Pharmaceutical combinations of 1, 3, 5-triazine derivatives

Abstract

The invention relates to a pharmaceutical composition of a 1, 3, 5-triazine derivative, in particular to a pharmaceutical composition of a compound shown as a formula I, a tautomer or pharmaceutically acceptable salt of the compound and azacitidine and medical application of the pharmaceutical composition. # imgabs0 #

Description

Drug combinations of 1,3,5-triazine derivatives

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202210803457.0 filed with the State Intellectual Property Office of China on July 7, 2022, and the contents disclosed in said application are incorporated herein by reference in their entirety. Technical Field

[0003] The present application belongs to the field of medicinal chemistry and relates to a pharmaceutical combination of 1,3,5-triazine derivatives, and specifically relates to a pharmaceutical combination of a compound of formula I, its tautomers or pharmaceutically acceptable salts thereof and its medical uses. Background Art

[0004] Isocitrate dehydrogenase (IDH) is a family of oxidoreductases that uses NAD + or NADP + As a coenzyme, it catalyzes the oxidative decarboxylation of isocitrate into α-ketoglutarate (α-KG), and at the same time converts NAD + or NADP + Reduction to NADH or NADPH. The generated α-KG and NADH / NADPH participate in a variety of important physiological functions in the body, including DNA and histone demethylation, oxidative energy supply of the tricarboxylic acid cycle, fatty acid biosynthesis, and the reduced state of glutathione. The IDH enzyme family consists of three main members: NADP-dependent IDH1 and IDH2, and NAD-dependent IDH3. IDH2 mutations are associated with the development and progression of various malignancies. When somatic mutations occur in the gene encoding IDH2, the residues in the enzyme's active site are altered, conferring new functions on the mutant cell, catalyzing the conversion of α-KG to 2-hydroxyglutarate (2-HG). Inhibiting the mutant IDH2 enzyme, thereby suppressing downstream 2-HG levels and reducing DNA and histone methylation levels, allows somatic cells to resume normal growth and proliferation, making it an effective target for tumor treatment. Azacitidine is a DNA methyltransferase inhibitor that nonspecifically reduces DNA methylation levels by inhibiting DNA methyltransferase activity. The combined use of IDH2 mutant protein inhibitors and azacitidine may produce synergistic anti-tumor effects.

[0005] WO2017016513 discloses a series of compounds as IDH2 inhibitors, and specifically discloses a compound of formula I with the following structure:

[0006] SUMMARY OF THE INVENTION

[0007] The present application provides a pharmaceutical combination comprising a compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof and azacitidine,

[0008] In another aspect, the present application provides a pharmaceutical combination for treating a blood tumor in a patient, comprising a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and azacitidine.

[0009] In some embodiments of the present application, the drug combination is used to treat a patient's blood tumor. In some embodiments of the present application, in the drug combination, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine are each in the form of a pharmaceutical composition.

[0010] In some embodiments of the present application, in the drug combination, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially or intermittently.

[0011] In some embodiments of the present application, in the pharmaceutical combination, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine are each administered in a single dose or multiple doses.

[0012] In some embodiments of the present application, the drug combination is packaged in the same medicine box, which also includes instructions for using the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine in combination to treat blood tumors in patients.

[0013] In some embodiments of the present application, the pharmaceutical combination comprises: a pharmaceutical composition of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of azacitidine.

[0014] In some embodiments of the present application, the drug combination is packaged in the same medicine box, which also includes instructions for the combined use of a pharmaceutical composition of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of azacitidine to treat a patient's blood tumor.

[0015] In some embodiments of the present application, in the drug combination, the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine are separately packaged in respective medicine boxes, and the medicine box further includes instructions for the combined use of the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine to treat a patient's blood tumor.

[0016] On the other hand, the present application provides a drug kit comprising the drug combination of the present application and instructions for using the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine in combination to treat hematological tumors.

[0017] On the other hand, the present application provides a drug kit for treating blood tumors, which includes the drug combination of the present application and instructions for using the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine in combination to treat blood tumors.

[0018] In another aspect, the present application provides use of the above-mentioned drug combination in the preparation of a medicament for treating a blood tumor in a patient.

[0019] In another aspect, the present application provides use of the above-described drug combination in treating a blood tumor in a patient.

[0020] In another aspect, the present application provides a method for treating a hematological tumor in a patient, comprising administering to the patient a therapeutically effective amount of the drug combination described above.

[0021] In another aspect, the present application provides use of the kit described above in the preparation of a pharmaceutical / medicinal product for treating a blood tumor in a patient.

[0022] In another aspect, the present application provides use of the kit as described above in treating a hematological tumor in a patient.

[0023] In another aspect, the present application provides a method for treating a hematological tumor in a patient, the method comprising administering to the patient a therapeutically effective amount of the kit as described above.

[0024] In some embodiments of the present application, the pharmaceutical combination contains 20-500 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, calculated as the compound of formula I.

[0025] In some embodiments of the present application, the pharmaceutical combination contains 25-300 mg, 50-200 mg, 50-100 mg, 75-150 mg or 75-100 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0026] In some embodiments of the present application, the pharmaceutical combination contains 75-150 mg or 75-100 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, calculated as the compound of formula I.

[0027] In some embodiments of the present application, the pharmaceutical combination contains 75 mg, 100 mg or 150 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, calculated as the compound of formula I.

[0028] In some embodiments of the present application, the pharmaceutical combination contains 75 mg or 100 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, calculated as the compound of formula I.

[0029] In some embodiments of the present application, the pharmaceutical combination contains 100 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof, calculated as the compound of formula I.

[0030] In some embodiments of the present application, in the pharmaceutical combination, the pharmaceutical composition of the compound of formula I, its tautomers or pharmaceutically acceptable salts thereof is in a single dose or multiple dose form. In some embodiments of the present application, in the pharmaceutical combination, the composition of the compound of formula I, its tautomers or pharmaceutically acceptable salts thereof is in a multiple dose form.

