TW201717968A - Compounds and compositions that induce RIG-I and other pattern recognition receptors - Google Patents

Abstract

This invention relates to compounds and compositions for the induction of expression of a pattern recognition receptor (e.g., RIG-I, NOD2, or STING) and methods of use thereof.

Description

Compounds and compositions that induce RIG-I and other pattern recognition receptors Related application

The present application claims priority to U.S. Provisional Application Serial No. 62/192,438, filed on Jul. 14, the entire disclosure of which is hereby incorporated by reference.

The present invention relates to compounds and compositions for inducing expression of a pattern recognition receptor (e.g., RIG-I) and methods of use thereof.

A key feature of the innate immune system is the identification and elimination of microbial pathogens. Identification of such pathogenic invaders occurs through host identification of an evolutionarily conserved microbial structure known as a pathogen-associated molecular pattern (PAMP) (Jensen, S. and Thomsen, AR J Virol (2012) 86: 2900-2910). Such PAMPs include a variety of molecular structures that are widely shared by a variety of microbial species, such as nucleic acids, lipopolysaccharides, and glycoproteins, and are critical for their survival and/or pathogenicity. Host identification can occur by a variety of pathways, such as activation of a pattern recognition receptor (PRR), which ultimately causes downstream signaling events and ends with an initiation of an immune response.

The retinoic acid-inducible gene-I (RIG-I) protein is a DNA helicase and also acts as a sensor for microbial-derived RNA. RIG-I is an important factor in host identification of RNA viruses from a variety of different viral families, including Flaviviridae (eg, West Nile virus, Hepatitis C virus). , Japanese encephalitis virus, Dengue virus, Paramyxoviridae (such as Sendai virus, Newcastle disease virus, Respiratory syncytial) Virus), measles virus, Rhabdoviridae (eg Rabies virus), Orthomyxoviridae (eg (influenza A, influenza B) and sand) Arenaviridae (e.g., Lassa virus). In addition, recent work has shown that RIG-I acts as an effective sensor: Ebola virus (Cardenas, WB J Virol ( 2006) 80:5168-5178), Hepatitis B virus (Sato, S. et al., Immunity (2015) 42: 123-132), human immunodeficiency virus (Berg, RK et al., PLoS One) (2012) 7: e29 291) and various bacteria (Dixit, E. and Kagan, JCAdv Immunol (2013) 117: 99-125; Abdullah, Z. et al, EMBO J (2012) 31: 4153-4164), and prediction of such as hepatocellular carcinoma Biomarkers for the prognosis of certain types of cancer (Hou, J. et al., Cancer Cell (2014) 25: 49-63). In addition to RIG-I, other PRRs also play a role in sensing microbial-derived nucleic acids, Nucleic acids include NOD2, STING, LGP2, MDA5, and various purine-like receptors (TLRs) expressed on the cell surface and in the endosomal compartment. The viral genotypes of these PRRs are unknown and will recognize the type and resistance. Viral mutants. Recent evidence suggests that activation of RIG-I can play an important role in eradicating latent HIV in reservoirs.

Many of the major obstacles currently available for antiviral therapy are the emergence of drug resistant variants that occur over time. In addition, many available treatments require long-lasting and long-term treatment, which often produces undesirable side effects and the risk of recurrence upon treatment interruption. In addition, many viruses can be It is subdivided into different genotypes, and certain drugs developed for one genotype may be active against other genotypes. In contrast, the use of small molecule mimics capable of PRR-induced virus-derived RNA provides an alternative approach to the treatment of viral infections, as the genotypes of such compounds may be unknown and may have direct antiviral activity and the ability to activate host immune responses. And may limit the development of drug resistance and toxicity.

Recent publications have highlighted the importance of RIG-I and STING as mediators of innate and adaptive immunity, and RIG-I and STING agonists have been regarded as immuno-oncology agents in cancer treatment (Li, XY, etc.) Human, Mol Cell Oncol (2014) 1: e968016; Woo, SR Trends in Immunol (2015) 36: 250-256). In particular, RIG-I is involved in the regulation of basal cell methods, such as hematopoietic proliferation and differentiation, maintenance of leukemia stem and hepatocellular carcinoma, indicating that RIG-I is a major function of tumor suppressor. In addition, the STING (stimulator of interferon gene) pathway of cytosolic DNA sensing has been shown to play an important catalytic role in innate immune sensing, thereby driving the production of type I IFN in cancer. Likewise, there is a need for a new generation of treatments that induce the expression of PRRs, such as RIG-I, which are used to treat disease and as a diagnostic tool.

In one aspect, the invention features a method of inducing expression of a pattern recognition receptor (PRR) in an individual, the method comprising administering to the individual a compound of formula (I), wherein the compound is selected from the group consisting of:

Or a prodrug or a pharmaceutically acceptable salt thereof to treat the individual. In some embodiments, the prodrug of formula (I) is a compound of formula (II), wherein the compound is selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof. In some embodiments, the PRR comprises a RIG-I-like receptor or a NOD-like receptor. In some embodiments, the PRR comprises RIG-I, NOD2, MDA5, LPG2 Or STING (for example RIG-I). In some embodiments, the PRR comprises RIG-I. In some embodiments, the PRR comprises NOD2. In some embodiments, the PRR comprises STING.

In some embodiments, a composition comprising a mixture of a compound of formula (I), such as formula (Ib) and formula (Ic), is administered to an individual. In some embodiments, the composition comprises Formula (Ib) and comprises less than about 5% of Formula (Ic) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (Ic)), or substantially free of formula (Ic). In some embodiments, the composition comprises Formula (Ic) and comprises less than about 5% of Formula (Ib) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (Ib), or substantially free of formula (Ib)).

In some embodiments, a composition comprising a mixture of a compound of formula (II), such as formula (IIb) and formula (IIc), is administered to an individual. In some embodiments, the composition comprises Formula (IIb) and comprises less than about 5% of Formula (IIc) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (IIc), or substantially free of formula (IIc)). In some embodiments, the composition comprises Formula (IIc) and comprises less than about 5% of Formula (IIb) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (IIb), or substantially free of formula (IIb)).

In some embodiments, the induction of the expression of the PRR in the individual comprises an increase, augmentation, or initiation of a PRR (eg, RIG-I or NOD2, eg, in the liver). In some embodiments, the increase or increase in performance of the PRR (eg, RIG-I or NOD2, eg, in the liver) is between about 5% and about 95% (eg, at about 10) compared to a reference standard or a reference treatment. Between % and about 90%). In some embodiments, the performance of the induced PRR (eg, RIG-I or NOD2) relative to a reference standard is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, About 150, about 200, about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the induction of the expression of the PRR (eg, RIG-I or NOD2) is about 10 minutes after administration of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof to the subject. 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours , about 8 hours, about 10 hours, about 12 hours or longer. In some embodiments, the induction of the expression of the PRR (eg, RIG-I or NOD2) persists after administration of the compound of Formula (I) or Formula (II).

In some embodiments, the induction of PRR expression in an individual comprises an increase, augmentation or initiation of a PRR (eg, STING) manifestation. In some embodiments, the induction of PRR expression (eg, STING performance) occurs in a cancer cell microenvironment (eg, in a tumor microenvironment). In some embodiments, the induction of PRR expression (eg, STING expression) occurs in antigen presenting cells (eg, dendritic cells) in a cancer cell microenvironment (eg, a tumor microenvironment). In some embodiments, an increase or increase in the performance of a PRR (eg, STING, eg, in a tumor microenvironment) is between about 5% and about 95% compared to a reference standard or a reference treatment (eg, at about 10%) About 90%). In some embodiments, the performance of the induced PRR (eg, STING) relative to a reference standard is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200, about 250, About 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the induction of the expression of a PRR (eg, STING) is administered to a subject by administering a compound of Formula (I) or Formula (II) or About 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about about pharmaceutically acceptable salts Occurs 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 10 hours, about 12 hours or longer. In some embodiments, the induction of the performance of the PRR (eg, STING) persists after administration of the compound of Formula (I) or Formula (II).

In some embodiments, the individual is a mammal. In some embodiments, the individual is a human. In some embodiments, the individual is a non-human animal, such as a hamster (eg, oriental hamster) or a mouse.

In some embodiments, the individual has a microbial infection (eg, a viral infection, a bacterial infection, a fungal infection, or a parasitic infection) or cancer.

In some embodiments, the cancer is selected from the group consisting of breast, bone, brain, cervix, colon, gastrointestinal tract, eyes, gallbladder, lymph nodes, blood, lung, liver, skin, mouth, prostate, ovary, penis, pancreas, uterus, testis Cancer of the stomach, thymus, thyroid or other parts of the body. In some embodiments, the cancer comprises a solid tumor (eg, a carcinoma, sarcoma, or lymphoma). In some embodiments, the cancer comprises hepatocellular carcinoma. In some embodiments, the cancer comprises breast cancer, renal cell carcinoma, colon cancer, melanoma, ovarian cancer, head and neck squamous cell carcinoma, pancreatic cancer, prostate cancer, lung cancer, brain cancer, or gastrointestinal matrix cancer. In some embodiments, the cancer is leukemia. In some embodiments, a cancer cell (eg, a tumor cell) comprises a specific cancer-associated antigen that induces a T cell response.

In some embodiments, a microbial infection (eg, a viral infection) comprises infection with an RNA virus or a DNA virus. In some embodiments, the RNA virus or DNA virus comprises a single chain virus (eg, a positive single strand or a negative single strand) or a double stranded virus. In some specific examples, RNA The virus or DNA virus comprises a virus in a Group I, Group II, Group III, Group IV, Group V, Group VI or Group VII virus class.

In some embodiments, the RNA virus comprises a dsRNA virus, a ssRNA virus (eg, a positive strand ssRNA virus or a minus strand ssRNA virus) or an ssRNA RT virus. In some embodiments, the dsRNA virus is a member of the following family: Birnaviridae , Chrysoviridae , Cystoviridae , Endornaviridae , Low Toxicity ( Hypoviridae ), Megabirnaviridae , Partitiviridae , Picobirnaviridae , Reoviridae or Totiviridae or dsRNA Other sections. In some instances, positive-strand ssRNA viruses of the following members: arteritis virus family (Arteriviridae), coronavirus family (Coronaviridae), Medvedev virus family (Mesoniviridae), rod-shaped sleeve virus family (Roniviridae), two cis-trans sub virus family (Dicistroviridae), softening infectious virus family (Iflaviridae), marine RNA virus families (Marnaviridae), small RNA virus family (Piconaviridae), small plant RNA virus families (Secoviridae), linear influenza virus family (Alphaflexiviridae), Betaflexiviridae , Gammaflexiviridae , Tymoviridae , Alphatetraviridae , Alvernaviridae , Astroviridae (Astroviridae), tuberculosis-like RNA virus family (Barnaviridae), bromoviridae (bromoviridae), calicivirus Branch (Caliciviridae), Karnofsky virus family (Carmotetraviridae), long-shaped virus family (Closteroviridae), flaviviruses Flaviviridae , Leviviridae , Luteoviridae , Naked RNA virus families (Narnaviridae), nodaviridae (Nodaviridae), Paasche virus family (Permutotetraviridae), potato virus Y Branch (Potyviridae), Togaviridae (Togaviridae) or broom-like virus family (Virgaviridae) or positive strand ( Justice) Other families of ssRNA viruses. In some embodiments, the minus-strand ssRNA virus is a member of the following species: Bornaviridae , Filoviridae , Paramyxoviridae , Rhabdoviridae , Niche virus family (Nyamiviridae), Arenaviridae (Arenaviridae), Bunyaviridae (Bunyaviridae), snake-like virus family (Ophioviridae) or Orthomyxoviridae (Orthomyxoviridae), or other negative strand (antisense) ssRNA virus family . In some embodiments, the ssRNA RT virus is a member of the Transviridae , Pseudoviridae , or Retroviridae or other families of the ssRNA RT virus. In some embodiments, the ssRNA RT virus is a member of the Lentivirus genus (eg, human immunodeficiency virus 1 (HIV) or a subtype, species or variant thereof). In some embodiments, the ssRNA RT virus is HIV or a subtype, species or variant thereof.

In some embodiments, the DNA virus comprises a dsDNA virus, a ssDNA virus, or a dsDNA RT virus. In some instances, dsDNA viruses of the following members: myoviridae (Myoviridae), short-tailed virus family (Podoviridae), long-tailed virus family (Siphoviridae), different herpes virus family (Alloherpesviridae), the herpes virus family (Herpesviridae) , Malacoherpesviridae , Lipothrixviridae , Rudiviridae , Adenoviridae , Ampullaviridae , Ascoviridae , Asfarviridae , Baculoviridae , Bicaudaviridae , Clavaviridae , Corticoviridae , Fuselloviridae , Fuselloviridae Barr virus families (Globuloviridae), guttaviridae (guttaviridae), salivary gland hypertrophy virus family (Hytrosaviridae), Iridoviridae (Iridoviridae), Marseille virus family (Marseilleviridae), polar virus family (Nimaviridae), pandoravirus families (Pandoraviridae ), papillomavirus Branch (Papillomaviridae) Algal DNA virus families (Phycodnaviridae), multisection DNA viruses (Polydnaviruses), polyomaviridae (Polymaviridae), poxviridae (Poxviridae), Freund virus family (Sphaerolipoviridae), tectivirus (Tectiviridae) spiro cone or viral families ( Turriviridae ) or other family of dsDNA viruses. In some embodiments, the ssDNA virus is a member of the group consisting of : Anelloviridae , Bacillariodnaviridiae , Bidnaviridae , Circoviridae , Geminiviridae , silk. Inoviridae , Microviridae , Nanoviridae , Parvoviridae or Spiraviridae or other families of ssDNA viruses. In some instances, dsDNA RT viral liver DNA virus family (Hepadnaviridae) or the cauliflower mosaic virus family (Caulimoviridae) or other members of the families of dsDNA RT viruses.

In some embodiments, the virus can be in a latent phase. In some embodiments, the virus is a ssRNA retrovirus (ssRNA RT virus), such as a Group VI virus, and is, for example, latent within the cell. In some embodiments, the virus is human immunodeficiency virus 1 (HIV) or a subtype, a species or variant thereof, and is, for example, latent in a cell. In some embodiments, the individual is infected with HIV and is asymptomatic.

In some embodiments, the bacterial infection comprises infection with Gram-negative bacteria or Gram-positive bacteria. In some examples, the bacterial infection comprises bacteria selected from the group of: Lee genus (Listeria) (e.g. increased Listeria monocytogenes (Listeria monocytogenes)), Escherichia Francis (to Francisella) (e.g. heat Tula Francisella tularensis , Mycobacteria (eg Mycobacteria tuberculosis ), Brucella (eg Brucella abortis), Streptococcus genus (Streptococcus) (e.g. group B Streptococcus), Legionella (of Legionella) (e.g. of Legionella pneumophila (Legionella pneumophila)), the genus Escherichia (Escherichia) (e.g. E. coli (Escherichia coli)), Pseudomonas (such as Psuedomonas aeruginosa ), Salmonella (such as Salmonella typhi ), Shigella (such as Shigella flexneri ) ), flexuous genus (Campylobacter) (e.g. Campylobacter jejuni (Campylobacter jejuni)), Clostridium (Clostridium) (e.g. Clostridium botulinum Coli (Clostrodium botulinum)), Enterococcus (of Enterococcus) (e.g. Enterococcus faecalis (Enterococcus faecalis)), Vibrio (Vibrio) (e.g. Vibrio cholerae (Vibrio cholera)), Yersinia (Yersinia) ( For example, Yersinia pestis and Staphylococcus (such as Staphylococcus aureus ), or other genus, species, subtype or variant thereof.

In some embodiments, the methods described herein further comprise analyzing or accepting an analysis of a biopsy or biological tissue sample from an individual at least once prior to the end of treatment. In some embodiments, the biopsy sample is a liver biopsy sample. In some embodiments, liver biopsy samples are analyzed by immunohistochemical staining. In some embodiments, the liver biopsy sample analyzes the degree of induction of PRR (eg, RIG-I or NOD2) by immunohistochemical staining. In some embodiments, immunohistochemical staining is indicative of a compound of formula (I) or formula (II) or The distribution of PRR expression (eg, RIG-I performance or NOD2 performance) in the liver during treatment of its pharmaceutically acceptable salt is increased. In some embodiments, the distribution of PRR (eg, RIG-I or NOD2) expression in the liver from treatment initiation to end of treatment is increased between about 5% and about 95%.

In some embodiments, the amount of one or more microbial infection markers of the liver biopsy sample, such as viral DNA, viral RNA, viral antigen, cccDNA, bacterial load, is analyzed. In some embodiments, the amount of interferon (e.g., interferon alpha or interferon beta), interferon stimulating protein (e.g., ISG15, CXCL10, OAS 1) or other cytokines in a liver biopsy sample is analyzed. In some embodiments, liver inflammation, necrosis, steatosis, or fibrosis reduction in liver biopsy samples are analyzed.

