Use of IFN-I activity as biomarker for TLR inhibitor treatment

Abstract

The present invention provides the use of IFN-I activity as a predictive biomarker for the treatment of a patient with a Toll-like receptor (TLR) inhibitor, and related uses and methods.

Description

Technical field of the present invention

[0001] The present invention provides the use of IFN-I activity as a predictive biomarker for patients treated with Toll-like receptor (TLR) inhibitors, as well as related uses and methods. Background Art

[0002] The TLR family includes multiple members with different specificities and is part of the cell pathogen pattern recognition system, which has evolved into a defense mechanism for defending against a variety of infections. The functional expression of the selected TLRs in tissues is highly different. Some receptors are located on the cell surface, such as TLR4 (stimulated by E. coli lipopolysaccharide LPS), for example on epithelial cells, while other receptors, such as TLR3, 7, 8 and 9, are located on the endosomal membrane of specific immune cells. The latter are all activated by nucleic acids, but recognize different types of nucleic acids. For example, TLR9 is activated by single-stranded DNA containing CpG subsequences, TLR7 and 8 are activated by single-stranded RNA, and TLR3 is activated by double-stranded RNA. Activation of TLRs triggers various downstream signal transduction cascades, including signaling through nuclear factor-κB (NF-κB), interferon (IFN) response factors (IRFs), and mitogen-activated protein (MAP) kinases, leading to the transcription of various immune response genes, including inflammatory cytokines, stimulatory immune cytokines, chemokines, and co-stimulatory molecules (Farrugia and Baron, Int J Inflam. 2017; 2017: 8391230).

[0003] TLRs are associated with various autoimmune and inflammatory diseases, the clearest example being the role of TLR7 in the pathogenesis of systemic lupus erythematosus (Barrat and Coffman, Immunol Rev, 223: 271-283, 2008). TLR7 is also associated with systemic sclerosis, myositis, and rheumatoid arthritis (Duffy and O'Reilly, Immunotargets Ther. 2016; 5: 69-80). In turn, TLR8 is particularly associated with diseases such as rheumatoid arthritis and systemic sclerosis (Duffy and O'Reilly, cited above).

[0004] Type I interferons (IFN-I) are also part of the innate immune response to pathogens. They form part of one of several parallel signal transduction cascades triggered, for example, by TLR7 and TLR8. In addition to TLRs, IFN-I can also be induced by a series of other host pattern recognition receptors after recognizing pathogen components, including Rig-I-like receptors (RLRs), NOD-like receptors (NLRs) and DNA sensors. Subsequently, the released IFN-I binds to the IFN-α receptor (IFNAR), triggering a signal transduction cascade that leads to the expression of interferon-stimulated genes (ISGs). Like TLRs, IFN-I signaling has also been associated with various diseases, particularly autoimmune diseases, and IFN-I activity has been explored as a possible biomarker for such diseases by measuring the expression of one or more genes regulated by IFN-I. For some treatments, a correlation between clinical treatment response and IFN-I activity has been observed, although a positive correlation was observed in some cases and an inverse correlation was observed in others (Psarras et al., Rheumatology (Oxford), 2017 Oct 1; 56(10): 1662-1675).

[0005] There remains a need to identify patients who are more likely to respond to TLR inhibitor therapy. Summary of the Invention

[0006] The present invention relates to the use of IFN-I activity as a predictive biomarker for outcome of TLR inhibitor treatment.

[0007] In one aspect, the present invention provides a method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the therapeutic effect of the TLR inhibitor.

[0008] In another aspect, the invention provides a method of predicting the suitability of a diseased individual to initiate TLR inhibitor therapy, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the suitability of the individual to initiate said therapy.

[0009] In another aspect, the invention provides a method for predicting the suitability of a diseased individual who is being treated with a TLR inhibitor to continue said treatment, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the suitability of the individual to continue said treatment.

[0010] In another aspect, the present invention provides a method for using a TLR inhibitor to treat a disease in an individual, comprising administering the TLR inhibitor to the individual, wherein the treatment is based on IFN-I activity in a sample from the individual.

[0011] IFN-I activity can be assessed directly or indirectly, for example, by determining the expression of an individual's IFN-I signature. Such an IFN-I signature can comprise one or more genes selected from the group consisting of BST2, CMPK2, CXCL10, EPSTI1, GBP5, HERC5, HERC6, IFI6, IFI27, IFI44, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3, IRF7, ISG15, LY6E, MX1, MX2, OAS1, OAS2, OAS3, OASL, PKR, RSAD2, SIGLEC1, STAT1, TNFSF10, and USP18. For example, it can comprise HERC5, IFI27, IFIT1, and RSAD2.

[0012] In some embodiments, the TLR inhibitor is a TLR7 and / or TLR8 inhibitor. For example, the TLR7 and / or TLR8 inhibitor can be selected from the following groups: 5-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoline-8-carbonitrile; (3R,5S)-1-(8-methoxy-1,7-naphthyridin-5-yl)-5-methylpiperidin-3-amine; 2-{4-[2-(7,8-dimethyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(propan-2-yl)-1H-indol-5-yl]piperidin-1-yl}acetamide; rel-(2R,6R)-4-(8-cyanoquinolin-5-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-6-methylmorpholin-2-carboxamide amide hydrochloride; (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide; and (R)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide or pharmaceutically acceptable salts of these compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 shows a) the correlation between the IFN-I signature scores for various IFN-I signatures determined for a SLE patient population (expressed as the correlation coefficient r), and b) an exemplary graph plotting the IFN-I signature score for the Dx_4 IFN-I signature determined for the SLE patient population relative to the IFN-I signature score for the EMD_9 IFN-I signature.

[0014] Figure 2 Shown are the cumulative distribution functions of a) time to recovery and b) time to clinical worsening in the unstratified population of patients who received placebo or 50 mg or 100 mg of enpatoran twice daily (BID) (safety analysis set).

[0015] Figure 3 Shown are the cumulative distribution functions of time to recovery for patients with a) high IFN-I signature scores and b) low IFN-I signature scores at baseline and when receiving placebo or 50 mg or 100 mg empatolan twice daily (BID).

[0016] Figure 4 Figures show the ability of CMPD2 to reverse the effect of IFN-α pretreatment on Dex. (A) Dose-response curves of the effect of Dex on IL-6 in PBMCs with or without IFN-α pretreatment 16 hours after R848 stimulation. (B) Representative bar graphs of IL-6 secretion after treatment with 41nM Dex and / or 7.8nM CMPD2 with or without IFN-α pretreatment. (C) Quantification of the synergistic effect score of the interaction between Dex and CMPD2 on IL-6 inhibition in PBMCs (untreated or pretreated with IFNα) 16 hours after R848 stimulation in a Combefit Loewe matrix plot (area under the curve). Panels (AC) show pooled data from 5 donors. In (A) and (B), data have been normalized to R848-stimulated controls. Paired t-test: **p<0.005.

[0017] Figure 5 The ability of CMPD2 to reverse the reduction in Dex potency caused by IFN-α pretreatment is shown. Dose-response curves for the effect of Dex alone or in combination with different doses of CMPD2 on IL-6 16 hours after R848 stimulation, without (A) or with (B) IFN-α pretreatment. Combenefit analysis shows a Loewe matrix plot of the interaction between Dex and CMPD2 on IL-6 inhibition in R848-stimulated cells 16 hours after R848 stimulation, without (B) or with (D) IFNα pretreatment. For (A) and (C), data have been normalized to R848 control and data from 5 donors are pooled.

[0018] Figure 6Patient-derived immune complexes activate TLR7 / 8 in human PBMCs. IgG was isolated from plasma samples from HC patients and patients with SLE, LN, IBM, PM, and DM and combined with necrotic cell lysates to form immune complexes, which were used to stimulate healthy donor PBMCs. A) After 24 hours of treatment, supernatants were collected from PBMCs and IFN-α levels were measured using an AlphaLISA. The mean of 2–4 experiments for each IgG is shown; each symbol represents a single IgG sample. B) For samples with stimulatory activity, PBMCs were pretreated with empatoplastin for 30 minutes before immune complexes were added to the cells, and IFN-α was measured 24 hours after treatment. All IgG samples were tested using 2–4 healthy donor PBMCs. DM dermatomyositis, HC healthy controls, IBM inclusion body myositis, IC immune complexes, IFN-α interferon-α, IgG immunoglobulin G, PBMC peripheral blood mononuclear cells, PM polymyositis, SLE systemic lupus erythematosus, TLR7 / 8 toll-like receptor 7 / 8.

[0019] Figure 7 shows changes in gene expression induced by patient-derived immune complexes. IgG was isolated from plasma samples of HC and patients with SLE, LN, IBM, PM, and DM, then combined with necrotic cell lysates to form immune complexes for stimulation of healthy donor PBMCs. After 24 hours of treatment, cells were collected and analyzed by NanoString to measure changes in gene expression. A) Heat map shows Log2 FC compared to HC IgG samples. Each column represents an individual IgG sample, with patient groups indicated by shading. Samples that stimulate IFN-α protein production are indicated by black bars above the columns. B) IFN-I signature scores were calculated using the ISGs shown in the heat map, and scores were plotted for each individual sample. For each IgG sample, data were averaged from independent experiments performed using two PBMC donors. DM dermatomyositis, FC fold change, HC healthy control, IBM inclusion body myositis, IFN-α interferon-α, IgG immunoglobulin G, ISG interferon-stimulated genes, PBMC peripheral blood mononuclear cells, PM polymyositis, SLE systemic lupus erythematosus. DETAILED DESCRIPTION

[0020] Each embodiment described herein can be combined with any other embodiment described herein, as long as they do not conflict with each other. In addition, unless incompatible with the given context, as long as it is specified that the compound is capable of ionization (e.g., protonation or deprotonation), the definition of the compound includes any pharmaceutically acceptable salt thereof. Therefore, all compounds described herein implicitly include "or a pharmaceutically acceptable salt thereof."

[0021] The present invention can be more easily understood based on the detailed description above and below of specific and preferred embodiments and the examples included herein. It should be understood that all terms herein are only for describing specific embodiments and are not intended to be limiting. It should also be understood that, unless specifically defined herein, the terms used herein will be given their conventional meanings known in the relevant art. In order to make the present invention easier to understand, certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs. General Definition

[0022] Unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" include plural referents. Thus, "a", "one or more", and "at least one" can be used interchangeably.

[0023] The term "about" when used to modify a parameter defined by a numerical value indicates the smallest change in the parameter that does not alter the overall effect (e.g., the efficacy of a drug in treating a disease or disorder). In some embodiments, the term "about" indicates that the parameter can be within a range of 10% above or below the value recited for the parameter.

[0024] The term "about" when used to refer to a value (e.g., an upper range limit or a reference value, such as a reference IFN-1 activity or a reference IFN-1 signature score) refers to any value that is reasonably close to the value. For example, any value that is greater than the 90th or 95th percentile. In some embodiments, "about" refers to an exact value.

[0025] "Administering" or "applying" a drug to a patient (including grammatically equivalent expressions of this phrase) refers to direct administration and / or indirect administration. The direct administration may be medication given to a patient by a medical professional or self-administration. The indirect administration may be prescription behavior, such as a physician instructing a patient to self-administer medication or issuing a drug prescription to a patient, which is also a doctor administering the drug to the patient. It should be understood that the therapeutic agent (e.g., TLR inhibitor) mentioned herein is administered in a therapeutically effective amount.

[0026] "Biomarkers" generally refer to biological molecules and their quantitative and qualitative indicators that indicate disease status. "Prognostic biomarkers" are related to disease outcome and have nothing to do with treatment. For example, tumor hypoxia is a negative prognostic marker. The higher the degree of tumor hypoxia, the higher the possibility of a negative disease outcome. "Predictive biomarkers" indicate whether a patient is likely to respond positively to a particular therapy. For example, HER2 typing is often used in breast cancer patients to determine whether these patients will respond to Herceptin (Trastuzumab, Genentech). "Response biomarkers" provide an indicator of response to therapy, thereby indicating whether the therapy is effective. For example, a decrease in prostate-specific antigen levels generally indicates that anti-cancer therapy for prostate cancer patients is effective. When identifying or selecting patients for treatment described herein based on a marker, the marker can be measured before and / or during treatment, and the resulting value is used by the clinician to assess any of the following: (a) whether the individual is likely to be suitable for starting treatment; and (b) whether the individual is likely to be unsuitable for starting treatment; (c) responsiveness to treatment; (d) whether the individual is likely to be suitable for continuing treatment; (e) whether the individual is likely to be unsuitable for continuing treatment; (f) dose adjustment; (g) predicted likelihood of clinical benefit; or (h) toxicity. As will be appreciated by those skilled in the art, measurement of a biomarker in a clinical setting clearly indicates that the parameter is used as the basis for initiating, continuing, adjusting, and / or stopping administration of a treatment described herein.

[0027] "Combination therapy" or "in combination with..." herein refers to the use of any form of concurrent, parallel, simultaneous, sequential or intermittent treatment of at least two different treatment modalities (i.e., compounds, ingredients, targeting agents, therapeutic agents or pharmaceutical agents). Therefore, the term refers to administering one treatment modality to a subject before, during or after administering another treatment modality to the subject. The modalities in the combination can be administered in any order. The therapeutically active modalities are administered together (e.g., simultaneously in the form of the same or separate compositions, formulations or dosage forms) or separately (e.g., on the same day or different days in any order that conforms to the respective appropriate dosing regimens of each composition, formulation or dosage form), and the mode of administration and dosing regimen are in accordance with the instructions of the medical staff or the regulations of the regulatory agency. Typically, various treatment modalities are administered according to the dose plan and / or time plan determined for the treatment modality. Optionally, four or more modalities can be used in the combination therapy. In addition, the combination therapy provided herein can be used in combination with other types of therapies. For example, other anti-cancer treatments can be selected from chemotherapy, surgery, radiotherapy (irradiation) and / or hormone therapy, and also include other therapies associated with the current standard of care for the subject.

[0028] As used herein, "comprising" is intended to indicate that the compositions and methods include the listed elements, but not to the exclusion of others. When used to define compositions and methods, "consisting essentially of" excludes other elements that are of any substantial significance to the compositions and methods. "Consisting of" excludes other components other than trace elements with respect to the claimed composition and excludes substantial method steps. Embodiments defined by each of these transitions are included within the scope of the present invention. Therefore, it should be understood that the methods and compositions may include additional steps and components (comprising) or optionally include insignificant steps and compositions (consisting essentially of) or include only the explicitly stated method steps or compositions (consisting of).

[0029] "Dose" and "dose" refer to a specific amount of an active substance or therapeutic agent for administration. Such an amount is contained in a "dosage form," which refers to physically discrete units suitable for single dosage amounts for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce the desired onset, tolerability, and therapeutic effect, in association with one or more suitable pharmaceutical excipients (e.g., carriers).

[0030] "IFN-I activity" refers to the level of activity of type I interferon. In some embodiments, IFN-I activity refers to the level of signal transduction activity of type I interferon as reflected, for example, by the expression level of ISG.

[0031] An "IFN-1 signature" refers to one or more genes whose expression is regulated by IFN-1 and whose expression pattern is reflective of IFN-1 activity.

[0032] "IFN-I signature score" means the arithmetic mean of the normalized expression levels of the genes in the IFN-I signature.

[0033] By "IFN-1 signature expression pattern" is meant the expression levels of the genes in the IFN-1 signature.

[0034] "Patient," "subject," and "individual" are used interchangeably herein to refer to a mammal in need of treatment for a disease or condition. Generally, a "patient," "subject," or "individual" is a human who has been diagnosed with, or is at risk for developing, one or more symptoms of a disease or condition. In some embodiments, a "patient," "subject," or "individual" may refer to a non-human mammal, such as a non-human primate, dog, cat, rabbit, pig, mouse, or rat, or an animal used, for example, to screen, characterize, and evaluate drugs and therapies.

[0035] "Pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or treatment of a mammal. "Pharmaceutically acceptable carriers" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate-buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof.

[0036] As used herein, "predictions," for example, of the therapeutic effect of a TLR inhibitor, the suitability of a patient to initiate TLR inhibitor therapy, or the suitability of a patient currently receiving TLR inhibitor therapy to continue therapy, merely provide an indication of the likelihood of a TLR inhibitor treatment outcome and do not accurately predict a treatment outcome. For example, a patient predicted to be therapeutically effective with a TLR inhibitor simply has a higher likelihood of being therapeutically effective, while a patient predicted not to be therapeutically effective with a TLR inhibitor simply has a lower likelihood of being therapeutically effective. Similarly, a patient predicted to be suitable for initiating TLR inhibitor therapy simply has a higher likelihood of being therapeutically effective with a TLR inhibitor, while a patient predicted not to be suitable for initiating TLR inhibitor therapy simply has a lower likelihood of being therapeutically effective with a TLR inhibitor. Similarly, a patient predicted to be suitable for continuing TLR inhibitor therapy simply has a higher likelihood of being therapeutically effective with a TLR inhibitor, while a patient predicted not to be suitable for continuing TLR inhibitor therapy simply has a lower likelihood of being therapeutically effective with a TLR inhibitor.

