Combination of trifluoromethyl-containing compound and chemotherapeutic drug for treatment of hematologic tumors

Abstract

The invention belongs to the field of medicine, relates to application of a combination containing a trifluoromethyl compound and a chemotherapeutic drug including a demethylated drug to treatment of hematologic tumors, and particularly relates to application of a combination of a salt shown as a formula I-1 or pharmaceutically acceptable salt thereof and a chemotherapeutic drug to treatment of hematologic tumors. # imgabs0 #

Description

Technical Field

[0001] This application belongs to the field of medicine and relates to the combination of a compound containing a trifluoromethyl group and a chemotherapeutic drug, including a demethylating drug, for the treatment of hematological malignancies. Specifically, it relates to the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a chemotherapeutic drug in the treatment of hematological malignancies. Background Art

[0002] The BCL-2 protein is divided into three families: the BCL-2 family (whose family members include BCL-2, BCL-XL, etc.), the BAX family, and the BH3-only family. Among them, the BCL-2 family plays an anti-apoptotic role, and the members of the latter two families play a pro-apoptotic role.

[0003] Anti-apoptotic BCL-2 family proteins are associated with many diseases and are being studied as potential therapeutic drug targets. These targets for intervention therapies include, for example, BCL-2 family proteins such as BCL-2 and BCL-XL. Inhibitors of BCL-2 family proteins are inhibitors of binding to target proteins, and the compound binding affinity is only one of many parameters to be considered. One goal is to produce such compounds that preferentially bind to one protein relative to another protein, i.e., selectivity for it. To show this selectivity, it is well known that a compound shows a high binding affinity for a specific protein and a lower binding affinity for another member. Compounds that selectively inhibit BCL-2 protein can be used to treat hyperproliferative diseases such as tumors.

[0004] The combination of a compound that selectively inhibits BCL-2 protein (BCL-2 inhibitor) and a chemotherapeutic drug, including a demethylating drug such as azacitidine, seems to bring clinical benefits to patients. Summary of the Invention

[0005] On the one hand, this application provides the use of a BCL-2 inhibitor in the preparation of a drug for the treatment of hematological malignancies.

[0006] On the other hand, this application provides the use of a BCL-2 inhibitor in the preparation of a drug for the treatment of hematological malignancies, wherein the treatment further includes administering a chemotherapeutic drug.

[0007] On the other hand, this application provides the use of a BCL-2 inhibitor in the preparation of a drug for the treatment of hematological malignancies, wherein the drug is used in combination with a chemotherapeutic drug.

[0008] On the other hand, this application provides the use of a BCL-2 inhibitor in the preparation of a drug for the treatment of hematological malignancies, wherein the BCL-2 inhibitor is used in combination with a chemotherapeutic drug.

[0009] On the other hand, the present application provides the use of a BCL-2 inhibitor in the preparation of a medicament for treating hematological malignancies, as well as instructions for the combined use of a BCL-2 inhibitor and a chemotherapeutic drug.

[0010] On the other hand, the present application provides the use of a BCL-2 inhibitor in the preparation of a kit for treating hematological malignancies, the kit comprising a BCL-2 inhibitor, as well as instructions for the combined use of a BCL-2 inhibitor and other drugs.

[0011] On the other hand, the present application provides the use of a BCL-2 inhibitor in the preparation of a medicament for combined use with a chemotherapeutic drug to treat hematological malignancies.

[0012] On the one hand, the present application provides a method for treating hematological malignancies, comprising administering to a subject a therapeutically effective amount of a BCL-2 inhibitor.

[0013] On the one hand, the present application also provides a BCL-2 inhibitor for treating hematological malignancies.

[0014] On the one hand, the present application also provides the use of a BCL-2 inhibitor for treating hematological malignancies.

[0015] In some embodiments, the BCL-2 inhibitor, the method for treating hematological malignancies, or the use for treating hematological malignancies further comprises administering a chemotherapeutic drug to a subject in need of treatment.

[0016] In some embodiments, the BCL-2 inhibitor, the method for treating hematological malignancies, or the use for treating hematological malignancies, wherein the BCL-2 inhibitor is used in combination with a chemotherapeutic drug.

[0017] On the one hand, the present application provides a combination of a BCL-2 inhibitor and a chemotherapeutic drug.

[0018] On the one hand, the present application provides a combination of a BCL-2 inhibitor and a demethylating agent (such as azacitidine or a pharmaceutically acceptable salt thereof).

[0019] On the one hand, the present application provides a method for treating hematological malignancies, comprising administering to a subject a therapeutically effective amount of a combination of a BCL-2 inhibitor and a chemotherapeutic drug such as azacitidine or a pharmaceutically acceptable salt thereof. On the one hand, the present application provides a method for treating hematological malignancies, comprising administering to a subject a therapeutically effective amount of a combination of a BCL-2 inhibitor and a therapeutically effective amount of a chemotherapeutic drug such as azacitidine or a pharmaceutically acceptable salt thereof.

[0020] On the other hand, the present application provides the use of a combination of a BCL-2 inhibitor and a chemotherapeutic drug such as azacitidine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hematological malignancies.

[0021] On the other hand, the present application also provides a combination of a BCL-2 inhibitor and a chemotherapeutic drug such as azacitidine or a pharmaceutically acceptable salt thereof for treating hematological malignancies.

[0022] On the other hand, the present application also provides the use of a combination of a BCL-2 inhibitor and a chemotherapeutic drug such as azacitidine or a pharmaceutically acceptable salt thereof for treating hematological malignancies.

[0023] In some embodiments, the present application also provides a kit for treating hematological malignancies, which contains a BCL-2 inhibitor; optionally, it also includes instructions for the combined use of the BCL-2 inhibitor and a chemotherapeutic drug such as azacitidine or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the present application also provides a kit for treating hematological malignancies, which contains a BCL-2 inhibitor; optionally, it also includes instructions for the combined use of the BCL-2 inhibitor and a chemotherapeutic drug such as azacitidine or a pharmaceutically acceptable salt thereof for treating hematological malignancies.

[0025] In some embodiments, the present application also provides a kit for treating hematological malignancies, which contains: a combination containing a BCL-2 inhibitor and a chemotherapeutic drug (such as azacitidine) or a pharmaceutically acceptable salt thereof; optionally, it also includes instructions for the use of the combination of the BCL-2 inhibitor and a chemotherapeutic drug (such as azacitidine) or a pharmaceutically acceptable salt thereof. In some embodiments, the instructions are instructions for guiding a subject to administer the combination of the BCL-2 inhibitor and a chemotherapeutic drug (such as azacitidine) or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the BCL-2 inhibitor and the chemotherapeutic drug (such as azacitidine) or a pharmaceutically acceptable salt thereof in the combination are each packaged in an independent kit, and the independent kit also includes instructions for the combined use of the BCL-2 inhibitor and the chemotherapeutic drug (such as azacitidine) or a pharmaceutically acceptable salt thereof for treating hematological malignancies.

[0027] In some embodiments, the BCL-2 inhibitor and the chemotherapeutic drug such as azacitidine or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially.

[0028] In some embodiments, the BCL-2 inhibitor can be a pharmaceutical composition comprising a BCL-2 inhibitor. In some embodiments, the chemotherapeutic drug can be a pharmaceutical composition comprising a chemotherapeutic drug. In some embodiments, the azacitidine or a pharmaceutically acceptable salt thereof can be a pharmaceutical composition comprising azacitidine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0029] In some embodiments, the combination is a fixed combination or a non-fixed combination. In some embodiments, the BCL-2 inhibitor and the chemotherapeutic agent such as azacitidine or a pharmaceutically acceptable salt thereof are co-formulated in a pharmaceutical composition or are separately formulated into separate pharmaceutical compositions. In some embodiments, the BCL-2 inhibitor and the chemotherapeutic agent such as azacitidine are separately formulated into separate pharmaceutical compositions and are separately packaged in separate kits.

[0030] In some embodiments, the BCL-2 inhibitor is selected from compounds of formula I-1 or a pharmaceutically acceptable salt thereof,

[0031]

[0032] wherein R 11 is selected from hydrogen, halogen or C 1-6 alkyl;

[0033] Ring A is selected from 5- to 6-membered heteroalkyl,

[0034] R 22 are each independently selected from 4- to 6-membered heteroalkyl, C 3-6 cycloalkyl, -COR aa 、-SO2R bb 、or optionally halogen-substituted C 1-6 alkyl;

[0035] R aa or R bb are each independently selected from H, 4- to 6-membered heteroalkyl, C 3-6 cycloalkyl, or C 1-6 alkyl, the C 1-6 alkyl being optionally substituted by halogen, CN, -N(C 1-6 alkyl)2, -NHC 1-6 alkyl, or -OC 1-6 alkyl;

[0036] p is selected from 0, 1, 2 or 3.

[0037] In some embodiments, the structural fragment is selected from

[0038] In some embodiments, R 11 is selected from hydrogen, halogen or C 1-3 alkyl. In some embodiments, R 11 is selected from hydrogen, fluorine, chlorine or methyl. In some embodiments, R 11 is selected from hydrogen, chlorine or methyl.

[0039] In some embodiments, ring A is selected from 6-membered heterocycloalkyl. In some embodiments, ring A is selected from 6-membered heterocycloalkyl containing one or more O atoms. In some embodiments, ring A is selected from dioxane or pyran ring.

[0040] In some embodiments, R 22 is independently selected from 4-6 membered heterocycloalkyl, C 4-6 cycloalkyl, -COR aa , -SO2R bb , or C 1-4 alkyl optionally substituted with halogen.

