WO2017198122A1

WO2017198122A1 - Anti-influenza small molecule compound and preparation method and use thereof

Info

Publication number: WO2017198122A1
Application number: PCT/CN2017/084301
Authority: WO
Inventors: 杨胜勇; 魏于全
Original assignee: 四川大学
Priority date: 2016-05-19
Filing date: 2017-05-15
Publication date: 2017-11-23
Also published as: CN109071567A; CN109071567B

Abstract

The present invention belongs to the field of chemical medicine, and in particular, relates to an anti-influenza small molecule compound and a preparation method and use thereof. The technical problems to be solved by the invention are that there are a small number and few kinds of anti-influenza drugs able to be used clinically at present, and the anti-influenza drugs have a drug resistance, a narrow therapeutic window, great toxic side effects, poor clinical efficacy, etc. The solution of the invention to solve the technical problems is to provide an anti-influenza small molecule compound having the structure as shown in formula I. Also provided are a preparation method for and a use of the anti-influenza small molecule compound. The compound provided by the present invention may overcome the problems of drug resistance, poor efficacy and a narrow therapeutic window of the neuraminidase inhibitor and M2 ion channel inhibitor and other drugs used clinically at present, and has a great development value.

Description

抗流感小分子化合物及其制备方法和用途Anti-influenza small molecule compound, preparation method and use thereof

技术领域Technical field

本发明属于化学医药领域，具体涉及抗流感小分子化合物及其制备方法和用途。The invention belongs to the field of chemical medicine, and particularly relates to an anti-influenza small molecule compound, a preparation method thereof and use thereof.

背景技术Background technique

流行性感冒(简称流感，Flu)是由流感病毒(Influenza virus)引起的呼吸***疾病。根据病毒核蛋白和基质蛋白的抗原决定簇的差异，可将流感病毒分为甲(A)、乙(B)、丙(C)三种类型，其中A型流感最为常见，致病性强，易发生大范围流行，严重威胁人类生命与健康。禽流感病毒(Avian influenza virus)属于A型流感病毒，正常情况下仅在禽类等动物之间传播。但是有些变异株直接由禽类等动物传染给人类，给人类带来严重健康威胁，例如高致病性禽流感H5N1、H7N9等，其致死率可达30％。历史上曾发生过多次严重的流感大流行，造成了上百万人死亡，给人类社会带来严重损失。Influenza (Flu) is a respiratory disease caused by Influenza virus. According to the difference of antigenic determinants of viral nuclear proteins and matrix proteins, influenza viruses can be divided into three types: A (A), B (B), and C (C). Among them, influenza A is the most common and pathogenic. It is prone to widespread epidemics and poses a serious threat to human life and health. Avian influenza virus belongs to influenza A virus and is normally transmitted only between animals such as poultry. However, some variants are directly transmitted to humans by animals such as poultry, which pose serious health threats to humans, such as highly pathogenic avian influenza H5N1 and H7N9, with a mortality rate of 30%. There have been many serious influenza pandemics in history, causing millions of deaths and causing serious losses to human society.

预防和治疗流感，通常采用疫苗接种和抗流感药物治疗两种方法。疫苗接种是目前预防流感的一种有效措施。成年人接种后可以达到较好预防效果，但是婴幼儿、老年人等免疫力较低者接种后效果并不理想。而且流感病毒不断地变异，旧疫苗难以对抗新病毒。化学药物是治疗流感的另一种重要手段，但是迄今为止，上市抗流感化学药物数量少，应用较多的是M2离子通道抑制剂、神经氨酸酶(NA)抑制剂以及核苷类抗病毒药物。To prevent and treat influenza, it is usually treated with vaccination and anti-influenza drugs. Vaccination is an effective measure to prevent influenza. Adults can achieve better preventive effects after vaccination, but the lower immunity of infants, the elderly and other people after vaccination is not satisfactory. And the flu virus is constantly mutating, and old vaccines are difficult to fight against new viruses. Chemical drugs are another important means of treating influenza, but so far, the number of listed anti-influenza chemicals is small, and M2 ion channel inhibitors, neuraminidase (NA) inhibitors, and nucleoside anti-viruses are widely used. drug.

目前，上市的M2离子通道抑制剂仅有金刚烷胺(Amantadine，1966年上市)、金刚乙胺(Rimantadine，1987年上市)，但仅对A型流感病毒有效，且金刚烷胺具有较大中枢神经***不良反应，近年来涌现了较多耐药病毒株，耐药性成为了该类药物面临的重大问题。神经氨酸酶抑制剂(NAI)是一类强效的抗流感药物，除了FDA批准上市的奥司他韦(Oseltamivir，达菲，1999年上市)和扎拉米韦(Zanamivir，1999年上市)，还有在局部地区上市的帕拉米韦(Peramivir，日本、韩国、中国上市)和拉尼那米韦(Laninamivir，日本上市)。尽管这类药物在体外显示了较好的抗流感效果，但来自国际循证医学协作组(Cochrane Collaboration)的报告指出，在临床上，目前并无证据支持奥司他韦具有防止流感病毒传播、或降低患者住院率和并发症风险的作用。另外，患者在感染流感病毒48h后，服用奥司他韦并不能起到抗流感效果。而且NAI也出现了严重的耐药情况。核苷类代表药物是利巴韦林(Ribavirin)和法匹拉韦(Favipiravir，T-705)。利巴韦林是一种广谱抗病毒上市药物，对DNA和RNA病毒均有抑制效果，作用机制尚不明确，在体内能引起溶血性贫血、心肺方面的毒性反应，所以临床应用受限。法匹拉韦主要抑制RNA病毒的复制，与利巴韦林相比具有活性较高、细胞毒性较小的优点，目前仅在日本上市。另外，盐酸阿比朵尔(arbidol hydrochloride)是1993年在俄罗斯上市抗流感病毒药物。它的作用机制尚不明确，可能是抑制HA，通过阻止流感病毒外壳与宿主细胞细胞膜的接触、黏附和融合，抑制病毒与细胞浆膜的融合及病毒与内吞囊泡之间的膜融合而达到抗病毒作用。Currently, the listed M2 ion channel inhibitors are only amantadine (Amantadine, marketed in 1966) and rimantadine (Rimantadine, marketed in 1987), but only effective against influenza A virus, and amantadine has a larger central nervous system. In the nervous system, many drug-resistant strains have emerged in recent years, and drug resistance has become a major problem for such drugs. Neuraminidase inhibitors (NAIs) are a class of potent anti-influenza drugs, with the exception of the FDA-approved oseltamivir (Oseltamivir, Tamiflu, marketed in 1999) and Zalamivir (listed in 1999). There are also local products listed in Peramivir (Japan, Korea, China) and Laninamivir (listed in Japan). Although these drugs show better anti-influenza effects in vitro, reports from the International Copulinary Collaboration Group (Cochrane Collaboration) indicate that there is currently no evidence to support oseltamivir in preventing the spread of influenza virus. Or reduce the risk of hospitalization and risk of complications. In addition, taking oseltamivir after 48 hours of infection with the flu virus did not have an anti-influenza effect. And NAI also has serious drug resistance. Representative drugs for nucleosides are Ribavirin and Favipiravir (T-705). Ribavirin is a broad-spectrum antiviral drug that has inhibitory effects on both DNA and RNA viruses. The mechanism of action is still unclear. It can cause hemolytic anemia and cardiopulmonary toxicity in vivo, so its clinical application is limited. Fapiravir mainly inhibits the replication of RNA viruses, and has the advantages of higher activity and less cytotoxicity than ribavirin, and is currently only marketed in Japan. In addition, arcidol hydrochloride is an anti-influenza virus marketed in Russia in 1993. Its mechanism of action is still unclear, it may be to inhibit HA, by blocking the flu virus shell and The contact, adhesion and fusion of the cell membrane of the host cell inhibits the fusion of the virus with the plasma membrane and the membrane fusion between the virus and the endocytic vesicle to achieve an antiviral effect.

近年来，流感RNA聚合酶(RdRp)受到了广泛关注。RdRp是由PA、PB1和PB2三个亚基组成的异源三聚体，在流感病毒基因组转录和复制过程中发挥重要作用。流感病毒RNA的转录具有特殊的“夺帽”机制，在此过程中，PB2亚基负责识别和结合宿主前体mRNA的“帽子结构”，然后PA亚基剪切宿主mRNA得到引物，启动转录过程。抑制“夺帽”可以阻断转录过程，达到抑制流感病毒增殖的效果。因此，PB2被认为是很有前途的抗流感药物靶标，已引起了制药公司和学术研究机构的高度重视。In recent years, influenza RNA polymerase (RdRp) has received extensive attention. RdRp is a heterotrimer composed of three subunits, PA, PB1 and PB2, which play an important role in the transcription and replication of influenza virus genome. The transcription of influenza virus RNA has a special "cap" mechanism, in which the PB2 subunit is responsible for recognizing and binding to the "hat structure" of the host precursor mRNA, and then the PA subunit cleaves the host mRNA to obtain primers that initiate the transcription process. . Inhibition of "caps" can block the transcription process and achieve the effect of inhibiting the proliferation of influenza virus. Therefore, PB2 is considered to be a promising anti-influenza drug target, which has attracted the attention of pharmaceutical companies and academic research institutions.

发明内容Summary of the invention

本发明要解决的技术问题是目前临床上能运用的抗流感药物数量和种类都较少，而且这些抗流感药物存在耐药性、治疗窗窄、毒副作用大、临床疗效差等问题。The technical problem to be solved by the present invention is that the number and types of anti-influenza drugs currently available in clinical practice are small, and these anti-influenza drugs have problems such as drug resistance, narrow therapeutic window, large side effects, and poor clinical efficacy.

本发明解决上述技术问题的方案是提供一种抗流感小分子化合物，其结构如式Ⅰ所示：The solution to the above technical problem of the present invention is to provide an anti-influenza small molecule compound having the structure shown in Formula I:

其中，X为-H、卤素、氰基、-CF₃、C1～C4烷氧基、C1～C4烷基、氨基或C1～C3氨酰基；Wherein X is -H, halogen, cyano, -CF ₃ , C1 - C4 alkoxy, C1 - C4 alkyl, amino or C1 - C3 aminoacyl;

L为饱和或不饱和的4～10元杂环烷基、饱和或不饱和的C4～C10环烷基；所述饱和或不饱和的4～10元杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3；L is a saturated or unsaturated 4 to 10 membered heterocycloalkyl group, a saturated or unsaturated C4 to C10 cycloalkyl group; and the hetero atom of the saturated or unsaturated 4 to 10 membered heterocycloalkyl group is N, O. Or S, the number of the hetero atoms is 1-3;

R₁和R₂组合成取代或未取代的5～8元饱和杂环烷基，所述的杂原子为N，杂原子个数为1～2个；所述取代5～8元饱和杂环烷基的取代基为-H、-NH₂、卤素、-CF₃、氰基、C1～C4烷基、

a、b为0～4；R ₁ and R _{2 are} combined to form a substituted or unsubstituted 5-8 membered saturated heterocycloalkyl group, said hetero atom is N, and the number of hetero atoms is 1-2; said substituted 5-8-membered saturated heterocyclic ring The substituent of the alkyl group is -H, -NH ₂ , halogen, -CF ₃ , cyano, C1 to C4 alkyl,

a, b is 0 to 4;

或者R₁为-H或C1～C10烷基；R₂为

n为0～4；Or R ₁ is -H or C1 - C10 alkyl; R ₂ is

n is 0 to 4;

R₄、R₅独立的为-H或C1～C10烷基；或者R₄和R₅组合形成环，所述的环为C5～C10环烷基、C5～C10的桥环烷基、C5～C10的稠环烷基、5～10元饱和杂环烷基、5～10元桥环杂环烷基或5～10元螺环杂环烷基；所述5～10元饱和杂环烷基、5～10元桥环杂环烷基、5～10元螺环杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3；R₃为

R₉为C1～C5烷基，R₁₀ 为氢或C1～C5烷基；R ₄ and R _{5 are} independently -H or C1 to C10 alkyl; or R ₄ and R _{5 are} combined to form a ring, said ring being a C5-C10 cycloalkyl group, a C5-C10 bridged cycloalkyl group, C5~ a fused cycloalkyl group of C10, a 5- to 10-membered saturated heterocycloalkyl group, a 5- to 10-membered bridged heterocycloalkyl group or a 5- to 10-membered spirocycloheterocycloalkyl group; said 5- to 10-membered saturated heterocycloalkyl group The hetero atom of the 5- to 10-membered bridged heterocycloalkyl group and the 5- to 10-membered spirocycloheterocycloalkyl group is N, O or S, and the number of the hetero atom is 1-3; R ₃ is

R ₉ is a C1-C5 alkyl group, and R ₁₀ is hydrogen or a C1-C5 alkyl group;

R₆、R₇独立的为C1～C4烷基、取代或未取代的C5～C10芳基、取代或未取代的苄基、

或-CONH₂；所述取代C5～C10芳基或苄基的取代基为C1～C6烷基、C1～C6烷氧基、卤素、-CF₃或氰基；a、b为0～4；R ₆ and R _{7 are} independently a C 1 -C 4 alkyl group, a substituted or unsubstituted C 5 -C 10 aryl group, a substituted or unsubstituted benzyl group,

Or -CONH _2; said substituted C5 ~ C10 aryl group or a benzyl group substituents are C1 ~ C6 alkyl group, C1 ~ C6 alkoxy, halogen, -CF _3, or a cyano group; a, b is from 0 to 4;

R₈为取代或未取代的C5～C10环烷基、取代或未取代的5～10元饱和或不饱和杂环、取代或未取代的C5～C10不饱和环或取代或未取代的C5～C15的桥环烷基；所述5～10元饱和或不饱和杂环的杂原子为N、O、S，杂原子个数为1～3个；所述取代C5～C10环烷基的取代基为-H、

卤素、C1～C4烷基或-COOH；所述取代C5～C10不饱和环的取代基为-H、-OH、-SO₂NH₂、-CF₃、卤素、C1～C4烷基或-COOH；所述取代5～10元饱和或不饱和杂环的取代基为卤素取代的苄基、卤素、苯基、苄基、-OH、-CF₃、C1～C4烷基、C1～C4羰基、-COOH或-NH₂；所述取代C5～C15的桥环烷基的取代基为-H、-OH、-COOH、C1～C4烷基或-NH₂；a为0～4。R ₈ is a substituted or unsubstituted C5-C10 cycloalkyl group, a substituted or unsubstituted 5-10 membered saturated or unsaturated heterocyclic ring, a substituted or unsubstituted C5-C10 unsaturated ring or a substituted or unsubstituted C5~ a bridged cycloalkyl group of C15; wherein the hetero atom of the 5- to 10-membered saturated or unsaturated heterocyclic ring is N, O, and S, and the number of hetero atoms is 1 to 3; and the substitution of the substituted C5-C10 cycloalkyl group Base is -H,

Halogen, C1-C4 alkyl or -COOH; the substituent of the substituted C5-C10 unsaturated ring is -H, -OH, -SO ₂ NH ₂ , -CF ₃ , halogen, C1 - C4 alkyl or -COOH The substituent substituted with a 5- to 10-membered saturated or unsaturated heterocyclic ring is a halogen-substituted benzyl group, a halogen, a phenyl group, a benzyl group, an -OH group, a -CF ₃ group, a C1 to C4 alkyl group, a C1 to C4 carbonyl group, -COOH or -NH ₂ ; the substituent of the substituted C5-C15 bridged cycloalkyl group is -H, -OH, -COOH, C1 - C4 alkyl or -NH ₂ ; a is 0-4.

作为本发明优选的方案，当R₁为H，R₂为

R₃为

时，其结构如式Ⅱ所示：As a preferred embodiment of the present invention, when R ₁ is H, R ₂ is

R ₃ is

The structure is as shown in Equation II:

其中，X为卤素或C1～C4烷基；L为饱和或不饱和的5～8元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～8元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₄、R₅独立地为-H或C1～C8烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基、C5～C8的稠环烷基、5～8元饱和杂环烷基、5～8元桥环杂环烷基或5～10元螺环杂环烷基；所述5～8元饱和杂环烷基、5～8元桥环杂环烷基、5～10元螺环杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3。Wherein X is a halogen or a C1-C4 alkyl group; L is a saturated or unsaturated 5- to 8-membered heterocycloalkyl group, a saturated or unsaturated C5-C8 cycloalkyl group; and the 5- to 8-membered heterocycloalkyl group The hetero atom is N, O or S, the hetero atom is 1-3; R ₄ , R _{5 are} independently -H or C1 - C8 alkyl; or R ₄ and R _{5 are} combined to form a ring, The ring is a C5-C8 cycloalkyl group, a C5-C8 bridged cycloalkyl group, a C5-C8 fused ring alkyl group, a 5- to 8-membered saturated heterocycloalkyl group, a 5- to 8-membered bridged heterocycloalkyl group or 5 ～10-membered spirocycloheterocycloalkyl; the hetero atom of the 5- to 8-membered saturated heterocycloalkyl group, the 5- to 8-membered bridged heterocycloalkyl group, and the 5- to 10-membered spirocycloheterocycloalkyl group is N, O Or S, the number of the hetero atoms is 1-3.

