Application of pyrrolopyrimidine compound in treatment of middle-high risk myelofibrosis

Abstract

The invention belongs to the field of medical chemistry, and relates to application of pyrrolopyrimidine compounds in treatment of middle-risk or high-risk myelofibrosis, in particular to application of compounds shown as a formula I, stereoisomers of the compounds, or pharmaceutically acceptable salts of the compounds, or pharmaceutical compositions containing the compounds in treatment of middle-risk or high-risk myelofibrosis. The compound as shown in the formula I, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof has a good treatment effect. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202380028670.1, application date March 20, 2023, and invention name “Use of pyrrolopyrimidine compounds in the treatment of intermediate and high-risk myelofibrosis”. Technical Field

[0002] The present application belongs to the field of medicinal chemistry and relates to the use of pyrrolopyrimidine compounds in treating intermediate- and high-risk myelofibrosis, and specifically relates to the use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in treating intermediate- or high-risk myelofibrosis. Background Art

[0003] Janus kinases (JAKs) are a class of non-receptor tyrosine kinases (PTKs) found intracellularly, transducing cytokine-stimulated signals through the JAK-STAT pathway. The JAK-STAT pathway transmits extracellular chemical signals across the cell membrane to gene promoters located on DNA within the cell nucleus, ultimately influencing changes in DNA transcription and activity levels in the cell. The JAK-STAT pathway consists of three main components: 1) receptors; 2) Janus kinases (JAKs); and 3) signal transducers and activators of transcription (STATs). The receptor can be activated by interferons, interleukins, growth factors or other chemical messengers, which leads to the autophosphorylation of JAK; STAT protein then binds to the phosphorylated receptor, causing STAT to be phosphorylated by JAK; the phosphorylated STAT protein then dissociates from the receptor, dimerizes and translocates into the cell nucleus to bind to specific DNA sites and alter transcription (Scott, MJ, CJ Godshall et al. (2002). "Jaks, STATs, Cytokines, and Sepsis" Clin Diagn Lab Immunol 9(6): 1153-9).

[0004] The JAK family plays a role in cell proliferation and functional cytokine-dependent regulation of immune responses. Currently, there are four known mammalian JAK family members: JAK1, JAK2, JAK3, and TYK2 (Tyrosine kinase 2). The size range of JAK proteins is 120-140 kDa, and they contain 7 conserved JAK homology (JH) domains; one of which is a functional catalytic kinase domain, and the other is a pseudokinase domain that effectively plays a regulatory role and / or acts as a docking site for STAT (Scott, Godshall et al. 2002, supra).

[0005] Myelofibrosis (MF) is a chronic, progressive myeloproliferative neoplasm caused by collagen proliferation in the hematopoietic tissue of the bone marrow, resulting in fibrous tissue that 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, and early-stage patients can often survive for 10 years or longer. However, the overall median survival is 5 to 7 years, with the median survival for high-risk or mid-risk patients being 2.7 years.

[0006] 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. SUMMARY OF THE INVENTION

[0007] In one aspect, the present application provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for treating intermediate-risk or high-risk myelofibrosis that has previously failed ruxolitinib treatment:

[0008]

[0009] On the other hand, the present application provides a pharmaceutical composition for treating intermediate-risk or high-risk myelofibrosis that has failed previous treatment with ruxolitinib, wherein the pharmaceutical composition comprises a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0010] On the other hand, the present application provides a method for treating intermediate-risk or high-risk myelofibrosis that has failed previous treatment with ruxolitinib, comprising administering to the patient an effective amount of the compound of formula I as described above, its stereoisomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0011] On the other hand, the present application provides the use of the compound of formula I as described above, its stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of a drug for treating intermediate-risk or high-risk myelofibrosis that has failed previous treatment with ruxolitinib.

[0012] On the other hand, the present application provides the use of the compound of formula I as described above, its stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the treatment of intermediate-risk or high-risk myelofibrosis that has failed previous treatment with ruxolitinib. Detailed Description of the Invention

[0013] The present application provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for treating intermediate-risk or high-risk myelofibrosis that has failed prior ruxolitinib treatment:

[0014]

[0015] On the other hand, the present application provides a pharmaceutical composition for treating intermediate-risk or high-risk myelofibrosis that has failed previous treatment with ruxolitinib, wherein the pharmaceutical composition comprises a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0016] On the other hand, the present application provides a method for treating intermediate-risk or high-risk myelofibrosis that has previously failed treatment with ruxolitinib, comprising administering to a patient in need thereof an effective amount of a compound of Formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0017] On the other hand, the present application provides the use of a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating intermediate-risk or high-risk myelofibrosis that has previously failed treatment with ruxolitinib.