[0041] In some embodiments, R aa or R bb is independently selected from H, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, or C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted with halogen, CN, -N(C 1-4 alkyl)2, -NHC 1-4 alkyl, or -OC 1-4 alkyl.

[0042] In some embodiments, R 22 is independently selected from -C(O)H, -COC(CH3)3, -COCF3, -COCH2CN, -COCH2N(CH3)2, -SO2CH2CH3, -SO2CF3, -SO2C2F5, -CF3, -C2F5, tetrahydropyran, monoxetane, -SO 2- cyclopropane, -CO-cyclopropane, -CO-monoxetane, -SO 2- monoxetane, or -SO 2- cyclobutane.

[0043] In some embodiments, p is selected from 0 or 1.

[0044] In some embodiments, the BCL-2 inhibitor is selected from compounds of formula I, formula II, formula III, or formula IV or a pharmaceutically acceptable salt thereof,

[0045]

[0046] In some embodiments, the BCL-2 inhibitor is selected from compounds of formula I or a pharmaceutically acceptable salt thereof; or from compounds of formula II or a pharmaceutically acceptable salt thereof; or from compounds of formula III or a pharmaceutically acceptable salt thereof; or from compounds of formula IV or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compounds of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compounds of formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compounds of formula III or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compounds of formula IV or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the chemotherapeutic agent is selected from demethylating agents.

[0049] In some embodiments, the chemotherapeutic agent or demethylating agent is selected from azacitidine or a pharmaceutically acceptable salt thereof.

[0050] On the one hand, the present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hematological malignancies.

[0051] On the other hand, the present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hematological malignancies, wherein the treatment further comprises administering azacitidine or a pharmaceutically acceptable salt thereof.

[0052] On the other hand, the present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the present application in the preparation of a medicament for the treatment of hematological malignancies, wherein the medicament is used in combination with azacitidine or a pharmaceutically acceptable salt thereof.

[0053] On the other hand, the present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hematological malignancies, wherein the compound of formula I-1 or a pharmaceutically acceptable salt thereof is used in combination with azacitidine or a pharmaceutically acceptable salt thereof.

[0054] On the other hand, the present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hematological malignancies, and instructions for the combined use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof.

[0055] On the other hand, the present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hematological malignancies in combination with azacitidine or a pharmaceutically acceptable salt thereof.

[0056] On the other hand, the present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a kit for the treatment of hematological malignancies, wherein the kit comprises the compound of formula I-1 or a pharmaceutically acceptable salt thereof, and instructions for the combined use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof for the treatment of hematological malignancies.

[0057] On the one hand, the present application provides a method for treating hematological malignancies, comprising administering to a subject a therapeutically effective amount of a compound of formula I-1 or a pharmaceutically acceptable salt thereof.

[0058] On the one hand, the present application also provides a compound of formula I-1 or a pharmaceutically acceptable salt thereof for treating hematological malignancies.

[0059] On the one hand, the present application also provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof for treating hematological malignancies.

[0060] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, the method for treating hematological malignancies, or the use for treating hematological malignancies further comprises administering azacitidine or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0061] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, the method for treating hematological malignancies, or the use for treating hematological malignancies, wherein the compound of formula I-1 or a pharmaceutically acceptable salt thereof is used in combination with azacitidine or a pharmaceutically acceptable salt thereof.

[0062] On the one hand, the present application provides a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof.

[0063] On the one hand, the present application provides a method for treating hematological malignancies, comprising administering to a subject a therapeutically effective amount of the combination described in the present application.

[0064] On the other hand, the present application provides the use of the combination described above in the preparation of a medicament for treating hematological malignancies.

[0065] On the other hand, the present application also provides the combination described above for treating hematological malignancies.

[0066] On the other hand, the present application also provides the use of the combination described above for treating hematological malignancies.

[0067] In some embodiments, the present application also provides a kit for treating hematological malignancies, which comprises: a compound containing formula I-1 or a pharmaceutically acceptable salt thereof; optionally, instructions for the combined use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the present application also provides a kit for treating hematological malignancies, which comprises: a compound containing formula I-1 or a pharmaceutically acceptable salt thereof; optionally, instructions for the combined use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof for treating hematological malignancies.

[0069] In some embodiments, the present application also provides a kit for treating hematological malignancies, which comprises: the combination described in the present application; optionally, instructions for the use of the combination. In some embodiments, the instructions are to guide the subject to administer the combination.

[0070] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof in the combination are each packaged in separate kits, and the separate kits further include instructions for the combined use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof for the treatment of hematological malignancies. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof may be a pharmaceutical composition comprising the compound of formula I-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the azacitidine or a pharmaceutically acceptable salt thereof may be a pharmaceutical composition comprising azacitidine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0071] In some embodiments, the combination is a fixed combination or a non-fixed combination. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof and the azacitidine or a pharmaceutically acceptable salt thereof are co-formulated in a pharmaceutical composition or are separately formulated into separate pharmaceutical compositions. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof are separately formulated into separate pharmaceutical compositions and are separately packaged in separate kits.

[0072] Hematological malignancies

[0073] In some embodiments, the hematological malignancy is selected from advanced hematological malignancies. In some embodiments, the hematological malignancy is selected from relapsed and / or refractory hematological malignancies. In some embodiments, the hematological malignancy is selected from relapsed and / or refractory advanced hematological malignancies.

[0074] In some embodiments, the hematological malignancy is selected from hematological malignancies clearly diagnosed by histology or cytology. In some embodiments, the above diagnosis conforms to the 2016 diagnostic criteria of the World Health Organization (WHO).

[0075] In some embodiments, the hematological malignancy is selected from myeloid neoplasms. In some embodiments, the hematological malignancy is selected from myeloid malignancies. In some embodiments, the hematological malignancy or myeloid malignancy is selected from myeloid malignancies diagnosed in accordance with the WHO 2016 Revised Classification of Tumours of Haematopoietic and Lymphoid Tissues.

[0076] In some embodiments, the hematological malignancy or myeloid malignancy is selected from acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

[0077] In some embodiments, the hematological malignancy or myeloid malignancy is selected from acute myeloid leukemia (AML).

[0078] In some embodiments, the hematologic malignancy or its subject has not been treated with a prior treatment regimen. In some embodiments, the hematologic malignancy or its subject has been treated with one or more prior treatment regimens. In some embodiments, the hematologic malignancy or its subject has been treated with one, two, three, four, or five prior treatment regimens.

[0079] In some embodiments, the hematologic malignancy is selected from de novo hematologic malignancies. In some embodiments, the hematologic malignancy is selected from newly diagnosed hematologic malignancy patients aged ≥65 years old and / or unfit for intensive induction chemotherapy.

[0080] In some embodiments, the hematologic malignancy is selected from relapsed and / or refractory hematologic malignancies. In some embodiments, the hematologic malignancy is selected from relapsed and / or refractory advanced hematologic malignancies. In some embodiments, the relapsed and refractory subjects include those who are ineffective, intolerant, or inaccessible to standard treatment regimens. In some embodiments, the relapsed and refractory subjects have previously received at least one line of systemic standard treatment. In some embodiments, the last-line treatment of the relapsed and refractory subjects is refractory without remission (including but not limited to stable disease after 4 or more cycles of standard treatment or disease progression after 1 or more cycles of standard treatment) or relapse after remission.

[0081] In some embodiments, the hematologic malignancy or its subject is selected from those with recurrence or treatment failure after prior treatment. In some embodiments, the hematologic malignancy or its subject is selected from those with recurrence or treatment failure after prior standard treatment. In some embodiments, the hematologic malignancy or its subject is selected from those with prior treatment failure. In some embodiments, the hematologic malignancy or its subject is selected from those with treatment failure after standard treatment. In some embodiments, the hematologic malignancy or its subject is selected from those intolerant to prior treatment regimens. In some embodiments, the hematologic malignancy or its subject is selected from those intolerant to standard treatment regimens. In some embodiments, the hematologic malignancy or its subject is selected from those intolerant to prior treatment regimens and having no other better treatment options. In some embodiments, the hematologic malignancy or its subject is selected from those intolerant to standard treatment regimens and having no other better treatment options.

[0082] In some embodiments, the hematologic malignancy or the subject thereof is selected from those who have received at least 1 prior systemic treatment regimen, with disease progression or intolerance during or after the most recent treatment, or no remission after adequate treatment. In some embodiments, the hematologic malignancy or the subject thereof is selected from those who have received at least 1, 2, 3, or 4 prior systemic treatment regimens. In some embodiments, the hematologic malignancy or the subject thereof is selected from those who have received at least 1 or 2 prior systemic treatment regimens, with disease progression or intolerance during or after the most recent treatment, or no remission after adequate treatment.

[0083] In some embodiments, the previously received treatment regimens include first-line treatment regimen, second-line treatment regimen, third-line treatment regimen, fourth-line treatment regimen, fifth-line treatment regimen, and / or sixth-line treatment regimen. In some embodiments, the previously received treatment regimens include first-line treatment regimen, second-line treatment regimen, and / or third-line treatment regimen.

[0084] Acute myeloid leukemia (AML)

[0085] In some embodiments, the acute myeloid leukemia is selected from newly diagnosed (or de novo) acute myeloid leukemia patients.

[0086] In some embodiments, the acute myeloid leukemia is selected from newly diagnosed (or de novo) adult acute myeloid leukemia patients.

