4-amino-imidazoquinoline compounds and their uses

Abstract

4-amino-imidazoquinoline compounds and uses thereof are disclosed. The compounds of the present invention are Toll-like receptor 7 (TLR7) and TLR8 dual agonists and exhibit the activity of inducing the expression of IL-12 and IP-10 without excessively inducing IL-6. TLR7 / 8 dual agonists may be useful pharmaceuticals as immune response modifiers. Use of the compounds of the present invention or salts thereof in the manufacture of a medicament for treating a disease or condition in a subject in need thereof in which activation of TLR7 and / or TLR8 would be beneficial is disclosed. Compounds or pharmaceutical compositions for use in treating viral infections, cancers, and / or allergic diseases in a subject in need thereof, or for activating an effective immune response against viral infections, tumors, and / or allergic diseases, are also disclosed.

Description

[Technical Field]

[0001] The present invention relates typically to Toll-like receptor (TLR) agonists, and more particularly to dual TLR7 and TLR8 agonists. [Background technology]

[0002] Toll-like receptors (TLRs) are pathogen-recognition receptors that play a key role in activating both innate and adaptive immunity. Several TLRs have been identified in humans and mice. Some TLRs are present on the cell surface (e.g., TLRs 1, 2, 4, 5, and 6), while others are known to reside in endosomal compartments (e.g., TLRs 3, 7, 8, and 9). TLRs are expressed on various immune cells, particularly monocytes, dendritic cells (DCs), and macrophages. TLR activation leads to cytokine secretion (e.g., IFN-α, TNF-α, IL-12), as well as increased phagocytosis by macrophages and cytolytic activity by natural killer (NK) cells. TLR activation also leads to enhanced antigen presentation, resulting in the expression of antigen-specific CD8 + Activates adaptive immune responses, including cytotoxic T lymphocytes.

[0003] Small molecule TLR 7 and / or TLR 8 agonists are identified in U.S. Patent Nos. 8,728,486, 9,334,268, 9,884,866, and U.S. Patent Publication No. 20190062329. There remains a need to develop TLR7 and / or TLR8 agonists, particularly TLR7 / 8 agonists with improved efficacy and / or cytokine profile. Summary of the Invention

[0004] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: JPEG0007773011000001.jpg3245 where, R1 is hydroxy, hydroxy-C 1-6-Alkyl, C 1-6 -alkoxy, or C 1-6 -Alkoxy-C 1-6 -alkyl, R2 is C 1-6 -Alkyl, C 1-6 -haloalkyl, C 1-6 -Haloalkyl-OC 1-6 -Alkyl, C 1-6 -Haloalkyl-SC 1-6 -Alkyl or hydroxy-C 1-6 -alkyl, and R3 is hydrogen, hydroxy, halogen, C 1-6 -Alkyl, Hydroxy-C 1-6 -Alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, or C 1-6 -Alkoxy-C 1-6 -alkyl, Here, the above C 1-6 -Alkyl, Hydroxy-C 1-6 -Alkyl, C 1-6 -alkoxy, C 1-6 -Alkoxy-C 1-6 -Alkyl, C 1-6 -haloalkyl and C 1-6 -Haloalkyl-SC 1-6 Each -alkyl is independently unsubstituted or substituted with at least one substituent, wherein each of said substituents is independently —NH, aryl, C 1-6 -alkyl and C 1-6 -alkyl-aryl; provided that when R1 is 2-hydroxy-2-methylpropyl, R2 is not methyl, ethyl, butyl or hydroxymethyl, and when R1 is dimethyl-hydroxymethyl, R2 is not isobutyl; or a pharmaceutically acceptable salt thereof.

[0005] In another aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof: JPEG0007773011000002.jpg2940 wherein R1 and R2 are as defined above, relating to a compound or a pharmaceutically acceptable salt thereof.

[0006] In one embodiment of the present invention, R1 is hydroxy-C 1-6 -alkyl, or C 1-6 -Alkoxy-C 1-6 - alkyl.

[0007] In another embodiment, R1 is hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, or 2-hydroxy-2-methylpropyl.

[0008] In yet another embodiment, R1 is methoxymethyl, 2-methoxyethyl, ethoxymethyl, or 2-ethoxyethyl.

[0009] In another embodiment, R2 is a straight or branched C 1-6 - alkyl.

[0010] In another embodiment, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, 1-methylbutyl, tert-pentyl, neopentyl, n-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2,2-dimethyl-1-butyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, 2,3-dimethyl-2-butyl, or 3,3-dimethyl-2-butyl.

[0011] In another embodiment, R2 is sec-butyl, tert-butyl, or 3,3-dimethyl-1-butyl.

[0012] In another embodiment, R2 is C1-6 -monohaloalkyl, C 1-6 -dihaloalkyl, or C 1-6 -trihaloalkyl.

[0013] In another embodiment, R2 is trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-fluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, 3,3,3-trifluoro-2-methylpropyl, 4,4,4-trifluoro-3-methylbutyl, or 5,5,5-trifluoro-4-methylpentyl.

[0014] In another embodiment, R2 is -CH2-CH2-O-CH2-CF3, -CH2-CH2-O-CH2-CH2-CF3, -CH2-O-CH2-CF3, -CH2-O-CH2-CH2-CF3, or -CH2-O-CH2-CH2-CH2-CF3. 1-6 -Haloalkyl-OC 2-6 - alkyl.

