Method for treating sjogren's syndrome by using bruton's tyrosine kinase inhibitor

Abstract

To provide a compound to be used in treating Sjogren's syndrome.SOLUTION: A compound of the formula (I) or a pharmaceutically acceptable salt thereof is used.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure provides a method for treating Sjogren's syndrome using Bruton's tyrosine kinase (BTK) inhibitors. The present invention relates to a method for treating a flock. [Background technology]

[0002] Sjögren's syndrome (SjS) is characterized by lymphatic infiltration and progressive destruction of exocrine glands. It is a systemic autoimmune disease of unknown cause (Brito-Zeron P., et al., (2016)Treating the Underlying Pathophysics ology of Primary Sjogren Syndrome:Recent Advances and Future Prospects.Drugs p.1 601-1623).

[0003] Although the disease primarily affects the lacrimal and salivary glands, the inflammatory process can target any organ. Approximately 15% of patients show severe extraglandular findings (Baldini C., et al(2014)Primary Sjogren's syndrome as a multi-organ disease:impact of the serolo clinical profile on the clinical presentati on of the disease in a large cohort of I talian patients.Rheumatology(Oxford)p.83 9-44) Clinical symptoms are mainly dry mouth and eyes, salivary gland and lacrimal gland dysfunction. However, symptoms can be very heterogeneous and range from dryness to almost This includes musculoskeletal pain and fatigue that affect all patients, but in a more limited subset Severe extraglandular and systemic involvement (characterized by periepithelial lymphocytic infiltration and immune complex deposition) The underlying mechanism of SjS development is the combination of autoreactive B and T cells. The result is destruction of the epithelium of the exocrine glands (Brito-Zeron P., et al. (2016)Treating the Underlying Pathophysics ology of Primary Sjogren Syndrome:Recent Advances and Future Prospects.Drugs p.1 Even at a very early stage, autoantibodies, especially those against Ro / SSA, are present. The high prevalence of autoreactive B cells suggests that autoreactive B cells contribute to the pathogenesis of SjS. Nocturne G., et al. (2018) B cells in the pathogenesis of primary Sjogren synd rome.Nat Rev Rheumatol p.133-145).

[0004] As a result of B-cell pathology, there is also an increased risk for malignant transformation, with B-cell involvement in 5% of SjS patients. 10-fold increased lifetime risk of follicular lymphoma (Baldini C., et al., (20 14)Primary Sjogren's syndrome as a multi -organ disease: impact of the serologica l profile on the clinical presentation o f the disease in a large cohort of Italy an patient.Rheumatology(Oxford)p.839-44 The estimated prevalence of SjS is 0.3 to 1 per 1,000 people (Qin B., et al. (2015) Epidemiology of primary Sjogre n's syndrome: a systematic review and met a-analysis.Ann.Rheum.Dis.p.1983-9), systemic self It is the second most common immune disease after rheumatoid arthritis. The disease has a female / male ratio of 9 Symptoms of SjS: 1. It primarily affects women and can occur at any age. The main impact of this disease is a severe impact on quality of life and productivity. It is often caused by the fatigue that accompanies the disease and interferes with daily life (Ma riette X.,et al.(2018)Primary Sjogren's Syndrome. N. Engl. J. Med. p. 931-939). Arthritis, skin hemorrhage ductitis, peripheral neuropathy, glomerulonephritis, interstitial nephritis, biliary cholangitis, and bronchiolitis obliterans. It can involve multiple organ systems, including the cerebrospinal fluid (CEF), occurs in 20-40% of patients, and can be severe. There are also many systemic complications (Seror R., et al (2014) Outcome measures for primary Sjogren's syndrome :a comprehensive review.J.Autoimmun.p.51 -6).

[0005] The clinical features of Sjögren's syndrome are characterized by medically evaluable findings and symptomatic findings of the patient. Currently, both of these clinical manifestations of SjS can be captured as disease activity. There is no single evaluation tool. Rheumatism(EULAR)Sjogren Syndrome(SS)Pat ient Reported Index (ESSPRI) and EULAR SS D The Esophageal Severity Activity Index (ESSDAI) is a serologic and It is widely accepted and validated for measuring systemic findings (Franceschi Ni F., et al, (2017), BMC Medicine, 15:69).

[0006] Regarding the current treatment status, there are no internationally approved systemic therapies available for SjS. As far as dry mouth and dry eyes are concerned, treatment for SjS patients is symptomatic. Steroids and typical DMARDs are largely ineffective, making daily life difficult There are no effective pharmaceutical interventions for severe fatigue. The lack of effective treatment options has led to this extreme The findings highlight the need to evaluate newer therapeutic approaches to this highly debilitating disease. The pattern of B cell autoreactivity is somewhat similar to that of systemic lupus and rheumatoid arthritis, Recently, anti-CD20 monoclonal antibodies have been used for both the glandular and extraglandular manifestations of SjS and for the management of lymphoma. B-cell depletion therapy using the clonal antibody (mAb) rituximab has been evaluated, with response rates of However, this approach is not currently an approved treatment for SjS. The ineffectiveness of ximab may be due to incomplete B cell depletion in affected tissues. (Brito-Zeron P et al (2016) Treat ing the Underlying Pathophysiology of Pr. imary Sjogren Syndrome:Recent Advances a nd Future Prospects.Drugs p.1601-1623).

[0007] Despite the availability of treatments for SjS, new treatments for SjS subjects There remains a strong medical need for options. Summary of the Invention [Means for solving the problem]

[0008] An object of the present invention is to provide a method for treating Sjogren's syndrome in a subject in need of such treatment. The present invention provides a novel method for treating N-type steroid syndrome, comprising administering a therapeutically effective amount of N-type steroid hormone to a subject. -(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidine -4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluoro administering to said subject lobenzamide or a pharmaceutically acceptable salt thereof.

[0009] Therefore, a subject in need of treatment for Sjögren's syndrome (SjS) may be administered N-(3-(6- Amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)- 5-Fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof, in a daily dose of about 0.5 mg to about 600 mg, preferably about A daily dose of 10 mg to about 200 mg or more preferably a dose of about 10 mg to about 100 mg Disclosed herein is a method for treating Sjögren's syndrome (SjS) comprising administering is shown.

[0010] N-(3-(6-amino-5-(2-(N-methylacetyl)-N-methylpropional)) for use in the treatment of SjS 4-(2 ... -4-cyclopropyl-2-fluorobenzamide; or a pharmaceutically acceptable salt thereof. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharmaceutically acceptable salt thereof is administered in an amount of about 0.5 mg to about 600 mg. g daily dose, preferably about 10 mg to about 200 mg daily dose, most preferably about 10 It is administered at a daily dose of between 100 mg and about 100 mg. [Brief explanation of the drawings]

[0011] [Figure 1] Blood concentration-time course of Compound (I) after single ascending doses of 0.5 mg to 600 mg. [Figure 2] Blood concentration-time course of Compound (I) after multiple ascending doses of 10 mg to 400 mg, qd. [Figure 3] Blood concentration-time course of Compound (I) following multiple ascending doses of 100 mg bid and 200 mg bid. [Figure 4] Food effect as observed after a single oral dose of 60 mg of a compound of formula (I). [Figure 5] Figure 16. Mean (SD) percent BTK occupancy in peripheral blood following a single dose of a compound of formula (I). [Figure 6] Median percent inhibition of basophil activation versus total daily dose of compound of formula (I) on day 12 of repeated ascending administration of compound of formula (I). [Figure 7] Reduction in wheal size on skin prick testing with repeated ascending doses. DETAILED DESCRIPTION OF THE INVENTION

[0012] Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase that mediates TEC kinase activity. BTK is a member of the mitochondrial kinase family. It is expressed in B cells, macrophages, basophils, and mast cells. BTK is expressed in cells of both the adaptive and innate immune systems, including erythrocytes and platelets. The Psilon receptor (FcεR1 for IgE) and the activated Fc gamma receptor (IgG essential for signal transduction through the FcγR (FcγR for the B cell antigen receptor) and the BCR BTK inhibition has been shown to be an effective strategy for treating B-cell malignancies. The covalent BTK inhibitor ibrutinib (Imbruvica®), Labrutinib (Calquence®) and zanubrutinib (Brukinsa®) (registered trademark) is approved for the treatment of certain B-cell malignancies (Thompson et al., 2004). son PA,et al,(2018)Bruton's tyrosine kin ase inhibitors: first and second generat ion agents for patients with Chronic Lym phocytic Leukemia(CLL).Expert Opin Inves BTK inhibition has been shown to be effective in preclinical and clinical trials. It has shown promising efficacy against cellular autoimmunity (Tan SL., et al., (201 3)Targeting the SYK-BTK axis for the tre atment of immunology and hematologica l disorders:recent progress and therapy tic perspectives.Pharmacol.Ther.p.294-30 9;Whang JA,et al.(2014)Bruton's tyrosi ne kinase inhibitors for the treatment o f rheumatoid arthritis.Drug Discov.Today p.1200-4;Satterthwaite AB(2017)Bruton 's Tyrosine Kinase, a Component of B Cell Signaling Pathways, Has Multiple Roles i n the Pathogenesis of Lupus.Front Immuno l p.1986;Rip J.,et al,(2018)The Role of Bruton's Tyrosine Kinase in Immune Cell Signaling and Systemic Autoimmunity.Crit .Rev.Immunol.p.17-62). Therefore, inhibition of BTK is thought to be a potential treatment for rheumatoid arthritis. , multiple sclerosis, systemic lupus erythematosus, chronic urticaria, atopic dermatitis, asthma and primary An attractive therapy for treating various autoimmune and chronic inflammatory diseases, including Egren's syndrome This is a concept (Tan SL, Liao C, Lucas MC, et al (2013) Targeting the SYK-BTK axis for the treat ment of immunological and hematological disorders:recent progress and therapy c perspectives.Pharmacol.Ther.p.294-309; Whang JA,Chang BY(2014)Bruton's tyrosine Kinase inhibitors for the treatment of rheumatoid arthritis.Drug Discov.Today p .1200-4).

[0013] Furthermore, a significant percentage of SjS patients are associated with high serum rheumatoid factor (RF) levels. BTK levels have been shown to be elevated in circulating B cells at different stages (Corneth et al., 2013). OBJ et al. (2017) Enhanced Bruton's Tyrosi ne Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune ne Disease.p.1313-1324).