[0031] In some embodiments of the present application, the content of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is a daily dose.

[0032] In some embodiments of the present application, the content of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is a once-daily dose.

[0033] In some embodiments of the present application, the content of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is a dose once a day, and each dose is a single dose or multiple doses, usually multiple doses.

[0034] In some embodiments of the present application, the pharmaceutical combination comprises a single dose of 5 mg, 25 mg and / or 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutical composition of a pharmaceutical composition of a pharmaceutical composition of a compound of Formula I. Alternatively, the pharmaceutical combination is in the form of a single-dose formulation, comprising 5 mg, 25 mg and / or 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutical composition thereof, calculated as a compound of Formula I.

[0035] In some embodiments of the present application, the pharmaceutical combination comprises a single dose of 5 mg and / or 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, calculated as a compound of Formula I. Alternatively, the pharmaceutical combination is in the form of a single-dose formulation, comprising 5 mg and / or 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as a compound of Formula I.

[0036] In some embodiments of the present application, the pharmaceutical combination comprises a single dose of 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutical composition of a pharmaceutical composition of a pharmaceutical composition, calculated as a compound of Formula I. Alternatively, the pharmaceutical combination is in the form of a single-dose formulation, comprising 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutical composition thereof, calculated as a compound of Formula I.

[0037] In some embodiments of the present application, the drug combination contains 50-150 mg / m2 based on the subject's body surface area. 2 50-100mg / m 2 or 75–100 mg / m 2 Azacitidine, or a pharmaceutical composition thereof.

[0038] In some embodiments of the present application, the drug combination contains 50 mg / m 2 , 75mg / m 2 , 100mg / m 2 or 150 mg / m 2 Azacitidine, or a pharmaceutical composition thereof.

[0039] In some embodiments of the present application, the drug combination contains 75 mg / m 2 or 100 mg / m 2 Azacitidine, or a pharmaceutical composition thereof.

[0040] In some embodiments of the present application, the drug combination contains 75 mg / m 2 Azacitidine, or a pharmaceutical composition thereof.

[0041] In some embodiments of the present application, in the drug combination, the pharmaceutical composition of azacitidine is in the form of a single dose or multiple doses.

[0042] In some embodiments of the present application, in the pharmaceutical combination, the pharmaceutical composition of azacitidine is in the form of multiple doses.

[0043] In some embodiments of the present application, in the drug combination, the pharmaceutical composition of azacitidine is a daily dose.

[0044] In some embodiments of the present application, in the drug combination, the pharmaceutical composition of azacitidine is a once-daily dose.

[0045] In some embodiments of the present application, the pharmaceutical combination contains a single dose of 100 mg of azacitidine or a pharmaceutical composition thereof. Alternatively, the pharmaceutical combination is in the form of a single-dose formulation containing 100 mg of azacitidine or a pharmaceutical composition thereof.

[0046] In some embodiments of the present application, the drug combination contains 25-500 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and 50-150 mg / m2 of the body surface area of ​​the subject. 2 Azacitidine.

[0047] In some embodiments of the present application, the drug combination contains 75-150 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I, and 75-100 mg / m2 of the body surface area of ​​the subject. 2 Azacitidine.

[0048] In some embodiments of the present application, the drug combination contains a daily dose of 75 mg, 100 mg or 150 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and 75 mg / m2 of the subject's body surface area. 2 or 100 mg / m 2 daily dose of azacitidine.

[0049] In some embodiments of the present application, the drug combination contains a daily dose of 75 mg or 100 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and 75 mg / m2 of the subject's body surface area. 2 daily dose of azacitidine.

[0050] In some embodiments of the present application, the drug combination contains a daily dose of 100 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and 75 mg / m2 of the compound of formula I, based on the body surface area of ​​the subject. 2 daily dose of azacitidine.

[0051] In some embodiments of the present invention, every 2-6 weeks is a treatment cycle, for example, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks or every 6 weeks, and the period within the range of any two days is a treatment cycle. In some embodiments of the present invention, every 28 days is a treatment cycle.

[0052] In some embodiments of the present application, the pharmaceutical combination comprises: a pharmaceutical composition comprising a single dose of 5 mg, 25 mg, and / or 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of Formula I, and a pharmaceutical composition comprising a single dose of 100 mg of azacitidine. Alternatively, the pharmaceutical combination is in the form of a single-dose formulation, comprising: a pharmaceutical composition comprising 5 mg, 25 mg, and / or 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of Formula I, and 100 mg of azacitidine or a pharmaceutical composition thereof.

[0053] In some embodiments of the present application, the pharmaceutical combination comprises: a single dose of 5 mg and / or 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, calculated as a compound of Formula I, and a single dose of 100 mg of azacitidine. Alternatively, the pharmaceutical combination is in the form of a single-dose formulation, comprising: 5 mg and / or 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as a compound of Formula I, and 100 mg of azacitidine or a pharmaceutical composition thereof.

[0054] In some embodiments of the present application, the pharmaceutical combination comprises: a single dose of 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, calculated as a compound of Formula I, and a single dose of 100 mg of azacitidine. Alternatively, the pharmaceutical combination is in the form of a single-dose formulation, comprising: 50 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as a compound of Formula I, and 100 mg of azacitidine or a pharmaceutical composition thereof.

[0055] In some embodiments of the present application, the drug combination is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition having a total dose of 1400 mg to 4200 mg of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a single dose of 100 mg of azacitidine.

[0056] In some embodiments of the present application, the drug combination is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition of a compound of formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, with a total dose of 1400 mg to 4200 mg based on the compound of formula I, and a total dose of 350 mg / m2 based on the body surface area of ​​the subject. 2 ~700 mg / m 2 A pharmaceutical composition of azacitidine.

