Treatment of behçet's disease

Abstract

Disclosed is a method of treating Behçet's disease. The method comprises administering to a subject in need a therapeutically effective amount of a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Description

Treatment of Behçet syndrome

[0001] Citation of Related Applications

[0002] This disclosure claims all rights and interests in the Chinese invention patent application with application number 202311515655.8, filed with the State Intellectual Property Office of the People's Republic of China on November 14, 2023, and entitled "Treatment of Behçet's Syndrome," and incorporates the entire contents thereof into this disclosure by reference.

[0003] field

[0004] The present disclosure relates generally to the field of medicine and, more particularly, to the treatment of Behçet's syndrome.

[0005] background

[0006] Behçet's disease (BD), also known as Behçet's syndrome, is a chronic systemic vascular inflammatory disease characterized by recurrent oral and genital ulcers, eye inflammation, and skin lesions. It can also affect the blood vessels, heart, nervous system, digestive tract, joints, lungs, kidneys, and epididymis. BD varies regionally, with a higher incidence in East Asia, the Middle East, and the Mediterranean region. It is also known as the Silk Road disease. It most commonly affects people between the ages of 16 and 40. Overall, the male-female ratio is evenly distributed.

[0007] Currently, there are no specific biomarkers or histopathological features for Behçet's disease. Diagnosis is primarily based on clinical symptoms. There is no specific treatment for Behçet's disease; the primary goal of treatment is to alleviate symptoms, reduce relapses, delay disease progression, and prevent serious complications. Mucocutaneous and mucosal manifestations typically relapse and remit in a self-limited course. While these manifestations are not life-threatening, they can negatively impact quality of life. Patients with Behçet's disease often have compromised or disrupted immune function, increasing their risk of infection. Long-term use of existing Behçet's disease medications can further weaken their immune system, further increasing their risk of infection. Mycobacterium tuberculosis is a common pathogen during treatment. Approximately one-third of the global population is infected with Mycobacterium tuberculosis, and 90% of infected individuals can harbor the bacteria for a long time, becoming latent TB patients. Latent TB infection, as a breeding ground for active TB, presents a highly uncertain outcome for patients with latent TB infection, making it a hidden minefield in TB control. Patients with latent tuberculosis (LTB) infection have a weakened immune system, which can easily lead to the progression of LTB to active TB. Focusing on the special patient population with LTB infection during treatment, providing appropriate treatment options for Behçet's disease patients and those with LTB infection or a history of TB, improving efficacy, reducing adverse reactions and the potential risk of developing active TB, and striving for greater benefits for patients is of far-reaching significance and impact.

[0008] Overview

[0009] In one aspect, the present disclosure relates to a method for treating Behçet's syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0010] In one aspect, the present disclosure relates to a method for treating oral ulcers associated with Behçet's syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0011] In one aspect, the present disclosure relates to a method for treating genital ulcers associated with Behçet's syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0012] In another aspect, the present disclosure relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating Behçet's syndrome in an individual.

[0013] In another aspect, the present disclosure relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating oral ulcers associated with Behçet's syndrome in a subject.

[0014] In another aspect, the present disclosure relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating genital ulcers associated with Behçet's syndrome in a subject.

[0015] In yet another aspect, the present disclosure relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating Behçet's syndrome in an individual.

[0016] In yet another aspect, the present disclosure relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating oral ulcers associated with Behcet's syndrome in an individual.

[0017] In yet another aspect, the present disclosure relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating genital ulcers associated with Behçet's syndrome in an individual.

[0018] In yet another aspect, the present disclosure relates to a pharmaceutical composition for treating Behçet's syndrome in an individual, comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient,

[0019] In yet another aspect, the present disclosure relates to a pharmaceutical composition for treating oral ulcers associated with Behçet's syndrome in an individual, comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient,

[0020] In yet another aspect, the present disclosure relates to a pharmaceutical composition for treating genital ulcers associated with Behçet's syndrome in an individual, comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient,

[0021] Details

[0022] In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can still be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0023] Unless otherwise required in this application, throughout the specification and the appended claims, the words "including," "comprising," "containing," and "having" are to be construed in an open, inclusive sense, ie, "including but not limited to."

[0024] As used in this disclosure and the appended claims, singular references without indications of quantity include plural references unless the context clearly dictates otherwise.

[0025] Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that at least one embodiment includes the specific referenced elements, structures, or features described in connection with that embodiment. Thus, appearances of the phrases "in one embodiment," "in an embodiment," "in another embodiment," or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0026] It should be understood that the singular articles "a," "an," and "the" as used in the specification and appended claims of this disclosure include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a pharmaceutical composition comprising "an excipient" includes pharmaceutical compositions of one excipient or pharmaceutical compositions of two or more excipients.

[0027] definition

[0028] Accordingly, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims shall have the following meanings:

[0029] In the present disclosure, the term "Behçet's syndrome" is also known as Behçet's disease, oral-ophthalmitis-genital triad, etc. It is a chronic systemic vascular inflammatory disease, mainly manifested by recurrent oral ulcers, genital ulcers, eye inflammation and skin lesions. It can also involve blood vessels, nervous system, digestive tract, joints, lungs, kidneys, epididymis and other organs. Most patients have a good prognosis, while those with eye, central nervous system and large blood vessels involved have a poor prognosis. Currently, the International Diagnostic (Classification) Criteria for Behçet's Disease (ICBD-2013) formulated by the International Study Group (ISG) on Behçet's Disease in 2013 are clinically adopted: oral ulcers, genital ulcers and eye lesions (anterior uveitis, posterior uveitis or retinal vasculitis) are each scored as 2 points, skin lesions (pseudofolliculitis, skin ulcers, erythema nodosum), central nervous system involvement and vascular lesions (arterial thrombosis, large vein thrombosis, phlebitis or superficial phlebitis) are each scored as 1 point. A positive acupuncture reaction is scored as 1 point. Cases with a total score ≥ 4 points were diagnosed as Behçet's syndrome.

[0030] In the present disclosure, the term "complete relief of oral ulcer" refers to the time when the oral ulcer is completely healed after the first occurrence; ulcer healing is defined as: the ulcer surface is completely flattened, without congestion and pain.

[0031] In this disclosure, the term "oral ulcer pain visual analog scale score" is used to assess pain. This is widely used clinically in China. The basic method uses a 10-cm-long sliding ruler with 10 scale marks on one side, with 0 and 10 marks at the ends, respectively. 0 represents no pain, and 10 represents the most severe, unbearable pain.

[0032] In this disclosure, the term "physician global assessment" refers to the overall assessment of BD-related skin lesions of the subjects completed by the investigator.

[0033] In this disclosure, the term "BDCAF" is used in the Behçet's Disease Current Symptom Activity Scale, developed by the International Behçet's Disease Scientific Committee for routine monitoring of subjects and clinical research. This questionnaire is administered by researchers to quantify clinical disease manifestations over the past four weeks on a 12-point scale, with higher scores indicating greater activity. The BDCAF is a validated questionnaire for assessing mucocutaneous, joint, and skin lesions in BD, and can also assess general symptoms and non-mucocutaneous manifestations of BD.

[0034] In the present disclosure, the term "Ritchie joint index score" is divided into 4 degrees (mild, mild, moderate, severe), and the higher the score, the worse the subject's joint condition.

[0035] In this disclosure, the term "BVAS" refers to the Birmingham Vasculitis Activity Score. The subject will be assessed by the researcher at the prescribed visit. BVAS is a new manifestation or worsening of the disease caused by vasculitis within 4 weeks before the assessment date. The score will score the subject's general condition (maximum score 3 points), skin (maximum score 6 points), mucous membranes / eyes (maximum score 6 points), ENT (maximum score 6 points), chest (maximum score 6 points), cardiovascular (maximum score 6 points), abdomen (maximum score 9 points), kidney (maximum score 12 points), and nervous system (maximum score 9 points). Each system score has a maximum limit, and the maximum total score is 63 points. 15 points or more are considered active.

[0036] In this disclosure, the term "AUC" is calculated using the linear trapezoidal method. The sum of the areas of the trapezoids between two adjacent oral ulcer assessment visits is the AUC for the subject.

[0037] An analysis of covariance (ANCOVA) model was used, with treatment group and subject sex as fixed variables and the number of oral ulcers at baseline as a covariate. The least squares mean difference and 95% CI for the AUC between groups were calculated. Multiple imputation was used to account for missing data on the number of oral ulcers in the AUC calculation.