[0087] In some embodiments, the acute myeloid leukemia is selected from those who have not received treatment for AML. In some embodiments, the acute myeloid leukemia is selected from those who are not suitable for intensive induction chemotherapy. In some embodiments, the acute myeloid leukemia is selected from those who have not received treatment for AML and are not suitable for intensive induction chemotherapy.

[0088] In some embodiments, the acute myeloid leukemia is selected from treatment-naive subjects who cannot receive standard treatment. In some embodiments, the acute myeloid leukemia is selected from treatment-naive subjects who cannot receive standard treatment due to reasons such as age, comorbidities, performance status, and / or poor risk factors.

[0089] In some embodiments, the acute myeloid leukemia is selected from newly diagnosed adult AML subjects aged ≥ 65 years and / or not suitable for intensive induction chemotherapy.

[0090] In some embodiments, the acute myeloid leukemia is selected from treatment-naive AML patients aged ≥ 65 years.

[0091] In some embodiments, the acute myeloid leukemia is selected from relapsed and / or refractory (R / R) acute myeloid leukemia.

[0092] In some embodiments, the acute myeloid leukemia is selected from acute myeloid leukemia that is intolerant to standard treatment regimens and has no other better treatment options.

[0093] Myelodysplastic syndromes (MDS)

[0094] In some embodiments, the myelodysplastic syndrome is selected from MDS with >5% blasts. In some embodiments, the myelodysplastic syndrome is selected from MDS with a Revised International Prognostic Scoring System (IPSS-R) >3.5 points.

[0095] In some embodiments, the myelodysplastic syndrome is selected from relapsed and / or refractory myelodysplastic syndrome.

[0096] In some embodiments, the myelodysplastic syndrome is selected from relapsed and / or refractory intermediate-high risk (IPSS-R) myelodysplastic syndrome. In some embodiments, the subjects with myelodysplastic syndrome are selected from subjects who transform into acute myeloid leukemia during or after treatment.

[0097] Dosing regimens

[0098] The method of administration can be determined comprehensively according to the activity, toxicity of the drug, and the tolerance of the subject / patient, etc. Those skilled in the art can determine the appropriate amount, dose, or dosage of each drug used in combination in the present invention to administer to the subject / patient. Those skilled in the art can adjust the dose and dosing regimen according to methods well-known in the art of treatment. For example, the maximum tolerated dose can be easily determined, the effective amount that provides a detectable therapeutic benefit to the subject / patient can also be determined, and the time requirement for administering each drug to provide a detectable therapeutic benefit to the subject / patient can also be determined. Therefore, although certain doses and dosing regimens are illustrated in the present invention, these examples in no way limit the doses and dosing regimens that can be provided to patients in practicing the present invention.

[0099] The present application provides a method for treating hematological malignancies with a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof, which comprises administering to a subject a dose (per day or per administration) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof selected from 20 - 2000 mg, 20 - 1200 mg, or 100 - 1200 mg.

[0100] The present application provides the use of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating hematological malignancies, wherein the drug (per day or per administration) comprises 20 - 2000 mg, 20 - 1200 mg, or 100 - 1200 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the present application provides the use of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of hematological malignancies, wherein the administration dose (per day or per administration) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 20-2000 mg, 20-1200 mg, or 100-1200 mg.

[0102] The present application also provides a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof for the treatment of hematological malignancies, wherein the administration dose (per day or per administration) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 20-2000 mg, 20-1200 mg, or 100-1200 mg.

[0103] The present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the combined use with azacitidine or a pharmaceutically acceptable salt thereof for the treatment of hematological malignancies, wherein the medicament (per day or per administration) comprises 20-2000 mg, 20-1200 mg, or 100-1200 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof. The present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the combined use with azacitidine or a pharmaceutically acceptable salt thereof for the treatment of hematological malignancies, wherein the medicament (per day or per administration) comprises 20-2000 mg, 20-1200 mg, or 100-1200 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof. In some embodiments, the present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the combined use with azacitidine or a pharmaceutically acceptable salt thereof for the treatment of hematological malignancies, wherein the medicament comprises a single dose or multiple doses of the compound of formula I-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the present application provides the use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the combined use with azacitidine or a pharmaceutically acceptable salt thereof for the treatment of hematological malignancies, wherein the medicament comprises a single dose or multiple doses of a combination of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof.

[0104] The present application also provides the use of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof according to the present application for the treatment of hematological malignancies, wherein the administration dose (per day or per administration) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 20-2000 mg, 20-1200 mg, or 100-1200 mg.

[0105] In some embodiments, the present application also provides a kit for treating tumors, which contains: a compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof; optionally, instructions for use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof are further included, and the instructions for use relate to the administration dose (daily or each time) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof selected from 20-2000 mg, 20-1200 mg or 100-1200 mg. In some embodiments, the instructions for use are to direct a subject to administer the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 10-5000 mg, 20-5000 mg, or 20-4000 mg, or 20-3000 mg, or 20-2000 mg, or 50-1500 mg, or 100-1200 mg, or 200-1000 mg, or 200-800 mg, or 200-600 mg, or 200-400 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg or 2000 mg, or any value within the range formed by any of the above values. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 100-1200 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 200-1000 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 10-800 mg or 20 mg-800 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 10-300 mg, 20-400 mg, 20-200 mg or 20-100 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg or 400 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 2200 mg, 400 mg, 600 mg, 800 mg, 1000 mg or 1200 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 100-800 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 400-600 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 200 mg, 400 mg, 500 mg or 600 mg.In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 20 mg, 50 mg, 100 mg, 200 mg or 400 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 100 mg, 200 mg or 400 mg. In some embodiments, the daily or per-dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is selected from 200 mg, 400 mg, or 600 mg.

[0107] In some embodiments of the present application, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered at 0.0001 to 20 mg / kg body weight per administration.

[0108] In some embodiments, the dosing frequency of the compound of formula I-1 or a pharmaceutically acceptable salt thereof can be 3 times a day, 2 times a day, 1 time a day, once every two days, once every three days, once every four days, once every five days, once every six days, 3 times a week, 2 times a week, 1 time a week, once every two weeks, or once every three weeks. In some embodiments, the dosing frequency of the compound of formula I-1 or a pharmaceutically acceptable salt thereof can be 1 or 2 times a day. In some embodiments, the dosing frequency of the compound of formula I-1 or a pharmaceutically acceptable salt thereof can be 1 time a day.

[0109] In some embodiments, an effective amount of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is administered to a subject continuously every day.

[0110] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered in a single dose or multiple doses.

[0111] In some embodiments, the administration of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is by oral administration.

[0112] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is orally administered within 30 minutes after starting a meal.

[0113] In some embodiments, the administration of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is by oral administration on an empty stomach.

[0114] In some embodiments, one dosing cycle is 8 - 32 days, for example, one dosing cycle is 8 - 28 days, 8 - 21 days, 8 - 15 days, 15 - 28 days, 15 - 21 days, 21 - 28 days, 21 - 32 days, 28 - 32 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, or 32 days. In some embodiments, one dosing cycle is 28 days or 32 days. In some embodiments, one dosing cycle is 28 days.

[0115] In some embodiments, the administration method of the compound of formula I - 1 or its pharmaceutically acceptable salt is: taking 20 mg - 1200 mg, 100 mg - 1200 mg, or 100 mg - 800 mg each time, and continuously administering for one or more dosing cycles daily (for example, once a day); optionally, one dosing cycle is 8 - 32 days (for example, every 28 days).

[0116] In some embodiments, the compound of formula I - 1 or its pharmaceutically acceptable salt is administered for 1 day, 2 days, 5 days, 7 days, 10 days, 14 days, 21 days, or 28 days, etc. per cycle. In some embodiments, it is administered for 5 - 7 days, 7 - 10 days, 10 - 14 days, or 10 - 21 days per cycle. In some embodiments, the compound of formula I - 1 or its pharmaceutically acceptable salt is administered for 5 days, or 7 days, 10 days, 14 days, 21 days, 28 days per cycle.

[0117] In some embodiments, the administration method of the compound of formula I - 1 or its pharmaceutically acceptable salt is: taking 20 - 1200 mg, 100 - 1200 mg, 100 - 800 mg, 100 - 600 mg, 200 - 600 mg, 20 - 400 mg, 100 - 400 mg, or 400 - 600 mg (for example, 100 mg, 200 mg, 400 mg, or 600 mg) each time, and continuously administering once a day; optionally, every 28 days is one dosing cycle.

[0118] In some embodiments, the administration method of the compound of formula I - 1 or its pharmaceutically acceptable salt is: taking 20 - 400 mg, 100 - 1200 mg, 100 - 800 mg, or 100 - 600 mg each time, once a day, orally; optionally, every 28 days is one dosing cycle.

[0119] In some embodiments, the treatment cycle of the compound of formula I-1 or its pharmaceutically acceptable salt is 4 - 10 or 8 - 20 dosing cycles. In some embodiments, the treatment cycle of the compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition, is when the above dosing cycle is repeated until the subject can no longer benefit, the disease progresses, or intolerable toxic reactions occur.

[0120] In some embodiments, the daily or per-dose of the compound of formula I-1 or its pharmaceutically acceptable salt is the treatment-period dose (or fixed treatment dose).

[0121] In some embodiments, during the induction period, the compound of formula I-1 or its pharmaceutically acceptable salt is administered at at least one escalating dose (hereinafter also referred to as "escalating dose"), wherein the first escalating dose in the at least one escalating dose is lower than the dose in the dosing cycle. In some embodiments, the at least one escalating dose may include a first escalating dose and additional escalating doses. In particular, for the case where the induction period includes multiple escalating doses, the last escalating dose is less than the dose used in the dosing cycle. In a preferred embodiment, the escalating dose and the fixed dose are administered in the same dosing manner and dosing frequency.