[0015] In another embodiment, R2 is -CH2-CH2-S-CH2-CF3, -CH2-CH2-S-CH2-CH2-CF3, -CH2-S-CH2-CF3, -CH2-S-CH2-CH2-CF3, -CH2-S-CH2-CH2-CF3, or -CH2-S-CH2-CH2-CH2-CF3.

[0016] In another embodiment, R2 is 2-hydroxyethyl, 3-hydroxypropyl, or 4-hydroxybutyl.

[0017] In another embodiment, R3 is C 1-6 -haloalkyl. 1-6 The -haloalkyl may be a trifluoroalkyl group.

[0018] In another embodiment, R3 is H, OH, F, Cl, Br, I, or trifluoromethyl.

[0019] In another embodiment, R1 is 2-hydroxy-2-methylpropyl and R2 is n-propyl, isobutyl, n-pentyl, isopentyl, 4-methylpentyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-fluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, 3,3,3-trifluoro-2-methylpropyl, 4,4,4-trifluoro-3-methylbutyl, 5,5,5-trifluoro-4-methylpentyl, -CH2-S-CH2-CF3, -CH2-S-CH2-CH2-CF3, -CH2-S-CH2-CH2-CH2-CF3, 2-hydroxyethyl, 3-hydroxypropyl, or 4-hydroxybutyl.

[0020] In another embodiment, R1 is 2-hydroxy-2-methylpropyl and R2 is n-propyl, isobutyl, n-pentyl, 4,4,4-fluorobutyl, 5,5,5-trifluoropentyl, or 3,3,3-trifluoro-2-methylpropyl.

[0021] In another embodiment, R1 is 2-hydroxy-2-methylpropyl, R2 is n-propyl, isobutyl, n-pentyl, 4,4,4-fluorobutyl, 5,5,5-trifluoropentyl, or 3,3,3-trifluoro-2-methylpropyl, and R3 is H.

[0022] In another embodiment of the present invention, the compound of formula (I) is selected from the compounds set forth in Table 2 of the present application.

[0023] In another embodiment, the compound of formula (I) of the present invention is 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 1), 1-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 2), 1-(4-amino-2-isobutyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 3), 1-(4-amino-2-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 9), 1-(4-amino-2-(5,5,5-trifluoropentyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 10), and 1-(4-amino-2-(3,3,3-trifluoro-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (Compound 12).

[0024] A further aspect of the invention is a process for producing a compound of formula (I).

[0025] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or adjuvant.

[0026] In another aspect, the present invention relates to the use of a compound according to the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a viral infection, cancer, an allergic disease or a liver disease in a subject in need thereof.

[0027] The present invention also relates to a method for treating a viral infection, cancer, an allergic disease or a liver disease, which method comprises administering a therapeutically effective amount of a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0028] The present invention also relates to a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment of a viral infection, cancer, an allergic disease or a liver disease in a subject in need thereof.

[0029] In another embodiment, the viral infection is an infection associated with hepatitis C virus (HCV), hepatitis B virus (HBV), hepatitis D virus (HDV), human papillomavirus (HPV), or herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2).

[0030] In one embodiment, the cancer is selected from the group consisting of esophageal, stomach, colon, rectum, pancreas, lung, breast, cervix, uterine corpus, ovary, bladder, head and neck, endometrium, osteosarcoma, prostate, and neuroblastoma.

[0031] In another embodiment, the cancer is a HER2-positive cancer or a PD-1-positive cancer.

[0032] In another embodiment, the allergic disease is allergic rhinitis (AR) or asthma.

[0033] In another embodiment, the liver disease is alcoholic fatty liver disease or non-alcoholic fatty liver disease (NAFLD), wherein NAFLD is selected from the group consisting of steatosis, non-alcoholic steatohepatitis (NASH), NASH-associated fibrosis, and NASH-associated cirrhosis.

[0034] In yet another aspect, the present invention relates to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition benefiting from activation of TLR7 and / or TLR8 in a subject in need thereof.

[0035] In yet another aspect, the present invention relates to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for activating an effective immune response against a viral infection, a tumor, an allergic disease, or a liver disease in a subject in need thereof.

[0036] These and other aspects will become apparent from the following description of preferred embodiments taken in conjunction with the following drawings, in which variations and modifications can be effected without departing from the spirit and scope of the novel concepts disclosed herein.

[0037] The accompanying drawings illustrate one or more embodiments of the invention and, together with the description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment. [Brief explanation of the drawings]

[0038] [Figure 1A-C] Figures 1A-C show the relative IL-6 induction from human PBMCs stimulated with various concentrations of test compounds (compounds 2, 9, and 10) and reference compounds (Ref. 1-3). Compound Ref. 1 is resiquimod (TLR7 / 8 dual agonist). Compound Ref. 2 is 1-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (TLR7 / 8 dual agonist). Compound Ref. 3 is VTX2337 (TLR8 agonist). [Figure 2A-C] Figures 2A-C show the relative IL-12p70 induction from human PBMCs stimulated with various concentrations of test and reference compounds, which are the same as those in Figures 1A-C. [Figure 3A-C] Figures 3A-C show the relative IP-10 induction from human PBMCs stimulated with various concentrations of test and reference compounds, which are the same as those in Figures 1A-C. Detailed Description of the Invention

[0039] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Furthermore, the following definitions are set forth to illustrate and define the meaning and scope of various terms used to describe the present invention.

[0040] The nomenclature used in this application is based on IUPAC systematic nomenclature unless otherwise indicated.

[0041] As used herein, the article "a" or "an" refers to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. Furthermore, the use of the term "including" and other forms such as "include," "includes," and "included" is not limiting.