优选的，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基、C5～C8的稠环烷基、5～8元饱和杂环烷基、5～8元桥环杂环烷基或5～10元螺环杂环烷基；所述5～8元饱和杂环烷基、5～8元桥环杂环烷基、5～10元螺环杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3。 Preferably, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C8 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. Or O or S, the hetero atom is 1 to 3; R ₄ and R _{5 are} independently -H or C1 to C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, and the ring is C5 - C8 cycloalkyl, C5-C8 bridged cycloalkyl, C5-C8 fused cycloalkyl, 5- to 8-membered saturated heterocycloalkyl, 5- to 8-membered bridged heterocycloalkyl or 5- to 10-membered spiro a heterocycloalkyl group; the hetero atom of the 5- to 8-membered saturated heterocycloalkyl group, the 5- to 8-membered bridged heterocycloalkyl group, and the 5- to 10-membered spirocycloheterocycloalkyl group is N, O or S, The number of heteroatoms is 1 to 3.

再进一步优选的，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基、C5～C8的稠环烷基或5～8元饱和杂环烷基；所述5～8元饱和杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3。Still more preferably, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and a hetero atom of the 5- to 6-membered heterocycloalkyl group. Is N, O or S, the hetero atom is 1-3; R ₄ , R _{5 are} independently -H or C1 - C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, the ring is a C5-C8 cycloalkyl group, a C5-C8 bridged cycloalkyl group, a C5-C8 fused ring alkyl group or a 5- to 8-membered saturated heterocycloalkyl group; and the hetero atom of the 5- to 8-membered saturated heterocycloalkyl group is N, O or S, the number of the hetero atoms is 1-3.

更进一步优选的，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基、C5～C8的稠环烷基或5～8元饱和杂环烷基；所述5～8元饱和杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3。Still more preferably, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and a hetero atom of the 5- to 6-membered heterocycloalkyl group; Is N, O or S, the hetero atom is 1-2; R ₄ , R _{5 are} independently -H or C1 - C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, the ring is a C5-C8 cycloalkyl group, a C5-C8 bridged cycloalkyl group, a C5-C8 fused ring alkyl group or a 5- to 8-membered saturated heterocycloalkyl group; and the hetero atom of the 5- to 8-membered saturated heterocycloalkyl group is N, O or S, the number of the hetero atoms is 1-3.

优选的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基、C5～C8的稠环烷基或5～8元饱和杂环烷基；所述5～8元饱和杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～2。Preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N, O. Or S, the hetero atom is 1 or 2; R ₄ and R _{5 are} independently -H or C1 - C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, and the ring is a C5 to C8 ring. An alkyl group, a C5-C8 bridged cycloalkyl group, a C5-C8 fused ring alkyl group or a 5- to 8-membered saturated heterocycloalkyl group; and the hetero atom of the 5- to 8-membered saturated heterocycloalkyl group is N, O or S, the number of the hetero atoms is 1-2.

进一步优选的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基或C5～C8的稠环烷基。Further preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. O or S, the hetero atom is 1 or 2; R ₄ and R _{5 are} independently -H or C1 - C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, and the ring is C5 - C8 A cycloalkyl group, a C5-C8 bridged cycloalkyl group or a C5-C8 fused ring alkyl group.

更进一步优选的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基或C5～C8的桥环烷基。Still more preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. Or O or S, wherein the hetero atom is 1-2; R ₄ and R _{5 are} independently -H or C1 - C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, and the ring is C5 - C8 cycloalkyl or C5-C8 bridged cycloalkyl.

最优的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1个；R₄、R₅独立地为-H或C1～C4烷基；或R₁和R₂组合形成环，所述的环为C5～C6环烷基或C5～C8的桥环烷基。Most preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. O or S, the hetero atom is one; R ₄ and R _{5 are} independently -H or C1 to C4 alkyl; or R ₁ and R _{2 are} combined to form a ring, and the ring is a C5 to C6 naphthenic ring. A group or a C5 to C8 bridged cycloalkyl group.

上述抗流感小分子化合物中，当R₁为H，R₂为

时，其结构如式Ⅲ所示：In the above anti-influenza small molecule compound, when R ₁ is H, R ₂ is

When the structure is as shown in Equation III:

其中，X为卤素或C1～C4烷基；L为饱和或不饱和的5～8元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～8元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₆、R₇独立的为C1～C4烷基、取代或未取代的C5～C8芳基、取代或未取代的苄基、

或-CONH₂；所述取代C5～C8芳基或苄基的取代基为C1～C4烷基、卤素、-CF₃或氰基；a、b为0～3。Wherein X is a halogen or a C1-C4 alkyl group; L is a saturated or unsaturated 5- to 8-membered heterocycloalkyl group, a saturated or unsaturated C5-C8 cycloalkyl group; and the 5- to 8-membered heterocycloalkyl group heteroatoms are N, O or S, the heteroatom is 1 to 3; R _6, R ₇ independently is C1 ~ C4 alkyl group, a substituted or unsubstituted C5 ~ C8 aryl group, a substituted or unsubstituted Benzyl,

Or -CONH _2; C5 ~ C8 said substituted aryl group or a benzyl group substituents are C1 ~ C4 alkyl, halogen, -CF _3, or a cyano group; a, b is 0 to 3.

优选的，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₆、R₇独立的为C1～C4烷基、取代或未取代的C5～C6芳基、取代或未取代的苄基、

或-CONH₂；所述取代C5～C6芳基或苄基的取代基为C1～C4烷基、卤素、-CF₃或氰基；a、b为0～2。Preferably, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C8 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. , O or S, the hetero atom is 1 to 3; R ₆ and R _{7 are} independently a C1 to C4 alkyl group, a substituted or unsubstituted C5-C6 aryl group, a substituted or unsubstituted benzyl group,

₂ or -CONH2; said substituted C5 - C6 unsubstituted aryl group or benzyl group is C1 ~ C4 alkyl, halogen, -CF _3, or a cyano group; a, b is from 0 to 2.

再进一步优选的，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₆、R₇独立的为C1～C4烷基、取代或未取代的苯基、取代或未取代的苄基、

或-CONH₂；所述取代苯基或苄基的取代基为C1～C4烷基或卤素；a、b为0～2。Still more preferably, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and a hetero atom of the 5- to 6-membered heterocycloalkyl group. Is N, O or S, the hetero atom is 1 to 3; R ₆ and R _{7 are} independently a C1 to C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group,

Or -CONH ₂ ; the substituent of the substituted phenyl or benzyl group is a C1-C4 alkyl group or a halogen; and a and b are 0-2.

更进一步优选的，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；R₆、R₇独立的为C1～C4烷基、取代或未取代的苯基、取代或未取代的苄基、

或-CONH₂；所述取代苯基或苄基的取代基为C1～C4烷基、-F、-Cl或-Br；a、b为0～2。Still more preferably, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and a hetero atom of the 5- to 6-membered heterocycloalkyl group; Is N, O or S, wherein the hetero atom is 1-2; R ₆ and R _{7 are} independently a C 1 -C 4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group,

Or -CONH ₂ ; the substituent of the substituted phenyl or benzyl group is a C1-C4 alkyl group, -F, -Cl or -Br; a and b are 0-2.

最优的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1个；R₆、R₇独立的为C1～C4烷基、取代或未取代的苯基、取代或未取代的苄基、

或-CONH₂；所述取代苯基或苄基的取代基为C1～C4烷基、-F、-Cl或-Br；a、b为0～2。Most preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. O or S, the hetero atom is one; R ₆ and R _{7 are} independently a C1 to C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group,

上述抗流感小分子化合物，当R₁为H，R₂为

时，其结构如式Ⅳ所示：The above-mentioned anti-influenza small molecule compound, when R ₁ is H, R ₂ is

When the structure is as shown in formula IV:

其中，n为0～4，X为卤素或C1～C4烷基；L为饱和或不饱和的5～8元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～8元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；Wherein n is 0 to 4, X is a halogen or a C1 to C4 alkyl group; L is a saturated or unsaturated 5 to 8 membered heterocycloalkyl group, a saturated or unsaturated C5 to C8 cycloalkyl group; The hetero atom of the 8-membered heterocycloalkyl group is N, O or S, and the hetero atom is 1 to 3;

R₈为取代或未取代的C5～C8环烷基、取代或未取代的5～8元芳杂基、取代或未取代的5～8元饱和杂环烷基、取代或未取代的5～8元不饱和杂环烷基、取代或未取代的C5～C10芳基、取代或未取代的C5～C10不饱和环烷基或取代或未取代的C5～C12的桥环烷基；所述5～8元饱和或不饱和杂环烷基、5～8元芳杂基的杂原子为N、O、S，杂原子个数为1～3个；所述取代C5～C8环烷基的取代基为-H或所述取代5～8元芳杂基、5～8元饱和杂环烷基、5～8元不饱和杂环烷基的取代基为卤素取代的苄基、卤素、苯基、苄基、-CF₃或C1～C4羰基；所述取代C5～C10芳基的取代基为卤素、-OH、-SO₂NH₂、-CF₃或-COOH；所述取代C5～C10不饱和环烷基的取代基为-OH、卤素、-CF₃或-COOH；所述取代C5～C12的桥环烷基的取代基为-H、-OH或-COOH，a为0～3。R ₈ is a substituted or unsubstituted C 5 -C 8 cycloalkyl group, a substituted or unsubstituted 5-8 membered aryl group, a substituted or unsubstituted 5-8 membered saturated heterocycloalkyl group, a substituted or unsubstituted 5 ～ 8-membered unsaturated heterocycloalkyl, substituted or unsubstituted C5-C10 aryl, substituted or unsubstituted C5-C10 unsaturated cycloalkyl or substituted or unsubstituted C5-C12 bridged cycloalkyl; The heteroatoms of a 5- to 8-membered saturated or unsaturated heterocycloalkyl group and a 5- to 8-membered aryl group are N, O, and S, and the number of heteroatoms is 1 to 3; and the substituted C5-C8 cycloalkyl group The substituent is -H or The substituent of the substituted 5- to 8-membered aryl group, the 5- to 8-membered saturated heterocycloalkyl group, and the 5- to 8-membered unsaturated heterocycloalkyl group is a halogen-substituted benzyl group, a halogen group, a phenyl group, a benzyl group, and a CF ₃ or a C 1 -C 4 carbonyl group; the substituent of the substituted C 5 -C 10 aryl group is a halogen, -OH, -SO ₂ NH ₂ , -CF ₃ or -COOH; the substituted C5-C10 unsaturated cycloalkyl group The substituent is -OH, halogen, -CF ₃ or -COOH; the substituent of the substituted C5 to C12 bridged cycloalkyl group is -H, -OH or -COOH, and a is 0 to 3.

优选的，n为0～4，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；Preferably, n is 0 to 4, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C8 cycloalkyl group; and the 5- to 6-membered heterocycloalkane The hetero atom of the group is N, O or S, and the hetero atom is 1 to 3;

R₈为取代或未取代的C5～C6环烷基、取代或未取代的5～6元芳杂基、取代或未取代的5～6元饱和杂环烷基、取代或未取代的5～6元不饱和杂环烷基、取代或未取代的C5～C8芳基、取代或未取代的C5～C10不饱和环烷基或取代或未取代的C5～C12的桥环烷基；所述5～6元饱和或不饱和杂环烷基、5～6元芳杂基的杂原子为N、O、S，杂原子个数为1～2个；所述取代C5～C6环烷基的取代基为-H或

所述取代5～6元芳杂基、5～6元饱和杂环烷基、5～6元不饱和杂环烷基的取代基为卤素取代的苄基、卤素、苯基、苄基、-CF₃或C1～C3羰基；所述取代C5～C8芳基的取代基为卤素、-OH、-SO₂NH₂、-CF₃或-COOH；所述取代C5～C10不饱和环烷基的取代基为-OH、-CF₃或-COOH；所述取代C5～C12的桥环烷基的取代基为-H、-OH或-COOH；a为0～3。R ₈ is a substituted or unsubstituted C 5 -C 6 cycloalkyl group, a substituted or unsubstituted 5-6-membered aryl group, a substituted or unsubstituted 5-6-membered saturated heterocycloalkyl group, a substituted or unsubstituted 5 ～ a 6-membered unsaturated heterocycloalkyl group, a substituted or unsubstituted C5-C8 aryl group, a substituted or unsubstituted C5-C10 unsaturated cycloalkyl group or a substituted or unsubstituted C5-C12 bridged cycloalkyl group; The hetero atom of a 5- to 6-membered saturated or unsaturated heterocycloalkyl group or a 5- to 6-membered aryl group is N, O, and S, and the number of hetero atoms is 1-2; and the substituted C5-C6 cycloalkyl group The substituent is -H or

The substituent of the substituted 5- to 6-membered arylhetero group, the 5- to 6-membered saturated heterocycloalkyl group, and the 5- to 6-membered unsaturated heterocycloalkyl group is a halogen-substituted benzyl group, a halogen group, a phenyl group, a benzyl group, and a CF ₃ or C1 to C3 carbonyl group; the substituent of the substituted C5 to C8 aryl group is a halogen, -OH, -SO ₂ NH ₂ , -CF ₃ or -COOH; the substituted C5-C10 unsaturated cycloalkyl group The substituent is -OH, -CF ₃ or -COOH; the substituent of the substituted C5-C12 bridged cycloalkyl group is -H, -OH or -COOH; a is 0-3.

更优选的，n为0～3，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；More preferably, n is 0 to 3, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the 5- to 6-membered heterocyclic ring The hetero atom of the alkyl group is N, O or S, and the hetero atom is 1 or 2;

R₈为取代或未取代的C5～C6环烷基、取代或未取代的5～6元芳杂基、取代或未取代的5～6元饱和杂环烷基、取代或未取代的5～6元不饱和杂环烷基、取代或未取代的C5～C6芳基、取代或未取代的C5～C10不饱和环烷基或取代或未取代的C5～C12的桥环烷基；所述5～6元饱和或不饱和杂环烷基、5～6元芳杂基的杂原子为N、O、S，杂原子个数为1～2个；所述取代C5～C6环烷基的取代基为-H或

所述取代 5～6元芳杂基、5～6元饱和杂环烷基、5～6元不饱和杂环烷基的取代基为卤素取代的苄基、卤素、苯基、苄基、-CF₃或C1～C3羰基；所述取代C5～C6芳基的取代基为卤素、-OH、-SO₂NH₂、-CF₃或-COOH；所述取代C5～C10不饱和环烷基的取代基为-OH、-CF₃或-COOH；所述取代C5～C12的桥环烷基的取代基为-H、-OH或-COOH；a为0～3。R ₈ is a substituted or unsubstituted C 5 -C 6 cycloalkyl group, a substituted or unsubstituted 5-6-membered aryl group, a substituted or unsubstituted 5-6-membered saturated heterocycloalkyl group, a substituted or unsubstituted 5 ～ a 6-membered unsaturated heterocycloalkyl group, a substituted or unsubstituted C5-C6 aryl group, a substituted or unsubstituted C5-C10 unsaturated cycloalkyl group or a substituted or unsubstituted C5-C12 bridged cycloalkyl group; The hetero atom of a 5- to 6-membered saturated or unsaturated heterocycloalkyl group or a 5- to 6-membered aryl group is N, O, and S, and the number of hetero atoms is 1-2; and the substituted C5-C6 cycloalkyl group The substituent is -H or

The substituent of the substituted 5- to 6-membered arylhetero group, the 5- to 6-membered saturated heterocycloalkyl group, and the 5- to 6-membered unsaturated heterocycloalkyl group is a halogen-substituted benzyl group, a halogen group, a phenyl group, a benzyl group, and a CF ₃ or C1 to C3 carbonyl group; the substituent of the substituted C5 to C6 aryl group is a halogen, -OH, -SO ₂ NH ₂ , -CF ₃ or -COOH; the substituted C5-C10 unsaturated cycloalkyl group substituent is -OH, -CF ₃ or -COOH; a substituted bridged cycloalkyl of C5 ~ C12 substituents are -H, -OH, or -COOH; a is 0 to 3.

