Methods of treating chronic spontaneous urticaria using bruton's tyrosine kinase inhibitor

Abstract

To provide methods for treating Chronic Spontaneous Urticaria.SOLUTION: The present disclosure provides methods for treating Chronic Spontaneous Urticaria using a compound N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof. The present disclosure also provides the compound or a pharmaceutically acceptable salt thereof for treating Chronic Spontaneous Urticaria patients, as well as medicaments, dosing regimens, pharmaceutical formulations, dosage forms, and kits for use in the disclosed uses and methods.SELECTED DRAWING: None

Description

[Technical field]

[0001] Technical Field The present disclosure relates to the use of Bruton's tyrosine kinase inhibitors to treat chronic spontaneous urticaria (CSU) The present invention relates to a method for treating skin diseases caused by basophils and mast such as erythrocytes and erythrocytes.

[0002] Background of the disclosure Urticaria is a heterogeneous group of disorders characterized by itchy hives and / or angioedema. Chronic urticaria is defined as urticaria that occurs continuously or intermittently for more than 6 weeks (M aurer M et al.(2013)Revisions to the int. ernational guidelines on the diagnosis a nd therapy of chronic urticaria. Dermatol Ges.;Bernstein JA,Lang DM,Khan DA,et al(2014)The diagnosis and managem ent of acute and chronic urticaria: 2014 update.J Allergy Clin Immunol;133(5):12 70-7). Chronic urticaria is further divided into two subgroups: chronic spontaneous urticaria Chronic irritant-induced urticaria (CSU) and chronic irritant-induced urticaria (IU). The latter includes heat urticaria, cold urticaria or These include physical urticaria, such as pressure urticaria, and special subtypes such as cholinergic urticaria. U is a patient with a pruritic wheal, angioedema, or both for 6 weeks of known or unknown cause. It is defined as something that emerges spontaneously beyond the normal range of motion (Zuberbier T, et al. (2018)The EAACI / GA(2)LEN / EDF / WAO Guideli ne for the definition, classification, dia gnosis,and management of urticaria:the 2 017 revision and update.Allergy;73(7):13 93-1414) The combination of symptomatic dermatographic urticaria and CSU is frequently observed. In some cases, both CSU and irritant-induced urticaria may be combined.

[0003] Previously, all chronic urticaria with unknown triggers was named "chronic idiopathic urticaria" (CIU). With advances in medicine, it has become clear that some types of urticaria that were previously considered "idiopathic" are actually It is now known that there are some cases in which autoantibodies can be detected. The day-to-day fluctuating manifestations of this chronic urticaria remain unpredictable and the trigger is unclear. Since the disease is not caused by autoantibodies, symptoms appear spontaneously. To accurately reflect in its terminology that there are some Following the guidelines, it is now called chronic spontaneous urticaria (CSU) (Maurer M et al.(2013)Revisions to the internat ional guidelines on the diagnosis and th erapy of chronic urticaria.J Dtsch Derma tol Ges.;Zuberbier T,et al.(2018)The EAA CI / GA(2)LEN / EDF / WAO Guideline for the de finition, classification, diagnosis, and ma nagement of urticaria:the 2017 revision and update. Allergy;73(7):1393-1414). The use of the term "chronic idiopathic urticaria" in the current medical literature is no longer recommended. The new naming convention has not been implemented in all parts of the world, and in countries such as the United States, The patient population with chronic urticaria of nonspecific etiology or unknown trigger is called chronic idiopathic urticaria (CIU). In accordance with international guidelines and for the sake of consistency, this entity is referred to in this document as The term "CSU" will be used throughout.

[0004] The lifetime prevalence of CSU is approximately 1.8%, and more than 20% of CSU patients still have this condition 20 years later. may have a disease (Greaves M (2000) Chronic Ur ticaria.J Allergy Clin Immunol;105(4):66 4-72;Zuberbier T, Balke M, Worm M, et al(20 10)Epidemiology of urticaria:a represent ative cross-sectional population survey. Clin Exp Dermatol;35(8):869-73). Affected patients have erythema Patients frequently experience pruritic urticaria accompanied by episodes of angioedema and / or angioedema. It has been reported to be involved in approximately 33-67% of cases (Juhlin L (1981) Re current urticaria: clinical investigation of 330 patients.Br J Dermatol;104(4):3 69-81;Toubi E, Kessel A, Avshovich N, et al (2004)Clinical and laboratory parameters in predicting chronic urticaria duration n: a prospective study of 139 patients.A llergy;59(8):869-73;Zuberbier T, Balke M, Worm M,et al(2010)Epidemiology of urtica ria: a representative cross-sectional po pulation survey. Clin Exp Dermatol;35(8) :869-73;Maurer M,Weller K,Bindslev-Jense n C,et al(2011)Unmet clinical needs in c hronic spontaneous urticaria. A GA 2 LEN t ask force report.Allergy;66(3):317-30). strawberry The typical skin lesions of measles are pale raised lesions and wheals and redness with surrounding erythema. They range in size from a few millimeters to a few centimeters, usually occur in clusters, and often They coalesce to form large confluent lesions. CSU is accompanied by intense pruritus and can affect the patient's well-being and quality of life. It has been suggested that the impact on quality of life is comparable to that of severe coronary artery disease. (Greaves MW(2003) Chronic idiopathic urti caria.Curr Opin Allergy Clin Immunol;3(5 ):363-8.Review;Powell RJ, Du Toit GL, Sidd ique N,et al(2007)BSACI guidelines for t he management of chronic urticaria and a ngio-oedema.Clin Exp Allergy;37(5):631-5 0). Symptoms of urticaria and urticaria-associated angioedema can adversely affect daily activities and sleep ( O'Donnell BF, Lawlor F, Simpson J, et al(19 97).The impact of chronic urticaria on t he quality of life.Br J Dermatol;136(2): 197-201). Therefore, when managing patients with urticaria, it is important to consider patient-related outcomes (e.g. For example, the DLQI is an important measure of treatment (Kaplan A., et al. (2 013)Omalizumab in patients with symptoms tic chronic idiopathic / spontaneous urtic aria despite standard combination therapy y. J Allergy Clin Immunol;132(1):101-9;M aurer M et al.(2013)Revisions to the int. ernational guidelines on the diagnosis a nd therapy of chronic urticaria.J Dtsch Dermatol Ges;Zuberbier T,Aberer W,Asero R,et al(2018)The EAACI / GA(2)LEN / EDF / WAO Guideline for the definition,classificat ion, diagnosis, and management of urticari a:the 2017 revision and update.Allergy;7 3(7):1393-1414).

[0005] The etiology of CSU is not fully understood. Up to 50% of CSU cases are high-affinity Histamine release in response to multiple antigens, including IgE receptors (FcεRI) or IgE antibodies The clinical significance of these autoantibodies is unclear, but they may be involved in the pathogenesis of the disease. It has been suggested that this may be contributing to the urticaria--new concepts regarding pathog enesis and treatment.Curr Allergy Asthma Rep;2(4):263-4;Sabroe RA,Greaves MW(200 6) Chronic idiopathic urticaria with func tional autoantibodies: 12 years on.Br J Dermatol;154(5):813-9.Review). In addition, Basophils show a clear shift towards FcεRIα-mediated degranulation, independent of the potential role of autoantibodies. It has been suggested that there may be a possibility of asophil phenotypes in chronic idiopathic urticaria in relation to disease activi ty and autoantibodies. J Invest Dermatol ;128(8):1956-63).

[0006] The treatment of CSU is challenging and requires the use of non-sedating (second generation) H1-antihistamines (H1-AH ) is the mainstay of symptomatic treatment for CSU. H1-AH at approved doses provides relief in some patients. However, more than 50% of patients do not respond to conventional doses of H1-AH. Line (Zuberbier T,et al.(2018)The EAACI / GA (2)LEN / EDF / WAO Guideline for the definit ion, classification, diagnosis, and management ent of urticaria: the 2017 revision and Treatment algorithm for Allergy update;73(7):1393-1414 According to the second step of the study, even increasing the dose to four times the approved dose caused significant patient This area does not experience control of urticaria symptoms (Maurer M, Weller K ,Bindslev-Jensen C,et al(2011)Unmet clin ical needs in chronic spontaneous urtica ria.A GA 2 LEN task force report.Allergy; 66(3):317-30;Marrouche N, Grattan C(2014) Update and insights into treatment optio ns for chronic spontaneous urticaria.Exp ert Rev Clin Immunol;10(3):397-403). For patients whose disease has not been controlled with high doses of H1-AH, The third step of the treatment algorithm for ovarian cancer is expected to include the addition of omalizumab. Cyclosporine can be used as a last resort treatment after ineffective treatment with cyclosporine.

[0007] Evidence for the efficacy of leukotriene receptor antagonists (LTRAs) in urticaria With the availability of omalizumab, (off-label) LTRAs are 1- No longer recommended for the treatment of CSU unresponsive to antihistamine therapy (Zu Berbier 2018). Third level treatment regimen if progression requires this. Systemic corticosteroids may be added to the treatment for a short period (up to 10 days). Longer-term treatment is not advisable due to the side effects associated with chronic systemic exposure to ruticosteroids. Intravenous immunoglobulin G, dapsone, hydroxychloroquine, H2-antihistamines (H2 -AH), methotrexate, and cyclophosphamide, among other previously used Treatment options have an unfavorable benefit-risk profile or a significant side-effect profile. and is no longer recommended for the treatment of CSU (Kaplan AP 2002) Chronic urticaria--new concepts reg arding pathogenesis and treatment.Curr A llergy Asthma Rep;2(4):263-4;Powell RJ,D u Toit GL,Siddique N,et al(2007)BSACI gu idelines for the management of chronic u rticaria and angio-oedema.Clin Exp Aller gy;37(5):631-50;Zuberbier T,et al.(2018) The EAACI / GA(2)LEN / EDF / WAO Guideline for the definition, classification, diagnosis ,and management of urticaria:the 2017 re vision and update.Allergy;73(7):1393-141 4).

[0008] Omalizumab is an approved treatment for CSU resistant to standard treatments and has been shown to be effective. It exhibits a favorable benefit-risk profile due to its binding to C3 (FcεRI) of IgE molecules. A recombinant humanized IgG1 monoclonal antibody that binds to an IgE-specific epitope within the fusion region. It is a monoclonal antibody that is effective in treating poorly controlled moderate to severe asthma and CSU resistant to standard treatment. Treatment is needed in many countries. How does Omalizumab work in patients with CSU? The exact mechanism of action is unknown. Omalizumab is administered as an injectable solution to CSUs. It is administered to the affected patient.

[0009] Despite being available for the treatment of CSU, new therapeutic options for CSU patients There remains a high medical need for treatment with second generation H1-antihistamines. Fewer than 40% of patients with CSU treated with CT do not respond adequately (Guillen-Aguinag a et al 2016,Br J Dermatol;175(6):1153-6 5) Furthermore, the signs and symptoms of CSU were completely controlled in patients treated with omalizumab. Less than 50% of the data are available (Kaplan et al. 2016, J Al lergy Clin Immunol;137(2):474-81).

[0010] Summary of the Invention The object of the present invention is to provide a method for treating chronic spontaneous urticaria and atopic dermatitis, which is characterized by the action of basophils and mast cells. A novel method for treating or preventing a skin disease by administering the compound to a subject in need of such treatment. A therapeutically effective amount of N-(3-(6-amino-5-(2-(N-methylacrylamide ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclohexyl administering chloropropyl-2-fluorobenzamide to the subject. This is what we should do.

