Combination of trifluoromethyl-containing compound and furopyrrole-containing compound for use in treating blood tumors

Abstract

A combination of a trifluoromethyl-containing compound and a furopyrrole-containing 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-containing compounds and furanopyrrole-containing compounds for treating hematological tumors

[0001] Citation of Related Applications

[0002] This application claims 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

[0003] 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 for treating 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 treating blood tumors. Background Art

[0004] 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 members of the latter two families play a pro-apoptotic role.

[0005] Anti-apoptotic BCL-2 family proteins are associated with numerous diseases and are being investigated as potential therapeutic drug targets. These targets for interventional therapy include, for example, the BCL-2 family proteins BCL-2 and BCL-XL. Inhibitors of BCL-2 family proteins are inhibitors of target protein binding. Compound binding affinity is only one of many parameters to be considered, and one goal is to produce compounds that preferentially bind to one protein relative to another, i.e., are selective for it. To demonstrate this selectivity, it is known that a compound exhibits high binding affinity for a particular protein and lower binding affinity for another member. Compounds that selectively inhibit BCL-2 proteins can be used to treat hyperproliferative diseases, such as tumors.

[0006] Bruton's tyrosine kinase (BTK) is primarily expressed in B cells and distributed throughout the lymphatic, hematopoietic, and blood systems. It is a member of the Tec family of non-receptor tyrosine kinases, which also includes TEC, ITK / TSK / EMT, and BMX, all of which are highly structurally homologous. BTK plays a crucial role in the B-cell signaling pathway that connects cell-surface B-cell receptor stimulation to downstream intracellular responses. It is a key regulator of B-cell development, activation, signaling, and survival. Recent studies on B cells, particularly those targeting B-cell non-Hodgkin's lymphoma and rheumatoid arthritis, have found that BTK often exhibits abnormal expression. The development of small molecule targeted drugs based on the BTK signaling pathway provides a novel approach for the treatment of B-cell tumors such as leukemia, multiple myeloma, and B-cell immune diseases.

[0007] The combination of compounds that selectively inhibit the BCL-2 protein (BCL-2 inhibitors) with BTK inhibitors appears to bring clinical benefits to patients.

[0008] SUMMARY OF THE INVENTION

[0009] In one aspect, the present application provides use of a BCL-2 inhibitor in the preparation of a medicament for treating hematological tumors.

[0010] In another aspect, the present application provides use of a BCL-2 inhibitor in the preparation of a medicament for treating a hematological tumor, wherein the treatment further comprises administering other drugs.

[0011] In another aspect, the present application provides use of a BCL-2 inhibitor in the preparation of a medicament for treating hematological tumors, wherein the medicament is used in combination with other drugs.

[0012] In another aspect, the present application provides use of a BCL-2 inhibitor in the preparation of a medicament for treating hematological tumors, wherein the BCL-2 inhibitor is used in combination with other drugs.

[0013] On the other hand, the present application provides the use of a BCL-2 inhibitor in the preparation of a drug for treating hematological tumors, as well as instructions for the combined use of a BCL-2 inhibitor and other drugs.

[0014] In another aspect, the present application provides a use of a BCL-2 inhibitor in preparing a kit for treating hematological tumors, wherein the kit comprises a BCL-2 inhibitor and instructions for using the BCL-2 inhibitor in combination with other drugs.

[0015] In another aspect, the present application provides use of a BCL-2 inhibitor in the preparation of a medicament for use in combination with other drugs in the treatment of hematological tumors.

[0016] In another aspect, the present application provides use of a combination of a BCL-2 inhibitor and other drugs in the preparation of a medicament for treating hematological tumors.

[0017] 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.

[0018] In one aspect, the present application also provides a BCL-2 inhibitor for treating hematological tumors.

[0019] In one aspect, the present application also provides use of a BCL-2 inhibitor for treating hematological tumors.

[0020] In some embodiments, the method of treating a hematological tumor, or the use of a BCL-2 inhibitor for treating a hematological tumor, further comprises administering other drugs to a subject in need of treatment.

[0021] In some embodiments, the aforementioned 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.

[0022] 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.

[0023] In one aspect, the present application provides a combination of a BCL-2 inhibitor and a BTK inhibitor.

[0024] 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.

[0025] In one embodiment, the methods of treating hematological neoplasms described herein comprise administering to a subject a therapeutically effective amount of a BCL-2 inhibitor in combination with a therapeutically effective amount of a BTK inhibitor.

[0026] In some embodiments, the BCL-2 inhibitor and the BTK inhibitor are administered simultaneously or sequentially.

[0027] 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.

[0028] On the other hand, the present application also provides a combination of a BCL-2 inhibitor and a BTK inhibitor for treating hematological tumors.

[0029] 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.

[0030] In some embodiments, the present application also provides a kit for treating hematological tumors, comprising a BCL-2 inhibitor; optionally, further comprising instructions for the combined use of the BCL-2 inhibitor and a BTK inhibitor.

[0031] In some embodiments, the present application also provides a kit for treating hematological tumors, comprising a BCL-2 inhibitor; optionally, further comprising instructions for using the BCL-2 inhibitor in combination with a BTK inhibitor to treat hematological tumors.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] On the other hand, the present application provides the use of a BTK inhibitor in the preparation of a medicament for treating hematological tumors, as well as instructions for the combined use of a BTK inhibitor and a BCL-2 inhibitor.

[0036] In another aspect, the present application provides a use of a BTK inhibitor in preparing a kit for treating hematological tumors, wherein the kit comprises a BTK inhibitor and instructions for combined use of the BTK inhibitor and a BCL-2 inhibitor.

[0037] 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.

[0038] In some embodiments, the present application also provides a kit for treating hematological tumors, comprising a BTK inhibitor; and instructions for the combined use of a BCL-2 inhibitor and a BTK inhibitor.

[0039] In some embodiments, the present application also provides a kit for treating hematological tumors, comprising a BTK inhibitor; and instructions for using a BCL-2 inhibitor and a BTK inhibitor in combination to treat hematological tumors.

[0040] In some embodiments, the present application also provides a kit for treating hematological tumors, comprising: a combination of a BCL-2 inhibitor and a BTK inhibitor; and optionally, instructions for use of the combination of the BCL-2 inhibitor and the BTK inhibitor. In some embodiments, the instructions are instructions for administering the combination of the BCL-2 inhibitor and the BTK inhibitor to a subject.

