TLR7 / 8 antagonists for the treatment of coronavirus infection

Abstract

The present invention encompasses TLR7 / 8 antagonists, alone or in combination with one or more additional therapeutic agents, for use in the treatment of coronavirus infections, including COVID-19.

Description

[Technical Field]

[0001] Technical field of inventions This invention provides Toll-like receptor 7 / 8 (TLR7 / 8) inhibitors and their use in the treatment of coronavirus infections, including SARS-CoV infections such as COVID-19. [Background technology]

[0002] Background of the Invention Toll-like receptors (TLRs), currently comprising a gene family of 10 receptors with distinct specificities, are part of the cellular pathogen pattern recognition system, which has evolved to defend against various infectious diseases (bacteria, viruses, and fungi). TLR activation leads to cytokine responses, such as interferon release, and the activation of specific immune cells. The functional expression of selected TLRs in tissues is highly diverse. Some of these receptors are localized on the cell surface, such as TLR4 on epithelial cells (stimulated by E. coli lipopolysaccharide LPS), or TLR3, 7, 8, and 9 localized on the endosomal membrane of specific immune cells. The latter are all activated by nucleic acids, but recognize various types of them. For example, TLR9 is activated by single-stranded DNA containing CpG sub-sequences, TLR7 and 8 are activated by single-stranded RNA, and TLR3 is activated by double-stranded RNA.

[0003] TLRs are involved in various autoimmune and inflammatory diseases, the most obvious example being the role played by TLR7 in the pathogenesis of systemic lupus erythematosus (Barrat and Coffman, Immunol Rev, 223:271-283, 2008). In addition, TLR8 polymorphisms are associated with rheumatoid arthritis (Enevold et al., J Rheumatol, 37:905-10, 2010).

[0004] coronavirus Coronaviruses (CoVs) are positive-sense single-stranded RNA (ssRNA) viruses belonging to the order Nidovirales, family Coronaviridae. There are four subtypes of coronaviruses—alpha, beta, gamma, and delta—and alpha- and beta-coronaviruses infect most mammals, including humans. In the last 20 years, three major novel coronaviruses have emerged that jumped from non-human mammalian hosts to infect humans: severe acute respiratory syndrome (SARS-CoV-1), which appeared in 2002; Middle East respiratory syndrome (MERS-CoV), which appeared in 2012; and most recently, COVID-19 (SARS-CoV-2), which appeared in 2019. In the first five months after SARS-CoV-2 was identified, it is estimated that more than 4 million people were infected and nearly 300,000 died. Both figures likely represent a significant underestimation of the impact of this disease.

[0005] COVID-19 SARS-CoV-2 is closely similar to SARS-CoV-1, the causative agent of the 2002-03 SARS outbreak (Fung et al., Annu. Rev. Microbiol. 2019. 73:529-57). Severe illness has been reported in approximately 15% of patients infected with SARS-CoV-2, and one-third of these progress to serious illness (e.g., respiratory failure, shock, or multiple organ failure) (Siddiqi et al., J. Heart and Lung Trans. (2020), doi: https: / / doi.org / 10.1016 / j.healun.2020.03.012; Zhou et al., Lancet 2020; 395: 1054-62. https: / / doi.org / 10.1016 / S0140-6736(20)30566-3). A complete understanding of the mechanisms of viral pathogenicity and immune responses triggered by SARS-CoV-2 will be crucial for theoretically designing therapeutic interventions beyond antiviral and supportive care. Much is still being discovered about the various ways in which COVID-19 affects the health of those who develop the disease.

[0006] The exceptionally GU-rich single-stranded RNA identified from the SARS coronavirus contributes to an excessive innate immune response. In in vitro experiments, results showed that representative SARS-CoV ssRNAs possess potent immunostimulatory activity, inducing significant levels of inflammatory cytokine release of TNF-α, IL-6, and IL-12 via TLR7 and TLR8 (Li et al., Microbes and Infection (15:2, 88-95 (2013))). Point mutation bias in SARS-CoV-2 variants leads to increased ability to stimulate inflammatory responses. Compared to stimulation with ssRNA sequences of viruses isolated in Wuhan, the degree of U increase in SARS-CoV-2 variants correlates with enhanced cytokine production, such as TNF-α and IL-6, in cell lines. Consistent with previous reports, cytokine production from ssRNA-stimulated THP-1 is dependent on TLR7 (Kosuge et al., Scientific Reports (10:17766 (2020))).

[0007] Severe acute respiratory syndrome (SARS) coronavirus-2 (CoV-2) is the virulence factor of coronavirus disease 2019 (COVID-19), which has caused a global pandemic affecting more than 4 million people worldwide, with a case fatality rate of 2-4% as of May 2020. This virus has a high transmissibility, which is likely linked to a high initial viral load and lack of pre-existing immunity (He et al., Nat Med 2020 https: / / doi.org / 10.1038 / s41591-020-0869-5). This causes severe illness, particularly in the elderly and individuals with comorbidities. The global burden of COVID-19 is immeasurable, and the need for therapeutic approaches to combat this disease is increasing. Intuitive antiviral approaches, including those developed for enveloped RNA viruses such as HIV-1 (lopinavir + ritonavir) and Ebola virus (remdesivir), are being tested as investigational drugs (Grein et al., NEJM 2020 https: / / doi.org / 10.1056 / NEJMoa2007016; Cao et al., NEJM 2020 DOI: 10.1056 / NEJMoa2001282). However, since many patients with severe illness also have immunopathology, a host-directed immunomodulatory approach should also be considered, either as a stepwise approach or in combination with antiviral drugs (Metha et al., The Lancet 2020; 395(10229) DOI: https: / / doi.org / 10.1016 / S0140-6736(20)30628-0; Stebbing et al., Lancet Infect Dis 2020. https: / / doi.org / 10.1016 / S1473-3099(20)30132-8).

[0008] Despite the existence of numerous therapies being considered for use in the treatment of COVID-19, there are currently no approved drug therapies or vaccines available to treat this disease. To date, treatment typically consists only of symptomatic management with available clinical mainstays and oxygen therapy on ventilators for patients with respiratory failure. Therefore, there is an urgent need for novel therapies to address the different stages of the SARS-CoV-2 infection cycle (Siddiqi et al.). [Brief explanation of the drawing]

[0009] Brief explanation of the drawing [Figure 1] Figure 1 shows an overview of disease progression, including two phases: 1) the viral response phase and 2) the host inflammatory response phase. There are also roughly three stages that can be identified by this disease, with the most severe case being Stage III, in which the patient suffers from a severe cytokine storm.

[0010] [Figure 2A] Figures 2A and 2B show the effects of compound 3 versus hydroxychloroquine administration on IL-6 and TNF-α production in samples stimulated with either a TLR7 or TLR8 agonist. Compound 3 significantly reduces the amount of cytokines observed, even at low concentrations, compared to hydroxychloroquine. Figure 2C shows the amount of IFN-α in Alu-stimulated cells treated with compound 3 or hydroxychloroquine compared to the control, and Figure 2D shows the amount of TNF-α in miR-122-stimulated cells treated with compound 3 or hydroxychloroquine compared to the control. [Figure 2B] Same as above. [Figure 2C] Same as above. [Figure 2D] Same as above.

[0011] [Figure 3A]Figures 3A-3D show the results of the administration of Compound 3 in a mouse lupus model. Figure 3A shows survival over time (Figure 3A); Figure 3B shows proteinuria plotted over time; Figure 3C shows the AUC of individual mice over time; and Figure 3D shows blood gene expression analysis performed on a panel of 17 IFN-regulated genes to calculate the IFN gene signature score compared to healthy control mice. [Figure 3B] Same as above. [Figure 3C] Same as above. [Figure 3D] Same as above.

[0012] [Figure 4A] Figures 4A-4E show the effects of different concentrations of Compound 4 on plasma stimulated with different agonists of TLR7, TLR8, and TLR7 / 8 on IL-6 levels (Figures 4C-4E) and IFN-α levels (Figures 4A, 4B). [Figure 4B] Same as above. [Figure 4C] Same as above. [Figure 4D] Same as above. [Figure 4E] Same as above.

[0013] [Figure 5] Figure 5 shows a graph representing the confluence of Calu-3 cells when treated with 81 μM of Compound 4 of the present invention (“NCE3”) compared to non-infected and infected cells not exposed to the therapeutic agent. This figure shows that the confluence of the treated cells is similar to that of the non-infected cells in this experiment.

[0014] [Figure 6] Figure 6 shows a graph representing the confluence of Calu-3 cells when treated with 81 μM of Compound 3 (“NCE5”) compared to non-infected and infected control cells. This figure shows that the confluence of the treated cells is similar to that of the non-infected cells in this experiment.

[0015] [Figure 7A] Figure 7A shows the concentration of IFN-α after stimulation in the presence or absence of compound 3 (also known as “M5049”). Figure 7B shows the concentration of IL-6 after stimulation in the presence or absence of compound 3. Figure 7C shows the concentration of TNF-α after stimulation in the presence or absence of compound 3. All figures show a significant decrease in inflammatory cytokines upon exposure to compound 3. [Figure 7B] Same as above. [Figure 7C] Same as above.

