Immediate-release formulations of a TYK2 inhibitor

Abstract

Described herein are immediate-release, oral tablet compositions for treating a TYK2-mediated disorder. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.

Description

IMMEDIATE-RELEASE FORMULATIONS OF A TYK2 INHIBITORCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 583,934, filed on September 20, 2023; the content of which is hereby incorporated by reference herein in its entirety.BACKGROUND

[0002] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g., IFN-a, IFN-P, IFN-K, IFN-5, IFN-s, IFN-T, IFN-CO, and IFN-^ (also known as limitin), and interleukins (e.g., IL-4, IL-6, IL- 10, IL-11, IL- 12, IL- 13, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). The activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0003] TYK2 activation by IL-23, has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome-wide association study of 2,622 individuals with psoriasis identified associations between disease susceptibility and TYK2. Knockout or tyrphostin inhibition of TYK2 significantly reduces both IL-23 and IL-22-induced dermatitis.

[0004] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucous hypersecretion is mediated by IL-13-induced activation of TYK2, which in turn activates STAT6.

[0005] Decreased TYK2 activity leads to protection of joints from collagen antibody- induced arthritis, a model of human rheumatoid arthritis. Mechanistically, decreased Tyk2 activity reduced the production of Thl / Thl7-related cytokines and matrix metalloproteases, and other key markers of inflammation.

[0006] TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)), with no infiltration of CD4 T cells in the spinal cord, as compared to controls, suggesting that TYK2 is essential to pathogenic CD4-mediated disease development in MS. This corroborates earlier studies linking increased TYK2 expression with MS susceptibility. Loss of function mutation in TYK2, leads to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.

[0007] TYK2 is the sole signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice.

[0008] Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder), showed a strong, and significant correlation between loss of function mutations to TYK2 and decreased prevalence of SLE in families with affected members. Genome-wide association studies of individuals with SLE versus an unaffected cohort showed highly significant correlation between the TYK2 locus and SLE.

[0009] TYK2 has been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response and accelerated tumor development. However, these effects were linked to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 has been suggested as a superior target because of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects.

[0010] Studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via TYK2 via STATl-mediated signal transduction to maintain cancer cell survival through upregulation of anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations to TYK2 that promote cancer cell survival include those to the FERM domain (G36D, S47N, and R425H), the JH2 domain (V731I), and the kinase domain (E957D andR1027H). However, it was also identified that the kinase function of TYK2 is required for increased cancer cell survival, as TYK2 enzymes featuring kinase-dead mutations (M978Y or M978F) in addition to an activating mutation (E957D) resulted in failure to transform.

[0011] Thus, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL- 10 and / or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases. TYK2 mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid-P (AP) peptide. Decreased TYK2 phosphorylation of STAT3 following Ap administration lead to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients. Inhibition of JAK- STAT signaling pathways is also implicated in hair growth, and the reversal of the hair loss associated with alopecia areata.

[0012] Accordingly, there is a need to provide compositions for inhibiting the activity of TYK2 to treat one or more of the conditions described herein, without the side-effects associated with the inhibition of JAK2.SUMMARY

[0013] Described herein, in part, are immediate-release, oral tablet compositions useful in treating a TYK2 -mediated disorder. For example, disclosed herein is an immediate-release, oral tablet composition comprising: about 20 mg, about 40 mg or about 60 mg of a compound A-(4-((2-methoxy-3-(l -(methyl2, 4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3- t / 3)pyridin-2-yl)cyclopropanecarboxamide, wherein the 20 mg, 40 mg, or 60 mg is based on the free base amount of the compound; and wherein the compound is present as a salt; and a pharmaceutically acceptable excipient; wherein the composition has greater than 85% dissolution within 20 minutes as measured by USP Apparatus II (paddle) dissolution method at 75 rpm, 900 mL pH 4.5 (50 mM acetate) with 0.25% sodium lauryl sulfate at 37 °C).

[0014] In some embodiments, the compound A-(4-((2-methoxy-3-(l-(methyl-t / 3)- 1H- 1,2,4- triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide is present as a hydrochloride salt. For example, disclosed herein is an immediate-release, fixed dose oral tablet composition comprising: an intragranular component comprising: 20 mg, 40 mg, or 60 mg of a compound A-(4-((2-methoxy-3-(l-(methyl-t / 3)- 1 / 7-1, 2, 4-triazol-3- yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 20 mg is based on the free base amount of the compound; a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and anextragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0015] For example, disclosed herein is an immediate-release, oral tablet composition, comprising: an intragranular component comprising about 20 mg to about 60 mg of 7V-(4-((2- methoxy-3-(l-(methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3- t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 20 mg to 60 mg is based on the free base amount of the compound, microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, sodium stearyl fumarate; optionally copovidone, and optionally succinic acid; and an extragranular component comprising crospovidone, colloidal silicon dioxide, and sodium stearyl fumarate.

[0016] In addition, disclosed herein is an immediate-release, oral tablet composition of the present disclosure comprises: an intragranular component comprising about 20 mg to about 60 mg of the compound, wherein the 20 mg to 60 mg is based on the free base amount of the compound, from about 33 weight percent to about 35 weight percent of microcrystalline cellulose; from about 33 weight percent to about 35 weight percent of mannitol; from about 4 weight percent to about 6 weight percent of crospovidone; from about 0.5 weight percent to about 1.5 weight percent of colloidal silicon dioxide; and from about 0.5 weight percent to about 1.5 weight percent of sodium stearyl fumarate; and an extragranular component comprising about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate; wherein each weight percent is based on the total weight of the intragranular and extragranular components.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 depicts dissolution studies of Tablet A20, Tablet B20, and Tablet C20 under non-sink dissolution conditions in a pH 4 buffered medium.

[0018] FIG. 2 depicts dissolution and stability studies of tablet B20 after storage under various temperature and humidity conditions for up to 3 months, up to 6 months, or up to 9 months.

