CN111372931B - 作为蛋白激酶抑制剂的杂环化合物 - Google Patents

作为蛋白激酶抑制剂的杂环化合物 Download PDF

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CN111372931B
CN111372931B CN201880067864.1A CN201880067864A CN111372931B CN 111372931 B CN111372931 B CN 111372931B CN 201880067864 A CN201880067864 A CN 201880067864A CN 111372931 B CN111372931 B CN 111372931B
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cyclopropylcarboxamide
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CN111372931A (zh
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李赫雨
池美京
金承灿
刘哈娜
郑秀娟
朴志研
李芸琳
李豪烈
奇小映
金东圭
金命重
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Inoon Ltd
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Abstract

本发明提供具有蛋白激酶抑制活性的新化合物、其立体异构体或其药学上可接受的盐。本发明的化合物、其立体异构体或其药学上可接受的盐显示蛋白激酶抑制活性，因而有效预防或治疗与蛋白激酶相关的疾病，如癌症、自身免疫病、神经疾病、代谢疾病、感染等。

Description

作为蛋白激酶抑制剂的杂环化合物
技术领域
本发明涉及抑制蛋白激酶活性以预防或治疗与这种蛋白激酶活性相关的疾病的新化合物及其用途。
背景技术
蛋白激酶是通过磷酸化其他蛋白质并调整它们的活性、位置和功能来控制各种细胞内过程的酶。这种蛋白激酶的异常控制功能与诸如癌症、自身免疫病、神经疾病、代谢疾病、感染等的疾病的机制密切相关。
Janus激酶(下文称为JAK)是由约1,150个氨基酸组成并且分子量为约120-130kDa的蛋白质，其中JAK被分为四种类型：JAK1、JAK2、JAK3和TYK2。JAK位于炎性细胞因子的细胞内受体中，其中所述炎性细胞因子(IL-2、IL-4、IL-6、IL-7、IL-9、IL15、IL-21、GM-CSF、G-CSF、EPO、TPO、IFN-a、 IFN-b、IFN-G等)与所述受体结合，并且然后被磷酸化，之后JAK通过与STAT分子作用将炎性细胞因子信号传递至细胞。通过这样的各种炎性细胞因子过度激活信号传递导致的结果是我们机体的免疫***攻击人体，这导致自身免疫病。因此，预期开发用于抑制自身免疫病中的这样的炎性细胞因子的受体激酶的药物会显示出比现有治疗剂更加改善的治疗效果。
发明内容
技术问题
本发明的目的是提供显示蛋白激酶抑制活性的新化合物、其立体异构体或其药学上可接受的盐。
此外，本发明的目的是提供用于制备本发明的化合物、其立体异构体或其药学上可接受的盐的方法。
本发明的目的是提供用于治疗或预防与蛋白激酶相关的疾病的药物组合物，其中其含有作为有效组分的本发明的化合物、其立体异构体或其药学上可接受的盐。
此外，本发明的目的是提供用于治疗或预防与蛋白激酶相关的疾病的方法，其中所述方法包括给药有效治疗剂量的本发明的化合物、其立体异构体或其药学上可接受的盐。
另外，本发明的目的是提供本发明的化合物、其立体异构体或其药学上可接受的盐用于制备药物的用途，所述药物用于预防或治疗与蛋白激酶相关的疾病。
技术方案
蛋白激酶抑制剂化合物
为了解决上述问题，本发明提供具有下式1的化合物、其立体异构体或其药学上可接受的盐：
Figure BDA0002455210850000011
[式1]
其中
X为C-A3或N；
Y为C-A4或N；
Z为N或N-O；
A1至A4各自独立地为H或C1-C6烷基、C1-C6烷氧基、C1-C6羟基烷基、C1-C6卤代烷基、C1-C6 氰基烷基、C(＝O)-OH、C(＝O)-O-C1-C6烷基、S(＝O)2-C1-C6烷基、芳基或杂芳基；
B1为-(CH2)m-、-C(＝O)-、-C(＝S)-、-C(＝NR1)-、-C(＝O)-NR1-、-S(＝O)2-或者不存在，其中-(CH2)m-的至少一个H可以被C1-C6烷基、卤素或氰基替代，或者其可以与至少一个碳原子彼此连接以形成环；
B2为H、C1-C6烷基、C3-C7环烷基、5-6元杂环烷基、芳基、杂芳基、C1-C6烷基-芳基或C1-C6 烷基-杂芳基，其中C3-C7环烷基、5-6元杂环烷基、芳基、杂芳基、C1-C6烷基-芳基或C1-C6烷基-杂芳基的至少一个H可以被C1-C6烷基、羟基或卤素替代；
B3为H或C1-C6烷基；
环状连接基是C3-C7环烷基、C3-C7环烯基、5-6元杂环烷基、5-6元杂环烯基、芳基或杂芳基；
C1和C2各自独立地为H、C1-C6烷基、C1-C6烷氧基、C1-C6羟基烷基、C1-C6氰基烷基、C1-C6 卤代烷基、羟基、氰基、卤素、C(＝O)-OH、C(＝O)-O-C1-C6烷基、S(＝O)2-C1-C6烷基、芳基或杂芳基；
或者C1和C2可以通过至少一个碳原子彼此连接以形成双环或螺环；
D1为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure BDA0002455210850000021
Figure BDA0002455210850000022
或者不存在，其中-(CH2)m-或-(CH2)m-NR1-的至少一个H可以被C1-C6烷基、卤素或氰基替代，或者其可以与至少一个碳原子彼此连接以形成环；且
Figure BDA0002455210850000023
Figure BDA0002455210850000024
的至少一个H可以被C1-C6烷基、C1-C6羟基烷基、C1-C6 卤代烷基或C1-C6氰基烷基替代；/>
D2为-C(＝O)-、-C(＝O)-CH2-C(＝O)-、-C(＝S)-、-S(＝O)2-或者不存在，其中-C(＝O)-CH2-C(＝O)-的至少一个H可以被C1-C6烷基或卤素替代；
D3为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure BDA0002455210850000025
或者不存在，其中-(CH2)m-或-(CH2)m-NR1- 的至少一个H可以被C1-C6烷基、卤素或氰基替代，或者其可以与至少一个碳原子彼此连接以形成环；
D4为H、C1-C6烷基、C1-C6烯基、C1-C6烷氧基烷基、C1-C6羟基烷基、C1-C6卤代烷基、C1-C6 氰基烷基、S(＝O)2-C1-C6烷基、C3-C7环烷基、
Figure BDA0002455210850000026
芳基或杂芳基，
(其中C1-C6烷基、C1-C6烯基、C1-C6烷氧基烷基、C1-C6羟基烷基、C1-C6卤代烷基或C1-C6 氰基烷基的至少一个H可以被C3-C7环烷基替代；
C3-C7环烷基或
Figure BDA0002455210850000027
的至少一个H可以被C1-C6烷基、C1-C6卤代烷基、C1-C6氰基烷基、氰基、卤素、-C(＝O)-R4或-C(＝O)-O-R4替代；且
芳基或杂芳基的至少一个H可以被C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6羟基烷基、 C1-C6氰基烷基、C1-C6硫烷基、羟基、氰基、硝基、卤素、-C(＝O)-R4、-C(＝O)-NR1-R4、-S(＝O)2-R4、 -S(＝O)2-NR1-R4、-NR1-R5、
Figure BDA0002455210850000028
芳基或杂芳基替代，其中此时/>
Figure BDA0002455210850000029
的至少一个H可以被C1-C6烷基或(＝O)替代)；
R1和R2各自独立地为H或C1-C6烷基；
R3为H、C1-C6烷基、-C(＝O)-R4、-C(＝O)-O-R4、-S(＝O)2-R4或-S(＝O)2-NR1-R4，其中如果W为-O-、 -C(＝O)-或-S(＝O)2-，则R3不存在；
R4为H、C1-C6烷基或C1-C6卤代烷基；
R5为H、C1-C6烷基、
Figure BDA0002455210850000031
芳基或杂芳基，其中/>
Figure BDA0002455210850000032
的至少一个H 可以被C1-C6烷基或(＝O)替代；且芳基或杂芳基的至少一个H可以被C1-C6烷基或卤素替代；
V为-CH-或-N-；
W为-CH-、-N-、-O-、-S-、-C(＝O)-、-S(＝O)-或-S(＝O)2-，其中如果V为-CH-，则W不是-CH-；
a至d各自独立地为1、2或3；且
m为1、2或3。
根据本发明的一个具体实施方案，可以提供的是
X为C-A3或N；
Y为C-A4或N；
Z为N或N-O；
A1至A4各自独立地为H或C1-C6烷基或C1-C6氰基烷基；
B1为-(CH2)m-、-C(＝O)-、-C(＝S)-、-C(＝NR1)-、-C(＝O)-NR1-、-S(＝O)2-或者不存在，其中-(CH2)m-的至少一个H可以被C1-C6烷基、卤素或氰基替代，或者其可以与至少一个碳原子彼此连接以形成环；
B2为H、C1-C6烷基、C3-C7环烷基、芳基、杂芳基或C1-C6烷基-芳基，其中C3-C7环烷基、芳基、杂芳基或C1-C6烷基-芳基的至少一个H可以被C1-C6烷基替代；
B3为H或C1-C6烷基；
环状连接基是C3-C7环烷基、C3-C7环烯基、5-6元杂环烷基、5-6元杂环烯基、芳基或杂芳基；
C1和C2各自独立地为H、C1-C6烷基、C1-C6卤代烷基、羟基、氰基、卤素、C(＝O)-OH、C(＝O)-O-C1-C6 烷基或芳基，
或者C1和C2可以通过至少一个碳原子彼此连接以形成双环或螺环；
D1为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure BDA0002455210850000033
Figure BDA0002455210850000034
或者不存在，其中-(CH2)m-或-(CH2)m-NR1-的至少一个H可以被C1-C6烷基或卤素取代，或者其可以与至少一个碳原子彼此连接以形成环；且
Figure BDA0002455210850000035
Figure BDA0002455210850000036
的至少一个H可以被C1-C6烷基或C1-C6氰基烷基替代；
D2为-C(＝O)-、-C(＝O)-CH2-C(＝O)-、-C(＝S)-、-S(＝O)2-或者不存在，其中-C(＝O)-CH2-C(＝O)-的至少一个H可以被C1-C6烷基替代；
D3为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure BDA0002455210850000037
或者不存在，其中-(CH2)m-或-(CH2)m-NR1- 的至少一个H可以被氰基替代；
D4为H、C1-C6烷基、C1-C6烯基、C1-C6烷氧基烷基、C1-C6羟基烷基、C1-C6卤代烷基、C1-C6 氰基烷基、S(＝O)2-C1-C6烷基、C3-C7环烷基、
Figure BDA0002455210850000038
芳基或杂芳基，
(其中C1-C6烷基、C1-C6烯基、C1-C6烷氧基烷基、C1-C6羟基烷基、C1-C6卤代烷基或C1-C6 氰基烷基的至少一个H可以被C3-C7环烷基替代；
C3-C7环烷基或
Figure BDA0002455210850000041
的至少一个H可以被C1-C6烷基、C1-C6卤代烷基、C1-C6氰基烷基、氰基、卤素或-C(＝O)-O-R4替代；且
芳基或杂芳基的至少一个H可以被C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6硫烷基、羟基、氰基、硝基、卤素、-C(＝O)-R4、-C(＝O)-NR1-R4、-S(＝O)2-R4、-S(＝O)2-NR1-R4、-NR1-R5或
Figure BDA0002455210850000042
替代，其中此时/>
Figure BDA0002455210850000043
的至少一个H可以被(＝O)替代)；
R1和R2各自独立地为H或C1-C6烷基；
R3为H、C1-C6烷基、-C(＝O)-R4、-C(＝O)-O-R4、-S(＝O)2-R4或-S(＝O)2-NR1-R4，其中如果W为-O-、 -C(＝O)-或-S(＝O)2-，则R3不存在；
R4为H、C1-C6烷基或C1-C6卤代烷基；
R5为H、
Figure BDA0002455210850000044
或芳基，其中/>
Figure BDA0002455210850000045
的至少一个H可以被(＝O)替代；且芳基或杂芳基的至少一个H可以被C1-C6烷基或卤素替代；
V为-CH-或-N-；
W为-CH-、-N-、-O-、-S-、-C(＝O)-、-S(＝O)-或-S(＝O)2-，其中如果V为-CH-，则W不是-CH-；
a至d各自独立地为1、2或3；且
m为1或2。
化合物、其立体异构体或其药学上可接受的盐。
根据本发明的其他具体实施方案，可以提供的是
X为C-A3；
Y为C-A4；
Z为N或N-O；
A1至A4各自独立地为H或C1-C6烷基或C1-C6氰基烷基；
B1为-(CH2)m-、-C(＝O)-、-C(＝S)-、-C(＝NR1)-、-C(＝O)-NR1-、-S(＝O)2-或者不存在；
B2为H、C1-C6烷基、C3-C7环烷基、芳基、杂芳基或C1-C6烷基-芳基，其中C3-C7环烷基、芳基、杂芳基或C1-C6烷基-芳基的至少一个H可以被C1-C6烷基替代；
B3为H；
环状连接基是C3-C7环烷基、C3-C7环烯基、5-6元杂环烷基、5-6元杂环烯基、芳基或杂芳基；
C1和C2各自独立地为H、C1-C6烷基、C1-C6卤代烷基、羟基、氰基、卤素、C(＝O)-OH、C(＝O)-O-C1-C6 烷基或芳基，
或者C1和C2可以通过至少一个碳原子彼此连接以形成双环或螺环；
D1为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure BDA0002455210850000046
/>
Figure BDA0002455210850000047
或者不存在，其中-(CH2)m-或-(CH2)m-NR1-的至少一个H可以被C1-C6烷基或卤素替代，或者其可以与至少一个碳原子彼此连接以形成环；且
Figure BDA0002455210850000048
Figure BDA0002455210850000049
的至少一个H可以被C1-C6烷基或C1-C6氰基烷基替代；
D2为-C(＝O)-、-C(＝O)-CH2-C(＝O)-、-C(＝S)-、-S(＝O)2-或者不存在，其中-C(＝O)-CH2-C(＝O)-的至少一个H可以被C1-C6烷基替代；
D3为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure BDA0002455210850000051
或者不存在，其中-(CH2)m-或-(CH2)m-NR1- 的至少一个H可以被氰基替代；
D4为H、C1-C6烷基、C1-C6烯基、C1-C6烷氧基烷基、C1-C6卤代烷基、C1-C6氰基烷基、S(＝O)2-C1-C6 烷基、C3-C7环烷基、
Figure BDA0002455210850000052
芳基或杂芳基，
(其中C1-C6烷基、C1-C6烯基、C1-C6烷氧基烷基、C1-C6卤代烷基或C1-C6氰基烷基的至少一个H可以被C3-C7环烷基替代；
C3-C7环烷基或
Figure BDA0002455210850000053
的至少一个H可以被C1-C6烷基、C1-C6卤代烷基、C1-C6氰基烷基、氰基、卤素或-C(＝O)-O-R4替代；且
芳基或杂芳基的至少一个H可以被C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6硫烷基、羟基、氰基、硝基、卤素、-C(＝O)-R4、-C(＝O)-NR1-R4、-S(＝O)2-R4、-S(＝O)2-NR1-R4、-NR1-R5或
Figure BDA0002455210850000054
替代，其中此时/>
Figure BDA0002455210850000055
的至少一个H可以被(＝O)替代)；
R1和R2各自独立地为H或C1-C6烷基；
R3为H、C1-C6烷基、-C(＝O)-R4、-C(＝O)-O-R4、-S(＝O)2-R4或-S(＝O)2-NR1-R4，其中如果W为-O-、 -C(＝O)-或-S(＝O)2-，则R3不存在；
R4为H、C1-C6烷基或C1-C6卤代烷基；
R5为H、
Figure BDA0002455210850000056
或芳基，其中/>
Figure BDA0002455210850000057
的至少一个H可以被(＝O)替代；且芳基或杂芳基的至少一个H可以被C1-C6烷基或卤素替代；
V为-CH-或-N-；
W为-CH-、-N-、-O-、-S-、-C(＝O)-、-S(＝O)-或-S(＝O)2-，其中如果V为-CH-，则W不是-CH-；
a至d各自独立地为1、2或3；且
m为1或2。
根据本发明的另一具体实施方案，可以提供的是
X为C-A3；
Y为N；
Z为N；
A1至A3各自独立地为H或C1-C6烷基；
B1为-C(＝O)-；
B2为C3-C7环烷基或芳基，这里C3-C7环烷基或芳基的至少一个H可以被C1-C6烷基替代；
B3为H或C1-C6烷基；
环状连接基是5-6元杂环烷基、5-6元杂环烯基、芳基或杂芳基；
C1和C2各自独立地为H、C1-C6烷基或卤素；
或者C1和C2可以通过至少一个碳原子彼此连接以形成双环；
D1为-(CH2)m、-NR1-或者不存在；
D2为-C(＝O)-、-C(＝S)-、-S(＝O)2-或者不存在；
D3为-(CH2)m、-NR1-、-O-或者不存在；
D4为C1-C6烷基、C1-C6烯基、C1-C6羟基烷基、C1-C6卤代烷基、C1-C6氰基烷基、C3-C7环烷基、
Figure BDA0002455210850000061
芳基或杂芳基，
其中C3-C7环烷基或
Figure BDA0002455210850000062
的至少一个H可以被C1-C6烷基或氰基替代；且
芳基或杂芳基的至少一个H可以被C1-C6烷基、氰基、卤素或-C(＝O)-NR1-R4替代；
R1为H或C1-C6烷基；
R4为H；
V为-CH-或-N-；
W为-O-或-S(＝O)2-；
a和b各自独立地为1、2或3；且
m为1或2。
根据本发明的另一具体实施方案，可以提供的是
X为N；
Y为C-A4；
Z为N；
A1、A2和A4各自独立地为H或C1-C6烷基；
B1为-C(＝O)-；
B2为C3-C7环烷基，其中C3-C7环烷基的至少一个H可以被C1-C6烷基替代；
B3为H；
环状连接基为芳基；
C1和C2各自独立地为H、C1-C6烷基或卤素；
D1为-(CH2)m-或-NR1-；
D2为-S(＝O)2-或者不存在；
D3不存在；
D4为C1-C6烷基、C1-C6卤代烷基或杂芳基，
其中C1-C6烷基或C1-C6卤代烷基的至少一个H可以被C3-C7环烷基替代；且
杂芳基的至少一个H可以被C1-C6烷基替代；
R1为H；且
m为1或2
根据本发明的另一具体实施方案，可以提供的是
X为N；
Y为N；
Z为N；
A1和A2各自独立地为H或C1-C6烷基；
B1为-C(＝O)-；
B2为C3-C7环烷基，其中C3-C7环烷基的至少一个H可以被C1-C6烷基替代；
B3为H；
环状连接基为芳基；
C1和C2各自独立地为H、C1-C6烷基或卤素；
D1为-(CH2)m-、-NR1-、-NR1-或-O-；
D2为-S(＝O)2-或者不存在；
D3不存在；
D4为C1-C6烷基、C1-C6卤代烷基、
Figure BDA0002455210850000063
芳基或杂芳基，
(其中C1-C6烷基或C1-C6卤代烷基的至少一个H可以被C3-C7环烷基替代；且
芳基或杂芳基的至少一个H可以被氰基或卤素替代)；
R1为H；
V为-N-；
W为-O-或-S(＝O)2-；
a和b各自独立地为1、2或3；且
m为1或2。
在本说明书中，用于定义式1的化合物的概念如下。以下定义也适用于本说明书中单独使用或作为更大基团的一部分使用的术语，除非另有特别说明：
术语“烷基”分别指单独使用或以组合方式使用(例如“杂烷基”)时的直链、支链或环状烃基团，其中每个碳原子可以任意地被至少一个氰基(cyano)、羟基、烷氧基、氧代、卤素、羰基、磺酰基、氰基(cyanyl) 等取代。
术语“烷氧基”是指-O-烷基，其中烷基如上定义。
术语“杂烷基”是指包含选自N、O和S的至少一个杂原子的烷基。
术语“芳基”是指包括苯基、萘基等的芳香基团，并且其可以任意地被至少一个烷基、烷氧基、卤素、羟基、羰基、磺酰基、氰基等取代。
术语“杂环”包含选自N、O和S的1至4个杂原子，并且是指饱和或部分饱和或芳香形式的，其可以与苯并或环烷基任意地稠合。
术语“卤素(halo(gen))”是指选自氟、氯、溴和碘的取代产物。
除非另有定义，本说明书中使用的其他术语和缩略语均具有它们的原始含义。
在本发明中，由上式1表示的化合物的代表性实例如下。
Figure BDA0002455210850000071
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Figure BDA0002455210850000081
/>
Figure BDA0002455210850000091
/>
Figure BDA0002455210850000101
/>
Figure BDA0002455210850000111
/>
Figure BDA0002455210850000121
/>
Figure BDA0002455210850000131
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Figure BDA0002455210850000141
/>
Figure BDA0002455210850000151
/>
Figure BDA0002455210850000161
/>
Figure BDA0002455210850000171
/>
Figure BDA0002455210850000181
/>
Figure BDA0002455210850000191
/>
Figure BDA0002455210850000201
/>
Figure BDA0002455210850000211
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Figure BDA0002455210850000221
/>
Figure BDA0002455210850000231
/>
Figure BDA0002455210850000241
/>
Figure BDA0002455210850000251
/>
Figure BDA0002455210850000261
/>
Figure BDA0002455210850000271
/>
Figure BDA0002455210850000281
/>
Figure BDA0002455210850000291
在下文中，为方便起见，除非另有说明，否则式1的化合物包括并且是指所有本发明的式1的化合物、其立体异构体及其药学上可接受的盐。
本发明的化合物可以形成药学上可接受的盐。这样的药学上可接受的盐包括酸加成盐，其中酸形成无毒的酸加成盐，例如通过以下酸形成的酸加成盐：无机酸如盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸等；有机碳酸如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、富马酸、马来酸等；磺酸如甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸等；等等。本发明的式1的化合物可以通过常规方法转化为其盐。
同时，本发明的化合物可以具有不对称碳，并且可以作为R或S异构体、外消旋体、非对映异构体混合物和单个非对映异构体存在，其中所有异构体和混合物均包括在本发明的范围内。换言之，在式1 结构中包括不对称碳的情况下，应理解所有立体异构体都包括在其中，除非其方向是单独描述的。
式1化合物的制备方法
本发明还提供用于制备式1的化合物的方法。在下文中，为了更好地理解本发明，基于示例性反应式描述用于制备式1的化合物的方法，但应理解，本发明所属领域的技术人员可以基于式1的结构通过各种方法制备式1的化合物，其中这样的方法均包括在本发明的范围内。换言之，应理解，可以通过任意地组合本说明书中描述或现有技术中公开的几种合成方法来制备式1的化合物，其中这样的制备落入本发明的范围内。在以下反应式中，除非另有说明，所有取代基均如上所定义。
就本发明的化合物中使用的酸、碱和反应溶剂而言，本领域中通常使用的那些可以没有限制地使用。例如，作为酸，可以使用无机酸如盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸等；有机碳酸如酒石酸、甲酸、柠檬酸、乙酸、己二酸、三氯乙酸、三氟乙酸、葡糖酸、苯甲酸、乳酸、富马酸、马来酸等；和磺酸如甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸等。作为碱，可以使用NaH、K2CO3、Na2CO3、NaHCO3、 K3PO4、KOH、NaOH、LiOH、n-BuLi、sec-BuLi、LiHMDS等碱。作为反应溶剂，可以使用DCM、THF、1,4-二氧杂环己烷、MeOH、EtOH、己烷、EtOAC、***、DMF、DMSO、甲苯、二甲苯等或其混合溶剂等。
本发明的上式1的化合物的合成方法可以作为实例示出，如以下反应式1或2：
[反应式1]
Figure BDA0002455210850000301
其中
A2、B1、B2、C1、C2、X、Y、Z和环状连接基如在式1中所定义；且
D和D’是用于引入式1中所定义的D1-D2-D3-D4的类似物或者D1-D2-D3-D4本身。
在以上反应式1中，如果卤素＝OTf，则可以通过以下反应式1-1的方法合成中间体化合物：
Figure BDA0002455210850000302
[反应式1-1]
Figure BDA0002455210850000303
其中
C1、C2和D’分别与以上反应式1中所定义的那些相同；且
()n表示多边环状化合物。
除以上反应式1的方法外，还可以通过以下反应式2进行合成：
[反应式2]
Figure BDA0002455210850000311
其中
化合物(III)对应于反应式1的化合物(III)。
A2、B1、B2、C1、C2、X、Y、Z和环状连接基如式1中所定义；且
D和D’是用于引入式1中所定义的D1-D2-D3-D4的类似物或者D1-D2-D3-D4本身。
在以上反应式1中，化合物(I)可以常规购买或合成。
本发明的式1的化合物可以通过几种方法如结晶、硅胶柱色谱等从以上反应式1和2的产物中分离或纯化。以这种方式，本发明的化合物以及用于制备其的起始物、中间体等可以通过各种方法合成，并且应理解，这样的方法包括在就式1的化合物的制备而言的本发明的范围内。
式1的化合物的医学用途
本发明提供由下式1表示的化合物、其立体异构体或其药学上可接受的盐的医学用途：
[式1]
Figure BDA0002455210850000312
其中上式1如以上所定义。
根据本发明的一个具体实施方案，本发明提供用于治疗或预防与蛋白激酶相关的疾病的药物组合物，其中其包含作为有效组分的由上式1表示的化合物、其立体异构体或其药学上可接受的盐。
根据本发明的其他具体实施方案，本发明提供上式1的化合物、其立体异构体或其药学上可接受的盐用于制备药物的用途，所述药物用于治疗癌症、自身免疫病、神经疾病、代谢疾病或感染。
根据本发明的另一具体实施方案，本发明提供用于治疗癌症、自身免疫病、神经疾病、代谢疾病或感染的方法，其中所述方法包括给药治疗有效剂量的上式1的化合物、其立体异构体或其药学上可接受的盐。
根据本发明的另一具体实施方案，本发明还提供用于抑制蛋白激酶的方法，其中所述方法包括给药治疗有效剂量的上式1的化合物、其立体异构体或其药学上可接受的盐。
本发明的式1的化合物、其立体异构体或其药学上可接受的盐显示蛋白激酶抑制活性，从而实现预防或治疗与蛋白激酶相关的疾病的显著效果。
在本发明中，所述与蛋白激酶相关的疾病包括癌症、自身免疫病、神经疾病、代谢疾病或感染。
有益效果
本发明的由式1表示的化合物、其立体异构体或其药学上可接受的盐具有蛋白激酶抑制活性，从而实现显著的预防或治疗与蛋白激酶相关的疾病的优异效果。
发明的实施方式
在下文中，为了更好地理解本发明，将提出优选实施例。但是，仅出于说明本发明的目的提供以下实施例，并且因此本发明不限于此。
用于合成本发明的化合物的起始材料的各种合成方法是已知的。如果所述起始材料是市售的，则其可以从其供应商处购买并随后使用。作为试剂供应商，有Sigma-Aldrich、TCI、Wako、Kanto、Fluorchem、 Acros、Alfa、Fluka、Combi-Blocks、Dae-Jung等公司，但不限于此。此外，除非另有说明，否则所有市售材料可以在不进行任何额外纯化的情况下使用。
在下文中，本领域技术人员可以在本发明的范围内适当改变和修改以下实施例。
制备例：N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850000321
[步骤1]4-氯-1H-吡咯并[2,3-b]吡啶7-氧化物3-氯苯甲酸盐的合成
Figure BDA0002455210850000322
将4-氯-7-氮杂吲哚(15.0g，98.3mmol)溶于800ml乙酸正丁酯/正庚烷＝3/5(v/v)中，然后在0℃下向其中缓慢逐滴加入间氯过氧苯甲酸(77％，24.2g，108.1mmol)，并在室温下搅拌12小时。滤出产生的固体并减压干燥。最后，由此得到标题化合物(30g，94％)。
1H NMR(400MHz,DMSO-d6)δ13.37(br s,1H),12.90(br s,1H),8.15(d,J＝6.6Hz,1H),7.89(m,2H) 7.68(d,J＝8.0Hz,1H),7.56(d,J＝3.1Hz,1H),7.52(t,J＝8.1Hz,1H),7.20(d,J＝6.6Hz,1H),6.58(d,J＝3.1Hz, 1H).
MS(ESI+)m/z 169,171(M+H)+
[步骤2]4-氯-1H-吡咯并[2,3-b]吡啶-6-胺的合成
Figure BDA0002455210850000323
将步骤1中得到的化合物(30g，92.3mmol)悬浮于乙腈(300ml)中，然后在室温下向其中逐滴加入硫酸二甲酯(9.6ml，101.5mmol)，然后升温至55℃，并且然后搅拌12小时。
将反应混合物冷却至0℃，然后向其中加入过量的氨乙醇溶液，然后升温至45℃，并且然后搅拌3 天。之后，将所得混合物冷却至室温，并且然后滤出不溶性固体并除去。之后，将剩余溶液减压浓缩，然后溶于二氯甲烷(1L)中，然后用10％碳酸钠水溶液洗涤，并且然后用无水硫酸镁干燥。之后，减压浓缩剩余过滤溶液。通过柱色谱分离所得浓缩物，由此得到标题化合物(10g，42.4mmol)。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),7.00(s,1H),6.33(s,1H),6.19(s,1H),5.83(s,2H).
MS(ESI+)m/z 168,170(M+H)+
[步骤3]N-(4-氯-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000331
将步骤2中得到的化合物(11.0g，65.6mmol)溶于吡啶(100ml)中，然后在0℃下向其中缓慢逐滴加入环丙基甲酰氯(7.5g，72.2mmol)，并在相同温度下搅拌1小时。将反应混合物加入水(350ml)中，然后滤出产生的固体并减压干燥。最后，由此得到标题化合物(12.7g，53.9mmol)。
1H NMR(400MHz,DMSO-d6)δ11.77(s,1H),10.79(s,1H),8.02(s,1H),7.44(d,1H),6.25(d,1H), 2.00(m,1H),0.88(m,4H).
MS(ESI+)m/z 236,238(M+H)+
[步骤4]N-(4-氯-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000332
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将步骤3中得到的化合物(12.7g，53.9mmol)溶于二甲基甲酰胺(100ml)中，然后在0℃下向其中缓慢逐滴加入氢化钠(3.2g，80.8mmol)，然后向其中缓慢逐滴加入对甲苯磺酰氯(11.3g，59.3mmol)，并搅拌30分钟。向所得混合物中加入乙酸乙酯(300ml)，然后用水洗涤(300ml，两次)，并且然后用无水硫酸镁干燥。之后，减压蒸馏剩余过滤溶液，并通过柱色谱进行分离，由此得到标题化合物(13.0g，33.3 mmol)。
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.16(m,3H),7.80(s,1H),7.42(m,2H),6.74(s,1H), 2.34(s,3H),2.08(m,1H),0.87(m,4H).
MS(ESI+)m/z 390,392(M+H)+
[步骤5]N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000333
向1,4-二氧杂环己烷(200ml)中加入步骤4中得到的化合物(20.0g，51.3mmol)以及双联频哪醇硼酸酯(26.0g，102.6mmol)、醋酸钯(0.2g，1.02mmol)、2-(二环己基)膦联苯(0.7g，2.05mmol)和醋酸钾(10.1 g，102.6mmol)，并在100℃下加热2小时。将所得混合物冷却至室温并减压蒸馏。之后，向其中加入二氯甲烷(300ml)，并用蒸馏水洗涤(300ml，两次)。用无水硫酸镁干燥分离的有机层，并且然后减压蒸馏剩余的过滤溶液并通过柱色谱进行分离，由此得到标题化合物(24.0g，49.8mmol)。
1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),8.34(s,1H),8.16(d,2H),7.74(d,1H),7.41(d,2H),6.82 (d,1H),2.33(s,3H),2.15(m,1H),1.30(s,12H),0.87(m,4H)
实施例1：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000341
[步骤1]
Figure BDA0002455210850000342
将4.0g(10.3mmol)由以上反应式3制备的N-(4-氯-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺溶于DMF/H2O＝2:1溶液中，并且然后将2.7g(12.4mmol)2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯胺、1.3g(1.5mmol)Pd(dppf)Cl2和2.6g(12.4mmol)K3PO4添加进其中，并在80-90℃下搅拌1小时。一旦反应完成后，将所述混合物在室温下冷却，然后加入水，并且然后使用乙酸乙酯进行萃取。之后，将从中萃取的溶液用无水硫酸镁干燥并减压浓缩，由此得到残余物。残余物经硅胶柱色谱(正己烷/乙酸乙酯＝2:1)分离，由此得到N-(4-(4-氨基-3-氟苯基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺。
MS(ESI+)m/z 465(M+H)+
[步骤2]
Figure BDA0002455210850000343
将以上步骤1中得到的N-(4-(4-氨基-3-氟苯基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺(100mg)添加到二氯甲烷中，并且然后向其中加入3当量Et3N。将2当量乙磺酰氯添加到所述混合物中，并在室温下搅拌。一旦反应完成后，向所述混合物中加入d-HCl，然后使用二氯甲烷进行萃取，并且然后分离有机层。将混合物浓缩后，将所得浓缩物溶于MeOH/THF(1:1)溶液中，然后向其中加入2 N氢氧化钠水溶液，并在30-40℃下搅拌4小时。一旦反应完成后，将所述混合物冷却至室温，并在搅拌的同时向其中加入饱和NH4Cl水溶液。滤出产生的固体，由此得到N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.66(s,1H),9.82(s,1H),8.02(s,1H),7.64–7.52(m, 3H),7.49–7.41(m,1H),6.61–6.53(m,1H),3.18(q,J＝7.2Hz,2H),2.04(dd,J＝5.0,10.1Hz,1H),1.29(t, J＝7.3Hz,3H),0.89–0.78(m,4H).
MS(ESI+)m/z 403(M+H)+
实施例2至213
在下文的实施例2至213中，通过与实施例1所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例2：N-(4-(4-((3,4-二氟苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000351
MS(ESI+)m/z 469(M+H)+
实施例3：N-(4-(4-((3-氟丙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000352
1H NMR(400MHz,甲醇-d4)δ7.89(s,1H),7.82–7.74(m,2H),7.48–7.37(m,2H),7.32(d,J＝3.6Hz, 1H),6.60(d,J＝3.6Hz,1H),4.59(s,1H),4.47(s,1H),3.27(d,J＝5.6Hz,1H),2.32–2.10(m,2H),1.12(d,J ＝6.1Hz,1H),0.95(ddt,J＝3.1,8.1,40.7Hz,5H).
MS(ESI+)m/z 417(M+H)+
实施例4：N-(4-(4-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000353
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.59(s,1H),10.01(s,1H),7.99(s,1H),7.75–7.63(m, 2H),7.46–7.29(m,3H),6.54(dd,J＝1.9,3.5Hz,1H),3.17(d,J＝7.4 Hz,2H),2.06(d,J＝16.6Hz,1H), 1.23(t,J＝7.3Hz,4H),0.89–0.75(m,4H).
MS(ESI+)m/z 385(M+H)+
实施例5：N-(4-(4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000354
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),10.00(s,1H),8.00(s,1H),7.81–7.64(m, 2H),7.38(ddd,J＝2.4,6.2,8.6Hz,3H),6.54(dd,J＝1.9,3.5Hz,1H),3.22–3.05(m,2H),2.06(d,J＝16.5 Hz,1H),1.72(td,J＝6.2,8.3,8.8Hz,2H),0.96(t,J＝7.4Hz,4H),0.81(ddd,J＝2.6,6.4,10.6Hz,5H).
MS(ESI+)m/z 399(M+H)+
实施例6：N-(4-(4-(丁基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000361
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.59(s,1H),10.13–9.90(m,1H),7.99(s,1H),7.72– 7.64(m,2H),7.42–7.30(m,3H),6.54(dd,J＝1.8,3.5Hz,1H),3.21–3.10(m,2H),2.09–1.99(m,1H), 1.73–1.61(m,2H),1.38(dt,J＝7.5,15.0Hz,2H),0.89–0.75(m,7H).
MS(ESI+)m/z 413(M+H)+
实施例7：N-(4-(4-(环己基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000362
MS(ESI+)m/z 439(M+H)+
实施例8：N-(4-(4-((2-氟乙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000363
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.73(s,1H),7.86(s,1H),7.61(d,J＝8.1Hz,2H),7.42 (d,J＝8.5Hz,1H),7.37(t,J＝2.9Hz,1H),6.89(d,J＝8.8Hz,2H),6.60(s,1H),2.74(t,J＝7.0Hz,2H),2.02 (d,J＝7.9Hz,1H),1.24(s,2H),0.93–0.76(m,4H).
MS(ESI+)m/z 403(M+H)+
实施例9：N-(4-(4-((1,1-二氧化四氢-2H-噻喃)-4-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000364
MS(ESI+)m/z 489(M+H)+
实施例10：N-(4-(4-((1,1-二氧化四氢噻吩)-3-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000371
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.61(s,1H),10.41(s,1H),8.00(s,1H),7.75–7.66(m, 2H),7.44–7.34(m,3H),6.54(dd,J＝1.9,3.7Hz,1H),4.30–4.19(m,1H),3.52(dd,J＝9.4,14.0Hz,1H), 3.27–3.18(m,2H),2.43–2.33(m,1H),2.03(d,J＝7.4Hz,1H),0.81(dt,J＝4.3,9.9Hz,4H).
MS(ESI+)m/z 475(M+H)+
实施例11：N-(4-(4-((1,1-二氧化硫杂环丁基)-3-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000372
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.62(d,J＝6.0Hz,1H),10.49(d,J＝13.3Hz,1H), 8.01(d,J＝3.0Hz,1H),7.78–7.69(m,2H),7.46–7.36(m,3H),6.58–6.48(m,2H),4.68–4.57(m,2H), 4.52–4.40(m,2H),2.03(s,2H),0.83–0.76(m,4H).
MS(ESI+)m/z 461(M+H)+
实施例12：N-(4-(4-((6-氯吡啶)-3-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000373
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.78(s,1H),10.59(s,1H),8.79(d,J＝2.6Hz,1H), 8.19(dd,J＝2.6,8.5Hz,1H),7.96(s,1H),7.76(d,J＝8.5Hz,1H),7.64(d,J＝8.1Hz,2H),7.38(t,J＝3.0Hz, 1H),7.28(d,J＝8.3Hz,2H),6.49(d,J＝3.4Hz,1H),2.03(s,1H),0.86–0.75(m,4H).
MS(ESI+)m/z 468,480(M+H)+
实施例13：N-(4-(4-((4-氟苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000381
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.56(d,J＝15.6Hz,2H),7.94(s,1H),7.92–7.83(m, 2H),7.60(d,J＝8.3Hz,2H),7.46–7.34(m,3H),7.25(d,J＝8.5Hz,2H),6.48(dd,J＝1.9,3.7Hz,1H),2.02 (d,J＝8.7Hz,1H),0.80(q,J＝5.9,8.6Hz,4H).
MS(ESI+)m/z 451(M+H)+
实施例14：N-(4-(4-((4-氯苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000382
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.58(s,2H),7.94(s,1H),7.87–7.75(m,2H),7.62(dd, J＝8.2,18.3Hz,4H),7.37(t,J＝3.1Hz,1H),7.24(d,J＝8.2Hz,2H),6.48(dd,J＝1.9,3.6Hz,1H),2.02(d,J ＝9.2Hz,1H),0.79(t,J＝7.2Hz,4H).
MS(ESI+)m/z 467,469(M+H)+
实施例15：N-(4-(4-((1-甲基-1H-咪唑)-5-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000383
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.58(s,1H),10.45(s,1H),7.92(d,J＝22.8Hz,2H), 7.75(s,1H),7.59(d,J＝8.4Hz,2H),7.37(t,J＝3.0Hz,1H),7.31(d,J＝8.2Hz,2H),6.50(s,1H),3.67(s, 3H),2.03(s,1H),0.85–0.76(m,4H).
MS(ESI+)m/z 437(M+H)+
实施例16：N-(4-(4-((1-甲基-1H-吡唑)-4-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000391
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.59(s,1H),10.36(s,1H),8.29(s,1H),7.97(s,1H), 7.75(s,1H),7.63(d,J＝8.3Hz,2H),7.38(t,J＝3.0Hz,1H),7.34–7.25(m,2H),6.51(dd,J＝1.9,3.7Hz, 1H),3.84(s,3H),2.04(d,J＝7.0Hz,1H),0.80(tt,J＝3.8,10.6Hz,4H).
MS(ESI+)m/z 437(M+H)+
实施例17：4-(N-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)氨磺酰基)苯甲酰胺的合成
Figure BDA0002455210850000392
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.62(s,1H),10.59(s,1H),8.11(s,1H),7.99(d,J＝8.2 Hz,2H),7.93(s,1H),7.89(d,J＝8.1Hz,2H),7.61(d,J＝8.5Hz,2H),7.57(s,1H),7.39–7.34(m,1H),7.28 (d,J＝8.3Hz,2H),6.47(d,J＝3.0Hz,1H),2.03(s,1H),0.84–0.76(m,4H).
MS(ESI+)m/z 476(M+H)+
实施例18：N-(4-(4-((1-乙酰基哌啶)-4-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000393
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.26(s,1H),8.17(s,1H),7.73(d,J＝8.1Hz,2H),7.34(d,J ＝8.2Hz,2H),6.81(s,1H),6.62(d,J＝3.1Hz,1H),4.72(d,J＝12.9Hz,1H),3.93(d,J＝14.0Hz,1H),3.49 (s,3H),3.28(d,J＝12.3Hz,1H),3.06(t,J＝12.9Hz,1H),2.55(t,J＝12.5Hz,1H),2.15(d,J＝9.9Hz,2H), 2.09(s,3H),1.85(d,J＝12.2Hz,2H),1.13(d,J＝3.9Hz,3H),0.95–0.78(m,9H).
MS(ESI+)m/z 482(M+H)+
实施例19：N-(4-(4-((4-异丙氧基苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000401
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.58(s,2H),7.95–7.84(m,3H),7.59(d,J＝8.2Hz, 2H),7.39–7.19(m,6H),6.54–6.38(m,1H),2.03(s,1H),0.85–0.77(m,4H).
MS(ESI+)m/z 491(M+H)+
实施例20：N-(4-(4-((4-溴苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000402
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1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),7.93(s,1H),7.72(dd,J＝8.0,5.5Hz,4H), 7.55(d,J＝8.5Hz,2H),7.39–7.33(m,1H),7.18(d,J＝8.6Hz,2H),6.53–6.44(m,1H),2.03(s,1H),0.86– 0.74(m,4H).
MS(ESI+)m/z 512(M+H)+
实施例21：N-(4-(4-((4-氰基苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000403
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.67(s,1H),10.59(s,1H),8.03–7.84(m,5H),7.61(d, J＝8.3Hz,2H),7.39–7.23(m,3H),6.48(s,1H),2.03(s,1H),0.82–0.75(m,4H).
MS(ESI+)m/z 458(M+H)+
实施例22：N-(4-(4-((2,3-二氢苯并呋喃)-5-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000411
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.58(s,1H),10.36(s,1H),7.94(s,1H),7.68(s,1H), 7.63–7.55(m,3H),7.40–7.32(m,1H),7.29–7.21(m,2H),6.88(d,J＝8.4Hz,1H),6.52–6.43(m,1H), 4.60(t,J＝8.7Hz,2H),3.22(t,J＝8.8Hz,2H),2.03(s,1H),0.84–0.74(m,4H).
MS(ESI+)m/z 475(M+H)+
实施例23：N-(4-(4-((6-甲氧基吡啶)-3-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000412
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.59(s,2H),8.64–8.54(m,1H),8.07–7.92(m,2H), 7.63(d,J＝8.1Hz,2H),7.39–7.26(m,3H),7.00(d,J＝8.6Hz,1H),6.49(s,1H),3.89(s,4H),2.03(s,1H), 0.82–0.75(m,4H).
MS(ESI+)m/z 464(M+H)+
实施例24：N-(4-(4-(苯磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000413
1H NMR(400MHz,DMSO-d6)δ11.50(d,J＝7.6Hz,1H),10.55(d,J＝22.8Hz,2H),7.93(s,1H),7.89 –7.80(m,2H),7.69–7.54(m,5H),7.40–7.34(m,1H),7.27(d,J＝8.7Hz,2H),6.53–6.38(m,1H),2.02(d, J＝8.1Hz,1H),0.80(q,J＝8.4,6.4Hz,4H).
MS(ESI+)m/z 433(M+H)+
实施例25：N-(4-(4-((3-氟苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000421
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.60(d,J＝19.3Hz,2H),7.94(s,1H),7.71–7.57(m, 5H),7.49(t,J＝7.5Hz,1H),7.41–7.33(m,1H),7.31–7.16(m,2H),6.56–6.43(m,1H),2.03(d,J＝9.3Hz, 1H),0.87–0.65(m,4H).
MS(ESI+)m/z 451(M+H)+
实施例26：N-(4-(4-((3-氯苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000422
1H NMR(400MHz,氯仿-d)δ7.94–7.77(m,2H),7.68(d,J＝7.8Hz,1H),7.58(dd,J＝6.6,4.3Hz, 2H),7.51–7.43(m,1H),7.36(t,J＝7.9Hz,1H),7.28–7.18(m,4H),6.58(d,J＝3.6Hz,1H),1.89(tt,J＝8.6, 4.6Hz,1H),1.09–1.01(m,3H),0.92(dq,J＝7.8,4.1Hz,2H),0.87–0.72(m,4H).
MS(ESI+)m/z 467,469(M+H)+
实施例27：N-(4-(4-((4-甲基苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000423
1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.46(s,1H),7.87(s,1H),7.62(d,J＝7.9Hz,2H),7.32 (dd,J＝19.4,5.6Hz,3H),7.18(d,J＝7.9Hz,2H),6.94(d,J＝8.3Hz,2H),6.56–6.44(m,1H),2.29(s,3H), 2.00(d,J＝11.3Hz,1H),0.88–0.66(m,4H).
MS(ESI+)m/z 447(M+H)+
实施例28：N-(4-(4-((4-(甲硫基)苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000431
1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),10.44(s,1H),7.86(s,1H),7.74–7.55(m,2H),7.30(dd, J＝14.1,5.6Hz,3H),7.26–7.15(m,2H),6.90(d,J＝8.4Hz,2H),6.64–6.31(m,1H),2.02(s,1H),0.89– 0.68(m,4H).
MS(ESI+)m/z 479(M+H)+
实施例29：N-(4-(4-(乙基磺酰氨基)-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000432
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.63(s,1H),9.86(s,1H),7.75(s,1H),7.54–7.06(m, 6H),6.09(s,1H),3.16(q,J＝7.6Hz,3H),2.14(s,3H),2.04(s,1H),1.23(t,J＝7.5Hz,4H),0.78(d,J＝9.5 Hz,4H).
MS(ESI+)m/z 399(M+H)+
实施例30：N-(4-(4-(乙基磺酰氨基)-2-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000433
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.63(s,1H),10.26(s,1H),7.94(s,1H),7.56(t,J＝8.4 Hz,1H),7.45–7.32(m,1H),7.17(d,J＝11.3Hz,2H),6.38–6.26(m,1H),3.23(q,J＝7.2Hz,2H),2.04(s, 1H),1.23(t,J＝7.2Hz,3H),0.92–0.71(m,4H).
MS(ESI+)m/z 403(M+H)+
实施例31：N-(4-(4-((4-溴-3-氟苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000441
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.52(s,1H),7.91(s,1H),7.83(t,J＝7.6Hz,1H),7.65 (dd,J＝2.0,8.5Hz,1H),7.57–7.44(m,3H),7.33(t,J＝2.9Hz,1H),7.10(d,J＝8.4Hz,2H),6.56–6.44(m, 1H),2.02(s,1H),0.86–0.72(m,4H).
MS(ESI+)m/z 529,531(M+H)+
实施例32：N-(4-(4-((4-溴-2-氟苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000442
1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.45(s,1H),7.87(s,1H),7.69(t,J＝8.0Hz,1H),7.54 –7.42(m,1H),7.42–7.24(m,4H),6.96–6.82(m,2H),6.57–6.42(m,1H),2.00(d,J＝12.5Hz,1H),0.87– 0.68(m,4H).
MS(ESI+)m/z 529,531(M+H)+
实施例33：N-(4-(4-((4-氯-3-(三氟甲基)苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000443
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.70(s,1H),10.59(s,1H),8.13(d,J＝2.3Hz,1H), 8.10–8.03(m,1H),7.96(d,J＝7.7Hz,2H),7.64(d,J＝8.2Hz,2H),7.49–7.35(m,1H),7.27(d,J＝8.3Hz, 2H),6.53–6.40(m,1H),2.02(d,J＝8.5Hz,1H),0.85–0.70(m,4H).
