Pyrrolopyrimidine compositions for the treatment of ITK-mediated conditions

Abstract

The present disclosure relates to oral compositions of Compound I or its derivatives. Several dosage ranges are disclosed, along with SAD, MAD, and PK data. Comparative data between Compound I, tofacitinib, ritrecitinib, and cyclosporin A are also disclosed. Methods of use for treating inflammatory conditions are also disclosed.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 382,835, filed November 8, 2022, and U.S. Provisional Patent Application No. 63 / 538,913, filed September 18, 2023. The disclosures of both of these applications are incorporated herein by reference. The disclosure of this application is incorporated herein by reference. Summary of the Invention

[0002] The present disclosure is directed to a method of treating an inflammatory condition in a human subject in need thereof, the method comprising administering from about 10 mg / day to about 80 mg / day of Compound I [ka] or a derivative thereof to a human subject to treat said inflammatory condition.

[0003] The present disclosure is further directed to oral pharmaceutical compositions comprising Compound I or a derivative thereof, the oral composition comprising about 1 mg to about 100 mg of Compound I and a pharmaceutically acceptable carrier. [Brief explanation of the drawings]

[0004] [Figure 1] FIG. 1 shows the observed human Compound I PK (1-80 mg, preliminary PK parameters). [Figure 2] Figure 2 shows the effect of food on the AUC data at 15 mg. [Figure 3] Figure 3 shows the effect of formulation on the AUC data at 25 mg. [Figure 4] FIG. 4 shows αCD3 / αCD28 stimulated IL2 mRNA production. [Figure 5] FIG. 5 shows αCD3 / αCD28 stimulated IFNγ mRNA production. [Figure 6]FIG. 6 shows IL2-stimulated pSTAT5 in lymphocytes. [Figure 7] FIG. 7 shows IL2-stimulated pSTAT5 in CD3+ T cells. [Figure 8] FIG. 8 shows αCD3 / IL15 stimulated IFNγ protein production. [Figure 9] 9A-C show the SAD exposure response (9A) and SAD calculated response at Cmax by dose (9B) for TCR (IL2 mRNA). [Figure 10] 10A-C show the SAD exposure response (10A) and the SAD calculated response at Cmax by dose (10B) for ITK (IFNγ mRNA). [Figure 11] 11A-C show SAD exposure response (11A) and SAD calculated response at Cmax by dose (11B) on JAK3 signaling (pSTAT5, lymphatic). [Figure 12] 12A-C show the SAD exposure response (12A) and SAD calculated response at Cmax by dose (12B) on JAK3 signaling (pSTAT5, CD3+T). [Figure 13] 13A-C show the SAD exposure response (13A) and the SAD calculated response at Cmax by dose (13B) for TCR and JAK signaling (IFNγ protein). [Figure 14] FIG. 14 shows the doses of Compound I in Cohorts 1 to 5 of Example 2. [Figure 15] FIG. 15 shows the pharmacokinetics of Compound I at several doses. [Figure 16] Figures 16A-C show αCD3 and αCD28 stimulated IL2 mRNA (16A), IL15 stimulated IFNγ production (16B), and αCD3 and αCD28 stimulated IFNγ production (16C) of the BID cohort. [Figure 17]Figures 17A-C show αCD3 and αCD28 stimulated IL2 mRNA (17A), IL15 stimulated IFNγ production (17B), and αCD3 and αCD28 stimulated IFNγ production (17C) comparing 30 mg QD, 15 mg BID, and 10 mg TID cohorts. [Figure 18] Figures 18A-C show MAD exploratory pharmacodynamic dose-response data for Compound I against all cohorts of αCD3 and αCD28 stimulated IL2 mRNA (18A), IL15 stimulated IFNγ protein (18B), and αCD3 and IL15 stimulated IFNγ protein (18C). [Figure 19] FIG. 19 shows a comparison of QD and BID administration of Compound I in rat antigen-induced arthritis (AIA). [Figure 20] Figures 20A and B show simulated data comparing a 50 mg dose of ritrecitinib (11A) with several doses of Compound I (11B). [Figure 21] FIG. 21 shows the rate of change in the initial body weight of mice in a mouse T cell transfer model. [Figure 22] 22A-C show the histopathological scores in the mouse T cell transfer model in the proximal colon (22A), distal colon (22B), and ileum (22C). [Figure 23] FIG. 23 shows a mouse colitis model comparing Compound I with lierecitinib. [Figure 24] FIG. 24 shows a mouse colitis model comparing Compound I with tofacitinib. DETAILED DESCRIPTION OF THE INVENTION

[0005] definition Before the present compositions and methods are described, it should be understood that the present invention is not limited to the particular processes, formulations, compositions, or methodologies described. It should also be understood that the terms used herein are for the purpose of describing particular versions or embodiments only, and are not intended to limit the scope of the embodiments herein, which are limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although any methods and materials similar or equivalent to those described herein can be used to practice or test the embodiments herein, preferred methods, devices, and materials are described herein. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein should be construed as an admission that the embodiments herein are not entitled to antedate such disclosure by prior invention.

[0006] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to an ITK inhibitor is a reference to one or more ITK inhibitors and equivalents thereof known to those skilled in the art.

[0007] The transitional phrase "comprising," which is synonymous with "comprising" or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. In contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the claim to the particular materials or steps in the claim and to materials or steps that do not materially affect the basic characteristics and novel features" of the claimed invention. The compositions and methods of the present disclosure can comprise, consist essentially of, or consist of the disclosed components or steps.

[0008] As used herein, the term "about" is intended to qualify the numerical value it modifies and indicates such value as a variable within a margin of error. Unless a specific margin of error is recited, such as the standard deviation for a mean value presented in a chart or table of data, the term "about" should be understood to mean ±10% of the numerical value with which it is used. Thus, approximately 50 mg means a range of 45 mg to 55 mg.

[0009] When used in conjunction with a therapeutic means for administering a therapeutic agent to a patient, "administration" refers to the positive effect of the therapeutic agent on the tissue targeted by the therapeutic agent. Thus, as used herein, the term "administration," when used in conjunction with an ITK inhibitor compound, can include, but is not limited to, providing the ITK inhibitor compound in or on the target tissue, for example, providing the ITK inhibitor compound systemically to a patient via oral administration, where the therapeutic agent reaches the target tissue.

[0010] As used herein, the term "derivative thereof" refers to a salt thereof, a pharmaceutically acceptable salt thereof, an ester thereof, a free acid form thereof, a free base form thereof, a solvate thereof, a deuterated derivative thereof, a hydrate thereof, an N-oxide thereof, a clathrate thereof, a prodrug thereof, a polymorph thereof, a stereoisomer thereof, a geometric isomer thereof, a tautomer thereof, a mixture of tautomers thereof, an enantiomer thereof, a diastereomer thereof, a racemate thereof, a mixture of stereoisomers thereof, an isotope thereof (e.g., tritium, deuterium), or a combination thereof.

[0011] As used herein, the term "substantially free," alone or in combination, refers to the absence of isomers within the detection limits of analytical methods such as nuclear magnetic resonance (NMR), gas chromatography / mass spectrometry (GC / MS), high performance liquid chromatography (HPLC), or liquid chromatography / mass spectrometry (LC / MS).

[0012] As used herein, the term "condition" is intended to be generally synonymous with, and is used interchangeably with, the terms "disorder," "syndrome," and "disease," in that all reflect an abnormal condition of the body or one of its parts that impairs normal function in a human or animal, is typically manifested by noticeable signs and symptoms, and causes the human or animal to have a reduced lifespan or quality of life.

[0013] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents substantially simultaneously, for example, in a single capsule having a fixed ratio of active ingredients, or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses the sequential use of each type of therapeutic agent. In either case, the treatment regimen provides the beneficial effect of the drug combination in treating the condition or disorder described herein.

[0014] As used herein, the term "ITK inhibitor" refers to an inhibitor of an ITK activity that has an IC50 or IC60 of about 100 μM or less, more typically about 50 μM or less, as measured in an ITK enzyme assay generally described herein. 50 It is used to refer to compounds that exhibit IC 50 is the concentration of an inhibitor that reduces the activity of an enzyme (e.g., ITK) to half of its maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibition of ITK. In certain embodiments, compounds have an IC for ITK of about 10 μM or less. 50 and in a further embodiment, the compound exhibits an IC 50 and in a further embodiment, the compound exhibits an IC 50 and in a further embodiment, the compound has an IC for ITK of about 200 nM or less as measured in the ITK binding assay described herein. 50 Shows.

[0015] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from bases or acids that are acceptable for administration to patients, such as mammals. The term "pharmaceutically acceptable salts" encompasses salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Such salts may be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids.

[0016] Suitable pharmaceutically acceptable acid addition salts of Compound I of the embodiments herein can be prepared from inorganic or organic acids. All of these salts can be prepared by conventional means from the corresponding compound of the embodiments herein, for example, by treating the compound with the appropriate acid or base.

[0017] Pharmaceutically acceptable acids include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, phosphoric acid, and diphosphoric acid, as well as carboxylic acids such as, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, pantothenic acid, benzenesulfonic acid, toluenesulfonic acid, sulfanilic acid, mesylic acid, cyclohexylamino acid, and the like. These include both organic acids such as sulfonic acid, stearic acid, algenic acid, beta-hydroxybutyric acid, malonic acid, galactaric acid, galacturonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, ascorbic acid, oxalate, pantothenic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, xinafoic acid (1-hydroxy-2-naphthoic acid), napadisilic acid (1,5-naphthalenedisulfonic acid), and others.

[0018] Salts derived from pharmaceutically acceptable inorganic bases suitable for the formulations described herein include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include primary, secondary, and tertiary amines, including alkylamines, arylalkylamines, heterocyclylamines, cyclic amines, naturally occurring amines, and the like, including arginine, betaine, caffeine, choline, chloroprocaine, diethanolamine, N-methylglucamine, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0019] Other preferred salts according to embodiments herein are quaternary ammonium compounds in which the equivalent of an anion (X-) is associated with the positive charge of the N atom. X- can be the anion of various mineral acids (e.g., chloride, bromide, iodide, sulfate, nitrate, phosphate) or the anion of organic acids (e.g., acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate, p-toluenesulfonate). X - is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate, or trifluoroacetate. - More preferably, is a chloride, bromide, trifluoroacetate, or methanesulfonate salt.

[0020] Compound I of the embodiments herein can exist in both unsolvated and solvated forms. The term solvate is used herein to describe a molecular complex comprising a compound of the embodiments herein and one or more pharmaceutically acceptable solvent molecules. The term hydrate is used when the solvent is water. Examples of solvated forms include, but are not limited to, Compound I of the embodiments herein associated with water, acetone, dichloromethane, 2-propanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or a mixture thereof. It is specifically contemplated in the embodiments herein that one solvent molecule may be associated with one molecule of Compound I of the embodiments herein, such as a hydrate.

[0021] In some embodiments herein, one solvent molecule may be associated with one molecule of a compound described herein, such as a hydrate. In some embodiments, two or more solvent molecules may be associated with one molecule of a compound described herein, such as a dihydrate. Furthermore, in some embodiments herein, less than one solvent molecule may be associated with one molecule of a compound described herein, such as a hemihydrate. Furthermore, solvates of embodiments herein are contemplated as solvates of the compounds described herein that retain the biological effectiveness of the unsolvated form of the compound.

[0022] Embodiments herein also include isotopically labeled compounds I of embodiments herein, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from that normally found in nature. Examples of isotopes suitable for inclusion in compounds I of embodiments herein include hydrogen, 2 H and 3 H carbon, e.g. 11 C. 13 C and 14 C, chlorine, e.g. 31 Cl, fluorine, e.g. 18 F, iodine, e.g. 123 I and 125 I, nitrogen, e.g. 13N and 15N, oxygen, e.g. 15 O. 17 O and 18 O, phosphorus, e.g. 32 P, as well as sulfur, e.g. 35 Certain isotopically labeled compounds I of the embodiments herein, for example, those incorporating a radioactive isotope, are useful for drug and / or substrate tissue distribution studies. 3 H, and carbon-14, 14 C is particularly useful for this purpose in view of its ease of incorporation and ready means of detection. 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosing requirements, and therefore may be preferable in some circumstances. 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0023] Isotopically labeled compounds I of embodiments herein can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described herein, substituting an appropriate isotopically labeled reagent for an otherwise used non-labeled reagent.

[0024] Preferred isotopically labeled compounds include deuterated derivatives of Compound I of the embodiments herein. As used herein, the term "deuterated derivative" encompasses Compound I of the embodiments herein, in which at least one hydrogen atom is replaced by deuterium at a specific position. Deuterium (D or 2 H) is a stable isotope of hydrogen that exists at a natural abundance of 0.015 mole percent.

