Use of IFN-I activity as a biomarker for TLR inhibitor therapy

Abstract

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

Description

[Technical Field]

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

[0002] The TLR family is composed of multiple members with different specificities and is part of a cellular pathogen pattern recognition system that has evolved as a defense against various infections. The functional expression of selected TLRs in tissues varies greatly. Some receptors, such as TLR4 (stimulated by E. coli lipopolysaccharide (LPS)), are located on the cell surface, e.g., on epithelial cells, whereas others, such as TLR3, 7, 8, and 9, are located on the endosomal membrane of certain immune cells. All of the latter are activated by nucleic acids, but they recognize various types of nucleic acids. For example, TLR9 is activated by single-stranded DNA containing CpG subsequences, TLR7 and 8 are activated by single-stranded RNA, and TLR3 is activated by double-stranded RNA. TLR activation triggers various downstream signaling cascades, including signaling through nuclear factor kB (NF-kB), interferon (IFN) response factors (IRFs), and mitogen-activated protein (MAP) kinases, resulting in the transcription of various immune response genes, including proinflammatory cytokines, stimulatory immune cytokines, chemokines, and costimulatory molecules (Farrugia and Baron, Int J Inflam. 2017;2017:8391230).

[0003] TLRs are involved in a variety of autoimmune and inflammatory diseases, the most obvious example being the role played by TLR7 in the pathogenesis of systemic lupus erythematosus (Barrat and Coffman, Immunol Rev, 223:271-283, 2008). TLR7 has also been implicated in systemic sclerosis, myositis, and rheumatoid arthritis (Duffy and O'Reilly, Immunotargets Ther. 2016;5:69-80). Similarly, TLR8 has been associated with rheumatoid arthritis and systemic sclerosis, among others (Duffy and O'Reilly, loc.cit).

[0004] Type I interferons (IFN-I) are also part of the innate immune response to pathogens. They form part of several parallel signaling cascades, elicited, for example, by TLR7 and TLR8. Apart from TLRs, IFN-I can be induced by a series of other host pattern recognition receptors, including Rig-I-like receptors (RLRs), NOD-like receptors (NLRs), and DNA sensors, following recognition of pathogen components. The released IFN-I then binds to the IFN-α receptor (IFNAR), triggering a signaling cascade that leads to the expression of interferon-inducible genes (ISGs). Similar to TLRs, IFN-I signaling has also been implicated in various diseases, particularly autoimmune disorders, and IFN-I activity has been investigated as a possible biomarker for such diseases by determining the expression of one or more genes regulated by IFN-I. For some treatments, a correlation between clinical response to treatment and IFN-I activity has been observed, with some positive correlations and others negative correlations (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 treatment with TLR inhibitors. Summary of the Invention

[0006] The present invention relates to the use of IFN-I activity as a predictive biomarker of therapeutic outcome to therapy with TLR inhibitors.

[0007] In one aspect, the present invention provides a method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, the method comprising determining IFN-I activity of a sample from the individual, wherein the IFN-I activity of the sample is indicative of the therapeutic efficacy of the TLR inhibitor.

[0008] In another aspect, the present invention provides a method for predicting the suitability of an individual having a disease to initiate treatment with a TLR inhibitor, the method comprising determining the IFN-I activity of a sample from the individual, wherein the IFN-I activity of the sample is indicative of the individual's suitability for initiating treatment.

[0009] In another aspect, the present invention provides a method for predicting the suitability of an individual having a disease who is being treated with a TLR inhibitor to continue the treatment, the method comprising determining the IFN-I activity of a sample from the individual, wherein the IFN-I activity of the sample is indicative of the individual's suitability for continuing the treatment.

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

[0011] IFN-I activity can be assessed either directly or indirectly, for example, by determining the expression of an individual's IFN-I signature. Such an IFN-I signature may include 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 may include HERC5, IFI27, IFIT1, and RSAD2.

[0012] In some embodiments, the TLR inhibitor is a TLR7 and / or TLR8 inhibitor. For example, TLR7 and / or TLR8 inhibitors include 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, and (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]octan-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]octan-1-yl)morpholine-3-carboxamide, or a pharmaceutically acceptable salt of either of these compounds. [Brief explanation of the drawings]

[0013] [Figure 1a] a) shows the correlation, as indicated by the correlation coefficient r, between the IFN-I signature scores of various IFN-I signatures determined for a population of SLE patients, and b) shows an exemplary graph plotting the IFN-I signature score of the Dx_4 IFN-I signature against the IFN-I signature score of the EMD_9 IFN-I signature determined for said population of SLE patients. [Figure 1b]a) shows the correlation, as indicated by the correlation coefficient r, between the IFN-I signature scores of various IFN-I signatures determined for a population of SLE patients, and b) shows an exemplary graph plotting the IFN-I signature score of the Dx_4 IFN-I signature against the IFN-I signature score of the EMD_9 IFN-I signature determined for said population of SLE patients.

[0014] [Figure 2-1] Cumulative distribution functions of a) time to recovery and b) time to clinical progression are shown for an unstratified patient population (safety analysis population) receiving placebo or empatran 50 mg or 100 mg twice daily. [Figure 2-2] Cumulative distribution functions of a) time to recovery and b) time to clinical progression are shown for an unstratified patient population (safety analysis population) receiving placebo or empatran 50 mg or 100 mg twice daily.

[0015] [Figure 3-1] Figure 1 shows the cumulative distribution functions of time to recovery for a) patients with a high baseline IFN-I signature score, and b) patients with a low baseline IFN-I signature score who received placebo or empatran 50 mg or 100 mg twice daily. [Figure 3-2] Figure 1 shows the cumulative distribution functions of time to recovery for a) patients with a high baseline IFN-I signature score, and b) patients with a low baseline IFN-I signature score who received placebo or empatran 50 mg or 100 mg twice daily.

[0016] [Figure 4]These results demonstrate that CMPD2 reverses the ability of IFN-α pretreatment to reduce the efficacy of Dex. (A) Dose-response curve of Dex affecting IL-6 in PBMCs with or without IFN-α pretreatment at 16 hours after R848 stimulation. (B) Representative bar graph of IL-6 secretion after treatment with 41 nM Dex and / or 7.8 nM CMPD2 with or without IFN-α pretreatment. (C) Quantification of synergy scores from a Loewe matrix plot (area under the curve) by Combinefit for the interaction of Dex and CMPD2 on the inhibition of IL-6 in R848-stimulated PBMCs untreated or pretreated with IFNα at 16 hours after stimulation. Figures (A–C) show pooled data from five donors. In (A) and (B), data are normalized to the R848-stimulated control. Paired t-test: **p<0.005.

[0017] [Figure 5-1] Figure 1 shows that CMPD2 reverses the ability of IFN-α pretreatment to reduce the efficacy of Dex. Dose-response curves for Dex alone or with various doses of CMPD2 affecting IL-6 16 hours after R848 stimulation without (A) or with (B) IFN-α pretreatment. Combined benefit analysis showing Loewe matrix plots of the interaction of Dex and CMPD2 on IL-6 suppression in R848-stimulated cells 16 hours after stimulation without (B) or with (D) IFN-α pretreatment. In (A) and (C), data are normalized to the R848 control and pooled from five donors. [Figure 5-2]Figure 1 shows that CMPD2 reverses the ability of IFN-α pretreatment to reduce the efficacy of Dex. Dose-response curves for Dex alone or with various doses of CMPD2 affecting IL-6 16 hours after R848 stimulation without (A) or with (B) IFN-α pretreatment. Combined benefit analysis showing Loewe matrix plots of the interaction of Dex and CMPD2 on IL-6 suppression in R848-stimulated cells 16 hours after stimulation without (B) or with (D) IFN-α pretreatment. In (A) and (C), data are normalized to the R848 control and pooled from five donors.

[0018] [Figure 6] Activation of TLR7 / 8 in human PBMCs by patient-derived immune complexes is shown. IgG was isolated from plasma samples from patients with HC, SLE, LN, IBM, PM, and DM, and combined with necrotic cell lysates to form immune complexes, which were then used to stimulate PBMCs from healthy donors. A) After 24 hours of treatment, supernatants were collected from PBMCs, and IFN-α was measured by AlphaLISA. The average of two to four experiments for each IgG is shown, and each symbol represents an IgG sample. B) For samples with stimulatory activity, PBMCs were pretreated with empatran for 30 minutes, after which the immune complexes were added to the cells, and IFN-α was measured 24 hours after treatment. All IgG samples were tested using PBMCs from two to four healthy donors. DM dermatomyositis, HC healthy control, IBM inclusion body myositis, IC immune complex, IFN-α interferon-alpha, IgG immunoglobulin G, PBMC peripheral blood mononuclear cells, PM polymyositis, SLE systemic lupus erythematosus, TLR7 / 8 toll-like receptor 7 / 8.

[0019] [Figure 7A]Figure 1 shows changes in gene expression induced by patient-derived immune complexes. IgG was isolated from plasma samples from patients with HC and SLE, LN, IBM, PM, and DM. It was then combined with necrotic cell lysates to form immune complexes, which were then used to stimulate PBMCs from healthy donors. After 24 hours of treatment, cells were harvested and analyzed by NanoString to determine changes in gene expression. A) The heatmap shows the Log2 FC compared to HC IgG samples. Each column represents a separate IgG sample, and patient groups are indicated by shading. Samples that stimulated IFN-α protein production are indicated by black bars above the columns. B) The ISGs shown in the heatmap were used to calculate IFN-I signature scores, and scores were plotted for each individual sample. Data were averaged from independent experiments performed with two PBMC donors for each IgG sample. DM dermatomyositis, FC fold change, HC healthy control, IBM inclusion body myositis, IFN-α interferon-alpha, IgG immunoglobulin G, ISG interferon-inducible gene, PBMC peripheral blood mononuclear cell, PM polymyositis, SLE systemic lupus erythematosus. [Figure 7B]Figure 1 shows changes in gene expression induced by patient-derived immune complexes. IgG was isolated from plasma samples from patients with HC and SLE, LN, IBM, PM, and DM. It was then combined with necrotic cell lysates to form immune complexes, which were then used to stimulate PBMCs from healthy donors. After 24 hours of treatment, cells were harvested and analyzed by NanoString to determine changes in gene expression. A) The heatmap shows the Log2 FC compared to HC IgG samples. Each column represents a separate IgG sample, and patient groups are indicated by shading. Samples that stimulated IFN-α protein production are indicated by black bars above the columns. B) The ISGs shown in the heatmap were used to calculate IFN-I signature scores, and scores were plotted for each individual sample. Data were averaged from independent experiments performed with two PBMC donors for each IgG sample. DM dermatomyositis, FC fold change, HC healthy control, IBM inclusion body myositis, IFN-α interferon-alpha, IgG immunoglobulin G, ISG interferon-inducible gene, PBMC peripheral blood mononuclear cell, PM polymyositis, SLE systemic lupus erythematosus. DETAILED DESCRIPTION OF THE INVENTION

[0020] Each embodiment described herein can be combined with any other embodiment described herein that is not inconsistent with the embodiment with which it is combined. Furthermore, unless inconsistent in a given context, whenever a compound that can be ionized (e.g., protonated or deprotonated) is specified, the definition of that compound includes all pharmaceutically acceptable salts thereof. Thus, the phrase "or a pharmaceutically acceptable salt thereof" is implicit in the description of all compounds described herein.

[0021] The present invention may be more readily understood by reference to the above and below detailed descriptions of specific and preferred embodiments of the present invention and the examples contained herein. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be further understood that, unless specifically defined herein, terms used herein should be given their conventional meaning as known in the relevant art. In order that the present invention may be more readily understood, certain technical and scientific terms are specifically defined below. Unless otherwise defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0022] General definition The terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0023] The term "about," when used to modify a numerically defined parameter, refers to any minimal change in such parameter that does not alter the overall effect, e.g., the effectiveness of an agent in treating a disease or disorder. In some embodiments, the term "about" means that the parameter can vary by up to 10% above and below the numerical value stated for that parameter.

[0024] The term "approximately," when used in reference to a value, e.g., the upper limit of a range or a reference value, e.g., a reference value for IFN-I activity or a reference IFN-I signature score, refers to any value that is reasonably close to the referenced value, e.g., any value above the 90th or 95th percentile. In some embodiments, the term "approximately" refers to the exact value.

[0025] "Administering" or "administration" (and grammatical equivalents of this phrase) of a drug to a patient refers to direct administration, which may be administration to the patient by a medical professional or self-administration, and / or indirect administration, which may be the act of prescribing a drug; for example, a physician who instructs a patient to self-administer a drug or provides a patient with a prescription for a drug is administering a drug to a patient. It is understood that the therapeutic agents described herein, such as TLR inhibitors, are administered in therapeutically effective amounts.

[0026] "Biomarker" generally refers to a biological molecule that indicates a disease state and its quantitative and qualitative determination. "Prognostic biomarkers" correlate with disease outcome regardless of treatment. For example, intratumoral hypoxia is a negative prognostic marker; the higher the intratumoral hypoxia, the more likely the disease outcome will be negative. "Predictive biomarkers" indicate whether a patient is likely to respond positively to a particular therapy; for example, HER2 profiling is commonly used in breast cancer patients to determine whether they are likely to respond to Herceptin (trastuzumab, Genentech). "Response biomarkers" provide a measure of response to therapy and therefore provide an indication of whether the treatment is effective. For example, a decrease in prostate-specific antigen levels generally indicates that an anti-cancer therapy is effective for prostate cancer patients. When a marker is used as the basis for identifying or selecting patients for the treatments described herein, the marker may be determined before and / or during the treatment, and the resulting value is used by the clinician in assessing any of the following: (a) the likelihood or probability that an individual will be suitable for the treatment for the first time, (b) the likelihood or probability that an individual will not be suitable for the treatment for the first time, (c) responsiveness to the treatment, (d) the likelihood or probability that an individual will be suitable for continuing the treatment, (e) the likelihood or probability that an individual will not be suitable for continuing the treatment, (f) dosage adjustment, (g) prediction of likely clinical benefit, or (h) toxicity. As will be well understood by those skilled in the art, measurement of a biomarker in a clinical setting clearly indicates that this parameter has been used as the basis for initiating, continuing, adjusting, and / or ceasing the administration of the treatments described herein.

[0027] As used herein, "combination therapy" or "in combination with" refers to any form of combined, concurrent, simultaneous, sequential, or intermittent treatment using at least two distinct therapeutic modalities (i.e., compounds, components, targeted agents, therapeutic agents, or therapies). Thus, these terms refer to the administration of one therapeutic modality before, during, or after the administration of another therapeutic modality to a subject. The combined modalities can be administered in any order. Therapeutically effective modalities are administered together (e.g., simultaneously in the same or separate compositions, formulations, or unit dosage forms) or separately (e.g., on the same or different days, in any order following appropriate dosing protocols for the separate compositions, formulations, or unit dosage forms), in a manner and dosing regimen prescribed by a physician or in accordance with a regulatory agency. Generally, each therapeutic modality is administered at a dose and / or time schedule determined for that therapeutic modality. Optionally, four or more modalities may be used in a combination therapy. Additionally, the combination therapies provided herein may be used in conjunction with other types of treatment. For example, the other anti-cancer treatment may be selected from the group consisting of chemotherapy, surgery, radiotherapy (radiation), and / or hormone therapy, among other treatments associated with the current standard of care for the subject.

[0028] As used herein, "comprising" is intended to mean that the compositions and methods include the recited elements, but do not exclude others. "Consisting essentially of," when used to define compositions and methods, is intended to mean excluding all other elements of essential importance to the composition or method. "Consisting of" is intended to mean excluding more than trace amounts of other components for the claimed composition and substantial method steps. Embodiments defined by each of these transitional terms are within the scope of the present invention. Thus, it is intended that the methods and compositions may include (comprise) additional steps and components, or may comprise (consist essentially of) insignificant steps and compositions, or may contemplate (consist of) only the recited method steps or compositions.