MS(ESI+)m/z 535,537(M+H)+
实施例34：N-(4-(4-(苯并[d][1,3]二氧杂环戊烯-5-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000451
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.59(s,1H),10.40(s,1H),7.94(s,1H),7.61(d,J＝8.3 Hz,2H),7.37(dd,J＝5.7,2.7Hz,2H),7.27(dd,J＝5.3,3.2Hz,3H),7.05(d,J＝7.8Hz,1H),6.49(s,1H), 6.14(s,2H),2.10–1.92(m,2H),1.24(s,5H),0.86–0.70(m,5H).
MS(ESI+)m/z 477(M+H)+
实施例35：N-(4-(4-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)-2-甲基环丙基-1-甲酰胺的合成
Figure BDA0002455210850000452
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.59(s,1H),10.02(s,1H),7.96(d,J＝5.8Hz,1H), 7.69(dd,J＝4.1,8.6Hz,2H),7.47(d,J＝7.8Hz,1H),7.39(dd,J＝4.4,7.5Hz,3H),7.11(d,J＝7.9Hz,1H), 6.63–6.49(m,1H),3.17(q,J＝7.3Hz,2H),1.86–1.74(m,1H),1.34–1.17(m,5H),1.17–0.93(m,4H).
MS(ESI+)m/z 399(M+H)+
实施例36：N-(4-(4-(((4-氟苯基)甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000453
MS(ESI+)m/z 465(M+H)+
实施例37：N-(4-(4-((4-(N,N-二甲基氨磺酰基)苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000461
MS(ESI+)m/z 540(M+H)+
实施例38：N-(4-(4-((2,3-二氢苯并[b][1,4]二噁英)-6-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000462
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.58(s,1H),7.94(s,1H),7.60(s,2H),7.27(s,5H), 7.01(s,2H),6.49(s,1H),4.28(s,4H),2.03(s,1H),0.80(s,4H).
MS(ESI+)m/z 491(M+H)+
实施例39：N-(4-(4-((4-(1H-四唑-1-基)苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000463
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.58(s,1H),10.39(s,1H),8.12(d,J＝21.2Hz,1H), 7.94(s,1H),7.74(d,J＝8.7Hz,1H),7.61(t,J＝9.0Hz,2H),7.39–7.00(m,6H),6.48(s,1H),2.03(s,1H), 0.80(s,4H).
MS(ESI+)m/z 501(M+H)+
实施例40：N-(4-(4-((6-氰基吡啶)-3-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000471
1H NMR(400MHz,DMSO-d6)δ11.47(d,J＝19.4Hz,1H),10.56(d,J＝12.4Hz,1H),9.00(d,J＝55.6 Hz,1H),8.46–7.81(m,4H),7.56(d,J＝37.7Hz,2H),7.41–7.11(m,3H),6.48(d,J＝8.3Hz,1H),2.02(s, 1H),0.79(s,4H).
MS(ESI+)m/z 459(M+H)+
实施例41：N-(4-(4-((1-甲基乙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000472
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),9.96(s,1H),7.99(s,1H),7.67(d,J＝8.2 Hz,2H),7.39(d,J＝6.8Hz,3H),6.54(s,1H),2.04(s,1H),1.30–1.24(m,6H),0.81(s,4H).
MS(ESI+)m/z 399(M+H)+
实施例42：N-(4-(4-((1-乙基丙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000473
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.62(s,1H),10.04(s,1H),7.99(s,1H),7.70–7.62(m, 2H),7.41–7.34(m,3H),6.54(dd,J＝3.5,1.8Hz,1H),2.97(dd,J＝8.7,3.7Hz,1H),2.03(d,J＝5.0Hz,1H), 1.87(ddd,J＝14.7,7.6,5.1Hz,2H),1.70(dt,J＝14.3,7.2Hz,2H),0.96(t,J＝7.5Hz,6H),0.80(t,J＝5.5Hz, 4H).
MS(ESI+)m/z 427(M+H)+
实施例43：N-(4-(4-((2-甲基丙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000481
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),10.00(s,1H),8.00(s,1H),7.69(d,J＝8.7 Hz,2H),7.37(t,J＝9.9Hz,3H),6.55(s,1H),3.06(d,J＝6.8Hz,2H),2.17(s,1H),2.04(s,1H),1.05–0.95 (m,6H),0.81(s,4H).
MS(ESI+)m/z 413(M+H)+
实施例44：N-(4-(4-((2,2-二甲基丙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000482
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),9.99(s,1H),8.00(s,1H),7.69(d,J＝6.8 Hz,2H),7.44–7.29(m,3H),6.55(s,1H),3.11(s,2H),2.04(s,1H),1.11(q,J＝7.5,5.8Hz,9H),0.81(s,4H).
MS(ESI+)m/z 427(M+H)+
实施例45：N-(4-(4-((3-甲基丁基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000483
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),10.00(s,1H),8.00(s,1H),7.69(d,J＝8.4 Hz,2H),7.37(d,J＝9.7Hz,3H),6.53(s,1H),3.14(d,J＝8.8Hz,2H),2.04(s,1H),1.60(s,3H),0.82(s, 10H).
MS(ESI+)m/z 427(M+H)+
实施例46：N-(4-(4-((环丙基甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000491
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),10.06(s,1H),7.99(s,1H),7.74–7.61(m, 2H),7.38(d,J＝8.9Hz,3H),6.54(s,1H),3.21–3.07(m,2H),2.04(s,1H),1.02(s,1H),0.81(s,4H),0.56(s, 2H),0.27(s,2H).
MS(ESI+)m/z 411(M+H)+
实施例47：N-(4-(4-((环己基甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000492
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),10.01(s,1H),8.00(s,1H),7.68(d,J＝7.9 Hz,2H),7.37(t,J＝10.1Hz,3H),6.54(s,1H),3.11–2.99(m,2H),2.03(s,1H),1.85(s,2H),1.63(s,2H), 1.24(s,2H),1.06(s,2H),0.81(s,4H).
MS(ESI+)m/z 453(M+H)+
实施例48：N-(4-(4-(烯丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000493
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.63(s,1H),10.12(s,1H),8.00(s,1H),7.69(d,J＝8.3 Hz,2H),7.38(dd,J＝8.2,5.6Hz,3H),6.55(dd,J＝3.7,1.9Hz,1H),5.81(ddd,J＝17.2,10.1,7.3Hz,1H), 5.36(dd,J＝19.3,13.6Hz,2H),3.98(d,J＝7.2Hz,2H),2.04(s,1H),0.85–0.76(m,4H).
MS(ESI+)m/z 397(M+H)+
实施例49：N-(4-(4-((氟甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000501
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.61(s,2H),8.00(s,1H),7.69(d,J＝8.1Hz,2H),7.38 (d,J＝11.9Hz,3H),6.54(s,1H),5.59(s,1H),5.48(s,1H),2.05(s,1H),0.81(s,4H).
MS(ESI+)m/z 389(M+H)+
实施例50：N-(4-(4-((二氟甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000502
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),11.16(s,1H),10.62(s,1H),8.01(s,1H),7.72(d,J＝8.6 Hz,2H),7.50–7.30(m,3H),7.14(d,J＝51.5Hz,1H),6.53(s,1H),2.05(s,1H),0.92–0.71(m,4H).
MS(ESI+)m/z 407(M+H)+
实施例51：N-(4-(4-((2,2-二氟乙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000503
1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.48(s,1H),7.92(s,1H),7.44(s,2H),7.32(s,1H), 6.70(s,2H),6.54(s,1H),5.40(s,2H),4.03(s,1H),2.03(s,1H),0.79(d,J＝14.6Hz,4H).
MS(ESI+)m/z 421(M+H)+
实施例52：N-(4-(4-((3-氰基丙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000504
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.60(s,1H),10.22–9.95(m,1H),8.00(s,1H),7.70(d, J＝8.1Hz,2H),7.39(s,3H),6.54(s,1H),3.24(d,J＝6.7Hz,2H),2.67(t,J＝7.4Hz,2H),2.02(d,J＝12.0 Hz,3H),0.81(s,4H).
MS(ESI+)m/z 424(M+H)+
实施例53：N-(4-(4-((2-乙氧基乙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000511
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),9.89(s,1H),8.01(d,J＝15.2Hz,1H), 7.68(d,J＝8.9Hz,2H),7.48–7.29(m,3H),6.54(s,1H),3.83–3.68(m,2H),3.49–3.39(m,4H),2.05(s, 1H),1.13–0.98(m,3H),0.91–0.73(m,4H).
MS(ESI+)m/z 429(M+H)+
实施例54：N-(4-(4-(((四氢呋喃-3-基)甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000512
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.61(s,1H),9.93(s,1H),8.00(s,1H),7.80–7.63(m, 2H),7.38(d,J＝11.3Hz,3H),6.55(s,1H),3.89(d,J＝10.3Hz,1H),3.66(d,J＝29.1Hz,2H),2.09(d,J＝ 20.8Hz,2H),1.64(d,J＝12.5Hz,1H),0.82(s,4H).
MS(ESI+)m/z 441(M+H)+
实施例55：N-(4-(4-(((四氢-2H-吡喃-4-基)甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000513
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.62(d,J＝12.6Hz,1H),9.93(s,1H),8.00(s,1H), 7.68(d,J＝9.5Hz,2H),7.51–7.22(m,3H),6.55(d,J＝11.0Hz,1H),3.81(s,2H),3.14(q,J＝6.7Hz,2H), 2.09(d,J＝30.9Hz,2H),1.76(s,2H),1.32(s,2H),0.82(s,4H).
MS(ESI+)m/z 455(M+H)+
实施例56：N-(4-(4-((2-(甲基磺酰基)乙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000521
MS(ESI+)m/z 463(M+H)+
实施例57：N-(4-(4-(环丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000522
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),9.94(s,1H),8.00(s,1H),7.68(dd,J＝ 11.1,4.7Hz,2H),7.40(d,J＝8.1Hz,3H),6.54(s,1H),2.71(s,1H),2.04(s,1H),0.97(d,J＝9.6Hz,4H), 0.80(d,J＝12.4Hz,4H).
MS(ESI+)m/z 397(M+H)+
实施例58：N-(4-(4-(环丁基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000523
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.62(s,1H),9.93(s,1H),7.99(s,1H),7.70–7.64(m, 2H),7.39(dd,J＝3.5,2.5Hz,1H),7.35(d,J＝8.6Hz,2H),6.53(dd,J＝3.6,1.9Hz,1H),3.99(p,J＝8.0Hz, 1H),2.32(d,J＝18.7Hz,2H),2.20(dt,J＝8.4,4.4Hz,2H),2.02(d,J＝13.0Hz,1H),1.95–1.82(m,2H), 0.81(d,J＝4.4Hz,4H).
MS(ESI+)m/z 411(M+H)+
实施例59：N-(4-(3-氰基-4-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000524
MS(ESI+)m/z 410(M+H)+
实施例60：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1-甲基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000531
1H NMR(400MHz,DMSO-d6)δ10.77(d,J＝19.2Hz,1H),8.06(d,J＝14.7Hz,1H),7.69–7.46(m, 4H),6.57(dd,J＝3.7,1.8Hz,1H),3.82(d,J＝4.9Hz,3H),2.08(s,1H),1.27(dt,J＝18.9,7.1Hz,5H),0.86– 0.80(m,4H).
MS(ESI+)m/z 417(M+H)+
实施例61：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1-丙基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000532
1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),8.07(s,1H),7.68–7.50(m,4H),6.59(d,J＝3.6Hz,1H), 4.20(t,J＝7.3Hz,2H),3.60(t,J＝7.0Hz,3H),2.10(s,1H),1.84(q,J＝7.2Hz,2H),1.42(q,J＝7.5Hz,2H), 1.31–1.27(m,3H),0.84–0.78(m,4H).
MS(ESI+)m/z 445(M+H)+
实施例62：N-(1-(氰基甲基)-4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000533
1H NMR(400MHz,DMSO-d6)δ10.88(d,J＝15.7Hz,1H),9.86(s,1H),8.14(d,J＝12.2Hz,1H),7.70 –7.48(m,4H),6.70(d,J＝3.8Hz,1H),5.43(d,J＝4.2Hz,2H),2.12(s,1H),1.28(d,J＝6.7Hz,3H),1.23(s, 2H),0.85–0.81(m,4H).
MS(ESI+)m/z 442(M+H)+
实施例63：N-(4-(3-氯-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000541
1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),10.70(s,1H),9.65(s,1H),8.02(s,1H),7.76(d,J＝2.0 Hz,1H),7.70(dd,J＝2.0,8.4Hz,1H),7.63(d,J＝8.4Hz,1H),7.45(dd,J＝2.5,3.6Hz,1H),6.53(dd,J＝1.8, 3.5Hz,1H),3.20–3.12(m,2H),2.03(q,J＝5.9,7.3Hz,1H),1.84–1.74(m,2H),0.99(t,J＝7.4Hz,3H), 0.85–0.75(m,4H).
MS(ESI+)m/z 433,435(M+H)+
实施例64：N-(4-(4-(乙基磺酰氨基)-3-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000542
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),10.65(s,1H),9.21(s,1H),8.00(s,1H),7.58–7.50(m, 2H),7.50–7.38(m,2H),6.54(dd,J＝1.9,3.5Hz,1H),3.15(q,J＝7.3Hz,2H),2.41(s,3H),2.08–1.97(m, 1H),1.28(t,J＝7.3Hz,3H),0.89–0.74(m,4H).
MS(ESI+)m/z 399(M+H)+
实施例65：N-(4-(3-甲基-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000543
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.64(s,1H),9.11(s,1H),8.00(s,1H),7.58–7.50(m, 2H),7.47–7.37(m,2H),6.54(dd,J＝1.9,3.5Hz,1H),3.16–3.06(m,2H),2.39(s,3H),2.09–1.99(m,1H), 1.76(q,J＝7.5Hz,2H),0.99(t,J＝7.4Hz,3H),0.87–0.75(m,4H).
MS(ESI+)m/z 413(M+H)+
实施例66：N-(4-(3-氟-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000551
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.68(s,1H),9.84(s,1H),8.02(s,1H),7.62–7.52(m, 3H),7.49–7.40(m,1H),6.56(dd,J＝3.5,1.8Hz,1H),3.23–3.10(m,2H),2.08–1.97(m,1H),1.84–1.71 (m,2H),0.99(t,J＝7.4Hz,3H),0.80(dd,J＝10.1,3.5Hz,4H).
MS(ESI+)m/z 417(M+H)+
实施例67：N-(4-(4-(丁基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000552
1H NMR(400MHz,氯仿-d)δ11.59(s,1H),10.65(s,1H),9.82(s,1H),8.02(s,1H),7.62–7.53(m, 3H),7.43(t,J＝3.0Hz,1H),6.56(dd,J＝3.5,1.8Hz,1H),3.21–3.13(m,2H),2.11–1.98(m,1H),1.73(p,J ＝7.7Hz,2H),1.41(q,J＝7.4Hz,2H),0.89(d,J＝7.3Hz,3H),0.83–0.76(m,4H).
MS(ESI+)m/z 431(M+H)+
实施例68：N-(4-(4-(环己基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000553
1H NMR(400MHz,氯仿-d)δ11.59(s,1H),10.65(s,1H),9.78(s,1H),8.02(s,1H),7.60(t,J＝8.4Hz, 1H),7.54(dd,J＝8.7,4.7Hz,2H),7.43(d,J＝5.8Hz,1H),6.56(dd,J＝3.4,1.7Hz,1H),3.06(t,J＝11.8Hz, 1H),2.12(d,J＝12.3Hz,2H),2.05(s,1H),1.79(d,J＝12.7Hz,2H),1.62(d,J＝13.0Hz,1H),1.44(q,J＝ 12.4Hz,2H),1.34–1.25(m,2H),1.15(t,J＝12.7Hz,1H),0.84–0.77(m,4H).
MS(ESI+)m/z 457(M+H)+
实施例69：N-(4-(4-(环丙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000561
1H NMR(400MHz,氯仿-d)δ11.59(s,1H),10.65(s,1H),9.80(s,1H),8.01(s,1H),7.58(dt,J＝11.8, 6.9Hz,3H),7.43(d,J＝5.9Hz,1H),6.56(dd,J＝3.5,1.8Hz,1H),2.74(td,J＝7.8,3.8Hz,1H),2.08–1.98 (m,1H),1.01–0.93(m,4H),0.83–0.79(m,4H).
MS(ESI+)m/z 415(M+H)+
实施例70：N-(4-(4-((环己基甲基)磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000562
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.69(s,1H),9.87(s,1H),8.02(s,1H),7.60–7.52(m, 3H),7.44(t,J＝3.1Hz,1H),6.56(dd,J＝3.6,1.8Hz,1H),3.07(d,J＝6.0Hz,2H),2.04(s,1H),1.89(t,J＝ 14.8Hz,3H),1.62(dd,J＝27.0,12.4Hz,3H),1.30–0.97(m,7H),0.86-0.75(m,4H).
MS(ESI+)m/z 471(M+H)+
实施例71：N-(4-(4-(烯丙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000563
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.69(s,1H),9.92(s,1H),8.02(s,1H),7.58(dd,J＝16.4,8.0Hz,3H),7.44(t,J＝2.9Hz,1H),6.56(d,J＝4.7Hz,1H),5.86(td,J＝17.1,7.2Hz,1H),5.50–5.37 (m,2H),3.99(d,J＝7.2Hz,2H),2.06–1.99(m,1H),0.81(d,J＝4.8Hz,4H).
MS(ESI+)m/z 415(M+H)+
实施例72：N-(4-(3-氟-4-(((四氢呋喃-3-基)甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000571
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.68(s,1H),9.96(s,1H),8.02(s,1H),7.64–7.52(m, 3H),7.44(dd,J＝3.5,2.5Hz,1H),6.56(dd,J＝3.6,1.8Hz,1H),3.88(dd,J＝8.6,7.2Hz,1H),3.72(td,J＝ 8.3,5.0Hz,1H),3.63(d,J＝7.8Hz,1H),2.70–2.61(m,1H),2.17–2.07(m,1H),2.06–1.97(m,1H),1.68 (dq,J＝12.3,7.7Hz,1H),0.83–0.78(m,4H).
MS(ESI+)m/z 459(M+H)+
实施例73：N-(4-(3-氟-4-(((四氢-2H-吡喃-4-基)甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000572
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.69(s,1H),9.91(s,1H),8.03(s,1H),7.62–7.53(m, 3H),7.46–7.41(m,1H),6.56(dd,J＝3.5,1.8Hz,1H),3.85–3.76(m,2H),3.28(dd,J＝11.7,2.0Hz,2H), 3.16(d,J＝6.4Hz,2H),2.18(q,J＝6.0,4.1Hz,1H),2.03(d,J＝8.7Hz,1H),1.78(d,J＝13.0Hz,2H),1.35 (qd,J＝12.2,4.4Hz,2H),0.84–0.75(m,4H).
MS(ESI+)m/z 473(M+H)+
实施例74：N-(4-(4-(乙基磺酰氨基)苯基)-2-甲基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000573
MS(ESI+)m/z 399(M+H)+
实施例75：N-(4-(3-氟-4-((2-甲基丙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000581
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.68(s,1H),8.02(s,1H),7.62–7.50(m,3H),7.44(dd, J＝3.5,2.5Hz,1H),6.56(dd,J＝3.5,1.8Hz,1H),3.08(d,J＝6.4Hz,2H),2.21(dq,J＝13.3,6.6Hz,1H), 2.04(h,J＝6.2,5.4Hz,1H),1.04(d,J＝6.7Hz,6H),0.83–0.78(m,4H).
MS(ESI+)m/z 431(M+H)+
实施例76：N-(4-(3-氟-4-((3-氟丙基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000582
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.68(s,1H),9.98(s,1H),8.02(s,1H),7.61–7.54(m, 3H),7.44(t,J＝3.0Hz,1H),6.56(dd,J＝3.6,1.8Hz,1H),4.62(t,J＝5.9Hz,1H),4.50(t,J＝6.0Hz,1H), 3.28(d,J＝15.4Hz,2H),2.12(ddd,J＝33.0,16.5,9.7Hz,3H),0.83–0.78(m,4H).
MS(ESI+)m/z 435(M+H)+
实施例77：N-(4-(4-((3-氰基丙基)磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000583
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.68(s,1H),10.03(s,1H),8.02(s,1H),7.61–7.55(m, 3H),7.44(dd,J＝3.5,2.5Hz,1H),6.56(dd,J＝3.5,1.8Hz,1H),3.30–3.24(m,2H),2.70(t,J＝7.3Hz,2H), 2.06(p,J＝7.2Hz,3H),0.85-0.77(m,4H).
MS(ESI+)m/z 442(M+H)+
实施例78：N-(4-(4-(环丁基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000584
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.68(s,1H),9.77(s,1H),8.02(s,1H),7.62–7.50(m, 3H),7.44(t,J＝3.0Hz,1H),6.55(t,J＝2.5Hz,1H),4.00(t,J＝8.1Hz,1H),2.42–1.82(m,6H),0.81(t,J＝6.5Hz,4H).
MS(ESI+)m/z 429(M+H)+
实施例79：N-(4-(4-((2,2-二甲基丙基)磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000591
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.68(s,1H),8.02(s,1H),7.62–7.51(m,3H),7.44(t,J ＝2.8Hz,1H),6.57(s,1H),3.14(s,2H),2.03(d,J＝12.4Hz,1H),1.11(s,9H),0.81(d,J＝4.6Hz,4H).
MS(ESI+)m/z 445(M+H)+
实施例80：N-(4-(4-((环丙基甲基)磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000592
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.67(s,1H),9.88(s,1H),8.01(s,1H),7.60(t,J＝8.4 Hz,1H),7.53(t,J＝8.4Hz,2H),7.43(t,J＝3.0Hz,1H),6.56(d,J＝3.2Hz,1H),3.14(d,J＝7.0Hz,2H), 2.04(s,1H),1.08(s,1H),0.87–0.74(m,4H),0.56(q,J＝5.8Hz,2H),0.34(q,J＝5.1Hz,2H).
MS(ESI+)m/z 429(M+H)+
实施例81：N-(4-(4-(乙基磺酰氨基)-3,5-二氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000593
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),10.73(s,1H),9.64(s,1H),8.03(s,1H),7.53–7.42(m, 3H),6.58(dd,J＝1.8,3.5Hz,1H),3.19(q,J＝7.4Hz,2H),2.09–1.99(m,1H),1.34(t,J＝7.3Hz,3H),0.83 –0.77(m,4H).
MS(ESI+)m/z 421(M+H)+
实施例82：N-(4-(3,5-二氟-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000601
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),10.73(s,1H),9.64(s,1H),8.03(s,1H),7.51–7.45(m, 3H),6.58(dd,J＝1.8,3.6Hz,1H),3.21–3.12(m,2H),2.04(dd,J＝5.7,11.3Hz,1H),1.83(q,J＝7.6Hz, 2H),1.02(t,J＝7.4Hz,3H),0.86-0.78(m,4H).
MS(ESI+)m/z 435(M+H)+
实施例83：N-(4-(4-(乙基磺酰氨基)-2,5-二氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000602
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),10.69(s,1H),10.12(s,1H),7.96(s,1H),7.54–7.46(m, 1H),7.45–7.38(m,2H),6.32(d,J＝2.1Hz,1H),3.23(q,J＝7.3Hz,2H),2.03(d,J＝5.8Hz,1H),1.26(q,J ＝7.8,8.3Hz,4H),0.84-0.75(m,4H).
MS(ESI+)m/z 421(M+H)+
实施例84：N-(4-(2,5-二氟-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000603
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.70(s,1H),10.12(s,1H),7.97(s,1H),7.50(dd,J＝ 6.7,10.6Hz,1H),7.46–7.37(m,2H),6.32(d,J＝2.6Hz,1H),3.25–3.17(m,2H),2.09–1.98(m,1H),1.75 (dt,J＝7.6,15.2Hz,2H),0.99(t,J＝7.4Hz,3H),0.85-0.78(m,4H).
MS(ESI+)m/z 435(M+H)+
实施例85：N-(4-(4-(((1-氰基环丙基)甲基)磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000611
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.67(s,1H),10.18(s,1H),8.01(s,1H),7.56(d,J＝ 13.3Hz,3H),7.43(s,1H),6.55(s,1H),2.02(s,1H),1.33(d,J＝42.9Hz,2H),1.23(s,2H),0.81(s,4H).
MS(ESI+)m/z 454(M+H)+
实施例86：N-(4-(4-(((1-(氰基甲基)环丙基)甲基)磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850000612
MS(ESI+)m/z 468(M+H)+
实施例87：N-(4-(4-((3-氰基-3-甲基丁基)磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000613
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.68(s,1H),10.03(s,1H),8.02(s,1H),7.57(t,J＝5.9 Hz,3H),7.44(s,1H),6.59–6.49(m,1H),2.06(d,J＝12.8Hz,5H),1.23(s,6H),0.85-0.77(m,4H).
MS(ESI+)m/z 470(M+H)+
实施例88：N-(4-(4-(((1-氰基环丙基)甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000621
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.62(s,1H),7.99(s,1H),7.68(d,J＝8.5Hz,2H),7.41 –7.32(m,3H),6.53(dd,J＝3.5,1.8Hz,1H),3.54(s,2H),2.06–1.94(m,2H),1.36(q,J＝4.9Hz,2H),1.20 –1.14(m,2H),0.83–0.75(m,4H).
MS(ESI+)m/z 436(M+H)+
实施例89：N-(4-(4-(((1-(氰基甲基)环丙基)甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000622
1H NMR(400MHz,甲醇-d4)δ11.52(s,1H),10.62(s,1H),10.23(s,1H),7.99(s,1H),7.69(d,J＝8.5 Hz,2H),7.42–7.31(m,3H),6.54(dd,J＝3.6,1.8Hz,1H),3.30(s,2H),2.86(s,2H),2.09–1.92(m,1H), 0.80(td,J＝7.9,2.9Hz,4H),0.75–0.63(m,4H).
MS(ESI+)m/z 450(M+H)+
实施例90：N-(4-(4-(环丙基磺酰氨基)-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000623
1H NMR(400MHz,氯仿-d)δ11.47(s,1H),10.62(s,1H),9.80(s,1H),7.77(s,1H),7.33(dd,J＝3.5, 2.4Hz,1H),7.26–7.15(m,3H),6.08(dd,J＝3.5,1.9Hz,1H),2.15(s,3H),2.06–2.00(m,1H),0.99–0.96 (m,4H),0.82-0.74(m,4H).
MS(ESI+)m/z 411(M+H)+
实施例91：N-(4-(4-(环丁基磺酰氨基)-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000631
1H NMR(400MHz,氯仿-d)δ11.47(s,1H),10.62(s,1H),9.77(s,1H),7.76(s,1H),7.33(dd,J＝3.5, 2.5Hz,1H),7.25–7.09(m,3H),6.07(dd,J＝3.5,1.9Hz,1H),3.99(p,J＝8.1Hz,1H),2.36(dd,J＝19.7,9.4 Hz,2H),2.23–2.17(m,2H),2.13(s,3H),2.03(s,1H),1.95–1.84(m,2H),0.82-0.74(m,4H).
MS(ESI+)m/z 425(M+H)+
实施例92：N-(4-(4-((环丙基甲基)磺酰氨基)-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000632
1H NMR(400MHz,氯仿-d)δ11.47(s,1H),10.61(s,1H),9.91(s,1H),7.76(s,1H),7.33(d,J＝2.4Hz, 1H),7.28–7.10(m,3H),6.08(dd,J＝3.5,1.9Hz,1H),3.13(d,J＝7.1Hz,2H),2.14(s,3H),2.07–1.94(m, 1H),1.02(td,J＝7.5,3.8Hz,1H),0.78(dd,J＝8.4,2.5Hz,4H),0.58–0.53(m,2H),0.28(dt,J＝6.3,4.5Hz, 2H).
MS(ESI+)m/z 425(M+H)+
实施例93：N-(4-(4-(乙基磺酰氨基)苯基)-3-甲基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000633
1H NMR(400MHz,氯仿-d)δ11.17(s,1H),10.56(s,1H),7.72(s,1H),7.42–7.38(m,2H),7.31(d,J＝ 6.8Hz,2H),7.10(s,1H),3.15(q,J＝7.2Hz,2H),2.03(s,1H),1.87(s,3H),1.24–1.20(m,5H),0.81–0.74 (m,4H).
MS(ESI+)m/z 399(M+H)+
实施例94：N-(3-甲基-4-(4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000641
1H NMR(400MHz,氯仿-d)δ11.17(d,J＝2.4Hz,1H),10.57(s,1H),7.72(s,1H),7.39(d,J＝8.5Hz, 2H),7.34–7.28(m,3H),7.10(d,J＝2.1Hz,1H),3.12(t,J＝2.1Hz,2H),2.02(d,J＝2.1Hz,1H),1.86(s, 3H),1.74–1.70(m,2H),0.95(d,J＝7.5Hz,3H),0.81-0.73(m,4H).
MS(ESI+)m/z 413(M+H)+
实施例95：N-(4-(2-甲基-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000642
1H NMR(400MHz,氯仿-d)δ11.48(s,1H),10.62(s,1H),9.84(s,1H),7.77(s,1H),7.33(dd,J＝3.5, 2.5Hz,1H),7.23(s,1H),7.19–7.10(m,2H),6.08(dd,J＝3.5,1.8Hz,1H),3.16–3.11(m,2H),2.14(s,3H), 2.09–2.01(m,1H),1.72(h,J＝7.5Hz,2H),0.97(t,J＝7.4Hz,3H),0.83–0.73(m,4H).
MS(ESI+)m/z 413(M+H)+
实施例96：N-(4-(4-((3-氰基丙基)磺酰氨基)-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000643
1H NMR(400MHz,氯仿-d)δ11.47(s,1H),10.62(s,1H),7.76(s,1H),7.37–7.31(m,1H),7.24(t,J＝ 7.1Hz,1H),7.20–7.14(m,2H),6.11–6.04(m,1H),3.25(dd,J＝8.5,6.6Hz,2H),2.68(t,J＝7.3Hz,2H), 2.14(s,3H),2.04–1.98(m,2H),1.92(d,J＝8.2Hz,1H),0.82-0.74(m,4H).
MS(ESI+)m/z 438(M+H)+
实施例97：6-(环丙基甲酰氨基)-4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶7-氧化物的合成
Figure BDA0002455210850000651
1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),10.78(s,1H),9.84(s,1H),8.16(s,1H),7.61–7.50(m, 3H),7.46(t,J＝2.8Hz,1H),6.71(dd,J＝3.5,1.8Hz,1H),3.18(q,J＝7.2Hz,2H),2.41(q,J＝6.5,5.3Hz, 1H),1.28(t,J＝7.3Hz,3H),0.89(d,J＝7.9Hz,4H).
MS(ESI+)m/z 419(M+H)+
实施例98：N-(4-(4-(乙基磺酰氨基)-3-(三氟甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000652
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.64(s,1H),10.32(s,1H),7.82(s,1H),7.67(d,J＝2.2 Hz,1H),7.60–7.52(m,1H),7.43(d,J＝8.4Hz,1H),7.34–7.26(m,1H),6.01(dd,J＝3.6,1.8Hz,1H),3.24 (d,J＝7.4Hz,2H),2.07–1.98(m,1H),1.25(t,J＝7.3Hz,3H),0.81-0.72(m,4H).
MS(ESI+)m/z 453(M+H)+
实施例99：N-(4-(2-乙基-4-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000653
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.61(s,1H),9.85(s,1H),7.77(s,1H),7.32(dd,J＝3.5, 2.4Hz,1H),7.24–7.12(m,3H),6.05(dd,J＝3.5,1.9Hz,1H),3.16(q,J＝7.3Hz,2H),2.46(d,J＝7.6Hz, 2H),2.11–1.97(m,1H),1.23(t,J＝7.3Hz,3H),0.95(t,J＝7.5Hz,3H),0.81-0.72(m,4H).
MS(ESI+)m/z 413(M+H)+
实施例100：N-(4-(3-氟-2-甲基-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000661
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.66(s,1H),9.70(s,1H),7.79(s,1H),7.36(dd,J＝5.4, 2.5Hz,2H),7.12(d,J＝8.4Hz,1H),6.16–6.08(m,1H),3.19–3.09(m,2H),2.08(d,J＝2.6Hz,3H),2.05– 2.01(m,1H),1.83–1.73(m,2H),1.00(t,J＝7.2Hz,3H),0.84–0.74(m,4H).
MS(ESI+)m/z 431(M+H)+
实施例101：N-(4-(4-(乙基磺酰氨基)-3-氟-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000662
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.66(s,1H),9.71(s,1H),7.79(s,1H),7.40–7.30(m, 2H),7.18–7.06(m,1H),6.11(dd,J＝3.5,1.9Hz,1H),3.16(t,J＝7.3Hz,2H),2.08(d,J＝2.7Hz,3H),2.03 –1.95(m,1H),1.29(t,J＝7.3Hz,3H),0.82–0.73(m,4H).
MS(ESI+)m/z 417(M+H)+
实施例102：N-(4-(4-(((1-氰基环丙基)甲基)磺酰氨基)-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000663
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.61(s,1H),9.91(s,1H),7.76(s,1H),7.33(dd,J＝3.5, 2.4Hz,1H),7.23(d,J＝8.3Hz,1H),7.18(d,J＝2.2Hz,1H),7.14(dd,J＝8.1,2.3Hz,1H),6.07(dd,J＝3.5, 1.9Hz,1H),3.52(s,2H),2.14(s,3H),1.99(dt,J＝14.0,7.8Hz,2H),1.38–1.33(m,2H),1.22–1.16(m,2H), 0.80–0.74(m,4H).
MS(ESI+)m/z 450(M+H)+
实施例103：N-(4-(4-(((1-(氰基甲基)环丙基)甲基)磺酰氨基)-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850000671
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.61(s,1H),7.76(s,1H),7.32(dd,J＝3.4,2.4Hz,1H), 7.24(d,J＝8.3Hz,1H),7.17–7.11(m,2H),2.86(s,2H),2.14(s,3H),2.05–1.95(m,2H),0.79(d,J＝3.8Hz, 2H),0.75–0.65(m,4H).
MS(ESI+)m/z 464(M+H)+
实施例104：N-(4-(4-((3-氰基丙基)磺酰氨基)-2,5-二氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000672
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),10.69(s,1H),7.96(d,J＝1.2Hz,1H),7.52(dd,J＝6.6, 10.6Hz,1H),7.47–7.39(m,4H),6.31(dt,J＝2.0,3.9Hz,1H),3.37(s,2H),2.70(t,J＝7.3Hz,2H),2.11– 1.99(m,3H),0.85-0.76(m,4H).
MS(ESI+)m/z 460(M+H)+
实施例105：N-(4-(4-(((1-氰基环丙基)甲基)磺酰氨基)-2,5-二氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000673
1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),10.67(s,1H),7.96(s,1H),7.47(ddd,J＝6.8,11.0,15.3 Hz,2H),7.40(dd,J＝2.5,3.5Hz,1H),6.31(dd,J＝1.9,3.6Hz,1H),3.62(s,2H),2.07–2.00(m,1H),1.38(q, J＝4.1,4.8Hz,2H),1.30–1.22(m,2H),0.84-0.75(m,4H).
MS(ESI+)m/z 472(M+H)+
实施例106：N-(4-(4-(((1-(氰基甲基)环丙基)甲基)磺酰氨基)-2,5-二氟苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850000681
MS(ESI+)m/z 486(M+H)+
实施例107：N-(4-(4-(((1-氰基环丙基)甲基)磺酰氨基)-3,5-二氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000682
MS(ESI+)m/z 472(M+H)+
实施例108：N-(4-(4-(((1-(氰基甲基)环丙基)甲基)磺酰氨基)-3,5-二氟苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850000683
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),10.71(s,1H),8.03(s,1H),7.52–7.44(m,3H),6.58(dd, J＝1.8,3.5Hz,1H),3.38(s,2H),2.86(s,2H),2.04(td,J＝3.8,7.4,7.8Hz,1H),0.93–0.87(m,2H),0.82 (ddd,J＝2.3,6.2,9.5Hz,4H),0.74–0.68(m,2H).
MS(ESI+)m/z 486(M+H)+
实施例109：N-(4-(4-(((1-氰基环丙基)甲基)磺酰氨基)-2-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000691
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.63(s,1H),10.23(s,1H),7.77(s,1H),7.32(s,1H), 7.25–7.09(m,3H),6.04(d,J＝3.2Hz,1H),3.52(s,2H),2.04(d,J＝14.3Hz,1H),1.36(s,2H),1.20(d,J＝ 5.2Hz,2H),0.95(t,J＝7.6Hz,3H),0.77(d,J＝7.3Hz,4H).
MS(ESI+)m/z 464(M+H)+
实施例110：N-(4-(4-(((1-(氰基甲基)环丙基)甲基)磺酰氨基)-2-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850000692
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.63(s,1H),10.08(s,1H),7.77(s,1H),7.32(s,1H), 7.19(d,J＝10.0Hz,2H),7.12(d,J＝8.6Hz,1H),6.04(s,1H),2.85(s,2H),2.03(s,1H),0.95(t,J＝7.6Hz, 3H),0.78(s,4H),0.73(s,2H),0.66(s,2H).
MS(ESI+)m/z 478(M+H)+
实施例111：N-(4-(4-((3-氰基丙基)磺酰氨基)-2-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000693
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.64(s,1H),10.01(s,1H),7.78(s,1H),7.32(s,1H), 7.18(dd,J＝23.0,9.1Hz,3H),6.05(s,1H),3.25(t,J＝7.9Hz,2H),2.68(t,J＝7.3Hz,2H),2.02(q,J＝7.5 Hz,3H),0.96(t,J＝7.5Hz,3H),0.77(d,J＝7.7Hz,4H).
MS(ESI+)m/z 452(M+H)+
实施例112：N-(4-(4-(环己基磺酰氨基)-2-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000701
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.65(s,1H),9.86(d,J＝13.7Hz,1H),7.79(s,1H), 7.41–7.07(m,4H),6.05(s,1H),3.06(s,1H),2.06(s,3H),1.77(s,2H),1.59(s,1H),1.34(d,J＝77.0Hz,3H), 1.17–1.05(m,1H),0.93–0.81(m,5H).
MS(ESI+)m/z 467(M+H)+
实施例113：N-(4-(4-(环丙基磺酰氨基)-2-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000702
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.64(s,1H),9.82(s,1H),7.78(s,1H),7.32(d,J＝3.1 Hz,1H),7.25(s,1H),7.18(s,2H),6.04(d,J＝3.0Hz,1H),3.38(d,J＝6.4Hz,1H),2.74–2.65(m,1H),2.04 (d,J＝6.9Hz,1H),1.09(t,J＝7.2Hz,1H),0.97(d,J＝7.2Hz,7H),0.82-0.74(m,4H).
MS(ESI+)m/z 425(M+H)+
实施例114：N-(4-(4-(环丁基磺酰氨基)-2-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000703
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.64(s,1H),9.78(s,1H),7.77(s,1H),7.32(s,1H), 7.14(dd,J＝24.3,10.7Hz,3H),6.04(s,1H),4.06–3.91(m,1H),2.46(s,2H),2.39–2.30(m,2H),2.20(s, 2H),2.07–1.98(m,1H),1.93(dd,J＝19.3,10.2Hz,2H),0.94(t,J＝7.6Hz,3H),0.82-0.73(m,4H).
MS(ESI+)m/z 439(M+H)+
实施例115：N-(4-(2-乙基-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000711
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.64(s,1H),9.87(s,1H),7.78(s,1H),7.32(s,1H), 7.16(dd,J＝22.3,9.1Hz,3H),6.05(s,1H),3.13(t,J＝7.4Hz,2H),2.42(s,2H),2.02(d,J＝7.2Hz,1H), 1.72(q,J＝7.7Hz,2H),0.96(q,J＝7.8,7.1Hz,6H),0.82-0.74(m,4H).
MS(ESI+)m/z 427(M+H)+
实施例116：N-(4-(4-(丁基磺酰氨基)-2-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000712
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.63(s,1H),9.87(s,1H),7.78(s,1H),7.32(d,J＝3.1 Hz,1H),7.16(dd,J＝22.4,9.6Hz,3H),6.04(d,J＝2.9Hz,1H),3.14(t,J＝7.9Hz,2H),2.42(t,J＝7.3Hz, 2H),2.04(d,J＝5.7Hz,1H),1.69(q,J＝8.0Hz,2H),1.38(q,J＝7.6Hz,2H),0.94(q,J＝6.1,4.6Hz,3H), 0.84(t,J＝7.4Hz,3H),0.81-0.75(m,4H).
MS(ESI+)m/z 441(M+H)+
实施例117：N-(4-(2-甲基-4-((4,4,4-三氟丁基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000713
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.64(s,1H),7.77(s,1H),7.38–7.29(m,1H),7.25(d,J ＝8.2Hz,1H),7.21–7.11(m,2H),6.07(dd,J＝1.8,3.5Hz,1H),3.28(t,J＝7.7Hz,2H),2.47–2.35(m,2H), 2.14(s,3H),1.99(d,J＝33.4Hz,1H),1.91(dd,J＝5.7,8.6Hz,2H),0.83–0.74(m,4H).
MS(ESI+)m/z 481(M+H)+
实施例118：N-(4-(4-(环丙基磺酰氨基)-2-(三氟甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000714
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.67(s,1H),10.30(s,1H),7.83(s,1H),7.69(t,J＝1.7 Hz,1H),7.59(d,J＝8.4Hz,1H),7.44(d,J＝8.4Hz,1H),7.33(t,J＝2.6Hz,1H),6.00(dt,J＝3.4,1.6Hz, 1H),2.80(p,J＝6.5Hz,1H),2.06–1.96(m,1H),1.04–0.95(m,4H),0.77(d,J＝6.5Hz,4H).
MS(ESI+)m/z 465(M+H)+
实施例119：N-(4-(4-(丙基磺酰氨基)-2-(三氟甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000721
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.67(s,1H),10.34(s,1H),7.83(s,1H),7.65(s,1H), 7.56(d,J＝8.5Hz,1H),7.43(d,J＝8.4Hz,1H),7.32(d,J＝2.5Hz,1H),6.04–5.98(m,1H),3.22(t,J＝7.6 Hz,2H),2.05–1.98(m,1H),1.73(q,J＝7.7Hz,2H),1.02–0.91(m,3H),0.77(d,J＝6.4Hz,4H).
MS(ESI+)m/z 467(M+H)+
实施例120：N-(4-(4-(环丁基磺酰氨基)-2-(三氟甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000722
/>
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.67(s,1H),10.26(s,1H),7.82(s,1H),7.65(s,1H), 7.54(d,J＝8.3Hz,1H),7.42(d,J＝8.3Hz,1H),7.33(d,J＝3.3Hz,1H),6.00(t,J＝2.2Hz,1H),4.08(p,J＝ 8.2Hz,1H),2.35(p,J＝9.7Hz,2H),2.22(s,2H),2.02(d,J＝6.4Hz,1H),1.98–1.83(m,2H),0.77(d,J＝ 6.3Hz,4H).
MS(ESI+)m/z 479(M+H)+
实施例121：N-(4-(4-((3,4-二氟苯基)磺酰氨基)-2-(三氟甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000723
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.63(s,1H),7.84(s,1H),7.76(s,1H),7.67(s,2H), 7.46(s,1H),7.30(s,3H),5.93(s,1H),2.01(s,1H),0.77(s,4H).
MS(ESI+)m/z 537(M+H)+
实施例122：N-(4-(4-((3-氟苯基)磺酰氨基)-2-(三氟甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000731
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.97(s,1H),10.65(s,1H),7.76(s,1H),7.68(s,2H), 7.63(d,J＝8.6Hz,1H),7.57(d,J＝8.8Hz,1H),7.53(s,1H),7.46(d,J＝8.6Hz,1H),7.38(d,J＝8.3Hz,1H), 7.31(d,J＝3.2Hz,1H),5.90(s,1H),2.06–1.95(m,1H),0.81-0.73(m,4H).
MS(ESI+)m/z 519(M+H)+
实施例123：N-(4-(4-(((1-氰基环丙基)甲基)磺酰氨基)-3-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000732
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),10.64(s,1H),9.47(s,1H),8.01(s,1H),7.59(d,J＝2.0 Hz,1H),7.52(dd,J＝8.3,2.1Hz,1H),7.45(d,J＝8.2Hz,1H),7.41(t,J＝3.0Hz,1H),6.52(dd,J＝3.6,1.8 Hz,1H),3.54(s,2H),2.81(q,J＝7.5Hz,2H),2.09–1.98(m,1H),1.40(q,J＝4.8,3.9Hz,2H),1.29(t,J＝ 3.7Hz,2H),1.22(t,J＝7.5Hz,3H),0.86–0.73(m,4H).
MS(ESI+)m/z 464(M+H)+
实施例124：N-(4-(3-乙基-4-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000733
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.64(s,1H),9.18(s,1H),8.01(s,1H),7.59(d,J＝2.1 Hz,1H),7.53(dd,J＝8.2,2.1Hz,1H),7.45–7.39(m,2H),6.52(dd,J＝3.5,1.8Hz,1H),3.17(q,J＝7.3Hz, 2H),2.81(q,J＝7.5Hz,2H),2.04(d,J＝7.0Hz,1H),1.30(t,J＝7.3Hz,3H),1.22(t,J＝7.5Hz,3H),0.83– 0.78(m,4H).
MS(ESI+)m/z 413(M+H)+
实施例125：N-(4-(4-(环丙基磺酰氨基)-3-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000741
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.64(s,1H),9.22(s,1H),8.02(s,1H),7.59(d,J＝2.0 Hz,1H),7.55–7.47(m,2H),7.41(dd,J＝3.5,2.5Hz,1H),6.53(dd,J＝3.6,1.9Hz,1H),2.84(q,J＝7.5Hz, 2H),2.72–2.67(m,1H),2.03(t,J＝6.5Hz,1H),1.22(t,J＝7.5Hz,3H),1.03–0.95(m,2H),0.94–0.89(m, 2H),0.84-0.76(m,4H).
MS(ESI+)m/z 425(M+H)+
实施例126：N-(4-(3-乙基-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000742
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.64(s,1H),9.19(s,1H),8.01(s,1H),7.59(d,J＝2.1 Hz,1H),7.55–7.50(m,1H),7.46–7.38(m,2H),6.53(dd,J＝3.5,1.8Hz,1H),3.17–3.09(m,2H),2.81(q, J＝7.5Hz,2H),2.04(s,1H),1.78(h,J＝7.4Hz,2H),1.21(t,J＝7.5Hz,3H),1.01(t,J＝7.5Hz,3H),0.85- 0.76(m,4H).
MS(ESI+)m/z 427(M+H)+
实施例127：N-(4-(4-(丁基磺酰氨基)-3-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000743
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.64(s,1H),9.19(s,1H),8.01(s,1H),7.58(d,J＝2.1 Hz,1H),7.53(d,J＝8.1Hz,1H),7.45–7.36(m,2H),6.52(dd,J＝3.5,1.9Hz,1H),3.18–3.12(m,2H),2.81 (q,J＝7.5Hz,2H),2.04(s,1H),1.72(q,J＝7.7Hz,2H),1.43(h,J＝7.3Hz,2H),1.21(t,J＝7.5Hz,3H), 0.89(t,J＝7.4Hz,3H),0.84–0.76(m,4H).
MS(ESI+)m/z 441(M+H)+
实施例128：N-(4-(4-(环丁基磺酰氨基)-3-乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000751
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.64(s,1H),9.15(s,1H),8.01(s,1H),7.57(d,J＝2.0 Hz,1H),7.51(dd,J＝8.2,2.2Hz,1H),7.44–7.34(m,2H),6.52(dd,J＝3.5,1.8Hz,1H),3.97(p,J＝8.2Hz, 1H),2.79(q,J＝7.5Hz,2H),2.38–2.23(m,4H),2.03(d,J＝4.8Hz,1H),1.97–1.86(m,2H),1.21(t,J＝7.5 Hz,3H),0.84–0.76(m,4H).
MS(ESI+)m/z 439(M+H)+
实施例129：N-(4-(6-(甲基磺酰氨基)-[1,1'-联苯]-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000752
1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),10.47(d,J＝3.2Hz,1H),10.04(t,J＝2.8Hz,1H),7.68 (d,J＝3.2Hz,1H),7.42–7.28(m,3H),7.17–7.04(m,6H),5.86(s,1H),3.22(d,J＝6.5Hz,2H),1.98(d,J＝ 7.2Hz,1H),1.25(q,J＝7.0,5.7Hz,3H),0.74(d,J＝5.9Hz,4H).
MS(ESI+)m/z 447(M+H)+
实施例130：N-(4-(6-(环丙基磺酰氨基)-[1,1'-联苯]-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000753
1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),10.48(s,1H),9.98(s,1H),7.69(s,1H),7.41–7.30(m, 3H),7.19–7.07(m,6H),5.85(s,1H),2.78(d,J＝7.9Hz,1H),1.98(d,J＝7.5Hz,1H),1.01(t,J＝4.6Hz, 4H),0.75(d,J＝6.1Hz,4H).
