WO2025124487A1 - Combination of trifluoromethyl-containing compound and furan-containing pyrrole compound for use in treating blood tumors - Google Patents

Abstract

A combination of a trifluoromethyl-containing compound and a furan-containing pyrrole compound for use in treating blood tumors. Specifically, the invention relates to the use of a combination of formula (I-1) or a pharmaceutically acceptable salt thereof and a compound of formula (II-1) or a pharmaceutically acceptable salt thereof in the treatment of blood tumors.

Description

Combination of trifluoromethyl compounds and furanopyrrole compounds for treating blood tumors

Citation of Related Applications

This application claims the priority and benefits of Chinese Patent Application No. 202311700719.1 filed with the State Intellectual Property Office of the People's Republic of China on December 12, 2023 and Chinese Patent Application No. 202411487255.5 filed with the State Intellectual Property Office of the People's Republic of China on October 23, 2024, the entire contents of which are hereby incorporated by reference into the text in their entirety.

Technical Field

The present application belongs to the field of medicine and relates to the use of a combination of a trifluoromethyl compound and a furanopyrrole compound in the treatment of blood tumors, and specifically relates to the use of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the treatment of blood tumors.

Background Art

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

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

Bruton's tyrosine kinase (BTK) is mainly expressed in B cells and distributed in the lymphatic system, hematopoietic system and blood system. It is a member of the non-receptor tyrosine kinase Tec family, which also includes TEC, ITK/TSK/EMT and BMX, which are highly homologous in structure. BTK plays a vital role in the B cell signaling pathway that connects the stimulation of the cell surface B cell receptor (B-cell receptor) to the downstream intracellular response. It is a key regulator of B cell development, activation, signaling and survival. In recent years, studies on B cells, especially B cell non-Hodgkin's lymphoma and rheumatoid arthritis, have found that BTK often shows abnormal expression. The development of small molecule targeted drugs based on the BTK signaling pathway provides a new approach for the treatment of B cell tumors such as leukemia, multiple myeloma and B cell immune diseases.

The combination of compounds that selectively inhibit the BCL-2 protein (BCL-2 inhibitors) with BTK inhibitors appears to bring clinical benefits to patients.

SUMMARY OF THE INVENTION

In one aspect, the present application provides use of a BCL-2 inhibitor in the preparation of a medicament for treating hematological tumors.

In another aspect, the present application provides use of a BCL-2 inhibitor in the preparation of a medicament for treating a blood tumor, wherein the treatment further comprises administering other drugs.

In another aspect, the present application provides use of a BCL-2 inhibitor in the preparation of a drug for treating blood tumors, wherein the drug is used in combination with other drugs.

On the other hand, the present application provides use of a BCL-2 inhibitor in the preparation of a drug for treating blood tumors, wherein the BCL-2 inhibitor is used in combination with other drugs.

On the other hand, the present application provides the use of a BCL-2 inhibitor in the preparation of a drug for treating blood tumors, and instructions for the combined use of a BCL-2 inhibitor and other drugs.

In another aspect, the present application provides a use of a BCL-2 inhibitor in preparing a kit for treating blood tumors, wherein the kit comprises a BCL-2 inhibitor and instructions for using the BCL-2 inhibitor in combination with other drugs.

On the other hand, the present application provides the use of a BCL-2 inhibitor in the preparation of a drug for treating blood tumors in combination with other drugs.

On the other hand, the present application provides use of a combination of a BCL-2 inhibitor and other drugs in the preparation of a drug for treating hematological tumors.

In one aspect, the present application provides a method for treating a hematological tumor, comprising administering a therapeutically effective amount of a BCL-2 inhibitor to a subject.

In one aspect, the present application also provides a BCL-2 inhibitor for treating hematological tumors.

In one aspect, the present application also provides use of a BCL-2 inhibitor for treating hematological tumors.

In some embodiments, the method of treating a blood tumor or the use of a BCL-2 inhibitor for treating a blood tumor further comprises administering other drugs to a subject in need of treatment.

In some embodiments, the above-mentioned BCL-2 inhibitor, method for treating a hematological tumor, or use for treating a hematological tumor, wherein the BCL-2 inhibitor is used in combination with other drugs.

In one aspect, the present application provides a combination of a BCL-2 inhibitor and other drugs. In some embodiments, the other drug is selected from a BTK inhibitor.

In one aspect, the present application provides a combination of a BCL-2 inhibitor and a BTK inhibitor.

In one aspect, the present application provides a method for treating a hematological tumor, comprising administering to a subject a therapeutically effective amount of a combination of a BCL-2 inhibitor and a BTK inhibitor.

In one embodiment, the method of treating a hematological tumor described herein comprises administering to a subject a combination of a therapeutically effective amount of a BCL-2 inhibitor and a therapeutically effective amount of a BTK inhibitor.

In some embodiments, the BCL-2 inhibitor and the BTK inhibitor are administered simultaneously or sequentially.

In another aspect, the present application provides use of a combination of a BCL-2 inhibitor and a BTK inhibitor in the preparation of a medicament for treating hematological tumors.

On the other hand, the present application also provides a combination of a BCL-2 inhibitor and a BTK inhibitor for treating hematological tumors.

On the other hand, the present application also provides use of a combination of a BCL-2 inhibitor and a BTK inhibitor for treating hematological tumors.

In some embodiments, the present application also provides a kit for treating hematological tumors, which comprises a BCL-2 inhibitor; optionally, it also comprises instructions for the combined use of the BCL-2 inhibitor and the BTK inhibitor.

In some embodiments, the present application also provides a kit for treating a blood tumor, which comprises a BCL-2 inhibitor; optionally, it also comprises instructions for using the BCL-2 inhibitor and a BTK inhibitor in combination to treat a blood tumor.

In another aspect, the present application provides use of a BTK inhibitor in the preparation of a medicament for treating a hematological tumor, wherein the treatment further comprises administering a BCL-2 inhibitor.

On the other hand, the present application provides use of a BTK inhibitor in the preparation of a medicament for treating hematological tumors, wherein the medicament is used in combination with a BCL-2 inhibitor.

On the other hand, the present application provides use of a BTK inhibitor in the preparation of a medicament for treating hematological tumors, wherein the BTK inhibitor is used in combination with a BCL-2 inhibitor.

On the other hand, the present application provides the use of a BTK inhibitor in the preparation of a medicament for treating blood tumors, and instructions for the combined use of a BTK inhibitor and a BCL-2 inhibitor.

On the other hand, the present application provides a use of a BTK inhibitor in the preparation of a kit for treating a hematological tumor, wherein the kit comprises a BTK inhibitor and instructions for the combined use of the BTK inhibitor and a BCL-2 inhibitor.

On the other hand, the present application provides the use of a BTK inhibitor in the preparation of a medicament for treating hematological tumors in combination with a BCL-2 inhibitor.

In some embodiments, the present application also provides a kit for treating blood tumors, which comprises a BTK inhibitor; and also includes instructions for the combined use of a BCL-2 inhibitor and a BTK inhibitor.

In some embodiments, the present application also provides a kit for treating blood tumors, which comprises a BTK inhibitor; and also includes instructions for using a BCL-2 inhibitor and a BTK inhibitor in combination to treat blood tumors.

In some embodiments, the present application also provides a kit for treating a blood tumor, comprising: a combination of a BCL-2 inhibitor and a BTK inhibitor; optionally, instructions for use of the combination of the BCL-2 inhibitor and the BTK inhibitor. In some embodiments, the instructions for use are instructions for instructing a subject to administer the combination of the BCL-2 inhibitor and the BTK inhibitor.

In some embodiments, the BCL-2 inhibitor and the BTK inhibitor in the combination are each packaged in a separate kit, which further includes instructions for the combined use of the BCL-2 inhibitor and the BTK inhibitor to treat a hematological tumor.

In some embodiments, the BCL-2 inhibitor and the BTK inhibitor are administered simultaneously or sequentially.

In some embodiments, the BCL-2 inhibitor may be a pharmaceutical composition comprising a BCL-2 inhibitor. In some embodiments, the BTK inhibitor may be a pharmaceutical composition comprising a BTK inhibitor. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

In some embodiments, the combination is a fixed combination or a non-fixed combination. In some embodiments, the BCL-2 inhibitor and the BTK inhibitor are co-formulated in a pharmaceutical composition or are separately formulated into separate pharmaceutical compositions. In some embodiments, the BCL-2 inhibitor and the BTK inhibitor are separately formulated into separate pharmaceutical compositions and are separately packaged in separate kits.

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

wherein R ¹¹ is selected from hydrogen, halogen or C _1-6 alkyl;

Ring A is selected from 5-6 membered heterocycloalkyl,

R ²² is independently selected from 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, -COR ^aa , -SO ₂ R ^bb , or C _1-6 alkyl optionally substituted by halogen;

^Raa or ^Rbb are each independently selected from H, 4-6 membered heterocycloalkyl, _C3-6 cycloalkyl, or _C1-6 alkyl, wherein the _C1-6 alkyl is optionally substituted with halogen, CN, -N( _C1-6 alkyl) ₂ , _-NHC1-6 alkyl, or _-OC1-6 alkyl;

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

In some embodiments, the structural fragment Selected from

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.

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 6-membered heterocycloalkyl containing 1 or 2 O atoms. In some embodiments, ring A is selected from dioxane or pyran ring.

In some embodiments, R ²² is each independently selected from 4-6 membered heterocycloalkyl, C _4-6 cycloalkyl, -COR ^aa , -SO ₂ R ^bb , or C _1-4 alkyl optionally substituted with halogen.

In some embodiments, ^Raa or ^Rbb are each independently selected from H, 4-6 membered heterocycloalkyl, _C3-6 cycloalkyl, or _C1-4 alkyl, said _C1-4 alkyl optionally substituted with halogen, CN, -N( _C1-4 alkyl) ₂ , _-NHC1-4 alkyl, or _-OC1-4 alkyl.

In some embodiments, R ²² is each independently selected from -C(O)H, -COC(CH ₃ ) ₃ , -COCF ₃ , -COCH ₂ CN, -COCH ₂ N(CH ₃ ) ₂ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CF ₃ , -SO ₂ C ₂ F ₅ , -CF ₃ , -C ₂ F ₅ , tetrahydropyran, monooxetane, -SO ₂ -cyclopropane, -CO-cyclopropane, -CO-monooxetane, -SO ₂ -monooxetane, or -SO ₂ -cyclobutane.

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

In some embodiments, the BCL-2 inhibitor described herein can be selected from Compound I, Compound II, Compound III, or Compound IV or a pharmaceutically acceptable salt thereof.