[0014] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidinyl) (4-phenyl-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-phenyl Fluorobenzamide or a pharmaceutically acceptable salt thereof is referred to herein as a compound of formula (I) BTK inhibitors called: [ka] or a pharmaceutically acceptable salt thereof.

[0015] This compound is disclosed in the pamphlet of International Publication No. 2015 / 079417 filed on June 4, 2015. Attorney docket number PAT05602 1-WO-PCT). This compound selectively inhibits Bruton's tyrosine kinase (BTK). It is a potent, irreversible covalent inhibitor and may be used in the treatment of BTK-mediated diseases or disorders.

[0016] Therefore, the inventors now report the compound N-(3-(6-amino-5-(2-(N-methyl (Ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl (4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof We have devised a dosing regimen for treating SjS patients.

[0017] Definition: For the purposes of interpreting this specification, the following definitions shall apply and terms used in the singular shall mean: Where appropriate, the plural is also included and vice versa.

[0018] As used herein, the phrase "pharmaceutically acceptable" means a compound that is acceptable to the public using sound medical judgment. within the limits of reasonable benefit / risk ratios, without excessive toxicity, irritation, or allergies. - Use in contact with human and animal tissues without reactions or other problems or complications "compounds, substances, compositions and / or dosage forms" refers to those compounds, substances, compositions and / or dosage forms that are suitable for

[0019] Any formula given herein represents unlabeled and isotopically labeled forms of the compounds. It is also contemplated that isotopically labeled compounds have one or more atoms with a selected atomic mass or mass. By the formula given herein except that the atoms are replaced by those having the numbers Isotopes that can be incorporated into compounds of the present disclosure include, for example, 3 H , 11 C. 13 C. 14 C. 15 N, 18 F and 36 Hydrogen, carbon, nitrogen, oxygen, such as Cl , fluorine and chlorine isotopes. Thus, the present disclosure provides, for example, 3 H and 14 C radioisotopes, or 2 H and 13 The aforementioned, including those in which non-radioactive isotopes such as C are present. It should be understood that the present invention includes compounds incorporating one or more of any of the isotopes. Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction rate tests (e.g. 2 H Kuha 3 H), positron emission tomography ( detection or imaging techniques such as PET (positron emission tomography) or single photon emission computed tomography (SPECT) are useful in imaging techniques or in the radiation treatment of patients. 18 F or label Compounds may be particularly desirable for PET or SPECT studies. These typically involve, for example, the use of suitable isotopically labeled reagents in place of previously utilized unlabeled reagents. and can be prepared by conventional techniques known to those skilled in the art.

[0020] The term "drug combination" as used herein refers to a combination of two or more active ingredients. A drug combination means a product resulting from the use or mixing or combination of drugs. When used herein, it is understood to include both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of formula (I) or A pharmaceutically acceptable salt thereof and one or more combination partners may be administered as a single entity or dosage form. In such cases, the term refers to a single unit dosage form ( refers to a fixed dose combination in a capsule, tablet or sachet. The terms "combination" and "kit" both refer to the active ingredients, e.g., the compounds of the present disclosure and one or more combination partners and / or one or more co-agents t) as separate objects, simultaneously, at the same time, or consecutively without specific time limits, may be administered to a patient independently or simultaneously, and such administration may be indicative of a physiological effect on the patient. These time intervals provide therapeutically effective levels of the two compounds in the body. This allows the combination partners to exhibit a cooperative, e.g., additive or synergistic, effect. The term "non-fixed combination" also refers to cocktail therapy, e.g., a combination of three or more The term "non-fixed combination" therefore applies to the administration of the active ingredients. The compounds described herein may be administered independently of each other, i.e., at the same time or at different times. In this sense, the term "non-fixed combination" specifically refers to an administration, use, composition or formulation. The term "prescription" also refers to each individual formulation having a distinct amount of active ingredient contained therein, It is understood that this also encompasses the use of a single agent together with one or more fixed combination products. The combination products described herein, as well as the "non-fixed combinations" The term encompasses active ingredients (including compounds described herein) and is intended to encompass any fully separate pharmaceutical dosage form. The combination partners are administered as pharmaceutical formulations marketed as a single agent or independently of each other. It is further understood that instructions for use of the non-fixed combination may be found on the packaging. leaflets or other information provided to doctors and / or medical staff Then, the product or the formulation is provided or can be provided in a separate formulation. The components of the composition may be administered simultaneously or chronologically staggered, i.e. Each individual part of the kit may be at a different time relative to any of the kit's parts. and / or at equal or different time intervals. The interval is determined so that the effect of the combined use of the components on the disease being treated is greater than that of the compound of formula (I) alone. are selected to be greater / higher than the effect obtained by use; The compounds used in the described drug combinations are jointly active. The ratio of the total amount of the compound of Formula I to the second agent to be administered as It can be modified to better address the needs of specific patient subpopulations or the needs of a single patient. The dose may be adjusted or adjusted, which may depend, for example, on the patient's age, sex, weight, etc.

[0021] The terms "co-administration" or "administration in combination" and the like, as used herein, , a combination part selected for a single subject (e.g., a patient or subject) in need thereof. It is intended to encompass administering one or more compounds described herein together with a toner. and treatment regimens in which the compounds are not necessarily administered by the same route of administration and / or at the same time. This includes Jimen.

[0022] The term "pharmaceutical composition" is used herein to describe a pharmaceutical composition for treating a particular disease or condition affecting warm-blooded animals. A small amount of a compound intended for administration to a warm-blooded animal, such as a mammal or a human, for the prevention or treatment of refers to a mixture (e.g., a solution or emulsion) containing at least one active ingredient or therapeutic agent. It is defined as something that

[0023] The "therapeutic utility" of the compounds of the present disclosure (i.e., compounds of formula (I) or pharmaceutically acceptable salts thereof) The term "effective amount" refers to the biological or medical response of a subject (subject patient), e.g., an enzyme or The decrease or inhibition of protein activity or the amelioration of symptoms, alleviation of the condition, slowing of disease progression or The compound or pharmaceutical composition of the present disclosure may be used to induce or delay or prevent a disease. The therapeutically effective dose of the composition or combination thereof will depend on the species, weight, age, sex and individual characteristics of the patient. It depends on the condition, disorder or disease being treated and its severity. or a veterinarian may prescribe each active ingredient necessary to prevent, treat, or inhibit the progression of a disorder or disease. The effective amount can be readily determined.

[0024] The frequency of dosing will depend on the compound used and the particular condition being treated or prevented. Generally, it is preferred to use the minimum dosage sufficient to provide effective treatment. Patients will generally be tested for therapeutic effectiveness using assays appropriate to the condition being treated or prevented. This can be monitored as will be apparent to those skilled in the art.

[0025] As used herein, the term "carrier" or "pharmaceutically acceptable carrier" refers to a , any and all solvents, dispersion media, coating agents, and the like, as known to those skilled in the art. Surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption delaying agents, salts Classes, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc., and combinations thereof (e.g., Remington's Pharm aceutical Sciences,18th Ed.Mack Printing Company, 1990, pp. 1289-1329). All conventional carriers are Except insofar as any active ingredient is incompatible, its use in therapeutic or pharmaceutical compositions is contemplated.

[0026] As used herein, the term "subject" refers to an animal. Typically, an animal is The subject is a mammal. The subject may be, for example, a primate (e.g., a human, male or female), a cow, a sheep, a goat, It also refers to horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, The subject is a primate. In a preferred embodiment, the subject is a human. The term "subject" , when it refers to a human, is used interchangeably with "patient."

[0027] As used herein, a subject is "in need of" treatment if such subject: Those who would benefit biologically, medically or in quality of life from such treatment This is the case.

[0028] As used herein, the phrase "patient population" is used to mean a group of patients. It is used.

[0029] The term "comprising" is used interchangeably with "including" and and "consisting of," e.g., "comprises" X. The "single" composition may consist exclusively of X or may contain some additional (e.g. X+Y).

[0030] The term "about" in relation to a numerical value x means, for example, + / - 10%. When used before a list of numbers, the term "about" applies to each number in turn, e.g. The phrase "about 1 to 5" should be interpreted as "about 1 to about 5", or, for example, "about 1, 2 , 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc."

[0031] The terms "treatment" or "treat" are used herein to refer to In the specification, a compound according to the present disclosure (Formula (I)) is administered to a subject or an isolated tissue or cell line derived from the subject. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound. The subject is defined as a specific disease (e.g., SjS), a disease (e.g., SjS)-related If applicable, you have a predisposition to the development of a condition or disease (e.g., SjS) that is associated with this condition. The goal is to cure (if applicable), delay the onset of, reduce the severity of, or alleviate one or more symptoms of a disease. , remission, improvement of the disease, reduction or amelioration of any associated symptoms of the disease, or the onset of the disease. "Treatment" or "treating" is the reduction or amelioration of a predisposition to The term "treat" refers to patients suspected of having a disease as well as patients who are ill or including treating patients who have been diagnosed with a disease or medical condition. This also includes suppression of clinical recurrence.

[0032] As used herein, "selecting" in relation to a patient means " and "selected" refers to specific patients with predetermined criteria. The specific selection of a particular patient from a larger patient population based on (or resulting from) Similarly, "selectively treating" refers to treating a patient with a particular disease. refers to providing treatment to specific patients who meet predetermined criteria. Similarly, "selectively administering" refers to specifically selecting from a larger patient population based on A larger patient population based on (or resulting from) specific patients with pre-defined criteria "Select," "selective treatment," refers to administering a drug to a patient specifically selected from the group. "Selectively administering" and "selectively administering" refer to the patient's membership in a larger group only. Rather than providing a standard treatment regimen based on the patient's individual treatment history (e.g., previous therapeutic intervention, e.g., prior treatment with a biological agent), biological factors (e.g., specific gene markers), Individualized treatment based on the patient's condition (e.g., those not meeting specific diagnostic criteria) and / or symptoms As used herein, in the context of a method of treatment, means providing a patient with Selecting does not refer to the incidental treatment of patients with specific criteria, but rather to the treatment of patients with specific criteria. Selective treatment / administration therefore refers to the deliberate selection of a patient to receive treatment based on the patient's , which differ from standard treatment / administration and are not related to the individual's medical history, disease presentation, and / or biology. In some embodiments, Sj Patients were selected for treatment based on having S.

