USE OF ISOTHIAZOLO[5,4-d]PYRIMIDINE COMPOUND IN TREATING INFLAMMATORY DISEASES

Abstract

The present disclosure belongs to the technical field of medicines, and relates to the use of an isothiazolo[5,4-d]pyrimidine compound in treating inflammatory diseases, in particular to the use of a compound shown as formula (I) or pharmaceutically acceptable salts thereof in treating rheumatoid arthritis. The compound of formula (I) or the pharmaceutically acceptable salts or pharmaceutical compositions thereof of the present disclosure can achieve good safety while achieving good therapeutic effects, including but not limited to a relatively low incidence of adverse reactions.

Description

Use of an isothiazolo[5,4-d]pyrimidine compound in treating inflammatory diseases

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and the benefits of Chinese patent application No. 202310436550.7, filed with the State Intellectual Property Office of the People's Republic of China on April 21, 2023, entitled "Use of an isothiazolo[5,4-d]pyrimidine compound for treating inflammatory diseases", the entire contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure belongs to the field of medical technology and relates to the use of an isothiazolo[5,4-d]pyrimidine compound for treating inflammatory diseases, and specifically relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating rheumatoid arthritis. Background Art

[0004] Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by joint invasion. It has long been considered an "immortal cancer." RA can occur at any age and is a highly prevalent disease. Epidemiological surveys show that the global incidence of RA is 0.5% to 1%, with an incidence of 0.42% in mainland China. The total affected population is approximately 5 million, with a male-to-female ratio of approximately 1:4. The peak incidence occurs between the ages of 30 and 50. The pathogenesis of RA remains unclear, but it is generally believed to be a complex interaction of the immune system, environmental, and genetic factors, leading to immune system dysregulation and imbalance in self-tolerance. RA not only reduces patients' physical function, quality of life, and social participation, but also imposes a significant economic burden on patients' families and society.

[0005] Currently, there is no cure for rheumatoid arthritis. Treatment is treat-to-target, meaning that medications are used to effectively relieve symptoms and control the disease. Current treatment aims to control symptoms, prevent ongoing damage to joints and bone structure, restore physiological function, improve daily living abilities, and maximize health-related quality of life. Early diagnosis and introduction of disease-modifying anti-rheumatic drugs (DMARDs), along with the use of a combination of indicators to strictly control disease progression and the selection of appropriately intensified anti-rheumatic drugs, are the most effective treatment strategies for rheumatoid arthritis. These DMARDs are further categorized as traditional synthetic agents (including methotrexate, leflunomide, and sulfasalazine), biologics (including anti-TNF-α, anti-IL-6, anti-CD20, and anti-CD80 / 86 drugs), and targeted synthetic agents (including JAK-STAT inhibitors). Although there are many therapeutic drugs and options for rheumatoid arthritis on the market, the remission rate is low, the treatment cost is expensive, and the side effects are large. To date, there is still no drug that can completely cure rheumatoid arthritis. Clinically, there is an urgent need to develop new targets, new mechanisms of action, and oral drugs with low toxicity and side effects to provide new options for the treatment of different subtypes of rheumatoid arthritis and provide patients with more effective and safe treatment.

[0006] Summary of the Invention

[0007] SUMMARY OF THE INVENTION

[0008] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating or preventing rheumatoid arthritis.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present disclosure provides a method for treating or preventing rheumatoid arthritis in a patient, comprising administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0011] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preparing a medicament for treating or preventing rheumatoid arthritis in a patient.

[0012] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating or preventing rheumatoid arthritis in a patient.

[0013] Detailed Description of the Invention

[0014] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating or preventing rheumatoid arthritis.

[0015] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, the present disclosure provides a method for treating or preventing rheumatoid arthritis in a patient, comprising administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0017] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preparing a medicament for treating or preventing rheumatoid arthritis in a patient.

[0018] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating or preventing rheumatoid arthritis in a patient.

[0019] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used as a single active agent.

[0020] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof described in the present disclosure may be a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments of the present disclosure, the pharmaceutical composition is packaged in a kit, which further comprises instructions for using the compound of formula (I) or a pharmaceutically acceptable salt thereof to treat or prevent rheumatoid arthritis.

[0022] In some embodiments of the present disclosure, in the pharmaceutical composition, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt, such as the dihydrochloride salt of the compound of formula (I) (compound of formula (II)).

[0023] In some embodiments of the present disclosure, the pharmaceutical composition contains 25-600 mg, 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 200-400 mg or 200-300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or the pharmaceutical composition contains 50-1200 mg, 100-1200 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 400-800 mg or 400-600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or the pharmaceutical composition contains 100-200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I).

[0024] In some embodiments of the present disclosure, the pharmaceutical composition contains 100-200 mg, 100-300 mg, 100-400 mg, 100-500 mg, 100-600 mg, 100-700 mg, 100-800 mg, 200-300 mg, 200-400 mg, 200-500 mg, 200-600 mg, 200-700 mg, 200-800 mg, 300 ~400mg, 300-500mg, 300-600mg, 300-700mg, 300-800mg, 400-500mg, 400-600mg, 400-700mg, 400-800mg, 500-600mg, 500-700mg, 500-800mg, 600-700mg, 600-800mg or 700-800mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments of the present disclosure, the pharmaceutical composition contains 100-400 mg, 200-400 mg or 200-300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or the pharmaceutical composition contains 100-200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or the pharmaceutical composition contains 200-800 mg, 400-800 mg or 400-600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I).

[0026] In some embodiments of the present disclosure, the pharmaceutical composition contains 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or the pharmaceutical composition contains 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I).

[0027] In some embodiments of the present disclosure, the pharmaceutical composition contains 100 mg, 200 mg, 300 mg or 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or the pharmaceutical composition contains 200 mg, 400 mg, 600 mg or 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I).

[0028] In some embodiments of the present disclosure, the pharmaceutical composition contains 200 mg, 300 mg or 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or the pharmaceutical composition contains 400 mg, 600 mg or 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I).

[0029] In some embodiments of the present disclosure, the pharmaceutical composition contains 200 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); or the pharmaceutical composition contains 400 mg or 600 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0030] In some embodiments of the present disclosure, the pharmaceutical composition contains 100 mg or 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); or the pharmaceutical composition contains 200 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0031] In some embodiments of the present disclosure, the pharmaceutical composition contains 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); or the pharmaceutical composition contains 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0032] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a single dose or multiple dose form. In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a single dose form. In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a multiple dose form.

[0033] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in each dose.

[0034] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a daily dose.

[0035] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once or twice daily; preferably twice daily.

[0036] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily, and each dose is a single dose or multiple doses, usually multiple doses; or usually a single dose.

[0037] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily, with each dose being the same.

[0038] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily, each dose is the same, and each dose is a single dose or multiple doses, preferably multiple doses; or preferably a single dose.