In some embodiments, the biopsy sample is a cancer biopsy sample (eg, a tumor biopsy sample). In some embodiments, a cancer biopsy sample (eg, a tumor biopsy sample) is analyzed by immunohistochemical staining. In some embodiments, a cancer biopsy sample (eg, a tumor biopsy sample) is analyzed by immunohistochemical staining for the degree of induction of a PRR (eg, RIG-I or STING). In some embodiments, immunohistochemical staining indicates PRR performance (eg, RIG-I expression) in a cancer (eg, a tumor) during treatment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof Or the distribution of STING performance) increased. In some embodiments, the distribution of PRR (e.g., RIG-I or STING) expression in the cancer (e.g., tumor) from treatment initiation to treatment end is increased by between about 5% and about 95%.

In some embodiments, the individual is untreated. In some embodiments, an individual has previously been treated for a microbial infection (eg, a viral infection, a bacterial infection, a fungal infection, or a parasitic infection) or cancer. In some embodiments, an individual has previously been treated for HBV infection or HCV infection. In some embodiments, the individual has previously been targeted to a bacterial infection or cancer Treatment.

In some embodiments, a compound of formula (I) or formula (II) is administered orally (for example, a compound of formula (II) is orally administered). In some embodiments, a compound of formula (I) or formula (II) is administered parenterally (eg, parenterally administered a compound of formula (II)). In some embodiments, the method comprises administering the compound daily. In some specific examples, it is administered once a day. In some embodiments, the method comprises administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, for between about 1 week and 20 weeks. In some embodiments, the method comprises administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, for between about 1 week and 12 weeks.

In some embodiments, the dose of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, comprises from about 0.5 mg/kg to about 100 mg/kg. In some embodiments, the dose of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof comprises from 0.5 mg/kg to about 50 mg/kg. In some embodiments, the dose of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof comprises from 5 mg/kg to about 50 mg/kg.

In some embodiments, the dosage comprises a liquid or solid dosage form. In some embodiments, the liquid dosage form comprises a suspension, solution, sweetener, emulsion, beverage, elixir or syrup. In some embodiments, the solid dosage form comprises a capsule, lozenge, powder, dragee or microencapsulated dosage form.

In some embodiments, the method further comprises administering a therapeutically effective amount of the additional agent. In some embodiments, the additional agent is an antiviral, antibacterial, or anticancer agent. In some embodiments, the antiviral agent comprises an interferon, a nucleoside analog, a non-nucleoside antiviral agent, or a small molecule immunopotentiator. In some embodiments, the antiviral agent comprises a capsid inhibitor, an entry inhibitor, a secretion inhibitor, a microRNA, an antisense RNA agent, an RNAi agent, or is designed to inhibit Other agents for making viral RNA or DNA. In some embodiments, the antiviral agent comprises entecavir, lamuvidine, adefovir, darunavir, sofosbuvir, terra Telaprevir, tenofovir, zidovudine and ribavirin. In some embodiments, the antibacterial agent comprises gentamicin, kanamycin, streptomycin, chloramphenicol, ceftobiprole, amoxicillin (amoxicillin), penicillin, bacitracin, tetracycline, rifabutin, tigcycline, and vancomycin. In some embodiments, the anticancer agent is selected from the group consisting of methotrexate, 5-fluorouracil, doxorubicin, vincristine, bleomycin, Vinblastine, dacarbazine, toposide, cisplatin, epirubicin, and sorafenib tosylate.

In another aspect, the invention features a method of inducing expression of a pattern recognition receptor in an individual having a microbial infection or cancer, the method comprising administering to the individual a compound of formula (I), wherein the compound is selected from the group consisting of :

Or a prodrug or a pharmaceutically acceptable salt thereof to treat the individual. In some embodiments, the prodrug of formula (I) is a compound of formula (II), wherein the compound is selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof. In some embodiments, the PRR comprises a RIG-I-like receptor or a NOD-like receptor. In some embodiments, the PRR comprises RIG-I, NOD2, MDA5, LPG2, or STING (eg, RIG-I). In some embodiments, the PRR comprises RIG-I. In some embodiments, the PRR comprises NOD2. In some embodiments, the PRR comprises STING.

In some embodiments, a composition comprising a mixture of a compound of formula (I), such as formula (Ib) and formula (Ic), is administered to an individual. In some embodiments, the composition comprises Formula (Ib) and comprises less than about 5% of Formula (Ic) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (Ic)), or substantially free of formula (Ic). in In some embodiments, the composition comprises Formula (Ic) and comprises less than about 5% of Formula (Ib) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or Less than about 0.1% of formula (Ib), or substantially free of formula (Ib)).

In some embodiments, a composition comprising a mixture of a compound of formula (II), such as formula (IIb) and formula (IIc), is administered to an individual. In some embodiments, the composition comprises Formula (IIb) and comprises less than about 5% of Formula (IIc) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (IIc), or substantially free of formula (IIc)). In some embodiments, the composition comprises Formula (IIc) and comprises less than about 5% of Formula (IIb) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (IIb), or substantially free of formula (IIb)).

In some embodiments, the induction of the expression of the PRR in the individual comprises an increase, augmentation, or initiation of a PRR (eg, RIG-I or NOD2, eg, in the liver). In some embodiments, the increase or increase in performance of the PRR (eg, RIG-I or NOD2, eg, in the liver) is between about 5% and about 95% (eg, at about 10) compared to a reference standard or a reference treatment. Between % and about 90%). In some embodiments, the performance of the induced PRR (eg, RIG-I or NOD2) is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, relative to a reference standard. About 2, about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200 , about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the induction of the expression of the PRR (eg, RIG-I or NOD2) is about 10 minutes after administration of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof to the subject. 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, Approximately 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 10 hours, about 12 hours or more occur. In some embodiments, the induction of the expression of the PRR (eg, RIG-I or NOD2) persists after administration of the compound of Formula (I) or Formula (II).

In some embodiments, the induction of PRR expression in an individual comprises an increase, augmentation or initiation of a PRR (eg, STING) manifestation. In some embodiments, the induction of PRR expression (eg, STING performance) occurs in a cancer cell microenvironment (eg, in a tumor microenvironment). In some embodiments, the induction of PRR expression (eg, STING expression) occurs in antigen presenting cells (eg, dendritic cells) in a cancer cell microenvironment (eg, a tumor microenvironment). In some embodiments, an increase or increase in the performance of a PRR (eg, STING, eg, in a tumor microenvironment) is between about 5% and about 95% compared to a reference standard or a reference treatment (eg, at about 10%) About 90%). In some embodiments, the performance of the induced PRR (eg, STING) relative to a reference standard is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200, about 250, About 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the induction of the expression of the PRR (eg, STING) is about 10 minutes, about 15 minutes, about 10 minutes after the administration of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof to the individual. 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours , about 10 hours, about 12 hours or longer. In some embodiments, the induction of the performance of the PRR (eg, STING) persists after administration of the compound of Formula (I) or Formula (II).

In some embodiments, the individual is a mammal. In some specific examples, The individual is a human being. In some embodiments, the individual is a non-human animal, such as a hamster (eg, oriental hamster) or a mouse.

In some embodiments, the cancer is selected from the group consisting of breast, bone, brain, cervix, colon, gastrointestinal tract, eyes, gallbladder, lymph nodes, blood, lung, liver, skin, mouth, prostate, ovary, penis, pancreas, uterus, testis Cancer of the stomach, thymus, thyroid or other parts of the body. In some embodiments, the cancer comprises a solid tumor (eg, a carcinoma, sarcoma, or lymphoma). In some embodiments, the cancer comprises hepatocellular carcinoma. In some embodiments, the cancer comprises breast cancer, renal cell carcinoma, colon cancer, melanoma, ovarian cancer, head and neck squamous cell carcinoma, pancreatic cancer, prostate cancer, lung cancer, brain cancer, or gastrointestinal matrix cancer. In some embodiments, the cancer is leukemia. In some embodiments, a cancer cell (eg, a tumor cell) comprises a specific cancer-associated antigen that induces a T cell response.

In some embodiments, a microbial infection (eg, a viral infection) comprises infection with an RNA virus or a DNA virus. In some embodiments, the RNA virus or DNA virus comprises a single chain virus (eg, a positive single strand or a negative single strand) or a double stranded virus. In some embodiments, the RNA virus or DNA virus comprises a virus in a Group I, Group II, Group III, Group IV, Group V, Group VI, or Group VII virus class.

In some embodiments, the RNA virus comprises a dsRNA virus, a ssRNA virus (eg, a positive strand ssRNA virus or a minus strand ssRNA virus) or an ssRNA RT virus. In some embodiments, the dsRNA virus is a member of the group consisting of: a double ribonucleic acid family, a golden virion family, a cystic phage family, an endoviridae family, a low toxicity virus family, a giant bipartite RNA virus family, a split virus family. , small double-section RNA virus family, reoviridae or whole virus family or other families of dsRNA viruses. In some embodiments, the positive-stranded ssRNA virus is a member of the following: arteritis virus Department, Coronaviridae, Mei's Virology, Rod-shaped Virology, Dictioviridae, Infectious Softening Virus, Marine RNA Virus, Small RNA Virus, Plant Small RNA Virus, A-Line Virus Branch, B-type linear virus, C-type linear virus, phthalocyanine yellow mosaic virus, A-type genus, Affolidae, Astrovirus, Bacillus ribavirin, Brome mosaic virus Department, Calicivirus, Cartesianidae, Long-line Virus, Flaviviridae, Smooth Virology, Flavivirus, Naked RNA Virus, Nodaviridae, Paekiviridae, Potato Y Virus, Membraneviridae or Vibriovirus or other families of positive-strand (sense) ssRNA viruses. In some embodiments, the minus-strand ssRNA virus is a member of the following species: Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Nicotinidae, Sarcidae, Bunia virus Family, Serpentidae or Orthomyxoviridae, or other negative (antisense) ssRNA virus family. In some embodiments, the ssRNA RT virus is a member of the transpotoviridae, the pseudoviridae, or the retroviridae or other families of the ssRNA RT virus. In some embodiments, the ssRNA RT virus is a member of a lentivirus genus (eg, human immunodeficiency virus 1 (HIV) or a subtype, species or variant thereof). In some embodiments, the ssRNA RT virus is HIV or a subtype, species or variant thereof.

In some embodiments, the DNA virus comprises a dsDNA virus, a ssDNA virus, or a dsDNA RT virus. In some embodiments, the dsDNA virus is a member of the following: Muscle-tailed phage, Short-tailed virus, Long-tailed virus, Herpesculosis, Herpesvirus, Mollus herpesviridae, lipophages, small rods Phage, Adenoviridae, Bottlerviridae, Vesicular Virus, African porcine virus, baculoviridae, two-tailed virus, Klebsivirus, lipoviridae, microspindle phage, Grignard Virology, Department of Virology, Salivary Gland, Virology, Iridescent Virus, Marseille Virus, Line Virus, Pandora Virus, Papillomavirus, Algae DNA Virus, Multi-DNA Virus, Polyomavirus, Pox virus Family, Freund's Virology, stratified phage or Conoviridae or other families of dsDNA viruses. In some embodiments, the ssDNA virus is a member of the group consisting of: a ring virulence family, a bacillus family, a double virion family, a circoviridae, a geminiviridae, a filamentous phage family, a microphage family, a dwarf virus family, a parvovirus Other families of families or circoviruses or ssDNA viruses. In some embodiments, the dsDNA RT virus is a member of the hepatic DNA virus family or the cauliflower mosaic virus family or other families of the dsDNA RT virus.

In some embodiments, the virus can be in a latent phase. In some embodiments, the virus is a ssRNA retrovirus (ssRNA RT virus), such as a Group VI virus, and is, for example, latent within the cell. In some embodiments, the virus is human immunodeficiency virus 1 (HIV) or a subtype, a species or variant thereof, and is, for example, latent in a cell. In some embodiments, the individual is infected with HIV and is asymptomatic.

In some embodiments, the bacterial infection comprises infection with Gram-negative bacteria or Gram-positive bacteria. In some embodiments, the bacterial infection comprises a bacterium selected from the group consisting of a genus of the genus Listeria (such as Listeria monocytogenes), a genus of the genus Francis (such as the genus Francia genus), and a genus Mycobacterium (eg, M. tuberculosis), Brucella (eg, Brucella abortus), Streptococcus (eg, group B streptococci), Legionella (eg, Legionella vulgaris), Escherichia ( For example, Escherichia coli), Pseudomonas (such as Pseudomonas aeruginosa), Salmonella (such as Salmonella typhi), Shigella (such as Shigella flexneri), Mycobacterium (such as Campylobacter jejuni), Clostridium (eg Clostridium botulinum), Enterococcus (eg Enterococcus faecalis), Vibrio (eg Vibrio cholerae), Yersinia (eg Yersinia pestis) and Staphylococcus (eg gold Staphylococcus aureus, or other genus, species, subtype or variant thereof.

In some embodiments, the methods described herein further comprise analyzing or accepting an analysis of a biopsy or biological tissue sample from an individual at least once prior to the end of treatment. In some embodiments, the biopsy sample is a liver biopsy sample. In some embodiments, liver biopsy samples are analyzed by immunohistochemical staining. In some embodiments, the liver biopsy sample analyzes the degree of induction of PRR (eg, RIG-I or NOD2) by immunohistochemical staining. In some embodiments, immunohistochemical staining indicates PRR expression in the liver (eg, RIG-I performance or NOD2 expression) during treatment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof The distribution has increased. In some embodiments, the distribution of PRR (eg, RIG-I or NOD2) expression in the liver from treatment initiation to end of treatment is increased between about 5% and about 95%.

In some embodiments, the amount of one or more microbial infection markers of the liver biopsy sample, such as viral DNA, viral RNA, viral antigen, cccDNA, bacterial load, is analyzed. In some embodiments, the amount of interferon (e.g., interferon alpha or interferon beta), interferon stimulating protein (e.g., ISG15, CXCL10, OAS 1) or other cytokines in a liver biopsy sample is analyzed. In some embodiments, liver inflammation, necrosis, steatosis, or fibrosis reduction in liver biopsy samples are analyzed.

In some embodiments, the biopsy sample is a cancer biopsy sample (eg, a tumor biopsy sample). In some embodiments, a cancer biopsy sample (eg, a tumor biopsy sample) is analyzed by immunohistochemical staining. In some embodiments, a cancer biopsy sample (eg, a tumor biopsy sample) is analyzed by immunohistochemical staining for the degree of induction of a PRR (eg, RIG-I or STING). In some embodiments, immunohistochemical staining indicates PRR performance (eg, RIG-I expression) in a cancer (eg, a tumor) during treatment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof Or the distribution of STING performance) increased. In some specific examples, The distribution of PRR (e.g., RIG-I or STING) performance in cancer (e.g., tumor) from treatment initiation to treatment end is increased by between about 5% and about 95%.

In some embodiments, the individual is untreated. In some embodiments, an individual has previously been treated for a microbial infection (eg, a viral infection, a bacterial infection, a fungal infection, or a parasitic infection) or cancer. In some embodiments, an individual has previously been treated for HBV infection or HCV infection. In some embodiments, an individual has previously been treated for a bacterial infection or cancer.

In some embodiments, a compound of formula (I) or formula (II) is administered orally (for example, a compound of formula (II) is orally administered). In some embodiments, a compound of formula (I) or formula (II) is administered parenterally (eg, parenterally administered a compound of formula (II)). In some embodiments, the method comprises administering the compound daily. In some specific examples, it is administered once a day. In some embodiments, the method comprises administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, for between about 1 week and 20 weeks. In some embodiments, the method comprises administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, for between about 1 week and 12 weeks.

In some embodiments, the dose of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, comprises from about 0.5 mg/kg to about 100 mg/kg. In some embodiments, the dose of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof comprises from 0.5 mg/kg to about 50 mg/kg. In some embodiments, the dose of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof comprises from 5 mg/kg to about 50 mg/kg.

In some embodiments, the dosage comprises a liquid or solid dosage form. In some embodiments, the liquid dosage form comprises a suspension, solution, sweetener, emulsion, beverage, elixir or syrup. In some embodiments, the solid dosage form comprises a capsule, a lozenge, a powder, a dragee or a microencapsulating agent. type.

In some embodiments, the method further comprises administering a therapeutically effective amount of the additional agent. In some embodiments, the additional agent is an antiviral, antibacterial, or anticancer agent. In some embodiments, the antiviral agent comprises an interferon, a nucleoside analog, a non-nucleoside antiviral agent, or a small molecule immunopotentiator. In some embodiments, the antiviral agent comprises a capsid inhibitor, an entry inhibitor, a secretion inhibitor, a microRNA, an antisense RNA agent, a RNAi agent, or other agent designed to inhibit viral RNA or DNA. In some embodiments, the antiviral agent comprises inferfur, lamivudine, adendron, darunavir, sofosbuvir, telaprevir, tonofol, zidovudine, and ribavi forest. In some embodiments, the antibacterial agent comprises gentamicin, kanamycin, streptomycin, chloramphenicol, cefepept, amoxicillin, penicillin, bacitracin, tetracycline, rifabutin, Tiger Cyclomycin and vancomycin. In some embodiments, the anticancer agent is selected from the group consisting of methotrexate, 5-fluorouracil, cranberry, vincristine, bleomycin, vinblastine, dacarbazine, tolose, cisplatin, epirubicin Star and sorafenib tosylate.