[0038] In the present disclosure, the term "HADS" refers to the Hospital Anxiety and Depression Scale, which is used to screen anxiety and depression in patients in general hospitals. The questionnaire is simple, concise and practical, and has been widely studied in general medical settings. The questionnaire contains 7 questions related to anxiety (A) and 7 questions related to depression (D). The answers to all questions are based on a 4-point system (0 to 3 points). The total score for anxiety or depression is the sum of the scores of each answer to the anxiety- or depression-related questions, and the score range is 0 to 21 points, where 0 to 7 points indicate no anxiety or depression, 8 to 10 points indicate mild anxiety or depression, 11 to 14 points indicate moderate anxiety or depression, and 15 to 21 points indicate severe anxiety or depression.

[0039] In the present disclosure, there are two commonly used classification methods for classifying adverse events occurring in clinical trials. One is to classify adverse reactions into mild, moderate and severe categories. Mild means that they are usually transient and generally do not affect the subject's daily life activities and may only require minimal treatment. Moderate means that the subject feels uncomfortable and his daily life activities are affected, usually requiring treatment to relieve, but there is no risk of major or permanent harm to the subject. Severe means that it has a significant impact on the subject's daily life, or seriously affects the clinical condition, and requires intensive treatment and intervention. Another classification method is to refer to the Common Terminology Criteria for Adverse Events (CTCAE) and grade them from 1 to 5. Grade 1, mild, no clinical symptoms or mild clinical symptoms; only clinical or diagnostic observations; no treatment required. Grade 2, moderate, requiring minor, local or non-invasive treatment; age-appropriate instrumental activities of daily living (ADL) are limited, instrumental activities of daily living refer to cooking, buying clothes, using the phone, managing finances, etc. Instrumental activities of daily living include cooking, shopping for clothes, using the phone, and managing finances; self-care activities of daily living include bathing, dressing and undressing, eating, washing, and taking medications, without being bedridden. Grade 3: Severe or medically significant but not immediately life-threatening; resulting in hospitalization or prolonged hospitalization; disability; or limitation of self-care activities of daily living. Self-care activities of daily living include bathing, dressing and undressing, eating, washing, and taking medications, without being bedridden. Grade 4: Life-threatening, requiring urgent medical attention. Grade 5: Death related to the adverse event.

[0040] As used herein, the term "latent tuberculosis infection (LTBI)" refers to infection with Mycobacterium tuberculosis without clinical tuberculosis, clinical symptoms, or bacteriological or radiological evidence of active tuberculosis. The diagnostic criteria for latent tuberculosis are a positive T-lymphocyte spot test (T-SPOT) for Mycobacterium tuberculosis infection and the absence of clinical manifestations of active tuberculosis.

[0041] In the present disclosure, the term "activation" refers to the transformation of the patient's Mycobacterium tuberculosis infection status from latent tuberculosis infection to active tuberculosis infection, that is, the patient's Mycobacterium tuberculosis infection status turns to the active stage, the patient is in an active tuberculosis state, and requires active and standardized treatment.

[0042] In this disclosure, the term "titrated dosing" refers to gradually achieving a desired drug level by administering low doses of the drug.

[0043] In the present disclosure, the term "compound of formula (I)" refers to N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, the structural formula of which is shown below:

[0044] In the present disclosure, the term "compound of formula (I) and its stereoisomers" refers to (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide, the structural formula of which is shown below:

[0045] In this disclosure, the term "pharmaceutically acceptable" refers to carriers, vehicles, diluents, excipients and / or salts that must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0046] In the present disclosure, the term "pharmaceutically acceptable carrier, diluent or excipient" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition.

[0047] In this disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

[0048] In the present disclosure, the term "pharmaceutically acceptable salt" includes "acceptable acid addition salts" and "acceptable base addition salts".

[0049] In this disclosure, the term "acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are biologically or otherwise suitable and are formed using inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0050] In this disclosure, the term "acceptable base addition salts" refers to salts that retain the biological effectiveness and properties of the free acids, and the base addition salts are biologically or otherwise suitable. These salts are prepared by adding inorganic or organic bases to the free acids. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0051] In this disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans, etc. In certain embodiments, the mammal includes humans.

[0052] In the present disclosure, the term "pharmaceutical composition" refers to a formulation of a compound of formula (I) or a pharmaceutically acceptable salt thereof described herein and a medium generally accepted in the art for delivering the bioactive compound to mammals such as humans. Such a medium includes any pharmaceutically acceptable carrier, diluent, or excipient.

[0053] In the present disclosure, the term "therapeutically effective amount" refers to an amount of a compound or combination of compounds that improves, reduces, or eliminates a particular disease or condition and the symptoms of a particular disease or condition, or that prevents or delays the onset of a particular disease or condition or the symptoms of a particular disease or condition. The amount of a compound of formula (I) described in the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, and the age, weight, etc. of the mammal to be treated, but the amount of a compound described in the present disclosure can be determined routinely by those skilled in the art based on their own knowledge and this disclosure.

[0054] As used herein, "treating" or "treatment" encompasses treating a relevant disease or condition in a mammal, such as a human, suffering from the relevant disease or condition, and includes:

[0055] (i) preventing a disease or disease state from occurring in a mammal, particularly where the mammal is susceptible to said disease state but has not yet been diagnosed with such disease state;

[0056] (ii) inhibiting the disease or disease state, i.e., preventing its occurrence; or

[0057] (iii) ameliorating the disease or condition, even if the disease or condition regresses or does not progress.

[0058] In this disclosure, the term "unit dose" refers to a dose for a single use. For example, for tablets, a unit dose refers to the dose of one tablet of medicine.

[0059] Compounds of the present disclosure or their pharmaceutically acceptable salts can contain one or more asymmetric centers and therefore can produce enantiomers, diastereomers and other stereoisomeric forms, which can be defined as (R)- or (S)-, or (D)- or (L)- of amino acids according to absolute stereochemistry. The application is intended to include all of these possible isomers, as well as their racemic forms and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or can be separated using conventional techniques, such as HPLC using chiral columns. When compounds as described herein contain alkene double bonds or other geometric asymmetric centers, unless otherwise indicated, it is meant that compounds include E and Z geometric isomers. Similarly, it is also meant to include all tautomeric forms.

[0060] In the present disclosure, the term "stereoisomer" refers to a compound composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers and mixtures thereof. DETAILED DESCRIPTION

[0061] In one aspect, the present disclosure relates to a method for treating Behçet's syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0062] In one aspect, the present disclosure relates to a method for treating oral ulcers associated with Behçet's syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0063] In one aspect, the present disclosure relates to a method for treating genital ulcers associated with Behçet's syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0064] In certain embodiments, the subject is administered 30 mg to 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0065] In certain embodiments, a subject is administered 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, or 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0066] In certain embodiments, the subject is administered 60 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0067] In certain embodiments, the subject is administered 90 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0068] In certain embodiments, the subject is administered 30 mg, 45 mg, 60 mg, 90 mg, 120 mg, 150 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0069] In certain embodiments, the subject is administered 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0070] In certain embodiments, the subject is administered 120 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily. In certain embodiments, the subject is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at least once daily.

[0071] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily.

[0072] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0073] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject three times daily.

[0074] In certain embodiments, the subject is administered 30 mg to 75 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0075] In certain embodiments, the subject is administered 30 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0076] In certain embodiments, the subject is administered 45 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0077] In certain embodiments, illustrative examples of unit doses of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and 150 mg.

[0078] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 75 mg.

[0079] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 150 mg.

[0080] In certain embodiments, the unit dosage of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is 15 mg, 30 mg, 60 mg, and 75 mg.

[0081] In certain embodiments, the unit dosage of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 120 mg, and 150 mg.

[0082] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject in the form of a tablet or capsule.

[0083] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered orally to a subject.

[0084] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0085] In certain embodiments, illustrative examples of mammals that can be used in the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0086] In certain embodiments, the subject is a human.

[0087] In certain embodiments, the subject has latent tuberculosis infection. In certain embodiments, the subject has a history of pulmonary tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0088] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of Behçet's syndrome.

[0089] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have good compliance in the treatment of Behçet's syndrome.

[0090] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of Behçet's syndrome.

[0091] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating Behçet's syndrome.

[0092] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating Behçet's syndrome.

[0093] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have good safety in the treatment of Behçet's syndrome.