[0039] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 50-100 mg, 50-150 mg, 50-200 mg, 50-250 mg, 50-300 mg, 50-350 mg, 50-400 mg, 100-150 mg, 100-200 mg, 100-250 mg, 100-300 mg, 100-350 mg, 100-400 mg, 150-200 mg, 150-250 mg, 150-300 mg, 150-350 mg, 150-400 mg, 200-250 mg, 200-300 mg, 200-350 mg, 200-400 mg, 250-300 mg, 250-350 mg, 250-400 mg, 300-350 mg, 300-400 mg or 350-400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, the pharmaceutical composition is in the form of a single-dose preparation, and the pharmaceutical composition contains 50-100 mg, 50-150 mg, 50-200 mg, 50-250 mg, 50-300 mg, 50-350 mg, 50-400 mg, 100-150 mg, 100-200 mg, 100-250 mg, 100-300 mg, 100-350 mg, 100-400 mg, 15 0-200 mg, 150-250 mg, 150-300 mg, 150-350 mg, 150-400 mg, 200-250 mg, 200-300 mg, 200-350 mg, 200-400 mg, 250-300 mg, 250-350 mg, 250-400 mg, 300-350 mg, 300-400 mg or 350-400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 50-100 mg, 50-150 mg, 50-200 mg, 100-150 mg, or 100-200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition is in the form of a single-dose formulation, containing 50-100 mg, 50-150 mg, 50-200 mg, 100-150 mg, or 100-200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0041] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 25 mg, 100 mg, or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition is in the form of a single-dose formulation, containing 25 mg, 100 mg, or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0042] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 100 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition is in the form of a single-dose formulation, containing 100 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0043] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition is in the form of a single-dose formulation, containing 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0044] In some embodiments of the present disclosure, the pharmaceutical composition is a pharmaceutical composition for each dose, wherein each dose of the pharmaceutical composition contains 25-600 mg, 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 200-400 mg or 200-300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 100-400 mg, 200-400 mg or 200-300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg of the compound of formula (I). , 350 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; preferably 100 mg, 200 mg, 300 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 200 mg, 300 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 200 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 100 mg or 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0045] In some embodiments of the present disclosure, the pharmaceutical composition is a daily dose pharmaceutical composition, which contains 50-1200 mg, 100-1200 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 400-800 mg or 400-600 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 200-800 mg, 400-800 mg or 400-600 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; preferably 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg of the compound of formula (I). 0mg, 700mg or 800mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably 200mg, 400mg, 600mg or 800mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 400mg, 600mg or 800mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 400mg or 600mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 200mg or 400mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 200mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0046] In some embodiments of the present disclosure, one treatment cycle is every 28 days (4 weeks) and / or one treatment cycle is every 42 days (6 weeks).

[0047] In some embodiments of the present disclosure, one treatment cycle is every 28±3 days and / or one treatment cycle is every 42±3 days.

[0048] In some embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., one treatment cycle every 4 weeks), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 5.6 to 22.4 g (e.g., 5.6 g, 11.2 g, 16.8 g, 22.4 g, or a range formed by any two values) calculated as the compound of formula (I).

[0049] In some embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., one treatment cycle every 4 weeks), and the receptive preparation comprises: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 11.2 g, 16.8 g or 22.4 g, calculated as a compound of formula (I).

[0050] In some embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., one treatment cycle every 4 weeks), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 11.2 g or 16.8 g, calculated as a compound of formula (I).

[0051] In some embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., one treatment cycle every 4 weeks), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 5.6 g or 11.2 g, calculated as the compound of formula (I).

[0052] In some embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., one treatment cycle every 4 weeks), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 5.6 g, calculated as the compound of formula (I).

[0053] In another aspect, the present disclosure further provides a kit comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the present disclosure.

[0054] On the other hand, the present disclosure also provides a kit of pharmaceutical compositions for treating or preventing rheumatoid arthritis, which contains the compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the present disclosure.

[0055] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 50-100 mg, 50-150 mg, 50-200 mg, 50-250 mg, 50-300 mg, 50-350 mg, 50-400 mg, 100-150 mg, 100-200 mg, 100-250 mg, 100-300 mg, 100-350 mg, 10 ...500 mg, 100-1500 mg, 100-200 mg, 100-250 mg, 100-300 mg, 100-350 mg, 100-400 mg, 100-500 mg, 100- 150-200 mg, 150-250 mg, 150-300 mg, 150-350 mg, 150-400 mg, 200-250 mg, 200-300 mg, 200-350 mg, 200-400 mg, 250-300 mg, 250-350 mg, 250-400 mg, 300-350 mg, 300-400 mg or 350-400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0057] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 25 mg, 100 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0058] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 100 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0059] In some embodiments of the present disclosure, in the pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0060] On the other hand, the present disclosure also provides a method for treating or preventing rheumatoid arthritis, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for example, administering to an individual in need thereof a therapeutically effective amount of the pharmaceutical composition described above of the present disclosure.

[0061] On the other hand, the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing rheumatoid arthritis, for example, the use of the pharmaceutical composition described in the present disclosure in the preparation of a medicament for treating or preventing rheumatoid arthritis.

[0062] On the other hand, the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for treating or preventing rheumatoid arthritis, for example, the use of the pharmaceutical composition of the present disclosure for treating or preventing rheumatoid arthritis.

[0063] In some embodiments of the present disclosure, in the above-mentioned methods or uses, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition is a daily dose, which is administered as follows: the compound of formula (I) or its pharmaceutically acceptable salt is administered once or more daily. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered once or twice daily. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered twice daily, each dose being the same. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered twice daily in a single dose or multiple doses, each dose being the same. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered twice daily in a multiple dose form, each dose being the same. . In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered twice daily in a single dose form, each dose being the same. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered twice daily in a multiple dose solid oral dosage form, each dose being the same. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered twice daily in the form of a single dose of solid oral preparation, and each dose is the same. In a specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered twice daily after meals in the form of multiple doses of solid oral preparation, and each dose is the same. In a specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered twice daily after meals in the form of a single dose of solid oral preparation, and each dose is the same. In a more specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily after breakfast and dinner in the form of multiple doses of solid oral preparation, and each dose is the same. In a more specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily after breakfast and dinner in the form of a single dose of solid oral preparation, and each dose is the same.

[0064] In some embodiments of the present disclosure, in the above methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient, for example, based on the results of a routine blood test of the subject / patient, including platelet count, neutrophil count, or hemoglobin concentration. In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 25-600 mg, 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 200-400 mg or 200-300 mg. In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 100-400 mg, 200-400 mg or 200-300 mg. In some specific embodiments, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 25mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg or 400mg. In some specific embodiments, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 100mg, 200mg, 300mg or 400mg. In a specific embodiment, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 200mg, 300mg or 400mg. In a more specific embodiment, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 200mg or 300mg. In a more specific embodiment, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 100mg or 200mg. In a more specific embodiment, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 100mg.

[0065] In some embodiments of the present disclosure, in the above methods or uses, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is 50-1200 mg, 100-1200 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 400-800 mg or 400-600 mg. In some embodiments, the dose of the compound of formula (I) or its pharmaceutically acceptable salt is 200-400 mg, 200-600 mg, 200-800 mg, 400-600 mg, 400-800 mg or 600-800 mg. In some embodiments, the dose of the compound of formula (I) or its pharmaceutically acceptable salt is 200-800 mg, 400-800 mg or 400-600 mg. In some specific embodiments, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg or 800mg. In some specific embodiments, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 200mg, 400mg, 600mg or 800mg. In a specific embodiment, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 400mg, 600mg or 800mg. In a more specific embodiment, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 400mg or 600mg. In a more specific embodiment, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 200mg or 400mg. In a more specific embodiment, each dose of the compound of formula (I) or its pharmaceutically acceptable salt is 200mg.

[0066] In some embodiments of the present disclosure, 28 days is one treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is continuously administered on days 1 to 28 of each cycle.

[0067] In some embodiments of the present disclosure, 28 days is one treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered continuously daily on days 1 to 28 of each cycle.

[0068] In some embodiments of the present disclosure, 28 days is one treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily continuously on days 1 to 28 of each cycle.

[0069] In some embodiments of the present disclosure, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily on days 1 to 28 of each cycle, with the same dose each time.

[0070] In some embodiments of the present disclosure, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day after meals on days 1 to 28 of each cycle, with the same dose each time.

[0071] In some embodiments of the present disclosure, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once after breakfast and dinner every day from day 1 to day 28 of each cycle, with the same dose each time.