进一步优选的，n为0～3，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；Further preferably, n is 0 to 3, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the 5- to 6-membered heterocycloalkyl group The hetero atom is N, O or S, and the hetero atom is 1 or 2;

R₈为取代或未取代的C5～C6环烷基、取代或未取代的5～6元芳杂基、取代或未取代的5～6元饱和杂环烷基、取代或未取代的5～6元不饱和杂环烷基、取代或未取代的苯基、取代或未取代的C5～C10不饱和环烷基或取代或未取代的C5～C12的桥环烷基；所述5～6元饱和或不饱和杂环烷基、5～6元芳杂基的杂原子为N、O，杂原子个数为1～2个；所述取代C5～C6环烷基的取代基为-H或

所述取代5～6元芳杂基、5～6元饱和杂环烷基、5～6元不饱和杂环烷基的取代基为氟取代的苄基、-F、-Cl、-Br、苯基、苄基、-CF₃或C1～C2羰基；所述取代苯基的取代基为-F、-Cl、-Br、-OH、-SO₂NH₂、-CF₃或-COOH；所述取代C5～C10不饱和环烷基的取代基为-OH、-CF₃或-COOH；所述取代C5～C12的桥环烷基的取代基为-H、-OH或-COOH；a为0～2。R ₈ is a substituted or unsubstituted C 5 -C 6 cycloalkyl group, a substituted or unsubstituted 5-6-membered aryl group, a substituted or unsubstituted 5-6-membered saturated heterocycloalkyl group, a substituted or unsubstituted 5 ～ a 6-membered unsaturated heterocycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C5-C10 unsaturated cycloalkyl group or a substituted or unsubstituted C5-C12 bridged cycloalkyl group; said 5-6 The hetero atom of the monosaturated or unsaturated heterocycloalkyl group, the 5- to 6-membered aryl group is N, O, and the number of hetero atoms is 1-2; the substituent of the substituted C5-C6 cycloalkyl group is -H or

The substituent of the substituted 5- to 6-membered arylhetero group, the 5- to 6-membered saturated heterocycloalkyl group, and the 5- to 6-membered unsaturated heterocycloalkyl group is a fluorine-substituted benzyl group, -F, -Cl, -Br, a phenyl group, a benzyl group, a -CF ₃ or a C1 to C2 carbonyl group; the substituent of the substituted phenyl group is -F, -Cl, -Br, -OH, -SO ₂ NH ₂ , -CF ₃ or -COOH; The substituent of the substituted C5-C10 unsaturated cycloalkyl group is -OH, -CF ₃ or -COOH; the substituent of the substituted C5-C12 bridged cycloalkyl group is -H, -OH or -COOH; 0 to 2.

最优的，n为0～3，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1个；Most preferably, n is 0 to 3, X is a halogen; L is an unsaturated 5 to 6 membered heterocycloalkyl group, a saturated or unsaturated C5 to C6 cycloalkyl group; and the 5 to 6 membered heterocycloalkyl group The hetero atom is N, O or S, and the hetero atom is one;

R₈为

R ₈ is

上述抗流感小分子化合物的具体结构式为： The specific structural formula of the above-mentioned anti-influenza small molecule compound is:

本发明还提供了上述抗流感小分子化合物的制备方法，其合成路线为：The invention also provides a preparation method of the above-mentioned anti-influenza small molecule compound, wherein the synthetic route is:

a, b is 0 to 4;

或者R₁为-H或C1～C10烷基；R₂为

n为0～4；Or R ₁ is -H or C1 - C10 alkyl; R ₂ is

n is 0 to 4;

R₉为C1～C5烷基，R₁₀为氢或C1～C5烷基；R ₄ and R _{5 are} independently -H or C1 to C10 alkyl; or R ₄ and R _{5 are} combined to form a ring, said ring being a C5-C10 cycloalkyl group, a C5-C10 bridged cycloalkyl group, C5~ a fused cycloalkyl group of C10, a 5- to 10-membered saturated heterocycloalkyl group, a 5- to 10-membered bridged heterocycloalkyl group or a 5- to 10-membered spirocycloheterocycloalkyl group; said 5- to 10-membered saturated heterocycloalkyl group The hetero atom of the 5- to 10-membered bridged heterocycloalkyl group and the 5- to 10-membered spirocycloheterocycloalkyl group is N, O or S, and the number of the hetero atom is 1-3; R ₃ is

R ₉ is a C1-C5 alkyl group, and R ₁₀ is hydrogen or a C1-C5 alkyl group;

或-CONH₂；所述取代C5～C10芳基或苄基的取代基为C1～C6烷基、C1～C6烷氧基、卤素、-CF₃或氰基；a、b为0～4；R _6, R ₇ independently is C1 ~ C4 alkyl group, a substituted or unsubstituted C5 ~ C10 aryl group, a substituted or unsubstituted benzyl group,

上述抗流感小分子化合物制备方法的操作步骤包括：The steps of the above preparation method of the anti-influenza small molecule compound include:

a、原料1与卤代试剂进行卤代反应制备得到中间体1；所述的卤代试剂为NIS(N-碘代丁二酰亚胺)、NBS(N-溴代丁二酰亚胺)、Br₂、I₂、ICl、IBr等中的任意一种；所述原料1与卤代试剂的摩尔比为1︰1.2～2；所述反应的温度为0℃～80℃；所述反应的时间为0.5h～8h。 a, the raw material 1 and the halogenated reagent are halogenated to prepare the intermediate 1; the halogenated reagent is NIS (N-iodosuccinimide), NBS (N-bromosuccinimide) Any one of Br ₂ , I ₂ , ICl, IBr, etc.; the molar ratio of the starting material 1 to the halogenating agent is 1..1.2 to 2; the temperature of the reaction is 0 ° C to 80 ° C; The time is from 0.5h to 8h.

b、中间体1在碱存在下与酰氯反应制备得到中间体2；所述的碱为NaH、KOH、NaOH、K₂CO₃、Na₂CO₃、Cs₂CO₃等中的任意一种；所述的酰氯为TsCl(对甲苯磺酰氯)、苯磺酰氯、甲磺酰氯等中的任意一种；所述中间体1与碱、酰氯的摩尔比为1︰2～4︰1～1.5；所述反应的温度为0℃～50℃；所述反应的时间为0.5h～4h。b, the intermediate 1 is reacted with an acid chloride in the presence of a base to obtain an intermediate 2; the base is any one of NaH, KOH, NaOH, K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO _{3 ,} etc.; The acid chloride is any one of TsCl (p-toluenesulfonyl chloride), benzenesulfonyl chloride, methanesulfonyl chloride, etc.; the molar ratio of the intermediate 1 to the base, acid chloride is 1.. 2 ~ 4.. 1 ~ 1.5; The temperature of the reaction is from 0 ° C to 50 ° C; the reaction time is from 0.5 h to 4 h.

c、中间体2在过渡金属催化下，与硼酸酯试剂在碱存在下反应制备得到中间体3；所述的过渡金属为Pd₄(PPh₃)₄、PdAc₂、Pd₂(dba)₃、Pd(PPh₃)₂Cl₂、Pd(PPh₃)₂Cl₂DCM等中的任意一种；所述的硼酸酯试剂为联硼酸频那醇酯等；所述的碱为KOAc、K₂CO₃、Na₂CO₃、Cs₂CO₃等中的任意一种；所述中间体2与过渡金属、硼酸酯试剂、碱的摩尔比为1︰0.05～0.2︰1.5～2︰2～4；所述反应的温度为60℃～90℃；所述反应的时间为0.5h～24h。c, intermediate 2 is catalyzed by a transition metal, and reacted with a borate reagent in the presence of a base to obtain intermediate 3; the transition metal is Pd ₄ (PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (dba) ₃ And any one of Pd(PPh ₃ ) ₂ Cl ₂ , Pd(PPh ₃ ) ₂ Cl ₂ DCM, etc.; the borate reagent is boronic acid pinacol ester; the base is KOAc, K ₂ CO ₃ , Na ₂ CO ₃ , Cs ₂ CO ₃ or the like; the molar ratio of the intermediate 2 to the transition metal, the borate reagent, and the base is 1..0.05-0.2..1.5-2..2 ～4; The temperature of the reaction is from 60 ° C to 90 ° C; the reaction time is from 0.5 h to 24 h.

d、原料2或中间体4与原料3在碱存在下反应制备得到中间体5；所述的碱为DIEA(N,N-二异丙基乙胺)、TEA(三乙胺)、KOAc、K₂CO₃、Na₂CO₃、Cs₂CO₃等中的任意一种；所述中间体4与原料3、碱的摩尔比为1︰1～1.2︰2～4；所述反应的温度为室温～90℃；所述反应的时间为5h～48h。若中间体5含有异构体，则采用制备SFC或制备HPLC进行手性拆分。d, the starting material 2 or the intermediate 4 and the starting material 3 are reacted in the presence of a base to obtain the intermediate 5; the base is DIEA (N,N-diisopropylethylamine), TEA (triethylamine), KOAc, K ₂ CO _3, any one of _{_{_{Na 2 CO 3, Cs 2 CO}}} 3 and the like; 3, molar ratio of the base 4 and the intermediate material is 1︰1 1.2︰2 ~ 4 ~; temperature of the reaction It is room temperature to 90 ° C; the reaction time is 5 h to 48 h. If intermediate 5 contains isomers, chiral resolution is carried out using preparative SFC or preparative HPLC.

其中中间体4的制备为：若原料2中R₂包含-COOH，需经酸或二氯亚砜(SOCl₂)催化成酯反应制备得到中间体4；所述的酸为浓硫酸等；所述原料2与酸或SOCl₂的摩尔比为1︰5～15；所述反应的温度为0℃～90℃；所述反应的时间为4h～24h。Wherein intermediate 4 is prepared as follows: if R _{2 of the} starting material 2 comprises -COOH, it is prepared by esterification of acid or thionyl chloride (SOCl ₂ ) to obtain intermediate 4; the acid is concentrated sulfuric acid; The molar ratio of the raw material 2 to the acid or SOCl ₂ is 1.. 5 to 15; the temperature of the reaction is 0 ° C to 90 ° C; and the reaction time is 4 h to 24 h.

e、中间体5与中间体3在过渡金属催化下、碱存在下发生偶联反应，制备得到中间体6；所述的过渡金属为Pd₄(PPh₃)₄、PdAc₂、Pd₂(dba)₃、Pd(PPh₃)₂Cl₂、Pd(PPh₃)₂Cl₂DCM等中的任意一种；所述的碱为Cs₂CO₃、KOAc、K₂CO₃、Na₂CO₃、KOH、NaOH等中的任意一种；所述中间体5与中间体3、过渡金属、碱的摩尔比为1︰1～1.2︰0.05～0.2︰2～4；所述反应的温度为室温～90℃；所述反应的时间为5h～48h。e, intermediate 5 and intermediate 3 are coupled under the transition metal catalysis in the presence of a base to prepare intermediate 6; the transition metal is Pd ₄ (PPh ₃ ) ₄ , PdAc ₂ , Pd ₂ (dba ) any one of _{_{_{3, Pd (PPh 3) 2}}} Cl 2, Pd (PPh 3) 2 Cl 2 DCM , and the like; and the base is _{_{Cs 2 CO 3, KOAc, K}} 2 CO 3, Na 2 CO 3, Any one of KOH, NaOH, etc.; the molar ratio of the intermediate 5 to the intermediate 3, the transition metal, and the base is 1..1 to 1.2..0.05 to 0.2..2 to 4; the temperature of the reaction is room temperature. 90 ° C; the reaction time is 5h ~ 48h.

f、中间体6在碱存在下，0～50℃反应脱去保护基R和上述中间体4引入的酯保护，可制备得到化合物7；所述的碱为KOH、NaOH、甲醇钠、乙醇钠等中的任意一种；所述中间体6与碱的摩尔比为1︰4～10；所述碱性反应的时间为5h～24h。f, intermediate 6 in the presence of a base, 0 to 50 ° C reaction to remove the protecting group R and the ester protection introduced by the above intermediate 4, can be prepared to obtain compound 7; the base is KOH, NaOH, sodium methoxide, sodium ethoxide Any one of the above; the molar ratio of the intermediate 6 to the base is 1.. 4 to 10; and the time of the basic reaction is 5 to 24 hours.

本发明上述抗流感小分子化合物包括其互变异构体、立体异构体及其所有比例的混合物，还包括其同位素取代的化合物。The above-mentioned anti-influenza small molecule compounds of the present invention include tautomers, stereoisomers and mixtures thereof in all ratios, and also include isotopically substituted compounds thereof.

本发明还提供了上述抗流感小分子化合物药学上可接受的盐。The present invention also provides a pharmaceutically acceptable salt of the above-mentioned anti-influenza small molecule compound.

本发明所用的术语“药学上可接受的”是指在在合理的医学判断范围，能适于用来与人类和其他哺乳动物的组织接触，而没有不当毒性、刺激、过敏反应等，其在对受者给药时能直接或间接地提供本发明的化合物或化合物的前药。As used herein, the term "pharmaceutically acceptable" means that it is suitable for use in contact with tissues of humans and other mammals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment. A prodrug of a compound or compound of the invention can be provided, directly or indirectly, when administered to a recipient.

本发明还提供了上述抗流感小分子化合物药学上可接受的水合物。术语“水合物”表示进一步通过非共价分子间作用力结合化学计量或非化学计量的水的化合物。The present invention also provides a pharmaceutically acceptable hydrate of the above-mentioned anti-influenza small molecule compound. The term "hydrate" means a compound that further binds stoichiometric or non-stoichiometric amounts of water by non-covalent intermolecular forces.

本发明还提供了上述抗流感小分子化合物药学上可接受的多晶型物。术语“多晶型物”表示化合物或其复合物的固体结晶形式，其可以通过物理方法，例如X.射线粉末衍射图或红外光谱进行表征。The present invention also provides a pharmaceutically acceptable polymorph of the above-mentioned anti-influenza small molecule compound. The term "polymorph" means a solid crystalline form of a compound or complex thereof, which may be by physical means, such as X. ray powder. Characterization by photographic or infrared spectroscopy.

本发明还提供了上述抗流感小分子化合物药学上可接受的药物组合物，这种药物组合物是由式I所示的抗流感小分子化合物及其盐或水合物添加药学上可以接受的辅助性成分制备而成的。The present invention also provides a pharmaceutically acceptable pharmaceutical composition for the above-mentioned anti-influenza small molecule compound, which is a pharmaceutically acceptable auxiliary agent for the anti-influenza small molecule compound of the formula I and a salt or hydrate thereof Made of sexual ingredients.

上述药物组合物可以为液体形式或固体形式。其中，所述的液体形式可以为水溶液形式。所述的固体形式可以为粉末、颗粒、片剂或冻干粉形式。该药物组合物还含有注射用水、盐水溶液、葡萄糖水溶液、注射/输注用盐水、注射/输注用葡萄糖、格林氏溶液或含有乳酸盐的格林氏溶液。The above pharmaceutical composition may be in liquid form or in solid form. Wherein, the liquid form may be in the form of an aqueous solution. The solid form can be in the form of a powder, granule, tablet or lyophilized powder. The pharmaceutical composition further contains water for injection, saline solution, aqueous dextrose, saline for injection/infusion, glucose for injection/infusion, Green's solution or Grignard solution containing lactate.

式I所示的抗流感小分子化合物及其盐、水合物或药物组合物在制备抗流感药物中的用途。Use of an anti-influenza small molecule compound of formula I, and a salt, hydrate or pharmaceutical composition thereof, for the preparation of an anti-influenza drug.

本发明还提供了上述式I所示的抗流感小分子化合物及其盐、水合物或药物组合物在制备口服或静脉注射制剂中的用途。所述的口服或静脉注射制剂至少包含一种式I所示的抗流感小分子化合物及其盐、水合物或药物组合物以及任意的赋形剂和/或佐剂。The present invention also provides the use of the anti-influenza small molecule compound of the above formula I and a salt, hydrate or pharmaceutical composition thereof for the preparation of an oral or intravenous preparation. The oral or intravenous preparation comprises at least one anti-influenza small molecule compound of the formula I and a salt, hydrate or pharmaceutical composition thereof, and any excipients and/or adjuvants.

本发明的有益效果在于：首先，本系列化合物在体外对流感病毒具有很强的抑制效果，在抗流感活性测试中，大部分化合物对流感病毒H1N1(A/PR/8/34)的EC₅₀(半数有效浓度)达到了纳摩尔级水平，活性最优的化合物7z对流感病毒H1N1感染导致的小鼠死亡和肺部炎症有显著保护和抑制效果作用。其次，本系列化合物毒性较小，大部分化合物对MDCK细胞(马丁狗肾细胞)的CC₅₀(半数毒性浓度)在10uM以上，化合物选择性较好。再次，本系列化合物针对的是靶标是流感RNA聚合酶(RdRP)的PB2亚基(碱性蛋白2)，该亚基是近年来的开发抗流感药物的热点靶标，但是目前尚无上市药物。针对该靶标的抑制剂，可能克服目前临床使用的神经氨酸酶抑制剂和M2离子通道抑制剂等药物的耐药性、疗效差、治疗窗窄等问题，具有较大的开发价值。The beneficial effects of the present invention are as follows: Firstly, the compounds of this series have a strong inhibitory effect on influenza virus in vitro, and the EC _{50 of} most compounds against influenza virus H1N1 (A/PR/8/34) in the anti-influenza activity test. (Half effective concentration) reached the nanomolar level, and the most active compound 7z has a significant protective and inhibitory effect on mouse death and lung inflammation caused by influenza virus H1N1 infection. Secondly, this series of compounds is less toxic, and most of the compounds have a CC ₅₀ (half the toxic concentration) of MDCK cells (Martin's kidney cells) above 10 uM, and the compound selectivity is better. Again, this series of compounds targets the PB2 subunit (basic protein 2) of influenza RNA polymerase (RdRP), a hotspot target for the development of anti-influenza drugs in recent years, but there are currently no marketed drugs. Inhibition of the target may overcome the problems of drug resistance, poor therapeutic effect, narrow therapeutic window and the like of the currently used neuraminidase inhibitors and M2 ion channel inhibitors, and has great development value.