[0025] Hydrogen-deuterium exchange (deuterium incorporation) is a chemical reaction in which a covalently bonded hydrogen atom is replaced by a deuterium atom. The exchange (incorporation) reaction can be total or partial.

[0026] Typically, deuterated derivatives of the compounds of embodiments herein have an isotopic enrichment factor (the ratio between the isotopic abundance and the natural abundance of that isotope) (the proportion of incorporation of deuterium at a given position in a molecule in place of hydrogen) of at least 3500 (52.5% deuterium incorporation) for each deuterium present at a site designated as a potential site of deuteration on the compound.

[0027] In some embodiments, the isotopic enrichment factor is at least 5000 (75% deuterium). In some embodiments, the isotopic enrichment factor is at least 6333.3 (95% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 6633.3 (99.5% deuterium incorporation). It is understood that the isotopic enrichment factor of each deuterium present at a site designated as a deuteration site is independent of other deuteration sites.

[0028] The term "subject," as used herein, and used interchangeably with "patient," includes, but is not limited to, humans and non-human vertebrates, such as wild, domestic, and farm animals. In certain embodiments, a subject described herein is an animal. In certain embodiments, a subject is a mammal. In certain embodiments, a subject is a human. In certain embodiments, a subject is a non-human animal. In certain embodiments, a subject is a non-human mammal. In certain embodiments, a subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, a subject is a companion animal, such as a dog or cat. In certain embodiments, a subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In another embodiment, a subject is a research animal, such as a rodent, dog, or non-human primate. In certain embodiments, a subject is a non-human transgenic animal, such as a transgenic mouse or a transgenic pig.

[0029] The phrase "therapeutically effective" is intended to qualify the amount of active ingredient used to treat a disease or disorder or to affect a clinical endpoint.

[0030] The term "therapeutically acceptable" refers to those compounds and derivatives thereof that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0031] As used herein, the term "BID" refers to "bis in die" or "twice daily."

[0032] As used herein, the term "TID" refers to "ter in die" or "three times a day."

[0033] As used herein, the term "treatment" refers to both therapeutic treatment and prophylactic or preventative measures, the goal being to prevent or slow (reduce) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, reduction in the severity of a condition, disorder, or disease, stabilization (i.e., no worsening) of the condition, disorder, or disease state, delay or slowing of the progression of a condition, disorder, or disease, improvement of the condition, disorder, or disease state, and remission of a condition, disorder, or disease (whether partial or total, regardless of induction or maintenance), whether detectable or undetectable, or with or without enhancement or improvement. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival in the absence of treatment. Treatment may also be preemptive in nature, i.e., including prevention of disease. Prevention of disease may involve complete protection from disease, as in the case of, for example, prevention of infection by a pathogen, or may involve prevention of disease progression. For example, preventing a disease may not mean completely suppressing any effects associated with the disease at any level, but instead may mean preventing symptoms of the disease to a clinically significant or detectable level. Prevention of a disease can also mean preventing the progression of the disease to a later stage of the disease, and increasing disease-free survival compared to not receiving treatment, and increasing disease-free survival compared to not receiving treatment.

[0034] Embodiments herein are directed to oral pharmaceutical compositions that inhibit ITK activity and methods of treatment comprising administering an oral dose of an ITK inhibitor compound to a human subject in need thereof. Some embodiments include methods of treating a disease in a human subject in need thereof comprising orally administering an ITK inhibitor compound described herein.

[0035] The Tec (Tyrosine Kinase Expressed in Hepatocellular Carcinoma) family of tyrosine kinases (TFTKs) consists of five family members: Tec, BTK (Bruton's Tyrosine Kinase), BMX (Myeloid Kinase on the X Chromosome, also known as ETK), RLK (Restless Lymphocyte Kinase, also known as TXK), and ITK (Interleukin-2-Inducible T-Cell Kinase, also known as EMT and TSK). These kinases are central to regulating hematopoietic cell biology, more specifically the development and activity of lymphoid and myeloid cells. While TFTKs share structural similarities with other nonreceptor tyrosine kinases, they also exhibit some family-specific motifs, resulting in diversity in domain architecture related to complex localization, scaffolding, and activation mechanisms. Broadly, TFTKs consist of an amino-terminal pleckstrin homology domain (PH domain), which is involved in lipid interactions and membrane targeting, followed by a Zn-terminal pleckstrin homology domain (PH domain), which is involved in lipid interactions and membrane targeting. 2+ TFTK contains a BTK homology domain (BH) that binds the SH3 domain, which is typically involved in proline-rich domain binding. A phosphotyrosine-binding SH2 domain and a carboxy-terminal ATP-binding kinase domain complete the TFTK structure. TFTK expression is generally restricted to hematopoietic lineage cells, with the exception of ETK and TEC, which are expressed in hepatocytes and endothelial cells, respectively. BMX is expressed in monocytes, granulocytes, and cardiac endothelium, while BTK is expressed in B cells and mast cells but not in plasma cells or T cells. TEC, RLK, and ITK are all expressed in T cells. To date, the TFTK with the most defined biological role in T cells is ITK.

[0036] Antigen / MHC-dependent activation of the T cell receptor (TCR) has been shown to transduce its signal through ITK. TCR stimulation leads to activation of the kinase LCK and subsequent phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) on CD3, inducing the binding and activation of the kinase ZAP70. ZAP70 then phosphorylates the adaptor proteins LAT and SLP-76, which, together with LCK and other proteins, activate PI3K and form a heteromultimeric signaling complex that generates PIP3 on the plasma membrane. ITK binds to this signaling complex through its SH2 and SH3 domains and binds PIP3 through its PH domain, leading to LCK-dependent phosphorylation of ITK Y511 and subsequent autophosphorylation of ITK Y180. Upon activation, activated ITK phosphorylates PLCγ1, which hydrolyzes PIP2 into the second messengers IP3 and DAG. The subsequent cellular consequences of these events include calcium mobilization and flux, PKC and MEK / ERK pathway activation, and transcriptional activation via AP1, NFκB, and NFAT. As a key enzyme in the TCR activation pathway, ITK influences T cell function in many ways, including positive and negative selection, cell differentiation, and cytokine production and release.

[0037] The role of ITK in T cell function has been elucidated through gene knockdown / kinase inactivation of the ITK gene in rodents and by characterizing human ITK mutant individuals. Mice with null mutations in the itk gene exhibited reduced numbers of mature T cells, blocked thymocyte development, and reduced TCR-driven T cell proliferative responses. Interestingly, IL2 and CD28 signaling and PMA / ionomycin-driven responses were unaltered, suggesting that ITK responses are membrane-proximal and stimulus-specific. Because dual knockdown of TFTK-, ITK-, and RLK-expressing T cells in mice produced a more complete TCR-inactivated phenotype compared with ITK gene deletion alone, ITK appears to be involved in amplifying TCR signaling compared with an "on / off" switch. In contrast to the regulatory effect of ITK on naive T cell activation, it plays a more important role in T helper cell differentiation. Several studies in ITK-deficient mice demonstrated reduced Th2 protective responses against parasitic infection. This reduction in Th2 responses was associated with reduced concentrations of the Th2 cytokines IL4, IL5, IL13, and IL10, as well as reduced RLK expression. In contrast to the requirement for ITK to mount Th2-driven responses, its effect on Th1 responses is modest. For example, IFNγ production in ITK knockout cells is partially inhibited, while double ITK / RLK knockouts have a more severe phenotype. Evaluation of Th17 T helper cells in ITK knockouts in vivo and in vitro studies showed reduced IL17A mRNA and protein, while IL17F was barely affected. The role of ITK in cytotoxic CD8+ T cells was investigated using ITK knockout mice. Stimulation of ITK-deficient CD8+ T cells resulted in reduced activation of PLCg1, ERK, and p38 MAPK, as well as Ca2+ expression. 2+It results in a loss of response and a decrease in proliferative responses and effector cytokine production (IL2, IL4, and IFNγ) while not affecting the cytolytic capacity of these cells. In addition to the defects observed in CD4+ and CD8+ T cells, ITK knockout cells and animals have reduced natural killer T cell development and TCR-stimulated responses.

[0038] Rodent gene knockout studies reflect the impact of enzyme expression on biological responses, not necessarily its catalytic activity. Through its multiple domain structure, ITK plays a role in scaffold formation in addition to its catalytic role. It is important to delineate the cell biology implications of blocking each of these functions. Kinase-independent ITK activities include actin polymerization (PH and SH2 domain-dependent), antigen receptor stimulation, and recruitment of the guanine nucleotide exchange factor VAV to the plasma membrane, which is associated with receptor activation of SRF. However, ITK knockout mice expressing an ITK kinase domain deletion transgene demonstrated that the kinase domain is essential for the induction of normal Th2 responses.

[0039] The relationship between ITK expression and activity and human disease has recently been reported in studies characterizing individuals with mutations in the gene encoding this protein and / or a correlation between expression and disease. The ITK gene was found to be elevated in peripheral blood T cells from patients with moderate to severe atopic dermatitis, a Th2-driven chronic inflammatory skin disease. A study of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis identified ITK as a significant risk factor. Human primary immunodeficiency was identified in siblings who died from immune dysregulation and developed lymphoproliferation after Epstein-Barr virus (EBV) infection. This disorder was associated with a missense (R335W) mutation in the SH2 domain of ITK, resulting in structural instability and reduced steady-state levels of the enzyme. This finding was confirmed and expanded in a study identifying three patients harboring a C1764G nonsense mutation in ITK, resulting in a premature stop codon and reduced protein expression and / or activity. These patients presented with EBV-positive Hodgkin lymphoma. These two reports suggest that mutational disruption of the ITK gene in humans results in an autosomal recessive lymphoproliferative disorder and identify this kinase as a key regulator in T cell biology.

[0040] In addition to the human genetic data summarized above, animal models support ITK as a therapeutic target for autoimmune and inflammatory diseases. ITK knockout mice show reduced airway hyperresponsiveness and inflammation in models of allergic asthma. In mouse models of atopic dermatitis, ITK-deficient mice fail to develop inflammation, whereas ITK inhibition reduces responses in wild-type mice. TCR-dependent Ca2+ expression is also observed. 2+ ITK-dependent regulation of recruitment and transcription factor induction is a key factor in protecting against influenza A and HIV infection and viral replication. ITK inhibitors have been shown to alter HIV replication at multiple stages and have potential as effective HIV therapeutics.

[0041] From an oncological perspective, studies have shown that ITK inhibitors selectively target acute lymphoblastic T-cell leukemia and cutaneous T-cell lymphoma, while minimally affecting normal T cells. ITK is highly expressed in transformed T-cell lines compared with normal T cells and other cancer cell lines. The effect of ITK inhibition on T-cell tumors was confirmed in mouse xenograft models. Cancer evasion of the immune system as a result of tumor antigen tolerance induction compared with priming is important for tumor survival. Tumors that develop a microenvironment that induces T-cell unresponsiveness exhibit altered T-cell gene expression suggesting a skew toward a Th2 phenotype. ITK inhibition favors Th1 differentiation and may be used to enhance cancer immunotherapy.

[0042] The utility of simultaneously inhibiting signals downstream of both T cell receptors and cytokine receptors is best exemplified by the field of organ transplantation (Halloran). Standard treatment in the immediate post-transplant setting is to prevent immunological graft rejection by administering a cocktail of inhibitors that affect lymphocyte activation at different time points. The most common agents used in both the initial post-transplant period and in the hospital discharge setting are calcineurin inhibitors, such as Prograf or Neoral, which block TCR signaling, and antimetabolites, such as mycophenolate mofetil or rapamycin, which block proliferation induced downstream of cytokines such as IL-2 or IL-15. These agents cannot be used as monotherapy because they require higher doses and result in drug-specific toxicity. By using these agents simultaneously at suboptimal doses, synergistic immunosuppression with reduced toxicity is achieved. ITK is downstream of the TCR, and JAK3 is downstream of the common g-chain of cytokine receptors. By covalently modifying cysteines in the catalytic domains of both kinases, it is possible to inhibit both enzymes with a single agent, thereby synergistically inhibiting T cell activation.

[0043] Also provided are embodiments in which any embodiment described herein may be combined with any one or more of these embodiments, provided that the combinations are not mutually exclusive.

[0044] Oral Composition Embodiments herein include a pharmaceutical composition formulated for oral administration ("oral pharmaceutical composition") comprising about 1 mg to about 100 mg of Compound I, as shown below. [ka] or a derivative thereof, and a pharmaceutically acceptable carrier.

[0045] Compound I is also referred to herein by its chemical name, 1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one.

[0046] Compound I may be prepared according to the methods described in US Pat. No. 11,021,482, which is incorporated herein by reference in its entirety.

[0047] In any embodiment, the oral pharmaceutical composition disclosed herein comprises 1 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 3 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 5 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 10 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 15 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 25 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 30 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 40 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 50 mg of Compound I. In any embodiment, the oral pharmaceutical composition disclosed herein comprises 80 mg of Compound I.

