CN117126134A - 新型四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 - Google Patents
新型四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途 Download PDFInfo
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- CN117126134A CN117126134A CN202210557284.9A CN202210557284A CN117126134A CN 117126134 A CN117126134 A CN 117126134A CN 202210557284 A CN202210557284 A CN 202210557284A CN 117126134 A CN117126134 A CN 117126134A
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Abstract
本发明提供了一种新型四氢异喹啉类化合物、其制备方法、包含此类化合物的药物组合物及其用途,具体地,本发明提供了一种通式(I)所示的含氮杂环类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体。所述的化合物可以用于制备治疗与4型松弛素家族受体活性或表达量相关的疾病或病症的药物组合物。
Description
技术领域
本发明涉及新型含氮杂环类化合物、其制备方法、包含此类化合物的药物组合物及其用途,属于医药技术领域。涉及通式(I)所示的新型含氮杂环类化合物,其药物上可接受盐、异构体、溶剂化物、代谢产物、代谢前体,含有他们的药物组合以及这类化合物在预防和、或治疗与RXFP4激动活性相关的便秘、厌食症、糖尿病、非酒精性脂肪肝炎等疾病或病症中的用途。
背景技术
人类的松弛素(R)/胰岛素(INS)超家族,包括INS、胰岛素样生长因子(IGF)1、IGF2、R1、R2、INSL3、INSL4、INSL5、INSL6和INSL7(R3)。松弛素和相关激素肽具有多种功能,涉及多种生理、病理过程,包括生殖、神经信号转导、伤口愈合、胶原代谢和肿瘤的发生等。胰岛素样肽5(INSL5)是松弛素/胰岛素超家族的成员之一,其结构组成包括信号肽、A链、B链和起连接作用的C链。A链和B链通过2个二硫键连接,同时A链内部还存在1个二硫键。在酶的作用下C肽链水解去除后,INSL5方可被激活发挥其生物活性。Northern印迹检测结果显示,人类的子宫和消化道中有INSL5表达,其中在直肠中的表达最多,在升结肠、降结肠中也有表达;定量反转录聚合酶链反应(RT-PCR)检测发现,人类INSL5存在于多种外周组织中,尤其是结肠、直肠、子宫,也存在于人类大脑中,主要存在于脑垂体中。
松弛素家族肽通过与G蛋白耦联受体结合产生进一步的生物信号转导。目前已经发现4种松弛素受体,它们分别被命名为RXFP 1-4。2003年Liu在人类基因组数据库中首次发现RXFP4,原命名为GPR100,最初将其描述为缓激肽受体。2005年的研究发现,GPR100为INSL5的受体,于是它被重命名为RXFP4,又名G蛋白耦联受体142(GPCR142)。INSL5是RXFP4的特异性激动剂,人类RXFP4由374个氨基酸组成,通过一个独立的外显子编码,属于A类神经肽样G蛋白耦联受体(视紫红质样受体),由细胞外区的短N末端、7个α螺旋跨膜结构域和细胞内的C末端组成。INSL5与RXFP4结合后,RXFP4耦联的Gi蛋白构象改变,α亚基被活化,诱发Giα-二磷酸鸟苷(GDP)与三磷酸鸟苷(GTP)交换,生成Giα-GTP;继而Giα-GTP与β亚基、γ亚基分离,并移至邻近的腺苷酸环化酶(AC),抑制AC,从而抑制细胞内环磷酸腺苷(cAMP)的产生,使得表达RXFP4的组织内的cAMP浓度下降。Northern印迹法检测显示人类RXFP4表达于心脏、骨骼肌、肾脏、肝脏和胎盘,而在胰腺中的表达最多;RT-PCR检测发现,人类RXFP4表达于心脏、骨骼肌、肾脏、肝脏和胎盘,同时在人类的结肠、甲状腺、唾液腺、前列腺、胸腺、睾丸和大脑中也有表达;Western印迹法检测发现,人类RXFP4表达于下丘脑、垂体、睾丸、附睾、卵巢、子宫、胰腺和肝脏;免疫组织化学法检测发现,人类RXFP4表达于胰腺胰岛B细胞内,也表达于垂体、睾丸和卵巢。RXFP4仅在一些物种中表达,大鼠、狗的RXFP4为假基因,小鼠的RXFP4较人类RXFP4保守性差,而对猴子、牛、猪的RXFP4的进一步研究证实,这几个物种的RXFP4与人类RXFP4均有很高的同源性,而且在体外的表现与人类受体相似。
食欲调节是当前医疗领域关注的主要问题之一,胃肠激素在肠道外有着多种生理功能,对食物摄取行为、食欲变化与营养物质代谢过程起到关键作用。INSL5是肠道L细胞分泌的一种胃肠激素,是继胃饥饿素后第二种被发现的促食欲激素。INSL5与RXFP4主要在结肠部位表达和分布,因此与胃饥饿素主要分布于脑部垂体的受体相比,INSL5及其类似物不必通过血脑屏障,可以直接通过影响肠神经系统发挥生理功能,这也使其受体RXFP4作为药物治疗靶点具有潜在优势。
便秘,指因粪便会太硬或太干而排便不顺或难以排出的状况。便秘通常有许多成因,常见原因包含内有粪便的结肠运动慢、患有肠躁症或骨腔疾病等,相关的潜在性疾病包含甲状腺功能减退症、腹泻、帕金森氏症、结肠癌、憩室炎、炎症性肠病等。近期的研究表明,RXFP4激动剂可以促进肠道蠕动,显著降低便秘小鼠模型的排便时间,这提示着RXFP4激动剂的发现有望提供新一类安全有效的便秘药物治疗手段。
综上,RXFP4靶点与食欲调节、肠道蠕动等人体重要生理功能息息相关,相关激动剂的设计和发现可以为后续对INSL5-RXFP4系统的研究提供有力的支持,也有望提供新一类治疗代谢相关疾病的药物。
发明内容
本发明的一个目的在于提供一种通式(I)所示的含氮杂环类化合物、其药学上可接受的盐、对映异构体、非对映异构体或外消旋体。
本发明的另一个目的在于提供一种上述通式(I)所示化合物的制备方法。
本发明的再一个目的在于提供一种包含治疗有效量的一种或多种上述通式(I)所示化合物或其药学上可接受的盐的药物组合物。
本发明的又一个目的在于提供上述通式(I)所示化合物在制备用于治疗便秘、厌食症、糖尿病、非酒精性脂肪肝炎等糖脂代谢性疾病的药物中的用途。
本发明的化合物可用于激动4型松弛素家族受体(RXFP4)。
本发明的第一方面,提供了一种通式(I)所示的含氮杂环类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体:
其中,
手性碳原子C*独立地为S型、R型、消旋体,或其组合;
n=0、1或2;
R1和R2各自独立地选自下组:氢、氘、氚、卤素、羟基、羧基、取代或未取代的C1~C6烷基、取代或未取代的C1~C6烷氧基、取代或未取代的C6~C10芳基、取代或未取代的5-7元的杂环、取代或未取代的C1~C6烷基苯基、取代或未取代的C1~C6烷基5-7元杂芳基、取代或未取代的C3~C12环烷基、取代或未取代的C2~C10酰基、取代或未取代的C2~C10酯基、氨基、取代或未取代的C1-C6烷胺基、取代或未取代的C1-C6酰胺基、-SOR5、-OSOR5、-OCOR5;
且当n=0时,所述的R1和R2不同时为甲基;当n=1时,所述的R1和R2不同时为氢;
或所述的R1和R2和相邻的(CH2)nO以及C=C共同构成取代或未取代的5-7元的杂环,其中,所述的杂环为全部饱和的杂环、部分不饱和的杂环或芳杂环;
X为O或S;
Y为选自下组的连接基团:化学键、C1~C6直链或支链烷基、-CH2NH-、C2~C6直链或支链烯基、-CH2O-、-CH2S-、-CONH-、-NHCO-、-COO-、-OOC-、
A环为取代或未取代的选自下组的基团:5~12元氮杂杂环基(其中连接位点优选位于氮原子上)、C6~C12芳基(优选为C6~C10芳基)、5~12元杂芳基(优选为5~7元杂芳基);其中,所述的杂环基或杂芳基包括选自下组的杂原子作为环骨架:N、NH、S、O、S(O)2;
R4选自未被取代或者被1-3个取代基取代的以下基团:C3~C7环烷基、5~12元杂环基、C6~C12芳基、5~12元杂芳基(优选为5-7元杂芳基,或苯并5~7元杂芳基);其中,各个所述杂环基或杂芳基含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自卤素、C1~C6直链或支链烷基、C2~C6直链或支链烯基、C2~C6直链或支链炔基、C1~C6直链或支链烷氧基、C1~C6直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、羧基、巯基、C1~C4酰基、酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,或者两个位于相邻环原子上的取代基连同与其连接的碳原子构成5-7元环;
R3和R5各自独立地选自下组:氢、氘、氚、卤素、未取代或由1-3个卤素取代的C1-C6的烷基、或未取代或由1-3个卤素取代的C3-C6环烷基、未取代或由1-3个卤素取代的C6~C10芳基、未取代或由1-3个卤素取代的C1-C3烷基-C6~C10芳基、未取代或由1-3个卤素取代的5-7元杂芳基。
在另一优选例中,所述的A环选自下组:氮丙啶基、氮杂环丁烷基、吡咯烷基、哌啶基、氮杂环庚烷基、吗啉基、哌嗪基、高哌嗪基、硫代吗啉基、环硫被亚砜或砜替代的硫代吗啉基、咪唑烷基、吡嗪基、六氢嘧啶基或且所述的A环任选地被1-2个选自氢、C1-C3直链或支链烷基、卤素、羟基和C1-C4烷氧羰基中的基团所取代。
在另一优选例中,所述的A环选自下组: 且所述的A环任选地被1-2个选自氢、C1-C3直链或支链烷基、卤素、羟基和C1-C4烷氧羰基中的基团所取代。
在另一优选例中,R1和R2各自独立地选自下组:氢、氘、氚、卤素、羟基、羧基、苯基、取代或未取代的C1~C6烷基、取代或未取代的C1~C6烷氧基、取代或未取代的5-7元的杂环、取代或未取代的C1~C6烷基5-7元杂芳基、取代或未取代的C3~C8环烷基、取代或未取代的C2~C10酰基、取代或未取代的C2~C10酯基、氨基、取代或未取代的C1-C6烷胺基、取代或未取代的C1-C6酰胺基、-SOR5、-OSOR5、-OCOR5。
在另一优选例中,X为O;
Y选自下组:-CH2-、-CH2-CH2-、-CH2-CH2-CH2-、-CH2NH-、-CH2O-、或-CH2S-。
在另一优选例中,R4选自未被取代或者被1-3个取代基取代的以下基团:C6-C10芳基、5-7元杂芳基,或苯并5~7元杂芳基;优选地,所述基团中的杂环和杂芳环部分选自吲哚、苯并二氧杂环戊烯、异噁唑、吡啶、吡唑、二氢咪唑并吡啶、咪唑并吡啶、苯并噻吩、二氢苯并二氧六环、喹喔林、吡咯、苯并呋喃、吲唑、苯并咪唑、喹啉、1,3-二氧代异吲哚啉形成的基团。
在另一优选例中,氢、氘、氚、卤素、未取代或由1-3个卤素取代的C1-C6的烷基、或未取代或由1-3个卤素取代的C3-C6环烷基。
在另一优选例中,手性碳原子C*为S型。
本发明的第二方面,提供了如本发明第一方面所述的式(I)化合物的制备方法,所述方法包括步骤:
(1)在惰性溶剂中,在缩合剂存在下,用式II化合物和式Ic化合物反应,得到式Id化合物;优选地,所述的缩合剂为EDCI(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐);
(2)在惰性溶剂中,用式Id化合物进行Bischler-Napieralski关环反应,得到式Ie化合物;优选地,所述的关环反应用三氯氧磷作为路易斯酸;