In another aspect, the invention features a method of activating a pattern recognition receptor (PRR) in an individual, the method comprising administering to the individual a compound of formula (I), wherein the compound is selected from the group consisting of:

Or a prodrug or a pharmaceutically acceptable salt thereof to treat the individual. In some embodiments, the prodrug of formula (I) is a compound of formula (II), wherein the compound is selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof. In some embodiments, the PRR comprises a RIG-I-like receptor or a NOD-like receptor. In some embodiments, the PRR comprises RIG-I, NOD2, MDA5, LPG2, or STING (eg, RIG-I). In some embodiments, the PRR comprises RIG-I. In some embodiments, the PRR comprises NOD2. In some embodiments, the PRR comprises STING.

In some embodiments, a composition comprising a mixture of a compound of formula (I), such as formula (Ib) and formula (Ic), is administered to an individual. In some embodiments, the composition comprises Formula (Ib) and comprises less than about 5% of Formula (Ic) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (Ic)), or substantially free of formula (Ic). in In some embodiments, the composition comprises Formula (Ic) and comprises less than about 5% of Formula (Ib) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, or Less than about 0.1% of formula (Ib), or substantially free of formula (Ib)).

In some embodiments, a composition comprising a mixture of a compound of formula (II), such as formula (IIb) and formula (IIc), is administered to an individual. In some embodiments, the composition comprises Formula (IIb) and comprises less than about 5% of Formula (IIc) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (IIc), or substantially free of formula (IIc)). In some embodiments, the composition comprises Formula (IIc) and comprises less than about 5% of Formula (IIb) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (IIb), or substantially free of formula (IIb)).

In some embodiments, activation of a PRR (eg, RIG-I or NOD2, eg, in the liver) comprises a downstream signaling protein (eg, a pro-inflammatory cytokine, an anti-inflammatory cytokine, a type I interferon (IFN-[alpha], IFN-) Activation of β) or interferon-stimulated genes) or downstream signaling pathways. In some embodiments, activation of the PRR (eg, RIG-I or NOD2, eg, in the liver) is between about 5% and about 95% (eg, at about 10% and about) compared to a reference standard or reference treatment. Between 90%). In some embodiments, the activated PRR (eg, RIG-I or NOD2) is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, relative to a reference standard. , about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200, about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, activation of the PRR (eg, RIG-I or NOD2) is about 10 minutes, about 15 minutes after administration of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof to the individual. About 20 Minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, It takes about 10 hours, about 12 hours or longer.

In some embodiments, activation of the PRR (eg, RIG-I or NOD2) is continued after administration of the compound of Formula (I) or Formula (II).

In some embodiments, activation of a PRR (eg, RIG-I or STING) comprises a downstream signaling protein (eg, a pro-inflammatory cytokine, an anti-inflammatory cytokine, a type I interferon (IFN-[alpha], IFN-[beta]), or an interferon. Stimulation of genes) or activation of downstream signaling pathways. In some embodiments, activation of a PRR (eg, RIG-I or STING) occurs in a cancer cell microenvironment (eg, in a tumor microenvironment). In some embodiments, activation of a PRR (eg, RIG-I or STING) occurs in antigen presenting cells (eg, dendritic cells) in a cancer cell microenvironment (eg, a tumor microenvironment). In some embodiments, the activation of the PRR (eg, RIG-I or STING) is between about 5% and about 95% (eg, between about 10% and about 90%) compared to a reference standard or a reference treatment. . In some embodiments, the activated PRR (eg, RIG-I or STING) is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, relative to a reference standard. , about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200, about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the activation of the performance of the PRR (eg, RIG-I or STING) is about 10 minutes after administration of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof to the individual. 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours , about 8 hours, about 10 Hour, about 12 hours or longer.

In some embodiments, activation of the PRR (eg, RIG-I or STING) continues after administration of the compound of Formula (I) or Formula (II).

In some embodiments, activation of a PRR (eg, RIG-I or NOD2) results in the induction of expression of a PRR (eg, RIG-I or NOD2). In some embodiments, the induction of the expression of the PRR in the individual comprises an increase, augmentation, or initiation of a PRR (eg, RIG-I or NOD2, eg, in the liver). In some embodiments, the increase or increase in performance of the PRR (eg, RIG-I or NOD2, eg, in the liver) is between about 5% and about 95% (eg, at about 10) compared to a reference standard or a reference treatment. Between % and about 90%). In some embodiments, the induced RR (eg, RIG-I or NOD2) exhibits a performance of about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, relative to a reference standard. About 2, about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200 , about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the induction of the expression of the PRR (eg, RIG-I or NOD2) is about 10 minutes after administration of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof to the subject. 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours , about 8 hours, about 10 hours, about 12 hours or longer. In some embodiments, the induction of the expression of the PRR (eg, RIG-I or NOD2) persists after administration of the compound of Formula (I) or Formula (II).

In some embodiments, activation of a PRR (eg, RIG-I NOD2) does not result in the induction of a PRR (eg, RIG-I or NOD2).

In some embodiments, activation of a PRR (eg, RIG-I or STING) results in the induction of expression of a PRR (eg, RIG-I or STING). In some embodiments, the induction of expression of a PRR in an individual comprises the expression of increasing, enhancing, or initiating a PRR (eg, RIG-I or STING, eg, in a microenvironment of a cancer (eg, a tumor)). In some embodiments, the increase or increase in performance of the PRR (eg, RIG-I or STING, eg, in the microenvironment of a cancer (eg, a tumor)) is between about 5% and about 95% compared to a reference standard or a reference treatment. Between (for example between about 10% and about 90%). In some embodiments, the performance of the induced PRR (eg, RIG-I or STING) is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, relative to a reference standard. About 2, about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200 , about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the induction of the expression of the PRR (eg, RIG-I or STING) is about 10 minutes after administration of the compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof to the subject. 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours , about 8 hours, about 10 hours, about 12 hours or longer. In some embodiments, the induction of the expression of the PRR (eg, RIG-I or STING) persists after administration of the compound of Formula (I) or Formula (II).

In some embodiments, activation of a PRR (eg, RIG-I or STING) does not result in the induction of a PRR (eg, RIG-I or STING).

In some embodiments, the individual is a mammal. In some embodiments, the individual is a human. In some embodiments, the individual is a non-human animal, such as a squirrel (eg, Oriental soil squirrels) or mice.

In some embodiments, the individual has a microbial infection (eg, a viral infection, a bacterial infection, a fungal infection, or a parasitic infection) or cancer.

In some embodiments, the cancer is selected from the group consisting of breast, bone, brain, cervix, colon, gastrointestinal tract, eyes, gallbladder, lymph nodes, blood, lung, liver, skin, mouth, prostate, ovary, penis, pancreas, uterus, testis Cancer of the stomach, thymus, thyroid or other parts of the body. In some embodiments, the cancer comprises a solid tumor (eg, a carcinoma, sarcoma, or lymphoma). In some embodiments, the cancer comprises hepatocellular carcinoma. In some embodiments, the cancer comprises breast cancer, renal cell carcinoma, colon cancer, melanoma, ovarian cancer, head and neck squamous cell carcinoma, pancreatic cancer, prostate cancer, lung cancer, brain cancer, or gastrointestinal matrix cancer. In some embodiments, the cancer is leukemia. In some embodiments, a cancer cell (eg, a tumor cell) comprises a specific cancer-associated antigen that induces a T cell response.

In some embodiments, a microbial infection (eg, a viral infection) comprises infection with an RNA virus or a DNA virus. In some embodiments, the RNA virus or DNA virus comprises a single chain virus (eg, a positive single strand or a negative single strand) or a double stranded virus. In some embodiments, the RNA virus or DNA virus comprises a virus in a Group I, Group II, Group III, Group IV, Group V, Group VI, or Group VII virus class.

In some embodiments, the RNA virus comprises a dsRNA virus, a ssRNA virus (eg, a positive strand ssRNA virus or a minus strand ssRNA virus) or an ssRNA RT virus. In some embodiments, the dsRNA virus is a member of the group consisting of: a double ribonucleic acid family, a golden virion family, a cystic phage family, an endoviridae family, a low toxicity virus family, a giant bipartite RNA virus family, a split virus family. , small bifamily RNA virus, reoviridae or whole virus or dsRNA virus Other subjects. In some embodiments, the positive-stranded ssRNA virus is a member of the following families: Arteriviridae, Coronavirus, Mei's Virology, Pleurotus, Dictioviridae, Infectious Softening Virus, Marine RNA Virology, Small RNA Virus, Plant Small RNA Virus, A-Line Virus, B-type Virology, C-Line Virus, Phthalocyanin Yellow Mosaic Virus, A-type Virgoviridae, Aviridae , Astroviridae, Bacillus ribavirin, Brome mosaic virus, Calicivirus, Cartesian, Long-line virus, Flaviviridae, Smooth Virology, Flavivirus, Naked RNA Virology, Nodaviridae, Paekiviridae, Potato Yviridae, Togaviridae or Coronavirus or other families of positive-strand (sense) ssRNA viruses. In some specific examples, the minus-strand ssRNA virus is a member of the following species: Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Nicotianaviridae, Sarcidae, Bunia Virology, Serpentidae or Orthomyxoviridae, or other negative (antisense) ssRNA viruses. In some embodiments, the ssRNA RT virus is a member of the transpotoviridae, the pseudoviridae, or the retroviridae or other families of the ssRNA RT virus. In some embodiments, the ssRNA RT virus is a member of a lentivirus genus (eg, human immunodeficiency virus 1 (HIV) or a subtype, species or variant thereof). In some embodiments, the ssRNA RT virus is HIV or a subtype, species or variant thereof.

In some embodiments, the DNA virus comprises a dsDNA virus, a ssDNA virus, or a dsDNA RT virus. In some embodiments, the dsDNA virus is a member of the following: Muscle-tailed phage, Short-tailed virus, Long-tailed virus, Herpesculosis, Herpesvirus, Mollus herpesviridae, lipophages, small rods Phage, Adenoviridae, Bottlerviridae, Vesicular Virus, African porcine virus, baculoviridae, two-tailed virus, Klebsivirus, lipoviridae, microspindle phage, Grignard Virology, Dentivirus, Salivary Gland, Virology, Iridescent Virus, Marseille Virus, Line Virus, Pandora Virus, Papillomavirus family, algae DNA virus family, multi-DNA virus, polyomavirus family, poxvirus family, Freund's disease family, stratified phage family or cone rotviridae or other families of dsDNA viruses. In some embodiments, the ssDNA virus is a member of the group consisting of: a ring virulence family, a bacillus family, a double virion family, a circoviridae, a geminiviridae, a filamentous phage family, a microphage family, a dwarf virus family, a parvovirus Other families of families or circoviruses or ssDNA viruses. In some embodiments, the dsDNA RT virus is a member of the hepatic DNA virus family or the cauliflower mosaic virus family or other families of the dsDNA RT virus.

In some embodiments, the virus can be in a latent phase. In some embodiments, the virus is a ssRNA retrovirus (ssRNA RT virus), such as a Group VI virus, and is, for example, latent within the cell. In some embodiments, the virus is human immunodeficiency virus 1 (HIV) or a subtype, a species or variant thereof, and is, for example, latent in a cell. In some embodiments, the individual is infected with HIV and is asymptomatic.

In some embodiments, the bacterial infection comprises infection with Gram-negative bacteria or Gram-positive bacteria. In some embodiments, the bacterial infection comprises a bacterium selected from the group consisting of a genus of the genus Listeria (such as Listeria monocytogenes), a genus of the genus Francis (such as the genus Francia genus), and a genus Mycobacterium (eg, M. tuberculosis), Brucella (eg, Brucella abortus), Streptococcus (eg, group B streptococci), Legionella (eg, Legionella vulgaris), Escherichia ( For example, Escherichia coli), Pseudomonas (such as Pseudomonas aeruginosa), Salmonella (such as Salmonella typhi), Shigella (such as Shigella flexneri), Mycobacterium (such as Campylobacter jejuni), Clostridium (eg Clostridium botulinum), Enterococcus (eg Enterococcus faecalis), Vibrio (eg Vibrio cholerae), Yersinia (eg Yersinia pestis) and Staphylococcus (eg gold Staphylococcus aureus, or other genus, species, subtype or variant body.

In some embodiments, the methods described herein further comprise analyzing or accepting an analysis of a biopsy or biological tissue sample from an individual at least once prior to the end of treatment. In some embodiments, the biopsy sample is a liver biopsy sample. In some embodiments, liver biopsy samples are analyzed by immunohistochemical staining. In some embodiments, the liver biopsy sample analyzes the degree of induction of RRR (eg, RIG-I or NOD2) by immunohistochemical staining. In some embodiments, immunohistochemical staining indicates PRR expression in the liver (eg, RIG-I performance or NOD2 expression) during treatment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof The distribution has increased. In some embodiments, the distribution of PRR (eg, RIG-I or NOD2) expression in the liver from treatment initiation to end of treatment is increased between about 5% and about 95%.

In some embodiments, the amount of one or more microbial infection markers of the liver biopsy sample, such as viral DNA, viral RNA, viral antigen, cccDNA, bacterial load, is analyzed. In some embodiments, the amount of interferon (e.g., interferon alpha or interferon beta), interferon stimulating protein (e.g., ISG15, CXCL10, OAS 1) or other cytokines in a liver biopsy sample is analyzed. In some embodiments, liver inflammation, necrosis, steatosis, or fibrosis reduction in liver biopsy samples are analyzed.

In some embodiments, the biopsy sample is a cancer biopsy sample (eg, a tumor biopsy sample). In some embodiments, a cancer biopsy sample (eg, a tumor biopsy sample) is analyzed by immunohistochemical staining. In some embodiments, a cancer biopsy sample (eg, a tumor biopsy sample) is analyzed by immunohistochemical staining for the degree of induction of a PRR (eg, RIG-I or STING). In some embodiments, immunohistochemical staining indicates PRR in a cancer (eg, a tumor) during treatment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof The distribution of performance (eg RIG-I performance or STING performance) increases. In some embodiments, the distribution of PRR (e.g., RIG-I or STING) expression in the cancer (e.g., tumor) from treatment initiation to treatment end is increased by between about 5% and about 95%.

In some embodiments, the individual is untreated. In some embodiments, an individual has previously been treated for a microbial infection (eg, a viral infection, a bacterial infection, a fungal infection, or a parasitic infection) or cancer. In some embodiments, an individual has previously been treated for HBV infection or HCV infection. In some embodiments, an individual has previously been treated for a bacterial infection or cancer.

In some embodiments, a compound of formula (I) or formula (II) is administered orally (for example, a compound of formula (II) is orally administered). In some embodiments, a compound of formula (I) or formula (II) is administered parenterally (eg, parenterally administered a compound of formula (II)). In some embodiments, the method comprises administering the compound daily. In some specific examples, it is administered once a day. In some embodiments, the method comprises administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, for between about 1 week and 20 weeks. In some embodiments, the method comprises administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, for between about 1 week and 12 weeks.

In some embodiments, the dose of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, comprises from about 0.5 mg/kg to about 100 mg/kg. In some embodiments, the dose of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof comprises from 0.5 mg/kg to about 50 mg/kg. In some embodiments, the dose of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof comprises from 5 mg/kg to about 50 mg/kg.

In some embodiments, the dosage comprises a liquid or solid dosage form. In some embodiments, the liquid dosage form comprises a suspension, solution, sweetener, emulsion, beverage, elixir or syrup. In some embodiments, the solid dosage form comprises a capsule, lozenge, powder, dragee or microencapsulated dosage form.

In some embodiments, the method further comprises administering a therapeutically effective amount of the additional agent. In some embodiments, the additional agent is an antiviral, antibacterial, or anticancer agent. In some embodiments, the antiviral agent comprises an interferon, a nucleoside analog, a non-nucleoside antiviral agent, or a small molecule immunopotentiator. In some embodiments, the antiviral agent comprises a capsid inhibitor, an entry inhibitor, a secretion inhibitor, a microRNA, an antisense RNA agent, a RNAi agent, or other agent designed to inhibit viral RNA or DNA. In some embodiments, the antiviral agent comprises inferfur, lamivudine, adendron, darunavir, sofosbuvir, telaprevir, tonofol, zidovudine, and ribavi forest. In some embodiments, the antibacterial agent comprises gentamicin, kanamycin, streptomycin, chloramphenicol, cefepept, amoxicillin, penicillin, bacitracin, tetracycline, rifabutin, Tiger Cyclomycin and vancomycin. In some embodiments, the anticancer agent is selected from the group consisting of methotrexate, 5-fluorouracil, cranberry, vincristine, bleomycin, vinblastine, dacarbazine, tolose, cisplatin, epirubicin Star and sorafenib tosylate.