[0037] A "reference IFN-I activity," "reference IFN-I signature expression pattern," or "reference IFN-I signature score" allows for identification of patients who are more likely to respond to TLR inhibitor treatment and / or patients who are less likely to respond to TLR inhibitor treatment, e.g., based on comparing a reference IFN-I activity, a reference IFN-I signature expression pattern, or a reference IFN-I signature score to the IFN-I activity, IFN-I signature expression pattern, or IFN-I signature score of such patients. The IFN-I activity, IFN-I signature expression pattern, or IFN-I signature score indicates which treatment outcome depends on how the corresponding reference is defined. For example, a reference IFN-I activity or a reference IFN-I signature score can be defined to divide patients into those who are more likely to respond to TLR inhibitor treatment and those who are less likely to respond. In this case, patients whose IFN-I activity is higher than the reference IFN-I activity or whose IFN-I signature score is lower than the reference IFN-I signature score are more likely to respond to TLR inhibitor treatment than those whose IFN-I activity is lower than the reference IFN-I activity or whose IFN-I signature score is lower than the reference IFN-I signature score. Similarly, a reference IFN-I activity or a reference IFN-I signature score can be defined that is a characterization of a patient population that is more likely to respond to TLR inhibitor treatment, for example, the arithmetic mean or median of the IFN-I activity or IFN-I signature score in the patient population, and patients whose IFN-I activity or IFN-I signature score is close to or higher than the corresponding reference value are determined to be more likely to respond to treatment (and vice versa). Similarly, for example, if a patient's IFN-I signature gene expression is similar to the characteristic gene expression pattern of a patient population that is more likely to respond to TLR inhibitor treatment (i.e., the reference IFN-I signature expression pattern), then, similarly, the patient is more likely to respond to TLR treatment, and vice versa. It will be understood that the IFN-I signature of the reference IFN-I signature expression pattern or the reference IFN-I signature score is based on the same IFN-I signature as that used to determine the patient's (whose therapeutic outcome will be predicted according to the methods or uses of the invention) IFN-I signature expression pattern or IFN-I signature score. Those skilled in the art are well aware of how to define such reference IFN-I activity, reference IFN-I signature expression pattern or reference IFN-I signature score.For example, it can come from a post-hoc analysis of a patient population, wherein the IFN-I activity, IFN-I signature expression pattern or IFN-I signature score before treatment of different patients are compared with the treatment outcomes of different patients, thereby subsequently dividing the population into patients who are more effectively treated and patients who are less effectively treated, and, for example, defining a threshold value of IFN-I activity or IFN-I signature score to distinguish these patient populations, or defining an IFN-I activity, IFN-I signature score or IFN-I signature expression pattern characteristic of them for any one or both of these patient populations. The IFN-I activity, IFN-I signature expression pattern or IFN-I signature score thus defined can subsequently be used as a reference IFN-I activity, a reference IFN-I signature expression pattern and a reference IFN-I signature score, respectively. Similarly, a reference IFN-I activity, a reference IFN-I signature expression pattern or a reference IFN-I signature score can, for example, be derived from a healthy population, because a healthy population can be considered as a baseline or population with low IFN-I activity, because the IFN-I pathway is generally less active in healthy individuals. Thus, the IFN-I activity, IFN-I signature expression pattern, or IFN-I signature score of different individuals in such a healthy population can be determined, and the IFN-I activity or IFN-I signature score that is, for example, close to the upper limit of the determined range or corresponding to the arithmetic mean or median can be defined as a reference IFN-I activity or a reference IFN-I signature score, respectively. Similarly, the expression pattern of genes in the IFN-I signature that characterizes such a population can be defined as a reference IFN-I signature expression pattern. In some embodiments, having "high" IFN-I activity means that the IFN-I activity is higher than the reference IFN-I activity, for example, as reflected by an IFN-I signature score that is higher than the reference IFN-I signature score, and having "low" IFN-I activity means that the IFN-I activity is lower than the reference IFN-I activity, for example, as reflected by an IFN-I signature score that is lower than the reference IFN-I signature score.

[0038] As used herein, "sample" refers to any biological sample from an individual that allows determination of IFN-1 activity, such as determination of an IFN-1 signature expression pattern or an IFN-1 signature score. The sample may, for example, refer to individual body fluids, cells, and tissues. It may also refer to individual blood samples and extracted RNA.

[0039] "Small molecule" refers to a chemical compound, typically an organic compound, of low molecular weight (eg, a molecular weight ≤ 1000 Daltons or ≤ 900 Daltons).

[0040] A "therapeutically effective amount" of a therapeutic agent means an amount that, when used in a patient at the necessary dosage and for the necessary duration, will have the desired therapeutic effect, such as alleviation, improvement, alleviation or elimination of one or more disease or condition manifestations in the patient, or any other clinical outcome in the patient during treatment. The therapeutic effect does not necessarily occur after administration of a single dose, but may occur after administration of a series of doses. Therefore, a therapeutically effective amount can be administered in one or more administrations. This therapeutically effective amount can vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the ability of the therapeutic agent to elicit a desired response in the individual. A therapeutically effective amount also refers to an amount in which the therapeutically beneficial effects of the therapeutic agent outweigh any toxic or deleterious effects.

[0041] "Therapeutic effect" means a favorable therapeutic response, such as alleviation or amelioration of one or more disease symptoms; reduction in disease severity; delay or slowing of disease progression; improvement, remission, or stabilization of the disease state; or other beneficial results. For example, a therapeutic effect may refer to the time to recovery from a disease (e.g., COVID-19).

[0042] "TLR inhibitor" refers to a compound that inhibits the activity of one or more members of the human TLR protein family through a direct interaction between the TLR inhibitor and the TLR. TLR inhibitors can, for example, work by stabilizing TLRs in a resting, inactive state. In some embodiments, TLR inhibitors inhibit the activity of human TLR7 (also referred to as "TLR7 inhibitors"). In some embodiments, TLR inhibitors inhibit the activity of human TLR8 (also referred to as "TLR8 inhibitors"). In some embodiments, TLR inhibitors inhibit the activity of human TLR7 and / or TLR8 (also referred to as "TLR7 and / or TLR8 inhibitors"). In some embodiments, TLR inhibitors inhibit the activity of human TLR7 and TLR8 (also referred to as "TLR7 and TLR8 inhibitors"). In some embodiments, TLR inhibitors selectively inhibit human TLR7 and / or TLR8. TLR inhibitors can be, for example, small molecules, nucleic acids (e.g., oligonucleotides), or polypeptides (e.g., antibodies). In some embodiments, TLR inhibitors are small molecules. Possible effects of inhibiting TLR pathways include inhibiting inflammatory processes. The inhibition described herein does not have to be complete or 100% inhibition. In contrast, inhibition means reducing, decreasing or eliminating the activity of a TLR pathway or inflammatory process, respectively. Inhibition can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%, or statistically significant inhibition compared to a control. In some embodiments, a TLR inhibitor inhibits the IC 50The IC value is less than 10 μM, less than 2 μM, less than 1 μM, less than 250 nM, less than 100 nM, less than 50 nM or less than 25 nM. In some embodiments, the IC value is determined in HEK293 cells. 50 Value. In the exemplary scheme, HEK293 cells are stably transfected with TLR7 or TLR8 and NF-κB-luciferase reporter genes. In order to test TLR inhibitors, cells are seeded in 384-well black transparent bottom plates, incubated overnight at 37°C and 5% CO2, and TLR inhibitor dilutions (in duplicate) are added. HEK TLR7 or HEKTLR8 cells are then stimulated with 10 μM R848 or 30 μM R848 for testing. After incubation for 5 hours at 37°C and 5% CO2, SteadyGlo substrate reagent (Promega, Madison, Wisconsin) is added to each well, and the luminescence value is measured using an instrument such as a Perkin Elmer Envision Multilabel plate reader.

[0043] "Treatment" or "treatment" of a condition or patient refers to taking steps to obtain a beneficial or desired result, including a clinical outcome. For the purposes of this invention, a beneficial or desired clinical outcome includes, but is not limited to, alleviation or amelioration of one or more symptoms of a disease; reduction in the severity of the disease; delay or slowing of the progression of the disease; improvement, remission, or stabilization of the disease state; or other beneficial results. It is understood that references to "treating" or "treatment" include prevention as well as relief of existing symptoms. "Treatment" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the onset of the condition, disorder, or condition in a subject who may have or be susceptible to the condition, disorder, or condition but who does not yet experience or exhibit clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the onset, progression, or recurrence (in the case of maintenance therapy) of the condition, disorder, or condition, or at least one of its clinical or subclinical symptoms, or (3) resolving or ameliorating the condition, i.e., causing regression of the condition, disorder, or condition, or at least one of its clinical or subclinical symptoms.

[0044] Herein, for convenience, a plurality of items, structural elements, composition elements and / or materials may be presented together in lists, however, these lists should be understood as if each member of the list is individually identified as a separate and unique member.

[0045] Concentration, amount and other numerical data can be expressed or presented in the format of range in this article. It should be understood that such range format is only for simplicity and should therefore be flexibly interpreted as not only including the numerical values clearly recorded as range limits, but also including all individual numerical values or subranges within the range, just as each numerical value and subrange is clearly recorded. For example, the numerical range of "about 1 to about 5" should be understood as including not only the numerical values clearly recorded from about 1 to about 5, but also including individual numerical values and subranges within the range. Therefore, included in this numerical range are individual values, such as 2, 3 and 4, and subranges, such as from 1-3, 2-4 and 3-5, etc., as well as 1, 2, 3, 4 and 5. The same principle applies to the range of only listing a minimum or maximum value. And, no matter how the amplitude of the range or feature is recorded, this interpretation should be adopted. Compound Definition

[0046] For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, e.g., the CAS version, Handbook of Chemistry and Physics, 75th ed. In addition, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001.

[0047] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocycle," "cycloaliphatic," or "cycloalkyl") that is fully saturated or contains one or more unsaturated units but is non-aromatic, having a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units but is non-aromatic, having a single point of attachment to the rest of the molecule. Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0048] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, or phosphorus (including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0049] As used herein, the term "unsaturated" refers to a moiety having one or more units of unsaturation.

[0050] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain” refers to straight or branched divalent alkylene, alkenylene and alkynylene chains as defined herein.

[0051] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0052] The term "alkenylene" refers to a divalent alkenyl group. Substituted alkenylene chains are polymethylene groups containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0053] The term "halogen" refers to F, Cl, Br or I.

[0054] The term "aryl" used alone or as part of a larger group, such as "aralkyl", "aralkyloxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aromatic ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, etc., which optionally contain one or more substituents. The term "aryl" as used herein also includes within its scope groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl or tetrahydronaphthyl, etc.

[0055] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger group, such as "heteroaralkyl" or "heteroaralkoxy", refer to a group having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; sharing 6, 10 or 14 electrons in the cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. The terms "heteroaryl" and "heteroaryl-" as used herein also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclic rings, wherein the free radical or point of attachment is located on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido [2,3-b] -1,4-oxazine -3 (4H) -one. The heteroaryl group is optionally monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which encompass rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0056] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety which may be saturated or partially unsaturated and which has, in addition to carbon atoms, one or more (preferably 1 to 4) heteroatoms as defined above. The term "nitrogen" when used to refer to a ring atom of a heterocycle includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or + NR (as in N-substituted pyrrolidinyl).

[0057] The heterocyclic ring may be attached to any heteroatom or carbon atom of its pendant group so as to form a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepine, oxazolidinyl ... Oxazolin thiazolinone The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, wherein the radical or point of attachment is on the heterocyclyl ring. The heterocyclyl group is optionally monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl moieties are independently and optionally substituted.

[0058] As used herein, the term "partially unsaturated" refers to a ring moiety containing at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but does not include aryl or heteroaryl moieties as defined herein.

[0059] As described herein, certain compounds contain "optionally substituted (optionally substituted)" moieties. In general, the term "substituted," whether or not preceded by the term "optionally (optionally)," refers to the replacement of one or more hydrogen atoms of the designated moiety with a suitable substituent. "Substituted" is used when one or more hydrogen atoms are replaced, either explicitly or implicitly, in a structure (e.g., At least and At least Unless otherwise indicated, an "optionally substituted" group has a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein means that the compound does not undergo substantial alteration when subjected to conditions that allow its production, detection, and, in certain embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0060] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently deuterium; halogen; -(CH2); 0–4 R o ; –(CH2) 0–4 OR o ;-O(CH2) 0-4 R o 、–O–(CH2) 0–4 C(O)OR°;–(CH2) 0–4 CH(OR o )2;–(CH2) 0– 4SR o ; –(CH2) 0–4 Ph, which may be optionally substituted by R°; –(CH2) 0–4 O(CH2) 0–1 Ph, which may be optionally substituted by R°; –CH═CHPh, which may be optionally substituted by R°; –(CH2) 0–4 O(CH2) 0–1 -pyridinyl, which may be optionally substituted by R°; -NO2; -CN; -N3; -(CH2) 0–4 N(R o )2;–(CH2) 0–4 N(R o )C(O)R o ;–N(R o )C(S)R o ; –(CH2) 0–4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2;–(CH2) 0–4 N(R o )C(O)OR o ;–N(R o )N(R o )C(O)R o ;-N(Ro )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;–(CH2) 0–4 C(O)R o ;–C(S)R o ;–(CH2) 0–4 C(O)OR o ;–(CH2) 0–4 C(O)SR o ;-(CH2) 0–4 C(O)OSiR o 3;–(CH2) 0–4 OC(O)R o ;–OC(O)(CH2) 0–4 SR o 、SC(S)SR°;–(CH2) 0–4 SC(O)R o ;–(CH2) 0–4 C(O)NR o 2;–C(S)NR o 2;–C(S)SR°;–SC(S)SR°、-(CH2) 0–4 OC(O)NR o 2;-C(O)N(OR o )R o ;–C(O)C(O)R o ;–C(O)CH2C(O)R o ;–C(NOR o )R o ;-(CH2) 0–4 SSR o ;-(CH2) 0–4 S(O)2R o ;–(CH2) 0–4 S(O)2OR o ;–(CH2) 0–4 OS(O)2R o ;–S(O)2NR o 2;-(CH2) 0–4 S(O)R o ;-N(R o )S(O)2NR o 2;–N(R o )S(O)2R o ;–N(OR o )R o ;–C(NH)NRo 2;–P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;–OP(O)(OR o )2;SiR o 3;–(C 1–4 linear or branched alkylene)O–N(R o )2; or –(C 1–4 linear or branched alkylene) C(O)O–N(R o )2, where each R o may be optionally substituted as defined below and are independently hydrogen, C 1-6 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, -CH2-(5-6 membered heteroaromatic ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o Together with one or more atoms therebetween, they form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be optionally substituted as defined below.

[0061] R o (or two independent occurrences of R o Suitable monovalent substituents on the ring formed by the atoms therebetween are independently deuterium, halogen, –(CH2) 0–2 R · 、–(halogenated R · ),–(CH2) 0–2 OH, –(CH2) 0–2 OR · 、–(CH2) 0–2 CH(OR · )2;-O(halogenated R · ), –CN, –N3, –(CH2) 0–2 C(O)R · 、–(CH2) 0–2 C(O)OH, –(CH2) 0–2 C(O)OR · 、–(CH2) 0–2 SR · 、–(CH2) 0– 2SH, –(CH2) 0–2 NH2, –(CH2) 0–2 NHR · 、–(CH2) 0–2 NR· 2. –NO2, –SiR · 3. –OSiR · 3. -C(O)SR · 、–(C 1–4 linear or branched alkylene)C(O)OR · or –SSR · , where each R · is unsubstituted, or when preceded by "halogen / halo", is substituted only by one or more halogens, and is independently selected from C 1-4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0062] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2. =NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、–O(C(R * 2)) 2–3 O–or–S(C(R * 2)) 2–3 S-, wherein each independent occurrence of R* is selected from hydrogen, C substituted as defined below 1-6 An aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to an ortho-substitutable carbon atom of an "optionally substituted" group include: -O(CR * 2) 2–3 O-, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0063] Suitable substituents on the aliphatic group of R* include halogen, –R · 、-(halogenated R · ),-OH, –OR · 、–O(halogenated R · ), –CN, –C(O)OH, –C(O)OR· , –NH2, –NHR · ,–NR · 2 or –NO2, where each R · is unsubstituted, or when preceded by "halo" is substituted only by one or more halogens, and is independently C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0064] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include Each of them is independently hydrogen, optionally substituted as defined below 1-6 aliphatic, unsubstituted -OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two independent occurrences of Together with one or more atoms therebetween, they form an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0065] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogenated R · ),-OH, –OR · 、–O(halogenated R · ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · ,–NR · 2 or –NO2, where each R · is unsubstituted, or when preceded by "halo" is substituted only by one or more halogens, and is independently C 1–4 Aliphatic, –CH2Ph, –O(CH2) 0–1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0066] In certain embodiments, the terms "optionally substituted," "optionally substituted alkyl," "optionally substituted alkenyl," "optionally substituted alkynyl," "optionally substituted carbocyclyl," "optionally substituted aryl," "optionally substituted heteroaryl," "optionally substituted heterocyclyl," and any other optionally substituted groups as used herein refer to groups that are substituted or unsubstituted by independently replacing one, two, or three or more hydrogen atoms thereon with typical substituents, including but not limited to: -F, -Cl, -Br, -I, deuterium, -OH, protected hydroxy, alkoxy, oxo, thiooxo, -NO2, -CN, CF3, N3, -NH2, protected amino, -NH alkyl, -NH alkenyl, -NH alkynyl, -NH cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocyclyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclyl, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkynyl, -C(O)-carbocyclyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl, -CONH2, -CONH-alkyl, -CONH-alkenyl, -CONH-alkynyl, -CONH-carbocyclyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl, -OCO2-alkyl, -OCO2-alkenyl, -OCO2-alkynyl, -OCO2-carbocyclyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocyclyl, -OCONH2, -OCONH-alkyl, -OCONH-alkenyl, -OCONH-alkynyl, -OCONH-carbocyclyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclyl, -NHC(O)-alkyl, -NHC(O)-alkenyl, -NHC(O)-alkynyl, -NHC(O)-carbocyclyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclyl, -NHCO2-alkyl, -NHCO2-alkenyl, -NHCO2-alkynyl, -NHCO2-carbocyclyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocyclyl, -NHC(O)NH2, -NHC(O)NH-alkyl, -NHC(O)NH-alkenyl, -NHC(O)NH-alkenyl, -NHC(O)NH-carbocyclyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocyclyl, NHC(S)NH2, -NHC(S)NH-alkyl, -NHC(S)NH-alkenyl, -NHC(S)NH-alkynyl, -NHC(S)NH-carbocyclyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocyclyl, -NHC(NH)NH2, -NHC(NH)NH-alkyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH-carbocyclyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocyclyl, -NHC(NH)-alkyl, -NHC(NH)-alkenyl, -NHC(NH)-alkenyl, -NHC(NH)NH-carbocyclyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocyclyl, -NHC(NH)-alkyl, -NHC(NH)-alkenyl, -NHC(NH)-alkenyl, -NHC(NH)-carbocyclyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocyclyl, -C(NH)NH-alkyl, -C(NH)NH-alkenyl, -C(NH)NH-alkynyl, -C(NH)NH-carbocyclyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocyclyl, -S(O)-alkyl, -S(O)-alkenyl, -S(O)-alkynyl, -S(O)-carbocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocyclyl-SO2NH2, -SO2NH-alkyl, -SO2NH-alkenyl, -SO2NH-alkynyl, -SO2NH-carbocyclyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocyclyl, -NHSO2-alkyl, -NHSO2-alkenyl, -NHSO2-alkynyl, -NHSO2-carbocyclyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocyclyl, -CH2NH2, -CH2SO2CH3, -mono-, di- or tri-alkylsilyl groups, -alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic, -heterocyclyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl, -S-alkenyl, -S-alkynyl, -S-carbocyclyl, -S-aryl, -S-heteroaryl, -S-heterocyclyl, or methylthiomethyl.

[0067] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19. Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts 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 adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconoheptate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, dodecylsulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0068] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, 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.

[0069] Unless otherwise indicated, the structures and compounds described herein are also meant to include all isomeric (e.g., enantiomers, diastereomers, and geometric (or conformational)) forms of the structures; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds described herein are within the scope of the present invention.

[0070] Furthermore, unless otherwise stated, structures and compounds described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures include the replacement of hydrogen with deuterium or tritium, or the replacement of hydrogen with an isotopically enriched atom. 13 C- or 14 In some embodiments, the group comprises one or more deuterium atoms.

