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CN108658972A - A kind of substituted lactams compounds and its preparation method and application - Google Patents

A kind of substituted lactams compounds and its preparation method and application Download PDF

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Publication number
CN108658972A
CN108658972A CN201710191265.8A CN201710191265A CN108658972A CN 108658972 A CN108658972 A CN 108658972A CN 201710191265 A CN201710191265 A CN 201710191265A CN 108658972 A CN108658972 A CN 108658972A
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China
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base
alkyl
aliphatic
amino
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Inventor
邵长伦
牟晓凤
魏美燕
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Ocean University of China
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Ocean University of China
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Priority to CN201710191265.8A priority Critical patent/CN108658972A/en
Priority to PCT/CN2018/080728 priority patent/WO2018177297A1/en
Publication of CN108658972A publication Critical patent/CN108658972A/en
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及一种取代内酰胺类化合物,或其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或其盐的溶剂化物,或前药,以及包含该化合物的药物组合物。本发明还公开了这类化合物及其药物组合物作为药物尤其是作为抗病毒药物的用途。The present invention relates to a substituted lactam compound, or tautomers, stereoisomers, racemates, non-equivalent mixtures of enantiomers, geometric isomers, solvates, pharmaceutically An acceptable salt or a solvate of the salt, or a prodrug, and a pharmaceutical composition comprising the compound. The invention also discloses the application of this compound and its pharmaceutical composition as medicine, especially as antiviral medicine.

Description

一种取代内酰胺类化合物及其制备方法和用途A kind of substituted lactam compound and its preparation method and application

技术领域technical field

本发明属于药物领域, 并具体涉及一种取代内酰胺类化合物及其药物组合物以及其作为药物尤其是作为抗病毒药物的用途。The invention belongs to the field of medicine, and specifically relates to a substituted lactam compound and its pharmaceutical composition and its use as a medicine, especially as an antiviral medicine.

背景技术Background technique

病毒按其外壳是否包裹着富含脂质的膜可简单地分为无囊膜病毒与有囊膜病毒两类。无囊膜病毒主要是通过吞饮作用在网格蛋白介导下进入被感染细胞;有囊膜病毒的入侵主要是病毒囊膜与宿主细胞膜的融合过程。目前抗病毒制剂的研究开发主要基于两方面来设计, 一是从病毒浸染层面, 二是从宿主细胞防御层面。目前已上市大部分抗病毒药物是基于病毒本身的, 即作用受体为病毒本身。干扰素 (IFN) 是最早开发的一代抗病毒药物, 因其具有“干扰”病毒复制的能力而命名。近年来越来越多的抗病毒药物被研发出来, 并广泛使用于临床的治疗上。例如, 继干扰素之后的另一类能干扰病毒转录或复制的核苷类药物, 利巴韦林(ribavirin), 阿昔洛韦 (acyclovir), 伐昔洛韦(valacyiclovir), 齐多夫定(zidovudine), 替比夫定 (telbivudine) 等。Viruses can be simply divided into non-enveloped viruses and enveloped viruses according to whether their shells are wrapped with lipid-rich membranes. Non-enveloped viruses mainly enter the infected cells through pinocytosis mediated by clathrin; the invasion of enveloped viruses is mainly the fusion process of the viral envelope and the host cell membrane. At present, the research and development of antiviral agents are mainly designed based on two aspects, one is from the level of virus infection, and the other is from the level of host cell defense. Most antiviral drugs currently on the market are based on the virus itself, that is, the receptor for the action is the virus itself. Interferon (IFN) was the first generation of antiviral drugs developed, named for their ability to "interfere" with viral replication. In recent years, more and more antiviral drugs have been developed and widely used in clinical treatment. For example, after interferon, another class of nucleoside drugs that can interfere with viral transcription or replication, ribavirin, acyclovir, valacyiclovir, zidovudine (zidovudine), telbivudine (telbivudine), etc.

虽然许多的抗病毒药物陆续被有效使用于临床, 但近年来抗药性病毒也日见浮现。抗药性产生的原因主要是病毒的基因产生突变而使得抗病毒药物丧失其作用的靶点所致。例如: HSV的胸苷激酶基因发生突变, 无法将阿昔洛韦 (acyclovir) 及更昔洛韦(ganciclovir) 等在细胞内转化成有效的成份, 因此对该些药物产生抗药性; 流感A病毒的M2蛋白基因突变, 则会对金刚烷胺或金刚乙胺(rimantadine)产生抗药性; HIV逆转录酶或蛋白酶基因的变异亦是导致抗药性产生的主因; HCV的非结构性5A及包膜基因2-糖蛋白的基因变异会使HCV对干扰素产生抗药性。综上所述, 开发新型抗病毒药物迫在眉睫。Although many antiviral drugs have been effectively used clinically, drug-resistant viruses have also emerged in recent years. Drug resistance is mainly caused by mutations in the genes of viruses, which make antiviral drugs lose their targets. For example: the thymidine kinase gene of HSV has a mutation, which cannot convert acyclovir and ganciclovir into effective components in cells, so it is resistant to these drugs; influenza A virus Mutations in the M2 protein gene of HIV will lead to drug resistance to amantadine or rimantadine; HIV reverse transcriptase or protease gene mutations are also the main cause of drug resistance; HCV non-structural 5A and envelope Genetic variation in the gene 2-glycoprotein confers resistance to interferon in HCV. In summary, the development of new antiviral drugs is imminent.

WO 2016034512专利公开了如下化合物在肿瘤治疗方面的应用。WO 2016034512 patent discloses the application of the following compounds in tumor treatment.

JP 2003146972专利公开了如下化合物在抑制子宫平滑肌收缩方面的应用, 制备如早产、流产、月经不调等治疗药物。JP 2003146972 patent discloses the application of the following compounds in inhibiting the contraction of uterine smooth muscle to prepare therapeutic drugs such as premature labor, miscarriage, and irregular menstruation.

CN103127112专利公开了如下化合物在肿瘤治疗方面的应用。CN103127112 patent discloses the application of the following compounds in tumor treatment.

WO2015050379韩国专利公开了如下化合物在制备治疗慢性肺功能障碍, 哮喘等疾病的应用。WO2015050379 Korean patent discloses the application of the following compounds in the preparation and treatment of chronic pulmonary dysfunction, asthma and other diseases.

WO2014044615公开了如下所示化合物具有杀虫活性。WO2014044615 discloses that the compounds shown below have insecticidal activity.

中国专利201510917619.3和201510918196.7分别公开了如下所示化合物的抗污损活性和抗HSV-1病毒活性。Chinese patents 201510917619.3 and 201510918196.7 respectively disclose the anti-fouling activity and anti-HSV-1 virus activity of the compounds shown below.

中国专利201510150071.4和专利201510150737.6公开了如下所示化合物均具有抗RSV病毒活性。Chinese patent 201510150071.4 and patent 201510150737.6 disclose that the compounds shown below all have anti-RSV virus activity.

美国专利US20150291531 公开了如下所示化合物具有抗H1N1病毒活性。US Patent US20150291531 discloses that the compounds shown below have anti-H1N1 virus activity.

专利201510918373.1公开了一系列喹啉酮类化合物的抗HSV-1病毒活性。Patent 201510918373.1 discloses the anti-HSV-1 virus activity of a series of quinolinone compounds.

本发明在以上专利的基础上, 研究一种取代内酰胺类化合物在制备抗病毒药物方面的应用, 现有技术中, 公开的化合物虽与本发明化合物有一定的相似之处, 但本发明所示的化合物与现有技术是有显著区别的, 本发明中取代内酰胺类化合物的抗病毒活性得到极大的提高, 且毒性降低, 功效毒性比远强于现有抗病毒药物如利巴韦林等。On the basis of the above patents, the present invention studies the application of a substituted lactam compound in the preparation of antiviral drugs. In the prior art, although the disclosed compounds have certain similarities with the compounds of the present invention, the compounds disclosed in the present invention are The compound shown is significantly different from the prior art. The antiviral activity of the substituted lactam compound in the present invention is greatly improved, and the toxicity is reduced, and the efficacy-toxicity ratio is far stronger than that of existing antiviral drugs such as ribavir Lin et al.

发明内容Contents of the invention

一种式I和式II结构的取代内酰胺类化合物, 其互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或其盐的溶剂化物, 其特征在于化合物具有如下结构：, 其中A,B各自独立的为五元或六元芳环, 杂芳环, 碳环或碳杂环; “”为单键或不存在; n =1, 2, 3, 或4; k = 1, 2, 3, 4 或5; R1, R2, R3, R4的定义如下所示：A substituted lactam compound of formula I and formula II, its tautomers, stereoisomers, racemates, unequal mixtures of enantiomers, geometric isomers, solvates . A pharmaceutically acceptable salt or a solvate of a salt thereof, characterized in that the compound has the following structure: , where A and B are independently five-membered or six-membered aromatic rings, heteroaromatic rings, carbocycles or carboheterocycles; " ” is a single bond or does not exist; n =1, 2, 3, or 4; k = 1, 2, 3, 4 or 5; R 1 , R 2 , R 3 , R 4 are defined as follows:

各R1, R4可以相同或不同, 各自独立地为氢, 卤素, 羟基, 氨基, 硝基, 氰基, 羧基,烷基, 卤代烷基, 烷氧基, 烷氨基, 烷基酰基, 羟基烷氧基, 羟基烷氨基, 羟基烷酰基, 卤代烷氧基, 卤代烷氨基, 卤代烷酰基, 氨基烷氧基, 环烷基, 环烷基氧基, 环烷基氨基, 环烷基酰基, 烯基, 烯基烷氧基, 烯基烷氨基, 烯基烷酰基, 炔基, 炔基烷氧基, 炔基烷氨基, 炔基烷酰基, 芳基, 芳氧基, 芳酰基, 芳氨基, 芳基烷氧基, 芳基烷氨基, 杂芳基, 杂芳氧基, 杂芳酰基, 杂芳氨基, 杂芳基烷氧基, 杂芳基烷氨基, 杂环基烷酰基, 杂环烷基, 杂环基氧基, 杂环基氨基, 杂环基酰基, 杂环基烷氧基, 杂环基烷氨基, 杂环基烷酰基, 叠氮基烷氧基, 稠合双环基, 稠合杂双环基, 稠合双环基脂肪族, 稠合杂双环基脂肪族, 稠合双环基氧基, 稠合杂双环基氧基, 稠合双环基氨基, 稠合杂双环基氨基, 稠合双环基烷氧基, 稠合杂双环基烷氧基, 稠合双环基烷氨基, 稠合杂双环基烷氨基, 稠合双环基氧基烷氧基, 稠合杂双环基氧基烷氧基, 稠合双环基氨基烷氧基, 稠合杂双环基氨基烷氧基, 稠合双环基-C(=O)-, 稠合双环基-C(=O)O-, 稠合杂双环基-C(=O)-, 稠合杂双环基-C(=O)O-, 稠合双环基氨基-C(=O)-, 稠合杂双环基氨基-C(=O)-, 稠合双环基-C(=O)N(R6)-, 稠合杂双环基-C(=O)N(R6)-, 螺双环基, 螺杂双环基, 螺双环基脂肪族, 螺杂双环基脂肪族, 螺双环基氧基, 螺杂双环基氧基, 螺双环基氨基, 螺杂双环基氨基, 螺双环基烷氧基, 螺杂双环基烷氧基, 螺双环基烷氨基, 螺杂双环基烷氨基, 螺双环基氧基烷氧基, 螺杂双环基氧基烷氧基, 螺双环基氨基烷氧基,螺杂双环基氨基烷氧基, 螺双环基-C(=O)-, 螺双环基-C(=O)O-, 螺杂双环基-C(=O)-,螺杂双环基-C(=O)O-, 螺双环基氨基-C(=O)-, 螺杂双环基氨基-C(=O)-, 螺双环基-C(=O)N(R5)-, 螺杂双环基-C(=O)N(R5)-, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5,-N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N-烷基, R5S(=O)t-烷基, R5R6N-C(=O)-烷基, R6R5N-烷氧基, R5S(=O)t-烷氧基, R5R6N-C(=O)-烷氧基,芳基-(CH2)p-G-(CH2)m-, 杂芳基-(CH2)p-G-(CH2)m-, 杂环基-(CH2)p-G-(CH2)m-, 或环烷基-(CH2)p-G-(CH2)m-, 其中G是O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t-, 或-OS(=O)tN(R5)-; t是l或2; p和m各自独立地为0, l, 2, 3或4; 或者其中芳基-(CH2)p-G-(CH2)m-, 杂芳基-(CH2)p-G-(CH2)m-, 杂环基-(CH2)p-G-(CH2)m-, 或环烷基-(CH2)p-G-(CH2)m-可以被一个或多个选自F, Cl, Br, I, 烷基, 烯基, 炔基, 烷氧基或氰基的取代基取代;Each R 1 and R 4 may be the same or different, each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, alkyl, haloalkyl, alkoxy, alkylamino, alkylacyl, hydroxyalkane Oxy, Hydroxyalkylamino, Hydroxyalkanoyl, Haloalkoxy, Haloalkylamino, Haloalkanoyl, Aminoalkoxy, Cycloalkyl, Cycloalkyloxy, Cycloalkylamino, Cycloalkylacyl, Alkenyl, Alkene Alkenylalkoxy, alkenylalkylamino, alkenylalkanoyl, alkynyl, alkynylalkoxy, alkynylalkylamino, alkynylalkanoyl, aryl, aryloxy, aroyl, arylamino, arylalkane Oxygen, Arylalkylamino, Heteroaryl, Heteroaryloxy, Heteroaroyl, Heteroarylamino, Heteroarylalkoxy, Heteroarylalkylamino, Heterocyclylalkanoyl, Heterocycloalkyl, Hetero Cyclooxy, Heterocyclylamino, Heterocyclylacyl, Heterocyclylalkoxy, Heterocyclylalkylamino, Heterocyclylalkanoyl, Azidoalkoxy, Fused Bicyclyl, Fused Heterobicyclo radical, fused bicyclylaliphatic, fused heterobicyclylaliphatic, fused bicyclyloxy, fused heterobicyclyloxy, fused bicyclylamino, fused heterobicyclylamino, fused bicyclylalkane Oxygen, Fused Heterobicyclylalkoxy, Fused Bicyclylalkylamino, Fused Heterobicyclylalkylamino, Fused Bicyclyloxyalkoxy, Fused Heterobicyclyloxyalkoxy, Fused Bicyclylaminoalkoxy, Fused Heterobicyclylaminoalkoxy, Fused Bicyclyl-C(=O)-, Fused Bicyclyl-C(=O)O-, Fused Heterobicyclyl-C( =O)-, Fused Heterobicyclyl-C(=O)O-, Fused Bicyclylamino-C(=O)-, Fused Heterobicyclylamino-C(=O)-, Fused Bicyclyl -C(=O)N(R 6 )-, Fused Heterobicyclyl-C(=O)N(R 6 )-, Spirobicyclyl, Spiroheterobicyclyl, Spirobicyclylaliphatic, Spiroheterobicyclyl Aliphatic, spirobicyclyloxy, spiroheterobicyclyloxy, spirobicyclylamino, spiroheterobicyclylamino, spirobicyclylalkoxy, spiroheterobicyclylalkoxy, spirobicyclylalkylamino, spirohetero Bicyclylalkylamino, Spirobicyclyloxyalkoxy, Spirobicyclyloxyalkoxy, Spirobicyclylaminoalkoxy, Spirobicyclylaminoalkoxy, Spirobicyclyl-C(=O) -, spirobicyclyl-C(=O)O-, spiroheterobicyclyl-C(=O)-, spiroheterobicyclyl-C(=O)O-, spirobicyclylamino-C(=O)- , spiroheterobicyclylamino-C(=O)-, spirobicyclyl-C(=O)N(R 5 )-, spiroheterobicyclyl-C(=O)N(R 5 )-, R 6 R 5 N-, -C(=O)NR 5 R 6 , -OC(=O)NR 5 R 6 , -OC(=O)OR 5 ,-N(R 5 )C(=O)NR 5 R 6 , -N(R 5 )C(=O)OR 6 , -N(R 5 )C(=O)-R 6 , R 5 R 6 NS(=O) t -, R 5 S(=O) t -, R 5 S(=O) t N(R 6 )-, R 6 R 5 N-alkyl, R 5 S(=O) t -alkyl, R 5 R 6 NC(=O)-alkyl , R 6 R 5 N-alkoxy, R 5 S(=O) t -alkoxy, R 5 R 6 NC(=O)-alkoxy, aryl-(CH 2 ) p -G-( CH 2 ) m -, heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, heterocyclyl-(CH 2 ) p -G-(CH 2 ) m -, or cycloalkyl-( CH 2 ) p -G-(CH 2 ) m -, where G is O, S, NR 7 , S(=O), S(=O) 2 ,C(=O), -C(=O)N (R 5 )-, -OC(=O)N(R 5 )-, -OC(=O)-, -N(R 5 )C(=O)N(R 5 )-, -(R 5 ) NS(=O) t -, -OS(=O) t -, or -OS(=O) t N(R 5 )-; t is l or 2; p and m are each independently 0, l, 2 , 3 or 4; or where aryl-(CH 2 ) p -G-(CH 2 ) m -, heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, heterocyclyl-(CH 2 ) p -G-(CH 2 ) m -, or cycloalkyl-(CH 2 ) p -G-(CH 2 ) m - can be selected from F, Cl, Br, I, alkyl by one or more , substituents of alkenyl, alkynyl, alkoxy or cyano;

R2可以相同或不同, 各自独立地为氢, 烷基, 卤代烷基, 烷基酰基, 羟基烷酰基,卤代烷酰基, 环烷基, 环烷基酰基, 烯基, 烯基烷酰基, 炔基, 炔基烷酰基, 芳基, 芳酰基, 杂芳基, 杂芳酰基, 杂环基烷酰基, 杂环烷基, 杂环基酰基, 杂环基烷酰基, 叠氮基烷基, 稠合双环基, 稠合杂双环基, 稠合双环基-C(=O)-, 稠合杂双环基-C(=O)-,稠合双环基氨基-C(=O)-, 稠合杂双环基氨基-C(=O)-, 螺双环基, 螺杂双环基, 螺双环基脂肪族, 螺杂双环基脂肪族, 螺双环基-C(=O)-, 螺杂双环基-C(=O)-, 螺双环基氨基-C(=O)-, 螺杂双环基氨基-C(=O)-, -C(=O)NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N-烷基, R5S(=O)t-烷基, R5R6N-C(=O)-烷基, 芳基-(CH2)p-G-(CH2)m-, 杂芳基-(CH2)p-G-(CH2)m-, 杂环基-(CH2)p-G-(CH2)m-, 或环烷基-(CH2)p-G-(CH2)m-, 其中G是O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t-, 或-OS(=O)tN(R5)-; t是l或2; p和m各自独立地为0, l, 2, 3或4; 或者其中的芳基-(CH2)p-G-(CH2)m-, 杂芳基-(CH2)p-G-(CH2)m-, 杂环基-(CH2)p-G-(CH2)m-, 或环烷基-(CH2)p-G-(CH2)m-可以被一个或多个选自F, Cl, Br, I, 氰基, 烷基,烯基, 炔基, 烷氧基, 芳基, 杂芳基, 碳环基, 杂环基的取代基取代;R can be the same or different, each independently hydrogen , alkyl, haloalkyl, alkylacyl, hydroxyalkanoyl, haloalkanoyl, cycloalkyl, cycloalkylacyl, alkenyl, alkenylalkanoyl, alkynyl, Alkynylalkanoyl, Aryl, Aroyl, Heteroaryl, Heteroaroyl, Heterocyclylalkanoyl, Heterocycloalkyl, Heterocyclylacyl, Heterocyclylalkanoyl, Azidoalkyl, Fused bicyclic Radical, Fused Heterobicyclyl, Fused Bicyclyl-C(=O)-, Fused Heterobicyclyl-C(=O)-, Fused Bicyclylamino-C(=O)-, Fused Heterobicyclyl Amino-C(=O)-, spirobicyclyl, spiroheterobicyclyl, spirobicyclylaliphatic, spiroheterobicyclylaliphatic, spirobicyclyl-C(=O)-, spiroheterobicyclyl-C( =O)-, spirobicyclylamino-C(=O)-, spiroheterobicyclylamino-C(=O)-, -C(=O)NR 5 R 6 , R 5 R 6 NS(=O) t -, R 5 S(=O) t -, R 6 R 5 N-alkyl, R 5 S(=O) t -alkyl, R 5 R 6 NC(=O)-alkyl, aryl- (CH 2 ) p -G-(CH 2 ) m -, Heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, Heterocyclyl-(CH 2 ) p -G-(CH 2 ) m -, or cycloalkyl-(CH 2 ) p -G-(CH 2 ) m -, where G is O, S, NR 7 , S(=O), S(=O) 2 ,C(=O ), -C(=O)N(R 5 )-, -OC(=O)N(R 5 )-, -OC(=O)-, -N(R 5 )C(=O)N(R 5 )-, -(R 5 )NS(=O) t -, -OS(=O) t -, or -OS(=O) t N(R 5 )-; t is l or 2; p and m Each independently is 0, l, 2, 3 or 4; or the aryl-(CH 2 ) p -G-(CH 2 ) m -, heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, heterocyclyl-(CH 2 ) p -G-(CH 2 ) m -, or cycloalkyl-(CH 2 ) p -G-(CH 2 ) m - can be selected from one or more Substituents of F, Cl, Br, I, cyano, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocyclyl, heterocyclyl;

R3可以相同或不同, 各自独立地为氢, 卤素, 羟基, 氨基, 硝基, 氰基, 羧基,烷基, 卤代烷基, 烷氧基, 烷氨基, 烷基酰基, 羟基烷氧基, 羟基烷氨基, 羟基烷酰基,卤代烷氧基, 卤代烷氨基, 卤代烷酰基, 氨基烷氧基, 环烷基, 环烷基氧基, 环烷基氨基, 环烷基酰基, 烯基, 烯基烷氧基, 烯基烷氨基, 烯基烷酰基, 炔基, 炔基烷氧基,炔基烷氨基, 炔基烷酰基, 芳基, 芳氧基, 芳酰基, 芳氨基, 芳基烷氧基, 芳基烷氨基,杂芳基, 杂芳氧基, 杂芳酰基, 杂芳氨基, 杂芳基烷氧基, 杂芳基烷氨基, 杂环基烷酰基, 杂环烷基, 杂环基氧基, 杂环基氨基, 杂环基酰基, 杂环基烷氧基, 杂环基烷氨基,杂环基烷酰基, 叠氮基烷氧基, 稠合双环基, 稠合杂双环基, 稠合双环基脂肪族, 稠合杂双环基脂肪族, 稠合双环基氧基, 稠合杂双环基氧基, 稠合双环基氨基, 稠合杂双环基氨基, 稠合双环基烷氧基, 稠合杂双环基烷氧基, 稠合双环基烷氨基, 稠合杂双环基烷氨基, 稠合双环基氧基烷氧基, 稠合杂双环基氧基烷氧基, 稠合双环基氨基烷氧基,稠合杂双环基氨基烷氧基, 稠合双环基-C(=O)-, 稠合双环基-C(=O)O-, 稠合杂双环基-C(=O)-, 稠合杂双环基-C(=O)O-, 稠合双环基氨基-C(=O)-, 稠合杂双环基氨基-C(=O)-,稠合双环基-C(=O)N(R6)-, 稠合杂双环基-C(=O)N(R6)-, 螺双环基, 螺杂双环基, 螺双环基脂肪族, 螺杂双环基脂肪族, 螺双环基氧基, 螺杂双环基氧基, 螺双环基氨基, 螺杂双环基氨基, 螺双环基烷氧基, 螺杂双环基烷氧基, 螺双环基烷氨基, 螺杂双环基烷氨基, 螺双环基氧基烷氧基, 螺杂双环基氧基烷氧基, 螺双环基氨基烷氧基, 螺杂双环基氨基烷氧基, 螺双环基-C(=O)-, 螺双环基-C(=O)O-, 螺杂双环基-C(=O)-, 螺杂双环基-C(=O)O-, 螺双环基氨基-C(=O)-, 螺杂双环基氨基-C(=O)-, 螺双环基-C(=O)N(R5)-, 螺杂双环基-C(=O)N(R5)-, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-,R6R5N-烷基, R5S(=O)t-烷基, R5R6N-C(=O)-烷基, R6R5N-烷氧基, R5S(=O)t-烷氧基,R5R6N-C(=O)-烷氧基,芳基-(CH2)p-G-(CH2)m-, 杂芳基-(CH2)p-G-(CH2)m-, 杂环基-(CH2)p-G-(CH2)m-, 或环烷基-(CH2)p-G-(CH2)m-, 其中G是O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t-, 或-OS(=O)tN(R5)-; t是l或2; p和m各自独立地为0, l, 2, 3或4; 或者其中芳基-(CH2)p-G-(CH2)m-, 杂芳基-(CH2)p-G-(CH2)m-, 杂环基-(CH2)p-G-(CH2)m-, 或环烷基-(CH2)p-G-(CH2)m-可以被一个或多个选自F, Cl, Br, I, 烷基, 烯基, 炔基, 烷氧基或氰基的取代基取代; R3 can be the same or different, each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, alkyl, haloalkyl, alkoxy, alkylamino, alkylacyl, hydroxyalkoxy, hydroxyl Alkylamino, Hydroxyalkanoyl, Haloalkoxy, Haloalkanoyl, Haloalkanoyl, Aminoalkoxy, Cycloalkyl, Cycloalkyloxy, Cycloalkylamino, Cycloalkylacyl, Alkenyl, Alkenylalkoxy , alkenylalkylamino, alkenylalkanoyl, alkynyl, alkynylalkoxy, alkynylalkylamino, alkynylalkanoyl, aryl, aryloxy, aroyl, arylamino, arylalkoxy, aryl Heteroalkylamino, Heteroaryl, Heteroaryloxy, Heteroaroyl, Heteroarylamino, Heteroarylalkoxy, Heteroarylalkylamino, Heterocyclylalkanoyl, Heterocycloalkyl, Heterocyclyloxy , Heterocyclylamino, Heterocyclylacyl, Heterocyclylalkoxy, Heterocyclylalkylamino, Heterocyclylalkanoyl, Azidoalkoxy, Fused Bicyclyl, Fused Heterobicyclyl, Fused Bicyclylaliphatic, Fused Heterobicyclylaliphatic, Fused Bicyclyloxy, Fused Heterobicyclyloxy, Fused Bicyclylamino, Fused Heterobicyclylamino, Fused Bicyclylalkoxy, Fused Heterobicyclylalkoxy, Fused Bicyclylalkylamino, Fused Heterobicyclylalkylamino, Fused Bicyclyloxyalkoxy, Fused Heterobicyclyloxyalkoxy, Fused Bicyclylaminoalkane Oxygen, Fused Heterobicyclylaminoalkoxy, Fused Bicyclyl-C(=O)-, Fused Bicyclyl-C(=O)O-, Fused Heterobicyclyl-C(=O)- , Fused Heterobicyclyl-C(=O)O-, Fused Bicyclylamino-C(=O)-, Fused Heterobicyclylamino-C(=O)-, Fused Bicyclyl-C(= O)N(R 6 )-, Fused Heterobicyclyl-C(=O)N(R 6 )-, Spirobicyclyl, Spiroheterobicyclyl, Spirobicyclylaliphatic, Spiroheterobicyclylaliphatic, Spiro Bicyclyloxy, spirobicyclyloxy, spirobicyclylamino, spiroheterobicyclylamino, spirobicyclylalkoxy, spiroheterobicyclylalkoxy, spirobicyclylalkylamino, spiroheterobicyclylalkylamino , spirobicyclyloxyalkoxy, spiroheterobicyclyloxyalkoxy, spirobicyclylaminoalkoxy, spiroheterobicyclylaminoalkoxy, spirobicyclyl-C(=O)-, spirobicyclo Base-C(=O)O-, Spirobicyclyl-C(=O)-, Spirobicyclyl-C(=O)O-, Spirobicyclylamino-C(=O)-, Spirobicyclyl Amino-C(=O)-, spirobicyclyl-C(=O)N(R 5 )-, spiroheterobicyclyl-C(=O)N(R 5 )-, R 6 R 5 N-, -C(=O)NR 5 R 6 , -OC(=O)NR 5 R 6 , -OC(=O)OR 5 , -N(R 5 )C(=O)NR 5 R 6 , -N( R 5 )C(=O)OR 6 , -N(R 5 )C(=O)-R 6 , R 5 R 6 NS(=O) t -, R 5 S(=O) t -, R 5 S( =O) t N(R 6 )-,R 6 R 5 N-Alkyl, R 5 S(=O) t -Alkyl, R 5 R 6 NC(=O)-Alkyl, R 6 R 5 N -alkoxy, R 5 S(=O) t -alkoxy, R 5 R 6 NC(=O)-alkoxy, aryl-(CH 2 ) p -G-(CH 2 ) m -, Heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, Heterocyclyl-(CH 2 ) p -G-(CH 2 ) m -, or Cycloalkyl-(CH 2 ) p -G -(CH 2 ) m -, where G is O, S, NR 7 , S(=O), S(=O) 2 ,C(=O), -C(=O)N(R 5 )-, -OC(=O)N(R 5 )-, -OC(=O)-, -N(R 5 )C(=O)N(R 5 )-, -(R 5 )NS(=O) t -, -OS(=O) t -, or -OS(=O) t N(R 5 )-; t is 1 or 2; p and m are each independently 0, 1, 2, 3 or 4; or Among them, aryl-(CH 2 ) p -G-(CH 2 ) m -, heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, heterocyclyl-(CH 2 ) p -G- (CH 2 ) m -, or cycloalkyl-(CH 2 ) p -G-(CH 2 ) m - can be replaced by one or more selected from F, Cl, Br, I, alkyl, alkenyl, alkynyl , substituted by alkoxy or cyano substituents;

R7可以相同或不同, 各自独立地为氢, R5R6NC(=O)-, R5OC(=O)-, R5C(=O)-, R5R6NS(=O)-, R5OS(=O)-, R5S(=O)-, R5R6NS(=O)2-, R5OS(=O)2-, R5S(=O)2-, 脂肪族, 卤代脂肪族, 羟基脂肪族, 氨基脂肪族, 烷氧基脂肪族, 烷氨基脂肪族, 烷硫基脂肪族, 芳基脂肪族, 杂芳基脂肪族, 杂环基脂肪族, 环烷基脂肪族, 芳氧基脂肪族, 杂环基氧基脂肪族, 环烷基氧基脂肪族, 芳氨基脂肪族, 杂环基氨基脂肪族, 环烷基氨基脂肪族, 芳基, 杂芳基, 杂环基或碳环基;R 7 may be the same or different, each independently hydrogen, R 5 R 6 NC(=O)-, R 5 OC(=O)-, R 5 C(=O)-, R 5 R 6 NS(=O )-, R 5 OS(=O)-, R 5 S(=O)-, R 5 R 6 NS(=O) 2 -, R 5 OS(=O) 2 -, R 5 S(=O) 2 -, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclyl Aliphatic, Cycloalkylaliphatic, Aryloxyaliphatic, Heterocyclyloxyaliphatic, Cycloalkyloxyaliphatic, Araminoaliphatic, Heterocyclylaminoaliphatic, Cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;

各R5和R6独立地为氢, 脂肪族, 卤代脂肪族, 羟基脂肪族, 氨基脂肪族, 烷氧基脂肪族, 烷氨基脂肪族, 烷硫基脂肪族, 芳基脂肪族, 杂芳基脂肪族, 杂环基脂肪族, 环烷基脂肪族, 芳氧基脂肪族, 杂环基氧基脂肪族, 环烷基氧基脂肪族, 芳氨基脂肪族,杂环基氨基脂肪族, 环烷基氨基脂肪族, 芳基, 杂芳基, 杂环基或环烷基; 当R5和R6连在同一个氮原子上, R5, R6和氮原子可以任意地形成取代或非取代的3-8元环, 稠合双环或螺双环; 上述基团中涉及的杂环基、杂芳基、稠合杂双环基、螺杂双环基中的杂原子为独立地选自N、O、S、Se中的1-5个杂原子;Each of R and R is independently hydrogen, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic , alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic , hetero Arylaliphatic, Heterocyclylaliphatic, Cycloalkylaliphatic, Aryloxyaliphatic, Heterocyclyloxyaliphatic, Cycloalkyloxyaliphatic, Araminoaliphatic, Heterocyclylaminoaliphatic , cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or cycloalkyl; when R 5 and R 6 are connected to the same nitrogen atom, R 5 , R 6 and the nitrogen atom can be optionally substituted Or unsubstituted 3-8 membered ring, fused bicyclic or spirobicyclic; the heteroatoms in the heterocyclic group, heteroaryl group, fused heterobicyclic group and spiro heterobicyclic group involved in the above groups are independently selected from 1-5 heteroatoms in N, O, S, Se;

上述R1, R2, R3, R4, R5, R6, R7基团可任被氘, 卤素, 羟基, 羟甲基, 羧基, 乙酰氨基, 烷基（如甲基、乙基、丙基）, 烷氧基（如甲氧基、乙氧基、叔丁氧基）, 烷氨基, 环烷基, 烯基, 炔基, 三氟甲基, 三氟乙酰基, 巯基, 卤素, 硝基, 氨基, 叠氮基 (-N3),胍基, 氰基, 叔丁氧羰基 (-Boc), 羰基 (-C=O), 氧代 (=O), 硫代 (=S), 磺酰基, 芳基, 杂芳基, 杂环基中的一个或多个取代。The above R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 groups can be optionally replaced by deuterium, halogen, hydroxyl, hydroxymethyl, carboxyl, acetamido, alkyl (such as methyl, ethyl , propyl), alkoxy (e.g. methoxy, ethoxy, tert-butoxy), alkylamino, cycloalkyl, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl, mercapto, halogen , nitro, amino, azido (-N 3 ), guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thioxo (=S ), one or more of sulfonyl, aryl, heteroaryl, heterocyclyl.