[0018] On the other hand, the present application provides the use of a compound of formula I as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the treatment of intermediate-risk or high-risk myelofibrosis that has previously failed treatment with ruxolitinib.

[0019] In some embodiments of the present application, the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof described herein are used as a single active agent. In some embodiments of the present application, the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof described herein are used as the sole active agent.

[0020] In some embodiments of the present application, the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt described in the present application can be a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0021] In some embodiments of the present application, the pharmaceutical composition described herein may further include a pharmaceutically acceptable adjuvant (also referred to as "pharmaceutically acceptable carrier", "pharmaceutical excipient"). The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with a suitable pharmaceutically acceptable adjuvant, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc. The pharmaceutical composition of the present application can be manufactured using methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill methods, grinding methods, emulsification methods, freeze-drying methods, etc. Suitable adjuvants include, but are not limited to, adhesives, diluents, wetting agents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0022] In some embodiments of the present application, the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, pills, pastes, powders, etc., with tablets and capsules being preferred. The oral preparation can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art. Pharmaceutically acceptable carriers include diluents, binders, wetting agents, disintegrants, lubricants, etc. Diluents include microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, or mixtures thereof; binders include hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, gelatin, polyvinyl pyrrolidone, starch, sucrose, glucose, or mixtures thereof; wetting agents include magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate, micropowdered silica, or mixtures thereof; disintegrants include sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methylcellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl methylcellulose, or cross-linked polyvinylpyrrolidone, or mixtures thereof; lubricants include magnesium stearate, colloidal silicon dioxide, talc, polyethylene glycol, stearic acid, sodium stearyl fumarate, or mixtures thereof. Pharmaceutical excipients also include colorants, sweeteners, and coating agents.

[0023] The compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt

[0024] In some embodiments of the present application, the compound of formula I described in the present application is a compound of formula II

[0025] The compounds of formula I and formula II of the present application can be prepared by referring to the preparation methods in WO2016095805 or WO2017215627.

[0026] In some embodiments of the present application, the compound of formula I or the compound of formula II is administered in the form of a free base. In some embodiments of the present application, the compound of formula I or the compound of formula II is administered in the form of a crystalline free base. In some embodiments of the present application, the free base crystals of the compound of formula II can be selected from Form A or Form B disclosed in WO2017215630.

[0027] In some embodiments of the present application, the compound of formula II is administered in the form of a hydrochloride. In some embodiments of the present application, the hydrochloride of the compound of formula II can be selected from the hydrochlorides disclosed in WO2017101777.

[0028] Myelofibrosis

[0029] In some embodiments of the present application, the myelofibrosis includes primary myelofibrosis (PMF), myelofibrosis secondary to polycythemia vera (Post-PV-MF), and myelofibrosis secondary to essential thrombocythemia (Post-ET-MF).

[0030] In some embodiments of the present application, the treatment failure includes refractory and / or relapse and / or intolerance.

[0031] In some schemes of the present application, the term "refractory" refers to a patient who has taken ruxolitinib for a cumulative period of ≥3 months, and MRI or CT examination shows that the spleen volume is reduced by <10% or increased compared with before taking ruxolitinib, or palpation shows that the spleen is reduced by <30% or increased compared with before taking the JAK inhibitor (such as ruxolitinib).

[0032] In some schemes of the present application, the recurrence refers to the patient taking ruxolitinib treatment for a cumulative period of ≥3 months, and compared with before taking the JAK inhibitor (such as ruxolitinib), the spleen enlarges again after response and the spleen volume is reduced by <10% on MRI or CT examination compared with before taking ruxolitinib, or the spleen is reduced by <30% on palpation.

[0033] In some schemes of this application, the intolerance refers to patients who have taken ruxolitinib for a cumulative period of ≥28 days (excluding those caused by allergies) and: still require red blood cell transfusions or increase the frequency of transfusions during ruxolitinib treatment, or have a decrease in platelet count of grade 3 or above, or have anemia of grade 3 or above, or have hematoma or bleeding of grade 3 or above.

