Inherent immune activation drug and use thereof

Abstract

The invention provides an innate immune activation drug. The drug has broad-spectrum antiviral activity, immunologic adjuvant activity, immunotherapy promotion and antitumor activity. Specifically, the invention provides application of a compound shown as a formula I or a tautomer, a meracemate, a raceme, an enantiomer, a diastereoisomer, or a mixture form thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof in preparation of an innate immune activation drug. The compound disclosed by the invention can be used for inducing generation of I-type interferon, remarkably inhibiting virus infection, promoting immune function and resisting tumors. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular, the present invention relates to an innate immune activating drug having broad-spectrum antiviral activity and used for immunotherapy, anti-tumor and immune adjuvant, and its use. Background Art

[0002] Viral infection can cause a variety of diseases, and innate immunity is the first natural defense line of the host's immune system against pathogenic microorganisms. The antiviral innate immune response induces host cells to produce interferon to inhibit the reproduction and proliferation of viruses. Viruses will escape the innate immune response during evolution. Therefore, inducing the innate immune response to produce interferon provides a new idea for antiviral treatment.

[0003] At present, recombinantly expressed interferon is widely used in the treatment of viral infection, inflammation, immune dysfunction, etc., but it is a protein polypeptide, lacks post-translational modification, is unstable in structure, cannot be taken orally, and requires high storage conditions. It can only be administered by injection, and the administration method is single. In addition, its half-life is short and high concentrations can cause serious toxic side effects. The prominent disadvantage of interferon recombinantly expressed by Escherichia coli is the lack of glycosylation modification and limited activity; while the cost of glycosylated interferon expressed and purified by eukaryotic system is high, and the price of finished drug is expensive.

[0004] In summary, there is an urgent need in this field to develop new drugs that have the ability to induce the production of interferon.

[0005] In addition, the body's immune system can play an immune surveillance function to fight tumors. On the one hand, the immune system can identify and specifically eliminate malignant cells through immune mechanisms to resist the occurrence and development of tumors; on the other hand, malignant cells may escape the body's immune surveillance through various mechanisms, rapidly proliferate in the body, and form tumors. The occurrence and outcome of tumors depend on the results of these two aspects. As a tumor treatment drug, antibodies have excellent therapeutic effects due to their strong specificity. In addition, in the process of animal antibody production, due to factors such as the body's slow and poor immune response to antigens, the amount of antibodies produced is small, which limits its application and requires the help of immune adjuvants. Immune adjuvants, referred to as adjuvants, refer to auxiliary substances that are injected into the body before or at the same time as antigens to enhance the body's immune response to antigens or change the type of immune response. The immunobiological effects of adjuvants include prolonging the retention time of antigens in the body, enhancing the processing and presentation of antigens, and enhancing and amplifying immune responses. Since immune adjuvants have the effect of enhancing immune responses, they are widely used. Immune adjuvants should have the following characteristics: less side effects for specific animals; long-lasting and stable adjuvant effects; the production cost should be as low as possible; the immune response produced should be appropriate, and it is best to be able to induce the body's cellular or humoral immunity to meet the protection requirements, etc. Therefore, the development of new immune adjuvants that are highly efficient and low-toxic and can improve the body's immune level, cytokine secretion and immune memory is one of the current research hotspots.

[0006] Therefore, there is a need in the art to develop drugs that promote tumor immunotherapy and serve as immune adjuvants. Summary of the invention

[0007] The present invention aims to solve the current technical problem of lack of new drugs that can effectively enhance human innate immunity, and to provide an innate immunity activating drug that can not only induce the production of interferon to fight viral infection, but also promote tumor immunotherapy and be used as an immune adjuvant.

[0008] In one aspect of the present invention, there is provided a compound of formula I or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof for use in preparing an innate immune activating drug,

[0009]

[0010] Wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, alkenyl, alkynyl, amino, hydroxyl, sulfhydryl, carboxyl, alkoxy, cycloalkyloxy, haloalkyl, cyano, sulfanyl, sulfonyl, sulfone, sulfoxide, phosphate, and the alkyl, cycloalkyl, alkoxy, cycloalkyloxy, amino, heterocyclic group, aryl or heteroaryl may be substituted by one or more substituents selected from hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, The invention further comprises one or more substituents selected from the group consisting of cycloalkyloxy, heterocyclic group, aryl, halogenated aryl, halogenated alkyl, heteroaryl, alkenyl, alkynyl, amino, thiol, carboxyl, ester, alkoxycarbonyl, acyloxy, amide, urea, alkylsulfonyl, aromatic sulfonyl, cyano, nitro, nitroso, thiocyanate, isothiocyanate, sulfanyl, sulfonyl, phosphate, phosphonate, alkylphosphate, alkylphosphonate, arylphosphate, arylphosphonate, or is empty; the heterocyclic group contains at least one N atom, or contains 1, 2, or 3 heteroatoms selected from N, S and O.

