WO2024092047A1 - Administration of pyrrolopyrimidine-based kinase inhibitors for treatment of psoriasis - Google Patents

Abstract

Provided herein, inter alia, is a method for treating psoriasis comprising administering an effective amount of pyrrolopyrimidine-based kinase inhibitor of Formula (I).

Description

Attorney Docket No.01223-0128-00PCT ADMINISTRATION OF PYRROLOPYRIMIDINE-BASED KINASE INHIBITORS FOR TREATMENT OF PSORIASIS This application claims the benefit of priority under 35 U.S.C. §119 to U.S. provisional application No.63/419,479, filed October 26, 2022, the entire contents of which are incorporated by reference in its entirety. Throughout this application various publications, patents, and/or patent applications are referenced. The disclosures of the publications, patents and/or patent applications are hereby incorporated by reference in their entireties into this application in order to more fully describe the state of the art to which this disclosure pertains. TECHNICAL FIELD The present disclosure provides a method for treating psoriasis comprising administering an effective amount of pyrrolopyrimidine-based kinase inhibitor. BACKGROUND Certain pyrrolopyrimidine compounds are modulators of protein kinases and are therefore useful in protein kinase-mediated diseases, including cancer and chronic inflammation (International Publication Nos. WO2014025486, WO2017059702, and WO2018184206). Abivertinib is a pyrrolopyrimidine-based irreversible tyrosine kinase inhibitor (TKI) that inhibits the epidermal growth factor receptor (EGFR), Bruton’s tyrosine kinase (BTK) and Janus kinase (JAK) as shown in International Publication Nos. WO2014025486, WO2017059702, and WO2018184206, which are incorporated herein by reference in their entireties. O NH N F O N N N ^{N N} H _H Abivertinib Attorney Docket No.01223-0128-00PCT Tyrosine kinases are intracellular enzymes mediating tyrosine phosphorylation of downstream molecules. They play a critical role in signal transduction by various cell surface receptors including, among others, growth factor receptors, adhesion receptors, immunoreceptors, and cytokine receptors. Non-receptor tyrosine kinases are intracellular tyrosine kinases without a direct role in sensing extracellular cues. Nevertheless, these tyrosine kinases are often coupled to various cell surface receptors and are intimately involved in the transmission of extracellular signals to downstream intracellular signaling pathways and cellular effector functions. Non-receptor tyrosine kinases of the JAK, SRC, SYK, and BTK families play major roles in various immune-mediated disorders (Szilveszter K. et al. (2019) Front. Immunol. 10:art1862; Morris R. et al. (2018) Protein Science 27:1984-2009; Neys S. et al. (2021) Front. Cell Dev. Biol.9:art668131). Autoimmune and inflammatory skin diseases represent a broad spectrum of immune-mediated diseases. One example of such skin disease is psoriasis. Psoriasis is a chronic relapsing disease of the skin characterized by variable clinical features. Psoriasis is characterized by discrete areas of skin inflammation with redness, thickening, intense scaling, and in some cases, itching. There are seven general forms of psoriasis, namely: plaque, guttate, inverse, pustular, erythrodermic, scalp, and nail. Plaque (also called plaque-type or chronic plaque) psoriasis, which presents with erythrosquamous plaques, is the most frequent clinical presentation and, therefore, also called psoriasis vulgaris. While the pathogenesis of psoriasis has not yet been fully elucidated, accumulating evidence indicates that psoriasis is a multi-factorial disorder caused by the concerted action of multiple disease genes in a single individual, triggered by environmental factors, furthermore, epidermal changes occur as a secondary response to cellular immune infiltrates in the skin. It has been speculated that psoriasis could be due to the effects of a chronic inflammatory condition. Regardless of the origin, once psoriasis has appeared as a localized disease, it persists throughout life, manifesting at often unpredictable intervals. The disease has a significant impact on the quality of life of affected individuals, both physically and psychologically. There is no known cure for psoriasis. Treatments for psoriasis are typically divided into three main types: topical treatments, light therapy and/or oral medications. Topical treatments include, for example, corticosteroids, vitamin D analogues, anthralin, retinoids, calcineurin inhibitors, salicylic acid, coal tar, and moisturizers. Light therapy or treatments include, for example, sunlight, UVB phototherapy, narrowband UVB therapy, Attorney Docket No.01223-0128-00PCT photochemotherapy, or psoralen plus ultraviolet A (PUVA), and excimer laser. Oral medications include, for example, retinoids, methotrexate, cyclosporine, hydroxyurea, immunomodulator drugs (biologics) (McClure et al. (2001) Drug Safety 25:913-27; Ferrandiz et al. (2010) Clinics in Dermatology 28:81-87; Sullivan and Preda (2009) Aust. Prescr.32:14-18; Korkina et al. (2010) Drugs of Today 46:119-36). Unfortunately, none of the above-identified treatments provide sufficient therapeutic relief from the debilitating effects of psoriasis without material drawbacks. Accordingly, there is a need in the art for improved treatment of psoriasis, that is safe and well tolerated. SUMMARY The present disclosure aims to meet this need and/or provide other benefits. Provided herein are methods of administering a compound of Formula (I) for treatment of psoriasis to a subject in need thereof. Additionally, provided herein are methods of administering abivertinib for treatment of psoriasis to a subject in need thereof. In an aspect, provided herein is a method for treating psoriasis, comprising administering to a subject in need of treatment of psoriasis, a therapeutically effective amount of a compound of Formula (I): R¹ O , or a stereoisomer,

or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: R¹ and R² are each independently hydrogen, halo, C1-6 alkyl, or C1-6 haloalkyl; Attorney Docket No.01223-0128-00PCT each R³ is independently hydrogen, halo, hydroxyl, C1-6 alkyl, C1-6 alkoxy, cyano, or nitro; R⁴ is hydrogen or C1-6 alkyl; and n is an integer from 0 to 4. In an aspect, provided herein is a composition comprising a therapeutically effective amount of a compound of Formula (I) for use in a method of treating psoriasis, the method comprising administering the compound of Formula (I): R¹ O , or a stereoisomer, or isotopic

variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: R¹ and R² are each independently hydrogen, halo, C1-6 alkyl, or C1-6 haloalkyl; each R³ is independently hydrogen, halo, hydroxyl, C1-6 alkyl, C1-6 alkoxy, cyano, or nitro; R⁴ is hydrogen or C_1-6 alkyl; and n is an integer from 0 to 4; to a subject in need of treatment of psoriasis. In embodiments, the compound of Formula (I) is abivertinib: O NH N F O N N N N ^N H _H Abivertinib, Attorney Docket No.01223-0128-00PCT or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In embodiments, a dose of 5 mg/kg to 10 mg/kg, or 10 mg/kg to 15 mg/kg, or 15 mg/kg to 20 mg/kg, or 20 mg/kg to 25 mg/kg, or 25 mg/kg to 30 mg/kg, or 30 mg/kg to 35 mg/kg, or 35 mg/kg to 40 mg/kg, or 40 mg/kg to 45 mg/kg, or 45 mg/kg to 50 mg/kg, or 50 mg/kg to 55 mg/kg, or 55 mg/kg to 60 mg/kg, or 60 mg/kg to 65 mg/kg, or 65 mg/kg to 70 mg/kg, or 70 mg/kg to 75 mg/kg, or 75 mg/kg to 80 mg/kg, or 80 mg/kg to 85 mg/kg, or 85 mg/kg to 90 mg/kg, or 90 mg/kg to 100 mg/kg, or 100 mg/kg to 110 mg/kg of a compound of Formula (I), such as abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered. In embodiments, a compound of Formula (I), such as abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a dose of about 25 mg/kg. In embodiments, a compound of Formula (I), such as abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a dose of about 50 mg/kg. In embodiments, a compound of Formula (I), such as abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a dose of about 100 mg/kg. In embodiments, a compound of Formula (I), such as abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in one dose. In embodiments, a compound of Formula (I), such as abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in repeated doses. In embodiments, a compound of Formula (I), such as abivertinib, or a stereoisomer, enantiomer, Attorney Docket No.01223-0128-00PCT mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered daily. In embodiments, administration is topical, parenteral, or oral administration. In embodiments, the subject is a mammal. In embodiments, the mammal is human. In embodiments, the psoriasis is plaque psoriasis. In embodiments, the method comprises administering a pharmaceutical composition comprising the compound of Formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable carrier. In embodiments, the method comprises administering a pharmaceutical composition comprising the abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable carrier. In embodiments, the pharmaceutical composition is in an oral dosage form. In embodiments, the oral dosage form is a tablet, capsule, solution, or suspension. In embodiments, the pharmaceutical composition is administered topically. In embodiments, the pharmaceutical composition further comprises a second therapeutic agent. FIGURES FIG.1A shows skin images of IMQ induced psoriasis mouse model compared to a control (Vaseline). FIGs.1B-1D show changes in body weight (FIG.1B), skin thickness (FIG.1C), and PASI score (FIG.1D) of mice following IMQ induced psoriasis. The bars through each data point represent the standard deviation in measurement. T-test: *) P<0.05, **) P<0.01, ***) P<0.001. FIG.1E shows the Psoriasis scoring system for erythema, skin thickness and scaling. FIG.2A shows skin images of mice (with IMQ induced psoriasis) following topical treatments with tofacitinib (JAK inhibitor), ibrutinib (BTK inhibitor), or vehicle. FIGs.2B-2D show changes in body weight (FIG.2B), skin thickness (FIG.2C), and PASI score (FIG.2D) of mice (with IMQ induced psoriasis) following topical treatments Attorney Docket No.01223-0128-00PCT with tofacitinib (JAK inhibitor), ibrutinib (BTK inhibitor), or vehicle. The bars through each data point represent the standard deviation in measurement. T-test: *) P<0.05, **) P<0.01, ***) P<0.001. FIG.3 shows images of Western blot illustrating JAK inhibition by abivertinib, tofacitinib, and ibrutinib in human T cells and mouse T cells. FIG.4A shows skin images of mice (with IMQ induced psoriasis) following treatments with abivertinib, dexamethasone (positive control), or vehicle (CMC sodium; negative control). FIGS.4B-F show changes in various skin parameters of mice (with IMQ induced psoriasis) whose skin images are shown in FIG.4A. Skin thickness (FIG.4B), erythema score (FIG.4C), thickness score (FIG.4D), scaling score (FIG.4E), and PASI cumulative score (FIG.4F). The bars through each data point represent the standard deviation in measurement. T- test: *) P<0.05, **) P<0.01, ***) P<0.001. FIG.5 shows a schematic representation of normal skin and psoriasis afflicted skin. FIG.6 shows skin histopathologies of mice: normal skin vs. skin of mice, with IMQ induced psoriasis, following treatment with abivertinib, dexamethasone (positive control) or vehicle (CMC sodium; negative control). DETAILED DESCRIPTION Definitions Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying drawings. While the invention will be described in conjunction with the illustrated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the invention as defined by the appended claims. Before describing the present teachings in detail, it is to be understood that the disclosure is not limited to specific compositions or process steps, as such may vary. It should be noted that, as used in this specification and the appended claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, Attorney Docket No.01223-0128-00PCT reference to “a conjugate” includes a plurality of conjugates and reference to “a cell” includes a plurality of cells and the like. It is understood the use of the alternative (e.g., “or”) herein is taken to mean either one or both or any combination thereof of the alternatives. The term “and/or” used herein is to be taken to mean specific disclosure of each of the specified features or components with or without the other. For example, the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). As used herein, terms “mcg”, “µg”, and “ug” are interchangeable and refer to micrograms. As used herein, the term “about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, “about” or “approximately” can mean within one or more than one standard deviation per the practice in the art. Alternatively, “about” or “approximately” can mean a range of up to 10% (i.e., ±10%) or more depending on the limitations of the measurement system. For example, about 5 mg can include any number between 4.5 mg and 5.5 mg. Furthermore, particularly with respect to biological systems or processes, the terms can mean up to an order of magnitude or up to 5-fold of a value. When particular values or compositions are provided in the instant disclosure, unless otherwise stated, the meaning of “about” or “approximately” should be assumed to be within an acceptable error range for that particular value or composition. In embodiments, “about” encompasses variation within 10%, 5%, 2%, 1%, or 0.5% of a stated value. Numeric ranges are inclusive of the numbers defining the range. Measured and measurable values are understood to be approximate, taking into account significant digits and the error associated with the measurement. Also, all ranges are to be interpreted as encompassing the endpoints in the absence of express exclusions such as “not including the endpoints”; thus, for example, “ranging from 1 to 10” includes the values 1 and 10 and all integer and (where appropriate) non-integer values greater than 1 and less than 10. Attorney Docket No.01223-0128-00PCT As used herein, terms “comprise”, “comprises”, “comprising”, “having”, “contain”, “contains”, “containing”, “include”, “includes”, and “including” are not intended to be limiting. It is to be understood that both the foregoing general description and detailed description are exemplary and explanatory only and are not restrictive of the teachings. Unless specifically noted in the above specification, embodiments in the specification that recite “comprising” various components are also contemplated as “consisting of” or “consisting essentially of” the recited components; embodiments in the specification that recite “consisting of” various components are also contemplated as “comprising” or “consisting essentially of” the recited components; and embodiments in the specification that recite “consisting essentially of” various components are also contemplated as “consisting of” or “comprising” the recited components (this interchangeability does not apply to the use of these terms in the claims). As used herein, “imiquimod (IMQ)-induced psoriasis model” refers to the use of imiquimod to produce a cutaneous phenotype in mice frequently studied as an acute model of human psoriasis. IMQ-induced mouse model is widely used as a pre-clinical animal model for drug screening and testing before clinical testing on psoriatic patients. In vivo evaluation of parameters including body weight, skin thickness, skin scaling, and erythema (skin redness). The combination of (subjective) scores for skin thickness, scaling and redness, performed visually or with calipers, provides the PASI score, which is used to measure the severity of psoriasis. Ex vivo evaluation of parameters including thickness of epidermis, dermis, and dermis infiltration, is performed using histology. “Imiquimod” (IMQ) is a toll-like receptor (TLR7) agonist that can be applied to mouse skin to elicit erythema, scaling, epidermis hyperplasia, hyperkeratosis, parakeratosis and dermis inflammation. IMQ also induces IL-17/IL-23 axis cytokines. The terms “treating”, or “treatment” refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term "treating" and conjugations Attorney Docket No.01223-0128-00PCT thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing. “Treating” or “treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms; fully or partially remove the disease’s underlying cause; shorten a disease’s duration; or do a combination of these things. "Treating" and "treatment" as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient. In embodiments, the treating or treatment is not prophylactic treatment. An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a Attorney Docket No.01223-0128-00PCT “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of a compound required to decrease the activity of an enzyme relative to the absence of the compound. A “function disrupting amount,” as used herein, refers to the amount of a compound required to disrupt the function of an enzyme or protein relative to the absence of the compound. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. In one embodiment, a therapeutically effective amount will depend on certain aspects of the subject to be treated and the disorder to be treated and may be ascertained by one skilled in the art using known techniques. In addition, as is known in the art, adjustments Attorney Docket No.01223-0128-00PCT for body weight, general health, time of administration, drug interaction, and the severity of the disease may be necessary. The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least about 5%, about 10%, about 15%, about 20%, about 25%, about 40%, about 50%, about 60%, about 75%, about 80%, about 90%, or at least about 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least about a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure, should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state. As used herein, the term "administering" means oral administration, administration as a suppository, topical route (or administration), intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. In embodiments, the administering does not include administration of any active agent other than the recited active agent. Exemplary routes of administration for the formulations disclosed herein include a non- Attorney Docket No.01223-0128-00PCT parenteral route (i.e., local), e.g., topical or epidermal route of administration. In one embodiment, the formulation is administered topically to the skin (affected by psoriasis) in the form of solution, suspension, cream, lotion, gel, paste, spray, powder, or ointment. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. “Patient” or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a subject is human. The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Attorney Docket No.01223-0128-00PCT Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art. The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent. Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, Attorney Docket No.01223-0128-00PCT salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethyl cellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure. The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers. An “alkoxy” is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds. The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, and stereoisometric forms that may be defined, in terms of absolute Attorney Docket No.01223-0128-00PCT stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure. The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. Attorney Docket No.01223-0128-00PCT Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. The section headings used herein are for organizational purposes only and are not to be construed as limiting the desired subject matter in any way. In the event that any literature incorporated by reference contradicts any term defined in this specification, this specification controls. While the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. Overview Abivertinib is a pyrrolopyrimidine-based irreversible tyrosine kinase inhibitor (TKI) that inhibits the epidermal growth factor receptor (EGFR), Bruton’s tyrosine kinase (BTK) and Janus kinase (JAK) (PCT Publication Nos. WO2014/025486, WO 2017/059702, and WO 2018184206, which are incorporated herein by reference in their entireties). O