[0048] In any embodiment, the oral pharmaceutical compositions described herein contain Compound I in an amount of about 1 mg to about 100 mg, or any amount therebetween. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 2 mg to about 100 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 3 mg to about 100 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 4 mg to about 100 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 5 mg to about 100 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 10 mg to about 100 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 15 mg to about 100 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 20 mg to about 100 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 25 mg to about 100 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 30 mg to about 100 mg. In one embodiment, compound I is present in the pharmaceutical composition in an amount of about 35 mg to about 100 mg. In one embodiment, compound I is present in the pharmaceutical composition in an amount of about 40 mg to about 100 mg. In one embodiment, compound I is present in the pharmaceutical composition in an amount of about 45 mg to about 100 mg. In one embodiment, compound I is present in the pharmaceutical composition in an amount of about 50 mg to about 100 mg. In one embodiment, compound I is present in the pharmaceutical composition in an amount of about 1 mg to about 90 mg. In one embodiment, compound I is present in the pharmaceutical composition in an amount of about 1 mg to about 80 mg. In one embodiment, compound I is present in the pharmaceutical composition in an amount of about 1 mg to about 70 mg. In one embodiment, compound I is present in the pharmaceutical composition in an amount of about 1 mg to about 60 mg. In one embodiment, compound I is present in the pharmaceutical composition in an amount of about 1 mg to about 50 mg. In one embodiment, compound I is present in the pharmaceutical composition in an amount of about 1 mg to about 40 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 1 mg to about 30 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 1 mg to about 20 mg. In one embodiment, Compound I is present in the pharmaceutical composition in an amount of about 1 mg to about 10 mg. In one embodiment, the oral pharmaceutical composition described herein comprises Compound I in an amount of about 10 mg to about 80 mg.In one embodiment, the oral pharmaceutical compositions described herein contain Compound I in an amount of about 5 mg to about 40 mg.

[0049] In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 0.1 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 0.5 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 1 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 2 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 3 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 4 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 5 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 6 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 7 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 8 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 9 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 10 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 11 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 12 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 13 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 14 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 15 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 16 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 17 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 18 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 19 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 20 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 21 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 22 mg.In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 23 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 24 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 25 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 26 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 27 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 28 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 29 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 30 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 31 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 32 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 33 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 34 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 35 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 36 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 37 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 38 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 39 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 40 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 41 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 42 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 43 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 44 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 45 mg.In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 46 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 47 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 48 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 49 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 50 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 51 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 52 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 53 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 54 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 55 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 56 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 57 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 58 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 59 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 60 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 61 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 62 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 63 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 64 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 65 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 66 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 67 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 68 mg.In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 69 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 70 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 71 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 72 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 73 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 74 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 75 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 76 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 77 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 78 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 79 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 80 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 81 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 82 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 83 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 84 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 85 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 86 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 87 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 88 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 89 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 90 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 91 mg.In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 92 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 93 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 94 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 95 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 96 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 97 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 98 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 99 mg. In one embodiment, Compound I is present in the pharmaceutical compositions described herein in an amount of about 100 mg. In preferred embodiments, Compound I is present in the pharmaceutical compositions described herein in an amount of about 1 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, or about 80 mg.

[0050] In some embodiments, Compound I of the oral compositions disclosed herein comprises a free base. In some embodiments, Compound I of the oral compositions disclosed herein comprises a pharmaceutically acceptable salt.

[0051] In any embodiment, the pharmaceutically acceptable salt is an acid addition salt.Suitable acid addition salts include those formed with both organic and inorganic acids.Pharmaceutically acceptable acids include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, phosphoric acid and diphosphoric acid, and for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, pantothenic acid, benzenesulfonic acid, toluenesulfonic acid, sulfanilic acid, mesylic acid, cyclohexylamino acid, methyl ... These include both organic acids such as sulfonic acid, stearic acid, algenic acid, beta-hydroxybutyric acid, malonic acid, galactaric acid, galacturonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, ascorbic acid, oxalate, pantothenic acid, succinic acid, tartaric acid, benzoic acid, acetic acid, xinafoic acid (1-hydroxy-2-naphthoic acid), napadisilic acid (1,5-naphthalenedisulfonic acid), and others.

[0052] In any embodiment, the pharmaceutically acceptable salt is a base addition salt. Base addition salts can be prepared during the final isolation and purification of the compound by reacting the carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia, or an organic primary amine, secondary amine, or tertiary amine. Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, aluminum, and non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0053] In any embodiment, Compound I of the oral composition is in an unsolvated form or a solvated form. In any embodiment herein, one solvent molecule may be associated with one molecule of Compound I described herein, such as a hydrate. In some embodiments, two or more solvent molecules may be associated with one molecule of Compound I described herein, such as a dihydrate. Furthermore, in some embodiments herein, less than one solvent molecule may be associated with one molecule of Compound I described herein, such as a hemihydrate. Furthermore, the solvates of the embodiments herein are contemplated as solvates of Compound I described herein that retain the biological effectiveness of the unsolvated form of Compound I.

[0054] In some embodiments, Compound I of the oral composition is a deuterated derivative. As used herein, the term "deuterated derivative" encompasses Compound I of embodiments herein, in which at least one hydrogen atom is replaced by deuterium at a specific position. Deuterium (D or 2 H) is a stable isotope of hydrogen that exists at a natural abundance of 0.015 mole percent.

[0055] In any embodiment, the oral compositions of the present disclosure comprise Compound I as disclosed herein formulated in admixture with a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Compound I and a physiologically acceptable diluent or carrier. In certain embodiments, the pharmaceutical composition further comprises one or more additional therapeutic ingredients and / or adjuvants.

[0056] In any embodiment, the oral compositions disclosed herein may further comprise pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water-soluble vehicles, emulsifiers, buffers, wetting agents, humectants, solubilizers, preservatives, etc. Means and methods for preparation and administration are known in the art, and those skilled in the art can refer to various pharmacological references for guidance. See, for example, Banker, GS, & Rhodes, CT (2002). Modern pharmaceutics. New York: Marcel Dekker., and Goodman, LS, Brunton, LL, Chabner, B., & Knollmann, BC (2011). Goodman & Gilman's pharmacological basis of therapeutics. New York: McGraw-Hill.

[0057] The oral pharmaceutical compositions disclosed herein can be easily formulated by combining Compound I with pharmaceutically acceptable carriers known in the art. Such carriers allow Compound I of the embodiments herein to be formulated as nanoparticles, nanoparticle suspensions, tablets, lozenges, pills, dragees, capsules, powders, liquids, gels, syrups, slurries, suspensions, etc. for oral ingestion by the treated subject. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the compound in the fluid carrier is orally applied, swished in the mouth, expectorated, or swallowed. Pharmaceutical preparations for oral administration can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, if desired, after adding suitable auxiliary agents, to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars including lactose, sucrose, mannitol, and sorbitol, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC), and cellulose preparations such as polyvinylpyrrolidone (PVP).If necessary, disintegrants can be added, such as, but not limited to, cross-linked PVP, agar, or alginic acid or its salt, such as sodium alginate.

[0058] Dragee core can be provided with suitable coating.For this purpose, can use concentrated sugar solution, which can optionally contain gum arabic, talc, PVP, carbopol gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.Dyes or pigments can be added to tablet or dragee coating to identify or characterize different combinations of active compound dosage.

[0059] Orally administered pharmaceutical preparations include, but are not limited to, push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient in a mixture with one or more fillers (e.g., lactose), one or more binders (e.g., starch), and / or one or more lubricants (e.g., talc or magnesium stearate), and optionally one or more stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid PEG. Additionally, stabilizers can be added. All compositions for oral administration should be in a dosage appropriate for such administration (e.g., about 1 mg to about 100 mg).

[0060] In some embodiments, oral compositions may take the form of lozenges, tablets, or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, PVP, or HPMC), fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, or silica), disintegrants (e.g., potato starch or sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated, for example, with sugars, films, or enteric coatings by methods well known in the art. Furthermore, pharmaceutical compositions containing Compound I disclosed herein may be in any form suitable for oral use, including, for example, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives in order to provide a pharmaceutically flavorful and palatable preparation.

[0061] In one embodiment, the oral pharmaceutical composition disclosed herein is a tablet. The tablet may contain Compound I in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate, granulating and disintegrating agents (e.g., corn starch, or alginic acid), binders (e.g., starch, gelatin, or acacia), and lubricants (e.g., magnesium stearate, stearic acid, or talc). The tablet may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. In some embodiments, the tablet is formulated for immediate release. In some embodiments, the tablet is formulated for controlled release. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotic therapeutic tablets for control release. The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions.

[0062] In some embodiments, the oral composition comprises Compound I and a buffer. In some embodiments, the buffer may be selected from the group consisting of citric acid monohydrate, sodium phosphate, water, and combinations thereof. In some embodiments, the oral composition comprises Compound I and a stabilizer. In some embodiments, the stabilizer is selected from the group consisting of povidone, sodium benzoate, water, sodium lauryl sulfate, and combinations thereof. In some embodiments, the oral composition further comprises a buffer, an acid, sodium benzoate, sodium phosphate, citric acid, or a combination thereof. In some embodiments, the oral composition comprises Compound I, a stabilizer, and a buffer. In some embodiments, the oral composition further comprises a lubricant, a pH adjuster, a binder, a diluent, a granulating agent, a glidant, a disintegrant, a filler, an absorbent, an anti-adhesive, a colorant, a compression aid, a coating material, a sweetener, a preservative, an antioxidant, or a combination thereof. In some embodiments, Compound I is in a therapeutically effective amount (e.g., about 5 mg to about 100 mg). In some embodiments, the oral composition is a suspension, tablet, capsule, nanoparticle powder, nanoparticle suspension, cachet, pellet, pill, powder, granule, or a combination thereof.

[0063] In some embodiments, the lubricant may be selected from the group consisting of stearic acid or its salts (e.g., magnesium stearate, calcium stearate), sodium lauryl sulfate, PEG, mineral oil, sodium benzoate, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, and combinations thereof.

[0064] In some embodiments, the pH adjuster may be an acid (eg, hydrochloric acid, acetic acid, citric acid, phosphoric acid, sulfuric acid, or a combination thereof).

[0065] In some embodiments, the binder may be selected from the group consisting of natural or synthetic polymers (e.g., starch, sugars, sugar alcohols, or cellulose derivatives), such as gelatin, glucose, lactose, sorbitol, xylitol, maltitol, methylcellulose, microcrystalline cellulose (MCC), ethylcellulose, HPMC, hydroxypropyl cellulose (HPC), starch, PVP, PEG, sodium alginate, CMC, and combinations thereof.

[0066] In some embodiments, the compression aid may be selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, a physical mixture of MCC-colloidal silicon dioxide, and combinations thereof.

[0067] In some embodiments, the disintegrant may be selected from the group consisting of starches, cellulose derivatives and alginates, PVP, croscarmellose sodium, sodium starch glycolate, and combinations thereof.

[0068] In some embodiments, the filler may be selected from the group consisting of lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, magnesium stearate, vegetable cellulose, dibasic calcium phosphate, dibasic sodium phosphate, vegetable fats and oils, and combinations thereof.

[0069] In some embodiments, the diluent may be selected from the group consisting of sugar compounds (e.g., sucrose, lactose, dextrin, glucose, sorbitol, etc.), inorganic compounds (e.g., silicates, calcium salts, or magnesium salts), sodium chloride, potassium chloride, and combinations thereof.

[0070] In some embodiments, the preservative may be selected from the group consisting of antioxidants (e.g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium), amino acids (e.g., cysteine ​​or methionine), citric acid, sodium citrate, synthetic preservatives (e.g., parabens such as methylparaben or propylparaben), and combinations thereof.

[0071] In some embodiments, the lubricant may be selected from the group consisting of colloidal silicon anhydride and other silica compounds such as fumed silica, magnesium carbonate, colloidal silicon dioxide (AEROSIL®), corn starch, talc, and combinations thereof.

[0072] In some embodiments, the oral composition comprising Compound I is a capsule. In some embodiments, the capsule comprises an inner coating made from a high-fat emulsion. In some embodiments, the capsule comprises a high-fat coating on either the inside or outside of the capsule. In some embodiments, the capsule comprises HPMC. In some embodiments, the capsule may be an HPMC capsule. In some embodiments, the capsule may be enteric coated. In some embodiments, the capsule may be a silica capsule, such as silica sold under the trade name SYLOID®. In some embodiments, the capsule comprises a cyclodextrin. In some embodiments, the capsule may be a cyclodextrin complex enteric capsule.