[0094] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment for Behçet's syndrome in individuals with latent tuberculosis infection.

[0095] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are not activated following treatment for Behçet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0096] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin of the oral ulcer mucosa of a subject in the treatment of Behçet's syndrome.

[0097] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the area under the curve of oral ulcers in the treatment of Behçet's syndrome.

[0098] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the number of oral ulcers in the treatment of Behçet's syndrome.

[0099] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0100] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of Behçet's syndrome.

[0101] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve Behçet's syndrome-related genital ulcers and / or improve genital ulcer pain.

[0102] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin and mucosal involvement of a subject in the treatment of Behçet's syndrome.

[0103] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of Behçet's syndrome.

[0104] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the subject during the treatment of Behçet's syndrome.

[0105] In certain embodiments, the subject's immunity is not reduced during the treatment of Behçet's syndrome by the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein.

[0106] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of oral ulcers associated with Behçet's syndrome.

[0107] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof have good compliance in the treatment of oral ulcers associated with Behçet's syndrome.

[0108] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of oral ulcers associated with Behçet's syndrome.

[0109] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are more rapidly effective in treating oral ulcers associated with Behçet's syndrome.

[0110] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating oral ulcers associated with Behcet's syndrome.

[0111] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have a good safety profile in the treatment of oral ulcers associated with Behçet's syndrome.

[0112] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment of oral ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0113] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment of oral ulcers associated with Behçet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0114] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein improves the skin of the oral ulcer mucosa of a subject in the treatment of oral ulcer associated with Behçet's syndrome.

[0115] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present disclosure reduces the area under the oral ulcer curve in the treatment of oral ulcers associated with Behcet's syndrome.

[0116] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the treatment of oral ulcers associated with Behcet's syndrome, reduces the number of oral ulcers.

[0117] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of oral ulcers associated with Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0118] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of oral ulcers associated with Behcet's syndrome.

[0119] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are effective in treating oral ulcers associated with Behçet's syndrome, improving genital ulcers, and / or improving genital ulcer pain.

[0120] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin and mucosal involvement of a subject in the treatment of oral ulcers associated with Behçet's syndrome.

[0121] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of oral ulcers associated with Behçet's syndrome.

[0122] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the treatment of oral ulcers associated with Behçet's syndrome.

[0123] In certain embodiments, the subject's immunity is not reduced in the treatment of oral ulcers associated with Behcet's syndrome by the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0124] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of genital ulcers associated with Behçet's syndrome.

[0125] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof have good compliance in the treatment of genital ulcers associated with Behçet's syndrome.

[0126] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of genital ulcers associated with Behçet's syndrome.

[0127] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating genital ulcers associated with Behçet's syndrome.

[0128] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating genital ulcers associated with Behçet's syndrome.

[0129] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof have a good safety profile in the treatment of genital ulcers associated with Behçet's syndrome.

[0130] In certain embodiments, the compounds of formula (I) of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment for genital ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0131] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are not activated following treatment of genital ulcers associated with Behcet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0132] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin of the oral ulcer mucosa of a subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0133] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present disclosure reduces the area under the curve for oral ulcers in the treatment of genital ulcers associated with Behçet's syndrome.

[0134] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the number of oral ulcers in the treatment of genital ulcers associated with Behçet's syndrome.

[0135] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of genital ulcers associated with Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0136] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein improves oral ulcer pain in the treatment of genital ulcers associated with Behçet's syndrome.

[0137] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein can improve genital ulcers and / or genital ulcer pain in the treatment of genital ulcers associated with Behçet's syndrome.

[0138] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the mucocutaneous and mucosal involvement of a subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0139] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0140] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the treatment of genital ulcers associated with Behçet's syndrome.

[0141] In certain embodiments, the subject's immunity is not reduced in the treatment of genital ulcers associated with Behçet's syndrome by the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein.

[0142] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good safety in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0143] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0144] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good compliance in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0145] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, does not require titration in the treatment of Behçet's syndrome in patients with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection.

[0146] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, is more effective in treating Behçet's syndrome in patients with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection.

[0147] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated after treatment of Behçet's syndrome in individuals with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection, or genital ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0148] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, is not activated after treatment in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy who are experiencing Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, or genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0149] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof improves the skin of the oral ulcer mucosa of an individual in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0150] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof reduces the area under the curve for oral ulcers in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0151] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, reduces the number of oral ulcers in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0152] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection, shortens the time required for oral ulcer healing, and / or reduces the recurrence of oral ulcers, and / or prolongs the duration of complete remission of oral ulcers.

[0153] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof improves oral ulcer pain in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0154] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof are effective in treating Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and the associated genital ulcers are improved, and / or the pain of the genital ulcers is improved.

[0155] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, improve the skin and mucosal involvement of individuals in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0156] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, improve joint involvement in the subject in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0157] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection, do not cause anxiety or depression or aggravate anxiety or depression in individuals.

[0158] In certain embodiments, the subject's immunity is not reduced when the compound of formula (I) disclosed herein, its stereoisomers or pharmaceutically acceptable salts thereof treats Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0159] In another aspect, the present disclosure relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating Behçet's syndrome in an individual.

[0160] In another aspect, the present disclosure relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating oral ulcers associated with Behçet's syndrome in a subject.

[0161] In another aspect, the present disclosure relates to a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating genital ulcers associated with Behçet's syndrome in a subject.

[0162] In certain embodiments, the subject is administered 30 mg to 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0163] In certain embodiments, a subject is administered 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, or 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0164] In certain embodiments, the subject is administered 60 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0165] In certain embodiments, the subject is administered 90 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0166] In certain embodiments, the subject is administered 30 mg, 45 mg, 60 mg, 90 mg, 120 mg, or 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0167] In certain embodiments, the subject is administered 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0168] In certain embodiments, the subject is administered 120 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0169] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least once daily.

[0170] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily.

[0171] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0172] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject three times daily.

[0173] In certain embodiments, the subject is administered 30 mg to 75 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0174] In certain embodiments, the subject is administered 30 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0175] In certain embodiments, the subject is administered 45 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0176] In certain embodiments, illustrative examples of unit doses of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and 150 mg.

[0177] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 75 mg.

[0178] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 150 mg.

[0179] In certain embodiments, illustrative examples of unit dosages of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 15 mg, 30 mg, 60 mg, and 75 mg.

[0180] In certain embodiments, the unit dosage of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 120 mg, and 150 mg.

[0181] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject in the form of a tablet or capsule.

[0182] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered orally to a subject.

[0183] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0184] In certain embodiments, illustrative examples of mammals that can be used in the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0185] In certain embodiments, the subject is a human.

[0186] In certain embodiments, the individual has latent tuberculosis infection.

[0187] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0188] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of Behçet's syndrome.

[0189] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have good compliance in the treatment of Behçet's syndrome.

[0190] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of Behçet's syndrome.

[0191] In certain embodiments, administration of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject, either short-term or long-term, does not result in depression in the subject.

[0192] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating Behçet's syndrome.

[0193] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating Behçet's syndrome.

[0194] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have a good safety profile in Behçet's syndrome.

[0195] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment for Behçet's syndrome in individuals with latent tuberculosis infection.

[0196] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are not activated following treatment for Behçet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0197] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin of the oral ulcer mucosa of a subject in the treatment of Behçet's syndrome.

[0198] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the area under the curve of oral ulcers in the treatment of Behçet's syndrome.

[0199] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the number of oral ulcers in the treatment of Behçet's syndrome.

[0200] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0201] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of Behçet's syndrome.

[0202] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve Behçet's syndrome-related genital ulcers and / or improve genital ulcer pain.

[0203] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin and mucosal involvement of a subject in the treatment of Behçet's syndrome.

[0204] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of Behçet's syndrome.

[0205] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the subject during the treatment of Behçet's syndrome.

[0206] In certain embodiments, the subject's immunity is not reduced during the treatment of Behçet's syndrome by the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein.

[0207] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of oral ulcers associated with Behçet's syndrome.

[0208] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof have good compliance in the treatment of oral ulcers associated with Behçet's syndrome.

[0209] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of oral ulcers associated with Behçet's syndrome.

[0210] In certain embodiments, administration of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject, either short-term or long-term, does not result in depression in the subject.

[0211] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are more rapidly effective in treating oral ulcers associated with Behçet's syndrome.

[0212] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating Behçet's syndrome.

[0213] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have a good safety profile in oral ulcers associated with Behçet's syndrome.

