Combined pharmaceutical composition of pyrrolo [2, 3-c] pyridone compound and application thereof

Abstract

The invention relates to a combined pharmaceutical composition of pyrrolo [2, 3-c] pyridone compounds and application of the combined pharmaceutical composition. Specifically, the invention relates to a combined pharmaceutical composition of a compound shown as a formula (I) and application of the combined pharmaceutical composition to treatment of myelofibrosis.

Description

A combined pharmaceutical composition of a pyrrolo[2,3-c]pyridinone compound and its use

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and the rights of Chinese patent application No. 202310518474.4, filed with the State Intellectual Property Office of the People's Republic of China on May 9, 2023, entitled "A combination pharmaceutical composition of a pyrrolo[2,3-c]pyridinone compound and its use", 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 a combination pharmaceutical composition of a pyrrolo[2,3-c]pyridinone compound and its use. Specifically, it relates to a combination pharmaceutical composition of a compound of formula (I) and its use in treating myelofibrosis. Background Art

[0004] Myelofibrosis (MF) is a chronic, progressive myeloproliferative neoplasm caused by collagen proliferation and fibrosis in the bone marrow, which severely impairs hematopoietic function. It includes primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV-MF), and post-essential thrombocythemia myelofibrosis (post-ET-MF). Its main characteristics are varying degrees of myelofibrosis, blood cell abnormalities / anemia, splenomegaly, and systemic symptoms (such as fatigue, night sweats, weight loss, and left upper abdominal distension). MF generally progresses slowly, with early-stage patients typically surviving for 10 years or longer. However, the overall median survival is 5 to 7 years, with high-risk patients having a median survival of 2.7 years.

[0005] Currently, there is a lack of safe and effective treatments for MF. For patients in the early and middle stages, who generally have a longer survival period, the usual treatment strategy is symptomatic treatment. This involves providing appropriate treatment based on clinical features such as anemia, splenomegaly, constitutional symptoms, and symptomatic extramedullary hematopoiesis, combined with prognostic analysis.

[0006] WO2020020288 discloses 4-{3-(2,4-difluorophenoxy)-6-{[dimethyl(oxo)-λ 6 -sulfydene]amino}pyridin-2-yl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (hereinafter referred to as the compound of formula (I)) and its use in treating cancer.

[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 myelofibrosis.

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

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

[0011] In another aspect, the present disclosure provides the use of a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating myelofibrosis. Alternatively, the present disclosure provides a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating myelofibrosis.

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

[0013] 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.

[0014] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be provided in the form of a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments of the present disclosure, the pharmaceutical composition is packaged in a medicine kit, which further includes instructions for using the compound of formula (I) or a pharmaceutically acceptable salt thereof to treat myelofibrosis.

[0016] In some embodiments of the present disclosure, the pharmaceutical composition contains 0.01 to 10 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0017] In some embodiments of the present disclosure, the pharmaceutical composition contains 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg of the compound of formula (I). 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, or a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, preferably at least 10 mg, 2.8 mg, 2.9 mg, 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4.2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg, 5.5 mg, 5.6 mg, 5.7 mg, 5.8 mg, 5.9 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, or a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof,

[0018] In some embodiments of the present disclosure, the pharmaceutical composition contains 0.01-5 mg, 0.01-2 mg, 0.05-5 mg, 0.05-2 mg, 0.05-1 mg, 0.05-0.5 mg, 0.05-0.2 mg, 0.05-0.15 mg, 0.05-0.1 mg, 0.1-0.15 mg, 0.01-1 mg, 0.01-0.2 mg, 0.01-0.5 mg or 0.01-0.15 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments of the present disclosure, the pharmaceutical composition contains 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg or 1.0 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0020] In some embodiments of the present disclosure, the pharmaceutical composition contains 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.5 mg or 1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I). In some embodiments of the present disclosure, the pharmaceutical composition contains 0.05 mg, 0.1 mg, 0.15 mg or 0.2 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I). In some embodiments of the present disclosure, the pharmaceutical composition contains 0.05 mg, 0.1 mg or 0.15 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I). In some embodiments of the present disclosure, the pharmaceutical composition contains 0.05 mg or 0.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I).

[0021] In some embodiments of the present disclosure, the pharmaceutical composition contains 0.05 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). In some embodiments of the present disclosure, the pharmaceutical composition contains 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). In some embodiments of the present disclosure, the pharmaceutical composition contains 0.15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0022] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is in single-dose or multi-dose form. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is in single-dose form. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is in multi-dose form. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is in multi-dose form, and the multi-dose form is composed of the same or different single-dose forms; preferably composed of the same single-dose form.

[0023] In some embodiments of the present disclosure, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above-mentioned pharmaceutical composition is a daily dose.

[0024] In some embodiments of the present disclosure, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above-mentioned pharmaceutical composition is a once-daily dose.

[0025] In some embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, the content of the compound of formula (I) or its pharmaceutically acceptable salt is a once-daily dose, and each dose is a single dose or multiple doses. In some embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, the content of the compound of formula (I) or its pharmaceutically acceptable salt is a once-daily dose, and each dose is a single dose. In some embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, the content of the compound of formula (I) or its pharmaceutically acceptable salt is a once-daily dose, and each dose is a multiple dose. In some embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, the content of the compound of formula (I) or its pharmaceutically acceptable salt is a once-daily dose, and each dose is a multiple dose, and the multiple doses are composed of the same or different single doses; preferably composed of the same single dose.

[0026] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 0.05 mg and / or 0.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I). Alternatively, the pharmaceutical composition is in the form of a single-dose formulation containing 0.05 mg and / or 0.1 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 a single dose of 0.05 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 0.05 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0028] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 0.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I). Alternatively, the pharmaceutical composition is in the form of a single-dose formulation, containing 0.1 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 of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single-dose pharmaceutical composition, and the single dose may be composed of 0.05 mg or 0.1 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, and the multiple doses may be composed of a single dose of 0.05 mg and / or 0.1 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments of the present disclosure, the pharmaceutical composition contains multiple doses of 0.1 mg, 0.15 mg or 0.2 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and the multiple doses may be composed of a pharmaceutical composition with a single dose of 0.05 mg, or 0.1 mg, or 0.05 mg and 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments of the present disclosure, the pharmaceutical composition contains multiple doses of 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and the multiple doses may be composed of a pharmaceutical composition with a single dose of 0.05 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments of the present disclosure, the pharmaceutical composition contains multiple doses of 0.15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and the multiple doses may be composed of a pharmaceutical composition with a single dose of 0.05 mg, or 0.05 mg and 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments of the present disclosure, one treatment cycle is every 2-6 weeks. In some embodiments of the present disclosure, one treatment cycle is every 28 days.

[0035] In some embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition having a total dose of 0.28 mg to 280 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or a pharmaceutical composition having a total dose of 0.28 mg to 140 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or a pharmaceutical composition having a total dose of 0.28 mg to 140 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I). The pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt in an amount of 1.4 mg to 28 mg; or the preparation comprises: a pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt in a total dose of 1.4 mg to 14 mg based on the compound of formula (I); or the preparation comprises: a pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt in a total dose of 1.4 mg to 5.6 mg based on the compound of formula (I); or the preparation comprises: a pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt in a total dose of 1.4 mg to 4.2 mg based on the compound of formula (I). (I) compound or a pharmaceutically acceptable salt thereof; or, the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 2.8 mg to 4.2 mg based on the compound of formula (I); or, the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 1.4 mg, 2.8 mg, 4.2 mg or 5.6 mg based on the compound of formula (I); or, the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 1.4 mg, 2.8 mg, 4.2 mg or 5.6 mg based on the compound of formula (I); or the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 1.4 mg, calculated as a compound of formula (I); or, the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 2.8 mg, calculated as a compound of formula (I); or, the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 4.2 mg, calculated as a compound of formula (I).

[0036] In some embodiments of the present disclosure, one treatment cycle is every 2-6 weeks. In some embodiments of the present disclosure, one treatment cycle is every 21 days.

[0037] In some embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle), comprising: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.14 mg to 140 mg, calculated as a compound of formula (I); or, the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.14 mg to 70 mg, calculated as a compound of formula (I); or, the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.7 mg to 14 mg, calculated as a compound of formula (I). or the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.7 mg to 7 mg based on the compound of formula (I); or the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.7 mg to 2.8 mg based on the compound of formula (I); or the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.7 mg to 2.1 mg based on the compound of formula (I); or the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 1.4 mg to 2.1 mg based on the compound of formula (I); a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; or, the preparation comprises: a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 0.7 mg to 1.4 mg, calculated as the compound of formula (I); or, the preparation comprises: a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 0.7 mg, 1.4 mg, 2.1 mg or 2.8 mg, calculated as the compound of formula (I); or, the preparation comprises: a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 0.7 mg, 1.4 mg or 2.1 mg, calculated as the compound of formula (I); Alternatively, the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.7 mg or 1.4 mg, calculated as the compound of formula (I); or the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.7 mg, calculated as the compound of formula (I); or, the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 1.4 mg, calculated as the compound of formula (I); or, the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 2.1 mg, calculated as the compound of formula (I).

