Treatment of moderate to severe plaque psoriasis

Abstract

Disclosed are a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which can be useful in the treatment of moderate and severe plaque psoriasis.

Description

Treatment of moderate to severe plaque psoriasis

[0001] Citation of Related Applications

[0002] This disclosure claims all rights and interests in the Chinese invention patent application with application number 202311518258.6, filed with the State Intellectual Property Office of the People's Republic of China on November 14, 2023, and entitled "Treatment of Moderate to Severe Plaque Psoriasis," 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 moderate to severe plaque psoriasis.

[0005] background

[0006] Psoriasis, commonly known as "psoriasis", is a chronic inflammatory skin disease stimulated by environmental factors, controlled by multi-gene inheritance, and mediated by abnormal immune response. It is typically manifested as scaly erythema or plaques, which are limited to one place or widely distributed throughout the body.

[0007] In addition to skin symptoms, psoriasis patients often have other systemic diseases, such as psychological disorders. Conditions significantly associated with psoriasis are now referred to as psoriasis comorbidities. A systematic analysis based on a large sample size revealed that the prevalence of anxiety among psoriasis comorbidities was 30.2% (range, 21.7%-38.8%), and the prevalence of depression was 21.7% (range, 15.1%-28.3%).

[0008] Psoriasis patients have an increased prevalence of anxiety and depression. The stress and shame associated with exposed skin lesions may contribute to these symptoms. Depression may also exacerbate psoriasis through shared inflammatory pathways. Psoriasis patients with comorbid depression have significantly increased vascular inflammation and coronary artery plaque burden.

[0009] There is no cure for psoriasis. All treatments should be effective and safe for long-term use, aiming to improve quality of life. Simultaneously, controlling psoriasis-related complications, reducing comorbidities, and improving patients' physical, psychological, and social functioning, thereby enhancing quality of life, are also our treatment goals.

[0010] Psoriasis patients often have weakened or disrupted immune function, increasing their risk of infection with pathogens. Psoriasis patients require medication, and long-term use of immunosuppressants and other drugs in existing psoriasis treatments can further weaken their immune system, further increasing their risk of infection. Mycobacterium tuberculosis is a common infectious pathogen during treatment. Approximately one-third of the global population is infected with Mycobacterium tuberculosis, and 90% of infected individuals can harbor the pathogen for a long time, becoming latent tuberculosis patients. Latent tuberculosis, a breeding ground for active tuberculosis, poses a high degree of uncertainty in the outcome of patients with latent tuberculosis infection, making it a hidden minefield in tuberculosis control. The weakened immune system in patients with latent tuberculosis can easily lead to the progression of latent tuberculosis to active tuberculosis.

[0011] Safety is a prominent requirement in the treatment principles of psoriasis. During the treatment of psoriasis, common drugs such as methotrexate, glucocorticoids, and biologics must be regularly confirmed for tuberculosis infection before and / or during use. The risk of tuberculosis increases after treatment with biologics. Following the principles of safe and effective treatment, attention should be paid to special patient populations with latent tuberculosis infection, pulmonary tuberculosis infection / tuberculosis / tuberculous pleurisy in the treatment of psoriasis. Providing appropriate treatment options for patients with moderate to severe plaque psoriasis and those with latent tuberculosis infection or a history of tuberculosis, reducing adverse reactions and the potential risk of developing active tuberculosis, and striving for greater benefits for patients is of far-reaching significance and impact.

[0012] Overview

[0013] In one aspect, the present disclosure relates to a method for treating moderate to severe plaque psoriasis, 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,

[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 moderate to severe plaque psoriasis in an individual.

[0015] In 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 moderate to severe plaque psoriasis in an individual.

[0016] In another aspect, the present disclosure relates to a pharmaceutical composition for treating moderate to severe plaque psoriasis 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.

[0017] Details

[0018] 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.

[0019] Unless otherwise required in this application, throughout the specification and the appended claims, the words "including," "comprising," "containing," and "having" should be interpreted in an open, inclusive sense, that is, "including but not limited to."

[0020] As used in this disclosure and the appended claims, singular references without indications of quantity include plural references unless the context clearly dictates otherwise.

[0021] 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.

[0022] 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.

[0023] definition

[0024] Accordingly, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims shall have the following meanings:

[0025] In the present disclosure, the term "psoriasis" refers to a skin disease that is stimulated by environmental factors, controlled by polygenic inheritance, and mediated by immunity, and is typically manifested as scaly erythema or plaques that are confined to one place or widely distributed throughout the body.

[0026] In this disclosure, the term "plaque psoriasis" refers to a clinical classification of psoriasis, characterized by dark red plaques or infiltrated erythema covered with white or silvery scales, which may be accompanied by waxy patches, filmy patches, and punctate hemorrhages. In this disclosure, the term "moderate to severe plaque psoriasis" is used to categorize the severity of psoriasis. The three-tiered classification is generally based on BSA, PASI, and DLQI. The grading criteria are shown in Table 1.

[0027] Table 1. Clinical grading criteria for the severity of psoriasis

[0028] Note: BSA, body surface area; PASI, psoriasis area and severity index; DLQI, dermatology life quality index.

[0029] The above classification indicators are defined as follows:

[0030] 1. PASI: This is the most commonly used clinical indicator for assessing the severity of psoriasis and is also widely used to evaluate treatment effectiveness. The PASI score is a key indicator for assessing the severity of psoriasis, quantifying the severity of the condition. It includes a lesion area score and a lesion severity score. It provides a numerical representation of the severity of psoriasis, with higher scores indicating larger lesion areas and more severe lesions.

[0031] 2. BSA: The flexor area of ​​a single palm and finger of the patient is defined as 1% of the body surface area. The total area of ​​the patient's skin lesions on the whole body is evaluated to determine how many palms of the patient's body surface area is covered, which is recorded as BSA.