Abivertinib Dysregulation of the JAK-STAT signaling pathway has been implicated in the pathogenesis of autoimmune diseases, inflammatory diseases, and cancer (Benci J.L. et al. (2016) Cell 167:1540-1554). JAK inhibitors inhibit the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT Attorney Docket No.01223-0128-00PCT signaling pathway in lymphocytes. JAK inhibitors block the cytokine receptors, thus preventing phosphorylation of these receptors, which in turn prevents recruitment and phosphorylation of the STAT transcription factors (which modulate gene transcription). The blocking, by JAK inhibitors, of cytokines pathway may suppress the expression of many cytokines important for pathogenesis of psoriasis. JAK inhibitors are currently under clinical investigation for oral and topical treatment of psoriasis (Virtanen A.T. et al. (2019) BioDrugs 33:15; Cornejo M.G. et al. (2009) Int. J. Biochem. Cell Biol.41:2376-2379; Kim J. et al. (2018) J. Investig. Dermatol.138:273-281). Currently, three JAK inhibitors, tofacitinib, baricitinib, and ruxolitinib, have been approved for clinical use in psoriasis in the United States of America and Europe (Virtanen A.T. et al. (2019) BioDrugs 33:15; Elli E.M. et al. (2019) Front. Oncol.9:1186). Tofacitinib can be used orally or topically, and besides being used in psoriasis, it is used as an off-label indication in alopecia areata, vitiligo and atopic dermatitis. It is also used in skin diseases such as moderate to severe active rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis (Kvist-Hansen A. et al. (2020) Dermatol. Ther.10:29-42). Bruton's tyrosine kinase (BTK) is involved in several signaling pathways in B cells and myeloid cells, though it is best known for its critical role in BCR signaling. Bruton's tyrosine kinase (BTK) has been reported to execute important signaling functions in innate immune cells such as dendritic cells (DCs) and gamma delta T cells. It was recently discovered that ibrutinib (a BTK inhibitor) attenuates psoriasis inflammation through downregulation of oxidative stress in neutrophils and CD11c⁺ dendritic cells (Al-Harbi N. et al. (2020) Eur. J. Pharmacol. 877:173088; Nadeem A. et al. (2020) Int. Immunopharmacol.80:106215). Currently, the most effective drugs for treatment of psoriasis are corticosteroids such as for example dexamethasone. Unfortunately, these drugs have many undesirable side effects. Thus, there is a need for better treatments for psoriasis. BTK and JAK inhibitors are promising therapeutic targets to treat psoriatic inflammation. The present disclosure provides dual BTK and JAK inhibitors, compounds of Formula (I) such as abivertinib, which is a promising therapeutic to treat psoriasis. Attorney Docket No.01223-0128-00PCT Exemplary Methods and Compositions for Use In an aspect, provided herein is a method for treating psoriasis, comprising administering to a subject in need of treatment of psoriasis, a therapeutically effective amount of a compound of Formula (I): R¹ O , or a stereoisomer, or isotopic

variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: R¹ and R² are each independently hydrogen, halo, C1-6 alkyl, or C1-6 haloalkyl; each R³ is independently hydrogen, halo, hydroxyl, C1-6 alkyl, C1-6 alkoxy, cyano, or nitro; R⁴ is hydrogen or C_1-6 alkyl; and n is an integer from 0 to 4. In another aspect, provided herein is a composition comprising a therapeutically effective amount of a compound of Formula (I) for use in a method of treating psoriasis, the method comprising administering the compound of Formula (I): R¹ O , or a stereoisomer,

or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: Attorney Docket No.01223-0128-00PCT R¹ and R² are each independently hydrogen, halo, C1-6 alkyl, or C1-6 haloalkyl; each R³ is independently hydrogen, halo, hydroxyl, C1-6 alkyl, C1-6 alkoxy, cyano, or nitro; R⁴ is hydrogen or C_1-6 alkyl; and n is an integer from 0 to 4; to a subject in need of treatment of psoriasis. In embodiments, R⁴ is C_1-6 alkyl. In embodiments, R⁴ is hydrogen. In embodiments, R⁴ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl. In embodiments, R⁴ is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In embodiments, R⁴ is methyl. In embodiments, R⁴ is ethyl. In embodiments, R⁴ is propyl. In embodiments, R⁴ is butyl. In embodiments, R⁴ is pentyl. In embodiments, R⁴ is hexyl. In embodiments, each R³ is independently hydrogen, halo, hydroxyl, or C1-6 alkyl. In embodiments, each R³ is independently hydrogen, halo, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl. In embodiments, each R³ is independently hydrogen, fluoro, chloro, bromo, hydroxyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl. In embodiments, each R³ is hydrogen, fluoro, chloro, methyl, or ethyl. In embodiments, each R³ is independently hydrogen, halo, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In embodiments, each R³ is independently hydrogen, halo, hydroxyl, methyl, ethyl, or propyl. In embodiments, each R³ is independently hydrogen, halo, methyl, ethyl, or propyl. In embodiments, each R³ is hydrogen. In embodiments, each R³ is fluoro. In embodiments, each R³ is chloro. In embodiments, each R³ is bromo. In embodiments, each R³ is methyl. In embodiments, each R³ is ethyl. In embodiments, each R³ is propyl. In embodiments, each R³ is butyl. In embodiments, each R³ is pentyl. In embodiments, each R³ is hexyl. In embodiments, each R³ is hydroxyl. In embodiments, R¹ and R² are each independently hydrogen, halo, or C_1-6 alkyl. In embodiments, R¹ and R² are each independently hydrogen, halo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl. In embodiments, R¹ and R² are each independently hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, or hexyl. In embodiments, R¹ and R² are each independently hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In embodiments, R¹ and R² Attorney Docket No.01223-0128-00PCT are each independently hydrogen, fluoro, chloro, methyl, ethyl, or propyl. In embodiments, R¹ and R² are each independently hydrogen, methyl, or ethyl. In embodiments, R¹ and R² are each a hydrogen. In embodiments, n is 0, 1, 2, or 3. In embodiments, n is 0, 1, or 2. In embodiments, n is 0 or 1. In embodiments, n is 0. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4. In embodiments, provided herein is a method or composition for use for treating psoriasis, comprising administering to a subject in need of treatment of psoriasis, a therapeutically effective amount of abivertinib: O abivertinib, or a stereoisomer,

