WO2025157254A1 - Pharmaceutical composition of compound containing sulfonyl group, and use thereof - Google Patents

Abstract

A pharmaceutical composition of a compound containing a sulfonyl group, and a use thereof. The present invention relates to a pharmaceutical composition of a compound represented by formula (I), and a use thereof in the treatment of myelofibrosis.

Description

A pharmaceutical combination of a compound containing a sulfonyl group and its use

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority and benefits of Chinese patent application No. 202410115028.3 filed with the State Intellectual Property Office of China on January 26, 2024, the contents of which are incorporated herein by reference in their entirety.

Technical Field

The present disclosure belongs to the field of medical technology and relates to a pharmaceutical combination of a compound containing a sulfonyl group and its use. Specifically, it relates to a pharmaceutical combination of a compound of formula (I) and its use in treating myelofibrosis.

Background Art

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.

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.

Compounds that selectively inhibit BCL-2 proteins can be used to treat hyperproliferative diseases, such as tumors. For example, WO2019185025, WO2020088442, and WO2020238785 disclose compounds or pharmaceutically acceptable salts thereof as BCL-2 inhibitors.

Summary of the Invention

In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating myelofibrosis.

wherein R ¹ is selected from hydrogen, halogen or C _1-6 alkyl;

Ring A is selected from 5-6 membered heterocycloalkyl,

R ² is independently selected from 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, -COR ^a , -SO ₂ R ^b , or C _1-6 alkyl optionally substituted by halogen;

R ^a or R ^b are each independently selected from H, 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, or C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with halogen, CN, -N(C _1-6 alkyl) ₂ , -NHC _1-6 alkyl, or -OC _1-6 alkyl;

m is selected from 0, 1, 2 or 3.

In some embodiments of the present disclosure, the structural fragment Selected from

In some embodiments of the present disclosure, R ¹ is selected from hydrogen, halogen, or C _1-3 alkyl. In some embodiments of the present disclosure, R ¹ is selected from hydrogen, fluorine, chlorine, or methyl. In some embodiments of the present disclosure, R ¹ is selected from hydrogen, chlorine, or methyl.

In some embodiments of the present disclosure, Ring A is selected from a 6-membered heterocycloalkyl group. In some embodiments of the present disclosure, Ring A is selected from a 6-membered heterocycloalkyl group containing one or more O atoms. In some embodiments of the present disclosure, Ring A is selected from a dioxane ring or a pyran ring.

In some embodiments of the present disclosure, R ² is independently selected from 4-6 membered heterocycloalkyl, C _4-6 cycloalkyl, -COR ^a , -SO ₂ R ^b , or C _1-4 alkyl optionally substituted with halogen.

In some embodiments of the present disclosure, ^Ra or ^Rb is independently selected from H, 4-6 membered heterocycloalkyl, _C3-6 cycloalkyl, or _C1-4 alkyl, wherein the _C1-4 alkyl is optionally substituted with halogen, CN, -N( _C1-4 alkyl) ₂ , _-NHC1-4 alkyl, or _-OC1-4 alkyl.

In some embodiments of the present disclosure, R ² is each independently selected from -C(O)H, -COC(CH ₃ ) ₃ , -COCF ₃ , -COCH ₂ CN, -COCH ₂ N(CH ₃ ) ₂ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CF ₃ , -SO ₂ C ₂ F ₅ , -CF ₃ , -C ₂ F ₅ , tetrahydropyran, monooxetane, -SO _2- cyclopropane, -CO-cyclopropane, -CO-monooxetane, -SO _2- monooxetane, or -SO _2- cyclobutane.

In some aspects of the present disclosure, m is selected from 0 or 1.

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.

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.

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 the preparation of a medicament for treating myelofibrosis.

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.

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 or in combination with other drugs.

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.

In some embodiments of the present disclosure, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally, may further comprise other drugs.

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.

In some embodiments of the present disclosure, the pharmaceutical composition contains 10 to 2000 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 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the pharmaceutical composition contains 10-1200 mg, 10-1000 mg, 10-800 mg, 100-1200 mg, 100-800 mg, 100-500 mg, 100-400 mg, 200-800 mg, 200-400 mg, 100-600 mg, 200-600 mg, 10-100 mg, 10-200 mg or 10-400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the pharmaceutical composition contains 10 mg, 50 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg of a 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 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg or 600 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 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

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

In some other embodiments of the present disclosure, the pharmaceutical composition contains 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the pharmaceutical composition contains 400 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 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, the same single-dose forms.

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.

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.

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.

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

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 a single dose of 100 mg of the pharmaceutical composition of 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 multi-dose pharmaceutical composition, and the multiple doses may be composed of a single dose of 100 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the pharmaceutical composition contains multiple doses of 200 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). The multiple doses may be composed of a pharmaceutical composition with a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the pharmaceutical composition contains multiple doses of 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple doses may be composed of a pharmaceutical composition with a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some other embodiments of the present disclosure, the pharmaceutical composition contains multiple doses of 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple doses can be composed of a pharmaceutical composition with a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the pharmaceutical composition contains multiple doses of 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple doses may be composed of a pharmaceutical composition with a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

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

In some embodiments of the present disclosure, the 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 of a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 280 mg to 56 g, 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 280 mg to 33.6 g, 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 2.8 g to 22.4 g, 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 2.8 g to 11.2 g, 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 2.8g to 8.4g calculated on the basis of 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 5.5g to 8.4g calculated on the basis of 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 2.8g to 10.7g or 2.8g to 11.2g calculated on the basis of 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 2.8g to 8.1g or 2.8g to 8.4g calculated on the basis of 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 2.8g to 8.1g or 2.8g to 8.4g calculated on the basis of the compound of formula (I); The pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is 5.5g to 8.1g or 5.6g to 8.4g in total dose 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 is 2.8g, 5.5g, 5.6g, 8.1g, 8.4g, 10.7g or 11.2g in total dose 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 is 2.8g, 5.5g, 5.6g, 8.1g or 8.4g in total dose 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 is 2.8g, 5.5g, 5.6g, 8.1g or 8.4g in total dose based on the compound of formula (I). In some schemes, the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is The total dose is preferably 2.8g; or preferably 5.5g or 5.6g; or preferably 8.1g or 8.4g of a pharmaceutical composition of a compound of formula (I) 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 5.6g 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 5.5g 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 8.1g 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 8.4g based on the compound of formula (I).

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.

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.

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.

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. In some embodiments of the present disclosure, the pharmaceutical composition is any of the pharmaceutical compositions described above in the present disclosure.

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.

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.

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.

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, twice, three times or four times daily; more preferably once daily.

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, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily in a single dose. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily in a single dose of an oral solid preparation.

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, the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily in multiple doses of an oral solid preparation.

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 10 to 800 mg; or, a daily dose of 100 to 800 mg; or, a daily dose of 100 to 600 mg; or, a daily dose of 100 to 400 mg; or, a daily dose of 100 to 300 mg; or, a daily dose of 200 to 400 mg; or, a daily dose of 200 to 300 mg; or, a daily dose of 300 to 400 mg.

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 100 mg; or, a daily dose of 200 mg; or, a daily dose of 300 mg; or, a daily dose of 400 mg.

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 100 mg; or, a daily dose of 200 mg; or, a daily dose of 300 mg.

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 200 mg; or, a daily dose of 300 mg. In some embodiments of the present disclosure, in the above methods, therapies, or uses, 28 days constitute a treatment cycle, and a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof is continuously administered on days 1 to 28 of each treatment cycle.

In some embodiments of the present disclosure, in the above methods, therapies or uses, 28 days constitutes a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered continuously daily from day 1 to day 28 of each treatment cycle.

In some embodiments of the present disclosure, in the above methods, therapies or uses, 28 days constitutes a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily continuously from day 1 to day 28 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 100 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, 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 200 mg, 300 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; preferably, the multiple dose is 200 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; also preferably, the multiple dose is 200 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, in the above-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 200 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple dose is composed of a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, in the above methods, 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. On the 1st day of the first treatment cycle, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a single dose, and the single dose is 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; on the 2nd to the 28th day, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as multiple doses, and the multiple doses are 200 mg. g of the compound of formula (I) or its pharmaceutically acceptable salt, wherein the multiple doses consist of a single dose of 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt; on days 1 to 28 of the second treatment cycle, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily continuously, wherein each dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a multiple dose, wherein the multiple dose is 200 mg of the compound of formula (I) or its pharmaceutically acceptable salt, wherein the multiple doses consist of a single dose of 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt. Starting from the third treatment cycle, the administration mode of each treatment cycle is the same as that of the second treatment cycle.

In some other embodiments of the present disclosure, in the above 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 administered once a day continuously from the 1st to the 28th day of each treatment cycle. On the first day of the first treatment cycle, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is administered as a single dose, and the single dose is 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt; on the second day of the first treatment cycle, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is administered as a single dose, and the single dose is 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt. The compound of formula (I) or its pharmaceutically acceptable salt is administered as a multiple dose of 200 mg of the compound of formula (I) or its pharmaceutically acceptable salt, and the multiple doses are composed of a single dose of 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt; the pharmaceutical composition of formula (I) or its pharmaceutically acceptable salt is administered on days 3-28 of the first treatment cycle, and each dose is a multiple dose, and the multiple doses are 300 mg of the compound of formula (I) or its pharmaceutically acceptable salt, and the multiple doses are composed of a single dose of 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt. The pharmaceutical composition of formula (I) or its pharmaceutically acceptable salt is administered once a day continuously on days 1-28 of the second treatment cycle, and each dose of the pharmaceutical composition of formula (I) or its pharmaceutically acceptable salt is a multiple dose, and the multiple doses are 300 mg of the compound of formula (I) or its pharmaceutically acceptable salt, and the multiple doses are composed of a single dose of 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt. Starting from the third treatment cycle, the administration method of each treatment cycle is the same as that of the second treatment cycle.