在一些实施方案中, 本发明化合物为通式III和IV所示的化合物, 或通式III和IV所示化合物的立体异构体几何异构体、互变异构体、氮氧化物、消旋体、水合物、溶剂化物、代谢产物、药学上可接受的盐或前药：In some embodiments, the compounds of the present invention are compounds represented by general formulas III and IV, or stereoisomers, geometric isomers, tautomers, nitroxides, and elimination of compounds represented by general formulas III and IV. Helicoids, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs:

, ,

其中T1, T2, T3, T4各自独立的为N或CR1, 且至多有三个可以为N; V1, V2, V3, V4,V5各自独立的为N或CR4, 且之多有三个可以为N; “”为单键或不存在; 各R1, R2, R3,R4如下所示：Among them, T 1 , T 2 , T 3 , T 4 are independently N or CR 1 , and at most three can be N; V 1 , V 2 , V 3 , V 4 , V 5 are independently N or CR 4 , and at most three can be N; " "is a single bond or does not exist; each of R 1 , R 2 , R 3 , and R 4 is as follows:

各R1, R4可以相同或不同, 各自独立地为H, F, Cl, Br, I, 羟基, 氨基, 硝基, 氰基, 羧基, C1-C20烷基, C1-C20卤代烷基, C1-C20烷氧基, C1-C20烷氨基, C1-C20烷基酰基, 羟基C1-C20烷氧基, 羟基C1-C20烷氨基, 羟基C1-C20烷酰基, C1-C20卤代烷氧基,C1-C20卤代烷氨基, C1-C20卤代烷酰基, C1-C20氨基烷氧基, C3-C10环烷基, C3-C10环烷基氧基, C3-C10环烷基氨基, C3-C10环烷基酰基, C2-C8烯基, C2-C8炔基, C6-C10芳基, C6-C10芳氧基, C6-C10芳酰基, C6-C10芳氨基, C6-C10芳基C1-C6烷氧基, C6-C10芳基烷氨基, C5-C12杂芳基, C5-C12杂芳氧基, C5-C12杂芳酰基, C5-C12杂芳氨基, C5-C12杂芳基C1-C6烷氧基, C5-C12杂芳基C1-C6烷氨基, C4-C12杂环基C1-C6烷酰基, C4-C12杂环烷基, C4-C12杂环基氧基, C4-C12杂环基氨基, C4-C12杂环基酰基, C4-C12杂环基C1-C6烷氧基, C4-C12杂环基C1-C6烷氨基, C4-C12杂环基C1-C6烷酰基, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- C1-C6烷基, R5S(=O)t- C1-C6烷基, R5R6N-C(=O)-C1-C6烷基, R6R5N-C1-C6烷氧基, R5S(=O)t-C1-C6烷氧基, R5R6N-C(=O)-C1-C6烷氧基, C6-C10芳基-(CH2)p-G-(CH2)m-, C5-C12杂芳基-(CH2)p-G-(CH2)m-, C4-C12杂环基-(CH2)p-G-(CH2)m-, 或C3-C10环烷基-(CH2)p-G-(CH2)m-, 其中G是O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R6)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t-, 或-OS(=O)tN(R5)-; t是l或2; p和m各自独立地为0, l, 2, 3或4; 或者其中C6-C10芳基-(CH2)p-G-(CH2)m-, C5-C12杂芳基-(CH2)p-G-(CH2)m-, C4-C12杂环基-(CH2)p-G-(CH2)m-, 或C3-C1环烷基-(CH2)p-G-(CH2)m-可以被一个或多个选自F,Cl, Br, I, 烷基, 烯基, 炔基, 烷氧基或氰基的取代基取代;Each R 1 and R 4 may be the same or different, each independently being H, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, carboxyl, C1-C20 alkyl, C1-C20 haloalkyl, C1 -C20 alkoxy, C1-C20 alkanoyl, C1-C20 alkanoyl, hydroxy C1-C20 alkoxy, hydroxy C1-C20 alkamino, hydroxy C1-C20 alkanoyl, C1-C20 haloalkoxy, C1- C20 haloalkylamino, C1-C20 haloalkanoyl, C1-C20 aminoalkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkyloxy, C3-C10 cycloalkylamino, C3-C10 cycloalkylacyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C10 aryl, C6-C10 aryloxy, C6-C10 aroyl, C6-C10 arylamino, C6-C10 arylC1-C6 alkoxy, C6 -C10 arylalkylamino, C5-C12 heteroaryl, C5-C12 heteroaryloxy, C5-C12 heteroaroyl, C5-C12 heteroarylamino, C5-C12 heteroarylC1-C6 alkoxy, C5 -C12 HeteroarylC1-C6 Alkylamino, C4-C12 HeterocyclylC1-C6 Alkanoyl, C4-C12 Heterocycloalkyl, C4-C12 Heterocyclyloxy, C4-C12 Heterocyclylamino, C4- C12 heterocyclyl acyl, C4-C12 heterocyclyl C1-C6 alkoxy, C4-C12 heterocyclyl C1-C6 alkylamino, C4-C12 heterocyclyl C1-C6 alkanoyl, R 6 R 5 N-, -C(=O)NR 5 R 6 , -OC(=O)NR 5 R 6 , -OC(=O)OR 5 , -N(R 5 )C(=O)NR 5 R 6 , -N( R 5 )C(=O)OR 6 , -N(R 5 )C(=O)-R 6 , R 5 R 6 NS(=O) t -, R 5 S(=O) t -, R 5 S(=O) t N(R 6 )-, R 6 R 5 N- C1-C6 alkyl, R 5 S(=O) t - C1-C6 alkyl, R 5 R 6 NC(=O)- C1-C6 alkyl, R 6 R 5 N-C1-C6 alkoxy, R 5 S(=O) t -C1-C6 alkoxy, R 5 R 6 NC(=O)-C1-C6 alkoxy radical, C6-C10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C5-C12 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, C4-C12 heterocycle Group-(CH 2 ) p -G-(CH 2 ) m -, or C3-C10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m -, where G is O, S, NR 7 , S(=O), S(=O) 2 ,C(=O), -C(=O)N( R 6 )-, -OC(=O)N(R 5 )-, -OC(=O)-, -N(R 5 )C(=O)N(R 5 )-, -(R 5 )NS (=O) t -, -OS(=O) t -, or -OS(=O) t N(R 5 )-; t is l or 2; p and m are each independently 0, l, 2, 3 or 4; or where C6-C10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C5-C12 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, C4 -C12 heterocyclyl-(CH 2 ) p -G-(CH 2 ) m -, or C3-C1 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m - can be selected by one or more Substituents from F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano;

R2各自独立地为H, C1-C20烷基, C1-C20卤代烷基, C1-C20烷基酰基, C1-C20羟基烷酰基, C1-C20卤代烷酰基, C3-C10环烷基, C3-C10环烷基酰基, C2-C8烯基, C2-C8烯基烷酰基, C2-C8炔基, C2-C8炔基烷酰基, C6-C10芳基, C6-C10芳酰基, C5-C12杂芳基,C5-C12杂芳酰基, C4-C12杂环基烷酰基, C4-C12杂环烷基, C4-C12杂环基酰基, C4-C12杂环基C1-C6烷酰基, C5-C12稠合双环基, C5-C12稠合杂双环基, -C(=O)NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N-C1-C6烷基, R5S(=O)t-C1-C6烷基, R5R6N-C(=O)-C1-C6烷基,C6-C10芳基-(CH2)p-G-(CH2)m-, C5-C12杂芳基-(CH2)p-G-(CH2)m-, C4-C12杂环基-(CH2)p-G-(CH2)m-, 或C3-C10环烷基-(CH2)p-G-(CH2)m-, 其中G是O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -(R5)N-S(=O)t-, -OS(=O)t-, 或-OS(=O)tN(R5)-; t是l或2; p和m各自独立地为0, l, 2, 3或4; 或者其中C6-C10芳基-(CH2)p-G-(CH2)m-, C5-C12杂芳基-(CH2)p-G-(CH2)m-, C4-C12杂环基-(CH2)p-G-(CH2)m-, 或C3-C10环烷基-(CH2)p-G-(CH2)m-可以被一个或多个选自F, Cl, Br, I, 氰基, 烷基, 烯基,炔基, 烷氧基, 芳基, 杂芳基, 碳环基, 杂环基的取代基取代;R 2 are each independently H, C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkanoyl, C1-C20 hydroxyalkanoyl, C1-C20 haloalkanoyl, C3-C10 cycloalkyl, C3-C10 Cycloalkylacyl, C2-C8alkenyl, C2-C8alkenylalkanoyl, C2-C8alkynyl, C2-C8alkynylalkanoyl, C6-C10aryl, C6-C10aroyl, C5-C12heteroaryl C5-C12 Heteroaroyl, C4-C12 Heterocyclylalkanoyl, C4-C12 Heterocycloalkyl, C4-C12 Heterocyclyl acyl, C4-C12 HeterocyclylC1-C6 Alkanoyl, C5-C12 Fused fused bicyclyl, C5-C12 fused heterobicyclyl, -C(=O)NR 5 R 6 , R 5 R 6 NS(=O) t -, R 5 S(=O) t -, R 6 R 5 N-C1-C6 alkyl, R 5 S(=O) t -C1-C6 alkyl, R 5 R 6 NC(=O)-C1-C6 alkyl, C6-C10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C5-C12 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, C4-C12 heterocyclyl-(CH 2 ) p -G-(CH 2 ) m -, or C3-C10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m -, where G is O, S, NR 7 , S(=O), S(=O) 2 , C(=O), -C(=O)N(R 5 )-, -OC(=O)N(R 5 )-, -OC(=O)-, -(R 5 )NS(=O) t -, -OS(=O) t -, or -OS(=O) t N(R 5 )-; t is 1 or 2; p and m are each independently 0, 1, 2, 3 or 4; Or where C6-C10 aryl-(CH 2 ) p -G-(CH 2 ) m -, C5-C12 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, C4-C12 heterocycle The group -(CH 2 ) p -G-(CH 2 ) m -, or C3-C10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m - can be selected from one or more of F, Cl , Br, I, cyano, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, carbocyclyl, heterocyclyl substituents;

R3各自独立地为H, F, Cl, Br, I, 羟基, 氨基, 硝基, 氰基, 羧基, C1-C20烷基,C1-C20卤代烷基, C1-C20烷氧基, C1-C20烷氨基, C1-C20烷基酰基, 羟基C1-C20烷氧基,羟基C1-C20烷氨基, 羟基C1-C20烷酰基, C1-C20卤代烷氧基, C1-C20卤代烷氨基, C1-C20卤代烷酰基, C1-C20氨基烷氧基, C3-C10环烷基, C3-C10环烷基氧基, C3-C10环烷基氨基, C3-C10环烷基酰基, C2-C8烯基, C2-C8炔基, C6-C10芳基, C6-C10芳氧基, C6-C10芳酰基, C6-C10芳氨基, C6-C10芳基C1-C6烷氧基, C6-C10芳基烷氨基, C5-C12杂芳基, C5-C12杂芳氧基, C5-C12杂芳酰基, C5-C12杂芳氨基, C5-C12杂芳基C1-C6烷氧基,C5-C12杂芳基C1-C6烷氨基, C4-C12杂环基C1-C6烷酰基, C4-C12杂环烷基, C4-C12杂环基氧基, C4-C12杂环基氨基, C4-C12杂环基酰基, C4-C12杂环基C1-C6烷氧基, C4-C12杂环基C1-C6烷氨基, C4-C12杂环基C1-C6烷酰基, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- C1-C6烷基, R5S(=O)t- C1-C6烷基, R5R6N-C(=O)-C1-C6烷基, R6R5N-C1-C6烷氧基, R5S(=O)t-C1-C6烷氧基, R5R6N-C(=O)-C1-C6烷氧基, C6-C10芳基-(CH2)p-G-(CH2)m-, C5-C12杂芳基-(CH2)p-G-(CH2)m-, C4-C12杂环基-(CH2)p-G-(CH2)m-, 或C3-C10环烷基-(CH2)p-G-(CH2)m-, 其中G是O, S, NR7, S(=O), S(=O)2,C(=O),-C(=O)N(R6)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(=O)t-, 或-OS(=O)tN(R5)-; t是l或2; p和m各自独立地为0, l, 2, 3或4; 或者其中C6-C10芳基-(CH2)p-G-(CH2)m-, C5-C12杂芳基-(CH2)p-G-(CH2)m-, C4-C12杂环基-(CH2)p-G-(CH2)m-, 或C3-C1环烷基-(CH2)p-G-(CH2)m-可以被一个或多个选自F, Cl, Br, I, 烷基,烯基, 炔基, 烷氧基或氰基的取代基取代;R 3 are each independently H, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, carboxyl, C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkoxy, C1-C20 Alkylamino, C1-C20 Alkanoyl, Hydroxy C1-C20 Alkoxy, Hydroxy C1-C20 Alkylamino, Hydroxy C1-C20 Alkanoyl, C1-C20 Haloalkoxy, C1-C20 Haloalkamino, C1-C20 Haloalkanoyl , C1-C20 aminoalkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkyloxy, C3-C10 cycloalkylamino, C3-C10 cycloalkylacyl, C2-C8 alkenyl, C2-C8 Alkynyl, C6-C10 aryl, C6-C10 aryloxy, C6-C10 aroyl, C6-C10 arylamino, C6-C10 arylC1-C6 alkoxy, C6-C10 arylalkylamino, C5- C12 heteroaryl, C5-C12 heteroaryloxy, C5-C12 heteroaroyl, C5-C12 heteroarylamino, C5-C12 heteroarylC1-C6 alkoxy, C5-C12 heteroarylC1-C6 alkane Amino, C4-C12heterocyclylC1-C6alkanoyl, C4-C12heterocycloalkyl, C4-C12heterocyclyloxy, C4-C12heterocyclylamino, C4-C12heterocyclylacyl, C4-C12 Heterocyclyl C1-C6 alkoxy, C4-C12 heterocyclyl C1-C6 alkylamino, C4-C12 heterocyclyl C1-C6 alkanoyl, R 6 R 5 N-, -C(=O)NR 5 R 6 , -OC(=O)NR 5 R 6 , -OC(=O)OR 5 , -N(R 5 )C(=O)NR 5 R 6 , -N(R 5 )C(=O)OR 6 , -N(R 5 )C(=O)-R 6 , R 5 R 6 NS(=O) t -, R 5 S(=O) t -, R 5 S(=O) t N(R 6 )-, R 6 R 5 N- C1-C6 alkyl, R 5 S(=O) t - C1-C6 alkyl, R 5 R 6 NC(=O)-C1-C6 alkyl, R 6 R 5 N-C1-C6 alkoxy, R 5 S(=O) t -C1-C6 alkoxy, R 5 R 6 NC(=O)-C1-C6 alkoxy, C6-C10 aryl-( CH 2 ) p -G-(CH 2 ) m -, C5-C12 heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, C4-C12 heterocyclyl-(CH 2 ) p -G -(CH 2 ) m -, or C3-C10 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m -, where G is O, S, NR 7 , S(=O), S(=O) 2 ,C(=O),-C(=O)N(R 6 )-, -OC(=O )N(R 5 )-, -OC(=O)-, -N(R 5 )C(=O)N(R 5 )-, -(R 5 )NS(=O) t -, -OS( =O) t -, or -OS(=O) t N(R 5 )-; t is 1 or 2; p and m are each independently 0, 1, 2, 3 or 4; or wherein C6-C10 aromatic Group-(CH 2 ) p -G-(CH 2 ) m -, C5-C12 Heteroaryl-(CH 2 ) p -G-(CH 2 ) m -, C4-C12 Heterocyclyl-(CH 2 ) p -G-(CH 2 ) m -, or C3-C1 cycloalkyl-(CH 2 ) p -G-(CH 2 ) m - can be selected from F, Cl, Br, I, alkane by one or more Substituents of radical, alkenyl, alkynyl, alkoxy or cyano;

其中各R7可以相同或不同, 各自独立地为H, R5R6NC(=O)-, R5OC(=O)-, R5C(=O)-,R5R6NS(=O)-, R5OS(=O)-, R5S(=O)-, R5R6NS(=O)2-, R5OS(=O)2-, R5S(=O)2-, C1-C3脂肪族, C1-C3卤代脂肪族, C1-C3羟基脂肪族, C1-C3氨基脂肪族, C1-C3烷氧基C1-C3脂肪族, C1-C3烷氨基C1-C3脂肪族, C1-C3烷硫基C1-C3脂肪族, C6-C10芳基C1-C3脂肪族,C5-C9杂芳基C1-C3脂肪族, C4-C10杂环基C1-C3脂肪族, C3-C10环烷基C1-C3脂肪族, C6-C10芳氧基C1-C3脂肪族, C4-C10杂环基氧基C1-C3脂肪族, C3-C10环烷基氧基C1-C3脂肪族, C6-C10芳氨基C1-C3脂肪族, C4-C10杂环基氨基C1-C3脂肪族, C3-C10环烷基氨基C1-C3脂肪族, C6-C10芳基, C5-C10杂芳基, C4-C10杂环基或C3-C10环烷基;Wherein each R 7 may be the same or different, each independently being H, R 5 R 6 NC(=O)-, R 5 OC(=O)-, R 5 C(=O)-, R 5 R 6 NS( =O)-, R 5 OS(=O)-, R 5 S(=O)-, R 5 R 6 NS(=O) 2 -, R 5 OS(=O) 2 -, R 5 S(= O) 2 -, C1-C3 Aliphatic, C1-C3 Haloaliphatic, C1-C3 Hydroxyaliphatic, C1-C3 Aminoaliphatic, C1-C3 AlkoxyC1-C3 Aliphatic, C1-C3 Alkylamino C1-C3 aliphatic, C1-C3 alkylthio C1-C3 aliphatic, C6-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocyclyl C1-C3 Aliphatic, C3-C10cycloalkylC1-C3aliphatic, C6-C10aryloxyC1-C3aliphatic, C4-C10heterocyclyloxyC1-C3aliphatic, C3-C10cycloalkyloxyC1 -C3 aliphatic, C6-C10 arylamino C1-C3 aliphatic, C4-C10 heterocyclylamino C1-C3 aliphatic, C3-C10 cycloalkylamino C1-C3 aliphatic, C6-C10 aryl, C5- C10 heteroaryl, C4-C10 heterocyclyl or C3-C10 cycloalkyl;

其中各R5和R6独立地为H, D, C1-C3脂肪族, C1-C3卤代脂肪族, C1-C3羟基脂肪族,C1-C3氨基脂肪族, C1-C3烷氧基C1-C3脂肪族, C1-C3烷氨基C1-C3脂肪族, C1-C3烷硫基C1-C3脂肪族, C6-C10芳基C1-C3脂肪族, C5-C9杂芳基C1-C3脂肪族, C4-C10杂环基C1-C3脂肪族, C3-C10环烷基C1-C3脂肪族, C6-C10芳氧基C1-C3脂肪族, C4-C10杂环基氧基C1-C3脂肪族, C3-C10环烷基氧基C1-C3脂肪族, C6-C10芳氨基C1-C3脂肪族, C4-C10杂环基氨基C1-C3脂肪族, C3-C10环烷基氨基C1-C3脂肪族, C6-C10芳基, C5-C10杂芳基, C4-C10杂环基或C3-C10环烷基; 当R5和R6连在同一个氮原子上, R5, R6和氮原子可以任意地形成取代或非取代的3-8元环;Wherein each R 5 and R 6 are independently H, D, C1-C3 aliphatic, C1-C3 halogenated aliphatic, C1-C3 hydroxyaliphatic, C1-C3 amino aliphatic, C1-C3 alkoxy C1- C3 aliphatic, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio C1-C3 aliphatic, C6-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocyclyl C1-C3 aliphatic, C3-C10 cycloalkyl C1-C3 aliphatic, C6-C10 aryloxy C1-C3 aliphatic, C4-C10 heterocyclyloxy C1-C3 aliphatic, C3-C10 cycloalkyloxy C1-C3 aliphatic, C6-C10 arylamino C1-C3 aliphatic, C4-C10 heterocyclylamino C1-C3 aliphatic, C3-C10 cycloalkylamino C1-C3 aliphatic , C6-C10 aryl, C5-C10 heteroaryl, C4-C10 heterocyclyl or C3-C10 cycloalkyl; when R 5 and R 6 are connected to the same nitrogen atom, R 5 , R 6 and nitrogen atom A substituted or unsubstituted 3-8 membered ring can be formed arbitrarily;

上述R1, R2, R3, R4, R5, R6, R7基团可任被氘, 卤素, 羟基, 羟甲基, 羧基, 乙酰氨基, 烷基（如甲基、乙基、丙基）, 烷氧基（如甲氧基、乙氧基、叔丁氧基）, 烷氨基, 环烷基, 烯基, 炔基, 三氟甲基, 三氟乙酰基, 巯基, 卤素, 硝基, 氨基, 叠氮基 (-N3),胍基, 氰基, 叔丁氧羰基 (-Boc), 羰基 (-C=O), 氧代 (=O), 硫代 (=S), 磺酰基, 芳基, 杂芳基, 杂环基中的一个或多个取代。The above R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 groups can be optionally replaced by deuterium, halogen, hydroxyl, hydroxymethyl, carboxyl, acetamido, alkyl (such as methyl, ethyl , propyl), alkoxy (e.g. methoxy, ethoxy, tert-butoxy), alkylamino, cycloalkyl, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl, mercapto, halogen , nitro, amino, azido (-N 3 ), guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thioxo (=S ), one or more of sulfonyl, aryl, heteroaryl, heterocyclyl.

在一些实施方案中, 本发明中的化合物各R1, R4可以相同或不同, 各自独立地为H, 甲基, 乙基, 丙基, 异丙基, 丁基, 叔丁基, C5H11, C6H13, C8H17, 三氟甲基, 羟基甲基, 氨基甲基, 3-羟基-丙基, 乙酰基, 三氟乙酰基, 氰基乙酰基, 甲基氨基乙酰基, 丙酰基, 异丙酰基, 2-羟基丙酰基, 2-氨基丙酰基, 2-氯丙酰基, 2-溴丙酰基, 戊酰基,己酰基, 庚酰基, 异丁烯酰基, 苯基, 苯甲酰基, 对硝基苯基, 对甲基苯甲酰基, 间氟苯甲酰基, 对氨基苯甲酰基, 对甲氧基苯甲酰基, 2,4-二甲基苯甲酰基, 间叠氮基苯甲酰基, 苄基, 对氯苄基, 乙烯基, 丙烯基, 烯丙基, 正丁烯基, 异丁烯基, 正戊烯基,异戊烯基, 环丙酰基, 环戊酰基, 环己酰基, 3-吡啶甲酰基, 萘基, 苯乙基咪唑基, 吡啶基, 吡咯基, 噁唑基, 异恶唑基, 三氮唑基, 四氮唑基, 呋喃基, 噻吩基, 噻唑基,哌啶基, 哌嗪基, 吲哚基, 咔唑基, 苯并呋喃基 四氢呋喃基, 四氢吡喃基, 嘧啶碱基,嘌呤碱基, -N(CH3)2, -C(C=O)NH-C1-C4 烷基, -OC(C=O)-NH-C1-C4烷 基, -OC(O=O)O-C1-C4 烷基, -NHC(=O)NH-C1-C4 烷基,-NHC(=O)O-C1-C4 烷基, -NHC(=O)-C1-C4 烷基,C1-C4烷基-NH-S(=O)2-, C1-C4烷基S(=O)2-, C1-C4烷基S(=O)2NH-, 苯基-(CH2)P-G-(CH2)m-, 氟代苯基-(CH2)P-G-(CH2) m-, 噻唑基-(CH2)p-G-(CH2)m-, 吡啶基-(CH2)p-G-(CH2)m-, 苯基乙基, 环己基-(CH2)p-G-(CH2)m-, 其中 G 是O, S, S(=O), S (=O)2, C(=O); p和m各自独立地为0, 1, 2或3; 或者其中C6-C10芳基-(CH2)P-G-(CH2)m-可以被一个或多个选自 F, Cl, Br, I, 甲基, 乙基, 丙基, 乙炔基, 丙炔基, 丁炔基, 甲氧基, 乙氧基或者氰基的取代基取代; 或上述R1, R4可任意的被D, F, Cl, Br, I, 羟基, 羟基,羟甲基, 羧基, 乙酰氨基, C1-C6烷基（如甲基、乙基、丙基）, C1-C6烷氧基, C1-C6烷氨基, 三氟甲基, 三氟乙酰基, 巯基, 硝基, 氨基, 叠氮基（-N3）, 胍基, 氰基, 叔丁氧羰基（-Boc）, 羰基（-C=O）, 氧代（=O）, 硫代（=S）, 磺酰基, 苯基中的一个或多个取代;In some embodiments, each R 1 and R 4 of the compounds of the present invention may be the same or different, each independently being H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C 5 H 11 , C 6 H 13 , C 8 H 17 , trifluoromethyl, hydroxymethyl, aminomethyl, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl Propionyl, propionyl, isopropionyl, 2-hydroxypropionyl, 2-aminopropionyl, 2-chloropropionyl, 2-bromopropionyl, pentanoyl, hexanoyl, heptanoyl, methacryloyl, phenyl, benzyl Acyl, p-nitrophenyl, p-methylbenzoyl, m-fluorobenzoyl, p-aminobenzoyl, p-methoxybenzoyl, 2,4-dimethylbenzoyl, m-azido Benzoyl, benzyl, p-chlorobenzyl, vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, cyclopropanoyl, cyclopentanoyl, cyclohexyl Acyl, 3-pyridinecarbonyl, naphthyl, phenethylimidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl ,Piperidinyl, Piperazinyl, Indolyl, Carbazolyl, Benzofuryltetrahydrofuryl, Tetrahydropyranyl, Pyrimidine base, Purine base, -N(CH 3 ) 2 , -C(C =O)NH-C1-C4 alkyl, -OC(C=O)-NH-C1-C4 alkyl, -OC(O=O)O-C1-C4 alkyl, -NHC(=O)NH- C1-C4 alkyl, -NHC(=O)O-C1-C4 alkyl, -NHC(=O)-C1-C4 alkyl, C1-C4 alkyl-NH-S(=O) 2 -, C1 -C4alkylS(=O) 2 -, C1-C4alkylS(=O) 2 NH-, phenyl-(CH 2 ) P -G-(CH 2 ) m -, fluorophenyl-( CH 2 ) P -G-(CH 2 ) m -, Thiazolyl-(CH 2 ) p -G-(CH 2 ) m -, Pyridyl-(CH 2 ) p -G-(CH 2 ) m -, Phenylethyl, cyclohexyl-(CH 2 ) p -G-(CH 2 ) m -, where G is O, S, S(=O), S (=O) 2 , C(=O); p and m are each independently 0, 1, 2 or 3; or wherein C6-C10 aryl-(CH 2 ) P -G-(CH 2 ) m -can be selected from F, Cl, Br, I, Substituents of methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, ethoxy or cyano; or The above R 1 , R 4 can be optionally replaced by D, F, Cl, Br, I, hydroxyl, hydroxyl, hydroxymethyl, carboxyl, acetamido, C1-C6 alkyl (such as methyl, ethyl, propyl), C1-C6 alkoxy, C1-C6 alkylamino, trifluoromethyl, trifluoroacetyl, mercapto, nitro, amino, azido (-N 3 ), guanidino, cyano, tert-butoxycarbonyl ( One or more of -Boc), carbonyl (-C=O), oxo (=O), thio (=S), sulfonyl, phenyl;