MS(ESI+)m/z 473(M+H)+
实施例131：N-(4-(4-(乙基磺酰氨基)-2,3-二甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000761
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.63(s,1H),9.15(d,J＝4.1Hz,1H),7.75(d,J＝4.2Hz, 1H),7.33(s,1H),7.28–7.00(m,2H),6.04(s,1H),3.11(p,J＝7.4Hz,2H),2.31(t,J＝2.9Hz,3H),2.07(t,J ＝2.9Hz,3H),2.03(s,1H),1.29(dt,J＝11.0,5.8Hz,3H),0.77(d,J＝8.2Hz,4H).
MS(ESI+)m/z 413(M+H)+
实施例132：N-(4-(2,3-二甲基-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000762
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.63(s,1H),9.15(d,J＝4.4Hz,1H),7.76(t,J＝3.2Hz, 1H),7.33(s,1H),7.22(d,J＝7.8Hz,1H),7.10(t,J＝6.4Hz,1H),6.04(s,1H),3.08(q,J＝6.4,4.8Hz,2H), 2.30(d,J＝4.4Hz,3H),2.06(d,J＝4.1Hz,3H),2.03(s,1H),1.78(q,J＝7.4Hz,2H),1.01(t,J＝7.0Hz,3H), 0.82-0.76(m,4H).
MS(ESI+)m/z 427(M+H)+
实施例133：N-(4-(4-(环丙基磺酰氨基)-2,3-二甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000763
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.63(d,J＝3.3Hz,1H),9.18(d,J＝3.1Hz,1H),7.76 (d,J＝3.5Hz,1H),7.33(s,1H),7.25(d,J＝4.5Hz,1H),7.09(d,J＝8.9Hz,1H),6.03(s,1H),2.64(s,1H), 2.34(d,J＝2.9Hz,3H),2.07(d,J＝4.8Hz,3H),0.93(d,J＝29.3Hz,4H),0.82-0.74(m,4H).
MS(ESI+)m/z 425(M+H)+
实施例134：6-(环丙基甲酰氨基)-4-(4-(乙基磺酰氨基)-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶7-氧化物的合成
Figure BDA0002455210850000771
MS(ESI+)m/z 415(M+H)+
实施例135：6-(环丙基甲酰氨基)-4-(3-乙基-4-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶7-氧化物的合成
Figure BDA0002455210850000772
/>
MS(ESI+)m/z 429(M+H)+
实施例136：6-(环丙基甲酰氨基)-4-(4-(环丙基磺酰氨基)-2,3-二甲基苯基)-1H-吡咯并[2,3-b]吡啶7- 氧化物的合成
Figure BDA0002455210850000773
MS(ESI+)m/z 441(M+H)+
实施例137：4-(4-(((1-氰基环丙基)甲基)磺酰氨基)-2-乙基苯基)-6-(环丙基甲酰氨基)-1H-吡咯并 [2,3-b]吡啶7-氧化物的合成
Figure BDA0002455210850000774
MS(ESI+)m/z 480(M+H)+
实施例138：N-(4-(4-(((1-氰基环丙基)甲基)磺酰氨基)-3,5-二乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850000781
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),10.97(s,1H),10.65(s,1H),8.23(s,1H),7.53(s,2H), 7.11(d,J＝7.8Hz,1H),6.58–6.47(m,1H),3.06(s,2H),2.60(q,J＝7.5Hz,4H),2.05(s,1H),1.40(d,J＝ 10.4Hz,4H),1.19(t,J＝7.5Hz,6H),0.85–0.74(m,4H).
MS(ESI+)m/z 492(M+H)+
实施例139：N-(4-(4-((3,4-二氟苯基)磺酰氨基)-3,5-二乙基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000782
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.62(s,1H),9.73(s,1H),8.00(s,1H),7.84–7.67(m, 2H),7.63(d,J＝9.6Hz,1H),7.41(s,3H),6.48(dd,J＝3.6,1.9Hz,1H),2.05(d,J＝5.8Hz,1H),1.05(t,J＝ 7.5Hz,6H),0.85-0.74(m,4H).
MS(ESI+)m/z 525(M+H)+
实施例140：2-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-5-(乙基磺酰氨基)苯甲酸甲酯的合成
Figure BDA0002455210850000783
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.60(s,1H),10.19(s,1H),7.79(s,1H),7.66(s,1H), 7.50(s,2H),7.33(s,1H),6.09(s,1H),3.46(s,3H),3.21(q,J＝7.3Hz,2H),2.04(s,1H),1.23(t,J＝7.3Hz, 3H),0.82-0.75(m,4H).
MS(ESI+)m/z 443(M+H)+
实施例141：2-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-5-(丙基磺酰氨基)苯甲酸甲酯的合成
Figure BDA0002455210850000791
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.60(s,1H),10.19(s,1H),7.79(s,1H),7.65(t,J＝1.5 Hz,1H),7.50(d,J＝1.5Hz,2H),7.33(dd,J＝3.5,2.4Hz,1H),6.09(dd,J＝3.6,1.9Hz,1H),3.46(s,3H), 3.23–3.10(m,2H),2.08–1.99(m,1H),1.78–1.61(m,2H),0.97(t,J＝7.4Hz,3H),0.83–0.72(m,4H).
MS(ESI+)m/z 457(M+H)+
实施例142：5-(((1-氰基环丙基)甲基)磺酰氨基)-2-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基) 苯甲酸甲酯的合成
Figure BDA0002455210850000792
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.60(s,1H),7.79(s,1H),7.66(d,J＝1.5Hz,1H),7.49 (d,J＝1.5Hz,2H),7.32(t,J＝3.0Hz,1H),6.07(dd,J＝3.5,1.9Hz,1H),3.59(s,2H),3.45(s,3H),2.03(s, 1H),1.37(q,J＝4.8Hz,2H),1.20(q,J＝5.3,4.9Hz,2H),0.81–0.70(m,4H).
MS(ESI+)m/z 494(M+H)+
实施例143：5-(((1-氰基环丙基)甲基)磺酰氨基)-2-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基) 苯甲酸的合成
Figure BDA0002455210850000793
MS(ESI+)m/z 480(M+H)+
实施例144：N-(4-(2-氰基-4-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000801
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),10.72(s,1H),10.40(s,1H),7.98(s,1H),7.75–7.59(m, 3H),7.42(t,J＝3.0Hz,1H),6.27(dd,J＝3.6,1.8Hz,1H),3.29(q,J＝7.3Hz,2H),2.10–1.98(m,1H),1.25 (t,J＝7.3Hz,3H),0.85–0.70(m,4H).
MS(ESI+)m/z 410(M+H)+
实施例145：N-(4-(2-氰基-4-(丙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000802
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),10.72(s,1H),10.39(s,1H),7.98(s,1H),7.70–7.57(m, 3H),7.42(t,J＝3.0Hz,1H),6.27(dd,J＝3.5,1.7Hz,1H),3.30–3.23(m,2H),2.10–1.97(m,1H),1.73(h,J ＝7.5Hz,2H),0.98(t,J＝7.4Hz,3H),0.88–0.68(m,4H).
MS(ESI+)m/z 424(M+H)+
实施例146：N-(4-(2-氰基-4-((3,4-二氟苯基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000803
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.04(s,1H),10.71(s,1H),7.97(d,J＝8.3Hz,1H), 7.93(s,1H),7.73(d,J＝3.5Hz,1H),7.72–7.67(m,1H),7.64–7.60(m,2H),7.54(dd,J＝8.5,2.3Hz,1H), 7.41(t,J＝3.0Hz,1H),6.20(dd,J＝3.6,1.8Hz,1H),2.09–1.97(m,1H),0.85-0.76(m,4H).
MS(ESI+)m/z 494(M+H)+
实施例147：N-(4-(2-氰基-4-(((1-氰基环丙基)甲基)磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000811
1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),10.78(s,1H),10.72(s,1H),7.98(s,1H),7.70–7.57(m, 3H),7.42(t,J＝3.0Hz,1H),6.25(t,J＝2.6Hz,1H),3.70(s,2H),2.09–1.98(m,1H),1.09(t,J＝7.0Hz,4H), 0.83-0.77(m,4H).
MS(ESI+)m/z 461(M+H)+
实施例148：N-(4-(6-(乙基磺酰氨基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000812
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.78(s,1H),10.68(s,1H),8.57(s,1H),8.08(dd,J＝ 2.5,8.6Hz,1H),8.01(s,1H),7.43(dd,J＝2.5,3.5Hz,1H),7.16(d,J＝8.6Hz,1H),6.54(dd,J＝1.9,3.5Hz, 1H),3.52(s,2H),2.04(t,J＝5.0Hz,1H),1.25(t,J＝7.3Hz,4H),0.85–0.73(m,4H).
MS(ESI+)m/z 386(M+H)+
实施例149：N-(4-(5-(乙基磺酰氨基)-6-氟吡啶-2-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000813
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.67(s,1H),8.39(s,1H),8.01(d,J＝9.7Hz,1H),7.92 (d,J＝8.3Hz,1H),7.47(t,J＝3.0Hz,1H),6.89(dd,J＝1.9,3.5Hz,1H),3.20(d,J＝7.4Hz,2H),2.10–1.97 (m,1H),1.28–1.22(m,3H),0.87–0.76(m,4H).
MS(ESI+)m/z 404(M+H)+
实施例150：N-(4-(6-氟-5-(丙基磺酰氨基)吡啶-2-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000821
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.68(s,1H),10.14(s,1H),8.40(s,1H),8.12–8.01(m, 1H),7.94(d,J＝8.1Hz,1H),7.48(dd,J＝2.6,3.5Hz,1H),6.89(dd,J＝1.9,3.5Hz,1H),3.26–3.16(m,2H), 2.04(t,J＝3.9Hz,1H),1.76(h,J＝7.5Hz,2H),0.99(t,J＝7.4Hz,3H),0.89–0.78(m,4H).
MS(ESI+)m/z 418(M+H)+
实施例151：N-(4-(4-(乙基磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000822
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.52(s,1H),7.83(s,1H),7.31(t,J＝3.0Hz,1H),7.22 (d,J＝7.3Hz,1H),6.50(d,J＝3.4Hz,1H),6.18(s,1H),3.06(q,J＝7.3Hz,2H),2.24(d,J＝9.8Hz,1H), 2.01(s,2H),1.76–1.61(m,1H),1.21(d,J＝7.4Hz,3H),0.82-0.74(m,4H).
MS(ESI+)m/z 389(M+H)+
实施例152：N-(4-(4-(丙基磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000823
1H NMR(400MHz,氯仿-d)δ11.39(s,1H),10.52(s,1H),7.83(s,1H),7.31(t,J＝2.9Hz,1H),7.21(d, J＝7.4Hz,1H),6.51(dd,J＝1.8,3.5Hz,1H),6.18(s,1H),3.11–2.99(m,2H),2.22(dd,J＝9.0,17.2Hz, 1H),2.01(s,2H),1.76–1.63(m,3H),0.99(t,J＝7.4Hz,3H),0.81–0.72(m,4H).
MS(ESI+)m/z 403(M+H)+
实施例153：N-(4-(4-((三氟甲基)磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000831
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.56(s,1H),9.62(d,J＝7.9Hz,1H),7.82(s,1H),7.32 (t,J＝3.0Hz,1H),6.53(dd,J＝1.8,3.5Hz,1H),6.18(s,1H),3.71(s,2H),2.70–2.55(m,5H),2.34(d,J＝ 8.2Hz,1H),2.02(s,2H),1.82(s,1H),0.84-0.76(m,4H).
MS(ESI+)m/z 429(M+H)+
实施例154：N-(4-(4-(环丙基磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000832
1H NMR(400MHz,氯仿-d)δ11.37(s,1H),10.49(s,1H),7.83(s,1H),7.31(dd,J＝2.4,3.5Hz,1H), 7.22(d,J＝7.5Hz,1H),6.51(dd,J＝1.9,3.5Hz,1H),6.19(s,1H),3.54(d,J＝3.3Hz,1H),2.68–2.55(m, 4H),2.30–2.19(m,1H),2.08(d,J＝13.3Hz,1H),2.00(dt,J＝4.8,8.4Hz,1H),1.72(ddt,J＝5.7,10.1,15.5 Hz,1H),0.98–0.93(m,4H),0.84-0.75(m,4H).
MS(ESI+)m/z 401(M+H)+
实施例155：N-(4-(4-((2-氰基乙基)磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000833
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.49(s,1H),7.83(s,1H),7.33–7.27(m,1H),6.50(dd, J＝1.4,3.5Hz,1H),6.18(t,J＝3.4Hz,1H),3.49(q,J＝9.4,10.2Hz,2H),3.20–3.14(m,2H),2.68(t,J＝7.2 Hz,2H),2.58(d,J＝18.9Hz,3H),2.28–2.17(m,1H),2.06–1.96(m,4H),1.77–1.64(m,1H),0.85-0.76 (m,4H).
MS(ESI+)m/z 414(M+H)+
实施例156：N-(4-(4-(((1-(氰基甲基)环丙基)甲基)磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850000841
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.49(s,1H),7.83(s,1H),7.39(d,J＝6.9Hz,1H),7.31 (dd,J＝2.5,3.5Hz,1H),6.50(dd,J＝1.9,3.5Hz,1H),6.18(s,1H),3.51(s,1H),3.18(s,2H),2.83(s,2H), 2.58(d,J＝22.9Hz,3H),2.23(dd,J＝12.2,23.6Hz,1H),2.01(s,2H),1.78–1.63(m,1H),0.84–0.79(m, 4H),0.79–0.73(m,2H),0.71-0.65(m,2H).
MS(ESI+)m/z 454(M+H)+
实施例157：N-(4-(4-(((1-氰基环丙基)甲基)磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850000842
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.49(s,1H),7.83(s,1H),7.51(s,1H),7.31(dd,J＝2.5, 3.5Hz,1H),6.50(dd,J＝1.9,3.5Hz,1H),6.18(s,1H),3.52(d,J＝16.4Hz,1H),3.37(s,2H),2.59(d,J＝ 29.8Hz,3H),2.24(dd,J＝9.4,16.1Hz,1H),2.12–1.97(m,2H),1.78–1.63(m,1H),1.36(t,J＝3.5Hz,2H), 1.29–1.23(m,2H),0.86–0.74(m,4H).
MS(ESI+)m/z 440(M+H)+
实施例158：N-(4-(4-((3-氰基丙基)磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000843
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.49(s,1H),7.83(s,1H),7.40(d,J＝6.4Hz,1H),7.31 (dd,J＝2.4,3.5Hz,1H),6.50(dd,J＝1.8,3.5Hz,1H),6.18(s,1H),3.49(s,2H),3.17(dd,J＝6.4,8.7Hz, 2H),2.68(t,J＝7.3Hz,2H),2.58(d,J＝18.3Hz,3H),2.23(dd,J＝8.9,17.2Hz,1H),2.00(h,J＝6.2,7.3Hz, 4H),1.76–1.63(m,1H),0.83–0.75(m,4H).
MS(ESI+)m/z 428(M+H)+
实施例159：N-(4-(4-((3-氟丙基)磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000851
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.52(s,1H),7.83(s,1H),7.36(d,J＝7.3Hz,1H),7.31 (dd,J＝2.5,3.5Hz,1H),6.51(dd,J＝1.9,3.5Hz,1H),6.18(d,J＝4.3Hz,1H),4.62(t,J＝6.0Hz,1H),4.51 (t,J＝6.0Hz,1H),3.50(s,1H),3.24–3.11(m,2H),2.55(s,3H),2.23(dd,J＝8.8,15.7Hz,1H),2.13–1.98 (m,4H),1.71(tt,J＝8.0,15.8Hz,1H),0.83–0.74(m,4H).
MS(ESI+)m/z 421(M+H)+
实施例160：N-(4-(4-(烯丙基磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000852
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.52(s,1H),7.83(d,J＝3.0Hz,1H),7.34–7.26(m, 2H),6.50(dt,J＝1.6,3.2Hz,1H),6.17(s,1H),5.45–5.36(m,1H),3.87(d,J＝7.2Hz,1H),2.57(d,J＝23.0 Hz,2H),2.23(d,J＝7.5Hz,1H),2.01(s,2H),1.87(dd,J＝1.5,6.7Hz,1H),1.77–1.60(m,1H),0.83–0.75 (m,4H).
MS(ESI+)m/z 401(M+H)+
实施例161：N-(4-(4-((环丙基甲基)磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000853
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.52(s,1H),7.83(s,1H),7.31(dd,J＝2.3,3.5Hz,1H), 7.21(d,J＝6.1Hz,1H),6.50(dd,J＝1.6,3.5Hz,1H),6.18(s,1H),3.51(s,1H),3.01(d,J＝6.9Hz,2H),2.58 (d,J＝20.5Hz,3H),2.23(dd,J＝9.2,16.8Hz,1H),2.02(s,2H),1.79–1.63(m,1H),1.12–0.98(m,1H), 0.84–0.74(m,4H).
MS(ESI+)m/z 415(M+H)+
实施例162：N-(4-(4-((3,4-二氟苯基)磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000861
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.51(s,1H),7.92(ddd,J＝2.2,7.4,9.8Hz,1H),7.80(s, 1H),7.78–7.61(m,2H),7.29(dd,J＝2.2,3.5Hz,1H),6.47(dd,J＝1.5,3.5Hz,1H),6.15–6.07(m,1H), 3.42–3.36(m,2H),2.40–2.28(m,1H),2.12(ddd,J＝3.1,8.3,18.0Hz,1H),2.00(tt,J＝4.9,7.8Hz,1H), 1.85–1.77(m,1H),1.68–1.53(m,1H),0.82–0.73(m,4H).
MS(ESI+)m/z 473(M+H)+
实施例163：N-(4-(4-((3-氟苯基)磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000862
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.50(s,1H),7.79(s,1H),7.75–7.63(m,3H),7.56– 7.48(m,1H),7.29(dd,J＝2.2,3.5Hz,1H),6.47(dd,J＝1.5,3.5Hz,1H),6.09(d,J＝4.1Hz,1H),2.49(s, 3H),2.39–2.25(m,1H),2.12(ddd,J＝3.0,8.5,18.1Hz,1H),1.99(dt,J＝4.9,7.5Hz,1H),1.83–1.73(m, 1H),1.69–1.54(m,1H),0.77(tdd,J＝4.0,6.4,9.9Hz,4H).
MS(ESI+)m/z 455(M+H)+
实施例164：N-(4-(4-((4-氰基苯基)磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000863
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.51(s,1H),8.21–8.15(m,1H),8.13–8.07(m,2H), 8.07–8.01(m,2H),7.79(s,1H),7.29(dd,J＝2.5,3.5Hz,1H),6.47(dd,J＝1.9,3.5Hz,1H),6.09(t,J＝3.7 Hz,1H),3.40(s,2H),3.17(d,J＝3.2Hz,1H),2.36–2.29(m,1H),2.16–2.05(m,1H),2.04–1.95(m,1H), 1.80(d,J＝12.2Hz,1H),1.63(td,J＝5.8,10.8,11.7Hz,1H),0.80–0.73(m,4H).
MS(ESI+)m/z 462(M+H)+
实施例165：N-(4-(4-(环丁基磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000871
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.51(s,1H),7.82(s,1H),7.31(dd,J＝2.5,3.5Hz,1H), 7.18(d,J＝7.7Hz,1H),6.50(dd,J＝1.8,3.5Hz,1H),6.17(s,1H),3.94(p,J＝8.2Hz,1H),3.65–3.54(m, 1H),2.37–2.14(m,5H),2.06–1.80(m,4H),1.69(dd,J＝6.2,11.5Hz,1H),0.85–0.75(m,4H).
MS(ESI+)m/z 415(M+H)+
实施例166：N-(4-(1-(乙基磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000872
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),7.87(s,1H),7.35(t,J＝2.9Hz,1H),6.57 (dd,J＝1.7,3.6Hz,1H),6.35(d,J＝3.8Hz,1H),4.00(q,J＝2.9Hz,2H),3.49(t,J＝5.7Hz,4H),3.14(q,J＝ 7.3Hz,2H),2.62(s,2H),2.07–1.95(m,1H),1.24(t,J＝7.3Hz,3H),0.84-0.77(m,4H).
MS(ESI+)m/z 375(M+H)+
实施例167：N-(4-(1-((3-氟丙基)磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000873
MS(ESI+)m/z 407(M+H)+
实施例168：N-(4-(1-(环丙基磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000881
MS(ESI+)m/z 387(M+H)+
实施例169：N-(4-(1-(((四氢-2H-吡喃-4-基)甲基)磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000882
MS(ESI+)m/z 445(M+H)+
实施例170：N-(4-(1-((3-氰基丙基)磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000883
MS(ESI+)m/z 414(M+H)+
实施例171：N-(4-(1-(((1-(氰基甲基)环丙基)甲基)磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000884
MS(ESI+)m/z 440(M+H)+
实施例172：N-(4-(1-(((1-氰基环丙基)甲基)磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850000891
MS(ESI+)m/z 426(M+H)+
实施例173：N-(4-(1-((3,4-二氟苯基)磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000892
MS(ESI+)m/z 459(M+H)+
实施例174：N-(4-(8-(乙基磺酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000893
MS(ESI+)m/z 401(M+H)+
实施例175：N-(4-(8-((3-氟丙基)磺酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850000901
MS(ESI+)m/z 433(M+H)+
实施例176：N-(4-(8-(丙基磺酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000902
MS(ESI+)m/z 415(M+H)+
实施例177：N-(4-(8-(环丙基磺酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000903
MS(ESI+)m/z 413(M+H)+
实施例178：N-(4-(8-((3,4-二氟苯基)磺酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000911
MS(ESI+)m/z 485(M+H)+
实施例179：N-(4-(1-(乙基磺酰基)-3,3-二甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850000912
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.53(s,1H),7.74(s,1H),7.28(dd,J＝2.4,3.5Hz,1H), 6.28(dd,J＝1.9,3.5Hz,1H),5.62(t,J＝3.2Hz,1H),3.89(d,J＝3.2Hz,2H),3.19(s,2H),3.15(t,J＝7.3Hz, 2H),2.01(s,1H),1.27(t,J＝7.4Hz,3H),1.04(s,6H),0.82–0.75(m,4H).
MS(ESI+)m/z 403(M+H)+
实施例180：N-(4-(1-((3-氰基丙基)磺酰基)-3,3-二甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000913
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.54(s,1H),7.74(s,1H),7.29(dd,J＝2.4,3.5Hz,1H), 6.28(dd,J＝1.9,3.5Hz,1H),5.62(t,J＝3.2Hz,1H),3.90(d,J＝3.2Hz,2H),3.28–3.18(m,4H),2.68(t,J＝ 7.2Hz,2H),2.03(q,J＝7.5Hz,3H),1.05(s,6H),0.82–0.76(m,4H).
MS(ESI+)m/z 442(M+H)+
实施例181：N-(4-(4-((3,4-二氟苯基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000921
MS(ESI+)m/z 470(M+H)+
实施例182：N-(4-(4-(乙基磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000922
MS(ESI+)m/z 386(M+H)+
实施例183：N-(4-(4-(环己基磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000923
MS(ESI+)m/z 440(M+H)+
实施例184：N-(4-(4-((4,4,4-三氟丁基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000924
MS(ESI+)m/z 468(M+H)+
实施例185：N-(4-(4-((3-氟丙基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000925
MS(ESI+)m/z 418(M+H)+
实施例186：N-(4-(4-((3-氰基丙基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000931
MS(ESI+)m/z 425(M+H)+
实施例187：N-(4-(4-((4-氯苯基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000932
MS(ESI+)m/z 468,470(M+H)+
实施例188：N-(4-(4-((4-氟苯基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000933
MS(ESI+)m/z 452(M+H)+
实施例189：N-(4-(4-((4-溴苯基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000934
MS(ESI+)m/z 512,514(M+H)+
实施例190：N-(4-(4-(丙基磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000941
MS(ESI+)m/z 400(M+H)+
实施例191：N-(4-(4-(丁基磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000942
MS(ESI+)m/z 414(M+H)+
实施例192：N-(4-(4-((3-氟苯基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000943
MS(ESI+)m/z 452(M+H)+
实施例193：N-(4-(4-((3,4-二氟-N-甲基苯基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000944
MS(ESI+)m/z 484(M+H)+
实施例194：N-(4-(4-((3,3,3-三氟丙基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000951
MS(ESI+)m/z 454(M+H)+
实施例195：N-(4-(4-((1,1-二氧化四氢-2H-噻喃)-4-磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000952
MS(ESI+)m/z 490(M+H)+
实施例196：N-(4-(4-((1,1-二氧化四氢噻吩)-3-磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000953
/>
MS(ESI+)m/z 476(M+H)+
实施例197：N-(4-(4-((6-氰基吡啶)-3-磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000954
MS(ESI+)m/z 460(M+H)+
实施例198：N-(4-(4-((1-甲基-1H-咪唑)-5-磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000961
MS(ESI+)m/z 438(M+H)+
实施例199：N-(4-(4-((1-甲基-1H-吡唑)-4-磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000962
MS(ESI+)m/z 438(M+H)+
实施例200：4-(N-(4-(2-(环丙基甲酰氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)苯基)氨磺酰基)苯甲酰胺的合成
Figure BDA0002455210850000963
MS(ESI+)m/z 477(M+H)+
实施例201：N-(4-(3-氟-4-(甲基磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000964
1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),10.62(s,1H),8.06(d,J＝9.4Hz,2H),7.62(t,J＝8.4Hz, 1H),7.52(s,1H),6.88(s,1H),3.13(s,3H),2.17(s,1H),0.82(d,J＝17.7Hz,4H).
MS(ESI+)m/z 390(M+H)+
实施例202：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000971
1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),10.62(s,1H),9.94(s,1H),8.15–7.99(m,2H),7.63(t,J ＝8.3Hz,1H),7.57–7.47(m,1H),6.94–6.84(m,1H),3.21(q,J＝7.3Hz,2H),2.17(s,1H),1.28(t,J＝7.1 Hz,3H),0.88–0.75(m,4H)
MS(ESI+)m/z 404(M+H)+
实施例203：N-(4-(3-氟-4-((3-氟丙基)磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000972
1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),10.62(s,1H),10.08(s,1H),8.06(d,J＝9.9Hz,2H), 7.63(t,J＝8.2Hz,1H),7.56–7.48(m,1H),6.95–6.85(m,1H),4.55(dt,J＝6.0,47.4Hz,2H),2.14(dd,J＝ 8.0,22.9Hz,3H),0.84–0.78(m,4H).
MS(ESI+)m/z 436(M+H)+
实施例204：N-(4-(4-((3-氰基丙基)磺酰氨基)-3-氟苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000973
1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),10.63(s,1H),10.12(s,1H),8.06(d,J＝10.0Hz,2H), 7.62(t,J＝8.3Hz,1H),7.58–7.46(m,1H),6.95–6.78(m,1H),2.69(t,J＝7.1Hz,2H),2.17(s,1H),2.07(q, J＝7.3Hz,2H),0.88–0.80(m,4H).
MS(ESI+)m/z 443(M+H)+
实施例205：N-(4-(4-((3,4-二氟苯基)磺酰氨基)-3-氟苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000974
1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),10.67(s,1H),10.62(s,1H),8.06–7.93(m,2H),7.91– 7.83(m,1H),7.76–7.61(m,2H),7.57–7.44(m,2H),6.91–6.78(m,1H),2.14(s,1H),0.90–0.74(m,4H).
MS(ESI+)m/z 488(M+H)+
实施例206：(N-(4-(3-氟-4-(丙基磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺)的合成
Figure BDA0002455210850000981
MS(ESI+)m/z 418(M+H)+
实施例207：N-(7-(4-(乙基磺酰氨基)苯基)-3H-咪唑并[4,5-b]吡啶-5-基)环丙基甲酰胺的合成
Figure BDA0002455210850000982
MS(ESI+)m/z 386(M+H)+
实施例208：N-(6-(4-((3,4-二氟苯基)磺酰氨基)苯基)-9H-嘌呤-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000983
1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),10.72(s,1H),8.81–8.61(m,2H),8.45(s,1H),7.92 (ddd,J＝9.7,7.3,2.2Hz,1H),7.76–7.59(m,2H),7.36–7.28(m,2H),2.16(s,1H),0.85–0.77(m,4H).
MS(ESI+)m/z 471(M+H)+
实施例209：N-(6-(4-(乙基磺酰氨基)苯基)-9H-嘌呤-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000984
1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),10.18(s,1H),8.77(d,J＝8.4Hz,2H),8.46(d,J＝1.3 Hz,1H),7.46–7.34(m,2H),3.26–3.18(m,2H),2.26–2.13(m,1H),1.22(td,J＝7.4,1.3Hz,3H),0.92– 0.80(m,4H).
MS(ESI+)m/z 387(M+H)+
实施例210：N-(6-(4-((3-氰基丙基)磺酰氨基)苯基)-9H-嘌呤-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000991
1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),10.32(s,1H),8.83–8.75(m,2H),8.48(s,1H),7.45– 7.36(m,2H),3.59(dq,J＝12.1,6.0Hz,2H),3.35–3.25(m,2H),2.19(dt,J＝7.8,3.3Hz,1H),2.00(dq,J＝ 9.5,7.4Hz,2H),1.03(d,J＝6.1Hz,6H),0.91–0.79(m,4H).
MS(ESI+)m/z 426(M+H)+
实施例211：N-(6-(4-((4,4,4-三氟丁基)磺酰氨基)苯基)-9H-嘌呤-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850000992
1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),10.31(s,1H),8.78(d,J＝8.7Hz,2H),8.47(s,1H),7.43 –7.35(m,2H),3.34(t,J＝7.6Hz,2H),2.49–2.34(m,2H),2.19(td,J＝7.3,3.7Hz,1H),1.97–1.84(m,2H), 0.86–0.78(m,4H).
MS(ESI+)m/z 469(M+H)+
实施例212：N-(4-(1-(丙基磺酰基)-2,5-二氢-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850000993
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),10.61(s,1H),7.82(s,1H),7.43(t,J＝2.9Hz,1H),6.70 (td,J＝1.9,3.6,4.2Hz,2H),4.58(t,J＝4.4Hz,2H),4.40(q,J＝3.8Hz,2H),3.26–3.15(m,2H),2.03(tt,J＝ 4.5,7.7Hz,1H),1.80–1.65(m,2H),1.00(t,J＝7.4Hz,3H),0.83-0.76(m,4H).
MS(ESI+)m/z 375(M+H)+
实施例213：N-(4-(1-(((1-氰基环丙基)甲基)磺酰基)-2,5-二氢-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850000994
1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),10.62(s,1H),7.83(s,1H),7.52–7.35(m,1H),6.75– 6.65(m,2H),4.64(dd,J＝3.1,6.2Hz,2H),4.46(q,J＝3.2,3.7Hz,2H),3.61(s,2H),2.02(td,J＝4.0,7.6Hz, 1H),1.40(q,J＝4.3,4.7Hz,2H),1.22(q,J＝4.9Hz,2H),0.89–0.73(m,4H).
MS(ESI+)m/z 412(M+H)+
实施例214：N-(4-(4-(吗啉-4-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001001
在1ml吡啶中搅拌起始材料，即N-(4-(4-氨基苯基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺(100mg)。将1.5当量的吗啉-4-磺酰氯添加到其中，并在40℃下搅拌16小时。一旦反应完成后，向所述混合物中加入d-HCl，然后使用二氯甲烷进行萃取，并且然后由此分离有机层。将混合物浓缩后，将所得浓缩物溶于MeOH/THF(1:1)溶液中，然后向其中加入2N氢氧化钠水溶液，并在30℃下搅拌12小时。一旦反应完成后，将所述混合物冷却至室温，并在搅拌的同时向其中加入饱和NH4Cl 水溶液。滤出产生的固体，并由此最终得到产物，即N-(4-(4-吗啉-4-磺酰氨基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺。
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.69(s,1H),10.24(s,1H),7.97(d,J＝5.7Hz,1H), 7.69(d,J＝7.6Hz,2H),7.47(d,J＝8.2Hz,1H),7.43–7.33(m,3H),7.11(d,J＝7.8Hz,1H),6.62–6.51(m, 1H),3.63–3.50(m,5H),3.18–3.06(m,5H),2.05(d,J＝8.9Hz,1H),0.88–0.77(m,4H).
MS(ESI+)m/z 442(M+H)+
实施例215至238
在下文的实施例215至238中，通过与实施例214所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例215：N-(4-(4-((N-乙基-N-甲基氨磺酰基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001002
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.59(s,1H),10.07(s,1H),7.99(s,1H),7.71–7.60(m, 2H),7.43–7.35(m,1H),7.31(d,J＝8.5Hz,2H),6.58–6.48(m,1H),3.18(q,J＝7.2Hz,2H),2.74(s,3H), 2.04(s,1H),1.04(t,J＝7.0Hz,3H),0.88–0.74(m,4H).
MS(ESI+)m/z 414(M+H)+
实施例216：N-(4-(4-((N,N-二乙基氨磺酰基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001011
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.59(s,1H),10.02(s,1H),7.99(s,1H),7.65(d,J＝8.0 Hz,2H),7.44–7.19(m,3H),6.54(d,J＝10.6Hz,1H),3.23(t,J＝6.9Hz,4H),2.04(s,1H),1.01(t,J＝7.2 Hz,6H),0.88–0.76(m,4H).
MS(ESI+)m/z 428(M+H)+
实施例217：N-(4-(4-((N-环丙基-N-甲基氨磺酰基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001012
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.59(s,1H),10.26(s,1H),7.98(s,1H),7.65(d,J＝8.1 Hz,2H),7.45–7.26(m,3H),6.54(s,1H),2.80(t,J＝5.5Hz,3H),2.34(s,1H),2.04(s,1H),0.88–0.76(m, 4H),0.63(d,J＝22.6Hz,4H).
MS(ESI+)m/z 426(M+H)+
实施例218：N-(4-(4-(吡咯烷-1-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001013
MS(ESI+)m/z 426(M+H)+
实施例219：N-(4-(4-(哌啶-1-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001021
MS(ESI+)m/z 440(M+H)+
实施例220：N-(4-(4-((2,6-二甲基吗啉)-4-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001022
MS(ESI+)m/z 470(M+H)+
实施例221：N-(4-(4-((3-氰基氮杂环丁烷)-1-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001023
MS(ESI+)m/z 437(M+H)+
实施例222：N-(4-(4-((N-异丙基-N-甲基氨磺酰基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001024
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.58(s,1H),10.06(s,1H),7.98(s,1H),7.65(d,J＝7.9 Hz,2H),7.38(s,1H),7.26(d,J＝9.5Hz,2H),6.52(s,1H),4.03(s,1H),2.65(t,J＝5.8Hz,3H),2.04(s,1H), 1.03–0.95(m,6H),0.81(s,4H).
MS(ESI+)m/z 428(M+H)+
实施例223：N-(4-(4-((N-(2-甲氧基乙基)-N-甲基氨磺酰基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001031
MS(ESI+)m/z 444(M+H)+
实施例224：N-(4-(3-氟-4-(哌啶-1-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001032
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.68(s,1H),9.85(s,1H),8.02(s,1H),7.61(t,J＝8.2 Hz,1H),7.54(d,J＝9.9Hz,2H),7.43(t,J＝3.0Hz,1H),6.58–6.54(m,1H),3.12(d,J＝6.2Hz,4H),2.04(s, 1H),1.47(d,J＝20.7Hz,6H),0.85-0.78(m,4H).
MS(ESI+)m/z 458(M+H)+
实施例225：N-(4-(3-氟-4-(吡咯烷-1-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001033
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.67(s,1H),9.81(s,1H),8.01(s,1H),7.62(t,J＝8.3 Hz,1H),7.53(d,J＝8.4Hz,2H),7.43(t,J＝3.0Hz,1H),6.55(dd,J＝3.6,1.9Hz,1H),3.21(d,J＝6.0Hz, 4H),2.04(s,1H),1.83–1.72(m,4H),0.90–0.70(m,4H).
MS(ESI+)m/z 444(M+H)+
实施例226：N-(4-(3-氟-4-(吗啉-4-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001041
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.69(s,1H),10.02(s,1H),8.03(s,1H),7.63(t,J＝8.4 Hz,1H),7.60–7.52(m,2H),7.44(t,J＝3.0Hz,1H),6.56(dd,J＝3.6,1.9Hz,1H),3.60(t,J＝4.7Hz,4H), 3.10(t,J＝4.7Hz,4H),2.04(s,1H),0.90–0.68(m,4H).
MS(ESI+)m/z 460(M+H)+
实施例227：N-(4-(2-甲基-4-((N-(2,2,2-三氟乙基)氨磺酰基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001042
1H NMR(400MHz,DMSO-d6)δ11.59–11.42(m,1H),10.63(s,1H),7.76(s,1H),7.38–7.26(m,1H), 7.21(d,J＝8.1Hz,1H),7.15(d,J＝2.2Hz,1H),7.09(dd,J＝2.4,8.3Hz,1H),6.07(dd,J＝1.9,3.5Hz,1H), 3.70(q,J＝9.6Hz,2H),2.14(s,3H),2.04(d,J＝7.2Hz,1H),0.82–0.75(m,4H).
MS(ESI+)m/z 468(M+H)+
实施例228：N-(4-(2-甲基-4-((N-甲基-N-(2,2,2-三氟乙基)氨磺酰基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001043
1H NMR(400MHz,DMSO-d6)δ11.50(d,J＝6.3Hz,1H),10.64(s,1H),7.77(s,1H),7.34(d,J＝3.7Hz, 1H),7.23(d,J＝8.0Hz,1H),7.17–7.07(m,2H),6.09–6.04(m,1H),4.06(d,J＝10.1Hz,2H),2.92–2.85 (m,3H),2.14(s,3H),2.04(s,1H),0.82-0.75(m,4H).
MS(ESI+)m/z 482(M+H)+
实施例229：N-(4-(4-((1,1-二氧化硫代吗啉)-4-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001044
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.61(s,1H),10.39(s,1H),8.01(s,1H),7.71(d,J＝8.3 Hz,2H),7.38(t,J＝6.7Hz,3H),6.58–6.50(m,1H),3.66(d,J＝5.5Hz,4H),3.16(d,J＝5.3Hz,4H),2.04(s, 1H),0.85-0.76(m,4H).
MS(ESI+)m/z 490(M+H)+
实施例230：N-(4-(4-((4-(甲基磺酰基)哌嗪)-1-磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001051
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.61(s,1H),10.30(s,1H),8.00(s,1H),7.69(d,J＝8.3 Hz,2H),7.42–7.34(m,3H),6.54(d,J＝2.9Hz,1H),3.26(t,J＝4.8Hz,4H),3.13(d,J＝5.5Hz,4H),2.85(s, 3H),2.04(s,1H),0.85–0.77(m,4H).
MS(ESI+)m/z 519(M+H)+
实施例231：N-(4-(4-(吗啉-4-磺酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001052
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.52(s,1H),7.83(d,J＝3.1Hz,1H),7.31(s,1H),6.51 (s,1H),6.19(d,J＝4.1Hz,1H),3.66(d,J＝4.7Hz,4H),3.06–2.99(m,4H),2.58(d,J＝22.0Hz,4H),2.25 (d,J＝14.2Hz,1H),2.01(d,J＝12.6Hz,2H),1.70(s,1H),0.84-0.76(m,4H).
MS(ESI+)m/z 446(M+H)+
实施例232：N-(4-(1-(N-(2,2,2-三氟乙基)氨磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001053
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.55(s,1H),8.10(s,1H),7.87(s,1H),7.41–7.29(m, 1H),6.57(s,1H),6.36(s,1H),3.89(s,2H),3.79(d,J＝10.4Hz,2H),2.64(s,2H),2.07–1.97(m,1H),0.79 (d,J＝12.6Hz,4H).
MS(ESI+)m/z 444(M+H)+
实施例233：N-(4-(1-(N-甲基-N-(2,2,2-三氟乙基)氨磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001061
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.55(s,1H),7.87(d,J＝3.8Hz,1H),7.36(s,1H),6.56 (s,1H),6.35(s,1H),4.11(d,J＝10.7Hz,2H),3.96(s,2H),3.48(s,4H),2.93(d,J＝3.8Hz,2H),2.63(s,2H), 2.02(s,1H),0.79(d,J＝12.0Hz,4H).
MS(ESI+)m/z 458(M+H)+
实施例234：N-(4-(1-(吗啉代磺酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001062
MS(ESI+)m/z 432(M+H)+
实施例235：N-(4-(4-(吗啉-4-磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001063
MS(ESI+)m/z 443(M+H)+
实施例236：N-(4-(4-((N,N-二甲基氨磺酰基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001064
MS(ESI+)m/z 401(M+H)+
实施例237：N-(4-(4-((2,6-二甲基吗啉)-4-磺酰氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001071
1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),10.56(s,1H),10.30(s,1H),8.19–8.13(m,2H),7.51– 7.45(m,2H),7.38(dd,J＝2.1,9.1Hz,2H),6.84(dd,J＝1.8,3.7Hz,1H),3.53–3.45(m,4H),2.41(d,J＝ 14.6Hz,2H),2.19(d,J＝9.7Hz,1H),1.06(dd,J＝2.9,6.4Hz,6H),0.89–0.75(m,4H).
MS(ESI+)m/z 471(M+H)+
实施例238：N-(6-(4-(吗啉-4-磺酰氨基)苯基)-9H-嘌呤-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001072
1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),10.39(s,1H),8.77(d,J＝8.5Hz,2H),8.47(s,1H),7.39 (d,J＝8.4Hz,2H),3.55(t,J＝4.8Hz,4H),3.13(t,J＝4.7Hz,4H),2.18(dd,J＝8.7,4.3Hz,1H),0.90–0.77 (m,4H).
MS(ESI+)m/z 444(M+H)+
实施例239：N-(4-(4-(2-氰基乙酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001073
将1.2当量的2-氰基乙酸添加到二氯甲烷溶液中，并向其中加入1.6当量的EDCI。将1.4当量的 HOBt、1.1当量的DMAP和合成的N-(4-(4-氨基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺(100mg) 添加到混合物中，并在室温下搅拌。一旦反应完成后，向所述混合物中加入H2O，然后使用二氯甲烷进行萃取，并且然后由此分离有机层。将混合物浓缩后，通过柱色谱分离所得浓缩物，并最终得到产物。即，由此得到N-(4-(4-(4-(2-氰基乙酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.61(s,1H),10.50(s,1H),8.19(d,J＝6.7Hz,2H), 8.02(s,1H),7.40(s,1H),6.89(d,J＝6.8Hz,2H),6.56(s,1H),3.13(s,2H),0.81(d,J＝6.6Hz,4H)
MS(ESI+)m/z 360(M+H)+
实施例240至430
在下文的实施例240至430中，通过与实施例239所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例240：N-(4-(4-(2-氰基乙酰氨基)-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001081
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.62(s,1H),10.41(s,1H),7.78(s,1H),7.54(s,1H), 7.49(d,J＝8.5Hz,1H),7.33(t,J＝2.9Hz,1H),7.25(d,J＝8.2Hz,1H),6.07(dd,J＝3.4,1.8Hz,1H),3.93(s, 2H),2.15(s,3H),2.03(s,1H),0.84-0.75(m,4H).
MS(ESI+)m/z 374(M+H)+
实施例241：N-(4-(4-(2-(1-氰基环丙基)乙酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001082
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),10.19(s,1H),8.10(d,J＝6.2Hz,1H), 7.78(d,J＝8.5Hz,2H),7.69(d,J＝8.4Hz,2H),7.40(t,J＝3.0Hz,1H),6.56(t,J＝2.5Hz,1H),2.05(s,1H), 1.28(t,J＝3.8Hz,2H),1.06(q,J＝5.1Hz,2H),0.88-0.79(m,4H).
MS(ESI+)m/z 400(M+H)+
实施例242：N-(4-(4-丙酰氨基环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001083
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.52(s,1H),7.89–7.74(m,2H),7.31(dd,J＝2.5,3.5 Hz,1H),6.51(dd,J＝1.8,3.5Hz,1H),6.26–6.18(m,1H),3.90(s,1H),2.14(d,J＝13.0Hz,1H),2.08(t,J＝ 7.6Hz,2H),2.05–1.88(m,2H),1.69–1.58(m,1H),1.01(t,J＝7.6Hz,3H),0.84-0.76(m,4H).
MS(ESI+)m/z 353(M+H)+
实施例243：N-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)环己-3-烯-1-基)苯甲酰胺的合成
Figure BDA0002455210850001091
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.53(s,1H),8.40(d,J＝7.7Hz,1H),7.88(dt,J＝1.6, 7.1Hz,3H),7.56–7.43(m,3H),7.32(dd,J＝2.4,3.5Hz,1H),6.54(dd,J＝1.8,3.6Hz,1H),6.32–6.22(m, 1H),4.15(d,J＝3.5Hz,1H),2.71–2.54(m,4H),2.41–2.29(m,1H),2.04(d,J＝13.0Hz,2H),1.81(tq,J＝ 5.6,11.8Hz,1H),0.85-0.74(m,4H).
MS(ESI+)m/z 401(M+H)+
实施例244：N-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)环己-3-烯-1-基)-2-甲基环丙基-1- 甲酰胺的合成
Figure BDA0002455210850001092
MS(ESI+)m/z 379(M+H)+
实施例245：N-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)环己-3-烯-1-基)环戊基甲酰胺的合成
Figure BDA0002455210850001093
MS(ESI+)m/z 393(M+H)+
实施例246：N-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)环己-3-烯-1-基)环丙基甲酰胺的合成
Figure BDA0002455210850001094
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.51(s,1H),8.13(d,J＝7.5Hz,1H),7.84(s,1H),7.31 (d,J＝3.5Hz,1H),6.52(d,J＝3.5Hz,1H),6.24(d,J＝4.5Hz,1H),3.92(s,1H),2.60–2.54(m,2H),2.20–2.09(m,1H),2.00(d,J＝5.0Hz,1H),1.94(d,J＝12.3Hz,1H),1.70–1.54(m,2H),0.82–0.74(m,4H),0.71 –0.59(m,4H).
MS(ESI+)m/z 365(M+H)+
实施例247：N-(4-(4-(2-氰基乙酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001101
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.54(s,1H),8.31(d,J＝7.3Hz,1H),7.82(s,1H),7.36 –7.26(m,1H),6.53(dd,J＝1.9,3.6Hz,1H),6.24(s,1H),3.94(s,1H),3.64(s,2H),2.56(d,J＝6.3Hz,3H), 2.21–2.09(m,1H),2.05–1.98(m,1H),1.98–1.90(m,1H),1.76–1.65(m,1H),0.87-0.72(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例248：N-(4-(4-(4,4,4-三氟丁酰氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001102
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.49(s,1H),8.06(d,J＝7.5Hz,1H),7.85(d,J＝7.5Hz, 1H),7.31(q,J＝3.0,3.6Hz,1H),6.52(dd,J＝1.9,3.6Hz,1H),6.23(d,J＝4.4Hz,1H),3.94(d,J＝10.0Hz, 1H),2.92(d,J＝22.6Hz,1H),2.74–2.65(m,2H),2.55(s,3H),2.38(dd,J＝6.4,8.7Hz,2H),2.18–2.07(m, 1H),2.05–1.98(m,1H),1.93(dd,J＝4.9,12.4Hz,1H),1.67(q,J＝9.7,12.2Hz,1H),1.25–1.19(m,4H), 0.86–0.74(m,4H).
MS(ESI+)m/z 421(M+H)+
实施例249：N-(4-(1-(1,1-二氧化四氢-2H-噻喃-4-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001103
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.54(s,1H),7.87(s,1H),7.35(s,1H),6.57(s,1H), 6.34(d,J＝29.7Hz,1H),4.38–3.97(m,3H),3.75(d,J＝15.9Hz,2H),3.11(d,J＝14.9Hz,5H),2.64(s,2H), 2.02(d,J＝20.0Hz,6H),1.26–1.12(m,2H),0.85-0.76(m,4H).
MS(ESI+)m/z 443(M+H)+
实施例250：N-(4-(1-(2-氰基乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001111
1H NMR(400MHz,氯仿-d)δ11.44(s,1H),10.53(s,1H),7.86(s,1H),7.41–7.31(m,1H),6.55(s, 1H),6.31(d,J＝25.9Hz,1H),4.26–4.04(m,4H),3.77–3.67(m,1H),3.59(t,J＝5.3Hz,1H),3.17(s,1H), 2.65(s,1H),2.02(s,1H),0.84–0.78(m,4H).
MS(ESI+)m/z 350(M+H)+
实施例251：N-(4-(1-(2-(1,1-二氧化硫代吗啉代)乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001112
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.54(s,1H),7.87(s,1H),7.35(t,J＝3.1Hz,1H),6.56 (s,1H),6.33(d,J＝24.9Hz,1H),4.51–4.36(m,2H),4.35–4.20(m,2H),4.06–3.93(m,1H),3.86–3.67 (m,2H),3.64–3.48(m,2H),3.21(d,J＝14.0Hz,2H),3.08(d,J＝12.0Hz,3H),2.02(s,1H),0.80(d,J＝8.0 Hz,4H).
