CN113166094A - 作为蛋白激酶抑制剂的新型化合物和包含其的药物组合物 - Google Patents
作为蛋白激酶抑制剂的新型化合物和包含其的药物组合物 Download PDFInfo
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- CN113166094A CN113166094A CN201980075052.6A CN201980075052A CN113166094A CN 113166094 A CN113166094 A CN 113166094A CN 201980075052 A CN201980075052 A CN 201980075052A CN 113166094 A CN113166094 A CN 113166094A
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- alkyl
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- heteroaryl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Abstract
本发明提供具有蛋白激酶抑制活性的新型化合物、其立体异构体或其药物上可接受的盐。由于具有蛋白激酶抑制活性,根据本发明的化合物、其立体异构体或其药物上可接受的盐可有效地预防或治疗蛋白激酶相关疾病,例如癌症、自身免疫性疾病、神经疾病、代谢性疾病和感染等。
Description
技术领域
本发明涉及一种作为蛋白激酶抑制剂的新型化合物、包括其的药物组合物、以及其药物用途,该新型化合物抑制作为磷酸酶的蛋白激酶的活性,并且因此可以有价值地用于预防或治疗与其相关的疾病。
背景技术
蛋白激酶是通过使其它蛋白质磷酸化从而调节蛋白质的活性、位置和功能来控制细胞内各种过程的酶。此类蛋白激酶控制功能的异常与癌症、自身免疫性疾病、神经疾病、代谢性疾病、感染等疾病的机制密切相关。
Janus激酶(JAK)是一种在细胞因子的信号转导系统中起重要作用的激酶。JAK在造血、先天免疫和获得性免疫中起关键作用,并且因此成为治疗诸如癌症、自身免疫性疾病、神经疾病、代谢性疾病、感染等疾病的治疗剂的重要靶标。
JAK是一种由约1,150个氨基酸组成的蛋白质并且其分子量约为120至130kDa,并且JAK被分类成四种类型:JAK1、JAK2、JAK3和TYK2。JAK位于炎性细胞因子的细胞内受体中。炎性细胞因子(IL-2、IL-4、IL-6、IL-7、IL-9、IL-15、IL-21、GM-CSF、G-CSF、EPO、TPO、IFN-a(IFN-α)、IFN-b(IFN-β)、IFN-G(IFN-γ)等)与受体结合,然后磷酸化,然后通过与STAT分子的作用将炎性细胞因子的信号递送至细胞中。通过此类不同炎症性细胞的信号传导的过度激活会使得人体免疫系统攻击人体,并且因此导致自身免疫性疾病的发生。
因此,预期通过开发一种用于抑制此类炎性细胞因子的受体激酶的药物,发现比现有治疗剂对自身免疫性疾病更有改善的治疗效果。
发明内容
技术问题
本发明的目的是提供一种具有蛋白激酶抑制活性的新型化合物、其立体异构体或其药物上可接受的盐。
而且,本发明的目的是提供一种用于制备本发明化合物、其立体异构体或其药物上可接受的盐的方法。
此外,本发明的目的是提供一种用于治疗或预防蛋白激酶相关疾病的药物组合物,该药物组合物包含作为活性成分的本发明化合物、其立体异构体或其药物上可接受的盐。
此外,本发明的目的是提供一种用于预防或治疗蛋白激酶相关疾病的方法,该方法包括将治疗有效量的本发明化合物、其立体异构体或其药物上可接受的盐给药至个体的步骤。
另外,本发明的目的是提供一种本发明化合物、其立体异构体或其药物上可接受的盐在制备用于预防或治疗蛋白激酶相关疾病的药物中的用途。
此外,本发明的目的还是提供一种本发明化合物、其立体异构体或其药物上可接受的盐用于预防或治疗蛋白激酶相关疾病的用途。
问题的解决方案
蛋白激酶抑制剂化合物和用于制备其的方法
为了解决以上问题,本发明提供一种由以下式1表示的化合物、其立体异构体或其药物上可接受的盐:
[式1]
在式1中,
R1为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
X为C-A1或N,
Y为C-A2或N-A4,
Z为C-A3或N-A5,其中X、Y和Z中的至少一个包括N;
X与Y之间的键或Y与Z之间的键中的至少一个是双键,并且如果X与Y之间的键是双键,则A1或A4不存在;
A1至A5各自独立地为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6卤代烷基、C1-6氰基烷基、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、-C(=O)-N-C1-6卤代烷基、芳基或杂芳基;
R2为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
n和m各自独立地为0、1、2或3;
B1为-C(=O)-、-C(=S)-、-C(=O)-NR3-或单键;
B2为C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
B3为H或C1-6烷基;
D1为-NR3-;
D2为-C(=O)-、-C(=S)-、-S(=O)2-或单键;
D4为H、C1-6烷基、C1-6烯基、C1-6卤代烷基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基、C1-6卤代烷基或C1-6氰基烷基中的至少一个H可以被C3-7环烷基、芳基、杂芳基或氰基取代,
C3-7环烷基或5至6元杂环烷基中的至少一个H可以被C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、氰基或卤素取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟烷基、C1-6氰基烷基、C1-6硫代烷基、羟基、氰基、硝基或卤素取代;以及
R3和R4各自独立地为H、C1-6烷基或C1-6卤代烷基。
根据本发明的一个实施方案,由式1表示的化合物可以包括由以下式1-1、式1-2和式1-3表示的化合物中的一个:
[式1-1]
[式1-2]
[式1-3]
在这些式中,
R1为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
A2至A5各自独立地为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6卤代烷基、C1-6氰基烷基、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、-C(=O)-N-C1-6卤代烷基、芳基或杂芳基;
R2为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
n和m各自独立地为0、1、2或3;
B1为-C(=O)-、-C(=S)-、-C(=O)-NR3-或单键;
B2为C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
B3为H或C1-6烷基;
D1为-NR3-;
D2为-C(=O)-、-C(=S)-、-S(=O)2-或单键;
D4为H、C1-6烷基、C1-6烯基、C1-6卤代烷基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基、C1-6卤代烷基或C1-6氰基烷基中的至少一个H可以被C3-7环烷基、芳基、杂芳基或氰基取代,
C3-7环烷基或5至6元杂环烷基中的至少一个H可以被C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、氰基或卤素取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟烷基、C1-6氰基烷基、C1-6硫代烷基、羟基、氰基、硝基或卤素取代;以及
R3和R4各自独立地为H、C1-6烷基或C1-6卤代烷基。
根据本发明的一个实施方案,由式1表示的化合物可以包括由以下式2表示的化合物:
[式2]
在式2中,
R1为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
X为C-A1或N,
Y为C-A2或N-A4,
Z为C-A3或N-A5,其中X、Y和Z中的至少一个包括N;
X与Y之间的键或Y与Z之间的键中的至少一个是双键,并且如果X与Y之间的键是双键,则A1或A4不存在;
A1至A5各自独立地为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6卤代烷基、C1-6氰基烷基、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、-C(=O)-N-C1-6卤代烷基、芳基或杂芳基;
R2为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
n和m各自独立地为0或1;
D2为-C(=O)-、-C(=S)-、-S(=O)2-或单键;
D4为H、C1-6烷基、C1-6烯基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基或C1-6氰基烷基中的至少一个H可以被C3-7环烷基、芳基、杂芳基或氰基取代,
C3-7环烷基或5至6元杂环烷基中的至少一个H可以被C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、氰基或卤素取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟烷基、C1-6氰基烷基、C1-6硫代烷基、羟基、氰基、硝基或卤素取代;以及
R3和R4各自独立地为H、C1-6烷基或C1-6卤代烷基。
根据本发明的另一实施方案方面,在式1中,
R1为H、C1-6烷基或C1-6烷氧基;
X为C-A1或N,
Y为C-A2或N-A4,
Z为C-A3或N-A5,其中X、Y和Z中的至少一个包括N;
X与Y之间的键或Y与Z之间的键中的至少一个是双键,并且如果X与Y之间的键是双键,则A1或A4不存在;
A1至A5各自独立地为H、C1-6烷基或-C(=O)-N-C1-6卤代烷基;
R2为H、C1-6烷基或C1-6杂芳基;
n和m各自独立地为0或1;
D2为-C(=O)-;
D4为H、C1-6烷基、C1-6烯基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基或C1-6氰基烷基中的至少一个H可以被C3-7环烷基、芳基、杂芳基或氰基取代,
C3-7环烷基或4至6元杂环烷基中的至少一个H可以被C1-6烷基、C1-6氰基烷基或氰基取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6烷氧基、C1-6卤代烷基或氰基取代;以及
R3和R4各自独立地为H、C1-6烷基或C1-6卤代烷基。
根据本发明的另一实施方案方面,在式1中,
R1为H;
X为N;
Y为C-A2;
Z为C-A3;
Y与Z之间的键是双键;
A2和A3各自独立地为H;
R2为H;
n和m各自独立地为0;
D2为-C(=O)-;
D4为H、C1-6烷基、C1-6烯基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基或C1-6氰基烷基中的至少一个H可以被芳基、杂芳基或氰基取代,
C3-7环烷基或5至6元杂环烷基中的至少一个H可以被C1-6氰基烷基或氰基取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6烷氧基、氰基、硝基或卤素取代;以及
R3和R4各自独立地为H或C1-6烷基。
根据本发明的另一实施方案方面,在式1中,
R1为H、C1-6烷基或C1-6烷氧基;
X为C-A1;
Y为C-A2;
Z为N-A5,其中X、Y和Z中的至少一个包括N;
X与Y之间的键是双键,并且如果X与Y之间的键是双键,则A1不存在;
A2和A5各自独立地为H、C1-6烷基或-C(=O)-N-C1-6卤代烷基。
R2为H或C1-6烷基;
n和m各自独立地为0或1;
D2为-C(=O)-;