附图说明DRAWINGS

图1化合物7j的ITC测试结果：得到7j与PB2_318-483蛋白的K_d值为0.87～1.6μM，ΔH为-14530±782,8cal/mol，ΔS为-21.5cal/mol/deg。ITC results of FIG. 1 Compound 7j: 7j obtained with _K _d PB2 318-483 protein is between 0.87 ~ 1.6μM, ΔH is -14530 ± 782,8cal / mol, ΔS is -21.5cal / mol / deg.

具体实施方式detailed description

实施例1：3-碘-5-氯-1H-吡咯并[2,3-b]吡啶(中间体1a)的制备Example 1: Preparation of 3-iodo-5-chloro-1H-pyrrolo[2,3-b]pyridine (Intermediate 1a)

向500mL圆底烧瓶中加入5-氯-1H-吡咯并[2,3-b]吡啶(5g，32.77mmol),用150mL丙酮溶解完全，分批加入NIS(8.86g，39.4mmol)，常温搅拌，10min后有白色固体析出，30min后反应完毕，减压蒸馏除去溶剂，加入1M的硫代硫酸钠水溶液20mL，常温搅拌，滤出固体，用水洗涤3次，干燥后重结晶得到白色固体，产率91％。Add 5-chloro-1H-pyrrolo[2,3-b]pyridine (5 g, 32.77 mmol) to a 500 mL round bottom flask, dissolve completely with 150 mL of acetone, add NIS (8.86 g, 39.4 mmol) in portions, and stir at room temperature. After 10 min, a white solid precipitated. After 30 min, the reaction was completed. The solvent was evaporated under reduced pressure. A solution of 1M sodium thiosulfate aqueous solution (20 mL) was added, and the mixture was stirred at room temperature. The solid was filtered, washed three times with water, and then recrystallized to give a white solid. The rate is 91%.

¹H NMR(400MHz，DMSO-d₆)12.35(s,1H)，8.30(d,J＝2.0Hz,1H)，7.94(d,J＝1.6Hz, 1H)，7.84(d,J＝2.0Hz,1H)ppm；ESI-MS m/z:278.6[M+H]⁺。 ^{1 H NMR (400MHz, DMSO-} d 6) 12.35 (s, 1H), 8.30 (d, J = 2.0Hz, 1H), 7.94 (d, J = 1.6Hz, 1H), 7.84 (d, J = 2.0Hz , 1H) ppm; ESI-MS m/z: 278.6 [M+H] ⁺ .

按照中间体1a类似的制备方法，以5-X-1H-吡咯并[2,3-b]吡啶为原料，以NIS或NBS等为卤代试剂，以DMF、THF、丙酮等为溶剂，常温、低温或加热反应，可得到中间体1b-e。According to a similar preparation method of the intermediate 1a, 5-X-1H-pyrrolo[2,3-b]pyridine is used as a raw material, NIS or NBS is used as a halogenating reagent, and DMF, THF, acetone or the like is used as a solvent, and the temperature is normal temperature. Intermediate, 1b-e can be obtained by low temperature or heating reaction.

表1中间体1b-e的结构、¹H NMR和ESI-MSTable 1 Structure of Intermediate 1b-e, ¹ H NMR and ESI-MS

实施例2：3-碘-5-氯-1-对甲苯磺酰基-吡咯并[2,3-b]吡啶(中间体2a)的制备Example 2: Preparation of 3-iodo-5-chloro-1-p-toluenesulfonyl-pyrrolo[2,3-b]pyridine (Intermediate 2a)

向250mL圆底烧瓶中加入3-碘-5-氯-1H-吡咯并[2,3-b]吡啶(8.35g，30mmol)，溶于50mL无水四氢呋喃，冰浴，搅拌，缓慢分批加入NaH(1.44g，60mmol)，有气泡产生。15min后，缓慢滴加TsCl(6.86g，36mmol)四氢呋喃溶液20mL，30min后滴加完毕，移至室温反应30min。反应完毕后，减压蒸馏除去溶剂，得到固体粗品，加入40mL二氯甲烷溶解粗品，用水萃取3次，分离出DCM层，用无水硫酸镁干燥，过滤，蒸干滤液即得到产品，浅黄色固体，产率99％；ESI-MS m/z：432.9[M+H]⁺。Add 3-iodo-5-chloro-1H-pyrrolo[2,3-b]pyridine (8.35 g, 30 mmol) to a 250 mL round bottom flask, dissolve in 50 mL of anhydrous tetrahydrofuran, ice bath, stir, and slowly add in portions. NaH (1.44 g, 60 mmol) was bubbled. After 15 min, 20 mL of TsCl (6.86 g, 36 mmol) tetrahydrofuran solution was slowly added dropwise, and after 30 min, the addition was completed, and the reaction was carried out to room temperature for 30 min. After completion of the reaction, the solvent was evaporated under reduced pressure to dryness crystals crystals crystals crystals crystals crystals crystals solid, yield 99%; ESI-MS m / z: 432.9 [m + H] +.

按照中间体2a类似的制备方法，3-卤-5-X-1H-吡咯并[2,3-b]吡啶为原料，与对甲苯磺酰氯、苯磺酰氯等反应，可得According to a similar preparation method of the intermediate 2a, 3-halo-5-X-1H-pyrrolo[2,3-b]pyridine is used as a raw material, and reacted with p-toluenesulfonyl chloride, benzenesulfonyl chloride or the like to obtain

表2中间体2b-g的结构、¹H NMR和ESI-MSTable 2 Structure of Intermediate 2b-g, ¹ H NMR and ESI-MS

实施例3：3-硼酸频哪醇酯-5-氯-1-对甲苯磺酰基-吡咯并[2,3-b]吡啶(中间体3a)的制备Example 3: Preparation of 3-boronic acid pinacol ester-5-chloro-1-p-toluenesulfonyl-pyrrolo[2,3-b]pyridine (Intermediate 3a)

向50mL双颈瓶中加入3-碘-5-氯-1-对甲苯磺酰基-吡咯并[2,3-b]吡啶(10.7g，25mmol)、醋酸钾(4.9g，50mmol)、PdCl₂(dppf)DCM(2.04g，2.5mmol)以及联硼酸频哪醇酯(7.62g，30mmol)，溶于20mL的1,4-二氧六环中，抽真空，氮气置换3次，80℃反应过夜。反应完毕后，减压蒸馏除去溶剂，重新加入DCM溶解，用弗洛里硅土过滤，滤液蒸干后，用正己烷和甲基叔丁基醚重结晶可得到产品3a，黄棕色固体，产率52％。To a 50 mL two-necked flask was added 3-iodo-5-chloro-1-p-toluenesulfonyl-pyrrolo[2,3-b]pyridine (10.7 g, 25 mmol), potassium acetate (4.9 g, 50 mmol), PdCl ₂ (dppf) DCM (2.04 g, 2.5 mmol) and boronic acid pinacol ester (7.62 g, 30 mmol), dissolved in 20 mL of 1,4-dioxane, vacuumed, replaced with nitrogen three times, 80 ° C reaction overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, dissolved in DCM, filtered, evaporated, evaporated, evaporated, evaporated, evaporated. The rate is 52%.

¹H NMR(400MHz,CDCl₃)：8.36(d,J＝1.6Hz,1H)，8.17(d,J＝1.6Hz,2H)，8.09(m,2H)，7.30(m,2H)，2.39(s,3H)，1.37(s,12H)ppm；ESI-MS m/z：433.1[M+H]⁺。 ^{_{1 H NMR (400MHz, CDCl 3}} ): 8.36 (d, J = 1.6Hz, 1H), 8.17 (d, J = 1.6Hz, 2H), 8.09 (m, 2H), 7.30 (m, 2H), 2.39 ( s, 3H), 1.37 (s, 12H) ppm; ESI-MS m/z: 433.1 [M+H] ⁺ .

按照中间体3a类似的制备方法，可以得到中间体3b-e。Intermediate 3b-e can be obtained according to a similar preparation of intermediate 3a.

表3中间体3b-e的结构、¹H NMR和ESI-MSTable 3 Structure of Intermediate 3b-e, ¹ H NMR and ESI-MS

实施例4：(S)-3-氨基丁酸甲酯盐酸盐(中间体4a)的合成Example 4: Synthesis of (S)-3-aminobutyric acid methyl ester hydrochloride (Intermediate 4a)

将(S)-3-氨基丁酸(500mg，4.85mmol)分散于20mL甲醇中，冰浴，缓慢滴加3mL二氯亚砜，固体逐渐消失，反应液变澄清。滴加完毕后，移至80℃反应过夜。反应完全后，旋干溶剂，得到无色油状物即为产品，产率约100％。(S)-3-Aminobutyric acid (500 mg, 4.85 mmol) was dispersed in 20 mL of methanol, and ice-cooled, 3 mL of thionyl chloride was slowly added dropwise, and the solids gradually disappeared, and the reaction mixture became clear. After the dropwise addition was completed, the reaction was carried out at 80 ° C overnight. After the reaction is completed, the solvent is evaporated to give a colorless oil which is a product of about 100%.

¹H NMR(400MHz,CDCl₃)δ8.48(br s,2H)，7.73(br s,1H),，3.84～3.70(m,1H)，3.75(s,3H)，2.92(dd,J＝17.2,7.2Hz,1H)，2.77(dd,J＝17.2,4.8Hz,1H)，1.53(d,J＝6.4Hz,3H)ppm；ESI-MS m/z：118.0[M+H]⁺。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ8.48 (br s, 2H), 7.73 (br s, 1H) ,, 3.84 ~ 3.70 (m, 1H), 3.75 (s, 3H), 2.92 (dd, J = 17.2, 7.2 Hz, 1H), 2.77 (dd, J = 17.2, 4.8 Hz, 1H), 1.53 (d, J = 6.4 Hz, 3H) ppm; ESI-MS m/z: 118.0 [M+H] ⁺ .

按照中间体4a类似的制备方法，可以得到中间体4b-j。Intermediate 4b-j can be obtained according to a similar preparation of intermediate 4a.

表4中间体4b-j的结构、¹H NMR和ESI-MSTable 4 Structure of Intermediate 4b-j, ¹ H NMR and ESI-MS

实施例5：(1S,2S)-2-氨基环己甲酸甲酯(中间体4k)的合成Example 5: Synthesis of methyl (1S,2S)-2-aminocyclohexanecarboxylate (intermediate 4k)

将(1S,2S)-2-氨基环己甲酸(500mg，3.49mmol)溶于15mL甲醇，冰浴下缓慢加入2mL浓硫酸，滴加完毕后，升温至80℃回流过夜。反应完毕后，蒸干溶剂，加入10mL冰水，用稀氢氧化钠溶液调节pH至8～9，用DCM萃取水层3次，合并有机层，用无水硫酸镁干燥，过滤，蒸干滤液即得到产品，无色油状物，产率96％。(1S, 2S)-2-Aminocyclohexanecarboxylic acid (500 mg, 3.49 mmol) was dissolved in 15 mL of methanol, and 2 mL of concentrated sulfuric acid was slowly added to the ice bath. After the dropwise addition was completed, the mixture was heated to 80 ° C and refluxed overnight. After the completion of the reaction, the solvent was evaporated to dryness, then 10 mL of ice water was added, and the pH was adjusted to 8 to 9 with dilute sodium hydroxide solution. The aqueous layer was extracted 3 times with DCM. The product was obtained as a colorless oil in a yield of 96%.

¹H NMR(400MHz,DMSO-d₆)δ3.59(s,3H)，2.63(td,J＝10.8,4.0Hz,1H)，2.01(ddd,J＝12.0,10.0,3.6Hz,1H)，1.84～1.71(m,2H)，1.71～1.57(m,2H)，1.51(br s,2H)，1.39～0.96(m,4H)ppm；ESI-MS m/z:158.3[M+H]⁺。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.59 (s, 3H), 2.63 (td, J = 10.8, 4.0 Hz, 1H), 2.01 (ddd, J = 12.0, 10.0, 3.6 Hz, 1H), 1.84 to 1.71 (m, 2H), 1.71 to 1.57 (m, 2H), 1.51 (br s, 2H), 1.39 to 0.96 (m, 4H) ppm; ESI-MS m/z: 158.3 [M+H] ⁺ .

按照中间体4k类似的制备方法，可得到中间体4l。Intermediate 41 can be obtained according to a similar preparation of intermediate 4k.

表5中间体4l的结构、¹H NMR和ESI-MSTable 5 Structure of Intermediate 4l, ¹ H NMR and ESI-MS

实施例6：(S)-3-((2-氯呋喃并[3,2-d]嘧啶-4-基)氨基)丁酸甲酯(中间体5a)的制备Example 6: Preparation of methyl (S)-3-((2-chlorofuro[3,2-d]pyrimidin-4-yl)amino)butanoate (Intermediate 5a)

将2,4-二氯呋喃并[3,2-d]嘧啶(250mg，1.32mmol)、DIEA(0.87mL，5.28mmol)和中间体4a(203mg，1.32mmol)用20mL甲醇溶解完全，80℃回流过夜，反应完毕后，减压蒸馏除去溶剂，拌样，柱层析，以PE:EA＝3:1洗脱得到产品，白色固体，产率60％。2,4-Dichlorofuro[3,2-d]pyrimidine (250 mg, 1.32 mmol), DIEA (0.87 mL, 5.28 mmol) and Intermediate 4a (203 mg, 1.32 mmol). After refluxing overnight, after completion of the reaction, the solvent was evaporated under reduced pressure, and the mixture was applied,jjjjjjjjj

¹H NMR(400MHz,CDCl₃)δ7.73(d,J＝2.0Hz，1H)，6.78(d,J＝2.0Hz,1H)，5.95(d,J＝2.8Hz,1H)，4.79(ddt,J＝9.2,6.8,5.2Hz,1H)，3.72(s,3H)，2.70(qd,J＝16.0,5.2Hz,2H)，1.40(d,J＝6.8Hz,3H)ppm；ESI-MS m/z：270.1[M+H]⁺。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.73 (d, J = 2.0Hz, 1H), 6.78 (d, J = 2.0Hz, 1H), 5.95 (d, J = 2.8Hz, 1H), 4.79 (ddt , J=9.2, 6.8, 5.2 Hz, 1H), 3.72 (s, 3H), 2.70 (qd, J = 16.0, 5.2 Hz, 2H), 1.40 (d, J = 6.8 Hz, 3H) ppm; ESI-MS m/z: 270.1 [M+H] ⁺ .

按照中间体5a类似的制备方法，以含不同取代基的胺类化合物与氯代嘧啶类衍生物为原料，以DIEA、碳酸钠、碳酸铯等有机碱或无机碱作碱，乙醇、乙腈、四氢呋喃等作溶剂，常温或加热反应，得到中间体5b-5z、5aa-af，表征数据如下：According to a similar preparation method of the intermediate 5a, an amine compound containing a different substituent and a chloropyrimidine derivative are used as a raw material, and an organic or inorganic base such as DIEA, sodium carbonate or cesium carbonate is used as a base, ethanol, acetonitrile or tetrahydrofuran. Waiting for the solvent, the reaction at room temperature or heating gives intermediates 5b-5z, 5aa-af, and the characterization data is as follows:

表6中间体5b-5z、5aa-af的结构、¹H NMR和ESI-MSTable 6 Structure of Intermediates 5b-5z, 5aa-af, ¹ H NMR and ESI-MS

实施例7：(R)-3-((2-氯-5-甲苯磺酰-5H-吡咯并[3,2-d]嘧啶-4-基)氨基)-4,4-二甲基戊酸甲酯(中间体5ag)的制备Example 7: (R)-3-((2-chloro-5-toluenesulfonyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)-4,4-dimethylpentyl Preparation of methyl ester (intermediate 5ag)

第一步，制备2,4-二氯-5-对甲苯磺酰-5H-吡咯并[3,2-d]嘧啶：In the first step, 2,4-dichloro-5-p-toluenesulfonyl-5H-pyrrolo[3,2-d]pyrimidine is prepared:

将2,4-二氯吡咯并[3,2-d]嘧啶(500mg，2.67mmol)溶于15mL无水THF，冰浴，缓慢分批加入NaH(64mg，5.34mmol)。15min后，缓慢滴入TsCl(510mg，2.67mmol)的THF溶液10mL，30min后滴加完毕，室温反应1h。减压蒸馏除去溶剂，残留物用DCM溶解，用水萃取三次，DCM层用无水硫酸镁干燥，过滤除去硫酸镁，蒸干滤液，即得到中间体2,4-二氯-5-对甲苯磺酰-5H-吡咯并[3,2-d]嘧啶，白色固体，产率98％。2,4-Dichloropyrrolo[3,2-d]pyrimidine (500 mg, 2.67 mmol) was dissolved in 15 mL of dry THF. After 15 min, 10 mL of a THF solution of TsCl (510 mg, 2.67 mmol) was slowly added dropwise, and after 30 min, the addition was completed, and the mixture was reacted at room temperature for 1 h. The solvent was evaporated under reduced pressure. the residue was evaporated.jjjjjjjjjjjjjjjjjjjj Acyl-5H-pyrrolo[3,2-d]pyrimidine, white solid, yield 98%.