[0032] 3. PGA: The overall score of erythema, scaling, and plaque infiltration is calculated. Erythema is scored as 0 to 5, with scores ranging from no erythema (may have pigmentation), mild, light red, moderate red, bright red, and dark red. Scaling is scored as 0 to 5, with scores ranging from no scaling, very mild fine scaling, mild fine scaling, moderate rough scaling, severe non-adhesive scaling, and very severe adherent scaling. Infiltration is scored as 0 to 5, with scores ranging from no elevation, very mild elevation, mild elevation, moderate elevation, and very severe elevation. The sum of the three scores is divided by 3 to obtain the PGA score.

[0033] sPGA: Static Physician Global Assessment, which determines the overall extent of psoriasis damage at a given point in time. The score assesses the overall extent of damage, including infiltration, erythema, and scaling, and provides a numerical value to reflect the severity of the damage.

[0034] 4. DLQI: Assess the patient's subjective perception of the impact of the disease on their quality of life in the past week. DLQI is a simple, concise, and practical questionnaire used in clinical studies of skin diseases to assess the impact of skin diseases. The questionnaire contains 10 items related to the subject's skin. The total DLQI score is the sum of all items, ranging from 0 to 30 points, with 30 points representing the worst living condition and 0 points representing the best living condition.

[0035] 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.

[0036] In the present disclosure, the term "biologics" refers to TNF-α inhibitors (including but not limited to etanercept, infliximab, adalimumab, and benzaluzumab), IL-12 / 23 inhibitors (including but not limited to ustekinumab), IL-17 inhibitors (including but not limited to secukinumab, ixekizumab, and brolimumab), IL-23 (p19 subunit) inhibitors (including but not limited to guselkumab and telolimumab), IL-36 receptor inhibitors (including but not limited to pesolizumab), etc. currently used in the treatment of psoriasis.

[0037] 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.

[0038] 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.

[0039] As used herein, the term "activation" refers to the transition of a patient's Mycobacterium tuberculosis infection from latent to active tuberculosis. This refers to the transition of a patient's Mycobacterium tuberculosis infection from latent to active tuberculosis, signifying that the patient is in a state of active tuberculosis and requires aggressive, standardized treatment. As used herein, the term "titrated dosing" refers to the administration of low doses of a drug to gradually achieve the desired drug level.

[0040] 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:

[0041] 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:

[0042] 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.

[0043] 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.

[0044] 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.

[0045] In the present disclosure, the term "pharmaceutically acceptable salt" includes "acceptable acid addition salts" and "acceptable base addition salts".

[0046] 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 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, Glycerol phosphate, 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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:

[0052] (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;

[0053] (ii) inhibiting the disease or disease state, i.e., preventing its occurrence; or

[0054] (iii) ameliorating the disease or condition, even if the disease or condition regresses or does not progress.

[0055] 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.

[0056] 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.

[0057] 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

[0058] In one aspect, the present disclosure relates to a method for treating moderate to severe plaque psoriasis, 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,

[0059] 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.

[0060] 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.

[0061] 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.

[0062] In certain embodiments, the subject is administered 60 mg to 120 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0063] In certain embodiments, the subject is administered 30 mg, 60 mg, 120 mg, or 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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, or the like.

[0077] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered orally to a subject.

[0078] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0079] In certain embodiments, illustrative examples of mammals that can be used with the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0080] In certain embodiments, the subject is a human.

[0081] In certain embodiments, the individual has latent tuberculosis infection.

[0082] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0083] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof of the present disclosure are well tolerated in the treatment of moderate to severe plaque psoriasis.

[0084] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis.

[0085] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration in the treatment of moderate to severe plaque psoriasis.

[0086] 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.

[0087] 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 worsening of depression in the subject.

[0088] 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 moderate to severe plaque psoriasis.

[0089] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0090] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0091] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis, also have excellent therapeutic effects on individuals who have failed biologic treatment. In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis, reduce the area of ​​psoriasis lesions in the individual, and / or reduce the psoriasis lesion area and severity index, and / or reduce the dermatological life quality index.

[0092] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof in the present disclosure improve the sPGA (static physician global assessment) of a subject in the treatment of moderate to severe plaque psoriasis, especially reaching a score of 0 or 1.

[0093] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or aggravate anxiety in the treatment of moderate to severe plaque psoriasis.

[0094] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not induce or aggravate depression in a subject in the treatment of moderate to severe plaque psoriasis.

[0095] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not reduce the immunity of the individual in the treatment of moderate to severe plaque psoriasis.

[0096] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have a good safety profile in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0097] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof of the present disclosure are well tolerated in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0098] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0099] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0100] 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 moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0101] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0102] In certain embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof disclosed herein also have excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis with latent tuberculosis infection.

[0103] In certain embodiments, the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis with latent tuberculosis infection, also has excellent therapeutic effects on individuals who have failed biologic treatment. In certain embodiments, when the compound of formula (I) of the present disclosure, its stereoisomers, or pharmaceutically acceptable salts thereof, is administered to an individual for the treatment of moderate to severe plaque psoriasis with latent tuberculosis infection, either short-term or long-term, the individual does not develop depression.

[0104] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are useful in treating moderate to severe plaque psoriasis in patients with latent tuberculosis infection, but which has not been activated following treatment.

[0105] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with latent tuberculosis infection, reduces the area of ​​psoriasis lesions, and / or reduces the Psoriasis Lesion Area and Severity Index, and / or reduces the Dermatology Life Quality Index.

[0106] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection, improves the sPGA (static physician's global assessment) of the subject, in particular, can reach a score of 0 or 1.

[0107] In certain embodiments, the compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein does not induce or aggravate anxiety in the treatment of moderate to severe plaque psoriasis in individuals with latent tuberculosis infection.

[0108] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not induce or aggravate depression in subjects with moderate to severe plaque psoriasis and latent tuberculosis infection.