[0071] In addition, unless otherwise indicated, reference to a compound herein includes isotopically labeled forms thereof. An isotopically labeled form of a compound referred to herein is identical to the compound except that one or more atoms of the compound have been replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that are readily commercially available and can be incorporated into the compounds by known methods include 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 Cl. Compounds described herein containing one or more of the above isotopes and / or other isotopes of other atoms, their prodrugs or pharmaceutically acceptable salts thereof are intended to be part of the present invention. Isotopically labeled compounds have a variety of beneficial uses. For example, the incorporation of radioactive isotopes (e.g. 3 H or 14 C) isotope-labeled compounds are useful in drug and / or substrate tissue distribution assays. These radioactive isotopes, namely tritium ( 3 H) and carbon-14 ( 14 C), are particularly preferred due to their ease of preparation and excellent detectability. 2H)) incorporation into a compound has therapeutic advantages because such isotopically labeled compounds have greater metabolic stability. Greater metabolic stability translates directly into an increase in in vivo half-life or a reduction in dosage, which in most cases represents a preferred embodiment of the present invention. Isotopically labeled compounds can generally be prepared by following the steps disclosed in the synthetic schemes and associated descriptions in the Examples and Preparations sections herein, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0072] Deuterium ( 2 H) is incorporated into the compounds described herein to manipulate the oxidative metabolism of the compounds through the primary kinetic isotope effect. The primary kinetic isotope effect refers to the change in the rate of a chemical reaction caused by isotopic nuclear exchange, which in turn is caused by the change in the ground state energy required to form a covalent bond after the isotope exchange. The exchange of heavier isotopes generally results in a decrease in the ground state energy of the chemical bond, thereby reducing the rate of rate-limiting bond breaking. If the bond breakage occurs in or near the saddle-point region of the multi-product reaction coordinate system, the product distribution rate may change significantly. The specific explanation is as follows: If deuterium is bonded to a carbon atom in a non-exchangeable position, the rate difference is generally k M / k D = 2-7. If this reaction rate difference is successfully applied to easily oxidizable compounds, the in vivo distribution of the compound can be greatly changed, thereby improving the pharmacokinetic properties.

[0073] When discovering and developing therapeutic drugs, those skilled in the art are able to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic properties are susceptible to oxidative metabolism. Currently available in vitro liver microsome assays provide valuable information about such oxidative metabolic processes, making it possible to rationally design deuterated compounds that improve stability by resisting such oxidative metabolism. This can significantly improve the pharmacokinetic properties of compounds and improve their efficacy by in vivo half-life (t / 2), maximum therapeutic concentration (C 最大值 ), increases in the area under the dose-response curve (AUC), and F; and reductions in clearance, dose, and material cost.

[0074] The following illustrates this: A compound with multiple potential sites of oxidative metabolic attack, such as benzylic hydrogen atoms and nitrogen-bonded hydrogen atoms, is prepared as a series of analogs in which various combinations of these hydrogen atoms are replaced with deuterium atoms, such that some, most, or all of the hydrogen atoms are replaced with deuterium atoms. Half-life determination can advantageously and reliably determine the extent of the improvement in antioxidant metabolic capacity. In this way, it can be determined that the half-life of the parent compound can be extended by up to 100% due to this type of deuterium-hydrogen exchange.

[0075] Deuterium-hydrogen exchange in a compound can also be used to achieve favorable modifications of the metabolic profile of the starting compound to reduce or eliminate undesirable toxic metabolites. For example, if toxic metabolites are produced by oxidative carbon-hydrogen (C-H) bond cleavage, it is reasonable to assume that deuterated analogs will greatly reduce or eliminate the production of undesirable metabolites, even if the specific oxidation is not the rate-limiting step. For more information on the state of the art of deuterium-hydrogen exchange, see, for example, Hanzlik et al., J.Org.Chem.55,3992-3997,1990, Reider et al., J.Org.Chem.52,3326-3334,1987, Foster, Adv.Drug Res.14,1-40,1985, Gillette et al., Biochemistry 33(10)2927-2937,1994 and Jarman et al. Carcinogenesis 16(4),683-688,1993.

[0076] The variants and combinations of substituents contemplated by the present invention are those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that are sufficiently stable to allow manufacture and that maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0077] Reference to a list of groups in any definition of a variable herein includes definitions of that group as any single element or combination of listed groups. Reference to an embodiment for a variation herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof. How to use

[0078] The present invention relates to the use of IFN-I activity as a predictive biomarker, which refers to a predictive biomarker for treating an individual with a disease or condition using a TLR inhibitor. Specifically, it has been found that TLR inhibitors are more likely to have a therapeutic effect on individuals with high IFN-I activity. IFN-I activity can be indirectly determined by measuring IFN-I expression levels through, for example, the PBMC assay outlined in Example 4, or by an IFN-I signature reflecting IFN-I activity. Subsequently, such IFN-I signatures can be used to determine an IFN-I signature score or an IFN-I signature expression pattern, and by comparing with a reference IFN-I signature score or a reference IFN-I signature expression pattern, it can be determined whether the individual's IFN-I activity is high or low. Such biomarker information can be used, for example, to predict the suitability of a patient's initial TLR inhibitor treatment, the suitability of a patient's continued TLR inhibitor treatment, and the likelihood of a patient receiving a clinical benefit when receiving a TLR inhibitor treatment.

[0079] Furthermore, the present inventors have found that administration of TLR inhibitors increases the efficacy of glucocorticoids even in the presence of IFN-α pretreatment.

[0080] Therefore, provided herein are methods for predicting the therapeutic effect of TLR inhibitors in patients, predicting the suitability of sick individuals starting to use TLR inhibitors for treatment, predicting the suitability of patients continuing to use TLR inhibitors for treatment, and / or using TLR inhibitors to treat patients based on determining IFN-1 activity. In addition, provided herein are methods for predicting the therapeutic effect of TLR inhibitors and corticosteroids in patients, predicting the suitability of sick individuals starting to use TLR inhibitors and corticosteroids for treatment, predicting the suitability of patients continuing to use TLR inhibitors and corticosteroids for treatment, and / or using TLR inhibitors and corticosteroids combination treatment patients based on determining IFN-1 activity.

[0081] Provided herein is a method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the therapeutic effect of the TLR inhibitor. In some embodiments, if the individual has high IFN-I activity, the TLR inhibitor is predicted to have a therapeutic effect. In some embodiments, the IFN-I activity is compared with a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the TLR inhibitor is predicted to have a therapeutic effect on the individual; if the individual's IFN-I activity is lower than the reference IFN-I activity, the TLR inhibitor is predicted to have no therapeutic effect on the individual. In some embodiments, the reference IFN-I activity is selected to distinguish individuals who are more likely to have a therapeutic effect from individuals who are less likely to have a therapeutic effect, and therefore, if the individual's IFN-I activity is higher than the reference IFN-I activity, the individual is predicted to have a therapeutic effect; if the individual's IFN-I activity is lower than the reference IFN-I activity, the individual is predicted to have no therapeutic effect. In some embodiments, a reference IFN-1 activity indicates treatment effectiveness, and thus, if the individual's IFN-1 activity is similar to or higher than the reference IFN-1 activity, then the treatment is predicted to be effective for the individual. In some embodiments, a reference IFN-1 activity indicates treatment ineffectiveness, and thus, if the individual's IFN-1 activity is similar to or lower than the reference IFN-1 activity, then the treatment is predicted to be ineffective for the individual.

[0082] Provided herein is a method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining an IFN-I characteristic expression pattern in a sample from an individual, wherein the IFN-I characteristic expression pattern in the sample indicates the therapeutic effect of the TLR inhibitor. In some embodiments, the IFN-I characteristic expression pattern is compared with one or more reference IFN-I characteristic expression patterns. In some embodiments, the reference IFN-I characteristic expression pattern indicates therapeutic effectiveness, and therefore, the therapeutic effectiveness is predicted by the correlation between the determined IFN-I characteristic expression pattern and the reference IFN-I characteristic expression pattern, and the absence of the correlation between the determined IFN-I characteristic expression pattern and the reference IFN-I characteristic expression pattern is predicted to be therapeutic effectiveness. In some embodiments, the reference IFN-I characteristic expression pattern indicates a absence of therapeutic effectiveness, and therefore, the therapeutic effectiveness is predicted by the lack of correlation between the determined IFN-I characteristic expression pattern and the reference IFN-I characteristic expression pattern, and the absence of therapeutic effectiveness is predicted by the correlation between the determined IFN-I characteristic expression pattern and the reference IFN-I characteristic expression pattern. In some embodiments, there is a first reference IFN-I signature expression pattern indicative of therapeutic effectiveness of a TLR inhibitor and a second reference IFN-I signature expression pattern indicative of a lack of therapeutic effectiveness of the TLR inhibitor, and if there is a correlation between the determined IFN-I signature expression pattern and the first reference IFN-I signature expression pattern, then the TLR inhibitor is predicted to be therapeutically effective for the individual, and if there is a correlation between the determined IFN-I signature expression pattern and the second reference IFN-I signature expression pattern, then the TLR inhibitor is predicted to be not therapeutically effective for the individual.

[0083] Also provided herein is a method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining an IFN-I signature score in a sample from the individual, wherein the IFN-I signature score in the sample indicates a therapeutic effect. In some embodiments, if the determined IFN-I signature score is higher than a reference IFN-I signature score, the TLR inhibitor is predicted to have a therapeutic effect in the individual; if the determined IFN-I signature score is lower than the reference IFN-I signature score, the TLR inhibitor is predicted to not have a therapeutic effect in the individual. In some embodiments, the reference IFN-I signature score is selected to distinguish individuals who are more likely to have a therapeutic effect from individuals who are less likely to have a therapeutic effect. Therefore, if the individual's IFN-I signature score is higher than the reference IFN-I signature score, the individual is predicted to have a therapeutic effect; if the individual's IFN-I signature score is lower than the reference IFN-I signature score, the individual is predicted to not have a therapeutic effect. In some embodiments, the reference IFN-I signature score indicates the effectiveness of the treatment. Therefore, if the individual's IFN-I signature score is similar to or higher than the reference IFN-I signature score, the treatment is predicted to be effective for the individual. In some embodiments, a reference IFN-I signature score is indicative of treatment ineffectiveness, and thus, if an individual's IFN-I signature score is similar to or lower than the reference IFN-I signature score, then the individual is predicted to be ineffective for treatment.

[0084] In some embodiments of any of the methods for predicting the therapeutic effectiveness of a TLR inhibitor in an individual having a disease disclosed herein, the TLR inhibitor is administered to the individual if therapeutic effectiveness is predicted for such individual.

[0085] Also provided herein is a method for predicting the suitability of a sick individual to initiate TLR inhibitor therapy, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the suitability of the individual to initiate the therapy. In some embodiments, individuals with high IFN-I activity are assessed as suitable for initiating therapy. In some embodiments, IFN-I activity is compared with a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the individual is assessed to be suitable for initiating therapy, and if the individual's IFN-I activity is lower than the reference IFN-I activity, the individual is assessed to be unsuitable for initiating therapy. In some embodiments, the reference IFN-I activity is selected to distinguish individuals who are more likely to have a therapeutic effect from individuals who are less likely to have a therapeutic effect, and therefore, if the individual's IFN-I activity is higher than the reference IFN-I activity, the individual is predicted to be suitable for initiating therapy using a TLR inhibitor, and if the individual's IFN-I activity is lower than the reference IFN-I activity, the individual is predicted to be unsuitable for initiating therapy using a TLR inhibitor. In some embodiments, a reference IFN-I activity indicates treatment effectiveness, and thus, if an individual's IFN-I activity is similar to or higher than the reference IFN-I activity, then the individual is predicted to be suitable for initiating treatment with a TLR inhibitor. In some embodiments, a reference IFN-I activity indicates treatment ineffectiveness, and thus, if an individual's IFN-I activity is similar to or lower than the reference IFN-I activity, then the individual is predicted to be unsuitable for initiating treatment with a TLR inhibitor.

[0086] Also provided herein is a method for predicting the suitability of a sick individual to initiate TLR inhibitor treatment, comprising determining an IFN-I signature expression pattern in a sample from the individual, wherein the IFN-I signature expression pattern in the sample indicates the suitability of the individual to initiate the treatment. In some embodiments, the IFN-I signature expression pattern is compared with one or more reference IFN-I signature expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates the suitability of initiating treatment with a TLR inhibitor, and therefore, the suitability of initiating treatment is indicated by the correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, and the lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern indicates that initiating treatment lacks suitability. In some embodiments, the reference IFN-I signature expression pattern indicates the lack of suitability of initiating treatment with a TLR inhibitor, and therefore, the suitability of initiating treatment is indicated by the lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, and the lack of suitability of initiating treatment is indicated by the correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern. In some embodiments, there is a first reference IFN-I signature expression pattern indicating the suitability of an individual to initiate treatment with a TLR inhibitor and a second reference IFN-I signature expression pattern indicating the unsuitability of the individual to initiate treatment with a TLR inhibitor, and if there is a correlation between the determined IFN-I signature expression pattern and the first reference IFN-I signature expression pattern, the individual is assessed as suitable for initiating the treatment, and if there is a correlation between the determined IFN-I signature expression pattern and the second reference IFN-I signature expression pattern, the individual is assessed as unsuitable for initiating the treatment.

[0087] Also provided herein is a method for predicting the suitability of a diseased individual to initiate TLR inhibitor therapy, comprising determining an IFN-I signature score in a sample from the individual, wherein the IFN-I signature score in the sample indicates the suitability of the individual to initiate the therapy. In some embodiments, if the determined IFN-I signature score is higher than a reference IFN-I signature score, the individual is assessed as suitable for initiating the therapy; if the determined IFN-I signature score is lower than the reference IFN-I signature score, the individual is assessed as unsuitable for initiating the therapy. In some embodiments of any method disclosed herein for predicting the suitability of initiating TLR inhibitor therapy for a diseased individual, if the individual is assessed as suitable for initiating the therapy, the individual is administered a TLR inhibitor. In some embodiments, the reference IFN-I signature score is selected to distinguish individuals who are more likely to respond to therapy from individuals who are less likely to respond to therapy, and thus, if the individual's IFN-I signature score is higher than the reference IFN-I signature score, the individual is predicted to be suitable for initiating therapy with a TLR inhibitor, and if the individual's IFN-I signature score is lower than the reference IFN-I signature score, the individual is predicted to be unsuitable for initiating therapy with a TLR inhibitor. In some embodiments, a reference IFN-I signature score is indicative of treatment effectiveness, and thus, if an individual's IFN-I signature score is similar to or higher than the reference IFN-I signature score, then the individual is predicted to be suitable for initiating treatment with a TLR inhibitor. In some embodiments, a reference IFN-I signature score is indicative of treatment ineffectiveness, and thus, if an individual's IFN-I signature score is similar to or lower than the reference IFN-I signature score, then the individual is predicted to be unsuitable for initiating treatment with a TLR inhibitor.

[0088] Also provided herein is a method for predicting the suitability of a sick individual receiving TLR inhibitor treatment to continue the treatment, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the suitability of the individual to continue the treatment. In some embodiments, an individual with high IFN-I activity is assessed as suitable for continuing treatment. In some embodiments, the IFN-I activity is compared with a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the individual is assessed to be suitable for continuing the treatment, and if the individual's IFN-I activity is lower than the reference IFN-I activity, the individual is assessed to be unsuitable for continuing the treatment. In some embodiments, the reference IFN-I activity is selected to distinguish individuals who are more likely to have a therapeutic effect from individuals who are less likely to have a therapeutic effect, and therefore, if the individual's IFN-I activity is higher than the reference IFN-I activity, the individual is predicted to be suitable for continuing treatment with a TLR inhibitor, and if the individual's IFN-I activity is lower than the reference IFN-I activity, the individual is predicted to be unsuitable for continuing treatment with a TLR inhibitor. In some embodiments, a reference IFN-I activity indicates treatment effectiveness, and thus, if an individual's IFN-I activity is similar to or higher than the reference IFN-I activity, then the individual is predicted to be suitable for continued treatment with a TLR inhibitor. In some embodiments, a reference IFN-I activity indicates treatment ineffectiveness, and thus, if an individual's IFN-I activity is similar to or lower than the reference IFN-I activity, then the individual is predicted to be unsuitable for continued treatment with a TLR inhibitor.

[0089] The present invention provides a method for predicting the suitability of a sick individual who is receiving TLR inhibitor treatment to continue the treatment, comprising determining an IFN-I signature expression pattern in a sample from the individual, wherein the IFN-I signature expression pattern in the sample indicates the suitability of the individual to continue the treatment. In some embodiments, the IFN-I signature expression pattern is compared with one or more reference IFN-I signature expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates the suitability of continuing treatment with a TLR inhibitor, and thus, the suitability of continuing treatment is indicated by the correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, and the lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern indicates the lack of suitability of continuing treatment. In some embodiments, the reference IFN-I signature expression pattern indicates a lack of suitability for continued treatment with a TLR inhibitor, and thus, suitability for continued treatment is indicated by a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, and lack of suitability for continued treatment is indicated by a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern. In some embodiments, there is a first reference IFN-I signature expression pattern that indicates suitability for continued treatment with a TLR inhibitor for an individual and a second reference IFN-I signature expression pattern that indicates unsuitability for continued treatment with a TLR inhibitor for an individual, and if there is a correlation between the determined IFN-I signature expression pattern and the first reference IFN-I signature expression pattern, the individual is assessed as suitable for continuing the treatment, and if there is a correlation between the determined IFN-I signature expression pattern and the second reference IFN-I signature expression pattern, the individual is assessed as unsuitable for continuing the treatment.

[0090] The present invention also provides a method for predicting the suitability of a sick individual who is receiving a TLR inhibitor treatment to continue the treatment, comprising determining an IFN-I signature score in a sample from the individual, wherein the IFN-I signature score in the sample indicates the suitability of the individual to continue the treatment. In some embodiments, if the determined IFN-I signature score is higher than a reference IFN-I signature score, the individual is assessed as suitable for continuing the treatment; if the determined IFN-I signature score is lower than a reference IFN-I signature score, the individual is assessed as unsuitable for continuing the treatment. In some embodiments of any method for predicting the suitability of a sick individual who is receiving a TLR inhibitor treatment for continuing to receive a treatment disclosed herein, if the individual is assessed as suitable for continuing the treatment, the TLR inhibitor is administered to the individual. In some embodiments, a reference IFN-I signature score is selected to distinguish individuals who are more likely to have a therapeutic effect from individuals who are less likely to have a therapeutic effect, and therefore, if the individual's IFN-I signature score is higher than the reference IFN-I signature score, the individual is predicted to be suitable for continued treatment with a TLR inhibitor, and if the individual's IFN-I signature score is lower than the reference IFN-I signature score, the individual is predicted to be unsuitable for continued treatment with a TLR inhibitor. In some embodiments, a reference IFN-I signature score indicates treatment effectiveness, and therefore, if the individual's IFN-I signature score is similar to or higher than the reference IFN-I signature score, the individual is predicted to be suitable for continued treatment with a TLR inhibitor. In some embodiments, a reference IFN-I signature score indicates treatment ineffectiveness, and therefore, if the individual's IFN-I signature score is similar to or lower than the reference IFN-I signature score, the individual is predicted to be unsuitable for continued treatment with a TLR inhibitor.

