CN115960106B - 线粒体rna聚合酶抑制剂及其衍生物、药物组合物和医药用途 - Google Patents
线粒体rna聚合酶抑制剂及其衍生物、药物组合物和医药用途 Download PDFInfo
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- CN115960106B CN115960106B CN202211372984.7A CN202211372984A CN115960106B CN 115960106 B CN115960106 B CN 115960106B CN 202211372984 A CN202211372984 A CN 202211372984A CN 115960106 B CN115960106 B CN 115960106B
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Abstract
本发明公开了一类具有线粒体RNA聚合酶抑制作用以及抗肿瘤活性的衍生物及其制备方法,还公开了含有所述化合物的药用组合物,以及所述化合物或其药用盐或含有其的组合物在制备治疗肿瘤的药物中的应用。本发明的化合物、衍生物及其组合物具备较强的抗癌细胞增殖活性以及较强的肿瘤抑制率。
Description
技术领域
本发明属于药物技术领域,涉及线粒体RNA聚合酶抑制剂及其衍生物、药物组合物和医药用途,具体涉及一类作为线粒体RNA聚合酶抑制剂的新化合物或者其立体异构体、溶剂化物、前药、代谢产物、氘代物、药学上可接受的盐或共晶,其药物组合物以及在制备线粒体RNA聚合酶抑制剂的用途。
背景技术
目前为止,人们对癌症治疗进行了大量的研究工作,但是癌症仍然是世界范围内公认的最突出的公共卫生问题之一,即便有医学手段和患者自身的天然抵抗力,全球每天仍然有约1500名癌症病人因病情失控而去世。在中国人群中,癌症是死亡的第一主要原因。因此,除了已建立的化学疗法,放射疗法和即将到来的免疫治疗外,人们迫切需要新的和改进的对抗癌症的治疗方法。
代谢是癌症生物学的关键调控因子,然而,其在治疗耐药性中的作用在很大程度上仍未得到解决。一些新的研究揭示线粒体代谢和氧化磷酸化至少在一定程度上驱动了癌症的化疗耐药性,因此对靶向和更有效的化疗具有重要意义。已有报道表明,癌细胞的生长和治疗耐药性癌症干细胞取决于线粒体的氧化磷酸化(OXPHOS)。因此,这些发现为使用OXPHOS和线粒体功能抑制剂进行抗癌治疗提供了理论基础和新策略。
线粒体RNA聚合酶(POLRMT,也被称为h-mtRNAP)负责线粒体翻译所需的OXPHOS复合物的13个亚基、2个rRNA和22个tRNA的转录,并且充当线粒体DNA复制的RNA引发酶。因此POLRMT对人类线粒体的生物发生起着至关重要的作用。
此外,近来的研究表明靶向POLRMT能有效治疗急性髓性白血病,此外靶向线粒体RNA聚合酶的策略也可以更广泛地适用于其他依赖氧化磷酸化的癌症类型,例如某些类型的乳腺癌,以及黑色素瘤和胰腺癌的亚群等。
因此,发明新的化合物特异性靶向POLRMT能有效治疗依赖氧化磷酸化的癌症。特别的,需要可用于治疗癌症的新化合物,所述癌症优选为黑色素瘤,肝癌、胰腺癌、淋巴癌、急性髓性白血病、乳腺癌、成胶质细胞瘤、宫颈癌、肾癌、结直肠癌或卵巢癌。
目前获得能够治疗癌症的特异性POLRMT小分子抑制剂的活性化合物是存在困难的。
发明内容:
发明目的:本发明所要解决的技术问题是提供了一类用于治疗癌症的特异性POLRMT小分子抑制剂,其结构通式如式(I)所示。
本发明还要解决的技术问题是提供了如式(I)所示化合物的立体异构体、水合物、代谢产物、氘代物、溶剂化物、药学上可接受的盐或共晶。
本发明还要解决的技术问题是提供了包含前所述的化合物的药物组合物。
本发明还要解决的技术问题是提供了化合物、立体异构体、水合物、代谢产物、氘代物、溶剂化物、药学上可接受的盐或共晶或药物组合物在制备线粒体RNA聚合酶抑制剂或抗肿瘤药物中的用途。
技术方案:为了解决上述技术问题,本发明提供了一个或多个实施方案为式(I)所示化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、氘代物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药:
其中:
W选自6至10元芳基、5至10元杂芳基或者3至8元杂环烷基;所述的杂芳基含有1至3个选自N、O或者S的杂原子,所述的芳基或者杂芳基任选地被0至4个Rt0取代,所述的杂环烷基被0至4个Rt1取代;
Rt0相同或者不同,各自独立选自C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤素、羟基、氰基、硝基、羧基、-NH2、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(=O)C1-6烷基、-C(=O)C1-6烷基、-OC(=O)C1-6烷基、-C(=O)OC3-8环烷基、-OC(=O)C3-8环烷基、-OC(=O)C3-8杂环烷基、-C(=O)OC3-8杂环烷基、-C(=O)C6-10芳基、-C(=O)OC6-10芳基、-OC(=O)C6-10芳基、-C(=O)C5-10杂芳基、-C(=O)OC5-10杂芳基、-OC(=O)C5-10杂芳基、-NHC1-6烷基、-N(C1-6烷基)2、-NHC(=O)C1-6烷基、-NHC(=O)(C1-6烷基)2、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C3-8环烷基、-NHC(=O)C1-6烷基、-NHC(=O)C2-6炔基、-NHC(=O)C2-6烯基、-NH(C=NRt1)NRt2Rt3、-C(=O)NRt4Rt5、-SH、-SC1-6烷基、-S(=O)C1-6烷基、-S(=O)2C1-6烷基或者-S(=O)2NRt2Rt3,其中所述的杂环烷基或者杂芳基各自含有1至3个选自N、O或者S的杂原子,其中所述的烷基、烷氧基、NH2、烯基、炔基、杂环烷基、环烷基、芳基或者杂芳基任选进一步被1个或者多个选自氘、OH、卤素、氰基、=O、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRt4Rt5、=NRt6、-C(=O)OC1-6烷基、-OC(=O)C1-6烷基、-C(=O)NRt4Rt5、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(=O)OC6-10芳基、-OC(=O)C6-10芳基、-OC(=O)C5-10杂芳基、-C(=O)OC5-10杂芳基、-OC(=O)C3-8杂环烷基、-C(=O)OC3-8杂环烷基、-OC(=O)C3-8环烷基、-C(=O)OC3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C2-6烯基或者-NHC(=O)C2-6炔基的取代基所取代,且其中所述的取代基C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8杂环烷基或者-NHC(=O)C3-8环烷基任选进一步被1至3个选自OH、卤素、C1-6烷基、C1-6烷氧基、-NRt4Rt5或者=O的取代基所取代;
或者至少一对Rt0及其相连的原子形成4至10元的碳环或者5至10元的杂环,其中所述的杂环含有1至2个选自N、O或者S的杂原子,所述的碳环或者杂环任选地进一步被1个或者多个选自OH、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRt4Rt5、=NRt6、-C(=O)OC1-6烷基或者-C(=O)NRt4Rt5的取代基所取代,且所述的C1-6烷基或者C1-6烷氧基任选进一步被选自OH、卤素、=O、-NRt4Rt5、=NRt6、-C(=O)OC1-6烷基、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基或者-C(=O)NRt4Rt5的取代基所取代。
Rt1选自C1-6烷基、C1-6烷氧基或者C5-10芳基;
Rt2、Rt3选自H或者C1-6烷基;
Rt4、Rt5选自H、C1-6烷基、-NH(C=NRt1)NRt2Rt3、-S(=O)2NRt2Rt3、-C(=O)Rt1或者-C(=O)NRt2Rt3,所述的C1-6烷基任选进一步被1个或者多个选自OH、卤素、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基或者C3-8杂环烷基的取代基所取代;或者Rt4与Rt5及N原子形成3至8元杂环;所述的杂环含有1个至3个选自N、O或者S的杂原子;
Rt6为C1-6烷基;
G1,G2,G3各自独立选自CH或者N;
R1,R2各自独立选自氘、H、F、Cl、Br、I、CN、NH2、OH、C1-6烷基;
R1和R2也可环合形成环丁烷或环丙烷;
n1,n2,n3为0,1或2;
n4为1,2或3;
A选自O、S、Se、S(O)、S(O)2、Se(O)、Se(O)2、NRa或者CRa;
Ra选自氘、氢、F、C1-6烷基、甲酸基、乙酸基、-C(=O)Rt1、-C(=O)NRt1、3至10元碳环基或者C5-10芳基,所述的C1-6烷基进一步被1至4个选自F、Cl、Br、I、C1-6烷基、C1-6烷氧基、3至10元碳环基或者3至10元杂环基的取代基所取代,所述的杂环基任选地含有1至3个选自N、O或者S的杂原子;
进一步地:
W选自6元芳基、5至6元杂芳基或者3至8元杂环烷基;所述的杂芳基含有1至3个选自N、O或者S的杂原子,所述的芳基或者杂芳基任选地被0至4个Rt0取代,所述的杂环烷基被0至4个Rt1取代;
Rt0相同或者不同,各自独立选自C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤素、羟基、氰基、硝基、羧基、-NH2、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(=O)C1-6烷基、-C(=O)C1-6烷基、-OC(=O)C1-6烷基、-C(=O)OC3-8环烷基。
Rt1选自C1-6烷基、C1-6烷氧基或者C5-10芳基;
G1,G2,G3各自独立选自CH或者N;
R1,R2各自独立选自氘、氢、F、C1-6烷基;
R1和R2也可环合形成环丁烷或环丙烷;
n1,n2,n3为0,1或2;
n4为1,2或3;
A选自O、NRa或者CRa;
Ra选自氘、氢、F、C1-6烷基、甲酸基、乙酸基、-C(=O)Rt1、-C(=O)NRt1、3至10元碳环基或者C5-10芳基,所述的C1-6烷基;所述的C1-6烷基进一步被1至4个选自F、Cl、Br、I、C1-6烷基取代;
进一步地:
W选自6元芳基、5至6元杂芳基或者3至8元杂环烷基;所述的杂芳基含有1至3个选自N、O或者S的杂原子,所述的芳基或者杂芳基任选地被0至4个Rt0取代,所述的杂环烷基被0至4个Rt1取代;