(3)在惰性溶剂中,用式Ie化合物进行还原反应,得到式If化合物;优选地,所述的还原反应用硼氢化物作为还原剂或用Noyori催化剂作为不对称还原催化剂;
(4)在惰性溶剂中,用式If化合物与进行成缩合反应,得到式(I)化合物;
上述各式中,各基团的定义如本发明第一方面所述。
本发明的第三方面,提供了一种药物组合物,所述的药物组合物包括:治疗有效量的如本发明第一方面所述的式(I)化合物,或其药学上可接受的盐,和药学上可接受的载体。
本发明的第四方面,提供了一种如本发明第一方面所述的式(I)化合物的用途,其特征在于,用于制备治疗与4型松弛素家族受体活性或表达量相关的疾病或病症的药物组合物;较佳地,所述的化合物用于制备治疗选自下组的疾病或病症的药物组合物:便秘、厌食症,或糖脂代谢相关疾病。
在另一优选例中,所述的化合物用于制备治疗4型松弛素家族受体活性或表达量过低引起的疾病或病症的药物组合物。
在另一优选例中,所述的糖脂代谢相关疾病选自下组:糖尿病、非酒精性脂肪肝炎。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究,制备得到了一类能够激动4型松弛素家族受体(RXFP4)的式I化合物。且与现有技术中的4型松弛素家族受体(RXFP4)相比,所述的化合物具有更高的抑制活性和选择性。基于上述发现,发明人完成了本发明。
术语
在本文中,除特别说明之处,术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:C1~C10烷基、C3~C10环烷基、C1~C10烷氧基、卤素、羟基、羧基(-COOH)、C1~C10醛基、C2~C10酰基、C2~C10酯基、氨基、苯基;所述的苯基包括未取代的苯基或具有1-3个取代基的取代苯基,所述取代基选自:卤素、C1-C10烷基、氰基、羟基、硝基、C3~C10环烷基、C1~C10烷氧基、氨基。
除特别说明之处,本发明的所有化合物之中,各手性碳原子可以任选地为R构型或S构型,或R构型和S构型的混合物。
术语“C1~C6烷基”指具有1~6个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“3-8元杂环基”指具有选自下组的1-3个杂原子的3~8元饱和环失去一个氢原子形成的基团:N、S、O;例如吡咯烷基、哌啶基、哌嗪基、吗啉基、或类似基团。
术语“6-10元芳基”指6~10元芳基失去一个氢原子形成的基团;例如苯基、萘基,或类似基团。
术语“5-10元杂芳基”指具有选自下组的1-3个杂原子的5~8元芳基失去一个氢原子形成的基团:N、S、O,其中每个杂芳基的环状体系可以是单环或多环的;例如吡咯基、吡啶基、噻吩基、呋喃基、咪唑基、嘧啶基、苯并噻吩基、吲哚基、咪唑并吡啶基、喹啉基或类似基团。
术语“C1~C6烷氧基”指具有1-6个碳原子的直链或支链烷氧基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“C2-C6酯基”指具有2-6个碳原子的R-O-C(=O)-基团,如-COOCH3、-COOC2H5、-COOC3H7、-COOC4H9,或类似基团。
术语“C2-C6烯基”指具有2-6个碳原子的烯烃失去一个或两个氢原子所形成的基团,所述的烯烃可以是单烯烃、二烯烃或三烯烃,例如-CH=CH2、-C2H4=CH2、-CH=C2H4,或类似基团。
术语“卤素”指F、Cl、Br和I。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑,化合价互变异构体包括通过一些成键电子重组而进行互变。
在本文中,形如“C1~C6”,表示该基团可以具有1个至6个碳原子,例如1个、2个、3个、4个或5个。
式(I)所示的四氢异喹啉类化合物
本发明提供一种通式(Ⅰ)表示的四氢异喹啉类化合物,其对映异构体、非对映异构体、外消旋体及其混合物或其药学上可接受的盐,
其中,各基团的定义如上所述。
在另一优选例中,n、X、Y、R1、R2、R3、R4各自独立地为实施例中各个具体化合物所对应的相应基团。
特别地,本发明所述的四氢异喹啉类化合物优选自下表A中所示的化合物:
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式(I)化合物的制备
本发明还提供了一种具有通式I的化合物的合成方法,具体地,所述的式I化合物通过下列所示流程进行制备:
步骤a:将Ic溶解在溶剂中,在缩合剂辅助下与II进行缩合反应得到化合物Id;所述溶剂为二氯甲烷;
步骤b:将Id溶解在溶剂中,加入过量三氯氧磷,回流搅拌,得化合物Ie;所述溶剂为无水乙腈;
步骤c:将Ie溶解在溶剂中,加入过量硼氢化钠,搅拌至反应完全,旋干溶剂得化合物If,所述溶剂为甲醇;或加入Noyori催化剂,搅拌至反应完全,所述溶剂为水和甲醇混合溶剂。
步骤d:将If溶于溶剂中,与相应原料反应得到化合物Ig;所述溶剂为二氯甲烷;
X、Y、R1、R2、R3、R4与前述要求中的定义相同。
含有式(I)化合物的药物组合物
本发明还涉及一种药物组合物,所述药物组合物包含治疗有效量的选自式(Ⅰ)表示的含氮杂环类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种以及任选地,药学上可接受的载体,其可用于治疗银屑病等自身免疫性相关的疾病。所述药物组合物可以根据不同给药途径而制备成各种形式。
本发明所述的式(Ⅰ)表示的醛基类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种,或者上述包含治疗有效量的选自式(Ⅰ)表示的四氢异喹啉类化合物、其药用盐、其前药及其水合物和溶剂合物中的一种或多种的药物组合物可以作为磷酸二酯酶4(PDE4)抑制剂,用于治疗便秘、厌食症、糖尿病、非酒精性脂肪肝炎等糖脂代谢性疾病。
本发明化合物的药用盐的制备,可以采用化合物的游离碱与无机或有机酸直接成盐反应进行。无机或有机酸可选自盐酸、硫酸、磷酸、硝酸、氢氟酸、氢溴酸、甲酸、乙酸、苦味酸、柠檬酸、马来酸、甲烷磺酸、三氟甲烷磺酸、乙烷磺酸和对甲苯磺酸等。
由于本发明化合物具有优异的对松弛素家族受体4(RXFP4)的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗以及缓解与松弛素家族受体4(RXFP4)相关的疾病。根据现有技术,本发明化合物可用于治疗以下疾病:便秘、厌食症、糖尿病、非酒精性脂肪肝炎等糖脂代谢性疾病等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有5-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
如上所述的根据本发明的化合物可对哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺、或者胃肠道等的给药途径,更优选为口服。日剂量优选为0.01~200mg/kg体重,一次性服用,或0.01~100mg/kg体重分次服用。不管用何种服用方法,个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
在以下的实施例中将进一步举例说明本发明。这些实施例仅用于说明本发明,但不以任何方式限制本发明。实施例中的所有参数以及其余的说明,除另有说明外,都是以质量为说明依据的。
样品的分析数据由以下仪器测定:核磁共振由GEMINI-300型、Bruker AMX-400型和INVOA-600型核磁共振仪测定,TMS(四甲基硅烷)为内标,化学位移单位为ppm,耦合常数单位为Hz;质谱由Finnigan MAT-711型,MAT-95和LCQ-DECA型质谱仪以及IonSpec4.7Tesla质谱仪测定。
柱层析用硅胶200-300目(青岛海洋化工厂生产);TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析预制板;石油醚沸程为60-90℃;采用紫外灯,碘缸显色。除另有说明外,以下实施例中所用常规试剂、药品均购自国药集团。实验中所用试剂及溶剂均按反应具体情况处理。
实施例A1:化合物A1的合成
合成路线:
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化合物1-3的合成:
1-1溶于丙酮,加入碳酸钾、滴加1-2,氩气保护下回流搅拌过夜。反应液过滤,蒸干,二氯甲烷稀释,加水搅拌10分钟,静置分层,有机层蒸干得黄色固体1-3,未经纯化直接投下一步。
化合物1-4的合成:
1-3溶于硝基甲烷,加醋酸铵回流2小时,蒸干溶剂,加入冰水中搅拌2小时,静置,过滤,滤饼用乙酸乙酯洗涤,得黄色固体,产率90%。1H NMR(500MHz,CDCl3)δ7.95(s,2H),7.41(dd,J=8.5,2.0Hz,1H),7.21(d,J=1.9Hz,1H),6.99(d,J=8.4Hz,1H),4.09(q,J=7.0Hz,2H),3.87(s,2H),1.43(t,J=6.9Hz,3H).ESI-MS m/z 224.2[M+H]+.
化合物1-5的合成:
冰浴下分批将四氢铝锂加入氩气保护的四氢呋喃中,搅拌下滴加1-4的四氢呋喃溶液,加毕,室温搅拌2小时,冰浴下缓慢加水淬灭反应,过滤,乙酸乙酯、甲醇洗涤滤饼,蒸干得微黄透明油状物。未经纯化直接投下步。
化合物2-3的合成:
化合物2-1和2-2溶于甲苯,回流18小时。冷却,蒸干溶剂,经柱层析(二氯甲烷:甲醇100:1)得到白色固体,产率85%。1H NMR(500MHz,CDCl3)δ9.49(d,J=2.5Hz,1H),8.10(d,J=15.9Hz,1H),7.83(d,J=2.7Hz,1H),7.47(d,J=2.7Hz,1H),7.08(d,J=8.4Hz,1H),6.80(dd,J=8.4,2.7Hz,1H),6.39(d,J=15.9Hz,1H),3.86(s,3H),3.75(s,3H).ESI-MS m/z 232.2[M+H]+.
化合物2-4的合成:
化合物2-3溶于甲醇中,加入氢氧化钯碳,60℃反应6小时。抽滤除去钯碳,旋干溶剂得白色固体。未经纯化直接用于下一步反应。
化合物2-5的合成:
化合物2-4溶于甲醇中,加入1M氢氧化钠水溶液,50℃反应2小时。旋蒸除去大部分甲醇,二氯甲烷洗去大部分杂质,水相用1M盐酸调pH 1-2,乙酸乙酯萃取。合并乙酸乙酯层,无水硫酸钠干燥,旋干溶剂得白色固体。直接用于下一步反应。
化合物3-6的合成:
2-5溶于二氯甲烷中,加入EDCI,HOBT,TEA搅拌30分钟,缓慢加入1-5的二氯甲烷溶液,搅拌过夜,加二氯甲烷稀释,依次用饱和碳酸氢钠、饱和氯化铵、饱和氯化钠洗涤,无水硫酸钠干燥,蒸干,石油醚/乙酸乙酯=1:1柱层析纯化得黄白色固体1.2g,收率为92%。1HNMR(500MHz,CDCl3)δ9.48(t,J=2.3Hz,1H),7.22(dd,J=8.4,2.0Hz,1H),7.04(dd,J=12.4,2.6Hz,2H),6.87–6.81(m,1H),6.80–6.70(m,2H),6.66(dt,J=9.1,0.9Hz,2H),4.08(q,J=7.0Hz,2H),3.84(d,J=7.9Hz,6H),3.42(td,J=5.6,4.4Hz,2H),3.06(t,J=7.8Hz,2H),2.74(tt,J=5.6,1.0Hz,2H),2.65(t,J=7.8Hz,2H),1.43(t,J=7.0Hz,3H).ESI-MSm/z 397.2[M+H]+.