[0041] 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 using the BCL-2 inhibitor and the BTK inhibitor in combination to treat hematological cancers.

[0042] In some embodiments, the BCL-2 inhibitor and the BTK inhibitor are administered simultaneously or sequentially.

[0043] In some embodiments, the BCL-2 inhibitor can be a pharmaceutical composition comprising a BCL-2 inhibitor. In some embodiments, the BTK inhibitor can be a pharmaceutical composition comprising a BTK inhibitor. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0044] 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 each formulated as a separate pharmaceutical composition. In some embodiments, the BCL-2 inhibitor and the BTK inhibitor are each formulated as a separate pharmaceutical composition and are each packaged in a separate kit.

[0045] In some embodiments, the BCL-2 inhibitor is selected from a compound of formula I-1 or a pharmaceutically acceptable salt thereof,

[0046] Among them, R 11 Selected from hydrogen, halogen or C 1-6 alkyl;

[0047] Ring A is selected from 5-6 membered heterocycloalkyl,

[0048] R 22 are independently selected from 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, -COR aa 、-SO2R bb , or C optionally substituted by halogen 1-6 alkyl;

[0049] R aa or R bb are independently selected from H, 4-6 membered heterocycloalkyl, C 3-6Cycloalkyl, or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with halogen, CN, -N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, or -OC 1-6 Alkyl substitution;

[0050] p is selected from 0, 1, 2 or 3.

[0051] In some embodiments, the structural fragment Selected from

[0052] In some embodiments, R 11 Selected from hydrogen, halogen or C 1-3 In some embodiments, R 11 In some embodiments, R 11 is selected from hydrogen, chlorine or methyl.

[0053] In some embodiments, Ring A is selected from a 6-membered heterocycloalkyl group. In some embodiments, Ring A is selected from a 6-membered heterocycloalkyl group containing one or more O atoms. In some embodiments, Ring A is selected from a 6-membered heterocycloalkyl group containing 1 or 2 O atoms. In some embodiments, Ring A is selected from a dioxane or pyran ring.

[0054] In some embodiments, R 22 are independently selected from 4-6 membered heterocycloalkyl, C 4-6 Cycloalkyl, -COR aa 、-SO2R bb , or C optionally substituted by halogen 1-4 alkyl.

[0055] In some embodiments, R aa or R bb are independently selected from H, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with halogen, CN, -N(C 1-4 Alkyl)2, -NHC 1-4 Alkyl, or -OC 1-4 Alkyl substitution.

[0056] In some embodiments, R 22Each is independently selected from -C(O)H, -COC(CH3)3, -COCF3, -COCH2CN, -COCH2N(CH3)2, -SO2CH2CH3, -SO2CF3, -SO2C2F5, -CF3, -C2F5, tetrahydropyran, monooxetane, -SO2-cyclopropane, -CO-cyclopropane, -CO-monooxetane, -SO2-monooxetane, or -SO2-cyclobutane.

[0057] In some embodiments, p is selected from 0 or 1.

[0058] 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.

[0059] In some embodiments, the BCL-2 inhibitor is selected from Compound I or a pharmaceutically acceptable salt thereof; or Compound II or a pharmaceutically acceptable salt thereof; or Compound III or a pharmaceutically acceptable salt thereof; or Compound IV or a pharmaceutically acceptable salt thereof.

[0060] 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.

[0061] 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.

[0062] In some embodiments, the BTK inhibitor described herein is selected from a compound of formula II-1 or a pharmaceutically acceptable salt thereof,

[0063] Among them, R 1 are independently selected from halogen or C optionally substituted by fluorine 1-3 alkyl;

[0064] m is selected from 0, 1 or 2;

[0065] R 2 are independently selected from halogen, -OH, -NH2 or C 1-3 alkyl;

[0066] n is selected from 0, 1 or 2;

[0067] R 3 Selected from R aC(O)-,R a Selected from C 2-3 Alkynyl, C 2-3 Alkenyl, C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0068] In some embodiments, R 1 It is trifluoromethyl.

[0069] In some embodiments, m is selected from 0 or 1. In some embodiments, m is 0.

[0070] In some embodiments, m is 1, R 1 It is trifluoromethyl.

[0071] In some embodiments, R 2 are independently selected from halogen. 2 are independently fluorine.

[0072] In some embodiments, n is selected from 0 or 1. In some embodiments, n is 0.

[0073] In some embodiments, n is 1, R 2 For fluorine.

[0074] In some embodiments, R a Selected from propynyl, C 2-3 alkenyl or cyclopropyl.

[0075] In some embodiments, R a Selected from CH3C≡C-, CH2=CH- or cyclopropyl.

[0076] In some embodiments, m and n are 0; or, m and n are both 1. In some embodiments, m is 1, R 1 is trifluoromethyl, and n is 1, R 2 For fluorine.

[0077] In some embodiments, the BTK inhibitor is selected from Compound A, Compound B, Compound C, Compound D, or a pharmaceutically acceptable salt thereof:

[0078] 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.

[0079] 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.

[0080] 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 hematological tumors.

[0081] In another aspect, 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 hematological tumor, wherein the treatment further comprises administering a compound of formula II-1 or a pharmaceutically acceptable salt thereof. In another aspect, 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 hematological tumor, wherein the treatment further comprises administering a compound of formula I-1 or a pharmaceutically acceptable salt thereof.

[0082] In another aspect, 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 hematological tumor, wherein the medicament is used in combination with a compound of formula II-1 or a pharmaceutically acceptable salt thereof. In another aspect, 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 hematological tumor, wherein the medicament is used in combination with a compound of formula I-1 or a pharmaceutically acceptable salt thereof.

[0083] In another aspect, 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 hematological 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. In another aspect, 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 hematological 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.

[0084] In another aspect, 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, 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. In another aspect, 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, 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.

[0085] In another aspect, 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 hematological 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. In another aspect, 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 hematological 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.

[0086] 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.

[0087] 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 medicament for treating hematological tumors.

[0088] In one aspect, the present application provides a method for treating hematological tumors, comprising administering to a subject a therapeutically effective amount of a compound of Formula I-1 or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the present application provides a method for treating hematological tumors, 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.