[0109] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not reduce the immunity of individuals suffering from latent tuberculosis infection and moderate to severe plaque psoriasis.

[0110] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, reduces the area of ​​psoriasis lesions, and / or reduces the psoriasis lesion area and severity index, and / or reduces the dermatology life quality index.

[0111] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good safety in treating moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0112] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are well tolerated in the treatment of moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0113] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0114] In certain embodiments, the compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not require titration in the treatment of moderate to severe plaque psoriasis in patients with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0115] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0116] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0117] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0118] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects in treating moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy who have failed treatment with biological agents.

[0119] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, when administered short-term or long-term, does not cause depression in subjects with moderate to severe plaque psoriasis who have a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0120] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein are used to treat moderate to severe plaque psoriasis in patients with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy, but the disease is not activated after treatment.

[0121] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, reduces the area of ​​psoriasis lesions, and / or reduces the psoriasis lesion area and severity index, and / or reduces the dermatology life quality index.

[0122] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, improves the sPGA (static physician's global assessment), in particular, can reach a score of 0 or 1.

[0123] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or aggravate anxiety in individuals with moderate to severe plaque psoriasis who have a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0124] In certain embodiments, the disclosed compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, does not cause depression or aggravate depression. In certain embodiments, the disclosed compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, does not reduce the immunity of the individual.

[0125] 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 moderate to severe plaque psoriasis in an individual.

[0126] 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.

[0127] 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.

[0128] In certain embodiments, the subject is administered 30 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0129] In certain embodiments, the subject is administered 60 mg to 120 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0130] In certain embodiments, the subject is administered 30 mg, 60 mg, 120 mg, or 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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. 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.

[0141] In certain embodiments, illustrative examples of unit dosages of 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, 75 mg, 120 mg, and 150 mg.

[0142] 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, or the like.

[0143] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered orally to a subject.

[0144] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0145] In certain embodiments, illustrative examples of mammals that can be used with the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0146] In certain embodiments, the subject is a human.

[0147] In certain embodiments, the individual has latent tuberculosis infection.

[0148] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0149] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof of the present disclosure are well tolerated in the treatment of moderate to severe plaque psoriasis.

[0150] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis.

[0151] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration in the treatment of moderate to severe plaque psoriasis.

[0152] 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.

[0153] 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 worsening of depression in the subject.

[0154] 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 moderate to severe plaque psoriasis.

[0155] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0156] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0157] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have failed biological therapy in the treatment of moderate to severe plaque psoriasis.

[0158] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis, reduce the area of ​​psoriasis lesions in the subject, and / or reduce the psoriasis lesion area and severity index, and / or reduce the dermatology life quality index.

[0159] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof in the present disclosure improve the sPGA (static physician global assessment) of a subject in the treatment of moderate to severe plaque psoriasis, especially reaching a score of 0 or 1.

[0160] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or aggravate anxiety in the treatment of moderate to severe plaque psoriasis.

[0161] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not induce or aggravate depression in a subject in the treatment of moderate to severe plaque psoriasis.

[0162] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not reduce the immunity of the individual in the treatment of moderate to severe plaque psoriasis.

[0163] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have a good safety profile in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0164] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof of the present disclosure are well tolerated in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0165] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0166] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0167] 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 moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0168] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0169] In certain embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof disclosed herein also have excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis with latent tuberculosis infection.

[0170] In certain embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof disclosed herein also have excellent therapeutic effects in treating moderate to severe plaque psoriasis with latent tuberculosis infection in individuals who have failed treatment with biological agents.

[0171] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are useful in treating moderate to severe plaque psoriasis in patients with latent tuberculosis infection, but which has not been activated following treatment.

[0172] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with latent tuberculosis infection, reduces the area of ​​psoriasis lesions, and / or reduces the Psoriasis Lesion Area and Severity Index, and / or reduces the Dermatology Life Quality Index.

[0173] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection, improves the sPGA (static physician's global assessment) of the subject, in particular, can reach a score of 0 or 1.

[0174] In certain embodiments, the compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein does not induce or aggravate anxiety in the treatment of moderate to severe plaque psoriasis in individuals with latent tuberculosis infection.

[0175] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not induce or aggravate depression in subjects with moderate to severe plaque psoriasis and latent tuberculosis infection.

[0176] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not reduce the immunity of individuals suffering from latent tuberculosis infection and moderate to severe plaque psoriasis.

[0177] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good safety in treating moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0178] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are well tolerated in the treatment of moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0179] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0180] In certain embodiments, the compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not require titration in the treatment of moderate to severe plaque psoriasis in patients with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0181] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0182] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, also has excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0183] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0184] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects in treating moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy who have failed treatment with biological agents.

[0185] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein are used to treat moderate to severe plaque psoriasis in patients with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy, but the disease is not activated after treatment.

[0186] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, reduces the area of ​​psoriasis lesions, and / or reduces the psoriasis lesion area and severity index, and / or reduces the dermatology life quality index.

[0187] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, improves the sPGA (static physician's global assessment), in particular, can reach a score of 0 or 1.

[0188] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or aggravate anxiety in individuals with moderate to severe plaque psoriasis who have a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0189] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, does not cause depression or aggravate depression.

[0190] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not reduce the immunity of individuals suffering from moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0191] In 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 moderate to severe plaque psoriasis in an individual.

[0192] 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.

[0193] 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.

[0194] In certain embodiments, the subject is administered 30 mg to 150 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0195] In certain embodiments, the subject is administered 60 mg to 120 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0196] In certain embodiments, the subject is administered 30 mg, 60 mg, or 120 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] In certain embodiments, illustrative examples of unit dosages of 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, 75 mg, 120 mg, and 150 mg.

[0209] 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, or the like.

[0210] In certain embodiments, a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered orally to a subject.