[0042] The term "hydroxy" or "hydroxyl" refers to the group --OH.

[0043] The term "alkyl," alone or in combination with other groups, means a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms, particularly 1 to 16 carbon atoms, and more particularly 1 to 10 carbon atoms. The term "alkyl" also encompasses lower alkyl groups as defined below.

[0044] The terms "lower alkyl" or "C 1-6 The term "-alkyl," alone or in combination, refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, in particular a straight or branched chain alkyl group having 1 to 5 carbon atoms, more in particular a straight or branched chain alkyl group having 1 to 4 carbon atoms. 1-6Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, the isomeric pentyls (e.g., n-pentyl, isopentyl, 1-methylbutyl, tert-pentyl, neopentyl), and the isomeric hexyls (e.g., n-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl, 3-methyl-3-pentyl, 2,2-dimethyl-1-butyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, 2,3-dimethyl-2-butyl, or 3,3-dimethyl-2-butyl). Preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 4-methyl-1-pentyl and 3,3-dimethyl-1-butyl.

[0045] The term "hydroxy-C 1-6 "-alkyl" refers to a lower alkyl group, as defined above, in which at least one of the hydrogen atoms of the lower alkyl group has been replaced with a hydroxy group. Of particular interest is hydroxy-C 1-6 Among the -alkyl groups are hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, or 2-hydroxy-2-methylpropyl. 1-6 The alkyl group is 2-hydroxy-2-methylpropyl.

[0046] The term “C 1-6 "-alkoxy" refers to the group R'-O-, where R' is lower alkyl as defined above. 1-6 Examples of -alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Preferably, it is methoxy, ethoxy or n-propoxy.

[0047] The term “C 1-6-Alkoxy-C 1-6 "-alkyl" means a lower alkyl group in which at least one of the hydrogen atoms of the lower alkyl group is a C 1-6 - refers to a lower alkyl group as defined above, substituted with an alkoxy group. 1-6 -Alkoxy-C 1-6 Among the -alkyl groups are methoxymethyl, 2-methoxyethyl, ethoxymethyl and 2-ethoxyethyl, most particularly ethoxymethyl.

[0048] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom. More specifically, halogen refers to fluorine or chlorine. Most specifically, halogen refers to fluorine. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl.

[0049] The term “C 1-6 -haloalkyl" or "halogen-C 1-6 "C-alkyl" means a lower alkyl group as defined above, wherein at least one of the hydrogen atoms of the lower alkyl group is replaced with at least one halogen atom. 1-6 -haloalkyl groups are C 1-6 -monohaloalkyl, C 1-6 -dihaloalkyl or C 1-6 -trihaloalkyl. More specifically, C 1-6 -haloalkyl groups are C 1-6 -trihaloalkyl. C 1-6Among the -haloalkyl groups of particular interest are trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-fluorobutyl, 5,5,5-trifluoropentyl, 6,6,6-trifluorohexyl, 3,3,3-trifluoro-2-methylpropyl, 4,4,4-trifluoro-3-methylbutyl and 5,5,5-trifluoro-4-methylpentyl, and of more particular interest are 4,4,4-fluorobutyl, 5,5,5-trifluoropentyl or 3,3,3-trifluoro-2-methylpropyl.

[0050] The term “C 1-6 -Haloalkyl-OC 1-6 -alkyl" or "C 1-6 -Haloalkoxy-C 1-6 -alkyl" means that one of the hydrogen atoms of the lower alkyl group is C 1-6 -means a lower alkyl group as defined above substituted with a haloalkoxy group. For example, C 1-6 -Haloalkyl-OC 1-6 The alkyl group may be -CH2-CH2-O-CH2-CF3, -CH2-CH2-O-CH2-CH2-CF3, -CH2-O-CH2-CF3, -CH2-O-CH2-CF3, -CH2-O-CH2-CH2-CF3, or -CH2-O-CH2-CH2-CH2-CF3.

[0051] The term “C 1-6 -Haloalkyl-SC 1-6 -alkyl" or "C 1-6 -Haloalkylthio-C 1-6 -alkyl" means that one of the hydrogen atoms of the lower alkyl group is C 1-6 -means a lower alkyl group as defined above substituted with a haloalkylthio group. For example, C 1-6 -Haloalkyl-SC 1-6 The alkyl group may be -CH2-CH2-S-CH2-CF3, -CH2-CH2-S-CH2-CH2-CF3, -CH2-S-CH2-CF3, -CH2-S-CH2-CF3, -CH2-S-CH2-CH2-CF3, or -CH2-S-CH2-CH2-CH2-CF3.

[0052] The term “C 1-6 " and "(C1-C6)" can be read interchangeably.

[0053] "C 1-6 " or "(C1-C6)" means that all integer unit amounts in the range of 1 to 6 are specifically disclosed as part of this invention. Thus, C1, C2, C3, C4, C5, C6, (C1-C2), (C1-C3), (C1-C4), (C1-C5), (C1-C6), (C2-C3), (C2-C4), (C2-C5), (C2-C6), (C3-C4), (C3-C5), (C3-C6), (C4-C5), (C4-C6), and (C5-C6) unit amounts are also included as embodiments of this invention.

[0054] "Substituent" means an atom or group of atoms that replaces a hydrogen atom on a parent molecule.

[0055] The term "aryl" refers to a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked. A fused-ring aryl refers to multiple rings fused together, at least one of the fused rings being an aryl ring.

