mmol,1.0M in toluene)逐滴加入其中。-78℃下搅拌1小时后,加甲醇(2.0mL)淬灭反应,用碳酸氢钠溶液(30mL)稀释,乙酸乙酯(30mL*3)萃取,盐洗(50mL),无水硫酸钠干燥,过滤,浓缩。粗品通过柱层析色谱法(石油醚/乙酸乙酯=10/1)纯化得到10-b(142mg,21%)为淡黄色固体。LC-MS(ESI):m/z=176.0[M+H]+.
化合物10-a的合成
将10-b(142mg,0.81mmol)和9-c(128mg,0.81mmol)溶于甲醇(8mL)中,并加入一滴甲酸,室温下反应3小时。反应结束后,将溶剂旋干,残留物用石油醚/乙酸乙酯(1/1)洗涤得到10-a(174mg,68%)为棕色固体。LC-MS(ESI):m/z=316.0[M+H]+.
化合物10的合成
氮气氛围下,将10-a(174mg,0.55mmol),对甲基苯磺酰甲基异腈(162mg,0.83mmol)和碳酸钾(160mg,1.16mmol)的DMF/DME(2mL/1.67mL)溶液加热至100℃搅拌过夜。反应结束后,取三分之一的反应液过滤,粗品通过Prep-HPLC纯化得到10(15mg+60mg粗品,38%)为白色固体。LC-MS(ESI):m/z=355.0[M+H]+;1H NMR(500MHz,MeOD):δ8.92(t,1H,J=1.0Hz),8.38(s,1H),8.13(s,1H),8.05-8.02(m,2H),7.89(s,1H),7.82(q,1H,J=0.5,9.5Hz),7.61-7.55(m,2H).
化合物11的合成路线
化合物11的合成
将30%双氧水(1mL)加入到10(60mg,0.17mmol)剩余的三分之二的DMF/DME反应液,常温搅拌2小时,反应结束后,过滤,粗品通过Prep-HPLC纯化得到11(38mg,60%)为白色固体。LC-MS(ESI):m/z=373.0[M+H]+;1H NMR(500MHz,DMSO-d6):δ9.55(s,1H),8.42(s,1H),8.17(s,1H),8.06(s,3H),7.92(s,1H),7.74(d,1H,J=8.5Hz),7.63(s,1H),7.46(d,2H,J=9.5Hz).
化合物13的合成路线
化合物13-c的合成
将咪唑[1,2-a]并吡啶-6-甲酸(4.86g,30.0mmol)的混合物溶于二氯甲烷(250mL)中。在冰浴下,向溶液中加入草酰氯(10mL)后慢慢将DMF(0.5mL)加入到反应液中。反应升至室温后继续反应4小时。反应液减压浓缩至干燥,后加入二氯甲烷(300mL)稀释。在冰浴下,将该溶液慢慢滴加三乙胺(50mL)和N,O-二甲羟氨盐酸盐(6g,60.0mmol)到反应液中,在0℃下反应10分钟,再升至室温搅拌2小时。浓缩除去二氯甲烷溶液,再将水(100mL)加入到水相稀释剧烈搅拌1小时。过滤,水洗,干燥固体。得到白色固体13-c(4.6g,75%)。LC-MS(ESI):m/z=206.1[M+H]+.
化合物13-b的合成
将2,6-二甲基吡啶(8.6g,80.0mmol)的混合物溶于四氢呋喃(200mL)中。在-78℃干冰浴下,向溶液中缓慢滴加正丁基锂(2.5M,32mL,80.0mmol)。在此温度下继续反应2小时。将13-c(4.2g,20.0mmol)加入到反应液中,在-78℃下反应10分钟,再升至室温搅拌0.5小时。浓缩有机相,柱层析(P/E=3/1)得到黄色固体13-b(2.8g,56%)。LC-MS(ESI):m/z=252.1[M+H]+.
化合物13-a的合成
将化合物13-b(0.5g,2.0mmol)和DMF-DMA(1mL)的混合物加热至于100℃下,后反应3小时,浓缩得到化合物13-a直接投入下步反应。LC-MS(ESI):m/z=307.3[M+H]+.
化合物13的合成
将化合物13-a(0.62g,2.0mmol),盐酸羟胺(0.84g,12.0mmol)和乙醇(10mL)的混合物加热至于100℃下反应3小时,浓缩。再将饱和碳酸氢钠(100mL)加入到产品中碱化,剧烈搅拌1小时。过滤,水洗,干燥固体。得到固体13(0.5g,91%)。LC-MS(ESI):m/z=277.1[M+H]+;1H NMR(500MHz,MeOD):δ9.36(s,1H),8.88(s,1H),7.98(s,1H),7.77(t,J=7.5Hz,1H),7.64(d,J=9.5Hz,1H),7.60(dd,J=2.0,9.5Hz,2H),7.46(d,J=7.5Hz,1H),7.30(d,J=8.0Hz,1H),2.59(s,3H).
化合物14的合成路线
化合物14的合成
将化合物13(0.14g,0.5mmol),NBS(0.1g,0.56mmol)和二氯甲烷(10mL)的混合物于室温下反应3小时,浓缩。再将水(10mL)加入到产品中,剧烈搅拌1小时。过滤,水洗,干燥,得到固体14(0.18g,100%)。LC-MS(ESI):m/z 355[M+H]+;1H NMR(400MHz,MeOD):δ9.24(s,1H),8.91(s,1H),7.81(m,3H),7.73(d,J=6.4Hz,1H),7.51(d,J=6.0Hz,1H),7.32(d,J=6.0Hz,1H),2.63(s,3H).
化合物15的合成路线
化合物15的合成
将化合物氰化锌(0.12g,1.0mmol),14(0.15g,0.42mmol),四三苯基膦钯(0.115g,0.1mmol),DMF(10mL)的混合物于氮气氛围下在封管内,加热到150℃反应48小时。反应物冷至室温后浓缩,加入稀盐酸(10mL,30mmol)乙酸乙酯(300mL*3)萃取。碳酸氢钠水溶液碱化至pH至8,过滤、干燥,高效制备液相纯化,得到化合物15(0.006g,3.7%)为淡黄色固体。LC-MS(ESI):m/z=320.0[M+H]+;1H NMR(500MHz,MeOD):δ10.03(s,1H),8.25(s,1H),7.93(t,J=8.0Hz,1H),7.83(dd,J=9.0,1.5Hz,1H),7.64(d,J=9.5Hz,1H),7.54(d,J=9.5Hz,1H),7.31(d,J=8.5Hz,1H),7.05(d,J=7.5Hz,1H),2.57(s,3H).
化合物16的合成路线
将化合物13(0.276g,1.0mmol),Pd/C(0.1g)和乙醇(10mL)在室温条件下混合,氢气置换后,常温搅拌反应3小时。过滤,浓缩。得到固体16-a(0.26g,94%)。LC-MS(ESI):m/z=279.1[M+H]+.
将化合物16-a(0.26g,0.93mmol),碘(0.5g,2.0mmol),P2S5(0.44g,2.0mmol)和二氯甲烷(60mL)在室温条件下混合,常温搅拌反应24小时。饱和的亚硫酸氢钠(60mL)淬灭反应,二氯甲烷(100*3mL)萃取,浓缩有机相。柱层析(P/E=1/3)得到固体16(0.05g,18%)。LC-MS(ESI):m/z=293.0[M+H]+;1H NMR(500MHz,MeOD):δ8.84(s,1H),8.76(s,1H),7.93(s,1H),7.70(t,J=6.0Hz,1H),7.65(d,J=1.5Hz,1H),7.56(d,J=9.5Hz,1H),7.27(s,1H),7.26(s,1H),7.15(d,J=9.5,1.5Hz,1H),2.53(s,3H).
