TLR7 / 8 antagonists and uses thereof

Abstract

The present invention relates to compounds of the present invention and pharmaceutically acceptable compositions thereof, which are useful as TLR7 / 8 antagonists.

Description

[Technical Field]

[0001] Technical field of the present invention The present invention provides compounds of formula (I) as Toll-like receptor 7 / 8 (TLR7 / 8) antagonists and their use in the treatment of immunodeficiency and other diseases associated with TLR7 / 8 overexpression. [Background technology]

[0002] Background of the present invention Toll-like receptors (TLRs), currently comprising a family of 10 receptor genes with distinct specificities, are part of the cellular pathogen pattern recognition system and have evolved to defend against various infectious diseases (bacteria, viruses, and fungi). Activation of TLRs leads to cytokine responses, such as interferon release and activation of specific immune cells. The functional expression of selected TLRs in different tissues is highly diverse. Some receptors, such as TLR4 (stimulated by E. coli lipopolysaccharide LPS), are located on the cell surface, for example, on epithelial cells, while TLR3, 7, 8, and 9 are located in specific immune cells and on the endosomal membrane. All of the latter are activated by nucleic acids, but they recognize various types of nucleic acids. For example, TLR9 is activated by single-stranded DNA containing CpG 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, with 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). Various inhibitors of TLR7, TLR8, and TLR9 have been described, but further TLR inhibitors are desired. In particular, polynucleotides with inhibitory motifs for one or more of TLR7, TLR8, and TLR9 are needed to strictly inhibit the immune response in subjects (e.g., patients with autoimmune diseases or inflammatory disorders).

[0004] For the past few years, there has been a significant global effort to utilize potent immune activation induced by TLR7, 8, or 9 agonists for cancer treatment. However, cancer immunotherapy has a long history of failure. In recent years, however, our understanding of cancer immune surveillance and the resulting function of immune cell subsets has dramatically improved. TLR7 or TLR9 agonists are currently in clinical development for cancer monotherapy, combination therapy, or as vaccine adjuvants. The TLR agonist approach for cancer immunotherapy differs from previous struggles using cytokines, interferons, or monovalent vaccines, for example. TLR agonist-mediated immune activation is multifaceted, mediated by specific immune cells (primarily dendritic cells and B cells, followed by other cells), and this activation leads to both innate and adaptive immune responses. Moreover, not only one type of interferon, but rather many different isoforms are simultaneously induced, and not only type I (α, β) but also type II (γ, NK cells) are (indirectly) induced. [Overview of the project]

[0005] Summary of the present invention In one embodiment, the present invention has the following chemical formula: [ka] The present invention provides compounds selected from the group consisting of and / or pharmaceutically acceptable salts thereof.

[0006] In another embodiment, the present invention provides compounds of the present invention that are dual antagonists of TLR7 and TLR8. In another embodiment, the present invention provides compounds of the present invention suitable for treating and / or preventing disorders related to TLR7 / 8. In another embodiment, the present invention provides compounds that can modulate, or particularly inhibit, the activity or function of TLR7 / 8 in mammalian, and especially human, pathological conditions.

[0007] According to another aspect of the present invention, a method for treating and / or preventing autoimmune disorders is provided.

[0008] In another aspect, the present invention provides a previously described compound that is selective for TLR7 or TLR8.

[0009] In another aspect, the present invention provides compounds that are selective for TLR7 and TLR8. [Brief explanation of the drawing]

[0010] [Figure 1-1] Figure 1 shows pyronarizines in the BioMAP® Diversity PLUS panel at 10, 3.3, 1.1, and 0.3 μM. The latter system models T cell-dependent B cell proliferation, activation, and class switching occurring in germinal centers of secondary lymphoid organs. This system is not limited to these but is particularly relevant to indications involving B cell activation and antibody production, including systemic lupus erythematosus (SLE), other autoimmune indications, hematological malignancies, and allergies. [Figure 1-2]Figure 1 shows pyronarizines in the BioMAP® Diversity PLUS panel at 10, 3.3, 1.1, and 0.3 μM. The latter system models T cell-dependent B cell proliferation, activation, and class switching occurring in germinal centers of secondary lymphoid organs. This system is not limited to these but is particularly relevant to indications involving B cell activation and antibody production, including systemic lupus erythematosus (SLE), other autoimmune indications, hematological malignancies, and allergies.

[0011] [Figure 2-1] Figure 2 shows the superposition of 3.3 μM pyronaridine and 33 μM hydroxychloroquine in BioMAP® Diversity PLUS panels at 10, 3.3, 1.1, and 0.3 μM. Hydroxychloroquine shows a remarkably similar pattern to pyronaridine at one-tenth the concentration (i.e., 3.3 μM). [Figure 2-2] Figure 2 shows the superposition of 3.3 μM pyronaridine and 33 μM hydroxychloroquine in BioMAP® Diversity PLUS panels at 10, 3.3, 1.1, and 0.3 μM. Hydroxychloroquine shows a remarkably similar pattern to pyronaridine at one-tenth the concentration (i.e., 3.3 μM). [Modes for carrying out the invention]

[0012] Detailed description of a specific embodiment 1. General description of the compound of the present invention In one embodiment, the present invention provides an antagonist of TLR7 / 8. In some embodiments, such a compound includes a compound represented by the formula described herein, or a pharmaceutically acceptable salt thereof, where each variant is as defined and described herein.

[0013] 2. Compounds and Definitions The compounds of the present invention include those generally described above, as well as pharmaceutically acceptable salts thereof and / or mixtures thereof.

[0014] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within reasonable medical judgment, is suitable for use in contact with human and lower animal tissues, without excessive toxicity, hypersensitivity, allergic reactions, etc., and is balanced by a reasonable risk-benefit ratio. pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and inorganic bases, as well as organic acids and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, bicarbonate, boric acid, butyric acid, camphoric acid, camphor sulfonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecyl sulfate, ethanesulfonic acid, formic acid, fumaric acid, glucoheptonic acid, glycerophosphate, gluconic acid, hemisulfate, heptanoic acid, hexanoic acid, hydroiodic acid, and 2-hydroxyethanesulfate. This includes lactic acid, lactobionic acid, lactic acid, lauric acid, lauryl sulfate, malic acid, maleic acid, malonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pectinic acid, persulfate, 3-phenylpropionic acid, phosphoric acid, pivalic acid, propionic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecanoic acid, and salts of valeric acid.

[0015] In addition, unless stated otherwise, structures depicted herein also mean that they include compounds that differ only in the presence of one or more atoms with enriched isotopes. For example, replacement of hydrogen by deuterium or tritium, or replacement of carbon by 14 C or 14 replacement of carbon by carbon enriched with 2 C, compounds having such structures are within the scope of the present invention. In some embodiments, the group contains one or more deuterium atoms. It is also further intended that the compounds of the present invention include their isotopically labeled forms. Examples of isotopes that are commercially readily available and can be incorporated into the compounds of the present invention by well-known methods are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 CI. Compounds of the present invention, or any pharmaceutically acceptable salts thereof containing one or more of the above isotopes and / or other isotopes of other atoms, are intended to be part of the present invention.

[0016] As used herein, the term "modulator" is defined as a compound that binds to and / or inhibits a target with measurable affinity. In certain embodiments, the modulator has an IC50 and / or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 10 nM.

[0017] The terms "measurable affinity" and "measurably inhibit", as used herein, mean a measurable change in TLR7 / 8 activity between a sample containing a compound of the present invention or its composition and TLR7 / 8 (and an equivalent sample containing TLR7 / 8 without the compound or its composition).

[0018] ​ 3. Use, Formulation, and Administration Medicinally acceptable compositions In other embodiments, the present invention provides compositions comprising the compound of the present invention or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is such that it is effective in inhibiting TLR7 / 8 to a measurable degree in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is such that it is effective in inhibiting TLR7 / 8 to a measurable degree in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient requiring such a composition.

[0019] When used herein, the terms “patient” or “subject” mean an animal, preferably a mammal, most preferably a human.

[0020] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound formulated with it. pharmaceutically acceptable carriers, adjuvants, or vehicles used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glyceride mixtures, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0021] The compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, transrectally, transnasally, orally, transvaginally, or via implanted reservoir. The term “parenterally,” as used herein, encompasses subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intracisional, intracerebral, intramedullary, intrahepatic, intrafocal, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable forms of the compositions of the present invention encompass aqueous or oily suspensions. These suspensions are formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, or as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents employed are water, Ringer's solution, and isotonic sodium chloride solutions. In addition, sterilized fixative oils have conventionally been used as solvents or suspension media.