In some embodiments of the present disclosure, in the above 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 day 1 to day 28 of each treatment cycle. The pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered on day 1 of the first treatment cycle is a single dose, and the single dose is 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered on day 2 of the first treatment cycle is a multiple dose, and the multiple dose is 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple dose consists of a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered on days 3 to 28 of the first treatment cycle is a multiple dose, and each dose is 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple dose consists of a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. The second treatment cycle is a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, administered once daily continuously from day 1 to day 28. Each dose of the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, each of which is 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, each of which is composed of a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Starting from the third treatment cycle, the administration method of each treatment cycle is the same as that of the second treatment cycle.

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.

In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses, 28 days constitutes 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 280 mg to 56 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 280 mg to 33.6 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 2.8 g to 22.4 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 2.8 g to 11.2 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 2.8 g to 8.4 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 5.5 g to 8.4 g. 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 2.8g to 8.1g or 2.8g to 8.4g. 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 5.5g to 8.1g or 5.6g to 8.4g. 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 2.8g, 5.5g, 5.6g, 8.1g, 8.4g, 10.7g, 11.2g or 16.8g. 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 2.8g, 5.5g, 5.6g, 8.1g or 8.4g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 2.8 g; or preferably 5.6 g; or preferably 8.4 g; or preferably 11.2 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 2.8 g; or preferably 5.5 g; or preferably 8.1 g; or preferably 10.7 g.

In some embodiments of the present disclosure, in the above-mentioned 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 2.8 g, 5.5 g, 5.6 g, 8.1 g or 8.4 g.

In some embodiments of the present disclosure, in the above-mentioned 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 2.8 g; or the total dose is 5.5 g; or the total dose is 5.6 g; or the total dose is 8.1 g; or the total dose is 8.4 g.

In some embodiments of the present disclosure, in the above-mentioned 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, with the same dosage each time. Each administration of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 100 mg, 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 2.8 g.

In some embodiments of the present disclosure, in the above-mentioned 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, with the same dosage each time. Each administration of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 200 mg, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 5.6 g.

In some other embodiments of the present disclosure, in the above-mentioned 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, with the same dosage each time. Each administration of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 300 mg, and the total dosage of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 8.4 g.

In some embodiments of the present disclosure, in the above-mentioned 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, with the same dosage each time. Each administration of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 400 mg, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 11.2 g.

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 its pharmaceutically acceptable salt is administered once a day for 28 consecutive days, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is 100 mg on the first day of the first treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is 200 mg on each day from the 2nd to the 28th day of the first treatment cycle. The total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt in the first treatment cycle is 5.5 g. The pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt in the second treatment cycle is administered once a day for 28 consecutive days, with the same dosage each time, and the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is 200 mg each time. The total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt in each treatment cycle is 5.6 g. Starting from the third treatment cycle, the administration method of each treatment cycle is the same as that of the second treatment cycle.

In some other embodiments of the present disclosure, in the above-mentioned 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, 100 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on the first day of the first treatment cycle, 200 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on the second day of the first treatment cycle, 300 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered every day from the 3rd to the 28th day of the first treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in the first treatment cycle is 8.1 g. In the second treatment cycle, the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily for 28 consecutive days, with the same dosage each time. Each administration of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 300 mg, and the total dosage of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof per treatment cycle is 8.4 g. Starting from the third treatment cycle, the administration method of each treatment cycle is the same as that of the second treatment cycle.

In some embodiments of the present disclosure, in the above-mentioned 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, 100 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on the first day of the first treatment cycle, 200 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on the second day of the first treatment cycle, 400 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered every day from the 3rd to the 28th day of the first treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in the first treatment cycle is 10.7 g. In the second treatment cycle, the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily for 28 consecutive days, with the same dosage each time. Each administration of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 400 mg, and the total dosage of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof per treatment cycle is 11.2 g. Starting from the third treatment cycle, the administration method of each treatment cycle is the same as that of the second treatment cycle.

In some embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, method, therapy or use, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of formula IA, formula IB, formula IC, or formula ID, or a pharmaceutically acceptable salt thereof,

In some embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, method, therapy or use, the patient is a patient who does not respond well to JAK inhibitors, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously with the JAK inhibitor.

In some embodiments of the present disclosure, in the above-mentioned pharmaceutical compositions, methods, therapies or uses, when the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered, the JAK inhibitor can be gradually reduced or stopped, and its dosage cannot exceed the dosage level before administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, in the above-mentioned pharmaceutical compositions, methods, therapies or uses, when the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered, the dosage of ruxolitinib can be gradually reduced or stopped, and its dosage cannot exceed the dosage level before administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, method, therapy or use, before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the administration of ruxolitinib is twice daily, 10 mg or 15 mg each time.

In some embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, method, therapy or use, before the administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the administration of ruxolitinib is twice daily, 10 mg or 15 mg each time, and each dose is the same or different.

In another aspect, the present disclosure provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and ruxolitinib,

In some embodiments of the present disclosure, the above-mentioned drug combination, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and ruxolitinib are packaged in the same kit, and the kit further comprises instructions for using the compound of formula (I) or a pharmaceutically acceptable salt thereof and ruxolitinib in combination to treat myelofibrosis.

In some embodiments of the present disclosure, the above-mentioned drug combination, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and ruxolitinib are separately packaged in respective medicine boxes, and the respective medicine boxes also include instructions for the combined use of the compound of formula (I) or a pharmaceutically acceptable salt thereof and ruxolitinib to treat myelofibrosis.

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

In some embodiments of the present disclosure, the above-mentioned drug combination, wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of ruxolitinib 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 ruxolitinib in combination to treat myelofibrosis.

In some embodiments of the present disclosure, the above-mentioned drug combination, wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of ruxolitinib are separately packaged in respective medicine boxes, and the respective kits further contain instructions for using the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of ruxolitinib in combination to treat myelofibrosis.

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

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

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 drug combinations described in the present disclosure.

It should be understood that the above-mentioned “compound of formula (I) or a pharmaceutically acceptable salt thereof” in the present disclosure is also applicable to the pharmaceutical combination described in the present disclosure.

In some embodiments of the present disclosure, the above-mentioned drug combination contains 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 ruxolitinib, or a pharmaceutical combination thereof.

In some embodiments of the present disclosure, the above-mentioned drug combination 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 ruxolitinib, or a pharmaceutical combination thereof.

In some embodiments of the present disclosure, the above-mentioned drug combination contains 5 mg, 10 mg, 15 mg or 20 mg of ruxolitinib, or a pharmaceutical composition thereof.

In some embodiments of the present disclosure, the above-mentioned drug combination contains 10 to 20 mg of ruxolitinib, or a pharmaceutical composition thereof.

In some embodiments of the present disclosure, the above-mentioned drug combination contains 10 to 15 mg of ruxolitinib, or a pharmaceutical composition thereof.

In some embodiments of the present disclosure, the above-mentioned drug combination contains 10 mg, 15 mg or 20 mg of ruxolitinib, or a pharmaceutical composition thereof.

In some specific embodiments of the present disclosure, the above-mentioned drug combination contains 10 mg of ruxolitinib, or a pharmaceutical composition thereof.

In some specific embodiments of the present disclosure, the above-mentioned drug combination contains 15 mg of ruxolitinib, or a pharmaceutical composition thereof.

In some embodiments of the present disclosure, the above-mentioned drug combination, the pharmaceutical composition of ruxolitinib is in the form of a single dose or multiple doses.

In some embodiments of the present disclosure, the above-mentioned drug combination, the pharmaceutical composition of ruxolitinib is in a multiple-dose form.

In some embodiments of the present disclosure, the pharmaceutical composition of ruxolitinib is administered daily. In some embodiments of the present disclosure, the pharmaceutical composition of ruxolitinib is administered twice daily. In some embodiments of the present disclosure, the two doses are the same or different.

In some embodiments of the present disclosure, the pharmaceutical composition of ruxolitinib is dosed twice daily, and each dose is a single dose or multiple doses.

In some embodiments of the present disclosure, the pharmaceutical composition of ruxolitinib is a twice-daily dose, each dose being a multiple dose consisting of a single dose of 5 mg, 10 mg, 15 mg and/or 20 mg of ruxolitinib. In some embodiments of the present disclosure, the pharmaceutical composition consists of a single dose of 5 mg of ruxolitinib.

In some embodiments of the present disclosure, the pharmaceutical composition of ruxolitinib is a twice-daily dose, each dose is a multiple dose, and the multiple dose is 10 mg or 15 mg of ruxolitinib.

In some embodiments of the present disclosure, the pharmaceutical composition of ruxolitinib is packaged in a kit, and the kit also contains instructions for using ruxolitinib to treat myelofibrosis.

In some embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains a pharmaceutical composition of 10-1200 mg, 10-1000 mg, 10-800 mg, 100-1200 mg, 100-800 mg, 100-500 mg, 100-400 mg, 100-300 mg, 200-800 mg, 200-400 mg, 100-600 mg, 200-600 mg, 10-100 mg, 10-200 mg or 10-400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing 1-50 mg, 5-50 mg of dapoxetine. The pharmaceutical composition of ruxolitinib is preferably a single dose, a multiple dose, or a combination thereof, wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, a multiple dose, or a combination thereof; 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 ruxolitinib is a multiple dose; equally 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 ruxolitinib is a multiple dose.