[0029] "Dose" and "dosage" refer to a specific amount of an active or therapeutic agent for administration. Such amounts are encompassed by "dosage forms," ​​which refer to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce a desired duration of onset, tolerability, and therapeutic effect, together with one or more suitable pharmaceutical excipients, such as 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 type I interferon signaling activity, for example, as reflected by the expression level of ISGs.

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

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

[0033] "IFN-I signature expression pattern" refers to the expression levels of genes in an IFN-I signature.

[0034] The terms "patient," "subject," and "individual" are used interchangeably herein to refer to a mammal in need of treatment for a disease or disorder. Generally, a "patient," "subject," or "individual" is a human who has been diagnosed with, or is at risk for, one or more symptoms of a disease or disorder. In some embodiments, a "patient," "subject," or "individual" can 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, in screening, characterizing, and evaluating drugs and therapies.

[0035] "Pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal being treated therewith. "Pharmaceutically acceptable carriers" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like 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, as well as combinations thereof.

[0036] As referred to herein, for example, a "prediction" of the therapeutic effectiveness of a TLR inhibitor, the suitability of an individual with a disease to begin treatment with a TLR inhibitor, or the suitability of an individual with a disease being treated with a TLR inhibitor to continue treatment only provides an indication of the likelihood of therapeutic outcome with a TLR inhibitor, but does not reliably predict the therapeutic outcome. For example, an individual for whom a TLR inhibitor is predicted to be therapeutically effective only has a higher likelihood of therapeutic effectiveness, while an individual for whom a TLR inhibitor is predicted to be therapeutically ineffective only has a lower likelihood of therapeutic effectiveness. Similarly, an individual predicted to be suitable for initiating treatment with a TLR inhibitor only has a higher likelihood of therapeutically effective treatment in such an individual, while an individual predicted not suitable for initiating treatment with a TLR inhibitor only has a lower likelihood of therapeutically effective treatment in such an individual. Similarly, for individuals who are predicted to be suitable for continued treatment with a TLR inhibitor, treatment with the TLR inhibitor in such individuals is simply more likely to be therapeutically effective, whereas for individuals who are predicted not to be suitable for continued treatment with a TLR inhibitor, treatment with the TLR inhibitor in such individuals is simply less likely to be therapeutically effective.

[0037] A "reference IFN-I activity," "reference IFN-I signature expression pattern," or "reference IFN-I signature score" can identify patients who are more likely to respond to treatment with a TLR inhibitor and / or patients who are less likely to respond to treatment with a TLR inhibitor, for example, based on a comparison of the reference IFN-I activity, reference IFN-I signature expression pattern, or reference IFN-I signature score with the IFN-I activity, IFN-I signature expression pattern, or IFN-I signature score, respectively, of such patient. Which IFN-I activity, IFN-I signature expression pattern, or IFN-I signature score indicates which treatment outcome depends on how the corresponding reference was defined. For example, a reference IFN-I activity or reference IFN-I signature score may be defined to distinguish between patients who are more likely to respond to treatment with a TLR inhibitor and patients who are less likely to respond. In such cases, patients having an IFN-I activity that exceeds the reference IFN-I activity or an IFN-I signature score that exceeds the reference IFN-I signature score are more likely to respond to treatment with a TLR inhibitor than patients having an IFN-I activity that is below the reference IFN-I activity or an IFN-I signature score that is below the reference IFN-I activity. Similarly, a reference IFN-I activity or reference IFN-I signature score that is characteristic 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 this patient population, may be defined, and patients having an IFN-I activity or IFN-I signature score that is around or above the respective reference value, are determined to be more likely to respond to treatment (and vice versa). Similarly, patients with expression patterns of these genes characteristic of patient populations more likely to respond to treatment with, for example, TLR inhibitors, i.e., expression of genes in an IFN-I signature similar to a reference IFN-I signature expression pattern, are also more likely to respond to TLR treatment, and vice versa.It is understood that the IFN-I signature on which the IFN-I signature of the reference IFN-I signature expression pattern or reference IFN-I signature score is based is identical to the IFN-I signature used to determine the IFN-I signature expression pattern or IFN-I signature score of a patient whose outcome is predicted according to the method or use of the present invention. Those skilled in the art will fully understand how to define such a reference IFN-I activity, reference IFN-I signature expression pattern or reference IFN-I signature score. For example, it may be derived from a post-hoc analysis of a patient population, in which each patient's pre-treatment IFN-I activity, IFN-I signature expression pattern, or IFN-I signature score is compared with each patient's treatment outcome, and the population is then divided into a group of patients for whom treatment was more effective and a group of patients for whom treatment was less effective, and, for example, a threshold value for IFN-I activity or IFN-I signature score that separates these patient populations is defined, or an IFN-I activity, IFN-I signature score, or IFN-I signature expression pattern characteristic of either or both of these patient populations is defined. The IFN-I activity, IFN-I signature expression pattern, or IFN-I signature score thus defined can then serve as the reference IFN-I activity, reference IFN-I signature expression pattern, and reference IFN-I signature score, respectively. Similarly, because the IFN-I pathway is generally less active in healthy individuals, such a population can be considered a population with baseline or low IFN-I activity, and therefore, for example, a reference IFN-I activity, reference IFN-I signature expression pattern, or reference IFN-I signature score may be derived from a healthy population. Thus, the IFN-I activity, IFN-I signature expression pattern, or IFN-I signature score of each individual in such a healthy population can be determined, and, for example, an IFN-I activity or IFN-I signature score that is near the upper limit of the determined range or corresponds to the arithmetic mean or median can be defined as the reference IFN-I activity or reference IFN-I signature score, respectively.Similarly, the expression pattern of genes in an IFN-I signature characteristic of such a population can be defined as a reference IFN-I signature expression pattern. In some embodiments, having "high" IFN-I activity means IFN-I activity that exceeds the reference IFN-I activity, e.g., as reflected by an IFN-I signature score that exceeds the reference IFN-I signature score, and having "low" IFN-I activity means IFN-I activity that is lower than the reference IFN-I activity, e.g., as reflected by an IFN-I signature score that is below the reference IFN-I signature score.

[0038] As referred to herein, a "sample" is any biological sample from an individual from which IFN-I activity can be determined, e.g., an IFN-I signature expression pattern or an IFN-I signature score can be determined. A sample can refer to, for example, an individual's body fluids, cells, and tissues. It can also refer to an individual's blood sample and extracted RNA.

[0039] A "small molecule" is a chemical, usually organic, compound with a low molecular weight, such as ≦1000 daltons or ≦900 daltons.

[0040] A "therapeutically effective amount" of a therapeutic agent refers to an amount effective, at the necessary dosage and for the necessary duration, that, when administered to a patient, will have the intended therapeutic effect, such as alleviating, ameliorating, reducing, or eliminating one or more symptoms of a disease or disorder in the patient, or any other clinical result in the course of treating the patient. The therapeutic effect does not necessarily occur by administering a single dose, but may occur only after administering a series of doses. Thus, a therapeutically effective amount can be administered in one or more administrations. Such a therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, as well as the ability of the therapeutic agent to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or harmful effects of the therapeutic agent are outweighed by the therapeutically beneficial effects.

[0041] "Therapeutic efficacy" refers to a favorable therapeutic response, e.g., alleviation, amelioration of one or more symptoms of a disease, reduction in the extent of the disease, delay or slowing of the progression of the disease, improvement, relief, or stabilization of the disease state, or other beneficial outcome. For example, therapeutic efficacy may refer to the time to recovery from a particular 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 family of proteins through direct interaction between the TLR inhibitor and the TLR. A TLR inhibitor may function, for example, by stabilizing a TLR in its resting, inactive state. In some embodiments, a TLR inhibitor inhibits the activity of human TLR7 (also referred to as a "TLR7 inhibitor"). In some embodiments, a TLR inhibitor inhibits the activity of human TLR8 (also referred to as a "TLR8 inhibitor"). In some embodiments, a TLR inhibitor inhibits the activity of human TLR7 and / or TLR8 (also referred to as a "TLR7 and / or TLR8 inhibitor"). In some embodiments, a TLR inhibitor inhibits the activity of human TLR7 and TLR8 (also referred to as a "TLR7 and TLR8 inhibitor"). In some embodiments, a TLR inhibitor selectively inhibits human TLR7 and / or TLR8. A TLR inhibitor may be, for example, a small molecule, a nucleic acid such as an oligonucleotide, or a polypeptide such as an antibody. In some embodiments, the TLR inhibitor is a small molecule. Possible effects of inhibiting the TLR pathway include suppression of inflammatory processes. Inhibition in this context need not be complete or 100%. Instead, inhibition means reducing, diminishing, or suppressing the activity of the TLR pathway or inflammatory process, respectively. Inhibition may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%, or statistically significant inhibition, as compared to a control. In some embodiments, the IC of a TLR inhibitor for inhibition of a TLR is 50 In some embodiments, the IC 50Values ​​are determined in HEK293 cells. In an exemplary protocol, HEK293 cells are stably transfected with either TLR7 or TLR8 and an NF-κB-luciferase reporter gene. For TLR inhibitor testing, cells are seeded into 384-well black, clear-bottom plates and incubated overnight at 37°C and 5% CO2, followed by the addition of duplicate dilutions of TLR inhibitors. Cells are then stimulated with 10 μM R848 or 30 μM R848 for testing HEK TLR7 or HEK TLR8 cells, respectively. After 5 hours of incubation at 37°C and 5% CO2, SteadyGlo substrate reagent (Promega, Madison, Wisconsin) is added to each well, and luminescence is measured, for example, using a PerkinElmer Envision Multilabel Reader.

[0043] "Treating" a condition or patient or "treatment" thereof refers to taking measures to obtain beneficial or desired results, including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of one or more symptoms of a disease, amelioration, reduction in the extent of a disease, delaying or slowing the progression of a disease, improvement, palliation, or stabilization of a disease state, or other beneficial results. It should be understood that references to "treating" or "treatment" include prophylaxis, as well as the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or medical condition includes (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or medical condition in a subject who may be suffering from or susceptible to the condition, disorder, or medical condition but who has not yet experienced or exhibited clinical or preclinical symptoms of the condition, disorder, or medical condition; (2) inhibiting the condition, disorder, or medical condition, i.e., arresting, reducing, or delaying the onset or recurrence of the disease (in the case of maintenance treatment), or at least one clinical or preclinical symptom thereof; or (3) relieving or attenuating the disease, i.e., causing regression of the condition, disorder, or medical condition, or at least one clinical or preclinical symptom thereof.

[0044] As used herein, a plurality of items, structural elements, compositional elements, and / or materials may be presented in common lists for convenience, however, such lists should be construed as though each member of the list is individually identified as a separate and unique member.

[0045] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It should be understood that such range format is used merely for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values ​​explicitly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were explicitly recited. By way of illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values ​​of about 1 to about 5, but also each individual value and subrange within the stated range. Thus, this numerical range includes individual values ​​such as 2, 3, and 4, as well as subranges such as 1 to 3, 2 to 4, and 3 to 5, and individually 1, 2, 3, 4, and 5. This same principle applies to ranges reciting only one numerical value as the minimum or maximum value. Furthermore, such interpretation should apply regardless of the breadth of the range or characteristic being described.

[0046] Compound Definition For the purposes of this invention, chemical elements are defined as follows: th Further, the general principles of organic chemical reactions are identified in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5 thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0047] As used herein, the terms "aliphatic" or "aliphatic group" mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl") and has 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 still 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, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Exemplary aliphatic groups are straight-chain or branched, substituted or unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

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

[0049] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0050] As used herein, "divalent C" 1~8 or (C 1~6 The term "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 -, where 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 group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0052] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

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

[0054] The term "aryl," used alone or as part of a larger moiety, such as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, where at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" is used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl, and the like, which optionally include one or more substituents. As used herein, the term aryl also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, tetrahydronaphthyl, and the like.

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

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

[0057] A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and all ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclyl radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclyl group," "heterocyclyl moiety," and "heterocyclyl radical" are used interchangeably herein and also include groups in which the heterocyclyl ring, where the radical or point of attachment is on the heterocyclyl ring, is fused to one or more aryl, heteroaryl, or alicyclic rings, e.g., indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups are optionally monocyclic or bicyclic. The term "heterocycloalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl moieties independently are optionally substituted.

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

[0059] As described herein, certain compounds contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. "Substituted" applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., [ka] At least [ka] refers to, and [ka] At least [ka] Unless otherwise specified, 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 envisioned by the present invention are preferably those that provide for the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that are substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0060] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently deuterium, halogen, -(CH2) 0-4 R°, -(CH2) 0-4 OR°, -O(CH2) 0-4 R o , -O-(CH2) 0-4 C(O)OR°, -(CH2) 0-4 CH(OR°)2, -(CH2) 0-4 SR°, optionally substituted with R° -(CH2) 0-4 Ph, optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 Ph, optionally substituted with R° -CH=CHPh, optionally substituted with R° -(CH) 0-4 O(CH2) 0-1 -Pyridyl, -NO2, -CN, -N3, -(CH2) 0~4 N(R°)2, -(CH2) 0-4 N(R°)C(O)R°, -N(R°)C(S)R°, -(CH2) 0-4 N(R°)C(O)NR°2, -N(R°)C(S)NR°2, -(CH2) 0-4 N(R°)C(O)OR°, -N(R°)N(R°)C(O)R°, -N(R°)N(R°)C(O)NR°2, -N(R°)N(R°)C(O)OR°, -(CH2) 0-4 C(O)R°, -C(S)R°, -(CH2) 0-4 C(O)OR°, -(CH2) 0-4 C(O)SR°, -(CH2) 0-4 C(O)OSiR°3, -(CH2) 0-4 OC(O)R°, -OC(O)(CH2) 0-4 SR°, SC(S)SR°, -(CH2) 0-4 SC(O)R°, -(CH2) 0-4 C(O)NR°2, -C(S)NR°2, -C(S)SR°, -SC(S)SR°, -(CH2) 0-4 OC(O)NR°2, -C(O)N(OR°)R°, -C(O)C(O)R°, -C(O)CH2C(O)R°, -C(NOR°)R°, -(CH2) 0-4 SSR°, -(CH2) 0-4S(O)2R°, -(CH2) 0-4 S(O)2OR°, -(CH2) 0-4 OS(O)2R°, -S(O)2NR°2, -(CH2) 0-4 S(O)R°, -N(R°)S(O)2NR°2, -N(R°)S(O)2R°, -N(OR°)R°, -C(NH)NR°2, -P(O)2R°, -P(O)R°2, -OP(O)R°2, -OP(O)(OR°)2, SiR°3, -(C 1~4 linear or branched alkylene)ON(R°)2, or -(C 1~4 linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted as defined below and independently represents hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl 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 definition, two independently occurring R° together with their intervening atoms form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is optionally substituted as defined below.