在另一些实施方案中, 本发明化合物中各R2为H, 甲基, 乙基, 丙基, 异丙基, 丁基, 叔丁基, C5H11, C6H13, C8H17, 三氟甲基, 羟基甲基, 氨基甲基, 3-羟基-丙基, 乙酰基, 三氟乙酰基, 氰基乙酰基, 甲基氨基乙酰基, 丙酰基, 异丙酰基, 2-羟基丙酰基,2-氨基丙酰基, 2-氯丙酰基, 2-溴丙酰基, 戊酰基, 己酰基, 庚酰基, 异丁烯酰基, 苯基, 苯甲酰基, 对硝基苯基, 对甲基苯甲酰基, 间氟苯甲酰基, 对氨基苯甲酰基, 对甲氧基苯甲酰基, 2,4-二甲基苯甲酰基, 间叠氮基苯甲酰基, 苄基, 对氯苄基, 乙烯基,丙烯基, 烯丙基, 正丁烯基, 异丁烯基, 正戊烯基, 异戊烯基, 环丙基, 环丙酰基, 环戊酰基, 环己酰基, 3-吡啶甲酰基, 萘基, 苯乙基咪唑基, 吡啶基, 吡咯基, 噁唑基,异恶唑基, 三氮唑基, 四氮唑基, 呋喃基, 吡喃基, 噻吩基, 噻唑基, 哌啶基, 哌嗪基,吲哚基, 咔唑基, 苯并呋喃基 四氢呋喃基, 四氢吡喃基, 嘧啶碱基, 嘌呤碱基, 五碳糖基, 六碳糖基, -(C=O)NH-C1-C4 烷基, C1-C4烷基-NH-S(=O)2-, C1-C4烷基S(=O)2-, 苯基-(CH2)P-G-(CH2)m-, 氟代苯基-(CH2)P-G-(CH2) m-, 噻唑基-(CH2)p-G-(CH2)m-, 吡啶基-(CH2)p-G-(CH2)m-, 苯基乙基, 环己基-(CH2)p-G-(CH2)m-, 其中 G 是O, S, S(=O), S (=O)2, C(=O); p和m各自独立地为0, 1, 2或3; 或者其中C6-C10芳基-(CH2)P-G-(CH2)m-可以被一个或多个选自 F, Cl, Br, I, 甲基, 乙基, 丙基, 乙炔基, 丙炔基, 丁炔基, 甲氧基, 乙氧基或者氰基的取代基取代; 或上述R2可任意的被D, F, Cl, Br, I, 羟基, 羟基, 羟甲基, 羧基, 乙酰氨基, C1-C6烷基（如甲基、乙基、丙基）, C1-C6烷氧基, C1-C6烷氨基, 三氟甲基, 三氟乙酰基, 巯基, 硝基, 氨基, 叠氮基 (-N3), 胍基, 氰基, 叔丁氧羰基(-Boc), 羰基 (-C=O), 氧代 (=O), 硫代 (=S), 磺酰基, 苯基中的一个或多个取代In other embodiments, each R 2 in the compounds of the present invention is H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C 5 H 11 , C 6 H 13 , C 8 H 17 , trifluoromethyl, hydroxymethyl, aminomethyl, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2- Hydroxypropionyl, 2-aminopropionyl, 2-chloropropionyl, 2-bromopropionyl, pentanoyl, hexanoyl, heptanoyl, methacryloyl, phenyl, benzoyl, p-nitrophenyl, p-methyl Benzoyl, m-fluorobenzoyl, p-aminobenzoyl, p-methoxybenzoyl, 2,4-dimethylbenzoyl, m-azidobenzoyl, benzyl, p-chlorobenzyl , vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, cyclopropyl, cyclopropenyl, cyclopentanoyl, cyclohexanoyl, 3-pyridinecarbonyl , naphthyl, phenethyl imidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, pyryl, thienyl, thiazolyl, piperidine Base, piperazinyl, indolyl, carbazolyl, benzofuryltetrahydrofuranyl, tetrahydropyranyl, pyrimidine base, purine base, five-carbon sugar group, six-carbon sugar group, -(C=O )NH-C1-C4 alkyl, C1-C4 alkyl-NH-S(=O) 2 -, C1-C4 alkyl S(=O) 2 -, phenyl-(CH 2 ) P -G-( CH 2 ) m -, fluorophenyl-(CH 2 ) P -G-(CH 2 ) m -, thiazolyl-(CH 2 ) p -G-(CH 2 ) m -, pyridyl-(CH 2 ) p -G-(CH 2 ) m -, phenylethyl, cyclohexyl-(CH 2 ) p -G-(CH 2 ) m -, where G is O, S, S(=O), S ( =O) 2 , C(=O); p and m are each independently 0, 1, 2 or 3; or wherein C6-C10 aryl-(CH 2 ) P -G-(CH 2 ) m - can be One or more substituents selected from F, Cl, Br, I, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, ethoxy or cyano; or The above R2 can be optionally replaced by D, F, Cl, Br, I, hydroxyl, hydroxyl, hydroxymethyl, carboxyl, acetamido, C1-C6 alkyl (such as methyl, ethyl, propyl), C1-C6 Alkoxy, C1-C6 alkylamino, trifluoromethyl, trifluoroacetyl, mercapto, nitro, amino, azido (-N 3 ), guanidino, cyano One or more of tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thio (=S), sulfonyl, phenyl

在一些实施方案中, 本发明化合物中R3各自独立的为H, 甲基, 乙基, 丙基, 异丙基, 丁基, 叔丁基, C5H11, C6H13, C8H17, 三氟甲基, 羟基甲基, 氨基甲基, 3-羟基-丙基, 乙酰基, 三氟乙酰基, 氰基乙酰基, 甲基氨基乙酰基, 丙酰基, 异丙酰基, 2-羟基丙酰基, 2-氨基丙酰基, 2-氯丙酰基, 2-溴丙酰基, 戊酰基, 己酰基, 庚酰基, 异丁烯酰基, 苯基, 苯甲酰基, 对硝基苯基, 对甲基苯甲酰基, 间氟苯甲酰基, 对氨基苯甲酰基, 对甲氧基苯甲酰基, 2,4-二甲基苯甲酰基, 间叠氮基苯甲酰基, 苄基, 对氯苄基,乙烯基, 丙烯基, 烯丙基, 正丁烯基, 异丁烯基, 正戊烯基, 异戊烯基, 环丙酰基, 环戊酰基, 环己酰基, 3-吡啶甲酰基, 萘基, 苯乙基咪唑基, 吡啶基, 吡咯基, 噁唑基,异恶唑基, 三氮唑基, 四氮唑基, 呋喃基, 噻吩基, 噻唑基, 哌啶基, 哌嗪基, 吲哚基,咔唑基, 苯并呋喃基 四氢呋喃基, 四氢吡喃基, 嘧啶碱基, 嘌呤碱基, -N(CH3)2, -C(C=O)NH-C1-C4 烷基, -OC(C=O)-NH-C1-C4烷 基, -OC(O=O)O-C1-C4 烷基, -NHC(=O)NH-C1-C4 烷基,-NHC(=O)O-C1-C4 烷基, -NHC(=O)-C1-C4 烷基, C1-C4烷基-NH-S(=O)2-, C1-C4烷基S(=O)2-, C1-C4烷基S(=O)2NH-, 苯基-(CH2)P-G-(CH2)m-, 氟代苯基-(CH2)P-G-(CH2) m-, 噻唑基-(CH2)p-G-(CH2)m-, 吡啶基-(CH2)p-G-(CH2)m-, 苯基乙基, 环己基-(CH2)p-G-(CH2)m-, 其中 G 是O, S, S(=O), S (=O)2, C(=O); p和m各自独立地为0, 1, 2或3; 或者其中C6-C10芳基-(CH2)P-G-(CH2)m-可以被一个或多个选自 F, Cl, Br, I, 甲基, 乙基, 丙基, 乙炔基, 丙炔基, 丁炔基, 甲氧基, 乙氧基或者氰基的取代基取代;或上述R3可任意的被D, F, Cl, Br, I, 羟基, 羟基, 羟甲基, 羧基, 乙酰氨基, C1-C6烷基（如甲基、乙基、丙基）, C1-C6烷氧基, C1-C6烷氨基, 三氟甲基, 三氟乙酰基, 巯基,硝基, 氨基, 叠氮基（-N3）, 胍基, 氰基, 叔丁氧羰基（-Boc）, 羰基（-C=O）, 氧代（=O）,硫代（=S）, 磺酰基, 苯基中的一个或多个取代。In some embodiments, R 3 in the compounds of the present invention are each independently H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C 5 H 11 , C 6 H 13 , C 8 H 17 , trifluoromethyl, hydroxymethyl, aminomethyl, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropionyl, 2 -Hydroxypropionyl, 2-aminopropionyl, 2-chloropropionyl, 2-bromopropionyl, pentanoyl, hexanoyl, heptanoyl, methacryloyl, phenyl, benzoyl, p-nitrophenyl, p-methyl phenylbenzoyl, m-fluorobenzoyl, p-aminobenzoyl, p-methoxybenzoyl, 2,4-dimethylbenzoyl, m-azidobenzoyl, benzyl, p-chlorobenzyl yl,vinyl, propenyl, allyl, n-butenyl, isobutenyl, n-pentenyl, isopentenyl, cyclopropionyl, cyclopentanoyl, cyclohexanoyl, 3-pyridineformyl, naphthyl , phenethylimidazolyl, pyridyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl, piperidyl, piperazinyl, indole Indolyl, Carbazolyl, Benzofuryltetrahydrofuranyl, Tetrahydropyranyl, Pyrimidinyl, Purine, -N(CH 3 ) 2 , -C(C=O)NH-C1-C4 Alkyl , -OC(C=O)-NH-C1-C4alkyl, -OC(O=O)O-C1-C4alkyl, -NHC(=O)NH-C1-C4alkyl,-NHC(= O)O-C1-C4 alkyl, -NHC(=O)-C1-C4 alkyl, C1-C4 alkyl-NH-S(=O) 2 -, C1-C4 alkylS(=O) 2 -, C1-C4 alkyl S(=O) 2 NH-, phenyl-(CH 2 ) P -G-(CH 2 ) m -, fluorophenyl-(CH 2 ) P -G-(CH 2 ) m -, thiazolyl-(CH 2 ) p -G-(CH 2 ) m -, pyridyl-(CH 2 ) p -G-(CH 2 ) m -, phenylethyl, cyclohexyl-(CH 2 ) p -G-(CH 2 ) m -, where G is O, S, S(=O), S (=O) 2 , C(=O); p and m are each independently 0, 1, 2 or 3; or wherein C6-C10 aryl-(CH 2 ) P -G-(CH 2 ) m -can be selected from F, Cl, Br, I, methyl, ethyl, propyl by one or more , ethynyl, propynyl, butynyl, methoxy, ethoxy or cyano substituents; or the above R 3 can be arbitrarily replaced by D, F, Cl, Br, I, hydroxy, hydroxy, hydroxymethyl, carboxyl, acetamido, C1-C6 alkyl (such as methyl, ethyl, propyl), C1-C6 alkoxy, C1-C6 alkylamino, tris Fluoromethyl, trifluoroacetyl, mercapto, nitro, amino, azido (-N 3 ), guanidino, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo One or more substitutions among (=O), thio (=S), sulfonyl, phenyl.

在另一些实施方案中, 本发明化合物包含如下之一的结构或以下之一结构的互变异构体、立体异构体、外消旋体、对映异构体的非等量混合物、几何异构体、溶剂化物、药学上可接受的盐或其盐的溶剂化物, 或前药:In other embodiments, the compounds of the present invention comprise one of the following structures or tautomers, stereoisomers, racemates, non-equivalent mixtures of enantiomers, geometric Isomers, solvates, pharmaceutically acceptable salts or solvates of their salts, or prodrugs:

。 .

本发明一方面涉及药物组合物, 包含本发明的化合物, 或其立体异构体, 几何异构体, 互变异构体, 氮氧化物, 水合物, 溶剂化物, 代谢产物, 药学上可接受的盐或它们的前药, 或任选药学上可接受的载体, 赋形剂, 稀释剂, 辅剂, 媒介物, 或它们的组合。One aspect of the present invention relates to a pharmaceutical composition comprising a compound of the present invention, or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs, or optionally a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

本发明一方面涉及预防、处理、治疗或减轻患者由病毒引起的各种疾病的方法,包括使用本发明化合物的药物组合物药学上可接受的有效剂量对患者进行给药。One aspect of the present invention relates to a method for preventing, treating, treating or alleviating various diseases caused by viruses in a patient, comprising administering to the patient a pharmaceutically effective dose of the pharmaceutical composition of the compound of the present invention.

本发明一方面涉及预防、处理、治疗或减轻患者由病毒引起的各种疾病的方法,包括使用本发明化合物药学上可接受的有效剂量对患者进行给药。One aspect of the present invention relates to a method for preventing, treating, treating or alleviating various diseases caused by viruses in a patient, comprising administering to the patient a pharmaceutically acceptable effective dose of the compound of the present invention.

本发明另一方面涉及本发明的化合物用于制备用于预防、处理、治疗或减轻患者由病毒引起的各种疾病的药物的用途。Another aspect of the present invention relates to the use of the compounds of the present invention for the preparation of medicaments for preventing, treating, treating or alleviating various diseases caused by viruses in patients.

本发明另一方面涉及使用一种包含本发明的化合物的药物组合物用于制备用于预防、处理、治疗或减轻患者由病毒引起的各种疾病的药物的用途。Another aspect of the present invention relates to the use of a pharmaceutical composition comprising the compound of the present invention for the preparation of medicaments for preventing, treating, treating or alleviating various diseases caused by viruses in patients.

另一方面, 本发明涉及一种使用本发明化合物或其药物组合物在预防或治疗动物或人体由病毒引起的各种疾病的方法用途, 该用途包含使用本发明的化合物或其药物组合物的药学上可接受的有效治疗量对人体或动物进行给药。In another aspect, the present invention relates to a method for using the compound of the present invention or its pharmaceutical composition in the prevention or treatment of various diseases caused by viruses in animals or humans, and the use includes the use of the compound of the present invention or its pharmaceutical composition A pharmaceutically acceptable and effective therapeutic dose is administered to humans or animals.

其中一些实施方案是, 本发明所述的由RSV、HSV、EV71、H1N1、H3N2、H5N1、H7N9、Cox-B3、HBV、HIV、FMDV、SARS等引起的疾病的药物中的应用, 所述疾病选呼吸道疾病、肺炎、龈口炎、角膜结膜炎、脑炎、肝炎、生殖系统感染、手、足、口腔等部位的皮疹、疱疹和疱疹性咽峡炎、手足口病、免疫性疾病、炎性疾病等。Some of the embodiments are the application of the present invention in medicines for diseases caused by RSV, HSV, EV71, H1N1, H3N2, H5N1, H7N9, Cox-B3, HBV, HIV, FMDV, SARS, etc., said diseases Respiratory diseases, pneumonia, gingivostomatitis, keratoconjunctivitis, encephalitis, hepatitis, reproductive system infection, rashes on hands, feet, oral cavity, herpes and herpetic angina, hand, foot and mouth disease, immune diseases, inflammation disease etc.

其中一些实施方案是, 本发明所述的药物用于治疗呼吸道合胞病毒（RSV)、单纯疱疹病毒（HSV）、乙肝病毒（HBV）、肠道病毒71 (EV71)、流感病毒 (H1N1、H3N2、H5N1、H7N9)、口蹄疫病毒 (FMDV)、人体免疫缺陷病毒 (HIV)、SARS病毒引起的疾病。In some embodiments, the medicament of the present invention is used to treat respiratory syncytial virus (RSV), herpes simplex virus (HSV), hepatitis B virus (HBV), enterovirus 71 (EV71), influenza virus (H1N1, H3N2 , H5N1, H7N9), foot-and-mouth disease virus (FMDV), human immunodeficiency virus (HIV), SARS virus-induced diseases.

前面所述内容只概述了本发明的某些方面, 但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The foregoing merely outlines certain aspects of the invention, but is not intended to be limiting. These and other aspects will be described in more detail and more fully below.

详细说明书Detailed instructions

定义和一般术语Definitions and General Terms

本发明将会把确定的具体化的内容所对应的文献详细列出, 实施方案都伴随有结构式和化学式的图解。本发明有预期地涵盖所有的选择余地、变体和同等物, 这些可能像权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质, 这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似的物质与本发明申请相区别或抵触, 其中包括但绝不限于术语的定义, 术语的用法, 描述的技术, 或像本发明申请所控制的范围。The present invention will list in detail the literature corresponding to the determined specific content, and the implementation plans are accompanied by diagrams of structural formulas and chemical formulas. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The invention is in no way limited to the description of the methods and materials. There are many documents and similar materials that differ from or contradict the present application, including but in no way limited to the definitions of terms, usage of terms, techniques described, or the scope of control like the present application.

本发明将应用以下定义除非其他方面表明。根据本发明的目的, 化学元素根据元素周期表, CAS版本和化学药品手册, 75, thEd, 1994来定义。另外, 有机化学一般原理见“Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito:1999, and “March's Advanced Organic Chemistry,” by Michael B. Smith and JerryMarch,John. Wiley&Sons, New York: 2007, 因此所有的内容都融合了参考文献。The following definitions shall apply to the present invention unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS Edition and Handbook of Chemicals, 75, th Ed, 1994. Also, general principles of organic chemistry in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito:1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and JerryMarch,John. Wiley&Sons, New York: 2007, so all The contents are incorporated with references.

像本发明所描述的, 本发明的化合物可以任选地被一个或多个取代基所取代,如上面的通式化合物, 或者像实施例里面特殊的例子, 子类, 和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言, 术语“任选地”不论是否位于术语“取代的”之前, 表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明, 一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被为具体基团的一个或多个取代基所取代, 那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是, 但并不限于, 卤代烷基, 羟基, 氨基, 卤素, 氰基, 芳基, 杂芳基, 烷氧基,烷氨基, 烷硫基, 烷基, 烯基, 炔基, 杂环基, 巯基, 硝基, 芳氧基, 杂芳氧基, 氧代(=O), 羧基, 羟基取代的烷氧基, 羟基取代的烷基-C(=O)-, 烷基-C(=O)-, 烷基-S(=O)-, 烷基-S(=O)2-, 羟基取代的烷基-S(=O)-, 羟基取代的烷基-S(=O)2-, 羧基烷氧基等等。As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "optionally", whether or not preceded by the term "substituted", indicates that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents of a specific group, then the substituents can be substituted at each position the same or differently. The substituents mentioned therein can be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, Alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo(=O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, Alkyl-C(=O)-, Alkyl-S(=O)-, Alkyl-S(=O) 2 -, Hydroxyl-Substituted Alkyl-S(=O)-, Hydroxy-Substituted Alkyl- S(=O) 2 -, carboxyalkoxy, etc.

本发明使用的术语“脂肪族”或“脂肪族基团”, 表示直链（即非支链）或支链, 取代或非取代的完全饱和或含有一个或多个不饱和度的烃链。除非另外详细说明, 脂肪族基团含有1-20个碳原子, 其中一些实施例是, 脂肪族基团含有1-10个碳原子, 另外一些实施例是, 脂肪族基团含有1-8个碳原子, 另外一些实施例是, 脂肪族基团含有1-6个碳原子, 另外一些实施例是, 脂肪族基团含有1-4个碳原子, 另外一些实施例是, 脂肪族基团含有1-3个碳原子。合适的脂肪族基团包括, 但并不限于, 直链或支链, 取代或非取代的烷基, 烯基或炔基, 如甲基, 乙基, 丙基, 异丙基, 丁基, 叔丁基, 己基, 异丁基, 仲丁基, 乙烯基等。The term "aliphatic" or "aliphatic group", as used herein, means a straight chain (ie, unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more degrees of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms, some examples are, aliphatic groups contain 1-10 carbon atoms, and in other embodiments, aliphatic groups contain 1-8 carbon atom, some other embodiments are that the aliphatic group contains 1-6 carbon atoms, some other embodiments are that the aliphatic group contains 1-4 carbon atoms, some other embodiments are that the aliphatic group contains 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, hexyl, isobutyl, sec-butyl, vinyl etc.

本发明使用的术语“卤代脂肪族”表示脂肪族基团被一个或多个相同或不同的卤原子所取代, 其中脂肪族基团具有如本发明所述的含义, 卤原子即氟、氯、溴或碘, 这样的实例包括, 但并不限于三氟甲基, 三氟乙基, 氯甲基, 2-氯乙烯基等。The term "halogenated aliphatic" used in the present invention means that the aliphatic group is substituted by one or more identical or different halogen atoms, wherein the aliphatic group has the meaning as described in the present invention, and the halogen atoms are fluorine, chlorine , bromine or iodine, examples of which include, but are not limited to, trifluoromethyl, trifluoroethyl, chloromethyl, 2-chlorovinyl and the like.

本发明使用的术语“羟基脂肪族”表示脂肪族基团被一个或多个羟基基团所取代,其中脂肪族基团具有如本发明所述的含义, 这样的实例包括, 但并不限于羟乙基, 2-羟基丙基, 羟甲基等。As used herein, the term "hydroxyaliphatic" means that an aliphatic group is substituted by one or more hydroxyl groups, wherein the aliphatic group has the meaning as described herein, examples of which include, but are not limited to, hydroxy Ethyl, 2-hydroxypropyl, hydroxymethyl, etc.

本发明使用的术语“氨基脂肪族”表示脂肪族基团被一个或多个氨基基团所取代,其中脂肪族基团具有如本发明所述的含义, 这样的实例包括, 但并不限于氨基甲基, 2-氨基乙基, 2-氨基异丙基等。The term "aminoaliphatic" used in the present invention means that an aliphatic group is substituted by one or more amino groups, wherein the aliphatic group has the meaning as described in the present invention, such examples include, but are not limited to amino Methyl, 2-aminoethyl, 2-aminoisopropyl, etc.

本发明使用的术语“烷基”包括1-20个碳原子, 或1-10个碳原子, 或1-6个碳原子, 或1-4个碳原子, 或1-3个碳原子饱和直链或支链的单价烃基, 其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。烷基更进一步的实例包括, 但并不限于, 甲基(Me, -CH3), 乙基(Et, -CH2CH3), 正丙基(n-Pr, -CH2CH2CH3), 异丙基(i-Pr, -CH(CH3)2), 正丁基(n-Bu, -CH2CH2CH2CH3), 异丁基(i-Bu, -CH2CH(CH3)2), 仲丁基(s-Bu,-CH(CH3)CH2CH3), 叔丁基(t-Bu, -C(CH3)3), 正戊基(-CH2CH2CH2CH2CH3), 2-戊基(-CH(CH3)CH2CH2CH3), 3-戊基(-CH(CH2CH3)2), 2-甲基-2-丁基(-C(CH3)2CH2CH3), 3-甲基-2-丁基(-CH(CH3)CH(CH3)2), 3-甲基-1-丁基(-CH2CH2CH(CH3)2), 2-甲基-1-丁基(-CH2CH(CH3)CH2CH3), 正己基(-CH2CH2CH2CH2CH2CH3), 2-己基(-CH(CH3)CH2CH2CH2CH3), 3-己基(-CH(CH2CH3)(CH2CH2CH3)), 2-甲基-2-戊基(-C(CH3)2CH2CH2CH3), 3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3), 4-甲基-2-戊基(-CH (CH3)CH2CH(CH3)2), 3-甲基-3-戊基(-C(CH3)(CH2CH3)2), 2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2), 2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2), 3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3), 正庚基, 正辛基, 等等。术语“烷基”和其前缀“烷”在此处使用, 都包含直链和支链的饱和碳链。The term "alkyl" used in the present invention includes 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms saturated straight Chain or branched monovalent hydrocarbon groups, wherein the alkyl groups can be independently and optionally substituted with one or more substituents described in the present invention. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu,-CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-Pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-Pentyl (-CH(CH 2 CH 3 ) 2 ), 2-Methyl -2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1- Butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH (CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH (CH 3 ) 2 ), 3,3-Dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alk" are used herein to include straight and branched saturated carbon chains.

术语“烯基”表示2-12个碳原子, 或2-8个碳原子, 或2-6个碳原子, 或2-4个碳原子直链或支链的一价烃基, 其中至少一个位置为不饱和状态, 即一个C-C为sp2双键, 其中链烯基的基团可以独立任选地被一个或多个本发明所描述的取代基所取代, 包括基团有“反”“正”或”E∥Z”的定位, 其中具体的实例包括, 但并不限于, 乙烯基(-CH=CH2), 烯丙基(-CH2CH=CH2), 等等。The term "alkenyl" means a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, in which at least one position It is an unsaturated state, that is, one CC is a sp 2 double bond, and the alkenyl group can be independently and optionally replaced by one or more substituents described in the present invention, including groups with "anti" and "normal"" or "E∥Z" positioning, where specific examples include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), etc.

术语“炔基”表示2-12个碳原子, 或2-8个碳原子, 或2-6个碳原子, 或2-4个碳原子直链或支链的一价烃基, 其中至少一个位置为不饱和状态, 即一个C-C为sp三键, 其中炔基基团可以独立任选地被一个或多个本发明所描述的取代基所取代, 具体的实例包括,但并不限于, 乙炔基(-C三CH), 炔丙基(-CH2C三CH), 等等。The term "alkynyl" means a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, in which at least one position It is an unsaturated state, that is, one CC is an sp triple bond, wherein the alkynyl group can be independently and optionally replaced by one or more substituents described in the present invention, specific examples include, but are not limited to, ethynyl (-C triCH), propargyl (-CH 2 C triCH), etc.

术语“羟基取代的烷基”表示烷基基团被一个或多个羟基基团所取代, 其中烷基基团具有本发明所述的含义。这样的实例包含, 但并不限于羟甲基, 羟乙基, l, 2-二羟基乙基等。The term "hydroxyl-substituted alkyl" means that an alkyl group is substituted by one or more hydroxy groups, wherein the alkyl group has the meaning described herein. Such examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like.

术语 “碳环”、“碳环基”、“环烷基”是指一价或多价, 非芳香族, 饱和或部分不饱和环, 且不包含杂原子, 其中包括3-12个碳原子的单环或7-12个碳原子的二环或三环。具有7-12个原子的双碳环可以是二环[4, 5], [5, 5], [5, 6]或[6, 6]体系, 同时具有9或10个原子的双碳环可以是二环[5, 6]或[6, 6]体系。合适的环状脂肪族基团包括, 但并不限于, 环烷基, 环烯基和环炔基。环状脂肪族基团的实例进一步包括, 但绝不限于, 环丙基, 环丁基, 环戊基, 1-环戊基-1-烯基, 1-环戊基-2-烯基, 1-环戊基-3-烯基, 环己基, 1-环己基-1-烯基, 1-环己基-2-烯基, 1-环己基-3-烯基, 环己二烯基, 环庚基, 环辛基, 环壬基, 环癸基, 环十一烷基, 环十二烷基, 金刚烷基等等。并且所述“碳环”、“碳环基”、“环烷基”可以是取代或非取代的, 其中取代基可以是, 但并不限于, 卤代烷基,羟基, 氨基, 卤素, 氰基, 芳基, 杂芳基, 烷氧基, 烷氨基, 烷基, 烯基, 炔基, 杂环基, 巯基, 硝基, 芳氧基, 羟基取代的烷氧基, 羟基取代的烷基-C(=O)-, 烷基-C(=O)-,烷基-S(=O)-, 烷基-S(=O)2-, 羟基取代的烷基-S(=O)-, 羟基取代的烷基-S(=O)2-, 羧基烷氧基等等。The terms "carbocycle", "carbocyclyl", "cycloalkyl" refer to monovalent or polyvalent, non-aromatic, saturated or partially unsaturated rings containing no heteroatoms, including 3-12 carbon atoms A monocyclic ring or a bicyclic or tricyclic ring with 7-12 carbon atoms. Bicarbocycles with 7-12 atoms can be bicyclic [4, 5], [5, 5], [5, 6] or [6, 6] systems, while bicarbocycles with 9 or 10 atoms It can be a bicyclic [5, 6] or [6, 6] system. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of cycloaliphatic groups further include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, Cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, etc. And the "carbocycle", "carbocyclyl" and "cycloalkyl" can be substituted or unsubstituted, wherein the substituents can be, but not limited to, haloalkyl, hydroxyl, amino, halogen, cyano, Aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=O)-, Alkyl-C(=O)-, Alkyl-S(=O)-, Alkyl-S(=O) 2 -, Alkyl-S(=O)-substituted by hydroxy, Hydroxy-substituted alkyl-S(=O) 2 -, carboxyalkoxy and the like.

术语“环烷基氧基”或“碳环基氧基”包括任选取代的环烷基或碳环基, 如本发明所定义的, 连接到氧原子上, 并且由氧原子与其余分子相连, 这样的实例包括, 但并不限于环丙基氧基, 环戊基氧基, 环己基氧基, 羟基取代的环丙基氧基等。The terms "cycloalkyloxy" or "carbocyclyloxy" include optionally substituted cycloalkyl or carbocyclyl groups, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule , such examples include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like.

术语“环烷基氨基”表示氨基基团被一个或两个环烷基基团所取代, 其中环烷基具有如本发明所述的含义, 这样的实例包括, 但并不限于环丙基氨基, 环戊基氨基, 环己基氨基, 羟基取代的环丙基氨基, 二环己基氨基, 二环丙基氨基等。The term "cycloalkylamino" means that an amino group is substituted by one or two cycloalkyl groups, wherein cycloalkyl has the meaning described herein, such examples include, but are not limited to, cyclopropylamino , cyclopentylamino, cyclohexylamino, hydroxyl-substituted cyclopropylamino, dicyclohexylamino, dicyclopropylamino, etc.

术语“环烷基氧基脂肪族”表示脂肪族基团被一个或多个环烷基氧基基团所取代,其中脂肪族基团和环烷基氧基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于环丙基氧基甲基, 环丙基氧基乙基, 环戊基氧基甲基, 环戊基氧基乙基, 环己基氧基乙基, 卤代环丙基氧基乙基等。The term "cycloalkyloxyaliphatic" means that an aliphatic group is substituted by one or more cycloalkyloxy groups, wherein the aliphatic group and the cycloalkyloxy group have the meaning, such examples include, but are not limited to, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxyethyl, Halocyclopropyloxyethyl etc.

术语“环烷基氨基脂肪族”表示脂肪族基团被一个或多个环烷基氨基基团所取代,其中脂肪族基团和环烷基氨基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于环丙基氨基甲基, 环丙基氨基己基, 环戊基氨基甲基, 环戊基氨基乙基, 环己基氨基乙基, 卤代环丙基氨基乙基等。The term "cycloalkylaminoaliphatic" means that the aliphatic group is substituted by one or more cycloalkylamino groups, wherein the aliphatic group and the cycloalkylamino group have the meanings as described in the present invention, such that Examples include, but are not limited to, cyclopropylaminomethyl, cyclopropylaminohexyl, cyclopentylaminomethyl, cyclopentylaminoethyl, cyclohexylaminoethyl, halocyclopropylaminoethyl, etc. .