In some embodiments, the BCL-2 inhibitor is selected from Compound I or a pharmaceutically acceptable salt thereof; or selected from Compound II or a pharmaceutically acceptable salt thereof; or selected from Compound III or a pharmaceutically acceptable salt thereof; or selected from Compound IV or a pharmaceutically acceptable salt thereof.

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

In one aspect, the present application provides a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a BTK inhibitor.

In some embodiments, the BTK inhibitor described herein is selected from a compound of formula II-1 or a pharmaceutically acceptable salt thereof,

wherein R ¹ is independently selected from halogen or C _1-3 alkyl optionally substituted by fluorine;

m is selected from 0, 1 or 2;

R ² are each independently selected from halogen, -OH, -NH ₂ or C _1-3 alkyl;

n is selected from 0, 1 or 2;

^R3 is selected from ^RaC (O)-, ^Ra is selected from _C2-3alkynyl , _C2-3alkenyl , _C1-3alkyl or _{C3-4cycloalkyl} .

In some embodiments, R ¹ is trifluoromethyl.

In some embodiments, m is selected from 0 or 1. In some embodiments, m is 0.

In some embodiments, m is 1 and R ¹ is trifluoromethyl.

In some embodiments, R ² is each independently selected from halogen. In some embodiments, R ² is independently fluorine.

In some embodiments, n is selected from 0 or 1. In some embodiments, n is 0.

In some embodiments, n is 1 and ^R2 is fluoro.

In some embodiments, ^Ra is selected from propynyl, _C2-3alkenyl , or cyclopropyl.

In some embodiments, ^Ra is selected from _CH3C≡C- , _CH2 =CH-, or cyclopropyl.

In some embodiments, m and n are 0; alternatively, m and n are both 1. In some embodiments, m is 1, R ¹ is trifluoromethyl, and n is 1, R ² is fluoro.

In some embodiments, the BTK inhibitor is selected from Compound A, Compound B, Compound C, Compound D, or a pharmaceutically acceptable salt thereof:

In some embodiments, the BTK inhibitor is selected from Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the BTK inhibitor is selected from Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the BTK inhibitor is selected from Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the BTK inhibitor is selected from Compound D or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula B or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula C or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula D or a pharmaceutically acceptable salt thereof.

In one aspect, the present application provides use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating blood tumors.

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 treating a blood tumor, wherein the treatment further comprises administering a compound of formula II-1 or a pharmaceutically acceptable salt thereof. On the other hand, the present application provides the use of a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a blood tumor, wherein the treatment further comprises administering a compound of formula I-1 or a pharmaceutically acceptable salt thereof.

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 drug for treating a blood tumor, wherein the drug is used in combination with a compound of formula II-1 or a pharmaceutically acceptable salt thereof. On the other hand, the present application provides the use of a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a blood tumor, wherein the drug is used in combination with a compound of formula I-1 or a pharmaceutically acceptable salt thereof.

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 drug for treating a blood tumor, wherein the compound of formula I-1 or a pharmaceutically acceptable salt thereof is used in combination with a compound of formula II-1 or a pharmaceutically acceptable salt thereof. On the other hand, the present application provides the use of a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a blood tumor, wherein the compound of formula II-1 or a pharmaceutically acceptable salt thereof is used in combination with a compound of formula I-1 or a pharmaceutically acceptable salt thereof.

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 drug for treating a blood tumor, and a description of the combined use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof. On the other hand, the present application provides the use of a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a blood tumor, and a description of the combined use of a compound of formula II-1 or a pharmaceutically acceptable salt thereof and a compound of formula I-1 or a pharmaceutically acceptable salt thereof.

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 treating a blood tumor, the kit comprising a compound of formula I-1 or a pharmaceutically acceptable salt thereof, and instructions for the combined use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof. On the other hand, the present application provides the use of a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a kit for treating a blood tumor, the kit comprising a compound of formula II-1 or a pharmaceutically acceptable salt thereof, and instructions for the combined use of a compound of formula II-1 or a pharmaceutically acceptable salt thereof and a compound of formula I-1 or a pharmaceutically acceptable salt thereof.

On the other hand, the present application provides the use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating blood tumors in combination with the compound of formula II-1 or a pharmaceutically acceptable salt thereof.

On the other hand, the present application provides use of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating blood tumors.

In one aspect, the present application provides a method for treating a blood tumor, comprising administering a therapeutically effective amount of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof to a subject.

In some embodiments, the present application provides a method for treating a hematological tumor, comprising administering to a subject a therapeutically effective amount of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a compound of formula II-1 or a pharmaceutically acceptable salt thereof in combination.

In one aspect, the present application also provides a compound of formula I-1 or a pharmaceutically acceptable salt thereof for use in treating blood tumors.

In some embodiments, the present application also provides a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof for treating a blood tumor.

In one aspect, the present application also provides use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof for treating blood tumors.

In some embodiments, the present application also provides use of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof for treating hematological tumors.

In some embodiments, the method or use of the compound of formula I-1 or its pharmaceutically acceptable salt for treating blood tumors further comprises administering the compound of formula II-1 or its pharmaceutically acceptable salt to a subject in need of treatment. In some embodiments, the method or use of the compound of formula II-1 or its pharmaceutically acceptable salt for treating blood tumors further comprises administering the compound of formula I-1 or its pharmaceutically acceptable salt to a subject in need of treatment.

In some embodiments, the above-mentioned compound of formula I-1 or its pharmaceutically acceptable salt for treating blood tumors, methods for treating blood tumors, or uses for treating blood tumors, wherein the compound of formula I-1 or its pharmaceutically acceptable salt is used in combination with the compound of formula II-1 or its pharmaceutically acceptable salt. In some embodiments, the above-mentioned compound of formula II-1 or its pharmaceutically acceptable salt for treating blood tumors, methods for treating blood tumors, or uses for treating blood tumors, wherein the compound of formula II-1 or its pharmaceutically acceptable salt is used in combination with the compound of formula I-1 or its pharmaceutically acceptable salt.

In one aspect, the present application provides a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof.

In one aspect, the present application provides a method for treating a hematological tumor, comprising administering to a subject a therapeutically effective amount of the combination described herein.

On the other hand, the present application provides use of the combination in preparing a medicament for treating blood tumors.

On the other hand, the present application also provides the combination for treating hematological tumors.

On the other hand, the present application also provides use of the combination for treating blood tumors.

On the other hand, the present application provides a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof for treating a blood tumor. In some embodiments, the present application also provides a kit for treating a blood tumor, comprising: containing a compound of formula I-1 or a pharmaceutically acceptable salt thereof; optionally, also including instructions for the combined use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the present application also provides a kit for treating a blood tumor, comprising: containing a compound of formula II-1 or a pharmaceutically acceptable salt thereof; also including instructions for the combined use of a compound of formula II-1 or a pharmaceutically acceptable salt thereof and a compound of formula I-1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application also provides a kit for treating blood tumors, which comprises: a compound of formula I-1 or a pharmaceutically acceptable salt thereof; optionally, instructions for using the compound of formula I-1 or a pharmaceutically acceptable salt thereof and the compound of formula II-1 or a pharmaceutically acceptable salt thereof in combination to treat blood tumors. In some embodiments, the present application also provides a kit for treating blood tumors, which comprises: a compound of formula II-1 or a pharmaceutically acceptable salt thereof; instructions for using the compound of formula II-1 or a pharmaceutically acceptable salt thereof and the compound of formula I-1 or a pharmaceutically acceptable salt thereof in combination to treat blood tumors.

In some embodiments, the present application also provides a kit for treating blood tumors, comprising: the combination described in the present application; optionally, instructions for use of the combination. In some embodiments, the instructions for use are to guide the subject to administer the combination.

In some embodiments, the present application also provides a kit for treating blood tumors, comprising: a compound of formula I-1 or a pharmaceutically acceptable salt thereof; and a compound of formula II-1 or a pharmaceutically acceptable salt thereof; optionally, also including instructions for using the compound of formula I-1 or a pharmaceutically acceptable salt thereof and the compound of formula II-1 or a pharmaceutically acceptable salt thereof in combination to treat blood tumors.

In some embodiments, the compound of formula I-1 or its pharmaceutically acceptable salt and the compound of formula II-1 or its pharmaceutically acceptable salt in the combination are each packaged in an independent kit, and the independent kit also includes instructions for the combined use of the compound of formula I-1 or its pharmaceutically acceptable salt and the compound of formula II-1 or its pharmaceutically acceptable salt to treat hematological tumors.

In some embodiments, the compound of formula I-1 or its pharmaceutically acceptable salt and the compound of formula II-1 or its pharmaceutically acceptable salt are administered simultaneously or sequentially. In some embodiments, the compound of formula I-1 or its pharmaceutically acceptable salt may be a pharmaceutical composition comprising the compound of formula I-1 or its pharmaceutically acceptable salt. In some embodiments, the compound of formula II-1 or its pharmaceutically acceptable salt may be a pharmaceutical composition comprising the compound of formula II-1 or its pharmaceutically acceptable salt. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

In some embodiments, the combination is a fixed combination or a non-fixed combination. In some embodiments, the compound of formula I-1 or its pharmaceutically acceptable salt and the compound of formula II-1 or its pharmaceutically acceptable salt 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 its pharmaceutically acceptable salt and the compound of formula II-1 or its pharmaceutically acceptable salt are separately formulated into separate pharmaceutical compositions and are separately contained in separate kits.

Hematologic malignancies

In some embodiments, the blood tumor is selected from an advanced blood tumor. In some embodiments, the blood tumor is selected from a relapsed and/or refractory blood tumor. In some embodiments, the blood tumor is selected from a relapsed and/or refractory advanced blood tumor.

In some embodiments, the blood tumor is selected from blood tumors clearly diagnosed by histology or cytology.In some embodiments, the above diagnosis meets the 2016 diagnostic criteria of WHO.

In some embodiments, the hematological tumor is selected from lymphoid tumors.

In some embodiments, the hematological tumor is selected from non-Hodgkin's lymphoma (NHL). In some embodiments, the hematological tumor is selected from non-Hodgkin's B-cell lymphoma.

In some embodiments, the hematological neoplasm or non-Hodgkin's lymphoma is selected from mantle cell lymphoma, chronic lymphocytic leukemia, and/or small lymphocytic lymphoma.