[0011] Wherein, the "substituted" refers to that one or more (preferably 1, 2, 3, 4, 5, 6, 7 or 8) hydrogen atoms on a ring or group are replaced by a substituent selected from the following group: hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, heterocyclic group, aryl, halogenated aryl, halogenated alkyl, heteroaryl, alkenyl, alkynyl, amino, thiol, carboxyl, ester, alkoxycarbonyl, acyloxy, amide, urea, alkylsulfonyl, aromatic sulfonyl, cyano, nitro, nitroso, thiocyanate, isothiocyanate, sulfanyl, sulfonyl, sulfo, phosphate, phosphonate, alkylphosphate, alkylphosphonate, arylphosphate and arylphosphonate.

[0012] The heteroaryl group has 1 to 4 (preferably 1, 2, 3 or 4) heteroatoms selected from N, O and S on the heterocyclic ring.

[0013] In another preferred embodiment, R1, R2, R5, R7, and R10 are each independently hydrogen, substituted or unsubstituted C1-C10 alkyl, or substituted or unsubstituted C3-C12 cycloalkyl.

[0014] In another preferred embodiment, R1, R2, R5, R7, and R10 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl.

[0015] In another preferred embodiment, R1, R2, R5, R7, and R10 are each independently hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl.

[0016] In another preferred embodiment, R1, R2, R5, R7, and R10 are each independently hydrogen, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl.

[0017] In another preferred embodiment, R1, R2, R5, R7, and R10 are each independently hydrogen, methyl, ethyl, propyl or butyl.

[0018] In another preferred embodiment, R3 and R4 are each independently hydrogen, substituted or unsubstituted C1-C8 alkoxy, or substituted or unsubstituted C1-C8 alkylthio.

[0019] In another preferred embodiment, R3 and R4 are each independently hydrogen, substituted or unsubstituted C1-C6 alkoxy, or substituted or unsubstituted C1-C6 alkylthio.

[0020] In another preferred embodiment, R3 and R4 are each independently hydrogen, substituted or unsubstituted C1-C4 alkoxy, or substituted or unsubstituted C1-C4 alkylthio.

[0021] In another preferred embodiment, R3 and R4 are each independently hydrogen, substituted or unsubstituted C1-C2 alkoxy, or substituted or unsubstituted C1-C2 alkylthio.

[0022] In another preferred embodiment, R6 is a substituted or unsubstituted amino group, a substituted or unsubstituted heterocyclic group, a heterocyclic alkyl group or an alkyl heterocyclic group.

[0023] In another preferred embodiment, R8 is a halogenated alkyl group.

[0024] In another preferred embodiment, R9 is hydrogen, halogen, or amino.

[0025] In another preferred embodiment, the compound of formula I comprises:

[0026]

[0027] Preferably, the innate immunity activating drug comprises:

[0028] (a) Broad-spectrum antiviral drugs;

[0029] (b) anti-tumor drugs;

[0030] (c) drugs for the prevention and / or treatment of cancer;

[0031] (d) drugs for treating or preventing type I interferon-related diseases;

[0032] (e) immune adjuvants;

[0033] and / or (f) cytokine inducers.

[0034] In another preferred embodiment, the cytokine is selected from the following group: interferon, tumor necrosis factor, interleukin, or a combination thereof.

[0035] In another preferred embodiment, the interferon is selected from the following group: type I interferon, type II interferon, type III interferon, or a combination thereof.

[0036] In another preferred embodiment, the interferon is selected from the following group: IFNβ (interferon-β), IFNλ (interferon-λ), TNFα (tumor necrosis factor-α), or a combination thereof.

[0037] In another preferred embodiment, the interleukin is selected from the following group: IL6 (interleukin-6), IL1α (interleukin-1α), or a combination thereof.

[0038] In another preferred embodiment, the cytokines include cytokines in blood, serum or plasma.

[0039] In another preferred embodiment, the cytokine inducer increases the level or content of the cytokine.

[0040] In another preferred embodiment, the blood includes peripheral blood.

[0041] In another preferred embodiment, the inducing agent includes:

[0042] (i) inducing the expression of cytokines; and / or

[0043] (i) Inducing an increase in the levels of cytokines.

[0044] In another preferred embodiment, the inducing agent includes inducing the increase of cytokines in peripheral blood.

[0045] In another preferred embodiment, the adjuvant comprises an antibody adjuvant.

[0046] In another preferred embodiment, the immune adjuvant is used to enhance the immune titer of the antibody.

[0047] In another preferred embodiment, the immune adjuvant is used to promote the production of antibodies or as an antibody production promoter.

[0048] In another preferred embodiment, the antibodies include serum antibodies.

[0049] In another preferred embodiment, the antigen targeted by the antibody includes a protein antigen.

[0050] In another preferred embodiment, the protein antigen includes albumin antigen.

[0051] In another preferred embodiment, the albumin antigen includes ovalbumin antigen.

[0052] In another preferred embodiment, the immune adjuvant is used to prepare antibodies, vaccines, immunotherapeutic drugs and / or immune activators.

[0053] In another preferred embodiment, the antibody is selected from the following group: IgG, IgM, or a combination thereof.

[0054] In another preferred embodiment, the IgG includes IgG1.

[0055] In another preferred embodiment, the vaccine comprises a tumor vaccine.

[0056] In another preferred embodiment, the type I interferon-related disease refers to a disease that is improved, treated or prevented by increasing the level of type I interferon in the body.