[0091] Also provided herein is a method for treating an individual disease with a TLR inhibitor, comprising administering the TLR inhibitor to the individual, wherein the treatment is based on IFN-I activity in a sample from the individual. In some embodiments, the TLR inhibitor is administered to an individual with high IFN-I activity. In some embodiments, the IFN-I activity is compared to a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the TLR inhibitor is administered to the individual. In some embodiments, the reference IFN-I activity is selected to distinguish individuals who are more likely to have a therapeutic effect from individuals who are less likely to have a therapeutic effect, so if the individual's IFN-I activity is higher than the reference IFN-I activity, the TLR inhibitor is administered to the individual; if the individual's IFN-I activity is lower than the reference IFN-I activity, the TLR inhibitor is not administered to the individual. In some embodiments, the reference IFN-I activity indicates the effectiveness of the treatment, so if the individual's IFN-I activity is similar to or higher than the reference IFN-I activity, the TLR inhibitor is administered to the individual. In some embodiments, the reference IFN-1 activity is indicative of treatment ineffectiveness, and thus, a TLR inhibitor is not administered to an individual if the individual's IFN-1 activity is similar to or lower than the reference IFN-1 activity.

[0092] Provided herein is a method for treating a disease in an individual with high IFN-I activity using a TLR inhibitor, comprising administering the TLR inhibitor to the individual. Also provided herein is a method for treating an individual disease using a TLR inhibitor, comprising administering the TLR inhibitor to the individual, wherein treatment is based on the IFN-I characteristic expression pattern in a sample from the individual. In some embodiments, the IFN-I characteristic expression pattern is compared with one or more reference IFN-I characteristic expression patterns. In some embodiments, the administration of a TLR inhibitor is indicated with reference to an IFN-I characteristic expression pattern, and therefore, if there is a correlation between the determined IFN-I characteristic expression pattern and the reference IFN-I characteristic expression pattern, the TLR inhibitor is administered, and if the lack of correlation between the determined IFN-I characteristic expression pattern and the reference IFN-I characteristic expression pattern is determined, the TLR inhibitor is not administered. In some embodiments, the reference IFN-I signature expression pattern indicates that a TLR inhibitor is not administered, and thus, if there is a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is administered, and if there is a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is not administered. In some embodiments, there is a first reference IFN-I signature expression pattern that indicates administration of a TLR inhibitor and a second reference IFN-I signature expression pattern that indicates not administration of a TLR inhibitor, and if there is a correlation between the determined IFN-I signature expression pattern and the first reference IFN-I signature expression pattern, the TLR inhibitor is administered, and if there is a correlation between the determined IFN-I signature expression pattern and the second reference IFN-I signature expression pattern, the TLR inhibitor is not administered.

[0093] Also provided herein is a method for treating an individual disease with a TLR inhibitor, comprising administering the TLR inhibitor to the individual, wherein treatment is based on an IFN-I signature score in a sample from the individual. In some embodiments, if the IFN-I signature score in the individual's sample is higher than a reference IFN-I signature score, the TLR inhibitor is administered to the individual. Also provided herein is a method for treating an individual disease with a TLR inhibitor, comprising determining an IFN-I signature score in a sample from the individual, and if the IFN-I signature score is higher than a reference IFN-I signature score, the TLR inhibitor is administered to the individual. In some embodiments, the reference IFN-I signature score is selected to distinguish individuals who are more likely to have a therapeutic effect from individuals who are less likely to have a therapeutic effect, therefore, if the individual's IFN-I signature score is higher than a reference IFN-I signature score, the TLR inhibitor is administered to the individual; if the individual's IFN-I signature score is lower than a reference IFN-I signature score, the TLR inhibitor is not administered to the individual. In some embodiments, a reference IFN-I signature score indicates treatment effectiveness, and thus, if the individual's IFN-I signature score is similar to or higher than the reference IFN-I signature score, a TLR inhibitor is administered to the individual. In some embodiments, a reference IFN-I signature score indicates treatment ineffectiveness, and thus, if the individual's IFN-I signature score is similar to or lower than the reference IFN-I signature score, a TLR inhibitor is administered to the individual.

[0094] Also provided herein is a method for treating an individual disease with a TLR inhibitor, comprising selecting a patient whose IFN-I signature score is higher than a reference IFN-I signature score, and administering the TLR inhibitor to the individual. Also provided herein is a method for treating an individual disease with a TLR inhibitor, comprising selecting a patient whose IFN-I signature score is higher than a reference IFN-I signature score, wherein the selection is to distinguish an individual who is more likely to have a therapeutic effect from an individual who is less likely to have a therapeutic effect, and administering the TLR inhibitor to the individual. Also provided herein is a method for treating an individual disease with a TLR inhibitor, comprising administering the TLR inhibitor to the individual, wherein the individual's sample has an IFN-I signature score higher than a reference IFN-I signature score. Also provided herein is a method for treating an individual disease with a TLR inhibitor, comprising administering the TLR inhibitor to the individual, wherein the IFN-I signature score in the sample from the individual is higher than the reference IFN-I signature score, and the selection is to distinguish an individual who is more likely to have a therapeutic effect from an individual who is less likely to have a therapeutic effect.

[0095] Also provided herein is a method for treating an individual disease, comprising administering the TLR inhibitor to the individual, wherein treatment is based on the IFN-I activity in a sample from the individual. In some embodiments, the TLR inhibitor is administered to an individual with high IFN-I activity. In some embodiments, the IFN-I activity is compared with a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the TLR inhibitor is administered to the individual. Provided herein is a method for treating an individual disease with high IFN-I activity, comprising administering the TLR inhibitor to the individual. Also provided herein is a method for treating an individual disease, comprising administering the TLR inhibitor to the individual, wherein treatment is based on the IFN-I signature expression pattern in a sample from the individual. In some embodiments, the IFN-I signature expression pattern is compared with one or more reference IFN-I signature expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates the administration of a TLR inhibitor, and thus, if there is a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is administered, and if there is a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is not administered. In some embodiments, the reference IFN-I signature expression pattern indicates not to administer a TLR inhibitor, and thus, if there is a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is administered, and if there is a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is not administered. In some embodiments, there is a first reference IFN-I signature expression pattern indicating that a TLR inhibitor is given and a second reference IFN-I signature expression pattern indicating that a TLR inhibitor is not given, and if there is a correlation between the determined IFN-I signature expression pattern and the first reference IFN-I signature expression pattern, the TLR inhibitor is given, and if there is a correlation between the determined IFN-I signature expression pattern and the second reference IFN-I signature expression pattern, the TLR inhibitor is not given. A method for treating an individual disease is also provided herein, comprising administering a TLR inhibitor to the individual, wherein treatment is based on an IFN-I signature score in a sample from the individual. In some embodiments, if the IFN-I signature score in the individual's sample is higher than a reference IFN-I signature score, the TLR inhibitor is administered to the individual. A method for treating an individual disease is also provided herein, comprising determining an IFN-I signature score in a sample from the individual, and if the IFN-I signature score is higher than a reference IFN-I signature score, the individual TLR inhibitor is administered.Also provided herein is a method for treating an individual disease, comprising selecting a patient whose IFN-I signature score is higher than a reference IFN-I signature score, and administering a TLR inhibitor to the individual. Also provided herein is a method for treating an individual disease, comprising administering a TLR inhibitor to the individual, wherein the individual's sample has an IFN-I signature score higher than a reference IFN-I signature score.

[0096] Also provided herein is a use of a TLR inhibitor for treating an individual disease, comprising administering the TLR inhibitor to the individual, wherein treatment is based on the IFN-I activity in a sample from the individual. In some embodiments, a TLR inhibitor is administered to an individual with high IFN-I activity. In some embodiments, the IFN-I activity is compared with a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the TLR inhibitor is administered to the individual. Also provided herein is a use of a TLR inhibitor for treating an individual disease, comprising administering the TLR inhibitor to the individual. Also provided herein is a use of a TLR inhibitor for treating an individual disease, comprising administering the TLR inhibitor to the individual, wherein treatment is based on the IFN-I characteristic expression pattern in a sample from the individual. In some embodiments, the IFN-I characteristic expression pattern is compared with one or more reference IFN-I characteristic expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates the administration of a TLR inhibitor, and thus, if there is a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is administered, and if there is a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is not administered. In some embodiments, the reference IFN-I signature expression pattern indicates not to administer a TLR inhibitor, and thus, if there is a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is administered, and if there is a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is not administered. In some embodiments, there is a first reference IFN-I characteristic expression pattern indicating that a TLR inhibitor is given and a second reference IFN-I characteristic expression pattern indicating that a TLR inhibitor is not given, and if there is a correlation between the determined IFN-I characteristic expression pattern and the first reference IFN-I characteristic expression pattern, the TLR inhibitor is given, if there is a correlation between the determined IFN-I characteristic expression pattern and the second reference IFN-I characteristic expression pattern, the TLR inhibitor is not given. Also provided herein is a method for treating an individual disease, comprising administering a TLR inhibitor to the individual, wherein treatment is based on the IFN-I characteristic score in the sample from the individual. In some embodiments, if the IFN-I characteristic score in the sample of the individual is higher than the reference IFN-I characteristic score, the TLR inhibitor is administered to the individual.Also provided herein is a use of a TLR inhibitor for treating an individual disease, comprising determining an IFN-I signature score in a sample from the individual, and if the IFN-I signature score is higher than a reference IFN-I signature score, the TLR inhibitor is administered to the individual. Also provided herein is a use of a TLR inhibitor for treating an individual disease, comprising selecting a patient whose IFN-I signature score is higher than a reference IFN-I signature score, and administering the TLR inhibitor to the individual. Also provided herein is a use of a TLR inhibitor for treating an individual disease, comprising administering the TLR inhibitor to the individual, wherein the individual's sample has an IFN-I signature score higher than a reference IFN-I signature score.

[0097] Also provided herein is a use of a TLR inhibitor for the preparation of a medicament for treating an individual disease, comprising administering the TLR inhibitor to the individual, wherein treatment is based on IFN-I activity in a sample from the individual. In some embodiments, the TLR inhibitor is administered to an individual with high IFN-I activity. In some embodiments, the IFN-I activity is compared with a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the TLR inhibitor is administered to the individual. Provided herein is a use of a TLR inhibitor for the preparation of a medicament for treating an individual disease with high IFN-I activity, comprising administering the TLR inhibitor to the individual. Also provided herein is a use of a TLR inhibitor for the preparation of a medicament for treating an individual disease, comprising administering the TLR inhibitor to the individual, wherein treatment is based on a characteristic expression pattern of IFN-I in a sample from the individual. In some embodiments, the characteristic expression pattern of IFN-I is compared with one or more reference IFN-I characteristic expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates the administration of a TLR inhibitor, and thus, if there is a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is administered, and if there is a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is not administered. In some embodiments, the reference IFN-I signature expression pattern indicates not to administer a TLR inhibitor, and thus, if there is a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is administered, and if there is a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, the TLR inhibitor is not administered. In some embodiments, there is a first reference IFN-I signature expression pattern indicating that a TLR inhibitor is given and a second reference IFN-I signature expression pattern indicating that a TLR inhibitor is not given, and if there is a correlation between the determined IFN-I signature expression pattern and the first reference IFN-I signature expression pattern, the TLR inhibitor is given, and if there is a correlation between the determined IFN-I signature expression pattern and the second reference IFN-I signature expression pattern, the TLR inhibitor is not given. Also provided herein is a use of a TLR inhibitor for the preparation of a medicament for treating an individual disease, comprising administering the TLR inhibitor to the individual, wherein treatment is based on an IFN-I signature score in a sample from the individual. Also provided herein is a use of a TLR inhibitor for the preparation of a medicament for treating an individual disease, comprising determining an IFN-I signature score in a sample from the individual, and if the IFN-I signature score is higher than the reference IFN-I signature score, the TLR inhibitor is administered to the individual.Also provided herein is a use of a TLR inhibitor for the preparation of a medicament for treating a disease in an individual, comprising selecting a patient whose IFN-I signature score is higher than a reference IFN-I signature score, and administering the TLR inhibitor to the individual. Also provided herein is a use of a TLR inhibitor for the preparation of a medicament for treating a disease in an individual, comprising administering the TLR inhibitor to the individual, wherein a sample from the individual has an IFN-I signature score that is higher than a reference IFN-I signature score.

[0098] The present disclosure also provides the following uses of a combination of a TLR inhibitor and a corticosteroid.

[0099] Also provided herein is a TLR inhibitor and corticosteroid (such as TLR7 and / or TLR8 inhibitor and glucocorticoid), for treating the method for the disease of the individual with high IFN-I activity, wherein the method includes giving the TLR inhibitor and corticosteroid to the individual. Also provided herein is a TLR inhibitor and corticosteroid (such as TLR7 and / or TLR8 inhibitor and glucocorticoid), for treating the method for the disease of the individual with IFN-I activity higher than reference IFN-I activity, wherein the method includes giving the TLR inhibitor and corticosteroid to the individual. Provided herein is a TLR inhibitor and corticosteroid (such as TLR7 and / or TLR8 inhibitor and glucocorticoid), for treating the method for the disease of the individual, comprising: (i) determining the IFN-I activity of the individual; (ii) comparing the determined IFN-I activity with the reference IFN-I activity; and (iii) according to the comparison result, giving the TLR inhibitor and corticosteroid to the individual. In some embodiments, the reference IFN-I activity is selected to distinguish individuals for whom a TLR inhibitor is more likely to have a therapeutic effect from individuals for whom a TLR inhibitor is less likely to have a therapeutic effect, and thus, if the individual's IFN-I activity is higher than the reference IFN-I activity, the individual is administered a TLR inhibitor and a corticosteroid, and if the individual's IFN-I activity is lower than the reference IFN-I activity, the individual is not administered a TLR inhibitor and a corticosteroid. In some embodiments, the reference IFN-I activity indicates the therapeutic effectiveness of a TLR inhibitor, and thus, if the individual's IFN-I activity is similar to or higher than the reference IFN-I activity, the individual is administered a TLR inhibitor and a corticosteroid. In some embodiments, the reference IFN-I activity indicates the therapeutic ineffectiveness of a TLR inhibitor, and thus, if the individual's IFN-I activity is similar to or lower than the reference IFN-I activity, the individual is not administered a TLR inhibitor and a corticosteroid. Provided herein is a TLR inhibitor and a corticosteroid (e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticoid), for use in treating a method for an individual disease, comprising administering a TLR inhibitor and a corticosteroid to an individual, wherein the individual has an IFN-I signature score higher than a reference IFN-I signature score. Provided herein is a TLR inhibitor and a corticosteroid (e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticoid), for use in treating a method for an individual disease, comprising: (i) determining an individual's IFN-I signature score; (ii) comparing the determined IFN-I signature score with a reference IFN-I signature score; and (iii) administering a TLR inhibitor and a corticosteroid to the individual based on the comparison results.In some embodiments, a reference IFN-I signature score is selected to distinguish an individual in which a TLR inhibitor is less likely to have a therapeutic effect from an individual in which a TLR inhibitor is less likely to have a therapeutic effect, therefore, if the individual's IFN-I signature score is higher than the reference IFN-I signature score, a TLR inhibitor and a corticosteroid are administered to the individual, and if the individual's IFN-I signature score is lower than the reference IFN-I signature score, a TLR inhibitor and a corticosteroid are not administered to the individual. In some embodiments, a reference IFN-I signature score indicates the therapeutic effectiveness of a TLR inhibitor, therefore, if the individual's IFN-I signature score is approximately or higher than the reference IFN-I signature score, a TLR inhibitor and a corticosteroid are administered to the individual. In some embodiments, a reference IFN-I signature score indicates the therapeutic ineffectiveness of a TLR inhibitor, therefore, if the individual's IFN-I signature score is approximately or lower than the reference IFN-I signature score, a TLR inhibitor and a corticosteroid are not administered to the individual. In some embodiments, the IFN-I activity or IFN-I signature score of the treated individual is determined in a sample from the individual. In some embodiments, the effective amount of the corticosteroid administered (including but not limited to dose volume, dose concentration, and / or total drug dose administered) is reduced when administered with a TLR inhibitor.

[0100] Provided herein is a method for treating a disease in an individual with high IFN-I activity, comprising administering a TLR inhibitor and a corticosteroid (such as a TLR7 and / or TLR8 inhibitor and a glucocorticoid) to the individual. Provided herein is a method for treating a disease in an individual with IFN-I activity higher than reference IFN-I activity, wherein the method comprises administering a TLR inhibitor and a corticosteroid (such as a TLR7 and / or TLR8 inhibitor and a glucocorticoid) to the individual. Provided herein is a method for treating a disease in an individual, comprising administering a TLR inhibitor and a corticosteroid (such as a TLR7 and / or TLR8 inhibitor and a glucocorticoid) to the individual, wherein the individual has an IFN-I feature score higher than reference IFN-I feature score. In some embodiments, in a sample from an individual, determine that the IFN-I activity or the IFN-I feature score of the individual being treated is measured. In some embodiments, when administered together with a TLR inhibitor, administer the corticosteroid of a reduced effective dose (including but not limited to dose volume, dosage concentration and / or the total drug dose administered).

[0101] Provided herein are TLR inhibitors and corticosteroids (such as TLR7 and / or TLR8 inhibitors and glucocorticoids) for the treatment of the purposes of the disease of the individual with high IFN-1 activity, including giving TLR inhibitors and corticosteroids to the individual.Also provided herein are TLR inhibitors and corticosteroids (such as TLR7 and / or TLR8 inhibitors and glucocorticoids) for the treatment of the purposes of the disease of the individual with IFN-1 activity higher than reference IFN-1 activity, wherein said method includes giving the TLR inhibitor and corticosteroids to the individual.Provided herein are TLR inhibitors and corticosteroids (such as TLR7 and / or TLR8 inhibitors and glucocorticoids) for the treatment of the purposes of individual disease, including giving TLR inhibitors and corticosteroids to individual, wherein individual has the IFN-1 feature score higher than reference IFN-1 feature score.In some embodiments, the IFN-1 activity or IFN-1 feature score of treated individual is determined in the sample from individual. In some embodiments, the effective amount of the corticosteroid administered (including but not limited to dose volume, dose concentration, and / or total drug dose administered) is reduced when administered with a TLR inhibitor.