[0016] [Figure 8A] Figure 8A shows the decrease in IFN-α after administration of compound 3 in an in vivo model. Figure 8B shows the decrease in IL-6 after administration of compound 3 in an in vivo model. [Figure 8B] Same as above.

[0017] [Figure 9A] Figure 9A shows the IFN gene signature scores for various concentrations of compound 3 (M5049)—this shows a decrease in expression (correlated to a reduction in lung inflammation) with increasing doses of M5049, with 10 mg / kg of compound 3 completely eliminating IFN. Figure 9B shows the NF-κB gene signature scores for various concentrations of compound 3 (M5049)—this shows a decrease in NF-κB expression (correlated to a reduction in lung inflammation) with increasing doses of M5049, with 10 mg / kg completely eliminating NF-κB. [Figure 9B] Same as above. [Overview of the project]

[0018] Summary of the Invention In one embodiment, the present invention relates to the following TLR7 / 8 inhibitor: [ka] Or provide a salt that is acceptable as a medicine.

[0019] In another embodiment, the present invention provides a TLR7 / 8 inhibitor for use in the treatment of viral infections in subjects requiring treatment. In one aspect of this embodiment, the viral infection is a coronavirus infection. In one aspect of this embodiment, the viral infection is a SARS-CoV-1, MERS-CoV, or SARS-CoV-2 infection. In one aspect of this embodiment, the viral infection is a SARS-CoV-2 infection.

[0020] One embodiment is a method for treating coronavirus infection in a subject in need, comprising administering to the subject an effective amount of a TLR7 / 8 inhibitor, or a pharmaceutically acceptable salt thereof. In one aspect of this embodiment, the subject has COVID-19 pneumonia. In another aspect, the subject has an excessive inflammatory host immune response resulting from SARS-CoV-2 infection. In a further aspect of this embodiment, the subject has moderate to severe COVID-19 requiring medical intervention.

[0021] Another embodiment of the present invention is a method for treating coronavirus infection in a subject in need, comprising administering an effective amount of a TLR7 / 8 inhibitor, or a pharmaceutically acceptable salt thereof, wherein the administration reduces the viral load in the subject. In one aspect of this embodiment, the TLR7 / 8 inhibitor is administered before the onset of COVID-19 pneumonia. In another aspect of this embodiment, the TLR7 / 8 inhibitor is administered to the subject before the onset of a severe cytokine storm. In a further aspect of this embodiment, the subject has a mild to moderate SARS-CoV-2 infection. In an additional aspect of this embodiment, the subject is asymptomatic at the start of the administration regimen. [Modes for carrying out the invention]

[0022] Detailed explanation Given the urgent need for therapies to address the potent host inflammatory response phase of COVID-19, small-molecule immunomodulatory compounds such as the pattern recognition receptor TLR7 and TLR8 dual inhibitors of the present invention can be valuable tools to provide relief to COVID-19 patients. The compounds of the present invention can inhibit the central mechanism of virus-associated cytokine storms in COVID-19 and can be targeted to a sufficient degree to halt severe immunopathology without compromising viral clearance.

[0023] In the initial antiviral response phase (Figure 1), if the virus primarily infects specific ACE2-expressing epithelial cells (type II lung cells) in the alveoli, direct antiviral therapy or immunostimulatory therapy (e.g., IFN-I, including Levif) can be demonstrated to have the advantage of minimizing contact transmission and preventing progression to severe disease (Hoffmann et al., Cell 2020. DOI: https: / / doi.org / 10.1016 / j.cell.2020.02.052; Sungnak et al., Qbio pre-review manuscript; arXiv:2003.06122 [q-bio.CB]; Zou et al., Front Med 2020 https: / / doi.org / 10.1007 / s11684-020-0754-0; Zhao et al., BioRxv pre-review manuscript). https: / / doi.org / 10.1101 / 2020.01.26.919985; Qi et al., BBRC 2020 https: / / doi.org / 10.1016 / j.bbrc.2020.03.044; Taccone et al., Lancet Resp. Med. (2020) https: / / doi.org / 10.1016 / S2213-2600(20)30172-7). In fact, recent papers suggest a correlation between SARS-CoV-2 viral load, symptom severity, and viral shedding (He et al.; Liu et al., Lancet Infect Dis 2020. https: / / doi.org / 10.1016 / S1473-3099(20)30232-2). Antiviral drugs administered at the onset of symptoms to slow coronavirus replication are in the clinical trial phase (Grein et al.; Taccone et al.).

[0024] In contrast, immunomodulatory therapy has been proposed as a staged approach, either to enable an early antiviral immune response or to be used in combination with antiviral drugs in patients with advanced disease (Figure 1, Stage II) (Stebbing et al.; Richardson et al., Lancet 2020. https: / / doi.org / 10.1016 / S0140-6736(20)30304-4). Here, localized inflammation, systemic inflammatory markers, lung disease, and viral pneumonia are more apparent and require more supportive care (e.g., hospitalization, oxygen support) (Siddiqi et al.). In this setting, anti-inflammatory therapy may be beneficial in preventing the progression of the disease to a stage requiring mechanical ventilation.

[0025] Some immunomodulatory drugs currently in clinical trials are theorized to treat the symptoms of cytokine storms associated with the host inflammatory phase of this disease (Figure 1, Stage III). However, some drug therapies currently being evaluated are either too specific in their targeting to calm cytokine storms (e.g., tocilizumab), too indiscriminate to be effective in calming cytokine storms without causing too many adverse events (e.g., Jak1 / 2 inhibitors), their targeting is too weak and / or nonspecific (e.g., hydroxychloroquine), and / or have serious side effects (Richardson et al.; Chen et al., medRxiv 2020 pre-review manuscript doi: https: / / doi.org / 10.1101 / 2020.03.22.20040758). However, none of these therapies currently used clinically target the underlying drivers that regulate observed cytokine storms at their initiation. Therefore, even if multiple drug therapies are evaluated in clinical trials, there remains an urgent need for effective drug therapies to calm cytokine storms and reduce viral load in patients infected with COVID-19.

[0026] Stimulation of TLR7 / 8 activates an antiviral response (by IFN-I) as well as an inflammatory cytokine response through the production of IL-6 and TNF-α. A potent pro-inflammatory response after infection (also known as a "cytokine storm") is a prominent feature of severe cases of COVID-19 (Chow et al., Annu. Rev. Immunol. 2018. 36:667-94; Huang et al., Lancet (2020), 395:497-506). IL-6 is a cytokine characterized by pleiotropic activity; among its many effects, it induces the synthesis of acute-phase proteins such as CRP, serum amyloid A, fibrinogen, and hepcidin in hepatocytes. IL-6 also plays an important role in the adaptive immune response by stimulating antibody production and effector T cell development. The main role of another cytokine, TNF, is to regulate immune cells; among its many effects, it is particularly associated with inflammation and viral replication. Therefore, antagonism of TLR7 / 8 leads to the suppression of both IL-6 and TNF-α, among other cytokines, and to a weakened pro-inflammatory response, which in turn reduces or prevents the progression of the target to a severe cytokine storm.

[0027] GU-containing RNA induces IFN-α, and the magnitude of its release correlates with the total number of GUs per sequence. GU-rich sequences were initially identified in HIV (Heil et al., Science 2004 https: / / doi.org / 10.1126 / science.1093620) and have also been found in human miRNAs, including in the let-7 family and currently in SARS-CoV-2 (Kosuge et al., Scientific Reports (10:17766 (2020))). Based on our internal analysis, we found that the SARS-CoV-2 genome has alignments of GU trimer sequences (GUUGUGUUGUGUUGU) containing approximately 229 GU ssRNA fragments per sequence and three GUUGU motifs identified in HIV. These are known to be potent activators of 96 unique regions identified in TLR7 / 8 within the SARS-CoV-2 genome, accompanied by at least 7 and up to 11 matching nucleotides. See Table 1. [Table 1] The TLR7 / 8 inhibitor of the present invention inhibits the secretion of GU-rich RNA-induced IFN-α and IL-6 in experiments using GU-rich miRNAs with sequences similar to those found in the SARS-CoV-2 genome (see Figures 7A-7C).