[0033] Embodiments of the present invention Sjogren's Syndrome and Efficacy of Treatment According to the Present Invention The disclosed BTK inhibitors, i.e., compounds of formula (I) or pharmaceutically acceptable salts thereof, are can be used in vitro or ex vivo to treat patients (e.g., human patients) or incorporated into a pharmaceutical composition and administered in vivo.

[0034] The effectiveness of the treatment of Sjogren's syndrome depends on the status of Sjogren's syndrome and / or the severity of Sjogren's syndrome. Clinical response can be assessed using a variety of known methods and tools. For example, EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI), Physician Globa l Assessment Scale (PhGA), EULAR Sjogren' s Syndrome Patient Reported Index (ESSPRI) ), The Functional Assessment of Chronic I llness Therapy-Fatigue Scale(FACIT-Fatigue ue) and EQ5D.

[0035] Effectiveness Clinical efficacy measures for the primary and secondary objectives are outlined below.

[0036] EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) The ESSDAI is a validated disease outcome measure for Sjögren's syndrome. , applied to the test subject (Seror R, et al (2015) Validation n of EULAR primary Sjogren's syndrome di sease activity(ESSDAI) and patient index es(ESSPRI).Ann.Rheum.Dis.p.859-66). This method It contains 12 organ-specific regions that contribute to disease activity. The characteristics of disease activity are scored on a 3 or 4 level according to their severity. The formula sums these scores across the 12 domains to provide a total score. The symptoms are as follows: constitution (3), lymphadenopathy (4), glandular symptoms (2), joint (2) ), skin (3), lungs (5), kidneys (5), muscles (6), PNS (5), CNS (5), blood Fluid (2) and biological findings (1). The maximum possible score is 123.

[0037] In our study, all 12 subjects were randomly assigned to each study at all planned time points to calculate the ESSDAI. Each organ area must be evaluated individually (from the screening visit to the end of the study) ) Enter your domain ratings in the table (provided by the central vendor) , and calculate the ESSDAI score by the software.

[0038] X-ray examination, high-resolution computed tomography (HRCT), pulmonary function tests (DLCO, FVC), estimated glomerular filtration rate (eGFR), electromyography (EMG), muscle (or any Other) biopsies, including those not listed in the protocol as mandatory tests, but which estimate ESSDAI At the investigator's discretion, any assessments that may be required to determine the correct ESSDAI reading will be considered. These are assessed based on the patient's signs and symptoms to provide a solution. The definitions and weights of the domains and items of the ESSDAI are summarized in Table 1. R:

[0039] [Table 1]

[0040] [Table 2]

[0041] [Table 3]

[0042] [Table 4]

[0043] Physician Global Assessment Scale (PhGA) 100mm VA ranging from "no disease activity" (0) to "maximum disease activity" (100) To assess the disease activity of the patient, the physician in charge will use the Physician Global Assessment Schedule (PMS) rules are used.

[0044] To promote objectivity, physicians should not use specific The reported outcome measures of the patients should not be known. Therefore, the overall disease activity score should not be used. This assessment must be done before looking at the patient's overall assessment.

[0045] EULAR Sjogren's Syndrome Patient Report d Index (ESSPRI) ESSPRI is an established disease outcome measure for Sjögren's syndrome (Seror R,et al(2011)EULAR Sjogren's Synd rome Patient Reported Index(ESSPRI):deve lopment of a consensus patient index for primary Sjogren's syndrome.Ann.Rheum.Di sp968-72). It consists of three areas: dryness, pain, and fatigue. Symptoms experienced by the subject on a single 0-10 numeric scale for each of the three areas The severity can be assessed by the ESSPRI score, calculated as the average of the scores from the three scales. Defined: (dryness + pain + fatigue) / 3.

[0046] FACIT-Fatigue The Functional Assessment of Chronic Il Fatigue Therapy-Fatigue Scale (FACIT-F v4) , a short-term study to measure an individual's fatigue level during the subject's typical daily activities over the past week. It is an easy-to-administer tool with 13 items. Fatigue levels are rated on a 5-point Likert scale. Rate the level (0 = not at all, 1 = slightly, 2 = somewhat, 3 = quite a bit, 4 = very (Webster K, et al. (2003) The Functional Assessment of Chronic Illness Therapy(F ACIT)Measurement System:properties,appli cations,and interpretation.Health Qual L ife Outcomes p.79).

[0047] EQ5D The EQ-5D is a standardized instrument that measures health-related quality of life. The -5D consists of a descriptive system and an EQ VAS scale.

[0048] This description system includes five aspects: mobility, self-care, usual activities, pain / discomfort, and Pleasure and anxiety / depression, which are quantitative measures of health outcomes that reflect patients' own judgments The scores for these five aspects are presented as a health profile. or a single aggregate that reflects a more favorable health profile compared to other health profiles. The results can be converted into a usefulness index.

[0049] The EQ VAS is a scale where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. Patients self-assessed their health on a vertical visual analogue scale representing their "able health" Record.

[0050] Appropriateness of efficacy evaluation The efficacy measure in this study was primarily the ESSDAI, which measures organ-specific disease criteria. (EULAR SS Disease Activity Index) and patient subjective ESSPRI (European League Against Infectious Diseases) st Rheumatism[EULAR]Sjogren Syndrome[SS] Both instruments are based on widely accepted The gold standard for systemic and symptomatic findings of SjS, respectively, has been established and validated. The ESSDAI is a useful guideline. It is based on 12 different weighted domains (biological findings, , blood, joints, glandular symptoms, skin, constitution, lymphadenopathy, kidneys, lungs, PNS, CNS and muscles ) and the Systemic Disease Activity Index, which classifies disease activity on three or four levels. The composite weighted score, when validated in multiple cohort studies, has demonstrated a high sensitivity to change. provides an accurate assessment of disease activity with good sensitivity (Seror R et al (2 015)Validation of EULAR primary Sjogren' s syndrome disease activity(ESSDAI)and p patient indexes(ESSPRI).Ann.Rheum.Dis.p.8 59-66). On the other hand, the ESSPRI tool measures visual analysis scores of 0 to 10 during the preceding two weeks. Patient-reported composite scores of symptoms of dryness, pain in extremities, and fatigue rated on a log scale. Core (Seror R et al (2011) EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) :development of a consensus patient inde x for primary Sjogren's syndrome.Ann.Rhe um.Dis.p.968-72). Patient-reported scores are used to assess changes in disease activity. Although the sensitivity of the ESSPRI is low, among the available tools, ESSPRI has a significantly better sensitivity. A recent prospective study showed a correlation between the systematic score and the patient score. reported that the two indices assess complementary components of disease activity. Therefore, it is important to consider both parameters to arrive at a correct assessment of disease activity and its changes. The importance of meter evaluation is emphasized (Seror R et al (2015) Val idation of EULAR primary Sjogren's syndr ome disease activity(ESSDAI)and patient indexes(ESSPRI).Ann.Rheum.Dis.p.859-66).

[0051] Pharmaceutical Composition The BTK inhibitor, i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof, is When combined with a suitable carrier, it can be used as a pharmaceutical composition. In addition to the compounds of formula (I), carriers, various diluents, fillers, salts, buffers, stabilizers, soluble It may contain solubilizing agents and other materials known in the art. The characteristics of the carrier will depend on the route of administration. The pharmaceutical compositions used in the disclosed methods may also be used to treat specific target disorders. For example, the pharmaceutical composition may also include an anti-inflammatory or anti-itch agent. Such additional factors and / or agents may produce a synergistic effect with the compounds of formula (I). or to minimize the side effects caused by the compounds of formula (I), In a preferred embodiment, the pharmaceutical compositions for use in the disclosed methods include , 10 mg, 20 mg, 25 mg, 50 mg or about 100 mg of a compound of formula (I) Includes.

[0052] Suitable compositions for oral administration include tablets, lozenges, aqueous or oily suspensions. , dispersible powder or granules, emulsion, hard or soft capsule, or syrup or or elixir containing an effective amount of a compound of the present invention. is prepared according to any method known in the art for producing a pharmaceutical composition, Such compositions may contain sweeteners to provide a pharmaceutically accurate and palatable preparation. The tablet may contain one or more agents selected from the group consisting of flavoring agents, coloring agents, and preservatives. The formulation contains the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be, for example, calcium carbonate, sodium carbonate, lactose, inert diluents such as calcium phosphate or sodium phosphate; granulating and disintegrating agents, e.g. starch or alginic acid; binders, such as starch, gelatin or gum arabic; and and lubricants such as magnesium stearate, stearic acid or talc. Uncoated or coated to delay disintegration and absorption in the gastrointestinal tract, thereby coated by known techniques to provide a longer lasting effect. For example, time delay emulsions such as glyceryl monostearate or glyceryl distearate Formulations for oral use may be prepared by dissolving the active ingredient in an inert solid diluent, such as a carbonated As hard gelatin capsules mixed with calcium, calcium phosphate or kaolin, or the active ingredient is in water or an oily medium, such as peanut oil, liquid paraffin or olive oil It may be provided as a soft gelatin capsule mixed with oil.

[0053] Pharmaceutical compositions for use in the disclosed methods may be prepared in a conventional manner. In some cases, the pharmaceutical composition is provided for oral administration. For example, the pharmaceutical composition may contain: It is a tablet or gelatin capsule containing the active ingredients together: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, Thor, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and and / or polyethylene glycol; also for tablets, c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth cellulose, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone; as needed d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt or effervescent mixtures; and / or e) Absorbents, colorants, flavors and sweeteners. Tablets may be either film coated or enteric coated according to methods known in the art. It can be done.

[0054] combination: In practicing some of the disclosed methods of treatment or use, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient, eg, a mammal (eg, a human). The disclosed method comprises administering to a subject a drug using a compound of formula (I) or a pharmaceutically acceptable salt thereof. While it is understood that this treatment provides treatment for patients with rheumatoid arthritis, this treatment is not necessarily a monotherapy. In practice, when a patient is selected for treatment with a compound of formula (I), or a pharmaceutically acceptable salt thereof may be used alone or in combination with other drugs in patients with Sjogren's disease. in combination with a therapy for treating, for example, at least one additional Sjogren's drug In combination with one or more additional agents, the present invention may be administered in accordance with the methods of the present disclosure. When co-administered with an SjS agent, the compound of formula (I) or a pharmaceutically acceptable salt thereof It can be administered either simultaneously or sequentially with other agents. If administered sequentially, The attending physician may administer a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with other drugs. Determine the appropriate sequence of administration and appropriate dosages for simultaneous delivery.