Rt0相同或者不同,各自独立选自C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤素、羟基、氰基、硝基、羧基、-NH2、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(=O)C1-6烷基、-C(=O)C1-6烷基、-OC(=O)C1-6烷基、-C(=O)OC3-8环烷基。
Rt1选自C1-6烷基、C1-6烷氧基或者C5-10芳基;
G1,G2,G3各自独立选自CH或者N;
R1,R2各自独立选自氘、氢、F、C1-6烷基;
R1和R2也可环合形成环丁烷或环丙烷;
n1,n2,n3为0,1或2;
n4为1,2或3;
A选自O、NRa或者CRa;
Ra选自H、C1-6烷基、甲酸基、-C(=O)Rt1、-C(=O)NRt1、3至10元碳环基或者C5-10芳基;
本发明的一个或多个实施方案提供通式(I)所示的化合物或其立体异构体、水合物、代谢产物、氘代物、溶剂化物、药学上可接受的盐或共晶:
本发明的一个或多个实施方案提供的化合物选自但不限于以下结构:
本发明的一个或多个实施方式提供了药物组合物,所述药物组合物包含所述的通式(I)的化合物或者上述具体结构或其立体异构体、溶剂化物、代谢产物、氘代物、药学上可接受的盐、共晶或者前药和一种或者多种药学上可接受的载体和/或赋形剂。
本申发明的一个或多个实施方式提供了本申请的药物组合物、通式(I)的化合物或者上述具体结构或其立体异构体、溶剂化物、代谢产物、氘代物、药学上可接受的盐、共晶或者前药在制备POLRMT抑制剂中的用途。
在本发明的一个或多个实施方式中,所述的POLRMT抑制剂治疗的疾病选自:卵巢癌、黑色素瘤、转移性黑色素瘤、胰腺癌、肝细胞癌、淋巴癌、急性髓性白血病、乳腺癌、成胶质细胞瘤、宫颈癌、肾癌或结肠直肠癌。
本发明的一个或多个实施方式提供了抑制POLRMT的方法,其包括将本申请通式(I)的化合物或者上述具体结构或其立体异构体、溶剂化物、代谢产物、氘代物、药学上可接受的盐、共晶或者前药或本申请的组合物与有此需要的对象接触。
本发明的一个或多个实施方式提供了治疗与POLRMT相关的疾病的方法,其包括将本
本发明通式(I)的化合物或者上述具体结构或其立体异构体、溶剂化物、代谢产物、氘代物、药学上可接受的盐、共晶或者前药或本申请的组合物施用于有此需要的对象。
本发明的一个或多个实施方式提供了通式(I)的化合物或者上述具体结构或其立体异构体、溶剂化物、代产物、氘代物、药学上可接受的盐、共晶或者前药,其用于治疗与POLRMT相关的疾病或者用作POLRMT抑制剂。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“烯基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基,更优选2至8个碳原子的烯基,进一步优选2至6个碳原子的烯基。非限制性实施例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。
“炔基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键,由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基,优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基,更优选2至8个碳原子的炔基,进一步优选2至6个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被一至多个取代基所取代。
“芳基”是指是指取代的或未取代的芳香环,其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,其可以是桥环或者螺环,非限制性实施例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。
“杂芳基”是指取代的或未取代的芳香环,其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子,优选5至8元杂芳基,杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂芳基可以连接在杂原子或者碳原子上,杂芳基可以是桥环或者螺环,非限制性实施例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。
“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时,其定义与上文“芳基”的定义相同;当为非芳香环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,可以是桥环或者螺环,非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基。所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。
“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环,当为芳香性杂环时,其定义与上文“杂芳基”定义相同;当为非芳香性杂环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子,优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态;“杂环基”或“杂环”可以连接在杂原子或者碳原子上;“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡咯啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”可以任选进一步被1个或者多个取代基所取代。
“环烷基”是指饱和的环烃基其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多环体系,环碳原子优选3至10个碳原子,进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时,可以任选进一步被1个或者多个取代基所取代。
“杂环烷基”是指取代的或未取代的饱和非芳香环基,其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1、2或3个来自N、O或S的杂原子,优选3至8元杂环基。“杂环烷基”的环中选择性取代的1、2或3个N、S可被氧化成各种氧化态;“杂环烷基”可以连接在杂原子或者碳原子上;“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。
当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时,可以选进
一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C1-6烷基氨基、=O、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRt4Rt5,=NRt6,-C(=O)OC1-6烷基、-OC(=O)C1-6烷基、-C(=O)NRt4Rt5、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(=O)OC6-10芳基、-OC(=O)C6-10芳基、-OC(=O)C5-10杂芳基、-C(=O)OC5-10杂芳基、-OC(=O)C3-8杂环烷基、-C(=O)OC3-8杂环烷基、-OC(=O)C3-8环烷基、-C(=O)OC3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C2-6烯基或者-NHC(=O)C2-6炔基的取代基所取代,且其中所述的取代基C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-NHC(=O)C6-10芳基、-NHC(=0)C5-10杂芳基、-NHC(=O)C3-8杂环烷基或者-NHC(=O)C3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、-NRt4Rt5或者=O的取代基所取代;Rt1选自C1-6烷基、C1-6烷氧基或者C6-10芳基;Rt2、Rt3选自H或者C1-6烷基;其中,Rt4、Rt5选自H、C1-6烷基、-NH(C=NRt1)NRt2Rt3、-S(=O)2NRt2Rt3、-C(=O)Rt1或者-C(=0)NRt2Rt3,其中所述的C1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基或者C3-8杂环烷基的取代基所取代;或者Rt4与Rt5及N原子形成一个3至8元杂环,所述杂环可以含有1个或者多个选自N、O或者S的杂原子。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特
性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。当本发明的前药被施予哺乳动物个体时,前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“任选地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
有益效果:与现有技术相比,本发明具备以下优点:本发明首次制备得到了一类可以线粒体RNA聚合酶抑制剂,特别是POLRMT抑制剂,该类抑制剂可治疗该抑制剂相关的疾病以及各种肿瘤疾病效果良好,具备较强的抗癌细胞增殖活性以及较强的肿瘤抑制率。
附图说明
图1实施例1、2、5、20的化合物、对照、阳性药IMT1B的肿瘤抑制效果比较,肿瘤体积大小的变化;
图2实施例1、2、5、20的化合物、对照、阳性药IMT1B的肿瘤抑制效果,小鼠体重的变化。
具体实施方式
以下通过实施例形式展示具体的实施方式,对本发明内容进行进一步的详细说明,但不应当将此理解为本发明上述主题的范围仅限于以下的实施例,凡是基于本发明上述内容在本领域内所能实现的技术均应属于本发明的内容。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance 500或Bruker Avance 300)核磁仪,测定溶剂为氘带氯仿(CDCl3)内标为四甲基硅烷(TMS);
方案1:本发明式(I)化合物的示例性制备:
对于本领域技术人员显而易见的是,合成步骤的顺序取决于中间体的可用性和官能团的相容性,并且可以随化合物而变化。
对于该发明中描述的化合物,在中间体7到终产物的步骤中,为酰胺缩合,按照不同底物而言,有些化合物还需要进一步的酯水解或者脱保护,脱保护后还需要烷基化。