D4为H、C1-6烷基、C1-6烯基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基或C1-6氰基烷基中的至少一个H可以被C3-7环烷基、杂芳基或氰基取代,
C3-7环烷基或5至6元杂环烷基中的至少一个H可以被C1-6烷基或氰基取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6卤代烷基或氰基取代;以及
R3和R4各自独立地为H、C1-6烷基或C1-6卤代烷基。
根据本发明的另一实施方案方面,在式1中,
R1为H;
X为C-A1;
Y为N-A4;
Z为N-A5;
X与Y之间的键是双键;
A1、A4和A5各自独立地为H;
R2为H;
n和m各自独立地为0;
D2为-C(=O)-;
D3为单键;
D4为C1-6烯基,其中C1-6烯基中的至少一个H可以被氰基取代;以及
R3为H。
在整个本说明书中,当定义式1和式2的化合物时,使用如下定义的概念。除非另有特别指示,否则以下定义也适用于在整个本说明书中单独使用或作为其较大组的一部分使用的术语。
术语“烷基”分别指独立地或与“杂烷基”组合使用时的直链、支链或环状烃基,其中每个碳原子可以被氰基、羟基、烷氧基、氧代基、卤素、羰基、磺酰基、cyanyl等中的至少一个任意取代。
术语“烷氧基”是指-O-烷基,其中烷基与上文中所定义的相同。
术语“杂烷基”指包括至少一个选自N、O和S的杂原子的烷基。
术语“芳基”指包括苯基、萘基等的芳香族基团,并且可以被烷基、烷氧基、卤素、羟基、羰基、磺酰基、cyanyl等中的至少一个任意取代。
术语“杂芳基”是指:5至7元芳香族单环,其包括至少一个、选自N、O和S的杂原子,例如1至4个杂原子,或在一些示例性实施方案中为1至3个杂原子,并且其中剩余的环原子是碳;8至12元双环,其包括至少一个选自N、O和S的杂原子,例如1至4个杂原子,或在一些示例性实施方案中为1至3个杂原子,并且其中剩余的环原子是碳,至少一个环是芳香族的,并且在芳香族环中存在至少一个杂原子;以及11至14元三环,其包括至少一个选自N、O和S的杂原子,例如1至4个杂原子,或在一些示例性实施方案中为1至3个杂原子,并且其中剩余的环原子是碳,至少一个环是芳香族的,并且在芳香族环中存在至少一个杂原子。杂芳基的实例包括吡啶基、吡嗪基、2,4-嘧啶基、3,5-嘧啶基、2,4-咪唑基、异噁唑基、噁唑基、噻唑基、噻二唑基、四唑基、噻吩基、苯并噻吩基、呋喃基、苯并呋喃基、苯并咪唑基、吲哚基、吲哚啉基、吡咯基、苯硫基、哒嗪基、三唑基、喹啉基、吡唑基、吡咯并吡啶基、吡唑并吡啶基、苯并噁唑基、苯并噻唑基、吲唑基和5,6,7,8-四氢异喹啉,但不限于此。
术语“杂环烷基”是指包括1至4个选自N、O和S的杂原子、可以与苯并或环烷基任意稠合、并且是饱和或部分饱和或芳香族的形式。适当的杂环烷基可以例如包括哌啶基、哌嗪基、四氢呋喃基、吡咯烷基、吡喃基等,但不限于此。
术语“卤代(卤素)”指选自氟代、氯代、溴代和碘代的取代基。
而且,在式1、式1-1至1-3以及式2中,“n”指可以被取代的取代基的数目。如果n为0,则其意味着氢原子全部被取代。
此外,在本发明中,除去一个氢的单价取代基可能为零的表述指“不存在”,并且除去两个氢的二价取代基可能为零的表述指“单键”。
此外,除非另有定义,否则本说明书中所使用的术语和缩写还具有它们的原始含义。
在本发明中,由式1表示的化合物的实例如下。
同时,根据本发明的化合物可以具有不对称碳,并且可以以R或S异构体、外消旋体、非对映异构体的混合物、以及单个非对映异构体的形式存在,并且所有的异构体和混合物均包括在本发明的范围内。换句话说,如果不对称碳包括在式1的结构中,则应当认识到,除非另外描述其方向,否则立体异构体全部包括在其中。
在下文中,为更好地理解本发明,基于示例性反应式描述用于制备由式2表示的化合物的方法,其是式1的一个实施方案。然而,本发明所属领域的技术人员应当认识的是,式1或式2的化合物可以通过基于式1或式2的结构的各种方法来制备,并且此类方法全部都包括在本发明的范围内。换句话说,应当认识到,可以通过将本说明书中所描述的或现有技术中所公开的各种合成方法进行任意组合来制备根据本发明的化合物,并且这属于本发明的范围。在以下反应式中,除非另有指示,否则所有取代基均与上文中所定义的相同。
作为本发明化合物中所使用的酸、碱和反应溶剂,可以没有限制地使用本领域中通常所使用的那些。例如,作为酸,可以使用以下各项:无机酸,如盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸等;有机羧酸,如酒石酸、甲酸、柠檬酸、乙酸、己二酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富马酸、马来酸等;以及磺酸,如甲基磺酸、苯磺酸、对甲苯磺酸、萘磺酸等。作为碱,可以使用以下各项:NaH、K2CO3、Na2CO3、NaHCO3、K3PO4、KOH、NaOH、LiOH、n-BuLi、sec-BuLi、LiHMDS等。作为反应溶剂,可以使用以下各项:DCM、THF、二噁烷、MeOH、EtOH、己烷、EtOAC、乙醚、DMF、DMSO、甲苯、二甲苯等、或其混合溶剂等。
在一个实施方案中,可以通过以下反应式1来举例说明用于合成根据本发明的式2的化合物的方法:
[反应式1]
在反应式1中,
R1、R2、X、Y和Z与式2中所定义的相同,其中R1可以被多达m个取代,并且R2可以被多达n个取代,其中m和n与式2中所定义的相同;
A指卤素原子,其包括F、Cl、Br、I等;以及
D是合并式2中所定义的D2-D3-D4的类似物、或D2-D3-D4本身。
在反应式1中,步骤1为通过使化合物(IV)与N-溴代丁二酰亚胺(NBS)进行反应来制备化合物(V)。
在反应式1中,步骤2为通过双戊酰二硼(bis(pinacolato)diboron)由化合物(V)来制备化合物(VI)。
在反应式1中,步骤3为通过将化合物(VI)的NO2基团还原成NH2基团来制备化合物(VII)。
在反应式1中,步骤4为通过化合物(VII)与化合物(III)之间的铃木(suzuki)偶联反应来制备化合物(VIII)。
在反应式1中,步骤5为制备化合物(IX),该化合物合(IX)是在化合物(VIII)中接入衍生物。
在反应式1中,化合物(III)可以通过以下反应式1-1的方法来合成:
[反应式1-1]
根据反应式1-1,化合物(III)是通过将所述化合物(I)与化合物(II)进行反应来制备的。
除反应式1的方法之外,还可以通过反应式2来进行合成。
在一个实施方案中,可以通过以下反应式2来举例说明用于合成根据本发明的式2的化合物的方法:
[反应式2]
在反应式2中,
R1、R2、X、Y和Z与式2中所定义的相同,其中R1可以被多达m个取代,并且R2可以被多达n个取代,其中m和n与式2中所定义的相同;
A指卤素原子,其包括F、Cl、Br、I等;以及
D是合并式2中所定义的D2-D3-D4的类似物、或D2-D3-D4本身。
在反应式2中,步骤1为通过化合物(IV')与化合物(III)之间的SNAr反应来制备化合物(V')。
在反应式2中,步骤2为通过将化合物(V')的NO2基团还原成NH2基团来制备化合物(VI')。
在反应式2中,步骤3为制备化合物(VIII'),该化合物(VIII')是在化合物(VII')中接入衍生物。
在反应式1和2中,如果将化合物(IV)(在X=CH的情况下)用作起始材料,则优选遵循反应式1。如果将化合物(IV')(在X=NH的情况下)用作起始材料,则优选遵循反应式2。
在反应式1、反应式1-1或反应式2中,化合物(I)、(II)、(IV)和(IV')可以常规地购买或合成。
可以通过如结晶、硅胶柱层析法等各种方法,将根据本发明的式1的化合物从反应式1和2的产物中分离或纯化出来。因此,可以通过各种方法来合成根据本发明的化合物、用于制备该化合物的引发物、中间体等,并且应当认识到,关于式1的化合物的制备,此类方法包括在本发明的范围内。
含有式1的化合物的组合物及其用途
本发明提供一种药物组合物以及一种治疗或预防蛋白激酶相关疾病的用途,该组合物包含作为活性成分的由以下式1表示的化合物、其立体异构体或其药物上可接受的盐:
[式1]
式1与上文中所定义的相同。
如本文所用,术语“预防”指通过给药根据本发明的药物组合物来抑制蛋白激酶相关疾病或延迟其发生的所有行为。
如本文所用,术语“治疗”指通过给药根据本发明的药物组合物,使得蛋白激酶相关疾病的症状有好转或有好的转机的所有行为。
通过示出蛋白激酶抑制活性,根据本发明的式1的化合物、其立体异构体或其药物上可接受的盐对预防或治疗蛋白激酶相关疾病具有显著效果。
在本发明中,蛋白激酶可以是janus激酶(JAK),但不限于此。
在本发明中,所述蛋白激酶相关疾病包括:癌症;自身免疫性疾病,如银屑病(psoriasis)、类风湿性关节炎(rheumatoid arthritis)、狼疮(lupus)、炎症性肠病、慢性阻塞性肺病等;神经疾病;代谢性疾病;或感染。
在本发明中,药物上可接受的盐指药物工业中常规所使用的盐,例如,由钙、钾、钠、镁等制备的无机离子盐;由盐酸、硝酸、磷酸、溴酸、碘酸、高氯酸、酒石酸、硫酸等制备的无机酸盐;由乙酸、三氟乙酸、柠檬酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡萄糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸、氢碘酸等制备的有机酸盐;由甲基磺酸、乙基磺酸、苯磺酸、对甲苯磺酸、萘磺酸等制备的磺酸盐;由甘氨酸、精氨酸、赖氨酸等制备的氨基酸盐;由三甲胺、三乙胺、氨、吡啶、皮考啉等制备的胺盐;等等,但本发明中所指的盐的类型不限于那些列出的盐。在本发明中,优选的盐包括盐酸、三氟乙酸、柠檬酸、溴酸、马来酸、磷酸、硫酸和酒石酸。
为了给药所述药物组合物,除由式1表示的化合物、其立体异构体或其药物上可接受的盐以外,本发明的药物组合物还可以进一步含有至少一种类型的药物上可接受的载体。并且如果需要,也可以经添加诸如抗氧化剂、缓冲溶液、抑菌剂等其它常规添加剂而使用。而且,可以以另外将稀释剂、分散剂、表面活性剂、粘结剂和润滑剂添加至该药物组合物中的方式来配制此种药物组合物。
本发明的组合物可以根据预定方法口服给药或非肠道给药(例如,静脉内、皮下、腹膜内或局部施用),其中其剂量范围取决于患者的体重、年龄、性别、健康状况和饮食、给药时间、给药方法、排泄率、疾病严重程度等而变化。由本发明的式1表示的化合物的日剂量为约0.001至1000mg/kg,并且可以每天给药一次或分成几次给药。
除由式1表示的化合物、其立体异构体或其药物上可接受的盐以外,本发明的所述药物组合物还可以进一步含有至少一种具有与该化合物相同或相似的药用效果的活性成分。
本发明提供一种用于预防或治疗蛋白激酶相关疾病的方法,该方法包括将治疗有效量的由式1表示的化合物、其立体异构体或其药物上可接受的盐给药至个体。
如本文所用,“个体”指包括人类的哺乳动物,并且“给药”指通过任何适当的方法向患者提供预先确定的材料。
如本文所用,术语“治疗有效量”是指有效预防或治疗蛋白激酶相关疾病的由式1表示的化合物、其立体异构体或其药物上可接受的盐的量。
根据本发明的用于预防或治疗蛋白激酶相关疾病的方法包括不仅在疾病本身的症状表达之前对其进行处理,而且包括通过给药由式1表示的化合物、其立体异构体或其药物上可接受的盐来抑制或避免此类症状。在控制疾病中,某种活性成分的预防或治疗用量可以根据疾病或病症的性质和严重程度以及该活性成分的给药途径而变化。其用量和频次可以根据个体患者的年龄、体重和反应而变化。本领域技术人员自然地考虑到此类因素,可以容易地选择合适的用量和剂量。而且,根据本发明的用于预防或治疗蛋白激酶相关疾病的方法可以进一步包括连同由式1表示的化合物、其立体异构体或其药物上可接受的盐给药有助于治疗疾病的治疗有效量的额外活性剂,并且该额外活性剂可以与由式1表示的化合物、其立体异构体或其药物上可接受的盐一起表现出协同效果或相加效果。
为了制备药物,由式1表示的化合物、其立体异构体或其药物上可接受的盐可以与可接受的佐剂、稀释剂、载体等组合,并且可以与其它活性剂一起被制备成复合制剂,并且因此具有活性成分的协同作用。
在本发明的用途、组合物和治疗方法中提及的事项如果彼此不矛盾,则可以等同地应用。
有利效果
由于具有蛋白激酶抑制活性,由根据本发明的式1表示的化合物、其立体异构体或其药物上可接受的盐对预防或治疗蛋白激酶相关疾病具有显著的优异效果。
具体实施方式
