TYK2 INHIBITORS AND USES THEREOF

Abstract

Described herein are methods and compositions for treating TYK2-mediated disorders.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

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 324,754, filed March 29, 2022; U.S. Provisional Patent Application No. 63 / 344,126, filed May 20, 2022; U.S. Provisional Patent Application No. 63 / 408,572, filed September 21, 2022; and U.S. Provisional Patent Application No. 63 / 429,720, filed December 2, 2022, the contents of each of which are incorporated by reference in their entirety herein. [Background technology]

[0002]

[0002] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors and interferon type I and III receptors and is activated by these receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitins) 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). Activated TYK2 then proceeds to phosphorylate additional signaling proteins, such as STAT family members including STAT1, STAT2, STAT4, and STAT6.

[0003]

[0003] TYK2 activation by IL-23 has been associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Knockout of TYK2 or inhibition of tyrphostins significantly reduced both IL-23-induced 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 mucus hypersecretion are mediated by IL-13-induced activation of TYK2, which in turn activates STAT6.

[0005]

[0005] Reduction of TYK2 activity protects joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, reduction of Tyk2 activity reduced production of Th1 / Th17-associated cytokines and matrix metalloproteinases, as well as other key markers of inflammation.

[0006]

[0006] TYK2 knockout mice exhibit complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) and lack CD4 T cell infiltration in the spinal cord compared to controls, suggesting that TYK2 is essential for the development of pathogenic CD4-mediated disease in MS. This confirms earlier studies linking increased TYK2 expression with MS susceptibility. Loss-of-function mutations in TYK2 result in reduced demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0007] TYK2 is the only 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-trinitrobenzenesulfonic acid-induced colitis in mice.

[0008]

[0008] Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder) have shown a strong, significant correlation between loss-of-function mutations in TYK2 and reduced prevalence of SLE in families with affected members. Genome-wide association studies comparing individuals with SLE with unaffected cohorts have shown a 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 impaired cytotoxic T cell responses and accelerated tumor development. However, these effects were associated with efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors are highly suitable for the treatment of autoimmune disorders or graft 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 it is involved in fewer, more closely related signaling pathways and produces fewer off-target effects.

[0010]

[0010] Studies of T-cell acute lymphoblastic leukemia (T-ALL) suggest that T-ALL is critically dependent on IL-10 via STAT1-mediated signaling through TYK2 to maintain cancer cell survival via upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations on TYK2 that promote cancer cell survival include activating mutations on the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for increased cancer cell viability. This was because TYK2 enzymes characterized by kinase-inactivating mutations (M978Y or M978F) in addition to activating mutations (E957D) resulted in failed conversion.

[0011]

[0011] Thus, selective inhibition of TYK2 has been proposed as a suitable target for patients with IL-10 and / or BCL2-dependent 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 beta (Aβ) peptide. Reduction of TYK2 phosphorylation of STAT3 after Aβ administration resulted in reduced neuronal cell death, and increased phosphorylation of STAT3 was observed in postmortem brains of Alzheimer's patients. Inhibition of the JAK-STAT signaling pathway has also been implicated in hair growth and reversal of hair loss associated with alopecia areata. Summary of the Invention [Problem to be solved by the invention]

[0012]

[0012] Therefore, there is a need to provide a method for inhibiting the activity of TYK2 to treat one or more of the conditions described herein without causing the side effects associated with inhibition of JAK2. [Means for solving the problem]

[0013] Methods and compositions useful for treating TYK2-mediated disorders are described in part herein. For example, a method for treating a TYK2-mediated disease or disorder in a patient in need of such treatment includes the steps of:

[0014] [ka]

[0015] Disclosed herein are methods comprising orally administering to a patient once or twice daily 30 mg, 40 mg, 60 mg, or 80 mg of a compound represented by the formula:

[0014] A method of treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need of treatment, each comprising:

[0016] [ka]

[0017] administering to the patient once daily two tablets of an oral tablet composition comprising 30 mg of a compound represented by the formula: Optionally, orally administering rabeprazole to the patient; and Optionally, the patient is fed at the time of administration of the compound. Also disclosed herein are methods comprising:

[0018] A method for treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need of such treatment, comprising:

[0019] [ka]

[0020] Further disclosed herein are methods comprising orally administering to a patient once daily or twice daily 30 mg, 60 mg, or 80 mg of a compound represented by the formula:

[0021]

[0016] Here,

[0022] [ka]

[0023] and a pharma- ceutical acceptable excipient. For example,

[0024] [ka]

[0025] Disclosed herein is an oral tablet composition comprising about 30 mg of a compound represented by the formula: [Brief description of the drawings]

[0026] [Figure 1]

[0018] This represents an experiment investigating the relative bioavailability of Compound A from an oral tablet composition versus a liquid formulation in healthy participants, and the effect of food or reduced gastric acidity on the pharmacokinetics of the disclosed compound or oral tablet composition. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027]

[0019] The features and other details of the present disclosure will now be described more particularly. Before further description of the present disclosure, certain terms utilized in the specification, examples, and appended claims are collected here. These definitions should be read as understood by those skilled in the art in view of the remainder of the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. definition

[0020] 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 of skill in the art, and so forth. When ranges are used herein, it is intended to include all combinations and subcombinations of ranges and specific embodiments therein. The term "about," when referring to a number or numerical range, means that the stated number or numerical range is an approximation within experimental variation (or statistical experimental error), and thus the number or numerical range, in some cases, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms, e.g., "comprise" or "comprises" or "having" or "including") is not intended to exclude that in certain other embodiments, for example, any compositions of matter, compositions, methods, or processes described herein "consist" or "consist essentially of" the described features.

[0028]

[0021] The terms "treat", "prevent", "ameliorate" and "inhibit", and words derived therefrom, as used herein, do not necessarily mean 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are different degrees of treatment, prevention, amelioration, and inhibition that one of skill in the art would recognize as potentially beneficial or having a therapeutic effect. In this regard, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of a disorder in a mammal. For example, a disorder, including its symptoms or conditions, can be reduced, for example, by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, 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 a disorder, e.g., cancer or inflammatory disease. For purposes of this specification, "treating," "preventing," "ameliorating," or "inhibiting" also includes delaying the onset of a disorder, or a symptom or condition thereof.

[0029]

[0022] The term "effective amount" or "therapeutically effective amount" as used herein refers to the administration of a sufficient amount of a compound or composition (e.g., an oral tablet composition) disclosed herein to alleviate to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or 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 change in a biological system. For example, an "effective amount" for use in therapy is the amount of a composition containing a compound disclosed herein that is required to produce a clinically significant reduction in a disease symptom. In some embodiments, the appropriate "effective" amount in any individual case is determined using techniques such as dose escalation studies.

[0030]

[0023] As used herein, the term "TYK2-mediated" disorder, disease, and / or condition, 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. Methods and Compositions For example, a method of treating a TYK2-mediated disease or disorder in a patient in need of such treatment, comprising:

[0031] [ka]

[0032] Disclosed herein are methods comprising orally administering to a patient once or twice daily 30 mg, 40 mg, 60 mg, or 80 mg of a compound represented by the formula:

[0025] In some embodiments, the methods described herein further comprise orally administering a proton pump inhibitor to the patient. For example, in some embodiments, the proton pump inhibitor is selected from the group consisting of, for example, rabeprazole, omeprazole, esomeprazole, lansoprazole, pantoprazole, and dexlansoprazole. In certain embodiments, the proton pump inhibitor is rabeprazole.

[0033] In some embodiments, the disclosed compound is administered to the patient in a fasted state. In other embodiments, the methods described herein further comprise administering food to the patient prior to or at the time of administration of the disclosed compound.