实施例1 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮的制备
按照方案1制备,包括以下步骤:
第一步:/>
操作:将氢化钠(52.15mmol)溶于100mL无水四氢呋喃中,降温至0℃,随后滴加商业购买的2-氯-4-氟-苯乙酮(28.59mmol),随后在室温下搅拌反应半小时,随后滴加碳酸二乙酯(86.91mmol)。升温至65℃反应约3小时。待反应结束后,降至室温,用饱和氯化铵100mL淬灭反应,加入乙酸乙酯100mL,萃取三次,浓缩有机层,PE∶EA(V/V)=150∶1柱层析得到中间体b,产率80.22%。
第二步:
操作:将中间体b(23.24mmol)和间苯二酚(22.08mmol)溶于甲基磺酸(30mL/g)中,升温至45℃反应2小时,待反应结束后,降至室温,加入乙酸乙酯100mL和冰水100mL萃取三次,浓缩有机层,PE∶EA(V/V)=4∶1柱层析得到中间体c,产率75.35%。
第三步:
操作:将中间体c(8.60mmol)与三苯基膦(9.46mmol)溶于无水四氢呋喃中,加入(S)-2-羟基丙酸乙酯(12.90mmol)。将反应液冷却至0℃,逐滴加入DIAD(9.46mmol),升至室温反应4小时。待反应结束后,降至室温,加入乙酸乙酯100mL和冰水100mL萃取三次,浓缩有机层,PE∶EA(V/V)=10∶1柱层析得到中间体d,产率63.25%。
第四步:
操作:将中间体d(8.60mmol)溶于四氢呋喃50mL中,降温至0℃,加入2M NaOH 50mL溶液,随后升至室温反应3小时。待反应结束后,加入2M HCl调至PH=2,搅拌30分钟,加入乙酸乙酯(100mL),萃取三次,浓缩有机层后得到中间体e直接投下一步。
第五步:
将中间体e(1.65mmoL)溶于无水二氯甲烷20mL中,随后加入HATU(2.48mmol),搅拌反应30分钟,随后加入3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(1.98mmol)和DIPEA(2.48mmol)。反应1小时,待反应结束后,加入二氯甲烷100mL和冰水100mL萃取三次,浓缩有机层,PE∶EA(V/V)=2∶1柱层析得到中间体f,产率82.36%。
第六步:
将中间体f(1mmol)溶于二氯甲烷10mL中,滴入三氟乙酸(5mL),在室温下反应1小时,待到反应结束,浓缩溶剂,加入饱和碳酸氢钠溶液将溶液调成PH=8,随后加入乙酸乙酯100mL和水100mL萃取三次,浓缩有机层,DCM∶MeOH(V/V)=30∶1柱层析得到化合物1,产率77.83%。化合物1的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.30(d,J=7.5Hz,1H),7.22-7.14(m,2H),7.05(dd,J=7.4,1.9Hz,1H),6.88(d,J=2.0Hz,1H),6.28(s,1H),5.16(s,1H),3.56(s,2H),3.50(s,2H),3.40(s,1H),3.33(s,2H),1.83(s,2H),1.73(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.92,159.69,156.62,154.78,153.10,132.86,132.41,129.69,125.29,116.85,116.19,114.83,114.76,112.64,105.00,72.60,55.24,50.64,26.15,16.29.
实施例2 4-(2-氯-4-氟苯基)-7-(((2R)-1-(8-甲基-3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-2H-色烯-2-酮的制备
前六步操作同实施例1,增加第七步甲基化。
第七步:
将化合物1(1mmol)溶于四氢呋喃20mL中,加入NaH(1.5mmol),室温反应半小时,随后滴加碘甲烷(1.3mmol),室温过夜反应,待反应结束后,滴加饱和氯化铵溶液(20mL)淬灭反应,随后加入乙酸乙酯100mL和水100mL萃取三次,浓缩有机层,DCM∶MeOH(V/V)=50∶1柱层析得到化合物2,产率55.34%。化合物2的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.29(d,J=7.5Hz,1H),7.22-7.14(m,2H),7.05(dd,J=7.5,2.0Hz,1H),6.88(d,J=2.0Hz,1H),6.28(s,1H),5.16(s,1H),3.81(s,2H),3.69(s,2H),3.34(s,2H),2.40(s,3H),1.69(d,J=8.2Hz,5H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.94,159.69,156.62,154.78,153.10,132.86,132.82,129.69,125.29,116.81,116.16,114.83,114.76,112.69,103.25,72.36,55.26,51.09,38.82,28.63,16.30.
实施例3 4-(2,4-二甲基苯基)-7-(((2R)-1-(8-甲基-3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-2H-色烯-2-酮的制备
操作同实施例1,其中将第一步的2-氯-4-氟-苯乙酮替换为2,4-二甲基-苯乙酮制备得到化合物3。化合物3的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.33(d,J=7.4Hz,1H),7.16-7.02(m,4H),6.93(d,J=1.9Hz,1H),6.83(tt,J=2.0,1.1Hz,1H),6.28(s,1H),5.16(s,1H),3.81(s,2H),3.71(s,2H),3.34(s,2H),2.39(s,3H),2.33(t,J=1.0Hz,4H),2.21(d,J=1.1Hz,4H),1.69(d,J=8.2Hz,5H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.94,156.62,154.75,150.62,138.89,136.71,136.28,128.66,128.55,125.46,125.42,116.46,114.76,112.64,103.25,72.60,55.26,51.09,38.63,28.63,21.92,21.10,16.29.
实施例4 7-(((2R)-1-(3,6-二氮杂二环[3.1.1]庚烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮
操作同实施例1,其中将第五步的3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯替换为6-N-Boc-3,6-二氮杂双环[3.1.1]庚烷制备得到化合物4。化合物4的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.32(d,J=7.4Hz,1H),7.22-7.14(m,2H),7.06(dd,J=7.5,2.0Hz,1H),6.93(d,J=1.9Hz,1H),6.28(s,1H),5.16(s,1H),3.62(s,2H),3.53(s,2H),3.43(s,2H),3.40(s,1H),1.89(s,1H),1.76(s,1H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.80,159.94,156.62,154.78,153.10,132.46,132.41,129.01,125.29,116.85,116.19,114.83,114.76,112.64,105.00,72.60,55.45,49.87,36.30,16.29.
实施例5 7-(((2R)-1-(8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮
操作同实施例1,仅需前五步即可,其中将第五步的3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯替换为8-氧杂-3-氮杂双环[3,2,1]辛烷制备得到化合物5。化合物5的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.30(d,J=7.5Hz,1H),7.22-7.14(m,2H),7.05(dd,J=7.4,1.9Hz,1H),6.88(d,J=2.0Hz,1H),6.28(s,1H),5.15(s,1H),4.09(s,2H),3.69(s,2H),3.58(s,2H),1.82(s,2H),1.70(s,2H),1.51(s,3H).13CNMR(125MHz,Chloroform-d)δ170.81,160.92,159.69,156.62,154.78,153.10,132.86,132.41,129.69,125.29,116.85,116.19,114.83,114.76,112.64,105.00,75.74,72.81,52.62,31.15,16.29.
实施例6 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-8-基)-1-羰基丙烷-2-基)氧代)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮
操作同实施例1,其中将第五步的3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯替换为3-Boc-3,8-二氮杂双环[3.2.1]辛烷制备得到化合物6。化合物6的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.30(d,J=7.5Hz,1H),7.22-7.14(m,2H),7.05(dd,J=7.4,1.9Hz,1H),6.88(d,J=2.0Hz,1H),6.28(s,1H),5.03(s,1H),3.83(s,2H),3.25(s,2H),3.21(s,2H),2.31(d,J=1.0Hz,1H),1.83(d,J=16.9Hz,4H),1.50(s,3H).
13C NMR(125MHz,Chloroform-d)δ171.10,160.92,159.69,156.62,154.78,153.10,132.86,132.41,129.69,125.29,116.85,116.19,114.83,114.76,112.64,105.00,73.55,57.29,47.78,26.66,16.29.
