Tapinaro and its analogues for the treatment of AhR-mediated diseases

Abstract

The present invention is directed to a method for treating certain diseases comprising administering a compound or pharmaceutical composition of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Pharmaceutical compositions comprising a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are also described.

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 373,926, filed August 30, 2022, and U.S. Provisional Application No. 63 / 387,011, filed December 12, 2022, the entire contents of each of which are incorporated herein by reference. Summary of the Invention

[0002] Various embodiments provide methods for treating and preventing conditions associated with AhR imbalance, AhR-mediated diseases, and inflammatory diseases, comprising administering the compounds and compositions described herein. Such compounds described herein bind to and activate the aryl hydrocarbon receptor (AhR), providing novel methods for treating inflammatory disease states.

[0003] Some embodiments disclosed herein are directed to a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of formula (I) or a salt, solvate, or hydrate thereof, [ka] where: R 1 is an unsubstituted or substituted alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group or aralkyl group, halo, or COR 9 is selected from the group consisting of R 2 and R 3 is independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl, or acyl; R 4 , R 5 , R 6 , R 7 , and R 8are not simultaneously H and independently represent H, an unsubstituted or substituted alkylalkenyl group, an alkynyl group, an aryl group or an aralkyl group, a halo, a nitro, a CN, a COR 9 , N.R. 10 R 11 , S(O)NR 10 R 11 , S(O) n R 10 , n=0~2, OR 12 , a cyclic group, or a heterocyclic group, with the proviso that R 1 is an unsaturated group consisting of 1 to 3 isoprene units, R 6 is not a hydroxy group or an alkyloxy group, R 9 is H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl, or NR 10 R 11 , or OR 10 is selected from R 10 and R 11 is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl, and R 12 is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl or acyl.

[0004] Some embodiments disclosed herein are directed to a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of formula (II) or a salt, solvate, or hydrate thereof, [ka] where R 1 is selected from the group consisting of unsubstituted or substituted alkyl having 1 to 18 carbon atoms; unsubstituted or substituted alkenyl having 2 to 18 carbon atoms, unsubstituted or substituted cycloalkyl having 3 to 18 carbon atoms, unsubstituted or substituted alkynyl having 2 to 18 carbon atoms, halo, alkoxy having 1 to 18 carbon atoms, and acyl having 1 to 18 carbon atoms; R 2 and R3 is independently selected from the group consisting of H, unsubstituted or substituted alkyl having 1 to 18 carbon atoms, or acyl having 1 to 18 carbon atoms; R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, unsubstituted or substituted alkyl having 1 to 18 carbon atoms, unsubstituted or substituted alkenyl having 2 to 18 carbon atoms, unsubstituted or substituted cycloalkyl having 3 to 18 carbon atoms, unsubstituted or substituted alkynyl having 2 to 18 carbon atoms, unsubstituted or mono-substituted or di-substituted amino group having 1 to 18 carbon atoms, nitro, halo, carboxy, acyloxy having 1 to 18 carbon atoms, alkoxy having 1 to 18 carbon atoms, hydroxy, and acyl group having 1 to 18 carbon atoms; Here, the configuration of the epoxide portion of the compound can be either (R,S), (S,R), (S,S) or (R,R).

[0005] Some embodiments disclosed herein are directed to a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of formula (III) or a salt, solvate, or hydrate thereof, [ka] where R 1 teeth, a).H, b). Unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl, or aralkyl; c).Halo, d).CN, e).COOR 6 , f).NR 7 R 8 , g).S(O)2NR 7 R 8 , h).COR 9 , i).OR 10 , j).S(O) n R 11, n=0~2, and k). substituted or unsubstituted cyclic or heterocyclic groups; R 2 and R 3 is, independently, a).H, b). Unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl, or aralkyl; c).Halo, d).CN, e).COOR 6 , f).NR 7 R 8 , g).S(O)2NR 7 R 8 , h).COR 9 , i).OR 10 , j).S(O) n R 11 , n=0~2, and k) is selected from the group consisting of substituted or unsubstituted cyclic or heterocyclic groups; R 4 and R 5 are each independently a).H, b) Unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl, and c). acyl, R 6 teeth, a).H, b) selected from unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl; R 7 and R 8 are each independently a).H, b) selected from the group consisting of unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl; R 9 teeth, a).H, b) Unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl, and c).NR 7 R 8 is selected from R 10 teeth, a).H, b) Unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl, and c). selected from acyl; R 11 teeth, a).H, b) selected from unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl; Ar is a) Unsubstituted, monosubstituted or polysubstituted phenyl (provided that R 2 and R 3 cannot be set to H at the same time, b) Unsubstituted, monosubstituted or polysubstituted 5-membered heterocyclic rings containing O, S and / or N c). Unsubstituted, monosubstituted or polysubstituted 6-membered heterocyclic rings containing O, S, or N.

[0006] In some embodiments, the compound administered is a bacterially derived natural product of formula (IV), also known as 3,5-dihydroxy-4-isopropyl-trans-stilbene, (E)-2-isopropyl-5-stilbenzene-1,3-diol, or tapinarof. [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0007] Some embodiments disclosed herein are directed to a method of treating a disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier or diluent.

[0008] In some embodiments, methods are described for treating or preventing a condition in a mammal associated with AhR imbalance, comprising administering to the mammal a therapeutically effective amount of any compound or pharmaceutical composition described herein.

[0009] Some embodiments describe methods for treating or preventing a disease in a subject, comprising administering to the subject a therapeutically effective amount of any compound or pharmaceutical composition described herein. In some embodiments, the compound or pharmaceutical composition treats such a disease by enhancing regulatory B cell activity and suppressing inflammation. In some embodiments, the compound or pharmaceutical composition treats such a disease by inhibiting polymorphonuclear leukocyte activation and migration. In some embodiments, the compound or pharmaceutical composition treats such a disease through inhibition of AhR signaling in dendritic cells / antigen-presenting cells and T cells, and activation of monocyte-derived dendritic cells / antigen-presenting cells, including the production of inflammatory cytokines and upregulation of costimulatory molecules. In some embodiments, the compound or pharmaceutical composition treats such a disease through inhibition of mast cell activation. In some embodiments, the compound or pharmaceutical composition treats such a disease through suppression or inhibition of angiogenesis. In some embodiments, the compound or pharmaceutical composition treats such a disease through inhibition of ILC3 dysregulation, ILC2 dysregulation, and promoting the anti-tumor effects of ILCs and NK cells. In some embodiments, the compound or pharmaceutical composition treats such diseases by modulating macrophages and phagocytosing apoptotic cells. In some embodiments, the compound or pharmaceutical composition treats such diseases through modulating epithelial cells (including skin, intestinal, and / or respiratory epithelial cells) and / or interacting with or affecting signaling between such epithelial cells and immune cells. In some embodiments, the compound or pharmaceutical composition treats such diseases through suppression of antigen-presenting cell activity. In some embodiments, the compound or pharmaceutical composition treats such diseases by affecting the activity of B cells and plasma cells, thereby suppressing the production of autoantibodies and / or pathogenic antibodies.

[0010] Some embodiments describe a method for treating or preventing a disease in a subject, comprising administering to the subject a therapeutically effective amount of any compound or pharmaceutical composition described herein. In some embodiments, the disease is selected from the group consisting of pemphigus foliaceus, pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid, epidermolysis bullosa acquisita, lupus erythematosus, dermatomyositis, myasthenia gravis, Goodpatcher's syndrome, and autoimmune thyroiditis. In some embodiments, the disease is selected from the group consisting of Sweet's syndrome, pustular psoriasis, pyoderma gangrenosum, hidradenitis suppurativa, leukocytoclastic vasculitis, Wegener's granulomatosis, and neutrophilic dermatosis. In some embodiments, the disease is selected from the group consisting of allergic diseases, autoimmune diseases, inflammatory airway diseases, allergic rhinitis, autoimmune bullous diseases including pemphigus vulgaris and pemphigus foliaceus, bullous pemphigoid, inflammatory joint diseases, Schamberg's disease or other pigmented purpuric dermatoses (PPD), lupus vulgaris, and dermatomyositis. In some embodiments, the disease is selected from the group consisting of mastocytosis, urticaria, rosacea, fibromyalgia, chronic pain syndromes, chronic pruritus, chronic itch, and allergic rhinitis. In some embodiments, the disease is selected from the group consisting of arteriosclerosis, benign tumor growth, and malignant tumor growth. In some embodiments, the disease is selected from the group consisting of inflammatory airway diseases, allergic rhinitis, Schamberg's disease or other pigmented purpuric dermatoses (PPD), and inflammatory joint diseases. In some embodiments, the disease is vitiligo. In some embodiments, the disease is an oral disease selected from the group consisting of gingivitis (including gingivitis with a TH17-driven component), mucositis, edentulous stomatitis, lichen planus, and erosive oral lichen planus. In some embodiments, the disease is an ophthalmological disease selected from the group consisting of blepharitis, dry eye disease, meibomian gland dysfunction, keratoconjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, conjunctivitis, uveitis, and age-related macular degeneration. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0011] The aryl hydrocarbon receptor (AhR), a member of the bHLH-PAS family of transcription factors, is a cytoplasmic ligand-activated transcription factor that senses a variety of endogenous and exogenous molecules and mediates multiple biological activities. It is best known for mediating the toxic effects of environmental pollutants such as TCDD (dioxin) and various other xenobiotics. Recent evidence suggests that the AhR is a highly conserved pathway that regulates inflammatory responses, and therefore the AhR pathway may be an important target for treating inflammatory diseases.