[0102] Provided herein are TLR inhibitors and corticosteroids (such as TLR7 and / or TLR8 inhibitors and glucocorticoids) for the preparation of the medicine for the disease of the individual with high IFN-I activity, including giving TLR inhibitors and corticosteroids to the individual.Also provided herein are TLR inhibitors and corticosteroids (such as TLR7 and / or TLR8 inhibitors and glucocorticoids) for the preparation of the medicine for the disease of the individual with IFN-I activity higher than reference IFN-I activity, wherein the method includes giving the TLR inhibitor and glucocorticoids to the individual.Provided herein are TLR inhibitors and corticosteroids (such as TLR7 and / or TLR8 inhibitors and glucocorticoids) for the preparation of the medicine for the treatment of individual disease, including giving TLR inhibitors and corticosteroids to individual, wherein individual has the IFN-I feature score higher than reference IFN-I feature score.In some embodiments, the IFN-I activity or IFN-I feature score of the treated individual are determined in the sample from the individual. In some embodiments, the effective amount of the corticosteroid administered (including but not limited to dose volume, dose concentration, and / or total drug dose administered) is reduced when administered with a TLR inhibitor.

[0103] In some embodiments of any of the methods or uses herein relating to IFN-1 activity in an individual, determining the IFN-1 activity comprises (i) obtaining a sample from the individual; (ii) measuring the IFN-1 activity in the sample; and (iii) normalizing the IFN-1 activity.

[0104] In some embodiments of any of the methods or uses herein relating to an IFN-I signature expression pattern in an individual, determining the IFN-I signature expression pattern comprises (i) obtaining a sample from the individual; (ii) measuring the expression level of each gene in the IFN-I signature in the sample; and (iii) normalizing the expression levels of each gene to obtain the IFN-I signature expression pattern.

[0105] In some embodiments of any of the methods or uses herein relating to an IFN-I signature score in an individual, determining the IFN-I signature score comprises (i) obtaining a sample from the individual; (ii) measuring the expression level of each gene in the IFN-I signature in the sample; (iii) normalizing the expression levels of each gene; and (iii) calculating the arithmetic mean of the normalized gene expression levels to obtain the IFN-I signature score.

[0106] In certain embodiments of any of the methods or uses disclosed herein, the sample is a blood sample or a tissue sample. In certain embodiments of any of the methods or uses disclosed herein, the sample comprises peripheral blood mononuclear cells (PBMC) and / or skin tissue. In some embodiments, the sample is extracted RNA.

[0107] The expression levels of genes in the IFN-1 signature can be measured at the mRNA or protein level. In certain embodiments of any method or use disclosed herein, the gene expression levels of the IFN-1 signature are measured by measuring the mRNA levels of the IFN-1 signature genes. In certain embodiments of any method or use disclosed herein, the gene expression levels of the IFN-1 signature are measured by measuring the protein levels of the IFN-1 signature genes.

[0108] Methods for measuring mRNA and protein levels are well known in the art. For example, mRNA expression levels can be determined using Northern blotting, quantitative polymerase chain reaction (qPCR) or microarrays, while protein expression levels can be determined using ELISA, Western blotting and mass spectrometry.

[0109] In some embodiments, the measured expression levels are normalized. For example, expression levels can be normalized to the expression levels of genes whose expression is known to be unchanged across samples. Genes commonly used for normalization include housekeeping genes such as GAPDH, ACTB, TFRC, UBC, and SDHA. In some embodiments, genes ACTB, GAPDH, and TFRC are used for normalization.

[0110] Certain embodiments disclosed herein relate to a reference IFN-I activity, a reference IFN-I signature expression pattern, or a reference IFN-I signature score, which can be derived from, for example, a second individual with or without the disease, or from a population of individuals with or without the disease. In some embodiments, the reference IFN-I activity, the reference IFN-I signature expression pattern, or the reference IFN-I signature score are retrospectively determined based on the IFN-I activity, the IFN-I signature expression pattern, or the reference IFN-I signature score before treatment with a TLR inhibitor, respectively. The patient population can then be divided into two groups, one group showing a certain therapeutic outcome, while the other group does not. In some embodiments, the IFN-I activity or IFN-I signature score between the two groups is defined as a reference IFN-I activity or a reference IFN-I signature score, respectively. In other embodiments, the characteristic IFN-I activity or IFN-I signature score of one of the two groups is defined as a reference IFN-I activity or a reference IFN-I signature score, respectively. In some embodiments, a characteristic IFN-I signature expression pattern of one or two groups is defined as a reference IFN-I signature expression pattern. Subsequently, an individual having an IFN-I activity or IFN-I signature score comparable to one of the two groups (groups with or without therapeutic effect) can be defined as an individual for whom TLR inhibitor therapy is effective or an individual for whom TLR inhibitor therapy is ineffective. In alternative embodiments, the definition of reference IFN-I activity, reference IFN-I signature expression pattern, or reference IFN-I signature score is independent of treatment outcome. For example, for a patient population having a bimodal distribution of IFN-I activity or IFN-I signature score, the reference IFN-I activity or reference IFN-I signature score can be defined as an IFN-I activity or IFN-I signature score located at the bottom of the bimodal distribution, or can be defined as an IFN-I activity or IFN-I signature score that characterizes one of the two groups. In addition, a reference IFN-I activity or reference IFN-I signature score reflecting each of the two groups can also be defined. Subsequently, IFN-I activity or IFN-I feature score and one of the two groups of comparable individuals can be defined as having high IFN-I activity (prediction TLR inhibitor treatment is effective) or with low IFN-I activity (prediction TLR inhibitor treatment is ineffective). Similarly, in this colony with bimodal distribution, the IFN-I feature expression pattern as the feature of the group with lower IFN-I activity and / or higher IFN-I activity can be defined as one or more reference IFN-I feature expression patterns. In one embodiment, for healthy individual colony, reference IFN-I activity or reference IFN-I feature score can be defined as the IFN-I activity or IFN-I feature score close to the colony IFN-I activity range or IFN-I feature score range upper limit.In another embodiment, the IFN-I activity or IFN-I signature score of a healthy individual can be defined as a reference IFN-I activity and a reference IFN-I signature score, respectively.

[0111] In some embodiments, the reference IFN-1 activity is defined as follows: (i) define the population of healthy individuals; (ii) determining the IFN-1 activity of a sample from each individual in the population; and (iii) The IFN-I activity close to the upper limit of the range of IFN-I activity determined in the population is defined as the reference IFN-I activity.

[0112] Such reference IFN-I activity can then be used to distinguish between individuals who are more likely to respond to treatment (IFN-I activity higher than the reference IFN-I activity) and individuals who are less likely to respond to treatment (IFN-I activity lower than the reference IFN-I activity).

[0113] In some embodiments, the reference IFN-1 activity is defined as follows: (i) defining a patient population having the same disease as the individual whose IFN-I activity is determined according to the methods or uses of the present invention and being treated with the same TLR inhibitor as the individual; (ii) determining IFN-I activity in a sample from each patient in the patient population prior to treatment with the TLR inhibitor; (iii) determining the treatment effect for each patient in the patient population after treatment with the TLR inhibitor; (iv) stratifying the patient population into groups with better or worse treatment outcomes; and (v) The IFN-I activity dividing the patients into two groups was defined as the reference IFN-I activity.

[0114] Such reference IFN-I activity can then be used to distinguish between individuals who are more likely to respond to treatment (IFN-I activity higher than the reference IFN-I activity) and individuals who are less likely to respond to treatment (IFN-I activity lower than the reference IFN-I activity).

[0115] In some embodiments, the reference IFN-1 activity is defined as follows: (vi) defining a patient population having the same disease as the individual whose IFN-I activity is determined according to the methods or uses of the present invention and being treated with the same TLR inhibitor as the individual; (vii) determining IFN-I activity in a sample from each patient in the patient population prior to treatment with the TLR inhibitor; (viii) determining the treatment effect for each patient in the patient population after treatment with the TLR inhibitor; (ix) dividing the patient population into a group with better treatment efficacy and a group with worse treatment efficacy; and (x) The characteristic IFN-I activity of one or both of the two groups of patients is defined as the reference IFN-I activity.

[0116] Such reference IFN-I activity can then be used to identify individuals who are more likely to have a therapeutic effect (if the IFN-I activity characteristic of a patient group with a better therapeutic effect is selected as the reference IFN-I activity) and / or individuals who are less likely to have a therapeutic effect (if the IFN-I activity characteristic of a patient group with a poorer therapeutic effect is selected as the reference IFN-I activity).

[0117] In some embodiments, a reference IFN-1 signature expression pattern is defined as follows: (i) define the population of healthy individuals; (ii) determining a signature expression pattern of IFN-I for a sample from each individual in the population; and (iii) defining the characteristic IFN-I signature expression pattern of the population as the reference IFN-I signature expression pattern.

[0118] Such reference IFN-I signature expression patterns derived from healthy populations may then indicate a lack of therapeutic efficacy.

[0119] In some embodiments, a reference IFN-1 signature expression pattern is defined as follows: (i) defining a patient population suffering from the same disease as the individual whose IFN-I signature expression pattern is determined according to the method or use of the present invention and being treated with the same TLR inhibitor as the individual; (ii) determining an IFN-I signature expression pattern in a sample from each patient in the patient population prior to treatment with the TLR inhibitor, wherein the IFN-I signature is identical to the IFN-I signature of the individual for whom the IFN-I signature expression pattern was determined according to the method or use of the present invention; (iii) determining the treatment effect for each patient in the patient population after treatment with the TLR inhibitor; (iv) stratifying the patient population into groups with better or worse treatment outcomes; and (v) defining the characteristic IFN-I signature expression patterns of one or both patient groups as one or more reference IFN-I signature expression patterns.

[0120] One or more such reference IFN-I signature expression patterns derived from a patient population can then indicate the presence or absence of therapeutic efficacy, respectively.

[0121] In some embodiments, a reference IFN-1 signature score is defined as follows: (iv) define the population of healthy individuals; (v) determining an IFN-1 signature score for a sample from each individual in the population; and (vi) The IFN-I signature score that is close to the upper limit of the range of IFN-I signature scores determined in the population is defined as the reference IFN-I signature score.

[0122] Such a reference IFN-I signature score can then be used to distinguish individuals who are more likely to respond to treatment (IFN-I signature score higher than the reference IFN-I signature score) from individuals who are less likely to respond to treatment (IFN-I activity lower than the reference IFN-I signature score).

[0123] In some embodiments, a reference IFN-1 signature score is defined as follows: (i) defining a patient population having the same disease as the individual whose IFN-I signature score is determined according to the method or use of the present invention and being treated with the same TLR inhibitor as the individual; (ii) determining an IFN-I signature score in a sample from each patient in the patient population prior to treatment with the TLR inhibitor, wherein the IFN-I signature score is based on the same IFN-I signature as the IFN-I signature score for the individual for whom the IFN-I signature score was determined according to the method or use of the invention; (iii) determining the treatment effect for each patient in the patient population after treatment with the TLR inhibitor; (iv) stratifying the patient population into groups with better or worse treatment outcomes; and (v) The IFN-I signature score that divided the patients into two groups was defined as the reference IFN-I signature score.

[0124] Such a reference IFN-I signature score can then be used to distinguish individuals who are more likely to respond to treatment (IFN-I signature score higher than the reference IFN-I signature score) from individuals who are less likely to respond to treatment (IFN-I activity lower than the reference IFN-I signature score).

[0125] In some embodiments, a reference IFN-1 signature score is defined as follows: (xi) defining a patient population having the same disease as the individual whose IFN-I signature score is determined according to the method or use of the present invention and being treated with the same TLR inhibitor as the individual; (xii) determining an IFN-I signature score in a sample from each patient in the patient population prior to treatment with the TLR inhibitor; (xiii) determining the treatment effect for each patient in the patient population after treatment with the TLR inhibitor; (xiv) stratifying the patient population into groups with better or worse outcomes; and (xv) The characteristic IFN-I signature score of one or both groups of patients is defined as the reference IFN-I signature score.

[0126] Such reference IFN-I signature scores can then be used to identify individuals who are more likely to have a therapeutic effect (if an IFN-I signature score characteristic of a patient group with a better therapeutic effect is selected as the reference IFN-I signature score) and / or individuals who are less likely to have a therapeutic effect (if an IFN-I signature score characteristic of a patient group with a poorer therapeutic effect is selected as the reference IFN-I signature score).

[0127] The disease that IFN-I activity (and IFN-I characteristic expression pattern or IFN-I characteristic score) can be used as biomarker includes any disease caused, mediated and / or propagated by TLR activity (such as TLR7 and / or TLR8 activity).In some embodiments, the disease is an autoimmune disease.In some embodiments, the disease is an idiopathic inflammatory myopathy, such as polymyositis or dermatomyositis, or lupus disease, such as systemic lupus erythematosus or lupus nephritis.In some aspects, the disease is selected from the group consisting of arthritis, pancreatitis, mixed connective tissue disease, lupus, myositis, antiphospholipid syndrome, systemic onset arthritis and irritable bowel syndrome. In some embodiments, the disease is selected from the group consisting of rheumatoid arthritis, autoimmune pancreatitis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, type I diabetes, multiple sclerosis, antiphospholipid syndrome, sclerosing cholangitis, systemic onset arthritis, irritable bowel disease, scleroderma, Sjogren's disease, vitiligo, polymyositis, dermatomyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), autoimmune hepatitis, hypopituitarism, graft-versus-host disease, autoimmune skin disease, uveitis, pernicious anemia, and hypoparathyroidism. In some embodiments, the disease is selected from polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold illness. In other aspects, the disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, autoimmune skin disease, and multiple sclerosis. In other aspects, the disease is selected from the group consisting of pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type I diabetes. In some aspects, the disease is diabetes and / or diabetes-related diseases or conditions. In some embodiments, the disease is an inflammatory disease. In some variants, the disease is associated with chronic pathogen stimulation. In some variants, the disease is a viral disease, such as caused by infection with HIV or SARS-CoV-2 (e.g., COVID-19). In some embodiments, the disorder is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, polymyositis, dermatomyositis, psoriasis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, Crohn's disease, ulcerative colitis, hyperimmunoglobulinemia D and periodic fever syndromes, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA, Alzheimer's disease, Parkinson's disease, and cancer. TLR inhibitors

[0128] In some embodiments, the uses and methods of the present invention involve administering a TLR inhibitor. In one embodiment, the TLR inhibitor is a TLR7 and / or TLR8 inhibitor. In one embodiment, the TLR inhibitor is a TLR7 and TLR8 inhibitor. In one embodiment, the TLR inhibitor is a small molecule, such as a small molecule inhibitor of TLR7 and / or TLR8.

[0129] In one embodiment, the TLR inhibitor is selected from the group consisting of 5-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoline-8-carbonitrile; (3R,5S)-1-(8-methoxy-1,7-naphthyridin-5-yl)-5-methylpiperidin-3-amine; 2-{4-[2-(7,8-dimethyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(propan-2-yl)-1H-indol-5-yl]piperidin-1-yl}acetamide; rel-(2R,6R)-4-(8-cyanoquinolin-5-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-6-methylmorpholine-2-carboxamide hydrochloride; (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide; and (R)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide or pharmaceutically acceptable salts of these compounds.

[0130] In some embodiments, the TLR7 and / or TLR8 inhibitor is a quinoline derivative.

[0131] In some embodiments, the TLR7 and / or TLR8 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: Ring A is aryl or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted; Ring B is aryl or heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted; R 1 is -Me, -CF3, -OMe, -OEt or –CN; Each R 2is independently –R, halogen, -haloalkyl, –OR, –SR, –CN, –NO2, –S02R, –SOR, –C(O)R, –C02R, –C(O)N(R)2, –NRC(O)R, –NRC(O)N(R)2, –NRS02R, or –N(R)2; Each R 3 is independently –R, halogen, -haloalkyl, –OR, –SR, –CN, –NO2, –S02R, –SOR, –C(O)R, –C02R, –C(O)N(R)2, –NRC(O)R, –NRC(O)N(R)2, –NRS02R, or –N(R)2; X is C(R 4 )2、O、NR 4 、S、S(R 4 ) or S(R 4 )2; Each R 4 is independently –R, halogen, -haloalkyl, –OR, –SR, –CN, –NO2, –S02R, –SOR, –C(O)R, –C02R, –C(O)N(R)2, –NRC(O)R, –NRC(O)N(R)2, –NRS02R, or –N(R)2; Each R 5 is independently –R, halogen, -haloalkyl, –OR, –SR, –CN, –NO2, –S02R, –SOR, –C(O)R, –C02R, –C(O)N(R)2, –NRC(O)R, –NRC(O)N(R)2, –NRS02R, or –N(R)2; Each R is independently hydrogen, C 1-6 Aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted; or Two R groups on the same atom together with the atoms to which they are attached form a C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted; k is 0 or 1; n is 0, 1, or 2; p is 0, 1, or 2; r is 0, 1, or 2; and t is 0, 1, or 2.

[0132] In certain embodiments, Ring A is C6 aryl or a 6-membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

[0133] In certain embodiments, Ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; each of which is optionally substituted.

[0134] In certain embodiments, Ring A is phenyl, pyridinyl, or pyrimidinyl; each of which is optionally substituted.

[0135] In certain embodiments, Ring B is C6 aryl or a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

[0136] In certain embodiments, Ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole, or thiazole; each of which is optionally substituted.

[0137] In certain embodiments, Ring A and Ring B are

[0138] In certain embodiments, Ring A and Ring B are

[0139] In certain embodiments, Ring A and Ring B are

[0140] In certain embodiments, Ring A and Ring B are

[0141] In certain embodiments, Ring A and Ring B are

[0142] In certain embodiments, R 1 is -OMe or -CN.

[0143] In certain embodiments, each R 2 Independently C 1-6 Aliphatic, C 3-10 Aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted.

[0144] In certain embodiments, each R 2is independently methyl, ethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, straight-chain or branched pentyl or straight-chain or branched hexyl; each of which is optionally substituted.

[0145] In certain embodiments, each R 2and independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctyl, [4.3.0]bicyclononyl, [4.4.0]bicyclodecyl, [2.2.2]bicyclooctyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, acridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, , 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl , 1,2,4-oxadiazolyl; -1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl , quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted.

[0146] In certain embodiments, each R 2is independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRS02R, or -N(R)2.

[0147] In certain embodiments, each R 2 Independently -F.

[0148] In certain embodiments, each R 3 Independently C 1-6 Aliphatic, C 3-10 Aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted.

[0149] In certain embodiments, each R 3 is independently methyl, ethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, straight-chain or branched pentyl or straight-chain or branched hexyl; each of which is optionally substituted.

[0150] In certain embodiments, each R 3 is independently methyl.

[0151] In certain embodiments, each R 3and independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctyl, [4.3.0]bicyclononyl, [4.4.0]bicyclodecyl, [2.2.2]bicyclooctyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, acridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, , 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl , 1,2,4-oxadiazolyl; -1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl , quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted.

[0152] In certain embodiments, each R 3is independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRS02R, or -N(R)2.

[0153] In certain embodiments, each R 3 Independently -F.

[0154] In certain embodiments, X is C(R 4 )2 or O.

[0155] In certain embodiments, X is C(R 4 ) 2. In certain embodiments, X is CH 2 .

[0156] In certain embodiments, X is O.

[0157] In certain embodiments, each R 4 Independently C 1-6 Aliphatic, C 3-10 Aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted.

