CN113015726B - 酮酰胺类化合物及其制备方法、药物组合物和用途 - Google Patents
酮酰胺类化合物及其制备方法、药物组合物和用途 Download PDFInfo
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- CN113015726B CN113015726B CN201980052674.7A CN201980052674A CN113015726B CN 113015726 B CN113015726 B CN 113015726B CN 201980052674 A CN201980052674 A CN 201980052674A CN 113015726 B CN113015726 B CN 113015726B
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- 238000001308 synthesis method Methods 0.000 description 1
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- LAXANRIIICOVJY-UHFFFAOYSA-N tert-butyl 2-isocyanopropanoate Chemical compound [C-]#[N+]C(C)C(=O)OC(C)(C)C LAXANRIIICOVJY-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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Abstract
一种酮酰胺类化合物及其制备方法、药物组合物和用途。具体地,一种式(A)所示的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药。酮酰胺类化合物可有效抑制冠状病毒或埃博拉病毒,进而实现对与冠状病毒相关的疾病或者与埃博拉病毒相关的疾病的预防或治疗。
Description
技术领域
本发明涉及药物化学和药物治疗学领域,具体涉及作为冠状病毒或者埃博拉病毒抑制剂的酮酰胺类化合物、其制备方法、含此类化合物的药物组合物及其用途。
背景技术
冠状病毒(coronavirus)在系统分类上属冠状病毒科(Coronaviridae)冠状病毒属(Coronavirus),成熟的冠状病毒直径约为60nm-220nm,电镜下呈日冕状或者皇冠状,故被命名为冠状病毒,是许多脊柱动物包括人类疾病的重要病原。
冠状病毒属于单股正链RNA病毒,其基因组大小为27-32kb,是目前已知的基因组最大的RNA病毒,其包含6-12个开放阅读框,其与真核细胞的mRNA类似,冠状病毒的复制是在胞浆中进行的,感染细胞之后,病毒在胞浆中脱壳,随后正链基因组RNA活化,呈现mRNA的作用。该病毒引起的感染主要发生在冬季和早春。在美国密执安州的一次家庭检查中,证明冠状病毒可以感染各个年龄组,0-4岁占29.2%,40岁以上占22%,在15-19岁年龄组发病率最高。这与其它上呼吸道病毒的流行情况不尽相同,例如呼吸道合胞病毒,大多随着年龄的增加而发病率降低。
冠状病毒根据血清学特性可以分为四个属α、β、γ和δ,其中一种新型的β属的冠状病毒MERS-CoV(Middle East Respiratory Syndrome-coronavirus)正在对全球的公共卫生造成重大影响。MERS-CoV最早于2012在沙特被发现,2013年被重命名为中东呼吸综合征,据世界卫生组织(WHO)公布数据显示,截止到2018年3月19号,全球27个国家共计有2143患者确诊感染MERS-CoV,其中750例死亡,致死率接近35%。
人类感染MERS-CoV后,临床表现为发热、咳嗽、呼吸急促等,其中大多数患者还会出现发烧、发冷/寒颤、咳嗽、呼吸急促和肌肉疼痛等症状。绝大多数MERS-CoV患者为患有慢性疾病的人群,年龄在15岁以下的小孩和65岁以上的老人、孕妇、患有心血管、肺炎等慢性病和抵抗力较差的病人,都是易感人群。
MERS-CoV致病性强,不仅可以进行跨物种传播,也能进行人与人传播,并且MERS-CoV具有超过30%的病死率,主要传播方式是飞沫传播和接触传播。
SARS-CoV与MERS-CoV同属于冠状病毒β属,SARS病毒通过呼吸道分泌物排出体外,经口液、喷嚏、接触传染,并通过空气飞沫传播,感染高峰在秋冬和早春。
综上所述,本领域迫切需要开发针对MERS-CoV和SARS-CoV的抑制剂,这不仅是国际抗病毒研究的热点,也是我国传染病防治的重要工作。
发明内容
本发明的目的在于提供一类对冠状病毒或埃博拉病毒具有抑制作用的式A所示的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药,及其制备方法、药物组合物和用途。
在本发明的第一方面,提供了一种式A所示的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药:
其中:
R1和R2各自独立地选自下组:氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10环烷基C1-C10亚烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C3-C10杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C10亚烯基、取代或未取代的C3-C20杂芳基C2-C10亚烯基、酰基、磺酰基;
R3选自下组:取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C10亚烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C3-C8杂环烷基C1-C10亚烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C10亚烷基、取代或未取代的C3-C20杂芳基C1-C10亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C2-C6亚炔基;
R4选自下组:取代或未取代的C1-C10烷基、取代或未取代的C2-C10烯基、取代或未取代的C2-C10炔基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C6-C20芳基C2-C6亚炔基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、取代或未取代的C3-C20杂芳基C2-C9亚炔基;
当-NHR5与其相邻的-(C=O)-CH2-成环时,R5为-(CH2)n-,n为2或3;
当-NHR5不与其相邻的-(C=O)-CH2-成环时,R5选自下组:氢、氘、氚、氨基、羟基、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C6-C20芳基、取代或未取代的C3-C20杂芳基、取代或未取代的C6-C20芳基C1-C6亚烷基、取代或未取代的C6-C20芳基C2-C6亚烯基、取代或未取代的C3-C20杂芳基C1-C9亚烷基、取代或未取代的C3-C20杂芳基C2-C9亚烯基、酰基、磺酰基;
其中,在R1、R2、R3、R4和R5中,所述取代各自独立地指被选自下组的1、2、3或4个取代基取代:卤素、羟基、巯基、硝基、氰基、胺基、亚胺基、叔胺基、叠氮基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、C1-C6烷基羰基、C1-C6烷硫基、C1-C8烷氧基羰基、三氟甲基;所述杂环烷基和所述杂芳基各自独立地包含1、2、3或4个选自N、O、S的杂原子。
在另一优选例中,R1和R2各自独立地选自下组:氢、氘、氚、氨基、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C5亚烷基、取代或未取代的C3-C10杂环烷基、取代或未取代的C3-C10杂环烷基C1-C5亚烷基、取代或未取代的C6-C14芳基、取代或未取代的C3-C10杂芳基、取代或未取代的C6-C14芳基C1-C5亚烷基、取代或未取代的C3-C10杂芳基C1-C5亚烷基、取代或未取代的C6-C10芳基C2-C5亚烯基、取代或未取代的C3-C10杂芳基C2-C5亚烯基、酰基、磺酰基;
R3选自下组:取代或未取代的C1-C6烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C5亚烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C3-C8杂环烷基C1-C5亚烷基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10杂芳基、取代或未取代的C6-C10芳基C1-C5亚烷基、取代或未取代的C3-C10杂芳基C1-C5亚烷基、取代或未取代的C6-C10芳基C2-C4亚烯基、取代或未取代的C3-C10杂芳基C2-C4亚烯基、取代或未取代的C6-C10芳基C2-C4亚炔基、取代或未取代的C3-C10杂芳基C2-C4亚炔基;
其中,在R1、R2和R3中,所述取代各自独立地指被选自下组的1、2或3个取代基取代:卤素、羟基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C4烷基羰基、C1-C4烷硫基、C1-C6烷氧基羰基、三氟甲基;所述杂环烷基和所述杂芳基各自独立地包含1或2个选自N、O、S的杂原子。
在另一优选例中,所述化合物为式AA所示的化合物,
其中,R1、R2、R3、R4、R5和n如上文中所限定;
*表示碳原子的立体化学异构可以分别独立地为R或S。
在另一优选例中,R4选自下组:含1、2或3个选自N、O、S的杂原子的9-10元杂芳环、含1、2或3个选自N、O、S的杂原子的5-6元杂芳环;上述基团为取代或未取代的;其中,所述取代指基团上的氢原子被1、2、3或4个选自下组的取代基取代:卤素、羟基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基。
在另一优选例中,所述杂芳基是5、6、7、8、9或10元的饱和或部分饱和的杂芳环。
在另一优选例中,所述杂环烷基是5、6、7、8、9或10元的不饱和杂环。
在另一优选例中,R4选自下组:
取代或未取代的喹喔啉基、取代或未取代的喹唑啉基、取代或未取代的噌啉基、取代或未取代的吲哚基、取代或未取代的异吲哚基、
取代或未取代的1,3-苯并二噁茂基、
取代或未取代的苯并咪唑基、取代或未取代的吲唑基、
取代或未取代的咪唑[1,2-A]吡啶基、取代或未取代的咪唑[1,5-A]吡啶基、
取代或未取代的吡唑基、取代或未取代的咪唑基、取代或未取代的噻唑基、取代或未取代的噁唑基、取代或未取代的异噁唑基、取代或未取代的1,2,3-三唑基、取代或未取代的1,2-噻二唑基、取代或未取代的1,2,4-三嗪基、
取代或未取代的吡啶基、取代或未取代的吡咯基、取代或未取代的吡嗪基、取代或未取代的嘧啶基、
取代或未取代的3,8a二氢-2H-苯并吡喃基、取代或未取代的苯并吡喃基、
取代或未取代的喹啉基、取代或未取代的异喹啉基、
取代或未取代的苯并噁唑基、取代或未取代的苯并噻唑基、
取代或未取代的苯并噻吩基、
取代或未取代的苯并呋喃基;
其中,所述取代指基团上的氢原子被1、2或3个选自下组的取代基取代:F、Cl、Br、I、羟基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基。
在本文中,R4为咪唑[1,2-A]吡啶对应本发明编号为A156至A161的化合物。
在本文中,“咪唑[1,2-A]吡啶”、“咪唑[1,2-a]吡啶”、“咪唑并[1,2-A]吡啶”和“咪唑并[1,2-a]吡啶”可互换使用。
在本文中,“咪唑[1,5-A]吡啶”、“咪唑[1,5-a]吡啶”、“咪唑并[1,5-A]吡啶”和“咪唑并[1,5-a]吡啶”可互换使用。
在本文中,R4为3,8a二氢-2H-苯并吡喃对应本发明编号为A132至A137的化合物。
在另一优选例中,当-NHR5与其相邻的-(C=O)-CH2-成环时,R5为-(CH2)n-,n为3;
当-NHR5不与其相邻的-(C=O)-CH2-成环时,R5选自下组:氢、氘、氚、羟基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8杂环烷基、取代或未取代的C6-C10芳基、取代或未取代的C3-C10杂芳基、取代或未取代的C6-C10芳基C1-C4亚烷基、取代或未取代的C6-C10芳基C2-C4亚烯基、取代或未取代的C3-C10杂芳基C1-C4亚烷基、取代或未取代的C3-C10杂芳基C2-C4亚烯基;
其中,所述取代各自独立地指被选自下组的1、2或3个取代基取代:F、Cl、Br、I、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基;所述杂环烷基和所述杂芳基各自独立地包含1、2或3个选自N、O、S的杂原子。
在另一优选例中,所述化合物选自表1所列化合物。
本发明的第二方面,提供了一种本发明第一方面所述酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药的制备方法,包括如下步骤:
步骤(6):在惰性溶剂中,将化合物Ⅶ与氧化剂进行氧化反应,得到化合物Ⅷ;
上述各式中,R1、R2、R3、R4、R5和n如本发明第一方面中所限定。
在另一优选例中,在步骤(6)之前还包括如下步骤:
步骤(5):在有机溶剂存在下,将化合物Ⅵ和碱性物质反应,得到化合物Ⅶ。
在另一优选例中,所述有机溶剂为醇类溶剂,优选地选自下组:甲醇、乙醇、丙醇、异丙醇、丁醇、乙二醇、芳香醇。
在另一优选例中,所述碱性物质选自下组:LiOH、NaOH、KOH、碳酸锂、碳酸钠、碳酸钾、碳酸氢锂、碳酸氢钠、碳酸氢钾、叔丁醇钾、叔丁醇钠、叔丁醇锂、1,8-二氮杂二环十一碳-7-烯。
在另一优选例中,所述惰性溶剂选自下组:二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、二氧六环、氯仿。
在另一优选例中,所述氧化剂选自下组:Dess-Martin氧化剂、二甲基亚砜、草酰氯、PCC氧化剂、PDC氧化剂。
在另一优选例中,在步骤(5)之前还包括如下步骤:
步骤(4):在惰性溶剂中,在醋酸存在下,将化合物Ⅴ和异氰化合物反应,得到化合物Ⅵ。
在另一优选例中,所述异氰化合物选自下组:苄基异氰、环己基异氰、异氰基乙酸甲酯、叔丁基异氰、2-异氰基丙酸叔丁酯。
在另一优选例中,在步骤(4)之前还包括如下步骤:
步骤(3):在惰性溶剂中,将化合物Ⅳ与氧化剂进行氧化反应,得到化合物Ⅴ。
在另一优选例中,在步骤(3)之前还包括如下步骤:
步骤(2):在惰性溶剂中,将化合物Ⅲ与还原剂进行还原反应,得到化合物Ⅳ。
在另一优选例中,所述还原剂为硼氢化物,优选地选自下组:硼氢化钠、硼氢化锂、氰基硼氢化钠。
在另一优选例中,在步骤(2)之前还包括如下步骤:
步骤(1):在惰性溶剂中,在缩合剂的存在条件下,将化合物Ⅱ和化合物Ⅰc反应,得到化合物Ⅲ。
在另一优选例中,所述缩合剂优选为EDCI(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐)和/或HATU(2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)。
本发明的第三方面,提供了一种药物组合物,所述药物组合物包含如下组分:
i)治疗有效量的一种或多种本发明第一方面所述酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药;和
ii)药学上可接受的载体或赋形剂。
本发明的第四方面,提供了一种酮酰胺类抑制剂,所述抑制剂含有一种或多种本发明第一方面所述的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药。
本发明的第五方面,提供了一种本发明第一方面所述酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药的用途,用于制备药物组合物或制剂,所述药物组合物或所述制剂用于治疗或预防与冠状病毒相关的疾病或者与埃博拉病毒相关的疾病。
在另一优选例中,所述冠状病毒选自下组:SARS病毒、MERS病毒。
在另一优选例中,所述与冠状病毒相关的疾病选自下组:普通感冒、上呼吸道感染、重症急性呼吸综合征、多发性硬化症、中耳炎、胃肠道疾病。
在另一优选例中,所述与埃博拉病毒相关的疾病选自下组:出血热、急性起病发热、肌痛出血皮疹。
在另一优选例中,本发明第一方面所述酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药与其它抗病毒药物联合用药。
本发明的第六方面,提供了一种体外非治疗性的抑制冠状病毒或埃博拉病毒的方法,将本发明第一方面所述酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药与冠状病毒或埃博拉病毒接触。
本发明的第七方面,提供了一种预防或治疗与冠状病毒相关的疾病或者与埃博拉病毒相关的疾病的方法,包括步骤:将治疗有效量的一种或多种本发明第一方面所述酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药施用于所需患者。
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。
附图说明
图1A是HCoV-OC43感染靶细胞HCT-8后可导致空泡化等细胞病变现象(CPE),而A13(1μM)可有效抑制HCoV-OC43的感染,各图是在相同放大倍数下测得的。
图1B是不同浓度A13对靶细胞中CPE的抑制效果,其中“-”代表没有CPE,“+/-”代表<10%CPE,“+”代表30%CPE,“++”代表60%CPE,“+++”代表>90%CPE。
图1C是根据CCK8方法,评估不同浓度A13对HCoV-OC43感染的抑制活性。
图2是化合物A13对MERS-CoV,SARS-CoV,HCoV-229E和VSV-G假病毒抑制活性(A),化合物A13对靶细胞(Huh-7)的细胞毒性(B)。
图3A-3D是化合物A13(100mg/kg)或DMSO(100μL)进行Balb/c小鼠腹腔给药(n=4),然后分别在给药后2小时(A)、12小时(B)和24小时(C)取血,分离血清,进行抗MERS-CoV假病毒活性检测,然后比较其血清的抗病毒活性(D)。(EC50:半数效应浓度,以血清稀释倍数为单位)。
图4是化合物A13(100mg/kg)或DMSO(100μL)进行Balb/c小鼠腹腔给药(n=4),连续给药7天(每天1次),然后记录这段时间小鼠体重变化。
具体实施方式
本发明人通过长期广泛而深入的研究,合成了一类能够抑制冠状病毒和/或埃博拉病毒的式A化合物。与已有的冠状病毒抑制剂相比,所述的化合物具有更高的抑制活性。在此基础上,发明人完成了本发明。
术语
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
在本发明中,术语“卤素”指F、Cl、Br或I。
在本发明中,术语“C1-C10烷基”是指具有1至10个碳原子的直链或支链烷基,优选C1-C6烷基,更优选C1-C4烷基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等。
在本发明中,术语“C3-C10环烷基”是指在环上具有3至10个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基和环癸基等。优选为C3-C8环烷基、C3-C7环烷基或C3-C6环烷基。
在本发明中,术语“芳环”或“芳基”具有相同的含义,优选为“C6-C20芳基”,较优选为“C6-C14芳基”,更优选为“C6-C10芳基”。术语“C6-C10芳基”是指在环上不含杂原子的具有6至10个碳原子的芳香族环基,如苯基、萘基等。
在本发明中,术语“芳香杂环”或“杂芳基”具有相同的含义,指包含一个到多个杂原子的杂芳族基团。例如“C3-C20杂芳基”是指含有1~4个选自氧、硫和氮中的杂原子以及3-20个碳原子的芳香杂环。非限制性例子包括:呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中,术语“卤代”是指被卤素取代。
在本发明中,术语“C2-C10烯基”是指具有2至10个碳原子的含有一个双键的直链或支链烯基,非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。优选为C2-C6烯基。
在本发明中,术语“C2-C10炔基”是指具有2至10个碳原子的含有一个三键的直链或支链炔基,非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。优选为C2-C6炔基。
在本发明中,术语“C1-C8烷氧基”是指具有1至8个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。
在本发明中,术语“酰基”是指具有1至8个碳原子的直链或支链的酰基,非限制性的包括甲酰基、乙酰基、丙酰基等。优选为C1-C4烷酰基。
在本发明中,术语“磺酰基”是指具有1至8个碳原子的直链或支链的磺酰基,非限制性的包括甲磺酰基、乙磺酰基、丙磺酰基等。优选为C1-C4烷磺酰基。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):卤素、羟基、羧基(-COOH)、C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C8烷氧基、C1-C10磺酰基等。
化合物
本发明提供了式A所示的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药物活性的代谢物,或其药学上可接受的盐、溶剂化物或前药:
其中,R1、R2、R3、R4、R5和n如上文中所限定。
在另一优选例中,所述的化合物中,R1、R2、R3、R4、R5和n中任一个分别为表1中所述具体化合物中所对应的基团。
在另一优选例中,所述化合物优选为实施例中所制备的化合物。
在另一优选例中,所述化合物A1-A236分别为实施例1—236所制备的化合物。
在另一优选例中,所述化合物选自表1所列化合物。
表1
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本发明的化合物可用于抑制肠道病毒和冠状病毒,特别是抑制MERS病毒。
本发明化合物还可以具有不对称中心,并且可以以外消旋体、R-异构体或S-异构体或它们的混合物的形式存在。本领域技术人员能够采用常规技术手段由外消旋体拆分获得R-异构体和/或S-异构体。
盐
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、胺基磺酸、磷酸等无机酸;柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铝盐、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、乙醇胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。
术语“前药”包括其本身可以是具有生物学活性的或非活性的,当用适当的方法服用后,其在人体内进行代谢或化学反应而转变成式A的一类化合物,或式A的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
制备方法
下面更具体地描述本发明式A化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
典型地,本发明化合物的制备工艺流程如下,其中所用原料和试剂如无特殊说明,均可通过商业途径购买。
步骤(1):在惰性溶剂中,在缩合剂的存在条件下,用化合物Ⅱ和化合物Ⅰc反应,得到化合物Ⅲ;其中缩合剂优选为EDCI(1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐);
步骤(2):在惰性溶剂中,化合物Ⅲ在一定条件下进行还原反应,得到化合物Ⅳ;其中还原剂优选为硼氢化物;
步骤(3):在惰性溶剂中,化合物Ⅳ在一定条件下进行氧化反应,得到化合物Ⅴ;其中氧化剂优选为Dess-Martin氧化剂或二甲基亚砜和草酰氯作为氧化剂;
步骤(4):在惰性溶剂中,在醋酸的存在条件下,用化合物Ⅴ和异氰化合物反应,得到化合物Ⅵ;
步骤(5):在甲醇做溶剂条件下,用化合物Ⅵ和碱反应,得到化合物Ⅶ;其中碱优选为LiOH和碳酸钾;
步骤(6):在惰性溶剂中,化合物Ⅶ在一定条件下进行氧化反应,得到化合物Ⅷ;其中氧化剂优选为Dess-Martin氧化剂或二甲基亚砜和草酰氯作为氧化剂;
上述各式中,各基团的定义如上文所述。
具体地,本发明还提供了一种式A化合物的合成方法,通过下列所示流程进行制备:
步骤a:将Boc保护的氨基酸C1与C2溶于溶剂中,在缩合剂辅助下进行缩合反应得到化合物C3;所述溶剂为二氯甲烷或DMF;
步骤b:将C3溶解在溶剂中,搅拌至反应完全,旋干反应溶剂得化合物C4;所述溶剂为二氯甲烷和三氟乙酸混合溶剂;
步骤c:将取代羧酸C5与C4溶于溶剂中,在缩合剂辅助下进行缩合反应得到化合物C6;所述溶剂为二氯甲烷或DMF;
步骤d:将化合物C6溶于溶剂中,加入硼氢化钠,搅拌,得化合物C7;所述溶剂为甲醇、四氢呋喃、乙醇;
步骤e:将化合物C7溶解在溶剂中,加入氧化剂,加入碱,搅拌,得化合物C8;所述溶剂为二氯甲烷或四氢呋喃;所述氧化剂为Dess-Martin氧化剂或二甲基亚砜和草酰氯;所述碱为碳酸氢钠或三乙基胺;
步骤f:将化合物C8溶解在溶剂中,加入醋酸和异氰化合物反应,得到化合物C9;所述溶剂为二氯甲烷;
步骤g:将化合物C9溶解在溶剂中,加入碱搅拌,得到化合物C10;其中碱优选为LiOH和碳酸钾;
步骤h:将化合物C10溶解在溶剂中,加入氧化剂,加入碱,搅拌,得化合物C11;所
述溶剂为二氯甲烷或四氢呋喃;所述氧化剂为Dess-Martin氧化剂或二甲基亚砜和草酰氯;所述碱为碳酸氢钠或三乙基胺;
R1、R2、R3、R4、R5和n与上文中的定义相同。
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A表示的酮酰胺类化合物、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,其可用于治疗冠状病毒或者埃博拉病毒感染的相关疾病。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10-1000mg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。
本发明所述的式A表示的酮酰胺类化合物、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A表示的酮酰胺类化合物、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MERS抑制剂,用于治疗冠状病毒感染或者埃博拉病毒感染的相关疾病。
本发明所提供的药物组合物优选含有重量比为1-99%的活性成份,其优选的比例是,通式A所示的化合物作为活性成分占总重量的65wt%-99wt%,其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
本发明所提供的化合物和药物组合物可以是多种形式,如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等,并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中包含1mg-700mg通式A所示的化合物,优选地,制剂配方的单位计量中包含25mg-300mg通式A化合物。
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。
本发明化合物具有优异的对埃博拉和冠状病毒复制的抑制活性,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、预防以及缓解与埃博拉病毒和冠状病毒相关的疾病。
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;(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其他化合物(如其它抗病毒药)联合给药。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
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。
本发明的主要优点如下:
相比于现有的冠状病毒抑制剂,所述化合物具有更高的抑制活性,更低的毒性。
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,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,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。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
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1化合物A1
化合物1-2的合成:
氩气保护下,将N-叔丁氧羰基-L-谷氨酸二甲酯(1-1)(6g,21.8mmol)溶于60mL无水四氢呋喃中,于-78℃条件下缓慢滴LiHMDS(1M in THF)的四氢呋喃溶液(47mL,47mmol),滴加过程保持温度稳定在-78℃,约持续1小时。滴毕后在-78℃条件搅拌1小时。将溴乙腈(2.79g,23.3mmol)溶于20ml四氢呋喃中,随后将该溶液缓慢滴入到反应体系中,滴加过程持续1~2小时。控温-78℃,继续反应3小时。TLC监测(碱性高锰酸钾显色)反应完毕后,向反应液中加入NH4Cl溶液淬灭反应,搅拌10min后升至室温。倾入40mL饱和氯化钠溶液充分搅拌,可见反应体系分层。分离有机层,并用乙酸乙酯(EA)萃取水相,合并有机层后用无水硫酸钠干燥,浓缩,柱层析(Flash,PE:EA=1:5)得到淡黄色油状物1-2 3.9g,收率为58%。
化合物1-3的合成:
将1-2(1g,3.15mmol)溶于无水甲醇25mL,冰浴下搅拌至0℃后加入六水合二氯化钴(450mg,1.89mmol)。10min后分次少量加入硼氢化钠(715mg,18.9mmol),反应液继续在冰浴下反应1h后转为室温反应。15h后用饱和NH4Cl溶液5mL淬灭后继续搅拌10min,利用滤除固体后将滤液蒸干,用水20mL和乙酸乙酯30×3mL萃取,合并有机相,以无水Na2SO4干燥1h后减压浓缩,柱层析分离[PE:EA=1:2]得到白色粉末状固体460mg,产率51%。
化合物1-4的合成:
将化合物1-3(2.6g)溶于三氟乙酸的二氯甲烷溶液(1/1,v/v)中,室温搅拌1小时,浓缩后加入二氯甲烷100ml,饱和碳酸钠溶液洗,有机层用无水硫酸钠干燥,浓缩得油状物1-4(2.7g),收率99%。
化合物1-5的合成:
将Boc-环己基丙氨酸(1.26g,5mmol)和EDCI(1.36g,6mmol)、HOBt(0.822g,6mmol)加入到80ml二氯甲烷溶液中,室温搅拌30min。随后加入化合物1-4(0.896g,5mmol),滴入1.2当量的三乙胺,室温下搅拌。TLC监测(紫外)反应完全后采用二氯甲烷萃取,经稀盐酸、饱和碳酸氢钠溶液和饱和氯化钠洗涤后,合并有机层无水硫酸钠干燥,浓缩后得白色粘稠状固体1.2g,产率60%。
化合物1-6的合成:
将化合物1-5(2.5g)溶于三氟乙酸的二氯甲烷溶液(1/1,v/v)中,室温搅拌1小时,浓缩后加入二氯甲烷100ml,饱和碳酸钠溶液洗,有机层用无水硫酸钠干燥,浓缩得油状物1-6(2.61g),收率99%。
化合物1-7的合成:
将吲哚2-甲酸(0.795g,5mmol)和EDCI(1.36g,6mmol)、HOBt(0.822g,6mmol)加入到80ml二氯甲烷溶液中,室温搅拌30min。随后加入化合物1-6(2.2g,5mmol),滴入1.2当量的三乙胺,室温下搅拌。TLC监测(紫外)反应完全后采用二氯甲烷萃取,经稀盐酸、饱和碳酸氢钠溶液和饱和氯化钠洗涤后,合并有机层无水硫酸钠干燥,浓缩后得白色粘稠状固体1.3g,产率60%。
化合物1-8的合成:
将1-7(243mg,0.51mmol)溶于20ml甲醇中,分批缓慢加入硼氢化钠(107mg,2.9mmol),室温下搅拌约2小时反应完全。待反应完毕后,加入约20ml饱和食盐水淬灭反应,浓缩反应体系甲醇后,加入二氯甲烷萃取。有机相经饱和食盐水洗涤、无水硫酸钠干燥后,浓缩得到白色固体物质1-8,可直接用于下步反应。
化合物1-9的合成:
将中间体1-8(129mg,0.29mmol)溶于20ml二氯甲烷溶于中,加入戴斯-马汀氧化剂(147mg,0.35mmol)和碳酸氢钠固体(29mg,0.35mmol),在室温下搅拌。TLC监测(紫外)反应完全后,抽滤反应体系,所得滤液用饱和碳酸氢钠溶于萃取,有机层经饱和食盐
水洗涤,无水硫酸钠干燥后浓缩。经快速柱色谱(CH2Cl2:MeOH=20:1)分离纯化,得到白色固体粉末化合物1共77mg,产率60%。
化合物1-10的合成:
将化合物1-9(129mg,0.29mmol)溶解在二氯甲烷溶剂中,加入醋酸(19.2mg,0.32mmol)和苄基异氰(37.6mg,0.32mmol)反应,得到化合物1-10,经快速柱色谱(CH2Cl2:MeOH=20:1)分离纯化,得到白色固体粉末化合物1-10共126mg,产率70%。
化合物1-11的合成:
将化合物1-10(187mg,0.3mmol)溶解在甲醇溶剂中,加入LiOH(0.6mmol)搅拌,得到化合物1-11,经快速柱色谱(CH2Cl2:MeOH=20:1)分离纯化,得到白色固体粉末化合物1-11共148mg,产率85%。
化合物1-12的合成:
将化合物1-11(174mg,0.3mmol)溶解在二氯甲烷溶剂中,加入Dess-Martin氧化剂(152mg,0.36mmol),加入碳酸氢钠(30mg,0.36mmol),搅拌,得化合物白色固体粉末化合物1-12共140mg,产率80%.