[0012] AhR is widely expressed in several cell types in the skin, including keratinocytes, fibroblasts, melanocytes, and cutaneous immune cells. In keratinocytes, AhR signaling regulates the expression of epidermal differentiation genes, such as filaggrin, loricrin, and hornerin, promoting skin barrier formation. Furthermore, AhR plays an important role as a regulator of both innate and adaptive immune responses by influencing the balance between Th17 and Treg T cells. Th17-associated cytokines, including IL-17, contribute to the immunopathogenesis of inflammatory skin diseases such as psoriasis. Therefore, AhR has recently gained attention as a target for the treatment and prevention of inflammatory skin diseases, highlighting the need for better topical treatments.

[0013] Compounds as described herein that bind to and activate the aryl hydrocarbon receptor (AhR) provide a novel class of anti-inflammatory compounds with AhR-dependent cytokine modulating activity that are useful in the treatment of the disease states described herein.

[0014] Thus, the beneficial effects of AhR activation provide new therapeutic interventions for the treatment of certain disease states. There is a need for better topical treatments for skin diseases, particularly chronic inflammatory skin diseases. Compounds that advantageously bind to and activate the aryl hydrocarbon receptor (AhR) in multiple cell types, including cells of human skin, provide novel and useful treatments for inflammatory disease states. Accordingly, the present invention provides a novel class of anti-inflammatory compounds with AhR-dependent cytokine-modulating activity for the treatment thereof.

[0015] definition As used herein, the terms "a" and "an" should be understood to refer to "one or more" of the referenced component. It will be clear to those skilled in the art that the use of the singular includes the plural unless otherwise specified.

[0016] The term "about" means within an acceptable range of the specified particular parameter as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 10% of a given value. For example, about 55% means 45% to 55%.

[0017] As used herein, "acyl" refers to an alkyl or aryl group bonded through a carbonyl group -C(O)-. For example, acyl includes C 1-6 Representative acyl groups include acetyl and benzoyl groups.

[0018] As used herein, the terms "administer" and "administration" refer to any method, in sound medical practice, of delivering a compound or pharmaceutical composition thereof to a subject in a manner that provides a desired therapeutic effect. In some embodiments, the compound is in a pharmaceutical emulsion composition.

[0019] As used herein, the term "alkoxy" refers to an -O-alkyl group containing the specified number of carbon atoms. For example, C 1-6 Alkoxy means an alkoxy group containing at least 1 and at most 6 carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy, or hexyloxy.

[0020] As used herein, "alkyl" refers to a monovalent saturated hydrocarbon chain having a specified number of carbon member atoms. For example, C 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms. Alkyl groups can be straight-chained or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, s-butyl, t-butyl), n-pentyl, and the like.

[0021] The term "alkylene" refers to a linker that is a straight or branched carbon chain having 1 to 6 carbon atoms and having two attachment sites. 1-6 Examples of alkylene linker groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, ?-CH2CH(CH3)CH2-, and the like.

[0022] As used herein, the term "and / or" covers the individual members of a list so linked in addition and in the alternative, with these members being understood as being alternatively linked by "and" or, respectively, "or." Furthermore, terms used in the singular naturally include the plural.

[0023] As used herein, the term "applying" refers to any method, in sound medical or cosmetic practice, of delivering a topical composition to a subject in a manner that produces a positive effect on a dermatological disorder, condition, or appearance.

[0024] As used herein, the term "aryl" refers to a substituted or unsubstituted hydrocarbon aromatic ring such as phenyl, naphthyl, etc.

[0025] As used herein, unless otherwise indicated, the term "arylalkyl" or "araalkyl" refers to an aryl ring and a linking C 1-6 Refers to an alkyl moiety, e.g., -(CH2)n Phenyl (where n is 1 to 6)

[0026] As used herein, the term "compound(s) of the invention" or "compound(s) of the invention" includes any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof), as defined herein, and any physical form (e.g., non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, particular polymorphic forms, solvated forms, including hydrate forms (e.g., mono-, di-, and hemihydrates)), as well as mixtures of various forms.

[0027] Throughout this application, descriptions of various embodiments use the phrase "comprising," although in some specific instances, embodiments may instead be described using the phrase "consisting essentially of" or "consisting of."

[0028] As used herein, the term "pharmaceutically acceptable excipient or diluent" refers to any inactive ingredient present in a composition for use in the pharmaceutical compositions described herein.

[0029] As used herein, the terms "effective amount," "pharmaceutically effective amount," or "therapeutically effective amount" refer to an amount of an active ingredient sufficient to have a therapeutic effect upon administration, e.g., an amount that causes an improvement or change in the pathological condition for which it is administered. The effective amount will vary depending on the particular condition being treated, the severity of the condition, the duration of treatment, the stage of the condition, the body surface area affected by the clinical condition (in the case of topical administration), and the particular components of the composition. The amount will be sufficient to treat the disorder, disease, or condition, or one or more of its symptoms, and / or prevent the onset of the disease or disorder, and can be determined by standard clinical techniques. The appropriate amount in any given instance can be readily determined by one of ordinary skill in the art or by routine experimentation. In some embodiments, the compositions of the present invention are generally applied topically to the affected area, i.e., to the area of ​​skin where a clinical abnormality is manifest.

[0030] As used herein, the term "haloalkyl" or "halo-substituted alkyl" means a straight or branched saturated hydrocarbon chain containing the specified number of carbon atoms substituted with a halo atom. For example, haloC 1-6 Alkyl means a straight or branched chain alkyl group containing at least 1 and at most 6 carbon atoms substituted with 1 to 3 halo atoms per carbon atom. Examples of "haloalkyl" as used herein include, but are not limited to, fluoromethyl, difluoromethyl, and trifluoromethyl.

[0031] As used herein, the terms "halogen" and "halo" include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo and iodo, respectively.

[0032] As used herein, the terms "heteroaryl ring," "heteroaryl moiety," and "heteroaryl" refer to a monocyclic 5- to 7-membered unsaturated hydrocarbon ring containing at least one heteroatom selected from oxygen, nitrogen, and sulfur. Examples of heteroaryl rings include furyl, pyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, oxathiadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and uracil. As used herein, the terms "heteroaryl ring," "heteroaryl moiety," and "heteroaryl" also refer to fused aromatic rings containing at least one heteroatom selected from oxygen, nitrogen, and sulfur. Each of the fused rings may contain 5 or 6 ring atoms. Examples of fused aromatic rings include, but are not limited to, indolyl, isoindolyl, indazolyl, indolizinyl, azaindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, purinyl, and phthalazinyl.

[0033] As used herein, unless otherwise stated, the term "heteroarylalkyl" refers to a C alkyl group, as defined above (unless otherwise stated), attached to a heteroaryl moiety, also defined herein. 1-6 It means alkyl.

[0034] As used herein, unless otherwise specified, the term "heterocyclalklyl" or "heterocyclylalkyl" refers to a heterocyclyl group, as defined above, attached to a heterocycle moiety, also defined herein. 1-6 It means alkyl.

[0035] As used herein, the terms "heterocyclic" or "heterocyclyl" (alone or in any combination, such as "heterocyclylalkyl") are used to mean saturated or partially unsaturated 4- to 10-membered ring systems in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, S, or S(O)q, where q is 0 or an integer having a value of 1 or 2. Examples include, but are not limited to, tetrahydropyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl (including oxidized versions of the sulfur moiety), pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl (including oxidized versions of the sulfur moiety), or imidazolidinyl.

[0036] As used herein in in vitro skin permeation testing, the term "epidermis" includes the stratum corneum and tissue or layers up to the basement membrane separated by a heat separation process.

[0037] As used herein in in vitro skin penetration studies using ex vivo human abdominal skin incisions at a thickness of 500 microns (±100 microns) or 750 microns (±100 microns), the term "epidermis" refers to the most superficial / superficial layer obtained after the washing / tape stripping procedure followed by thermal separation, and the term "dermis" refers to the layer below that.

[0038] As used herein, the term "independently" means that when multiple substituents are selected from multiple possible substituents, the substituents can be the same or different, i.e., each substituent is separately selected from the entire group of possible substituents stated.

[0039] The term "modulate" or "modulate(s)" refers to an increase or decrease in the quantity, quality, or effect of a particular activity.

[0040] As used herein, the term "oxo" refers to a double-bonded oxygen moiety, e.g., when attached directly to a carbon atom, it forms a carbonyl moiety (C=O).

[0041] As used herein, the term "hydroxy" or "hydroxyl" is intended to mean the radical --OH.

[0042] As used herein, the term "sulfinyl" refers to the oxide S(O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(O) moiety.

[0043] As used herein, the term "optionally" means that the subsequently described event may or may not occur, and includes both events that occur and events that do not occur.

[0044] As used herein, unless otherwise defined herein, "optionally substituted" means that the moiety is independently selected from the group consisting of halo, e.g., fluoro, chloro, bromo, or iodo; hydroxy; hydroxy-substituted C 1-3 Alkyl; C such as methoxy or ethoxy 1-3 Alkoxy; Halo-substituted C 1-3 Alkoxy; S(O) such as methylthio, methylsulfinyl or methylsulfonyl m C 1-3 Alkyl;NR 22 R 23 , where R 22 and R 23 are independently H or C 1-3 alkyl, or R 22 and R 23 form a 5- to 7-membered ring together with the nitrogen to which they are attached, optionally containing an additional heteroatom selected from O, N, or S; C 1-3 Alkyl; C 3-7 Cycloalkyl, or C 3-7 Cycloalkyl C 1-3 Alkyl groups, such as cyclopropylmethyl; halo-substituted C 1-3alkyl, for example, CF2CF2H, or CF3; optionally substituted aryl, for example, phenyl, or optionally substituted arylC 1-3 alkyl, for example, benzyl or phenethyl, where these aryl-containing moieties may also be substituted one to two times by halo; hydroxy; hydroxy-substituted C 1-3 Alkyl; C 1-3 Alkoxy;S(O) m C 1-3 Alkyl; Amino, Mono- and Di-substituted C 1-3 Alkylamino;C 1-3 Alkyl, or CF3. Furthermore, it will be understood by those skilled in the art that the compounds of the present invention may exist in other tautomeric forms, depending on further substitution. All tautomers of the compounds described herein are intended to be encompassed within the scope of the present invention. It should be understood that a reference to a named compound of the present invention is intended to encompass all tautomers of the named compound and mixtures of tautomers of the named compound.