In another aspect, the invention features a method of inducing expression of a pattern recognition receptor in an individual having cancer, the method comprising administering to the individual a compound of formula (I), wherein the compound is selected from the group consisting of:

Or a prodrug or a pharmaceutically acceptable salt thereof to treat the individual. In some embodiments, the prodrug of formula (I) is a compound of formula (II), wherein the compound is selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof. In some embodiments, the PRR comprises a RIG-I-like receptor or a NOD-like receptor. In some embodiments, the PRR comprises RIG-I, NOD2, MDA5, LPG2 Or STING (for example RIG-I). In some embodiments, the PRR comprises RIG-I. In some embodiments, the PRR comprises NOD2. In some embodiments, the PRR comprises STING.

In some embodiments, a composition comprising a mixture of a compound of formula (I), such as formula (Ib) and formula (Ic), is administered to an individual. In some embodiments, the composition comprises Formula (Ib) and comprises less than about 5% of Formula (Ic) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (Ic)), or substantially free of formula (Ic). In some embodiments, the composition comprises Formula (Ic) and comprises less than about 5% of Formula (Ib) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (Ib), or substantially free of formula (Ib)).

In some embodiments, a composition comprising a mixture of a compound of formula (II), such as formula (IIb) and formula (IIc), is administered to an individual. In some embodiments, the composition comprises Formula (IIb) and comprises less than about 5% of Formula (IIc) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (IIc), or substantially free of formula (IIc)). In some embodiments, the composition comprises Formula (IIc) and comprises less than about 5% of Formula (IIb) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%) Or less than about 0.1% of formula (IIb), or substantially free of formula (IIb)).

In some embodiments, the induction of PRR expression in an individual comprises increasing, enhancing, or initiating the performance of a PRR (eg, RIG-I, NOD2, or STING). In some embodiments, the induction of PRR expression (eg, RIG-I expression, NOD2 expression, or STING performance) occurs in a cancer cell microenvironment (eg, in a tumor microenvironment). In some embodiments, the induction of PRR expression (eg, STING expression) occurs in antigen presenting cells (eg, dendritic cells) in a cancer cell microenvironment (eg, a tumor microenvironment). In some specific examples, with reference standards or references The increase or enhancement in performance of the PRR (e.g., RIG-I, NOD2, or STING) is between about 5% and about 95% (e.g., between about 10% and about 90%). In some embodiments, the performance of the induced PRR (eg, RIG-I, NOD2, or STING) relative to a reference standard is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, About 200, about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the induction of expression of a PRR (eg, RIG-I, NOD2, or STING) is about 10 minutes after administration of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof to an individual. About 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about Occurs in 7 hours, about 8 hours, about 10 hours, about 12 hours or longer. In some embodiments, the induction of the expression of the PRR (eg, RIG-I, NOD2, or STING) persists after administration of the compound of Formula (I) or Formula (II).

In some embodiments, the individual is a mammal. In some embodiments, the individual is a human. In some embodiments, the individual is a non-human animal, such as a hamster (eg, oriental hamster) or a mouse.

In some embodiments, the cancer is selected from the group consisting of breast, bone, brain, cervix, colon, gastrointestinal tract, eyes, gallbladder, lymph nodes, blood, lung, liver, skin, mouth, prostate, ovary, penis, pancreas, uterus, testis Cancer of the stomach, thymus, thyroid or other parts of the body. In some embodiments, the cancer comprises a solid tumor (eg, a carcinoma, sarcoma, or lymphoma). In some embodiments, the cancer comprises hepatocellular carcinoma. In some embodiments, the cancer comprises breast cancer, renal cell carcinoma, colon cancer, melanoma, ovarian cancer, head and neck squamous cell carcinoma, pancreas Dirty cancer, prostate cancer, lung cancer, brain cancer or gastrointestinal matrix cancer. In some embodiments, the cancer is leukemia. In some embodiments, a cancer cell (eg, a tumor cell) comprises a specific cancer-associated antigen that induces a T cell response.

In some embodiments, the methods described herein further comprise analyzing or accepting an analysis of a biopsy or biological tissue sample from an individual at least once prior to the end of treatment. In some embodiments, the biopsy sample is a cancer biopsy sample (eg, a tumor biopsy sample). In some embodiments, a cancer biopsy sample (eg, a tumor biopsy sample) is analyzed by immunohistochemical staining. In some embodiments, a cancer biopsy sample (eg, a tumor biopsy sample) is analyzed by immunohistochemical staining for the degree of induction of a PRR (eg, RIG-I or STING). In some embodiments, immunohistochemical staining indicates PRR performance (eg, RIG-I expression) in a cancer (eg, a tumor) during treatment of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof Or the distribution of STING performance) increased. In some embodiments, the distribution of PRR (e.g., RIG-I or STING) expression in the cancer (e.g., tumor) from treatment initiation to treatment end is increased by between about 5% and about 95%.

In some embodiments, the individual is untreated. In some embodiments, an individual has previously been treated for cancer. In some embodiments, the individual has relapsed. In some embodiments, the individual has relapsed more than once (eg, two, three, four times). In some embodiments, the cancer is a relapsed or refractory cancer.

In some embodiments, a compound of formula (I) or formula (II) is administered orally (for example, a compound of formula (II) is orally administered). In some embodiments, a compound of formula (I) or formula (II) is administered parenterally (eg, parenterally administered a compound of formula (II)). In some embodiments, the method comprises administering the compound daily. In some specific examples, it is administered once a day. In some In a specific example, the method comprises administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, for between about 1 week and 20 weeks. In some embodiments, the method comprises administering a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, for between about 1 week and 12 weeks.

In some embodiments, the dose of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, comprises from about 0.5 mg/kg to about 100 mg/kg. In some embodiments, the dose of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof comprises from 0.5 mg/kg to about 50 mg/kg. In some embodiments, the dose of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof comprises from 5 mg/kg to about 50 mg/kg.

In some embodiments, the dosage comprises a liquid or solid dosage form. In some embodiments, the liquid dosage form comprises a suspension, solution, sweetener, emulsion, beverage, elixir or syrup. In some embodiments, the solid dosage form comprises a capsule, lozenge, powder, dragee or microencapsulated dosage form.

In some embodiments, the method further comprises administering a therapeutically effective amount of the additional agent. In some embodiments, the additional therapeutic agent is an anticancer agent. In some embodiments, the anticancer agent is selected from the group consisting of methotrexate, 5-fluorouracil, cranberry, vincristine, bleomycin, vinblastine, dacarbazine, tolose, cisplatin, epirubicin Star and sorafenib tosylate.

1-7 are slides depicting the induction of the expression of RIG-I in the liver of two chronic WHV-infected woodchucks when formula (II) was administered. Induction of RIG-I expression was evaluated by treatment of formula (II) at week 0 (before treatment, Figures 1 and 4 ), week 6 (during administration, Figure 5 ), week 12 (formula (II) At the end of the administration, Fig. 2 and Fig. 6 ) and the 20th week (the end of the recovery period, Fig. 3 and Fig. 7 ) were determined by immunohistochemical staining of the liver biopsy samples obtained. Figures 1-3 refer to samples from the ground buck, and Figures 4-7 refer to samples from the ground buck. All images are shown at 10x magnification. Evaluation of RIG-I performance was performed by scoring color intensity and distribution frequency during histochemical staining analysis.

Figures 8A-8B show agarose gels depicting siRNA-mediated RIG-I and NOD2 silencing in human lung epithelial (HLE) cells. The degree of induction of NOD2 and RIG-I in HLE cells transfected with NOD2 siRNA, RIG-I siRNA or control siRNA was monitored by RT-PCR.

Figure 9 is a graph illustrating the association between NOD2 and RIG-I expression and interferon-β (IFN-β) induction. HLE cells were transfected with NOD2 siRNA, RIG-I siRNA or control siRNA and then treated with formula (II) 24 hours after transfection. After 12 hours, the content of IFN-β was determined by ELISA analysis.

Figures 10A-10B are graphs depicting the dose-dependent binding of a compound of formula (I) to RIG-I ( Figure 10A ) or STING ( Figure 10B ). The RIG-I or STING was immobilized on a microplate, and then different doses of the biotin-labeled formula (I) were incubated. The sample was then exposed to HRP-bound streptavidin and the difference in absorbance at 450 nm (OD 450 nm) was determined.

The present invention relates to methods of inducing the expression of a PRR (e.g., RIG-I, NOD2, or STING) in an individual. In some embodiments, the method comprises administering a compound of formula (I) or a prodrug thereof (e.g., a compound of formula (II)) or a pharmaceutically acceptable salt.

definition

As used herein, the article "a" or "an" refers to one or more than one (eg, at least one) grammatical target of the article.

"About" and "approximately" generally mean that the degree of error in the measured quantity is acceptable in view of the nature or accuracy of the measured value. The exemplary degree of error is within 20 percent (%) of the specified value or range of values, typically within 10%, and more typically within 5%.

As used herein, the term "acquired/acquiring" as used herein as a term refers to obtaining a physical entity (eg, a sample, such as a blood sample or a liver biopsy sample) or a value (eg, a numerical value) by "direct access." Or "indirectly acquire" a physical entity or value implementation. "Direct acquisition" means performing a process (such as an analysis method) to obtain a physical entity or value. “Indirect Acquisition” means a physical entity or value that is received from another party or source (for example, a third-party laboratory that directly acquires physical entities or values). Directly obtaining a value includes performing a process including physical changes of a sample or another substance, such as performing an analytical process involving physical changes of a substance (eg, a sample), performing an analytical method, such as a method as described herein, such as by, for example, mass spectrometry. Analysis (eg, LC-MS) is performed by performing sample analysis on body fluids, such as blood.

As used herein, the term "inducing/induction of" refers to an increase or enhancement of a function, such as an increase or enhancement in the performance of a pattern recognition receptor (eg, RIG-I, NOD2, or STING). In some embodiments, "induction of PRR expression" refers to induction (eg, increase or enhancement) of PRR RNA transcription, eg, RIG-I RNA, NOD2 RNA, or STING RNA (eg, mRNA), or eg Transformation (eg, increase or enhancement) of the PRR protein of the RIG-I protein, the NOD2 protein, or the STING protein. In some embodiments, the induction of PRR expression (eg, RIG-I expression, NOD2 expression, or STING expression) refers to, for example, PRR RNA in a cell (eg, RIG-I RNA, NOD2 RNA or STING RNA (eg, mRNA)) or RIG An increase or increase in the concentration of the -I protein, NOD2 protein or STING protein. In some embodiments, the induction of PRR expression (eg, RIG-I expression, NOD2 expression, or STING expression) refers to, for example, PRR RNA (eg, RIG-I RNA, NOD2 RNA, STING RNA (eg, mRNA)) or PRR in a cell. An increase in the number of copies of a protein (eg, RIG-I protein, NOD2 protein, or STING protein). In some embodiments, the expression of a PRR (eg, RIG-I, NOD2, or STING) can be initiated to initiate transcription of a PRR RNA (eg, RIG-I RNA, NOD2 RNA, or STING RNA (eg, mRNA)) or a PRR protein (eg, RIG-I protein, NOD2 protein or STING protein) transformation. In some embodiments, the expression of a PRR (eg, RIG-I, NOD2, or STING) can be expressed as an increase in the rate of transcription of a PRR RNA (eg, RIG-I RNA, NOD2 RNA, or STING RNA (eg, mRNA)) or a PRR protein ( For example, the rate of expression of RIG-I protein, NOD2 protein or STING protein) is increased.

As used herein, the term "activate/activation" refers to stimulating or triggering a function, such as a downstream path, such as a downstream signaling pathway. In some embodiments, activation of a pattern recognition receptor (PRR) (eg, RIG-I, NOD2, STING) refers, for example, via a downstream signaling partner (eg, IFN-beta promoter stimulator 1 (IPS-1)) The interaction of IRF3, IRF7, NF-KB, interferon (eg, IFN-[alpha] or IFN-[beta]) and/or cytokines stimulates specific proteins or pathways. In some embodiments, activation is different from induction of PRR performance. In some embodiments, the PRR can be activated without causing induced PRR performance (eg, performance of RIG-I, performance of NOD2, performance of STING). In some embodiments, activation can include the induction of performance of PRRs (eg, RIG-I, NOD2, STING). In some embodiments, activation of PRR may trigger induction of PRR (eg, RIG-I, NOD2, STING) as compared to a reference standard (eg, a basic performance of PRR (eg, RIG-I, NOD2, STING)) About 0.1%, about 0.5%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95% or more than 95%.

As used herein, the amount of a compound, conjugate or substance effective to treat a condition, such as a condition described herein, "therapeutically effective amount", "effective amount" or "effective course of action" """"""""""""""""""""""""""""""""""""""""""""""""""" The amount of substance or composition.

As used herein, the term "latent" refers to a microbial infection (eg, a viral infection) in which the microorganism has entered a latent phase (eg, in a cell) and is no longer substantially replicated. In some embodiments, the viral latency refers to the source portion of the viral replication cycle. In some embodiments, the incubation period can refer to a microbial infection of a host, such as an individual described herein. In such cases, the infected individual may experience symptoms associated with the infection or may be substantially asymptomatic.

As used herein, the term "prevent/preventing" as used in the context of a condition or disease refers to administration of an agent to an individual, for example, administration of a compound of the invention (eg, a compound of formula (I) or a prodrug (eg, to an individual) (eg, The compound of formula (II))) is such as to delay the onset of at least one symptom of the condition or disease as seen in the absence of administration of the agent.

As used herein, the term "reference treatment" or "reference standard" refers to a standard amount or standard treatment used as a comparison substrate. In some embodiments, a reference standard or reference treatment is a standard or treatment that is recognized, well known, or well characterized in the art. In some embodiments, the results of the methods described herein are described with reference to standards. In some embodiments, reference standards describe, for example, the use of compounds or compositions described herein. The amount of label in an individual or sample prior to initiation of treatment (eg, the degree of induction of PRR (eg, RIG-I, NOD2, STING)). In some embodiments, reference standards describe, for example, a measure of the presence, progression, or severity of a disease or symptom thereof, for example, prior to initiation of treatment with a compound or composition described herein.

As used herein, the term "subject" is intended to include both human and non-human animals. Exemplary human subjects include human patients having a condition, such as a condition described herein, or a normal individual. The term "non-human animals" includes all vertebrates, such as non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domestic and/or agriculturally useful. Animals such as sheep, dogs, cats, cows, pigs, etc. In an exemplary embodiment of the invention, the individual is a ground squirrel (e.g., Marmot monkey ( Marmota monax )).

As used herein, the term "treat/treating" is a system having a condition or disease that refers to subjecting an individual to a therapy, such as administration of a compound of formula (I) or a prodrug thereof (eg, a compound of formula (II)) or medicinal science. An acceptable salt, or a composition comprising a compound of formula (I) or a prodrug thereof (e.g., a compound of formula (II)) or a pharmaceutically acceptable salt, which cures, heals, relieves at least one symptom of the condition or disease , mitigate, change, remedy, improve or improve. Treatment includes administering an amount effective to alleviate, alleviate, alter, correct, ameliorate, ameliorate or affect the condition or condition of the condition or condition. Treatment can inhibit the deterioration or worsening of the symptoms of the condition or disease.

This document provides a number of ranges, such as the range of amounts of the drug administered per day. In some embodiments, the range includes two endpoints. In other embodiments, the scope does not include one or two endpoints. As an example, the range may not include lower endpoints. Therefore, in such specific examples, the range of 250 to 400 mg/day excluding the lower endpoint will cover an amount greater than 250, ie Less than or equal to 400 mg / day.

Pattern recognition receptor

The invention presented herein features activating and inducing an individual, such as a PRR manifestation in an individual having a microbial infection (eg, a viral infection, a bacterial infection, a fungal infection, or a parasitic infection) (eg, RIG-I performance, NOD2 performance, or The method of STING performance). Pattern recognition receptors (PRRs) are a wide variety of proteins that recognize patterns of pathogen-associated molecules (PAMP) that are preserved in pathogenic invaders. PAMP is typically a product of biosynthetic pathways essential for the survival and/or infectivity of pathogens, such as lipopolysaccharides, glycoproteins, and nucleic acids. Identification of PAMP by its homologous PRR activates the signaling pathway, thereby producing immune defense factors such as pro-inflammatory and anti-inflammatory cytokines, type I interferons (IFN-α, IFN-β) and/or interferon stimulation. Gene (ISG). It is well known that inducing innate immune signaling also results in activation of T cell responses and induction of adaptive immunity. These downstream immunizations are essential for clearing the virus by cytotoxic T lymphocytes and other defense mechanisms that cause apoptosis and death of infected cells. It is also well known that interferon acts on ISRE (interferon response element) which triggers ISG production, which plays an important role in antiviral cell defense.