[0057] In some embodiments of the present application, the drug combination is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition of a compound of formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, with a total dose of 2100 mg to 2800 mg based on the compound of formula I, and a total dose of 525 mg / m2 based on the body surface area of ​​the subject. 2 ~700 mg / m 2 A pharmaceutical composition of azacitidine.

[0058] In some embodiments of the present application, the drug combination is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, with a total dose of 2100 mg or 2800 mg based on the compound of Formula I, and a total dose of 525 mg / m2 based on the body surface area of ​​the subject. 2 or 700 mg / m 2 A pharmaceutical composition of azacitidine.

[0059] In some embodiments of the present application, the drug combination is a preparation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof at a total dose of 2800 mg based on the compound of Formula I, and a pharmaceutical composition of a tautomer thereof at a total dose of 525 mg / m2 based on the body surface area of ​​the subject. 2 A pharmaceutical composition of azacitidine.

[0060] In some embodiments of the present application, in the drug combination, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine can be in the form of a pharmaceutical composition separately or together.

[0061] On the other hand, the present application also provides a kit comprising (a) a first pharmaceutical composition comprising the compound of Formula I described herein, its tautomers or pharmaceutically acceptable salts thereof; and (b) a second pharmaceutical composition comprising azacitidine.

[0062] On the other hand, the present application also provides a kit of pharmaceutical compositions for treating hematological tumors in patients, comprising (a) a first pharmaceutical composition comprising a compound of Formula I described herein, a tautomer thereof, or a pharmaceutically acceptable salt thereof; and (b) a second pharmaceutical composition comprising azacitidine.

[0063] In some embodiments of the present application, in the kit, the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared as a first pharmaceutical composition containing 5 mg, 25 mg or 50 mg of the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof in a unit preparation, and the azacitidine is prepared as a second pharmaceutical composition containing 100 mg of azacitidine in a unit preparation.

[0064] In some embodiments of the present application, in the kit, the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a first pharmaceutical composition containing 5 mg or 50 mg of the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof in a unit preparation, and the azacitidine is prepared into a second pharmaceutical composition containing 100 mg of azacitidine in a unit preparation.

[0065] In some embodiments of the present application, in the kit, the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a first pharmaceutical composition containing 50 mg of the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof in a unit preparation, and the azacitidine is prepared into a second pharmaceutical composition containing 100 mg of azacitidine in a unit preparation.

[0066] On the other hand, the present application provides a drug kit comprising the drug combination of the present application and instructions for using the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine in combination to treat hematological tumors.

[0067] On the other hand, the present application provides a drug kit for treating blood tumors, which includes the drug combination of the present application and instructions for using the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof and azacitidine in combination to treat blood tumors.

[0068] In some embodiments of the present application, in the drug combination, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 5 mg, 25 mg or 50 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I, and the azacitidine is prepared as a unit preparation containing 100 mg of azacitidine.

[0069] In some embodiments of the present application, in the drug combination, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 5 mg or 50 mg of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I, and the azacitidine is prepared into a unit preparation containing 100 mg of azacitidine.

[0070] In some embodiments of the present application, in the drug combination, the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 50 mg of the compound of Formula I, its tautomer or a pharmaceutically acceptable salt thereof, calculated as the compound of Formula I, and the azacitidine is prepared into a unit preparation containing 100 mg of azacitidine.

[0071] On the other hand, the present application also provides a method for treating a patient's hematological tumor, comprising administering a therapeutically effective amount of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof and azacitidine to a patient (or individual) in need thereof, for example, administering a therapeutically effective amount of the drug combination described herein to a patient (or individual) in need thereof.

[0072] On the other hand, the present application also provides a method for treating a patient's hematological tumor, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and azacitidine, for example, administering to an individual in need thereof a therapeutically effective amount of the drug combination described above in the present application.

[0073] On the other hand, the present application also provides a combination therapy for treating an individual with a hematological tumor, the combination therapy comprising administering to the individual a therapeutically effective amount of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and administering a therapeutically effective amount of azacitidine.

[0074] In another aspect, the present application further provides the use of a compound of Formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof in combination with azacitidine in the preparation of a medicament for treating a patient's hematological tumor, such as the use of the above-mentioned drug combination in the preparation of a medicament for treating a patient's hematological tumor. In some embodiments of the present application, the drug combination is any of the drug combinations described above in the present application.

[0075] On the other hand, the present application also provides the use of a compound of formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof in combination with azacitidine for treating a patient's blood tumor, for example, the use of the above-mentioned drug combination of the present application for treating a patient's blood tumor.

[0076] In some embodiments of the present application, in the method, combination therapy or use, the definitions of the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof, and azacitidine are the same as those of the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof, and azacitidine in the drug combination described above, such as content, dosage, form of existence, packaging form, etc.

[0077] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine are each in the form of a pharmaceutical composition and can be administered simultaneously, separately, concurrently, sequentially or intermittently.

[0078] In some embodiments of the present application, in the methods, combination therapies, or uses, the compound of Formula I, its tautomers, or pharmaceutically acceptable salts thereof, and azacitidine may have the same or different treatment cycles. In some specific embodiments of the present application, in the methods, combination therapies, or uses, the compound of Formula I, its tautomers, or pharmaceutically acceptable salts thereof, and azacitidine have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks as one treatment cycle. Preferably, every 4 weeks is one treatment cycle.

[0079] In some embodiments of the present application, in the method, combination therapy or use, the content of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is a daily dose, which is administered in the following manner: the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered once a day.

[0080] In some embodiments of the present application, in the method, combination therapy or use, the content of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is a daily dose, wherein the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered in a single dose or multiple doses, usually in multiple doses; further, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered once a day in multiple doses.