[0072] In some embodiments of the present disclosure, 42 days is one treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is continuously administered on days 1 to 42 of each cycle.

[0073] In some embodiments of the present disclosure, 42 days is one treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered continuously daily on days 1 to 42 of each cycle.

[0074] In some embodiments of the present disclosure, 42 days is one treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily continuously on days 1 to 42 of each cycle.

[0075] In some embodiments of the present disclosure, 42 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily on days 1 to 42 of each cycle, with the same dose each time.

[0076] In some embodiments of the present disclosure, 42 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day after meals on days 1 to 42 of each cycle, with the same dose each time.

[0077] In some embodiments of the present disclosure, 42 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once after breakfast and dinner every day from day 1 to day 42 of each cycle, with the same dose each time.

[0078] In some embodiments of the present disclosure, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day continuously on days 1 to 28 of each cycle, and each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the single dose is 100 mg or 300 mg of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salt.

[0079] In some embodiments of the present disclosure, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day continuously on days 1 to 28 of each cycle, and each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the single dose is 100 mg of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salt.

[0080] In some embodiments of the present disclosure, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day continuously on days 1 to 28 of each cycle, and each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the multiple dose is 200 mg, 300 mg or 400 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0081] In some embodiments of the present disclosure, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day continuously on days 1 to 28 of each cycle, and each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the multiple dose is 200 mg or 300 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0082] In some embodiments of the present disclosure, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day continuously on days 1 to 28 of each cycle, and each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the multiple dose is 200 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0083] In some embodiments of the present disclosure, 42 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day continuously on days 1 to 42 of each cycle, and each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the single dose is 100 mg or 300 mg of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salt.

[0084] In some embodiments of the present disclosure, 42 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day continuously on days 1 to 42 of each cycle, and each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the single dose is 100 mg of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salt.

[0085] In some embodiments of the present disclosure, 42 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day continuously on days 1 to 42 of each cycle, and each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the multiple dose is 200 mg, 300 mg or 400 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0086] In some embodiments of the present disclosure, 42 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day continuously on days 1 to 42 of each cycle, and each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the multiple dose is 200 mg or 300 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0087] In some embodiments of the present disclosure, 42 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day continuously on days 1 to 42 of each cycle, and each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the multiple dose is 200 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0088] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, which contains a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof at a 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, 7-day, 8-day, 9-day, 10-day, 11-day, 12-day, 13-day, 14-day, 15-day, 16-day, 17-day, 18-day, 19-day, 20-day, 21-day, 22-day, 23-day, 24-day, 25-day, 26-day, 27-day or 28-day dose, or a dose range consisting of any of the foregoing values ​​as endpoints. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, which contains a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, or 28 days, or a dose range consisting of any of the foregoing values ​​as endpoints.

[0089] In some embodiments of the present disclosure, 28 days is a treatment cycle, and the total dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt administered in each treatment cycle is 5.6 to 22.4 g (calculated as the active ingredient, the compound of formula (I) itself). In some embodiments of the present disclosure, the total dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 5.6 g, 11.2 g, 16.8 g, 22.4 g or the range formed by any two of the above values ​​(calculated as the active ingredient, the compound of formula (I) itself). In some embodiments of the present disclosure, the total dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is preferably 11.2 to 16.8 g (calculated as the active ingredient, the compound of formula (I) itself). In some embodiments of the present disclosure, the total dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is preferably 11.2 g or 16.8 g (calculated as the active ingredient, the compound of formula (I) itself). In some embodiments of the present disclosure, the total dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 5.6 g or 11.2 g (calculated as the active ingredient, the compound of formula (I) itself). In some embodiments of the present disclosure, the total dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 5.6 g (calculated as the active ingredient, the compound of formula (I) itself).

[0090] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, which contains a 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, 7-day, 8-day, 9-day, 10-day, 11-day, 12-day, 13-day, 14-day, 15-day, 16-day, 17-day, 18-day, 19-day, 20-day, 21-day, 22-day, 23-day, 24-day, 25-day, 26-day, 27-day, 28-day, 29-day, 30-day, 31-day, 32-day, 33-day, 34-day, 35-day, 36-day, 37-day, 38-day, 39-day, 40-day, 41-day, or 42-day dose, or a range of doses using any of the foregoing values ​​as endpoints. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, which contains a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof at a 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, 7-day, 14-day, 21-day, 28-day, 35-day, or 42-day dose, or a dose range consisting of any of the foregoing values ​​as endpoints.

[0091] In some embodiments of the present disclosure, 42 days is a treatment cycle, and the total dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt administered in each treatment cycle is 8.4 to 33.6 g (calculated as the active ingredient, the compound of formula (I) itself). In some embodiments of the present disclosure, the total dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 8.4 g, 16.8 g, 25.2 g, 33.6 g or the range formed by any two of the above values ​​(calculated as the active ingredient, the compound of formula (I) itself). In some embodiments of the present disclosure, the total dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is preferably 16.8 to 25.2 g (calculated as the active ingredient, the compound of formula (I) itself). In some embodiments of the present disclosure, the total dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is preferably 16.8 g or 25.2 g (calculated as the active ingredient, the compound of formula (I) itself). In some embodiments of the present disclosure, the total dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 8.4 g or 16.8 g (calculated as the active ingredient, the compound of formula (I) itself). In some embodiments of the present disclosure, the total dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 8.4 g (calculated as the active ingredient, the compound of formula (I) itself).

[0092] In some embodiments of the present disclosure, in the above methods or uses, the first three treatment cycles are 28 days each as a treatment cycle, and starting from the fourth treatment cycle, every 42 days is a treatment cycle. The administration method of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof in each treatment cycle is as described in the above methods or uses.

[0093] In some embodiments of the present disclosure, in the above methods or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is continued to be administered daily after the end of the previous treatment cycle to enter the next treatment cycle.

[0094] In some embodiments of the present disclosure, the above-described treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

[0095] Combination drug composition

[0096] In one aspect, the present disclosure provides a combination pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate,

[0097] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate.

[0098] In some embodiments of the present disclosure, the combination pharmaceutical composition is packaged in the same kit, which further comprises instructions for using the compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate in combination to treat or prevent rheumatoid arthritis.

[0099] In some embodiments of the present disclosure, the combination pharmaceutical composition includes: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of methotrexate.

[0100] In some embodiments of the present disclosure, the combination pharmaceutical composition is packaged in the same kit, which further comprises instructions for using the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the pharmaceutical composition of methotrexate to treat or prevent rheumatoid arthritis.

[0101] In some embodiments of the present disclosure, the combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is characterized as described in the present disclosure.

[0102] It should be understood that the above-mentioned embodiments of the present disclosure for all "compounds of formula (I) or pharmaceutically acceptable salts thereof" and the embodiments of the present disclosure for all "pharmaceutical compositions of compounds of formula (I) or pharmaceutically acceptable salts thereof" are applicable to the combined pharmaceutical compositions described in the present disclosure.

[0103] In some embodiments of the present disclosure, the combination pharmaceutical composition contains a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which is packaged in a kit, and the kit also contains instructions for using the compound of formula (I) or a pharmaceutically acceptable salt thereof to treat or prevent rheumatoid arthritis.

[0104] In some embodiments of the present disclosure, the combination pharmaceutical composition contains 2.5-30 mg, 5-25 mg, 7.5-25 mg, 10-25 mg, 12.5-25 mg, 15-25 mg, 17.5-25 mg or 20-25 mg of methotrexate, or a pharmaceutical combination thereof.

[0105] In some embodiments of the present disclosure, the combination pharmaceutical composition contains 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg or 25 mg of methotrexate, or a pharmaceutical combination thereof.

[0106] In some embodiments of the present disclosure, the combination pharmaceutical composition contains 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of methotrexate, or a pharmaceutical combination thereof.