[0038] In some embodiments of the present disclosure, the pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle), comprising: a pharmaceutical composition having a total dose of 0.14 mg to 140 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or, the pharmaceutical composition having a total dose of 0.14 mg to 70 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); or, the pharmaceutical composition having a total dose of 0.35 mg to 7 mg of a compound of formula (I), calculated as a compound of formula (I). or the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.35 mg to 3.5 mg based on the compound of formula (I); or the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.35 mg to 2.1 mg based on the compound of formula (I); or the preparation comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.35 mg to 1.4 mg based on the compound of formula (I); or the preparation comprises The invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.35 mg to 0.7 mg based on the compound of formula (I); or, the preparation comprises a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.35 mg, 0.7 mg, 1.4 mg or 2.1 mg based on the compound of formula (I); or, the preparation comprises a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.35 mg, 0.7 mg or 1.4 mg based on the compound of formula (I); or, the preparation comprises a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.35 mg, 0.7 mg or 1.4 mg based on the compound of formula (I); The invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.35 mg or 0.7 mg calculated as the compound; or the preparation comprises: a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.35 mg calculated as the compound; or the preparation comprises: a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 0.7 mg calculated as the compound; or the preparation comprises: a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 1.4 mg calculated as the compound.

[0039] In another aspect, the present disclosure further provides a kit for a pharmaceutical composition for treating myelofibrosis, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein. Furthermore, the kit further comprises instructions for treating myelofibrosis with the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0040] On the other hand, the present disclosure also provides a method for treating myelofibrosis, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need. Specifically, a therapeutically effective amount of the pharmaceutical composition described above in the present disclosure can be administered to an individual in need.

[0041] On the other hand, the present disclosure also provides a therapy for treating myelofibrosis, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the individual alone. Specifically, a therapeutically effective amount of the pharmaceutical composition described above in the present disclosure can be administered to the individual alone.

[0042] On the other hand, the present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating myelofibrosis, specifically including the use of the above-mentioned pharmaceutical composition of the present disclosure in the preparation of a medicament for treating myelofibrosis. Alternatively, the present disclosure also provides the above-mentioned pharmaceutical composition for treating myelofibrosis. In some embodiments of the present disclosure, the pharmaceutical composition is any of the pharmaceutical compositions described above in the present disclosure.

[0043] 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 myelofibrosis, specifically including the use of the above-mentioned pharmaceutical composition of the present disclosure for treating myelofibrosis.

[0044] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, the definition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is the same as that of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition described above, such as content, dosage, form of existence, packaging form, etc.

[0045] In some embodiments of the present disclosure, in the above methods, therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered every 2-6 weeks as a treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks as a treatment cycle. Preferably, every 4 weeks as a treatment cycle. Or preferably, every 3 weeks as a treatment cycle.

[0046] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is a daily dose, which is administered in the following manner: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once or more daily; preferably once or twice daily; more preferably once daily.

[0047] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition 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 a single dose; further, the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily in a single dose. In one embodiment, a single dose of an oral solid preparation is administered once daily.

[0048] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition 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; further, the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily in multiple doses. In one embodiment, multiple doses of an oral solid preparation are administered once daily.

[0049] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 0.01 to 5 mg; or, a daily dose of 0.05 to 5 mg; or, a daily dose of 0.05 to 1 mg; or, a daily dose of 0.05 to 0.5 mg; or, a daily dose of 0.05 to 0.2 mg; or, a daily dose of 0.05 to 0.15 mg; or, a daily dose of 0.05 to 0.1 mg; or, a daily dose of 0.1 to 0.15 mg.

[0050] In some embodiments of the present disclosure, in the above methods, therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 0.01 mg; or, a daily dose of 0.05 mg; or, a daily dose of 0.1 mg; or, a daily dose of 0.15 mg; or, a daily dose of 0.2 mg.

[0051] In some embodiments of the present disclosure, in the above methods, therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 0.05 mg; or, a daily dose of 0.1 mg; or, a daily dose of 0.15 mg.

[0052] In some embodiments of the present disclosure, in the above methods, therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 0.05 mg; or, a daily dose of 0.1 mg.

[0053] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is continuously administered on the 1st to 28th day of each treatment cycle. In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is continuously administered on the 1st to 28th day of each treatment cycle. In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is continuously administered on the 1st to 28th day of each treatment cycle. In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 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 a day continuously from the 1st to the 28th day of each treatment 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 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 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 a day continuously from the 1st to the 28th day of each treatment 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 0.1 mg, 0.15 mg or 0.2 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; preferably, the multiple dose is 0.1 mg or 0.15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 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 a day continuously from the 1st to the 28th day of each treatment 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 0.1 mg or 0.15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple dose consists of a single dose of 0.05 mg, or 0.05 mg and 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, which contains the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days or 28 days, or a dose of a 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 1-day, 2-day, 3-day, 4-day, 5-day, 6-day, 7-day, 14-day, 21-day, or 28-day dose, or a dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, with any of the foregoing values ​​as endpoints.

[0057] In some embodiments of the present disclosure, in the above methods, therapies or uses, 28 days is a treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt administered continuously on days 1 to 28 of each treatment cycle is 0.28 mg to 280 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.28 mg to 140 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 1.4 mg to 28 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 1.4 mg to 14 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 1.4 mg to 5.6 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 1.4 mg to 4.2 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1.4 mg to 2.8 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 2.8 mg to 4.2 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1.4 mg, 2.8 mg, 4.2 mg or 5.6 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 1.4 mg; or preferably 2.8 mg; or preferably 4.2 mg.

[0058] In some embodiments of the present disclosure, in the above methods, 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 once 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 1.4 mg, 2.8 mg, 4.2 mg, or 5.6 mg. In some embodiments of the present disclosure, in the above methods, 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 once 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 1.4 mg. In some embodiments of the present disclosure, in the above methods, 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 once 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 per treatment cycle is 2.8 mg. In some embodiments of the present disclosure, in the above methods, 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 once 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 per treatment cycle is 4.2 mg.

[0059] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is continuously administered daily from the 1st to the 14th day of each treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is stopped from the 15th to the 21st day of each treatment cycle. In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is continuously administered once a day from the 1st to the 14th day of each treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is stopped from the 15th to the 21st day of each treatment cycle.

[0060] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day continuously from the 1st to the 14th day of each treatment cycle, and the administration of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is stopped from the 15th to the 21st day of each treatment cycle. 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 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day continuously from the 1st to the 14th day of each treatment cycle, and the administration of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is stopped from the 15th to the 21st day of each treatment cycle. 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 0.1 mg, 0.15 mg or 0.2 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; preferably, the multiple dose is 0.1 mg or 0.15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments of the present disclosure, in the above methods, therapies or uses, 21 days constitute a treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is continuously administered on days 1 to 14 of each treatment cycle, and the administration of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is stopped on days 15 to 21 of each treatment cycle. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.14 mg to 70 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.7 mg to 14 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.7 mg to 7 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.7 mg to 2.8 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.7 mg to 2.1 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.7 mg to 1.4 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 1.4 mg to 2.1 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.7 mg, 1.4 mg, 2.1 mg or 2.8 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.7 mg or 1.4 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 0.7 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 1.4 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 2.1 mg.

[0063] In some embodiments of the present disclosure, in the above methods, therapies, or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 14 consecutive days, and the administration is stopped on days 15-21. 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 0.7 mg, 1.4 mg, 2.1 mg, or 2.8 mg. In some embodiments of the present disclosure, in the above methods, therapies, or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 14 consecutive days, and the administration is stopped on days 15-21. 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 0.7 mg or 1.4 mg.

[0064] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 14 consecutive days, and the administration is stopped on the 15th to 21st day. 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 0.7 mg.

[0065] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 14 consecutive days, and the administration is stopped on the 15th to 21st day. 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 1.4 mg.

[0066] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 14 consecutive days, and the administration is stopped on the 15th to 21st day. 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 2.1 mg.

[0067] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is continuously administered daily from the 1st to the 7th day of each treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is stopped from the 8th to the 21st day of each treatment cycle. In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is continuously administered once a day from the 1st to the 7th day of each treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is stopped from the 8th to the 21st day of each treatment cycle.

[0068] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day continuously from the 1st to the 7th day of each treatment cycle, and the administration of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is stopped from the 8th to the 21st day of each treatment cycle. 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 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day continuously from the 1st to the 7th day of each treatment cycle, and the administration of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is stopped from the 8th to the 21st day of each treatment cycle. 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 0.1 mg, 0.15 mg or 0.2 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; preferably, the multiple dose is 0.1 mg or 0.15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments of the present disclosure, in the above methods, therapies or uses, 21 days constitute a treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is continuously administered on days 1 to 7 of each treatment cycle in a dose of 0.14 mg to 140 mg, and the administration of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is stopped on days 8 to 21 of each treatment cycle. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.14 mg to 70 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.35 mg to 7 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.35 mg to 2.1 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.35 mg to 1.4 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.35 mg to 0.7 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.35 mg, 0.7 mg, 1.4 mg or 2.1 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 0.35 mg or 0.7 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 0.35 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 0.7 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 1.4 mg.