[0028] SARS-CoV-2 directly enters cells expressing ACE2 via receptor-mediated endocytosis (Hoffmann et al.). Successful viral replication requires acidification of host endosomes to release the viral genome into the host cytosol. Innate immune cells such as monocytes, macrophages, and neutrophils do not highly express ACE2 but possess abundant Fc receptors (Zou et al.; Qi et al.; Lu et al., Nat. Rev. Imm. 2018 https: / / doi.org / 10.1038 / nri.2017.106). In Stage II (Figure 1), antibodies that bind to this virus can mediate viral uptake into myeloid cell endosomes via the Fc receptor (FcR) or complement receptor (CR) (Lu et al.; Dandekar et al., Nat. Rev. Imm. 2005, https: / / doi.org / 10.1038 / nri1732). Therefore, ACE2, FcR, and CR present three mechanisms by which SARS-CoV-2 enters endosomes and triggers TLR7 / 8-driven excessive inflammation, leading to cytokine storms and severe disease. In addition, ssRNA viruses can induce TLR7 / 8-dependent NETosis in neutrophils (Saitoh et al., Cell Host Microbe (2012), 19;12(1):109-16), which leads to the release of DNA and RNA, creating a feedforward loop that further fuels TLR7 / 8-driven inflammation (Herster et al., Nat Commun 2020; 11, 105 https: / / doi.org / 10.1038 / s41467-019-13756-4), and this has been proposed to be a driver of severe COVID-19 (Barnes et al., J Exp med 2020; 217 (6) https: / / doi.org / 10.1084 / jem.20200652).SARS-CoV-1-driven ssRNAs have been shown to mediate severe TLR7 / 8-driven lung pathology in animal models and have been presented as a potential driver of virus-associated cytokine storms (Li et al., Microbes Infect 2013; 15 (2) 88-95. https: / / doi.org / 10.1016 / j.micinf.2012.10.008). Furthermore, infiltration of TLR8-expressing innate immune cells has been observed in the lungs of severely affected patients (Liao et al., medRxiv pre-review manuscript doi: https: / / doi.org / 10.1101 / 2020.02.23.20026690). In this context, inhibiting TLR7 / 8 activation could be a unique, targeted therapy that fundamentally suppresses the harmful inflammatory cascade triggered by coronaviruses, including SARS-CoV-2, and thus provides selective immunosuppression that does not impair the initial natural elimination of the virus.

[0029] The ability to slow viral replication in the early stages of infection can help prevent severe illness in the subject. This potential antiviral effect can also include, as previously discussed, the attenuation or avoidance of cytokine storms associated with severe viral infections. Therefore, the compounds of the present invention offer a unique opportunity to effectively treat subjects infected with coronaviruses such as SARS-CoV-2.

[0030] The compounds of the present invention are thought to alter the pH of the cell membrane surface, thereby inhibiting the fusion of viruses to the cell membrane. It is hypothesized that the compounds of the present invention can inhibit nucleic acid replication, glycosylation of viral proteins, viral aggregation, transport of novel viral particles, and / or viral release. Administration of the compounds of the present invention would consequently reduce viral replication, which in turn would reduce viral load and alleviate disease severity. Regardless of the precise mechanism of action regarding the antiviral properties of the compounds of the present invention, it is proposed that their administration may have one or more clinical benefits, as further described herein.

[0031] "COVID-19" is the name of the disease caused by SARS-CoV-2 infection. While care must be taken to describe both the infection and the disease using precise technical terms, "COVID-19" and "SARS-CoV-2 infection" are broadly equivalent terms.

[0032] As described in this application, the determination and characterization of the severity of COVID-19 patients / symptoms have not been definitively established. However, in the context of the present invention, “mild to moderate” COVID-19 occurs when a subject is asymptomatic or has no evidence of pneumonia and exhibits low-severity clinical symptoms (e.g., mild or no fever (<39.1°C), cough, mild to moderate discomfort) and generally does not require medical attention. “Moderate to severe” infection generally refers to patients exhibiting more severe clinical symptoms (e.g., fever >39.1°C, shortness of breath, persistent cough, pneumonia, etc.). As used herein, “moderate to severe” infection typically requires medical intervention, including hospitalization. During disease progression, a subject may move from “mild to moderate” to “moderate to severe” and revert to a course of the infection (bout).

[0033] Treatment of COVID-19 using the method of the present invention involves administering an effective dose of the TLR7 / 8 inhibitor of the present invention at any stage of the infection to prevent or alleviate associated symptoms. Typically, a subject is administered an effective dose of the TLR7 / 8 inhibitor of the present invention after a definitive diagnosis and after the appearance of symptoms consistent with SARS-CoV-2 infection, and the administration reduces the severity of the infection and / or prevents progression to a more severe state. The clinical benefits of such administration are described in more detail in the following sections.

[0034] 1. Compounds and Definitions One embodiment involves a compound selected from the group consisting of the following: [ka] or a pharmaceutically acceptable salt thereof. In one aspect of this embodiment, the TLR7 / 8 inhibitor of the present invention is: [ka] In another embodiment of this embodiment, the TLR7 / 8 inhibitor of the present invention is: [ka] That is the case.

[0035] Suitable salts derived from bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 This includes alkyl) tetrasalts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, where appropriate.

[0036] Unless otherwise stated, the structures described herein also mean all isomers of this structure (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)); for example, R and S configurations, Z and E double bond isomers, and Z and E conformers for each chiral center. Accordingly, the stereochemical isomers of the compound individually, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformers), are within the scope of the present invention.

[0037] Furthermore, unless otherwise stated, the structures described herein also mean that the compounds may differ only in the presence of one or more isotopically enriched atoms. For example, the substitution of hydrogen with deuterium or tritium, or carbon 13 C- or 14Compounds having this structure, including substitution with C-enriched carbon, are within the scope of the present invention. In some embodiments, these groups include one or more deuterium atoms.

[0038] 2. Use, Formulation, and Administration As used herein, the terms “patient” or “subject” mean an animal, preferably a human. However, “subject” may include companion animals such as dogs and cats. In one embodiment, the subject is an adult human patient. In another embodiment, the subject is a pediatric patient. A pediatric patient includes any human being under 18 years of age at the start of treatment. An adult patient includes any human being 18 years of age or older at the start of treatment. In one embodiment, the subject is a member of a high-risk group, such as a human being 65 years of age or older, a human being of any age in an immunodeficient state, a human being with a chronic lung condition (such as asthma, COPD, or cystic fibrosis), and a human being with other comorbidities. In one aspect of this embodiment, other comorbidities are obesity, diabetes, and / or hypertension.

[0039] The compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, intraoral, vaginally, or via implanted storage. Preferably, the compositions are administered orally. In one embodiment, the oral formulation of the compounds of the present invention is in the form of tablets or capsules. In another embodiment, the oral formulation is a liquid or suspension that can be administered to a subject requiring it via the mouth or a nasogastric tube. Any oral formulation of the present invention may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0040] The pharmaceutically acceptable compositions of the present invention are administered orally in any orally acceptable dosage form. Exemplary oral dosage forms include capsules, tablets, aqueous suspensions, or liquids. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. Specific sweeteners, flavorings, or colorants are also optionally added, if desired.

[0041] The amount of the compound of the present invention, which can be optionally combined with a carrier material for producing a composition in a single dosage form, will vary depending on the host being treated and the specific mode of administration. Preferably, the compositions provided should be formulated so that they can be administered to patients receiving these compositions at doses of the compound from 0.01 to 100 mg / kg body weight / day.

[0042] In one embodiment, the total amount of TLR7 / 8 inhibitor administered to a subject requiring it is approximately 10 mg to 500 mg per day. In one aspect of this embodiment, the total amount of TLR7 / 8 inhibitor administered is approximately 50 mg to 300 mg per day. In another aspect, the total amount of TLR7 / 8 inhibitor administered is approximately 100 mg to 200 mg per day.

[0043] In another embodiment, the TLR7 / 8 inhibitor is administered once daily. In another aspect of this embodiment, the TLR7 / 8 inhibitor is administered twice daily.

[0044] In one embodiment, the amount of TLR7 / 8 inhibitor administered to a subject requiring it is approximately 50 mg twice daily. In another embodiment, the amount of TLR7 / 8 inhibitor administered to a subject requiring it is approximately 100 mg twice daily.

[0045] In any of the embodiments described above, the TLR7 / 8 inhibitor is administered for a period of approximately 7 to 21 days. In one aspect of any of the embodiments described above, the TLR7 / 8 inhibitor is administered for approximately 14 days.

[0046] In one embodiment of the present invention, 50 mg of the TLR7 / 8 inhibitor of the present invention is administered twice daily for approximately 14 days. In another embodiment of the present invention, 100 mg of the TLR7 / 8 inhibitor of the present invention is administered twice daily for approximately 14 days.

[0047] In one embodiment of the present invention, the subject is suffering from COVID-19 pneumonia. In one embodiment of the present invention, the subject is suffering from an extreme pro-inflammatory response caused by COVID-19, which may be present in any major organ of the body. In one embodiment of the present invention, the subject is suffering from acute respiratory distress syndrome (ARDS) caused by COVID-19. In one embodiment of the present invention, the subject is suffering from one or more symptoms selected from chest congestion, cough, blood oxygen saturation (SpO2) level below 94%, shortness of breath, dyspnea, fever, chills, recurrent chills, muscle pain and / or weakness, headache, pharyngitis and / or new loss of taste or smell.