In some embodiments of the present disclosure, the above-mentioned drug combination contains a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg or 600 mg, calculated as the compound of formula (I), and a pharmaceutical composition of 5 mg, 10 mg, 15 mg or 20 mg, or a range formed by any of the above values, of ruxolitinib, 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 ruxolitinib 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 ruxolitinib is a multiple dose; equally 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 ruxolitinib is a multiple dose.

In some embodiments of the present disclosure, the above-mentioned drug combination contains a pharmaceutical composition of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of 10 mg, 15 mg or 20 mg of ruxolitinib, calculated as the 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 ruxolitinib 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 ruxolitinib is a multiple dose; equally 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 ruxolitinib is a multiple dose.

In some embodiments of the present disclosure, the above-mentioned drug combination contains a pharmaceutical composition of 100 mg, 200 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and 10 mg or 15 mg of a pharmaceutical composition of ruxolitinib, calculated as the 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 ruxolitinib 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 ruxolitinib is a multiple dose; equally 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 ruxolitinib is a multiple dose.

In some embodiments of the present disclosure, the above-mentioned drug combination contains a pharmaceutical composition of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of 10 mg of ruxolitinib, calculated as the 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 ruxolitinib 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 ruxolitinib is a multiple dose.

In some embodiments of the present disclosure, the above-mentioned drug combination contains a pharmaceutical composition of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of 15 mg of ruxolitinib, calculated as the 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 ruxolitinib 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 ruxolitinib is a multiple dose.

In some embodiments of the present disclosure, the above-mentioned drug combination contains a pharmaceutical composition of 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of 10 mg of ruxolitinib, calculated as the 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 ruxolitinib 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 ruxolitinib is a multiple dose.

In some embodiments of the present disclosure, the above-mentioned drug combination contains a pharmaceutical composition of 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of 15 mg of ruxolitinib, calculated as the 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 ruxolitinib 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 ruxolitinib is a multiple dose.

In some embodiments of the present disclosure, the above-mentioned drug combination contains a pharmaceutical composition of 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of 10 mg of ruxolitinib, calculated as the 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 ruxolitinib 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 ruxolitinib is a multiple dose.

In some embodiments of the present disclosure, the above-mentioned drug combination contains a pharmaceutical composition of 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of 15 mg of ruxolitinib, calculated as the 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 ruxolitinib 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 ruxolitinib is a multiple dose.

In some embodiments of the present disclosure, every 28 days is one treatment cycle.

In some embodiments of the present disclosure, the pharmaceutical combination comprises: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a single dose of 100 mg, calculated as a compound of formula (I); and a pharmaceutical composition of a single dose of 5 mg, calculated as ruxolitinib. Alternatively, the pharmaceutical combination is in the form of a single-dose formulation, comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and a pharmaceutical composition of 5 mg, calculated as ruxolitinib.

In some embodiments of the present disclosure, the above-mentioned drug combination is a pharmaceutical composition suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), comprising a pharmaceutical composition containing 280 mg to 56 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 140 to 840 mg of ruxolitinib or a pharmaceutical composition thereof, calculated as ruxolitinib; or, comprising a pharmaceutical composition containing 2.8 g to 22.4 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 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 ruxolitinib, or a pharmaceutical composition thereof, calculated as ruxolitinib. A pharmaceutical composition; or a pharmaceutical composition comprising 2.8 g to 8.4 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 280 to 840 mg of ruxolitinib or a pharmaceutical composition thereof; or a pharmaceutical composition comprising 5.5 g to 8.4 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 280 to 840 mg of ruxolitinib or a pharmaceutical composition thereof; or a pharmaceutical composition comprising 2.8 g, 5.5 g, 5.6 g, 10.7 g or 11.2 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 280 mg ... 60 mg or 840 mg of ruxolitinib or a pharmaceutical composition thereof; or, a pharmaceutical composition comprising 5.5 g or 5.6 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 560 mg or 840 mg of ruxolitinib or a pharmaceutical composition thereof; or, a pharmaceutical composition comprising 8.1 g or 8.4 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 560 mg or 840 mg of ruxolitinib or a pharmaceutical composition thereof; or, a pharmaceutical composition comprising 5.5 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 560 mg or 840 mg of ruxolitinib or a pharmaceutical composition thereof. 40 mg of ruxolitinib or a pharmaceutical composition thereof; or, a pharmaceutical composition containing 5.6 g of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and 560 mg or 840 mg of ruxolitinib or a pharmaceutical composition thereof; or, a pharmaceutical composition containing 8.1 g of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and 560 mg or 840 mg of ruxolitinib or a pharmaceutical composition thereof; or, a pharmaceutical composition containing 8.4 g of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and 560 mg or 840 mg of ruxolitinib or a pharmaceutical composition thereof.

In some embodiments of the present disclosure, the above-mentioned drug combination 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 ruxolitinib or a pharmaceutical composition thereof, with a total dose ratio of (5-50):1, for example, (6.7-50):1, (6.7-20):1, 6.7:1, 10:1, 13.3:1 or 20:1, or any ratio within the above-mentioned ranges, 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 ruxolitinib or a pharmaceutical composition thereof is calculated based on ruxolitinib.

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

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 ruxolitinib or a pharmaceutical composition thereof.

In another aspect, the present disclosure further 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 ruxolitinib or a pharmaceutical composition thereof. Alternatively, the present disclosure further provides a pharmaceutical combination for treating myelofibrosis, comprising: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and ruxolitinib or a pharmaceutical composition thereof.

In some embodiments of the present disclosure, in the above-mentioned drug combination, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and the ruxolitinib is prepared into a unit preparation containing 5 mg of ruxolitinib.

On the other hand, the present disclosure also provides a method for treating myelofibrosis, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and ruxolitinib to an individual in need thereof, for example, administering a therapeutically effective amount of the drug combination described above of the present disclosure to an individual in need thereof.

In another aspect, the present disclosure also provides a combination therapy for treating an individual with myelofibrosis, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of ruxolitinib.

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 ruxolitinib in the preparation of a medicament for treating myelofibrosis, for example, the use of the above-mentioned drug combination of the present disclosure in the preparation of a medicament for treating myelofibrosis. In some embodiments of the present disclosure, the drug combination is any of the drug combinations described above in the present disclosure.

On the other hand, the present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a medicament for use in combination with ruxolitinib in treating myelofibrosis, for example, the use of the above-mentioned drug combination of the present disclosure in preparing a medicament for treating myelofibrosis. In some embodiments of the present disclosure, the drug combination is any of the drug combinations described above in the present disclosure.

On the other hand, the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with ruxolitinib for treating myelofibrosis, for example, the use of the above-mentioned drug combination of the present disclosure for treating myelofibrosis.

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

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

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 ruxolitinib 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 ruxolitinib 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. 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 ruxolitinib have the same treatment cycle, and the treatment cycle is one treatment cycle every 4 weeks.

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 pharmaceutical combination 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.

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 pharmaceutical combination 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.

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 100 mg; or, a daily dose of 200 mg; or, a daily dose of 300 mg; or, a daily dose of 400 mg.

In some other embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 200 mg; or, a daily dose of 300 mg.

In some other 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 pharmaceutical combination is administered in a single dose, and the single dose is a pharmaceutical composition of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the above-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.

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

In some embodiments of the present disclosure, in the above-mentioned methods, conjoint therapies or uses, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical combination is the dosage per treatment cycle, which is administered in the following manner: the compound of formula (I) or its pharmaceutically acceptable salt is administered daily. Wherein, the compound of formula (I) 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).

In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the content of ruxolitinib in the pharmaceutical combination is a daily dose, which is administered in the following manner: ruxolitinib is administered twice a day.

In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the content of ruxolitinib in the pharmaceutical combination is a daily dose, which is administered as follows: ruxolitinib is administered twice a day, with the same dose or different doses each time.

In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the content of ruxolitinib in the drug combination is a daily dose, wherein ruxolitinib is administered in a single dose or multiple doses, usually in multiple doses; further, ruxolitinib is administered twice a day, and the dose is the same each time.

In some embodiments of the present disclosure, in the above methods, combination therapies or uses, ruxolitinib is 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.

In some embodiments of the present disclosure, in the above methods, combination therapies or uses, ruxolitinib is 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, ruxolitinib is administered as follows: twice daily, each dose is 10 mg; or, each dose is 15 mg.

In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, ruxolitinib in the pharmaceutical combination is administered in multiple doses, each of which consists of a single dose of 5 mg of a pharmaceutical composition of ruxolitinib. In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, ruxolitinib is administered in a continuous daily dosing manner.

In some embodiments of the present disclosure, in the above methods, combination therapies, or uses, the amount of ruxolitinib in the pharmaceutical combination is a dose per treatment cycle, which is administered as follows: ruxolitinib is administered daily, wherein ruxolitinib 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).

In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is administered in multiple doses, and the multiple doses consist of a pharmaceutical composition having a single dose of 100 mg of the compound of formula (I), 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.

In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the ruxolitinib is administered as follows: a daily dose of 20 mg; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 100 mg; or the ruxolitinib is administered as follows: a daily dose of 30 mg; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 100 mg; or the ruxolitinib is administered as follows: a daily dose of 20 mg; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows : The daily dose is 200 mg; alternatively, the ruxolitinib is administered as follows: the daily dose is 30 mg; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: the daily dose is 200 mg; alternatively, the ruxolitinib is administered as follows: the daily dose is 20 mg; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: the daily dose is 300 mg; alternatively, the ruxolitinib is administered as follows: the daily dose is 30 mg; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: the daily dose is 300 mg.