[0073] In some embodiments, the oral formulation comprising Compound I is a tablet. In some embodiments, the tablet contains Compound I in the form of nanoparticles. In some embodiments, the tablet may be coated. In some embodiments, the tablet may be coated with an enteric coating. In some embodiments, the tablet may be coated with a coating selected from sugar coating, film coating, organic film coating, aqueous film coating, pan coating, dip coating, electrostatic coating, compression coating, plasticizer dry coating, heat dry coating, electrostatic dry coating, etc. Some ingredients used in the coating may include an acrylic enteric aqueous system such as that sold under the trade name ACRYL-EZE®, OPADRY®, HPMC, methylhydroxyethylcellulose, ethylcellulose, povidone, cellulose acetate phthalate, acrylate polymers (such as those sold under the trade names EUDRAGIT® L and EUDRAGIT® S), HPMC phthalate, or a combination thereof.

[0074] In some embodiments, the oral composition comprises Compound I in the form of a nanoparticle suspension (nanosuspension). In some embodiments, the nanosuspension comprises Compound I, a stabilizer, and a buffer. In some embodiments, the nanosuspension may further comprise a pH adjuster. In some embodiments, the pH adjuster may be selected from the group consisting of hydrochloric acid, acetic acid, citric acid, phosphoric acid, sulfuric acid, and combinations thereof. In some embodiments, the pH adjuster may be hydrochloric acid. In some embodiments, the hydrochloric acid may be 1.0 N hydrochloric acid. In some embodiments, the stabilizer may be selected from the group consisting of povidone, sodium lauryl sulfate, sodium benzoate, WFI quality water such as that sold under the trade name HYCLONE™, or a combination thereof. In some embodiments, the buffer may comprise WFI quality water, sodium phosphate (dibasic, heptahydrate, crystalline), citric acid monohydrate, or a combination thereof.

[0075] Nanoparticle suspensions may be produced by suspending active particles in an excipient, reducing the particles to the desired particle size using a grinding medium, and then diluting the suspension to a final volume. In some embodiments, the grinding medium used may be selected from ceramic, agate, silicon nitride, sintered corundum, zirconia, stainless steel, chromium steel, Cr-Ni steel, tungsten carbide, glass (yttrium stabilized), cross-linked polystyrene resin, plastic polyamide, pearl, or a combination thereof. In some embodiments, the mill may be a static agitator or a recirculating mill.

[0076] Tablets can be manufactured by spraying the nanosuspension (described above) onto sucrose to form a spray granulation intermediate, granulating the spray granulation intermediate with excipients to form final granules, and compressing the final granules to form tablets. Sucrose can be any sugar, including, for example, glucose, fructose, maltose, galactose, lactose, etc. In some embodiments, excipients in tablet formulations can include lactose monohydrate, PVP, silicified microcrystalline cellulose (e.g., sold under the trade name PROSOLV® SMCC HD 90), magnesium stearate, or combinations thereof. In some embodiments, tablets contain about 1 mg to about 100 mg of Compound I.

[0077] In some embodiments, the oral compositions described herein are dry powders. In some embodiments, the dry powders may be encapsulated or made into suspensions. In some embodiments, the suspensions may be nanoparticle suspensions or milled suspensions.

[0078] In some embodiments, the liquid preparation for oral administration may take the form of, for example, elixir, solution, syrup, or suspension, or may be presented as a dry product to be reconstituted with water or other suitable vehicle before use.These liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, CREMOPHORE® or fractionated vegetable oils), and preservatives (e.g., methyl or propyl-p-hydroxybenzoic acid or sorbic acid).Preparation may also contain buffer salts, preservatives, flavoring agents, coloring agents, and sweeteners as needed.

[0079] Pharmaceutical compositions of the compounds may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers (e.g., PEG).

[0080] The composition may further comprise one or more additional pharmaceutical agents, such as anti-inflammatory agents, anti-atherosclerotic agents, immunosuppressants, immunomodulatory agents, cytostatic agents, angiogenesis inhibitors, kinase inhibitors, cytokine blockers, and inhibitors of cell adhesion molecules.

[0081] How to use Some embodiments herein are directed to methods of modulating ITK-mediated function in a human subject, comprising administering an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In some embodiments, methods of inhibiting ITK in a human subject comprise administering an oral dose of about 10 mg / day to about 80 mg / day of Compound I.

[0082] The present invention also relates to methods for inhibiting at least one ITK function, comprising contacting ITK with a compound I described herein. Cell phenotype, cell proliferation, activity of ITK, changes in biochemical output produced by active ITK, expression of ITK, or binding of ITK to a natural binding partner can be monitored. Such methods can also be methods for treating disease, biological assays, cellular assays, biochemical assays, and the like.

[0083] Compound I of the present invention can be useful as a JAK3 kinase inhibitor as well as an ITK inhibitor. This dual use of a single compound, inhibiting either the ITK pathway or the JAK3 pathway individually or both pathways simultaneously, can provide beneficial effects. As a result, Compound I of the present invention can find utility in the treatment of a wide range of diseases or conditions mediated by ITK activity, JAK3 activity, or both. Accordingly, some embodiments herein are directed to the treatment or prevention of diseases or conditions in which JAK, particularly JAK3, plays an active role using Compound I disclosed herein. In some embodiments, a method of treating a JAK3-mediated disease or disorder in a human subject comprises administering a compound of an embodiment herein to the human subject. Some embodiments provide a method for treating a JAK3-mediated disorder in a human subject in need of such treatment, comprising administering a therapeutically effective amount of a compound or composition according to the present disclosure to the human subject. Also provided is the use of Compound I disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by inhibition of JAK3, ITK, or a combination thereof. The embodiments discussed herein directed to methods of treating an ITK-mediated condition or disease may also be applied to methods of treating a JAK3-mediated condition or disease.

[0084] Also provided herein is a method for treating an ITK-mediated disease or a JAK3-mediated disease, comprising administering an oral dose of about 10 mg / day to about 80 mg / day of Compound I, a derivative thereof, or a combination thereof. In certain embodiments, the oral dose of about 10 mg / day to about 80 mg / day of Compound I, a derivative thereof, or a combination thereof may be in the form of a pharmaceutical composition. In embodiments, the pharmaceutical composition may include a pharmaceutically acceptable excipient.

[0085] In some embodiments, the present invention provides a method for treating an ITK-mediated disease or a JAK3-mediated disease or disorder in a human subject in need thereof, the method comprising orally administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I, wherein the ITK-mediated disease or disorder or JAK3-mediated disease or disorder is an autoimmune disorder, an immune-mediated disorder, a chronic inflammatory disorder, an acute inflammatory disorder, and / or an autoinflammatory disorder, and such a disease or disorder is treated. In some embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID. Such ITK-mediated diseases or disorders include, but are not limited to, those diseases or disorders described herein.

[0086] In some embodiments, the ITK kinase or JAK3 kinase-related disease or disorder treated by the compounds of the invention includes an autoimmune disorder, an immune-mediated disorder, a chronic inflammatory disorder, an acute inflammatory disorder, and / or an autoinflammatory disorder.

[0087] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is arthritis and arthropathy.Arthritis and arthropathy include but are not limited to idiopathic arthritis, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis, adult-onset Still's disease, seronegative spondyloarthritis, spondyloarthropathies, ankylosing spondylitis, spondylitis, spondyloarthritis, enthesitis, enthesopathy, psoriatic arthritis, reactive arthritis, inflammatory arthritis, inflammatory bowel disease-related arthritis, cystic fibrosis-related arthritis, gout, Reiter's syndrome and Lyme disease-related arthritis.

[0088] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is myositis and inflammatory myopathies, including, but not limited to, autoimmune myositis, dermatomyositis, polymyositis, and juvenile dermatomyositis.

[0089] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is scleroderma, including but not limited to systemic sclerosis / scleroderma, progressive systemic sclerosis, CREST syndrome (calcinosis, Raynaud's syndrome, esophageal insufficiency, sclerodactyly, telangiectasia), systemic sclerosis without skin sclerosis, localized scleroderma, morphea, linear scleroderma, scleroderma en coup de sabre, and juvenile scleroderma.

[0090] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is lupus, including, but not limited to, systemic lupus erythematosus, pediatric systemic lupus erythematosus, cutaneous lupus, subacute cutaneous lupus, chronic cutaneous lupus, discoid lupus, lupus erythematosus, chilblain lupus erythematosus, and lupus-related specific organ manifestations (e.g., lupus nephritis, lupus arthritis, CNS lupus, etc.).

[0091] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an autoinflammatory condition, including, but not limited to, VEXAS syndrome, Muckle-Wells syndrome, familial cold autoinflammatory syndrome, neonatal-onset multisystem inflammatory disease (NOMID), TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever, cryopyrin-associated periodic fever syndrome (CAPS), autoinflammatory disorders, and hyper-IgD syndrome / mevalonate kinase deficiency.

[0092] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is vasculitis, including, but not limited to, large-vessel vasculitis, medium-vessel vasculitis, small-vessel vasculitis, ANCA+ vasculitis, ANCA-negative vasculitis, Takayasu's arteritis, Wegener's granulomatosis, giant cell arteritis, polyarteritis nodosa, and Kawasaki disease.

[0093] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a gastrointestinal disorder and / or liver disorder. Gastrointestinal and liver disorders include enteritis, colitis, enterocolitis, gastritis, esophagitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, bulbar colon, acute and chronic pancreatitis, celiac disease, periodontitis, gingivitis, eosinophilic gastritis, gastric and duodenal ulcers, peritonitis, autoimmune atrophic gastritis of pernicious anemia, gastrointestinal or gastrointestinal fibrosis, primary biliary cholangitis, primary sclerosing cholangitis, hepatic fibrosis ... These include, but are not limited to, fibrosis (e.g., secondary to nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma), cirrhosis (e.g., secondary to primary biliary cholangitis or cirrhosis due to fatty liver disease) (e.g., secondary to alcoholic steatosis and nonalcoholic steatosis), autoimmune and inflammatory hepatitis / liver disease, cholestasis, cholestatic liver injury / disease, and intrahepatic cholestasis during pregnancy.

[0094] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is pulmonary respiratory disorder.Pulmonary respiratory disorder includes but is not limited to pulmonary inflammation, sinusitis, rhinitis, pneumonia, bronchitis, pulmonary fibrosis, idiopathic pulmonary fibrosis, asthma, bronchial asthma, allergic asthma, eosinophilic asthma, bronchial asthma, Churg-Strauss syndrome, bronchiolitis, bronchiolitis obliterans, chronic obstructive pulmonary disease (COPD), interstitial lung disease, acute lung injury, adult respiratory distress syndrome, drug-induced lung injury and autoimmune interstitial lung disease.

[0095] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an endocrine and / or metabolic disorder, including, but not limited to, diabetes mellitus, diabetes, type I diabetes, autoimmune thyroid disorders, Hashimoto's disease, Graves' disease, Addison's disease, autoimmune ovarian failure, obesity, steroid resistance, glucose intolerance, metabolic syndrome, metabolic bone disorders, thyroid disease, metabolic disorders, hyperparathyroidism, and menopause.

[0096] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a blood disease, including but not limited to autoimmune hemolytic syndrome, autoimmune hemolytic anemia, autoimmune thrombocytopenia, secondary hematological manifestations of autoimmune diseases (e.g., anemia), polycythemia vera, essential thrombocythemia, iron deficiency anemia, myelofibrosis with myelofibrosis (MMM), primary myelofibrosis (PMF), and immune-mediated bone marrow failure disorders.

[0097] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a neurological and / or psychiatric disorder, including, but not limited to, autoimmune encephalomyelitis, PANDA syndrome, neuromuscular disorders, neurodegenerative disorders, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), familial ALS, Alzheimer's disease, myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), Guillain-Barré syndrome, meningitis, encephalitis, traumatic brain injury, stroke, spinal cord injury, nerve ischemia, peripheral neuropathy, CNS scarring, nerve irritation, nervous system damage, dysregulation of neurites and sensory perception, peripheral neuropathy, psychogenic pruritus, tactile hallucinations, paresthesia, cerebrovascular accidents, delusional parasitosis, paraesthesia obsessive-compulsive disorder, transverse myelitis, optic neuritis, and neuromyelitis optica.

[0098] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is renal disease.Renal disease includes but is not limited to nephropathy, IgA nephropathy, immune-mediated glomerulonephropathy, autoimmune nephropathy, membranous glomerulopathy, chronic progressive nephropathy, diabetic nephropathy, renal fibrosis, ischemia / reperfusion injury-related, HIV-related nephropathy, ureteral obstructive nephropathy, glomerulosclerosis, nephrotic syndrome, proteinuria, polycystic kidney disease, diabetes-related kidney disease, nephritis, glomerulonephritis, diffuse proliferative glomerulonephritis, focal glomerulosclerosis, membranous glomerulonephritis, lupus glomerulonephritis, immune complex glomerulonephritis, fibrotic glomerulonephritis, chronic kidney disease, diabetic nephropathy, hypertension-induced nephropathy, immune-mediated nephropathy, uremia, and glomerulosclerosis disorder.