[0057] In another preferred embodiment, the type I interferon (IFN) related diseases include: viral infection, and multiple sclerosis and / or chronic myeloid leukemia.

[0058] In another preferred embodiment, the viruses include DNA viruses and RNA viruses.

[0059] In another preferred embodiment, the DNA virus includes: HSV (herpes simplex virus), HBV (hepatitis B virus), HAV (hepatitis A virus), HPV (human papillomavirus) and / or EBV (Epstein-Barr virus).

[0060] In another preferred embodiment, the RNA virus includes: VSV (vesicular stomatitis virus), HCV (hepatitis C virus), EMCV (encephalomyocarditis virus), Ebola (Ebola virus), HIV (human immunodeficiency virus) and / or Zika virus.

[0061] In another aspect of the present invention, a method for inducing a subject to produce type I interferon is provided, wherein the method comprises the step of contacting the subject with a compound of formula I, thereby inducing the subject to produce type I interferon.

[0062] In another preferred embodiment, the object is a cell.

[0063] In another preferred embodiment, the cells include: Vero cells, THP-1 cells, HEK293 cells, HEK293T cells, and / or A549 cells.

[0064] In another preferred embodiment, the method is non-therapeutic in vitro.

[0065] In another preferred embodiment, the method comprises the step of: culturing the subject in a system containing the compound of formula I, thereby inducing the subject to produce interferon.

[0066] In another preferred embodiment, in the system containing the compound of formula I, the concentration of the compound of formula I is ≥1 μM; preferably, ≥3 μM.

[0067] In another preferred embodiment, the incubation time is 10 min to 48 h.

[0068] In another preferred embodiment, the type I interferon includes IFNβ.

[0069] In another aspect of the present invention, a method for inhibiting viral infection is provided, comprising the steps of:

[0070] The subject is contacted with a compound of Formula I, thereby inhibiting infection of the subject with a virus.

[0071] In another preferred embodiment, the object is a cell.

[0072] In another preferred embodiment, the cells include: Vero cells, THP-1 cells, HEK293 cells, HEK293T cells, and / or A549 cells.

[0073] In another preferred embodiment, the viruses include DNA viruses and RNA viruses.

[0074] In another preferred embodiment, the DNA virus includes: HSV (herpes simplex virus), HBV (hepatitis B virus), HAV (hepatitis A virus), HPV (human papillomavirus) and / or EBV (Epstein-Barr virus) and the like.

[0075] In another preferred embodiment, the RNA virus includes: VSV (vesicular stomatitis virus), HCV (hepatitis C virus), EMCV (encephalomyocarditis virus), Ebola (Ebola virus), HIV (human immunodeficiency virus) and / or Zika virus, etc.

[0076] In another preferred embodiment, the method is non-therapeutic in vitro.

[0077] In another preferred embodiment, the method comprises the step of: culturing the subject in a system containing the compound of formula I, thereby inducing the subject to produce interferon.

[0078] In another aspect of the present invention, a method for increasing the level of type I interferon in vivo is provided, wherein the method comprises the steps of:

[0079] A compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof.

[0080] In another preferred embodiment, the subject is a mammal; preferably, selected from the group consisting of humans, mice, and rats.

[0081] In another aspect of the present invention, a broad-spectrum antiviral pharmaceutical composition is provided, comprising: a compound of formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0082] In another aspect of the present invention, an immune composition is provided, comprising: a compound of formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and an antigen.

[0083] In another preferred embodiment, the antigen comprises a protein antigen.

[0084] In another preferred embodiment, the protein antigen includes albumin antigen.

[0085] In another preferred embodiment, the albumin antigen includes ovalbumin antigen.

[0086] In another aspect of the present invention, an anti-tumor pharmaceutical composition is also provided, which comprises: a compound of formula I or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0087] In another aspect of the present invention, a composition is also provided, comprising

[0088] (a) a first active ingredient, wherein the first active ingredient is a compound of formula I, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and

[0089] (b) a therapeutically effective amount of a second active ingredient, wherein the second active ingredient comprises: an immunotherapy activator, a type I interferon modulator, or an antiviral agent.

[0090] In another aspect of the present invention, a medicine kit is provided, comprising:

[0091] (A) a first preparation containing a first active ingredient, wherein the first active ingredient is a compound of formula I, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and

[0092] (B) A second formulation comprising a second active ingredient, wherein the second active ingredient comprises: an immunotherapy activator, a type I interferon modulator, or an antiviral agent.

[0093] In another preferred embodiment, the immunotherapy activator includes PD-1 or PD-L1 antibody. The compound represented by formula I of the present invention and PD-1 or PD-L1 antibody are used in combination to exert a synergistic effect, significantly increase the inhibitory effect on tumor growth, and significantly improve the survival period.

[0094] In another aspect of the present invention, there is also provided a use of the above composition or the above kit for preparing an innate immune activation drug, the drug comprising:

[0095] (a) Broad-spectrum antiviral drugs;

[0096] (b) anti-tumor drugs;

[0097] (c) drugs for the prevention and / or treatment of cancer;

[0098] (d) drugs for treating or preventing type I interferon-related diseases;

[0099] (e) immune adjuvants;

[0100] and / or (f) cytokine inducers.