[0061] Suitable monovalent substituents on R° (or the ring formed by two independent R° together with the intervening atoms) are independently deuterium, halogen, -(CH2), 0-2 R ● ,-(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2, -O(HaloR) ● ), -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) 0~2 SH, -(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, independently, if preceded by "halo", substituted only with one or more halogens; 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. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0062] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: ═O, ═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-, where each R * is hydrogen, substituted C as defined below 1~6 An "optionally substituted" group is an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR * 2)2-3 O-, where each R * is hydrogen, optionally substituted C as defined below 1~6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0063] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, independently, if preceded by "halo", substituted only with one or more halogens; 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 -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † S(O)2R † where each R † are independently hydrogen, optionally substituted C as defined below 1~6an 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 independently occurring R † together with the intervening atoms form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0065] R + Suitable substituents on the aliphatic group are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● is unsubstituted or, independently, if preceded by "halo", substituted only with one or more halogens; 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 all other optionally substituted groups as used herein refer to groups that are substituted or remain unsubstituted by independently replacing one, two, or three or more hydrogen atoms thereon with exemplary substituents, including, but not limited to, -F, -Cl, -Br, -I, deuterium -OH, protected hydroxy, alkoxy, oxo, thioxo, -NO2, -CN, CF3, N3, -NH, 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, -CONH, -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, -OCONHalkyl, -OCONHalkenyl, -OCONHalkynyl, -OCONHcarbocyclyl, -OCONHaryl, -OCONHheteroaryl, -OCONHheterocyclyl, -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-alkynyl 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)NH, -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)-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, -SONH, -SONH-alkyl, -SONH-alkenyl, -SONH-alkynyl, -SONH-carbocyclyl, -SONH-aryl, -SONH-heteroaryl, -SONH-heterocyclyl, -NHSO2-alkyl, -NHSO2-alkenyl, -NHSO2-alkynyl, -NHSO2-carbocyclyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocyclyl, -CH2NH2, -CH2SO2CH3 mono-, di-, or tri-alkylsilyl, Examples include -alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclyl, -heterocyclyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl, -S-alkenyl, -S-alkynyl, -S-carbocyclyl, -S-aryl, -S-heteroaryl, -S-heterocyclyl, and methylthiomethyl.

[0067] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or 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, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and 2-hydroxyethanesulfonate. Examples of salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, 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, and valerate.

[0068] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts also include non-toxic ammonium, quaternary ammonium, and amine cations, optionally formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate.

[0069] Unless otherwise specified, structures depicted and compounds referred to herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomeric) forms of the structures, e.g., R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise specified, all tautomeric forms of the compounds described herein are within the scope of the invention.

[0070] Additionally, unless otherwise stated, structures depicted and compounds referred to herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium; 13 C or 14 Compounds having the present structures including the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure. In some embodiments, the group includes one or more deuterium atoms.

[0071] Furthermore, unless otherwise specified, the compounds referred to herein are intended to include their isotopically labeled forms.Isotopically labeled forms of the compounds referred to herein are identical to the compounds except for the fact that one or more atoms of the compound are replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the normal naturally occurring atom.Examples of isotopes that are readily commercially available and can be incorporated into 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 Examples of isotopes include Cl. Compounds referred to herein, their prodrugs, or any pharmaceutically acceptable salts thereof, containing one or more of the above isotopes and / or other isotopes of other atoms are intended to be part of the present invention. Isotopically labeled compounds can be used in many beneficial ways. For example, 3 H or 14 Isotopically labeled compounds incorporating radioactive isotopes such as C are suitable, for example, for drug and / or substrate tissue distribution assays. These radioactive isotopes, namely tritium ( 3 H) and carbon-14 ( 14 C) is particularly preferred due to its ease of preparation and excellent detectability. Heavier isotopes, such as deuterium ( 2Incorporating H) into a compound has therapeutic advantages due to the higher metabolic stability of the isotopically labeled compound. Higher metabolic stability directly translates into longer in vivo half-lives or reduced dosages, which in most cases are preferred embodiments of the present invention. Isotopically labeled compounds can typically be prepared by following the procedures disclosed in the synthetic schemes and associated description, examples, and preparation sections of this document, substituting readily available isotopically labeled reactants for non-isotopically labeled reactants.

[0072] deuterium( 2 H) can also be incorporated into the compounds referred to herein for the purpose of manipulating the oxidative metabolism of the compound through the primary kinetic isotope effect. The primary kinetic isotope effect is the change in the rate of a chemical reaction caused by the exchange of an isotope nucleus, which is caused by the change in the ground state energy required for covalent bond formation after this isotope exchange. The exchange of a heavier isotope usually lowers the ground state energy of the chemical bond, thus slowing the rate of rate-limiting bond cleavage. If bond cleavage occurs in or near a saddle point region along the coordinate of a multi-product reaction, the product distribution ratio can be substantially altered. By way of illustration, when deuterium is attached to a carbon atom at a non-exchangeable position, typically k M / k D = 2 to 7. When this rate differential is successfully applied to a compound that is susceptible to oxidation, the in vivo profile of the compound can be dramatically altered, resulting in improved pharmacokinetic properties.

[0073] When discovering and developing therapeutic agents, those skilled in the art can optimize pharmacokinetic parameters while retaining desired in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information regarding the course of this type of oxidative metabolism, allowing the rational design of deuterated compounds with improved stability due to resistance to such oxidative metabolism. This can result in significant improvements in the pharmacokinetic profile of the compound, improving in vivo half-life (t / 2), the concentration at maximum therapeutic effect (C max ), area under the dose-response curve (AUC), and F, as well as reduced clearance, dose, and material costs.

[0074] The following is intended to exemplify the above: a compound having multiple potential attack sites for oxidative metabolism, such as benzylic hydrogen atoms and nitrogen-bonded hydrogen atoms, is prepared as a series of analogs in which some, most, or all of these hydrogen atoms are replaced with deuterium atoms by replacing the hydrogen atoms with deuterium atoms in various combinations. Determination of half-life allows the precise degree of improvement in resistance to oxidative metabolism to be determined. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as a result of this type of deuterium-hydrogen exchange.

[0075] Deuterium-hydrogen exchange in compounds can also be used to favorably modify the metabolite spectrum of a starting compound to reduce or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises from the oxidative cleavage of a carbon-hydrogen (CH) bond, it can be reasonably expected that a deuterated analog will significantly reduce or eliminate the production of the undesired metabolite, even if the specific oxidation is not the rate-limiting step. Further information on the state of the art regarding deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al. 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] Only combinations of substituents and variables that result in the formation of stable compounds are contemplated herein. As used herein, the term "stable" refers to compounds that have sufficient stability to permit their manufacture and maintain their integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0077] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes any single embodiment or that embodiment in combination with any other embodiment or portion thereof.

[0078] How to use The present invention relates to the use of IFN-I activity as a predictive biomarker for treatment of individuals suffering from a disease or disorder with a TLR inhibitor. In particular, it has been found that TLR inhibitors are more likely to be therapeutically effective in individuals with high IFN-I activity. IFN-I activity can be determined indirectly by measuring IFN-I expression levels, for example, using a PBMC assay as outlined in Example 4, or using an IFN-I signature that reflects IFN-I activity. Such IFN-I signatures can then be used to determine an IFN-I signature score or an IFN-I signature expression pattern, and by comparison with a reference IFN-I signature score or reference IFN-I signature expression pattern, respectively, it can be determined whether the individual has high or low IFN-I activity. Such biomarker information can be used, for example, to predict the suitability of a patient for initial treatment with a TLR inhibitor, to predict the suitability of a patient for continued treatment with a TLR inhibitor, and to predict the likelihood of clinical benefit from treating a patient with a TLR inhibitor.

[0079] Furthermore, the present inventors found that administration of a TLR inhibitor enhanced the efficacy of glucocorticosteroids, even in the setting of prior treatment with IFN-α.

[0080] Accordingly, provided herein are methods based on determining IFN-I activity for predicting the therapeutic efficacy of a TLR inhibitor in a patient, for predicting the suitability of an individual with a disease for initiating treatment with a TLR inhibitor, for predicting the suitability of a patient for continuing treatment with a TLR inhibitor, and / or for treating a patient with a TLR inhibitor. Also provided herein are methods based on determining IFN-I activity for predicting the therapeutic efficacy of a TLR inhibitor and a corticosteroid in a patient, for predicting the suitability of an individual with a disease for initiating treatment with a TLR inhibitor and a corticosteroid, for predicting the suitability of a patient for continuing treatment with a TLR inhibitor and a corticosteroid, and / or for treating a patient with a TLR inhibitor in combination with a corticosteroid.

[0081] Provided herein are methods for predicting the therapeutic efficacy of a TLR inhibitor in an individual with a disease, the methods comprising determining the IFN-I activity of a sample from the individual, wherein the IFN-I activity of the sample indicates the therapeutic efficacy of the TLR inhibitor. In some embodiments, if the individual has high IFN-I activity, the TLR inhibitor is predicted to be therapeutically effective. In some embodiments, the IFN-I activity is compared to a reference IFN-I activity, and the TLR inhibitor is predicted to be therapeutically effective in the individual if the individual's IFN-I activity is higher than the reference IFN-I activity, and is predicted to be ineffective if the individual's IFN-I activity is lower than the reference IFN-I activity. In some embodiments, the reference IFN-I activity is selected to distinguish individuals who are likely to be more therapeutically effective from individuals who are likely to be less therapeutically effective, such that if the individual's IFN-I activity is higher than the reference IFN-I activity, therapeutic efficacy for the individual is predicted, and if the individual's IFN-I activity is lower than the reference IFN-I activity, the TLR inhibitor is predicted to be ineffective. In some embodiments, the reference IFN-I activity is indicative of therapeutic efficacy, such that if an individual's IFN-I activity is near or above the reference IFN-I activity, therapeutic efficacy for the individual is predicted. In some embodiments, the reference IFN-I activity is indicative of therapeutic ineffectiveness, such that if an individual's IFN-I activity is near or below the reference IFN-I activity, therapeutic ineffectiveness for the individual is predicted.

[0082] Provided herein are methods for predicting the therapeutic efficacy of a TLR inhibitor in an individual with a disease, the methods comprising determining an IFN-I signature expression pattern of a sample from the individual, wherein the IFN-I signature expression pattern of the sample is indicative of the therapeutic efficacy of the TLR inhibitor. In some embodiments, the IFN-I signature expression pattern is compared to one or more reference IFN-I signature expression patterns. In some embodiments, the reference IFN-I signature expression pattern is indicative of therapeutic efficacy, such that a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern predicts therapeutic efficacy, and a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern predicts lack of therapeutic efficacy. In some embodiments, the reference IFN-I signature expression pattern is indicative of lack of therapeutic efficacy, and thus a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern is predictive of therapeutic efficacy, and a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern is predictive of lack of therapeutic efficacy. In some embodiments, there is a first reference IFN-I signature expression pattern indicative of therapeutic efficacy of a TLR inhibitor and a second reference IFN-I signature expression pattern indicative of lack of therapeutic efficacy of the TLR inhibitor, and a correlation between the determined IFN-I signature expression pattern and the first reference IFN-I signature expression pattern predicts that the TLR inhibitor will be therapeutically effective in the individual, and a correlation between the determined IFN-I signature expression pattern and the second reference IFN-I signature expression pattern predicts that the TLR inhibitor will not be therapeutically effective in the individual.

[0083] Also provided herein are methods for predicting the therapeutic efficacy of a TLR inhibitor in an individual with a disease, the methods comprising determining an IFN-I signature score of a sample from the individual, wherein the IFN-I signature score of the sample indicates therapeutic efficacy. In some embodiments, the TLR inhibitor is predicted to be therapeutically effective in the individual if the determined IFN-I signature score is higher than a reference IFN-I signature score, and is predicted to be therapeutically ineffective in the individual if the determined IFN-I signature score is lower than the reference IFN-I signature score. In some embodiments, the reference IFN-I signature score is selected to distinguish individuals who are likely to be more therapeutically effective from individuals who are likely to be less therapeutically effective, such that therapeutic efficacy for the individual is predicted if the individual's IFN-I signature score is higher than the reference IFN-I signature score, and therapeutic ineffectiveness is predicted if the individual's IFN-I signature score is lower than the reference IFN-I signature score. In some embodiments, the reference IFN-I signature score is indicative of therapeutic efficacy, such that therapeutic efficacy for an individual is predicted if the individual's IFN-I signature score is near or above the reference IFN-I signature score. In some embodiments, the reference IFN-I signature score is indicative of therapeutic ineffectiveness, such that therapeutic ineffectiveness for an individual is predicted if the individual's IFN-I signature score is near or below the reference IFN-I signature score.

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

[0085] Provided herein are methods for predicting the suitability of an individual with a disease for initiating treatment with a TLR inhibitor, the methods comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity of the sample indicates the individual's suitability for initiating treatment. In some embodiments, individuals with high IFN-I activity are assessed as suitable for initiating treatment. In some embodiments, the IFN-I activity is compared to a reference IFN-I activity, and the individual is assessed as suitable for initiating treatment if the individual's IFN-I activity is higher than the reference IFN-I activity, and as unsuitable for initiating treatment if the individual's IFN-I activity is lower than the reference IFN-I activity. In some embodiments, the reference IFN-I activity is selected to distinguish individuals who are likely to be more effective at treatment from individuals who are likely to be less effective at treatment. Thus, an individual is predicted to be suitable for initiating treatment with a TLR inhibitor if the individual's IFN-I activity is higher than the reference IFN-I activity, and is predicted to be unsuitable if the individual's IFN-I activity is lower than the reference IFN-I activity. In some embodiments, the reference IFN-I activity indicates therapeutic efficacy, such that if an individual's IFN-I activity is near or above the reference IFN-I activity, the individual is predicted to be suitable for initiating treatment with a TLR inhibitor. In some embodiments, the reference IFN-I activity indicates therapeutic ineffectiveness, such that if an individual's IFN-I activity is near or below the reference IFN-I activity, the individual is predicted to be unsuitable for initiating treatment with a TLR inhibitor.

[0086] Provided herein is a method for predicting suitability of an individual with a disease for initiating treatment with a TLR inhibitor, the method comprising determining an IFN-I signature expression pattern of a sample from the individual, wherein the IFN-I signature expression pattern of the sample indicates the individual's suitability for initiating treatment. In some embodiments, the IFN-I signature expression pattern is compared to one or more reference IFN-I signature expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates suitability for initiating treatment with a TLR inhibitor, and thus suitability for initiating treatment is indicated by a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, and lack of suitability for initiating treatment is indicated by a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern. In some embodiments, the reference IFN-I signature expression pattern indicates lack of suitability for initiating treatment with a TLR inhibitor, and thus suitability for initiating treatment is indicated by lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, and lack of suitability for initiating treatment is indicated by 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 indicative of the individual's suitability for initiating treatment with a TLR inhibitor, and a second reference IFN-I signature expression pattern indicative of the individual's unsuitability for initiating 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 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 treatment.

[0087] Also provided herein are methods for predicting the suitability of an individual with a disease for initiating treatment with a TLR inhibitor, the methods comprising determining an IFN-I signature score of a sample from the individual, wherein the IFN-I signature score of the sample indicates the individual's suitability for initiating treatment. In some embodiments, the individual is assessed as suitable for initiating treatment if the determined IFN-I signature score is higher than a reference IFN-I signature score, and is assessed as not suitable for initiating treatment if the determined IFN-I signature score is lower than the reference IFN-I signature score. In some embodiments of any of the methods for predicting the suitability of an individual with a disease for initiating treatment with a TLR inhibitor disclosed herein, if such an individual is assessed as suitable for initiating treatment, a TLR inhibitor is administered to the individual. In some embodiments, the reference IFN-I signature score is selected to distinguish individuals who are likely to be more therapeutically effective from individuals who are likely to be less therapeutically effective, such that an individual is predicted to be suitable for initiating treatment with a TLR inhibitor if their IFN-I signature score is higher than the reference IFN-I signature score, and is predicted to be unsuitable if their IFN-I signature score is lower than the reference IFN-I signature score. In some embodiments, the reference IFN-I signature score indicates therapeutic effectiveness, such that an individual's IFN-I signature score is near or above the reference IFN-I signature score, and thus the individual is predicted to be suitable for initiating treatment with a TLR inhibitor. In some embodiments, the reference IFN-I signature score indicates therapeutic ineffectiveness, such that an individual's IFN-I signature score is near or below the reference IFN-I signature score, and thus the individual is predicted to be unsuitable for initiating treatment with a TLR inhibitor.