¹H NMR(400MHz,DMSO-d₆)δ8.69(d,J＝4.0Hz,1H)，7.92(d,J＝8.4Hz,2H)，7.49(d,J＝8.0Hz,2H)，7.15(d,J＝4.0Hz,1H)，2.40(s,3H)ppm。 ^{1 H NMR (400MHz, DMSO-} d 6) δ8.69 (d, J = 4.0Hz, 1H), 7.92 (d, J = 8.4Hz, 2H), 7.49 (d, J = 8.0Hz, 2H), 7.15 (d, J = 4.0 Hz, 1H), 2.40 (s, 3H) ppm.

第二步，制备(R)-3-((2-氯-5-甲苯磺酰-5H-吡咯并[3,2-d]嘧啶-4-基)氨基)-4,4-二甲基戊酸甲酯：In the second step, (R)-3-((2-chloro-5-toluenesulfonyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino)-4,4-dimethyl Methyl valerate:

将上一步得到的中间体(342mg，1.0mmol)用20mL的MeCN溶解，加入三乙胺(202mg，2mmol)和中间体4d(235mg，1.2mmol)，80℃回流过夜。反应完毕后，减压蒸干溶剂，残留物拌样过柱，以PE:EA＝4:1洗脱得到产物5ag，白色固体，产率43％。The intermediate obtained in the previous step (342 mg, 1.0 mmol) was dissolved in 20 mL of EtOAc, EtOAc (EtOAc, EtOAc) After completion of the reaction, the solvent was evaporated to dryness.

¹H NMR(400MHz,DMSO-d₆)δ8.12(d,J＝4.0Hz,1H)，7.71(d,J＝8.4Hz,2H)，7.65(d,J＝8.0Hz,1H)，7.44(d,J＝8.0Hz,2H)，6.82(d,J＝4.0Hz,1H)，4.63(td,J＝10.0,3.2Hz,1H)，3.47(s,3H)，2.84(dd,J＝14.8,3.2Hz,1H)，2.42(dd,J＝14.8,10.0Hz,1H)，2.36(s,3H)，0.98(s,9H)ppm。ESI-MS m/z：465.1[M+H]⁺。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (d, J = 4.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 4.0 Hz, 1H), 4.63 (td, J = 10.0, 3.2 Hz, 1H), 3.47 (s, 3H), 2.84 (dd, J = 14.8, 3.2 Hz, 1H), 2.42 (dd, J = 14.8, 10.0 Hz, 1H), 2.36 (s, 3H), 0.98 (s, 9H) ppm. ESI-MS m/z: 465.1 [M+H] ⁺ .

实施例8：(R)-3-((2-氯-6,7-二氢-5H-环戊二烯并[d]嘧啶-4-基)氨基)-4,4-二甲基戊酸甲酯(中间体5ah)的制备Example 8: (R)-3-((2-Chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-4,4-dimethylpentyl Preparation of methyl ester (intermediate 5ah)

第一步，制备2-脲基环戊-1-烯-1-羧酸甲酯：In the first step, the preparation of methyl 2-ureidocyclopent-1-ene-1-carboxylate:

将甲基-2-氧代环戊烷-1-羧酸(5g，35.17mmol)用25mL甲醇溶解，加入尿素(4.225 g，70.3mmol)以及2mL浓盐酸，80℃回流，10min后有白色固体析出，回流过夜。反应完全后，过滤得到中间体2-脲基环戊-1-烯-1-羧酸甲酯，产率90％。¹H NMR(400MHz,DMSO-d₆)δ9.41(s,1H),6.75(s,2H),3.64(s,3H),3.02(t,J＝7.6Hz,2H),2.38(t,J＝7.6Hz,2H),1.82–1.70(m,2H)ppm。Methyl-2-oxocyclopentane-1-carboxylic acid (5 g, 35.17 mmol) was dissolved in 25 mL of methanol, urea (4.225 g, 70.3 mmol) and 2 mL concentrated hydrochloric acid were added, refluxed at 80 ° C, white solid after 10 min Precipitate and reflux overnight. After completion of the reaction, the intermediate was obtained by filtration to give the title compound, 2-uretyl-cyclopent-1-ene-1-carboxylic acid methyl ester, yield 90%. ^{1 H NMR (400MHz, DMSO-} d 6) δ9.41 (s, 1H), 6.75 (s, 2H), 3.64 (s, 3H), 3.02 (t, J = 7.6Hz, 2H), 2.38 (t, J = 7.6 Hz, 2H), 1.82 - 1.70 (m, 2H) ppm.

第二步，制备2,4-二氯-6,7-二氢-5H-环戊二烯并[d]嘧啶：In the second step, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine is prepared:

将上一步得到的中间体用10mL三氯氧磷溶解，80℃回流，反应液黄棕色。5h反应完全后，减压蒸馏除去溶剂，得到棕色油状物，加入10mL冰水，立即有棕色固体析出，过滤，干燥即得中间体2,4-二氯-6,7-二氢-5H-环戊二烯并[d]嘧啶，黄棕色固体，产率54％。The intermediate obtained in the previous step was dissolved in 10 mL of phosphorus oxychloride, refluxed at 80 ° C, and the reaction liquid was yellowish brown. After the completion of the reaction for 5 h, the solvent was evaporated under reduced pressure to give a brown oil, which was then evaporated. Cyclopenta[d]pyrimidine, yellow-brown solid, yield 54%.

¹H NMR(400MHz,DMSO-d₆)δ3.04(t,J＝7.6Hz,2H),2.93(t,J＝7.6Hz,2H),2.20–2.07(m,2H)ppm；ESI-MS m/z:188.9[M+H]⁺。 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.04 (t, J = 7.6 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.20 - 2.07 (m, 2H) ppm; ESI-MS m/z: 188.9 [M+H] ⁺ .

第三步，制备(R)-3-((2-氯噻吩并[3,2-d]嘧啶-4-基)氨基)-4,4-二甲基戊酸甲酯：In the third step, methyl (R)-3-((2-chlorothieno[3,2-d]pyrimidin-4-yl)amino)-4,4-dimethylpentanoate is prepared:

将上一步得到的中间体(500mg，2.64mmol)用20mL乙腈溶解，加入DIEA(0.8ml，5.28mmol)和中间体4d(442mg，2.77mmol)，升温至80℃反应。24h后，反应完毕，拌样柱层析，以PE:EA＝4:1洗脱得到中间体5ah，白色固体，产率31％。The intermediate obtained in the previous step (500 mg, 2.64 mmol) was dissolved in 20 mL of acetonitrile, and DIEA (0.8 ml, 5.28 mmol) and intermediate 4d (442 mg, 2.77 mmol) were added and the mixture was warmed to 80 ° C. After 24 h, the reaction was completed, and the mixture was subjected to chromatography, eluting with PE: EA = 4:1 to afford intermediate 5 ah, white solid, yield 31%.

¹H NMR(400MHz,DMSO-d₆)δ6.88(d,J＝9.2Hz,1H),4.50(t,J＝8.8Hz,1H),3.49(s,3H),2.76–2.65(m,3H),2.65-2.57(dd,J＝11.2,3.2Hz,3H),2.10–1.92(m,2H),0.88(s,9H)ppm；ESI-MS m/z:312.1[M+H]⁺。 ^{1 H NMR (400MHz, DMSO-} d 6) δ6.88 (d, J = 9.2Hz, 1H), 4.50 (t, J = 8.8Hz, 1H), 3.49 (s, 3H), 2.76-2.65 (m, 3H), 2.65-2.57 (dd, J = 11.2, 3.2 Hz, 3H), 2.10 - 1.92 (m, 2H), 0.88 (s, 9H) ppm; ESI-MS m/z: 312.1 [M+H] ⁺ .

实施例9：中间体5ai-ao的合成Example 9: Synthesis of intermediate 5ai-ao

按照实施例6所述的合成方法，可得到5ai-ao的消旋体，再用制备级超临界流体色谱进行手性拆分，可得到中间体5ai-ao，表征数据如下：According to the synthesis method described in Example 6, the racemic body of 5ai-ao can be obtained, and then chiral resolution is carried out by preparative supercritical fluid chromatography to obtain the intermediate 5ai-ao. The characterization data is as follows:

表7中间体5ai-ao的结构、¹H NMR和ESI-MSTable 7 Structure of the intermediate 5ai-ao, ¹ H NMR and ESI-MS

实施例10：(S)-3-((5-氯-1-对甲苯磺酰基-1H-吡咯并[2,3-d]吡啶-3-基)呋喃并[3,2-d]嘧啶-4-基)氨基)-丁酸甲酯(中间体6a)的合成Example 10: (S)-3-((5-Chloro-1-p-toluenesulfonyl-1H-pyrrolo[2,3-d]pyridin-3-yl)furo[3,2-d]pyrimidine Synthesis of -4-yl)amino)-butyric acid methyl ester (intermediate 6a)

将(R)-3-((2-氯呋喃并[3,2-d]嘧啶-4-基)氨基)-丁酸甲酯5a(160mg，0.593mmol)、中间体3a(308mg，0.7119mmol)、碳酸铯(390mg，1.2mmol)和PdCl₂(dppf)DCM(49mg，0.06mmol)用10mL的1,4-二氧六环溶解，加入2mL水，抽真空，氮气置换三次，置于80℃反应，6h后反应完毕。减压蒸馏除去溶剂，残留物用DCM溶解，拌样，柱层析，以PE:EA＝4:1洗脱得到中间体6a，白色固体，产率85％。(R)-3-((2-Chlorofuro[3,2-d]pyrimidin-4-yl)amino)-butyric acid methyl ester 5a (160 mg, 0.593 mmol), Intermediate 3a (308 mg, 0.7119 mmol ), cesium carbonate (390 mg, 1.2 mmol) and PdCl ₂ (dppf) DCM (49 mg, 0.06 mmol) were dissolved in 10 mL of 1,4-dioxane, 2 mL of water was added, vacuum was applied, and nitrogen was replaced three times. The reaction was carried out at ° C, and the reaction was completed after 6 h. The solvent was evaporated under reduced pressure and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

¹H NMR(400MHz,DMSO-d₆)8.94(d,J＝2.0Hz,1H),8.49(s,1H),8.48(d,J＝2.4Hz,1H),8.28(d,J＝2.4Hz,1H),8.07(d,J＝8.4Hz,2H),7.99(d,J＝9.2Hz,1H),7.45(d,J＝8.4Hz,2H),7.08(d,J＝2.0Hz,1H),4.83(dt,J＝14.0,7.2Hz,1H),3.55(s,3H),2.81(dd,J＝15.2,7.2Hz,1H),2.63(dd,J＝15.2,6.6Hz,1H),2.36(s,3H),1.35(d,J＝6.6Hz,3H)ppm；ESI-MS m/z:540.1[M+H]⁺。 ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.94 (d, J = 2.0 Hz, 1H), 8.49 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz) , 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 2.0 Hz, 1H) ), 4.83 (dt, J = 14.0, 7.2 Hz, 1H), 3.55 (s, 3H), 2.81 (dd, J = 15.2, 7.2 Hz, 1H), 2.63 (dd, J = 15.2, 6.6 Hz, 1H) , 2.36 (s, 3H), 1.35 (d, J = 6.6 Hz, 3H) ppm; ESI-MS m/z: 540.1 [M+H] ⁺ .

按照中间体6a类似的制备方法，可以得到中间体6b-6z、6aa-6az和6ba-6bb，表征数据如下：Intermediate 6b-6z, 6aa-6az and 6ba-6bb can be obtained according to a similar preparation method of intermediate 6a, and the characterization data is as follows:

表8中间体6b-6z、6aa-6az和6ba-6bb的结构、¹H NMR和ESI-MSTable 8 Structures of the intermediates 6b-6z, 6aa-6az and 6ba-6bb, ¹ H NMR and ESI-MS

实施例11：(S)-3-((2-(5-氯-1H-吡咯并[2,3-b]吡啶-3-基)呋喃并[3,2-d]嘧啶-4-基)氨基)丁酸(化合物7a)的制备Example 11: (S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)furo[3,2-d]pyrimidin-4-yl Preparation of amino)butyric acid (compound 7a)

将得到的中间体6a(80mg，0.15mmol)用MeOH:THF＝1:1溶解完全，加入3mL饱和氢氧化钠水溶液，50℃搅拌过夜。反应完全后，减压蒸馏除去溶剂，加入5mL水，EA萃取一次，弃去有机层。水层用盐酸调pH至7，有大量白色固体析出，过滤，用水洗涤所得固体3次，干燥，重结晶即得产物7a，近白色固体，产率81％。The obtained intermediate 6a (80 mg, 0.15 mmol) was dissolved in MeOH: THF = 1:1. After the reaction was completed, the solvent was evaporated under reduced pressure, and 5 mL of water was added, and then extracted with EA, and the organic layer was discarded. The aqueous layer was adjusted to pH 7 with hydrochloric acid, and a large white solid was precipitated, filtered, and the obtained solid was washed three times with water, dried and recrystallized to give product 7a as a white solid, yield 81%.

¹H NMR(400MHz,DMSO-d₆)δ15.04(br s,1H),12.94(s,1H),9.45(br s,1H),8.94(s,1H),8.78(s,1H),8.49(s,1H),8.40(d,J＝2.0Hz,1H),7.16(d,J＝1.6Hz,1H),5.01～4.81(m,1H),2.82(dd,J＝16.0,7.2Hz,1H),2.72～2.56(m,1H),1.41(d,J＝6.6Hz,3H)ppm；ESI-MS m/z:370.6[M-H]^-。 ^{1 H NMR (400MHz, DMSO-} d 6) δ15.04 (br s, 1H), 12.94 (s, 1H), 9.45 (br s, 1H), 8.94 (s, 1H), 8.78 (s, 1H), 8.49 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 5.01 to 4.81 (m, 1H), 2.82 (dd, J = 16.0, 7.2 Hz) , 1H), 2.72 to 2.56 (m, 1H), 1.41 (d, J = 6.6 Hz, 3H) ppm; ESI-MS m/z: 370.6 [MH] ^- .

化合物7b-z、7aa-7az及7ba-bb用上述类似方法可得到，其表征数据如表9所示：Compounds 7b-z, 7aa-7az and 7ba-bb were obtained in a similar manner as described above, and their characterization data are shown in Table 9:

表9化合物7b-z、7aa-7az及7ba-bb的结构、¹H NMR和ESI-MSTable 9 Structures of the compounds 7b-z, 7aa-7az and 7ba-bb, ¹ H NMR and ESI-MS

实施例12：化合物的抗流感活性测试Example 12: Anti-influenza activity test of compounds

实验采用测定流感病毒神经氨酸酶(NA)活性来检测病毒的复制水平。The assay used to measure influenza virus neuraminidase (NA) activity to detect viral replication levels.

实验材料：MUNANA(2'-(4-Methylumbellifery)-α-D-N-acetylneuraminic acid，2'-(4-甲基伞型酮)-α-D-N-乙酰神经氨酸)、MDCK细胞(马丁狗肾细胞)、流感病毒H1N1(A/PR/8/34)、利巴韦林(Ribavirin)均来源于武汉威立得生物医药有限公司。VX-787((2S,3S)-3-((5-氟-2-(5-氟-1H-吡咯[2,3-b]吡啶-3-基)嘧啶-4-基)氨基)二环[2.2.2]辛烷-2-羧酸)来源于四川大学生物治疗国家重点实验室。Experimental materials: MUNANA (2'-(4-Methylumbellifery)-α-DN-acetylneuraminic acid, 2'-(4-methylumbelliferone)-α-DN-acetylneuraminic acid), MDCK cells (Martin dog kidney) The cells), influenza virus H1N1 (A/PR/8/34), and ribavirin (Ribavirin) were all derived from Wuhan Weide Biomedical Co., Ltd. VX-787((2S,3S)-3-((5-fluoro-2-(5-fluoro-1H-pyrrole[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino) Ring [2.2.2] octane-2-carboxylic acid) is from the State Key Laboratory of Biotherapy of Sichuan University.