In some embodiments, the blood tumor or the subject has not been treated with a previous treatment regimen. In some embodiments, the blood tumor or the subject has been treated with one or more previous treatment regimens. In some embodiments, the blood tumor or the subject has been treated with one, two, three, four, five or six or more (including six) previous treatment regimens.

In some embodiments, the blood tumor is selected from a newly treated blood tumor. In some embodiments, the blood tumor is selected from a relapsed and/or refractory blood tumor. In some embodiments, the blood tumor is selected from a relapsed and/or refractory advanced blood tumor. In some embodiments, the relapsed and refractory subject includes a subject for whom standard treatment regimens are ineffective, intolerant, or inaccessible.

In some embodiments, the blood tumor or the subject is selected from those who have relapsed or failed treatment after previous treatment. In some embodiments, the blood tumor or the subject is selected from those who have relapsed or failed treatment after previous standard treatment. In some embodiments, the blood tumor or the subject is selected from those who have failed previous treatment. In some embodiments, the blood tumor or the subject is selected from those who have failed after standard treatment. In some embodiments, the blood tumor or the subject is selected from those who are intolerant to previous treatment regimens. In some embodiments, the blood tumor or the subject is selected from those who are intolerant to standard treatment regimens. In some embodiments, the blood tumor or the subject is selected from those who are intolerant to previous treatment regimens and have no other better treatment options. In some embodiments, the blood tumor or the subject is selected from those who are intolerant to standard treatment regimens and have no other better treatment options.

In some embodiments, the blood tumor or the subject is selected from those who have previously received at least one systemic systemic treatment regimen, have disease progression or intolerance during or after the most recent treatment, or have not been relieved after adequate treatment. In some embodiments, the blood tumor or the subject is selected from those who have previously received at least one, two, three, four, five or six systemic systemic treatment regimens, have disease progression or intolerance during or after the most recent treatment, or have not been relieved after adequate treatment. In some embodiments, the blood tumor or the subject is selected from those who have previously received at least one, two, three or four systemic systemic treatment regimens, have disease progression or intolerance during or after the most recent treatment, or have not been relieved after adequate treatment. In some embodiments, the blood tumor or the subject is selected from those who have previously received at least one or two systemic systemic treatment regimens, have disease progression or intolerance during or after the most recent treatment, or have not been relieved after adequate treatment.

In some embodiments, the previously received treatment regimen includes a first-line treatment regimen, a second-line treatment regimen, a third-line treatment regimen, a fourth-line treatment regimen, a fifth-line treatment regimen, and/or a sixth-line treatment regimen. In some embodiments, the previously received treatment regimen includes a first-line treatment regimen, a second-line treatment regimen, and/or a third-line treatment regimen.

In some embodiments, the hematological tumor or the subject has at least one lesion/measurable disease that is evaluable for efficacy.

In some embodiments, the non-Hodgkin's lymphoma or the subject has at least one radiologically measurable tumor lesion in two perpendicular directions (e.g., the long diameter of the intranodal lesion is >15 mm, and the long diameter of the extranodal lesion is >10 mm) as assessed by CT or MRI.

In some embodiments, the blood tumor or the subject has been previously treated with a BCL-2 inhibitor. In some embodiments, the blood tumor or the subject has been previously treated with a BTK inhibitor. In some embodiments, the blood tumor or the subject has not been previously treated with a combination of a BCL-2 inhibitor and a BTK inhibitor. In some embodiments, the BCL-2 inhibitor includes but is not limited to venetoclax or pelcitoclax.

In some embodiments, optionally, the subject with hematological tumor has the following comorbidities:

For patients who have had or are currently suffering from other malignant tumors within 5 years before the first use of the drug, the tumor patients can be patients with other malignant tumors who have been treated with a single surgery and achieved 5 consecutive years of disease-free survival (DFS);

Alternatively, the patient with the tumor or advanced malignancy may be a cured patient of carcinoma in situ of the cervix, non-melanoma skin cancer, and superficial bladder tumors including but not limited to Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor invading basement membrane).

In some embodiments, the subject with the hematological tumor does not have any one or more of the following conditions:

1) Patients diagnosed with Burkitt lymphoma, lymphoblastic lymphoma/leukemia; and/or,

2) Central nervous system (CNS) involvement; and/or,

3) Previously received allogeneic hematopoietic stem cell transplantation; and/or,

4) Unresolved toxicity of ≥CTC AE grade 1 due to any prior treatment, excluding alopecia; and/or,

5) The presence of active or uncontrolled primary autoimmune cytopenia, including autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), etc.; and/or,

6) Arterial/venous thrombotic events occurred within 6 months before the first use of the drug; and/or,

7) Patients with any severe and/or uncontrolled illness; and/or,

8) Patients who have received chemotherapy or radiotherapy within 4 weeks before the first use of the drug, or have received immune checkpoint inhibitors or CAR-T treatment within 12 weeks before the first use of the drug, and other anti-tumor treatments received before the first use of the drug (the washout period is calculated from the end of the last treatment) are within 5 half-lives.

In some embodiments, the arterial/venous thrombotic event occurring within 6 months before the first medication in 6) above may optionally refer to cerebrovascular accident (including but not limited to transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism, etc.

In some embodiments, patients with any severe and/or uncontrolled diseases mentioned in 7) above include: 1. Patients with ≥ grade 2 myocardial ischemia or myocardial infarction, arrhythmia (QTc>450ms for males, QTc>470ms for females) and ≥ grade 2 congestive heart failure (New York Heart Association (NYHA) classification) within 6 months prior to the first medication; 2. Patients with active serious infection (≥CTC AE grade 2 infection), left ventricular ejection fraction (LVEF) assessed by cardiac ultrasound <50%; 3. Active hepatitis; 4. Patients with a history of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency diseases, or a history of organ transplantation; 5. Patients with epilepsy and requiring treatment.

Mantle Cell Lymphoma (MCL)

In some embodiments, the hematological tumor, lymphoid tumor, or non-Hodgkin's lymphoma is selected from mantle cell lymphoma.

In some embodiments, the mantle cell lymphoma is selected from relapsed and/or refractory mantle cell lymphoma. In some embodiments, the relapsed and/or refractory mantle cell lymphoma subjects include subjects for whom standard treatment regimens are ineffective, or cannot be tolerated, or are inaccessible. The relapsed and/or refractory mantle cell lymphoma subjects have at least received treatment with immunochemotherapy and/or BTK inhibitors. In some embodiments, the relapsed and/or refractory mantle cell lymphoma subjects have previously received at least one line of systemic standard treatment (e.g., anti-CD20 therapy). In some embodiments, the relapsed and/or refractory mantle cell lymphoma subjects have no remission after the last line of treatment (including but not limited to 4 cycles of standard treatment and more stable disease or 1 cycle of standard treatment and more disease progression) or relapse after remission.

In some embodiments, the mantle cell lymphoma or the subject is selected from patients who are treatment naive and cannot tolerate intensive chemotherapy.

In some embodiments, the mantle cell lymphoma is selected from treatment-naive mantle cell lymphoma. In some embodiments, the mantle cell lymphoma or the subject is selected from patients who have not previously received systemic treatment for mantle cell lymphoma.

In some embodiments, the mantle cell lymphoma is selected from mantle cell lymphoma that meets the WHO 2016 diagnostic criteria.

In some embodiments, the mantle cell lymphoma is selected from mantle cell lymphoma that is positive for CD5 and CD20 by immunohistochemistry or flow cytometry. In some embodiments, the mantle cell lymphoma is selected from mantle cell lymphoma that is positive for cyclin D1 and/or has a t(11;14) translocation. In some embodiments, the mantle cell lymphoma is selected from mantle cell lymphoma that is positive for CD5 and CD20 by immunohistochemistry or flow cytometry, and is positive for cyclin D1 and/or has a t(11;14) translocation.

In some embodiments, the mantle cell lymphoma or the subject has at least one imaging measurable tumor lesion in two perpendicular directions as assessed by CT or MRI. Optionally, the tumor lesion is selected from intranodal lesions with a long diameter of >15 mm and extranodal lesions with a long diameter of >10 mm.

In some embodiments, the mantle cell lymphoma or the subject has not been treated with a prior treatment regimen. In some embodiments, the mantle cell lymphoma or the subject has been treated with one or more prior treatment regimens. In some embodiments, the mantle cell lymphoma or the subject has been treated with one, two, three, four, or five prior treatment regimens.

In some embodiments, the mantle cell lymphoma or the subject has previously received at least one systemic treatment regimen, and there is disease progression or intolerance during or after the most recent treatment, or there is no relief after adequate treatment. In some embodiments, the mantle cell lymphoma or the subject is selected from those who have previously received at least one or two systemic treatment regimens, there is disease progression or intolerance during or after the most recent treatment, or there is no relief after adequate treatment. In some embodiments, the mantle cell lymphoma or the subject is selected from those who have previously received at least one, two, three or four systemic treatment regimens, there is disease progression or intolerance during or after the most recent treatment, or there is no relief after adequate treatment.

In some embodiments, the mantle cell lymphoma or the subject has previously received at least one line of systemic standard treatment, and the last line of treatment is refractory and has no remission or relapses after remission. In some embodiments, the refractory and no remission refers to 4 cycles of standard treatment and more stable disease or 1 cycle of standard treatment and more disease progression. In some embodiments, the previously received treatment regimen includes a first-line treatment regimen, a second-line treatment regimen, a third-line treatment regimen, a fourth-line treatment regimen, a fifth-line treatment regimen, and/or a sixth-line treatment regimen. In some embodiments, the previously received treatment regimen includes a first-line treatment regimen, a second-line treatment regimen, a third-line treatment regimen, and/or a fourth-line treatment regimen. In some embodiments, the previously received treatment regimen includes a first-line treatment regimen, a second-line treatment regimen, and/or a third-line treatment regimen.

In some embodiments, the mantle cell lymphoma or the subject's prior treatment included anti-CD20 therapy.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)

In some embodiments, the hematological tumor, lymphoid tumor, or non-Hodgkin's lymphoma is selected from chronic lymphocytic leukemia or small lymphocytic lymphoma.

In some embodiments, the lymphoid tumor or non-Hodgkin's lymphoma is selected from chronic lymphocytic leukemia or small lymphocytic lymphoma that has not been previously treated with systemic treatment for CLL/SLL. In some embodiments, the lymphoid tumor or non-Hodgkin's lymphoma is selected from chronic lymphocytic leukemia or small lymphocytic lymphoma that has not previously been treated with systemic treatment for CLL/SLL.