[0034]

[0027] In further embodiments, the TYK2-mediated disease or disorder is selected from the group consisting of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

[0035] For example, a method for treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need of treatment, each comprising:

[0036] [ka]

[0037] administering to the patient once daily two tablets of an oral tablet composition comprising 30 mg of a compound represented by the formula: Optionally, orally administering rabeprazole to the patient; and Optionally, the patient is fed at the time of administration of the compound. A method is described herein that includes:

[0038] A method of treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need of such treatment, comprising:

[0039] [ka]

[0040] orally administering to a patient once or twice daily 30 mg, 60 mg, or 80 mg of a compound represented by the formula: Also described herein are methods in which the patient is in a fasting or fed state.

[0041]

[0030] In addition,

[0042] [ka]

[0043] Disclosed herein are fixed unit dose pharmaceutical compositions for oral administration comprising 30 mg, 40 mg, 60 mg, or 80 mg of a compound represented by the formula: and a pharma- ceutically acceptable excipient.

[0044]

[0031] In some embodiments, the disclosed fixed dose pharmaceutical compositions are formulated as tablets.

[0032] Furthermore,

[0045] [ka]

[0046] Disclosed herein is an oral tablet composition comprising about 30 mg of a compound represented by the formula: Also described herein is a method of treating a TYK2-mediated disease or disorder in a patient in need thereof, comprising administering to the patient an effective amount of the disclosed oral tablet composition. In some embodiments, the administration is a once-daily administration. In other embodiments, the administration is a twice-daily administration. Pharmaceutical Compositions In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as pharma- ceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier), selected based on the selected route of administration (e.g., oral administration) and standard pharmaceutical practice, e.g., those described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub. Co., Easton, PA (2005)).

[0047]

[0035] In certain embodiments, the compounds provided herein are substantially pure in the sense that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, e.g., unreacted intermediates or synthetic by-products produced in one or more steps of a synthetic method.

[0048]

[0036] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the condition of the patient, the type and severity of the patient's disease, the specific 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 a therapeutic and / or prophylactic benefit (e.g., improved clinical outcome, e.g., more frequent, complete or partial remission, or longer disease-free and / or overall survival, or reduced severity of symptoms). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body mass, weight, or blood volume.

[0049] For example, in some embodiments, the disclosed compounds or compositions (e.g., oral tablet compositions) can be administered to a patient once a day. In other embodiments, the disclosed compounds or compositions (e.g., oral tablet compositions) can be administered to a patient twice a day.

[0050] In some embodiments, the disclosed compounds or pharmaceutical compositions are formulated for oral, topical (including oral buccal and sublingual), rectal, vaginal, transdermal, parenteral, pulmonary, intradermal, intrathecal, and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, intranasal, topical, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, pill, capsule, liquid, inhalant, nasal solution, suppository, suspension, gel, colloid, dispersion, suspension, solution, emulsion, ointment, lotion, eye drop, or ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0051] In some embodiments, for example, the disclosed compounds or pharmaceutical compositions are formulated for oral administration. In some embodiments, the pharmaceutical compositions are formulated as tablets, pills, capsules, liquids, suspensions, dispersions, solutions, or emulsions. In some embodiments, the pharmaceutical compositions are formulated as tablets, for example, tablets formulated for oral administration.

[0052]

[0040] Appropriate doses and dosage regimens are determined by conventional titration techniques known to those skilled in the art. Generally, treatment is initiated with small doses that are lower than the optimal dose of the compounds disclosed herein. Thereafter, the dose is increased in small increments until the optimal effect under the circumstances is reached. In some embodiments, the method of the present invention includes administration of at least one compound disclosed herein at about 0.1 μg to about 50 mg per kg of subject body weight. For a 70 kg patient, a dose of the compounds disclosed herein at about 10 μg to about 200 mg is more commonly used, depending on the physiological response of the subject.

[0053]

[0041] By way of example only, the dose of the compounds described herein for the methods for treating the diseases described herein is from about 0.001 to about 1 mg / kg (body weight of the subject) per day, e.g., 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 a compound described herein for the methods described is from about 1 to about 1000 mg / kg (of the body weight of the subject undergoing treatment) per day, e.g., 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.

[0054]

[0042] Furthermore, the dose of the compound for the methods of treating the diseases described herein may be, by way of example only, a fixed dose, such as, for example, 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. Treatment Method

[0043] The methods described herein are useful for inhibiting the kinase activity of one or more enzymes. In some embodiments, the kinase is TYK2.

[0055]

[0044] Provided herein is a method for treating a disease or disorder, wherein the disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-associated disorder, the method comprising administering to a patient in need of treatment for the disease or disorder an effective amount of a compound or composition described herein (e.g., an oral tablet composition).

[0056] 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.

[0057] 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, or inflammatory bowel disease.

[0058]

[0047] 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 thrombocytosis or thrombocytosis.

[0059] In some embodiments, the disease or disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes. In some embodiments, the disease or disorder is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease.

[0060] In some embodiments, the proliferation 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.

[0061] In some embodiments, the disease or disorder is associated with a transplant. In some embodiments, the disease or disorder is associated with a transplant is transplant rejection, or graft-versus-host disease. 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.

[0062]

[0053] Provided herein are methods for treating inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo vulgaris, hypersensitivity vasculitis, 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.

[0063] Methods for treating other diseases or conditions, e.g., diseases or conditions having an inflammatory component, e.g., treatment of ocular diseases and conditions, e.g., ocular allergies, conjunctivitis, sicca, and diseases affecting the nose, including vernal conjunctivitis, allergic rhinitis, and inflammatory diseases in which the involvement of an autoimmune reaction is suggested or which have an autoimmune component or cause, including autoimmune blood diseases (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, and the like. granulamatosis), dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity lung disease inflammation, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, dry conjunctivitis and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic-onset juvenile idiopathic arthritis, cryopyrin-associated periodic fever syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. idiopathic nephrotic syndrome or minimal disease) change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle fatigue, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and nonallergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinosinusitis,Ocular allergies, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling or reduced disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis Provided herein are methods for treating inflammatory bowel disease, endometritis, enteritis, enteritis, epicondylitis, epididymitis, fasciitis, connectivitis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0064]

[0055] In some embodiments, the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), or osteoarthritis.

[0065] In some embodiments, the inflammatory disease is a Th1 or Th17 mediated disease. In some embodiments, the Th17 mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0066]

[0057] In some embodiments, the inflammatory disease is Sjogren's syndrome, an allergic disease, osteoarthritis, an eye condition such as eye allergy, conjunctivitis, dry conjunctivitis, vernal conjunctivitis, or a disease affecting the nose such as allergic rhinitis. Combination therapy

[0058] In certain cases, a compound or composition described herein (e.g., the disclosed oral tablet compositions) is administered in combination with a second therapeutic agent, e.g., a proton pump inhibitor, e.g., rabeprazole.

[0067]

[0059] In some embodiments, the benefit received by the patient is increased by administering the compounds described herein in combination with a second therapeutic agent (including also a therapeutic regimen) that also has a therapeutic benefit.

[0068]

[0060] In one particular embodiment, a compound or composition described herein is co-administered with a second therapeutic agent, where the compound or composition described herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0069] In any event, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply the sum of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0070] In certain embodiments, when the compounds disclosed herein are administered in combination with a second therapeutic agent, different therapeutically effective dosages of the compounds disclosed herein are utilized in the formulation of pharmaceutical compositions (e.g., oral tablet compositions) and / or treatment regimens. The therapeutically effective dosages of drugs and other agents for use in combination treatment regimens may be determined by means similar to those described herein above for the active substances themselves. Additionally, the methods of prevention / treatment described herein include the use of regular dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, combination treatment regimens include treatment regimens in which administration of the compound or composition is initiated before, during, or after treatment with a second agent described herein, and continues at any time during treatment with the second agent or after cessation of treatment with the second agent. Combination treatment regimens also include treatments in which the compound or composition and the second agent used in combination are administered at the same time or at different times, and / or the intervals are reduced or increased during the treatment period. Combination treatments further include cyclical treatments that are started and stopped at different times to aid in the clinical management of the patient.