[0107] In some embodiments of the present disclosure, the combination pharmaceutical composition contains 7.5 to 25 mg of methotrexate, or a pharmaceutical composition thereof.

[0108] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the methotrexate pharmaceutical composition is in the form of a single dose or multiple doses.

[0109] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the methotrexate pharmaceutical composition is in a multiple-dose form.

[0110] In some embodiments of the present disclosure, the methotrexate in the combination pharmaceutical composition is in a dosage for once-weekly administration.

[0111] In some embodiments of the present disclosure, the combination pharmaceutical composition comprises a single dose of 2.5 mg of methotrexate or a pharmaceutical composition thereof. Alternatively, the combination pharmaceutical composition is in the form of a single-dose formulation comprising 2.5 mg of methotrexate or a pharmaceutical composition thereof.

[0112] In some embodiments of the present disclosure, the pharmaceutical composition of methotrexate contained in the combination pharmaceutical composition is packaged in a kit, and the kit also contains instructions for using methotrexate to treat or prevent rheumatoid arthritis.

[0113] In some embodiments of the present disclosure, the pharmaceutical composition of methotrexate contained in the combination pharmaceutical composition is packaged in a kit, and the kit further contains instructions for using methotrexate to treat or prevent rheumatoid arthritis, and the instructions can be the instructions in the instructions of the commercially available methotrexate tablet kit. In some embodiments of the present disclosure, the instructions are the instructions for methotrexate tablets (e.g., ) instructions in the manual.

[0114] In some embodiments of the present disclosure, the combination pharmaceutical composition contains 25-600 mg, 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 200-400 mg or 200-300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 2.5-30 mg, 5-25 mg, 7.5-25 mg, 10-25 mg, 12.5-25 mg, 15-25 mg, 17.5-25 mg or 20-25 mg of methotrexate.

[0115] In some embodiments of the present disclosure, the combination pharmaceutical composition contains, calculated as the compound of formula (I), 100-400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and 7.5-25 mg of methotrexate.

[0116] In some embodiments of the present disclosure, the combination pharmaceutical composition contains, calculated as the compound of formula (I), 100-200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and 7.5-25 mg of methotrexate.

[0117] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg per dose; and a weekly therapeutic dose of methotrexate of 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg.

[0118] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 100 mg or 200 mg per dose, calculated as a compound of formula (I); and a weekly therapeutic dose of methotrexate of 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg.

[0119] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a compound of formula (I) or a pharmaceutically acceptable salt thereof at a dose of 100 mg per dose, calculated as a compound of formula (I); and a weekly therapeutic dose of methotrexate of 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg.

[0120] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a weekly therapeutic dose of 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of methotrexate.

[0121] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 400 mg, 600 mg or 800 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and a weekly therapeutic dose of 7.5 to 25 mg of methotrexate.

[0122] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 600 mg or 800 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and a weekly therapeutic dose of 7.5 to 25 mg of methotrexate.

[0123] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 200 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and a weekly therapeutic dose of 7.5 to 25 mg of methotrexate.

[0124] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and a weekly therapeutic dose of 7.5 to 25 mg of methotrexate.

[0125] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 600 mg or 800 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and a weekly therapeutic dose of 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of methotrexate.

[0126] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 200 mg or 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and a weekly therapeutic dose of 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of methotrexate.

[0127] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and a weekly therapeutic dose of 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of methotrexate.

[0128] In some embodiments of the present disclosure, one treatment cycle is every 28 days and / or one treatment cycle is every 42 days.

[0129] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a single dose of 25 mg, 100 mg, or 300 mg, calculated as a compound of formula (I); and a pharmaceutical composition of methotrexate in a single dose of 2.5 mg. Alternatively, the combination pharmaceutical composition is in the form of a single-dose formulation, comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof in a single dose of 25 mg, 100 mg, or 300 mg, calculated as a compound of formula (I); and a pharmaceutical composition of methotrexate in a single dose of 2.5 mg.

[0130] In some embodiments of the present disclosure, the combination pharmaceutical composition comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a single dose of 100 mg, calculated as a compound of formula (I); and a pharmaceutical composition comprising a single dose of 2.5 mg, calculated as methotrexate. Alternatively, the combination pharmaceutical composition is in the form of a single-dose formulation, comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and 2.5 mg, calculated as methotrexate, or a pharmaceutical composition thereof.

[0131] In some embodiments of the present disclosure, the combination pharmaceutical composition comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a single dose of 300 mg of the compound of formula (I); and a pharmaceutical composition comprising a single dose of 2.5 mg of methotrexate. Alternatively, the combination pharmaceutical composition is in the form of a single-dose formulation, comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and a pharmaceutical composition of methotrexate, calculated as 2.5 mg of methotrexate.

[0132] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, with a total dose of 5.6 to 22.4 g (e.g., 5.6 g, 11.2 g, 16.8 g, 22.4 g) calculated as the compound of formula (I); and a pharmaceutical composition containing methotrexate, with a total dose of 30 to 100 mg calculated as methotrexate.

[0133] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 11.2 g or 16.8 g, calculated as a compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 30 to 100 mg, calculated as methotrexate.

[0134] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 5.6 g or 11.2 g, calculated as a compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 30 to 100 mg, calculated as methotrexate.

[0135] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 5.6 g calculated as the compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 30 to 100 mg calculated as methotrexate.

[0136] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within the first treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 11.2 g or 16.8 g, calculated as a compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 30 mg, 40 mg, 60 mg, 80 mg or 100 mg, calculated as methotrexate.

[0137] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within the first treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 5.6 g or 11.2 g, calculated as a compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 30 mg, 40 mg, 60 mg, 80 mg or 100 mg, calculated as methotrexate.

[0138] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within the first treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 5.6 g calculated as a compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 30 mg, 40 mg, 60 mg, 80 mg or 100 mg calculated as methotrexate.

[0139] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 42-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 8.4 to 33.6 g (e.g., 8.4 g, 16.8 g, 25.2 g, 33.6 g) calculated as the compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 45 to 150 mg calculated as methotrexate.

[0140] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 42-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 16.8 g or 25.2 g, calculated as a compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 45 to 150 mg, calculated as methotrexate.

[0141] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 42-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 8.4 g or 16.8 g calculated as a compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 45 to 150 mg calculated as methotrexate.

[0142] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 42-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 8.4 g calculated as the compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 45 to 150 mg calculated as methotrexate.

[0143] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within the first treatment cycle (e.g., a 42-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof at a total dose of 16.8 g or 25.2 g, calculated as a compound of formula (I); and a pharmaceutical composition containing methotrexate at a total dose of 45 mg, 60 mg, 90 mg, 120 mg or 150 mg, calculated as methotrexate.

[0144] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within the first treatment cycle (e.g., a 42-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 8.4 g or 16.8 g calculated as a compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 45 mg, 60 mg, 90 mg, 120 mg or 150 mg calculated as methotrexate.

[0145] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within the first treatment cycle (e.g., a 42-day treatment cycle), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 8.4 g calculated as the compound of formula (I); and a pharmaceutical composition containing methotrexate in a total dose of 45 mg, 60 mg, 90 mg, 120 mg or 150 mg calculated as methotrexate.

[0146] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing methotrexate at a total dose ratio of (56-746):1, for example, (112-373):1, (168-560):1 or (224-746):1 or any ratio within the above range, wherein the dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is calculated based on the compound of formula (I), and the dose of the pharmaceutical composition containing methotrexate is calculated based on methotrexate.