In some embodiments, the lymphoid tumor or non-Hodgkin's lymphoma is selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma that meet the diagnostic criteria of the International Working Group on Chronic Lymphocytic Lymphoma (iwCLL) and meet at least one treatment indication.

In some embodiments, the chronic lymphocytic leukemia or small lymphocytic lymphoma is selected from relapsed and/or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. In some embodiments, the relapsed and/or refractory CLL/SLL subjects include subjects who are ineffective, intolerant, or inaccessible to standard treatment regimens. The relapsed and/or refractory CLL/SLL subjects have at least received treatment with immunochemotherapy and/or BTK inhibitors. In some embodiments, the relapsed and/or refractory CLL/SLL subjects have previously received at least one first-line systemic standard treatment (e.g., anti-CD20 treatment). In some embodiments, the relapsed and/or refractory CLL/SLL subjects have no remission (including but not limited to standard treatment for 4 cycles and above of stable disease or standard treatment for 1 cycle and above of disease progression) or relapse after remission.

In some embodiments, the chronic lymphocytic leukemia or small lymphocytic lymphoma is selected from relapsed and/or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma that meets the iwCLL diagnostic criteria and meets at least one treatment indication.

In some embodiments, the chronic lymphocytic leukemia or small lymphocytic lymphoma or the subject has not been treated with a prior treatment regimen (e.g., systemic therapy). In some embodiments, the chronic lymphocytic leukemia or small lymphocytic lymphoma or the subject has been treated with one or more prior treatment regimens. In some embodiments, the chronic lymphocytic leukemia or small lymphocytic lymphoma or the subject has been treated with one, two, three, four, five, or six prior treatment regimens. In some embodiments, the chronic lymphocytic leukemia or small lymphocytic lymphoma or the subject has been treated with one, two, three, four, or five prior treatment regimens.

In some embodiments, the chronic lymphocytic leukemia or small lymphocytic lymphoma or the subject is selected from those who have received at least one line of systemic standard treatment in the past, and the last line of treatment is refractory without remission or relapses after remission. In some embodiments, the refractory without remission refers to 4 cycles of standard treatment and more stable disease or 1 cycle of standard treatment and more disease progression. In some embodiments, the previously accepted treatment regimen includes a first-line treatment regimen, a second-line treatment regimen, a third-line treatment regimen, a fourth-line treatment regimen, a fifth-line treatment regimen and/or a sixth-line treatment regimen. In some embodiments, the previously accepted treatment regimen includes a first-line treatment regimen, a second-line treatment regimen, and/or a third-line treatment regimen.

In some embodiments, the chronic lymphocytic leukemia or small lymphocytic lymphoma or the subject has previously received at least one systemic systemic treatment regimen, and there is disease progression or intolerance during or after the most recent treatment, or there is no remission after adequate treatment. In some embodiments, the chronic lymphocytic leukemia or small lymphocytic lymphoma or the subject is selected from those who have previously received at least one or two systemic systemic treatment regimens, there is disease progression or intolerance during or after the most recent treatment, or there is no remission after adequate treatment. In some embodiments, the chronic lymphocytic leukemia or small lymphocytic lymphoma or the subject is selected from those who have previously received at least one, two, three, four, five and/or six systemic systemic treatment regimens, there is disease progression or intolerance during or after the most recent treatment, or there is no remission after adequate treatment.

In some embodiments, the chronic lymphocytic leukemia or the subject has a peripheral blood monoclonal B lymphocyte count>5×10 ⁹ /L, or there are imaging measurable lesions. In some embodiments, the chronic lymphocytic leukemia or the subject has at least one imaging measurable tumor lesion in two perpendicular directions as assessed by CT or MRI. Optionally, the tumor lesion is selected from the group consisting of intranodal lesions with a long diameter>15mm and extranodal lesions with a long diameter>10mm.

In some embodiments, the small lymphocytic lymphoma or the subject has at least one imaging-measurable tumor lesion in two perpendicular directions as assessed by CT or MRI. Optionally, the tumor lesion is selected from intranodal lesions with a long diameter of >15 mm and extranodal lesions with a long diameter of >10 mm.

Dosage regimen

The method of administration can be comprehensively determined according to the activity, toxicity and tolerance of the subject/patient of the drug. Those skilled in the art can determine the appropriate amount, dosage or dosage of each drug used in combination of the present invention to be applied to the subject/patient. Those skilled in the art can adjust the dosage and dosage regimen according to methods well known in the therapeutic field. For example, the maximum tolerated dose can be easily determined, and the effective amount that can be detected for the subject/patient can also be determined, and the time requirement for applying each drug to provide a detectable therapeutic benefit to the subject/patient can also be determined. Therefore, although the application illustrates certain dosages and dosage regimens, these examples are by no means limited to the dosages and dosage regimens that can be provided to the subject/patient when practicing the present invention.

The present application provides a method for treating hematological tumors, comprising administering to a subject a dose (daily or each time) selected from 20-2000 mg, 20-1200 mg or 100-1200 mg of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and 10-500 mg of a compound of formula II-1 or a pharmaceutically acceptable salt thereof.

The present application provides the use of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating blood tumors, wherein the drug (daily or each time) contains 20-2000 mg, 20-1200 mg or 100-1200 mg of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and 10-500 mg of a compound of formula II-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 drug for treating blood tumors in combination with a compound of formula II-1 or a pharmaceutically acceptable salt thereof, wherein the drug (daily or each time) contains 20-2000 mg, 20-1200 mg or 100-1200 mg of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and 10-500 mg of a compound of formula II-1 or a pharmaceutically acceptable salt thereof. The present application provides the use of a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for use in combination with a compound of formula I-1 or a pharmaceutically acceptable salt thereof to treat blood tumors, wherein the drug (daily or each time) contains 20-2000 mg, 20-1200 mg or 100-1200 mg of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and 10-500 mg of a compound of formula II-1 or a pharmaceutically acceptable salt thereof. 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 a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating blood tumors, wherein the drug contains a single dose or multiple doses of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof.

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 a compound of formula II-1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hematological tumors, wherein the dosage (daily or each time) 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, and the dosage (daily or each time) of the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from 10-500 mg.

The present application also provides a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof for treating hematological tumors, wherein the dosage of the compound of formula I-1 or its pharmaceutically acceptable salt (daily or each time) is selected from 20-2000 mg, 20-1200 mg or 100-1200 mg, and the dosage of the compound of formula II-1 or its pharmaceutically acceptable salt (daily or each time) is selected from 10-500 mg.

The present application also provides the use of a combination of the compound of formula I-1 or its pharmaceutically acceptable salt and the compound of formula II-1 or its pharmaceutically acceptable salt for treating blood tumors, wherein the dosage of the compound of formula I-1 or its pharmaceutically acceptable salt (daily or each time) is selected from 20-2000 mg, 20-1200 mg or 100-1200 mg, and the dosage of the compound of formula II-1 or its pharmaceutically acceptable salt (daily or each time) is selected from 10-500 mg.

In some embodiments, the present application also provides a kit for treating tumors, comprising: a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof; optionally, instructions for use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and the compound of formula II-1 or a pharmaceutically acceptable salt thereof, the instructions for use involving the administration dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof (daily or each time) selected from 20-2000 mg, 20-1200 mg or 100-1200 mg, and the administration dose of the compound of formula II-1 or a pharmaceutically acceptable salt thereof (daily or each time) selected from 10-500 mg. In some embodiments, the instructions for use refer to guiding the subject to administer the compound of formula I-1 or a pharmaceutically acceptable salt thereof and the compound of formula II-1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the daily or each dose of the compound of formula I-1 of the present application 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. In some embodiments, the daily or each dose of the compound of formula I-1 of the present application 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 any value in the range formed by any of the above values. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt is selected from 100-1200mg, 100-800mg, 200-800mg or 200-600mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt is selected from 200-1000mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt is selected from 10-800mg or 20mg-800mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt is selected from 10-300mg, 20-400mg, 20-200mg or 20-100mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt is selected from 10mg, 20mg, 50mg, 100mg, 200mg, 300mg or 400mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt is selected from 200mg, 400mg, 600mg, 800mg, 1000mg or 1200mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt is selected from 100-800mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt is selected from 400-600mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt is selected from 200mg, 400mg, 500mg or 600mg. In some embodiments, the daily or each dose of the formula I-1 compound of the present application or its pharmaceutically acceptable salt is selected from 20mg, 50mg, 100mg, 200mg or 400mg. In some embodiments, the daily or each dose of the compound of formula I-1 of the present application or a pharmaceutically acceptable salt thereof is selected from 100 mg, 200 mg or 400 mg.

In some embodiments of the present application, the compound of formula I-1 or its pharmaceutically acceptable salt is administered at 0.0001 to 20 mg/kg weight each time. In some embodiments of the present application, the compound of formula I-1 or its pharmaceutically acceptable salt is administered at 0.001 to 20 mg/kg weight each time.

In some embodiments, the frequency of administration of the compound of formula I-1 or its pharmaceutically acceptable salt may be 3 times a day, 2 times a day, 1 time a day, 1 time every two days, 1 time every three days, 1 time every four days, 1 time every five days, 1 time every six days, 3 times a week, 2 times a week, 1 time a week, 1 time every two weeks, or 1 time every three weeks. In some embodiments, the frequency of administration of the compound of formula I-1 or its pharmaceutically acceptable salt may be 1 time or 2 times a day. In some embodiments, the frequency of administration of the compound of formula I-1 or its pharmaceutically acceptable salt may be 1 time a day.

In some embodiments, administering an effective amount of the compound of formula I-1 of the present application or a pharmaceutically acceptable salt thereof to a subject is continuous daily administration.

In some embodiments, the compound of Formula 1-1 or a pharmaceutically acceptable salt thereof is administered in a single dose or multiple doses.

In some embodiments, the administration of the compound of Formula 1-1 or a pharmaceutically acceptable salt thereof is by oral administration.

In some embodiments, the compound of Formula I-1 or a pharmaceutically acceptable salt thereof can be administered orally within 30 minutes after starting a meal.

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

In some embodiments, 8-32 days are 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 are used as one dosing cycle. In some embodiments, 28 days or 32 days are used as one dosing cycle. In some embodiments, 28 days are used as one dosing cycle.

In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered in a dosage of 20 mg-1200 mg, 100 mg-1200 mg or 100 mg-800 mg per dose, administered continuously daily (e.g., once a day) for one or more dosing cycles; optionally, one dosing cycle is 8-32 days (e.g., every 28 days).