[0019] FIG. 3 depicts dissolution and stability studies of tablet C20 after storage under various temperature and humidity conditions for up to 3 months or up to 6 months.DETAILED DESCRIPTION

[0020] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Definitions

[0021] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range, for example, a ± 10% variation from the nominal value unless otherwise indicated or inferred. Where the use of the term “about” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0022] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, thetreatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease. Also, for purposes herein, “treatment,” “prevention,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof.

[0023] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound or composition (e.g., an oral tablet composition) disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.

[0024] “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.

[0025] The term “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0026] The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable excipients.

[0027] The term “pharmaceutically acceptable salt(s)” or “salt(s)” as used herein refers to salts of basic groups that may be present in compounds used in the compositions. In some embodiments, the compounds described herein exist as their pharmaceutically acceptablesalts. In some embodiments, the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.

[0028] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0029] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2- naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3 -phenylpropionic acid,trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0030] As used herein, the term “TYK2-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which TYK2 or a mutant thereof is known to play a role. Accordingly, another embodiment relates to treating or lessening the severity of one or more diseases in which TYK2, or a mutant thereof, is known to play a role. Such TYK2-mediated disorders include but are not limited to autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders and disorders associated with transplantation.Compositions

[0031] Disclosed herein, for example, is a an immediate-release, oral tablet composition comprising: about 20 mg, about 40 mg or about 60 mg of a compound A-(4-((2-methoxy-3-(l- (methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, wherein the 20 mg, 40 mg, or 60 mg is based on the free base amount of the compound; and wherein the compound is present as a salt; and a pharmaceutically acceptable excipient; wherein the composition has greater than 85% dissolution within 20 minutes as measured by USP Apparatus II (paddle) dissolution method at 75 rpm, 900 mL pH 4.5 (50 mM acetate) with 0.25% sodium lauryl sulfate at 37 °C).

[0032] In other embodiments, a disclosed immediate-release, oral tablet composition comprises, for example: an intragranular component comprising about 20 mg, about 40 mg or about 60 mg of the compound A-(4-((2-methoxy-3-(l-(methyl-t / 3)-l / 7-l,2,4-triazol-3-yl)phenyl) amino)-5- (propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, wherein the 20 mg, 40 mg, or 60 mg is based on the free base amount of the compound; and wherein the compound is present as a salt; and one or more pharmaceutically acceptable excipients; and an extragranular component comprising one or more pharmaceutically acceptable excipients.

[0033] In some embodiments, compound A-(4-((2-methoxy-3-(l-(methyl-t / 3)- \H-\, 2,4- triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide ispresent as a hydrochloride salt. For example, in some embodiments a disclosed immediate- release, oral tablet composition comprises, e.g.: an intragranular component comprising: about 20 mg, about 40 mg, or about 60 mg of the compound V-(4-((2- methoxy-3-(l-(methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3- t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt, wherein the 20 mg, 40 mg, or 60 mg is based on the free base amount of the compound; a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and an extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0034] In some embodiments, an immediate-release, oral tablet composition of the present disclosure comprises, for example, about 20 mg of the compound 7V-(4-((2-methoxy-3-(l- (methyl-t / 3)-l / 7-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 20 mg is based on the free base amount of the compound. In other embodiments, an immediate-release, oral tablet composition of the present disclosure comprises, for example, about 40 mg of the compound 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)-l / 7-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3- t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 40 mg is based on the free base amount of the compound.