[0056] The compound of formula (I) can form pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, which are biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts. Examples of salts include acid addition salts of the compound of formula (I) with physiologically compatible mineral acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, sulfuric acid, sulfurous acid, or phosphoric acid, or organic acids, such as methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, malonic acid, tartaric acid, benzoic acid, cinnamic acid, mandelic acid, ebonic acid, succinic acid, or salicylic acid. Additionally, pharmaceutically acceptable salts can be prepared by addition of inorganic or organic bases to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, piperazine, N-ethylpiperidine, piperazine, and polyamine resins. Compounds of formula (I) can also exist in zwitterionic form. Pharmaceutically acceptable salts of compounds of formula (I) of particular interest are sodium salts or salts with tertiary amines.

[0057] The term "half maximal effective concentration (EC 50 )" refers to the plasma concentration of a particular compound required to obtain 50% of the maximum of a particular effect in vivo.

[0058] The term "therapeutically effective amount" means an amount of a compound of the invention that, when administered to a subject, (i) treats or prevents a disease, condition, or disorder described herein, (ii) attenuates, ameliorate, or eliminates one or more symptoms of a disease, condition, or disorder described herein, or (iii) prevents or delays the onset of one or more symptoms of a disease, condition, or disorder described herein. A therapeutically effective amount may vary depending on the compound, the disease state being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0059] The term "treatment" or "treating" refers to the application or administration of a therapeutic agent, i.e., a compound provided herein, to a patient having a disease, symptoms of a disease, or likelihood of developing a disease, or to an isolated tissue or cell line from a patient (e.g., for diagnostic or ex vivo applications), with the purpose of curing, alleviating, mitigating, altering, relieving, ameliorating, or affecting the disease, symptoms of a disease, or likelihood of developing a disease. Such treatments may be specifically tailored or modified, based on knowledge gained from the field of pharmacogenomics.

[0060] The term "ammonia solution" may particularly refer to a solution having a solvent to which ammonia has been added; for example, ammonia may be dissolved in an aqueous solvent or an organic solvent. Ammonia is a compound of nitrogen and hydrogen, with the formula NH3. The ammonia solution may be an aqueous solution of NH3. Ammonia is characterized by its basicity, and therefore may form alkaline solutions with water, i.e., solutions with a pH above 7. Furthermore, the ammonia solution may be a solution of NH3 in methanol.

[0061] HER2-positive cancer cells have abnormally high levels of the HER2 protein. HER2-negative cancer cells do not have abnormally high levels of the HER2 protein. PD-1-positive cancer cells have abnormally high levels of the PD-1 protein. PD-1-negative cancer cells do not have abnormally high levels of the PD-1 protein.

[0062] The compounds of formula (I) of the present invention and their pharmaceutically acceptable salts can be used as medicines in the form of pharmaceutical compositions / preparations suitable for enteral, parenteral or topical administration. The medicines can be used for systemic administration (e.g., parenteral administration) or local administration (e.g., local or intralesional injection). The route of administration of the medicines can be topical, parenteral, intravaginal, intrauterine, intranasal, or by inhalation.

[0063] Certain tissues may be preferred targets for TLR agonists, hi one embodiment, lymph nodes, spleen, bone marrow, blood, tumor sites, and tissues exposed to viruses are preferred sites for administration of the TLR agonists of the present invention.

[0064] Techniques for preparing various dosage forms, parenteral, oral, transdermal, and pulmonary, are all well known to those skilled in the art. Effective amounts will vary depending on the route of administration, excipient usage, and the possibility of co-administration with other therapeutic treatments, as will be recognized by those skilled in the art.

[0065] The "Guidance for Industry and Reviewers Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers" published by the US Food and Drug Administration discloses that the "human equivalent dose" can be obtained by calculation from the following formula: HED = Animal dose mg / kg × (animal body weight kg / human body weight kg). 0.33 [Example]

[0066] Preparation of Compounds of the Invention Typical synthesis scheme Compounds of formula (I) can be produced according to the exemplary synthetic scheme shown below. JPEG0007773011000003.jpg55140

[0067] Typically, the method for producing the compound of formula (I) of the present invention comprises the following steps: (a) reacting a compound of formula (Ia) JPEG0007773011000004.jpg2041 is reacted with NH2-R1 in the presence of a catalyst to form a compound of formula (Ib) obtaining a compound of formula JPEG0007773011000005.jpg2240, wherein R1 and R3 are as defined above, (b) reducing the compound of formula (Ib) in the presence of a reducing agent to obtain a compound of formula (Ic) obtaining a compound of formula JPEG0007773011000006.jpg2642, wherein R1 and R3 are as defined above, (c) reacting a compound of formula (Ic) with Cl-C(O)-R2 to form a compound of formula (Id) obtaining JPEG0007773011000007.jpg2245, where R1, R2 and R3 are as defined above; and (d) reacting the compound of formula (Id) with aqueous ammonia to form a compound of formula (I) JPEG0007773011000008.jpg2943, wherein R1, R2 and R3 are as defined above.

[0068] In step (a), the compound of formula (Ib) can be obtained in the presence of a solution of triethylamine (TEA) in dichloromethane (DCM) at 40°C to 60°C, preferably 50°C to 60°C, or 50°C for at least 1 hour, preferably 1 to 4 hours, more preferably 2 to 3 hours.

[0069] In step (b), the compound of formula (Ib) may be reduced in the presence of Fe / NH4Cl at a temperature of 70°C to 100°C, preferably 80°C to 90°C, or 80°C for at least 1 hour, preferably 1 to 4 hours, more preferably 2 to 3 hours.