[0022] For this purpose, any inoffensive fixing oil employed includes synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable preparations, such as naturally pharmaceutically acceptable oils (particularly their polyoxyethylated forms), such as olive oil or castor oil. Solutions or suspensions of these oils also contain diluents or dispersants of long-chain alcohols, such as carboxymethylcellulose or similar dispersants (commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions). Other commonly used surfactants, such as Tween®, Span, and other emulsifiers or bioavailability enhancers, are also commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, but are used for formulation purposes.

[0023] 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 solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. Useful diluents for oral administration in capsule form include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or colorings may also be optionally added.

[0024] The pharmaceutically acceptable compositions of the present invention are optionally administered by nasal aerosol or inhalation. Such compositions are prepared according to well-known techniques in the art of pharmaceutical formulations, and are prepared as a solution in physiological saline, benzyl alcohol or other suitable preservative, an absorption enhancer to increase bioavailability, fluorinated carbon, and / or other conventional solubilizers or dispersants.

[0025] The pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations 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.

[0026] The amount of the compound of the present invention, which can be optionally combined with a carrier material to produce a single-dosage-form composition, will vary depending on the host being treated and the specific mode of administration. Preferably, the compositions provided should be formulated so that a dosage of the compound between 0.01 and 100 mg / kg body weight / day can be administered to a patient receiving these compositions.

[0027] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, timing of administration, elimination rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

[0028] 4. Use of compounds and pharmaceutically acceptable compositions The present invention further relates to a method for treating subjects suffering from TLR7 / 8-related disorders, wherein the method comprises the following chemical formula: [ka] The present invention comprises administering an effective amount of a compound selected from the group consisting of and / or a pharmaceutically acceptable salt thereof to the subject.

[0029] The compounds of the present invention are useful as anticancer agents for cancers that respond to TLR7 activation. In certain embodiments, cancers include, but are not limited to, cancers of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, sarcoma, cancers of the ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva; hereditary cancers, retinoblastoma and Wilms' tumor; leukemia, lymphoma, non-Hodgkin's disease, chronic and acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin's disease, multiple myeloma and T-cell lymphoma; myelodysplastic syndromes, plasma cell neoplasms, paraneoplastic syndromes, cancers of unknown primary sites and AIDS-related malignancies.

[0030] In certain embodiments, the compounds of the present invention are used to treat cancers of the skin or kidney. The sensitivity of a given cancer to TLR7 activation may be assessed by, but are not limited to, measuring a reduction in primary or metastatic tumor cell volume (micro-reduction, partial reduction, or complete reduction), altered blood count, altered hormone or cytokine blood concentrations, inhibition of further tumor cell volume increase, stabilization of the disease in the patient, assessment of disease-related biomarkers or surrogate markers, extended overall survival in the patient, extended time to disease progression in the patient, extended survival without progression in the patient, extended disease-free survival in the patient, improved quality of life in the patient, or modulation of disease comorbidities (e.g., pain, cachexia, mobilization, hospitalization, altered blood count, weight loss, wound healing, fever).

[0031] The compounds according to the present invention may also be useful as immunomodulators that can regulate immune responses from numerous different angles (making them useful in treating various disorders).

[0032] Provided herein are methods for inhibiting an individual's immune response, comprising administering an effective amount of a TLR7 and / or TLR8 inhibitor (e.g., TLR inhibitor) to the individual using the compounds described herein. In some variations, the TLR inhibitor inhibits a TLR7-dependent immune response. In some variations, the TLR inhibitor inhibits a TLR8-dependent immune response. In some variations, the TLR inhibitor inhibits both TLR7-dependent and TLR8-dependent immune responses. In some variations, the TLR inhibitor inhibits TLR7-dependent, TLR8-dependent, and other TLR-dependent immune responses. Unless otherwise noted, the term TLR inhibitor refers to any one of the TLR inhibitors disclosed herein. In some preferred embodiments, the individual is a human patient.

[0033] Methods of immunomodulation provided herein include suppressing and / or inhibiting immune responses, which include but are not limited to immune responses. The disclosure also provides methods for restoring symptoms associated with unwanted immune activation, which include but are not limited to autoimmune symptoms. Immunosuppression and / or inhibition by the methods described herein may be practiced on individuals, including individuals suffering from disorders associated with unwanted activation of immune responses. The disclosure also provides methods for inhibiting responses induced by TLR7 and / or TLR8 (e.g., in vitro or in vivo). In some variations, cells are exposed to a TLR inhibitor in an amount effective in inhibiting the response from cells contributing to the immune response.

[0034] Inhibition of TLR7 and / or TLR8 is useful for treating a variety of cytokine-responsive diseases or disorders. Conditions for which TLR7 and / or TLR8 inhibitors may be used as treatment include, but are not limited to, autoimmune diseases and inflammatory disorders. Provided herein are methods for treating a disease or disorder in an individual, comprising administering an effective amount of a TLR7 and / or TLR8 inhibitor to the individual. Also provided are methods for restoring symptoms associated with a disease or disorder, comprising administering an effective amount of a TLR7 and / or TLR8 inhibitor to an individual having a disease or disorder. Methods for delaying the onset of a disease or disorder are also provided herein, the methods comprising administering an effective amount of one or more TLR7 and / or TLR8 inhibitors to an individual having a disease or disorder. In certain embodiments, the inhibitor is a compound as described herein.

[0035] Provided herein are methods for inhibiting an immune response in an individual, the methods comprising administering to the individual at least one TLR inhibitor as disclosed herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is related to an autoimmune disease. In a further embodiment, inhibiting the immune response herein restores one or more symptoms of an autoimmune disease. In yet another embodiment, inhibiting the immune response herein treats an autoimmune disease. In yet another embodiment, inhibiting the immune response herein prevents or delays the onset of an autoimmune disease. In some variations, the TLR inhibitor inhibits a TLR7-dependent immune response. In some variations, the TLR inhibitor inhibits a TLR8-dependent immune response. In some variations, the TLR inhibitor inhibits both TLR7-dependent and TLR8-dependent immune responses. In some embodiments, at least one TLR inhibitor is administered in an amount effective to inhibit the immune response in the individual.

[0036] Also provided herein are methods for treating or preventing autoimmune diseases in an individual, comprising administering an effective amount of TLR7 and / or TLR8 inhibitors to the individual. In some embodiments, the autoimmune disease is characterized by arthralgia, positive antinuclear antibody test, cheek rash, or discoid rash. In some embodiments, the autoimmune disease is related to the skin, muscle tissue, and / or connective tissue. In some embodiments, the autoimmune disease is not apparent in the individual from symptoms of the skin, muscle tissue, and / or connective tissue. In some embodiments, the autoimmune disease is systemic. Autoimmune diseases include, but are not limited to, rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type 1 diabetes mellitus, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic arthritis, irritable bowel disease (IBD), scleroderma, Sjögren's disease, vitiligo, polymyositis, inflammatory bowel diseases including pemphigus vulgaris, pemphigus foliaceus, Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases may also include, but are not limited to, polyangiitis duplication syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold sensitivity.

[0037] In some embodiments, autoimmune diseases are selected from the group consisting of arthritis, pancreatitis, mixed connective tissue disease (MCTD), lupus, antiphospholipid syndrome (APS), systemic arthritis, and irritable bowel syndrome.

[0038] In another embodiment, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune skin diseases, and multiple sclerosis.

[0039] In other embodiments, the autoimmune disease is selected from the group consisting of pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type 1 diabetes. In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the autoimmune disease is autoimmune pancreatitis (AIP). In some embodiments, the autoimmune disease is glomerulonephritis. In some embodiments, the autoimmune disease is pyelonephritis. In some embodiments, the autoimmune disease is sclerosing cholangitis. In some embodiments, the autoimmune disorder is psoriasis. In some embodiments, the autoimmune disease is a rheumatoid-like disease or disorder. In some embodiments, the rheumatoid-like disease or disorder is rheumatoid arthritis. In some embodiments, the disease is diabetes and / or diabetes-related disease or disorder. In some embodiments, the autoimmune disease here is associated with RNA-containing immune complexes. In some embodiments, the autoimmune disease is Sjögren's disease.