[0099] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an ocular disorder.Eye disorders include but are not limited to dry eye, anterior uveitis, posterior uveitis, acute uveitis, chronic uveitis, keratoconjunctivitis sicca, scleritis, episcleritis, keratitis, keratopathy, chorditis, retinal vasculitis, optic neuritis, retinopathy, diabetic retinopathy, immune-mediated retinopathy, macular degeneration, wet macular degeneration, dry (age-related) macular degeneration, ocular malignancy, ocular inflammation, ocular scarring, and sympathetic ophthalmia.

[0100] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is allergy and / or allergic reaction, including, but not limited to, hypersensitivity reactions such as type I hypersensitivity reactions, including atopy and anaphylaxis, type II hypersensitivity reactions, including Goodpasture's syndrome and autoimmune hemolytic anemia, type III hypersensitivity reactions, including Arthus reaction and serum sickness, and type IV hypersensitivity reactions, including contact dermatitis, and allograft rejection.

[0101] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a skin disease, including skin disorders, atopy, atopic dermatitis, eczema, contact dermatitis, allergic contact sensitization, allergic dermatitis, acne, acne vulgaris, whiteheads, inflammatory acne, cystic acne, scarring acne, keloid acne nuchalensis, hidradenitis suppurativa, neutrophilic dermatosis, pyoderma gangrenosum, acute febrile neutrophilic dermatosis (Sweet's syndrome), erythema elevatum elevans (EED), hidradenitis exudativa, histiocytoid neutrophilic dermatosis, intestinal bypass syndrome dermatosis, palisaded neutrophilic granulomatous dermatitis, neutrophilic urticarial dermatitis, chronic variant with lipodystrophy and fever, Neutrophilic skin syndrome (candle syndrome), hair loss disorders, alopecia, non-cicatricial alopecia, alopecia areata (AA), patchy AA, alopecia totalis (AT), alopecia universalis (AU), androgenetic alopecia (AGA), male / female pattern AGA, alopecia serpiginosa, alopecia areata (sisaihpo pattern), telogen effluvium, tinea capitis, hypotrichosis, hereditary hypotrichosis simplex, cicatricial alopecia, lichen planus pilaris, parietal centrifugal cicatricial alopecia, frontal fibrosing alopecia, alopecia nigra, alopecia nasalis, vitiligo, segmental vitiligo, monosegmental vitiligo, bisegmental vitiligo or multisegmental vitiligo, acral, facial or quadratic Non-segmental vitiligo including limb-facial vitiligo, centro-facial vitiligo, mucosal vitiligo, scattered small vitiligo, trichrome vitiligo, inflammatory raised margin vitiligo, tetrachromatic vitiligo, blue vitiligo, Koebner phenomenon, vitiligo vulgaris, generalized vitiligo, generalized vitiligo, mixed vitiligo (non-segmental type associated with segmental vitiligo), focal vitiligo, isolated mucosal vitiligo or vitiligo with or without leukoderma (involvement of body hair), bullous diseases, immune bullous diseases, pemphigoid, cicatricial pemphigoid, pemphigus vulgaris, linear IgA bullous dermatosis, cutaneous drug reactions, idiopathic chronic pruritus, pruritic (itchy) conditions, atopic pruritus, atopic dermatitis Dermatitis-associated pruritus, dry pruritus, pruritus associated with psoriasis ("psoriatic pruritus"), acute pruritus, chronic pruritus, idiopathic pruritus, brachioradialis pruritus, neurogenic pruritus, neuropathic pruritus, chronic idiopathic pruritus, hepatobiliary-associated pruritus, biliary pruritus, renal-associated pruritus, uremic pruritus, lichen simplex chronicus-associated pruritus, prurigo nodularis, pruritus associated with type II diabetes, pruritus associated with hypophysitis, pruritus associated with idiopathic thrombocytopenic purpura, pruritic urticarial papules of pregnancy (PUPP), swimmer's itch, pruritus associated with lymphoma, pruritus associated with leukemia, pruritic papules occurring in HIV patients,These include, but are not limited to, punctate palmoplantar keratoderma, psoriasis, plaque psoriasis, skin sensitization, skin inflammation, skin rash, inflammatory skin diseases, severe drug eruptions, skin diseases of pregnancy, eosinophilic folliculitis, foreign bodies or devices on the skin, fungal infections of the skin, pemphigoid of pregnancy, dandruff, ultraviolet dermatitis, scar growth, seborrheic dermatitis, stasis dermatitis, sunburn, urticaria, itch in urticaria, urticarial papules, chronic idiopathic urticaria, chronic urticaria, wound healing, wound or scar healing, surgical scarring, lichen planus, lichen sclerosis, insect bites, insect stings, dorsal paresthesia, and xerosis.

[0102] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is an infection and / or parasitic infestation, including, but not limited to, acute and chronic infections, sepsis syndrome, sepsis, septic shock, endotoxin shock, exotoxin-induced toxic shock, gram-negative sepsis, gram-positive sepsis, fungal sepsis, toxic shock syndrome, bacterial infection, body lice, pruritic papular pubic lice, head lice, herpes, cutaneous larva migrans, scarring, blisters, viral infections, parasitic infections, pediculosis, insect infestation, infectious arthritis, and Lyme disease.

[0103] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a neoplastic condition. Oncological conditions include cancer, neoplasms, visceral cancer, malignant tumors, myeloproliferative disorders, hematopoietic neoplasms, myeloid neoplasms, lymphoid neoplasms, non-small cell lung cancer, small cell lung cancer, skin cancer, myeloproliferative disorders, myelodysplastic syndromes, leukemias (e.g., acute and chronic leukemia, acute lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, or promyelocytic leukemia, chronic myelomonocytic leukemia), lymphomas (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, hairy cell lymphoma, Burkitt lymphoma, mast cell tumor, Hodgkin's disease or non-Hodgkin's disease, cutaneous lymphomas including mycosis fungoides and cutaneous T-cell lymphoma), myeloid malignancies, myelodysplasia These include, but are not limited to, thyroid cancer, thyroid follicular carcinoma, thyroid cancer ...

[0104] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a transplant-related therapeutic or prophylactic measure, including, but not limited to, prevention or treatment of organ transplant rejection, prevention or treatment of bone marrow transplant rejection, graft-versus-host reaction, graft-versus-host disease, chronic graft-versus-host disease, acute graft-versus-host disease, allograft rejection, acute allograft rejection, and chronic allograft rejection.

[0105] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is cardiovascular disorder.Cardiovascular disorder includes but is not limited to atherosclerosis, restenosis, atherosclerotic coronary restenosis, acute coronary syndrome, myocardial infarction, cardiac allograft vasculopathy, cardiac fibrosis, myocardial fibrosis, pericardial fibrosis, atrial fibrosis, recurrent pericarditis, chronic pericarditis, myocarditis, myocarditis, myocarditis, carditis, myocarditis and angiogenesis disorder.

[0106] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is a pain disorder (eg, acute pain, chronic pain, neuropathic pain, or fibromyalgia).

[0107] In some embodiments, the ITK-mediated or JAK3-mediated disease or disorder is fibrotic disorder.Fibrotic disorder includes but is not limited to fibrosis and scarring disorder (for example, liver fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, low-grade scarring, for example, scleroderma, increased fibrosis, keloid, postoperative scar, etc.), myelofibrosis, primary myelofibrosis, idiopathic myelofibrosis (IMF), radiation-induced fibrosis (for example, head and neck, gastrointestinal or pulmonary), fibrosclerosis, mediastinal fibrosis, retroperitoneal fibrosis, progressive massive fibrosis and nephrogenic systemic fibrosis.

[0108] In some embodiments, the disease or disorder is an ITK-mediated or JAK3-mediated disease or disorder, including inflammation, inflammatory conditions, chronic inflammatory disorders, acute inflammatory disorders, connective tissue diseases, autoimmune conditions / disorders / responses, autoimmune connective tissue diseases, Sjogren's syndrome, mixed connective tissue disease, polymyalgia rheumatica, sarcoidosis, autoimmune orchitis, Goodpasture's syndrome, Behcet's disease, metal-induced autoimmunity, autoimmune hearing loss (e.g., Meniel's disease), interstitial cystitis, polychondritis, relapsing polychondritis, autoimmune orchitis, silicone implant-associated autoimmunity, These include epidemics, drug-induced autoimmunity, HIV-associated autoimmune syndromes, widespread activation of the immune response, bone resorption disease, SAVI (Stimulator of Interferon Genes (STING)-associated vasculopathy with onset in infancy), hyperoxia-induced inflammation, reperfusion injury, postoperative trauma, tissue damage, cystic fibrosis, Th17-associated inflammation, increased accumulation of exogenous or synthetic opioids, jaundice, mastocytosis, Castleman's disease, systemic immunosenescence, transplant arteriopathy, hypereosinophilic syndrome (HES), systemic mast cell disease (SMCD), and macrophage activation syndrome.

[0109] In some embodiments, the ITK-mediated disease or JAK3-mediated disease is selected from the group consisting of atopic dermatitis, palmoplantar pustulosis, fibrous interstitial lung disease, peripheral T-cell lymphoma, celiac disease, asthma, cryopyrin-associated periodic fever syndromes (CAPS), recurrent pericarditis, VEXAS syndrome, ulcerative colitis, acute severe ulcerative colitis, Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute inflammatory psoriasis, genital psoriasis, autoimmune hepatitis, systemic lupus erythematosus (SLE), organ transplant rejection, chronic graft-versus-host disease (cGvHD), primary sclerosing cholangitis, or a combination thereof.

[0110] Another embodiment of the present disclosure provides a method for treating an inflammatory condition in a human subject in need thereof, the method comprising administering to a human subject having an inflammatory condition an oral dose of about 10 mg / day to about 80 mg / day of Compound I, wherein the inflammatory condition is selected from the group consisting of a chronic inflammatory condition, an acute inflammatory condition, an immune-mediated inflammatory condition, an autoimmune inflammatory condition, an inflammatory disease, or a combination thereof, and such condition is treated. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0111] In some embodiments, the inflammatory condition is selected from the group consisting of a chronic inflammatory condition, an acute inflammatory condition, an immune inflammatory condition, an autoimmune inflammatory condition, an inflammatory disease, or a combination thereof.

[0112] In some embodiments, the inflammatory condition is selected from the group consisting of atopic dermatitis, palmoplantar pustulosis, fibrous interstitial lung disease, peripheral T-cell lymphoma, celiac disease, asthma, cryopyrin-associated periodic fever syndromes (CAPS), recurrent pericarditis, VEXAS syndrome, ulcerative colitis, acute severe ulcerative colitis, Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute inflammatory psoriasis, genital psoriasis, autoimmune hepatitis, systemic lupus erythematosus (SLE), organ transplant rejection, chronic graft-versus-host disease (cGvHD), primary sclerosing cholangitis, or a combination thereof.

[0113] In some embodiments, the inflammatory condition is atopic dermatitis.

[0114] In some embodiments, the inflammatory condition is palmoplantar pustulosis.

[0115] In some embodiments, the inflammatory condition is a fibrotic interstitial lung disease.

[0116] In some embodiments, the inflammatory condition is peripheral T-cell lymphoma.

[0117] In some embodiments, the inflammatory condition is celiac disease.

[0118] In some embodiments, the inflammatory condition is asthma.

[0119] In some embodiments, the inflammatory condition is acute severe ulcerative colitis.

[0120] In some embodiments, the inflammatory condition is Crohn's disease.

[0121] In some embodiments, the inflammatory condition is psoriatic arthritis.

[0122] In some embodiments, the inflammatory condition is ankylosing spondylitis.

[0123] In some embodiments, the inflammatory condition is acute inflammatory psoriasis.

[0124] In some embodiments, the inflammatory condition is genital psoriasis.

[0125] In some embodiments, the inflammatory condition is autoimmune hepatitis.

[0126] In some embodiments, the inflammatory condition is systemic lupus erythematosus (SLE).

[0127] In some embodiments, the inflammatory condition is organ transplant rejection.

[0128] In some embodiments, the inflammatory condition is chronic graft-versus-host disease (cGvHD).

[0129] In some embodiments, the inflammatory condition is primary sclerosing cholangitis.

[0130] In some embodiments, the inflammatory condition is cryopyrin-associated periodic fever syndromes (CAPS).

[0131] In some embodiments, the inflammatory condition is recurrent pericarditis.

[0132] In some embodiments, the inflammatory condition is VEXAS syndrome.

[0133] In some embodiments, the inflammatory condition is ulcerative colitis.

[0134] In some embodiments, the inflammatory condition is rheumatoid arthritis.

[0135] In some embodiments, the inflammatory condition is inflammatory bowel disease.

[0136] In some embodiments, inflammation resulting from inflammatory bowel disease is treated.

[0137] In some embodiments, the inflammation resulting from inflammatory bowel disease is in the proximal portion of the intestine.