[0101] The main advantages of the innate immune activating drug of the present invention include:

[0102] (a) The present invention discovered that the compound of formula I exhibits a strong ability to induce the expression of interferon (such as IFNβ).

[0103] (b) The present invention finds that the compound of formula I has excellent ability to inhibit viral infection and antiviral activity.

[0104] (c) The present invention finds that the compound of formula I can efficiently and safely induce the production of cytokines, and thus can be used to treat cytokine-related diseases such as tumors.

[0105] (d) The present invention finds that the compound of formula I can be used as an immune adjuvant to significantly increase the immune titer of antibodies and promote the production of antibodies, thereby being used to prepare antibodies, vaccines, immunotherapeutic drugs and immune activators, thereby improving the application value of antibodies.

[0106] (e) The compounds of the present invention have high efficacy, good drugability and low side effects.

[0107] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0108] After extensive and in-depth research, the inventors found that a class of three-membered heterocyclic compounds can activate the host's inherent immunity and induce different cells to express or produce cytokines such as type I interferon IFNβ. In addition, this type of compound has a broad-spectrum inhibitory effect (dose-related) on RNA virus (such as VSV) and DNA virus (such as HSV) infection. Thus, a new drug with the ability to induce cells to produce IFNβ and potential broad-spectrum antiviral effects in clinical treatment is provided. It was unexpectedly found that the compound of formula I described in the present invention has an excellent induction effect on cytokines and is used to treat diseases such as tumors. At the same time, the compound of formula I described in the present invention can also be used as an immune adjuvant to significantly improve the immune titer of antibodies and promote the production of antibodies, thereby being used to prepare antibodies, vaccines, immunotherapy drugs and immune activators, and improving the application value of antibodies.

[0109] Innate immunity

[0110] The host's innate immunity is the first line of defense of the immune system against pathogenic microorganisms. Viruses in nature are pathogens that can cause a variety of diseases. The host cell's antiviral innate immune response can induce the production of interferon to inhibit the reproduction and proliferation of viruses. The antiviral innate immune response is mediated by the signal transduction pathway. Previous studies have revealed how the innate immune system recognizes viral invasion and quickly triggers immune defense functions, thereby effectively clearing viral infections. This is an important study in the field of life sciences and medicine, providing a theoretical basis for the design of related drugs and bringing new hope for the prevention and treatment of viral infections. After detecting pathogenic microorganisms, host cells induce the production of interferon, proinflammatory factors, and chemokines through the innate immune signaling pathway. On the one hand, these effector factors can inhibit the replication of pathogens, thereby playing a role in rapidly controlling the proliferation of pathogens; on the other hand, these cytokines can mobilize other immune cells of the host, including antigen presenting cells and T and B lymphocytes in the adaptive immune system, to activate adaptive immunity. In addition, the induction and activation of the innate immune response also has an anti-tumor effect and can enhance the effects of radiotherapy and chemotherapy.

[0111] The innate immune signaling pathway starts with the recognition of the molecular patterns of pathogenic microorganisms by the pattern recognition receptors of the host cells. The innate immune signaling pathways related to viral infection that have been discovered so far mainly include the RLR-MAVS signaling pathway that recognizes RNA viruses in the cytoplasm, the cGAS-STING signaling pathway that recognizes DNA viruses, and the TLRs signaling pathway. After activation, both RLRs and cGAS signaling pathways recruit and activate TBK1 through downstream transduction proteins. TBK1 phosphorylates the transcription factor IRF3 and enters the nucleus to induce the production of type I interferon, ultimately achieving the effect of inhibiting the virus. In the long-term evolution process, some viruses have also acquired some mechanisms to escape the innate immune response.

[0112] Since innate immunity plays an important role in every aspect of the body's life activities, innate immunity has important guiding significance for the development of vaccines and drugs.

[0113] the term

[0114] Active ingredients

[0115] As used herein, the term "compound of the present invention" refers to a compound of formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, isomers, hydrates, solvates or prodrugs of the compound of formula I.

[0116] The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a compound of the present invention and an acid. Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid. Another preferred salt is a salt of the compound of the present invention and a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0117] The compound of formula I described in the present invention can be converted into its pharmaceutically acceptable salt by conventional methods. For example, a solution of the corresponding acid can be added to a solution of the above compound. After the salt is completely formed, the solvent is removed to obtain the corresponding salt of the compound described in the present invention.

[0118] As used herein, the term "prodrug" includes a prodrug which may be biologically active or inactive, and when taken by an appropriate method, undergoes metabolism or chemical reaction in the human body to be converted into a compound of Formula I, or a salt or solution composed of a compound of Formula I. The prodrug includes (but is not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like forms of the compound.

[0119] First active ingredient

[0120] The first active ingredient of the present invention is a compound of formula I, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a racemate thereof, or a solvate thereof, or a prodrug thereof.

[0121] As used herein, "compounds of the present invention", "compounds of formula I of the present invention", or "compounds of formula I" are used interchangeably to refer to compounds of formula I, or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof. It should be understood that the term also includes mixtures of the above components.