1H NMR(500MHz,Chloroform)δ9.76(s,1H),7.73(s,1H),7.39(s,1H),7.32-7.26(m,2H),7.22(s,1H),7.20-7.10(m,3H),7.01(s,1H),6.82(s,1H),6.68(s,1H),6.14(s,1H),5.57(s,1H),5.43(s,1H),4.38(s,1H),4.32(d,J=19.2Hz,2H),3.45(s,1H),3.35(s,1H),3.06(s,1H),2.20(dd,J=15.4,2.3Hz,4H),2.12-2.03(m,2H),1.92(s,1H),1.77(s,1H),1.73-1.67(m,3H),1.66-1.53(m,6H),1.37(s,1H).;
实施例2 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A2)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),7.51(d,J=18.0Hz,2H),7.38(s,1H),7.12(s,1H),7.06(s,1H),6.26(s,1H),6.04(s,1H),5.80(s,1H),5.25(s,1H),4.81(s,1H),4.67(s,1H),3.45(s,1H),3.35(s,1H),2.55(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.96-1.91(m,3H),1.73-1.52(m,5H),1.40-1.36(m,2H),1.35-1.29(m,10H),1.20-1.09(m,3H).
实施例3 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A3)
1H NMR(500MHz,Chloroform)δ8.28(s,1H),7.48(d,J=1.2Hz,2H),7.34(s,1H),7.10(d,J=1.0Hz,2H),7.03(s,1H),6.05(s,1H),5.59(s,1H),5.30(s,1H),4.63(s,1H),4.45(s,1H),3.58(s,1H),3.45(s,1H),3.35(s,1H),2.95(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.98-1.90(m,3H),1.73-1.67(m,3H),1.65-1.61(m,2H),1.51(dtd,J=12.9,8.9,1.3Hz,13H),1.45-1.39(m,3H),1.38-1.34(m,2H).
实施例4 N-((S)-3-环己基-1-(((S)-4-(新戊基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A4)
1H NMR(500MHz,Chloroform)δ8.46(s,1H),7.53(d,J=3.4Hz,2H),7.40(d,J=17.1Hz,2H),7.12(s,1H),7.06(s,1H),6.16(d,J=14.3Hz,2H),5.65(s,1H),5.23(s,1H),4.44(s,1H),3.44(d,J=11.4Hz,2H),3.35(s,1H),3.09(s,1H),2.97(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.75-1.68(m,4H),1.62(s,1H),1.48(dt,J=16.0,8.0Hz,5H),1.37-1.31(m,2H),1.28(s,1H),1.09-1.05(m,9H).
实施例5 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A5)
1H NMR(500MHz,Chloroform)δ8.22(s,1H),7.96(s,1H),7.53(s,1H),7.42(s,1H),7.38(s,1H),7.29-7.24(m,4H),7.17(d,J=29.6Hz,2H),7.07(s,1H),6.54(s,1H),5.74(s,1H),5.27(s,1H),5.06(s,1H),4.49(s,1H),4.41(s,1H),4.31(s,1H),3.24(d,J=17.4Hz,2H),2.56(s,1H),2.08-2.04(m,2H),1.95-1.88(m,2H),1.78(d,J=6.9Hz,2H),1.69(dt,J=6.3,3.5Hz,7H),1.51(s,1H),1.40-1.36(m,2H),1.32(s,1H),1.15-1.11(m,2H),1.08(s,1H).
实施例6 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A6)
1H NMR(500MHz,Chloroform)δ8.30(s,2H),7.48(s,2H),7.43(s,2H),7.35(s,2H),7.10(s,2H),7.03(s,2H),6.45(s,2H),5.99(s,2H),5.76(s,2H),5.25(s,2H),4.81(s,2H),4.29(s,2H),3.24(d,J=17.1Hz,4H),2.75(s,2H),2.05(t,J=8.9Hz,6H),1.79(s,2H),1.71(t,J=2.5Hz,7H),1.58-1.54(m,3H),1.51-1.33(m,10H),1.33-1.29(m,20H),1.23(s,2H),1.15-1.11(m,3H),0.94-0.90(m,3H)..
实施例7 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A7)
1H NMR(500MHz,Chloroform)δ9.29(s,1H),8.69(s,1H),7.52(s,1H),7.43(d,J=15.1Hz,2H),7.13(s,1H),7.06(s,1H),5.93(s,1H),5.59(d,J=3.5Hz,2H),5.11(s,1H),4.51(s,1H),3.41(s,1H),3.24(d,J=16.6Hz,2H),2.66(s,1H),2.54(s,1H),2.08-2.04(m,2H),2.01-1.89(m,2H),1.89-1.77(m,4H),1.73-1.61(m,7H),1.55-1.50(m,3H),1.48(s,1H),1.44-1.39(m,2H),1.39-1.35(m,2H),1.31(s,1H),1.09-0.99(m,3H).
实施例8 N-((S)-3-环己基-1-(((S)-4-(新戊基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A8)
1H NMR(500MHz,Chloroform)δ8.45(s,4H),7.50(d,J=31.7Hz,8H),7.46-7.46(m,1H),7.39(s,5H),7.13(s,4H),7.06(s,4H),6.01(s,4H),5.44(s,4H),5.40(s,4H),5.23(s,4H),4.89(s,4H),4.47(s,4H),3.30-3.20(m,12H),3.13(s,4H),2.30(s,4H),2.10-2.02(m,8H),1.97(s,3H),1.81-1.76(m,11H),1.71(t,J=1.6Hz,11H),1.69-1.63(m,13H),1.50(s,3H),1.39-1.35(m,7H),1.31(s,4H),1.14-1.05(m,44H),1.02(s,3H).
实施例9 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A9)
1H NMR(500MHz,Chloroform)δ7.66(s,1H),7.34-7.28(m,5H),7.22(d,J=7.1Hz,2H),7.10(s,1H),6.72(s,1H),6.17(s,1H),5.97(s,1H),5.84(s,1H),5.47(s,1H),4.42(s,1H),4.34(d,J=9.3Hz,2H),3.45(s,1H),3.35(s,1H),3.22(s,1H),2.64(s,1H),2.18(s,1H),2.09-2.05(m,2H),2.05-1.98(m,2H),1.92(s,1H),1.75-1.66(m,4H),1.66-1.55(m,6H),1.36(s,1H).
实施例10 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A10)
1H NMR(500MHz,Chloroform)δ9.59(s,1H),8.31(s,1H),7.63(s,1H),7.50(s,1H),7.41(s,1H),7.22(s,1H),7.16(s,1H),6.40(s,1H),5.82(s,1H),4.81(s,1H),4.64(s,1H),3.97(s,1H),3.35(s,1H),2.69(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.94-1.88(m,3H),1.76-1.66(m,2H),1.66-1.48(m,3H),1.36-1.32(m,11H),1.28(s,1H),1.20(s,1H),0.99-0.95(m,2H).
实施例11 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A11)
1H NMR(500MHz,Chloroform)δ7.63(s,4H),7.47(s,4H),7.36(s,4H),7.26(s,4H),7.21(s,4H),7.14(s,4H),5.98(s,4H),5.77(s,4H),5.16(s,4H),4.60(s,4H),4.32(s,4H),3.53(s,3H),3.45(s,4H),3.35(s,3H),2.58(s,3H),2.19(s,3H),2.09-2.05(m,8H),1.95-1.88(m,11H),1.74-1.68(m,27H),1.65-1.61(m,6H),1.61-1.47(m,31H),1.44-1.39(m,8H),1.35-1.31(m,6H),1.24(s,3H).
实施例12 N-((S)-3-环己基-1-(((S)-4-(新戊基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A12)
1H NMR(500MHz,Chloroform)δ8.31(s,4H),7.60(s,4H),7.49(s,4H),7.40(s,4H),7.21(s,4H),7.15(s,4H),6.18(s,4H),5.46(s,4H),5.25(s,4H),5.12(s,4H),4.63(s,4H),3.43(d,J=18.9Hz,8H),3.35(s,3H),3.11(s,4H),2.76(s,4H),2.17(s,3H),2.13-2.01(m,8H),1.93(s,4H),1.85-1.81(m,6H),1.73-1.69(m,7H),1.69-1.62(m,7H),1.61-1.42(m,16H),1.33-1.29(m,6H),1.26(s,3H),1.14-1.10(m,3H).
实施例13 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A13)
1H NMR(500MHz,Chloroform)δ7.59(s,4H),7.51(d,J=1.4Hz,1H),7.46(d,J=36.6Hz,7H),7.32-7.14(m,29H),6.56(s,4H),5.75(s,4H),5.66(s,4H),5.09(s,4H),4.56(s,4H),4.41(s,4H),4.32(s,4H),3.24(d,J=17.0Hz,8H),2.32(s,4H),2.10-2.02(m,9H),1.99(s,4H),1.97-1.89(m,8H),1.79(s,4H),1.75-1.52(m,28H),1.40-1.36(m,7H),1.32(s,4H),1.23-1.19(m,8H),1.16(s,3H).
实施例14 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A14)
1H NMR(500MHz,Chloroform)δ7.63(s,1H),7.50(s,1H),7.37(s,1H),7.22(s,1H),7.16(s,1H),6.25(s,1H),6.08(s,1H),5.76(s,1H),4.70(d,J=19.7Hz,2H),3.24(d,J=14.7Hz,2H),2.83(s,1H),2.08-2.04(m,2H),2.01(s,1H),1.90(s,1H),1.85-1.78(m,3H),1.75-1.64(m,5H),1.56-1.41(m,6H),1.32(s,1H),1.25-1.21(m,9H).
实施例15 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A15)
1H NMR(500MHz,Chloroform)δ9.45(s,1H),8.16(s,1H),7.51(s,1H),7.42(s,1H),7.22(s,1H),7.16(s,1H),6.16(s,1H),6.07(s,1H),5.85(s,1H),5.08(s,1H),4.48(s,1H),3.32(s,1H),3.24(d,J=16.1Hz,2H),2.92(s,1H),2.16-2.08(m,2H),2.08-2.04(m,2H),2.02(s,1H),1.80(s,1H),1.76-1.66(m,8H),1.65(s,1H),1.57(s,1H),1.55-1.40(m,8H),1.40-1.37(m,1H),1.31(s,1H),1.12(s,1H),0.90-0.82(m,2H).
实施例16 N-((S)-3-环己基-1-(((S)-4-(新戊基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-2-羧酰胺(A16)
1 1H NMR(500MHz,Chloroform)δ7.60(s,1H),7.49(s,1H),7.40(s,1H),7.21(s,1H),7.15(s,1H),6.20(s,1H),5.99(s,1H),5.91(s,1H),5.65(s,1H),4.86(s,1H),4.76(s,1H),3.30(s,1H),3.24(d,J=17.4Hz,2H),2.92(s,1H),2.65(s,1H),2.08-2.04(m,2H),2.01(s,1H),1.90-1.84(m,2H),1.82(s,1H),1.77-1.65(m,5H),1.60-1.53(m,4H),1.52-1.48(m,2H),1.40(s,1H),1.34(s,1H),1.07-1.03(m,9H).
实施例17 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A17)
1H NMR(500MHz,Chloroform)δ8.13(s,5H),7.89(s,5H),7.65(s,5H),7.28(dd,J=7.5,4.2Hz,20H),7.21(dd,J=4.2,2.6Hz,2H),7.20-7.08(m,13H),6.14(s,5H),5.53(s,5H),5.37(s,5H),4.39-4.32(m,15H),4.24(s,5H),3.45(s,5H),3.35(s,4H),3.24(s,5H),2.94(s,4H),2.19(s,4H),2.09-2.05(m,10H),1.92(s,4H),1.80-1.67(m,25H),1.59-1.49(m,15H),1.46-1.38(m,19H),1.23(s,5H).
实施例18 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A18)
1H NMR(500MHz,Chloroform)δ8.37(s,1H),7.89(s,1H),7.73(s,1H),7.31(d,J=1.5Hz,2H),6.28(s,1H),6.05(s,1H),5.80(s,1H),5.25(s,1H),4.82(s,1H),4.68(s,1H),3.45(s,1H),3.35(s,1H),2.56(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.95-1.88(m,3H),1.73-1.52(m,5H),1.41-1.37(m,2H),1.35-1.29(m,10H),1.18-1.09(m,3H).
实施例19 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A19)
1H NMR(500MHz,Chloroform)δ8.95(s,1H),8.43(s,1H),8.26(s,1H),7.90(s,1H),7.74(s,1H),7.61(s,1H),7.31(d,J=2.0Hz,2H),5.94(s,1H),4.69(s,1H),4.53(s,1H),3.44(d,J=9.6Hz,2H),3.35(s,1H),2.95(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.91(t,J=7.7Hz,3H),1.75-1.68(m,5H),1.68-1.63(m,2H),1.62-1.58(m,2H),1.58-1.46(m,8H),1.45-1.40(m,2H),1.22-1.14(m,2H),1.07(s,1H).
实施例20 N-((S)-3-环己基-1-(((S)-4-(新戊基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A20)
1H NMR(500MHz,Chloroform)δ8.36(s,1H),7.88(s,1H),7.73(s,1H),7.30(d,J=2.5Hz,2H),6.53(s,1H),6.04(s,1H),5.82(s,1H),5.52(s,1H),4.68(d,J=6.4Hz,2H),3.45(s,1H),3.35(d,J=3.1Hz,2H),2.90(s,1H),2.43(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.91(t,J=5.9Hz,3H),1.74-1.65(m,4H),1.60-1.51(m,6H),1.34(s,1H),1.08-1.04(m,9H).
实施例21N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A21)
1H NMR(500MHz,Chloroform)δ8.31(s,1H),7.92(s,1H),7.74(s,1H),7.34-7.23(m,6H),7.20(s,1H),6.76(s,1H),5.59(s,1H),5.49(s,1H),5.08(s,1H),4.52(s,1H),4.42(s,1H),4.34(s,1H),3.24(d,J=17.6Hz,2H),2.68(s,1H),2.08-2.04(m,2H),1.74-1.67(m,5H),1.64(dd,J=2.9,1.7Hz,4H),1.36-1.32(m,2H),1.30(s,1H),1.26(s,1H),1.17(s,1H),1.13-1.05(m,2H),0.98(s,1H).
实施例22 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A22)
1H NMR(500MHz,Chloroform)δ8.34(s,1H),8.22(s,1H),7.88(s,1H),7.72(s,1H),7.30(d,J=1.5Hz,2H),6.15(s,1H),6.10(s,1H),5.41(s,1H),4.64(d,J=11.7Hz,2H),3.24(d,J=14.8Hz,2H),2.90(s,1H),2.11-2.01(m,2H),1.89-1.81(m,4H),1.77(s,1H),1.73-1.68(m,4H),1.66-1.59(m,5H),1.55-1.49(m,2H),1.35(s,1H),1.32-1.28(m,9H).
实施例23 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并噻吩-2-羧酰胺(A23)
1H NMR(500MHz,Chloroform)δ8.93(s,1H),8.55(s,1H),7.91(s,1H),7.72(s,1H),7.30(d,J=2.6Hz,2H),6.05(s,1H),5.83(s,1H),5.68(s,1H),5.13(s,1H),4.34(s,1H),3.33(s,1H),3.24(d,J=15.0Hz,2H),2.73(s,1H),2.43(s,1H),2.08-2.04(m,5H),1.85(s,1H),1.78(s,1H),1.73-1.67(m,5H),1.66-1.52(m,7H),1.51(s,2H),1.44-1.39(m,3H),1.34-1.30(m,2H),1.27(s,1H),0.83-0.72(m,2H).
实施例24 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A24)
1H NMR(500MHz,Chloroform)δ7.61(s,2H),7.40-7.26(m,10H),7.18(dd,J=24.7,8.9Hz,9H),6.51(s,2H),6.14(s,2H),5.17(s,2H),4.61(s,2H),4.40(s,2H),4.27(s,2H),4.19(s,2H),3.60-3.56(m,6H),3.52(s,2H),3.45(s,2H),3.35(s,2H),2.87(s,2H),2.18(s,2H),2.09-2.05(m,4H),1.92(s,2H),1.73-1.69(m,4H),1.60-1.50(m,11H),1.36-1.32(m,3H),1.18(s,2H),1.07-1.03(m,3H).
实施例25 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A25)
1H NMR(500MHz,Chloroform)δ7.40(s,1H),7.27(d,J=5.4Hz,2H),7.18(d,J=11.2Hz,2H),6.05(d,J=0.5Hz,2H),5.79(s,1H),5.25(s,1H),4.80(s,1H),4.65(s,1H),3.88-3.84(m,3H),3.45(s,1H),3.35(s,1H),2.58(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.95-1.91(m,3H),1.73-1.52(m,5H),1.41-1.37(m,2H),1.35-1.29(m,10H),1.19-1.09(m,3H).
实施例26 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A26)
1H NMR(500MHz,Chloroform)δ7.24(s,1H),7.17(s,1H),7.12(d,J=0.8Hz,2H),7.05(s,1H),6.01(s,1H),5.68(d,J=17.0Hz,2H),4.92(s,1H),4.81(s,1H),3.98(s,1H),3.81(s,1H),3.74-3.70(m,3H),3.35(s,1H),2.62(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.95-1.91(m,3H),1.90-1.77(m,4H),1.73-1.69(m,2H),1.66-1.54(m,13H),1.39-1.35(m,2H),1.33(s,1H).
实施例27 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A27)
1H NMR(500MHz,Chloroform)δ7.43(s,1H),7.38-7.24(m,7H),7.20(d,J=8.0Hz,2H),5.93(s,1H),5.87(s,1H),5.57(s,1H),5.47(s,1H),4.73(s,1H),4.55(s,1H),4.39(d,J=18.9Hz,2H),3.61-3.57(m,3H),3.23(d,J=15.5Hz,2H),2.08-2.04(m,2H),1.96-1.92(m,3H),1.85(s,1H),1.73-1.64(m,6H),1.61(s,1H),1.41(t,J=7.7Hz,3H),1.32(s,1H),1.24(s,1H),1.14-1.07(m,2H).
实施例28 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A28)
1H NMR(500MHz,Chloroform)δ7.46(s,47H),7.26(d,J=19.3Hz,98H),7.17(d,J=7.3Hz,95H),6.39(s,47H),5.92(d,J=11.5Hz,95H),5.44(s,47H),4.71(s,46H),4.53(s,46H),3.74-3.70(m,141H),3.24(d,J=18.1Hz,90H),2.77(s,44H),2.11-2.01(m,97H),1.91(s,34H),1.81(s,43H),1.77-1.69(m,222H),1.66-1.62(m,70H),1.61-1.42(m,241H),1.49-1.42(m,10H),1.40-1.36(m,70H),1.32-1.22(m,478H).
实施例29 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A29)
1H NMR(500MHz,Chloroform)δ7.41(s,1H),7.35-7.22(m,2H),7.19(d,J=7.5Hz,2H),5.92(s,1H),5.54(s,1H),5.38(s,1H),5.23(s,1H),5.04(s,1H),4.34(s,1H),3.99-3.95(m,3H),3.86(s,1H),3.24(d,J=15.7Hz,2H),2.86(s,1H),2.08-2.02(m,4H),1.99(s,1H),1.81(s,1H),1.78-1.67(m,7H),1.66-1.51(m,10H),1.43(s,1H),1.41-1.37(m,2H),1.30(s,1H),0.77-0.70(m,2H).
实施例30 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A30)
1H NMR(500MHz,Chloroform)δ7.87(s,1H),7.29(t,J=9.9Hz,3H),7.22-7.11(m,2H),6.98(s,1H),6.61(s,1H),6.43(s,1H),6.20(s,1H),5.62(s,1H),4.55(s,1H),4.43(d,J=15.9Hz,2H),4.32(s,1H),3.45(s,1H),3.35(s,1H),3.12(s,1H),2.33(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.94-1.88(m,3H),1.74-1.66(m,4H),1.63-1.55(m,6H),1.35(s,1H).
实施例31 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A31)
1H NMR(500MHz,Chloroform)δ9.04(s,1H),8.68(s,1H),8.53(s,1H),7.42(s,1H),7.38(s,1H),7.06(s,1H),6.78(s,1H),5.77(s,1H),4.93(s,1H),4.55(s,1H),3.99(s,1H),3.35(s,1H),2.63(s,1H),2.19(s,1H),2.10-2.04(m,4H),1.93(s,1H),1.69(dt,J=18.2,9.1Hz,5H),1.41-1.37(m,2H),1.35-1.27(m,11H),1.24(s,1H),1.05-1.01(m,2H).
实施例32 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A32)
1H NMR(500MHz,Chloroform)δ8.86(s,1H),8.48(s,1H),7.54(s,1H),7.41(s,1H),7.06(s,1H),6.01(s,1H),5.47(s,1H),5.20(s,1H),5.05(s,1H),4.55(s,1H),4.00(s,1H),3.58(s,1H),3.51(s,1H),3.35(s,1H),2.19(s,1H),2.12-2.02(m,2H),2.00-1.96(m,2H),1.94-1.87(m,3H),1.73-1.46(m,14H),1.40-1.36(m,2H),1.32(s,1H),1.12-1.06(m,3H).
实施例33 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A33)
1H NMR(500MHz,Chloroform)δ8.68(s,11H),7.45(s,11H),7.38(s,11H),7.31-7.23(m,34H),7.23-7.17(m,26H),7.16(s,8H),7.11(s,11H),5.89(s,11H),5.79(s,11H),4.76(s,11H),4.51(s,11H),4.35(s,11H),4.29(s,11H),3.24(d,J=17.5Hz,21H),2.73(s,11H),2.10-2.04(m,23H),2.02(s,9H),1.83(s,10H),1.81-1.74(m,33H),1.73-1.65(m,23H),1.65-1.50(m,45H),1.52(d,J=5.6Hz,2H),1.34-1.30(m,19H),1.28(s,11H),0.99-0.93(m,32H).