[0071] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 7 consecutive days, and the administration is stopped on the 8th to 21st day. 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 0.35 mg, 0.7 mg, 1.4 mg or 2.1 mg.

[0072] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 7 consecutive days, and the administration is stopped on the 8th to 21st day. 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 0.35 mg or 0.7 mg.

[0073] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 7 consecutive days, and the administration is stopped on the 8th to 21st day. 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 0.35 mg.

[0074] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 7 consecutive days, and the administration is stopped on the 8th to 21st day. 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 0.7 mg.

[0075] In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 7 consecutive days, and the administration is stopped on the 8th to 21st day. 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 1.4 mg.

[0076] In the disclosed regimens, the above-described treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

[0077] In another aspect, the present disclosure provides a combination pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0078] In some embodiments of the present disclosure, in the above-mentioned combination pharmaceutical composition, the compound of formula (I) or its pharmaceutically acceptable salt and the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt are packaged in the same kit, and the kit further comprises instructions for using the compound of formula (I) or its pharmaceutically acceptable salt and the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt in combination to treat myelofibrosis. Preferably, the compound of formula (I) or its pharmaceutically acceptable salt and the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt are each separately packaged in the same kit (for example, the two are each packaged in separate small boxes).

[0079] In some embodiments of the present disclosure, in the above-mentioned combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof are separately packaged in respective kits, and the respective kits further include instructions for the combined use of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof for the treatment of myelofibrosis.

[0080] 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 a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt in the above-mentioned combination pharmaceutical composition are packaged in the same kit, and the kit further comprises instructions for using the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt in combination to treat myelofibrosis. Preferably, the two aforementioned pharmaceutical compositions are each separately packaged in the same kit (for example, the two are each packaged in separate small boxes).

[0082] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in the above-mentioned combination pharmaceutical composition are separately packaged in respective kits, and the respective kits also contain instructions for using the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in combination to treat myelofibrosis.

[0083] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the above-mentioned combination pharmaceutical composition are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially or intermittently.

[0084] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the characteristics of which are as described in the present disclosure.

[0085] 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.

[0086] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 1 to 50 mg, 5 to 50 mg, 5 to 40 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg, 10 to 20 mg, 10 to 15 mg or 20 to 30 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (based on the amount of the compound of formula (II)). In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 5 mg, 10 mg, 15 mg or 20 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 10 to 20 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 10 to 15 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 5 to 15 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 10 mg, 15 mg or 20 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 5 mg, 10 mg or 15 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 10 mg or 15 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some specific embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 5 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some specific embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 10 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some specific embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 15 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition.

[0087] In some embodiments of the present disclosure, in the above-mentioned combination pharmaceutical composition, the pharmaceutical composition of the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is in a single-dose or multi-dose form. In some embodiments of the present disclosure, in the above-mentioned combination pharmaceutical composition, the pharmaceutical composition of the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is in a multi-dose form.

[0088] In some embodiments of the present disclosure, in the above-mentioned combination pharmaceutical composition, the pharmaceutical composition of the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is a daily dose. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is a twice-daily dose. In some embodiments of the present disclosure, each of the two doses is the same.

[0089] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice daily, with each dose being a single dose or multiple doses.

[0090] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is twice daily dose, each dose is a multiple dose, which consists of a single dose of 5 mg, 10 mg, 15 mg and / or 20 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt. In some embodiments of the present disclosure, the pharmaceutical composition consists of a single dose of 5 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt.

[0091] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is twice daily dosed, each dose being a multiple dose, and the multiple doses are 10 mg or 15 mg of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is twice daily dosed, each dose being a multiple dose, and the multiple doses are 10 mg or 15 mg of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, which consists of a single dose of 5 mg of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is packaged in a kit, which also contains instructions for using the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt to treat myelofibrosis.

[0093] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 0.01-5 mg, 0.01-2 mg, 0.05-5 mg, 0.05-2 mg, 0.05-1 mg, 0.05-0.5 mg, 0.05-0.2 mg, 0.05-0.15 mg, 0.05-0.1 mg, 0.1-0.15 mg, 0.01-1 mg, 0.01-0.2 mg, 0.01-0.5 mg g or 0.01-0.15 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing 1-50 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-20 mg, 10-15 mg or 20-30 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is Single dose or multiple doses, wherein the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a single dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is multiple doses; further preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a single dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose; preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is multiple doses, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose; further preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is multiple doses, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is multiple doses.

[0094] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.5 mg or 1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 5 mg, 10 mg, 15 mg or 20 mg or a range formed by any of the above values ​​(calculated as a compound of formula (II)) of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, wherein the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the compound of formula (I) or The pharmaceutical composition of the pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a multiple dose; further preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a single dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose; further preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a multiple dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose; further preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a multiple dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a multiple dose.

[0095] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 0.05 mg, 0.1 mg, 0.15 mg or 0.2 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 10 mg, 15 mg or 20 mg of a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, wherein the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose; further preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose.

[0096] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 0.05 mg, 0.1 mg or 0.15 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 10 mg or 15 mg of a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and wherein the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose; further preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose.

[0097] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains a pharmaceutical composition of 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I) and a pharmaceutical composition of 10 mg or 15 mg of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (II), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and wherein the pharmaceutical composition of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is a multiple dose; further preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is a multiple dose.

[0098] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 0.05 mg or 0.1 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 5 mg of a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and wherein the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose; further preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is multiple doses, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose.

[0099] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 0.05 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 10 mg of a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, wherein the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose.

[0100] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 0.05 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 15 mg of a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and wherein the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose.

[0101] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 0.1 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 10 mg of a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and wherein the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose.

[0102] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 0.1 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 15 mg of a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and wherein the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose.

[0103] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition contains 0.15 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 15 mg of a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and wherein the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose.

[0104] 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 in a single dose of 0.05 mg or 0.1 mg, calculated as a compound of formula (I); and a pharmaceutical composition of a compound of formula (II) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in a single dose of 5 mg, calculated as a compound of formula (II). 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 0.05 mg or 0.1 mg, calculated as a compound of formula (I); and a compound of formula (II) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in a single dose of 5 mg, calculated as a compound of formula (II).

[0105] In some embodiments of the present disclosure, one treatment cycle is every 21 days and / or one treatment cycle is every 28 days.

[0106] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition is a pharmaceutical composition suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), including a pharmaceutical composition containing 0.28 mg to 280 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and a pharmaceutical composition containing 140 to 840 mg of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); or, a pharmaceutical composition containing 1.4 mg to 5.6 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II), and a pharmaceutical composition containing 140 mg, 280 mg, 420 mg, 560 mg, 700 mg, 840 mg, or a range formed by any two of the above values, calculated as a compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; or, a pharmaceutical composition containing 1.4 mg to 5.6 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof; The invention also provides a pharmaceutical composition comprising: a pharmaceutical composition comprising 1.4 mg, 2.8 mg, 4.2 mg or 5.6 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing 280 to 840 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); or a pharmaceutical composition comprising 1.4 mg, 2.8 mg, 4.2 mg or 5.6 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); and a pharmaceutical composition containing 280 mg, 560 mg or 840 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); or a pharmaceutical composition comprising 1.4 mg, 2.8 mg or 4.2 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and a pharmaceutical composition containing 560 mg or 840 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II).

[0107] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition is a pharmaceutical composition suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle), comprising a pharmaceutical composition containing 0.14 mg to 140 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I) and a pharmaceutical composition containing 105 to 630 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); or a pharmaceutical composition containing 0.7 mg to 2.8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I) and a pharmaceutical composition containing 105 to 630 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II). The present invention relates to a pharmaceutical composition comprising 105 mg, 210 mg, 315 mg, 420 mg, 525 mg, 630 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as 105 mg, 210 mg, 315 mg, 420 mg, 525 mg, 630 mg or a range formed by any two of the above values; or a pharmaceutical composition comprising 0.7 mg to 2.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 210 to 630 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as 105 mg, 210 mg, 315 mg, 420 mg, 525 mg, 630 mg or a range formed by any two of the above values; or a pharmaceutical composition comprising 0.7 mg to 2.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising 0.7 mg to 2.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising 0.7 mg to 2.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising 7 mg, 1.4 mg, 2.1 mg or 2.8 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing 210 mg, 420 mg or 630 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); or a pharmaceutical composition comprising 0.7 mg, 1.4 mg or 2.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I) and 420 mg or 630 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II). A pharmaceutical composition; or, a pharmaceutical composition comprising 0.7 mg or 1.4 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 420 mg or 630 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); or, a pharmaceutical composition comprising 0.7 mg or 1.4 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 210 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II).