[0122]

[0123] In Formula I, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic group, alkenyl, alkynyl, amino, hydroxyl, sulfhydryl, carboxyl, alkoxy, cycloalkyloxy, haloalkyl, cyano, sulfanyl, sulfonyl, sulfone, sulfoxide, and phosphate, and the alkyl, cycloalkyl, alkoxy, cycloalkyloxy, amino, heterocyclic group, aryl, or heteroaryl may be substituted with one or more substituents selected from hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, The invention further comprises one or more substituents selected from the group consisting of cycloalkyloxy, heterocyclic group, aryl, halogenated aryl, halogenated alkyl, heteroaryl, alkenyl, alkynyl, amino, thiol, carboxyl, ester, alkoxycarbonyl, acyloxy, amide, urea, alkylsulfonyl, aromatic sulfonyl, cyano, nitro, nitroso, thiocyanate, isothiocyanate, sulfanyl, sulfonyl, phosphate, phosphonate, alkylphosphate, alkylphosphonate, arylphosphate, arylphosphonate, or is empty; the heterocyclic group contains at least one N atom, or contains 1, 2, or 3 heteroatoms selected from N, S and O.

[0124] Preferred compounds of the present invention include:

[0125]

[0126] Second active ingredient

[0127] The second active ingredient of the present invention is an antiviral, antitumor, immunomodulatory and immune adjuvant drug, which can be used in combination with PD-1 or PD-L1 antibodies for immunotherapy.

[0128] As used in this article, the term "PD-L1" is programmed cell death-ligand 1, which is an important immunosuppressive molecule. PD-L1 is expressed on the surface of tumors and binds to PD-1 on the surface of T cells, inhibiting T cell proliferation and cytokine secretion, negatively regulating lymphocyte activation, and participating in tumor immune escape.

[0129] Pharmaceutical compositions and methods of administration

[0130] Since the compounds of the present invention have excellent ability to induce the production of type I interferon, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to type I interferon (especially those diseases that can be improved, treated or prevented by regulating the level of interferon in the body, such as increasing the level of interferon). According to the prior art, the compounds of the present invention can be used to treat the following diseases: viral infection, multiple sclerosis, systemic lupus erythematosus and chronic myeloid leukemia, etc.

[0131] As used herein, the terms "induce the production of interferon", "induce the production of type I interferon", "induce the production of type I interferon" or "induce the production of interferon" can be used interchangeably and are intended to include: increasing the expression, transcription or protein content level of type I interferon or proteins, cytokines, etc. associated with type I interferon.

[0132] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-500 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0133] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0134] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0135] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0136] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0137] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0138] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0139] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0140] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0141] Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0142] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0143] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0144] Composition or formulation, combination of active ingredients and kit and method of administration

[0145] The present invention also provides a composition or preparation, a combination of active ingredients and a medicine kit, which can be used to prepare innate immunity activating drugs, and the drugs include: (a) broad-spectrum antiviral drugs; (b) anti-tumor drugs; (c) drugs for preventing and / or treating cancer; (d) drugs for treating or preventing type I interferon-related diseases; (e) immune adjuvants; and / or (f) cytokine inducers.

[0146] The composition of the present invention is preferably a pharmaceutical composition. The composition of the present invention may include a pharmaceutically acceptable carrier.

[0147] The pharmaceutical preparation should match the mode of administration. The preferred modes of administration are oral administration and injection (such as intratumoral injection). When used, a therapeutically effective amount of the drug is administered to the desired subject (such as a human or non-human mammal). As used herein, the term "therapeutically effective amount" refers to an amount that produces a function or activity on humans and / or animals and can be accepted by humans and / or animals. It should be understood by those of ordinary skill in the art that the "therapeutically effective amount" may vary depending on the form of the pharmaceutical composition, the route of administration, the excipients of the drug used, the severity of the disease, and the combination with other drugs.

[0148] In one mode of administration, the safe and effective daily dose of the first active ingredient is usually at least about 0.1 mg, and in most cases does not exceed about 2500 mg. Preferably, the dose is 1 mg-500 mg; the safe and effective amount of the second active ingredient is usually at least about 0.01 mg, and in most cases does not exceed 2500 mg. Preferably, the dose range is 0.1 mg to 2500 mg. Of course, the specific dose should also take into account factors such as the route of administration and the patient's health status, which are all within the skill range of skilled physicians.

[0149] Example 1 Compounds of the present invention induce cells to secrete interferon

[0150] 1. Transfer various cells such as HEK293, HEK293T, THP-1 and A549 in the logarithmic growth phase into 12-well cell culture plates, with 5×10 cells per well. 5 After the cells adhered for 6 hours, the cell culture supernatant was replaced with culture medium containing the compound of the present invention at final concentrations of 1 μM, 3 μM and 10 μM, respectively, and the culture was continued for 12 hours. Finally, the cells were collected and the total cellular RNA was extracted.

[0151] Then, qPCR was used to detect the expression of IFNβ mRNA induced by drugs in various cells such as HEK293, HEK293T, THP-1 and A549. The results showed that the compounds of the present invention can induce an increase in the transcription level of IFNβ in cells.

[0152] 2. HEK293, HEK293T, THP-1 and A549 cells in logarithmic growth phase were transferred into 12-well cell culture plates, with 5×10 cells per well. 5 After the cells were attached for 6 hours, the cell culture supernatant was replaced with culture medium containing the compound of the present invention at final concentrations of 1 μM, 3 μM and 10 μM, respectively, and the culture was continued for 12 hours, and finally the cell culture supernatant was collected.