实施例34 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A34)
1H NMR(500MHz,Chloroform)δ8.35(s,1H),7.62(s,1H),7.39(s,1H),7.05(s,1H),6.43(s,1H),5.97(s,1H),5.59(s,1H),5.50(d,J=15.7Hz,2H),4.67(s,1H),3.24(d,J=17.3Hz,2H),2.48(s,1H),2.08-2.04(m,2H),1.87(t,J=9.6Hz,3H),1.78(s,1H),1.72(dd,J=8.3,4.2Hz,4H),1.67(s,1H),1.65-1.50(m,6H),1.45(s,1H),1.36-1.28(m,10H).
实施例35 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A35)
1H NMR(500MHz,Chloroform)δ8.51(s,1H),8.33(s,1H),8.28(s,1H),7.42(s,1H),7.07(s,1H),6.66(s,1H),6.41(s,1H),5.86(s,1H),5.04(s,1H),4.52(s,1H),3.32(s,1H),3.24(d,J=16.6Hz,2H),2.97(s,1H),2.16-2.01(m,5H),2.01-1.92(m,2H),1.82(s,1H),1.78-1.69(m,8H),1.65(d,J=15.4Hz,2H),1.56-1.46(m,3H),1.44-1.40(m,4H),1.32(s,1H),1.17(s,1H),1.07-1.00(m,2H).
实施例36 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A36)
1H NMR(500MHz,Chloroform)δ8.98(s,1H),8.03(d,J=1.1Hz,2H),7.63(d,J=5.1Hz,2H),7.37-7.27(m,4H),7.21(s,1H),6.95(s,1H),6.43(s,1H),6.01(s,1H),4.94(s,1H),4.85(s,1H),4.67(s,1H),4.41(s,1H),4.32(s,1H),3.45(s,1H),3.35(s,1H),2.77(s,1H),2.19(s,1H),2.13-2.01(m,2H),1.89(s,1H),1.83-1.74(m,2H),1.74-1.69(m,2H),1.66(d,J=5.7Hz,2H),1.58-1.49(m,6H),1.31(s,1H).
实施例37 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A37)
1H NMR(500MHz,Chloroform)δ9.39(s,1H),8.47(s,1H),8.11(s,1H),7.62(d,J=3.2Hz,2H),6.17(d,J=6.0Hz,2H),5.59(s,1H),5.27(s,1H),4.98(s,1H),4.91(s,1H),3.45(s,1H),3.35(s,1H),2.51(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.98-1.95(m,2H),1.92(s,1H),1.73-1.61(m,5H),1.41-1.37(m,2H),1.34-1.28(m,10H),1.21-1.11(m,3H).
实施例38 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A38)
1H NMR(500MHz,Chloroform)δ9.09(s,1H),8.31(s,1H),8.03(d,J=4.8Hz,2H),7.61(d,J=2.2Hz,2H),6.41(s,1H),6.06(s,1H),5.27(s,1H),5.20(s,1H),4.45(s,1H),3.72(s,1H),3.45(s,1H),3.35(s,1H),2.73(s,1H),2.39-2.31(m,2H),2.19(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.76-1.56(m,15H),1.55-1.45(m,6H),1.30(s,1H).
实施例39 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A39)
1H NMR(500MHz,Chloroform)δ9.55(s,1H),9.32(s,1H),8.12(s,1H),7.96(s,1H),7.64(d,J=11.6Hz,2H),7.29-7.22(m,4H),7.19(s,1H),6.56(s,1H),6.06(s,1H),5.63(s,1H),5.02(s,1H),4.71(s,1H),4.41(s,1H),4.31(s,1H),3.24(d,J=17.3Hz,2H),2.37(s,1H),2.10-2.02(m,2H),2.02-1.96(m,3H),1.82(s,1H),1.72(t,J=9.8Hz,3H),1.69-1.57(m,3H),1.53(s,1H),1.38-1.34(m,2H),1.31(s,1H),1.13-1.04(m,3H).
实施例40 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A40)
1H NMR(500MHz,Chloroform)δ9.29(s,1H),8.16(s,1H),8.11(s,1H),7.65(d,J=4.6Hz,2H),7.22(s,1H),5.87(d,J=8.3Hz,2H),5.65(s,1H),4.94(s,1H),4.46(s,1H),3.24(d,J=14.8Hz,2H),2.72(s,1H),2.11-2.01(m,2H),1.79(d,J=1.0Hz,2H),1.76-1.62(m,5H),1.59(s,1H),1.49-1.42(m,4H),1.35-1.28(m,11H),1.25(s,1H),1.21-1.15(m,2H).
实施例41 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A41)
1H NMR(500MHz,Chloroform)δ9.64(s,4H),8.11(d,J=10.4Hz,8H),7.65(d,J=1.9Hz,8H),6.00(s,4H),5.76(s,4H),5.70(s,4H),5.64(s,4H),5.04(s,4H),4.45(s,4H),3.86(s,4H),3.24(d,J=17.3Hz,8H),2.85(s,4H),2.11-2.01(m,9H),1.99-1.91(m,12H),1.91-1.80(m,9H),1.75(s,2H),1.75-1.53(m,62H),1.55-1.53(m,1H),1.51(s,3H),1.38-1.34(m,7H),1.30(s,4H),1.06(s,3H),1.03-0.99(m,8H).
实施例42 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A42)
1H NMR(500MHz,Chloroform)δ8.56(s,1H),8.19(s,1H),7.82(s,1H),7.58(s,1H),7.42(s,1H),7.42-7.28(m,5H),7.21(s,1H),6.00(d,J=2.7Hz,2H),4.43(s,1H),4.33(s,1H),4.11(s,1H),3.83(d,J=3.7Hz,2H),3.45(s,1H),3.35(s,1H),3.25(s,1H),2.15(s,1H),2.09-2.05(m,2H),1.91(s,1H),1.73-1.69(m,2H),1.62-1.55(m,3H),1.36-1.27(m,6H),1.23(s,1H),1.20-1.14(m,2H).
实施例43 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A43)
1H NMR(500MHz,Chloroform)δ9.34(s,1H),8.46(s,1H),8.17(s,1H),7.82(s,1H),7.72(s,1H),7.55(s,1H),7.50(s,1H),5.96(s,1H),5.84(s,1H),5.40(s,1H),5.22(s,1H),4.77(s,1H),3.45(s,1H),3.35(s,1H),2.83(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.94-1.81(m,3H),1.73-1.63(m,5H),1.40-1.36(m,2H),1.36-1.27(m,10H),1.18(s,1H),1.14-1.10(m,2H).
实施例44 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A44)
1H NMR(500MHz,Chloroform)δ8.47(s,1H),8.24(s,1H),8.06(s,1H),7.73(s,1H),7.65(s,1H),7.43(d,J=13.7Hz,2H),6.58(s,1H),6.06(s,1H),5.40(s,1H),5.20(s,1H),4.45(s,1H),3.73(s,1H),3.45(s,1H),3.35(s,1H),2.72(s,1H),2.34-2.30(m,2H),2.19(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.77-1.56(m,15H),1.55-1.46(m,6H),1.30(s,1H).
实施例45 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A45)
1H NMR(500MHz,Chloroform)δ8.42(s,1H),8.15(s,1H),7.79(s,1H),7.69(s,1H),7.47(s,1H),7.42(s,1H),7.34-7.25(m,4H),7.20(s,1H),6.77(s,1H),5.89(s,1H),5.82(s,1H),5.57(d,J=7.5Hz,2H),4.42(d,J=5.7Hz,2H),4.34(s,1H),3.24(d,J=19.0Hz,2H),2.81(s,1H),2.43(s,1H),2.11-2.01(m,2H),1.95(s,1H),1.86(s,1H),1.81-1.74(m,3H),1.69(dt,J=17.1,8.6Hz,5H),1.47(s,1H),1.41-1.37(m,2H),1.31(s,1H),0.84-0.77(m,2H).
实施例46 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A46)
1H NMR(500MHz,Chloroform)δ8.46(s,3H),8.13(s,3H),7.79(s,3H),7.69(d,J=0.8Hz,6H),7.44(d,J=32.8Hz,6H),6.55(s,3H),6.05(s,3H),5.75(s,3H),4.77(d,J=2.1Hz,6H),3.25(s,3H),3.21(s,3H),2.70(s,3H),2.11-2.01(m,6H),1.96-1.87(m,6H),1.79(d,J=13.1Hz,5H),1.70(dt,J=19.3,3.5Hz,19H),1.60-1.51(m,18H),1.35-1.30(m,30H).
实施例47 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-喹啉-2-羧酰胺(A47)
1H NMR(500MHz,Chloroform)δ9.06(s,3H),8.44(s,3H),8.15(s,3H),7.79(s,3H),7.75(s,3H),7.70(s,3H),7.48(d,J=8.2Hz,6H),7.38(s,3H),5.73(s,3H),4.96(s,3H),4.57(s,3H),3.90(s,3H),3.24(d,J=14.7Hz,6H),2.92(s,3H),2.15-2.11(m,5H),2.11-2.01(m,9H),1.99(t,J=7.9Hz,7H),1.80(s,2H),1.76-1.65(m,18H),1.65-1.58(m,24H),1.45(t,J=13.5Hz,10H),1.36(dd,J=21.5,15.7Hz,2H),1.33(s,3H),1.20(s,2H),1.11-1.04(m,6H).
实施例48 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A48)
1H NMR(500MHz,Chloroform)δ8.36(s,1H),7.55(d,J=12.3Hz,2H),7.34(t,J=21.8Hz,3H),7.30-7.17(m,9H),7.15(d,J=2.2Hz,2H),7.09(s,1H),6.35(s,1H),6.01(s,1H),5.67(s,1H),5.03(s,1H),4.88(s,1H),4.37(s,1H),4.30(s,1H),3.45(s,1H),3.35(s,1H),3.15(d,J=18.6Hz,2H),2.94(s,1H),2.19(s,1H),2.10-2.04(m,2H),1.92(s,1H).
实施例49 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A49)
1H NMR(500MHz,Chloroform)δ8.26(s,1H),7.46(s,1H),7.32(t,J=17.0Hz,3H),7.20(dd,J=7.8,5.2Hz,4H),7.12(s,1H),7.06(s,1H),6.01(s,1H),5.57(s,1H),4.84(s,1H),4.69(s,1H),4.53(s,1H),3.45(s,1H),3.41(s,1H),3.35(s,1H),3.30(s,1H),3.19(s,1H),2.96(s,1H),2.16(s,1H),2.13-2.01(m,2H),1.89(s,1H),1.30-1.26(m,9H).
实施例50 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A50)
1H NMR(500MHz,Chloroform)δ8.35(s,1H),7.90(s,1H),7.52(d,J=25.5Hz,2H),7.39(s,1H),7.29-7.21(m,4H),7.14(d,J=3.6Hz,2H),7.08(s,1H),6.52(s,1H),6.16(s,1H),5.70(s,1H),4.92(s,1H),4.78(s,1H),3.46(d,J=5.2Hz,2H),3.35(s,1H),3.21(s,1H),2.85(d,J=4.0Hz,2H),2.17(s,1H),2.13-2.02(m,2H),2.00-1.90(m,3H),1.68(s,1H),1.56-1.50(m,2H),1.49-1.45(m,3H),1.44-1.40(m,2H).
实施例51 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A51)
1H NMR(500MHz,Chloroform)δ8.70(s,1H),7.50(s,1H),7.39-7.20(m,5H),7.20-7.11(m,4H),7.09(d,J=4.4Hz,2H),7.06-6.94(m,2H),6.90(s,1H),6.19(s,1H),5.93(s,1H),5.51(s,1H),4.70(s,1H),4.25(d,J=17.1Hz,2H),3.79(d,J=9.5Hz,2H),3.24(t,J=8.3Hz,3H),3.04(s,1H),2.16(s,1H),2.12-2.04(m,3H),1.78(s,1H),1.72(s,1H),1.62(s,1H).
实施例52 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A52)
1H NMR(500MHz,Chloroform)δ8.64(d,J=17.0Hz,2H),8.19(s,1H),7.56(s,1H),7.43(s,1H),7.36-7.27(m,2H),7.27-7.22(m,2H),7.14(d,J=12.9Hz,2H),7.08(s,1H),5.63(s,1H),5.01(d,J=14.2Hz,2H),4.78(d,J=1.3Hz,2H),3.24(d,J=18.2Hz,2H),3.18(s,1H),3.03(s,1H),2.97(s,1H),2.06(t,J=3.5Hz,3H),1.94(s,1H),1.88(s,1H),1.81(s,1H),1.21-1.17(m,9H).
实施例53 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-2-羧酰胺(A53)
1H NMR(500MHz,Chloroform)δ8.76(s,1H),7.53(s,1H),7.41(d,J=25.5Hz,2H),7.27-7.21(m,2H),7.21-7.18(m,2H),7.15(d,J=7.6Hz,2H),7.08(s,1H),5.95(s,1H),5.61(s,1H),5.25(s,1H),5.14(s,1H),4.78(s,1H),3.42(s,1H),3.25(t,J=12.6Hz,3H),2.87(s,1H),2.70(s,1H),2.56(s,1H),2.08-2.04(m,2H),2.02-1.90(m,2H),1.87(s,1H),1.80(s,1H),1.68(d,J=3.3Hz,2H),1.55-1.51(m,4H),1.48(s,1H),1.45-1.39(m,2H).
实施例54 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A54)
1H NMR(500MHz,Chloroform)δ7.51(d,J=8.2Hz,2H),7.41(s,1H),7.30-7.12(m,12H),6.67(s,1H),5.69-5.61(m,3H),5.09(s,1H),4.88(s,1H),4.41(s,1H),4.33(s,1H),3.45(s,1H),3.35(s,1H),3.26(s,1H),3.16(s,1H),3.07(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.92(s,1H).
实施例55 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A55)
1H NMR(500MHz,Chloroform)δ7.54(s,1H),7.47(d,J=17.7Hz,2H),7.28-7.22(m,3H),7.18(dd,J=20.8,5.2Hz,4H),6.42(s,1H),6.05(s,1H),5.83(s,1H),5.27(s,1H),4.98(s,1H),4.85(s,1H),3.45(s,1H),3.35(s,1H),3.19(s,1H),2.96(s,1H),2.61(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.93(s,1H),1.34-1.30(m,9H).
实施例56 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A56)
1H NMR(500MHz,Chloroform)δ8.77(s,2H),8.67(s,2H),7.56(s,1H),7.50(s,3H),7.41(s,2H),7.28-7.19(m,6H),7.16(d,J=4.9Hz,4H),7.13-7.04(m,4H),6.04(s,2H),5.93(s,2H),5.05(s,2H),4.66(s,2H),3.70(s,2H),3.45(s,2H),3.35(s,1H),3.25(s,2H),3.05(s,2H),2.88(s,2H),2.19(s,2H),2.09-2.05(m,4H),1.97-1.91(m,5H),1.68-1.64(m,3H),1.64-1.43(m,13H).
实施例57 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A57)
1H NMR(500MHz,Chloroform)δ7.48(s,1H),7.29(d,J=38.0Hz,2H),7.25(s,1H),7.27-7.19(m,3H),7.19-7.05(m,10H),6.97(s,1H),6.43(s,1H),6.07(s,1H),5.18(d,J=3.4Hz,2H),4.73(s,1H),4.63(s,1H),4.36(s,1H),4.29(s,1H),3.24(d,J=16.8Hz,2H),3.10(s,1H),2.86(d,J=21.8Hz,2H),2.43(s,1H),2.08-2.04(m,2H),1.85(s,1H),1.79(s,1H),1.64(s,1H).
实施例58 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A58)
1H NMR(500MHz,Chloroform)δ9.35(s,5H),7.60(s,5H),7.48(d,J=29.1Hz,10H),7.28-7.18(m,27H),7.16(d,J=17.5Hz,8H),5.86(s,5H),5.55(s,5H),4.94(s,5H),4.69(s,5H),3.24(t,J=10.0Hz,14H),2.90(s,5H),2.66(s,5H),2.09-2.02(m,10H),1.92(s,4H),1.84-1.80(m,8H),1.76(s,4H),1.30-1.26(m,44H).
实施例59 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并呋喃-2-羧酰胺(A59)
1H NMR(500MHz,Chloroform)δ9.35(s,5H),7.60(s,5H),7.48(d,J=29.1Hz,10H),7.28-7.18(m,27H),7.16(d,J=17.5Hz,8H),5.86(s,5H),5.55(s,5H),4.94(s,5H),4.69(s,5H),3.24(t,J=10.0Hz,14H),2.90(s,5H),2.66(s,5H),2.09-2.02(m,10H),1.92(s,4H),1.84-1.80(m,8H),1.76(s,4H),1.30-1.26(m,44H).
实施例60 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A60)
1H NMR(500MHz,Chloroform)δ8.40(s,1H),7.91(s,1H),7.76(s,1H),7.33(d,J=3.7Hz,2H),7.32-7.16(m,10H),7.13(d,J=16.7Hz,2H),6.27(s,1H),5.97(s,1H),5.64(s,1H),5.03(s,1H),4.89(s,1H),4.34(d,J=4.2Hz,2H),3.45(s,1H),3.35(s,1H),3.15-3.11(m,2H),2.94(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.92(s,1H).
实施例61 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A61)
1H NMR(500MHz,Chloroform)δ8.93(s,1H),7.82(d,J=4.4Hz,2H),7.28(dd,J=20.7,7.2Hz,4H),7.22-7.11(m,3H),6.05(s,1H),4.70(s,1H),4.64(s,1H),4.59(s,1H),4.39(s,1H),3.99(s,1H),3.55(s,1H),3.45(s,1H),3.35(s,1H),3.15(s,1H),2.95(s,1H),2.17(s,1H),2.13-2.02(m,2H),1.89(s,1H),1.21-1.17(m,9H).
实施例62 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A62)
1H NMR(500MHz,Chloroform)δ8.73(s,1H),8.54(s,1H),8.35(s,1H),7.91(s,1H),7.74(s,1H),7.32(d,J=1.5Hz,2H),7.28-7.23(m,2H),7.15(s,1H),7.12-7.05(m,2H),6.14(s,1H),5.94(s,1H),5.04(s,1H),4.66(s,1H),3.45(d,J=3.2Hz,2H),3.35(s,1H),3.26(s,1H),3.05(s,1H),2.89(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.95-1.91(m,3H),1.73-1.64(m,3H),1.56-1.52(m,2H),1.50(s,1H),1.46-1.40(m,2H).
实施例63 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A63)
1H NMR(500MHz,Chloroform)δ8.49(s,1H),8.30(s,1H),8.00(s,1H),7.63(s,1H),7.29(dd,J=19.0,2.9Hz,4H),7.18-7.07(m,5H),7.07-6.97(m,3H),6.33(s,1H),6.11(s,1H),4.93-4.89(m,2H),4.36(d,J=9.1Hz,2H),4.29(s,1H),3.28-3.20(m,3H),2.92(s,1H),2.58(s,1H),2.16(s,1H),2.08-2.04(m,2H),1.83(s,1H),1.77(s,1H),1.73(s,1H).
实施例64 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A64)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),7.90(s,1H),7.75(s,1H),7.30(dd,J=17.5,1.0Hz,4H),7.26-7.19(m,2H),7.17(s,1H),7.02(s,1H),6.45(s,1H),6.10(s,1H),5.93(s,1H),4.93(s,1H),4.86(s,1H),3.27-3.11(m,3H),2.95(s,1H),2.83(s,1H),2.11-2.01(m,2H),1.95(s,1H),1.83(s,1H),1.76(s,1H),1.56(s,1H),1.35-1.31(m,9H).
实施例65 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-苯并噻吩-2-羧酰胺(A65)
1H NMR(500MHz,Chloroform)δ8.28(s,6H),7.86(s,6H),7.60(s,6H),7.27(dd,J=17.2,1.6Hz,20H),7.24-7.12(m,22H),5.78(s,6H),5.41(s,6H),5.09(s,6H),4.97(s,6H),4.85(s,6H),3.31-3.10(m,30H),2.97(s,6H),2.60(s,4H),2.51(s,5H),2.12-2.00(m,12H),1.97-1.86(m,12H),1.71(t,J=16.5Hz,17H),1.58-1.45(m,30H),1.45-1.36(m,12H),1.12(s,4H).
实施例66 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A66)
1H NMR(500MHz,Chloroform)δ8.78(s,1H),7.69(s,1H),7.49(s,1H),7.34-7.13(m,12H),7.13-7.05(m,2H),6.10(s,1H),5.99(s,1H),5.07(s,1H),4.69(s,1H),4.36(d,J=3.5Hz,2H),3.78-3.74(m,3H),3.45(s,1H),3.35(s,1H),3.24(s,1H),3.06(s,1H),2.88(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.93(s,1H).
实施例67 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A67)
1H NMR(500MHz,Chloroform)δ7.38(s,1H),7.29-7.13(m,9H),6.07(s,1H),5.82(d,J=4.8Hz,2H),5.28(s,1H),4.94(s,1H),4.87(s,1H),3.67-3.63(m,3H),3.45(s,1H),3.35(s,1H),3.19(s,1H),2.93(s,1H),2.68(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.94(s,1H),1.34-1.30(m,9H).
实施例68 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A68)
1H NMR(500MHz,Chloroform)δ7.49(s,3H),7.34-7.20(m,23H),7.20(s,3H),7.15(s,2H),6.73(s,3H),6.27(s,3H),5.73(s,3H),5.11(s,3H),4.83(s,3H),3.98(s,2H),3.76(s,3H),3.58-3.54(m,9H),3.35(s,2H),3.22(s,3H),2.88(s,3H),2.63(s,3H),2.19(s,2H),2.09-2.05(m,6H),1.95-1.91(m,7H),1.76-1.66(m,7H),1.66-1.55(m,20H).
实施例69 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A69)
1H NMR(500MHz,Chloroform)δ7.35-7.29(m,2H),7.29-7.26(m,1H),7.26-7.06(m,11H),6.67(s,1H),6.05(d,J=11.7Hz,2H),5.74(s,1H),4.95(s,1H),4.77(s,1H),4.39(s,1H),4.34(s,1H),3.86-3.82(m,3H),3.29-3.17(m,3H),2.95(s,1H),2.56(s,1H),2.44(s,1H),2.12-2.00(m,2H),1.85(s,1H),1.78(s,1H),1.41(s,1H),1.15(s,1H).
实施例70 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A70)
1H NMR(500MHz,Chloroform)δ7.51(s,1H),7.31(s,1H),7.22(ddd,J=42.8,13.4,8.7Hz,8H),6.91(s,1H),6.06(s,1H),5.93(s,1H),5.54(s,1H),4.80(s,1H),4.71(s,1H),3.73-3.69(m,3H),3.26(t,J=14.0Hz,3H),2.82(d,J=27.3Hz,2H),2.11-2.01(m,2H),1.92(s,1H),1.82(s,1H),1.75(s,1H),1.54(s,1H),1.32-1.28(m,9H).
实施例71 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A71)
1H NMR(500MHz,Chloroform)δ8.25(s,1H),7.38(s,1H),7.28(dd,J=15.9,3.4Hz,4H),7.24-7.12(m,5H),5.93(s,1H),5.32(s,1H),5.07(s,1H),4.75(s,1H),4.41(s,1H),3.85-3.77(m,4H),3.27-3.20(m,3H),3.04(s,1H),2.84(s,1H),2.49(s,1H),2.17-2.10(m,2H),2.10-2.02(m,2H),1.86-1.75(m,6H),1.65(s,1H),1.58-1.52(m,4H).
实施例72 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A72)
1H NMR(500MHz,Chloroform)δ8.55(s,1H),7.52(s,1H),7.44(s,1H),7.38(s,1H),7.32-7.27(m,4H),7.27-7.12(m,8H),7.10(s,1H),6.00(s,1H),5.04(s,1H),4.92(s,1H),4.77(s,1H),4.38(s,1H),4.30(s,1H),3.45(s,1H),3.35(s,1H),3.27(s,1H),3.12(s,1H),2.87(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.92(s,1H).
实施例73 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A73)
1H NMR(500MHz,Chloroform)δ8.55(s,1H),8.14(s,1H),7.52(s,1H),7.44(s,1H),7.28-7.22(m,2H),7.22-7.11(m,3H),7.09(s,1H),6.01(s,1H),5.55(s,1H),5.12(s,1H),4.74(s,1H),4.31(s,1H),3.45(s,1H),3.35(s,1H),3.30(s,1H),3.08(s,1H),2.92(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.39-1.35(m,9H).
实施例74 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A74)
1H NMR(500MHz,Chloroform)δ8.85(s,1H),8.44(s,1H),8.39(s,1H),7.58(s,1H),7.42(s,1H),7.28-7.23(m,2H),7.15(s,1H),7.12-7.06(m,3H),6.10(s,1H),5.94(s,1H),5.03(s,1H),4.66(s,1H),3.45(d,J=5.0Hz,2H),3.35(s,1H),3.27(s,1H),3.06(s,1H),2.90(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.95-1.91(m,3H),1.72-1.68(m,3H),1.56-1.52(m,2H),1.50(s,1H),1.46-1.41(m,2H).
实施例75 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A75)
1H NMR(500MHz,Chloroform)δ8.67(s,13H),7.46(s,13H),7.30-7.24(m,28H),7.24-7.14(m,80H),7.12-7.00(m,30H),7.00(s,11H),6.93(d,J=12.0Hz,26H),6.07(s,13H),4.91(s,13H),4.80(s,13H),4.36(s,13H),4.31(s,13H),4.27(s,13H),4.04(s,13H),3.31(d,J=52.2Hz,35H),3.22(s,5H),3.01(s,14H),2.86(s,11H),2.31(s,9H),2.08-2.04(m,25H),1.83(s,12H),1.77(s,10H),1.54(s,9H).