[0090] In one aspect, the present application further provides a compound of formula I-1 or a pharmaceutically acceptable salt thereof for use in treating hematological tumors.

[0091] 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 hematological tumors.

[0092] In one aspect, the present application also provides use of a compound of formula I-1 or a pharmaceutically acceptable salt thereof for treating hematological tumors.

[0093] 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.

[0094] In some embodiments, the method or use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof for treating a blood tumor further comprises administering a compound of formula II-1 or a pharmaceutically acceptable salt thereof to a subject in need of treatment. In some embodiments, the method or use of the compound of formula II-1 or a pharmaceutically acceptable salt thereof for treating a blood tumor further comprises administering a compound of formula I-1 or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0095] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof for treating a hematological tumor, a method for treating a hematological tumor, or the use for treating a hematological 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. In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof for treating a hematological tumor, a method for treating a hematological tumor, or the use for treating a hematological 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.

[0096] 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.

[0097] 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.

[0098] On the other hand, the present application provides use of the combination in preparing a medicament for treating hematological tumors.

[0099] On the other hand, the present application also provides the combination for treating hematological tumors.

[0100] On the other hand, the present application also provides use of the combination for treating hematological tumors.

[0101] In another 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 for treating a hematological tumor. In some embodiments, the present application also provides a kit for treating a hematological tumor, comprising: a compound of formula I-1 or a pharmaceutically acceptable salt thereof; optionally, instructions for the combined use of the compound of formula I-1 or a pharmaceutically acceptable salt thereof and the compound of formula II-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the present application also provides a kit for treating a hematological tumor, comprising: a compound of formula II-1 or a pharmaceutically acceptable salt thereof; instructions for the combined use of 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.

[0102] In some embodiments, the present application also provides a kit for treating a hematological tumor, comprising: 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 in combination with a compound of formula II-1 or a pharmaceutically acceptable salt thereof to treat a hematological tumor. In some embodiments, the present application also provides a kit for treating a hematological tumor, comprising: 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 in combination with a compound of formula I-1 or a pharmaceutically acceptable salt thereof to treat a hematological tumor.

[0103] In some embodiments, the present application also provides a kit for treating hematological tumors, comprising: the combination described herein; and optionally, instructions for use of the combination. In some embodiments, the instructions for use are for directing a subject to administer the combination.

[0104] 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, 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.

[0105] 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 a separate kit, which further 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 blood tumors.

[0106] 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 can 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 can 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.

[0107] 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.

[0108] Hematologic malignancies

[0109] In some embodiments, the hematological tumor is selected from an advanced hematological tumor. In some embodiments, the hematological tumor is selected from a relapsed and / or refractory hematological tumor. In some embodiments, the hematological tumor is selected from a relapsed and / or refractory advanced hematological tumor.

[0110] In some embodiments, the hematological tumor is selected from hematological tumors clearly diagnosed by histology or cytology.In some embodiments, the above diagnosis meets the 2016 diagnostic criteria of the WHO.

[0111] In some embodiments, the hematological tumor is selected from lymphoid tumors.

[0112] In some embodiments, the hematological neoplasm is selected from non-Hodgkin's lymphoma (NHL).In some embodiments, the hematological neoplasm is selected from non-Hodgkin's B-cell lymphoma.

[0113] 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.

[0114] In some embodiments, the hematological tumor or the subject has not been treated with a prior treatment regimen. In some embodiments, the hematological tumor or the subject has been treated with one or more prior treatment regimens. In some embodiments, the hematological tumor or the subject has been treated with one, two, three, four, five, or six or more (including six) prior treatment regimens.

[0115] In some embodiments, the hematological tumor is selected from a newly diagnosed hematological tumor. In some embodiments, the hematological tumor is selected from a relapsed and / or refractory hematological tumor. In some embodiments, the hematological tumor is selected from a relapsed and / or refractory advanced hematological tumor. In some embodiments, the relapsed and refractory subject includes a subject for whom standard treatment regimens are ineffective, intolerant, or unavailable.

[0116] In some embodiments, the hematological tumor or the subject is selected from those who have relapsed or failed treatment after previous treatment. In some embodiments, the hematological tumor or the subject is selected from those who have relapsed or failed treatment after previous standard treatment. In some embodiments, the hematological tumor or the subject is selected from those who have failed treatment in the past. In some embodiments, the hematological tumor or the subject is selected from those who have failed standard treatment. In some embodiments, the hematological tumor or the subject is selected from those who are intolerant to previous treatment regimens. In some embodiments, the hematological tumor or the subject is selected from those who are intolerant to standard treatment regimens. In some embodiments, the hematological 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 hematological tumor or the subject is selected from those who are intolerant to standard treatment regimens and have no other better treatment options.

[0117] In some embodiments, the blood tumor or the subject is selected from those who have previously received at least one systemic treatment regimen, and there is disease progression or intolerance during or after the most recent treatment, or no relief 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 treatment regimens, and there is disease progression or intolerance during or after the most recent treatment, or no relief 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 treatment regimens, and there is disease progression or intolerance during or after the most recent treatment, or no relief 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 treatment regimens, and there is disease progression or intolerance during or after the most recent treatment, or no relief after adequate treatment.

[0118] 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.

[0119] In some embodiments, the hematological tumor or the subject has at least one lesion / measurable disease that is evaluable for efficacy.

[0120] 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.

[0121] In some embodiments, the hematologic malignancy or the subject has previously been treated with a BCL-2 inhibitor. In some embodiments, the hematologic malignancy or the subject has previously been treated with a BTK inhibitor. In some embodiments, the hematologic malignancy or the subject has not previously been 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.

[0122] In some embodiments, the subject with hematological tumors optionally has the following comorbidities:

[0123] For patients who have had or currently have other malignant tumors within 5 years before the first use of the drug, the tumor patients can be other malignant tumors that have been treated with a single surgery and have achieved 5 consecutive years of disease-free survival (DFS);

[0124] Alternatively, the patient with the tumor or advanced malignancy may be a patient cured 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).