In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered as follows: 20-1200 mg, 100-1200 mg, 100-800 mg, 20-400 mg, 100-400 mg or 400-600 mg (e.g., 100 mg, 200 mg or 400 mg) per dose, administered continuously daily (e.g., once a day) for one or more dosing cycles; optionally, one dosing cycle is 28 days.

In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered orally at a dosage of 20-400 mg, 100-1200 mg or 100-800 mg once a day (one or more administration cycles); optionally, one administration cycle is 28 days.

In some embodiments, the administration of the compound of formula I-1 or a pharmaceutically acceptable salt thereof may be 2-40 or more administration cycles, for example 4-10 or 8-20 administration cycles, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 administration cycles. In some embodiments, the administration of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is repeated until the subject can no longer benefit, the disease progresses, or an intolerable toxic reaction occurs.

In some embodiments, the treatment cycle of the compound of formula I-1 or its pharmaceutically acceptable salt is 2-40 or more dosing cycles, such as 4-10 or 8-20 dosing cycles, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 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-mentioned dosing cycle is repeated until the subject can no longer benefit, the disease progresses, or an intolerable toxic reaction occurs.

In some embodiments, the daily or each dose of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is a treatment dose (also called a fixed treatment dose or a fixed dose).

In some embodiments, the subject is administered a gradient increasing dose (ie, lead-in period or lead-in phase) of the compound of formula I-1 or a pharmaceutically acceptable salt thereof before receiving a fixed therapeutic dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the introduction phase is administered with at least one gradient increasing dose (hereinafter also referred to as "gradient dose"), wherein the first gradient dose in the at least one gradient dose is lower than the dose in the administration cycle. In some embodiments, the at least one gradient dose may include a first gradient dose and another gradient dose. In particular, for the case where multiple gradient doses are included in the introduction phase, the last gradient dose is less than the dose used in the administration cycle. In a preferred embodiment, the gradient dose is administered with the same administration mode and frequency of administration as the fixed dose.

In some embodiments, for the case where the introduction phase includes multiple gradient doses, the difference between each gradient dose can be the same or different. In some embodiments, for the case where the introduction phase includes multiple gradient doses, 1-14 gradient doses can be included, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 gradient doses.

In some embodiments, the first increasing dose can be selected from: 10 mg, 20 mg, 50 mg or 100 mg. In a preferred embodiment, each increasing dose can be administered for 1-10 days, for example, for 1 day, or continuously administered for 2-10 days.

In some embodiments, the gradient increasing dose includes at least one of the following: 20mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1200mg. In some embodiments, the gradient increasing dose includes at least one of the following: 20mg, 50mg, 100mg, 200mg, 400mg, 600mg, 800mg or 1200mg. In some embodiments, the gradient increasing dose includes 20mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg or 800mg. In some embodiments, the gradient increasing dose includes 20mg, 50mg, 100mg, 200mg, 400mg, 600mg or 800mg.

In some embodiments, after the introduction period (i.e., after the gradient dose is increased to a specific dose), the compound of formula I-1 or its pharmaceutically acceptable salt is subsequently administered at a fixed dose every day for treatment. In some embodiments, before the subject receives a fixed treatment dose, the subject is administered a gradient increasing dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt. The gradient increasing dose includes changing a dose every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days or every week (7 days) for a gradient increasing dose. In some embodiments, the first gradient dose of the gradient increasing dose can be selected from 10mg or 20mg. In some embodiments, the second gradient dose of the gradient increasing dose can be selected from 20mg or 50mg. Optionally, the gradient increasing dose also includes a third gradient dose. In some embodiments, the third gradient dose of the gradient increasing dose is selected from 50mg or 100mg. In some embodiments, optionally, the gradient increasing dose also includes a fourth gradient dose. In some embodiments, optionally, the gradient increasing dose also includes a fourth gradient dose, which is selected from 100mg or 200mg. In some embodiments, optionally, the gradient increasing dose also includes a fifth gradient dose. In some embodiments, optionally, the gradient increasing dose also includes a fifth gradient dose, which is selected from 200mg or 400mg. In some embodiments, optionally, the gradient increasing dose also includes a sixth gradient dose. In some embodiments, optionally, the gradient increasing dose also includes a sixth gradient dose, which is selected from 400mg or 600mg. In some embodiments, optionally, the gradient increasing dose also includes a seventh gradient dose. In some embodiments, optionally, the gradient increasing dose also includes a seventh gradient dose, which is selected from 600mg or 800mg. In some embodiments, optionally, the gradient increasing dose also includes an eighth gradient dose. In some embodiments, optionally, the gradient increasing dose also includes an eighth gradient dose, which is selected from 800mg or 1200mg.

In some embodiments, after the introduction phase (i.e., after the gradient dose is increased to a specific dose), the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is subsequently administered at a fixed dose every day for treatment. In some embodiments, the fixed dose is as defined above. In one embodiment, for example, the fixed dose can be selected from 100 mg-400 mg. The second gradient dose, for example, 50 mg, completes the incremental phase, and the subsequent fixed dose is 100 mg; the third gradient dose, for example, 100 mg, completes the incremental phase, and the subsequent fixed dose is 200 mg; for example, the fourth gradient dose, for example, 200 mg, completes the incremental phase, and the subsequent fixed dose is 400 mg.

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, selected from 100 mg, 200 mg or 400 mg; in some embodiments, selected from 100 mg; in some embodiments, selected from 200 mg; in some embodiments, selected from 400 mg.

In some embodiments, before the subject receives fixed dose treatment, the subject is administered a daily or weekly gradient increasing dose of the formula I-1 compound of the present application or a pharmaceutically acceptable salt thereof. Optionally, after increasing to a specific dose (e.g., 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg), a fixed dose (e.g., 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg) of the formula I-1 compound or a pharmaceutically acceptable salt thereof is subsequently administered daily.

In some embodiments, before the subject receives a fixed dose treatment, the subject is administered a daily or weekly gradient increasing dose of the compound of formula I-1 of the present application or a pharmaceutically acceptable salt thereof. Optionally, after increasing to a specific dose such as 50 mg, 100 mg, or 200 mg, the corresponding 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, the duration of the daily gradient increasing dose is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days or the duration of the range formed by any of the above values. In some embodiments, the duration of the daily gradient increasing dose is 2-10 days, 2-4 days, 3-4 days or 5-7 days.

In some embodiments, the daily gradient increasing dose includes: 20 mg on the first day, 50 mg on the second day. In some embodiments, the daily gradient increasing dose includes: 20 mg on the first day, 50 mg on the second day, and 100 mg on the third day. In some embodiments, the daily gradient increasing dose includes: 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, and 200 mg on the fourth day. In some embodiments, the daily gradient increasing dose includes: 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, 200 mg on the fourth day, and 400 mg on the fifth day. In some embodiments, the daily gradient increasing dose includes: 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, 200 mg on the fourth day, 400 mg on the fifth day, and 600 mg on the sixth day. The treatment of the subsequent dosing cycle uses the above-mentioned fixed dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the daily gradient increasing dose includes: 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, 200 mg on the fourth day, 400 mg on the fifth day, 600 mg on the sixth day, and 800 mg on the seventh day. In some embodiments, the daily gradient increasing dose includes: 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, 200 mg on the fourth day, 400 mg on the fifth day, 600 mg on the sixth day, 800 mg on the seventh day, and 1200 mg on the eighth day. The treatment of the subsequent dosing cycle uses the above-mentioned fixed dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the daily gradient increasing dose includes: 100 mg on the first day, 200 mg on the second day. In some embodiments, the daily gradient increasing dose includes: 100 mg on the first day, 200 mg on the second day, and 400 mg on the third day. In some embodiments, the daily gradient increasing dose includes: 100 mg on the first day, 200 mg on the second day, 400 mg on the third day, and 600 mg on the fourth day. In some embodiments, the daily gradient increasing dose includes: 100 mg on the first day, 200 mg on the second day, 400 mg on the third day, and 800 mg on the fourth day. The treatment of subsequent dosing cycles uses the above-mentioned fixed dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the daily gradient increasing dose includes: 10 mg on the first day, 20 mg on the second day, 50 mg on the third day, and 100 mg on the fourth day. In some embodiments, the daily gradient increasing dose includes: 10 mg on the first day, 20 mg on the second day, 50 mg on the third day, 100 mg on the fourth day, and 200 mg on the fifth day. In some embodiments, the daily gradient increasing dose includes: 10 mg on the first day, 20 mg on the second day, 50 mg on the third day, 100 mg on the fourth day, 200 mg on the fifth day, and 300 mg on the sixth day. In some embodiments, the daily gradient increasing dose includes: 10 mg on the first day, 20 mg on the second day, 50 mg on the third day, 100 mg on the fourth day, 200 mg on the fifth day, and 400 mg on the sixth day.

In some embodiments, the duration of the application of the weekly gradient increasing dose is 1, 2, 3, 4, 5, 6 or 7 weeks or the duration of the range formed by any of the above values. In some embodiments, the duration of the application of the weekly gradient increasing dose is 2-5 or 2-3 or 3-4 weeks. In some embodiments, the duration of the application of the weekly gradient increasing dose is 4 weeks.

In some embodiments, the weekly gradient increasing dose includes: 20 mg per day in the first week, 50 mg per day in the second week, 100 mg per day in the third week, and 200 mg per day in the fourth week. Optionally, a fixed dose of 400-600 mg (such as 400 mg, 500 mg or 600 mg) is applied every day in the fifth week and thereafter. In some embodiments, the weekly gradient increasing dose includes: 10 mg per day in the first week, 20 mg per day in the second week, 50 mg per day in the third week, 100 mg per day in the fourth week, and 200 mg per day 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 applied every day in the sixth week and thereafter. In some embodiments, the daily or weekly gradient increasing dose of the compound of Formula I-1 or its pharmaceutically acceptable salt is an introduction dose.

In certain embodiments, the pre-dosing incremental period (or introduction period) is used as part of the first dosing cycle (or treatment cycle). For example, when implementing the administration of the present application, the first dosing cycle (or treatment cycle) may include a 1-day, 2-14-day or 1-3-week introduction period (e.g., a daily gradient incremental dose or a weekly gradient incremental dose), and the pre-dosing incremental period ends with a fixed dose for the remaining days of the first dosing cycle; then subsequent dosing cycles, such as the second dosing cycle and the third dosing cycle, are implemented in the form of a fixed dose. In some embodiments, during the first treatment cycle (e.g., 28 days is a treatment cycle), the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is administered in the manner shown in Table 1 below to complete the introduction period, and a fixed dose of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is used in the subsequent dosing cycle.