[0071]

[0063] It is understood that dosage regimens for treating, preventing, or ameliorating the condition(s) for which relief is sought will be modified according to 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 cases, the dosage regimen actually utilized will vary and, in some embodiments, will deviate from the dosage regimens set forth herein.

[0072] For the combination therapies described herein, the doses of the co-administered compounds vary depending on the type of codrug utilized, the particular drug utilized, the disease or condition being treated, etc. In additional embodiments, when co-administered with a second therapeutic agent, the compounds provided herein are administered simultaneously or sequentially with the second therapeutic agent.

[0073] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. When administration is simultaneous, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills), by way of example only.

[0074] The compounds and compositions described herein are administered before, during, or after the onset of a disease or condition, and the timing of administering the composition containing the compound varies. Thus, in one embodiment, the compounds and compositions described herein are used prophylactically and administered continuously to a subject prone to developing a condition or disease to prevent the onset of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during the onset of symptoms or as soon as possible after the onset of symptoms. In certain embodiments, the compounds or compositions described herein are administered as soon as possible after the onset of a disease or condition is detected or suspected, for the time required for the treatment of the disease. In some embodiments, the length of time required for treatment varies, and the length of time of treatment is adjusted to suit the particular needs of each subject. For example, in certain embodiments, the compounds or formulations containing the compounds described herein are administered for at least 2 weeks, about 1 month to about 5 years.

[0075] In some embodiments, the compounds or compositions described herein are administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds or compositions described herein is enhanced by administration of an adjuvant (i.e., the adjuvant has a minimal therapeutic benefit by itself, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). EXAMPLES

[0076]

[0068] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0069] N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propanoyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (compound A) can be prepared according to the synthetic procedures described in WO2020 / 086616, the entire contents of which are incorporated herein by reference.

[0077] Example 1 Test description:

[0070] Investigate the relative bioavailability of Compound A from an oral tablet composition versus a liquid formulation and the effect of food or reduced gastric acidity on the pharmacokinetics of the disclosed compound or the oral tablet composition in healthy participants. Primary objectives: to assess the relative bioavailability of 60 mg Compound A administered as two 30 mg immediate release tablets versus a liquid formulation in healthy participants; to assess the effect of food on the pharmacokinetics (PK) of 60 mg Compound A administered as two 30 mg immediate release tablets in healthy participants; to assess the effect of gastric acid reduction with rabeprazole on the PK of 60 mg Compound A administered as two 30 mg immediate release tablets in healthy participants. Secondary objectives include to assess the safety and tolerability of a single dose of 60 mg Compound A in healthy participants and / or to assess the effect of a single dose of 60 mg Compound A on selected pharmacodynamic (PD) markers in healthy participants. Experimental Design: The study was a single-center, in-house, open-label, four-period, partially randomized crossover study in approximately 15 healthy participants. The study population was 18-60 years old, 18-34 kg / m 2Include healthy male and female participants with a body mass index (BMI) between 0.01 and 0.05. The expected study duration will include: screening period: up to 28 days; treatment period: 17 days; and follow-up period: 6-10 days after the last dose.

[0078] Each participant will receive a single dose of Compound A under four conditions: A. 60 mg of the liquid formulation is administered in fasting state. · B. 60 mg (two 30 mg tablets) is administered in fasting state. · C. 60 mg (two 30 mg tablets) is administered with a high-calorie breakfast. · D. 60 mg (two 30 mg tablets) is administered on an empty stomach on the fifth day of a five-day course of rabeprazole 20 mg once daily.

[0079] The order of regimens A, B, and C is randomized (ABC, BCA, CAB), with regimen D occurring last. Eligible participants will be admitted to the Clinical Trial Unit (CRU) before the first dose of study drug (day -1, period 1) and will remain in the CRU for 18 days. An end-of-study (EOS) visit will occur 6-10 days after the last dose of Compound A. Administration of Compound A in the fasted state (A and B): Compound A, 60 mg, as two 30 mg tablets or 60 mg as a liquid formulation, is administered with 240 mL of water after at least a 10 hour overnight fast, followed by another 4 hour fast. Water is allowed ad libitum, except 1 hour before and 1 hour after administration of Compound A. Administration of Compound A in the fed state (C): Compound A, 60 mg, is administered as two 30 mg tablets with 240 mL of water at the end of a standardized high-calorie meal. The meal is administered after an overnight fast of at least 10 hours, followed by another 4-hour fast. Water is allowed ad libitum, except 1 hour before and 1 hour after administration of Compound A. Administration of Rabeprazole in the fasted state and Compound A in the fasted state (D):

[0076] On days 3, 4, 5 and 6 of Phase 3, 20 mg of rabeprazole is administered with 240 mL of water after an overnight fast of at least 10 hours. An additional hour of fasting is allowed after administration. On day 1 of Phase 4, after an overnight fast of at least 10 hours, 20 mg of rabeprazole is administered with 60 mg of Compound A (two 30 mg tablets) and 240 mL of water, followed by an additional 4 hour fast. Water is allowed ad libitum, except 1 hour before and 1 hour after administration of rabeprazole and / or Compound A.

[0080] The following PK parameters for Compound A are determined as needed: C max : Maximum plasma concentration of compound A determined directly from the concentration-time profile T max : Time of maximum plasma concentration of Compound A determined directly from the concentration-time profile AUC 0-last : Time from pre-dose (time 0) to last quantifiable concentration (t last ) area under the concentration-time curve AUC 0-inf : Extrapolated from pre-dose (time 0) to infinity (AUC 0-last +C last / λz ) Area under the concentration-time curve AUC %extrap :t last AUC by extrapolation beyond 0-inf Percentage of λ z : Terminal elimination rate constant determined by selecting at least three data points in the terminal phase of the concentration-time curve ·t 1 / 2 :ln2 / λ z Terminal elimination half-life calculated as: ·CL / F: Dose / AUC inf Apparent total body clearance calculated as: ·Vz / F: Dose / (AUC inf *λ z ): Apparent volume distribution calculated as Ae 0-48Cumulative urinary excretion of unchanged drug in the complete collection up to 48 hours calculated as: urinary concentration of compound A * urine volume: Percentage of drug excreted unchanged in urine, calculated as %Fe:(Ae / dose)*100: ·CLr:Ae 0-48 / AUC 0-48 Renal clearance of unchanged drug from plasma, calculated as: Participants who meet the following criteria will be considered eligible to participate in the clinical study: Participants will be able to understand and comply with experimental procedures, will understand the risks involved, and will provide written informed consent in accordance with federal, local, and institutional guidelines prior to any clinical screening activities; Participants will be male or female, aged 18-60 years (inclusive) at the time of the screening visit; Participants will be 18 kg / m2 or over at the time of the screening visit. 2 ~34kg / m 2participants will be healthy as determined by medical history, physical examination, vital signs, and routine clinical laboratory parameters (chemistry, hematology, serology, and urinalysis), as well as screening ECG at visit and on day -1. Laboratory values ​​outside the normal range will be accepted if deemed clinically insignificant. Screening assessments may be repeated once at the investigator's discretion; female participants must not be pregnant (negative pregnancy test if of childbearing potential at screening and check-in) or breastfeeding, and if sexually active must meet the following criteria: if of childbearing potential, must use highly effective (<1% failure rate) contraceptive methods (e.g., non-hormonal, intrauterine device, azoospermic partner, sexual abstinence) during study participation and until at least 3 months after the last dose of experimental drug, or be surgically sterilized (i.e., hysterectomy, bilateral tubal ligation or bilateral oophorectomy) at least 6 months prior to the first dose of experimental drug, or be menopausal (defined as 12 consecutive months of amenorrhea and documented plasma follicle-stimulating hormone (FSH) levels >40 IU / mL). Sexually active male participants with female sexual partners must be surgically sterilized (e.g., vasectomy) for 6 months or must use condoms in conjunction with spermicidal foam / gel / film / cream / suppository from the screening visit until 3 months after the last dose of experimental drug (to prevent drug penetration by semen, even if their partner is a non-fertile woman) and must abstain from sperm donation throughout the same period.