[0108] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition is a pharmaceutical composition suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle), including a pharmaceutical composition containing 0.14 mg to 140 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I) and a pharmaceutical composition containing 105 to 630 mg of the compound of formula (II), its stereoisomers, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); or, a pharmaceutical composition containing 0.35 mg to 2.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I) and a pharmaceutical composition containing 105 mg, 210 mg, 315 mg, 420 mg, 525 mg, 630 mg of the compound of formula (II) or a range formed by any two of the above values, calculated as a compound of formula (II). , its stereoisomers, or pharmaceutically acceptable salts thereof; or, a pharmaceutical composition comprising 0.35 mg to 1.4 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 210 to 630 mg of a compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof, calculated as a compound of formula (II); or, a pharmaceutical composition comprising 0.35 mg, 0.7 mg, 1.4 mg or 2.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II), and 210 mg, 420 mg or 630 mg of a compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof, calculated as a compound of formula (II); or, a pharmaceutical composition comprising 0.35 mg, 0.7 mg, 1.4 mg or 2.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); a pharmaceutical composition comprising 0.7 mg or 1.4 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing 420 mg or 630 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); or a pharmaceutical composition comprising 0.35 mg or 0.7 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and a pharmaceutical composition containing 420 mg or 630 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); or a pharmaceutical composition comprising 0.35 mg or 0.7 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and a pharmaceutical composition containing 210 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II);

[0109] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), comprising a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, with a total dose ratio of 1:(25-600), for example, 1:(50-600), 1:(66.7-600), 1:(100-600) or 1:(133.3-600) 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 the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is calculated based on the compound of formula (II).

[0110] In some embodiments of the present disclosure, the above-mentioned combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle), comprising a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, with a total dose ratio of 1:(37.5-1800) or 1:(37.5-900), for example, 1:(75-900), 1:(100-900), 1:(150-900) or 1:(200-900) 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 the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is calculated based on the compound of formula (II).

[0111] In some embodiments of the present disclosure, in the above-mentioned combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can be in the form of a pharmaceutical composition separately or together.

[0112] 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 a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0113] On the other hand, the present disclosure also provides a kit for treating myelofibrosis, comprising (a) a first pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein; and (b) a second pharmaceutical composition comprising a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Alternatively, the present disclosure also provides a combination pharmaceutical composition for treating myelofibrosis, comprising: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments of the present disclosure, in the above-mentioned combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 5 mg of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0115] On the other hand, the present disclosure also provides a method for treating myelofibrosis, 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 a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for example, administering to an individual in need thereof a therapeutically effective amount of the combined pharmaceutical composition described above of the present disclosure.

[0116] On the other hand, the present disclosure also provides a combination therapy for treating an individual with myelofibrosis, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and administering to the individual a therapeutically effective amount of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0117] 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 a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating myelofibrosis, for example, the use of the above-mentioned combination pharmaceutical composition of the present disclosure in the preparation of a medicament for treating myelofibrosis. In some embodiments of the present disclosure, the combination pharmaceutical composition is any of the combination pharmaceutical compositions described above in the present disclosure.

[0118] 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 a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for treating myelofibrosis, for example, the use of the above-mentioned combination pharmaceutical composition of the present disclosure for treating myelofibrosis.

[0119] 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 its pharmaceutically acceptable salt and the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt are the same as those of the compound of formula (I) or its pharmaceutically acceptable salt and the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt in the combination pharmaceutical composition described above, such as content, dosage, form of existence, packaging form, etc.

[0120] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition and can be administered simultaneously, separately, concurrently, sequentially or intermittently.

[0121] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof have the same or different treatment cycles, respectively. In some specific embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof 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.

[0122] 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 once a day.

[0123] 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 a single dose, or usually in multiple doses; further, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.

[0124] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 0.01 mg; or, a daily dose of 0.05 mg; or, a daily dose of 0.1 mg; or, a daily dose of 0.15 mg; or, a daily dose of 0.2 mg.

[0125] 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 0.05 mg; or, a daily dose of 0.1 mg; or, a daily dose of 0.15 mg.

[0126] 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 0.05 mg; or, a daily dose of 0.1 mg.

[0127] In some embodiments of the present disclosure, in the above-mentioned 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 of 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily administration manner.

[0128] 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 single dose of 0.05 mg, or 0.1 mg, or 0.05 mg and 0.1 mg of a pharmaceutical composition 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.

[0129] 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, 21 aliquots, 28 aliquots, 35 aliquots, 42 aliquots or more).

[0130] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof in the combination pharmaceutical composition is a daily dose, which is administered as follows: the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered twice a day.

[0131] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof in the combination pharmaceutical composition is a daily dose, which is administered as follows: the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered twice a day, with the same dose each time.

[0132] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof in the combination pharmaceutical composition is a daily dose, wherein the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered in a single dose or multiple doses, usually in multiple doses; further, the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered twice a day.

[0133] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered as follows: a daily dose of 10 mg; or, a daily dose of 20 mg; or, a daily dose of 30 mg; or, a daily dose of 40 mg.

[0134] In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered as follows: a daily dose of 20 mg; or, a daily dose of 30 mg. In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered as follows: a daily dose of 10 mg.

[0135] In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered as follows: twice daily, at a dose of 10 mg each time; or, at a dose of 15 mg each time. In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered as follows: twice daily, at a dose of 5 mg each time.

[0136] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (II), its stereoisomer, 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 5 mg of the compound of formula (II), its stereoisomer, 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.

[0137] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt in the combination pharmaceutical composition is the dosage per treatment cycle, which is administered in the following manner: daily administration of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt. Wherein, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 21 aliquots, 28 aliquots, 35 aliquots, 42 aliquots or more aliquots).

[0138] In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered as follows: a daily dose of 20 mg; the compound of formula (I) or its pharmaceutically acceptable salt is administered as follows: a daily dose of 0.05 mg; or the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered as follows: a daily dose of 30 mg; the compound of formula (I) or its pharmaceutically acceptable salt is administered as follows: a daily dose of 0.05 mg; or, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered as follows: a daily dose of 20 mg; the compound of formula (I) or its pharmaceutically acceptable salt is administered as follows: a daily dose of 0.1 mg; or, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt The compound of formula (I) or its pharmaceutically acceptable salt is administered in the following manner: a daily dose of 30 mg; the compound of formula (I) or its pharmaceutically acceptable salt is administered in the following manner: a daily dose of 0.1 mg; or the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered in the following manner: a daily dose of 30 mg; the compound of formula (I) or its pharmaceutically acceptable salt is administered in the following manner: a daily dose of 0.15 mg; or the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered in the following manner: a daily dose of 10 mg; the compound of formula (I) or its pharmaceutically acceptable salt is administered in the following manner: a daily dose of 0.05 mg; or the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered in the following manner: a daily dose of 10 mg; the compound of formula (I) or its pharmaceutically acceptable salt is administered in the following manner: a daily dose of 0.1 mg.

[0139] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 28 days is a treatment cycle, and the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered daily on days 1-28 of each treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1-28 of each treatment cycle. In some specific embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 28 days is a treatment cycle, and the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered twice a day on days 1-28 of each treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-28 of each treatment cycle.

[0140] 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 once 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 1.4 mg to 5.6 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1.4 mg, 2.8 mg, 4.2 mg or 5.6 mg 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 a pharmaceutically acceptable salt thereof is preferably 1.4 mg to 4.2 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 1.4 mg, 2.8 mg or 4.2 mg.

[0141] 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 (II), its stereoisomers, or its pharmaceutically acceptable salts administered in each treatment cycle is 140 to 840 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts is preferably 140 mg, 280 mg, 420 mg, 560 mg, 700 mg, 840 mg 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 (II), its stereoisomers, or its pharmaceutically acceptable salts is preferably 280 to 840 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts is preferably 560 mg or 840 mg.

[0142] 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 once 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 1.4 mg, 2.8 mg, 4.2 mg or 5.6 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof administered in each treatment cycle is 560 mg or 840 mg. 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 once 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 1.4 mg, 2.8 mg or 4.2 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof in each treatment cycle is 560 mg or 840 mg.

[0143] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle, and the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered daily on days 1-21 of each treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1-14 of each treatment cycle, and the administration of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is stopped on days 15-21 of each treatment cycle. In some specific embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle, and the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered twice a day on days 1-21 of each treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-14 of each treatment cycle, and the administration of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is stopped on days 15-21 of each treatment cycle.

[0144] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-14 of each treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is stopped on days 15-21 of each treatment cycle, 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 0.7 mg to 2.8 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.7 mg, 1.4 mg, 2.1 mg or 2.8 mg 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 a pharmaceutically acceptable salt thereof is preferably 0.7 mg to 2.1 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 0.7 mg, 1.4 mg or 2.1 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 0.7 mg or 1.4 mg.

[0145] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle, the drug is administered twice a day for 21 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts administered in each treatment cycle is 105 to 630 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts is preferably 105 mg, 210 mg, 315 mg, 420 mg, 525 mg, 630 mg 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 (II), its stereoisomers, or its pharmaceutically acceptable salts is preferably 210 to 630 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts is preferably 420 mg or 630 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is preferably 210 mg.

[0146] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-14, and the administration is stopped on days 15-21. 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 0.7 mg, 1.4 mg, 2.1 mg or 2.8 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day for 21 consecutive days. The total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof administered in each treatment cycle is 420 mg or 630 mg.