[0147] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 42-day treatment cycle), comprising a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing methotrexate at a total dose ratio of (56-746):1, for example, (112-373):1, (168-560):1 or (224-746):1 or any ratio within the above range, wherein the dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is calculated based on the compound of formula (I), and the dose of the pharmaceutical composition containing methotrexate is calculated based on methotrexate.

[0148] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate can be in the form of a pharmaceutical composition separately or together.

[0149] On the other hand, the present disclosure also provides a kit comprising (a) a first pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the present disclosure; and (b) a second pharmaceutical composition comprising methotrexate.

[0150] In another aspect, the present disclosure further provides a kit for treating or preventing rheumatoid arthritis, comprising: (a) a first pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a second pharmaceutical composition comprising methotrexate. Alternatively, the present disclosure further provides a combination pharmaceutical composition for treating or preventing rheumatoid arthritis, comprising: a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition comprising methotrexate.

[0151] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 25 mg, 100 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and the methotrexate is prepared as a unit preparation containing 2.5 mg of methotrexate.

[0152] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 100 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and the methotrexate is prepared as a unit preparation containing 2.5 mg of methotrexate.

[0153] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and the methotrexate is prepared as a unit preparation containing 2.5 mg of methotrexate.

[0154] On the other hand, the present disclosure also provides a method for treating or preventing rheumatoid arthritis, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate, for example, administering to an individual in need thereof a therapeutically effective amount of the combination pharmaceutical composition described above of the present disclosure.

[0155] In another aspect, the present disclosure also provides a combination therapy for treating an individual suffering from rheumatoid arthritis, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of methotrexate.

[0156] On the other hand, the present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with methotrexate in the preparation of a medicament for treating or preventing rheumatoid arthritis, for example, the use of the above-mentioned combination pharmaceutical composition of the present disclosure in the preparation of a medicament for treating or preventing rheumatoid arthritis. In some embodiments of the present disclosure, the combination pharmaceutical composition is any of the combination pharmaceutical compositions described above in the present disclosure.

[0157] On the other hand, the present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with methotrexate for treating or preventing rheumatoid arthritis, for example, the use of the above-mentioned combination pharmaceutical composition of the present disclosure for treating or preventing rheumatoid arthritis.

[0158] In some embodiments of the present disclosure, in the above-mentioned kits, methods, combination therapies or uses, the definitions of the compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate are the same as those of the compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate in the combination pharmaceutical composition described above, such as content, dosage, form of existence, packaging form, etc.

[0159] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate are each in the form of a pharmaceutical composition and can be administered simultaneously, separately, concurrently, sequentially or intermittently.

[0160] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate have the same or different treatment cycles, respectively. In some specific embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks or every 6 weeks is a treatment cycle; preferably every 4 weeks is a treatment cycle.

[0161] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is per dose, which is administered as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day.

[0162] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is a daily dose, which is administered as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day.

[0163] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is a daily dose, which is administered as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day, with the same dose each time.

[0164] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is a daily dose, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a single dose or multiple doses, usually in multiple doses; or usually in a single dose; further, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day.

[0165] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 200 mg; or, a daily dose of 400 mg; or, a daily dose of 600 mg; or, a daily dose of 800 mg.

[0166] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 400 mg; or, a daily dose of 600 mg.

[0167] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 200 mg; or, a daily dose of 400 mg.

[0168] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 200 mg.

[0169] In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is administered in multiple doses, and the multiple doses are composed of a pharmaceutical composition with a single dose of 25 mg, 100 mg, or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily manner.

[0170] In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is administered in multiple doses, and the multiple doses consist of a pharmaceutical composition with a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily manner.

[0171] In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is administered in a single dose, and the single dose is a pharmaceutical composition consisting of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily manner.

[0172] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is a dosage per treatment cycle, which is administered as follows: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily. Wherein, the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots, 35 aliquots, 42 aliquots or more).

[0173] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of methotrexate in the combination pharmaceutical composition is a dosage for each treatment cycle, which is administered in the following manner: methotrexate is administered once a week. Wherein, methotrexate is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 6 aliquots or more aliquots). In some embodiments of the present disclosure, methotrexate is administered once a week, and the weekly dosage is the same. In some embodiments of the present disclosure, methotrexate is administered once a week, and the weekly dosage is the same, and it is administered on the same day of each week.

[0174] In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the amount of methotrexate in the combination pharmaceutical composition is a dose per treatment cycle, wherein methotrexate is administered in a single dose or multiple doses. In some embodiments of the present disclosure, wherein methotrexate is administered in multiple doses.

[0175] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of methotrexate in the combination pharmaceutical composition is the dose per treatment cycle, wherein methotrexate is administered in multiple doses, and the multiple doses consist of a single dose of 2.5 mg of the pharmaceutical composition of methotrexate.

[0176] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, 28 days is a treatment cycle, methotrexate is administered once a week, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 28 of each treatment cycle.

[0177] In some specific embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 28 days is a treatment cycle, methotrexate is administered once a week, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day on days 1 to 28 of each treatment cycle.

[0178] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 28 days is a treatment cycle, the drug is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt administered in each treatment cycle is 5.6 to 22.4 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 5.6 g, 11.2 g, 16.8 g, 22.4 g or the range formed by any two of the above values. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 11.2 to 16.8 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 11.2 g, 16.8 g or 22.4 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 11.2 g, 16.8 g or 22.4 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 11.2 g or 16.8 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 5.6 g or 11.2 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 5.6 g.

[0179] In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, 28 days is a treatment cycle, and 7.5-25 mg of methotrexate is administered once a week.

[0180] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 11.2 g or 16.8 g; and methotrexate 7.5-25 mg is administered once a week.

[0181] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 5.6 g or 11.2 g; and methotrexate 7.5-25 mg is administered once a week.

[0182] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 5.6 g; and methotrexate 7.5-25 mg is administered once a week.

[0183] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, 42 days is a treatment cycle, methotrexate is administered once a week, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 42 of each treatment cycle.

[0184] In some specific embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 42 days is a treatment cycle, methotrexate is administered once a week, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day on days 1 to 42 of each treatment cycle.

[0185] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 42 days is a treatment cycle, the drug is administered twice a day for 42 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt administered in each treatment cycle is 8.4 to 33.6 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 8.4 g, 16.8 g, 25.2 g, 33.6 g or the range formed by any two of the above values. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 16.8 to 25.2 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 16.8 g or 25.2 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 8.4 g or 16.8 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 8.4 g.

[0186] In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, 42 days is a treatment cycle, and 7.5-25 mg of methotrexate is administered once a week.

[0187] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 42 days is one treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day for 42 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 16.8 g or 25.2 g; and methotrexate 7.5-25 mg is administered once a week.

[0188] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 42 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day for 42 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 8.4 g or 16.8 g; and methotrexate 7.5-25 mg is administered once a week.

[0189] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 42 days is one treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day for 42 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 8.4 g; and 7.5 to 25 mg of methotrexate is administered once a week.

[0190] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is a daily dose, and its administration method is as described above for the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the first three treatment cycles are each 28 days as one treatment cycle, and starting from the fourth treatment cycle, each 42 days is one treatment cycle. The administration mode of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate in each treatment cycle is as described in the above-mentioned methods, combination therapies or uses.

[0192] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, after the end of the previous treatment cycle, the compound of formula (I) or a pharmaceutically acceptable salt thereof is continued to be administered daily, and methotrexate is administered once a week to enter the next treatment cycle.

[0193] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, methotrexate is administered concurrently with oral administration of folic acid, and the folic acid dosage is at least 5 mg per week.

[0194] In embodiments of the present disclosure, the above-described treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

[0195] A compound of formula I or a pharmaceutically acceptable salt thereof

[0196] The compounds of formula (I) disclosed herein can be administered in their free base form, or in the form of their pharmaceutically acceptable salts, hydrates, and prodrugs, which are converted into the compound of formula (I) in vivo. For example, pharmaceutically acceptable salts of the compounds of formula (I) are within the scope of the present disclosure and can be produced from various organic and inorganic acids according to methods known in the art.