术语“环烷基脂肪族”或“碳环基脂肪族”表示脂肪族基团可被一个或多个环烷基基团或碳环基基团所取代, 其中环烷基, 或碳环基和脂肪族基团具有如本发明所述的含义, 这样的实例包括, 但并不限于环丙基甲基, 环丙基乙基, 环丙基丙基, 环戊基甲基,环己基乙基等。The term "cycloalkylaliphatic" or "carbocyclylaliphatic" means that the aliphatic group may be substituted by one or more cycloalkyl groups or carbocyclyl groups, wherein cycloalkyl, or carbocyclyl and aliphatic groups have the meanings described herein, examples of which include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclohexylethyl Base etc.

术语“杂环”, “杂环基”, “杂脂环族”或“杂环的”在此处可交换使用, 都是指单环, 双环, 或三环体系, 萁中环上一个或多个原子独立任选地被杂原子所取代, 环可以是完全饱和的或包含一个或多个不饱和度, 但绝不是芳香族类, 只有一个连接点连接到其他分子上去。一个或多个环上的氢原子独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是, “杂环”“杂环基”“杂脂环族”或“杂环的”基团是3-7元环的单环（1-6个碳原子和为N, O, P, S的1-3个杂原子, 在此S或P任选地被一个或多个氧原子所取代得到像SO, SO2, PO, PO2的基团, 当所述的环为三元环时, 其中只有一个杂原子),或7-10元的双环（4-9个碳原子和为N, O, P, S的1-3个杂原子, 在此S或P任选地被一个或多个氧原子所取代得到像SO, SO2, PO, PO2的基团）。The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein to refer to monocyclic, bicyclic, or tricyclic ring systems in which one or more Atoms independently optionally substituted by heteroatoms, rings may be fully saturated or contain one or more degrees of unsaturation, but are never aromatic, have only one point of attachment to other molecules. One or more ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. In some examples, a "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and N, O , P, 1-3 heteroatoms of S, where S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO 2 , PO, PO 2 , when the ring is In the case of a three-membered ring, there is only one heteroatom), or a 7-10-membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms of N, O, P, S, where S or P is optional substituted by one or more oxygen atoms to get groups like SO, SO 2 , PO, PO 2 ).

杂环基可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括, 但并不限于, 吡咯烷基, 四氢呋喃基,二氢呋喃基, 四氢噻吩基, 四氢吡喃基, 二氢吡喃基, 四氢噻喃基, 哌啶基, 吗啉基,硫代吗啉基, 噻噁烷基, 哌嗪基, 高哌嗪基, 氮杂环丁基, 氧杂环丁基, 硫杂环丁基,哌啶基, 高哌啶基, 环氧丙基, 氮杂环庚基, 氧杂环庚基, 硫杂环庚基, 4-甲氧基-哌啶-1-基, l, 2, 3, 6-四氢吡啶-1-基, 氧氮杂卓基, 二氮杂卓基, 硫氮杂卓基, 吡咯啉-1-基, 2-吡咯啉基, 3-吡咯啉基, 二氢吲哚基, 二氢吡喃基, 四氢吡喃基, 二氧杂环己基, l, 3-二氧戊基, 吡唑啉基, 二噻烷基, 二噻茂烷基, 二氢噻吩基, 吡唑烷基咪唑啉基, 咪唑烷基, l, 2, 3, 4-四氢异喹啉基, l, 2, 6-噻二嗪烷l,1-二氧-2-基, 4-羟基-l, 4-氮杂磷烷4-氧化物-1-基, 2-羟基-1-（哌嗪-1-基）乙酮-4-基, 2-羟基-1-（5, 6-二氢-l, 2, 4-三嗪-l（4H）-基）乙酮-4-基, 5, 6-二氢-4H-1, 2, 4-噁二嗪-4-基, 2-羟基-1-（5, 6-二氢吡啶-l（2H）-基）乙酮-4-基, 3-氮杂双环[3.1.0]己基, 3-氮杂双环[4.1.0]庚基, 氮杂双环[2.2.2]己基, 2-甲基-5, 6, 7, 8-四氢-[1, 2, 4]三唑[1,5-c]嘧啶-6-基, 4, 5, 6, 7一四氢异噁唑[4, 3-c]吡啶-5-基, 3H-吲哚基2-氧-5-氮杂双环[2.2.1]庚烷-5-基, 2-氧-5-氮杂双环[2.2.2]辛烷-5-基, 喹嗪基和N-吡啶基尿素。杂环基团的实例还包括, l,1-二氧硫代吗啉基, 和其中环上两个碳原子被氧原子所取代如嘧啶二酮基。并且所述杂环基可以是取代或非取代的, 其中取代基可以是, 但并不限于, 卤代烷基, 氧代(=O), 羟基, 氨基, 卤素, 氰基, 杂芳基, 烷氧基, 烷氨基, 烷基, 烯基,炔基, 杂环基, 巯基, 硝基, 芳氧基, 羟基取代的烷氧基, 羟基取代的烷基-C(=O)-, 烷基-C(=O)-, 烷基-S(=O)-, 烷基-S(=O)2- 羟基取代的烷基-S(=O)-, 羟基取代的烷基-S(=O)2-, 羧基烷氧基等等。A heterocyclic group may be a carbon group or a heteroatom group. "Heterocyclyl" also includes the combination of a heterocyclic group and a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, Thiomorpholinyl, Thioxanyl, Piperazinyl, Homopiperazinyl, Azetidinyl, Oxetanyl, Thietanyl, Piperidinyl, Homopiperidinyl , epoxypropyl, azepanyl, oxepyl, thiepanyl, 4-methoxy-piperidin-1-yl, l, 2, 3, 6-tetrahydropyridine-1 -yl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, dihydropyranyl yl, tetrahydropyranyl, dioxanyl, l, 3-dioxolyl, pyrazolinyl, dithianyl, dithianyl, dihydrothienyl, pyrazolidinyl imidazoline base, imidazolidinyl, l, 2, 3, 4-tetrahydroisoquinolinyl, l, 2, 6-thiadiazidinyl, 1-dioxo-2-yl, 4-hydroxy-l, 4- Azaphosphine 4-oxide-1-yl, 2-hydroxy-1-(piperazin-1-yl)ethanon-4-yl, 2-hydroxy-1-(5,6-dihydro-l, 2, 4-Triazin-l(4H)-yl)ethanon-4-yl, 5, 6-dihydro-4H-1, 2, 4-oxadiazin-4-yl, 2-hydroxyl-1- (5,6-dihydropyridin-l(2H)-yl)ethanon-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, aza Bicyclo[2.2.2]hexyl, 2-methyl-5, 6, 7, 8-tetrahydro-[1, 2, 4]triazol[1,5-c]pyrimidin-6-yl, 4, 5, 6, 7-Tetrahydroisoxazol[4, 3-c]pyridin-5-yl, 3H-indolyl 2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2- Oxy-5-azabicyclo[2.2.2]octan-5-yl, quinazinyl and N-pyridylurea. Examples of the heterocyclic group also include, 1,1-dioxothiomorpholinyl, and a pyrimidinedione group in which two carbon atoms on the ring are replaced by oxygen atoms. And the heterocyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, haloalkyl, oxo (=O), hydroxyl, amino, halogen, cyano, heteroaryl, alkoxy radical, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl- C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 - hydroxy substituted alkyl-S(=O)-, hydroxy substituted alkyl-S(=O ) 2 -, carboxyalkoxy, etc.

术语“杂环基脂肪族”表示杂环基取代的脂肪族基团, 其中杂环基和脂肪族基团具有如本发明所述的含义, 这样的实例包括, 但并不限于吡咯-2-甲基, 哌啶-2-乙基,哌嗪-2-乙基, 哌啶-2-甲基等。The term "heterocyclylaliphatic" means a heterocyclyl-substituted aliphatic group, wherein the heterocyclyl and aliphatic groups have the meanings described herein, examples of which include, but are not limited to, pyrrole-2- Methyl, piperidine-2-ethyl, piperazine-2-ethyl, piperidine-2-methyl, etc.

术语“杂环基氧基”包括任选取代的杂环基, 如本发明所定义的, 连接到氧原子上, 其中氧原子与分子的其余部分相连, 这样的实例包括, 但并不限于吡咯-2-氧基, 吡咯-3-氧基, 哌啶-2-氧基, 哌啶-3-氧基, 哌嗪-2-氧基, 哌啶-4-氧基等。The term "heterocyclyloxy" includes optionally substituted heterocyclyl groups, as defined herein, attached to an oxygen atom which is attached to the rest of the molecule, examples of which include, but are not limited to, pyrrole -2-oxyl, pyrrole-3-oxyl, piperidine-2-oxyl, piperidine-3-oxyl, piperazine-2-oxyl, piperidine-4-oxyl, etc.

术语“杂环基氨基”表示氨基基团被一个或两个杂环基基团所取代, 其中氮原子与分子的其余部分相连, 并且杂环基具有如本发明所述的含义, 这样的实例包括, 但并不限于吡咯-2-氨基, 吡咯-3-氨基, 哌啶-2-氨基, 哌啶-3-氨基, 哌啶-4-氨基, 哌嗪-2-氨基, 二吡咯-2-氨基等。The term "heterocyclylamino" means that the amino group is substituted by one or two heterocyclyl groups, wherein the nitrogen atom is attached to the rest of the molecule, and the heterocyclyl has the meaning as described in the present invention, such examples Including, but not limited to, pyrrole-2-amino, pyrrole-3-amino, piperidine-2-amino, piperidine-3-amino, piperidine-4-amino, piperazine-2-amino, dipyrrole-2 -Amino etc.

术语“杂环基氧基脂肪族”表示脂肪族基团被一个或多个杂环基氧基基团所取代,其中脂肪族基团和杂环基氧基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于吡咯-2-氧基甲基, 哌嗪-3-氧基乙基, 哌嗪-2-氧基乙基, 吗啉-2-氧基甲基, 哌啶-2-氧基乙基等。术语“杂环基氨基脂肪族”表示脂肪族基团被一个或多个杂环基氨基基团所取代, 其中脂肪族基团和杂环基氨基基团具有如本发明所述的含义, 这样的实例包括,但并不限于吡咯-2-氨基甲基, 哌嗪-3-氨基乙基, 哌嗪-2-氨基乙基, 哌啶-2-氨基乙基,吗啉-2-氨基甲基等。The term "heterocyclyloxyaliphatic" means that an aliphatic group is substituted by one or more heterocyclyloxy groups, wherein the aliphatic group and the heterocyclyloxy group have the Meaning, such examples include, but are not limited to, pyrrole-2-oxymethyl, piperazine-3-oxyethyl, piperazine-2-oxyethyl, morpholine-2-oxymethyl, Piperidine-2-oxyethyl etc. The term "heterocyclylaminoaliphatic" means that the aliphatic group is substituted by one or more heterocyclylamino groups, wherein the aliphatic group and the heterocyclylamino group have the meanings as described in the present invention, such that Examples include, but are not limited to, pyrrole-2-aminomethyl, piperazine-3-aminoethyl, piperazine-2-aminoethyl, piperidine-2-aminoethyl, morpholine-2-aminomethyl Base etc.

术语“杂原子”表示一个或多个O, S, N, P和Se, 包括N, S和P任何氧化态的形式; 伯、仲、叔胺和季铵盐的形式; 或者杂环中氮原子上的氢被取代的形式, 例如, N(像3, 4-二氢-2H-吡咯基中的N), NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。The term "heteroatom" means one or more of O, S, N, P, and Se, including the form of any oxidation state of N, S, and P; the form of primary, secondary, and tertiary amines, and quaternary ammonium salts; or the nitrogen in a heterocyclic ring The form in which the hydrogen on the atom is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidine NR in the base).

术语“卤素”是指F, Cl, Br或I。The term "halogen" refers to F, Cl, Br or I.

在本发明中所使用的术语“不饱和的”表示部分含有一个或多个不饱和度。As used herein, the term "unsaturated" means that a moiety contains one or more degrees of unsaturation.

本发明中所使用的术语“烷氧基”, 涉及到烷基, 像本发明所定义的, 通过氧原子（“烷氧基”）连接到主要的碳链上, 这样的实例包括, 但并不限于甲氧基, 乙氧基, 丙氧基, 丁氧基等。并且所述烷氧基可以是取代或非取代的, 其中取代基可以是, 但并不限于, 羟基, 氨基, 卤素, 氰基, 烷氧基, 烷基, 烯基, 炔基, 巯基, 硝基等等。The term "alkoxy" as used herein refers to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom ("alkoxy"), examples of which include, but do not Not limited to methoxy, ethoxy, propoxy, butoxy, etc. And the alkoxy group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, hydroxyl, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro base and so on.

术语“羟基取代的烷氧基”或“羟基烷氧基”表示烷氧基基团被一个或多个羟基基团所取代, 其中烷氧基具有如本发明所述的含义, 这样的实例包括, 但并不限于羟甲氧基, 2-羟基乙氧基, 2-羟基丙氧基, 2-羟基异丙氧等。The term "hydroxy-substituted alkoxy" or "hydroxyalkoxy" means that an alkoxy group is substituted by one or more hydroxy groups, wherein alkoxy has a meaning as described herein, examples of which include , but not limited to hydroxymethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy, etc.

术语“氨基烷氧基”表示烷氧基基团被一个或多个氨基基团所取代, 其中烷氧基具有如本发明所述的含义, 这样的实例包括, 但并不限于氨甲氧基, 2-氨基乙氧基, 2-氨基丙氧基, 2-氨基异丙氧基等。The term "aminoalkoxy" means that an alkoxy group is substituted by one or more amino groups, where alkoxy has a meaning as described herein, examples of which include, but are not limited to, aminomethoxy , 2-aminoethoxy, 2-aminopropoxy, 2-aminoisopropoxy, etc.

术语“卤代烷基”“卤代烯基”和“卤代烷氧基”表示烷基, 烯基或烷氧基可以被一个或多个卤素原子所取代的情况, 这样的实例包括, 但并不限于三氟甲基, 2-氯-乙烯基, 三氟甲氧基等。The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" denote an alkyl, alkenyl or alkoxy group which may be substituted with one or more halogen atoms, examples of which include, but are not limited to, three Fluoromethyl, 2-chloro-vinyl, trifluoromethoxy, etc.

术语“芳基”表示共含有6-14元环的单环, 双环, 和三环的碳环体系, 其中, 至少一个环体系是芳香族的, 其中每一个环体系包含3-7元环, 且只有一个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用, 如芳香环可以包括苯基, 萘基和蒽。并且所述芳基可以是取代或非取代的, 其中取代基可以是, 但并不限于, 卤代烷基, 羟基, 氨基, 卤素, 氰基, 芳基, 杂芳基, 烷氧基, 烷氨基, 烷基, 烯基, 炔基,杂环基, 巯基, 硝基, 芳氧基, 羟基取代的烷氧基, 羟基取代的烷基-C(=O)-, 烷基-C(=O)-, 烷基-S(=O)-, 烷基-S(=O)2-, 羟基取代的烷基-S(=O)-, 羟基取代的烷基-S (=O)2-, 羧基烷氧基等等。The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 membered rings, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 membered rings, And only one attachment point is connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring", such as aromatic rings can include phenyl, naphthyl and anthracene. And the aryl group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, Alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O) -, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) 2 -, Carboxyalkoxy and the like.

术语“氟代苯基”表示苯基基团被一个或多个氟原子所取代。The term "fluorophenyl" means that a phenyl group is substituted with one or more fluorine atoms.

术语“芳基脂肪族”表示脂肪族基团被一个或多个芳基基团所取代, 其中脂肪族基团和芳基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于苯乙基, 苯甲基, 对甲苯乙基, 苯乙烯基等。The term "arylaliphatic" means that an aliphatic group is substituted by one or more aryl groups, wherein aliphatic and aryl groups have the meanings described herein, examples of which include, but do not Not limited to phenethyl, benzyl, p-tolyl, styryl, etc.

术语“芳氧基”或“芳基氧基”包括任选取代的芳基, 如本发明所定义的, 连接到氧原子上, 并且由氧原子与分子其余部分相连, 其中芳基基团具有如本发明所述的含义,这样的实例包括, 但并不限于苯氧基, 甲苯氧基, 乙苯氧基等。The terms "aryloxy" or "aryloxy" include optionally substituted aryl groups, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule, wherein the aryl group has Such examples include, but are not limited to, phenoxy, methylphenoxy, ethylphenoxy, etc. within the meaning of the present invention.

术语“芳氨基”表示氨基基团被一个或两个芳基基团所取代, 其中芳基具有如本发明所述的含义, 这样的实例包括, 但并不限于苯基氨基, 对氟苯基氨基, 二苯基氨基,二甲苯基氨基, 二对甲苯基氨基等。The term "arylamino" means that an amino group is substituted by one or two aryl groups, wherein aryl has the meaning as described in the present invention, such examples include, but are not limited to, phenylamino, p-fluorophenyl Amino, diphenylamino, xylylamino, di-p-tolylamino, etc.

术语“芳氧基脂肪族”表示脂肪族基团被一个或多个芳氧基基团所取代, 其中芳氧基和脂肪族基团具有如本发明所述的含义, 这样的实例包括, 但并不限于苯氧基甲基,苯氧基乙基, 甲苯氧基乙基, 苯氧基丙基等。The term "aryloxyaliphatic" means that an aliphatic group is substituted by one or more aryloxy groups, wherein aryloxy and aliphatic groups have the meanings described herein, examples of which include, but Not limited to phenoxymethyl, phenoxyethyl, tolyloxyethyl, phenoxypropyl, etc.

术语“杂芳氧基脂肪族”表示脂肪族基团被一个或多个杂芳氧基基团所取代, 其中杂芳氧基和脂肪族基团具有如本发明所述的含义, 这样的实例包括, 但并不限于呋喃氧基甲基, 嘧啶氧基乙基等。The term "heteroaryloxyaliphatic" means that the aliphatic group is substituted by one or more heteroaryloxy groups, wherein the heteroaryloxy group and the aliphatic group have the meanings as described in the present invention, such examples Including, but not limited to furyloxymethyl, pyrimidinyloxyethyl, etc.

术语“芳氨基脂肪族”表示表示脂肪族基团被一个或多个芳氨基基团所取代, 其中芳氨基和脂肪族基团具有如本发明所述的含义, 这样的实例包括, 但并不限于苯氨基甲基, 苯氨基乙基, 甲苯氨基乙基, 苯氨基丙基, 苯氨基烯丙基等。The term "arylaminoaliphatic" means that an aliphatic group is substituted by one or more arylamino groups, wherein arylamino and aliphatic groups have the meanings described in the present invention, such examples include, but are not Limited to anilinomethyl, anilinoethyl, tolylaminoethyl, anilinopropyl, anilinoallyl, etc.

术语“芳基烷氧基”表示烷氧基基团被一个或多个芳基所取代, 其中芳基和烷氧基具有本发明所述的含义, 这样的实例包括, 但并不限于苯基甲氧基, 苯基乙氧基, 对甲苯基甲氧基, 苯基丙氧基等。并且所述芳基可以是取代或非取代的, 其中取代基可以是, 但并不限于, 卤代烷基, 羟基, 氨基, 卤素, 氰基, 芳基, 杂芳基, 烷氧基, 烷氨基, 烷基, 烯基, 炔基, 杂环基, 巯基, 硝基, 芳氧基, 羟基取代的烷氧基, 羟基取代的烷基-C(=O)-, 烷基-C(=O)-, 烷基-S(=O)-, 烷基-S(=O)2-, 羟基取代的烷基-S(=O)-,羟基取代的烷基-S (=O)2-, 羧基烷氧基等等。The term "arylalkoxy" means an alkoxy group substituted by one or more aryl groups, where aryl and alkoxy have the meanings described herein, examples of which include, but are not limited to, phenyl Methoxy, Phenylethoxy, p-Tolylmethoxy, Phenylpropoxy, etc. And the aryl group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, Alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O) -, Alkyl-S(=O)-, Alkyl-S(=O) 2 -, Alkyl substituted with hydroxy-S(=O)-, Alkyl substituted with hydroxy-S(=O) 2 -, Carboxyalkoxy and the like.

术语“芳基烷氨基”表示烷氨基基团被一个或多个芳基基团所取代, 其中芳基和烷氧基具有本发明所述的含义, 这样的实例包括, 但并不限于苯基甲氨基, 苯基乙氨基,苯基丙氨基, 对甲苯基甲氨基等。The term "arylalkylamino" means that an alkylamino group is substituted by one or more aryl groups, wherein aryl and alkoxy have the meanings described herein, examples of which include, but are not limited to, phenyl Methylamino, phenylethylamino, phenylpropylamino, p-tolylmethylamino, etc.

术语“杂芳基”可以单独使用或作为“杂芳基烷基”或“杂芳基烷氧基”的一大部分,表示共含有5-14元环的单环, 双环, 和三环体系, 其中至少一个环体系是芳香族的, 且至少一个环体系包含一个或多个杂原子, 其中每一个环体系包合3-7元环, 且只有一个附着点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或非取代的, 其中取代基可以是, 但并不限于, 卤代烷基, 羟基, 氨基, 卤素, 氰基, 芳基, 杂芳基, 烷氧基, 烷氨基, 烷基, 烯基, 炔基,杂环基, 巯基, 硝基, 芳氧基, 羟基取代的烷氧基, 羟基取代的烷基-C(=O)-, 烷基-C(=O)-, 烷基-S(=O)-, 烷基-S(=O)2-, 羟基取代的烷基-S(=O)-, 羟基取代的烷基-S (=O)2-, 羧基烷氧基等等。The term "heteroaryl" may be used alone or as part of "heteroarylalkyl" or "heteroarylalkoxy" to denote monocyclic, bicyclic, and tricyclic ring systems containing a total of 5-14 ring members , wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, each of which contains 3-7 membered rings, and only one point of attachment is connected to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". And the heteroaryl can be substituted or unsubstituted, wherein the substituents can be, but not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino , alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O )-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) 2 - , carboxyalkoxy and so on.

另外一些实施例是, 芳杂环包括以下的单环, 但并不限于这些单环：2-呋喃基,3-呋喃基, N-咪唑基, 2-咪唑基, 4-咪唑基, 5-咪唑基, 3-异噁唑基, 4-异噁唑基, 5-异噁唑基, 2-噁唑基, 4-噁唑基, 5-噁唑基, 4-甲基异噁唑-5-基, N-吡咯基, 2-吡咯基, 3-吡咯基, 2-吡啶基, 3-吡啶基, 4-吡啶基, 2-嘧啶基, 4-嘧啶基, 嘧啶-5-基, 哒嗪基（如3-哒嗪基）, 2-噻唑基, 4-噻唑基, 5-噻唑基, 四唑基（如5-四唑基）, 三唑基（如2-三唑基和5-三唑基）, 2-噻吩基, 3-噻吩基, 吡唑基（如2-吡唑基）, 异噻唑基, l, 2,3-噁二唑基, l, 2, 5-噁二唑基, l, 2, 4-噁二唑基, l, 2, 3-三唑基, l, 2, 3-硫代二唑基, l, 3, 4-硫代二唑基, l, 2, 5-硫代二唑基, l, 3, 4-噻二唑-2-基, 吡嗪基,吡嗪-2-基, l, 3, 5-三嗪基, 苯并[d]噻唑-2-基, 咪唑并[1, 5-a]吡啶-6-基; 也包括以下的双环, 但绝不限于这些双环：苯并咪唑基, 苯并呋喃基, 苯并噻吩基, 苯并噻唑基, 吲哚基（如2-吲哚基）, 嘌呤基, 喹啉基（如2-喹啉基, 3-喹啉基, 4-喹啉基）, 和异喹啉基（如1-异喹啉基, 3-异喹啉基或4-异喹啉基）。In some other embodiments, aromatic heterocycles include, but are not limited to, the following monocycles: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazolyl- 5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, Pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, l, 2,3-oxadiazolyl, l, 2, 5- Oxadiazolyl, l, 2, 4-oxadiazolyl, l, 2, 3-triazolyl, l, 2, 3-thiodiazolyl, l, 3, 4-thiodiazolyl, l, 2, 5-thiodiazolyl, l, 3, 4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, l, 3, 5-triazinyl, benzo[ d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl; also include, but are by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl , benzothiazolyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

术语“杂芳基氧基”包括任选取代的杂芳基, 如本发明所定义的, 连接到氧原子上, 并且由氧原子与分子其余部分相连, 其中杂芳基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于吡啶-2-氧基, 噻唑-2-氧基, 咪唑-2-氧基, 嘧啶-2-氧基等。The term "heteroaryloxy" includes optionally substituted heteroaryl groups, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule, wherein the heteroaryl group has In the stated meaning, such examples include, but are not limited to, pyridin-2-oxyl, thiazole-2-oxyl, imidazol-2-oxyl, pyrimidin-2-oxyl and the like.

术语“羧基烷氧基”表示烷氧基基团被一个或多个羧基基团所取代, 其中烷氧基和羧基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于羧基甲氧基, 羧基乙氧基等。The term "carboxyalkoxy" means that an alkoxy group is substituted by one or more carboxyl groups, wherein the alkoxy and carboxyl groups have the meanings described herein, examples of which include, but are not limited to Carboxymethoxy, carboxyethoxy, etc.

术语“烷硫基”包括Cl-C10直链或支链的烷基连接到二价的硫原子上。其中一些实施例是, 烷硫基是较低级的C1-C3烷硫基, 这样的实例包括, 但并不限于甲硫基（CH3S-）。术语“卤代烷硫基”包括Cl-C10的卤代烷基连接到二价硫原子上。其中一些实施例是, 卤代烷硫基是较低级的C1-C3卤代烷硫基, 这样的实例包括, 但并不限于三氟甲硫基。The term "alkylthio" includes Cl-C10 straight or branched chain alkyl attached to a divalent sulfur atom. In some embodiments, the alkylthio group is a lower C1-C3 alkylthio group, such examples include, but are not limited to, methylthio (CH 3 S-). The term "haloalkylthio" includes Cl-C10 haloalkyl attached to a divalent sulfur atom. In some embodiments, the haloalkylthio group is a lower C1-C3 haloalkylthio group, such examples include, but are not limited to, trifluoromethylthio.

术语“烷基氨基”, 或“烷氨基”, 包括“N-烷基氨基”和“N, N-二烷基氨基”, 其中氨基团分别独立地被一个或两个烷基基团所驭代。其中一些实施例是, 烷基氨基是一个或两个C1-C6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是, 烷基氨基是C1-C3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基,这样的实例包括, 但并不限于, N-甲氨基, N-乙氨基, N, N-二甲氨基, N, N-二乙氨基等等。The term "alkylamino", or "alkylamino", includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently replaced by one or two alkyl groups generation. In some embodiments, the alkylamino group is a lower alkylamino group with one or two C1-C6 alkyl groups attached to a nitrogen atom. In some other embodiments, the alkylamino group is a C1-C3 lower alkylamino group. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N -Diethylamino and the like.

术语“杂芳基氨基”表示氨基团被一个或两个杂芳基所取代, 其中杂芳基具有本发明所述的含义, 这样的实例包括, 但并不限于N-噻吩基氨基等。其中一些实施例是, 杂芳基氨基上的杂芳环可以进一步被取代。The term "heteroarylamino" means that the amino group is substituted by one or two heteroaryl groups, wherein the heteroaryl group has the meaning described in the present invention, such examples include, but are not limited to, N-thienylamino and the like. In some of these examples, the heteroaryl ring on the heteroarylamino group can be further substituted.

术语“杂芳基脂肪族”表示脂肪族基团被一个或多个杂芳基所取代, 其中杂芳基和脂肪族基团具有本发明所述的含义, 这样的实例包括, 但并不限于噻吩-2-丙烯基, 吡啶-4-乙基, 咪唑-2-甲基, 呋喃-2-乙基, 吲哚-3-甲基等。The term "heteroarylaliphatic" means that an aliphatic group is substituted by one or more heteroaryl groups, wherein heteroaryl and aliphatic groups have the meanings described herein, examples of which include, but are not limited to Thiophene-2-propenyl, pyridine-4-ethyl, imidazol-2-methyl, furan-2-ethyl, indole-3-methyl, etc.

术语“杂芳基烷基”表示烷基基团被一个或多个杂芳基所取代, 其中杂芳基和烷基基团具有本发明所述的含义, 这样的实例包括．但并不限于咪唑-2-甲基, 呋喃-2-乙基, 吲哚-3-甲基等。The term "heteroarylalkyl" means that an alkyl group is substituted by one or more heteroaryl groups, wherein heteroaryl and alkyl groups have the meanings stated in the present invention, such examples include. But not limited to imidazol-2-methyl, furan-2-ethyl, indole-3-methyl, etc.

术语“杂芳基烷氨基”包括含有氮原子的杂芳基烷基基团通过氮原子连接到其他基团上, 其中杂芳基烷基具有如本发明所述的含义, 这样的实例包括, 但并不限于吡啶-2-基甲氨基, 噻唑-2-基乙氨基, 咪唑-2-基乙氨基, 嘧啶-2-基丙氨基, 嘧啶-2-基甲氨基等。The term "heteroarylalkylamino" includes heteroarylalkyl groups containing a nitrogen atom attached to other groups through the nitrogen atom, wherein heteroarylalkyl has the meanings described herein, examples of which include, But not limited to pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino, etc.

术语“杂芳基烷氧基”包括含有氧原子的杂芳基烷基基团通过氧原子连接到其他基团上, 其中杂芳基烷基具有如本发明所述的含义, 这样的实例包括, 但并不限于吡啶-2-基甲氧基, 噻唑-2-基乙氧基, 咪唑-2-基乙氧基, 嘧啶-2-基丙氧基, 嘧啶-2-基甲氨基。The term "heteroarylalkoxy" includes a heteroarylalkyl group containing an oxygen atom attached to another group through an oxygen atom, wherein heteroarylalkyl has a meaning as described herein, examples of which include , but not limited to pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethylamino.

术语“稠合双环”, “稠环”, “稠合双环基”, “稠环基”表示饱和或不饱和的稠环体系, 涉及到非芳香族的双环体系。这样的体系可以包含独立的或共轭的不饱和状态, 但其核心结构不包含芳香环或芳杂环（但是芳香族可以作为其上的取代基）。稠合双环中的每一个环要么是碳环要么是杂脂环族, 这样的实例包括, 但并不限于, 六氢呋喃并[3, 2-b]呋喃, 2, 3, 3a, 4, 7, 6-六氢-1H-茚, 7-氮杂双环[2.3.0]庚烷, 稠合双环[3.3.0]辛烷, 稠合双环[3.1.0]己烷, l, 2, 3, 4, 4a, 5, 8, 8a-八氢萘, 这些都包含在稠合双环的体系之内。并且所述稠合双环基可以是取代或非取代的, 其中取代基可以是, 但并不限于, 卤代烷基, 氧代(=O), 羟基, 氨基, 卤素, 氰基, 芳基, 杂芳基, 烷氧基, 烷氨基, 烷基, 烯基, 炔基, 杂环基, 巯基, 硝基, 芳氧基, 羟基取代的烷氧基, 羟基取代的烷基-C(=O)-, 烷基-C(=O)-, 烷基-S(=O)-, 烷基-S(=O)2-, 羟基取代的烷基-S(=O)-, 羟基取代的烷基-S (=O)2-, 羧基烷氧基等等。The terms "fused bicyclic", "fused ring", "fused bicyclyl", "fused cycloyl" denote saturated or unsaturated fused ring systems and relate to non-aromatic bicyclic systems. Such a system can contain independent or conjugated unsaturation, but its core structure does not contain aromatic rings or aromatic heterocycles (although aromatics can be used as substituents on it). Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic, examples of which include, but are not limited to, hexahydrofuro[3,2-b]furan, 2, 3, 3a, 4, 7, 6-hexahydro-1H-indene, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, l, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthalene, these are included in the fused bicyclic system. And the fused bicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, haloalkyl, oxo (=O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl radical, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)- , Alkyl-C(=O)-, Alkyl-S(=O)-, Alkyl-S(=O) 2 -, Hydroxyl-Substituted Alkyl-S(=O)-, Hydroxyl-Substituted Alkyl -S (=O) 2 -, carboxyalkoxy and the like.