实施例7 4-(2-氯-4-氟苯基)-7-(((R)-1-((3aR,6aS)-六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1-羰基丙烷-2-基)氧代)-2H-色烯-2-酮
操作同实施例1,其中将第五步的3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯替换为顺式-2-Boc-六氢吡咯并[3,4-c]吡咯制备得到化合物7。化合物7的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.30(d,J=7.5Hz,1H),7.22-7.14(m,2H),7.05(dd,J=7.4,1.9Hz,1H),6.93(d,J=1.9Hz,1H),6.28(s,1H),5.15(s,1H),3.62(s,4H),3.00(d,J=9.4Hz,2H),2.94(d,J=9.6Hz,3H),2.44(d,J=4.9Hz,2H),1.50(s,2H).13C NMR(125MHz,Chloroform-d)δ170.74,160.92,159.69,156.62,154.78,153.10,132.86,132.41,129.69,125.29,116.85,116.19,114.83,114.76,112.64,105.00,72.81,48.39,46.75,37.62,37.05,16.31.
实施例8 4-(2-氯-4-氟苯基)-7-(((R)-1-((3aR,6aS)-5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)-1-羰基丙烷-2-基)氧代)-2H-色烯-2-酮
操作同实施例2,其中将第五步中的3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯替换为顺式-2-Boc-六氢吡咯并[3,4-c]吡咯制备得到化合物8。化合物8的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.29(d,J=7.5Hz,1H),7.22-7.14(m,2H),7.05(dd,J=7.4,1.9Hz,1H),6.93(d,J=1.9Hz,1H),6.28(s,1H),5.15(s,1H),3.65-3.57(m,4H),2.95(d,J=9.5Hz,2H),2.72(d,J=9.3Hz,2H),2.36(s,1H),2.27(s,2H),1.51(s,2H).13C NMR(125MHz,Chloroform-d)δ170.74,160.94,159.69,156.62,154.78,153.10,132.86,132.82,129.69,125.29,116.81,116.16,114.83,114.76,112.69,103.25,72.60,57.53,47.69,44.31,36.46,36.16,16.31.
实施例9 7-(((2R)-1-(2,5-二氮杂二环[2.2.1]庚烷-2-基)-1-羰基丙烷-2-基)氧代)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮
操作同实施例1,其中将第五步的3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯替换为2,5-二氮杂双环[2.2.1]庚烷-2-羧酸-1,1-二甲基乙酯制备得到化合物9。化合物9的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.32(d,J=7.4Hz,1H),7.22-7.14(m,2H),7.06(dd,J=7.5,2.0Hz,1H),6.93(d,J=1.9Hz,1H),6.28(s,1H),5.12(s,1H),4.05(s,1H),3.70(s,2H),3.55(s,1H),3.33(s,1H),3.25(d,J=9.5Hz,1H),3.18(d,J=9.5Hz,1H),1.80(s,1H),1.75(s,1H),1.50(s,3H).13C NMR(125MHz,Chloroform-d)δ170.78,160.80,159.94,156.62,154.78,153.10,132.46,132.41,129.01,125.29,116.85,116.19,114.83,114.76,112.64,105.00,73.55,55.96,54.54,47.78,47.66,37.12,16.29.
实施例10 4-(2-氯-4-氟苯基)-7-(((2R)-1-(8-乙基-3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-2H-色烯-2-酮
操作同实施例2,其中将第七步的碘甲烷替换为碘乙烷制备得到化合物10。化合物10的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.84(d,J=7.5Hz,1H),7.29(d,J=7.5Hz,1H),7.22-7.13(m,2H),7.05(dd,J=7.5,2.0Hz,1H),6.88(d,J=2.0Hz,1H),6.32(s,1H),5.16(s,1H),3.69(s,2H),3.65(s,2H),3.51(s,2H),2.55(d,J=12.3Hz,1H),2.49(d,J=12.5Hz,1H),1.78(s,2H),1.70(s,2H),1.51(s,3H),1.13(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.94,159.94,156.79,154.75,153.10,132.86,132.82,129.81,124.68,117.13,116.81,116.16,114.83,112.69,103.25,72.60,56.97,51.09,47.54,29.11,16.30,12.86.
实施例11 7-(2-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-2-羰基乙氧基)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮
按照方案1制备,操作同实施例1,其中第三步不同,改为如下操作:
操作:将中间体c(1mmol)溶于10mL乙腈中,加入溴乙酸乙酯(1.2mmol)和碳酸钾(1.5mmol)。升温至回流反应2小时,待反应结束后,抽滤除去碳酸钾,浓缩溶剂,加入乙酸乙酯100mL和冰水100mL萃取三次,浓缩有机层,PE∶EA(V/V)=10∶1柱层析得到中间体11b,产率75.26%。中间体11b即化合物11,化合物11的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.32(d,J=7.4Hz,1H),7.22-7.14(m,2H),7.036.96(m,2H),6.28(s,1H),4.854.76(m,2H),3.56(s,2H),3.50(s,2H),3.40(s,1H),3.33(s,2H),1.83(s,2H),1.73(s,2H).13C NMR(125MHz,Chloroform-d)δ170.59,160.80,159.94,159.71,154.78,153.10,132.46,132.41,129.01,125.29,116.85,116.19,114.83,113.13,112.64,101.55,66.67,55.24,49.87,27.20.
实施例12 7-(2-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1,1-二氟-2-羰基乙氧基)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮
操作同实施例11,其中第三步将溴乙酸乙酯替换为二氟溴乙酸乙酯,制备得到化合物12,化合物12的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.34(d,J=7.4Hz,1H),7.22-7.14(m,3H),6.82(d,J=2.0Hz,1H),6.28(s,1H),3.68(s,2H),3.55(s,2H),3.43(s,2H),3.40(s,1H),1.82(s,2H),1.78(s,2H).13C NMR(125MHz,Chloroform-d)δ169.84,160.94,159.40,154.75,153.10,148.99,132.86,132.82,129.69,124.30,117.12,116.81,116.16,114.83,112.69,108.87,102.82,53.15,51.38,27.54.
实施例13 7-((1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-2-甲基-1-羰基丙烷-2-基)氧代)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮
操作同实施例11,其中第三步将溴乙酸乙酯替换为2-溴-2-甲基丙酸乙酯,制备得到化合物13,化合物13的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.33(d,J=7.5Hz,1H),7.22-7.14(m,2H),7.03(dd,J=7.5,2.0Hz,1H),6.83(d,J=2.0Hz,1H),6.28(s,1H),3.63(s,2H),3.55(s,2H),3.40(s,1H),3.33(s,2H),1.88(s,2H),1.78(s,2H),1.61(s,3H),1.57(s,3H).
13C NMR(125MHz,Chloroform-d)δ170.32,160.94,159.69,154.78,154.73,153.10,132.86,132.82,129.69,125.29,116.81,116.16,114.83,113.63,112.69,102.82,80.75,54.16,50.91,26.15,25.75.
实施例14 7-(1-(3,8-二氮杂二环[3.2.1]辛烷-3-羰基)环丁氧基)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮
操作同实施例11,其中第三步将溴乙酸乙酯替换为乙基1-溴环丁烷甲酸酯制备得到化合物14,化合物14的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.84(d,J=7.5Hz,1H),7.33(d,J=7.5Hz,1H),7.22-7.13(m,2H),7.01(dd,J=7.4,1.9Hz,1H),6.83(d,J=2.0Hz,1H),6.32(s,1H),3.68(s,2H),3.55(s,2H),3.43(s,2H),3.40(s,1H),2.18(d,J=13.0Hz,2H),2.03(d,J=13.0Hz,2H),1.88(s,2H),1.83(d,J=13.0Hz,1H),1.78(s,2H),1.65(d,J=13.0Hz,1H).13CNMR(125MHz,Chloroform-d)δ171.16,160.92,159.94,154.75,153.10,152.90,132.86,132.82,129.81,124.68,116.81,116.16,115.56,114.83,112.69,102.82,78.07,54.16,50.91,31.27,26.15,23.11.
实施例15 7-(1-(3,8-二氮杂二环[3.2.1]辛烷-3-羰基)环丙氧基)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮
操作同实施例11,其中第三步将溴乙酸乙酯替换为乙基1-溴环丙烷甲酸酯,制备得到化合物15,化合物15的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.83(d,J=7.4Hz,1H),7.32(d,J=7.4Hz,1H),7.22-7.14(m,2H),7.03(dd,J=7.5,2.0Hz,1H),6.83(d,J=2.0Hz,1H),6.28(s,1H),3.63(s,2H),3.55(s,2H),3.40(s,1H),3.33(s,2H),2.39(d,J=4.9Hz,2H),2.33(d,J=4.9Hz,2H),1.88(s,2H),1.78(s,2H).13C NMR(125MHz,Chloroform-d)δ171.16,160.94,159.69,154.78,153.10,152.66,132.86,132.82,129.69,124.68,116.81,116.19,114.83,113.63,112.69,102.82,78.56,52.84,50.91,34.76,26.15.