[0088] Provided herein are methods for predicting the suitability of an individual having a disease undergoing treatment with a TLR inhibitor for continuing the treatment, the methods comprising determining the IFN-I activity of a sample from the individual, wherein the IFN-I activity of the sample indicates the individual's suitability for continuing the treatment. In some embodiments, an individual with high IFN-I activity is assessed as suitable for continuing the treatment. In some embodiments, the IFN-I activity is compared to a reference IFN-I activity, and the individual is assessed as suitable for continuing the treatment if the individual's IFN-I activity is higher than the reference IFN-I activity, and as unsuitable for continuing the treatment if the individual's IFN-I activity is lower than the reference IFN-I activity. In some embodiments, the reference IFN-I activity is selected to distinguish individuals who are likely to have a higher therapeutic efficacy from individuals who are likely to have a lower therapeutic efficacy; thus, an individual is predicted to be suitable for continuing treatment with a TLR inhibitor if the individual's IFN-I activity is higher than the reference IFN-I activity, and is predicted to be unsuitable if the individual's IFN-I activity is lower than the reference IFN-I activity. In some embodiments, the reference IFN-I activity indicates therapeutic efficacy, such that if an individual's IFN-I activity is near or above the reference IFN-I activity, the individual is predicted to be suitable for continued treatment with a TLR inhibitor. In some embodiments, the reference IFN-I activity indicates therapeutic ineffectiveness, such that if an individual's IFN-I activity is near or below the reference IFN-I activity, the individual is predicted to be unsuitable for continued treatment with a TLR inhibitor.

[0089] Provided herein are methods for predicting the suitability of an individual having a disease undergoing treatment with a TLR inhibitor for continuing the treatment, the methods comprising determining an IFN-I signature expression pattern of a sample from the individual, wherein the IFN-I signature expression pattern of the sample indicates the individual's suitability for continuing the treatment. In some embodiments, the IFN-I signature expression pattern is compared to one or more reference IFN-I signature expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates suitability for continuing the treatment with the TLR inhibitor, and thus suitability for continuing the treatment is indicated by a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, and lack of suitability for continuing the treatment is indicated by a lack of correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern. In some embodiments, the reference IFN-I signature expression pattern indicates incompetence for continuing treatment with the TLR inhibitor, and thus fitness for continuing 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 incompetence for continuing 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 indicative of the individual's suitability for continuing treatment with a TLR inhibitor, and a second reference IFN-I signature expression pattern indicative of the individual's unsuitability for continuing 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 continuing 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 treatment.

[0090] Also provided herein are methods for predicting the suitability of an individual having a disease undergoing treatment with a TLR inhibitor for continuing the treatment, the methods comprising determining an IFN-I signature score of a sample from the individual, wherein the IFN-I signature score of the sample indicates the individual's suitability for continuing the treatment. In some embodiments, the individual is assessed as suitable for continuing the treatment if the determined IFN-I signature score is higher than a reference IFN-I signature score, and is assessed as not suitable for continuing the treatment if the determined IFN-I signature score is lower than the reference IFN-I signature score. In some embodiments of any of the methods for predicting the suitability of an individual having a disease undergoing treatment with a TLR inhibitor disclosed herein for continuing the treatment, if such individual is assessed as suitable for continuing the treatment, a TLR inhibitor is administered to the individual. In some embodiments, the reference IFN-I signature score is selected to distinguish individuals who are likely to have a higher therapeutic efficacy from individuals who are likely to have a lower therapeutic efficacy, such that an individual is predicted to be suitable for continuing treatment with a TLR inhibitor if their IFN-I signature score is higher than the reference IFN-I signature score, and is predicted to be unsuitable if their IFN-I signature score is lower than the reference IFN-I signature score. In some embodiments, the reference IFN-I signature score indicates therapeutic efficacy, such that an individual's IFN-I signature score is near or above the reference IFN-I signature score, and thus an individual is predicted to be suitable for continuing treatment with a TLR inhibitor. In some embodiments, the reference IFN-I signature score indicates therapeutic ineffectiveness, such that an individual's IFN-I signature score is near or below the reference IFN-I signature score, and thus an individual is predicted to be unsuitable for continuing treatment with a TLR inhibitor.

[0091] Provided herein are TLR inhibitors for use in methods of treating a disease in an individual, wherein the method includes administering the TLR inhibitor to the individual, and 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 the TLR inhibitor is administered to the individual if the individual's IFN-I activity is higher than the reference IFN-I activity. In some embodiments, the reference IFN-I activity is selected to distinguish individuals who are likely to be more therapeutically effective from individuals who are likely to be less therapeutically effective; thus, if the individual's IFN-I activity is higher than the reference IFN-I activity, the TLR inhibitor is administered, and if the individual's IFN-I activity is lower than the reference IFN-I activity, the TLR inhibitor is not administered. In some embodiments, the reference IFN-I activity indicates therapeutic efficacy; thus, if the individual's IFN-I activity is near or above the reference IFN-I activity, the individual is administered the TLR inhibitor. In some embodiments, the reference IFN-I activity indicates therapeutic ineffectiveness, and thus, if the individual's IFN-I activity is near or below the reference IFN-I activity, the individual is not administered a TLR inhibitor.

[0092] Provided herein are TLR inhibitors for use in methods of treating a disease in an individual with high IFN-I activity, wherein the method comprises administering the TLR inhibitor to the individual. Provided herein are TLR inhibitors for use in methods of treating a disease in an individual, wherein the method comprises administering the TLR inhibitor to the individual, and the treatment is based on an IFN-I signature expression pattern of a sample from the individual. In some embodiments, the IFN-I signature expression pattern is compared to one or more reference IFN-I signature expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates administration of a TLR inhibitor; 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; if there is no 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 that a TLR inhibitor should not be administered, and thus, if there is no correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, a 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, a TLR inhibitor is not administered. In some embodiments, if 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 that a TLR inhibitor should not be administered, and if there is a correlation between the determined IFN-I signature expression pattern and the first reference IFN-I signature expression pattern, a 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, a TLR inhibitor is not administered.

[0093] Also provided herein are TLR inhibitors for use in methods of treating a disease in an individual, wherein the method includes administering the TLR inhibitor to the individual, and the treatment is based on an IFN-I signature score of a sample from the individual. In some embodiments, the TLR inhibitor is administered to the individual if the IFN-I signature score of the individual's sample is higher than a reference IFN-I signature score. Also provided herein are TLR inhibitors for use in methods of treating a disease in an individual, wherein the method includes determining an IFN-I signature score of a sample from the individual, and administering the TLR inhibitor to the individual if the IFN-I signature score is higher than the reference IFN-I signature score. In some embodiments, the reference IFN-I signature score is selected to distinguish individuals who are likely to have a more effective treatment from individuals who are likely to have a less effective treatment, such that an individual is administered a TLR inhibitor if their IFN-I signature score is higher than the reference IFN-I signature score, and is not administered a TLR inhibitor if their IFN-I signature score is lower than the reference IFN-I signature score. In some embodiments, the reference IFN-I signature score indicates therapeutic efficacy, such that an individual is administered a TLR inhibitor if their IFN-I signature score is near or above the reference IFN-I signature score. In some embodiments, the reference IFN-I signature score indicates therapeutic ineffectiveness, such that an individual is administered a TLR inhibitor if their IFN-I signature score is near or below the reference IFN-I signature score.

[0094] Also provided herein is a TLR inhibitor for use in a method of treating a disease in an individual, the method comprising selecting a patient having an IFN-I signature score that exceeds a reference IFN-I signature score and administering a TLR inhibitor to the individual. Also provided herein is a TLR inhibitor for use in a method of treating a disease in an individual, the method comprising selecting a patient having an IFN-I signature score that exceeds a reference IFN-I signature score selected to distinguish individuals who are likely to be more effective at treatment from individuals who are likely to be less effective at treatment, and administering a TLR inhibitor to the individual. Also provided herein is a TLR inhibitor for use in a method of treating a disease in an individual, the method comprising administering a TLR inhibitor to an individual, and the individual having a higher IFN-I signature score in a sample from the individual compared to the reference IFN-I signature score. Also provided herein is a TLR inhibitor for use in a method of treating a disease in an individual, wherein the method comprises administering the TLR inhibitor to an individual, and wherein the individual has a higher IFN-I signature score in a sample from the individual compared to a reference IFN-I signature score selected to distinguish individuals more likely to be treated effectively from individuals less likely to be treated effectively.

[0095] Provided herein are methods of treating a disease in an individual, the methods comprising administering a 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 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. Provided herein are methods of treating a disease in an individual with high IFN-I activity, the method comprising administering a TLR inhibitor to the individual. Provided herein are methods of treating a disease in an individual, the method comprising administering a TLR inhibitor to the individual, wherein treatment is based on an IFN-I signature expression pattern in a sample from the individual. In some embodiments, the IFN-I signature expression pattern is compared to one or more reference IFN-I signature expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates administration of a TLR inhibitor, such that if there is a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, a TLR inhibitor is administered, and if there is no correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, a TLR inhibitor is not administered. In some embodiments, the reference IFN-I signature expression pattern indicates not administering a TLR inhibitor, such that if there is no correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, a 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, a TLR inhibitor is not administered.In some embodiments, there is a first reference IFN-I signature expression pattern indicative of administration of a TLR inhibitor and a second reference IFN-I signature expression pattern indicative of not administering 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. Also provided herein are methods of treating a disease in an individual, the methods comprising administering a TLR inhibitor to the individual, wherein treatment is based on an IFN-I signature score of a sample from the individual. In some embodiments, the TLR inhibitor is administered to the individual if the IFN-I signature score of the individual's sample is higher than the reference IFN-I signature score. Also provided herein is a method for treating a disease in an individual, comprising determining an IFN-I signature score of 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. Also provided herein is a method for treating a disease in an individual, comprising selecting a patient having an IFN-I signature score higher than the reference IFN-I signature score, and administering a TLR inhibitor to the individual. Also provided herein is a method for treating a disease in an individual, comprising administering a TLR inhibitor to the individual, wherein the individual has a higher IFN-I signature score of a sample from the individual compared to the reference IFN-I signature score.

[0096] Provided herein is the use of a TLR inhibitor to treat a disease in an individual, wherein the treatment comprises administering a TLR inhibitor to the individual, and wherein the treatment is based on the IFN-I activity of 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 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. Provided herein is the use of a TLR inhibitor to treat a disease in an individual with high IFN-I activity, wherein the treatment comprises administering a TLR inhibitor to the individual. Provided herein is the use of a TLR inhibitor to treat a disease in an individual, wherein the treatment comprises administering a TLR inhibitor to the individual, and wherein the treatment is based on an IFN-I signature expression pattern of a sample from the individual. In some embodiments, the IFN-I signature expression pattern is compared to one or more reference IFN-I signature expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates administration of a TLR inhibitor, such that if there is a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, a TLR inhibitor is administered, and if there is no correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, a TLR inhibitor is not administered. In some embodiments, the reference IFN-I signature expression pattern indicates not administering a TLR inhibitor, such that if there is no correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, a 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, a TLR inhibitor is not administered.In some embodiments, there is a first reference IFN-I signature expression pattern indicative of administration of a TLR inhibitor and a second reference IFN-I signature expression pattern indicative of not administering 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. Also provided herein is the use of a TLR inhibitor for treating a disease in an individual, wherein the treatment comprises administering a TLR inhibitor to the individual, and the treatment is based on an IFN-I signature score of a sample from the individual. In some embodiments, if the IFN-I signature score of the individual's sample is higher than the reference IFN-I signature score, the TLR inhibitor is administered to the individual. Also provided herein is the use of a TLR inhibitor for treating a disease in an individual, wherein the treatment comprises determining an IFN-I signature score of a sample from the individual, and administering a TLR inhibitor to the individual if the IFN-I signature score is higher than the reference IFN-I signature score. Also provided herein is the use of a TLR inhibitor for treating a disease in an individual, wherein the treatment comprises selecting a patient having an IFN-I signature score higher than the reference IFN-I signature score, and administering a TLR inhibitor to the individual. Also provided herein is the use of a TLR inhibitor for treating a disease in an individual, wherein the treatment comprises administering a TLR inhibitor to the individual, and wherein the individual has a higher IFN-I signature score of a sample from the individual compared to the reference IFN-I signature score.

[0097] Provided herein is the use of a TLR inhibitor for the manufacture of a medicament for treating a disease in an individual, wherein the treatment comprises administering a TLR inhibitor to the individual, and wherein the treatment is based on IFN-I activity of 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 to a reference IFN-I activity, and if the individual's IFN-I activity is higher than the reference IFN-I activity, a TLR inhibitor is administered to the individual. Provided herein is the use of a TLR inhibitor for the manufacture of a medicament for treating a disease in an individual with high IFN-I activity, wherein the treatment comprises administering a TLR inhibitor to the individual. Provided herein is the use of a TLR inhibitor for the manufacture of a medicament for treating a disease in an individual, wherein the treatment comprises administering a TLR inhibitor to the individual, and wherein the treatment is based on an IFN-I signature expression pattern of a sample from the individual. In some embodiments, the IFN-I signature expression pattern is compared to one or more reference IFN-I signature expression patterns. In some embodiments, the reference IFN-I signature expression pattern indicates administration of a TLR inhibitor, such that if there is a correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, a TLR inhibitor is administered, and if there is no correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, a TLR inhibitor is not administered. In some embodiments, the reference IFN-I signature expression pattern indicates not administering a TLR inhibitor, such that if there is no correlation between the determined IFN-I signature expression pattern and the reference IFN-I signature expression pattern, a 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, a TLR inhibitor is not administered.In some embodiments, there is a first reference IFN-I signature expression pattern indicative of administration of a TLR inhibitor and a second reference IFN-I signature expression pattern indicative of not administering 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. Also provided herein is the use of a TLR inhibitor for the manufacture of a medicament for treating a disease in an individual, wherein the treatment comprises administering a TLR inhibitor to the individual, and the treatment is based on the IFN-I signature score of a sample from the individual. Also provided herein is the use of a TLR inhibitor for the manufacture of a medicament for treating a disease in an individual, wherein the treatment comprises determining an IFN-I signature score of a sample from the individual, and administering a TLR inhibitor to the individual if the IFN-I signature score is higher than the reference IFN-I signature score. Also provided herein is the use of a TLR inhibitor for the manufacture of a medicament for treating a disease in an individual, wherein the treatment comprises selecting a patient having an IFN-I signature score higher than the reference IFN-I signature score, and administering a TLR inhibitor to the individual. Also provided herein is the use of a TLR inhibitor for the manufacture of a medicament for treating a disease in an individual, wherein the treatment comprises administering a TLR inhibitor to the individual, and wherein the individual has a higher IFN-I signature score of a sample from the individual compared to the reference IFN-I signature score.