术语“稠合杂双环基”表示饱和或不饱和的稠环体系, 涉及到非芳香族的双环体系。这样的体系可以包含独立的或共轭的不饱和状态, 但其核心结构不包含芳香环或芳杂环（但是芳香族可以作为其上的取代基）。且至少一个环体系包含一个或多个杂原子, 其中每一个环体系包含3-7元环, 即包含1-6个碳原子和为N, O, P, S的1-3个杂原子, 在此S或P任选地被一个或多个氧原子所取代得到像SO, SO2, PO, PO2的基团, 这样的实例包括,但并不限于六氢呋喃并[3, 2-b]呋喃, 7-氮杂双环[2.3.0]庚烷等。并且所述稠合杂双环基可以是取代或非取代的, 其中取代基可以是, 但并不限于, 卤代烷基, 氧代(=O), 羟基, 氨基, 卤素, 氰基, 芳基, 杂芳基, 烷氧基, 烷氨基, 烷基, 烯基, 炔基, 杂环基,巯基, 硝基, 芳氧基, 羟基取代的烷氧基, 羟基取代的烷基-C(=O)-, 烷基-C(=O)-, 烷基-S(=O)-, 烷基-S(=O)2-, 羟基取代的烷基-S(=O)-, 羟基取代的烷基-S (=O)2-, 羧基烷氧基等等。The term "fused heterobicyclyl" denotes a saturated or unsaturated fused ring system, involving non-aromatic bicyclic ring systems. Such a system can contain independent or conjugated unsaturation, but its core structure does not contain aromatic rings or aromatic heterocycles (although aromatics can be used as substituents on it). And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 membered rings, that is, contains 1-6 carbon atoms and 1-3 heteroatoms of N, O, P, S, Here S or P is optionally substituted by one or more oxygen atoms to obtain groups like SO, SO 2 , PO, PO 2 , examples of which include, but are not limited to, hexahydrofuro[3,2- b]furan, 7-azabicyclo[2.3.0]heptane, etc. And the fused heterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, haloalkyl, oxo (=O), hydroxyl, amino, halogen, cyano, aryl, hetero Aryl, Alkoxy, Alkylamino, Alkyl, Alkenyl, Alkynyl, Heterocyclyl, Mercapto, Nitro, Aryloxy, Hydroxy-substituted Alkoxy, Hydroxy-substituted Alkyl-C(=O) -, Alkyl-C(=O)-, Alkyl-S(=O)-, Alkyl-S(=O) 2 -, Alkyl-S(=O)-substituted with hydroxy, Alkane-S(=O)-substituted with hydroxy group -S (=O) 2 -, carboxyalkoxy and the like.

术语“稠合双环基脂肪族”表示脂肪族基团被一个或多个稠合双环基基团所取代,其中脂肪族基团和稠合双环基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于l, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基乙基, l, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基甲基, l, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基丙基, 稠合双环[3.3.0]辛烷基甲基, 稠合双环[3.1.0]己烷基乙基等。The term "fused bicyclyl aliphatic" means that an aliphatic group is substituted by one or more fused bicyclyl groups, wherein the aliphatic group and the fused bicyclyl group have the meanings described herein, such that Examples of include, but are not limited to, l, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylethyl, l, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthalene ylmethyl, l, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylpropyl, fused bicyclo[3.3.0]octylmethyl, fused bicyclo[3.1.0]hexyl Alkyl ethyl etc.

术语“稠合杂双环基脂肪族”表示脂肪族基团被一个或多个稠合杂双环基基团所取代, 其中脂肪族基团和稠合杂双环基基团具有如本发明所述的含义, 这样的实例包括,但并不限于六氢呋喃并[3, 2-b]呋喃-2-基乙基, 六氢呋喃并[3, 2-b]呋喃-2-基甲基,7-氮杂双环[2.3.0]庚烷-2-基甲基, 7-氮杂双环[2.3.0]庚烷-2-基乙基, 7-氮杂双环[2.3.0]庚烷-4-基甲基等。The term "fused heterobicyclylaliphatic" means that an aliphatic group is substituted by one or more fused heterobicyclyl groups, wherein the aliphatic group and the fused heterobicyclyl group have the Meaning, such examples include, but are not limited to, hexahydrofuro[3,2-b]furan-2-ylethyl, hexahydrofuro[3,2-b]furan-2-ylmethyl,7 -Azabicyclo[2.3.0]heptane-2-ylmethyl, 7-azabicyclo[2.3.0]heptane-2-ylethyl, 7-azabicyclo[2.3.0]heptane- 4-ylmethyl etc.

术语“稠合双环基氧基”包括任选取代的稠合双环基, 像本发明所定义的, 连接到氧原子上, 并且由氧原子与分子其余部分相连, 这样的实例包括, 但并不限于l, 2,3, 4, 4a, 5, 8, 8a-八氢萘基氧基, 稠合双环[3.3.0]辛烷-2-氧基, 稠合双环[3.1.0]己烷-2-氧基等。The term "fused bicyclyloxy" includes optionally substituted fused bicyclyl groups, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule, examples of which include, but are not Limited to 1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyloxy, fused bicyclo[3.3.0]octane-2-oxyl, fused bicyclo[3.1.0]hexane -2-oxyl, etc.

术语“稠合杂双环基氧基”包括任选取代的稠合杂双环基, 像本发明所定义的,连接到氧原子上, 并且由氧原子与分子其余部分相连, 这样的实例包括, 但并不限于六氢-呋喃并[3, 2-b]呋喃-2-基氧基, 7-氮杂双环[2.3.0]庚烷-2-基氧基, 7-氮杂双环[2.3.0]庚烷-4-基氧基等。The term "fused heterobicyclyloxy" includes optionally substituted fused heterobicyclyl groups, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule, examples of which include, but Not limited to hexahydro-furo[3,2-b]furan-2-yloxy, 7-azabicyclo[2.3.0]heptane-2-yloxy, 7-azabicyclo[2.3. 0] Heptan-4-yloxy and the like.

术语“稠合双环基氨基”表示氨基基团被一个或两个稠合双环基所取代, 其中稠合双环基具有如本发明所述的含义, 这样的实例包括, 但并不限于l, 2, 3, 4, 4a, 5,8, 8a-八氢萘基氨基, 二（1, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基）氨基, 稠合双环[3.3.0]辛烷基氨基, 稠合双环[3.1.0]己烷基氨基等。The term "fused bicyclylamino" means that the amino group is substituted by one or two fused bicyclic groups, wherein the fused bicyclic groups have the meanings described in the present invention, such examples include, but are not limited to 1, 2 , 3, 4, 4a, 5,8, 8a-octahydronaphthylamino, bis(1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyl)amino, fused bicyclo[3.3. 0]octylamino, fused bicyclo[3.1.0]hexylamino, etc.

术语“稠合杂双环基氨基”表示氨基基团被一个或两个稠合杂双环基所取代, 其中稠合杂双环基具有如本发明所述的含义, 这样的实例包括, 但并不限于六氢-呋喃并[3, 2-b]呋喃-2-基氨基, 7-氮杂双环[2.3.0]庚烷-2基氨基, 7-氮杂双环[2.3.0]庚烷-4-基氨基等。The term "fused heterobicyclylamino" means that the amino group is substituted by one or two fused heterobicyclyl groups, wherein the fused heterobicyclyl has the meaning as described in the present invention, such examples include, but are not limited to Hexahydro-furo[3, 2-b]furan-2-ylamino, 7-azabicyclo[2.3.0]heptane-2 ylamino, 7-azabicyclo[2.3.0]heptane-4 - Base amino and so on.

术语“稠合双环基烷氨基”表示烷氨基基团被一个或多个稠合双环基所取代, 其中稠合双环基具有如本发明所述的含义, 这样的实例包括, 但并不限于l, 2, 3, 4, 4a,5, 8, 8a-八氢萘基甲氨基, 二（1, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基）甲氨基, 稠合双环[3.3.0]辛烷基甲氨基, 稠合双环[3.1.0]己烷基甲氨基等。The term "fused bicyclylalkylamino" means that an alkylamino group is substituted by one or more fused bicyclic groups, wherein the fused bicyclic groups have the meanings described in the present invention, such examples include, but are not limited to l , 2, 3, 4, 4a,5, 8, 8a-octahydronaphthylmethylamino, bis(1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyl)methylamino, fused Bicyclo[3.3.0]octylmethylamino, fused bicyclo[3.1.0]hexylmethylamino, etc.

术语“稠合杂双环基烷氨基”表示烷氨基基团被一个或多个稠合杂双环基所取代,其中稠合杂双环基具有如本发明所述的含义, 这样的实例包括, 但并不限于六氢-呋喃并[3, 2-b]呋喃-2-基甲氨基, 7-氮杂双环[2.3.0]庚烷-2-基甲氨基, 7-氮杂双环[2.3.0]庚烷-4-基甲氨基等。The term "fused heterobicyclylalkylamino" means that an alkylamino group is substituted by one or more fused heterobicyclyls, wherein fused heterobicyclyls have the meanings described herein, examples of which include, but are not Not limited to hexahydro-furo[3,2-b]furan-2-ylmethylamino, 7-azabicyclo[2.3.0]heptan-2-ylmethylamino, 7-azabicyclo[2.3.0 ] heptane-4-ylmethylamino and the like.

术语“稠合双环基烷氧基”表示烷氧基被一个或多个稠合双环基基团所取代, 其中烷氧基和稠合双环基具有如本发明所述的含义, 这样的实例包括, 但并不限于l, 2,3, 4, 4a, 5, 8, 8a-八氢萘基甲氧基, l, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基乙氧基,稠合双环[3.3.0]辛烷乙氧基, 稠合双环[3.1.0]己烷-丙氧基等。The term "fused bicyclylalkoxy" means an alkoxy group substituted by one or more fused bicyclyl groups, wherein alkoxy and fused bicyclyl have the meanings described herein, examples of which include , but not limited to l, 2,3, 4, 4a, 5, 8, 8a-octahydronaphthyl methoxyl, l, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyl ethyl Oxygen, fused bicyclo[3.3.0]octaneethoxy, fused bicyclo[3.1.0]hexane-propoxy, etc.

术语“稠合杂双环基烷氧基”表示烷氧基被一个或多个稠合杂双环基基团所取代,其中烷氧基和稠合杂双环基具有如本发明所述的含义, 这样的实例包括, 但并不限于六氢-呋喃并[3, 2-b]呋喃-2-基丙氧基, 7-氮杂双环[2.2.1]庚烷-2-基乙氧基, 7-氮杂双环[2.3.0]庚烷-4-基丙氧基, 六氢-呋喃并[3, 2-b]呋喃-2-基乙氧基, 7-氮杂双环[2.3.0]庚烷-2-基丙氧基, 7-氮杂双环[2.3.0]庚烷-4-基乙氧基等。The term "fused heterobicyclylalkoxy" means that an alkoxy group is substituted by one or more fused heterobicyclyl groups, wherein alkoxy and fused heterobicyclyl have the meanings described herein, such that Examples include, but are not limited to, hexahydro-furo[3,2-b]furan-2-ylpropoxy, 7-azabicyclo[2.2.1]heptan-2-ylethoxy, 7 -Azabicyclo[2.3.0]heptan-4-ylpropoxy, Hexahydro-furo[3, 2-b]furan-2-ylethoxy, 7-Azabicyclo[2.3.0] Heptan-2-ylpropoxy, 7-azabicyclo[2.3.0]heptan-4-ylethoxy, etc.

术语“稠合双环基氧基烷氧基”表示烷氧基被一个或多个稠合双环基氧基基团所取代, 其中烷氧基和稠合双环基氧基具有如本发明所述的含义, 这样的实例包括, 但并不限于l, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基氧基甲氧基, l, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基氧基乙氧基, 稠合双环[3.3.0]辛烷-2-氧基乙氧基, 稠合双环[3.1.0]己烷-2-氧基丙氧基等。The term "fused bicyclyloxyalkoxy" means that an alkoxy group is substituted by one or more fused bicyclyloxy groups, wherein the alkoxy and fused bicyclyloxy groups have Meaning, such examples include, but are not limited to, l, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyloxymethoxy, l, 2, 3, 4, 4a, 5, 8 , 8a-octahydronaphthyloxyethoxy, fused bicyclo[3.3.0]octane-2-oxyethoxy, fused bicyclo[3.1.0]hexane-2-oxypropoxy Wait.

术语“稠合杂双环基氧基烷氧基”表示烷氧基被一个或多个稠合杂双环基氧基基团所取代, 其中烷氧基和稠合杂双环基氧基具有如本发明所述的含义, 这样的实例包括,但并不限于六氢-呋喃并[3, 2-b]呋喃-2-基氧基丙氧基, 7-氮杂双环[2.2.1]庚烷-2-基氧基乙氧基, 7-氮杂双环[2.3.0]庚烷-4-基氧基丙氧基, 六氢-呋喃并[3, 2-b]呋喃-2-基氧基乙氧基, 7-氮杂双环[2.3.0]庚烷-2-基氧基丙氧基, 7-氮杂双环[2.3.0]庚烷-4-基氧基乙氧基等。The term "fused heterobicyclyloxyalkoxy" means that an alkoxy group is substituted by one or more fused heterobicyclyloxy groups, wherein the alkoxy and fused heterobicyclyloxy groups have In the meaning stated, such examples include, but are not limited to, hexahydro-furo[3,2-b]furan-2-yloxypropoxy, 7-azabicyclo[2.2.1]heptane- 2-yloxyethoxy, 7-azabicyclo[2.3.0]heptan-4-yloxypropoxy, hexahydro-furo[3, 2-b]furan-2-yloxy Ethoxy, 7-azabicyclo[2.3.0]heptan-2-yloxypropoxy, 7-azabicyclo[2.3.0]heptan-4-yloxyethoxy, etc.

术语“稠合双环基氨基烷氧基”表示烷氧基被一个或多个稠合双环基氨基所取代,其中烷氧基和稠合双环基氨基具有如本发明所述的含义, 这样的实例包括, 但并不限于l, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基氨基乙氧基, l, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基氨基丙氧基, 二（1, 2, 3, 4, 4a, 5, 8, 8a-八氢萘基）氨基丙氧基, 稠合双环[3.3.0]辛烷-2-氨基乙氧基, 稠合双环[3.1.0]己烷-2-氨基丙氧基等。The term "fused bicyclylaminoalkoxy" means that an alkoxy group is substituted by one or more fused bicyclylamino groups, wherein the alkoxy group and the fused bicyclylamino group have the meanings described in the present invention, such examples Including, but not limited to l, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthylaminoethoxy, l, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthalene Aminopropoxy, bis(1, 2, 3, 4, 4a, 5, 8, 8a-octahydronaphthyl)aminopropoxy, fused bicyclo[3.3.0]octane-2-aminoethoxy base, fused bicyclo[3.1.0]hexane-2-aminopropoxy, etc.

术语“稠合杂双环基氨基烷氧基”表示烷氧基被一个或多个稠合杂双环基氨基所取代, 其中烷氧基和稠合杂双环基氨基具有如本发明所述的含义, 这样的实例包括, 但并不限于7-氮杂双环[2.2.1]庚烷-2-基氨基乙氧基, 7-氮杂双环[2.3.0]庚烷-4-基氨基丙氧基, 六氢-呋喃并[3, 2-b]呋喃-2-基氨基乙氧基, 六氢-呋喃并[3, 2-b]呋喃-2-基氨基丙氧基, 六氢-呋喃并[3, 2-b]呋喃-2-基氨基甲氧基等。The term "fused heterobicyclylaminoalkoxy" means that an alkoxy group is substituted by one or more fused heterobicyclylamino groups, wherein alkoxy and fused heterobicyclylamino groups have the meanings as described in the present invention, Such examples include, but are not limited to, 7-azabicyclo[2.2.1]heptan-2-ylaminoethoxy, 7-azabicyclo[2.3.0]heptan-4-ylaminopropoxy , Hexahydro-furo[3,2-b]furan-2-ylaminoethoxy, Hexahydro-furo[3,2-b]furan-2-ylaminopropoxy, Hexahydro-furo[3,2-b]furan-2-ylaminopropoxy, Hexahydro-furo [3, 2-b]furan-2-ylaminomethoxy, etc.

术语“螺环基”, “螺环”, “螺双环基”, “螺双环”表示一个环起源于另一个环上特殊的环状碳。例如, 像下面所描述的, 一个饱和的桥环体系（环B和B’）被称为“稠合双环”, 反之环A和环B在两个饱和的环体系中共享一个碳原子, 则被称为“螺环”。螺环里面的每一个环要么是碳环要么是杂脂环族。这样的实例包括, 但并不限于2, 7-二氮杂螺[4.4]壬烷-2-基, 7-氧-2-氮杂螺[4.5]癸烷-2-基, 4-氮杂螺[2.4]庚烷-5-基, 4-氧杂螺[2.4]庚烷-5-基, 5-氮杂螺[2.4]庚烷-5-基, 螺[2.4]庚烷基, 螺[4.4]壬烷基, 7-羟基-5-氮杂螺[2.4]庚烷-5-基等。并且所述螺双环基可以是取代或非取代的, 其中取代基可以是, 但并不限于, 卤代烷基, 氧代(=O), 羟基, 氨基, 卤素, 氰基, 芳基, 杂芳基, 烷氧基, 烷氨基, 烷基, 烯基, 炔基, 杂环基, 巯基, 硝基, 芳氧基, 羟基取代的烷氧基,羟基取代的烷基-C(=O)-, 烷基-C(=O)-, 烷基-S(=O)-, 烷基-S(=O)2-, 羟基取代的烷基-S(=O)-, 羟基取代的烷基-S (=O)2-, 羧基烷氧基等等。The terms "spirocyclyl", "spirocycle", "spirobicyclyl", "spirobicyclyl" indicate that one ring originates from another ring at a specific cyclic carbon. For example, as described below, a saturated bridged ring system (rings B and B') is called a "fused bicyclic ring", whereas ring A and ring B share a carbon atom in two saturated ring systems, then Known as a "spiral". Each ring within a spirocycle is either carbocyclic or heteroalicyclic. Such examples include, but are not limited to, 2,7-diazaspiro[4.4]nonan-2-yl, 7-oxo-2-azaspiro[4.5]decane-2-yl, 4-azaspiro[4.4]decane-2-yl, Spiro[2.4]heptan-5-yl, 4-oxaspiro[2.4]heptan-5-yl, 5-azaspiro[2.4]heptan-5-yl, spiro[2.4]heptanyl, spiro [4.4] Nonyl, 7-Hydroxy-5-azaspiro[2.4]heptane-5-yl, etc. And the spirobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, haloalkyl, oxo (=O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl , alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, Alkyl-C(=O)-, Alkyl-S(=O)-, Alkyl-S(=O) 2 -, Hydroxyl-Substituted Alkyl-S(=O)-, Hydroxy-Substituted Alkyl- S (=O) 2 -, carboxyalkoxy and the like.

术语“螺杂双环基”表示一个环起源于另一个环上特殊的环状碳。例如, 像上面所描述的, 一个饱和的桥环体系（环B和B’）被称为“稠合双环”, 反之环A和环B在两个饱和的环体系中共享一个碳原子, 则被称为“螺环”。且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含3-7元环, 即包含1-6个碳原子和为N, O, P, S的1-3个杂原子, 在此S或P任选地被一个或多个氧原子所取代得到像SO, SO2, PO, PO2, 的基团, 这样的实例包括, 但并不限于4-氮杂螺[2.4]庚烷-5-基, 4-氧杂螺[2.4]庚烷-5-基, 5-氮杂螺[2.4]庚烷-5-基, 7-羟基-5-氮杂螺[2.4]庚烷-5-基等。并且所述螺杂双环基可以是取代或非取代的, 其中取代基可以是, 但并不限于, 卤代烷基, 氧代(=O), 羟基, 氨基, 卤素, 氰基, 芳基, 杂芳基, 烷氧基, 烷氨基, 烷基, 烯基, 炔基, 杂环基, 巯基, 硝基, 芳氧基, 羟基取代的烷氧基, 羟基取代的烷基-C(=O)-, 烷基-C(=O)-, 烷基-S(=O)-, 烷基-S(=O)2-, 羟基取代的烷基-S(=O)-, 羟基取代的烷基-S (=O)2-, 羧基烷氧基等等。The term "spiroheterobicyclyl" means that one ring is derived from a specific cyclic carbon on another ring. For example, as described above, a saturated bridged ring system (rings B and B') is called a "fused bicyclic ring", whereas ring A and ring B share a carbon atom in two saturated ring systems, then Known as a "spiral". And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 membered rings, that is, contains 1-6 carbon atoms and 1-3 heteroatoms of N, O, P, S, Here S or P is optionally substituted with one or more oxygen atoms to obtain groups like SO, SO 2 , PO, PO 2 , examples of which include, but are not limited to, 4-azaspiro[2.4] Heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, 7-hydroxy-5-azaspiro[2.4]heptane Alk-5-yl, etc. And the spiro heterobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but not limited to, haloalkyl, oxo (=O), hydroxyl, amino, halogen, cyano, aryl, heteroaryl radical, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)- , Alkyl-C(=O)-, Alkyl-S(=O)-, Alkyl-S(=O) 2 -, Hydroxyl-Substituted Alkyl-S(=O)-, Hydroxyl-Substituted Alkyl -S (=O) 2 -, carboxyalkoxy and the like.

术语“螺双环基脂肪族”表示脂肪族基团被一个或多个螺双环基基团所取代, 其中脂肪族基团和螺双环基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于螺[2.4]庚烷基甲基, 螺[2.4]庚烷基乙基, 螺[2.4]庚烷基丙基, 螺[4.4]壬烷基甲基,螺4.4]壬烷基乙基, 4-氮杂螺[2.4]庚烷-5-基甲基, 4-氮杂螺[2.4]庚烷-5-基乙基, 4-氧杂螺[2.4]庚烷-5-基乙基, 5-氮杂螺[2.4]庚烷-5-基丙基, 7-羟基-5-氮杂螺[2.4]庚烷-5-基丙基等。The term "spirobicyclyl aliphatic" means that the aliphatic group is substituted by one or more spirobicyclyl groups, wherein the aliphatic group and the spirobicyclyl group have the meanings described in the present invention, such examples include , but not limited to spiro[2.4]heptylmethyl, spiro[2.4]heptylethyl, spiro[2.4]heptylpropyl, spiro[4.4]nonylmethyl, spiro4.4]nonane ylethyl, 4-azaspiro[2.4]heptane-5-ylmethyl, 4-azaspiro[2.4]heptane-5-ylethyl, 4-oxaspiro[2.4]heptane-5 -ylethyl, 5-azaspiro[2.4]heptane-5-ylpropyl, 7-hydroxy-5-azaspiro[2.4]heptane-5-ylpropyl, etc.

术语“螺杂双环基脂肪族”表示脂肪族基团被一个或多个螺杂双环基基团所取代,其中脂肪族基团和螺杂双环基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于4-氮杂螺[2.4]庚烷-5-基甲基, 4-氮杂螺[2.4]庚烷-5-基乙基, 4-氧杂螺[2.4]庚烷-5-基乙基, 5-氮杂螺[2.4]庚烷-5-基丙基, 7-羟基-5-氮杂螺[2.4]庚烷-5-基丙基等。The term "spiroheterobicyclylaliphatic" means that the aliphatic group is substituted by one or more spiroheterobicyclyl groups, wherein the aliphatic group and the spiroheterobicyclyl group have the meanings as described in the present invention, such that Examples include, but are not limited to, 4-azaspiro[2.4]heptan-5-ylmethyl, 4-azaspiro[2.4]heptan-5-ylethyl, 4-oxaspiro[2.4] Heptane-5-ylethyl, 5-azaspiro[2.4]heptan-5-ylpropyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-ylpropyl, etc.

术语“螺双环基氧基”包括任选取代的螺双环基, 像本发明所定义的, 连接到氧原子上, 并且由氧原子与分子其余部分相连, 这样的实例包括, 但并不限于螺[2.4]庚烷-2-氧基, 螺[2.4]庚烷-3-氧基, 螺[2.4]庚烷-4-氧基, 螺[4.4]壬烷-2-氧基, 螺[4.4]壬烷-4-氧基, 4-氮杂螺[2.4]庚烷-5-氧基等。The term "spirobicyclyloxy" includes optionally substituted spirobicyclyl groups, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule, examples of which include, but are not limited to spiro [2.4]heptane-2-oxyl, spiro[2.4]heptane-3-oxyl, spiro[2.4]heptane-4-oxyl, spiro[4.4]nonane-2-oxyl, spiro[4.4 ]nonane-4-oxyl, 4-azaspiro[2.4]heptane-5-oxyl, etc.

术语“螺杂双环基氧基”包括任选取代的螺杂双环基, 像本发明所定义的, 连接到氧原子上, 并且由氧原子与分子其余部分相连, 这样的实例包括, 但并不限于4-氮杂螺[2.4]庚烷-5-基氧基, 4-氧杂螺[2.4]庚烷-5-基氧基, 5-氮杂螺[2.4]庚烷-5-基氧基等。The term "spiroheterobicyclyloxy" includes optionally substituted spiroheterobicyclyl groups, as defined herein, attached to an oxygen atom and connected by the oxygen atom to the rest of the molecule, examples of which include, but are not Limited to 4-azaspiro[2.4]heptan-5-yloxy, 4-oxaspiro[2.4]heptan-5-yloxy, 5-azaspiro[2.4]heptan-5-yloxy Base etc.

术语“螺双环基氨基”表示氨基基团被一个或两个螺双环基基团所取代, 其中螺双环基具有如本发明所述的含义, 这样的实例包括, 但并不限于螺[2.4]庚烷-2-氨基,螺[2.4]庚烷-3-氨基, 螺[2.4]庚烷-4-氨基, 螺[4.4]壬烷-2-氨基, 螺[4.4]壬烷-4-氨基, 4-氮杂螺[2.4]庚烷-5-氨基等。The term "spirobicyclylamino" means that the amino group is substituted by one or two spirobicyclyl groups, wherein spirobicyclyl has the meaning described in the present invention, examples of which include, but are not limited to, spiro[2.4] Heptane-2-amino, spiro[2.4]heptane-3-amino, spiro[2.4]heptane-4-amino, spiro[4.4]nonane-2-amino, spiro[4.4]nonane-4-amino , 4-azaspiro[2.4]heptane-5-amino, etc.

术语“螺杂双环基氨基”表示氨基基团被一个或两个螺杂双环基基团所取代, 其中螺杂双环基具有如本发明所述的含义, 这样的实例包括, 但并不限于4-氮杂螺[2.4]庚烷-5-基氨基, 4-氮杂螺[2.4]庚烷-2-基氨基, 4-氧杂螺[2.4]庚烷-5-基氨基, 5-氮杂螺[2.4]庚烷-5-基氨基等。The term "spiroheterobicyclylamino" means that the amino group is substituted by one or two spiroheterobicyclyl groups, wherein spiroheterobicyclyl has the meaning as described in the present invention, such examples include, but are not limited to 4 -Azaspiro[2.4]heptane-5-ylamino, 4-azaspiro[2.4]heptane-2-ylamino, 4-oxaspiro[2.4]heptane-5-ylamino, 5-azaspiro[2.4]heptane-5-ylamino Heterospiro[2.4]heptan-5-ylamino, etc.

术语“螺双环基烷氧基”表示烷氧基基团被一个或多个螺双环基所取代, 其中螺双环基和烷氧基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于螺[2.4]庚烷-2-甲氧基, 螺[2.4]庚烷-3-乙氧基, 螺[2.4]庚烷-4-乙氧基, 螺[4.4]壬烷-2-甲氧基, 螺[4.4]壬烷-4-丙氧基, 4-氮杂螺[2.4]庚烷-5-甲氧基等。The term "spirobicyclylalkoxy" means that an alkoxy group is substituted by one or more spirobicyclyl groups, wherein the spirobicyclyl and alkoxy groups have the meanings described in the present invention, examples of which include, But not limited to spiro[2.4]heptane-2-methoxy, spiro[2.4]heptane-3-ethoxy, spiro[2.4]heptane-4-ethoxy, spiro[4.4]nonane- 2-methoxy, spiro[4.4]nonane-4-propoxy, 4-azaspiro[2.4]heptane-5-methoxy, etc.

术语“螺杂双环基烷氧基”表示烷氧基基团被一个或多个螺杂双环基所取代, 其中螺杂双环基和烷氧基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于4-氮杂螺[2.4]庚烷-5-基甲氧基, 4-氮杂螺[2.4]庚烷-2-基乙氧基, 4-氧杂螺[2.4]庚烷-5-基乙氧基, 5-氮杂螺[2.4]庚烷-5-基丙氧基等。The term "spiroheterobicyclylalkoxy" means that an alkoxy group is substituted by one or more spiroheterobicyclyl groups, wherein the spiroheterobicyclyl and alkoxy groups have the meanings as described in the present invention, such Examples include, but are not limited to, 4-azaspiro[2.4]heptan-5-ylmethoxy, 4-azaspiro[2.4]heptan-2-ylethoxy, 4-oxaspiro[2.4 ]heptan-5-ylethoxy, 5-azaspiro[2.4]heptan-5-ylpropoxy, etc.

术语“螺双环基烷氨基”表示烷氨基基团被一个或多个螺双环基所取代, 其中螺双环基和烷氨基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于螺[2.4]庚烷-2-甲氨基, 螺[2.4]庚烷-3-乙氨基, 螺[2.4]庚烷-4-乙氨基, 螺[4.4]壬烷-2-甲氨基, 螺[4.4]壬烷-4-丙氨基, 4-氮杂螺[2.4]庚烷-5-甲氨基等。The term "spirobicyclylalkylamino" means that an alkylamino group is substituted by one or more spirobicyclyl groups, wherein the spirobicyclyl and alkylamino groups have the meanings described in the present invention, such examples include, but do not Limited to spiro[2.4]heptane-2-methylamino, spiro[2.4]heptane-3-ethylamino, spiro[2.4]heptane-4-ethylamino, spiro[4.4]nonane-2-methylamino, spiro [4.4] Nonane-4-propylamino, 4-azaspiro[2.4]heptane-5-methylamino, etc.