Table 1

In some embodiments, the daily or each dose of the formula II-1 compound of the present application or its pharmaceutically acceptable salt is selected from 10-500mg, 20-400mg, 50-350mg, 50-300mg, 50-250mg, 100-250mg or 100-200mg. In some embodiments, the daily or each dose of the formula II-1 compound of the present application or its pharmaceutically acceptable salt is selected from 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg or 500mg or any value in the range formed by any of the above values. In some embodiments, the daily or each dose of the formula II-1 compound of the present application or its pharmaceutically acceptable salt is selected from 100-300mg. In some embodiments, the daily or per dose of the compound of formula II-1 of the present application or its pharmaceutically acceptable salt is selected from 100-200 mg. In some embodiments, the daily or per dose of the compound of formula II-1 of the present application or its pharmaceutically acceptable salt is selected from 200 mg.

In some embodiments of the present application, the compound of formula II-1 or its pharmaceutically acceptable salt is administered at 0.0001 to 20 mg/kg weight each time. In some embodiments of the present application, the compound of formula II-1 or its pharmaceutically acceptable salt is administered at 0.001 to 20 mg/kg weight each time.

In some embodiments, the administration frequency of the compound of formula II-1 or its pharmaceutically acceptable salt may be 3 times a day, 2 times a day, 1 time a day, 1 time every two days, 1 time every three days, 1 time every four days, 1 time every five days, 1 time every six days, 3 times a week, 2 times a week, 1 time a week, 1 time every two weeks, or 1 time every three weeks. In some embodiments, the administration frequency of the compound of formula II-1 or its pharmaceutically acceptable salt may be 1 time or 2 times a day. In some embodiments, the administration frequency of the compound of formula II-1 or its pharmaceutically acceptable salt may be 1 time a day.

In some embodiments, administering an effective amount of the compound of Formula II-1 of the present application or a pharmaceutically acceptable salt thereof to a subject is continuous daily administration.

In some embodiments, the compound of Formula II-1 or a pharmaceutically acceptable salt thereof is administered in a single dose or multiple doses.

In some embodiments, the administration of the compound of Formula II-1 or a pharmaceutically acceptable salt thereof is by oral administration.

In some embodiments, 8-32 days are 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 are used as one dosing cycle. In some embodiments, 28 days or 32 days are used as one dosing cycle. In some embodiments, 28 days are used as one dosing cycle.

In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is administered in the following manner: 50-300 mg, 50-250 mg, 100-250 mg, or 100-200 mg (e.g., 200 mg) per dose, administered continuously daily (e.g., once a day) for one or more dosing cycles; optionally, one dosing cycle is 8-32 days (e.g., every 28 days).

In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is administered in the following manner: 50-300 mg, 50-250 mg, 100-250 mg, or 100-200 mg (e.g., 200 mg) per dose, administered continuously daily (e.g., once a day) for one or more dosing cycles; optionally, one dosing cycle is 28 days.

In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is administered orally at a dosage of 100-250 mg or 100-200 mg (eg, 200 mg) once a day (one or more administration cycles); optionally, one administration cycle is 28 days.

In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is administered orally at a dose of 200 mg once a day (one or more administration cycles); optionally, one administration cycle is 28 days.

In some embodiments, the treatment cycle of the compound of formula II-1 or its pharmaceutically acceptable salt is 4-10 or 8-20 administration cycles. In some embodiments, the treatment cycle of the compound of formula II-1 or its pharmaceutically acceptable salt is repeated until the subject can no longer benefit, the disease progresses, or an intolerable toxic reaction occurs.

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

In some embodiments, the method for treating hematological tumors provided herein comprises:

1) Identifying the subject as a patient with a hematological malignancy; and;

2) administering a therapeutically effective amount of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof to the identified patient.

In some embodiments, the method for treating hematological tumors provided herein comprises:

1) performing an assay on a sample obtained from a patient to determine whether the patient has a hematological tumor; and

2) administering a therapeutically effective amount of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof to a patient with a blood tumor.

In some embodiments, the treating includes inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of the patient's cancer.

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

In some embodiments, the I-1 compound or its pharmaceutically acceptable salt may be a pharmaceutical composition comprising the I-1 compound or its pharmaceutically acceptable salt. In some embodiments, the formula II-1 compound or its pharmaceutically acceptable salt may be a pharmaceutical composition comprising the formula II-1 compound or its pharmaceutically acceptable salt. In some embodiments, the formula I-1 compound or its pharmaceutically acceptable salt and the formula II-1 compound or its pharmaceutically acceptable salt may be co-formulated in a pharmaceutical composition or separately formulated into separate pharmaceutical compositions.

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

In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula B or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula C or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula D or a pharmaceutically acceptable salt thereof.

Compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition

The compound of formula I-1 of the present application can be administered in the form of its free base, or in the form of its pharmaceutically acceptable salt, hydrate and prodrug, which can be converted into the free base form of the compound of formula I-1 in vivo. The compound of formula I-1 of the present application or its pharmaceutically acceptable salt exists in a crystalline form or an amorphous form.

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

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

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.

In some embodiments, the pharmaceutical composition of the compound of formula I-1 or its pharmaceutically acceptable salt is a pharmaceutical composition with a single dose of 5mg-500mg, preferably 10mg-200mg, and most preferably 10mg-100mg. Specifically, a pharmaceutical composition selected from a single dose of 5mg, 10mg, 15mg, 20mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, or 500mg or any value in 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 its pharmaceutically acceptable salt is selected from 10mg, 50mg or 100mg.

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 may 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 may be composed of a single dose of 10 mg, 50 mg or 100 mg of a pharmaceutical composition containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof.

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

Compound of formula II-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition

The compound of formula II-1 of the present application can be administered in the form of its free base, or in the form of its pharmaceutically acceptable salt, hydrate and prodrug, wherein the prodrug can be converted into the free base form of the compound of formula II-1 in vivo.

The pharmaceutical composition of the compound of formula II-1 or a pharmaceutically acceptable salt thereof of the present application comprises the compound of formula II-1 or a pharmaceutically acceptable salt thereof, and further contains a pharmaceutically acceptable excipient.

In some embodiments, the compound of formula II-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10-500mg, 20-400mg, 50-350mg, 50-300mg, 50-250mg, 100-250mg, or 100-200mg of the compound of formula II-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the compound of formula II-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, or 500mg, or the range formed by any of the above values. Compound of formula II-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the compound of formula II-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100-300 mg of the compound of formula II-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the compound of formula II-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100-200 mg of the compound of formula II-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the compound of formula II-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200 mg of the compound of formula II-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition.

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

In some embodiments, the single dose of the pharmaceutical composition of the compound of formula II-1 or its pharmaceutically acceptable salt is 5mg-100mg, preferably 10mg-100mg, most preferably 20mg-100mg. Specifically selected from a single dose of 10mg, 20mg, 50mg, 100mg, 150mg, or 200mg or a range formed by any of the above values. In some embodiments, the single dose of the pharmaceutical composition containing the compound of formula II-1 or its pharmaceutically acceptable salt is selected from 50mg.

In some embodiments, the pharmaceutical composition containing the compound of formula II-1 or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, and the multi-dose may be composed of multiple single-dose pharmaceutical compositions containing the compound of formula II-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition containing the compound of formula II-1 or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, and the multi-dose may be composed of a single dose of 10 mg, 20 mg, 50 mg or 100 mg of a pharmaceutical composition containing the compound of formula II-1 or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula A or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula B or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula C or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from a compound of formula D or a pharmaceutically acceptable salt thereof.

Definition and Description

Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered ambiguous or unclear without special definition, but should be understood according to its ordinary meaning in the art.

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

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted ( _-CH2CH3 ), _{monosubstituted} (such _{as -CH2CH2F} ), polysubstituted (such as _-CHFCH2F , _-CH2CHF2 , _etc. ) or fully substituted ( _{-CF2CF3 )} . It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced.

Herein, C _mn means that the moiety has an integer number of carbon atoms in 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.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "alkyl" refers to a hydrocarbon group of the general formula _{CnH2n +1} . The alkyl group may be straight-chain or branched. For example, the term " _C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., 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.). For another example, the term " _C1-4 alkyl" refers to an alkyl group containing 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.).

The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting 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, etc.

The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting 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-CH ₃ ), 2-propynyl (-CH ₂ -C≡CH), and the like.

The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic 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, etc.

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

Unless otherwise stated, the dosages and ranges provided herein for compounds of formula I-1, such as compound I or its pharmaceutically acceptable salt or pharmaceutical compositions thereof, are calculated based on the molecular weight of the compound of formula I-1, such as compound I free base.

Unless otherwise stated, the dosages and ranges provided in this application for compounds of formula II-1, such as compound A or its pharmaceutically acceptable salt or pharmaceutical compositions thereof, are calculated based on the molecular weight of the compound of formula II-1, such as compound A free base.

The term "administering" or "giving" or "administration" means physically introducing a therapeutic agent or a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. The terms "administering" or "giving" or "administration" are used interchangeably herein.

The term "treat" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of a disease and/or side effects resulting from a disease. As used herein, "treat" encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of a disease, i.e., arrests its development; or (b) alleviates the symptoms of a disease, i.e., causes regression of the disease or symptoms.

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

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

Herein, the combination of the BCL-2 inhibitor and the BTK inhibitor encompasses the situation where the two are present separately or in a mixture, but is not limited to the simultaneous or co-administration of the two in the form of a mixture. For example, optionally, the BCL-2 inhibitor and the BTK inhibitor can be administered separately, simultaneously, or co-administered, for example, in the form of separate presence or in the form of a mixture.

The term "fixed combination" means that the active ingredients (e.g., BCL-2 inhibitor or BTK inhibitor) are 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 or the same capsule or the same medicine bag.

The term "non-fixed combination" refers to two or more active ingredients as independent entities (e.g., pharmaceutical compositions, pharmaceutical preparations) administered to an individual simultaneously, concurrently or sequentially and without specific time limits, wherein the active ingredients administered to the individual reach a therapeutically effective level. An example of a non-fixed combination is cocktail therapy, e.g., administration of 2, 3 or more active ingredients. In a non-fixed combination, the individual active ingredients may be packaged, sold or administered as completely independent pharmaceutical compositions. The "non-fixed combination" also includes the combined use of "fixed combinations" or "fixed combinations" with any one or more independent entities of the active ingredients.

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

The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance 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.

The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid preparations such as tablets, pills, capsules, etc.