[0040] Provided herein are methods for inhibiting an immune response in an individual, the methods comprising administering to the individual at least one TLR inhibitor as disclosed herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is related to an inflammatory disorder. As used herein, the term “inflammatory disorder” encompasses inflammatory conditions without known autoimmune components (e.g., atherosclerosis, asthma, etc.). In a further embodiment, inhibiting the immune response restores one or more symptoms of an inflammatory disorder. In yet another embodiment, inhibiting the immune response treats an inflammatory disorder. In yet another embodiment, inhibiting the immune response prevents or delays the onset of an inflammatory disorder. In some embodiments, the inflammatory disorder is selected from the group consisting of non-rheumatoid arthritis, renal fibrosis, and hepatic fibrosis. In some embodiments, the inflammatory disorder is interfacial dermatitis. In some further embodiments, interfacial dermatitis is selected from the group consisting of lichen planus, lichenoid rash, lichenoid keratosis, linear lichen, chronic lichenoid keratosis, erythema multiforme, fixed drug eruption, pityriasis lichenoid, phototoxic dermatitis, radiodermatitis, viral exanthema, dermatomyositis, secondary syphilis, sclerosing atrophic lichen, mycosis fungoides, bullous pemphigoid, lichen yellow, porokeratosis, chronic atrophic acrodermatitis, and degenerative melanoma. In some embodiments, the inflammatory condition is a skin disorder such as atopic dermatitis (eczema). In some embodiments, the inflammatory disorder is a sterile inflammatory condition such as drug-induced inflammation of the liver and / or pancreas. In some further embodiments, the inflammatory disease is inflammatory liver disease. In some other further embodiments, the inflammatory disease is inflammatory pancreatic disease.

[0041] Provided herein are methods for inhibiting an immune response in an individual, the methods comprising administering to the individual at least one TLR inhibitor as disclosed herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is related to chronic pathogen stimulation. In some variations, the immune response is related to HIV infection. In a further embodiment, inhibiting the immune response herein restores one or more symptoms of a viral disease or disorder resulting from HIV infection. In yet another embodiment, inhibiting the immune response herein treats a viral disease or disorder resulting from HIV infection. In yet another embodiment, inhibiting the immune response herein prevents or delays the onset of a viral disease or disorder resulting from HIV infection. Other variations provided herein relate to immunosuppressive therapy for individuals exposed to or infected with HIV. Administration of a TLR inhibitor to an individual exposed to or infected with HIV results in suppression of HIV-induced cytokine production. In some embodiments, at least one TLR inhibitor is administered to an individual exposed to or infected with HIV in a dose effective in suppressing HIV-induced cytokine production.

[0042] Provided herein are methods for inhibiting a TLR7 and / or TLR8-dependent immune response in an individual, the method comprising administering a TLR inhibitor to the individual in an amount effective in inhibiting the immune response in the individual. In some variations, the immune response is associated with an autoimmune disease. In some embodiments, the autoimmune disease is rheumatoid arthritis. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of rheumatoid arthritis. In some embodiments, the autoimmune disease is multiple sclerosis. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of multiple sclerosis. In some embodiments, the autoimmune disease is lupus. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of lupus. In some embodiments, the autoimmune disease is pancreatitis. In some embodiments, the TLR inhibitor is effective in suppressing one or more symptoms of pancreatitis. In some embodiments, the autoimmune disease is diabetes mellitus. In some embodiments, TLR inhibitors are effective in suppressing one or more symptoms of diabetes. In some embodiments, the disease is Sjögren's disease. In some embodiments, TLR inhibitors are effective in suppressing one or more symptoms of Sjögren's disease. In some variants, the immune response is related to inflammatory disorders. In some embodiments, TLR inhibitors are effective in suppressing one or more symptoms of inflammatory disorders. In some variants, the immune response is related to chronic pathogen stimulation. In some embodiments, TLR inhibitors are effective in suppressing one or more symptoms of chronic pathogen stimulation. In some variants, the immune response is related to viral diseases resulting from HIV infection. In some embodiments, TLR inhibitors are effective in suppressing one or more symptoms of viral diseases resulting from HIV infection.

[0043] In some embodiments of any method involving the administration of a TLR inhibitor to an individual (e.g., a method to inhibit an immune response or treat an autoimmune disease or inflammatory disorder), the TLR inhibitor has a therapeutically acceptable safety profile. The TLR inhibitor has a therapeutically acceptable histological profile that includes, for example, a tolerably low level of toxicity (if any) to the liver, kidneys, pancreas, or other organs. In some embodiments, the TLR inhibitor has an unexpected and advantageous safety profile. In some embodiments, the safety profile includes an assessment of toxicity, histological profile, and / or necrosis (e.g., liver, kidneys, and / or heart). In some embodiments, the TLR inhibitor has a therapeutically acceptable level of toxicity. In some embodiments, the TLR inhibitor has a reduced level of toxicity compared to other TLR inhibitors. In some embodiments, the TLR inhibitor induces a therapeutically acceptable reduction in body weight compared to the initial body weight of the treated individual. In some embodiments, the TLR inhibitor induces a reduction of less than 5%, 7.5%, 10%, 12.5%, or 15% in total body weight. In some embodiments, the TLR inhibitor has a therapeutically acceptable histological profile. In some embodiments, the TLR inhibitor has a better histological profile (e.g., a lower severity score) compared to, for example, a reference TLR inhibitor. In some embodiments, the TLR inhibitor has a better histological profile (e.g., a lower severity score) when evaluating, for example, the liver, kidneys, and / or heart. In some embodiments, the TLR inhibitor has a therapeutically acceptable necrosis score. In some embodiments, the TLR inhibitor has reduced necrosis and / or a better (e.g., a lower) necrosis score compared to, for example, a reference TLR inhibitor. In some embodiments, the TLR inhibitor has, for example, a reduced renal and / or hepatocyte necrosis score and / or a better renal and / or hepatocyte necrosis score compared to a reference TLR inhibitor.

[0044] Consequently, the present invention provides a method for activating TLR7 in animals, particularly mammals, preferably humans, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to the animal. As with all compositions for inhibiting immune responses, the effective amount of a specific TLR inhibitor formulation and the method of administration thereof may vary based on the individual, the condition being treated, and other factors that are apparent to those skilled in the art. The effective amount of the compound will vary according to factors known in the art, but is expected to be in doses of about 0.1–10 mg / kg, 0.5–10 mg / kg, 1–10 mg / kg, 0.1–20 mg / kg, 0.1–20 mg / kg, or 1–20 mg / kg.

[0045] The present invention also provides a method for treating a viral infection in an animal, comprising administering an effective amount of the compound of the present invention to the animal. An effective amount for treating or inhibiting a viral infection is an amount that would cause a reduction in one or more of the signs of viral infection, such as viral lesions, viral load, viral production rate, and mortality, compared to an untreated control animal. The exact amount will vary according to factors known in the art, but is expected to be a dose as previously indicated with respect to TLR7 activation, or a dose of about 100 ng / kg to about 50 mg / kg, preferably about 10 μg / kg to about 5 mg / kg. In one embodiment of this invention, the viral infection is caused by a coronavirus. In a further embodiment of this invention, the coronavirus is selected from SARS (Severe Acute Respiratory Syndrome), MERS (Middle East Respiratory Syndrome), and COVID-19. In one embodiment of this invention, the viral infection is caused by COVID-19.

[0046] The method of the present invention can be carried out either in vitro or in vivo. The sensitivity of specific cells to treatment with the compounds according to the present invention can be specifically determined by in vitro testing, whether in a research process or in clinical application. Typically, cell cultures are combined with the compounds according to the present invention at various concentrations for a period sufficient for the activator to inhibit TLR7 / 8 activity, usually about 1 hour to 1 week. In vitro treatment can be performed using cells cultured from biopsy samples or cell lines.

[0047] The host or patient may belong to any mammalian species, such as primates, specifically humans; rodents, including mice, rats, and hamsters; rabbits; horses, cattle, dogs, cats, etc. Animal models are the subject of experimental investigations and provide models for the treatment of human diseases.

[0048] To identify signaling pathways and to detect interactions between various signaling pathways, scientists have developed suitable models or model systems, such as cell culture models and transgenic animal models. To determine a stage in a signaling cascade, interacting compounds can be used to modulate the signal. The compounds according to the present invention can also be used as reagents to test TLR7 / 8-dependent signaling pathways in animal and / or cell culture models, or in clinical diseases referred to in this application.

[0049] Furthermore, the following teachings herein relating to the use of the compounds according to the present invention for the manufacture of pharmaceuticals for prophylactic or therapeutic treatment and / or monitoring are considered to be effective and applicable without limitation to the use of the compounds for inhibition of TLR7 / 8 activity.

[0050] The present invention also relates to the use of compounds according to the present invention or pharmaceutically acceptable salts thereof for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or transmitted by TLR7 / 8 activity. Furthermore, the present invention relates to the use of compounds according to the present invention or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or transmitted by TLR7 / 8 activity. In certain embodiments, the present invention provides the use of compounds according to the present invention or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals for the prophylactic or therapeutic treatment of TLR7 / 8-mediated disorders.