[0081] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 50 mg; or, a daily dose of 75 mg; or, a daily dose of 100 mg; or, a daily dose of 150 mg.

[0082] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 75 mg; or, a daily dose of 100 mg.

[0083] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 100 mg.

[0084] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof in the pharmaceutical combination is administered in multiple doses, and the multiple doses are composed of a pharmaceutical composition with a single dose of 5 mg and / or 50 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof. In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof is administered in a continuous daily dosing manner.

[0085] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof in the pharmaceutical combination is administered in multiple doses, and the multiple doses are composed of a single dose of 50 mg of the pharmaceutical composition of the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof. In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof is administered in a continuous daily dosing manner.

[0086] In some embodiments of the present application, in the methods, conjoint therapies, or uses, the content of the compound of formula I, its tautomer, or a pharmaceutically acceptable salt thereof in the drug combination is a dosage per treatment cycle, which is administered as follows: daily administration of the compound of formula I, its tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The compound of formula I, its tautomer, or a pharmaceutically acceptable salt thereof is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots, or more).

[0087] In some embodiments of the present application, in the method, combination therapy or use, the content of azacitidine in the pharmaceutical combination is a daily dose, which is administered in the following manner: azacitidine is administered once a day.

[0088] In some embodiments of the present application, in the method, combination therapy or use, the content of azacitidine in the drug combination is a daily dose, wherein azacitidine is administered in a single dose or multiple doses, usually in multiple doses; further, wherein azacitidine is administered once a day in multiple doses.

[0089] In some embodiments of the present application, in the method, combination therapy or use, the azacitidine is administered in the following manner: a daily dose of 50 mg / m2 based on the body surface area of ​​the subject. 2 Alternatively, a daily dose of 75 mg / m 2 Alternatively, a daily dose of 100 mg / m 2 Alternatively, a daily dose of 150 mg / m 2 .

[0090] In some embodiments of the present application, in the method, combination therapy or use, the azacitidine is administered in the following manner: a daily dose of 75 mg / m2 based on the body surface area of ​​the subject. 2 Alternatively, a daily dose of 100 mg / m 2 .

[0091] In some embodiments of the present application, in the method, combination therapy or use, the azacitidine is administered in the following manner: a daily dose of 75 mg / m2 based on the body surface area of ​​the subject. 2 .

[0092] In some embodiments of the present application, in the methods, combination therapies, or uses, the azacitidine in the pharmaceutical combination is administered in multiple doses, wherein the multiple doses consist of a pharmaceutical composition having a single dose of 100 mg of azacitidine. In some embodiments of the present application, in the methods, combination therapies, or uses, the azacitidine is administered as continuous daily dosing.

[0093] In some embodiments of the present application, in the methods, combination therapies, or uses, the amount of azacitidine in the pharmaceutical combination is a dose for each treatment cycle (e.g., a 28-day treatment cycle), which is administered in the following manner: azacitidine is administered daily for the first 5-10 days (e.g., days 1-7) of each cycle, and azacitidine is not administered on the remaining days (e.g., days 8-28). Azacitidine is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots, or more).

[0094] In some embodiments of the present application, in the methods, combination therapies, or uses, the amount of azacitidine in the pharmaceutical combination is a dose for each treatment cycle (e.g., a 28-day treatment cycle), which is administered in the following manner: azacitidine is administered daily on days 1 to 7 of each cycle, and azacitidine is not administered on days 8 to 28. Azacitidine is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots, or more).

[0095] In some embodiments of the present application, in the method, combination therapy or use, 28 days is a treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula I, its tautomer or its pharmaceutically acceptable salt is continuously administered on days 1 to 28 of each treatment cycle is 1400 mg to 4200 mg (calculated as the compound of formula I). ​​In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I, its tautomer or its pharmaceutically acceptable salt is selected from 2100 mg or 2800 mg (calculated as the compound of formula I). ​​In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I, its tautomer or its pharmaceutically acceptable salt is preferably 2800 mg (calculated as the compound of formula I).

[0096] In some embodiments of the present application, in the method, combination therapy or use, 28 days is a treatment cycle, and a total dose of 350 mg / m2 of azacitidine is continuously administered on days 1 to 7 of each treatment cycle. 2 ~700 mg / m 2 In some regimens, the total dose of azacitidine is selected from 525 mg / m 2 or 700 mg / m 2 In some regimens, the total dose of azacitidine is preferably 525 mg / m 2 .

[0097] In some embodiments of the present application, in the method, combination therapy or use, 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula I, its tautomer 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, its tautomer or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 2100 mg or 2800 mg (calculated as the compound of formula I); and azacitidine is administered once a day on days 1 to 7 of each treatment cycle, and the total dose of azacitidine administered in each treatment cycle is 525 mg / m 2 or 700 mg / m 2 .

[0098] In some embodiments of the present application, in the method, combination therapy or use, 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula I, its tautomer 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, its tautomer or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 2800 mg (calculated as the compound of formula I); and azacitidine is administered once a day on days 1 to 7 of each treatment cycle, and the total dose of azacitidine administered in each treatment cycle is 525 mg / m 2 .

[0099] In the present application's regimen, the above treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

[0100] Compound of formula I, its tautomer or its pharmaceutically acceptable salt

[0101] In some embodiments of the present application, the compound of formula I described in the present application can be obtained by referring to the preparation method in WO2017016513 or WO2018133856.

[0102] The compounds of Formula I of the present application can be administered in their free base form, or in the form of their pharmaceutically acceptable salts, hydrates, and prodrugs, which are converted in vivo to the compounds of Formula I. For example, pharmaceutically acceptable salts of the compounds of Formula I are within the scope of the present application, and such salts can be produced from various organic and inorganic acids according to methods well known in the art.

[0103] Regarding the pharmaceutically acceptable salts of the compounds of Formula I described herein, the molar ratio of the compound of Formula I to the acid ion forming the pharmaceutically acceptable salt may be 1:1.