[0011] Thus, provided herein is a method for treating chronic spontaneous urticaria (CSU). Therefore, N-(3-(6-amino-5-(2-(N-methyl)) (ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylfuran phenyl)-4-cyclopropyl-2-fluorobenzamide (which is represented by the following formula (I) or a pharma- ceutical acceptable salt thereof), Preferably about 10 mg to about 200 mg, or more preferably about 10 mg to about 100 mg. A method is disclosed comprising administering a daily dose. [ka]

[0012] and N-(3-(6-amino- 5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro (4-cyclopropyl-2-fluorobenzamide), and a pharma- ceutically acceptable salt of the N-(3-(6-amino-5-(2-(N-methyl (Ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl cyclopropyl-4-fluorobenzamide, or a pharma- ceutically acceptable salt thereof The salt is administered in a daily dose of about 0.5 mg to about 600 mg, preferably about 10 mg to about 200 mg. and most preferably at a daily dose of about 10 mg to about 100 mg. [Brief description of the drawings]

[0013] [Figure 1] Inhibitory effect of compounds of formula (I) in the reverse passive Arthus reaction [Diagram 2] BTK occupancy in the spleen 5 hours after administration [Diagram 3] Compounds of formula (I) inhibit PCA following low dose IgE sensitization [Figure 4] BTK occupancy in the spleen in response to low-dose IgE sensitization [Diagram 5] Time course of blood concentration of Compound (I) after single dose escalation from 0.5mg to 600mg [Figure 6] Time course of blood concentration of Compound (I) after repeated dose escalation from 10 mg to 400 mg (qd administration) [Figure 7] Time course of blood concentrations of Compound (I) after repeated dose escalation of 100 mg (bid) and 200 mg (bid) [Figure 8] Food effects observed following a single oral dose of 60 mg of compound of formula (I) [Figure 9] Arithmetic mean (standard deviation) of BTK occupancy in peripheral blood after a single dose of compound of formula (I) [Figure 10] Median Percentage Inhibition of Basophil Activation vs. Total Daily Dose of Compound of Formula (I) on Day 12 of Multiple Dose Escalation of Compound of Formula (I) [Figure 11] Reduction in skin prick test wheal size with repeated ascending doses

[0014] Detailed Description of Disclosure Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and a TEC kinase. BTK is a member of the IL-1 kinase family. It is expressed in B cells, macrophages, and mast cells / lostridium β-lactams. It is expressed in selected cells of the adaptive and innate immune systems, including basophils and platelets. BTK binds to the Fc epsilon receptor as well as the B cell antigen receptor (BCR) and BTK inhibitors. The activating Fc gamma receptor (FcεR1 for IgE) and the activating Fc gamma receptor (FcγR for IgG) ) signaling. BTK inhibitors such as ibrutinib have been shown to It has been approved for the treatment of malignant tumors (Hendriks et al. 2014). Recently, inhibition of BTK has been shown to inhibit activation / degranulation of mast cells and basophils in vitro. This resulted in wheal rash in prick tests of patients suffering from IgE-mediated allergies. It has been shown to reduce noise (Smiljkovic et al. 2017 ; Dispenza et al 2018). Thus, inhibition of BTK may be a potent inhibitor of rheumatoid arthritis. Machi, multiple sclerosis, systemic lupus erythematosus, chronic urticaria, atopic dermatitis, asthma, For treating various autoimmune and chronic inflammatory diseases, including primary Sjogren's syndrome This is an attractive therapeutic concept (Tan et al. 2013; Whang and Cha ng2014).

[0015] N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidinyl) 4-cyclopropyl-2-phenyl-5-fluoro-2-methylphenyl The compound is disclosed in International Publication No. 2015 / 079417 filed on June 4, 2015. This is listed in the pamphlet (Attorney Reference Number PAT056021-WO-PCT). This compound induces selective, potent, irreversible covalent binding of Bruton's tyrosine kinase (BTK). It is a synthetic inhibitor.

[0016] In the present invention, the present inventors have synthesized N-(3-(6-amino-5-(2-(N-methylamino) Acrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl )-4-Cyclopropyl-2-fluorobenzamide showed similar pathological characteristics compared to CSU. Basophil activation underlying the mechanism of inflammatory bowel disease was investigated in healthy volunteers and atopic patients. We demonstrated that this effectively inhibits CD63 upregulation, as measured by inhibition of CD63 upregulation. The inventors have discovered that N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) Pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropane 2-fluorobenzamide reduced wheal size in prick tests. This demonstrated that:

[0017] Therefore, the inventors have determined that the compound N-(3-(6-amino-5-(2-(N-methyl Acrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl 4-Cyclopropyl-2-fluorobenzamide, or a pharma- ceutically acceptable salt thereof We devised a medication regimen to treat patients with CSU using

[0018] definition For the purposes of interpreting this specification, the following definitions shall apply and terms used in the singular shall have the appropriate meaning. When a word is plural, it always includes the plural and vice versa.

[0019] The phrase "pharmacologically acceptable" as used herein means a compound that is acceptable according to good medical judgment. without undue toxicity, irritation, allergic responses, or other problems or complications. are suitable for use in contact with human and animal tissues and have reasonable benefit / risk This refers to compounds, materials, compositions and / or dosage forms that meet a cost ratio.

[0020] Any formulas given herein also represent unlabeled and isotopically labeled forms of the compounds. An isotopically labeled compound is one in which one or more atoms have a selected atomic mass or mass number. The compounds having the structure shown by the formulas set forth herein, except for the substitution of the atoms shown in the formula (I) with the atoms shown in the formula (I) are substituted with the atoms shown in the formula (I). Isotopes that can be incorporated into the compounds of the present disclosure include, for example, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, and 36 Cl, hydrogen, carbon, nitrogen, oxygen, fluorine The present disclosure therefore includes, for example, isotopes of 3 H and Beauty 14 Radioisotopes such as C, or 2 H and 13 Those with non-radioactive isotopes such as C isotopes, including compounds incorporating one or more of any of the aforementioned isotopes. It should be understood that such isotope-labeled compounds may be used in metabolic studies ( 14 C), reaction rate test Experience (e.g., 2 H or 3 H), including drug or substrate tissue distribution assays Neutron emission tomography (PET) or single photon emission computed tomography (SPE) CT) or in radiotherapy of patients. .especially, 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds can generally be prepared by conventional techniques known to those of skill in the art, e.g. Prepare the compound by substituting an appropriate isotopically labeled reagent for the unlabeled reagent previously used. It is possible.

[0021] As used herein, the term "pharmaceutical combination" refers to the administration of two or more active ingredients. As used herein, means a product resulting from the use or mixture or combination of: Pharmaceutical combinations include fixed and non-fixed combinations of active ingredients. It should be understood that the term "fixed combination" includes both Combination of one or more components, such as a compound of formula (I) or a pharma- ceutically acceptable salt thereof This means that the two partners are administered to a patient simultaneously as a single entity or dosage form. In such cases, the term refers to a single unit dosage form (e.g., capsule, tablet, or sachet). Refers to fixed-dose combinations. Also referred to as "non-fixed combinations" or "kits of parts." All terms refer to an active ingredient, e.g., a compound of the present disclosure and one or more combination parts. The ner and / or one or more auxiliary agents are administered to the patient simultaneously, in parallel, independently as separate entities. or sequentially or simultaneously without any specific time limit, The administration of these combination partners at different times, in particular at different time intervals, may be required to ensure that the combination partners have a synergistic effect, e.g., additive. When the compound is capable of exhibiting a therapeutically effective or synergistic effect in a patient, the compound is said to have a therapeutically effective effect in the patient. The term "non-fixed combination" also refers to cocktail therapy. This also applies to the administration of, for example, three or more active ingredients. The term "combination" refers to the use of the compounds described herein independently of one another, i.e. simultaneously or In particular, the administration, use, composition or formulation may be The term "non-fixed combination" also means one or more fixed combinations. The term includes the use of a single drug together with a single product, and each separate formulation is It should also be understood that the amounts of active ingredients may vary. and the term "unfixed combination" refers to combinations in which the combination partners are completely separate. Effectiveness when administered as pharmaceutical dosage forms or as pharmaceutical preparations marketed independently of each other It is to be understood that the term also encompasses components (including compounds described herein). Instructions for using unsuitable combinations are provided on the packaging, e.g. in a leaflet. or in other information provided to physicians and / or medical staff; In this case, a separate formulation or part of a formulation, product or composition may be provided, The administration can be simultaneous or chronologically staggered, i.e., the individual components of the kit of parts. Parts may be mixed at different times and / or in equal quantities for any part in a kit of parts. In particular, the time intervals for administration may be set at the same or different time intervals. The effect on the disease treated by the combined use of the compound of formula (I) or its pharmaceutical composition is The effect is selected to be greater than that obtained by using only a commercially acceptable salt, Thus, the compounds used in the pharmaceutical combinations described herein are both active The compound of formula (I) or The ratio of the total amount of the pharma- ceutically acceptable salts may vary depending on the needs of the particular patient subpopulation being treated or on the individual. Depending on the patient's needs (these needs may be due, for example, to the patient's age, sex, weight, etc.) The parameters can be changed or adjusted to better suit the application.

[0022] The terms "co-administration" or "combined administration" and the like, as used herein, one or more compounds described herein, together with a selected combination partner, It is meant to encompass administration to a single subject (e.g., a patient or subject) in need thereof. and the compounds are not necessarily administered by the same route and / or at the same time. This includes treatment regimens that are not

[0023] The term "pharmaceutical composition" as used herein refers to an administration to a warm-blooded animal, such as a mammal or a human, A small amount of the compound administered to prevent or treat a particular disease or condition affecting the warm-blooded animal. A mixture (e.g., a solution or emulsion) containing at least one active ingredient or therapeutic agent. It is defined as referring to the following.

[0024] The compounds of the present disclosure (i.e., compounds of formula (I) or pharma- ceutically acceptable salts thereof) are The term "therapeutically effective amount" refers to a therapeutically effective amount that is effective to induce a biological or medical response in a subject (subject patient), such as an enzyme or or induce a decrease or inhibition of protein activity, or improve symptoms or alleviate pathological conditions. , an amount of a compound of the present disclosure that delays or slows the progression of a disease, or prevents a disease, etc. The therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof will depend on the type of patient. , weight, age, sex, and the particular condition, disorder or disease, or the severity thereof, for which treatment is being received. A physician, clinician or veterinarian of ordinary skill may determine whether or not to prevent or treat the progression of a disorder or disease. The effective amount of each of the active ingredients required to treat or inhibit can be readily determined. do.

[0025] The frequency of dosing may vary depending on the compound used and the particular condition being treated or prevented. In general, the use of the smallest dosage sufficient to provide effective treatment is preferred. The effectiveness of the treatment may then be monitored using an assay appropriate for the condition being treated or prevented. This will be well known to those skilled in the art.

[0026] As used herein, the term "carrier" or "pharmaceutically acceptable carrier" includes any term known in the art. Any and all solvents, dispersion media, coatings, surfactants, etc. known to the art. , antioxidants, preservatives (e.g., antibacterial, antifungal), isotonicity agents, absorption delaying agents, salts, Preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, colorants, etc. and combinations thereof (e.g., Remington's Pharm aceutical Sciences,18th Ed.Mack Printing (See Company, 1990, pp. 1289-1329). Any conventional carrier may be Unless incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. can be obtained.

[0027] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. The subject may be, for example, a primate (e.g., a human (male or female)), cow, sheep, goat, horse, , 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, it is used interchangeably with "patient."

[0028] As used herein, a subject is "in need of" a treatment if such subject is In some cases, a patient would benefit biologically, medically, or in quality of life from such treatment.

[0029] As used herein, the phrase "patient population" means a group of patients. Used for.

[0030] The term "comprising" includes the words "including" and "common." and "consisting of" are included, for example, "comprising" X. The "rising" composition may consist exclusively of X or may have some additional It may include (e.g., X+Y).