of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In embodiments, provided herein is a method or a composition for use for treating psoriasis, comprising administering to a subject in need of treatment of psoriasis, a therapeutically effective amount of abivertinib. In embodiments, compounds of Formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered orally. In embodiments, compounds of Formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered topically. In embodiments, compounds of Formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered in one dose. In embodiments, compounds of Formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, Attorney Docket No.01223-0128-00PCT solvate, or hydrate thereof, are administered in repeated doses. In embodiments, compounds of Formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered every day. In embodiments, compounds of Formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered every other day. In embodiments, compounds of Formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered twice a week. In embodiments, compounds of Formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered once a week. In embodiments, abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered orally. In embodiments, abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered topically. In embodiments, abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in one dose. In embodiments, abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in repeated doses. In embodiments, abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered every day. In embodiments, abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered every other day. In embodiments, abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered twice a week. In embodiments, abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of Attorney Docket No.01223-0128-00PCT diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered once a week. In embodiments, abivertinib is administered orally. In embodiments, abivertinib is administered topically. In embodiments, administration is by intradermal, transdermal, or subcutaneious parenteral delivery. In embodiments, abivertinib is administered in one dose. In embodiments, abivertinib is administered in repeated doses. In embodiments, abivertinib is administered every day. In embodiments, abivertinib is administered every other day. In embodiments, abivertinib is administered twice a week. In embodiments, abivertinib is administered once a week. In embodiments, the subject is a mammal. In embodiments, the mammal is a human. In embodiments, the mammal is a cat. In embodiments, the mammal is a dog. Dosage In embodiments, the compounds of formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered (e.g., orally) at a dose of 5 mg/kg to 10 mg/kg, or 10 mg/kg to 15 mg/kg, or 15 mg/kg to 20 mg/kg, or 20 mg/kg to 25 mg/kg, or 25 mg/kg to 30 mg/kg, or 30 mg/kg to 35 mg/kg, or 35 mg/kg to 40 mg/kg, or 40 mg/kg to 45 mg/kg, or 45 mg/kg to 50 mg/kg, or 50 mg/kg to 55 mg/kg, or 55 mg/kg to 60 mg/kg, or 60 mg/kg to 65 mg/kg, or 65 mg/kg to 70 mg/kg, or 70 mg/kg to 75 mg/kg, or 75 mg/kg to 80 mg/kg, or 80 mg/kg to 85 mg/kg, or 85 mg/kg to 90 mg/kg, or 90 mg/kg to 100 mg/kg. In embodiments, abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered (e.g., orally) at a dose of 5 mg/kg to 10 mg/kg, or 10 mg/kg to 15 mg/kg, or 15 mg/kg to 20 mg/kg, or 20 mg/kg to 25 mg/kg, or 25 mg/kg to 30 mg/kg, or 30 mg/kg to 35 mg/kg, or 35 mg/kg to 40 mg/kg, or 40 mg/kg to 45 mg/kg, or 45 mg/kg to 50 mg/kg, or 50 mg/kg to 55 mg/kg, or 55 mg/kg to 60 mg/kg, or 60 mg/kg to 65 mg/kg, or 65 mg/kg to 70 mg/kg, or 70 mg/kg to 75 mg/kg, or 75 mg/kg to 80 mg/kg, or 80 mg/kg to 85 mg/kg, or 85 mg/kg to 90 mg/kg, or 90 mg/kg to 100 mg/kg. In embodiments, abivertinib is administered (e.g., orally) at a dose of 5 mg/kg to 10 mg/kg, or 10 mg/kg to 15 mg/kg, or 15 mg/kg to 20 mg/kg, or 20 mg/kg to 25 mg/kg, or 25 Attorney Docket No.01223-0128-00PCT mg/kg to 30 mg/kg, or 30 mg/kg to 35 mg/kg, or 35 mg/kg to 40 mg/kg, or 40 mg/kg to 45 mg/kg, or 45 mg/kg to 50 mg/kg, or 50 mg/kg to 55 mg/kg, or 55 mg/kg to 60 mg/kg, or 60 mg/kg to 65 mg/kg, or 65 mg/kg to 70 mg/kg, or 70 mg/kg to 75 mg/kg, or 75 mg/kg to 80 mg/kg, or 80 mg/kg to 85 mg/kg, or 85 mg/kg to 90 mg/kg, or 90 mg/kg to 100 mg/kg. In embodiments, compounds of formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, are administered (e.g., orally) at a dose of about 25 mg/kg, or about 50 mg/kg, or about 100 mg/kg. In embodiments, abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered (e.g., orally) at a dose of about 25 mg/kg, or about 50 mg/kg, or about 100 mg/kg. In embodiments, abivertinib is administered (e.g., orally) at a dose of about 25 mg/kg, or about 50 mg/kg, or about 100 mg/kg. Pharmaceutical Compositions In an aspect, provided herein is a pharmaceutical composition including any of the compounds as described herein, including embodiments, and a pharmaceutically acceptable carrier. In embodiments, the compound as described herein is included in a therapeutically effective amount. In embodiments of the pharmaceutical compositions, the compound, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is included in a therapeutically effective amount. In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g., therapeutic agent). In embodiments of the pharmaceutical compositions, the pharmaceutical composition includes a second agent (e.g., therapeutic agent) in a therapeutically effective amount. In embodiments, the second agent is an anti-inflammatory agent. In embodiments, the administering does not include administration of any active agent other than the recited active agent (e.g., a compound described herein). The pharmaceutical compositions may include optical isomers, diastereomers, or pharmaceutically acceptable salts of the compounds disclosed herein. The pharmaceutical compositions may include a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variants. The pharmaceutical compositions may include Attorney Docket No.01223-0128-00PCT pharmaceutically acceptable salts, solvates, or hydrates. The compound included in the pharmaceutical composition may be covalently attached to a carrier moiety. Alternatively, the compound included in the pharmaceutical composition is not covalently linked to a carrier moiety. In embodiments, the pharmaceutical compositions described herein, including in embodiments, may be administered orally. In embodiments, the pharmaceutical composition is in an oral dosage. In embodiments, the pharmaceutical compositions described herein, including in embodiments, may be administered topically. In embodiments, the pharmaceutical composition is a topical formulation. In embodiments, tablets, powders, capsules, pills, cachets, solution, suspension, and lozenges can be used as solid dosage forms suitable for oral administration. In embodiments, oral dosage form is a tablet, capsule, solution, or suspension. In embodiments, solutions, lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols can be used for topical administration. One or more thickening agents, humectants, and stabilizing agents can be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like. Formulations In embodiments, the compounds described herein, including embodiments, which may be at the dosages discussed above, are administered with a pharmaceutically acceptable carrier. In embodiments, the pharmaceutically acceptable carrier comprises water. In embodiments, the pharmaceutically acceptable carrier comprises carboxymethyl cellulose (CMC). In embodiments, the pharmaceutically acceptable carrier comprises sodium carboxymethyl cellulose (Na CMC). In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.01 to about 2% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.01% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.05% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.1% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.2% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.3% w/v. In embodiments, the concentration of sodium Attorney Docket