[0197] Regarding the pharmaceutically acceptable salts of the compounds of formula (I) described in the present disclosure, the molar ratio of the compound of formula (I) to the acid ion forming the pharmaceutically acceptable salt may be 1:1 or 1:2.

[0198] The pharmaceutically acceptable salt of the compound of formula (I) may be the hydrochloride salt of the compound of formula (I) (eg the dihydrochloride salt of the compound of formula (I)).

[0199] The pharmaceutically acceptable salt of the compound of formula (I) may be as shown in the following compound of formula (II):

[0200] The dosage of the compound of formula (I) or its pharmaceutically acceptable salt referred to in the present disclosure is based on the amount of the compound of formula (I) unless otherwise stated.

[0201] In some embodiments of the present disclosure, the pharmaceutically acceptable salt of the compound of formula (I) exists as the hydrochloride salt of the compound of formula (I).

[0202] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be in a crystalline form, such as a crystal of the compound of formula (II).

[0203] The compound of formula (I) or its pharmaceutically acceptable salt used in the present disclosure, and the crystals of the compound of formula (I) or its pharmaceutically acceptable salt can be prepared by methods in the prior art, for example, by referring to the method of WO2021147968A1.

[0204] Pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof

[0205] In some embodiments of the present disclosure, a single dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 100 mg or 300 mg calculated as the compound of formula (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 100 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the compound of formula (I).

[0206] In some embodiments of the present disclosure, a single dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 100 mg calculated as the compound of formula (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the compound of formula (I).

[0207] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0208] In some embodiments of the present disclosure, the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof further contains a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, adhesives, disintegrants, lubricants, etc. In some embodiments of the present disclosure, the pharmaceutical composition includes but is not limited to preparations suitable for oral, parenteral, and topical administration. In some embodiments, the pharmaceutical composition is a preparation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid preparation suitable for oral administration. In some embodiments, the pharmaceutical composition includes but is not limited to tablets and capsules.

[0209] In some embodiments of the present disclosure, the pharmaceutical composition is a solid pharmaceutical composition.

[0210] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0211] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a tablet containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0212] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0213] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0214] Rheumatoid arthritis

[0215] In some embodiments of the present disclosure, the rheumatoid arthritis is moderately to severely active rheumatoid arthritis.

[0216] In some embodiments of the present disclosure, the rheumatoid arthritis is moderately to severely active rheumatoid arthritis that has been previously treated.

[0217] In some embodiments of the present disclosure, the patient has been previously treated (treated) with conventional synthetic antirheumatic drugs (csDMARDs).

[0218] In some embodiments of the present disclosure, the rheumatoid arthritis patient has or has not previously received one or more of the following drug treatments: (1) traditional Chinese medicine, Chinese patent medicine; (2) nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids; (3) opioids.

[0219] In some embodiments of the present disclosure, the diagnosis of rheumatoid arthritis complies with the rheumatoid arthritis (RA) classification criteria jointly developed by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) in 2010.

[0220] In some embodiments of the present disclosure, the rheumatoid arthritis has been diagnosed for at least 3 months.

[0221] In some embodiments of the present disclosure, the moderately to severely active rheumatoid arthritis refers to: joint swelling (based on 66 joints) ≥ 6, and joint tenderness (based on 68 joints) ≥ 6, and DAS28-CRP ≥ 3.2, and CRP> 10 mg / L or ESR> 28 mm / h.

[0222] In some embodiments of the present disclosure, the traditional synthetic anti-rheumatic drugs include but are not limited to one or two of methotrexate, flunomide or sulfasalazine.

[0223] In some embodiments of the present disclosure, the traditional synthetic anti-rheumatic drug is methotrexate. In some embodiments of the present disclosure, the moderately to severely active rheumatoid arthritis includes subjects who have previously received methotrexate treatment for ≥12 weeks.

[0224] In some embodiments of the present disclosure, the moderately to severely active rheumatoid arthritis includes subjects who have previously received methotrexate treatment for ≥12 weeks and whose methotrexate dose is stable.

[0225] In some embodiments of the present disclosure, the moderately to severely active rheumatoid arthritis includes subjects who have previously received methotrexate treatment for ≥12 weeks and whose methotrexate dose has been stable for ≥4 weeks.

[0226] In some embodiments of the present disclosure, the moderately to severely active rheumatoid arthritis includes subjects who have previously received methotrexate treatment for ≥12 weeks and whose methotrexate dose has been stable for ≥4 weeks, and the methotrexate dose is 7.5-25 mg / week.

[0227] In some embodiments of the present disclosure, the moderately to severely active rheumatoid arthritis includes subjects who have previously received methotrexate treatment for ≥12 weeks and whose methotrexate dose has been stable for ≥4 weeks, and the methotrexate treatment dose is 7.5-25 mg / week, and the methotrexate dose is stable at 7.5-25 mg / week.

[0228] In some embodiments of the present disclosure, the moderately to severely active rheumatoid arthritis includes subjects who have previously received methotrexate treatment for ≥12 weeks and whose methotrexate dose has been stable for ≥4 weeks, and who continue to use a stable dose of methotrexate during the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments of the present disclosure, the moderately to severely active rheumatoid arthritis includes subjects who have previously received methotrexate treatment for ≥12 weeks and whose methotrexate dose has been stable for ≥4 weeks, and who continue to use a stable dose of methotrexate during the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and are treated with oral folic acid at least 5 mg / week; and / or the moderately to severely active rheumatoid arthritis subjects have stopped using csDMARDs (except MTX) for ≥4 weeks and leflunomide for ≥8 weeks before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and / or the moderately to severely active rheumatoid arthritis subjects have stopped using traditional Chinese medicine or Chinese patent medicine to treat rheumatoid arthritis for ≥4 weeks, preferably ≥2 weeks, before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments of the present disclosure, if the subject with moderately to severely active rheumatoid arthritis is taking oral nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids, the dosage of the nonsteroidal anti-inflammatory drugs (NSAIDs) must be stable for at least 2 weeks before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and / or before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, oral corticosteroids (equivalent to prednisone ≤10 mg / day) or inhaled corticosteroids are allowed, but the dosage must be stable for at least 4 weeks before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments of the present disclosure, the subject with moderately to severely active rheumatoid arthritis stops taking all opioids for at least 1 week before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments of the present disclosure, the previously treated (treated) refers to moderate to severe active rheumatoid arthritis that has been previously treated with traditional synthetic anti-rheumatic drugs (csDMARDs) but has poor efficacy (e.g., ineffectiveness).

[0233] In some embodiments of the present disclosure, the previously treated (treated) refers to moderate to severe active rheumatoid arthritis that has been previously treated with disease-modifying antirheumatic drugs (DMARDs) but has poor efficacy (e.g., ineffective).

[0234] In some embodiments of the present disclosure, the moderately to severely active rheumatoid arthritis is moderately to severely active rheumatoid arthritis that is poorly responsive (eg, ineffective) to traditional synthetic antirheumatic drugs (csDMARDs), including methotrexate.

[0235] In some embodiments of the present disclosure, the moderately to severely active rheumatoid arthritis is moderately to severely active rheumatoid arthritis that is poorly responsive (e.g., ineffective) to disease-modifying antirheumatic drugs (DMARDs), including methotrexate. In some embodiments of the present disclosure, the previously treated (treated) refers to moderately to severely active rheumatoid arthritis that has previously been treated with conventional synthetic antirheumatic drugs (csDMARDs) and has not responded adequately to a stable dose of methotrexate (MTX).