实施例76 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A76)
1H NMR(500MHz,Chloroform)δ8.53(s,8H),7.62(s,8H),7.43(s,8H),7.38(s,8H),7.26-7.21(m,16H),7.21-7.14(m,21H),7.14-7.11(m,4H),7.09(s,8H),5.81(s,8H),5.66(s,8H),5.34(s,8H),4.92(s,8H),4.75(s,8H),3.33-3.20(m,24H),2.87(s,7H),2.59(s,7H),2.08-2.04(m,16H),1.86(s,6H),1.80(s,7H),1.73(s,6H),1.48(s,6H),1.34-1.30(m,72H).
实施例77 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A77)
1H NMR(500MHz,Chloroform)δ9.14(s,1H),9.09(s,1H),7.58(s,1H),7.47(s,1H),7.33-7.27(m,2H),7.27-7.14(m,3H),7.10(s,1H),6.82(s,1H),5.96(s,1H),5.80(s,1H),4.98(s,1H),4.82(s,1H),3.35(s,1H),3.24(d,J=14.7Hz,2H),3.16(s,1H),2.96(s,1H),2.83(s,1H),2.16-2.04(m,5H),1.82(s,1H),1.75(dd,J=19.9,8.6Hz,4H),1.59-1.49(m,4H),1.44-1.40(m,2H).
实施例78 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A78)
1H NMR(500MHz,Chloroform)δ9.21(s,1H),8.80(s,1H),8.10(d,J=21.9Hz,2H),7.71(s,1H),7.63(d,J=6.0Hz,2H),7.30-7.11(m,10H),6.38(s,1H),5.97(s,1H),4.90(s,1H),4.69(s,1H),4.36(d,J=4.9Hz,2H),3.45(s,1H),3.35(s,1H),3.16(s,1H),2.95(s,1H),2.86(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.93(s,1H).
实施例79 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A79)
1H NMR(500MHz,Chloroform)δ9.43(s,1H),9.01(s,1H),8.10(d,J=11.8Hz,2H),7.68-7.64(m,2H),7.25-7.19(m,1H),7.19-7.09(m,4H),6.12(s,1H),6.04(s,1H),5.51(s,1H),5.09(s,1H),4.74(s,1H),3.45(s,1H),3.35(d,J=2.3Hz,2H),3.11(s,1H),2.89(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.39-1.35(m,9H).
实施例80 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A80)
1H NMR(500MHz,Chloroform)δ9.46(s,1H),8.10(d,J=1.3Hz,2H),7.64(d,J=1.4Hz,2H),7.29-7.21(m,4H),7.15(s,1H),6.17(s,1H),5.60(s,1H),5.41(s,1H),5.16(s,1H),4.42(s,1H),3.77(s,1H),3.45(s,1H),3.35(d,J=2.0Hz,2H),2.94(s,1H),2.49(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.93(s,1H),1.81-1.74(m,6H),1.74-1.70(m,2H),1.57-1.51(m,2H).
实施例81 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A81)
1H NMR(500MHz,Chloroform)δ9.04(s,1H),8.07(d,J=5.3Hz,2H),7.62(d,J=0.9Hz,2H),7.30-7.20(m,5H),7.20-7.12(m,5H),7.10(s,1H),6.69(s,1H),5.68(d,J=19.5Hz,2H),5.14(s,1H),5.08(s,1H),4.42(s,1H),4.34(s,1H),3.37(s,1H),3.24(d,J=17.2Hz,2H),2.95(s,1H),2.15(s,1H),2.09-2.03(m,2H),1.76(s,1H),1.70(s,1H),1.63(s,1H),1.43(s,1H).
实施例82 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A82)
1H NMR(500MHz,Chloroform)δ9.37(s,1H),8.11(d,J=1.9Hz,2H),7.64(d,J=1.0Hz,2H),7.32-7.26(m,2H),7.26-7.13(m,3H),6.08(s,1H),5.93(d,J=13.8Hz,2H),5.60(s,1H),4.97(s,1H),4.83(s,1H),3.24(d,J=16.7Hz,2H),3.18(s,1H),2.93(s,1H),2.70(s,1H),2.11-2.01(m,2H),1.98(s,1H),1.78(s,1H),1.71(s,1H),1.42(s,1H),1.35-1.31(m,9H).
实施例83 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹喔啉-2-羧酰胺(A83)
1H NMR(500MHz,Chloroform)δ9.67(s,6H),8.12(d,J=8.3Hz,12H),7.66(d,J=1.4Hz,12H),7.26-7.16(m,25H),7.14(s,6H),6.12(s,6H),5.79(s,6H),5.56(s,6H),5.33(s,6H),5.10(s,6H),4.95(s,6H),3.84(s,6H),3.27(t,J=34.6Hz,16H),3.21(d,J=6.1Hz,2H),3.02(s,6H),2.83(s,6H),2.11-2.01(m,13H),2.01-1.94(m,18H),1.75(s,4H),1.71-1.55(m,59H).
实施例84 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A84)
1H NMR(500MHz,Chloroform)δ8.46(s,1H),8.12(s,1H),7.78(s,1H),7.65(s,1H),7.54(s,1H),7.44(s,1H),7.31-7.24(m,4H),7.24-7.14(m,4H),7.12(s,2H),5.72(s,1H),5.54(s,1H),5.14(s,1H),4.70(s,1H),4.59(s,1H),4.29(d,J=9.5Hz,2H),3.74(s,1H),3.35(s,1H),3.31(s,1H),3.08(s,1H),2.72(s,1H),2.17(s,1H),2.10-2.05(m,2H),1.89(s,1H).
实施例85 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A85)
1H NMR(500MHz,Chloroform)δ8.40(d,J=39.3Hz,11H),8.36-8.34(m,1H),8.19(s,6H),7.80(s,6H),7.71(s,6H),7.49(d,J=5.7Hz,12H),7.30-7.25(m,12H),7.25-7.15(m,14H),7.14(s,4H),6.20(s,6H),5.92(s,6H),5.07(s,6H),4.75(s,6H),3.45(s,6H),3.38(d,J=25.1Hz,12H),3.32(s,1H),3.02(s,6H),2.35(s,5H),2.19(s,4H),2.09-2.05(m,12H),1.92(s,5H),1.36-1.32(m,53H).
实施例86 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A86)
1H NMR(500MHz,Chloroform)δ8.46(s,1H),8.12(s,1H),7.81(s,1H),7.69(s,1H),7.49(d,J=7.1Hz,2H),7.26-7.20(m,2H),7.20-7.09(m,3H),5.94(d,J=1.5Hz,2H),5.63(s,1H),5.44(s,1H),4.91(s,1H),4.76(s,1H),3.89(s,1H),3.45(s,1H),3.34(d,J=11.1Hz,2H),3.01(s,1H),2.19(d,J=10.9Hz,2H),2.14-2.04(m,4H),1.92(s,1H),1.65-1.49(m,8H).
实施例87 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A87)
1H NMR(500MHz,Chloroform)δ8.46(s,1H),8.10(s,1H),7.78(s,1H),7.66(s,1H),7.55(s,1H),7.45(s,1H),7.26-7.11(m,10H),6.86(s,1H),5.98(s,1H),5.89(s,1H),5.56(d,J=16.8Hz,2H),4.75(s,1H),4.44(s,1H),4.32(s,1H),3.44(s,1H),3.23(d,J=18.1Hz,2H),2.84(s,1H),2.72(s,1H),2.11-2.01(m,2H),1.98(s,1H),1.63(s,1H),1.56(s,1H),1.25(s,1H).
实施例88 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A88)
1H NMR(500MHz,Chloroform)δ8.50(d,J=13.8Hz,2H),8.17(s,1H),7.81(s,1H),7.69(s,1H),7.65(s,1H),7.48(s,1H),7.28-7.24(m,1H),7.24-7.11(m,4H),6.95(s,1H),6.17(s,1H),5.50(s,1H),5.00(s,1H),4.79(s,1H),3.24(d,J=15.4Hz,2H),3.08(s,1H),2.90(s,1H),2.69(s,1H),2.11-2.01(m,2H),1.90(s,1H),1.84(d,J=3.8Hz,2H),1.78(s,1H),1.29-1.25(m,9H).
实施例89 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-喹啉-2-羧酰胺(A89)
1H NMR(500MHz,Chloroform)δ9.70(s,4H),8.44(s,4H),8.18(s,4H),7.80(s,4H),7.69(d,J=18.4Hz,8H),7.48(d,J=4.0Hz,8H),7.32-7.26(m,8H),7.23-7.13(m,12H),6.67(s,4H),5.84(s,4H),4.95(s,4H),4.88(s,4H),3.90(s,4H),3.31(d,J=56.1Hz,10H),3.22(s,2H),2.99(s,4H),2.86(s,4H),2.11-2.04(m,8H),2.01(t,J=7.0Hz,12H),1.81(s,3H),1.74(s,3H),1.67-1.60(m,35H),1.45(s,3H).
实施例90 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A90)
1H NMR(500MHz,Chloroform)δ8.36(s,1H),7.52(d,J=19.2Hz,2H),7.39(s,1H),7.26-7.19(m,4H),7.18(s,1H),7.13(s,1H),7.07(s,1H),6.32(s,1H),6.24(s,1H),6.05(s,1H),5.47(s,1H),5.27(s,1H),4.61(s,1H),4.41(s,1H),4.32(s,1H),3.59(s,1H),3.45(s,1H),2.17(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.73(d,J=11.4Hz,2H),1.63(s,1H),1.55(s,1H),1.12-0.99(m,6H).
实施例91 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A91)
1H NMR(500MHz,Chloroform)δ9.33(s,1H),8.28(s,1H),7.46(d,J=15.1Hz,2H),7.35(s,1H),7.10(s,1H),7.03(s,1H),6.79(s,1H),6.12(s,1H),5.28(s,1H),4.95(s,1H),4.31(s,1H),3.45(s,1H),3.35(s,1H),2.75(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.70(d,J=19.2Hz,2H),1.44(s,1H),1.36-1.32(m,9H),0.99-0.85(m,6H).
实施例92 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A92)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),7.51(d,J=17.6Hz,2H),7.37(s,1H),7.12(s,1H),7.06(s,1H),6.50(s,1H),6.00(s,1H),5.60(s,1H),5.50(s,1H),5.00(s,1H),4.68(s,1H),3.45(s,1H),3.35(s,1H),3.29(s,1H),2.71(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.97-1.91(m,3H),1.70(t,J=9.1Hz,3H),1.59-1.55(m,2H),1.50(dd,J=10.4,1.1Hz,4H),1.43-1.38(m,2H),1.13-1.00(m,6H).
实施例93 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A93)
1H NMR(500MHz,Chloroform)δ8.63(s,1H),7.56(s,1H),7.46(d,J=25.5Hz,2H),7.29-7.24(m,2H),7.24-7.17(m,3H),7.17-7.06(m,3H),6.14(s,1H),5.63(s,1H),5.02(d,J=15.0Hz,2H),4.43(s,1H),4.37(s,1H),4.30(s,1H),3.24(d,J=17.4Hz,2H),2.81(s,1H),2.21(s,1H),2.08-2.04(m,2H),1.85(s,1H),1.77(t,J=13.2Hz,3H),1.51(s,1H),1.41(s,1H),1.04-0.90(m,6H).
实施例94 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A94)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),8.13(s,1H),7.49(s,1H),7.41(s,1H),7.37(s,1H),7.12(s,1H),7.04(s,1H),5.95(s,1H),5.30(d,J=18.0Hz,2H),4.86(s,1H),4.51(s,1H),3.23(d,J=15.7Hz,2H),2.45(s,1H),2.19(s,1H),2.08-2.04(m,2H),1.96(s,1H),1.75(s,1H),1.69(d,J=8.0Hz,2H),1.51(s,1H),1.36-1.27(m,10H),1.12-0.99(m,6H).
实施例95 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1H-吲哚-2-羧酰胺(A95)
1H NMR(500MHz,Chloroform)δ9.04(s,1H),8.28(s,1H),7.50(d,J=31.2Hz,2H),7.38(s,1H),7.13(s,1H),7.06(s,1H),6.19(s,1H),5.81(s,1H),5.63(s,1H),4.78(s,1H),4.59(s,1H),3.94(s,1H),3.24(d,J=18.2Hz,2H),2.35(s,1H),2.13-2.04(m,4H),2.00(s,1H),1.83-1.60(m,8H),1.57(s,1H),1.52-1.46(m,2H),1.45-1.41(m,2H),1.33(s,1H),1.13-1.01(m,6H).
实施例96 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A96)
1H NMR(500MHz,Chloroform)δ7.74(s,1H),7.42(s,1H),7.36-7.26(m,4H),7.23(s,1H),7.17(s,1H),7.07(s,1H),6.96(s,1H),6.46(s,1H),6.22(s,1H),5.75(s,1H),5.06(s,1H),4.63(s,1H),4.46(d,J=17.5Hz,2H),4.34(s,1H),3.45(s,1H),3.35(s,1H),3.28(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.93(s,1H),1.67(s,1H),1.55(s,1H),1.19(s,1H),1.07-0.94(m,6H).
实施例97 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A97)
1H NMR(500MHz,Chloroform)δ8.17(s,1H),7.45(d,J=28.3Hz,2H),7.22(s,1H),7.15(s,1H),6.41(s,1H),6.00(s,1H),5.96(s,1H),4.94(s,1H),4.55(s,1H),3.45(s,1H),3.35(s,1H),2.53(s,1H),2.18(s,1H),2.13-2.02(m,2H),1.93(s,1H),1.76(s,1H),1.65(s,1H),1.35-1.31(m,9H),1.25(s,1H),1.07-0.94(m,6H).
实施例98 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A98)
1H NMR(500MHz,Chloroform)δ7.59(s,4H),7.55-7.39(m,12H),7.22(s,4H),7.15(s,4H),6.04(s,4H),5.94(s,4H),5.89(s,4H),4.87(s,4H),4.48(s,4H),3.80(s,4H),3.45(s,4H),3.35(s,3H),2.58(s,4H),2.18(s,4H),2.11-2.04(m,8H),1.95-1.88(m,19H),1.87(t,J=3.1Hz,4H),1.75(d,J=29.9Hz,6H),1.71(d,J=3.3Hz,2H),1.69-1.64(m,8H),1.62(s,3H),1.59-1.51(m,8H),1.06-0.93(m,24H).
实施例99 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A99)
1H NMR(500MHz,Chloroform)δ7.58(s,1H),7.52(d,J=13.8Hz,2H),7.38-7.32(m,2H),7.30(s,1H),7.26(s,1H),7.23-7.16(m,3H),6.21(s,1H),5.77(s,1H),5.68(s,1H),4.86(s,1H),4.82(s,1H),4.56(s,1H),4.37(s,1H),4.33(s,1H),3.24(d,J=17.0Hz,2H),2.63(s,1H),2.05(t,J=5.4Hz,3H),1.82(s,1H),1.75(s,1H),1.60(d,J=3.4Hz,2H),1.48(s,1H),1.39(s,1H),1.09-1.00(m,6H).
实施例100 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A100)
1H NMR(500MHz,Chloroform)δ7.58(s,1H),7.52(d,J=13.8Hz,2H),7.38-7.32(m,2H),7.30(s,1H),7.26(s,1H),7.23-7.16(m,3H),6.21(s,1H),5.77(s,1H),5.68(s,1H),4.86(s,1H),4.82(s,1H),4.56(s,1H),4.37(s,1H),4.33(s,1H),3.24(d,J=17.0Hz,2H),2.63(s,1H),2.05(t,J=5.4Hz,3H),1.82(s,1H),1.75(s,1H),1.60(d,J=3.4Hz,2H),1.48(s,1H),1.39(s,1H),1.09-1.00(m,6H).
实施例101 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并呋喃-2-羧酰胺(A101)
1H NMR(500MHz,Chloroform)δ7.59(s,1H),7.48(d,J=9.6Hz,2H),7.20(s,1H),7.14(s,1H),5.80(s,1H),5.26(s,1H),5.11(d,J=5.2Hz,2H),4.91(s,1H),3.81(s,1H),3.24(d,J=17.3Hz,2H),2.61(s,1H),2.09-2.02(m,4H),1.95-1.87(m,2H),1.84(s,1H),1.77(s,1H),1.69(s,1H),1.58(d,J=5.5Hz,2H),1.51-1.44(m,4H),1.26-1.22(m,4H),1.08-0.95(m,6H).
实施例102 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A102)
1H NMR(500MHz,Chloroform)δ8.47(s,1H),7.91(s,1H),7.78(s,1H),7.33(d,J=6.1Hz,2H),7.28-7.17(m,5H),6.42(s,1H),6.05(s,1H),5.73(s,1H),5.38(s,1H),5.27(s,1H),4.46(s,1H),4.36(d,J=16.9Hz,2H),3.45(s,1H),3.35(s,1H),2.67(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.82(s,1H),1.70(s,1H),1.52(s,1H),1.10-0.96(m,6H).
实施例103 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A103)
1H NMR(500MHz,Chloroform)δ8.37(s,1H),7.89(s,1H),7.73(s,1H),7.30(d,J=2.2Hz,2H),6.58(s,1H),6.03(s,1H),5.61(s,1H),5.53(s,1H),5.02(s,1H),4.70(s,1H),3.45(s,1H),3.35(s,1H),2.69(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.93(s,1H),1.69(d,J=8.4Hz,2H),1.49(s,1H),1.32-1.28(m,9H),1.10-1.02(m,6H).
实施例104 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A104)
1H NMR(500MHz,Chloroform)δ8.63(s,1H),7.91(s,1H),7.74(s,1H),7.34-7.30(m,2H),6.18(d,J=11.5Hz,2H),6.02(s,1H),4.62(s,1H),4.48(s,1H),3.45(s,1H),3.35(s,1H),3.27(s,1H),2.56(s,1H),2.19(s,1H),2.11-2.05(m,3H),1.92(s,1H),1.83-1.70(m,3H),1.69(s,1H),1.59-1.54(m,3H),1.50(t,J=6.7Hz,3H),1.42-1.37(m,2H),1.12-0.98(m,6H).
实施例105 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A105)
1H NMR(500MHz,Chloroform)δ8.43(s,1H),7.93(d,J=0.7Hz,2H),7.74(s,1H),7.33(d,J=2.2Hz,2H),7.30-7.25(m,4H),7.20(s,1H),6.65(s,1H),6.05(s,1H),5.58(s,1H),4.71(s,1H),4.52(s,1H),4.40(s,1H),4.30(s,1H),3.23(d,J=15.8Hz,2H),2.73(s,1H),2.16(s,1H),2.08-2.04(m,2H),1.80(s,1H),1.69(d,J=6.6Hz,2H),1.63(s,1H),1.44(s,1H),1.35(s,1H),1.12-0.99(m,6H).
实施例106 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A106)
1H NMR(500MHz,Chloroform)δ8.39(s,1H),7.91(s,1H),7.71(s,1H),7.31(d,J=2.6Hz,2H),6.50(s,1H),5.87(s,1H),5.71(s,1H),5.57(s,1H),4.80(s,1H),4.75(s,1H),3.23(d,J=15.7Hz,2H),2.64(s,1H),2.08-2.04(m,2H),1.87(d,J=17.5Hz,2H),1.68(d,J=6.0Hz,2H),1.61(d,J=2.0Hz,2H),1.37(s,1H),1.32-1.28(m,9H),1.10-0.97(m,6H).
实施例107 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-苯并噻吩-2-羧酰胺(A107)
1H NMR(500MHz,Chloroform)δ8.30(s,15H),8.25(s,15H),7.87(s,15H),7.71(s,15H),7.30(d,J=1.3Hz,30H),6.03(s,15H),5.58(s,15H),5.39(s,15H),5.03(s,15H),4.37(s,15H),3.85(s,15H),3.24(d,J=16.7Hz,29H),2.67(s,11H),2.57(s,13H),2.08-2.04(m,30H),1.96-1.90(m,46H),1.86(s,15H),1.79(s,12H),1.76-1.53(m,169H),1.58(d,J=5.6Hz,3H),1.05-0.92(m,93H).
实施例108 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A108)
1H NMR(500MHz,Chloroform)δ7.39(d,J=5.1Hz,10H),7.31-7.22(m,12H),7.22-7.06(m,35H),5.99(s,5H),5.29(s,5H),4.40(d,J=4.6Hz,10H),4.30(d,J=5.3Hz,1H),4.24(d,J=52.5Hz,9H),3.68-3.64(m,15H),3.58(s,5H),3.45(s,5H),2.78(s,5H),2.17(s,3H),2.15-1.95(m,17H),1.89(s,4H),1.81(s,5H),1.62(s,5H),1.48(s,4H),1.07-0.94(m,31H).
实施例109 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A109)
1H NMR(500MHz,Chloroform)δ8.20(s,1H),7.48(s,1H),7.27(d,J=17.1Hz,2H),7.18(d,J=7.0Hz,2H),6.13(s,1H),5.90(s,1H),5.38(s,1H),5.08(s,1H),4.65(s,1H),3.79-3.75(m,3H),3.45(s,1H),3.35(s,1H),2.81(s,1H),2.17(s,1H),2.13-2.02(m,2H),1.93(s,1H),1.67(s,1H),1.60(s,1H),1.55(s,1H),1.34-1.30(m,9H),1.13-1.00(m,6H).
实施例110 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A110)
1H NMR(500MHz,Chloroform)δ7.37(s,3H),7.28(d,J=4.7Hz,6H),7.19(d,J=11.4Hz,6H),6.24(s,3H),5.90(s,3H),5.81(s,3H),5.30(s,3H),4.90(s,3H),4.68(s,3H),3.90-3.86(m,9H),3.45(s,3H),3.37-3.33(m,5H),2.70(s,3H),2.19(s,3H),2.12-2.04(m,6H),1.93(s,3H),1.86-1.76(m,9H),1.71-1.60(m,11H),1.60-1.54(m,1H),1.51(dd,J=18.4,1.5Hz,11H),1.44-1.38(m,6H),1.08-0.95(m,18H).
实施例111 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A111)
1H NMR(500MHz,Chloroform)δ7.62(s,1H),7.34(s,1H),7.30-7.17(m,8H),6.58(s,1H),6.10(s,1H),5.61(s,1H),5.41(s,1H),4.83(s,1H),4.48(s,1H),4.37(s,1H),4.32(s,1H),3.76-3.72(m,3H),3.24(d,J=17.6Hz,2H),2.57(s,1H),2.08-2.04(m,2H),1.80(s,1H),1.76(s,1H),1.71-1.65(m,2H),1.56(d,J=15.2Hz,2H),1.21(s,1H),1.10-0.97(m,6H).
实施例112 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A112)
1H NMR(500MHz,Chloroform)δ7.57(s,1H),7.51(s,1H),7.31(s,1H),7.25(s,1H),7.18(d,J=5.1Hz,2H),5.92(s,1H),5.59(s,1H),5.43(s,1H),4.99(s,1H),4.47(s,1H),3.74-3.70(m,3H),3.24(d,J=16.8Hz,2H),2.71(s,1H),2.41(s,1H),2.08-2.04(m,2H),1.76(dd,J=34.2,16.8Hz,4H),1.55(s,1H),1.45(s,1H),1.30-1.26(m,9H),1.09-0.96(m,6H).
实施例113 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-1-甲基-1H-吲哚-2-羧酰胺(A113)
1H NMR(500MHz,Chloroform)δ7.57(s,1H),7.51(s,1H),7.31(s,1H),7.25(s,1H),7.18(d,J=5.1Hz,2H),5.92(s,1H),5.59(s,1H),5.43(s,1H),4.99(s,1H),4.47(s,1H),3.74-3.70(m,3H),3.24(d,J=16.8Hz,2H),2.71(s,1H),2.41(s,1H),2.08-2.04(m,2H),1.76(dd,J=34.2,16.8Hz,4H),1.55(s,1H),1.45(s,1H),1.30-1.26(m,9H),1.09-0.96(m,6H).
实施例114 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A114)
1H NMR(500MHz,Chloroform)δ9.48(s,5H),7.69(s,5H),7.37(s,5H),7.29(d,J=6.5Hz,3H),7.28-7.15(m,23H),7.06(s,5H),6.19(s,5H),5.64(s,5H),5.49(s,5H),5.18(s,5H),4.42(s,5H),4.35(d,J=14.2Hz,10H),3.45(s,5H),3.35(d,J=1.5Hz,9H),3.05(s,5H),2.19(s,4H),2.09-2.05(m,10H),1.92(s,4H),1.68(s,5H),1.58(s,5H),1.52(s,5H),1.02-0.89(m,31H).
实施例115 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A115)
1H NMR(500MHz,Chloroform)δ8.36(s,1H),7.60(s,1H),7.40(s,1H),7.06(s,1H),6.45(s,1H),6.04(s,1H),5.52(d,J=2.2Hz,2H),4.99(s,1H),4.68(s,1H),3.45(s,1H),3.35(s,1H),2.72(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.93(s,1H),1.70(d,J=9.3Hz,2H),1.49(s,1H),1.32-1.28(m,9H),1.11-1.02(m,6H).
实施例116 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A116)
1H NMR(500MHz,Chloroform)δ9.33(s,1H),8.27(s,1H),7.54(s,1H),7.37(s,1H),7.03(s,1H),6.84(s,1H),6.14(s,1H),5.29(s,1H),4.95(s,1H),4.31(s,1H),3.83(s,1H),3.45(s,1H),3.35(s,1H),2.73(s,1H),2.19(s,1H),2.09-2.05(m,2H),2.05-1.90(m,3H),1.72(s,1H),1.70-1.44(m,9H),1.44(d,J=5.3Hz,1H),0.98-0.85(m,6H).