[0045] As used herein, "patient" or "subject" (used interchangeably) includes human patients, including adults, teenagers, and children (e.g., pediatric patients). Pediatric patients can include teenagers under the age of 18. As used herein, children refer to those under the age of 12.

[0046] As used herein, "pharmaceutically acceptable" refers to compounds, materials, compositions, and dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The terms "pharmaceutically acceptable" and "dermatologically acceptable" mean approved by a regulatory agency or listed in a pharmacopoeia or other generally recognized guide for use in animals, and more particularly in humans.

[0047] The term "pharmaceutically acceptable salts thereof" refers to salts that are safe and effective for use in patients and possess the desired pharmacological activity. The salts encompassed by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention. Such salts include compounds in which the parent compound is modified by making acid or base salts thereof.

[0048] As used herein, the term "skin penetration" refers to the diffusion of a compound, preferably a compound of formula (I) or a pharmaceutically acceptable salt thereof, through the stratum corneum into the epidermis and / or dermis of the skin.

[0049] "Substantially free" of a particular component refers to a composition that contains less than about 1% by weight of the particular component. "Free" of a particular component refers to a composition in which the particular component is not present.

[0050] As used herein, the term "substituted" with respect to a group indicates that one or more hydrogen atoms bonded to a member atom within the group are replaced with a substituent selected from the defined group of substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution is in accordance with the allowed valences of the replacement atom and substituent, and that the substitution results in a stable compound (i.e., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, or elimination, etc., and that is sufficiently robust to withstand isolation from a reaction mixture). When a group is described as optionally containing one or more substituents, one or more (appropriate) member atoms within the group may be substituted. Furthermore, a single member atom within the group may be substituted with one or more substituents, provided that such substitution is in accordance with the allowed valences of the atom. Suitable substituents are defined herein for each substituent or optionally substituted group.

[0051] The term "topical" administration or "topical" administration refers to the application of a drug-containing formulation to the skin with the intention of directing the drug's pharmacological effects substantially to or within the skin to directly treat cutaneous symptoms of a skin disorder or disease. The term "topical" administration also includes transdermal, inhalation, and ocular / oral administration. "Topical" administration also refers to application to and diffusion through the stratum corneum, including, but not limited to, application to psoriatic lesions and broken skin.

[0052] As used herein, the term "treating" or "treatment" refers to the administration of a compound or agent to a subject having or at risk of developing a disorder with the intent to cure, alleviate, mitigate, ameliorate, delay the onset of, prevent, or ameliorate the disorder, the symptoms of the disorder, a disease state secondary to the disorder, or the predisposition to the disorder. Treatment need not mean that the condition or disorder is completely cured. Pharmaceutical compositions, e.g., pharmaceutical emulsion compositions, useful herein need only mean reducing the severity of the condition or disorder, reducing the severity of symptoms associated therewith, providing an improvement in the patient's quality of life, or delaying, preventing, or inhibiting the onset of the condition or disorder. As recognized in the medical and pharmaceutical fields, a treatment need not be effective in all members of a population, e.g., a population of atopic dermatitis patients, to have clinical utility.

[0053] Concentrations, amounts, solubilities, and other numerical data may be presented herein in a range format. It should be understood that such range formats are used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values ​​expressly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within the range, as if each numerical value and subrange were expressly recited. All numerical values ​​expressing quantities, percentages, or ratios, and other numerical values ​​used herein should be understood to be modified in all instances by the term "about."

[0054] For example, a concentration range of 0.1-5 ng / ml should be interpreted to include not only the explicitly stated concentration limits of 0.1 ng / ml and 5 ng / ml, but also individual concentrations such as 0.2 ng / ml, 0.8 ng / ml, 1.0 ng / ml, 2.2 ng / ml, and 3.6 ng / mol, as well as subranges such as 0.3-2.5 ng / ml, 1.8-3.2 ng / ml, etc. This interpretation should apply regardless of the breadth of the range or the properties described.

[0055] Any concentration range, percentage range, or ratio range described herein, unless otherwise indicated, is understood to include any integer and fraction thereof, such as tenths or hundredths of an integer, concentration, percentage, or ratio within that range.

[0056] Other terms used herein are intended to be defined by their well-known meanings in the art.

[0057] The alternative definitions of the various groups and substituents of Formula (I) and Formula (Ia) provided throughout this specification are intended to specifically describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of the present invention includes any combination of these group and substituent definitions.

[0058] Compounds administered in the method embodiments described herein In some embodiments, the present disclosure provides a compound of formula (I) [ka] or a salt, solvate or hydrate thereof.

[0059] The substituent R of formula (I) 1 is an unsubstituted or substituted alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group or aralkyl group, halo, or COR 9 is selected from the group consisting of:

[0060] The substituent R of formula (I) 2 and R 3 is independently selected from the group consisting of H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl, or acyl.

[0061] The substituent R of formula (I) 4 , R 5 , R 6 , R 7 , and R 8 are not simultaneously H and independently represent H, an unsubstituted or substituted alkylalkenyl group, an alkynyl group, an aryl group, or an aralkyl group, halo, nitro, CN, COR 9 , N.R. 10 R 11 , S(O)NR 10 R 11 , S(O) n R 10 , n=0~2, OR 12 , a cyclic group, or a heterocyclic group, with the proviso that R 1 is an unsaturated group consisting of 1 to 3 isoprene units, R 6 is not a hydroxy group or an alkyloxy group.

[0062] The substituent R of formula (I) 9 is H, unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl, or NR 10 R 11 , or OR 10 is selected from.

[0063] The substituent R of formula (I) 10 and R 11 is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl.

[0064] The substituent R of formula (I) 12 is selected from H, unsubstituted or substituted alkyl, cycloalkyl, aryl, aralkyl, or acyl.

[0065] In some embodiments, the substituent R of formula (I)4 , R 5 , R 6 , R 7 , and R 8 is H, unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl group, halo, nitro, CN, COR 9 , N.R. 10 R 11 , S(O)NR 10 R 11 , S(O) n R 10 , n=0~2, OR 12 , a cyclic group, or a heterocyclic group, and R 4 , R 5 , R 6 , R 7 and R 8 is F. The double bond configuration of the compound of formula (I) is E or Z.

[0066] In a further preferred embodiment, R 1 is selected from the group consisting of substituted and unsubstituted alkyls having 1 to 18 carbon atoms, substituted and unsubstituted alkenyls having 2 to 18 carbon atoms, substituted and unsubstituted cyclic alkyls having 3 to 18 carbon atoms, and halides.

[0067] Each R 4 , R 5 , R 6 , R 7 , or R 8 are independently selected from the group consisting of hydrogen, methyl, acetoxyl, hydroxyl, methoxyl, halide, and acetyl; R 2 and R 3 are each independently selected from the group consisting of an acyl group having 1 to 18 carbon atoms, hydrogen, and a methyl group, and are pharmaceutically acceptable salts thereof.

[0068] In embodiments, the present disclosure provides a compound of formula (II) [ka] or a salt, solvate or hydrate thereof.

[0069] The substituent R of formula (II) 1 is selected from the group consisting of unsubstituted or substituted alkyl having 1 to 18 carbon atoms, unsubstituted or substituted alkenyl having 2 to 18 carbon atoms, unsubstituted or substituted cycloalkyl having 3 to 18 carbon atoms, unsubstituted or substituted alkynyl having 2 to 18 carbon atoms, halo, alkoxy having 1 to 18 carbon atoms, and acyl having 1 to 18 carbon atoms.

[0070] The substituent R of formula (II) 2 and R 3 is independently selected from the group consisting of H, unsubstituted or substituted alkyl having 1 to 18 carbon atoms, or acyl having 1 to 18 carbon atoms.

[0071] The substituent R of formula (II) 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from H, unsubstituted or substituted alkyl having 1 to 18 carbon atoms; unsubstituted or substituted alkenyl having 2 to 18 carbon atoms, unsubstituted or substituted cycloalkyl having 3 to 18 carbon atoms, unsubstituted or substituted alkynyl having 2 to 18 carbon atoms, unsubstituted or mono- or di-substituted amino group having 1 to 18 carbon atoms, nitro, halo, carboxy, acyloxy having 1 to 18 carbon atoms, alkoxy having 1 to 18 carbon atoms, hydroxy, and acyl group having 1 to 18 carbon atoms.

[0072] In embodiments, the present disclosure provides a compound of formula (III) [ka] or a salt, solvate or hydrate thereof.

[0073] The substituent R of formula (III) 1 is a).H, b).unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl, c).halo, d).CN, e).COOR 6 ,f).NR 7 R 8 , g).S(O)2NR 7 R8 ,h).COR 9 ,i).OR 10 ,j).S(O) n R 11 , n=0-2, and k) are selected from the group of substituted or unsubstituted cyclic or heterocyclic groups.

[0074] The substituent R of formula (III) 2 and R 3 is a).H, b).unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl or aralkyl, c).halo, d).CN, e).COOR 6 ,f).NR 7 R 8 , g).S(O)2NR 7 R 8 ,h).COR 9 ,i).OR 10 ,j).S(O) n R 11 , n=0-2, and k) are selected from the group of substituted or unsubstituted cyclic or heterocyclic groups.

[0075] The substituent R of formula (III) 4 and R 5 is selected from the group consisting of: a) H, b) unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl, and c) acyl.

[0076] The substituent R of formula (III) 6 a). Unsubstituted or substituted alkyl, cycloalkyl, aryl or aralkyl.

[0077] The substituent R of formula (III) 7 and R 8 is selected from the group consisting of: a). H, and b). unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl.

[0078] The substituent R of formula (III) 9 is a). H, b). unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl, and c). NR 7 R8 is selected from.