化合物17的合成路线
化合物17-c的合成
将化合物1-d(7.2g,30.1mmol),联硼酸酯(22.86g,90mmol),醋酸钾(8.82g,90mmol),Pd(dppf)Cl2(0.43g,0.53mmol)和干燥的二氧六环(80mL)的混合物于氮气氛围下加热到100℃反应3小时。将反应物冷至室温后浓缩,加入水(200mL)并搅拌,过滤,干燥。将得到的固体用乙酸乙酯(200mL)溶解,在搅拌下加入饱和的乙酸乙酯盐酸溶液(20mL),过滤并干燥,得化合物17-c(5.96g,97%)。LC-MS(ESI):m/z=206[M+H]+。1H NMR(400MHz,CD3OD):δ9.96(s,1H),8.54(s,1H),8.13(d,J=8.0Hz,1H),7.89(d,J=8.0Hz,1H)。
化合物17-b的合成
往反应瓶中加入2,3-二溴噻吩(500mg,2.07mmol),17-c(424mg,2.07mmol),四(三苯基膦)钯(120mg,0.1mmol),碳酸钠(878mg,8.28mmol),1,4-二氧六环(20mL)和水(5mL)。反应混合物用N2置换,于100℃反应过夜。反应结束后,浓缩除去有机溶剂,粗品经柱层析(DCM:MeOH=30:1)纯化得到化合物17-b(0.27g,41%)为白色固体。LC-MS(ESI):m/z=321.8[M+H]+.
化合物17-a的合成
往反应瓶中加入17-b(0.27g,0.84mmol),双联频哪醇硼酸酯(255mg,1mmol),Pd(dppf)Cl2(31mg,0.042mmol),醋酸钾(165mg,1.68mmol),1,4-二氧六环(10mL)和甲苯(10mL)。反应混合物用N2置换,于90℃反应过夜。反应结束后,浓缩除去有机溶剂,粗品经柱层析(DCM:MeOH=20:1)纯化得到化合物17-a(0.22g,71%)为黄色固体。LC-MS(ESI):m/z=370.0[M+H]+.
化合物17的合成
往反应瓶中加入17-a(0.22g,0.59mmol),2-溴-6-甲基吡啶(123mg,0.72mmol),四(三苯基膦)钯(69mg,0.06mmol),碳酸钠(126mg,1.19mmol),1,4-二氧六环(15mL)和水(3mL)。反应混合物用N2置换,于90℃反应过夜。反应结束后,浓缩除去有机溶剂,粗品经Prep-HPLC纯化得到化合物17(45mg,23%)为白色固体。LC-MS(ESI):m/z=335.0[M+H]+;1HNMR(500MHz,DMSO):δ9.61(s,1H),8.35(s,1H),7.99(brs,1H),7.71(d,J=5.0Hz,1H),7.65(d,J=9.5Hz,1H),7.58(t,J=7.5Hz,1H),7.52(d,J=5.0Hz,1H),7.41(brs,1H),7.25(dd,J=9.5,1.5Hz,1H),7.15(d,J=8.0Hz,1H),7.15(d,J=8.0Hz,1H),2.38(s,3H).
化合物18的合成路线
化合物18-c的合成
往反应瓶中加入4-溴-2-甲基噻吩(1g,5.65mmol),DMF(5mL),NBS(1.1g,6.18mmol)。混合物在室温下反应过夜后,加入水(30mL),用石油醚(30mL)萃取,有机相依次用水洗,饱和氯化钠水溶液洗,无水硫酸钠干燥。过滤,旋干,粗品经柱层析(用纯石油醚为流动相)纯化得到化合物18-c(1.25g,86%)为黄色液体。1H NMR(500MHz,CDCl3):δ6.59(d,J=1.1Hz,1H),2.41(d,J=1.0Hz,3H).
化合物18-b的合成
往反应瓶中加入18-c(1g,3.9mmol),17-c(801mg,3.9mmol),四(三苯基膦)钯(225mg,0.20mmol),碳酸钠(1.65g,15.6mmol),1,4-二氧六环(30mL),水(5mL)。反应混合物用N2置换,于100℃反应过夜。反应结束后,浓缩除去有机溶剂,粗品经柱层析(DCM:MeOH=20:1)纯化得到化合物18-b(0.51g,39%)为黄色固体。LC-MS(ESI):m/z=335.9[M+H]+.
化合物18-a的合成
往反应瓶中加入18-b(0.51g,1.52mmol),双联频哪醇硼酸酯(0.46g,1.82mmol),Pd(dppf)Cl2(56mg,0.076mmol),醋酸钾(298mg,3.04mmol),1,4-二氧六环(30mL)和甲苯(20mL)。反应混合物用N2置换,于90℃反应过夜。反应结束后,浓缩除去有机溶剂,粗品经柱层析(DCM:MeOH=20:1)纯化得到化合物18-a(0.46g,79%)为黑色固体。LC-MS(ESI):m/z=384.1[M+H]+.
化合物18的合成
往反应瓶中加入18-a(0.46g,1.2mmol),2-溴-6-甲基吡啶(0.25g,1.44mmol),四(三苯基膦)钯(69mg,0.06mmol),碳酸钠(254mg,2.4mmol),1,4-二氧六环(15mL)和水(3mL)。反应混合物用N2置换,于90℃反应过夜。反应结束后,浓缩除去有机溶剂,粗品经Prep-HPLC纯化得到化合物18(70mg,17%)为黄色固体。LC-MS(ESI):m/z=349.0[M+H]+;1HNMR(500MHz,DMSO-d6):δ9.56(s,1H),8.34(s,1H),7.96(brs,1H),7.63(d,J=9.5Hz,1H),7.56(t,J=8.0Hz,1H),7.37(brs,1H),7.23(d,J=1.0Hz,1H),7.21(dd,J=9.5,2.0Hz,1H),7.10(t,J=7.0Hz,2H),2.52(s,3H),2.37(s,3H).
化合物19的合成路线
化合物19-d的合成
往反应瓶中加入3-溴-2-甲氧基吡啶(2g,10.6mmol),联硼酸频那醇酯(2.74g,12.8mmol),Pd(dppf)Cl2(388mg,0.53mmol),醋酸钾(2.08g,21.2mmol)和甲苯(20mL)。反应混合物用N2置换,于90℃反应过夜。反应结束后,浓缩,加入水(20mL),用乙酸乙酯(30mL*2)萃取,有机相用无水硫酸钠干燥。过滤,浓缩后粗品经柱层析(PE:EA=4:1)纯化得到粗品化合物19-d(2.2g,88%)为黄色油状物。LC-MS(ESI):m/z=236.1[M+H]+.
化合物19-c的合成
往反应瓶中加入2-溴-6-甲基吡啶(0.9g,5.23mmol),19-d(1.6g,6.8mmol),Pd(dppf)Cl2(191mg,0.26mmol),碳酸钠(1.11g,10.46mmol),1,4-二氧六环(20mL)和水(4mL)。反应混合物用N2置换,于80℃反应过夜。反应结束后,浓缩,加入水(20mL),用乙酸乙酯(30mL*2)萃取,有机相用无水硫酸钠干燥,过滤,浓缩后粗品经柱层析(PE:EA=30:1)纯化得到化合物19-c(0.97g,92%)为黄色固体,LC-MS(ESI):m/z=201.1[M+H]+.
化合物19-b的合成
将19-c(0.97g,4.84mmol)溶于二氯甲烷(15mL)中,干冰丙酮浴冷却,慢慢滴加三溴化硼的二氯甲烷溶液(1.0M,14.5mL,14.5mmol),温度慢慢升至室温,反应过夜后,加入饱和碳酸氢钠水溶液淬灭反应,用二氯甲烷(30mL*2)萃取,有机相用无水硫酸钠干燥,过滤,浓缩后粗品经柱层析(PE:EA=5:1到DCM:MeOH=30:1)纯化得到化合物19-b(0.33g,37%)为黄色固体。LC-MS(ESI):m/z=187.3[M+H]+.
化合物19-a的合成
将19-b(0.33g,1.77mmol)和吡啶(0.7g,8.85mmol)溶于二氯甲烷(10mL)中,冰水浴冷却,慢慢加入三氟甲磺酸酐(1g,3.54mmol),混合物于室温下搅拌过夜。浓缩,粗品经柱层析(PE:EA=5:1)纯化即得到化合物19-a(415mg,74%)为黄色油状物。LC-MS(ESI):m/z=319.1[M+H]+.