[0122] In some embodiments, for the case where the induction period includes multiple escalating doses, the difference between each escalating dose may be the same or different. In some embodiments, for the case where the induction period includes multiple escalating doses, there may be 1 - 14 escalating doses, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 escalating doses.

[0123] In some embodiments, the first escalating dose may be selected from: 10 mg, 20 mg, 50 mg, or 100 mg. In a preferred embodiment, each escalating dose may be administered for 1 - 10 days, for example, it may be administered for 1 day, or continuously administered for 2 - 10 days.

[0124] In some embodiments, the escalating dose comprises at least one of the following: 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg. In some embodiments, the escalating dose comprises at least one of the following: 20 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg. In some embodiments, the escalating dose comprises 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg. In some embodiments, the escalating dose comprises 20 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, or 800 mg.

[0125] In some embodiments, after the induction period (i.e., after escalating to a specific dose by a gradient dose), the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered daily at a fixed dose for treatment.

[0126] In some embodiments, before the subject receives the fixed treatment dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof during the treatment period, an escalating dose (i.e., induction period) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, the administration of the escalating dose (i.e., induction period) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof to the subject is only required in the first treatment cycle, and the induction period is not required in subsequent treatment cycles, and the treatment period dose is directly adopted.

[0127] In some embodiments, before administering a fixed therapeutic dose during a treatment period to a subject, a gradually increasing dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof according to the present application is administered to the subject. The gradually increasing dose includes increasing the dose in a gradient manner by changing the dose every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, or every week (7 days). In some embodiments, the first gradient dose of the gradually increasing dose is selected from 10 mg, 20 mg, 50 mg, or 100 mg. In some embodiments, the first gradient dose of the gradually increasing dose is selected from 50 mg or 100 mg. In some embodiments, the first gradient dose of the gradually increasing dose is selected from 100 mg. Optionally, the gradually increasing dose further comprises a second gradient dose. In some embodiments, the second gradient dose of the gradually increasing dose is selected from 20 mg, 50 mg, 100 mg, or 200 mg. In some embodiments, the second gradient dose of the gradually increasing dose is selected from 100 mg or 200 mg. In some embodiments, the second gradient dose of the gradually increasing dose is selected from 200 mg. Optionally, the gradually increasing dose further comprises a third gradient dose. In some embodiments, the third gradient dose of the gradually increasing dose is selected from 50 mg, 100 mg, 200 mg, or 400 mg. In some embodiments, the third gradient dose of the gradually increasing dose is selected from 200 mg or 400 mg. In some embodiments, the third gradient dose of the gradually increasing dose is selected from 400 mg. In some embodiments, optionally, the gradually increasing dose further comprises a fourth gradient dose. In some embodiments, optionally, the gradually increasing dose further comprises a fourth gradient dose, which is selected from 100 mg, 200 mg, 400 mg, or 600 mg. In some embodiments, optionally, the gradually increasing dose further comprises a fourth gradient dose, which is selected from 400 mg or 600 mg. In some embodiments, optionally, the gradually increasing dose further comprises a fifth gradient dose. In some embodiments, optionally, the gradually increasing dose further comprises a fifth gradient dose, which is selected from 200 mg, 400 mg, 600 mg, or 800 mg. In some embodiments, optionally, the gradually increasing dose further comprises a sixth gradient dose. In some embodiments, optionally, the gradually increasing dose further comprises a sixth gradient dose, which is selected from 400 mg or 600 mg. In some embodiments, optionally, the gradually increasing dose further comprises a seventh gradient dose. In some embodiments, optionally, the gradually increasing dose further comprises a seventh gradient dose, which is selected from 600 mg or 800 mg. In some embodiments, optionally, the gradually increasing dose further comprises an eighth gradient dose. In some embodiments, optionally, the gradually increasing dose further comprises an eighth gradient dose, which is selected from 800 mg or 1200 mg.

[0128] In some embodiments, after the gradient dose is increased to a specific dose (i.e., after the induction period), the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at a fixed dose daily for treatment.

[0129] In some embodiments, the fixed dose is selected from 100 mg - 600 mg, 100 mg - 400 mg, or 200 mg - 600 mg. Specifically, for example, when the first gradient dose, such as 100 mg, completes the escalation period (or induction period), the subsequent fixed dose is 200 mg. When the second gradient dose, such as 200 mg, completes the escalation period, the subsequent fixed dose is 400 mg; when the third gradient dose, such as 400 mg, completes the escalation period, the subsequent fixed dose is 600 mg; for example, when the fourth gradient dose, such as 400 mg, completes the escalation period, the subsequent fixed dose is 600 mg.

[0130] In some embodiments, the fixed dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg; in some embodiments, it is selected from 100 mg, 200 mg, or 400 mg; in some embodiments, it is selected from 200 mg, 400 mg, or 600 mg; in some embodiments, it is selected from 200 mg; in some embodiments, it is selected from 400 mg; in some embodiments, it is selected from 600 mg.

[0131] In some embodiments, before the subject receives the fixed-dose treatment, a daily or weekly escalating dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is administered to the subject. Optionally, after escalating to a specific dose (such as 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg), a fixed dose (such as 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered daily thereafter. Optionally, after escalating to a specific dose (such as 100 mg, 200 mg, or 400 mg), a fixed dose (such as 200 mg, 400 mg, or 600 mg) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered daily thereafter.

[0132] In some embodiments, before administering a fixed dose treatment to the subject, a daily or weekly escalating dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is administered to the subject. Optionally, after escalating to a specific dose, such as 50 mg, 100 mg, or 200 mg, the corresponding subsequent daily fixed doses are 100 mg, 200 mg, and 400 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, respectively. In some embodiments, before administering a fixed dose treatment to the subject, a daily or weekly escalating dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application is administered to the subject. Optionally, after escalating to a specific dose, such as 100 mg, 200 mg, or 400 mg, the corresponding subsequent daily fixed doses are 200 mg, 400 mg, and 600 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, respectively.

[0133] In some embodiments, the duration of administering the daily escalating dose is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or the duration of a range formed by any of the above values. In some embodiments, the duration of administering the daily escalating dose is 2 - 10 days, 2 - 4 days, 3 - 4 days, or 5 - 7 days.

[0134] In some embodiments, the daily escalating dose includes: 20 mg is administered on the first day and 50 mg is administered on the second day. In some embodiments, the daily escalating dose includes: 20 mg is administered on the first day, 50 mg is administered on the second day, and 100 mg is administered on the third day. In some embodiments, the daily escalating dose includes: 20 mg is administered on the first day, 50 mg is administered on the second day, 100 mg is administered on the third day, and 200 mg is administered on the fourth day. In some embodiments, the daily escalating dose includes: 20 mg is administered on the first day, 50 mg is administered on the second day, 100 mg is administered on the third day, 200 mg is administered on the fourth day, and 400 mg is administered on the fifth day. In some embodiments, the daily escalating dose includes: 20 mg is administered on the first day, 50 mg is administered on the second day, 100 mg is administered on the third day, 200 mg is administered on the fourth day, 400 mg is administered on the fifth day, and 600 mg is administered on the sixth day. The subsequent dosing cycles are treated with the above fixed doses of the compound of formula I-1 or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the daily escalating dose comprises: 20 mg administered on the first day, 50 mg administered on the second day, 100 mg administered on the third day, 200 mg administered on the fourth day, 400 mg administered on the fifth day, 600 mg administered on the sixth day, and 800 mg administered on the seventh day. In some embodiments, the daily escalating dose comprises: 20 mg administered on the first day, 50 mg administered on the second day, 100 mg administered on the third day, 200 mg administered on the fourth day, 400 mg administered on the fifth day, 600 mg administered on the sixth day, 800 mg administered on the seventh day, and 1200 mg administered on the eighth day. The subsequent treatment administers the compound of formula I-1 or a pharmaceutically acceptable salt thereof at the above fixed dose.

[0136] In some embodiments, the daily escalating dose comprises: 100 mg administered on the first day. In some embodiments, the daily escalating dose comprises: 100 mg administered on the first day and 200 mg administered on the second day. In some embodiments, the daily escalating dose comprises: 100 mg administered on the first day, 200 mg administered on the second day, and 400 mg administered on the third day. In some embodiments, the daily escalating dose comprises: 100 mg administered on the first day, 200 mg administered on the second day, 400 mg administered on the third day, and 600 mg administered on the fourth day. In some embodiments, the daily escalating dose comprises: 100 mg administered on the first day, 200 mg administered on the second day, 400 mg administered on the third day, and 800 mg administered on the fourth day. The subsequent treatment administers the compound of formula I-1 or a pharmaceutically acceptable salt thereof at the above fixed dose.

[0137] In some embodiments, the daily escalating dose comprises: 10 mg administered on the first day, 20 mg administered on the second day, 50 mg administered on the third day, and 100 mg administered on the fourth day. In some embodiments, the daily escalating dose comprises: 10 mg administered on the first day, 20 mg administered on the second day, 50 mg administered on the third day, 100 mg administered on the fourth day, and 200 mg administered on the fifth day. In some embodiments, the daily escalating dose comprises: 10 mg administered on the first day, 20 mg administered on the second day, 50 mg administered on the third day, 100 mg administered on the fourth day, 200 mg administered on the fifth day, and 300 mg administered on the sixth day. In some embodiments, the daily escalating dose comprises: 10 mg administered on the first day, 20 mg administered on the second day, 50 mg administered on the third day, 100 mg administered on the fourth day, 200 mg administered on the fifth day, and 400 mg administered on the sixth day.