[0055] A variety of therapeutic agents may be used in combination with the disclosed compounds of formula (I) or pharmaceutically acceptable salts thereof during the treatment of SjS. Such therapeutic agents may be beneficially combined with the salts thereof. corticosteroids, e.g., prednisone or equivalent; DMARDs, e.g., hydroxychloroquine; Plaquenil, methotrexate (Trexall), sulfasalazine Azulfidine, minocycline or leflunomide or B cell depleting drugs such as rituximab.

[0056] Those skilled in the art will appreciate that the disclosed compounds of formula (I) or pharmaceutically acceptable salts thereof can be co-delivered. It is possible to determine the appropriate dosage of the SjS agent for this purpose.

[0057] Kits of the Invention The present disclosure also encompasses kits for treating SjS. Such kits include a BT K inhibitors, such as N-(3-(6-amino-5-(2-(N-methylacrylamide) (5-fluoro-2-methylphenyl)-4-cyclopropoxypyrimidin-4-yl Furthermore, such kits include propyl-2-fluorobenzamide or pharmaceutical compositions thereof. The package may include instructions for use.

[0058] In one embodiment, the kit comprises two or more separate pharmaceutical compositions, of which At least one contains a compound of formula (I) or a pharmaceutically acceptable salt thereof. In this form, the kit may be a container, a divided bottle, or a divided foil pouch, etc. Examples of such kits include packages of tablets, capsules, etc. It is a blister pack such as is commonly used for packaging.

[0059] The kits of the present disclosure may contain separate compositions for administration in different dosage forms, e.g., oral and parenteral. to administer the compositions at different dosage intervals or to determine the amounts of the separate compositions relative to each other. To aid in compliance, the kits of the present disclosure typically include instructions for administration. Includes instructions.

[0060] In the combination therapy of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof and and other SjS agents (as defined herein) may be manufactured by the same or different manufacturers. and / or may be formulated. Furthermore, a compound of formula (I) or a pharmaceutically acceptable salt thereof and Other SjS agents may be grouped together in combination therapy: (i) combination therapy for physicians; Prior to the launch of a product (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof and other Sj (ii) by a physician (or under the guidance of a physician) immediately before administration; (iii) administering to the patient himself, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof; During the sequential administration of salts and other SjS drugs may be combined.

[0061] Further embodiments The compound of formula (I) or a pharmaceutically acceptable salt thereof is conveniently administered in a dose of about 10 mg to about 200 mg per day. The compound is administered to the patient (preferably orally) in a dose of 100 mg.

[0062] The compound of formula (I) or a pharmaceutically acceptable salt thereof is conveniently administered in a dose of about 10 mg to about 20 mg per day. The drug is administered to patients (preferably orally) at a daily dose of 0 mg.

[0063] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 It is administered at a daily dose of between 100 mg and about 100 mg.

[0064] In another embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg. It is administered at a daily dose of

[0065] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg. It is administered in a daily dose.

[0066] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 35 mg. It is administered in a daily dose.

[0067] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 25 mg. It is administered in a daily dose.

[0068] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 20 mg. It is administered in a daily dose.

[0069] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 mg, about It is administered once daily at a dose of 35 mg, about 50 mg or about 100 mg.

[0070] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 mg, It is administered twice daily at a dose of about 25 mg, about 50 mg, or about 100 mg.

[0071] Certain patients, e.g., those with a Sjogren's scoring system (e.g., as disclosed herein), For patients with Sjögren's syndrome who have an inadequate response (as measured by any of the following systems): It will be appreciated that dose escalation may be required. Symptoms of adverse events or adverse reactions to treatment with the compound or a pharmaceutically acceptable salt thereof It will also be appreciated that dose tapering may also be required for Eglen's patients. The dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is about 10 mg, about 20 mg, It may be less than about 25 mg, about 50 mg, or about 100 mg.

[0072] The timing of administration generally ranges from the first dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the first dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof. The timing of administration is generally measured from the day of administration (also known as the "baseline"). The first day of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof (referred to as "baseline") It is measured from the

[0073] However, healthcare providers use different naming conventions to identify dosing schedules. For clarity, as disclosed herein, the first day of administration is referred to as Day 1. However, this naming convention is used solely for consistency and should not be construed as limiting. i.e., the daily dose is the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof. It is understood by those skilled in the art that a physician may refer to a particular day as "Day 0" or "Day 1." It will be understood.

[0074] A patient in need of treatment for Sjögren's syndrome (SjS) is administered a compound or drug of formula (I). and administering to a subject a therapeutically acceptable salt thereof. The method for administering the compound is disclosed herein, and the dose is about 10 mg to about 200 mg.

[0075] A patient in need of treatment for Sjögren's syndrome (SjS) is administered a compound or drug of formula (I). and administering to a subject a therapeutically acceptable salt thereof. The present specification also discloses a method for administering the compound, the daily dose of which is about 10 mg to about 200 mg.

[0076] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of SjS. The daily dose of this compound is disclosed in the specification as being from about 10 mg to about 200 mg.

[0077] In one embodiment of the disclosed methods, uses and kits, a compound of formula (I) or a pharmaceutically acceptable salt thereof is Acceptable salts thereof are administered in a daily dose of about 10 mg to about 100 mg.

[0078] In another embodiment of the disclosed methods, uses and kits, a compound of formula (I) or a pharmaceutically acceptable salt thereof is Acceptable salts thereof include about 10 mg, about 20 mg, about 25 mg, about 35 mg, about 50 mg, It is administered in a daily dose of about 100 mg or about 200 mg.

[0079] In another embodiment of the disclosed methods, uses and kits, a compound of formula (I) or a pharmaceutically acceptable salt thereof is Acceptable salts thereof are administered in a daily dose of about 100 mg.

[0080] In another embodiment of the disclosed methods, uses and kits, a compound of formula (I) or a pharmaceutically acceptable salt thereof is Acceptable salts thereof are administered in a daily dose of about 50 mg.

[0081] In another embodiment of the disclosed methods, uses and kits, a compound of formula (I) or a pharmaceutically acceptable salt thereof is Acceptable salts thereof are administered in a daily dose of about 35 mg.

[0082] In another embodiment of the disclosed methods, uses and kits, a compound of formula (I) or a pharmaceutically acceptable salt thereof is Acceptable salts thereof are administered in a daily dose of about 25 mg.

[0083] In another embodiment of the disclosed methods, uses and kits, a compound of formula (I) or a pharmaceutically acceptable salt thereof is Acceptable salts thereof are administered in a daily dose of about 20 mg.

[0084] In another embodiment of the disclosed methods, uses and kits, a compound of formula (I) or a pharmaceutically acceptable salt thereof is Acceptable salts thereof are administered in doses of about 10 mg, about 35 mg, about 50 mg, or about 100 mg. It is administered once daily.

[0085] In another embodiment of the disclosed methods, uses and kits, a compound of formula (I) or a pharmaceutically acceptable salt thereof is Acceptable salts thereof are administered in doses of about 10 mg, about 25 mg, about 50 mg, or about 100 mg. It is administered twice a day.

[0086] In another embodiment of the disclosed methods, uses and kits, the patient has moderate to severe SjS. Patients with moderate to severe SjS may be administered a compound of formula (I) or a pharmaceutically acceptable salt thereof. Before salt treatment, eight defined areas (biological, blood, joint, skin, glandular, and lymph node) were examined. ESSDAI score of ≥ 5 (i.e., at least 5) from the following categories: swelling, kidney, and constitution (shown in Table 1) Patients with an ESSPRI score of at least 5 (based on a weighted score as likely to be used) is defined as a person.

[0087] In another embodiment of the disclosed methods, uses and kits, the patient is an adult.

[0088] In another embodiment of the disclosed methods, uses and kits, the patient receives or by week 24, patient- and / or physician-reported outcomes (i.e., ESSPRI, F Change from baseline in at least one of the following: ACIT-F, EQ-5D, PhGA Achieve this.

[0089] In another embodiment of the disclosed methods, uses and kits, the patient receives or achieve a change from baseline in ESSPRI score by week 24.

[0090] In another embodiment of the disclosed methods, uses and kits, the patient receives or achieve a reduction in ESSPRI score by week 24.

[0091] In another embodiment of the disclosed methods, uses and kits, the patient receives or an ESS of at least 1 point, preferably at least 2 points, by week 24 Achieve a reduction in PRI score.

[0092] In another embodiment of the disclosed methods, uses and kits, the patient receives or achieve a reduction in ESSPRI score by week 24. In another embodiment of the kit, the patient receives ESS by week 12 or by week 24 of treatment. At least 15%, at least 25%, at least 35%, at least 5% of the PRI score Achieve a 0% or at least a 60% reduction in ESSPRI score as follows: Calculated:

number

[0093] In another embodiment of the disclosed methods, uses and kits, the patient receives or achieve a reduction in ESSDAI score by week 24.

[0094] In another embodiment of the disclosed methods, uses and kits, the patient is Achieve at least a 3-point reduction in ESSDAI score by week 24 or by week 26 .

[0095] In another embodiment of the disclosed methods, uses and kits, the patient receives or achieve a change from baseline in ESSDAI score by week 24.

[0096] In preferred embodiments of the disclosed methods, uses and kits, the patient is an adult. In some embodiments of the methods, uses and kits described herein, the patient is an adolescent.