实验原理：流感病毒NA是一种具有酶活性的表面糖蛋白，在病毒感染末期，能水解HA-SA糖苷键，切断病毒与宿主细胞的联系，对流感病毒的释放与传播有重要作用。MUNANA是流感病毒NA的特异性荧光底物，在NA作用下产生的催化产物在激发光照射下，可以产生荧光，荧光强度的变化，可以灵敏反映NA活性与数量，间接反映流感病毒增殖情况。Experimental principle: Influenza virus NA is an enzymatically active surface glycoprotein. At the end of viral infection, it can hydrolyze HA-SA glycosidic bonds, cut off the connection between virus and host cells, and plays an important role in the release and spread of influenza virus. MUNANA is a specific fluorescent substrate for influenza virus NA. The catalytic product produced by the action of NA can produce fluorescence under the irradiation of excitation light. The change of fluorescence intensity can reflect the activity and quantity of NA sensitively and reflect the flow indirectly. The virus is proliferated.

方法步骤：MDCK细胞(马丁狗肾细胞)接种于96孔细胞培养板中，37℃培养过夜后备用。MDCK细胞用PBS洗两遍后同时加入药物(本发化合物)及流感病毒H1N1(A/PR/8/34)，药物设置八个浓度，两个复孔。加药完毕后，置于37℃细胞培养箱培养24h，显微镜下观察细胞病变(CPE)，并取培养液上清进行神经氨酸酶活力检测。实验设置空白对照孔(正常MDCK细胞)，病毒对照孔(病毒感染后未加药物)，阳性药物对照孔(感染后加利巴韦林或者VX-787)。Method step: MDCK cells (Martin dogs kidney cells) were seeded in 96-well cell culture plates and cultured overnight at 37 ° C until use. After MDCK cells were washed twice with PBS, the drug (the present compound) and the influenza virus H1N1 (A/PR/8/34) were added simultaneously, and the drug was set to eight concentrations, two duplicate wells. After the drug was added, it was cultured in a 37 ° C cell culture chamber for 24 hours, and the cell lesion (CPE) was observed under a microscope, and the supernatant of the culture solution was taken for detection of neuraminidase activity. The experiment set blank control wells (normal MDCK cells), virus control wells (no drug added after viral infection), positive drug control wells (addition of ribavirin or VX-787 after infection).

抑制率(％)＝100-(样品孔-空白对照)/(病毒对照-空白对照)*100％Inhibition rate (%) = 100 - (sample well - blank control) / (virus control - blank control) * 100%

最后用Graphpad Prism软件拟合得出半数有效浓度(EC₅₀)。Finally, the half effective concentration (EC ₅₀ ) was obtained by fitting with Graphpad Prism software.

实施例13：药物对MDCK细胞的毒性Example 13: Toxicity of drugs to MDCK cells

采用了

(Invitrogen)试剂盒检测药物对细胞的毒性作用。Adopted

The (Invitrogen) kit detects the toxic effects of drugs on cells.

实验原理：

是一种氧化还原指示剂，能根据代谢活性产生吸光度变化和荧光信号。

易溶于水，其氧化形式进入细胞后经线粒体酶还原产生可测量的荧光及颜色变化，用于细胞活性和细胞增殖的定量分析以及体外细胞毒性研究。这种测定是基于具有代谢活性的细胞将试剂转换成荧光和比色指示剂的能力，受损和无活性细胞具有较低的天然代谢活性，对应的信号较低。因此荧光信号强弱，可以反映细胞活性的高低。Experimental principle:

It is a redox indicator that produces absorbance changes and fluorescent signals based on metabolic activity.

Soluble in water, its oxidized form enters cells and is reduced by mitochondrial enzymes to produce measurable fluorescence and color changes for quantitative analysis of cell viability and cell proliferation as well as in vitro cytotoxicity studies. This assay is based on the ability of metabolically active cells to convert reagents into fluorescent and colorimetric indicators, with impaired and inactive cells having lower native metabolic activity and corresponding lower signals. Therefore, the fluorescence signal is strong and can reflect the level of cell activity.

方法步骤：MDCK细胞接种于96孔细胞培养板中，细胞贴壁后加入含药培养基。药物终浓度为100μM、33.33μM、11.11μM、3.70μM、1.23μM、0.41μM、0.14μM、0.046μM共八个浓度，两个复孔。加药培养后，光镜下观察药物引起的细胞病变效应(CPE)，加入

37℃孵育2h，荧光检测

的还原情况，激发光570nm，发射光595nm。Method step: MDCK cells were seeded in a 96-well cell culture plate, and the cells were adhered to the drug-containing medium. The final concentration of the drug was 100 μM, 33.33 μM, 11.11 μM, 3.70 μM, 1.23 μM, 0.41 μM, 0.14 μM, and 0.046 μM in eight concentrations, two duplicate wells. After the drug was cultured, the cytopathic effect (CPE) caused by the drug was observed under light microscope.

Incubate at 37 ° C for 2 h, fluorescence detection

The reduction was performed at 570 nm for excitation and 595 nm for emission.

细胞活性(％)＝(样品孔-空白对照)/(细胞对照-空白对照)*100％Cell viability (%) = (sample well - blank control) / (cell control - blank control) * 100%

最后用Graphpad Prism软件拟合得出细胞半数抑制浓度(CC₅₀)。Finally, the cell half-inhibitory concentration (CC ₅₀ ) was obtained by fitting with Graphpad Prism software.

表10为测试化合物对流感病毒H1N1(A/PR/8/34)的抑制活性以及细胞毒性，其中，A表示<100nM，B表示100nM～500nM，C表示500nM～1μM，D表示1μM～10μM，E表示>10μM。Table 10 shows the inhibitory activity and cytotoxicity of the test compound against influenza virus H1N1 (A/PR/8/34), wherein A represents <100 nM, B represents 100 nM to 500 nM, C represents 500 nM to 1 μM, and D represents 1 μM to 10 μM. E represents >10 μM.

表10化合物对流感病毒H1N1(A/PR/8/34)的抑制活性以及细胞毒性Table 10 Inhibitory activity and cytotoxicity of compounds against influenza virus H1N1 (A/PR/8/34)

化合物Compound	H1N1(A/PR/8/34)CPE EC₅₀ H1N1(A/PR/8/34)CPE EC ₅₀	MDCK CC₅₀ MDCK CC ₅₀
7a7a	DD	EE
7b7b	DD	EE
7c7c	BB	EE
7d7d	AA	EE
7e7e	CC	EE
7f7f	BB	EE

7g7g	BB	EE
7h7h	BB	EE
7i7i	AA	DD
7j7j	BB	DD
7k7k	AA	EE
7l7l	CC	EE
7m7m	BB	EE
7n7n	AA	EE
7o7o	AA	EE
7p7p	AA	EE
7q7q	AA	EE
7r7r	AA	EE
7s7s	AA	EE
7t7t	BB	EE
7u7u	DD	EE
7v7v	AA	EE
7w7w	BB	EE
7x7x	BB	EE
7y7y	AA	EE
7z7z	AA	EE
7aa7aa	BB	EE
7ab7ab	AA	EE
7ac7ac	AA	DD
7ad7ad	AA	EE
7ae7ae	AA	DD
7af7af	AA	EE
7ag7ag	AA	EE
7ah7ah	EE	EE
7ai7ai	CC	EE
7aj7aj	CC	EE
7ak7ak	CC	EE
7al7al	EE	EE
7am7am	EE	EE
7an7an	BB	EE

7ao7ao	EE	EE
7ap7ap	DD	EE
7aq7aq	EE	EE
7ar7ar	BB	DD
7as7as	DD	EE
7at7at	CC	EE
7au7au	EE	EE
7av7av	EE	EE
7aw7aw	CC	EE
7ax7ax	CC	DD
7ay7ay	BB	EE
7az7az	BB	EE
7ba7ba	CC	EE
7bb7bb	CC	EE
利巴韦林Ribavirin	14.37μM14.37μM	>500μM>500μM
VX-787VX-787	3nM3nM	>10μM>10μM

由上表可知，该系列化合物对流感病毒H1N1(A/PR/8/34)具有很好的抑制活性。EC₅₀均明显优于阳性对照利巴韦林。大部分化合物与VX-787相比，EC₅₀、CC₅₀处于相同数量级水平。As can be seen from the above table, the series of compounds have a good inhibitory activity against influenza virus H1N1 (A/PR/8/34). The EC ₅₀ was significantly better than the positive control ribavirin. Most compounds have EC ₅₀ and CC ₅₀ at the same order of magnitude compared to VX-787.

实施例14：测定PB2_318-483蛋白与小分子之间的Kd值Example 14: Determination of the Kd value between PB2 _318-483 protein and small molecules

实验目的：检测化合物7j与PB2_318-483蛋白的结合能力。选择等温滴定量热仪(ITC)测定小分子和蛋白的Kd值。Experimental purpose: To test the binding ability of compound 7j to PB2 _318-483 protein. The isothermal titration calorimeter (ITC) was chosen to determine the Kd values of small molecules and proteins.

实验材料：PB2_318-483蛋白(流感RNA聚合酶PB2亚基的318-483肽段，即“帽子”结合域)来源于四川大学生物治疗国家重点实验室。Experimental material: PB2 _318-483 protein (318-483 peptide of the PB2 subunit of influenza RNA polymerase, the "hat" binding domain) was obtained from the State Key Laboratory of Biotherapy of Sichuan University.

实验步骤：Experimental steps:

1)利用过分子筛的磷酸盐缓冲液和DMSO(二甲基亚砜)，配制不同浓度的PB2_318-483蛋白溶液和小分子溶液。蛋白溶液的终浓度分别为5μM、10μM、20μM、50μM，DMSO含量为1％。再根据蛋白和小分子浓度为1:10的比例配制小分子溶液。1) Different concentrations of PB2 _318-483 protein solution and small molecule solution were prepared by using molecular sieve phosphate buffer and DMSO (dimethyl sulfoxide). The final concentration of the protein solution was 5 μM, 10 μM, 20 μM, 50 μM, respectively, and the DMSO content was 1%. The small molecule solution was prepared according to the ratio of protein to small molecule concentration of 1:10.

2)取350μL蛋白溶液和80μL小分子溶液，13000rpm离心2min。将蛋白溶液缓慢的加到ITC的样品池内，防止产生气泡；将小分子溶液加入到滴定针内，开始滴定。设置滴定条件为25℃；第一滴0.5μL，2s，其余每滴2μL，4s，共20滴；间隔150s。滴定完毕后，分析滴定结果。2) Take 350 μL of protein solution and 80 μL of small molecule solution, and centrifuge at 13,000 rpm for 2 min. The protein solution was slowly added to the sample cell of the ITC to prevent the generation of bubbles; the small molecule solution was added to the titration needle and titration was started. Set the titration conditions to 25 ° C; the first drop 0.5 μL, 2 s, the remaining 2 μL per drop, 4 s, a total of 20 drops; interval 150s. After the titration is completed, the titration results are analyzed.

实验结果：图1为化合物7j的ITC测试结果，得到7j与PB2_318-483蛋白的K_d值为0.87～1.6μM，△H(焓变)为-14530±782.8cal/mol，△S(熵变)为-21.5cal/mol/deg，其中△H反映小分子与蛋白的特异性结合能力，△S反映溶剂效应以及化合物构象转变等。由数据可知化合物7j能特异性结合PB2_318-483蛋白，K_d值处于微摩尔级水平。Results: FIG. 1 is a compound of 7j ITC results, obtained with the _K _d PB2 318-483 7j protein is between 0.87 ~ 1.6μM, △ H (enthalpy variation) of -14530 ± 782.8cal / mol, △ S ( entropy The change is -21.5 cal/mol/deg, wherein ΔH reflects the specific binding ability of the small molecule to the protein, and ΔS reflects the solvent effect and the conformational transition of the compound. It is known from the data that the compound 7j can specifically bind to the PB2 _318-483 protein, and the K _d value is at the micromolar level.

实施例15：化合物的药代动力学研究Example 15: Pharmacokinetic Study of Compounds

实验目的：单次给予SD大鼠受试药物，于不同时间点采集血样，LC-MS/MS测定给予受试物后大鼠血浆中受试物的浓度并计算相关参数。OBJECTIVE: A single dose of SD rats was administered with blood samples at different time points. LC-MS/MS was used to determine the concentration of the test substance in the plasma of rats after administration of the test substance and calculate relevant parameters.

实验材料：SPF级SD大鼠(雄性，6周，体重160-180g)来源于上海西普尔-必凯实验动物有限公司。受试药物最终配置浓度为1mg/mL，溶媒为5％DMSO+10％(乙醇：蓖麻油＝1:1)+85％saline。Experimental materials: SPF grade SD rats (male, 6 weeks, weight 160-180 g) were obtained from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. The final concentration of the test drug was 1 mg/mL, and the solvent was 5% DMSO + 10% (ethanol: castor oil = 1:1) + 85% saline.

实验步骤：Experimental steps:

1)所有动物给药前禁食10-14小时，SD大鼠单次静脉注射和口服给予受试药物，给药后4小时恢复给食。1) All animals were fasted for 10-14 hours before administration, and SD rats were given a single intravenous injection and oral administration of the test drug, and the food was resumed 4 hours after administration.

2)样品采集与处理：经颈静脉穿刺采血，每个样品采集约0.20mL，肝素钠抗凝，采血时间点如下：静脉给药组采血时间：给药后2min,5min,15min,30min，1h,2h,3h,4h,6h,8h,12h,24h,36h,48h,72h。口服给药组采血时间：给药后5min,10min,15min,30min,1h,2h,3h,4h,6h,8h,12h,24h,6h,48h,72h。血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃，收集的血浆分析前存放于–80℃。2) Sample collection and treatment: blood was collected by jugular vein puncture, and each sample was collected about 0.20 mL. Heparin sodium was anticoagulated. The time of blood collection was as follows: blood collection time of intravenous administration group: 2 min, 5 min, 15 min, 30 min, 1 h after administration , 2h, 3h, 4h, 6h, 8h, 12h, 24h, 36h, 48h, 72h. Blood collection time in the oral administration group: 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 24 h, 6 h, 48 h, 72 h. Blood samples were collected and placed on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 ° C, and collected plasma was stored at –80 °C before analysis).

3)药物代谢动力学分析：根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算供试品的药代动力学参数。3) Pharmacokinetic analysis: According to the blood drug concentration data of the drug, the pharmacokinetic parameters of the test article were calculated using the non-compartment model of the pharmacokinetic calculation software WinNonlin5.2.

实验结果：以7z为例，其药代动力学参数如表11所示。Experimental results: Taking 7z as an example, the pharmacokinetic parameters are shown in Table 11.

表11 SD大鼠单次静脉注射或口服7z的主要药代动力学参数Table 11 Main pharmacokinetic parameters of single intravenous injection or oral 7z in SD rats

实施例16：化合物对甲型流感病毒A/FM/1/47(H1N1)感染小鼠的保护作用Example 16: Protection of compounds against influenza A virus A/FM/1/47 (H1N1)-infected mice

实验材料：甲型流感病毒鼠肺适应株A/FM/1/47(H1N1)，接种鸡胚，收集尿囊液保存。ICR小鼠，体重18～22g,来源于扬州大学比较医学中心，许可证号：SCXK(苏)2012-0004。给药期间自由进食、饮水，每天12小时光照，12小时黑暗，温度22±2℃，湿度55-70％。Experimental material: Influenza A virus mouse lung adaptor strain A/FM/1/47 (H1N1), inoculated with chicken embryos, collected for allantoic fluid preservation. ICR mice, weighing 18-22 g, were obtained from the Comparative Medical Center of Yangzhou University, license number: SCXK (Su) 2012-0004. Free to eat, drink, 12 hours of light per day, 12 hours of darkness, temperature 22 ± 2 ° C, humidity 55-70%.