[0138] In some embodiments, the duration of administering the escalating weekly dose is 1, 2, 3, 4, 5, 6, or 7 weeks, or a duration within the range formed by any of the above values. In some embodiments, the duration of administering the escalating weekly dose is 2 - 5 or 2 - 3 or 3 - 4 weeks. In some embodiments, the duration of administering the escalating weekly dose is 4 weeks.

[0139] In some embodiments, the escalating weekly dose includes: 20 mg administered daily in the first week, 50 mg administered daily in the second week, 100 mg administered daily in the third week, and 200 mg administered daily in the fourth week. Optionally, a fixed dose of 400 - 600 mg (such as 400 mg, 500 mg, or 600 mg) is administered daily in the fifth week and thereafter. In some embodiments, the escalating weekly dose includes: 10 mg administered daily in the first week, 20 mg administered daily in the second week, 50 mg administered daily in the third week, 100 mg administered daily in the fourth week, and 200 mg administered daily in the fifth week. Optionally, a fixed dose of 200 mg - 600 mg (such as 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg) is administered daily in the sixth week and thereafter. In some embodiments, the daily or escalating weekly dose of the compound of formula I - 1 or its pharmaceutically acceptable salt is the induction dose.

[0140] In certain embodiments, the pre - dosing escalation period (or induction period) is part of the first dosing cycle (or treatment cycle). For example, when administering the drugs of the present application, the first dosing cycle (or treatment cycle) may include a pre - dosing escalation period of 2 - 14 days or 1 - 3 weeks (such as administering an escalating daily dose or an escalating weekly dose), and after the end of the pre - dosing escalation period, a fixed dose is administered for the remaining days of the first dosing cycle; then subsequent dosing cycles are implemented in the form of a fixed dose, such as the second dosing cycle, the third dosing cycle.

[0141] In some embodiments, the escalating weekly dose includes: 100 mg administered daily in the first week; optionally, the escalating dose continues in the second week, with 200 mg administered daily in the second week; optionally, the escalating dose continues in the third week, with 400 mg administered daily in the third week.

[0142] In some embodiments, within the first treatment cycle (28 days), the compound of formula I - 1 or its pharmaceutically acceptable salt is administered in the manner shown in the following table to complete the induction period, and a fixed dose of the compound of formula I - 1 or its pharmaceutically acceptable salt is used in subsequent cycles.

[0143] Table 1

[0144]

[0145] In some embodiments, the dose of azacitidine or a pharmaceutically acceptable salt thereof in the present application is selected from 75 mg / m 2 / day. In some embodiments, the dose of azacitidine or a pharmaceutically acceptable salt thereof in the present application is selected from 75 mg / m 2 / day, and the dose is adjusted adaptively according to the patient's condition.

[0146] In some embodiments, azacitidine or a pharmaceutically acceptable salt thereof in the present application is administered daily on days 1-7 of each treatment cycle.

[0147] In some embodiments, azacitidine or a pharmaceutically acceptable salt thereof in the present application is administered by subcutaneous injection.

[0148] In some embodiments, azacitidine or a pharmaceutically acceptable salt thereof in the present application is administered daily on days 1-7 of each treatment cycle, by subcutaneous injection, at a dose of 75 mg / m 2 / day.

[0149] In some embodiments, regardless of the baseline hematological laboratory test values, the recommended starting dose of azacitidine or a pharmaceutically acceptable salt thereof in the present application for the first treatment cycle is 75 mg / m 2 , administered subcutaneously daily for 7 days.

[0150] In some embodiments, each treatment cycle of azacitidine or a pharmaceutically acceptable salt thereof in the present application is 4 weeks. In some embodiments, if no beneficial effect is observed after 2 treatment cycles and no toxicity other than nausea and vomiting occurs, the dose can be increased to 100 mg / m 2 . In some embodiments, the patient receives at least 6 cycles of treatment. In some embodiments, for patients with complete or partial remission, additional treatment cycles may be required as long as the patient continues to benefit and can continue treatment.

[0151] In some embodiments, during the administration of azacitidine or a pharmaceutically acceptable salt thereof, the patient's hematological remission and renal toxicity should be monitored, and the administration can be delayed or the dose can be reduced if necessary.

[0152] In some embodiments, when monitoring the patient's hematological remission and renal toxicity, if necessary, the dose can be adjusted as follows:

[0153] For patients with a baseline (at the start of treatment) WBC ≥ 3.0×10 9 / L, ANC ≥ 1.5×10 9 / L and platelets ≥ 75.0×10 9 / L, based on the lowest value count in any treatment cycle, the dose adjustment is as shown in Table 2 below:

[0154] Table 2

[0155]

[0156] In some embodiments, when monitoring the hematological remission and renal toxicity of a patient, if necessary, dose adjustment can be carried out as follows: For patients with a baseline count of WBC < 3.0×10 9 / L, ANC < 1.5×10 9 / L or platelets < 75.0×10 9 / L, the dose adjustment should be based on the lowest value count and the bone marrow biopsy cell composition at the lowest value, as shown in Table 3 below, unless there is a significant improvement in cell differentiation in the next cycle (a higher percentage of mature granulocytes, ANC higher than at the start of the treatment course), in which case the dose of the current treatment should be continued.

[0157] Table 3

[0158]

[0159] If the lowest value defined in Table 2 or 3 above occurs, and if both the WBC and platelet counts subsequently increase by > 25% from the lowest value and are rising, the next treatment course should be carried out 28 days after the start of the previous treatment course. If in the previous cycle, an increase of > 25% from the lowest value is not observed until day 28, the counts should be re-evaluated every 7 days. If a 25% increase is not observed until day 42, the patient should subsequently be treated with 50% of the planned dose.

[0160] In some embodiments, when monitoring the hematological remission and renal toxicity of a patient, dose adjustment is based on serum electrolytes and renal toxicity. If an unexplained decrease in serum bicarbonate level to < 20 mEq / L occurs, the dose in the next treatment course should be reduced by 50%. Similarly, if an unexplained increase in blood urea nitrogen (BUN) or serum creatinine occurs, the next cycle should be delayed until the above laboratory values return to normal or baseline, and the dose in the next treatment course should be reduced by 50%.

[0161] It is known that azacitidine and its metabolites are excreted substantially through the kidneys, and patients with impaired renal function may have a greater risk of toxic reactions to this product. Since elderly patients are more likely to have a decline in renal function, dose selection should be cautious and monitoring of renal function may be useful.

[0162] In some embodiments, the specifications of the azacitidine or its pharmaceutically acceptable salts of the present application are selected from 100 mg.

[0163] In some embodiments, the treatment cycle of the azacitidine or a pharmaceutically acceptable salt thereof is 4 - 10 or 8 - 20 dosing cycles. In some embodiments, the treatment cycle of the azacitidine or a pharmaceutically acceptable salt thereof is when the above dosing cycle is repeated until the subject can no longer benefit, the disease progresses, or intolerable toxic reactions occur.

[0164] In some embodiments, the combination or its treatment regimen, use or method may optionally further comprise other drugs.

[0165] In some embodiments, the method for treating hematological malignancies provided by the present application includes:

[0166] 1) Identifying a subject as a patient with hematological malignancies; and;

[0167] 2) Administering to the identified patient a therapeutically effective amount of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the method for treating hematological malignancies provided by the present application includes:

[0169] 1) Measuring a sample obtained from a patient to determine whether the patient has hematological malignancies; and

[0170] 2) Administering to a patient with hematological malignancies a therapeutically effective amount of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered orally once a day for continuous administration, with 28 days as a treatment cycle. On days 1 - 7 of each treatment cycle, injectable azacitidine or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection at 75 mg / m 2 / day (optionally adjusting the dose of azacitidine or a pharmaceutically acceptable salt thereof according to the specific situation of the patient, according to Table 2 or 3 above).

[0172] In some embodiments, the treatment includes inhibiting the cancer of the patient, reducing its severity, reducing its risk, or inhibiting its metastasis.

[0173] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof and azacitidine or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially.

[0174] In some embodiments, the I-1 compound or a pharmaceutically acceptable salt thereof may be a pharmaceutical composition comprising the I-1 compound or a pharmaceutically acceptable salt thereof. In some embodiments, the azacitidine or a pharmaceutically acceptable salt thereof may be a pharmaceutical composition comprising the azacitidine or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof and the azacitidine or a pharmaceutically acceptable salt thereof may be co-formulated in a pharmaceutical composition or separately formulated into individual pharmaceutical compositions.

[0175] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compound of formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compound of formula III or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compound of formula IV or a pharmaceutically acceptable salt thereof.

[0176] Compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof

[0177] The compound of formula I-1 in the present application can be administered in its free base form, or in the form of its pharmaceutically acceptable salts, hydrates and prodrugs, and the prodrug can be converted into the free base form of the compound of formula I-1 in vivo. The compound of formula I-1 or a pharmaceutically acceptable salt thereof in the present application exists in crystalline form or amorphous form.

[0178] The compound of formula I-1 or a pharmaceutically acceptable salt thereof in the present application is selected from the compound of formula I or a pharmaceutically acceptable salt thereof. The compound of formula I-1 or a pharmaceutically acceptable salt thereof in the present application is selected from the compound of formula II or a pharmaceutically acceptable salt thereof. The compound of formula I-1 or a pharmaceutically acceptable salt thereof in the present application is selected from the compound of formula III or a pharmaceutically acceptable salt thereof. The compound of formula I-1 or a pharmaceutically acceptable salt thereof in the present application is selected from the compound of formula IV or a pharmaceutically acceptable salt thereof.