[0035] Also disclosed herein, for example, is an immediate-release, fixed dose oral tablet composition comprising: an intragranular component comprising:20 mg of a compound 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)- H- 1,2, 4-triazol-3- yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 20 mg is based on the free base amount of the compound;a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and an extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0036] Further disclosed herein is an immediate-release, fixed dose oral tablet composition comprising: an intragranular component comprising:40 mg of a compound 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)- H- 1,2, 4-triazol-3- yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 40 mg is based on the free base amount of the compound; a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and an extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0037] In addition, disclosed herein, for example, is an immediate-release, fixed dose oral tablet composition comprising: an intragranular component comprising:60 mg of a compound 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)- 1H- 1,2, 4-triazol-3- yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 60 mg is based on the free base amount of the compound;a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and an extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0038] Also disclosed herein is an immediate-release, oral tablet composition, comprising: an intragranular component comprising: about 10 weight percent to about 26 weight percent of 7V-(4-((2-methoxy-3-(l- (methyl-t / 3)-l / 7-l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, hydrochloride salt; a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and an extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0039] In some embodiments, the intragranular component of an immediate-release, oral tablet composition contemplated herein comprises, for example, from about 20 weight percent to about 24 weight percent of the compound 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)- 1H- l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropane carboxamide, hydrochloride salt; wherein the weight percent is based on the total weight of the intragranular and extragranular components. For example, in some embodiments the intragranular component comprises, for example, from about 10 weight percent to about 26 weight percent, from about 10 weight percent to about 24 weight percent, from about 12weight percent to about 26 weight percent, from about 12 weight percent to about 24 weight percent, from about 16 weight percent to about 24 weight percent, from about 18 weight percent to about 24 weight percent, from about 18 weight percent to about 26 weight percent, from about 20 weight percent to about 26 weight percent, from about 22 weight percent to about 26 weight percent, from about 20 weight percent to about 24 weight percent, from about 20 weight percent to about 22 weigh percent, from about 21 weight percent to about 22 weight percent, about 18 weight percent, about 20 weight percent, about 21 weight percent, about 22 weight percent, about 23 weight percent, about 24 weight percent, about 25 weight percent, or about 26 weight percent of the compound 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)-l / Z- l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, hydrochloride salt; wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0040] In other embodiments, the disintegrant in the intragranular component of an immediate-release, oral tablet composition contemplated herein comprises, e.g., crospovidone. For example, in some embodiments the intragranular component comprises from about 4 weight percent to about 10 weight percent, from about 5 weight percent to about 10 weight percent, from about 2 weight percent to about 8 weight percent, from about 3 weight percent to about 7 weight percent, from about 4 weight percent to about 6 weight percent, about 3 weight percent to about 5 weight percent, about 4 weight percent to about 5 weight percent, about 2 weight percent, about 5 weight percent, about 6 weight percent, about 7 weight percent, or about 8 weight percent of crospovidone, wherein the weight percent is based on the total weight of the intragranular and extragranular components. For example, in certain embodiments intragranular component comprises from about 4 weight percent to about 6 weight percent of crospovidone, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In certain embodiments intragranular component comprises about 5 weight percent of crospovidone, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0041] In some embodiments, the glidant in the intragranular component of an immediate- release, oral tablet composition contemplated herein comprises, for example, colloidal silicon dioxide. For example, in some embodiments the intragranular component comprises from about 0.5 weight percent to about 2.0 weight percent, from about 0.5 weight percent to about 1.5 weight percent, from about 0.5 weight percent to about 1.0 weight percent, from about 1.0weight percent to about 1.5 weight percent, about 0.5 weight percent, about 1.0 weight percent, about 1.5 weight percent, or about 2.0 weight percent of colloidal silicon dioxide, wherein the weight percent is based on the total weight of the intragranular and extragranular components. For example, in certain embodiments the intragranular component comprises, e.g., about 1.0 weight percent of colloidal silicon dioxide, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0042] In some embodiments, a contemplated lubricant in the intragranular component of an immediate-release, oral tablet composition contemplated herein comprises, for example, sodium stearyl fumarate. For example, in some embodiments the intragranular component comprises from about 0.5 weight percent to about 2.0 weight percent, from about 0.5 weight percent to about 1.5 weight percent, from about 0.5 weight percent to about 1.0 weight percent, from about 1.0 weight percent to about 1.5 weight percent, about 0.5 weight percent, about 1.0 weight percent, about 1.5 weight percent, or about 2.0 weight percent of sodium stearyl fumarate, wherein the weight percent is based on the total weight of the intragranular and extragranular components. For example, in certain embodiments the intragranular component comprises, e.g., about 1.0 weight percent of sodium stearyl fumarate, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0043] In some embodiments, the diluent in the intragranular component of an immediate- release, oral tablet composition contemplated herein comprises, for example, microcrystalline cellulose and mannitol. For example, in some embodiments the intragranular component comprises, for example, from about 10 weight percent to about 24 weight percent, from about 12 weight percent to about 26 weight percent, from about 12 weight percent to about 24 weight percent, from about 16 weight percent to about 24 weight percent, from about 18 weight percent to about 24 weight percent, from about 18 weight percent to about 26 weight percent, from about 20 weight percent to about 26 weight percent, from about 22 weight percent to about 26 weight percent, from about 20 weight percent to about 24 weight percent, from about 20 weight percent to about 22 weigh percent, from about 21 weight percent to about 22 weight percent, about 18 weight percent, about 20 weight percent, about 21 weight percent, about 22 weight percent, about 23 weight percent, about 24 weight percent, about 25 weight percent, or about 26 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In other embodiments, for example, the intragranular component comprises from about 20weight percent to about 23 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In further embodiments, the intragranular component comprises from about 21 weight percent to about 22 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components. For example, in certain embodiments the intragranular component comprises about 22 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0044] In some embodiments, the diluent in the extragranular component of an immediate- release, oral tablet composition contemplated herein comprises, for example, microcrystalline cellulose and mannitol. For example, in some embodiments the intragranular component comprises, for example, from about 10 weight percent to about 24 weight percent, from about 12 weight percent to about 26 weight percent, from about 12 weight percent to about 24 weight percent, from about 16 weight percent to about 24 weight percent, from about 18 weight percent to about 24 weight percent, from about 18 weight percent to about 26 weight percent, from about 20 weight percent to about 26 weight percent, from about 22 weight percent to about 26 weight percent, from about 20 weight percent to about 24 weight percent, from about 20 weight percent to about 22 weigh percent, from about 21 weight percent to about 22 weight percent, about 18 weight percent, about 20 weight percent, about 21 weight percent, about 22 weight percent, about 23 weight percent, about 24 weight percent, about 25 weight percent, or about 26 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In other embodiments, for example, the intragranular component comprises from about 20 weight