[0034] In some embodiments of the present application, the myelofibrosis is intermediate-risk or high-risk myelofibrosis that is refractory and / or relapsed and / or intolerant to ruxolitinib.

[0035] In some schemes of the present application, the myelofibrosis is myelofibrosis in which the patient has been treated with ruxolitinib for a cumulative period of ≥3 months, and MRI or CT examination shows that the spleen volume is reduced by <10% or increased compared with before taking ruxolitinib, or palpation shows that the spleen is reduced by <30% or increased compared with before taking ruxolitinib.

[0036] In some schemes of the present application, the myelofibrosis is myelofibrosis in which the patient has been treated with ruxolitinib for a cumulative period of ≥3 months, and the spleen has enlarged again after response compared with before taking ruxolitinib, and the spleen volume has decreased by <10% on MRI or CT examination compared with before taking ruxolitinib, or the spleen has decreased by <30% on palpation.

[0037] In some schemes of the present application, the myelofibrosis is myelofibrosis in which the patient has been treated with ruxolitinib for a cumulative period of ≥28 days (excluding allergic causes) and: still requires red blood cell transfusion or increased transfusion frequency during ruxolitinib treatment, or has a decrease in platelet count of grade 3 or above, or has anemia of grade 3 or above, or has hematoma or bleeding of grade 3 or above.

[0038] In some embodiments of the present application, the myelofibrosis is that the patient's spleen margin reaches or exceeds at least 5 cm below the ribs on palpation.

[0039] In some embodiments of the present application, the myelofibrosis is when the patient's peripheral blood primitive cells and bone marrow primitive cells are both ≤ 10%.

[0040] In some schemes of the present application, the patients with myelofibrosis did not receive growth factors and / or colony stimulating factors and / or thrombopoietic factors and / or platelet transfusions within 2 weeks before the examination, and the hemoglobin (HGB) was ≥80 g / L and the platelet count (PLT) was ≥100×10 within 7 days before the first medication. 9 / L and neutrophil absolute count (NEUT) ≥1.0×10 9 / L.

[0041] In the present application, the myelofibrosis includes myelofibrosis with gene mutations, and the mutated genes include but are not limited to JAK2 (e.g., JAK2 V617F), MPL, CALR, ASXL1 / SRSF2 / IDH1 / 21, JAK2 exon 12, TP53, SH2B3 / IDH2 / U2AF1 / SF3B1 / EZH2 / TP53, MPL p.W515L / K, CALR Type 1 / Type 1-like, triple negative (JAK2, MPL, and CALR without mutations), ASXL1, EZH2, IDH1 / 2, SRSF2, SF3B1, CALR / ASXL1, TP53, or U2AF1 Q157.

[0042] Dosage regimen

[0043] In some of the schemes of the present application, the dosing cycle for treating the patient's intermediate-risk or high-risk myelofibrosis is 2 to 6 weeks. In some of the schemes of the present application, the dosing cycle for treating the patient's intermediate-risk or high-risk myelofibrosis is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or a range formed by any of the above values. In some of the schemes of the present application, the dosing cycle for treating the patient's intermediate-risk or high-risk myelofibrosis is 4 weeks. In some of the schemes of the present application, a compound of formula I of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them is administered to a patient with intermediate-risk or high-risk myelofibrosis who has failed ruxolitinib treatment with a dosing cycle of 2 to 6 weeks, for example, 3 to 5 weeks, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks. In some of the schemes of the present application, during the dosing cycle, the patient is administered a compound of formula I of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising them, every day or at regular intervals.

[0044] The amount of the compound of the present application, its stereoisomer, or pharmaceutically acceptable salt thereof can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health status of the patient, for example, based on the results of a routine blood test of the subject / patient, including platelet count, neutrophil count, or hemoglobin concentration. In some embodiments, the daily dose of the compound of the present application, its stereoisomer, or pharmaceutically acceptable salt thereof is 1 mg to 100 mg. In some embodiments, the daily dose of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can be selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg, or a range consisting of any of the foregoing values as endpoints or any value therein, for example, 1 mg to 90 mg, 5 mg to 80 mg, 10 mg to 70 mg, 15 mg to 60 mg, 20 mg to 50 mg, 20 mg to 40 mg, 30 mg to 40 mg, etc. In some specific embodiments, the daily dose of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can be selected from 1 mg to 50 mg, 5 mg to 50 mg, 5 mg to 45 mg, 5 mg to 40 mg, 10 mg to 35 mg, 10 mg to 30 mg, 20 mg to 40 mg, 30 mg to 40 mg. In some specific embodiments, the daily dose of the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can be selected from 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg or 50 mg, or a range consisting of any of the aforementioned values as endpoints or any value therein, for example, 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5 mg to 20 mg, 20 mg to 40 mg, 30 mg to 40 mg, etc.