[0153] ELISA was used to detect the contents of IFNβ, TNFα and IL-6 in the cell culture supernatant. The results showed that the compound of the present invention can induce A549 cells to secrete IFNβ.

[0154] Example 2 Effects of the compounds of the present invention on RNA virus (such as VSV or IAV) infection

[0155] Vesicular stomatitis virus (VSV) was selected as a representative of RNA viruses; specifically, the VSV-GFP virus strain (donated by the Southwestern Medical Center, USA) was used, that is, VSV itself can express green fluorescent protein GFP, which is conducive to indicating the proliferation and load of the virus.

[0156] Vero cells in the logarithmic growth phase were transferred into 12-well cell culture plates, with 5×10 cells per well. 5 After the cells adhered for 6 hours, the cell culture supernatant was replaced with a medium containing different final concentrations of the compound of the present invention (or DMSO) and a titer of VSV-GFP of 0.5, and the culture was continued for 16 hours. At this time, the cell culture supernatant was discarded, and after the cells were fixed, the cell nuclei were stained with Hoechst (a fluorescent dye that stains the cell nucleus), and the expression of green fluorescent protein and the staining of the cell nucleus were observed under a fluorescence microscope. The results showed that the signal of GFP expressed by the VSV virus was significantly weakened in the drug-treated group compared with the control group, i.e., the DMSO-treated group, indicating that VSV-GFP infection was inhibited. Moreover, this inhibitory effect increased with the increase of drug concentration.

[0157] Under the condition of VSV-GFP infection of Vero cells, after treatment with different concentrations of the compound of the present invention, the EC50 (half effective concentration) of the inhibitory effect of the compound of the present invention on VSV-GFP infection was calculated according to the degree of virus inhibition. The results showed that the compound of the present invention has excellent antiviral activity and safety.

[0158] Example 3 Effects of the compounds of the present invention on DNA virus (such as HSV) infection

[0159] Herpes simplex virus HSV was selected as a representative of DNA viruses; specifically, the HSV-1-GFP virus strain (donated by Shanghai Pasteur Institute, Chinese Academy of Sciences) was used, that is, HSV itself can express green fluorescent protein GFP, which can indicate the proliferation and load of the virus.

[0160] Vero cells in the logarithmic growth phase were transferred into 12-well cell culture plates, with 5×10 cells per well. 5 After the cells adhered for 6 hours, the cell culture supernatant was replaced with a medium containing different final concentrations of the compound of the present invention (or DMSO) and a titer of HSV-GFP of 0.5, and the culture was continued for 16 hours. At this time, the cell culture supernatant was discarded, and after the cells were fixed, the cell nuclei were stained with Hoechst, and the expression of green fluorescent protein and the staining of the cell nucleus were observed under a fluorescence microscope. The results showed that the compound of the present invention had a significant inhibitory effect on HSV virus infection.

[0161] Under the condition of HSV-GFP infection of Vero cells, after treatment with different concentrations of the compound of the present invention, the EC50 (half effective concentration) of the inhibitory effect of the compound of the present invention on HSV-GFP infection was calculated according to the degree of virus inhibition. The results showed that the compound of the present invention has excellent antiviral activity and safety.

[0162] Example 4 The compounds of the present invention have anti-tumor effects and promote tumor immunotherapy

[0163] 1. Methods

[0164] In this experiment, the B16-F10 melanoma cell line was purchased from the cell bank of the Chinese Academy of Sciences in Shanghai. It was routinely cultured in DMEM medium containing 10% FBS and placed in a 5% CO2 incubator at 37°C. Cells in the exponential proliferation phase were digested with 0.25% trypsin, centrifuged and resuspended in PBS for counting. The viable cell rate was detected to be above 95%. After counting, the concentration of the cell suspension was adjusted to 2*10^ 6 L -1 The resuspended tumor cells were dispensed into sterile EP tubes and placed on ice for later use.

[0165] The hair on the back of the mouse was removed with an electric shaver, and the hair removal area was about 9 cm 2 . Take the prepared B16-F10 cells and inject 100 μL of tumor cell suspension subcutaneously on the back of each mouse. Observe the tumor growth of mice every day. On the 4th day, the formation of melanoma was visible to the naked eye. Mice without tumor formation were eliminated and the remaining mice were randomly divided into 7 groups, with 6-8 mice in each experimental group.