[0079] The substituent R of formula (III) 10 is selected from a) H, b) unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl, and c) acyl.

[0080] The substituent R of formula (III) 11 is selected from a) H, b) unsubstituted or substituted alkyl, cycloalkyl, aryl, or aralkyl.

[0081] Some embodiments of the present invention provide 3,5-dihydroxy-4-isopropyl-trans-stilbene, also known as (E)-2-isopropyl-5-stilbenzene-1,3-diol or tapinarof, of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, a naturally occurring product of bacterial origin.

[0082] The present invention also includes various isomers of compounds according to any embodiment described herein, and mixtures thereof. Isomers are compounds that have the same composition and molecular weight but different physical and / or chemical properties. The structural differences may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). Compounds according to any embodiment described herein may contain one or more asymmetric centers, also referred to as chiral centers, and therefore may exist as individual enantiomers, diastereomers, or other stereoisomers, or as mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the present invention. Chiral centers may also be present in substituents, such as alkyl groups. If the stereochemistry of a chiral center present in a formula or in any chemical structure illustrated herein is not specified, the structure is intended to encompass any stereoisomers and all mixtures thereof. Thus, compounds according to any embodiment described herein that contain one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or enantiomerically pure individual stereoisomers. A mixture containing unequal portions of enantiomers is described as having an "enantiomeric excess" (ee) of either the R or S compound. The excess of one enantiomer in a mixture is often expressed as % enantiomeric excess. The ratio of enantiomers can also be defined by "optical purity," which compares the degree to which a mixture of enantiomers rotates plane-polarized light with the individual optically pure R and S compounds. A compound can also be a substantially pure (+) or (-) enantiomer of a compound described herein. In some embodiments, a composition can comprise a substantially pure enantiomer of a compound according to any embodiment described herein that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of one enantiomer. In certain embodiments, a composition can comprise a substantially pure enantiomer of a compound according to any embodiment described herein that is at least 99.5% of one enantiomer.

[0083] Individual stereoisomers of compounds according to any embodiment described herein containing one or more asymmetric centers can be resolved by methods known to those skilled in the art. For example, such separations can be carried out by (1) the formation of diastereomeric salts, complexes, or other derivatives; (2) selective reaction with stereoisomer-specific reagents, e.g., by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, e.g., on a chiral support such as silica bearing bound chiral ligands or in the presence of a chiral solvent. Those skilled in the art will understand that if the desired stereoisomer is converted to a different chemical entity by one of the above-described separation procedures, additional steps will be necessary to liberate the desired form. Alternatively, specific stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to the other by asymmetric transformation. Further embodiments include prodrugs of compounds according to any embodiment described herein, i.e., compounds that release an active compound according to any embodiment described herein in vivo when administered to a mammalian subject. A prodrug is a pharmacologically active compound that is converted into a pharmacologically active drug by metabolic conversion, or more typically, an inactive compound. Prodrugs of the compounds according to any embodiment described herein are prepared by modifying functional groups present in the compound so that the modifications can be cleaved in vivo to release the parent compound. In vivo, prodrugs easily undergo chemical changes under physiological conditions (e.g., hydrolysis or acted upon by naturally occurring enzymes), resulting in the release of pharmacologically active drugs. Prodrugs include compounds according to any embodiment described herein in which a hydroxyl group, an amino group, or a carboxy group is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl group, an amino group, or a carboxy group, respectively.Examples of prodrugs include, but are not limited to, esters of compounds according to any embodiment described herein (e.g., acetate, formate, and benzoate derivatives), or any other derivative that is converted to the active parent drug upon return to physiological pH or by enzymatic action. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described in the art.

[0084] Certain compounds of the present invention can form salts with one or more equivalents of an acid (if the compound contains a basic moiety) or base (if the compound contains an acidic moiety). The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.

[0085] When a compound of the present invention contains a basic moiety, the desired salt form can be prepared by any suitable method known in the art, including treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, and the like; a pyranosidyl acid, such as glucuronic acid, galacturonic acid, and the like; an α-hydroxy acid, such as citric acid, tartaric acid, and the like; an amino acid, such as aspartic acid, glutamic acid, and the like; an aromatic acid, such as benzoic acid, cinnamic acid, and the like; a sulfonic acid, such as toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and the like.

[0086] Suitable addition salts include those derived from acids which form non-toxic salts, such as acetate, p-aminobenzoate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bismethylenesalicylate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, cyclohexylsulfamate, edetate, edisylate, estolate, esylate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycolylsanilate, hexylresorcinate, hydrobromide, hydrochloride, dihydrochloride, fumarate, hydrogen phosphate, and hydrogen iodide. , hydromaleate, hydrogen succinate, hydroxynaphthoate, isethionate, itaconate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, oxaloacetate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, pyruvate, polygalacturonate, propionate, saccharate, salicylate, stearate, acetate, succinate, sulfate, tannate, tartrate, teocronate, tosylate, triethiodide, trifluoroacetate, and valerate.

[0087] Other exemplary acid addition salts include pyrosulfate, sulfite, bisulfite, decanoate, caprylate, acrylate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, suberate, sebacate, butyne-1,4-dioate, hexyne-1,6-dioate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, phenylacetate, phenylpropionate, phenylbutyrate, lactate, g-hydroxybutyrate, mandelate, and sulfonates such as xylenesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and the like.

[0088] When a basic compound of the invention is isolated as a salt, the corresponding free base form of the compound will react with the salt to form an inorganic or organic base, preferably a base with a higher pK than the free base form of the compound. a The compound can be prepared by any suitable method known in the art, including treating the compound with an inorganic or organic base having the formula:

[0089] When the compound of the present invention contains an acidic moiety, the desired salt can be prepared by any suitable method known in the art, including treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, etc. Examples of suitable salts include the Seritech salts derived from amino acids such as glycine, arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as N-methyl-D-glucamine, diethylamine, isopropylamine, trimethylamine, ethylenediamine, dicyclohexylamine, ethanolamine, piperidine, morpholine, and piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0090] Compounds of the invention that contain both a basic and an acidic moiety may be in the form of a zwitterion, an acid addition salt of the basic moiety, or a base salt of the acidic moiety.

[0091] For their potential use in medicine, salts of the compounds of the invention are preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts will be known to those skilled in the art.

[0092] These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or may be prepared by separately treating the purified compound in the form of a free acid or free base with an appropriate base or acid, respectively.

[0093] In certain embodiments, the compounds of the present invention may contain an acidic functional group and thus may form pharmaceutically acceptable base addition salts by treatment with an appropriate base. Examples of such bases include, but are not limited to, a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; and b) primary, secondary, and tertiary amines, such as aliphatic amines, aromatic amines, aliphatic diamines, and hydroxyalkylamines, such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.

[0094] In certain embodiments, the compounds of the present invention may contain basic functional groups, and therefore can be treated with a suitable acid to form pharmaceutically acceptable acid addition salts.Suitable acids include pharmaceutically acceptable inorganic and organic acids.Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, succinic acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methylsulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, etc.

[0095] The present invention also provides for the conversion of a pharmaceutically acceptable salt of a compound of the present invention into another pharmaceutically acceptable salt of a compound of the present invention.

[0096] The compounds according to any embodiment described herein can exist in solid or liquid form. In the solid state, they may exist as crystalline or amorphous forms, or mixtures thereof. Those skilled in the art will recognize that pharmaceutically acceptable solvates can be formed from crystalline compounds in which solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates include, but are not limited to, non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, ethyl acetate, and the like, and may also include water as the solvent incorporated into the crystalline lattice. Solvates in which water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates and compositions containing variable amounts of water. The present invention encompasses all such solvates.

[0097] Regarding the solvates of the compounds according to any embodiment described herein, including solvates, those skilled in the art will understand that in crystalline form, solvent molecules may be incorporated into the crystal lattice during crystallization, forming pharmaceutically acceptable solvates.Solvates may contain non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, or may contain water as the solvent incorporated into the crystal lattice.Solvates in which the solvent incorporated into the crystal lattice is water are typically referred to as "hydrates."Hydrates include stoichiometric hydrates and compositions containing variable amounts of water.The present invention encompasses all such solvates.

[0098] Those skilled in the art will further understand that compounds according to any embodiment described herein that exist in crystalline form (including various solvates thereof) may exhibit polymorphism (i.e., the ability to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The present invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometric arrangement, and other descriptive properties of the crystalline solid state. Thus, polymorphs may have different physical properties, such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which can be used for identification. Those skilled in the art will understand that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents used in making the compound. For example, changes in temperature, pressure, or solvents may result in polymorphism. Furthermore, one polymorph may spontaneously transform into another polymorph under certain conditions.

[0099] The subject invention also includes isotopically labeled compounds, which are identical to those described in the compounds of the invention and subsequent compounds except for the fact that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention and their pharmaceutically acceptable salts, solvates or hydrates include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I can be mentioned.

[0100] Compounds according to any embodiment described herein, and pharmaceutically acceptable salts, solvates, or hydrates of said compounds that contain the aforementioned isotopes and / or isotopes of other atoms, are within the scope of the present invention. Isotopically labeled compounds of the present invention, e.g. 3 H, 14 Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. Tritium, i.e. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 The F isotope is particularly useful in PET (positron emission tomography), 125 The I isotope is particularly useful in SPECT (single photon emission computed tomography) and is also useful in brain imaging. 2 Substitution with heavy isotopes such as H can provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds according to any embodiment described herein can generally be prepared by carrying out the procedures disclosed in the following schemes and / or examples, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0101] The present invention also encompasses isolated compounds, which refer to compounds that represent at least 10%, preferably at least 20%, more preferably at least 50%, and most preferably at least 80% of the compounds present in a mixture.