[0104] As used herein, the pharmaceutically acceptable salt of the compound of formula I may be a methanesulfonate salt of the compound of formula I, such as a monomethanesulfonate salt (monomesylate salt) of the compound of formula I. The dosage of the compound of formula I, its tautomers, or pharmaceutically acceptable salts thereof referred to herein, unless otherwise indicated, is based on the molecular weight (in C) of the compound of formula I. 19 H 17 F6N7O meter).

[0105] In some embodiments of the present application, the monomethanesulfonate of the compound of formula I described in the present application can be obtained by referring to the preparation method in WO2018133856.

[0106] Pharmaceutical compositions of compounds of formula I, their tautomers or their pharmaceutically acceptable salts

[0107] In some embodiments of the present application, the compound of formula I, its tautomer, or a pharmaceutically acceptable salt thereof is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, its tautomer, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments of the present application, the pharmaceutical composition contains a single dose of 5 mg, 25 mg, or 50 mg of the compound of Formula I, its tautomer, or a pharmaceutically acceptable salt thereof, calculated as the compound of Formula I. Alternatively, the pharmaceutical composition of the compound of Formula I, its tautomer, or a pharmaceutically acceptable salt thereof is prepared as a unit dosage form containing 5 mg, 25 mg, or 50 mg of the compound of Formula I, its tautomer, or a pharmaceutically acceptable salt thereof, calculated as the compound of Formula I.

[0109] In some embodiments of the present application, the pharmaceutical composition contains a single dose of 5 mg or 50 mg of the compound of Formula I, its tautomer, or a pharmaceutically acceptable salt thereof, calculated as the compound of Formula I. Alternatively, the pharmaceutical composition of the compound of Formula I, its tautomer, or a pharmaceutically acceptable salt thereof is prepared as a unit dosage containing 5 mg or 50 mg of the compound of Formula I, its tautomer, or a pharmaceutically acceptable salt thereof, calculated as the compound of Formula I.

[0110] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0111] In some embodiments of the present application, the pharmaceutical composition is in a formulation suitable for administration by various routes, including but not limited to, formulations suitable for oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes) administration.

[0112] In some embodiments of the present application, the pharmaceutical composition is in a suitable dosage form, 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), emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.

[0113] In some embodiments of the present application, 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.

[0114] In some embodiments of the present application, the pharmaceutical composition is a solid pharmaceutical composition.

[0115] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition containing the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is a tablet containing the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof.

[0117] The pharmaceutical composition of the compound of formula I, its tautomers or pharmaceutically acceptable salts thereof of the present application may further contain a pharmaceutically acceptable carrier and / or excipient and / or auxiliary material.

[0118] The pharmaceutical compositions of the compound of formula I, its tautomers or pharmaceutically acceptable salts thereof of the present application 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.

[0119] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then processing the mixture into granules to obtain tablets, capsules, or dragee cores. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0120] Azacitidine

[0121] As used herein, azacitidine is chemically known as 5-azacytidine, and has the structure shown in the following formula II:

[0122] In some embodiments of the present application, the pharmaceutical composition of azacitidine further comprises a pharmaceutically acceptable carrier and / or excipient and / or auxiliary material. Preferably, the pharmaceutically acceptable auxiliary material includes a filler, an absorbent, a wetting agent, a binder, a disintegrant, a lubricant, water for injection, etc.

[0123] In some embodiments of the present application, the pharmaceutical composition is in a preparation for use in various suitable ways, including but not limited to, a preparation suitable for oral or parenteral administration (by intravenous, intramuscular, topical or subcutaneous route). In some embodiments, the drug combination is suitable for oral administration or injection administration, such as intravenous or subcutaneous injection.

[0124] In some embodiments of the present application, the pharmaceutical composition is in a suitable dosage form, 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), emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.

[0125] In some embodiments of the present application, the azacitidine is in the form of an injectable preparation.

[0126] This application uses any commercially available form of azacitidine, including but not limited to azacitidine for injection produced by Zhengda Tianqing Pharmaceutical Group Co., Ltd. (trade name ).

[0127] In some embodiments of the present application, the azacitidine pharmaceutical composition is a single dose of 100 mg of azacitidine for injection.

[0128] Hematologic malignancies

[0129] In some embodiments of the present application, the blood tumor is a myeloid tumor.

[0130] In some embodiments of the present application, the myeloid neoplasms include chronic myeloproliferative diseases, myelodysplasia / myeloproliferative diseases, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

[0131] In some embodiments of the present application, the blood tumor is selected from myelodysplastic syndrome and acute myeloid leukemia.

[0132] In some embodiments of the present application, the blood tumor is selected from acute myeloid leukemia.

[0133] In some embodiments of the present application, the hematological tumor patient is a patient with advanced hematological tumor.

[0134] In some embodiments of the present application, the hematological tumor patient is a patient with advanced hematological malignancy.

[0135] In some embodiments of the present application, the blood tumor is a blood tumor with an IDH2 gene mutation.

[0136] In some embodiments of the present application, the IDH2 gene mutation includes but is not limited to one or more mutations of R140Q, R140G, R140L, R140W, R172K, R172S, R172M, R172G or R172W.

[0137] In some embodiments of the present application, the hematological tumor is a refractory and / or relapsed advanced hematological tumor.

[0138] In some embodiments of the present application, the hematological tumor is refractory and / or relapsed myelodysplastic syndrome.

[0139] In some embodiments of the present application, the blood tumor is refractory and / or relapsed acute myeloid leukemia.

[0140] In some embodiments of the present application, the relapse refers to the reappearance of >5% of primitive cells in the bone marrow after complete remission, or the reappearance of bone marrow primitive cells in the peripheral blood; or the appearance of extramedullary lesions.