[0070] In step (c), the compound of formula (Ic) may be dissolved in acetonitrile (ACN) and reacted with Cl-C(O)-R2 at a temperature of 15°C to 35°C or at room temperature for at least 1 hour, preferably 1 to 5 hours, and more preferably 2 to 4 hours.

[0071] In step (d), the desired compound of formula (I) can be obtained in the presence of a solution of NH3 in methanol at 120°C-180°C, preferably 130°C-160°C or 150°C for at least 24 hours, preferably 30-50 hours, more preferably 35-40 hours.

[0072] Compounds of formula (I) of the present invention can be prepared using the exemplary schemes described above. Table 2 lists compounds of the present invention. The synthesis of representative compounds is described in more detail below for illustrative purposes.

[0073] Synthesis of intermediate compound A JPEG0007773011000009.jpg35122

[0074] Compound a1 was dissolved in dichloromethane (DCM) containing triethylamine (TEA) and selectively substituted with primary amine compound a2 at 50°C for 2 hours to obtain nitroquinoline compound a3. Compound a3 was then mixed with EtOH / HO and reduced by reaction with Fe / NH4Cl at 80°C for 2 hours to obtain intermediate compound A (Scheme A). The resulting intermediate compound A was used in the following examples.

[0075] Analysis of test compounds All reactions were carried out using Merck 60 F 254 Completion was monitored by thin layer chromatography (TLC) using silica gel glass-backed plates (20 × 20 cm). Visualization of the resulting chromatogram was detected visually under UV irradiation (254 nm).

[0076] To analyze test compounds, 1H NMR spectra were recorded on a Varian Mercury-400 spectrometer, and chemical shifts were reported in parts per million (ppm, δ). Multiplicities are reported as s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sxt (sextet), and m (multiplet). Coupling constants (J) are expressed in Hertz. For liquid chromatography-mass spectrometry (LC-MS), electrospray mass spectra (ESMS) were recorded as m / z values ​​using a Waters mass spectrometer. For high-performance liquid chromatography (HPLC), a Waters ACQUITY Arc system was used with a C18 column (Waters XSelect HSS T3 column, 5 μm, 4.6 mm x 250 mm) operated at 40 °C to determine the purity of the final compound. Elution was performed using a mobile phase of water and methanol containing 0.1% trifluoroacetic acid. The flow rate of the mobile phase was 1 mL / min, and peaks were detected between 210 and 400 nm.

[0077] Synthesis of Compound No. 1 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 1) was synthesized according to Scheme 1. JPEG0007773011000010.jpg39119

[0078] Intermediate compound A was dissolved in acetonitrile (ACN) and reacted with butyryl chloride (compound No. 1a) at room temperature for 3 hours to give the corresponding amine compound No. 1b. Compound No. 1b was reacted with aqueous ammonia (7N in methanol) at 150°C for 36 hours to form the imidazole ring and displace the 4-chloro substituent, affording compound No. 1. The crude product was purified by column chromatography to give the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 1 H), 7.18 (t, J = 8.0 Hz, 1 H), 6.40 (s, 2 LCMS (ESI) m / z 299.3 [M+H] + . HPLC purity: 99.65%.

[0079] Synthesis of Compound No. 2 1-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (compound 2) was synthesized according to Scheme 2. JPEG0007773011000011.jpg39137

[0080] Intermediate compound A was dissolved in acetonitrile (ACN) and reacted with hexanoyl chloride (compound No. 2a) at room temperature for 3 hours to give the corresponding amine compound No. 2b. Compound No. 2b was reacted with aqueous ammonia (7N in methanol) at 150°C for 36 hours to form the imidazole ring and displace the 4-chloro substituent, affording compound No. 2. The crude product was purified by column chromatography to give the title compound as a beige powder. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 7.8 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.18 (t, J = 7.8 Hz, 1 H), 6.40 (s, 2 H), 4.78 (s, 2 H), 4.54 (br s, 2 H), 3.01 (t, J = 7.8 Hz, 2 H), 1.80 (quin, J = 7.2 Hz, 2 H), 1.49-1.28 (m, 4 H), 1.17 (s., 6 H), 0.89 (t, J = 7.2 Hz, 3 H).LCMS (ESI) m / z 327.4 [M+H] + . HPLC purity: 99.42%.

[0081] Synthesis of Compound No. 9 1-(4-amino-2-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (Compound No. 9) was synthesized according to Scheme 4. JPEG0007773011000012.jpg40126

[0082] Intermediate compound A was dissolved in acetonitrile (ACN) and reacted with 5,5,5-trifluoropentanoyl chloride (compound No. 9a) at room temperature for 3 hours to give the corresponding amine compound No. 9b. Compound No. 9b was reacted with aqueous ammonia (7N in methanol) at 150°C for 36 hours to form the imidazole ring and displace the 4-chloro substituent, yielding compound No. 9. The crude product was purified by column chromatography to give the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 7.8 Hz, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.37 (t, J = 7.8 Hz, 1 H), 7.19 (t, J = 7.8 Hz, 1 H), 6.44 (s, 2 LCMS (ESI) m / z 367.4 [M+H] + . HPLC purity: 96.95%.