RIG-I is a founding member of the PRR family called RIG-I-like receptor (RLR), which primarily detects RNA derived from an external source. It is a key sensor for microbial infections (eg, viral infections) in most cells and is constitutively expressed in cytosol at low levels. After ligand binding, the performance of RIG-I is rapidly enhanced, resulting in an increase in RIG-I concentration in cells (Jensen, S. and Thomsen, AR J Virol (2012) 86: 2900-2910; Yoneyama M. et al. Nat Immunol (2004) 5: 730-737). RIG-I is an ATP-related helicase containing a central DExD/H-box ATPase domain and a tandem N-terminal kaspase recruitment domain (CARD) that mediates downstream signaling. The C-terminus of RIG-I contains a ssRNA/dsRNA binding domain that is used to silence the N-terminal CARD function when not bound. Without wishing to be bound by theory, it is believed that when the target RNA structure is identified, the two N-terminal CARDs are exposed, allowing for the CARD interaction with the downstream binding partner IFN-β promoter stimulator 1 (IPS-1), which is downstream. Binding partners are also known as mitochondrial antiviral signaling molecules (MAVS) and CARDIF. This interaction in turn further triggers downstream signaling, such as induction of IRF3, IRF7, NF-κB, IFNs, and cytokine production that initiates the host immune response.

RIG-I binds to RNA structures, especially double-stranded RNA (dsRNA) and single-stranded RNA (ssRNA) with uncapped 5'-triphosphate (Jensen, S. and Thomsen, ARJ Virol (2012) 86: 2900 -2910). RIG-I is able to distinguish between foreign ssRNA and self-ssRNAs, such as mRNA and tRNA, primarily via the presence of uncapped 5'-triphosphate groups in foreign ssRNAs, since self-ssRNAs typically do not have exposed triphosphates at the 5'-end. In addition, self-mRNA was modified by 5'-7-methylguanosine cap translation, which was further subjected to 2'-O-methylation. This 2'-O-methylation was shown to act to prevent RIG-I recognition (Daffis, S. et al., Nature (2010) 468: 452-456). Similarly, self-tRNA undergoes 5' cleavage and a series of base modifications, and is also generally associated with preventing ribosome binding to RIG-I (Jensen, S. and Thomsen, AR J Virol (2012) 86: 2900-2910). . Recent work has further shown that the RIG-I ssRNA ligand has an internal enriched uridine sequence in addition to the uncapped 5' triphosphate, and in some cases, the 3'-phosphonium group can replace the 5'-triphosphate ( Malathi, K. et al., RNA (2010) 16: 2108-2119).

Other RLRs are homologous to RIG-I and function in a similar manner, including MDA5, LGP2, and RNase L. MDA5 is highly homologous to RIG-I and has been shown to use picornaviruses (eg, encephalomyelitis virus (EMCV), Theiler's virus, and Mengo virus), Sendai virus, rabies virus, West Nile virus, rabies virus, rotavirus Toxic, murine hepatitis virus and murine norovirus infection are critical for triggering cytokine responses. LPG2 lacks the CARD domain seen in RIG-I and MDA5, which results in direct interaction with IPS-1 to initiate downstream signaling. Similarly, the salt LPG2 appears to be a regulator of the innate immune response as well as other RLRs with CARD, such as RIG-I and MDA5.

Another class of PRRs encompasses nucleotide binding and oligomerization domain (NOD)-like receptors or the NLR family (Caruso, R. et al., Immunity (2014) 41: 898-908), which includes the microbial sensor NOD2. NOD2 consists of an N-terminal CARD, a centrally located nucleotide-binding oligomeric domain, and a C-terminal leucine-rich repeating domain that results in the binding of a microbial PAMP such as a bacterial peptidoglycan fragment and a microbial nucleic acid. Ligand binding activates NOD2 and is driven by interaction with the CARD-containing kinase RIPK2, which in turn activates a variety of downstream proteins including NF-κB, MAPK, IRF7 and IRF3, the latter of which induces type 1 interferon. NOD2 is expressed in a diverse set of cell types, including macrophages, dendritic cells, pannet cells, epithelial cells (eg, lung epithelial cells, intestinal epithelial cells), and osteoblasts. NOD2 has been identified as a sensor infected by a plurality of pathogenic invaders, such as protozoa (eg, Toxoplasma gondii and Plasmodium berghei ), Bacteria (such as Bacillus anthracis , Borrelia burgdorferi , Burkholderia pseudomallei , Helicobacter hepaticus , Legionella pneumophilia , Mycobacterium tuberculosis (Mycobacterium tuberculosis), Propionibacterium acnes (Propionibacterium acne), Aeromonas Porphyromonas gingivalis (Porphyromonas gingivalis), Salmonella enterica (Salmonella enterica) and Streptococcus pneumoniae (Streptococcus pneumonia)) and viruses (e.g. respiratory engagement Respiratory syncytial virus and murine norovirus-1 (Moreira, LO and Zamboni, DS Front Immunol (2012) 3: 1-12). Recent work has shown that mutations in NOD2 can promote inflammatory diseases, such as Crohn's disease, resulting in an abnormal inflammatory response upon stimulation.

In addition to their PRRs described above, other PRRs play a key role in the host immunity of antimicrobial invaders. The stimulator of the interferon gene (STING) is a DNA sensor derived from a cytosolic microorganism that has been shown to be particularly sensitive to double-stranded DNA (Burdette, DL and Vance, RE (2013) Nat Immunol 14: 19-26). The two STING molecules form a homodimer mediated by an alpha-helix present in the C-terminal dimeric domain, and molecular binding studies have shown that each STING dimer binds to one microbial nucleic acid molecule. Upon ligand binding, STING activates an innate immune response via interaction with RIG-I and IPS-1, resulting in interferon production (eg, IFN-[alpha] and IFN-[beta]) and other downstream signaling events. Since its discovery, STING has been shown to act as a virus (eg adenovirus, herpes simplex virus, hepatitis B virus, vesicular stomatitis virus, hepatitis C virus), bacteria (eg, Listeria monocytogenes, lungophilic Key sensory for Legionella, Mycobacterium tuberculosis, and protozoa (P. falciparum, Plasmodium berghei). In addition, STING has been shown to play a major role in the innate immune response against tumor antigens, thereby driving dendritic cell activation and subsequent T cell activation in several cancers. (Woo, SR et al. Trends in Immunol (2015) 36: 250-256).

Compound

The invention features a method of inducing a PRR performance (eg, RIG-I performance, NOD2 performance, or STING performance) in an individual (eg, an individual having a microbial infection, such as a viral infection, a bacterial infection, a fungal infection, or a parasitic infection) A compound of formula (I) or a prodrug thereof or a pharmaceutically acceptable salt thereof is administered. The active agent is of formula (I), which can be described by any of formula (Ia), formula (Ib) and formula (Ic), or a combination thereof:

The composition of the present invention may comprise a prodrug of formula (I), wherein the prodrug is a compound of formula (II). A prodrug (eg, a compound of formula (II)) can be described by any of formula (IIa), formula (IIb), and formula (IIc), or a combination thereof:

Formula (I) and its prodrug (II) are small molecule nucleic acid hybrid (dinucleotide) compounds that bind antiviral and immunomodulatory activities. The latter activity modulates controlled apoptosis of, for example, hepatocytes infected with the virus by stimulating an innate immune response, similar to that achieved by IFN-[alpha] treatment in patients with viral infection.

Without wishing to be bound by theory, the mechanism of action of formula (I) and its prodrug (II) can be divided into two parts. The first part elicits host immunostimulatory activity of formula (I), which induces endogenous IFN via activation of PRRs (eg, RIG-I, NOD2, and STING) (Takeuchi, O. and Akira S. Cell (2010) 140:805- 820; Sato, S. et al., Immunity (2015) 42: 123-132; Sabbah, A. et al., Nat Immunol (2009) 10: 1073-1080). Activation can occur by binding the formula (I) to the nucleotide binding domain of a PRR (eg, RIG-I, NOD2 or STING) as previously described, and can further induce PRR expression (eg, RIG-I expression, NOD2 expression) Or STING performance).

The second part of the mechanism of action of formula (I) and its prodrugs (II) relates to its direct antiviral activity, which inhibits viral nucleic acid synthesis by steric hindrance of viral polymerases. Blocking can be achieved by interaction of formula (I) and PRR (eg, RIG-I, NOD2, or STING) as described earlier, which in turn can prevent polymerase and replication nucleic acid templates (eg, virus-derived) RNA) meshing. The cytotoxic potential of formula (I) has been initially assessed using a panel of cell lines. Similarly to the parent drugs, showed excellent safety characteristics of formula (II), wherein concentration of 50% cell cytotoxicity (CC ₅₀₎ is greater than 1000μM (Coughlin, JE et al. Bioorg Med Chem Lett (2010) 20 : 1783-1786). The antiviral activity of formula (II) has been further evaluated, such as anti-HBV activity in cell-based assays for wild-type HBV and lamivudine-(3TC) and adendron-(ADV) resistant mutant HBV and Anti-HCV activity.

In some embodiments, the methods described herein comprise administering a compound of formula (I) Or a pharmaceutically acceptable salt thereof. In other embodiments, the methods described herein comprise administering a prodrug of Formula (I) (eg, a compound of Formula (II)) or a pharmaceutically acceptable salt thereof. In other embodiments, the methods herein describe administering a composition comprising a combination of a compound of formula (I) and a compound of formula (II) or a pharmaceutically acceptable salt thereof. It has been well established that the prodrugs of formula (I) have been shown to be converted to the active pharmaceutical formula (I) upon administration (for example Rp- and Sp-formis (I) isomers, formula (Ib) and formula (Ic)).

The compounds provided herein may contain one or more asymmetric centers and thus appear as racemates and racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers. . All such isomeric forms of such compounds are expressly included within the scope. Unless otherwise indicated, when a compound is named or depicted by a structure that does not specify a stereochemistry and has one or more chiral centers, it is understood to mean all possible stereoisomers of the compound. The compounds provided herein may also contain linkages (e.g., carbon-carbon bonds, phosphorus-oxygen bonds, or phosphorus-sulfur bonds) or substituents that limit bond rotation, such as by the presence of ring or double bonds.

Instructions

The present invention relates to a method of inducing the expression of PRR (e.g., RIG-I, NOD2, STING) in an individual by administering Formula (I) or Prodrug Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, an individual can have a condition as described below, such as a viral infection (eg, a viral incubation period), a bacterial infection, or a cancer.

Treating viral infections

Pattern recognition receptors such as RIG-I, NOD2, MDA5 and STING have been shown to be important factors in host identification of multiple RNA viruses from a variety of different viral families. In some embodiments, the induced PRR (eg, RIG-I, NOD2, STING) disclosed herein is expressed The method comprises administering to a subject infected with a microbial organism a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the microbial infection is a virus. In some embodiments, the virus is an RNA virus (eg, a double-stranded RNA (dsRNA) virus, a single-stranded RNA (ssRNA) virus (eg, a positive-stranded (sense) ssRNA virus or a minus-strand (antisense) ssRNA virus) or a ssRNA reverse transcription Virus) or DNA virus (eg dsDNA virus, ssDNA virus or dsDNA retrovirus). In some embodiments, for example, according to the Baltimore classification system, the virus can be a Group I, Group II, Group III, Group IV, Group V, Group VI, or Group VII virus class.

In some embodiments, the virus is a dsRNA virus, such as a Group III virus. In some embodiments, the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced via host-derived or virus-derived RNA. In some embodiments, the virus is a dsRNA virus and is a member of the group: a ribonuclear acid family, a golden virology family, a cystic phage family, an endoviridae family, a low toxicity virus family, a giant bipartite RNA virus family, Department of Virology, Small Double-section RNA Virus, Reoviridae or Whole Virology or other families of dsRNA viruses. Exemplary dsRNA viruses and virus genus include, but are not limited to, Picobirnavirus , Rotavirus , Seadornavirus , Coltivirus , Circovirus ( Orbivirus ) and Orthoreovirus or its subtypes, species or variants.

In some embodiments, the virus is a ssRNA virus, such as a positive (sense) ssRNA virus, such as a Group IV virus. In some embodiments, the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced via host-derived or virus-derived RNA. In some embodiments, the virus is a positive-strand (sense) ssRNA virus and is a member of the following: arteritis virus, coronaviridae, meivirus, bacillus, cistronic, infectious Sexually softening virus family, marine RNA virus family, small RNA virus family, plant small RNA virus family, A linear virus family, B-type linear virus family, C-type linear virus family, turnip yellow-inlaid virus family, A-type Virology, Aviridae, Astrovirus, Bacillus ribavirin, Brome mosaic virus, Calicivirus, Cartesian, Long-lineviridae, Flaviviridae, Smooth Virology, Yellow virus family, naked RNA virus family, Noda virus family, Paeki virus family, potato Y virus family, togaviridae or scorpion virus family or other families of positive-strand (sense) ssRNA viruses. Exemplary positive-strand (sense) ssRNA viruses and viral genus include, but are not limited to, Yellow fever virus, West Nile virus, Hepatitis C virus, Dengue fever virus, Rubella virus , Ross River virus, Sindbis virus, Chikungya virus, Norwalk virus, Japanese encephalitis virus, tick-borne encephalitis Tick-borne encephalitis virus, St. Louis encephalitis virus, Murray Valley encephalitis virus, Caesar forest disease virus (Cassano Forest disease virus) For example, macaque disease virus), Western Equine encephalitis virus, Eastern Equine encephalitis virus, Venezuelan Equine encephalitis virus, Sapporo virus, norovirus (norovirus), sapovirus (sapovirus), calicivirus (calicivirus), bis Umberto Eco virus (Parechovirus), A type hepatitis disease Rhinovirus (Rhinovirus) (e.g., rhinovirus A, rhinovirus B and rhinovirus C), enteroviruses (e.g. Enterovirus A, enterovirus B enterovirus C (e.g. poliomyelitis virus), enteroviruses D, intestinal Virus E, Enterovirus F, Enterovirus G or Enterovirus H), Apthovirus (such as foot-and-mouth disease virus), and Nidovirales (such as Cavally virus, Nanding virus ( Nam Dinh virus), Middle East respiratory syndrome coronavirus (MERS-CoV), coronavirus HKU1, coronavirus NL63, SARS-CoV, coronavirus OC43 and coronavirus 229E), beet Benyvirus , Blunevirus , Cilevirus , Hepevirus (eg hepatitis E virus), Higrevirus , Idaeovirus , Negevirus , Ourmiavirus , Polemovirus , Sobemovirus or Umbravirus or subtypes, variants thereof or variants thereof.

In some embodiments, the virus is a ssRNA virus, such as a minus-strand (antisense) ssRNA virus, such as a Group V virus. In some embodiments, the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced via host-derived or virus-derived RNA. In some embodiments, the virus is a minus-strand (antisense) ssRNA virus and is a member of the following: Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Nicotinaceae, Sand Phytophthora, Buniaviridae, Serpentidae or Orthomyxoviridae or other families of negative-chain (antisense) ssRNA viruses. Exemplary negative (antisense) ssRNA viruses and viral genus include, but are not limited to, Brona disease virus, Ebola virus, Marburg virus, Measles virus, and epidemics Mumps virus, Nipah virus, Hendra virus, Respiratory syncytial virus, Influenza, and Parainfluenza viruses, Metapneumovirus, Newcastle disease virus, Deltavirus (eg, hepatitis D virus), Dichohavirus , Emaravirus , Nia Virus ( Nyavirus ), Tenuivirus , Varicosavirus , or a subtype, species or variant thereof.

In some embodiments, the virus is a ssRNA retrovirus (ssRNA RT virus), such as a Group VI virus. In some embodiments, the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced via host-derived or virus-derived RNA. In some embodiments, the virus is a ssRNA RT virus and is a member of the transpotoviridae, the pseudoviridae, or the retroviridae or other families of the ssRNA RT virus. Exemplary ssRNA RT viruses and virus genus include, but are not limited to, Metavirus , Errantivirus , Alpharetrovirus (eg, Avian leukosis virus, Lloyd's sarcoma virus) (Rous sarcoma virus)), β retroviruses (Betaretrovirus) (such as mouse mammary tumor virus), retroviruses gamma] (Gammaretrovirus) (e.g. murine leukemia virus, feline leukemia virus), retroviruses [delta] ( for example, human T lymphotropic virus), ε retroviruses (e.g. fish eyes transdermal sarcoma virus (Walleye dermal sarcoma virus)), lentiviruses (lentivirus-) (e.g., human immunodeficiency virus 1 (HIV)), or a Asian Type, species or variant.