化合物3-7的合成:
将化合物3-6 1g溶于100mL无水乙腈中,加入三氯氧磷,在氩气保护下,回流搅拌。TLC监测反应完全后减压蒸干,加入冰的饱和碳酸氢钠调至弱碱性,二氯甲烷萃取,无水硫酸钠干燥,蒸干得橙色油状物,未经纯化直接投下一步反应。
化合物3-8的合成:
将化合物3-7溶于甲醇中,冰浴下分批加入硼氢化钠,室温搅拌4小时,饱和氯化铵溶液淬灭反应,加入二氯甲烷萃取,饱和碳酸氢钠,饱和氯化钠洗涤,无水硫酸钠干燥有机层,浓缩,柱层析(二氯甲烷:甲醇20:1)得黄色固体,两步收率70%。1H NMR(500MHz,CDCl3)δ9.74(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.1Hz,1H),7.08(d,J=2.6Hz,1H),7.03(d,J=2.9Hz,1H),6.86(d,J=1.1Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.62(t,J=1.0Hz,1H),4.19–4.01(m,2H),3.85(d,J=11.5Hz,5H),3.78(dtd,J=7.3,5.3,1.0Hz,1H),3.44(dddd,J=14.2,5.7,4.7,3.8Hz,1H),3.41–3.31(m,1H),2.98(dt,J=14.6,7.2Hz,1H),2.97–2.81(m,3H),2.33(dtd,J=13.6,7.3,5.2Hz,1H),2.26–2.13(m,2H),1.42(t,J=6.9Hz,3H).ESI-MS m/z 381.3[M+H]+.
化合物A1的合成:
将3-8 100mg溶于二氯甲烷中,加入吗啉酰氯和三乙胺,室温搅拌2小时。TLC监测反应完全后,加入饱和氯化铵,二氯甲烷萃取3次,合并有机相,饱和氯化钠洗涤。无水硫酸钠干燥,蒸干溶剂,柱层析(石油醚:乙酸乙酯1:1)得白色固体A1,收率为90%。1H NMR(500MHz,CDCl3)δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.0Hz,1H),7.07(d,J=2.5Hz,1H),7.02(d,J=2.8Hz,1H),6.94(d,J=1.1Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.61(t,J=1.0Hz,1H),5.21(td,J=5.4,1.0Hz,1H),4.14(dq,J=10.1,6.9Hz,1H),4.11–4.01(m,2H),3.83(d,J=1.8Hz,6H),3.63–3.51(m,5H),3.16–3.03(m,4H),2.98–2.85(m,3H),2.50(dt,J=14.7,7.2Hz,1H),2.40(dtd,J=12.6,7.3,5.3Hz,1H),2.29(dtd,J=12.6,7.2,5.3Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m/z 494.2[M+H]+.
实施例(S)-A1:化合物(S)-A1的合成
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将3-7溶于少量甲醇,加入去离子水,加入(R,R)-Noyori催化剂、六氟锑酸银、三氟甲烷磺酸镧、二水合甲酸钠,氩气保护下室温搅拌过夜,二氯甲烷萃取,水洗,有机层硅藻土助滤,浓缩,二氯甲烷/甲醇=40:1柱层析得4-8,参考化合物A1的合成方法,得到化合物(S)-A1。1H NMR(500MHz,CDCl3)δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.0Hz,1H),7.07(d,J=2.5Hz,1H),7.02(d,J=2.8Hz,1H),6.94(d,J=1.1Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.61(t,J=1.0Hz,1H),5.21(td,J=5.4,1.0Hz,1H),4.14(dq,J=10.1,6.9Hz,1H),4.11–4.01(m,2H),3.83(d,J=1.8Hz,6H),3.63–3.51(m,5H),3.16–3.03(m,4H),2.98–2.85(m,3H),2.50(dt,J=14.7,7.2Hz,1H),2.40(dtd,J=12.6,7.3,5.3Hz,1H),2.29(dtd,J=12.6,7.2,5.3Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m/z 494.2[M+H]+.
实施例(R)-A1:化合物(R)-A1的合成
用(S,S)-Noyori催化剂替换实施例中的(R,R)-Noyori催化剂,参考化合物(S)-A1的合成方法,得到化合物(R)-A1。1H NMR(500MHz,CDCl3)δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.0Hz,1H),7.07(d,J=2.5Hz,1H),7.02(d,J=2.8Hz,1H),6.94(d,J=1.1Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.61(t,J=1.0Hz,1H),5.21(td,J=5.4,1.0Hz,1H),4.14(dq,J=10.1,6.9Hz,1H),4.11–4.01(m,2H),3.83(d,J=1.8Hz,6H),3.63–3.51(m,5H),3.16–3.03(m,4H),2.98–2.85(m,3H),2.50(dt,J=14.7,7.2Hz,1H),2.40(dtd,J=12.6,7.3,5.3Hz,1H),2.29(dtd,J=12.6,7.2,5.3Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m/z494.2[M+H]+.
实施例A2:化合物A2的合成
用化合物5-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A2。1H NMR(500MHz,CDCl3)δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.5,2.0Hz,1H),7.07(d,J=2.5Hz,1H),7.02(d,J=2.8Hz,1H),6.93(d,J=1.0Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.61(t,J=0.9Hz,1H),5.17(td,J=5.4,1.0Hz,1H),4.14(dq,J=10.1,6.9Hz,1H),4.11–3.99(m,2H),3.83(d,J=4.2Hz,6H),3.59(ddd,J=12.1,6.3,4.4Hz,1H),3.56–3.50(m,4H),2.98–2.85(m,3H),2.83(dt,J=14.8,7.3Hz,1H),2.41(dtd,J=12.7,7.3,5.4Hz,1H),2.28(dtd,J=12.6,7.2,5.3Hz,1H),1.67–1.57(m,6H),1.42(t,J=7.0Hz,3H).ESI-MS m/z492.3[M+H]+.
实施例A3:化合物A3的合成
将化合物4-8溶于二氯甲烷中,加入饱和碳酸氢钠。向该二相体系中加入三光气的二氯甲烷溶液。室温反应1小时后,分离二氯甲烷相。水相用二氯甲烷萃取两次。无水硫酸钠干燥。将溶液转移至单口瓶中,加入6-3和二异丙基乙胺,室温反应过夜。TLC监测反应完全后,加入饱和氯化铵,二氯甲烷萃取3次,合并有机相,饱和氯化钠洗涤。无水硫酸钠干燥,蒸干溶剂,柱层析(石油醚:乙酸乙酯1:1)得白色固体A3,收率为90%。1H NMR(500MHz,CDCl3)δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.1Hz,1H),7.07(d,J=2.5Hz,1H),7.02(d,J=2.8Hz,1H),6.76–6.69(m,2H),6.61(t,J=1.0Hz,1H),5.21(td,J=5.3,1.0Hz,1H),4.69(p,J=4.2Hz,1H),4.60(p,J=4.2Hz,1H),4.20–3.95(m,5H),3.83(d,J=1.0Hz,5H),3.60(dddd,J=13.2,10.6,7.3,4.9Hz,3H),3.00–2.78(m,4H),2.39(dtd,J=12.7,7.3,5.3Hz,1H),2.28(dtd,J=12.6,7.2,5.3Hz,1H),2.06–1.79(m,5H),1.42(t,J=6.9Hz,3H).ESI-MSm/z 510.0[M+H]+.
实施例A4:化合物A4的合成
用化合物7-1替换实施例A3中的6-10,合成方法参考化合物A3,得化合物A4。1HNMR(500MHz,CDCl3)δ9.63(t,J=2.4Hz,1H),7.23(dd,J=8.4,1.9Hz,1H),7.09(d,J=2.5Hz,1H),7.05(d,J=1.7Hz,1H),6.97(d,J=1.0Hz,1H),6.75(dd,J=8.4,2.0Hz,1H),6.63(t,J=1.0Hz,1H),5.18(td,J=5.2,1.0Hz,1H),4.20–4.02(m,5H),3.83(s,5H),3.68(ddd,J=12.1,6.5,4.2Hz,2H),3.42(ddd,J=11.9,6.5,4.1Hz,1H),3.02(dddd,J=14.5,6.4,4.2,0.9Hz,1H),2.90(dddd,J=14.6,6.6,4.1,1.0Hz,1H),2.68–2.58(m,1H),2.55–2.40(m,2H),2.40–2.29(m,1H),2.32–2.21(m,2H),2.14(tddd,J=21.0,14.5,6.5,4.2Hz,2H),1.42(t,J=7.0Hz,3H).ESI-MS m/z 528.3[M+H]+.
实施例A5:化合物A5的合成
用化合物8-1替换实施例A3中的6-10,合成方法参考化合物A3,得化合物A5。1HNMR(500MHz,CDCl3)δ9.63(t,J=2.4Hz,1H),7.23(dd,J=8.4,1.9Hz,1H),7.09(d,J=2.6Hz,1H),7.05–6.97(m,2H),6.74(dd,J=8.4,1.8Hz,1H),6.63(t,J=1.0Hz,1H),5.11(td,J=5.3,1.0Hz,1H),4.15(dq,J=10.1,6.9Hz,1H),4.12–3.96(m,2H),3.83(d,J=0.7Hz,6H),3.66(dt,J=10.8,4.9Hz,2H),3.62–3.50(m,3H),3.05–2.92(m,2H),2.90(dt,J=14.6,7.4Hz,1H),2.80(t,J=4.9Hz,4H),2.52–2.37(m,2H),2.29(dtd,J=12.6,7.4,5.3Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m/z 526.1[M+H]+.
实施例A6:化合物A6的合成
用化合物9-1替换实施例A3中的6-10,合成方法参考化合物A3,得化合物A6。1HNMR(500MHz,CDCl3)δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.1Hz,1H),7.06(dd,J=13.2,2.6Hz,2H),6.85(d,J=1.1Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.63(t,J=1.0Hz,1H),5.13(td,J=5.3,0.9Hz,1H),4.20–4.01(m,3H),3.83(s,5H),3.67(dt,J=10.8,5.0Hz,2H),3.61(dt,J=10.5,5.1Hz,2H),3.56(ddd,J=12.1,6.4,4.2Hz,1H),3.26(t,J=5.1Hz,4H),2.97(dddd,J=14.5,6.4,4.2,0.9Hz,1H),2.91(dddd,J=14.5,6.3,4.1,0.9Hz,1H),2.85(dt,J=14.7,7.2Hz,1H),2.68–2.58(m,1H),2.38(dtd,J=12.7,7.3,5.4Hz,1H),2.27(dtd,J=12.6,7.3,5.5Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m/z 542.2[M+H]+.
实施例A7:化合物A7的合成
用化合物10-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A7。1H NMR(500MHz,DMSO-d6)δ8.69–8.64(m,2H),7.77–7.72(m,2H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.93–4.86(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.83–3.73(m,8H),2.91(tt,J=7.1,0.8Hz,2H),2.78–2.64(m,2H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m/z 486.1[M+H]+.
实施例A8:化合物A8的合成
用化合物11-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A8。1H NMR(500MHz,DMSO-d6)δ9.01(d,J=1.5Hz,1H),8.75(dd,J=7.5,1.6Hz,1H),8.15(dt,J=7.5,1.5Hz,1H),7.43(t,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.93–4.86(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.84–3.77(m,8H),2.91(tt,J=7.1,0.9Hz,2H),2.78–2.64(m,2H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m/z486.1[M+H]+.
实施例A9:化合物A9的合成
用化合物12-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A9。1H NMR(500MHz,DMSO-d6)δ8.64(dd,J=7.5,1.5Hz,1H),7.91(td,J=7.5,1.6Hz,1H),7.79(dd,J=7.4,1.6Hz,1H),7.57(td,J=7.5,1.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.98–4.92(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.87–3.75(m,9H),2.91(tt,J=7.1,0.8Hz,2H),2.78–2.64(m,2H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m/z 486.1[M+H]+.