[0045] The compounds of the present application, their stereoisomers, or pharmaceutically acceptable salts thereof can be administered once or more daily. In some embodiments, the compounds of the present application, their stereoisomers, or pharmaceutically acceptable salts thereof are administered once or twice daily. In some embodiments, the compounds of the present application, their stereoisomers, or pharmaceutically acceptable salts thereof are administered twice daily.

[0046] The compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can also be administered in a single dose. In one embodiment, the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt is administered once or twice a day in a single dose. In one embodiment, the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt is administered once or twice a day in a single dose of an oral solid formulation. In a specific embodiment, the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt is administered twice a day in a single dose of an oral solid formulation.

[0047] The compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt can also be administered in multiple doses. In one embodiment, the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt is administered once or twice daily in multiple doses. In one embodiment, it is administered once or twice daily in multiple doses of oral solid formulations. In a specific embodiment, the compound of the present application, its stereoisomer, or its pharmaceutically acceptable salt is administered twice daily in multiple doses of oral solid formulations.

[0048] In some embodiments of the present application, the compound of formula I, its stereoisomer or its pharmaceutically acceptable salt is provided in the form of a pharmaceutical composition, preferably a single-dose pharmaceutical composition. In some embodiments, the pharmaceutical composition contains 1mg to 50mg of the compound of the present application, its stereoisomer or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition contains 1mg, 2mg, 5mg, 8mg, 10mg, 12mg, 15mg, 18mg, 20mg, 22mg, 25mg, 28mg, 30mg, 32mg, 35mg, 38mg, 40mg, 42mg, 45mg, 48mg or 50mg or any of the aforementioned values as the scope of endpoints or any value therein, the compound of the present application, its stereoisomer or its pharmaceutically acceptable salt, such as 2mg to 50mg, 10mg to 40mg, 5mg to 30mg, 5mg to 20mg, 20mg to 40mg, 30mg to 40mg, etc.

[0049] In some embodiments of the present application, the pharmaceutical composition of the compound of Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is provided in the form of a daily dose. In some embodiments of the present application, the pharmaceutical composition of the compound of Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is administered in two doses per day. In some embodiments of the present application, each dose of the two doses is the same.

[0050] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is administered in doses twice a day, with each dose being a single dose or multiple doses.

[0051] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered in doses twice daily, each dose being a multiple dose consisting of a single dose of 5 mg, 10 mg, 15 mg and / or 20 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt. In some embodiments of the present application, the pharmaceutical composition consists of a single dose of 5 mg of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0052] In some schemes of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is packaged in a kit, and the kit also contains instructions for the use of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt or pharmaceutical composition for treating intermediate-risk or high-risk myelofibrosis after previous treatment with ruxolitinib; further preferably, the kit also contains instructions for the use of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt or pharmaceutical composition for treating intermediate-risk or high-risk myelofibrosis that is refractory and / or relapsed and / or intolerant to ruxolitinib treatment.

[0053] In some embodiments of the present application, in the method or use for treating intermediate-risk or high-risk myelofibrosis previously treated with ruxolitinib, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is provided in the form of a daily dose, which is administered in the following manner: the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered once or twice a day; in some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice a day, and each dose is the same; in some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice a day, and each dose is the same, and each administration is separated by at least 8 hours; in some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is administered twice a day, and each dose is the same, and each administration is separated by 12 hours.

[0054] In some schemes of the present application, in the method or use for treating intermediate-risk or high-risk myelofibrosis after previous treatment with ruxolitinib, the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is provided in the form of a daily dose, which is administered as follows: the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day on an empty stomach, with the same dose each time and an interval of 12 hours between each administration.