[0211] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0212] In certain embodiments, illustrative examples of mammals that can be used with the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0213] In certain embodiments, the subject is a human.

[0214] In certain embodiments, the individual has latent tuberculosis infection.

[0215] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0216] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof of the present disclosure are well tolerated in the treatment of moderate to severe plaque psoriasis.

[0217] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis.

[0218] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration in the treatment of moderate to severe plaque psoriasis.

[0219] 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.

[0220] 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 worsening of depression in the subject.

[0221] 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 moderate to severe plaque psoriasis.

[0222] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0223] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0224] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have failed biological therapy in the treatment of moderate to severe plaque psoriasis.

[0225] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis, reduce the area of ​​psoriasis lesions in the subject, and / or reduce the psoriasis lesion area and severity index, and / or reduce the dermatology life quality index.

[0226] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof in the present disclosure improve the sPGA (static physician global assessment) of a subject in the treatment of moderate to severe plaque psoriasis, especially reaching a score of 0 or 1.

[0227] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or aggravate anxiety in the treatment of moderate to severe plaque psoriasis.

[0228] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not induce or aggravate depression in a subject in the treatment of moderate to severe plaque psoriasis.

[0229] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not reduce the immunity of the individual in the treatment of moderate to severe plaque psoriasis.

[0230] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have a good safety profile in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0231] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof of the present disclosure are well tolerated in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0232] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0233] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0234] 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 moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0235] In certain embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof disclosed herein also have excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis with latent tuberculosis infection.

[0236] In certain embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof disclosed herein also have excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis with latent tuberculosis infection.

[0237] In certain embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof disclosed herein also have excellent therapeutic effects in treating moderate to severe plaque psoriasis with latent tuberculosis infection in individuals who have failed treatment with biological agents.

[0238] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are useful in treating moderate to severe plaque psoriasis in patients with latent tuberculosis infection, but which has not been activated following treatment.

[0239] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with latent tuberculosis infection, reduces the area of ​​psoriasis lesions, and / or reduces the Psoriasis Lesion Area and Severity Index, and / or reduces the Dermatology Life Quality Index.

[0240] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection, improves the sPGA (static physician's global assessment) of the subject, in particular, can reach a score of 0 or 1.

[0241] In certain embodiments, the compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein does not induce or aggravate anxiety in the treatment of moderate to severe plaque psoriasis in individuals with latent tuberculosis infection.

[0242] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not induce or aggravate depression in subjects with moderate to severe plaque psoriasis and latent tuberculosis infection.

[0243] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not reduce the immunity of individuals suffering from latent tuberculosis infection and moderate to severe plaque psoriasis.

[0244] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good safety in treating moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0245] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are well tolerated in the treatment of moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0246] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0247] In certain embodiments, the compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not require titration in the treatment of moderate to severe plaque psoriasis in patients with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0248] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have a faster onset of action in treating moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0249] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0250] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0251] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects in treating moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy who have failed treatment with biological agents.

[0252] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein are used to treat moderate to severe plaque psoriasis in patients with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy, but the disease is not activated after treatment.

[0253] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, reduces the area of ​​psoriasis lesions, and / or reduces the psoriasis lesion area and severity index, and / or reduces the dermatology life quality index.

[0254] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, improves the sPGA (static physician's global assessment), in particular, can reach a score of 0 or 1.

[0255] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or aggravate anxiety in individuals with moderate to severe plaque psoriasis who have a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0256] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, does not cause depression or aggravate depression.

[0257] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not reduce the immunity of individuals suffering from moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0258] In another aspect, the present disclosure relates to a pharmaceutical composition for treating moderate to severe plaque psoriasis 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] In certain embodiments, the subject is administered 60 mg to 120 mg of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof daily.

[0263] In certain embodiments, the subject is administered 30 mg, 60 mg, 120 mg, or 150 mg daily of a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0264] In certain embodiments, the subject is administered 120 mg daily of a compound of Formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0265] In certain embodiments, the subject is administered 150 mg daily of a compound of Formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0266] 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.

[0267] 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.

[0268] In certain embodiments, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to a subject twice daily.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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, 15 mg, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg, 150 mg.

[0276] 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, or the like.

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

[0278] In certain embodiments, illustrative examples of individuals that can be used with the present disclosure include, but are not limited to, mammals.

[0279] In certain embodiments, illustrative examples of mammals that can be used with the present disclosure include, but are not limited to, dogs, cats, cows, sheep, horses, and humans.

[0280] In certain embodiments, the subject is a human.

[0281] In certain embodiments, the individual has latent tuberculosis infection.

[0282] In certain embodiments, the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

[0283] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof of the present disclosure are well tolerated in the treatment of moderate to severe plaque psoriasis.

[0284] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis.

[0285] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration in the treatment of moderate to severe plaque psoriasis.

[0286] 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.

[0287] 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 worsening of depression in the subject.

[0288] 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 moderate to severe plaque psoriasis.

[0289] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0290] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis.

[0291] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have failed biological therapy in the treatment of moderate to severe plaque psoriasis.

[0292] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis, reduce the area of ​​psoriasis lesions in the subject, and / or reduce the psoriasis lesion area and severity index, and / or reduce the dermatology life quality index.

[0293] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof in the present disclosure improve the sPGA (static physician global assessment) of a subject in the treatment of moderate to severe plaque psoriasis, especially reaching a score of 0 or 1.

[0294] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or aggravate anxiety in the treatment of moderate to severe plaque psoriasis.

[0295] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not induce or aggravate depression in a subject in the treatment of moderate to severe plaque psoriasis.

[0296] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not reduce the immunity of the individual in the treatment of moderate to severe plaque psoriasis.