In some embodiments, the virus is a DNA virus, such as a dsDNA virus or a ssDNA virus. In some embodiments, the virus is a dsDNA virus, such as a Group I virus, and the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced via host-derived or virus-derived RNA. In some embodiments, the virus is a dsDNA virus and is a member of the following: Muscle phage, Escherichia coli, Long-tailed virology, Herpesviridae, Herpesviridae, Mollusic herpesviridae, Limulus phage, Small rod-shaped phage, adenoviridae, bottleviridae, vesicular virus family, African swine fever virus, baculovirus family, two-tailed virus family, kluyveridae, lipoviridae, micro spindle phage , Grignard virus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus, genus Family, Poxviridae, Freund's Virology, stratified phage or Conoviridae or other families of dsDNA viruses. Exemplary dsDNA viruses and viral genus include, but are not limited to, Dinodnavirus , Nudivirus , smalllpox, human herpes virus, Varicella Zoster virus ), polyomavirus 6 (polyomavirus 6), polyomavirus 7, polyomavirus 9, polyomavirus 10, JC virus, BK virus, KI virus, WU virus, Merkel cell polyomavirus, Trichodysplasia spinulosa-associated polyomavirus, MX polyomavirus, Simian virus 40 or subtypes, variants thereof or variants thereof.

In some embodiments, the virus is a ssDNA virus, such as a Group II virus, and the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced via host production or virus-derived RNA. In some embodiments, the virus is a ssDNAss DNA virus and is a member of the group consisting of: a ring virulence family, a bacillus family, a double DNA virus family, a circoviridae family, a geminiviridae, a filamentous bacteriophage family, a microphage family, a dwarf virus family. , Parvoviridae or the family of the circovirus family or other ssDNA viruses. Exemplary ssDNA viruses and virus genus include, but are not limited to, Torque teno virus, Torque teno midi virus, Torque teno mini virus, Gyrovirus , Circovirus , Parvovirus B19, Bocaparvovirus , Dependoparvovirus , Erythroparvovirus , Protoparvovirus , Tetraparvovirus ), type 2 Bombyx mori densovirus type 2, lymphoidal parvo-like virus, hepatopancreatic parvo-like virus or its subtype, Species or variants.

In some embodiments, the virus is a dsDNA reverse transcriptase (RT) virus, such as a Group VII virus, and the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced by host production or by virus-derived RNA. . In some embodiments, the virus is a dsDNA RT virus and is a member of the family of hepatic DNA virus or the cauliflower mosaic virus family or the dsDNA RT virus. Exemplary dsDNA RT viruses and viral genus include, but are not limited to, hepatitis B virus or a subtype, species or variant thereof.

In some embodiments, a virus, such as a virus described herein, is for example, lurking within a cell. In some embodiments, the virus is an RNA virus (eg, a double-stranded RNA (dsRNA) virus, a single-stranded RNA (ssRNA) virus (eg, a positive-stranded (sense) ssRNA virus or a minus-strand (antisense) ssRNA virus) or a ssRNA reverse transcription A virus) or a DNA virus (such as a dsDNA virus, ssDNA virus or dsDNA retrovirus) and is, for example, latent in cells. In some embodiments, such as according to the Baltimore classification system, the virus can be a Group I, Group II, Group III, Group IV, Group V, Group VI, or Group VII virus class, and for example, lurking in cells Inside.

In some embodiments, the virus is an RNA virus (such as an RNA virus described herein) and is, for example, latent within the cell. In some embodiments, the virus is a ssRNA retrovirus (ssRNA RT virus), such as a Group VI virus, and is, for example, latent within the cell. In some embodiments, the virus is human immunodeficiency virus 1 (HIV) or a subtype, a species or variant thereof, and is, for example, latent in a cell.

In some embodiments, the methods disclosed herein for inducing the expression of one or more PRRs (eg, RIG-I, NOD2, STING) in an individual with a viral infection result in a PPR table Now (for example, RIG-I performance, NOD2 performance, STING performance) increase. In some embodiments, the performance of inducing one or more PRRs (eg, RIG-I, NOD2, STING) is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9. , about 2, about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200, about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced by administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof of about 5 Occurs within minutes. In some embodiments, the induction of the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is administered to a subject a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. After about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about It occurs 6 hours, about 7 hours, about 8 hours, about 10 hours, about 12 hours or longer.

Treating bacterial infections

Recent studies have shown that PRRs (eg, RIG-I, NOD2, STING) play a key role in host identification from bacterial infections of multiple species (Dixit, E. and Kagan, JC Adv Immunol (2013) 117:99- 125). In some cases, the bacteria may secrete nucleic acids during the exponential growth phase (eg, Listeria monocytogenes; Abdullah, Z. et al., EMBO J (2012) 31: 4153-4164), which in turn is by such as RIG -I's PRR detection and thus prompted to induce further PRR performance. In other cases, such as for Lungophilic Legionella, bacterial DNA enters the cytosol via an infection process and is transcribed into an RNA ligand for RIG-I (Chiu, YH et al., Cell (2009) 138 :576-591), thus triggering downstream PRR-mediated signaling events. PRR performance (eg, RIG-I performance, NOD2 performance, STING performance) can be further induced when identifying RNA released during bacterial phagocytic absorption. In addition, bacterial cell wall components, such as peptidoglycans (e.g., cell wall dipeptides, i.e., MDP), can serve as ligands for the activation and induction of PRR, i.e., NOD2, and bacterially derived nucleic acids, such as A circulating dinucleotide (eg, a circulating di-GMP) can bind to and activate the PRR, particularly STING. In some embodiments, the performance of one or more PRRs can be induced by other means not explicitly described herein.

In some embodiments, the methods disclosed herein for inducing expression of one or more PRRs (eg, RIG-I, NOD2, STING) comprise administering to an individual infected with a microbial infection, such as a bacterial infection, Formula (I) or Formula (II) a compound or a pharmaceutically acceptable salt thereof. In some embodiments, the bacterium is a Gram-negative bacterium or a Gram-positive bacterium. Exemplary bacteria include, but are not limited to, Listeria (eg, Listeria monocytogenes), Francis (eg, T. genus), Mycobacterium (eg, Mycobacterium tuberculosis) ), Brucella (eg, Brucella abortus), Streptococcus (eg, Group B Streptococcus), Legionella (eg, Legionella vulgaris), Escherichia (eg, E. coli), False Monocytogenes (eg, Pseudomonas aeruginosa), Salmonella (eg, Salmonella typhi), Shigella (eg, Shigella flexneri), Aspergillus (eg, Campylobacter jejuni), Clostridium (eg, botulinum fusiform) Bacillus), Enterococcus (eg, Enterococcus faecalis), Vibrio (eg, Vibrio cholerae), Yersinia (eg, Yersinia pestis), Staphylococcus (eg, Staphylococcus aureus) or Other genus, species, subtype or variant.

In some embodiments, the methods disclosed herein for inducing expression of one or more PRRs (eg, RIG-I, NOD2, STING) in an individual having a bacterial infection result in PRR performance (eg, RIG-I performance, NOD2 performance, STING performance) increased. In some specific examples, Inducing the performance of one or more PRRs (eg, RIG-I, NOD2, STING) of about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.5 , about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200, about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced by administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof of about 5 Occurs within minutes. In some embodiments, the induction of expression of one or more PRRs (eg, RIG-I, NOD2, STING) is about after administration of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours , occurs about 7 hours, about 8 hours, about 10 hours, about 12 hours or longer.

cure cancer

Identification of RNA ligands by PRR (eg RIG-I, NOD2 or STING) stimulates the production of type I interferons (eg IFN-α or IFN-β), thus triggering a cascade downstream of apoptosis in sensitive cells Signaling events. In recent years, the association between the induction of RIG-I expression and various cancers has been found. For example, RIG-I has been shown to be significantly down-regulated in hepatocellular carcinoma, and patients exhibiting low RIG-I performance in tumors have shorter survival and have a poorer response to IFN-α therapy (Hou, J) Et al, Cancer Cell (2014) 25:49-63). Similarly, RIG-I performance has been shown to be useful as a biomarker for predicting the prognosis and response of immunotherapy. In other cases, induction of RIG-I expression has been shown to induce pancreatic cancer cells, prostate cancer cells, and breast cancer cells. Immunogenic cell death of skin cancer cells and lung cancer cells (Duewell, P. et al., Cell Death Differ (2014) 21: 1825-1837; Besch, R. et al., J Clin Invest (2009) 119: 2399-2411 Kaneda, Y. Oncoimmunology (2013) 2: e23566; Li, XY et al, Mol Cell Oncol (2014) 1: e968016), highlighting novel approaches to immune-mediated cancer therapy.

The role of STING in responding to cancer in stimulating innate immunity has also been identified. Recent studies have shown the presence of tumor-derived DNA in the cytosol of certain antigen presenting cells, such as dendritic cells that may be infiltrated by tumor cell stress or cell death. This tumor-derived DNA has been shown to activate STING, resulting in the production of a related type 1 interferon and sensing (Woo, SR et al, Immunity (2014) 41: 830-842). Stimulation of STING and the resulting downstream signaling pathway may also promote the recruitment of effector T cells to the inflamed tumor microenvironment (Woo, SR Trends in Immunol (2015) 36: 250-256). In some embodiments, a method of inducing expression of a PRR (eg, a PRR as described herein) comprises administering to a subject having cancer a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, a method of inducing expression of RIG-I disclosed herein comprises administering to a subject having cancer a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods disclosed herein for inducing the expression of NOD2 comprise administering to a subject having cancer a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the one disclosed herein that induces the performance of STING comprises administering to a subject having cancer a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is selected from the group consisting of breast, bone, brain, cervix, colon, gastrointestinal tract, eyes, gallbladder, lymph nodes, blood, lung, liver, skin, mouth, prostate, ovary, penis, pancreas, uterus, testis Cancer of the stomach, thymus, thyroid or other parts of the body. In some embodiments, the cancer comprises a solid tumor (eg, a carcinoma, sarcoma, or lymphoma). In some embodiments, the cancer is hepatocellular carcinoma or other cancer of the liver. In some embodiments, the cancer is leukemia or other cancer of the blood. In some embodiments, the cancer comprises breast cancer, renal cell carcinoma, colon cancer, melanoma, ovarian cancer, head and neck squamous cell carcinoma, pancreatic cancer, prostate cancer, lung cancer, brain cancer, or gastrointestinal matrix cancer. In some embodiments, a cancer cell (eg, a tumor cell) comprises a specific cancer-associated antigen that induces a T cell response.

In some embodiments, the methods disclosed herein for inducing expression of one or more PRRs (eg, RIG-I, NOD2, STING) in an individual having cancer result in PRR performance (eg, RIG-I performance, NOD2 performance, STING) Performance) increased. In some embodiments, the performance of inducing one or more PRRs (eg, RIG-I, NOD2, STING) is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9. , about 2, about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200, about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. In some embodiments, the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced by administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof of about 5 Occurs within minutes. In some embodiments, the expression of one or more PRRs (eg, RIG-I, NOD2, STING) is induced by administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof of about 5 Occurs within minutes. In some embodiments, the induction of expression of one or more PRRs (eg, RIG-I, NOD2, STING) is about after administration of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours , occurs about 7 hours, about 8 hours, about 10 hours, about 12 hours or longer.

Pharmaceutical composition

The invention features a method of inducing expression of one or more PRRs (e.g., RIG-I, NOD2, STING) in an individual, the method comprising administering a compound of formula (I) or a prodrug thereof (e.g., a compound of formula (II) Or a pharmaceutically acceptable salt thereof.

Although a compound of the invention (e.g., a compound of formula (I) or a prodrug thereof (e.g., a compound of formula (II))) may be administered alone, it is preferred to administer the compound in the form of a pharmaceutical composition or formulation wherein the compound One or more pharmaceutically acceptable diluents, excipients or carrier combinations. The compounds according to the invention may be formulated for administration in any suitable manner suitable for use in human or veterinary medicine. In certain embodiments, a compound included in a pharmaceutical preparation may be active by itself, or may be, for example, a drug (for example, a compound of formula (II)) which can be converted into an active compound in a physiological environment. The compounds of the invention and/or the pharmaceutical compositions of the invention may be formulated to be pharmaceutically acceptable, regardless of the route of administration selected, such as described below or by other conventional methods known to those skilled in the art, in a suitable hydrated form. Formulation.

The amount and concentration of a compound of the invention (e.g., a compound of formula (I) or a prodrug thereof (e.g., a compound of formula (II))) and a pharmaceutical composition administered to an individual in a pharmaceutical composition can be selected based on clinically relevant factors, Such clinically relevant factors are, for example, medically relevant individual characteristics (eg, age, weight, sex, other medical conditions, and the like), solubility of the compound in a pharmaceutical composition, potency and activity of the compound, and administration of the pharmaceutical composition. Ways to give. For further information on routes of administration and dosage regimens, the reader is referred to the Comprehensive Medicinal Chemistry Volume 5, Chapter 25.3 (Corwin Hansch; Chairman of the Board), Pergamon Press 1990.

Accordingly, another aspect of the invention provides a pharmaceutically acceptable composition comprising a therapeutically effective amount or a prophylactically effective amount of a compound described herein (eg, a compound of formula (I) or Prodrugs (e.g., compounds of formula (II)) are formulated with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be administered in a solid or liquid form, optionally in a form suitable for oral or parenteral administration, for example by oral dose or by For example, a sterile solution or suspension is administered subcutaneously, intramuscularly or intravenously. However, in certain embodiments, the target compound can be simply dissolved or suspended in sterile water. In some embodiments, the pharmaceutical preparation is non-pyrogenic, that is, does not increase the patient's body temperature.

As used herein, the terms "systemic administration/administered systemically" and "peripheral administration/administered peripherally" mean the administration of a compound, drug or other substance other than direct administration to the central nervous system. It is allowed to enter the patient system and is therefore subject to metabolism and other similar processes, such as subcutaneous administration.

The phrase "pharmaceutically acceptable" is used herein to mean that it is suitable for contact with human and animal tissues without reasonable toxicity, irritation, allergic reactions or other problems or complications, and reasonable benefits within the scope of sound medical judgment. / Risk ratios of commensurate compounds, substances, compositions and/or dosage forms.

As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition or vehicle, such as a liquid or solid filler, diluent, stabilizer, A agent, solvent or encapsulating substance which involves transporting or transporting a target antagonist from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Some examples of substances that can serve as pharmaceutically acceptable carriers include (but are not limited to To: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and Cellulose acetate; (4) powdered xanthine; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oil, such as peanut oil, Cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; 12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) ascorbic acid; Pyrogen water; (18) isotonic saline; (19) Ringer's solution; (20) ethanol; (21) phosphate buffer solution; (22) cyclodextrin, such as Captisol®; 23) Other non-toxic compatible substances used in pharmaceutical formulations, such as antioxidants and antibacterial agents.

As indicated above, certain specific examples of the compounds described herein may contain basic functional groups, such as amines, and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this aspect, the term "pharmaceutically acceptable salt" means a relatively non-toxic, inorganic and organic acid addition salt of a compound of the present invention. Such salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting the purified compound of the invention in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. . Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, Benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonic acid Salts, gluconates, lactobions and lauryl sulfonates and the like (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).

In other instances, the compounds of the invention may contain one or more acidic functional groups and are therefore capable of forming a pharmaceutically acceptable salt with a pharmaceutically acceptable base. In such cases, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic bases of the compounds of the invention (eg, a compound of formula (I) or a prodrug thereof (eg, a compound of formula (II)). A salt. These salts can likewise be prepared in situ during the final isolation and purification of the compound, or by separately bringing the purified compound in its free acid form with a suitable base such as a hydroxide or carbonate of a pharmaceutically acceptable metal cation. Prepared by the reaction of either bicarbonate, ammonia or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Representative organic amines suitable for use in forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate) as well as coloring agents, mold release agents, coating agents, sweeteners, flavoring and fragrances, preservatives and antioxidants may also be present In the composition. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteamine hydrochloride, sodium hydrogen sulfate, sodium metabisulfite, sodium sulfite, and the like; (2) Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxymethoxybenzene (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; And (3) a metal chelating agent such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Pharmaceutically acceptable carriers as well as wetting agents, emulsifiers, lubricants, colorants, mold release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, antioxidants, and other additional components The amount can be present at about 0.001% and 99% of the compositions described herein. For example, Such pharmaceutically acceptable carriers as well as wetting agents, emulsifiers, lubricants, colorants, mold release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, antioxidants, and other additional groups The fraction may be about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 3 of the compositions described herein. %, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, About 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 85%, about 90%, about 95% or about 99% are present.

The pharmaceutical composition of the present invention may be in a form suitable for oral administration, such as a liquid or solid oral dosage form. In some embodiments, the liquid dosage form comprises a suspension, solution, sweetener, emulsion, beverage, elixir or syrup. In some embodiments, the solid dosage form comprises a capsule, lozenge, dragee or powder. The pharmaceutical composition may be in unit dosage form suitable for single administration of precise dosages. A pharmaceutical composition can comprise a pharmaceutically acceptable carrier in addition to a compound described herein (eg, a compound of Formula (I) or a prodrug thereof (eg, a compound of Formula (II)), or a pharmaceutically acceptable salt thereof, and Optionally, one or more pharmaceutically acceptable excipients, such as stabilizers (e.g., binders such as polymers, such as precipitation inhibitors, diluents, binders, and lubricants), may be included.