化合物19的合成
往反应瓶中加入19-a(215mg,0.68mmol),17-c(166mg,0.81mmol),四(三苯基膦)钯(39mg,0.034mmol),碳酸钠(144mg,1.36mmol),甲苯(6mL),乙醇(6mL)和水(3mL)。反应混合物用N2置换,于90℃反应过夜。反应结束后,浓缩除去有机溶剂,加入水(20mL),用乙酸乙酯(30mL)萃取,有机相依次用水洗,饱和氯化钠水溶液洗,无水硫酸钠干燥,过滤,旋干,粗品经Prep-HPLC得到化合物19(88mg,40%)为白色固体。LC-MS(ESI):m/z=330.1[M+H]+;1HNMR(500MHz,DMSO-d6):δ9.63(s,1H),8.77(dd,J=4.5,1.5Hz,1H),8.33(s,1H),8.04(dd,J=7.5,1.5Hz,1H),7.93(brs,1H),7.55-7.61(m,2H),7.37(brs,1H),7.18(d,J=8.0Hz,1H),7.13(dd,J=9.5,1.5Hz,1H),7.08(d,J=8.0Hz,1H),2.43(s,3H).
化合物20的合成路线
化合物20-a的合成
参考17-c的合成路线,以1-e为原料制备得到。
化合物20的合成
往反应瓶中加入19-a(200mg,0.63mmol),20-a(208mg,0.69mmol),四(三苯基膦)钯(36mg,0.032mmol),碳酸钠(133mg,1.26mmol),甲苯(6mL),乙醇(6mL)和水(3mL)。反应混合物用N2置换,于90℃反应过夜。反应结束后,浓缩除去有机溶剂,加入水(30mL),用乙酸乙酯(30mL)萃取,有机相依次用水洗,饱和氯化钠水溶液洗,无水硫酸钠干燥,过滤,旋干,粗品经Prep-HPLC得到化合物20(52mg,24%)为白色固体。LC-MS(ESI):m/z=344.1[M+H]+;1HNMR(500MHz,DMSO-d6):δ9.65(s,1H),8.76(dd,J=4.5,1.5Hz,1H),8.38-8.48(m,1H),8.26(s,1H),8.04(dd,J=7.5,1.5Hz,1H),7.61–7.55(m,2H),7.51(d,J=8.5Hz,1H),7.19(d,J=8.0Hz,1H),7.11–7.05(m,2H),2.80(d,J=4.5Hz,3H),2.43(s,3H).
化合物21的合成路线
化合物21-c的合成
往反应瓶中加入3-溴-1-甲基吡咯(310mg,1.93mmol),19-d(543mg,2.31mmol),Pd(dppf)Cl2(70mg,0.095mmol),碳酸钠(403mg,3.8mmol),1,4-二氧六环(20mL)和水(4mL)。反应混合物用N2置换,于90℃反应过夜。反应结束后,浓缩,加入水(20mL),用乙酸乙酯(30mL*2)萃取,有机相用无水硫酸钠干燥,过滤,浓缩后粗品经柱层析(PE:EA=5:1)纯化得到化合物21-c(200mg,55%)为黄色固体。LC-MS(ESI):m/z=190.1[M+H]+.
化合物21-b的合成
将21-c(200mg,1.06mmol)溶于二氯甲烷(10mL)中,干冰丙酮浴冷却,慢慢滴加三溴化硼的二氯甲烷溶液(1.0M,2.11mL,2.11mmol),温度慢慢升至室温,反应过夜后,加入饱和碳酸氢钠水溶液淬灭反应,用二氯甲烷(30mL*2)萃取,水相旋干,加入二氯甲烷(20mL),过滤,合并的有机相用无水硫酸钠干燥,过滤,浓缩后粗品经柱层析(DCM:MeOH=20:1)纯化得到化合物21-b(139mg,74%)为黄色固体。LC-MS(ESI):m/z=176.1[M+H]+.
化合物21-a的合成
将21-b(139mg,0.79mmol)和吡啶(312mg,3.95mmol)溶于二氯甲烷(10mL)中,冰水浴冷却,慢慢加入三氟甲磺酸酐(448mg,0.267mL,1.59mmol),混合物于室温下搅拌过夜。浓缩,粗品经柱层析(PE:EA=1:1)纯化即得到化合物21-a(244mg,100%)为黄色油状物。LC-MS(ESI):m/z=308.0[M+H]+.
化合物21的合成
往反应瓶中加入21-a(244mg,0.79mmol),17-c(195mg,0.95mmol),四(三苯基膦)钯(46mg,0.040mmol),碳酸钠(167mg,1.58mmol),甲苯(8mL),乙醇(8mL)和水(4mL)。反应混合物用N2置换,于90℃反应过夜。反应结束后,浓缩除去有机溶剂,加入水(20mL),用乙酸乙酯(30mL*2)萃取,有机相依次用水洗,饱和氯化钠水溶液洗,无水硫酸钠干燥,过滤,旋干,粗品经Prep-HPLC得到化合物21(90mg,36%)为白色固体。LC-MS(ESI):m/z=319.1[M+H]+;1H NMR(500MHz,DMSO-d6):δ9.68(s,1H),8.67(dd,J=4.5,1.5Hz,1H),8.36(s,1H),8.07(dd,J=8.0,1.5Hz,1H),7.98(brs,1H),7.64–7.59(m,2H),7.51(dd,J=8.0,4.5Hz,1H),7.40(brs,1H),7.28(dd,J=9.5,1.5Hz,1H),5.91(d,J=2.2Hz,1H),3.83(s,3H).
化合物22的合成路线
化合物22-c的合成
往反应瓶中加入化合物2-溴-4-甲基噻唑(225mg,1.26mmol),19-d(440mg,1.87mmol,),Pd(dppf)Cl2(92mg,0.12mmol),Na2CO3(265mg,2.5mmol),二氧六环(15mL)和水(3mL)。反应液用N2置换,在80℃下搅拌过夜。反应液浓缩,粗品经硅胶柱层析分离(PE:EA=10:1)得到产物22-c(225mg,86%)为黄色固体。LC-MS(ESI):m/z=207.1[M+H]+.
化合物22-b的合成
将化合物22-c(225mg,1.1mmol)溶于干燥的二氯甲烷(10mL)中,干冰/丙酮浴冷却至-78℃,向反应瓶中慢慢滴加三溴化硼的二氯甲烷溶液(1.0M,1.2mL,1.2mmo),加完后反应液温度慢慢升至室温,搅拌过夜,反应液在冰浴下慢慢滴加饱和碳酸氢钠水溶液,分出有机相,水层用二氯甲烷(30mL*2)萃取,无水硫酸钠干燥,浓缩,得化合物22-b为黄色固体(100mg,48%)。LC-MS(ESI):m/z=193.1[M+H]+.
化合物22-a的合成
将22-b(100mg,0.52mmol)和吡啶(123mg,1.56mmol)溶于二氯甲烷(15mL)中,冰水浴冷却,慢慢加入三氟甲磺酸酐(220mg,0.78mmol),混合物于室温搅拌过夜后,浓缩,加入水(20mL),用二氯甲烷(20mL*2)萃取,合并的有机相用无水硫酸钠干燥,过滤,浓缩后经Prep-TLC纯化(PE:EA=10:1),得化合物22-a(20mg,12%)为黄色固体。LC-MS(ESI):m/z=324.9[M+H]+.
化合物22的合成
往反应瓶中加入22-a(20mg,0.06mmol),17-c(13mg,0.06mmol),Pd(dppf)Cl2(4mg,0.006mmol),碳酸钠(13mg,0.12mmol),1,4-二氧六环(10mL)和水(2mL)。反应混合物用N2置换,于80℃反应过夜。反应结束后,浓缩,粗品经Prep-HPLC得到化合物22(4mg,20%)为白色固体。LC-MS(ESI):m/z=336.0[M+H]+;1H NMR(400MHz,MeOD)δ9.72(s,1H),8.79(dd,J=4.8,1.6Hz,1H),8.38–8.27(m,2H),7.73–7.60(m,2H),7.49(dd,J=9.3,1.8Hz,1H),7.21(s,1H),2.41(s,3H).