[0031] The term "about" in relation to a numerical value x means, for example, + / - 10%. When used before a list of values, the term "about" applies to each value in turn, e.g. For example, the phrase "about 1 to 5" should be interpreted as "about 1 to about 5", or, for example, "about 1, The phrase "2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc."

[0032] The term "treatment" or "treating" as used herein refers to the administration of a compound according to the present disclosure (Formula (I) or a pharma- ceutical composition comprising said compound. This is defined as the application or administration to an animal or tissue or cell line isolated from a subject. In this regard, the subject is a patient having a particular disease (e.g., CSU), a symptom associated with the disease (e.g., CSU), or a predisposition to developing a disease (e.g., CSU) (where applicable), and the purpose of this is to Cure (where applicable), delay in onset, reduction in severity, relief, or amelioration of one or more symptoms of the disease, The term "improvement of the disease, reduction or amelioration of any symptoms associated with the disease, or predisposition to the occurrence of the disease." The term "treatment" or "treating" refers to a patient suspected of having a disease, as well as a patient or includes treating a patient diagnosed with a disease or medical condition, and Including inhibition of clinical recurrence.

[0033] As used herein, "not previously treated with systemic therapy for CSU" Or the term "naive" refers to the use of systemic agents for CSU, e.g., cyclosporine A, mofetil, Intelkast, cyclosporine, H1-antihistamines (H1-AH), H2-antihistamines Anti-inflammatory drugs (H2-AH), leukotriene receptor antagonists (LTRA), biological agents (e.g. This refers to patients with CSU who have not been previously treated with systemic agents (e.g., omalizumab). (i.e., drugs administered orally, by injection, etc.) are administered when a systemic drug is delivered to a patient. in that it has a systemic (whole body) effect on Different from topical agents (e.g., external agents and phototherapy agents). In some embodiments of the kits and pharmaceutical compositions, the patient has previously received a systemic therapeutic agent for the CSU. Never been administered.

[0034] As used herein, "previously treated with a systemic agent for CSU" The term refers to patients who have previously been treated with CSU using systemic agents. For such patients, H1-antihistamines or drugs such as omalizumab are used. Patients previously treated with biologics such as cyclosporine and patients previously treated with non-biologics such as cyclosporine In some embodiments of the present disclosure, the patient is a patient receiving systemic medication for CSU. In some embodiments, the patient has previously received a systemic anti-inflammatory drug (CSU). Patients were previously treated with medications (e.g., cyclosporine) but were not prescribed Systemic biologics (i.e., drugs produced by living organisms, e.g., antibodies, receptor decoys) In this case, the patient has not received a biologic In some embodiments, the patient is referred to as "biological agent naive."

[0035] As used herein, the terms "select" and "selected" in reference to a patient are used interchangeably herein. A patient population based on (or resulting from) a specific patient with defined criteria. Similarly, the term "selective" is used to mean that certain patients are specifically selected. "Treating a patient to a specific disease" refers to providing treatment to a patient who has a specific disease, Specifically selected from a larger patient population based on specific patients with defined criteria Similarly, "selective administration" refers to the selective administration of a drug to specific patients who meet predetermined criteria. Administering drugs to specifically selected patients from a larger patient population "Selecting," "selectively treating," and "selectively administering" refer to Providing a standard treatment regimen based solely on a patient's membership in a larger group Rather than relying on the individual patient history (e.g., previous therapeutic interventions, e.g., previous treatment with biologics), treatment), biological factors (e.g., certain genetic markers) and / or symptoms (e.g., certain This means providing individualized treatment to patients based on their condition (i.e., those who do not meet diagnostic criteria). As used in the specification, selection in relation to a treatment method refers to the occurrence of patients who meet certain criteria. It does not refer to emergent treatment, but rather to providing treatment to patients based on the patient meeting certain criteria. Therefore, selective treatment / administration is based on personal history, disease symptoms and / or outcome. A standardized approach to deliver a specific drug to all patients with a specific disease, regardless of biochemical factors. In some embodiments, a patient is treated / administered based on having a CSU. A treatment is selected.

[0036] EMBODIMENTS OF THE PRESENTINVENTION Chronic urticaria and the efficacy of treatment according to the present invention The disclosed BTK inhibitors, i.e., compounds of formula (I) or pharma- ceutically acceptable salts thereof, It may be used in vitro, ex vivo, or incorporated into a pharmaceutical composition to treat CSU patients. The compounds may be administered in vivo to treat a subject (eg, a human patient).

[0037] Urticaria is a heterogeneous group of disorders characterized by itchy hives and / or angioedema.

[0038] Chronic urticaria is defined as urticaria that occurs continuously or intermittently for more than 6 weeks (Ma Bernstein et al 2013, Bernstein et al 2014). chronic Urticaria is further divided into two subgroups: chronic spontaneous urticaria (CSU) and Chronic irritant-induced urticaria (IU). The latter includes heat urticaria, cold urticaria, and pressure urticaria. It includes specific subtypes such as rational urticaria and cholinergic urticaria. CSU may be either known or unknown. Spontaneous onset of itchy wheals, angioedema, or both for 6 weeks or more depending on cause (Zuberbier, et al 2018). Combinations of CSU and irritant-induced urticaria, such as symptomatic dermatographic urticaria and CSU, have been reported. Sometimes both are combined.

[0039] The efficacy of CSU treatment was evaluated using a variety of established methods that measure CSU disease status and / or CSU clinical response. The assessment is carried out using known methods and tools, such as the Urticaria Patient Diary (UPD). DD), Angioedema Activity Score (AAS), Weekly Urticaria Severity Score (HSS7), Weekly Pruritus Severity Score (ISS7), Weekly Urticaria Activity Score (UAS7), and Dermatological QOL evaluation index (Dermatology Life Quality Index) Improvement in health-related quality of life (HLQI) is one of the most important outcomes.

[0040] Urticaria patient diary (UPDD) The UPDD includes a urticaria activity score (UAS), which assesses the severity of pruritus and the number of hives twice daily. AS), use of rescue medications, sleep and activity disturbances, occurrence of angioedema, its management, medical care Includes records of calls to HCPs. The components are shown in Table 1 and the associated weekly scores are given below.

[0041] [Table 1]

[0042] In some embodiments, when a population of CSU patients is treated according to the methods of the present disclosure, The patient's UPDD score improves.

[0043] Weekly Urticaria Severity Score (HSS7) The urticaria (wheal) severity score was defined by the number of hives and ranged from 0 (none) to 3 (one Subjects were asked to record their weekly scores twice daily in an electronic diary on a scale of >2 hives / 12 hours (Table 2). Core (HSS7) is calculated by adding the average daily scores for the 7 days prior to the visit. The possible range for weekly scores is 0-21.

[0044] [Table 2]

[0045] In some embodiments, when a population of CSU patients is treated according to the methods of the present disclosure, The urticaria severity score (HSS7) improved by at least 5 points. When compared with the placebo group, the difference between the treatment group and the placebo group should be at least 4 points, preferably At least 5 points. In one embodiment, the patient is treated according to the methods of the present disclosure. In this case, the urticaria severity score (HSS7) is less than 6, preferably less than 4, preferably less than 2. , most preferably the HSS7 score is 0.

[0046] Weekly pruritus severity score (ISS7) The severity of pruritus was assessed on a scale from 0 (none) to 3 (severe) (Table 3) and subjects were asked to enter daily scores in an electronic diary. The weekly score (ISS7) is calculated by adding the average daily scores for the 7 days prior to the visit. Therefore, the possible range of weekly scores is 0-21.

[0047] [Table 3]

[0048] In some embodiments, when a population of CSU patients is treated according to the methods of the present disclosure, The pruritus severity score (ISS7) improved by at least 5 points. When compared, the difference between the treatment and placebo groups should be at least 4 points, preferably less than 10 points. In one embodiment, when a patient is treated according to the methods of the present disclosure, In this case, the pruritus severity score (HSS7) is less than 6, preferably less than 4, preferably less than 2, and most preferably Most preferably, the ISS7 score is 0.

[0049] Weekly Urticaria Activity Score (UAS7) The UAS7 is the sum of the HSS7 and ISS7 scores. The possible range of weekly UAS7 scores is 0 to 42 (highest activity). In some embodiments, the CSU patient is administered a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In response to treatment with a salt of the same invention, improvement of UAS7 is achieved. In a preferred embodiment, a CSU patient, when treated with the method of the present invention, has a 5-fold improvement in schizophrenia by week 4. or a reduction in urticaria and pruritus, characterized by UAS7≦6 by week 12. In a most preferred embodiment, a CSU patient, when treated with the methods of the present invention, By the end of the study, there was complete resolution of urticaria and pruritus, as assessed by UAS7=0. Furthermore, when compared with the placebo group, the difference between the treatment group and the placebo group was at least 8 points, preferably at least 10 points.

[0050] Weekly sleep disturbance score Sleep disturbance is assessed by subjects once daily in the morning in an electronic diary. The weekly scores are scored on a scale of 0 to 3. The range of weekly scores is 0 to 21 (Table 4).

[0051] [Table 4]

[0052] In some embodiments, when a population of CSU patients is treated according to the methods of the present disclosure, The sleep disturbance score improves by at least 5 points. When treated according to the method of the present invention, the sleep disturbance score is less than 6, preferably less than 4, preferably less than 2, and most preferably a sleep disturbance score of 0.

[0053] Weekly Activity Disruption Score Activity interference was rated by subjects once a day in the evening on a scale of 0 to 3 in an electronic diary. Daily activities include work, school, sports, hobbies, and activities with friends and family. Weekly activity interference scores range from 0 to 21 (Table 5).

[0054] [Table 5]

[0055] In some embodiments, when a population of CSU patients is treated according to the methods of the present disclosure, The activity interference score improves by at least 5 points. When treated according to the method of the present invention, the weekly activity interference score is less than 6, preferably less than 4, or less than 2, and most preferably a weekly interference score of 0.

[0056] Use of H1-antihistamine rescue medication Use of Lesquisol in the past 24 hours to control conditions such as pruritus or hives The number of rescue medication pills taken per day was recorded by the subjects in an electronic diary once a day at night. The dose was calculated as the number of tablets per day x the dose of each tablet, then multiplied by the number of tablets per day for 7 days. The weekly dose of rescue medication is calculated as the sum of the doses of each of the above. In some embodiments, when a population of CSU patients is treated according to the methods of the present disclosure, The dose or number of rescue medications per week is reduced. The use of cue medication is no longer necessary.

[0057] Number of calls to doctors or nurses Number of calls to physicians, nurses, or nurse practitioners due to subject skin condition is to be recorded by subjects once per day in an electronic diary.

[0058] Angioedema Activity Score (AAS) The AAS is recorded by subjects once daily in the evening in an electronic diary. This validated tool This study evaluates the occurrence and severity of chronic edema (Weller et al. (2013) The incidence of angioedema was 1.1% in subjects who received 100 mg of These angioedema episodes were recorded in an electronic diary once a day. Please also record the following in your electronic diary (multiple answers possible): Did nothing Taking prescription or over-the-counter medications Called your doctor, nurse, or nurse practitioner Visited a doctor, nurse, or nurse practitioner I went to the hospital emergency room. Hospitalized

[0059] If the subject answers the opening question with "no," the AAS score for that day is 0. If the answer to question 1 is "yes," the subject will be asked to provide a summary of the duration, severity, and impact on daily functioning, as well as The patient then answers questions about the appearance of the angioedema and the severity of the pain. All questions are scored on a 0–3 scale. The AAS score for this study is reported as the weekly AAS (AAS7). The possible minimum and maximum AAS7 scores range from 0 to 105. A higher score indicates greater severity. In some embodiments, when a population of CSU patients is treated according to the methods of the present disclosure, The patient's AAS7 score will decrease by week 12, preferably to an AAS7 score of 0. In another aspect of this embodiment, the patient is treated with the treatment for several weeks, e.g., for at least 4 weeks. for at least 8 weeks of treatment or for the full 12 weeks of treatment Achieve an AAS7 score of zero over the period. In some embodiments, when a population of CSU patients is treated according to the methods of the present disclosure, Patients were expected to have ≥95.5% angioedema-free days (AAS=0) from weeks 4 to 12. Furthermore, when compared with the placebo group, the difference between the treatment group and the placebo group is at least The rate is 6%.