[0102] It will be readily understood that, because the compounds according to any embodiment described herein are intended for use in pharmaceutical compositions, they are preferably provided in substantially pure form, e.g., at least 60% pure, more preferably at least 75% pure, and preferably at least 85%, particularly at least 98% pure (percentages are by weight). In some embodiments, the compounds according to any embodiment described herein are at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure. Impurity preparations of the compounds can be used to prepare purer forms for use in pharmaceutical compositions.

[0103] Pharmaceutical compositions administered in the method embodiments described herein Some embodiments describe administering a pharmaceutical composition comprising a compound according to any embodiment described herein, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof; and a pharmaceutically acceptable carrier or diluent. Pharmaceutical compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes, depending on whether local or systemic treatment is desired and the area to be treated.

[0104] While it is possible for a compound as described in any embodiment herein to be administered as a bulk substance, it is preferable to present the compound in a pharmaceutical formulation, e.g., where the active agent is in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

[0105] In particular, the present disclosure provides for the administration of a pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any embodiment described herein, and optionally a pharmaceutically acceptable carrier.

[0106] Some embodiments include 3,5-dihydroxy-4-isopropyl-trans-stilbene, also known as (E)-2-isopropyl-5-styrylbenzene-1,3-diol or tapinarof. [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent.

[0107] Treatment method AhR activation has been shown to enhance regulatory B cell activity, which suppresses inflammation. 1 Therefore, the compounds described herein are proposed to inhibit B cell-driven pathologies, including those due to deficiencies in regulatory B cell activity or pathology-driven B cell differentiation, including autoantibody and / or pathogenic antibody production, including, but not limited to, pemphigus foliaceus, pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid, epidermolysis bullosa acquisita, lupus erythematosus, dermatomyositis, myasthenia gravis, Goodpatcher's syndrome, and autoimmune thyroiditis.

[0108] Because AhR agonism inhibits the activation and migration of polymorphonuclear leukocytes, the compounds described herein are proposed to inhibit neutrophil disorders or diseases in which polymorphonuclear leukocytes contribute to the pathology, including, but not limited to, Sweet's syndrome, pustular psoriasis, pyoderma gangrenosum, pyoderma suppurativa, leukocytoclastic vasculitis, Wegener's granulomatosis, and neutrophilic dermatosis.

[0109] Ahr agonists have been demonstrated to promote long-term graft acceptance in vivo through a mechanism dependent on AHR signaling in dendritic cells / antigen-presenting cells and T cells. In vitro, AhR agonists inhibit the activation of monocyte-derived DCs (moDCs) / antigen-presenting cells, including the production of inflammatory cytokines such as IL-6 and the upregulation of costimulatory molecules. Therefore, the compounds described herein are proposed to inhibit inflammation and inflammatory diseases in which antigen-presenting cells stimulate immune responses. These diseases include, but are not limited to, inflammatory airway diseases, allergic rhinitis, autoimmune bullous diseases including pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid, inflammatory joint diseases including Schamberg's disease and other pigmented purpuric dermatoses (PPD), inflammatory joint diseases including lupus vulgaris, and allergic and autoimmune diseases including dermatomyositis.

[0110] Mast cells express AhR, and their activity and histamine release are inhibited by repeated stimulation of AhR6. Accordingly, the compounds described herein are proposed to inhibit mast cell activation disorders, including, but not limited to, mastocytosis, urticaria, rosacea, fibromyalgia, chronic pain syndromes, chronic pruritus, chronic itching, and allergic rhinitis.

[0111] AhR plays a normal physiological role in vascular growth and function. Studies have shown that inhibition of endothelial cell proliferation and stimulation of cancer cell death can lead to tumor growth inhibition. The compounds described herein are proposed to inhibit angiogenesis, which may lead to tumor growth inhibition. Thus, the compounds described herein are proposed to inhibit angiogenesis and the associated disorders of the stromal environment, vascular function, and atherosclerosis, as well as tumor growth, which may include both benign and malignant tumors.

[0112] AhR is a key regulator of innate lymphoid cells and is involved in the development and function of ILCs, particularly type 3 ILCs (iLCs), which are abundant in the gastrointestinal tract but relatively rare in other tissues. ILCs specifically respond to IL-23, IL-1β, IL-15, and IL-18. These cells are known to express the following effector molecules: IL-22, IFNγ, GM-CSF, and IL-17. ILCs are involved in the clearance of bacterial and fungal infections, the control of enteric viral infections, and the maintenance of microbiota homeostasis. ILCs have been shown to be involved in ILC-driven colitis, and disruption of iLC3 composition correlates with disease severity. The compounds described herein are proposed to inhibit diseases associated with dysregulation of ILCs in the intestine.

[0113] ILC2 cells are involved in asthma because they produce large amounts of IL-5 and IL-13. Studies have shown that ILC2s are increased in the airways of patients with severe asthma. Although the exact function of ILC2s remains unclear, several AhR ligands have been shown to suppress allergic airway inflammation in mouse models by suppressing the expression of type 2 cytokines (IL-4 and IL-5), eosinophilia, and specific IgE. The ILC2 population in the lungs is also capable of producing IL-17, and this specific subset may be involved in the pathogenesis of asthma.

[0114] AhR has been shown to promote the antitumor activity of NK cells, and although the exact function of AhR in ILC-mediated tumor immunology is still largely unknown, AhR agonism may promote the antitumor effects of ILCs and NK cells, and therefore, the compounds described herein are proposed to confer the antitumor effects of ILCs and NK cells.

[0115] AhR regulates macrophage function, is involved in the phagocytosis of apoptotic cells, and has been demonstrated to be a key regulator of macrophage responsiveness and homeostasis during inflammatory responses. Diseases to which AhR regulation of macrophages may contribute, and for which the compounds described herein are therefore proposed as therapeutic agents, include, but are not limited to, allergic and autoimmune diseases, including inflammatory airway diseases, allergic rhinitis, Schamberg's disease or other pigmented purpuric dermatoses (PPD), and inflammatory joint diseases.

[0116] Furthermore, interactions between these various immune cells contribute to the inflammatory cascade that leads to inflammation and autoimmune diseases. Thus, AhR agonism acts both on individual cell types and collectively through the interactions between these cells that promote inflammation. Therefore, the compounds described herein are proposed to further suppress inflammatory and autoimmune pathologies by acting not only on the cell-specific targets cited above, but also through the inflammatory network comprised of these cells.

[0117] Thus, the present invention provides a method for the treatment of a disorder associated with the above-mentioned diseases or disorders, comprising administering to a subject in need thereof at least one compound described in any embodiment herein, therefore in an effective amount.

[0118] In some embodiments, the present disclosure provides a method for preventing or treating an AhR-mediated disease, including administering to the subject an effective amount of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof; or a pharmaceutical composition according to any embodiment described herein. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0119] In some embodiments, the present invention is directed to a disease or condition that is associated with pemphigus foliaceus, pemphigus vulgaris, paraneoplastic pemphigoid, bullous pemphigoid, epidermolysis bullosa acquisita, lupus erythematosus, dermatomyositis, myasthenia gravis, Goodpatcher's syndrome, autoimmune thyroiditis; Sweet's syndrome, pustular psoriasis, pyoderma gangrenosum, hidradenitis suppurativa, leukocytoclastic vasculitis, Wegener's granulomatosis, neutrophilic dermatoses, allergic diseases, autoimmune diseases, inflammatory airway diseases, allergic rhinitis, autoimmune bullous diseases, pemphigus vulgaris and pemphigus foliaceus, bullous pemphigoid, inflammatory joint diseases, Schaumburg's disease or other pigmented purpuric dermatoses (P). PDs), lupus vulgaris, dermatomyositis; mastocytosis, urticaria, rosacea, fibromyalgia, chronic pain syndromes, chronic pruritus, chronic itch, allergic rhinitis; arteriosclerosis, benign tumor growth and malignant tumor growth; inflammatory airway disease, allergic rhinitis, Schamberg's disease or other pigmented purpuric dermatoses (PPDs), and inflammatory joint disease, comprising administering an effective amount of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any embodiment described herein.