[0081]

[0080] Participants who meet one or more of the following criteria will be considered ineligible for participation in the clinical study: Participant has previously taken Compound A; Participant has a history of hypersensitivity to Compound A or any of the raw ingredients of rabeprazole; Participant has a history or presence of immunosuppressive or significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immune, skin or neurological disease, including any acute illness or major surgery determined by the investigator to be clinically significant, within the past 3 months; Participant has a history of gastrointestinal, hepatic (including Gilbert's syndrome), renal, or other conditions known to interfere with drug absorption, distribution, metabolism, or excretion (s / p cholecystectomy is permitted); Participant has a history of malignancy within 10 years from day -1 (in the case of intraepithelial cervical carcinoma, 5 years for surgically excised nonmelanoma skin cancer and 2 years for surgically excised nonmelanoma skin cancer); participants had a positive serological test at screening for infection with human immunodeficiency virus (HIV-1 and HIV-2), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibodies; participants had a history of active, latent, or inadequately treated tuberculosis infection, or a positive QuantiFERON test at screening; participants had a positive test for alcohol or drugs of dependence at screening or on day -1; participants had used prescription medications within 28 days of day -1, had received a vaccination within 14 days of day -1, or had received over-the-counter medications (including herbal preparations and supplements) within 14 days of day -1 (100 mg / day).Up to 5 g of acetaminophen is permitted; Participant has used or will use systemic immunosuppressants (e.g., corticosteroids, methotrexate, azathioprine, cyclosporine) or immune modulating medications (e.g., IFN) during the study or within 3 months prior to first study drug administration; Participant has history or evidence of any other clinically significant disorder, condition, or disease that, in the investigator's opinion, poses a risk to the participant's safety or interferes with study evaluations, procedures, or completion; Participant is receiving treatment for any condition or condition that may interfere with the performance of the study or that, in the investigator's opinion, poses a risk to the participant's participation in the study. This includes, but is not limited to: alcoholism, drug addiction or abuse, and psychiatric conditions; the participant currently uses any tobacco or nicotine-containing product, more than 10 cigarettes per day or the equivalent; the participant has received an investigational drug (or is currently using an investigational device) within 30 days prior to screening or within at least 5 times the respective elimination half-life (t1 / 2) (whichever is longer); the participant is unable to comply with any experimental restrictions / requirements including the intake of a high-calorie diet, e.g., is lactose intolerant, has an egg allergy, is vegetarian; the participant has donated more than 500 mL of blood within the last 60 days prior to the screening visit or plasma within the last 2 weeks.

[0082] Dosing day: Dosing on regimens A, B, and D is performed after an overnight fast of at least 10 hours. Water intake is permitted up to 1 hour before dosing and 1 hour after dosing. Fasting restrictions continue for at least 4 hours after dosing (no food or drink other than water allowed). Compound A is administered with 240 mL of water at the end of the meal.

[0083] Fed State: A standardized high-calorie breakfast is administered after an overnight fast of at least 10 hours, which should be consumed within approximately 30 minutes. Compound A is administered with 240 mL of water at the end of the meal.

[0084] Example 2 Experiment Description A blinded, randomized, placebo-controlled, multiple-dose study will be conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound A tablets administered to healthy participants over a 14-day period. Primary Objectives: To evaluate the safety and tolerability of Compound A tablets administered to healthy participants over a 14 day period; To evaluate the pharmacokinetics (PK) of Compound A tablets in healthy participants at steady state. Experimental Design: This is a single-center, in-house, sponsor-disclosed, double-blind, randomized, placebo-controlled, parallel-group, multiple-dose study in up to six cohorts of healthy participants. Participants are admitted to the investigational unit the day before the first dose of investigational medicinal product (IMP) (day -1) and remain until 48 hours after the last dose of a 14-day course of IMP. For doses administered more than once daily, the last dose is the first (morning) dose on day 14. The end-of-study visit will occur 5-7 days after the last dose of IMP. Participant numbers will be approximately 48 healthy adult participants (up to six cohorts of 8 participants each, randomization ratio 3:1 for Compound A to placebo). Ages 18-60 years, body mass index (BMI) 18-32 kg / m 2 Healthy male and female participants with pulmonary embolism and pulmonary edema are planned to be enrolled.

[0085] The IMP consists of 10 and 30 mg tablets of Compound A and their matching placebo. Single doses of up to 100 mg of Compound A have been administered to healthy participants in FIH studies without clinically significant safety concerns. max The mean C0-inf was 949ng / mL (maximum 1,160n / mL) and the mean AUC0-inf was 11,286ng*h / mL (maximum 13,705ng*h / ml). max [C max,ss ]: 433 ng / mL, mean AUC from time 0 to 12 hours at steady state [AUC 0-12,ss]:3620ng*h / mL) have been studied and were well tolerated in the study. Dose levels for the first two cohorts are 20mg qd and 20mg q12h, respectively. Other dose levels will depend on the relative bioavailability of the tablet versus the suspension. Dosing can be done qd or q12h, and the maximum dose to be studied is a mean steady-state C not exceeding 949ng / mL and 11,286ng*h / mL, respectively. max and AUC 0-24 Assuming there is bioequivalence between the tablet and suspension, the maximum dose to be studied would be 60 mg q12h or 80 mg qd. If there is a 50% decrease in bioavailability of the tablet vs. the suspension, the maximum dose to be studied would be 120 mg q12h or 160 mg qd. These are the highest possible doses planned for this study.

[0086] The following safety variables will be recorded at regular intervals during the study: adverse events (AEs); clinical laboratory tests (hematology, clinical chemistry, and urinalysis); vital signs (systolic and diastolic blood pressure, temperature, pulse, and respiratory rate); 12-lead electrocardiogram (ECG) and continuous Holter ECG; and physical examination. Pharmacokinetic endpoints recorded are: maximum observed concentration (C max ); C after the first and last dose max Time to max ); the lowest AM concentration on days 3, 5, 7, 9, 12, 13, and 14 (C trough ); area under the concentration-time curve from time 0 to the time of the last quantifiable concentration after the last dose (AUC 0-t ); area under the concentration-time curve (AUC 0-tau ); Accumulation ratio (RAUC = AUC after the last dose 0-tau / AUC after first dose 0-tau );C max The accumulation ratio (Rac[C max ]); apparent terminal elimination half-life after the last dose (t 1 / 2 ); the final elimination rate constant after the final dose (λ z); apparent total body clearance (CL / F) after oral administration at steady state; apparent volume distribution (V ss / F);Ae 0-24 : Cumulative urinary excretion of unchanged drug during the complete 24-hour collection, calculated as: urinary concentration of Compound A * urine volume; %Fe: urinary percentage of unchanged drug excreted, calculated as: (Ae 0-24 / dose administered over 24 hours)*100; CLr: renal clearance of unchanged drug from plasma, calculated as follows: Ae in the qd cohort 0-24 / AUC 0-24 , and Ae in the q12h cohort. 0-24 / 2*AUC 0-12 .