percent to about 23 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In further embodiments, the intragranular component comprises from about 21 weight percent to about 22 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components. For example, in certain embodiments the intragranular component comprises about 22 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0045] In further embodiments, the intragranular component of a disclosed immediate- release, oral tablet composition comprises, for example, from about 32 weight percent toabout 36 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In other embodiments, the intragranular component comprises from about 33 weight percent to about 35 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In certain embodiments, the intragranular component comprises, for example, about 34 weight percent of microcrystalline cellulose, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0046] In some embodiments, the intragranular component of an immediate-release, oral tablet composition contemplated herein comprises, for example, from about 10 weight percent to about 24 weight percent, from about 12 weight percent to about 26 weight percent, from about 12 weight percent to about 24 weight percent, from about 16 weight percent to about 24 weight percent, from about 18 weight percent to about 24 weight percent, from about 18 weight percent to about 26 weight percent, from about 20 weight percent to about 26 weight percent, from about 22 weight percent to about 26 weight percent, from about 20 weight percent to about 24 weight percent, from about 20 weight percent to about 22 weigh percent, from about 21 weight percent to about 22 weight percent, about 18 weight percent, about 20 weight percent, about 21 weight percent, about 22 weight percent, about 23 weight percent, about 24 weight percent, about 25 weight percent, or about 26 weight percent of mannitol, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In other embodiments, for example, the intragranular component comprises from about 20 weight percent to about 23 weight percent of mannitol, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In further embodiments, the intragranular component comprises from about 21 weight percent to about 22 weight percent of mannitol, wherein the weight percent is based on the total weight of the intragranular and extragranular components. For example, in certain embodiments the intragranular component comprises about 22 weight percent of mannitol, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0047] In further embodiments, the intragranular component of a disclosed immediate- release, oral tablet composition comprises, for example, from about 32 weight percent to about 36 weight percent of mannitol, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In other embodiments, wherein theintragranular component comprises, for example, from about 33 weight percent to about 35 weight percent of mannitol, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In certain embodiments, the intragranular component comprises, for example, about 34 weight percent of mannitol, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0048] In other embodiments, for example, the intragranular component of a disclosed immediate-release, oral tablet composition further comprises, e.g., copovidone. In some embodiments, the intragranular component further comprises from about 10 weight percent to about 20 weight percent, from about 12 weight percent to about 18 weight percent, from about 13 weight percent to about 17 weight percent, from about 14 weight percent to about 16 weight percent, from about 15 weight percent to about 20 weight percent, from about 15 weight percent to about 18 weight percent, from about 15 weight percent to about 16 weight percent, about 12 weight percent, about 13 weight percent, about 14 weight percent, about 15 weight percent, about 16 weight percent, about 17 weight percent, or about 18 weight percent of copovidone, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In further embodiments, the intragranular component further comprises, for example, from about 14 weight percent to about 16 weight percent of copovidone, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In certain embodiments, for example, the intragranular component further comprises about 15 weight percent of copovidone, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0049] In other embodiments, for example, the intragranular component of a disclosed immediate-release, oral tablet composition further comprises, e.g., succinic acid. In some embodiments, the intragranular component of a disclosed immediate-release, oral tablet composition further comprises, for example, from about 5 weight percent to about 15 weight percent, from about 7 weight percent to about 13 weight percent, from about 9 weight percent to about 11 weight percent, from about 5 weight percent to about 10 weight percent, from about 7 weight percent to about 10 weight percent, from about 8 weight percent to about 10 weight percent, from about 9 weight percent to about 12 weight percent, from about 9 weight percent to about 10 weight percent, about 5 weight percent, about 6 weight percent, about 7 weight percent, about 8 weight percent, about 9 weight percent, about 10 weight percent, about 11 weight percent, about 12 weight percent, about 13 weight percent, about 14 weight percent, or about 15 weight percent of succinic acid, wherein the weight percent is based onthe total weight of the intragranular and extragranular components. In some embodiments, the intragranular component of a disclosed immediate-release, oral tablet composition further comprises, for example, from about 8 weight percent to about 12 weight percent of succinic acid, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In other embodiments, the intragranular component further comprises, for example, from about 9 weight percent to about 11 weight percent of succinic acid, wherein the weight percent is based on the total weight of the intragranular and extragranular components. In certain embodiments, the intragranular component further comprises, for example, about 10 weight percent of succinic acid, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0050] In some embodiments, the extragranular component of an immediate-release, oral tablet composition contemplated herein comprises, for example, crospovidone. For example, in some embodiments the intragranular component comprises from about 0.5 weight percent to about 2.0 weight percent, from about 0.5 weight percent to about 1.5 weight percent, from about 0.5 weight percent to about 1.0 weight percent, from about 1.0 weight percent to about 1.5 weight percent, about 0.5 weight percent, about 1.0 weight percent, about 1.5 weight percent, or about 2.0 weight percent of crospovidone, wherein the weight percent is based on the total weight of the intragranular and extragranular components. For example, in certain embodiments the intragranular component comprises, e.g., about 1.0 weight percent of crospovidone, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0051] In some embodiments, the extragranular component of an immediate-release, oral tablet composition contemplated herein comprises, for example, colloidal silicon dioxide. For example, in some embodiments the intragranular component comprises from about 0.5 weight percent to about 2.0 weight percent, from about 0.5 weight percent to about 1.5 weight percent, from about 0.5 weight percent to about 1.0 weight percent, from about 1.0 weight percent to about 1.5 weight percent, from about 0.25 weight percent to about 1.0 weight percent, from about 0.25 weight percent to about 0.75 weight percent, from about 0.25 weight percent to about 0.5 weight percent, about 0.25 weight percent, about 0.5 weight percent, about 0.75 weight percent, about 1.0 weight percent, about 1.5 weight percent, or about 2.0 weight percent of colloidal silicon dioxide, wherein the weight percent is based on the total weight of the intragranular and extragranular components. For example, in certain embodiments the intragranular component comprises, e.g., about 0.5 weight percent ofcolloidal silicon dioxide, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0052] In some embodiments, the extragranular component of an immediate-release, oral tablet composition contemplated herein comprises, for example, sodium stearyl fumarate. For example, in some embodiments the intragranular component comprises from about 0.5 weight percent to about 2.0 weight percent, from about 0.5 weight percent to about 1.5 weight percent, from about 1.0 weight percent to about 1.5 weight percent, from about 1.0 weight percent to about 2.0 weight percent, from about 1.25 weight percent to about 1.75 weight percent, from about 1.25 weight percent to about 1.5 weight percent, about 1.0 weight percent, about 1.25 weight percent, about 1.5 weight percent, about 1.75 weight percent, or about 2.0 weight percent of sodium stearyl fumarate, wherein the weight percent is based on the total weight of the intragranular and extragranular components. For example, in certain embodiments the intragranular component comprises, e.g., about 1.5 weight percent of sodium stearyl fumarate, wherein the weight percent is based on the total weight of the intragranular and extragranular components.