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

In some other specific embodiments of the present disclosure, in the above methods, combination therapies or uses, 28 days is a treatment cycle, and ruxolitinib is administered twice daily on days 1 to 28 of each treatment cycle, at a dose of 10 mg or 15 mg each time, and the doses are the same or different each time; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily on days 1 to 28 of each treatment cycle, at a dose of 100 mg per day; or, 28 days is a treatment cycle, and ruxolitinib is administered twice daily on days 1 to 28 of each treatment cycle, at a dose of 10 mg or 15 mg each time, and the doses are the same or different each time; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily on days 1 to 28 of each treatment cycle, at a dose of 200 mg per day; or, 28 days is a treatment cycle, and ruxolitinib is administered twice daily on days 1 to 28 of each treatment cycle, at a dose of 10 mg or 15 mg each time, and the doses are the same or different each time; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily on days 1 to 28 of each treatment cycle, at a dose of 300 mg per day.

In some specific embodiments of the present disclosure, in the above methods, combination therapies, or uses, 28 days is a treatment cycle, and ruxolitinib is administered twice daily on days 1-28 of each treatment cycle, 10 mg or 15 mg each time, with the same or different doses each time; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily on days 1-28 of each treatment cycle, 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 1 of the first treatment cycle, and 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered each time on days 2-28; 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily on days 1-28 of the second treatment cycle, and the administration of ruxolitinib is the same as that of the first treatment cycle. Starting from the third treatment cycle, the administration of the compound of formula (I), ruxolitinib, or their respective pharmaceutically acceptable salts in each treatment cycle is the same as that of the second treatment cycle.

In some other specific embodiments of the present disclosure, in the above methods, combination therapies or uses, 28 days is a treatment cycle, and ruxolitinib is administered twice daily on days 1-28 of each treatment cycle, 10 mg or 15 mg each time, with the same or different doses each time; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily on days 1-28 of each treatment cycle, 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 1 of the first treatment cycle, 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 2, and 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 3-28; 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily on days 1-28 of the second treatment cycle, and the administration mode of ruxolitinib is the same as that of the first treatment cycle. Starting from the third treatment cycle, the administration mode of the compound of formula (I), ruxolitinib or their respective pharmaceutically acceptable salts in each treatment cycle is the same as that of the second treatment cycle.

In some specific embodiments of the present disclosure, in the above methods, combination therapies, or uses, 28 days is a treatment cycle, and ruxolitinib is administered twice daily on days 1-28 of each treatment cycle, 10 mg or 15 mg each time, with the same or different doses each time; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily on days 1-28 of each treatment cycle, 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 1 of the first treatment cycle, 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 2, and 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 3-28; 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily on days 1-28 of the second treatment cycle, and the administration mode of ruxolitinib is the same as that of the first treatment cycle. Starting from the third treatment cycle, the administration mode of the compound of formula (I), ruxolitinib, or their respective pharmaceutically acceptable salts in each treatment cycle is the same as that of the second treatment cycle.

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 2.8g to 11.2g. 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 5.5g to 8.4g. 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 2.8g, 5.5g, 5.6g, 8.1g or 8.4g 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 2.8g to 8.1g or 2.8g to 8.4g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 5.5g to 8.1g or 5.6g to 8.4g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 2.8g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 5.5g; or preferably 5.6g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 8.1g; or preferably 8.4g.

In some embodiments of the present disclosure, in the above 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 ruxolitinib administered in each treatment cycle is 140 to 840 mg. In some embodiments, the total dose of the pharmaceutical composition containing ruxolitinib 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 ruxolitinib is preferably 280 to 840 mg. In some embodiments, the total dose of the pharmaceutical composition containing ruxolitinib is preferably 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 administered in each treatment cycle is 2.8 g, 5.5 g, 5.6 g, 8.1 g or 8.4 g; the pharmaceutical composition containing ruxolitinib is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing ruxolitinib 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 administered in each treatment cycle is 2.8 g; or the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5.5 g or 8.1 g; or the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5.6 g or 8.4 g; the pharmaceutical composition containing ruxolitinib is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing ruxolitinib 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 administered in each treatment cycle is 5.5 g; or the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5.6 g; the pharmaceutical composition containing ruxolitinib is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing ruxolitinib administered in each treatment cycle is 560 mg or 840 mg.

In some other 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 8.1 g; or the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 8.4 g; the pharmaceutical composition containing ruxolitinib is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing ruxolitinib 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 administered in each treatment cycle is 10.7 g; or the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 11.2 g; the pharmaceutical composition containing ruxolitinib is administered twice a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing ruxolitinib administered in each treatment cycle is 560 mg or 840 mg.

In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses or the above-mentioned methods, combination therapies or uses, 28 days is a treatment cycle, and the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 28 consecutive days; wherein, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered during the lead-in period in the first treatment cycle, and the lead-in period includes administration of 100 mg on day 1 and administration of 200 mg on days 2-28; or the lead-in period includes administration of 100 mg on day 1, administration of 200 mg on day 2; and administration of 300 mg on days 3-28.

In another aspect, the present disclosure provides a pharmaceutical combination 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,

In some embodiments of the present disclosure, the above-mentioned drug combination, wherein 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 packaged in the same kit, and the kit further comprises instructions for using 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 combination to treat myelofibrosis.

In some embodiments of the present disclosure, the above-mentioned drug combination, wherein 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 medicine boxes, and the respective medicine boxes 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 to treat myelofibrosis.

In some embodiments of the present disclosure, the pharmaceutical combination 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.

In some embodiments of the present disclosure, the above-mentioned drug combination, wherein 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 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 a pharmaceutically acceptable salt thereof in combination to treat myelofibrosis.

In some embodiments of the present disclosure, the above-mentioned drug combination, wherein 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 are separately packaged in respective medicine boxes, and the respective kits further 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.

In some embodiments of the present disclosure, the above-mentioned drug combination, wherein 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 each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially or intermittently.

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

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 drug combinations described in the present disclosure.

It should be understood that the above-mentioned “compound of formula (I) or a pharmaceutically acceptable salt thereof” in the present disclosure is also applicable to the pharmaceutical combination described in the present disclosure.

In some embodiments of the present disclosure, the above-mentioned drug combination contains 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 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 drug combination 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 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 pharmaceutical combination contains 5 mg, 10 mg, 15 mg or 20 mg of the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salt, or its pharmaceutical composition.

In some embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains 10 to 20 mg of the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salt, or its pharmaceutical composition.

In some embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains 10 to 15 mg of the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salt, or its pharmaceutical composition.

In some embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains 10 mg, 15 mg or 20 mg of the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salt, or its pharmaceutical composition.

In some specific embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains 10 mg of the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salt, or its pharmaceutical composition.

In some specific embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains 15 mg of the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salt, or its pharmaceutical composition.

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

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

In some embodiments of the present disclosure, the above-mentioned drug combination, the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a daily dose. In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a twice-daily dose. In some embodiments of the present disclosure, each dose of the two doses is the same or different.

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.

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.

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 dosed twice a day, and each dose is a multiple dose, and the multiple dose is 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 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.

In some embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains 10-1200 mg, 10-1000 mg, 10-800 mg, 100-1200 mg, 100-800 mg, 100-500 mg, 100-400 mg, 100-300 mg, 200-800 mg, 200-400 mg, 100-600 mg, 200-600 mg, 10-100 mg, 10-200 mg or 10-400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 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 to 30 mg of a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, wherein the pharmaceutical composition of a 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose; equally preferably, the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose.

In some embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg or 600 mg of a compound of formula (I) or a pharmaceutical composition of a pharmaceutically acceptable salt thereof and a pharmaceutical composition of a compound of formula (II) in an amount of 5 mg, 10 mg, 15 mg or 20 mg or a range formed by any of the above values, wherein the compound of formula (I) or a pharmaceutical composition of a pharmaceutically acceptable salt thereof is The pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a single dose or a multiple dose, wherein the pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose or 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 multiple dose; equally 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.

In some embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 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, 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; equally 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.

In some embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains 100 mg, 200 mg or 300 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; equally 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.

In some embodiments of the present disclosure, the above-mentioned drug combination contains a pharmaceutical composition of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of 10 mg of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof, calculated as the 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), 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.

In some embodiments of the present disclosure, the above-mentioned drug combination contains, calculated as 100 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, 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.

In some embodiments of the present disclosure, the above-mentioned drug combination contains 200 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.

In some embodiments of the present disclosure, the above-mentioned drug combination contains 200 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), its stereoisomer, 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), 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.

In some embodiments of the present disclosure, the above-mentioned drug combination contains 300 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.

In some embodiments of the present disclosure, the above-mentioned drug combination contains 300 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.

In some embodiments of the present disclosure, every 28 days is one treatment cycle.

In some embodiments of the present disclosure, the above-mentioned pharmaceutical combination contains: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a single dose of 100 mg calculated as a compound of formula (I); and a pharmaceutical composition of a compound of formula (II), 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 pharmaceutical combination is in the form of a single-dose formulation, the pharmaceutical combination containing: a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in a single dose of 100 mg calculated as a compound of formula (I); and a compound of formula (II), 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).