在下文中,提供优选的实施例,以更好地理解本发明。然而,以下实施例仅是出于说明本发明的目的提供,并且因此本发明不限于此。当制备本发明的化合物时,可以适当地修改反应顺序。换句话说,任何反应步骤均可以早于本文描述的执行,或者可以插入任何取代基改变,并且如有必要,可以使用除了示例性试剂外的任何试剂。
已知用于起始材料的各种合成方法用来合成本发明的化合物。如果所述起始材料是可商购的,则此种材料可以从其供应商处购买并且可以使用。作为试剂供应商,有如Sigma-Aldrich、TCI、Wako、Kanto、Fluchem、Acros、Alfa、Fluka、Combi-Blocks、Dae-Jung等公司,但不限于此。而且,除另有规定之外,所有商业材料均不经任何额外纯化而使用。
首先,如以下制备实施例中所示的,制备用于下文实施例中的合成的化合物。本领域技术人员可以在本发明的范围内适当地改变和修改以下实施例。
实施例1:N-(4-(7-(2-氰基-3-甲基丁-2-烯酰胺基)-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
[步骤1]N-(4-溴吡啶-2-基)环丙烷甲酰胺的合成
将4-溴吡啶-2-胺(2.0g,11.56mmol)溶解在二氯甲烷中,随后在0℃下向其中逐滴添加吡啶(1.8ml)和环丙烷甲酰氯(1.2ml,13.87mmol),然后在同一温度下搅拌一小时。将反应混合物添加到水中(100ml),随后过滤所得固体,然后在减压下干燥,以获得标题化合物(2.1g,8.7mmol)。
1H NMR(400MHz,DMSO-d6)δ10.99-11.14(m,1H),8.33(d,J=1.83Hz,1H),8.22(d,J=5.31Hz,1H),7.29-7.42(m,1H),1.94-2.07(m,1H),0.83(d,J=6.04Hz,4H)
MS(ESI+)m/z 241,243(M+H)+
[步骤2]7-硝基-1-甲苯磺酰基-1H-吲哚的合成
将7-硝基-1H-吲哚(20g,123.3mmol)溶解在二甲基甲酰胺(1.2L)中,随后在0℃下向其中缓慢地逐滴添加氢化钠(3.2g,135.6mmol),以便向其中缓慢地逐滴添加甲苯磺酰氯(26g,135.6mmol),并且搅拌两小时。将二氯甲烷(300ml)添加到所得混合物中,然后用水(300ml,两次)洗涤,然后用无水硫酸镁干燥,然后过滤,随后在减压下蒸馏所得滤液。将乙醚添加到所得的真空蒸馏的滤液中,随后过滤所得固体,然后在减压下干燥,以获得标题化合物(21g,66.4mmol)。
1H NMR(400MHz,DMSO-d6)δ8.05(d,J=3.66Hz,1H),7.97(d,J=7.68Hz,1H),7.82(d,J=7.87Hz,1H),7.78(d,J=8.42Hz,2H),7.40-7.50(m,3H),7.08(d,J=3.66Hz,1H),2.37(s,3H)
MS(ESI+)m/z 317(M+H)+
[步骤3]3-溴代-7-硝基-1-甲苯磺酰基-1H-吲哚的合成
将7-硝基-1-甲苯磺酰基-1H-吲哚(21g,66.4mmol)溶解在乙腈(664ml)中,随后向其中添加N-溴代丁二酰亚胺(24g,132.78mmol),然后加热至50℃保持18小时。将所得混合物冷却至室温,随后过滤所得固体,然后在减压下干燥,以获得标题化合物(24.9g,63mmol)。
1H NMR(400MHz,DMSO-d6)δ8.44-8.51(m,1H),7.94-8.00(m,1H),7.84-7.90(m,3H),7.57-7.64(m,1H),7.45-7.52(m,2H),2.40(s,3H)
MS(ESI+)m/z 395,397(M+H)+
[步骤4]7-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-甲苯磺酰基-1H-吲哚的合成
将3-溴代-7-硝基-1-甲苯磺酰基-1H-吲哚(24.9g,63mmol)、二片呐醇硼烷(32g,126mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(5.2g,6.4mmol)、乙酸钾(12g,122.2mmol)添加到二噁烷(630ml)中,然后加热至100℃保持两小时。将所得混合物冷却至室温,然后在减压下蒸馏,随后向其中添加二氯甲烷(300ml),然后用蒸馏水(300ml,两次)洗涤。用无水硫酸镁干燥分离出的有机层,然后过滤,随后在减压下蒸馏所得滤液。用柱层析法进行分离,以获得标题化合物(16.9g,38.2mmol)。
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.16-8.21(m,1H),7.95-8.01(m,2H),7.84-7.90(m,1H),7.47-7.57(m,3H),2.42(s,3H),1.34(s,12H)
MS(ESI+)m/z 443(M+H)+
[步骤5]3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-甲苯磺酰基-1H-吲哚-7-胺的合成
将7-硝基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-甲苯磺酰基-1H-吲哚(16.9g,38.2mmol)溶解在乙醇/蒸馏水(2/1,330ml)中,随后向其中添加铁(6.4g,114.6mmol)和氯化铵(20g,382mmol),然后加热至80℃保持三小时。将所得混合物冷却至室温,随后向其中添加甲醇,然后过滤,以从其中去除铁。在减压下蒸馏所得滤液,然后用柱层析法分离,以获得标题化合物(7.4g,17.9mmol)。
1H NMR(400MHz,DMSO-d6)δ7.80-7.83(m,1H),7.75-7.80(m,2H),7.59-7.62(m,1H),7.37-7.43(m,2H),7.32-7.36(m,1H),7.03-7.09(m,1H),2.31-2.34(m,3H),2.28-2.30(m,1H)1.30(s,12H)1.14-1.19(m,4H)
MS(ESI+)m/z 413(M+H)+
[步骤6]N-(4-(7-氨基-1-甲苯磺酰基-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
将3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-甲苯磺酰基-1H-吲哚-7-胺(7.4g,17.9mmol)溶解在二甲基甲酰胺/蒸馏水(2:1)溶液中,随后向其中添加从制备实施例1中获得的N-(4-溴吡啶-2-基)环丙烷甲酰胺(5.1g,21.48mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(2.2g,2.68mmol)和磷酸钾(4.7g,21.48mmol),然后在100℃下搅拌一小时。当反应完成时,将所述混合物冷却至室温,随后向其中添加水,以便用乙酸乙酯进行萃取。用无水硫酸镁干燥萃取的溶液,然后在减压下浓缩,以获得所得残余物。用柱层析法分离该残余物,以获得标题化合物(5g,11.2mmol)。
MS(ESI+)m/z 447(M+H)+
[步骤7]N-(4-(7-氨基-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
将N-(4-(7-氨基-1-甲苯磺酰基-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺(5g,11.2mmol)加入到四氢呋喃/甲醇(1/1,100ml)中,随后向其中添加2N氢氧化钠水溶液,然后在30至40℃下搅拌三小时。当反应完成时,将所述混合物冷却至室温,随后在搅拌的同时向其中添加饱和NH4Cl水溶液。将有机层用二氯甲烷萃取,然后在减压下浓缩,随后用柱层析法分离所得残余物,以获得标题化合物(2.7g,9.2mmol)。
1H NMR(DMSO-d6,400MHz)δ11.24(br s,1H),10.71(s,1H),8.53(s,1H),8.22(d,1H,J=5.3Hz),7.90(d,1H,J=2.7Hz),7.37(dd,1H,J=1.3,5.3Hz),7.22(d,1H,J=8.1Hz),6.88(t,1H,J=7.8Hz),6.42(d,1H,J=7.5Hz),1.9-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 293(M+H)+
[步骤8]N-(4-(7-(2-氰基-3-甲基丁-2-烯酰胺基)-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
将1.5当量的2-氰基-3-甲基丁-2-烯酸、1.5当量的HATU、2当量的DIPEA、以及合成的N-(4-(7-氨基-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺(100mg)加入到二氯甲烷溶液中,然后在室温下搅拌。在反应完成之后,将H2O添加到所述混合物中,随后用二氯甲烷进行萃取,以从其中分离有机层。在浓缩混合物之后,用柱层析法分离所得浓缩物,以获得产物,即,N-(4-(7-(2-氰基-3-甲基丁-2-烯酰胺基)-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺。
1H NMR(DMSO-d6,400MHz)δ10.79(br s,1H),10.34(br d,1H,J=0.9Hz),8.55(brs,1H),8.27(s,1H),7.98(br s,1H),7.42(br d,1H,J=4.8Hz),7.37(br s,1H),7.1-7.2(m,1H),2.24(br s,3H),2.18(br s,3H),2.0-2.0(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 400(M+H)+
实施例2至41
在下文中,实施例2至41中的化合物通过如实施例1中所示的相同方法来制备,但考虑到反应式1以及要制备的化合物的结构而用适当的反应物来制备。
实施例2:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-3,5-二氟苯甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.79(s,1H),10.39(s,1H),8.58(s,1H),8.2-8.3(m,1H),8.01(s,1H),7.8-7.9(m,1H),7.80(br s,2H),7.5-7.6(m,1H),7.4-7.5(m,1H),7.3-7.4(m,1H),7.1-7.2(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 433(M+H)+
实施例3:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)环己烷甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.04(s,1H),8.5-8.6(m,1H),8.5-8.5(m,1H),8.4-8.5(m,1H),8.1-8.2(m,1H),7.5-7.6(m,1H),7.4-7.5(m,1H),6.9-7.0(m,1H),2.0-2.1(m,1H),1.2-1.3(m,8H),1.1-1.2(m,2H),0.8-0.9(m,4H)
MS(ESI+)m/z 403(M+H)+
实施例4:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-2-氟异烟酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.8-10.8(m,1H),10.5-10.6(m,1H),8.5-8.6(m,1H),8.5-8.5(m,1H),8.2-8.3(m,1H),8.0-8.1(m,1H),7.9-8.0(m,1H),7.9-7.9(m,1H),7.8-7.8(m,1H),7.44(br d,1H,J=1.5Hz),7.36(br s,1H),7.21(br s,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 416(M+H)+