化合物23的合成路线
化合物23-c的合成
往20mL微波管中加入2-氰基-3-羟基吡啶(500mg,4.16mmol),二硫代磷酸二乙酯(853mg,4.58mmol)和水(6mL)。微波管密封,反应液在90℃条件下搅拌过夜。反应结束后,过滤,滤饼干燥得到化合物23-c(535mg,83%)为黄色固体。LC-MS(ESI):m/z=155.1[M+H]+;1H NMR(500MHz,DMSO-d6):δ12.85(s,1H),10.02-10.39(m,2H),8.18(dd,J=4.0,1.5Hz,1H),7.55(dd,J=8.5,4.0Hz,1H),7.46(dd,J=8.5,1.5Hz,1H).
化合物23-b的合成
往反应瓶中加入化合物23-c(500mg,3.24mmol),氯丙酮(0.52mL,6.49mmol)和乙醇(20mL)。反应液加热回流搅拌过夜。反应结束后浓缩,粗品经硅胶柱层析分离(PE:EA=5:1)得到产物23-b(0.55g,88%)为白色固体。LC-MS(ESI):m/z=193.0[M+H]+.
化合物23-a的合成
将吡啶(93mg,1.17mmol)和23-b(150mg,0.78mmol)溶于二氯甲烷(10mL)中,冰水浴冷却,慢慢加入三氟甲磺酸酐(0.2mL,1.17mmol),混合物于室温搅拌过夜。加入水(10mL),分出有机层,水层用二氯甲烷(10mL*2)萃取,合并的有机相无水硫酸钠干燥,浓缩后经柱层析纯化(PE:EA=5:1)得化合物23-a(150mg,59%)。LC-MS(ESI):m/z=325.0[M+H]+.
化合物23的合成
将23-a(150mg,0.46mmol),17-c(94.8mg,0.46mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(33.8mg,0.046mmol),碳酸钠(147.1mg,1.39mmol),二氧六环(10.0mL)和水(2.0mL)加入反应瓶中。反应液用N2置换,于85℃反应过夜。反应结束后,浓缩得到粗品。粗品经高效液相制备色谱分离得到产物23(75mg,48%)为白色固体。LC-MS(ESI):m/z=336.0[M+H]+;1H NMR(500MHz,DMSO-d6):δ9.47(s,1H),8.72(dd,J=4.5,1.5Hz,1H),8.37(s,1H),8.00(brs,1H),7.97(dd,J=7.5,2.5Hz,1H),7.65(d,J=9.0Hz,1H),7.60(dd,J=8,4.5Hz,1H),7.40(brs,1H),7.35(dd,J=9.0,1.5Hz,1H),7.33(s,1H),2.05(s,3H).
化合物24的合成路线
化合物24-c的合成
将化合物24-d(2.2g,10.0mmol),二苯甲酮亚胺(1.8g,10.0mmol),Pd2(dba)3(0.23g,0.4mmol),BINAP(0.25g,0.4mmol),叔丁醇钠(2.0g,20.0mmol),甲苯(100mL)的混合物于氮气氛围下加热到100℃反应1小时。反应物冷至室温后浓缩。加入稀盐酸(100mL,300mmol)乙酸乙酯(30 0mL*3)萃取。碳酸氢钠水溶液碱化水相至PH至8,过滤、干燥。得到灰色固体24-c(1.28g,80%)。LC-MS(ESI):m/z=159.1[M+H]+.
化合物24-b的合成
将化合物24-c(0.16g,1.0mmol),甲醇(20mL),1-甲基吡咯-3-甲醛(0.14g,1.27mmol),甲酸(0.20mL)的混合物于室温下搅拌3小时。凝缩反应液,加入乙酸乙酯(5mL)、石油醚(30mL)过滤,得到固体24-b(0.25g,100%)。LC-MS(ESI):m/z=251.1[M+H]+.
化合物24-a的合成
将化合物对甲基苯磺酰甲基异腈(0.38g,2.0mmol),24-b(0.25g,1.0mmol),碳酸钾(0.28g,2.0mmol),DME(4mL),DMF(10mL)的混合物于氮气氛围下在封管内,加热到100℃反应12小时。反应物冷至室温后浓缩。乙酸乙酯(300mL)洗涤,过滤,浓缩得到化合物24-a直接投入下一步。LC-MS(ESI):m/z=290.2[M+H]+.
化合物24的合成
将化合物24-a(0.14g,0.5mmol),DMSO(4mL),碳酸钾(0.138g,1.0mmol)的混合物于0℃下,缓慢滴加30%H2O2(3mL)后反应3小时,浓缩。水(10mL)稀释,过滤,乙酸乙酯打浆(10mL)纯化得到灰色固体24(0.059g,38%)。LC-MS(ESI):m/z=308.0[M+H]+;1H NMR(500MHz,MeOD):δ9.72(d,J=1.5Hz,1H),8.38(s,1H),8.02(s,1H),7.75(d,J=9.5Hz,1H),7.53(d,J=2.0Hz,1H),7.48(dd,J=9.5,2.0Hz,1H),7.39(s,1H),6.17(d,J=2.5Hz,1H),3.81(s,3H).
化合物25的合成路线
化合物25-d的合成
将1-Boc-吲哚-2-硼酸(1.4g,5.36mmol),2-溴-6-甲基吡啶(922mg,5.36mmol),Pd(dppf)Cl2(438mg,0.54mmol),碳酸钠(1.7g,16.08mmol),二氧六环(10mL)和水(2mL)加入反应瓶中。反应液用N2置换,于85℃反应过夜。反应结束后,反应液用乙酸乙酯稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干。粗品经硅胶柱层析分离(PE:EA=10:1)得到产物25-d(1g,60%)为白色固体。LC-MS(ESI):m/z=309.1[M+H]+.
化合物25-c的合成
将25-d(1g,3.24mmol)溶于二氯甲烷(20mL)和三氟乙酸(10mL),室温搅拌过夜。反应结束后,减压浓缩除去有机溶剂,加入饱和碳酸氢钠水溶液(10mL)和DCM(10mL),分液。水层用二氯甲烷萃取,合并有机层,用无水硫酸钠干燥,过滤,浓缩得到25-c(400mg,59%)为白色固体。LC-MS(ESI):m/z=209.1[M+H]+.
化合物25-a的合成
往反应瓶中加入化合物25-c(50mg,0.24mmol),1-c(53.3mg,0.24mmol),碘化亚铜(5mg,0.024mmol),N,N'-二甲基乙二胺(4.2mg,0.048mmol),磷酸钾(102mg,0.48mmol)和甲苯(2mL)。反应液用N2置换,在110℃下搅拌过夜。反应结束后,用乙酸乙酯稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干。粗品经硅胶柱层析分离(PE:EA=1:1)得到化合物25-a(50mg,60%)为白色固体。LC-MS(ESI):m/z=350.1[M+H]+.
化合物25的合成
在冰浴下,往25-a(50mg,0.143mmol)和碳酸钾(3mg,0.021mmol)的二甲亚砜(2mL)溶液中滴加入过氧化氢(19.5mg,0.57mmol)。混合物升至室温,搅拌过夜。反应结束后,缓慢加入水(5mL)淬灭,搅拌半小时,有白色沉淀析出,过滤,收集固体,干燥得到化合物25(10mg,19%)为白色固体。LC-MS(ESI):m/z=368.0[M+H]+;1H NMR(500MHz,MeOD):δ9.62(d,J=1.5Hz,1H),8.38(s,1H),7.72-7.77(m,2H),7.66(t,J=7.5Hz,1H),7.50(d,J=8.0Hz,1H),7.47(dd,J=9.5,2.0Hz,1H),7.30(d,J=8.5Hz,1H),7.26(t,J=7.0Hz,1H),7.22(t,J=8.0Hz,1H),7.18(s,1H),7.09(d,J=8.0Hz,1H),2.23(s,3H).