实施例16 4-(2-氯-4-氟苯基)-7-(((2R)-1-羰基-1-(8-丙基-3,8-二氮杂二环[3.2.1]辛烷-3-基)丙烷-2-基)氧代)-2H-色烯-2-酮
操作同实施例2,其中第七步将碘乙烷替换为1-碘丙烷,制备得到化合物16,化合物16的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.85(d,J=7.5Hz,1H),7.30(d,J=7.5Hz,1H),7.21(d,J=1.9Hz,1H),7.16(dd,J=7.5,2.0Hz,1H),7.06(dd,J=7.5,2.0Hz,1H),6.88(d,J=2.0Hz,1H),6.29(s,1H),5.15(s,1H),3.81(s,2H),3.72(s,2H),3.12(s,2H),2.58(d,J=12.5Hz,1H),2.52(d,J=12.3Hz,1H),1.78(s,2H),1.70(s,2H),1.63(s,2H),1.51(s,3H),0.96(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.92,160.16,156.79,154.67,153.10,132.86,132.82,129.81,125.29,116.81,116.28,116.16,114.83,112.69,103.25,72.60,57.14,54.53,51.09,29.11,21.61,16.31,11.87.
实施例17 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(萘-1-基)-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为1-乙酰基萘,制备得到化合物17,化合物17的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.87(d,J=0.8Hz,1H),7.82(s,1H),7.77(s,1H),7.50-7.45(m,5H),7.34(d,J=7.5Hz,1H),7.05(dd,J=7.4,1.9Hz,1H),6.93(d,J=1.9Hz,1H),6.62(s,1H),5.16(s,1H),3.58(s,2H),3.53(s,2H),3.40(s,1H),3.33(s,2H),1.83(s,2H),1.73(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.92,156.62,154.75,151.90,134.31,134.16,130.06,128.98,127.54,127.50,127.31,126.33,125.51,125.35,125.29,115.83,115.48,112.64,103.25,72.60,55.24,50.64,25.51,16.29.
实施例18 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-环己基-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为甲基酮环己酯,制备得到化合物18,化合物18的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.35(d,J=7.5Hz,1H),7.06(dd,J=7.5,2.0Hz,1H),6.93(d,J=2.0Hz,1H),6.06(s,1H),5.16(s,1H),3.60(s,2H),3.55(s,2H),3.40(s,1H),3.33(s,2H),2.39(s,1H),1.83(s,2H),1.79-1.69(m,7H),1.58(dd,J=22.5,13.0Hz,3H),1.55-1.49(m,5H),1.44(d,J=13.0Hz,1H).13C NMR(125MHz,Chloroform-d)δ170.81,160.91,156.40,154.83,125.32,123.86,118.22,115.10,109.95,103.25,72.05,53.70,50.15,42.00,28.62,27.20,26.04,25.92,16.24.
实施例19 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-环戊基-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为甲基酮环戊酯,制备得到化合物19,化合物19的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.35(d,J=7.5Hz,1H),7.05(dd,J=7.5,2.0Hz,1H),6.92(d,J=1.9Hz,1H),6.06(s,1H),5.18(s,1H),3.62(s,2H),3.56(s,2H),3.40(s,1H),3.33(s,2H),2.36(s,1H),1.81-1.75(m,4H),1.75-1.68(m,4H),1.60(d,J=13.0Hz,2H),1.53-1.47(m,6H).13C NMR(125MHz,Chloroform-d)δ170.81,160.93,156.29,154.96,125.56,123.05,115.93,115.66,110.21,103.19,71.47,52.57,49.57,41.10,27.56,27.46,24.45,16.30.
实施例20 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(adamantan-1-基)-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为1-金刚烷甲酮,制备得到化合物20,化合物20的表征数据如下:。
1H NMR(500MHz,Chloroform-d)δ7.34(d,J=7.5Hz,1H),7.05(dd,J=7.5,2.0Hz,1H),6.88(d,J=2.0Hz,1H),6.55(s,1H),5.16(s,1H),3.58(s,2H),3.53(s,2H),3.40(s,1H),3.33(s,2H),2.04(s,3H),1.88(s,2H),1.78(d,J=4.4Hz,10H),1.71(s,6H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.74,160.74,156.62,154.67,138.62,125.21,116.28,115.67,111.67,103.25,72.36,55.24,51.03,50.64,37.84,33.67,29.20,25.51,16.29.
实施例21 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(呋喃-3-基)-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为2-乙酰基呋喃,制备得到化合物21,化合物21的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.61(d,J=16.1Hz,2H),7.42(d,J=7.5Hz,1H),7.06-6.97(m,2H),6.86(s,1H),6.18(s,1H),5.18(s,1H),3.62(s,2H),3.56(s,2H),3.40(s,1H),3.33(s,2H),1.79(s,2H),1.70(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.02,156.29,154.75,149.84,143.22,140.16,123.86,122.05,116.83,116.21,113.01,109.53,104.14,71.47,52.57,49.57,27.56,16.30.
实施例22 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(吡啶-4-基)-2H-色烯-2-酮的制备
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为4-乙酰吡啶,制备得到化合物22,化合物22的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ8.64-8.59(m,2H),7.49-7.39(m,4H),7.03(dd,J=7.5,2.0Hz,1H),6.93(d,J=1.9Hz,1H),6.28(s,1H),5.16(s,1H),3.60(s,2H),3.55(s,2H),3.40(s,1H),3.33(s,2H),1.79(s,2H),1.70(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.09,156.40,154.75,153.55,149.32,132.81,125.29,121.21,117.20,115.10,112.69,103.25,71.65,52.57,50.15,27.20,16.24.
实施例23 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(吡咯烷-1-基)-2H-色烯-2-酮
按照方案1制备,操作同实施例1,其中第一步和第二步不同,替换为如下反应:
第一步:
操作:将4-羟基-7-甲氧基-2H-苯并吡喃-2-酮(10mmol)溶于100mL三氯氧磷中,加热回流1小时,待反应完毕后,降至室温,浓缩溶剂,加入100mL二氯甲烷和100mL冰水萃取三次,浓缩溶剂,随后将中间体23a溶于100mL二氯甲烷中,加入三溴化硼(15mmol),室温反应24小时,待反应完毕后,加入100mL二氯甲烷和100mL冰水萃取三次,浓缩溶剂,柱层析得到中间体23b。产率25.26%。
第二步:
操作:将中间体23b(5mmol)溶于20mL DMF中,加入四氢吡咯(6.0mmol)和DIPEA(6.0mmol),加热至60℃反应2小时,待反应结束后,加入100mL水和100mL乙酸乙酯萃取三次,浓缩有机层,柱层析得到中间体23c,制备得到化合物23,化合物23的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.70(d,J=7.4Hz,1H),7.03(dd,J=7.5,2.0Hz,1H),6.94(d,J=2.0Hz,1H),5.98(s,1H),5.18(s,1H),3.62(s,2H),3.56(s,2H),3.49(d,J=0.7Hz,5H),3.40(s,1H),3.33(s,2H),1.95(d,J=9.5Hz,5H),1.79(s,2H),1.70(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.79,156.42,154.62,138.64,124.74,113.70,113.39,103.38,99.66,71.47,52.57,50.29,49.57,27.56,25.27,16.30.
实施例24 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-异丙基-2H-色烯-2-酮
操作同实施例1,其中第二步中的中间体b替换为异丁酰乙酸乙酯,制备得到化合物24,化合物24的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.45(d,J=7.4Hz,1H),7.02-6.95(m,3H),6.13(s,1H),5.12(s,1H),3.60(s,2H),3.55(s,2H),3.40(s,1H),3.19(s,2H),2.90(s,1H),1.80(s,2H),1.73(s,2H),1.51(s,3H),1.15(s,3H),1.10(s,3H).13C NMR(125MHz,Chloroform-d)δ170.99,160.93,156.62,154.75,137.72,125.29,116.44,115.48,111.15,103.25,71.65,54.63,49.57,35.76,27.56,20.70,16.30.
实施例257-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-氯-4-氟苯基)-2H-吡喃并[2,3-b]吡啶-2-酮
操作同实施例1,其中第二步将间苯二酚替换为2,6-二羟基吡啶,制备得到化合物25,化合物25的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.79(d,J=7.5Hz,1H),7.73(d,J=8.1Hz,1H),7.20(d,J=2.0Hz,1H),7.13-7.03(m,2H),6.25(s,1H),5.01(s,1H),3.75(s,2H),3.40(s,1H),3.33(s,2H),3.25(s,2H),1.83(s,2H),1.73(s,2H),1.52(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.57,160.56,159.69,152.73,151.90,132.41,129.69,123.94,116.85,114.83,112.79,108.78,108.24,72.05,55.24,50.64,26.15,16.41.