[0120] Some embodiments describe a method for treating or preventing an AhR-mediated disease selected from pemphigus foliaceus, pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid, epidermolysis bullosa acquisita, lupus erythematosus, dermatomyositis, myasthenia gravis, and autoimmune thyroiditis, including Goodpadture syndrome, in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any of the embodiments described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0121] Some embodiments describe a method for treating or preventing an AhR-mediated disease selected from Sweet's syndrome, pustular psoriasis, pyoderma gangrenosum, hidradenitis pustularis, leukocytoclastic vasculitis, Wegener's granulomatosis, and neutrophilic dermatosis in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0122] Some embodiments describe a method for treating or preventing an AhR-mediated disease selected from allergic diseases, autoimmune diseases, inflammatory airway diseases, allergic rhinitis, autoimmune bullous diseases, pemphigus vulgaris and pemphigus foliaceus, bullous pemphigoid, Schamberg's disease or other pigmented purpuric dermatoses (PPD), inflammatory joint diseases, lupus vulgaris, and dermatomyositis in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any of the embodiments described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 23,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0123] Some embodiments describe a method for treating or preventing an AhR-mediated disease selected from mastocytosis, urticaria, rosacea, fibromyalgia, chronic pain syndrome, chronic pruritus, chronic pruritus, and allergic rhinitis in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0124] Some embodiments describe a method for treating or preventing an AhR-mediated disease selected from inflammatory airway disease, Schamberg's disease, pigmented purpuric dermatoses (PPDs), and inflammatory joint disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0125] Some embodiments describe a method for treating or preventing an AhR-mediated disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0126] Some embodiments describe a method for treating or preventing an AhR-mediated disease selected from inflammatory airway disease, allergic rhinitis, Schamberg's disease or other pigmented purpuric dermatoses (PPD), and inflammatory joint disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0127] Some embodiments describe methods for treating or preventing an AhR-mediated disease selected from skin inflammation, sumac contact dermatitis, eczema, chronic atopic dermatitis, acute flare-ups of atopic dermatitis, plaques of psoriasis vulgaris, mild to moderate psoriasis, palmoplantar pustulosis, erythematous papules and plaques, vesicles, exudates and crusts, sores and scales, acute radiation dermatitis, chronic radiation dermatitis, acute erythema, scabbing, desquamation, fibrosis, telangiectasia, morphea, skin atrophy, inflammatory mucosal conditions, inflammatory mucosal conditions caused by cancer radiotherapy or chemotherapy treatment, oral mucositis, mucositis induced by radiation therapy or chemotherapy treatment for head and neck cancer. The present invention relates to a method for treating oral mucositis, itching in atopic dermatitis, intense itching and / or constant itching, skin barrier dysfunction, skin barrier dysfunction, visible skin lesions, acute flare-ups, T cell-mediated hypersensitivity, contact hypersensitivity, delayed-type hypersensitivity, autoimmune alopecia, alopecia areata, utica, scleroderma, mycosis fungoides, chronic actinic dermatitis, acanthosis nigricans-induced by imiquimod, and inflammatory skin lesions in a subject in need thereof, by administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0128] Some embodiments describe a method for treating or preventing an AhR-mediated disease selected from clinical transplantation (such as organ transplant, acute transplant, xenograft, or allograft rejection; ischemia or reperfusion injury; ischemia or reperfusion injury occurring during organ transplantation, myocardial infarction, stroke, or other causes) in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0129] Some embodiments describe methods for treating or preventing diseases that exhibit an inflammatory component, diseases that are ameliorated by inhibition of IL-17A and IL-17F expression, respiratory allergies, hay fever, skin allergies, chronic obstructive pulmonary disease (COPD), multiple sclerosis, systemic sclerosis, inflammatory bowel disease, irritable bowel disease (IBD), immune system dysregulation, abnormal cellular infiltration, production of inflammatory mediators, delatinization, intestinal inflammation, Crohn's disease, ulcerative colitis, joint inflammation, and the like. In a subject in need of treatment for rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, gluten-sensitive enteropathy (celiac disease), Hashimoto's thyroiditis, Sjogren's syndrome, Guillain-Barré syndrome, Graves' disease, Addison's disease (an autoimmune disease of the adrenal gland), autoimmune polyarthritis (autoimmune polyarthritis syndrome), pernicious anemia, autoimmune hypopituitarism, glomerulonephritis, serum sickness, acute respiratory distress syndrome, acute inflammation, Behcet's disease, and Sézary syndrome, the method comprises administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0130] Some embodiments describe a method for treating or preventing an AhR-mediated disease selected from inflammatory eye disease, eye injury, age-related macular degeneration, neovascular (dry) age-related macular degeneration, neovascular (wet) age-related macular degeneration, Fuchs endothelial corneal dystrophy, and uveitis in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0131] Vitiligo is a depigmentation disorder caused by the selective destruction of melanocytes, where AhR mediates the link between solar UVB radiation and skin pigmentation. A reduced risk of vitiligo has been reported in association with specific mutations in the AhR gene. Researchers have also found that AhR mutations promote the transcriptional activity of Ahr and its interaction with the SP1 transcription factor, resulting in increased AhR expression and IL-10 production in humans.

[0132] Some embodiments of the present specification describe a method for treating or preventing vitiligo in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in combination with another therapeutic agent.

[0133] Some embodiments describe a method of treating such diseases in a subject in need thereof, comprising administering a therapeutically effective amount of 3,5-dihydroxy-4-isopropyl-trans-stilbene to the subject: [ka] or a pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical composition thereof.

[0134] The compounds according to any embodiment described herein may be used in a veterinary or medical setting. It is recognized that the subject or patient may be an animal, for example, a domestic animal such as a mammal, including a horse, cow, pig, sheep, poultry, fish, cat, dog, and zoo animal. In some embodiments, the subject is an animal

[0135] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the human is an adult or a pediatric patient. In some embodiments, the human is a pediatric patient. In some embodiments, the pediatric patient is a child. In some embodiments, the pediatric patient is between 3 months and 2 years of age or older. In some embodiments, the human is an adult.

[0136] Some embodiments describe a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in therapy. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0137] Some embodiments describe a compound according to any of the embodiments described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in treating or preventing AhR-mediated diseases. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0138] Some embodiments describe the use of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, in the manufacture of a medicament for treating an AhR-mediated disease in a subject in need thereof. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0139] Some embodiments describe the use of a compound according to any of the embodiments described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for the treatment or prevention of AhR-mediated diseases. In some embodiments, the compound is a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0140] For the pharmaceutical compositions and methods / uses described herein, the compound of any embodiment described herein may be administered in combination with one or more other therapies and / or active agents. In some embodiments, the compound of any embodiment described herein is administered in combination with a second agent indicated for a disorder or disease described herein, either concomitantly with, prior to, or after the administration of the second agent. In some embodiments, the second agent is in the same formulation as the compound according to any embodiment described herein. In some embodiments, the second agent is in a separate formulation. The second therapeutic agent may be administered by the same route as the compound according to any embodiment described herein, or by a different route than the compound according to any embodiment described herein. For example, the compound according to any embodiment described herein may be administered topically, and the second agent may be administered topically, orally, intravenously, intramuscularly, ophthalmically, intravaginally, intrarectally, etc. In some embodiments, the second agent is administered simultaneously with the compound of the invention. In some embodiments, the second agent is administered before the compound of the invention. In some embodiments, the second agent is administered after the compound of this invention.

[0141] In other words, compounds according to any embodiment described herein can be administered to the site of administration or desired site of action together, simultaneously, or sequentially in any order. The order of administration is not considered necessary. However, when administered locally, it may be preferable for two or more active agents to be in contact together at the site of administration or desired site of action at some point. Alternatively, it may be desirable for the time period for the appropriate mode of action of the active agent to be appropriately timed in the delivery time of the active agent. Having both in the same vehicle facilitates administration to the patient and may possibly improve compliance, but is not essential to the invention herein.

[0142] When a compound according to any embodiment described herein is administered in combination with one or more other therapeutic and / or active agents described herein, each of the active drug components (i.e., the compound of the invention and the second agent) is included in an effective dosage.

[0143] In some embodiments, the second agent is an agent for treating or preventing a condition associated with an imbalance in the AhR.

[0144] In some embodiments, the other agent(s) are useful for the prevention or treatment of allergic, inflammatory, or autoimmune diseases. In some embodiments, the agent(s) are antigen immunotherapeutics; antihistamines; corticosteroids such as fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, and flunisolide; NSAIDs; leukotriene modifiers such as montelukast, zafirlukast, and pranlukast; iNOS inhibitors; triptothecin-resistant steroids; tase inhibitors; IKK2 inhibitors; p38 inhibitors; Syk inhibitors; protease inhibitors; elastase inhibitors; integrin antagonists, e.g., β2 integrin antagonists; adenosine A2a agonists; mediator release inhibitors, e.g., sodium cromoglycate, 5-lipoxygenase inhibitors (Zyflo); DP1 antagonists; DP2 antagonists; PI3K delta inhibitors; ITK inhibitors; LP (lysophosphatidine) inhibitors; or FLAP (5-lipoxygenase inhibitors) oxigenase-activating protein) inhibitors, such as sodium 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate; bronchodilators, such as muscarinic antagonists and beta2 agonists; methotrexate and similar agents; monoclonal antibody therapies, such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapeutics, such as etanercept and similar agents; antigen-nonspecific immunotherapy, such as interferons and other cytokines / chemokines, chemokine receptor modulators such as CCR3, CCR4, CXCR2 antagonists, other cytokine / chemokine agonists or antagonists, TLR agonists and similar agents.

[0145] In some embodiments, the other agent(s) are agents to support transplantation, including cyclosporine, tacrolimus, mycophenolate mofetil, prednisone, azathioprine, sirolimus, daclizumab, basiliximab, or OKT3.

[0146] In some embodiments, the other agent(s) is an agent for treating diabetes, such as metformin (a biguanide), a meglitinide, a sulfonylurea, a DPP-4 inhibitor, a thiazolidinedione, or an α-glucosidase inhibitor, an amylin mimetic, an incretin mimetic, or insulin.

[0147] In some embodiments, the other agent is an antihypertensive agent such as a diuretic, an ACE inhibitor, an ARBS, a calcium channel blocker, or a beta blocker.

[0148] Thus, in a further aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound according to any embodiment described herein or a pharmaceutically acceptable derivative thereof; a second active agent; and, optionally, a pharmaceutically acceptable carrier.

[0149] It will be understood that if combined in the same formulation, the two or more compounds must be stable with each other and compatible with the other components of the formulation, and if formulated separately, may be provided in any convenient formulation, in such manner as is known for such compounds in the art.

[0150] Preservatives, stabilizers, dyes and flavorings can be provided in any pharmaceutical composition described herein.Examples of preservatives include sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid.Antioxidants and suspending agents can also be used.

[0151] For combinations including biologics such as monoclonal antibodies or fragments, suitable excipients are generally employed for parenteral administration, e.g., intravenous administration, to prevent aggregation and stabilize the antibody or fragment in a low-endotoxin solution. See, e.g., Formulation and Delivery Issues of Monoclonal Antibody Therapeutics, Daugherty et al., Current Trends in Monoclonal Antibody Development and Manufacturing, Part 4, 2010, Springer, New York, pp 103-129.