[0179] The pharmaceutical composition of the compound of formula I-1 or a pharmaceutically acceptable salt thereof in the present application comprises the compound of formula I-1 or a pharmaceutically acceptable salt thereof, and also contains pharmaceutically acceptable excipients. In some embodiments, by weight, the content of the compound of formula I-1 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 0.01 to 99.5%; or, selected from 1 to 90%.

[0180] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10 - 5000 mg, 20 - 5000 mg, or 20 - 4000 mg, or 20 - 3000 mg, or 20 - 2000 mg, or 50 - 1500 mg, or 100 - 1200 mg, or 200 - 1000 mg, or 200 - 800 mg, or 200 - 600 mg, or 200 - 400 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg or 2000 mg, or a compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, within the range formed by any of the above values. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 100 - 1200 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 200 - 1000 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10 - 800 mg or 20 mg - 800 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10 - 300 mg, 20 - 400 mg, 20 - 200 mg or 20 - 100 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg or 400 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, of the present application is selected from 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg or 1200 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 100 - 800 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 400 - 600 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is selected from 200 mg, 400 mg, 500 mg, or 600 mg of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0181] In some embodiments, the pharmaceutical composition of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions, including but not limited to tablets or capsules.

[0182] In some embodiments, the single dose of the pharmaceutical composition of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is 5 mg - 500 mg, preferably 10 mg - 200 mg, most preferably 10 mg - 100 mg of the pharmaceutical composition. Specifically selected from single doses of 5 mg, 10 mg, 15 mg, 20 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg, or a pharmaceutical composition within the range formed by any of the above values. In some embodiments, the single dose of the pharmaceutical composition containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 10 mg, 50 mg, or 100 mg.

[0183] In some embodiments, the pharmaceutical composition containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, and the multi-dose can be composed of multiple single-dose pharmaceutical compositions containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, and the multi-dose can be composed of single-dose pharmaceutical compositions containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof with a single dose of 10 mg, 50 mg, or 100 mg.

[0184] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compound of formula II or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compound of formula III or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from the compound of formula IV or a pharmaceutically acceptable salt thereof.

[0185] Azacitidine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof

[0186] Azacitidine of the present application can be administered in the form of its free base or in the form of its pharmaceutically acceptable salts, and the structure is as follows Azacitidine of the present application or its pharmaceutically acceptable salts exist in crystalline form or amorphous form.

[0187] The pharmaceutical composition of azacitidine of the present application or its pharmaceutically acceptable salts contains azacitidine or its pharmaceutically acceptable salts, and also contains pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients are selected from mannitol, sodium hydroxide and / or hydrochloric acid.

[0188] In some embodiments, the dosage of azacitidine of the present application or its pharmaceutically acceptable salts, or its pharmaceutical composition is selected from 75 mg / m 2 / day, 100 mg / m 2 / day. In some embodiments, according to the patient's ANC count, WBC count, platelet count, and the cell composition (percentage of mature granulocytes) of the bone marrow biopsy at the lowest value, the dosage can be adjusted to 33-100% of the initial dosage, such as 33%, 50%, 67%, 75% or 100%.

[0189] In some embodiments, the pharmaceutical composition of azacitidine or its pharmaceutically acceptable salts is selected from liquid preparations, such as subcutaneous injections.

[0190] In some embodiments, the single dose of the pharmaceutical composition of azacitidine or its pharmaceutically acceptable salts is 100 mg

[0191] In some embodiments, the pharmaceutical composition containing azacitidine or its pharmaceutically acceptable salts is a multi-dose pharmaceutical composition, and the multi-dose can be composed of multiple single-dose pharmaceutical compositions containing azacitidine or its pharmaceutically acceptable salts. In some embodiments, the pharmaceutical composition containing azacitidine or its pharmaceutically acceptable salts is a multi-dose pharmaceutical composition, and the multi-dose can be composed of pharmaceutical compositions containing azacitidine or its pharmaceutically acceptable salts with a single dose of 10 mg, 20 mg, 50 mg or 100 mg.

[0192] Definitions and explanations

[0193] Unless otherwise specified, the following terms used in the present application have the following meanings. A specific term should not be considered uncertain or unclear without a special definition, but should be understood according to the ordinary meaning in the art.

[0194] Unless otherwise specified, the dosages and their ranges provided in the present application for compounds of formula I-1, such as compounds of formula I or their pharmaceutically acceptable salts or their pharmaceutical compositions, are calculated based on the molecular weight of the free base of compounds of formula I-1, such as compounds of formula I.

[0195] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence state of the particular atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0196] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, "optionally" substituted by a halogen for an ethyl group means that the ethyl group can be unsubstituted (-CH2CH3), monosubstituted (such as -CH2CH2F), polysubstituted (such as -CHFCH2F, -CH2CHF2, etc.) or fully substituted (-CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible to exist and / or cannot be synthesized will be introduced.

[0197] C in this article m-n , means that this part has an integer number of carbon atoms within a given range. For example, "C 1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0198] The term "halogen" means fluorine, chlorine, bromine and iodine.

[0199] The term "alkyl" means a hydrocarbon group having the general formula C n H 2n+1 . The alkyl group can be straight-chain or branched-chain. For example, the term "C 1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Another example is that the term "C 1-4 alkyl" refers to an alkyl group containing 1 to 4 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.).

[0200] The term "alkenyl" means a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0201] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡C-C≡CH), and the like.

[0202] The term "cycloalkyl" refers to a carbocyclic ring that is completely saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 10-membered ring, preferably a 4- to 6-membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0203] The term "heterocycloalkyl" refers to a cyclic group that is completely saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3- to 7-membered ring, such as a 4- to 6-membered ring or a 5- to 6-membered ring, containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen, and / or nitrogen.

[0204] The terms "administer" or "give" or "administration" mean physically introducing a therapeutic agent or a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. The terms "administer" or "give" or "administration" are used interchangeably herein.

[0205] The term "treatment" generally refers to obtaining the desired pharmacological and / or physiological effect. The effect can be therapeutic depending on partially or completely stabilizing or curing the disease and / or the side effects resulting from the disease. "Treatment" as used herein encompasses any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing regression of the disease or the symptoms.

[0206] The term "effective amount" or "therapeutically effective amount" means the amount of the compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present application 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 the present disclosure.

[0207] The terms "subject", "patient" or "individual" are used interchangeably herein and refer to an animal, preferably a mammal, more preferably a primate, including human and non-human primates (such as apes, monkeys, orangutans and chimpanzees, such as cynomolgus monkeys, spider monkeys and macaques, such as rhesus monkeys), and most preferably a human, that has become the subject of treatment, observation or experiment. In some embodiments, the subject has experienced and / or exhibited at least one symptom of a disease or disorder to be treated and / or prevented. The term "individual" can be a mammal, preferably a primate, and most preferably a human.

[0208] The term "about" should be understood to include within three standard deviations of the mean or within the standard tolerances in a particular field. In certain embodiments, "about" should be understood to be a variation of no more than 0.5. "About" modifies all the recited values that follow it. For example, "about 1, 2, 3" means "about 1", "about 2", "about 3".

[0209] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their pharmaceutical combinations or their salts and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present application or their pharmaceutical combinations to a subject.

[0210] The term "pharmaceutically acceptable excipient" refers to those excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0211] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid preparations, such as tablets, pills, capsules, etc.

[0212] The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugarcoating pill methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0213] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0214] Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tabletting methods. For example, they can be obtained by the following method: mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of tablets, capsules or dragees. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0215] The term "pharmaceutically acceptable salt" or "medicinally acceptable salt" refers to salts of the compounds of the present application that fall within the definition of "pharmaceutically acceptable".

[0216] Unless otherwise specifically stated, singular terms encompass plural terms, and plural terms encompass singular terms. Unless otherwise specifically stated, the word "a" or "an" means "at least one" or "at least one kind". Unless otherwise stated, the use of "or" means "and / or".

[0217] In this document, unless otherwise stated, the terms "comprising, including and containing" or equivalents are open-ended expressions, meaning that other unspecified elements, components and steps may be covered in addition to the listed elements, components and steps.

[0218] 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 vial of injection is a single dose. The term "multiple doses" consists of multiple single doses. The pharmaceutical compositions of the present application can be formulated into pharmaceutical compositions suitable for single or multiple administrations. The pharmaceutical combinations of the present application can be single-dose or multi-dose pharmaceutical compositions.

[0219] The term "fixed combination" refers to the active components (such as BCL-2 inhibitors or azacitidine) being administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation. In some embodiments, for example, they are present in the same tablet, the same capsule or the same sachet.

[0220] The term "non-fixed combination" refers to two or more active components being administered to an individual simultaneously, in parallel or sequentially without a specific time limit as independent entities (such as pharmaceutical compositions, pharmaceutical formulations), where the active ingredients administered to the individual reach a therapeutically effective amount level. Examples of non-fixed combinations that can be cited are combination therapies, such as administering 2, 3 or more active components. In a non-fixed combination, the individual active components can be packaged, sold or administered as completely independent pharmaceutical compositions. The "non-fixed combination" also includes the combined use between "fixed combinations", or between "fixed combinations" and independent entities of any one or more active components.