实施例5:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-3,5-二甲基苯甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ 11.0-11.1(m,1H),8.5-8.6(m,1H),8.5-8.5(m,1H),8.5-8.5(m,1H),8.1-8.2(m,1H),7.5-7.6(m,1H),7.4-7.5(m,1H),6.94(d,1H,J=4.0Hz),2.0-2.1(m,1H),1.06(s,10H),0.85(br s,4H),0.7-0.7(m,1H)
MS(ESI+)m/z 425(M+H)+
实施例6:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)噻唑-5-甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.48(br s,1H),10.79(s,1H),10.15(s,1H),8.58(s,1H),8.4-8.5(m,1H),8.27(d,1H,J=5.5Hz),7.96(d,1H,J=2.7Hz),7.82(d,1H,J=7.7Hz),7.67(s,2H),7.3-7.5(m,2H),7.25(s,1H),7.17(t,1H,J=7.9Hz),2.33(m,1H),0.6-0.9(m,4H)
MS(ESI+)m/z 404(M+H)+
实施例7:N-(4-(7-丁酰胺基-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.2-11.3(m,1H),10.6-10.8(m,1H),9.6-9.8(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),7.9-8.0(m,1H),7.7-7.8(m,1H),7.4-7.5(m,1H),7.4-7.4(m,1H),7.1-7.2(m,1H),2.4-2.4(m,2H),2.0-2.1(m,1H),1.6-1.8(m,2H),0.97(s,3H),0.8-0.9(m,4H)
MS(ESI+)m/z 363(M+H)+
实施例8:N-(4-(7-(2-氰基乙酰胺基)-1H-吲哚-3-基)-5-甲基吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,氯仿-d)δ11.29-11.40(m,1H),10.71-10.80(m,1H),10.08-10.24(m,1H),8.33-8.43(m,1H),7.94-8.02(m,1H),7.77-7.86(m,1H),7.24-7.34(m,2H),7.09-7.17(m,1H),3.92-4.03(m,2H),2.42-2.47(m,3H),2.00-2.10(m,1H),0.77-0.88(m,4H)
MS(ESI+)m/z 374(M+H)+
实施例9:N-(4-(7-(2-氰基-3-甲基丁-2-烯酰胺基)-1H-吲哚-3-基)-6-甲基吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,CHLOROFORM-d)δ11.14-11.30(m,1H),10.71(s,1H),10.34(s,1H),8.23(s,2H),7.63-7.76(m,1H),7.45-7.55(m,1H),7.32-7.41(m,1H),7.03-7.15(m,1H),2.68(s,6H),2.28-2.34(m,3H),2.14-2.27(m,6H),1.95-2.06(m,1H),0.75-0.87(m,4H)
MS(ESI+)m/z 414(M+H)+
实施例10:N-(4-(7-(2-氰基乙酰胺基)-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.37(br s,1H),10.7-10.8(m,1H),10.1-10.2(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),8.0-8.0(m,1H),7.8-7.9(m,1H),7.4-7.5(m,1H),7.3-7.3(m,1H),7.2-7.3(m,1H),7.1-7.2(m,1H),3.98(br s,2H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 360(M+H)+
实施例11:4-氰基-N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)四氢-2H-吡喃-4-甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.3-11.4(m,1H),11.3-11.3(m,1H),10.8-10.8(m,1H),10.1-10.2(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),8.0-8.0(m,1H),7.8-7.9(m,1H),7.4-7.5(m,1H),7.17(br d,2H,J=3.1Hz),4.0-4.1(m,2H),3.5-3.6(m,2H),2.2-2.3(m,4H),1.9-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 430(M+H)+
实施例12:N-(4-(7-(2-氰基-3-甲基丁-2-烯酰胺基)-1H-吲哚-3-基)-5-甲基吡啶-2-基)环丙烷甲酰胺的合成
MS(ESI+)m/z 414(M+H)+
实施例13:N-(4-(7-(2-(1-氰基环丙基)乙酰胺基)-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.41(br s,1H),10.79(s,1H),9.92(s,1H),8.55(s,1H),8.27(d,1H,J=5.3Hz),8.01(d,1H,J=2.7Hz),7.76(d,1H,J=7.9Hz),7.54(d,1H,J=7.5Hz),7.41(d,1H,J=5.4Hz),7.14(t,1H,J=7.8Hz),2.72(s,2H),2.0-2.1(m,1H),1.2-1.2(m,4H),0.8-0.9(m,4H)
MS(ESI+)m/z 400(M+H)+
实施例14:N-(4-(7-(2-氰基丙酰胺基)-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ10.80(s,1H),10.23(s,1H),8.55(s,1H),8.27(d,1H,J=5.3Hz),8.02(d,1H,J=2.9Hz),7.82(d,1H,J=8.1Hz),7.43(d,1H,J=5.4Hz),7.34(d,1H,J=7.5Hz),7.1-7.2(m,1H),1.99(br d,1H,J=7.3Hz),1.62(d,3H,J=7.3Hz),0.8-0.9(m,4H)
MS(ESI+)m/z 374(M+H)+
实施例15:N-(4-(7-(2-氰基-3-甲基丁-2-烯酰胺基)-5-甲基-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.20(br s,1H),10.76(s,1H),10.28(br s,1H),8.48(br s,1H),8.27(br d,1H,J=5.7Hz),7.89(br s,1H),7.61(br s,1H),7.4-7.5(m,1H),7.26(br s,1H),2.42(br s,3H),2.23(br s,2H),2.1-2.2(m,2H),0.8-0.9(m,4H)
MS(ESI+)m/z 414(M+H)+
实施例16:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-5-甲基-1H-吲哚-7-基)-5-甲基吡嗪-2-甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.50(br s,1H),10.76(br s,1H),10.63(br s,1H),9.19(br s,1H),8.75(br s,1H),8.50(br s,1H),8.27(br d,1H,J=5.3Hz),7.88(br s,1H),7.65(br s,1H),7.43(br d,1H,J=4.8Hz),7.32(br s,1H),2.5-2.7(m,4H),2.4-2.5(m,6H),2.05(br s,1H),0.7-0.9(m,4H)
MS(ESI+)m/z 427(M+H)+
实施例17:N-(4-(7-(2,3-二甲基丁-2-烯酰胺基)-3H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.3-11.3(m,1H),10.78(s,1H),9.7-9.7(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),7.9-8.0(m,1H),7.7-7.8(m,1H),7.6-7.7(m,1H),7.4-7.4(m,1H),7.1-7.2(m,1H),2.0-2.1(m,1H),1.91(s,3H),1.82(s,3H),1.76(s,3H),0.8-0.9(m,4H)
MS(ESI+)m/z 389(M+H)+
实施例18:N-(4-(7-(2-(4-甲基哌嗪-1-基)丙酰胺基)-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.4-11.4(m,1H),10.78(s,1H),9.7-9.8(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),8.0-8.0(m,1H),7.7-7.8(m,1H),7.5-7.5(m,1H),7.4-7.4(m,1H),7.1-7.2(m,1H),2.7-2.7(m,1H),2.69(s,3H),2.4-2.4(m,3H),2.3-2.3(m,1H),2.0-2.1(m,1H),1.2-1.3(m,8H),0.8-0.9(m,4H)
MS(ESI+)m/z 447(M+H)+
实施例19:N-(4-(7-(2-氰基-3-甲基丁-2-烯酰胺基)-1H-吲哚-3-基)-6-甲氧基吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.12-11.27(m,1H),10.52-10.71(m,1H),10.29(s,1H),8.47-8.61(m,1H),8.09-8.19(m,1H),7.44-7.54(m,1H),7.30-7.39(m,1H),7.08-7.18(m,2H),3.86-3.90(m,3H),2.23-2.26(m,3H),2.17-2.20(m,3H),2.10-2.15(m,1H),0.83-0.87(m,4H)
MS(ESI+)m/z 430(M+H)+
实施例20:N-(4-(7-(2-氰基乙酰胺基)-1H-吲哚-3-基)-6-甲氧基吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.11-11.26(m,1H),10.50-10.63(m,1H),10.05-10.12(m,1H),8.51-8.59(m,1H),8.12-8.20(m,1H),7.48-7.57(m,1H),7.19-7.28(m,1H),7.05-7.16(m,2H),3.97(s,2H),3.86(s,3H),2.09-2.19(m,1H),0.79-0.90(m,4H)
MS(ESI+)m/z 390(M+H)+
实施例21:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-4-(三氟甲基)噻唑-2-甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.99(s,1H),10.8-10.9(m,1H),8.8-8.9(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),7.9-8.1(m,1H),7.9-7.9(m,1H),7.4-7.5(m,1H),7.2-7.3(m,1H),7.1-7.2(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 472(M+H)+