实施例26 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-苯基-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为苯乙酮,制备得到化合物26,化合物26的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.58-7.52(m,2H),7.52-7.44(m,4H),7.34(d,J=7.5Hz,1H),7.06(dd,J=7.5,2.0Hz,1H),6.93(d,J=2.0Hz,1H),6.29(s,1H),5.16(s,1H),3.60(s,2H),3.55(s,2H),3.40(s,1H),3.33(s,2H),1.79(s,2H),1.70(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.09,156.40,154.75,153.23,134.37,128.29,127.71,127.27,125.29,117.07,115.10,112.69,103.25,71.65,52.57,49.57,27.20,16.24.
实施例27 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(o-苯甲基)-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为2-甲基苯乙酮,制备得到化合物27,化合物27的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.38-7.31(m,2H),7.29-7.20(m,4H),7.06(dd,J=7.5,2.0Hz,1H),6.97(d,J=2.0Hz,1H),6.28(s,1H),5.16(s,1H),3.60(s,2H),3.55(s,2H),3.40(s,1H),3.33(s,2H),2.17(d,J=0.8Hz,4H),1.83(s,2H),1.73(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.09,156.40,154.70,148.98,136.39,134.26,128.65,128.19,127.91,127.21,125.46,115.83,114.76,112.79,104.14,72.36,55.24,50.15,27.20,20.89,16.29.
实施例28 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-(三氟甲基)苯基)-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为2-三氟甲基苯乙酮,制备得到化合物28,化合物28的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.69(dd,J=7.5,2.0Hz,1H),7.61(dd,J=7.5,2.0Hz,1H),7.51(td,J=7.5,2.0Hz,1H),7.38-7.29(m,2H),7.02(dd,J=7.5,2.0Hz,1H),6.93(d,J=1.9Hz,1H),6.53(s,1H),5.16(s,1H),3.58(s,2H),3.53(s,2H),3.40(s,1H),3.33(s,2H),1.88(s,2H),1.78(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.94,156.62,154.78,147.48,128.37,127.99,127.95,127.45,126.11,125.29,123.80,122.69,116.59,116.28,112.69,103.25,72.36,54.16,50.64,26.15,16.30.
实施例29 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2,4-二甲基苯基)-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为2,4-二甲基苯乙酮,制备得到化合物29,化合物29的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.33(d,J=7.5Hz,1H),7.15-7.02(m,4H),6.97(d,J=2.0Hz,1H),6.83(dt,J=1.9,0.9Hz,1H),6.28(s,1H),5.16(s,1H),3.58(s,2H),3.50(s,2H),3.40(s,1H),3.33(s,2H),2.33(d,J=1.1Hz,3H),2.17(d,J=0.9Hz,3H),1.83(s,2H),1.73(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.92,156.40,154.70,148.98,138.20,136.71,136.28,128.55,128.12,125.46,125.38,116.13,114.76,112.64,105.00,72.60,55.24,50.64,26.67,21.93,21.14,16.29.
实施例30 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-氟苯基)-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为2-氟苯乙酮,制备得到化合物30,化合物30的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.58(dd,J=7.4,2.1Hz,1H),7.43-7.29(m,4H),7.13(dd,J=7.5,2.1Hz,1H),7.06(dd,J=7.5,2.0Hz,1H),6.99(d,J=2.0Hz,1H),6.23(s,1H),5.16(s,1H),3.60(s,2H),3.55(s,2H),3.40(s,1H),3.33(s,2H),1.83(s,2H),1.73(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,161.02,160.01,156.40,154.75,151.90,129.21,128.92,126.80,125.77,124.87,115.46,115.32,114.76,112.93,104.14,72.36,55.24,50.15,27.20,16.29.
实施例31 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-甲氧苯基)-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为2-甲氧基苯乙酮,制备得到化合物31,化合物31的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.38-7.26(m,4H),7.18(td,J=7.4,2.0Hz,1H),7.02(dd,J=7.5,2.0Hz,1H),6.99-6.89(m,2H),6.25(s,1H),5.16(s,1H),3.84(s,3H),3.58(s,2H),3.50(s,2H),3.40(s,1H),3.33(s,2H),1.83(s,2H),1.73(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.45,156.41,156.40,154.75,153.32,129.20,129.19,124.30,123.24,121.48,115.66,115.10,114.21,113.01,105.00,72.60,55.57,55.24,50.64,26.67,16.29.
实施例32 7-(((2R)-1-(3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-氯苯基)-2H-色烯-2-酮
操作同实施例1,其中第一步将2-氯-4-氟苯乙酮替换为2-氯苯乙酮,制备得到化合物32,化合物32的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.54(dd,J=7.1,2.4Hz,1H),7.41-7.28(m,5H),7.06(dd,J=7.5,2.0Hz,1H),6.97(d,J=2.0Hz,1H),6.26(s,1H),5.16(s,1H),3.58(s,2H),3.53(s,2H),3.40(s,1H),3.33(s,2H),1.83(s,2H),1.73(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.80,156.40,154.78,150.62,133.35,133.16,130.39,129.46,128.21,127.69,125.29,115.83,114.76,112.64,105.00,72.60,55.24,50.18,27.20,16.29.
实施例33 4-(2-氯苯基)-7-(((2R)-1-(8-环己基-3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-2H-色烯-2-酮
操作同实施例32,增加第七步
第七步:将中间体33a(1mmol)溶于二氯甲烷(20mL)中,加入环己烷基甲醛(1.1mmol),加入催化量的醋酸,搅拌反应1小时,随后加入三乙酰氧基硼氢化钠(1.1mmol),室温反应1小时,待反应完毕后,加入10mL饱和氯化铵淬灭反应,随后加入100mL二氯甲烷和100mL冰水萃取三次,浓缩溶剂,柱层析得到化合物33。产率62.3%。化合物33的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.61-7.56(m,1H),7.39-7.29(m,5H),7.06(dd,J=7.5,2.0Hz,1H),6.93(d,J=1.9Hz,1H),6.28(s,1H),5.15(s,1H),3.78(s,2H),3.72(s,2H),3.47(s,2H),2.61(s,1H),1.79(d,J=6.0Hz,5H),1.71(d,J=13.0Hz,2H),1.62(s,1H),1.60-1.50(m,6H),1.43(dd,J=13.0,11.9Hz,3H),1.35(d,J=13.0Hz,1H).13C NMR(125MHz,Chloroform-d)δ170.46,160.92,156.79,154.28,150.62,133.35,132.66,130.27,129.30,128.23,127.62,124.68,117.90,116.16,112.54,103.25,72.60,61.04,56.74,51.09,31.96,28.05,26.30,25.09,16.37.
实施例34 4-(2-氯苯基)-7-(((2R)-1-羰基-1-(8-苯基-3,8-二氮杂二环[3.2.1]辛烷-3-基)丙烷-2-基)氧代)-2H-色烯-2-酮
操作同实施例33,其中将环己烷基甲醛替换为苯甲醛,制备得到化合物34,化合物34的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.61-7.55(m,1H),7.40-7.26(m,6H),7.29-7.20(m,1H),7.06(dd,J=7.5,2.0Hz,1H),7.02-6.96(m,2H),6.93(d,J=2.0Hz,1H),6.28(s,1H),5.15(s,1H),3.95(d,J=11.2Hz,3H),3.75(s,1H),1.92(d,J=3.7Hz,4H),1.52(s,2H).13C NMR(125MHz,Chloroform-d)δ170.56,160.92,156.79,154.28,150.62,147.19,133.35,132.89,130.27,129.30,129.05,128.23,127.62,124.68,119.26,117.13,116.16,115.95,112.54,103.25,72.81,54.70,50.92,28.95,16.31.
实施例35 4-(2-氯苯基)-7-(((2R)-1-羰基-1-(8-(吡啶-4-基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)丙烷-2-基)氧代)-2H-色烯-2-酮
操作同实施例33,其中将环己烷基甲醛替换为4-吡啶甲醛制备得到化合物35,化合物35的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ8.24-8.20(m,2H),7.61-7.55(m,1H),7.40-7.30(m,4H),7.14-7.10(m,2H),7.06(dd,J=7.5,2.0Hz,1H),6.93(d,J=2.0Hz,1H),6.28(s,1H),5.15(s,1H),3.91(d,J=3.8Hz,4H),3.71(s,2H),1.91(d,J=8.8Hz,4H),1.52(s,2H).13C NMR(125MHz,Chloroform-d)δ170.56,160.92,156.79,154.28,150.62,149.15,145.90,133.35,132.89,130.27,129.30,128.23,127.62,124.68,117.13,116.16,112.54,109.79,103.25,72.81,54.70,50.92,29.49,16.31.