[0166] Experiment 1 was divided into a control group, a 10 μg compound of the present invention group, and a 30 μg compound of the present invention group; Experiment 2 was divided into a control group, a 10 μg compound of the present invention group, a 200 μg anti-PD-L1 antibody (B7-H1) (Clone: ​​10F.9G2) group, and a 10 μg compound of the present invention + 200 μg anti-PD-L1 antibody (B7-H1) (Clone: ​​10F.9G2) group, with 6-8 mice in each group. The experimental method was as follows: on the fifth day after tumor cell injection, the tumor-bearing mice were administered according to the grouping, and the mice were fed with the compound of the present invention by gavage, and two dose groups were set: 10 μg / mouse and 30 μg / mouse. Anti-PD-L1 antibody was administered by intraperitoneal injection, and one dose group was set: 200 μg / mouse. The solvent buffer system for administration was PBS buffer solution. The control group was gavaged with the same volume of PBS buffer solution. For the compound of the present invention, each mouse was administered once every 4 days, for a total of 3 times. The administration volume was 100 μL. For anti-PD-L1 antibodies, each mouse was given the drug once every 4 days, for a total of 3 times. The dosing volume was 50μL. Specifically, the drug was given on the 5th, 9th, and 13th days, with an interval of 4 days, for a total of 3 times. The tumor size was measured every other day, the survival of the mice was observed and the relevant data were recorded. The tumor volume was measured using an electronic caliper, and the volume calculation formula was: π / 6x length x width x height. The tumor volume was greater than 2000mm 2 Tumor-bearing mice were killed.

[0167] 2. Experimental results

[0168] 2.1 The compounds of the present invention can increase the levels of cytokines in serum

[0169] Six hours after different doses of the compound of the present invention were intraperitoneally injected into mice, the changes in the levels of various cytokines in serum were detected by ELISA. The results showed that the compound of the present invention could increase the levels of cytokines IFNβ (interferon-β), IFNλ (interferon-λ), TNFα (tumor necrosis factor-α), IL6 (interleukin-6) and IL1α (interleukin-1α) in serum, and in particular, the compound of the present invention could significantly increase the levels of cytokines type I interferon IFNβ and type III interferon IFNλ in serum.

[0170] 2.2 The compounds of the present invention inhibit the growth of subcutaneous melanoma in mice and increase the survival period of tumor-bearing mice.

[0171] By establishing a subcutaneous melanoma-bearing mouse model, the inhibitory effect of the compound of the present invention and the compound of the present invention + anti-PD-L1 on tumor growth and the improvement of the survival of tumor-bearing mice were detected. The results showed that compared with the control group, the single administration of the compound of the present invention had a significant dose-dependent inhibitory effect on the growth of melanoma and improved the survival of tumor-bearing mice.

[0172] Compared with the control group and the single administration of the compound of the present invention, anti-PD-L1 can significantly enhance the inhibitory effect of the compound of the present invention on melanoma growth and improve the survival of mice. From the result data, it can be seen that the combination of the compound of the present invention + anti-PD-L1 can play a synergistic role, and the inhibitory effect on melanoma growth and the improvement of the survival of mice are more significant.

[0173] As can be seen from this example, the compounds of the present invention can induce the increase of various cytokines such as interferon in peripheral blood, have excellent inhibitory effects on tumors such as melanoma and improve survival. Anti-PD-L1 can significantly enhance the inhibitory effect of the compounds of the present invention on the growth of tumors such as melanoma and improve survival. The combination of the compounds of the present invention + anti-PD-L1 has a synergistic effect in inhibiting tumor growth and improving survival. Therefore, the compounds of the present invention can be used as a drug that induces various cytokines such as interferon, has anti-tumor effects and promotes tumor immunotherapy.

[0174] Example 5 The compounds of the present invention have immune adjuvant activity

[0175] 1. Detection of the compounds of the present invention as immunostimulants

[0176] First, the effect of the compound of the present invention as an immunostimulant on mice was investigated. In the experimental group, mice were intraperitoneally injected with different concentrations of the compound of the present invention (10μg, 30μg or 90μg), and the injection dose was 50μL / each. Blank group (injection of the same volume of PBS). 6 hours after the injection, blood was collected from the mouse eyeballs, and the serum was collected. After dilution, the content of corresponding cytokines in the mouse serum was detected by ELISA. The results showed that the experimental group of the compound of the present invention can significantly increase the level of interferon in the serum, including the level of type I interferon IFNβ and type III interferon IFNλ, and also increase the levels of TNFα, IL1α and IL-6, indicating that the compound of the present invention can be used as a new type of immunostimulant.

[0177] 2. Detection of the effect of the compounds of the present invention as immune adjuvants on mouse antibody production

[0178] The experiment was divided into a blank group (injected with the same volume of PBS), an antigen group and an antigen / compound of the present invention group (including different concentration gradients), with 5 mice in each group. The antigen ovalbumin OVA and the compound of the present invention were dissolved in PBS to obtain an antigen solution and a compound of the present invention solution, and the compound of the present invention solution containing different concentration gradients of the antigen was prepared according to the concentration requirements. Each mouse in the experimental group was immunized with 100 μl of antigen solution or antigen solution and Mepacrine solution each time, and the immunization method was intramuscular injection. The blank group mice were injected with the same volume of PBS solution as the experimental group. The first immunization was set as day 0, and booster immunization was performed once on the 7th day and the 14th day, respectively. After the immunization on the 21st day, blood was collected from the mouse eyeballs, and serum was collected. After dilution, the antibody content in the mouse serum was detected by ELISA. The results showed that compared with the antigen group, the total amount of OVA-specific IgG and IgG1 antibodies in the serum of mice in the antigen and compound of the present invention groups was significantly increased, and the statistical difference was significant, indicating that the compound of the present invention has obvious immune adjuvant activity.