In some embodiments of the present disclosure, the above-mentioned drug combination is a pharmaceutical composition suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), comprising a pharmaceutical composition containing 280 mg to 56 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 140 to 840 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as a compound of formula (II); or, comprising a pharmaceutical composition containing 2.8 g to 22.4 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I), and 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), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; or, comprising 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). or a pharmaceutical composition comprising 2.8 g to 8.4 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a pharmaceutical composition of formula (I) and 280 to 840 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a pharmaceutical composition of formula (II); or a pharmaceutical composition comprising 5.5 g to 8.4 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a pharmaceutical composition of formula (II) and 280 to 840 mg of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a pharmaceutical composition of formula (II); or a pharmaceutical composition comprising 2.8 g, 5.5 g, 5.6 g, 10.7 g or 11.2 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a pharmaceutical composition of formula (II) and 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 pharmaceutical composition of formula (II). or a pharmaceutical composition comprising 5.5 g or 5.6 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I) and 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 8.1 g or 8.4 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (II) and 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 5.5 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I) and 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 5.6 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I) and 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 8.1 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I) and 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 8.4 g of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I) and 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).

In some embodiments of the present disclosure, the above-mentioned drug combination 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), its stereoisomers, or its pharmaceutically acceptable salts or pharmaceutical compositions thereof, with a total dose ratio of (5-50):1, for example, (6.7-50):1, (6.7-20):1, 6.7:1, 10:1, 13.3:1 or 20:1, or any ratio within the above-mentioned ranges, wherein the dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salts is calculated based on the compound of formula (I), and the dose of the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts or pharmaceutical compositions thereof is calculated based on the compound of formula (II).

In some embodiments of the present disclosure, in the above-mentioned drug combination, 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.

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 or a pharmaceutical combination thereof.

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, or a pharmaceutical composition thereof. Alternatively, the present disclosure also provides a pharmaceutical combination 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, or a pharmaceutical composition thereof.

In some embodiments of the present disclosure, in the above-mentioned drug combination, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, 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.

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 drug combination described above of the present disclosure.

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.

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 drug combination of the present disclosure in the preparation of a medicament for treating myelofibrosis. In some embodiments of the present disclosure, the drug combination is any of the drug combinations described above in the present disclosure.

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 drug combination of the present disclosure for treating myelofibrosis.

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 stereoisomers, 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 stereoisomers, or its pharmaceutically acceptable salt in the drug combination described above, such as content, dosage, form of existence, packaging form, etc.

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.

In some embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the compound of formula (I) or its pharmaceutically acceptable salt and the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt respectively have the same or different treatment cycles. In some specific embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the compound of formula (I) or its pharmaceutically acceptable salt and the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt 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. In some specific embodiments of the present disclosure, in the above-mentioned methods, combination therapies or uses, the compound of formula (I) or its pharmaceutically acceptable salt and the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt have the same treatment cycle, and the treatment cycle is every 4 weeks as a treatment cycle.

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 pharmaceutical combination 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.

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 pharmaceutical combination 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.

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 100 mg; or, a daily dose of 200 mg; or, a daily dose of 300 mg; or, a daily dose of 400 mg.

In some other embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 200 mg; or, a daily dose of 300 mg.

In some other 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 pharmaceutical combination is administered in a single dose, and the single dose is a pharmaceutical composition of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the above-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.

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

In some embodiments of the present disclosure, in the above-mentioned methods, conjoint therapies or uses, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical combination is the dosage per treatment cycle, which is administered in the following manner: the compound of formula (I) or its pharmaceutically acceptable salt is administered daily. Wherein, the compound of formula (I) 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).

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 pharmaceutical combination 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.

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 pharmaceutical combination 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.

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 pharmaceutical combination 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, and the dose is the same each time.

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.

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: twice a day, each dose is 10 mg; or, each dose is 15 mg.

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 pharmaceutical combination 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 (II) or a pharmaceutically acceptable salt thereof is administered in a continuous daily manner.

In some embodiments of the present disclosure, in the above-mentioned methods, conjoint therapies or uses, the content of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt in the drug combination 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).

In some embodiments of the present disclosure, in the above methods, combination therapies or uses, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is administered in multiple doses, and the multiple doses consist of a pharmaceutical composition having a single dose of 100 mg of the compound of formula (I), 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.

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 100 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 100 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: : The daily dose is 200 mg; or, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered as follows: the daily dose is 30 mg; the compound of formula (I) or its pharmaceutically acceptable salt is administered as follows: the daily dose is 200 mg; or, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered as follows: the daily dose is 20 mg; the compound of formula (I) or its pharmaceutically acceptable salt is administered as follows: the daily dose is 300 mg; or, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered as follows: the daily dose is 30 mg; the compound of formula (I) or its pharmaceutically acceptable salt is administered as follows: the daily dose is 300 mg.

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 to 28 of each treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 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 to 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 to 28 of each treatment cycle.

In some other specific embodiments of the present disclosure, in the above methods, combination therapies or uses, 28 days is a treatment cycle, and the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered twice a day on days 1 to 28 of each treatment cycle, 10 mg or 15 mg each time, and each dose is the same or different; the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day on days 1 to 28 of each treatment cycle, 100 mg per day; or, 28 days is a treatment cycle, and the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof are administered twice a day on days 1 to 28 of each treatment cycle. or a pharmaceutically acceptable salt thereof, 10 mg or 15 mg each time, the dose each time being the same or different; administering the compound of formula (I) or a pharmaceutically acceptable salt thereof once daily on days 1 to 28 of each treatment cycle, 200 mg per day; or, 28 days being a treatment cycle, administering the compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof twice daily on days 1 to 28 of each treatment cycle, 10 mg or 15 mg each time, the dose each time being the same or different; administering the compound of formula (I) or a pharmaceutically acceptable salt thereof once daily on days 1 to 28 of each treatment cycle, 300 mg per day.

In some specific embodiments of the present disclosure, in the above methods, combination therapies or uses, 28 days is a treatment cycle, and the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is administered twice a day on days 1-28 of each treatment cycle, 10 mg or 15 mg each time, with each dose being the same or different; the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day on days 1-28 of each treatment cycle, 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered on day 1 of the first treatment cycle, and 200 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered each time on days 2-28; 200 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day on days 1-28 of the second treatment cycle, and the administration mode of the compound of formula (II) or its pharmaceutically acceptable salt is the same as that of the first treatment cycle. Starting from the third treatment cycle, the administration mode of the compound of formula (I), the compound of formula (II) or their respective pharmaceutically acceptable salts in each treatment cycle is the same as that of the second treatment cycle.

In some other 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 pharmaceutically acceptable salt thereof is administered twice a day on days 1 to 28 of each treatment cycle, 10 mg or 15 mg each time, and each dose is the same or different; the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day on days 1 to 28 of each treatment cycle, 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered on day 1 of the first treatment cycle, 200 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered on day 2, and 300 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered daily on days 3 to 28; 300 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day on days 1 to 28 of the second treatment cycle, and the administration method of the compound of formula (II) or its pharmaceutically acceptable salt is the same as that of the first treatment cycle. Starting from the third treatment cycle, the administration mode of the compound of formula (I), the compound of formula (II) or their respective pharmaceutically acceptable salts in each treatment cycle is the same as that of the second 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 to 28 of each treatment cycle, 10 mg or 15 mg each time, and each dose is the same or different; the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1 to 28 of each treatment cycle, 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 1 of the first treatment cycle, 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on day 2, and 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 3 to 28; 400 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1 to 28 of the second treatment cycle, and the administration method of the compound of formula (II) or a pharmaceutically acceptable salt thereof is the same as that of the first treatment cycle. Starting from the third treatment cycle, the administration mode of the compound of formula (I), the compound of formula (II) or their respective pharmaceutically acceptable salts in each treatment cycle is the same as that of the second treatment cycle.

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 2.8g to 11.2g. 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 5.5g to 8.4g. 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 2.8g, 5.5g, 5.6g, 8.1g or 8.4g 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 2.8g to 8.1g or 2.8g to 8.4g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 5.5g to 8.1g or 5.6g to 8.4g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 2.8g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 5.5g; or preferably 5.6g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 8.1g; or preferably 8.4g.

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.

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 2.8 g, 5.5 g, 5.6 g, 8.1 g or 8.4 g; 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 administered in each treatment cycle is 2.8 g; or the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5.5 g or 8.1 g; or the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5.6 g or 8.4 g; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts 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 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 administered in each treatment cycle is 5.5 g; or the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5.6 g; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts 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 560 mg or 840 mg.

In some other 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 8.1 g; or the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 8.4 g; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts 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 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 administered in each treatment cycle is 10.7 g; or the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is 11.2 g; the pharmaceutical composition containing the compound of formula (II), its stereoisomers, or its pharmaceutically acceptable salts 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 560 mg or 840 mg.

In some embodiments of the present disclosure, in the above-mentioned methods, therapies or uses or the above-mentioned methods, combination therapies or uses, 28 days is a treatment cycle, and the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for 28 consecutive days; wherein, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered during the lead-in period in the first treatment cycle, and the lead-in period administration includes administration of 100 mg on day 1 and administration of 200 mg on days 2-28; or the lead-in period administration includes administration of 100 mg on day 1, administration of 200 mg on day 2; and administration of 300 mg on days 3-28.

In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered only in the first treatment cycle as an introduction phase, and is administered at a stable dose starting from the second treatment cycle.

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

In the disclosed regimens, either the first treatment cycle or the second treatment cycle is repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

In the regimen of the present disclosure, after the previous treatment cycle is completed, administration is continued on the next day to enter the next treatment cycle.