实施例A10:化合物A10的合成
用化合物13-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A10。1H NMR(500MHz,DMSO-d6)δ9.43(d,J=1.5Hz,1H),8.84(d,J=7.5Hz,1H),7.72(dd,J=7.5,1.6Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.60(t,J=1.0Hz,1H),4.98–4.92(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.84–3.75(m,8H),2.91(tt,J=7.1,0.8Hz,2H),2.78(dt,J=12.3,7.1Hz,1H),2.70(dt,J=12.3,7.0Hz,1H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m/z 487.3[M+H]+.
实施例A11:化合物A11的合成
用化合物14-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A11。1H NMR(500MHz,DMSO-d6)δ9.21(s,2H),9.07(s,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.60(t,J=1.0Hz,1H),4.92–4.85(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.84–3.77(m,8H),2.91(tt,J=7.2,1.0Hz,2H),2.78–2.64(m,2H),2.35–2.18(m,2H),1.44–1.37(m,3H).ESI-MS m/z 487.3[M+H]+.
实施例A12:化合物A12的合成
用化合物15-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A12。1H NMR(500MHz,DMSO-d6)δ9.22(s,1H),8.82(d,J=1.8Hz,2H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.95(td,J=6.9,0.6Hz,1H),4.06(qd,J=8.0,1.3Hz,2H),3.89–3.77(m,8H),2.91(tt,J=7.1,0.9Hz,2H),2.78(dt,J=12.3,7.1Hz,1H),2.70(dt,J=12.3,7.1Hz,1H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m/z 487.3[M+H]+.
实施例A13:化合物A13的合成
用化合物16-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A13。1H NMR(500MHz,DMSO-d6)δ8.82(dd,J=7.5,1.5Hz,1H),8.13(dd,J=7.5,1.5Hz,1H),7.95(t,J=7.4Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(d,J=1.0Hz,1H),4.95(td,J=6.9,0.7Hz,1H),4.06(qd,J=8.0,1.3Hz,2H),3.89–3.77(m,8H),2.91(tt,J=7.1,0.9Hz,2H),2.78(dt,J=12.3,7.1Hz,1H),2.70(dt,J=12.2,7.1Hz,1H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m/z 487.3[M+H]+.
实施例A14:化合物A14的合成
用化合物17-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A14。1H NMR(500MHz,DMSO-d6)δ9.46(d,J=1.5Hz,1H),9.25(d,J=7.5Hz,1H),7.97(dd,J=7.5,1.6Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.93–4.86(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.84–3.71(m,9H),2.91(tt,J=7.1,0.8Hz,2H),2.78–2.64(m,2H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m/z 487.3[M+H]+.
实施例A15:化合物A15的合成
用化合物18-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A15。1H NMR(500MHz,DMSO-d6)δ8.19(s,1H),8.15(d,J=8.2Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.60(t,J=1.0Hz,1H),5.01–4.95(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.87–3.77(m,7H),2.96(dt,J=12.3,7.1Hz,1H),2.91(tt,J=7.1,0.9Hz,2H),2.70(dt,J=12.4,7.1Hz,1H),2.36–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 475.2[M+H]+.
实施例A16:化合物A16的合成
用化合物19-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A16。1H NMR(500MHz,CDCl3)δ9.52(t,J=2.4Hz,1H),7.56–7.51(m,2H),7.23(dd,J=8.4,2.1Hz,1H),7.09(d,J=2.6Hz,1H),7.02(d,J=1.8Hz,1H),6.95(d,J=0.9Hz,1H),6.75(dd,J=8.4,1.8Hz,1H),6.64(t,J=1.0Hz,1H),5.06(td,J=5.5,1.1Hz,1H),4.19–3.96(m,3H),3.88–3.80(m,7H),3.12–3.01(m,2H),2.98–2.86(m,2H),2.42(dtd,J=12.6,7.3,5.3Hz,1H),2.29(dtd,J=12.6,7.3,5.4Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m/z 475.2[M+H]+.
实施例A17:化合物A17的合成
用化合物20-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A17。1H NMR(500MHz,DMSO-d6)δ8.34(d,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.96(d,J=7.5Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.97(t,J=6.9Hz,1H),4.08(qd,J=8.0,4.6Hz,2H),3.87–3.77(m,7H),2.96(dt,J=12.3,7.1Hz,1H),2.91(tt,J=7.1,0.8Hz,2H),2.70(dt,J=12.4,7.1Hz,1H),2.36–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z475.2[M+H]+.
实施例A18:化合物A18的合成
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用化合物21-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A18。1H NMR(500MHz,DMSO-d6)δ8.18(d,J=1.4Hz,1H),8.06(dd,J=5.9,1.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.59(d,J=1.0Hz,1H),4.92–4.85(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.84–3.77(m,8H),2.96(dt,J=12.3,7.1Hz,1H),2.91(tt,J=7.2,0.9Hz,2H),2.70(dt,J=12.3,7.1Hz,1H),2.34–2.17(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z475.2[M+H]+.
实施例A19:化合物A19的合成
用化合物22-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A19。1H NMR(500MHz,DMSO-d6)δ8.34(d,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),7.00(d,J=7.5Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(s,1H),6.59(t,J=0.9Hz,1H),4.89–4.83(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.80(d,J=13.7Hz,5H),3.72(td,J=7.0,1.2Hz,2H),2.91(tt,J=7.0,0.8Hz,2H),2.74(qt,J=12.5,7.1Hz,2H),2.35–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 476.2[M+H]+.
实施例A20:化合物A20的合成
用化合物23-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A20。1H NMR(500MHz,DMSO-d6)δ8.29(s,1H),8.05(s,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.59(t,J=0.9Hz,1H),4.89–4.83(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.80(d,J=13.7Hz,5H),3.72(td,J=7.0,1.2Hz,2H),2.91(tt,J=7.0,0.8Hz,2H),2.74(qt,J=12.5,7.1Hz,2H),2.35–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 476.2[M+H]+.
实施例A21:化合物A21的合成
用化合物24-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A22。1H NMR(500MHz,DMSO-d6)δ8.07(d,J=7.5Hz,1H),7.47(d,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.59(t,J=0.9Hz,1H),4.94–4.87(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.83–3.72(m,7H),2.91(tt,J=7.1,0.8Hz,2H),2.74(qt,J=12.5,7.1Hz,2H),2.36–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 476.2[M+H]+.
实施例A22:化合物A22的合成
用化合物25-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A22。1H NMR(500MHz,DMSO-d6)δ8.93(d,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.85–6.76(m,2H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.95(td,J=6.9,0.6Hz,1H),4.08(qd,J=8.0,4.6Hz,2H),3.87–3.77(m,7H),2.91(tt,J=7.1,0.9Hz,2H),2.78(dt,J=12.3,7.1Hz,1H),2.72(dt,J=12.2,7.1Hz,1H),2.35–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 476.2[M+H]+.
实施例A23:化合物A23的合成
用化合物26-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A23。1H NMR(500MHz,DMSO-d6)δ9.02(d,J=1.4Hz,1H),8.38(d,J=1.4Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.59(d,J=1.0Hz,1H),4.92–4.85(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.83–3.77(m,8H),2.91(tt,J=7.2,0.9Hz,2H),2.79–2.66(m,2H),2.34–2.17(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 476.2[M+H]+.
实施例A24:化合物A24的合成
用化合物27-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A24。1H NMR(500MHz,DMSO-d6)δ8.25(d,J=1.4Hz,1H),7.99(d,J=1.4Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.60(t,J=1.0Hz,1H),4.95(td,J=6.9,0.6Hz,1H),4.08(qd,J=8.0,4.6Hz,2H),3.87–3.77(m,8H),2.91(tt,J=7.1,0.9Hz,2H),2.83–2.67(m,2H),2.35–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 476.2[M+H]+.
实施例A25:化合物A25的合成
用化合物28-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A25。1H NMR(500MHz,DMSO-d6)δ8.47(dd,J=7.5,1.6Hz,1H),7.72(dd,J=7.5,1.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.77–6.71(m,2H),6.60(t,J=1.0Hz,1H),4.98–4.92(m,1H),4.15–4.00(m,2H),3.88–3.77(m,8H),2.96(dt,J=12.3,7.1Hz,1H),2.91(tt,J=7.1,0.9Hz,2H),2.70(dt,J=12.4,7.1Hz,1H),2.35–2.18(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 475.2[M+H]+.
实施例A26:化合物A26的合成
用化合物29-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A26。1H NMR(500MHz,DMSO-d6)δ8.27(s,1H),7.28–7.23(m,2H),7.22(d,J=7.5Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.93–4.87(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.88–3.75(m,8H),2.96(dt,J=12.3,7.1Hz,1H),2.91(tt,J=7.1,1.1Hz,2H),2.70(dt,J=12.3,7.1Hz,1H),2.33–2.17(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 475.2[M+H]+.
实施例A27:化合物A27的合成
用化合物30-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A27。1H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.75(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.07(qd,J=7.9,4.4Hz,2H),3.80(d,J=13.5Hz,7H),3.56(dddt,J=7.5,6.1,2.9,1.5Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),2.91(tt,J=7.1,0.9Hz,2H),2.78–2.64(m,2H),2.37–2.19(m,2H),1.98–1.86(m,4H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 478.3[M+H]+.
实施例A28:化合物A28的合成
用化合物31-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A28。1H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.75(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.90–4.84(m,1H),4.08(qd,J=8.0,2.9Hz,2H),3.80(d,J=12.1Hz,7H),3.57(t,J=7.1Hz,2H),3.52–3.43(m,3H),2.96(dt,J=12.3,7.1Hz,1H),2.91(tt,J=7.1,0.9Hz,2H),2.70(dt,J=12.4,7.1Hz,1H),2.37–2.19(m,2H),1.93(p,J=7.1Hz,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 464.2[M+H]+.
实施例A29:化合物A29的合成
用化合物32-1替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A29。1H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.4,1.5Hz,1H),6.74(s,1H),6.60(t,J=0.9Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.06(qd,J=8.1,2.1Hz,2H),3.83–3.74(m,7H),3.52–3.42(m,5H),2.91(tt,J=7.1,0.9Hz,2H),2.77–2.64(m,2H),2.45(t,J=7.1Hz,4H),2.28(s,3H),2.36–2.18(m,2H),1.44–1.37(m,3H).ESI-MS m/z 506.3[M+H]+.
实施例A30:化合物A30的合成
用化合物1-6替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A30。1HNMR(500MHz,DMSO-d6)δ7.42(ddt,J=7.8,1.9,1.0Hz,2H),7.36(ddt,J=7.5,6.5,1.0Hz,2H),7.36–7.28(m,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.76(d,J=0.6Hz,1H),6.60(d,J=1.0Hz,1H),5.16(dt,J=12.5,1.0Hz,1H),5.08(dt,J=12.4,1.1Hz,1H),4.87(td,J=7.0,0.6Hz,1H),3.83–3.74(m,7H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.13(dt,J=12.5,7.0Hz,2H),2.96(dt,J=12.5,7.2Hz,2H),2.91(tt,J=7.1,1.1Hz,2H),2.77–2.65(m,2H),2.36–2.18(m,2H).ESI-MS m/z 556.3[M+H]+.
实施例A31:化合物A31的合成
用化合物1-7替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A31。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.15(d,J=1.8Hz,1H),7.10(d,J=8.4Hz,1H),6.85–6.79(m,2H),6.59(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.84–4.75(m,1H),3.79(d,J=4.4Hz,8H),3.55–3.43(m,5H),3.13(dt,J=12.5,7.0Hz,2H),3.00–2.86(m,4H),2.77–2.65(m,2H),2.36–2.18(m,2H),1.76–1.66(m,1H),1.70–1.63(m,2H),1.66–1.56(m,1H),1.57(ddt,J=4.2,3.2,1.6Hz,1H).ESI-MS m/z534.3[M+H]+.