实施例117 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A117)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),7.67(s,1H),7.42(s,1H),7.29-7.22(m,4H),7.19(s,1H),7.10(d,J=11.4Hz,2H),6.65(s,1H),5.62(s,1H),5.55(s,1H),4.99(s,1H),4.48(s,1H),4.37(s,1H),4.33(s,1H),3.24(d,J=16.8Hz,2H),2.56(s,1H),2.45(s,1H),2.08-2.04(m,2H),1.80(d,J=3.6Hz,2H),1.72(d,J=14.6Hz,2H),1.55(s,1H),1.46(s,1H),1.10-0.97(m,6H).
实施例118 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A118)
1H NMR(500MHz,Chloroform)δ8.59(s,1H),7.55(s,1H),7.41(s,1H),7.05(s,1H),6.20(s,1H),5.74(s,1H),5.41(s,1H),4.71(s,1H),4.48(s,1H),3.24(d,J=17.3Hz,2H),2.48(s,1H),2.06(t,J=2.1Hz,3H),1.86-1.74(m,3H),1.68(s,1H),1.58(s,1H),1.53(s,1H),1.32-1.28(m,9H),1.15-1.01(m,6H).
实施例119 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A119)
1H NMR(500MHz,Chloroform)δ8.63(s,1H),8.33(s,1H),7.58(s,1H),7.40(s,1H),7.07(s,1H),6.32(s,1H),5.80(s,1H),5.52(s,1H),4.79(s,1H),4.59(s,1H),3.96(s,1H),3.24(d,J=17.9Hz,2H),2.36(s,1H),2.15-2.08(m,2H),2.08-2.04(m,2H),2.00(s,1H),1.74-1.68(m,5H),1.68-1.60(m,3H),1.60-1.50(m,5H),1.33(s,1H),1.13-1.01(m,6H).
实施例120 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A120)
1H NMR(500MHz,Chloroform)δ8.79(s,1H),8.05(s,1H),8.01(s,1H),7.64(d,J=1.5Hz,2H),7.36-7.25(m,4H),7.20(s,1H),5.82(s,1H),5.78(s,1H),5.24(s,1H),4.97(s,1H),4.68(s,1H),4.36(s,1H),4.23(s,1H),3.68(s,1H),3.45(s,1H),3.35(s,1H),2.21(s,1H),2.09-2.05(m,2H),1.90(d,J=15.7Hz,2H),1.76(s,1H),1.65(s,1H),1.45(s,1H),1.10-0.97(m,6H).
实施例121 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A121)
1H NMR(500MHz,Chloroform)δ9.24(s,1H),8.11(d,J=7.7Hz,2H),7.85(s,1H),7.65(d,J=1.9Hz,2H),6.22(s,1H),6.11(s,1H),5.66(s,1H),4.77(s,1H),4.62(s,1H),3.45(s,1H),3.35(s,1H),2.79(s,1H),2.17(s,1H),2.13-2.02(m,2H),1.92(s,1H),1.67(d,J=2.5Hz,2H),1.51(s,1H),1.34-1.30(m,9H),1.11-1.02(m,6H).
实施例122 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A122)
1H NMR(500MHz,Chloroform)δ9.29(s,1H),8.09(d,J=18.4Hz,2H),7.60(d,J=2.0Hz,2H),6.27(s,1H),6.23(s,1H),5.90(s,1H),5.24(s,1H),4.80(s,1H),4.70(s,1H),3.45(s,1H),3.35(d,J=1.2Hz,2H),2.58(s,1H),2.18(s,1H),2.11-2.03(m,2H),1.93(s,1H),1.86-1.71(m,3H),1.71-1.60(m,4H),1.55-1.46(m,4H),1.44-1.39(m,2H),1.09-0.96(m,6H).
实施例123 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A123)
1H NMR(500MHz,Chloroform)δ9.35(s,1H),8.12(s,1H),7.95(s,1H),7.64(d,J=15.8Hz,2H),7.33-7.26(m,3H),7.26-7.21(m,2H),6.55(s,1H),6.29(s,1H),5.62(d,J=10.0Hz,2H),4.84(s,1H),4.54(s,1H),4.16(d,J=16.2Hz,2H),3.24(d,J=17.4Hz,2H),2.98(s,1H),2.32(s,1H),2.10-2.04(m,3H),1.85(s,1H),1.78(s,1H),1.71(s,1H),1.59(s,1H),1.45(s,1H),1.13-1.00(m,6H).
实施例124 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A124)
1H NMR(500MHz,Chloroform)δ9.23(s,1H),8.12(d,J=11.8Hz,2H),7.65(d,J=2.9Hz,2H),6.31(s,1H),6.08(s,1H),5.70(s,1H),5.63(s,1H),4.89(s,1H),4.62(s,1H),3.24(d,J=17.3Hz,2H),2.62(s,1H),2.04(t,J=12.6Hz,3H),1.80(s,1H),1.76-1.69(m,3H),1.51(s,1H),1.40(s,1H),1.33-1.29(m,9H),1.12-0.99(m,6H).
实施例125 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹喔啉-2-羧酰胺(A125)
1H NMR(500MHz,Chloroform)δ9.32(s,1H),8.97(s,1H),8.11(d,J=3.7Hz,2H),7.65(d,J=2.2Hz,2H),5.73(s,1H),5.60(s,1H),5.56(s,1H),4.72(s,1H),4.51(s,1H),3.31-3.20(m,3H),2.59(s,1H),2.08-2.00(m,5H),1.81(s,1H),1.69(d,J=9.0Hz,2H),1.62(s,1H),1.60-1.54(m,3H),1.53-1.42(m,3H),1.39(dd,J=11.3,3.2Hz,4H),1.09-0.96(m,6H).
实施例126 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A126)
1H NMR(500MHz,Chloroform)δ8.47(s,1H),8.14(s,1H),7.80(s,1H),7.68(s,1H),7.52(s,1H),7.47(s,1H),7.30-7.26(m,1H),7.26-7.17(m,5H),6.50(s,1H),6.42(s,1H),6.10(s,1H),5.27(s,1H),4.65(d,J=5.3Hz,2H),4.40(s,1H),4.32(s,1H),3.45(s,1H),3.35(s,1H),2.65(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.93(s,1H),1.69(s,1H),1.59(d,J=10.7Hz,2H),1.13-1.00(m,7H).
实施例127 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A127)
1H NMR(500MHz,Chloroform)δ8.36(s,1H),8.14(s,1H),7.77(s,1H),7.69(s,1H),7.46(s,1H),7.40(s,1H),6.36(s,1H),6.13(s,1H),6.02(s,1H),5.67(s,1H),4.93(s,1H),4.61(s,1H),3.45(s,1H),3.35(s,1H),2.63(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.73(d,J=1.3Hz,2H),1.52(s,1H),1.33-1.29(m,9H),1.09-1.03(m,6H).
实施例128 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A128)
1H NMR(500MHz,Chloroform)δ9.46(s,1H),8.44(s,1H),8.17(s,1H),7.80(s,1H),7.71(s,1H),7.47(d,J=10.8Hz,2H),5.88(s,1H),5.82(s,1H),5.18(s,1H),4.96(s,1H),4.52(s,1H),3.74(s,1H),3.45(s,1H),3.35(s,1H),2.64(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.95(t,J=7.9Hz,3H),1.71(s,1H),1.57(tt,J=16.6,2.2Hz,9H),1.44(s,1H),1.11-0.98(m,6H).
实施例129 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-4-甲基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A129)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),8.18(s,1H),7.81(s,1H),7.72(s,1H),7.47(d,J=14.9Hz,2H),7.29-7.21(m,4H),7.19(s,1H),6.66(s,1H),6.36(s,1H),5.90(s,1H),5.60(s,1H),5.00(s,1H),4.50(s,1H),4.34(d,J=14.6Hz,2H),3.24(d,J=16.9Hz,2H),2.47(d,J=1.9Hz,2H),2.08-2.04(m,2H),1.80(s,1H),1.77-1.69(m,3H),1.55(s,1H),1.46(s,1H),1.09-0.96(m,6H).
实施例130 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A130)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),8.17(s,1H),7.81(s,1H),7.71(s,1H),7.48(d,J=2.3Hz,2H),5.90(s,1H),5.74(s,1H),5.54(s,1H),5.27(s,1H),5.13(s,1H),4.51(s,1H),3.24(d,J=17.6Hz,2H),2.61(s,1H),2.08-2.04(m,2H),1.89-1.64(m,5H),1.48(d,J=18.1Hz,2H),1.33-1.29(m,9H),1.09-0.96(m,6H).
实施例131 N-((S)-3-环己基-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代戊-2-基)-喹啉-2-羧酰胺(A131)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),8.17(s,1H),7.81(s,1H),7.71(s,1H),7.49(d,J=4.2Hz,2H),6.05(s,1H),5.83(s,1H),5.54(s,1H),5.39(s,1H),5.11(s,1H),4.52(s,1H),3.30-3.20(m,3H),2.61(s,1H),2.08-2.04(m,2H),2.02-1.90(m,2H),1.87-1.77(m,3H),1.75-1.68(m,5H),1.55-1.44(m,5H),1.44-1.39(m,2H),1.09-0.96(m,6H).
实施例132 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A132)
1H NMR(500MHz,Chloroform)δ7.39-7.29(m,2H),7.29-7.20(m,7H),7.18(s,1H),6.65(s,1H),6.45(d,J=4.2Hz,2H),6.24(s,1H),6.13(d,J=3.8Hz,2H),6.03(s,1H),5.47(s,1H),4.93(d,J=16.9Hz,2H),4.66(s,1H),4.42(s,1H),4.33(s,1H),3.66(s,1H),3.45(s,1H),3.40-3.30(m,3H),3.18(s,1H),2.96(d,J=11.1Hz,2H),2.18(s,1H),2.12-2.02(m,2H),1.93(s,1H).
实施例133 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A133)
1H NMR(500MHz,Chloroform)δ7.27-7.21(m,2H),7.21-7.11(m,3H),7.10(s,1H),6.49(s,1H),6.31(s,1H),6.20(s,1H),6.13(s,1H),5.96(d,J=15.6Hz,2H),5.67(s,1H),4.90(s,1H),4.85(s,1H),4.66(s,1H),4.14(s,1H),3.69(s,1H),3.42(d,J=26.2Hz,2H),3.33(d,J=15.0Hz,2H),3.23(s,1H),2.83(s,1H),2.68(s,1H),2.17(s,1H),2.09-2.05(m,2H),1.91(s,1H),1.36-1.32(m,10H).
实施例134 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A134)
1H NMR(500MHz,Chloroform)δ8.76(s,5H),8.45(s,5H),7.29-7.23(m,10H),7.16(s,5H),7.14-7.05(m,10H),6.44(s,5H),6.29(s,5H),6.03(s,5H),5.93(d,J=10.5Hz,10H),5.21(s,5H),5.05(s,5H),4.64(d,J=18.2Hz,10H),3.67(s,4H),3.48-3.46(m,2H),3.43(t,J=11.4Hz,14H),3.37(dt,J=43.5,18.6Hz,29H),3.05(s,5H),2.86(s,5H),2.19(s,5H),2.09-2.05(m,10H),1.95-1.86(m,15H),1.72-1.64(m,15H),1.56-1.52(m,9H),1.50(s,6H),1.45-1.40(m,10H).
实施例135 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A135)
1H NMR(500MHz,Chloroform)δ7.82(s,1H),7.30-7.22(m,4H),7.21-7.07(m,6H),6.48(s,1H),6.29(s,1H),6.16(s,1H),6.09(s,1H),5.96(d,J=19.6Hz,2H),5.31(s,1H),4.94(s,1H),4.66(s,1H),4.61(s,1H),4.41(s,1H),4.33(s,1H),3.72(s,1H),3.51-3.12(m,5H),3.24(d,J=16.9Hz,2H),3.24(d,J=16.9Hz,2H),2.96(s,1H),2.43(s,1H),2.19(s,1H),2.08-2.03(m,2H),1.80(s,1H),1.73(s,1H),1.55(s,1H).
实施例136 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A136)
1H NMR(500MHz,Chloroform)δ7.32-7.26(m,2H),7.18(s,1H),7.15-7.08(m,2H),6.45(s,1H),6.28(s,1H),6.02(s,1H),5.94(d,J=3.0Hz,2H),5.80(s,1H),5.63(s,1H),5.14(s,1H),4.66(s,1H),4.55(s,1H),3.91(s,1H),3.65(s,1H),3.49-3.10(m,5H),3.25(t,J=14.8Hz,3H),3.25(t,J=14.8Hz,3H),3.01(s,1H),2.53(s,1H),2.08-2.04(m,2H),1.94(s,1H),1.80(d,J=1.0Hz,2H),1.73(s,1H),1.34-1.30(m,9H).
实施例137 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氯-3,8a-二氢-2H-苯并吡喃-3-羧酰胺(A137)
1H NMR(500MHz,Chloroform)δ7.30-7.26(m,1H),7.26-7.14(m,4H),6.52(s,1H),6.47(s,1H),6.14(s,1H),6.04(s,1H),5.96(s,1H),5.87(d,J=16.5Hz,2H),5.02(d,J=1.5Hz,2H),4.66(s,1H),4.48(s,1H),3.68(s,1H),3.51(s,1H),3.40(s,1H),3.31(d,J=10.7Hz,2H),3.24(d,J=17.3Hz,2H),3.01(d,J=17.6Hz,2H),2.12-2.04(m,5H),1.96(s,1H),1.82(s,1H),1.75(s,1H),1.71-1.64(m,3H),1.56-1.52(m,2H),1.48(s,1H),1.45-1.40(m,2H).
实施例138 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A138)
1H NMR(500MHz,Chloroform)δ7.52(s,1H),7.43-7.23(m,8H),7.23-7.19(m,3H),7.16(s,1H),6.92(s,1H),6.04(s,1H),5.92-5.88(m,2H),5.21(s,1H),4.83(s,1H),4.75(s,1H),4.44(s,1H),4.38(s,1H),3.45(s,1H),3.36(d,J=13.2Hz,2H),2.95(s,1H),2.80(s,1H),2.18(s,1H),2.09-2.05(m,2H),1.92(s,1H).
实施例139 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A139)
1H NMR(500MHz,Chloroform)δ7.48(s,1H),7.32(s,1H),7.29-7.23(m,2H),7.23-7.14(m,3H),6.91(s,1H),5.95(s,1H),5.92-5.88(m,2H),4.76(d,J=1.1Hz,2H),4.71(s,1H),3.46(d,J=12.3Hz,2H),3.35(s,1H),3.08(s,1H),2.99(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.93(s,1H),1.40-1.36(m,9H).
实施例140 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A140)
1H NMR(500MHz,Chloroform)δ7.30(dd,J=21.6,15.7Hz,4H),7.28-7.23(m,1H),7.28-7.14(m,4H),6.89(s,1H),6.05(s,1H),5.92-5.88(m,2H),5.08(s,1H),4.75(d,J=16.1Hz,2H),3.59(s,1H),3.45(d,J=2.5Hz,2H),3.35(s,1H),3.12(s,1H),2.99(s,1H),2.19(s,1H),2.10-2.04(m,4H),1.93(s,1H),1.81-1.70(m,3H),1.58-1.54(m,2H),1.51(s,1H),1.47-1.42(m,2H).
实施例141 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A141)
1H NMR(500MHz,Chloroform)δ7.41(s,1H),7.36(s,1H),10.00-7.08(m,14H),6.54(s,1H),6.07(s,1H),5.92-5.88(m,2H),5.10(s,1H),4.42(s,1H),4.37(d,J=6.5Hz,2H),4.30(s,1H),3.60(s,1H),3.25(t,J=13.9Hz,3H),3.03(s,1H),2.73(s,1H),2.09-2.03(m,2H),1.79(d,J=5.2Hz,2H),1.73(s,1H),1.57(s,1H).
实施例142 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A142)
1H NMR(500MHz,Chloroform)δ8.38(s,28H),7.44(s,29H),7.30-7.23(m,86H),7.23-7.15(m,82H),7.15(d,J=1.8Hz,4H),6.98(s,29H),5.92-5.85(m,85H),5.21(s,28H),5.00(s,27H),4.81(s,28H),4.66(s,28H),3.26(t,J=21.5Hz,87H),2.91(s,30H),2.78(s,26H),2.21(s,20H),2.11-2.02(m,61H),2.00(s,21H),1.83(s,25H),1.77(s,21H),1.32-1.28(m,251H).
实施例143 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A143)
1H NMR(500MHz,Chloroform)δ8.29(s,1H),7.48(s,1H),7.38(s,1H),7.28-7.23(m,2H),7.23-7.11(m,3H),6.94(s,1H),6.09(s,1H),5.92-5.88(m,2H),5.06(s,1H),4.91(s,1H),4.73(s,1H),4.38(s,1H),3.36(s,1H),3.31-3.20(m,3H),3.07(s,1H),2.85(s,1H),2.08-2.03(m,4H),1.88(s,1H),1.81(s,1H),1.78-1.69(m,3H),1.67(s,1H),1.58(s,1H),1.51(t,J=7.6Hz,3H),1.43-1.39(m,2H).
实施例144 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)苯[d][1,3]间二氧杂环戊烯-5-羧酰胺(A144)
1H NMR(500MHz,Chloroform)δ8.29(s,1H),7.48(s,1H),7.38(s,1H),7.28-7.23(m,2H),7.23-7.11(m,3H),6.94(s,1H),6.09(s,1H),5.92-5.88(m,2H),5.06(s,1H),4.91(s,1H),4.73(s,1H),4.38(s,1H),3.36(s,1H),3.31-3.20(m,3H),3.07(s,1H),2.85(s,1H),2.08-2.03(m,4H),1.88(s,1H),1.81(s,1H),1.78-1.69(m,3H),1.67(s,1H),1.58(s,1H),1.51(t,J=7.6Hz,3H),1.43-1.39(m,2H).
实施例145 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟烟酰胺(A145)
1H NMR(500MHz,Chloroform)δ8.60(d,J=2.3Hz,2H),7.83(s,1H),7.23(d,J=6.4Hz,1H),7.22-7.08(m,5H),5.97(s,1H),5.48(s,1H),4.88(s,1H),4.38(s,1H),4.01(s,1H),3.45(s,1H),3.35(s,1H),3.26(s,1H),2.96(s,1H),2.69(s,1H),2.40(s,1H),2.16(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.32-1.28(m,10H).
实施例146 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟烟酰胺(A146)
1H NMR(500MHz,Chloroform)δ8.82(s,1H),8.50(s,1H),7.89(s,1H),7.31-7.24(m,4H),7.17(s,1H),6.22(s,1H),5.95(s,1H),5.47(s,1H),5.14(s,1H),4.38(s,1H),3.45(s,1H),3.37(d,J=16.6Hz,2H),3.29(s,1H),2.86(s,1H),2.47(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.93(s,1H),1.91-1.79(m,2H),1.70(s,1H),1.58-1.51(m,4H),1.50(s,1H),1.45-1.40(m,2H).
实施例147 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟烟酰胺(A147)
1H NMR(500MHz,Chloroform)δ8.80(s,1H),8.58(s,1H),7.99(s,1H),7.41-7.32(m,2H),7.32-7.18(m,6H),7.16(s,1H),7.09(s,1H),6.51(s,1H),6.23(s,1H),5.85(s,1H),4.87(s,1H),4.36(s,1H),4.30(d,J=5.9Hz,2H),3.24(d,J=15.2Hz,2H),3.09(s,1H),2.82(s,1H),2.57(s,1H),2.08-2.04(m,2H),1.98(s,1H),1.82(s,1H),1.76(s,1H),1.65(s,1H).
实施例148 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟烟酰胺(A148)
1H NMR(500MHz,Chloroform)δ8.82(s,1H),8.52(s,1H),8.05(s,1H),7.30-7.22(m,4H),7.15(s,1H),6.03(s,1H),5.79(s,1H),5.01(s,1H),4.84(s,1H),4.27(s,1H),3.36(s,1H),3.24(d,J=14.9Hz,2H),2.95(s,1H),2.72(s,1H),2.07(t,J=5.5Hz,3H),1.85(s,1H),1.78(s,1H),1.70(s,1H),1.32-1.28(m,9H).
实施例149 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟烟酰胺(A149)
1H NMR(500MHz,Chloroform)δ8.86(s,7H),8.52(s,7H),7.93(s,7H),7.42(s,7H),7.24-7.19(m,14H),7.14(s,7H),7.12-7.04(m,14H),6.15(d,J=16.5Hz,14H),5.79(s,7H),4.89(s,7H),4.62(s,7H),3.87(s,7H),3.27(t,J=22.0Hz,22H),3.17(t,J=12.5Hz,1H),3.11(d,J=17.0Hz,14H),2.12(s,5H),2.10-2.01(m,16H),2.01-1.94(m,14H),1.87(s,5H),1.80(s,5H),1.67-1.58(m,67H).
实施例150 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A150)
1H NMR(500MHz,Chloroform)δ7.52(s,5H),7.32-7.14(m,55H),7.13(t,J=1.5Hz,1H),7.07(s,5H),6.09(s,5H),6.01(s,5H),5.64(s,5H),5.02(s,5H),4.84(s,5H),4.36(s,5H),4.29(s,5H),3.89-3.85(m,15H),3.45(s,5H),3.35(s,4H),3.17(s,4H),3.11(s,5H),2.93(s,5H),2.19(s,4H),2.10-2.04(m,10H),1.92(s,4H).
实施例151 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A151)
1H NMR(500MHz,Chloroform)δ7.86(s,1H),7.42(s,1H),10.00-7.19(m,6H),7.17(s,1H),7.05(s,1H),5.92(d,J=15.2Hz,2H),5.77(s,1H),5.06(s,1H),4.87(s,1H),3.89-3.85(m,3H),3.45(s,1H),3.35(s,1H),3.18(s,1H),2.88(d,J=18.2Hz,2H),2.17(s,1H),2.13-2.02(m,2H),1.92(s,1H),1.34-1.30(m,9H).
实施例152 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A152)
1H NMR(500MHz,Chloroform)δ7.28-7.17(m,5H),7.15(s,1H),7.08(s,1H),6.04(s,1H),5.89(s,1H),4.77(s,1H),4.30(s,1H),4.02-3.98(m,3H),3.83(s,1H),3.71(s,1H),3.45(s,1H),3.35(s,1H),3.30(s,1H),3.05(s,1H),2.97(s,1H),2.65(s,1H),2.20(s,1H),2.09-2.05(m,2H),2.04-2.00(m,1H),1.91(s,1H),1.67-1.55(m,7H).
实施例153 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A153)
1H NMR(500MHz,Chloroform)δ8.58(s,7H),8.29(s,7H),7.42(s,7H),7.32-7.24(m,28H),7.18(dt,J=57.0,25.2Hz,40H),7.08-7.07(m,2H),6.51(s,7H),6.01(s,7H),5.10(s,7H),4.81(s,7H),4.38(s,7H),4.32(s,7H),3.93-3.89(m,21H),3.30(d,J=53.3Hz,17H),3.21(s,3H),3.21(s,6H),2.99(s,7H),2.17(s,6H),2.11-2.01(m,14H),1.76(d,J=12.9Hz,12H),1.68(s,5H),1.42(s,6H).
实施例154 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A154)
1H NMR(500MHz,Chloroform)δ9.02(s,1H),7.53(s,1H),7.31-7.25(m,2H),7.17(dd,J=16.8,9.4Hz,4H),6.20(s,1H),6.11(s,1H),5.60(s,1H),5.16(s,1H),4.76(s,1H),3.90-3.86(m,3H),3.24(d,J=15.4Hz,2H),3.12(s,1H),2.92(d,J=17.7Hz,2H),2.05(t,J=4.4Hz,3H),1.82(s,1H),1.76(s,1H),1.56(s,1H),1.31-1.27(m,9H).
实施例155 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1-甲基-1H-吡唑-4-羧酰胺(A155)
1H NMR(500MHz,Chloroform)δ8.38(s,1H),7.28-7.22(m,2H),7.22-7.11(m,3H),7.04(s,1H),6.62(s,1H),5.99(s,1H),4.76(s,1H),4.62(s,1H),4.30(s,1H),3.83-3.79(m,3H),3.26(dd,J=17.5,12.1Hz,4H),3.05(s,1H),3.01(s,1H),2.72(s,1H),2.20-2.13(m,3H),2.09-2.03(m,2H),1.86(s,1H),1.80(s,1H),1.72-1.66(m,3H),1.56(t,J=5.2Hz,3H),1.49(s,1H),1.46-1.41(m,2H).
实施例156 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A156)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),7.77(s,1H),7.68(s,1H),7.58(s,1H),7.40(s,1H),7.32-7.26(m,4H),7.26-7.11(m,7H),6.00(s,1H),5.04(s,1H),4.92(s,1H),4.77(s,1H),4.38(s,1H),4.30(s,1H),3.45(s,1H),3.35(s,1H),3.27(s,1H),3.11(s,1H),2.85(s,1H),2.19(s,1H),2.09-2.05(m,2H),1.92(s,1H).
实施例157 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A157)
1H NMR(500MHz,Chloroform)δ8.80(s,1H),8.37(s,1H),7.69(d,J=2.2Hz,2H),7.59(s,1H),7.28-7.21(m,2H),7.21-7.11(m,3H),6.78(s,1H),5.98(s,1H),5.45(s,1H),4.93(s,1H),4.66(s,1H),3.45(s,1H),3.35(s,1H),3.22(s,1H),2.96(d,J=29.5Hz,2H),2.19(s,1H),2.09-2.05(m,2H),1.92(s,1H),1.34-1.30(m,9H).