[0051] The compounds according to the present invention may act therapeutically when administered once or several times before or after the onset of a disease. The compounds and pharmaceuticals described above for use in the present invention are specifically used for therapeutic treatment. The therapeutically relevant effects include alleviating one or more symptoms of a disorder to some extent, or partially or completely restoring one or more physiological or biochemical parameters related to or causing a disease or pathological condition to normal. Monitoring can be considered a type of treatment, for example, by administering the compound at distinguishable intervals to boost the response and completely eliminate the pathogen and / or symptoms of the disease. Either the same compound or different compounds may be applied. 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 a disorder related to TLR7 / 8 activity, or to treat the symptoms that have occurred and persisted.

[0052] The present invention further relates to a pharmaceutical comprising (including mixtures thereof in any ratio) at least one compound according to the present invention and / or a pharmaceutically acceptable salt thereof. In particular embodiments, the present invention relates to a pharmaceutical comprising at least one compound according to the present invention and / or a pharmaceutically acceptable salt thereof.

[0053] In the sense of the present invention, “pharmaceutical” means any agent in the medical field that comprises one or more compounds of the present invention or preparations thereof (e.g., pharmaceutical compositions or pharmaceutical formulations) and can be used in the treatment, monitoring or aftercare of patients suffering from diseases related to TLR7 / 8 activity in such a way that pathogenic alterations to their systemic condition or the condition of a specific region of their organism can only become permanent, at least temporarily.

[0054] In various embodiments, the active ingredient may be administered alone or in combination with other treatments. Synergistic effects may be achieved by using more than one compound in the pharmaceutical composition, i.e., the compound of the present invention may be combined as an active ingredient with one or more other agents (which may be another compound of the present invention or a compound of a different structural framework). The active ingredients may be used simultaneously or sequentially.

[0055] In some embodiments, the TLR inhibitor described herein is administered in combination with a corticosteroid. In some embodiments, the corticosteroid is a glucocorticosteroid. In some embodiments, the corticosteroid is a mineralocorticoid. Corticosteroids include corticosterone and derivatives, their prodrugs, isomers and analogs; cortisone and derivatives, their prodrugs, isomers and analogs (i.e., Cortone); aldosterone and derivatives, their prodrugs, isomers and analogs; dexamethasone and derivatives, their prodrugs, isomers and analogs (i.e., Decadron); prednisone and derivatives, their prodrugs, isomers and analogs (i.e., Prelone); fludrocortisone and derivatives, their prodrugs, isomers and analogs; hydrocortisone and derivatives, their prodrugs, isomers and analogs (i.e., cortisol or Cortef); hydroxycortisone and derivatives, their prodrugs, isomers and analogs; betamethasone and derivatives, their prodrugs, isomers and analogs (i.e., Celestone); budesonide and derivatives, their prodrugs, isomers and analogs (i.e., Entocort This includes, but is not limited to, fludrocortisone (EC), methylprednisolone and its derivatives, prodrugs, isomers and analogs (i.e., Medrol), prednisolone and its derivatives, prodrugs, isomers and analogs (i.e., Deltasone, Crtan, Meticorten, Orasone, or Sterapred), triamcinolone and its derivatives, prodrugs, isomers and analogs (i.e., Kenacort or Kenalog), etc. In some embodiments, the corticosteroid is fludrocortisone or its derivatives, prodrugs, isomers or analogs. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the corticosteroid is hydroxycortisone or its derivatives, prodrugs, isomers or analogs. In some embodiments, the corticosteroid is hydroxycortisone.

[0056] In some embodiments, corticosteroids are administered in doses between approximately 0.001 mg and 1 mg, 0.5 mg and 1 mg, 1 mg and 2 mg, 2 mg and 20 mg, 20 mg and 40 mg, 40 mg and 80 mg, 80 mg and 120 mg, 120 mg and 200 mg, 200 mg and 500 mg, or 500 mg and 1000 mg per day. In some embodiments, corticosteroids are administered in doses between approximately 0.1 mg / kg and 0.5 mg / kg, 0.5 mg / kg and 1 mg / kg, 1 mg / kg and 2 mg / kg, 2 mg / kg and 5 mg / kg, 5 mg / kg and 10 mg / kg, 10 mg / kg and 15 mg / kg, 15 mg / kg and 20 mg / kg, 20 mg / kg and 25 mg / kg, 25 mg / kg and 35 mg / kg, or 35 mg / kg and 50 mg / kg per day.

[0057] In some embodiments, the TLR inhibitor used in combination therapy is given in the amount of TLR inhibitor delivered, which may be, for example, about 0.1–10 mg / kg, 0.5–10 mg / kg, 1–10 mg / kg, 0.1–20 mg / kg, 0.1–20 mg / kg, or 1–20 mg / kg.

[0058] In some embodiments, the TLR inhibitor is administered simultaneously with one or more additional active ingredients, including but not limited to corticosteroids (concurrent administration). In some embodiments, the TLR inhibitor is administered sequentially with an additional therapeutic agent, including but not limited to corticosteroids (sequential administration). In some embodiments, sequential administration involves administering the TLR inhibitor or additional therapeutic agent consecutively for approximately 1 minute, 5 minutes, 30 minutes, 1 hour, 5 hours, 24 hours, 48 ​​hours, or within 1 week. In some embodiments, the TLR inhibitor is administered via the same route of administration as the additional therapeutic agent. In some embodiments, the TLR inhibitor is administered via a different route of administration than the additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered parenterally (e.g., by central venous line, intra-arterial, intra-vein, intramuscular, intraperitoneal, intradermal, or subcutaneous injection), orally, gastrointestinally, topically, nasopharyngally, and transpulmonaryly (e.g., by inhalation or intranasal injection). In some embodiments, the additional therapeutic agent is a corticosteroid.

[0059] The compounds disclosed in this invention may be administered in combination with one or more additional active ingredients, including anticancer agents. As used herein, the term “anticancer agent” refers to any agent administered to a patient with cancer for the purpose of treating cancer.