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

[0099] Provided herein are a TLR inhibitor and a corticosteroid, e.g., 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, the method comprising administering the TLR inhibitor and the corticosteroid to the individual. Provided herein are a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid, for use in a method of treating a disease in an individual with IFN-I activity higher than a reference IFN-I activity, the method comprising administering the TLR inhibitor and the corticosteroid to the individual. Provided herein are a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid, for use in a method of treating a disease in an individual, the method 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) administering the TLR inhibitor and the corticosteroid to the individual depending on the results of the comparison. In some embodiments, the reference IFN-I activity is selected to distinguish individuals who are likely to receive a greater therapeutic benefit from the TLR inhibitor from individuals who are likely to receive a lesser therapeutic benefit from the TLR inhibitor, such that if the individual's IFN-I activity is higher than the reference IFN-I activity, the individual is administered the 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 the TLR inhibitor and a corticosteroid. In some embodiments, the reference IFN-I activity indicates the therapeutic efficacy of the TLR inhibitor, such that if the individual's IFN-I activity is near or above the reference IFN-I activity, the individual is administered the TLR inhibitor and a corticosteroid. In some embodiments, the reference IFN-I activity indicates the therapeutic ineffectiveness of the TLR inhibitor, such that if the individual's IFN-I activity is near or below the reference IFN-I activity, the individual is not administered the TLR inhibitor and a corticosteroid.Provided herein are TLR inhibitors and corticosteroids, e.g., TLR7 and / or TLR8 inhibitors and glucocorticosteroids, for use in methods of treating a disease in an individual, the method comprising administering the TLR inhibitor and corticosteroid to the individual, and the individual having an IFN-I signature score higher than a reference IFN-I signature score. Provided herein are TLR inhibitors and corticosteroids, e.g., TLR7 and / or TLR8 inhibitors and glucocorticosteroids, for use in methods of treating a disease in an individual, the method comprising (i) determining an IFN-I signature score for the individual, (ii) comparing the determined IFN-I signature score to a reference IFN-I signature score, and (iii) administering a TLR inhibitor and a corticosteroid to the individual depending on the results of the comparison. In some embodiments, the reference IFN-I signature score is selected to distinguish individuals who are likely to receive a greater therapeutic benefit from the TLR inhibitor from individuals who are likely to receive a lesser therapeutic benefit from the TLR inhibitor, such that an individual is administered a TLR inhibitor and a corticosteroid if their IFN-I signature score is higher than the reference IFN-I signature score, and is not administered a TLR inhibitor and a corticosteroid if their IFN-I signature score is lower than the reference IFN-I signature score. In some embodiments, the reference IFN-I signature score indicates the therapeutic benefit of the TLR inhibitor, such that an individual is administered a TLR inhibitor and a corticosteroid if their IFN-I signature score is near or above the reference IFN-I signature score. In some embodiments, the reference IFN-I signature score indicates therapeutic ineffectiveness of the TLR inhibitor, and thus, if the individual's IFN-I signature score is near or below the reference IFN-I signature score, the individual is not administered the TLR inhibitor and the corticosteroid. 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, a reduced effective amount (including but not limited to, administration volume, administration concentration, and / or total drug dose administered) of a corticosteroid is administered when administered with a TLR inhibitor.

[0100] Provided herein are methods for treating a disease in an individual with high IFN-I activity, the method comprising administering to the individual a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid. Provided herein are methods for treating a disease in an individual with IFN-I activity higher than a reference IFN-I activity, the method comprising administering to the individual a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid. Provided herein are methods for treating a disease in an individual, the method comprising administering to the individual a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid, wherein the individual has an IFN-I signature score higher than the reference IFN-I signature score. 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, a reduced effective amount (including but not limited to, administration volume, administration concentration, and / or total drug dose administered) of a corticosteroid is administered when administered with a TLR inhibitor.

[0101] Provided herein is the use of a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid, for treating a disease in an individual with high IFN-I activity, wherein the treatment comprises administering the TLR inhibitor and the corticosteroid to the individual. Provided herein is the use of a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid, for treating a disease in an individual with IFN-I activity higher than a reference IFN-I activity, wherein the method comprises administering the TLR inhibitor and the corticosteroid to the individual. Provided herein is the use of a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid, for treating a disease in an individual, wherein the individual has an IFN-I signature score higher than a reference IFN-I signature score, wherein the treatment comprises administering the TLR inhibitor and the corticosteroid 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, a reduced effective amount (including, but not limited to, administration volume, administration concentration, and / or total drug dose administered) of a corticosteroid is administered when administered with a TLR inhibitor.

[0102] Provided herein is the use of a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid, for the manufacture of a medicament for treating a disease in an individual with high IFN-I activity, wherein the treatment comprises administering the TLR inhibitor and the corticosteroid to the individual. Provided herein is the use of a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid, for the manufacture of a medicament for treating a disease in an individual with IFN-I activity higher than a reference IFN-I activity, wherein the method comprises administering the TLR inhibitor and the corticosteroid to the individual. Provided herein is the use of a TLR inhibitor and a corticosteroid, e.g., a TLR7 and / or TLR8 inhibitor and a glucocorticosteroid, for the manufacture of a medicament for treating a disease in an individual, wherein the treatment comprises administering the TLR inhibitor and the corticosteroid to the individual, and wherein the individual has an IFN-I signature score higher than a reference IFN-I signature score. 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, a reduced effective amount (including, but not limited to, administration volume, administration concentration, and / or total drug dose administered) of a corticosteroid is administered when administered with a TLR inhibitor.

[0103] In some embodiments of any of the methods or uses herein relating to IFN-I activity in an individual, determining the IFN-I activity includes (i) obtaining a sample from the individual, (ii) measuring the IFN-I activity of the sample, and (iii) normalizing the IFN-I 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 of the sample; and (iii) normalizing each of the gene expression levels 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 of the sample; (iii) normalizing each of the gene expression levels; and (iii) calculating the arithmetic mean of the normalized gene expression levels to obtain the IFN-I signature score.

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

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

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

[0109] In some embodiments, the measured expression level is normalized. For example, the expression level may be normalized to the expression level of a gene known not to significantly change expression between different 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 refer to a reference IFN-I activity, a reference IFN-I signature expression pattern, or a reference IFN-I signature score, which can be obtained, for example, from a second individual with or without a disease, or from a population of individuals with or without a disease. In some embodiments, the reference IFN-I activity, the reference IFN-I signature expression pattern, or the reference IFN-I signature score is retrospectively determined based on the IFN-I activity, the IFN-I signature expression pattern, or the IFN-I signature score, respectively, in a patient population before treatment with a TLR inhibitor, and the treatment outcome. The patient population may then be divided into two groups, one of which showed a particular treatment outcome and the other of which did not. In some embodiments, the IFN-I activity or the IFN-I signature score between these two groups is defined as the reference IFN-I activity or the reference IFN-I signature score, respectively. In other embodiments, an IFN-I activity or IFN-I signature score that is characteristic of one of the two groups is defined as the reference IFN-I activity or reference IFN-I signature score, respectively. In some embodiments, an IFN-I signature expression pattern that is characteristic of one or both groups is defined as the reference IFN-I signature expression pattern. Individuals having an IFN-I activity or IFN-I signature score that corresponds to one of the two groups (those that show a therapeutic effect or those that do not show a therapeutic effect) can then be defined as individuals for whom TLR inhibitor treatment is predicted to be therapeutically effective or individuals for whom TLR inhibitor treatment is predicted to be therapeutically ineffective. In another embodiment, the reference IFN-I activity, reference IFN-I signature expression pattern, or reference IFN-I signature score is defined independently of treatment outcome. For example, in the case of a patient population with a bimodal distribution of IFN-I activity or IFN-I signature score, the reference IFN-I activity or reference IFN-I signature score may be defined as the IFN-I activity or IFN-I signature score, respectively, that falls within the valley of the bimodal distribution, or as the IFN-I activity or IFN-I signature score, respectively, that is characteristic of one of the two groups.Furthermore, a reference IFN-I activity or reference IFN-I signature score may be defined that reflects each of the two groups. Individuals with an IFN-I activity or IFN-I signature score that corresponds to one of the two groups can then be defined as having high IFN-I activity, which predicts that TLR inhibitor treatment will be therapeutically effective, or as having low IFN-I activity, which predicts that TLR inhibitor treatment will be therapeutically ineffective. Similarly, in such a population with a bimodal distribution, an IFN-I signature expression pattern characteristic of the group with lower IFN-I activity and / or the group with higher IFN-I activity may be defined as the reference IFN-I signature expression pattern. In one embodiment, for a population of healthy individuals, a reference IFN-I activity or reference IFN-I signature score may be defined as an IFN-I activity or IFN-I signature score near the upper end of the range of IFN-I activity or IFN-I signature score for this population. In another embodiment, the IFN-I activity or IFN-I signature score of a healthy individual may be defined as a reference IFN-I activity and a reference IFN-I signature score, respectively.

[0111] In some embodiments, the reference IFN-I activity is as follows: (i) defining a population of healthy individuals; (ii) determining the IFN-I activity of a sample from each individual in the population; (iii) defining an IFN-I activity near the upper end of the range of the determined IFN-I activity in the population as the reference IFN-I activity.

[0112] Such reference IFN-I activity can then be used to distinguish individuals who are likely to be more therapeutically effective (IFN-I activity above the reference IFN-I activity) from individuals who are likely to be less therapeutically effective (IFN-I activity below the reference IFN-I activity).

[0113] In some embodiments, the reference IFN-I activity is as follows: (i) defining a population of patients who have the same disease as an individual whose IFN-I activity is determined according to the method or use of the invention and who are to be treated with the same TLR inhibitor as said individual; (ii) determining the IFN-I activity of a sample from each patient in the patient population prior to treatment with a TLR inhibitor; (iii) determining the efficacy of treatment for each patient in the patient population following treatment with a TLR inhibitor; (iv) differentiating the patient population into groups exhibiting higher therapeutic efficacy and groups exhibiting lower therapeutic efficacy; (v) defining an IFN-I activity that distinguishes between the two patient groups as a reference IFN-I activity.

[0114] Such reference IFN-I activity can then be used to distinguish individuals who are likely to be more therapeutically effective (IFN-I activity above the reference IFN-I activity) from individuals who are likely to be less therapeutically effective (IFN-I activity below the reference IFN-I activity).

[0115] In some embodiments, the reference IFN-I activity is as follows: (vi) defining a population of patients who have the same disease as the individual whose IFN-I activity is determined according to the method or use of the invention and who are treated with the same TLR inhibitor as said individual; (vii) determining the IFN-I activity of a sample from each patient in the patient population prior to treatment with a TLR inhibitor; (viii) determining the therapeutic efficacy for each patient in the patient population following treatment with a TLR inhibitor; (ix) differentiating the patient population into a group exhibiting a higher therapeutic efficacy and a group exhibiting a lower therapeutic efficacy; (x) defining the IFN-I activity characteristic of one or both of the two patient groups as a reference IFN-I activity.

[0116] Such a reference IFN-I activity can then be used to identify individuals who are likely to be more therapeutically effective (if an IFN-I activity characteristic of a patient group exhibiting higher therapeutic efficacy is selected as the reference IFN-I activity) and / or individuals who are likely to be less therapeutically effective (if an IFN-I activity characteristic of a patient group exhibiting lower therapeutic efficacy is selected as the reference IFN-I activity).

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

[0118] Therefore, such a reference IFN-I signature expression pattern derived from a healthy population may indicate a lack of therapeutic efficacy.

[0119] In some embodiments, the reference IFN-I signature expression pattern is one of the following: (i) defining a population of patients who have the same disease as an individual whose IFN-I signature expression pattern is determined according to the method or use of the present invention and who are treated with the same TLR inhibitor as said individual; (ii) determining an IFN-I signature expression pattern of a sample from each patient in the patient population prior to treatment with a TLR inhibitor, wherein the IFN-I signature is the same IFN-I signature as the IFN-I signature of the individual whose IFN-I signature expression pattern is determined according to the method or use of the invention; (iii) determining the therapeutic efficacy for each patient in the patient population following treatment with a TLR inhibitor; (iv) differentiating the patient population into groups exhibiting higher therapeutic efficacy and groups exhibiting lower therapeutic efficacy; (v) defining a characteristic IFN-I signature expression pattern for one or both patient groups as a reference IFN-I signature expression pattern.

[0120] Such reference IFN-I signature expression patterns derived from a patient population can therefore indicate therapeutic efficacy or lack thereof, respectively.

[0121] In some embodiments, the reference IFN-I signature score is: (iv) defining a population of healthy individuals; (v) determining an IFN-I signature score for a sample from each individual in the population; (vi) defining an IFN-I signature score near the upper end of the range of determined IFN-I signature scores in the population as a reference IFN-I signature score.

[0122] Such a reference IFN-I signature score can then be used to distinguish individuals who may be more therapeutically effective (IFN-I signature score above the reference IFN-I signature score) from individuals who may be less therapeutically effective (IFN-I activity below the reference IFN-I signature score).

[0123] In some embodiments, the reference IFN-I signature score is: (i) defining a population of patients who have the same disease as an individual whose IFN-I signature score is determined according to the method or use of the present invention and who are to be treated with the same TLR inhibitor as said individual; (ii) determining an IFN-I signature score for a sample from each patient in the patient population prior to treatment with a TLR inhibitor, wherein the IFN-I signature score is based on the same IFN-I signature as the IFN-I signature on which the IFN-I signature score of the individual whose IFN-I signature score is determined according to the method or use of the invention is based; (iii) determining the efficacy of treatment for each patient in the patient population following treatment with a TLR inhibitor; (iv) differentiating the patient population into groups exhibiting higher therapeutic efficacy and groups exhibiting lower therapeutic efficacy; (v) defining an IFN-I signature score that distinguishes between the two patient groups as a reference IFN-I signature score.

[0124] Such a reference IFN-I signature score can then be used to distinguish individuals who may be more therapeutically effective (IFN-I signature score above the reference IFN-I signature score) from individuals who may be less therapeutically effective (IFN-I activity below the reference IFN-I signature score).

[0125] In some embodiments, the reference IFN-I signature score is: (xi) defining a population of patients who have the same disease as the individual whose IFN-I signature score is determined according to the method or use of the invention and who are treated with the same TLR inhibitor as said individual; (xii) determining an IFN-I signature score for a sample from each patient in the patient population prior to treatment with a TLR inhibitor; (xiii) determining the therapeutic efficacy for each patient in the patient population following treatment with a TLR inhibitor; (xiv) differentiating the patient population into groups exhibiting higher therapeutic efficacy and groups exhibiting lower therapeutic efficacy; (xv) defining an IFN-I signature score characteristic of one or both of the two patient groups as a reference IFN-I signature score.

[0126] Such a reference IFN-I signature score can then be used to identify individuals who are likely to be more therapeutically effective (if an IFN-I signature score characteristic of a patient group exhibiting higher therapeutic efficacy is selected as the reference IFN-I signature score) and / or individuals who are likely to be less therapeutically effective (if an IFN-I signature score characteristic of a patient group exhibiting lower therapeutic efficacy is selected as the reference IFN-I signature score).

[0127] Diseases for which IFN-I activity (and IFN-I signature expression pattern or IFN-I signature score) may serve as biomarkers include 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 a 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 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 1 diabetes, multiple sclerosis, antiphospholipid syndrome, sclerosing cholangitis, systemic 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 diseases, uveitis, pernicious anemia, and hypoparathyroidism. In some embodiments, the disease is selected from the group consisting of polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cryopathy. In other aspects, the disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, autoimmune skin diseases, and multiple sclerosis. In other aspects, the disease is selected from the group consisting of pancreatitis, glomerulonephritis, pyelitis, sclerosing cholangitis, and type 1 diabetes. In some aspects, the disease is diabetes and / or a diabetes-related disease or disorder. In some embodiments, the disease is an inflammatory disease. In some variations, the disease is associated with chronic pathogen stimulation. In some variations, the disease is a viral disease resulting from infection with, for example, HIV or SARS-CoV-2, such as COVID-19.In some embodiments, the disease is selected from 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, periodic fever syndromes, cryopyrin-associated periodic fever 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 comprise administration of 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 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]octan-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]octan-1-yl)morpholine-3-carboxamide, or a pharmaceutically acceptable salt of either 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: [ka] or a pharmaceutically acceptable salt thereof, wherein Ring A is an aryl or heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted; Ring B is an aryl or heteroaryl having 1 to 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 2 are independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO, —SOR, —SOR, —C(O)R, —COR, —C(O)N(R), —NRC(O)R, —NRC(O)N(R), —NRSOR, or —N(R); Each R 3 are independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO, —SOR, —SOR, —C(O)R, —COR, —C(O)N(R), —NRC(O)R, —NRC(O)N(R), —NRSOR, or —N(R); X is C(R 4 )2, O, NR 4 , S, S(R 4 ), or S(R 4 )2, Each R 4 are independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO, —SOR, —SOR, —C(O)R, —COR, —C(O)N(R), —NRC(O)R, —NRC(O)N(R), —NRSOR, or —N(R); Each R 5 are independently —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO, —SOR, —SOR, —C(O)R, —COR, —C(O)N(R), —NRC(O)R, —NRC(O)N(R), —NRSOR, or —N(R); Each R is independently hydrogen, C 1~6 aliphatic, C 3~10aryl, a 3-8 membered saturated or partially unsaturated carbocyclyl ring, a 3-7 membered heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl 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 atom to which they are attached, form a C 3~10 forming an aryl, a 3-8 membered saturated or partially unsaturated carbocyclyl ring, a 3-7 membered heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl 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; t is 0, 1 or 2).