MS(ESI+)m/z 458(M+H)+
实施例252：N-(4-(1-(3-氰基丙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001113
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.53(s,1H),7.87(s,1H),7.34(t,J＝3.0Hz,1H),6.59 –6.52(m,1H),6.33(d,J＝21.2Hz,1H),4.21(s,2H),3.70(dt,J＝30.9,5.5Hz,2H),2.82(dt,J＝24.0,6.8Hz, 2H),2.70–2.59(m,4H),2.01(d,J＝6.2Hz,1H),0.86-0.74(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例253：N-(4-(1-(3,3,3-三氟丙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001121
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.53(d,J＝3.5Hz,1H),7.86(s,1H),7.34(s,1H),6.55 (s,1H),6.31(d,J＝27.5Hz,1H),4.19(s,2H),3.64(p,J＝6.8,6.0Hz,7H),2.62(s,2H),2.01(s,1H),0.85- 0.76(m,4H).
MS(ESI+)m/z 393(M+H)+
实施例254：N-(4-(1-(4,4,4-三氟丁酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001122
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.52(s,1H),7.85(s,1H),7.34(s,1H),6.55(s,1H), 6.34(s,1H),4.19(d,J＝6.5Hz,2H),3.75(s,2H),3.24(d,J＝10.1Hz,4H),2.65(d,J＝27.0Hz,2H),2.00(s, 1H),0.78(d,J＝11.5Hz,4H).
MS(ESI+)m/z 407(M+H)+
实施例255：N-(4-(8-(3-氰基丙酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001123
MS(ESI+)m/z 390(M+H)+
实施例256：N-(4-(8-(环丙基羰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001131
MS(ESI+)m/z 377(M+H)+
实施例257：N-(4-(8-(2-氰基乙酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001132
MS(ESI+)m/z 376(M+H)+
实施例258：N-(4-(8-(4,4,4-三氟丁酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001133
MS(ESI+)m/z 433(M+H)+
实施例259：N-(4-(1-(1-氰基环丙基-1-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001134
/>
MS(ESI+)m/z 376(M+H)+
实施例260：N-(4-(1-(3,3-二氟环丁基-1-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001141
1H NMR(400MHz,DMSO-d6)δ11.53–11.35(m,1H),10.53(s,1H),7.86(s,1H),7.34(d,J＝2.8Hz, 1H),6.63–6.48(m,1H),6.38–6.24(m,1H),4.19(d,J＝8.8Hz,2H),3.68(dt,J＝5.6,47.7Hz,2H),2.81 (ddt,J＝5.7,11.0,21.2Hz,4H),2.59(s,2H),2.00(d,J＝14.4Hz,1H),0.85–0.73(m,4H)
MS(ESI+)m/z 401(M+H)+
实施例261：N-(4-(8-(3,3,3-三氟丙酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001142
MS(ESI+)m/z 419(M+H)+
实施例262：N-(4-((1S,5R)-8-(2-氰基乙酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001143
MS(ESI+)m/z 376(M+H)+
实施例263：N-(4-(1-(2,2-二氟环丙基-1-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001144
1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.06(d,J＝2.3Hz,1H),7.91(d,J＝4.2Hz,1H),6.94 (dd,J＝5.8,4.1Hz,1H),6.32(s,1H),5.17(q,J＝10.6Hz,1H),4.56–4.28(m,1H),4.28–4.12(m,1H),3.93 (s,1H),3.77(t,J＝5.8Hz,2H),2.75(s,1H),2.38–2.29(m,1H),2.23(d,J＝11.8Hz,1H),2.06–1.80(m, 4H),0.86(d,J＝5.7Hz,4H).
MS(ESI+)m/z 387(M+H)+
实施例264：N-(4-(1-(环丙基羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001151
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.53(s,1H),7.87(s,1H),7.34(dd,J＝2.5,3.5Hz,1H), 6.56(dd,J＝1.9,3.6Hz,1H),6.35(s,1H),4.32(d,J＝110.2Hz,2H),3.82(d,J＝78.9Hz,2H),2.65(d,J＝ 9.9Hz,1H),2.13–1.92(m,2H),0.84–0.70(m,8H).
MS(ESI+)m/z 351(M+H)+
实施例265：N-(4-(1-(4-氰基丁酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001152
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.53(s,1H),7.86(s,1H),7.37–7.30(m,1H),6.56(dd, J＝1.9,3.5Hz,1H),6.33(d,J＝17.7Hz,1H),4.20(dd,J＝3.2,15.0Hz,2H),3.70(dt,J＝5.6,18.5Hz,2H), 2.64–2.52(m,6H),2.01(q,J＝3.1,3.7Hz,1H),1.84(p,J＝7.4Hz,2H),0.86–0.77(m,4H).
MS(ESI+)m/z 378(M+H)+
实施例266：N-(4-(1-丙烯酰基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001153
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.53(s,1H),7.87(s,1H),7.34(t,J＝3.0Hz,1H),6.98 –6.76(m,1H),6.56(s,1H),6.34(d,J＝24.5Hz,1H),6.16(d,J＝16.6Hz,1H),5.72(d,J＝10.2Hz,1H), 4.30(d,J＝40.6Hz,2H),3.85–3.74(m,2H),2.61(s,2H),2.02(s,1H),0.82-0.74(m,4H).
MS(ESI+)m/z 337(M+H)+
实施例267：N-(4-(1-((1S,2S)-2-氰基环丙基-1-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001161
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.54(s,1H),7.88(s,1H),7.35(s,1H),6.57(d,J＝2.4 Hz,1H),6.35(s,1H),4.50(d,J＝3.2Hz,1H),4.19(s,1H),4.00–3.87(m,1H),3.83–3.64(m,1H),3.03– 2.80(m,1H),2.10(dt,J＝5.2,9.7Hz,1H),2.02(s,1H),1.45(s,1H),1.35(d,J＝4.1Hz,1H),0.86–0.73(m, 4H).
MS(ESI+)m/z 376(M+H)+
实施例268：N-(4-(1-(2-(1-氰基环丙基)乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001162
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.53(s,1H),7.86(s,1H),7.34(t,J＝3.0Hz,1H),6.56 (d,J＝4.1Hz,1H),6.32(d,J＝37.2Hz,1H),4.21(s,1H),4.14(s,1H),3.74(t,J＝5.6Hz,1H),3.59(t,J＝4.9 Hz,1H),2.79(s,1H),2.74(s,1H),2.61(s,1H),2.05–1.96(m,2H),1.18(s,1H),0.94(dd,J＝7.3,4.8Hz, 2H),0.89–0.74(m,5H).
MS(ESI+)m/z 390(M+H)+
实施例269：N-(4-(1-(2-氰基丙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001163
MS(ESI+)m/z 364(M+H)+
实施例270：N-(4-(1-(丁-3-烯酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001171
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.57(s,1H),7.84(s,1H),7.35(t,J＝3.0Hz,1H),6.56 (d,J＝2.7Hz,1H),6.34(d,J＝23.8Hz,1H),6.02–5.85(m,1H),5.15–5.08(m,2H),4.25-4.14(m,2H), 3.24(dd,J＝18.3,6.7Hz,2H),3.02(d,J＝6.7Hz,1H),2.69(s,2H),2.06–1.95(m,2H),0.86-0.78(m,4H).
MS(ESI+)m/z 351(M+H)+
实施例271：N-(4-(1-(2-氰基丁酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001172
MS(ESI+)m/z 378(M+H)+
实施例272：N-(4-(1-(2,2,2-三氟乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001173
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),7.88(s,1H),7.36(t,J＝3.0Hz,1H),6.57 (td,J＝1.8,3.5Hz,1H),6.46–6.31(m,1H),4.42–4.28(m,2H),3.85(dt,J＝5.6,10.9Hz,2H),2.66(d,J＝ 15.5Hz,2H),2.02(ddd,J＝3.4,7.5,14.4Hz,1H),0.83-0.70(m,4H).
MS(ESI+)m/z 379(M+H)+
实施例273：N-(4-(1-(2-甲基环丙基-1-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001181
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.56(s,1H),7.88(s,1H),7.40–7.26(m,1H),6.56(dd, J＝1.9,3.6Hz,1H),6.35(s,1H),4.44(s,1H),4.16(s,1H),3.90(s,1H),3.70(s,1H),2.65(d,J＝12.4Hz, 1H),2.02(s,1H),1.77(d,J＝49.4Hz,1H),1.26–1.09(m,5H),0.95(d,J＝6.2Hz,1H),0.83–0.76(m,4H).
MS(ESI+)m/z 365(M+H)+
实施例274：N-(4-(1-(2-氟环丙基-1-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001182
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.54(s,1H),7.86(s,1H),7.33(t,J＝3.0Hz,1H),6.55 (t,J＝2.7Hz,1H),6.33(s,1H),4.74(d,J＝5.4Hz,1H),4.46(s,1H),4.15(s,1H),3.92(s,1H),3.78–3.58(m, 1H),2.71–2.61(m,2H),2.00(s,1H),1.43(s,1H),1.18(dt,J＝7.0,13.0Hz,1H),0.84-0.73(m,4H).
MS(ESI+)m/z 369(M+H)+
实施例275：4-(1-(2-氰基乙酰基)-1,2,3,6-四氢吡啶-4-基)-6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶 7-氧化物的合成
Figure BDA0002455210850001183
MS(ESI+)m/z 366(M+H)+
实施例276：N-(4-(1-(2-(3,4-二氟苯基)乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001191
1H NMR(400MHz,甲醇-d4)δ11.45(s,1H),10.56(s,1H),7.87(s,1H),7.42–7.30(m,3H),7.10(s, 1H),6.53(dd,J＝1.8,3.5Hz,1H),6.33(d,J＝21.7Hz,1H),4.30(s,1H),4.20(s,1H),3.82(d,J＝17.6Hz, 2H),3.75(t,J＝6.4Hz,2H),2.68(d,J＝7.4Hz,2H),2.02(s,1H),0.87-0.76(m,4H).
MS(ESI+)m/z 437(M+H)+
实施例277：N-(4-(1-异烟酰基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001192
1H NMR(400MHz,甲醇-d4)δ11.46(s,1H),10.56(s,1H),8.70(d,J＝5.1Hz,2H),7.88(s,1H),7.53– 7.43(m,2H),7.35(d,J＝11.1Hz,1H),6.64–6.51(m,1H),6.32(d,J＝82.1Hz,1H),4.36(s,1H),4.08(s, 1H),3.91(s,1H),3.51(s,1H),2.63(s,2H),2.02(s,1H),0.85–0.74(m,4H).
MS(ESI+)m/z 388(M+H)+
实施例278：N-(4-(1-(呋喃-3-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001193
1H NMR(400MHz,甲醇-d4)δ11.45(s,1H),10.56(s,1H),8.15(s,1H),7.89(s,1H),7.80–7.72(m, 1H),7.43–7.27(m,1H),6.76(d,J＝1.9Hz,1H),6.59(s,1H),6.36(s,1H),4.32(s,2H),3.81(s,2H),2.68(d, J＝7.1Hz,2H),2.01(d,J＝8.1Hz,1H),0.83–0.75(m,4H)
MS(ESI+)m/z 377(M+H)+
实施例279：N-(4-(1-(4-氟苯甲酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001201
1H NMR(400MHz,甲醇-d4)δ11.45(s,1H),10.56(s,1H),7.88(s,1H),7.57(dd,J＝5.5,8.5Hz,2H), 7.38–7.19(m,3H),6.59(s,1H),6.42(s,1H),4.24(d,J＝60.2Hz,2H),3.68–3.52(m,2H),2.66(d,J＝24.6 Hz,2H),2.01(s,1H),0.83–0.71(m,4H).
MS(ESI+)m/z 405(M+H)+
实施例280：N-(4-(1-(1-甲基吡咯烷-3-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001202
1H NMR(400MHz,甲醇-d4)δ11.45(s,1H),10.55(s,1H),7.86(s,1H),7.35(s,1H),6.56(s,1H),6.34 (d,J＝24.0Hz,1H),4.22(d,J＝32.6Hz,2H),3.71(d,J＝5.4Hz,2H),2.67(s,2H),2.36–2.21(m,4H),2.00 (s,3H),0.88–0.71(m,4H).
MS(ESI+)m/z 394(M+H)+
实施例281：N-(4-(1-(二甲基甘氨酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001203
1H NMR(400MHz,甲醇-d4)δ11.47(s,1H),10.57(s,1H),7.88(d,J＝4.4Hz,1H),7.36(s,1H),6.56 (d,J＝3.6Hz,1H),6.40–6.28(m,1H),4.20(d,J＝37.1Hz,4H),3.78(s,1H),3.60(s,1H),2.77(s,6H),2.62 (d,J＝36.3Hz,3H),2.05–1.97(m,1H),0.79(s,4H).
MS(ESI+)m/z 368(M+H)+
实施例282：N-(4-(1-(2-(三氟甲基)环丙基-1-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001211
1H NMR(400MHz,甲醇-d4)δ11.45(s,1H),10.55(s,1H),7.87(s,1H),7.35(s,1H),6.56(s,1H),6.34 (s,1H),4.47(d,J＝16.4Hz,1H),4.20(s,1H),3.92(s,1H),3.64(s,2H),2.67–2.61(m,2H),2.26(s,1H), 2.01(s,1H),0.78(d,J＝9.3Hz,4H).
MS(ESI+)m/z 419(M+H)+
实施例283：N-(4-(1-(2-氰基乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001212
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.57(s,1H),7.84(d,J＝10.2Hz,1H),7.34(d,J＝3.1 Hz,1H),6.48(dd,J＝1.8,3.7Hz,1H),6.17–6.03(m,1H),4.31–4.01(m,6H),3.96–3.62(m,2H),3.02(m, J＝36.6Hz,1H),2.02(s,1H),0.88(s,3H),0.84–0.73(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例284：N-(4-(1-(3-氰基丙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001213
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.56(s,1H),7.85(d,J＝5.5Hz,1H),7.34(d,J＝3.5Hz, 1H),6.49(dt,J＝2.0,3.5Hz,1H),6.11(d,J＝15.7Hz,1H),4.31(d,J＝24.5Hz,1H),4.14–3.90(m,2H), 3.57(d,J＝4.5Hz,2H),3.00(d,J＝27.7Hz,2H),2.85(dd,J＝7.7,15.5Hz,4H),2.02(s,1H),0.88(d,J＝ 10.7Hz,3H),0.82–0.76(m,4H).
MS(ESI+)m/z 378(M+H)+
实施例285：N-(4-(1-(4-氰基丁酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001221
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.56(s,1H),7.84(d,J＝5.1Hz,1H),7.33(s,1H),6.49 (s,1H),6.11(d,J＝10.4Hz,1H),4.44–4.24(m,1H),3.93(d,J＝17.1Hz,1H),3.66–3.56(m,2H),2.98(d,J ＝26.6Hz,1H),2.68(s,4H),2.04(d,J＝19.1Hz,1H),1.84(p,J＝6.3,6.9Hz,2H),0.93–0.84(m,3H),0.83 –0.71(m,4H).
MS(ESI+)m/z 392(M+H)+
实施例286：N-(4-(1-(1,2,5-噁二唑-3-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001222
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.57(s,1H),9.32(d,J＝10.0Hz,1H),7.89(s,1H), 7.36(dt,J＝6.3,3.2Hz,1H),6.57(ddd,J＝8.5,3.6,1.9Hz,1H),6.36(d,J＝47.7Hz,1H),4.42(d,J＝3.9Hz, 2H),3.96(t,J＝5.6Hz,1H),3.84(t,J＝5.6Hz,1H),2.68(d,J＝6.7Hz,2H),2.04–1.99(m,1H),0.82–0.75 (m,4H).
MS(ESI+)m/z 379(M+H)+
实施例287：N-(4-(1-(异噁唑-4-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001223
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),9.46(s,1H),8.94(s,1H),7.89(s,1H), 7.36(s,1H),6.58(d,J＝18.3Hz,1H),6.34(d,J＝47.3Hz,1H),4.35(d,J＝34.0Hz,2H),3.81(d,J＝39.9Hz, 2H),2.73(s,1H),2.61(s,1H),2.00(d,J＝13.2Hz,1H),0.85-0.74(m,4H).
MS(ESI+)m/z 378(M+H)+
实施例288：N-(4-(1-(异噁唑-5-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001231
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),8.79(t,J＝2.9Hz,1H),7.89(d,J＝4.7Hz, 1H),7.36(s,1H),7.07–7.00(m,1H),6.58(d,J＝13.4Hz,1H),6.35(d,J＝45.2Hz,1H),4.36(s,2H),3.91(s, 1H),3.75(d,J＝6.0Hz,1H),2.70(s,1H),2.64(s,1H),2.00(d,J＝9.2Hz,1H),0.85-0.76(m,4H).
MS(ESI+)m/z 378(M+H)+
实施例289：N-(4-(1-(2-氰基乙酰基)-1,2,3,6-四氢吡啶-4-基)-5-甲基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001232
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.12(s,1H),7.37(t,J＝2.9Hz,1H),6.31(s,1H),5.69 (d,J＝7.0Hz,1H),4.20–4.07(m,4H),3.62(t,J＝5.8Hz,2H),2.42(s,1H),2.37-2.26(m,1H),2.11(s,3H), 1.92–1.80(m,1H),0.79(d,J＝6.0Hz,4H)
MS(ESI+)m/z 364(M+H)+
实施例290：N-(5-甲基-4-(1-(3,3,3-三氟丙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001233
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.04(s,1H),7.35(t,J＝3.0Hz,1H),6.26(d,J＝2.5Hz, 1H),5.68(d,J＝6.8Hz,1H),4.26–4.12(m,2H),3.84–3.66(m,4H),2.41(s,1H),2.30(s,1H),2.09(s,3H), 1.83(q,J＝6.3Hz,1H),0.76(d,J＝6.2Hz,4H).
MS(ESI+)m/z 407(M+H)+
实施例291：N-(4-(1-(噻唑-4-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001241
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.56(s,1H),9.22(s,1H),8.24(d,J＝2.0Hz,1H),7.89 (s,1H),7.35(s,1H),6.57(d,J＝14.9Hz,1H),6.37(d,J＝60.7Hz,1H),4.40(d,J＝35.2Hz,2H),3.88(d,J＝ 19.6Hz,2H),2.65(s,2H),2.01(d,J＝5.7Hz,1H),1.24(m,2H),0.80(m,2H).
MS(ESI+)m/z 394(M+H)+
实施例292：N-(4-(1-(异噻唑-4-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001242
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),8.65(d,J＝1.8Hz,1H),7.89(s,1H),7.77 (s,1H),7.35(s,1H),6.60(s,1H),6.35(d,J＝53.1Hz,1H),4.36(d,J＝3.1Hz,2H),3.91(s,1H),3.74(s,1H), 2.71–2.65(m,2H),2.02(dd,J＝8.9,4.0Hz,1H),1.25(m,2H),0.87–0.73(m,2H).
MS(ESI+)m/z 394(M+H)+
实施例293：N-(4-(1-(4-氰基苯甲酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001243
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.56(s,1H),7.96(d,J＝7.8Hz,2H),7.88(s,1H),7.69 (d,J＝7.9Hz,2H),7.36(s,1H),6.57(d,J＝30.7Hz,1H),6.32(d,J＝87.2Hz,1H),4.35(s,1H),3.99(d,J＝ 68.8Hz,2H),3.50(s,1H),2.62(s,2H),2.04–1.96(m,1H),0.80(d,J＝5.2Hz,4H).
MS(ESI+)m/z 412(M+H)+
实施例294：N-(4-(1-(2-氰基乙酰基)-3-乙基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001251
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.56(s,1H),7.83(d,J＝10.8Hz,1H),7.34(s,1H), 6.48(d,J＝3.2Hz,1H),6.10(d,J＝22.6Hz,1H),4.34–4.19(m,2H),4.04(dd,J＝9.2,18.5Hz,2H),3.62–3.57(m,1H),2.76(s,1H),2.00(d,J＝12.4Hz,1H),1.28(s,2H),1.03(d,J＝6.2Hz,3H),0.87–0.73(m, 7H).
MS(ESI+)m/z 378(M+H)+
实施例295：N-(4-(1-(3-氰基丙酰基)-3-乙基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001252
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.56(s,1H),7.84(d,J＝5.5Hz,1H),7.33(s,1H),6.49 (d,J＝2.9Hz,1H),6.13(d,J＝23.5Hz,1H),4.50–4.26(m,2H),3.98(dd,J＝19.2,50.3Hz,1H),3.76–3.48 (m,3H),2.87(s,2H),2.73(d,J＝6.4Hz,2H),2.00(d,J＝12.8Hz,1H),1.36–1.14(m,3H),0.98–0.68(m, 7H).
MS(ESI+)m/z 392(M+H)+
实施例296：N-(4-(1-(2-氰基乙酰基)-5-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001253
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.57(s,1H),7.67(s,1H),7.31(t,J＝3.0Hz,1H),6.24 (tt,J＝1.5,3.3Hz,1H),4.14(dd,J＝1.2,3.5Hz,2H),4.07–3.94(m,2H),3.70(t,J＝5.7Hz,1H),3.57(t,J＝5.7Hz,1H),2.34(s,1H),2.05–1.95(m,1H),1.52(s,3H),1.24(d,J＝8.3Hz,1H),0.83–0.75(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例297：N-(4-(1-(2-溴乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001261
MS(ESI+)m/z 404(M+H)+
实施例298：N-(4-(1-(2-氯乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001262
MS(ESI+)m/z 359,361(M+H)+
实施例299：N-(4-(1-(2-氰基乙酰基)-3,3-二甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001263
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.56(s,1H),7.73(d,J＝7.5Hz,1H),7.28(s,1H),6.30 (s,1H),5.67–5.54(m,1H),4.19–4.06(m,4H),3.48(s,2H),2.01(s,1H),1.01(dd,J＝3.7,13.5Hz,6H), 0.80(d,J＝5.3Hz,4H).
MS(ESI+)m/z 378(M+H)+
实施例300：N-(4-(1-(3-氰基丙酰基)-3,3-二甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001264
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.56(s,1H),7.74(d,J＝8.2Hz,1H),7.28(s,1H),6.34 –6.24(m,1H),5.60(d,J＝10.1Hz,1H),4.13(dd,J＝3.3,14.9Hz,2H),3.50–3.44(m,2H),2.82(d,J＝3.8 Hz,2H),2.67(d,J＝4.4Hz,2H),2.01(s,1H),1.03(s,3H),0.99(s,3H),0.81-0.74(m,4H).
MS(ESI+)m/z 392(M+H)+
实施例301：N-(4-(1-(2-氰基乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)呋喃-2-甲酰胺的合成
Figure BDA0002455210850001271
MS(ESI+)m/z 376(M+H)+
实施例302：N-(4-(5-(3-氰基丙酰基)-5-氮杂螺[2.5]辛-7-烯-8-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001272
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.59–10.52(m,1H),7.55(d,J＝8.5Hz,1H),7.30(q,J ＝3.0Hz,1H),6.27(ddd,J＝10.1,3.5,1.9Hz,1H),5.69(dt,J＝7.0,3.3Hz,1H),4.23(dd,J＝11.8,3.2Hz, 2H),3.63(dt,J＝6.6,3.3Hz,2H),3.57(d,J＝19.1Hz,2H),3.21–3.09(m,2H),2.81(dt,J＝23.9,6.8Hz, 2H),2.67(t,J＝6.3Hz,2H),2.00(d,J＝7.2Hz,1H),0.81–0.76(m,4H).
MS(ESI+)m/z 390(M+H)+
实施例303：N-(4-(5-(2-氰基乙酰基)-5-氮杂螺[2.5]辛-7-烯-8-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001273
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.53(s,1H),7.86(d,J＝2.4Hz,1H),7.35(t,J＝3.0Hz, 1H),6.55(dd,J＝3.5,1.8Hz,1H),6.31(d,J＝26.1Hz,1H),4.21–4.17(m,1H),4.13(d,J＝23.2Hz,3H), 3.72(t,J＝5.6Hz,1H),3.59(t,J＝5.5Hz,1H),2.64(s,2H),2.55(s,1H),2.01(d,J＝4.8Hz,1H),0.83–0.77 (m,4H).
MS(ESI+)m/z 376(M+H)+
实施例304：(S)-N-(4-(1-(2-氰基乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001281
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.57(s,1H),7.84(d,J＝10.2Hz,1H),7.34(d,J＝3.1 Hz,1H),6.48(dd,J＝1.8,3.7Hz,1H),6.17–6.03(m,1H),4.31–4.01(m,6H),3.96–3.62(m,2H),3.02(m J＝36.6Hz,1H),2.02(s,1H),0.88(s,3H),0.84–0.73(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例305：((R)-N-(4-(1-(2-氰基乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺)的合成
Figure BDA0002455210850001282
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.57(s,1H),7.84(d,J＝10.2Hz,1H),7.34(d,J＝3.1 Hz,1H),6.48(dd,J＝1.8,3.7Hz,1H),6.17–6.03(m,1H),4.31–4.01(m,6H),3.96–3.62(m,2H),3.02(m, J＝36.6Hz,1H),2.02(s,1H),0.88(s,3H),0.84–0.73(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例306：(N-(4-(3-甲基-1-(2-甲基噻唑-5-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺)的合成
Figure BDA0002455210850001283
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.03(s,1H),7.85(s,1H),7.33(d,J＝3.5 Hz,1H),6.51(s,1H),6.12(s,1H),4.51(d,J＝18.2Hz,1H),4.25(s,1H),3.83(s,2H),3.07(s,1H),2.70(d,J ＝2.8Hz,3H),2.01(d,J＝8.8Hz,1H),0.90(d,J＝6.7Hz,3H),0.86-0.74(m,4H).
MS(ESI+)m/z 422(M+H)+
实施例307：N-(4-(1-(2,4-二甲基噻唑-5-羰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001291
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),7.83(s,1H),6.48(s,1H),6.11(s,1H), 4.41(s,1H),4.09(d,J＝18.6Hz,1H),3.66(s,2H),3.01(s,1H),2.64(d,J＝3.3Hz,3H),2.32(d,J＝3.4Hz, 3H),2.02(s,1H),0.86(d,J＝6.5Hz,3H),0.78(d,J＝9.6Hz,4H).
MS(ESI+)m/z 436(M+H)+
实施例308：N-(4-(3-甲基-1-(4-甲基噻唑-5-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001292
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),9.12(d,J＝2.1Hz,1H),7.84(d,J＝2.6Hz, 1H),7.33(q,J＝2.9Hz,1H),6.48(dt,J＝4.2,2.0Hz,1H),6.12(s,1H),4.51(s,1H),4.09(d,J＝18.1Hz,1H), 3.74–3.59(m,1H),3.01(s,1H),2.41(d,J＝2.3Hz,3H),2.02(tt,J＝8.8,5.2Hz,1H),0.94–0.83(m,3H), 0.82–0.74(m,4H).
MS(ESI+)m/z 422(M+H)+
实施例309：N-(4-(1-(2-氟异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001293
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.37(d,J＝5.1Hz,1H),7.83(d,J＝11.6 Hz,1H),7.44(s,1H),7.33(s,2H),6.50(d,J＝14.2Hz,1H),6.08(d,J＝71.4Hz,1H),4.54(d,J＝19.5Hz, 1H),4.11(d,J＝49.6Hz,2H),3.60(d,J＝13.1Hz,1H),2.02(s,1H),0.95(d,J＝6.8Hz,1H),0.84–0.73(m, 6H).
MS(ESI+)m/z 420(M+H)+
实施例310：N-(4-(1-(2-氯异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001301
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.54(d,J＝5.0Hz,1H),7.83(d,J＝12.1 Hz,1H),7.65(d,J＝7.4Hz,1H),7.51(s,1H),7.32(d,J＝8.5Hz,1H),6.50(d,J＝11.5Hz,1H),6.08(d,J＝ 67.3Hz,1H),4.58–4.10(m,1H),4.05(s,1H),3.60(d,J＝12.9Hz,1H),3.02(d,J＝41.1Hz,1H),2.01(s, 1H),0.94(d,J＝6.6Hz,1H),0.86-0.74(m,6H).
MS(ESI+)m/z 436,438(M+H)+
实施例311：N-(4-(1-(3,4-二氟苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001302
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(s,1H),7.67–7.49(m,3H),7.33(s, 2H),6.50(s,1H),4.12(s,2H),3.63(d,J＝12.5Hz,1H),3.01(s,1H),2.01(s,1H),0.92(s,1H),0.86-0.74(m, 6H).
MS(ESI+)m/z 437(M+H)+
实施例312：N-(4-(1-(3-氟-4-甲氧基苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001303
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(s,1H),7.39–7.23(m,4H),6.49(s, 1H),6.10(s,1H),4.13(d,J＝18.7Hz,1H),3.65(d,J＝11.9Hz,1H),3.02(s,1H),2.02(s,1H),0.92–0.68(m, 7H).
MS(ESI+)m/z 449(M+H)+
实施例313：N-(4-(3-甲基-1-(1H-吡咯-2-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001311
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),11.42(s,1H),10.55(s,1H),7.86(s,1H),7.32(s,1H), 6.91(s,1H),6.62(s,1H),6.56–6.47(m,1H),6.16(s,2H),4.59(d,J＝19.0Hz,1H),4.30(d,J＝19.2Hz,1H), 4.08–3.96(m,1H),3.06(s,1H),2.02(s,1H),0.92(d,J＝6.7Hz,3H),0.79(s,4H).
MS(ESI+)m/z 390(M+H)+
实施例314：N-(4-(1-(3-氟异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001312
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.74(s,1H),8.62–8.47(m,1H),7.84(d,J ＝14.4Hz,1H),7.57(d,J＝5.3Hz,1H),7.34(d,J＝5.1Hz,1H),6.49(d,J＝10.0Hz,1H),6.09(d,J＝71.3 Hz,1H),4.17(t,J＝19.7Hz,1H),3.99(s,1H),3.60(d,J＝13.8Hz,1H),3.01(d,J＝56.3Hz,1H),2.02(s, 1H),0.95(d,J＝6.8Hz,1H),0.79(d,J＝7.4Hz,6H).
MS(ESI+)m/z 420(M+H)+
实施例315：N-(4-(1-(3-(2-(3,5-二氧代吗啉代)乙基)苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001313
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.81(d,J＝17.3Hz,1H),7.40(t,J＝7.7 Hz,1H),7.30(d,J＝9.5Hz,4H),6.50(s,1H),6.09(d,J＝71.6Hz,1H),4.05(d,J＝28.5Hz,2H),3.91(t,J＝ 7.4Hz,3H),3.62(dd,J＝13.1,4.2Hz,1H),3.38(q,J＝7.0Hz,2H),2.98(s,1H),2.84(t,J＝7.4Hz,2H),2.01 (d,J＝5.1Hz,1H),1.09(t,J＝7.0Hz,2H),0.93(s,1H),0.89–0.69(m,7H).
MS(ESI+)m/z 542(M+H)+
实施例316：N-(4-(3-甲基-1-(3-(苯基氨基)苯甲酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001321
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.55(s,1H),9.20(s,1H),8.18(d,J＝4.9Hz,1H),7.84 (s,1H),7.58(ddd,J＝8.7,7.1,2.0Hz,1H),7.37–7.29(m,2H),6.94(d,J＝7.6Hz,1H),6.84(d,J＝8.3Hz, 1H),6.76(dd,J＝7.0,4.9Hz,1H),6.49(s,1H),4.46(s,1H),4.27–4.05(m,2H),3.67(s,1H),3.04(s,1H), 2.02(s,1H),0.88–0.69(m,7H)
MS(ESI+)m/z 492(M+H)+
实施例317：N-(4-(1-(6-(2,4-二氟苯基)-2-氧代-1,2-二氢吡啶-3-羰基)-3-甲基-1,2,3,6-四氢吡啶-4- 基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001322
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.37(d,J＝7.5Hz,1H),7.84–7.75(m,2H),7.52–7.41 (m,2H),7.36–7.20(m,3H),6.88(dd,J＝7.6,1.5Hz,1H),4.20–4.05(m,1H),4.01(p,J＝6.6Hz,1H),3.49 (dt,J＝14.8,6.9Hz,1H),3.15(q,J＝9.1Hz,1H),2.07–1.99(m,1H),1.94(q,J＝12.1,10.2Hz,1H),1.25– 1.17(m,3H),0.81(td,J＝14.7,12.6,5.0Hz,4H).
MS(ESI+)m/z 530(M+H)+
实施例318：1-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-1,2,3,6-四氢吡啶-1-羰基) 环丁基-1-甲酸甲酯的合成
Figure BDA0002455210850001323
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.54(s,1H),7.82(d,J＝3.4Hz,1H),7.39–7.26(m, 1H),6.45(d,J＝15.8Hz,1H),6.06(d,J＝43.3Hz,1H),4.32–4.00(m,2H),2.93(s,1H),2.07–1.90(m,3H), 1.82(s,1H),1.31–1.19(m,1H),0.98–0.69(m,10H).
MS(ESI+)m/z 437(M+H)+
实施例319：1-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-1,2,3,6-四氢吡啶-1-羰基) 环丙基-1-甲酸甲酯的合成
Figure BDA0002455210850001331
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.55(s,1H),7.84(d,J＝7.6Hz,1H),7.41–7.26(m, 1H),6.48(s,1H),6.11(d,J＝6.0Hz,1H),4.28(t,J＝20.9Hz,2H),4.06(d,J＝15.8Hz,2H),3.68(d,J＝8.6 Hz,5H),2.99(d,J＝27.0Hz,1H),2.02(s,1H),1.40(q,J＝11.2,7.4Hz,4H),1.32–1.21(m,2H),0.88(t,J＝ 7.4Hz,4H),0.84–0.74(m,4H).
MS(ESI+)m/z 423(M+H)+
实施例320：3-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-3,6-二氢吡啶-1(2H)- 基)-2-甲基-3-氧代丙酸甲酯的合成
Figure BDA0002455210850001332
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),7.85(s,1H),7.34(s,1H),6.48(d,J＝8.4 Hz,1H),6.12(d,J＝16.1Hz,1H),4.21–3.97(m,6H),3.68(d,J＝19.0Hz,1H),3.00(s,1H),2.03(s,1H), 1.26(dd,J＝7.6,4.2Hz,4H),0.87–0.74(m,7H).
MS(ESI+)m/z 411(M+H)+
实施例321：N-(4-(1-(6-(叔丁基)-2-氧代-1,2-二氢吡啶-3-羰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001333
1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),11.41(s,1H),10.54(s,1H),7.83(d,J＝12.1Hz,1H), 7.48(t,J＝6.5Hz,1H),7.36–7.25(m,1H),6.48(s,1H),6.09(d,J＝37.7Hz,2H),4.26(dd,J＝94.3,20.9Hz, 1H),4.05(s,1H),3.60–3.41(m,1H),3.26(dd,J＝13.0,5.2Hz,1H),3.04(d,J＝24.5Hz,1H),2.00(d,J＝ 13.7Hz,1H),1.28(s,9H),0.84–0.72(m,7H).
MS(ESI+)m/z 474(M+H)+
实施例322：N-(4-(1-(6-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-羰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H- 吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001341
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),11.42(s,1H),10.54(s,1H),8.00–7.80(m,3H),7.64(d, J＝7.4Hz,1H),7.35(t,J＝8.6Hz,3H),6.49(t,J＝2.0Hz,1H),6.10(d,J＝44.8Hz,1H),4.26–4.03(m,2H), 3.69–3.44(m,2H),3.05(s,1H),2.02(s,1H),0.91–0.70(m,7H).
MS(ESI+)m/z 512(M+H)+
实施例323：N-(4-(1-(3-氟-4-((2-吗啉代乙基)氨基)苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001342
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.43–7.28(m,1H),7.25–7.12(m,2H), 6.78(t,J＝8.6Hz,1H),6.56–6.44(m,1H),6.10(s,1H),5.64(s,1H),4.42–4.07(m,2H),3.69(s,2H),3.64 –3.52(m,4H),3.26(t,J＝6.2Hz,2H),3.03(s,1H),2.43(s,2H),2.11–1.94(m,1H),0.85(d,J＝6.8Hz,4H), 0.83–0.74(m,4H).
MS(ESI+)m/z 547(M+H)+
实施例324：N-(4-(1-(5-溴烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001343
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.82(d,J＝2.4Hz,1H),8.68(d,J＝4.6Hz, 1H),8.22(d,J＝8.6Hz,1H),7.84(d,J＝8.6Hz,1H),7.33(s,1H),6.50(d,J＝12.8Hz,1H),6.09(d,J＝63.9 Hz,1H),4.16(d,J＝15.0Hz,2H),3.64(s,1H),3.36(d,J＝7.5Hz,1H),3.04(d,J＝25.2Hz,1H),2.00(d,J＝ 14.1Hz,1H),0.89–0.71(m,7H).
MS(ESI+)m/z 480,482(M+H)+
实施例325：N-(4-(1-(2,3-二氢苯并[b][1,4]二噁英-6-羰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并 [2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001351
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.82(s,1H),7.35–7.25(m,1H),7.00– 6.88(m,3H),6.49(s,1H),6.10(s,1H),4.27(s,4H),4.17–4.04(m,1H),3.72–3.57(m,1H),3.00(s,1H), 2.01(td,J＝7.8,7.4,3.7Hz,1H),0.85(s,3H),0.84–0.76(m,4H).
MS(ESI+)m/z 459(M+H)+
实施例326：N-(4-(1-(苯并[d][1,3]二氧杂环戊烯-5-羰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并 [2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001352
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.54(s,1H),7.82(s,1H),7.32(t,J＝3.0Hz,1H),7.04 (s,1H),6.98(d,J＝2.4Hz,2H),6.49(d,J＝3.4Hz,1H),6.09(s,3H),4.18–4.02(m,1H),3.69–3.57(m, 1H),3.01(s,1H),2.01(td,J＝7.4,3.6Hz,1H),0.84(s,3H),0.81–0.75(m,4H).
MS(ESI+)m/z 445(M+H)+
实施例327：N-(4-(1-(1H-吲哚-6-羰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001353
1H NMR(400MHz,DMSO-d6)δ11.42(d,J＝2.8Hz,1H),11.31(s,1H),10.55(s,1H),7.88–7.82(m, 1H),7.61(d,J＝8.1Hz,1H),7.51(d,J＝1.4Hz,1H),7.47(t,J＝2.7Hz,1H),7.32(t,J＝3.0Hz,1H),7.10 (dd,J＝8.1,1.5Hz,1H),6.49(t,J＝2.5Hz,2H),6.12(s,1H),4.22–4.11(m,1H),3.75–3.65(m,1H),3.03 (s,1H),2.02(td,J＝8.6,7.9,4.2Hz,1H),0.88(s,3H),0.83–0.74(m,4H).
MS(ESI+)m/z 440(M+H)+
实施例328：N-(4-(3-甲基-1-(1H-吡咯并[2,3-b]吡啶-4-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001354
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(s,1H),7.32(t,J＝3.0Hz,1H),7.10 –6.96(m,3H),6.49(s,1H),6.11(s,1H),4.13(d,J＝18.8Hz,1H),3.80(d,J＝4.3Hz,6H),3.66(dd,J＝12.9, 4.2Hz,1H),3.02(s,1H),2.02(dq,J＝8.6,4.2,3.3Hz,1H),0.95–0.84(m,3H),0.84–0.70(m,4H).
MS(ESI+)m/z 441(M+H)+
实施例329：N-(4-(1-(3,4-二甲氧基苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001361
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(s,1H),7.39(t,J＝7.9Hz,1H),7.32 (s,1H),7.07–6.96(m,3H),6.49(s,1H),4.17–3.99(m,2H),3.80(s,3H),3.62(dd,J＝13.0,4.1Hz,1H), 2.98(s,1H),2.06–1.98(m,1H),0.92(s,1H),0.86–0.72(m,6H).
MS(ESI+)m/z 461(M+H)+
实施例330：N-(4-(1-(3-甲氧基苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001362
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(s,1H),7.39(t,J＝7.9Hz,1H),7.32 (s,1H),7.06–7.01(m,2H),6.99(d,J＝4.8Hz,1H),6.49(s,1H),4.19–4.00(m,2H),3.80(s,3H),3.62(dd, J＝13.0,4.1Hz,1H),2.98(s,1H),2.02(td,J＝7.7,3.9Hz,1H),0.92(s,1H),0.86–0.74(m,6H).
MS(ESI+)m/z 431(M+H)+
实施例331：N-(4-(3-甲基-1-(4-硝基苯甲酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001363
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.32(dd,J＝8.5,6.1Hz,3H),7.84(d,J＝ 9.3Hz,1H),7.75(d,J＝8.1Hz,2H),7.32(d,J＝9.2Hz,1H),6.50(d,J＝17.8Hz,1H),6.09(d,J＝79.2Hz, 1H),4.37(dd,J＝155.6,19.8Hz,1H),4.13–3.94(m,2H),3.62(d,J＝11.6Hz,1H),3.04(d,J＝44.3Hz,1H), 2.02(dq,J＝8.0,3.9,2.8Hz,1H),0.95(d,J＝6.8Hz,1H),0.83–0.74(m,6H).
MS(ESI+)m/z 446(M+H)+
实施例332：N-(4-(1-(3-乙酰基苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001371
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.55(s,1H),8.08–8.03(m,1H),8.01(s,1H),7.84(s, 1H),7.74(d,J＝7.5Hz,1H),7.64(t,J＝7.8Hz,1H),7.32(s,1H),6.50(s,1H),6.10(d,J＝74.1Hz,1H),4.65 –4.15(m,1H),4.08(d,J＝33.0Hz,1H),3.64(d,J＝13.1Hz,1H),3.03(d,J＝33.6Hz,1H),2.63(d,J＝1.4 Hz,3H),2.02(dd,J＝8.6,4.2Hz,1H),0.95(s,1H),0.85–0.73(m,6H).
MS(ESI+)m/z 443(M+H)+
实施例333：N-(4-(1-(4-氯苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001372
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(s,1H),7.53(t,J＝9.6Hz,4H),7.32 (s,1H),6.50(s,1H),6.09(d,J＝63.6Hz,1H),4.52(d,J＝19.2Hz,1H),4.10(s,1H),3.63(dd,J＝13.0,4.2 Hz,1H),3.00(s,1H),2.06–1.97(m,1H),0.92(s,1H),0.82–0.75(m,6H).
MS(ESI+)m/z 435,437(M+H)+
实施例334：N-(4-(1-(3-溴苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001373
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(s,1H),7.68(d,J＝11.0Hz,2H), 7.45(d,J＝8.0Hz,2H),7.32(s,1H),6.50(s,1H),6.09(d,J＝61.5Hz,1H),4.55(d,J＝19.7Hz,1H),4.09(s, 1H),3.68–3.55(m,1H),3.01(d,J＝23.9Hz,1H),2.02(s,1H),0.93(s,1H),0.84–0.74(m,6H).
MS(ESI+)m/z 479,481(M+H)+
实施例335：N-(4-(1-(6-氯烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001381
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.55(s,1H),8.59–8.51(m,1H),7.99(d,J＝8.0Hz, 1H),7.83(s,1H),7.64(d,J＝8.2Hz,1H),7.32(s,1H),6.50(d,J＝13.3Hz,1H),6.08(d,J＝69.0Hz,1H), 4.57–4.17(m,1H),4.14(s,1H),3.65(d,J＝12.5Hz,1H),3.02(s,1H),2.02(dq,J＝8.1,3.9,2.8Hz,1H), 0.93(s,1H),0.85-0.75(m,6H).
MS(ESI+)m/z 436,438(M+H)+
实施例336：N-(4-(1-异烟酰基-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001382
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.74–8.64(m,2H),7.83(d,J＝10.7Hz, 1H),7.48–7.44(m,2H),7.32(dt,J＝10.4,2.9Hz,1H),6.56–6.44(m,1H),6.22–5.96(m,1H),4.35(dd,J ＝166.5,19.8Hz,1H),4.06(d,J＝9.2Hz,1H),3.60(dd,J＝13.4,5.2Hz,1H),3.02(d,J＝39.5Hz,1H),2.01 (td,J＝7.8,7.4,3.7Hz,1H),0.94(d,J＝6.8Hz,1H),0.84–0.74(m,6H).
MS(ESI+)m/z 402(M+H)+
实施例337：N-(4-(1-(6-溴吡啶甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001383
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),7.94–7.89(m,1H),7.85(d,J＝6.6Hz, 1H),7.78(dd,J＝8.1,1.0Hz,1H),7.69(dd,J＝7.5,3.8Hz,1H),7.32(dt,J＝10.3,2.9Hz,1H),6.49(ddd,J＝ 8.0,3.5,1.9Hz,1H),6.11(dt,J＝60.3,3.4Hz,1H),4.61–4.17(m,1H),4.16–4.11(m,1H),3.63(dd,J＝ 13.1,3.5Hz,1H),3.52(dd,J＝13.3,4.1Hz,1H),3.04(d,J＝32.1Hz,1H),2.05–1.99(m,1H),0.90(dd,J＝ 35.3,6.8Hz,3H),0.83–0.72(m,4H).
MS(ESI+)m/z 480,482(M+H)+
实施例338：N-(4-(1-(3-溴丁酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001391
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.55(s,1H),7.83(s,1H),7.32(t,J＝2.9Hz,1H),6.49 (s,1H),6.11(s,1H),5.25(s,1H),5.05(s,1H),2.97(s,1H),2.02(s,1H),1.91(s,3H),0.90–0.84(m,4H), 0.83–0.74(m,6H).
MS(ESI+)m/z 445,447(M+H)+
实施例339：(E)-N-(4-(1-(5-溴戊-2-烯酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001392
MS(ESI+)m/z 457,459(M+H)+
实施例340：N-(4-(1-(2-环戊基乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001393
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.53(s,1H),7.83(d,J＝3.8Hz,1H),7.32(s,1H),6.48 (dd,J＝3.5,1.8Hz,1H),6.10(d,J＝12.7Hz,1H),4.36(t,J＝17.9Hz,1H),3.96–3.87(m,1H),2.96(d,J＝ 19.7Hz,1H),2.02(d,J＝5.6Hz,1H),1.78(d,J＝7.5Hz,2H),1.59(s,2H),1.50(d,J＝7.3Hz,2H),1.15(s, 2H),0.89(d,J＝6.8Hz,2H),0.84–0.77(m,7H)
MS(ESI+)m/z 407(M+H)+
实施例341：N-(4-(1-(2-(4-甲氧基苯基)乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001401
MS(ESI+)m/z 445(M+H)+
实施例342：N-(4-(3-甲基-1-(3-甲基噻吩-2-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001402
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(s,1H),7.59(d,J＝5.0Hz,1H),7.32 (d,J＝2.9Hz,1H),6.96(s,1H),6.47(dd,J＝3.5,1.8Hz,1H),6.12(s,1H),4.08(d,J＝18.8Hz,2H),2.01(s, 1H),0.86(d,J＝6.9Hz,6H),0.81–0.78(m,4H).
MS(ESI+)m/z 421(M+H)+
实施例343：N-(4-(3-甲基-1-(吡嗪-2-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001403
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),8.90(dd,J＝6.0,1.6Hz,1H),8.77(d,J＝ 2.5Hz,1H),8.74–8.70(m,1H),7.83(d,J＝10.3Hz,1H),7.32(dt,J＝8.9,3.0Hz,1H),6.49(ddd,J＝9.7, 3.5,1.8Hz,1H),6.21–5.96(m,1H),4.31–4.11(m,2H),2.01(s,1H),0.95(d,J＝6.8Hz,2H),0.82–0.74 (m,7H).
MS(ESI+)m/z 403(M+H)+
实施例344：N-(4-(3-甲基-1-(5-甲基吡嗪-2-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001411
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),8.76(d,J＝7.1Hz,1H),8.61(s,1H),7.83 (d,J＝9.7Hz,1H),7.36–7.29(m,1H),6.48(d,J＝9.3Hz,1H),6.10(d,J＝72.7Hz,1H),4.23–4.10(m, 2H),2.01(s,1H),1.23(s,3H),0.81–0.77(m,7H).
MS(ESI+)m/z 417(M+H)+
实施例345：N-(4-(3-甲基-1-(2-(噻吩-2-基)乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001412
/>
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.53(s,1H),7.82(d,J＝7.2Hz,1H),7.35(dd,J＝26.6, 4.3Hz,3H),7.00–6.93(m,3H),6.45(s,1H),6.09(d,J＝15.0Hz,1H),4.52–4.16(m,2H),4.04(dd,J＝ 17.1,3.4Hz,2H),2.95(d,J＝8.0Hz,1H),2.01(s,1H),0.84(d,J＝6.9Hz,3H),0.81–0.77(m,4H).
MS(ESI+)m/z 421(M+H)+
实施例346：N-(4-(1-(2-(3-氟苯基)乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001413
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.53(s,1H),7.82(d,J＝5.9Hz,1H),7.36(dd,J＝6.4, 2.8Hz,1H),7.33–7.31(m,1H),7.13(d,J＝9.0Hz,1H),7.10–7.03(m,2H),6.44(p,J＝2.1Hz,1H),6.09 (dd,J＝18.3,3.5Hz,1H),4.37(dd,J＝28.8,18.3Hz,1H),4.12(dd,J＝11.4,6.1Hz,1H),3.85(d,J＝13.5Hz, 2H),3.71(s,2H),2.04–1.98(m,1H),0.83(dd,J＝6.9,2.0Hz,3H),0.80–0.74(m,4H).