术语“螺杂双环基烷氨基”烷氨基基团被一个或多个螺杂双环基所取代, 其中螺杂双环基和烷氨基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于4-氮杂螺[2.4]庚烷-5-基甲氨基, 4-氮杂螺[2.4]庚烷-2-基乙氨基, 4-氧杂螺[2.4]庚烷-5-基乙氨基, 5-氮杂螺[2.4]庚烷-5-基丙氨基等。The term "spiroheterobicyclylalkylamino" has an alkylamino group substituted by one or more spiroheterobicyclyl groups, wherein the spiroheterobicyclyl and alkylamino groups have the meanings described herein, examples of which include, but Not limited to 4-azaspiro[2.4]heptane-5-ylmethylamino, 4-azaspiro[2.4]heptane-2-ylethylamino, 4-oxaspiro[2.4]heptane-5- Ethylamino, 5-azaspiro[2.4]heptan-5-ylpropylamino, etc.

术语“螺双环基氧基烷氧基”表示烷氧基被一个或多个螺双环基氧基基团所取代,其中螺双环基氧基和烷氧基基团具有如本发明所述的含义, 这样的实例包括, 但并不限于螺[2.4]庚烷-2-氧基乙氧基, 螺[2.4]庚烷-3-氧基丙氧基, 螺[2.4]庚烷-4-氧基丙氧基, 螺[4.4]壬烷-2-氧基乙氧基, 螺[4.4]壬烷-4-氧基丙氧基, 4-氮杂螺[2.4]庚烷-5-氧基丙氧基等。The term "spirobicyclyloxyalkoxy" means that an alkoxy group is substituted by one or more spirobicyclyloxy groups, wherein the spirobicyclyloxy and alkoxy groups have the meanings described herein , such examples include, but are not limited to, spiro[2.4]heptane-2-oxyethoxy, spiro[2.4]heptane-3-oxypropoxy, spiro[2.4]heptane-4-oxy ylpropoxy, spiro[4.4]nonane-2-oxyethoxy, spiro[4.4]nonane-4-oxypropoxy, 4-azaspiro[2.4]heptane-5-oxy Propoxy etc.

术语“螺杂双环基氧基烷氧基”表示烷氧基被一个或多个螺杂双环基氧基基团所取代, 其中螺杂双环基氧基和烷氧基基团具有如本发明所述的含义, 这样的实例包括,但并不限于4-氮杂螺[2.4]庚烷-5-基氧基乙氧基, 4-氧杂螺[2.4]庚烷-5-基氧基乙氧基,5-氮杂螺[2.4]庚烷-5-基氧基乙氧基, 4-氮杂螺[2.4]庚烷-5-基氧基丙氧基, 4-氧杂螺[2.4]庚烷-5-基氧基丙氧基, 5-氮杂螺[2.4]庚烷-5-基氧基丙氧基等等。The term "spirobicyclyloxyalkoxy" means that an alkoxy group is substituted by one or more spirobicyclyloxy groups, wherein the spirobicyclyloxy and alkoxy groups have Such examples include, but are not limited to, 4-azaspiro[2.4]heptan-5-yloxyethoxy, 4-oxaspiro[2.4]heptan-5-yloxyethoxy, Oxygen, 5-azaspiro[2.4]heptane-5-yloxyethoxy, 4-azaspiro[2.4]heptane-5-yloxypropoxy, 4-oxaspiro[2.4 ]heptan-5-yloxypropoxy, 5-azaspiro[2.4]heptan-5-yloxypropoxy and the like.

术语“螺双环基氨基烷氧基”表示烷氧基被一个或多个螺双环基氨基所取代, 其中烷氧基和螺双环基氨基具有如本发明所述的含义, 这样的实例包括, 但并不限于螺[2.4]庚烷-2-氨基乙氧基, 螺[2.4]庚烷-3-氨基丙氧基, 螺[2.4]庚烷-4-氨基乙氧基,螺[4.4]壬烷-2-氨基乙氧基, 螺[4.4]壬烷-4-氨基丙氧基, 4-氮杂螺[2.4]庚烷-5-氨基丙氧基等。The term "spirobicyclylaminoalkoxy" means that an alkoxy group is substituted by one or more spirobicyclylamino groups, wherein alkoxy and spirobicyclylamino groups have the meanings described herein, examples of which include, but Not limited to spiro[2.4]heptane-2-aminoethoxy, spiro[2.4]heptane-3-aminopropoxy, spiro[2.4]heptane-4-aminoethoxy, spiro[4.4]nonane Alkane-2-aminoethoxy, spiro[4.4]nonane-4-aminopropoxy, 4-azaspiro[2.4]heptane-5-aminopropoxy, etc.

术语“螺杂双环基氨基烷氧基”表示烷氧基被一个或多个螺杂双环基氨基所取代,其中烷氧基和螺杂双环基氨基具有如本发明所述的含义, 这样的实例包括, 但并不限于4-氮杂螺[2.4]庚烷-5-基氨基乙氧基, 4-氮杂螺[2.4]庚烷-2-基氨基两氧基, 4-氧杂螺[2.4]庚烷-5-基氨基乙氧基, 5-氮杂螺[2.4]庚烷-5-基氨基丙氧基等。The term "spiroheterobicyclylaminoalkoxy" means that an alkoxy group is substituted by one or more spiroheterobicyclylamino groups, wherein alkoxy group and spiroheterobicyclylamino group have the meanings as described in the present invention, such examples Including, but not limited to, 4-azaspiro[2.4]heptane-5-ylaminoethoxy, 4-azaspiro[2.4]heptane-2-ylaminodioxy, 4-oxaspiro[ 2.4] Heptane-5-ylaminoethoxy, 5-azaspiro[2.4]heptane-5-ylaminopropoxy, etc.

除非其他方面表明, 本发明所描述的结构式包括所有的同分异构形式（如对映异构, 非对映异构, 和几何异构（或构象异构））：例如含有不对称中心的R、S构型, 双键的(Z)、(E)异构体, 和(Z)、(E)的构象异构体。因此, 本发明的化合物的单个立体化学异构体或其对映异构体, 非对映异构体, 或几何异构体（或构象异构体）的混合物都属于本发明的范围。Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereoisomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomer, and (Z), (E) conformational isomer. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present invention.

本发明所使用的术语“前药”, 代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯, 在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族( Cl-C24)酯类, 酰氧基甲基酯类, 碳酸酯, 氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基, 即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯, 如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T. Higuchi and V．Stella, Pro-drugsas NovelDelivery Systems, Vol. 140f the A.C.S.Symposium Series, Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American Pharmaceutical Associationand Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and ClinicalApplications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J. Heckeret al, Prodrugs of Phosphates and Phosphonates, Journal of MedicinalChemistry, 2008, 51, 2328-2345.The term "prodrug" used in the present invention represents the conversion of a compound into a compound represented by formula (I) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug with phenyl esters, aliphatic (Cl-C24) esters, acyloxymethyl esters, carbonates, Carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphate esters, which are phosphorylated by the parent hydroxyl group. A complete discussion of prodrugs can be found in: T. Higuchi and V. Stella, Pro-drugsas NovelDelivery Systems, Vol. 140f the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J. Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

除非其他方面表明, 本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外, 除非其他方面表明, 本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定, 其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化, 还原, 水解, 酰氨化, 脱酰氨作用, 酯化, 脱脂作用, 酶裂解等等方法得到。相应地, 本发明包括化合物的代谢产物, 包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。 "Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. A compound's metabolites can be identified by techniques known in the art, and its activity can be characterized using assays as described herein. Such products can be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like. Accordingly, the present invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a substantial period of time.

本发明的化合物可以包含不对称中心或手性中心, 因此存在不同的立体异构体。本发明的化合物所有的立体异构形式, 包括但绝不限于, 非对映体, 对映异构体, 阻转异构体, 和它们的混合物, 如外消旋混合物, 组成了本发明的一部分。很多有机化合物都以光学活性形式存在, 即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时,前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀D、L或(+)、（一）用来命名化合物平面偏振光旋转的符号, （一）或L是指化合物是左旋的, 前缀(+)或D是指化合物是右旋的。这些立体异构体的化学结构是相同的, 但是它们的立体结构不一样。特定的立体异构体可以是对映体, 异构体的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体, 这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物, 缺乏光学活性。The compounds of the present invention may contain asymmetric centers or chiral centers and thus exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of molecular chiral centers. The prefixes D, L or (+), (one) are used to name the symbol of the plane polarized light rotation of the compound, (one) or L means that the compound is left-handed, and the prefix (+) or D means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their three-dimensional structures are different. A specific stereoisomer can be an enantiomer, and a mixture of isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体（即质子移变的互变异构体）包括通过质子迁移的互变, 如酮式一烯醇式和亚肢一烯胺的同分异构化作用。原子价（化合价）互变异构体包括重组成键电子的互变。The term "tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions through migration of the proton, such as the isomerization of keto-enol and imide-enol. Atomic (valence) tautomers include interconversions of rearranged bonding electrons.

本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的, 如文献：S. M. Berge et al., describepharmaceutically acceptable salts in detail. J. Pharmaceutical Sciences, 66：1-19, 1977所记载的。药学上可接受的无毒的酸形成的盐包括, 但并不限于, 与氨基基团反应形成的无机酸盐有盐酸盐, 氢溴酸盐, 磷酸盐, 硫酸盐, 高氯酸盐, 和有机酸盐如乙酸盐, 草酸盐, 马来酸盐, 酒石酸盐, 柠檬酸盐, 琥珀酸盐, 丙二酸盐, 或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐, 藻酸盐, 抗坏血酸盐, 天冬氨酸盐, 苯磺酸盐, 苯甲酸盐, 重硫酸盐, 硼酸盐, 丁酸盐, 樟脑酸盐, 樟脑磺酸盐, 环戊基丙酸盐, 二葡萄糖酸盐, 十二烷基硫酸盐, 乙磺酸盐, 甲酸盐, 反丁烯二酸盐, 葡庚糖酸盐, 甘油磷酸盐, 葡萄糖酸盐, 半硫酸盐, 庚酸盐, 己酸盐, 氢碘酸盐, 2-羟基-乙磺酸盐, 乳糖醛酸盐, 乳酸盐, 月桂酸盐, 月桂基硫酸盐, 苹果酸盐, 丙二酸盐, 甲磺酸盐, 2-萘磺酸盐, 烟酸盐, 硝酸盐, 油酸盐, 棕榈酸盐, 扑酸盐, 果胶酸盐, 过硫酸盐, 3-苯基丙酸盐, 苦味酸盐, 特戊酸盐, 丙酸盐,硬脂酸盐, 硫氰酸盐, 对甲苯磺酸盐, 十一酸盐, 戊酸盐, 等等。通过适当的碱得到的盐包括碱金属, 碱土金属, 铵和N+ (C1-C4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠, 锂, 钾, 钙, 镁, 等等。药学上可接受的盐进一步包括适当的、无毒的铵, 季铵盐和抗平衡离子形成的胺阳离子, 如卤化物, 氢氧化物, 羧化物, 硫酸化物, 磷酸化物, 硝酸化物, C1-C8磺酸化物和芳香磺酸化物。The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as documented in SM Berge et al., describe pharmaceutically acceptable salts in detail. J. Pharmaceutical Sciences , 66:1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange method recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, Camphorsulfonate, Cyclopentylpropionate, Digluconate, Lauryl Sulfate, Ethylate, Formate, Fumarate, Glucoheptonate, Glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Hexanoate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobionate, Lactate, Laurate, Lauryl Sulfate, Malate, Malonate, Methanesulfonate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3 - Phenylpropionate, Picrate, Pivalate, Propionate, Stearate, Thiocyanate, P-Toluenesulfonate, Undecanoate, Valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1-C4 alkyl) 4 salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1- C8 sulfonates and aromatic sulfonates.

本发明的部分化合物的盐可以用如下列出的具体化合物的盐来说明，但并不限定本发明：The salts of some compounds of the present invention can be illustrated with the salts of the specific compounds listed below, but the present invention is not limited:

。 .

本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括, 但并不限于, 水, 异丙醇, 乙醇, 甲醇, 二甲亚砜, 乙酸乙酯, 乙酸, 氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

本发明的部分化合物的溶剂化物或其盐的溶剂化物可以用如下列出的具体化合物的盐来说明，但并不限定本发明：The solvates of some compounds of the present invention or the solvates of their salts can be illustrated by the salts of the specific compounds listed below, but the present invention is not limited:

。 .

本发明包含本发明化合物及其药学上可接受的盐的应用, 用于生产医药产品治疗患者由病毒引起的疾病, 包括那些本发明所描述的疾病。本发明包含药物组合物, 该药物组合物包括式I-IV所代表的化合物与至少一种药学上可接受的载体, 赋形剂, 稀释剂,辅剂, 媒介物的结合所需的有效治疗量。The present invention encompasses the use of compounds of the present invention and pharmaceutically acceptable salts thereof for the manufacture of medicinal products for the treatment of patients with diseases caused by viruses, including those described herein. The present invention includes a pharmaceutical composition, the pharmaceutical composition comprising a compound represented by formula I-IV combined with at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle required for effective treatment quantity.

本发明同样包含治疗或减轻患者由病毒引起的疾病, 或对此病症敏感的方法,该方法包含使用式I-IV所代表化合物的治疗有效量对患者进行治疗。The present invention also includes a method for treating or alleviating a patient's disease caused by a virus, or being susceptible to it, the method comprising treating the patient with a therapeutically effective amount of a compound represented by formulas I-IV.

除非其他方面表明, 本发明的化合物所有的立体异构体, 几何异构体, 互变异构体, 氮氧化物．水合物, 溶剂化物, 代谢产物, 盐和药学上可接受的前药都属于本发明的范围。Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides of the compounds of the present invention. Hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs are within the scope of the present invention.

具体地说, 盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学地, 与组成制剂的其他组分和用于治疗的哺乳动物有关。Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically appropriate in relation to the other ingredients making up the formulation and the mammal being used for treatment.

本发明的化合物的盐还包括用于制备或纯化式I-IV所示化合物的中间体或式I-IV所示化合物分离的对映异构体的盐, 但不一定是药学上可接受的盐。The salts of the compounds of the present invention also include salts of intermediates used in the preparation or purification of compounds shown in formula I-IV or separated enantiomers of compounds shown in formula I-IV, but not necessarily pharmaceutically acceptable Salt.

如果本发明的化合物是碱性的, 则想得到的盐可以通过文献上提供的任何合适的方法制备得到, 例如, 使用无机酸, 如盐酸, 氢溴酸, 硫酸, 硝酸和磷酸等等。或者使用有机酸, 如乙酸, 马来酸, 琥珀酸, 扁桃酸, 富马酸, 丙二酸, 丙酮酸, 草酸, 羟乙酸和水杨酸; 吡喃糖酸, 如葡萄糖醛酸和半乳糖醛酸; α-羟酸, 如柠檬酸和酒石酸; 氨基酸, 如天门冬氨酸和谷氨酸; 芳香族酸, 如苯甲酸和肉桂酸; 磺酸, 如对甲苯磺酸,乙磺酸, 等等。If the compound of the present invention is basic, the desired salt can be prepared by any suitable method given in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Alternatively use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acids such as glucuronic acid and galactose Alkyd acids; α-hydroxy acids, such as citric acid and tartaric acid; Amino acids, such as aspartic acid and glutamic acid; Aromatic acids, such as benzoic acid and cinnamic acid; Sulfonic acids, such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.

如果本发明的化合物是酸性的, 则想得到的盐可以通过合适的方法制备得到,如, 使用无机碱或有机碱, 如氨（伯氨, 仲氨, 叔氨）, 碱金属氢氧化物或碱土金属氢氧化物, 等等。合适的盐包括, 但并不限于, 从氨基酸得到的有机盐, 如甘氨酸和精氨酸,氨, 如伯氨、仲氨和叔氨, 和环状氨, 如哌啶, 吗啉和哌嗪等, 和从钠, 钙, 钾, 镁,锰, 铁, 铜, 锌, 铝和锂得到无机盐。If the compound of the invention is acidic, the desired salt can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides or alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine. etc., and inorganic salts obtained from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

根据另一方面, 本发明的药物组合物的特点包括式I-IV的化合物, 本发明所列出的化合物, 或实施例所示的化合物, 和药学上可接受的载体, 辅剂, 或赋形剂。本发明的组合物中化合物的量能有效地可探测地治疗或减轻患者由病毒引起的疾病。According to another aspect, the pharmaceutical composition of the present invention is characterized by comprising the compound of formula I-IV, the compound listed in the present invention, or the compound shown in the examples, and a pharmaceutically acceptable carrier, adjuvant, or excipient Forming agent. The amount of compound in the compositions of the present invention is effective to detectably treat or alleviate the disease caused by the virus in a patient.

本发明的化合物存在自由形态, 或合适的、作为药学上可接受的衍生物。根据本发明, 药学上可接受的衍生物包括, 但并不限于, 药学上可接受的前药, 盐, 酯, 酯类的盐, 或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物, 本发明其他方面所描述的化合物, 其代谢产物或他的残留物。The compounds of the present invention exist in free form, or as appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other compounds that can be administered directly or indirectly according to the needs of patients. Adducts or derivatives, compounds described in other aspects of the invention, their metabolites or their residues.

像本发明所描述的, 本发明药学上可接受的组合物进一步包含药学上可接受的载体, 辅剂, 或赋形剂, 这些像本发明所应用的, 包括任何溶剂, 稀释剂, 或其他液体赋形剂, 分散剂或悬浮剂, 表面活性剂, 等渗剂, 增稠剂, 乳化剂, 防腐剂, 固体粘合剂或润滑剂, 等等, 适合于特有的目标剂型。如以下文献所描述的：In Remington: TheScience and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy,Lippincott Williams&Wilkins, Philadelphia, and Encyclopedia of PharmaceuticalTechnology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, NewYork. 综合此处文献的内容, 表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物不相容的范围, 例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用, 它们的用途也是本发明所考虑的范围。As described herein, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used in the present invention, includes any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the specific target dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams&Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, NewYork. A synthesis of the literature herein shows that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except to the extent that any conventional carrier media is incompatible with the compounds of the present invention, such as any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, they The purposes of the present invention are also considered scope.

可作为药学上可接受载体的物质包括, 但并不限于, 离子交换剂, 铝, 硬脂酸铝, 卵磷脂, 血清蛋白, 如人血清蛋白, 缓冲物质如磷酸盐, 甘氨酸, 山梨酸, 山梨酸钾, 饱和植物脂肪酸的部分甘油酯混合物, 水, 盐或电解质, 如硫酸鱼精蛋白, 磷酸氢二钠, 磷酸氢钾, 氯化钠, 锌盐, 胶体硅, 三硅酸镁, 聚乙烯吡咯烷酮, 聚丙烯酸脂,蜡, 聚乙烯-聚氧丙烯-阻断聚合体, 羊毛脂, 糖, 如乳糖, 葡萄糖和蔗糖; 淀粉如玉米淀粉和土豆淀粉; 纤维素和它的衍生物如羧甲基纤维素钠, 乙基纤维素和乙酸纤维素;树胶粉; 麦芽; 明胶; 滑石粉; 辅料如可可豆脂和栓剂蜡状物; 油如花生油, 棉子油,红花油, 麻油, 橄榄油, 玉米油和豆油; 二醇类化合物, 如丙二醇和聚乙二醇; 酯类如乙基油酸酯和乙基月桂酸酯; 琼脂; 缓冲剂如氢氧化镁和氢氧化铝; 海藻酸; 无热原的水; 等渗盐; 林格（氏）溶液; 乙醇, 磷酸缓冲溶液, 和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁, 着色剂, 释放剂, 包衣衣料, 甜味剂, 调味剂和香料, 防腐剂和抗氧化剂。Substances which may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid potassium phosphate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidones, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil, and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed Acids; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solutions, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, Sweeteners, Flavors and Perfumes, Preservatives and Antioxidants.

本发明的药物组合物可以是口服给药, 注射给药, 喷雾吸入法, 局部给药, 经直肠给药, 经鼻给药, 含服给药, 阴道给药或通过植入性药盒给药。可以是胶囊, 片剂,丸剂, 粉剂、粒剂和水制悬浮液或溶液。口服给药可以用如下形式：片剂、丸剂、胶囊、可分散的粉末、颗粒或悬浮液、糖浆、和酏剂, 或以外用方式给药：软膏剂、凝胶、含药胶布等,或者以无菌可注射溶液或悬浮液形式进行非肠胃给药。本发明化合物也可肠胃外或腹腔内给药。也可在适当混合有表面活性剂（如羟丙基纤维素、聚乙烯吡咯烷酮）的水中制备这些活性化合物（作为游离碱或药学上可接受的盐）的溶液或悬浮液。还可在甘油、液体、聚乙二醇及其在油中的混合物中制备分散液。在常规储存和使用条件下, 这些制剂中含有防腐剂以防止微生物生长。The pharmaceutical composition of the present invention can be administered orally, by injection, by spray inhalation, topically, rectally, nasally, buccally, vaginally or via an implantable kit medicine. It can be capsules, tablets, pills, powders, granules and aqueous suspensions or solutions. Oral administration may be in the form of tablets, pills, capsules, dispersible powders, granules or suspensions, syrups, and elixirs, or externally: ointments, gels, medicated plasters, etc., or Parenteral administration is in the form of sterile injectable solutions or suspensions. The compounds of this invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds (as free base or pharmaceutically acceptable salts) can also be prepared in water suitably mixed with a surfactant (eg, hydroxypropylcellulose, polyvinylpyrrolidone). Dispersions can also be prepared in glycerol, liquid, polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

适于注射的药物形式包括：无菌水溶液或分散液和无菌粉（用于临时制备无菌注射溶液或分散液）。在所有情况下, 这些形式必须是无菌的且必须是流体以易于注射器排出流体。在制造和储存条件下必须是稳定的, 且必须能防止微生物（如细菌和真菌）的污染影响。载体可以是溶剂或分散介质, 其中含有如水、醇（如甘油、丙二醇和液态聚乙二醇）、它们的适当混合物和植物油。The pharmaceutical forms suitable for injection include: sterile aqueous solutions or dispersions and sterile powders (for the extemporaneous preparation of sterile injectable solutions or dispersion). In all cases, these forms must be sterile and must be fluid for easy syringe expulsion. Must be stable under the conditions of manufacture and storage and must be protected against the contaminating influence of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, alcohols (such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

化合物可以以局部方式施用, 而不以系统方式施用。例如通常以稀释制剂或持续释放制剂的形式将化合物直接注射至器官内。此外, 含有本发明化合物的药物组合物可以在靶向药物传递系统中使用, 例如在用器官特异性抗体包衣的脂质体中递送。所述脂质体将靶向所述器官并被该器官选择性摄取。此外, 含有本发明化合物的组合物可以以快速释放制剂、延时释放制剂或即时释放制剂的形式提供。The compounds can be administered in a local rather than systemic manner. For example, the compound is injected directly into the organ, usually in a dilute formulation or a sustained release formulation. In addition, pharmaceutical compositions containing compounds of the invention can be used in targeted drug delivery systems, such as in liposomes coated with organ-specific antibodies. The liposomes will be targeted to and selectively taken up by the organ. In addition, compositions containing compounds of the invention may be provided as immediate release formulations, delayed release formulations or immediate release formulations.

对于吸入施用, 本发明的化合物可以是气溶胶、气雾剂或粉末形式。本发明化合物的药物组合物可以方便地以气溶胶喷雾剂形式递送, 所述气溶胶喷雾剂可以装在压力容器或雾化器中, 使用合适的抛射剂例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。在压力气溶胶的情况下, 剂量单位可以通过阀门进行确定以递送计量量。例如, 以胶囊剂和药筒为例, 用于吸入器或吹药器的明胶可以制备为含有所述化合物与适当粉末基质例如乳糖或淀粉的粉末混合物。For administration by inhalation, the compounds of the invention may be in aerosol, aerosol or powder form. Pharmaceutical compositions of compounds of this invention can be conveniently delivered in the form of an aerosol spray, which can be packed in a pressurized container or nebulizer, using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, or Methane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by a valve to deliver a metered amount. For example, gelatin for use in inhalers or insufflators, in the case of capsules and cartridges, may be prepared containing a powder mix of the compound with a suitable powder base such as lactose or starch.

本发明化合物还可以制备为直肠组合物例如灌肠剂、直肠凝胶剂、直肠泡沫剂、直肠气溶胶、栓剂、凝胶栓剂（gel suppository）或保留灌肠剂（retention enema）, 其中含有常规的栓剂基质例如可可脂或其他甘油酯以及合成聚合物例如聚乙烯吡咯烷酮、PEG等。在组合物的栓剂形式中, 低熔点蜡例如但不限于脂肪酸甘油酯任选与可可脂的混合物首先被熔化。The compounds of the present invention may also be prepared in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel suppositories or retention enemas, containing conventional suppositories Bases such as cocoa butter or other glycerides and synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository form of the composition, a low melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally with cocoa butter, is first melted.

此外, 本发明化合物还可与其他抗病毒药物联用。具体包括但不限于, 病毒唑、盐酸金刚乙胺、盐酸金刚烷胺、阿昔洛韦、伐昔洛韦、更昔洛韦、干扰素、齐多夫定、阿糖腺苷、利巴韦林、替比夫定等。In addition, the compound of the present invention can also be used in combination with other antiviral drugs. Specifically including but not limited to, ribavirin, rimantadine hydrochloride, amantadine hydrochloride, acyclovir, valacyclovir, ganciclovir, interferon, zidovudine, vidarabine, ribavir Lin, telbivudine, etc.

可以根据常规方式用一种或多种生理学可接受的载体制备药物组合物, 其中包括可帮助将活性化合物加工为可药用制剂的赋形剂和辅剂。所选择的施用途径决定适当的剂型。任何熟知的技术、载体和赋形剂都可以根据现有技术中的理解适当的使用。含有本发明化合物的药物组合物可以根据常规方法制备, 例如通过常规的混合、溶解、制粒、制锭、研磨、乳化、包囊、包封或压制过程制备。Pharmaceutical compositions may be prepared in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. The chosen route of administration will determine the appropriate dosage form. Any well-known techniques, carriers and excipients can be used as appropriate according to the understanding in the art. Pharmaceutical compositions containing the compounds of the present invention can be prepared according to conventional methods, for example by conventional mixing, dissolving, granulating, dragging, levigating, emulsifying, encapsulating, encapsulating or compressing processes.

药物组合物将包含至少一种可药用载体、稀释剂或赋形剂和游离酸、游离碱或可药用盐形式的本发明的化合物作为活性成分。此外, 药物组合物还可包括其它医学或药学活性剂、载体、辅剂、例如防腐剂、稳定剂、湿润剂或乳化剂、溶解促进剂、调节渗透压的盐或缓冲剂。此外, 药物组合物还可含有其它有治疗价值的物质。Pharmaceutical compositions will comprise at least one pharmaceutically acceptable carrier, diluent or excipient and a compound of the present invention in free acid, free base or pharmaceutically acceptable salt form as an active ingredient. In addition, the pharmaceutical composition may also include other medically or pharmaceutically active agents, carriers, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution accelerators, salts or buffers for adjusting osmotic pressure. In addition, the pharmaceutical composition may contain other therapeutically valuable substances.

含有本文所述化合物的组合物的制备方法包括将化合物与一种或多种惰性的可药用赋形剂或载体一起制备为固体、半固体或液体形式。固体组合物包括但不限于散剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。液体组合物包括其中溶解有化合物的溶液剂、含有化合物的乳剂、含有包含本文公开化合物的脂质体、胶团或纳米粒子的溶液剂。半固体组合物包括但不限于凝胶剂、混悬剂和乳膏剂。组合物可以是液体溶液剂或混悬剂形式、适合于在使用前溶解或悬浮在液体中的固体形式或乳剂形式。这些组合物还可以含有少量无毒的辅剂, 例如湿润剂或乳化剂、pH缓冲剂等。Methods of preparing compositions containing the compounds described herein include preparing the compounds in solid, semi-solid or liquid form together with one or more inert pharmaceutically acceptable excipients or carriers. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, solutions containing liposomes, micelles or nanoparticles containing the compounds disclosed herein. Semisolid compositions include, but are not limited to, gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to use, or emulsions. These compositions may also contain minor amounts of nontoxic adjuvants, such as wetting or emulsifying agents, pH buffering agents, and the like.

本发明的化合物优选地按制剂配方制备成剂量单位型以减轻给药量和剂量的均匀性。术语“剂量单位型”在此处是指患者得到适当治疗所需药物的物理分散单位。然而,应了解本发明的化合物或组合物每日总的用法将通过主治医生根据可靠的医学范围判断来确定。具体的有效剂量水平对于任何一个特殊的患者或有机体将取决于许多因素包括被治疗的病症和病症的严重性, 具体化合物的活性, 所用的具体组合物, 患者的年龄、体重、健康状况、性别和饮食习惯, 给药时间, 给药途径和所用具体化合物的排泄速率, 治疗的持续时间, 药物应用于联合用药或与有特效的化合物联用, 以及其他一些药学领域公知的因素。The compounds of the present invention are preferably formulated in dosage unit form to ease administration and uniformity of dosage. The term "dosage unit form" as used herein refers to a physically discrete unit of drug required to adequately treat a patient. However, it should be understood that the total daily usage of the compounds or compositions of the present invention will be determined by the attending physician based on sound medically sound judgment. The specific effective dosage level for any particular patient or organism will depend on many factors including the condition being treated and the severity of the condition, the activity of the particular compound, the particular composition employed, the age, weight, health, sex of the patient and dietary habits, timing of administration, route of administration and rate of excretion of the specific compound used, duration of treatment, whether the drug is used in combination or with specific compounds, and other factors well known in the art of pharmacy.

可以将本发明化合物通过附加适宜的官能团进行修饰以提高选择性生物特性。这样的修饰是本领域己知的并且包括向生物腔隙（例如血液、淋巴系统、中枢神经系统）渗透、提高口服有效性、提高溶解性以便可以通过注射给药、改变代谢和改变排泄的修饰。可以将本发明化合物通过附加适宜的官能团进行修饰以提高选择性生物特性。这样的修饰是本领域己知的并且包括向生物腔隙（例如血液、淋巴系统、中枢神经系统）渗透、提高口服有效性、提高溶解性以便可以通过注射给药、改变代谢和改变排泄的修饰。Compounds of the invention may be modified by appending suitable functional groups to enhance selective biological properties. Such modifications are known in the art and include modifications to penetrate biological compartments (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility so that administration by injection can be made, alter metabolism, and alter excretion . Compounds of the invention may be modified by appending suitable functional groups to enhance selective biological properties. Such modifications are known in the art and include modifications to penetrate biological compartments (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility so that administration by injection can be made, alter metabolism, and alter excretion .