[0158] In certain embodiments, each R 4 is independently methyl, ethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, straight-chain or branched pentyl or straight-chain or branched hexyl; each of which is optionally substituted.

[0159] In certain embodiments, each R 4and independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctyl, [4.3.0]bicyclononyl, [4.4.0]bicyclodecyl, [2.2.2]bicyclooctyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, acridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, , 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl , 1,2,4-oxadiazolyl; -1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl , quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted.

[0160] In certain embodiments, each R 4is independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRS02R, or -N(R)2.

[0161] In certain embodiments, each R 4 Independently –H, C 1–6 aliphatic, -OR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; each of which is optionally substituted.

[0162] In certain embodiments, each R 4 Independently –H, C 1–6 aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of which is optionally substituted.

[0163] In certain embodiments, each R 4 Independently

[0164] In certain embodiments, each R 4 Independently

[0165] In certain embodiments, each R 4 Independently

[0166] In certain embodiments, each R 5 Independently C 1-6 Aliphatic, C 3-10 Aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted.

[0167] In certain embodiments, each R 5 is independently methyl, ethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, straight-chain or branched pentyl or straight-chain or branched hexyl; each of which is optionally substituted.

[0168] In certain embodiments, each R 5and independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctyl, [4.3.0]bicyclononyl, [4.4.0]bicyclodecyl, [2.2.2]bicyclooctyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, acridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, , 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl , 1,2,4-oxadiazolyl; -1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl , quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted.

[0169] In certain embodiments, each R 5is independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRS02R, or -N(R)2.

[0170] In certain embodiments, each R 5 is independently methyl, cyclopropyl, -F or -CF3.

[0171] In certain embodiments, each R 5 Independently -F or –CF3.

[0172] In certain embodiments, k=1. In certain embodiments, r=1. In certain embodiments, t=1. In certain embodiments, n=0. In certain embodiments, p=0. In certain embodiments, n=0 and p=0. In certain embodiments, r=1 and t=1. In certain embodiments, r=1 and t=1 and k=1. In certain embodiments, r=1 and t=1 and k=1 and n=0 and p=0.

[0173] In certain embodiments, X, Ring A, Ring B, R 1 、R 2 、R 3 、R 4 、R 5 , k, m, n, p, r and t are each as defined above and as described above and in the embodiments, classes and subclasses herein, alone or in combination.

[0174] In certain embodiments, the TLR7 and / or TLR8 inhibitor is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is

[0175] In one embodiment, the TLR inhibitor is a TLR7 and / or TLR8 inhibitor selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0176] In certain embodiments, the TLR7 and / or TLR8 inhibitor is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof, wherein X is O or CH2, R 4 for R 5 It is methyl or -CF3.

[0177] In one embodiment, the TLR inhibitor is a TLR7 and / or TLR8 inhibitor selected from or a pharmaceutically acceptable salt thereof.

[0178] In one embodiment, the TLR inhibitor is empatoran, E6742, or afimetoran. Interferon characteristics

[0179] The choice of IFN-I signature is not particularly limited, particularly since IFN-I signatures tend to correlate well.

[0180] In one embodiment, the IFN-I signature comprises one or more genes selected from the group consisting of BST2, CMPK2, CXCL10, EPSTI1, GBP5, HERC5, HERC6, IFI6, IFI27, IFI44, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3, IRF7, ISG15, LY6E, MX1, MX2, OAS1, OAS2, OAS3, OASL, PKR, RSAD2, SIGLEC1 , STAT1, TNFSF10 and USP18, one or more genes selected from the group consisting of BST2, CMPK2, CXCL10, GBP5, HERC6, IFI44, IFIH1, IFIT1, IFIT2, IFIT3, IRF7, ISG15, MX1, MX2, OAS1, OAS2, OAS3, OASL, RSAD2, STAT1, TNFSF10 and USP18, one or more genes selected from the group consisting of CMPK2, CXCL10 , EPSTI1, HERC5, IFI27, IFI44, IFI44L, IFI6, IFIT1, IFIT3, ISG15, LY6E, MX1, OAS1, OAS2, OAS3, OASL, RSAD2, SIGLEC1, and USP18, one or more genes selected from the group consisting of HERC5, IFI27, IFIT1, and RSAD, one or more genes selected from the group consisting of ISG15, MX1, and OAS1, one or more genes selected from the group consisting of E PSTI1, HERC5, IFI44L, ISG15, LY6E, MX1, MX2, and RSAD2, one or more genes selected from the group consisting of IFIT1, MX1, and PKR, one or more genes selected from the group consisting of CMPK2, EPSTI, and HERC5, one or more genes selected from the group consisting of IFI6, IFI27, IFI44, IFI44L, and RSAD2, or one or more genes selected from the group consisting of IFI27, IFI44, IFI44L, and RSAD2. In one embodiment, the IFN-I signature comprises at least two genes, at least three genes, or all genes from a group consisting of the genes in the preceding sentence.

[0181] In some embodiments, an IFN-I signature score that is higher than a reference IFN-I signature score is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 500%, or 1000% higher than a reference IFN-I signature score. In some embodiments, an IFN-I signature score that is lower than a reference IFN-I signature score is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% lower than a reference IFN-I signature score.

[0182] In some embodiments, an IFN-I activity that is greater than a reference IFN-I activity is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 500%, or 1000% greater than a reference IFN-I activity. In some embodiments, an IFN-I activity that is less than a reference IFN-I activity is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% less than a reference IFN-I activity. Preparation and administration

[0183] The TLR inhibitors and other therapeutic agents disclosed herein are administered as is or in the form of a pharmaceutically acceptable composition. They can be administered orally, parenterally, by inhalation aerosol, topically, rectally, intranasally, buccally, vaginally, or by implantation of a reservoir. In one embodiment, the TLR inhibitor is a small molecule and is administered orally. In one embodiment, the oral formulation is a tablet or capsule. In another embodiment, the oral formulation is a solution or suspension that can be administered to a subject in need by mouth or nasogastric tube. Any oral formulation of the present invention can be administered with or without food. In some embodiments, the pharmaceutically acceptable composition of the present invention is administered without food. In other embodiments, the pharmaceutically acceptable composition of the present invention is administered with food.

[0184] The pharmaceutically acceptable compositions of the present invention are administered orally in any orally acceptable dosage form. Exemplary oral dosage forms are capsules, tablets, aqueous suspensions, or solutions. For oral tablets, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral capsule forms, useful diluents include lactose and dried corn starch. When an oral aqueous suspension is desired, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may optionally be added.

[0185] The amount of the compound of the present invention, optionally in combination with a carrier material, to produce a single dosage form of the composition will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions provided are formulated so that a patient receiving these compositions can receive a dosage of 0.01-100 mg / kg body weight / day of the compound.

[0186] In one embodiment, the total amount of the TLR inhibitor administered to a subject in need thereof is between about 10 mg and about 500 mg per day. In one aspect of this embodiment, the total amount of the TLR inhibitor administered per day is between about 50 mg and about 300 mg. In another aspect, the total amount of the TLR inhibitor administered per day is between about 100 mg and about 200 mg.

[0187] In another embodiment, the TLR inhibitor is administered once daily. In another aspect of this embodiment, the TLR inhibitor is administered twice daily.

[0188] In one embodiment, about 50 mg of a TLR inhibitor is administered to a subject in need thereof twice daily. In another embodiment, about 100 mg of a TLR inhibitor is administered to a subject in need thereof twice daily. In another embodiment, about 200 mg of a TLR inhibitor is administered to a subject in need thereof twice daily.

[0189] In any of the above embodiments, the TLR inhibitor is administered for about 7 days to about 21 days. In one aspect of any of the above embodiments, the TLR inhibitor is administered for about 14 days. In one embodiment, the TLR inhibitor is administered for a longer period, such as several months or years. In one embodiment, the TLR inhibitor is administered in an indefinite period.

[0190] In one embodiment of the invention, 50 mg of a TLR inhibitor of the invention is administered twice daily for about 14 days. In one embodiment of the invention, 50 mg of a TLR inhibitor of the invention is administered twice daily for an indefinite period. In another embodiment of the invention, 100 mg of a TLR inhibitor of the invention is administered twice daily for about 14 days. In one embodiment of the invention, 100 mg of a TLR inhibitor of the invention is administered twice daily for an indefinite period. In another embodiment of the invention, 200 mg of a TLR inhibitor of the invention is administered twice daily for about 14 days. In one embodiment of the invention, 200 mg of a TLR inhibitor of the invention is administered twice daily for an indefinite period. Combination therapy

[0191] In any of the treatment methods disclosed herein, a TLR inhibitor can be administered in combination with other known therapeutic agents.

[0192] In one aspect of this embodiment, the one or more additional therapeutic agents are selected from the group consisting of anti-inflammatory agents, antibiotics, anticoagulants, antiparasitic agents, antiplatelet agents and dual antiplatelet therapy, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, beta-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 binding agents, 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 drugs.

[0193] In one embodiment, a TLR 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, alone or in combination with ribavirin and interferon beta.

[0194] In one embodiment, the TLR inhibitor is administered in combination with a broad-spectrum antibiotic.

[0195] Although previous studies have shown that for SLE patients with the higher IFN-I feature score, the efficacy of glucocorticoid therapy is lower, the inventors have surprisingly found that, in the case of IFN-α pretreatment, when glucocorticoid is used in combination with TLR7 and / or 8 inhibitors, its effectiveness is improved. This shows that, in patients with the higher activity of IFN-I, TLR inhibitor treatment may even play the effect of reducing glucocorticoid dosage (glucocorticosteroid-sparing) in a clinical setting. Therefore, in some embodiments, TLR inhibitor as herein described is given in combination with a corticosteroid. In some embodiments, the corticosteroid is a glucocorticoid. In some embodiments, the corticosteroid is a mineralocorticoid. Corticosteroids include, but are not limited to, corticosterone and its derivatives, prodrugs, isomers and analogs, cortisone and its derivatives, prodrugs, isomers and analogs (i.e., Cortone), aldosterone and its derivatives, prodrugs, isomers and analogs, dexamethasone and its derivatives, prodrugs, isomers and analogs (i.e., Decadron), prednisone and its derivatives, prodrugs, isomers and analogs (i.e., Prelone), fludrocortisone and its derivatives, prodrugs, isomers and analogs (e.g., Cortisol or Cortef), hydrocortisone and its derivatives, prodrugs, isomers and analogs, hydroxycortisone and its derivatives, prodrugs, isomers and analogs, betamethasone and its derivatives, prodrugs, isomers and analogs (i.e., Celestone), budesonide and its derivatives, prodrugs, isomers and analogs (i.e., Entocort In some embodiments, the corticosteroid is fludrocortisone or its derivative, prodrug, isomer or analog. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the corticosteroid is hydroxycortisone or its derivative, prodrug, isomer or analog. In some embodiments, the corticosteroid is hydroxycortisone.

[0196] In one embodiment, the TLR inhibitor is administered in combination with chloroquine or hydroxychloroquine. In one aspect of this embodiment, the TLR inhibitor is further combined with azithromycin.

[0197] In one embodiment, a TLR inhibitor is combined with an interferon Combined giving.

[0198] In one embodiment, the TLR inhibitor is administered in combination with dexamethasone.

[0199] In one embodiment, the TLR inhibitor is administered in combination with one or more additional therapeutic agents selected from the group consisting of hydroxychloroquine, chloroquine, ivermectin, tranexamic acid, nafamostat, ribavirin, lopinavir / ritonavir, favipiravir, arbidol, levofloxacin, interferon beta-1a, interferon beta-1b, beta-interferon, azithromycin, nitrazoxamide, lovastatin, clazakizumab, adalimumab, etanercept, golimumab, infliximab, salimumab, tocilizumab, anakinra, emapalumab, pirfenidone, belimumab, rituximab, orifuzumab. Aspirin, anifrolumab, ravulizumab-cwvz, eculizumab, bevacizumab, heparin, enoxaparin, apremilast, warfarin, baricitinib, ruxolitinib, dapagliflozin, methotrexate, leflunomide, azathioprine, sulfasalazine, mycophenolate mofetil, colchicine, fingolimod, ifenprodil, prednisone, cortisol, dexamethasone, methylprednisolone, melatonin, otilimab, ATR-002, APN-01, camostat mesylate mesylate), brilacidin, IFX-1, PAX-1-001, BXT-25, NP-120, intravenous immunoglobulin (IVIG), and solnatide.

[0200] In one embodiment, the TLR inhibitor is administered in combination with one or more anti-inflammatory agents. In one aspect of this embodiment, the anti-inflammatory agent is selected from corticosteroids, steroids, COX-2 inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). In one aspect of this embodiment, the anti-inflammatory agent is diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, meclofenamate, mefenamic acid, or fenampicin. acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, prednisone, hydrocortisone, fludocortisone, betamethasone, prednisolone, triamcinolone, methylprednisone, dexamethasone, fluticasone, and budesonide (alone or in combination with formoterol, salmeterol, or vilanterol).

[0201] In one embodiment, a TLR 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 (dapson), cyclosporine, cyclophosphamide, etc.

[0202] In one embodiment, TLR inhibitors are given 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 a penicillin, an anti-staphylococcal penicillin, a cephalosporin, an aminopenicillin (usually given together with a beta-lactamase inhibitor), a monoamine bacterium (monobactam), a quinoline, an aminoglycoside, a lincosamide, a macrolide, a tetracycline, a glycopeptide, an antimetabolite, or a nitroimidazole. In another aspect of this embodiment, the antibiotic is selected from penicillin G, benzylpenicillin, amoxicillin, cefazolin, cephalexin, cephotetan, cefoxitin, ceftriaxone, augmentin, amoxicillin, ampicillin (plus sulbactam), piperacillin (plus tazobactam), ertapenem, ciprofloxacin, imipenem, meropenem, levofloxacin, moxifloxacin, amikacin, clindamycin, azithromycin, doxycycline, vancomycin, Bactrim and metronidazole.

[0203] In one embodiment, the TLR 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.

[0204] In one embodiment, the TLR inhibitor is administered in combination with one or more antiplatelet agents and / or dual antiplatelet therapy. In one aspect of this embodiment, the antiplatelet agent and / or dual antiplatelet therapy is selected from aspirin, clopidogrel, dipyridamole, prasugrel, and ticagrelor.

[0205] In one embodiment, the TLR 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, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.

[0206] In one embodiment, the TLR 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.

[0207] In one embodiment, the TLR 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.

[0208] In one embodiment, the TLR inhibitor is administered in combination with one or more alpha and beta-blockers. In one aspect of this embodiment, the alpha and beta-blocker is carvedilol or labetalol hydrochloride.

[0209] In one embodiment, a TLR inhibitor is administered in combination with one or more interferons.

[0210] In one embodiment, the TLR 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.

[0211] In one embodiment, the TLR 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.

[0212] In one embodiment, the TLR inhibitor is administered in combination with one or more vasodilators. In one aspect of this embodiment, the one or more vasodilators are selected from isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, and minoxidil.

[0213] In one embodiment, the TLR inhibitor is administered in combination with one or more diuretics. In one aspect of this embodiment, the one or more diuretics are selected from acetazolamide, amiloride, bumetanide, chlorothiazide, chlorthalidone, furosemide, hydrochlorothiazide, indapamide, metolazone (metalozone), spironolactone and torsemide.

[0214] In one embodiment, TLR inhibitors are administered in combination with one or more muscle relaxants. In one aspect of the present embodiment, the muscle relaxant is a spasmolytic or antispasmodic agent. In another aspect of the present embodiment, one or more muscle relaxants are selected from carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, orphenadrine, tizanidine, baclofen, dantrolene and diazepam.

[0215] In one embodiment, the TLR inhibitor is administered in combination with one or more antiviral drugs. In one aspect of this embodiment, the antiviral drug is remdesivir.

[0216] In one embodiment, a TLR inhibitor is administered in combination with one or more additional therapeutic agents selected from antiparasitic drugs (including but not limited to hydroxychloroquine, chloroquine, ivermectin), antivirals (including but not limited to tranexamic acid, nafamostat, ribavirin, lopinavir / ritonavir, favipiravir, levitra, interferon beta-1a, interferon beta-1b, beta-interferon), intracellularly active antibiotics (including but not limited to azithromycin, nitrazoxamide) statins and other combined cholesterol-lowering and anti-inflammatory drugs (including but not limited to lovastatin), specific cytokine inhibitors (including but not limited to clazakizumab, adalimumab, etanercept, golimumab, infliximab, salimbizumab, tocilizumab, anakinra, ipavacumab, pirfenidone), complement inhibitors (including but not limited to ravulizumab-cwvz, eculizumab), anti-VEGF therapy (including but not limited to bevacizumab), anticoagulants (including but not limited to heparin, enoxaparin, apremilast, warfarin (coumadin)), JAK inhibitors (including but not limited to baricitinib, ruxolitinib, dapagliflozin), anti-inflammasome therapy (including but not limited to colchicine), sphingosine-1 phosphate receptor binding agents (including but not limited to fingolimod), N-methyl-d-aspartate (NDMA) receptor glutamate receptor antagonists (including but not limited to ifenprodil), l)), corticosteroids (including but not limited to prednisone, cortisol, dexamethasone, methylprednisolone), GM-CSF, anti-GM-CSF (otilimab), ATR-002, APN-01, camostat mesylate, arbidol, bramectin, IFX-1, PAX-1-001, BXT-25, NP-120, intravenous immunoglobulin (IVIG) and solnatide.