[0048] In one embodiment, the subject suffers from an excessive inflammatory host immune response to SARS-CoV-2 infection. In one aspect of this embodiment, the excessive inflammatory host immune response is manifested by: 1) decreased levels of lymphocytes, particularly natural killer (NK) cells, in the peripheral blood; 2) high levels of inflammatory parameters (e.g., C-reactive protein [CRP], ferritin, d-dimer) and inflammatory cytokines (e.g., IL-6, TNFα, IL-8, and / or IL-1β); and 3) lymphopenia and / or atrophy of the spleen and lymph nodes, accompanied by lymphopenia of lymphoid organs, indicating an immune system It is associated with one or more clinical signs selected from: worsening; 4) dysfunction of pulmonary physiological processes, characterized by minimal lymphocyte infiltration resulting in decreased blood oxygenation, but represented by pulmonary lesions infiltrated by monocytes, macrophages, and / or neutrophils; 5) acute respiratory distress syndrome (ARDS); 6) vasculitis; 7) encephalitis, Guillain-Barré syndrome, and other neurological disorders; 8) renal dysfunction and renal failure; 9) hypercoagulation, such as arterial thrombosis; and 10) any combination thereof resulting in injury and death of terminal organs.

[0049] In one embodiment, subjects with COVID-19 are pediatric patients suffering from vasculitis, including Kawasaki disease (i.e., Kawasaki syndrome) and related diseases of Kawasaki disease.

[0050] In one embodiment of the present invention, the subject is an inpatient being treated in a hospital setting. In another embodiment, the subject is being treated in an outpatient setting. In one aspect of the preceding embodiment, the subject may continue to receive TLR7 / 8 inhibitor after transitioning from an inpatient hospital setting to an outpatient setting.

[0051] In one embodiment, administration of a TLR7 / 8 inhibitor results in one or more clinical benefits. In one aspect of this embodiment, one or more clinical benefits are selected from the group consisting of: shorter hospital stay, shorter intensive care unit (ICU) stay, reduced likelihood of admission to the ICU, reduced mortality, reduced likelihood of renal failure requiring dialysis, reduced likelihood of non-invasive or invasive mechanical ventilation, shorter time to recovery, reduced likelihood of needing oxygen supplementation, improved or normalized peripheral capillary oxygen saturation (SpO2 levels) without mechanical intervention, reduced severity of pneumonia as determined by chest imaging (e.g., CT or chest X-ray), reduced cytokine production, reduced severity of acute respiratory distress syndrome (ARDS), reduced likelihood of ARDS development, clinical resolution of COVID-19 pneumonia, improved PaO2 / FiO2 ratio, and reduced inflammatory response in the subject.

[0052] In another embodiment, one or more of these clinical benefits include improvement or normalization of peripheral capillary oxygen saturation (SpO2 levels) in subjects not using a ventilator or membrane oxygenator.

[0053] In one embodiment, this one or more clinical benefit includes a reduction in the inflammatory response of the subject. In one aspect of this embodiment, the reduction in the inflammatory response of the subject results in a decrease in the release of inflammatory cytokines driven by NFκB (NF-kappa B), IL-1b, IL-6, IL-8, IL-12, IL-18, IL-23, or IL-27, either alone or in combination with inhibition of cytokine release driven by IRF3 / 7, such as type I IFNs including IFNα and / or IFNβ. In one aspect of this embodiment, this one or more clinical benefit includes avoidance of a severe cytokine storm in the subject.

[0054] In further embodiments, one or more clinical benefits include a reduced likelihood of hospitalization, a reduced likelihood of admission to the ICU, a reduced likelihood of intubation (invasive mechanical ventilation), a reduced likelihood of needing oxygen supplementation, a shorter hospital stay, a reduced likelihood of death, and / or a reduced likelihood of recurrence, including a reduced likelihood of readmission.

[0055] Methods of immunomodulation provided herein include, but are not limited to, methods of suppressing and / or inhibiting an immune response, including an immune response. Immunosuppression and / or inhibition according to the methods described herein may be practiced on individuals, including individuals suffering from disorders associated with undesirable activation of an immune response, such as viral infection.

[0056] The present invention also provides a method for treating a viral infection in a subject requiring such treatment, comprising administering an effective amount of the compound of the present invention to the subject. An effective amount for treating or inhibiting a viral infection is an amount that causes a reduction in the manifestation of one or more viral infections, such as viral lesions, viral load, viral production rate, and mortality rate, compared to an untreated control subject.

[0057] A method for inhibiting an immune response in an individual is provided herein, the method comprising administering to the individual an amount effective in inhibiting the immune response in the individual, of at least one TLR inhibitor disclosed herein. In some variations, the immune response is associated with chronic pathogen stimulation. In some variations, the immune response is associated with viral infection. In a further context, inhibition of the immune response improves one or more symptoms of a viral disease or disorder resulting from infection with SARS-CoV-2. In another further context, inhibition of the immune response treats a viral disease or disorder resulting from infection with SARS-CoV-2. In yet another context, inhibition of the immune response prevents or delays the development of a viral disease or disorder resulting from infection with SARS-CoV-2. Other variations provided herein relate to immunosuppressive therapy for individuals exposed to or infected with SARS-CoV-2. Administration of TLR inhibitors to individuals exposed to or infected with SARS-CoV-2 suppresses COVID-19-induced excessive cytokine production. In some cases, at least one TLR inhibitor is administered in a dose effective in suppressing COVID-19-induced cytokine production in individuals exposed to or infected with SARS-CoV-2.

[0058] In one embodiment, administration of a TLR7 / 8 inhibitor selectively reduces an over-inflammatory host immune response state while not interfering with the subject's natural interferon response to viral infection. In one aspect of this embodiment, the over-inflammatory host immune response state is reduced before the subject develops a severe cytokine storm.

[0059] One embodiment of the present invention is a method for treating coronavirus infection in a subject requiring such treatment, comprising administering an effective amount of a TLR7 / 8 inhibitor, or a pharmaceutically acceptable salt thereof, to the subject. In one aspect of this embodiment, the subject is infected with SARS-CoV-2. In another aspect of this embodiment, administration of the TLR7 / 8 inhibitor results in a reduction of the viral load in the subject. In a further aspect of this embodiment, administration of the TLR7 / 8 inhibitor reduces the viral load by increasing the pH of endosomes, reducing the ability of the virus to enter cells, and / or interfering with terminal glycosylation of the cell receptor ACE2. In another aspect of this embodiment, administration of the TLR7 / 8 inhibitor of the present invention provides a reduction in viral replication. In a further aspect of this embodiment, administration of the TLR7 / 8 inhibitor can inhibit one or more of the following: nucleic acid replication, glycosylation of viral proteins, viral aggregation, transport of novel viral particles, and viral release.

[0060] In one embodiment, the TLR7 / 8 inhibitor is administered before the onset of COVID-19 pneumonia. In another embodiment, the TLR7 / 8 inhibitor is administered before the subject develops a cytokine storm. In yet another embodiment, the subject has mild to moderate SARS-CoV-2 infection. In yet another embodiment, the subject is asymptomatic at the start of this administration regimen. In yet another embodiment, the subject is known to have been in contact with a patient diagnosed with SARS-CoV-2 infection. In an additional embodiment, administration of the TLR7 / 8 inhibitor is initiated before the subject is formally diagnosed with COVID-19.

[0061] One embodiment is a method for treating a subject with COVID-19, comprising administering an effective dose of a TLR7 / 8 inhibitor to the subject. In one aspect of this embodiment, the subject has been previously vaccinated with a SARS-CoV-2 vaccine and is experiencing a vaccine-related exacerbation of the infection, such as an antibody-dependent enhancement or antibody-mediated mechanism of vaccine / antibody-related exacerbation.

[0062] In any of the preceding embodiments, administration of a TLR7 / 8 inhibitor results in one or more clinical benefits for the subject. In one aspect of this embodiment, one or more clinical benefits are a reduction in the duration of infection, a reduced likelihood of hospitalization, a reduced likelihood of death, a reduced likelihood of ICU admission, a reduced likelihood of requiring mechanical ventilation, a reduced likelihood of needing oxygen supplementation, and / or a reduction in hospital stay. In another aspect of this embodiment, one or more clinical benefits are the avoidance of a significant pro-inflammatory reaction. In a further aspect of this embodiment, one or more clinical benefits are the subject's failure to develop serious symptoms of COVID-19.

[0063] The compounds of the present invention can be administered before or immediately following the onset of SARS-CoV-2 infection, or after an acute infection has been diagnosed in a subject. The aforementioned compounds and medical products used in the invention are particularly intended for therapeutic purposes. The therapeutically relevant effects include alleviating one or more symptoms of the disorder to some extent, or restoring one or more physiological or biochemical parameters associated with or causing the disease or pathological condition to normal, either partially or completely. Monitoring is considered a form of treatment, provided that the compounds are administered at regular intervals, for example, to boost the response and eradicate the pathogen and / or symptoms of the disease. The methods of the present invention may also be used to reduce the likelihood of developing a disorder, or even to prevent the onset of COVID-19-related disorders prior to the manifestation of mild to moderate illness, or to treat the onset and persistence of acute infections.

[0064] Treatment for mild to moderate COVID-19 is typically performed in an outpatient setting. Treatment for moderate to severe COVID-19 is typically performed in an inpatient setting. In addition, treatment may be continued in an outpatient setting after the subject has been discharged from the hospital.