MS(ESI+)m/z 433(M+H)+
实施例347：N-(4-(1-(2-(3-溴苯基)乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001421
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),8.12(d,J＝6.2Hz,1H),7.83(d,J＝6.5Hz, 1H),7.49(d,J＝15.6Hz,1H),7.44(dt,J＝6.6,3.1Hz,1H),7.28(s,1H),6.74–6.68(m,1H),6.47–6.41(m, 1H),6.09(dt,J＝15.0,3.4Hz,1H),4.08(d,J＝50.7Hz,2H),3.84(d,J＝15.6Hz,2H),3.71(s,2H),2.96(s, 1H),2.01(t,J＝4.9Hz,1H),0.84(d,J＝6.8Hz,3H),0.81–0.76(m,4H).
MS(ESI+)m/z 494(M+H)+
实施例348：N-(4-(1-(2-氯乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001422
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(d,J＝7.2Hz,1H),7.32(t,J＝3.0Hz, 1H),6.48(d,J＝3.1Hz,1H),6.10(d,J＝13.3Hz,1H),4.52–4.41(m,2H),4.37–4.04(m,2H),2.97(s,1H), 2.00(q,J＝7.3,6.1Hz,1H),0.88(dd,J＝17.0,6.9Hz,3H),0.79(dd,J＝9.1,6.0Hz,4H).
MS(ESI+)m/z 373,375(M+H)+
实施例349：N-(4-(1-(2-氯烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001423
MS(ESI+)m/z 436,438(M+H)+
实施例350：N-(4-(1-(4-羟基苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001431
MS(ESI+)m/z 417(M+H)+
实施例351：N-(4-(1-(3,5-二氯-2-羟基苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001432
MS(ESI+)m/z 486(M+H)+
实施例352：N-(4-(1-(苯并呋喃-2-羰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001433
MS(ESI+)m/z 441(M+H)+
实施例353：N-(4-(1-(3,4-二氯苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001434
MS(ESI+)m/z 469,471,473(M+H)+
实施例354：N-(4-(3-甲基-1-(4-(甲基磺酰基)苯甲酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001441
MS(ESI+)m/z 479(M+H)+
实施例355：N-(4-(1-(2-氯-4-氟苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001442
MS(ESI+)m/z 453,455(M+H)+
实施例356：N-(4-(1-(2,4-二甲氧基苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001443
MS(ESI+)m/z 461(M+H)+
实施例357：N-(4-(3-甲基-1-(2-(甲硫基)苯甲酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001444
/>
MS(ESI+)m/z 447(M+H)+
实施例358：N-(4-(1-(3,5-二氟苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001451
MS(ESI+)m/z 437(M+H)+
实施例359：N-(4-(1-(2-氰基-3-(4-氟苯基)丙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001452
MS(ESI+)m/z 472(M+H)+
实施例360：N-(4-(1-(2-氰基-3-苯基丙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001453
MS(ESI+)m/z 454(M+H)+
实施例361：N-(4-(1-(1-氰基环戊基-1-羰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001454
MS(ESI+)m/z 418(M+H)+
实施例362：N-(4-(3-甲基-1-(3-吗啉代-3-氧代丙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001461
MS(ESI+)m/z 452(M+H)+
实施例363：N-(4-(1-(2-氰基乙酰基)-2-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001462
MS(ESI+)m/z 364(M+H)+
实施例365：N-(4-(3-甲基-1-(2-苯基乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001463
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.53(s,1H),7.82(d,J＝8.0Hz,1H),7.33–7.23(m, 6H),6.41(d,J＝3.8Hz,1H),6.07(d,J＝23.4Hz,1H),4.37(dd,J＝29.9,18.8Hz,1H),4.13–4.01(m,1H), 3.81(dd,J＝11.9,4.6Hz,2H),2.88(s,1H),2.08(d,J＝1.5Hz,2H),2.01(d,J＝1.5Hz,1H),0.86–0.77(m, 7H).
MS(ESI+)m/z 415(M+H)+
实施例366：N-(4-(9-(2-氟异烟酰基)-9-氮杂双环[3.3.1]壬-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001464
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.55(d,J＝3.3Hz,1H),8.35(t,J＝5.6Hz,1H),7.90(d, J＝3.2Hz,1H),7.47–7.38(m,1H),7.37–7.25(m,2H),6.53(ddd,J＝33.6,3.5,1.8Hz,1H),6.30(dd,J＝ 68.3,5.4Hz,1H),5.34–4.94(m,1H),4.31–3.88(m,1H),2.96(dd,J＝17.4,8.2Hz,1H),2.37(d,J＝17.9 Hz,1H),2.02(s,1H),1.86–1.54(m,6H),0.89-0.71(m,4H).
MS(ESI+)m/z 446(M+H)+
实施例367：N-(4-(9-(2-氯异烟酰基)-9-氮杂双环[3.3.1]壬-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001471
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.66–10.23(m,1H),8.52(dd,J＝7.0,5.0Hz,1H), 7.90(d,J＝3.4Hz,1H),7.62(d,J＝24.1Hz,1H),7.54–7.42(m,1H),7.35(dt,J＝6.7,2.9Hz,1H),6.53(ddd, J＝31.9,3.6,1.9Hz,1H),6.31(dd,J＝63.6,5.4Hz,1H),5.36–4.91(m,1H),4.33–3.82(m,1H),2.97(dt,J ＝17.0,7.9Hz,1H),2.37(d,J＝18.0Hz,1H),2.01(d,J＝8.1Hz,1H),1.89–1.55(m,6H),0.86–0.72(m, 4H).
MS(ESI+)m/z 462,464(M+H)+
实施例368：N-(4-(9-(6-氯烟酰基)-9-氮杂双环[3.3.1]壬-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001472
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.55(s,1H),8.53(dd,J＝12.8,2.3Hz,1H),7.97(ddd, J＝16.5,8.3,2.4Hz,1H),7.90(s,1H),7.62(t,J＝8.2Hz,1H),7.35(dt,J＝8.3,2.8Hz,1H),6.61–6.47(m, 1H),6.31(dd,J＝63.7,5.4Hz,1H),5.35–4.89(m,1H),4.23(d,J＝141.9Hz,1H),2.99(dd,J＝18.2,7.2Hz, 1H),2.38(d,J＝17.9Hz,1H),2.08–1.97(m,1H),1.87–1.57(m,6H),0.85–0.71(m,4H).
MS(ESI+)m/z 462,464(M+H)+
实施例369：N-(4-(9-(3-氟异烟酰基)-9-氮杂双环[3.3.1]壬-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001473
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.56(s,1H),8.72(d,J＝2.5Hz,1H),8.54(dt,J＝4.4, 2.1Hz,1H),7.90(d,J＝7.1Hz,1H),7.58(t,J＝5.3Hz,1H),7.36(dt,J＝8.5,3.0Hz,1H),6.51(ddd,J＝30.4, 3.6,1.9Hz,1H),6.31(dd,J＝71.8,5.5Hz,1H),5.20(d,J＝113.1Hz,1H),4.04(d,J＝127.2Hz,1H),2.92 (td,J＝21.1,18.1,6.8Hz,1H),2.39(d,J＝17.9Hz,1H),2.02(d,J＝7.6Hz,1H),1.86(d,J＝10.6Hz,2H), 1.74(d,J＝34.5Hz,3H),1.62(d,J＝12.4Hz,1H),0.86-0.72(m,4H).
MS(ESI+)m/z 446(M+H)+
实施例370：N-(4-(9-(4-硝基苯甲酰基)-9-氮杂双环[3.3.1]壬-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001474
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),8.31(dd,J＝8.4,5.7Hz,2H),7.91(d,J＝ 2.6Hz,1H),7.73(dd,J＝14.0,8.4Hz,2H),7.36(dt,J＝10.5,3.0Hz,1H),6.61–6.47(m,1H),6.31(dd,J＝82.6,5.4Hz,1H),5.16(d,J＝118.0Hz,1H),4.13(d,J＝138.3Hz,1H),2.97(ddd,J＝25.3,18.1,7.3Hz,1H), 2.38(d,J＝17.9Hz,1H),2.01(d,J＝14.0Hz,1H),1.81(d,J＝30.8Hz,3H),1.64(d,J＝22.4Hz,3H),0.83– 0.74(m,4H).
MS(ESI+)m/z 472(M+H)+
实施例371：N-(4-(9-(3-溴苯甲酰基)-9-氮杂双环[3.3.1]壬-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001481
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.55(s,1H),7.90(s,1H),7.68(d,J＝7.1Hz,1H),7.63 (d,J＝15.3Hz,1H),7.50–7.39(m,2H),7.36(dd,J＝7.1,3.9Hz,1H),6.59–6.46(m,1H),6.32(dd,J＝60.3, 5.3Hz,1H),5.12(d,J＝114.0Hz,1H),4.20(d,J＝137.6Hz,1H),3.03–2.84(m,1H),2.45–2.33(m,1H), 2.02(s,1H),1.83(s,3H),1.71(d,J＝24.0Hz,2H),1.61(d,J＝9.5Hz,1H),0.85–0.73(m,4H).
MS(ESI+)m/z 506(M+H)+
实施例372：N-(4-(1-(2,6-二氯异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001482
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(d,J＝13.7Hz,1H),7.72(d,J＝6.8 Hz,2H),7.36–7.29(m,1H),6.49(d,J＝9.7Hz,1H),6.07(d,J＝65.0Hz,1H),4.50(d,J＝19.2Hz,1H), 4.17–4.01(m,3H),2.01(s,1H),1.23(s,3H),0.80(d,J＝7.3Hz,4H).
MS(ESI+)m/z 471(M+H)+
实施例373：N-(4-(1-(2,5-二氯异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001483
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.54(s,1H),8.65(s,1H),7.86(d,J＝5.7Hz,1H),7.81 –7.75(m,1H),7.35–7.28(m,1H),6.48(d,J＝19.5Hz,1H),6.08(d,J＝63.9Hz,1H),4.62–4.09(m,1H), 3.92(d,J＝32.5Hz,1H),2.02(d,J＝7.1Hz,1H),0.97(s,2H),0.83–0.74(m,7H).
MS(ESI+)m/z 471(M+H)+
实施例374：N-(4-(1-(3,5-二氯异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001484
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.78(d,J＝4.8Hz,2H),7.83(d,J＝15.9 Hz,1H),7.33(s,1H),6.46(d,J＝11.8Hz,1H),6.09(d,J＝71.5Hz,1H),4.30–4.19(m,1H),2.01(s,2H), 0.99(d,J＝6.9Hz,2H),0.87–0.71(m,7H).
MS(ESI+)m/z 470,472,474(M+H)+
实施例375：N-(4-(1-(2-氯-6-甲基异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001491
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(d,J＝12.0Hz,1H),7.41(d,J＝8.0 Hz,1H),7.35(d,J＝10.1Hz,1H),7.31(t,J＝3.6Hz,1H),6.50(dd,J＝10.5,2.8Hz,1H),6.08(d,J＝65.0Hz, 1H),4.32(dd,J＝170.8,19.5Hz,1H),4.05(s,1H),3.59(d,J＝10.5Hz,1H),2.96(s,1H),2.03–1.97(m,1H), 0.94(d,J＝6.8Hz,2H),0.85–0.70(m,7H).
MS(ESI+)m/z 450,452(M+H)+
实施例376：N-(4-(1-(3-氯异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001492
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.54(s,1H),8.77(s,1H),8.64(d,J＝5.1Hz,1H),7.83 (d,J＝16.8Hz,1H),7.53(d,J＝4.7Hz,1H),7.35–7.30(m,1H),6.47(d,J＝13.2Hz,1H),6.09(d,J＝68.6 Hz,1H),4.37(d,J＝21.7Hz,1H),3.91(s,1H),2.01(s,1H),0.98(s,2H),0.88–0.74(m,7H).
MS(ESI+)m/z 436,438(M+H)+
实施例377：N-(4-(1-(3-羟基异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001493
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(d,J＝5.8Hz,1H),8.26(s,1H),8.11(d,J＝4.8Hz, 1H),7.80(s,1H),7.21(t,J＝3.6Hz,1H),6.48(s,1H),6.03(d,J＝21.4Hz,1H),5.81(d,J＝7.7Hz,1H),4.53 (d,J＝19.6Hz,1H),3.93(s,1H),2.96(s,2H),2.01(s,1H),1.00–0.90(m,3H),0.76(d,J＝6.4Hz,4H).
MS(ESI+)m/z 418(M+H)+
实施例378：N-(4-(1-(2,3-二氟苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001494
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.20–8.09(m,1H),7.83(d,J＝14.1Hz, 1H),7.52(d,J＝4.4Hz,1H),7.33(q,J＝5.2,4.0Hz,1H),6.48(d,J＝8.4Hz,1H),6.07(d,J＝75.5Hz,1H), 4.63–4.19(m,1H),4.15(s,1H),4.04(d,J＝7.8Hz,1H),2.93(s,1H),2.01(s,1H),0.95–0.77(m,7H).
MS(ESI+)m/z 437(M+H)+
实施例379：N-(4-(3-甲基-1-(2-甲基异烟酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001501
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),8.55(d,J＝5.0Hz,1H),7.83(d,J＝10.1 Hz,1H),7.31(d,J＝8.6Hz,2H),7.24(s,1H),6.49(d,J＝14.8Hz,1H),6.08(d,J＝70.1Hz,1H),4.33(dd,J ＝173.7,19.7Hz,1H),4.04(s,1H),2.52(s,3H),2.01(s,1H),0.94–0.77(m,7H).
MS(ESI+)m/z 416(M+H)+
实施例380：N-(4-(1-(6-甲氧基烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001502
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),8.32–8.24(m,1H),7.82(d,J＝11.3Hz, 1H),7.32(d,J＝8.5Hz,1H),7.03(d,J＝5.2Hz,1H),6.86(s,1H),6.49(d,J＝13.4Hz,1H),6.08(d,J＝67.4 Hz,1H),4.58–4.08(m,1H),4.04(s,1H),3.89(s,3H),3.59(d,J＝13.6Hz,2H),2.95(s,1H),2.01(s,1H), 0.94–0.77(m,7H).
MS(ESI+)m/z 432(M+H)+
实施例381：N-(4-(1-(2-氨基异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001503
MS(ESI+)m/z 417(M+H)+
实施例382：N-(4-(1-(2-溴异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001504
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),8.51(d,J＝5.0Hz,1H),7.83(d,J＝12.2 Hz,1H),7.76(d,J＝8.0Hz,1H),7.59–7.48(m,1H),7.33(dd,J＝7.4,4.4Hz,1H),6.55–6.41(m,1H),6.08 (d,J＝65.3Hz,1H),4.33(dd,J＝166.6,19.5Hz,1H),4.05(d,J＝3.5Hz,1H),3.59(dd,J＝13.2,4.2Hz,1H), 3.02(d,J＝40.4Hz,1H),2.00(dt,J＝7.9,4.7Hz,1H),0.95–0.77(m,7H).
MS(ESI+)m/z 481(M+H)+
实施例383：N-(4-(1-(2-羟基异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001511
MS(ESI+)m/z 418(M+H)+
实施例384：N-(4-(3-甲基-1-(2-(三氟甲基)异烟酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001512
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1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),8.90(d,J＝4.9Hz,1H),8.03–7.77(m, 3H),7.37–7.26(m,1H),6.50(d,J＝12.5Hz,1H),6.08(d,J＝73.2Hz,1H),4.62–4.13(m,1H),4.07(s,1H), 2.98(s,1H),2.07–1.96(m,1H),0.97–0.77(m,7H).
MS(ESI+)m/z 470(M+H)+
实施例385：N-(4-(1-(2-氟异烟酰基)-2,2-二甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001513
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),8.34(d,J＝5.1Hz,1H),7.90(s,1H),7.43 –7.33(m,2H),7.27(d,J＝2.2Hz,1H),6.54(dd,J＝3.6,1.9Hz,1H),6.45(t,J＝4.6Hz,1H),3.95(d,J＝4.5 Hz,2H),2.72(s,2H),2.03(hept,J＝4.7Hz,1H),1.58(s,6H),0.87–0.71(m,4H).
MS(ESI+)m/z 434(M+H)+
实施例386：N-(4-(1-(2-氯异烟酰基)-2,2-二甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001514
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),8.57–8.44(m,1H),7.90(s,1H),7.59(s, 1H),7.45(s,1H),7.35(s,1H),6.49(d,J＝35.6Hz,2H),3.95(s,2H),2.72(s,2H),2.03(s,1H),1.57(d,J＝ 5.9Hz,6H),0.83(d,J＝20.3Hz,4H).
MS(ESI+)m/z 450,452(M+H)+
实施例387：N-(4-(1-(2-氰基乙酰基)-2,2-二甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001521
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.56(s,1H),7.89(s,1H),7.36(t,J＝3.0Hz,1H),6.54 (dd,J＝3.5,1.8Hz,1H),6.46(t,J＝4.6Hz,1H),4.09(s,2H),4.02(d,J＝4.6Hz,2H),2.64(s,2H),2.05– 1.98(m,1H),1.47(s,6H),0.85–0.71(m,4H).
MS(ESI+)m/z 378(M+H)+
实施例388：(R)-N-(4-(1-(2-氰基乙酰基)-6-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001522
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.53(s,1H),7.85(d,J＝3.4Hz,1H),7.35(t,J＝3.0Hz, 1H),6.60–6.38(m,1H),6.24(dd,J＝24.2,3.9Hz,1H),4.99-4.41(m,1H),4.59–3.69(ddd,J＝13.8,5.2 Hz,1H),4.14(m,1H),3.04–2.75(m,1H),2.46–2.31(m,1H),2.08–1.93(m,1H),1.31(dd,J＝42.5,6.8 Hz,3H),0.80(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例389：(R)-N-(4-(1-(2-氰基乙酰基)-2-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001523
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.54(s,1H),7.85(s,1H),7.35(t,J＝3.0Hz,1H),6.53 (d,J＝3.0Hz,1H),6.28(d,J＝23.9Hz,1H),5.02–4.88(m,1H),4.66(d,J＝20.0Hz,1H),4.28–3.95(m, 4H),3.66(d,J＝20.5Hz,1H),3.01(d,J＝17.1Hz,1H),2.37–2.26(m,1H),2.08–1.93(m,1H),1.31-1.18 (m,3H),0.82(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例390：(S)-N-(4-(1-(2-氰基乙酰基)-6-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001524
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.53(s,1H),7.85(d,J＝3.7Hz,1H),7.35(t,J＝3.0Hz, 1H),6.53(dd,J＝3.4,1.7Hz,1H),6.33–6.13(m,1H),4.99-4.40(m,1H),4.56-3.71(dd,J＝13.7,5.2Hz, 1H),4.34–3.97(m,2H),3.39-3.23(m,1H),2.87(dt,J＝46.3,13.5Hz,1H),2.48-2.31(m,1H),2.1-1.95 (m,1H),1.31(dd,J＝42.6,6.7Hz,3H),0.80(dt,J＝11.5,5.5Hz,4H).
MS(ESI+)m/z 364(M+H)+
实施例391：(S)-N-(4-(1-(2-氰基乙酰基)-2-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001531
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.54(s,1H),7.85(s,1H),7.35(t,J＝3.0Hz,1H),6.53 (d,J＝3.0Hz,1H),6.28(d,J＝23.9Hz,1H),5.02–4.88(m,1H),4.66(d,J＝20.0Hz,1H),4.28–3.95(m, 4H),3.66(d,J＝20.5Hz,1H),3.01(d,J＝17.1Hz,1H),2.37–2.26(m,1H),2.08–1.93(m,1H),1.31-1.18 (m,3H),0.82(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例392：N-(4-(1-(2-氰基异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001532
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.59(d,J＝3.2Hz,1H),8.87(d,J＝5.4Hz,1H),8.20 (d,J＝9.9Hz,1H),7.83(q,J＝4.9Hz,2H),7.33(d,J＝9.6Hz,1H),6.50(d,J＝15.1Hz,1H),6.07(d,J＝75.8Hz,1H),4.59–4.15(m,1H),4.06(s,1H),3.58(s,1H),3.26(s,1H),3.03(d,J＝43.5Hz,1H),2.00(s, 1H),0.95–0.76(m,7H).
MS(ESI+)m/z 427(M+H)+
实施例393：N-(4-(1-(2-氰基乙酰基)-2-(三氟甲基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001533
MS(ESI+)m/z 418(M+H)+
实施例394：N-(4-(9-(2-氰基乙酰基)-9-氮杂双环[3.3.1]壬-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001534
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.55(s,1H),7.89(s,1H),7.35(d,J＝3.2Hz,1H),6.55 (d,J＝11.5Hz,1H),6.29(d,J＝13.7Hz,1H),5.17(s,1H),4.71(d,J＝141.5Hz,1H),4.22–4.11(m,2H), 3.18–3.07(m,1H),2.91–2.64(m,1H),2.38(d,J＝18.0Hz,2H),2.02(s,1H),1.80(d,J＝8.8Hz,2H),1.62 (d,J＝31.9Hz,2H),0.79(d,J＝11.9Hz,4H).
MS(ESI+)m/z 390(M+H)+
实施例395：(S)-N-(4-(1-(2-氟异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001541
MS(ESI+)m/z 420(M+H)+
实施例396：((S)-N-(4-(1-(2,3-二氟异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺)的合成
Figure BDA0002455210850001542
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.55(s,1H),8.21–8.13(m,1H),7.84(d,J＝14.3Hz, 1H),7.58–7.49(m,1H),7.33(dt,J＝5.5,2.8Hz,1H),6.48(d,J＝8.5Hz,1H),6.08(dd,J＝75.5,3.0Hz,1H), 4.63–4.22(m,1H),4.18(d,J＝18.5Hz,1H),4.12–3.92(m,1H),3.61(dd,J＝30.9,12.6Hz,1H),3.01(d,J ＝64.9Hz,1H),2.02(s,1H),0.97–0.91(m,1H),0.84–0.73(m,6H).
MS(ESI+)m/z 438(M+H)+
实施例397：(S)-N-(4-(1-(3-溴苯甲酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001543
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.83(s,1H),7.67(t,J＝8.0Hz,2H),7.45 (d,J＝8.6Hz,2H),7.32(s,1H),6.50(s,1H),6.21–5.96(m,1H),4.59–4.12(m,1H),4.09(s,1H),3.61(d,J ＝12.3Hz,1H),3.02(d,J＝28.7Hz,1H),2.01(d,J＝7.7Hz,1H),0.94–0.75(m,7H).
MS(ESI+)m/z 479,481(M+H)+
实施例398：(S)-N-(4-(3-甲基-1-(4-硝基苯甲酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001544
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.33(d,J＝8.0Hz,2H),7.84(d,J＝9.4Hz, 1H),7.75(d,J＝8.1Hz,2H),7.33(s,1H),6.50(d,J＝17.6Hz,1H),6.09(d,J＝79.5Hz,1H),4.37(dd,J＝ 155.9,19.7Hz,1H),4.08(d,J＝23.1Hz,1H),3.61(d,J＝13.3Hz,1H),3.13–2.93(m,1H),2.02(s,1H), 0.98–0.90(m,1H),0.79(t,J＝8.0Hz,6H).
MS(ESI+)m/z 446(M+H)+
实施例399：(S)-N-(4-(1-(2-氯异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001551
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.61–8.46(m,1H),7.84(d,J＝12.1Hz, 1H),7.65(d,J＝7.5Hz,1H),7.50(d,J＝5.6Hz,1H),7.38–7.26(m,1H),6.53–6.42(m,1H),6.23–5.97(m, 1H),4.34(dd,J＝164.5,20.3Hz,1H),4.05(s,1H),3.63–3.53(m,1H),3.12–2.93(m,1H),2.01(d,J＝7.4 Hz,1H),0.94(d,J＝6.8Hz,1H),0.84–0.74(m,6H).
MS(ESI+)m/z 436,438(M+H)+
实施例400：(S)-N-(4-(1-(6-氯烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001552
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.55(s,1H),7.99(d,J＝7.8Hz,1H),7.84 (s,1H),7.64(d,J＝8.2Hz,1H),7.33(d,J＝5.2Hz,1H),6.50(d,J＝13.3Hz,1H),6.09(d,J＝69.3Hz,1H), 4.57–4.18(m,1H),4.14(s,1H),3.65(d,J＝12.1Hz,1H),3.05(d,J＝23.3Hz,1H),2.01(d,J＝7.4Hz,1H), 0.94(s,1H),0.83–0.74(m,6H).
MS(ESI+)m/z 436,438(M+H)+
实施例401：(S)-N-(4-(1-(2-氯乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001553
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),7.84(d,J＝6.9Hz,1H),7.33(s,1H),6.48 (s,1H),6.10(d,J＝14.2Hz,1H),4.54–4.40(m,2H),4.37–3.97(m,2H),3.77–3.36(m,2H),3.02(d,J＝ 32.0Hz,1H),2.01(d,J＝7.2Hz,1H),0.92–0.84(m,3H),0.83–0.69(m,4H).
MS(ESI+)m/z 373,375(M+H)+
实施例402：(S)-N-(4-(1-(3-氟异烟酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001554
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.74(s,1H),8.64–8.50(m,1H),7.84(d,J ＝14.3Hz,1H),7.58(d,J＝4.9Hz,1H),7.33(dd,J＝7.1,3.4Hz,1H),6.49(d,J＝10.2Hz,1H),6.09(d,J＝71.2Hz,1H),4.70–4.08(m,2H),3.99(s,1H),3.59(t,J＝14.5Hz,1H),3.12–2.90(m,1H),2.02(s,1H), 0.95(d,J＝6.9Hz,1H),0.79(q,J＝6.6Hz,6H).
MS(ESI+)m/z 420(M+H)+
实施例403：(S)-N-(4-(1-(2-氰基-3-(噻吩-2-基)丙烯酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并 [2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001561
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),8.20–8.03(m,1H),7.95(s,1H),7.86(q,J ＝3.1Hz,1H),7.57(d,J＝6.6Hz,1H),7.37–7.27(m,2H),6.50(s,1H),6.15(d,J＝13.1Hz,1H),4.45(d,J＝ 18.5Hz,1H),4.39–3.46(m,3H),3.10(s,1H),2.09–1.97(m,1H),0.96–0.87(m,3H),0.83–0.74(m,4H).
MS(ESI+)m/z 458(M+H)+
实施例404：(S)-N-(4-(1-(2-(氰基甲基)-3-苯基丙烯酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并 [2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001562
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.56(s,1H),7.99–7.91(m,2H),7.87(d,J＝8.8Hz, 1H),7.58(d,J＝4.2Hz,2H),7.50(s,1H),7.34(s,1H),6.51(s,1H),6.13(s,1H),4.47(s,1H),4.37–4.07(m, 1H),3.97(d,J＝22.1Hz,1H),3.80–3.45(m,1H),3.10(s,1H),2.01(d,J＝8.0Hz,1H),0.92(d,J＝7.1Hz, 3H),0.79(t,J＝8.3Hz,4H).
MS(ESI+)m/z 466(M+H)+
实施例405：(S)-N-(4-(3-甲基-1-(1-甲基-2-氧代-1,2-二氢吡啶-3-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001563
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.54(s,1H),7.82(d,J＝12.8Hz,2H),7.51(d,J＝6.6 Hz,1H),7.32(d,J＝6.5Hz,1H),6.48(s,1H),6.29(d,J＝7.0Hz,1H),6.08(d,J＝54.1Hz,1H),4.27(dd,J＝ 137.1,19.1Hz,2H),4.00(s,1H),3.56(s,1H),3.49(s,3H),2.98(s,1H),2.02(s,1H),0.94(d,J＝6.9Hz,1H), 0.85–0.72(m,6H).
MS(ESI+)m/z 432(M+H)+
实施例406：(S)-N-(4-(1-(2-(1-氰基环己基)乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001571
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.84(d,J＝7.1Hz,1H),7.33(s,1H),6.49 (s,1H),6.09(d,J＝20.9Hz,1H),4.43–4.27(m,1H),4.13–3.93(m,1H),3.72–3.51(m,1H),3.38(d,J＝ 12.6Hz,1H),2.99(d,J＝23.7Hz,1H),2.84(d,J＝9.4Hz,1H),2.69(d,J＝8.1Hz,1H),2.09(d,J＝13.0Hz, 2H),2.01(d,J＝7.2Hz,1H),1.67(d,J＝11.6Hz,3H),1.54–1.33(m,4H),1.18(dd,J＝20.2,9.7Hz,1H), 0.87(dd,J＝17.1,6.8Hz,3H),0.83–0.71(m,4H).
MS(ESI+)m/z 446(M+H)+
实施例407：(S)-N-(4-(1-(4-氰基四氢-2H-吡喃-4-羰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并 [2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001572
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.84(d,J＝6.7Hz,1H),7.32(t,J＝3.0Hz, 1H),6.48(dt,J＝4.7,2.3Hz,1H),6.09(dt,J＝28.1,3.4Hz,1H),4.28(dd,J＝52.8,18.4Hz,1H),4.07–3.96 (m,1H),3.94–3.57(m,1H),3.43(ddd,J＝12.4,7.9,4.5Hz,1H),3.00(s,1H),2.90–2.62(m,2H),2.01(td,J ＝7.4,3.7Hz,1H),1.34–1.14(m,3H),1.01–0.89(m,2H),0.87(dd,J＝6.9,5.1Hz,3H),0.84–0.73(m, 4H).
MS(ESI+)m/z 434(M+H)+
实施例408：(S)-N-(4-(1-(2-氰基-3-甲基丁-2-烯酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001573
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.56(s,1H),7.84(s,1H),7.33(s,1H),6.48(s,1H), 6.11(d,J＝21.5Hz,1H),4.58–4.23(m,1H),4.07(t,J＝22.3Hz,2H),3.77–3.55(m,1H),3.54–3.44(m, 1H),3.03(s,1H),2.14(s,3H),2.02(s,1H),1.93(d,J＝7.1Hz,3H),0.88(d,J＝6.7Hz,3H),0.79(dd,J＝ 13.1,5.2Hz,4H).
MS(ESI+)m/z 404(M+H)+
实施例409：N-(4-(1-(2-氰基乙酰基)-2,6-二乙基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001581
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.55(s,1H),7.85(s,1H),7.44–7.34(m,1H),6.46(dd, J＝3.8,1.8Hz,1H),6.30(t,J＝3.0Hz,1H),4.70–4.55(m,1H),4.29–4.01(m,2H),3.90(d,J＝6.7Hz,1H), 2.01(d,J＝5.2Hz,1H),1.65(dddd,J＝51.1,21.4,14.7,7.4Hz,4H),1.23(s,2H),1.08–0.97(m,3H),0.88 (dt,J＝13.5,7.3Hz,3H),0.83–0.71(m,4H).
MS(ESI+)m/z 406(M+H)+
实施例410：N-(4-(1-(2-氰基乙酰基)-2-异丙基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001582
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.54(s,1H),7.87(s,1H),7.35(s,1H),6.58–6.40(m, 1H),6.37–6.19(m,1H),4.29–4.08(m,2H),4.08–3.89(m,1H),3.84–3.54(m,1H),3.01–2.81(m,1H), 2.37(s,1H),2.01(s,2H),1.23(s,2H),1.06(d,J＝6.6Hz,2H),0.92(t,J＝5.7Hz,2H),0.87(dd,J＝13.0,6.5 Hz,2H),0.83–0.75(m,4H).
MS(ESI+)m/z 392(M+H)+
实施例411：N-(4-(1-(2-氰基乙酰基)-6-丙基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001583
MS(ESI+)m/z 392(M+H)+
实施例412：N-(4-(6-(叔丁基)-1-(2-氰基乙酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001584
MS(ESI+)m/z 406(M+H)+
实施例413：N-(4-(1-(2-氰基乙酰基)-2-乙基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001591
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.54(s,1H),7.85(s,1H),7.35(t,J＝2.9Hz,1H),6.52 (s,1H),6.25(d,J＝28.2Hz,1H),4.81–4.65(m,1H),4.20–4.08(m,2H),4.00–3.90(m,1H),3.01(d,J＝ 17.1Hz,1H),2.08–1.91(m,1H),1.74–1.46(m,2H),1.23(s,2H),0.86(dd,J＝12.2,7.3Hz,3H),0.86-0.69 (m,4H).
MS(ESI+)m/z 378(M+H)+
实施例414：N-(4-(5-(2-氰基乙酰基)-5-氮杂螺[3.5]壬-7-烯-8-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001592
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.54(s,1H),7.86(s,1H),7.37–7.15(m,1H),6.55(s, 1H),6.28(s,1H),4.03(s,4H),2.36(s,2H),2.12–1.97(m,3H),1.79(dt,J＝28.8,10.1Hz,2H),0.83–0.74 (m,4H).
MS(ESI+)m/z 390(M+H)+
实施例415：(S)-N-(4-(1-(2-(1-氰基环丙基)乙酰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001593
MS(ESI+)m/z 404(M+H)+
实施例416：(R)-N-(4-(1-(2-氰基乙酰基)-6-乙基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001594
MS(ESI+)m/z 378(M+H)+
实施例417：(R)-N-(4-(1-(2-氰基乙酰基)-2-乙基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001595
MS(ESI+)m/z 378(M+H)+
实施例418：N-(4-(1-(3-氰基丙酰基)-1,4,5,6-四氢吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001601
MS(ESI+)m/z 364(M+H)+
实施例419：N-(4-(1-(2-氰基乙酰基)-1,4,5,6-四氢吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001602
MS(ESI+)m/z 350(M+H)+
实施例420：N-(4-(1-(2-氰基乙酰基)-1,2,5,6-四氢吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001603
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.55(d,J＝5.3Hz,1H),7.84(d,J＝7.8Hz,1H),7.36 (q,J＝2.7Hz,1H),6.60–6.50(m,1H),6.48–6.33(m,1H),4.35(dd,J＝40.1,2.7Hz,2H),4.15(d,J＝5.6 Hz,2H),3.61(dt,J＝43.3,5.8Hz,2H),2.46–2.28(m,2H),2.02(d,J＝6.0Hz,1H),0.90-0.71(m,4H).
MS(ESI+)m/z 350(M+H)+
实施例421：N-(4-(1-(3-氰基丙酰基)-1,2,5,6-四氢吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001604
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.55(s,1H),7.86(d,J＝4.1Hz,1H),7.35(t,J＝3.0Hz, 1H),6.58–6.51(m,1H),6.48–6.39(m,1H),4.46–4.29(m,2H),3.65(dt,J＝24.4,5.8Hz,2H),2.82(dt,J＝14.1,6.8Hz,2H),2.64(dt,J＝14.0,6.7Hz,2H),2.38(d,J＝39.9Hz,2H),2.01(d,J＝7.9Hz,1H),0.85– 0.76(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例422：N-(4-(1-(2-氰基乙酰基)-2,5,6,7-四氢-1H-氮杂环庚三烯-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001611
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1H NMR(400MHz,DMSO-d6)δ11.40(d,J＝7.3Hz,1H),10.57–10.47(m,1H),7.79(d,J＝8.5Hz, 1H),7.32(q,J＝3.0Hz,1H),6.40(ddd,J＝1.9,3.6,8.7Hz,1H),6.24(dt,J＝5.4,32.4Hz,1H),4.15(dd,J＝ 5.4,11.3Hz,2H),4.08(d,J＝20.8Hz,2H),3.67(dt,J＝5.9,41.9Hz,2H),2.71(dt,J＝5.7,16.7Hz,2H),2.01 (t,J＝5.9Hz,1H),1.96(s,1H),1.91(d,J＝12.1Hz,1H),0.84-0.75(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例423：N-(4-(1-(2-氟异烟酰基)-2,5,6,7-四氢-1H-氮杂环庚三烯-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001612
MS(ESI+)m/z 420(M+H)+
实施例424：N-(4-(1-(2,3-二氟异烟酰基)-2,5,6,7-四氢-1H-氮杂环庚三烯-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001613
MS(ESI+)m/z 438(M+H)+
实施例425：N-(4-(1-(2-氰基乙酰基)-1,2,3,6-四氢吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001614
1H NMR(400MHz,DMSO-d6)δ11.95(s,1H),10.44(d,J＝5.0Hz,1H),7.42(s,1H),6.89(d,J＝11.4 Hz,1H),6.70(s,1H),4.24(d,J＝16.4Hz,2H),4.14(d,J＝17.7Hz,2H),3.65(dt,J＝5.8,50.5Hz,2H),2.85 –2.62(m,2H),2.17(s,1H),0.81–0.77(m,4H).
MS(ESI+)m/z 351(M+H)+
实施例426：N-(4-(1-(2-氰基乙酰基)-2,5-二氢-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001621
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),10.61(s,1H),7.85(d,J＝3.2Hz,1H),7.43(s,1H),6.74 (d,J＝20.3Hz,2H),4.75(s,1H),4.55(d,J＝16.5Hz,2H),4.38(s,1H),4.15(d,J＝3.5Hz,1H),4.04(d,J＝ 3.2Hz,1H),2.03(s,1H),0.81(s,4H).
MS(ESI+)m/z 336(M+H)+
实施例427：N-(4-(1-(3-氰基丙酰基)-2,5-二氢-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001622
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),10.60(s,1H),7.86(d,J＝5.1Hz,1H),7.43(d,J＝2.3Hz, 1H),6.79–6.69(m,2H),4.77(s,1H),4.56(s,2H),4.40–4.31(m,1H),2.96(s,1H),2.83(t,J＝6.9Hz,1H), 2.77–2.72(m,1H),2.68(q,J＝6.6Hz,2H),2.02(dd,J＝4.8,9.6Hz,1H),0.81(dt,J＝4.0,18.4Hz,4H).
MS(ESI+)m/z 350(M+H)+
实施例428：N-(4-(1-(3,3,3-三氟丙酰基)-2,5-二氢-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001623
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),10.60(d,J＝2.7Hz,1H),7.86(d,J＝2.8Hz,1H),7.43 (d,J＝3.1Hz,1H),6.81–6.63(m,2H),4.80(d,J＝4.2Hz,1H),4.58(s,2H),4.38(d,J＝4.0Hz,1H),3.72 (dq,J＝11.0,41.9Hz,2H),2.02(q,J＝3.0,4.8Hz,1H),0.87–0.74(m,4H).
MS(ESI+)m/z 379(M+H)+
实施例429：N-(4-(1-(4,4,4-三氟丁酰基)-2,5-二氢-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001624
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),10.62(s,1H),7.87(s,1H),7.43(s,1H),6.74(t,J＝11.6 Hz,2H),4.80(s,1H),4.57(d,J＝10.9Hz,2H),4.37(s,1H),2.74–2.61(m,2H),2.04–1.98(m,1H),1.15(s, 2H),0.82(dd,J＝6.5,21.7Hz,4H).
MS(ESI+)m/z 393(M+H)+
实施例430：N-(4-(1-(1-氰基环丙基-1-羰基)-2,5-二氢-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001631
MS(ESI+)m/z 362(M+H)+
实施例431：N-(4-(4-(3-乙基脲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001632
将N-(4-(4-氨基苯基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺(100mg)与吡啶搅拌。将4当量的异氰酸乙酯添加到混合物中，并在室温下搅拌12小时。一旦反应完成后，向所述混合物中加入d-HCl，然后使用二氯甲烷进行萃取，并且然后分离有机层。将混合物浓缩后，将所得浓缩物溶于MeOH/THF(1:1)溶液中，然后向其中加入2N氢氧化钠水溶液，并在30-40℃下搅拌4小时。一旦反应完成后，将所述混合物冷却至室温，并在搅拌的同时向其中加入饱和氯化铵水溶液。滤出产生的固体，并由此最终得到产物，即N-(4-(4-(3-乙基脲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),8.68(s,1H),7.98(s,1H),7.58(q,J＝8.2, 8.7Hz,4H),7.37(s,1H),6.55(s,1H),6.22(s,1H),5.75(s,1H),3.14(d,J＝6.4Hz,2H),2.04(s,1H),1.07(t, J＝6.7Hz,3H),0.88–0.75(m,4H).
MS(ESI+)m/z 364(M+H)+
实施例432至453
在下文的实施例432至453中，通过与实施例431所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例432：N-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)吗啉-4-甲酰胺的合成
Figure BDA0002455210850001633
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.57(s,1H),8.73(s,1H),8.00(s,1H),7.73–7.56(m, 4H),7.37(d,J＝3.5Hz,1H),6.56(d,J＝3.2Hz,1H),3.63(s,4H),3.46(s,4H),2.04(s,1H),0.87–0.78(m, 4H).
MS(ESI+)m/z 406(M+H)+
实施例433：N-(4-(4-(3-丁基脲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001634
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.56(s,1H),8.63(s,1H),7.98(s,1H),7.70–7.51(m, 5H),7.46–7.36(m,1H),6.55(s,1H),6.21(d,J＝5.7Hz,1H),3.19–3.07(m,2H),2.05(s,1H),1.37(ddd,J ＝7.0,14.2,40.2Hz,5H),0.90(t,J＝7.2Hz,4H),0.88–0.73(m,4H).
MS(ESI+)m/z 392(M+H)+
实施例434：N-(4-(4-(3-(4-氟苯基)脲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001641
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.58(s,1H),9.07–8.95(m,1H),8.87(s,1H),8.01(s, 1H),7.65(q,J＝8.6Hz,4H),7.49(dd,J＝5.3,8.8Hz,2H),7.39(s,1H),7.13(t,J＝8.6Hz,2H),6.61–6.53 (m,1H),3.60(s,1H),2.05(s,1H),1.76(s,1H),1.24(s,2H),0.81(d,J＝16.8Hz,4H).
MS(ESI+)m/z 380(M+H)+
实施例435：N-(4-(4-(3-(2,2,2-三氟乙基)脲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001642
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.59(s,1H),9.07(s,1H),7.99(s,1H),7.61(q,J＝8.5 Hz,4H),7.38(d,J＝3.1Hz,1H),6.92(s,1H),6.59–6.47(m,1H),3.95(dd,J＝6.5,14.9Hz,2H),2.03(s, 1H),0.81(s,4H).
MS(ESI+)m/z 418(M+H)+
实施例436：N-(4-(2-甲基-4-(3-(2,2,2-三氟乙基)脲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001643
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.61(s,1H),8.92(s,1H),7.76(s,1H),7.41(s,1H), 7.33(dd,J＝5.7,8.6Hz,2H),7.17(d,J＝8.3Hz,1H),6.89(s,1H),6.12–5.99(m,1H),3.97–3.89(m,2H), 2.13(s,4H),2.03(s,1H),0.79(s,4H).
MS(ESI+)m/z 432(M+H)+
实施例437：N-(4-(4-(3-环丙基脲基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001644
MS(ESI+)m/z 377(M+H)+
实施例438：N-(4-(4-(3-乙基脲基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001651
MS(ESI+)m/z 365(M+H)+
实施例439：N-(4-(4-(3-丁基脲基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001652
MS(ESI+)m/z 393(M+H)+
实施例440：N-(4-(4-(3-(3,4-二氟苯基)脲基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001653
MS(ESI+)m/z 449(M+H)+
实施例441：N-(4-(4-(3-(4-氟苯基)脲基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001654
MS(ESI+)m/z 431(M+H)+
实施例442：N-(4-(4-(3-(2,2,2-三氟乙基)脲基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001655
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.50(s,1H),7.86(d,J＝3.9Hz,1H),7.37–7.27(m, 1H),6.51(dd,J＝1.9,3.6Hz,1H),6.44(t,J＝6.5Hz,1H),6.33–6.19(m,2H),3.83(dq,J＝6.7,9.8,16.0Hz, 3H),2.15–1.88(m,3H),1.68(d,J＝9.0Hz,1H),0.86–0.75(m,4H).
MS(ESI+)m/z 422(M+H)+
实施例443：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-N-(2,2,2-三氟乙基)-3,6-二氢吡啶 -1(2H)-甲酰胺的合成
Figure BDA0002455210850001661
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.55(s,1H),7.86(s,1H),7.42–7.32(m,1H),7.22(t,J ＝5.8Hz,1H),6.54(dd,J＝1.9,3.7Hz,1H),6.33(s,1H),4.10(s,2H),3.93–3.81(m,3H),3.61(t,J＝5.3Hz, 2H),2.02(s,1H),0.82–0.75(m,4H).
MS(ESI+)m/z 408(M+H)+
实施例444：N-丁基-4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酰胺的合成
Figure BDA0002455210850001662
MS(ESI+)m/z 382(M+H)+
实施例445：N-(4-(1-(1,1-二氧化硫代吗啉-4-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001663
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.53(s,1H),7.87(s,1H),7.34(s,1H),6.56(s,1H), 6.34(s,1H),4.03(d,J＝8.9Hz,2H),3.63(d,J＝18.8Hz,6H),3.45(s,3H),3.22–3.14(m,4H),2.00(s,1H), 1.20(d,J＝25.7Hz,2H),1.04(d,J＝6.1Hz,2H),0.80(s,4H).
MS(ESI+)m/z 444(M+H)+
实施例446：N-(4-(1-(吗啉-4-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001664
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.53(s,1H),7.86(s,1H),7.34(s,1H),6.56(s,1H), 6.34(s,1H),3.96(s,2H),3.60(s,6H),3.17(d,J＝5.2Hz,4H),2.02(s,1H),1.04(d,J＝5.6Hz,2H),0.80(s, 4H).
MS(ESI+)m/z 396(M+H)+
实施例447：N-(氰基甲基)-4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,6-二氢吡啶-1(2H)- 甲酰胺的合成
Figure BDA0002455210850001671
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.53(s,1H),7.85(s,1H),7.34(s,1H),6.54(s,1H), 6.31(s,1H),4.12(s,2H),4.03(d,J＝6.8Hz,1H),3.65(s,3H),3.63(s,2H),2.00(d,J＝12.2Hz,2H),0.78(d, J＝13.1Hz,4H).
MS(ESI+)m/z 365(M+H)+
实施例448：3-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-N-(2,2,2-三氟乙基)-8-氮杂双环 [3.2.1]辛-2-烯-8-甲酰胺的合成
Figure BDA0002455210850001672
MS(ESI+)m/z 434(M+H)+
实施例449：N-丁基-3-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8- 甲酰胺的合成
Figure BDA0002455210850001673
MS(ESI+)m/z 408(M+H)+
实施例450：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-N-(1-环丙基-2,2,2-三氟乙基)-3,6- 二氢吡啶-1(2H)-甲酰胺的合成
Figure BDA0002455210850001674
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),10.05(dd,J＝3.0,8.9Hz,1H),7.84(d,J＝4.0Hz,1H), 7.81(d,J＝4.8Hz,1H),6.89(d,J＝4.1Hz,1H),6.36(d,J＝4.6Hz,1H),4.43(d,J＝3.2Hz,1H),4.32(s,1H), 4.08(p,J＝8.7Hz,1H),3.93(t,J＝5.5Hz,1H),3.80(t,J＝5.7Hz,1H),2.68(s,2H),1.94(q,J＝6.2Hz,1H), 1.55(dd,J＝6.6,12.0Hz,1H),1.16–1.10(m,1H),0.92–0.86(m,4H),0.72(dd,J＝5.6,22.3Hz,2H),0.64 (d,J＝25.9Hz,1H),0.46–0.35(m,1H).
MS(ESI+)m/z 448(M+H)+
实施例451：N-(4-(1-(1H-咪唑-1-羰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001681
1H NMR(400MHz,甲醇-d4)δ11.46(s,1H),10.57(s,1H),8.13(s,1H),7.90(s,1H),7.58(d,J＝1.4Hz, 1H),7.36(t,J＝3.0Hz,1H),7.06(s,1H),6.60(d,J＝2.8Hz,1H),6.34(s,1H),4.29(d,J＝3.6Hz,2H),3.71 (d,J＝6.3Hz,2H),2.72(s,2H),1.99(s,1H),0.85–0.69(m,4H).
MS(ESI+)m/z 377(M+H)+
实施例452：N-(4-(1-(1H-咪唑-1-羰基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001682
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.57(s,1H),8.13(s,1H),7.85(s,1H),7.58(d,J＝1.8 Hz,1H),7.38–7.30(m,1H),7.07(s,1H),6.59–6.50(m,1H),6.10(s,1H),4.37–4.22(m,2H),3.70(s,2H), 3.14(s,1H),2.00(d,J＝15.8Hz,1H),0.90(d,J＝7.0Hz,3H),0.85–0.72(m,4H).
MS(ESI+)m/z 391(M+H)+
实施例453：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-N-(2,2,2-三氟乙基)-3,6-二氢吡啶-1(2H)-甲酰胺的合成
Figure BDA0002455210850001683
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.56(s,1H),7.83(s,1H),7.39–7.30(m,1H),7.25– 7.16(m,1H),6.46(dd,J＝2.0,3.6Hz,1H),6.10(d,J＝3.5Hz,1H),4.23(d,J＝18.2Hz,1H),3.99–3.84(m, 3H),3.62–3.49(m,2H),2.94(s,1H),2.03(d,J＝8.3Hz,1H),0.86(d,J＝6.9Hz,3H),0.82–0.73(m,4H).