[0055] In some embodiments of the present application, in the method or use for treating intermediate-risk or high-risk myelofibrosis after previous treatment with ruxolitinib, the dose of the pharmaceutical composition of the compound of Formula I, its stereoisomer, or its pharmaceutically acceptable salt is 1 mg to 50 mg per dose. In some embodiments, the dose of the pharmaceutical composition is 5 mg to 30 mg per dose. In some embodiments, the dose of the pharmaceutical composition is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or any of the aforementioned values as endpoints or any value therein, for example, 5 mg to 30 mg, 5 mg to 25 mg, 5 mg to 20 mg, 5 mg to 15 mg, 10 mg to 20 mg, 10 mg to 20 mg, 10 mg to 15 mg, etc. In some embodiments, the dose of the pharmaceutical composition is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg. In some embodiments, the dose of the pharmaceutical composition is 15 mg per dose.

[0056] In some embodiments of the present application, in the method or use for treating intermediate-risk or high-risk myelofibrosis after previous treatment with ruxolitinib, the daily dose of the pharmaceutical composition of the compound of Formula I, its stereoisomer, or its pharmaceutically acceptable salt is 1 mg to 50 mg. In some embodiments, the daily dose of the pharmaceutical composition is 5 mg to 50 mg. In some embodiments, the daily dose of the pharmaceutical composition is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or any of the aforementioned values as endpoints or any value therein, for example, 5 mg to 50 mg, 10 mg to 50 mg, 15 mg to 40 mg, 15 mg to 30 mg, 20 mg to 40 mg, 20 mg to 30 mg, etc. In some embodiments, the daily dose of the pharmaceutical composition is 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg. In some embodiments, the daily dose of the pharmaceutical composition is 30 mg.

[0057] In some regimens of the present application, 28 days constitutes a treatment cycle, and the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is continuously administered daily from day 1 to day 28 of each cycle.

[0058] In some regimens of the present application, 28 days constitutes a treatment cycle, and the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice daily on days 1 to 28 of each cycle.

[0059] In some schemes of the present application, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day continuously on days 1 to 28 of each cycle, with each dose of the pharmaceutical composition being 15 mg.

[0060] In some schemes of the present application, 28 days is a treatment cycle, and the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is administered twice a day continuously on days 1 to 28 of each cycle, with each dose of the pharmaceutical composition being 15 mg and the daily dose being 30 mg.

[0061] In some schemes of the present application, 28 days is a treatment cycle, and the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt administered in each treatment cycle is 140 to 840 mg (calculated as the active ingredient formula (I) compound itself). In some schemes of the present application, the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is selected from 140 mg, 280 mg, 420 mg, 560 mg, 700 mg, 840 mg or the range formed by any two of the above values (calculated as the active ingredient formula (I) compound itself). In some schemes of the present application, the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is preferably 560 to 840 mg (calculated as the active ingredient formula (I) compound itself). In some schemes of the present application, the total dose of the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt is preferably 840 mg (calculated as the active ingredient formula (I) compound itself).

[0062] In some embodiments of the present application, the above-mentioned treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

[0063] The compounds of the present application, their stereoisomers, or pharmaceutically acceptable salts thereof can be administered by a variety of routes, including but not limited to the following: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, by inhalation, vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular or intrathecal. In a specific embodiment, the compound is administered orally.

[0064] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof can be formulated into a dosage form suitable for oral administration to humans, such as but not limited to tablets, pills, capsules, powders or granules.

[0065] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt may be in the form of a single-day dosing formulation or a single-cycle dosing formulation. In some embodiments, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt may be in the form of a single-day dosing formulation comprising 1 or more (e.g., 1-6) discrete units, each of which contains 5 mg-30 mg of the compound of formula I. In some embodiments, the pharmaceutical composition of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt may be in a single-cycle dosing formulation comprising discrete units, each of which contains 5 mg-30 mg of the compound of formula I.

[0066] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is an oral tablet (eg, a scored tablet).

[0067] In some embodiments of the present application, the single-dose strength of the oral tablet of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salt is 5 mg.

[0068] Technical Effects

[0069] The compound of formula I of the present application, its stereoisomer or its pharmaceutically acceptable salt or its pharmaceutical composition can have good therapeutic effect, which is embodied in, but not limited to, better disease control rate, longer survival (such as median survival, progression-free survival or overall survival), and longer duration of disease remission (DOR). The compound of formula I of the present application, its stereoisomer or its pharmaceutically acceptable salt or its pharmaceutical composition can have good safety when having good therapeutic effect, including but not limited to a lower incidence of adverse reactions.