实施例A32:化合物A32的合成
用化合物1-8替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A32。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.75(d,J=0.6Hz,1H),6.61(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),3.94(dd,J=12.4,7.0Hz,1H),3.86(dd,J=12.4,7.1Hz,1H),3.82–3.74(m,7H),3.53(s,1H),3.53–3.43(m,4H),3.07–3.01(m,1H),3.01(d,J=7.1Hz,1H),2.98(d,J=7.2Hz,1H),2.98–2.91(m,1H),2.91(tt,J=7.2,0.9Hz,2H),2.71(td,J=7.1,0.9Hz,2H),2.36–2.18(m,2H),1.26(hept,J=7.0Hz,1H),0.72–0.59(m,2H),0.48–0.35(m,2H).ESI-MS m/z 520.3[M+H]+.
实施例A33:化合物A33的合成
用化合物1-9替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A33。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.15(d,J=1.8Hz,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.75(d,J=0.6Hz,1H),6.59(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.15(dt,J=12.5,7.1Hz,1H),4.09(dt,J=12.5,7.1Hz,1H),3.83–3.74(m,7H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–3.01(m,1H),3.03–2.86(m,6H),2.80(dt,J=12.4,7.1Hz,1H),2.76–2.65(m,2H),2.35(s,5H),2.36–2.25(m,1H),2.27–2.18(m,1H).ESI-MS m/z 537.3[M+H]+.
实施例A34:化合物A34的合成
用化合物1-10替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A34。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.15(d,J=1.8Hz,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.75(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.24(t,J=7.1Hz,2H),3.83–3.74(m,7H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–3.01(m,1H),3.01(d,J=7.1Hz,1H),2.97(d,J=7.0Hz,1H),2.97–2.91(m,1H),2.91(tt,J=7.2,0.9Hz,2H),2.84–2.65(m,4H),2.36–2.18(m,2H).ESI-MS m/z 538.2[M+H]+.
实施例A35:化合物A35的合成
用化合物1-11替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A35。1HNMR(500 MHz,DMSO-d6)δ7.26(d,J=7.6 Hz,1H),7.14(d,J=1.8 Hz,1H),7.09(d,J=8.4Hz,1H),6.86–6.79(m,2H),6.70(t,J=1.0 Hz,1H),4.87(td,J=7.0,0.6 Hz,1H),4.06(qd,J=8.0,2.2 Hz,2H),3.83–3.74(m,7H),3.52(t,J=7.1 Hz,4H),3.47(dt,J=12.5,7.1 Hz,1H),3.03(dt,J=12.5,7.0 Hz,2H),2.98(d,J=7.2 Hz,1H),2.98–2.91(m,1H),2.91(ddd,J=7.1,6.6,1.0 Hz,2H),2.78–2.64(m,2H),2.36–2.18(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 494.3[M+H]+.
实施例A36:化合物A36的合成
用化合物1-12替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A36。1HNMR(500 MHz,DMSO-d6)δ7.42(ddt,J=7.8,1.9,0.9 Hz,2H),7.36(ddt,J=7.5,6.5,1.0Hz,2H),7.36–7.28(m,1H),7.26(d,J=7.6 Hz,1H),7.14(d,J=1.4 Hz,1H),7.10(d,J=8.4 Hz,1H),6.87(d,J=0.7 Hz,1H),6.82(dd,J=7.5,1.6 Hz,1H),6.70(t,J=1.1Hz,1H),5.14(dt,J=12.5,1.0 Hz,1H),5.09(dt,J=12.4,1.0 Hz,1H),4.87(td,J=6.9,0.6Hz,1H),3.79(d,J=12.3 Hz,7H),3.52(t,J=7.1 Hz,4H),3.47(dt,J=12.5,7.1 Hz,1H),3.13(dt,J=12.5,7.0 Hz,2H),2.96(dt,J=12.5,7.2 Hz,2H),2.91(tt,J=7.1,1.1Hz,2H),2.77–2.65(m,2H),2.36–2.18(m,2H).ESI-MS m/z 556.3[M+H]+.
实施例A37:化合物A37的合成
用化合物1-13替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A37。1HNMR(500 MHz,DMSO-d6)δ7.26(d,J=7.6 Hz,1H),7.15(d,J=1.8 Hz,1H),7.10(d,J=8.4Hz,1H),6.87(s,1H),6.82(dd,J=7.5,1.6 Hz,1H),6.75(t,J=1.1 Hz,1H),4.87(td,J=7.0,0.6 Hz,1H),4.84–4.75(m,1H),3.83–3.74(m,7H),3.52(t,J=7.1 Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.13(dt,J=12.5,7.0Hz,2H),2.96(dt,J=12.5,7.2Hz,2H),2.91(tt,J=7.1,1.1Hz,2H),2.77–2.65(m,2H),2.36–2.18(m,2H),1.76–1.50(m,6H).ESI-MS m/z534.3[M+H]+.
实施例A38:化合物A38的合成
用化合物1-14替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A38。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.15(d,J=1.8Hz,1H),7.10(d,J=8.4Hz,1H),6.87(d,J=0.7Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.69(d,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.20–4.05(m,2H),3.83–3.74(m,7H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–3.01(m,1H),3.03–2.86(m,6H),2.80(dt,J=12.4,7.1Hz,1H),2.76–2.65(m,2H),2.35(s,5H),2.36–2.25(m,1H),2.27–2.18(m,1H).ESI-MS m/z 537.3[M+H]+.
实施例A39:化合物A39的合成
用化合物1-15替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A39。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.85–6.79(m,2H),6.77(t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.68–4.58(m,2H),3.83–3.74(m,7H),3.52(d,J=7.2Hz,3H),3.52–3.43(m,2H),3.02–2.87(m,6H),2.77–2.64(m,2H),2.36–2.18(m,2H).ESI-MS m/z 524.2[M+H]+.
实施例A40:化合物A40的合成
用化合物1-16替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A40。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.84–6.79(m,2H),6.59(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.59(hept,J=6.8Hz,1H),3.83–3.74(m,7H),3.54–3.43(m,5H),3.02–2.94(m,2H),2.97–2.87(m,4H),2.77–2.69(m,1H),2.71–2.64(m,1H),2.36–2.18(m,2H),1.35(d,J=6.9Hz,3H),1.30(d,J=6.8Hz,3H).ESI-MS m/z 508.3[M+H]+.
实施例A41:化合物A41的合成
用化合物1-17替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A41。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.89(d,J=0.6Hz,1H),6.82(dd,J=7.4,1.5Hz,1H),6.76(t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.59(hept,J=6.8Hz,1H),3.83–3.74(m,7H),3.54–3.43(m,5H),3.02–2.94(m,2H),2.97–2.87(m,4H),2.77–2.69(m,1H),2.71–2.64(m,1H),2.36–2.18(m,2H),1.32(d,J=6.8Hz,3H),1.27(d,J=6.8Hz,3H).ESI-MS m/z 508.3[M+H]+.
实施例A42:化合物A42的合成
用化合物1-18替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A42。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),7.03(d,J=0.7Hz,1H),6.82(dd,J=7.4,1.5Hz,1H),6.66(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),3.85(s,2H),3.79(dt,J=12.5,7.1Hz,1H),3.78(s,3H),3.51(t,J=7.0Hz,4H),3.47(dd,J=12.4,7.1Hz,1H),3.02–2.94(m,2H),2.97–2.86(m,4H),2.77–2.69(m,1H),2.71–2.64(m,1H),2.36–2.18(m,2H),2.25(s,3H).ESI-MS m/z 508.2[M+H]+.
实施例A43:化合物A43的合成
用化合物1-19替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A43。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.90–6.85(m,2H),6.82(dd,J=7.4,1.5Hz,1H),4.87(td,J=6.9,0.6Hz,1H),3.82(s,2H),3.78(s,3H),3.76(dt,J=12.5,7.2Hz,1H),3.51(t,J=7.0Hz,4H),3.47(dd,J=12.5,7.1Hz,1H),3.02–2.94(m,2H),2.97–2.87(m,4H),2.77–2.64(m,2H),2.36–2.18(m,2H),2.25(s,3H).ESI-MS m/z 508.2[M+H]+.
实施例A44:化合物A44的合成
用化合物1-20替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A44。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.75(d,J=0.7Hz,1H),6.61(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.36(dt,J=12.5,7.1Hz,1H),4.24(dt,J=12.5,7.1Hz,1H),3.83–3.74(m,7H),3.58(td,J=7.2,4.0Hz,2H),3.52(d,J=7.2Hz,3H),3.52–3.43(m,2H),3.37(s,2H),3.02–2.94(m,2H),2.97–2.86(m,4H),2.77–2.64(m,2H),2.36–2.18(m,2H).ESI-MSm/z 524.3[M+H]+.
实施例A45:化合物A45的合成
用化合物1-21替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A45。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.85–6.79(m,2H),6.70(t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.36(dt,J=12.5,7.0Hz,1H),4.25(dt,J=12.5,7.1Hz,1H),3.83–3.74(m,7H),3.58(td,J=7.2,4.0Hz,2H),3.52(d,J=7.1Hz,3H),3.52–3.43(m,2H),3.37(s,2H),3.02–2.94(m,2H),2.97–2.86(m,4H),2.77–2.64(m,2H),2.36–2.18(m,2H).ESI-MS m/z524.3[M+H]+.
实施例A46:化合物A46的合成
用化合物1-22替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A46。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.61(d,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.32(td,J=7.1,2.8Hz,2H),3.86–3.77(m,7H),3.53(d,J=7.1Hz,3H),3.50(s,1H),3.52–3.43(m,2H),3.45–3.38(m,1H),3.07–3.01(m,1H),3.04–2.91(m,3H),2.96(s,3H),2.91(tt,J=7.2,0.9Hz,2H),2.77–2.65(m,2H),2.36–2.18(m,2H).ESI-MS m/z 572.2[M+H]+.
实施例A47:化合物A47的合成
用化合物1-23替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A47。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.86–6.79(m,2H),6.73(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.38–4.26(m,2H),3.86–3.77(m,7H),3.53(d,J=7.1Hz,3H),3.50(s,1H),3.52–3.43(m,2H),3.45–3.38(m,1H),3.07–3.01(m,1H),3.01(d,J=7.2Hz,1H),2.98(d,J=7.2Hz,1H),2.96(s,3H),2.98–2.91(m,1H),2.94–2.86(m,2H),2.77–2.65(m,2H),2.36–2.18(m,2H).ESI-MS m/z572.2[M+H]+.
实施例A48:化合物A48的合成
用化合物1-24替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A48。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.86–6.79(m,2H),6.77(t,J=1.0Hz,1H),6.73(d,J=7.7Hz,1H),6.67(d,J=7.7Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.61–4.52(m,2H),3.83–3.74(m,7H),3.53(s,1H),3.52(s,2H),3.52–3.43(m,2H),3.02–2.87(m,6H),2.77–2.69(m,1H),2.71–2.64(m,1H),2.36–2.18(m,2H).ESI-MS m/z 523.2[M+H]+.
实施例A49:化合物A49的合成
用化合物1-25替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A49。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.85–6.77(m,2H),6.73(d,J=7.7Hz,1H),6.67(d,J=7.7Hz,1H),6.62(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.64–4.53(m,2H),3.83–3.74(m,7H),3.52(d,J=7.2Hz,3H),3.52–3.43(m,2H),3.02–2.86(m,6H),2.77–2.69(m,1H),2.71–2.64(m,1H),2.36–2.18(m,2H).ESI-MS m/z 523.2[M+H]+.