实施例22:(E)-N-(4-(7-(2-氰基-3-苯基丙烯酰胺基)-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.7-10.8(m,1H),10.4-10.5(m,1H),8.5-8.6(m,1H),8.2-8.3(m,4H),8.0-8.1(m,2H),8.00(br s,1H),7.86(br dd,1H,J=3.7,8.2Hz),7.4-7.5(m,1H),7.3-7.4(m,1H),7.1-7.2(m,1H),3.5-3.7(m,1H),3.0-3.2(m,3H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 448(M+H)+
实施例23:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-1H-吡咯-2-甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.7-11.8(m,1H),11.48(br s,1H),10.78(br s,1H),9.73(s,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),7.9-8.0(m,1H),7.7-7.8(m,1H),7.4-7.5(m,2H),7.14(br d,2H,J=19.4Hz),6.99(br d,1H,J=2.0Hz),6.2-6.2(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 386(M+H)+
实施例24:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-4-甲基烟酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.4-11.5(m,1H),10.7-10.8(m,1H),10.34(s,1H),8.8-8.9(m,1H),8.58(br s,2H),8.2-8.3(m,1H),8.0-8.0(m,1H),7.8-7.9(m,1H),7.5-7.6(m,1H),7.4-7.5(m,2H),7.1-7.2(m,1H),3.4-3.4(m,3H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 412(M+H)+
实施例25:(E)-N-(4-(7-(2-氰基-3-(噻吩-2-基)丙烯酰胺基)-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.5-11.5(m,1H),10.7-10.8(m,1H),10.29(s,1H),8.59(d,2H,J=19.2Hz),8.2-8.3(m,1H),8.1-8.2(m,1H),7.9-8.0(m,2H),7.8-7.9(m,1H),7.3-7.5(m,2H),7.20(br d,2H,J=19.0Hz),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 454(M+H)+
实施例26:N-(4-(7-(2-氰基-3-甲基丁-2-烯酰胺基)-1-甲基-1H-吲哚-3-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),10.43(s,1H),8.49-8.54(m,1H),8.25-8.31(m,1H),8.17-8.23(m,1H),7.91(s,1H),7.32-7.37(m,1H),7.17-7.23(m,1H),7.01-7.08(m,1H),2.21(s,3H),2.01-2.08(m,1H),1.16-1.26(m,6H),0.78-0.87(m,4H)
MS(ESI+)m/z 414(M+H)+
实施例27:4-氰基-N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)苯甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.7-10.9(m,1H),10.4-10.5(m,1H),8.5-8.6(m,1H),8.2-8.3(m,1H),8.22(br d,2H,J=8.1Hz),8.07(d,2H,J=8.2Hz),8.00(d,1H,J=2.6Hz),7.8-7.9(m,1H),7.4-7.5(m,1H),7.38(d,1H,J=7.5Hz),7.20(s,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 422(M+H)+
实施例28:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-6-甲基烟酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.53(br s,1H),10.79(s,1H),10.34(s,1H),9.0-9.1(m,1H),8.58(s,1H),8.27(br d,2H,J=5.3Hz),7.99(d,1H,J=2.4Hz),7.8-7.9(m,1H),7.4-7.5(m,2H),7.38(s,1H),7.19(s,1H),2.58(s,3H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 412(M+H)+
实施例29:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-6-(三氟甲基)烟酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.80(s,1H),10.75(s,1H),9.0-9.1(m,1H),8.6-8.6(m,1H),8.4-8.5(m,1H),8.2-8.3(m,2H),8.0-8.1(m,1H),7.9-7.9(m,1H),7.4-7.5(m,1H),7.3-7.4(m,1H),7.2-7.3(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 466(M+H)+
实施例30:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-5,6-二氟烟酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.4-11.5(m,1H),10.80(s,1H),10.67(s,1H),8.58(s,1H),8.27(s,2H),8.04(d,1H,J=1.8Hz),7.8-7.9(m,2H),7.44(br d,2H,J=6.8Hz),7.21(s,1H),2.0-2.1(m,1H),0.7-0.9(m,4H)
MS(ESI+)m/z 434(M+H)+
实施例31:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-5-氟烟酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.4-11.5(m,1H),10.8-10.8(m,1H),8.8-8.8(m,1H),8.6-8.7(m,1H),8.6-8.7(m,1H),8.5-8.6(m,1H),8.57(s,1H),8.2-8.3(m,1H),8.0-8.0(m,1H),7.87(br s,2H),7.5-7.5(m,1H),7.4-7.4(m,1H),7.2-7.3(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 416(M+H)+
实施例32:6-氯-N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)烟酰胺的合成
1H NMR(DMSO-d6,400MHz)δ8.61-8.69(m,1H),8.31-8.39(m,1H),8.26(d,1H,J=5.1Hz),8.12(s,1H),7.98(br s,2H),7.8-7.8(m,1H),7.62(br d,1H,J=1.1Hz),7.4-7.5(m,1H),7.1-7.2(m,1H),2.0-2.1(m,1H),0.87(br d,4H,J=1.1Hz)
MS(ESI+)m/z 433(M+H)+
实施例33:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-1H-吡唑-3-甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.7-10.8(m,1H),10.0-10.1(m,1H),8.57(s,1H),8.2-8.3(m,1H),7.93(br d,1H,J=1.8Hz),7.9-8.0(m,1H),7.8-7.8(m,1H),7.5-7.5(m,1H),7.4-7.4(m,1H),7.1-7.2(m,1H),6.83(br s,1H),2.05(br d,1H,J=2.4Hz),0.8-0.9(m,4H)
MS(ESI+)m/z 387(M+H)+
实施例34:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-1-甲基-2-氧代-1,2-二氢吡啶-3-甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ12.08(s,1H),11.3-11.5(m,1H),10.8-11.0(m,1H),8.50(br dd,2H,J=2.1,7.2Hz),8.26(br d,2H,J=5.5Hz),7.9-8.0(m,1H),7.83(s,1H),7.4-7.5(m,1H),7.31(s,1H),7.19(s,1H),6.64(s,1H),3.68(s,3H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 428(M+H)+
实施例35:2-氰基-N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)异烟酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.5-11.6(m,1H),10.8-10.8(m,1H),10.7-10.7(m,1H),9.0-9.1(m,1H),8.6-8.7(m,1H),8.5-8.6(m,1H),8.29(s,2H),8.0-8.1(m,1H),7.9-7.9(m,1H),7.4-7.5(m,1H),7.4-7.4(m,1H),7.2-7.2(m,1H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 423(M+H)+
实施例36:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-4-乙基-1H-吡咯-2-甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.5-11.5(m,1H),11.4-11.5(m,1H),10.7-10.8(m,1H),9.5-9.7(m,1H),8.57(s,1H),8.2-8.3(m,1H),7.95(s,1H),7.7-7.8(m,1H),7.43(s,2H),7.1-7.2(m,1H),7.0-7.0(m,1H),6.8-6.8(m,1H),2.0-2.1(m,1H),1.23(br s,2H),1.18(t,4H,J=7.6Hz),0.85(br d,4H,J=14.3Hz)
MS(ESI+)m/z 414(M+H)+
实施例37:3-(2-(环丙烷甲酰胺基)吡啶-4-基)-N-(2,2,2-三氟乙基)-7-(3-(2,2,2-三氟乙基)脲基)-1H-吲哚-1-甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.98(br s,1H),10.79(s,1H),8.58(s,1H),8.2-8.3(m,2H),8.03(d,1H,J=8.2Hz),7.96(s,1H),7.44(br d,1H,J=5.3Hz),7.25(t,1H,J=8.0Hz),7.05(d,1H,J=7.7Hz),3.8-4.0(m,4H),2.0-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 543(M+H)+