In some embodiments of the present disclosure, in the above-mentioned drug combination, method, combination therapy or use, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of formula IA, formula IB, formula IC, or formula ID, or a pharmaceutically acceptable salt thereof,

In some other embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, method, therapy or use, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of formula IA or a pharmaceutically acceptable salt thereof,

In some other embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, method, therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a compound of formula IB or a pharmaceutically acceptable salt thereof,

In some other embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, method, therapy or use, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of formula IC or a pharmaceutically acceptable salt thereof,

In some other embodiments of the present disclosure, in the above-mentioned pharmaceutical composition, method, therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula ID or a pharmaceutically acceptable salt thereof,

Myelofibrosis

In some embodiments of the present disclosure, the myelofibrosis includes primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV-MF), and post-essential thrombocythemia myelofibrosis (Post-ET-MF).

In some embodiments of the present disclosure, the myelofibrosis comprises intermediate-risk and/or high-risk myelofibrosis.

In some embodiments of the present disclosure, the myelofibrosis comprises myelofibrosis that has been previously refractory to JAK inhibitor treatment.

In some embodiments of the present disclosure, the myelofibrosis comprises myelofibrosis not treated with a JAK inhibitor.

In some embodiments of the present disclosure, the myelofibrosis includes intermediate-risk and/or high-risk myelofibrosis that has been poorly treated with previous JAK inhibitors.

In some embodiments of the present disclosure, the myelofibrosis comprises intermediate-risk and/or high-risk myelofibrosis not treated with a JAK inhibitor.

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

In some embodiments of the present disclosure, the myelofibrosis is JAK2-mutated myelofibrosis.

In some embodiments of the present disclosure, the myelofibrosis is myelofibrosis without a JAK2 mutation.

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.

In some embodiments of the present disclosure, the DIPSS-assessed intermediate-risk and/or high-risk patients are required to have relevant symptoms such as splenomegaly and a Myeloproliferative Neoplasm Symptom Assessment Scale (MNP-10) score of ≥5.

In some embodiments of the present disclosure, the high-risk myelofibrosis is myelofibrosis assessed as higher risk/high risk according to the NCCN guidelines prognostic grading criteria.

In some embodiments of the present disclosure, the high-risk myelofibrosis patient has MIPSS-70: ≥4 or MIPSS-70+V2.0: ≥4, DIPSS-Plus: >1, DIPSS: >2, and MYSEC-PM: ≥14.

In some embodiments of the present disclosure, patients with higher/high-risk myelofibrosis assessed by the NCCN Guidelines prognostic grading criteria are required to have related symptoms such as splenomegaly and a Myeloproliferative Neoplasm Symptom Assessment Scale (MNP-10) score of ≥5 points.

In some embodiments of the present disclosure, poor treatment with JAK inhibitors refers to cumulative treatment with JAK inhibitors for ≥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 response compared with before treatment, or the MPN-SAF total symptom score is reduced by <50%.

In some embodiments of the present disclosure, the JAK inhibitor is discontinued for patients who are not adequately treated with the JAK inhibitor at least 2 days before the first use of the drug or drug combination of the present application.

In some embodiments of the present disclosure, the myelofibrosis that has not been well treated with previous JAK inhibitors, wherein the 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.

In some embodiments of the present disclosure, the myelofibrosis that has not been adequately treated with previous JAK inhibitors, wherein the JAK inhibitor comprises ruxolitinib or a compound of formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the myelofibrosis is previously refractory to treatment with a JAK inhibitor, wherein the JAK inhibitor comprises ruxolitinib.

In some embodiments of the present disclosure, the myelofibrosis was previously poorly treated with JAK inhibitors, wherein the JAK inhibitor includes ruxolitinib for continuous treatment at a stable dose for more than 8 weeks, and the dose of ruxolitinib is ≥10 mg each time, twice a day.

In some embodiments of the present disclosure, the splenomegaly refers to a spleen margin palpated to or exceeding at least 5 cm below the ribs or a spleen volume assessed by MRI/CT of ≥450 cm ³ .

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

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 prior to the examination, and had hemoglobin (HGB) ≥ 80 g/L, platelet count PLT) ≥ 100×10 ⁹ /L, and absolute neutrophil count (NEUT) ≥ 1.0×10 ⁹ /L within 7 days prior to the first medication.

In some embodiments of the present disclosure, the myelofibrosis patient has normal major organ functions 7 days before the first medication.

In some embodiments of the present disclosure, the normal function of the major organs includes 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 requirements: 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%.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered 72 hours before the first dose, and the patient is required to take an oral uric acid-lowering drug and oral hydration is initiated 48 hours prior to the first dose for tumor lysis syndrome (TLS) prophylaxis; and/or the patient is hospitalized the day before the first dose until the TLS risk-safe discharge day, and receives intravenous hydration daily while closely monitoring and promptly addressing any metabolic changes suggestive of tumor lysis.

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

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 WO2020088442.

The compounds of formula (I) disclosed herein can be administered in their free base form or in their pharmaceutically acceptable salt form. For example, pharmaceutically acceptable salts of the compounds of formula (I) are within the scope of the present disclosure and can be produced from various organic and inorganic acids according to methods known in the art.

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.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-A) or a pharmaceutically acceptable salt thereof.

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

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.

In some embodiments of the present disclosure, the pharmaceutical composition contains a single dose of 100 mg, 200 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

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.

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.

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 tablet containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

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.

The pharmaceutical compositions of the compound of formula (I) or pharmaceutically acceptable salts thereof disclosed herein can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, making sugar-coated pills, grinding, emulsifying, freeze-drying, etc.

The solid oral composition of the compound of formula (I) or its pharmaceutically acceptable salt disclosed herein 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 excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

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

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 by referring to the preparation method in WO2016095805 or WO2017215627.

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

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 in its crystalline form.

As used in this disclosure, the compound of formula (II) is in its amorphous solid form.

The dosage of the compound of formula (II), its isomers or pharmaceutically acceptable salts thereof referred to in the present disclosure is based on the molecular weight of the compound of formula (II) (calculated as C ₁₇ H ₁₉ N ₇ ) unless otherwise specified.

In some embodiments of the present disclosure, the crystals of the compound of formula (III) described in the present disclosure can be obtained by referring to the preparation method in WO2017215630.

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

In some embodiments of the present disclosure, the compound of formula (II), its isomer or pharmaceutically acceptable salt thereof is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (II), its isomer or pharmaceutically acceptable salt thereof.

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 a pharmaceutically acceptable salt thereof, calculated as the compound of formula (II). Alternatively, the pharmaceutical composition of the compound of formula (II), its isomer, or a pharmaceutically acceptable salt thereof is prepared so that a unit dosage contains 5 mg of the compound of formula (II), its isomer, or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (II).

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.

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.

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 isomers or pharmaceutically acceptable salts thereof is a solid pharmaceutical composition containing the compound of formula (II) or a pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula (II), its isomers or pharmaceutically acceptable salts thereof is a tablet containing the compound of formula (II) or pharmaceutically acceptable salts thereof.

The pharmaceutical composition of the compound of formula (II), its isomers or pharmaceutically acceptable salts thereof disclosed herein may further contain a pharmaceutically acceptable carrier and/or excipient.

The pharmaceutical compositions of the compound of formula (II), its isomers or pharmaceutically acceptable salts thereof disclosed herein can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

The solid oral composition of the compound of formula (II) of the present disclosure, 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 a sugar-coated agent. Suitable auxiliary materials include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

Administration

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

The components of the pharmaceutical composition of the present disclosure can be administered individually or in part or in whole by various suitable routes, including but not limited to, orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present disclosure can be administered individually or in part or in whole by oral administration or injection, such as intravenous or intraperitoneal injection.

The components of the pharmaceutical composition of the present invention can be in the form of suitable dosage forms, either independently or in combination, including but not limited to tablets, buccal tablets, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.

The components in the pharmaceutical combination of the present disclosure may each independently, or some or all of them may contain a pharmaceutically acceptable carrier and/or excipient.

The pharmaceutical combination of the present disclosure may further comprise an additional therapeutic agent. In one embodiment, the additional therapeutic agent may be a proliferative disease therapeutic agent known in the art.

Technical Effects

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 good indicators: a high proportion of subjects with a spleen volume reduction of ≥35% at the end of week 24 of treatment (SVR35), a good splenic response, a good MF-related symptom score, a good molecular response, a good response in subjects with high-risk mutations, 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.

The pharmaceutical combination of the present disclosure will be helpful in at least one or more of the following aspects:

(1) Compared with the administration of any drug in the combination alone, it produces better therapeutic effects in the treatment of myelofibrosis, including but not limited to the above indicators, and has excellent synergistic effects;

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

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

(4) provide a longer survival time (e.g., median survival, progression-free survival, or overall survival) for the patients treated;

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

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

Definition and Description

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.

As used herein, the term "pharmaceutical combination" 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 "pharmaceutical combination" and "drug combination" are used interchangeably herein.

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.

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.

The term "administer" means to physically introduce 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, as well as in vivo electroporation. Administration can also be performed, for example, once, multiple times, and/or over one or more extended time periods.

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.

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

The term "pharmaceutically acceptable salt" or "pharmaceutically usable salt" includes salts formed between basic ions and free acids or salts formed between acid ions and free bases.

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.

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."

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.

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.

The term "multiple doses" consists of a plurality of single doses.

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

The term "daily dose" refers to the dose administered to a patient on a daily basis.

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.

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.

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

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

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.