[0087] Example 3 Experiment Description A randomized, double-blind, placebo-controlled study is conducted to evaluate the efficacy and safety of Compound A in patients with moderate to severe plaque psoriasis. Primary Objective: To compare Psoriasis Area and Severity Index (PASI-75) between Compound A and placebo medications after 12 weeks of treatment. Primary endpoint: Proportion of patients with moderate to severe psoriasis between Compound A and placebo achieving a ≥ 75% reduction in PASI score at 12 weeks. Secondary Objectives: To evaluate the safety and tolerability of Compound A dosing in patients with moderate to severe psoriasis; to characterize the pharmacokinetics (PK) of Compound A; to evaluate the response rate in Physician's Global Assessment (sPGA) score after 12 weeks of treatment; to evaluate the response rate in PASI-50, 90, and 100 scores after 12 weeks of treatment; to compare the response rate in PASI-75 between each treatment of Compound A; to evaluate the effect on %BSA affected by psoriasis after 12 weeks of treatment; and to evaluate the change in Dermatology Life Quality Index (DLQI). Secondary endpoints: incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs); plasma concentrations and PK parameters of Compound A; proportion of patients achieving sPGA scores of "0" ("eliminated") or "1" ("minimal") after 12 weeks of treatment compared to placebo; proportion of patients achieving PASI-50, 90, and 100 after 12 weeks of Compound A treatment compared to placebo; proportion of patients achieving PASI-75 at 12 weeks compared between Compound A treatments; change from baseline in %BSA after 12 weeks of Compound A treatment compared to placebo; change from baseline in DLQI at 12 weeks for Compound A compared to placebo. Exploratory objectives: To assess changes in itch numeric rating scale (NRS) after 12 weeks of treatment; to assess changes in EQ-5D; to assess changes in skin-based biomarkers related to psoriasis and TYK2 with Compound A treatment; to assess changes in blood-based biomarkers related to psoriasis and TYK2 with Compound A treatment; to assess changes in blood and skin transcriptomic and proteomic based biomarkers with Compound A treatment. Exploratory endpoints: change from baseline in NRS score after 12 weeks of Compound A treatment compared to placebo; change from baseline in EQ-5D at week 12 with Compound A compared to placebo; change from baseline in skin biomarkers associated with psoriasis and TYK2 in response to Compound A treatment; change from baseline in skin biomarkers associated with psoriasis and TYK2 in response to Compound A treatment; change from baseline in transcriptomic and proteomic expression in response to Compound A treatment. Experimental Design:

[0088] This is a randomized, double-blind, placebo-controlled study in patients with moderate to severe psoriasis. The purpose of this study is to evaluate the clinical efficacy, safety, PK, and PD of Compound A compared to placebo in patients with moderate to severe psoriasis. The total study duration is approximately 20 weeks. The screening period is 4 weeks, the treatment period is 12 weeks, and the safety follow-up period is 4 weeks. For the entire study, study completion is defined as the last patient's last visit for any protocol-related activity (last patient, last visit). For individual patients, study completion is defined as the time of the patient's last data collection. Efficacy (including PASI, sPGA, QoL measures), safety, and PK will be evaluated. Preliminary pharmacodynamic (PD) assessments include blood- and skin-based RNA, proteome, and other molecular markers. Continued treatment will be provided in a separate open-label study extension.

[0088]

[0089] The experimental population will consist of male and female adult patients with moderate to severe psoriasis. Patients must meet all enrollment criteria and must not meet any of the exclusion criteria. Patients who meet all eligibility criteria will be randomized in a 1:1:1:1:1:1:1 fashion to receive oral administration of Compound A or placebo at one of five dose levels (10mgQD, 20mgQD, 40mgQD, 20mgBID, 40mgBID). Approximately 210 patients will be randomized to one of six experimental arms (35 patients per arm). Compound A will be provided as tablets in two dose strengths, 10mg and 20mg. Matching placebo tablets will be similar in size, shape, and appearance to the Compound A 10mg and 20mg active drug tablets. The dose levels of Compound A administered in each experimental arm are outlined in Table 1. Patients will be randomized to blinded Compound A or placebo.

[0089] [Table 1]

[0090]

[0090] Enrollment criteria included patients with a diagnosis of plaque psoriasis for ≧6 months; plaques covering ≧10% of body surface area (BSA); a Psoriasis Area Severity Index (PASI) score ≧12 and a Static Physician's Global Assessment (sPGA) score ≧3.

[0091]

[0091] A diagnosis of non-plaque psoriasis (guttate, inverse, pustular, erythrodermic, drug-induced) and / or other immune-mediated conditions commonly associated with psoriasis (e.g., uveitis, inflammatory bowel disease) or other inflammatory skin conditions that may interfere with experimental evaluation; a diagnosis of psoriatic arthritis, i.e., currently requiring medical treatment with systemic (oral, SC, IM or IV) immunosuppressants (including corticosteroids, immunosuppressants, biologics) or who, in the investigator's opinion, should or are expected to develop unstable disease, may be exclusion criteria for the study.