[0141] In some embodiments of the present application, the hematological malignancy patient is a treatment-naive myelodysplastic syndrome patient or a treatment-naive acute myeloid leukemia patient.

[0142] In some embodiments of the present application, the hematological tumor patient is a myelodysplastic syndrome patient who is unable to receive standard treatment due to age, physical condition, or the presence of risk factors and is receiving the first treatment, or an acute myeloid leukemia patient who is unable to receive standard treatment due to age, physical condition, or the presence of risk factors and is receiving the first treatment.

[0143] In some embodiments of the present application, the myelodysplastic syndrome patient is a myelodysplastic syndrome patient with extremely high risk (>6 points), high risk (>4.5 points-≤6 points), or intermediate risk (>3 points-≤4.5 points) according to the revised International Prognostic Scoring System (IPSS-R).

[0144] In some embodiments of the present application, the hematological tumor patient is a hematological tumor patient who has previously received previous treatment.

[0145] In some embodiments of the present application, the hematological malignancy patient is a hematological malignancy patient whose disease progressed during previous drug treatment or who did not achieve complete remission (CR) within 3-5 cycles of treatment or who achieved complete remission with incomplete hematological recovery (CRi).

[0146] In some embodiments of the present application, the hematological tumor patient is a hematological tumor patient whose disease progresses during treatment with the compound of formula I or who does not achieve complete remission (CR) within 3-5 cycles of treatment or who achieves complete remission with incomplete hematological recovery (CRi).

[0147] In some embodiments of the present application, the hematological malignancy patient is a hematological malignancy patient who has previously received one or more prior treatments. In some embodiments, the hematological malignancy patient is a hematological malignancy patient who has previously received one, two, three, four or five prior treatments.

[0148] In some embodiments of the present application, the prior treatment includes supportive care, drug therapy or hematopoietic stem cell transplantation.

[0149] In some schemes of the present application, the supportive care includes component transfusion therapy, erythropoietin (EPO) therapy, granulocyte colony-stimulating factor (G-CSF) therapy, granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy, or iron removal therapy. In some schemes of the present application, the iron removal therapy drugs include deferoxamine, deferasirox, etc.

[0150] In some embodiments of the present application, the drugs used for the drug treatment include but are not limited to cytarabine, idarubicin, daunorubicin, homoharringtonine, aclarubicin, mitoxantrone, fludarabine, cladribine, decitabine, venetoclax, etoposide, azacitidine, ivosidenib, enasidinib, glasdegib, thalidomide, lenalidomide, gemtuzumab ozogamicin, danazol, stanozolol, testosterone undecanoate, gilteritinib, sorafenib, or a combination of one or more of the above drugs.

[0151] In some embodiments of the present application, the blood tumor optionally includes any one or a combination of two or more of the above-mentioned types of blood tumors.

[0152] The azacitidine described in this application is azacitidine for injection, and the administration method is subcutaneous injection.

[0153] The dosage of subcutaneous azacitidine described in this application is calculated based on the patient's body surface area. The body surface area calculation formula is: body surface area BSA (㎡) = 0.00616 × height (cm) + 0.01286 × weight (kg) - 0.1529.

[0154] The dosage of subcutaneous azacitidine administered in this application can be adjusted in subsequent treatment cycles. For example, if no beneficial effect is observed after two treatment cycles and no toxicity other than nausea and vomiting occurs, the dosage can be increased, for example, from the daily dose of 75 mg / m2 in the first treatment cycle to 2 Increase to 100 mg / m2 daily 2 The administration method of the subsequent treatment cycle is the same as that of the first treatment cycle.

[0155] Administration

[0156] The following does not limit the administration method of the drug combination of the present application.

[0157] The components of the drug combination of the present application can be administered independently or partially or all thereof together in 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 drug combination of the present application can be administered independently or partially or all thereof together orally or by injection, such as intravenous or subcutaneous injection.

[0158] The components of the pharmaceutical combination of the present application can be in the form of suitable dosage forms, either independently or in part or in whole, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.

[0159] Technical Effects

[0160] The drug combination of the present application has good safety and anti-tumor activity, and patients have good tolerance in receiving the treatment of the drug combination of the present application. The drug combination of the present application has a higher complete remission (CR) rate and a complete remission (CRi) rate with incomplete hematological recovery, a good ECOG score, a better disease control rate (DCR) and objective response rate (ORR), a longer duration of disease remission (DOR), and a longer survival period (such as median survival, progression-free survival or overall survival) in the treated patients.

[0161] The drug combination of the present application also has synergistic anti-tumor activity. Specifically, the drug combination of the present application has a higher complete remission (CR) rate, complete remission with incomplete hematological recovery (CRi) rate or objective response rate (ORR) than treatment with the compound of Formula I or azacitidine alone.

[0162] Definition and Description

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] The term "pharmaceutically acceptable salts" includes salts formed between basic ions and free acids or between acid ions and free bases.

[0168] As used herein, the content of the compound of formula I, its tautomers, or pharmaceutically acceptable salts thereof, such as the amount administered, dosage, or content in a pharmaceutical composition, is calculated based on the free base form.

[0169] 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.

[0170] The terms "patient," "subject," or "individual" are mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals, and the terms are used interchangeably herein. In some embodiments, the patient, subject, or individual is a human.

[0171] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, their isomers (e.g., tautomers), or salts thereof, and a pharmaceutically acceptable carrier and / or excipient and / or adjuvant. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention, their isomers (e.g., tautomers), or salts thereof to a patient.

[0172] 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.

[0173] 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.

[0174] The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine, for example, each tablet of medicine is a single dose; a box of medicine has seven capsules, each capsule is a single dose; or each bottle of injection is a single dose.