[0125] In some embodiments, the subject with the hematological tumor does not have any one or more of the following:

[0126] 1) Patients diagnosed with Burkitt lymphoma, lymphoblastic lymphoma / leukemia; and / or,

[0127] 2) Central nervous system (CNS) involvement; and / or,

[0128] 3) Previously received allogeneic hematopoietic stem cell transplantation; and / or,

[0129] 4) Unresolved toxicity of ≥CTC AE grade 1 due to any previous treatment, excluding alopecia; and / or,

[0130] 5) The presence of active or uncontrolled primary autoimmune cytopenia, including autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), etc.; and / or,

[0131] 6) Arterial / venous thrombotic events occurred within 6 months before the first use of the drug; and / or,

[0132] 7) Patients with any severe and / or uncontrolled illness; and / or,

[0133] 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.

[0134] 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.

[0135] In some embodiments, patients with any severe and / or uncontrolled diseases in 7) above include: 1. Patients with ≥ grade 2 myocardial ischemia or myocardial infarction, arrhythmia (QTc>450ms for men, QTc>470ms for women) and ≥ grade 2 congestive heart failure (New York Heart Association (NYHA) classification) within 6 months prior to the first medication; 2. Patients with active severe infection (≥CTC AE grade 2 infection) and left ventricular ejection fraction (LVEF) <50% assessed by cardiac ultrasound; 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.

[0136] Mantle cell lymphoma (MCL)

[0137] In some embodiments, the hematological neoplasm, lymphoid neoplasm, or non-Hodgkin's lymphoma is selected from mantle cell lymphoma.

[0138] 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 subject includes a subject for whom standard treatment regimens are ineffective, or cannot be tolerated, or are inaccessible. The relapsed and / or refractory mantle cell lymphoma subject has at least received treatment with immunochemotherapy and / or BTK inhibitors. In some embodiments, the relapsed and / or refractory mantle cell lymphoma subject has previously received at least one line of systemic standard treatment (e.g., anti-CD20 treatment). In some embodiments, the relapsed and / or refractory mantle cell lymphoma subject has no remission after the last line of treatment (including but not limited to 4 cycles of standard treatment and more disease stabilization or 1 cycle of standard treatment and more disease progression) or relapsed after remission.

[0139] In some embodiments, the mantle cell lymphoma or the subject is selected from patients who are treatment naive and cannot tolerate intensive chemotherapy.

[0140] In some embodiments, the mantle cell lymphoma is selected from a patient with previously untreated mantle cell lymphoma. In some embodiments, the mantle cell lymphoma or the subject is selected from a patient who has not previously received systemic treatment for mantle cell lymphoma.

[0141] In some embodiments, the mantle cell lymphoma is selected from mantle cell lymphoma that meets the WHO 2016 diagnostic criteria.

[0142] In some embodiments, the mantle cell lymphoma is selected from a 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 a 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 a mantle cell lymphoma that is positive for CD5 and CD20 by immunohistochemistry or flow cytometry, and positive for cyclin D1 and / or has a t(11;14) translocation.

[0143] In some embodiments, the mantle cell lymphoma or the subject has at least one radiologically measurable tumor lesion in two perpendicular directions as assessed by CT or MRI. Optionally, the tumor lesion is selected from a nodal lesion with a long diameter greater than 15 mm and an extranodal lesion with a long diameter greater than 10 mm.

[0144] 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.

[0145] 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 remission 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, 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 mantle cell lymphoma or the subject is selected from those who have previously received at least one, two, three or four systemic treatment regimens, and there is disease progression or intolerance during or after the most recent treatment, or there is no remission after adequate treatment.

[0146] 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 stabilization of the disease after 4 cycles or more of standard treatment or progression of the disease after 1 cycle or more of standard 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, 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.

[0147] In some embodiments, the mantle cell lymphoma or the subject's prior treatment included anti-CD20 therapy.

[0148] Chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL)

[0149] In some embodiments, the hematological neoplasm, lymphoid neoplasm, or non-Hodgkin's lymphoma is selected from chronic lymphocytic leukemia or small lymphocytic lymphoma.

[0150] In some embodiments, the lymphoid neoplasm or non-Hodgkin's lymphoma is selected from chronic lymphocytic leukemia or small lymphocytic lymphoma that has not previously received systemic treatment for CLL / SLL. In some embodiments, the lymphoid neoplasm or non-Hodgkin's lymphoma is selected from chronic lymphocytic leukemia or small lymphocytic lymphoma that has not previously received systemic treatment for CLL / SLL.

[0151] In some embodiments, the lymphoid tumor or non-Hodgkin's lymphoma is selected from the group consisting of treatment-naive chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma that meets the diagnostic criteria of the International Working Group on Chronic Lymphocytic Lymphoma (IWCLL) and at least one treatment indication.

[0152] 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 subject includes a subject for whom standard treatment regimens are ineffective, or cannot be tolerated, or are inaccessible. The relapsed and / or refractory CLL / SLL subject has at least received treatment with immunochemotherapy and / or BTK inhibitors. In some embodiments, the relapsed and / or refractory CLL / SLL subject has previously received at least one first-line systemic standard treatment (e.g., containing anti-CD20 treatment). In some embodiments, the relapsed and / or refractory CLL / SLL subject has no remission after the last line of treatment (including but not limited to standard treatment for 4 cycles and above of stable disease or standard treatment for 1 cycle and above of progressive disease) or relapses after remission.

[0153] 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 diagnostic criteria for iwCLL and meets at least one treatment indication.

[0154] 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.

[0155] 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 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 disease stabilization 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, and / or a third-line treatment regimen.

[0156] In some embodiments, the chronic lymphocytic leukemia or small lymphocytic 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 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 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 treatment regimens, there is disease progression or intolerance during or after the most recent treatment, or there is no remission after adequate treatment.

[0157] In some embodiments, the chronic lymphocytic leukemia or the subject has a peripheral blood monoclonal B lymphocyte count > 5×10 9 / L, or the presence of a measurable lesion on imaging. In some embodiments, the chronic lymphocytic leukemia or the subject has at least one measurable tumor lesion on imaging in two perpendicular directions as assessed by CT or MRI. Optionally, the tumor lesion is selected from a nodal lesion with a long diameter greater than 15 mm and an extranodal lesion with a long diameter greater than 10 mm.

[0158] In some embodiments, the small lymphocytic lymphoma or the subject has at least one radiologically measurable tumor lesion in two perpendicular directions as assessed by CT or MRI. Optionally, the tumor lesion is selected from a nodal lesion with a long diameter greater than 15 mm and an extranodal lesion with a long diameter greater than 10 mm.