[0297] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have a good safety profile in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0298] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof of the present disclosure are well tolerated in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0299] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0300] In certain embodiments, the disclosed compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, do not require titration in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0301] 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 moderate to severe plaque psoriasis in patients with latent tuberculosis infection.

[0302] In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or their pharmaceutically acceptable salts also have excellent therapeutic effects on individuals who have not been treated with biologics in the treatment of moderate to severe plaque psoriasis. In certain embodiments, the compounds of formula (I) disclosed herein, their stereoisomers, or their pharmaceutically acceptable salts also have excellent therapeutic effects on individuals who have been treated with biologics in the treatment of moderate to severe plaque psoriasis.

[0303] In certain embodiments, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof disclosed herein also have excellent therapeutic effects in treating moderate to severe plaque psoriasis with latent tuberculosis infection in individuals who have failed treatment with biological agents.

[0304] In certain embodiments, administration of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject for the treatment of moderate to severe plaque psoriasis with latent tuberculosis infection, either short-term or long-term, does not result in depression in the subject.

[0305] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are useful in treating moderate to severe plaque psoriasis in patients with latent tuberculosis infection, but which has not been activated following treatment.

[0306] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with latent tuberculosis infection, reduces the area of ​​psoriasis lesions, and / or reduces the Psoriasis Lesion Area and Severity Index, and / or reduces the Dermatology Life Quality Index.

[0307] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in patients with latent tuberculosis infection, improves the sPGA (static physician's global assessment) of the subject, in particular, can reach a score of 0 or 1.

[0308] In certain embodiments, the compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein does not induce or aggravate anxiety in the treatment of moderate to severe plaque psoriasis in individuals with latent tuberculosis infection.

[0309] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not induce or aggravate depression in subjects with moderate to severe plaque psoriasis and latent tuberculosis infection.

[0310] In certain embodiments, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is used to treat moderate to severe plaque psoriasis in patients with latent tuberculosis infection, and the individual's immunity is not reduced.

[0311] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good safety in treating moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0312] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein are well tolerated in the treatment of moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0313] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein have good compliance in the treatment of moderate to severe plaque psoriasis in patients with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0314] In certain embodiments, the compound of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not require titration in the treatment of moderate to severe plaque psoriasis in patients with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0315] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals who have not been treated with biological agents in the treatment of moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0316] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects on individuals treated with biological agents in the treatment of moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0317] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof also has excellent therapeutic effects in treating moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy who have failed treatment with biological agents.

[0318] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein are used to treat moderate to severe plaque psoriasis in patients with a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy, but the disease is not activated after treatment.

[0319] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, reduces the area of ​​psoriasis lesions, and / or reduces the psoriasis lesion area and severity index, and / or reduces the dermatology life quality index.

[0320] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, improves the sPGA (static physician's global assessment), in particular, can reach a score of 0 or 1.

[0321] In certain embodiments, the compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof disclosed herein do not cause anxiety or aggravate anxiety in individuals with moderate to severe plaque psoriasis who have a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0322] In certain embodiments, the compound of formula (I) disclosed herein, its stereoisomers, or pharmaceutically acceptable salts thereof, in the treatment of moderate to severe plaque psoriasis in individuals with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy, does not cause depression or aggravate depression.

[0323] In certain embodiments, the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof disclosed herein do not reduce the immunity of individuals suffering from moderate to severe plaque psoriasis with a history of pulmonary tuberculosis infection, tuberculosis, or tuberculous pleurisy.

[0324] 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.

[0325] Example

[0326] Glossary:

[0327] PASI: Psoriasis Area and Severity Index

[0328] The formula for calculating the PASI score change rate (PASI score improvement) is: (baseline PASI score - visit PASI score) / baseline PASI score * 100%. PASI-75: PASI score improvement ≥ 75%

[0329] PASI-90: ≥90% improvement in PASI score

[0330] PASI-50: ≥50% improvement in PASI score

[0331] sPGA: Static Physician Global Assessment, which determines the overall damage of the patient's psoriasis at a given time point. The score is used to assess the overall damage of infiltration, erythema and scaling, and the severity of the damage is reflected in a specific number.

[0332] BSA: total psoriasis lesion area

[0333] DLQI: Dermatology Life Quality Index

[0334] BID: twice daily

[0335] HADS: Hospital Anxiety and Depression Scale

[0336] Example 1

[0337] Preparation of compounds of formula (I)

[0338] 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

[0339] Prepared by referring to the preparation method 2 of Example 3 in CN101885731A.

[0340] Example 2

[0341] Preparation of stereoisomers of compounds of formula (I)

[0342] (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

[0343] The obtained product was prepared according to the preparation method of Example 1 in CN116332954 A.

[0344] Example 3

[0345] This study enrolled patients with moderate-to-severe chronic plaque psoriasis. Enrollment criteria were established for disease duration and severity (≥6 months of psoriasis history, PASI score ≥12, sPGA score ≥3, and BSA ≥10%). A total of 305 subjects (211 in the experimental group and 94 in the placebo group, including 105 with positive T-SPOT but non-active tuberculosis) were enrolled. PASI-75 was the primary efficacy endpoint, with secondary efficacy endpoints including sPGA score of 0 or 1 with a ≥2-point decrease from baseline, PASI-90, PASI-50, sPGA score, PASI-75 with sPGA 0 / 1 and a ≥2-point decrease from baseline, and relapse rate. Improvement in pruritus and changes in DLQI scores were also assessed. Clinical observation was performed over a 16-week core treatment period, a 36-week extension period, and a 4-week follow-up period. The experimental group of subjects was administered 60 mg BID of the compound of Example 2, and the placebo group was administered 60 mg BID of the compound of Example 2 during the extended treatment period.

[0346] Results of this clinical study:

[0347] 1. Effectiveness

[0348] Primary efficacy indicator: Compared with baseline, the proportion of subjects with a PASI-75 score at week 16 of treatment was 53.6% in the Example 2 group, which was statistically significantly different from the placebo group (16.0%) (P<0.0001). The difference in rate between the Example 2 group and the placebo group was 37.6%, demonstrating that Example 2 was more effective than placebo.