[0060] Dermatology-related Quality of Life Index (DLQI) The Dermatology-Related Quality of Life Index (DLQI) is a skin disease-specific quality of life (QoL) scale. (Finlay et al 1994). Subjects were asked about their skin symptoms and the impact of their skin condition on various aspects of their lives over the past 7 days. Rate the following. A total score was calculated and scaled from 0 to 30 (higher scores indicate worse disease-related QoL). Domain scores are calculated for: symptoms and sensations (0–6); Daily activities (0-6), leisure (0-6), work and school (0-3), relationships (0-6) ), and treatment (0–3). The overall DLQI score range was divided into score bands (Hongbo et al 2005), and in terms of meaning / relevance to patients, the following were identified:

[0061] [Table 6]

[0062] A DLQI score above 10 is associated with a very significant impact on the patient's life. For example, this is relevant to the justification of biologic prescriptions in psoriasis (Kaplan et al. The DLQI questionnaire was administered at randomization (day 1), week 4 (day 29) and 12 The DLQI is completed on week 85 (day 85). The DLQI is completed before any other assessment and after administration of the compound of formula (I) or should be completed prior to administration of the pharma- ceutical salt thereof.

[0063] In some embodiments, the CSU patient is administered a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, an improvement in DLQI is achieved in response to treatment with a salt of the CSU. Patients will achieve a DLQI score of 0 or 1 at week 4 or 12 of treatment.

[0064] Chronic urticaria index (CU index) CU-Index® is a commercially available in vitro basophil histamine release assay. Patient serum is mixed with donor basophils and the levels of released histamine are quantitatively assayed using an enzymatic assay. A CU-Index value of 10 or greater indicates that the patient has a disease. The autoimmune basis of the disease (autoantibodies against IgE, FcεRI, or anti-FcεRII; positive results The results do not indicate which autoantibody is involved, or alternative histamine releasing factor. (Biagtan MJ, Viswanathan RK, Evans MD, et al(2011)Clinical utility of the Chronic Urticaria Index.J Allergy Clin Immunol;1 27(6):1626-7).

[0065] In some embodiments, a CSU patient is administered a compound of formula (I) or a pharma- ceutical acceptable salt thereof. In response to treatment with salt, CSU pathogenesis-related antibodies (e.g., IgE, FcεRI, or anti-F They experience a decrease in the titer of autoantibodies against cεRII.

[0066] In another embodiment, the CSU patient is treated with a compound of formula (I) or a pharma- ceutical acceptable salt thereof. In response to treatment with CS, the patient experiences a decrease in the CU index value. U patients experience a reduction in the CU index to less than 10 at week 4 or week 12 of treatment.

[0067] In some embodiments, the patient is treated with at least 4 weeks, at least 12 weeks, at least 16 weeks, at least 48 weeks, or at least 2 years Receive CSU treatment according to the method.

[0068] In a preferred embodiment, the patient is receiving conventional systemic CSU therapy (e.g., second generation H1-antihistamines). Previously had an inadequate response to anti-inflammatory drugs (anti-inflammatory drugs).

[0069] In another preferred embodiment, the patient is an adult patient (18 years of age or older) with moderate to severe CSU. Moderate to severe CSU is defined as a 7-day urticaria activity score (UAS7) of Patients were defined as those with a urticaria severity score of 16 or higher and / or a 7-day urticaria severity score (HSS7) of 8 or higher. It is justified.

[0070] In some embodiments, the patient responds to treatment with the claimed methods. Participants were assessed for schizophrenia at 4 weeks after first dose or after first dose as measured by UAS7 scoring. At 12 weeks, patients experience a rapid reduction in urticaria pruritus. Experience a reduction in urticaria and pruritus with a UAS7 score of 6 or less at week 4 or week 12 In the most preferred embodiment, patients experience complete resolution of urticaria and pruritus at 4 weeks or 12 weeks. experience a loss (UAS7=0).

[0071] In some embodiments, the patient responds to treatment with the claimed methods. Participants were assessed for schizophrenia within 4 weeks of first treatment or within 2 weeks of first treatment, as measured by AAS7 scoring. After 12 weeks from administration of the compound, the patient experiences a rapid reduction in the frequency and severity of angioedema. Patients should experience complete resolution of angioedema for at least 8 weeks of the 12-week treatment. (This is measured as an AAS7 score of zero for at least 8 weeks of the 12-week treatment. In a preferred embodiment, patients experience complete relief of angioedema over the entire treatment period. experience a complete disappearance of symptoms (as measured by an AAS7 score of zero for 12 weeks). can be).

[0072] In some embodiments, the patient responds to treatment with the claimed methods. Patients were found to have CSU pathogenesis-related antibodies (autoantibodies against IgE, FcεRI, or anti-FcεRII). experience a decrease in titer and / or a decrease in CU index value to less than 10.

[0073] Pharmaceutical Compositions The BTK inhibitor, i.e., the compound of formula (I) or a pharma- ceutically acceptable salt thereof, is When combined with an acceptable carrier, it can be used as a pharmaceutical composition. Such compositions may contain, in addition to the compound of formula (I) or a pharma- ceutically acceptable salt thereof, a carrier, various Diluents, fillers, salts, buffers, stabilizers, solubilizers, and other agents known in the art. The characteristics of the carrier will depend on the route of administration. The compositions may also contain additional therapeutic agents for the treatment of a particular targeted disorder. The pharmaceutical composition may also include an anti-inflammatory or anti-pruritic agent. The agent is used to produce a synergistic effect with the compound of formula (I) or a pharma- ceutically acceptable salt thereof. or a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In order to minimize the risk of side effects, the method of the present disclosure may be included in a pharmaceutical composition. The pharmaceutical composition for use in the present invention comprises a compound of formula (I) or a pharma- ceutical acceptable salt thereof, Contains about 5 mg, about 10 mg, about 20 mg, about 25 mg, about 50 mg, or about 100 mg nothing.

[0074] Compositions suitable for oral administration include tablets, lozenges, aqueous or topical formulations each containing an effective amount of a compound of the present invention. or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or Compositions intended for oral use include pharmaceutical compositions in the form of syrups or elixirs. The composition may be prepared according to any method known in the art for producing such products, and Such compositions may contain sweetening agents, flavoring agents, and / or other additives to provide a pharma- ceutically elegant and palatable preparation. It may contain one or more agents selected from the group consisting of agents, colorants and preservatives. Tablets are prepared by mixing the active ingredient with non-toxic pharma- ceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be, for example, calcium carbonate, sodium carbonate, lauryl sulfate, etc. inert diluents such as lactose, calcium phosphate or sodium phosphate; granules and disintegrants Disintegrants, such as corn starch, or alginic acid; binders, such as starch, gelatin, etc. tin or acacia; and lubricants such as magnesium stearate, stearic acid or The tablets are uncoated or coated to aid in disintegration and absorption in the gastrointestinal tract. The present invention provides a method for the preparation of a pharmaceutical composition comprising the steps of: For example, glyceryl monostearate or glyceryl distearate A time delay material such as lysyl can be used. Formulations for oral use may contain Mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin or as a hard gelatin capsule containing the active ingredient in water or an oil medium, e.g. Soft gelatin capsules mixed with nut oil, liquid paraffin or olive oil; It may also be provided.

[0075] The pharmaceutical compositions used in the methods of the present disclosure may be prepared in a conventional manner. The pharmaceutical composition is provided for oral administration. For example, the pharmaceutical composition may be administered in combination with A tablet or gelatin capsule containing the active ingredient: 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. salts, and / or polyethylene glycol; for tablets, c) Binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanthus Cant, methylcellulose, sodium carboxymethylcellulose, and / or polyvinyl chloride dipyrrolidone; as required d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescents. Gender Mixture; and / or e) Absorbents, colouring agents, flavouring agents and sweeteners. Tablets may be film coated or enteric coated by methods known in the art. It may be tinged.

[0076] combination: In practicing some of the methods of treatment or use of the present disclosure, a therapeutically effective amount of a compound of formula (I) is The compound or a pharma- ceutically acceptable salt thereof is administered to a patient, e.g., a mammal (e.g., a human). The disclosed method comprises treating a CSU patient with a compound of formula (I) or a pharma- ceutical acceptable salt thereof. It is understood that the purpose of the present invention is to provide treatment for patients with a variety of conditions, but that treatment is not necessarily a monotherapy. Indeed, it is not possible for a patient to receive treatment with a compound of formula (I) or a pharma- ceutical acceptable salt thereof. Regardless of which is selected, compounds of formula (I) may be used alone or in combination with other compounds to treat CSU patients according to the methods of the present disclosure. In combination with other drugs and therapies for treating the pulmonary circulation, e.g., at least one additional CS When co-administered with one or more additional CSU drugs, The compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered simultaneously or sequentially with other drugs. When administered sequentially, the attending physician may determine whether the compound of formula (I) in combination with the other drug is effective. The appropriate sequence of administration of the I) compounds, and appropriate dosages for co-delivery, will be determined.

[0077] In treating CSU, various therapies may be advantageously combined with compounds of formula (I) of the present disclosure. Such treatments include topical treatments (creams [non-steroidal or steroidal [medication, cleaning agents, disinfectants], systemic treatments (e.g., biological agents, antibiotics, or chemicals) ), and antiseptics, photodynamic therapy, and surgical intervention (laser, drainage or incision, excision) ) are included.

[0078] Topical use with the disclosed compounds of formula (I) or pharma- ceutically acceptable salts thereof Non-limiting examples of CSU agents include benzoyl peroxide, topical steroid creams, cleansing creams, and topical steroids. Topical antibiotics of the aminoglycoside group, such as damycin, gentamicin, and erythromycin Substances include resorcinol cream, iodine scrub, and chlorhexidine.

[0079] Systemic Use with the Disclosed Compounds of Formula (I) or Pharmaceutically Acceptable Salts Thereof Non-limiting examples of CSU drugs used in treatment include IgE antagonists (omalizumab), Examples of anti-cancer drugs include rivaroxaban and ligelizumab.

[0080] Further compounds for use in combination with the disclosed compounds of formula (I) in the treatment of CSU are disclosed herein. CSU drugs include cyclosporine and corticosteroids (injectable or oral). Some examples include:

[0081] The above C, co-delivered with the disclosed compound of formula (I) or a pharma- ceutically acceptable salt thereof. Appropriate dosages of SU agents will be known to those of skill in the art.

[0082] Kit of the invention: The present invention also provides a kit for treating CSU. Such a kit includes In one embodiment, the kit comprises a K inhibitor, such as a compound of formula (I) or a pharmaceutical composition thereof. comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) or and a pharma- ceutically acceptable salt thereof. In one embodiment, the kit comprises a container, a divided It includes a means for keeping the compositions separate, such as a bottle or a divided foil pouch. Examples of such kits include those commonly used for packaging tablets, capsules, etc. There is a lister pack.

[0083] The kits of the present disclosure may be packaged in separate compositions for administration in different dosage forms, e.g., oral and parenteral. To administer the compositions at different dosage intervals or to titrate separate compositions relative to each other. To aid in compliance, the kits of the present disclosure typically include instructions for administration. Includes.