[0214] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment of oral ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0215] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment of oral ulcers associated with Behçet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0216] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein improves the skin of the oral ulcer mucosa of a subject in the treatment of oral ulcer associated with Behçet's syndrome.

[0217] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present disclosure reduces the area under the oral ulcer curve in the treatment of oral ulcers associated with Behcet's syndrome.

[0218] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the treatment of oral ulcers associated with Behcet's syndrome, reduces the number of oral ulcers.

[0219] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of oral ulcers associated with Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0220] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of oral ulcers associated with Behcet's syndrome.

[0221] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are effective in treating oral ulcers associated with Behçet's syndrome, improving genital ulcers, and / or improving genital ulcer pain.

[0222] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin and mucosal involvement of a subject in the treatment of oral ulcers associated with Behçet's syndrome.

[0223] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of oral ulcers associated with Behçet's syndrome.

[0224] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the treatment of oral ulcers associated with Behçet's syndrome.

[0225] In certain embodiments, the subject's immunity is not reduced in the treatment of oral ulcers associated with Behcet's syndrome by the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0226] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of genital ulcers associated with Behçet's syndrome.

[0227] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof have good compliance in the treatment of genital ulcers associated with Behçet's syndrome.

[0228] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of genital ulcers associated with Behçet's syndrome.

[0229] In certain embodiments, administration of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject, either short-term or long-term, does not result in depression in the subject.

[0230] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating genital ulcers associated with Behçet's syndrome.

[0231] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating genital ulcers associated with Behçet's syndrome.

[0232] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have a good safety profile in genital ulcers associated with Behçet's syndrome.

[0233] In certain embodiments, the compounds of formula (I) of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment for genital ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0234] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are not activated following treatment of genital ulcers associated with Behcet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0235] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin of the oral ulcer mucosa of a subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0236] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present disclosure reduces the area under the curve for oral ulcers in the treatment of genital ulcers associated with Behçet's syndrome.

[0237] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the number of oral ulcers in the treatment of genital ulcers associated with Behçet's syndrome.

[0238] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of genital ulcers associated with Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0239] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of genital ulcers associated with Behçet's syndrome.

[0240] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein can improve genital ulcers and / or genital ulcer pain in the treatment of genital ulcers associated with Behçet's syndrome.

[0241] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the mucocutaneous and mucosal involvement of a subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0242] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0243] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the treatment of genital ulcers associated with Behçet's syndrome.

[0244] In certain embodiments, the subject's immunity is not reduced in the treatment of genital ulcers associated with Behçet's syndrome by the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein.

[0245] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good safety in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0246] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0247] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good compliance in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0248] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, does not require titration in the treatment of Behçet's syndrome in patients with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection.

[0249] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, is more effective in treating Behçet's syndrome in patients with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection.

[0250] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have a good safety profile in genital ulcers associated with Behçet's syndrome.

[0251] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good safety in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0252] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0253] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good compliance in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0254] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, does not require titration in the treatment of Behçet's syndrome in patients with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection.

[0255] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, is more effective in treating Behçet's syndrome in patients with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection.

[0256] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated after treatment of Behçet's syndrome in individuals with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection, or genital ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0257] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, is not activated after treatment in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy who are experiencing Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, or genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0258] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof improves the skin of the oral ulcer mucosa of an individual in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0259] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof reduces the area under the curve for oral ulcers in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0260] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, reduces the number of oral ulcers in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0261] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection, shortens the time required for oral ulcer healing, and / or reduces the recurrence of oral ulcers, and / or prolongs the duration of complete remission of oral ulcers.

[0262] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof improves oral ulcer pain in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0263] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof are effective in treating Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and the associated genital ulcers are improved, and / or the pain of the genital ulcers is improved.

[0264] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, improve the skin and mucosal involvement of individuals in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0265] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, improve joint involvement in the subject in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0266] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection, do not cause anxiety or depression or aggravate anxiety or depression in individuals.

[0267] In certain embodiments, the subject's immunity is not reduced when the compound of formula (I) disclosed herein, its stereoisomers or pharmaceutically acceptable salts thereof treats Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0268] In yet another aspect, the present disclosure relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating Behçet's syndrome in an individual.

[0269] In yet another aspect, the present disclosure relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating oral ulcers associated with Behçet's syndrome in an individual.

[0270] In yet another aspect, the present disclosure relates to the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating genital ulcers associated with Behçet's syndrome in an individual.

[0271] In certain embodiments, the subject is administered 30 mg to 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0272] In certain embodiments, a subject is administered 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, or 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0273] In certain embodiments, the subject is administered 60 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0274] In certain embodiments, the subject is administered 90 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0275] In certain embodiments, the subject is administered 30 mg, 45 mg, 60 mg, 90 mg, 120 mg, 150 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0276] In certain embodiments, the subject is administered 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0277] In certain embodiments, the subject is administered 120 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0278] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least once daily.

[0279] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily.

[0280] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0281] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject three times daily.

[0282] In certain embodiments, the subject is administered 30 mg to 75 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0283] In certain embodiments, the subject is administered 30 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0284] In certain embodiments, the subject is administered 45 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0285] In certain embodiments, illustrative examples of unit doses of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and 150 mg.

[0286] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 75 mg.

[0287] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 150 mg.

[0288] In certain embodiments, illustrative examples of unit dosages of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 15 mg, 30 mg, 45 mg, 60 mg, and 75 mg.

[0289] In certain embodiments, the unit dosage of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 120 mg, and 150 mg.

[0290] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject in the form of a tablet or capsule.

[0291] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered orally to a subject.

[0292] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0293] In certain embodiments, illustrative examples of mammals that can be used in the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0294] In certain embodiments, the subject is a human.

[0295] In certain embodiments, the individual has latent tuberculosis infection.

[0296] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0297] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of Behçet's syndrome.

[0298] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have good compliance in the treatment of Behçet's syndrome.

[0299] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of Behçet's syndrome.

[0300] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating Behçet's syndrome.

[0301] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating Behçet's syndrome.

[0302] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have good safety in the treatment of Behçet's syndrome.

[0303] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment for Behçet's syndrome in individuals with latent tuberculosis infection.

[0304] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are not activated following treatment for Behçet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0305] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin of the oral ulcer mucosa of a subject in the treatment of Behçet's syndrome.

[0306] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the area under the curve of oral ulcers in the treatment of Behçet's syndrome.

[0307] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the number of oral ulcers in the treatment of Behçet's syndrome.

[0308] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0309] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of Behçet's syndrome.

[0310] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve Behçet's syndrome-related genital ulcers and / or improve genital ulcer pain.

[0311] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin and mucosal involvement of a subject in the treatment of Behçet's syndrome.

[0312] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of Behçet's syndrome.

[0313] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the subject during the treatment of Behçet's syndrome.

[0314] In certain embodiments, the subject's immunity is not reduced during the treatment of Behçet's syndrome by the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein.

[0315] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of oral ulcers associated with Behçet's syndrome.

[0316] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof have good compliance in the treatment of oral ulcers associated with Behçet's syndrome.

[0317] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of oral ulcers associated with Behçet's syndrome.

[0318] In certain embodiments, administration of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject, either short-term or long-term, does not result in depression in the subject.

[0319] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are more rapidly effective in treating oral ulcers associated with Behçet's syndrome.

[0320] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating oral ulcers associated with Behcet's syndrome.

[0321] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have a good safety profile in the treatment of oral ulcers associated with Behçet's syndrome.

[0322] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment of oral ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0323] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment of oral ulcers associated with Behçet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0324] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein improves the skin of the oral ulcer mucosa of a subject in the treatment of oral ulcer associated with Behçet's syndrome.

[0325] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present disclosure reduces the area under the oral ulcer curve in the treatment of oral ulcers associated with Behcet's syndrome.

[0326] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the treatment of oral ulcers associated with Behcet's syndrome, reduces the number of oral ulcers.

[0327] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of oral ulcers associated with Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0328] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of oral ulcers associated with Behcet's syndrome.

[0329] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve genital ulcers and / or genital ulcer pain in the treatment of oral ulcers associated with Behçet's syndrome.

[0330] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin and mucosal involvement of a subject in the treatment of oral ulcers associated with Behçet's syndrome.

[0331] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of oral ulcers associated with Behçet's syndrome.

[0332] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the treatment of oral ulcers associated with Behçet's syndrome.