[0152] Route of Administration and Unit Dosage Form Compounds according to any embodiment described herein and pharmaceutical compositions incorporating said compounds can be conveniently administered by any route conventionally used for drug administration, such as, for example, oral, topical, transdermal, parenteral, or inhalation. The compounds can be administered in conventional dosage forms prepared by combining a compound according to any embodiment described herein with a standard pharmaceutical carrier according to conventional procedures. Compounds according to any embodiment described herein can also be administered in conventional dosage amounts in combination with a known second therapeutically active compound, as further described herein. These procedures can include mixing, granulating, and compressing or dissolving the ingredients as appropriate for the desired formulation. It will be understood that the form and characteristics of the pharmaceutically acceptable carrier or diluent are dictated by the amount of active ingredient with which it is combined, the route of administration, and other well-known variables. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0153] The compounds according to any embodiment described herein can be administered topically, i.e., non-systemically. This includes external application of the compound to the epidermis, buccal cavity, or injection of such compounds into the ear, eye, and nose, such that the compound does not significantly enter the bloodstream. Systemic administration, on the other hand, refers to oral, intravenous, intraperitoneal, or intramuscular administration.

[0154] Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as liniments, lotions, creams, gels, solutions, ointments, pastes, and drops suitable for administration to the skin, eye, ear, or nose.

[0155] Lotions according to the present invention include those suitable for application to the skin, ears, nose, or eyes. Eye lotions consist of a sterile aqueous solution, optionally containing a bactericide, and can be prepared in a manner similar to the preparation of eye drops. Lotions or liniments for application to the skin may also contain agents to hasten drying and cooling the skin, such as alcohol or acetone, and / or humectants such as glycerol, or oils such as castor oil or arachis oil.

[0156] Creams, gels, ointments, or pastes according to the present invention are semi-solid formulations of active ingredients for external application. They can be prepared by mixing the active ingredient (i.e., a compound according to any embodiment described herein) alone or in finely divided or powdered form in a solution or suspension in an aqueous or non-aqueous fluid with an oleaginous or non-oleaginous base using a suitable machine. The base can comprise hydrocarbons such as hard, soft, or liquid paraffin, glycerol, beeswax, or metal soaps; mucilage; naturally occurring oils such as almond oil, corn oil, arachis oil, castor oil, or olive oil; wool fat or its derivatives; or fatty acids such as steric or oleic acid, together with alcohols such as propylene glycol or macrogels. The formulations can incorporate any suitable surface-active agent, such as anionic, cationic, or nonionic surfactants, such as sorbitan esters or their polyoxyethylene derivatives. Other ingredients, such as suspending agents, such as natural gums, cellulose derivatives, inorganic materials such as silicate silica, and lanolin, can also be incorporated.

[0157] Drops according to the present invention consist of sterile aqueous or oily solutions or suspensions, prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericide and / or fungicide and / or any other suitable preservative, preferably including a surfactant. The resulting solution can then be clarified by filtration, transferred to a suitable container, sealed, and sterilized by autoclaving or maintaining at 98-100°C for 30 minutes. Alternatively, the solution can be sterilized by filtration and transferred to a container using an aseptic technique. Examples of bactericides and fungicides suitable for incorporation into eye drops include phenyl nitrate or phenyl acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate (0.01%). Suitable solvents for preparing oily solutions include glycerol, diluted alcohol, and propylene glycol.

[0158] In some embodiments, a compound according to any embodiment described herein is administered topically as a cream, gel ointment, paste, drop, or lotion. In some embodiments, a compound according to any embodiment described herein is administered as a gel or cream. In some embodiments, a compound according to any embodiment described herein is administered as a gel. In some embodiments, a compound according to any embodiment described herein is administered as a cream.

[0159] In some embodiments, the pharmaceutical formulation comprises a compound according to any embodiment described herein, a pharmaceutically acceptable excipient or diluent, and an antioxidant, a preservative, a gelling agent, a pH adjuster, or a stabilizer, or a mixture thereof, suitable for topical administration to the skin, eye, or ear of a patient.

[0160] In some embodiments, the composition is a cream or gel composition and the compound of Formula (I) is 3,5-dihydroxy-4-isopropyl-trans-stilbene.

[0161] In some embodiments, the composition is a cream formulation. In some embodiments, the composition is a cream formulation 1 comprising: [Table 1]

[0162] It will be understood that when 3,5-dihydroxy-4-isopropyl-trans-stilbene in Cream Formulation 1 is present at a specific concentration (ranging from 0 to 1%), the formulation may be referred to as X% Cream Formulation 1. For example, in some embodiments, the composition is Cream Formulation 1, which includes 1% 3,5-dihydroxy-4-isopropyl-trans-stilbene (1% Cream Formulation 1). Thus, 1% Cream Formulation 1 consists of: [Table 2]

[0163] In some embodiments, the composition is a 0.5% cream formulation 1 comprising: [Table 3]

[0164] In some embodiments, the composition is a 0.1% cream formulation 1 comprising: [Table 4]

[0165] In some embodiments, the composition is a cream formulation 2 comprising: [Table 5]

[0166] In some embodiments, the composition is a cream formulation 3 comprising: [Table 6]

[0167] In some embodiments, the composition is a 1% cream formulation 3 comprising: [Table 7]

[0168] In some embodiments, the composition is a 0.5% cream formulation 3 comprising: [Table 8]

[0169] In some embodiments, the composition is a cream formulation 4 comprising: [Table 9]

[0170] In some embodiments, the composition is a cream formulation 5 comprising: [Table 10]

[0171] In some embodiments, the composition is a cream formulation 6 comprising: [Table 11]

[0172] In some embodiments, the composition is a cream formulation 7 comprising: [Table 12]

[0173] In some embodiments, the composition is a gel formulation (Gel Formulation 1) comprising: [Table 13] .

[0174] In some embodiments, the composition is a gel formulation (1% Gel Formulation 1) comprising: [Table 14]

[0175] In some embodiments, the composition is a gel formulation (Gel Formulation 2) comprising: [Table 15]

[0176] In some embodiments, the composition is a gel formulation (Gel Formulation 3) comprising: [Table 16]

[0177] In some embodiments, the composition is a gel formulation (Gel Formulation 4) comprising: [Table 17]

[0178] In some embodiments, the composition is formulation 17, formulation 21, formulation 22, formulation 23, formulation 24, formulation 25, formulation 26, formulation 27, formulation 28, and / or formulation 29, as shown in the table below. [Table 18]

[0179] Although topical administration is the preferred route of administration, the compounds according to any embodiment described herein can also be administered parenterally, i.e., intravenously, intramuscularly, subcutaneously, intranasally, rectally, intravaginally, or intraperitoneally. For parenteral administration, subcutaneous and intramuscular administration are generally preferred. Suitable dosage forms for such administration can be prepared by conventional techniques. The compounds according to any embodiment described herein can also be administered by inhalation, i.e., intranasally and oral inhalation. Suitable dosage forms for such administration, such as aerosol formulations or metered-dose inhalers, can be prepared by conventional techniques.

[0180] The dosage of the compound according to any embodiment described herein as the active ingredient of the present invention can be varied to obtain a suitable dosage form.The active ingredient can be administered to subjects (animals and humans) in need of such treatment at a dosage that provides optimal pharmaceutical efficacy.The selected dosage depends on the desired therapeutic effect, the administration route, and the duration of treatment.The dosage will vary from patient to patient depending on the nature and severity of the disease, the patient's weight, the special diet the patient is currently following, concurrent medications, and other factors recognized by those skilled in the art.

[0181] In some embodiments, the amount of compound administered can range from about 0.1 to about 100 mg / kg / day. Generally, a dosage of between 0.1 and 10 mg / kg of body weight per day is administered to a patient, e.g., a human. In some embodiments, a therapeutically effective amount is, with the lower limit being about 0.1 mg / kg body weight, about 0.2 mg / kg body weight, about 0.3 mg / kg body weight, about 0.4 mg / kg body weight, about 0.5 mg / kg body weight, about 0.6 mg / kg body weight, about 0.7 mg / kg body weight, about 0.8 mg / kg body weight, about 0.9 mg / kg body weight, about 1 mg / kg body weight, about 5 mg / kg body weight, about 10 mg / kg body weight, about 15 mg / kg body weight, about 20mg / kg body weight, approximately 25mg / kg body weight, approximately 30mg / kg body weight, approximately 35mg / kg body weight, approximately 40mg / kg body weight, approximately 45mg / kg body weight, approximately 50mg / kg body weight, approximately 55mg / kg body weight, approximately 60mg / kg body weight, approximately 65mg / kg body weight, approximately 70mg / kg body weight, approximately 75mg / kg body weight, approximately 80mg / kg body weight, approximately 85mg / kg body weight, approximately 80mg / kg body weight, approximately 95mg / kg body weight, approximately 100mg / kg; and upper limit 100mg / kg body weight, about 95mg / kg body weight, about 90mg / kg body weight, about 85mg / kg body weight, about 80mg / kg body weight, about 75mg / kg body weight, about 70mg / kg body weight, about 65mg / kg body weight, about 60mg / kg body weight, about 55mg / kg body weight, 50mg / kg body weight, about 45mg / kg body weight, about 40mg / kg body weight, about 35mg / kg body weight, about 30mg / kg body weight, About 25 mg / kg of body weight, about 20 mg / kg of body weight, about 15 mg / kg of body weight, about 10 mg / kg of body weight, about 5 mg / kg of body weight, about 1 mg / kg of body weight, about 0.9 mg / kg of body weight, about 0.8 mg / kg of body weight, about 0.7 mg / kg of body weight, about 0.6 mg / kg of body weight, about 0.5 mg / kg of body weight, about 0.4 mg / kg of body weight, about 0.3 mg / kg of body weight, about 0.2 mg / kg of body weight, and about 0.1 mg / kg of body weight / day.