The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

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

Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain the core of a tablet or capsule or dragee. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

The term "pharmaceutically acceptable salt" or "pharmaceutically usable salt" refers to salts of the compounds of the present application within the definition of "pharmaceutically acceptable".

Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass singular terms. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one". Unless otherwise stated, the use of "or" means "and/or".

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

The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine, for example, if a box of medicine has seven capsules, each capsule is a single dose; or each bottle of injection is a single dose. The term "multiple doses" consists of multiple single doses. The pharmaceutical composition of the present application can be formulated into a pharmaceutical composition suitable for single or multiple administrations. The drug combination of the present application can be a single-dose or multi-dose pharmaceutical composition.

For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of the contents of these documents 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 contents of these documents. Furthermore, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

The term "objective response rate (ORR)" refers to the proportion of subjects who achieved objective response based on tumor assessment, including but not limited to complete response (CR) and partial response (PR).

The term "disease control rate (DCR)" is used to evaluate the proportion of patients achieving remission and stable disease, including but not limited to cases of CR, PR and stable disease (SD).

The term "progression-free survival (PFS)" is the time from the first dose of the drug to disease progression (PD) or death before PD; if there is no PD or death before PD, the date of the last imaging assessment is used as the cutoff date.

The term “duration of response (DOR)” is the time from the first tumor assessment as CR or PR to PD or death before PD in subjects with CR or PR; if the subject with CR or PR does not experience PD or death before PD, the date of the last imaging assessment is used as the cutoff date.

CRi: Complete remission without bone marrow recovery.

PR-L: partial remission with lymphocytosis.

The term "refractory" refers to a subject or mammal that does not respond to anticancer therapy or responds inadequately to anticancer therapy. Specifically, for example, patients who have failed treatment (failed to obtain PR or CR) or whose disease progressed within 6 months after the last treatment, more specifically, patients who did not obtain PR or above remission.

The term “relapse” refers to disease progression >6 months after achieving PR or CR.

The term "adverse event (AE)" refers to all adverse medical events that occur after the subject receives the investigational drug, which may be manifested as symptoms, signs, diseases or laboratory test abnormalities, but may not necessarily have a causal relationship with the investigational drug. The evaluation criteria for the nature and severity of adverse events are based on the Common Toxicity Criteria of the National Cancer Institute of the United States (NCI-CTC AE v5.0). Items that cannot be evaluated according to this standard can be evaluated according to the following standards:

Mild: Only slight impact on the patient's daily life.

Moderate: Significantly affects the patient's daily life.

Severe: Causes functional impairment or seriously interferes with daily life.

The term “OS” refers to the overall survival time of tumor patients.

The term "DFS": refers to the disease-free survival of cancer patients.

The term "TTP" refers to the time to disease progression in cancer patients.

The term "CBR": refers to clinical benefit rate.

The term "SAE": refers to serious adverse event.

Term “TRAEs”: treatment-related adverse events.

Technical Effects

The treatment scheme of the present application has good efficacy in treating blood tumors. The combination of the compound of formula I-1 (e.g., compound I) or its pharmaceutically acceptable salt, or its pharmaceutical composition and the compound of formula II-1 (e.g., compound A) or its pharmaceutically acceptable salt, or its pharmaceutical composition described in the present application has excellent effects in at least one aspect of objective response rate (ORR), complete response (CR) rate, complete response (CRi) without bone marrow recovery, CR/CRi rate, CR/CRi duration (DOCR), duration of response (DOR), time to first CR/CRi (TTCR), time to first response (TTR), peripheral blood and bone marrow minimal residual disease (MRD) negative rate at the end of combined treatment, partial response (PR), partial response with increased lymphocytes (PR-L), median progression-free survival (PFS), median overall survival (OS), 2-year PFS rate, 2-year OS rate, and reduction of target lesion SPD baseline. In addition, the combination described in the present application has good tolerance and small side effects, including small effects on cardiovascular function, respiratory system, and central nervous system.

Among them, regarding the effectiveness evaluation criteria: chronic lymphocytic leukemia (CLL) can refer to the IWCLL2018 evaluation criteria; small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL) and other non-Hodgkin lymphomas (NHL) can refer to the 2014 Lugano conference revised criteria.

DETAILED DESCRIPTION

The present application is described in detail below by examples, but it is not intended to constitute any adverse restriction to the present application. The compounds of the present application can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination thereof with other chemical synthesis methods and equivalent substitution methods well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present application. It will be apparent to those skilled in the art that various changes and improvements are made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

All reagents used in this application were commercially available and used without further purification.

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

Compounds of formula II-1, such as compound A, can be prepared by referring to the method disclosed in WO2020052628 A1.

Example 1 Combination Clinical Trial

1. Trial Drugs

Compound I: specifications: 10 mg, 100 mg, tablets.

Compound A: specifications: 10 mg, 100 mg, tablets.

2. Patients enrolled

Inclusion criteria:

Article 1: The disease diagnosis meets any of the following conditions:

1) Non-Hodgkin's B-cell lymphoma confirmed by histology or cytology (in accordance with the WHO 2016 diagnostic criteria);

2) CLL/SLL that meets the iwCLL diagnostic criteria and meets at least one treatment indication for iwCLL;

3) MCL that meets the WHO 2016 diagnostic criteria.

Article 2: Optionally, previous treatment meets any of the following conditions:

Treatment-naive patients: those who have not received systemic treatment for CLL/SLL or MCL before;

Relapsed and/or refractory patients: Patients who have received at least one line of systemic standard treatment and have no response or relapsed after response after the last line of treatment.

Article 3: At least one measurable lesion for efficacy evaluation.

3. Dosage regimen

Compound I tablets, taken orally, with warm water within 30 minutes after starting a meal, 20mg-1200mg each time, once a day, 28 days as a treatment cycle. The length of the lead-in period will depend on the therapeutic dose level (i.e., fixed therapeutic dose). The day when the therapeutic dose level is reached is regarded as C1D1 of the treatment period.

Compound A tablets, oral, 200 mg each time, once a day, 28 days as a treatment cycle.

For Compound I tablets, the patient introduction period was carried out as follows, all of which were orally administered once a day in a daily increasing manner, and the last dose was the therapeutic dose:

100 mg dose group: 20 mg → 50 mg → 100 mg

200 mg dose group: 20 mg → 50 mg → 100 mg → 200 mg

400 mg dose group: 20 mg → 50 mg → 100 mg → 200 mg → 400 mg

600 mg dose group: 20 mg → 50 mg → 100 mg → 200 mg → 400 mg → 600 mg

800mg dose group: 20mg→50mg→100mg→200mg→400mg→600mg→800mg

1200mg dosage group: 20mg→50mg→100mg→200mg→400mg→600mg→800mg→1200mg.

4. Effectiveness and safety indicators

Effectiveness indicators include complete remission (CR), ORR, PFS, OS, complete remission without bone marrow recovery (CRi), minimal residual disease (MRD)-negative rate in peripheral blood and bone marrow at the end of combination treatment, CR/CRi rate, duration of CR/CRi (DOCR), duration of remission (DOR), time to first CR/CRi (TTCR), time to first remission (TTR), 2-year PFS rate, 2-year OS rate, and target lesion SPD changes.

Adverse events: The occurrence of all adverse events (AEs), serious adverse events (SAEs) and treatment-related adverse events (TRAEs), including, for example, the grade of adverse reactions, the overall incidence of adverse events, etc.

5. Test results

Efficacy analysis showed that the above combination therapy showed anti-tumor activity in patients with MCL and CLL/SLL. Safety data showed that adverse events (TRAEs) associated with the combination therapy were mainly hematological adverse events, mostly grade 1-2, and no serious bleeding events occurred.

For MCL patients,

In one patient under evaluation (Compound I 200 mg dose group), the baseline SPD of the patient's lymph node target lesions was 1054 square millimeters, which shrank to 551 square millimeters after 2 cycles.

For patients with CLL/SLL,

In one patient under evaluation (Compound I 200 mg dose group), the baseline SPD of the patient's lymph node target lesions was 1360 square millimeters, which shrank to 962 square millimeters after 4 cycles.

Table 2 below is a representative case:

Table 2

Example 2 Single-drug clinical trial

1. Trial Drugs

Compound I: specifications: 10 mg, 100 mg, tablets.

2. Patients enrolled

Inclusion criteria:

1) Hematological malignancies confirmed by histology or cytology;

2) Patient population: non-Hodgkin's lymphoma, etc.

3) At least 1 lesion/measurable disease that can be evaluated for efficacy.

3. Dosage regimen

The compound of formula I is taken orally with warm water within 30 minutes after the start of a meal, 20 mg to 1200 mg each time, once a day, and 28 days is a dosing cycle. The length of the lead-in period will depend on the therapeutic dose level. The day when the therapeutic dose level is reached is the C1D1 of the treatment period.

The patient introduction period is as follows. The following are all administered orally once a day in a daily increasing manner, and the last dose is the therapeutic dose:

100 mg dose group: 20 mg → 50 mg → 100 mg

200 mg dose group: 20 mg → 50 mg → 100 mg → 200 mg

400 mg dose group: 20 mg → 50 mg → 100 mg → 200 mg → 400 mg

600 mg dose group: 20 mg → 50 mg → 100 mg → 200 mg → 400 mg → 600 mg

800mg dose group: 20mg→50mg→100mg→200mg→400mg→600mg→800mg

1200mg dosage group: 20mg→50mg→100mg→200mg→400mg→600mg→800mg→1200mg.

4. Effectiveness and safety indicators

Effectiveness indicators include CR rate, ORR, DOR, PFS, OS, etc.

Adverse events: The occurrence of all adverse events (AEs), serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs), including, for example, the grade of adverse reactions, the overall incidence of adverse events, etc.

5. Test results

There were few adverse events, and compound I-related adverse events (TRAEs) were mainly hematological adverse events and abnormal laboratory test values, mostly grade 1-2.

In MCL patients, the ORR was 45% to 68%, and the CR rate was 15% to 50%. In the 200-600 mg dose group, the ORR was 45% to 68%, and the CR rate was 14% to 50%.

In patients with CLL/SLL, the ORR was 89% to 95%, and the CR rate was 45% to 55%. In the 200-600 mg dose group, the ORR was 89% to 95%, and the CR rate was 44% to 55%.

In patients with MCL, CLL/SLL, the number of complete remissions/(number of objective remissions + number of complete remissions) reached 25% to 100%.

Some efficacy data:

In the 100-600 mg dose group, 22 MCL patients were evaluated, 3 achieved CR, 8 achieved PR, the ORR was 50%, and the CR rate was 14%.