[0333] In certain embodiments, the disclosed compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof are used to treat oral ulcers associated with Behçet's syndrome without reducing individual immunity. In certain embodiments, the disclosed compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof are well tolerated in treating genital ulcers associated with Behçet's syndrome.

[0334] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof have good compliance in the treatment of genital ulcers associated with Behçet's syndrome.

[0335] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of genital ulcers associated with Behçet's syndrome.

[0336] In certain embodiments, administration of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject, either short-term or long-term, does not result in depression in the subject.

[0337] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating genital ulcers associated with Behçet's syndrome.

[0338] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating genital ulcers associated with Behçet's syndrome.

[0339] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof have a good safety profile in the treatment of genital ulcers associated with Behçet's syndrome.

[0340] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good safety in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0341] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0342] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good compliance in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0343] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, does not require titration in the treatment of Behçet's syndrome in patients with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection.

[0344] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, is more effective in treating Behçet's syndrome in patients with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection.

[0345] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0346] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good safety in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0347] In certain embodiments, the compounds of formula (I) of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment for genital ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0348] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are not activated following treatment of genital ulcers associated with Behcet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0349] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin of the oral ulcer mucosa of a subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0350] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present disclosure reduces the area under the curve for oral ulcers in the treatment of genital ulcers associated with Behçet's syndrome.

[0351] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the number of oral ulcers in the treatment of genital ulcers associated with Behçet's syndrome.

[0352] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of genital ulcers associated with Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0353] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of genital ulcers associated with Behçet's syndrome.

[0354] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein can improve genital ulcers and / or genital ulcer pain in the treatment of genital ulcers associated with Behçet's syndrome.

[0355] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the mucocutaneous and mucosal involvement of a subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0356] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0357] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the treatment of genital ulcers associated with Behçet's syndrome.

[0358] In certain embodiments, the subject's immunity is not reduced in the treatment of genital ulcers associated with Behçet's syndrome by the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein.

[0359] In yet another aspect, the present disclosure relates to a pharmaceutical composition for treating Behçet's syndrome in an individual, comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient,

[0360] In yet another aspect, the present disclosure relates to a pharmaceutical composition for treating oral ulcers associated with Behçet's syndrome in an individual, comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient,

[0361] In yet another aspect, the present disclosure relates to a pharmaceutical composition for treating genital ulcers associated with Behçet's syndrome in an individual, comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient,

[0362] In certain embodiments, the subject is administered 30 mg to 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0363] In certain embodiments, a subject is administered 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, or 180 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0364] In certain embodiments, the subject is administered 60 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0365] In certain embodiments, the subject is administered 90 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0366] In certain embodiments, the subject is administered 30 mg, 60 mg, 45 mg, 90 mg, 120 mg, or 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0367] In certain embodiments, the subject is administered 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0368] In certain embodiments, the subject is administered 120 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0369] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least once daily.

[0370] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject at least twice daily.

[0371] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0372] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject three times daily.

[0373] In certain embodiments, the subject is administered 30 mg to 75 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0374] In certain embodiments, the subject is administered 30 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0375] In certain embodiments, the subject is administered 45 mg to 60 mg of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily.

[0376] In certain embodiments, illustrative examples of unit doses of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, and 150 mg.

[0377] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 75 mg.

[0378] In certain embodiments, the unit dose of the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof is 15 mg to 150 mg.

[0379] In certain embodiments, illustrative examples of unit dosages of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof that can be used in the present disclosure include, but are not limited to, 15 mg, 30 mg, 45 mg, 60 mg, and 75 mg.

[0380] In certain embodiments, the unit dosage of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, and 150 mg.

[0381] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject in the form of a tablet or capsule.

[0382] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered orally to a subject.

[0383] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0384] In certain embodiments, illustrative examples of mammals that can be used in the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0385] In certain embodiments, the subject is a human.

[0386] In certain embodiments, the individual has latent tuberculosis infection.

[0387] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0388] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of Behçet's syndrome.

[0389] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have good compliance in the treatment of Behçet's syndrome.

[0390] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of Behçet's syndrome.

[0391] In certain embodiments, administration of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject, either short-term or long-term, does not result in depression in the subject.

[0392] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating Behçet's syndrome.

[0393] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating Behçet's syndrome.

[0394] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have good safety in the treatment of Behçet's syndrome.

[0395] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment for Behçet's syndrome in individuals with latent tuberculosis infection.

[0396] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are not activated following treatment for Behçet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0397] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin of the oral ulcer mucosa of a subject in the treatment of Behçet's syndrome.

[0398] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the area under the curve of oral ulcers in the treatment of Behçet's syndrome.

[0399] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the number of oral ulcers in the treatment of Behçet's syndrome.

[0400] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0401] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of Behçet's syndrome.

[0402] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve Behçet's syndrome-related genital ulcers and / or improve genital ulcer pain.

[0403] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin and mucosal involvement of a subject in the treatment of Behçet's syndrome.

[0404] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of Behçet's syndrome.

[0405] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the subject during the treatment of Behçet's syndrome.

[0406] In certain embodiments, the subject's immunity is not reduced during the treatment of Behçet's syndrome by the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein.

[0407] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of oral ulcers associated with Behçet's syndrome.

[0408] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof have good compliance in the treatment of oral ulcers associated with Behçet's syndrome.

[0409] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of oral ulcers associated with Behçet's syndrome.

[0410] In certain embodiments, administration of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject, either short-term or long-term, does not result in depression in the subject.

[0411] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are more rapidly effective in treating oral ulcers associated with Behçet's syndrome.

[0412] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating oral ulcers associated with Behcet's syndrome.

[0413] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof have a good safety profile in the treatment of oral ulcers associated with Behçet's syndrome.

[0414] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment of oral ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0415] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment of oral ulcers associated with Behçet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0416] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein improves the skin of the oral ulcer mucosa of a subject in the treatment of oral ulcer associated with Behçet's syndrome.

[0417] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present disclosure reduces the area under the oral ulcer curve in the treatment of oral ulcers associated with Behcet's syndrome.

[0418] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the treatment of oral ulcers associated with Behcet's syndrome, reduces the number of oral ulcers.

[0419] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of oral ulcers associated with Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0420] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of oral ulcers associated with Behcet's syndrome.

[0421] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are effective in treating oral ulcers associated with Behçet's syndrome, improving genital ulcers, and / or improving genital ulcer pain.

[0422] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin and mucosal involvement of a subject in the treatment of oral ulcers associated with Behçet's syndrome.

[0423] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of oral ulcers associated with Behçet's syndrome.

[0424] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the treatment of oral ulcers associated with Behçet's syndrome.

[0425] In certain embodiments, the subject's immunity is not reduced in the treatment of oral ulcers associated with Behcet's syndrome by the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0426] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of genital ulcers associated with Behçet's syndrome.

[0427] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof have good compliance in the treatment of genital ulcers associated with Behçet's syndrome.

[0428] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration for the treatment of genital ulcers associated with Behçet's syndrome.

[0429] In certain embodiments, administration of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject, either short-term or long-term, does not result in depression in the subject.

[0430] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating genital ulcers associated with Behçet's syndrome.

[0431] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have excellent therapeutic effects in treating genital ulcers associated with Behçet's syndrome.

[0432] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof have a good safety profile in the treatment of genital ulcers associated with Behçet's syndrome.

[0433] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good safety in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0434] In certain embodiments, the compounds of formula (I) of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated following treatment for genital ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0435] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof are not activated following treatment of genital ulcers associated with Behcet's syndrome in individuals with a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0436] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the skin of the oral ulcer mucosa of a subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0437] In certain embodiments, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof of the present disclosure reduces the area under the curve for oral ulcers in the treatment of genital ulcers associated with Behçet's syndrome.

[0438] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein reduces the number of oral ulcers in the treatment of genital ulcers associated with Behçet's syndrome.

[0439] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of genital ulcers associated with Behçet's syndrome, shorten the time required for oral ulcer healing, and / or reduce the recurrence of oral ulcers, and / or prolong the duration of complete remission of oral ulcers.

[0440] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein can improve oral ulcer pain in the treatment of genital ulcers associated with Behçet's syndrome.

[0441] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein can improve genital ulcers and / or genital ulcer pain in the treatment of genital ulcers associated with Behçet's syndrome.

[0442] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve the mucocutaneous and mucosal involvement of a subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0443] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein improve joint involvement in the subject in the treatment of genital ulcers associated with Behçet's syndrome.