[0070] Definition and Description

[0071] Unless otherwise indicated, the terms used in this application have the following meanings. A specific term, unless specifically defined, should not be construed as undefined or unclear, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding commercial product or its active ingredient.

[0072] 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.

[0073] All patents, patent applications and other identified publications are expressly incorporated herein by reference for the purposes of description and disclosure. Any citation of such publications herein does not constitute an admission that the publication becomes part of the common general knowledge in the art.

[0074] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are 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.

[0075] The term "pharmaceutically acceptable salt" includes salts formed between an alkali ion and a free acid or between an acid ion and a free base. The pharmaceutically acceptable salt described herein is selected from maleate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, malonate, succinate, fumarate, malate, mandelate, tartrate, citrate, ascorbate, palmitate, benzoate, phenylacetate, cinnamate, salicylate, methanesulfonate, benzenesulfonate or methylbenzenesulfonate.

[0076] As used herein, the amount of the compound of Formula I, such as the amount administered, dosage, or content in a pharmaceutical composition, is calculated as its free base.

[0077] As used herein, the compounds in the present pharmaceutical combination may form acid addition salts if they have, for example, at least one basic center. If desired, corresponding acid addition salts with additionally present basic centers may also be formed. Compounds having at least one acidic group (e.g., COOH) may also form salts with bases. If, for example, the compound contains both a carboxyl group and an amino group, corresponding inner salts may also be formed.

[0078] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0079] The term "patient" refers to mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some embodiments, the patient is a human.

[0080] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or drug combinations thereof, or salts or stereoisomers thereof, and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention, or drug combinations thereof, to a subject.

[0081] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect, including partial or complete stabilization or cure of a disease and / or an effect resulting from a disease. As used herein, "treat" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

[0082] The term "effective amount" means an amount of a compound of the present invention that (i) treats a particular disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0083] The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single dose; or each bottle of injection is a single dose.

[0084] The term "multiple doses" consists of a plurality of single doses.

[0085] The terms "administering" and "administering" refer to the physical introduction of a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral administration.

[0086] The term "daily dose" refers to the dose administered to a patient daily.

[0087] The term "per dose" refers to a single dose administered to a patient.

[0088] 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.

[0089] Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise. DETAILED DESCRIPTION

[0090] The present invention is described in more detail by way of specific examples. The following examples are provided for illustrative purposes and should not be construed as limiting the present invention in any way.

[0091] Preparation Example 1: Preparation of 5 mg tablet solid pharmaceutical composition

[0092] The formulation composition of the 5mg tablet solid pharmaceutical composition is shown in Table 1:

[0093] Table 1 Composition of 5mg tablets

[0094] Element Prescription composition (mg) Compound of formula II 5 Mannitol 35.275 microcrystalline cellulose 70 Croscarmellose sodium 3.6 Sodium lauryl sulfate 0.125 Hydroxypropyl cellulose 4.8 magnesium stearate 1.2 purified water appropriate amount

[0095] Preparation process:

[0096] 1) Mix mannitol, microcrystalline cellulose, and croscarmellose sodium, and retain the resulting mixture A;

[0097] Preparation of the API suspension: Dissolve hydroxypropyl cellulose in the prescribed amount of purified water to prepare a 4% (w / w) hydroxypropyl cellulose solution; dissolve sodium lauryl sulfate; add the compound of formula II and stir to disperse to obtain the API suspension;

[0098] 2) Fluidized Bed Granulation and Drying: The API suspension was sprayed onto Mixture A for fluidized bed granulation. Granulation parameters: inlet air temperature 55-80°C, atomization pressure 600-1000 mbar, material temperature 25-35°C; drying was performed after spraying, with drying ending when the material temperature was above 45°C; granulation was performed using a granulation machine with a sieve aperture of 0.6-1.2 mm to obtain dry granules.

[0099] 3) The granulated dry granules and magnesium stearate are sequentially put into a hopper mixer and mixed thoroughly, and the obtained solid pharmaceutical composition is tableted.

[0100] Example 1 Clinical protocol for intermediate-risk or high-risk myelofibrosis after previous treatment with ruxolitinib

[0101] 1.1 Dosage regimen

[0102] Dosage: Orally take 15 mg twice daily on an empty stomach, with at least 8 hours between doses, preferably 12 hours. Each dosing cycle is 4 weeks. Dose adjustment may be made if toxic reactions related to the study drug occur.