[0147] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-14, and the administration is stopped on days 15-21. 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 0.7 mg, 1.4 mg or 2.1 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day for 21 consecutive days. The total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof administered in each treatment cycle is 420 mg or 630 mg. In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-14, and stopped on days 15-21. 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 0.7 mg or 1.4 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day for 21 consecutive days. The total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof administered in each treatment cycle is 420 mg or 630 mg. In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-14, and the administration is stopped on days 15-21. 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 0.7 mg or 1.4 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day for 21 consecutive days. The total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof administered in each treatment cycle is 210 mg.

[0148] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle, and the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered daily on days 1-21 of each treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1-7 of each treatment cycle, and the administration of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is stopped on days 8-21 of each treatment cycle. In some specific embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle, and the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered twice a day on days 1-21 of each treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-7 of each treatment cycle, and the administration of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is stopped on days 8-21 of each treatment cycle.

[0149] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-7 of each treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is stopped on days 8-21 of each treatment cycle, 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 0.35 mg to 2.1 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.35 mg, 0.7 mg, 1.4 mg or 2.1 mg 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 a pharmaceutically acceptable salt thereof is preferably 0.35 mg to 1.4 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 0.35 mg, 0.7 mg or 1.4 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 0.35 mg or 0.7 mg.

[0150] In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-7, and the administration is stopped on days 8-21. 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 0.35 mg, 0.7 mg, 1.4 mg or 2.1 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day for 21 consecutive days. The total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof administered in each treatment cycle is 420 mg or 630 mg. In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-7, and the administration is stopped on days 8-21. 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 0.35 mg, 0.7 mg or 1.4 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day for 21 consecutive days. The total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof administered in each treatment cycle is 420 mg or 630 mg. In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-7, and the administration is stopped on days 8-21. 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 0.35 mg or 0.7 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts is administered twice a day for 21 consecutive days. The total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts administered in each treatment cycle is 420 mg or 630 mg.In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, 21 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1-7, and the administration is stopped on days 8-21. 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 0.35 mg or 0.7 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day for 21 consecutive days. The total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof administered in each treatment cycle is 210 mg.

[0151] In the embodiment of the present disclosure, twice daily administration includes administration of the same or different doses each time, preferably the same dose.

[0152] 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.

[0153] Myelofibrosis

[0154] Myelofibrosis is a myeloproliferative disease that can be divided into primary and secondary myelofibrosis according to its cause.

[0155] In some embodiments of the present disclosure, the myelofibrosis includes primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV-MF), post-essential thrombocythemia myelofibrosis (Post-ET-MF). In some embodiments of the present disclosure, the myelofibrosis includes intermediate-risk and / or high-risk myelofibrosis.

[0156] In some embodiments of the present disclosure, the myelofibrosis comprises myelofibrosis that has not been treated with a JAK inhibitor in the past. In some embodiments of the present disclosure, the myelofibrosis comprises myelofibrosis that has not been treated with a JAK inhibitor in the past. In some embodiments of the present disclosure, the myelofibrosis comprises intermediate-risk and / or high-risk myelofibrosis that has not been treated with a JAK inhibitor in the past. In some embodiments of the present disclosure, the myelofibrosis comprises intermediate-risk and / or high-risk myelofibrosis that has not been treated with a JAK inhibitor in the past.

[0157] In some embodiments of the present disclosure, the myelofibrosis is diagnosed as PMF according to the WHO criteria (2016 edition), or diagnosed as Post-PV-MF or Post-ET-MF according to the IWG MRT criteria.

[0158] In some embodiments of the present disclosure, the myelofibrosis comprises a JAK2 mutation or a JAK2 unmutated mutation.

[0159] In some embodiments of the present disclosure, the intermediate-risk and / or high-risk myelofibrosis is myelofibrosis assessed as intermediate-risk or high-risk according to the Dynamic International Prognostic Scoring System (DIPSS) prognostic grading criteria. In some embodiments of the present disclosure, the intermediate-risk and / or high-risk myelofibrosis requires related symptoms such as splenomegaly.

[0160] In some embodiments of the present disclosure, poor treatment with JAK inhibitors refers to taking JAK inhibitors for a cumulative period of ≥3 months, and continuous treatment at a stable dose for more than 8 weeks, MRI / CI indicates that the spleen volume is reduced by <10% compared with before treatment, or ultrasound / spleen palpation indicates that the spleen is reduced by <30% compared with before treatment, or the spleen has enlarged again after responding to treatment.

[0161] In some embodiments of the present disclosure, for myelofibrosis that has not been well treated with previous JAK inhibitors, JAK inhibitors include but are not limited to: Tofacitinib, Ruxolitinib, Baricitinib, Pefitinib, Delgocitinib, Fedratinib, Upadacitinib, Filgotinib, Abrocitinib, Pacritinib, Deucravacitinib and one or two or more of the compound of formula (II), its isomers or pharmaceutically acceptable salts thereof.

[0162] In some embodiments of the present disclosure, for myelofibrosis that has not been well treated with previous JAK inhibitors, the JAK inhibitor includes ruxolitinib or a compound of formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, for myelofibrosis that has not been well treated with previous JAK inhibitors, the JAK inhibitor includes ruxolitinib.

[0163] In some embodiments of the present disclosure, the splenomegaly refers to the following splenomegaly: the spleen margin reaches or exceeds at least 5 cm below the ribs on palpation or the spleen volume assessed by MRI / CT is ≥450 cm 3 .

[0164] In some embodiments of the present disclosure, the myelofibrosis comprises peripheral blood blasts and bone marrow blasts ≤ 10%.

[0165] In some embodiments of the present disclosure, the myelofibrosis patient did not receive growth factors, colony stimulating factors, thrombopoietic factors or platelet transfusions within 2 weeks before the examination, and the hemoglobin (HGB) was ≥80 g / L and the platelet count (PLT) was ≥100×10 within 7 days before the first medication. 9 / L and neutrophil absolute count (NEUT) ≥1.0×10 9 / L.

[0166] Compound of formula (I) or a pharmaceutically acceptable salt thereof

[0167] In some embodiments of the present disclosure, the compound of formula (I) described in the present disclosure can be obtained by referring to the preparation method in WO2020020288.

[0168] 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 compounds of formula (I) in vivo. For example, pharmaceutically acceptable salts of compounds of formula (I) can be produced from various organic and inorganic acids according to methods well known in the art within the scope of the present disclosure.

[0169] As used in this disclosure, the compound of formula (I) is its free base. As used in this disclosure, the compound of formula (I) is its crystalline form. As used in this disclosure, the compound of formula (I) is its amorphous solid form. The dosage of the compound of formula (I) or its pharmaceutically acceptable salt involved in this disclosure, unless otherwise specified, is based on the molecular weight (in C) of the compound of formula (I). 21 H 18 In some embodiments of the present disclosure, the crystals of the compound of formula (I) described in the present disclosure can be obtained by referring to the preparation method in WO2021143922.

[0170] As used in the present disclosure, isomers of the compound of formula (I) are also included within the scope of the disclosure, for example, racemates of the compound of formula (I), enantiomers of the compound of formula (I), diastereomers of the compound of formula (I), or mixtures of the above isomers.

[0171] Pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0172] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, 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 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0174] In the scheme of the present disclosure, the method of administration can be comprehensively determined based on the activity, toxicity and patient tolerance of the drug.

[0175] 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.

[0176] In some embodiments of the present disclosure, the pharmaceutical composition is a solid pharmaceutical composition. 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. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0177] The pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof disclosed herein may further contain a pharmaceutically acceptable carrier and / or excipient.

[0178] The pharmaceutical composition of the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt can be manufactured by methods well known in the art, such as conventional mixing, dissolution, granulation, sugar-coated pill making, grinding, emulsification, freeze-drying, etc. The solid oral composition of the compound of formula (I) of the present disclosure or its pharmaceutically acceptable salt can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the compound of formula (I) or its pharmaceutically acceptable salt is mixed with a solid auxiliary material, optionally grinding the resulting mixture, adding other suitable auxiliary materials if necessary, and then processing the mixture into particles to obtain the core of a tablet or sugar-coated agent. Suitable auxiliary materials include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0179] The compound of formula (II), its isomer or its pharmaceutically acceptable salt

[0180] In some embodiments of the present disclosure, the compound of formula (II) described herein is a compound of formula (III) In some embodiments of the present disclosure, the compound of formula (II) described in the present disclosure can be obtained with reference to the preparation method in WO2016095805 or WO2017215627. The compound of formula (II) disclosed herein can be administered in its free base form, or in the form of its pharmaceutically acceptable salt, hydrate and prodrug, which is converted into the compound of formula (II) in vivo. For example, the pharmaceutically acceptable salt of the compound of formula (II) can be produced by different organic acids and inorganic acids according to methods well known in the art within the scope of the present disclosure.

[0181] As used in this disclosure, the compound of formula (II) is its free base. As used in this disclosure, the compound of formula (II) is its crystalline form. As used in this disclosure, the compound of formula (II) is its amorphous solid form. The dosage of the compound of formula (II), its isomers or pharmaceutically acceptable salts thereof referred to in this disclosure, unless otherwise stated, is based on the molecular weight (in C) of the compound of formula (II). 17 H 19 In some embodiments of the present disclosure, the crystal of the compound of formula (III) described in the present disclosure can be obtained by referring to the preparation method in WO2017215630.