实施例36 4-(2-氯苯基)-7-(((2R)-1-(8-(呋喃-3-基)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-2H-色烯-2-酮
操作同实施例33,其中将环己烷基甲醛替换为糠醛,制备得到化合物36,化合物38的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.77(s,1H),7.63(s,1H),7.60-7.54(m,1H),7.40-7.30(m,5H),7.06(dd,J=7.5,2.0Hz,1H),6.93(d,J=2.0Hz,1H),6.65(s,1H),6.28(s,1H),5.16(s,1H),3.96(s,2H),3.82(s,2H),3.78(s,2H),1.91(d,J=7.5Hz,5H),1.52(s,3H).13C NMR(125MHz,Chloroform-d)δ170.74,160.92,156.79,154.48,150.62,145.14,143.03,133.35,132.66,130.27,129.30,128.26,127.62,124.68,116.28,116.16,112.54,110.45,103.25,102.50,72.60,55.15,50.57,29.27,16.31.
实施例37 7-(((2R)-1-(8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2,4-二甲基苯基)-2H-色烯-2-酮
操作同实施例5,其中将第一步中的2-氯-4-氟苯乙酮替换为2,4二甲基苯乙酮,制备得到化合物37,化合物37的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.33(d,J=7.5Hz,1H),7.15-7.02(m,4H),6.97(d,J=2.0Hz,1H),6.83(dt,J=2.0,0.9Hz,1H),6.28(s,1H),5.15(s,1H),4.09(s,2H),3.69(s,2H),3.58(s,2H),2.33(t,J=1.0Hz,4H),2.17(d,J=0.9Hz,3H),1.82(s,2H),1.70(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.92,156.40,154.70,148.98,138.20,136.71,136.28,128.55,128.12,125.46,125.38,116.13,114.76,112.64,105.00,75.74,72.81,52.39,31.15,21.93,21.14,16.29.
实施例38 7-(((2R)-1-(8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-氯苯基)-2H-色烯-2-酮
操作同实施例5,其中将第一步中的2-氯-4-氟苯乙酮替换为2-氯苯乙酮,制备得到化合物38,化合物38的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.56(dd,J=7.1,2.4Hz,1H),7.41-7.28(m,5H),7.06(dd,J=7.5,2.0Hz,1H),6.97(d,J=2.0Hz,1H),6.26(s,1H),5.15(s,1H),4.09(s,2H),3.73(s,2H),3.62(s,2H),1.82(s,2H),1.70(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.80,156.62,154.78,150.62,133.35,133.16,130.39,129.46,128.21,127.69,125.29,115.83,114.76,112.64,105.00,75.74,72.81,52.39,31.15,16.29.
实施例39 7-(((2R)-1-(8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(o-苯甲基)-2H-色烯-2-酮
操作同实施例5,其中将第一步中的2-氯-4-氟苯乙酮替换为2-甲基苯乙酮,制备得到化合物39,化合物39的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.38-7.31(m,2H),7.297.20(m,4H),7.06(dd,J=7.5,2.0Hz,1H),6.97(d,J=2.0Hz,1H),6.28(s,1H),5.15(s,1H),4.09(s,2H),3.73(s,2H),3.62(s,2H),2.17(d,J=0.8Hz,4H),1.82(s,2H),1.70(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.09,156.40,154.70,148.98,136.39,134.26,128.65,128.19,127.91,127.21,125.46,115.83,114.76,112.79,104.14,75.74,72.60,52.39,31.15,20.89,16.29.
实施例40 7-(((2R)-1-(8-氧杂-3-氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-氯-4-甲基苯基)-2H-色烯-2-酮
操作同实施例5,其中将第一步中的2-氯-4-氟苯乙酮替换为2-氯-4-甲基苯乙酮制备得到化合物40,化合物40的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.47(d,J=7.4Hz,1H),7.37-7.26(m,2H),7.23(dt,J=2.0,1.0Hz,1H),7.05(dd,J=7.4,1.9Hz,1H),6.93(d,J=1.9Hz,1H),6.26(s,1H),5.15(s,1H),4.09(s,2H),3.69(s,2H),3.58(s,2H),2.41(t,J=1.0Hz,4H),1.82(s,2H),1.70(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.81,160.92,156.62,154.78,150.62,137.34,132.07,131.95,128.62,127.40,125.29,116.19,114.76,112.64,105.00,75.74,72.81,52.39,31.15,20.96,16.29.
实施例41 3-((R)-2-((4-(2-氯-4-氟苯基)-2-羰基-2H-色烯-7-基)氧代)丙酰)-3-氮杂二环[3.2.1]辛烷-8-羧酸
操作同实施例5,其中将第五步中的8-氧杂-3-氮杂双环[3,2,1]辛烷替换为甲基3-氮杂二环[3.2.1]辛烷-8v羧酸酯盐酸盐,随后将第六步改为如下反应:
将中间体A(1mmol)溶于10mL四氢呋喃中,加入氢氧化锂(1.5mmol)室温反应1小时,随后加入1N盐酸调至PH=2,加入水和乙酸乙酯,萃取三次,浓缩溶剂后柱层析得到化合物41,产率81.32%,化合物41的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.85(d,J=7.5Hz,1H),7.30(d,J=7.5Hz,1H),7.21(d,J=1.9Hz,1H),7.16(dd,J=7.4,1.9Hz,1H),7.06(dd,J=7.5,2.0Hz,1H),6.93(d,J=1.9Hz,1H),6.29(s,1H),5.15(s,1H),3.61(s,2H),3.55(s,2H),3.21(s,1H),2.57(s,2H),1.78(d,J=13.0Hz,2H),1.71(d,J=13.0Hz,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ178.24,170.56,160.92,160.16,156.79,154.67,153.10,132.86,132.82,129.81,125.29,116.81,116.28,116.16,114.83,112.69,103.25,72.81,50.01,48.65,37.81,28.89,16.31.
实施例42 7-(((2R)-1-(8-苯甲酰-3,8-二氮杂二环[3.2.1]辛烷-3-基)-1-羰基丙烷-2-基)氧代)-4-(2-氯-4-氟苯基)-2H-色烯-2-酮
操作同实施例1,增加一步第七步如下反应:
将化合物1(1.65mmol)溶于无水二氯甲烷20mL中,随后加入HATU(2.48mmol),搅拌反应30分钟,随后加入苯甲酸(1.98mmol)和DIPEA(2.48mmol)。反应1小时,待反应结束后,加入二氯甲烷100mL和冰水100mL萃取三次,浓缩有机层,PE∶EA(V/V)=2∶1柱层析得到化合物42,产率85.62%,化合物42的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ7.74(d,J=7.5Hz,1H),7.51-7.44(m,4H),7.44-7.37(m,2H),7.30(d,J=7.4Hz,1H),7.21(d,J=2.0Hz,1H),7.08(dd,J=7.5,2.0Hz,1H),6.99(dd,J=7.5,2.0Hz,1H),6.88(d,J=2.0Hz,1H),6.32(s,1H),5.09(s,1H),4.11(s,2H),3.78(s,2H),3.66(s,2H),1.91(s,2H),1.84(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.74,168.99,160.97,160.62,156.79,154.28,153.10,135.60,132.82,132.76,131.12,129.48,127.54,127.31,124.68,117.99,116.38,116.24,114.87,112.56,103.25,72.08,56.59,52.29,28.83,16.33.
实施例43 4-(2-氯-4-氟苯基)-7-(((2R)-1-羰基-1-(8-甲基吡啶酰-3,8-二氮杂二环[3.2.1]辛烷-3-基)丙烷-2-基)氧代)-2H-色烯-2-酮
操作同实施例42,将第七步中的苯甲酸替换为2-吡啶甲酸,得到化合物43,化合物43的表征数据如下:
1H NMR(500MHz,Chloroform-d)δ8.66(dd,J=5.1,1.3Hz,1H),7.91(td,J=8.0,1.2Hz,1H),7.787.71(m,2H),7.44(ddd,J=7.9,4.9,0.9Hz,1H),7.30(d,J=7.4Hz,1H),7.21(d,J=2.0Hz,1H),7.08(dd,J=7.5,2.0Hz,1H),6.99(dd,J=7.5,2.0Hz,1H),6.88(d,J=2.0Hz,1H),6.32(s,1H),5.09(s,1H),4.11(s,2H),3.78(s,2H),3.72(s,2H),1.89(s,2H),1.84(s,2H),1.51(s,3H).13C NMR(125MHz,Chloroform-d)δ170.74,165.31,160.97,160.62,156.79,154.28,153.10,149.33,144.75,136.91,132.82,131.12,127.54,124.68,124.30,120.74,117.99,116.70,116.24,114.87,112.56,103.25,72.08,57.39,52.29,29.10,16.33.