[0053] For example, in some embodiments the extragranular component of an immediate- release, oral tablet composition contemplated herein comprises crospovidone, colloidal silicon dioxide, and sodium stearyl fumarate. In certain embodiments, for example, the extragranular component of an immediate-release, oral tablet composition contemplated herein comprises, e.g., about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate.

[0054] In other embodiments, a disclosed immediate-release, oral tablet composition further comprises a film coating. In other embodiments, a disclosed immediate-release, oral tablet composition further comprises, for example, a film coating that is free of titanium dioxide. In certain embodiments, the film coating comprises, e.g., calcium carbonate.

[0055] Further disclosed herein, for example, is an immediate-release, oral tablet composition comprising: an intragranular component comprising: about 20 mg to about 60 mg of a compound 7V-(4-((2-methoxy-3-(l-(methyl- t / 3)-l / 7-l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 20 mg to 60 mg is based on the free base amount of the compound;a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and an extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0056] In some embodiments, an immediate-release, oral tablet composition contemplated herein comprises, for example: an intragranular component comprising about 20 mg to about 60 mg of the compound 7V-(4-((2-methoxy-3-(l -(methyl2, 4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3- t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt, wherein the 20 mg to 60 mg is based on the free base amount of the compound, microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, sodium stearyl fumarate; optionally copovidone, and optionally succinic acid; and an extragranular component comprising crospovidone, colloidal silicon dioxide, and sodium stearyl fumarate.

[0057] In other embodiments, an immediate-release, oral tablet composition contemplated herein comprises, for example: an intragranular component comprising about 20 mg to about 60 mg of the compound 7V-(4-((2-methoxy-3-(l -(methyl2, 4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3- t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt, wherein the 20 mg to 60 mg is based on the free base amount of the compound, from about 33 weight percent to about 35 weight percent of microcrystalline cellulose; from about 33 weight percent to about 35 weight percent of mannitol; from about 4 weight percent to about 6 weight percent of crospovidone; from about 0.5 weight percent to about 1.5 weight percent of colloidal silicon dioxide; and from about 0.5 weight percent to about 1.5 weight percent of sodium stearyl fumarate; andan extragranular component comprising about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0058] In other embodiments, an immediate-release, oral tablet composition contemplated herein comprises, for example: an intragranular component comprising about 20 mg to about 60 mg of the compound 7V-(4-((2-methoxy-3-(l -(methyl2, 4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3- t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt, wherein the 20 mg to 60 mg is based on the free base amount of the compound, from about 21 weight percent to about 22 weight percent of microcrystalline cellulose; from about 21 weight percent to about 22 weight percent of mannitol; from about 4 weight percent to about 6 weight percent of crospovidone; from about 0.5 weight percent to about 1.5 weight percent of colloidal silicon dioxide; from about 0.5 weight percent to about 1.5 weight percent of sodium stearyl fumarate; from about 14 to about 16 weight percent of copovidone; and from about 9 to about 11 weight percent of succinic acid; and an extragranular component comprising about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0059] In some embodiments, an immediate-release, oral tablet composition of the present disclosure comprises, for example, about 20 mg of the compound 7V-(4-((2-methoxy-3-(l- (methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 20 mg is based on the free base amount of the compound. In other embodiments, an immediate-release, oral tablet composition of the present disclosure comprises, for example, about 40 mg of the compound 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3- t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 40 mg is based on the free base amount of the compound. In other embodiments, an immediate-release, oral tablet composition of the present disclosure comprises, for example, about 60 mg of thecompound 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl)amino)-5- (propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 60 mg is based on the free base amount of the compound. In other embodiments, an immediate-release, oral tablet composition of the present disclosure comprises, for example, from about 20 mg to about 60 mg of the compound 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)-l / Z- l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 20 mg to 60 mg is based on the free base amount of the compound.

[0060] Further disclosed herein is an immediate-release, oral tablet composition comprising: an intragranular component comprising from about 21 weight percent to about 22 weight percent of 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl)amino)-5- (propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; from about 33 weight percent to about 35 weight percent of microcrystalline cellulose; from about 33 weight percent to about 35 weight percent of mannitol; from about 4 weight percent to about 6 weight percent of crospovidone; from about 0.5 weight percent to about 1.5 weight percent of colloidal silicon dioxide; and from about 0.5 weight percent to about 1.5 weight percent of sodium stearyl fumarate; and an extragranular component comprising about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0061] In addition, disclosed herein is an immediate-release, oral tablet composition comprising: an intragranular component comprising about 22 weight percent of 7V-(4-((2-methoxy- 3-(l-(methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, hydrochloride salt; about 34 weight percent of microcrystalline cellulose; about 34 weight percent of mannitol; about 5.0 weight percent of crospovidone; about 1.0 weight percent of colloidal silicon dioxide; and about 1.0 weight percent of sodium stearyl fumarate; andan extragranular component comprising about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0062] Also disclosed herein is immediate-release, oral tablet composition comprising: an intragranular component comprising from about 21 weight percent to about 22 weight percent of 7V-(4-((2-methoxy-3-(l-(methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl)amino)-5- (propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; from about 21 weight percent to about 22 weight percent of microcrystalline cellulose; from about 21 weight percent to about 22 weight percent of mannitol; from about 4 weight percent to about 6 weight percent of crospovidone; from about 0.5 weight percent to about 1.5 weight percent of colloidal silicon dioxide; from about 0.5 weight percent to about 1.5 weight percent of sodium stearyl fumarate; from about 14 to about 16 weight percent of copovidone; and from about 9 to about 11 weight percent of succinic acid; and an extragranular component comprising about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0063] Further disclosed herein is an immediate-release, oral tablet composition comprising: an intragranular component comprising about 22 weight percent of 7V-(4-((2-methoxy- 3-(l-(methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, hydrochloride salt; about 22 weight percent of microcrystalline cellulose; about 22 weight percent of mannitol; about 5.0 weight percent of crospovidone; about 1.0 weight percent colloidal silicon dioxide; about 1.0 weight percent of sodium stearyl fumarate; about 15.0 weight percent of copovidone; and about 10.0 weight percent of succinic acid; and an extragranular component comprising about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate;wherein each weight percent is based on the total weight of the intragranular and extragranular components.

[0064] In some embodiments, an immediate-release, oral tablet composition disclosed herein is substantially stable after storage at 25 °C and 60% relative humidity at 30 °C and 75% relative humidity, or at 40 °C and 75% relative humidity for, e.g., one month, or up to three months, or up to 6 months, or up to 9 months. In other embodiments, an immediate- release, oral tablet composition disclosed herein has greater than 85% dissolution within 20 minutes as measured by USP Apparatus II (paddle) dissolution method at 75 rpm, 900 mL pH 4.5 (50 mM acetate) with 0.25% sodium lauryl sulfate at 37 °C).