MS(ESI+)m/z 422(M+H)+
实施例454：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Figure BDA0002455210850001691
[步骤1]
将4.0g(8.3mmol)由以上反应式3制备的N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺溶于DMF/H2O＝2:1溶液中，然后将3.3g(10.0mmol) 4-(((三氟甲基)磺酰基)氧基)-3,6-脱氢吡啶-1(2H)-甲酸叔丁酯、0.9g(0.8mmol)Pd(PPh3)4和0.57mL2M K2CO3水溶液添加到其中，并在100-110℃下搅拌2小时。一旦反应完成后，将所述混合物在室温下冷却，然后向其中加入水，并且然后使用乙酸乙酯进行萃取。之后，将从中萃取的溶液用无水硫酸镁干燥并减压浓缩，由此得到残余物。残余物经NH-硅胶柱色谱(正己烷/乙酸乙酯＝5:1)分离，并最终由此得到4-(6-(环丙基甲酰氨基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-3,6-脱氢吡啶-1-(2H)-甲酸叔丁酯。
MS(ESI+)m/z 537(M+H)+
[步骤2]
将合成的材料溶于MeOH/THF(1:1)溶液中，然后向其中加入2N氢氧化钠水溶液，并在30-40℃下搅拌4小时。一旦反应完成后，将所述混合物冷却至室温，并在搅拌的同时向其中加入饱和氯化铵水溶液。滤出产生的固体，并最终由此得到产物，即4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,6- 脱氢吡啶-1(2H)-甲酸叔丁酯。
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.53(s,1H),7.86(s,1H),7.43–7.26(m,1H),6.61– 6.45(m,1H),6.31(s,1H),4.07(s,2H),3.67–3.46(m,2H),2.59–2.52(m,2H),2.02(td,J＝3.7,7.8Hz,1H), 1.44(s,9H),0.80(dt,J＝5.9,12.2Hz,4H).
MS(ESI+)m/z 383(M+H)+
实施例455至461
在下文的实施例455至461中，通过与实施例454所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例455：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸氰基甲酯的合成
Figure BDA0002455210850001692
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.56(s,1H),7.87(s,1H),7.41–7.30(m,1H),6.56(dd, J＝1.9,3.6Hz,1H),6.32(d,J＝14.8Hz,1H),4.98(s,2H),4.16(s,2H),3.67(q,J＝5.6,7.9Hz,2H),2.58(s, 3H),2.02(s,1H),0.85–0.73(m,4H).
MS(ESI+)m/z 366(M+H)+
实施例456：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Figure BDA0002455210850001693
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.56(s,1H),7.83(s,1H),7.32(t,J＝3.1Hz,1H),6.48 (d,J＝3.0Hz,1H),6.08(s,1H),4.25(s,1H),3.88(s,1H),3.68–3.37(m,2H),2.92(s,1H),2.01(s,1H),0.86 (d,J＝6.7Hz,3H),0.81–0.71(m,4H).
MS(ESI+)m/z 397(M+H)+
实施例457：4-(6-(环丙基甲酰氨基)-5-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Figure BDA0002455210850001701
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.03(s,1H),7.34(t,J＝2.9Hz,1H),6.23(dd,J＝3.5, 1.9Hz,1H),5.66(s,1H),4.03(s,2H),3.61(d,J＝5.7Hz,2H),2.30(s,2H),2.08(s,3H),1.45(s,9H),0.76(d, J＝6.2Hz,4H).
MS(ESI+)m/z 397(M+H)+
实施例458：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3-乙基-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Figure BDA0002455210850001702
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.55(s,1H),7.83(s,1H),7.42–7.25(m,1H),6.58– 6.48(m,1H),6.11(s,1H),4.33(dd,J＝19.3,44.4Hz,1H),4.10–3.67(m,2H),3.21(dd,J＝3.7,13.1Hz, 1H),2.67(d,J＝1.7Hz,1H),2.02(s,1H),1.44(s,9H),1.22(d,J＝15.5Hz,3H),0.87–0.73(m,7H).
MS(ESI+)m/z 411(M+H)+
实施例459：5-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,4-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Figure BDA0002455210850001703
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.46(s,1H),7.85(s,1H),7.68(s,1H),7.33(s,1H), 6.48(dd,J＝3.5,1.9Hz,1H),3.59(s,2H),2.46(s,2H),2.01(q,J＝6.3Hz,1H),1.93(t,J＝6.0Hz,2H),0.85 –0.71(m,4H).
MS(ESI+)m/z 383(M+H)+
实施例460：5-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的合成
Figure BDA0002455210850001704
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.55(s,1H),7.84(s,1H),7.35(t,J＝3.0Hz,1H),6.52 (s,1H),6.39(s,1H),4.26(s,2H),3.53(t,J＝5.8Hz,2H),2.34(td,J＝6.9,6.3,2.8Hz,2H),2.02(tt,J＝7.5, 4.5Hz,1H),1.43(s,9H),0.80(ddt,J＝10.9,5.4,3.0Hz,4H).
MS(ESI+)m/z 383(M+H)+
实施例461：3-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯的合成
Figure BDA0002455210850001711
MS(ESI+)m/z 369(M+H)+
实施例462：N-(4-(4-(3-乙基硫脲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001712
将N-(4-(4-氨基苯基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺(100mg)与吡啶搅拌。将4当量的异氰酸乙酯添加到混合物中，并在50-60℃下搅拌16小时。一旦反应完成后，将所述混合物浓缩并溶于MeOH/THF(1:1)溶液中。之后，向其中加入2N氢氧化钠水溶液，并在30-40℃下搅拌4小时。一旦反应完成后，将所述混合物冷却至室温，并且然后在搅拌的同时向其中加入饱和氯化铵水溶液。滤出产生的固体，并最终由此得到产物，即N-(4-(4-(3-乙基硫脲基)苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺。
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.60(s,1H),9.71(s,1H),7.99(d,J＝23.1Hz,2H), 7.63(dd,J＝8.6,31.6Hz,4H),7.40(s,1H),6.55(d,J＝3.5Hz,1H),2.05(s,1H),1.25–1.13(m,3H),0.82(d, J＝7.6Hz,4H).
MS(ESI+)m/z 380(M+H)+
实施例463至469
在下文的实施例463至469中，通过与实施例462所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例463：N-(4-(4-(3-丁基硫脲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001713
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.69(s,1H),9.78(s,1H),7.99(s,2H),7.65(q,J＝8.5 Hz,3H),7.41(d,J＝3.1Hz,1H),6.57(d,J＝3.3Hz,1H),3.49(s,2H),2.06(d,J＝13.5Hz,1H),1.60–1.49 (m,2H),1.34(q,J＝7.4Hz,2H),1.24(s,1H),0.92(t,J＝7.2Hz,3H),0.83(d,J＝6.8Hz,4H).
MS(ESI+)m/z 408(M+H)+
实施例464：N-(4-(4-(3-环己基硫脲基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001721
MS(ESI+)m/z 435(M+H)+
实施例465：N-(4-(4-(3-丁基硫脲基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001722
MS(ESI+)m/z 409(M+H)+
实施例466：N-(4-(4-(3-乙基硫脲基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001723
MS(ESI+)m/z 381(M+H)+
实施例467：N-(4-(4-(3-丙基硫脲基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001724
MS(ESI+)m/z 395(M+H)+
实施例468：N-(4-(1-(乙基硫代氨基甲酰基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001725
MS(ESI+)m/z 370(M+H)+
实施例469：N-(4-(8-(乙基硫代氨基甲酰基)-8-氮杂双环[3.2.1]辛-2-烯-3-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001731
MS(ESI+)m/z 396(M+H)+
实施例470：N-(4-(4-((环丙基甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001732
将N-(4-(4-氨基苯基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺(100mg)溶于二氯乙烷中，并且然后将3当量的环丙甲醛和3当量的乙酸添加到其中，并在室温下搅拌30分钟。向反应混合物中加入3当量的三乙酰氧基硼氢化钠，并在40℃下搅拌16小时。一旦反应完成后，将所述混合物浓缩并溶于MeOH/THF(1:1)溶液中。之后，向其中加入2N氢氧化钠水溶液，并在30-40℃下搅拌4 小时。一旦反应完成后，将所述混合物在室温下冷却，并使用二氯甲烷进行萃取。将从中萃取的溶液用无水硫酸镁干燥并减压浓缩，由此得到残余物。之后，对残余物应用制备TLC(DCM:MeOH＝30:1) 方法，并由此最终得到目标化合物，即N-(4-(4-((环丙基甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
MS(ESI+)m/z 347(M+H)+
实施例471至489
在下文的实施例471至489中，通过与实施例470所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例471：N-(4-(4-((环己基甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001733
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.50(s,1H),7.92(s,1H),7.48(d,J＝8.6Hz,2H),7.32 (dd,J＝2.4,3.5Hz,1H),6.69(d,J＝8.5Hz,2H),6.54(dd,J＝1.9,3.5Hz,1H),6.02(t,J＝5.7Hz,1H),3.64–3.55(m,2H),2.91(t,J＝6.2Hz,2H),2.03(s,1H),1.82–1.52(m,7H),1.25–1.12(m,3H),0.95(q,J＝12.0, 12.5Hz,2H),0.86–0.72(m,4H).
MS(ESI+)m/z 389(M+H)+
实施例472：N-(4-(4-(苄基氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001734
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.50(s,1H),7.91(s,1H),7.46(d,J＝8.6Hz,2H),7.42 –7.28(m,5H),7.24(t,J＝7.3Hz,1H),6.73(d,J＝8.6Hz,2H),6.63(t,J＝6.0Hz,1H),6.52(dd,J＝1.8,3.5 Hz,1H),4.34(d,J＝6.0Hz,2H),2.02(s,1H),0.83–0.72(m,4H).
MS(ESI+)m/z 383(M+H)+
实施例473：N-(4-(4-((4-氟苄基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001741
MS(ESI+)m/z 402(M+H)+
实施例474：N-(4-(4-((3-氟苄基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001742
MS(ESI+)m/z 402(M+H)+
实施例475：N-(4-(4-((4-氯苄基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001743
MS(ESI+)m/z 418,420(M+H)+
实施例476：N-(4-(4-((3-羟基丙基)氨基)苯基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001744
MS(ESI+)m/z 352(M+H)+
实施例477：N-(4-(1-(2-氰基乙基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001745
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.53(s,1H),8.50(s,1H),8.06(d,J＝9.1Hz,2H),7.48 –7.35(m,1H),7.00(s,1H),6.72(d,J＝4.1Hz,1H),4.57–4.45(m,2H),3.22–3.11(m,2H),2.05(s,1H), 0.82(d,J＝12.2Hz,4H).
MS(ESI+)m/z 321(M+H)+
实施例478：N-(4-(1-(环丙基甲基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001751
1H NMR(400MHz,DMSO-d6)δ11.42(d,J＝12.3Hz,1H),10.51(s,1H),8.39(s,1H),8.01(d,J＝32.6 Hz,2H),7.48–7.31(m,1H),6.72(s,1H),4.06(d,J＝7.7Hz,2H),2.04(s,1H),1.33(s,1H),0.89–0.74(m, 4H),0.62–0.38(m,4H).
MS(ESI+)m/z 322(M+H)+
实施例479：N-(4-(1-苄基-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001752
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.50(s,1H),8.54(s,1H),8.09–7.91(m,3H),7.35(d,J ＝13.5Hz,8H),7.23(s,1H),6.71(s,1H),5.42(d,J＝4.1Hz,2H),2.03(s,1H),0.82(s,4H).
MS(ESI+)m/z 358(M+H)+
实施例480：N-(4-(1-(2-氰基乙基)-3,5-二甲基-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001753
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.55(s,1H),7.72(s,1H),7.32(s,1H),6.14(s,1H), 4.33(d,J＝5.9Hz,2H),3.06(d,J＝5.9Hz,2H),2.27–2.17(m,3H),2.10(s,3H),2.02(s,1H),0.78(d,J＝ 12.9Hz,4H).
MS(ESI+)m/z 349(M+H)+
实施例481：N-(4-(1-苄基-1H-1,2,3-***-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001754
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.58(s,1H),8.93(s,1H),8.40(s,1H),7.51–7.30(m, 6H),6.88(dd,J＝3.5,1.9Hz,1H),5.69(s,2H)2.10–1.95(m,1H),0.96–0.72(m,4H).
MS(ESI+)m/z 421(M+H)+
实施例482：N-(4-(1-((6-氰基吡啶-3-基)甲基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850001755
1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),10.42(s,1H),9.16(s,1H),8.78(s,1H),8.71(d,J＝2.1 Hz,1H),8.29(d,J＝3.3Hz,1H),7.88–7.76(m,2H),7.43(d,J＝3.8Hz,1H),6.87(d,J＝3.8Hz,1H),5.60 (d,J＝6.2Hz,2H),2.20(s,1H),0.80(ddt,J＝3.0,4.9,10.7Hz,4H).
MS(ESI+)m/z 385(M+H)+
实施例483：N-(4-(1-(2-氰基乙基)-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001761
1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),10.44(s,1H),8.01(s,1H),7.56(d,J＝2.1Hz,1H),7.31 (d,J＝2.5Hz,1H),6.98(t,J＝2.5Hz,1H),6.71(d,J＝3.2Hz,1H),6.54(d,J＝2.5Hz,1H),4.27(t,J＝6.5 Hz,2H),3.09(t,J＝6.4Hz,2H),2.03(s,1H),0.83–0.76(m,4H).
MS(ESI+)m/z 320(M+H)+
实施例484：N-(4-(1-(2-吗啉代乙基)-2,5-二氢-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001762
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),10.61(s,1H),7.83(d,J＝8.0Hz,1H),7.42(d,J＝3.1Hz, 1H),6.81–6.64(m,2H),4.55(d,J＝10.5Hz,2H),4.37(s,2H),4.19(t,J＝6.7Hz,2H),3.57(d,J＝4.7Hz, 4H),2.59(d,J＝6.2Hz,2H),2.45(d,J＝4.6Hz,2H),2.03(s,1H),0.84–0.74(m,4H).
MS(ESI+)m/z 382(M+H)+
实施例485：N-(4-(1-(2-氰基乙基)-2,5-二氢-1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001763
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.55(s,1H),7.80(s,1H),7.38(t,J＝3.0Hz,1H),6.67 –6.57(m,2H),3.93(q,J＝3.7Hz,2H),3.73(td,J＝2.1,4.5Hz,2H),2.94(t,J＝6.7Hz,2H),2.73(t,J＝6.7 Hz,2H),2.02(tt,J＝4.5,7.7Hz,1H),0.80(ddd,J＝2.8,5.3,11.3Hz,4H).
MS(ESI+)m/z 322(M+H)+
实施例486：N-(4-(1-(2-氰基乙基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001764
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.50(s,1H),7.86(s,1H),7.33(d,J＝2.7Hz,1H),6.54 (d,J＝3.5Hz,1H),6.32(s,1H),3.23(t,J＝3.1Hz,2H),2.73(dd,J＝4.5,7.5Hz,5H),2.02(s,1H),0.82– 0.75(m,4H).
MS(ESI+)m/z 336(M+H)+
实施例487：N-(4-(1-((3-甲基氧杂环丁烷-3-基)甲基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001771
MS(ESI+)m/z 367(M+H)+
实施例488：N-(4-(1-(异噻唑-5-基甲基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001772
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.53(s,1H),8.50(d,J＝1.6Hz,1H),7.86(s,1H),7.33 (d,J＝2.1Hz,2H),6.55(d,J＝2.7Hz,1H),6.33(s,1H),3.29(d,J＝3.4Hz,2H),2.77(t,J＝5.6Hz,2H), 2.56(s,2H),2.01(d,J＝4.1Hz,1H),0.88–0.72(m,4H).
MS(ESI+)m/z 380(M+H)+
实施例489：N-(4-(1-((2,2-二氟环丙基)甲基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001773
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.52(s,1H),7.85(s,1H),7.35–7.29(m,1H),6.54(dd, J＝3.5,1.8Hz,1H),6.33(d,J＝3.4Hz,1H),3.25–3.19(m,2H),2.72(dp,J＝16.1,5.4Hz,3H),2.50(m,3H), 2.01(s,1H),1.90(tt,J＝13.8,6.9Hz,1H),1.62(qt,J＝12.1,5.9Hz,1H),1.19(dd,J＝7.9,3.8Hz,1H),0.87 –0.72(m,4H)
MS(ESI+)m/z 373(M+H)+
实施例490：N-(4-(1-(3-氰基环丁基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001774
将1.0g(3.37mmol)合成的N-(4-(4-氨基环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺和 3-氧代环丁烷-1-甲腈溶于THF溶液中，然后将NaBH(OAc)3和DIPEA添加到其中，并在室温下搅拌一天。一旦反应完成后，向其中加入水，并使用二氯甲烷进行萃取。将从中萃取的溶液用无水硫酸镁干燥并减压浓缩，由此得到残余物。残余物经硅胶柱色谱分离，并由此最终得到N-(4-(1-(3-氰基环丁基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
MS(ESI+)m/z 362(M+H)+
实施例491至518
在下文的实施例491至518中，通过与实施例490所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例491：N-(4-(4-((1-(3,5-二氟苯甲酰基)哌啶-4-基)氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001781
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.48(s,1H),7.82(s,1H),7.38–7.20(m,2H),7.17– 7.10(m,2H),6.48(dd,J＝3.5,1.8Hz,1H),6.23(s,1H),4.28(s,1H),3.47(s,1H),2.98(s,3H),2.00(s,3H), 1.81(s,1H),1.48(s,2H),1.25(d,J＝9.2Hz,5H),0.82–0.74(m,4H).
MS(ESI+)m/z 520(M+H)+
实施例492：N-(4-(4-((1-(环己基羰基)哌啶-4-基)氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001782
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.48(s,1H),7.82(s,1H),7.30(t,J＝3.0Hz,1H),6.49(dd, J＝3.6,1.9Hz,1H),6.22(s,1H),4.26(d,J＝13.7Hz,1H),3.88(d,J＝13.5Hz,1H),3.56(t,J＝7.0Hz,1H),3.14(dd, J＝7.5,5.6Hz,1H),2.19(d,J＝6.7Hz,1H),2.01(s,4H),1.70(d,J＝11.1Hz,4H),1.61(t,J＝6.9Hz,6H),1.30(s, 6H),1.18(d,J＝9.8Hz,2H),1.07(t,J＝7.2Hz,2H),0.82–0.77(m,4H).
MS(ESI+)m/z 490(M+H)+
实施例493：N-(4-(4-((1-(2-氟异烟酰基)哌啶-4-基)氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001783
1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.48(s,1H),8.33(d,J＝5.0Hz,1H),7.82(s,1H),7.32(dt, J＝18.3,3.9Hz,2H),7.23(s,1H),6.49(dd,J＝3.6,1.9Hz,1H),6.22(s,1H),4.32(d,J＝12.7Hz,1H),3.43(d, J＝13.8Hz,1H),3.04(dt,J＝39.7,12.3Hz,4H),1.98(d,J＝22.7Hz,4H),0.84–0.75(m,4H).
MS(ESI+)m/z 503(M+H)+
实施例494：N-(4-(4-((1-(4-硝基苯甲酰基)哌啶-4-基)氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001791
1H NMR(400MHz,DMSO-d6)δ11.35(d,J＝3.2Hz,1H),10.48(s,1H),8.32–8.25(m,2H),7.82(s,1H), 7.71–7.59(m,2H),7.29(t,J＝3.1Hz,1H),6.48(dd,J＝3.5,1.9Hz,1H),6.22(s,1H),4.32(d,J＝12.4Hz,1H), 3.43(d,J＝13.3Hz,1H),3.03(d,J＝52.9Hz,4H),2.00(d,J＝7.2Hz,4H),1.78(s,1H),1.47(s,2H),1.25 (d,J＝17.8Hz,4H),0.85–0.73(m,4H).
MS(ESI+)m/z 529(M+H)+
实施例495：N-(4-(4-((1-(3,5-二氟苯甲酰基)氮杂环丁烷-3-基)氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001792
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.47(s,1H),7.43(tt,J＝9.5,2.5Hz,1H),7.30(dq,J＝5.8, 2.1Hz,3H),7.19–7.12(m,1H),6.48(t,J＝2.7Hz,1H),6.21(d,J＝4.1Hz,1H),4.47(d,J＝8.4Hz,1H),4.22(d, J＝10.5Hz,1H),4.03(s,1H),3.78(dd,J＝7.0,3.8Hz,2H),3.63(t,J＝7.0Hz,1H),3.01(qd,J＝7.2,5.3Hz,1H), 1.91(d,J＝6.9Hz,1H),0.83–0.72(m,4H).
MS(ESI+)m/z 492(M+H)+
实施例496：N-(4-(4-((1-(2-氟异烟酰基)氮杂环丁烷-3-基)氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001793
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.48(s,1H),8.34(dd,J＝22.8,5.1Hz,1H),7.82(s,1H), 7.52(dt,J＝5.1,1.6Hz,1H),7.33(t,J＝1.7Hz,1H),7.29(t,J＝3.1Hz,1H),6.47(dt,J＝3.7,2.0Hz,1H),6.21(s, 1H),4.46(td,J＝7.6,6.5,3.9Hz,1H),4.24(d,J＝10.7Hz,1H),4.04-4.01(m,1H),3.79(dt,J＝7.7,4.2Hz,2H), 3.00(ddd,J＝8.6,6.9,5.3Hz,1H),2.80(s,1H),2.18(t,J＝3.4Hz,1H),2.03–1.99(m,2H),1.91(d,J＝5.9Hz,1H),0.82-0.74(m,4H).
MS(ESI+)m/z 475(M+H)+
实施例497：N-(4-(4-((1-(2-甲氧基异烟酰基)氮杂环丁烷-3-基)氨基)环己-1-烯-1-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001801
1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),10.48(s,1H),8.27(d,J＝5.3Hz,1H),7.81(s,1H),7.33– 7.26(m,1H),7.12(dd,J＝5.2,1.4Hz,1H),6.92(t,J＝1.0Hz,1H),6.53–6.43(m,1H),6.21(s,1H),4.43(s,1H), 4.23(s,1H),3.99(s,1H),3.78(s,2H),2.81(s,1H),2.00(d,J＝5.4Hz,2H),1.91(s,1H),1.48(s,2H),0.81- 0.74(m,4H).
MS(ESI+)m/z 487(M+H)+
实施例498：4-((4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-2-氟苯基)氨基)-N-苯基哌啶-1- 甲酰胺的合成
Figure BDA0002455210850001802
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.54(s,1H),8.52(s,1H),7.95(s,1H),7.51–7.45(m, 2H),7.42–7.33(m,3H),7.25–7.19(m,2H),7.00(t,J＝8.8Hz,1H),6.94–6.87(m,1H),6.56(dd,J＝3.5, 1.9Hz,1H),5.61(d,J＝7.9Hz,1H),4.15(d,J＝13.3Hz,2H),3.61(s,1H),2.96(t,J＝12.5Hz,2H),2.04(s,1H), 1.94(t,J＝14.5Hz,2H),1.52–1.42(m,3H),1.23(s,6H),0.82(dd,J＝8.8,5.0Hz,4H).
MS(ESI+)m/z 513(M+H)+
实施例499：N-(4-(4-((1-(3,5-二氟苯甲酰基)哌啶-4-基)氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001803
MS(ESI+)m/z 534(M+H)+
实施例500：N-(4-(3-氟-4-((1-(2-氟异烟酰基)哌啶-4-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001811
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.55(s,1H),8.35(d,J＝5.0Hz,1H),7.94(s,1H),7.42– 7.28(m,3H),7.24(s,1H),6.99(s,1H),6.58–6.48(m,1H),5.55(d,J＝9.0Hz,1H),5.32(s,1H),2.01(t, J＝7.5Hz,4H),1.91(s,1H),1.56–1.39(m,4H),1.23(s,9H),0.83(d,J＝14.1Hz,4H).
MS(ESI+)m/z 517(M+H)+
实施例501：4-((4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-2-氟苯基)氨基)-N-(2,4-二氟苯基)哌啶-1-甲酰胺的合成
Figure BDA0002455210850001812
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.58(s,1H),8.34(s,1H),7.95(s,1H),7.42–7.33(m, 5H),7.31–7.17(m,3H),7.00(q,J＝8.5Hz,2H),6.59–6.50(m,1H),5.68–5.60(m,1H),4.86–4.73(m,1H), 4.10(d,J＝13.3Hz,2H),3.60(s,2H),2.96(t,J＝12.6Hz,2H),2.18(t,J＝7.4Hz,1H),0.86–0.78(m,6H).
MS(ESI+)m/z 549(M+H)+
实施例502：N-(4-(4-(((2S)-1-(3,5-二氟苯甲酰基)-2-甲基哌啶-4-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001813
MS(ESI+)m/z 530(M+H)+
实施例503：N-(4-(4-(((2S)-1-(2-氟异烟酰基)-2-甲基哌啶-4-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001814
MS(ESI+)m/z 513(M+H)+
实施例504：(2S)-4-((4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)氨基)-2-甲基-N-(2,2,2- 三氟乙基)哌啶-1-甲酰胺的合成
Figure BDA0002455210850001821
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.53(s,1H),7.94(s,1H),7.54–7.47(m,2H),7.33(dd, J＝3.5,2.5Hz,1H),6.75(dd,J＝8.9,3.1Hz,2H),6.55(td,J＝3.4,1.9Hz,1H),3.93–3.77(m,3H),3.59(d, J＝2.8Hz,1H),2.05–2.00(m,1H),1.95–1.80(m,2H),1.66(dd,J＝30.6,12.3Hz,2H),1.23(s,2H),1.17(d, J＝6.7Hz,2H),0.83–0.77(m,4H).
MS(ESI+)m/z 515(M+H)+
实施例505：4-((4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-2-氟苯基)氨基)-N-(2,2,2-三氟乙基)哌啶-1-甲酰胺的合成
Figure BDA0002455210850001822
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),10.58(s,1H),7.95(s,1H),7.40–7.34(m,3H),7.17(t, J＝6Hz,1H),6.99(t,J＝8.8Hz,1H),6.55(m,1H),5.63(d,J＝8.4,1H),4.02(d,J＝13.6Hz,2H),3.87(m,2H), 3.57(m,1H),2.90(t,J＝12.4Hz,2H),2.03(m,1H),1.91(d,J＝10.8Hz,2H),1.42(m,2H),0.84(m,4H).
MS(ESI+)m/z 519(M+H)+
实施例506：(2S)-4-((4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)氨基)-N-(2,4-二氟苯基)-2-甲基哌啶-1-甲酰胺的合成
Figure BDA0002455210850001823
MS(ESI+)m/z 545(M+H)+
实施例507：N-(4-(4-((1-异烟酰基哌啶-4-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001831
MS(ESI+)m/z 481(M+H)+
实施例508：N-(4-(4-((1-(3,5-二氟苯甲酰基)哌啶-4-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001832
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.52(s,1H),7.94(d,J＝7.9Hz,1H),7.56–7.30(m, 4H),7.17(dt,J＝5.8,2.2Hz,2H),6.82–6.70(m,2H),6.53(dd,J＝3.5,1.9Hz,1H),5.94(d,J＝7.7Hz,1H), 4.32(d,J＝13.3Hz,1H),3.69–3.49(m,3H),3.16(d,J＝46.7Hz,3H),2.03(s,2H),1.91(s,1H),0.82–0.73 (m,4H).
MS(ESI+)m/z 516(M+H)+
实施例509：N-(4-(4-((1-(2-氟异烟酰基)哌啶-4-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001833
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.52(s,1H),8.35(d,J＝5.0Hz,1H),7.93(s,1H),7.53 –7.45(m,2H),7.37(dt,J＝4.9,1.8Hz,1H),7.33(dd,J＝3.5,2.5Hz,1H),7.26(t,J＝1.5Hz,1H),6.80– 6.73(m,2H),6.53(dd,J＝3.5,1.9Hz,1H),5.96(d,J＝7.8Hz,1H),4.33(d,J＝13.2Hz,1H),3.63(s,1H), 3.47(d,J＝13.9Hz,1H),3.22(t,J＝12.0Hz,1H),3.13(t,J＝11.5Hz,1H),2.06(d,J＝15.0Hz,2H),1.93(s, 1H),1.50–1.31(m,2H),0.79(m,4H).
MS(ESI+)m/z 499(M+H)+
实施例510：N-(4-(4-((1-(3,5-二氟苯甲酰基)氮杂环丁烷-3-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001841
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.94(s,1H),7.57–7.49(m,4H),7.46(tt, J＝9.2,2.4Hz,2H),7.34(dt,J＝6.2,2.1Hz,3H),6.68(dd,J＝11.8,7.5Hz,3H),6.53(dd,J＝3.5,1.9Hz, 1H),4.72(t,J＝7.9Hz,1H),4.46(t,J＝8.8Hz,1H),4.37–4.27(m,1H),4.13(dd,J＝8.6,4.9Hz,1H),3.93 (dd,J＝10.4,5.0Hz,1H),2.03(s,1H),0.82–0.75(m,4H).
MS(ESI+)m/z 488(M+H)+
实施例511：4-((4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)氨基)-N-(2,4-二氟苯基)哌啶-1-甲酰胺的合成
Figure BDA0002455210850001842
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.53(s,1H),8.94(d,J＝2.2Hz,1H),8.34(s,1H),8.10 (td,J＝9.2,6.1Hz,1H),7.94(d,J＝4.3Hz,1H),7.50(d,J＝8.6Hz,2H),7.35–7.30(m,1H),7.24(ddd,J＝ 10.7,9.1,2.9Hz,1H),7.08–6.93(m,1H),6.76(d,J＝8.7Hz,2H),6.55(dd,J＝3.5,1.9Hz,1H),5.96(d,J＝ 8.1Hz,1H),4.03(d,J＝13.4Hz,2H),3.55(d,J＝9.8Hz,1H),3.03(t,J＝11.7Hz,2H),2.11–1.92(m,3H), 1.41–1.31(m,2H),0.85–0.71(m,4H).
MS(ESI+)m/z 531(M+H)+
实施例512：4-((4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)氨基)-N-(2,2,2-三氟乙基) 哌啶-1-甲酰胺的合成
Figure BDA0002455210850001843
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.52(s,1H),7.93(s,1H),7.49(d,J＝8.6Hz,2H),7.33 (dd,J＝3.5,2.5Hz,1H),7.16(t,J＝6.2Hz,1H),6.74(d,J＝8.5Hz,2H),6.54(dd,J＝3.5,1.9Hz,1H),5.92 (d,J＝8.1Hz,1H),3.93(d,J＝13.4Hz,2H),3.84(dtd,J＝16.1,9.7,6.5Hz,3H),3.51(s,1H),2.94(t,J＝ 12.4Hz,2H),2.05(d,J＝17.6Hz,1H),1.92(d,J＝12.2Hz,2H),0.84-0.76(m,4H).
MS(ESI+)m/z 501(M+H)+
实施例513：3-((4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)氨基)-N-(2,4-二氟苯基)氮杂环丁烷-1-甲酰胺的合成
Figure BDA0002455210850001851
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),8.27(s,1H),7.95(s,1H),7.53(dq,J＝8.9, 3.1Hz,3H),7.34(dd,J＝3.5,2.5Hz,1H),7.26(ddd,J＝10.8,9.0,2.9Hz,1H),7.07–6.97(m,1H),6.69(d,J ＝8.8Hz,3H),6.54(dd,J＝3.5,1.9Hz,1H),4.32(m,3H),3.79(dd,J＝8.2,4.1Hz,2H),2.03(s,1H),0.84– 0.76(m,4H).
MS(ESI+)m/z 503(M+H)+
实施例514：3-((4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)氨基)-N-(2,2,2-三氟乙基) 氮杂环丁烷-1-甲酰胺的合成
Figure BDA0002455210850001852
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.95(d,J＝2.9Hz,2H),7.52(d,J＝8.6 Hz,2H),7.34(dd,J＝3.5,2.5Hz,1H),7.08(t,J＝6.3Hz,1H),6.67(d,J＝8.7Hz,2H),6.53(dd,J＝3.5,1.9 Hz,1H),4.26–4.22(m,2H),3.86–3.72(m,3H),3.71–3.65(m,2H),2.03(s,1H),0.87-076(m,4H).
MS(ESI+)m/z 473(M+H)+
实施例515：N-(4-(4-((1-(2-氰基乙酰基)氮杂环丁烷-3-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001853
MS(ESI+)m/z 415(M+H)+
实施例516：N-(4-(4-((1-(2-氰基乙酰基)哌啶-4-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001854
MS(ESI+)m/z 443(M+H)+
实施例517：N-(4-(4-((1-(3,3,3-三氟丙酰基)氮杂环丁烷-3-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001861
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.54(s,1H),7.95(s,1H),7.53(d,J＝8.4Hz,2H),7.34 (t,J＝3.0Hz,1H),6.67(d,J＝8.3Hz,3H),6.53(dd,J＝3.5,1.9Hz,1H),4.55(t,J＝7.7Hz,1H),4.29(d,J＝ 6.2Hz,2H),4.03–3.90(m,1H),3.75(d,J＝5.3Hz,1H),3.40(m,2H),2.03(s,1H),0.84–0.76(m,4H).
MS(ESI+)m/z 458(M+H)+
实施例518：N-(4-(4-((1-(3,3,3-三氟丙酰基)哌啶-4-基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001862
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.52(s,1H),7.94(s,1H),7.50(d,J＝8.6Hz,2H),7.33 (dd,J＝3.5,2.5Hz,1H),6.76(d,J＝8.6Hz,2H),6.54(dd,J＝3.5,1.9Hz,1H),5.95(d,J＝8.0Hz,1H),4.25 (d,J＝13.2Hz,1H),3.82(d,J＝13.8Hz,1H),3.76–3.53(m,3H),3.21(t,J＝11.9Hz,1H),2.90(t,J＝11.3 Hz,1H),2.05–1.90(m,3H),1.44–1.22(m,2H),0.85-0.76(m,4H).
MS(ESI+)m/z 486(M+H)+
实施例519：N-(4-(4-(2-氰基乙酰基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001863
将1.0g(2.1mmol)由以上反应式3制备的N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺溶于DMF/H2O＝2:1溶液中，然后将0.6g(2.5mmol)3-(4- 溴苯基)-3-氧代丙腈、0.2g(0.2mmol)Pd(PPh3)4和0.15ml 2M K2CO3水溶液添加到其中，并在100-110℃下搅拌2小时。一旦反应完成后，将所述混合物在室温下冷却，然后向其中加入水，并使用乙酸乙酯进行萃取。之后，将从中萃取的溶液用无水硫酸镁干燥并减压浓缩，由此得到残余物。将残余物经NH- 硅胶柱色谱(正己烷/乙酸乙酯＝5:1)分离，合成N-(4-(4-(2-氰基乙酰基)苯基)-1-对甲苯磺酰基-1H-吡咯并 [2,3-b]吡啶-6-基)环丙基甲酰胺。将合成的材料溶于MeOH/THF(1:1)溶液中，然后向其中加入2N氢氧化钠水溶液，并在30-40℃下搅拌4小时。一旦反应完成后，将所述混合物冷却至室温，并在搅拌的同时向其中加入饱和氯化铵水溶液。滤出产生的固体，并由此最终得到产物，即N-(4-(4-(2-氰基乙酰基) 苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
MS(ESI+)m/z 345(M+H)+
实施例520至598
在下文的实施例520至598中，通过与实施例519所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例520：N-(4-(4-(1,1-二氧化硫代吗啉-4-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001871
MS(ESI+)m/z 439(M+H)+
实施例521：N-(4-(4-(硫代吗啉-4-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001872
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),10.66(s,1H),8.17–8.01(m,1H),7.78(d,J＝7.7Hz, 2H),7.57(d,J＝7.7Hz,2H),7.43(s,1H),6.56(s,1H),3.76(d,J＝100.0Hz,6H),2.76–2.61(m,6H),2.07 (d,J＝13.0Hz,1H),0.80(d,J＝12.3Hz,4H).
MS(ESI+)m/z 407(M+H)+
实施例522：N-(4-(2-甲基-4-(吗啉-4-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001873
MS(ESI+)m/z 405(M+H)+
实施例523：N-(氰基甲基)-4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯甲酰胺的合成
Figure BDA0002455210850001874
1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.67(s,1H),9.32(s,1H),8.09(s,1H),8.04(d,J＝8.0 Hz,2H),7.84(d,J＝8.0Hz,2H),7.44(d,J＝3.3Hz,1H),6.55(d,J＝3.4Hz,1H),4.35(d,J＝5.2Hz,2H), 2.07(d,J＝12.0Hz,1H),0.87–0.75(m,4H).
MS(ESI+)m/z 360(M+H)+
实施例524：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-N-(2,2,2-三氟乙基)苯甲酰胺的合成
Figure BDA0002455210850001875
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.60(s,1H),8.02(s,1H),7.65(d,J＝8.0Hz,2H),7.42 (dd,J＝5.4,17.0Hz,3H),6.53(s,1H),3.54–3.47(m,2H),2.02(dd,J＝7.9,15.2Hz,1H),0.84–0.77(m, 4H).
MS(ESI+)m/z 403(M+H)+
实施例525：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-N-(2,2,2-三氟乙基)苯甲酰胺的合成
Figure BDA0002455210850001881
MS(ESI+)m/z 417(M+H)+
实施例526：N-(氰基甲基)-4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基苯甲酰胺的合成
Figure BDA0002455210850001882
MS(ESI+)m/z 374(M+H)+
实施例527：N-(氰基甲基)-4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-N,3-二甲基苯甲酰胺的合成
Figure BDA0002455210850001883
MS(ESI+)m/z 388(M+H)+
实施例528：N-(氰基甲基)-4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-2-氟苯甲酰胺的合成
Figure BDA0002455210850001884
MS(ESI+)m/z 378(M+H)+
实施例529：N-(氰基甲基)-4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-2,6-二氟苯甲酰胺的合成
Figure BDA0002455210850001885
MS(ESI+)m/z 396(M+H)+
实施例530：N-(氰基甲基)-4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)环己-3-烯-1-甲酰胺的合成
Figure BDA0002455210850001891
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.49(s,1H),8.62(t,J＝5.6Hz,1H),7.83(s,1H),7.31 (dd,J＝3.5,2.5Hz,1H),6.50(dd,J＝3.6,1.8Hz,1H),6.31(s,1H),4.16(d,J＝5.6Hz,2H),2.40(s,2H), 2.00(d,J＝12.1Hz,2H),1.72(ddt,J＝17.9,12.1,6.3Hz,1H),0.79(ddt,J＝13.1,5.1,3.0Hz,4H).
MS(ESI+)m/z 364(M+H)+
实施例531：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-N-(2,2,2-三氟乙基)环己-3-烯-1-甲酰胺的合成
Figure BDA0002455210850001892
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.49(s,1H),8.55(t,J＝6.4Hz,1H),7.83(s,1H),7.31 (dd,J＝3.5,2.4Hz,1H),6.49(dd,J＝3.6,1.9Hz,1H),6.32(d,J＝4.0Hz,1H),3.94(ddt,J＝11.6,9.1,4.9Hz, 2H),2.62–2.54(m,2H),2.39(d,J＝6.7Hz,2H),2.05–1.95(m,3H),1.73(ddt,J＝17.9,12.1,6.3Hz,1H), 0.87-0.72(m,4H).
MS(ESI+)m/z 407(M+H)+
实施例532：N-(2-氰基乙基)-4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)环己-3-烯-1-甲酰胺的合成
Figure BDA0002455210850001893
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1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),10.49(s,1H),8.27(t,J＝5.8Hz,1H),7.83(s,1H),7.38 –7.27(m,1H),6.50(dd,J＝3.6,1.9Hz,1H),6.31(s,1H),2.67(t,J＝6.5Hz,2H),2.56-2.43(m,3H)2.38(d, J＝6.0Hz,2H),2.06–1.93(m,3H),1.79–1.67(m,1H),0.85(t,J＝6.4Hz,1H),0.79(ddt,J＝10.1,5.0,2.6 Hz,4H).
MS(ESI+)m/z 378(M+H)+
实施例533：N-(4-(4-((N-甲基氨磺酰基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001894
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),10.66(s,1H),8.05(d,J＝4.7Hz,1H),7.73(d,J＝7.9Hz, 2H),7.54(d,J＝7.9Hz,2H),7.42(t,J＝3.1Hz,1H),7.04–6.94(m,1H),6.54(dd,J＝3.7,1.8Hz,1H),4.42 (s,2H),2.62(d,J＝4.7Hz,3H),2.07–2.00(m,1H),0.85-0.72(m,4H).
MS(ESI+)m/z 385(M+H)+
实施例534：N-(4-(4-((吗啉代磺酰基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001901
1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),10.66(s,1H),8.06(s,1H),7.75(d,J＝7.8Hz,2H),7.59 (d,J＝7.8Hz,2H),7.43(s,1H),6.54(s,1H),4.54(s,2H),3.61(s,4H),3.15(d,J＝5.8Hz,4H),2.05(s,1H), 0.86-0.75(m,4H).
MS(ESI+)m/z 441(M+H)+
实施例535：N-(4-(4-(2-(1,1-二氧化硫代吗啉代)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001902
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.62(s,1H),8.03(s,1H),7.67(d,J＝7.8Hz,2H),7.56 (s,1H),7.41(d,J＝6.9Hz,2H),6.54(s,1H),3.94–3.88(m,4H),3.16(d,J＝21.7Hz,4H),2.05(s,1H),0.89 -0.76(m,4H).
MS(ESI+)m/z 453(M+H)+
实施例536：N-(4-(4-(2-吗啉代-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001903
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.62(s,1H),8.03(s,1H),7.67(d,J＝7.7Hz,2H),7.39 (d,J＝7.5Hz,2H),6.54(s,1H),3.81(s,2H),3.53(s,6H),3.48(s,2H),2.05(s,1H),0.88-0.77(m,4H).
MS(ESI+)m/z 405(M+H)+
实施例537：N-(4-(4-(2-氧代-2-((2,2,2-三氟乙基)氨基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001904
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.63(s,1H),8.83(s,1H),8.02(s,1H),7.66(d,J＝7.7 Hz,2H),7.59–7.54(m,1H),7.42(t,J＝7.1Hz,2H),6.53(s,1H),4.00–3.91(m,2H),3.61(s,2H),2.05(s, 1H),0.87–0.76(m,4H).
MS(ESI+)m/z 417(M+H)+
实施例538：N-(4-(4-(2-((1,1-二氧化四氢噻吩-3-基)氨基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001911
MS(ESI+)m/z 453(M+H)+
实施例539：N-(4-(4-(2-(甲基氨基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001912
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.03(d,J＝8.0Hz,2H),7.69–7.60(m, 2H),7.47–7.36(m,3H),6.53(dd,J＝3.5,1.9Hz,1H),3.47(s,3H),2.60(d,J＝4.6Hz,2H),2.08–1.98(m, 1H),0.83–0.73(m,4H).
MS(ESI+)m/z 349(M+H)+
实施例540：N-(4-(4-(2-(二甲基氨基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001913
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.02(s,1H),7.71–7.62(m,2H),7.43– 7.35(m,3H),6.54(dd,J＝3.5,1.8Hz,1H),3.77(s,2H),3.04(s,3H),2.85(s,3H),2.03(d,J＝8.1Hz,1H), 0.83–0.76(m,4H).
MS(ESI+)m/z 363(M+H)+
实施例541：N-(4-(4-(2-(乙基氨基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001914
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.11(t,J＝5.2Hz,1H),8.02(s,1H),7.72 –7.59(m,2H),7.49–7.31(m,4H),6.53(dd,J＝3.5,1.9Hz,1H),3.45(s,2H),3.08(qd,J＝7.2,5.4Hz,2H), 2.09–1.98(m,1H),1.03(t,J＝7.2Hz,3H),0.85–0.72(m,4H).
MS(ESI+)m/z 363(M+H)+
实施例542：N-(4-(4-(2-(4-(甲基磺酰基)哌嗪-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001921
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.64(s,1H),8.03(s,1H),7.67(d,J＝8.1Hz,2H),7.46 –7.36(m,3H),6.54(dd,J＝3.5,1.9Hz,1H),3.84(s,2H),3.66(s,4H),3.09(d,J＝5.3Hz,4H),2.88(s,3H), 2.09–1.99(m,1H),0.84–0.73(m,4H).
MS(ESI+)m/z 482(M+H)+
实施例543：N-(4-(4-(2-(4-乙酰基哌嗪-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001922
MS(ESI+)m/z 446(M+H)+
实施例544：N-(4-(4-(2-(异噁唑-3-基氨基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001923
1H NMR(400MHz,氯仿-d)δ8.23(d,J＝1.7Hz,1H),8.01(s,1H),7.70(d,J＝7.8Hz,2H),7.42(d,J＝ 7.8Hz,2H),7.20(d,J＝3.5Hz,1H),7.01(s,1H),6.58(s,1H),3.75(s,2H),2.19–2.10(m,1H),1.97(d,J＝ 12.6Hz,1H),0.83–0.80(m,4H).
MS(ESI+)m/z 402(M+H)+
实施例545：N-(4-(4-(2-(1,1-二氧化硫代吗啉代)-2-氧代乙基)-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001924
MS(ESI+)m/z 467(M+H)+
实施例546：N-(4-(4-(2-(氮杂环丁烷-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001931
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.02(s,1H),7.71–7.62(m,2H),7.42– 7.36(m,3H),6.54(dd,J＝3.5,1.7Hz,1H),4.21(t,J＝7.7Hz,2H),3.84(dt,J＝16.3,8.0Hz,2H),3.48(s, 6H),2.19(p,J＝7.7Hz,1H),2.01(dd,J＝14.7,7.3Hz,3H),0.85–0.71(m,4H).
MS(ESI+)m/z 375(M+H)+
实施例547：N-(4-(4-(2-氧代-2-(吡咯烷-1-基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001932
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.02(s,1H),7.70–7.62(m,2H),7.43– 7.37(m,3H),6.54(dd,J＝3.5,1.9Hz,1H),3.70(s,2H),3.51(t,J＝6.8Hz,2H),3.31(t,J＝6.8Hz,2H),2.07 –1.97(m,1H),1.89(p,J＝6.8Hz,2H),1.77(p,J＝6.8Hz,2H),0.84–0.74(m,4H).
MS(ESI+)m/z 389(M+H)+
实施例548：N-(4-(4-(2-(4-氰基哌啶-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001933
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.02(s,1H),7.71–7.63(m,2H),7.44– 7.36(m,3H),6.53(dd,J＝3.5,1.9Hz,1H),3.89–3.78(m,3H),3.08(s,1H),2.07–1.94(m,2H),1.90–1.77 (m,2H),1.60(ddt,J＝12.8,8.9,4.7Hz,2H),0.83–0.75(m,4H).
MS(ESI+)m/z 428(M+H)+
实施例549：N-(4-(4-(2-氧代-2-(4-氧代哌啶-1-基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001934
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.02(s,1H),7.67(d,J＝7.9Hz,2H),7.46 –7.37(m,3H),6.54(dd,J＝3.6,1.9Hz,1H),3.90(s,2H),3.86–3.73(m,4H),2.36(q,J＝5.5,4.8Hz,2H), 2.06–1.96(m,2H),1.15(d,J＝6.6Hz,2H),0.80(m,4H).
MS(ESI+)m/z 417(M+H)+
实施例550：N-(4-(4-(2-(4-甲基哌嗪-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001941
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.03(s,1H),7.71–7.63(m,2H),7.42– 7.36(m,3H),6.53(dd,J＝3.5,1.8Hz,1H),3.79(s,2H),3.55–3.44(m,4H),2.24(q,J＝4.6Hz,4H),2.15(s, 3H),2.08–1.98(m,1H),0.80(m,4H).
MS(ESI+)m/z 418(M+H)+
实施例551：N-(4-(4-(2-(4-乙基哌嗪-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001942
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.03(s,1H),7.70–7.63(m,2H),7.43– 7.37(m,3H),6.56–6.50(m,1H),3.79(s,2H),3.55–3.44(m,4H),2.29(td,J＝8.4,7.8,5.2Hz,6H),2.04– 1.96(m,1H),0.98(t,J＝6.8Hz,3H),0.83–0.71(m,4H).
MS(ESI+)m/z 432(M+H)+
实施例552：N-(4-(4-(2-(4-异丙基哌嗪-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001943
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.02(s,1H),7.70–7.62(m,2H),7.49– 7.44(m,1H),7.42–7.35(m,3H),7.11(d,J＝7.8Hz,1H),6.53(dd,J＝3.5,1.9Hz,1H),3.79(s,2H),3.55– 3.43(m,4H),2.63(d,J＝6.5Hz,1H),2.37(d,J＝9.1Hz,4H),2.05–1.95(m,1H),0.94(d,J＝6.5Hz,6H), 0.81(qd,J＝9.0,7.8,4.5Hz,4H).