[0182] Pharmaceutical composition of the compound of formula (II), its isomer or its pharmaceutically acceptable salt

[0183] In some embodiments of the present disclosure, the compound of formula (II), its isomer or its pharmaceutically acceptable salt is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (II), its isomer or its pharmaceutically acceptable salt. In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 5 mg of the compound of formula (II), its isomer or its pharmaceutically acceptable salt calculated as the compound of formula (II). Alternatively, the pharmaceutical composition of the compound of formula (II), its isomer or its pharmaceutically acceptable salt is prepared into a unit preparation containing 5 mg of the compound of formula (II), its isomer or its pharmaceutically acceptable salt calculated as the compound of formula (II).

[0184] In the scheme of the present disclosure, the method of administration can be comprehensively determined based on the activity, toxicity and patient tolerance of the drug.

[0185] 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.

[0186] In some embodiments of the present disclosure, the pharmaceutical composition is a solid pharmaceutical composition. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (II), its isomer or its pharmaceutically acceptable salt is a solid pharmaceutical composition containing the compound of formula (II) or its pharmaceutically acceptable salt. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (II), its isomer or its pharmaceutically acceptable salt is a tablet containing the compound of formula (II) or its pharmaceutically acceptable salt. The pharmaceutical composition of the compound of formula (II) of the present disclosure, its isomer or its pharmaceutically acceptable salt may also contain a pharmaceutically acceptable carrier and / or excipient.

[0187] The pharmaceutical composition of the compound of formula (II) disclosed herein, its isomer or its pharmaceutically acceptable salt can be manufactured by methods well known in the art, such as conventional mixing, dissolution, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc. The solid oral composition of the compound of formula (II) disclosed herein, its isomer or its pharmaceutically acceptable salt can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the compound of formula (II), its isomer or its pharmaceutically acceptable salt is mixed with a solid auxiliary material, optionally grinding the resulting mixture, adding other suitable auxiliary materials if necessary, and then processing the mixture into particles to obtain the core of a tablet or sugar-coated agent. Suitable auxiliary materials include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0188] Administration

[0189] The following does not limit the mode of administration of the disclosed pharmaceutical combination.

[0190] The components in the pharmaceutical composition of the present disclosure can be each independently or part or all of them are used together with suitable various approaches, including but not limited to oral or parenteral (by intravenous, intramuscular, local or subcutaneous route). In some embodiments, the components of the pharmaceutical combination of the present disclosure can be each independently or part or all of them are used orally or injected together, such as intravenous injection or intraperitoneal injection. The components in the pharmaceutical composition of the present disclosure can be each independently or part or all of them are suitable dosage forms together, including but not limited to tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), emulsions, suspensions, solutions, dispersants and the dosage form of sustained-release preparations for oral or parenteral administration.

[0191] The components of the pharmaceutical combination of the present disclosure may each independently, or some or all of them together, contain a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical combination of the present disclosure may also include an additional therapeutic agent. In one embodiment, the additional therapeutic agent may be a proliferative disease therapeutic agent known in the art.

[0192] Technical Effects

[0193] The compound of formula (I) disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, has a good therapeutic effect, as demonstrated by the following favorable indicators: a high proportion of subjects with a spleen volume reduction of ≥35% at the end of the 12th and 24th weeks of treatment (SVR35), a good spleen response (including but not limited to a high best efficacy rate, a short onset of effect, a prolonged duration of a spleen volume reduction of ≥35% compared to baseline, etc.), a good MF-related symptom score, a longer progression-free survival (PFS), a longer leukemia-free survival (LFS), and a longer overall survival; and low adverse reactions and a good safety profile.

[0194] The combined pharmaceutical compositions of the present disclosure will contribute to at least one or more of the following aspects:

[0195] (1) Compared with the administration of any of the drugs in the combination alone, it produces a better therapeutic effect in the treatment of myelofibrosis, including but not limited to having an excellent synergistic effect in terms of the above-mentioned technical effect indicators;

[0196] (2) provide treatments that are well tolerated by patients with few adverse effects and / or complications;

[0197] (3) provide better disease control rates among treated patients;

[0198] (4) have a longer survival (e.g., median survival, progression-free survival, or overall survival) among the patients treated;

[0199] (5) provide for administration of a smaller amount of the drug in the combination than when either drug is administered alone;

[0200] (6) Provide a longer duration of disease remission (DOR).

[0201] Definition and Description

[0202] Unless otherwise indicated, the following 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.

[0203] As used herein, the term "combination pharmaceutical composition" refers to a combination of two or more active ingredients (administered as the respective active ingredients themselves, or as their respective pharmaceutically acceptable salts or esters, derivatives, prodrugs, or compositions) that are administered simultaneously or sequentially. The terms "combination pharmaceutical composition" and "drug combination" are used interchangeably herein.

[0204] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be therapeutic in terms of partial or complete stabilization or cure of a disease and / or side effects caused by the 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.

[0205] The term "effective amount" means an amount of the compound of the present disclosure that (i) treats a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of active substance (e.g., a fusion protein or compound of the present disclosure) that constitutes a "therapeutically effective amount" may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. The effective amount can also be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0206] The term "administer" refers 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. As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and in vivo electroporation. Administration can also be performed, for example, once, multiple times, and / or over one or more extended time periods.

[0207] Unless otherwise indicated, the term "dose" is used to refer to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). For example, a 60 kg human and a 100 kg human would receive the same dose of the fusion protein.

[0208] 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 humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio. The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" includes salts formed with an alkali ion and a free acid or with an acid ion and a free base.

[0209] As used herein, the terms "subject" or "patient" are used interchangeably. In some embodiments, the term "subject" or "patient" is a mammal. In some embodiments, the subject or patient is a mouse. In some embodiments, the subject or patient is a human.

[0210] The term "about" or "approximately" should be understood to include within three standard deviations of the mean or within the standard tolerance range in a particular field. In certain embodiments, "about" or "approximately" should be understood to mean a variation of no more than 0.5. "About" or "approximately" modifies all subsequent listed values. For example, "about 1, 2, 3" means "about 1," "about 2," "about 3."

[0211] As used herein, "combination use" or "combined use" means that two or more active substances can be administered to a subject simultaneously, each as a single formulation, or sequentially in any order, each as a single formulation.

[0212] The term "single dose" refers to the smallest packaging unit containing a specific amount of a drug. For example, if a box of medicine contains seven capsules, each capsule is a single dose; or, if a bottle of injection is a single dose, each capsule is a single dose. In this document, the terms "single dose" and "unit dose" have the same meaning and are used interchangeably.

[0213] The term "multiple doses" refers to a number of single doses. The term "daily dose" refers to a dose administered to a patient daily. The term "daily dose" refers to a dose administered to a patient on a single day.

[0214] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure or their pharmaceutical combination and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure or their pharmaceutical combination to a subject.

[0215] 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.

[0216] As used herein, unless otherwise indicated, the terms "comprise, include, and contain" 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. Singular terms herein encompass plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

[0217] For the purposes of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present disclosure. All statements regarding the dates of these documents or the representations of their contents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications in this disclosure does not constitute an admission that such publications are part of the common general knowledge in the art in any country. DETAILED DESCRIPTION

[0218] For the sake of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0219] Example 1 Evaluation of in vitro cell proliferation inhibitory activity of the compound of formula (I)

[0220] 1.1 HEL cell proliferation inhibitory activity assay

[0221] Take HEL cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 6×10 4 The cells were inoculated with 100 μL / well of a 96-well plate and cultured overnight in a cell culture incubator. Compounds were added using a nanoliter pipette to a final concentration of 10 μM-4.6 nM (with a 2-fold gradient between each concentration). Two replicate wells were set for each concentration, and a control (only culture medium without compound) was set up. After 72 hours of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 2 hours, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC. 50 The results showed that the compound of formula (I) had good proliferation inhibitory activity on HEL cells.

[0222] Example 2 In vivo efficacy evaluation of the compound of formula (I)

[0223] 2.1 Compound of formula (I) in MPL W515L Pharmacodynamic evaluation in the model

[0224] One week before bone marrow transplantation, eight-week-old female Balb / c mice (Shanghai Bike Biotechnology Co., Ltd.) were injected intraperitoneally with 150 mg / kg 5-fluorouracil. Five days later, the mice were sacrificed and bone marrow was harvested by femoral aspiration. Red blood cells were lysed using BD Pharma lysis buffer (BD Biosciences) and then washed with PBS. The remaining bone marrow was plated in 10% FBS / RPMI and placed in a standard cell incubator overnight. The next day, cells expressing MPL were cultured using the following procedure. W515L To infect bone marrow, add 1 mL of virus to 10 6 The infected cells were centrifuged in 6-well plates at 1800 rpm and 37°C for 90 minutes. After centrifugation, the infected cells were kept in a constant temperature incubator and injected into recipient mice the next day.