实验例1:活性试验
在以下实施例中,发明人以本发明的部分化合物为例,检测了本发明化合物的抗癌细胞增殖活性及实时定量PCR评估细胞活性
实施例A:抗细胞增殖活性试验
采用A2780、MDA-MB-468和DLD-1细胞系(来源于美国ATCC),将细胞以2000个/孔接种于96孔板中,次日加入本发明制备的化合物(1nM、10nM、100nM、1μM、10μM、100μM),随后按照以下SRB试验测得细胞存活率:
1)细胞固定:给药168小时后,吸去孔中的培养基,每孔加入200μL4℃预冷的10%TCA(三氯乙酸)溶液固定细胞。静置5min移入4℃冰箱中固定1h,取出用去离子水冲洗5遍,室温晾干。
2)染色:待96孔板室温下晾干后,每孔加入0.4%(w/v)的SRB染液(1%的乙酸配制)100μL,染色30min后倒掉染液,用1%(v/v)乙酸冲洗5次,去除未结合的染料,室温晾干。
3)检测:用100μL非缓冲Tris-base碱液(10mM,pH=10.5)溶解与细胞蛋白结合的染料,水平摇床上振荡20min,采用酶标仪545nM处测定光吸收值。抑制率的计算公式为:[1-(实验组吸光度变化/空白组吸光度变化)]×100%。化合物进行IC50的测定,方法为选取目标化合物的6个浓度测定抑制率(1nM、10nM、100nM、1μM、10μM、100μM),以摩尔浓度负对数与抑制率作线性回归,求得抑制率达到50%时的浓度即为该化合物的IC50值。
实施例B:实时定量PCR
采用MDA-MB-468细胞系,将细胞以50万个/孔接种于6孔板中,次日加入100nM浓度的化合物,孵育6小时后,采用试剂盒,提取RNA,随后测量RNA的浓度并进行逆转录,随后加入ND1引物(F:TCCTGCCATCATGACCCTTG,R:CTGCGGCGTATTCGATGTTG)并用实时定量PCR仪扩增,得到化合物中ND1相关RNA的量变化。
表1:本发明部分化合物的活性数据
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a给药组相对空白对照组中ND1 mRNA表达量的倍数
从表1可以看出,化合物1-32对A2780、MDAMB-468及DLD-1细胞系的抗增殖活性强于阳性药IMT1B,且对线粒体相关因子ND1的抑制强于阳性药IMT1B。
实验例2:人A2780卵巢癌裸鼠移植瘤的治疗效果
在第0天,将在指数生长期的A2780细胞皮下移植到Balb/c雌性裸鼠中,将裸鼠在独立通气笼(Individually VentilatedCages,IVC)中培养。裸小鼠移植瘤用游标卡尺测量移植瘤直径,待肿瘤生长至100-150mm3后将动物随机分3组,每组6只,开始给药,参见表2进行处理后,使用测量瘤径的方法,动态观察被试物抗肿瘤的效应。给药结束后,小鼠处死,手术剥取瘤块称重。肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2其中a、b分别表示长宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为:RTV=Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为相对肿瘤增殖率T/C(%),计算公式如下:
TRTV:治疗组RTV;CRTV:阴性对照组RTV。
抗肿瘤活性的评价指标:肿瘤生长抑制率(%),计算公式如下:
隔日测量动物体重、肿瘤长短径,绘制动物体重及肿瘤体积的变化曲线
表2
组别 | 裸鼠(n) | 处理 | 给药途径 | 给药时间 | 剂量 |
1 | 6 | 生理盐水 | 灌胃口服 | 25天 | - |
2 | 6 | 实施例1(化合物1) | 灌胃口服 | 25天 | 100mg/kg |
3 | 6 | 实施例2(化合物2) | 灌胃口服 | 25天 | 100mg/kg |
4 | 6 | 实施例5(化合物5) | 灌胃口服 | 25天 | 100mg/kg |
5 | 6 | 实施例20(化合物20) | 灌胃口服 | 25天 | 100mg/kg |
6 | 6 | 实施例41(化合物41) | 灌胃口服 | 25天 | 100mg/kg |
7 | 6 | 实施例42(化合物42) | 灌胃口服 | 25天 | 100mg/kg |
8 | 6 | 阳性药IMT1B | 灌胃口服 | 25天 | 100mg/kg |
实验结果:化合物1、2、5、20、41、42处理具有良好的耐受性,在较高剂量处理后,从图2可以看出,体重与对照组没有显著性差别,未观察到毒性迹象,通过100mg/kg给药后,从图1可以看出,化合物1、2、5、20、41、42处理的小鼠显示肿瘤生长抑制且抑瘤效果强于阳性药IMT-1B。
Claims (8)
1.一种通式I所示的化合物或其可药用的盐:
其中,W选自6至10元芳基、5至10元杂芳基或者3至8元杂环烷基;所述杂芳基含有1至3个选自N、O或者S的杂原子,所述芳基或者杂芳基任选地被0至4个Rt0取代,所述的杂环烷基被0至4个Rt1取代;
Rt0相同或者不同,各自独立选自C1-6烷基、C1-6烷氧基、卤素,所述的杂环烷基或者杂芳基各自含有1至3个选自N、O或者S的杂原子;
或者至少一对Rt0及其相连的原子形成4至10元的碳环或者5至10元的杂环,其中所述的杂环含有1至2个选自N、O或者S的杂原子。
Rt1选自C1-6烷基、C1-6烷氧基;
Rt2、Rt3选自H或者C1-6烷基;
Rt4、Rt5选自H、C1-6烷基、-NH(C=NRt1)NRt2Rt3、-S(=O)2NRt2Rt3、-C(=O)Rt1或者-C(=O)NRt2Rt3,所述的C1-6烷基任选进一步被1个或者多个选自OH、卤素、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基或者C3-8杂环烷基的取代基所取代;或者Rt4与Rt5及N原子形成3至8元杂环;所述的杂环含有1个至3个选自N、O或者S的杂原子;
Rt6为C1-6烷基;
G1各自独立选自CH或者N,G2,G3各自独立选自CH;
R1,R2各自独立选自H、甲基;
R1和R2也可环合形成环丁烷或环丙烷;
n1,n2,n3为0,1或2;
n4为1,2或3;
A选自O、NRa或者CRa,Ra选自氢、F、C1-6烷基、甲酸基、乙酸基、-C(=O)Rt1、-C(=O)NRt1、环己烷或者苯基。
2.权利要求1所述的化合物的衍生物或其可药用的盐,其特征在于,其中,W选自6元芳基、5至6元杂芳基或者3至8元杂环烷基;所述杂芳基含有1至3个选自N、O或者S的杂原子,所述芳基或者杂芳基任选地被0至4个Rt0取代,所述的杂环烷基被0至4个Rt1取代;Rt0相同或者不同,各自独立选自C1-6烷基、C1-6烷氧基、卤素;
Rt1选自C1-6烷基、C1-6烷氧基;
G1,G2,G3各自独立选自CH;
R1,R2各自独立选自氢、甲基;
R1和R2也可环合形成环丁烷或环丙烷;
n1,n2,n3为0或1;
n4为1或2;
A选自O、NRa或者CRa;
Ra选自氢、F、C1-6烷基、甲酸基、乙酸基、-C(=O)Rt1、环己烷或苯基。
3.化合物或其可药用的盐,其特征在于,其结构式如下中的任意一种:
4.权利要求1~3任一项所述的化合物或其可药用的盐在制备线粒体RNA聚合酶抑制剂药物中的应用。
5.权利要求1~3中任一项所述化合物或其可药用的盐在制备抗肿瘤药物中的应用,所述肿瘤包括胰腺癌、乳腺癌、成胶质细胞瘤、结直肠癌或卵巢癌。
6.一种药物组合物,包含权利要求1~3中任一项所述的化合物或其可药用的盐。
7.权利要求6所述的药物组合物在制备RNA聚合酶抑制剂药物中的应用。
8.权利要求6所述的药物组合物在制备抗肿瘤药物中的应用,所述肿瘤包括乳腺癌、结直肠癌、卵巢癌、胰腺癌或成胶质细胞瘤。
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CN110461841A (zh) * | 2017-06-19 | 2019-11-15 | 上海和誉生物医药科技有限公司 | 一种具有csf1r抑制活性的氮杂芳基衍生物、其制备方法和应用 |
CN111094317A (zh) * | 2017-12-29 | 2020-05-01 | 上海和誉生物医药科技有限公司 | 一种具有cd73抑制活性的膦酸衍生物、其制备方法和应用 |
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