[0092] Example 4 Experiment Description A Phase 2, randomized, double-blind, placebo-controlled study will be conducted to evaluate the safety, efficacy, and pharmacokinetics of multiple dose levels of Compound A in adult patients with systemic lupus erythematosus (SLE). Primary Objective: To compare the effect of Compound A dosing with placebo on disease activity as measured by the proportion of patients achieving a British Commonwealth Lupus Review Group (BILAG)-Based Complex Lupus Assessment (BICLA) response at 32 weeks. Primary Endpoint: A composite endpoint (BICLA) defined by meeting all of the following criteria: reduction in all BILAG-2004A to B / C / D and reduction in baseline BILAG-2004B to C / D, and no worsening of BILAG-2004 in other organ systems, as defined as ≥1 new BILAG-2004A or ≥2 new BILAG-2004B; no worsening from baseline in SLE Disease Activity Index 2000 (SLEDAI-2K), where worsening is defined as an increase of >0 points from baseline in the SLEDAI-2K; Patient Lupus Disease Activity no deterioration from baseline in physician assessment of sexual function, where deterioration is defined as an increase of ≥ 0.30 points on the Physician's Global Assessment (PGA) of 3 points; no interruption of investigational drug (IP) or use of rescue medication above protocol-allowed thresholds prior to evaluation; estimand is the difference in the rate of successful treatment between each treatment condition (compound A and placebo doses, regardless of interruption) in patients with moderate to severe disease SLE, where successful treatment is defined as a response in the BICLA at 32 weeks without the use of additional or alternative medications. Secondary Objectives: To evaluate the safety and tolerability of multiple dose levels of Compound A; To compare the effect on skin disease activity, as measured by the proportion of patients with a Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score ≥ 8 at baseline who achieve a ≥ 50% reduction in CLASI activity score at 32 weeks, between Compound A and placebo; To compare the effect on disease activity, as measured by the proportion of patients with a high interferon gene signature (IGS) subgroup who achieve a BICLA response at 32 weeks, between Compound A and placebo; To compare the effect on disease activity, as measured by the proportion of patients with a SLE Responder Index ≥ 4 (SRI[4 ]); to compare Lupus Low Disease Activity Status (LLDAS) responses at 32 weeks between Compound A and placebo; to compare steroid use in patients at 32 weeks; to compare the effect on Health Related Quality of Life (HRQOL) between Compound A and placebo; to compare disease specific QoL between Compound A and placebo; to compare fatigue as measured by FACIT-F between Compound A and placebo; to compare Patient Global Assessment of Disease Activity (PtGA) between Compound A and placebo. Secondary endpoints: incidence of treatment-emergent AEs (TEAEs) and SAEs, vital signs, physical examination, 12-lead ECG, and clinical laboratory tests (hematology, clinical chemistry, urinalysis); a 50% decrease in CLASI activity score compared to baseline defined by the following criteria: baseline CLASI activity score ≥ 8 with a ≥ 50% decrease in CLASI activity score compared to baseline at week 32; no interruption of IP or use of rescue medication above the protocol-allowed threshold prior to evaluation; BICLA response; a composite endpoint SRI (4), defined as a ≥ 4-point decrease from baseline in SLEDAI-2K with no new BILAG A, > 1 BILAG no B domain scores, no worsening from baseline in PGA ≥ 0.3; no interruption of IP or use of rescue medication above protocol-allowed thresholds prior to assessment; LLDAS as measured by achieving: SLEDAI-2K ≤ 4, no activity in major organ systems, and no hemolytic anemia or gastrointestinal activity, and no new lupus disease activity compared to previous SLEDAI-2K assessments; PGA ≤ 1 and current prednisone (or equivalent) daily dose ≤ 7.5 mg; standard maintenance dose tolerated in minutes; proportion of patients achieving a steroid dose of ≦5 mg / day prednisone equivalent; difference between baseline (day 1) and week 32 in the Short-Form 36 Health Survey, version 2, acute (SF-36v.2 acute) physical health (PCS) and / or mental health (MCS) summary scores; difference between baseline (day 1) and week 32 in lupus QoL; difference between baseline (day 1) and week 32 in FACIT-F; difference between baseline (day 1) and week 32 in PtGA. Secondary analysis objectives at 48 weeks: to compare BICLA response between Compound A and placebo dosing at 48 weeks; to compare the effect on skin disease activity, as measured by the proportion of patients with a CLASI activity score ≥ 8 at baseline who achieve a ≥ 50% reduction in CLASI activity score at 48 weeks, between Compound A and placebo dosing; to compare the effect on disease activity, as measured by the proportion of patients who achieve a BICLA response at 48 weeks, between Compound A and placebo dosing in the high IGS subgroup; to compare SRI(4) response; to compare LLDAS response at 48 weeks between Compound A and placebo; to compare annualized incidence of flare over 48 weeks; to compare glucocorticoid use in patients at 48 weeks; to compare the effect on HRQOL between Compound A and placebo; to compare disease-specific QoL between Compound A and placebo; to compare fatigue as measured by FACIT-F between Compound A and placebo; to compare Patient Global Assessment of Disease Activity (PtGA) between Compound A and placebo. Secondary analysis endpoints at 48 weeks: BICLA response at 48 weeks; CLASI at 48 weeks; SRI(4) at 48 weeks; LLDAS at 48 weeks; annualized incidence of flare defined as ≥1 BILAG A or ≥2 BILAG B scores with items rated as new or worsening; proportion of patients achieving a glucocorticoid dose of ≤5 mg / day prednisone equivalent; difference between baseline (day 1) and week 48 in SF-36v.2 acute PCS and / or MCS scores; difference between baseline (day 1) and week 48 in lupus QoL; difference between baseline (day 1) and week 48 in FACIT-F; difference between baseline (day 1) and week 48 in PtGA. Exploratory Objectives: Time to sustained BICLA response; to compare the proportion of patients with SRI(4) in the IFN study high subgroup at 32 and 48 weeks; to characterize the PK of multiple dose levels of Compound A; to evaluate the change from baseline in 28 joint count difference between Compound A and placebo; to evaluate differences between Compound A and placebo for the level of SRI response, the individual components of SRI, and measures of disease activity including swollen and tender joint counts over time to 32 and 48 weeks, and for SRI and BICLA over time; to evaluate the change from baseline in mean and median interferon-regulated gene (IRG) expression levels between Compound A and placebo dosing through 48 weeks; to evaluate changes in blood transcriptomic and proteomic-based biomarkers with Compound A treatment; to evaluate the change from baseline in mean complement (C3, C4) and anti-double-stranded DNA (dsDNA) antibodies through 48 weeks. Exploratory Endpoints: defined as the first BICLA response visit, sustained through and including 48 weeks; SRI(4) response; Compound A plasma PK parameters through 32 and 48 weeks; proportion of patients with at least 6 swollen or tender joint counts at baseline who achieved a 50% reduction at 32 and 48 weeks; SRI(4), SRI(5), SRI(6), SRI(7), SRI(8), BICLA response, BILAG-2004 score, SLEDAI-2K, PGA, and SRI(5) over time. joint counts; changes in mean and median IRG expression levels by 48 weeks; changes from baseline in transcriptomic and proteomic expression in response to Compound A treatment; proportion of patients with abnormal C3 or C4 or anti-dsDNA at baseline and normal C3 or C4 or anti-dsDNA antibodies at 32 or 48 weeks; evaluation of the effect of Compound A on measures of global SLE clinical response in patients based on IRG status (i.e., high vs. low IRG signature) by 48 weeks. Experimental Design:

[0093] This is a phase 2, randomized, double-blind, placebo-controlled study to evaluate the safety, efficacy, PK, and pharmacodynamics (PD) of three dose levels of Compound A (20 mg once daily [QD], 40 mg [20 mg taken twice daily (BID)], and 60 mg [30 mg taken twice daily (BID)]) in adult patients aged 18-70 years with moderately to aggressively active, autoantibody-positive SLE receiving standard of care (SOC). Randomization will be stratified using SLEDAI-2K score at screening (<10 points vs. ≥10 points), steroid dose on day 1 (<10 mg prednisone equivalent vs. ≥10 mg), and IGS score (high vs. low).

[0093]

[0094] The study will include protocol-defined steroid taper. Steroid taper will be attempted for all patients. The target will be a steroid dose ≦5 mg / day prednisone equivalent by week 24. Taper will begin by week 8 (or earlier) and progress until the target is reached. Taper will not be permitted between weeks 24 and 32, but may be resumed after the week 32 visit and up to week 40, at the investigator's discretion. No taper will be permitted between the week 40 and week 48 visits.

[0094]

[0095] Efficacy diagnostics include SLEDAI-2K, BILAG-2004, PGA VAS, CLASI, tender and swollen joint counts. Patient-reported outcome (PRO) measures include SF-36v.2 Acute, Lupus QoL, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue questionnaire and Patient Global Assessment (PtGA). Safety assessments include AE ​​monitoring, clinical laboratory tests, vital signs, ECG, and physical examinations. Observed concentration-time data will be used primarily for modeling and simulation purposes. PK parameters include mean maximum observed concentration (C max ) and C max Time to max ) The observed plasma concentration of compound A at the area minimum (C trough) can be determined if data permits. Preliminary PD and biomarker evaluation will include blood-based transcriptomic, proteomic, and other TYK2-related and disease-associated markers.

[0095]

[0096] Patients who meet all eligibility criteria will be randomized in a 1:1:1:1 ratio to receive oral Compound A at dose levels 1 to 3 or placebo, as outlined in Table 2.

[0096] [Table 2]

[0097] The total study participation period for each patient is approximately 57 weeks. The study includes a screening period of approximately 35 days, followed by a 48-week double-blind treatment period, followed by either a 4-week safety follow-up period or an open-label extension (OLE) study for eligible patients who choose to continue long-term treatment in the OLE study. Approximately 388 patients will be randomized into one of four study arms (three active Compound A + one placebo).