[0060] The anticancer treatments defined herein may be applied as monotherapy or in combination with conventional surgery, radiotherapy, or drug therapy in addition to the compounds of the present invention disclosed herein. Such drug therapy (e.g., chemotherapy or targeted therapy) includes one or more of the following antitumor agents, preferably one of them: Alkylating agents: Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Chlormethine, Cyclophosphamide, Dacarbazine, Ifosfamide, Improsulfan, Tosylate, Lomustine, Melphalan, Mitobronitol, Mitractol, Nimustine, Ranimustine, Temozolomide, Thiotepa, Treosulfan, Mechloretamine, Carbocon; Apadicone, Fotemustine, Gluphosphamide, Paliphosphamide, Pipobroman, Trophosphamide, Uramustine, TH-302 4 VAL-083 4 etc; Platinum compounds: carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lovaplatin, nedaplatin, picoplatin, satraplatin; lovaplatin, nedaplatin, picoplatin, satraplatin, etc. DNA modifiers: Amrubicin, Bisanthren, Decitabine, Mitoxantrone, Procarbazine, Trabectedin, Clofarabine; Amsacrin, Brostaricin, Pixantrone, Laromustine 1,3 etc; Topoisomerase inhibitors: Etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, berotecan, eriptinium acetate, boreroxine, etc. Microtubule modifying factors: cabazitaxel, docetaxel, eribulin, ixabepyrone, paclitaxel, vinplastin, vincristine, vinorelbine, vindesine, vinflunin; phospretabrine, tesetaxel, etc. Antimetabolite: Asparaginase 3 Azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, phloxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxyfluridine, ellacitabine, larcitrexed, cepacitabine, tegafur 2,3 , trimethotrexate, etc. Anticancer antibiotics: Bleomycin, Dactinomycin, Doxorubicin, Epirubicin, Idarubicin, Rebamisol, Miltefosine, Mitomycin C, Romidepsin, Sterptozocin, Barurubicin, Dinostatin, Zolubicin, Daunorubicin, Plicamycin; Acralubicin, Peplomycin, Pirarubicin, etc. Hormones / Antagonists: Abarelix, Abiraterone, Bicalutamide, Buserelin, Carsterone, Chlorotonianicene, Degarelix, Dexamethasone, Estradiol, Flutocortrone, Fluoxymesterone, Flutamide, Fulvestrant, Goserelin, Histrelin, Leuprorelin, Megesterol, Mitotane, Nafarelin, Nandrolone, Nylutamide, Octreotide, Prednisolone, Raloxifene, Tamoxifen, Thylotropin α, Toremifene, Trilostane, Triptorelin, Diethylstilbestrol; Acorbifen, Danazol, Deslorerin, Epithiostanol, Orteronel, Enzalutamide 1,3 etc; Aromatase inhibitors: aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestan, etc. Small molecule kinase inhibitors: crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, arisertib, dabrafenib, dacomitinib, dinaciclib Dovitinib, Enzastaurin, Nintedanib, Lenvatinib, Linifanib, Lincitinib, Masitinib, Midostaurin, Motesanib, Neratinib, Orantinib, Perifosin, Ponatinib, Radotinib, Rigosatib, Tipifanib, Tivantinib, Tivozanib, Trametinib, Pimasertib, Brivanib, Alaninate, Cejilanib, Apatinib 4 Cabozantinib S-Marat 1,3 ibrutinib 1,3 , icotinib 4 , Buparlisib 2 , sipatinib 4Cobimetinib 1,3 , Ideralicib 1,3 , Fedratinib 1 XL-647 4 etc; Photosensitizer: Methoxsalen 3 ;Polyphymer sodium, talaporfin, temoporfin, etc.; Antibodies: Alemtuzumab, Becilesomab, Brentuximab, Vedotin, Cetuximab, Denosumab, Ipilimumab, Ofatumumab, Panitumumab, Rituximab, Tocitumomab, Trastuzumab, Bevacizumab, Pertuzumab 2,3 Katsumakisomab, elotuzumab, epratuzumab, faretuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, okalatuzumab, olegobomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zaltumumab, zanorimumab, matsuzumab, dalotuzumab 1,2,3 Onartuzumab 1,3 Lacostomomab 1 Tabalmab 1,3 EMD-525797 4 nivolumab 1,3 etc; Cytokines: Aldesleukin, Interferon α 2 Interferon α2a 3 Interferon α2b 2,3 ; Selmoleukin, Tasonelmin, Teseloukin, Operelbekin 1,3 Recombinant interferon β-1a 4 etc; Drug conjugates: Denileukin difutitox, ibritumomab tiuxetan, iobengguan I123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; syntredequin besudotox, edtreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technitium (99mTc) alsitumomab 1,3 , vintafolide 1,3 etc; Vaccine: Cypreuser 3 Vitespen3 Emepepimto-S 3 Oncovax 4 Lindpepim 3 , Trovax 4 MGN-1601 4 MGN-1703 4 etc; and Others: Alitretinoin, Bexarotene, Bortezomib, Everolimus, Ibandronate, Imiquimod, Lenalidomide, Lentinan, Methylosine, Mifamlutide, Pamidronic Acid, Pegaspargase, Pentostatin, Cyprucel 3 Schizophyllan, Tamibarotene, Temsirolimus, Thalidomide, Tretinoin, Bismodegib, Zoledronic acid, Vorinostat; Celecoxib, Silenditide, Entinostat, Etanidazole, Ganetespib, Idronoxyl, Iniparib, Ixazomib, Ronidamine, Nimorazole, Parabinostat, Pelletinoin, Pritidepsin, Pomalidomide, Procodazole, Ridaforolimus, Tascinimod, Terotristat, Simalfasin, Tirapazamin, Tosedostat, Travedersen, Ubenimex, Valspodar, Gendicin 4 Picibanil 4 , Leolysine 4 Letaspimycin hydrochloride 1,3 Trevananib 2,3 bilirudin 4 , Carfilzomib 1,3 Endostatin 4 , Imnokotel 4 , Bellinostat 3 MGN-1703 4 . ( 1 Prop.INN(Proposed International Common Name); 2 Rec.INN (Recommended International Common Name); 3 USAN (United States Common Name); 4 (No INN)

[0061] In some embodiments, a combination of a TLR inhibitor and one or more additional active ingredients reduces the effective dose of the TLR inhibitor and / or one or more additional active ingredients administered to achieve the same result compared to the effective dose administered when the TLR inhibitor or the additional active ingredient is administered alone (including, but not limited to, the volume, concentration, and / or total drug dose administered). In some embodiments, a combination of a TLR inhibitor and a corticosteroid reduces the effective dose of the corticosteroid administered compared to the corticosteroid administered alone. In some embodiments, a combination of a TLR inhibitor and one or more additional active ingredients reduces the frequency of therapeutic agent administration compared to the administration of the additional active ingredient alone. In some embodiments, a combination of a TLR inhibitor and one or more additional active ingredients reduces the total duration of treatment compared to the administration of the additional active ingredient alone. In some embodiments, a combination of a TLR inhibitor and one or more additional active ingredients reduces the side effects associated with the administration of the additional active ingredient alone. In some embodiments, one or more additional active ingredients are corticosteroids. In some embodiments, the corticosteroid is fludrocortisone or a derivative, prodrug, isomer, or analog thereof. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the combination of an effective amount of TLR inhibitor and an additional active ingredient is more efficient than an effective amount of TLR inhibitor or the additional active ingredient alone.

[0062] In some embodiments, the TLR inhibitors described herein are administered in combination with an antiviral agent. In one embodiment of this embodiment, the antiviral agent is remdesivir. In one embodiment of this embodiment, the combination is useful for treating a viral infection. In a further embodiment of this embodiment, the viral infection is caused by a coronavirus. In one embodiment, the coronavirus is COVID-19.

[0063] TLR inhibitors may also be useful as vaccine adjuvants for use in conjunction with any material that modulates either humoral and / or cell-mediated immune responses (e.g., live viral, bacterial, or parasitic immunogens; inactivated viral, tumor-derived, protozoan, organism-derived, fungal, or bacterial immunogens, toxoids, toxins; autoantigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; recombinant proteins; glycoproteins; peptides; etc.). In some embodiments, combination therapies, including but not limited to combinations of TLR inhibitors and vaccines, are used in the treatment of autoimmune diseases or inflammatory disorders. In some embodiments, combination therapies, including but not limited to combinations of TLR inhibitors and vaccines, are used in the treatment of infectious diseases.

[0064] In some embodiments, combination therapies, including but not limited to combinations of TLR inhibitors and corticosteroids, are used in the treatment of autoimmune diseases or inflammatory disorders. In some embodiments, the autoimmune disease is selected from, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, autoimmune skin diseases, multiple sclerosis, pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type 1 diabetes. In some embodiments, the autoimmune disease is Sjögren's disease.

[0065] Also provided herein are kits containing TLR inhibitors as provided herein, and instructions for their use in methods of inhibiting TLR7 and / or TLR8-dependent immune responses.

[0066] The kit may include one or more containers containing a TLR inhibitor (or a formulation containing a TLR inhibitor) as described herein, and a set of instructions, generally written instructions. However, an electronic storage medium (e.g., a magnetic diskette or optical disk) containing instructions regarding the use and dosage of the TLR inhibitor or formulation for the intended treatment (e.g., suppression of response to TLR7 and / or TLR8 agonists, suppression of TLR7 and / or TLR8-dependent immune responses, reversal of one or more symptoms of an autoimmune disease, reversal of symptoms of a chronic inflammatory disease, reduction of cytokine production in response to a virus, and / or treatment of one or more symptoms of a disease or disorder mediated by TLR7 and / or TLR8) is also acceptable. The instructions included in the kit generally include information about the dosage, administration schedule, and route of administration for the intended treatment. The container for the TLR inhibitor (or formulation containing a TLR inhibitor) may be a unit dose, a multi-dose package (e.g., a multi-dose package) or a sub-unit dose. The kit may also include a container for the adjuvant.

[0067] In another embodiment, the present invention provides a kit comprising a separate pack of an effective amount of the compound according to the present invention and / or a pharmaceutically acceptable salt thereof (including mixtures thereof in any ratio), and optionally, an effective amount of one or more additional active ingredients. The kit includes a suitable container such as a box, individual bottles, bags, or ampoules. The kit may include, for example, separate ampoules, each containing an effective amount of the compound according to the present invention and / or a pharmaceutically acceptable salt thereof (including mixtures thereof in any ratio), and optionally, an effective amount of one or more additional active ingredients, in a dissolved or lyophilized form.

[0068] As used herein, the terms “treatment,” “to treat,” and “to treat” mean to prevent, alleviate, delay, or inhibit the onset of a disease or disorder, 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 when there are no symptoms. For example, the treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of the disease history, by exposure to a known pathogenic vector, and / or in light of genetic factors or other susceptibility factors). The treatment may also include administration after some or all of the symptoms have subsided, for example, to prevent or delay their recurrence.

[0069] According to one embodiment, the present invention relates to a method for inhibiting TLR7 / 8 activity in a biological sample, the method comprising the step of contacting the biological sample with the compound of the present invention or a composition containing the compound.

[0070] According to other embodiments, the present invention relates to a method for actively inhibiting TLR7 / 8 or its mutants or activity in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition containing the compound.