MS(ESI+)m/z 446(M+H)+
实施例553：N-(4-(4-(2-((2-氰基乙基)氨基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001944
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.63(s,1H),8.02(s,1H),7.65(d,J＝8.1Hz,2H),7.49 –7.36(m,3H),6.53(dd,J＝3.5,1.8Hz,1H),3.53(s,2H),3.31(m,2H),2.66(m,2H),2.07–1.96(m,1H), 0.82(m,4H).
MS(ESI+)m/z 388(M+H)+
实施例554：4-(2-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙酰基)哌嗪-1-甲酸叔丁酯的合成
Figure BDA0002455210850001951
1H NMR(400MHz,DMSO-d6)δ11.54(d,J＝2.6Hz,1H),10.63(s,1H),8.03(s,1H),7.72–7.63(m, 2H),7.44–7.35(m,3H),6.54(dd,J＝3.6,1.9Hz,1H),3.82(s,2H),3.58–3.43(m,4H),3.32–3.24(m,4H), 2.07–1.94(m,1H),1.40(s,9H),0.87–0.74(m,4H).
MS(ESI+)m/z 504(M+H)+
实施例555：3-(2-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙酰氨基)哌啶-1-甲酸叔丁酯的合成
Figure BDA0002455210850001952
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.63(s,1H),8.11(d,J＝7.5Hz,1H),8.02(s,1H),7.65 (d,J＝8.1Hz,2H),7.46–7.37(m,3H),6.53(dd,J＝3.4,1.8Hz,1H),3.64–3.53(m,2H),3.50(s,3H),2.00 (dt,J＝14.5,6.7Hz,2H),1.85–1.76(m,1H),1.73–1.61(m,1H),1.37(s,13H),1.23(s,5H),0.88–0.72(m, 6H).
MS(ESI+)m/z 518(M+H)+
实施例556：N-(4-(4-(2-((1-甲基-1H-吡唑-3-基)氨基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001953
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.68(s,1H),10.63(s,1H),8.02(s,1H),7.67(d,J＝8.1 Hz,2H),7.53(d,J＝2.2Hz,1H),7.48(d,J＝8.0Hz,2H),7.40(dd,J＝3.5,2.4Hz,1H),6.54(dd,J＝3.5,1.9 Hz,1H),6.42(d,J＝2.2Hz,1H),3.73(s,3H),3.68(s,2H),2.02(m,1H),0.84–0.73(m,4H).
MS(ESI+)m/z 415(M+H)+
实施例557：N-(4-(4-(2-氧代-2-(哌啶-1-基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001954
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.60(d,J＝3.9Hz,1H),8.03(d,J＝3.2Hz,1H),7.67 (d,J＝6.8Hz,2H),7.40(s,3H),6.53(s,1H),3.78(s,2H),3.60(s,2H),3.46(s,2H),2.04(s,1H),1.75(d,J＝ 4.4Hz,2H),1.55(s,2H),1.41(s,2H),0.82-0.75(m,4H).
MS(ESI+)m/z 403(M+H)+
实施例558：N-(4-(4-(2-氧代-2-(哌嗪-1-基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001961
1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.69(dd,J＝8.2,3.9Hz,2H),7.36–7.29(m,2H),7.20(q,J ＝3.1Hz,1H),6.57(q,J＝3.1Hz,1H),5.34–5.24(m,2H),3.84–3.73(m,2H),3.63(d,J＝5.2Hz,2H),3.45 (d,J＝5.3Hz,2H),2.81(s,2H),2.67(d,J＝5.3Hz,2H),1.65(s,1H),1.07(q,J＝3.9Hz,2H),0.85(m,2H).
MS(ESI+)m/z 404(M+H)+
实施例559：N-(4-(4-(2-(1,1-二氧化硫代吗啉代)-2-氧代乙基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001962
MS(ESI+)m/z 471(M+H)+
实施例560：N-(4-(4-(2-氧代-2-硫代吗啉代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001963
MS(ESI+)m/z 421(M+H)+
实施例561：N-(4-(4-(2-(4,4-二氟哌啶-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001964
MS(ESI+)m/z 439(M+H)+
实施例562：N-(4-(4-(2-氧代-2-(4-(三氟甲基磺酰基)哌嗪-1-基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001965
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),8.01(s,1H),7.65(d,J＝8.0Hz,2H),7.43 –7.31(m,3H),6.52(dd,J＝3.5,1.9Hz,1H),4.33(d,J＝4.3Hz,1H),3.77(s,2H),2.60(dd,J＝12.1,5.3Hz, 8H),2.00(m,1H),0.84-0.76(m,4H).
MS(ESI+)m/z 537(M+H)+
实施例563：N-(4-(4-(2-(4-(乙基磺酰基)哌嗪-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001971
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.61(s,1H),8.03(s,1H),7.67(d,J＝8.0Hz,2H),7.40 (d,J＝7.6Hz,3H),6.53(d,J＝3.4Hz,1H),3.84(s,2H),3.64-3.57(m,2H),3.20–3.10(m,4H),3.11– 2.99(m,4H),2.07–1.95(m,1H),1.24–1.14(m,3H),0.82(dd,J＝16.1,11.1Hz,4H).
MS(ESI+)m/z 497(M+H)+
实施例564：N-(4-(4-(2-氧代-2-(4-(丙基磺酰基)哌嗪-1-基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001972
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.61(s,1H),8.03(s,1H),7.67(d,J＝8.0Hz,2H),7.40 (dd,J＝6.2,2.1Hz,3H),6.54(dd,J＝3.5,1.9Hz,1H),3.84(s,2H),3.68–3.54(m,4H),3.14(m,4H),3.08- 2.99(m,2H),2.04–1.97(m,1H),1.75–1.60(m,2H),0.95(t,J＝7.4Hz,3H),0.85–0.74(m,4H).
MS(ESI+)m/z 511(M+H)+
实施例565：4-(2-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙酰基)哌嗪-1-甲酸乙酯的合成
Figure BDA0002455210850001973
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.61(s,1H),8.03(s,1H),7.66(d,J＝7.8Hz,2H),7.45 –7.35(m,3H),6.54(dd,J＝3.5,1.8Hz,1H),4.05(q,J＝7.0Hz,2H),3.83(s,2H),3.58–3.44(m,4H),2.07 –1.96(m,1H),1.18(t,J＝6.9Hz,3H),0.85–0.75(m,4H).
MS(ESI+)m/z 477(M+H)+
实施例566：(N-(4-(4-(2-氧代-2-(4-(N-(2,2,2-三氟乙基)氨磺酰基)哌嗪-1-基)乙基)苯基)-1H-吡咯并 [2,3-b]吡啶-6-基)环丙基甲酰胺)的合成
Figure BDA0002455210850001974
MS(ESI+)m/z 565(M+H)+
实施例567：N-(4-(4-(2-(3-氰基吡咯烷-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001981
MS(ESI+)m/z 414(M+H)+
实施例568：N-(4-(4-(2-(3-氰基氮杂环丁烷-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001982
MS(ESI+)m/z 400(M+H)+
实施例569：N-(4-(4-(2-(3,3-二氟吡咯烷-1-基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001983
1H NMR(400MHz,DMSO-d6)δ11.52(d,J＝4.0Hz,1H),10.60(d,J＝3.6Hz,1H),8.02(d,J＝3.4Hz, 1H),7.66(d,J＝6.0Hz,2H),7.40(s,3H),6.54(s,1H),4.11–3.98(m,1H),3.78(dd,J＝25.2,10.0Hz,5H), 3.55(s,2H),2.03(s,1H),0.82-0.75(s,4H).
MS(ESI+)m/z 425(M+H)+
实施例570：N-(4-(4-(2-氧代-2-(4-(三氟甲基)哌啶-1-基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001984
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.61(d,J＝2.9Hz,1H),8.02(d,J＝2.8Hz,1H),7.66(t, J＝6.1Hz,2H),7.40(d,J＝4.1Hz,3H),6.52(s,1H),4.56–4.47(m,1H),4.09(d,J＝13.9Hz,1H),3.85– 3.79(m,2H),3.06(t,J＝13.5Hz,1H),2.58(d,J＝12.3Hz,2H),2.03(s,1H),1.87–1.73(m,2H),1.25(d,J＝ 13.1Hz,2H),0.82-0.75(m,4H).
MS(ESI+)m/z 471(M+H)+
实施例571：N-(4-(4-(2-(1,1-二氧化硫代吗啉代)-1,1-二氟-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850001991
MS(ESI+)m/z 489(M+H)+
实施例572：N-(4-(4-(1,1-二氟-2-吗啉代-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001992
MS(ESI+)m/z 441(M+H)+
实施例573：N-(4-(4-(2-((氰基甲基)(甲基)氨基)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001993
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.67(s,1H),8.00(s,1H),7.68(d,J＝8.1Hz,2H),7.43 –7.37(m,3H),6.55(dd,J＝3.6,1.9Hz,1H),4.43(s,2H),3.88(s,3H),3.15(s,3H),2.06–2.02(m,1H),0.85 –0.80(m,4H).
MS(ESI+)m/z 388(M+H)+
实施例574：N-(4-(4-(2-(1-氧化硫代吗啉代)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850001994
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.65(s,1H),8.02(s,1H),7.68(d,J＝7.9Hz,2H),7.44 –7.38(m,3H),6.55(dd,J＝3.5,1.9Hz,1H),3.87(d,J＝11.3Hz,2H),3.62(dd,J＝6.6,3.9Hz,4H),3.13(tt, J＝7.4,3.7Hz,4H),2.04(d,J＝6.5Hz,1H),0.85–0.79(m,4H).
MS(ESI+)m/z 437(M+H)+
实施例575：N-(4-(4-(2-(4-氰基哌啶-1-基)-1,1-二氟-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850001995
MS(ESI+)m/z 464(M+H)+
实施例576：N-(4-(4-(2-(3-氰基吗啉代)-2-氧代乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002001
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.62(s,1H),8.04(s,1H),7.71–7.66(m,2H),7.45– 7.36(m,3H),6.54(dd,J＝3.5,1.8Hz,1H),4.03(d,J＝12.3Hz,2H),3.94–3.90(m,2H),3.62–3.56(m,1H), 3.46(s,1H),2.04(d,J＝9.1Hz,1H),1.28–1.23(m,4H),0.86–0.79(m,4H).
MS(ESI+)m/z 430(M+H)+
实施例577：N-(4-(4-(1-(1,1-二氧化硫代吗啉-4-羰基)环丙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002002
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.62(s,1H),8.03(s,1H),7.70(dd,J＝7.6,5.9Hz,3H), 7.42–7.40(m,1H),7.34(d,J＝8.3Hz,2H),6.53(dd,J＝3.5,1.9Hz,1H),3.39(s,2H),2.92(s,2H),2.04– 2.00(m,1H),1.51–1.47(m,2H),1.26(dd,J＝9.2,4.0Hz,4H),0.84–0.77(m,4H).
MS(ESI+)m/z 479(M+H)+
实施例578：N-(4-(1-(2-(1,1-二氧化硫代吗啉代)-2-氧代乙基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并 [2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002003
1H NMR(400MHz,氯仿-d)δ11.40(s,1H),10.51(s,1H),7.86(s,1H),7.37–7.28(m,1H),6.60–6.52 (m,1H),6.33(s,1H),3.99(s,2H),3.89(s,2H),3.39(s,2H),3.19(d,J＝37.2Hz,5H),2.74(t,J＝5.6Hz,2H), 2.00(d,J＝11.4Hz,1H),0.88–0.75(m,4H).
MS(ESI+)m/z 458(M+H)+
实施例579：N-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苄基)吗啉-4-甲酰胺的合成
Figure BDA0002455210850002004
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.62(s,1H),8.01(s,1H),7.66(d,J＝8.3Hz,2H),7.42 (d,J＝8.4Hz,3H),7.21(s,1H),6.53(s,1H),4.32(s,2H),2.42-2.83(m,4H),1.98-2.12(m,1H),1.21-1.41 (m,4H),0.72-0.95(m,4H).
MS(ESI+)m/z 420(M+H)+
实施例580：N-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苄基)硫代吗啉-4-甲酰胺1,1-二氧化物的合成
Figure BDA0002455210850002011
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.02(s,1H),7.67(d,J＝8.0Hz,2H),7.51 (d,J＝5.1Hz,1H),7.44(d,J＝7.9Hz,2H),7.42–7.38(m,1H),6.58–6.49(m,1H),4.34(d,J＝5.8Hz,2H), 3.82(d,J＝5.5Hz,4H),3.16–3.06(m,4H),2.04(s,1H),0.80(dd,J＝4.0,12.0Hz,4H).
MS(ESI+)m/z 468(M+H)+
实施例581：N-(4-(4-((3-(2,2,2-三氟乙基)脲基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002012
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),10.63(s,1H),8.02(s,1H),7.67(d,J＝7.8Hz,2H),7.45 –7.34(m,3H),6.75(t,J＝6.0Hz,1H),6.66(t,J＝6.6Hz,1H),6.55–6.47(m,1H),4.32(d,J＝6.0Hz,2H), 3.93–3.78(m,2H),2.04(s,1H),0.81(dt,J＝5.3,10.2Hz,4H).
MS(ESI+)m/z 432(M+H)+
实施例582：N-(4-(4-(((3,4-二氟苯基)磺酰氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002013
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.61(s,1H),8.24(br s,1H),7.99(s,1H),7.79(d,J＝ 2.3Hz,1H),7.69–7.58(m,4H),7.44–7.33(m,3H),6.52–6.43(m,1H),4.13(s,2H),2.04(d,J＝5.7Hz, 1H),0.88–0.74(m,4H).
MS(ESI+)m/z 483(M+H)+
实施例583：N-(4-(4-(丙基磺酰氨基甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002014
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),10.64(s,1H),8.05(d,J＝15.8Hz,1H),7.79–7.65(m, 3H),7.52(d,J＝8.1Hz,2H),7.41(s,1H),6.52(s,1H),4.22(d,J＝4.7Hz,2H),3.02–2.91(m,2H),2.05(s, 1H),1.72–1.59(m,2H),0.92(t,J＝7.4Hz,3H),0.81(d,J＝6.7Hz,4H).
MS(ESI+)m/z 413(M+H)+
实施例584：N-(4-(4-((1,1-二氧化硫代吗啉代)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002021
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.62(s,1H),8.03(s,1H),7.70(d,J＝7.9Hz,2H),7.51 (d,J＝7.9Hz,2H),7.40(t,J＝3.0Hz,1H),6.63–6.39(m,1H),3.75(s,2H),3.13(t,J＝5.1Hz,5H),3.01– 2.82(m,4H),2.05(t,J＝11.7Hz,1H),0.81(dt,J＝5.7,10.4Hz,4H).
MS(ESI+)m/z 425(M+H)+
实施例585：N-(4-(4-((4-氧代哌啶-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002022
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.62(s,1H),8.04(s,1H),7.78–7.66(m,2H),7.53(d,J ＝7.9Hz,2H),7.40(t,J＝3.0Hz,1H),6.55(dd,J＝1.8,3.5Hz,1H),3.70(s,2H),2.74(t,J＝6.0Hz,4H), 2.38(t,J＝6.0Hz,4H),2.04(d,J＝8.8Hz,1H),0.91–0.75(m,4H).
MS(ESI+)m/z 389(M+H)+
实施例586：N-(4-(4-((3-氰基氮杂环丁烷-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002023
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.61(s,1H),8.02(s,1H),7.75–7.64(m,2H),7.48– 7.41(m,2H),7.40(dd,J＝2.4,3.5Hz,1H),6.53(dd,J＝1.8,3.5Hz,1H),3.66(s,2H),3.55–3.45(m,4H), 2.04(d,J＝7.0Hz,1H),0.81(ddd,J＝2.6,6.4,11.7Hz,4H).
MS(ESI+)m/z 372(M+H)+
实施例587：N-(4-(4-((4-(甲基磺酰基)哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002024
MS(ESI+)m/z 454(M+H)+
实施例588：N-(4-(4-((1,1-二氧化硫代吗啉代)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)-2-甲基环丙基 -1-甲酰胺的合成
Figure BDA0002455210850002031
MS(ESI+)m/z 439(M+H)+
实施例589：N-(4-(4-(1-(1,1-二氧化硫代吗啉代)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002032
1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.62(s,1H),8.03(s,1H),7.70(d,J＝8.0Hz,2H),7.54 (d,J＝7.9Hz,2H),7.45–7.36(m,1H),6.55(s,1H),3.99(s,1H),3.10(s,4H),2.93(s,4H),2.05(s,1H),1.40 (d,J＝6.7Hz,3H),0.83–0.77(m,4H).
MS(ESI+)m/z 439(M+H)+
实施例590：N-(4-(3,5-二氟-4-(吗啉代甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002033
1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),10.72(s,1H),8.05(s,1H),7.47(d,J＝2.8Hz,1H),7.44 –7.35(m,2H),6.63–6.55(m,1H),3.63(s,2H),3.56(t,J＝4.5Hz,4H),2.45–2.42(m,2H),2.04(s,1H), 0.86–0.78(m,4H).
MS(ESI+)m/z 413(M+H)+
实施例591：N-(4-(4-(2-(1,1-二氧化硫代吗啉代)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002034
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.60(s,1H),8.01(s,1H),7.71–7.59(m,2H),7.50– 7.34(m,3H),6.52(dd,J＝3.5,1.7Hz,1H),3.10(d,J＝5.6Hz,4H),3.05–2.93(m,4H),2.86–2.73(m,4H), 2.03(m,1H),0.90–0.74(m,4H).
MS(ESI+)m/z 439(M+H)+
实施例592：N-(6-(4-((1,1-二氧化硫代吗啉代)甲基)苯基)-9H-嘌呤-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002041
1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.88–8.79(m,2H),8.51(s,1H),7.69–7.58(m,2H), 3.62–3.55(m,2H),3.29(d,J＝21.0Hz,8H),2.18(dd,J＝8.6,3.7Hz,1H),0.84(ddt,J＝10.7,4.9,2.9Hz, 4H).
MS(ESI+)m/z 427(M+H)+
实施例593：N-(7-(4-((5-甲基-2H-四唑-2-基)甲基)苯基)-3H-咪唑并[4,5-b]吡啶-5-基)环丙基甲酰胺的合成
Figure BDA0002455210850002042
MS(ESI+)m/z 375(M+H)+
实施例594：N-(7-(4-((5-甲基-1H-四唑-1-基)甲基)苯基)-3H-咪唑并[4,5-b]吡啶-5-基)环丙基甲酰胺的合成
Figure BDA0002455210850002043
MS(ESI+)m/z 375(M+H)+
实施例595：N-(4-(4-(((1,1-二氧化四氢噻吩-3-基)氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002044
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.61(s,1H),8.02(s,1H),7.74–7.65(m,2H),7.51(d,J ＝7.9Hz,2H),7.45–7.38(m,1H),6.58–6.46(m,1H),3.80(s,2H),3.48(s,1H),3.28–3.19(m,1H),3.05 (dt,J＝7.6,12.6Hz,1H),2.94(dd,J＝6.5,13.1Hz,1H),2.70(d,J＝23.9Hz,2H),2.30–2.23(m,1H),2.04 (dd,J＝7.2,13.5Hz,2H),0.88–0.78(m,4H)
MS(ESI+)m/z 425(M+H)+
实施例596：N-(4-(4-(((1,1-二氧化四氢-2H-噻喃-4-基)氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002051
1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),10.61(s,1H),8.02(s,1H),7.76–7.35(m,9H),6.65– 6.47(m,1H),3.78(s,1H),3.09(d,J＝53.8Hz,4H),2.01(d,J＝52.3Hz,5H),0.89–0.75(m,4H).
MS(ESI+)m/z 439(M+H)+
实施例597：N-(6-(4-(((4-氟苯基)氨基)甲基)苯基)-9H-嘌呤-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002052
1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.76(d,J＝7.9Hz,2H),8.42(s,1H),7.55(d,J＝8.1Hz, 2H),6.89(t,J＝8.7Hz,2H),6.58(dd,J＝8.8,4.5Hz,2H),6.24(t,J＝6.1Hz,1H),4.33(d,J＝6.1Hz,2H), 2.20(s,1H),0.91–0.79(m,4H).
MS(ESI+)m/z 403(M+H)+
实施例598：N-(6-(4-(((3-氟苯基)氨基)甲基)苯基)-9H-嘌呤-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002053
1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.72(d,J＝37.7Hz,2H),8.46(s,1H),7.56(d,J＝8.0 Hz,2H),7.05(q,J＝7.8Hz,2H),6.65(q,J＝9.8,8.1Hz,1H),6.44(d,J＝8.5Hz,1H),6.41–6.26(m,2H), 4.37(d,J＝6.1Hz,2H),2.19(s,1H),0.86–0.69(m,4H).
MS(ESI+)m/z 403(M+H)+
实施例599：N-(4-(1-(1-((三氟甲基)磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002054
步骤1)3-(4-(6-(环丙基甲酰氨基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)氮杂环丁烷-1-甲酸叔丁酯的合成
Figure BDA0002455210850002055
将2.5g(6.44mmol)合成的N-(4-氯-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺溶于DMF/H2O＝2:1溶液(50ml)中，然后将2.5g(7.1mmol)3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H- 吡唑-1-基)氮杂环丁烷-1-甲酸叔丁酯、0.8g(0.97mmol)Pd(dppf)Cl2和1.6g(7.7mmol)K3PO4添加到其中，并在80-90℃下搅拌2小时。一旦反应完成后，将所述混合物在室温下冷却，并向其中加入水和稀盐酸。之后，在pH4-5下使用乙酸乙酯进行萃取。然后，将从中萃取的溶液用无水硫酸镁干燥并减压浓缩，由此得到残余物。将残余物经硅胶柱色谱(正己烷/乙酸乙酯＝1:1)分离，并由此最终得到混合物，其中3-(4-(6-(环丙基甲酰氨基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑-1-基)氮杂环丁烷-1- 甲酸叔丁酯是主要产物。
MS(ESI+)m/z 577(M+H)+
步骤2)N-(4-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002061
将5g所述化合物，即3-(4-(6-(环丙基甲酰氨基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-4-基)-1H- 吡唑-1-基)氮杂环丁烷-1-甲酸叔丁酯溶于二氯甲烷(50mL)中，然后将TFA(5ml)添加到其中，并在室温下搅拌2小时。对于所述化合物，无单独分离方法而进行以下步骤：
MS(ESI+)m/z 477(M+H)+
步骤3)N-(1-对甲苯磺酰基-4-(1-(1-((三氟甲基)磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并 [2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002062
将合成的N-(4-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺(2g)溶于二氯甲烷(20mL)中，并且然后将Et3N(2当量，1.17mL)添加到其中并搅拌。在0℃下将三氟甲磺酰氯(1.5当量，1.06g)添加到其中并在室温下搅拌2小时，并且由此最终得到1.6g化合物，即N-(1-对甲苯磺酰基-4-(1-(1-((三氟甲基)磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺(41％，步骤3的滚动通过产出率(rolled throughput yield))。
MS(ESI+)m/z 609(M+H)+
步骤4)N-(4-(1-(1-((三氟甲基)磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002071
将合成的N-(1-对甲苯磺酰基-4-(1-(1-((三氟甲基)磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺溶于50mLMeOH/THF(2:1)中，然后向其中加入10mL2N氢氧化钠水溶液，并在30-40℃下搅拌4小时。一旦反应完成后，将所述混合物在室温下冷却，然后向其中加入稀盐酸水溶液，并且然后在pH中性下使用二氯甲烷进行萃取。然后，将从中萃取的溶液用无水硫酸镁干燥并减压浓缩，由此得到残余物。之后，对残余物应用制备TLC(DCM:MeOH＝30:1)方法。由此最终得到实施例599的目标化合物，即N-(4-(1-(1-((三氟甲基)磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H- 吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.53(s,1H),8.55(d,J＝9.1Hz,1H),8.20(s,1H),8.07 (s,1H),7.47–7.35(m,1H),6.82–6.70(m,1H),5.68–5.55(m,1H),4.71(dt,J＝7.2,15.1Hz,4H),2.06(d,J ＝18.0Hz,1H),0.88–0.76(m,4H).
MS(ESI+)m/z 455(M+H)+
实施例600至611
在下文的实施例600至611中，通过与实施例599所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例600：N-(4-(1-(氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002072
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.51(s,1H),8.48(s,1H),8.06(s,2H),7.37(s,1H), 6.73(s,1H),5.32(s,1H),4.04(s,2H),3.83(d,J＝10.2Hz,2H),2.00(s,3H),1.47(s,2H),0.84(s,4H).
MS(ESI+)m/z 323(M+H)+
实施例601：N-(4-(1-(1-(乙基磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002073
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.52(s,1H),8.50(s,1H),8.14(s,1H),8.06(s,1H), 7.38(s,1H),6.73(d,J＝3.5Hz,1H),5.41(p,J＝7.1Hz,1H),4.39(dd,J＝6.4,8.6Hz,2H),4.28(t,J＝8.2Hz, 2H),3.25(q,J＝7.4Hz,2H),2.07–1.99(m,1H),1.28(t,J＝7.3Hz,3H),0.81(dt,J＝3.3,15.8Hz,4H).
MS(ESI+)m/z 415(M+H)+
实施例602：N-(4-(1-(1-(丁基磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002081
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),10.53(d,J＝6.6Hz,1H),8.50(s,1H),8.10(d,J＝29.3 Hz,2H),7.38(s,1H),6.80–6.66(m,1H),5.41(s,1H),4.34(dq,J＝8.8,9.7,40.3Hz,4H),3.27–3.19(m, 2H),2.04(s,1H),1.71(d,J＝10.7Hz,2H),1.52–1.39(m,2H),1.03–0.89(m,4H),0.82(s,4H).
MS(ESI+)m/z 443(M+H)+
实施例603：N-(4-(1-(1-(甲基磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002082
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.53(s,1H),8.52(s,1H),8.10(d,J＝31.4Hz,2H), 7.38(s,1H),6.74(s,1H),5.50–5.31(m,1H),4.33(dd,J＝8.8,16.6Hz,4H),3.15(p,J＝6.0Hz,3H),2.03(s, 1H),0.83(d,J＝6.3Hz,4H).
MS(ESI+)m/z 401(M+H)+
实施例604：N-(4-(1-(1-(苯基磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002083
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.51(s,1H),8.21(s,1H),8.03–7.86(m,4H),7.76(q,J ＝8.2,14.4Hz,3H),7.36(s,1H),6.62(s,1H),5.24(s,1H),4.18(dt,J＝9.0,38.6Hz,4H),2.03(s,1H),0.88– 0.73(m,4H).
MS(ESI+)m/z 463(M+H)+
实施例605：N-(4-(1-(1-((3,4-二氟苯基)磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002084
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.51(s,1H),8.31(s,1H),7.98(d,J＝21.8Hz,2H), 7.75(d,J＝12.9Hz,2H),7.48(s,1H),7.36(s,1H),6.64(s,1H),5.23(s,1H),4.19(d,J＝24.7Hz,4H),3.96 (s,3H),2.02(s,1H),0.80(d,J＝15.3Hz,4H).
MS(ESI+)m/z 499(M+H)+
实施例606：N-(4-(1-(1-(环己基磺酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002085
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.52(s,1H),8.49(s,1H),8.11(d,J＝31.0Hz,2H), 7.44–7.30(m,1H),6.73(s,1H),5.40(d,J＝9.8Hz,1H),4.44–4.15(m,4H),3.11(s,1H),2.08(d,J＝12.9 Hz,3H),1.80(d,J＝11.5Hz,2H),1.64(s,1H),1.27(dd,J＝35.0,51.6Hz,7H),0.81(d,J＝16.2Hz,4H).
MS(ESI+)m/z 469(M+H)+
实施例607：N-(4-(1-(1-(甲基磺酰基)哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002091
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.50(s,1H),8.43(s,1H),8.02(d,J＝16.4Hz,2H), 7.36(s,1H),6.75(s,1H),4.44(s,1H),3.70(d,J＝11.9Hz,2H),2.95(d,J＝6.9Hz,5H),2.27–1.98(m,6H), 0.86–0.75(m,4H).
MS(ESI+)m/z 429(M+H)+
实施例608：N-(4-(1-(1-(乙基磺酰基)哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002092
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.49(s,1H),8.42(s,1H),8.02(d,J＝16.8Hz,2H), 7.42–7.32(m,1H),6.75(d,J＝3.2Hz,1H),4.44(d,J＝12.9Hz,1H),3.74(d,J＝12.2Hz,2H),3.07(ddd,J ＝8.6,13.4,31.8Hz,4H),2.20–1.96(m,5H),1.24(t,J＝7.3Hz,3H),0.80(d,J＝17.7Hz,4H).
MS(ESI+)m/z 443(M+H)+
实施例609：N-(4-(1-(1-((三氟甲基)磺酰基)哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002093
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.50(s,1H),8.41(d,J＝34.0Hz,1H),8.03(d,J＝12.2 Hz,2H),7.36(s,1H),6.75(s,1H),3.94(d,J＝13.2Hz,2H),2.90(d,J＝12.4Hz,1H),2.26–1.99(m,6H), 0.86–0.76(m,4H).
MS(ESI+)m/z 483(M+H)+
实施例610：N-(4-(1-(1-(2-氰基乙酰基)氮杂环丁烷-3-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002094
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.52(s,1H),8.56(s,1H),8.12(s,1H),8.07(s,1H), 7.38(t,J＝3.0Hz,1H),6.77–6.71(m,1H),5.41(t,J＝6.7Hz,1H),4.64(t,J＝8.6Hz,1H),4.56–4.49(m, 1H),4.41(t,J＝9.3Hz,1H),4.28(dd,J＝10.2,5.4Hz,1H),3.84(d,J＝3.5Hz,2H),2.04–1.96(m,1H),0.84 –0.77(m,4H).
MS(ESI+)m/z 390(M+H)+
实施例611：N-(4-(1-(1-(氰基甲基)哌啶-4-基)-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002101
1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),10.49(s,1H),8.39(s,1H),8.01(d,J＝19.9Hz,3H), 7.39–7.30(m,1H),6.73(s,1H),4.44–4.18(m,2H),2.93(d,J＝11.1Hz,4H),2.37(s,3H),2.09(d,J＝8.3 Hz,7H),0.80(d,J＝18.3Hz,7H).
MS(ESI+)m/z 390(M+H)+
实施例612：N-(4-(1-(3-(氰基甲基)氧杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850002102
将1.0g(3.5mmol)以上合成的N-(4-(1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺溶于乙腈中，然后将0.4g(3.9mmol)2-(氧杂环丁烷-3-亚基)乙腈和1.6g(10.5mmol)DBU添加到其中，并在30-40℃下搅拌16小时。一旦反应完成后，将所述混合物在室温下冷却，然后向其中加入水，并且然后使用乙酸乙酯进行萃取。之后，将从中萃取的溶液用无水硫酸镁干燥并减压浓缩，由此得到残余物。将残余物经硅胶柱色谱(DCM/MeOH＝30:1)分离，并由此最终得到N-(4-(1-(3-(氰基甲基)氧杂环丁烷-3- 基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
MS(ESI+)m/z 378(M+H)+
实施例613至628
在下文的实施例613至628中，通过与实施例612所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例613：N-(4-(1-(3-(氰基甲基)氧杂环丁烷-3-基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002103
1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.54(s,1H),7.81(s,1H),7.35–7.26(m,1H),6.46(d,J ＝3.8Hz,1H),6.09(s,1H),4.64(d,J＝6.6Hz,1H),4.53(d,J＝6.6Hz,1H),4.43(t,J＝7.0Hz,2H),3.27(d, J＝18.0Hz,1H),3.15(d,J＝17.0Hz,1H),3.08(d,J＝3.8Hz,2H),2.96(s,1H),2.76–2.65(m,2H),2.40(dd, J＝4.6,11.2Hz,1H),2.02(s,1H),0.91(d,J＝6.9Hz,3H),0.81–0.76(m,4H).
MS(ESI+)m/z 392(M+H)+
实施例614：3-(氰基甲基)-3-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,6-二氢吡啶 -1(2H)-基)氮杂环丁烷-1-甲酸叔丁酯的合成
Figure BDA0002455210850002104
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.53(s,1H),7.85(s,1H),7.33(t,J＝3.0Hz,1H),6.53 (dd,J＝3.6,1.8Hz,1H),6.31(d,J＝3.9Hz,1H),3.83(d,J＝35.4Hz,4H),3.29–3.21(m,2H),3.03(s,2H), 2.72–2.62(m,2H),2.55(s,2H),2.08–1.96(m,1H),1.39(s,9H),0.82-0.75(m,4H).
MS(ESI+)m/z 477(M+H)+
实施例615：N-(4-(1-(3-(氰基甲基)氮杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850002111
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),10.55(s,1H),7.86(s,1H),7.34(t,J＝3.1Hz,1H),6.53 (d,J＝2.6Hz,1H),6.35(s,1H),3.89(d,J＝10.4Hz,2H),3.76(d,J＝10.4Hz,2H),3.09(s,2H),2.75(t,J＝ 5.4Hz,2H),2.58(s,2H),2.02(s,1H),0.87–0.73(m,4H).
MS(ESI+)m/z 377(M+H)+
实施例616：N-(4-(1-(3-(氰基甲基)-1-(乙基磺酰基)氮杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002112
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.53(s,1H),7.86(s,1H),7.33(t,J＝3.0Hz,1H),6.54 (t,J＝2.7Hz,1H),6.33(d,J＝3.4Hz,1H),4.00(d,J＝8.2Hz,2H),3.75(d,J＝8.2Hz,2H),3.28(d,J＝3.3 Hz,2H),3.17(q,J＝7.3Hz,2H),3.11(s,2H),2.70(t,J＝5.4Hz,2H),2.55(s,2H),2.06–1.96(m,1H),1.25 (t,J＝7.3Hz,3H),0.82-0.75(m,4H).
MS(ESI+)m/z 469(M+H)+
实施例617：N-(4-(1-(3-(氰基甲基)-1-(异丙基磺酰基)氮杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4-基)-1H- 吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002113
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.53(s,1H),7.85(s,1H),7.36–7.29(m,1H),6.54(dd, J＝3.5,1.9Hz,1H),6.32(s,1H),4.01(d,J＝7.9Hz,2H),3.72(d,J＝7.9Hz,2H),3.24(s,2H),3.10(s,2H), 2.67(d,J＝6.0Hz,2H),2.02(s,1H),1.26(d,J＝6.8Hz,6H),1.17(s,1H),0.80(q,J＝3.4Hz,4H).
MS(ESI+)m/z 483(M+H)+
实施例618：N-(4-(1-(3-(氰基甲基)-1-((3-氰基丙基)磺酰基)氮杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4- 基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002114
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.53(s,1H),7.86(s,1H),7.34(t,J＝2.9Hz,1H),6.54 (dt,J＝5.0,2.5Hz,1H),6.32(s,1H),4.00(s,1H),3.78(d,J＝8.2Hz,1H),3.29(d,J＝6.3Hz,2H),3.14(d,J ＝12.4Hz,2H),2.71(d,J＝7.1Hz,2H),2.66(t,J＝7.3Hz,2H),2.56(s,2H),2.02(d,J＝7.5Hz,2H),0.82– 0.74(m,4H).
MS(ESI+)m/z 508(M+H)+
实施例619：N-(4-(1-(3-(氰基甲基)-1-((三氟甲基)磺酰基)氮杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4- 基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002121
1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),10.54(s,1H),7.86(s,1H),7.34(t,J＝3.0Hz,1H),6.54 (dd,J＝3.6,1.9Hz,1H),6.32(d,J＝3.8Hz,1H),4.35–4.18(m,4H),3.29(d,J＝3.4Hz,2H),3.15(s,2H), 2.71(t,J＝5.5Hz,2H),2.57(s,2H),2.01(d,J＝7.5Hz,1H),0.83–0.77(m,4H).
MS(ESI+)m/z 509(M+H)+
实施例620：N-(4-(1-(3-(氰基甲基)-1-(哌啶-4-基)氮杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002122
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),11.00(s,1H),9.45(s,1H),8.77(s,1H),7.80(s,1H), 7.39(s,1H),6.59(s,1H),6.39(s,1H),4.15(d,J＝10.7Hz,2H),3.70–3.58(m,2H),3.56(s,1H),3.54–3.46 (m,2H),3.46–3.33(m,2H),2.97(s,2H),2.84(dd,J＝22.8,10.4Hz,2H),2.67(s,2H),2.18–1.93(m,3H), 1.88–1.68(m,2H),0.83(m,4H).
MS(ESI+)m/z 460(M+H)+
实施例621：N-(4-(1-(3-(氰基甲基)-1-(1-(4-(三氟甲基)噻唑-2-羰基)哌啶-4-基)氮杂环丁烷-3- 基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002123
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.52(s,1H),8.77(s,1H),7.85(s,1H),7.38–7.30(m, 1H),6.53(s,1H),6.33(s,1H),4.47-4.44(m,1H),3.98-3.97(m,1H),3.83-3.78(m,1H),3.31-3.21(m,4H), 3.15-3.02(m,4H),2.72(m,2H),2.03–1.96(m,1H),1.78-1.69(m,2H),1.38-1.26(m,2H)0.79(dd,J＝9.4, 6.2Hz,4H).
MS(ESI+)m/z 639(M+H)+
实施例622：N-(4-(1-(1-(1-(2-氰基乙酰基)哌啶-4-基)-3-(氰基甲基)氮杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002124
1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.53(s,1H),7.84(s,1H),7.33(d,J＝3.3Hz,1H),6.53 (s,1H),6.32(s,1H),4.02(s,2H),3.90-3.18(m,1H),3.52(m,1H),3.30–3.18(m,4H),3.16-2.93(m,5H), 2.80-2.63(m,2H),2.43-2.25(m,2H),2.07-1.93(m,1H),1.71-1.53(m,2H),1.19-1.05(m,2H),0.85- 0.77(m,4H).
MS(ESI+)m/z 527(M+H)+
实施例623：N-(4-(1-(3-(氰基甲基)-1-((4-氟苯基)磺酰基)氮杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4- 基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002131
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.52(s,1H),7.98–7.91(m,2H),7.81(s,1H),7.50– 7.42(m,2H),7.33(dd,J＝3.5,2.4Hz,1H),6.48(dd,J＝3.5,1.9Hz,1H),6.18(d,J＝3.2Hz,1H),3.76(s, 4H),3.07(d,J＝3.5Hz,2H),2.96(s,2H),2.33(s,2H),2.01(d,J＝4.9Hz,1H),0.79(dt,J＝11.0,3.5Hz, 4H).
MS(ESI+)m/z 535(M+H)+
实施例624：3-(氰基甲基)-3-(4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,6-二氢吡啶 -1(2H)-基)-N-(2,2,2-三氟乙基)氮杂环丁烷-1-甲酰胺的合成
Figure BDA0002455210850002132
1H NMR(400MHz,DMSO-d6)δ11.42(d,J＝2.6Hz,1H),10.53(s,1H),7.85(s,1H),7.33(dd,J＝3.5, 2.5Hz,1H),6.53(dd,J＝3.6,1.9Hz,1H),6.34(d,J＝3.3Hz,1H),4.25(d,J＝9.2Hz,1H),4.12(d,J＝9.1 Hz,1H),3.93(d,J＝10.3Hz,1H),3.83(d,J＝10.2Hz,1H),3.41(dd,J＝11.3,3.4Hz,2H),3.10(s,2H),2.75 –2.66(m,2H),2.55(d,J＝7.1Hz,2H),2.01(q,J＝8.5,6.4Hz,1H),0.79(ddd,J＝11.3,6.3,2.6Hz,4H).
MS(ESI+)m/z 502(M+H)+
实施例625：N-(4-(1-(3-(氰基甲基)-1-(3,3,3-三氟丙酰基)氮杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4- 基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002133
1H NMR(400MHz,DMSO-d6)δ11.44–11.35(m,1H),10.53(s,1H),7.85(s,1H),7.36–7.27(m,1H), 7.17(t,J＝6.3Hz,1H),6.55(dd,J＝3.9,2.1Hz,1H),6.33(d,J＝3.6Hz,1H),3.88(d,J＝8.7Hz,2H),3.83– 3.72(m,4H),3.08(s,2H),2.69(d,J＝5.7Hz,2H),2.56(s,2H),2.02–1.97(m,1H),0.81–0.75(m,4H).
MS(ESI+)m/z 487(M+H)+
实施例626：N-(4-(1-(3-(氰基甲基)-1-(乙基磺酰基)氮杂环丁烷-3-基)-3-甲基-1,2,3,6-四氢吡啶-4- 基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002134
1H NMR(400MHz,氯仿-d)δ11.40(s,1H),10.54(s,1H),7.80(s,1H),7.36–7.25(m,1H),6.45(dd,J ＝1.9,3.5Hz,1H),6.07(s,1H),4.01(dd,J＝8.3,13.4Hz,1H),3.90(d,J＝8.3Hz,1H),3.73(dd,J＝8.1,11.7 Hz,2H),3.23–3.07(m,4H),2.95(s,1H),2.77–2.65(m,1H),2.07(s,3H),1.99(d,J＝6.5Hz,1H),1.25–1.21(m,3H),0.82–0.73(m,4H).
MS(ESI+)m/z 483(M+H)+
实施例627：(S)-N-(4-(1-(3-(氰基甲基)-1-(乙基磺酰基)氮杂环丁烷-3-基)-3-甲基-1,2,3,6-四氢吡啶-4- 基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002141
MS(ESI+)m/z 483(M+H)+
实施例628：(S)-N-(4-(1-(3-(氰基甲基)-1-((三氟甲基)磺酰基)氮杂环丁烷-3-基)-3-甲基-1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002142
/>
MS(ESI+)m/z 523(M+H)+
实施例629至644
在下文的实施例629至644中，通过与实施例1所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例629：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基乙磺酸酯的合成
Figure BDA0002455210850002143
MS(ESI+)m/z 386(M+H)+
实施例630：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基4-氟苯磺酸酯的合成
Figure BDA0002455210850002144
MS(ESI+)m/z 452(M+H)+
实施例631：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基丙-1-磺酸酯的合成
Figure BDA0002455210850002145
1HNMR(400MHz,DMSO-d6)δ11.59(s,1H),10.66(s,1H),8.05(s,1H),7.82(d,J＝8.1Hz,2H),7.50 (d,J＝8.1Hz,2H),7.44(s,1H),6.55(s,1H),3.58(t,J＝7.6Hz,2H),2.05(s,1H),1.89(q,J＝8.0,7.6Hz, 2H),1.06(t,J＝7.5Hz,3H),0.89–0.74(m,4H).
MS(ESI+)m/z 400(M+H)+
实施例632：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基丁-1-磺酸酯的合成
Figure BDA0002455210850002151
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),10.66(s,1H),8.04(s,1H),7.91–7.74(m,2H),7.50(d,J ＝8.3Hz,2H),7.44(t,J＝3.2Hz,1H),6.54(s,1H),3.67–3.53(m,2H),2.05(s,1H),1.84(s,2H),1.48(q,J＝ 7.6Hz,2H),0.93(t,J＝7.3Hz,3H),0.86–0.72(m,4H).
MS(ESI+)m/z 414(M+H)+
实施例633：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基丙-2-磺酸酯的合成
Figure BDA0002455210850002152
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),10.66(s,1H),8.04(s,1H),7.82(d,J＝8.1Hz,2H),7.49 (d,J＝8.1Hz,2H),7.44(s,1H),6.60–6.50(m,1H),3.87–3.73(m,1H),2.05(s,1H),1.47(d,J＝6.5Hz, 6H),0.89–0.72(m,4H).
MS(ESI+)m/z 400(M+H)+
实施例634：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基环己磺酸酯的合成
Figure BDA0002455210850002153
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),10.66(s,1H),8.04(s,1H),7.81(d,J＝8.3Hz,2H),7.48 (d,J＝8.3Hz,2H),7.44(s,1H),6.54(s,1H),3.61(s,1H),2.24(d,J＝12.1Hz,2H),2.05(s,1H),1.84(d,J＝ 12.8Hz,2H),1.70–1.53(m,3H),1.40(d,J＝13.4Hz,2H),1.24(t,J＝12.9Hz,1H),0.87–0.74(m,4H).
MS(ESI+)m/z 440(M+H)+
实施例635：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基3-氟丙-1-磺酸酯的合成
Figure BDA0002455210850002154
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.66(s,1H),8.05(s,1H),7.86–7.76(m,2H),7.52(d,J ＝8.2Hz,2H),7.44(d,J＝3.4Hz,1H),6.54(s,1H),4.61(dt,J＝47.2,6.0Hz,2H),3.70(t,J＝7.7Hz,2H), 2.27(d,J＝25.7Hz,3H),2.05(s,1H),0.87–0.75(m,4H).
MS(ESI+)m/z 418(M+H)+
实施例636：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基丙-2-烯-1-磺酸酯的合成
Figure BDA0002455210850002161
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.66(s,1H),8.05(s,1H),7.82(d,J＝8.3Hz,2H),7.57 –7.47(m,2H),7.45–7.38(m,1H),6.60–6.45(m,1H),5.95(ddt,J＝17.2,10.3,6.9Hz,1H),5.58(dd,J＝ 31.7,13.6Hz,2H),4.44(d,J＝7.2Hz,2H),2.04(d,J＝8.2Hz,1H),0.82(dt,J＝10.0,5.6Hz,4H).
MS(ESI+)m/z 398(M+H)+
实施例637：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基环己基甲磺酸酯的合成
Figure BDA0002455210850002162
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),10.66(s,1H),8.04(s,1H),7.82(d,J＝8.2Hz,2H),7.50 (d,J＝8.2Hz,2H),7.44(s,1H),6.54(s,1H),3.51(d,J＝6.5Hz,2H),2.04(s,2H),1.92(d,J＝12.8Hz,2H), 1.69(d,J＝11.0Hz,2H),1.63(s,1H),1.26(t,J＝12.6Hz,2H),1.20–1.07(m,3H),0.80(d,J＝11.1Hz,4H).
MS(ESI+)m/z 454(M+H)+
实施例638：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基(四氢呋喃-3-基)甲磺酸酯的合成
Figure BDA0002455210850002163
1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),10.66(s,1H),8.04(s,1H),7.82(d,J＝7.9Hz,2H),7.52 (d,J＝8.2Hz,2H),7.44(s,1H),6.54(s,1H),3.92(t,J＝7.8Hz,1H),3.77(d,J＝7.1Hz,3H),3.68(d,J＝8.0 Hz,1H),2.17(s,1H),2.05(s,1H),1.76(d,J＝11.5Hz,1H),1.15–1.03(m,1H),0.82(s,4H).
MS(ESI+)m/z 442(M+H)+
实施例639：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基3-氰基丙-1-磺酸酯的合成
Figure BDA0002455210850002164
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.66(s,1H),8.05(s,1H),7.83(d,J＝8.2Hz,2H),7.54 (d,J＝8.3Hz,2H),7.44(d,J＝3.7Hz,1H),6.54(s,1H),3.69(t,J＝7.5Hz,2H),2.73(t,J＝7.3Hz,2H),2.21 (q,J＝7.7Hz,2H),2.05(s,1H),0.85–0.76(m,4H).
MS(ESI+)m/z 425(M+H)+
实施例640：4-(1-(3-氰基丙基)-6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)苯基3-氰基丙-1-磺酸酯的合成
Figure BDA0002455210850002171
1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),8.28(s,1H),7.82(d,J＝8.3Hz,2H),7.69(d,J＝4.1Hz, 1H),7.57(d,J＝8.2Hz,2H),6.86(s,1H),4.12(d,J＝9.1Hz,2H),3.71(d,J＝8.0Hz,2H),2.72(d,J＝7.3Hz, 2H),2.63(d,J＝5.1Hz,2H),2.20(s,2H),1.92(s,1H),1.83(t,J＝7.2Hz,2H),0.85(d,J＝6.5Hz,4H).
MS(ESI+)m/z 492(M+H)+
实施例641：N-(4-(4-((4-氟苄基)氧基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002172
1H NMR(400MHz,甲醇-d4)δ11.49(s,1H),10.58(s,1H),7.99(s,1H),7.75–7.63(m,2H),7.55(dd,J ＝5.6,8.4Hz,2H),7.38(t,J＝2.9Hz,1H),7.29–7.13(m,5H),6.52(dd,J＝1.7,3.5Hz,1H),2.13–1.87(m, 2H),0.82(td,J＝6.2,12.0,14.1Hz,5H).
MS(ESI+)m/z 402(M+H)+
实施例642：N-(4-(4-(2-吗啉代乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002173
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.58(s,1H),7.99(s,1H),7.69–7.61(m,2H),7.38(dd, J＝2.5,3.5Hz,1H),7.17–7.07(m,2H),6.52(dd,J＝1.9,3.5Hz,1H),4.17(t,J＝5.7Hz,2H),3.66–3.53(m, 4H),2.73(t,J＝5.7Hz,2H),2.09–1.99(m,1H),1.24(d,J＝3.6Hz,3H),0.85–0.73(m,4H).