[0221] For purposes of description and disclosure, all patents, patent applications, and other identified publications are hereby expressly incorporated herein by reference. These publications are provided only because their disclosures precede the filing date of the present application. All statements as to the dates of these documents or the representation of the content thereof are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the content thereof. Moreover, in any country, any reference to these publications in this text does not constitute an admission that such publication is part of the common general knowledge in the art.

[0222] The term "objective response rate (ORR)": is the proportion of subjects in whom tumor assessment reaches an objective response, including but not limited to cases of complete response (CR), partial response (PR), and morphologic leukemia-free state (MLFS).

[0223] The term "disease control rate (DCR)": is the proportion of patients evaluated to have achieved a response and disease stabilization, including but not limited to cases of CR, PR, and stable disease (SD).

[0224] The term "progression-free survival (PFS)": is the time from the first administration of the drug until disease progression (PD) or death before PD; if PD or death before PD does not occur, the last imaging assessment date is used as the cut-off date.

[0225] The term "duration of response (DOR)": in subjects with CR or PR, is the time between the first assessment of the tumor as CR or PR until PD or death before PD; if subjects with CR or PR do not experience PD or death before PD, the last imaging assessment date is used as the cut-off date.

[0226] CRi: complete remission with un-recovered bone marrow.

[0227] PR-L: partial remission with increased lymphocytes.

[0228] The term "refractory" means that a subject or mammal does not respond to anti-cancer treatment or responds insufficiently to anti-cancer treatment. Specifically, for example, patients with treatment failure (failure to achieve PR or CR) or disease progression within 6 months after the last treatment, and more specifically, those who do not achieve a remission of PR or above.

[0229] The term "relapse" means that disease progression occurs more than 6 months after achieving PR or CR with treatment.

[0230] The term "Adverse Event (AE)" refers to all adverse medical events that occur after a subject receives the investigational medicinal product, which can manifest as symptoms, signs, diseases, or abnormal laboratory tests, but not necessarily have a causal relationship with the investigational medicinal product. The evaluation criteria for the nature and severity of adverse events shall follow the Common Terminology Criteria for Adverse Events of the National Cancer Institute of the United States (NCI-CTC AE v5.0). For items that cannot be evaluated according to this standard, the following criteria can be used for assessment:

[0231] Mild: Slightly affects the patient's daily life.

[0232] Moderate: Significantly affects the patient's daily life.

[0233] Severe: Causes dysfunction in the patient or seriously interferes with daily life.

[0234] The term "OS": Refers to the overall survival time of cancer patients.

[0235] The term "DFS": Refers to the disease-free survival period of cancer patients.

[0236] The term "TTP": Refers to the time to disease progression of cancer patients.

[0237] The term "CBR": Refers to the clinical benefit rate.

[0238] The term "SAE": Refers to serious adverse events.

[0239] The term "TRAEs": Treatment-related adverse events.

[0240] Technical effects

[0241] The treatment regimen of this application has good efficacy in the treatment of hematological malignancies.

[0242] AML: The combination of the compound of formula I-1 described in this application, such as the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition and azacitidine or its pharmaceutically acceptable salt, or its pharmaceutical composition, has excellent effects in at least one of the objective response rate (ORR), complete response (CR) rate, complete response + complete response with partial hematological recovery (CR+CRh) rate (about 60%), complete response + complete response with incomplete hematological recovery (CR+CRi) rate, duration of complete response (DOCR), duration of response (DOR), duration of CR+CRh (DOCR+CRh), time to first CR / CRh (TTCRh), time to first complete response (TTCR), event-free survival (EFS), and overall survival (OS). Among them, CRh is complete response with partial hematological recovery: bone marrow blasts < 5%, absolute neutrophil count [ANC] ≥ 0.5 × 109 / L, PLT ≥ 50×10 9 / L, and no extramedullary lesions.

[0243] MDS: The combination of the compound of formula I-1 as described in the present application, such as the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and azacitidine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, has excellent effects in at least one aspect of objective response rate (ORR), complete remission (CR) rate, hematological improvement (HI) rate, transfusion independence rate (no transfusion required for at least 56 consecutive days after baseline), event-free survival (EFS), and overall survival (OS).

[0244] Moreover, for the combination described in the present application, the adverse event rate is low, its tolerance is good, and the side effects are small, including little impact on cardiovascular function, respiratory system, and central nervous system; it has good pharmacokinetic parameters (AUC, Cmax, half-life, etc.).

[0245] Secondly, for the combination described in the present application, in terms of CR rate, duration of CR + CRh (DOCR+CRh), event-free survival (EFS), overall survival (OS), rate of complete remission + complete remission with incomplete hematological recovery (CR+CRi), percentage of subjects with at least 1 negative minimal residual disease (MRD) (multiparameter flow cytometry, <10 -3 ) among CR subjects / CR + CRh subjects and CR+CRi subjects, duration of complete remission (DOCR), time to first CR / CRh (TTCRh) and time to first complete remission (TTCR), incidence and severity of adverse events (AE) and serious adverse events (SAE), and abnormal laboratory test indicators, it has advantages in at least one aspect.

[0246] Especially in terms of the incidence and severity of adverse events (AE) and serious adverse events (SAE), abnormal laboratory test indicators, and the rate of complete remission + complete remission with partial hematological recovery (CR+CRh). Detailed implementation manners

[0247] For clarity, the present application is further illustrated by examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0248] The compound of formula I-1, such as the compound of formula I, can be prepared by referring to the method disclosed in WO2020088442A1.

[0249] Example 1 Combination clinical trial

[0250] 1. Test drugs

[0251] Compound of Formula I: Specifications 10 mg, 100 mg, tablets.

[0252] Azacitidine (e.g., commercially available ): Specification 100 mg, azacitidine for injection.

[0253] 2. Enrolled patients

[0254] Inclusion criteria:

[0255] 1) Myeloid malignancies (acute myeloid leukemia or myelodysplastic syndromes) diagnosed according to the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues, 2016 Revision;

[0256] For AML patients, newly diagnosed AML has not received treatment for AML and is not suitable for intensive induction chemotherapy.

[0257] For myelodysplastic syndromes: Blast cells > 5%, Revised International Prognostic Scoring System (IPSS-R) > 3.5 points.

[0258] 3. Administration schedule

[0259] Tablets of the compound of Formula I, orally administered, taken with warm water within 30 minutes after a meal, 20 mg - 1200 mg each time, once a day, 28 days (if severe hematological toxicity occurs, it can be 21 days or 14 days, etc.) as a treatment cycle. The duration of the induction period will depend on the treatment dose level. The day when the treatment dose level is reached is defined as C1D1 of the treatment period.

[0260] Azacitidine for injection, subcutaneous injection, subcutaneously injected on days 1 - 7 of each treatment cycle, 75 mg / m 2 / day (or the dose is adjusted adaptively according to the patient's condition), every 28 days as a treatment cycle.

[0261] For the tablets of the compound of Formula I, the patient's induction period is carried out as follows. All are administered orally once a day in a daily increasing manner, and the last dose is the treatment dose:

[0262] 200 mg dose group: 100 mg → 200 mg

[0263] 400 mg dose group: 100 mg → 200 mg → 400 mg

[0264] 600 mg dose group: 100 mg → 200 mg → 400 mg → 600 mg

[0265] 800 mg dose group: 100 mg → 200 mg → 400 mg → 800 mg.

[0266] 4. Efficacy and safety indicators

[0267] Efficacy indicators

[0268] AML: including complete remission (CR), complete remission (CR) rate, morphological leukemia-free state (MLFS), ORR, complete remission (CR) + complete remission with incomplete hematological recovery (CRi) rate, CR + CRh duration (DOCR+CRh), duration of response (DOR), duration of complete remission (DOCR), time to first CR / CRh (TTCRh), time to first complete remission (TTCR), event-free survival (EFS), overall survival (OS), etc.

[0269] MDS: including objective remission rate (ORR), complete remission (CR) rate, hematological improvement (HI) rate, transfusion independence rate (no transfusion required for at least 56 consecutive days after baseline), event-free survival (EFS), overall survival (OS), etc.

[0270] Other indicators include: the percentage of subjects who achieve minimal residual disease (MRD) negativity (by multiparameter flow cytometry, <10 -3 ) in at least 1 of the CR subjects / CR + CRh subjects and CR + CRi subjects, etc.

[0271] Adverse events: the occurrence of all adverse events (AE), serious adverse events (SAE), and treatment-related adverse events (TRAEs), specifically including, for example, adverse reaction grades, overall incidence of adverse events, etc.

[0272] 5. Trial results

[0273] There were few adverse events. The treatment-related adverse events (TRAEs) related to the compound of formula I were mainly hematological adverse events and abnormal laboratory test values, mostly grade 1 - 2.

[0274] In AML patients, the ORR was 60% - 95% or 66% - 85% (e.g., 83%), and the CR + CRi rate was 35% - 65% or 40% - 60%

[0275] (e.g., 62%).

[0276] Partial efficacy data:

[0277] For example, 8 AML patients were evaluated, 4 achieved CR / CRi, 1 achieved MLFS, and 1 achieved PR.

[0278] For example, 29 AML patients who had been evaluated, 18 achieved CR / CRi, 4 achieved MLFS, and 2 achieved PR.

[0279] For example, 2 MDS patients were evaluated and 2 achieved mCR.

[0280] Patients who have or have not received prior treatment can all show benefits (for example, they can show benefits for a longer time, have good efficacy, and low side effects).