No.01223-0128-00PCT carboxymethyl cellulose (Na CMC) is about 0.4% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.5% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.6% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.7% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.8% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 0.9% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 1.0% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 1.5% w/v. In embodiments, the concentration of sodium carboxymethyl cellulose (Na CMC) is about 2.0% w/v. EXAMPLES 1. Validation of Imiquimod (IMQ) Induced Psoriasis Mouse Model To test the ability of abivertinib to ameliorate the clinical severity of psoriasis in mice, a psoriasis animal model had to be created. One of the most widely approved psoriasis-like animal models is the imiquimod (IMQ)-induced mouse model (El Malki K. et al. (2013) J. Investig. Dermatol., 133:441-451; Chamcheu J.C. et al. (2016) Acta Derm. Venereol.96:854- 856). Five C57BL/6J mice at 8 to 10 weeks of age were used in this experiment. One day prior to the imiquimod (IMQ) application, the depilation of mice (n=5) was started with dorsal skin shaving by an electric hair trimmer and followed by hair remover lotion application. The mice received a daily topical dose of 62.5 mg of commercially available IMQ cream (5%) (Aldara; 3M Pharmaceuticals) on the shaved back for 6 consecutive days. Control mice were treated similarly with Vaseline cream. The induced psoriasis dermatitis from day 6 was shown in FIG.1A (skin images). Double fold dorsal skin thickness (divided by 2) was measured and averaged at two distinct sites on the back of each mouse daily for 11 days. Body weight and PASI score were measured daily. FIG.1B shows the percent change in body weight of the mice treated with IMQ and the mice treated with Vaseline (control). FIGs.1C-1D show the changes in skin thickness (FIG.1C) and PASI scores (FIG.1D) of the mice over the period of eleven days, with highest PASI scores between days 6-8. Skin returns to normal (compared to negative control) five days after the last application of IMQ. Attorney Docket No.01223-0128-00PCT Significant differences of body weight change, skin thickness and PASI score between Vaseline and IMQ treated group was indicated. Data represents mean ± SEM. * P<0.05, ** P<0.01, *** P<0.001. Scoring severity of psoriasis: To score the severity of inflammation of the back skin, an objective scoring system was developed based on the clinical Psoriasis Area and Severity Index (PASI). Erythema, scaling, and thickening were scored independently on a scale from 0 to 4: 0, absent; 1, mild; 2, moderate; 3, severe; 4, very severe. The cumulative score (erythema plus scaling plus thickening) served as a measure of the severity of inflammation (scale 0–12). Psoriasis scoring system for erythema, skin thickness and scaling is shown in FIG. 1E. 2. Treatment of IMQ Induced Psoriasis Mouse Model with JAK Inhibitor vs. BTK Inhibitor Eight mice were prepared and treated with IMQ as described in experiment 1 above (on day 1 to 6, 62.5mg 5% IMQ was applied on the dorsal skin of depilated C57BL/6J mice to generate psoriasis dermatitis). Additionally, starting on day 1, the back skin of the mice was treated with 2% tofacitinib (JAK inhibitor), 2% ibrutinib (BTK inhibitor) or vehicle (Aquaphor healing ointment®), twice a day for 6 days. Topical treatments were prepared as follows: tofacitinib was dissolved in DMSO at 238 mg/ml and ibrutinib at 255 mg/ml, then each solution was mixed with 50 mg Aquaphor to form 2% ointment (compound to Aquaphor w/w). The control vehicle was prepared by mixing DMSO with 50 mg Aquaphor. Aquaphor contains 41% petrolatum as well as mineral oil, ceresin, lanolin alcohol, panthenol, glycerin, and bisabolol, and is available from Beiersdorf Inc. Double fold dorsal skin thickness (divided by 2) was measured and averaged at two distinct sites on the back skin of each mouse daily. Body weight and PASI score were monitored daily. Significant differences of body weight change, skin thickness and PASI score between tofacitinib or ibrutinib and vehicle was indicated. Data represents mean ± SEM. * P<0.05, ** P<0.01, *** P<0.001. Skin images of mice following a six-day treatment of IMQ induced psoriasis, with 2% Tofacitinib, 2% Ibrutinib, or Vehicle are shown in FIG.2A. FIG.2B shows changes in body Attorney Docket No.01223-0128-00PCT weight of mice, with IMQ induced psoriasis, treated with 2% Tofacitinib, 2% Ibrutinib, or Vehicle. FIGs.2C-2D show the changes in skin thickness (FIG.2C) and PASI scores (FIG.2D) of these mice over the period of six days. Both tofacitinib and ibrutinib attenuate IMQ induced psoriasis in mice compared to vehicle (Aquaphor), although tofacitinib (a JAK inhibitor) is the better treatment. 3. JAK/STAT pathway Inhibition by Abivertinib, Tofacitinib, and Ibrutinib in Human and Mouse T Cells This example demonstrates a dose dependent effect of IL-2 signaling inhibition by abivertinib (dual inhibitor JAK and BTK), tofacitinib (JAK inhibitor), and ibrutinib (BTK inhibitor). Inhibition of JAK/STAT pathway in human and mouse T cells was demonstrated using Western blot (FIG.3). Pan T cell preparation: Frozen human PBMCs were quickly thawed in a 37°C water bath, washed and resuspended in MACS buffer at 1x10⁷ cells/40μl. Mouse spleens were passed through a 70μm strainer. The red blood cells were lysed with RBC lysis buffer. The splenocytes were then resuspended in MACS buffer at 1x10⁷ cells/40μl. Using the species-specific pan T cell isolation kits (Miltenyi Biotech; human Cat No.130-096-535; mouse Cat No.130-095-130), the cells were incubated with biotin-conjugated antibody cocktail for 5 min, then anti-biotin microbeads for 10 min on ice. The cells then ran through a selection column placed on a magnet. The negative flowthrough was collected. 2.0 x 10⁶ human or mouse pan T cells in 1 ml culture medium were seeded in 24- well plates and treated with vehicle (DMSO) or 10nM, 30nM, 100nM, 300nM, and 1000nM (in DMSO) abivertinib, ibrutinib, or tofacitinib for 1 hr at 37°C. Without washing off the inhibitors, the cells were then stimulated with 100 ng/ml recombinant human or mouse IL-2 for 15 min. The cells were washed with PBS and then lysed (cells were resuspended in 100μl RIPA buffer supplemented with protease inhibitor and phosphatase inhibitor cocktails and incubated on ice, shaking, for 30 min, then denatured by adding Laemmli buffer with 2-mercaptoethanol and boiling for 10 min). 20 μl denatured protein samples were loaded onto a pre-cast 7.5% SDS-PAGE gel and ran at constant 90V for 70min. The samples were then transferred to a PVDF membrane using the BioRAD Turbo Transfer system. The membranes were blocked with TBST containing 5% milk for 1 hr at RT, then incubated overnight with primary antibodies at 1/1000 dilution in Attorney Docket No.01223-0128-00PCT TBST containing 5% BSA at 4°C. The next day, the membranes were washed 4 times, then incubated with goat anti-rabbit IgG HRP at 1/5000 dilution in TBST containing 5% milk for 1 hr at RT. The membranes were then washed 4 times, reacted with Western ECL substrate and imaged on a Chemidoc MP system. FIG.3 shows STAT5 phosphorylation as detected by Western blot. FIG.3 shows that treatment with abivertinib and tofacitinib (but not ibrutinib) stops phosphorylation of STAT5, suggesting that abivertinib attenuates imiquimod-induced psoriasis- like inflammation via JAK inhibition pathway like tofacitinib. 4. Protein kinase inhibitor assays The enzymatic assay was outsourced to BPS Bioscience for the determination of JAK3 IC50 of each compound (abivertinib, tofacitinib, and ibrutinib). Briefly, the assay was performed using Kinase-Glo Plus luminescence kinase assay kit from Promega. The kit measures kinase activity by quantitating the amount of APT remaining in the solution following a kinase reaction. The data were analyzed using Graphpad Prism with a non-linear regression analysis of Sigmoidal dose-response curve. The IC50 values were determined by the concentration causing a half-maximal percent activity. Enzymatic IC50 (nM)