实施例A50:化合物A50的合成
用化合物1-26替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A50。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.93(t,J=1.0Hz,1H),6.86(d,J=0.7Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),4.87(td,J=7.0,0.6Hz,1H),3.84(s,2H),3.81–3.72(m,3H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–2.87(m,6H),2.77–2.65(m,2H),2.36–2.18(m,2H).ESI-MS m/z562.2[M+H]+.
实施例A51:化合物A51的合成
用化合物1-27替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A51。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.12–7.06(m,2H),6.82(dd,J=7.5,1.6Hz,1H),6.67(t,J=1.0Hz,1H),4.91–4.85(m,1H),3.84–3.74(m,6H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–3.01(m,1H),3.01(d,J=7.2Hz,1H),2.98(d,J=7.2Hz,1H),2.98–2.91(m,1H),2.94–2.86(m,2H),2.77–2.65(m,2H),2.37–2.19(m,2H).ESI-MS m/z 562.2[M+H]+.
实施例A52:化合物A52的合成
用化合物1-28替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A52。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.87–6.79(m,2H),6.70(t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.00(dd,J=12.3,7.0Hz,1H),3.87(dd,J=12.4,7.0Hz,1H),3.79(d,J=9.0Hz,7H),3.73(dt,J=12.4,7.1Hz,2H),3.63(dt,J=12.4,7.1Hz,2H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–2.86(m,6H),2.77–2.65(m,2H),2.36–2.18(m,2H),2.11(hept,J=7.0Hz,1H),1.83–1.68(m,4H).ESI-MS m/z 564.3[M+H]+.
实施例A53:化合物A53的合成
用化合物1-29替换实施例A1中的1-5,合成方法参考化合物A1,得化合物A53。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.75(d,J=0.6Hz,1H),6.61(t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),3.99(dd,J=12.4,7.0Hz,1H),3.87(dd,J=12.4,7.0Hz,1H),3.83–3.74(m,7H),3.73(dt,J=12.4,7.1Hz,2H),3.63(dt,J=12.4,7.1Hz,2H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–2.86(m,6H),2.77–2.65(m,2H),2.36–2.18(m,2H),2.11(hept,J=7.0Hz,1H),1.83–1.68(m,4H).ESI-MS m/z 564.3[M+H]+.
实施例A54:化合物A54的合成
用化合物2-6替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A54。1HNMR(500MHz,DMSO-d6)δ9.27(d,J=8.4Hz,1H),7.47–7.41(m,2H),7.28(d,J=7.3Hz,1H),6.93(d,J=0.6Hz,1H),6.81(dd,J=7.5,1.5Hz,1H),6.63(t,J=0.9Hz,1H),6.18(s,1H),4.08(qd,J=7.9,2.5Hz,2H),3.90(dt,J=12.4,7.1Hz,1H),3.82(d,J=4.2Hz,6H),3.57(q,J=7.2Hz,5H),3.12(td,J=7.1,0.9Hz,4H),2.91(tt,J=7.2,0.8Hz,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 466.2[M+H]+.
实施例A55:化合物A55的合成
用化合物2-7替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A55。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.5Hz,1H),7.18(d,J=8.4Hz,1H),7.12(d,J=1.4Hz,1H),6.81(dd,J=7.5,1.5Hz,1H),6.76(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),5.07–5.01(m,1H),4.06(qd,J=8.0,2.3Hz,2H),3.83–3.74(m,6H),3.61–3.49(m,4H),3.51–3.44(m,1H),3.13(dt,J=12.5,7.1Hz,2H),3.03–2.87(m,5H),2.83(dd,J=12.4,7.1Hz,1H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 480.2[M+H]+.
实施例A56:化合物A56的合成
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用化合物2-8替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A56。1HNMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.17–7.13(m,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.4,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.59(t,J=1.0Hz,1H),4.90–4.83(m,1H),4.06(qd,J=8.1,2.1Hz,2H),3.83–3.74(m,7H),3.54–3.43(m,5H),3.02–2.94(m,2H),2.97–2.86(m,4H),2.72–2.63(m,2H),2.06–1.88(m,3H),1.92–1.79(m,1H),1.44–1.37(m,3H).ESI-MS m/z 508.3[M+H]+.
实施例A57:化合物A57的合成
用化合物2-9替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A57。1HNMR(500MHz,DMSO-d6)δ7.86(t,J=1.0Hz,1H),7.47–7.40(m,2H),7.17(d,J=8.4Hz,1H),6.74(d,J=0.6Hz,1H),6.59(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.06(qd,J=8.0,1.3Hz,2H),3.83–3.74(m,3H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–2.86(m,6H),2.78(dt,J=12.3,7.1Hz,1H),2.70(dt,J=12.3,7.0Hz,1H),2.37–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m/z 489.2[M+H]+.
实施例A58:化合物A58的合成
用化合物2-10替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A58。1HNMR(500MHz,DMSO-d6)δ7.10–7.03(m,2H),6.81–6.77(m,1H),6.74(d,J=0.7Hz,1H),6.60(t,J=0.9Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.06(qd,J=8.1,2.1Hz,2H),3.81(s,3H),3.82–3.74(m,1H),3.58(s,2H),3.53(s,1H),3.53–3.43(m,4H),3.02–2.94(m,2H),2.97–2.86(m,4H),2.77–2.64(m,2H),2.33(s,3H),2.36–2.18(m,2H),1.44–1.37(m,3H).ESI-MSm/z 508.3[M+H]+.
实施例A59:化合物A59的合成
用化合物2-11替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A59。1HNMR(500MHz,DMSO-d6)δ7.29(s,1H),7.07(d,J=8.4Hz,1H),6.81(s,1H),6.74(d,J=0.7Hz,1H),6.60(t,J=0.9Hz,1H),6.03(d,J=3.7Hz,2H),4.87(td,J=6.9,0.6Hz,1H),4.06(qd,J=8.1,2.1Hz,2H),3.83–3.74(m,3H),3.53(s,1H),3.53–3.43(m,4H),3.02–2.94(m,2H),2.97–2.86(m,4H),2.77–2.64(m,2H),2.36–2.18(m,2H),1.44–1.37(m,3H).ESI-MSm/z 508.3[M+H]+.
实施例A60:化合物A60的合成
用化合物2-12替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A60。1HNMR(500MHz,DMSO-d6)δ7.48(dd,J=7.5,1.6Hz,1H),7.20(t,J=7.5Hz,1H),7.10(d,J=8.4Hz,1H),7.03(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.59(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.06(qd,J=8.0,1.3Hz,2H),3.83–3.74(m,3H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–2.86(m,6H),2.78–2.64(m,2H),2.61(qd,J=8.0,1.5Hz,2H),2.37–2.19(m,2H),1.44–1.37(m,3H),1.23–1.17(m,3H).ESI-MS m/z 492.3[M+H]+.
实施例A61:化合物A61的合成
用化合物2-13替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A61。1HNMR(500MHz,DMSO-d6)δ7.74–7.70(m,1H),7.36–7.28(m,2H),7.15(d,J=8.4Hz,1H),6.75(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.06(qd,J=8.0,2.2Hz,2H),3.83–3.74(m,3H),3.59–3.43(m,5H),3.13(dt,J=12.5,7.0Hz,2H),2.96(dt,J=12.5,7.2Hz,2H),2.91(tt,J=7.1,0.9Hz,2H),2.77–2.64(m,2H),2.36–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 542.2[M+H]+.
实施例A62:化合物A62的合成
用化合物2-14替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A62。1HNMR(500MHz,DMSO-d6)δ7.49–7.45(m,1H),7.39(d,J=7.5Hz,1H),7.13–7.07(m,2H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.1Hz,1H),4.87(t,J=6.9Hz,1H),4.07(qd,J=7.9,4.4Hz,2H),3.83–3.74(m,3H),3.61–3.53(m,2H),3.56–3.48(m,2H),3.47(dt,J=12.5,6.5Hz,1H),3.13(dt,J=12.5,7.0Hz,2H),3.00–2.86(m,4H),2.78–2.64(m,2H),2.41(s,2H),2.37–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 478.3[M+H]+.
实施例A63:化合物A63的合成
用化合物2-15替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A63。1HNMR(500MHz,DMSO-d6)δ7.91(d,J=1.5Hz,1H),7.57(dd,J=7.5,1.6Hz,1H),7.32(d,J=7.5Hz,1H),7.12(d,J=8.4Hz,1H),6.74(s,1H),6.60(d,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.14–4.00(m,2H),3.81(s,2H),3.79(dt,J=12.5,7.1Hz,1H),3.52(d,J=7.2Hz,3H),3.52–3.43(m,2H),3.02–2.86(m,6H),2.78–2.65(m,2H),2.37–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 532.2[M+H]+.
实施例A64:化合物A64的合成
用化合物2-16替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A64。1HNMR(500MHz,DMSO-d6)δ7.37(d,J=7.5Hz,1H),7.08(d,J=1.7Hz,1H),6.94(s,1H),6.83(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=0.9Hz,1H),4.87(t,J=6.9Hz,1H),4.06(qd,J=8.1,2.1Hz,2H),3.82(d,J=3.1Hz,6H),3.82–3.75(m,1H),3.73(s,3H),3.54–3.43(m,5H),3.02–2.94(m,2H),2.97–2.87(m,4H),2.79(t,J=7.0Hz,2H),2.26–2.08(m,2H),1.44–1.37(m,3H).ESI-MS m/z 508.3[M+H]+.
实施例A65:化合物A65的合成
用化合物2-17替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A65。1HNMR(500MHz,DMSO-d6)δ9.72(s,1H),7.78(d,J=1.4Hz,1H),7.49(dd,J=7.5,1.5Hz,1H),7.37(d,J=7.5Hz,1H),7.15(d,J=8.4Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=0.9Hz,1H),4.87(t,J=6.9Hz,1H),4.14–4.00(m,2H),3.81(s,2H),3.79(dt,J=12.5,7.1Hz,1H),3.52(t,J=7.1Hz,4H),3.47(dd,J=12.4,7.1Hz,1H),3.02–2.94(m,2H),2.97–2.86(m,4H),2.77–2.64(m,2H),2.37–2.19(m,2H),2.15(s,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z521.3[M+H]+.
实施例A66:化合物A66的合成
用化合物2-18替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A66。1HNMR(500MHz,DMSO-d6)δ7.69–7.63(m,2H),7.51(dd,J=7.5,1.6Hz,1H),7.31(td,J=7.5,1.5Hz,1H),7.23(td,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.91–4.84(m,1H),4.08(qd,J=8.0,2.9Hz,2H),3.83–3.74(m,3H),3.57(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.17–3.08(m,4H),2.91(tt,J=7.1,0.9Hz,2H),2.84–2.72(m,2H),2.21–2.03(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 465.2[M+H]+.
实施例A67:化合物A67的合成
用化合物2-19替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A67。1HNMR(500MHz,DMSO-d6)δ7.83–7.76(m,1H),7.76–7.69(m,1H),7.45–7.36(m,2H),7.31(s,1H),6.75(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.06(qd,J=8.0,1.1Hz,2H),3.83–3.74(m,3H),3.56(td,J=7.0,2.7Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.13(dt,J=12.5,7.0Hz,2H),2.96(dt,J=12.5,7.1Hz,2H),2.91(tt,J=7.2,0.9Hz,2H),2.84(td,J=7.1,3.1Hz,2H),2.26–2.07(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z481.2[M+H]+.