[0084] In the combination therapy of the present invention, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and other CSU drugs (as defined herein) may be manufactured by the same or different manufacturers. Further, the compound of formula (I) or a pharma- ceutical acceptable salt thereof may be prepared and / or formulated. The acceptable salts and other CSU drugs should be (i) tested prior to providing the combination product to the physician (e.g., A kit comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and another CSU agent. (ii) by a physician (or under the guidance of a physician) immediately before administration; (iii) by a patient For example, the compound of formula (I) or a pharma- ceutical acceptable salt thereof and other C While the SU agents are administered sequentially, they can be combined into a combination therapy.

[0085] Additional Embodiments The compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered at a dose of about 10 mg to about 200 mg per day. It is conveniently administered to the patient (preferably orally) in dosages.

[0086] The compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered at a dose of about 10 mg to about 200 mg per day. It is conveniently administered to the patient, preferably orally, in a daily dosage.

[0087] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 It is administered in a daily dose of between 100 mg and about 100 mg.

[0088] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 mg, about 20 mg, about 25 mg, about 35 mg, about 50 mg, about 100 mg or about 200 mg It is administered in a daily dose of g.

[0089] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of about 100 mg. is administered at a daily dose of

[0090] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of about 50 mg. It is administered in a daily dose.

[0091] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of about 35 mg. It is administered in a daily dose.

[0092] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of about 25 mg. It is administered in a daily dose.

[0093] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of about 20 mg. It is administered in a daily dose.

[0094] In one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 mg. , about 35 mg, about 50 mg, or about 100 mg administered once daily.

[0095] In one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 mg. , about 25 mg, about 50 mg, or about 100 mg administered twice daily.

[0096] For certain patients, e.g., for treatment with a compound of formula (I) or a pharma- ceutically acceptable salt thereof Inadequate response (e.g., a C-cell inhibitor as disclosed herein) by week 4 or week 12 of treatment Any of the SU scoring systems, e.g. the method according to any of the claims above. Thus, the patient is administered a method to achieve sustained response (including reduction in severity of urticaria and pruritus) as measured by adequate response. It is measured by the severity score UAS7) and the Dermatology-Related Quality of Life Index (DLQI), etc. It will be appreciated that CSU patients who demonstrate patients, e.g., those who are adversely affected by treatment with a compound of formula (I) or a pharma- ceutical acceptable salt thereof. It will also be appreciated that dose reductions may be necessary for CSU patients who experience events or adverse reactions. Thus, the dosage of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is about 10 mg. , about 20 mg, about 25 mg, about 50 mg, or less than about 100 mg.

[0097] The timing of administration is determined based on the day of the first administration of the compound of formula (I) or a pharma- ceutical acceptable salt thereof ( The timing of administration is generally determined by the formula (also known as the "baseline"). The date of first administration of compound I) or a pharma- ceutically acceptable salt thereof (also known as the “baseline”) It is generally judged from the

[0098] However, healthcare providers may 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 merely for consistency. Those skilled in the art will appreciate that this should not be construed as limiting. Administration refers to administration of a daily dose of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. A physician may refer to a particular day as "day 0" or "day 1."

[0099] Provided herein is a method for treating chronic spontaneous urticaria (CSU), comprising administering to a patient a A patient in need thereof is administered about 10 mg to about 2 mg of the compound of formula (I) or a pharma- ceutical acceptable salt thereof. The method includes administering a dose of 0.00 mg.

[0100] Provided herein is a method for treating chronic spontaneous urticaria (CSU), comprising administering to a patient a A patient in need thereof is administered about 10 mg to about 2 mg of the compound of formula (I) or a pharma- ceutical acceptable salt thereof. The method includes administering a daily dose of 0.00 mg to the subject.

[0101] Also provided herein is a compound of formula (I) or therefor for use in the treatment of CSU. and the daily dose of the compound is about 10 mg to about 200 mg. Disclose something.

[0102] In one embodiment of the methods, uses and kits of the disclosure, a compound of formula (I) or a pharma- ceutical thereof is Acceptable salts are administered in a daily dosage of about 10 mg to about 100 mg.

[0103] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical Acceptable salts for the above range are about 10 mg, about 20 mg, about 25 mg, about 35 mg, about 50 mg, about It is administered in a daily dose of 100 mg or about 200 mg.

[0104] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical Acceptable salts are administered in a daily dose of about 100 mg.

[0105] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical Acceptable salts are administered in a daily dose of about 50 mg.

[0106] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical An acceptable salt for is administered in a daily dose of about 35 mg.

[0107] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical An acceptable salt for is administered in a daily dose of about 25 mg.

[0108] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical An acceptable salt for is administered in a daily dose of about 20 mg.

[0109] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical Acceptable salts are administered at doses of about 10 mg, about 35 mg, about 50 mg, or about 100 mg per day. It is administered once.

[0110] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical Acceptable salts are administered at doses of about 10 mg, about 25 mg, about 50 mg, or about 100 mg per day. It is given in two doses.

[0111] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical Prior to treatment with a commonly tolerated salt, the patient had already been treated with a systemic CSU agent. In one aspect of this embodiment, the systemic agent is an H1-antihistamine (H1-AH), 2-Antihistamines (H2-AH), and leukotriene receptor antagonists (LTRAs), and combinations thereof.

[0112] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical Prior to treatment with the commonly accepted salt, the patient had not been treated with a systemic agent for CSU.

[0113] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical Prior to treatment with a commercially acceptable salt, the patient had moderate to severe CSU, i.e. Participants had a UAS7 score of 16 or greater and / or an HSS7 score of 8 or greater.

[0114] In another embodiment of the methods, uses, and kits of the present disclosure, a compound of formula (I) or a pharmaceutical composition thereof is Prior to treatment with a commercially acceptable salt, patients were screened for the autoimmune basis of their disease (IgE, Fc εRI, or autoantibodies against anti-FcεRII) or alternative histamine releasing factor.

[0115] In another embodiment of the methods, uses and kits of the present disclosure, a compound of formula (I) or a pharmaceutical Prior to treatment with a salt acceptable for this purpose, the patient has a CU index of 10 or greater. In certain embodiments, patients experience a reduction in CU index to less than 10 by week 4 or week 12 of treatment. do.

[0116] In another embodiment of the methods, uses and kits of the present disclosure, the patient meets at least one of the following criteria: Selected according to: a) Prior to treatment with a compound of formula (I) or a pharma- ceutical acceptable salt thereof, the patient is 16 or more years of age have a UAS7 score of; b) Prior to treatment with a compound of formula (I) or a pharma- ceutical acceptable salt thereof, the patient has 8 or more Has an HSS7 score.

[0117] In another embodiment of the methods, uses, and kits of the present disclosure, the patient is an adult.

[0118] In another embodiment of the methods, uses and kits of the present disclosure, the patient is By then, achieve at least one of the following: a) Reduction in urticaria and pruritus as judged by UAS≦6, or complete disappearance of urticaria and pruritus ( UAS7=0); b) Dermatology-related Quality of Life Index (DLQI) = 0–1; c) Absence of angioedema as determined by an Angioedema Activity Score (AAS7) of zero.

[0119] In another embodiment of the methods, uses and kits of the present disclosure, the patient is administered 4 weeks after completion of treatment: Complete urticaria and pruritus response ([UAS7]=0) and / or dermatology-related quality of life index Determined by (DLQI) = 0-1 and / or continued resolution of angioedema (AAS7 = 0) The objective of the present invention is to achieve a sustained response.

[0120] ENUMBERATION OF FURTHER EMBODIMENTS 1. A method for treating chronic spontaneous urticaria (CSU), comprising administering to a subject in need thereof: About 10 mg to about 200 mg of N-(3-(6-amino-5-(2-(N-methylacrylamide Amido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4 - a daily dose of cyclopropyl-2-fluorobenzamide or a pharma- ceutically acceptable salt thereof Administering 2. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 The daily dose of fluorobenzamide or a pharma- ceutical acceptable salt thereof is about 10 mg to about 10 2. The method of embodiment 1, wherein the dose is 0 mg. 3. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -The daily dose of fluorobenzamide or a pharma- ceutically acceptable salt thereof is about 100 mg. 2. The method according to embodiment 1. 4. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - the daily dose of fluorobenzamide or a pharma- ceutically acceptable salt thereof is about 50 mg; 2. The method of embodiment 1. 5. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - the daily dose of fluorobenzamide or a pharma- ceutically acceptable salt thereof is about 35 mg; 2. The method of embodiment 1. 6. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - the daily dose of fluorobenzamide or a pharma- ceutically acceptable salt thereof is about 25 mg; 2. The method of embodiment 1. 7. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 - the daily dose of fluorobenzamide or a pharma- ceutically acceptable salt thereof is about 20 mg; 2. The method of embodiment 1. 8. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide or a pharma- ceutically acceptable salt thereof is about 10 mg, about 35 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-methylacrylamide)ethoxy)pyridine Rimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2 -fluorobenzamide or a pharma- ceutically acceptable salt thereof is about 10 mg, about 25 mg, about 2. The method of embodiment 1, wherein the compound is administered at a dose of 50 mg or about 100 mg twice daily. 10. Prior to treatment, the subject has previously been treated with a systemic agent for CSU, as described above. 2. The method according to any one of embodiments. 11. Systemic drugs include H1-antihistamines (H1-AH), H2-antihistamines ( H2-AH), and leukotriene receptor antagonists (LTRAs), and combinations thereof 11. The method of embodiment 10, wherein the antibody is selected from the group consisting of: 12. Prior to treatment, subjects have not previously been treated with systemic agents for CSU. 10. The method according to any one of aspects 1 to 9. 13. The method of any one of the above embodiments, wherein the subject has moderate to severe CSU. method. 14. The subject is selected according to at least one of the following criteria: 13. Method 1: a) Prior to treatment with a compound of formula (I) or a pharma- ceutical acceptable salt thereof, the subject is 16 or more years of age have a UAS7 score of; b) Prior to treatment with a compound of formula (I) or a pharma- ceutical acceptable salt thereof, the subject has 8 or more Has an HSS7 score. 15. A method according to any one of the above embodiments, wherein the subject is an adult. 16. The subject will have at least one of the following by week 4 or week 12 of treatment: A method according to any one of the above embodiments, which achieves: a) Reduction in urticaria and pruritus as judged by UAS ≦6, or complete disappearance of urticaria and pruritus Missing (UAS7=0); or b) Dermatology-related Quality of Life Index (DLQI) = 0–1; c) Absence of angioedema as determined by an Angioedema Activity Score (AAS7) of zero. 17. The subject has a complete urticaria and pruritus response ([UAS7 ]=0) and / or Dermatology-Related Quality of Life Index (DLQI)=0-1 and / or vasodilatory The above embodiment achieves a sustained response as determined by continued disappearance of tumors (AAS7=0). The method according to any one of the aspects. 18. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- The 2-fluorobenzamide or a pharma- ceutical acceptable salt thereof is incorporated into a pharmaceutical preparation, The method of any one of the above embodiments, wherein the pharmaceutical formulation further comprises a pharma- ceutically acceptable carrier. Law. 19. N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl- 2-Fluorobenzamide or a pharma- ceutically acceptable salt thereof has a T of about 0.5 to 3 hours. max 19. The method according to any one of embodiments 1 to 18, comprising:

[0121] Abbreviation AE side effects Area under the AUC curve AUCinf: Plasma (or serum or blood) concentration-time curve from time zero to infinity Area under (mass x time / volume) AUClast Plasma (or serum or blood) concentration from time zero to the last measurable time point Area under the degree-time curve (mass x time / volume) AUCtau: The amount of plasma (or serum or blood) ) Area under the concentration-time curve (mass x time / volume) Bid twice a day BMI Body Mass Index Apparent total body (or total body) clearance from plasma (or serum or blood) after administration of CL / F Alignment (mass / volume) Cmax The maximum concentration after drug administration CSU Chronic spontaneous urticaria ECG Electrocardiogram Emax Maximum change in effect compared to placebo FcγR Fc gamma receptor FcεR Fc alpha receptor MRT average residence time PK Pharmacokinetics PD Pharmacodynamics PRO Patient-reported outcomes QoL Quality of Life qd once a day QTcF QT interval corrected by Fridericia's formula SAE Serious Adverse Reaction Tmax Time limit to reach maximum drug concentration after administration T1 / 2 Terminal elimination half-life Final concentration measurable time point of Tlast PK profile Apparent volume of distribution (volume) in the terminal phase after Vz / F administration EXAMPLES

[0122] Example 1: Preclinical trials Example 1a: BTK occupancy and preclinical PK / PD relationships The in vivo PD effects of irreversible BTK inhibitors such as compound (I) are shared by the inhibitors. The extent and duration of binding BTK occupancy is determined by the compound of formula (I) (compound ( BTK occupancy following treatment with IL-1) was measured by ex vivo immunoassay. The unoccupied BTK protein fraction was incubated in vitro with a covalently biotinylated BTK probe. After incubation, the compound (I) and the probe were analyzed. The unoccupied BTK and total BTK in lysates of selected tissues were Determine relative protein levels and compare unoccupied BTK levels with total BTK levels in the same sample. Normalized to protein levels.