[0217] In some embodiments, the combination of a TLR inhibitor and one or more additional therapeutic agents reduces the effective amount (including but not limited to dosage, dosage concentration and / or total dosage) of the TLR inhibitor and / or one or more additional therapeutic agents to achieve the same result compared to the effective amount when the TLR inhibitor or additional therapeutic agent is administered alone. In some embodiments, when a corticosteroid is co-administered with a TLR inhibitor, for example, in an individual with high IFN-I activity, the effective dose of the corticosteroid can be reduced. In some embodiments, the combination of a TLR inhibitor and an additional therapeutic agent reduces the total duration of treatment compared to administering an additional therapeutic agent alone. In some embodiments, the combination of a TLR inhibitor and an additional therapeutic agent reduces the side effects associated with administering an additional therapeutic agent alone. In some embodiments, the combination of an effective amount of a TLR inhibitor and an additional therapeutic agent is more effective than administering an effective amount of a TLR inhibitor or additional therapeutic agent alone. In one embodiment, the combination of an effective amount of a TLR inhibitor and one or more additional therapeutic agents can bring one or more additional clinical benefits compared to using any one of the drugs alone. Promotion Methods

[0218] On the one hand, the present invention provides a method for promoting TLR inhibitors, including recommending the TLR inhibitor to a target audience for the purposes of treating a disease in an individual based on IFN-I activity. On the other hand, the present invention provides a method for promoting TLR inhibitors, including recommending the TLR inhibitor to a target audience for the purposes of treating a disease in an individual with high IFN-I activity, for example, an individual with an IFN-I feature score higher than a reference IFN-I feature score. The recommendation can be carried out in any available manner. In some embodiments, the recommendation is carried out by enclosing a packaging plug-in of the TLR inhibitor. The recommendation can also be carried out by enclosing a packaging plug-in of another therapeutic agent (such as a therapeutic agent that can be combined with a TLR inhibitor as mentioned herein). In some embodiments, the recommendation is carried out by a packaging plug-in, wherein the packaging plug-in provides instructions for receiving TLR inhibitor treatment after measuring IFN-I activity (for example, by determining IFN-I feature score), and in some embodiments also includes combining with another therapeutic agent. In some embodiments, after the recommendation, the patient receives treatment with a TLR inhibitor in combination with or without combining other therapeutic agents. In some embodiments, the package insert indicates that if the patient's sample has high IFN-I activity (e.g., the patient's IFN-I signature score is higher than the reference IFN-I signature score), the patient is treated with a TLR inhibitor. In some embodiments, the package insert indicates that if the patient's sample has low IFN-I activity (e.g., the patient's IFN-I signature score is lower than the reference IFN-I signature score), the patient is not treated with a TLR inhibitor. In some embodiments, high IFN-I activity indicates that the measured IFN-I activity is associated with the likelihood of an improved therapeutic effect when the patient receives a TLR inhibitor treatment, or vice versa. Other embodiments disclosed in the present invention E1. A method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample is indicative of the therapeutic effect of the TLR inhibitor. E2. A method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the therapeutic effect of the TLR inhibitor, and wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E3. A method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample is indicative of the therapeutic effect of the TLR inhibitor, and wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E4. The method of any one of E1 to E3, wherein the TLR inhibitor is predicted to have a therapeutic effect if the individual has high IFN-I activity; and wherein the TLR inhibitor is predicted to have no therapeutic effect if the individual has low IFN-I activity. E5. The method of any one of E1 to E3, wherein the IFN-I activity is compared to a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the TLR inhibitor is predicted to have a therapeutic effect; if the individual's IFN-I activity is lower than the reference IFN-I activity, the TLR inhibitor is predicted to not have a therapeutic effect. E6. A method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining a signature expression pattern of IFN-I in a sample from the individual, wherein the signature expression pattern of IFN-I in the sample indicates the therapeutic effect of the TLR inhibitor. E7. A method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining a characteristic expression pattern of IFN-I in a sample from the individual, wherein the characteristic expression pattern of IFN-I in the sample indicates the therapeutic effect of the TLR inhibitor, and the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E8. A method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining a signature expression pattern of IFN-I in a sample from the individual, wherein the signature expression pattern of IFN-I in the sample indicates the therapeutic effect of the TLR inhibitor, and the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E9. A method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining an IFN-I signature score in a sample from the individual, wherein if the determined IFN-I signature score is higher than a reference IFN-I signature score, the TLR inhibitor is predicted to have a therapeutic effect, and if the determined IFN-I signature score is lower than the reference IFN-I signature score, the TLR inhibitor is predicted to not have a therapeutic effect. E10. A method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining an IFN-I signature score in a sample from the individual, wherein if the determined IFN-I signature score is higher than a reference IFN-I signature score, the TLR inhibitor is predicted to have a therapeutic effect, and if the determined IFN-I signature score is lower than the reference IFN-I signature score, the TLR inhibitor is predicted to not have a therapeutic effect, and wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E11. A method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining an IFN-I signature score in a sample from the individual, wherein if the determined IFN-I signature score is higher than a reference IFN-I signature score, then the TLR inhibitor is predicted to have a therapeutic effect, and if the determined IFN-I signature score is lower than the reference IFN-I signature score, then the TLR inhibitor is predicted to not have a therapeutic effect, and wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E12. A method of predicting the suitability of a diseased individual to initiate TLR inhibitor therapy, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the suitability of the individual to initiate said therapy. E13. A method for predicting the suitability of a diseased individual to initiate TLR inhibitor therapy, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the suitability of the individual to initiate said therapy and wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E14. A method for predicting the suitability of a diseased individual to initiate TLR inhibitor therapy, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the suitability of the individual to initiate said therapy, wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E15. The method of any one of E12 to E14, wherein individuals with high IFN-I activity are assessed as suitable for initiating treatment, and individuals with low IFN-I activity are assessed as unsuitable for initiating treatment. E16. The method of any one of E12 to E14, wherein the IFN-I activity is compared to a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the individual is assessed as suitable for initiating the treatment; and if the individual's IFN-I activity is lower than the reference IFN-I activity, the individual is assessed as unsuitable for initiating the treatment. E17. A method of predicting the suitability of a diseased individual to initiate TLR inhibitor therapy, comprising determining an IFN-I signature expression pattern in a sample from the individual, wherein the IFN-I signature expression pattern in the sample indicates the suitability of the individual to initiate said therapy. E18. A method for predicting the suitability of a diseased individual to initiate TLR inhibitor therapy, comprising determining an IFN-I signature expression pattern in a sample from the individual, wherein the IFN-I signature expression pattern in the sample indicates the suitability of the individual to initiate said therapy and wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E19. A method for predicting the suitability of a diseased individual to initiate TLR inhibitor therapy, comprising determining an IFN-I signature expression pattern in a sample from the individual, wherein the IFN-I signature expression pattern in the sample indicates the suitability of the individual to initiate said therapy, wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E20. A method for predicting the suitability of a diseased individual for initiating treatment with a TLR inhibitor, comprising determining an IFN-I signature score in a sample from the individual, wherein if the determined IFN-I signature score is higher than a reference IFN-I signature score, the individual is assessed as suitable for initiating treatment; if the determined IFN-I signature score is lower than the reference IFN-I signature score, the individual is assessed as unsuitable for initiating treatment. E21. A method for predicting the suitability of a diseased individual for initiating treatment with a TLR inhibitor, comprising determining an IFN-I signature score in a sample from the individual, wherein if the determined IFN-I signature score is higher than a reference IFN-I signature score, the individual is assessed as suitable for initiating treatment; if the determined IFN-I signature score is lower than the reference IFN-I signature score, the individual is assessed as unsuitable for initiating treatment, wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E22. A method for predicting the suitability of a diseased individual for initiating treatment with a TLR inhibitor, comprising determining an IFN-I signature score in a sample from the individual, wherein if the determined IFN-I signature score is higher than a reference IFN-I signature score, the individual is assessed as suitable for initiating treatment; if the determined IFN-I signature score is lower than the reference IFN-I signature score, the individual is assessed as unsuitable for initiating treatment, wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, Ia; or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E23. A method of predicting the suitability of a diseased individual receiving a TLR inhibitor therapy to continue said therapy, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the suitability of the individual to continue said therapy. E24. A method for predicting the suitability of a diseased individual who is being treated with a TLR inhibitor to continue said treatment, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the suitability of the individual to continue said treatment, and wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E25. A method for predicting the suitability of a diseased individual who is being treated with a TLR inhibitor to continue said treatment, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity in the sample indicates the suitability of the individual to continue said treatment, and wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E26. The method according to any one of E23 to E25, wherein individuals with high IFN-I activity are assessed as suitable for continued treatment, while individuals with low IFN-I activity are assessed as unsuitable for continued treatment. E27. According to the method described in any one of E23 to E25, the IFN-I activity is compared with the reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the individual is assessed as suitable for continuing the treatment; if the individual's IFN-I activity is lower than the reference IFN-I activity, the individual is assessed as not suitable for continuing the treatment. E28. A method for predicting the suitability of a diseased individual who is being treated with a TLR inhibitor to continue said treatment, comprising determining an IFN-I signature expression pattern in a sample from the individual, wherein the IFN-I signature expression pattern in the sample indicates the suitability of the individual to continue said treatment. E29. A method for predicting the suitability of a diseased individual who is being treated with a TLR inhibitor to continue said treatment, comprising determining an IFN-I signature expression pattern in a sample from the individual, wherein the IFN-I signature expression pattern in the sample indicates the suitability of the individual to continue said treatment, and wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E30. A method for predicting the suitability of a diseased individual who is being treated with a TLR inhibitor to continue said treatment, comprising determining an IFN-I signature expression pattern in a sample from the individual, wherein the IFN-I signature expression pattern in the sample indicates the suitability of the individual to continue said treatment, and wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4for R 5 is methyl or -CF3, and ring A is E31. A method for predicting the suitability of a diseased individual who is being treated with a TLR inhibitor to continue said treatment, comprising determining an IFN-I signature score in a sample from said individual, wherein if the determined IFN-I signature score is higher than a reference IFN-I signature score, said individual is assessed as suitable for continuing said treatment, and if the determined IFN-I signature score is lower than the reference IFN-I signature score, said individual is assessed as not suitable for continuing said treatment. E32. A method for predicting the suitability of a diseased individual who is being treated with a TLR inhibitor to continue the treatment, comprising determining an IFN-I signature score in a sample from the individual, wherein if the determined IFN-I signature score is higher than a reference IFN-I signature score, the individual is assessed as suitable for continuing the treatment, and if the determined IFN-I signature score is lower than the reference IFN-I signature score, the individual is assessed as not suitable for continuing the treatment, and wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E33. A method for predicting the suitability of a diseased individual who is being treated with a TLR inhibitor to continue said treatment, comprising determining an IFN-I signature score in a sample from the individual, wherein if the determined IFN-I signature score is higher than a reference IFN-I signature score, the individual is assessed as suitable for continuing said treatment, and if the determined IFN-I signature score is lower than the reference IFN-I signature score, the individual is assessed as unsuitable for continuing said treatment, and wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E34. A TLR inhibitor for use in a method of treating a disease in an individual, comprising administering said TLR inhibitor to said individual, wherein treatment is based on IFN-I activity in a sample from said individual. E35. A TLR inhibitor for use in a method of treating a disease in an individual, comprising administering the TLR inhibitor to the individual, wherein the treatment is based on IFN-I activity in a sample from the individual, and wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E36. A TLR inhibitor for use in a method of treating a disease in a subject, comprising administering said TLR inhibitor to said subject, wherein treatment is based on IFN-I activity in a sample from said subject, and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E37. A TLR inhibitor for use as described in any one of E34 to E36, wherein the IFN-I activity in a sample from the individual is compared with a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, the TLR inhibitor is administered to the individual. E38. A TLR inhibitor for use in a method of treating a disease in an individual, comprising selecting an individual suffering from the disease and having high IFN-I activity, and administering a TLR inhibitor to the individual. E39. A TLR inhibitor for use in a method of treating a disease in an individual, comprising selecting an individual suffering from the disease and having high IFN-I activity, and administering the TLR inhibitor to the individual, wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E40. A TLR inhibitor for use in a method of treating a disease in an individual, comprising selecting an individual suffering from the disease and having high IFN-I activity, and administering to the individual the TLR inhibitor, wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E41. A TLR inhibitor for use according to any one of E38 to E40, wherein the individual is selected as having high IFN-I activity by comparing the IFN-I activity in a sample from the individual with a reference IFN-I activity and determining that the IFN-I activity of the individual is higher than the reference IFN-I activity. E42. A TLR inhibitor for use in a method of treating a disease in an individual, comprising administering said TLR inhibitor to said individual, wherein treatment is based on a signature expression pattern of IFN-I in a sample from said individual. E43. A TLR inhibitor for use in a method of treating a disease in an individual, comprising administering the TLR inhibitor to the individual, wherein the treatment is based on a characteristic expression pattern of IFN-I in a sample from the individual, wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E44. A TLR inhibitor for use in a method of treating a disease in a subject, comprising administering said TLR inhibitor to said subject, wherein treatment is based on a characteristic expression pattern of IFN-I in a sample from said subject, wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E45. A TLR inhibitor for use in a method of treating a disease in an individual, comprising determining an IFN-I signature score in a sample from the individual, and if the IFN-I signature score is higher than a reference IFN-I signature score, administering a TLR inhibitor to the individual. E46. A method for treating a disease in an individual using a TLR inhibitor, comprising determining an IFN-I signature score in a sample from the individual, and administering a TLR inhibitor to the individual if the IFN-I signature score is higher than a reference IFN-I signature score, wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E47. A TLR inhibitor for use in a method of treating a disease in an individual, comprising determining an IFN-I signature score in a sample from the individual, and administering a TLR inhibitor to the individual if the IFN-I signature score is higher than a reference IFN-I signature score, wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is E48. A combination of a TLR inhibitor and a corticosteroid for use in a method of treating a disease in an individual, comprising selecting an individual suffering from said disease and having high IFN-I activity, and administering said combination to said individual. E49. A combination of a TLR inhibitor and a corticosteroid for use in a method of treating a disease in an individual, comprising selecting an individual suffering from the disease and having high IFN-I activity, and administering the combination to the individual, wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor and the corticosteroid is a glucocorticosteroid. E50. A method for treating a disease in an individual comprising selecting an individual having the disease and having high IFN-I activity and administering the combination to the individual, wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is The corticosteroid is a glucocorticosteroid. E51. The combination for use of any one of E48 to E50, wherein the individual is selected as having high IFN-I activity by comparing the IFN-I activity in a sample from the individual to a reference IFN-I activity and determining that the IFN-I activity of the individual is higher than the reference IFN-I activity. E52. A combination of a TLR inhibitor and a corticosteroid for use in a method of treating a disease in an individual, comprising determining an IFN-I signature score in a sample from the individual and administering the combination to the individual if the IFN-I signature score is higher than a reference IFN-I signature score. E53. A combination of a TLR inhibitor and a corticosteroid for use in a method of treating a disease in an individual, comprising determining an IFN-I signature score in a sample from the individual, and administering the combination to the individual if the IFN-I signature score is higher than a reference IFN-I signature score, wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor, and wherein the corticosteroid is a glucocorticosteroid. E54. A combination of a TLR inhibitor and a corticosteroid for use in a method of treating a disease in an individual, comprising determining an IFN-I signature score in a sample from the individual, and administering a TLR inhibitor to the individual if the IFN-I signature score is higher than a reference IFN-I signature score, wherein the TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is The corticosteroid is a glucocorticosteroid. E55. The method, TLR inhibitor for use, or combination as described in any one of E9, E10, E11, E20, E21, E22, E31, E32, E33, E45, E46, E47, E52, E53, and E54, wherein determining the IFN-I signature score comprises the following steps: (i) obtaining a sample from the individual; (ii) measuring the expression level of each gene in the IFN-I signature in the sample; (iii) normalizing the expression levels of individual genes; and (iv) Calculate the arithmetic mean of the normalized gene expression levels to obtain the IFN-I signature score. E56. The method or TLR inhibitor for use of any one of E6, E7, E8, E17, E18, E19, E28, E29, E30, E42, E43 and E44, wherein the IFN-I signature in the IFN-I signature expression pattern comprises one or more genes selected from the group consisting of BST2, CMPK2, CXCL10, EPSTI1, GBP5, HERC5, HERC6, IFI6, IFI27, IFI44, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3, IRF7, ISG15, LY6E, MX1, MX2, OAS1, OAS2, OAS3, OASL, PKR, RSAD2, SIGLEC1, STAT1, TNFSF10 and USP18. E57. A TLR inhibitor according to the method or use of E56, wherein the IFN-I signature of the IFN-I signature expression pattern comprises one or more genes selected from HERC5, IFI27, IFIT1 and RSAD2. E58. A TLR inhibitor according to the method or use of E57, wherein the IFN-I signature of the IFN-I signature expression pattern comprises or consists of HERC5, IFI27, IFIT1 and RSAD2. E59. The method, TLR inhibitor for use or combination of any one of E9, E10, E11, E20, E21, E22, E31, E32, E33, E45, E46, E47 and E55, wherein the IFN-I signature in the IFN-I signature score comprises one or more genes selected from the group consisting of BST2, CMPK2, CXCL10, EPSTI1, GBP5, HERC5, HERC6, IFI6, IFI27, IFI44, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3, IRF7, ISG15, LY6E, MX1, MX2, OAS1, OAS2, OAS3, OASL, PKR, RSAD2, SIGLEC1, STAT1, TNFSF10 and USP18. E60. The method, TLR inhibitor for use or combination of E59, wherein the IFN-I signature of the IFN-I signature score comprises one or more genes selected from HERC5, IFI27, IFIT1 and RSAD2. E61. The method, TLR inhibitor for use or combination of E60, wherein the IFN-I signature of the IFN-I signature score comprises or consists of HERC5, IFI27, IFIT1 and RSAD2. E62. The method, TLR inhibitor for use or combination of any one of E9, E10, E11, E20, E21, E22, E31, E32, E33, E45, E46, E47 and E55, wherein the IFN-I signature of the IFN-I signature score consists of genes HERC5, IFI27, IFIT1 and RSAD2, and the reference IFN-I signature score is -0.5. E63. The method, TLR inhibitor for use or combination of E55, wherein the IFN-I signature of the IFN-I signature score consists of genes HERC5, IFI27, IFIT1 and RSAD2, is normalized using ACTB, GAPDH and TFRC, and the reference IFN-I signature score is -0.5. E64. The method, TLR inhibitor for use or combination according to any one of E5, E16, E27, E37, E41 and E51, wherein the reference IFN-1 activity is defined as follows: (i) defining a patient population having the same disease as the individual for whom IFN-I activity is determined and being treated with the same TLR inhibitor as the individual; (ii) determining IFN-I activity in a sample from each patient in the patient population prior to treatment with the TLR inhibitor; (iii) determining the treatment effect for each patient in the patient population after treatment with the TLR inhibitor; (iv) stratifying the patient population into groups with better or worse treatment outcomes; and (v) The IFN-I activity dividing the patients into two groups was defined as the reference IFN-I activity. E65. The method, TLR inhibitor for use, or combination as described in any one of E9, E10, E11, E20, E21, E22, E31, E32, E33, E45, E46, E47, E52, E53, and E54, wherein the reference IFN-1 signature score is defined as follows: (i) defining a population of patients who have the same disease as the individual for whom the IFN-I signature score was determined and who are treated with the same TLR inhibitor as the individual; (ii) determining an IFN-I signature score in a sample from each patient in the patient population prior to treatment with the TLR inhibitor, wherein the IFN-I signature score is based on the same IFN-I signature as the IFN-I signature score for the individual for whom the IFN-I signature score was determined; (iii) determining the treatment effect for each patient in the patient population after treatment with the TLR inhibitor; (iv) stratifying the patient population into groups with better or worse treatment outcomes; and (v) The IFN-I signature score that divided the patients into two groups was defined as the reference IFN-I signature score. E66. The method, the TLR inhibitor for use or the combination according to any one of E1 to E65, wherein the disease is caused, mediated and / or propagated by TLR activity. E67. The method, the TLR inhibitor for use or the combination according to any one of E1 to E66, wherein the disease is an autoimmune disease or a viral disease. E68. The method, TLR inhibitor for use or combination according to any one of E1 to E67, wherein the disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, type I diabetes, multiple sclerosis, Sjogren's disease, polymyositis and dermatomyositis. E69. The method, the TLR inhibitor for use or the combination as described in any one of E1 to E66, wherein the disease is COVID-19. E70. The method, the TLR inhibitor for use or the combination according to any one of E1 to E66, wherein the disease is systemic lupus erythematosus or cutaneous lupus erythematosus. E71. The method, the TLR inhibitor for use or the combination according to any one of E1 to E66, wherein the disease is polymyositis or dermatomyositis. E72. The method, the TLR inhibitor for use or the combination according to any one of E1 to E71, wherein the TLR inhibitor is selected from the group consisting of: or a pharmaceutically acceptable salt thereof. E73. The method, TLR inhibitor or combination according to E72, wherein the TLR inhibitor is or a pharmaceutically acceptable salt thereof.