对比化合物12的合成路线
化合物12-b的合成
往反应瓶中加入化合物6-溴-[1,2,4]三唑并[1,5-a]吡啶(0.7g,3.54mmol),二苯甲酮亚胺(961mg,5.30mmol),叔丁醇钠(679.5mg,7.07mmol),Pd2(dba)3(162mg,0.18mmol),1,1'-联萘-2,2'-双二苯膦(220mg,0.35mmol)和甲苯(40mL)。反应液用N2置换,在100℃下搅拌一小时。反应结束后反应液用乙酸乙酯稀释,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋干得到黑色油状物。加入稀盐酸(2M,10mL),搅拌半小时,用碳酸氢钠固体中和至pH>7,用二氯甲烷萃取,有机相干燥,浓缩,所得粗产品经硅胶柱层析得到茶色固体12-b(0.3g,63%)。LC-MS(ESI):m/z=135.1[M+H]+.
化合物12-a的合成
往反应瓶中加入化合物6-甲基-2-吡啶甲醛(45mg,0.37mmol),12-b(50mg,0.37mmol),甲醇(10mL)和几滴甲酸。反应液在室温下搅拌过夜。反应结束后浓缩,所得固体用乙酸乙酯洗涤,干燥得到产物12-a(50mg,56%)为白色固体。LC-MS(ESI):m/z=238.1[M+H]+.
对比化合物12的合成
往反应瓶中加入化合物12-a(50mg,0.21mmol),对甲基苯磺酰甲基异腈(62mg,0.32mmol),碳酸钾(61mg,0.44mmol),DMF(4.6mL)和乙二醇二甲醚(3.75mL)。反应液用N2置换,在100℃下搅拌过夜。结束后,过滤,滤液经高效液相制备色谱得到固体12(15mg,26%)。LC-MS(ESI):m/z=277.1[M+H]+;1H NMR(500MHz,MeOD):δ9.16(s,1H),8.54(s,1H),8.10(s,1H),7.82(d,J=9.5,1H),7.69(t,J=8.0Hz,1H),7.62-7.66(m,2H),7.49(d,J=8.0Hz,1H),7.11(t,J=7.5Hz,1H),2.27(s,3H).
效果实施例1 ALK5酶活性抑制IC50评价实验
1.配制1x的激酶缓冲液:40mM Tris(pH 7.5),20mM MgCl2,0.10%BSA,1mMDTT。
2.化合物配制:化合物的检测终浓度为10μM,配置成100倍浓度,即1mM,在384孔板上第二个孔中加入100μL的100倍的化合物,其他孔加入60μL的100%DMSO。从第二孔中取30μL化合物加入第三孔中,依次往下做3倍稀释,共稀释10个浓度。用echo转移50nL化合物到反应板中。
3.激酶反应:将激酶加入1倍激酶缓冲液,形成2倍酶溶液。激酶溶液终浓度为ALK5:25nM。将多肽TGFbR1(购自Signal Chem公司,商品目录编号为T36-58)和ATP加入1倍激酶缓冲液,形成2倍底物溶液。底物溶液终浓度为多肽TGFbR1 0.1mg/mL,ATP 7μM。向384孔反应板中(已有50nL的100%DMSO溶解的化合物)加入2.5μL的2倍酶溶液,阴性对照孔加入1倍激酶缓冲液。室温下孵育10分钟。在384孔反应板中加入2.5μL的2倍底物溶液。将384孔板盖上盖子,于30℃下孵育1小时。将ADP-Glo试剂(购自Promege公司,商品目录编号为v9102)平衡到室温。转移5μL ADP-Glo试剂到384孔板反应孔中终止反应。
4.反应结果的检测:转移10μL激酶检测试剂到每个反应孔中,振荡1分钟,室温静置30分钟。在Synegy读取样品发光数值。
5.曲线拟合:从Synegy程序上复制发光读数的数据。将发光读数的值通过公式转换为抑制百分率(抑制百分率=(max-sample RLU)/(max-min)*100,其中,“min”为不加酶进行反应的对照样荧光读数;“max”为加入DMSO作为对照的样品荧光读数)。将数据导入MSExcel并使用GraphPad Prism进行曲线拟合。计算IC50值。
表1本发明的部分化合物对ALK5活性的IC50结果
其中,SB431542(CAS号:301836-41-9)是已知的ALK5抑制剂,其结构如下:
由上述试验的结果可以确认,本发明的化合物对ALK5的活性具有明显的抑制作用。
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改。因此,本发明的保护范围由所附权利要求书限定。
Claims (13)
1.一种通式I所示的芳香杂环化合物或其药学上可接受的盐:
其中,
为
环Q中,Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22各自独立地为氢、氘、卤素、磺酸基、取代或未取代的C1-6烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的C3-10环烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-10杂芳基、氰基、-OR61、-SR62、-NRa63Ra64、-C(O)R65、-C(O)OR66、-OC(O)R67、-OC(O)OR68、-C(O)NRa69Ra610、-N(R611)C(O)R612、S(O)R613、-S(O)2R614、-S(O)2NRa615Ra616、-OC(O)NRa617Ra618、-N(R619)C(O)OR620、-N(R621)C(O)NRa622Ra623、-N(R624)S(O)2R625或-OP(O)(OR626)2;R61、R62、Ra63、Ra64、R65、R66、R67、R68、Ra69、Ra610、R611、R612、R613、R614、Ra615、Ra616、Ra617、Ra618、R619、R620、R621、Ra622、Ra623、R624、R625和R626各自独立地为氢、取代或未取代的C1-6烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的C3-10环烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、或取代或未取代的C2-10杂芳基;
Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22中,所述的取代的C1-6烷基、取代的C2-8烯基、取代的C2-8炔基、取代的C3-10环烷基、取代的C2-8杂环烷基、取代的C6-20芳基、取代的C2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个:氘、卤素、C1-6烷基、卤素取代的C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基、C2-10杂芳基、氰基、-OR71、-SR72、-NRa73Ra74、-C(O)R75、-C(O)OR76、-OC(O)R77、-OC(O)OR78、-C(O)NRa79Ra710、-N(R711)C(O)R712、S(O)R713、-S(O)2R714、-S(O)2NRa715Ra716、-OC(O)NRa717Ra718、-N(R719)C(O)OR720、-N(R721)C(O)NRa722Ra723、-N(R724)S(O)2R725或-OP(O)(OR726)2;当取代基为多个时,所述的取代基相同或不同;R71、R72、Ra73、Ra74、R75、R76、R77、R78、Ra79、Ra710、R711、R712、R713、R714、Ra715、Ra716、Ra717、Ra718、R719、R720、R721、Ra722、Ra723、R724、R725和R726各自独立地为C1-6烷基、卤素取代的C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;
R61、R62、Ra63、Ra64、R65、R66、R67、R68、Ra69、Ra610、R611、R612、R613、Ra614、Ra615、Ra616、Ra617、Ra618、R619、R620、R621、Ra622、Ra623、R624、R625和R626中,所述的取代的C1-6烷基、取代的C2-8烯基、取代的C2-8炔基、取代的C3-10环烷基、取代的C2-8杂环烷基、取代的C6-20芳基或取代的C2-10杂芳基中的取代基为下列基团中的一个或多个:氘、卤素、氰基、C1-6烷基、卤素取代的C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基、C2-10杂芳基、-ORc、-SRc1、-NRb1Rb2、-C(O)Rc2、-C(O)ORc3、-OC(O)Rc4、-OC(O)ORc5、-C(O)NRb3Rb4、-N(Rc6)C(O)ORc7、S(O)Rc8、-S(O)2Rc9、-S(O)2NRb5Rb6、-N(Rc10)C(O)Rc11、-N(Rc12)C(O)NRb7Rb8或-N(Rc13)S(O)2Rc14;Rc、Rc1、Rb1、Rb2、Rc2、Rc3、Rc4、Rc5、Rb3、Rb4、Rc6、Rc7、Rc8、Rc9、Rb5、Rb6、Rc10、Rc11、Rc12、Rb7、Rb8、Rc13和Rc14各自独立地为氢、羟基、C1-6烷基、卤素取代的C1-6烷基、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;