[0444] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or depression or aggravate anxiety or depression in the treatment of genital ulcers associated with Behçet's syndrome.

[0445] In certain embodiments, the subject's immunity is not reduced in the treatment of genital ulcers associated with Behçet's syndrome by the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein.

[0446] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof are well tolerated in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0447] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof have good compliance in the treatment of Behçet's syndrome with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome with latent tuberculosis infection.

[0448] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, does not require titration in the treatment of Behçet's syndrome in patients with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection.

[0449] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, is more effective in treating Behçet's syndrome in patients with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome in patients with latent tuberculosis infection.

[0450] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, are not activated after treatment of Behçet's syndrome in individuals with latent tuberculosis infection, oral ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection, or genital ulcers associated with Behçet's syndrome in individuals with latent tuberculosis infection.

[0451] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, is not activated after treatment in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy who are experiencing Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, or genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0452] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof improves the skin of the oral ulcer mucosa of an individual in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0453] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof reduces the area under the curve of oral ulcers in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0454] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof reduces the number of oral ulcers in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0455] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection, shortens the time required for oral ulcer healing, and / or reduces the recurrence of oral ulcers, and / or prolongs the duration of complete remission of oral ulcers.

[0456] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof improves oral ulcer pain in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0457] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof are effective in treating Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and the associated genital ulcers are improved, and / or the pain of the genital ulcers is improved.

[0458] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, improve the skin and mucosal involvement of individuals in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0459] In certain embodiments, the compounds of formula (I) disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof, improve joint involvement in the subject in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0460] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection, do not cause anxiety or depression or aggravate anxiety or depression in individuals.

[0461] In certain embodiments, the subject's immunity is not reduced when the compound of formula (I) disclosed herein, its stereoisomers or pharmaceutically acceptable salts thereof treats Behçet's syndrome, oral ulcers associated with Behçet's syndrome due to latent tuberculosis infection, and genital ulcers associated with Behçet's syndrome due to latent tuberculosis infection.

[0462] Hereinafter, the present disclosure will be explained in detail through the following examples in order to better understand the various aspects and advantages of the present disclosure. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present disclosure.

[0463] Example

[0464] Glossary:

[0465] BID: twice daily

[0466] VAS: Visual Analogue Scale score for oral ulcer pain

[0467] PGA: Physician's Global Assessment

[0468] BVAS: Birmingham Vasculitis Activity Score

[0469] Ritchie: Joint Index Score

[0470] Example 1

[0471] Preparation of compounds of formula (I)

[0472] N-[5-[1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide

[0473] Prepared by referring to the preparation method 2 of Example 3 in CN101885731A.

[0474] Example 2

[0475] Preparation of stereoisomers of compounds of formula (I)

[0476] (S)-N-[5-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl]acetamide

[0477] The obtained product was prepared according to the preparation method of Example 1 in CN116332954 A.

[0478] Example 3

[0479] Clinical studies on patients

[0480] This study selected 90 patients with Behçet's syndrome (aged 18 to 75 years old (inclusive)) who were diagnosed with Behçet's disease according to the International Diagnostic (Classification) Criteria for Behçet's Disease (ICBD-2013) developed by an international research group in 2013. The subjects were randomly assigned in a ratio of 2:2:1:1 to the high-dose group (60 mg BID group) of Example 2, the low-dose group (45 mg BID group) of Example 2, the placebo (core treatment period) + 60 mg BID group (extended treatment period), or the placebo (core treatment period) + 45 mg BID group. BID group (extended treatment period). During the core treatment period, the drug is administered twice a day for 12 consecutive weeks. Subjects who received the high-dose or low-dose groups during the core treatment period will continue to receive the drug according to their core treatment dose for 12 weeks during the extension period. Subjects who received placebo during the core treatment period will enter the high-dose or low-dose group during the extension period and continue to receive the drug for 12 weeks. The subjects and researchers will remain blinded during this stage. Discontinuation observation period: All subjects in the study (including subjects who withdraw from treatment early for any reason) must be observed for 4 weeks after the last dose.

[0481] The primary efficacy endpoint was the area under the curve (AUC) for the number of oral ulcers in BD patients from baseline to week 12 of treatment.

[0482] Secondary efficacy endpoints: least squares mean (standard error / 95% CI) of the difference between the AUC of the test drug and the AUC of placebo; mean (standard deviation) of the number of oral ulcers at week 12; complete remission rate at week 12 (n / m, %).

[0483] Table 1. Effectiveness evaluation during the 12-week core treatment period

[0484] Table 2. Effectiveness evaluation during the 12-week core treatment period

[0485] Results of this clinical study:

[0486] 1. Effectiveness

[0487] Main efficacy indicators: Compared with the placebo group, the AUC of the number of oral ulcers in the 45mg BID and 60mg BID dose groups were significantly reduced from 0 to 12 weeks, which was statistically significant. Both dose groups showed significant statistical differences from placebo. Compared with the placebo group, the area under the curve (AUC) of the number of oral ulcers in the 45mg BID and 60mg BID dose groups decreased by 99.1 and 130.1, respectively. The complete remission rates of oral ulcers at the 12th week of treatment were 58.8% and 70.6%, respectively.

[0488] 2. Rapid clinical effect in treating oral ulcers associated with Behcet's disease:

[0489] On the third day of treatment, the initial drug effect was shown compared with the placebo group;

[0490] On the seventh day of treatment, more than 30% of the subjects in the active drug treatment group achieved complete relief of oral ulcers, and the drug efficacy remained stable throughout the treatment period;

[0491] 3. Security

[0492] The overall safety profile was well tolerated;

[0493] All adverse reactions were mild or moderate, most occurring in the early stages of treatment, and most resolved within one week without clinical treatment. No severe adverse reactions occurred during the trial.

[0494] Example 4

[0495] Clinical studies on patients

[0496] This study selected 90 patients with Behçet's syndrome (aged 18 to 75 years old (inclusive)) who were diagnosed with Behçet's disease according to the International Diagnostic (Classification) Criteria for Behçet's Disease (ICBD-2013) developed by an international research group in 2013. The subjects were randomly assigned in a ratio of 2:2:1:1 to the high-dose group (60 mg BID group) of Example 2, the low-dose group (45 mg BID group) of Example 2, the placebo (core treatment period) + 60 mg BID group (extended treatment period), or the placebo (core treatment period) + 45 mg BID group. BID group (extended treatment period). During the core treatment period, the drug is administered twice a day for 12 consecutive weeks. Subjects who received the high-dose or low-dose groups during the core treatment period will continue to receive the drug according to their core treatment dose for 12 weeks during the extension period. Subjects who received placebo during the core treatment period will enter the high-dose or low-dose group during the extension period and continue to receive the drug for 12 weeks. The subjects and researchers will remain blinded during this stage. Discontinuation observation period: All subjects in the study (including subjects who withdraw from treatment early for any reason) must be observed for 4 weeks after the last dose.

[0497] Inclusion criteria:

[0498] 1. Understand and voluntarily sign the informed consent form of this study;

[0499] 2. Aged 18 to 75 years (inclusive), regardless of gender;

[0500] 3. Patients were diagnosed with BD according to the International Criteria for Diagnosis (Classification) of Behçet's Disease (ICBD-2013);

[0501] 4. At least 2 oral ulcers were present during Visit 1 (Screening Period), and:

[0502] a. When Visit 2 occurs at least 14 days after Visit 1, the subject has at least 2 oral ulcers at Visit 2 (the day of randomization); or

[0503] b. When Visit 2 occurs 0 to 42 days after Visit 1, the subject has at least three oral ulcers at Visit 2 (the day of randomization);

[0504] 5. Suitable for systemic treatment of oral ulcers: Based on the severity of the disease and the extent of the affected area, the investigator determines that the subject's oral ulcer is not suitable for local treatment, or the oral ulcer cannot be effectively controlled by local treatment, and systemic treatment is selected;

[0505] 6. Female subjects of childbearing potential and male subjects who have not undergone vasectomy must take effective contraceptive measures (effective contraceptive measures include: vasectomy, abstinence, intrauterine device (IUD), hormones (oral, patch, ring, injection, implant) and barrier methods (diaphragm, cervical cap, sponge, condom)) throughout the study period starting from the signing of the informed consent form and within 3 months after the last dose;

[0506] 7. Ability to comply with follow-up schedule and other program requirements.