实施例A68:化合物A68的合成
用化合物2-20替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A68。1HNMR(500MHz,DMSO-d6)δ7.91(dd,J=7.5,1.6Hz,1H),7.56(dd,J=7.6,1.5Hz,1H),7.41(td,J=7.5,1.5Hz,1H),7.26(td,J=7.5,1.5Hz,1H),6.75(s,1H),6.60(t,J=1.0Hz,1H),4.96–4.89(m,1H),4.15–4.00(m,2H),3.83–3.73(m,3H),3.57(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.22(dt,J=12.4,7.1Hz,1H),3.20–3.11(m,4H),3.11(d,J=1.1Hz,1H),2.91(tt,J=7.1,1.1Hz,2H),2.48–2.31(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z465.2[M+H]+.
实施例A69:化合物A69的合成
用化合物2-21替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A69。1HNMR(500MHz,DMSO-d6)δ9.94(d,J=8.4Hz,1H),8.62(dd,J=7.5,1.6Hz,1H),8.38(dd,J=7.5,1.6Hz,1H),7.39(t,J=7.5Hz,1H),6.94(d,J=8.6Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.08(qd,J=8.0,2.9Hz,2H),3.83–3.74(m,3H),3.57(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.17–3.08(m,4H),2.99(dt,J=12.3,7.1Hz,1H),2.91(tt,J=7.1,0.9Hz,2H),2.78(dt,J=12.4,7.1Hz,1H),2.36–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 465.2[M+H]+.
实施例A70:化合物A70的合成
用化合物2-22替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A70。1HNMR(500MHz,DMSO-d6)δ8.43(dd,J=7.4,1.6Hz,1H),8.39(d,J=1.5Hz,1H),7.50(dt,J=7.5,1.5Hz,1H),7.26(t,J=7.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.91–4.84(m,1H),4.17–4.02(m,2H),3.85(dt,J=12.3,7.1Hz,1H),3.83(s,3H),3.78(dt,J=12.5,7.0Hz,1H),3.58(t,J=7.1Hz,4H),3.13(t,J=7.1Hz,4H),2.90(td,J=7.1,1.0Hz,2H),2.82(td,J=7.1,1.4Hz,2H),2.32–2.15(m,2H),1.40(t,J=8.0Hz,3H).ESI-MSm/z 426.2[M+H]+.
实施例A71:化合物A71的合成
用化合物2-23替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A71。1HNMR(500MHz,DMSO-d6)δ6.94(dd,J=7.3,1.6Hz,1H),6.81–6.72(m,3H),6.60(t,J=1.0Hz,1H),4.91–4.84(m,1H),4.17–4.02(m,2H),3.84(dt,J=12.5,7.1Hz,1H),3.82(s,3H),3.75(dt,J=12.5,7.1Hz,1H),3.58(t,J=7.1Hz,4H),3.22–3.08(m,4H),2.95–2.87(m,3H),2.89–2.82(m,1H),2.34–2.17(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 414.2[M+H]+.
实施例A72:化合物A72的合成
用化合物2-24替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A72。1HNMR(500MHz,DMSO-d6)δ8.51–8.46(m,2H),7.21–7.16(m,2H),6.74(d,J=0.6Hz,1H),6.59(t,J=1.0Hz,1H),4.91–4.84(m,1H),4.17–4.02(m,2H),3.85(dt,J=12.3,7.1Hz,1H),3.83(s,3H),3.78(dt,J=12.5,7.0Hz,1H),3.58(t,J=7.1Hz,4H),3.13(t,J=7.1Hz,4H),2.95–2.86(m,3H),2.79(dt,J=12.5,7.1Hz,1H),2.24–2.07(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 426.2[M+H]+.
实施例A73:化合物A73的合成
用化合物2-25替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A73。1HNMR(500MHz,DMSO-d6)δ7.37–7.31(m,2H),7.14–7.03(m,3H),6.74(d,J=0.6Hz,1H),6.60(d,J=1.0Hz,1H),4.99–4.92(m,1H),4.15–4.00(m,2H),3.83–3.73(m,3H),3.57(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.12(td,J=7.1,1.0Hz,4H),2.98–2.83(m,4H),2.30–2.13(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 464.2[M+H]+.
实施例A74:化合物A74的合成
用化合物2-26替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A74。1HNMR(500MHz,DMSO-d6)δ7.76(d,J=7.9Hz,1H),7.45–7.41(m,1H),7.12(d,J=7.5Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.74(s,1H),6.59(t,J=1.0Hz,1H),6.11(t,J=6.8Hz,1H),5.09–5.02(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.96(dt,J=12.4,6.8Hz,1H),3.87–3.79(m,7H),3.82–3.76(m,1H),3.78–3.71(m,1H),3.52(t,J=7.1Hz,4H),2.95(d,J=7.0Hz,3H),2.95–2.87(m,3H),1.44–1.37(m,3H).ESI-MS m/z 495.3[M+H]+.
实施例A75:化合物A75的合成
用化合物2-27替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A75。1HNMR(500MHz,DMSO-d6)δ7.44–7.40(m,1H),7.24(d,J=9.2Hz,1H),7.16(d,J=7.5Hz,1H),6.84–6.79(m,2H),6.59(t,J=1.1Hz,1H),5.30–5.23(m,1H),4.55(dd,J=12.3,7.0Hz,1H),4.46(dd,J=12.4,7.1Hz,1H),4.06(qd,J=8.1,1.4Hz,2H),3.81(d,J=3.1Hz,6H),3.76(t,J=7.1Hz,2H),3.52(t,J=7.1Hz,4H),3.07–2.98(m,4H),2.91(ddd,J=7.2,6.6,1.0Hz,2H),1.40(t,J=8.0Hz,3H).ESI-MS m/z 496.2[M+H]+.
实施例A76:化合物A76的合成
用碘甲烷替换实施例(S)-A1中的1-2,用化合物2-28替换实施例(S)-A1中的2-5,用化合物2-29替换实施例(S)-A1中的吗啉酰氯,合成方法参考化合物(S)-A1,得化合物A76。1H NMR(500MHz,Chloroform-d)δ9.91(d,J=8.6Hz,1H),7.55(d,J=7.5Hz,1H),7.17(dd,J=1.4,0.8Hz,1H),7.19–7.11(m,1H),6.98(dq,J=7.8,1.3Hz,1H),6.83(d,J=0.6Hz,1H),6.58(t,J=1.0Hz,1H),4.67–4.60(m,1H),3.83(d,J=6.2Hz,6H),3.81–3.74(m,2H),3.74(d,J=7.0Hz,1H),3.69(dt,J=12.3,7.1Hz,1H),3.55(dt,J=12.4,7.1Hz,2H),3.18(dt,J=12.3,7.1Hz,1H),3.02(dt,J=12.5,7.1Hz,1H),2.91(td,J=7.0,0.9Hz,2H),2.55(p,J=7.0Hz,1H),2.47(d,J=0.9Hz,2H),2.33(dq,J=12.5,7.1Hz,1H),2.25(dq,J=12.5,7.1Hz,1H),1.70(qd,J=7.1,4.3Hz,4H).ESI-MS m/z 492.3[M+H]+
实施例A77:化合物A77的合成
用碘甲烷替换实施例A1中的1-2,用化合物2-30替换实施例A1中的2-5,用化合物2-31替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A77。1H NMR(500MHz,Chloroform-d)δ9.94(d,J=8.4Hz,1H),8.70–8.65(m,2H),7.78–7.73(m,2H),7.60(dd,J=7.3,1.6Hz,1H),7.36(dd,J=7.4,1.7Hz,1H),7.18–7.12(m,2H),7.09(td,J=7.4,1.5Hz,1H),6.82(s,1H),6.58(t,J=1.0Hz,1H),4.93–4.86(m,1H),3.84(d,J=4.4Hz,6H),3.75–3.63(m,2H),3.18(dt,J=12.2,7.1Hz,1H),3.02(dt,J=12.5,7.1Hz,1H),2.90(td,J=7.0,0.9Hz,2H),2.35–2.18(m,2H).ESI-MS m/z 441.2[M+H]+.
实施例A78:化合物A78的合成
用碘甲烷替换实施例A1中的1-2,用化合物2-30替换实施例A1中的2-5,用化合物2-29替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A78。1H NMR(500MHz,Chloroform-d)δ9.94(d,J=8.4Hz,1H),7.60(dd,J=7.3,1.7Hz,1H),7.36(dd,J=7.4,1.7Hz,1H),7.18–7.12(m,2H),7.09(td,J=7.4,1.5Hz,1H),6.82(s,1H),6.58(t,J=1.0Hz,1H),4.91–4.84(m,1H),3.83(d,J=7.1Hz,6H),3.80–3.64(m,4H),3.53(dt,J=12.3,7.1Hz,2H),3.18(dt,J=12.3,7.1Hz,1H),3.02(dt,J=12.5,7.1Hz,1H),2.90(td,J=7.1,1.0Hz,2H),2.55(p,J=7.0Hz,1H),2.36–2.19(m,2H),1.74(qd,J=7.1,2.4Hz,4H).ESI-MS m/z 448.2[M+H]+.
实施例A79:化合物A79的合成
用化合物2-32替换实施例(S)-A1中的2-5,合成方法参考化合物(S)-A1,得化合物A79。1H NMR(500MHz,Chloroform-d)δ7.62(dd,J=7.5,1.6Hz,1H),7.35(dd,J=7.5,1.6Hz,1H),7.17(d,J=8.4Hz,1H),7.11(td,J=7.5,1.5Hz,1H),7.05(td,J=7.4,1.5Hz,1H),6.77(d,J=0.6Hz,1H),6.59(t,J=1.0Hz,1H),5.01–4.95(m,1H),4.09(q,J=8.0Hz,2H),3.87(dt,J=12.5,7.1Hz,1H),3.84(s,2H),3.76(dt,J=12.3,7.1Hz,1H),3.58(t,J=7.1Hz,4H),3.19(dd,J=12.5,7.0Hz,1H),3.17–3.09(m,4H),3.00(dd,J=12.3,7.0Hz,1H),2.90(td,J=7.1,1.0Hz,2H),1.45–1.38(m,3H).ESI-MS m/z 449.2[M+H]+.
实施例A80:化合物A80的合成
用化合物2-33替换实施例(S)-A1中的吗啉酰氯,合成方法参考化合物(S)-A1,得化合物A80。1H NMR(500MHz,Chloroform-d)δ9.07(d,J=2.7Hz,1H),7.27–7.20(m,2H),7.09(d,J=8.4Hz,1H),7.05(d,J=1.5Hz,1H),6.81(dd,J=7.5,1.5Hz,1H),6.75(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.82–4.76(m,1H),4.07(qd,J=7.9,1.6Hz,2H),3.82(d,J=12.8Hz,5H),3.72(t,J=7.1Hz,2H),2.92(tt,J=7.2,1.0Hz,2H),2.79(dt,J=12.2,7.0Hz,1H),2.66(dt,J=12.4,7.1Hz,1H),2.36–2.19(m,2H),1.45–1.38(m,3H).ESI-MS m/z 491.2[M+H]+.
实施例A81:化合物A81的合成
用碘甲烷替换实施例A1中的1-2,用化合物2-32替换实施例A1中的2-5,合成方法参考化合物A1,得化合物A81。1H NMR(500MHz,Chloroform-d)δ7.62(dd,J=7.1,1.8Hz,1H),7.38–7.33(m,1H),7.16(d,J=8.4Hz,1H),7.12–7.02(m,2H),6.84(d,J=0.6Hz,1H),6.58(t,J=1.0Hz,1H),5.06–4.99(m,1H),3.91–3.82(m,7H),3.78(dt,J=12.5,7.1Hz,1H),3.58(t,J=7.0Hz,4H),3.19(dd,J=12.5,7.0Hz,1H),3.17–3.09(m,4H),3.00(dd,J=12.4,7.1Hz,1H),2.90(td,J=7.1,1.0Hz,2H).ESI-MS m/z435.2[M+H]+.