Q3和Q31独立地为S或O;
Q4和Q41独立地为CRq23或N;Rq23与Rq1定义相同;
或者相邻的两个Rqx和与其相连的原子一起形成环状结构;所述的环状结构为取代或未取代的C3-10环烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、或取代或未取代的C2-10杂芳基;所述的环状结构中,所述的取代的C3-10环烷基、取代的C2-8杂环烷基、取代的C6-20芳基或取代的C2-10杂芳基中的取代基各自独立地为下列基团中的一个或多个:氘、卤素、氰基、C1-6烷基、卤素取代的C1-6烷基、C2-8烯基、C2-8炔基、-ORa15、-SRa16、-C(O)ORa17、-CORa18、-C(O)NH2、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;Ra15、Ra16、Ra17和Ra18各自独立地为氢或C1-6烷基;当取代基为多个时,所述的取代基相同或不同;
相邻的两个Rqx是指Rq1和Rq2;Rq2和Rq3;Rq4和Rq5;Rq5和Rq6;Rq7和Rq8;Rq9和Rq10;Rq17和Rq18;Rq18和Rq19;Rq20和Rq21;Rq21和Rq22;当Q4和Q41为CRq23时,相邻的两个Rqx还可为Rq15和Rq23;Rq16和Rq23;
为
环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、卤素、氰基、硝基、-NRa3Ra4、-ORa5、-SRa6、-C(O)ORa7、-C(O)NRa8Ra9、-CORa10、取代或未取代的C1-6烷基、取代或未取代的C2-8烯基、取代或未取代的C2-8炔基、取代或未取代的C3-10环烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C4-8环烯基、取代或未取代的C6-20芳基、或取代或未取代的C2-10杂芳基;
Ra4、Ra5、Ra6、Ra7、Ra9和Ra10各自独立地为氢、取代或未取代的C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;Ra3和Ra8各自独立地为氢、羟基、C1-6烷氧基、取代或未取代的C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;
R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1中,所述的取代的C1-6烷基、取代的C2-8烯基、取代的C2-8炔基、取代的C3-10环烷基、取代的C2-8杂环烷基、取代的C4-8环烯基、取代的C6-20芳基或取代的C2-10杂芳基中的取代基以及Ra3、Ra4、Ra5、Ra6、Ra7、Ra8、Ra9和Ra10中,所述的取代的C1-6烷基中的取代基各自独立地为下列基团中的一个或多个:氘、卤素、氰基、C1-6烷基、卤素取代的C1-6烷基、C2-8烯基、C2-8炔基、-ORa15、-SRa16、-C(O)ORa17、-CORa18、-C(O)NH2、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;Ra15、Ra16、Ra17和Ra18各自独立地为氢或C1-6烷基;当取代基为多个时,所述的取代基相同或不同;
R2为氢、氰基、C1-6烷基、C3-10环烷基、C2-8杂环烷基、-C(O)ORa19或被-ORa20取代的C1-6烷基;Ra19和Ra20各自独立地为C1-6烷基;
为
环B中,R5、R51、R5a、R5a1、R5a2、R5b、R5b1、R5c、R5c1、R5c2、R5d、R5d1、R5d2、R5e、R5e1和R5e2各自独立地为氢、氘或卤素;
R6、R6a、R6b、R6c、R6d和R6e与Rq1定义相同;条件是:R6、R6a、R6b、R6c、R6d和R6e不为氰基;
R7、R8、R9、R10、R11、R12和R13各自独立地为氢、氘或卤素;
或者上述各基团或取代基中,当存在NRXRY时,RX和RY与它们相连的N一起形成取代或未取代的3-8元杂环基;所述的3-8元杂环基中的杂原子选自N、N和O、N和S、或N、O和S;杂原子数为1、2、3或4;所述的取代的3-8元杂环基中的取代基为下列基团中的一个或多个:氘、卤素、氰基、C1-6烷基、C2-8烯基、C2-8炔基、-ORa81、-SRa82、-C(O)ORa83、-CORa84、-C(O)NH2、C3-10环烷基、C2-8杂环烷基、C6-20芳基或C2-10杂芳基;Ra81、Ra82、Ra83和Ra84各自独立地为氢或C1-6烷基;-NRXRY为-NRa3Ra4、-NRa8Ra9、-NRa63Ra64、-NRa69Ra610、-NRa615Ra616、-NRa617Ra618、-NRa622Ra623、-NRa73Ra74、-NRa79Ra710、-NRa715Ra716、-NRa717Ra718、-NRa722Ra723、-NRb1Rb2、-NRb3Rb4、-NRb5Rb6或-NRb7Rb8;
当Q环为时,不为
2.如权利要求1所述的通式I所示的芳香杂环化合物或其药学上可接受的盐,其特征在于,
所述的卤素为F、Cl、Br或I;
和/或,所述的取代或未取代的C1-6烷基中的C1-6烷基和所述的C1-6烷基独立地为C1-4烷基;所述的C1-4烷基优选甲基、乙基、正丙基、异丙基、正丁基、异丁基、或叔丁基;
和/或,所述的取代或未取代的C2-8烯基中的C2-8烯基和所述的C2-8烯基独立地为C2-4烯基;所述的C2-4烯基优选乙烯基、丙烯基、烯丙基、
和/或,所述的取代或未取代的C2-8炔基中的C2-8炔基和所述的C2-8炔基独立地为C2-4炔基;所述的C2-4炔基优选乙炔基、丙炔基、丁炔基或3-甲基丙炔基;
和/或,所述的取代或未取代的C3-10环烷基中的C3-10环烷基和所述的C3-10环烷基独立地为环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、双环[3.1.1]庚烷基、双环[2.2.1]庚烷基、双环[2.2.2]辛烷基、双环[3.2.2]壬烷基、双环[3.3.1]壬烷基或双环[4.2.1]壬烷基;
和/或,所述的取代或未取代的C2-8杂环烷基中的C2-8杂环烷基和所述的C2-8杂环烷基独立地为氮杂环丁烷基、氮杂环庚烷基、氮丙啶、二氮杂环庚烷基、1,3-二噁烷基、1,3-二氧戊环基、1,3-二硫戊环基、1,3-二噻烷基、咪唑啉基、咪唑烷基、异噻唑烷基、异噻唑基、异噁唑啉基、吗啉基、噁二唑啉基、噁二唑烷基、噁唑啉基、噁唑烷基、哌嗪基、哌啶基、吡喃基、吡唑啉基、吡唑烷基、吡咯啉基、吡咯烷基、四氢呋喃基、四氢噻吩基、噻二唑啉基、噻二唑烷基、噻唑啉基、噻唑烷基、硫代吗啉基、1,1-二氧硫代吗啉基、噻喃基、三噻烷基、2,3-二氢苯并呋喃-2-基、2,3-二氢苯并呋喃-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚-3-基、2,3-二氢苯并噻吩-2-基、十氢喹啉基、十氢异喹啉基、八氢-1H-吲哚基或八氢苯并呋喃基;
和/或,所述的取代或未取代的C4-8环烯基中的C4-8环烯基和所述的C4-8环烯基独立地为环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、降冰片烯基或双环[2.2.2]辛烯基;
和/或,所述的取代或未取代的C6-20芳基中的C6-20芳基或所述的C6-20芳基独立地为苯基、萘基、蒽基、菲基、薁基、二氢茚-1-基、二氢茚-2-基、二氢茚-3-基、二氢茚-4-基、2,3-二氢吲哚-4-基、2,3-二氢吲哚-5-基、2,3-二氢吲哚-6-基、2,3-二氢吲哚-7-基、茚-1-基、茚-2-基、茚-3-基、茚-4-基、二氢萘-2-基、二氢萘-3-基、二氢萘-4-基、二氢萘-1-基、5,6,7,8-四氢化萘-1-基、5,6,7,8-四氢化萘-2-基、2,3-二氢苯并呋喃-4-基、2,3-二氢苯并呋喃-5-基、2,3-二氢苯并呋喃-6-基、2,3-二氢苯并呋喃-7-基、苯并[d][1,3]间二氧杂环戊烯-4-基、苯并[d][1,3]间二氧杂环戊烯-5-基、2H-苯并呋喃-2-酮-5-基、2H-苯并呋喃-2-酮-6-基、2H-苯并呋喃-2-酮-7-基、2H-苯并呋喃-2-酮-8-基、异吲哚啉-1,3-二酮-4-基、异吲哚啉-1,3-二酮-5-基、茚-1-酮-4-基、茚-1-酮-5-基、茚-1-酮-6-基、茚-1-酮-7-基、2,3-二氢苯并[b][1,4]二噁烷-5-基、2,3-二氢苯并[b][1,4]二噁烷-6-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-5-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-6-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-7-基、2H-苯并[b][1,4]杂氧嗪3(4H)-酮-8-基、苯并[d]杂氧嗪-2(3H)-酮-5-基、苯并[d]杂氧嗪-2(3H)-酮-6-基、苯并[d]杂氧嗪-2(3H)-酮-7-基、苯并[d]杂氧嗪-2(3H)-酮-8-基、喹唑啉-4(3H)-酮-5-基、喹唑啉-4(3H)-酮-6-基、喹唑啉-4(3H)-酮-7-基、喹唑啉-4(3H)-酮-8-基、喹噁啉-2(1H)-酮-5-基、喹噁啉-2(1H)-酮-6-基、喹噁啉-2(1H)-酮-7-基、喹噁啉-2(1H)-酮-8-基、苯并[d]噻唑-2(3H)-酮-4-基、苯并[d]噻唑-2(3H)-酮-5-基、苯并[d]噻唑-2(3H)-酮-6-基或苯并[d]噻唑-2(3H)-酮-7-基;