本发明所述的由病毒引起的疾病为由RSV、HSV、EV71、H1N1、H3N2、H5N1、H7N9、Cox-B3、HBV、FMDV、SARS等病毒引起的疾病, 包括呼吸道疾病、肝脏疾病、手足口病、免疫性疾病、炎性疾病等。The diseases caused by viruses in the present invention are diseases caused by viruses such as RSV, HSV, EV71, H1N1, H3N2, H5N1, H7N9, Cox-B3, HBV, FMDV, SARS, etc., including respiratory diseases, liver diseases, hand, foot and mouth diseases, immunological diseases, inflammatory diseases, etc.

一般的, 本发明的化合物可以通过本发明说描述的方法制备得到, 除非有进一步的说明, 其中取代基的定义如式I, II, III, IV所示, 下面的反应方案和实施例用于进一步举例说明本发明的内容。Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless there are further instructions, wherein the definitions of the substituents are as shown in formulas I, II, III, and IV, and the following reaction schemes and examples are used for Further examples illustrate the content of the present invention.

实施例1. 3-甲氧基-1-戊烷基-4-（2-吡啶基）-1,6-萘啶-2 (1H)-酮Example 1. 3-methoxy-1-pentanyl-4-(2-pyridyl)-1,6-naphthyridin-2 (1 H )-one

步骤1) 在氮气保护下, 将 3-（4-氨基吡啶）-2-吡啶甲酮 (2 mmol), 甲氧基乙酰氯(3.8 mmol) 和N, N-二异丙基乙胺 (8 mmol) 溶于二氯甲烷 (5 mL) 中, 室温反应3小时。点板发现原料反应完毕, 反应液加水稀释后乙酸乙酯萃取, 有机相减压除掉溶剂后,残留物用硅胶柱色谱纯化得到3-（4-甲氧基乙酰胺基）-2-吡啶甲酮。Step 1) Under nitrogen protection, 3-(4-aminopyridine)-2-pyridinemethanone (2 mmol), methoxyacetyl chloride (3.8 mmol) and N, N-diisopropylethylamine (8 mmol) was dissolved in dichloromethane (5 mL) and reacted at room temperature for 3 hours. After pointing the plate, it was found that the reaction of the raw materials was complete. The reaction solution was diluted with water and extracted with ethyl acetate. After the organic phase was decompressed to remove the solvent, the residue was purified by silica gel column chromatography to obtain 3-(4-methoxyacetamido)-2-pyridine ketone.

步骤2）在氮气保护下, 3-（4-甲氧基乙酰胺基）-2-吡啶甲酮(1.0 mmol) 溶于四氢呋喃 (10 mL) 中, 加入t-BuOK (10 mmol) 室温反应5小时。反应液用饱和氯化铵溶液萃取, 乙酸乙酯萃取。减压除掉有机相后, 残留物用硅胶柱色谱纯化得到4-羟基-3-甲氧基-4-(2-吡啶)-3,4-二氢-1,6-萘啶-2(1H)-酮。Step 2) Under nitrogen protection, 3-(4-methoxyacetamido)-2-pyridinemethanone (1.0 mmol) was dissolved in tetrahydrofuran (10 mL), and t-BuOK (10 mmol) was added to react at room temperature 5 Hour. The reaction solution was extracted with saturated ammonium chloride solution and extracted with ethyl acetate. After removing the organic phase under reduced pressure, the residue was purified by silica gel column chromatography to obtain 4-hydroxy-3-methoxy-4-(2-pyridine)-3,4-dihydro-1,6-naphthyridine-2( 1 H )-ketone.

步骤3）在氢气氛围下, 4-羟基-3-甲氧基-4-(2-吡啶)-3, 4-二氢-1,6-萘啶-2(1H)-酮溶于MeOH (10 mL) 中, 加入10%Pd/C (0.1 mmol) 和碳酸钾(8 mmol)后50 oC反应过夜。减压除掉溶剂后, 残留物用硅胶柱色谱纯化得到3-甲氧基-4（2-吡啶基）-1,6-萘啶-2(1H)-酮。Step 3) Under hydrogen atmosphere, 4-hydroxy-3-methoxy-4-(2-pyridine)-3,4-dihydro-1,6-naphthyridin-2(1 H )-one was dissolved in MeOH (10 mL), add 10%Pd/C (0.1 mmol) and potassium carbonate (8 mmol) and react overnight at 50 o C. After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography to obtain 3-methoxy-4(2-pyridyl)-1,6-naphthyridin-2(1 H )-one.

步骤4）在氮气保护下, CuI (l mmol), Cs2CO3(20 mmol)和 2-氧代环己基甲酸乙酯（2 mmol)加入到DMSO(10 mL)中, 室温搅拌30 min。3-甲氧基-4（2-吡啶基）-1,6-萘啶-2(1H)-酮(10 mmol)和 溴代戊烷（10 mmol)的 DMSO(12 mL)溶液, 注射加入。加热至100°C过夜。冷却至室温, 过滤, 加入水（50 mL)和二氯甲烷（50 mL×3), 收集有机相, 减压蒸去溶剂, 粗产品经柱层析纯化得3-甲氧基-4（2-吡啶基）-1,6-萘啶-2(1H)-酮。Step 4) Under nitrogen protection, CuI (1 mmol), Cs 2 CO 3 (20 mmol) and ethyl 2-oxocyclohexylcarboxylate (2 mmol) were added to DMSO (10 mL), and stirred at room temperature for 30 min. 3-Methoxy-4(2-pyridyl)-1,6-naphthyridin-2( 1H )-one (10 mmol) and bromopentane (10 mmol) in DMSO (12 mL), injection join in. Heat to 100°C overnight. Cool to room temperature, filter, add water (50 mL) and dichloromethane (50 mL×3), collect the organic phase, evaporate the solvent under reduced pressure, and purify the crude product by column chromatography to obtain 3-methoxy-4(2 -pyridyl)-1,6-naphthyridin-2(1 H )-one.

ESI-MS (m/z): 324.24[M+H]+。ESI-MS (m/z): 324.24[M+H] + .

实施例2. 1-环戊烷基-3-甲氧基-4-（4-甲氧基苯基）-7-丙酰基-1,6-萘啶-2(1H)-酮Example 2. 1-cyclopentyl-3-methoxy-4-(4-methoxyphenyl)-7-propionyl-1,6-naphthyridin-2(1 H )-one

步骤1) 在氮气保护下, 将1- (4-氨基-5-(4-甲氧基苯甲酰基)-吡啶-2-丙基-1-酮(2 mmol), 甲氧基乙酰氯 (3.8 mmol) 和N,N-二异丙基乙胺 (8 mmol) 溶于二氯甲烷 (5mL) 中, 室温反应3小时。点板发现原料反应完毕, 反应液加水稀释后乙酸乙酯萃取, 有机相减压除掉溶剂后, 残留物用硅胶柱色谱纯化得到1- (4-甲氧基乙酰氨基-5-(4-甲氧基苯甲酰基)-吡啶-2-丙基-1-酮。Step 1) Under nitrogen protection, 1-(4-amino-5-(4-methoxybenzoyl)-pyridin-2-propyl-1-one (2 mmol), methoxyacetyl chloride ( 3.8 mmol) and N,N-diisopropylethylamine (8 mmol) were dissolved in dichloromethane (5mL), and reacted at room temperature for 3 hours. The reaction of the raw materials was found to be complete by spotting the plate, and the reaction solution was diluted with water and extracted with ethyl acetate. After removing the solvent from the organic phase under reduced pressure, the residue was purified by silica gel column chromatography to obtain 1-(4-methoxyacetamido-5-(4-methoxybenzoyl)-pyridine-2-propyl-1- ketone.

步骤2）在氮气保护下, 1- (4-甲氧基乙酰氨基-5-(4-甲氧基苯甲酰基)-吡啶-2-丙基-1-酮 (1.0 mmol) 溶于四氢呋喃 (10 mL) 中, 加入t-BuOK (10 mmol) 室温反应5小时。反应液用饱和氯化铵溶液萃取, 乙酸乙酯萃取。减压除掉有机相后, 残留物用硅胶柱色谱纯化得到4-羟基-3-甲氧基-4-（4-甲氧基苯基）-7-丙酰基-3,4-二氢-1,6-萘啶-2(1H)-酮。Step 2) Under nitrogen protection, 1-(4-methoxyacetamido-5-(4-methoxybenzoyl)-pyridin-2-propyl-1-one (1.0 mmol) was dissolved in THF ( 10 mL), added t-BuOK (10 mmol) and reacted at room temperature for 5 hours. The reaction solution was extracted with saturated ammonium chloride solution and ethyl acetate. After the organic phase was removed under reduced pressure, the residue was purified by silica gel column chromatography to obtain 4 -Hydroxy-3-methoxy-4-(4-methoxyphenyl)-7-propionyl-3,4-dihydro-1,6-naphthyridin-2(1 H )-one.

步骤3）在氢气氛围下, 4-羟基-3-甲氧基-4-（4-甲氧基苯基）-7-丙酰基-3, 4-二氢-1, 6-萘啶-2(1H)-酮溶于MeOH (10 mL) 中, 加入10%Pd/C (0.1 mmol) 和碳酸钾(8mmol)后50 oC反应过夜。减压除掉溶剂后, 残留物用硅胶柱色谱纯化得到3-甲氧基-4-（4-甲氧基苯基）-7-丙酰基-1,6-萘啶-2(1H)-酮。Step 3) Under hydrogen atmosphere, 4-hydroxy-3-methoxy-4-(4-methoxyphenyl)-7-propionyl-3,4-dihydro-1,6-naphthyridine-2 (1 H )-ketone was dissolved in MeOH (10 mL), and 10% Pd/C (0.1 mmol) and potassium carbonate (8 mmol) were added to react overnight at 50 o C. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 3-methoxy-4-(4-methoxyphenyl)-7-propionyl-1,6-naphthyridine-2( 1H ) -ketone.

步骤4）在氮气保护下, CuI (1 mmol), Cs2CO3(20 mmol)和 2-氧代环己基甲酸乙酯（2 mmol)加入到DMSO(10 mL)中, 室温搅拌30 min。3-甲氧基-4-（4-甲氧基苯基）-7-丙酰基-1,6-萘啶-2(1H)-酮(10 mmol)和 溴代环戊烷（10 mmol)的 DMSO(12 mL)溶液, 注射加入。加热至100°C过夜。冷却至室温, 过滤, 加入水（50 mL)和二氯甲烷（50 mL×3), 收集有机相, 减压蒸去溶剂, 粗产品经柱层析纯化得1-环戊烷基-3-甲氧基-4-（4-甲氧基苯基）-7-丙酰基-1,6-萘啶-2(1H)-酮。Step 4) Under nitrogen protection, CuI (1 mmol), Cs 2 CO 3 (20 mmol) and ethyl 2-oxocyclohexylcarboxylate (2 mmol) were added to DMSO (10 mL), and stirred at room temperature for 30 min. 3-methoxy-4-(4-methoxyphenyl)-7-propionyl-1,6-naphthyridin-2(1 H )-one (10 mmol) and bromocyclopentane (10 mmol ) in DMSO (12 mL), added by injection. Heat to 100°C overnight. Cool to room temperature, filter, add water (50 mL) and dichloromethane (50 mL×3), collect the organic phase, evaporate the solvent under reduced pressure, and purify the crude product by column chromatography to obtain 1-cyclopentyl-3- Methoxy-4-(4-methoxyphenyl)-7-propionyl-1,6-naphthyridin-2( 1H )-one.

ESI-MS (m/z): 407.48 [M+H]+。ESI-MS (m/z): 407.48 [M+H] + .

实施例3. N,N-二甲基甘氨酸-3-(3-甲氧基4-（3-甲氧基苯基)-2-氧喹啉-1(2H)-基）丙酯Example 3. N,N-Dimethylglycine-3-(3-methoxy4-(3-methoxyphenyl)-2-oxoquinolin-1(2 H )-yl)propyl ester

步骤1）3-甲氧基-4-（3-甲氧基苯基）喹啉-2(1H)-酮的合成方法参考实施例1和2。Step 1) Refer to Examples 1 and 2 for the synthesis method of 3-methoxy-4-(3-methoxyphenyl)quinolin-2(1 H )-one.

步骤2）在氮气保护下, CuI (1 mmol), Cs2CO3(20 mmol)和 2-氧代环己基甲酸乙酯（2 mmol)加入到DMSO(10 mL)中, 室温搅拌30 min。3-甲氧基-4-（3-甲氧基苯基）喹啉-2(1H)-酮(10 mmol)和 3-溴代-N,N-二甲基甘氨酸丙酯（10 mmol)的 DMSO(12 mL)溶液, 注射加入。加热至100°C过夜。冷却至室温, 过滤, 加入水（50 mL)和二氯甲烷（50 mL×3),收集有机相, 减压蒸去溶剂, 粗产品经柱层析纯化得N,N-二甲基甘氨酸-3-(3-甲氧基4-（3-甲氧基苯基)-2-氧喹啉-1(2H)-基）丙酯。Step 2) Under nitrogen protection, CuI (1 mmol), Cs 2 CO 3 (20 mmol) and ethyl 2-oxocyclohexylcarboxylate (2 mmol) were added to DMSO (10 mL), and stirred at room temperature for 30 min. 3-methoxy-4-(3-methoxyphenyl)quinolin-2(1 H )-one (10 mmol) and 3-bromo-N,N-dimethylglycine propyl ester (10 mmol ) in DMSO (12 mL), added by injection. Heat to 100°C overnight. Cool to room temperature, filter, add water (50 mL) and dichloromethane (50 mL×3), collect the organic phase, evaporate the solvent under reduced pressure, and purify the crude product by column chromatography to obtain N,N-dimethylglycine- 3-(3-Methoxy 4-(3-methoxyphenyl)-2-oxoquinolin-1(2 H )-yl)propyl ester.

ESI-MS (m/z): 425.23[M+H]+。ESI-MS (m/z): 425.23[M+H] + .

实施例4. 1-苄基-3-乙氧基-4-（3-羟基苯基)喹啉-2(1H)-酮Example 4. 1-benzyl-3-ethoxy-4-(3-hydroxyphenyl) quinoline-2( 1H )-one

步骤1）3-乙氧基-4-（3-羟基苯基）-喹啉-2(1H)-酮的合成方法参考实施例1和2。Step 1) Refer to Examples 1 and 2 for the synthesis method of 3-ethoxy-4-(3-hydroxyphenyl)-quinolin-2(1 H )-one.

步骤2）在氮气保护下, CuI (1 mmol), Cs2CO3(20 mmol)和 2-氧代环己基甲酸乙酯（2 mmol)加入到DMSO(10 mL)中, 室温搅拌30 min。33-乙氧基-4-（3-羟基苯基）-喹啉-2(1H)-酮(10 mmol)和苄溴（10 mmol)的 DMSO(12 mL)溶液, 注射加入。加热至100°C过夜。冷却至室温, 过滤, 加入水（50 mL)和二氯甲烷（50 mL×3), 收集有机相, 减压蒸去溶剂, 粗产品经柱层析纯化得1-苄基-3-乙氧基-4-（3-羟基苯基)喹啉-2(1H)-酮。Step 2) Under nitrogen protection, CuI (1 mmol), Cs 2 CO 3 (20 mmol) and ethyl 2-oxocyclohexylcarboxylate (2 mmol) were added to DMSO (10 mL), and stirred at room temperature for 30 min. A solution of 33-ethoxy-4-(3-hydroxyphenyl)-quinolin-2(1 H )-one (10 mmol) and benzyl bromide (10 mmol) in DMSO (12 mL) was added by injection. Heat to 100°C overnight. Cool to room temperature, filter, add water (50 mL) and dichloromethane (50 mL×3), collect the organic phase, evaporate the solvent under reduced pressure, and purify the crude product by column chromatography to obtain 1-benzyl-3-ethoxy Base-4-(3-hydroxyphenyl)quinolin-2( 1H )-one.

ESI-MS (m/z): 372.14[M+H]+。ESI-MS (m/z): 372.14[M+H] + .

实施例5. 1-(3-(N,N-二甲氨基)丙基)-3-甲氧基-4-苯基-1,6-萘啶-2(1H)-酮Example 5. 1-(3-(N,N-dimethylamino)propyl)-3-methoxy-4-phenyl-1,6-naphthyridin-2(1 H )-one

步骤1）3-甲氧基-4-苯基-1,6-萘啶-2(1H)-酮的合成方法参考实施例1和2。Step 1) Refer to Examples 1 and 2 for the synthesis method of 3-methoxy-4-phenyl-1,6-naphthyridin-2(1 H )-one.

步骤2）在氮气保护下, CuI (l mmol), Cs2CO3(20 mmol)和 2-氧代环己基甲酸乙酯（2 mmol)加入到DMSO(10 mL)中, 室温搅拌30 min。3-甲氧基-4-苯基-1,6-萘啶-2(1H)-酮(10 mmol)和 溴代戊烷（10 mmol)的 DMSO(12 mL)溶液, 注射加入。加热至100°C过夜。冷却至室温, 过滤, 加入水（50 mL)和二氯甲烷（50 mL×3), 收集有机相, 减压蒸去溶剂, 粗产品经柱层析纯化得1-(3-(N,N-二甲氨基)丙基)-3-甲氧基-4-苯基-1,6-萘啶-2(1H)-酮。Step 2) Under nitrogen protection, CuI (1 mmol), Cs 2 CO 3 (20 mmol) and ethyl 2-oxocyclohexylcarboxylate (2 mmol) were added to DMSO (10 mL), and stirred at room temperature for 30 min. A solution of 3-methoxy-4-phenyl-1,6-naphthyridin-2( 1H )-one (10 mmol) and bromopentane (10 mmol) in DMSO (12 mL) was added by injection. Heat to 100°C overnight. Cool to room temperature, filter, add water (50 mL) and dichloromethane (50 mL×3), collect the organic phase, evaporate the solvent under reduced pressure, and purify the crude product by column chromatography to obtain 1-(3-(N,N -Dimethylamino)propyl)-3-methoxy-4-phenyl-1,6-naphthyridin-2( 1H )-one.

ESI-MS (m/z):338.42[M+H]+。ESI-MS (m/z): 338.42 [M+H] + .

实施例6. 3-苄氧基-1-(2-呋喃)-6-甲基-4-苯基喹啉-2(1H)-酮Example 6. 3-Benzyloxy-1-(2-furan)-6-methyl-4-phenylquinolin-2(1 H )-one

步骤1) 3-苄氧基-4-苯基-6-甲基-喹啉-2(1H)-酮的合成方法参考实施例1和2。Step 1) Refer to Examples 1 and 2 for the synthesis method of 3-benzyloxy-4-phenyl-6-methyl-quinolin-2(1 H )-one.

步骤2）在氮气保护下, CuI (l mmol), Cs2CO3(20 mmol)和 2-氧代环己基甲酸乙酯（2 mmol)加入到DMSO(10 mL)中, 室温搅拌30 min。3-苄氧基-4-苯基-6-甲基-喹啉-2(1H)-酮 (10 mmol)和 溴代戊烷（10 mmol)的 DMSO(12 mL)溶液, 注射加入。加热至100 °C过夜。冷却至室温, 过滤, 加入水（50 mL)和二氯甲烷（50 mL×3), 收集有机相, 减压蒸去溶剂, 粗产品经柱层析纯化得3-苄氧基-1-(2-呋喃)-6-甲基-4-苯基喹啉-2(1H)-酮。Step 2) Under nitrogen protection, CuI (1 mmol), Cs 2 CO 3 (20 mmol) and ethyl 2-oxocyclohexylcarboxylate (2 mmol) were added to DMSO (10 mL), and stirred at room temperature for 30 min. A solution of 3-benzyloxy-4-phenyl-6-methyl-quinolin-2( 1H )-one (10 mmol) and bromopentane (10 mmol) in DMSO (12 mL) was added by injection. Heat to 100 °C overnight. Cool to room temperature, filter, add water (50 mL) and dichloromethane (50 mL×3), collect the organic phase, evaporate the solvent under reduced pressure, and purify the crude product by column chromatography to obtain 3-benzyloxy-1-( 2-furan)-6-methyl-4-phenylquinolin-2( 1H )-one.

ESI-MS (m/z): 408.17[M+H]+。ESI-MS (m/z): 408.17[M+H] + .

抗病毒活性测试Antiviral activity test

化合物测试抗病毒活性是依据细胞病变效应的方法进行的, 利巴韦林作为阳性对照药物。具体实验方案如下。The antiviral activity of compounds was tested based on the cytopathic effect method, and ribavirin was used as a positive control drug. The specific experimental scheme is as follows.

首先进行病毒增殖Virus multiplication

将测试病毒接种于该病毒的敏感细胞上, 将细胞置于无血清的 1640 培养液中, 然后让接种后的细胞在 5% 二氧化碳、37 ºC 的温度下培养, 至 90% 的细胞出现感染病毒病变, 将病变后的细胞定量分装后冷存在 -80 ºC 冰箱, 备用。Inoculate the test virus on the virus-sensitive cells, place the cells in serum-free 1640 culture medium, and then let the inoculated cells incubate at 5% carbon dioxide and 37 ºC until 90% of the cells are infected with the virus For lesions, the cells after lesions were quantitatively aliquoted and stored in a -80 ºC refrigerator for later use.

其次进行病毒毒力测定Followed by virus virulence assay

使用细胞维持液对增殖的病毒进行 10 倍比例的系列稀释。将病毒接种于 96 孔板内的 Hep-2 上, 并纵向重复 3 次作为对照试验。然后让接种后的细胞在 5% 二氧化碳、37ºC 的温度下培养, 每天要观察细胞病变情况。两到三天后, 将孔板内的细胞维持液吸弃,并重新再孔板内加入 100μL 的 1% 中性红, 在 37 ºC 的温度下染色 2 个小时, 后吸弃其染色液, 并用洗脱液在 37 ºC 的温度下脱色 10分钟。在 540 nm 左右的波长下用酶标仪测定其 OD 值, 并用公式计算细胞的病变率和细胞比距, 将其细胞比距高于 50% 的细胞病变率的稀释度的指数加和, 用 Reed-Muench 方法计算病毒的 TCID50 值为 10-5.5/mL。Serial 10-fold dilutions of the proliferating virus were performed using Cell Maintenance Medium. The virus was inoculated on Hep-2 in a 96-well plate, and repeated three times vertically as a control experiment. Then let the inoculated cells be cultured at 5% carbon dioxide and 37ºC, and observe the changes of the cells every day. Two to three days later, discard the cell maintenance solution in the well plate, and add 100 μL of 1% neutral red to the well plate again, stain at 37 ºC for 2 hours, and then discard the staining solution , and destain with eluent at 37 ºC for 10 minutes. Measure the OD value with a microplate reader at a wavelength of about 540 nm, and calculate the cell lesion rate and cell ratio using the formula, and add the index of the dilution of the cell lesion rate higher than 50% of the cell ratio, and use The TCID50 value of the virus calculated by the Reed-Muench method was 10 -5.5 /mL.

细胞存活率 = (各组 OD 值–空白对照 OD 值)/(正常细胞 OD 值-空白对照 OD值)Cell survival rate = (OD value of each group – OD value of blank control)/(OD value of normal cells – OD value of blank control)

细胞病变率 = 1细胞存活率Cytopathic rate = 1 Cell survival rate

细胞比距= (高于 50% 病变率–50%)/(高于 50% 病变率–低于 50% 病变率)Cell ratio = (more than 50% disease rate – 50%)/(more than 50% disease rate – less than 50% disease rate)

最后进行化合物的病毒抑制活性试验Finally, the virus inhibitory activity test of the compound was carried out

先准备单层细胞：将细胞用胰酶降解后置于 96 微孔板中, 可使其培养成为单层细胞以备用。Prepare monolayer cells first: Digest the cells with trypsin and place them in a 96-well plate to culture them into monolayer cells for future use.

病毒抑制活性实验：将受试化合物按照规格为100 μg/管进行准备, 备用。根据测试化合物的档案, 用适合的溶剂 10 μL溶解每管测试化合物。用 2% 细胞培养液 (200 μL) 对化合物进行连续 10 次的 2 倍比例的稀释, 共需稀释 10 个梯度。然后将其接种于含有单层细胞的 96 微孔板中。并将其第 11 列设为病毒空白对照组, 第 12 列设定为细胞空白对照组。在 5% 二氧化碳、37 ºC 的温度下培养。每天要观察细胞病变情况。待病毒对照病变90%, 将孔板内的细胞维持液吸弃, 并重新再孔板内加入100 μL 的 1% 中性红,在 37℃ 的温度下染色2个小时, 后吸弃其染色液, 并用洗脱液在 37 ºC 的温度下脱色10 分钟。在 40 nm左右的波长下用酶标仪测定其 OD 值。最后, 用公式计算细胞病变率和细胞存活率, 用 Reed-Muench 方法计算化合物对病毒的半数抑制浓度 (EC50) 和化合物对细胞的半数中毒浓度 (TC50), 并将化合物对细胞的半数中毒浓度 (TC50) 除以化合物对病毒的半数抑制浓度 (EC50) 得出抑毒指数 (TI), 即为测试化合物对病毒的抑制活性。Virus inhibitory activity experiment: the test compound was prepared according to the specification of 100 μg /tube, and set aside. Dissolve each tube of test compound with 10 µL of the appropriate solvent according to the test compound profile. With 2% cell culture medium (200 μL ), the compound was serially diluted 10 times by 2 times, and a total of 10 gradients were required. They were then seeded in 96 microwell plates containing monolayers of cells. And the 11th column was set as the virus blank control group, and the 12th column was set as the cell blank control group. Incubate at 37 ºC in 5% carbon dioxide. The cytopathic condition should be observed every day. When the virus control was 90% diseased, the cell maintenance solution in the well plate was aspirated and discarded, and 100 μL of 1% neutral red was added to the well plate again, stained at 37°C for 2 hours, and then aspirated and discarded. Staining solution, and destained with eluent at 37 ºC for 10 minutes. The OD value was measured with a microplate reader at a wavelength of about 40 nm. Finally, calculate the cell lesion rate and cell survival rate with the formula, use the Reed-Muench method to calculate the half inhibitory concentration (EC 50 ) of the compound on the virus and the half toxic concentration (TC 50 ) of the compound on the cell, and calculate the half value of the compound on the cell The toxic concentration (TC 50 ) was divided by the half inhibitory concentration (EC 50 ) of the compound on the virus to obtain the inhibitory index (TI), which was the inhibitory activity of the test compound on the virus.

病毒抑制活性数据如下：The virus inhibitory activity data are as follows:

表中“A”表示化合物浓度小于0.05μM, “B”表示化合物浓度为0.05-5 μM, “C”表示化合物浓度为5-50μM, “D”表示化合物浓度为50-120μM; “E”表示化合物浓度大于120 μM;“++++”表示TC50大于300 μM, “+++”表示TC50在100-300 μM之间, “++”表示TC50在50-100 μM之间, “+”表示TC50在10-50 μM之间。"A" in the table indicates that the concentration of the compound is less than 0.05 μM , "B" indicates that the concentration of the compound is 0.05-5 μM, "C" indicates that the concentration of the compound is 5-50 μM, and "D" indicates that the concentration of the compound is 50-120 μM M; "E" indicates that the concentration of the compound is greater than 120 μM ; "++++" indicates that the TC 50 is greater than 300 μM , "+++" indicates that the TC 50 is between 100-300 μM, "++" indicates that the TC 50 is between 50-100 μM , “+” means TC 50 is between 10-50 μM .

活性测试表明：本发明化合物抗病毒活性强于阳性药或与阳性药相当, 显示出较好的应用前景。The activity test shows that the antiviral activity of the compound of the present invention is stronger than or equal to that of the positive drug, showing good application prospects.