[0065] In some embodiments, a disclosed immediate-release, oral tablet composition comprises from about 20 mg to about 24 mg of A-(4-((2-methoxy-3 -(l-(methyl-t / 3)- 1H- 1,2,4- triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropane carboxamide, hydrochloride salt. In other embodiments, a disclosed immediate-release, oral tablet comprises from about 42 mg to about 46 mg of A-(4-((2-methoxy-3 -(l-(methyl-t / 3)- 1H- 1,2,4- triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropane carboxamide, hydrochloride salt. In other embodiments, a disclosed immediate-release, oral tablet comprises from about 62 mg to about 66 mg of A-(4-((2-methoxy-3 -(l-(methyl-t / 3)- 1H- 1,2,4- triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropane carboxamide, hydrochloride salt.Pharmaceutical Compositions

[0066] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0067] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, orlonger disease-free and / or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0068] For example, in some embodiments a disclosed compound or composition (e.g., an oral tablet composition) may be administered once daily to the patient. In other embodiments, a disclosed compound or composition (e.g., an oral tablet composition) may be administered twice daily to the patient.

[0069] Suitable doses and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present method involves the administration of about 0.1 pg to about 50 mg of at least one compound described herein per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 pg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject’s physiological response.

[0070] By way of example only, the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg / kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg / kg body weight per day. In some embodiments, the dose of compound described herein for the described methods is about 1 to about 1000 mg / kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day, wherein the fixed dose amount is equivalent to the amount of 7V-(4-((2-methoxy-3-(l- (methyl-t / 3)-l / 7-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, free base.

[0071] Further, by way of example only, the dose of the compound for methods of treating a disease as described herein may be a fixed dose, e.g., a fixed dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, or 80 mg,wherein the fixed dose amount is equivalent to the amount of 7V-(4-((2-methoxy-3-(l- (methyl-t / 3)-l / 7-l,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, free base.Methods of Treatment

[0072] The methods described herein are useful for the inhibition of kinase activity of one or more enzymes. In some embodiments the kinase is TYK2.

[0073] Provided herein are methods for treating a disease or disorder, wherein the disease or disorder is an autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or disorders associated with transplantation, said method comprising administering to a patient in need thereof, an effective amount of a composition (e.g., an immediate-release, oral tablet composition) described herein.

[0074] In some embodiments, the disease or disorder is an autoimmune disorder. In some embodiments the disease or disorder is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0075] In some embodiments, the disease or disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

[0076] In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocytosis.

[0077] In some embodiments, the disease or disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

[0078] In some embodiments, the disease or disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0079] In some embodiments the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0080] In some embodiments, the disease or disorder is associated with transplantation. In some embodiments the disease or disorder associated with transplantation is transplant rejection, or graft versus host disease.

[0081] In some embodiments the disease or disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments the disease or disorder is associated with type I interferon signaling. In some embodiments the disease or disorder is associated with IL-10 signaling. In some embodiments the disorder is associated with IL-12 signaling. In some embodiments the disease or disorder is associated with IL-23 signaling.

[0082] Provided herein are methods for treating an inflammatory or allergic condition of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0083] Provided herein are methods for treating other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis,multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid- induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0084] In some embodiments the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic juvenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), or osteoarthritis.

[0085] In some embodiments the inflammatory disease is a Thl or Thl7 mediated disease. In some embodiments the Thl7 mediated disease is selected from Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0086] In some embodiments the inflammatory disease is Sjogren's syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, or diseases affecting the nose such as allergic rhinitis.

[0087] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

[0088] The compounds and compositions describe herein are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compositions described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a composition described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.EXAMPLES

[0089] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0090] A-(4-((2-Methoxy-3-(l-(methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl)amino)-5- (propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt (Compound A) can be prepared according to the synthetic procedures described in WO 2020 / 086616, the entire content of which is incorporated by reference herein. Compound A is, for example, a modulator of tyrosine kinase 2 (TYK2), e.g., an inhibitor of TYK2, the free base form of which is shown as follows:Example 1: Compositions

[0091] An immediate-release oral tablet composition containing the equivalent of 10 mg of Compound A free base (Tablet A10) and an immediate-release oral tablet composition containing the equivalent of 20 mg of Compound A free base (Tablet A20) were prepared according to Table 1.Table 1.'Equiv alent to 10 mg or 20 mg of Compound A freebase.' Purified water is a processing aid that is removed as a part of the film-coating process.

[0092] An immediate-release oral tablet composition containing the equivalent of 20 mg of Compound A free base (Tablet B20), an immediate-release oral tablet composition containing the equivalent of 40 mg of Compound A free base (Tablet B40), an immediate-release oral tablet composition containing the equivalent of 20 mg of Compound A free base (Tablet C20), an immediate-release oral tablet composition containing the equivalent of 40 mg of Compound A free base (Tablet C40), were prepared according to Table 2.Table 2.'Equiv alent to 20 mg of Compound A freebase.'Equiv alent to 40 mg of Compound A freebase.