[0349] Secondary efficacy indicators: The Example 2 group also showed significant statistical differences compared with the placebo group (P<0.0001), further demonstrating the efficacy of Example 2.

[0350] 2. Security

[0351] The severity of drug-related adverse events that occurred was mainly grade 1 or 2;

[0352] No deaths occurred;

[0353] No serious adverse events related to the drug occurred;

[0354] Adverse events leading to drug discontinuation: All were grade 1 or 2 in severity, with no grade 3 or higher adverse events leading to drug discontinuation.

[0355] By the end of the clinical study, none of the subjects with positive T-SPOT results but non-active tuberculosis had recurrence of tuberculosis, and no abnormalities were found in chest imaging examinations at the 16th week visit;

[0356] By the end of the clinical study, no depression or suicidal tendencies were observed in any of the subjects.

[0357] Table 2. Clinical response information during the 16-week core treatment period:

[0358] Example 4

[0359] 1. Trial Drug

[0360] The tablets of the compound described in Example 2 have a specification of 15 mg / tablet.

[0361] Control drug: placebo tablets of the test drug, with a specification of 0 mg / tablet.

[0362] 2. Inclusion criteria

[0363] 1) Aged ≥ 18 years old when signing the informed consent form (ICF), regardless of gender;

[0364] 2) Patients clinically diagnosed with stable plaque psoriasis with a history of psoriasis ≥ 6 months (from the time of randomization);

[0365] 3) Patients must meet the following requirements at screening and baseline:

[0366] a. Psoriasis Area and Severity Index (PASI) score ≥ 12, and;

[0367] b. Static Physician Global Assessment (sPGA) score ≥ 3 points (based on the sPGA 0-4 point scale), and;

[0368] c. Psoriasis skin lesion area (BSA) ≥ 10%.

[0369] 4) Female subjects of fertile potential and male subjects who have not undergone vasectomy are willing to take effective contraceptive measures (effective contraceptive measures include: vasectomy, abstinence, intrauterine contraceptive 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 ICF and within 3 months after the last dose of the study drug); female subjects of fertile potential must have a negative serum pregnancy test (blood human chorionic gonadotropin [HCG]) within 7 days before randomization; male subjects cannot donate sperm within 3 months after the first dose of the study drug to the last dose;

[0370] Note: Fertile potential can be defined as: non-menopausal women who have experienced menarche, have not undergone sterilization surgery (hysterectomy / bilateral oophorectomy / bilateral tubal ligation), or have undergone sterilization surgery but not for less than 6 months (menopause refers to continuous natural menopause for ≥12 months).

[0371] 5) The subjects voluntarily participated in the trial and signed the informed consent form.

[0372] 3. Dosage regimen

[0373] The treatment period was divided into two stages. During the double-blind core treatment period, subjects received 60 mg of the trial drug BID or placebo for 16 weeks (Week 0 to Week 16); during the open extension treatment period, all subjects received 60 mg of the trial drug BID for 36 weeks (Week 16 to Week 52).

[0374] 4. Test results

[0375] A total of 305 subjects were included in the trial (211 in the experimental group and 94 in the placebo group; the patients included 105 subjects with positive T-SPOT but non-active tuberculosis, 7 patients with previous diagnosis of pulmonary tuberculosis, 76 patients with previous tuberculosis, and 1 patient with previous tuberculous pleurisy).

[0376] The primary efficacy endpoint was the proportion of subjects achieving a PASI-75 score at week 16 compared to baseline. A key secondary efficacy endpoint was the percentage of subjects achieving an sPGA score of 0 or 1 with a ≥2-point decrease from baseline at week 16. Secondary efficacy endpoints included PASI-90, PASI-75, PASI-50, PASI-75 with a sPGA score of 0 / 1 and a ≥2-point decrease from baseline at each visit, and the rate of change in BSA. Clinical observation and evaluation were conducted over a 16-week core treatment period, a 36-week extension treatment period, and a 4-week follow-up period. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale at screening, at the end of the 16-week core period, and 4 weeks after the last dose.

[0377] 1) Effectiveness

[0378] Table 3. Clinical responses at week 16 in a phase III study of moderate to severe plaque psoriasis

[0379] 2) Security

[0380] The main adverse reactions and their incidence rates were nausea (23.7%), diarrhea (11.4%), vomiting (10.0%), increased bowel movement frequency (10.4%), dizziness (9.0%), headache (8.1%), hypertriglyceridemia (5.7%), and fatigue (8.5%), all of which were Grade 1 or 2. There were no special safety risks associated with the trial drug during clinical use. Gastrointestinal reactions (nausea, vomiting, diarrhea, etc.) and various neurological abnormalities (dizziness, headache) mostly occurred in the first two weeks of administration, and most subjects recovered on their own without the need for medication.

[0381] No deaths occurred;

[0382] No drug-related serious adverse events occurred during the core treatment period;

[0383] Adverse events leading to drug discontinuation: All were grade 1 or 2 in severity, with no grade 3 or higher adverse events leading to drug discontinuation.

[0384] 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 cases of tuberculosis reactivation, and no tuberculosis-related clinical abnormalities were found in chest X-ray or CT examinations of any subject.

[0385] Table 4. Depression Scale Scores in Phase III Clinical Study of Moderate to Severe Plaque Psoriasis

[0386] By the end of the clinical study, there were no statistically significant differences in the mean HADS anxiety scores and mean HADS 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.

[0387] By the end of the clinical study, the drug had demonstrated good efficacy in patients who had failed biologic therapy. Two subjects who had failed adalimumab achieved the PASI-50 efficacy endpoint in this trial.