实施例38:N-(3-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-7-基)-3-氟苯甲酰胺的合成
1H NMR(DMSO-d6,400MHz)δ11.24(br s,1H),10.71(s,1H),8.53(s,1H),8.22(d,1H,J=5.3Hz),7.90(d,1H,J=2.7Hz),7.37(dd,1H,J=1.3,5.3Hz),7.22(d,1H,J=8.1Hz),6.88(t,1H,J=7.8Hz),6.42(d,1H,J=7.5Hz),1.9-2.1(m,1H),0.8-0.9(m,4H)
MS(ESI+)m/z 415(M+H)+
实施例39:N-(4-(7-(3-(2,2,2-三氟乙基)脲基)-3H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.21-11.33(m,1H),10.71-10.80(m,1H),8.67-8.76(m,1H),8.51-8.56(m,1H),8.21-8.29(m,1H),7.90-7.95(m,1H),7.65-7.71(m,1H),7.36-7.43(m,1H),7.23-7.29(m,1H),7.05-7.12(m,1H),6.89-6.96(m,1H),3.92-4.03(m,2H),1.99-2.09(m,1H),0.79-0.88(m,4H)
MS(ESI+)m/z 418(M+H)+
实施例40:N-(4-(4-(2-氰基-3-甲基丁-2-烯酰胺基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
[步骤1]N-(4-氟吡啶-2-基)环丙烷甲酰胺的合成
将2-氨基-4-氟吡啶(5g,44.6mmol)溶解在二氯甲烷中,随后在0℃下向其中缓慢地逐滴添加吡啶(10.5mL)和环丙烷甲酰氯(4.9mL,53.5mmol),然后在同一温度下搅拌两小时。将反应混合物添加到水中,随后过滤所得固体,然后在减压下干燥,以获得标题化合物(5.67g,90.1mmol)(70%)。
MS(ESI+)m/z 181(M+H)+
[步骤2]N-(4-(4-硝基-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
将4-硝基-1H-吲哚(4.3g,26.6mmol)溶解在二甲基甲酰胺(50mL)中,随后在0℃下向其中缓慢地添加在油中的60%NaH(1.1g,26.6mmol)。在向其中添加N-(4-氟吡啶-2-基)环丙烷甲酰胺(4.0g,22.2mmol),以便搅拌反应混合物之后,搅拌所得混合物0.5小时。当反应完成时,在室温下搅拌所述混合物,随后在搅拌的同时向其中添加饱和NH4Cl水溶液。将有机层用二氯甲烷萃取,然后在减压下浓缩,随后用柱层析法分离所得残余物,以获得标题化合物。
1H NMR(400MHz,DMSO-d6)δ11.09-11.27(m,1H),8.46-8.56(m,1H),8.34-8.42(m,1H),8.13-8.24(m,3H),7.46-7.55(m,1H),7.39-7.46(m,1H),7.30-7.37(m,1H),1.99-2.12(m,1H),0.79-0.93(m,4H)
MS(ESI+)m/z 323(M+H)+
[步骤3]N-(4-(4-氨基-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
将N-[4-(4-硝基吲哚-1-基)-2-吡啶基]环丙烷甲酰胺(5g,15.5mmol)插入到甲醇(100mL)中,随后向其中添加Pd/C(500mg),然后于40至50℃在氢气气氛下搅拌六小时。当反应完成时,将所述混合物冷却至室温,然后用赛力特硅藻土过滤。在减压下蒸馏所得滤液,然后用柱层析法分离,以获得标题化合物(3.9g,87%)。
MS(ESI+)m/z 293(M+H)+
[步骤4]N-(4-(4-(2-氰基-3-甲基丁-2-烯酰胺基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
进行与实施例1的步骤8基本相同的工艺,以获得产物,即、N-(4-(4-(2-氰基-3-甲基丁-2-烯酰胺基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺。
1H NMR(400MHz,DMSO-d6)δ11.04-11.12(m,1H),10.41-10.54(m,1H),8.42-8.48(m,1H),8.38-8.42(m,1H),7.75-7.80(m,1H),7.58-7.66(m,2H),7.36-7.40(m,1H),7.24-7.30(m,1H)6.91-6.98(m,1H),2.20(s,3H),2.13(s,3H),2.02-2.07(m,1H),1.19-1.26(m,2H),0.83-0.87(m,4H).
MS(ESI+)m/z 400(M+H)+
实施例41至62
在下文中,实施例41至62中的化合物通过如实施例40中所示的相同方法来制备,但考虑到反应式2以及要制备的化合物的结构而用适当的反应物来制备。
实施例41:N-(4-(4-(2-氰基乙酰胺基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ10.99-11.17(m,1H),10.03-10.22(m,1H),8.42-8.48(m,1H),8.37-8.42(m,1H),7.75-7.81(m,1H),7.67-7.73(m,1H),7.54-7.60(m,1H),7.34-7.41(m,1H),7.21-7.30(m,1H),6.97-7.05(m,1H),3.99-4.10(m,2H),2.00-2.09(m,1H),0.77-0.89(m,4H)
MS(ESI+)m/z 360(M+H)+
实施例42:N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)-1H-吡咯-2-甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.67-11.80(m,1H),10.98-11.13(m,1H),9.66-9.81(m,1H),8.43(s,2H),7.71-7.80(m,1H),7.56-7.64(m,1H),7.48-7.56(m,1H),7.35-7.42(m,1H),7.22-7.32(m,1H),7.11-7.21(m,1H),6.95-7.02(m,1H),6.85-6.95(m,1H),6.11-6.25(m,1H),1.97-2.14(m,1H),0.77-0.94(m,4H)
MS(ESI+)m/z 386(M+H)+
实施例43:N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)-2-甲基噻唑-5-甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.02-11.14(m,1H),10.03-10.15(m,1H),8.40-8.49(m,2H),8.33(s,1H),7.75-7.83(m,1H),7.67-7.73(m,1H),7.59-7.66(m,1H),7.36-7.45(m,1H),7.26-7.34(m,1H),6.75-6.84(m,1H),2.80(s,3H),1.99-2.11(m,1H),0.86(br d,J=4.76Hz,4H)
MS(ESI+)m/z 418(M+H)+
实施例44:N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)-3,5-二氟苯甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.45(s,1H),8.44(s,2H),7.78(s,3H),7.64-7.70(m,1H),7.48-7.59(m,2H),7.37-7.43(m,1H),7.26-7.35(m,1H),6.89-6.99(m,1H),2.00-2.10(m,1H),0.80-0.91(m,4H)
MS(ESI+)m/z 433(M+H)+
实施例45:N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)-1-甲基-2-氧代-1,2-二氢吡啶-3-甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ12.71-12.87(m,1H),10.96-11.22(m,1H),8.38-8.62(m,3H),8.16-8.26(m,2H),7.78-7.94(m,1H),7.48-7.66(m,1H),7.34-7.45(m,1H),7.23-7.33(m,1H),6.83-6.97(m,1H),6.55-6.72(m,1H),3.64-3.76(m,3H),1.97-2.17(m,1H),0.77-0.96(m,4H)
MS(ESI+)m/z 428(M+H)+
实施例46:N-(4-(4-(2-氰基-3-(噻吩-2-基)丙烯酰胺基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.02-11.12(m,1H),10.25-10.40(m,1H),8.57-8.64(m,1H),8.40-8.49(m,2H),8.11-8.20(m,1H),7.94-8.01(m,1H),7.76-7.83(m,1H),7.61-7.70(m,1H),7.45-7.50(m,1H),7.34-7.42(m,2H),7.24-7.33(m,1H),6.85-6.93(m,1H),2.00-2.13(m,1H),0.73-0.92(m,4H)
MS(ESI+)m/z 454(M+H)+
实施例47:4-氰基-N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)苯甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.04-11.14(m,1H),10.48-10.62(m,1H),8.40-8.49(m,2H),8.14-8.23(m,2H),7.99-8.09(m,2H),7.74-7.83(m,1H),7.61-7.70(m,1H),7.52-7.60(m,1H),7.35-7.42(m,1H),7.26-7.34(m,1H),6.91-6.97(m,1H),2.00-2.11(m,1H),0.80-0.90(m,4H)
MS(ESI+)m/z 422(M+H)+
实施例48:N-(4-(4-(2-氰基-3-苯基丙烯酰胺基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.05-11.14(m,1H),10.37-10.49(m,1H),8.41-8.49(m,2H),8.35-8.40(m,1H),8.00-8.09(m,2H),7.78-7.84(m,1H),7.60-7.69(m,4H),7.47-7.54(m,1H),7.38-7.43(m,1H),7.26-7.34(m,1H),6.90-6.98(m,1H),1.98-2.11(m,1H),0.79-0.90(m,4H)
MS(ESI+)m/z 448(M+H)+
实施例49:N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)-1-甲基-1H-吲哚-2-甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.04-11.12(m,1H),10.31-10.40(m,1H),8.40-8.48(m,2H),7.76-7.82(m,1H),7.69-7.74(m,1H),7.61-7.67(m,1H),7.52-7.61(m,2H),7.37-7.44(m,2H),7.27-7.35(m,2H),7.09-7.19(m,1H),6.92-7.01(m,1H),3.99-4.10(m,3H),2.00-2.11(m,1H),0.78-0.89(m,4H)ppm.