实施例158 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A158)
1H NMR(500MHz,Chloroform)δ8.39(s,1H),7.69(d,J=16.1Hz,2H),7.60(s,1H),7.36-7.20(m,9H),7.19(d,J=13.6Hz,2H),6.50(s,1H),6.28(s,1H),6.16(s,1H),6.10(s,1H),4.75(d,J=4.7Hz,2H),4.39(s,1H),4.30(s,1H),3.24(t,J=8.9Hz,3H),3.01(s,1H),2.72(s,1H),2.11-2.01(m,2H),1.84(s,1H),1.80(s,1H),1.73(s,1H),1.36(s,1H).
实施例159 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A159)
1H NMR(500MHz,Chloroform)δ8.41(s,1H),8.18(s,1H),7.79-7.57(m,3H),7.27-7.21(m,2H),7.21-7.10(m,3H),6.09(s,1H),5.52(s,1H),5.08(s,1H),4.74(s,1H),4.45(s,1H),3.25(t,J=9.9Hz,3H),3.01(s,1H),2.85(s,1H),2.10-2.02(m,2H),1.88(s,1H),1.81(s,1H),1.68(s,1H),1.60(s,1H),1.35-1.31(m,9H).
实施例160 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-溴咪唑并[1,2-a]吡啶-2-羧酰胺(A160)
1H NMR(500MHz,Chloroform)δ9.87(s,1H),8.26(s,1H),7.68(s,1H),7.57(d,J=11.2Hz,2H),7.27-7.21(m,2H),7.21-7.10(m,3H),6.07(s,1H),4.94(s,1H),4.78(s,1H),4.51(s,1H),3.54(s,1H),3.45(s,1H),3.24(d,J=16.2Hz,2H),3.17(s,1H),2.97(s,1H),2.92(s,1H),2.28(s,1H),2.09-2.04(m,4H),1.81(s,1H),1.74(s,1H),1.70(s,1H),1.59-1.52(m,4H),1.49(d,J=1.6Hz,2H),1.47-1.41(m,2H).
实施例161 N-((S)-1-(((S)-4-(苯基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A161)
1H NMR(500MHz,Chloroform)δ7.62(d,J=18.9Hz,2H),7.34-7.23(m,9H),7.23-7.12(m,3H),6.92(s,1H),6.17(s,1H),5.35(s,1H),5.03(s,1H),4.70(d,J=4.7Hz,2H),4.38(s,1H),4.33(s,1H),4.03(s,1H),3.35(s,1H),3.27(s,1H),3.04(s,1H),2.82(s,1H),2.17(s,1H),2.12-2.03(m,2H),1.93(s,1H).
实施例162 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A162)
1H NMR(500MHz,Chloroform)δ7.68(s,1H),7.59(s,1H),7.30-7.25(m,2H),7.22-7.16(m,2H),7.16-7.06(m,3H),6.17(s,1H),5.89(s,1H),5.84(s,1H),5.11(s,1H),4.98(s,1H),3.45(s,1H),3.35(s,1H),3.25(s,1H),3.04(s,1H),2.28(s,1H),2.19(s,1H),2.11-2.03(m,2H),1.92(s,1H),1.35-1.31(m,9H).
实施例163 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A163)
1H NMR(500MHz,Chloroform)δ7.70(s,1H),7.57(d,J=4.5Hz,2H),7.22(dd,J=17.6,7.1Hz,4H),7.18-7.07(m,3H),5.97(s,1H),5.74(s,1H),5.03(s,1H),4.50(d,J=11.0Hz,2H),4.41(s,1H),3.61(s,1H),3.45(s,1H),3.35(s,1H),3.21(s,1H),3.03(s,1H),2.80(s,1H),2.17(s,1H),2.09-2.05(m,2H),1.93-1.78(m,3H),1.71(s,1H),1.64-1.60(m,2H),1.58-1.54(m,2H),1.50(s,1H),1.48-1.42(m,2H).
实施例164 N-((S)-1-(((S)-4-(苯基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A164)
1H NMR(500MHz,Chloroform)δ7.73(s,1H),7.67(s,1H),7.38(t,J=17.9Hz,3H),7.27-7.13(m,9H),7.11(s,1H),6.99(s,1H),6.45(s,1H),5.48(s,1H),4.94(d,J=7.2Hz,2H),4.89(s,1H),4.32(s,1H),4.26(s,1H),3.42(s,1H),3.24(d,J=18.2Hz,2H),3.06(s,1H),2.92(s,1H),2.13(s,1H),2.11-2.00(m,2H),1.92(s,1H),1.86(s,1H),1.79(s,1H).
实施例165 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A165)
1H NMR(500MHz,Chloroform)δ9.34(s,4H),7.98(s,4H),7.79(s,4H),7.62(s,4H),7.54(s,4H),7.42-7.28(m,23H),7.28-7.26(m,2H),7.16(s,4H),5.87(s,4H),5.43(s,4H),5.16(s,4H),4.27(s,4H),3.33-3.20(m,12H),2.94(s,4H),2.82(s,4H),2.08-2.04(m,8H),1.96(s,3H),1.82(s,3H),1.76(s,3H),1.63(s,3H),1.33-1.29(m,36H).
实施例166 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A166)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),8.24(s,1H),7.65(s,1H),7.60(s,1H),7.53(s,1H),7.24(dd,J=20.9,2.1Hz,4H),7.16-7.04(m,3H),5.61(s,1H),5.36(s,1H),5.09(s,1H),4.63(s,1H),3.50(s,1H),3.41(s,1H),3.24(d,J=15.7Hz,2H),2.98(s,1H),2.66(s,1H),2.57(s,1H),2.27-2.16(m,2H),2.08-2.04(m,2H),1.98(s,1H),1.85(s,1H),1.78(s,1H),1.72(s,1H),1.63-1.55(m,4H),1.55-1.44(m,3H).
实施例167 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A167)
1H NMR(500MHz,Chloroform)δ9.78(s,1H),8.99(s,1H),8.23(s,1H),7.81(s,1H),7.49(d,J=90.0Hz,2H),7.40-7.38(m,4H),7.30(d,J=15.0Hz,5H),7.19(s,34H),7.14(s,4H),7.07(s,1H),6.56(s,1H),6.10(s,1H),5.29(s,1H),5.09(s,1H),4.85(s,1H),4.34(s,2H),3.63(s,21H),3.51(s,1H),3.33(s,1H),3.08(s,1H),2.65(s,1H),2.20(s,1H),2.02(s,1H),1.90(s,1H).
实施例168 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A168)
1H NMR(500MHz,Chloroform)δ8.95(s,1H),8.26(d,J=60.3Hz,2H),7.78(s,1H),7.55(s,1H),7.31-7.18(m,4H),7.16(s,1H),7.31-6.84(m,7H),6.55(d,J=16.4Hz,2H),5.97(s,1H),5.15(s,1H),4.79(s,1H),3.63(s,1H),3.51(s,1H),3.32(s,1H),3.07(s,1H),2.54(s,1H),2.21(s,1H),2.02(s,1H),1.91(s,1H),1.26(s,9H).
实施例169 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A169)
1H NMR(500MHz,Chloroform)δ8.98(s,13H),8.34(s,13H),8.22(s,14H),7.80(s,13H),7.57(s,14H),7.37-7.20(m,2H),7.18(s,14H),7.37-6.87(m,82H),6.56(s,13H),6.49(s,13H),5.99(s,13H),5.17(s,7H),4.95(s,5H),4.79(s,7H),3.64(s,6H),3.52(s,6H),3.33(s,15H),3.08(s,14H),2.55(s,5H),2.20(d,J=14.4Hz,31H),2.02(s,14H),1.88(d,J=38.0Hz,37H),1.80(s,5H),1.62(s,9H),1.37(s,27H),1.31(s,11H),1.20(s,23H).
实施例170 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A170)
1H NMR(500MHz,Chloroform)δ8.99(s,2H),8.23(s,2H),8.06(s,2H),7.81(s,2H),7.58(s,2H),7.29(d,J=15.0Hz,9H),7.19(s,1H),7.14(s,9H),7.05(d,J=24.0Hz,3H),6.56(s,2H),6.06(s,2H),5.05(s,2H),4.76(s,1H),4.34(s,4H),3.55-2.80(m,10H),3.48-2.77(m,10H),3.28-2.80(m,8H),2.87-2.77(m,1H),2.70(s,1H),2.34(s,1H),2.01(s,1H),1.91(d,J=2.6Hz,2H),1.60(s,1H).
实施例171 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A171)
1H NMR(500MHz,Chloroform)δ8.99(s,1H),8.23(s,1H),7.91(s,1H),7.81(s,1H),7.58(s,1H),7.26-7.21(m,4H),7.19(s,1H),7.26-6.88(m,6H),6.57(d,J=15.1Hz,2H),6.06(s,1H),5.06(s,1H),4.71(s,1H),3.33(s,1H),3.21(d,J=15.0Hz,2H),3.08(s,1H),2.93(s,1H),2.43(s,1H),2.39(s,1H),2.01(s,1H),1.91(d,J=1.1Hz,1H),1.58(s,13H),1.27(s,9H).
实施例172 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-1H-吲哚-5-羧酰胺(A172)
1H NMR(500MHz,Chloroform)δ8.99(s,1H),8.23(s,1H),7.81(s,1H),7.68(s,1H),7.58(s,1H),7.26-7.21(m,7H),7.19(s,1H),7.26-6.88(m,6H),6.53(d,J=28.7Hz,2H),6.50-6.48(m,5H),6.08(s,1H),5.06(s,1H),4.95(s,1H),4.70(s,1H),3.33(s,1H),3.21(d,J=15.0Hz,2H),3.08(s,1H),2.94(s,1H),2.44(d,J=13.0Hz,2H),2.19(s,2H),2.03-1.73(m,5H),1.84(s,3H),1.84(s,2H),1.60(d,J=15.4Hz,2H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例173 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A173)
1H NMR(500MHz,Chloroform)δ8.75(s,2H),8.14(s,2H),7.54(d,J=24.9Hz,4H),7.37-7.24(m,13H),7.17(s,1H),7.11(d,J=10.0Hz,11H),6.85(s,2H),6.14(s,2H),5.18(s,2H),4.86(s,1H),4.33(s,4H),3.65(s,1H),3.53(s,1H),3.28(s,4H),3.03(s,1H),2.54(s,2H),2.22(s,2H),2.02(s,2H),1.93(s,1H).
实施例174 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A174)
1H NMR(500MHz,Chloroform)δ8.73(s,1H),8.12(s,1H),7.55(d,J=25.0Hz,2H),7.51(s,3H),7.16(dd,J=31.6,6.6Hz,7H),6.56(s,1H),6.10(s,1H),5.19(s,1H),4.83(s,1H),3.65(s,1H),3.54(s,1H),3.29(s,1H),3.04(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,5H),1.27(s,9H).
实施例175 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A175)
1H NMR(500MHz,Chloroform)δ8.74(s,1H),8.08(s,1H),7.55(d,J=25.0Hz,2H),7.51(s,3H),7.19(d,J=2.2Hz,2H),7.13(d,J=10.0Hz,5H),6.44(s,1H),6.11(s,1H),5.19(s,1H),4.83(s,1H),3.67(d,J=15.7Hz,1H),3.54(s,1H),3.29(s,1H),3.04(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.74(s,1H),1.46(t,J=12.5Hz,3H),1.21(s,1H),1.11(s,1H).
实施例176 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A176)
1H NMR(500MHz,Chloroform)δ8.71(s,2H),8.61(s,2H),7.69(s,2H),7.58(s,2H),7.53(s,1H),7.33-7.20(m,12H),7.19(s,1H),7.13(d,J=10.0Hz,10H),5.84(s,2H),5.09(s,1H),4.57(s,1H),4.34(s,4H),3.29(s,1H),3.21(d,J=15.0Hz,4H),3.04(s,2H),2.73(s,1H),2.41(s,1H),2.28(s,1H),2.01(s,1H),1.91(d,J=4.5Hz,2H),1.53(s,1H).
实施例177 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A177)
1H NMR(500MHz,Chloroform)δ8.68(s,1H),8.29(s,1H),7.54(d,J=25.0Hz,2H),7.49(s,3H),7.24(s,1H),7.17(s,1H),7.11(d,J=10.0Hz,5H),6.61(s,1H),5.90(s,1H),5.05(s,1H),4.68(s,1H),3.28(s,1H),3.22(s,1H),3.11(d,J=77.9Hz,2H),2.85(s,1H),2.33(s,1H),2.13(s,1H),2.01(s,1H),1.89(d,J=13.2Hz,11H),1.53(s,5H),1.27(s,9H).
实施例178 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-氟-1H-吲哚-2-羧酰胺(A178)
1H NMR(500MHz,Chloroform)δ8.69(s,1H),8.21(s,1H),7.58(s,1H),7.53(s,1H),7.23(s,1H),7.19(s,1H),7.13(d,J=10.0Hz,5H),6.53(s,1H),5.93(s,1H),5.07(s,1H),4.95(s,1H),4.67(s,1H),3.29(s,1H),3.25-2.88(m,3H),2.85(s,1H),2.36(s,1H),2.17(d,J=18.2Hz,3H),2.01(s,1H),1.90(d,J=11.3Hz,1H),1.84(s,2H),1.62(s,1H),1.53(s,1H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例179 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A179)
1H NMR(500MHz,Chloroform)δ8.73(s,1H),8.13(s,1H),7.95(s,1H),7.32-7.18(m,7H),7.08(d,J=49.9Hz,6H),7.03(s,1H),7.03(s,1H),6.74(s,1H),6.16(s,1H),5.20(s,1H),4.86(s,1H),4.33(s,2H),3.66(s,1H),3.54(s,1H),3.16(d,J=124.8Hz,2H),3.01(d,J=6.4Hz,1H),2.57(s,1H),2.22(s,1H),2.02(s,1H),1.93(s,1H).
实施例180 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A180)
1H NMR(500MHz,Chloroform)δ8.71(s,1H),8.11(s,1H),7.96(s,1H),7.46-6.88(m,8H),7.04(s,1H),7.04(s,1H),6.57(s,1H),6.10(s,1H),5.19(s,1H),4.83(s,1H),3.65(s,1H),3.54(s,1H),3.29(s,1H),3.04(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.27(s,9H).
实施例181 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A181)
1H NMR(500MHz,Chloroform)δ8.71(s,2H),8.04(s,2H),7.96(s,2H),7.46-6.88(m,16H),7.04(s,2H),7.04(s,2H),6.46(s,2H),6.12(s,2H),5.20(s,2H),4.83(s,1H),3.67(d,J=17.5Hz,3H),3.54(s,1H),3.29(s,3H),3.04(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,2H),1.93(s,1H),1.74(s,2H),1.46(t,J=12.5Hz,6H),1.21(s,3H),1.11(s,2H).
实施例182 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A182)
1H NMR(500MHz,Chloroform)δ8.68(s,2H),8.30(s,2H),7.96(s,2H),7.40(s,2H),7.28(t,J=11.5Hz,12H),7.15(dd,J=57.0,32.0Hz,15H),7.04(s,2H),7.04(s,2H),5.92(s,2H),5.05(s,1H),4.71(s,1H),4.34(s,4H),3.29(s,1H),3.21(d,J=15.0Hz,4H),3.04(s,2H),2.86(s,1H),2.39(s,1H),2.18(s,1H),2.01(s,1H),1.90(d,J=6.3Hz,4H),1.54(s,1H).
实施例183 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A183)
1H NMR(500MHz,Chloroform)δ8.68(s,1H),8.30(s,11H),7.96(s,1H),7.45-6.97(m,8H),7.04(s,1H),7.04(s,1H),6.62(s,1H),5.92(s,1H),5.06(s,1H),4.69(s,1H),3.29(s,1H),3.21(d,J=15.0Hz,2H),3.04(s,1H),2.85(s,1H),2.33(s,1H),2.13(s,1H),2.01(s,1H),1.90(d,J=13.5Hz,1H),1.53(s,1H),1.27(s,9H).
实施例184 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-6-氟-1H-吲哚-2-羧酰胺(A184)
1H NMR(500MHz,Chloroform)δ8.67(s,1H),8.20(s,1H),7.96(s,1H),7.45-6.89(m,8H),7.14(s,4H),7.09(d,J=50.0Hz,5H),7.04(s,1H),6.53(s,1H),5.93(s,1H),5.07(s,1H),4.95(s,1H),4.67(s,1H),3.29(s,1H),3.25-2.88(m,3H),2.85(s,1H),2.35(s,1H),2.17(d,J=17.6Hz,3H),2.01(s,1H),1.90(d,J=11.7Hz,1H),1.84(s,1H),1.62(s,1H),1.53(s,1H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例185 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A185)
1H NMR(500MHz,Chloroform)δ8.92(s,2H),8.83(s,2H),7.84(s,2H),7.49(s,2H),7.33-7.26(m,11H),7.22(s,2H),7.02(d,J=21.6Hz,6H),6.97(dd,J=5.6,2.6Hz,1H),6.77(s,2H),6.28(s,2H),5.16(s,2H),4.91(s,1H),4.34(s,4H),3.67(s,1H),3.55(s,1H),3.29(s,3H),3.04(s,1H),2.61(s,1H),2.23(s,2H),2.02(s,2H),1.93(s,1H).
实施例186 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A186)
1H NMR(500MHz,Chloroform)δ8.75(s,1H),7.97(s,1H),7.45(s,1H),7.31-7.15(m,3H),6.97(d,J=7.1Hz,5H),6.50(s,1H),6.15(s,1H),5.18(s,1H),4.82(s,1H),3.65(s,1H),3.53(s,1H),3.27(s,1H),3.03(s,3H),2.60(s,1H),2.22(s,1H),2.01(s,1H),1.92(s,1H),1.26(s,9H).
实施例187 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A187)
1H NMR(500MHz,Chloroform)δ8.79(s,2H),8.00(s,2H),7.48(s,2H),7.31(d,J=14.5Hz,4H),7.19(s,2H),7.01(d,J=5.2Hz,5H),6.40(s,2H),6.18(s,2H),5.20(s,2H),4.85(s,1H),3.68(d,J=15.6Hz,3H),3.55(s,1H),3.29(s,1H),3.04(s,3H),2.61(s,2H),2.23(s,1H),2.02(s,2H),1.93(s,1H),1.74(s,2H),1.46(t,J=12.5Hz,6H),1.21(s,3H),1.11(s,2H).
实施例188 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A188)
1H NMR(500MHz,Chloroform)δ9.00(s,4H),8.91(s,4H),7.70(s,4H),7.49(d,J=3.7Hz,8H),7.29(dd,J=9.6,5.4Hz,26H),7.21(s,5H),7.00(d,J=5.1Hz,11H),6.69(s,4H),4.96(d,J=17.8Hz,6H),4.33(s,8H),3.29(s,3H),3.21(d,J=15.0Hz,8H),2.96(d,J=80.6Hz,8H),2.85-2.81(m,1H),2.48(s,4H),2.27(s,4H),2.00(d,J=2.8Hz,4H),1.91(s,6H),1.53(s,2H).
实施例189 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A189)
1H NMR(500MHz,Chloroform)δ8.57(s,1H),7.45(s,1H),7.32(d,J=18.3Hz,2H),7.20(d,J=6.7Hz,2H),7.04(s,1H),7.00(s,1H),6.57(s,1H),5.75(s,1H),5.11(s,1H),4.79(s,1H),3.29(s,1H),3.21(d,J=15.0Hz,2H),3.04(s,1H),2.75(s,1H),2.47(s,1H),2.36(s,1H),2.01(s,1H),1.95(s,1H),1.91(s,1H),1.51(s,1H),1.27(s,9H).
实施例190 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3-氟苯基)-1-氧代丙-2-基)-4,6-二氯-1H-吲哚-2-羧酰胺(A190)
1H NMR(500MHz,Chloroform)δ8.77(s,1H),7.93(s,1H),7.48(s,41H),7.34-7.15(m,3H),7.00(s,1H),6.83(s,2H),6.56(s,1H),6.15(s,1H),5.71(s,1H),5.05(s,2H),4.95(s,2H),4.90(s,1H),3.36-3.12(m,4H),3.20(s,1H),3.12(d,J=78.0Hz,2H),2.32(s,2H),2.31-2.17(m,3H),2.03-1.86(m,3H),1.84(s,2H),1.62(s,1H),1.49(s,2H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例191 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A191)
1H NMR(500MHz,Chloroform)δ8.78(s,1H),8.27(s,1H),7.75-7.37(m,3H),7.38(s,1H),7.38(s,1H),7.28(d,J=15.0Hz,5H),7.20-6.87(m,6H),6.90(s,1H),6.90(s,1H),6.78(s,1H),5.71(s,1H),5.15(s,1H),5.06(s,1H),4.33(s,2H),3.80(s,3H),3.63(s,1H),3.50(s,1H),3.29(s,2H),3.04(s,1H),2.54(s,1H),2.22(s,1H),2.02(s,2H),1.91(s,1H).
实施例192 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A192)
1H NMR(500MHz,Chloroform)δ8.78(s,1H),8.27(s,1H),7.75-7.37(m,3H),7.38(s,1H),7.38(s,1H),7.28(d,J=15.0Hz,5H),7.20-6.87(m,6H),6.90(s,1H),6.90(s,1H),6.78(s,1H),5.71(s,1H),5.15(s,1H),5.06(s,1H),4.33(s,2H),3.80(s,3H),3.63(s,1H),3.50(s,1H),3.29(s,2H),3.04(s,1H),2.54(s,1H),2.22(s,1H),2.02(s,2H),1.91(s,1H),1.27(s,9H).
实施例193 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A193)
1H NMR(500MHz,Chloroform)δ8.68(s,1H),8.12(s,1H),7.59(s,1H),7.45(s,1H),7.16(t,J=12.5Hz,6H),6.79(s,1H),6.44(s,1H),6.10(s,1H),5.19(s,1H),4.95(s,1H),4.82(s,2H),3.81(s,3H),3.65(s,1H),3.54(s,1H),3.29(s,1H),3.04(s,1H),2.58(s,2H),2.21(d,J=16.4Hz,2H),2.02(s,1H),1.88(d,J=41.9Hz,3H),1.80(s,1H),1.62(s,2H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例194 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A194)
1H NMR(500MHz,Chloroform)δ8.66(s,1H),8.34(s,1H),7.59(s,1H),7.45(s,1H),7.29(d,J=15.0Hz,5H),7.24-6.99(m,7H),6.79(s,1H),5.90(s,1H),5.04(s,1H),4.72(s,1H),4.34(s,2H),3.81(s,3H),3.29(s,1H),3.21(d,J=15.0Hz,2H),3.04(s,1H),2.86(s,1H),2.29(s,1H),2.11(s,1H),2.01(s,21H),1.90(d,J=11.7Hz,1H),1.52(s,1H).
实施例195 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A195)
1H NMR(500MHz,Chloroform)δ8.46(s,1H),7.57(s,1H),7.43(s,1H),7.17(s,1H),7.12(s,4H),7.00(s,1H),6.92(s,1H),6.77(s,1H),6.49(s,1H),5.75(s,1H),5.20(s,1H),4.67(s,1H),3.80(s,3H),3.28(s,1H),3.20(d,J=15.0Hz,2H),3.03(s,1H),2.77(s,1H),2.40(s,1H),2.30(s,1H),2.00(s,1H),1.94(s,41H),1.90(s,1H),1.51(s,1H),1.27(s,9H).
实施例196 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-5-甲氧基-1H-吲哚-2-羧酰胺(A196)
1H NMR(500MHz,Chloroform)δ8.61(s,1H),8.10(s,1H),7.59(s,1H),7.45(s,1H),7.19(d,J=2.6Hz,2H),7.14(s,4H),6.72(d,J=66.4Hz,2H),5.95(s,1H),5.05(s,1H),4.95(s,1H),4.71(s,1H),3.81(s,3H),3.29(s,1H),3.21(d,J=15.0Hz,2H),3.04(s,1H),2.86(s,1H),2.37(s,61H),2.21-2.17(m,2H),2.01(s,1H),1.90(d,J=11.5Hz,1H),1.84(s,2H),1.62(s,1H),1.54(s,1H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例197 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丙基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A197)
1H NMR(500MHz,Chloroform)δ8.60(s,1H),7.97(s,1H),7.59(s,1H),7.38(s,1H),7.29(d,J=15.0Hz,5H),7.16(s,1H),7.10(d,J=9.2Hz,2H),6.97(s,1H),6.16(s,1H),4.87(s,1H),4.67(s,1H),4.34(s,2H),3.65(s,1H),3.54(s,1H),2.61(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.76(s,1H),1.11(s,1H),0.60(s,1H),0.35(s,1H).
实施例198 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丙基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A198)
1H NMR(500MHz,Chloroform)δ8.59(s,1H),7.98(s,1H),7.61(d,J=10.9Hz,2H),7.12(d,J=16.2Hz,2H),6.98(s,1H),6.56(s,1H),6.12(s,1H),4.81(s,1H),4.67(s,1H),3.65(s,1H),3.54(s,1H),2.59(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.76(s,1H),1.27(s,9H),1.11(s,1H),0.58(s,1H),0.33(s,1H).
实施例199 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丙基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A199)
1H NMR(500MHz,Chloroform)δ8.65(s,1H),8.25(s,1H),7.98(s,1H),7.60(s,1H),7.12(d,J=24.7Hz,2H),7.10-7.07(m,1H),6.98(s,1H),6.41(s,1H),6.15(s,1H),4.82(s,1H),4.58(s,1H),3.66(d,J=5.6Hz,2H),3.54(s,1H),2.59(s,1H),2.23(s,1H),2.02(s,1H),1.93(s,1H),1.75(d,J=10.0Hz,3H),1.46(t,J=12.5Hz,3H),1.21(s,2H),1.11(d,J=0.5Hz,2H),0.57(s,21H),0.28(s,1H).