[0098] Participants who meet the following criteria will be considered eligible for participation in the clinical study: able and willing to provide written informed consent (signed and dated) to participate in this study and to comply with all requirements in the study protocol; male or female, aged 18-70 years (inclusive) at the time of informed consent; body mass index 18-40 kg / m 2and total body weight >40 kg (88 lbs); sufficient venipuncture; diagnosed with SLE ≥6 months prior to screening and 2019 European League Against Rheumatism (EULAR) / American College of Rheumatology (ACRA)-compliant at screening Meet American College of Rheumatology (ACR) criteria and have either a positive antinuclear antibody test by immunofluorescence assay with a titer of ≥ 1:80 or elevated anti-dsDNA antibodies in a central laboratory at screening, or anti-Smith antibodies determined by a central laboratory, or C3 or C4 below the lower limit of normal at screening; a SLEDAI score > 6 at screening and a "clinical" SLEDAI-2K score ≥ 4 points during screening and before the first dose of experimental drug ("clinical" SLEDAI-2K is the SLEDAI-2K assessment score that does not include points attributable to any urine or laboratory results, including immunological measurements (including points from the following clinical components: arthritis, myositis, rash, alopecia, mucosal ulcers, pleuritis, pericarditis, and vasculitis).at least one of the following: BILAG-2004 index level A disease in at least one body / organ system and / or BILAG-2004 index level B disease in more than one body / organ system (scores from lupus headache are excluded); PGA score >1.0 on a VAS of 0 to 3 at screening; clinical SLEDAI-2K score ≥4 points with skin involvement before first dose of experimental drug; currently receiving at least one of the following: oral corticosteroids (≤40 mg / day prednisone or equivalent) for a minimum of 2 weeks prior to signing the informed consent form (ICF), and / or any of the following medications have been administered for a minimum of 12 weeks prior to signing the ICF, and have been administered a stable dose for a minimum of 8 weeks prior to signing the ICF, and by Day 1: : azathioprine ≤ 200 mg / day, antimalarial (e.g., chloroquine, hydroxychloroquine, quinacrine), mycophenolate mofetil ≤ 2 g / day or mycophenolate ≤ 1.44 g / day, oral, subcutaneous, or intramuscular (IM) methotrexate ≤ 20 mg / week (≤ 1 immunosuppressant treatment may be used concomitantly; if corticosteroids are the only medication being used for SLE activity, doses must be ≥ 10 mg and ≤ 40 mg prednisone equivalent for a minimum of 8 weeks prior to screening and must be at a stable dose ≥ 10 mg and ≤ 40 mg for at least 2 weeks prior to screening); negative serum beta-human chorionic gonadotropin (β-hCG) test at screening (women of childbearing potential [WOCBP] only); "clinical" SLEDAI-2K score ≥ 4 points at screening and at least 2 weeks of stable OC dose on Day 1 prior to randomization.

[0099] Participants who meet the following general exclusion criteria will be considered ineligible to participate in the clinical study: evidence of any acute or chronic disease / condition, or unstable medical condition, that in the investigator's judgment would substantially increase the risk to him or her if the patient were to participate in the study; presence or history of psychiatric illness (within 1 year) that, in the investigator's opinion, is likely to interfere with the patient's ability to provide informed consent, comply with the experimental procedures, or place the patient at a higher risk by participating in the study; current status or history of alcohol or drug abuse (excluding cannabis) within 1 year of screening, based on the investigator's clinical judgment; becoming pregnant, breastfeeding, or planning to become pregnant during the study and within 3 months of completion or discontinuation of the study; patients with a QTcF >450 msec (males) or >470 msec (females) at screening; unstable cardiovascular disease, defined as recent clinical deterioration (e.g., unstable angina, rapid atrial fibrillation) or cardiac hospitalization within the last 3 months; having any of the following laboratory abnormalities at screening: absolute neutrophil count <1 × 10 9 / L, hemoglobin <8 g / dL, platelet count <25,000 / μL, aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≥ 2 × upper limit of normal (ULN) unless due to lupus hepatitis, total bilirubin ≥ 2 × ULN (unless the patient has documented Gilbert's syndrome), estimated glomerular filtration rate (eGFR by the Modification of Diet in Renal Disease [MDRD] formula) <30 indicating moderate or severe renal insufficiency, and / or UPCR >3.5 g / day.

[0100] Participants meeting the following exclusion criteria related to SLE and other diseases will be considered ineligible to participate in the clinical study: drug-induced SLE or other autoimmune disease that, in the investigator's opinion, is likely to confound the diagnosis of efficacy; active, proliferative lupus nephritis that, in the investigator's opinion, may require treatment not permitted by the protocol; current disease other than SLE that, in the investigator's opinion, is likely to interfere with the SLE disease activity assessment (examples include severe fibromyalgia, severe osteoarthritis, other severe cardiorespiratory diseases); active severe or unstable neuropsychiatric SLE, including, but not limited to: aseptic meningitis; cerebral vasculitis; myelopathy; demyelinating syndromes (ascending, transverse, acute inflammatory demyelinating polyradiculopathy); acute confusional state; impaired level of consciousness; psychosis; acute stroke or stroke syndrome; cranial neuropathy; new onset seizures; cerebellar ataxia; and mononeuritis multiplex that prevented the patient from fully understanding the ICF or that, in the opinion of the principal investigator, indicated the use of more aggressive therapeutic measures (e.g., intravenous (IV) cyclophosphamide and / or high-dose IV pulse corticosteroid therapy or the addition of other procedures not permitted to the protocol); history or current diagnosis of fulminant antiphospholipid syndrome within 12 months prior to signing the ICF (antiphospholipid syndrome well controlled with anticoagulant therapy for at least 3 months is acceptable; clinically symptomless antiphospholipid antibody positivity is not exclusive); history of any recurrent non-SLE disease requiring treatment with oral or parenteral corticosteroids for a total of more than 2 weeks within the last 52 weeks prior to signing the ICF (treatment with steroids for conditions where relapse was not expected (e.g., poison ivy) is not excluded).

[0101] Participants who meet the following exclusion criteria related to concomitant medications will be considered ineligible to participate in the clinical study: received any investigational product (small molecule or biologic agent) within 3 months or 5 half-lives (whichever is longer) prior to signing the ICF or are currently enrolled in an investigational study; received any marketed biologic agent within 5 half-lives prior to signing the ICF; received B-cell depleting therapy (including but not limited to obinutuzumab, ocrelizumab, or rituximab) <6 months prior to signing the ICF or received B-cell depleting therapy if the therapy was administered >6 months prior to signing the ICF. below the lower limit of normal or baseline values ​​(whichever is lower) prior to signing the ICF;receiving any therapeutic agent targeting IL-12, IL-17, or IL-23 within 6 months prior to signing the ICF, or any tumor necrosis factor alpha inhibitor(s) within 12 weeks prior to signing the ICF;receiving a JAK inhibitor (e.g., baricitinib, tofacitinib) or TYK2 inhibitor within 12 weeks prior to signing the ICF;currently receiving a PPI, e.g., omeprazole or esomeprazole (replacing a histamine 2 receptor blocker, or oral antacid prior to study day 1 is permitted);Receiving any of the following: intra-articular, IM, or IV glucocorticosteroids within 6 weeks prior to Day 1; receiving any live or attenuated vaccine within 4 weeks prior to signing the ICF (administration of inactivated vaccines is permitted); receiving a blood transfusion within 4 weeks prior to signing the ICF; and / or receiving any of the following restricted medications if the washout period has not been met: abatacept (12 weeks), adalimumab (12 weeks), anakinra (4 weeks), anifrolumab (12 weeks), belimumab (12 weeks), BTK inhibitors (12 weeks), certolizumab pegol (12 weeks), cyclophosphamide (IV or oral, 24 weeks), cyclosporine (oral, 8 weeks). ), danazol (4 weeks), dapsone (4 weeks), eculizumab (8 weeks), etanercept (12 weeks), golimumab (12 weeks), infliximab (12 weeks), IV immunoglobulin (8 weeks), JAK inhibitors (12 weeks), leflunomide (after cholestyramine washout, 36 weeks or 2 weeks), lenalidomide (8 weeks), natalizumab (12 weeks), ocre rituximab (48 weeks), pimecrolimus (4 weeks), plasmapheresis (8 weeks), retinoids (4 weeks), rituximab (48 weeks), ruxolitinib (4 weeks), B-cell depleting agents (48 weeks), sulfasalazine (4 weeks), sirolimus (4 weeks), tacrolimus (12 weeks), thalidomide (8 weeks), tocilizumab (12 weeks), investigational agents (5 half-lives for 30 days);