[0103] Drug: Tablets of the compound of formula I, 5 mg strength, wherein the compound of formula I is represented by its stereoisomer compound of formula II 1.2 Inclusion criteria

[0104] 1) The subjects voluntarily participated in this study, signed the informed consent form, and had good compliance.

[0105] 2) Age: 18 years and above (at the time of signing the informed consent); ECOGPS score: 0-2 points; expected survival time is more than 24 weeks;

[0106] 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;

[0107] 4) Patients with intermediate-risk or high-risk myelofibrosis according to the DIPSS prognostic grading criteria;

[0108] 5) MF subjects who have previously received ruxolitinib treatment and are refractory / relapsed / intolerant (refractory: patients who have taken ruxolitinib for a total of ≥3 months, and MRI or CT examinations show that the spleen volume is reduced by <10% or enlarged compared with the pre-ruxolitinib period, or the spleen is reduced by <30% or enlarged compared with the pre-ruxolitinib period on palpation; relapse: patients who have taken ruxolitinib for a total of ≥3 months, and the spleen enlarges again after responding to ruxolitinib and the spleen volume is reduced by <10% on MRI or CT examination, or the spleen is reduced by <30% on palpation compared with the pre-ruxolitinib period; intolerance: patients who have taken ruxolitinib for a total of ≥28 days (excluding allergic reactions) and still require red blood cell transfusions or increase the frequency of transfusions during ruxolitinib treatment, or develop grade 3 or higher thrombocytopenia, grade 3 or higher anemia, or grade 3 or higher hematoma or bleeding);

[0109] 6) Splenomegaly: the spleen margin reaches or exceeds at least 5 cm below the ribs on palpation;

[0110] 7) Peripheral blood blasts and bone marrow blasts ≤ 10%;

[0111] 8) No growth factors, colony stimulating factors, thrombopoietic factors or platelet transfusions were received within 2 weeks before the examination, and hemoglobin (HGB) ≥ 80 g / L and platelet count (PLT) ≥ 100 × 10 within 7 days before the first medication. 9 / L and neutrophil absolute count (NEUT) ≥1.0×10 9 / L;

[0112] 9) Seven days before the first dose, the major organ functions were normal, that is, they met the following criteria: total bilirubin (TBIL) ≤ 2 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN; serum creatinine (Cr) ≤ 1.5 times ULN or creatinine clearance (Ccr) ≥ 50 ml / min; coagulation function tests must meet the following requirements: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (not receiving anticoagulant therapy); left ventricular ejection fraction (LVEF) assessed by cardiac ultrasound ≥ 50%;

[0113] 10) 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.

[0114] 1.3 Evaluation Method

[0115] 1.3.1 Effectiveness Evaluation

[0116] The 2013 ELN and IWG MRT consensus criteria were used to evaluate the efficacy.

[0117] Starting from Day 1 of Cycle 1, spleen volume assessment and myelofibrosis efficacy assessment will be performed every 12 weeks ± 3 days until the patient experiences radiographic disease progression. If there is a discrepancy between spleen palpation and CT results during the efficacy assessment, the CT result will prevail.

[0118] Evaluation indicators:

[0119] The proportion of subjects who achieved a ≥35% reduction in spleen volume at the end of treatment at Week 24 (SVR35);

[0120] Splenic response: ① Best efficacy: the proportion of subjects with at least one spleen volume reduction of ≥35% compared to baseline; ② Onset of effect: the time interval from the first dose to the date when the spleen volume was first reduced by ≥35% compared to baseline; ③ Duration of spleen volume reduction of ≥35% compared to baseline (DoMSR): the time interval from the date when the spleen volume was first reduced by ≥35% compared to baseline to the date when the spleen volume was reduced by <35% compared to baseline;

[0121] MF-related symptom scores: ① The proportion of subjects whose total symptom score on the Myeloproliferative Neoplasms Symptom Assessment Form-Total Symptom Score (MPN-SAFTSS) decreased by ≥50% compared with baseline at week 24; ② The decrease in the total symptom score on the MPN-SAFTSS compared with baseline;

[0122] Progression-free survival (PFS): The time interval from the first dose to the date of occurrence of any of the following events, whichever occurs first: ① spleen volume increases by ≥25% compared with the screening period; ② death caused by any cause;

[0123] Leukemia-free survival (LFS): The time interval from the first dose of the drug to the date of any of the following events, whichever occurs first: ① the date when the first bone marrow smear shows blasts ≥ 20%; ② the date when the first peripheral blood smear shows blasts ≥ 20% and the absolute number of blasts ≥ 1×10 9 / L and lasts for at least 2 weeks; ③ Death caused by any reason;

[0124] Overall survival (OS): The time from the first dose of the drug to death from any cause.