[0097] Further enumerated embodiments 1. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidinyl)-2-methyl ... rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -about 10 mg to about 200 mg of fluorobenzamide or a pharmaceutically acceptable salt thereof and administering a daily dose of the compound to a subject in need of treatment for Sjögren's syndrome (SjS). , a method for treating Sjögren's syndrome (SjS). 2. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidinyl)-2-methyl ... rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - the daily dose of fluorobenzamide or a pharmaceutically acceptable salt thereof is from about 10 mg to about 1 2. The method of embodiment 1, wherein the dose is 0.00 mg. 3. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidinyl)-2-methyl ... rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - a daily dose of about 100 mg of fluorobenzamide or a pharmaceutically acceptable salt thereof , The method of embodiment 1. 4. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidinyl)-2-methyl ... rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - the daily dose of fluorobenzamide or a pharmaceutically acceptable salt thereof is about 50 mg, 2. The method of embodiment 1. 5. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidinyl)-2-methyl ... rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - the daily dose of fluorobenzamide or a pharmaceutically acceptable salt thereof is about 35 mg; 2. The method of embodiment 1. 5. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidinyl)-2-methyl ... rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - the daily dose of fluorobenzamide or a pharmaceutically acceptable salt thereof is about 25 mg; 2. The method of embodiment 1. 7. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidinyl)-2-methyl ... rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - the daily dose of fluorobenzamide or a pharmaceutically acceptable salt thereof is about 20 mg, 2. The method of embodiment 1. 8. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidinyl)-2-methyl ... rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - about 10 mg, about 35 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 280 mg, about 290 mg, about 300 mg, about 2. The method of embodiment 1, wherein the compound is administered once daily at a dose of 50 mg or about 100 mg. 9. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidinyl)-2-methyl ... rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - about 10 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 25 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, 2. The method of embodiment 1, wherein the compound is administered at a dose of 50 mg or about 100 mg twice daily. 10. Any one of embodiments 1-9 above, wherein the subject has moderate to severe SjS. The method described. 11. Embodiments 1-10, wherein the subject is selected according to at least one of the following criteria: One of the following methods: a) prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, the subject is having a score ≥ 5; b) prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, the subject has a biological Eight types of symptoms can be selected from: appearance, blood, joints, skin, gland symptoms, lymphadenopathy, kidneys, and constitution. From the region considered, have an ESSDAI based on a weighted score ≥ 5. 12. The method of any one of embodiments 1 to 11, wherein the patient is an adult. 13. The subject experiences at least one of the following by week 12 or by week 24 of treatment: The method according to any one of embodiments 1 to 12, which achieves one of the following: a) A decrease in ESSPRI score; and / or b) Decrease in ESSDAI score. 14. The subject has a mean age of 18 years or older as measured by ESSPRI or ESSDAI 5 weeks after completing treatment. 14. The method of any one of embodiments 1 to 13, wherein a sustained response is achieved if 15. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-fluorobenzamide or a pharmaceutically acceptable salt thereof is placed in a pharmaceutical formulation, Any one of embodiments 1 to 14, wherein the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier. The method described. 16. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- T of 2-fluorobenzamide or a pharmaceutically acceptable salt thereof max takes about 5 to 3 hours The method according to any one of embodiments 1 to 15.

[0098] The details of one or more embodiments of the present disclosure are set forth in the accompanying description above. or testing any methods and materials similar or equivalent to those described herein. Although any of the above methods and materials may be used, the preferred methods and materials are described herein. Further advantages and advantages will be apparent from the description and claims. To the extent permitted, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein are within the meaning of the present disclosure. It has the same meaning as commonly understood by a person skilled in the art to which it pertains. All patents and publications cited are incorporated by reference. The following examples illustrate the principles of this disclosure. These examples are provided to further illustrate the preferred embodiments. shall not be construed as limiting the scope of the disclosed subject matter as defined by the claims. You must not do so.

[0099] Abbreviation AE Adverse Event Area under the AUC curve AUCinf Area under the plasma (or serum or blood) concentration-time curve from time 0 to infinity (mass x time / volume) AUClast Plasma (or serum or blood) concentration-time curve from time 0 to the final quantifiable concentration Area under the line (mass x time / volume) AUCtau Plasma (or serum or blood) concentration from time 0 to the end of the administration interval tau - time Area under the curve (mass x time / volume) BCR B cell receptor Bid or bid twice a day (Latin: “bis in die”) BMI body mass index BTK Bruton's tyrosine kinase CBC complete blood count cm centimeters Apparent systemic (or total body) clearance from plasma (or serum or blood) after CL / F administration Lance (mass / volume) CNS central nervous system CV coefficient of variation DMARDs Disease-modifying antirheumatic drugs ECG electrocardiogram eGFR Estimated glomerular filtration rate ELISA enzyme-linked immunosorbent assay EMG electromyography EQ-5D EuroQual 5 dimensions (health-related quality of life) Standard means for measuring biodiversity ESSDAI EULAR Sjogren's Syndrome Disease Activity Index ESSPRI EULAR Sjogren's Syndrome Patient Reported Index EULAR European League against Rheumatism FACIT-F Functional Assessment of Chronic Illness Therapy-Fatigue FIH First in Human h time HRCT High-resolution computed tomography iv intravenous IA interim analysis INR International Normalized Ratio kg kilogram LC-MS / MS Liquid Chromatography / Mass Spectrometry-Mass Spectrometry mAb Monoclonal antibody MCP-Mod Multiple Comparison Procedures - Modeling MMRM Mixed Effects Model Repeated Measures MRT average residence time NOACs (novel oral anticoagulants) NSAIDs (nonsteroidal anti-inflammatory drugs) PD Pharmacodynamics PhGA Physician Global Assessment Scale PK Pharmacokinetics PNS Peripheral Nervous System PT Prothrombin Time PTT Partial Thromboplastin Time Qd or qd once a day (Latin: "quaque die") QTcF QT interval corrected by Fridericia's formula Racc Drug accumulation coefficient SAE serious adverse event SjS Sjögren's syndrome SOM Site Operations Manual SPT Skin Prick Test SS Safety Set TEC tyrosine-protein kinase Apparent volume of distribution (volume) during the terminal elimination phase after Vz / F administration [Example]

[0100] Example 1: Preclinical studies Example 1a: BTK Occupancy and Preclinical PK / PD Relationship The extent and duration of covalent BTK occupancy by the inhibitor may determine whether compound (I) The in vivo PD effects of a novel irreversible BTK inhibitor were investigated. BTK occupancy after treatment with the compound (also referred to as BTK) was measured in an ex vivo immunoassay. (I) and the probe bind mutually exclusively to BTK, so covalently biotinylated BTK protease inhibitors are used. The fraction of unoccupied BTK protein was assayed after in vitro incubation with the antibody. Determine unoccupied BTK as well as total BTK relative protein levels in tissue lysates and the same samples The levels of unoccupied BTK were normalized to the total BTK protein levels in the medium.

[0101] In female rats, a single oral dose of 3 mg / kg of Compound (I) resulted in complete splenic BT. K occupancy occurred, with occupancy rates of 76% to 81% at a dose of 1 mg / kg, while 0. After a single dose of 3 mg / kg, only a partial occupancy of 30% was reached. TK occupancy reached levels consistent with those observed in the spleen. Oral doses as low as 3 mg / kg were sufficient to achieve full BTK occupancy in some tissues. It was clear that a short, transient systemic exposure to Compound (I) was sufficient for The blood exposure of Compound (I) after kg administration reached 49.1 nM at 0.5 hours and 5 hours after administration. This very low and transient systemic exposure was comparable to that of an irreversible inhibitor. This is consistent with a typical PK / PD model.

[0102] The spleen, blood, lymph nodes and lungs were measured in rats and mice after a single oral administration of Compound (I). The duration of BTK occupancy was investigated in mice. In rats, BTK occupancy lasted approximately 8 It showed a long blood half-life of 7 hours. The estimated BTK occupancy half-life in the rat spleen was only 1.5 hours. The difference in metabolic turnover rate was due to the difference in the B TK-expressing B cells and monocytes are quiescent and metabolically relatively inactive compared to the spleen This may reflect the fact that BTK occupancy persists longer in the blood than previously reported. (Advani et al 2013, J Clin Onc;31(1):88- 94) All other tissues analyzed (lung and lymph nodes) showed similar BTK turnover and The occupied half-life was shown.

[0103] The level of BTK-expressing cells in the skin was too low to measure their occupancy, so we used mast cells. In the reverse passive arthus (RPA) model of FcγRIII-mediated inflammation, a single dose The duration of the PD effect in the skin after administration was evaluated. In this model, inhibition of skin swelling was observed. was greatest when Compound (I) was administered 2 hours before inducing the Arthus reaction. This effect gradually weakened, and the Arthus reaction was not induced 45 hours after administration of Compound (I). This resulted in a baseline for BTK occupancy in the skin compared with that in the spleen, lung, and liver. It is suggested that the time course is similar to that of lymph nodes.

[0104] In these preclinical pharmacology studies, BTK occupancy and the individual pharmacological readouts showed strong correlation. Therefore, BTK occupancy may be a suitable PD biomarker for use in clinical trials. car and therefore was used in a Phase 1 clinical trial.

[0105] Example 2: Phase 1 Clinical Trial In healthy volunteers and subjects with atopic diathesis, once daily (qd) and twice daily (qd) bid) the safety and tolerability of single and repeated doses of Compound (I), both as an oral dose; First-in-human trials to evaluate pharmacokinetics (PK) and pharmacodynamics (PD) This study supported the further clinical development of Compound (I) in autoimmune diseases. also investigated the effect of food intake.

[0106] First-in-human studies in up to approximately 168 healthy volunteers (HVs) In the study, 64 of the patients (parts 2 and 4) had asymptomatic atopic eczema. Part 1 was a double-blind (subject and investigator blinded, sponsor blinded) study with 10 cohorts. This was a non-blinded, placebo-controlled, single ascending dose (SAD) titration study (N=80). It was. Part 2 was a cohort study of asymptomatic, atopic, healthy volunteers (N=48). A double-blind (subject and investigator blinded, sponsor blinded) study using once-daily dosing in a single-dose setting (unblinded), placebo-controlled multiple ascending dose (MAD) (13 doses over 12 days) This was an escalation study of the dose of 100mg of benzodiazepine (B6). Part 3 is a single-dose, open-label, crossover food effect study in 12HV It was. Part 4 was a 1-day study in two cohorts of asymptomatic atopic healthy volunteers. A double-blind (subjects and investigators blinded, sponsors blinded) study using two doses The study was a placebo-controlled multiple-dose (25 doses over 12 days) study (N=16).