[0388] Example 5

[0389] 1. Trial Drug

[0390] The tablets of the compound described in Example 2 have a specification of 15 mg / tablet.

[0391] Control drug: placebo tablets of the test drug, with a specification of 0 mg / tablet.

[0392] 2. Inclusion criteria

[0393] 1) Aged ≥18 and ≤75 years old, regardless of gender;

[0394] 2) Patients with plaque psoriasis, with a history of psoriasis ≥ 6 months;

[0395] 3) Patients must meet the following requirements at screening and baseline: Psoriasis Area and Severity Index (PASI) score ≥ 12, static physician global assessment (sPGA) score ≥ 3 (moderate to severe), and psoriasis skin lesion area (BSA) ≥ 10%;

[0396] 4) Patients assessed by researchers as suitable for systemic treatment of psoriasis;

[0397] 5) 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 contraceptive 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;

[0398] 6) Provided informed consent for this study and voluntarily signed a written informed consent form.

[0399] 3. Dosage regimen

[0400] A multicenter, randomized, double-blind, placebo-controlled, parallel-controlled design was used to enroll 216 subjects. They were randomly assigned in a 1:1:1:1 ratio to a low-dose group (15 mg BID), a medium-dose group (30 mg BID), a high-dose group (60 mg BID), and a placebo group for a 16-week core treatment period. Following the core treatment period, subjects in the low-dose, medium-dose, and high-dose groups maintained their original doses for a 36-week extension period. Subjects in the placebo group completed the core treatment period and were transferred to the medium-dose group for an additional 36 weeks of extension treatment. All groups completed a total of 52 weeks of treatment. Subjects who completed 52 weeks of treatment or discontinued treatment midway were required to enter a 4-week observation period.

[0401] 4. Test results

[0402] primary efficacy endpoint;

[0403] The proportion of subjects with a ≥75% reduction in PASI score (PASI-75) at Week 16 compared to baseline;

[0404] Secondary efficacy endpoints:

[0405] Compared with baseline, the sPGA score at week 16 of treatment was 0 or 1 and decreased by ≥2 points compared with baseline; compared with baseline, the PASI-90, PASI-75, BSA change rate, PASI score change, PASI-50, Dermatology Life Quality Index (DLQI) change, and the proportion of patients with PASI-75 and sPGA 0 / 1 and a decrease of ≥2 points compared with baseline at each visit point were used as secondary efficacy endpoints. Clinical observation and evaluation were conducted during the 16-week core treatment period, the 36-week extended treatment period, and the follow-up period (4 weeks).

[0406] 1. Effectiveness

[0407] 2. Safety: Adverse events related to the trial drug during the double-blind core period (weeks 1-16) with an incidence of ≥5% in any of the low-, medium-, and high-dose groups include: increased triglycerides, increased lipids, diarrhea, nausea, abdominal discomfort, hyperlipidemia, headache, fatigue, etc.; those with an incidence of ≥10% include: diarrhea, nausea, headache, fatigue.

[0408] No deaths occurred;

[0409] No drug-related serious adverse events occurred during the core treatment period;

[0410] Adverse events leading to drug discontinuation: All were grade 1 or 2 in severity, with no grade 3 or higher adverse events leading to drug discontinuation.

[0411] By the end of the clinical study, no adverse events of depression or anxiety were reported by subjects in the experimental group or the placebo group, and no depression or suicidal tendencies were observed.

[0412] By the end of the clinical study, the drug demonstrated good efficacy in patients who had failed biologic therapy. One subject who had failed adalimumab, one who had failed secukinumab, and one who had failed anti-TNF-α monoclonal antibody therapy all achieved the PASI-50 efficacy endpoint in this trial. One subject who had failed adalimumab also achieved both the PASI-75 and PASI-90 efficacy endpoints.

[0413] 3. Other results

[0414] Population pharmacokinetic and exposure-efficacy effect analyses showed that the efficacy response rate increased with increasing dose.

[0415] Example 6

[0416] Clinical studies on patients

[0417] 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.

[0418] 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.

[0419] 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 moderate to severe plaque psoriasis, 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. The method of claim 1, wherein the subject is administered 30 mg to 180 mg of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof daily.

3. The method of claim 1 or 2, wherein 60 mg to 150 mg of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is administered to the subject daily.

4. The method of claim 1 or 3, wherein 60 mg to 120 mg of the compound of formula (I), its stereoisomer 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 120 mg of the compound of formula (I), its stereoisomer 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 of any one of claims 1 to 6, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is administered to the subject at least once 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 twice daily.

9. The method according to any one of claims 1 to 8, 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.

10. The method according to any one of claims 1 to 9, wherein the subject is administered 30 mg to 60 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 unit dose of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is 2.5 mg to 150 mg.

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 15 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, 30 mg, 45 mg, 60 mg, 75 mg, 120 mg or 150 mg.

14. The method of any one of claims 1 to 13, 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.

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 orally administered to the subject.

16. The method of any one of claims 1 to 15, wherein the subject is a mammal, preferably a human.

17. The method of any one of claims 1 to 16, wherein the individual has latent tuberculosis infection.

18. The method of any one of claims 1 to 17, wherein the individual has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

19. A method as claimed in any one of claims 1 to 18, without the need for titration of administration.

20. The method of any one of claims 1 to 18, wherein the subject has latent tuberculosis infection that has not reactivated after treatment.

21. The method of any one of claims 1 to 18, 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 18, wherein the subject has a reduction in psoriasis lesion area, and / or a reduction in Psoriasis Lesion Area and Severity Index, and / or a reduction in Dermatology Life Quality Index.

23. The method according to any one of claims 1 to 18, wherein the subject's sPGA (static Physician's Global Assessment) improves, in particular to a score of 0 or 1.