[0083] Synthesis of Compound No. 10 1-(4-amino-2-(5,5,5-trifluoropentyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (Compound No. 10) was synthesized according to Scheme 5. JPEG0007773011000013.jpg40135

[0084] Intermediate compound A was dissolved in acetonitrile (ACN) and reacted with 6,6,6-trifluorohexanoyl chloride (compound No. 10a) at room temperature for 3 hours to give the corresponding amine compound No. 10b. Compound No. 10b was reacted with aqueous ammonia (7N in methanol) at 150°C for 36 hours to form an imidazole ring and displace the 4-chloro substituent, yielding compound No. 10. The crude product was purified by column chromatography to give the title compound as a white powder. 1H NMR (600 MHz, DMSO-d6) δ 8.26 (d, J = 8.4 Hz, 1H), 7.57 (dd, J = 8.4, 1.2 Hz, 1H), 7.36 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.20 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 6.37 (s, 2H), 4.48 (s, 1H), 4.55 (br s, 2H), 3.06 (t, J = 7.8 Hz, 2H), 2.37-2.29 (m, 2H), 1.90 (quintet, J = 7.8 Hz, 2H), 1.64 (quintet, J = 7.8 Hz, 2H), 1.17 (br s, 6H). LCMS (ESI) m / z 381.4 [M+H] + . HPLC purity: 99.34%.

[0085] Using a similar synthetic scheme as described above, the other compounds shown in Table 2 could be readily produced. For example, compound No. 3 was prepared using a procedure similar to the synthesis of compound 1, except that 3-methylbutanoyl chloride was used instead of butyryl chloride. Compound No. 22 was prepared using a procedure similar to the synthesis of compound No. 9, except that 3-amino-2-chloro-4-((2-hydroxy-2-methylpropyl)amino)quinolin-7-ol was used instead of intermediate compound A.

[0086] Analysis of in vitro TLR7 and TLR8 agonist activity To analyze hTLR7 agonist activity, 3 × 10 HEK-Blue hTLR7 cells transfected with the secreted embryonic alkaline phosphatase (SEAP) reporter were cultured in 100 wells. 4Cells were seeded at 1000 kJ / well and treated with various concentrations of test compounds (Compounds 1, 2, 9, and 10). For comparison, two reference compounds, Ref. 1 (a TLR7 / 8 dual agonist called resiquimod) and Ref. 2 (1-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol), were used. Ref. 2 is a more potent TLR7 / 8 dual agonist than resiquimod (see Ganapathi L. et al. (2015), PLOS ONE, 10(8): e0134640). The SEAP reporter was specifically designed to measure secreted placental alkaline phosphatase (AP) in the conditioned cell culture medium from transfected cells. HEK-Blue hTLR7 cells were used to measure the biological activity of TLR7 via SEAP upon NF-κB activation after TLR7 stimulation.

[0087] To analyze hTLR8 agonist activity, HEK-Blue hTLR8 cells transfected with the SEAP reporter were cultured at 3 × 10 4 Cells were seeded at 1000kJ / well and treated with various concentrations of test compounds (compounds 1, 2, 9, and 10). Two reference compounds, Ref. 1 and Ref. 2, were used for comparison. HEK-Blue hTLR8 cells were used to measure the biological activity of TLR8 via SEAP upon NF-κB activation after TLR8 stimulation.

[0088] Water was used as a negative control in the SEAP reporter gene assay described above. After incubation at 37°C in 5% CO2 for approximately 16 hours, SEAP was measured at a wavelength of 635 nm using a spectrophotometer. The dose-response curve was fitted with a four-parameter logistic curve (SigmaPlot, version 9.0). EC values ​​of the test compounds and reference compounds were calculated. 50 The values ​​were calculated. Table 1 shows the analysis results of TLR7 and TLR8 agonist activity.

[0089] [Table 1]

[0090] In Table 1, all the test compounds exhibited TLR7 and TLR8 dual agonist activity. Among them, Compound No. 2 had an EC 50 The TLR8 EC values ​​of compounds No. 2, 9, and 10 were the most potent TLR7 / 8 dual agonists. 50 and TLR7 EC 50 The ratio of TLR7 to TLR8 was lower than that of the two reference compounds, and these compounds activated TLR7 and TLR8 with very similar efficacy ratios, which may provide the advantage of precisely regulating the activation of TLR7 and TLR8.

[0091] Ex vivo cytokine profile analysis Three test compounds (compounds No. 2, 9, and 10) were used to evaluate their effects on cytokine induction. For comparison, three reference compounds were used: Ref. 1 (a TLR7 / 8 dual agonist, resiquimod), Ref. 2 (a TLR7 / 8 dual agonist, 1-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol), and Ref. 3 (a TLR8 agonist, motolimod or VTX2337).

[0092] Cryopreserved human PBMCs from four normal adult volunteers were purchased from EPBMC® (IMMUNOSPOT®). PBMCs were thawed at 37°C for 10 minutes and centrifuged at 300 x g for 5 minutes at room temperature. Pelleted PBMCs were transferred to RPMI-1640 medium containing 10% FBS, 1% PSA, and incubated at 37°C, 5% CO2.