实施例200 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环丙基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A200)
1H NMR(500MHz,Chloroform)δ8.62(s,1H),8.00(d,J=20.6Hz,2H),7.60(s,1H),7.30(d,J=15.0Hz,5H),7.18(d,J=6.9Hz,2H),7.10(s,1H),6.98(s,1H),6.09(s,1H),4.85(s,1H),4.33(d,J=13.7Hz,3H),3.21(d,J=15.0Hz,2H),2.91(s,1H),2.62(s,1H),2.54(s,1H),2.01(s,1H),1.92(d,J=12.0Hz,1H),1.76(s,2H),1.59(s,1H),1.11(s,1H),0.45(s,1H),0.13(s,1H).
实施例201 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A201)
1H NMR(500MHz,Chloroform)δ7.98(s,1H),7.60(s,1H),7.29(d,J=15.0Hz,5H),7.10(s,1H),6.98(s,1H),4.34(s,2H),2.75(s,1H),2.67(s,1H),2.09(s,1H),2.03(d,J=6.8Hz,4H),1.94(s,1H),1.92-1.82(m,3H),1.76(s,1H),1.66(d,J=10.0Hz,2H),1.61(s,1H),0.45(s,1H),
实施例202 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A202)
1H NMR(500MHz,Chloroform)δ7.98(s,1H),7.60(s,1H),7.29(m,3H),7.10(s,1H),6.98(s,1H),6.29(m,3H),2.75(s,1H),2.67(s,1H),2.09(s,2H),2.03(d,J=6.8Hz,3H),1.94(s,1H),1.92-1.82(m,3H),1.76(s,1H),1.66(d,J=10.0Hz,2H),1.61(s,1H),1.27(s,9H),0.45(s,1H)
实施例203 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A203)
1H NMR(500MHz,Chloroform)δ7.98(s,1H),7.60(s,1H),7.10(s,1H),6.98(s,1H),4.95(s,1H),2.74(s,1H),2.66(s,1H),2.19(s,2H),2.09(s,1H),2.03(d,J=6.9Hz,2H),1.94(s,1H),1.86(dd,J=18.2,10.2Hz,5H),1.76(s,2H),1.64(dd,J=22.9,7.1Hz,3H),1.37(s,1H),1.31(s,2H),1.20(s,2H),0.45(s,1H)
实施例204 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A204)
1H NMR(500MHz,Chloroform)δ7.98(s,1H),7.60(s,1H),7.29(d,J=15.0Hz,4H),7.10(s,1H),6.98(s,1H),6.05(m,2H),4.34(s,2H),3.21(d,J=15.0Hz,2H),2.09(s,1H),2.06-1.69(m,9H),1.76(s,2H),1.76(s,2H),1.65(s,1H),1.61(s,1H),0.53(s,1H),0.39(s,1H).
实施例205 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A205)
1H NMR(500MHz,Chloroform)δ8.62(s,1H),8.00(d,J=20.6Hz,2H),7.60(s,1H),7.30(d,J=15.0Hz,5H),7.18(d,J=6.9Hz,2H),7.10(s,1H),6.98(s,1H),6.09(s,1H),4.85(s,1H),4.33(d,J=13.7Hz,3H),3.21(d,J=15.0Hz,2H),2.91(s,1H),2.62(s,1H),2.54(s,1H),2.01(s,1H),1.92(d,J=12.0Hz,1H),1.76(s,2H),1.59(s,1H),1.27(s,9H),1.11(s,3H),0.45(s,1H),0.13(s,1H).
实施例206 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环丁基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A206)
1H NMR(500MHz,Chloroform)δ8.62(s,1H),8.00(d,J=20.6Hz,2H),7.60(s,1H),7.30(d,J=15.0Hz,5H),7.18(d,J=6.9Hz,2H),7.10(s,1H),6.98(s,1H),6.09(s,1H),4.85(s,1H),4.33(d,J=13.7Hz,3H),3.21(d,J=15.0Hz,2H),2.91(s,1H),2.62(s,1H),2.54(s,1H),2.01(s,1H),1.92(d,J=12.0Hz,1H),1.76(s,2H),1.59(s,1H),1.11(s,1H),0.45(s,21H),0.13(s,1H).
实施例207 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A207)
1H NMR(500MHz,Chloroform)δ8.57(s,1H),7.98(s,1H),7.60(s,1H),7.38(s,1H),7.30(d,J=15.0Hz,5H),7.13-7.07(m,2H),6.98(d,J=4.1Hz,2H),6.13(s,1H),4.81(d,J=3.3Hz,1H),4.34(s,2H),3.65(s,1H),3.55(s,1H),2.60(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,3H),1.76(s,3H),1.66(d,J=4.7Hz,3H),1.36(s,1H),1.23(s,1H).
实施例208 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A208)
1H NMR(500MHz,Chloroform)δ8.60(s,1H),7.98(s,1H),7.77(s,1H),7.60(s,1H),7.11(d,J=5.1Hz,82H),6.98(s,1H),6.57(s,1H),6.14(s,1H),4.83(s,1H),4.61(s,1H),3.66(s,1H),3.54(s,1H),2.59(s,1H),2.22(s,1H),2.02(s,1H),1.93(s,1H),1.76(s,3H),1.65(d,J=11.9Hz,5H),1.34(s,4H),1.26(d,J=8.6Hz,9H).
实施例209 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A209)
1H NMR(500MHz,Chloroform)δ8.54(s,1H),7.98(s,1H),7.60(s,1H),7.28(s,1H),7.08(d,J=16.5Hz,2H),6.98(s,1H),6.46(s,1H),6.14(s,1H),4.80(s,1H),4.75(s,1H),3.64(d,J=19.8Hz,2H),3.54(s,1H),2.59(s,1H),2.22(s,1H),2.02(s,1H),1.93(s,1H),1.75(d,J=10.0Hz,6H),1.65(d,J=6.5Hz,63H),1.46(t,J=12.5Hz,4H),1.35(s,3H),1.27(s,1H),1.21(s,2H),1.11(s,1H).
实施例210 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A210)
1H NMR(500MHz,Chloroform)δ8.51(s,1H),7.98(s,1H),7.60(s,1H),7.30(d,J=15.0Hz,5H),7.24(s,1H),7.09(d,J=13.7Hz,2H),6.98(s,1H),6.89(s,1H),6.11(s,1H),4.79(s,1H),4.65(s,11H),4.34(s,2H),3.21(d,J=15.0Hz,2H),2.91(s,1H),2.50(d,J=13.8Hz,2H),2.01(s,1H),1.92(d,J=5.3Hz,1H),1.76(s,3H),1.65(d,J=5.8Hz,3H),1.58(s,1H),1.36(s,1H),1.23(s,1H).
实施例211 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A211)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),7.98(s,1H),7.60(s,1H),7.10(s,1H),7.00(d,J=18.5Hz,2H),6.89(s,1H),6.53(s,1H),6.10(s,1H),4.78(s,1H),4.65(s,1H),3.21(d,J=15.0Hz,2H),2.90(s,1H),2.49(d,J=13.5Hz,2H),2.01(s,1H),1.91(d,J=1.6Hz,1H),1.76(s,3H),1.63(t,J=21.9Hz,4H),1.55-1.52(m,1H),1.37(s,1H),1.27(s,9H),1.22(s,1H).
实施例212 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环戊基-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A212)
1H NMR(500MHz,Chloroform)δ8.45(s,1H),7.98(s,1H),7.60(s,1H),7.10(s,1H),7.00(d,J=19.1Hz,42H),6.88(s,1H),6.44(s,1H),6.10(s,1H),4.95(s,1H),4.77(s,1H),4.64(s,1H),3.21(d,J=15.0Hz,2H),2.90(s,1H),2.49(d,J=19.3Hz,2H),2.19(s,2H),2.01(s,1H),1.93-1.89(m,1H),1.84(s,2H),1.76(s,3H),1.73-1.60(m,6H),1.57(s,1H),1.37(d,J=2.4Hz,3H),1.31(s,1H),1.21(d,J=13.0Hz,2H).
实施例213 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A213)
1H NMR(500MHz,Chloroform)δ7.97(s,1H),7.61(s,1H),7.49(s,1H),7.55-7.23(m,6H),7.55-6.98(m,8H),6.13(s,1H),4.86(s,1H),4.49(s,1H),4.34(s,2H),3.66(s,1H),3.54(s,1H),2.59(s,1H),2.23(s,1H),2.02(s,1H),1.93(s,1H),1.80(s,3H),1.69(d,J=10.0Hz,3H),1.31(s,1H),1.26(s,1H),1.11(s,1H),1.03(s,1H).
实施例214 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A214)
1H NMR(500MHz,Chloroform)δ7.73(s,1H),7.61(s,1H),7.49(s,1H),7.16(s,1H),6.52(s,1H),6.13(s,1H),4.83(s,1H),4.55(s,1H),3.66(s,1H),3.54(s,1H),2.58(s,1H),2.22(s,1H),2.02(s,1H),1.93(s,1H),1.80(s,2H),1.58(s,1H),1.51(d,J=15.0Hz,3H),1.48-1.41(m,4H),1.28(d,J=5.4Hz,9H).
实施例215 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A215)
1H NMR(500MHz,Chloroform)δ7.55(d,J=60.0Hz,2H),7.16(d,J=2.8Hz,2H),6.45(s,1H),6.14(s,1H),4.95(s,1H),4.77(s,1H),4.66(s,1H),3.66(s,1H),3.54(s,1H),2.58(s,1H),2.21(d,J=17.0Hz,2H),2.02(s,1H),1.92(s,1H),1.84(s,2H),1.80(s,1H),1.64(d,J=16.1Hz,3H),1.51(d,J=15.0Hz,2H),1.44(dd,J=12.8,7.8Hz,6H),1.37(s,3H),1.31(s,1H),1.20(s,2H).
实施例216 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A216)
1H NMR(500MHz,Chloroform)δ7.55(d,J=60.0Hz,2H),7.46-7.26(m,6H),7.16(s,1H),7.09(s,1H),6.08(s,1H),4.79(s,1H),4.41(s,1H),4.34(s,2H),3.21(d,J=15.0Hz,2H),2.85(s,1H),2.53(d,J=12.1Hz,2H),2.01(s,1H),1.91(d,J=3.6Hz,1H),1.80(s,1H),1.72(s,1H),1.58(s,1H),1.52(d,J=15.0Hz,2H),1.48-1.41(m,4H),1.34(s,1H).
实施例217 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A217)
1H NMR(500MHz,Chloroform)δ7.61(s,2H),7.49(s,2H),7.16(s,2H),6.89(s,2H),6.53(s,2H),6.09(s,2H),4.76(s,1H),4.44(s,1H),3.21(d,J=15.0Hz,4H),2.88(s,2H),2.49(d,J=3.0Hz,4H),2.01(s,1H),1.93-1.89(m,2H),1.80(s,3H),1.69(d,J=10.0Hz,2H),1.57(s,1H),1.31(d,J=4.8Hz,2H),1.27(s,9H),1.11(s,1H),1.03(s,3H).
实施例218 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A218)
1H NMR(500MHz,Chloroform)δ7.58(s,1H),7.46(s,1H),7.13(s,1H),6.47(d,J=5.5Hz,2H),5.81(s,1H),4.93(d,J=6.0Hz,2H),4.37(s,1H),3.34(s,1H),3.20(d,J=15.0Hz,2H),2.37(d,J=18.2Hz,2H),2.18(s,2H),2.00(s,1H),1.90(d,J=0.5Hz,1H),1.81(d,J=19.9Hz,6H),1.69(s,2H),1.64(d,J=29.9Hz,3H),1.51(s,1H),1.37(s,3H),1.31(s,2H),1.18(d,J=16.6Hz,3H),1.11(s,1H),1.03(s,2H).
实施例219 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-羧酰胺(A219)
1H NMR(500MHz,Chloroform)δ7.58(s,1H),7.46(s,1H),7.13(s,1H),6.47(d,J=5.5Hz,2H),5.81(s,1H),4.93(d,J=6.0Hz,2H),4.37(s,1H),3.34(s,1H),3.20(d,J=15.0Hz,2H),2.37(d,J=18.2Hz,2H),2.18(s,2H),2.00(s,1H),1.90(d,J=0.5Hz,1H),1.81(d,J=19.9Hz,6H),1.69(s,2H),1.64(d,J=29.9Hz,3H),1.51(s,1H),1.37(s,3H),1.31(s,2H),1.18(d,J=16.6Hz,3H),1.11(s,1H),1.03(s,2H).
实施例220 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A220)
1H NMR(500MHz,Chloroform)δ9.90(s,1H),8.66(s,1H),8.26(s,1H),7.77(s,1H),7.30(d,J=15.0Hz,5H),7.23-7.03(m,6H),6.71(s,1H),6.26(s,1H),5.98(s,1H),5.15(s,1H),4.87(s,1H),4.34(s,2H),3.79(s,6H),3.64(s,1H),3.52(s,1H),3.29(s,1H),3.04(s,1H),2.52(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,2H).
实施例221 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A221)
1H NMR(500MHz,Chloroform)δ8.60(s,1H),8.35(s,1H),7.76(s,1H),7.17(d,J=25.0Hz,5H),6.69(s,1H),6.58(s,1H),6.23(s,1H),6.00(s,1H),5.18(s,1H),4.81(s,1H),3.79(s,6H),3.64(s,1H),3.53(s,1H),3.29(s,1H),3.04(s,1H),2.55(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.27(s,9H).
实施例222 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A222)
1H NMR(500MHz,Chloroform)δ8.59(s,1H),8.10(s,1H),7.68(s,1H),7.15(d,J=25.0Hz,5H),6.67(s,1H),6.45(s,1H),6.21(s,1H),6.07(s,1H),5.18(s,1H),4.94(s,1H),4.80(s,1H),3.78(s,6H),3.64(s,1H),3.53(s,1H),3.28(s,1H),3.03(s,1H),2.56(s,1H),2.20(d,J=16.3Hz,3H),2.02(s,1H),1.88(d,J=41.4Hz,3H),1.80(s,1H),1.62(s,1H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例223 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A223)
1H NMR(500MHz,Chloroform)δ8.65(s,1H),8.29(s,1H),8.02(s,1H),7.27(d,J=15.0Hz,5H),7.14(d,J=24.9Hz,5H),6.92(s,1H),6.59(s,1H),6.20(s,1H),6.08(s,1H),5.01(s,1H),4.76(s,1H),4.33(s,2H),3.78(s,6H),3.28(s,1H),3.20(d,J=15.0Hz,2H),3.03(s,1H),2.85(d,J=1.0Hz,2H),2.32(s,1H),2.00(s,1H),1.90(d,J=1.3Hz,1H),1.61(s,1H).
实施例224 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A224)
1H NMR(500MHz,Chloroform)δ8.80(d,J=11.2Hz,2H),7.09(t,J=61.7Hz,6H),6.94(s,1H),6.94(s,1H),6.77(s,1H),6.63(s,1H),6.56(s,1H),5.04(d,J=1.0Hz,2H),4.99(s,1H),3.79(s,6H),3.29(s,1H),3.21(d,J=15.0Hz,3H),2.93(d,J=106.3Hz,2H),2.79-2.70(m,1H),2.40(s,1H),2.27(s,1H),2.01(s,1H),1.92(d,J=8.4Hz,1H),1.46(s,1H),1.27(s,9H).
实施例225 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-1-氧代-3-苯基丙-2-基)-4,6-二甲氧基-1H-吲哚-2-羧酰胺(A225)
1H NMR(500MHz,Chloroform)δ8.67(s,1H),7.80(s,1H),7.65(s,1H),7.08(t,J=67.3Hz,6H),6.91(s,1H),6.91(s,1H),6.55(s,1H),6.49(s,1H),6.07(s,1H),5.09(s,1H),4.95(s,1H),4.69(s,1H),3.79(s,6H),3.29(s,1H),3.21(d,J=15.0Hz,2H),3.04(s,1H),2.93(s,1H),2.42(d,J=15.8Hz,2H),2.19(s,2H),2.03-1.73(m,5H),1.84(s,3H),1.84(s,2H),1.60(d,J=16.9Hz,2H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例226 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A226)
1H NMR(500MHz,Chloroform)δ8.76(s,1H),8.12(s,1H),7.98(s,1H),7.89(s,1H),7.60(s,1H),7.29(d,J=15.0Hz,5H),7.19(d,J=17.1Hz,2H),7.10(d,J=2.2Hz,2H),6.99(d,J=15.0Hz,2H),6.31(s,1H),5.05(s,1H),4.91(s,1H),4.34(s,2H),3.67(s,1H),3.56(s,1H),3.29(s,1H),3.04(s,1H),2.70(s,1H),2.23(s,1H),2.02(s,2H),1.93(s,1H).
实施例227 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A227)
1H NMR(500MHz,Chloroform)δ8.72(s,1H),8.44(s,1H),7.96(s,1H),7.59(s,1H),7.25(s,1H),7.16(s,1H),7.09(d,J=2.1Hz,2H),6.98(d,J=15.0Hz,2H),6.60(s,1H),5.97(s,1H),5.12(s,1H),4.82(s,1H),3.64(s,1H),3.52(s,1H),3.28(s,1H),3.03(s,1H),2.54(s,1H),2.22(s,1H),2.02(s,1H),1.92(s,1H),1.27(s,9H).
实施例228 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A228)
1H NMR(500MHz,Chloroform)δ8.69(s,1H),8.41(s,1H),7.94(s,1H),7.56(s,1H),7.23(s,1H),7.13(s,1H),7.06(d,J=0.9Hz,2H),6.96(d,J=14.9Hz,2H),6.65(s,1H),5.95(s,1H),5.11(s,1H),4.92(s,1H),4.81(s,1H),3.63(s,1H),3.51(s,1H),3.27(s,1H),3.02(s,1H),2.53(s,1H),2.19(d,J=14.6Hz,2H),2.01(s,1H),1.87(d,J=40.1Hz,3H),1.79(s,1H),1.61(s,1H),1.36(s,2H),1.30(s,1H),1.19(s,2H).
实施例229 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A229)
1H NMR(500MHz,Chloroform)δ8.69(s,1H),8.11(s,1H),7.95(s,1H),7.57(s,1H),7.43(s,1H),7.27(d,J=15.0Hz,5H),7.14(s,1H),7.07(s,1H),6.97(d,J=15.0Hz,2H),6.82(s,1H),6.58(s,1H),6.04(s,1H),5.01(s,21H),4.83(s,1H),4.32(s,2H),3.28(s,1H),3.20(d,J=15.0Hz,2H),3.03(s,1H),2.89(s,1H),2.70(s,1H),2.25(s,1H),2.00(s,1H),1.90(d,J=2.9Hz,1H),1.60(s,1H).
实施例230 N-((S)-1-(((S)-4-(叔丁基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A230)
1H NMR(500MHz,Chloroform)δ8.74(s,1H),8.06(s,1H),7.98(s,1H),7.60(s,1H),7.17(s,1H),7.11(d,J=8.4Hz,2H),7.03-6.90(m,3H),6.53(s,1H),5.75(s,1H),5.12(s,1H),4.72(s,1H),3.29(s,1H),3.21(d,J=15.0Hz,2H),3.04(s,1H),2.75(s,1H),2.43(s,1H),2.33(s,1H),2.01(s,1H),1.96(s,1H),1.91(s,1H),1.52(s,1H),1.27(s,9H).
实施例231 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-(3,4-二氟苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A231)
1H NMR(500MHz,Chloroform)δ8.72(s,1H),7.99(d,J=25.5Hz,2H),7.59(s,1H),7.16(s,1H),7.09(d,J=4.0Hz,2H),6.97(t,J=11.7Hz,3H),6.45(s,1H),6.07(s,1H),5.09(s,1H),4.94(s,1H),4.68(s,1H),3.28(s,1H),3.21(d,J=15.0Hz,2H),3.03(s,1H),2.95(s,1H),2.44(d,J=17.0Hz,2H),2.19(s,2H),2.03-1.73(m,5H),1.84(s,2H),1.84(s,2H),1.60(d,J=13.6Hz,2H),1.37(s,2H),1.31(s,1H),1.20(s,2H).
实施例232 N-((S)-1-(((S)-4-(苄基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(环己基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A232)
1H NMR(500MHz,Chloroform)δ8.57(s,1H),7.94(s,1H),7.57(s,1H),7.40(s,1H),7.26(d,J=14.9Hz,4H),7.16-7.03(m,3H),6.95(s,1H),6.45(s,1H),5.67(s,1H),4.95(s,1H),4.48(s,1H),4.32(s,2H),3.79(s,1H),2.20(s,1H),2.15(s,1H),2.04(s,2H),1.77(d,J=19.9Hz,3H),1.68(d,J=10.0Hz,4H),1.37(s,1H),1.30(s,1H),1.11(s,1H),1.01(d,J=14.9Hz,6H).
实施例233 N-((S)-1-(((S)-4-(苄基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A233)
1H NMR(500MHz,Chloroform)δ8.85(s,1H),8.41(s,1H),7.98(s,1H),7.60(s,1H),7.29(d,J=15.0Hz,5H),7.20(d,J=16.0Hz,2H),7.12(d,J=20.0Hz,5H),6.98(s,1H),6.69(s,1H),5.05(s,1H),5.01(s,1H),4.74(s,1H),4.34(s,2H),3.81(s,1H),3.29(s,2H),3.04(s,1H),2.21(d,J=5.4Hz,2H),2.05(s,2H),1.00(s,6H).
实施例234 N-((S)-1-(((S)-4-(环己基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A234)
1H NMR(500MHz,Chloroform)δ8.73(s,1H),8.16(s,1H),7.98(s,1H),7.60(s,1H),7.27(s,1H),7.19(s,1H),7.12(d,J=20.0Hz,5H),7.07(s,1H),6.98(s,1H),6.53(s,1H),5.87(s,1H),5.64(s,1H),4.92(s,1H),4.86(s,1H),3.81(s,1H),3.29(s,3H),3.02(d,J=18.8Hz,3H),2.19(d,J=11.4Hz,2H),2.05(s,2H),1.80(s,1H),1.69(d,J=10.0Hz,3H),1.58(s,1H),1.31(s,1H),1.11(s,1H),1.01(d,J=15.0Hz,8H).
实施例235 N-((S)-1-(((S)-4-(环己基)-3,4-二酮-1-(环己基氨基)并-2-基)氨基)-3-(苯基)-1-氧代丙-2-基)-1H-吲哚-2-羧酰胺(A235)
1H NMR(500MHz,Chloroform)δ8.73(s,1H),8.14(s,1H),7.98(s,1H),7.60(s,1H),7.26(s,1H),7.19(s,1H),7.12(d,J=20.0Hz,5H),6.98(s,1H),6.56(s,1H),5.90(s,1H),5.63(s,1H),4.93(d,J=16.9Hz,2H),4.86(s,1H),3.29(s,1H),3.02(d,J=18.8Hz,3H),2.23-2.14(m,4H),2.05(s,2H),1.82(d,J=20.0Hz,4H),1.69(d,J=10.0Hz,3H),1.62(s,1H),1.37(d,J=0.9Hz,3H),1.31(s,3H),1.20(s,2H),1.11(s,1H),1.03(s,2H).
实施例236 N-((S)-1-(((S)-4-(苄基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(环己基)-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A236)
1H NMR(500MHz,Chloroform)δ9.45(s,1H),7.80(s,2H),7.67(s,2H),7.35-7.26(m,6H),7.11(s,1H),6.67(s,1H),5.75(s,1H),5.11(s,1H),4.33(d,J=6.4Hz,3H),3.81(s,1H),2.16(d,J=10.5Hz,2H),2.05(s,1H),1.76(s,1H),1.60(s,1H),1.51(d,J=15.0Hz,2H),1.48-1.41(m,4H),1.32(s,1H),1.00(s,6H).
实施例237 N-((S)-1-(((S)-4-(环己基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(环己基)-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A237)
1H NMR(500MHz,Chloroform)δ9.32(s,1H),8.17(s,1H),8.12(s,1H),7.76(s,1H),7.66(d,J=4.6Hz,2H),7.33-7.27(m,4H),7.19(s,1H),5.70(s,1H),4.93(s,1H),4.80(s,1H),4.75(s,1H),4.03(s,1H),3.98(s,1H),3.24(s,1H),3.02-2.98(m,3H),2.30-2.26(m,2H),2.18(s,1H),2.10(s,1H),1.82-1.75(m,2H),1.75-1.71(m,2H),1.67(s,1H),1.45-1.41(m,2H),1.33(s,1H),1.30-1.20(m,6H),1.14-1.07(m,3H).
实施例238 N-((S)-1-(((S)-4-(苄基)-3,4-二酮-1-(异丙基氨基)并-2-基)氨基)-3-(苯基)-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A238)
1H NMR(500MHz,Chloroform)δ9.34(s,1H),8.08(d,J=10.7Hz,2H),7.62(d,J=0.9Hz,2H),7.30-7.21(m,8H),7.19(s,1H),7.14(s,1H),6.23(s,1H),6.03(s,1H),5.22(s,1H),5.08(s,1H),4.95(s,1H),4.88(s,1H),4.33(s,1H),4.28(s,1H),3.96(s,1H),3.22(s,1H),2.99(s,1H),2.38-2.34(m,2H),2.21(s,1H),2.16(s,1H),1.33-1.20(m,6H).