实施例A82:化合物A82的合成
用碘甲烷替换实施例A1中的1-2,用化合物2-32替换实施例A1中的2-5,用化合物2-29替换实施例A1中的吗啉酰氯,合成方法参考化合物A1,得化合物A82。1H NMR(500MHz,Chloroform-d)δ7.62(dd,J=7.1,1.8Hz,1H),7.38–7.33(m,1H),7.19(d,J=8.4Hz,1H),7.12–7.02(m,2H),6.81(s,1H),6.59(t,J=1.0Hz,1H),5.03–4.96(m,1H),3.84(d,J=5.1Hz,6H),3.81–3.62(m,5H),3.53(dt,J=12.3,7.1Hz,2H),2.99(dd,J=12.4,7.0Hz,1H),2.90(td,J=7.1,0.9Hz,2H),2.55(p,J=7.0Hz,1H),1.75(qd,J=7.1,1.8Hz,4H).ESI-MS m/z 434.2[M+H]+.
实施例A83:化合物A83的合成
用碘甲烷替换实施例A1中的1-2,用化合物2-32替换实施例A1中的2-5,参考中间体3-8的合成方法,得到中间体3-9。将3-9溶于乙腈中,加入碳酸钾2-34,氩气保护下回流5小时。冷却,蒸干溶剂,二氯甲烷稀释,饱和氯化铵、氯化钠各洗2次。合并有机相,无水硫酸钠干燥后旋干溶剂,柱层析(石油醚:乙酸乙酯1:1)得类白色固体,收率90%。得化合物A83。1H NMR(500MHz,Chloroform-d)δ7.62(dd,J=7.1,1.8Hz,1H),7.38–7.33(m,1H),7.18(d,J=8.4Hz,1H),7.12–7.02(m,2H),6.78(d,J=0.6Hz,1H),6.57(t,J=1.0Hz,1H),3.90–3.82(m,7H),3.74(td,J=7.1,2.4Hz,4H),3.52(dd,J=12.4,7.1Hz,1H),3.06(dt,J=12.5,7.2Hz,1H),2.95(dt,J=12.3,6.9Hz,1H),2.87(dd,J=12.4,7.0Hz,1H),2.85–2.76(m,1H),2.74(dtd,J=12.3,7.2,0.9Hz,1H),2.61(dd,J=12.3,7.0Hz,1H),2.55(dd,J=12.4,6.9Hz,1H),1.95(hept,J=7.0Hz,1H),1.87–1.68(m,4H).ESI-MS m/z 420.2[M+H]+.
生物活性测试试验
1.检测方法:细胞内cAMP浓度测定
1.1试验材料与仪器
cAMP检测试剂盒(PerkinElmer)、细胞培养箱(Thermo Fisher Scientific)、EnVision多功能酶标仪(PerkinElmer)、Forskolin(Sigma-Aldrich)、IBMX(Sigma-Aldrich)、DSMO(Sigma-Aldrich)、hINSL5(Genova,人源胰岛素样肽5)、稳定表达人源RXFP4的hRXFP4-CHO稳转细胞株及待测化合物。
1.2试验方法
稳转细胞hRXFP4-CHO细胞于实验前一天以2.5×105个/mL接种使第二天培养皿中的细胞处于70%-80%的生长密度。实验当天使用无胰酶消化液或0.02%EDTA的PBS溶液消化细胞,细胞离心后弃上清,使用1×HBSS(无钙镁)溶液配制cAMP实验缓冲液(0.5mM IBMX+5mM HEPES+0.1%BSA)。重悬细胞并以4000个/孔接入384孔板,使用DMSO将化合物稀释至不同浓度后加入上述384孔板,同时加入500nM Forskolin并置室温孵育40分钟,随后根据cAMP检测试剂盒说明书分别加入Eu-cAMP和ULight-anti-cAMP工作液,室温孵育40分钟后使用EnVision多功能酶标仪读数(激发光波长为320或340nm,检测发射光为665nm)。
1.3试验结果
化合物的体外RXFP4激动活性测试结果如表1所示。
表1.化合物的体外RXFP4激动活性测试结果
a N.D.=Not determined
2.检测方法:配体受体亲和力检测
2.1试验材料与仪器
hRXFP4-CHO稳转细胞和Eu-R3/I5(镧系元素铕标记的嵌合肽R3/I5),BMGPOLARstar读板器(BMG Labtech)及待测化合物。
2.2试验方法
hRXFP4-CHO以80000个/孔接入96孔板,细胞培养箱培养24小时后弃上清,并用PBS洗一遍,加入含1%BSA的结合缓冲液室温孵育1小时,再使用PBS洗一遍细胞板,随即加入不同浓度的阳性对照及待测化合物和5nM Eu-R3/I5共同室温孵育1小时,PBS洗一遍细胞板后加入增强溶液,45分钟后于BMG POLARstar读板器测定荧光值(激发光波长为340nm,检测发射光为614nm)。
2.3试验结果
化合物的体外配体受体亲和力测试结果如表2所示
表2化合物的体外配体受体亲和力测试结果
a N.D.=Not determined
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种通式(I)所示的含氮杂环类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体:
其中,
手性碳原子C*独立地为S型、R型、消旋体,或其组合;
n=0、1或2;
R1和R2各自独立地选自下组:氢、氘、氚、卤素、羟基、羧基、取代或未取代的C1~C6烷基、取代或未取代的C1~C6烷氧基、取代或未取代的C6~C10芳基、取代或未取代的5-7元的杂环、取代或未取代的C1~C6烷基苯基、取代或未取代的C1~C6烷基5-7元杂芳基、取代或未取代的C3~C12环烷基、取代或未取代的C2~C10酰基、取代或未取代的C2~C10酯基、氨基、取代或未取代的C1-C6烷胺基、取代或未取代的C1-C6酰胺基、-SOR5、-OSOR5、-OCOR5;
且当n=0时,所述的R1和R2不同时为甲基;当n=1时,所述的R1和R2不同时为氢;
或所述的R1和R2和相邻的(CH2)nO以及C=C共同构成取代或未取代的5-7元的杂环,其中,所述的杂环为全部饱和的杂环、部分不饱和的杂环或芳杂环;
X为O或S;
Y为选自下组的连接基团:化学键、C1~C6直链或支链烷基、-CH2NH-、C2~C6直链或支链烯基、-CH2O-、-CH2S-、-CONH-、-NHCO-、-COO-、-OOC-、
A环为取代或未取代的选自下组的基团:5~12元氮杂杂环基(其中连接位点优选位于氮原子上)、C6~C12芳基(优选为C6~C10芳基)、5~12元杂芳基(优选为5~7元杂芳基);其中,所述的杂环基或杂芳基包括选自下组的杂原子作为环骨架:N、NH、S、O、S(O)2;
R4选自未被取代或者被1-3个取代基取代的以下基团:C3~C7环烷基、5~12元杂环基、C6~C12芳基、5~12元杂芳基(优选为5-7元杂芳基,或苯并5~7元杂芳基);其中,各个所述杂环基或杂芳基含有1~3个选自氧、硫和氮的杂原子;所述的取代基各自独立地选自卤素、C1~C6直链或支链烷基、C2~C6直链或支链烯基、C2~C6直链或支链炔基、C1~C6直链或支链烷氧基、C1~C6直链或支链烷基羰氧基、氰基、硝基、羟基、氨基、羟甲基、三氟甲基、三氟甲氧基、羧基、巯基、C1~C4酰基、酰胺基、磺酰基、氨基磺酰基、C1~C4烷基取代的磺酰基,或者两个位于相邻环原子上的取代基连同与其连接的碳原子构成5-7元环;
R3和R5各自独立地选自下组:氢、氘、氚、卤素、未取代或由1-3个卤素取代的C1-C6的烷基、或未取代或由1-3个卤素取代的C3-C6环烷基、未取代或由1-3个卤素取代的C6~C10芳基、未取代或由1-3个卤素取代的C1-C3烷基-C6~C10芳基、未取代或由1-3个卤素取代的5-7元杂芳基。
2.如权利要求1所述的含氮杂环类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,所述的A环选自下组:氮丙啶基、氮杂环丁烷基、吡咯烷基、哌啶基、氮杂环庚烷基、吗啉基、哌嗪基、高哌嗪基、硫代吗啉基、环硫被亚砜或砜替代的硫代吗啉基、咪唑烷基、吡嗪基、六氢嘧啶基或且所述的A环任选地被1-2个选自氢、C1-C3直链或支链烷基、卤素、羟基和C1-C4烷氧羰基中的基团所取代。
3.如权利要求1所述的含氮杂环类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,R1和R2各自独立地选自下组:氢、氘、氚、卤素、羟基、羧基、苯基、取代或未取代的C1~C6烷基、取代或未取代的C1~C6烷氧基、取代或未取代的5-7元的杂环、取代或未取代的C1~C6烷基5-7元杂芳基、取代或未取代的C3~C8环烷基、取代或未取代的C2~C10酰基、取代或未取代的C2~C10酯基、氨基、取代或未取代的C1-C6烷胺基、取代或未取代的C1-C6酰胺基、-SOR5、-OSOR5、-OCOR5。
4.如权利要求1所述的含氮杂环类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,
X为O;
Y选自下组:-CH2-、-CH2-CH2-、-CH2-CH2-CH2-、-CH2NH-、-CH2O-、或-CH2S-。
5.如权利要求1所述的含氮杂环类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,R4选自未被取代或者被1-3个取代基取代的以下基团:C6-C10芳基、5-7元杂芳基,或苯并5~7元杂芳基;优选地,所述基团中的杂环和杂芳环部分选自吲哚、苯并二氧杂环戊烯、异噁唑、吡啶、吡唑、二氢咪唑并吡啶、咪唑并吡啶、苯并噻吩、二氢苯并二氧六环、喹喔林、吡咯、苯并呋喃、吲唑、苯并咪唑、喹啉、1,3-二氧代异吲哚啉形成的基团。
6.如权利要求1所述的含氮杂环类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其特征在于,氢、氘、氚、卤素、未取代或由1-3个卤素取代的C1-C6的烷基、或未取代或由1-3个卤素取代的C3-C6环烷基。
7.如权利要求1所述的含氮杂环类化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体,其中,所述四氢异喹啉类化合物选自以下化合物:
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8.如权利要求1所述的式(I)化合物的制备方法,其特征在于,所述方法包括步骤:
(1)在惰性溶剂中,在缩合剂存在下,用式II化合物和式Ic化合物反应,得到式Id化合物;优选地,所述的缩合剂为EDCI(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐);
(2)在惰性溶剂中,用式Id化合物进行Bischler-Napieralski关环反应,得到式Ie化合物;优选地,所述的关环反应用三氯氧磷作为路易斯酸;
(3)在惰性溶剂中,用式Ie化合物进行还原反应,得到式If化合物;优选地,所述的还原反应用硼氢化物作为还原剂或用Noyori催化剂作为不对称还原催化剂;
(4)在惰性溶剂中,用式If化合物与进行成缩合反应,得到式(I)化合物;
上述各式中,各基团的定义如权利要求1-6任一所述。
9.一种药物组合物,其特征在于,所述的药物组合物包括:治疗有效量的如权利要求1所述的式(I)化合物,或其药学上可接受的盐,和药学上可接受的载体。
10.如权利要求1所述的式(I)化合物的用途,其特征在于,用于制备治疗与4型松弛素家族受体活性或表达量相关的疾病或病症的药物组合物;较佳地,所述的化合物用于制备治疗选自下组的疾病或病症的药物组合物:便秘、厌食症,或糖脂代谢相关疾病。
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