[0138] In some embodiments, the inflammation resulting from inflammatory bowel disease is in the distal portion of the intestine.

[0139] In some embodiments, the inflammation resulting from inflammatory bowel disease is in the ileum portion of the intestine.

[0140] In some embodiments, the inflammation resulting from inflammatory bowel disease is in the entire intestine.

[0141] In some embodiments, the human subject has a reduced incidence of anemia compared to the incidence of anemia when administered tofacitinib. In some embodiments, the human subject has a less than 4% chance of developing anemia. In some embodiments, the human subject has a less than 2% chance of developing anemia.

[0142] In some embodiments, the human subject has a reduced incidence of nephrotoxicity compared to the incidence of nephrotoxicity when administered ritrecitinib.

[0143] Another embodiment of the present disclosure provides a method of treating atopic dermatitis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In some embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0144] Another embodiment of the present disclosure provides a method for treating palmoplantar pustulosis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0145] Another embodiment of the present disclosure provides a method of treating fibrotic interstitial lung disease in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0146] Another embodiment of the present disclosure provides a method for treating peripheral T-cell lymphoma in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0147] Another embodiment of the present disclosure provides a method for treating celiac disease in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0148] Another embodiment of the present disclosure provides a method for treating asthma in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0149] Another embodiment of the present disclosure provides a method for treating acute severe ulcerative colitis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of Compound I of about 10 mg / day to about 80 mg / day. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0150] Another embodiment of the present disclosure provides a method for treating Crohn's disease in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0151] Another embodiment of the present disclosure provides a method for treating psoriatic arthritis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0152] Another embodiment of the present disclosure provides a method for treating ankylosing spondylitis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0153] Another embodiment of the present disclosure provides a method of treating acute inflammatory psoriasis in a human subject in need thereof, comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0154] Another embodiment of the present disclosure provides a method for treating genital psoriasis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0155] Another embodiment of the present disclosure provides a method for treating autoimmune hepatitis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0156] Another embodiment of the present disclosure provides a method for treating systemic lupus erythematosus (SLE) in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0157] Another embodiment of the present disclosure provides a method for treating organ transplant rejection in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0158] Another embodiment of the present disclosure provides a method for treating chronic graft-versus-host disease (cGvHD) in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0159] Another embodiment of the present disclosure provides a method for treating primary sclerosing cholangitis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0160] Another embodiment of the present disclosure provides a method for treating cryopyrin-associated periodic fever syndromes (CAPS) in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0161] Another embodiment of the present disclosure provides a method for treating recurrent pericarditis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0162] Another embodiment of the present disclosure provides a method for treating VEXAS syndrome in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0163] Another embodiment of the present disclosure provides a method for treating ulcerative colitis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0164] Another embodiment of the present disclosure provides a method for treating rheumatoid arthritis in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0165] Another embodiment of the present disclosure provides a method for treating inflammatory bowel disease in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0166] Another embodiment of the present disclosure provides a method for treating inflammation from inflammatory bowel disease in a human subject in need thereof, the method comprising administering to the human subject an oral dose of about 10 mg / day to about 80 mg / day of Compound I. In embodiments, the oral dose is about 5 mg BID to about 40 mg BID. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 5 mg BID. In some embodiments, the oral dose is about 15 mg BID. In some embodiments, the oral dose is about 25 mg BID. In some embodiments, the oral dose is about 40 mg BID. In some embodiments, the oral dose is about 10 mg TID.

[0167] As noted above, subjects suitable for treatment with the methods described herein include humans and non-human vertebrates, such as wild-type, domestic animals, and livestock. In some embodiments, the subjects described herein are animals. In some embodiments, the subjects are mammals. In some embodiments, the subjects are humans. In some embodiments, the subjects are non-human animals. In some embodiments, the subjects are non-human mammals. Dosing regimen

[0168] Compound I, or an oral pharmaceutical composition comprising it, is administered to a human subject at an oral dose of about 10 mg / day to about 80 mg / day of Compound I. Human subjects in need of such therapy are disclosed above. In some embodiments, the human subject has an inflammatory condition, such as a chronic inflammatory condition, an acute inflammatory condition, an autoimmune condition, or an inflammasome-related disease. According to the methods disclosed herein, a therapeutically effective amount of Compound I is administered at about 10 mg / day to about 80 mg / day. The dose administered to a particular subject depends on the characteristics of the treated subject, such as the specific subject being treated, age, weight, health, type of concomitant therapy (if any), and frequency of treatment, and can be readily determined by one of ordinary skill in the art (e.g., a clinician).

[0169] In any embodiment, a therapeutically effective amount of 1 mg / day of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 3 mg / day of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 5 mg / day of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 10 mg / day of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 15 mg / day of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 25 mg / day of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 30 mg / day of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 40 mg / day of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In some embodiments, a therapeutically effective amount of 50 mg / day of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In some embodiments, a therapeutically effective amount of 80 mg / day of Compound I is administered to a human subject having an inflammatory condition disclosed herein.

[0170] In any embodiment, the therapeutically effective amount of Compound I is from about 1 mg / day to about 100 mg / day, or any amount therebetween. In one embodiment, the therapeutically effective amount of Compound I is from about 2 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is from about 3 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is from about 4 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is from about 5 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is from about 10 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is from about 15 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is from about 20 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is from about 25 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 30 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 35 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 40 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 45 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 50 mg / day to about 100 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg / day to about 90 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg / day to about 80 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg / day to about 70 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg / day to about 60 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg / day to about 50 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg / day to about 40 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg / day to about 30 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg / day to about 20 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg / day to about 10 mg / day. In one embodiment, the therapeutically effective amount of Compound I is about 10 mg / day to about 80 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 0.1 mg / day.In one embodiment, the therapeutically effective amount of Compound I comprises about 0.5 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 1 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 2 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 3 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 4 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 5 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 6 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 7 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 8 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 9 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 10 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 11 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 12 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 13 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 14 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 15 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 16 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 17 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 18 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 19 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 20 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 21 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 22 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 23 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 24 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 10 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 26 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 27 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 28 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 29 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 30 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 31 mg / day.In one embodiment, a therapeutically effective amount of Compound I comprises about 32 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 33 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 34 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 35 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 36 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 37 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 38 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 39 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 40 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 41 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 42 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 43 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 44 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 45 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 46 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 47 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 48 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 49 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 50 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 51 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 52 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 53 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 54 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 55 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 56 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 57 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 58 mg / day. In one embodiment, a therapeutically effective amount of Compound I comprises about 59 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 60 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 61 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 62 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 63 mg / day.In one embodiment, the therapeutically effective amount of Compound I comprises about mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 66 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 67 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 68 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 69 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 70 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 71 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 72 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 73 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 74 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 75 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 76 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 77 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 78 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 79 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 80 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 81 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 82 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 83 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 84 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 85 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 86 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 87 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 88 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 89 mg / day, about 90 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 91 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 92 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 93 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 94 mg / day. In one embodiment, the therapeutically effective amount of Compound I comprises about 95 mg / day, about 96 mg / day, or about 97 mg / day.In one embodiment, the therapeutically effective amount of Compound I comprises about 98 mg / day, about 99 mg / day, hi one embodiment, the therapeutically effective amount of Compound I comprises about 100 mg / day.

[0171] In any embodiment, a therapeutically effective amount of 5 mg BID of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 10 mg BID of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 15 mg BID of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 25 mg BID of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, a therapeutically effective amount of 40 mg BID of Compound I is administered to a human subject having an inflammatory condition disclosed herein.

[0172] In any embodiment, the therapeutically effective amount of Compound I is from about 1 mg BID to about 100 mg BID, or any amount therebetween. In one embodiment, the therapeutically effective amount of Compound I is from about 2 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is from about 3 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is from about 4 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is from about 5 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is from about 10 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is from about 15 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is from about 20 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is from about 25 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is from about 30 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 35 mg BID to about 100 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 40 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 45 mg BID to about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg BID to about 45 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg BID to about 40 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg BID to about 35 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg BID to about 30 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg BID to about 25 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg BID to about 20 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg BID to about 15 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg BID to about 10 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg BID to about 5 mg BID. In one embodiment, the therapeutically effective amount of Compound I is about 1 mg BID to about 50 mg BID.In one embodiment, the therapeutically effective amount of Compound I is from about 5 mg BID to about 40 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 1 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 2 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 3 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 4 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 5 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 6 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 7 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 8 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 9 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 10 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 11 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 12 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 13 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 14 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 15 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 16 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 17 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 18 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 19 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 20 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 21 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 22 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 23 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 24 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 25 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 26 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 27 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 28 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 29 mg BID.In one embodiment, the therapeutically effective amount of Compound I comprises about 30 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 31 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 32 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 33 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 34 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 35 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 36 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 37 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 38 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 39 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 40 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 41 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 42 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 43 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 44 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 45 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 46 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 47 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 48 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 49 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 50 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 51 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 52 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 53 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 54 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 55 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 56 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 57 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 58 mg BID. In one embodiment, the therapeutically effective amount of Compound I comprises about 59 mg BID.In one embodiment, a therapeutically effective amount of Compound I comprises about 60 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 61 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 62 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 63 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 64 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 65 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 66 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 67 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 68 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 69 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 70 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 71 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 72 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 73 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 74 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 75 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 76 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 77 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 78 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 79 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 80 mg BID. In preferred embodiments, a therapeutically effective amount of Compound I comprises about 5 mg BID, about 10 mg BID, about 15 mg BID, about 25 mg BID, or 40 mg BID. In one embodiment, a therapeutically effective amount of Compound I comprises about 5 mg BID.

[0173] In any embodiment, 5 mg TID of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, 10 mg TID of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, 15 mg TID of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, 25 mg TID of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, 30 mg TID of Compound I is administered to a human subject having an inflammatory condition disclosed herein. In any embodiment, 40 mg TID of Compound I is administered to a human subject having an inflammatory condition disclosed herein.

[0174] In any embodiment, the therapeutically effective amount of Compound I is from about 1 mg TID to about 100 mg TID, or any amount therebetween. In any embodiment, the therapeutically effective amount of Compound I is from about 2 mg TID to about 50 mg TID. In any embodiment, the therapeutically effective amount of Compound I is from about 3 mg TID to about 50 mg TID. In any embodiment, the therapeutically effective amount of Compound I is from about 4 mg TID to about 50 mg TID. In any embodiment, the therapeutically effective amount of Compound I is from about 5 mg TID to about 50 mg TID. In any embodiment, the therapeutically effective amount of Compound I is from about 10 mg TID to about 50 mg TID. In any embodiment, the therapeutically effective amount of Compound I is from about 15 mg TID to about 50 mg TID. In any embodiment, the therapeutically effective amount of Compound I is from about 20 mg TID to about 50 mg TID. In any embodiment, the therapeutically effective amount of Compound I is from about 25 mg TID to about 50 mg TID. In some embodiments, the therapeutically effective amount of Compound I is about 30 mg TID to about 50 mg TID. In some embodiments, the therapeutically effective amount of Compound I is about 35 mg TID to about 100 mg TID. In some embodiments, the therapeutically effective amount of Compound I is about 40 mg TID to about 50 mg TID. In some embodiments, the therapeutically effective amount of Compound I is about 45 mg TID to about 50 mg TID. In some embodiments, the therapeutically effective amount of Compound I is about 1 mg TID to about 45 mg TID. In some embodiments, the therapeutically effective amount of Compound I is about 1 mg TID to about 40 mg TID. In some embodiments, the therapeutically effective amount of Compound I is about 1 mg TID to about 35 mg TID. In some embodiments, the therapeutically effective amount of Compound I is about 1 mg TID to about 30 mg TID. In some embodiments, the therapeutically effective amount of Compound I is about 1 mg TID to about 25 mg TID. In some embodiments, the therapeutically effective amount of Compound I is from about 1 mg TID to about 20 mg TID. In some embodiments, the therapeutically effective amount of Compound I is from about 1 mg TID to about 15 mg TID. In some embodiments, the therapeutically effective amount of Compound I is from about 1 mg TID to about 10 mg TID. In some embodiments, the therapeutically effective amount of Compound I is from about 1 mg TID to about 5 mg TID.In one embodiment, the therapeutically effective amount of Compound I is from about 1 mg TID to about 50 mg TID. In one embodiment, the therapeutically effective amount of Compound I is from about 2.5 mg TID to about 20 mg TID.