[0065] The present invention further relates to a pharmaceutical product containing at least one compound of the present invention or a pharmaceutically acceptable salt thereof.

[0066] In the sense of the present invention, “pharmaceutical” means any substance in the field of medicine, which comprises one or more compounds of the present invention or preparations thereof (e.g., pharmaceutical compositions or pharmaceutical formulations) and can be used for the prevention, treatment, monitoring or aftercare of patients who are suffering from clinical symptoms and / or who are known to have been exposed to COVID-19.

[0067] Combination therapy In various embodiments, this active ingredient may be administered alone or in combination with one or more additional therapeutic agents. Synergistic or enhancing effects may be achieved by using two or more compounds in this pharmaceutical composition. These active ingredients may be used simultaneously or sequentially.

[0068] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more additional therapeutic agents. In one aspect of this embodiment, one or more additional therapeutic agents are selected from anti-inflammatory agents, antibiotics, anticoagulants, antiparasitic agents, antiplatelet agents and dual antiplatelet therapy, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, β-blockers, statins and other combination cholesterol-lowering agents, specific cytokine inhibitors, complement inhibitors, anti-VEGF therapy, JAK inhibitors, immunomodulators, anti-inflammasome therapy, sphingosine-1-phosphate receptor conjugates, N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonists, corticosteroids, granulocyte-macrophage colony-stimulating factor (GM-CSF), anti-GM-CSF, interferons, angiotensin receptor-neprilysin inhibitors, calcium channel blockers, vasodilators, diuretics, muscle relaxants, and antiviral agents.

[0069] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with an antiviral agent. In one aspect of this embodiment, the antiviral agent is remdesivir. In another aspect of this embodiment, the antiviral agent is lopinavir-ritonavir, either alone or in combination with ribavirin and interferon-β.

[0070] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with a broad-spectrum antibiotic.

[0071] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with chloroquine or hydroxychloroquine. In one aspect of this embodiment, the TLR7 / 8 inhibitor is further administered in combination with azithromycin.

[0072] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with interferon-β-1a (Levif®).

[0073] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with dexamethasone.

[0074] In one embodiment, the TLR7 / 8 inhibitor is hydroxychloroquine, chloroquine, ivermectin, tranexamic acid, nafamostat, virazole, ribavirin, lopinavir / ritonavir, favipiravir, arbidol, leronlimab, interferon β-1a, interferon β-1b, β-interferon, azithromycin, nitrazoxamide, lovastatin, crazakizumab, adalimumab, etanercept, golimumab, infliximab, sarilumab, tocilizumab, anakinra, emaparmab, pirfenidone, belimumab, rituximab, ocrelizumab, aniflorumab, or ravulizumab-cw. It is administered in combination with one or more additional therapeutic agents selected from vz, eculizumab, bevacizumab, heparin, enoxaparin, apremilast, coumazin, baricitinib, ruxolitinib, dapagliflozin, methotrexate, leflunomide, azathioprine, sulfasalazine, mycophenolate mofetil, colchicine, fingolimod, ifenprodil, prednison, cortisol, dexamethasone, methylprednisolone, melatonin, ocilimab, ATR-002, APN-01, camostat mesylate, brilacidine, IFX-1, PAX-1-001, BXT-25, NP-120, intravenous immunoglobulin (IVIG), and sorunatide.

[0075] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more anti-inflammatory drugs. In one aspect of this embodiment, the anti-inflammatory drugs are selected from corticosteroids, steroids, COX-2 inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs). In one aspect of this embodiment, the anti-inflammatory drugs are diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, meclofename, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozine, piroxicam, sulindac, tolmetine, celecoxib, prednisone, hydrocortisone, fludrocortisone, betamethasone, prednisolone, triamcinolone, methylprednisone, dexamethasone, fluticasone, and budesonide (alone or in combination with formoterol, salmeterol, or vilanterol).

[0076] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more immunomodulators. In one aspect of this embodiment, the immunomodulator is a calcineurin inhibitor, an antimetabolite, or an alkylating agent. In another aspect of this embodiment, the immunomodulator is selected from azathioprine, mycophenolate mofetil, methotrexate, dapsone, cyclosporine, cyclophosphamide, and the like.

[0077] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more antibiotics. In one aspect of this embodiment, the antibiotic is a broad-spectrum antibiotic. In another aspect of this embodiment, the antibiotic is penicillin, anti-staphylococcal penicillin, cephalosporin, aminopenicillin (usually administered with a beta-lactamase inhibitor), monobactam, quinoline, aminoglycosides, lincosamide, macrolide, tetracycline, glycopeptide, antimetabolites, or nitroimidazole. In a further aspect of this embodiment, the antibiotic is selected from penicillin G, oxacillin, amoxicillin, cefazolin, cephalexin, cefotetan, cefoxitin, ceftriazon, augmentin, amoxicillin, ampicillin (+sulbactam), piberacillin (+tazobactam), ertapenem, ciprofloxacin, imipenem, meropenem, levofloxacin, moxifloxacin, amikacin, clindamycin, azithromycin, doxycycline, vancomycin, bactrim, and metronidazole.

[0078] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more anticoagulants. In one aspect of this embodiment, the anticoagulant is selected from apixaban, dabigatran, edoxaban, heparin, rivaroxaban, and warfarin.

[0079] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more antiplatelet agents and / or dual antiplatelet therapy. In one aspect of this embodiment, the antiplatelet agents and / or dual antiplatelet therapy are selected from aspirin, clopidogrel, dipyridamole, prasugrel, and ticagrelor.

[0080] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more ACE inhibitors. In one aspect of this embodiment, the ACE inhibitor is selected from benazepril, captopril, enalapril, hosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril.

[0081] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more angiotensin II receptor blockers. In one aspect of this embodiment, the angiotensin II receptor blocker is selected from azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan.

[0082] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more beta-blockers. In one aspect of this embodiment, the beta-blocker is selected from acebutolol, atenolol, betaxolol, bisoprolol / hydrochlorothiazide, bisoprolol, metoprolol, nadolol, propranolol, and sotalol.

[0083] In another embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more α and β-blockers. In one aspect of this embodiment, the α and β-blockers are carvedilol or labetalol hydrochloride.

[0084] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more interferons.

[0085] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more angiotensin receptor-neprilysin inhibitors. In one aspect of this embodiment, the angiotensin receptor-neprilysin inhibitor is sacubitril / valsartan.

[0086] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more calcium channel blockers. In one aspect of this embodiment, the calcium channel blocker is selected from amlodipine, diltiazem, felodipine, nifedipine, nimodipine, nisoldipine, and verapamil.

[0087] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more vasodilators. In one aspect of this embodiment, one or more vasodilators are selected from isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, and minoxidil.

[0088] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more diuretics. In one aspect of this embodiment, one or more diuretics are selected from acetazolamide, amiloride, bumetanide, chlorothiazide, chlorthalidone, furosemide, hydrochlorothiazide, indapamide, metrazone, spironolactone, and torasemide.

[0089] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more muscle relaxants. In one aspect of this embodiment, the muscle relaxant is an anticonvulsant or antispasmodic. In another aspect of this embodiment, one or more muscle relaxants are selected from carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine, tizanidine, baclofen, dantrolene, and diazepam.

[0090] In one embodiment, the TLR7 / 8 inhibitor is administered in combination with one or more antiviral agents. In one aspect of this embodiment, the antiviral agent is remdesivir.

[0091] In one embodiment, the TLR7 / 8 inhibitor is an antiparasitic drug (not limited to hydroxychloroquine, chloroquine, ivermectin), an antiviral drug (not limited to tranexamic acid, nafamostat, virazole [ribavirin], lopinavir / ritonavir, favipiravir, leronlimab, interferon β-1a, interferon β-1b, β-interferon), an intracellularly active antibiotic (not limited to azithromycin, (including nitazoxanide), statins and other concomitant cholesterol-lowering and anti-inflammatory drugs (not limited to lovastatin), specific cytokine inhibitors (not limited to crazakizumab, adalimumab, etanercept, golimumab, infliximab, sarilumab, tocilizumab, anakinra, emaparmab, pirfenidone), complement inhibitors (not limited to ravulizumab-cwvz, eculizumab), anti-VEGF therapy (not limited to bevacizumab) (including mab), anticoagulants (non-limited, including heparin, enoxaparin, apremilast, and coumadin), JAK inhibitors (non-limited, including baricitinib, ruxolitinib, and dapagliflozin), anti-inflammasome therapies (non-limited, including colchicine), sphingosine-1-phosphate receptor conjugates (non-limited, including fingolimod), N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonists (non-limited, including ifenprozin). It is administered in combination with one or more additional therapeutic agents selected from the following: (including ), corticosteroids (not limited to prednisone, cortisol, dexamethasone, and methylprednisolone), GM-CSF, anti-GM-CSF (otilimab), ATR-002, APN-01, camostat mesylate, arbidol, brilacidine, IFX-1, PAX-1-001, BXT-25, NP-120, intravenous immunoglobulin (IVIG), and sorunatide.