[0225] Five days before transplantation, eight-week-old Balb / c mice were bone marrow-ablated with 50 mg / kg 5-fluorouracil and then transplanted with MPL-expressing cells via retroviral infection. W515L Balb / c bone marrow (approximately 2×10 per recipient mouse) 5 Cells). Blood cell counts were performed 7 days after transplantation and grouped. Dosing began on the 8th day after transplantation and continued for 13 days. On the 14th day after transplantation, mice were sacrificed, blood was collected by cardiac puncture, and spleens were weighed. Blood was collected once a week through the orbital canal and a complete blood count (CBC) was determined.

[0226] The results showed that the compound of formula (I) could W515L The model normalized the number of peripheral blood cells, improved spleen enlargement, alleviated extramedullary hematopoiesis, reduced tissue fibrosis and decreased mutation load.

[0227] 2.2 Compounds of formula (I) in the expression of JAK2 V617F Pharmacodynamic evaluation of the HEL erythroleukemia mouse subcutaneous transplant tumor model

[0228] SPF female CB-17SCID mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) were subcutaneously inoculated with JAK2-expressing V617F HEL cells (mixed with matrigel at a volume ratio of 1:1), 1×10 7 When the average tumor volume reaches 150mm 3 Around 3 d, the animals were divided into groups (treatment group and vehicle control group).

[0229] The day of grouping was designated Day 0. Starting from Day 0, drugs were administered by gavage daily. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. The general condition of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[0230] The detection indicators and calculation formulas are as follows:

[0231] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0232] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[0233] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[0234] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[0235] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wt t is the weight of the mice at each measurement.

[0236] The results showed that the compound of formula (I) expressed JAK2 V617F It has a good tumor inhibitory effect on subcutaneous transplanted tumors in HEL erythroleukemia mice.

[0237] Example 3 Clinical Trial I

[0238] This study is to evaluate the efficacy and safety of the compound of formula (I) combined with the compound of formula (III) in subjects with intermediate- and high-risk myelofibrosis. 3.1 Inclusion Criteria:

[0239] 1) The subjects voluntarily participated in this study, signed the informed consent form, and had good compliance;

[0240] 2) Age: 18 years and above (at the time of signing the informed consent form); ECOGPS score: 0-2 points; expected survival time is more than 24 weeks;

[0241] 3) Patients diagnosed with PMF according to the WHO criteria (2016 version), or diagnosed with PostPVMF or PostETMF according to the IWGMRT criteria; regardless of whether they have JAK2 mutations;

[0242] 4) Patients with intermediate-risk or high-risk myelofibrosis according to the DIPSS prognostic grading criteria (intermediate-risk-1 patients must have splenomegaly and other related symptoms requiring treatment);

[0243] 5) Patients who have not responded well to JAK inhibitors (defined as: taking JAK inhibitors for a total of ≥ 3 months, and continuously treated at a stable dose for more than 8 weeks, MRI / CT shows that the spleen volume is less than 10% smaller than before treatment, or ultrasound / spleen palpation shows that the spleen is less than 30% smaller than before treatment, or the spleen has enlarged again after responding to treatment);

[0244] 6) Those who have not received JAK inhibitor treatment;

[0245] 7) Splenomegaly: Palpation of the spleen margin reaches or extends at least 5 cm below the ribs or the spleen volume assessed by MRI / CT is ≥450 cm 3 ;

[0246] 8) Peripheral blood blasts and bone marrow blasts ≤ 10%;

[0247] 9) No growth factors, colony stimulating factors, thrombopoietic factors or platelet transfusions were received within 2 weeks before the examination, and hemoglobin (HGB) ≥ 80 g / L and platelet count (PLT) ≥ 100 × 10 within 7 days before the first medication. 9 / L and neutrophil absolute count (NEUT) ≥1.0×10 9 / L;

[0248] 10) Seven days before the first dose, the major organ functions were normal, i.e., they met the following criteria: total bilirubin (TBIL) ≤ 2 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN; serum creatinine (Cr) ≤ 1.5 times ULN or creatinine clearance (Ccr) ≥ 50 mL / min; coagulation function tests must meet the following criteria: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN; left ventricular ejection fraction (LVEF) assessed by cardiac ultrasound ≥ 50%;

[0249] 11) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test should be negative within 7 days before the first medication, and the subjects must be non-breastfeeding; male subjects should agree to use contraceptive measures during the study and within 6 months after the end of the study.

[0250] 3.2 Investigational Drugs

[0251] Capsules of the compound of formula (I), specifications (based on the amount of the compound of formula (I)): 0.05 mg / capsule, 0.1 mg / capsule; tablets of the compound of formula (III), specifications (based on the amount of the compound of formula (III)): 5 mg / tablet.

[0252] 3.3 Dosage regimen

[0253] Administration of the compound of formula (I) in capsule form: Orally administer 0.05 mg or 0.1 mg once daily on an empty stomach, approximately at the same time each morning. A 21-day dosing cycle is defined as one cycle, with two dosing schedules: 1. Dosing schedule: Administer once daily (qd) from Days 1 to 14, with no dosing from Days 15 to 21; 2. Dosing schedule: Administer once daily (qd) from Days 1 to 7, with no dosing from Days 8 to 21.

[0254] Administration of the compound of formula (III): Orally take on an empty stomach, twice daily, 5 mg, 10 mg, or 15 mg each time, with at least 8 hours between doses, preferably 12 hours. A 21-day dosing cycle consists of two doses per day (bid) from D1 to D21.

[0255] 3.4 Evaluation Criteria

[0256] 3.4.1 Effectiveness evaluation criteria: The 2013 ELN and IWG-MRT consensus criteria were used to evaluate efficacy.

[0257] The spleen volume was assessed using thin-slice CT scans, with examination sites including the abdomen and pelvis. The evaluation method, machine, and technical parameters for the same subject should remain consistent throughout the study.

[0258] Evaluation indicators

[0259] The proportion of subjects with a ≥35% reduction in spleen volume at the end of treatment at week 24 (SVR35); Splenic response: ① Best response rate: The proportion of subjects with at least one ≥35% reduction in spleen volume compared to baseline; ② Onset of effect: The time interval from the first dose to the date of the first ≥35% reduction in spleen volume compared to baseline; ③ Duration of ≥35% reduction in spleen volume compared to baseline (DoMSR): The time interval from the date of the first ≥35% reduction in spleen volume compared to baseline to the date of <35% reduction in spleen volume compared to baseline;

[0260] MF-related symptom scores: ① The proportion of subjects whose total symptom score on the Myeloproliferative Neoplasms Symptom Assessment Form - Total Symptom Score (MPN-SAF TSS) decreased by ≥50% compared with baseline at week 24; ② The decrease in the total symptom score on the MPN-SAF TSS compared with baseline;

[0261] Progression-free survival (PFS): The time interval from the first dose of the drug to the date of occurrence of any of the following events, whichever occurs first: ① spleen volume increases by ≥25% compared with the screening period; ② death caused by any cause;

[0262] Leukemia-free survival (LFS) is the time interval from the first dose of the drug to the date of any of the following events, whichever occurs first: ① the date when the first bone marrow smear shows blasts ≥ 20%; ② the date when the first peripheral blood smear shows blasts ≥ 20% and the absolute number of blasts ≥ 1×10 9 / L and lasts for at least 2 weeks; ③ Death caused by any reason;

[0263] Overall survival (OS): the time from the first dose of the drug to death from any cause;

[0264] 3.4.2 Safety evaluation criteria: The NCI-CTCAE 5.0 criteria were used to determine the severity of adverse events.

[0265] 3.4.3 Test results

[0266] Security

[0267] No DLT events or serious AEs occurred in evaluable patients, and the overall safety and tolerability were good.

[0268] Effectiveness

[0269] For patients who do not respond well to JAK inhibitors, the SVR35 rate can be assessed to be over 40% at week 12 (C4), and the best effective rate of spleen response can be over 40%.

[0270] For patients who have not received JAK inhibitor treatment, the SVR35 rate can be assessed to be over 40% at week 12 (C4), and the best spleen response rate can be over 65%.

[0271] Table 1 shows the effect data of representative cases.

[0272] Table 1 “—” represents not tested; Cn represents n dosing cycles, each dosing cycle is 3 weeks (21 days).

[0273] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementation plans and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, and these adjusted solutions fall within the scope of protection of the present application.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating myelofibrosis, 2. A combination pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, and a compound of formula (II), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, 3. The combination pharmaceutical composition according to claim 2, comprising 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2 .8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg, 9.0mg, 9.5mg, 10.0mg or a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; Alternatively, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, containing 0.01 to 5 mg, 0.01 to 2 mg, 0.05 to 5 mg, 0.05 to 2 mg, 0.05 to 1 mg, 0.05 to 0.5 mg, 0.05 to 0.2 mg, 0.05 to 0.15 mg, 0.05 to 0.1 mg, 0.1 to 0.15 mg, 0.01 to 1 mg, 0.01 to 0.2 mg, 0.01 to 0.5 mg or 0.01 to 0.15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; Alternatively, containing 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.5 mg or 1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; Alternatively, containing 0.05 mg, 0.1 mg or 0.15 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; Alternatively, it contains 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

4. The combination pharmaceutical composition according to any one of claims 2 to 3, comprising 1 to 50 mg, 5 to 50 mg, 5 to 40 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg, 10 to 20 mg, 10 to 15 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, calculated as the compound of formula (II); Alternatively, a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, containing 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg of the compound of formula (II), calculated as the compound of formula (II); Alternatively, containing 5 mg, 10 mg, 15 mg or 20 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, calculated as the compound of formula (II); Alternatively, containing 10 mg, 15 mg or 20 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, calculated as the compound of formula (II); Alternatively, the compound of formula (II) contains 5 mg, 10 mg or 15 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable Acceptable salts, or pharmaceutical compositions thereof; Alternatively, it contains 10 mg or 15 mg of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, calculated as the compound of formula (II).