[0123] In female rats, a single oral dose of 3 mg / kg of Compound (I) induced complete splenic BTK expression. The administration of 1 mg / kg resulted in 76% to 81% occupancy, whereas the administration of 0.3 mg / kg resulted in 76% to 81% occupancy. After a single dose of 100 mg / kg, only a partial occupancy of 30% was reached. The prevalence was at the same level as that observed in the spleen. Short-term, transient systemic exposure has been shown to be effective in several tissues at oral doses as low as 1-3 mg / kg. It was clear that this was sufficient to achieve complete BTK occupancy. The blood exposure of compound (I) reached 49.1 nM at 0.5 hours and 5. This extremely low transient systemic exposure was consistent with the PK profile typical of an irreversible inhibitor. Consistent with the / PD model.

[0124] The BTK occupancy period was evaluated in rats and mice after a single oral dose of compound (I) in the spleen, blood, and In rats, BTK occupancy was measured in the blood, lymph nodes, and lungs. The estimated half-life of BTK occupancy in rat spleen was longer than that in blood. This difference in turnover rate is due to the Expressing B cells and monocytes are quiescent and metabolically relatively inactive compared to the spleen. This may reflect the fact that longer-lasting BTK occupancy in the blood has previously It has been reported in (Advani et al 2013, J Clin Onc;31 (1):88-94). All other tissues analyzed (lung and lymph nodes) showed similar B The TK turnover and occupancy half-life were shown.

[0125] Example 1B: In vivo efficacy in an acute mouse model of skin hypersensitivity The effect of compound (I) on FcγR- and FcεR-induced hypersensitivity was examined in two acute cutaneous mouse models. Compound (I) was evaluated in a mouse model because the PK of compound (I) in mice was not favorable. The combination was administered twice daily.

[0126] The duration of PD effect in the skin after a single dose was evaluated using the ELISA kit (Figure 1) as a function of mast cell FcγRIII-mediated inflammation. The study was evaluated in the reverse passive arthritis (RPA) model of rheumatoid arthritis. The IgG antibody is injected locally into the dermis, and the soluble antigen is given systemically by iv injection. In this mouse model, mast cell FcγRIII plays a key role, and the complement pathway is involved. The contribution is small (Hazenbos et al. 1998, Journal of immunology,161(6),pp.3026;Hazenbos et a l.,Immunity,1996,5(2),pp.181;Koehl&Gessn er 1999,Molecular immunology,36(13-14),p p.893;Sylvestre&Ravetch 1996,Immunity,5( 4),pp.387;Sylvestre&Ravetch 1994,Science , 265(5175), pp.1095). Genetically BTK-deficient mice show passive Arthritis It has been shown to be protective against skin reactions (Fiedler et al. 2011 ,blood,117(4),pp.1329).

[0127] Single doses of 3, 10, 30 and 100 mg / kg given 2 hours prior to induction of the RPA response. Oral treatment with Compound (I) in a single dose reduced skin swelling in a dose-dependent manner. and 100 mg / kg (73.0 and 61.2% inhibition, respectively) showed maximum efficacy. Partial efficacy was observed at 3 and 10 mg / kg (22.9 and 29.2% inhibition, respectively). The final splenic BTK occupancy rate observed 5 hours after administration was 1.0% relative to the skin swelling (Figure 1). Correlated with efficacy: 68.1% (3 mg / kg), 82.1% (10 mg / kg), The results were 91.3% (30 mg / kg) and 99.3% (100 mg / kg) (Figure 2).

[0128] In this model, compound (I) was administered 2 hours before induction of the Arthus reaction, resulting in a dermally The effect gradually decreased, and the Arthus reaction was suppressed by Compound (I) administration. When challenged at or after 45 hours, baseline levels were reached. These results suggest that BTK occupancy in the spleen, lung, and lymph nodes shows a similar time course. .

[0129] The effect of Compound (I) on acute cutaneous hypersensitivity was also investigated in passive cutaneous anaphylaxis (PC A) Compound (I) was orally administered twice to a mouse model (Ovary 1958) for evaluation. To minimize complement-dependent anaphylatoxins, the mouse PCA model uses low-cost A dose of sensitizing IgE antibody was used (Schaefer et al. 2013, The Journal of Clinical Chemistry, 2013). ournal of allergy and clinical immunology y,131(2),pp.541; Hata et al.1998,Journal of Experimental Medicine,187(8),pp.1235 ) Administered 14 hours and 2 hours before inducing hapten-induced cutaneous anaphylaxis. Two oral doses of 3, 10, 30, or 100 mg / kg of Compound (I) were administered. It showed a dose-dependent inhibition of skin edema measured as Evans Blue extravasation. The inhibition rate of skin edema measured by extravasation was 60.7% (3mg / kg) and 66.9% ( 10mg / kg), 69.2% (30mg / kg), and 87.4% (100mg / kg ) (Figure 3). The spleen occupancy rate 2.5 hours after the final administration was 89.1 to 99.7 % (representing peak occupancy) (Figure 4).

[0130] The studies in Examples 1a and 1b show that compound (I) reaches its target in the skin, This suggests that it effectively inhibits inflammatory responses in the skin.

[0131] In these preclinical pharmacology studies, BTK occupancy and the respective pharmacological readouts were , showed a strong correlation. Therefore, BTK occupancy and mast cell-mediated cutaneous hypersensitivity reactions were Because it is a suitable PD biomarker for use in clinical trials, it was used in a phase 1 clinical trial.

[0132] Example 2: Phase 1 Clinical Trial To support further clinical development of compound (I) in autoimmune diseases, The study was conducted on subjects with eczema and atopic predisposition, with oral administration once daily (qd) and twice daily ( The safety and tolerability of single and multiple doses of Compound (I) and its pharmacological properties were evaluated in both oral and postoperative patients (bid). A first-in-human study was conducted to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD). The study also investigated the effect of food intake.

[0133] First-in-human trials involving up to approximately 168 healthy volunteers (HVs) Of these, 64 patients (parts 2 and 4) had asymptomatic atopic predisposition. Part 1 was a double-blind (subject and investigator blinded, sponsor unblinded), placebo This was a controlled, single ascending dose (SAD) study with 10 cohorts (N=80) Part 2 consisted of six cohorts of asymptomatic, atopic, healthy volunteers (N= 48) was administered once daily in a double-blind study (subject and investigator blinded, clinical trial participants (unblinded), placebo-controlled multiple ascending dose (MAD) (13 doses over 12 days) It was a test. Part 3 is a single-dose, open-label, crossover food effect study in 12 HVs Was Part 4 consisted of two cohorts of asymptomatic, atopic, healthy volunteers (N= 16) was administered twice daily in a double-blind study (subject and investigator blinded, clinical trial participants This was a placebo-controlled, multiple-dose (25 doses over 12 days) study.

[0134] The SAD part (Part 1) had 10 dose levels, and the MAD part (Parts 2 and 4) Part 2 consisted of 6 cohorts using once-daily dosing, Part 4 (In the first cohort, 2 cohorts were administered twice daily). Eight subjects were randomly assigned to each cohort. In the AD and MAD parts, compound (I) or the corresponding placebo was randomly assigned in a 6:2 ratio (active: placebo). In the SAD part, the dose was approximately 4 times the estimated pharmacologically active dose (PAD). The doses up to 100 mg / kg / day will be evaluated, and then the SAD part will be If no vasopressin was detected, the MAD part of the study was started. The total daily dose of Compound (I) used in Part 1 (multiple dose bid regimen) and Part 2 (multiple dose bid regimen) was In addition, the total daily dose in Part 4 did not exceed the highest dose level of SAD administered in Part 2. The total daily dose of 2 was not exceeded.

[0135] In Part 1 (SAD), the first dose of sentinel vaccine was administered at each dose level as follows: The first two patients were administered the drug on the first day (one active, one placebo). After a 2-month observation period, the remaining six patients in the cohort (five receiving the active drug and one receiving a placebo) were treated.

[0136] Standard safety monitoring was used in all study parts. Potential skin damage events Evaluations specific to the patient included complete vital signs, physical examination, and and the subjects' medical history, ECG, adverse events, and laboratory safety parameters (blood chemistry, hematology, and urine tests), and 48-hour follow-up from the last dose from the previous dose group (if available). PK data up to 10 days after dose escalation were to be reviewed in a blinded fashion for each cohort prior to dose escalation. A summary safety report of reported adverse events, clinical safety laboratory parameters, QTc and heart rate was provided for each study. The reward was provided after the end of the training level.

[0137] In parts 1, 2, and 4, each subject will undergo a 28-day screening period (days -29 to -2 Participants participated in the baseline period, treatment period, and follow-up period, which included end-of-study assessments. .

[0138] In Part 1, baseline safety assessments and eligibility confirmation will be performed on Day -2 or - Subjects were admitted to the study site on Day 1. Eligible subjects were administered compound 100 mg under fasting conditions on Day 1. They received a single dose of either 1 or 5 mg of the compound (I) or placebo on the morning of days -1 to -5 (9 days after the last dose). He stayed at the facility until 6 hours later.

[0139] Parts 2 and 4 are intended to provide baseline safety assessment and qualification. Elephants were admitted on day -2 or day -1. Eligible subjects received compound (I) was administered initially, and the study drug was administered under fasting conditions until and including the 12th day. The subjects were randomly assigned to receive either the final dose of Compound (I) on Day -2 or Day -1 for 96 hours after the last dose. In Part 2 and Part 4, the subjects stayed in the facility until the morning of the 16th day, after 10 minutes of treatment. and study medication was administered twice daily (details are given in the evaluation schedule).

[0140] Part 3 is an open-label, randomized, two-arm, crossover, single-dose study to evaluate the effect of food. In part 3, each subject participated in a 28-day screening period (days -29 to - Day 2), two baseline (Day -1) periods, and two treatment periods (a single dose on Day 1, respectively) The first treatment period consisted of 14 consecutive days of treatment with 0.01 mg / kg / day of 0.1 mg / kg / day of 0.1 mg / kg / day of 0.0 ... These consisted of follow-up visits at days 22 and 40, respectively, and an end-of-study evaluation. The two treatment periods were separated by a washout period of at least 18 days (+ / - 1 day). Separated.