[0219] All references cited herein are incorporated by reference into the disclosure of the present invention.

[0220] Although methods and materials similar or equivalent to those described herein can be used to implement or test the present invention, suitable examples are described below. These examples should be construed as not being limited to the feature combinations explicitly shown; the illustrative features may be recombined in any manner as long as the technical problem of the present invention is solved. Similarly, features from any claim may be combined with features from one or more other claims. While the present invention has been generally and specifically described, it is not limited to the following examples. Example Example 1: Comparison of IFN-I characteristics

[0221] The aim of this study was to evaluate the correlation of the Dx_4IFN-I signature with various published IFN-I signatures listed in Table 1:

[0222] Table 1. IFN-I characteristics used for correlation analysis:

[0223] In order to compare IFN-I signatures, the gene expression data of 417 SLE patients receiving placebo from clinical study NCT01972568 were used. For each SLE patient, the IFN-I signature score of each IFN-I signature in Table 1 was calculated, and the correlation coefficient r was calculated (the closer r is to zero, the weaker the linear relationship, 1 and -1 represent complete positive correlation and complete negative correlation, respectively). As shown in Figure 1, all IFN-I signatures (including DX_4IFN-I signature) were found to be highly correlated. Therefore, DX_4IFN-I signature represents a comparable index of type I IFN status compared to other IFN-I signatures previously reported in the literature. Example 2: Use of IFN-I signature as a biomarker

[0224] An exploratory phase II clinical study was conducted in patients hospitalized with COVID-19 pneumonia, specifically to evaluate whether the TLR inhibitor enpatoran could shorten recovery time (NCT04448756).

[0225] Statistical testing was considered exploratory, and results were presented without correction for type I multiplicity. Recovery time, defined as the time from day 1 to the first occurrence of a 9-point WHO score of ≤3, was estimated using Kaplan-Meier (KM) analysis and presented with two-sided 95% confidence intervals (CIs). The efficacy of each dose level compared to placebo was assessed using a stratified log-rank test.

[0226] Before treatment, at baseline, patient blood was collected directly into PAXgene RNA tubes for gene expression measurement. IFN-I activity was measured by DxTerity Diagnostics (Rancho Dominguez, California, USA) using the IFN-1 test, a commercially available chemical ligation-dependent probe amplification and gene expression test with relative quantitative analysis by capillary electrophoresis. Samples were tested and analyzed as previously described (Kim et al., J Mol Diagn. 2015 Mar; 17(2): 118-27). The IFN-I test measures the expression levels of four IFN response genes (HERC5, IFI27, IFIT1, and RSAD2) relative to the expression levels of three housekeeping normalization genes (ACTB, GAPDH, and TFRC), i.e., the Dx-4 IFN-I signature. The standardized expression value for each corresponding response gene was calculated using the following function: standardized expression gene i = Log2 (height gene i) – mean (Log2 (normalization gene height)). IFN-1 characteristic score is calculated by averaging the standardized expression values of four response genes.The cutoff value (-0.5) between high IFN-1 characteristic score and low IFN-1 characteristic score is set as the mean+2SD (95th percentile) of the IFN-1 characteristic score of 281 healthy donors.This cutoff value falls into the trough range of the bimodal distribution of the IFN-1 characteristic score observed in the SLE patient group.

[0227] 149 patients received placebo (n = 49) or 50 mg (n = 54) or 100 mg (n = 46) of empatolan twice daily. The mean IFN-I signature score (50 mg BID – 0.84; 100 mg BID – 0.74; placebo – 0.91) and the proportion of patients with a high IFN-I signature score at baseline (50 mg BID 35%; 100 mg BID 43%; placebo 35%) were generally consistent across treatment groups, as shown in Table 2:

[0228] Table 2. Baseline IFN-Profiling:

[0229] Although both empatolan groups showed a numerical trend toward higher recovery rates (50 mg BID n=48, 88.9%, P=0.054; 100 mg BID n=42, 91.3%, P=0.107) compared with the placebo group (n=37, 75.5%), the primary efficacy endpoint of time to recovery from day 1 to day 28 was not met in the unstratified patient population. Median time to recovery was similar across groups (3.4-3.9 days), and differentiation did not occur until day 6 ( Figure 2 ).

[0230] In the subgroup with a high baseline IFN-I signature score, the KM-estimated cumulative recovery rate by day 14 was higher in patients who received empatolan (50 mg BID n=11, 78.6% [95% CI 55.2, 94.8]; 100 mg BID n=15, 88.2% [68.8, 98.0]) than in those who received placebo (n=8, 53.3% [31.1, 78.8]; Figure 3 This was consistent with the day 28 results, when recovery rates were 73.3% (P = 0.031) and 88.2% (P = 0.031) for empatolan 50 mg BID and 100 mg BID, respectively, compared with 53.3% for placebo. The day 28 recovery rate was higher in the placebo-treated patients in the low IFN-I signature score subgroup at baseline (n = 25, 86.2%) than in the high IFN-I signature score subgroup, with no significant difference between the placebo and empatolan groups (50 mg BID n = 28, 100%, P = 0.236; 100 mg BID n = 21, 91.3%, P = 0.458).

[0231] These exploratory analyses showed that patients with a high baseline IFN-I signature score, as determined by widespread immune activation, had a better time to recovery with empatolan than with placebo. More generally, this suggests that IFN-I activity is a potential predictive biomarker for TLR inhibitors such as empatolan in patients with COVID-19 and other autoimmune and inflammatory diseases such as lupus. Example 3: Combination therapy with TLR inhibitors and corticosteroids in the context of IFN-α pretreatment

[0232] Previous studies have shown that IFN-α can reduce the effectiveness of glucocorticoids (GC) (Guiducci et al., Nature. 2010 Jun 17; 465(7300): 937-41). Therefore, the purpose of this experiment was to determine whether IFN-α pretreatment would affect the response of peripheral blood mononuclear cells (PBMCs) to TLR7 and / or TLR8 agonists, and whether the effectiveness of the glucocorticoid dexamethasone (Dex) would be further reduced.

[0233] Materials and methods

[0234] Blood was obtained from healthy donors by leukopak (New York Blood Center, New York, USA). PBMCs were isolated using ACCUPSIN tubes according to the manufacturer's protocol (Sigma-Aldrich, Missouri, USA). Cell viability was assessed using trypan blue staining (BioRad, California, USA). Cells were cultured in RPMI 1640 medium (Gibco, ThermoFisher Scientific, Massachusetts, USA) containing 10% fetal bovine serum (Corning, Arizona, USA) and 1x penicillin-streptomycin (Gibco).

[0235] PBMCs were pretreated with Dex (Sigma-Aldrich) for 15 minutes at a starting concentration of 10 μM in a 3-fold serial dilution, followed by the addition of 1 μM CMPD2 (an in-house synthesized TLR7 and TLR8 inhibitor; structure published (Vlach et al., J Pharmacol Exp Ther. 2021 Mar;376(3):397-409)) in a 2-fold serial dilution. Cells were then stimulated with 3–5 μM of the TLR7 and TLR8 agonists R848 (InvivoGen, Toulouse, France), 3 μM of the TLR7 agonist CL-087 (in-house synthesized), or 1 μM of the TLR8 agonist motolimod (Selleckchem, TX, USA). Plates were incubated overnight at 37°C and 5% CO2. Cell viability was assessed using the CellTiter Glo Luminescent Cell Viability Assay (Promega, Wisconsin, USA).

[0236] Cytokine secretion in the supernatant was measured using AlphaLISA assay kits for human interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-α (IFN-α) according to the manufacturer's protocol (Perkin Elmer, Ohio, USA). When pretreatment with cytokines was indicated, PBMCs were exposed to 10 ng / mL IFN-α2a (Sigma-Aldrich) for 4–5 hours before treatment with the above-mentioned compounds and TLR7 and / or 8 agonists.

[0237] Data were analyzed using Graphpad Prism (Dotmatics, MA, USA). Group medians were determined and statistical significance was tested using the Kruskal-Wallis test, analysis of variance, or T-test (as indicated in the figure legends). Synergy was assessed on Loewe matrix plots using Combenefit (SourceForge, CA, USA) as described (DiVeroli et al., Bioinformatics. 2016 Sep 15; 32(18): 2866-8), and synergy scores were calculated based on the area under the curve.

[0238] result

[0239] The results showed that IFN-α pretreatment enhanced the responsiveness of PBMC to R848, as measured by IL-6 secretion ( Figure 4 A and B; Figure 5 A and C). Dex alone was less effective than the combination of Dex and CMPD2 in blocking R848-induced IL-6 secretion in IFN-α-pretreated cells. Low-dose Dex combined with CMPD2 treatment reduced this enhanced responsiveness ( Figure 4 B), and analyzed by Combenefit ( Figure 5 B and D) demonstrate synergy, with similar synergy scores in cells stimulated with R848 with and without IFN-α pretreatment ( Figure 4 C) These results were not due to changes in cell viability, which did not vary significantly across the matrix titration dose range tested (data not shown).

[0240] Taken together, these results suggest that even in a pre-existing proinflammatory milieu, as is conceivable in autoimmune diseases such as lupus, inhibition of TLR7 and / or TLR8 can enhance the effects of glucocorticoids, thereby providing a synergistic anti-inflammatory benefit.

[0241] Example 4: Stimulation of IFN-α by RNA-containing immune complexes

[0242] To further confirm the link between TLR7 and / or TLR8 and the expression of IFN-I and interferon-stimulated genes (ISGs), we examined the ability of immune complexes from patients with autoimmune diseases to stimulate the expression of IFN-α and ISGs by peripheral blood mononuclear cells (PBMCs) from healthy donors, and the ability of the TLR inhibitor empatolan to block this stimulation.

[0243] Materials and methods

[0244] Blood samples were collected from patients with lupus nephritis (LN), systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), and healthy controls (HC). Plasma was separated and frozen. Immunoglobulin G (IgG) was then purified using Protein A resin and the protein concentration was determined.

[0245] Immune complex formation and peripheral blood mononuclear cell (PBMC) stimulation: To generate necrotic cell lysates, human embryonic kidney 293 cells were cultured at 50 x 10 6 Cells were suspended in phosphate-buffered saline (PBS; Gibco, Grand Island, NY) at a concentration of 10 cells / mL. The cells were frozen at -80°C for 10 minutes and then thawed at 37°C. Four freeze / thaw cycles were performed. The lysate was centrifuged at 400 g for 5 minutes to separate unlysed cells, and the supernatant was collected as the necrotic cell lysate.

[0246] PBMCs were isolated from leukopacks collected from healthy donors (New York Blood Center, New York, NY) using Ficoll-Paque Plus (Cytiva Life Sciences, Uppsala, Sweden) in sodium heparin tubes. Cells were plated in 96-well U-bottom plates (4 x 10 5 PBMCs were cultured in RPMI 1640 medium (Gibco, Grand Island, NY) supplemented with 10% fetal bovine serum (FBS; Corning, The Woodlands, CA) (10 cells / well). Before stimulation, PBMCs were pretreated with 1 μM empatopan for 30 minutes. IgG purified from patient plasma (0.1 mg / mL) and necrotic cell lysate (10% volume / volume) were added to PBMCs and incubated at 37°C for 24 hours. Supernatants were collected and cytokine production was measured using AlphaLISA (PerkinElmer, Waltham, MA).

[0247] NanoString Analysis: Gene expression in purified RNA samples was analyzed using NanoString. A custom panel of 46 genes containing inflammatory markers was used. A total of 500 ng of RNA per sample was run on the nCounter Pro Analysis System (NanoString, Seattle, WA). Data were processed using nSolver (NanoString), and the Log2 fold change was calculated for each sample relative to cells treated with control PBMC supernatant.

[0248] result

[0249] IgG isolated from 69 patients with idiopathic inflammatory myopathies (IIMs), including DM, PM, and IBM, as well as 15 patients with lupus and 18 healthy controls, was combined with necrotic cell lysates to form immune complexes, which were then added to PBMCs from healthy donors. Immune complexes generated using IgG from 6 / 7 LN patients tested and 2 / 8 SLE patients tested stimulated IFN-α production ( Figure 6 A) Within the IIM subset, immune complexes from patients with PM and DM are reactive to IFN-α, whereas those from IBM are not.

[0250] When PBMCs were pretreated with empatolan, IFN-α production was completely inhibited ( Figure 6 B), indicating that IFN-α production is mediated by TLR7 and / or TLR8. IgG alone and necrotic cell lysate had no stimulatory activity (data not shown).

[0251] Gene expression analysis of PBMC lysates showed that samples stimulated with IFN-α protein also induced changes in gene expression, with the most significant effects being on IFN-stimulated genes (ISGs; Figure 7A ) was induced. The IFN-I signature score (IFN GS score), which is calculated based on ISG expression, was induced and was also significantly upregulated in patients with positive protein induction ( Figure 7B ).

[0252] The suitability of IFN-I activity as a predictive biomarker for TLR inhibition was further supported by the demonstration that stimulation of IFN-α and ISG expression by immune complexes in patients with autoimmune diseases is dependent on TLR7 and / or TLR8.

Claims

1. The use of IFN-I activity as a predictive biomarker for individuals with TLR inhibitors. The TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor.

2. A method for predicting the therapeutic effect of a TLR inhibitor in a diseased individual, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-1 activity in the sample is indicative of the therapeutic effect of the TLR inhibitor; and The TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor.

3. A method for predicting the suitability of a diseased individual for initiating TLR inhibitor therapy, comprising determining IFN-I activity in a sample from the individual, wherein IFN-1 activity in said sample indicates suitability of the individual to initiate said treatment; and The TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor.

4. A method for predicting the suitability of a diseased individual who is being treated with a TLR inhibitor to continue said treatment, comprising determining IFN-I activity in a sample from the individual, wherein IFN-1 activity in the sample indicates suitability of the individual to continue the treatment; and The TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor.

5. A TLR inhibitor for use in a method of treating a disease in an individual, comprising administering the TLR inhibitor to the individual, in, The treatment is based on IFN-I activity in a sample from the individual; and wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor.

6. The method according to claim 2, in, If the individual's IFN-I activity is determined to be high, the TLR inhibitor is predicted to have a therapeutic effect; if the individual's IFN-I activity is determined to be low, the TLR inhibitor is predicted to have no therapeutic effect.

7. The method according to claim 3, in, If the individual's IFN-I activity is determined to be high, the individual is assessed as suitable for initiating the treatment; if the individual's IFN-I activity is determined to be low, the individual is assessed as unsuitable for initiating the treatment.

8. The method according to claim 4, in, If the individual's IFN-I activity is determined to be high, the individual is assessed as suitable for continuing the treatment; if the individual's IFN-I activity is determined to be low, the individual is assessed as unsuitable for continuing the treatment.

9. The TLR inhibitor for use according to claim 5, in, If the individual's IFN-I activity is determined to be high, a TLR inhibitor is administered to the individual.

10. A TLR inhibitor for the method or use according to any one of claims 1 to 9, in, IFN-1 activity is determined by determining an IFN-1 signature expression pattern or IFN-1 signature score in a sample from an individual.

11. The method according to claim 2, in, determining IFN-1 activity by determining an IFN-1 signature score in a sample from the individual; and If the individual is determined to have high IFN-I activity based on a comparison of the IFN-I signature score in the sample from the individual with the reference IFN-I signature score, then the TLR inhibitor is predicted to have a therapeutic effect; and / or if the individual is determined to have low IFN-I activity based on a comparison of the IFN-I signature score in the sample from the individual with the reference IFN-I signature score, then the TLR inhibitor is predicted to not have a therapeutic effect.

12. The method according to claim 3, in, determining IFN-1 activity by determining an IFN-1 signature score in a sample from the individual; and wherein the individual is assessed as suitable for initiating the treatment if the individual is determined to have high IFN-I activity based on a comparison of the IFN-I signature score in the sample from the individual with the reference IFN-I signature score, and / or wherein the individual is assessed as unsuitable for initiating the treatment if the individual is determined to have low IFN-I activity based on a comparison of the IFN-I signature score in the sample from the individual with the reference IFN-I signature score.

13. The method according to claim 4, in, determining IFN-1 activity by determining an IFN-1 signature score in a sample from the individual; and wherein the individual is assessed as suitable for continuing the treatment if the individual is determined to have high IFN-I activity based on a comparison of the IFN-I signature score in the sample from the individual with the reference IFN-I signature score, and / or wherein the individual is assessed as unsuitable for continuing the treatment if the individual is determined to have low IFN-I activity based on a comparison of the IFN-I signature score in the sample from the individual with the reference IFN-I signature score.

14. The TLR inhibitor for use according to claim 5, in, determining IFN-1 activity by determining an IFN-1 signature score in a sample from the individual; and wherein the TLR inhibitor is administered to the individual if the individual is determined to have high IFN-I activity based on a comparison of the IFN-I signature score in a sample from the individual with a reference IFN-I signature score.

15. The method or TLR inhibitor for use according to any one of claims 1 to 14, wherein The TLR7 and / or TLR8 small molecule inhibitor is selected from the following group: 5-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoline-8-carbonitrile; (3R,5S)-1-(8-methoxy-1,7-naphthyridin-5-yl)-5-methylpiperidin-3-amine; 2-{4-[2-(7,8-dimethyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(propan-2-yl)-1H-indol-5-yl]piperidin-1-yl}acetamide; rel-(2R,6R)-4-(8-cyanoquinolin-5-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-6-methylmorpholine-2-carboxamide hydrochloride; (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide; and (R)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide or a pharmaceutically acceptable salt of any of these compounds.

16. The method or use of any one of claims 1 to 14, wherein the TLR7 and / or TLR8 small molecule inhibitor is a compound of formula Ia, Ia; or a pharmaceutically acceptable salt thereof, wherein R 1 is -OMe or -CN, X is O or CH2, R 4 for R 5 is methyl or -CF3, and ring A is 17. A TLR inhibitor for use as claimed in any one of claims 5, 9, 10 and 14, wherein the TLR inhibitor is administered in combination with a glucocorticosteroid.

18. A TLR7 and / or TLR8 inhibitor and a glucocorticosteroid for use in a method of treating a disease in an individual with high IFN-I activity, wherein the method comprises administering the TLR7 and / or TLR8 inhibitor and the glucocorticosteroid in combination to the individual.

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