. Ten mice were prepared and treated with IMQ as described in experiment 1 above. (On day 1 to 6, 62.5mg 5% IMQ was applied in the dorsal skin of C57BL/6J mice to induce the psoriasis dermatitis). Starting on day 1, the mice were treated with 50 mg/kg abivertinib (oral treatment), 20 mg/kg dexamethasone (intraperitoneal treatment), or 0.5% CMC-sodium vehicle (oral treatment), twice a day for 8 days. Oral treatments were prepared as follows: 0.1mL of vehicle (0.5% CMC-sodium cellulose solution), abivertinib formulated at 10 mg/mL in 0.5% CMC-sodium cellulose solution, and dexamethasone formulated at 5% in DMSO in 0.5% CMC- sodium cellulose solution. Treatment with abivertinib or dexamethasone (positive control) can ameliorate imiquimod-induced psoriasis-like inflammation (shown in skin images, FIG.4A). Double fold Attorney Docket No.01223-0128-00PCT dorsal skin thickness (divided by 2) was measured and averaged at two distinct sites on the back skin of each mouse daily. PASI score including erythema, thickness, and scaling scores was measured daily. Significant differences of skin thickness and PASI score between abivertinib or dexamethasone and vehicle was indicated by asterisk. Data represents mean ± SEM. * P<0.05, ** P<0.01, *** P<0.001. Skin images of mice after six-day treatment, of IMQ induced psoriasis, with 50mg/kg abivertinib, 20mg/kg dexamethasone, or 0.5% CMC-sodium (vehicle) are shown in FIG.4A. FIGS.4B-F show changes in skin thickness (FIG.4B), erythema score (FIG.4C), thickness score (FIG.4D), scaling score (FIG.4E), and PASI cumulative score (FIG.4F) of mice, with IMQ induced psoriasis, treated for eight days with 50mg/kg abivertinib, 20mg/kg dexamethasone, or vehicle (0.5% CMC-sodium). Both abivertinib and dexamethasone attenuate IMQ induced psoriasis in mice compared to vehicle (0.5% CMC-sodium). 6. Histopathological Skin Evaluation of IMQ Induced Psoriasis Mouse Model Following Treatment with Abivertinib Ten mice were prepared and treated with IMQ as described in experiment 1 above. (On day 1 to 6, 62.5mg 5% IMQ was applied in the dorsal skin of C57BL/6J mice to induce the psoriasis dermatitis). Starting on day 1, the mice were treated with 50mg/kg abivertinib (oral treatment), 20mg/kg dexamethasone (intraperitoneal treatment), or 0.5% CMC-sodium Vehicle (oral treatment), twice a day for six days. On day 6, the mice were euthanized and 1x1 cm² dorsal skin of mice from each group was dissected for hematoxylin and eosin (H&E) staining. The dissected skin was fixed in formalin solution for 24-48 hours, then transferred to 70% alcohol solution. The skin samples were analyzed by H&E staining in a week. H&E staining program is listed in Table 1 below. Table 1: Program 1 Program 2 with oven no oven p 0 0 0 0 0