[0102]

[0102] Participants who meet the following exclusion criteria related to infectious diseases and other factors will be considered ineligible to participate in the clinical study: history or evidence of suicidal ideation within the past 6 months based on the Columbia-Suicide Severity Rating Scale (C-SSRS) assessment at screening (severity level 4 [active: method and intent, but no plan] or 5 [active: method, intent, and plan]); or any suicidal act within the past 12 months; known history or underlying condition of primary immunodeficiency, e.g., HIV infection or splenectomy that predisposes the patient to infection; confirmed positive hepatitis B serology test for: hepatitis B surface antigen or hepatitis B core antibody (HBcAb) and hepatitis B virus (HBV) DNA (>169 copies / mL [29 IU / mL]) detected by reflex testing at screening; positive test for hepatitis C antibody; any severe herpes infection at any time prior to week 0 (day 1), including but not limited to multiple herpes (history), herpes encephalitis (history), recurrent herpes zoster (defined as two episodes within a 2-year period), or herpes eye infection (history); signed the ICF active herpes zoster infection within 12 weeks prior to screening; active herpes simplex virus within 4 weeks prior to Day 1; currently known malignancy or current evaluation of possible malignancy, or history of malignancy within the past 5 years prior to screening, except for documented successful curative therapy for squamous or basal cell carcinoma of the skin >3 months prior to Week 0 (Day 1) and / or apparently successful curative therapy for cervical carcinoma in situ >1 year prior to Week 0 (Day 1); any of the following: currently active, clinically significant infection of any kind, clinically significant chronic infection (e.g., osteomyelitis, bronchiectasis) within 8 weeks prior to signing the ICF (chronic nail infections are acceptable), any infection requiring hospitalization or treatment with IV anti-infectives where this hospitalization or treatment was not completed at least 4 weeks prior to signing the ICF, and / or any infection requiring oral anti-infectives (including antivirals) within 2 weeks prior to Day 1. Incorporation by Reference

[0103] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the case of conflict, the present application, including any definitions herein, will control. Equivalents and Scope

[0104] Claim articles such as "a," "an," and "the" may mean one or more than one, unless specifically indicated to the contrary or clear from the context. A claim or specification containing "or" between one or more members of a group is considered to be satisfied so long as one, more than one, or all of the members of the group are present, utilized, or relevant in a given product or process, unless specifically indicated to the contrary or clear from the context. The invention includes embodiments in which exactly one member of a group is present, utilized, or relevant in a given product or process. The invention includes embodiments in which more than one or all of the members of a group are present, utilized, or relevant in a given product or process.

[0103]

[0105] Furthermore, the present invention encompasses all variations, combinations, and permutations of one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims when they are introduced into another claim. For example, any claim that depends on another claim can be amended to include one or more limitations found in any other claim that depends on the same base claim. When elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element(s) may be removed from the group. In general, when the invention, or aspects of the invention, are referred to as comprising certain elements and / or features, it is to be understood that certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For simplicity, these embodiments are not specifically described in this language herein. It is also noted that the terms "comprise" and "contain" are intended to be open and allow for the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the ranges stated 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.

[0104]

[0106] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and the specification of the present invention, the present specification shall control. In addition, any particular embodiment of the present invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, since they are considered to be known to those skilled in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0105]

[0107] 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 embodiments of the invention described herein is not intended to be limited to the above specification, but rather as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications can be made to this specification without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. 1. A method of treating a TYK2-mediated disease or disorder in a patient in need of such treatment, comprising: 【Chemistry 1】 orally administering to a patient once or twice daily 30 mg, 40 mg, 60 mg, or 80 mg of a compound represented by the formula:

2. 10. The method of claim 1, further comprising orally administering a proton pump inhibitor to the patient.

3. 3. The method of claim 1 or 2, wherein the proton pump inhibitor is selected from the group consisting of rabeprazole, omeprazole, esomeprazole, lansoprazole, pantoprazole, and dexlansoprazole.

4. 4. The method of any one of claims 1 to 3, wherein the proton pump inhibitor is rabeprazole.

5. 5. The method of any one of claims 1 to 4, wherein the compound is administered to the patient in the fasted state.

6. 5. The method of any one of claims 1 to 4, further comprising administering food to the patient prior to or at the time of administration of the compound.

7. 7. The method of any one of claims 1 to 6, wherein the TYK2-mediated disease or disorder is selected from the group consisting of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

8. 1. A method of treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need of such treatment, comprising: Each of them, 【Chemistry 2】 administering to a patient once daily two tablets of an oral tablet composition comprising 30 mg of a compound represented by the formula: Optionally, orally administering rabeprazole to the patient; and Optionally, the patient is fed at the time of administration of the compound. The method includes:

9. 1. A method of treating one or more of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis in a patient in need of such treatment, comprising: 【Chemistry 3】 orally administering to a patient once daily or twice daily 10 mg, 20 mg, 30 mg, 60 mg, or 80 mg of a compound represented by the formula:

10. 【Chemical 4】 2. A fixed unit dose pharmaceutical composition for oral administration comprising 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, or 80 mg of a compound represented by the formula: and a pharma- ceutically acceptable excipient.

11. 11. The pharmaceutical composition of claim 10 formulated as a tablet.

12. 【Chemical 5】 20. An oral tablet composition comprising about 30 mg of a compound represented by the formula:

13. 13. A method of treating a TYK2-mediated disease or disorder in a patient in need of such treatment, comprising administering to the patient an effective amount of the oral tablet composition of claim 12.

14. 14. The method of claim 13, wherein administration is a once-daily administration.

15. 1. A method of treating a TYK2-mediated disease or disorder in a patient in need of such treatment, comprising: 【Chemistry 6】 orally administering to a patient once or twice daily 10 mg, 20 mg, 30 mg, 40 mg, 80 mg, 100 mg, 120 mg, or 160 mg of a compound represented by the formula:

16. 1. A method of treating moderate to severe psoriasis in a patient in need thereof, comprising: 【Chemistry 7】 orally administering to a patient once or twice daily 10 mg, 20 mg, 30 mg, 40 mg, 80 mg or more of a compound represented by the formula:

17. 1. A method of treating moderate to severe psoriasis in a patient in need thereof, comprising: 【Chemistry 8】 orally administering to a patient once or twice daily 10 mg, 20 mg, 30 mg, 40 mg, 80 mg or more of a compound represented by the formula:

18. 18. The method of claim 16 or 17, wherein the patient has at least one of the following prior to administration: a diagnosis of plaque psoriasis for ≧6 months; plaques covering ≧10% of the body surface area (BSA); a Psoriasis Area Severity Index (PASI) score of ≧12 and / or a Static Physician Global Assessment (sPGA) score of ≧3.

19. 19. The method of any one of claims 16 to 18, wherein 10 mg, 20 mg, 40 mg of the compound is administered once or twice daily.

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