[0071] The compounds of the present invention are useful in vitro as unique tools for understanding the biological role of TLR7 / 8 (including the evaluation of numerous factors that are thought to influence, and be influenced by, TLR7 / 8 production and TLR7 / 8 interactions). These compounds are also useful for the development of other compounds that interact with TLR7 / 8, because they provide important structure-activity relationship (SAR) information that facilitates their development. The compounds of the present invention that bind to TLR7 / 8 can be used as reagents for detecting TLR7 / 8 from living cells, fixed cells, biological fluids, tissue homogenates, purified natural biomaterials, and the like. For example, cells expressing TLR7 / 8 can be identified by labeling with such compounds. In addition, based on their binding ability to TLR7 / 8, the compounds of the present invention can be used in enzyme purification, such as in-situ staining, FACS (fluorescence-activated cell sorting), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and ELISA (enzyme-linked immunosorbent assay), or in the purification of cells expressing TLR7 / 8 within permeable cells. The compounds of the present invention can also be used as commercial research reagents for various medical research and diagnostic uses.Such uses include, but are not limited to: use as a calibration standard for quantifying the activity of candidate TLR7 / 8 inhibitors in various functional assays; use as a blocking reagent in random screening of compounds, i.e., in search of a new family of TLR7 / 8 ligands, the compound may be used to block the recovery of currently claimed TLR7 / 8 compounds; use in cocrystals with TLR7 / 8, i.e., the compound of the present invention will allow the determination of the enzyme / compound structure by X-ray crystallography by causing the formation of crystals of the compound bound to TLR7 / 8; other research and diagnostic applications, where TLR7 / 8 is preferably activated, or such activation is conveniently calibrated to known amounts such as TLR7 / 8 inhibitors; use in assays as a probe for determining the expression of TLR7 / 8 in cells; and developing assays for detecting compounds that bind to the same site as TLR7 / 8 binding ligands.

[0072] The compounds of the present invention may be applied either by themselves and / or in combination with physiometric measurements for diagnosing the effectiveness of treatment. Pharmaceutical compositions containing the compounds and the use of the compounds to treat conditions mediated by TLR7 / 8 represent a promising novel approach to a wide range of treatments that result in direct and immediate improvement of health conditions, whether in humans or animals. Orally bioavailable, and the chemical components of the present invention improve convenience for patients and compliance for physicians.

[0073] When used herein, the term “biological sample” includes, without limitation, cell cultures or extracts thereof; biopsy materials obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids, or extracts thereof.

[0074] Modulation of TLR7 / 8, or its mutants, and their activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, preservation of biological specimens, and biological assays. Example

[0075] As illustrated in the following examples, in one exemplary embodiment, the compound is prepared according to the following general procedure. While the general method describes the synthesis of a compound of the present invention, it will be understood that the following general method and other methods known to those skilled in the art may also be applied to all compounds as described herein, and to each of their subclasses and species.

[0076] The symbols and conventions used in the processes, schemes, and examples described below are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. [Examples]

[0077] Example 1: Synthesis of Compound 1 [ka]

[0078] Step 1: A suspension of 2,4-dichlorobenzoic acid (35.7 g, 0.186 mol), 6-methoxypyridine-3-amine (25 g, 0.201 mol), potassium carbonate (13 g, 0.094 mol), and CuO (0.15 g, 0.38 mol) in 100 mL of isopentanol was refluxed at 130 °C (with CO2 gas production). The reaction mixture was cooled to 100 °C after 10 hours and quenched with 35 mL of water. Next, the pH of the solvent was adjusted to 11 at the same temperature with 10% NaOHaq. The resulting solution was cooled to 40-50 °C and filtered to remove the copper salt. The filtrate was adjusted to pH 3 with 6 N HCl to obtain a gray precipitate. The precipitate was slurryed with hexane, filtered, and dried to obtain 4-chloro-2-(6-methoxypyridine-3-yl-amino)-benzoic acid (42 g, 94.09%). LCMS: C 13 H 11 The calculated value for ClN2O3 was 278.69, the measured value was 279.1 (M+H), the time to release was 2.27 minutes, and the maximum concentration was 99.30%. 1 HNMR (400MHz, DMSO-d 6 ):δ9.48(s,1H),8.13(d,J=2.80Hz,1H),7.88(d,J=8.40Hz,1H),7.70(dd,J=2.80,8.80Hz,1H ),6.90(d,J=8.80Hz,1H),6.75(dd,J=2.00,8.40Hz,1H),6.68(d,J=1.60Hz,1H),3.87(s,3H).

[0079] Step 2: To a stirred solution of 4-chloro-2-(6-methoxypyridine-3-yl-amino)benzoic acid (7 g, 0.025 mol) in ethylene dichloride (35 mL), POCl3 (11.6 mL, 0.125 mol) was added. The mixture was heated to reflux temperature for 2 hours. The reaction mixture was cooled to 10°C, and then MeOH (53 mL) was carefully added to the mixture, followed by the addition of a sodium hydroxide solution. The mixture was stirred at 20-30°C for 2 hours. The unpurified product was filtered and washed with MeOH and water. It was then dried under reduced pressure to obtain 7,10-dichloro-2-methoxybenzo[b]-1,5-naphthyridine (3.5 g, 49.92%). LCMS:C 13 The calculated value for H8Cl2N2O was 279.12, the measured value was 281.0 (M+H), the RT was 3.21 minutes, and the maximum was 97.58%. 1 HNMR (400MHz, DMSO-d 6 ): δ8.46(d,J=3.60Hz,1H),8.43(d,J=3.60Hz,1H),8.31(d,J=2.00Hz,1H),7.85(dd,J=2.00,9.20Hz,1H),7.52(d,J=9.20Hz,1H),4.16(s,3H).

[0080] Step 3: To a stirred solution of 4-aminophenol (6.7 g, 0.061 mol) in purified water (196 mL), sulfuric acid (12.0 g, 0.122 mol) was added, followed by 7,10-dichloro-2-methoxybenzo[b]-1,5-naphthiridine (13.0 g, 0.047 mol). The mixture was heated to 85°C for 7 hours and refluxed for 10 hours. The reaction mixture was cooled to 10-30°C, and sodium hydroxide solution was added to the reaction mixture. The mixture was stirred at 10-30°C for 1 hour. Next, it was filtered and washed with water and methanol to obtain 4-[(7-chloro-2-methoxybenzo[b]-1,5-naphthiridine-10-yl)amino]-phenol hemisulfate (17.3 g, 82.97%). LCMS: C 19 H 14 The calculated value for ClN3O2 was 351.79, the measured value was 352.2 (M+H), the RT was 1.54 minutes, and the maximum was 96.09%. 1 HNMR (400MHz, DMSO-d 6 ):δ9.92(s,1H),9.64(s,1H),8.22(d,J=9.16Hz,1H),7.92(d,J=1.48Hz,1H),7.74(d,J=8.96Hz,1H),7.43 (d,J=9.20Hz,1H),3.79(d,J=2809.32Hz,1H),7.15(d,J=8.56Hz,2H),6.84(d,J=8.60Hz,2H),3.94(s,3H).

[0081] Step 4: To a stirred solution of paraformaldehyde (29.3 g, 0.977 mol) in ethanol (110 mL), pyrrolidine (69.54 g, 0.977 mol) was added after cooling to -5°C to 5°C. The reaction mixture was then heated to 70°C for 15 minutes. The mixture was cooled to 25-35°C, and 4-[(7-chloro-2-methoxybenzo[b]-1,5-naphthyridine-10-yl)amino]phenol hemisulfate (17.2 g, 0.0488 mol) was added to the mixture. The mixture was stirred at 50°C for 15 hours. After the reaction was complete, purified water (140 mL) was added, and the mixture was cooled to 15-25°C. The mixture was stirred for 1 hour, filtered, and the product was washed with purified water (36.0 mL). Methanol (140 mL) was added, and the mixture was heated under reflux temperature for 1 hour. The mixture was cooled to 5-15°C, stirred for 2 hours, and then filtered. Next, it was washed with methanol (40 mL) and dried under reduced pressure to obtain 1 (20.3 g, 79.70%). LCMS:C 29 H 32 ClN5O2: Calculated value 518.06, measured value 518.06 (M+H), RT: 1.41 min, 99.29% (Max), HPLC: RT: 2.58 min, 99.66% (Max). 1 HNMR (400MHz, DMSO-d 6 ):δ9.05(s,1H),8.21(d,J=9.20Hz,1H),7.93(d,J=2.00Hz,1H),7.77(d,J=9.20Hz,1H),7.31(d,J =9.20Hz,1H),7.18(dd,J=2.00,9.40Hz,1H),3.94(s,3H),3.65(s,4H),2.50(m,8H),1.69(s,8H). 13 CNMR (100MHz, DMSO-d 6 ):δ159.2,152.6,148.2,144.3,142.7,140.4,133.8,133.5,127.7,12 7.5,126.8,124.1,122.9,122.8,118.9,115.0,55.1,53.7,53.1,23.1.