In the 200-600 mg dose group, 27 CLL/SLL patients were evaluated, 12 achieved CR/CRi, and 12 achieved PR, with an ORR of 89% and a CR rate of 44%.

For example, among the evaluated MCL patients, the number of complete remission cases/(number of objective remission cases + number of complete remission cases) reached 27%; among the evaluated CLL/SLL patients, the number of complete remission cases/(number of objective remission cases + number of complete remission cases) reached 50%.

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

Table 3 below is a representative case:

Table 3

Example 3 Animal or cell test

1. Determination of proliferation inhibition activity of MINO cells (MCL)

Take MINO cells in good growth state, collect them into centrifuge tubes, adjust the cell density to 5×10 ⁴ cells/mL, inoculate them on 96-well plates (100 μL/well), culture them in a cell culture incubator overnight, use a nanoliter pipette to add compounds, so that the final concentrations of compound A and compound I are 10000nM-0.61nM, 2 replicates, and set controls at the same time. After continuing to culture in the cell culture incubator for 72 hours, add the detection reagent CCK-8, incubate in the cell culture incubator for 4 hours, and detect its absorbance at 450nm with an Envision microplate reader. Four-parameter analysis, fitting of the dose-effect curve, and calculation of IC ₅₀ are performed. The results are shown in Table 4.

2. Jeko-1 cell (MCL) proliferation inhibition activity assay

Jeko-1 cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 2×10 ⁴ cells/mL, and the cells were inoculated on 96-well plates (100 μL/well), cultured overnight in a cell culture incubator, and the compounds were added using a nanoliter pipette to make the final concentrations of compound A and compound I 10000nM-0.61nM, 2 replicates, and a control was set at the same time. After continuing to culture in the cell culture incubator for 72 hours, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL/well) was added, and the cells were incubated in the cell culture incubator for 4 hours, and the absorbance was detected at 450nm using an Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate the IC ₅₀ .

3. Determination of proliferation inhibition activity of MEC-1 cells (CLL)

MEC-1 cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 8×10 ⁴ cells/mL, and inoculated on 96-well plates (100 μL/well), cultured overnight in a cell culture incubator, and the compounds were added using a nanoliter pipette to make the final concentrations of compound A and compound I 10000nM-0.61nM, 2 replicates, and a control was set at the same time. After continuing to culture in the cell culture incubator for 72 hours, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL/well) was added, and after incubation in the cell culture incubator for 4 hours, the absorbance value was detected at 450nm by Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate IC ₅₀ .

The test results show that the combination of compound I of the present application and compound A has the effect of inhibiting the proliferation of MINO cells, Jeko-1 cells or MEC-1 cells, showing synergistic effect.

Table 4

For MINO cells, according to the analysis of CompuSyn software, compound A and compound I had obvious synergistic effect. At different final concentrations, the synergistic index CI was between 0.04-0.7, and was <0.3 at most concentrations.

Claims (15)

Combination of BCL-2 inhibitor and BTK inhibitor, Wherein, the BCL-2 inhibitor is selected from the compound of formula I-1 or a pharmaceutically acceptable salt thereof,
wherein R ¹¹ is selected from hydrogen, halogen or C _1-6 alkyl; Ring A is selected from 5-6 membered heterocycloalkyl, R ²² is independently selected from 4-6 membered heterocycloalkyl, C _3-6 cycloalkyl, -COR ^aa , -SO ₂ R ^bb , or C _1-6 alkyl optionally substituted by halogen; ^Raa or ^Rbb are each independently selected from H, 4-6 membered heterocycloalkyl, _C3-6 cycloalkyl, or _C1-6 alkyl, wherein the _C1-6 alkyl is optionally substituted with halogen, CN, -N( _C1-6 alkyl) ₂ , _-NHC1-6 alkyl, or _-OC1-6 alkyl; p is selected from 0, 1, 2 or 3; Wherein, the BTK inhibitor is selected from the compound of formula II-1 or a pharmaceutically acceptable salt thereof
wherein R ¹ is independently selected from halogen or C _1-3 alkyl optionally substituted by fluorine; m is selected from 0, 1 or 2; R ² are each independently selected from halogen, -OH, -NH ₂ or C _1-3 alkyl; n is selected from 0, 1 or 2; ^R3 is selected from ^RaC (O)-, ^Ra is selected from _C2-3alkynyl , _C2-3alkenyl , _C1-3alkyl or _{C3-4cycloalkyl} . The combination according to claim 1, for use in treating hematological tumors. The combination according to claim 1 or 2, wherein Structure fragment Selected from and/or, R ¹¹ is selected from hydrogen, halogen or C _1-3 alkyl; and/or, R ¹¹ is selected from hydrogen, fluorine, chlorine or methyl; and/or, R ¹¹ is selected from hydrogen, chlorine or methyl; and/or, Ring A is selected from 6-membered heterocycloalkyl; and/or, Ring A is selected from 6-membered heterocycloalkyl groups containing one or more O atoms; and/or, Ring A is selected from dioxane or pyran ring; and/or, R ²² is independently selected from 4-6 membered heterocycloalkyl, C _4-6 cycloalkyl, -COR ^aa , -SO ₂ R ^bb , or C _1-4 alkyl optionally substituted by halogen; ^Raa or ^Rbb are each independently selected from H, 4-6 membered heterocycloalkyl, _C3-6 cycloalkyl, or _C1-4 alkyl, wherein the _C1-4 alkyl is optionally substituted by halogen, CN, -N( _C1-4 alkyl) ₂ , _-NHC1-4 alkyl, or _-OC1-4 alkyl; and/or, R ²² is independently selected from -C(O)H, -COC(CH ₃ ) ₃ , -COCF ₃ , -COCH ₂ CN, -COCH ₂ N(CH ₃ ) ₂ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CF ₃ , -SO ₂ C ₂ F ₅ , -CF ₃ , -C ₂ F ₅ , tetrahydropyran, monooxetane, -SO _2- cyclopropane, -CO-cyclopropane, -CO-monooxetane, -SO _2- monooxetane, or -SO _2- cyclobutane; and/or, p is selected from 0 or 1. The combination according to any one of claims 1 to 3, wherein the BCL-2 inhibitor is selected from Compound I, Compound II, Compound III, or Compound IV or a pharmaceutically acceptable salt thereof,
The combination according to any one of claims 1 to 4, wherein R ¹ is trifluoromethyl; and/or m is selected from 0 or 1; and/or, m is 1, ^R1 is trifluoromethyl; and/or, ^R2 is independently selected from halogen; and/or, ^R2 is independently fluorine; and/or, n is selected from 0 or 1; and/or, n is 0; and/or, n is 1, ^R2 is fluorine; and/or, R ^a is selected from propynyl, C _2-3 alkenyl or cyclopropyl; and/or, ^Ra is selected from _CH3C≡C- , _CH2 =CH- or cyclopropyl. The combination according to any one of claims 1 to 5, wherein the BTK inhibitor is selected from compound A, compound B, compound C, compound D or a pharmaceutically acceptable salt thereof:
The combination according to any one of claims 2 to 6, wherein the blood tumor is selected from advanced blood tumors; Alternatively, the blood tumor is selected from blood tumors clearly diagnosed by histology or cytology; Alternatively, the blood tumor is selected from lymphoid tumors; Alternatively, the blood tumor is selected from non-Hodgkin's lymphoma; Alternatively, the blood tumor is selected from non-Hodgkin's B-cell lymphoma; Alternatively, the hematological tumor or non-Hodgkin's lymphoma is selected from mantle cell lymphoma, chronic lymphocytic leukemia and/or small lymphocytic lymphoma; Alternatively, the subject with the blood tumor has not received treatment with a previous treatment regimen; or, the subject with the blood tumor has received treatment with one or more previous treatment regimens; Alternatively, the blood tumor is selected from relapsed and/or refractory blood tumors; Alternatively, the subject with the hematological tumor has at least one lesion/measurable disease that can be evaluated for efficacy; Alternatively, the non-Hodgkin's lymphoma subject has at least one radiologically measurable tumor lesion in two perpendicular directions as assessed by CT or MRI. The combination of claim 7, wherein the lymphoid tumor or non-Hodgkin's lymphoma is selected from mantle cell lymphoma; Alternatively, the mantle cell lymphoma is selected from mantle cell lymphoma that is CD5 and CD20 positive by immunohistochemistry or flow cytometry; and/or, The mantle cell lymphoma is selected from mantle cell lymphoma that is cyclin D1 positive and/or has t(11;14) translocation. The combination of claim 7, wherein the lymphoid tumor or non-Hodgkin's lymphoma is selected from chronic lymphocytic leukemia or small lymphocytic lymphoma; Alternatively, the subject with chronic lymphocytic leukemia has a peripheral blood monoclonal B lymphocyte count>5×10 ⁹ /L, or has measurable lesions on imaging; Alternatively, the subject with chronic lymphocytic leukemia has at least one radiologically measurable tumor lesion in two perpendicular directions as assessed by CT or MRI. The combination according to any one of claims 1 to 9, wherein the daily or each 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; Alternatively, 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 any value in a range formed by any of the above values; and/or, The administration frequency of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 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; and/or, optionally, before administration, at least one incremental dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered to the subject, wherein the first incremental dose is lower than the daily or per-administration dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof used for treatment; Optionally, the subject is administered daily or weekly increasing doses of the compound of formula I-1 or a pharmaceutically acceptable salt thereof; Optionally, the at least one incremental dose comprises a first incremental dose and an additional incremental dose, wherein the last incremental dose is less than or equal to the daily or per-administration dose of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof for treatment; Optionally, the step-wise increasing dose includes 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) for step-wise increasing dose. The combination according to any one of claims 1 to 10, wherein the daily or each dose of the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from 10-500 mg, 20-400 mg, 50-350 mg, 50-300 mg, 50-250 mg, 100-250 mg, or 100-200 mg; Alternatively, the daily or each dose of the compound of formula II-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, or 500 mg, or any value in the range formed by any of the above values. A method for treating a hematological tumor, comprising administering to a subject a therapeutically effective amount of the combination of any one of claims 1 to 11. Use of the combination according to any one of claims 1 to 11 in the preparation of a medicament for treating blood tumors. Use of compound I or a pharmaceutically acceptable salt thereof in preparing a drug for treating blood tumors in combination with compound A or a pharmaceutically acceptable salt thereof. A kit for treating blood tumors, comprising: the combination according to any one of claims 1 to 11; optionally, further comprising instructions for use of the combination.