MS(ESI+)m/z 450(M+H)+
实施例50:4-氰基-N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)四氢-2H-吡喃-4-甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.22-10.38(m,1H),8.37-8.49(m,2H),7.79(d,J=3.48Hz,1H),7.61-7.71(m,1H),7.34-7.42(m,1H),7.22-7.31(m,2H),7.00-7.09(m,1H),6.76(d,J=3.48Hz,1H),3.99(br d,J=11.89Hz,2H),3.54-3.68(m,2H),2.12-2.29(m,4H),1.99-2.10(m,1H),0.86(br d,J=4.03Hz,4H)
MS(ESI+)m/z 430(M+H)+
实施例51:2-氰基-N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)异烟酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.03-11.15(m,1H),10.65-10.80(m,1H),8.92-9.04(m,1H),8.60(s,1H),8.39-8.48(m,2H),8.21-8.28(m,1H),7.75-7.84(m,1H),7.55-7.72(m,2H),7.37-7.44(m,1H),7.25-7.34(m,1H),6.97-7.07(m,1H),2.00-2.12(m,1H),0.74-0.92(m,4H)
MS(ESI+)m/z 423(M+H)+
实施例52:N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)-2-氟异烟酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.01-11.16(m,1H),10.54-10.68(m,1H),8.41-8.51(m,3H),7.86-7.98(m,1H),7.72-7.83(m,2H),7.61-7.68(m,1H),7.52-7.60(m,1H),7.36-7.44(m,1H),7.26-7.36(m,1H),6.90-7.00(m,1H),1.99-2.10(m,1H),0.86(br s,4H)
MS(ESI+)m/z 416(M+H)+
实施例53:N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)-2,3-二氟异烟酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.52-10.81(m,1H),8.35-8.53(m,2H),8.14-8.29(m,1H),7.79(br d,J=3.48Hz,2H),7.70-7.76(m,1H),7.64(d,J=8.42Hz,1H),7.34-7.43(m,1H),7.22-7.34(m,1H),6.91-7.06(m,1H),2.00-2.10(m,1H),0.86(br d,J=4.21Hz,4H)
MS(ESI+)m/z 434(M+H)+
实施例54:N-(4-(4-(2-氰基丙酰胺基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.08(br s,1H),10.12-10.37(m,1H),8.36-8.49(m,2H),7.74-7.85(m,1H),7.64-7.71(m,1H),7.54-7.63(m,1H),7.34-7.44(m,1H),7.20-7.31(m,1H),6.93-7.05(m,1H),4.11-4.24(m,1H,1.97-2.13(m,1H),1.57(d,J=7.14Hz,3H),0.85(br s,4H)
MS(ESI+)m/z 374(M+H)+
实施例55:N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)-1H-吡唑-3-甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ10.99-11.18(m,1H),9.68-10.13(m,1H),8.35-8.52(m,2H),7.83-7.95(m,1H),7.71-7.82(m,1H),7.55-7.71(m,2H),7.35-7.46(m,1H),7.21-7.35(m,1H),6.71-6.93(m,2H),1.98-2.13(m,1H),0.73-0.92(m,4H)
MS(ESI+)m/z 387(M+H)+
实施例56:N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)-3-氟-4-甲氧苯甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.01-11.17(m,1H),10.10-10.30(m,1H),8.39-8.51(m,2H),7.87-8.02(m,2H),7.72-7.80(m,1H),7.59-7.68(m,1H),7.45-7.53(m,1H),7.24-7.42(m,3H),6.85-6.98(m,1H),3.94(s,3H),2.00-2.10(m,1H),0.86(br d,J=3.84Hz,4H)
MS(ESI+)m/z 445(M+H)+
实施例57:(1R,2S)-2-氰基-N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)环丙烷-1-甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ10.97-11.19(m,1H),10.25-10.47(m,1H),8.34-8.54(m,2H),7.70-7.85(m,2H),7.50-7.62(m,1H),7.34-7.42(m,1H),7.20-7.28(m,1H),7.03-7.12(m,1H),2.56-2.71(m,2H),2.21-2.35(m,1H),1.99-2.10(m,1H),1.40-1.56(m,2H),0.86(br d,J=3.84Hz,4H)
MS(ESI+)m/z 386(M+H)+
实施例58:N-(4-(4-(2-(1-氰基环丙基)乙酰胺基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.00-11.10(m,1H),9.80-9.91(m,1H),8.38-8.48(m,2H),7.72-7.81(m,2H),7.50-7.58(m,1H),7.32-7.41(m,1H),7.19-7.27(m,1H),6.99-7.07(m,1H),2.75(s,2H),2.02-2.11(m,1H),0.85(br s,4H)
MS(ESI+)m/z 400(M+H)+
实施例59:N-(1-(2-(环丙烷甲酰胺基)吡啶-4-基)-1H-吲哚-4-基)-6-甲基烟酰胺的合成
1H NMR(400MHz,DMSO-d6)δ10.99-11.14(m,1H),10.31-10.47(m,1H),8.98-9.11(m,1H),8.38-8.48(m,2H),8.20-8.33(m,1H),7.72-7.82(m,1H),7.61-7.67(m,1H),7.53-7.58(m,1H),7.42-7.47(m,1H),7.37-7.42(m,1H),7.24-7.34(m,1H),6.90-7.00(m,1H),2.58(s,3H),2.02-2.11(m,1H),1.22-1.31(m,5H),0.80-0.92(m,4H)
MS(ESI+)m/z 412(M+H)+
实施例60:N-(4-(4-(2,3-二甲基丁-2-烯酰胺基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ10.97-11.15(m,1H),9.69-9.87(m,1H),8.35-8.51(m,2H),7.65-7.78(m,2H),7.50-7.61(m,1H),7.31-7.41(m,1H),7.15-7.28(m,1H),6.96-7.07(m,1H),2.68(s,6H),2.00-2.10(m,1H),1.85-1.92(m,3H),1.78-1.85(m,3H),1.74(s,3H),0.77-0.91(m,4H)
MS(ESI+)m/z 389(M+H)+
实施例61:N-(4-(4-(3-(2,4-二氟苯基)脲基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ8.98-9.08(m,1H),8.80-8.91(m,1H),8.38-8.49(m,2H),8.10-8.30(m,1H),7.81-7.92(m,1H),7.74-7.81(m,1H),7.42-7.51(m,1H),7.28-7.42(m,2H),7.17-7.27(m,1H),7.03-7.13(m,1H),6.86-6.97(m,1H),2.01-2.12(m,1H),0.86(br d,J=4.39Hz,4H)
MS(ESI+)m/z 448(M+H)+
实施例62:N-(4-(4-(3-(2,2,2-三氟乙基)脲基)-1H-吲哚-1-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.64-8.77(m,1H),8.35-8.52(m,2H),7.71-7.86(m,2H),7.32-7.49(m,2H),7.12-7.23(m,1H),6.93-7.05(m,1H),6.73-6.90(m,3H),3.93-4.08(m,2H),3.84(m,4H),1.98-2.09(m,1H),0.78-0.93(m,4H)
MS(ESI+)m/z 418(M+H)+
在下文中,实施例63中的化合物以如此方式来制备:考虑到反应式1以及要制备的化合物的结构,通过如实施例1中所示的相同方法来进行合成,或使用适当的反应物。
实施例63:N-(4-(7-(2-氰基-3-甲基丁-2-烯酰胺基)-1H-吲唑-3-基)吡啶-2-基)环丙烷甲酰胺的合成
1H NMR(400MHz,DMSO-d6)δ11.25-11.42(m,1H),10.95-11.03(m,1H),8.79(s,1H),8.39-8.47(m,1H),7.81-7.90(m,1H),7.65-7.73(m,1H),7.32-7.41(m,1H),7.13-7.28(m,1H),4.96-5.48(m,1H),2.68(s,6H),2.02-2.10(m,1H),1.96-2.23(m,3H),0.81-0.91(m,4H)
MS(ESI+)m/z 401(M+H)+
实验实施例1:JAK1活性抑制能力的分析(ADP-GloTM激酶测定)
本发明化合物对JAK的抑制效果如下进行鉴定。
对照材料和测试材料通过使用DMSO按每种浓度稀释来制备。同时,ATP(250uM)以及JAK的底物(JAK1,IRS-1tide 40ng/mL)通过在激酶缓冲液(40mM Tris-HCl pH 7.5,20mMMgCl2,0.5mg/mL BSA,50uM DTT)中稀释来制备。
将每种浓度的测试药物、底物、ATP和JAK酶在eppendorf管中进行混合,然后在30℃的孵育器中进行反应达40分钟。