和/或,所述的取代或未取代的C2-10杂芳基中的C2-10杂芳基和所述的C2-10杂芳基独立地为呋喃基、咪唑基、异噁唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基、三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁二唑基、苯并噻唑基、噌啉基、5,6-二氢喹啉-2-基、5,6-二氢喹啉-1-基、呋喃并吡啶基、吲唑基、吲哚基、异喹啉基、萘啶基、嘌呤基、喹啉基、5,6,7,8-四氢喹啉-2-基、5,6,7,8-四氢喹啉-3-基、5,6,7,8-四氢喹啉-4-基、5,6,7,8-四氢异喹啉-1-基、噻吩并吡啶基、4,5,6,7-四氢并[c][1,2,5]噁二唑基或6,7-二氢并[c][1,2,5]噁二唑-4(5H)酮基。
3.如权利要求1所述的通式I所示的芳香杂环化合物或其药学上可接受的盐,其特征在于,
环Q中,Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22各自独立地为氢、氘、卤素、磺酸基、C1-6烷基、C2-8烯基、C2-8炔基、C3-10环烷基、C2-8杂环烷基、C6-20芳基、C2-10杂芳基、氰基、-OR61、-SR62、-NRa63Ra64、-C(O)R65、-C(O)OR66、-OC(O)R67、-OC(O)OR68、-C(O)NRa69Ra610、-N(R611)C(O)R612、S(O)R613、-S(O)2R614、-S(O)2NRa615Ra616、-OC(O)NRa617Ra618、-N(R619)C(O)OR620、-N(R621)C(O)NRa622Ra623、-N(R624)S(O)2R625或-OP(O)(OR626)2;R61、R62、Ra63、Ra64、R65、R66、R67、R68、Ra69、Ra610、R611、R612、R613、R614、Ra615、Ra616、Ra617、Ra618、R619、R620、R621、Ra622、Ra623、R624、R625和R626的定义均同前所述;或者相邻的两个Rqx和与其相连的原子一起形成环状结构;所述的环状结构为取代或未取代的C3-10环烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、或取代或未取代的C2-10杂芳基;所述的取代的C3-10环烷基、取代的C2-8杂环烷基、取代的C6-20芳基、或取代的C2-10杂芳基中的取代基的定义均同权利要求1所述;
和/或,环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、卤素、氰基、硝基、-NRa3Ra4、-ORa5、-SRa6、-C(O)ORa7、-C(O)NRa8Ra9、-CORa10、取代或未取代的C1-6烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、或取代或未取代的C2-10杂芳基;其中,Ra3、Ra4、Ra5、Ra6、Ra7、Ra8、Ra9和Ra10的定义均同前所述;所述的取代的C1-6烷基、取代的C2-8杂环烷基、取代的C6-20芳基和取代的C2-10杂芳基中的取代基的定义均同权利要求1所述;R2为氢、C1-6烷基或C3-10环烷基;
和/或,环B中,R5、R51、R5a、R5a1、R5a2、R5b、R5b1、R5c、R5c1、R5c2、R5d、R5d1、R5d2、R5e、R5e1、R5e2、R7、R8、R9、R10、R11、R12和R13各自独立地为氢;R6、R6a、R6b、R6c、R6d和R6e各自独立地为氢、卤素、取代或未取代的C1-6烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-10杂芳基、-OR61、-SR62、-NRa63Ra64、-C(O)R65、-C(O)OR66、-OC(O)R67、-OC(O)OR68、-C(O)NRa69Ra610、-N(R611)C(O)R612、S(O)R613、-S(O)2R614、-S(O)2NRa615Ra616、-OC(O)NRa617Ra618、-N(R619)C(O)OR620、-N(R621)C(O)NRa622Ra623、-N(R624)S(O)2R625或-OP(O)(OR626)2;R61、R62、Ra63、Ra64、R65、R66、R67、R68、Ra69、Ra610、R611、R612、R613、R614、Ra615、Ra616、Ra617、Ra618、R619、R620、R621、Ra622、Ra623、R624、R625和R626的定义均同前所述;所述的取代的C1-6烷基、取代的C2-8杂环烷基、取代的C6-20芳基或取代的C2-10杂芳基中取代基的定义均同权利要求1所述。
4.如权利要求3所述的通式I所示的芳香杂环化合物或其药学上可接受的盐,其特征在于,
环Q中,Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22各自独立地为氢、氘、卤素或C1-6烷基;
和/或,环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、卤素、-ORa5、-SRa6、-C(O)NRa8Ra9、或取代或未取代的C1-6烷基,其中,Ra5、Ra6、Ra8和Ra9的定义均同权利要求3所述;所述的取代的C1-6烷基中的取代基同权利要求3所述;进一步优选各自独立地为氢、卤素、-ORa5、或取代或未取代的C1-6烷基;其中,Ra5为氢或C1-6烷基,所述的取代的C1-6烷基中的取代基优选下列取代基中的一个或多个:氘或卤素;更进一步优选各自独立地为氢、C1-6烷基或卤素取代的C1-6烷基,所述的卤素的个数为一个或多个;
和/或,环A中,R2为氢、C1-6烷基或C3-10环烷基;
和/或,环B中,R5、R51、R5a、R5a1、R5a2、R5b、R5b1、R5c、R5c1、R5c2、R5d、R5d1、R5d2、R5e、R5e1、R5e2、R7、R8、R9、R10、R11、R12和R13为氢;R6、R6a、R6b、R6c、R6d和R6e各自独立地为氢、卤素、取代或未取代的C1-6烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-10杂芳基、-OR61、-SR62、-NRa63Ra64、-C(O)R65、-C(O)OR66、-OC(O)R67、-OC(O)OR68、-C(O)NRa69Ra610、-N(R611)C(O)R612、S(O)R613、-S(O)2R614、-S(O)2NRa615Ra616、-OC(O)NRa617Ra618、-N(R619)C(O)OR620、-N(R621)C(O)NRa622Ra623、-N(R624)S(O)2R625或-OP(O)(OR626)2;进一步优选各自独立地为氢、卤素、取代或未取代的C1-6烷基、取代或未取代的C2-8杂环烷基、取代或未取代的C6-20芳基、取代或未取代的C2-10杂芳基、-OR61、-SR62、-C(O)R65、-C(O)OR66或-C(O)NRa69Ra610;再进一步优选各自独立地为氢、卤素、-C(O)OR66或-C(O)NRa69Ra610;其中,R61、R62、Ra63、Ra64、R65、R66、R67、R68、Ra69、Ra610、R611、R612、R613、R614、Ra615、Ra616、Ra617、Ra618、R619、R620、R621、Ra622、Ra623、R624、R625和R626的定义均同权利要求3所述;所述的取代的C1-6烷基、取代的C2-8杂环烷基、取代的C6-20芳基或取代的C2-10杂芳基中取代基的定义均同权利要求3所述。
5.如权利要求4所述的通式I所示的芳香杂环化合物或其药学上可接受的盐,其特征在于,
环Q中,Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq9、Rq10、Rq11、Rq12、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22各自独立地为氢或C1-6烷基;