[0281] Exemplary results of the trial are as shown in Table 4 below:

[0282] Table 4

[0283]

[0284]

[0285] Example 2 Monotherapy Clinical Trial

[0286] 1. Test Drug

[0287] Compound of Formula I: Specifications 10 mg, 100 mg, tablets.

[0288] 2. Enrolled Patients

[0289] Inclusion Criteria:

[0290] 1) Hematological malignancies clearly diagnosed by histology or cytology;

[0291] 2) Patient population: Myeloid malignancies (acute myeloid leukemia)

[0292] 3) At least 1 lesion / measurable disease for efficacy evaluation.

[0293] 3. Administration Regimen

[0294] Tablet of Compound of Formula I, orally administered, taken with warm water within 30 minutes after a meal, 20 mg - 1200 mg each time, once a day, and 28 days (it can be 21 days or 14 days, etc. if severe hematological toxicity occurs) is one administration cycle.

[0295] The duration of the lead-in period will depend on the treatment dose level. The day when the treatment dose level is reached is defined as C1D1 of the treatment period.

[0296] For example, the lead-in period for patients is carried out as follows. All are administered orally once a day in a daily increasing manner, and the last dose is the treatment dose:

[0297] 200 mg dose group: 100 mg → 200 mg

[0298] 400 mg dose group: 100 mg → 200 mg → 400 mg

[0299] 600 mg dose group: 100 mg → 200 mg → 400 mg → 600 mg

[0300] 800 mg dose group: 100 mg → 200 mg → 400 mg → 800 mg.

[0301] 4. Efficacy and safety indicators

[0302] Efficacy indicators include CR rate, ORR, DOR, PFS, OS, etc.

[0303] Adverse events: The occurrence of all adverse events (AE), serious adverse events (SAE), and treatment-related adverse events (TEAEs), specifically including, for example, the grade of adverse reactions and the overall incidence of adverse events.

[0304] 5. Trial results

[0305] There were few adverse events. The treatment-related adverse events (TRAE) related to the compound of formula I were mainly hematological adverse events and abnormal laboratory test values, mostly grade 1 - 2.

[0306] In AML patients, the ORR was 25% - 65%, and the CR rate was 25% - 55%. In the 400 - 600 mg dose group, the ORR was 56 - 70%, and the CR rate was 44% - 60%.

[0307] Partial efficacy data:

[0308] For example, in the 400 - 600 mg dose group, 9 AML patients were evaluated, 4 achieved CR / CRi, and 1 achieved PR.

[0309] For example, in the evaluated AML patients, the number of complete remission cases / (the number of objective remission cases + the number of complete remission cases) reached 71%.

[0310] Patients who have received previous treatment (including first-line, second-line, third-line, or fourth-line) or have not received treatment can all show benefits (for example, they can show benefits for a longer time, have good efficacy, and low side effects).

[0311] The following Table 5 shows representative cases:

[0312] Table 5

[0313]

[0314] Example 3 Animal or cell experiments

[0315] 1. Determination of the combined activity of MOLM-13 cells (AML) proliferation inhibition drugs

[0316] Take MOLM-13 cells in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 2×10 4cells / mL, inoculated on a 96-well plate (100 μL / well), cultured overnight in a cell incubator, and the compounds were added using a nanoliter pipettor to make the final concentration of the compound of formula I 1000 nM - 0.06 nM or 10 nM - 0.0046 nM, and the final concentration of azacitidine 10000 nM - 0.6 nM (for example, 2000 nM - 0.91 nM), with 2 replicates, and single-drug groups, combination groups and control groups were set up. After continuing to culture in the cell incubator for 72 hours, the detection reagent CCK-8 was added, and after incubating in the cell incubator for 4 hours, the absorbance value was detected at 450 nm using an Envision microplate reader, and four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 and analyze the effect of drug combination.

[0317] The test results showed that the compound of formula I of the present application in combination with azacitidine had the effect of inhibiting the proliferation of MOLM-13 cells and showed synergistic effects.

[0318] Table 6

[0319] Compound <![CDATA[MOLM13 cells (IC 50 nM)]]> Azacitidine 128 Compound of formula I 0.64 Azacitidine + Compound of formula I 0.24

[0320] For MOLM13 cells, according to the analysis of CompuSyn software, azacitidine and the compound of formula I had a synergistic effect, and at most final concentrations, the combination index CI was between 0.3 and 0.8 (CI < 1 indicates a synergistic effect).

Claims

1. A combination of a BCL-2 inhibitor and a demethylating drug, wherein the BCL-2 inhibitor is selected from a compound of formula I-1 or a pharmaceutically acceptable salt thereof, R 11 Selected from hydrogen, halogen or C 1-6 alkyl; Ring A is selected from 5-6 membered heterocycloalkyl, R 22 are independently selected from 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, -COR aa 、-SO2R bb , or C optionally substituted by halogen 1-6 alkyl; R aa or R bb are independently selected from H, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with halogen, CN, -N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, or -OC 1-6 Alkyl substitution; p is selected from 0, 1, 2 or 3.

2. The combination according to claim 1, wherein the hypomethylating drug is selected from azacitidine or a pharmaceutically acceptable salt thereof.

3. The combination according to claim 1, for use in treating hematological tumors.

4. Use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a medicament for treating blood tumors in combination with azacitidine.

5. Use of a combination of a BCL-2 inhibitor and azacitidine or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating blood tumors, wherein the BCL-2 inhibitor is a compound of formula I-1 as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

6. A combination of a BCL-2 inhibitor and azacitidine or a pharmaceutically acceptable salt thereof for treating hematological tumors, wherein the BCL-2 inhibitor is a compound of formula I-1 as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

7. A kit for treating blood tumors, comprising: the BCL-2 inhibitor as claimed in claim 1, and instructions for using the BCL-2 inhibitor in combination with azacitidine or a pharmaceutically acceptable salt thereof to treat blood tumors.

8. The combination, kit or use according to any one of claims 1 to 7, wherein the BCL-2 inhibitor and azacitidine or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially.

9. The combination, kit or use according to any one of claims 1 to 8, wherein: Structure fragment Selected from Optionally, R 11 Selected from hydrogen, halogen or C 1-3 alkyl; Optionally, R 11 is selected from hydrogen, fluorine, chlorine or methyl; Optionally, R 11 is selected from hydrogen, chlorine or methyl; Optionally, Ring A is selected from 6-membered heterocycloalkyl; Optionally, Ring A is selected from 6-membered heterocycloalkyl containing one or more O atoms; Optionally, ring A is selected from dioxane or pyran ring; Optionally, R 22 are independently selected from 4-6 membered heterocycloalkyl, C 4-6 Cycloalkyl, -COR aa 、-SO2R bb , or C optionally substituted by halogen 1-4 alkyl; Optionally, R aa or R bb are independently selected from H, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with halogen, CN, -N(C 1-4 Alkyl)2, -NHC 1-4 Alkyl, or -OC 1-4 Alkyl substitution; Optionally, R 22 Each independently selected from -C(O)H, -COC(CH3)3, -COCF3, -COCH2CN, -COCH2N(CH3)2, -SO2CH2CH3, -SO2CF3, -SO2C2F5, -CF3, -C2F5, tetrahydropyran, monooxetane, -SO 2- Cyclopropane, -CO-cyclopropane, -CO-monooxetane, -SO 2- Monooxetane, or -SO 2- Cyclobutane; Optionally, p is selected from 0 or 1; Alternatively, the BCL-2 inhibitor or compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula I, formula II, formula III, or formula IV or a pharmaceutically acceptable salt thereof, 10. The combination, kit or use according to any one of claims 3 to 9, wherein the blood tumor is selected from advanced blood tumors; Optionally, the hematological tumor is selected from a myeloid tumor; Optionally, the hematological tumor or myeloid malignancy is selected from acute myeloid leukemia; Optionally, the blood tumor is selected from a treatment-naive blood tumor; Optionally, the blood tumor is selected from patients with newly diagnosed blood tumors who are ≥65 years old and / or are not suitable for strong induction chemotherapy; Optionally, the hematological tumor is selected from relapsed and / or refractory hematological tumors.

11. The combination, kit or use according to any one of claims 1 to 10, wherein the daily or per dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 10-5000 mg, 20-5000 mg, or 20-4000 mg, or 20-3000 mg, or 20-2000 mg, or 50-1500 mg, or 100-1200 mg, or 200-1000 mg, or 200-800 mg, or 200-600 mg, or 200-400 mg; Optionally, the daily or each dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg or 2000 mg, or a range formed by any of the above values; Optionally, the daily or each dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 100-800 mg; or, selected from 400-600 mg; Optionally, the administration frequency of the compound of formula I-1 or a pharmaceutically acceptable salt thereof can be 3 times a day, 2 times a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, 3 times a week, 2 times a week, once a week, once every two weeks, or once every three weeks; Optionally, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered orally within 30 minutes after starting a meal; Optionally, 8-32 days is used as one dosing cycle, for example, 8-28 days, 8-21 days, 8-15 days, 15-28 days, 15-21 days, 21-28 days, 21-32 days, 28-32 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, or 32 days is used as one dosing cycle; optionally, 28 days or 32 days is used as one dosing cycle; Optionally, before the subject receives a fixed therapeutic dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof during the treatment period, the subject is administered a gradient increasing dose (i.e., lead-in period) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof; Optionally, the dosage of azacitidine or a pharmaceutically acceptable salt thereof is selected from 75 mg / m 2 / sky; Optionally, azacitidine or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 7 of each treatment cycle; Optionally, the azacitidine or a pharmaceutically acceptable salt thereof is administered by subcutaneous injection.

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