[0141] [Table 7]

[0142] [Table 8]

[0143] [Table 9]

[0144] Selection Criteria 1. Age 18-65 years (inclusive) and meet the medical history, physical examination, and baseline Healthy subjects of both sexes who were determined to be in good health based on italic signs, electrocardiograms, and clinical examinations. Healthy subjects with atopic predisposition were randomized to either Part 2 or Part 4 of these specific study parts. Participants were selected according to eligibility for the study. Healthy volunteers with atopic dermatitis were enrolled at screening. A prick test to a known allergen had to be positive (atopic However, the patient was clinically asymptomatic and did not require systemic medication. 2. Subjects must weigh at least 50 kg and have a body mass index (BMI) of 18 or above. The BMI was required to be within the range of 30 kg / m2 (inclusive). g) / [Height (m)] 2 . 3. At screening and initial baseline, subjects will be required to remain still for at least 3 minutes. After that, vital signs (body temperature, systolic and diastolic blood pressure, and pulse rate) were evaluated in a sitting position. Vital signs in the sitting position were assessed in the following ranges: Required to be within (inclusive): ·Oral body temperature 35.0~37.5℃ Systolic blood pressure: 90-139mmHg Diastolic blood pressure: 50-89mmHg Pulse rate: 50~90bpm

[0145] Exclusion criteria 1. History of hypersensitivity to the study drug or to drugs of a similar chemical class. 2. Clinically significant ECG abnormalities at screening and / or prior treatment, or any of the following: History of any ECG abnormality: ·PR interval over 200msec ·QRS complex >120msec ·QTcF over 450msec (male) ·QTcF over 460msec (female) 3. Hemoglobin level at screening or initial baseline is less than 12.0 g / dL Full. 4. Platelet count outside the normal range (150 × 10 9 / L or less than 450 x 10 9 )Super). 5. Prothrombin time (PT), part, and pulmonary function at screening and / or baseline Standard coagulation tests, including minute thromboplastin time (PTT) or international normalized ratio (INR) Any clinically significant abnormality was detected in any of the tests. 6. History or presence of a thrombotic or thromboembolic event, or High risk of infection.

[0146] Therapeutic drug administered Part 1 (SAD) Subjects were assigned to one of 10 cohorts: each cohort had 8 subjects They were randomly assigned to receive either Compound (I) or a matching placebo in a 6:2 ratio overall. One sub-cohort will consist of one subject in Compound (I) and one subject in the corresponding placebo group. After a 48-hour observation period in the first two subjects, The remaining 6 subjects per cohort were randomized in a 5:1 ratio to receive treatment. Cohort 1: Single oral dose of 0.5 mg of compound (I) or matching placebo Cohort 2: Single oral dose of 1.5 mg of compound (I) or matching placebo Cohort 3: Single oral dose of 5 mg of compound (I) or matching placebo Cohort 4: Single oral dose of 15 mg of compound (I) or matching placebo Cohort 5: Single oral dose of 30 mg of compound (I) or matching placebo Cohort 6: Single oral dose of 60 mg of compound (I) or matching placebo Cohort 7: Single oral dose of 100 mg of compound (I) or matching placebo Cohort 8: Single oral dose of 200 mg of compound (I) or matching placebo Cohort 9: Single oral dose of 400 mg of compound (I) or matching placebo Cohort 10: Single oral dose of 600 mg of compound (I) or matching placebo

[0147] Part 2 (MAD, qd administration) Subjects were assigned to one of six cohorts: Patients were randomly assigned to receive Compound (I) or matching placebo in a 6:2 ratio. 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 of compound (I) or matching placebo

[0148] Part 3 (Dietary Effects) Subjects were randomly assigned in a 1:1 ratio to one of two treatment sequences (Table 9).

[0149] [Table 10]

[0150] Part 4 (MAD, administered bid) Subjects were assigned to one of the following cohorts: Patients were randomly assigned in a 6:2 ratio to receive either the combination (I) or matching placebo. Cohort 1: Repeated oral administration of 100 mg of compound (I) or matching placebo bid Administration Cohort 2: Repeated oral administration of 200 mg of compound (I) or matching placebo bid Administration

[0151] Pharmacokinetic data Biological analysis method: Pharmacokinetic samples were collected from blood and evaluated in all subjects at all dose levels. Samples from subjects were not analyzed. Samples for PK evaluation from subjects were Blood concentrations of Compound (I) were measured by an established LC-MS / MS method. It was determined.

[0152] Pharmacokinetics of single ascending doses of 0.5mg to 600mg: The mean blood concentration-time course of Compound (I) after single escalating doses is shown in FIG.

[0153] Compound (I) is absorbed rapidly over time, with a Cmax of approximately 1 to 1.5 hours for all doses. The absorption phase was characterized by a single, well-defined absorption peak in most subjects. The pharmacokinetics of the drug showed a biexponential decline. The majority of the drug was released during the initial distribution phase. Because the drug is excreted below the The apparent terminal elimination phase was not reached until 12 hours after administration, and The measurable terminal half-life was 4 hours (10 The mean residence time in the circulation (M The median time of renal function (MRT) ranged from 1 to 5 hours (MRT ≒ T1 / 2 / ln2). The oral blood clearance geometry after a single dose was 1 / 2. The calculated mean values ​​(CL / F) ranged from 250 to 506 L / h across the SAD cohort. , estimated at approximately 383 L / h for the entire cohort.

[0154] Pharmacokinetics of repeated oral doses Mean blood concentration-time course of Compound (I) after repeated dose escalation from 10 mg to 400 mg is shown in Figure 6.

[0155] Geometric mean apparent 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 compared with day 1, but this difference was The drug almost disappeared at doses of 100 mg or more (Table 8-1 (Day 1) and Table 8-2 (Day 12) The reason for this behavior is probably the covalent bonds that contribute to the early clearance of compound (I). This effect is most pronounced on day 1, which is consistent with the effect of On the day of the target clearance, the remaining target occupancy in the trough is the target clearance to clearance (CLss / F). This difference, of course, is due to the difference in the target concentration at the trough. Target occupancy decreases with increasing dose approaching full occupancy. Therefore, drug exposure (AUC, C max) was found to be higher on day 12 compared to day 1. This is due to the (within-subject) The cumulative ratios (Racc) range from 5 (low dose) to 1.2 (high dose). and is generally higher in AUC than in Cmax, which is related to the effect on total body clearance. It was confirmed that this may be the case.

[0156] [Table 11]

[0157] [Table 12]

[0158] In general, the blood concentration 24 hours after the final dose was 100 mg or more in several subjects, and In general, the results were consistent with those shown in Table 1, except that the subsequent administration showed almost complete washout of Compound (I). The latter also suggested that a steady state was reached after several doses. is.

[0159] Because BTK turnover is higher in tissues, bid administration was also investigated. Mean plasma concentration-time profiles obtained after repeated ascending doses of 00 mg and 200 mg twice daily The profile is shown in Figure 7. Consistent with results from other cohorts, Rapid absorption was observed with a Tmax of approximately 1 hour. The observed accumulation coefficient (Racc) was: The AUC was 1.5 (100 mg) and 2.0 (200 mg), and the Cmax was approximately 1.65 ( A dose-proportional increase in AUCtau was observed on day 12, but the Cmax In conclusion, compound (I) showed only a slight increase (1.33-fold). Bid dosing does not compromise the overall PK profile and does not require high-dose qd treatment. This provides an option to address faster target resynthesis in tissues between doses without requiring additional Provide.

[0160] Effect of diet: Part 3 results: PK data from the food effect cohort, summarized in Table 9 below, showed a Cmax of 1 The absorption rate was lower as shown by the 0.25-fold lower AUC0-24 of 1.4-fold The overall absorption was more complete, as indicated by the higher α-tocopherol concentration. This is a shift in mean Tmax from 1 hour (fasted) to more than 3 hours (fed). Figure 8)

[0161] [Table 13]

[0162] Pharmacodynamics Pharmacodynamics (PD) was characterized by assessing target occupancy and peripheral pathway inhibition. Measurement of BTK occupancy in human whole blood (free B) serves as a direct marker of target engagement. TK to total BTK ratio).

[0163] Efficacy and disease response to BTK occupancy, dose, systemic compound exposure, and complex in vivo pathways The relationship between the patient's readout and the efficacy and safety of the compound of formula (I) has been established in preclinical models. (See, for example, Example 1.) The compounds of formula (I) are irreversible inhibitors of BTK and determine the extent and duration of BTK occupancy. The PD effect of compound (I) was evaluated in two separate assays using Meso Scale. Enzyme-linked immunosorbent assay (ELISA) on the MSD e Diagnostics platform ( Both free (unbound) and total BTK were measured in whole blood by ELISA. The evaluation was carried out by determining the

[0164] The relationship between dose and pharmacodynamics is important in determining the level of BT in human blood, a direct marker of therapeutic target engagement. The BTK activity was characterized by measuring the K occupancy (obtained as the ratio of free and total BTK). K occupancy was assessed by single-dose escalation ranging from 0.5 to 400 mg qd, 10 mg to 4 Multiple dose escalation ranging from 0.00 mg to 100 mg and 200 mg bid A decision was made regarding multiple dose escalation.

[0165] Compounds of formula (I) induced a clear dose-dependent increase in both the extent and duration of peripheral blood BTK occupancy. Target occupancy generally peaked as early as 0.5 hours after administration, which is consistent with the Rapid onset with no associated hysteresis in drug effect relative to peak drug exposure Target occupancy, as determined by its ability to covalently bind BTK, It was maintained far beyond its distribution in the systemic circulation, demonstrating a non-equilibrium PK-PD relationship. We therefore conclude that the duration of BTK occupancy is governed by the rate of de novo synthesis of BTK. will be done.

[0166] Unlike the low-dose cohorts (0.5-1.5 mg), the single dose of 15 mg or more of Compound (I) The single dose established peak target occupancy close to 100% in nearly all subjects, with 8% of the target occupancy achieved in 24 hours. There was wide variability in response among subjects at 15 mg, but At doses of 100 mg or more, sustained (>24 hours) and nearly complete (>90%) occupancy was observed in all subjects. The BTK protein pool was then analyzed at pre-dose and post-treatment, and the inter-subject variability was significantly reduced. The time to refresh is about 10 days, with an average metabolic turnover T1 / 2 of about 48 hours. There was a match (Figure 9). After repeated administration of Compound (I), 10 mg of Compound (I) qd was administered on the 12th day before administration. The BTK occupancy rate in the blood has already reached over 96%.

[0167] Furthermore, ex vivo inhibition of basophil activation (by surface expression of CD63 and CD203c) The activity of compound (I) was monitored using the distal mechanism biomarker The downstream PD effect was examined. To determine the PD effect of compound (I) on basophil activation, To determine the degranulation rate, whole blood was stimulated ex vivo with anti-IgE. The percentage of CD63+ and CD203+ basophils was evaluated.

[0168] Following single-dose escalation of Compound (I), data indicate a potent inhibitor of FcεR1-mediated basophil activation. The dose-dependent inhibition of ex vivo blood basophil activation as measured by CD63 was , was almost completely inhibited (>89%) at a dose of 60 mg and at higher doses 24 hours after administration. In contrast, the CD2 Maximal inhibition of 03c (approximately 50% inhibition) was achieved only with 200 mg of Compound (I).

[0169] On day 12, 8 hours after qd or bid administration of the MAD of a compound of formula (I) The lowest tested dose of compound (I) (10 mg qd) already upregulated CD63. More than 90% inhibition of IL-1 mediated IL-1 mediated inhibition of CD63 was observed with Compound (I). At doses of 50 mg or more qd, the response rate was greater than 90% (Figure 10). The maximum trough inhibition of c activation was consistently higher after a single dose of Compound (I) and was This was achieved only with bid doses of 200 g and 200 mg of Compound (I).