Example 1 Determination of HEL cell proliferation inhibitory activity

Well-growing HEL cells were collected into centrifuge tubes, the cell density was adjusted to 5×10 ⁴ cells/mL, and the cells were seeded onto 96-well plates (100 μL/well). The cells were cultured overnight. Compounds were added using a nanoliter pipette to a final concentration of 1000 nM to 0.061 nM. Two replicate wells were set up for single-drug groups (compounds of Formula (I), such as Formula IA, Formula IB, Formula IC, or Formula ID) and a control group; and combination groups (compounds of Formula (I), such as Formula IA, Formula IB, Formula IC, or Formula ID combined with compounds of Formula (II), such as Formula (III)) and a control group. After further culture in a cell culture incubator for 72 hours, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL/well) was added. After incubation in a cell culture incubator for 4 hours, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and dose-effect curves were fitted to calculate IC ₅₀ and synergy index (CI) values.

Example 2 Pharmacodynamic Evaluation in a Subcutaneous Xenograft Tumor Model of HEL Erythroleukemia Mice Expressing JAK2 ^V617F

SPF female CB-17 SCID mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) were subcutaneously inoculated in the right axilla with 1× ^10⁷ cells/mouse expressing JAK2 ^V617F (mixed with Matrigel at a 1:1 ratio). Animals were divided into groups when the average tumor volume reached approximately 200 ^mm⁻³ .

The day of grouping was designated Day 0. Starting from Day 0, the treatment group received daily gavage administration of the drug, while the vehicle control group received an equal volume of vehicle daily. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

The detection indicators and calculation formulas are as follows:

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.

Relative tumor volume, RTV=TV _t /TV ₀ ; wherein TV ₀ is the tumor volume on day 0, and TV _t is the tumor volume at each measurement.

Relative tumor growth rate, T/C (%) = _TRTV / _CRTV × 100%, where _TRTV is the RTV of the treatment group; _CRTV is the RTV of the vehicle control group.

Tumor growth inhibition rate, TGI (%) = (1-TW/TW ₀ ) × 100%; wherein, TW is the tumor weight of the treatment group, and TW ₀ is the tumor weight of the vehicle control group.

Body weight change rate, WCR (%) = (Wt _t - Wt ₀ )/Wt ₀ × 100%; wherein Wt ₀ is the weight of the mouse on day 0, and Wt _t is the weight of the mouse at each measurement.

The therapeutic group is a compound of formula (I), such as a compound of formula I-A, formula I-B, formula I-C or formula I-D; or the therapeutic group is a compound of formula (I), such as a compound of formula I-A, formula I-B, formula I-C or formula I-D, in combination with a compound of formula (II), such as a compound of formula (III).

Example 3 Clinical Trial I

This study evaluates the efficacy and safety of a compound of formula (I) (e.g., a compound of formula I-A, formula I-B, formula I-C, or formula I-D) alone, or a compound of formula (I) (e.g., a compound of formula I-A, formula I-B, formula I-C, or formula I-D) in combination with a compound of formula (II) (e.g., a compound of formula (III)) in subjects with intermediate- and high-risk myelofibrosis.

3.1 Inclusion criteria:

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

2) Age: 18 years old and above (when signing the informed consent form);

3) Patients diagnosed with PMF according to the WHO criteria (2016 version), or diagnosed with Post-PV-MF or Post-ET-MF according to the IWG-MRT criteria; regardless of JAK2 mutation, they can be included in the study;

4) Patients with intermediate-risk or high-risk myelofibrosis according to the DIPSS prognostic grading criteria; or patients with high-risk myelofibrosis according to the NCCN guidelines prognostic grading criteria; both patients must have splenomegaly and other related symptoms requiring treatment and an MPN-10 score ≥ 5 points;

5) Splenomegaly;

6) peripheral blood blasts and bone marrow blasts ≤ 10%;

7) The main organ functions are normal 7 days before the first medication;

8) 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.

3.2 Investigational Drugs

Tablets of the compound of formula (I-A), strength: 100 mg/tablet; tablets of the compound of formula (III), strength: 5 mg/tablet.

3.3 Dosage regimen

Monotherapy with the compound of formula (I-A): Oral administration of the compound of formula (I-A) tablets on an empty stomach, once daily, 100 mg, 200 mg, 300 mg or 400 mg each time, at approximately the same time every morning.

Treatment with a compound of formula (I-A) in combination with a compound of formula (III): tablets of the compound of formula (I-A) are taken orally on an empty stomach, once daily, 100 mg, 200 mg, 300 mg or 400 mg each time, taken at approximately the same time every morning; tablets of the compound of formula (III) are taken orally on an empty stomach, twice daily, 10 mg or 15 mg each time, with at least 8 hours between the two doses, preferably 12 hours apart.

In the above dosing regimen, when the dose of the compound of formula (I-A) is greater than 100 mg, the subjects will uniformly receive an initial dose of 100 mg on the first day. If tolerated, the dose will be increased daily according to the regimen in Table 1 below until the target dose level is reached.

In the above dosing regimen, when the compound of formula (I-A) is used alone to treat subjects with poor efficacy of JAK inhibitors, completely stopping the treatment with JAK inhibitors (such as ruxolitinib) may cause severe withdrawal reactions, threatening the safety of the subjects. Therefore, when the compound of formula (I-A) is used alone for treatment, the JAK inhibitor can be gradually reduced or stopped, and the dosage used does not exceed the pre-enrollment dosage level.

The above dosage regimen has a cycle of 28 days (4 weeks).

Table 1. Daily escalating dosing regimen

“——” indicates that the target dose level has been achieved.

3.4 Evaluation Criteria

3.4.1 Efficacy Evaluation Criteria: Efficacy was evaluated using the 2013 ELN and IWG-MRT consensus criteria. The primary efficacy measure, spleen volume, was assessed using thin-slice unenhanced CT scans. Spleen volume and myelofibrosis efficacy were assessed every 12 weeks throughout the trial.

3.4.2 Safety evaluation standards: The NCI-CTCAE 5.0 standard was used to determine the severity of adverse events.

3.5 Trial Results: Safety: When the compound of formula (I-A) was used alone, the most common adverse events (TRAEs) were hematologic adverse events and abnormal laboratory values, mostly Grade 1-2, with no DLTs. The combination of the compound of formula (I-A) and the compound of formula (III) showed a good safety profile with no DLTs.

Efficacy: In the combination group with Formula (I-A) and Formula (III), the proportion of subjects with a ≥35% reduction in spleen volume at the end of treatment at Week 12 or Week 24 was greater than 10%, and the proportion of patients with a ≥50% reduction in the total symptom score on the MPN-SAF TSS scale at Week 12 or Week 24 was greater than 20%. In the group treated with Formula (I-A) alone, the proportion of patients with a ≥50% reduction in the total symptom score on the MPN-SAF TSS scale at Week 12 or Week 24 was greater than 20%.

Table 2 shows representative cases:

Table 2

“—” means not evaluated.

Claims (15)

Use of 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, in the preparation of a medicament for treating myelofibrosis,
wherein R ¹ is selected from hydrogen, halogen or C _1-6 alkyl; Ring A is selected from 5-6 membered heterocycloalkyl, R ² is independently selected from 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, -COR ^a , -SO ₂ R ^b , or C _1-6 alkyl optionally substituted by halogen; R ^a or R ^b are each independently selected from H, 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, or C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with halogen, CN, -N(C _1-6 alkyl) ₂ , -NHC _1-6 alkyl, or -OC _1-6 alkyl; m is selected from 0, 1, 2 or 3. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating myelofibrosis, wherein the structural fragment Selected from Alternatively, R ¹ is selected from hydrogen, halogen or C _1-3 alkyl; alternatively, R ¹ is selected from hydrogen, fluorine, chlorine or methyl; alternatively, R ¹ is selected from hydrogen, chlorine or methyl; alternatively, Ring A is selected from 6-membered heterocycloalkyl; alternatively, Ring A is selected from 6-membered heterocycloalkyl containing one or more O atoms; alternatively, Ring A is selected from dioxane or pyran ring; alternatively, R ² is independently selected from 4-6 membered heterocycloalkyl, C _4-6 cycloalkyl, -COR ^a , -SO ₂ R ^b , or C _1-4 alkyl optionally substituted by halogen; alternatively, R ^a or R ^b is independently selected from H, 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, or C _1-4 alkyl, said C _1-4 alkyl being optionally substituted by halogen, CN, -N(C _1-4 alkyl) ₂ , -NHC _1-4 alkyl, or -OC _1-4 alkyl; alternatively, R ² is independently selected from -C(O)H, -COC(CH ₃ ) ₃ , _-COCF3 , _-COCH2CN , _-COCH2N ( _CH3 ) _{2 , -SO2CH2CH3} , _-SO2CF3 , _-SO2C2F5 , _-CF3 , _-C2F5 , tetrahydropyran, monooxetane, _{-SO2 -} cyclopropane, -CO-cyclopropane, -CO- _monooxetane , _-SO2 - _monooxetane , or -SO2 _{- cyclobutane} ; or, m is selected from 0 or 1 _; Alternatively, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from a compound of formula IA, formula IB, formula IC, or formula ID, or a pharmaceutically acceptable salt thereof,