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

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

[0134] In certain embodiments, ring A is phenyl, pyridyl, or pyrimidinyl, each of which is optionally substituted.

[0135] In one embodiment, Ring B is a 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 one embodiment, ring A and ring B are [ka] is.

[0138] In one embodiment, ring A and ring B are [ka] is.

[0139] In one embodiment, ring A and ring B are [ka] is.

[0140] In one embodiment, ring A and ring B are [ka] is.

[0141] In one embodiment, ring A and ring B are [ka] is.

[0142] In one embodiment, R 1 is -OMe or -CN.

[0143] In some embodiments, each R 2 independently, C 1~6 aliphatic, C 3~10aryl, a 3- to 8-membered saturated or partially unsaturated carbocyclyl ring, a 3- to 7-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted.

[0144] In some embodiments, each R 2 is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight-chained or branched pentyl, or straight-chained or branched hexyl, each of which is optionally substituted.

[0145] In some embodiments, each R 2are independently selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, and benzotetrazolyl. Allyl, 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, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl nyl, 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, piperidyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, 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 some embodiments, each R 2 are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R), -NRC(O)R, -NRC(O)N(R), -NRSOR, or -N(R).

[0147] In one embodiment, R 2 are independently -F.

[0148] In some embodiments, each R 3 independently, C 1~6 aliphatic, C 3~10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocyclyl ring, a 3- to 7-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted.

[0149] In some embodiments, each R 3 is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight-chained or branched pentyl, or straight-chained or branched hexyl, each of which is optionally substituted.

[0150] In some embodiments, each R 3 are independently methyl.

[0151] In some embodiments, each R 3are independently selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, and benzotetrazolyl. Allyl, 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, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl nyl, 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, piperidyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, 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 some embodiments, each R 3 are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R), -NRC(O)R, -NRC(O)N(R), -NRSOR, or -N(R).

[0153] In one embodiment, R 3 are 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 CH2.

[0156] In certain embodiments, X is O.

[0157] In some embodiments, each R 4 independently, C 1~6 aliphatic, C 3~10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocyclyl ring, a 3- to 7-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted.

[0158] In some embodiments, each R 4is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight-chained or branched pentyl, or straight-chained or branched hexyl, each of which is optionally substituted.

[0159] In some embodiments, each R 4are independently selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, and benzotetrazolyl. Allyl, 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, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl nyl, 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, piperidyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, 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 some embodiments, each R 4 are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R), -NRC(O)R, -NRC(O)N(R), -NRSOR, or -N(R).

[0161] In some embodiments, each R 4 are independently -H, C 1~6 Aliphatic, -OR, -C(O)R, -CO2R, -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 some embodiments, each R 4 are 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 some embodiments, each R 4 is independent, [ka] [ka] [ka] [ka] [ka] [ka] is.

[0164] In some embodiments, each R 4 is independent, [ka] [ka] is.

[0165] In some embodiments, each R 4 is independent, [ka] is.

[0166] In some embodiments, each R 5 independently, C 1~6 aliphatic, C 3~10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocyclyl ring, a 3- to 7-membered heterocyclyl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted.

[0167] In some embodiments, each R 5 is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight-chained or branched pentyl, or straight-chained or branched hexyl, each of which is optionally substituted.

[0168] In some embodiments, each R 5are independently selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, and benzotetrazolyl. Allyl, 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, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl nyl, 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, piperidyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, 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 some embodiments, each R 5 are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO, -SOR, -SOR, -C(O)R, -COR, -C(O)N(R), -NRC(O)R, -NRC(O)N(R), -NRSOR, or -N(R).

[0170] In some embodiments, each R 5 is independently methyl, cyclopropyl, —F, or —CF 3 .

[0171] In some embodiments, each R 5 is independent, [ka] -F, or -CF3.

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

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

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

[0175] In one embodiment, the TLR inhibitor is [ka] or a pharmaceutically acceptable salt of any of these.

[0176] In certain embodiments, the TLR7 and / or TLR8 inhibitor is a compound of formula Ib: [ka] or a pharmaceutically acceptable salt thereof, wherein X is O or CH; and R 4 teeth [ka] and R 5 is methyl or -CF3.

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

[0178] In one embodiment, the TLR inhibitor is empatran, E6742, or affimetran.

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

[0180] In one embodiment, the IFN-I signature is 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; The present invention includes one or more genes selected from the group consisting of FIT1, 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 RSAD2, one or more genes selected from the group consisting of ISG15, MX1, and OAS1, one or more genes selected from the group consisting of IEPSTI1, 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, at least three, or all genes of one of the groups of 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 the 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 the reference IFN-I signature score.

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

[0183] Formulation and Administration The TLR inhibitors and other therapeutic agents disclosed herein may be administered neat or in a pharmaceutically acceptable composition. They may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted 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 thereof via mouth or nasogastric tube. Any oral formulation of the present invention may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0184] The pharmaceutically acceptable compositions herein can be orally administered in any orally acceptable dosage form.Exemplary oral dosage forms are capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also commonly added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavorings or coloring agents can also be optionally added.

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

[0186] In one embodiment, the total amount of TLR inhibitor administered to a subject in need thereof is about 10 mg to about 500 mg per day. In one aspect of this embodiment, the total amount of TLR inhibitor administered is about 5 mg to about 300 mg per day. In another aspect, the total amount of TLR inhibitor administered is about 100 mg to about 200 mg per day.

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

[0189] In any of the above embodiments, the TLR inhibitor is administered for a period of 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, e.g., over several months or years. In one embodiment, the TLR inhibitor is administered indefinitely.

[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 indefinitely. 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 indefinitely. 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 indefinitely.

[0191] Combination treatment In any of the methods of treatment disclosed herein, the 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 anti-inflammatory agents, antibiotics, anticoagulants, antiparasitic agents, antiplatelet and dual antiplatelet therapies, 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 therapies, JAK inhibitors, immunomodulatory agents, anti-inflammazone therapies, 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 antivirals.

[0193] In one embodiment, the 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] The inventors surprisingly found that, despite previous studies showing that glucocorticosteroid therapy is less potent in SLE patients with a high IFN-I signature score, the efficacy of glucocorticosteroids is increased when combined with a TLR7 and / or 8 inhibitor in the setting of IFN-α pretreatment. This suggests that treatment with a TLR inhibitor may have a glucocorticosteroid-sparing effect even in the clinical setting of patients with high IFN-I activity. Thus, in some embodiments, a TLR inhibitor described herein is administered in combination with a corticosteroid. In some embodiments, the corticosteroid is a glucocorticosteroid. In some embodiments, the corticosteroid is a mineralocorticoid. Corticosteroids include corticosterone and its derivatives, prodrugs, isomers, and analogs, cortisone and its derivatives, prodrugs, isomers, and analogs (i.e., Corton), 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., Prelon), fludrocortisone and its derivatives, prodrugs, isomers, and analogs, hydrocortisone and its derivatives, prodrugs, isomers, and analogs (i.e., Cortisol or Cortef), 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). EC), methylprednisolone and its derivatives, prodrugs, isomers and analogs (i.e., Medrol), prednisolone and its derivatives, prodrugs, isomers and analogs (i.e., Deltazone, Crtan, Methycortene, Orazone, or Sterapred), triamcinolone and its derivatives, prodrugs, isomers and analogs (i.e., Kenacort or Kenalog), and the like.In some embodiments, the corticosteroid is fludrocortisone or a derivative, prodrug, isomer, or analog thereof. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the corticosteroid is hydroxycortisone or a derivative, prodrug, isomer, or analog thereof. 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, the TLR inhibitor is administered in combination with interferon-1-beta (Rebif®).

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

[0199] In one embodiment, the TLR inhibitor is hydroxychloroquine, chloroquine, ivermectin, tranexamic acid, nafamostat, virazol, ribavirin, lopinavir / ritonavir, favipiravir, arbidol, leronlimab, interferon beta-1a, interferon beta-1b, beta-interferon, azithromycin, nitrazoxamide, lovastatin, clazakizumab, adalimumab, etanercept, golimumab, infliximab, sarilumab, tocilizumab, anakinra, emapalumab, pirfenidone, belimumab, rituximab, ocrelizumab, anifrolumab, ravulizumab-cwvz, eculizumab. and administered in combination with one or more additional therapeutic agents selected from mabu, bevacizumab, heparin, enoxaparin, apremilast, coumadin, baricitinib, ruxolitinib, dapagliflozin, methotrexate, leflunomide, azathioprine, sulfasalazine, mycophenolate mofetil, colchicine, fingolimod, ifenprodil, prednisone, cortisol, dexamethasone, methylprednisolone, melatonin, otilimab, ATR-002, APN-01, camostat 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, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, prednisone, hydrocortisone, fludocortosone, betamethasone, prednisolone, triamcinolone, methylprednisone, dexamethasone, fluticasone, and budesonide (alone or in combination with formoterol, salmeterol, or vilanterol).

[0201] In one embodiment, the TLR inhibitor is administered in combination with one or more immunomodulatory agents. In one aspect of this embodiment, the immunomodulatory agent is a calcineurin inhibitor, an antimetabolite, or an alkylating agent. In another aspect of this embodiment, the immunomodulatory agent is selected from azathioprine, mycophenolate mofetil, methotrexate, dapsone, cyclosporine, cyclophosphamide, and the like.

[0202] In one embodiment, the TLR inhibitor is administered in combination with one or more antibiotics. In one aspect of this embodiment, the antibiotic is a broad-spectrum antibiotic. In another aspect of this embodiment, the antibiotic is a penicillin, an antistalophylococcal penicillin, a cephalosporin, an aminopenicillin (usually administered with a beta-lactamase inhibitor), a monobactam, a quinoline, an aminoglycoside, a lincosamide, a macrolide, a tetracycline, a glycopeptide, an antimetabolite, or a nitroimidazole. In a further aspect of this embodiment, the antibacterial agent is selected from penicillin G, oxacillin, amoxicillin, cefazolin, cephalexin, cefotetan, cefoxitin, ceftriaxone, augmentin, amoxicillin, ampicillin (+sulbactam), piperacillin (+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 anticoagulants are 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 antiplatelet dual therapies. In one aspect of this embodiment, the antiplatelet agents and / or antiplatelet dual therapies are 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 trandolipril.

[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 blockers are 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 blockers are selected from acebutolol, atenolol, betaxolol, bisoprolol / hydrochlorothiazide, bisoprolol, metoprolol, nadolol, propranolol, and sotalol.

[0208] In another 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, the 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 blockers are 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, spironolactone, and torsemide.

[0214] In one embodiment, the TLR inhibitor is administered in combination with one or more muscle relaxants. In one aspect of this embodiment, the muscle relaxant is an antispasmodic or anticonvulsant. In another aspect of this embodiment, the 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 agents. In one aspect of this embodiment, the antiviral agent is remdesivir.

[0216] In one embodiment, the TLR inhibitor is selected from the group consisting of antiparasitic drugs (including but not limited to hydroxychloroquine, chloroquine, and ivermectin), antiviral drugs (including but not limited to tranexamic acid, nafamostat, virazole [ribavirin], lopinavir / ritonavir, favipiravir, leronlimab, interferon beta-1a, interferon beta-1b, and beta-interferon), and antibiotics with intracellular activity (including but not limited to azithromycin and nitrazoxamide). statins and other cholesterol-lowering drugs in combination with anti-inflammatory drugs (including, but not limited to, lovastatin); specific cytokine inhibitors (including, but not limited to, clazakizumab, adalimumab, etanercept, golimumab, infliximab, sarilumab, tocilizumab, anakinra, emapalumab, pirfenidone); anti-complement agents (including, but not limited to, ravulizumab-cwvz, eculizumab); anti-VEGF therapeutics (including, but not limited to, bevacizumab, Anticoagulants (including but not limited to heparin, enoxaparin, apremilast, coumadin), JAK inhibitors (including but not limited to baricitinib, ruxolitinib, dapagliflozin), antiflammasome 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 (ifenp). and / or solnatide), corticosteroids (including but not limited to, rozil), corticosteroids (including but not limited to, prednisone, cortisol, dexamethasone, methylprednisolone), GM-CSF, anti-GM-CSF (otilimab), ATR-002, APN-01, camostat mesylate, arbidol, brilacidin, IFX-1, PAX-1-001, BXT-25, NP-120, intravenous immunoglobulin (IVIG), and solnatide.

[0217] In some embodiments, the combination of a TLR inhibitor with one or more additional therapeutic agents reduces the effective amount (including, but not limited to, the administered volume, concentration, and / or total drug dose) of the TLR inhibitor and / or one or more additional therapeutic agents to achieve the same result, compared to the effective amount administered when the TLR inhibitor or additional therapeutic agent is administered alone. In some embodiments, for example, in individuals with high IFN-I activity, a reduced effective amount of a corticosteroid can be administered when co-administered with a TLR inhibitor. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent shortens the total treatment period compared to the administration of the additional therapeutic agent alone. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent reduces side effects associated with the administration of the additional therapeutic agent alone. In some embodiments, the combination of an effective amount of a TLR inhibitor with an additional therapeutic agent is more effective than 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 with one or more additional therapeutic agents provides one or more additional clinical benefits over the administration of either agent alone.