[0092] In some embodiments, the combination of a TLR inhibitor with one or more additional therapeutic agents reduces the effective dose of the TLR inhibitor and / or one or more additional therapeutic agents (including, but not limited to, the dosage, dosage concentration, and / or total amount of drug administered) administered to achieve the same results compared to the effective dose administered when the TLR inhibitor or the additional therapeutic agent is administered alone. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent shortens the overall treatment duration compared to the administration of the additional therapeutic agent alone. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent reduces the side effects associated with the administration of the additional therapeutic agent alone. In some embodiments, the effective dose combination of a TLR inhibitor with an additional therapeutic agent is more effective than the effective dose of the TLR inhibitor or the additional therapeutic agent alone. In one embodiment, the effective dose combination of a TLR inhibitor with one or more additional therapeutic agents results in one or more additional clinical benefits compared to the administration of either drug alone.

[0093] As used herein, the terms “treatment,” “to treat,” and “treating” refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a viral infection or one or more of its symptoms, as described herein. In some embodiments, the treatment is administered after the onset of one or more symptoms. In other embodiments, the treatment is administered in the absence of symptoms. For example, the treatment is administered to an susceptible individual before the onset of symptoms (e.g., considering known exposure to an infected person and / or comorbidities or other susceptibility factors that are predictors of severe illness). [Examples]

[0094] Example As described in the "Examples" below, in certain illustrative embodiments, the compounds are prepared according to the following general procedure. While this general method illustrates the synthesis of specific compounds of the present invention, it will be understood that the following general method and other methods known to those skilled in the art can be applied to all compounds and their respective subclasses and species as described herein.

[0095] The symbols and conventions used in the following descriptions of processes, schemes, and examples are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0096] Example 1: Synthesis of cis-5-(3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrile (Compound 1) [ka]

[0097] Cis-[1-(8-cyanoquinoline-5-yl)-5-trifluoromethylpiperidine-3-yl]-carbamate A mixture of tert-butyl ester, anhydrous tert-butanol (15 mL), 5-bromo-quinoline-8-carbonitrile (500 mg; 2.15 mmol), cis-3-(boc-amino)-5-(trifluoromethyl)piperidine (691 mg; 2.57 mmol), chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II),methyl-t-butyl ether adduct (88 mg; 0.11 mmol), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (50 mg; 0.11 mmol), and cesium carbonate (1.4 g; 4.3 mmol) was microwaved at 85°C for 8 hours. The reaction mixture was concentrated under reduced pressure, eluted with hexane and ethyl acetate, and purified by chromatography to obtain [1-(8-cyano-quinoline-5-yl)-5-trifluoromethyl-piperidine-3-yl]-carbamate tert-butyl ester (731 mg; 80%) as a bright yellow solid. 1 H NMR (400 MHz, CDCl3) δ 9.09 (dd, J = 4.2, 1.7 Hz, 1H), 8.44 (dd, J = 8.6, 1.7 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.57 (ddd, J = 8.3, 6.2, 4.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.50 (s, 1H), 4.06 (s, 1H), 3.75 (dd, J = 11.8, 4.6 Hz, 1H), 3.65 - 3.55 (m, 1H), 2.89 (t, J = 11.3 Hz, 1H), 2.79 (dtq, J = 15.3, 7.5, 3.8 Hz, 1H), 2.56 - 2.39 (m, 2H), 1.54 - 1.33 (m, 10H); MS: m / z = 421 [M+H] + .

[0098] To a solution of [1-(8-cyano-quinoline-5-yl)-5-trifluoromethyl-piperidine-1-yl]-quinoline-8-carbonitrile (720 mg; 1.71 mmol) in anhydrous methanol (17 mL), a solution of 4 M hydrochloric acid (12.8 mL; 51.4 mmol) in dioxane was added, and this orange solution was stirred overnight at room temperature. Ether (40 mL) was added to the reaction mixture, and this orange solution was stirred at room temperature for 20 minutes. This orange suspension was filtered, and the yellow solid was washed with ether and dried under vacuum to obtain 5-(3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrile hydrochloride (571 mg; 94%) as the yellow solid.

[0099] compound 1 : 1 H NMR (400 MHz, D2O) δ 8.94 (dd, J = 4.6, 1.7 Hz, 1H), 8.66 (dd, J = 8.6, 1.8 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.77 (dd, J = 8.8, 4.5 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 4.02 - 3.87 (m, 1H), 3.82 (dd, J = 11.5, 3.6 Hz, 1H), 3.71 (d, J = 11.8 Hz, 1H), 3.17 (td, J = 8.0, 3.9 Hz, 1H), 3.05 (td, J = MS: m / z = 321 [M+H] + .

[0100] Example 2: Separation of compound 1 into isomer 1 (compound 2) (5-((3S,5R)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrile and isomer 2 (compound 3) (5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrile). : [ka] The title compound was isolated by chiral SFC chromatography of Compound 1. (Column: 2.1×25.0 cm, Chiralpak AD-H from Chiral Technologies (West Chester, PA); CO2 co-solvent (Solvent B): methanol containing 0.2% ammonium hydroxide; isocratic method: 20% co-solvent at 80 g / min; system pressure: 100 bar; column temperature: 25 °C).

[0101] compound 2 : 1 H NMR (400 MHz, acetone-d6) δ 8.60 (dd, J = 4.2, 1.7 Hz, 1H), 8.06 (dd, J = 8.6, 1.7 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 8.6, 4.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.07 (dt, J = 12.0, 2.3 Hz, 1H), 3.05 - 2.96 (m, 1H), 2.66 (tt, J = 11.2, 4.3 Hz, 1H), 2.57 (ddd, J = 15.5, 7.4, 3.4 Hz, 1H), 2.40 (t, J = 11.4 Hz, 1H), 2.04 - 1.97 (m, 1H), 1.78 - 1.67 (m, 1H), 1.29 (s, 2H), 0.80 (q, J = 12.1 Hz, 1H). MS: m / z = 321 [M+H] + 。

[0102] compound 3 : 11H NMR (400 MHz, acetone-d6) δ 8.63 (dd, J = 4.2, 1.7 Hz, 1H), 8.12 (dd, J = 8.6, 1.7 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.6, 4.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.09 (dt, J = 12.0, 2.3 Hz, 1H), 3.11 - 2.99 (m, 1H), 2.66 (tt, J = 11.2, 4.3 Hz, 1H), 2.58 (ddd, J = 15.5, 7.4, 3.4 Hz, 1H), 2.47 (t, J = 11.4 Hz, 1H), 2.07 - 1.79 (m, 1H), 1.75 - 1.67 (m, 1H), 1.23 (s, 2H), 0.84 (q, J = 12.1 Hz, 1H). MS: m / z = 321 [M+H] + .

[0103] Example 3: Synthesis of (3R,5S)-1-(8-methoxy-[1,7]naphthyridine-5-yl)-5-methylpiperidine-3-ylamine (Compound 4) [Chemical formula] [(3R,5S)-1-(8-methoxy-[1,7]naphthirizine-5-yl)-5-methyl-piperizine-3-yl]-carbamic acid tert-butyl ester: In a microwave vial, 5-bromo-8-methoxy-[1,7]naphthirizine (0.58g; 2.43 mmol; 1.0 equivalent), ((3R,5S)-5-methyl-piperizine-3-yl)-carbamic acid tert-butyl ester (0.62 g; 2.91 mmol; 1.20 equivalents), chloro(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii),methyl-t-butyl ether adduct (99 mg; 0.12 mmol; 0.05 equivalents), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (56 mg; 0.12 mmol; 0.05 equivalents), and cesium carbonate (1.58 g; 4.85 mmol; 2.0 equivalents) were dissolved in anhydrous dioxane (11 ml). The reaction mixture was placed under nitrogen and heated in a microwave at 85°C for 8 hours. The reaction product was purified on silica using an ethyl acetate / hexane gradient to obtain the title compound (578 mg; 1.55 mmol; 64.0%). MS: 373.5 [M+H] + .

[0104] (3R,5S)-1-(8-methoxy-[1,7]naphthiridine-5-yl)-5-methyl-piperidine-3-ylamine:[(3R,5S)-1-(8-methoxy-[1,7]naphthiridine-5-yl)-5-methyl-piperidine-3-yl]-carbamic acid tert-butyl ester (185.0 mg; 0.50 mmol; 1.0 equivalent) was dissolved in dioxane (2 mL) in a reaction vial. Trifluoroacetic acid (4 mL; 2.48 mmol; 5.0 equivalents) was added, and the reaction mixture was stirred for 4 hours. This mixture was purified by preparative HPLC on an acetonitrile / water (modified to 0.1% NH4OH) gradient to obtain the title compound (114.0 mg; 0.42 mmol; 84.3%). MS: 273.4 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (dd, J = 4.3, 2.1 Hz, 1H), 8.38 - 8.33 (m, 1H), 7.78 (dd, J = 8.8, 4.0 Hz, 1H), 7.73 (s, 1H), 4.02 (d, J = 1.8 Hz, 3H), 3.27 - 3.18 (m, 1H), 3.10 (d, J = 11.4 Hz, 2H), 2.98 (s, 2H), 2.28 (t, J = 10.8 Hz, 2H), 1.94 (s, 2H), 0.91 (d, J = 6.3 Hz, 3H), 0.80 (q, J = 12.1 Hz, 1H).