实施例239 N-((S)-1-(((S)-4-(苄基)-3,4-二酮-1-(环己基氨基)并-2-基)氨基)-3-(苯基)-1-氧代丙-2-基)-喹喔啉-2-羧酰胺(A239)
1H NMR(500MHz,Chloroform)δ9.31(s,1H),8.12(d,J=31.2Hz,2H),7.73(s,1H),7.63(d,J=6.0Hz,2H),7.36-7.24(m,8H),7.17(d,J=11.8Hz,2H),6.32(s,1H),5.10(s,1H),4.76(s,1H),4.67(s,1H),4.36(s,1H),4.30(d,J=18.6Hz,2H),4.12(s,1H),3.24(s,1H),2.97(s,1H),2.31-2.27(m,2H),2.12(d,J=3.2Hz,2H),1.94-1.87(m,2H),1.73-1.63(m,4H),1.61-1.55(m,4H).
实施例240 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-吲哚-6-氟-2-羧酰胺(A240)
1H NMR(500MHz,Chloroform)δ8.12(s,1H),7.57(s,1H),7.52(s,1H),7.36-7.25(m,4H),7.20(d,J=7.7Hz,2H),6.84(s,1H),6.18(s,1H),5.49(d,J=11.0Hz,2H),4.70(s,1H),4.39(d,J=17.7Hz,2H),4.08(s,1H),3.24(d,J=17.5Hz,2H),2.54(s,1H),2.08-2.04(m,2H),1.82(s,1H),1.78-1.67(m,6H),1.66-1.62(m,2H),1.58(dd,J=9.5,3.3Hz,5H),1.44(s,1H),1.37-1.27(m,3H).
实施例241 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-甲基噁唑-2-羧酰胺(A241)
1H NMR(500MHz,Chloroform)δ7.33-7.27(m,4H),7.23(s,1H),6.79(d,J=13.7Hz,2H),6.29(s,1H),6.09(s,1H),5.05(s,1H),4.99(d,J=9.8Hz,2H),4.41(s,1H),4.34(s,1H),3.24(d,J=14.9Hz,2H),2.92(s,1H),2.36-2.32(m,3H),2.08-2.04(m,2H),1.85(s,1H),1.79(s,1H),1.74-1.55(m,11H),1.48(s,1H),1.46-1.23(m,3H).
实施例242 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-甲基噁唑-2-羧酰胺(A242)
1H NMR(500MHz,Chloroform)δ7.33-7.30(m,22H),7.28(t,J=15.0Hz,33H),6.83(s,9H),6.14(s,9H),6.09(s,9H),5.94(s,9H),5.19(s,9H),5.01(s,9H),4.36(d,J=0.5Hz,18H),3.45(s,9H),3.35(s,7H),2.59(s,9H),2.38-2.34(m,27H),2.18(s,8H),2.09-2.05(m,18H),1.96-1.88(m,24H),1.88(s,3H),1.73-1.60(m,46H),1.40-1.36(m,16H),1.32(s,9H),1.15(s,7H),1.12-1.08(m,17H).
实施例243 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并[d]1,3-二氧杂环戊烯-5-羧酰胺(A243)
1H NMR(500MHz,Chloroform)δ7.54(s,6H),7.45(s,6H),7.29-7.18(m,30H),6.96(s,6H),6.49(s,6H),6.01(s,6H),5.92-5.88(m,12H),5.58(s,6H),5.11(s,6H),4.93(s,6H),4.63(s,6H),4.29(s,6H),4.24(s,6H),3.24(d,J=17.5Hz,11H),2.86(s,6H),2.05(t,J=4.2Hz,18H),1.95-1.87(m,12H),1.84(s,6H),1.76(t,J=4.8Hz,17H),1.63(dd,J=40.8,34.9Hz,22H),1.51(dd,J=4.6,1.3Hz,1H),1.40-1.36(m,10H),1.32(s,6H),1.17-1.09(m,17H).
实施例244 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-1H-苯并[d]咪唑-2-羧酰胺(A244)
1H NMR(500MHz,Chloroform)δ7.84(s,1H),7.73(s,1H),7.62(s,1H),7.38(s,1H),7.31-7.23(m,6H),7.16(s,1H),6.17(s,1H),5.59(s,1H),5.10(s,1H),4.75(s,1H),4.53(s,1H),4.36(d,J=17.3Hz,2H),3.24(d,J=17.5Hz,2H),2.88(s,1H),2.06(t,J=2.7Hz,3H),1.96-1.81(m,3H),1.77(s,1H),1.73-1.60(m,5H),1.53(s,1H),1.40-1.36(m,2H),1.32(s,1H),1.22-1.15(m,3H).
实施例245 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-7-甲氧基-苯并呋喃-2-羧酰胺(A245)
1H NMR(500MHz,Chloroform)δ7.60(s,8H),7.34-7.22(m,33H),7.15(d,J=10.0Hz,16H),7.06(s,8H),6.81(s,8H),6.54(s,8H),6.22(s,8H),5.59(s,8H),5.08(s,8H),4.92(s,8H),4.63(s,8H),4.32(d,J=1.1Hz,16H),3.89-3.85(m,24H),3.24(d,J=17.4Hz,15H),2.94(s,8H),2.07(t,J=5.1Hz,23H),1.93-1.85(m,18H),1.84(s,6H),1.78(s,6H),1.73-1.51(m,49H),1.51(d,J=5.5Hz,1H),1.40-1.36(m,14H),1.32(s,8H),1.16-1.07(m,23H).
实施例246 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-3-甲基-苯并呋喃-2-羧酰胺(A246)
1H NMR(500MHz,Chloroform)δ7.60-7.40(m,3H),7.32-7.18(m,7H),6.67(s,1H),5.57(s,1H),5.15(s,1H),4.67(s,1H),4.55(s,1H),4.30(d,J=14.7Hz,2H),3.24(d,J=17.3Hz,2H),2.73(s,1H),2.15-2.10(m,4H),2.08-2.04(m,2H),1.88-1.81(m,3H),1.77(s,1H),1.73-1.59(m,5H),1.55(s,1H),1.40-1.36(m,2H),1.32(s,1H),1.14-1.05(m,3H).
实施例247 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-3,5-二甲基-苯并呋喃-2-羧酰胺(A247)
1H NMR(500MHz,Chloroform)δ7.50-7.34(m,3H),7.32-7.26(m,4H),7.23(s,1H),7.11(s,1H),6.68(s,1H),5.57(s,1H),5.15(s,1H),4.69(s,1H),4.55(s,1H),4.30(d,J=14.8Hz,2H),3.24(d,J=17.3Hz,2H),2.73(s,1H),2.45-2.41(m,3H),2.15-2.10(m,4H),2.08-2.04(m,2H),1.88-1.81(m,3H),1.77(s,1H),1.73-1.59(m,5H),1.55(s,1H),1.40-1.36(m,2H),1.32(s,1H),1.14-1.05(m,3H).
实施例248 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-4,7-二甲氧基-苯并呋喃-2-羧酰胺(A248)
1H NMR(500MHz,Chloroform)δ7.59(s,1H),7.34-7.27(m,2H),7.27-7.22(m,2H),7.10(s,1H),6.86(s,1H),6.82(s,1H),6.38(s,1H),6.32(s,1H),5.56(s,1H),5.35(s,1H),4.66(d,J=18.6Hz,2H),4.28(s,1H),4.17(s,1H),3.91-3.87(m,3H),3.85-3.81(m,3H),3.24(d,J=17.8Hz,2H),3.06(s,1H),2.05(t,J=6.8Hz,3H),1.96-1.88(m,2H),1.84(s,1H),1.77(s,1H),1.73-1.54(m,5H),1.52(s,1H),1.40-1.36(m,2H),1.32(s,1H),1.17-1.08(m,3H).
实施例249 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-苯并呋喃-3-羧酰胺(A249)
1H NMR(500MHz,Chloroform)δ8.07(s,91H),7.62(s,92H),7.58(s,94H),7.47(s,94H),7.27(dd,J=9.9,8.1Hz,379H),7.20(t,J=5.8Hz,274H),6.24(s,91H),5.61(s,91H),5.16(s,90H),4.93(s,91H),4.52(s,89H),4.32(d,J=0.6Hz,182H),3.24(d,J=17.5Hz,174H),2.89(s,93H),2.06(t,J=2.7Hz,257H),1.92-1.80(m,277H),1.81(s,7H),1.77(s,70H),1.73-1.51(m,541H),1.51(d,J=1.8Hz,6H),1.40-1.36(m,160H),1.32(s,86H),1.22-1.16(m,264H).
实施例250 N-((S)-1-(((S)-4-(苄基氨基)-3,4-二酮-1-((S)-2-氧代哌啶-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-6-氯-2H-色烯-3-羧酰胺(A250)
1H NMR(500MHz,Chloroform)δ8.16(s,1H),7.32(s,1H),7.32-7.24(m,4H),7.23-7.09(m,3H),6.84(s,1H),6.05(s,1H),5.64(s,1H),5.33(s,1H),5.06-5.02(m,2H),4.50(d,J=9.3Hz,2H),4.39(s,1H),4.32(s,1H),3.24(d,J=17.4Hz,2H),2.99(s,1H),2.15(s,1H),2.08-2.04(m,2H),1.85(s,1H),1.79(s,1H),1.73-1.69(m,2H),1.69-1.62(m,5H),1.55(s,1H),1.39-1.35(m,2H),1.31(s,1H),1.23-1.19(m,2H),1.17(s,1H).
实施例251 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-6-氯2,3-二氢苯并[b]1,4-二噁英-6-羧酰胺(A251)
1H NMR(500MHz,Chloroform)δ8.51(s,1H),7.66(s,1H),7.55(s,1H),7.11(s,1H),5.40(s,1H),5.16(s,1H),4.65(s,1H),4.52(s,1H),4.38-4.34(m,4H),3.45(s,1H),3.36(d,J=13.4Hz,2H),2.68(s,1H),2.18(s,1H),2.11-2.02(m,2H),1.99-1.84(m,3H),1.78-1.72(m,2H),1.71-1.62(m,5H),1.58(dd,J=9.0,3.3Hz,5H),1.55-1.50(m,2H),1.48(s,1H),1.43-1.39(m,4H),1.37-1.29(m,3H).
实施例252 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-苯基-1-氧代丙-2-基)-6-氯2,3-二氢苯并[b]1,4-二噁英-6-羧酰胺(A252)
1H NMR(500MHz,Chloroform)δ9.01(s,1H),7.52(s,1H),7.29-7.23(m,2H),7.23-7.17(m,2H),7.15(s,1H),7.04(s,1H),6.92(s,1H),6.21(s,1H),5.12(s,1H),5.05(s,1H),4.87(s,1H),4.52(s,1H),4.38-4.34(m,4H),3.44(d,J=12.5Hz,2H),3.37-3.20(m,3H),2.98(s,1H),2.19(s,1H),2.12-2.04(m,2H),1.92(s,1H),1.85-1.78(m,2H),1.66(s,1H),1.56-1.52(m,2H),1.48-1.39(m,3H),1.23-1.11(m,2H).
实施例253 N-((S)-1-(((S)-4-(环己基氨基)-3,4-二酮-1-((S)-2-氧代吡咯烷-3-基)丁-2-基)氨基)-3-环己基-1-氧代丙-2-基)-5-甲氧基吲哚-6-羧酰胺(A253)
1H NMR(500MHz,Chloroform)δ8.73(s,5H),8.50(s,5H),7.45(s,5H),7.37(s,5H),7.18(s,5H),6.75(s,5H),6.03(s,5H),5.67(s,5H),5.61(s,5H),4.89(s,5H),4.57(s,5H),3.84-3.80(m,15H),3.43(d,J=16.9Hz,10H),3.35(s,4H),2.70(s,5H),2.19(s,5H),2.09-2.06(m,9H),2.06-2.04(m,1H),2.06-1.91(m,16H),1.73-1.61(m,35H),1.60-1.46(m,47H),1.46-1.39(m,11H),1.35-1.26(m,9H),1.22(s,4H).
药理活性试验
1.1假病毒的包装
MERS-CoV假病毒的包装方法如下:
a)转染前24h消化293T细胞,铺板于10cm的组织培养皿中(2×106/dish);
b)转染前2h给细胞更换预温的新鲜DMEM培养基(含10%FBS);
c)转染时用两个1.5mL的EP管,其中EP管1中加入500μL 0.9%NaCl溶液,其中含有均为20μg的pcDNA3.1-S-IRES-GFP质粒(或VSV-G表达质粒)和pNL4-3.luc.RE质粒;EP管2中也加入500μL 0.9%NaCl,再加入染试剂vigofect 10μL,均静置5分钟;
d)将EP管2中的500μL溶液逐滴加入EP管1中,边加入边用枪头混匀,室温放置15min;
e)将上述1mL混合液体逐滴、均匀地加入到先前铺好的293T细胞培养皿中;
f)转染8~10h后,更换10mL含10%FBS的新鲜DMEM培养液;
g)48h后收集含有假病毒的上清液;
h)4000rpm离心4min去除细胞碎片,0.45μm无菌过滤器过滤,分装并储存在-80℃备用。
1.2假病毒滴度检测
a)MERS-CoV、HCoV-229E、VSV-G的假病毒感染实验中,以Huh-7为靶细胞;在感染实验前12小时,消化靶细胞,调整细胞浓度,铺于96孔细胞板中(每孔10000个细胞)。37℃5%CO2继续培养12h备用;
b)5倍梯度稀释假病毒于圆底96孔板中(体系为100μL);
c)弃取96孔板中靶细胞培养上清,然后加入病毒稀释液(100μL);
d)培养12h后,更换100μL新鲜DMEM培养基(含10%FBS);
e)继续培养48小时,后抽弃上清,并使用PBS洗细胞两次,动作轻柔以防止细胞脱落,并尽可能将PBS去除;
f)加入预先稀释好的裂解液50μL(使用ddH2O稀释5×细胞裂解液至1×浓度)。之后置涡旋混匀仪上震荡混匀直至细胞完全裂解(1-2h即可);
g)抽取30μL裂解液至96孔不透明白色酶标板中,注意更换枪头;
h)每孔中加入50μL萤火虫酶检测试剂,然后快速用功能酶标仪中检测荧光值。一般值为空白对照1000倍病毒稀释度,被选用于假病毒抑制实验。
1.3假病毒抑制实验
a)使用DMEM在96孔板中2倍稀释化合物(50μL体系),注意避免化合物的析出;
b)每孔加入一定稀释度的假病毒50μL,空白对照孔中加入DMEM(50μL),病毒与化合物混匀,37℃孵育30min;
c)去除靶细胞上清,并将化合物/病毒混合物(100μL)加入相应的靶细胞中;
12小时换液,再过48小时检测荧光值。
实验结果如表2所示。
表2 MERS-CoV假病毒抑制活性
化合物编号 | IC50(μM) | 化合物编号 | IC50(μM) |
A5 | 0.0005±0.0002 | A27 | 0.008±0.004 |
A15 | <0.0001 | A51 | <0.0001 |
A39 | 0.0005±0.0003 | A81 | 0.0002±0.0001 |
A232 | 0.0134±0.003 | A236 | 0.0166±0.004 |
A21 | 0.0082±0.0032 | A240 | 0.0159±0.007 |
A9 | 0.0010±0.0007 | A214 | 0.0079±0.0049 |
A241 | 0.0025±0.0013 | A242 | 0.0022±0.0008 |
A30 | 0.0162±0.006 | A217 | 0.0079±0.0053 |
A243 | 0.0107±0.0008 | A244 | 0.0126±0.0122 |
A245 | 0.0184±0.008 | A246 | 0.0108±0.0100 |
A247 | 0.0017±0.0004 | A248 | 0.0084±0.0017 |
A249 | 0.0006±0.0002 | A250 | 0.0007±0.0001 |
A251 | 0.0808±0.0213 | A42 | 0.0032±0.0006 |
A252 | 0.0264±0.0176 | A43 | 0.7858±0.4579 |
A175 | 0.4356±0.1807 | A26 | 0.0078±0.0035 |
A253 | 0.0225±0.0042 | A68 | 0.0209±0.0088 |
A44 | 0.0180±0.0056 | A176 | 0.0125±0.0026 |
A25 | 0.4070±0.3520 |
2.1对HCoV活病毒感染的体外抑制作用
目前我们拥有HCoV-OC43(ATCC-VR1558)活病毒,并按照ATCC提供的病毒培养条件,已建立其体外感染系统。在此系统上,我们检测了化合物A13对HCoV-OC43活病毒感染的抑制作用。在HCoV-OC43感染的HCT-8细胞中,会出现大量空泡等细胞病变现象(CPE),但在化合物A13(1μM)存在的条件下,可有效阻断病毒的感染及其导致的CPE(如图1A所示),并且其对靶细胞的保护效果呈现明显的剂量依赖性(如图1B所示)。我们采用CCK8方法,检测化合物A13对HCoV-OC43活毒感染的抑制效果,结果显示其抑制活性在低纳摩尔水平(IC50=86nM),如图1C所示。
具体地,从图1A可以看出:化合物A13在低浓度(1μM)条件下,可对HCoV-OC43感染具有较好的抑制效果;并且从图1B可以看出:化合物A13的抗病毒活性呈现明显的剂量依赖性;从图1C可以看出:化合物A13的具体抗病毒活性,其半数抑制活性(IC50)在低纳摩尔水平(IC50=86nM)。
2.2化合物A13抗病毒的广谱性评估
在α型人冠状病毒中我们选择HCoV-229E为代表,在β型人冠状病毒中选择MERS-CoV、SARS-CoV为代表,在这三种HCoVs的假病毒上,A13均展示出高效的抗病毒效果,其100nM的浓度下,均可达到近90%的病毒抑制效果,而在对照VSV-G介导的假病毒感染系统上,化合物A13则并没有展示出有效抑制效果(如图2A所示)。另外,在Huh-7为靶细胞的系统上,化合物A13展示出较小的细胞毒性,其CC50大于100μM(检测剂量的1000倍以上,如图2B所示)。
2.3化合物A13体内保护活性的初步评估
为了初步评估化合物A13在体内的稳定性和抗病毒活性,我们在Balb/c小鼠模型上,进行腹腔给药(100mg/kg)化合物或100μL DMSO,然后分别在给药后2小时、12小时和24小时取血,分离血清,进行抗MERS-CoV假病毒活性检测。结果显示,给药后2小时和12小时血清有很高的病毒抑制活性,分别是DMSO-本底血清的抑制活性24倍和15倍,而给药后24小时血清的抑制活性与DMSO-本底血清的抑制活性较为相似。该结果表明化合物A13在体内的具有较好的稳定性和抗病毒活性,并暗示着该化合物具有较好的体内半衰期较长,如图3所示。
具体从图3D可知:在Balb/c小鼠模型上,化合物A13(100mg/kg)进行腹腔给药后,在体内展示出较好的稳定性和抗病毒活性。给药后2小时和12小时的分离血清的半数效应浓度(EC50)分别是3181倍和1133倍血清稀释度,远高于DMSO对照组的相应EC50。
2.4化合物A13体内安全性的初步评估
接下来,我们进一步评估化合物A13在小鼠体内的安全性。药物组(100mg/kg)和DMSO对照组小鼠,分别通过腹腔给药途径给药,每天1次,连续给药7天,然后观察各组小鼠的生长状态及体重变化。结果如图4所示,在给药期间,药物组小鼠与PBS组小鼠的体重变化并无差异,从而表明化合物A13具有较好的体内安全性。
3.1系列化合物大鼠药代动力学研究
给药方案
CD-1小鼠9只,雄性,体重18-22g,随机分成3组,每组3只。按照如下方案分别灌胃、静脉和腹腔给予受试化合物。
试验前禁食12h,自由饮水。给药后2h统一进食。
实验分组、采血时间点及样品处理
每个时间点3只动物,分组及采血时间点见下表3:
表3
灌胃给药溶液以DMSO/0.5%HPMC(5/95,v/v)配制到最终浓度。静脉和腹腔给药以DMSO/PEG300/EtOH/NaCl(5/40/5/50,v/v/v)配制。给药溶液留样(分别在给药前及给药后,取50μL药液与50μL DMSO混匀)待测。
按上述给药剂量给予药物,记录给药时间,并在以上设定的时间点经小鼠股脉丛取血20μL,置肝素化试管中。立即11000rpm离心5min。立即准确吸取10μL血浆于预先加好100μL的PK-IS溶液(以甲醇:乙腈(1:1,v/v)配制)的离心管中,混匀,冻存于-20℃待测。
我们对化合物A9,A13,A42,A241和A242进行了药代动力学研究。其中,化合物A9口服暴露量584h*ng/mL,腹腔注射给药暴露量8191h*ng/mL(如表4所示)。化合物A13口服暴露量463h*ng/mL,生物利用度为7.99%;腹腔注射给药暴露量为7298h*ng/mL,生物利用度为126%(如表5所示)。A42口服暴露量为742h*ng/mL,腹腔注射给药暴露量为5491h*ng/mL(如表6所示)。化合物A241口服暴露量为663h*ng/mL,腹腔注射给药暴露量为4163h*ng/mL(如表7所示)。化合物A242口服暴露量为488h*ng/mL,腹腔注射给药暴露量为6890h*ng/mL(如表8所示)。
表4 A9主要药动学参数
表5 A13主要药动学参数
表6 A42主要药动学参数
表7 A241主要药动学参数
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表8 A242主要药动学参数
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 (9)
1.一种式A所示的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药学上可接受的盐:
其中:
R1选自下组:氢、氘、氚、取代或未取代的C1-C6烷基;
R2选自下组:氢、氘、氚、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C3-C8环烷基C1-C5亚烷基、取代或未取代的C6芳基C1-C5亚烷基;
R3选自下组:取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基C1-C5亚烷基、取代或未取代的C6芳基C1-C5亚烷基;
R4为含1、2或3个选自N、O、S的杂原子的9-10元杂芳环;上述基团为取代或未取代的;其中,所述取代指基团上的氢原子被1、2、3或4个选自下组的取代基取代:卤素、羟基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基;
当-NHR5与其相邻的-(C=O)-CH2-成环时,R5为-(CH2)n-,n为2或3;
当-NHR5不与其相邻的-(C=O)-CH2-成环时,R5选自下组:氢、氘、氚、取代或未取代的C1-C6烷基、取代或未取代的C3-C10环烷基;
其中,在R1、R2、R3、R4和R5中,所述取代各自独立地指被选自下组的1、2、3或4个取代基取代:卤素、羟基、巯基、硝基、氰基、胺基、亚胺基、叔胺基、叠氮基、C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷氧基、C1-C6烷基羰基、C1-C6烷硫基、C1-C8烷氧基羰基、三氟甲基。
2.如权利要求1所述的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药学上可接受的盐,其特征在于,所述化合物为式AA所示的化合物,
其中,R1、R2、R3、R4、R5和n如权利要求1中所限定;
*表示碳原子的立体化学异构可以分别独立地为R或S。
3.如权利要求1所述的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药学上可接受的盐,其特征在于,R4选自下组:
取代或未取代的喹喔啉基、取代或未取代的喹唑啉基、取代或未取代的噌啉基、
取代或未取代的吲哚基、取代或未取代的异吲哚基、
取代或未取代的1,3-苯并二噁茂基、
取代或未取代的苯并咪唑基、取代或未取代的吲唑基、
取代或未取代的咪唑[1,2-A]吡啶基、取代或未取代的咪唑[1,5-A]吡啶基、
取代或未取代的3,8a二氢-2H-苯并吡喃基、取代或未取代的苯并吡喃基、
取代或未取代的喹啉基、取代或未取代的异喹啉基、
取代或未取代的苯并噁唑基、取代或未取代的苯并噻唑基、
取代或未取代的苯并噻吩基、
取代或未取代的苯并呋喃基;
其中,所述取代指基团上的氢原子被1、2或3个选自下组的取代基取代:F、Cl、Br、I、羟基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷硫基、卤代C1-C6烷硫基。
4.如权利要求1所述的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药学上可接受的盐,其特征在于,
当-NHR5与其相邻的-(C=O)-CH2-成环时,R5为-(CH2)n-,n为3;
当-NHR5不与其相邻的-(C=O)-CH2-成环时,R5选自下组:氢、氘、氚、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基;
其中,所述取代各自独立地指被选自下组的1、2或3个取代基取代:F、Cl、Br、I、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6烷硫基。
5.如权利要求1所述的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药学上可接受的盐,其特征在于,所述化合物选自下组:
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6.一种权利要求1所述酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药学上可接受的盐的制备方法,其特征在于,包括如下步骤:
步骤(6):在惰性溶剂中,将化合物Ⅶ与氧化剂进行氧化反应,得到化合物Ⅷ;
上述各式中,R1、R2、R3、R4、R5和n如权利要求1中所限定。
7.一种药物组合物,其特征在于,所述药物组合物包含如下组分:
i)治疗有效量的一种或多种权利要求1所述酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药学上可接受的盐;和
ii)药学上可接受的载体或赋形剂。
8.一种酮酰胺类抑制剂,其特征在于,所述抑制剂含有一种或多种权利要求1-5任一项所述的酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药学上可接受的盐。
9.一种权利要求1所述酮酰胺类化合物、其外消旋体、对映异构体、非对映异构体或它们的混合物,或其药学上可接受的盐的用途,其特征在于,用于制备药物组合物或制剂,所述药物组合物或所述制剂用于治疗或预防与冠状病毒相关的疾病或者与埃博拉病毒相关的疾病。
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EP3835296A1 (en) | 2021-06-16 |
EP3835296A4 (en) | 2022-05-18 |
CN113015726A (zh) | 2021-06-22 |
US20220112177A1 (en) | 2022-04-14 |
JP2021534133A (ja) | 2021-12-09 |
KR20210043617A (ko) | 2021-04-21 |
CN110818691A (zh) | 2020-02-21 |
WO2020030143A1 (zh) | 2020-02-13 |
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