[0125] 1.3.2 Safety evaluation

[0126] The severity of adverse events was assessed using the NCI CTCAE 5.0 standard.

[0127] 1.4 Effect Data

[0128] 1.4.1 Validity

[0129] The subjects showed stable disease or partial remission after treatment with the above clinical regimen. Specific data are shown in the table below:

[0130]

[0131]

[0132] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementation modes and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, which all fall within the scope of protection of the present application.

Claims

1. Use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating intermediate-risk or high-risk myelofibrosis that has failed prior treatment with ruxolitinib:

2. The use of the compound of formula I, its stereoisomer, or its pharmaceutically acceptable salt according to claim 1, wherein: The compound of formula I, its stereoisomer, or pharmaceutically acceptable salt thereof is administered to a patient in need thereof at a daily dose of 1 mg to 100 mg; preferably, the daily dose is 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg, or a range consisting of any of the aforementioned values as endpoints or any value therein, for example, 1 mg to 90 mg, 5 mg to 80 mg, 10 mg to 70 mg, 15 mg to 60 mg, 20 mg to 50 mg, 20 mg to 40 mg, 30 mg to 40 mg; further preferably, the daily dose is 1 mg More preferably, the daily dose is 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg or 50 mg, or a range consisting of any of the aforementioned values as endpoints or any value therein, for example, 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5 mg to 20 mg, 20 mg to 40 mg, 30 mg to 40 mg.

3. The use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2, wherein: The compound of formula I, its stereoisomer, or pharmaceutically acceptable salt thereof is administered to a patient in need once or more daily; preferably, the compound of formula I, its stereoisomer, or pharmaceutically acceptable salt thereof is administered to a patient in need once or twice daily; preferably, 28 days is a treatment cycle, and the compound of formula I, its stereoisomer, or pharmaceutically acceptable salt thereof is administered continuously daily on days 1 to 28 of each cycle.

4. The use of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein: The compound of formula I is a compound of formula II:

5. Use of a pharmaceutical composition in the preparation of a medicament for treating intermediate-risk or high-risk myelofibrosis that has failed previous treatment with ruxolitinib, wherein: The pharmaceutical composition comprises a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

6. The use of the pharmaceutical composition according to claim 5, wherein The pharmaceutical composition is administered in two doses per day, each dose being a multiple dose consisting of a single dose of 5 mg, 10 mg, 15 mg and / or 20 mg of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; or preferably, the pharmaceutical composition consists of a single dose of 5 mg of a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. The use of the pharmaceutical composition according to claim 5 or 6, wherein The pharmaceutical composition is provided in the form of a daily dose, which is administered as follows: the pharmaceutical composition of the compound of Formula I, its stereoisomers, or pharmaceutically acceptable salts thereof is administered once or twice daily; preferably, the pharmaceutical composition is administered twice daily, and the dose is the same each time; further preferably, the pharmaceutical composition is administered twice daily, and the dose is the same each time, and the interval between each administration is at least 8 hours.

8. Use of the compound of formula I according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, or use of the pharmaceutical composition according to claim 5, wherein: The myelofibrosis includes primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (Post-PV-MF), and post-essential thrombocythemia myelofibrosis (Post-ET-MF).

9. Use of the compound of formula I according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, or use of the pharmaceutical composition according to claim 5, wherein: The treatment failure includes refractory and / or relapse and / or intolerance.

10. Use of the compound of formula I according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, or use of the pharmaceutical composition according to claim 5, wherein: The myelofibrosis includes myelofibrosis with gene mutations, and the mutated genes include JAK2, JAK2 V617F, MPL, CALR, ASXL1 / SRSF2 / IDH1 / 21, JAK2exon 12, TP53, SH2B3 / IDH2 / U2AF1 / SF3B1 / EZH2 / TP53, MPL p.W515L / K, CALR Type 1 / Type1-like, triple negative (JAK2, MPL, and CALR no mutation), ASXL1, EZH2, IDH1 / 2, SRSF2, SF3B1, CALR / ASXL1, TP53, or U2AF1 Q157.

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