[0159] Dosage regimen

[0160] 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 with 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 used to provide a detectable therapeutic benefit to the subject / patient can also be determined. It is also possible to determine the time requirement for administering each drug to provide a detectable therapeutic benefit to the subject / patient. Therefore, although the application illustrates certain dosages and dosage regimens, these examples are by no means limited to the dosage and dosage regimen that can be provided to the subject / patient when practicing the present invention.

[0161] 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.

[0162] 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 blood tumors, wherein the medicament (daily or each time) comprises 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 medicament for use in combination with a compound of formula II-1 or a pharmaceutically acceptable salt thereof for treating blood tumors, wherein the medicament (daily or each time) comprises 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 medicament for use in combination with a compound of formula I-1 or a pharmaceutically acceptable salt thereof for treating blood tumors, wherein the medicament (daily or each time) comprises 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 medicament for treating blood tumors, wherein the medicament comprises 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.

[0163] 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 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.

[0164] 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.

[0165] 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 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.

[0166] 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 a dosage of the compound of formula I-1 or a pharmaceutically acceptable salt thereof (daily or per time) selected from 20-2000 mg, 20-1200 mg or 100-1200 mg, and a dosage of the compound of formula II-1 or a pharmaceutically acceptable salt thereof (daily or per 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.

[0167] In some embodiments, the daily or per 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 per 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 a range formed by any of the above values. In some embodiments, the daily or each dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 100-1200 mg, 100-800 mg, 200-800 mg or 200-600 mg. In some embodiments, the daily or each dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 200-1000 mg. In some embodiments, the daily or each dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 10-800 mg or 20 mg-800 mg. In some embodiments, the daily or each dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 10-300 mg, 20-400 mg, 20-200 mg or 20-100 mg. In some embodiments, the daily or each dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg or 400 mg. In some embodiments, the daily or per dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg or 1200 mg. In some embodiments, the daily or per dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 100-800 mg. In some embodiments, the daily or per dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 400-600 mg.In some embodiments, the daily or per dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 200 mg, 400 mg, 500 mg or 600 mg. In some embodiments, the daily or per dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 20 mg, 50 mg, 100 mg, 200 mg or 400 mg. In some embodiments, the daily or per dose of the compound of formula I-1 of the present application or its pharmaceutically acceptable salt is selected from 100 mg, 200 mg or 400 mg.

[0168] In some embodiments of the present application, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered at a dose of 0.0001 to 20 mg / kg body weight per administration. In some embodiments of the present application, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered at a dose of 0.001 to 20 mg / kg body weight per administration.

[0169] In some embodiments, the frequency of administration of the compound of formula I-1 or a pharmaceutically acceptable salt thereof can be 3 times a day, 2 times a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, 3 times a week, 2 times a week, once a week, once every two weeks, or once every three weeks. In some embodiments, the frequency of administration of the compound of formula I-1 or a pharmaceutically acceptable salt thereof can be once or twice a day. In some embodiments, the frequency of administration of the compound of formula I-1 or a pharmaceutically acceptable salt thereof can be once a day.

[0170] 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.

[0171] In some embodiments, the compound of Formula 1-1 or a pharmaceutically acceptable salt thereof is administered in a single dose or multiple doses.

[0172] In some embodiments, the compound of Formula 1-1 or a pharmaceutically acceptable salt thereof is administered orally.

[0173] In some embodiments, the compound of Formula 1-1 or a pharmaceutically acceptable salt thereof can be administered orally within 30 minutes after starting a meal.

[0174] In some embodiments, the compound of Formula 1-1 or a pharmaceutically acceptable salt thereof is administered orally on an empty stomach.

[0175] In some embodiments, 8-32 days are used as a 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 a dosing cycle. In some embodiments, 28 days or 32 days are used as a dosing cycle. In some embodiments, 28 days are used as a dosing cycle.

[0176] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered in a dosage of 20 mg to 1200 mg, 100 mg to 1200 mg, or 100 mg to 800 mg per dose, daily (e.g., once a day) for one or more dosing cycles; optionally, one dosing cycle is 8 to 32 days (e.g., every 28 days).

[0177] In some embodiments, the compound of formula I-1 or a pharmaceutically acceptable salt thereof is administered in a dosage of 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, daily (e.g., once a day) for continuous administration (one or more dosing cycles); optionally, one dosing cycle is 28 days.

[0178] 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 dosing cycles); optionally, one dosing cycle is 28 days.

[0179] In some embodiments, the administration of the compound of formula I-1 or a pharmaceutically acceptable salt thereof can 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 no longer benefits, the disease progresses, or an intolerable toxic reaction occurs.

[0180] In some embodiments, the treatment cycle of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is 2-40 or more dosing cycles, for example 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is repeated until the subject no longer benefits, the disease progresses, or an intolerable toxic reaction occurs.

[0181] 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 fixed dose).

[0182] In some embodiments, the subject is administered a gradient increasing dose (ie, lead-in period or lead-in phase) of a compound of Formula 1-1 or a pharmaceutically acceptable salt thereof before receiving a fixed therapeutic dose of the compound of Formula 1-1 or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the introduction phase is administered with at least one gradient increasing dose (hereinafter also referred to as "gradient dose") to administer the compound of Formula I-1 or a pharmaceutically acceptable salt thereof, 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 cases where a plurality of 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 in the same manner and frequency of administration as a fixed dose.

[0184] In some embodiments, for the case where the lead-in phase comprises multiple gradient doses, the differences between the gradient doses can be the same or different. In some embodiments, for the case where the lead-in phase comprises 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.

[0185] 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.

[0186] In some embodiments, the incremental dose comprises at least one of: 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1200 mg. In some embodiments, the incremental dose comprises at least one of: 20 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1200 mg. In some embodiments, the incremental dose comprises 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 800 mg. In some embodiments, the incremental dose comprises 20 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, or 800 mg.