[0093] The test substance and reference compound were each dissolved in DMSO and then diluted 25-fold with PBS to prepare a stock solution with a concentration of 0.1 mM. The pre-incubated PBMCs were collected and resuspended in fresh RPMI-1640 medium containing 10% FBS and 1% PSA. Approximately 1 × 10 5PBMCs were added to each well of a 96-well plate and incubated with 0, 20, or 1000 nM of test compound in 5% CO 2 The cells were stimulated for 24 hours at 37°C in a humidified incubator. The culture supernatant was stored at -20°C for analysis of cytokine induction via TLR7 and TLR8. TM Human IL-6, IL-12p70, and IP-10 were quantified in the culture supernatants using an Immunoassay (Invitrogen) according to the manufacturer's instructions. Briefly, culture supernatant samples were thawed on ice and transferred to a microtiter plate. Magnetic bead-conjugated antibodies specific to the target cytokines were added to the samples to capture the analytes. The immobilized target cytokines were specifically detected with biotin-conjugated antibodies labeled with streptavidin-phycoerythrin (PE). The PE-labeled magnetic beads were then transferred to a LUMINEX™ microscope. TM 200 TM The detection and identification were performed using an analyzer. Data acquisition, processing, and analysis were performed by XPONENT. TM 3.1 software. Target cytokines were normalized to baseline cytokine levels and presented as relative cytokines.

[0094] Figures 1A-1C show the relative IL-6 induction from human PBMCs stimulated with various concentrations of test compounds (compounds No. 2, 9, and 10) and reference compounds (Ref. 1-3). Compounds No. 2, 9, and 10 all exhibited low IL-6-inducing activity, similar to that of Ref. 1 and 3. These results indicate that the compounds of the present invention do not excessively induce IL-6 expression, which is well known to have pathological effects in chronic inflammation and autoimmunity due to dysregulation of continuous IL-6 synthesis. On the contrary, Ref. 2 induced high IL-6 expression when treated at concentrations above 100 nM, particularly above 1000 nM. Therefore, Ref. 2 may excessively induce IL-6 expression and is unsuitable for pharmaceutical development. Given the structural similarity between compounds 2, 9, and 10 and Ref. 2, the low IL-6-inducing activity of the compounds of the present invention was unexpected.

[0095] 2A to 2C are graphs showing the relative IL-12p70 induction from human PBMCs stimulated with various concentrations of test compounds (compounds No. 2, 9, and 10) and reference compounds (Ref. 1 to 3). Compounds No. 2, 9, and 10 all showed high IL-12p70 induction activity. Here, the cytokine IL-12 stimulates NK cells and CD8 + It is well known to enhance the cytotoxic activity of cytotoxic T cells and to mediate anti-angiogenic activity.

[0096] Figures 3A to 3C show the relative IP-10 induction from human PBMCs stimulated with various concentrations of test compounds (compounds Nos. 2, 9, and 10) and reference compounds (Refs. 1 to 3). Compounds Nos. 2, 9, and 10 all showed high IP-10 induction activity. The cytokine IP-10 is well known to be involved in the suppression of angiogenesis and associated with antitumor activity.

[0097] In summary, the compounds of the present invention were able to simultaneously activate human TLR7 and TLR8 and increase the expression of IL-12 and IP-10 without excessively inducing the expression of undesirable IL-6.

[0098] [Table 2] JPEG0007773011000016.jpg248150JPEG0007773011000017.jpg248150JPEG0007773011000018.jpg159150

[0099] Toll-like receptor (TLR) ligation activates both the innate and adaptive immune systems and plays an important role in antiviral and antitumor immunity. The therapeutic potential of TLR agonists includes their use as adjuvants for vaccines, chemotherapy, or monotherapy. See Engel et. al. (2011), Expert Rev Clin Pharmacol., 4(2): 275-289.

[0100] TLR agonists have been widely adopted in therapeutic and preventative formulations useful for patients with asthma / allergic rhinitis (AR). AZD8848 (TLR7 agonist) and VTX-1463 (TLR8 agonist) as monotherapies have demonstrated efficacy in alleviating symptoms in patients with AR. Imiquimod, or R837 (TLR7 agonist), is an FDA-approved drug used to treat basal cell carcinoma of the skin, actinic keratosis, and external genital warts, and has been shown to have numerous off-label uses in other diseases, such as melanoma. Imiquimod also exhibited bronchodilatory activity in mouse and porcine models of airway hyperresponsiveness (AHR). Imiquimod can also promote antiviral defense and protect against virus-induced airway dysfunction. It appears to be an interesting agent for viral asthma. Resiquimod (a TLR7 / 8 dual agonist) is effective in suppressing acute asthma. See Aryan et al. (2014), Int Arch Allergy Immunol., 164: 46-63.

[0101] A possible link between Toll-like receptor 7 (TLR7) and liver disease has been suggested. The role of TLR7 signaling in liver fibrosis has been demonstrated. Imiquimod (a TLR7 ligand) attenuated unsaturated fatty acid (UFA)-induced lipid accumulation and reduced UFA-induced lipid peroxidation products. In vivo experiments using TLR7 knockout mice yielded consistent results with in vitro experiments. These results support that TLR7 prevents the progression of nonalcoholic fatty liver disease (NAFLD) through the induction of autophagy and the release of IGF-1 from the liver. These findings suggest therapeutic strategies for NAFLD. See Kim et al. (2016), Scientific Reports, 6: 27849.

[0102] The anti-tumor activity of TLR7 agonists has been found in tumor types including, but not limited to, squamous cell carcinoma, prostate cancer, bladder cancer, breast cancer, melanoma, glioma, acute myeloid leukemia, breast cancer, T-cell lymphoma, and pancreatic cancer. The anti-tumor activity of TLR8 has been found in tumor types including, but not limited to, glioma, acute myeloid leukemia, breast cancer, T-cell lymphoma, lymphoma, pancreatic cancer, and colon cancer. See Chi et al (2017) Front Pharmacol., 8: 304.