[0218] Advertising methods In one aspect, the present invention provides a method for promoting a TLR inhibitor, comprising promoting to a subject the use of the TLR inhibitor to treat a disease in an individual based on IFN-I activity. In another aspect, the present invention provides a method for promoting a TLR inhibitor, comprising promoting to a subject the use of the TLR inhibitor to treat a disease in an individual with high IFN-I activity, e.g., an IFN-I signature score that exceeds a reference IFN-I signature score. The promotion campaign can be carried out by any available means. In some embodiments, the promotion campaign is via a package insert accompanying the TLR inhibitor. The promotion campaign may also be via a package insert accompanying another therapeutic agent, such as a therapeutic agent described herein, with which the TLR inhibitor can be combined. In some embodiments, the promotion campaign is via a package insert, where the package insert provides instructions for administering treatment with the TLR inhibitor after determining IFN-I activity, e.g., by determining an IFN-I signature score, and in some embodiments, in combination with another therapeutic agent. In some embodiments, after the promotion campaign, the patient is treated with the TLR inhibitor, either in combination with another therapeutic agent or alone. In some embodiments, the package insert indicates that if the patient's sample is characterized by high IFN-I activity, e.g., a patient IFN-I signature score above a reference IFN-I signature score, then a TLR inhibitor should be used to treat the patient. In some embodiments, the package insert indicates that if the patient's sample is characterized by low IFN-I activity, e.g., a patient IFN-I signature score below the reference IFN-I signature score, then a TLR inhibitor should not be used to treat the patient. In some embodiments, high IFN-I activity means that the determined IFN-I activity correlates with the likelihood of increased therapeutic efficacy if the patient is treated with a TLR inhibitor, or vice versa. Further embodiments of the present disclosure E1. A method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, comprising determining IFN-I activity in a sample from the individual, wherein the IFN-I activity of the sample indicates the therapeutic efficacy of the TLR inhibitor. E2. A method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, comprising determining IFN-I activity in a sample from said individual, wherein the IFN-I activity of said sample is indicative of the therapeutic efficacy of said TLR inhibitor, and wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E3. A method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, comprising determining IFN-I activity in a sample from said individual, wherein the IFN-I activity of said sample is indicative of the therapeutic efficacy of said TLR inhibitor, and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia. [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E4. The method of any one of E1 to E3, wherein the TLR inhibitor is predicted to be therapeutically effective if the individual has high IFN-I activity, and the TLR inhibitor is predicted to be therapeutically ineffective 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 with a reference IFN-I activity, and the TLR inhibitor is predicted to be therapeutically effective if the IFN-I activity of the individual is higher than the reference IFN-I activity, and is predicted to be therapeutically ineffective if the IFN-I activity of the individual is lower than the reference IFN-I activity. E6. A method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, comprising determining an IFN-I signature expression pattern of a sample from said individual, wherein the IFN-I signature expression pattern of said sample is indicative of the therapeutic efficacy of said TLR inhibitor. E7. A method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, comprising determining an IFN-I signature expression pattern of a sample from said individual, wherein the IFN-I signature expression pattern of said sample is indicative of the therapeutic efficacy of said TLR inhibitor, and wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E8. A method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, comprising determining an IFN-I signature expression pattern of a sample from said individual, wherein the IFN-I signature expression pattern of said sample is indicative of the therapeutic efficacy of said TLR inhibitor, and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E9. A method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, comprising determining an IFN-I signature score of a sample from said individual, wherein said TLR inhibitor is predicted to be therapeutically effective if said determined IFN-I signature score is higher than a reference IFN-I signature score, and is predicted to be therapeutically ineffective if said determined IFN-I signature score is lower than the reference IFN-I signature score. E10. A method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, comprising determining an IFN-I signature score of a sample from said individual, wherein said TLR inhibitor is predicted to be therapeutically effective if said determined IFN-I signature score is higher than a reference IFN-I signature score, and is predicted to be therapeutically ineffective if said determined IFN-I signature score is lower than the reference IFN-I signature score, and wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E11. A method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, comprising the step of determining an IFN-I signature score of a sample from said individual, wherein said TLR inhibitor is predicted to be therapeutically effective if said determined IFN-I signature score is higher than a reference IFN-I signature score, and is predicted to be therapeutically ineffective if said determined IFN-I signature score is lower than said reference IFN-I signature score; and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia. [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E12. A method for predicting the suitability of an individual having a disease to initiate treatment with a TLR inhibitor, comprising determining IFN-I activity in a sample from said individual, wherein the IFN-I activity of said sample indicates the suitability of said individual to initiate treatment. E13. A method for predicting the suitability of an individual having a disease to initiate treatment with a TLR inhibitor, comprising determining IFN-I activity in a sample from said individual, wherein the IFN-I activity of said sample indicates the individual's suitability for initiating treatment, and wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E14. A method for predicting the suitability of an individual having a disease for initiating treatment with a TLR inhibitor, comprising determining the IFN-I activity of a sample from said individual, wherein the IFN-I activity of said sample indicates the suitability of said individual for initiating treatment, and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E15. The method according to any one of E12 to E14, wherein individuals with high IFN-I activity are assessed as suitable for initiating said treatment, and individuals with low IFN-I activity are assessed as unsuitable for initiating said treatment. E16. The method according to any one of E12 to E14, wherein the IFN-I activity is compared with a reference IFN-I activity, and if the IFN-I activity of the individual is higher than the reference IFN-I activity, the individual is evaluated as being suitable for initiating treatment, and if the IFN-I activity of the individual is lower than the reference IFN-I activity, the individual is evaluated as not being suitable for initiating treatment. E17. A method for predicting the suitability of an individual having a disease for initiation of treatment with a TLR inhibitor, comprising determining an IFN-I signature expression pattern of a sample from said individual, wherein the IFN-I signature expression pattern in said sample is indicative of the individual's suitability for initiation of treatment. E18. A method for predicting the suitability of an individual having a disease for initiation of treatment with a TLR inhibitor, comprising determining an IFN-I signature expression pattern of a sample from said individual, wherein the IFN-I signature expression pattern of said sample is indicative of said individual's suitability for initiation of treatment, and wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E19. A method for predicting the suitability of an individual having a disease for initiation of treatment with a TLR inhibitor, comprising determining an IFN-I signature expression pattern of a sample from said individual, wherein the IFN-I signature expression pattern of said sample indicates the suitability of said individual for initiation of treatment, and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia. [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E20. A method for predicting the suitability of an individual having a disease for initiation of treatment with a TLR inhibitor, comprising a step of determining an IFN-I signature score of a sample from said individual, wherein said individual is assessed as suitable for initiation of said treatment if said determined IFN-I signature score is higher than a reference IFN-I signature score, and as not suitable for initiation of said treatment if said determined IFN-I signature score is lower than the reference IFN-I signature score. E21. A method for predicting the suitability of an individual having a disease for initiation of treatment with a TLR inhibitor, comprising the step of determining an IFN-I signature score of a sample from said individual, wherein said individual is assessed as suitable for initiation of said treatment if said determined IFN-I signature score is higher than a reference IFN-I signature score, or as not suitable for initiation of treatment if said determined IFN-I signature score is lower than said reference IFN-I signature score, and wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E22. A method for predicting the suitability of an individual having a disease for initiation of treatment with a TLR inhibitor, comprising the step of determining an IFN-I signature score of a sample from said individual, wherein said individual is assessed as suitable for initiation of said treatment if said determined IFN-I signature score is higher than a reference IFN-I signature score, and is assessed as not suitable for initiation of said treatment if said determined IFN-I signature score is lower than said reference IFN-I signature score, and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E23. A method for predicting the suitability of an individual having a disease who is being treated with a TLR inhibitor to continue treatment, comprising determining the IFN-I activity of a sample from said individual, wherein the IFN-I activity of said sample indicates the suitability of said individual to continue treatment. E24. A method for predicting the suitability of an individual having a disease who is being treated with a TLR inhibitor to continue treatment, comprising determining the IFN-I activity of a sample from said individual, wherein the IFN-I activity of said sample indicates the suitability of said individual to continue treatment, and wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E25. A method for predicting the suitability of an individual having a disease being treated with a TLR inhibitor to continue treatment, said method comprising determining the IFN-I activity of a sample from said individual, wherein the IFN-I activity of said sample indicates the suitability of said individual to continue treatment, and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E26. The method according to any one of E23 to E25, wherein individuals with high IFN-I activity are assessed as suitable for continuing the treatment, and individuals with low IFN-I activity are assessed as unsuitable for continuing the treatment. E27. The method of any one of E23 to E25, wherein the IFN-I activity is compared to a reference IFN-I activity, and the individual is assessed as suitable for continuing the treatment if the individual's IFN-I activity is higher than the reference IFN-I activity, or as not suitable for continuing the treatment if the individual's IFN-I activity is lower than the reference IFN-I activity. E28. A method for predicting the suitability of an individual having a disease who is being treated with a TLR inhibitor for continuing treatment, comprising determining an IFN-I signature expression pattern of a sample from said individual, wherein the IFN-I signature expression pattern of said sample indicates the suitability of said individual for continuing treatment. E29. A method for predicting the suitability of an individual having a disease who is being treated with a TLR inhibitor to continue treatment, comprising determining an IFN-I signature expression pattern of a sample from said individual, wherein the IFN-I signature expression pattern of said sample is indicative of the individual's suitability for continuing treatment, and wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E30. A method for predicting the suitability of an individual having a disease being treated with a TLR inhibitor for continuing treatment, said method comprising determining an IFN-I signature expression pattern of a sample from said individual, wherein the IFN-I signature expression pattern of said sample indicates the suitability of said individual for continuing treatment, and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E31. A method for predicting the suitability of an individual having a disease undergoing treatment with a TLR inhibitor for continuing treatment, comprising a step of determining an IFN-I signature score of a sample from the individual, wherein the individual is assessed as suitable for continuing the treatment if the determined IFN-I signature score is higher than a reference IFN-I signature score, and is assessed as not suitable for continuing the treatment if the determined IFN-I signature score is lower than the reference IFN-I signature score. E32. A method for predicting the suitability of an individual having a disease being treated with a TLR inhibitor for continuing treatment, said method comprising a step of determining an IFN-I signature score of a sample from said individual, wherein said individual is assessed as suitable for continuing said treatment if said determined IFN-I signature score is higher than a reference IFN-I signature score, and is assessed as not suitable for continuing said treatment if said determined IFN-I signature score is lower than said reference IFN-I signature score, and wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor. E33. A method for predicting the suitability of an individual having a disease undergoing treatment with a TLR inhibitor to continue treatment, said method comprising a step of determining an IFN-I signature score of a sample from said individual, wherein said individual is assessed as suitable for continuing said treatment if said determined IFN-I signature score is higher than a reference IFN-I signature score, and wherein said individual is assessed as not suitable for continuing said treatment if said determined IFN-I signature score is lower than said reference IFN-I signature score, and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E34. A TLR inhibitor for use in a method of treating a disease in an individual, said method comprising administering said TLR inhibitor to said individual, wherein treatment is based on IFN-I activity of a sample from said individual. E35. A TLR inhibitor for use in a method of treating a disease in an individual, said method comprising the step of administering said TLR inhibitor to said individual, wherein treatment is based on IFN-I activity of a sample from said individual, and wherein said 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 an individual, said method comprising the step of administering said TLR inhibitor to said individual, wherein treatment is based on IFN-I activity in a sample from said individual, and wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E37. The TLR inhibitor for use according to any one of E34 to E36, wherein the IFN-I activity of a sample from the individual is compared to a reference IFN-I activity, and if the IFN-I activity of the individual 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, the method comprising the steps of selecting an individual having the disease and high IFN-I activity, and administering said TLR inhibitor to said individual. E39. A TLR inhibitor for use in a method of treating a disease in an individual, the method comprising the steps of selecting an individual having the disease and high IFN-I activity, and administering to said individual said TLR inhibitor, wherein said TLR inhibitor is a small molecule inhibitor of TLR7 and / or TLR8. E40. A TLR inhibitor for use in a method for treating a disease in an individual, the method comprising the steps of selecting an individual having the disease and high IFN-I activity, and administering to said individual said TLR inhibitor, wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E41. The 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 of a sample from the individual to a reference IFN-I activity and determining that the IFN-I activity of the individual exceeds the reference IFN-I activity. E42. A TLR inhibitor for use in a method of treating a disease in an individual, the method comprising administering said TLR inhibitor to said individual, wherein treatment is based on an IFN-I signature expression pattern of a sample from said individual. E43. A TLR inhibitor for use in a method of treating a disease in an individual, the method comprising the step of administering said TLR inhibitor to said individual, wherein treatment is based on an IFN-I signature expression pattern of a sample from said individual, and wherein said 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 an individual, the method comprising administering to said individual said TLR inhibitor, wherein treatment is based on an IFN-I signature expression pattern of a sample from said individual, and wherein said TLR inhibitor is a TLR7 inhibitor and / or a TLR8 inhibitor of Formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E45. A TLR inhibitor for use in a method of treating a disease in an individual, the method comprising determining an IFN-I signature score of a sample from said individual, and if said IFN-I signature score is higher than said reference IFN-I signature score, administering said TLR inhibitor to said individual. E46. A TLR inhibitor for use in a method of treating a disease in an individual, the method comprising determining an IFN-I signature score of a sample from said individual, and if said IFN-I signature score is higher than said reference IFN-I signature score, administering said TLR inhibitor to said individual, wherein said 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, the method comprising determining an IFN-I signature score of a sample from said individual, and if said IFN-I signature score is higher than said reference IFN-I signature score, administering said TLR inhibitor to said individual, wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof. E48. A combination of a TLR inhibitor and a corticosteroid for use in a method for treating a disease in an individual, the method comprising the steps of selecting an individual having the disease and high IFN-I activity, and administering the combination to said individual. E49. A combination of a TLR inhibitor and a corticosteroid for use in a method for treating a disease in an individual, the method comprising the steps of selecting an individual with the disease and high IFN-I activity, and administering said combination to said individual, wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor, and said corticosteroid is a glucocorticosteroid. E50. A combination of a TLR inhibitor and a corticosteroid for use in a method for treating a disease in an individual, the method comprising the steps of selecting an individual having the disease and high IFN-I activity, and administering said combination to said individual, wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof, and wherein said corticosteroid is a glucocorticosteroid. E51. The combination for use according to any one of E48 to E50, wherein the individual is selected as having high IFN-I activity by comparing the IFN-I activity of a sample from the individual to a reference IFN-I activity and determining that the IFN-I activity of the individual exceeds 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, the method comprising determining an IFN-I signature score of a sample from said individual, and if said IFN-I signature score is higher than a reference IFN-I signature score, administering said combination to said individual. E53. A combination of a TLR inhibitor and a corticosteroid for use in a method of treating a disease in an individual, the method comprising determining an IFN-I signature score of a sample from said individual, and if said IFN-I signature score is higher than a reference IFN-I signature score, administering said combination to said individual, wherein said TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor and said 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, the method comprising determining an IFN-I signature score of a sample from said individual, and if said IFN-I signature score is higher than a reference IFN-I signature score, administering said TLR inhibitor to said individual, wherein said TLR inhibitor is a TLR7 and / or TLR8 inhibitor of Formula Ia [ka] (In the formula, R 1 is -OMe or -CN, X is O or CH2, and R 4 teeth [ka] and R 5 is methyl or -CF3, and ring A is [ka] or a pharmaceutically acceptable salt thereof, and wherein said corticosteroid is a glucocorticosteroid. E55. The determination of the IFN-I signature score is (i) obtaining a sample from said individual; (ii) measuring the expression level of each gene in the IFN-I signature in the sample; (iii) normalizing the expression levels of each of the genes; (iv) calculating the arithmetic mean of the expression levels of the normalized genes to obtain the IFN-I signature score. E56. The TLR inhibitor for the method or use according to any one of E6, E7, E8, E17, E18, E19, E28, E29, E30, E42, E43 and E44, wherein the IFN-I signature of said 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. The TLR inhibitor for the method or use according to E56, wherein the IFN-I signature of said IFN-I signature expression pattern comprises one or more genes selected from the group consisting of HERC5, IFI27, IFIT1 and RSAD2. E58. The TLR inhibitor for the method or use according to E57, wherein the IFN-I signature of said 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 of said 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 or combination for use according to E59, wherein the IFN-I signature of said IFN-I signature score comprises one or more genes selected from the group consisting of HERC5, IFI27, IFIT1 and RSAD2. E61. The method, TLR inhibitor or combination for use according to E60, wherein the IFN-I signature of said IFN-I signature score comprises or consists of HERC5, IFI27, IFIT1 and RSAD2. E62. The method, TLR inhibitor for use or combination according to any one of E9, E10, E11, E20, E21, E22, E31, E32, E33, E45, E46, E47 and E55, wherein the IFN-I signature of said IFN-I signature score consists of the genes HERC5, IFI27, IFIT1 and RSAD2, and said reference IFN-I signature score is -0.5. E63. The method, use or combination of E55, wherein the IFN-I signature of said IFN-I signature score consists of the genes HERC5, IFI27, IFIT1 and RSAD2, and the genes ACTB, GAPDH and TFRC are used for normalization, and wherein said reference IFN-I signature score is -0.5. E64. The reference IFN-I activity is (i) defining a population of patients who have the same disease as the individual in whom IFN-I activity is to be determined and who are being treated with the same TLR inhibitor as said individual; (ii) determining the IFN-I activity of a sample from each patient in said patient population prior to treatment with said TLR inhibitor; (iii) determining the therapeutic efficacy for each patient in the patient population following treatment with the TLR inhibitor; (iv) differentiating the patient population into a group exhibiting a higher therapeutic efficacy and a group exhibiting a lower therapeutic efficacy; (v) defining the IFN-I activity that distinguishes between the two patient groups as the reference IFN-I activity. E65. The reference IFN-I signature score is: (i) defining a population of patients who have the same disease as the individual for whom the IFN-I signature score is determined and who are being treated with the same TLR inhibitor as said individual; (ii) determining an IFN-I signature score for a sample from each patient in said patient population prior to treatment with said TLR inhibitor, wherein said IFN-I signature score is based on the same IFN-I signature on which the IFN-I signature score of the individual for whom the IFN-I signature score is determined is based; (iii) determining the therapeutic efficacy for each patient in the patient population following treatment with the TLR inhibitor; (iv) differentiating the patient population into a group exhibiting a higher therapeutic efficacy and a group exhibiting a lower therapeutic efficacy; (v) defining an IFN-I signature score that distinguishes between the two patient groups as the reference IFN-I signature score. E66. The method, use or combination of any one of E1 to E65, wherein said disease is caused, mediated and / or propagated by TLR activity. E67. The method, TLR inhibitor or combination for use according to any one of E1 to E66, wherein said 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 said disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, type 1 diabetes, multiple sclerosis, Sjogren's syndrome, polymyositis, and dermatomyositis. E69. The method, TLR inhibitor or combination for use according to any one of E1 to E66, wherein said disease is COVID-19. E70. The method, use or combination according to any one of E1-E66, wherein said disease is systemic lupus erythematosus or cutaneous lupus erythematosus. E71. The method, TLR inhibitor or combination for use according to any one of E1 to E66, wherein said disease is polymyositis or dermatomyositis. E72. The TLR inhibitor is: [ka] or a pharmaceutically acceptable salt thereof. E73. The TLR inhibitor [ka] or a pharmaceutically acceptable salt thereof.