Attorney Docket No.01223-0128-00PCT W1 H₂O 00:30 00:30 6 Gills 3 Hem. 02:30 02:30 0 5 0 0 0 0 5 0 0 0 0 e

Abbreviation: Hem. is Hematoxylin FIG.5 shows a schematic representation of normal skin and psoriasis afflicted skin. FIG.6 shows microscope pictures of the dorsal skin of mice, with IMQ induced psoriasis, following treatment with abivertinib, dexamethasone, or vehicle. Psoriasiform hyperplasia was detected in the skin of mice in the vehicle group indicating psoriasis, but not in skin of mice treated with abivertinib or dexamethasone. Thus, treatment with abivertinib or dexamethasone attenuated imiquimod-induced psoriasis-like inflammation.

Claims

Attorney Docket No.01223-0128-00PCT CLAIMS: 1. A method for treating psoriasis, comprising administering to a subject in need of treatment of psoriasis, a therapeutically effective amount of a compound of Formula (I): R¹ O , or a stereoisomer, or isotopic

variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: R¹ and R² are each independently hydrogen, halo, C1-6 alkyl, or C1-6 haloalkyl; each R³ is independently hydrogen, halo, hydroxyl, C_1-6 alkyl, C_1-6 alkoxy, cyano, or nitro; R⁴ is hydrogen or C1-6 alkyl; and n is an integer from 0 to 4. 2. A composition comprising a therapeutically effective amount of a compound of Formula (I) for use in a method of treating psoriasis, the method comprising administering the compound of Formula (I): R¹ O R² NH R^{3 4} n R N F O N N N _N ^N H _H (I), Attorney Docket No.01223-0128-00PCT or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: R¹ and R² are each independently hydrogen, halo, C1-6 alkyl, or C1-6 haloalkyl; each R³ is independently hydrogen, halo, hydroxyl, C1-6 alkyl, C1-6 alkoxy, cyano, or nitro; R⁴ is hydrogen or C_1-6 alkyl; and n is an integer from 0 to 4; to a subject in need of treatment of psoriasis. 3. The method or composition for use of claim 1 or 2, wherein R⁴ is C_1-6 alkyl. 4. The method or composition for use of any one of claims 1-3, wherein R⁴ is methyl, ethyl, propyl, butyl, pentyl, or hexyl. 5. The method or composition for use of any one of claims 1-4, wherein R⁴ is methyl. 6. The method or composition for use of any one of claims 1-5, wherein each R³ is independently hydrogen, halo, methyl, ethyl, or propyl. 7. The method or composition for use of any one of claims 1-6, wherein each R³ is independently hydrogen, fluoro, chloro, methyl, or ethyl. 8. The method or composition for use of any one of claims 1-7, wherein R³ is hydrogen. 9. The method or composition for use of any one of claims 1-8, wherein R¹ and R² are each a hydrogen. 10. The method or composition for use of any one of claims 1-9, wherein the compound of Formula (I) is abivertinib: O abivertinib,

or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Attorney Docket No.01223-0128-00PCT 11. The method or composition for use of any one of claims 1-10, wherein a dose of 5 mg/kg to 10 mg/kg, or 10 mg/kg to 15 mg/kg, or 15 mg/kg to 20 mg/kg, or 20 mg/kg to 25 mg/kg, or 25 mg/kg to 30 mg/kg, or 30 mg/kg to 35 mg/kg, or 35 mg/kg to 40 mg/kg, or 40 mg/kg to 45 mg/kg, or 45 mg/kg to 50 mg/kg, or 50 mg/kg to 55 mg/kg, or 55 mg/kg to 60 mg/kg, or 60 mg/kg to 65 mg/kg, or 65 mg/kg to 70 mg/kg, or 70 mg/kg to 75 mg/kg, or 75 mg/kg to 80 mg/kg, or 80 mg/kg to 85 mg/kg, or 85 mg/kg to 90 mg/kg, 90 mg/kg to 100 mg/kg, or 100 mg/kg to 110 mg/kg of abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered. 12. The method or composition for use of claim 11, wherein abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a dose of about 25 mg/kg. 13. The method or composition for use of claim 11, wherein abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a dose of about 50 mg/kg. 14. The method or composition for use of claim 11, wherein abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a dose of about 100 mg/kg. 15. The method or composition for use of any one of claims 1-14, wherein the abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in one dose. 16. The method or composition for use of any one of claims 1-14, wherein the abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered in repeated doses. Attorney Docket No.01223-0128-00PCT 17. The method or composition for use of any one of claims 1-16, wherein the abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered daily. 18. The method or composition for use of any one of claims 1-17, wherein the subject is a mammal. 19. The method or composition for use of any one of claims 1-18, wherein the subject is a human. 20. The method or composition for use of any one of claims 1-19, wherein the psoriasis is plaque psoriasis. 21. The method or composition for use of any one of claims 1-20, wherein the method comprises administering a pharmaceutical composition comprising the compound of Formula (I), or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable carrier. 22. The method or composition for use of any one of claims 1-21, wherein the method comprises administering a pharmaceutical composition comprising the abivertinib, or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a pharmaceutically acceptable carrier. 23. The method or composition for use of claim 21 or 22, wherein the pharmaceutical composition is in an oral dosage form. 24. The method or composition for use of claim 23, wherein the oral dosage form is a tablet, capsule, solution, or suspension. 25. The method or composition for use of claim 21 or 22, wherein the pharmaceutical composition is administered topically. 26. The method or composition for use of claim 21 or 22, wherein the pharmaceutical composition is administered orally. 27. The method or composition for use of any one of claims 21-26, wherein the pharmaceutical composition further comprises a second therapeutic agent.