[0103] Therapeutic potential / use of TLR7 / 8 agonist targets in different diseases includes, but is not limited to, the treatment of virus-induced lesions (papillomavirus and herpes simplex virus), primary tumors, skin metastases, antivirals (HCV), and chronic lymphocytic leukemia. See Luke et al. (2009), Pharmacol Rev., 61(2): 177-197.

[0104] TLR7 / 8 agonists stimulate cells through Toll-like receptor (TLR) 7 and 8-dependent pathways, resulting in the activation of effective immune responses against viruses and tumor lesions. Resiquimoid is a topical drug for viral skin lesions and skin cancers such as actinic keratosis (AK). AK, also known as in situ SCC, is an early stage of skin cancer that can progress to invasive cutaneous squamous cell carcinoma (SCC). See Meyer et al. (2013), Expert Opin Investig Drugs, 22(1):149-159. In conclusion, the compound of the present invention is a TLR7 and TLR8 dual agonist. This compound exhibits the activity of inducing the expression of IL-12 and IP-10. This TLR7 / 8 dual agonist is potentially useful as an immune response modulator. The compounds can be used for the treatment of diseases or conditions in which activation of TLR7 and / or TLR8 would provide benefit in a patient, for example, for use in the treatment of viral infections, cancer, and / or allergic diseases, or for use in activating an effective immune response against viral infections, tumors, and / or allergic diseases in a subject in need thereof.

[0105] All documents cited and discussed herein are incorporated by reference in their entirety and to the same extent as if each document were individually incorporated by reference.

Claims

1. A pharmaceutical composition comprising a Toll-like receptor 7 and 8 (TLR7 / 8) dual agonist, (a) and a pharmaceutically acceptable salt thereof; and a dual agonist of TLR7 and TLR8 (TLR7 / 8) selected from the group consisting of (b) a pharmaceutically acceptable carrier and / or adjuvant A pharmaceutical composition comprising:

2. A pharmaceutical composition comprising the TLR7 / 8 dual agonist described in claim 1, wherein the TLR7 / 8 dual agonist is 1-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol or a pharmaceutically acceptable salt thereof.

3. For use in treating a viral infection, cancer, an allergic disease, or a liver disease in a subject in need thereof. or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising the TLR7 / 8 dual agonist of claim 1 or 2.

4. A TLR7 / 8 dual agonist or a pharmaceutical composition comprising a TLR7 / 8 dual agonist for use in the treatment of claim 3, wherein the cancer is one selected from the group consisting of esophagus, stomach, colon, rectum, pancreas, lung, breast, cervix, uterine body, ovary, bladder, head and neck, endometrium, osteosarcoma, prostate, and neuroblastoma.

5. For use in treating a disease or condition benefiting from activation of TLR7 and / or TLR8 in a subject in need thereof. or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising the TLR7 / 8 dual agonist of claim 1 or 2.

6. For use in activating an immune response effective against viral infection, cancer, allergic disease, or liver disease in a subject in need thereof. or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising the TLR7 / 8 dual agonist of claim 1 or 2.

7. 7. The TLR7 / 8 dual agonist or pharmaceutical composition comprising a TLR7 / 8 dual agonist for use in activating an immune response according to claim 6, wherein the cancer is one selected from the group consisting of esophageal, stomach, colon, rectum, pancreas, lung, breast, cervix, uterine corpus, ovary, bladder, head and neck, endometrium, osteosarcoma, prostate, and neuroblastoma.

8. A TLR7 / 8 dual agonist or a pharmaceutical composition comprising a TLR7 / 8 dual agonist for use in the treatment described in claim 3, wherein the allergic disease is allergic rhinitis or asthma, and the liver disease is alcoholic fatty liver disease or non-alcoholic fatty liver disease.

9. A TLR7 / 8 dual agonist or a pharmaceutical composition comprising a TLR7 / 8 dual agonist for use in activating an immune response as described in claim 6, wherein the allergic disease is allergic rhinitis or asthma, and the liver disease is alcoholic fatty liver disease or non-alcoholic fatty liver disease.

10. In the production of a medicament for the treatment of a viral infection, cancer, an allergic disease, or a liver disease in a subject in need thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the TLR7 / 8 dual agonist of claim 1 or 2.

11. In the manufacture of a medicament for the treatment of a disease or condition in a subject in need thereof that would benefit from activation of TLR7 and / or TLR8. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the TLR7 / 8 dual agonist of claim 1 or 2.

12. In the production of a medicament for activating an effective immune response against a viral infection, cancer, an allergic disease, or a liver disease in a subject in need thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the TLR7 / 8 dual agonist of claim 1 or 2.

13. The use of claim 10 or 12, wherein the cancer is one selected from the group consisting of esophagus, stomach, colon, rectum, pancreas, lung, breast, cervix, uterine body, ovary, bladder, head and neck, endometrium, osteosarcoma, prostate, and neuroblastoma.

14. The use according to claim 10 or 12, wherein the allergic disease is allergic rhinitis or asthma, and the liver disease is alcoholic fatty liver disease or non-alcoholic fatty liver disease.

15. A method for treating a viral infection, cancer, allergic rhinitis, asthma, alcoholic fatty liver disease, or non-alcoholic fatty liver disease in a subject in need thereof. or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising the TLR7 / 8 dual agonist of claim 1 or 2.

16. In the manufacture of a medicament for the treatment of viral infection, cancer, allergic rhinitis, asthma, alcoholic fatty liver disease, or non-alcoholic fatty liver disease in a subject in need thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the TLR7 / 8 dual agonist of claim 1 or 2.

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