[0107] The SAD part (Part 1) has 10 dose levels, and the MAD part (Part 2) and 4) were administered at eight dose levels (six cohorts using a single daily dose in Part 2 and Part 3). The study consisted of two cohorts (one using twice-daily doses of 4-hydroxybenzoates). Eight subjects were randomly assigned to each cohort. The SAD and MAD parts were randomly divided into two groups, with a ratio of 6:2 (active:placebo). During the SAD part, subjects were given either the compound (I) or a matching placebo. If no safety signals emerge from the study, the estimated pharmacologically active dose (PAD) Doses up to four times higher than the 200mg / kg dose were to be evaluated before the MAD part of the study began. Part 2 Compounds used in Part 1 (MAD qd regimen) and Part 2 (multiple-dose bid regimen) The total daily dose of (I) did not exceed the maximum SAD dose level investigated. The total daily dose in Part 4 did not exceed the total daily dose in Part 2.

[0108] In Part 1 (SAD), sentinel dosing was the first dose at each dose level as follows: The first two subjects were dosed on the first day (one with active drug and one with placebo). After the 48-hour observation period, the remaining 6 subjects in this cohort (5 with active drug) 1 patient was given placebo.

[0109] Standard safety monitoring was used throughout all study parts. Dedicated assessments included all vital signs, physical examination, and cardiology up to 96 hours after the last dose. Elephant medical history, ECG, adverse events and safety laboratory parameters (blood chemistry, hematology and urinalysis) and PK data from previous treatment groups up to 48 hours after the last dose (if available) ) were to be blindly reviewed for each cohort before dose escalation. After completion of the study, reported adverse events, safety laboratory parameters, QTc and heart rate A summary of safety reports was provided.

[0110] In Parts 1, 2, and 4, each subject participated in a 28-day screening period (Days -29 to 40). -2 days), baseline period, treatment period, and follow-up including end-of-study assessments. I participated during the promotion period.

[0111] Part 1: For baseline safety assessment and to confirm eligibility, Subjects were admitted to the study facility on Day 1 or Day -1. Eligible subjects were administered the compound A single dose of (I) or placebo was administered. Eligible subjects were allowed to stay for up to 10 minutes.

[0112] In Parts 2 and 4, for the baseline safety assessment and for qualification purposes Subjects were admitted to the hospital on Day -2 or -1 for the purpose of the study. On Day 1, eligible subjects were administered the compound The first dose of compound (I) was administered and the study medication was administered under fasting conditions up to and including the 12th day. From day -2 or -1, 96 hours after the final administration of Compound (I), Subjects were allowed to stay until the morning of Day 16, which was the day of the first semester of the study. and twice daily with study medication (details can be found in the evaluation schedule).

[0113] Part 3 is an open-label, randomized, two-arm crossover study to evaluate the effect of diet. In Part 3, each subject received 28 days of screening. The study period (Day -29 to Day -2), 2 baseline (Day -1) and single use on Day 1 Participants will participate in two treatment periods, each consisting of a single dose followed by safety and PK assessments up to day 5. Treatment period 2 consisted of follow-up visits and study evaluations at days 22 and 40, respectively. The two treatment periods were separated by a washout period of at least 18 days (+ / - 1 day). We divided it.

[0114] [Table 5]

[0115] [Table 6]

[0116] [Table 7]

[0117] Inclusion Criteria: 1. Ages between 18 and 65 years (inclusive) at the time of screening, and When determined based on past medical history, physical examination, vital signs, electrocardiogram and clinical tests Healthy male and female subjects in good health. Healthy subjects will be included in these specific studies. Part 2 or Part 4 participants with atopic diathesis are eligible for this study. Healthy atopic volunteers were screened for positive skin reactions to known allergens. A skin prick test was required (atopic constitution), but the patient was clinically asymptomatic. No systemic medication was required. 2. Subjects must weigh at least 50 kg and have a body mass index (BMI) of 18-30 kg. The BMI was required to be within the range of / m2 (including the relevant value). BMI = weight (kg) / [ Height (m)] 2 . 3. Subjects rested for at least 3 minutes at screening and initial baseline After 3 minutes in the standing position, and again (if necessary), vital signs (temperature, systolic and diastolic Vital signs in the sitting position were evaluated in the following ranges (including the relevant values): The following conditions were met: ·Oral body temperature 35.0~37.5℃ Systolic blood pressure 90-139mmHg Diastolic blood pressure 50-89mmHg Pulse rate: 50-90 bpm

[0118] Exclusion criteria 1. History of hypersensitivity to any of the study drugs or to drugs of a similar chemical class . 2. Clinically significant ECG abnormalities or ECG abnormalities at screening and / or pre-treatment Any history of CG abnormalities: ·PR interval>200msec ·QRS complex>120msec QTcF>450msec (male) QTcF>460msec (female) 3. Hemoglobin level 12.0 g / d at screening or initial baseline Less than L. 4. Platelet count outside the normal range (150x10) at screening or initial baseline 9 / L or less than 450x10 9 (exceeds). 5. Prothrombin time (PT), partial, at screening and / or baseline Standard coagulation tests, including thromboplastin time (PTT) or international normalized ratio (INR) Any clinically significant abnormality in any of the examinations. 6. History or presence of thrombotic or thromboembolic events or thrombotic or thromboembolic events Increased risk for

[0119] Treatment to be performed Part 1 (SAD) Subjects were assigned to one of the following 10 cohorts: Eight subjects were randomly assigned in a 6:2 ratio to either Compound (I) or matching placebo. One subject was treated with Compound (I) and one with a matching placebo in a 1:1 ratio. The first subcohort was randomly assigned to the first two subjects. The remaining 6 patients were randomized in a 5:1 ratio per cohort to receive treatment after the treatment period. Cohort 1: Single oral administration of 0.5 mg of Compound (I) or matching placebo Cohort 2: Single oral administration of 1.5 mg of Compound (I) or matching placebo Cohort 3: Single oral administration of 5 mg of Compound (I) or matching placebo Cohort 4: Single oral administration of 15 mg of Compound (I) or matching placebo Cohort 5: A single oral dose of 30 mg of Compound (I) or matching placebo Cohort 6: Single oral administration of 60 mg of Compound (I) or matching placebo Cohort 7: Single oral administration of 100 mg of Compound (I) or matching placebo Cohort 8: Single oral administration of 200 mg of Compound (I) or matching placebo Cohort 9: Single oral administration of 400 mg of Compound (I) or matching placebo Cohort 10: A single oral dose of 600 mg of Compound (I) or matching placebo

[0120] Part 2 (MAD, qd regimen) Subjects were assigned to one of six cohorts: in each cohort, a 6:2 ratio Eight subjects were randomly assigned to receive either Compound (I) or a matching placebo. Cohort 1: Repeated oral administration of 10 mg of Compound (I) or matching placebo Cohort 2: Repeated oral administration of 25 mg of Compound (I) or matching placebo Cohort 3: Repeated oral administration of 50 mg of Compound (I) or matching placebo Cohort 4: Repeated oral administration of 100 mg of Compound (I) or matching placebo Cohort 5: Repeated oral administration of 400 mg of Compound (I) or matching placebo Cohort 6: Repeated oral administration of 600 mg or less of Compound (I) or matching placebo

[0121] Part 3 (Dietary Effects) Subjects were randomly assigned to one of two treatment sequences in a 1:1 ratio.

[0122] [Table 8]

[0123] Part 4 (MAD, bid regimen) Subjects were assigned to one of the following cohorts: Eight subjects were randomly assigned to either substance (I) or a matching placebo. Cohort 1: 100 mg of Compound (I) or matching placebo in a bid regimen Repeated oral administration Cohort 2: 200 mg of Compound (I) or matching placebo in a bid regimen Repeated oral administration

[0124] Pharmacokinetic data Biological analysis methods Blood pharmacokinetic samples were obtained and evaluated in all subjects at all dose levels. These samples were not analyzed. Samples for PK evaluation were collected from subjects at designated time points during the study. Compound (I) concentrations were measured in blood by a validated LC-MS / MS method.

[0125] Pharmacokinetics of single ascending doses of 0.5 mg to 600 mg: The mean blood concentration-time course of Compound (I) after a single ascending dose is shown in Figure 1. Compound (I) was rapidly absorbed over time, with Cmax reaching approximately 1 to 1.5 hours across all doses. The absorption phase was characterized by one clear absorption peak in most subjects. During the initial distribution phase, most of the drug was eliminated, which resulted in a biexponential decline. These results suggest that qualitative drug clearance may occur before systemic tissue equilibration is achieved. The apparent terminal elimination phase was not reached until 12 hours after administration, which was consistent with doses of 100 mg and above. The measurable terminal half-life was 4 hours (100 mg) to 18 hours (600 mg), with a mean residence time of 1 to 5 hours in circulation. The distribution phase was approximately 1 hour after the main dose (MRT) (MRT ≒ T1 / 2 / ln2). The oral blood clearance (CL / F) after single dose administration was calculated. The mean ranged from 250 to 506 L / h across the SAD cohort, and the mean for the entire cohort The estimated value was approximately 383 L / h over the period.

[0126] Repeated oral dose pharmacokinetics The mean blood concentration-time course of Compound (I) after repeated dose escalation from 10 mg to 400 mg is shown. Shown in 2. Apparent geometric mean clearance at steady state after oral administration (CLss / F, day 12) MAD (qd) ranged from 246 L / h to 414 L / h across the cohort. In general, lower clearance was observed at steady state when compared to day 1; The difference between the two almost disappeared at doses of 100 mg or more (Table 2-1 (Day 1) and Table 2-2 (Day 1) The reason for this behavior is the covalent bond that contributes to the early clearance of Compound (I). The remaining target occupancy at trough levels on consecutive days was This effect is due to the fact that the presence of ATP reduces the contribution of target binding to clearance (CLss / F). The effect is most pronounced on day 1. Naturally, this difference is due to the near complete target occupancy at the trough level. In some cases, it decreases with increasing dose. Consequently, the (within-subject) drug accumulation coefficient (Ra As exemplified by cc), drug exposure (AUC, Cmax) increased on the second day compared to the first day. It was found that the α-to-β ratio was higher at 12 days, ranging from 5 (low dose) to 1.2 (high dose). Generally, AUC is higher than Cmax, which may affect systemic clearance. It was confirmed that this may be involved.