将ADP-GloTM激酶酶系统(Promega,USA,V9571)中所包括的ADP-Glo◎试剂加到每根eppendorf管中,然后在30℃的孵育器中进行反应达40分钟。
将ADP-GloTM激酶酶系统中所包括的激酶检测试剂加入到eppendorf管中,随后使用Wallac Victor 2TM(积分时间设置为1秒)来测量发光,以便分析测试材料对JAK磷酸化的抑制能力。与对照组相比,JAK酶活性抑制发生50%时的化合物浓度被确定为抑制剂的IC50(nM)。其结果示出在以下表1中。
[表1]:
工业适用性
由于具有蛋白激酶抑制活性,由根据本发明的式1表示的化合物、其立体异构体或其药物上可接受的盐对预防或治疗蛋白激酶相关疾病具有显著的优异效果,并且因此可以预期在相关药物工业中得到有价值的使用。
Claims (14)
1.由以下式1表示的化合物、其立体异构体或其药物上可接受的盐:
[式1]
在式1中,
R1为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
X为C-A1或N,
Y为C-A2或N-A4,
Z为C-A3或N-A5,其中X、Y和Z中的至少一个包含N;
X与Y之间的键或Y与Z之间的键中的至少一个是双键,并且如果X与Y之间的所述键是双键,则A1或A4不存在;
A1至A5各自独立地为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6卤代烷基、C1-6氰基烷基、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、-C(=O)-N-C1-6卤代烷基、芳基或杂芳基;
R2为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
n和m各自独立地为0、1、2或3;
B1为-C(=O)-、-C(=S)-、-C(=O)-NR3-或单键;
B2为C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
B3为H或C1-6烷基;
D1为-NR3-;
D2为-C(=O)-、-C(=S)-、-S(=O)2-或单键;
D4为H、C1-6烷基、C1-6烯基、C1-6卤代烷基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基、C1-6卤代烷基或C1-6氰基烷基中的至少一个H可以被C3-7环烷基、芳基、杂芳基或氰基取代,
C3-7环烷基或5至6元杂环烷基中的至少一个H可以被C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、氰基或卤素取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟烷基、C1-6氰基烷基、C1-6硫代烷基、羟基、氰基、硝基或卤素取代;以及
R3和R4各自独立地为H、C1-6烷基或C1-6卤代烷基。
2.根据权利要求1所述的由式1表示的化合物、其立体异构体或其药物上可接受的盐,其中由以上所述式1表示的所述化合物是由以下式1-1、1-2和1-3表示的化合物中的一种:
[式1-1]
[式1-2]
[式1-3]
在这些式中,
R1为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
A2至A5各自独立地为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6卤代烷基、C1-6氰基烷基、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、-C(=O)-N-C1-6卤代烷基、芳基或杂芳基;
R2为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
n和m各自独立地为0、1、2或3;
B1为-C(=O)-、-C(=S)-、-C(=O)-NR3-或单键;
B2为C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
B3为H或C1-6烷基;
D1为-NR3-;
D2为-C(=O)-、-C(=S)-、-S(=O)2-或单键;
D4为H、C1-6烷基、C1-6烯基、C1-6卤代烷基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基、C1-6卤代烷基或C1-6氰基烷基中的至少一个H可以被C3-7环烷基、芳基、杂芳基或氰基取代,
C3-7环烷基或5至6元杂环烷基中的至少一个H可以被C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、氰基或卤素取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟烷基、C1-6氰基烷基、C1-6硫代烷基、羟基、氰基、硝基或卤素取代;以及
R3和R4各自独立地为H、C1-6烷基或C1-6卤代烷基。
3.根据权利要求1所述的由式1表示的化合物、其立体异构体或其药物上可接受的盐,其中由式1表示的所述化合物是由以下式2表示的化合物:
[式2]
在式2中,
R1为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
X为C-A1或N,
Y为C-A2或N-A4,
Z为C-A3或N-A5,其中X、Y和Z中的至少一个包含N;
X与Y之间的键或Y与Z之间的键中的至少一个是双键,并且如果X与Y之间的所述键是双键,则A1或A4不存在;
A1至A5各自独立地为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6卤代烷基、C1-6氰基烷基、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、-C(=O)-N-C1-6卤代烷基、芳基或杂芳基;
R2为H、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6氰基烷基、C1-6卤代烷基、羟基、氰基、卤素、C(=O)-OH、C(=O)-O-C1-6烷基、S(=O)2-C1-6烷基、芳基或杂芳基;
n和m各自独立地为0或1;
D2为-C(=O)-、-C(=S)-、-S(=O)2-或单键;
D4为H、C1-6烷基、C1-6烯基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基或C1-6氰基烷基中的至少一个H可以被C3-7环烷基、芳基、杂芳基或氰基取代,
C3-7环烷基或5至6元杂环烷基中的至少一个H可以被C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、氰基或卤素取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟烷基、C1-6氰基烷基、C1-6硫代烷基、羟基、氰基、硝基或卤素取代;以及
R3和R4各自独立地为H、C1-6烷基或C1-6卤代烷基。
4.根据权利要求1所述的由式1表示的化合物、其立体异构体或其药物上可接受的盐,其中:
R1为H、C1-6烷基或C1-6烷氧基;
X为C-A1或N,
Y为C-A2或N-A4,
Z为C-A3或N-A5,其中X、Y和Z中的至少一个包含N;
X与Y之间的键或Y与Z之间的键中的至少一个是双键,并且如果X与Y之间的所述键是双键,则A1或A4不存在;
A1至A5各自独立地为H、C1-6烷基或-C(=O)-N-C1-6卤代烷基。
R2为H、C1-6烷基或C1-6杂芳基;
n和m各自独立地为0或1;
D2为-C(=O)-;
D4为H、C1-6烷基、C1-6烯基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基或C1-6氰基烷基中的至少一个H可以被C3-7环烷基、芳基、杂芳基或氰基取代,
C3-7环烷基或4至6元杂环烷基中的至少一个H可以被C1-6烷基、C1-6氰基烷基或氰基取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6烷氧基、C1-6卤代烷基或氰基取代;以及
R3和R4各自独立地为H、C1-6烷基或C1-6卤代烷基。
5.根据权利要求4所述的由式1表示的化合物、其立体异构体或其药物上可接受的盐,其中:
R1为H;
X为N;
Y为C-A2;
Z为C-A3;
Y与Z之间的键是双键;
A2和A3各自独立地为H;
R2为H;
n和m各自独立地为0;
D2为-C(=O)-;
D4为H、C1-6烷基、C1-6烯基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基或C1-6氰基烷基中的至少一个H可以被芳基、杂芳基或氰基取代,
C3-7环烷基或5至6元杂环烷基中的至少一个H可以被C1-6氰基烷基或氰基取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6烷氧基、氰基、硝基或卤素取代;以及
R3和R4各自独立地为H或C1-6烷基。
6.根据权利要求4所述的由式1表示的化合物、其立体异构体或其药物上可接受的盐,其中:
R1为H、C1-6烷基或C1-6烷氧基;
X为C-A1;
Y为C-A2;
Z为N-A5,其中X、Y和Z中的至少一个包含N;
X与Y之间的键是双键,并且如果X与Y之间的所述键是双键,则A1不存在;
A2和A5各自独立地为H、C1-6烷基或-C(=O)-N-C1-6卤代烷基;
R2为H或C1-6烷基;
n和m各自独立地为0或1;
D2为-C(=O)-;
D4为H、C1-6烷基、C1-6烯基、C1-6氰基烷基、C3-7环烷基、5至6元杂环烷基、芳基或杂芳基;
其中C1-6烷基、C1-6烯基或C1-6氰基烷基中的至少一个H可以被C3-7环烷基、杂芳基或氰基取代,
C3-7环烷基或5至6元杂环烷基中的至少一个H可以被C1-6烷基或氰基取代,并且
芳基或杂芳基中的至少一个H可以被C1-6烷基、C1-6卤代烷基或氰基取代;以及
R3和R4各自独立地为H、C1-6烷基或C1-6卤代烷基。
7.根据权利要求4所述的由式1表示的化合物、其立体异构体或其药物上可接受的盐,其中:
R1为H;
X为C-A1;
Y为N-A4;
Z为N-A5;
X与Y之间的键是双键;
A1、A4和A5各自独立地为H;
R2为H;
n和m各自独立地为0;
D2为-C(=O)-;
D3为单键;
D4为C1-6烯基,其中C1-6烯基中的至少一个H可以被氰基取代;以及
R3为H。
9.药物组合物,该组合物包含作为活性成分的根据权利要求1至8之一所述的化合物、其立体异构体或其药物上可接受的盐。
10.根据权利要求9所述的药物组合物,其中所述药物组合物用于预防或治疗蛋白激酶相关疾病。
11.根据权利要求10所述的药物组合物,其中所述蛋白激酶相关疾病选自癌症、自身免疫性疾病、神经疾病、代谢性疾病和感染。
12.根据权利要求1至8之一所述的化合物、其立体异构体或其药物上可接受的盐在制备用于预防或治疗蛋白激酶相关疾病的药物中的用途。
13.用于预防或治疗蛋白激酶相关疾病的方法,该方法包括将治疗有效量的根据权利要求1至8之一所述的化合物、其立体异构体或其药物上可接受的盐给药至个体的步骤。
14.根据权利要求1至8之一所述的化合物、其立体异构体或其药物上可接受的盐用于预防或治疗蛋白激酶相关疾病的用途。
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