24. The method of any one of claims 1 to 18, wherein the subject does not cause or exacerbate anxiety.

25. The method of any one of claims 1 to 18, wherein the subject does not induce or exacerbate depressive mood.

26. The method of any one of claims 1 to 18, wherein the subject also has a superior therapeutic effect on a subject not previously treated with a biologic.

27. The method of any one of claims 1 to 18, wherein the subject also has a superior therapeutic effect on a subject treated with a biologic.

28. The method of any one of claims 1 to 18, wherein the subject also has a superior therapeutic effect on a subject who has failed treatment with a biologic agent.

29. The method of any one of claims 1 to 18, wherein the subject does not have reduced immunity.

30. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof for use in treating moderate to severe plaque psoriasis in an individual.

31. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 30, wherein 30 mg to 180 mg of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is administered to the subject daily.

32. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 30 or 31, wherein 60 mg to 150 mg of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is administered to the subject daily.

33. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 30 or 32, wherein the subject is administered 60 mg to 120 mg of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof daily.

34. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 30 to 33, wherein the subject is administered 120 mg of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof daily.

35. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 30 to 34, wherein the subject is administered 150 mg of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof daily.

36. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 35, 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.

37. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 36, wherein the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is administered to the subject at least twice daily.

38. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 37, 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.

39. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 38, wherein the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is administered to the subject twice daily, 30 mg to 60 mg each time.

40. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 39, wherein the unit dose of the compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is 2.5 mg to 150 mg.

41. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 30 to 40, wherein the unit dose of the compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof is 15 mg to 150 mg.

42. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 30 to 41, 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, 120 mg, or 150 mg.

43. The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 30 to 42, 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.

44. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 43, wherein the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is orally administered to the subject.

45. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 44, wherein the subject is a mammal, preferably a human.

46. ​​A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 30 to 45, wherein the subject has latent tuberculosis infection.

47. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 46, wherein the subject has a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy.

48. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 30 to 47, which is administered without the need for titration.

49. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 30 to 47, wherein the subject has latent tuberculosis infection which has not reactivated after treatment.

50. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 47, wherein the subject has a history of tuberculosis infection, tuberculosis, or tuberculous pleurisy, but the disease has not been reactivated after treatment.

51. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 30 to 47, wherein the subject has a reduction in the area of ​​psoriasis lesions, and / or a reduction in the psoriasis lesion area and severity index, and / or a reduction in the dermatology life quality index.

52. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 47, wherein the subject's sPGA (static physician's global assessment) improves, in particular reaches a score of 0 or 1.

53. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 47, wherein the subject does not cause anxiety or aggravate anxiety.

54. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 47, wherein the subject does not cause or aggravate depressive mood.

55. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 47, wherein the subject also has an excellent therapeutic effect on a subject not treated with a biological agent.

56. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 47, wherein the subject also has a superior therapeutic effect on a subject treated with a biological agent.

57. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 30 to 47, wherein the compound also has an excellent therapeutic effect on subjects who have failed biological agent treatment.

58. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 30 to 47, wherein the subject does not have reduced immunity.

59. Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating moderate to severe plaque psoriasis in an individual, 60. The use according to claim 59, wherein the subject is administered 30 mg to 180 mg of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof daily.

61. The use of claim 59 or 60, wherein 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.

62. The use according to claims 59 to 61, wherein the subject is administered 60 mg to 120 mg daily of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

63. The use according to any one of claims 59 to 62, wherein the subject is administered 120 mg daily of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

64. The use according to any one of claims 59 to 63, wherein the subject is administered 150 mg of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof daily.

65. The use according to any one of claims 59 to 64, 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.

66. The use of any one of claims 59 to 65, wherein the subject is administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof at least twice daily.

67. The use according to any one of claims 59 to 66, 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.

68. The use according to any one of claims 59 to 67, wherein the subject is administered 30 mg to 60 mg twice 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 59 to 68, wherein the unit dose of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is 2.5 mg to 150 mg.

70. The use according to any one of claims 59 to 69, wherein the unit dose of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt is 15 mg to 150 mg.

71. The use according to any one of claims 59 to 70, 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, 120 mg or 150 mg.

72. The use according to any one of claims 59 to 71, wherein the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is administered to the subject in tablet / capsule form.

73. The use of any one of claims 59 to 72, wherein the subject is orally administered a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

74. The use according to any one of claims 59 to 73, wherein the subject is a mammal, preferably a human.

75. The use of any one of claims 59 to 74, wherein the subject has latent tuberculosis infection.

76. The use of any one of claims 59 to 75, wherein the subject has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy.

77. The use according to any one of claims 59 to 76, wherein titration of administration is not required.

78. The use of any one of claims 59 to 76, wherein the subject has latent tuberculosis infection that has not reactivated after treatment.

79. The use according to any one of claims 59 to 76, wherein the subject has a history of tuberculosis infection, tuberculosis disease, or tuberculous pleurisy, but the disease has not reactivated after treatment.

80. The use of any one of claims 59 to 76, wherein the subject has a reduction in psoriasis lesion area, and / or a reduction in the Psoriasis Lesion Area and Severity Index, and / or a reduction in the Dermatology Life Quality Index.

81. The use according to any one of claims 59 to 76, wherein the subject's sPGA (static Physician's Global Assessment) improves, in particular reaches a score of 0 or 1.

82. The use of any one of claims 59 to 76, wherein the subject does not cause or exacerbate anxiety.

83. The use of any one of claims 59 to 76, wherein the subject does not cause or aggravate depressive mood.

84. The use according to any one of claims 59 to 76, wherein the subject also has a superior therapeutic effect on a subject not treated with a biologic.

85. The use of any one of claims 59 to 76, wherein the subject also has a superior therapeutic effect on a subject treated with a biologic.

86. The method of any one of claims 59 to 76, wherein the subject also has a superior therapeutic effect on subjects who have failed treatment with biologic agents.

87. The use of any one of claims 59 to 76, wherein the subject does not have reduced immunity.

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