环A中,R3、R31、R32、R33、R3a、R3a1、R3b、R3b1、R3c、R3c1、R3c2、R3d、R3d1、R3d2、R3e、R3e1、R3f、R3f1、R3f2、R3g和R3g1各自独立地为氢、卤素、三氟甲基、二氟甲基、氘代甲基、甲基或甲氧基;
和/或,环B中,R6、R6a、R6b、R6c、R6d和R6e各自独立地为氢、卤素、-C(O)OR66或-C(O)NRa69Ra610;R66为氢或C1-6烷基;Ra69和Ra610独立地为氢或C1-6烷基。
6.如权利要求1所述的通式I所示的芳香杂环化合物或其药学上可接受的盐,其特征在于,
环Q为 Rq1、Rq2、Rq3、Rq4、Rq5、Rq6、Rq7、Rq8、Rq13、Rq14、Rq15、Rq16、Rq17、Rq18、Rq19、Rq20、Rq21和Rq22的定义同权利要求1所述;
和/或,为R3、R31、R32、R33、R3b、R3b1、R3e、R3e1和R2的定义均同前所述;
和/或,为R5a、R5a1、R5a2、R6a和R8的定义均同权利要求1所述。
7.如权利要求1所述的通式I所示的芳香杂环化合物或其药学上可接受的盐,其特征在于,
环Q为
和/或,为
和/或,为
8.如权利要求1-7任一项所述的通式I所示的芳香杂环化合物或其药学上可接受的盐,其特征在于,所述的通式I所示的芳香杂环化合物为下列任一化合物:
9.一种如权利要求1-8任一项所述的通式I所示的芳香杂环化合物的制备方法,其包括下列步骤:将化合物I-A与化合物I-B进行偶联反应得到通式I所示的芳香杂环化合物;
其中,Xa和Xb其中一个为H,另一个为卤素;
或者,Xa和Xb其中一个为有机锡试剂或者有机硼试剂,另一个为卤素;
或者Xa和Xb其中一个为-OPG1,PG1为对甲苯磺酰基或甲磺酰基;另一个为有机锡试剂或有机硼试剂;
环C1和环C2一个为环A,另一个为环B;环A、环B和环Q的定义同权利要求1-8任一项所述。
10.一种用于制备如权利要求1-8任一项所述的通式I所示的芳香杂环化合物的中间体化合物,其为下列任一化合物:
11.一种如权利要求1-8任一项所述的通式I所示的芳香杂环化合物或其药学上可接受的盐在制备ALK5抑制剂或者制备用于治疗和/或预防ALK5介导的疾病的药物中的应用。
12.如权利要求11所述的应用,其特征在于,所述的ALK5介导的疾病为癌症、器官纤维化、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中的一种或多种,所述的癌症优选结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头或颈癌、骨癌、皮肤癌、直肠癌、肝癌、结肠癌、食道癌、胃癌、胰腺癌、甲状腺癌、膀胱癌、淋巴瘤、白血病和黑色素瘤中的一种或多种;所述的器官纤维化优选为肾纤维化、肝纤维化和肺纤维化中的一种或多种。
13.一种药物组合物,其包含预防和/或治疗有效剂量的如权利要求1-8任一项所述的通式I所示的含氮芳香杂环化合物和其药学上可接受的盐中的一种或多种,以及药学上可接受的载体。
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CN114989173A (zh) * | 2021-03-01 | 2022-09-02 | 广州市恒诺康医药科技有限公司 | 咪唑类化合物、其药物组合物及其用途 |
US11584745B2 (en) | 2018-01-24 | 2023-02-21 | Shanghai Yingli Pharmaceutical Co., Ltd | Aromatic heterocyclic compound, intermediate thereof, preparation method therefor, and pharmaceutical composition and use thereof |
CN116535389A (zh) * | 2023-04-28 | 2023-08-04 | 四川大学 | 6-吡啶-3-喹喔啉脲类衍生物及其用途 |
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CN110066277B (zh) * | 2018-01-24 | 2021-07-23 | 上海璎黎药业有限公司 | 芳香杂环取代烯烃化合物、其制备方法、药物组合物和应用 |
CA3113233A1 (en) | 2018-09-18 | 2020-03-26 | Nikang Therapeutics, Inc. | Fused tricyclic ring derivatives as src homology-2 phosphatase inhibitors |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016133838A1 (en) * | 2015-02-20 | 2016-08-25 | Rigel Pharmaceuticals, Inc. | Gdf-8 inhibitors |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MXPA03010630A (es) | 2001-05-24 | 2004-03-09 | Lilly Co Eli | Nuevos derivados de pirrol como agentes farmaceuticos. |
EP1539748A1 (en) | 2002-07-31 | 2005-06-15 | Smithkline Beecham Corporation | 2-phenylpyridin-4-yl derivatives as alk5 inhibitors |
WO2004048383A1 (en) | 2002-11-21 | 2004-06-10 | Eli Lilly And Company | Mixed lineage kinase modulators |
UY31281A1 (es) | 2007-08-13 | 2009-03-31 | Aminas, benzamidas y sulfonamidas {[4-(5,6-dimetil-2-piridin-2-il-piridin-3-il) oxipiridin-2-il]amino} sustituidas, sus sales farmacéuticamente aceptables, composiciones contenniéndolas y aplicaciones. | |
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US8080568B1 (en) | 2010-06-29 | 2011-12-20 | Ewha University - Industry Collaboration Foundation | 2-pyridyl substituted imidazoles as therapeutic ALK5 and/or ALK4 inhibitors |
CN110066276B (zh) | 2018-01-24 | 2020-09-18 | 上海璎黎药业有限公司 | 芳香杂环化合物、其中间体、制备方法、药物组合物和应用 |
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Cited By (6)
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US11584745B2 (en) | 2018-01-24 | 2023-02-21 | Shanghai Yingli Pharmaceutical Co., Ltd | Aromatic heterocyclic compound, intermediate thereof, preparation method therefor, and pharmaceutical composition and use thereof |
CN114989173A (zh) * | 2021-03-01 | 2022-09-02 | 广州市恒诺康医药科技有限公司 | 咪唑类化合物、其药物组合物及其用途 |
WO2022184000A1 (zh) * | 2021-03-01 | 2022-09-09 | 广州市恒诺康医药科技有限公司 | 咪唑类化合物、其药物组合物及其用途 |
CN114989173B (zh) * | 2021-03-01 | 2024-03-19 | 广州市恒诺康医药科技有限公司 | 咪唑类化合物、其药物组合物及其用途 |
CN116535389A (zh) * | 2023-04-28 | 2023-08-04 | 四川大学 | 6-吡啶-3-喹喔啉脲类衍生物及其用途 |
CN116535389B (zh) * | 2023-04-28 | 2024-05-03 | 四川大学 | 6-吡啶-3-喹喔啉脲类衍生物及其用途 |
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