[0105] Example 4: Pharmaceutical preparation (A) Liquid preparation: A solution of the 100 mg powder in the bottle was prepared from 100 mg of compound 3, 100 g of sucrose, 18.2 g of citric acid monohydrate, and 5.3 g of sodium citrate in 930 mL of double-distilled water. The powder in this bottle was vigorously stirred or shaken until all the solute was dissolved. This liquid preparation is suitable for oral administration by mouth or via a nasogastric tube.

[0106] (B) Tablets: 25 mg film-coated tablets were manufactured to contain the following: [Table 2] The tablet components were thoroughly mixed and compressed using standard techniques. After tablet formation, these tablets were coated with Opadry® ZX321A220017 Yellow 5.0 mg. These tablets are suitable for oral administration.

[0107] Example 5: Stimulation of TLR7 and TLR8 Whole blood assayBlood was collected from healthy donors in EDTA-containing Vacutainer tubes (BD Biosciences) and assayed within 2 hours. Four parts of blood were diluted with one part of PBS and distributed to 96-well plates at a rate of 150 μl / well. Three dilutions of the compounds were added, and the plates were incubated at 37°C under 5% CO2 for 30 minutes. For the TLR7 / 8 test, R848 (Resikimod) was added to a concentration of 1 μM; for TLR7, the TLR7-selective agonist shown below was added to a concentration of 3 μM; and for TLR8, the TLR8-selective agonist shown below was added to a concentration of 0.5 μM. The plates were incubated overnight at 37°C under 5% CO2, and cytokine levels in the plasma were measured using AlphaLISA.

[0108] Human whole blood was treated with multiple concentrations of compound 3, compound 4, and hydroxychloroquine, and then stimulated with TLR7 and TLR8-specific small molecule agonists. IL-6, TNF-α, and IFN-α in the plasma were measured 16 hours later.

[0109] The TLR7 agonist used in the previous experiment was: [ka] The TLR8 agonist used was: [ka] That was the case.

[0110] Compounds 3 and 4 dose-dependently reduced IFNα and IL-6 production in mice challenged with a TLR-7 agonist, a TLR-8 agonist, and the TLR7 / 8 agonist R848 (Resikimod, a known TLR7 / 8 agonist). See Figures 2A-D and 4A-4E. Notably, IL-6 inhibition with compound 3 remained at 100% even at low doses (0.1 mg / kg), while corresponding IFNα inhibition at the same concentration was only partial. This suggests that compound 3 has a more potent inhibition of inflammatory cytokines beyond the antiviral response.

[0111] Example 6: In vivo inflammatory response BXSB-Yaa Model - Male BXSB-Yaa mice were purchased from Jackson Labs and treatment was initiated at 7-8 weeks of age. The mice were administered compound 3, formulated in 0.1M sodium citrate buffer pH 3, once daily by forced oral administration. After 14 weeks of treatment, the mice were euthanized by CO2 asphyxiation, and blood was collected via vena cava. Plasma was collected from a portion of this blood, and 100 μl of blood was stored in an animal blood protection tube (Qiagen) for gene expression analysis. To monitor proteinuria in BXSB-Yaa mice, urine was collected by bladder massage in the mornings for two consecutive days, and the samples were pooled. Urine albumin and creatinine levels were determined using an Advia 1800 clinical chemistry analyzer (Siemens). The urinary albumin-to-creatinine ratio (UACR) was calculated as the ratio of mg of albumin to 1 g of creatinine per 1 dl of urine.

[0112] These experiments demonstrated that compound 3 mitigated disease in a mouse lupus model. Compound 3 was administered to BXSB-Yaa mice by forced oral administration. Survival was tracked over time (Figure 3A), and renal disease was assayed by measuring proteinuria and plotting it over time (Figure 3B), or by plotting the AUC of individual mice over time (Figure 3C). Figure 3D shows blood gene expression analysis performed on a panel of 17 IFN-regulated genes to calculate IFN gene signature scores compared to healthy control mice. The time-course graph of proteinuria represents mean ± SEM, and all other data are graphed as medians. Statistical significance was determined by Kruskal-Wallis for proteinuria (*p<0.05) and by ANOVA for IFN scores (**p<0.01).

[0113] Treatment of mice with TLR7-driven autoimmune disease (BXSB-Yaa) with compound 3 resulted in dose-dependent improvements in survival (Figure 3A) and reductions in renal disease, as evidenced by lower proteinuria (Figures 3B, 3C). These mice exhibited a potent type I IFN response, which was inhibited by compound 3 (Figure 3D). Although type I IFN inhibition was observed only at high doses, immunopathology improved at 10 to 100 times lower doses, which is consistent with preferential inhibition of TLR7 / 8-induced inflammatory cytokines over antiviral type I IFN.

[0114] Results: Compound 3 is a potent, selective TLR7 / 8 inhibitor that dose-dependently inhibits inflammatory cytokines (e.g., IL6, TNF-α) induced by ssRNA viruses such as SARS-CoV-2, overcoming antiviral cytokines (e.g., IFN-α), thereby potentially mitigating immune-mediated pathologies that are overridden by antiviral immunity. This immunotherapy strategy is substantially more targeted than broader immunosuppressants (e.g., pan-JAK inhibitors such as baricitinib, corticosteroids, and hydroxychloroquine) in clinical trials where the risk of secondary bacterial infection may be increased. The data suggest that administration of compound 3 after the initial viral response phase (Figure 1) may prevent the second phase of antibody-dependent anabolism (elaboration) of cytokineemia while maintaining initial viral clearance without impairment.

[0115] Example 7: Clinical Trial Protocol The objective of this study is to evaluate the safety and efficacy of orally administered compound 3 in hospitalized COVID-19 pneumonia patients who are not yet admitted to the intensive care unit. This study is a randomized, double-blind, placebo-controlled design evaluating two dose levels of compound 3 administered over 14 days. The study design and monitoring of participant safety are based on data from first-in-human Phase I monotherapy and 14-day multidrug escalation healthy volunteer studies, preclinical evaluations of compound 3, and clinical trials of other anti-inflammatory drugs for COVID-19 (e.g., tocilizumab). Compound 3 exhibits dose-proportional pharmacokinetics (PK), has a half-life of ~7 to 11 hours, and is primarily metabolized by aldehyde oxidase rather than common CYP450 enzymes.

[0116] Compound 3 is a small molecule dual Toll-like receptor (TLR) 7 and TLR8 antagonist that has been shown to specifically inhibit the activity of various TLR7 / 8 ligands, including ssRNA, specific GU-rich microRNAs, and small molecule receptor agonists. TLR7 and TLR8 are expressed in endosomes of cells with innate immune function, where activation by ssRNA viruses (e.g., SARS-CoV-2) stimulates the secretion of type I interferon (IFN) and inflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha [TNFα], and others), cell maturation, and activation of other host immune mechanisms (Li et al.; and Chow et al.).

[0117] Two dose levels of compound 3, 100 mg twice daily and 50 mg twice daily, will be evaluated against placebo. This dose selection was guided by PK and pharmacodynamic data from a Phase I healthy volunteer trial, as well as doses proven effective in preclinical animal models of lupus. In the Phase I trial, compound 3 suppressed the secretion of ex vivo-stimulated cytokines, including IL-6, TNFα, and IFNα, in an exposure-dependent manner. Based on these data, preliminary modeling and simulations reflecting 100 mg twice daily would suppress ex vivo-stimulated IL-6 production by 90% in 87% of healthy volunteers, while 50 mg twice daily would suppress it by 50% in 90% of healthy volunteers. The magnitude of TLR7 and TLR8 inhibition required to suppress the explosive cytokine production observed in some COVID-19 patients progressing to acute respiratory disease syndrome is unknown, and the safety profile of compound 3 has not been described in this patient population; therefore, the clinical and pharmaceutical evaluation of a 50 mg twice daily dose in participants with progressive COVID-19 pneumonia is observed as reasonable.

[0118] Obtaining available data on compound 3 in a two-part human placebo-controlled trial is deemed necessary. This trial will begin with a focus on evaluating safety in a small number of participants (Part A) before expanding to a full Phase II clinical evaluation of the drug. Participants in this trial must not be enrolled in any other COVID-19 trial, and other immunomodulatory agents must not be used in conjunction with compound 3. The primary caregiver for participants in this trial may, with the permission of the local investigator, place the participant in locally recommended antiviral therapy (to be approved at the site prior to the trial).