[0179] The results of this example show that the compounds of the present invention can significantly increase the expression of related cytokines, especially type I and type III interferon factors, after intraperitoneal injection into mice as immunostimulants, indicating that the compounds of the present invention have the function of immunostimulants.

[0180] In this example, ovalbumin OVA was used as an antigen, and the compound of the present invention was used as an antigen adjuvant to immunize C57BL / 6 mice, and the humoral immune effect was detected by ELISA, including the level of serum OVA-specific IgG antibodies and subclass IgG antibody levels. The results showed that OVA alone could not produce a protective humoral immune response, and when OVA was combined with the compound of the present invention to immunize mice, the antibody production level could be significantly increased, indicating that the compound of the present invention has obvious immune adjuvant activity.

[0181] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

Claims

1. A use of a compound of formula I or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, for preparing an innate immune activating drug, in, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, amino, hydroxyl, sulfhydryl, carboxyl, alkoxy, cycloalkyloxy, haloalkyl, cyano, sulfanyl, sulfonyl, sulfone, sulfoxide, phosphate, and the alkyl, cycloalkyl, alkoxy, cycloalkyloxy, amino, heterocyclic, aryl or heteroaryl may be substituted with one or more substituents selected from hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, amino, heterocyclic, aryl or heteroaryl. The invention relates to a alkylene group, wherein the alkylene group comprises one or more substituents selected from the group consisting of oxy, heterocyclic, aryl, halogenated aryl, halogenated alkyl, heteroaryl, alkenyl, alkynyl, amino, thiol, carboxyl, ester, alkoxycarbonyl, acyloxy, amide, urea, alkylsulfonyl, aromatic sulfonyl, cyano, nitro, nitroso, thiocyanate, isothiocyanate, sulfanyl, sulfonyl, phosphate, phosphonate, alkylphosphate, alkylphosphonate, arylphosphate, and arylphosphonate, or is empty; the heterocyclic group contains at least one N atom, or contains 1, 2, or 3 heteroatoms selected from N, S, and O.

2. The use according to claim 1, characterized in that The compound of formula I includes:

3. The use according to claim 1 or 2, characterized in that The innate immune activating drugs include: (a) Broad-spectrum antiviral drugs; (b) anti-tumor drugs; (c) drugs for the prevention and / or treatment of cancer; (d) drugs for treating or preventing type I interferon-related diseases; (e) immune adjuvants; and / or (f) cytokine inducers.

4. The use according to claim 3, characterized in that The immune adjuvant is used to prepare antibodies, vaccines, immunotherapeutic drugs and / or immune activators.

5. A broad-spectrum antiviral drug composition, characterized in that: The pharmaceutical composition comprises: a compound of formula I according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

6. An immune composition, characterized in that The immune composition comprises: the compound of formula I according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, or its prodrug; and antigens.

7. An anti-tumor drug composition, characterized in that: The pharmaceutical composition comprises: a compound of formula I according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

8. A composition, characterized in that The composition comprises (a) a first active ingredient, wherein the first active ingredient is a compound represented by formula I, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and (b) a therapeutically effective amount of a second active ingredient, wherein the second active ingredient comprises: an immunotherapy activator, a type I interferon modulator, or an antiviral agent.

9. A medicine box, characterized in that: The medicine kit comprises: (A) a first preparation containing a first active ingredient, wherein the first active ingredient is a compound of formula I, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof; and (B) A second formulation comprising a second active ingredient, wherein the second active ingredient comprises: an immunotherapy activator, a type I interferon modulator, or an antiviral agent.

10. Use of the composition according to claim 8 or the kit according to claim 9, characterized in that: Used for preparing an innate immune activation drug, the drug comprising: (a) Broad-spectrum antiviral drugs; (b) anti-tumor drugs; (c) drugs for the prevention and / or treatment of cancer; (d) drugs for treating or preventing type I interferon-related diseases; (e) immune adjuvants; and / or (f) cytokine inducers.

11. A compound of formula I, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, in, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, alkynyl, amino, hydroxyl, sulfhydryl, carboxyl, alkoxy, cycloalkyloxy, haloalkyl, cyano, sulfanyl, sulfonyl, sulfone, sulfoxide, phosphate, and the alkyl, cycloalkyl, alkoxy, cycloalkyloxy, amino, heterocyclic, aryl or heteroaryl may be substituted with one or more substituents selected from hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, amino, heterocyclic, aryl or heteroaryl. The invention relates to a alkylene group, wherein the alkylene group comprises one or more substituents selected from the group consisting of oxy, heterocyclic, aryl, halogenated aryl, halogenated alkyl, heteroaryl, alkenyl, alkynyl, amino, thiol, carboxyl, ester, alkoxycarbonyl, acyloxy, amide, urea, alkylsulfonyl, aromatic sulfonyl, cyano, nitro, nitroso, thiocyanate, isothiocyanate, sulfanyl, sulfonyl, phosphate, phosphonate, alkylphosphate, alkylphosphonate, arylphosphate, and arylphosphonate, or is empty; the heterocyclic group contains at least one N atom, or contains 1, 2, or 3 heteroatoms selected from N, S, and O.

12. The compound according to claim 11, characterized in that The compound of formula I includes:

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