[0175] The term "relapsed" refers to the reappearance of ≥5% blasts in the bone marrow or bone marrow blasts in the peripheral blood after complete remission, or the appearance of extramedullary lesions. As used herein, relapsed acute myeloid leukemia (AML) refers to the reappearance of leukemic cells in the peripheral blood or ≥5% blasts in the bone marrow after complete remission of AML, or the appearance of extramedullary leukemic cell infiltration.

[0176] The term "refractory" includes patients who have not responded to two courses of standard treatment; patients who have relapsed within 12 months after complete remission and received consolidation and intensive treatment; patients who have relapsed after 12 months but have not responded to conventional chemotherapy; patients who have relapsed twice or more; and patients with persistent extramedullary leukemia.

[0177] The term "complete remission" refers to a bone marrow blast count of <5%, no Auer bodies, no extramedullary lesions, and a neutrophil count >1.0 × 10 9 / L, platelet count>100×10 9 / L; and not dependent on red blood cell transfusion.

[0178] The term "complete remission with incomplete hematologic recovery" refers to complete remission with the exception of a decrease in the residual neutrophil count (ANC < 1.0 × 10 9 / L) or decreased platelet count (PLT < 100 × 10 9 / L), all CR standards are met.

[0179] The term "combination" refers to a fixed combination in a dosage unit form, or a non-fixed combination (or kit of parts) for co-administration, wherein the compound of formula I and the other active ingredient in the combination can be administered separately at the same time or separately at certain time intervals. The term "fixed combination" refers to that the active ingredients, such as the compound of formula I and the other active ingredient in the combination are administered to the patient simultaneously as a single entity or dosage. The term "non-fixed combination" or "kit of parts" refers to that the active ingredients, such as the compound of formula I and the other active ingredient in the combination are each administered to the patient simultaneously or sequentially (without specific time limits) as separate entities.

[0180] The terms "administered in combination" and the like are intended to encompass the administration of selected therapeutic agents (ie, active ingredients) to a single patient, and are intended to include treatment regimens in which the therapeutic agents are not necessarily administered by the same route of administration or at the same time. DETAILED DESCRIPTION

[0181] 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.

[0182] Example 1 Tablets of the compound of formula I

[0183] The monomethanesulfonate of the compound of formula I is sieved and mixed with microcrystalline cellulose, mannitol, hydroxypropyl methylcellulose, cross-linked carboxymethyl cellulose sodium and sodium lauryl sulfate, and dry granulated. After the granules are granulated, magnesium stearate is added and mixed evenly, and dry-compressed on a tablet press to form tablets.

[0184] Example 2: Clinical trial of hematological tumors

[0185] This study enrolls patients with newly diagnosed AML / MDS who are not suitable for standard treatment regimens, or patients whose disease progresses during treatment with Formula I monotherapy with mesylate tablets or who do not achieve CR / CRi within 3-5 cycles of treatment. The study drugs are both Formula I monotherapy tablets combined with azacitidine for injection. The purpose of this study is to evaluate the safety and efficacy of Formula I monotherapy tablets combined with azacitidine for injection.

[0186] 2.1 Trial Drugs and Dosage Regimens

[0187] 2.1.1 Trial Drugs:

[0188] Tablets of the methanesulfonate salt of the compound of formula I, with a specification of 5 mg / tablet or 50 mg / tablet.

[0189] Azacitidine for injection, specification 100mg / bottle.

[0190] 2.1.2 Dosage regimen:

[0191] Tablets of the methanesulfonate salt of the compound of formula I: daily dose is 75 mg or 100 mg, taken orally on an empty stomach, once a day, for 28 consecutive days.

[0192] Days constitute a treatment cycle.

[0193] Azacitidine for injection: 1 treatment cycle is 28 days, with 75 mg / m2 subcutaneously injected daily on days 1 to 7 of each cycle 2 Azacitidine.

[0194] 2.2 Inclusion criteria

[0195] 1) Age ≥18 years; ECOG performance status: 0-1; expected survival ≥12 weeks;

[0196] 2) Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) diagnosed according to the World Health Organization (WHO) classification

[0197] Subjects, including AML subjects, should meet one of the following criteria:

[0198] a) Refractory or relapsed AML;

[0199] b) Subjects with newly diagnosed AML who are unable to receive standard treatment due to age, physical condition, or risk factors, as recognized by the investigator;

[0200] MDS subjects fall into the following prognostic risk categories according to the Revised International Prognostic Scoring System (IPSS-R):

[0201] a) Extremely high risk (>6 points)

[0202] b) High risk (>4.5 points to ≤6 points)

[0203] c) Intermediate risk (>3 points to ≤4.5 points)

[0204] 3) IDH2 gene mutation is confirmed;

[0205] 4) Platelet count (PLT) ≥ 20 × 10 9 / L (acceptable if blood transfusion reaches this standard); or PLT < 20 × 10 9 / L, but the subjects' condition is due to tumor reasons approved by the researchers;

[0206] 5) Liver function:

[0207] ALT, AST, ALP ≤ 2.5 × upper limit of normal (ULN), unless considered to be caused by leukemia;

[0208] Serum total bilirubin ≤1.5×ULN (for subjects with Gilbert syndrome, BIL ≤3×ULN);

[0209] 6) Renal function: serum Cr ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL / min;

[0210] 7) Toxic reactions caused by surgery, radiotherapy or other anti-tumor treatments have recovered to ≤ Grade I;

[0211] 8) Females must agree to use contraceptive measures (such as intrauterine devices [IUDs], birth control pills, or condoms) during the study and within 6 months after the study; the serum pregnancy test must be negative within 7 days before study enrollment, and the subjects must be non-breastfeeding; males must agree to use contraceptive measures during the study and within 6 months after the study; the subjects voluntarily participate in this study, sign the informed consent form, and have good compliance.