[0127] [Table 9]

[0128] [Table 10]

[0129] In general, blood concentrations 24 hours after the final dose are usually above 100 mg, except for a few subjects. This indicates that compound (I) was almost completely administered within two consecutive doses. The latter also reached a steady state within a few doses. It also suggests that

[0130] Because BTK turnover is higher in tissues, bid administration was also investigated. Mean plasma concentration-time profiles obtained after multiple ascending doses of 200 mg and 200 mg twice daily Consistent with results from other cohorts, the bid regimen resulted in a significant increase in the response to treatment. Rapid absorption was observed with Tmax around 1 h. The observed accumulation coefficient (Racc) was A UC was 1.5 (100 mg) and 2.0 (200 mg), and Cmax was approximately A dose-proportional increase in AUCtau was observed on day 12, whereas AUCtau reached 1.65 (both doses). Only a slight increase (1.33 times) in Cmax was observed. Bid administration of compound (I) was observed without compromising the overall PK profile and at high doses. To address faster target resynthesis in tissues during the dosing interval without the need for qd treatment Provide a choice of:

[0131] Dietary Effects: Part 3 Results: PK data from the food effect cohort summarized in Tables 2-3 below demonstrate a 1.25-fold lower C max, indicating a slower absorption rate and a 1.4-fold higher AUC0-24 Most importantly, the mean T The maximum shifted from 1 hour (fasting) to >3 hours (food intake) (Figure 4).

[0132] [Table 11]

[0133] Pharmacodynamics Pharmacodynamic (PD) characteristics were investigated by assessing target occupancy and distal pathway inhibition. Measurement of BTK occupancy in human whole blood (derived as the ratio of free and total BTK) is a promising therapeutic target. It is a direct marker of involvement.

[0134] Multiple in vivo pathways and disease lead-associated studies across preclinical models for compounds of formula (I) A relationship was established between BTK occupancy, dose, systemic compound exposure, and efficacy in rats. (See Example 1)

[0135] The compounds of formula (I) are irreversible inhibitors of BTK and inhibit the extent and duration of BTK occupancy. In two separate assays, Meso Scale Diagnostics by enzyme-linked immunosorbent assay (ELISA) on the cs(MSD) platform. By measuring both free (unbound) and total BTK in whole blood, the activity of compounds ( The PD effect of I) was evaluated.

[0136] BTK occupancy (free and total BTK) in human blood is a direct marker of therapeutic target engagement The relationship between dose and pharmacodynamics was characterized by measurement of the 0.5 Single ascending doses ranging from 10 mg to 400 mg, versus qd doses ranging from 10 mg to 400 mg For repeated escalation doses and for repeated escalation doses of 100 mg and 200 mg bid BTK occupancy was determined.

[0137] Compounds of formula (I) induce a clear dose-dependent increase in both the extent and duration of peripheral blood BTK occupancy. Peak target occupancy was generally observed as early as 0.5 h post-dose. This results in a rapid onset of drug effect with no associated hysteresis relative to peak drug exposure. As concluded from its ability to covalently bind to BTK, target occupancy was observed in the systemic circulation. The pharmacokinetics of benzodiazepine from 2000 to 2004 was well maintained over time, indicating a non-equilibrium PK-PD relationship. Therefore, the duration of BTK occupancy is governed by the rate of de novo synthesis of BTK. We can conclude.

[0138] Unlike the lower dose cohorts (0.5-1.5 mg), The single dose established peak target occupancy approaching 100% in nearly all subjects, with At 15 mg, there was a large inter-subject variability in response, whereas at 30 mg and above, The dose resulted in sustained (>24 h) and nearly complete (>90%) occupancy in all subjects. The BTK protein pool was restored to pre-treatment levels, demonstrating a significant reduction in inter-subject variability. The time to recovery was approximately 10 days, corresponding to a median turnover T1 / 2 of approximately 48 hours. (Figure 5).

[0139] After repeated administration of Compound (I), 10 mg of Compound (I) qd was already administered before the 12th day. The serum BTK occupancy rate reached >96%.

[0140] Furthermore, ex vivo inhibition of basophil activation (by surface expression of CD63 and CD203c) The downstream PD effects of compound (I) were monitored using the PD monitoring system as a terminal mechanistic biomarker. To determine the PD effect of Compound (I) on basophil activation, anti-IgE Whole blood was stimulated ex vivo with IgG. CD63+ and CD4+ were detected by flow cytometry. Degranulation was assessed by the percentage of 203+ basophils.

[0141] After a single escalating dose of Compound (I), data showed that the dose of FcεR1-mediated basophil activation Ex vivo blood basophil activation as measured by CD63 is shown to be dependent on ATP. , was almost completely inhibited (>89%) at the 60 mg dose and 24 hours after administration at higher doses On the other hand, the CD203 activity was significantly reduced 24 hours after a single administration of Compound (I). Maximum inhibition of c (approximately 50% inhibition) was achieved only with 200 mg of Compound (I).

[0142] On day 12, 8 hours after qd or bid administration of the MAD of a compound of formula (I), Already, the lowest tested dose of Compound (I) (10 mg qd) resulted in CD63 upregulation. >90% inhibition was observed, and trough level inhibition of CD63 was observed at Compound (I) doses ≥ 50 mg / kg. d. >90% (Figure 6). Maximum trough inhibition of CD203c activation on day 12 was consistently higher than after a single dose of Compound (I), and This was achieved only with a dose of 0 mg bid.

[0143] The ability of compound (I) to inhibit a defined allergen response is a first-in-human Skin prick testing (SP) in healthy atopic subjects in the MAD study portion of the Leeman study Pre-treatment (screening, baseline, and day 1 pre-treatment) and SPT was performed at different time points after the first dose (day 1) and 11 days after once-daily dosing (day 12). went.

[0144] Mean post-dose wheal compared to baseline as well as inhibition of ex vivo basophil activation There was a significant improvement in wheal diameter in multiple-escalation cohorts, as demonstrated by a reduction in size. A dose-dependent effect was discernible (Figure 7). The results began to plateau.

[0145] Rationale / Conclusions for Dose Selection Either given as a single dose or once or twice daily for up to 18 days It was administered to healthy volunteers in a Phase 1 clinical trial at doses ranging from 0.5 mg to 600 mg. Compound (I) was well tolerated and no adverse events were associated with the ingestion of Compound (I). There were no serious or severe adverse events observed in clinical trials. ) did not appear to be dose-related, were mostly single events, and were usually mild in nature Therefore, clinical safety information supports the dose selected for this Phase 2b study. The dose levels of the present invention were evaluated in the following analyses (BTK occupancy, basophilicity, and basophilicity in healthy volunteers). Inhibition of cytoplasmic activation (monitored by CD63 and CD203c upregulation); and asymptomatic atresia. Skin prick testing (SPT) in healthy volunteers - mast cells in the skin and This was derived from the effect on - instead of basophil inhibition.

[0146] In the above clinical trial, administration of 10 mg of Compound (I) qd resulted in blood Near-complete BTK occupancy occurred at 100% and CD63 upregulation was reduced by >90% (compound at steady state). 8 hours after administration of compound (I), the inhibition of wheal size in SPT was minimal. Therefore, q. 10 mg of compound (I) at d corresponds to the onset of biological activity. At 00 mg, the mean reduction in wheal size in SPT began to plateau. 100 mg of compound corresponds to the maximum effect of compound (I). The moderate dose of compound (I) is well suited to accurately represent the dose-response curve of compound (I) at qd. Suitable.

[0147] Compounds of formula (I) inhibit BTK by covalent binding. BTK occupancy in the blood is >24 hours. (h) whereas rapid BTK turnover in tissues (e.g., in rodent spleen) Approximately 5 hours) required bid administration of Compound (I) to reach maximum efficacy. Doses of 10 mg, 25 mg and 100 mg of Compound (I) bid are Each accurately represents the dose-response curve for Compound (I) when given twice daily.

[0148] Human safety For the analysis of adverse effects, all SAD and MAD cohorts (2 patients per cohort) and placebo subjects separated by SAD and MAD parts into one placebo group (n=20 for SAD and n=16 for MAD) were pooled and each single compound ( I) treatment group (n=6 each) and total compound (I) group (n=60 for SAD and n=60 for MAD) For both the SAD and MAD populations, placebo and active groups were compared. There were no significant differences in demographic data between the FI and FI groups. The safety evaluation of Study H revealed no significant safety concerns at doses up to 600 mg. Not possible.

[0149] Example 3: Efficacy and Safety Data in Subjects with Moderate to Severe SjS To further develop compounds for the treatment of this disease, we are investigating the efficacy and safety of steroids for moderate to severe SjS. To establish the safety and efficacy and characterize the dose response of compounds of formula (I) in A Phase 2 trial with compounds of formula (I) is being conducted, which is designed to:

[0150] [Table 12]

[0151] [Table 13]

[0152] [Table 14]

[0153] Study design This is an adaptive, phase 2, randomized, double-blind, placebo-controlled, multicenter, pooled dose-finding study. This study evaluated the efficacy of compound (I) in patients with moderate to severe Sjögren's syndrome (SjS). The study was conducted to evaluate the safety and efficacy of repeated doses of Severe SjS is defined as meeting the ACR / EULAR criteria and at least 5 (8 out of 12) Sjögren's syndrome as defined by the ESSDAI and at least 5 ESSPRI The study subjects are receiving certain concomitant treatments for their underlying diseases and meet the inclusion criteria. If still in agreement, these subjects will be considered if they remain stable until the end of this study. Stay on this treatment.

[0154] The study consists of two parts. Part 1 of the study will evaluate two different dosing regimens. It can be concluded that the single dose with the greatest biological activity (100 mg of the compound of formula (I) or or a pharmaceutically acceptable salt thereof) administered as: once daily (qd) or twice daily (bid) The study will be conducted with an expected sample size of 24 subjects per group and compared to a placebo group. A total of approximately 72 study subjects will be randomized equally among these three treatment groups. In Part 2, the dosing regimen selected (qd or bid) was determined based on the lowest ( Between the maximum (10 mg of the compound of formula (I)) and the maximum (100 mg of the compound of formula (I)) dose The dosing regimen will be extended to lower doses to assess the safety and dose response of the This resulted in four treatment arms; placebo plus three dose levels (100 mg bid / qd, 2 5 mg bid or 35 mg qd and 10 mg bid / qd) of a compound of formula (I) A total of approximately 180 subjects were randomly assigned equally to these four treatment groups. As a result, the sample size is expected to be 45 subjects per group.