[0187] In some embodiments, after the introduction phase (i.e., after the gradient dose is increased to a specific dose), the subsequent daily fixed dose administration of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is carried out for treatment. In some embodiments, before the subject receives a fixed treatment dose, a gradient increasing dose of the compound of formula I-1 of the present application or a pharmaceutically acceptable salt thereof is administered to the subject. 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 10 mg or 20 mg. In some embodiments, the second gradient dose of the gradient increasing dose can be selected from 20 mg or 50 mg. Alternatively, 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 50 mg or 100 mg. 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 100 mg or 200 mg. In some embodiments, optionally, the gradient increasing dose further comprises a fifth gradient dose. In some embodiments, optionally, the gradient increasing dose further comprises a fifth gradient dose, which is selected from 200 mg or 400 mg. In some embodiments, optionally, the gradient increasing dose further comprises a sixth gradient dose. In some embodiments, optionally, the gradient increasing dose further comprises a sixth gradient dose, which is selected from 400 mg or 600 mg. In some embodiments, optionally, the gradient increasing dose further comprises a seventh gradient dose. In some embodiments, optionally, the gradient increasing dose further comprises a seventh gradient dose, which is selected from 600 mg or 800 mg. In some embodiments, optionally, the gradient increasing dose further comprises an eighth gradient dose. In some embodiments, optionally, the gradient increasing dose further comprises an eighth gradient dose, which is selected from 800 mg or 1200 mg.

[0188] 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 daily 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 to 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.

[0189] 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.

[0190] 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 subsequent daily 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.

[0191] 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.

[0192] In some embodiments, the duration of administering 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 administering the daily gradient increasing dose is 2-10 days, 2-4 days, 3-4 days or 5-7 days.

[0193] In some embodiments, the daily escalating dose comprises: 20 mg on the first day, 50 mg on the second day. In some embodiments, the daily escalating dose comprises: 20 mg on the first day, 50 mg on the second day, and 100 mg on the third day. In some embodiments, the daily escalating dose comprises: 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 escalating dose comprises: 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 escalating dose comprises: 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. Subsequent dosing cycles of treatment use the above-mentioned fixed dose of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, the daily escalating dose comprises: 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 escalating dose comprises: 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. Subsequent dosing cycles of treatment use the above-mentioned fixed dose of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the daily gradient increasing dose comprises: 100 mg on the first day, 200 mg on the second day. In some embodiments, the daily gradient increasing dose comprises: 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 comprises: 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 comprises: 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. Subsequent dosing cycles of treatment use the above-mentioned fixed dose of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the daily gradient increasing dose comprises: 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 comprises: 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 comprises: 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 comprises: 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.

[0197] In some embodiments, the duration of the administration 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 administration of the weekly gradient increasing dose is 2-5 or 2-3 or 3-4 weeks. In some embodiments, the duration of the administration of the weekly gradient increasing dose is 4 weeks.

[0198] 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 administered 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 administered 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 a pharmaceutically acceptable salt thereof is an introduction dose.

[0199] In certain embodiments, the pre-dosing increment phase (or lead-in phase) 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 lead-in phase of 1 day, 2-14 days, or 1-3 weeks (e.g., administering a daily gradient escalating dose or a weekly gradient escalating dose), and the pre-dosing increment phase ends with administration in the form of a fixed dose for the remaining days of the first dosing cycle; subsequent dosing cycles, such as the second dosing cycle and the third dosing cycle, are then 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 lead-in phase, and a fixed dose of the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is used in subsequent dosing cycles.

[0200] Table 1

[0201] In some embodiments, the daily or each dose of the compound of formula II-1 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 compound of formula II-1 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 compound of formula II-1 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 a pharmaceutically acceptable salt thereof 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 a pharmaceutically acceptable salt thereof is selected from 200 mg.

[0202] In some embodiments of the present application, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is administered at a dose of 0.0001 to 20 mg / kg. In some embodiments of the present application, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is administered at a dose of 0.001 to 20 mg / kg.

[0203] In some embodiments, the frequency of administration of the compound of formula II-1 or its pharmaceutically acceptable salt can be 3 times a day, 2 times a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, 3 times a week, 2 times a week, once a week, once every two weeks, or once every three weeks. In some embodiments, the frequency of administration of the compound of formula II-1 or its pharmaceutically acceptable salt can be once or twice a day. In some embodiments, the frequency of administration of the compound of formula II-1 or its pharmaceutically acceptable salt can be once a day.

[0204] 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.

[0205] In some embodiments, the compound of Formula II-1 or a pharmaceutically acceptable salt thereof is administered in a single dose or multiple doses.

[0206] In some embodiments, the compound of Formula II-1 or a pharmaceutically acceptable salt thereof is administered orally.

[0207] In some embodiments, 8-32 days are used as a 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 a dosing cycle. In some embodiments, 28 days or 32 days are used as a dosing cycle. In some embodiments, 28 days are used as a dosing cycle.

[0208] In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is administered in a dosage of 50-300 mg, 50-250 mg, 100-250 mg, or 100-200 mg (e.g., 200 mg) per dose, 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).

[0209] In some embodiments, the compound of formula II-1 or a pharmaceutically acceptable salt thereof is administered in a dosage of 50-300 mg, 50-250 mg, 100-250 mg, or 100-200 mg (e.g., 200 mg) per dose, daily (e.g., once a day) for continuous administration (one or more dosing cycles); optionally, one dosing cycle is 28 days.

[0210] 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 (e.g., 200 mg) once a day (one or more dosing cycles); optionally, one dosing cycle is 28 days.

[0211] 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.

[0212] In some embodiments, the treatment cycle of the compound of formula II-1 or a pharmaceutically acceptable salt thereof is 4-10 or 8-20 administration cycles. In some embodiments, the treatment cycle of the compound of formula II-1 or a pharmaceutically acceptable salt thereof is repeated until the subject no longer benefits, the disease progresses, or an intolerable toxic reaction occurs.

[0213] In some embodiments, the combination or its treatment regimen, use or method may optionally further comprise other drugs.

[0214] In some embodiments, the method of treating hematological tumors provided herein comprises:

[0215] 1) Identifying the subject as a hematological malignancy patient; and;

[0216] 2) administering to the identified patient a therapeutically effective amount of a combination of a compound of formula I-1 or a pharmaceutically acceptable salt thereof and a compound of formula II-1 or a pharmaceutically acceptable salt thereof.

[0217] In some embodiments, the method of treating hematological tumors provided herein comprises:

[0218] 1) performing an assay on a sample obtained from a patient to determine whether the patient has a hematological tumor; and

[0219] 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 hematological tumor.

[0220] In some embodiments, the treatment includes inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of the patient's cancer.

[0221] 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.