In some embodiments, the compositions described herein comprise a liquid dosage form for oral administration, such as a solution or suspension. In other embodiments, the compositions described herein comprise a solid dosage form for oral administration that is capable of being directly compressed into a tablet. Additionally, the tablet may include other pharmaceutically or pharmaceutically acceptable agents, carriers, and/or adjuvants. Exemplary pharmaceutical compositions include compressed troches (e.g., direct compression troches), for example, a compound of the invention (e.g., a compound of formula (I) or a prodrug thereof (e.g., a compound of formula (II)) or a pharmaceutically acceptable salt thereof .

Formulations of the invention include those suitable for parenteral administration. Formulations are preferably presented in unit dosage form and may be prepared by any methods known in the art of pharmacy. The amount of active ingredient which may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient which may be combined with the carrier materials to produce a single dosage form is generally the amount of the compound which produces the therapeutic effect. This amount is usually in the range of from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, optimally from about 10% to about 30%. Pharmaceutical compositions of the invention suitable for parenteral administration comprise a compound of the invention in one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions or may be reconstituted only prior to use A sterile injectable solution or a combination of sterile powders of dispersions, which may contain an antioxidant, a buffer, a bacteriostatic agent, or a solubilizing or suspending or thickening agent which causes the formulation to be isotonic with the blood of the intended recipient .

Examples of suitable aqueous and non-aqueous vehicles that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as Olive oil) and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size (in the case of dispersions) and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial agents and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include an isotonic agent, such as sugar, sodium chloride, and the like, in the composition. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

In some cases, to extend the compounds of the invention (eg, compounds of formula (I) The action of a prodrug thereof, such as a compound of formula (II), may require slowing the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material having poor water solubility. The rate of drug absorption depends on its rate of dissolution, which depends on crystal size and crystalline form. Alternatively, delayed absorption of a compound of the invention in a parenterally administered form is accomplished by dissolving or suspending the compound in an oil vehicle.

In some embodiments, it may be advantageous to administer a compound of the invention (eg, a compound of formula (I) or a prodrug thereof (eg, a compound of formula (II)) in a sustained manner. It will be appreciated that any formulation that provides sustained absorption characteristics can be used. In certain embodiments, sustained absorption can be achieved by combining a compound of the invention with other pharmaceutically acceptable ingredients, diluents or carriers that slow the release of properties into the systemic circulation.

Route of administration

The compounds and compositions for use in the methods described herein can be administered to the individual in a variety of forms depending on the route of administration selected, as will be understood by those skilled in the art. Exemplary routes of administration for use in the compositions of the methods described herein include topical, enteral or parenteral applications. Surface administration includes, but is not limited to, upper epidermis, inhalation, enema, eye drops, ear drops, and administration via an in vivo mucosa. Intestinal applications include oral administration, rectal administration, vaginal administration, and gastric feeding. Parenteral administration includes intravenous, intraarterial, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and brainstem , intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time. In certain embodiments of the invention, a composition comprising a compound of formula (I) or a prodrug thereof (e.g., a compound of formula (II)) as described herein is administered orally. In other embodiments of the invention, a compound of formula (I) or a prodrug thereof (eg, The composition of (II) compound) is administered parenterally (for example intraperitoneally).

For intravenous, intraperitoneal or intrathecal delivery or direct injection, the composition must be sterile and fluid to the extent that the composition can be delivered by syringe. In addition to water, the carrier can be an isotonic buffered saline solution, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. For example, proper fluidity can be maintained by the use of a coating such as lecithin, by the maintenance of the necessary particle size in the case of dispersions, and by the use of surfactants. In many cases, the composition preferably includes an isotonic agent such as a sugar, a polyhydric alcohol such as mannitol or sorbitol, and sodium chloride. Long-term absorption of the injectable compositions can be brought about by the inclusion of a delayed absorbent (e.g., aluminum monostearate or gelatin) in the composition.

The choice of route of administration will depend on whether a partial or systemic effect is achieved. For example, for topical effects, the composition can be formulated for surface administration and applied directly where it is needed. For systemic long-term effects, the composition can be formulated for enteral administration and administration via the digestive tract. For immediate and/or short-term effects, the composition can be formulated for parenteral administration and by administration other than via the digestive tract.

dose

The compositions of the present invention are formulated into acceptable dosage forms by conventional methods known to those skilled in the art. The actual dosage concentration of the active ingredient (e.g., a compound of formula (I) or a prodrug thereof (e.g., a compound of formula (II)) in the compositions of the present invention can be varied to achieve an effective achievement of a particular individual, composition, and mode of administration. An active ingredient that is therapeutically responsive to one of the non-toxic individuals. The selected dosage concentration will depend on a number of pharmacokinetic factors, including the activity of the particular composition of the invention used; the route of administration; the time of administration The rate of absorption of the particular agent to be used; duration of treatment; other drugs, substances and/or used in combination with the particular composition used Or material; the age, sex, weight, condition, general health and prior medical history of the individual to be treated; and similar factors well known in the medical arts. An effective amount of the desired composition can be readily determined and prescribed by a physician or veterinarian who is generally familiar with the art. For example, a physician or veterinarian can begin to administer the materials of the invention used in the compositions at a concentration lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. In general, a suitable daily dose of a composition of the invention will be the lowest dose of the substance effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above. Preferably, the effective daily dose of the therapeutic composition can be taken as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, as appropriate, in unit dosage form. Cast.

Preferably, the therapeutic dose concentration is between about 0.1 mg/kg to about 1000 mg/kg (e.g., about 0.2 mg/kg) administered daily to an individual suffering from a condition described herein (e.g., an HBV infection) (e.g., orally or intraperitoneally). , 0.5mg/kg, 1.0mg/kg, 1.5mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/ Kg, 35mg/kg, 40mg/kg, 45mg/kg, 50mg/kg, 60mg/kg, 70mg/kg, 80mg/kg, 90mg/kg, 100mg/kg, 125mg/kg, 150mg/kg, 175mg/kg, Compositions of 200 mg/kg, 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg or 1000 mg/kg) . Preferably, the prophylactic dose concentration is administered to the individual (eg, orally or intraperitoneally) from about 0.1 mg/kg to about 1000 mg/kg per day (eg, about 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 1.5mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 35mg/kg, 40mg/kg, 45mg /kg, 50mg/kg, 60mg/kg, 70mg/kg, 80mg/kg, 90mg/kg, 100mg/kg, 125mg/kg, 150mg/kg, 175mg/kg, 200mg/kg, 250mg/kg, 300mg/kg , A composition of 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg or 1000 mg/kg). The dose can also be titrated (eg, the dose can be gradually increased until signs of toxicity such as headache, diarrhea, or nausea).

The frequency of treatment can also vary. An individual can be treated one or more times per day (eg, once, twice, three times, four times or more) or every few hours (eg, about every 2, 4, 6, 8, 12, or 24 hours). The composition can be administered 1 or 2 times every 24 hours. The treatment duration can be of different durations, such as two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days or more, two weeks, one month, two months, four Month, 6 months, 8 months, 10 months or more than one year. For example, treatment can last twice a day for three days, twice a day for seven days, and twice a day for ten days. The treatment cycle may be repeated, for example, once a week, once every two months, or once a month, which is separated by a time period in which no treatment is given. Treatment can be a single treatment or can last up to the life of an individual (eg, many years).

Patient selection and monitoring

The methods of the invention described herein must be administered to a subject a compound of formula (I) or a prodrug thereof (e.g., a compound of formula (II)) or a pharmaceutically acceptable salt thereof for inducing one or more PRRs (e.g., RIG-I , NOD2, STING) performance. In some embodiments, the individual has or is diagnosed with a condition such as a microbial infection or cancer. Thus, a patient and/or an individual can be selected for use of a compound of formula (I) or a prodrug thereof by first assessing the patient and/or the individual to determine whether the individual is infected with a microbial infection (eg, a viral infection or a bacterial infection) or cancer. (e.g., a compound of formula (II) or a pharmaceutically acceptable salt thereof. The subject can be assessed as an infectious microbial infection (e.g., a viral infection or a bacterial infection) or cancer using methods known in the art. a compound as described herein (eg, a compound of formula (I) or a prodrug thereof (eg, a compound of formula (II)) The individual is monitored after its pharmaceutically acceptable salt.

In some embodiments, the individual is a mammal. In some embodiments, the individual is a human. In some embodiments, the individual is an adult. In some embodiments, the individual has a microbial infection (eg, a viral infection, a bacterial infection, a fungal infection, or a parasitic infection). In some embodiments, the individual has a viral infection (eg, an infection caused by an RNA virus or a DNA virus). In some embodiments, the individual has a bacterial infection. In some embodiments, the individual has cancer.

In some embodiments, the individual is infected with a virus. In some embodiments, the individual is infected with the virus and the virus is in a latent phase. In some embodiments, the individual is infected with an RNA virus (eg, a double-stranded RNA (dsRNA) virus, a single-stranded RNA (ssRNA) virus (eg, a positive-stranded (sense) ssRNA virus or a minus-strand (antisense) ssRNA virus) or a ssRNA reverse transcription Virus) or DNA virus (eg dsDNA virus, ssDNA virus or dsDNA retrovirus) and the virus is in a latent phase. In some embodiments, the individual is infected, for example, according to Group I, Group II, Group III, Group IV, Group V, Group VI, or Group VII virus classes of the Baltimore classification system, and the virus is in a latent phase. In some embodiments, the individual is infected with an RNA virus (such as the RNA virus described herein) and the virus is in a latent phase. In some embodiments, the virus is a ssRNA retrovirus (ssRNA RT virus), such as a Group VI virus, and is, for example, latent within the cell. In some embodiments, the virus is human immunodeficiency virus 1 (HIV) or a subtype, a species or variant thereof, and is, for example, latent in a cell.

In some embodiments, the individual is infected with a virus and is symptomatic. In some embodiments, the individual is infected with HIV and is asymptomatic. In some embodiments, the individual is infected with a ssRNA retrovirus (ssRNA RT virus), such as a Group VI virus, and is asymptomatic. In some specific In the example, the individual is infected with HIV and is asymptomatic.

In some embodiments, the individual is a non-human mammal. In some embodiments, the individual is a squirrel, such as an oriental squirrel. Oriental hamsters (American marmot) are naturally infected with the hamster hepatitis virus (WHV), a hepadnavirus that is genetically closely related to human HBV. Woodchuck newborns are the main route of WHV-like (horizontal) transmission of human chronic HBV infection and show similar course of disease for patients with HBV infection. Therefore, chronic WHV infection in woodchucks is a fully immunocompetent model for studying CHB and HBV-induced HCC, and the efficacy and safety of current and new HBV therapeutics have been widely evaluated using chronic WHV carriers. A recent comparison of liver transcriptional characteristics in woodchucks and humans with acute self-limiting and chronic hepatic DNA virus infections identified important similarities in antiviral immune responses and demonstrated molecular similarity in HCC induced by WHV and HBV. Since these studies have determined the translational value of CHB in this animal model, woodchucks with chronic WHV infection can be used to assess antiviral efficacy, safety, and pharmacodynamics associated with treatment.

Combination therapy

In some embodiments, additional therapeutic agents can be administered to treat a microbial infection (eg, a viral infection, a bacterial infection, a fungal infection, or a parasitic infection), a cancer, or any symptom or related condition thereof, with a composition of the invention. When a combination therapy is used, the additional therapeutic agent can be administered as a separate formulation or can be combined with any of the compositions described herein.

For example, any of the methods described herein can further comprise administering a therapeutically effective amount of an additional agent. In some embodiments, the additional agent is an antiviral, antibacterial, or anticancer agent. In some embodiments, the antiviral agent comprises an interferon, a nucleoside analog, a non-nucleoside antiviral, or an immunopotentiator (eg, a non-interferon immunopotentiator or a small molecule immunopotentiator). In some embodiments, the antiviral agent is a capsid inhibitor, an entry inhibitor, a secretion inhibitor, a microRNA, an antisense RNA agent, an RNAi agent, or other agent designed to inhibit viral RNA or DNA. In some embodiments, the antiviral agent is selected from the group consisting of Invitro, Lamivudine, Adantivir, darinavir, sofosbuvir, telaprevir, tenofovir, zidovudine, and liba Welline. In some embodiments, the antibacterial agent is selected from the group consisting of gentamicin, kanamycin, streptomycin, chloramphenicol, cefepept, amoxicillin, penicillin, bacitracin, tetracycline, rifabutin, and Thai Cyclocycline and vancomycin. In some embodiments, the anticancer agent is selected from the group consisting of methotrexate, 5-fluorouracil, cranberry, vincristine, bleomycin, vinblastine, dacarbazine, tolose, cisplatin, epirubicin Star and sorafenib tosylate.

Example

Example 1. Induction of RIG-I expression in a model of HBV infection in soil drawing rats.

A woodchuck with a chronic WHV was used in this study. Formula (II) was orally administered to two groups of 5 woodchucks at two doses per day (15 mg/kg/day and 30 mg/kg/day) for 12 weeks. After the end of dosing, the animals were continuously monitored for 4 weeks.

At each time point in the study (0, 6, 12, and 20 weeks), liver biopsy samples were obtained by ultrasound imaging guided general-purpose needles under general anesthesia according to the progress of the study. The needle is inserted into the xiphoid cartilage at a site near the caudal side of the midline of the abdomen, and is guided to the left outer lobe of the liver via the dorsolateral and cranial sides. The biopsy samples were processed using standard conditions for histopathological studies. Tissue sections were stained by immunohistochemistry (IHC) for RIG-I induction using a commercially available anti-RIG-I antibody under standard protocols, and the results of this analysis are summarized in Table 1 below.

In the table, the intensity of IHC staining is described in a 0-3 scale, where 0 means unstained, 1 means weak staining, 2 means intermediate or moderate staining, and 3 means strong or strong staining. class Similarly, the distribution of staining in the entire biopsy sample is described by a score of 0-5, where 0 represents 0%, 1 represents 1%-20%, 2 represents 21%-40%, and 3 represents 41%-60%, and 5 means 81%-100%. The sum of the intensity and distribution columns is summarized in the column titled "Total".

Example 2. siRNA-mediated silencing of NOD2 and RIG-I in human lung epithelial (HLE) cells.

In this experiment, human lung epithelial (HLE) cells were transfected with 20 pmol of control siRNA (con siRNA), NOD2 siRNA or RIG-I siRNA using standard protocols. The performance of NOD2 and RIG-I was determined by RT-PCR analysis 24 hours after transfection. GAPDH performance served as an internal control. As shown in Figures 8A-8B, the performance of NOD2 (Figure 8A) and RIG-I (Figure 8B) was observed to decrease after transfection of NOD2 and RIG-I siRNAs, respectively.

Example 3. Induction of IFN-β by formula (II) requires NOD2 and RIG-I expression.

To investigate the association between formula (II) administration and IFN induction, HLE cells were transfected with 20 pmol of control siRNA (con siRNA), NOD2 siRNA or RIG-I siRNA as described in Example 2. The cells were treated with water (control) or formula (II) 24 hours after transfection. After 12 hours, the cells were pelleted and a clear layer was collected to analyze the IFN-[beta] content via ELISA analysis. The results of this analysis are depicted in Figure 9, where the Studden's t-test ELISA content is used. The mean standard deviation, and * indicates p < 0.05. As shown in Figure 9, in the cells treated with formula (II) transfected with RIG-I and NOD2 siRNA, a significant decrease in IFN-β induction and production was observed. No induction or production of IFN-[beta] was observed in the cells treated with water (data not shown). These results indicate that RIG-I and NOD2 are required for IFN-β induction when administered to formula (II).

Example 4. Dose-dependent binding of formula (I) to RIG-I and STING.

Analysis of the binding of formula (I) to PRR was performed using a sandwich ELISA assay. The anti-DDK antibody was immobilized on a microplate and used to capture RIG-I or STING, followed by 5'-biotinylated formula (I) at different concentrations (20 μg/mL, 10 μg/mL, 5 μg/mL, 2.5 Incubate together with μg/mL, 1.3 μg/mL, 0.6 μg/mL, 0.3 μg/mL, and 0 μg/mL. The biotinylated formula (I) bound to the microplate was detected by horseradish peroxidase (HRP) in combination with streptavidin. At the time of development, the absorbance at 450 nm (OD 450 nm) was measured and quantified ( Figs. 10A-10B ). In these figures, the y-axis represents the fold change in absorbance compared to the unadministered sample, and the error bars represent the standard deviation in the plurality of wells. In the case of RIG-I ( Fig. 10A ) and STING ( Fig. 10B ), an increase in the concentration of formula (I) causes a concomitant increase in absorbance at 450 nm, thereby indicating a dose-dependent binding of formula (I) to both PRRs.

Equivalent

The disclosures of each of the patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. Although the present invention has been described with reference to the specific embodiments thereof, it is apparent that those skilled in the art can devise other aspects and variations without departing from the true spirit and scope of the invention. The scope of the accompanying claims is intended to be understood to include all such aspects and equivalents. Any patents, publications, or other disclosures which are hereby incorporated by reference in their entirety herein in their entirety herein in their entirety herein in their entirety herein The extent to which the content is contradictory is incorporated herein. To the extent that the disclosure as explicitly set forth herein is substituted for any inconsistencies incorporated herein by reference.