[0507] Primary efficacy endpoint:

[0508] The area under the curve (AUC) of oral ulcer count in BD patients from baseline to week 12 of treatment.

[0509] Secondary efficacy endpoints:

[0510] The proportion of subjects who achieved complete relief of oral ulcers (healing of oral ulcers) at week 6 and maintained complete relief for 6 weeks;

[0511] Complete remission rate of oral ulcers at week 12 compared with the placebo group;

[0512] Change in oral ulcer pain visual analogue scale (VAS) score at week 12 compared with baseline;

[0513] Change in the number of oral ulcers at week 12 compared with baseline;

[0514] During the core treatment period, oral ulcer healing time (complete remission) is the time when the patient's first oral ulcer is completely relieved; ulcer healing is defined as: the ulcer surface is completely flattened, without congestion and pain;

[0515] The proportion of subjects without oral ulcers who first achieved complete remission and maintained complete remission during the core treatment period;

[0516] During the core treatment period, the number of oral ulcers that recurred after the patient had completely resolved was the number of oral ulcers that recurred for the first time after the patient had completely resolved;

[0517] Change in physician global assessment at week 12 in BD patients with skin lesions (acneform lesions, folliculitis, and erythema nodosum) at baseline during the core treatment phase;

[0518] Complete remission rate of genital ulcers (proportion of patients without genital ulcers) at week 12 of treatment compared with baseline.

[0519] Results of this clinical study:

[0520] 1. Effectiveness

[0521] Table 3. Core period effectiveness evaluation data

[0522] The proportion of patients who achieved complete relief of oral ulcers (no oral ulcers) at the 6th week of treatment and maintained complete relief for 6 weeks was 27.6% in the 45 mg group, 38.7% in the 60 mg group, and 3.3% in the placebo group; the inter-group differences between the 45 mg group, the 60 mg group, and the placebo group were 23.7% and 35.5%, respectively.

[0523] At week 12, the number of oral ulcers in the 45 mg, 60 mg, and placebo groups decreased by 2.7, 2.9, and 1.7, respectively, compared to baseline. The 60 mg group showed a statistically significant decrease compared to the placebo group (-1.3, p = 0.0016) and the 45 mg group showed a statistically significant decrease compared to the placebo group (-1.2, p = 0.00026).

[0524] The median healing time for oral ulcers in the 60 mg group was 16 days (95% CI: (8, 46)); the median healing time in the 45 mg group was 15 days (95% CI: (9, 29); the median healing time for placebo could not be estimated. The differences in oral ulcer healing time between the 45 mg and 60 mg groups compared with placebo during the core treatment period were statistically significant.

[0525] During the core treatment period, the proportions of patients who experienced complete relief of oral ulcers for the first time and maintained complete relief were 34.5%, 51.6%, and 13.3% in the 45mg, 60mg, and placebo groups, respectively.

[0526] At week 12, both subjects in the 45 mg dose group who had genital ulcers at baseline and were still in the group achieved complete remission of genital ulcers. At week 12, both subjects in the 60 mg dose group who had genital ulcers at baseline and were still in the group achieved complete remission of genital ulcers.

[0527] At week 12, the number of tender joints in two of the three patients in the 60 mg dose group who had tender joints at baseline remained in the group and decreased to zero.

[0528] At week 12, among the 9 patients in the 45 mg dose group who had lesions on baseline skin PGA assessment, 5 of them had their PGA scores reduced to 0. Specifically, 1 patient had acneiform lesions on baseline PGA, and the acne disappeared at week 12; 2 patients had erythema nodosum on baseline PGA, and the erythema nodosum disappeared at week 12; 1 patient had folliculitis on baseline PGA, and the folliculitis disappeared at week 12; and 1 patient had acne, folliculitis, and erythema nodosum on baseline, all of which disappeared at week 12. At week 12, among the 8 patients in the 60 mg dose group who had lesions on baseline skin PGA assessment, 5 of them had their PGA scores reduced to 0. Specifically, 2 patients had acne on baseline, and the lesions disappeared at week 12; and 3 patients had folliculitis on baseline, and the lesions disappeared at week 12.

[0529] 2. Rapid clinical effect in treating oral ulcers associated with Behçet's disease

[0530] On the third day of treatment, the initial drug effect was shown compared with the placebo group;

[0531] On the 7th day of treatment, more than 30% of the subjects in the active drug treatment group achieved complete relief of oral ulcers (4% in the placebo group) and the efficacy remained stable throughout the treatment period.

[0532] 3. Security

[0533] The overall safety profile was well tolerated;

[0534] Adverse reactions were all mild or moderate, with the most common being nausea, headache, diarrhea, upper respiratory tract infection, and vomiting. Most occurred in the early stages of treatment, and most resolved within a week without clinical treatment.

[0535] As of the end of the clinical study, no severe adverse reactions occurred.

[0536] As of the end of the clinical study, no deaths occurred;

[0537] As of the end of the clinical study, no adverse events of depression or anxiety were observed, and no cases of depression or suicidal tendencies were reported.

[0538] Three patients reported a history of tuberculosis: tuberculosis (1) and pulmonary tuberculosis (2). By the end of the study, no cases of tuberculosis reactivation or new tuberculosis cases had occurred.

[0539] 4. Other results

[0540] Population pharmacokinetic and exposure-efficacy effect analyses showed that the efficacy response rate increased with increasing dose.

[0541] Example 5

[0542] Clinical studies on patients

[0543] In a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase III clinical study evaluating the efficacy and safety of sedative fortified sedative fortified sedative in patients with moderate-to-severe chronic plaque psoriasis, including 105 subjects with T-SPOT-positive tuberculosis but not active, clinical observations and evaluations were conducted during a 16-week core treatment period, a 36-week extension treatment period, and a 4-week follow-up period. Anxiety and depression were also assessed using the Anxiety and Depression Scale during the screening period, at the end of the 16-week core period, and 4 weeks after the last dose.

[0544] The experimental results showed that by the end of the clinical study, 105 subjects with positive T-SPOT but non-active tuberculosis, 7 patients with previous pulmonary tuberculosis diagnosis, 76 patients with previous tuberculosis, and 1 patient with previous tuberculous pleurisy had no reactivation. No clinical abnormalities related to tuberculosis were found in chest X-ray or CT examinations of all subjects.

[0545] Table 4. Depression Scale Scores in Phase III Clinical Study of Moderate to Severe Plaque Psoriasis

[0546] By the end of the clinical study, there were no statistically significant differences in the mean Hospital Anxiety and Depression Scale anxiety scores and mean Hospital Anxiety and Depression Scale depression scores (± standard deviation) between the experimental and placebo groups (P>0.05). No adverse events of depression or anxiety related to the study drug were observed in the subjects, nor were there any reports of depression or suicidal tendencies.

[0547] Example 6

[0548] Clinical studies on patients

[0549] A total of 36 healthy Chinese subjects participated in a Phase I clinical study, with multiple oral administrations of Example 2 at doses of 15 mg BID, 30 mg BID, 60 mg BID, 75 mg BID and placebo. The clinical trial showed good safety and good tolerance.

[0550] Example 7

[0551] Clinical studies on patients

[0552] In a multicenter, randomized, double-blind, placebo-controlled Phase III clinical study of efficacy and safety in patients with Behçet's disease involving 78 subjects (including 1 patient with a previous diagnosis of pulmonary tuberculosis and 4 patients with latent tuberculosis infection), no tuberculosis reactivation occurred.

[0553] In this disclosure, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any actual relationship or order between these entities or operations.

[0554] It will be appreciated from the foregoing that, although specific embodiments of the present disclosure have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. Such modifications or variations are intended to fall within the scope of the appended claims of the present disclosure.

Claims

1. A method for treating Behcet's syndrome, comprising administering to an individual in need of said method a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, 2. A method for treating oral ulcers associated with Behcet's syndrome, comprising administering to an individual in need of said method a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, 3. A method for treating genital ulcers associated with Behcet's syndrome, comprising administering to an individual in need of said method a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, 4. The method according to any one of claims 1 to 3, wherein 30 mg to 180 mg of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is administered to the subject daily.

5. The method according to any one of claims 1 to 4, wherein 60 mg to 150 mg of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is administered to the subject daily.

6. The method according to any one of claims 1 to 5, wherein 150 mg of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is administered to the subject daily.

7. The method according to any one of claims 1 to 6, wherein the subject is administered 120 mg of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof daily.

8. The method of any one of claims 1 to 7, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the subject at least once daily.