[0222] In some embodiments, the compound of formula I-1 or its pharmaceutically acceptable salt can 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 can be a pharmaceutical composition comprising the compound of formula II-1 or its pharmaceutically acceptable salt. 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 can be co-formulated in a pharmaceutical composition or separately formulated into separate pharmaceutical compositions.

[0223] 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.

[0224] 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.

[0225] Compound of formula I-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition

[0226] The compound of formula I-1 of the present application can be administered in its free base form, or in the form of its pharmaceutically acceptable salts, hydrates, and prodrugs, 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 crystalline or amorphous form.

[0227] The pharmaceutical composition of the compound of formula I-1 or a pharmaceutically acceptable salt thereof of the present application comprises the compound of formula I-1 or a pharmaceutically acceptable salt thereof, and further comprises a pharmaceutically acceptable excipient. In some embodiments, the content of the compound of formula I-1 or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 0.01 to 99.5% by weight; or, selected from 1 to 90% by weight.

[0228] 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition 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 of the compound of formula I-1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in a range formed by any of the above values. In some embodiments, the present application's formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100-1200mg of formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the present application's formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 200-1000mg of formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the present application's formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10-800mg or 20mg-800mg of formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition. In some embodiments, the present application's formula I-1 compound or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 10-300mg, 20-400mg, 20-200mg or 20-100mg of 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg of the compound of formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the compound of formula I-1 of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, or 1200 mg of the compound of formula I-1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.In some embodiments, the compound of formula I-1 of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 100-800 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 400-600 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 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.

[0229] 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.

[0230] In some embodiments, the pharmaceutical composition of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is a pharmaceutical composition having a single dose of 5 mg to 500 mg, preferably 10 mg to 200 mg, and most preferably 10 mg to 100 mg. Specifically, a pharmaceutical composition having a single dose of 5 mg, 10 mg, 15 mg, 20 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg or any value within the range formed by any of the above values. In some embodiments, the single dose of the pharmaceutical composition containing the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 10 mg, 50 mg or 100 mg.

[0231] In some embodiments, the pharmaceutical composition containing the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, and the multi-dose can be composed of multiple single-dose pharmaceutical compositions containing the compound of Formula I-1 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition containing the compound of Formula I-1 or a pharmaceutically acceptable salt thereof is a multi-dose pharmaceutical composition, and the multi-dose can be composed of a single dose of 10 mg, 50 mg, or 100 mg of the pharmaceutical composition containing the compound of Formula I-1 or a pharmaceutically acceptable salt thereof.

[0232] 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.

[0233] Compound of formula II-1 or its pharmaceutically acceptable salt, or its pharmaceutical composition

[0234] 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 salts, hydrates and prodrugs, wherein the prodrug can be converted into the free base form of the compound of formula II-1 in vivo.

[0235] 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.

[0236] 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. 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.

[0237] 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.

[0238] In some embodiments, the single dose of the pharmaceutical composition of the compound of formula II-1 or a pharmaceutically acceptable salt thereof is 5 mg to 100 mg, preferably 10 mg to 100 mg, and most preferably 20 mg to 100 mg. Specifically, a pharmaceutical composition having a single dose of 10 mg, 20 mg, 50 mg, 100 mg, 150 mg, or 200 mg or a range formed by any of the above values ​​is selected. In some embodiments, the single dose of the pharmaceutical composition containing the compound of formula II-1 or a pharmaceutically acceptable salt thereof is selected from 50 mg.

[0239] 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 can 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 can be composed of a single dose of 10 mg, 20 mg, 50 mg or 100 mg of the pharmaceutical composition containing the compound of Formula II-1 or a pharmaceutically acceptable salt thereof.

[0240] 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.

[0241] Definition and Description

[0242] Unless otherwise specified, the following terms used in this application have the following meanings: A particular term should not be considered as ambiguous or unclear if it is not specifically defined, but should be understood according to its ordinary meaning in the art.

[0243] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom 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 an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0244] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (-CH2CH3), monosubstituted (e.g., -CH2CH2F), polysubstituted (e.g., -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 would be sterically impossible and / or incomposable to synthesize will be introduced.

[0245] In this article, C m-n , 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.

[0246] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0247] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 "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 example, the term "C 1-4 The term "alkyl" refers to an alkyl group containing 1 to 4 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.).

[0248] 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.

[0249] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one triple bond. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), etc.

[0250] 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, and the like.

[0251] 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 membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulfur, oxygen and / or nitrogen, for example a 4 to 6 membered ring or a 5 to 6 membered ring.

[0252] Unless otherwise stated, the dosages and ranges provided herein for compounds of formula I-1, such as Compound I, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are calculated based on the molecular weight of the compound of formula I-1, such as Compound I free base.

[0253] Unless otherwise stated, the dosages and ranges provided herein for compounds of formula II-1, such as compound A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are calculated based on the molecular weight of the compound of formula II-1, such as compound A free base.

[0254] The terms "administering" or "giving" or "administering" refer to the physical introduction of 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 "administering" are used interchangeably herein.

[0255] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be therapeutic in terms of partial or complete stabilization or cure of a disease and / or side effects caused by the disease. As used herein, "treat" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

[0256] The term "effective amount" or "therapeutically effective amount" means an amount of a compound of the present invention 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 a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0257] 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 (e.g., 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, most preferably a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or condition to be treated and / or prevented.

[0258] Herein, the combination of the BCL-2 inhibitor and the BTK inhibitor encompasses situations where the two are present separately or in a mixture, and is not limited to 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 or mixed administration.

[0259] The term "fixed combination" means that the active ingredients (e.g., a BCL-2 inhibitor or a 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, capsule or pouch.

[0260] The term "non-fixed combination" refers to two or more active ingredients administered to an individual as independent entities (e.g., pharmaceutical compositions, pharmaceutical preparations) 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 two, three 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 a "fixed combination" with any one or more independent entities of the active ingredients.

[0261] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application, or drug combinations thereof, or salts thereof, and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application, or drug combinations thereof, to a subject.

[0262] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0263] 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.

[0264] 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.

[0265] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0266] Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets, capsules, or dragee cores. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0267] The term "pharmaceutically acceptable salt" or "pharmaceutically usable salt" refers to salts of the compounds of the present application that fall within the definition of "pharmaceutically acceptable."

[0268] Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass the singular. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one." Unless otherwise specified, the use of "or" means "and / or."