[0175] In one embodiment, a therapeutically effective amount of Compound I comprises about 1 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 2 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 2.5 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 3 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 4 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 5 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 6 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 7 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 8 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 9 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 10 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 11 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 12 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 13 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 14 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 15 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 16 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 17 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 18 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 19 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 20 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 21 mg of TID, and in one embodiment, a therapeutically effective amount of Compound I comprises about 22 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 23 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 24 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 25 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 26 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 27 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 28 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 29 mg of TID.In one embodiment, a therapeutically effective amount of Compound I comprises about 30 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 31 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 32 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 33 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 34 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 35 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 36 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 37 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 38 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 39 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 40 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 41 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 42 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 43 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 44 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 45 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 46 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 47 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 48 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 49 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 50 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 51 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 52 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 53 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 54 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 55 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 56 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 57 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 58 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 59 mg of TID.In one embodiment, a therapeutically effective amount of Compound I comprises about 60 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 61 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 62 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 63 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 66 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 67 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 68 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 69 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 70 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 71 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 72 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 73 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 74 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 75 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 76 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 77 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 78 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 79 mg of TID. In one embodiment, a therapeutically effective amount of Compound I comprises about 80 mg of TID. In preferred embodiments, a therapeutically effective amount of Compound I comprises about 5 mg of TID, about 10 mg of TID, about 15 mg of TID, about 25 mg of TID, or 40 mg of TID.

[0176] In some embodiments, the oral dose of Compound I administered to a human subject according to the methods disclosed herein comprises the free base. In some embodiments, the oral dose of Compound I administered to a human subject according to the methods disclosed herein comprises a pharmaceutically acceptable salt.

[0177] In any embodiment, a human subject having an inflammatory condition is administered about 1 mg / day to about 100 mg / day of Compound I.

[0178] In any embodiment, a human subject having an inflammatory condition is administered about 1 mg BID to about 100 mg BID of Compound I.

[0179] In any embodiment, a human subject having an inflammatory condition is administered about 1 mg TID to about 100 mg TID of Compound I.

[0180] In any embodiment, a human subject having an inflammatory condition is administered about 10 mg / day to about 80 mg / day of Compound I.

[0181] In any embodiment, a human subject having an inflammatory condition is administered about 5 mg BID to about 40 mg BID of Compound I.

[0182] The dosage administered will be a therapeutically effective amount of the composition sufficient to result in the symptoms or amelioration of symptoms, and may vary depending on known factors such as the pharmacodynamic characteristics of the active ingredient and its mode of administration, the age, sex, health, and weight of the subject, the nature and extent of the symptoms, type of concurrent therapy, frequency of treatment, and the desired effect.

[0183] In some embodiments, the oral compositions comprising Compound I described herein can be administered to a subject once (e.g., as a single dose or application). In some embodiments, the oral compositions of embodiments herein are administered at least once daily, such as at least twice, three times, or four times daily. In some embodiments, the oral compositions of embodiments herein can be administered daily, twice daily, three times daily, weekly, twice weekly, every two weeks, every three weeks, monthly, or as directed by a physician, as needed. The oral compositions of embodiments herein can be administered at any interval to achieve a therapeutically desired effect, such as inducing or maintaining remission, preventing or alleviating symptoms. In some embodiments, the oral compositions of embodiments herein can be administered to a subject for 1, 2, 3, 4, 5, 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or a range of any two of these values. In some embodiments, treatment may continue for at least one week, one month, one year, or as otherwise directed by a physician. In some embodiments, treatment may extend for multiple years, the duration of the disease, or the lifespan of the subject. In some embodiments, the oral compositions of embodiments herein may be administered to a subject in need thereof once or twice daily for about 2 to about 28 days, or about 7 to about 10 days. The oral compositions of embodiments herein may also be administered to a subject once, twice, or three times daily for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or any combination thereof, per year.

[0184] In some embodiments, an oral composition comprising Compound I described herein is administered before, after, or with a meal. In some embodiments, an oral composition described herein is administered before, after, or with a high-fat meal. In some embodiments, an oral composition described herein is administered before, after, or with a standardized high-fat meal. In some embodiments, the high-fat meal is a high-calorie, high-fat meal. In some embodiments, the high-fat meal follows FDA guidance on high-fat meals. In some embodiments, the high-calorie, high-fat meal follows FDA guidance on high-fat and high-calorie meals. In some embodiments, the high-fat meal comprises a fat content of about 50% or more of the total calorie content of the meal. See Center for Drug Evaluation and Research, Food and Drug Administration, U.S. Department of Health and Human Services (2002). See Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies. Office of Training and Communications Division of Drug Information, HFD-240. In some embodiments, a high-calorie, high-fat diet comprises a fat content of at least 50% of the total calorie content of the diet, and a total calorie content of about 800 to about 1000 kilocalories.

[0185] In some embodiments, the oral compositions described herein are administered after fasting overnight.In some embodiments, the overnight fasting is at least about 6 hours, at least about 7 hours, at least about 8 hours, at least about 9 hours, or at least about 10 hours.For example, the oral compositions described herein can be administered after fasting overnight for at least 10 hours, followed by a high-fat, high-calorie meal.

[0186] While preferred embodiments have been shown and described in detail herein, it will be apparent to those skilled in the art that various modifications, additions, substitutions, and the like may be made therein without departing from the spirit of the invention, and are therefore deemed to be within the scope of the invention as defined in the following claims.

[0187] The present disclosure is further illustrated by the following examples. [Example]

[0188] [Example 1] A Phase I, Placebo-Controlled, Randomized, Observer-Blinded, Single Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Compound I in Healthy Subjects

[0189] Compound I is an orally available, small-molecule covalent inhibitor of interleukin-2-inducible T-cell kinase (ITK, also known as EMT or TSK), the tyrosine protein kinase TXK (also known as resting lymphocyte kinase or RLK), and Janus kinase (JAK) 3 for the treatment of T-cell-mediated autoimmune diseases. ITK and TXK are two members of the Tec family of tyrosine kinases, which consists of five family members: Tec, Bruton's tyrosine kinase (BTK), myeloid-expressed kinase (BMX), TXK, and ITK. These kinases play a central role in regulating hematopoietic cell biology, more specifically the development and activity of lymphoid and myeloid cells. The role of ITK and TXK in T-cell function has been delineated through genetic knockdown / kinase inactivation of these genes in rodents. JAK3 is a key signaling molecule downstream of numerous cytokines, including interleukin (IL) 2, 4, 7, 9, 15, and 21, which are members of the common gamma-chain family of cytokine receptors. These cytokines are involved in autoimmune responses. Inhibiting ITK, TXK, and JAK3 may be a specific and effective method for inhibiting T cell activation and survival.

[0190] The first therapeutic indication in human trials is moderate to severe plaque psoriasis. Additional therapeutic indications of interest include rheumatoid arthritis (RA), hidradenitis suppurativa (HS), psoriatic arthritis (PSoA), ulcerative colitis (UC), and Crohn's disease.

[0191] Study Rationale - This study provided an evaluation of the safety, tolerability, PK, and pharmacodynamics (PD) of Compound I following single ascending oral doses to healthy subjects. This study also evaluated the effect of formulation on the PK of Compound I following single oral doses of Compound I and will provide dosing guidance in future planned studies in moderate-to-severe plaque psoriasis (MSPP). The effect of food on the PK of Compound I following single oral doses was also evaluated.

[0192] Primary Objective—The safety, tolerability, and PK profile of Compound I were evaluated following a single oral dose of Compound I in healthy subjects.

[0193] Primary endpoints - number and rate of adverse events (AEs) and serious adverse events (SAEs); mean changes from baseline in clinical laboratory values, vital signs, and electrocardiogram (ECG) abnormalities.

[0194] Secondary Objectives - Evaluate the effect of food on the PK of Compound I after a single oral dose of Compound I. Evaluate the effect of formulation on the PK of Compound I after a single oral dose of Compound I. Evaluate the PD response to Compound I after a single oral dose of Compound I.

[0195] Secondary endpoints - plasma concentrations of Compound I. Mean changes from baseline in ex vivo stimulated pSTAT5 and pSTAT1 (signal transducer and activator of transcription), and ex vivo stimulated IFNγ mRNA (interferon gamma messenger ribonucleic acid). Overall study design and planning

[0196] Study Type - This was an FIH, randomized, observer-blinded, placebo-controlled study designed to evaluate the safety, tolerability, PK, and PD of Compound I in healthy subjects. The study consisted of a single ascending dose (SAD) cohort (1-80 mg / day) plus formulation bridging and food effect (FE) cohorts.

[0197] Approximately 64 male and female subjects were enrolled in eight planned cohorts of the SAD study. In each cohort, a total of eight subjects were randomized to receive a single oral capsule dose of Compound I (n=6) or placebo (n=2) in the morning with approximately 240 mL of water after at least an 8-hour overnight fast.

[0198] Dose levels are listed in Table 1.

[0199] Cohort 4 was the FE (food effect) cohort in which subjects fasted on day 1 and received Compound I capsules or placebo, followed by a 7-day washout period and a high-fat, high-calorie breakfast on day 8.

[0200] Cohort 5 was a formulation cross-linking cohort in which subjects received Compound I capsules or placebo on day 1 and, after a 7-day washout period, Compound I tablets or placebo on day 8.

[0201] The dosage form of Compound I in Cohorts 6, 7, and 8 is a capsule, and subjects receive a single oral dose of Compound I (n=6) capsule or placebo (n=2) on Day 1 after an overnight fast of at least 8 hours. [Table 1]

[0202] Data Overview PK was linear and absorption was rapid, indicating that Compound I has a favorable PK profile up to a single dose of 80 mg.

[0203] Exposure was dose-proportional (linear C max and AUC).

[0204] Absorption was rapid (Tmax 0.7-1.2 hours).

[0205] Absorption was rapid (Tmax 0.7-1.2 hours).

[0206] The half-life ranges from 1.5 to 2.5 hours.

[0207] The within-cohort exposure variability CV ranged from 21% to 64%.

[0208] Food Effect and Formulation - A high-calorie, high-fat meal reduced Cmax by 31% and delayed Tmax by 1 to 5 hours but had no significant effect on AUC, bioavailability, or T1 / 2 of a single 15 mg dose. There were no significant differences in PK parameters from a single 25 mg dose between the capsule formulation (SAD) and tablet formulation.

[0209] Observed human Compound I PK (1-80 mg, preliminary PK parameters) are shown in Figure 1 and Table 2. [Table 2]

[0210] The effect of food and formulation on the AUC data is shown in Figure 2 (15 mg), Figure 3 (25 mg), and Table 3. [Table 3]

[0211] SAD Exploratory PD Efforts—Both PD markers of ITK (αCD3 / αCD28-induced IL2 and IFNγ mRNA) and JAK3 (IL2-induced pSTAT5) activation were dose-dependently inhibited by Compound I. Concomitant activation of the ITK and JAK3 pathways (αCD3 / IL-15-induced IFNγ protein production) was dose-dependently inhibited by Compound I. Near-complete inhibition of dual ITK-stimulated IFNγ protein production and JAK3-stimulated IFNγ protein production was observed in the high-dose cohort, with >50% inhibition maintained for 12 hours.

[0212] αCD3 / αCD28-stimulated IL2 mRNA production is shown in FIG.

[0213] αCD3 / αCD28-stimulated IFNγ mRNA production is shown in FIG.

[0214] IL2-stimulated pSTAT5 in lymphocytes is shown in FIG.

[0215] IL2-stimulated pSTAT5 in CD3+ T cells is shown in FIG.

[0216] αCD3 / IL15-stimulated IFNγ protein production is shown in FIG.

[0217] Summary of Safety Data - Safety data were very encouraging. There were 17 TEAEs, 14 in Compound I-treated subjects and 3 in placebo subjects. All 14 TEAEs (13 subjects) in Compound I-treated subjects were mild and transient. No clinically significant changes in WBC counts were seen during treatment or at follow-up. Transient increases in transaminases (1 subject) and CK (2 subjects) were seen at follow-up in the highest dose group (80 mg), all of which resolved at subsequent follow-up.

[0218] Results: 63 subjects completed the SAD study. There were no deaths, serious AEs, or discontinuations due to AEs. Plasma concentrations of Compound I increased in a dose-dependent manner. Peak concentrations were reached within 2 hours after administration. Compound I caused dose- and time-dependent modulation of all PD biomarker readouts (αCD3 / αCD28-stimulated interleukin IL2 and interferon IFNγ mRNA levels, IL15-stimulated and αCD3 / IL-15-stimulated IFNγ protein production). Near-complete inhibition of biomarker readouts was observed 2 hours after treatment with Compound I at doses ranging from 15 mg to 80 mg.

[0219] Summary of SAD data: Figures 4-8 and Figures 9-13 show the results of ITK (IL2 mRNA), ITK (IFNγ mRNA), JAK3 (pSTAT5, lymphocytes), and JAK3 (pSTAT5, CD3 + T), and ITK & JAK (IFNγ protein), respectively,max Figure 1 shows the SAD dose response, SAD exposure response, and SAD calculated response in the SAD study. ... Figure 1 shows the SAD dose response, SAD exposure response, and SAD calculated response in the SAD study. Figure 1 shows the SAD dose response, SAD exposure response, and SAD calculated response in + T), and clinical and preclinical IC of ITK & JAK (IFNγ proteins) 50 The data are shown in Table 4. [Table 4]

[0220] Conclusions: Compound I was safe and well tolerated, producing a dose-dependent increase in plasma Compound I activity and PD effects consistent with inhibition of ITK and JAK3.