[0093] Further immediate-release oral tablet compositions of the present disclosure were prepared according to Table 3.Table 3.Example 2: Manufacturing Process

[0094] By way of example, tablet B20, tablet B40, tablet C20, and tablet C40 were manufactured via the dry granulation, compression, and coating process described below. This common blend process was used to prepare, for example, 20 mg and 40 mg tablets, andmay also be used to prepare, e.g., 60 mg tablets, or other size tablets by scaling up the components accordingly.1. Intra-granular blending a. Microcrystalline cellulose (MCC), Compound A HC1, mannitol, colloidal silicon dioxide, crospovidone, succinic acid (for immediate-release C tablets) and copovidone (for immediate release C tablets) 2ere premixed in a blender. b. The mixture was passed through a Comil to delump the mixture. c. The delumped powder was mixed in a blender in a main blending step. d. The blend was lubricated with screened sodium stearyl fumarate (SSF).2. Dry granulation was performed by roller compactor and built-in mill.3. Extra-granular blending a. The granules were mixed with extra-granular hand screened crospovidone and hand screened colloidal silicon dioxide. b. The blend was then lubricated with hand screened SSF.4. The final blend from Step 3 was compressed into 20 mg or 40 mg tablets. Smaller or larger tablets (e.g. 60 mg, 30mg may be prepared by appropriate scaling of the components.5. The tablets were film coated with Opadry coating in a pan coater.6. The tablets were then packaged into high-density polyethylene (HDPE) bottles with desiccant and induction-sealed with child-resistant caps.Example 3: Biorelevant Dissolution Studies

[0095] Tablets were compared in dissolution tests to examine differences in maximum solubility, supersaturation and sustainment in buffered media. The test was conducted under non-sink conditions as a single stage dissolution test at pH 4.0, wherein a 20 mg tablet (e.g., tablet A20, tablet B20, or tablet C20) and 250 mL of simulated gastric fluid were mixed at 100 RPM paddle speed at 37 °C in a IL type II dissolution apparatus. Samples were analyzed by fiber optic probes.

[0096] The results are shown in FIG. 1. As shown in FIG. 1, tablets B20 and C20 show significant improvement in non-sink dissolution at pH 4 relative to tablet A20.Example 4: Stability and Dissolution Studies

[0097] Samples of tablets B20 and C20 were stored in 30 mL HDPE bottles with a polypropylene cap containing 1 g of silica gel dessicant. The samples were stored at 25 °C and 60% relative humidity, at 30 °C and 75% relative humidity, or at 40 °C and 75% relative humidity for one month, up to three months, up to six months, or up to nine months. Samples were then subject to a dissolution method (USP Apparatus II (paddle), 75 rpm, 900 mL pH 4.5 (50 mM acetate) with 0.25% SLS, 37 °C). The specific test parameters are shown in Table 4 and the results are shown in FIG. 2 and FIG 3. FIG. 2 depicts dissolution and stability studies of tablet B20 after storage under various temperature and humidity conditions for up to 3 months, up to 6 months, or up to 9 months. FIG. 3 depicts dissolution and stability studies of tablet C20 after storage under various temperature and humidity conditions for up to 3 months or up to 6 months.Table 4.Example 5: Pharmacokinetic Studies

[0098] A study was conducted to investigate the relative bioavailability of single oral doses of Compound A in different compositions. Healthy human subjects (n=24) were administered Treatment A (2x20 mg tablet A20), Treatment B (2x20 mg tablet B20), Treatment C (2x20 mg tablet C20), or Treatment E (40 mg liquid formulation), and their pharmacokinetic parameters measured. The results are shown in Table 5. As shown in Table 5, absorption was rapid and Tmax was comparable among tablet formulations. T1 / 2 was about 8 hours for all tablet formulations. Both treatment B and C showed comparable absorption rates (Cmax) and bioavailability (AUC) to treatment A.Table 5.INCORPORATION BY REFERENCE

[0099] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS AND SCOPE

[0100] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0101] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted thatthe terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0102] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0103] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

[0104] What is claimed is:

Claims

CLAIMS1. An immediate-release, oral tablet composition comprising: about 20 mg, about 40 mg or about 60 mg of a compound 7V-(4-((2-methoxy-3-(l- (methyl-t / 3)-l / Z-l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, wherein the 20 mg, 40 mg, or 60 mg is based on the free base amount of the compound; and wherein the compound is present as a salt; and a pharmaceutically acceptable excipient; wherein the composition has greater than 85% dissolution within 20 minutes as measured by USP Apparatus II (paddle) dissolution method at 75 rpm, 900 mL pH 4.5 (50 mM acetate) with 0.25% sodium lauryl sulfate at 37 °C).

2. The immediate-release, oral tablet composition of claim 1, comprising: an intragranular component comprising about 20 mg, about 40 mg or about 60 mg of the compound, wherein the 20 mg, 40 mg, or 60 mg is based on the free base amount of the compound; and wherein the compound is present as a salt; and one or more pharmaceutically acceptable excipients; and an extragranular component comprising one or more pharmaceutically acceptable excipients.

3. The immediate-release, oral tablet composition of claim 1 or 2, wherein the compound is present as a hydrochloride salt.

4. The immediate-release, oral tablet composition of any one of claims 1-3, comprising: an intragranular component comprising: about 20 mg, about 40 mg, or about 60 mg of the compound A-(4-((2- methoxy-3-(l-(methyl-t / 3)-l / 7-l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3- t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt, wherein the 20 mg, 40 mg, or 60 mg is based on the free base amount of the compound; a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and an extragranular component comprising:about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

5. The immediate-release, oral tablet composition of any of claims 1-4, having 20 mg of the compound.

6. The immediate-release, oral tablet composition of any of claims 1-4, having 40 mg of the compound.

7. An immediate-release, fixed dose oral tablet composition comprising: an intragranular component comprising:20 mg of a compound A-(4-((2-methoxy-3-(l-(methyl-t / 3)- H- 1,2, 4-triazol-3- yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 20 mg is based on the free base amount of the compound; a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and an extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

8. An immediate-release, fixed dose oral tablet composition comprising: an intragranular component comprising:40 mg of a compound A-(4-((2-methoxy-3-(l-(methyl-t / 3)- 1H- 1,2, 4-triazol-3- yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 40 mg is based on the free base amount of the compound; a diluent; about 3 to about 7 weight percent disintegrant; anda glidant and / or lubricant; and an extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

9. An immediate-release, fixed dose oral tablet composition comprising: an intragranular component comprising:60 mg of a compound A-(4-((2-methoxy-3-(l-(methyl-t / 3)-l / 7- 1,2, 4-triazol-3- yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2-yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 60 mg is based on the free base amount of the compound; a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and an extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

10. An immediate-release, oral tablet composition, comprising: an intragranular component comprising: about 10 weight percent to about 26 weight percent of A-(4-((2-methoxy-3-(l- (methyl-t / 3)-l / 7-l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, hydrochloride salt; a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; andan extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

11. The immediate-release, oral tablet composition of claim 10, wherein the intragranular component comprises from about 20 weight percent to about 24 weight percent of the compound.