Claims (12)

1. the substituted lactams compounds of a kind of Formulas I and Formula II structure, tautomer, stereoisomer, racemic The solvent of body, the non-equal amount of mixture of enantiomter, geometric isomer, solvate, pharmaceutically acceptable salt or its salt Compound, it is characterised in that compound has the following structure：, Middle A, B separate are five yuan or hexa-atomic aromatic ring, hetero-aromatic ring, carbocyclic ring or carbon heterocyclic; “" it is singly-bound or to be not present; N=1,2,3, or 4;K=1,2,3,4 or 5; R1, R2, R3, R4Shown in being defined as follows：
Each R1, R4Can be identical or different, it is each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxylic Base, alkyl, halogenated alkyl, alkoxy, alkylamino, alkyl acyl, hydroxy alkoxy base, Hydroxyalkylamino, hydroxyl alkane acyl Base, halogenated alkoxy, halogenated alkylamino, ohaloalkanoyl, aminoalkoxy, naphthenic base, cycloalkyl oxy, cycloalkanes Base amino, cycloalkanoyl, alkenyl, alkenylalkoxy, alkenyl alkylamino, alkenyl alkanoyl, alkynyl, alkynyl alcoxyl Base, alkynyl alkylamino, alkynyl alkanoyl, aryl, aryloxy group, aroyl, fragrant amino, alkoxy aryl, aryl alkane Amino, heteroaryl, heteroaryloxy, 4-hetaroylpyrazol, heteroaryl amino, heteroarylalkoxy, heteroarylalkylamino, heterocycle Base alkanoyl, Heterocyclylalkyl, heterocycle oxygroup, heterocyclylamino group, heterocyclylacyl, heterocyclylalkoxy, heterocycle Alkylamino, heterocycle alkanoyl, azido alkoxy, condensed-bicyclic base condense miscellaneous bicyclic group, condensed-bicyclic base fat Race condenses miscellaneous bicyclic group aliphatic, and condensed-bicyclic base oxygroup condenses miscellaneous bicyclic group oxygroup, and condensed-bicyclic base amino is thick Miscellaneous bicyclic group amino is closed, condensed-bicyclic base alkoxy condenses miscellaneous bicyclic group alkoxy, and condensed-bicyclic base alkylamino condenses Miscellaneous bicyclic group alkylamino, condensed-bicyclic base oxygroup alkoxy condense miscellaneous bicyclic group oxygroup alkoxy, condensed-bicyclic base amino Alkoxy, condenses miscellaneous bicyclic group aminoalkoxy, and condensed-bicyclic base-C (=O)-, condensed-bicyclic base-C (=O) O- are condensed miscellaneous Bicyclic group-C (=O)-condenses miscellaneous bicyclic group-C (=O) O-, condensed-bicyclic base amino-C (=O)-, condenses miscellaneous bicyclic group amino- C (=O)-, condensed-bicyclic base-C (=O) N (R5)-, condenses miscellaneous bicyclic group-C (=O) N (R5)-, spiral shell bicyclic group, spiral shell are miscellaneous bicyclic Base, spiral shell bicyclic group aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group oxygroup, the miscellaneous bicyclic group oxygroup of spiral shell, spiral shell bicyclic group Amino, the miscellaneous bicyclic group amino of spiral shell, spiral shell bicyclic group alkoxy, the miscellaneous bicyclic group alkoxy of spiral shell, spiral shell bicyclic group alkylamino, spiral shell are miscellaneous Bicyclic group alkylamino, spiral shell bicyclic group oxygroup alkoxy, the miscellaneous bicyclic group oxygroup alkoxy of spiral shell, spiral shell bicyclic group aminoalkoxy, The miscellaneous bicyclic group aminoalkoxy of spiral shell, spiral shell bicyclic group-C (=O)-, spiral shell bicyclic group-C (=O) O-, the miscellaneous bicyclic group-C of spiral shell (=O)-, Miscellaneous bicyclic group-the C of spiral shell (=O) O-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-, spiral shell bicyclic group-C (= O)N(R5Miscellaneous bicyclic group-the C of)-, spiral shell (=O) N (R5)-, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(= O)tN(R6)-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, R6R5N- alkoxies, R5S(=O)tAlkane Oxygroup, R5R6N-C (=O)-alkoxy, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle- (CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(= O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, - OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or it is wherein fragrant Base-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base- (CH2)p-G-(CH2)mCan F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyanogen be selected from by one or more The substituent group of base replaces;
R2Can be identical or different, it is each independently hydrogen, alkyl, halogenated alkyl, alkyl acyl, hydroxyalkanoyl, halogen For alkanoyl, naphthenic base, cycloalkanoyl, alkenyl, alkenyl alkanoyl, alkynyl, alkynyl alkanoyl, aryl, fragrant acyl Base, heteroaryl, 4-hetaroylpyrazol, heterocycle alkanoyl, Heterocyclylalkyl, heterocyclylacyl, heterocycle alkanoyl, nitrine Base alkyl, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base-C (=O)-condenses miscellaneous bicyclic group-C (=O)-, thick Bicyclic group amino-C (=O)-is closed, miscellaneous bicyclic group amino-C (=O)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell bicyclic group are condensed Aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group-C (=O)-, the miscellaneous bicyclic group-C of spiral shell (=O)-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-,-C (=O) NR5R6, R5R6N-S(=O)t-, R5S(=O)t-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m-, Heterocycle-(CH2)p-G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(= O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(= O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or Person aryl-(CH therein2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m-, Or naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, cyano, alkyl, alkenyl, Alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle;
R3Can be identical or different, it is each independently hydrogen, halogen, hydroxyl, amino, nitro, cyano, carboxyl, alkyl, Halogenated alkyl, alkoxy, alkylamino, alkyl acyl, hydroxy alkoxy base, Hydroxyalkylamino, hydroxyalkanoyl are halogenated Alkoxy, halogenated alkylamino, ohaloalkanoyl, aminoalkoxy, naphthenic base, cycloalkyl oxy, cycloalkyl amino, Cycloalkanoyl, alkenyl, alkenylalkoxy, alkenyl alkylamino, alkenyl alkanoyl, alkynyl, alkynyl alkoxy, alkynyl Alkylamino, alkynyl alkanoyl, aryl, aryloxy group, aroyl, fragrant amino, alkoxy aryl, aryl alkane amino are miscellaneous Aryl, heteroaryloxy, 4-hetaroylpyrazol, heteroaryl amino, heteroarylalkoxy, heteroarylalkylamino, heterocycle alkanoyl, Heterocyclylalkyl, heterocycle oxygroup, heterocyclylamino group, heterocyclylacyl, heterocyclylalkoxy, heterocycle alkylamino are miscellaneous Ring group alkanoyl, azido alkoxy, condensed-bicyclic base condense miscellaneous bicyclic group, and condensed-bicyclic base aliphatic condenses miscellaneous Bicyclic group aliphatic, condensed-bicyclic base oxygroup condense miscellaneous bicyclic group oxygroup, and condensed-bicyclic base amino condenses miscellaneous bicyclic group Amino, condensed-bicyclic base alkoxy condense miscellaneous bicyclic group alkoxy, and condensed-bicyclic base alkylamino condenses miscellaneous bicyclic group alkane Amino, condensed-bicyclic base oxygroup alkoxy condense miscellaneous bicyclic group oxygroup alkoxy, and condensed-bicyclic base aminoalkoxy is thick Close miscellaneous bicyclic group aminoalkoxy, condensed-bicyclic base-C (=O)-, condensed-bicyclic base-C (=O) O-, condense miscellaneous bicyclic group-C (= O)-, miscellaneous bicyclic group-C (=O) O-, condensed-bicyclic base amino-C (=O)-are condensed, miscellaneous bicyclic group amino-C (=O)-is condensed, it is thick Close bicyclic group-C (=O) N (R6)-, condenses miscellaneous bicyclic group-C (=O) N (R6)-, spiral shell bicyclic group, the miscellaneous bicyclic group of spiral shell, spiral shell bicyclic group Aliphatic, the miscellaneous bicyclic group aliphatic of spiral shell, spiral shell bicyclic group oxygroup, the miscellaneous bicyclic group oxygroup of spiral shell, spiral shell bicyclic group amino, spiral shell are miscellaneous double Ring group amino, spiral shell bicyclic group alkoxy, the miscellaneous bicyclic group alkoxy of spiral shell, spiral shell bicyclic group alkylamino, the miscellaneous bicyclic group alkylamino of spiral shell, Spiral shell bicyclic group oxygroup alkoxy, the miscellaneous bicyclic group oxygroup alkoxy of spiral shell, spiral shell bicyclic group aminoalkoxy, the miscellaneous bicyclic group amino of spiral shell Alkoxy, spiral shell bicyclic group-C (=O)-, spiral shell bicyclic group-C (=O) O-, the miscellaneous bicyclic group-C of spiral shell (=O)-, the miscellaneous bicyclic group-C of spiral shell (= O) O-, spiral shell bicyclic group amino-C (=O)-, the miscellaneous bicyclic group amino-C of spiral shell (=O)-, spiral shell bicyclic group-C (=O) N (R5)-, spiral shell is miscellaneous Bicyclic group-C (=O) N (R5)-, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O) NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- alkyl, R5S(=O)tAlkyl, R5R6N-C (=O)-alkyl, R6R5N- alkoxies, R5S(=O)tAlkoxy, R5R6N-C (=O)-alkoxy, aryl-(CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p- G-(CH2)m, or naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C (=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(= O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein aryl- (CH2)p-G-(CH2)m, heteroaryl-(CH2)p-G-(CH2)m, heterocycle-(CH2)p-G-(CH2)m, or naphthenic base- (CH2)p-G-(CH2)mCan F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyanogen be selected from by one or more The substituent group of base replaces;
R7Can be identical or different, it is each independently hydrogen, R5R6NC(=O)-, R5OC(=O)-, R5C(=O)-, R5R6NS(= O)-, R5OS(=O)-, R5S(=O)-, R5R6NS(=O)2-, R5OS(=O)2-, R5S(=O)2, aliphatic, halogenated aliphatic Race, hydroxyl group aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio group aliphatic, aryl fat Fat race, heteroaryl aliphatic, heterocycle aliphatic, naphthenic base aliphatic, aryloxy group aliphatic, heterocycle oxygroup fat Race, cycloalkyl oxy aliphatic, fragrant amino aliphatic, heterocyclylamino group aliphatic, cycloalkyl amino aliphatic, aryl, Heteroaryl, heterocycle or carbocylic radical;
Each R5And R6It independently is hydrogen, aliphatic, halogenated aliphatic, hydroxyl group aliphatic, amino aliphatic, alkoxy fat Race, alkylamino aliphatic, alkylthio group aliphatic, aromatic yl aliphat, heteroaryl aliphatic, heterocycle aliphatic, cycloalkanes Base aliphatic, aryloxy group aliphatic, heterocycle oxygroup aliphatic, cycloalkyl oxy aliphatic, fragrant amino aliphatic are miscellaneous Ring group amino aliphatic, cycloalkyl amino aliphatic, aryl, heteroaryl, heterocycle or naphthenic base;Work as R5And R6It is connected in same On one nitrogen-atoms, R5, R6It can be randomly formed substituted or non-substituted 3-7 membered rings, condensed-bicyclic or spiral shell with nitrogen-atoms It is bicyclic;The hetero atom in heterocycle, heteroaryl, condensed miscellaneous bicyclic group, the miscellaneous bicyclic group of spiral shell involved in above-mentioned group is independently The 1-5 hetero atom in N, O, S, Se;
Above-mentioned R1, R2, R3, R4, R5, R6, R7Group can appoint by deuterium, halogen, hydroxyl, methylol, carboxyl, acetyl ammonia Base, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, naphthenic base, Alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine radicals, Cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, and aryl is miscellaneous Aryl, the substitution of one or more of heterocycle.
2. compound according to claim 1 is general formula III and IV compounds represented, or shown in general formula III and IV The stereoisomer geometric isomer of compound, tautomer, nitrogen oxides, raceme, hydrate, solvate, metabolism Product, pharmaceutically acceptable salt or prodrug：
,
Wherein T1, T2, T3, T4, separate is N or CR1, and at most there are three can be N; V1, V2, V3, V4, V5Separate is N or CR4, and as many as there are three can be N; “" it is singly-bound or to be not present;Each R1, R2, R3, R4As follows：
Each R1, R4Can be identical or different, it is each independently H, F, Cl, Br, I, hydroxyl, amino, nitro, cyanogen Base, carboxyl, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkoxies, C1-C20 alkylaminos, C1-C20 alkyl Acyl group, hydroxyl C1-C20 alkoxies, hydroxyl C1-C20 alkylaminos, hydroxyl C1-C20 alkanoyls, C1-C20 halogenated alkoxies, The halogenated alkylaminos of C1-C20, C1-C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 rings Alkyl oxy, C3-C10 cycloalkyl aminos, C3-C10 cycloalkanoyls, C2-C7 alkenyls, C2-C7 alkynyls, C5-C10 virtues Base, C5-C10 aryloxy group, C5-C10 aroyls, C5-C10 fragrant aminos, C5-C10 aryl C1-C5 alkoxies, C5-C10 virtues Base alkylamino, C5-C12 heteroaryls, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5- C12 heteroaryl C1-C5 alkoxies, C5-C12 heteroaryl C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, C4- C12 Heterocyclylalkyls, C4-C12 heterocycle oxygroups, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycles Base C1-C5 alkoxies, C4-C12 heterocycle C1-C5 alkylaminos, C4-C12 heterocycle C1-C5 alkanoyls, R6R5N-, -C(= O)NR5R6, -OC(=O)NR5R6, -OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)- R6, R5R6N-S(=O)t-, R5S(=O)t-, R5S(=O)tN(R6)-, R6R5N- C1-C5 alkyl, R5S(=O)t- C1-C5 alkane Base, R5R6N-C (=O)-C1-C5 alkyl, R6R5N-C1-C5 alkoxies, R5S(=O)t- C1-C5 alkoxies, R5R6N-C(=O)- C1-C5 alkoxies, C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m-, C4-C12 Heterocycle-(CH2)p-G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(= O), S(=O)2,C(=O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, - (R5)N-S(=O)t-, -OS(=O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 Or 4;Or wherein C5-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m-, C4-C12 Heterocycle-(CH2)p-G-(CH2)m, or C3-C1 naphthenic base-(CH2)p-G-(CH2)mCan F be selected from by one or more, The substituent group of Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano replaces;
R2It is each independently H, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkyl acyls, C1-C20 hydroxyl alkane Acyl group, C1-C20 ohaloalkanoyls, C3-C10 naphthenic base, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkenyls Alkanoyl, C2-C8 alkynyls, C2-C8 alkynyl alkanoyls, C6-C10 aryl, C6-C10 aroyls, C5-C12 heteroaryls, C5-C12 4-hetaroylpyrazols, C4-C12 heterocycle alkanoyls, C4-C12 Heterocyclylalkyls, C4-C12 heterocyclylacyls, C4-C12 Heterocycle C1-C6 alkanoyls, C5-C12 condensed-bicyclic bases, C5-C12 condense miscellaneous bicyclic group ,-C (=O) NR5R6, R5R6N-S (=O)t-, R5S(=O)t-, R6R5N-C1-C6 alkyl, R5S(=O)t- C1-C6 alkyl, R5R6N-C (=O)-C1-C6 alkyl, C6-C10 aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-(CH2)p- G-(CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(= O), -C(=O)N(R5)-, -OC(=O)N(R5)-, -OC(=O)-, -(R5)N-S(=O)t-, -OS(=O)t, or-OS (= O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein C6-C10 aryl-(CH2)p- G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-(CH2)p-G-(CH2)m, or C3- C10 naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, cyano, alkyl, alkenyl, Alkynyl, alkoxy, aryl, heteroaryl, carbocylic radical, the substituent group substitution of heterocycle;
R3It is each independently H, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, carboxyl, C1-C20 alkyl, C1-C20 halogenated alkyls, C1-C20 alkoxies, C1-C20 alkylaminos, C1-C20 alkyl acyls, hydroxyl C1-C20 alkoxies, Hydroxyl C1-C20 alkylaminos, hydroxyl C1-C20 alkanoyls, C1-C20 halogenated alkoxies, the halogenated alkylaminos of C1-C20, C1- C20 ohaloalkanoyls, C1-C20 aminoalkoxies, C3-C10 naphthenic base, C3-C10 cycloalkyl oxies, C3-C10 naphthenic base Amino, C3-C10 cycloalkanoyls, C2-C8 alkenyls, C2-C8 alkynyls, C6-C10 aryl, C6-C10 aryloxy group, C6- C10 aroyls, C6-C10 fragrant aminos, C6-C10 aryl C1-C6 alkoxies, C6-C10 aryl alkane aminos, C5-C12 heteroaryls Base, C5-C12 heteroaryloxies, C5-C12 4-hetaroylpyrazols, C5-C12 heteroaryl amino, C5-C12 heteroaryl C1-C6 alkoxies, C5-C12 heteroaryl C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 alkanoyls, C4-C12 Heterocyclylalkyls, C4-C12 heterocycles Base oxygroup, C4-C12 heterocyclylamino groups, C4-C12 heterocyclylacyls, C4-C12 heterocycle C1-C6 alkoxies, C4-C12 are miscellaneous Ring group C1-C6 alkylaminos, C4-C12 heterocycle C1-C6 alkanoyls, R6R5N-, -C(=O)NR5R6, -OC(=O)NR5R6, - OC(=O)OR5, -N(R5)C(=O)NR5R6, -N(R5)C(=O)OR6, -N(R5)C(=O)-R6, R5R6N-S(=O)t-, R5S(= O)t-, R5S(=O)tN(R6)-, R6R5N- C1-C6 alkyl, R5S(=O)t- C1-C6 alkyl, R5R6N-C (=O)-C1-C6 alkane Base, R6R5N-C1-C6 alkoxies, R5S(=O)t- C1-C6 alkoxies, R5R6N-C (=O)-C1-C6 alkoxies, C6-C10 virtues Base-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-(CH2)p-G- (CH2)m, or C3-C10 naphthenic base-(CH2)p-G-(CH2)m, wherein G is O, S, NR7, S(=O), S(=O)2,C(=O), -C(=O)N(R6)-, -OC(=O)N(R5)-, -OC(=O)-, -N(R5)C(=O)N(R5)-, -(R5)N-S(=O)t-, -OS(= O)t, or-OS (=O)tN(R5)-;T is l or 2;P and m is each independently 0, l, 2,3 or 4;Or wherein C6-C10 Aryl-(CH2)p-G-(CH2)m, C5-C12 heteroaryls-(CH2)p-G-(CH2)m, C4-C12 heterocycles-(CH2)p-G- (CH2)m, or C3-C1 naphthenic base-(CH2)p-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, alkyl, The substituent group of alkenyl, alkynyl, alkoxy or cyano replaces;
Wherein each R7Can be identical or different, it is each independently H, R5R6NC(=O)-, R5OC(=O)-, R5C(=O)-, R5R6NS(=O)-, R5OS(=O)-, R5S(=O)-, R5R6NS(=O)2-, R5OS(=O)2-, R5S(=O)2, C1-C3 fat Race, C1-C3 halogenated aliphatics, C1-C3 hydroxyl group aliphatics, C1-C3 amino aliphatic, C1-C3 alkoxy Cs 1-C3 fat Race, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio group C1-C3 aliphatic, C5-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycle C1-C3 aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C5- C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocycle oxygroup C1-C3 aliphatic, C3-C10 cycloalkyl oxies C1-C3 fat Race, C5-C10 fragrant amino C1-C3 aliphatic, C4-C10 heterocyclylamino group C1-C3 aliphatic, C3-C10 cycloalkyl aminos C1- C3 aliphatic, C5-C10 aryl, C5-C10 heteroaryls, C4-C10 heterocycles or C3-C10 naphthenic base;
Wherein each R5And R6It independently is H, D, C1-C3 aliphatic, C1-C3 halogenated aliphatics, C1-C3 hydroxyl group aliphatics, C1-C3 amino aliphatic, C1-C3 alkoxy C 1-C3 aliphatic, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio groups C1-C3 aliphatic, C5-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocycles C1-C3 Aliphatic, C3-C10 naphthenic base C1-C3 aliphatic, C5-C10 aryloxy group C1-C3 aliphatic, C4-C10 heterocycle oxygroups C1- C3 aliphatic, C3-C10 cycloalkyl oxy C1-C3 aliphatic, C5-C10 fragrant amino C1-C3 aliphatic, C4-C10 heterocycles Amino C1-C3 aliphatic, C3-C10 cycloalkyl amino C1-C3 aliphatic, C5-C10 aryl, C5-C10 heteroaryls, C4- C10 heterocycles or C3-C10 naphthenic base;Work as R5And R6It is connected on the same nitrogen-atoms, R5, R6It can be arbitrarily with nitrogen-atoms Form substituted or non-substituted 3-7 membered rings;
Above-mentioned R1, R2, R3, R4, R5, R6, R7Group can appoint by deuterium, halogen, hydroxyl, methylol, carboxyl, acetyl ammonia Base, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tert-butoxy）, alkylamino, naphthenic base, Alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, amino, azido (- N3), guanidine radicals, Cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, and aryl is miscellaneous Aryl, the substitution of one or more of heterocycle.
3. according to compound described in claim 1-2, wherein each R1, R4Can be identical or different, it is each independently H, D, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C5H13, C7H16, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, first Amino, ethylamino, isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino Acetyl group, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, Valeryl, caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to toluyl Base, fluoro benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls are folded Nitrogen base benzoyl, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, just Pentenyl, isopentene group, cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, Phenethyl imidazole radicals, pyridyl group, pyrrole radicals, oxazolyl, isoxazolyl, triazol radical, tetrazole base, furyl, Thienyl, thiazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, tetrahydrochysene pyrrole It mutters base, pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkane Base ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=O)- C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, phenyl- (CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group- (CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (= O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl-(CH2)P-G-(CH2)mIt can be with F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxy are selected from by one or more The substituent group of base, ethyoxyl or cyano replaces;Or above-mentioned R1, R4It is welcome by D, F, Cl, Br, I, hydroxyl, Methylol, carboxyl, acetylamino, alkyl（Such as methyl, ethyl, propyl）, alkoxy（Such as methoxyl group, ethyoxyl, tertiary fourth oxygen Base）, alkylamino, naphthenic base, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl group, sulfydryl, halogen, nitro, ammonia Base, azido (- N3), guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, aryl, heteroaryl, the substitution of one or more of heterocycle;
According to compound described in claim 1-2, wherein each R2Can be identical or different, it is each independently H, methyl, second Base, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino first Base, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl group, propiono, isopropyl Acyl group, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, valeryl, caproyl, heptan Acyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, fluoro benzoyl, P-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azidobenzoyl, benzyl, P-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene base, isopentene group, ring Propyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, phenethyl imidazole radicals, pyridyl group, Pyrrole radicals, oxazolyls, isoxazolyl, triazol radical, tetrazole base, furyl, pyranose, thienyl, thiazolyl, Piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, pyrimidine bases, Purine bases, pentose base, hexose base ,-(C=O) NH-C1-C4 alkyl, C1-C4 alkyl-NH-S (=O)2-, C1- C4 alkyl S (=O)2, phenyl-(CH2)P-G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2) m, thiazolyl-(CH2)p- G-(CH2)m, pyridyl group-(CH2)p-G-(CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S(=O), S (=O)2, C(=O);P and m is each independently 0,1,2 or 3;Or wherein C5-C10 aryl- (CH2)P-G-(CH2)mCan by one or more be selected from F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, The substituent group of propinyl, butynyl, methoxyl group, ethyoxyl or cyano replaces;Or above-mentioned R2It is welcome by D, F, Cl, Br, I, hydroxyl, hydroxyl, methylol, carboxyl, acetylamino, C1-C5 alkyl（Such as methyl, ethyl, propyl）, C1-C5 alkoxies, C1-C5 alkylaminos, trifluoromethyl, trifluoroacetyl group, sulfydryl, nitro, amino, azido (- N3), guanidine radicals, cyano, tertbutyloxycarbonyl (- Boc), carbonyl (- C=O), oxo (=O) is thio (=S), sulfonyl, One or more of phenyl replaces;
According to compound, R described in claim 1-23Can be identical or different, R3It is each independently H, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, C5H11, C6H13, C8H17, trifluoromethyl, hydroxymethyl, amino methyl, methoxyl group, ethyoxyl, tert-butoxy, methylamino, Ethylamino, isopropylamino, 3- hydroxyl-propyls, acetyl group, trifluoroacetyl group, Cyanoacetyl, methylamino acetyl Base, propiono, iso-propionyl, 2- hydroxypropanoyls, 2- aminopropionyls, 2- chlorine propionos, 2- bromine propionos, penta Acyl group, caproyl, heptanoyl group, methacrylyl, phenyl, benzoyl, p-nitrophenyl, to methyl benzoyl, Between fluoro benzoyl, p-benzoyl base, to methoxybenzoyl base, 2,4- dimethylbenzoyls, azido Benzoyl, benzyl, p-chlorobenzyl, vinyl, acrylic, allyl, n-butene base, isobutenyl, n-pentene Base, isopentene group, cyclopropyl, ring propiono, ring valeryl, cyclohexanoyl, 3- picolinoyls, naphthalene, benzene second Base imidazole radicals, pyridyl group, pyrrole radicals, oxazolyls, isoxazolyl, triazol radical, tetrazole base, furyl, thiophene Base, thiazolyl, piperidyl, piperazinyl, indyl, carbazyl, benzofuranyl tetrahydrofuran base, THP trtrahydropyranyl, Pyrimidine bases, purine bases ,-N (CH3)2,-C (C=O) NH-C1-C4 alkyl ,-OC (C=O)-NH-C1-C4 alkyl ,-OC (O=O) O-C1-C4 alkyl ,-NHC (=O) NH-C1-C4 alkyl ,-NHC (=O) O-C1-C4 alkyl ,-NHC (=O)-C1-C4 Alkyl, C1-C4 alkyl-NH-S (=O)2, C1-C4 alkyl S (=O)2, C1-C4 alkyl S (=O)2NH-, phenyl-(CH2)P- G-(CH2)m, difluorophenyl-(CH2)P-G-(CH2)m, thiazolyl-(CH2)p-G-(CH2)m, pyridyl group-(CH2)p-G- (CH2)m, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m, wherein G is O, S, S (=O), S (=O)2, C(= O);P and m is each independently 0,1,2 or 3;Or wherein C6-C10 aryl-(CH2)P-G-(CH2)mIt can be by one Or it is multiple selected from F, Cl, Br, I, methyl, ethyl, propyl, acetenyl, propinyl, butynyl, methoxyl group, second The substituent group of oxygroup or cyano replaces;Or above-mentioned R3It is welcome by D, F, Cl, Br, I, hydroxyl, hydroxyl, hydroxyl first Base, carboxyl, acetylamino, C1-C6 alkyl（Such as methyl, ethyl, propyl）, C1-C6 alkoxies, C1-C6 alkylaminos, three Methyl fluoride, trifluoroacetyl group, sulfydryl, nitro, amino, azido（-N3）, guanidine radicals, cyano, tertbutyloxycarbonyl（- Boc）, carbonyl（-C=O）, oxo（=O）, thio（=S）, sulfonyl, the substitution of one or more of phenyl.
4. according to compound described in claim 1-3, include the tautomerism of one of following structure or following one structure Body, racemic modification, the non-equal amount of mixture of enantiomter, geometric isomer, solvate, pharmaceutically may be used at stereoisomer The solvate of the salt of receiving or its salt, or prodrug:
。
5. claim 1-4 any one of them pharmaceutically acceptable salts are selected from：Hydrochloride, sulfate, phosphate, oxalic acid Salt, maleate, methane sulfonates, succinate, citrate, fumarate, glucuronate salt, formates, acetate, Succinate；The solvate of solvate or salt is selected from：Monohydrate, dihydrate, trihydrate, a methanol solvate, two Methanol solvate, an acetonitrile close object, diacetonitrile closes object, acetone conjunction object, two acetone close object, hemifumarate monohydrate, rich horse Hydrochlorate dihydrate, one ethanolates of fumarate;It is preferred that monohydrate, fumarate dihydrate, one ethyl alcohol of fumarate Close object.
6. a kind of pharmaceutical composition, it includes according to a kind of compound of claim 1-5 any one of them or several compounds Or the non-equal amount of mixture of its tautomer, stereoisomer, racemic modification, enantiomter, geometric isomer, solvation Any one or a few in the solvate of object, pharmaceutically acceptable salt or its salt is as active ingredient.
7. the pharmaceutical composition described in claim 6, it is characterised in that the pharmaceutical composition also includes that at least one pharmaceutically may be used Carrier, diluent or the excipient of receiving.
8. the pharmaceutical composition described in claim 7, it is characterised in that also comprising at least one, other are disease-resistant for the pharmaceutical composition Cytotoxic drug is specifically including but not limited to virazole, rimantadine hydrochloride, amantadine hydrochloride, acyclovir, Valaciclovir, more VACV, interferon, Zidovudine, arabinosy ladenosine, Ribavirin, Sebivo etc.;The pharmaceutical composition optimizing injection, Oral preparation, freeze drying powder injection, suspending agent etc..
9. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5, The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt Purposes of the pharmaceutical composition in preparing antiviral drugs described in any one of solvate or claim 6-8.
10. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5, The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt Pharmaceutical composition described in any one of solvate or claim 6-8 is preparing treatment and/or is preventing by respiratory syncystial Viral (RSV), herpes simplex virus (HSV), hepatitis B (HBV）, Enterovirus 71 (EV71), Coxsackie virus (Cox-B3), influenza virus (H1N1, H3N2, H5N1, H7N9), foot and mouth disease virus (FMDV), human immunodeficiency virus (HIV), the application in the drug of disease caused by SARS virus etc.;The disease include breathing problem, pneumonia, gingivostomatitis, The diseases such as keratoconjunctivitis, encephalitis, hepatitis, bleb and herpangina, enteritis, gastritis.
11. compound or its tautomer, its stereoisomer, its racemic modification described in any one of claim 1-5, The non-equal amount of mixture of its enantiomter, its geometric isomer, its solvate, its pharmaceutically acceptable salt or its salt Solvate is in anti respiratory syncytial virus (RSV), herpes simplex virus (HSV), coxsackie virus (Cox-B3), enteron aisle In the lead compound such as virus 71 (EV71), influenza virus (H1N1, H7N9), human immunodeficiency virus (HIV) Application.
12. the preparation method of compound of formula I described in claim 1 is:
;
Wherein A, B, R1, R2, R3, R4, n, k, “" definition with any of the above-described place of the present invention to A, B, R1, R2, R3, R4, n, k, “" definition;It is characterized in that it is characterized in that:
Step 1:Using substituted aryl ketone derivatives and carboxylic acid halides as raw material, acylation reaction occurs under nitrogen or argon, Obtain intermediate product 1;Acylation reaction condition is this field normal condition:In organic solvent, under alkali and acylating reagent effect Reaction, wherein acylating reagent is preferred, wherein X is halogen, preferably chlorine, bromine, iodine; R3Definition with this hair Bright any of the above-described place is to R3Definition;Alkali preferred alkali metal carbonate (preferably potassium carbonate, sodium carbonate, cesium carbonate), alkali metal Alcoholates (preferably sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, two Methylaniline, DMAP, 2,6- lutidines etc., the above-mentioned preferred dichloromethane of organic solvent, acetonitrile, benzene, toluene, Tetrahydrofuran, ether, DMF, dioxane react at 20-90 °C of temperature;
Step 2:Amide intermediate product 1 under nitrogen or argon, occurs Aldol condensation reactions and generates intermediate product 2; Aldol condensation reaction conditions are this field popular response condition:In organic solvent, react in the presence of alkali;Alkali is preferred Alkali carbonate (preferably potassium carbonate, sodium carbonate, cesium carbonate), alkali alcoholate (preferably sodium methoxide, sodium ethoxide, uncle Butanol potassium etc.), triethylamine, pyridine, sodium acetate, quinoline, imidazoles, dimethylaniline, DMAP, 2,6- lutidines Deng, the above-mentioned preferred dichloromethane of organic solvent, acetonitrile, benzene, toluene, tetrahydrofuran, ether, DMF, dioxane, It is reacted at 20-90 °C of temperature;
Step 3:After under nitrogen or argon dehydration occurs for intermediate product 2, hydrocarbonylation or acylation reaction obtain chemical combination Object I;Alkylation reaction condition is this field popular response condition:In organic solvent, reacted under alkali, the effect of hydrocarbonylation reagent, The wherein preferred R of hydrocarbonylation reagent2X, wherein X are halogen, preferably chlorine, bromine, iodine; R2Definition with any of the above-described place pair of the present invention R2Definition;Alkali preferred alkali metal carbonate (preferably potassium carbonate, sodium carbonate, cesium carbonate), alkali metal hydroxide is (preferably LiOH, NaOH, KOH), alkali metal hydride (preferably NaH, LiH, KH), alkali alcoholate (preferably sodium methoxide, Sodium ethoxide, potassium tert-butoxide etc.);Acylation reaction condition is also this field normal condition:In organic solvent, in alkali and acylated examination The lower reaction of agent effect, the wherein preferred R of acylating reagent2X (acyl chlorides) or R2OR2(acid anhydrides), wherein X are halogen, preferred chlorine, Bromine, iodine; R2Definition with any of the above-described place of the present invention to R2Definition;Alkali preferred alkali metal carbonate (preferably potassium carbonate, Sodium carbonate, cesium carbonate), alkali alcoholate (preferably sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.), triethylamine, pyridine, Sodium acetate, quinoline, imidazoles, dimethylaniline, DMAP, 2,6- lutidines etc., the above-mentioned preferred dichloro of organic solvent Methane, acetonitrile, benzene, toluene, tetrahydrofuran, ether, DMF, dioxane react at 20-90 °C of temperature.
CN201710191265.8A 2017-03-28 2017-03-28 A kind of substituted lactams compounds and its preparation method and application Pending CN108658972A (en)

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CN111100069A (en) * 2019-08-28 2020-05-05 遵义医科大学 3, 3-difluoro-3, 4-dihydroquinoline-2 (1H) -ketone compound and preparation method thereof
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