A pharmaceutical combination comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and a compound of formula (II), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof,
wherein R ¹ is selected from hydrogen, halogen or C _1-6 alkyl; Ring A is selected from 5-6 membered heterocycloalkyl, R ² is independently selected from 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, -COR ^a , -SO ₂ R ^b , or C _1-6 alkyl optionally substituted by halogen; R ^a or R ^b are each independently selected from H, 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, or C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with halogen, CN, -N(C _1-6 alkyl) ₂ , -NHC _1-6 alkyl, or -OC _1-6 alkyl; m is selected from 0, 1, 2 or 3. A pharmaceutical combination comprising a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and ruxolitinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof,
wherein R ¹ is selected from hydrogen, halogen or C _1-6 alkyl; Ring A is selected from 5-6 membered heterocycloalkyl, R ² is independently selected from 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, -COR ^a , -SO ₂ R ^b , or C _1-6 alkyl optionally substituted by halogen; R ^a or R ^b are each independently selected from H, 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, or C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with halogen, CN, -N(C _1-6 alkyl) ₂ , -NHC _1-6 alkyl, or -OC _1-6 alkyl; m is selected from 0, 1, 2 or 3. The pharmaceutical combination according to claim 3 or 4, which contains 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg 80 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg or 2000 mg, or a range formed by any of the foregoing values, or a pharmaceutical composition thereof; Alternatively, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, containing 10-1200 mg, 10-1000 mg, 10-800 mg, 100-1200 mg, 100-800 mg, 100-500 mg, 100-400 mg, 200-800 mg, 200-400 mg, 100-600 mg, 200-600 mg, 10-100 mg, 10-200 mg or 10-400 mg of the compound of formula (I); Alternatively, a pharmaceutical composition containing 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); Alternatively, the composition contains 100 mg, 200 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The pharmaceutical combination according to claim 3, which contains 1-50 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-20 mg, 10-15 mg of the compound of formula (II), its stereoisomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof; Alternatively, a pharmaceutical composition 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 a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (II); Alternatively, a pharmaceutical composition containing 5 mg, 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 (II); Alternatively, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt, or its pharmaceutical composition contains 10 mg, 15 mg or 20 mg of the compound of formula (II). The pharmaceutical combination according to claim 4, comprising 1-50 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-20 mg, 10-15 mg of ruxolitinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; Alternatively, a pharmaceutical composition 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 ruxolitinib, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; Alternatively, containing 5 mg, 10 mg, 15 mg or 20 mg of ruxolitinib, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; Alternatively, the invention contains 10 mg, 15 mg or 20 mg of ruxolitinib, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Use of the pharmaceutical combination according to any one of claims 3 to 7 in the preparation of a medicament for treating myelofibrosis. The use according to claim 1 or 8, wherein 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 patients diagnosed with PMF according to the WHO criteria (2016 edition), or patients diagnosed with Post-PV-MF or Post-ET-MF according to the IWG MRT criteria; Alternatively, the myelofibrosis is JAK2 mutation myelofibrosis; Alternatively, the myelofibrosis is myelofibrosis without JAK2 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. The use according to claim 9, wherein the myelofibrosis is selected from myelofibrosis that has not been well treated with previous JAK inhibitors, wherein the JAK inhibitor is selected from one or more of Tofacitinib, Ruxolitinib, Baricitinib, Pefitinib, Delgocitinib, Fedratinib, Upadacitinib, Filgotinib, Abrocitinib, Pacritinib, Deucravacitinib and the compound of formula (II), its isomers or pharmaceutically acceptable salts thereof. The pharmaceutical combination according to claim 3, which contains 10-1200 mg, 10-1000 mg, 10-800 mg, 100-1200 mg, 100-800 mg, 100-500 mg, 100-400 mg, 200-800 mg, 200-400 mg, 100-600 mg, 200-600 mg, 10-100 mg, 10-200 mg or 10-400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 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 (I). mg of a pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses, wherein the pharmaceutical composition of a 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose, and the pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose; equally preferably, the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof is a multiple dose, and the pharmaceutical composition of a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is a multiple dose; Alternatively, a pharmaceutical composition comprising 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg or 600 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 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 The pharmaceutical composition of the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is a single dose or 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 multiple dose; equally 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 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof 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 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; equally 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, the pharmaceutical composition contains 100 mg, 200 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and 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 (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), 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; equally 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. The pharmaceutical combination according to claim 4, which contains 10-1200 mg, 10-1000 mg, 10-800 mg, 100-1200 mg, 100-800 mg, 100-500 mg, 100-400 mg, 100-300 mg, 200-800 mg, 200-400 mg, 100-600 mg, 200-600 mg, 10-100 mg, 10-200 mg or 10-400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 1-50 mg, 5-50 mg, A pharmaceutical composition of 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-20 mg, 10-15 mg or 20-30 mg of ruxolitinib, 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 ruxolitinib 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 ruxolitinib is a multiple dose; equally 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 ruxolitinib is a multiple dose; Alternatively, a pharmaceutical composition containing 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg or 600 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 of ruxolitinib, 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 ruxolitinib 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 ruxolitinib is a multiple dose; equally 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 ruxolitinib is a multiple dose; Alternatively, a pharmaceutical composition containing 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof and 10 mg, 15 mg or 20 mg of ruxolitinib, calculated as the 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 ruxolitinib 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 ruxolitinib is a multiple dose; equally 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 ruxolitinib is a multiple dose; Alternatively, the pharmaceutical composition contains 100 mg, 200 mg or 300 mg of the compound of formula (I) or its pharmaceutically acceptable salt and 10 mg or 15 mg of ruxolitinib, calculated as the compound of formula (I), wherein the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a single dose or multiple doses, wherein the pharmaceutical composition of ruxolitinib 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 ruxolitinib is a multiple dose; equally preferably, the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a multiple dose, and the pharmaceutical composition of ruxolitinib is a multiple dose. The use according to claim 1 or 8, wherein the treatment cycle of the compound of formula (I) or a pharmaceutically acceptable salt thereof can be every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks or every 6 weeks as one treatment cycle; preferably, every 4 weeks as one treatment cycle; 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 compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 100 mg; or a daily dose of 200 mg; or a daily dose of 300 mg; or a daily dose of 400 mg; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 100 mg; or a daily dose of 200 mg; or a daily dose of 300 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 100 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 200 mg or 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple dose is composed of a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; Alternatively, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day continuously on the 1st to 28th days of each treatment cycle. The pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt administered on the 1st day of the first treatment cycle is a single dose, and the single dose is 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt; the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt administered on the 2nd to 28th days is a multiple dose, and the multiple dose is 200 mg of the compound of formula (I) or its pharmaceutically acceptable salt, and the multiple dose consists of a single dose. The present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the dosage is 100 mg; the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily continuously from day 1 to day 28 of the second treatment cycle, wherein each dosage 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 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple dose is composed of a single dose of 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; starting from the third treatment cycle, the administration mode of each treatment cycle is the same as that of the second treatment cycle; Alternatively, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day continuously on the 1st to 28th days of each treatment cycle. The pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt administered on the 1st day of the first treatment cycle is a single dose, and the single dose is 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt; the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt administered on the 2nd day of the first treatment cycle is a multiple dose, and the multiple dose is 200 mg of the compound of formula (I) or its pharmaceutically acceptable salt, and the multiple dose consists of a single dose of 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt; the compound of formula (I) or its pharmaceutically acceptable salt administered on the 3rd to 28th days of the first treatment cycle is a multiple dose. The pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily from day 1 to day 28 of the second treatment cycle, wherein each dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a multiple dose, wherein the multiple dose is 300 mg of the compound of formula (I) or its pharmaceutically acceptable salt, and the multiple dose is composed of a single dose of 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt; the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily from day 1 to day 28 of the second treatment cycle, wherein each dose of the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is a multiple dose, wherein the multiple dose is 300 mg of the compound of formula (I) or its pharmaceutically acceptable salt, and the multiple dose is composed of a single dose of 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt; starting from the third treatment cycle, the administration mode of each treatment cycle is the same as that of the second treatment cycle; Alternatively, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day continuously on the 1st to 28th days of each treatment cycle. The pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt administered on the 1st day of the first treatment cycle is a single dose, and the single dose is 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt; the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt administered on the 2nd day of the first treatment cycle is a multiple dose, and the multiple dose is 200 mg of the compound of formula (I) or its pharmaceutically acceptable salt, and the multiple dose consists of a single dose of 100 mg of the compound of formula (I) or its pharmaceutically acceptable salt; the compound of formula (I) or its pharmaceutically acceptable salt administered on the 3rd to 28th days of the first treatment cycle is a multiple dose. The pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day continuously from day 1 to day 28 of the second treatment cycle, and the pharmaceutical composition of the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day continuously ... The use according to claim 8, wherein the compound of formula (II), its stereoisomer, or pharmaceutically acceptable salt thereof has the same treatment cycle as the compound of formula (I) or its pharmaceutically acceptable salt, for example, every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks or every 6 weeks is a treatment cycle; preferably, every 4 weeks is a treatment cycle; 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 daily on days 1 to 28 of each treatment cycle; Alternatively, the compound of formula (II), its stereoisomer, or its pharmaceutically acceptable salt is 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; 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 pharmaceutical combination is administered in multiple doses, and the multiple doses consist of a single dose of 5 mg of the pharmaceutical composition of the compound of formula (II), its stereoisomer, or a pharmaceutically acceptable salt thereof. The use according to claim 8, wherein the ruxolitinib or a pharmaceutically acceptable salt thereof and the compound of formula (I) 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; preferably, every 4 weeks is a treatment cycle; Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof and ruxolitinib 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 ruxolitinib or a pharmaceutically acceptable salt thereof being administered twice daily on days 1 to 28 of each treatment cycle; Alternatively, ruxolitinib or a pharmaceutically acceptable salt thereof is 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; Alternatively, ruxolitinib or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 20 mg; or, a daily dose of 30 mg; Alternatively, ruxolitinib or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is administered in multiple doses, wherein the multiple doses consist of a single dose of 5 mg of the pharmaceutical composition of ruxolitinib or a pharmaceutically acceptable salt thereof.