[0155] Each individual study subject will initially undergo a screening period of up to 6 weeks, followed by a 24-week treatment extension period. and a follow-up period of 30 days after the last dose of study medication, and a visit before the end of the study. The total duration for each subject in this study, including screening, is up to 35 weeks. is.

[0156] For the entire duration of the treatment period (24 weeks), subjects will receive the selected dosing regimen. All subjects were blinded throughout the study and received either a compound of formula (I) or a placebo twice daily. Ensure that this is maintained.

[0157] Safety assessments included physical examination, ECG, vital signs, and standard clinical laboratory assessments (hematology, Clinical chemistry and urinalysis) and monitoring for adverse events and serious adverse events.

[0158] screening After signing the informed consent, subjects were assessed on the ESSDAI and ESSPRI. Evaluate the product, complete safety and other evaluations, and assess eligibility. Therefore, if deemed appropriate by the investigator, different Subjects who fail screening will be re-screened for one additional opportunity. Once a subject is identified as eligible for the study, the subject may be Guidance on how to use the wearable device is also provided (if the subject chooses to use it). If so, it will be provided to the subject.

[0159] Baseline Eligible subjects will return for a baseline visit on Day 1. Subjects will be randomly selected based on logistics. Patients may stay overnight at the study site for medical reasons, but this is not considered hospitalization. Prior to randomization, required baseline assessments will be completed prior to dosing on Day 1. If preferred by the site for scheduling purposes, some baseline An in-evaluation will be conducted the evening before Day 1.

[0160] Test treatment The investigational product will be provided in a properly blinded, labeled bottle. Each tablet contains 10 mg, 25 mg or 50 mg of the active substance (compound of formula (I)) or Each dose (2 capsules) contains a capsule containing either the placebo or the corresponding It should be swallowed with water and taken on an empty stomach. The administration interval should be maintained within 10 to 14 hours. requirements for the administration of the study drug and details of the instructions to be followed by subjects who will count, dispense, and take the study drug. The details are outlined in SOM.

[0161] treatment group In Part 1, on Day 1, subjects were randomized in a 1:1:1 ratio to one of three treatment arms: Assign to. Compound of formula (I), 100 mg bid 100 mg qd of the compound of formula (I) ·placebo

[0162] The dosing schedule and dose range for Part 2 will be based on data from IA. In 2, on Day 1, subjects were assigned in a 1:1:1:1 ratio to one of the following four treatment arms: Hit. Compound of formula (I), 100 mg bid or qd Compound of formula (I), 35 mg qd or 25 mg bid Compound of formula (I), 10 mg bid or qd ·placebo

[0163] Subjects will take two capsules at each dose. All subjects in both parts will take one capsule in the morning. There is an evening dose (2 capsules each).

[0164] The subjects were the 1st, 29th (4th week), 57th (8th week), 85th (12th week), On the 113th day (16th week), the 141st day (20th week) and the 169th day (24th week), All other morning doses and all The evening dose is administered by the participating subject, usually at home. All subjects will be administered at the study site. of the compound of formula (I) or placebo capsules every four weeks during scheduled visits to Receive their individual supplies.

[0165] Subjects will be randomized into individual treatment groups for each study part. Except in Japan, baseline E Randomization will be stratified by SSDAI (based on weighted score < or ≥ 10). Individual blocks of randomized numbers will be created for participating Japanese and foreign subjects, and for Japanese subjects This will ensure that the dose is equally distributed across all treatment arms in this study. (1st week), 29th day (4th week), 57th day (8th week), 85th day (12th week), 11th day At the clinical trial site on days 3 (Week 16), 141 (Week 20), and 169 (Week 24). Subjects will then receive their morning dose of a compound of formula (I) or a placebo. The subject may then return home and continue their daily dosing regimen (self-administration). Week 4 and At the Week 24 visit, subjects will also undergo post-dose safety and PK assessments. Patients will return to the study site at intervals of 12 weeks, with a further visit at the end of Week 2 (Day 15). ,Subjects were administered the ESSDAI and ESSPRI assessments and other scales / questionnaires, safety The efficacy and various PK, PD and biomarker sample collections were assessed as indicated in the evaluation schedule. Each week, subjects will be asked to complete a diary to record their SjS symptoms and medications. Ask them to do so.

[0166] The primary endpoint of this study will be assessed at the end of Part 2, after completion of 24 weeks of treatment. (Day 169; visit at the end of Week 24). An interim analysis was performed at 24 weeks of treatment in Part 1. As a surrogate for therapeutic outcome, efficacy and safety will be assessed after 12 weeks of treatment.

[0167] Rationale for dose / regimen and duration of treatment Dose / Regimen for Part 1 The maximum dose planned for this study (100 mg bid or qd) was cytoplasmic blockade) and predicted BTK occupancy in tissues and CD63 upregulation in basophils Based on the inhibition (IB) of Therefore, this dose is the most effective in tissues, including lymphoid tissues, against SjS. It can be concluded that this drug provides significant clinical benefit. Doses of up to 600 mg and 200 mg twice daily were administered in human volunteers. It has been tested and proven to be safe.

[0168] In Part 1, the dose concluded to provide the maximum effect (100 mg) was administered qd and The compound of formula (I) against intracellular BTK will be tested in a bid regimen and compared to placebo. Due to the covalent nature of the bond, the duration of therapeutic effect depends on the turnover rate of the BTK molecule. From the simulation model, it was found that 100 mg of the compound of formula (I) at steady state The qd regimen used achieved an average of 83% BTK occupancy 24 hours after administration (and immediately before the next administration). while the same single dose of 100 mg bid regimen resulted in a 24-hour The average BTK occupancy was shown to be 96%.

[0169] Furthermore, 70% BTK inhibition for approximately 90% of each dosing period at steady state is considered optimal clinically. Therefore, the qd- and qd-tested in Part 1 of this study are considered appropriate for efficacy. Both Compound (I) 100 mg dosing regimens in the bid regimen produce efficacy.

[0170] Dosage / Regimen for Part 2 Part 2 will evaluate the full dose range of selected dosing regimens at doses from 10 mg to 100 mg. In a first-in-human study using the compound of formula (I), g of a compound of formula (I) qd administration results in near complete BTK occupancy in the blood, >80% reduction in D63 upregulation but wheal in skin prick test (SPT) size was only minimally inhibited. Thus, 10 mg of compound of formula (I) qd It is concluded that the pharmacodynamic activity in tissues corresponds to the onset of biological activity. As a dose of 35 mg qd or 25 mg bid, the daily dose of a compound of formula (I) is To accurately represent the complete dose-response curve of a compound of formula (I) at qd or bid, respectively A double-blind treatment period of up to 24 weeks is considered appropriate. Ongoing safety and efficacy data for the compound will be provided.

[0171] Rationale for the choice of comparator (placebo) The comparator treatment was monitored for potential AEs and other safety data, as well as for the presence of steroids or other side effects of formula (I) during the 24-week study. The clinical efficacy and safety profile obtained from subjects treated with a compound of formula (I) or a pharmaceutically acceptable salt thereof. and placebo to provide objective evidence of PD data. Since there are no proven systemic treatments, the use of a placebo is justified. Sub-treatment is limited to symptomatic treatment of mucosal signs and symptoms (dryness) and steroids and Conventional DMARDs are often ineffective. There are no effective pharmacological interventions for fatigue to this extent.

Claims

1. Sjögren's syndrome (SjS) in a subject in need of treatment 1. A compound of formula (I) for use in the treatment of rheumatoid arthritis (SjS): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein the daily dose of the compound of formula (I) is from about 10 mg to about 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. 2. The method of claim 1, wherein the daily dose is from about 10 mg to about 100 mg. (I) or a pharmaceutically acceptable salt thereof.

3. 2. The compound of formula (I) for use according to claim 1, wherein the daily dose is about 100 mg. or a pharmaceutically acceptable salt thereof.

4. 2. The compound of formula (I) for use according to claim 1, wherein the daily dose is about 50 mg. or a pharmaceutically acceptable salt thereof.

5. 2. The compound of formula (I) for use according to claim 1, wherein the daily dose is about 35 mg. or a pharmaceutically acceptable salt thereof.

6. 2. The compound of formula (I) for use according to claim 1, wherein the daily dose is about 25 mg. or a pharmaceutically acceptable salt thereof.

7. 2. The compound of formula (I) for use according to claim 1, wherein the daily dose is about 20 mg. or a pharmaceutically acceptable salt thereof.

8. The compound of formula (I) is administered in an amount of about 10 mg, about 35 mg, about 50 mg, or about 100 mg.

2. The compound of formula (I) or pharmaceutical composition for use according to claim 1, wherein the compound is administered once a day in an amount of 0.1 mg / kg or more. its salts acceptable to.

9. administered twice daily at a dose of about 10 mg, about 25 mg, about 50 mg, or about 100 mg; 2. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to claim 1.

10. The use according to any one of claims 1 to 9, wherein the subject has moderate to severe SjS.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof for:

11. The subject meets the following criteria: a) prior to treatment with a compound of formula (I), the subject has an ESSPRI score of ≧5; b) prior to treatment with a compound of formula (I), said subject has a history of biological, blood, joint, skin, glandular Weighting from eight defined areas selected from symptoms, lymphadenopathy, kidneys, and constitution Having an ESSDAI based score of ≥ 5 11. The method for use according to claim 1, wherein the compound is selected from at least one of the following: , a compound of formula (I) or a pharmaceutically acceptable salt thereof.

12. The use of any one of claims 1 to 11, wherein the subject is an adult. or a pharmaceutically acceptable salt thereof.

13. The subject is one of: a) a decrease in ESSPRI score; and / or b) Decrease in ESSDAI score 13. The method of claim 1, wherein at least one of the following is achieved by the 12th week or by the 24th week of treatment: A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of the preceding claims.

14. The subject has a mean age of 18 years or older, as measured by ESSPRI or EDSSDAI at 5 weeks after completing the treatment.

14. The method of claim 1, wherein the compound of formula (I) is administered to a subject in need of treatment with steroids, for example, a steroid drug, for use according to any one of claims 1 to 13, which achieves a sustained response in the presence of steroids. ) or a pharmaceutically acceptable salt thereof.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof is placed in a pharmaceutical formulation; and and the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier.

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use as defined in claim 1.

16. T of about 0.5 to 3 hours ｍａｘ For use according to any one of claims 1 to 15, 2. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating or preventing atopic dermatitis.

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