[0236] In some embodiments of the present disclosure, the rheumatoid arthritis is in an adult patient (eg, a patient aged ≥18 years and ≤70 years).

[0237] In some embodiments of the present disclosure, the rheumatoid arthritis is moderate to severe active rheumatoid arthritis in adults who have previously received (been treated with) methotrexate with poor efficacy (eg, ineffectiveness).

[0238] In some embodiments of the present disclosure, the rheumatoid arthritis is moderately to severely active rheumatoid arthritis in adults that is refractory to methotrexate.

[0239] Technical Effects

[0240] The compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof has a good therapeutic effect, which is at least reflected in the proportion of patients achieving ACR20 at week 12, the proportion of patients achieving ACR20 and ACR50 remission in each treatment cycle, the patient's swollen joint count (SJC), the patient's tender joint count (TJC), DAS28-CRP, patient pain assessment (PVAS), patient's global assessment of the condition (PtGA), physician's global assessment of the condition (PhGA), health assessment questionnaire-disability index (HAQ-DI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) relative to baseline, and other one or more indicators such as the relief or improvement (relative to baseline).

[0241] The combined pharmaceutical composition of the present disclosure also has at least one or more of the following aspects:

[0242] (1) produce better therapeutic effects in the treatment of rheumatoid arthritis than any of the drugs in the combination administered alone, including but not limited to the above indicators;

[0243] (2) provide for administration of a smaller amount of the drug than would be possible with either drug alone;

[0244] (3) provide a treatment that is well tolerated by patients and has fewer adverse effects and / or complications than either drug given alone;

[0245] (4) Provide better disease control rates among treated patients.

[0246] Definition and Description

[0247] Unless otherwise indicated, the terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this disclosure, it is intended to refer to the corresponding commercial product or its active ingredient.

[0248] Herein, unless otherwise stated, the terms "comprise, comprise, and comprising" or equivalents are open-ended expressions, meaning that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included.

[0249] All patents, patent applications and other identified publications are expressly incorporated herein by reference for the purposes of description and disclosure. Any citation of such publications herein does not constitute an admission that the publication becomes part of the common general knowledge in the art.

[0250] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0251] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present disclosure, which are prepared by reacting the compounds of the present disclosure with relatively nontoxic acids or bases, having specific substituents. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a neat solution or a suitable inert solvent.

[0252] As used in this disclosure, the amount of the compound of formula (I), such as the amount administered, dosage, or content in a pharmaceutical composition, is calculated as its free base.

[0253] As used in the present disclosure, compounds in the pharmaceutical compositions of the present disclosure may form acid addition salts if they have, for example, at least one basic center. If desired, corresponding acid addition salts with additionally present basic centers may also be formed. Compounds having at least one acidic group (e.g., COOH) may also form salts with bases. If, for example, a compound contains both a carboxyl group and an amino group, corresponding inner salts may also be formed.

[0254] The term "patient" refers to mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the patient is a human.

[0255] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure, or pharmaceutical combinations thereof, or salts thereof, and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure, or pharmaceutical combinations thereof, to a subject.

[0256] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect, including partial or complete stabilization or cure of a disease and / or an effect resulting from a disease. As used herein, "treat" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

[0257] The term "effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0258] The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single dose; or each bottle of injection is a single dose.

[0259] The term "multiple doses" consists of a plurality of single doses.

[0260] The terms "administering" and "administering" refer to the physical introduction of a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral administration.

[0261] The term "daily dose" refers to the dose administered to a patient daily.

[0262] The term "per dose" refers to the dose administered to a patient per time.

[0263] The term "CRP" stands for C-reactive protein.

[0264] The term "ESR" stands for erythrocyte sedimentation rate.

[0265] The term "DAS28-CRP" is Disease Activity Score 28-C reactive protein.

[0266] When referring to a dosing regimen, the terms "day," "daily," and the like refer to times within a calendar day, starting at midnight and ending at the following midnight. BRIEF DESCRIPTION OF THE DRAWINGS

[0267] Figure 1 shows the AUC inhibition rate of the clinical score of collagen-induced arthritis mice, where "****" represents P < 0.0001 and "***" represents P < 0.001.

[0268] Figure 2 shows the pathological scoring results of arthritis, where “****” represents P < 0.0001, “***” represents P < 0.001, and “*” represents P < 0.05. DETAILED DESCRIPTION

[0269] The present disclosure is described in more detail by way of specific examples.The following examples are provided for illustrative purposes and should not be construed to limit the present disclosure in any way.

[0270] Example 1: In vivo efficacy study of the compound of formula (II) in collagen-induced arthritis in mice

[0271] This experiment was designed to evaluate the therapeutic effect of the compound of formula (II) on collagen-induced arthritis. Except for the normal group, all mice were injected subcutaneously with the prepared collagen emulsion in the tail on day 0, and LPS solution was injected intraperitoneally on day 23 to induce arthritis. On day 27, some mice began to show arthritis symptoms such as redness and swelling of the feet. They were randomly divided into groups according to the scores and began to receive medication. The positive drug group was given dexamethasone, and the test subjects were given various doses of the compound of formula (II) (50, 100, 150 mg / kg) (measured as C 26 H 37 The body weight and clinical scores of the mice were monitored during the experiment, and H&E staining of the right hind paw of the mice was performed for pathological analysis at the end of the experiment.

[0272] Results showed that mice in the vehicle control group developed severe clinical symptoms of arthritis under collagen induction. Later animal histopathological analysis also revealed severe bone tissue damage, indicating that the mouse CIA model was successfully established. The control drug, dexamethasone, significantly improved arthritis symptoms and tissue lesions. Each group of compound (II) had a moderate alleviating effect on collagen-induced joint damage in mice. Clinical score AUC inhibition rates in the 50, 100, and 150 mg / kg groups were 61.6%, 63.2%, and 73.8%, respectively. All groups were well tolerated by mice.

[0273] The results are shown in Figures 1 and 2.

[0274] The results showed that in the mouse CIA model, the compound of formula (II) significantly inhibited the paw arthritis of the mice in a dose-dependent manner and reduced the arthritis inflammation score of the mice.

[0275] Example 2: Clinical trial

[0276] This study is a randomized, double-blind, placebo-controlled, multicenter clinical study of the efficacy and safety of the compound of formula (II) in the treatment of patients with rheumatoid arthritis who have received previous treatment. The efficacy evaluation was performed at the 4th week (D28±3), the 8th week (D56±3), the 12th week (D84±3), the 18th week (D126±3), and the 24th week (D168±3) after administration on D1.

[0277] 1.1 Inclusion Criteria:

[0278] 1) The subjects voluntarily participated in this study and signed the informed consent form;

[0279] 2) Both male and female, aged ≥18 and ≤70 years (based on the date of signing the informed consent form);

[0280] 3) The diagnosis met the rheumatoid arthritis (RA) classification criteria jointly developed by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) in 2010, and the disease lasted for at least 3 months;

[0281] 4) moderate to severe active RA according to the following criteria: joint swelling ≥ 6 (based on 66 joints) and joint tenderness ≥ 6 (based on 68 joints) and DAS28-CRP ≥ 3.2, and CRP > 10 mg / L or ESR > 28 mm / h must also be met;

[0282] 5) Received methotrexate (dose 7.5-25 mg / week) for at least 12 weeks, and the dose was stable before the first dose of the study drug

[0283] (7.5-25 mg / week) ≥ 4 weeks (stable oral dose of methotrexate will continue as background therapy during the trial):

[0284] Must be willing to continue or start oral folic acid (at least 5 mg / week) treatment and receive treatment throughout the study period;

[0285] Before the first dose, subjects must have stopped taking csDMARDs (except MTX) for ≥4 weeks and leflunomide for ≥8 weeks;

[0286] Before the first dose, the subjects stopped using traditional Chinese medicine or Chinese patent medicine to treat rheumatoid arthritis for ≥4 weeks;

[0287] 6) During screening, if the subject is taking oral nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids, the following requirements must be met:

[0288] Before the first dose, the dose of nonsteroidal anti-inflammatory drugs (NSAIDs) must be stable for at least 2 weeks before administration;

[0289] Oral corticosteroids (equivalent to prednisone ≤ 10 mg / day) or inhaled corticosteroids are allowed before the first dose, but the dose must be stable for at least 4 weeks before the first dose;

[0290] 7) Subjects must have stopped taking all opioids for at least 1 week before the first dose;

[0291] 8) Male or female subjects of childbearing potential must agree and commit to use medically accepted contraceptive methods throughout the study and for at least 6 months after the last administration of the trial drug;

[0292] 9) The subjects are able to attend study visits on time and complete the visit content.