MS(ESI+)m/z 407(M+H)+
实施例643：N-(4-(4-丁氧基苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002174
1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.57(s,1H),7.99(s,1H),7.70–7.60(m,2H),7.38(d,J ＝3.5Hz,1H),7.13–7.05(m,2H),6.53(d,J＝3.5Hz,1H),4.05(t,J＝6.4Hz,2H),2.04(s,1H),1.78–1.67 (m,2H),1.47(h,J＝7.3Hz,2H),0.96(t,J＝7.4Hz,3H),0.87–0.75(m,4H).
MS(ESI+)m/z 350(M+H)+
实施例644：N-(6-(4-((6-氰基吡啶-3-基)甲氧基)苯基)-9H-嘌呤-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002181
1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.90(d,J＝2.0Hz,1H),8.84(d,J＝8.8Hz,2H),8.45(s, 1H),8.18(dd,J＝8.1,2.1Hz,1H),8.10(d,J＝7.9Hz,1H),7.27(d,J＝9.0Hz,2H),5.38(s,2H),2.20–2.13 (m,1H),0.84(tt,J＝8.0,3.1Hz,4H).
MS(ESI+)m/z 412(M+H)+
实施例645：N-(4-(4-(乙基磺酰氨基)环己基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002182
将1.0g以上合成的N-(4-(4-氨基环己-1-烯-1-基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺溶于20mL MeOH中，然后将0.1g Pd/C添加到其中，并在室温下在氢气下搅拌16小时。一旦反应完成后，将所述混合物通过硅藻土过滤，并用MeOH洗涤。对剩余溶液进行浓缩，并由此最终得到产物，即N-(4-(4-氨基环己基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
然后，将作为起始材料的得到的N-(4-(4-氨基环己基)-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺通过与实施例1中相同的方法进行处理，并由此得到最终产物，即N-(4-(4-(乙基磺酰氨基) 环己基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
MS(ESI+)m/z 391(M+H)+
实施例646至659
在下文的实施例646至659中，通过与实施例645所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例646：N-(4-(8-(乙基磺酰基)-8-氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002183
MS(ESI+)m/z 403(M+H)+
实施例647：N-(4-(8-(环丙基磺酰基)-8-氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002184
MS(ESI+)m/z 415(M+H)+
实施例648：N-(4-(8-((3-氟丙基)磺酰基)-8-氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002191
MS(ESI+)m/z 435(M+H)+
实施例649：N-(4-(8-((3,4-二氟苯基)磺酰基)-8-氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002192
MS(ESI+)m/z 487(M+H)+
实施例650：N-(4-(8-(环丙基羰基)-8-氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002193
MS(ESI+)m/z 379(M+H)+
实施例651：N-(4-(8-戊酰基-8-氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002194
MS(ESI+)m/z 395(M+H)+
实施例652：N-(4-(1-(2-氰基乙酰基)哌啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002195
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),10.49(s,1H),7.79(s,1H),7.32–7.26(m,1H),6.52(dd, J＝3.5,1.8Hz,1H),4.54–4.46(m,1H),4.10(q,J＝18.8Hz,2H),3.78(d,J＝13.8Hz,1H),3.28–3.14(m, 3H),2.78(t,J＝12.6Hz,1H),2.05–1.96(m,1H),1.82(dtt,J＝22.0,13.6,7.6Hz,3H),1.60–1.47(m,1H), 0.78(m,4H).
MS(ESI+)m/z 352(M+H)+
实施例653：N-丁基-4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)哌啶-1-甲酰胺的合成
Figure BDA0002455210850002201
MS(ESI+)m/z 384(M+H)+
实施例654：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-N-(2,2,2-三氟乙基)哌啶-1-甲酰胺的合成
Figure BDA0002455210850002202
MS(ESI+)m/z 410(M+H)+
实施例655：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3-羟基哌啶-1-甲酸叔丁酯的合成
Figure BDA0002455210850002203
MS(ESI+)m/z 401(M+H)+
实施例656：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3-氟哌啶-1-甲酸叔丁酯的合成
Figure BDA0002455210850002204
MS(ESI+)m/z 403(M+H)+
实施例657：N-(4-(8-(乙基硫代氨基甲酰基)-8-氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002205
MS(ESI+)m/z 398(M+H)+
实施例658：N-(4-(1-(乙基硫代氨基甲酰基)哌啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002211
MS(ESI+)m/z 372(M+H)+
实施例659：N-(4-(1-(丁基硫代氨基甲酰基)哌啶-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002212
1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),10.51(s,1H),7.78(s,1H),7.66(t,J＝5.4Hz,1H),7.29 (t,J＝2.7Hz,1H),6.48(dd,J＝1.8,3.5Hz,1H),4.89–4.75(m,2H),3.51(q,J＝6.6Hz,2H),3.23(t,J＝11.8 Hz,1H),3.09(t,J＝12.9Hz,2H),1.99(d,J＝7.8Hz,1H),1.83(d,J＝12.9Hz,2H),1.69–1.48(m,4H),1.29 (h,J＝7.4Hz,2H),0.90(t,J＝7.3Hz,3H),0.83–0.72(m,4H).
MS(ESI+)m/z 400(M+H)+
实施例660：N-(4-(4-(甲基磺酰基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002213
将1.0g(2.6mmol)以上合成的N-(4-氯-1-对甲苯磺酰基-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺溶于BuOH中，然后将0.6g(3.9mmol)1-(甲基磺酰基)哌嗪和1g(5.2mmol)DIPEA添加到其中，并在 120-130℃下搅拌3小时。一旦反应完成后，将所述混合物在室温下冷却，然后向其中加入水，并且然后使用乙酸乙酯进行萃取。之后，将从中萃取的溶液用无水硫酸镁干燥并减压浓缩，由此得到残余物。将残余物经硅胶柱色谱(DCM/MeOH＝30:1)分离并浓缩。将合成的材料溶于MeOH/THF(1:1)溶液中，然后向其中加入2N氢氧化钠水溶液，并在30-40℃下搅拌4小时。一旦反应完成后，将所述混合物冷却至室温，并在搅拌的同时向其中加入饱和氯化铵水溶液。滤出产生的固体，并由此最终得到产物，即 N-(4-(4-(甲基磺酰基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺。
MS(ESI+)m/z 364(M+H)+
实施例661至704
在下文的实施例661至704中，通过与实施例661所示相同的方法合成相应的化合物，或者在考虑反应式1以及要制备的化合物的结构的情况下，通过适当的反应物制备相应的化合物。
实施例661：N-(4-(8-(甲基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002214
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),10.32(s,1H),7.35(s,1H),7.11(t,J＝3.0Hz,1H),6.46 (dd,J＝3.7,2.0Hz,1H),4.30(d,J＝4.0Hz,2H),3.80(d,J＝10.3Hz,2H),3.08(d,J＝11.9Hz,2H),3.04(s, 3H),1.99(s,3H),1.86(d,J＝7.4Hz,2H),0.82–0.71(m,4H).
MS(ESI+)m/z 390(M+H)+
实施例662：N-(4-(4-(((1-氰基环丙基)甲基)磺酰基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002221
MS(ESI+)m/z 429(M+H)+
实施例663：N-(4-(4-((3-氟丙基)磺酰基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002222
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),10.39(s,1H),7.43(s,1H),7.16(s,1H),6.43(s,1H), 4.61(t,J＝6.0Hz,1H),4.49(t,J＝6.0Hz,1H),3.60(s,1H),3.40(d,J＝6.3Hz,5H),3.24–3.17(m,2H), 2.15–1.98(m,3H),1.76(s,1H),0.78(dd,J＝6.1,11.2Hz,4H).
MS(ESI+)m/z 410(M+H)+
实施例664：N-(4-(8-((3-氰基丙基)磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850002223
/>
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.31(s,1H),7.36(s,1H),7.17–7.05(m,1H),6.46(dd, J＝1.9,3.6Hz,1H),4.31(s,2H),3.80(d,J＝11.6Hz,2H),3.27(d,J＝7.7Hz,2H),3.11(d,J＝11.5Hz,2H), 2.72–2.64(m,2H),2.04(q,J＝7.4Hz,3H),1.89(s,2H),0.84–0.72(m,4H).
MS(ESI+)m/z 443(M+H)+
实施例665：N-(4-(8-(((1-(氰基甲基)环丙基)甲基)磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-1H-吡咯并 [2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002224
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),10.31(s,1H),7.35(s,1H),7.11(dd,J＝2.5,3.6Hz,1H), 6.46(dd,J＝2.0,3.6Hz,1H),4.33(s,2H),3.84–3.69(m,2H),3.12(d,J＝11.8Hz,2H),2.83(s,2H),2.00(s, 1H),1.89(d,J＝3.7Hz,2H),0.88–0.81(m,2H),0.76(ddt,J＝3.0,5.1,12.9Hz,4H),0.71–0.65(m,2H).
MS(ESI+)m/z 469(M+H)+
实施例666：N-(4-(8-((4,4,4-三氟丁基)磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶 -6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002231
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),10.31(s,1H),7.35(s,1H),7.11(dd,J＝2.5,3.6Hz,1H), 6.46(dd,J＝2.0,3.6Hz,1H),4.33(s,2H),3.84–3.69(m,2H),3.12(d,J＝11.8Hz,2H),2.83(s,2H),2.00(s, 1H),1.89(d,J＝3.7Hz,2H),0.88–0.81(m,2H),0.76(ddt,J＝3.0,5.1,12.9Hz,4H),0.71–0.65(m,2H).
MS(ESI+)m/z 486(M+H)+
实施例667：N-(4-(8-(((1-氰基环丙基)甲基)磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b] 吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002232
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.30(s,1H),7.35(s,1H),7.11(dd,J＝2.4,3.6Hz,1H), 6.45(dd,J＝1.9,3.6Hz,1H),4.68(s,1H),4.40–4.28(m,1H),3.85–3.75(m,1H),3.65(d,J＝11.2Hz,1H), 3.04(dd,J＝11.3,42.2Hz,2H),2.83–2.57(m,2H),1.98(d,J＝7.0Hz,1H),1.97–1.81(m,4H),1.24–1.17 (m,2H),1.02–0.90(m,2H),0.82–0.70(m,4H).
MS(ESI+)m/z 455(M+H)+
实施例668：N-(4-(4-(丙基磺酰基)哌嗪-1-基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002233
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),10.05(s,1H),7.09(d,J＝3.6Hz,1H),6.57(d,J＝3.6Hz, 1H),4.02–3.90(m,4H),3.28(s,4H),3.08–3.01(m,2H),2.18(s,1H),1.70(q,J＝7.5Hz,2H),0.98(t,J＝ 7.4Hz,3H),0.81–0.72(m,4H).
MS(ESI+)m/z 393(M+H)+
实施例669：N-(4-(8-(乙基磺酰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002234
MS(ESI+)m/z 405(M+H)+
实施例670：(S)-N-(4-(3-(丙基磺酰氨基)吡咯烷-1-基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002241
1H NMR(400MHz,DMSO-d6)δ11.44(s,1H),9.87(s,1H),7.49(d,J＝6.4Hz,1H),7.06–6.95(m,1H), 6.48(s,1H),4.07–3.57(m,7H),3.06(dd,J＝6.4,9.1Hz,2H),2.23(s,1H),1.97(s,1H),1.68(q,J＝7.6Hz, 2H),1.17(s,2H),0.98(t,J＝7.4Hz,3H).
MS(ESI+)m/z 393(M+H)+
实施例671：(S)-N-(4-(3-(烯丙基磺酰氨基)吡咯烷-1-基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002242
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),9.89(s,1H),7.62(s,1H),7.05–6.97(m,1H),6.53– 6.42(m,1H),5.89–5.74(m,4H),5.40(t,J＝13.6Hz,3H),3.94–3.85(m,7H),2.23(s,1H),1.94(d,J＝28.2 Hz,1H),0.80–0.73(m,4H).
MS(ESI+)m/z 391(M+H)+
实施例672：(S)-N-(4-(3-(N-甲基乙基磺酰氨基)吡咯烷-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002243
1H NMR(400MHz,DMSO-d6)δ10.97(s,1H),10.17(s,1H),7.09–6.94(m,2H),6.54(dd,J＝3.6,1.9 Hz,1H),4.52(p,J＝8.0Hz,1H),3.73(t,J＝8.9Hz,2H),3.56(q,J＝8.2Hz,2H),3.22–3.09(m,2H),2.82(s, 3H),2.18(q,J＝8.2,7.7Hz,2H),1.99(s,1H),1.22(t,J＝7.3Hz,3H),0.84–0.63(m,4H).
MS(ESI+)m/z 392(M+H)+
实施例673：N-(4-(4-(吗啉代磺酰基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002244
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),10.39(s,1H),7.43(s,1H),7.20–7.06(m,1H),6.43(dd, J＝1.9,3.6Hz,1H),3.63(t,J＝4.6Hz,4H),3.16(d,J＝5.1Hz,8H),2.00(s,1H),0.83-075(m,4H).
MS(ESI+)m/z 435(M+H)+
实施例674：N-(4-(4-(N,N-二甲基氨磺酰基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002251
1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),10.39(s,1H),7.43(s,1H),7.15(t,J＝3.0Hz,1H),6.43 (dd,J＝1.9,3.6Hz,1H),3.17(d,J＝5.2Hz,8H),2.81(s,6H),2.00(s,1H),0.85–0.70(m,4H).
MS(ESI+)m/z 393(M+H)+
实施例675：N-(4-(4-(2-氰基乙酰氨基)哌啶-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002252
MS(ESI+)m/z 367(M+H)+
实施例676：N-(4-(4-(2-氰基乙酰基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002253
1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),10.35(s,1H),7.40(s,1H),7.14(t,J＝3.0Hz,1H),6.44 (dd,J＝1.9,3.6Hz,1H),4.10(s,2H),3.66(s,2H),3.56(s,2H),3.38(s,4H),2.08(s,3H),2.00(s,1H),0.82– 0.73(m,4H).
MS(ESI+)m/z 353(M+H)+
实施例677：N-(4-(8-(2-氰基乙酰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002254
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.33(s,1H),7.36(s,1H),7.15–7.09(m,1H),6.45(dd, J＝3.8,2.0Hz,1H),4.64(s,1H),4.33(d,J＝6.5Hz,1H),4.09(d,J＝4.5Hz,2H),3.81(d,J＝11.4Hz,1H), 3.65(d,J＝11.6Hz,1H),3.16(d,J＝11.8Hz,1H),2.98(d,J＝11.4Hz,1H),2.00(q,J＝7.2Hz,2H),1.90(d, J＝5.5Hz,1H),1.87(s,2H),0.82–0.72(m,4H).
MS(ESI+)m/z 379(M+H)+
实施例678：N-(4-(3-(2-氰基乙酰基)-3,8-二氮杂双环[3.2.1]辛-8-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002261
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.33(s,1H),7.39(s,1H),7.17–7.09(m,1H),6.50(dd, J＝1.9,3.6Hz,1H),4.61–4.46(m,2H),4.18(d,J＝18.9Hz,1H),4.10–3.98(m,2H),3.87(d,J＝18.9Hz, 1H),1.97–1.84(m,3H),1.27–1.14(m,4H),0.77(ddt,J＝3.1,5.2,10.9Hz,4H).
MS(ESI+)m/z 379(M+H)+
实施例679：N-(4-((1S,4S)-5-(2-氰基乙酰基)-2,5-二氮杂双环[2.2.1]庚-2-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850002262
1H NMR(400MHz,DMSO-d6)δ11.01(d,J＝8.5Hz,1H),10.19(s,1H),7.09(s,1H),7.02(ddd,J＝6.6, 3.6,2.4Hz,1H),6.43(ddd,J＝13.9,3.5,1.9Hz,1H),4.84–4.61(m,2H),4.09–4.05(m,1H),4.04–3.97(m, 1H),3.90–3.72(m,3H),3.56(d,J＝28.4Hz,1H),3.43(d,J＝6.6Hz,1H),3.17(d,J＝5.1Hz,1H),2.12– 2.07(m,1H),1.24(s,1H),0.80–0.77(m,2H),0.74(dd,J＝7.6,3.5Hz,2H).
MS(ESI+)m/z 365(M+H)+
实施例680：N-(4-((1S,4S)-5-(3-氰基丙酰基)-2,5-二氮杂双环[2.2.1]庚-2-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850002263
1H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.19(s,1H),7.09(s,1H),7.02(td,J＝3.9,2.4Hz,1H), 6.44(ddd,J＝6.3,3.7,2.0Hz,1H),4.86–4.65(m,2H),3.87(d,J＝9.2Hz,1H),3.68–3.48(m,2H),3.43(s, 1H),2.89–2.65(m,2H),2.57(dd,J＝16.5,9.4Hz,2H),2.07(s,1H),0.79–0.71(m,4H).
MS(ESI+)m/z 379(M+H)+
实施例681：N-(4-((1R,4R)-5-(2-氰基乙酰基)-2,5-二氮杂双环[2.2.1]庚-2-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850002264
1H NMR(400MHz,DMSO-d6)δ11.03(d,J＝8.7Hz,1H),10.22(s,1H),7.09(s,1H),7.03(dt,J＝6.7, 3.1Hz,1H),6.43(d,J＝14.4Hz,1H),4.83–4.60(m,2H),4.08(q,J＝18.8Hz,2H),3.90–3.72(m,2H), 3.61–3.49(m,1H),3.43(d,J＝6.4Hz,1H),2.04(dt,J＝45.1,6.5Hz,2H),1.89(d,J＝9.3Hz,1H),0.81– 0.69(m,4H).
MS(ESI+)m/z 365(M+H)+
实施例682：N-(4-((1R,4R)-5-(3-氰基丙酰基)-2,5-二氮杂双环[2.2.1]庚-2-基)-1H-吡咯并[2,3-b]吡啶-6- 基)环丙基甲酰胺的合成
Figure BDA0002455210850002271
1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),10.22(s,1H),7.09(s,1H),7.02(q,J＝3.7Hz,1H),6.43 (s,1H),4.84–4.66(m,2H),3.87(d,J＝9.0Hz,1H),3.66–3.47(m,2H),3.16(d,J＝5.2Hz,2H),2.11–1.93 (m,4H),1.89(d,J＝10.0Hz,1H),0.75(ddd,J＝13.6,6.3,3.9Hz,4H).
MS(ESI+)m/z 379(M+H)+
实施例683：N-(4-(4-(2-(1-氰基环丙基)乙酰基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002272
1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),10.37(s,1H),7.40(s,1H),7.22–7.10(m,1H),6.50– 6.40(m,1H),3.68(s,2H),3.56(s,2H),2.73(d,J＝6.0Hz,4H),2.00(s,1H),0.95–0.90(m,2H),0.82–0.73 (m,4H).
MS(ESI+)m/z 393(M+H)+
实施例684：N-(4-(4-(3-氰基丙酰基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002273
1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),10.37(s,1H),7.40(s,1H),7.20–7.06(m,1H),6.56– 6.38(m,1H),3.65(d,J＝17.9Hz,4H),2.92–2.66(m,4H),2.66–2.53(m,4H),2.00(s,1H),0.81-0.71(m, 4H).
MS(ESI+)m/z 367(M+H)+
实施例685：N-(4-(6-(2-氰基乙酰基)-3,6-二氮杂双环[3.1.1]庚-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002274
MS(ESI+)m/z 365(M+H)+
实施例686：N-(4-(8-(3-氰基苯甲酰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002281
MS(ESI+)m/z 441(M+H)+
实施例687：N-(4-(4-(2-氰基乙酰基)哌嗪-1-基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002282
1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.03(s,1H),7.07(t,J＝2.9Hz,1H),6.56(d,J＝2.8Hz, 1H),4.10(s,2H),3.91(dt,J＝5.1,19.7Hz,3H),3.57(dt,J＝5.5,41.4Hz,4H),2.20(d,J＝10.8Hz,1H),0.76 (dt,J＝3.8,11.0Hz,4H).
MS(ESI+)m/z 354(M+H)+
实施例688：N-(4-(8-(2-氰基乙酰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002283
MS(ESI+)m/z 380(M+H)+
实施例689：N-(4-(8-(2-(1-氰基环丙基)乙酰基)-3,8-二氮杂双环[3.2.1]辛-3-基)-7H-吡咯并[2,3-d]嘧啶 -2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002284
MS(ESI+)m/z 420(M+H)+
实施例690：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-N-(2,2,2-三氟乙基)哌嗪-1-甲酰胺的合成
Figure BDA0002455210850002285
1H NMR(400MHz,DMSO-d6)δ11.18(s,1H),10.36(s,1H),7.40(s,1H),7.25(t,J＝6.1Hz,1H),7.14 (d,J＝3.5Hz,1H),6.88(s,1H),6.44(s,1H),3.85(dt,J＝5.9,10.8Hz,4H),3.59(d,J＝6.6Hz,2H),3.54(s, 4H),2.00(s,1H),0.81-0.74(m,4H).
MS(ESI+)m/z 411(M+H)+
实施例691：3-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-N-(2,2,2-三氟乙基)-3,8-二氮杂双环 [3.2.1]辛烷-8-甲酰胺的合成
Figure BDA0002455210850002291
1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),10.30(s,1H),7.33(d,J＝6.9Hz,2H),7.10(dd,J＝2.5, 3.6Hz,1H),6.45(dd,J＝1.9,3.6Hz,1H),4.42(s,2H),3.93–3.78(m,2H),3.70–3.61(m,2H),3.03(d,J＝ 11.3Hz,2H),1.99(s,1H),1.86(s,4H),0.83–0.71(m,4H).
MS(ESI+)m/z 437(M+H)+
实施例692：4-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)哌嗪-1-甲酸叔丁酯的合成
Figure BDA0002455210850002292
MS(ESI+)m/z 386(M+H)+
实施例693：3-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的合成
Figure BDA0002455210850002293
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.31(s,1H),7.34(s,1H),7.11(d,J＝3.0Hz,1H),6.46 (d,J＝3.1Hz,1H),4.26(d,J＝5.3Hz,2H),3.71(d,J＝11.5Hz,2H),3.00(d,J＝12.0Hz,2H),1.99(s,1H), 1.85(s,4H),1.42(s,9H),0.89–0.67(m,4H).
MS(ESI+)m/z 412(M+H)+
实施例694：8-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯的合成
Figure BDA0002455210850002294
1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),10.30(s,1H),7.36(s,1H),7.09(dd,J＝2.5,3.6Hz,1H), 6.49(dd,J＝2.0,3.7Hz,1H),4.49(s,2H),3.68(t,J＝16.9Hz,3H),3.42(d,J＝10.5Hz,1H),3.20–3.12(m, 1H),3.02(d,J＝12.4Hz,1H),2.03–1.92(m,3H),1.39(s,9H),0.80–0.72(m,4H).
MS(ESI+)m/z 412(M+H)+
实施例695：3-(2-(环丙基甲酰氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯的合成
Figure BDA0002455210850002295
MS(ESI+)m/z 413(M+H)+
实施例696：(S)-(1-(2-(环丙基甲酰氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)吡咯烷-3-基)氨基甲酸叔丁酯的合成
Figure BDA0002455210850002301
MS(ESI+)m/z 387(M+H)+
实施例697：(S)-(1-(6-(环丙基甲酰氨基)-1H-吡咯并[2,3-b]吡啶-4-基)吡咯烷-3-基)氨基甲酸叔丁酯的合成
Figure BDA0002455210850002302
MS(ESI+)m/z 386(M+H)+
实施例698：N-(4-(4-(异噻唑-5-基甲基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002303
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),10.34(s,1H),8.49(d,J＝1.7Hz,1H),7.39(s,1H),7.31 (d,J＝1.6Hz,1H),7.11(t,J＝3.0Hz,1H),6.39(dd,J＝1.9,3.6Hz,1H),4.11(t,J＝5.2Hz,1H),3.96(s,2H), 3.17(d,J＝5.2Hz,3H),2.66(t,J＝4.7Hz,4H),2.00(s,1H),0.82-0.74(m,4H).
MS(ESI+)m/z 383(M+H)+
实施例699：(S)-N-(4-(4-((2,2-二氟环丙基)甲基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002304
1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.57(s,1H),7.67(s,1H),7.31(t,J＝3.0Hz,1H),6.24 (tt,J＝1.5,3.3Hz,1H),4.14(dd,J＝1.2,3.5Hz,2H),4.07–3.94(m,2H),3.70(t,J＝5.7Hz,1H),3.57(t,J＝ 5.7Hz,1H),2.34(s,1H),2.05–1.95(m,1H),1.52(s,3H),1.24(d,J＝8.3Hz,1H),0.83–0.75(m,4H).
MS(ESI+)m/z 376(M+H)+
实施例700：N-(4-(4-(3-(氰基甲基)-1-(乙基磺酰基)氮杂环丁烷-3-基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002311
MS(ESI+)m/z 472(M+H)+
实施例701：N-(4-(8-(3-(氰基甲基)-1-(乙基磺酰基)氮杂环丁烷-3-基)-3,8-二氮杂双环[3.2.1]辛-3- 基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002312
1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),9.46(s,1H),7.49–7.37(m,2H),6.71–6.60(m,1H), 4.54(d,J＝9.2Hz,2H),4.24(d,J＝9.1Hz,2H),4.14(s,2H),3.87–3.74(m,2H),3.19(q,J＝7.3Hz,2H), 2.37(q,J＝7.4Hz,2H),1.99(s,5H),1.25–1.21(m,3H),1.05(t,J＝7.4Hz,3H),0.82-0.74(m,4H).
MS(ESI+)m/z 498(M+H)+
实施例702：N-(4-(4-(2-(1,1-二氧化硫代吗啉代)-2-氧代乙基)哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-6-基) 环丙基甲酰胺的合成
Figure BDA0002455210850002313
/>
MS(ESI+)m/z 461(M+H)+
实施例703：N-(4-(8-(2-((R)-2-氰基吡咯烷-1-基)-2-氧代乙基)-3,8-二氮杂双环[3.2.1]辛-3-基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基甲酰胺的合成
Figure BDA0002455210850002314
1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),9.96(s,1H),7.01(t,J＝2.9Hz,1H),6.53(d,J＝3.3Hz, 1H),4.31(dt,J＝8.5,4.3Hz,2H),3.74(dt,J＝9.8,6.3Hz,1H),3.63(s,2H),3.56(s,1H),3.28–3.14(m,4H), 2.24–2.11(m,2H),1.94–1.83(m,4H),1.54(d,J＝8.7Hz,2H),0.75(qd,J＝8.5,4.8Hz,4H).
MS(ESI+)m/z 448(M+H)+
实施例704：N-(4-(8-(2-(1,1-二氧化硫代吗啉代)-2-氧代乙基)-3,8-二氮杂双环[3.2.1]辛-3-基)-7H-吡咯并[2,3-d]嘧啶-2-基)环丙基甲酰胺的合成
Figure BDA0002455210850002321
MS(ESI+)m/z 488(M+H)+
实施例705：(S)-3-(4-(6-氨基-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-3,6-二氢吡啶-1(2H)-基)-3-氧代丙腈的合成
Figure BDA0002455210850002322
MS(ESI+)m/z 296(M+H)+
实施例706：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环戊基甲酰胺的合成
Figure BDA0002455210850002323
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),10.29(s,1H),9.83(s,1H),8.04(s,1H),7.58(d,J＝9.0 Hz,3H),7.43(s,1H),6.56(s,1H),3.18(q,J＝7.5Hz,2H),2.97(s,1H),1.85(s,2H),1.69(s,4H),1.55(s, 2H),1.29(t,J＝7.7Hz,4H).
MS(ESI+)m/z 417(M+H)+
实施例707：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环己基甲酰胺的合成
Figure BDA0002455210850002324
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),10.21(s,1H),8.22(s,1H),8.03(s,1H),7.56(s,3H), 7.42(s,2H),6.55(s,1H),3.17(q,2H),2.36(s,1H),1.76(d,J＝23.4Hz,4H),1.68–1.56(m,2H),1.41(d,J＝ 11.7Hz,4H),1.29(t,J＝7.1Hz,4H).
MS(ESI+)m/z 421(M+H)+
实施例708：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)丙酰胺的合成
Figure BDA0002455210850002331
1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),10.14(s,1H),7.94(s,1H),7.47–7.36(m,1H),7.33(s, 1H),7.26(t,J＝9.0Hz,2H),6.56(s,1H),2.79(q,J＝8.0Hz,2H),2.41(q,J＝7.7Hz,2H),1.17(t,3H),1.09 (t,J＝7.2Hz,3H).
MS(ESI+)m/z 433(M+H)+
实施例709：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)-2-苯基乙酰胺的合成
Figure BDA0002455210850002332
1H NMR(400MHz,DMSO-d6)δ11.71–11.50(s,1H),10.58(s,1H),9.81(s,1H),8.00(s,1H),7.56(d, J＝10.0Hz,3H),7.45(s,1H),7.41–7.27(m,5H),7.25(d,J＝7.4Hz,1H),6.56(s,1H),3.74(s,2H),3.23– 3.04(q,2H),1.35–1.25(t,3H).
MS(ESI+)m/z 494(M+H)+
实施例710：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)乙酰胺的合成
Figure BDA0002455210850002333
1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),10.34(s,1H),9.79(s,1H),7.99(s,1H),7.65–7.48(m, 3H),7.46–7.36(m,1H),6.55(d,J＝3.2Hz,1H),3.14(q,2H),2.11(s,3H),1.29(t,3H).
MS(ESI+)m/z 377(M+H)+
实施例711：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)异丁酰胺的合成
Figure BDA0002455210850002334
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),10.28(s,1H),9.83(s,1H),8.04(s,1H),7.58(d,J＝8.1 Hz,3H),7.49–7.38(m,1H),6.63–6.50(m,1H),3.18(q,J＝7.2Hz,2H),2.85–2.71(m,1H),1.29(t,J＝7.0 Hz,3H),1.10(d,J＝6.7Hz,6H).
MS(ESI+)m/z 405(M+H)+
实施例712：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)丁酰胺的合成
Figure BDA0002455210850002341
1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),10.29(s,1H),8.02(s,1H),7.70–7.51(m,3H),7.45– 7.37(m,1H),6.56(d,J＝3.4Hz,1H),2.37(q,J＝6.9Hz,2H),1.62(q,J＝7.5Hz,2H),1.34–1.26(m,5H), 0.92(t,J＝7.3Hz,3H).
MS(ESI+)m/z 405(M+H)+
实施例713：N-(4-(6-((环丙基甲基)氨基)-1H-吡咯并[2,3-b]吡啶-4-基)-2-氟苯基)乙磺酰胺的合成
Figure BDA0002455210850002342
MS(ESI+)m/z 389(M+H)+
实施例714：(Z)-N-(4-(4-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)-N'-甲基环丙基甲脒的合成
Figure BDA0002455210850002343
MS(ESI+)m/z 398(M+H)+
实施例715：N-(4-(4-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙基硫代甲酰胺的合成
Figure BDA0002455210850002344
MS(ESI+)m/z 401(M+H)+
实施例716：N-(4-(4-(乙基磺酰氨基)-3-氟苯基)-1H-吡咯并[2,3-b]吡啶-6-基)环丙磺酰胺的合成
Figure BDA0002455210850002345
1H NMR(400MHz,氯仿-d)δ10.37(s,1H),7.77(t,J＝8.3Hz,1H),7.65–7.47(m,3H),7.44–7.31(m, 1H),6.79(s,1H),6.70–6.57(m,1H),3.23(q,J＝7.3Hz,2H),2.65(tt,J＝8.3,4.7Hz,1H),1.45(t,J＝7.4Hz, 3H),0.99(dt,J＝7.8,3.7Hz,4H).
MS(ESI+)m/z 439(M+H)+
实施例717：1-环丙基-3-(4-(4-((1,1-二氧化硫代吗啉代)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-6-基)脲的合成
Figure BDA0002455210850002351
MS(ESI+)m/z 440(M+H)+
实施例718：N-(4-(2-(二甲基氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)苯基)-3,4-二氟苯磺酰胺的合成
Figure BDA0002455210850002352
1H NMR(400MHz,甲醇-d4)δ8.09–8.02(m,2H),7.77(ddd,J＝2.3,7.3,9.7Hz,1H),7.66(ddt,J＝ 1.8,3.9,8.6Hz,1H),7.42(ddd,J＝7.6,8.7,10.1Hz,1H),7.32–7.25(m,2H),7.02(d,J＝3.6Hz,1H),6.56 (d,J＝3.7Hz,1H),3.23(s,6H).
MS(ESI+)m/z 430(M+H)+
实施例719：N-(2-氟-4-(2-(苯基氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)苯基)乙磺酰胺的合成
Figure BDA0002455210850002353
1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),9.93(s,1H),9.30(s,1H),8.04–7.95(m,2H),7.93– 7.84(m,2H),7.62(t,J＝8.5Hz,1H),7.29(ddd,J＝1.8,5.4,8.5Hz,3H),6.90(dd,J＝6.8,8.0Hz,1H),6.75 (dd,J＝1.8,3.7Hz,1H),3.18(q,J＝7.3Hz,2H),1.28(t,J＝7.3Hz,3H).
MS(ESI+)m/z 412(M+H)+
实施例720：N-(4-(2-(苯基氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)苯基)乙磺酰胺的合成
Figure BDA0002455210850002354
MS(ESI+)m/z 394(M+H)+
实施例721：3-氧代-3-(3-(2-(苯基氨基)-7H-吡咯并[2,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛-8-基) 丙腈的合成
Figure BDA0002455210850002355
MS(ESI+)m/z 388(M+H)+
测试例1：式1的化合物JAK1活性抑制能力的分析(ADP-GloTM激酶测定)
如下鉴定本发明的化合物的JAK抑制能力。
准备各浓度的对照材料和测试材料，其方式是用DMSO稀释它们。同时，准备ATP(250uM)和JAK 底物(JAK1，IRS-1tide 40ng/mL)，其方式是用激酶缓冲液(40mM Tris-HClpH7.5，20mM MgCl2，0.5 mg/ml BSA，50μM DTT)稀释它们。
在微量离心管中混合各浓度的测试药物、底物、ATP和JAK酶，并在30℃培养箱中反应40分钟。
将ADP-GloTM激酶酶***(Promega，USA，V9571)中的ADP-GloTM试剂加入各微量离心管中，并在30℃培养箱中反应40分钟。
将ADP-GloTM激酶酶***中包含的激酶检测试剂添加到微量离心管中，然后通过使用Wallac Victor 2TM将整合时间设定为1秒，然后测量发光值，并且然后分析测试材料的JAK磷酸化抑制能力。与对照组相比引起50％JAK酶活性抑制的化合物浓度测定为抑制剂的IC50(nM)，其中其结果示于下表1中。
[表1]
Figure BDA0002455210850002371
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Figure BDA0002455210850002381
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Claims (7)

1.由下式1所示的化合物、其立体异构体或其药学上可接受的盐：
Figure FDA0003866373750000011
[式1]
其中
X为C-A3；
Y为C-A4；
z为N或N-O；
A1至A4各自独立地为H、C1-C6烷基或C1-C6氰基烷基；
B1为-C(＝O)-、-C(＝S)-、-C(＝NR1)-、-C(＝O)-NR1-或-S(＝O)2-；
B2为C1-C6烷基、C3-C7环烷基、呋喃基或C1-C6烷基-苯基，其中C3-C7环烷基的至少一个H可以被C1-C6烷基替代；
B3为H；
环状连接基是C3-C7环烷基、C3-C7环烯基、5-6元杂环烷基、5-6元杂环烯基、苯基、吡啶基、吡唑基、***基、吡咯基或四氢氮杂环庚三烯；
C1和C2各自独立地为H、C1-C6烷基、C1-C6卤代烷基、羟基、氰基、卤素、C(＝O)-OH、C(＝O)-O-C1-C6烷基或苯基；
或者环状连接基、C1和C2通过至少一个碳原子彼此连接以形成双环或螺环；
D1为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure FDA0003866373750000012
Figure FDA0003866373750000013
或者不存在，其中-(CH2)m-的至少一个H可以被C1-C6烷基或卤素替代，或者其可以与至少一个碳原子彼此连接以形成环；且
Figure FDA0003866373750000014
Figure FDA0003866373750000015
的至少一个H可以被C1-C6烷基或C1-C6氰基烷基替代；
D2为-C(＝O)-、-C(＝O)-CH2-C(＝O)-、-C(＝S)-、-S(＝O)2-或者不存在，其中-C(＝O)-CH2-C(＝O)-的至少一个H可以被C1-C6烷基替代；
D3为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure FDA0003866373750000021
或者不存在，其中-(CH2)m-的至少一个H可以被氰基替代；
D4为H、C1-C6烷基、C2-C6烯基、C1-C6烷氧基烷基、C1-C6卤代烷基、C1-C6氰基烷基、S(＝O)2-C1-C6烷基、C3-C7环烷基、
Figure FDA0003866373750000022
苯基、吡啶基、咪唑基、呋喃基、噁二唑基、异噁唑基、噻唑基、异噻唑基、吡咯基、吲哚基、吡咯并吡啶基、噻吩基、吡嗪基、吡唑基、苯并呋喃基、二氢苯并呋喃、苯并二氧杂环戊烯、二氢苯并二噁英或氧代哌啶，
其中C1-C6烷基、C2-C6烯基或C1-C6卤代烷基的至少一个H可以被C3-C7环烷基、C1-C6卤代烷基、C1-C6氰基烷基、氰基、苯基或噻吩基替代；
C3-C7环烷基或
Figure FDA0003866373750000023
的至少一个H可以被C1-C6烷基、C1-C6卤代烷基、C1-C6氰基烷基、氰基、卤素或-C(＝O)-O-R4替代；且
苯基、吡啶基、咪唑基、呋喃基、噁二唑基、异噁唑基、噻唑基、异噻唑基、吡咯基、吲哚基、吡咯并吡啶基、噻吩基、吡嗪基、吡唑基或苯并呋喃基的至少一个H可以被C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6硫烷基、羟基、氰基、硝基、卤素、-C(＝O)-R4、-C(＝O)-NR1-R4、-S(＝O)2-R4、-S(＝O)2-NR1-R4、-NR1-R5、
Figure FDA0003866373750000024
或四唑基替代，其中此时
Figure FDA0003866373750000025
的至少一个H可以被(＝O)替代；
R1和R2各自独立地为H或C1-C6烷基；
R3为H、C1-C6烷基、-C(＝O)-R4、-C(＝O)-O-R4、-S(＝O)2-R4或-S(＝O)2-NR1-R4，其中如果W为-O-、-C(＝O)-或-S(＝O)2-，则R3不存在；
R4为H、C1-C6烷基或C1-C6卤代烷基；
R5为H、
Figure FDA0003866373750000026
或苯基；
V为-CH-或-N-；
w为-CH-、-N-、-O-、-S-、-C(＝O)-、-S(＝O)-或-S(＝O)2-，其中如果V为-CH-，则w不是-CH-；
a至d各自独立地为1、2或3；且
m为1、2或3。
2.根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中：
X为C-A3；
Y为C-A4；
Z为N或N-O；
A1至A4各自独立地为H、C1-C6烷基或C1-C6氰基烷基；
B1为-C(＝O)-、-C(＝S)-、-C(＝NR1)-、-C(＝O)-NR1-或-S(＝O)2-；
B2为C1-C6烷基、C3-C7环烷基、呋喃基或C1-C6烷基-苯基，其中C3-C7环烷基的至少一个H可以被C1-C6烷基替代；
B3为H；
环状连接基是C3-C7环烷基、C3-C7环烯基、5-6元杂环烷基、5-6元杂环烯基、苯基、吡啶基、吡唑基、***基或吡咯基；
C1和C2各自独立地为H、C1-C6烷基、C1-C6卤代烷基、羟基、氰基、卤素、C(＝O)-OH、C(＝O)-O-C1-C6烷基或苯基，
或者C1和C2可以通过至少一个碳原子彼此连接以形成双环或螺环；
D1为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure FDA0003866373750000031
Figure FDA0003866373750000032
或者不存在，其中-(CH2)m-的至少一个H可以被C1-C6烷基或卤素取代，或者其可以与至少一个碳原子彼此连接以形成环；且
Figure FDA0003866373750000033
Figure FDA0003866373750000034
的至少一个H可以被C1-C6烷基或C1-C6氰基烷基替代；
D2为-C(＝O)-、-C(＝O)-CH2-C(＝O)-、-C(＝S)-、-S(＝O)2-或者不存在，其中-C(＝O)-CH2-C(＝O)-的至少一个H可以被C1-C6烷基替代；
D3为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure FDA0003866373750000035
或者不存在，其中-(CH2)m-的至少一个H可以被氰基替代；
D4为H、C1-C6烷基、C2-C6烯基、C1-C6烷氧基烷基、C1-C6卤代烷基、C1-C6氰基烷基、S(＝O)2-C1-C6烷基、C3-C7环烷基、
Figure FDA0003866373750000036
苯基、吡啶基、咪唑基、呋喃基、噁二唑基、异噁唑基、噻唑基、异噻唑基、吡咯基、吲哚基、吡咯并吡啶基、噻吩基、吡嗪基、吡唑基或苯并呋喃基，
其中C1-C6烷基、C2-C6烯基或C1-C6卤代烷基的至少一个H可以被C3-C7环烷基替代；
C3-C7环烷基或
Figure FDA0003866373750000037
的至少一个H可以被C1-C6烷基、C1-C6卤代烷基、C1-C6氰基烷基、氰基、卤素或-C(＝O)-O-R4替代；且
苯基、吡啶基、咪唑基、呋喃基、噁二唑基、异噁唑基、噻唑基、异噻唑基、吡咯基、吲哚基、吡咯并吡啶基、噻吩基、吡嗪基、吡唑基或苯并呋喃基的至少一个H可以被C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6硫烷基、羟基、氰基、硝基、卤素、-C(＝O)-R4、-C(＝O)-NR1-R4、-S(＝O)2-R4、-S(＝O)2-NR1-R4、-NR1-R5或
Figure FDA0003866373750000038
替代，其中此时
Figure FDA0003866373750000039
的至少一个H可以被(＝O)替代；
R1和R2各自独立地为H或C1-C6烷基；
R3为H、C1-C6烷基、-C(＝O)-R4、-C(＝O)-O-R4、-S(＝O)2-R4或-S(＝O)2-NR1-R4，其中如果W为-O-、-C(＝O)-或-S(＝O)2-，则R3不存在；
R4为H、C1-C6烷基或C1-C6卤代烷基；
R5为H、
Figure FDA0003866373750000041
或苯基；
V为-CH-或-N-；
W为-CH-、-N-、-O-、-S-、-C(＝O)-、-S(＝O)-或-S(＝O)2-，其中如果V为-CH-，则W不是-CH-；
a至d各自独立地为1、2或3；且
m为1或2。
3.化合物、其立体异构体或其药学上可接受的盐，其中其为选自以下化合物的化合物：
Figure FDA0003866373750000042
Figure FDA0003866373750000051
Figure FDA0003866373750000061
Figure FDA0003866373750000071
Figure FDA0003866373750000081
Figure FDA0003866373750000091
Figure FDA0003866373750000101
Figure FDA0003866373750000111
Figure FDA0003866373750000121
Figure FDA0003866373750000131
Figure FDA0003866373750000141
Figure FDA0003866373750000151
Figure FDA0003866373750000161
Figure FDA0003866373750000171
Figure FDA0003866373750000181
Figure FDA0003866373750000191
Figure FDA0003866373750000201
Figure FDA0003866373750000211
Figure FDA0003866373750000221
Figure FDA0003866373750000231
Figure FDA0003866373750000241
Figure FDA0003866373750000251
Figure FDA0003866373750000261
Figure FDA0003866373750000271
Figure FDA0003866373750000281
4.用于预防或治疗癌症、自身免疫病、神经疾病、代谢疾病或感染的药物组合物，其中所述药物组合物包含作为有效组分的权利要求1至3之一的化合物、其立体异构体或其药学上可接受的盐。
5.权利要求1至3之一的化合物、其立体异构体或其药学上可接受的盐用于制备药物的用途，所述药物用于治疗癌症、自身免疫病、神经疾病、代谢疾病或感染。
6.权利要求1至3之一的化合物、其立体异构体或其药学上可接受的盐用于制备药物的用途，所述药物用于抑制蛋白激酶。
7.根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中：
x为C-A3；
Y为C-A4；
z为N或N-O；
A1为H、C1-C6烷基或C1-C6氰基烷基；
A2至A4各自独立地为H或C1-C6烷基；
B1为-C(＝O)-；
B2为C3环烷基，其中C3环烷基的至少一个H可以被C1-C6烷基替代；
B3为H；
环状连接基为C3-C7环烷基、C3-C7环烯基、吡咯烷、哌嗪、哌啶、二氢吡咯、四氢氮杂环庚三烯、四氢吡啶、苯基、吡啶、吡咯、吡唑或***，且C1和C2各自独立地为H、C1-C6烷基、C1-C6卤代烷基、羟基、氰基、卤素、C(＝O)-OH、C(＝O)-O-C1-C6烷基或苯基；
或者当环状连接基、C1和C2通过至少一个碳原子彼此连接以形成双环或螺环时，所述双环或螺环为二氮杂双环辛烷、氮杂螺壬烯、氮杂双环壬烯、氮杂螺辛烯、氮杂双环辛烯、二氮杂双环庚烷、氮杂双环辛烷；
D1为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、-NR1-哌啶-、-NR1-氮杂环丁烷-、哌啶、氮杂环丁烷、氮杂环丁烷-哌啶或不存在，其中-(CH2)m-的至少一个H可以被C1-C6烷基或卤素替代，或者可以通过至少一个碳原子彼此连接以形成环烷基环，并且-NR1-哌啶-、-NR1-氮杂环丁烷-、哌啶、氮杂环丁烷或氮杂环丁烷-哌啶的至少一个H可以被C1-C6烷基或C1-C6氰基烷基替代；
D2为-C(＝O)-、-C(＝O)-CH2-C(＝O)-、-C(＝S)-、-S(＝O)2-或不存在，其中-C(＝O)-CH2-C(＝O)-的至少一个H可以被C1-C6烷基替代；
D3为-(CH2)m-、-(CH2)m-NR1-、-NR1-、-O-、
Figure FDA0003866373750000291
或不存在，其中-(CH2)m-的至少一个H可以被氰基替代；
D4为
H，
C1-C6烷基，
C2-C6烯基，其中C2-C6烯基的至少一个H可以被C1-C6卤代烷基、C1-C6氰基烷基、氰基、苯基或噻吩基替代，
C1-C6烷氧基烷基，
C1-C6卤代烷基，其中C1-C6卤代烷基的至少一个H可以被C3-C7环烷基替代，
C1-C6氰基烷基，
S(＝O)2-C1-C6烷基，
C3-C7环烷基，其中C3-C7环烷基的至少一个H可以被C1-C6烷基、C1-C6卤代烷基、C1-C6氰基烷基、氰基、卤素或-C(＝O)-O-R4替代，
哌嗪，其中哌嗪的至少一个H可以被C1-C6烷基、-C(＝O)-R4、-C(＝O)-O-R4、-S(＝O)2-R4或-S(＝O)2-NR1-R4替代，
氮杂环丁烷，其中氮杂环丁烷的至少一个H可以被-C(＝O)-O-R4、C1-C6氰基烷基或氰基替代，
哌啶，其中哌啶的至少一个H可以被-C(＝O)-R4、-C(＝O)-O-R4、C1-C6卤代烷基、氰基或卤素替代，
吡咯烷，其中吡咯烷的至少一个H可以被C1-C6烷基、氰基或卤素替代，
氧代哌啶，
吗啉，其中吗啉的至少一个H可以被C1-C6烷基或氰基替代，
硫代吗啉，
二氧化硫代吗啉，
被C1-C6烷基或C1-C6氰基烷基取代的氧杂环丁烷，
二氧化四氢噻吩，
苯基，其中苯基的至少一个H可以被C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6硫烷基、羟基、氰基、硝基、卤素、-C(＝O)-R4、-C(＝O)-NR1-R4、-S(＝O)2-R4、-S(＝O)2-NR1-R4、-NR1-苯基、-NR1-C1-C6烷基-吗啉基、C1-C6烷基-二氧代吗啉基或四唑替代，
吡啶，其中吡啶的至少一个H可以被C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、羟基、氰基、卤素或-NH2替代，
咪唑，其中咪唑的至少一个H可以被C1-C6烷基替代，
四氢吡喃，其中四氢吡喃的至少一个H可以被氰基替代，
四氢呋喃，
噁二唑，
吡咯并吡啶，
苯并呋喃，
噻唑，其中噻唑的至少一个H可以被C1-C6烷基或C1-C6卤代烷基替代，
噻吩，其中噻吩的至少一个H可以被C1-C6烷基替代，
异噻唑，
异噁唑，
吲哚，
呋喃，
被C1-C6烷基取代的吡唑，
吡嗪，其中吡嗪的至少一个H可以被C1-C6烷基替代，
吡咯，
二氢苯并呋喃，
苯并二氧杂环戊烯，
二氢苯并二噁英，
二氧化硫杂环丁烷，或
二氧化四氢噻喃，
R1和R2各自独立地为H或C1-C6烷基；
R4为H、C1-C6烷基或C1-C6卤代烷基；
m为1、2或3。
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