[0119] For this principle Phase II trial evaluating patients with clinically worsening COVID-19 pneumonia, the primary endpoint would be the time to maintain peripheral capillary oxygen saturation (SpO2) ≥ 94% for at least 24 hours in room air. To provide better information for future drug evaluations in this population, the trial will also measure additional clinical parameters (e.g., those accepted in severe influenza) as secondary endpoints. Specifically, at the end of day 14 of administration, this study will investigate: 1) whether the patient is discharged from the hospital without activity restrictions; 2) whether the patient is discharged but has activity restrictions; 3) whether the patient remains hospitalized but does not require oxygen therapy; 4) whether the patient remains hospitalized and requires oxygen support via mask or nasal cannula; 5) whether the patient remains hospitalized and receives non-invasive ventilation or a high oxygen flow rate of FiO2 < 0.50; 6) whether the patient remains hospitalized and is placed on a ventilator or ECMO; or 7) whether the patient dies from these conditions.

[0120] Participation criteria: 1. At the time of signing the informed consent form, the person's age is between ≥18 and ≤65 years old. 2. Based on local acceptance guidelines, the test for SARS-CoV-2 was positive. 3. Evidence of chest imaging consistent with COVID-19 pneumonia. 4. Without the use of a ventilator (invasive or non-invasive). 5. Under indoor air conditions, SpO2 < 94%, and PaO2 / FiO2 ≥ 150 with a maximum FiO2 of 0.4. 6. Hospitalization is required. 7. ≥18.5~≤35.0 kg / m 2 It has a body mass index (BMI) within the range.

[0121] Compound 3 may be administered as monotherapy or in combination with one or more additional therapies. The FDA recently granted remdesivir an Emergency Use Authorization (EUA) for the treatment of COVID-19 pneumonia. If a consulting physician recommends co-administration of compound 3 with remdesivir, data on the efficacy of this combination will be compiled. Similarly, compound 3 may be administered in combination with lopinavir / ritonavir and interferon 1-β. Furthermore, compound 3 may be administered co-administered to patients receiving convalescent plasma transfusions if a consulting physician recommends this combination.

[0122] The data collected from this trial will evaluate which dosages and frequencies are suitable for the safe and effective treatment of adults with COVID-19 pneumonia.

[0123] Example 8: Antiviral testing of compounds 3 and 4 Calu-3 cells were seeded on two 384-well plates. Plate 1 contained the compound and a multiplicity of infection (MOI) of 0.05 with SARS-CoV-2 / ZG / 297-20 passage 6, while Plate 2 contained only the compound. For each well, 15,000 Calu-3 cells were seeded at 50 μL / well in full growth medium (EMEM, 10% FCS, 1% Pen / strep). These cells were grown at 37°C and 5% CO2 for 48 hours. After this time, the medium in both plates was replaced, and fresh medium was added to each well.

[0124] In Plate 1: 5 μL of each compound at each concentration was added in pairs to the identified wells over 1 hour, followed by infection with SARS-CoV-2 with an MOI of 0.05. The final volume of each well contained 5 μL of compound, 5 μL of virus (diluted and adjusted to an MOI of 0.05), and 40 μL of EMEM complete medium, for a total of 50 μL per well. This plate was monitored using an Incucyte microscope at 2-hour intervals after virus addition, with a total observation time of 120 hours.

[0125] Cell viability was determined using Cell Glo reagent (Promega); 50 μL of the reagent was added to each well, incubated in the dark at RT for 10 minutes, and then luminescence was measured using a Biotek plate reader.

[0126] Figures 5 and 6 clearly show that treatment of Calu-3 cells with compounds 3 and 4 provides cellular confluence similar to that of uninfected cells by 60 hours, respectively.

[0127] Example 9 - In vitro effect of compound 3 administration Blood was collected from healthy donors, and PBMCs were separated using gradient centrifugation. The PBMCs were dispensed into 96-well plates, and dilution M5049 was added in sets of three to selected wells. The plates were incubated at 37°C and 5% CO2 for 30 minutes. Subsequently, RNA oligonucleotides were added to the cells at a concentration of 26 μg / ml for stimulation. The treated PBMCs were incubated overnight at 37°C and 5% CO2, and the following day, IFNα, TNFα, and IL-6 in the supernatant were measured by AlphaLISA. The results are shown in Figures 7A-7C; M5049 (compound 3) significantly suppressed the production of IFNα, TNFα, and IL-6 in treated cells.

[0128] Let-7a、UGA GGU AGU AGG UUG UAU AGU U;Let-7a、UGA GGU AGU AGG UUG UAU AGU U;Let-7a、UGA GGU AGU UG UG UG U;Let-7a U;Let-7c、UGA GGU AGU AGG UUG UAU GGU U;Let-7e、UGA GGU AGG AGG UUG UAU AGU U;Let-7f、UGA GGU AGU AGA UUG UAU AGU U;miR-122、UGG AGU AGU UG UG UG UG G;miR-223、CGU GUA UUU GAC AAG CUG AGU U;miR-21、UAG CUU AUC AGA CUG AUG UUG A;miR-574、UGA GUG UGU GUG UGU GAG UGU GU。

[0129] Example 10 - In vivo effect of compound 3 administration Healthy female C57BL / 6 mice were administered either a vehicle (0.1M sodium citrate, pH 3.0) or M5049 (0.1, 1, 10 mg / kg) in increasing doses. Thirty minutes later, the mice were administered 2 mg / kg of miR-122 (Sigma) conjugated with in vivofectamine (Life Technologies) by a single intravenous injection. Four hours after miRNA administration, the mice were euthanized, and blood was collected for cytokine analysis of the plasma, and lungs were collected for gene expression analysis. IFN-α and IL-6 in the plasma samples were measured using Alphalisa (Perkin Elmer). Lungs were homogenized in RLT buffer using OctoMacs and M-tubes (Qiagen), and RNA was extracted using the RNEasy mini-kit (Qiagen). Gene expression analysis was performed using a custom-ordered NanoString panel. Gene signature scores were determined by calculating the log-2 change relative to the vehicle alone, and then using the median of the log-2 changes for all genes in that signature as the signature score for each mouse. The genes used for the IFN gene signature were: OAS1, OAS2, OAS3, OASL, BST2, CMPK2, GBP5, HERC6, IFI44, IFIT1, IFIT2, IFIT3, IFIH1, CXCL10, ISG15, MX1, MX2, STAT1, TNFSF10, USP18, RSAD2, and IRF7. The genes used for the NF-κB gene signature were: IL1RN, TNFAIP3, CSF1, IRF1, IL1B, IL6, NFKBIA, PTGS2, TAP1, and TNF. Mice treated with the liposomal formulation miR-122 showed a significant increase in plasma levels of IFNα and IL-6 (paired Student's t-test), which was significantly reduced in a dose-dependent manner by M5049 (determined by one-way ANOVA, with P<0.0074 for all concentrations of IFNα, and P=0.0237 for IL-6 at 1 mg / g M5049, and P=0.0147 for IL-6 at 10 mg / kg M5049). See Figures 8A and 8B.Administration of miR-122 led to an increase in both IFN and NFκB gene signature scores, indicating localized lung inflammation. M5049 significantly reduced both gene signature scores at doses of 1 and 10 mg / kg (P<0.01, one-way ANOVA), indicating that M5049 is well distributed to the lungs and strongly reduces lung inflammation. See Figures 9A and 9B.

[0130] While many embodiments of the present invention are described herein, it is clear that the basic embodiments may be modified to provide other embodiments utilizing the compounds and methods of the present invention. Therefore, it will be clear that the scope of the present invention should be limited by the appended claims rather than by the specific embodiments represented by the examples.

Claims

1. A pharmaceutical composition for treating coronavirus infection in subjects requiring treatment, comprising an effective amount of a TLR7 / 8 inhibitor or a pharmaceutically acceptable salt thereof, The aforementioned TLR7 / 8 inhibitor 【Chemistry 1】 A pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the coronavirus causes SARS or MERS infection.

3. The pharmaceutical composition according to claim 1 or 2, wherein the coronavirus causes SARS-CoV-1, SARS-CoV-2, or MERS-CoV infection.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the coronavirus is SARS-CoV-2.

5. The pharmaceutical composition according to claim 4, wherein the subject is suffering from an excessive inflammatory host immune response to SARS-CoV-2 infection.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the subject has COVID-19 pneumonia.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the subject has moderate to severe COVID-19 requiring medical intervention.

8. A pharmaceutical composition according to any one of claims 1 to 7, which is administered once or twice a day.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the total amount of the TLR7 / 8 inhibitor administered is approximately 50 mg to approximately 300 mg per day.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein 50 mg or 100 mg of the TLR7 / 8 inhibitor is administered twice daily.

11. A pharmaceutical composition according to any one of claims 1 to 10, administered for approximately 7 to 21 days.

12. The pharmaceutical composition according to claim 11, which is administered for approximately 14 days.

13. The pharmaceutical composition according to any one of claims 1 to 9, wherein 100 mg of the TLR7 / 8 inhibitor is administered twice daily for 14 days to a subject in need thereof.

14. A pharmaceutical composition according to any one of claims 1 to 13, which is administered orally.

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