5. The combination pharmaceutical composition according to any one of claims 2 to 4, comprising 0.01 to 5 mg, 0.01 to 2 mg, 0.05 to 5 mg, 0.05 to 2 mg, 0.05 to 1 mg, 0.05 to 0.5 mg, 0.05 to 0.2 mg, 0.05 to 0.15 mg, 0.05 to 0.1 mg, 0.1 to 0.15 mg, 0.01 to 1 mg, 0.01 to 0.2 mg, 0.01 to 0. A pharmaceutical composition containing 5 mg or 0.01 to 0.15 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing 1 to 50 mg, 5 to 50 mg, 5 to 40 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg, 10 to 20 mg, 10 to 15 mg or 20 to 30 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof Preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a single dose or multiple doses, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a single dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is multiple doses; further preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a single dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose; preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is multiple doses, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose; further preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is multiple doses, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is multiple doses; Alternatively, a pharmaceutical composition containing 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.5 mg or 1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 5 mg, 10 mg, 15 mg or 20 mg or a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof within the range formed by any of the above values, wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses. Preferably, the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a multiple dose; preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a single dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose; preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a multiple dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose; preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a multiple dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a multiple dose; Alternatively, a pharmaceutical composition containing 0.05 mg, 0.1 mg, 0.15 mg or 0.2 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 10 mg, 15 mg or 20 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose; further preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose; Alternatively, a pharmaceutical composition containing 0.05 mg, 0.1 mg or 0.15 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 10 mg or 15 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose; further preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose; Alternatively, a pharmaceutical composition containing 0.05 mg or 0.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 10 mg or 15 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose. It is a multiple dose; also preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the pharmaceutical composition of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is a multiple dose; Alternatively, a pharmaceutical composition containing 0.05 mg or 0.1 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 5 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose or multiple doses; preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose; further preferably, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is multiple doses, and the pharmaceutical composition of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a single dose.

6. The combination pharmaceutical composition according to any one of claims 2 to 5, in, The compound of formula (I), a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the compound of formula (II), a stereoisomer thereof, a pharmaceutically acceptable salt or a pharmaceutical composition thereof are packaged in the same kit; Alternatively, the compound of formula (I), pharmaceutically acceptable salt or pharmaceutical composition thereof and the compound of formula (II), stereoisomer thereof, pharmaceutically acceptable salt or pharmaceutical composition thereof are separately packaged in respective kits.

7. A combination pharmaceutical composition according to any one of claims 2 to 6 for treating myelofibrosis.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the combined pharmaceutical composition for use as claimed in claim 7, in, The myelofibrosis is selected from primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV-MF), and post-essential thrombocythemia myelofibrosis (Post-ET-MF); Alternatively, the myelofibrosis is selected from intermediate-risk and / or high-risk myelofibrosis; Alternatively, the myelofibrosis is selected from myelofibrosis that has been poorly treated with previous JAK inhibitors; Alternatively, the myelofibrosis is selected from myelofibrosis not treated with a JAK inhibitor; Alternatively, the myelofibrosis is selected from those diagnosed as PMF according to the WHO criteria (2016 edition), or those diagnosed as Post-PV-MF or Post-ET-MF according to the IWG MRT criteria; Alternatively, the myelofibrosis comprises a JAK2 mutation or a JAK2 non-mutation; Alternatively, the myelofibrosis is selected from myelofibrosis assessed as intermediate-risk or high-risk according to the Dynamic International Prognostic Scoring System (DIPSS) prognostic grading criteria.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a combination pharmaceutical composition for use as claimed in claim 8, in, The JAK inhibitors include one or two or more of the following: Tofacitinib, Ruxolitinib, Baricitinib, Pefitinib, Delgocitinib, Fedratinib, Upadacitinib, Filgotinib, Abrocitinib, Pacritinib, Deucravacitinib, and a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

10. The combined pharmaceutical composition for use as claimed in claim 7, in, The combination pharmaceutical composition contains 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula (I), and 10 mg, 15 mg or 20 mg of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula (II); Alternatively, the combination pharmaceutical composition is a preparation suitable for administration within a treatment cycle of 21 days, comprising: a pharmaceutical composition containing a total dose of 0.35 mg to 2.1 mg, 0.35 mg to 1.4 mg, 0.7 mg to 1.4 mg, 0.35 mg, 0.7 mg, 1.4 mg or 2.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing a total dose of 105 to 630 mg, 210 to 630 mg, 210 mg, 420 mg or 630 mg of the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II); Alternatively, the combination pharmaceutical composition is a preparation suitable for administration in a single treatment cycle, comprising a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in a total dose ratio of 1: (37.5-900), 1: (75-900), 1: (100-900), 1: (150-900) or 1: (200-900) or any ratio within the above range. The invention relates to a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the dosage 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 dosage of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or a pharmaceutically acceptable salt thereof is calculated based on the compound of formula (II).

11. The combined pharmaceutical composition for use as claimed in claim 7, in, The compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 0.01 mg; or a daily dose of 0.05 mg; or a daily dose of 0.1 mg; or a daily dose of 0.15 mg; or a daily dose of 0.2 mg; Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 0.05 mg; or a daily dose of 0.1 mg.

12. The combination pharmaceutical composition for use as described in any one of claims 7 to 11, in, The compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered in the following manner: twice a day, each dose is 10 mg; or, each dose is 15 mg; or, each dose is 5 mg; Preferably, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered in the following manner: twice a day, each dose is 10 mg; or each dose is 15 mg.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof, or the combined pharmaceutical composition for use as claimed in claim 7, in, The treatment cycle of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be one treatment cycle every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks or every 6 weeks; preferably, one treatment cycle is every 4 weeks; or preferably, one treatment cycle is every 3 weeks; Alternatively, the treatment cycle can be 28 days, with the compound of formula (I) or a pharmaceutically acceptable salt thereof being administered once daily continuously from day 1 to day 28 of each treatment cycle; Alternatively, the treatment cycle can be 21 days, with the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt being administered once a day continuously on days 1 to 14 of each treatment cycle, and the administration of the compound of formula (I) or its pharmaceutically acceptable salt being stopped on days 15 to 21 of each treatment cycle; Alternatively, the treatment cycle can be 21 days, with the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt being administered once a day continuously on days 1 to 7 of each treatment cycle, and the administration of the compound of formula (I) or its pharmaceutically acceptable salt being stopped on days 8 to 21 of each treatment cycle; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 0.01 mg; or a daily dose of 0.05 mg; or a daily dose of 0.1 mg; or a daily dose of 0.15 mg; or a daily dose of 0.2 mg; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 0.05 mg; or, a daily dose of 0.1 mg; or, a daily dose of 0.15 mg; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 0.05 mg; or a daily dose of 0.1 mg; Alternatively, 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 0.05 mg or 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; Alternatively, each dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, wherein the multiple dose is 0.1 mg or 0.15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple dose is composed of a single dose of 0.05 mg, or 0.05 mg and 0.1 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

14. The combined pharmaceutical composition for use as claimed in claim 7, in, The compound of formula (I) or a pharmaceutically acceptable salt thereof and the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof have the same treatment cycle, preferably one treatment cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks or every 6 weeks; preferably, one treatment cycle is every 4 weeks; or preferably, one treatment cycle is every 3 weeks; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition and can be administered simultaneously, separately, concurrently, sequentially or intermittently; Alternatively, the treatment cycle can be 28 days, with the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt being administered twice a day on days 1 to 28 of each treatment cycle; Alternatively, the treatment cycle can be 21 days, with the compound of formula (II), its stereoisomers, or a pharmaceutically acceptable salt thereof; Alternatively, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered in the following manner: a daily dose of 10 mg; or, a daily dose of 20 mg; or, a daily dose of 30 mg; or, a daily dose of 40 mg; Alternatively, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered as follows: a daily dose of 20 mg; or, a daily dose of 30 mg; Alternatively, the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is administered in multiple doses, wherein the multiple doses consist of a single dose of 5 mg of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof.

15. The combined pharmaceutical composition for use as claimed in claim 14, in, 21 days is one treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1 to 14, and administration is stopped on days 15 to 21, 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 0.7 mg, 1.4 mg or 2.1 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered twice a day for 21 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in each treatment cycle is 210 mg, 420 mg or 630 mg; Alternatively, the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1 to 14, and administration is stopped on days 15 to 21. The total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in each treatment cycle is 0.7 mg or 1.4 mg; the pharmaceutical composition containing the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof is administered twice a day for 21 consecutive days. The total dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof in each treatment cycle is 420 mg or 630 mg.

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