[0221] [Example 2] A Phase I, Placebo-Controlled, Randomized, Investigator- and Participant-Blinded, Sponsor-Open, Combined Ascending-Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Compound I in Healthy Participants

[0222] Study Rationale - This study provided an evaluation of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of Compound I after ascending multiple-dose oral administration to healthy participants. The study also included a comparison of the effect of delivering a 30 mg daily dose as a single fixed dose (30 mg once daily [QD]) versus delivered in divided doses (10 mg three times daily [TID]) on the PK of Compound I to provide dosing guidance in future planned trials in ulcerative colitis (UC). Goals and evaluation items

[0223] Primary Objective - To evaluate the safety and tolerability of Compound I following multiple oral doses of Compound I in healthy participants.

[0224] Primary endpoints - number and rate of adverse events (AEs) and serious adverse events (SAEs); mean changes from baseline in clinical laboratory values, vital signs, and electrocardiogram (ECG).

[0225] Secondary Objective - To investigate the pharmacokinetic (PK) profile of Compound I following multiple oral doses of Compound I in healthy participants.

[0226] Secondary endpoints - Plasma concentrations and PK parameters of Compound I: AUC0-tau, AUC0-inf, Ctrough, Cmax, tmax, Kel, t1 / 2, CLss / F, Vss / F, Rac.

[0227] Exploratory Objective - To investigate the pharmacodynamic (PD) response to Compound I following multiple oral doses of Compound I in healthy participants.

[0228] Exploratory endpoints - Mean change from baseline in cellular, extracellular (secretory), and / or inflammatory message markers. Study design

[0229] Overall Design - This study was a randomized, investigator- and participant-blinded, sponsor-open, placebo-controlled study designed to evaluate the safety, tolerability, PK, and PD of Compound I in healthy participants. The study consisted of multiple cohorts evaluating escalating doses of Compound I.

[0230] Approximately 60 participants were enrolled in five cohorts. At each dose level / cohort, a total of 10 participants were randomized to receive 2 weeks of oral Compound I (n = 8) or placebo (n = 2). In Cohort 3, 20 participants were randomized to receive multiple oral doses of Compound I QD (n = 8), Compound I TID (n = 8), placebo QD (n = 2), or placebo TID (n = 2). Cohort 3 progressed in parallel with Cohorts 4 and 5 and did not require a meeting for dose escalation.

[0231] The study began with a planned dose of 5 mg twice daily (BID). Planned dose levels and dosing frequencies are listed in Tables 5 and 6 below. Escalation to the next higher cohort depended on safety and PK data from all participants in the previous cohort and was based on data from at least six participants up to at least 48 hours after the last dose. In no case did dose escalation steps exceed three times the previous dose level. [Table 5] [Table 6]

[0232] Results: Fifty-seven subjects completed the MAD study. There were no deaths, serious AEs, or discontinuations due to AEs. Plasma concentrations of Compound I increased in a dose-dependent manner. Peak concentrations were reached within 2 hours after administration. Compound I caused dose- and time-dependent modulation of all PD biomarker readouts (αCD3 / αCD28-stimulated interleukin IL2 and interferon IFNγ mRNA levels, IL15-stimulated and αCD3 / IL-15-stimulated IFNγ protein production). Near-complete inhibition of biomarker readouts was observed 2 hours after treatment with Compound I at doses ranging from 15 mg to 80 mg.

[0233] Summary of MAD Data: Table 7 shows the safety profile of Compound I from the MAD study. Figures 15-18 and Table 8 show the pharmacodynamic and pharmacokinetic data for oral administration of Compound I from the MAD study.

[0234] Table 7 shows that Compound I was safe and tolerable for up to 2 weeks of dosing in HV. One adverse event (AE) of particular note (shingles) at the highest dose tested is consistent with the known properties of JAK inhibitors. [Table 7]

[0235] Figure 15 and Table 8 show the pharmacokinetics of Compound I at several doses. max and AUC) increased slightly more than dose-proportionally. To reach the HWB dual stimulation EC50, human Compound I p >=3.47 (MAD PD data) or 4.19 (in vitro report) ng / mL. At steady state, C p EC50: 4.3 ng / mL for 12 hours / day. At steady state, C p The Cp was greater than EC50: 5.7 ng / mL with a duration of 16 hours / day. At 30 mg QD and steady state at 11.5 hours post-dose, the Cp was EC 50 :11.5 hours / day for a duration of more than about 4 ng / mL. [Table 8]

[0236] MAD exploratory pharmacodynamic dose-response data for Compound I in the BID cohort are shown in Figures 16A-C. Compound I demonstrated dose- and time-dependent modulation of all pharmacodynamic biomarker readouts, with 15-40 mg BID doses inhibiting biomarker readouts by approximately 50-90% over the dosing interval.

[0237] MAD exploratory pharmacodynamic dose-response data for Compound I comparing the 30 mg QD, 15 mg BID, and 10 mg TID cohorts are shown in Figures 17A-C. The 10 mg TID, 15 mg BID, and 30 mg BID doses inhibited biomarker readouts to similar degrees.

[0238] MAD exploratory pharmacodynamic dose-response data for Compound I for all cohorts are shown in Figures 18A-C. EC 50 and IC 50 The data are shown in Table 9. MAD Day 1 EC50 EC on days 7 and 15 50 No significant changes were observed when compared with [Table 9]

[0239] Conclusions: Compound I was safe and well tolerated, producing a dose-dependent increase in plasma Compound I activity and PD effects consistent with inhibition of ITK and JAK3.

[0240] [Example 3] 13-week toxicity study in rats and cynomolgus monkeys

[0241] Objective: To evaluate the toxicity and toxicokinetics (TK) of Compound I after 13 weeks of daily administration. The rat study design is shown in Table 10. [Table 10]

[0242] Rat evaluation: At 80 mpk, no adverse effects were observed and no adverse effect levels were observed. The margin of safety for the rat studies is shown in Tables 11-13. [Table 11] [Table 12] [Table 13]

[0243] The cynomolgus monkey study design is shown in Table 14. [Table 14]

[0244] Cynomolgus monkey evaluation: No adverse effects were observed on body weight (total) and food consumption (total), overall clinical pathology, anatomic pathology, or ophthalmology. Adverse effects included liquid and unformed feces associated with dehydration (more significant and persistent in the mid- and high-dose groups), clinical pathology findings, transient but significant weight loss during this period, dose-dependent opportunistic infections in the gastrointestinal tract, morbidity, and significant symptoms requiring unscheduled sacrifice and a drug holiday at 12 mpk. The occurrence and severity of these effects were generally dose-dependent, being mild / delayed in the low-dose group and moderate / significant in the mid- and high-dose groups. No adverse effect levels were observed at 3 mpk. The margin of safety for the cynomolgus monkey study is shown in Tables 15-17. [Table 15] [Table 16] [Table 17]

[0245] A summary of the 13-week cynomolgus monkey study is shown in Table 18. [Table 18]

[0246] [Example 4] Pharmacodynamic analysis of an antigen-induced arthritis rat model

[0247] This study evaluated the kinetics of ankle diameter swelling in rats treated with IAA. The treatment model used PO administration starting on day 6. There was no significant difference between 5 mpk BID, 15 mpk BID, and 30 mpk QD. BID administration is more effective than QD administration in this rat arthritis model. The results are shown in Figure 19.

[0248] [Example 5] Pharmacodynamic analysis of Compound I compared to ritrecitinib

[0249] Compound I and ritrecitinib are covalent inhibitors that can modify the cysteine ​​residues in the ATP sites of ITK kinase and JAK3 kinase. Compound I inhibits both ITK and JAK3 (3-fold selectivity for ITK), while ritrecitinib is a JAK3-selective inhibitor (12-fold selectivity for JAK3) (see Tables 19 and 20). [Table 19] [Table 20]

[0250] A comparison of Compound I administration with a 50 mg dose of ritrecitinib (simulated data) is shown in Figures 20A-B. Biomarker inhibition with Compound I 15 mg BID and 30 mg QD is similar to that of 50 mg ritrecitinib.

[0251] [Example 6] A murine T cell transfer model of inflammatory bowel disease

[0252] This study evaluated the dose-dependent ability of Compound I to inhibit inflammation in a murine T cell transfer model of inflammatory bowel disease. Compound I inhibited colitis in the murine T cell transfer model, dose-dependently reducing inflammation in the proximal and distal colon, as well as the ileum. The effect was greater than that of anti-IL12(P40), which significantly reduced inflammation in the proximal and distal colon. The results are shown in Figure 21 and Figure 22A-C.

[0253] [Example 7] Compound I UC for Ph2a / POC testing

[0254] Three related molecules have been approved or have positive Phase II / III data for UC:

[0255] Tofacitinib: Pan-JAKi approved but with a black box warning regarding CV risks

[0256] Ritrecitinib (PF-06651600): A Pfizer covalent JAK3 / ITK inhibitor with Phase 2 efficacy in UC

[0257] Cyclosporine A (CsA) is effective / approved for UC - rarely used due to nephrotoxicity

[0258] Compound I differs from all these drugs in important ways (key cellular data below):

[0259] Unlike tofacitinib, Compound I is completely specific for JAK3 and therefore does not have the problem of inhibiting other JAK kinases, such as JAK2, which can lead to anemia. Compound I is approximately 100 times more potent against ITK than ritrecitinib. Compound I and CsA are equivalent in terms of T cell receptor blockade, but toxicity studies of Compound I have shown no evidence of nephrotoxicity. [Table 21]

[0260] Potential endpoints: Clinical remission - defined as a modified Mayo score of 0 to 2. Clinical response - a reduction from baseline in the modified Mayo score (mMS) of 2 or less points and at least 30% better than input. Corticosteroid-free remission -Improvement in endoscopic examination Endoscopic remission Histological response / remission

[0261] Aclaris Experimental Colitis Data - Histological damage was assessed in the proximal / distal colon and ileum. Representative data shown here is from the distal colon, and Compound I was more protective than both controls across all three regions of digestive tissue analyzed. Results are shown in Figures 23 and 24.

[0262] Although the embodiments herein have been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible, and therefore, the spirit and scope of the appended claims should not be limited to the description and preferred versions contained herein.

Claims

1. 1. A method for treating an inflammatory condition in a human subject in need thereof, comprising: The human subject is administered about 10 mg / day to about 80 mg / day of Compound I 【Chemistry 1】 or a derivative thereof to a human subject to treat said inflammatory condition.

2. 10. The method of claim 1, wherein about 5 mg BID to about 40 mg BID of Compound I is administered to the subject.

3. 10. The method of claim 1, wherein about 30 mg / day of Compound I is administered to the subject.

4. 10. The method of claim 1, wherein about 5 mg BID of Compound I is administered to the subject.

5. 10. The method of claim 1, wherein about 15 mg BID of Compound I is administered to the subject.

6. 10. The method of claim 1, wherein about 25 mg BID of Compound I is administered to the subject.

7. 2. The method of claim 1, wherein the inflammatory condition is selected from the group consisting of a chronic inflammatory condition, an acute inflammatory condition, an immune inflammatory condition, an autoimmune inflammatory condition, an inflammasome-associated disease, or a combination thereof.

8. 2. The method of claim 1, wherein the inflammatory condition is selected from the group consisting of atopic dermatitis, palmoplantar pustulosis, fibrous interstitial lung disease, peripheral T-cell lymphoma, celiac disease, asthma, recurrent pericarditis, VEXAS syndrome, ulcerative colitis, acute severe ulcerative colitis, Crohn's disease, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute inflammatory psoriasis, genital psoriasis, autoimmune hepatitis, systemic lupus erythematosus (SLE), organ transplant rejection, chronic graft-versus-host disease (cGvHD), primary sclerosing cholangitis, or a combination thereof.

9. 9. The method of claim 8, wherein the inflammatory condition is recurrent pericarditis.

10. 9. The method of claim 8, wherein the inflammatory condition is VEXAS syndrome.

11. 9. The method of claim 8, wherein the inflammatory condition is ulcerative colitis.

12. 9. The method of claim 8, wherein the inflammatory condition is rheumatoid arthritis.

13. 9. The method of claim 8, wherein the inflammatory condition is inflammatory bowel disease.

14. 14. The method of claim 13, wherein the inflammation resulting from inflammatory bowel disease is in the proximal portion of the intestine.

15. 14. The method of claim 13, wherein the inflammation resulting from inflammatory bowel disease is in the distal portion of the intestine.

16. 14. The method of claim 13, wherein the inflammation resulting from inflammatory bowel disease is in the ileum portion of the intestine.

17. 14. The method of claim 13, wherein the inflammation resulting from inflammatory bowel disease is throughout the intestine.

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