实验方法：适应性饲养3天后，开始进行实验。除未感染对照组以外，其它各组小鼠用***轻度麻醉，鼻腔内接种用生理盐水稀释的相当于8×LD₅₀的流感病毒A/FM/1/47(H1N1)的鸡胚尿囊液50μL/只，阳性对照奥司他韦组小鼠于感染后2h首次灌胃给药，给药剂量为100mg/kg，供试给药组于病毒感染24h后以40mg/kg首次灌胃给药，以后每日1次，病毒对照组及未感染对照组同法口服生理盐水，每日1次，给药体积为0.1mL/10g体重。共7天。第5天，记录体重损失百分比。自感染之日起，连续14d，记录小鼠每日体重、死亡数、死亡时间，计算死亡保护率。Experimental method: After 3 days of adaptive feeding, the experiment was started. Except the uninfected control group, the mice in each group were lightly anesthetized with ether, and the chicken embryo allantoic sac corresponding to 8×LD ₅₀ of influenza virus A/FM/1/47 (H1N1) diluted with physiological saline was intranasally inoculated. The mice in the positive control oseltamivir group were intragastrically administered for 2 hours after infection at the dose of 100 mg/kg. The test administration group was given the first dose of 40 mg/kg after 24 hours of virus infection. The drug was administered once a day, the virus control group and the uninfected control group were orally administered with normal saline once a day, and the administration volume was 0.1 mL/10 g body weight. A total of 7 days. On day 5, the percentage of weight loss was recorded. From the day of infection, for 14 consecutive days, the daily weight, death, and death time of the mice were recorded, and the death protection rate was calculated.

死亡保护率(％)＝病毒对照组死亡率(％)-实验组死亡率(％)。Death protection rate (%) = virus control group mortality (%) - experimental group mortality (%).

实施例17：药物对流感病毒H1N1感染导致的小鼠肺部炎症的缓解作用Example 17: Relief effect of drugs on lung inflammation in mice caused by influenza virus H1N1 infection

实验方法：适应性饲养3天后，开始进行实验。除未感染对照组以外，其它各组小鼠用***轻度麻醉，鼻腔内接种用生理盐水稀释的相当于8×LD₅₀的流感病毒A/FM/1/47(H1N1)的鸡胚尿囊液50μL/只，阳性对照奥司他韦组小鼠于感染后2h首次灌胃给药，给药剂量为100mg/kg，供试给药组于病毒感染24h后以40mg/kg首次灌胃给药，以后每日1次，病毒对照组及未感染对照组同法口服生理盐水，每日1次，给药体积为0.1mL/10g体重。共5天。第6天每组取3只小鼠称重，摘除眼球放血致死，取出全肺，称重，计算肺指数及肺指数抑制率。Experimental method: After 3 days of adaptive feeding, the experiment was started. Except the uninfected control group, the mice in each group were lightly anesthetized with ether, and the chicken embryo allantoic sac corresponding to 8×LD ₅₀ of influenza virus A/FM/1/47 (H1N1) diluted with physiological saline was intranasally inoculated. The mice in the positive control oseltamivir group were intragastrically administered for 2 hours after infection at the dose of 100 mg/kg. The test administration group was given the first dose of 40 mg/kg after 24 hours of virus infection. The drug was administered once a day, the virus control group and the uninfected control group were orally administered with normal saline once a day, and the administration volume was 0.1 mL/10 g body weight. A total of 5 days. On the 6th day, 3 mice in each group were weighed, the eyeballs were removed and lethal, and the whole lung was taken out, weighed, and the lung index and lung index inhibition rate were calculated.

肺指数＝小鼠肺重/小鼠体重×100Lung index = mouse lung weight / mouse body weight × 100

表12化合物7z对流感病毒感染小鼠体重、生存率及肺部炎症的影响Table 12 Effect of Compound 7z on Body Weight, Survival Rate and Pulmonary Inflammation in Mice Infected with Influenza Virus

实验结果：以7z为例，口服给药40mg/kg/d，小鼠存活率达到了90％；在第五天，病毒对照组小鼠平均重量损失30％，化合物7z治疗组平均重量损失10％；小鼠的肺指数为1.16，与病毒对照组(2.09)相比有明显降低，肺指数抑制率达到了60.99％。因此化合物7z对流感病毒引起的死亡及肺部炎症有明显的保护和抑制作用，且效果优于奥司他韦对照组。 Experimental results: Taking 7z as an example, oral administration of 40 mg/kg/d, the survival rate of mice reached 90%; on the fifth day, the average weight loss of the virus control group mice was 30%, and the average weight loss of the compound 7z treatment group was 10 The lung index of mice was 1.16, which was significantly lower than that of the virus control group (2.09), and the lung index inhibition rate reached 60.99%. Therefore, compound 7z has obvious protective and inhibitory effects on influenza-induced death and pulmonary inflammation, and the effect is better than that of oseltamivir control group.

Claims

抗流感小分子化合物，其结构如式Ⅰ所示：An anti-influenza small molecule compound having the structure shown in Formula I:

其中，X为-H、卤素、氰基、-CF₃、C1～C4烷氧基、C1～C4烷基、氨基或C1～C3氨酰基；Wherein X is -H, halogen, cyano, -CF ₃ , C1 - C4 alkoxy, C1 - C4 alkyl, amino or C1 - C3 aminoacyl;

L为饱和或不饱和的4～10元杂环烷基、饱和或不饱和的C4～C10环烷基；所述饱和或不饱和的4～10元杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3；L is a saturated or unsaturated 4 to 10 membered heterocycloalkyl group, a saturated or unsaturated C4 to C10 cycloalkyl group; and the hetero atom of the saturated or unsaturated 4 to 10 membered heterocycloalkyl group is N, O. Or S, the number of the hetero atoms is 1-3;

R₁和R₂组合成取代或未取代的5～8元饱和杂环烷基，所述的杂原子为N，杂原子个数为1～2个；所述取代5～8元饱和杂环烷基的取代基为-H、-NH₂、卤素、-CF₃、氰基、C1～C4烷基、
或
a、b为0～4；R ₁ and R _{2 are} combined to form a substituted or unsubstituted 5-8 membered saturated heterocycloalkyl group, said hetero atom is N, and the number of hetero atoms is 1-2; said substituted 5-8-membered saturated heterocyclic ring The substituent of the alkyl group is -H, -NH ₂ , halogen, -CF ₃ , cyano, C1 to C4 alkyl,
or
a, b is 0 to 4;

或者R₁为-H或C1～C10烷基；R₂为
或
n为0～4；Or R ₁ is -H or C1 - C10 alkyl; R ₂ is
or
n is 0 to 4;

R₄、R₅独立的为-H或C1～C10烷基；或者R₄和R₅组合形成环，所述的环为C5～C10环烷基、C5～C10的桥环烷基、C5～C10的稠环烷基、5～10元饱和杂环烷基、5～10元桥环杂环烷基或5～10元螺环杂环烷基；所述5～10元饱和杂环烷基、5～10元桥环杂环烷基、5～10元螺环杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3；R₃为
或
R₉为C1～C5烷基，R₁₀为氢或C1～C5烷基；R ₄ and R _{5 are} independently -H or C1 to C10 alkyl; or R ₄ and R _{5 are} combined to form a ring, said ring being a C5-C10 cycloalkyl group, a C5-C10 bridged cycloalkyl group, C5~ a fused cycloalkyl group of C10, a 5- to 10-membered saturated heterocycloalkyl group, a 5- to 10-membered bridged heterocycloalkyl group or a 5- to 10-membered spirocycloheterocycloalkyl group; said 5- to 10-membered saturated heterocycloalkyl group The hetero atom of the 5- to 10-membered bridged heterocycloalkyl group and the 5- to 10-membered spirocycloheterocycloalkyl group is N, O or S, and the number of the hetero atom is 1-3; R ₃ is
or
R ₉ is a C1-C5 alkyl group, and R ₁₀ is hydrogen or a C1-C5 alkyl group;

R₆、R₇独立的为C1～C4烷基、取代或未取代的C5～C10芳基、取代或未取代的苄基、
或-CONH₂；所述取代C5～C10芳基或苄基的取代基为C1～C6烷基、C1～C6烷氧基、卤素、-CF₃或氰基；a、b为0～4；R _6, R ₇ independently is C1 ~ C4 alkyl group, a substituted or unsubstituted C5 ~ C10 aryl group, a substituted or unsubstituted benzyl group,
Or -CONH _2; said substituted C5 ~ C10 aryl group or a benzyl group substituents are C1 ~ C6 alkyl group, C1 ~ C6 alkoxy, halogen, -CF _3, or a cyano group; a, b is from 0 to 4;

R₈为取代或未取代的C5～C10环烷基、取代或未取代的5～10元饱和或不饱和杂环、取代或未取代的C5～C10不饱和环或取代或未取代的C5～C15的桥环烷基；所述5～10元饱和或不饱和杂环的杂原子为N、O、S，杂原子个数为1～ 3个；所述取代C5～C10环烷基的取代基为-H、
卤素、C1～C4烷基或-COOH；所述取代C5～C10不饱和环的取代基为-H、-OH、-SO₂NH₂、-CF₃、卤素、C1～C4烷基或-COOH；所述取代5～10元饱和或不饱和杂环的取代基为卤素取代的苄基、卤素、苯基、苄基、-OH、-CF₃、C1～C4烷基、C1～C4羰基、-COOH或-NH₂；所述取代C5～C15的桥环烷基的取代基为-H、-OH、-COOH、C1～C4烷基或-NH₂；a为0～4。R ₈ is a substituted or unsubstituted C5-C10 cycloalkyl group, a substituted or unsubstituted 5-10 membered saturated or unsaturated heterocyclic ring, a substituted or unsubstituted C5-C10 unsaturated ring or a substituted or unsubstituted C5~ a bridged cycloalkyl group of C15; wherein the hetero atom of the 5- to 10-membered saturated or unsaturated heterocyclic ring is N, O, and S, and the number of hetero atoms is 1 to 3; and the substitution of the substituted C5-C10 cycloalkyl group Base is -H,
Halogen, C1-C4 alkyl or -COOH; the substituent of the substituted C5-C10 unsaturated ring is -H, -OH, -SO ₂ NH ₂ , -CF ₃ , halogen, C1 - C4 alkyl or -COOH The substituent substituted with a 5- to 10-membered saturated or unsaturated heterocyclic ring is a halogen-substituted benzyl group, a halogen, a phenyl group, a benzyl group, an -OH group, a -CF ₃ group, a C1 to C4 alkyl group, a C1 to C4 carbonyl group, -COOH or -NH ₂ ; the substituent of the substituted C5-C15 bridged cycloalkyl group is -H, -OH, -COOH, C1 - C4 alkyl or -NH ₂ ; a is 0-4.
根据权利要求1所述的抗流感小分子化合物，当R₁为H，R₂为
R₃为
时，其结构如式Ⅱ所示：The anti-influenza small molecule compound according to claim 1, wherein R ₁ is H and R ₂ is
R ₃ is
The structure is as shown in Equation II:

其中，X为卤素或C1～C4烷基；L为饱和或不饱和的5～8元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～8元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；Wherein X is a halogen or a C1-C4 alkyl group; L is a saturated or unsaturated 5- to 8-membered heterocycloalkyl group, a saturated or unsaturated C5-C8 cycloalkyl group; and the 5- to 8-membered heterocycloalkyl group The hetero atom is N, O or S, and the hetero atom is 1 to 3;

R₄、R₅独立地为-H或C1～C8烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基、C5～C8的稠环烷基、5～8元饱和杂环烷基、5～8元桥环杂环烷基或5～10元螺环杂环烷基；所述5～8元饱和杂环烷基、5～8元桥环杂环烷基、5～10元螺环杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3。R ₄ and R _{5 are} independently -H or C1 to C8 alkyl; or R ₄ and R _{5 are} combined to form a ring, said ring being a C5-C8 cycloalkyl group, a C5-C8 bridged cycloalkyl group, C5~ a fused cycloalkyl group of C8, a 5- to 8-membered saturated heterocycloalkyl group, a 5- to 8-membered bridged heterocycloalkyl group or a 5- to 10-membered spirocycloheterocycloalkyl group; said 5- to 8-membered saturated heterocycloalkyl group; The hetero atom of the 5- to 8-membered bridged heterocycloalkyl group and the 5- to 10-membered spirocycloheterocycloalkyl group is N, O or S, and the number of the hetero atom is from 1 to 3.
根据权利要求2所述的抗流感小分子化合物，其特征在于：The anti-influenza small molecule compound according to claim 2, wherein:

X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基、C5～C8的稠环烷基、5～8元饱和杂环烷基、5～8元桥环杂环烷基或5～10元螺环杂环烷基；所述5～8元饱和杂环烷基、5～8元桥环杂环烷基、5～10元螺环杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3；X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C8 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N, O or S, the hetero atom is 1 to 3; R ₄ and R _{5 are} independently -H or C1 to C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, and the ring is a C5 to C8 naphthenic ring. a C5-C8 bridged cycloalkyl group, a C5-C8 fused ring alkyl group, a 5- to 8-membered saturated heterocycloalkyl group, a 5- to 8-membered bridged heterocycloalkyl group or a 5- to 10-membered spirocycloalkane. a hetero atom of the 5- to 8-membered saturated heterocycloalkyl group, a 5- to 8-membered bridged heterocycloalkyl group, or a 5- to 10-membered spirocycloheterocycloalkyl group, which is N, O or S, The number is 1 to 3;

再进一步优选的，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基、C5～C8的稠环烷基或5～8元饱和杂环烷基；所述5～8元饱和杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3；Still more preferably, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and a hetero atom of the 5- to 6-membered heterocycloalkyl group. Is N, O or S, the hetero atom is 1-3; R ₄ , R _{5 are} independently -H or C1 - C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, the ring is a C5-C8 cycloalkyl group, a C5-C8 bridged cycloalkyl group, a C5-C8 fused ring alkyl group or a 5- to 8-membered saturated heterocycloalkyl group; and the hetero atom of the 5- to 8-membered saturated heterocycloalkyl group is N, O or S, the number of the hetero atoms is 1-3;

更进一步优选的，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基、C5～C8的稠环烷基或5～8元饱和杂环烷基；所述5～8元饱和杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～3；Still more preferably, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and a hetero atom of the 5- to 6-membered heterocycloalkyl group; Is N, O or S, the hetero atom is 1-2; R ₄ , R _{5 are} independently -H or C1 - C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, the ring is a C5-C8 cycloalkyl group, a C5-C8 bridged cycloalkyl group, a C5-C8 fused ring alkyl group or a 5- to 8-membered saturated heterocycloalkyl group; and the hetero atom of the 5- to 8-membered saturated heterocycloalkyl group is N, O or S, the number of the hetero atoms is 1-3;

优选的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基、C5～C8的稠环烷基或5～8元饱和杂环烷基；所述5～8元饱和杂环烷基的杂原子为N、O或S，所述杂原子的个数为1～2；Preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N, O. Or S, the hetero atom is 1 or 2; R ₄ and R _{5 are} independently -H or C1 - C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, and the ring is a C5 to C8 ring. An alkyl group, a C5-C8 bridged cycloalkyl group, a C5-C8 fused ring alkyl group or a 5- to 8-membered saturated heterocycloalkyl group; and the hetero atom of the 5- to 8-membered saturated heterocycloalkyl group is N, O or S, the number of the hetero atoms is 1-2;

进一步优选的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基、C5～C8的桥环烷基或C5～C8的稠环烷基；Further preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. O or S, the hetero atom is 1 or 2; R ₄ and R _{5 are} independently -H or C1 - C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, and the ring is C5 - C8 a cycloalkyl group, a C5-C8 bridged cycloalkyl group or a C5-C8 fused ring alkyl group;

更进一步优选的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；R₄、R₅独立地为-H或C1～C4烷基；或R₄和R₅组合形成环，所述的环为C5～C8环烷基或C5～C8的桥环烷基；Still more preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. Or O or S, wherein the hetero atom is 1-2; R ₄ and R _{5 are} independently -H or C1 - C4 alkyl; or R ₄ and R _{5 are} combined to form a ring, and the ring is C5 - a C8 cycloalkyl group or a C5 to C8 bridged cycloalkyl group;

最优的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1个；R₄、R₅独立地为-H或C1～C4烷基；或R₁和R₂组合形成环，所述的环为C5～C6环烷基或C5～C8的桥环烷基。Most preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. O or S, the hetero atom is one; R ₄ and R _{5 are} independently -H or C1 to C4 alkyl; or R ₁ and R _{2 are} combined to form a ring, and the ring is a C5 to C6 naphthenic ring. A group or a C5 to C8 bridged cycloalkyl group.
根据权利要求1所述的抗流感小分子化合物，其特征在于：当R₁为H，R₂为
时，其结构如式Ⅲ所示： The anti-influenza small molecule compound according to claim 1, wherein R ₁ is H and R ₂ is
When the structure is as shown in Equation III:

其中，X为卤素或C1～C4烷基；L为饱和或不饱和的5～8元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～8元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₆、R₇独立的为C1～C4烷基、取代或未取代的C5～C8芳基、取代或未取代的苄基、
或-CONH₂；所述取代C5～C8芳基或苄基的取代基为C1～C4烷基、卤素、-CF₃或氰基；a、b为0～3。Wherein X is a halogen or a C1-C4 alkyl group; L is a saturated or unsaturated 5- to 8-membered heterocycloalkyl group, a saturated or unsaturated C5-C8 cycloalkyl group; and the 5- to 8-membered heterocycloalkyl group heteroatoms are N, O or S, the heteroatom is 1 to 3; R _6, R ₇ independently is C1 ~ C4 alkyl group, a substituted or unsubstituted C5 ~ C8 aryl group, a substituted or unsubstituted Benzyl,
Or -CONH _2; C5 ~ C8 said substituted aryl group or a benzyl group substituents are C1 ~ C4 alkyl, halogen, -CF _3, or a cyano group; a, b is 0 to 3.
根据权利要求4所述的抗流感小分子化合物，其特征在于：The anti-influenza small molecule compound according to claim 4, wherein:

X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₆、R₇独立的为C1～C4烷基、取代或未取代的C5～C6芳基、取代或未取代的苄基、
或-CONH₂；所述取代C5～C6芳基或苄基的取代基为C1～C4烷基、卤素、-CF₃或氰基；a、b为0～2；X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C8 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N, O or S, the hetero atom is 1 to 3; R ₆ and R _{7 are} independently a C1 to C4 alkyl group, a substituted or unsubstituted C5 to C6 aryl group, a substituted or unsubstituted benzyl group,
Or -CONH ₂ ; the substituted C5-C6 aryl or benzyl substituent is C1-C4 alkyl, halogen, -CF ₃ or cyano; a, b is 0 to 2;

再进一步优选的，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；R₆、R₇独立的为C1～C4烷基、取代或未取代的苯基、取代或未取代的苄基、
或-CONH₂；所述取代苯基或苄基的取代基为C1～C4烷基或卤素；a、b为0～2；Still more preferably, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and a hetero atom of the 5- to 6-membered heterocycloalkyl group. Is N, O or S, the hetero atom is 1 to 3; R ₆ and R _{7 are} independently a C1 to C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group,
Or -CONH ₂ ; the substituted phenyl or benzyl substituent is C1-C4 alkyl or halogen; a, b is 0 to 2;

更进一步优选的，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；R₆、R₇独立的为C1～C4烷基、取代或未取代的苯基、取代或未取代的苄基、
或-CONH₂；所述取代苯基或苄基的取代基为C1～C4烷基、-F、-Cl或-Br；a、b为0～2；Still more preferably, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and a hetero atom of the 5- to 6-membered heterocycloalkyl group; Is N, O or S, wherein the hetero atom is 1-2; R ₆ and R _{7 are} independently a C 1 -C 4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group,
Or -CONH ₂ ; the substituted phenyl or benzyl substituent is C1-C4 alkyl, -F, -Cl or -Br; a, b is 0 to 2;

最优的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1个；R₆、R₇独立的为C1～C4烷基、取代或未取代的苯基、取代或未取代的苄基、
或-CONH₂；所述取代苯基或苄基的取代基为C1～C4烷基、-F、-Cl或-Br；a、b为0～2。Most preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. O or S, the hetero atom is one; R ₆ and R _{7 are} independently a C1 to C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group,
Or -CONH ₂ ; the substituent of the substituted phenyl or benzyl group is a C1-C4 alkyl group, -F, -Cl or -Br; a and b are 0-2.
根据权利要求1所述的抗流感小分子化合物，其特征在于：当R₁为H， R₂为
时，其结构如式Ⅳ所示：The anti-influenza small molecule compound according to claim 1, wherein when R ₁ is H, R ₂ is
When the structure is as shown in formula IV:

其中，n为0～4，X为卤素或C1～C4烷基；L为饱和或不饱和的5～8元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～8元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；Wherein n is 0 to 4, X is a halogen or a C1 to C4 alkyl group; L is a saturated or unsaturated 5 to 8 membered heterocycloalkyl group, a saturated or unsaturated C5 to C8 cycloalkyl group; The hetero atom of the 8-membered heterocycloalkyl group is N, O or S, and the hetero atom is 1 to 3;

R₈为取代或未取代的C5～C8环烷基、取代或未取代的5～8元芳杂基、取代或未取代的5～8元饱和杂环烷基、取代或未取代的5～8元不饱和杂环烷基、取代或未取代的C5～C10芳基、取代或未取代的C5～C10不饱和环烷基或取代或未取代的C5～C12的桥环烷基；所述5～8元饱和或不饱和杂环烷基、5～8元芳杂基的杂原子为N、O、S，杂原子个数为1～3个；所述取代C5～C8环烷基的取代基为-H或
所述取代5～8元芳杂基、5～8元饱和杂环烷基、5～8元不饱和杂环烷基的取代基为卤素取代的苄基、卤素、苯基、苄基、-CF₃或C1～C4羰基；所述取代C5～C10芳基的取代基为卤素、-OH、-SO₂NH₂、-CF₃或-COOH；所述取代C5～C10不饱和环烷基的取代基为-OH、卤素、-CF₃或-COOH；所述取代C5～C12的桥环烷基的取代基为-H、-OH或-COOH，a为0～3。R ₈ is a substituted or unsubstituted C 5 -C 8 cycloalkyl group, a substituted or unsubstituted 5-8 membered aryl group, a substituted or unsubstituted 5-8 membered saturated heterocycloalkyl group, a substituted or unsubstituted 5 ～ 8-membered unsaturated heterocycloalkyl, substituted or unsubstituted C5-C10 aryl, substituted or unsubstituted C5-C10 unsaturated cycloalkyl or substituted or unsubstituted C5-C12 bridged cycloalkyl; The heteroatoms of a 5- to 8-membered saturated or unsaturated heterocycloalkyl group and a 5- to 8-membered aryl group are N, O, and S, and the number of heteroatoms is 1 to 3; and the substituted C5-C8 cycloalkyl group The substituent is -H or
The substituent of the substituted 5- to 8-membered aryl group, the 5- to 8-membered saturated heterocycloalkyl group, and the 5- to 8-membered unsaturated heterocycloalkyl group is a halogen-substituted benzyl group, a halogen group, a phenyl group, a benzyl group, and a CF ₃ or a C 1 -C 4 carbonyl group; the substituent of the substituted C 5 -C 10 aryl group is a halogen, -OH, -SO ₂ NH ₂ , -CF ₃ or -COOH; the substituted C5-C10 unsaturated cycloalkyl group The substituent is -OH, halogen, -CF ₃ or -COOH; the substituent of the substituted C5 to C12 bridged cycloalkyl group is -H, -OH or -COOH, and a is 0 to 3.
根据权利要求6所述的抗流感小分子化合物，其特征在于：The anti-influenza small molecule compound according to claim 6, wherein:

n为0～4，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C8环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～3个；n is 0 to 4, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C8 cycloalkyl group; and the 5- to 6-membered heterocycloalkyl group is hetero The atom is N, O or S, and the hetero atom is 1 to 3;

R₈为取代或未取代的C5～C6环烷基、取代或未取代的5～6元芳杂基、取代或未取代的5～6元饱和杂环烷基、取代或未取代的5～6元不饱和杂环烷基、取代或未取代的C5～C8芳基、取代或未取代的C5～C10不饱和环烷基或取代或未取代的C5～C12的桥环烷基；所述5～6元饱和或不饱和杂环烷基、5～6元芳杂基的杂原子为N、O、S，杂原子个数为1～2个；所述取代C5～C6环烷基的取代基为-H或
所述取代5～6元芳杂基、5～6元饱和杂环烷基、5～6元不饱和杂环烷基的取代基为卤素取代的苄基、卤素、苯基、苄基、-CF₃或C1～C3羰基；所述取代C5～C8芳基的取代基为卤素、-OH、-SO₂NH₂、-CF₃或-COOH；所述取代C5～C10不饱和环烷基的取代基为-OH、-CF₃或-COOH；所述取代C5～C12的桥环烷基的取代基为-H、-OH或-COOH；a为0～3；R ₈ is a substituted or unsubstituted C 5 -C 6 cycloalkyl group, a substituted or unsubstituted 5-6-membered aryl group, a substituted or unsubstituted 5-6-membered saturated heterocycloalkyl group, a substituted or unsubstituted 5 ～ a 6-membered unsaturated heterocycloalkyl group, a substituted or unsubstituted C5-C8 aryl group, a substituted or unsubstituted C5-C10 unsaturated cycloalkyl group or a substituted or unsubstituted C5-C12 bridged cycloalkyl group; The hetero atom of a 5- to 6-membered saturated or unsaturated heterocycloalkyl group or a 5- to 6-membered aryl group is N, O, and S, and the number of hetero atoms is 1-2; and the substituted C5-C6 cycloalkyl group The substituent is -H or
The substituent of the substituted 5- to 6-membered arylhetero group, the 5- to 6-membered saturated heterocycloalkyl group, and the 5- to 6-membered unsaturated heterocycloalkyl group is a halogen-substituted benzyl group, a halogen group, a phenyl group, a benzyl group, and a CF ₃ or C1 to C3 carbonyl group; the substituent of the substituted C5 to C8 aryl group is a halogen, -OH, -SO ₂ NH ₂ , -CF ₃ or -COOH; the substituted C5-C10 unsaturated cycloalkyl group The substituent is -OH, -CF ₃ or -COOH; the substituent of the substituted C5 - C12 bridged cycloalkyl group is -H, -OH or -COOH; a is 0 to 3;

优选的，n为0～3，X为卤素；L为饱和或不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；Preferably, n is 0 to 3, X is a halogen; L is a saturated or unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the 5- to 6-membered heterocycloalkane The hetero atom of the group is N, O or S, and the hetero atom is 1 or 2;

R₈为取代或未取代的C5～C6环烷基、取代或未取代的5～6元芳杂基、取代或未取代的5～6元饱和杂环烷基、取代或未取代的5～6元不饱和杂环烷基、取代或未取代的C5～C6芳基、取代或未取代的C5～C10不饱和环烷基或取代或未取代的C5～C12的桥环烷基；所述5～6元饱和或不饱和杂环烷基、5～6元芳杂基的杂原子为N、O、S，杂原子个数为1～2个；所述取代C5～C6环烷基的取代基为-H或
所述取代5～6元芳杂基、5～6元饱和杂环烷基、5～6元不饱和杂环烷基的取代基为卤素取代的苄基、卤素、苯基、苄基、-CF₃或C1～C3羰基；所述取代C5～C6芳基的取代基为卤素、-OH、-SO₂NH₂、-CF₃或-COOH；所述取代C5～C10不饱和环烷基的取代基为-OH、-CF₃或-COOH；所述取代C5～C12的桥环烷基的取代基为-H、-OH或-COOH；a为0～3；R ₈ is a substituted or unsubstituted C 5 -C 6 cycloalkyl group, a substituted or unsubstituted 5-6-membered aryl group, a substituted or unsubstituted 5-6-membered saturated heterocycloalkyl group, a substituted or unsubstituted 5 ～ a 6-membered unsaturated heterocycloalkyl group, a substituted or unsubstituted C5-C6 aryl group, a substituted or unsubstituted C5-C10 unsaturated cycloalkyl group or a substituted or unsubstituted C5-C12 bridged cycloalkyl group; The hetero atom of a 5- to 6-membered saturated or unsaturated heterocycloalkyl group or a 5- to 6-membered aryl group is N, O, and S, and the number of hetero atoms is 1-2; and the substituted C5-C6 cycloalkyl group The substituent is -H or
The substituent of the substituted 5- to 6-membered arylhetero group, the 5- to 6-membered saturated heterocycloalkyl group, and the 5- to 6-membered unsaturated heterocycloalkyl group is a halogen-substituted benzyl group, a halogen group, a phenyl group, a benzyl group, and a CF ₃ or C1 to C3 carbonyl group; the substituent of the substituted C5 to C6 aryl group is a halogen, -OH, -SO ₂ NH ₂ , -CF ₃ or -COOH; the substituted C5-C10 unsaturated cycloalkyl group The substituent is -OH, -CF ₃ or -COOH; the substituent of the substituted C5 - C12 bridged cycloalkyl group is -H, -OH or -COOH; a is 0 to 3;

进一步优选的，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1～2个；Further preferably, X is a halogen; L is an unsaturated 5- to 6-membered heterocycloalkyl group, a saturated or unsaturated C5-C6 cycloalkyl group; and the hetero atom of the 5- to 6-membered heterocycloalkyl group is N. O or S, the hetero atom is 1 or 2;

R₈为取代或未取代的C5～C6环烷基、取代或未取代的5～6元芳杂基、取代或未取代的5～6元饱和杂环烷基、取代或未取代的5～6元不饱和杂环烷基、取代或未取代的苯基、取代或未取代的C5～C10不饱和环烷基或取代或未取代的C5～C12的桥环烷基；所述5～6元饱和或不饱和杂环烷基、5～6元芳杂基的杂原子为N、O，杂原子个数为1～2个；所述取代C5～C6环烷基的取代基为-H或
所述取代5～6元芳杂基、5～6元饱和杂环烷基、5～6元不饱和杂环烷基的取代基为氟取代的苄基、-F、-Cl、-Br、苯基、苄基、-CF₃或C1～C2羰基；所述取代苯基的取代基为-F、-Cl、-Br、-OH、-SO₂NH₂、-CF₃或-COOH；所述取代C5～C10不饱和环烷基的取代基为-OH、-CF₃或-COOH；所述取代C5～C12的桥环烷基的取代基为-H、-OH或-COOH；a为0～2；R ₈ is a substituted or unsubstituted C 5 -C 6 cycloalkyl group, a substituted or unsubstituted 5-6-membered aryl group, a substituted or unsubstituted 5-6-membered saturated heterocycloalkyl group, a substituted or unsubstituted 5 ～ a 6-membered unsaturated heterocycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C5-C10 unsaturated cycloalkyl group or a substituted or unsubstituted C5-C12 bridged cycloalkyl group; said 5-6 The hetero atom of the monosaturated or unsaturated heterocycloalkyl group, the 5- to 6-membered aryl group is N, O, and the number of hetero atoms is 1-2; the substituent of the substituted C5-C6 cycloalkyl group is -H or
The substituent of the substituted 5- to 6-membered arylhetero group, the 5- to 6-membered saturated heterocycloalkyl group, and the 5- to 6-membered unsaturated heterocycloalkyl group is a fluorine-substituted benzyl group, -F, -Cl, -Br, a phenyl group, a benzyl group, a -CF ₃ or a C1 to C2 carbonyl group; the substituent of the substituted phenyl group is -F, -Cl, -Br, -OH, -SO ₂ NH ₂ , -CF ₃ or -COOH; The substituent of the substituted C5-C10 unsaturated cycloalkyl group is -OH, -CF ₃ or -COOH; the substituent of the substituted C5-C12 bridged cycloalkyl group is -H, -OH or -COOH; 0 to 2;

最优的，n为0～3，X为卤素；L为不饱和的5～6元杂环烷基、饱和或不饱和的C5～C6环烷基；所述5～6元杂环烷基的杂原子为N、O或S，所述的杂原子为1个； Most preferably, n is 0 to 3, X is a halogen; L is an unsaturated 5 to 6 membered heterocycloalkyl group, a saturated or unsaturated C5 to C6 cycloalkyl group; and the 5 to 6 membered heterocycloalkyl group The hetero atom is N, O or S, and the hetero atom is one;

R₈为

R ₈ is
根据权利要求1所述的抗流感小分子化合物，其特征在于：其结构式为：The anti-influenza small molecule compound according to claim 1, wherein the structural formula is:
权利要求1～8任一项所述抗流感小分子化合物药学上可接受的盐。A pharmaceutically acceptable salt of the anti-influenza small molecule compound according to any one of claims 1 to 8.
权利要求1～8任一项所述抗流感小分子化合物药学上可接受的水合物。The pharmaceutically acceptable hydrate of the anti-influenza small molecule compound according to any one of claims 1 to 8.
药物组合物，这种药物组合物是由权利要求1～8任一项所述抗流感小分子化合物、权利要求9所述的盐或权利要求10所述的水合物添加药学上可以接受的辅助性成分制备而成的。A pharmaceutical composition which is a pharmaceutically acceptable auxiliary comprising the anti-influenza small molecule compound according to any one of claims 1 to 8, the salt according to claim 9 or the hydrate according to claim 10. Made of sexual ingredients.
权利要求1～8任一项所述抗流感小分子化合物、权利要求9所述的盐、权利要求10所述的水合物或权利要求11所述的药物组合物在制备抗流感药物中的用途。 Use of the anti-influenza small molecule compound according to any one of claims 1 to 8, the salt according to claim 9, the hydrate of claim 10 or the pharmaceutical composition according to claim 11 for preparing an anti-influenza medicine .
权利要求1～8任一项所述抗流感小分子化合物、权利要求9所述的盐、权利要求10所述的水合物或权利要求11所述的药物组合物在制备口服或静脉注射制剂中的用途。 The anti-influenza small molecule compound according to any one of claims 1 to 8, the salt according to claim 9, the hydrate of claim 10 or the pharmaceutical composition according to claim 11 in the preparation of an oral or intravenous preparation the use of.