[0082] Example 2: Synthesis of Compound 2

Chem.

[0083] Step - 1: 4 - aminophenol (3 g, 21 mmol), diethylamine (9.8 mL, 94 mmol), and paraformaldehyde (2.85 g, 94 mmol) were placed in 20 mL of ethanol in a sealed tube and stirred at 80 °C for 18 h. Next, the reaction mixture was evaporated, and the residue was purified by column chromatography to obtain 2,6 - bis((diethylamino)methyl) - 4 - nitrophenol (1 g, 14.99%). LCMS: C 16 H 27 Calculated value of C₁₅H₂₄N₃O₃ is 309.41, measured value is 310.2 (M + H), RT. 0.36 min, 82.7% (Max), 1 ¹H NMR (400 MHz, DMSO - d 6 ₆): δ 8.00 (s, 2H), 3.77 (s, 4H), 2.63 - 2.68 (m, 8H), 1.06 (t, J = 7.12 Hz, 12H).

[0084] Step - 2: Iron powder (1.4 g, 25.8 mmol) and NH₄Cl (1.36 g, 25.8 mmol) were added to a stirred suspension of 2,6 - bis((diethylamino)methyl) - 4 - nitrophenol (1 g, 3.23 mmol) in ethanol and water (30 mL, 20:10). The reaction mixture was heated to 80 °C over 2 h. Completion of the reaction was confirmed by TLC. The resulting reaction mixture was filtered through a bed of celite, washed with dichloromethane, and concentrated to give 4 - amino - 2,6 - bis((diethylamino)methyl)phenol (0.8 g) as a brown solid, which was carried forward to the next step itself. LCMS: C 16 H 29 Calculated value of C₁₅H₂₄N₃O is 279.43, measured value is 280.2 (M + H), RT. 0.31 min, 89.3% (Max).

[0085] Step - 3: 0.5 mL of concentrated hydrochloric acid was added to a stirred solution of 4 - amino - 2,6 - bis((diethylamino)methyl)phenol (0.8 g, 2.86 mmol) and 4,7 - dichloroquinoline (0.68 g, 3.43 mmol) in 50 mL of ethanol, and the mixture was heated at reflux temperature overnight. Next, the reaction mixture was evaporated to dryness, and the residue was purified by column chromatography to give 2 (0.7 g, 57.3%) as a reddish - orange solid. LCMS:C 25 H 33 Calculated for ClN4O 441.02, found 441.2 (M + H), RT. 1.01 min, 97.61% (Max), HPLC: RT 1.97 min, 96.21% (Max). 1 HNMR (400 MHz, DMSO - d 6 ): δ 9.80 (s, 1H), 8.61 (d, J = 8.80 Hz, 1H), 8.45 (d, J = 6.00 Hz, 1H), 7.98 (s, 1H), 7.68 (d, J = 9.20 Hz, 1H), 7.37 (s, 2H), 6.76 (d, J = 6.00 Hz, 1H), 4.10 (br, 4H), 2.90 - 2.92 (m, 8H), 1.18 (t, J = 7.20 Hz, 12H). 13 CNMR (100 MHz, DMSO - d 6 ): 156.19, 151.86, 148.46, 145.28, 136.14, 129.79, 128.23, 126.18, 125.87, 124.25, 121.05, 117.36, 101.37, 52.28, 46.31, 9.92.

[0086] Example 3: Synthesis of Compound 3

Chemical Structure

[0087] Step 1: 4,7-dichloroquinoline (5 g, 25 mmol) and 4-aminophenol (2.75 g, 25 mmol) were refluxed in 125 mL of ethanol for 2 hours. Next, the reaction mixture was cooled to room temperature, and the precipitate was removed by filtration and washed sequentially with saturated aqueous solution of NaHCO3, water, methanol, and then petroleum ether to obtain 4-[(7-chloroquinoline-4-yl)amino]phenol (5.75 g, 84.1%) as a yellow powder. LCMS: C 15 H 11 Calculated value of ClN2O: 270.72, measured value: 271.1 (M+H), RT: 1.10 min, 99.8% (Max). 1 HNMR (400MHz, DMSO-d 6 ):δ9.59(s,1H),8.52(d,J=9.20Hz,1H),8.38(d,J=6.00Hz,1H),7.91(d,J=2.00Hz,1H),7.61(d d,J=2.00,8.80Hz,1H),7.18(d,J=8.80Hz,2H),6.88(d,J=8.80Hz,2H),6.56(d,J=6.00Hz,1H).

[0088] Step 2: 4-[(7-chloroquinoline-4-yl)amino]phenol (1 g, 3.6 mmol), pyrrolidine (1.1 g, 16 mmol), and a 37% aqueous solution of formaldehyde (1.3 mL, 16 mmol) were added to 5 mL of ethanol and stirred at 25°C for 18 hours. Next, the reaction mixture was removed by distillation, and the residue was purified by flash chromatography to obtain a reddish-orange solid, 3 (0.45 g, 31.1%). LCMS:C 25 H 29 ClN4O: Calculated value 436.98, measured value 437.2 (M+H), RT 2.07 min, 99.2% (Max). HPLC: RT 1.94 min, 98.84% (Max). 1 HNMR (400MHz, DMSO-d 6): δ9.04(s,1H),8.40-8.46(m,2H),7.87-7.88(m,1H),7.56(dd,J=1.96,9.00Hz ,2H),7.26(s,2H),6.73-6.74(m,1H),4.07(br,4H),2.92(br,8H),1.88(br,8H). 13 CNMR (100MHz, DMSO-d) 6 ):154.51,152.17,149.57,134.32,130.73,127.74,126.41,125.15,124.96,121.99,118.19,101.42,54.72,53.23,23.45.

[0089] Example 4: HEK Cell Transfection

[0090] Human whole blood from healthy donors was aspirated into EDTA vacuum tubes, and the experiment was started within 2 hours of aspiration. Four times the volume of blood was diluted with one time the volume of PBS. A 10 mM stock compound solution was serially diluted 11 times in a 1:3 ratio with DMSO. Each serial dilution was further diluted by transferring 3 μl to 100 μl of RPMI. For stimulation-only and unstimulated controls, 3 μl of 100% DMSO was transferred to 100 μl of RPMI. Next, 5 μl of each of these dilutions was transferred in triplicate 96-well tissue culture-grade U-bottom plates for each ligand and each donor. The final inhibitor concentrations were 10, 3.3, 1.1, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.00051, 0.00017, and 0.00006 μM. A control without inhibitor (stimulation only) was included in each donor's triplicate. Diluted blood was distributed at 150 μl / well onto the inhibitor dilution. The plates were incubated at 37°C in 5% CO2 for 30 minutes. For TLR7 stimulation, 10 mM stock solution of TLR7-specific small molecule agonist in DMSO was diluted to 90 μM with RPMI, and 5 μl was added to each donor's respective inhibitor dilution. The final concentration was 3 μM. For TLR8 stimulation, 10 mM stock solution of TLR8-specific small molecule agonist in DMSO was diluted to 15 μM with RPMI, and 5 μl was added to each donor's respective inhibitor dilution. The final concentration was 0.5 μM. An unstimulated control was included in each donor's triplicate. The plates were incubated overnight at 37°C in 5% CO2. The following day, plasma was collected, and IL-6 levels were measured using AlphaLISA (PerkinElmer AL223) according to the manufacturer's protocol.