[0170] The ability of compound (I) to inhibit a defined allergen response was demonstrated in first-in-human MA studies. Part D of the study was evaluated by skin prick testing (SPT) in healthy atopic subjects. SPT was performed before administration (at screening, baseline, and before administration on Day 1). ), at different time points after the first dose (day 1) and 11 days after once-daily dosing (day 12). It was done.

[0171] Mean wheal after dosing compared to baseline, as well as inhibition of ex vivo basophil activation The number of wheals in the multiple-dose escalation cohorts was 100, as indicated by a decrease in size. A dose-dependent effect on the diameter was observed (Figure 11). I started to plateau at g qd.

[0172] Dose Selection / Basis for Conclusions Healthy volunteers are exposed to Compound (I) in Phase 1 clinical trials and the use Amounts range from 0.5 mg to 600 mg and are administered as a single dose or once daily. Compound (I) was well tolerated and There were no serious or severe adverse events associated with the intake of I. Adverse events (AEs) observed did not appear to be dose-related, were mostly single events, and were generally Therefore, the clinical safety information supports the dose selected in this Phase 2b study. It is something that can be done.

[0173] The dose levels of the present invention were evaluated in the following analyses (BTK occupancy in healthy volunteers, basic Inhibition of cytoplasmic activation (monitored by upregulation of CD63 and CD203c) ), and asymptomatic atopy, a surrogate for mast cell and basophil inhibition in the skin. This was derived from the effect of the skin prick test (SPT) in healthy volunteers.

[0174] In the above clinical trial, administration of 10 mg qd of Compound (I) reduced blood Near complete BTK occupancy, >90% reduction in CD63 upregulation (steady state 8 hours after administration of Compound (I) in the nasal cavity), and the minimum wheal size in the SPT Thus, 10 mg qd of compound (I) inhibited the onset of biological activity. At 100 mg of the compound of formula (I), the mean reduction in wheal size in the SPT was Therefore, 100 mg of the compound was the maximum effective dose of Compound (I). The intermediate dose of 35 mg of Compound (I) qd corresponds to the use of Compound (I) qd. It is well suited to accurately describe dose-response curves.

[0175] The compounds of formula (I) inhibit BTK by covalent binding. BTK occupancy in blood is 24 Over time (h), but with fast BTK turnover in tissues (e.g., in rodent spleens) (giving 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, respectively. accurately describes the dose-response curve for Compound (I) when given twice daily.

[0176] Human safety For the analysis of side effects, placebo subjects from all SAD and MAD cohorts (1 cohort) were included. The subjects separated by the SAD and MAD parts are The subjects were pooled into one placebo group (n=20 for SAD, n=16 for MAD) and Each single-dose group (n = 6 each) and all compound (I) groups (n = 60 for SAD, n = 60 for MAD) For both the SAD and MAD groups, the placebo and active groups were compared. No significant differences in demographic data were evident between groups. In a safety evaluation of the FIH study in humans, serious safety concerns were not identified at doses up to 600 mg. The idea is not accepted.

[0177] Example 3: Efficacy in CSU patients with persistent symptoms despite treatment with standard of care Efficacy and Safety Data Phase 2b demonstrated inhibition of CSU despite treatment with (second-generation) H1-antihistamines. The safety of six dose groups of compounds of formula (I) administered orally in poorly controlled subjects was evaluated. A multicenter, randomized, double-blind, parallel-group, placebo-controlled study to investigate efficacy, tolerability, and efficacy. This will be carried out as a test. During the study period (i.e., from day -14 to day 113), subjects were Patients were receiving a stable treatment regimen with a second-generation H1-antihistamine at a dose of 100 mg / kg ("background medication"). is.

[0178] The subjects were second-generation H1-antihistamines, which are primarily eliminated by renal excretion as rescue drugs. Additional medications (e.g., cetirizine, levocetirizine, or bilastine) may be taken. - The H1-antihistamine must be different from the background H1-antihistamine and must be Daily treatment of intolerable symptoms of CSU (itching) throughout the period (from day -14 to day 113) It may be administered only to

[0179] All other CSU treatments (including H1-antihistamines in excess of approved doses) are prohibited (See Table 10).

[0180] The outline of the study design includes three periods: Screening period (10-14 days before randomization): During the screening period, Subjects who provided informed consent will be assessed for study eligibility. Treatment Period (Days 1-85): After screening, eligible subjects were assigned to one of the following treatment groups: Randomly assign participants to the study in a 1:1:1:1:1:1:1:1 ratio: Compound (I) 10 mg once a day 〇Compound (I) 35mg once a day 〇Compound (I) 100mg once a day Compound (I) 10 mg twice a day 〇Compound (I) 25mg twice a day 〇Compound (I) 100mg twice a day Placebo An interim analysis was performed after all subjects had completed the week 4 visit (primary endpoint). The dose-response relationship of the compounds of formula (I) is evaluated. Follow-up period (Days 86-113): Subjects are followed to assess durability of response after treatment cessation. The safety of the drug will be further evaluated.

[0181] [Table 14]

[0182] [Table 15]

[0183] [Table 16]

[0184] [Table 17]

[0185] [Table 18]

[0186] Primary Endpoint The primary variable of this study was the change from baseline in UAS7 at week 4. is the sum of the average daily UAS over a 7-day period. Weekly scores are the sum of the average daily UAS over the last 7 days prior to the visit. Note that the above is derived by using

[0187] Secondary Endpoints Efficacy of immediate methods will be analyzed by treatment group and visit (if applicable) using descriptive statistics. Descriptive statistics included absolute and relative frequencies for categorical variables and arithmetic means for continuous variables. , standard deviation, minimum, maximum, median, and first and third quartiles. For the secondary analyses, clinical complete response, controlled disease and AAS7=0, each compound ( I) Pairwise comparisons of doses with placebo will be performed.

[0188] UAS7 Absolute and percentage changes from baseline in UAS7 during the treatment and follow-up periods Approximate statistics will be analyzed by treatment group and visit.

[0189] Complete clinical response A clinical complete response, i.e., absence of urticaria and pruritus, was achieved when UAS7=0 was achieved. This is defined as the target. Number of subjects with UAS7=0 by treatment group and visit during treatment and follow-up periods. Pairwise comparisons between treatment groups (individual Compound (I) groups vs. placebo).

[0190] Controlled disease (UAS7≦6) Number of subjects with UAS7 ≤ 6 by treatment group and visit during treatment and follow-up periods. Pairwise comparisons between treatment groups (individual Compound (I) groups vs. placebo).

[0191] No angioedema (AAS7=0) Cumulative number of weeks of AAS7=0 response from baseline to week 12. This is derived based on the AAS electronic diary. Weekly AAS7 scores are calculated based on the 7 days prior to the visit. The AAS7 is calculated by adding up the daily scores between 0 and 105. If the assessment is missing, the response to the cumulative number of weeks in which the subject performs the AAS7=0 response calculation is Cumulative achievement of AAS7=0 response from baseline to week 12 Weeks were analyzed using the log-linked regression model with treatment group, randomization strata, and baseline AAS7=0 status. We model the model using a negative binomial regression model.

[0192] DLQI Seven scores are obtained from the DLQI. These are the scores for the six dimensions as well as the total score of the DLQI. Each score is calculated based on the developer's rules. Changes from baseline and percentage changes from baseline will also be calculated. Metrics will be calculated for absolute values, as well as change and percentage change stratified by visit and treatment group. Number of subjects with DLQI score of 0 or 1 by treatment group and visit.

[0193] Safety Endpoints All safety endpoints (i.e., AEs, clinical laboratory data, vital signs, and ECG, and potential risks defined in the safety profiling plan) Subjects will be summarized by treatment. All data will be analyzed, regardless of whether rescue medication was used. Include in the analysis.

[0194] Data from the above clinical trials and preclinical evidence support daily doses of 10 mg to 200 mg. Compound (I) of the present invention is safe and pharmacologically effective for the treatment of basophil and mast-driven skin diseases. This shows that.

Claims

1. For use in treating chronic spontaneous urticaria (CSU) in subjects in need of such treatment. Use of a compound of formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein the daily dose of the compound of formula (I) is from about 10 mg to about 200 mg of the compound of formula (I) or a pharma- ceutically acceptable salt thereof.

2. The daily dose is from about 10 mg to about 100 mg of the formula ( I) or a pharma- ceutically acceptable salt thereof.

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

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

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

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

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

8. The compound of formula (I) is administered at a dose of about 10 mg, about 35 mg, about 50 mg or about 100 mg. The compound of formula (I) or a pharmaceutical composition thereof for use according to claim 1, A commercially acceptable salt.

9. The compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 mg, about 25 mg, or about 2. The method of claim 1, wherein the dosage is 50 mg or about 100 mg twice a day. A compound of formula (I) or a pharma- ceutically acceptable salt thereof.

10. Prior to treatment with the compound of formula (I), the subject is already treated with a systemic drug for CSU. The compound of formula (I) or and pharma- ceutically acceptable salts thereof.

11. The systemic drugs include H1-antihistamines (H1-AH), H2-antihistamines (H 2-AH), and leukotriene receptor antagonists (LTRAs), and combinations thereof The compound of formula (I) or its derivatives for use according to claim 10 is selected from the group consisting of Pharmaceutically acceptable salts.

12. Prior to treatment with the compound of formula (I), the subject was treated with a systemic CSU drug. The compound of formula (I) or its derivatives for use according to any one of claims 1 to 9, Pharmaceutically acceptable salts.

13. The subject according to any one of claims 1 to 12, wherein the subject has moderate to severe CSU. A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use.

14. The subjects are subject to the following criteria: a) prior to treatment with a compound of formula (I) or a pharma- ceutical acceptable salt thereof, the subject has have a UAS7 score or greater; b) prior to treatment with the compound of formula (I) or a pharma- ceutically acceptable salt thereof, the subject Have an HSS7 score of 8 or higher For the use according to any one of claims 1 to 12, selected according to at least one of 2. A compound of formula (I) or a pharma- ceutically acceptable salt thereof.

15. The subject is an adult, the compound of formula (I) for use according to any one of claims 1 to 14. or a pharma- ceutically acceptable salt thereof.

16. The subject will have one of the following by week 4 or week 12 of treatment: a) Reduction in urticaria and pruritus as judged by UAS ≦6, or complete disappearance of urticaria and pruritus Missing (UAS7=0); or b) Dermatology-related Quality of Life Index (DLQI) = 0-1; c) Absence of angioedema as determined by an Angioedema Activity Score (AAS7) of zero The compound of formula (I) for use according to any one of claims 1 to 15, ) or a pharma- ceutically acceptable salt thereof.

17. The subject is required to have a complete urticaria and pruritus response ([UAS7]=0) and / or a dermatologically related Quality of Life Assessment Index (DLQI) = 0-1 and / or angioedema 4 weeks after completion of the treatment Achieving a sustained response as determined by continued resolution (AAS7=0) of claims 1 to 16 2. A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 11.

18. The compound of formula (I) or a pharma- ceutically acceptable salt thereof is incorporated into a pharmaceutical preparation, The use according to any one of claims 1 to 17, wherein the formulation further comprises a pharma- ceutically acceptable carrier.

2. A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of chronic obstructive pulmonary disease.

19. The compound of formula (I) or a pharma- ceutically acceptable salt thereof has a T of about 0.5 to 3 hours. ｍａｘ The compound of formula (I) or its derivatives for use according to any one of claims 1 to 17, A pharma- ceutically acceptable salt of

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