[0293] 1.2 Investigational Drugs

[0294] Tablets of the compound of formula (II): specification 100 mg.

[0295] Methotrexate tablets Produced by Shanghai SPH Sine Pharmaceuticals Co., Ltd. (formerly Shanghai Sine Pharmaceuticals Co., Ltd.).

[0296] folic acid tablets Produced by Changzhou Pharmaceutical Factory Co., Ltd.

[0297] 1.3 Dosage regimen

[0298] Tablets of the compound of formula (II): 100 mg / time, 200 mg / time, 300 mg / time, or 400 mg / time (calculated as the compound of formula (I)), orally taken after breakfast and dinner, twice a day.

[0299] Methotrexate tablets: Dosage and administration before continuing the study: methotrexate (dose 7.5-25 mg / week) should be administered on the same day of each week as much as possible.

[0300] Folic acid tablets: Dosage and administration before continuing the study: The recommended administration time of folic acid tablets (at least 5 mg / week) is 24 hours after oral methotrexate.

[0301] 1.4 Evaluation Method

[0302] Effectiveness evaluation criteria

[0303] Whether there are significant differences between the two groups in the proportion of patients achieving ACR20 and ACR50 remission at each follow-up point, the changes in the number of swollen joints (SJC), the number of tender joints (TJC), DAS28-CRP, patient pain assessment of joints (PVAS), patient's global assessment of the disease (PtGA), physician's global assessment of the disease (PhGA), Health Assessment Questionnaire-Disability Index (HAQ-DI), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) relative to baseline and the placebo group.

[0304] Safety evaluation standards

[0305] The severity of adverse events was determined using the NCI-CTC AE 5.0 criteria. During the trial, the adverse event record form should be filled out truthfully, including the time of occurrence, severity, relevance to the study treatment, duration, and measures taken.

[0306] 1.5 Evaluation results

[0307] Effectiveness

[0308] Among the 14 evaluable patients, the proportion of patients achieving ACR20 at week 4 was 28.6% (4 / 14), and 1 patient achieved ACR50.

[0309] Among the 8 evaluable patients, the proportion of patients achieving ACR20 at week 8 was 37.5% (3 / 8), of whom 2 patients achieved ACR50.

[0310] Among the three evaluable patients, the proportion of patients achieving ACR20 at week 12 was 33.3% (1 / 3), and one patient achieved ACR50.

[0311] Security

[0312] Among the 14 evaluable patients, no SAEs or serious AEs occurred, and the overall safety and tolerability were good.

Claims

1. A pharmaceutical composition for treating or preventing rheumatoid arthritis, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, 2. A combination pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate, 3. A pharmaceutical composition for treating or preventing rheumatoid arthritis, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and methotrexate, 4. The pharmaceutical composition according to claim 1, which contains 25-600 mg, 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 200-400 mg or 200-300 mg of the compound of formula (I) or its pharmaceutically acceptable salt, calculated as the compound of formula (I); or the pharmaceutical composition contains 100-200 mg of the compound of formula (I) or its pharmaceutically acceptable salt, calculated as the compound of formula (I).

5. The combination pharmaceutical composition according to claim 2, comprising 25-600 mg, 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 200-400 mg or 200-300 mg of the compound of formula (I) or its pharmaceutically acceptable salt and 2.5-30 mg, 5-25 mg, 7.5-25 mg, 10-25 mg, 12.5-25 mg, 15-25 mg, 17.5-25 mg or 20-25 mg of methotrexate; preferably, the combination pharmaceutical composition contains 100-200 mg of the compound of formula (I) or its pharmaceutically acceptable salt and 7.5-25 mg of methotrexate.

6. The pharmaceutical composition according to claim 1 or the combination pharmaceutical composition according to claim 2, wherein the content of the compound of formula (I) or its pharmaceutically acceptable salt is a daily dose, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered in a single dose or multiple doses, usually in multiple doses, or usually in a single dose; further, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered twice a day.

7. The pharmaceutical composition according to claim 1 or the combined pharmaceutical composition according to claim 2, which contains a single dose of 25 mg, 100 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably contains a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

8. The pharmaceutical composition according to claim 1, which is a pharmaceutical composition for each dose, wherein each dose of the pharmaceutical composition contains 25-600 mg, 50-600 mg, 100-600 mg, 100-500 mg, 100-400 mg, 200-400 mg or 200-300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 100-400 mg, 200-400 mg or 200-300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); preferably 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg of the compound of formula (I). , 350mg or 400mg of the compound of formula (I) or its pharmaceutically acceptable salt; preferably 100mg, 200mg, 300mg or 400mg of the compound of formula (I) or its pharmaceutically acceptable salt; preferably 200mg, 300mg or 400mg of the compound of formula (I) or its pharmaceutically acceptable salt; preferably 200mg or 300mg of the compound of formula (I) or its pharmaceutically acceptable salt; preferably 100mg or 200mg of the compound of formula (I) or its pharmaceutically acceptable salt; preferably 100mg of the compound of formula (I) or its pharmaceutically acceptable salt.

9. The combination pharmaceutical composition according to claim 2, which contains 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof per dose; and 7.5 mg, 10 mg, 15 mg, 20 mg or 25 mg of methotrexate in a weekly therapeutic dose; preferably containing 100 mg or 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof per dose, calculated as the compound of formula (I); and weekly therapeutic doses of methotrexate of 7.5 mg, 10 mg, 15 mg, 20 mg, or 25 mg.

10. The combination pharmaceutical composition according to claim 2, wherein the content of methotrexate is a dose for each treatment cycle, and the methotrexate is administered in the following manner: methotrexate is administered once a week.

11. Use of the pharmaceutical composition according to claim 1 or the combined pharmaceutical composition according to claim 2 in treating or preventing rheumatoid arthritis in a patient.

12. The use according to claim 11, wherein the rheumatoid arthritis is moderate to severe active rheumatoid arthritis that has been previously treated.

13. The use of the combination pharmaceutical composition according to claim 11, wherein one treatment cycle is 28 days, methotrexate is administered once a week, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 28 of each treatment cycle; preferably, one treatment cycle is 28 days, methotrexate is administered once a week, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day on days 1 to 28 of each treatment cycle.

14. The use of the combination pharmaceutical composition according to claim 11, wherein 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in each treatment cycle is 11.2 g or 16.8 g; 7.5 to 25 mg of methotrexate is administered once a week; or, 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in each treatment cycle is 5.6 g or 11.2 g; 7.5 to 25 mg of methotrexate is administered once a week.

15. The use according to claim 12, wherein the patient has previously received treatment with a traditional synthetic anti-rheumatic drug; the traditional synthetic anti-rheumatic drug includes but is not limited to one or two of methotrexate, flunomide or sulfasalazine; preferably, the traditional synthetic anti-rheumatic drug is methotrexate.

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