[0212] 2.3 Evaluation methods and indicators

[0213] Safety evaluation criteria: The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

[0214] Effectiveness evaluation criteria: The International Working Group (IWG) criteria were used to evaluate efficacy. Improvement or deterioration of general condition was expressed by the change in ECOG score before and after treatment.

[0215] 2.4 Test results

[0216] Of the 8 evaluable patients, 6 achieved a CR (complete response) for the best efficacy evaluation, with a CR rate of 75%. The drug combination of this application demonstrated good tolerability and safety, with overall manageable adverse events. The drug combination of this application also demonstrated significant clinical benefit.

[0217] Table 2 shows the experimental results of representative cases.

[0218] Table 2

[0219] Note: "C1D28" indicates that the drug is administered for one treatment cycle with 28 days as one cycle; "C2D28" indicates that the drug is administered for two consecutive treatment cycles with 28 days as one cycle; "SD" indicates stable disease; "CR" indicates complete remission; "CRi" indicates complete remission with incomplete hematological recovery; " / " indicates that efficacy evaluation was not performed; "--" indicates that the data are not yet available.

Claims

1. A pharmaceutical combination comprising a compound of formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof and azacitidine, 2. A pharmaceutical combination for treating a hematological tumor in a patient, comprising a compound of formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and azacitidine.

3. The pharmaceutical combination according to claim 1 or 2, wherein the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof and azacitidine are each in the form of a pharmaceutical composition; preferably, the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof is in the form of a tablet, and the azacitidine is azacitidine for injection.

4. The pharmaceutical combination according to any one of claims 1 to 3, comprising 20-500 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I; further, comprising 25-300 mg, 50-200 mg, 50-100 mg, 75-150 mg or 75-100 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I; further, comprising 75 mg, 100 mg or 150 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I; further, comprising 100 mg of the compound of formula I, its tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I.

5. The pharmaceutical combination according to claim 3 or 4, wherein the pharmaceutical composition of the compound of formula I, its tautomers, or pharmaceutically acceptable salts thereof is in single-dose or multi-dose form; wherein the pharmaceutical composition of the compound of formula I, its tautomers, or pharmaceutically acceptable salts thereof is a pharmaceutical composition of a single dose of 5 mg, 25 mg, and / or 50 mg of the compound of formula I, its tautomers, or pharmaceutically acceptable salts thereof; further, the pharmaceutical composition of the compound of formula I, its tautomers, or pharmaceutically acceptable salts thereof is a pharmaceutical composition of a single dose of 50 mg of the compound of formula I, its tautomers, or pharmaceutically acceptable salts thereof, calculated as a compound of formula I.

6. The pharmaceutical combination according to any one of claims 1 to 5, comprising 50-150 mg / m2 of 2 50-100mg / m 2 or 75–100 mg / m 2 Azacitidine, or a pharmaceutical composition thereof; further comprising 50 mg / m 2 , 75mg / m 2 , 100mg / m 2 or 150 mg / m 2 Azacitidine, or a pharmaceutical composition thereof; further comprising 75 mg / m 2 Azacitidine, or a pharmaceutical composition thereof.

7. The pharmaceutical combination according to claim 3 or 6, wherein the pharmaceutical composition of azacitidine is in the form of a single dose or multiple doses; wherein the pharmaceutical composition of azacitidine is a pharmaceutical composition containing a single dose of 100 mg of azacitidine.

8. The pharmaceutical combination according to any one of claims 1 to 7, comprising a daily dose of 75 mg, 100 mg or 150 mg of the compound of formula I, a tautomer thereof or a pharmaceutically acceptable salt thereof, and 75 mg / m2 of the compound of formula I, calculated on the body surface area of ​​the subject. 2 or 100 mg / m 2 A daily dose of azacitidine; further comprising a daily dose of 100 mg of a compound of formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I, and 75 mg / m2 of a body surface area of ​​the subject. 2 daily dose of azacitidine.

9. A drug kit comprising the pharmaceutical combination according to any one of claims 1 to 8, and instructions for use of the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine in combination for treating hematological malignancies.

10. Use of the pharmaceutical combination according to any one of claims 1 to 8 or the kit according to claim 9 in the preparation of a pharmaceutical / medicinal product for treating a blood tumor in a patient.

11. The use according to claim 10, wherein the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof, and azacitidine have the same treatment cycle; preferably, one treatment cycle is every 1 week, every 2 weeks, every 3 weeks or every 4 weeks; more preferably, one treatment cycle is every 4 weeks.

12. The use according to claim 10 or 11, wherein 28 days is one treatment cycle; the pharmaceutical composition containing the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered once a day for 28 consecutive days, preferably, the total dose of the pharmaceutical composition containing the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 2100 mg or 2800 mg; or, azacitidine is administered once a day on days 1 to 7 of each treatment cycle, preferably, the total dose of azacitidine administered in each treatment cycle is 525 mg / m 2 or 700 mg / m 2 ; Furthermore, 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof is administered once a day for 28 consecutive days, preferably, the total dose of the pharmaceutical composition containing the compound of formula I, its tautomer or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 2800 mg; and azacitidine is administered once a day on days 1 to 7 of each treatment cycle, preferably, the total dose of azacitidine administered in each treatment cycle is 525 mg / m 2 .

13. The use according to any one of claims 10 to 12, wherein the blood tumor is a myeloid tumor; preferably, the myeloid tumor includes chronic myeloproliferative disease, myelodysplastic / myeloproliferative disease, myelodysplastic syndrome and acute myeloid leukemia; more preferably myelodysplastic syndrome and acute myeloid leukemia.

14. The use according to any one of claims 10 to 12, wherein the patient with the hematological tumor is a patient with an advanced hematological tumor; or, the patient with the hematological tumor is a patient with an advanced malignant hematological tumor.

15. The use according to any one of claims 10 to 12, wherein the hematological tumor is a refractory and / or relapsed advanced hematological tumor.

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