9. The method of any one of claims 1 to 8, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the subject at least twice daily.

10. The method according to any one of claims 1 to 9, wherein the subject is administered 30 mg to 75 mg twice daily of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

11. The method according to any one of claims 1 to 10, wherein the subject is administered 45 mg to 60 mg twice daily of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

12. The method according to any one of claims 1 to 11, wherein the unit dose of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is 2.5 mg to 150 mg.

13. The method according to any one of claims 1 to 12, wherein the unit dose of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is 15 mg to 150 mg.

14. The method according to any one of claims 1 to 13, wherein the unit dose of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 120 mg or 150 mg.

15. The method of any one of claims 1 to 14, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the subject in the form of a tablet or capsule.

16. The method of any one of claims 1 to 15, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is orally administered to the subject.

17. The method of any one of claims 1 to 16, wherein the subject is a mammal, preferably a human.

18. The method of any one of claims 1 to 17, wherein the individual has latent tuberculosis infection.

19. The method of any one of claims 1 to 18, wherein the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

20. The method of any one of claims 1 to 19, wherein the subject has latent tuberculosis infection that has not reactivated after treatment.

21. The method of any one of claims 1 to 19, wherein the subject has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy that has not reactivated after treatment.

22. The method of any one of claims 1 to 19, wherein the subject's cutaneous manifestations of oral ulcer mucosa are improved.

23. The method of any one of claims 1 to 19, wherein the subject has a reduced area under the oral ulcer curve.

24. The method of any one of claims 1 to 19, wherein the subject has a reduced number of oral ulcers.

25. The method of any one of claims 1 to 19, wherein the time required for oral ulcer healing in the individual is shortened, and / or the recurrence of oral ulcer is reduced, and / or the duration of complete remission of oral ulcer is prolonged.

26. The method of any one of claims 1 to 19, wherein the subject's oral ulcer pain is improved.

27. The method of any one of claims 1 to 19, wherein the subject suffers from an improvement in genital ulcers and / or an improvement in genital ulcer pain.

28. The method of any one of claims 1 to 19, wherein the subject's mucocutaneous involvement is improved.

29. The method of any one of claims 1 to 19, wherein the subject's joint involvement is improved.

30. The method of any one of claims 1 to 19, wherein the individual is treated without titration.

31. The method of any one of claims 1 to 19, wherein the subject does not cause or aggravate anxiety / depression.

32. The method of any one of claims 1 to 19, wherein the individual does not have reduced immunity.

33. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for use in treating Behcet's syndrome in an individual.

34. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for use in treating oral ulcers associated with Behcet's syndrome in an individual, 35. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for use in treating genital ulcers associated with Behcet's syndrome in an individual.

36. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 33 to 35, wherein 30 mg to 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject daily.

37. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 33 to 36, wherein the subject is administered 60 mg to 150 mg of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof daily.

38. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 33 to 37, wherein the subject is administered 150 mg of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof daily.

39. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 33 to 38, wherein the subject is administered 120 mg of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof daily.

40. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 33 to 39, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the subject at least once a day.

41. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 33 to 40, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the subject at least twice daily.

42. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 33 to 41, wherein the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is administered to the subject twice daily, 30 mg to 75 mg each time.

43. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 33 to 42, wherein the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is administered to the subject twice daily, 45 mg to 60 mg each time.

44. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 33 to 43, wherein the unit dose of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is 2.5 mg to 150 mg.

45. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 33 to 44, wherein the unit dose of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is 15 mg to 150 mg.

46. ​​A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 33 to 45, wherein the unit dose of the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 120 mg, or 150 mg.

47. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 33 to 46, wherein the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is administered to the subject in the form of a tablet or capsule.

48. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 33 to 47, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally to the subject.

49. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 33 to 48, wherein the subject is a mammal, preferably a human.

50. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 33 to 49, wherein the subject has latent tuberculosis infection.

51. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 33 to 50, wherein the subject has a history of tuberculosis infection, tuberculosis disease or tuberculous pleurisy.

52. The method of any one of claims 33 to 50, wherein the subject has latent tuberculosis infection but has not reactivated after treatment.

53. The method of any one of claims 33 to 50, wherein the subject has a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy that has not been reactivated after treatment.

54. The method of any one of claims 33 to 50, wherein the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the skin of the oral ulcer mucosa of the subject is improved.

55. The method of any one of claims 33 to 50, wherein the subject has a reduced area under the oral ulcer curve, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

56. The method of any one of claims 33 to 50, wherein the number of oral ulcers in the subject is reduced, wherein the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is used.

57. A method as claimed in any one of claims 33 to 50, a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the time required for healing of oral ulcers in the individual is shortened, and / or the recurrence of oral ulcers is reduced, and / or the duration of complete remission of oral ulcers is prolonged.

58. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 33 to 50, wherein the subject's oral ulcer pain is improved.

59. The method according to any one of claims 33 to 50, wherein the subject has improved genital ulcers and / or improved genital ulcer pain.

60. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 33 to 50, wherein the subject's mucocutaneous involvement is improved.

61. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 33 to 50, wherein the subject's joint involvement is improved.

62. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 33 to 50, wherein the subject is treated without titration.

63. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 33 to 50, wherein the subject does not cause anxiety or depression or aggravate anxiety or depression.

64. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 33 to 50, wherein the individual's immunity is not reduced.

65. Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Behcet's syndrome in an individual, 66. Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating oral ulcers associated with Behcet's syndrome in an individual, 67. Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating genital ulcer associated with Behcet's syndrome in an individual, 68. The use according to any one of claims 65 to 67, wherein the subject is administered 30 mg to 180 mg daily of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

69. The use according to any one of claims 65 to 68, wherein the subject is administered 60 mg to 150 mg daily of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

70. The use according to any one of claims 65 to 69, wherein the subject is administered 150 mg of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof daily.

71. The use according to any one of claims 65 to 70, wherein the subject is administered 120 mg daily of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

72. The use of any one of claims 65 to 71, wherein the subject is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at least once daily.

73. The use according to any one of claims 65 to 72, wherein the subject is administered a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof at least twice daily.

74. The use according to any one of claims 65 to 73, wherein the subject is administered 30 mg to 75 mg twice daily of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

75. The use according to any one of claims 65 to 74, wherein the subject is administered 45 mg to 60 mg twice daily of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

76. The use according to any one of claims 65 to 75, wherein the unit dose of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is 2.5 mg to 150 mg.

77. The use according to any one of claims 65 to 76, wherein the unit dose of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is 15 mg to 150 mg.

78. The use of any one of claims 65 to 77, wherein the unit dose of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, 120 mg, 150 mg.

79. The use of any one of claims 65 to 78, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the subject in the form of a tablet or capsule.

80. The use of any one of claims 65 to 79, wherein the subject is orally administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

81. The use according to any one of claims 65 to 80, wherein the subject is a mammal, preferably a human.

82. The use of any one of claims 65 to 81, wherein the subject has latent tuberculosis infection.

83. The use of any one of claims 65 to 82, wherein the subject has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

84. The use of any one of claims 65 to 82, wherein the subject has latent tuberculosis infection that has not reactivated after treatment.

85. The use according to any one of claims 65 to 82, wherein the subject has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy which has not reactivated after treatment.

86. The use of any one of claims 65 to 82, wherein the subject has improved skin manifestations of oral ulcer mucosa.

87. The use of any one of claims 65 to 82, wherein the subject has a reduction in the area under the curve for oral ulcers.

88. The use of any one of claims 65 to 82, wherein the subject has a reduced number of oral ulcers.

89. The use of any one of claims 65 to 82, wherein the time required for healing of oral ulcers in the individual is shortened, and / or the recurrence of oral ulcers is reduced, and / or the duration of complete remission of oral ulcers is prolonged.

90. The use of any one of claims 65 to 82, wherein the subject has improved oral ulcer pain.

91. The use of any one of claims 65 to 82, wherein the subject has improved symptoms of genital ulcers and / or improved genital ulcer pain.

92. The use of any one of claims 65 to 82, wherein the subject's mucocutaneous involvement is improved.

93. The method of any one of claims 65 to 82, wherein the subject's joint involvement is improved.

94. The method of any one of claims 65 to 82, wherein the individual is treated without titration.

95. The method of any one of claims 65 to 82, wherein the subject does not cause or aggravate anxiety\depression.

96. The method of any one of claims 65 to 82, wherein the individual does not have reduced immunity.

Images