12. The immediate-release, oral tablet composition of any one of claims 6-11, wherein the disintegrant in the intragranular component comprises crospovidone.

13. The immediate-release, oral tablet composition of any one of claims 6-12, wherein the intragranular component comprises from about 4 weight percent to about 6 weight percent of crospovidone.

14. The immediate-release, oral tablet composition of any one of claims 6-13, wherein the glidant in the intragranular component comprises colloidal silicon dioxide.

15. The immediate-release, oral tablet composition of any one of claims 6-14, wherein the intragranular component comprises from about 0.5 weight percent to about 1.5 weight percent of colloidal silicon dioxide.

16. The immediate-release, oral tablet composition of any one of claims 6-15, wherein the lubricants in the intragranular component comprises sodium stearyl fumarate.

17. The immediate-release, oral tablet composition of any one of claims 6-16, wherein the intragranular component comprises from about 0.5 weight percent to about 1.5 weight percent of sodium stearyl fumarate.

18. The immediate-release, oral tablet composition of any one of claims 6-17, wherein the diluent in the intragranular component comprises microcrystalline cellulose and mannitol.

19. The immediate-release, oral tablet composition of any one of claims 6-18, wherein the intragranular component comprises from about 20 weight percent to about 36 weight percent of microcrystalline cellulose and from about 20 weight percent to about 36 weight percent of mannitol.

20. The immediate-release, oral tablet composition of any one of claims 6-19, wherein the intragranular component further comprises copovidone and succinic acid.

21. The immediate-release, oral tablet composition of any one of claims 6-20, wherein the intragranular component further comprises from about 13 weight percent to about 17 weight percent of copovidone and from about 8 weight percent to about 12 weight percent of succinic acid.

22. The immediate-release, oral tablet composition of any one of claims 6-21, wherein the extragranular component comprises crospovidone, colloidal silicon dioxide, and sodium stearyl fumarate.

23. The immediate-release, oral tablet composition of any one of claims 6-22, wherein the extragranular component comprises about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate.

24. An immediate-release, oral tablet composition comprising: an intragranular component comprising: about 20 mg to about 60 mg of a compound A-(4-((2-methoxy-3-(l-(methyl- t / 3)-l / 7-l,2,4-triazol-3-yl)phenyl) amino)-5-(propanoyl-3,3,3-t / 3)pyridin-2- yl)cyclopropanecarboxamide, hydrochloride salt; wherein the 20 mg to 60 mg is based on the free base amount of the compound; a diluent; about 3 to about 7 weight percent disintegrant; and a glidant and / or lubricant; and an extragranular component comprising: about 1 to 3 weight percent disintegrant; and a glidant and / or lubricants; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

25. The immediate-release, oral tablet composition of claim 24, comprising:an intragranular component comprising about 20 mg to about 60 mg of the compound, wherein the 20 mg to 60 mg is based on the free base amount of the compound, microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, sodium stearyl fumarate; optionally copovidone, and optionally succinic acid; and an extragranular component comprising crospovidone, colloidal silicon dioxide, and sodium stearyl fumarate.

26. The immediate release, oral tablet composition of claim 24, comprising: an intragranular component comprising about 20 mg to about 60 mg of the compound, wherein the 20 mg to 60 mg is based on the free base amount of the compound, from about 33 weight percent to about 35 weight percent of microcrystalline cellulose; from about 33 weight percent to about 35 weight percent of mannitol; from about 4 weight percent to about 6 weight percent of crospovidone; from about 0.5 weight percent to about 1.5 weight percent of colloidal silicon dioxide; and from about 0.5 weight percent to about 1.5 weight percent of sodium stearyl fumarate; and an extragranular component comprising about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate; wherein each weight percent is based on the total weight of the intragranular and extragranular components.

27. The immediate-release, oral tablet composition of claim 24, comprising: an intragranular component comprising about 20 mg to about 60 mg of the compound, wherein the 20 mg to 60 mg is based on the free base amount of the compound, from about 21 weight percent to about 22 weight percent of microcrystalline cellulose; from about 21 weight percent to about 22 weight percent of mannitol; from about 4 weight percent to about 6 weight percent of crospovidone; from about 0.5 weight percent to about 1.5 weight percent of colloidal silicon dioxide; from about 0.5 weight percent to about 1.5 weight percent of sodium stearyl fumarate; from about 14 to about 16 weight percent of copovidone; and from about 9 to about 11 weight percent of succinic acid; and an extragranular component comprising about 1.0 weight percent of crospovidone, about 0.5 weight percent of colloidal silicon dioxide, and about 1.5 weight percent of sodium stearyl fumarate;wherein each weight percent is based on the total weight of the intragranular and extragranular components.

28. The immediate-release, oral tablet composition of any one of claims 24-27, comprising about 20 mg of the compound, wherein the 20 mg is based on the free base amount of the compound.

29. The immediate-release, oral tablet composition of any one of claims 24-27, comprising about 40 mg of the compound, wherein the 40 mg is based on the free base amount of the compound.

30. The immediate-release, oral tablet composition of any one of claims 24-27, comprising about 60 mg of the compound, wherein the 60 mg is based on the free base amount of the compound.

31. The immediate-release, oral tablet composition of any one of claims 1-30, wherein the composition is substantially stable after storage at 25 °C and 60% relative humidity, at 30 °C and 75% relative humidity, or at 40 °C and 75% relative humidity for one month or three months.

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