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

[0220] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred examples are described below. The examples should not be construed as being limited to the combinations of features specifically and explicitly shown, but the exemplified features can be combined again without limit as long as the technical problem of the present invention is solved. Similarly, the features of any claim can be combined with the features of one or more other claims. Although the present invention has been summarized and described in detail, it is not limited to the examples shown below. [Example]

[0221] Example 1: Comparison of IFN-I signatures The purpose of this experiment was to assess the correlation of the Dx_4 IFN-I signature to various published IFN-I signatures in Table 1.

[0222] [Table 1]

[0223] To compare IFN-I signatures, we used gene expression data from 417 placebo-treated SLE patients from clinical trial NCT01972568. For each SLE patient, an IFN-I signature score was calculated for each of the IFN-I signatures in Table 1, and the correlation coefficient r was calculated (the closer r is to 0, the weaker the linear relationship, and values ​​of 1 and -1 indicate perfect positive and negative correlations, respectively). As reflected in Figure 1, all of the IFN-I signatures, including the DX_4 IFN-I signature, were found to be highly correlated. Thus, the DX_4 IFN-I signature represents a measure of type I IFN status comparable to other IFN-I signatures previously reported in the literature.

[0224] Example 2: Use of the IFN-I signature as a biomarker An exploratory phase II clinical trial in patients hospitalized with COVID-19 pneumonia was conducted to evaluate, among other things, whether the TLR inhibitor empatran improves time to recovery (NCT04448756).

[0225] Statistical tests were considered exploratory, and results are presented without adjustment for type I error for multiplicity. Time to recovery was defined as the time from day 1 to the first occurrence of a score ≤3 on the WHO 9-point ordinal scale and was estimated by Kaplan-Meier (KM) analysis and presented with two-sided 95% confidence intervals (CI). The effect of each dose level compared with placebo was assessed using the stratified log-rank test.

[0226] For gene expression measurements, blood was collected directly from patients at baseline before treatment into PAXgene RNA tubes. IFN-I activity was measured by DxTerity Diagnostics (Rancho Dominguez, CA, USA) using the IFN-I test, a commercially available gene expression test with chemical ligation-dependent probe amplification and relative quantification by capillary electrophoresis. Sample testing and analysis were performed 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-responsive genes (HERC5, IFI27, IFIT1, and RSAD2) relative to the expression levels of three housekeeping normalizer genes (ACTB, GAPDH, and TFRC), i.e., the Dx-4 IFN-I signature. Normalized expression values ​​for each response gene were calculated according to the following function: normalized expression = 1 / (normalized expression) ... 遺伝子i =Log2(height 遺伝子i) - Mean Log2(normalized gene height). IFN-I signature scores were calculated by averaging the normalized expression values ​​of the four response genes. The cutoff (-0.5) between high and low IFN-I signature scores was set at the mean + 2 SD (95th percentile) of the IFN-I signature scores from 281 healthy human donors. This cutoff falls within the trough of the bimodal distribution of IFN-I signature scores observed for the cohort of SLE patients.

[0227] One hundred forty-nine patients received either placebo (n=49) or empatran 50 mg (n=54) or 100 mg (n=46) twice daily. The mean IFN-I signature scores (50 mg twice daily, -0.84; 100 mg twice daily, -0.74; placebo, -0.91) and the proportion of patients with high IFN-I signature scores at baseline (50 mg twice daily, 35%, 100 mg twice daily, 43%, placebo, <35%) were fairly consistent across treatment groups, as reflected in Table 2.

[0228] [Table 2]

[0229] The primary efficacy endpoint of time to recovery from day 1 to day 28 was not met in the unstratified patient population, despite a numerical trend toward higher recovery rates in both empatran groups (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%). Median time to recovery was similar across groups (3.4-3.9 days) and was not differentiated by day 6 (Figure 2).

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

[0231] These preliminary analyses suggest that in patients with broad immune activation as determined by a high IFN-I signature score at baseline, time to recovery was improved with empatran versus placebo, suggesting IFN-I activity as a potential predictive biomarker for TLR inhibitors such as empatran more generally in patients with COVID-19 and other autoimmune and inflammatory diseases such as lupus.

[0232] Example 3: Combination treatment with TLR inhibitors and corticosteroids in the context of pretreatment with IFN-α Previous studies have shown that IFN-α can reduce the efficacy of GCs (Guiducci et al. 2010 Jun 17;465(7300):937-41). Therefore, the purpose of this experiment was to determine whether pretreatment with IFN-α affects the response of peripheral blood mononuclear cells (PBMCs) to TLR7 and / or TLR8 agonists and whether the efficacy of the glucocorticosteroid dexamethasone (Dex) is further reduced.

[0233] Materials and Methods

[0234] Blood was obtained from healthy donors using Leukopac (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 by trypan blue staining (Bio-Rad, California, USA). Cells were cultured in RPMI 1640 medium (Gibco) containing 10% fetal bovine serum (Corning, Arizona, USA) and 1x penicillin-streptomycin (Gibco, Thermo Fisher Scientific, Massachusetts, USA).

[0235] PBMCs were pretreated for 15 min with 3-fold serial dilutions of Dex (Sigma-Aldrich) starting at 10 μM and 2-fold serial dilutions of 1 μM CMPD2 (a TLR7 and TLR8 inhibitor synthesized in-house; structure previously published (Vlach et al. 2021 Mar;376(3):397-409)). Cells were then stimulated with 3–5 μM of the TLR7 and 8 agonist R848 (InvivoGen, Toulouse, France), 3 μM of the TLR7 agonist CL-087 (synthesized in-house), or 1 μM of the TLR8 agonist motolimod (SelleckChem, Texas, USA). Plates were incubated overnight at 37°C with 5% CO2. Cell viability was assessed using the CellTiter Glo Luminescent Cell Viability Assay (Promega, Wisconsin, USA).

[0236] Cytokine secretion in the supernatant was detected using AlphaLISA Detection Kits for human interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and IFN-alpha (IFN-α) according to the manufacturer's protocol (PerkinElmer, Ohio, USA). When cytokine pretreatment was required, PBMCs were exposed to 10 ng / mL IFN-α2a (Sigma-Aldrich) for 4–5 h before treatment with the above compounds and TLR7 and / or 8 agonists.

[0237] Data were analyzed using Graphpad Prism (Dotmatics, Massachusetts, USA). Group medians were determined, and statistical significance was tested using the Kruskal-Wallis test, ANOVA, or t-test (as described in the figure legends). Synergy was assessed using Loewe's matrix plots using Combenefit (SourceForge, California, USA), as described (Di Veroli et al., Bioinformatics. 2016 Sep;32(18):2866-8), and synergy scores were calculated from the area under the curve.

[0238] result

[0239] Pretreatment with IFN-α was found to increase PBMC responsiveness to R848, as measured by IL-6 secretion (Figures 4A and B, 5A and C). Dex alone was less potent than Dex combined with CMPD2 in blocking R848-induced IL-6 secretion in IFN-α-pretreated cells. Combined treatment with low-dose Dex and CMPD2 reduced this enhanced responsiveness (Figure 4B), and synergy was confirmed by Combenefit analysis (Figures 5B and D), with similar synergy scores in R848-stimulated cells pretreated with and without IFN-α (Figure 4C). These results were not due to changes in cell viability, which did not vary significantly across the matrix dose titrations tested (data not shown).

[0240] In summary, these results suggest that even in the context of a pre-existing pro-inflammatory environment, as may be expected in autoimmune diseases such as lupus, inhibition of TLR7 and / or TLR8 can potentiate the action of glucocorticosteroids, providing a synergistic anti-inflammatory effect.

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

[0242] To further confirm the association between TLR7 and / or TLR8 and the expression of IFN-α and interferon-inducible genes (ISGs), immune complexes from patients with autoimmune diseases were tested for their ability to stimulate the expression of IFN-α and ISGs in peripheral blood mononuclear cells (PBMCs) from healthy donors, and for the ability of the TLR inhibitor empatran to block such stimulation.

[0243] Materials and Methods

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

[0245] Immune complex formation and stimulation of peripheral blood mononuclear cells (PBMCs): To generate necrotic cell lysates, human embryonic kidney 293 cells were cultured at 50 × 10 in phosphate-buffered saline (PBS, Gibco, Grand Island, NY). 6 The cells were suspended at a concentration of 1000 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 400g for 5 minutes to separate unlysed cells, and the supernatant was collected as the necrotic cell lysate.

[0246] PBMCs were isolated from leukopaques collected from healthy donors (New York Blood Center, New York, NY) in sodium heparin tubes using Ficoll-Paque Plus (Cytiva Life Sciences, Uppsala, Sweden). Cells were seeded (4 × 10) in 96-well U-bottom plates in RPMI 1640 medium (Gibco, Grand Island, NY) supplemented with 10% fetal bovine serum (FBS, Corning, Woodland, CA). 5 Cells / well). Prior to stimulation, PBMCs were pretreated with 1 μM empatran for 30 min. Necrotic cell lysate (10% vol / vol) and IgG purified from patient plasma (0.1 mg / mL) were added to the PBMCs and incubated at 37°C for 24 h. Supernatants were collected, and cytokine production was measured by AlphaLISA (PerkinElmer, Waltham, MA).

[0247] NanoString Analysis: Gene expression in purified RNA samples was analyzed using NanoString. A 46-gene custom panel including markers of inflammation was used. A total of 500 ng of RNA per sample was analyzed using the nCounter Pro Analysis System (NanoString, Seattle, Washington). Data were processed using nSolver (NanoString) to calculate the Log2 fold change for each sample compared to cells treated with control PBMC-derived supernatant.

[0248] result

[0249] IgG isolated from 69 patients with idiopathic inflammatory myopathies (IIM), 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. IFN-α production was stimulated with immune complexes generated using IgG from 6 / 7 LN patients and 2 / 8 SLE patients (Figure 6A). In the IIM subset, immune complexes from patients with PM and DM, but not IBM, showed activity against IFN-α.

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

[0251] Gene expression analysis of PBMC lysates showed that IFN-α protein-stimulated samples also induced changes in gene expression, with the most prominent effect being the induction of IFN-inducible genes (ISGs, Figure 7A). The IFN-I signature score (IFN GS score), calculated based on the expression of ISGs, was upregulated in patients who were also positive for protein induction (Figure 7B).

[0252] 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 further supports that IFN-I activity may be suitable as a predictive biomarker for TLR inhibitors.

Claims

1. 1. Use of IFN-I activity as a predictive biomarker for TLR inhibitor treatment of an individual with a disease, comprising: wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor.

2. 1. A method for predicting the therapeutic efficacy of a TLR inhibitor in an individual having a disease, comprising determining IFN-I activity in a sample from said individual, wherein IFN-I activity of the sample indicates therapeutic efficacy of the TLR inhibitor; Also, the method wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor.

3. 1. A method for predicting the suitability of an individual having a disease for initiation of treatment with a TLR inhibitor, comprising determining IFN-I activity in a sample from said individual, wherein IFN-I activity in said sample indicates said individual's suitability for initiation of said treatment; Also, the method wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor.

4. 1. A method for predicting the suitability of an individual having a disease undergoing treatment with a TLR inhibitor to continue said treatment, the method comprising determining IFN-I activity in a sample from said individual, wherein IFN-I activity in said sample indicates said individual's suitability for continuing said treatment; Also, the method wherein the TLR inhibitor is a TLR7 and / or TLR8 small molecule inhibitor.

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

6. The TLR inhibitor is predicted to be therapeutically effective when the IFN-I activity of the individual is determined to be high, and is predicted to be therapeutically ineffective when the IFN-I activity of the individual is determined to be low. The method of claim 2.

7. If the IFN-I activity of the individual is determined to be high, the individual is evaluated as being suitable for initiating the treatment, and if the IFN-I activity of the individual is determined to be low, the individual is evaluated as being unsuitable for initiating the treatment. The method of claim 3.

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

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

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

11. determining the IFN-I activity by determining an IFN-I signature score for a sample from the individual; If the individual is determined to have high IFN-I activity based on a comparison of the IFN-I signature score of the sample from the individual with a reference IFN-I signature score, the TLR inhibitor is predicted to be therapeutically effective; and / or if the individual is determined to have low IFN-I activity based on a comparison of the IFN-I signature score of the sample from the individual with a reference IFN-I signature score, the TLR inhibitor is predicted to be therapeutically ineffective. The method of claim 2.

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

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

14. determining the IFN-I activity by determining an IFN-I signature score for a sample from the individual; If the individual is determined to have high IFN-I activity based on a comparison of the IFN-I signature score of the sample from the individual to a reference IFN-I signature score, then the TLR inhibitor is administered to the individual. A TLR inhibitor for use according to claim 5.

15. The TLR7 and / or TLR8 small molecule 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 15. The method or use according to any one of claims 1 to 14, wherein the TLR inhibitor is selected from the group consisting of (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]octan-1-yl)morpholine-3-carboxamide, (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]octan-1-yl)morpholine-3-carboxamide, or a pharmaceutically acceptable salt of either of these compounds.

16. The TLR7 and / or TLR8 small molecule inhibitor is a compound of formula Ia 【Chemistry 1】 (In the formula, R １ is -OMe or -CN, and X is O or CH ２ and R ４ teeth 【Chemistry 2】 and R ５ is methyl or -CF ３ and ring A is 【Transformation 3】 15. The method or use according to any one of claims 1 to 14, wherein the compound is:

17. 15. The TLR inhibitor for use according to any one of claims 5, 9, 10 and 14, administered in combination with a glucocorticosteroid.

18. 1. 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, said method comprising administering to said individual said TLR7 and / or TLR8 inhibitor in combination with said glucocorticosteroid.

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