Although the present invention has been particularly shown and described with reference to the preferred embodiments of the present invention, it will be understood by those skilled in the art Various changes in details.

Claims (87)

A method of inducing expression of a pattern recognition receptor (PRR) in an individual, the method comprising administering to the individual a compound of formula (I), wherein the compound is selected from the group consisting of: Or a prodrug or a pharmaceutically acceptable salt thereof to treat the individual. A method of inducing a pattern to recognize the expression of a receptor in an individual having a microbial infection or cancer, the method comprising administering to the individual a compound of formula (I), wherein the compound is selected from the group consisting of: Or a prodrug or a pharmaceutically acceptable salt thereof to treat the individual. A method of activating a pattern recognition receptor (PRR) in an individual, the method comprising administering to the individual a compound of formula (I), wherein the compound is selected from the group consisting of: Or a prodrug or a pharmaceutically acceptable salt thereof to treat the individual. The method of claim 1 to 3, wherein the prodrug of formula (I) is a compound of formula (II), wherein the compound is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. The method of claim 4, wherein the PRR comprises a RIG-I-like receptor or a NOD-like receptor. The method of claim 5, wherein the PRR comprises RIG-I, NOD2, MDA5, LPG2 or STING (eg RIG-I). The method of claim 6, wherein the PRR comprises RIG-I. The method of claim 6, wherein the PRR comprises NOD2. The method of claim 6, wherein the PRR comprises STING. The method of any one of claims 1 to 3, wherein the individual is administered a composition comprising a mixture of a compound of formula (I) of formula (Ib) and formula (Ic). The method of claim 10, wherein the composition comprises formula (Ib) and comprises less than about 5% of formula (Ic) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1) %, less than about 0.5% or less than about 0.1% of formula (Ic)) or substantially free of formula (Ic). The method of claim 10, wherein the composition comprises formula (Ic) and comprises less than about 5% of formula (Ib) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1) %, less than about 0.5% or less than about 0.1% of formula (Ib), or substantially free of formula (Ib)). The method of claim 4, wherein the individual is administered a composition comprising a mixture of a compound of formula (II), such as formula (IIb) and formula (IIc). The method of claim 13, wherein the composition comprises formula (IIb) and comprises less than about 5% of formula (IIc) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1) %, less than about 0.5% or less than about 0.1% of formula (IIc), or substantially free of formula (IIc)). The method of claim 13, wherein the composition comprises formula (IIc) and comprises less than about 5% of formula (IIb) (eg, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5% or less than about 0.1% of formula (IIb), or substantially free of formula (IIb)). The method of claim 4, wherein the induction of the expression of the PRR in the individual comprises increasing, enhancing or initiating the performance of RIG-I or NOD2 (eg, in the liver). The method of claim 16, wherein the increase or increase in performance of RIG-I or NOD2 (eg, in the liver) is between about 5% and about 95% compared to a reference standard or a reference treatment (eg, Between about 10% and about 90%). The method of claim 16, wherein the performance of inducing RIG-I or NOD2 is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about about the reference standard. 1.9, about 2, about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, About 200, about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. The method of claim 16, wherein the induction of the expression of RIG-I or NOD2 is about 10 minutes after the administration of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the individual. About 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about Occurs in 7 hours, about 8 hours, about 10 hours, about 12 hours or longer. The method of claim 19, wherein the induction of the expression of RIG-I or NOD2 is continued after the administration of the compound of formula (I) or formula (II). The method of claim 4, wherein the induction of the performance of the PRR in the individual comprises an increase, augmentation or initiation of the STING expression. The method of claim 21, wherein the induction by STING occurs in a cancer cell microenvironment (e.g., in a tumor microenvironment). The method of claim 22, wherein the induction by STING occurs in antigen presenting cells (e.g., dendritic cells) in the cancer cell microenvironment (e.g., the tumor microenvironment). The method of claim 21, wherein the increase or increase in performance of STING (eg, in a tumor microenvironment) is between about 5% and about 95% compared to a reference standard or a reference treatment (eg, at about 10% and about 90%). The method of claim 21, wherein the performance of inducing STING is about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, relative to the reference standard. , about 2.5, about 3, about 4, about 5, about 7.5, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 75, about 100, about 150, about 200, about 250, about 500, about 1000, about 1500, about 2500, about 5,000, about 10,000 or more times. The method of claim 21, wherein the induction of the performance of STING is about 10 minutes, about 15 minutes after the administration of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to the individual. About 20 minutes, about 25 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about Occurs in 8 hours, about 10 hours, about 12 hours or longer. The method of claim 26, wherein the induction of STING is continued after the administration of the compound of formula (I) or formula (II). The method of claim 4, wherein the individual is a mammal. The method of claim 28, wherein the individual is a human. The method of claim 4, wherein the individual has a microbial infection (eg, a viral infection, a bacterial infection, a fungal infection, or a parasitic infection) or cancer. The method of claim 30, wherein the cancer is selected from the group consisting of breast, bone, brain, cervix, colon, gastrointestinal tract, eyes, gallbladder, lymph nodes, blood, lung, liver, skin, mouth, prostate, ovary, penis Cancer of the pancreas, uterus, testes, stomach, thymus, thyroid or other parts of the body. The method of claim 30, wherein the cancer comprises a solid tumor (eg, a carcinoma, a sarcoma, or a lymphoma). The method of claim 32, wherein the cancer comprises hepatocellular carcinoma. The method of claim 33, wherein the cancer comprises breast cancer, renal cell carcinoma, colon cancer, melanoma, ovarian cancer, head and neck squamous cell carcinoma, pancreatic cancer, prostate cancer, lung cancer, brain cancer or gastrointestinal matrix. cancer. The method of claim 30, wherein the microbial infection (eg, a viral infection) comprises infection with an RNA virus or a DNA virus. The method of claim 35, wherein the RNA virus or DNA virus comprises a single chain virus (eg, a positive single strand or a negative single strand) or a double stranded virus. The method of claim 35, wherein the RNA virus or DNA virus comprises a virus in a virus group of Group I, Group II, Group III, Group IV, Group V, Group VI or Group VII . The method of claim 35, wherein the RNA virus comprises a dsRNA virus, an ssRNA virus (eg, a positive-stranded ssRNA virus or a minus-strand ssRNA virus) or an ssRNA RT virus. The method of claim 38, wherein the dsRNA virus is a member of the following family: Birnaviridae , Chrysoviridae , Cystoviridae , Endornaviridae ), Hypoviridae , Megabirnaviridae , Partitiviridae , Picobirnaviridae , Reoviridae or Whole Virology ( Totiviridae ) or other family of dsRNA viruses. The patentable scope of application of the method of 38, wherein the positive strand ssRNA viruses of the following members: Section arteritis virus (Arteriviridae), coronavirus family (Coronaviridae), Medvedev virus family (Mesoniviridae), rod-like sleeve virus family ( Roniviridae), two cistron virus family (Dicistroviridae), softening infectious virus family (Iflaviridae), marine RNA virus families (Marnaviridae), small RNA virus family (Piconaviridae), small plant RNA virus families (Secoviridae), linear alpha Department of Virology ( Alphaflexiviridae ), Betaflexiviridae , Gammaflexiviridae , Tymoviridae , Alphatetraviridae , Alfalaviridae ), Astroviridae (Astroviridae), tuberculosis-like RNA virus family (Barnaviridae), bromoviridae (Bromoviridae), calicivirus Branch (Caliciviridae), Karnofsky virus family (Carmotetraviridae), long-shaped virus family (Closteroviridae), Flaviviridae (Flaviviridae), leviviridae (leviviridae), yellow disease disease Section (Luteoviridae), naked RNA virus families (Narnaviridae), nodaviridae (Nodaviridae), Paasche virus family (Permutotetraviridae), potato virus Y Branch (Potyviridae), Togaviridae (Togaviridae) or broom-like virus family (Virgaviridae Or other families of positive-chain (sense) ssRNA viruses. The method of claim 38, wherein the negative-chain ssRNA virus is a member of the following species: Bornaviridae , Filoviridae , Paramyxoviridae , Rhabdoviridae (Rhabdoviridae), Nigerian style virus family (Nyamiviridae), Arenaviridae (Arenaviridae), Bunyaviridae (Bunyaviridae), snake-like virus family (Ophioviridae) or Orthomyxoviridae (Orthomyxoviridae), or other negative strand ( Antisense) ssRNA virus family. The method of claim 38, wherein the ssRNA RT virus is a member of the Transviridae , Pseudoviridae or Retroviridae or other families of the ssRNA RT virus. The method of claim 38, wherein the ssRNA RT virus is a member of the Lentivirus genus (eg, human immunodeficiency virus 1 (HIV) or a subtype, species or variant thereof). The method of claim 43, wherein the ssRNA RT virus is HIV or a subtype, a species or a variant thereof. The method of claim 35, wherein the DNA virus comprises a dsDNA virus, a ssDNA virus or a dsDNA RT virus. The method of claim 45, wherein the dsDNA virus is a member of the genus Myoviridae , Podoviridae , Siphoviridae , Alloherpesviridae , herpes virus family (Herpesviridae), mollusks herpes virus family (Malacoherpesviridae), lipothrixviridae (lipothrixviridae), small rod-shaped phage Branch (Rudiviridae), adenovirus family (Adenoviridae), bottle-shaped virus family (Ampullaviridae), vesicles Ascoviridae , Asfarviridae , Baculoviridae , Bicaudaviridae , Clavaviridae , Corticoviridae , Micro-spindle phage Section (Fuselloviridae), Grignard virus family (Globuloviridae), guttaviridae (Guttaviridae), salivary gland hypertrophy virus family (Hytrosaviridae), Iridoviridae (Iridoviridae), Marseille virus family (Marseilleviridae), polar virus family (Nimaviridae) , Pandoraviridae , papillomavirus ( Papillomaviridae ), Phycodnaviridae , Polydnaviruses , Polymaviridae , Poxviridae , Sphaerolipoviridae , Tectiviridae or Turivoviridae or other family of dsDNA viruses. The method of claim 45, wherein the ssDNA virus is a member of the group consisting of : Anelloviridae , Bacillariodnaviridiae , Bidnaviridae , Circoviridae , geminivirus Geminiviridae , Inoviridae , Microviridae , Nanoviridae , Parvoviridae or Spiraviridae or other families of ssDNA viruses. The method of application of the scope of patent 35, wherein the viral dsDNA RT liver DNA virus families (Hepadnaviridae) or the cauliflower mosaic virus families (Caulimoviridae) or other members of families of dsDNA RT virus. The method of claim 35, wherein the virus is in a latent stage. The method of claim 35, wherein the virus is a ssRNA retrovirus (ssRNA RT virus), such as Group VI viruses, and for example, are latent in cells. The method of claim 50, wherein the virus is human immunodeficiency virus 1 (HIV) or a subtype, a species or variant thereof, and is, for example, latent in a cell. The method of claim 51, wherein the individual is infected with the HIV virus and is asymptomatic. The method of claim 30, wherein the bacterial infection comprises infection with Gram-negative bacteria or Gram-positive bacteria. The method of claim 53, wherein the bacterial infection comprises a bacterium selected from the group consisting of Listeria (e.g., Listeria monocytogenes ), Francisella ( Francisella) (eg, Francisella tularensis ), Mycobacteria (eg Mycobacteria tuberculosis ), Brucella (eg Brucella) abortis)), Streptococcus (Streptococcus) (e.g. group B Streptococcus), Legionella (of Legionella) (e.g. of Legionella pneumophila (Legionella pneumophila)), the genus Escherichia (Escherichia) (e.g. E. coli (Escherichia coli)), Pseudomonas (of Pseudomonas) (e.g. Pseudomonas aeruginosa (Psuedomonas aeruginosa)), Salmonella (Salmonella) (e.g. Salmonella typhimurium (Salmonella typhi)), the genus Shigella (Shigella) (e.g. Freund shigellosis (Shigella flexneri)), flexuous genus (Campylobacter) (e.g. Campylobacter jejuni (Campylobacter jejuni)), Clostridium (Clostridi UM) (e.g. Clostridium botulinum (Clostrodium botulinum)), Enterococcus (of Enterococcus) (e.g. Enterococcus faecalis (Enterococcus faecalis)), Vibrio (Vibrio) (e.g. Vibrio cholerae (Vibrio cholera)), Yersinia (Yersinia) (e.g. Yersinia pestis (Yersinia pestis)) and Staphylococcus (Staphylococcus) (such as Staphylococcus aureus (Staphylococcus aureus)), or other genera, species, subtypes or variants body. The method of claim 4, further comprising analyzing or accepting an analysis of the biopsy or biological tissue sample from the individual at least once prior to the end of treatment. The method of claim 55, wherein the biopsy sample is a liver biopsy sample. The method of claim 55, wherein the liver biopsy sample is analyzed by immunohistochemical staining. The method of claim 57, wherein the liver biopsy sample analyzes the degree of induction of PRR (e.g., RIG-I or NOD2) by immunohistochemical staining. The method of claim 57, wherein the immunohistochemical staining indicates a PRR expression in the liver during treatment of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof (eg, RIG The distribution of -I performance or NOD2 performance) increased. The method of claim 59, wherein the increase in the distribution of PRR (e.g., RIG-I or NOD2) expression in the liver from the initiation of treatment to the end of treatment is between about 5% and about 95%. The method of claim 55, wherein the content of one or more microbial infection markers of the liver biopsy sample, such as viral DNA, viral RNA, viral antigen, cccDNA, bacterial load, is analyzed. The method of claim 56, wherein analyzing the performance of the liver biopsy sample of interferon (such as interferon alpha or interferon beta), interferon stimulating protein (such as ISG15, CXCL10, OAS 1) or other cytokines the amount. The method of claim 56, wherein the liver biopsy sample is analyzed for liver inflammation, necrosis, steatosis or fibrosis. The method of claim 4, wherein the individual is untreated. The method of claim 4, wherein the individual has previously been treated for a microbial infection (eg, a viral infection, a bacterial infection, a fungal infection, or a parasitic infection) or cancer. The method of claim 65, wherein the individual has previously been treated for HBV infection or HCV infection. The method of claim 65, wherein the individual has previously been treated for a bacterial infection or cancer. The method of claim 65, wherein the individual has previously been treated for viral infection and is asymptomatic. The method of claim 4, wherein the compound of the formula (I) or the formula (II) is administered orally (for example, the compound of the formula (II) is orally administered). The method of claim 4, wherein the compound of the formula (I) or the formula (II) is administered parenterally (for example, the compound of the formula (II) is administered parenterally). The method of claim 4, wherein the method comprises administering the compound daily. For example, the method of claim 4, wherein the administration is once a day. The method of claim 4, wherein the method comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for between about 1 week and 20 weeks. The method of claim 4, wherein the method comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof for between about 1 week and 12 weeks. The method of claim 4, wherein the dose of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof comprises from about 0.5 mg/kg to about 100 mg/kg. The method of claim 4, wherein the compound of formula (I) or formula (II) or The dose of the pharmaceutically acceptable salt comprises from 0.5 mg/kg to about 50 mg/kg. The method of claim 4, wherein the dose of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is from 5 mg/kg to about 50 mg/kg. The method of claim 4, wherein the dose comprises a liquid or solid dosage form. The method of claim 78, wherein the liquid dosage form comprises a suspension, a solution, a sweetener, an emulsion, a beverage, a tincture or a syrup. The method of claim 78, wherein the solid dosage form comprises a capsule, a lozenge, a powder, a dragee or a microencapsulated dosage form. The method of claim 4, further comprising administering a therapeutically effective amount of the additional agent. The method of claim 81, wherein the additional agent is an antiviral agent, an antibacterial agent or an anticancer agent. The method of claim 82, wherein the antiviral agent comprises an interferon, a nucleoside analog, a non-nucleoside antiviral agent or a small molecule immunopotentiator. The method of claim 82, wherein the antiviral agent comprises a capsid inhibitor, an entry inhibitor, a secretion inhibitor, a microRNA, an antisense RNA agent, an RNAi agent, or other designed to inhibit viral RNA or DNA. Pharmacy. The method of claim 82, wherein the antiviral agent comprises entecavir, lamuvidine, adefovir, darunavir, sofosbuvir (sofosbuvir), telaprevir, tenofovir, zidovudine and ribavirin. The method of claim 82, wherein the antibacterial agent comprises gentamicin (gentamicin), kanamycin, streptomycin, chloramphenicol, ceftobiprole, amoxicillin, penicillin, bacitracin , tetracycline, rifabutin, tigcycline and vancomycin. The method of claim 82, wherein the anticancer agent is selected from the group consisting of methotrexate, 5-fluorouracil, doxorubicin, vincristine, bleomycin, vinblastine. (vinblastine), dacarbazine, toposide, cisplatin, epirubicin, and sorafenib tosylate.