[0182] In some embodiments, a compound according to any embodiment described herein is administered to a subject at a total daily dose of about 0.01 to about 1000 mg / day. In some embodiments, the total daily dose is about 0.1 to about 100 mg / day. In some embodiments, the total daily dose is about 0.01 mg / day, about 0.05 mg / day, about 0.1 mg / day, about 0.5 mg / day, about 1 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 170 mg / day, about 180 mg / day, about 190 mg / day, about 210 mg / day, about 220 mg / day, about 230 mg / day, about 240 mg / day, about 250 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 290 mg / day, about 300 mg / day, about 310 mg / day, about 320 mg / day, about 330 mg / day, about 340 mg / day, about 350 mg / day, about 360 mg / day, about 370 mg / day, about 380 mg / day, about 390 mg / day, about 400 mg / day, about 410 mg / day, about 420 mg / day, about 430 mg / day, about 440 mg / day, about 450 mg / day, about 460 mg 90mg / day, about 200mg / day, about 210mg / day, about 220mg / day, about 230mg / day, about 240mg / day, about 250mg / day, about 260mg / day, about 270mg / day, about 280mg / day, about 290mg / day, about 300mg / day, about 310 mg / day, about 320 mg / day, about 330 mg / day, about 340 mg / day, about 350 mg / day, about 360 mg / day, about 370 mg / day, about 380 mg / day, about 390 mg / day, about 400 mg / day, about 410 mg / day, about 420 mg / day, about 430 mg / day daily, approximately 440mg / day, approximately 450mg / day, approximately 460mg / day, approximately 470mg / day, approximately 480mg / day, approximately 490mg / day, approximately 500mg / day, approximately 510mg / day, approximately 520mg / day, approximately 530mg / day, approximately 540mg / day, approximately 550mg / day, approximately 560mg / day, approximately 570mg / day, approximately 580mg / day, approximately 590mg / day, approximately 600mg / day, approximately 610mg / day, approximately 620mg / day, approximately 630mg / day, approximately 640mg / day, approximately 650mg / day, approximately 660mg / day, approximately 670mg / day, approximately 68 0mg / day, approximately 690mg / day, approximately 700mg / day, approximately 710mg / day, approximately 720mg / day, approximately 730mg / day, approximately 740mg / day, approximately 750mg / day, approximately 760mg / day, approximately 770mg / day, approximately 780mg / day, approximately 790mg / day, approximately 800mg / day, approximately 810mg / day, approximately 820mg / day, approximately 830mg / day, approximately 840mg / day, approximately 850mg / day, approximately 860mg / day, approximately 870mg / day, approximately 880mg / day, approximately 890mg / day, approximately 900mg / day, approximately 910mg / day, approximately 920mg / day,Approximately 930 mg / day, approximately 940 mg / day, approximately 950 mg / day, approximately 960 mg / day, approximately 970 mg / day, approximately 980 mg / day, approximately 990 mg / day, approximately 1000 mg / day, and upper limit of 1000 mg / day, approximately 990 mg / day, approximately 980 mg / day, approximately 970 mg / day, approximately 960 mg / day, approximately 950 mg / day, approximately 940 mg / day, approximately 930 mg / day, approximately 920 mg / day, approximately 910 mg / day, approximately 900 mg / day, approximately 890 mg / day, approximately 880 mg / day, approximately 870 mg / day, approximately 860 mg / day, approximately 850 mg / day, approximately 840 mg / day, approximately 830 mg / day, approximately 820 mg / day, approximately 810mg / day, approximately 800mg / day, approximately 790mg / day, approximately 780mg / day, approximately 770mg / day, approximately 760mg / day, approximately 750mg / day, approximately 740mg / day, approximately 730mg / day, approximately 720mg / day, approximately 710mg / day, approximately 700mg / day, approximately 690mg / day, approximately 680mg / day, approximately 670mg / day, approximately 660mg / day, approximately 650mg / day, approximately 640mg / day, approximately 630mg / day, approximately 620mg / day, approximately 610mg / day, approximately 600mg / day, approximately 590mg / day, approximately 580mg / day, approximately 570mg / day, approximately 560mg / day, approximately 550mg / day, approximately 540mg / day , about 530mg / day, about 520mg / day, about 510mg / day, about 500mg / day, about 490mg / day, about 480mg / day, about 470mg / day, about 460mg / day, about 450mg / day, about 440mg / day, about 430mg / day, about 420mg / day, about 410mg / day, about 400mg / day, about 390mg / day, about 380mg / day, about 370mg / day, about 360mg / day, about 350mg / day, about 340mg / day, about 330mg / day, about 320mg / day, about 310mg / day, about 300mg / day, about 290mg / day, about 280mg / day, about 270mg / day, about 260mg g / day, about 250 mg / day, about 240 mg / day, about 230 mg / day, about 220 mg / day, about 210 mg / day, about 200 mg / day, about 190 mg / day, about 180 mg / day, about 170 mg / day, about 160 mg / day, about 150 mg / day, about 140 mg / day, about 130 mg / day, about 120 mg / day, about 110 mg / day, about 100 mg / day, about 90 mg / day, about 80 mg / day, about 70 mg / day, about 60 mg / day, about 50 mg / day, about 40 mg / day, about 30 mg / day, about 10 mg / day, about 1 mg / day, about 0.5 mg / day, about 0.1 mg / day, about 0.01 mg / day.

[0183] It will be understood that the pharmaceutical composition of the present disclosure does not necessarily contain the entire amount of the compound effective for treating the disorder, since such an effective amount can be achieved by administering multiple divided doses of such pharmaceutical composition. The compound may be administered in a single dose per day, or in a regimen of multiple small doses (e.g., two, three, four, five, or more) per day so that the total daily dose is the same. The effective amount of the salt can be determined as a percentage of the effective amount of the compound according to any embodiment described herein. Similar dosage amounts should be appropriate for treating other conditions referred to herein for treatment. In general, the determination of the appropriate dosage can be easily achieved by those skilled in the art of medicine or pharmacy.

[0184] The active ingredient, i.e., a compound according to any embodiment described herein, may be for topical administration, being administered in about 0.001% w / w to about 10% w / w of the topical formulation. In some embodiments, the compound according to any embodiment described herein is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w / w of the topical formulation. In some embodiments, the compound according to any embodiment described herein is 1% to 2% w / w of the formulation. The daily topical dosage regimen can be from about 0.1 mg to 150 mg of a compound according to any embodiment described herein, administered one to four times per day.In some embodiments, the daily topical dosage is 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 1mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg , 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115 The initial dosage may be 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, or 150 mg. The initial dosage may also be estimated from in vivo data using animal models. Animal models useful for testing the efficacy of compounds for treating or preventing the above-mentioned various diseases are well known in the art.Administration of the compounds can be once per week, several times per week (eg, every other day), once per day, or multiple times per day, at the discretion of the prescribing physician.

[0185] It will also be recognized by those skilled in the art that the optimal amount and interval of individual doses of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, will be determined by the nature and extent of the condition being treated, the form, route, and site of administration, and the patient being treated, and that such optimal values ​​can be determined by conventional techniques. It will also be recognized by those skilled in the art that the optimal course of treatment, i.e., the number of doses of a compound according to any embodiment described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, administered per day for a defined number of days, can be ascertained by those skilled in the art using conventional course-of-treatment determination tests.

[0186] The compounds described herein can be prepared by the processes disclosed in U.S. Pat. No. 11,267,788 and International Publication No. WO2022 / 015423.

[0187] Appropriate amounts in any embodiment will be readily apparent to one skilled in the art or can be determined by routine experimentation. The compositions are generally applied topically to the affected area, i.e., to the area of ​​skin where a clinical abnormality is manifest.

[0188] Unless otherwise noted, all percentages are based on weight percent of the final composition prepared, and all totals equal 100 weight percent.

[0189] All publications cited in this specification, including but not limited to patents and patent applications, are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference herein to the same extent as if fully set forth.

[0190] The foregoing description fully discloses the present invention, including preferred embodiments thereof. Modifications and improvements to the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the examples herein are to be construed as merely illustrative and not as limiting the scope of the present invention in any way. Embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

Claims

1. A pharmaceutical composition for use in treating a disease, comprising formula (I), formula (II), formula (III), or formula (IV) 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by , or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the disease is selected from the group consisting of pemphigus foliaceus, pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid, acquired epidermolysis bullosa, lupus erythematosus, dermatomyositis, myasthenia gravis, Goodpatcher syndrome, and autoimmune thyroiditis.

2. A pharmaceutical composition for use in treating a disease, comprising formula (I), formula (II), formula (III), or formula (IV) 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by , or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the disease is selected from the group consisting of Sweet's syndrome, pustular psoriasis, pyoderma gangrenosum, hidradenitis suppurativa, leukocytoclastic vasculitis, Wegener's granulomatosis, and neutrophilic dermatosis.

3. A pharmaceutical composition for use in treating a disease, comprising formula (I), formula (II), formula (III), or formula (IV) 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by , or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the disease is selected from the group consisting of allergic diseases, autoimmune diseases, inflammatory airway diseases, allergic rhinitis, autoimmune bullous diseases, pemphigus vulgaris and pemphigus foliaceus, bullous pemphigoid, inflammatory joint diseases, Schamberg's disease, pigmented purpura dermatosis (PPDs), lupus vulgaris, and dermatomyositis.

4. A pharmaceutical composition for use in treating a disease, comprising formula (I), formula (II), formula (III), or formula (IV) 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by , or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the disease is selected from the group consisting of mastocytosis, urticaria, rosacea, fibromyalgia, chronic pain syndrome, chronic pruritus, chronic itching, and allergic rhinitis.

5. A pharmaceutical composition for use in treating a disease, comprising formula (I), formula (II), formula (III), or formula (IV) 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by , or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the disease is selected from the group consisting of arteriosclerosis, benign tumor growth, and malignant tumor growth.

6. A pharmaceutical composition for use in treating a disease, comprising formula (I), formula (II), formula (III), or formula (IV) 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by , or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the disease is an inflammatory joint disease.

7. A pharmaceutical composition for use in treating a disease, comprising formula (I), formula (II), formula (III), or formula (IV) 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 A pharmaceutical composition comprising a therapeutically effective amount of a compound represented by , or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the disease is vitiligo.

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the compound is 3,5-dihydroxy-4-isopropyl-trans-stilbene represented by the following formula 【Chemistry 29】 A pharmaceutical composition.

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