[0091] In a 384 culture plate (Corning 3707), 5000 c / w HEK293 TLR7 / NFKb reporter cells in phenol red-free DMEM, 10% ia FCS, and 2 mM L-glutamine were placed. The cells were incubated at 37°C, 10% carbon dioxide, and 90% relative humidity for 24 hours. 3 μL of control, standard, and compound were distributed into the wells and incubated for 30 minutes, then 3 μL of R848 agonist (Resiquimod) in 20 mM HEPES buffer was added. After 5 hours of incubation, the plate was allowed to stand at room temperature for 15 minutes. 10 μL of Steady-Glo substrate reagent was added, and the assay plate was shaken at 1500 rpm for 5 minutes. The assay plate was allowed to stand at room temperature for 30 minutes, and then read using an EnVision plate reader. [Table 1]

[0092] The results are shown in the table below. A:IC 50 <1μm B:IC 50 : 1μm~20μm C:IC 50 >20μm

[0093] [Table 2]

[0094] Example 5: Phenotypic testing in Biomap panels Pyrronarizines were profiled using the BioMAP® Diversity PLUS (BioSeek LLC, South San Francisco, CA) panel, which consists of well-characterized composite primary human cell lines in 10, 3.3, 1.1, and 0.3 μM concentrations. Pyrronarizines were tested through 12 BioMAP® systems containing early passaged primary human cells cultured alone or co-cultured and stimulated with various pro-inflammatory or immunomodulatory stimulants. These systems have been previously described (Xu et al., 2012), and the following: 3C [venous endothelial cells (HuVEC) / IL-1, TNF, and IFN], 4H (HuVEC / IL-4 and histamine), LPS (PBMC and HuVEC / LPS), Sag (PBMC and HuVEC / TCR ligand), BT (B cells and PBMC / anti-IgM and low levels of TCR ligand), BE3C (bronchial epithelial cells / IL1, TNF, and IFN), BF4T (bronchial epithelial cells and human dermal fibroblasts / TNF and IL-4), This includes HDF3CGF (human dermal fibroblasts / IL-1, TNF, IFN, epidermal growth factor, basic fibroblast growth factor, and platelet-derived growth factor-BB), KF3CT (keratinocytes and dermal fibroblasts / IL-1, TNF, and IFN), CASM3C (coronary artery smooth muscle cells / IL-1, TNF, and IFN), MyoF (pulmonary fibroblasts / TNF and transforming growth factor), and Mphg (HuVEC and macrophages / TLR2) (primary human cell types / stimulators). BioMAP activity profiles were created based on the levels of various readout parameters, including cytokine or growth factor expression, surface molecule expression, and cell proliferation. For more technical details, see (Xu et al. (2012). RN486, a selective Bruton's tyrosine kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents. J. Pharmacol. Exp. Ther. 341, 90-103).

[0095] The following eight common activities are noted within the system: HDF3CGF (PAI-1, Prolif72), MyoF (αSMA, VCAM-1, type I collagen, type III collagen, SRB), and lMphg (SRB-M).

[0096] The following systems contain 38 differentiation-inducing activities: 3C(TM, uPAR, Prolif), 4H(P-selectin, uPAR), LPS(MCP-1, TM, IL-8, IL-1α, M-CSF, sPGE2, sTNFα), BF4T(eotaxin 3), BE3C(uPAR, HLA-DR, MMP-9, PAI-1), CASM3C(uPAR, HLA-DR, M-CSF), HDF3CGF(MCP-1, VCAM-1, EGFR, M-CSF, MMP-1, TIMP-1, TIMP-2), KF3CT(MCP-1, MMP-9, PAI-1), MyoF(Type IV collagen, IL-8, MMP-1, TIMP-1), and lMphg(MCP-1, E-selectin, CD69, IL-8). Note that systems with detectable cytotoxicity (SAg and BT) were excluded from the analysis.

[0097] A distinguishing biomarker is defined when one profile has readouts outside a significant envelope with an effect size >20% (|log10 ratio|>0.1), and the readouts of other profiles are inside or in the opposite direction of that envelope. Example 6: Cell analysis of mouse splenocytes using R848 / CpG stimulation and inhibition with an antimalarial agent.

[0098] Mouse spleens from healthy female C57 / BL-6 / N mice (n=2) were removed and placed in 50 mL tubes containing B-cell medium, and the experiment was started immediately. The spleens were crushed through a cell filter using a syringe punch in a 50 mL Falcon tube. The cell filter and punch were rinsed with an appropriate amount of washing buffer to avoid cell loss. Next, the spleen cells were centrifuged at 552 × g (1600 rpm) at 4 °C for 10 minutes. Red blood cells in the cell pellet were hemolyzed by resuspending the pellet in 1 ml of ACK hemolysis buffer (4 °C) and incubating at RT for 1 minute. Hemolysis was stopped by filling the washing buffer to a maximum of 50 ml, and the cells were centrifuged at 552 × g (1600 rpm) at 4 °C for 10 minutes. Cells were washed and counted in B cell medium (IMDM + 25 mM HEPES + 10% FCS + pen / strep + NEAA 10 nM + Pyrovat sodium 100 nM, β-mercaptoethanol 50 nM) and seeded in 96-well MTP at a density of 148,500 cells per well (135 μl, 1.1 × 10⁶ c / ml). Cells were pre-treated with antimalarial agents (15 μl, at various concentrations ranging from 100 pM to 50 μM, following a dose-response curve) at 37°C, 5% CO₂ for 30 minutes, followed by TLR7 / 8 stimulation with R848 (15 μl, final concentration 1 μM) or TLR9 stimulation with CpG (15 μl, final concentration 5 μM), and incubated at 37°C, 5% CO₂ for 18–24 hours.

[0099] The supernatant was collected and transferred to a 96-well round-bottom MTP, and stored at -20°C until ELISA for mouse IL6 and mouse TNFα was performed. After the assay, the plate was read directly using an Envision Multiplate reader. The results were analyzed using GraphPadPrism V8.0. Dose-response curves were obtained by plotting the calculated amount of produced IL6 or TNFα in pg / ml units on the Y axis against the concentration of the respective MSCs on a semi-logarithmic scale on the X axis. IC was performed using GraphPad Prism analysis software. 50The values ​​were determined (X = log(X) and the transformation of Y values ​​using log inhibitor versus response; variable gradient (4 parameters). [Table 3]

[0100] Although numerous embodiments of the present invention are described herein, it is evident that other embodiments utilizing the compounds and methods of the present invention can be provided by modifying the basic examples. Therefore, it will be understood that the scope of the present invention should be defined by the appended claims rather than by the specific embodiments presented as examples.

[0101] Item 1 A method for inhibiting TLR7 and / or 8 in a biological sample, wherein the biological sample is as follows: [ka] A method comprising contacting a compound selected from the group consisting of and / or a pharmaceutically acceptable salt thereof with the compound. Item 2 A method for inhibiting TLR7 and / or TLR8 activity in patients requiring a method to inhibit TLR7 and / or TLR8 activity, the following: [ka] A method comprising the step of administering to the patient an effective amount of a compound selected from the group consisting of and / or a pharmaceutically acceptable salt thereof. Item 3 A method for treating TLR7 and / or TLR8-mediated disorders in patients requiring such treatment, the following: [ka] A method comprising the step of administering to the patient a compound selected from the group consisting of and / or a pharmaceutically acceptable salt thereof. Item 4 The method according to item 2, wherein the patient requiring the method has a disorder selected from rheumatoid arthritis (RA), psoriatic arthritis, osteoarthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis (MS), psoriasis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, hyperimmune globulinemia D and periodic fever syndromes, cryopin-associated periodic fever syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult Still's disease, gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor agonist deficiency), Alzheimer's disease, and Parkinson's disease. Item 5 The method according to item 4, wherein the disorder is selected from RA, SLE, LN, and MS. Item 6 The method according to item 3, wherein the disorder is selected from rheumatoid arthritis (RA), psoriatic arthritis, osteoarthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis (MS), psoriasis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, hyperimmune globulinemia D and periodic fever syndromes, cryopin-associated periodic fever syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult Still's disease, gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor agonist deficiency), Alzheimer's disease, and Parkinson's disease. Item 7 The method according to item 6, wherein the disorder is selected from RA, SLE, LN, and MS. Item 8 The method according to any one of items 1 to 7, wherein the compound is administered in combination with one or more additional active ingredients. Item 9 The method according to item 8, wherein one or more of the aforementioned additional active ingredients are useful for treating autoimmune diseases. Item 10 The method according to item 9, wherein the one or more additional active ingredients are corticosteroids. Item 11 A method for treating coronavirus infection in a person who needs a method for treating coronavirus infection, the following:

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Claims

1. A method for inhibiting TLR7 and / or 8 in a biological sample, wherein the biological sample is divided into the following compounds 【Chemistry 1】 A method comprising contacting the salt with a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition for use in inhibiting TLR7 and / or TLR8 activity in human patients requiring inhibition of TLR7 and / or TLR8 activity, comprising the following compounds 【Chemistry 2】 A pharmaceutical composition comprising and / or a pharmaceutically acceptable salt thereof, wherein the patient suffers from a TLR7 and / or 8-mediated disorder selected from rheumatoid arthritis (RA), lupus, systemic lupus erythematosus (SLE), lupus nephritis (LN), multiple sclerosis (MS), psoriasis, and Sjögren's disease.

3. The pharmaceutical composition according to claim 2, wherein the disorder is selected from RA, SLE, LN, and MS.

4. The pharmaceutical composition according to claim 2 or 3, wherein the compound is combined with one or more additional active ingredients.

5. The pharmaceutical composition according to claim 4, wherein the one or more additional active ingredients are useful for treating autoimmune diseases.

6. The pharmaceutical composition according to claim 5, wherein the one or more additional active ingredients are corticosteroids.

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