[0269] Herein, unless otherwise specified, the terms "comprise, include and contain" 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.

[0270] The term "single dose" refers to the smallest packaging unit containing a certain amount of a drug. For example, if a box of medicine contains seven capsules, each capsule is a single dose; or each bottle of injection is a single dose. The term "multiple dose" refers to a plurality of single doses. The pharmaceutical composition of the present application can be formulated as a pharmaceutical composition suitable for single or multiple administration. The pharmaceutical combination of the present application can be a single-dose or multi-dose pharmaceutical composition.

[0271] For the purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present application. All statements regarding the dates of these documents or the representations of their contents are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications constitute part of the common general knowledge in the art in any country.

[0272] The term "objective response rate (ORR)" refers to the proportion of subjects who achieved an objective response based on tumor assessment, including but not limited to complete response (CR) and partial response (PR).

[0273] The term "disease control rate (DCR)" is used to evaluate the proportion of patients who achieved remission and stable disease, including but not limited to CR, PR and stable disease (SD).

[0274] 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.

[0275] The term "duration of response (DOR)" is defined as the time between the first tumor assessment as CR or PR and 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.

[0276] CRi: Complete remission without bone marrow recovery.

[0277] PR-L: partial remission with lymphocytosis.

[0278] The term "refractory" refers to a subject or mammal that has not responded to, or has had an inadequate response to, anticancer therapy. Specifically, this refers to patients who have failed treatment (failed to achieve a PR or CR) or whose disease progressed within 6 months of the last treatment, or more specifically, who did not achieve a PR or higher response.

[0279] The term "relapse" refers to disease progression >6 months after achieving PR or CR.

[0280] The term "adverse event (AE)" refers to any adverse medical event that occurs after a subject receives an investigational drug. These events may manifest as symptoms, signs, illness, or laboratory abnormalities, but are not necessarily causally related to the investigational drug. The nature and severity of adverse events are evaluated according to the National Cancer Institute's Common Toxicity Criteria (NCI-CTC AE v5.0). Items that cannot be evaluated according to this standard may be assessed according to the following criteria:

[0281] Mild: Only slightly affects the patient's daily life.

[0282] Moderate: Significantly affects the patient's daily life.

[0283] Severe: Causes functional impairment or seriously interferes with daily life.

[0284] The term "OS" refers to the overall survival time of tumor patients.

[0285] The term "DFS" refers to the disease-free survival of cancer patients.

[0286] The term "TTP" refers to the time to disease progression in cancer patients.

[0287] The term "CBR" refers to clinical benefit rate.

[0288] The term "SAE" refers to a serious adverse event.

[0289] Term “TRAEs”: treatment-related adverse events.

[0290] Technical Effects

[0291] The treatment regimen of the present application has a good effect in treating blood tumors. The combination of the compound of formula I-1 (such as compound I) or its pharmaceutically acceptable salt, or its pharmaceutical composition and the compound of formula II-1 (such as compound A) or its pharmaceutically acceptable salt, or its pharmaceutical composition described herein has excellent effects in at least one aspect of objective response rate (ORR), complete remission (CR) rate, complete remission (CRi) without bone marrow recovery, CR / CRi rate, CR / CRi duration (DOCR), duration of remission (DOR), time to first CR / CRi (TTCR), time to first remission (TTR), peripheral blood and bone marrow minimal residual disease (MRD) negative rate at the end of combined treatment, partial remission (PR), partial remission with increased lymphocytes (PR-L), median progression-free survival (PFS), median overall survival (OS), 2-year PFS rate, 2-year OS rate, and target lesion SPD baseline reduction. 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.

[0292] 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

[0293] The present invention is described in detail below by way of examples, but is not intended to constitute any adverse restriction to the present invention. The compound of the present invention can be prepared by a variety of synthetic 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 replacement modes well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and improvements will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0294] All reagents used in this application were commercially available and used without further purification.

[0295] The compound of formula I-1, such as compound I, can be prepared by referring to the method disclosed in WO2020088442A1.

[0296] The compound of formula II-1, such as compound A, can be prepared by referring to the method disclosed in WO2020052628 A1.

[0297] Example 1 Combination Clinical Trial

[0298] 1. Trial Drug

[0299] Compound I: Specifications: 10 mg, 100 mg, tablets.

[0300] Compound A: specifications: 10 mg, 100 mg, tablets.

[0301] 2. Enrolled patients

[0302] Inclusion criteria:

[0303] Article 1: The disease diagnosis meets any of the following conditions:

[0304] 1) Non-Hodgkin's B-cell lymphoma confirmed by histology or cytology (in accordance with the WHO 2016 diagnostic criteria);

[0305] 2) CLL / SLL that meets the iwCLL diagnostic criteria and meets at least one treatment indication for iwCLL;

[0306] 3) MCL that meets the WHO 2016 diagnostic criteria.

[0307] Article 2: Optionally, previous treatment meets any of the following conditions:

[0308] Treatment-naive patients: those who have not received previous systemic treatment for CLL / SLL or MCL;

[0309] Relapsed and / or refractory patients: Patients who have previously received at least one line of systemic standard treatment and have no response or relapsed after response to the last line of treatment.

[0310] Article 3: At least one measurable lesion for efficacy evaluation.

[0311] 3. Dosage regimen

[0312] Compound I tablets are taken orally with warm water within 30 minutes after the start of a meal, 20 mg to 1200 mg per dose, once daily, for a 28-day treatment cycle. The duration of the run-in period will depend on the therapeutic dose level (i.e., fixed therapeutic dose). The day when the therapeutic dose level is reached is designated as C1D1 of the treatment period.

[0313] Compound A tablets, taken orally, 200 mg each time, once a day, 28 days as a treatment cycle.

[0314] For Compound I tablets, the patient lead-in period was conducted as follows. The following were all administered orally once a day in a daily increasing manner, with the last dose being the therapeutic dose:

[0315] 100 mg dose group: 20 mg → 50 mg → 100 mg

[0316] 200mg dose group: 20mg→50mg→100mg→200mg

[0317] 400mg dose group: 20mg→50mg→100mg→200mg→400mg

[0318] 600mg dose group: 20mg→50mg→100mg→200mg→400mg→600mg

[0319] 800mg dose group: 20mg→50mg→100mg→200mg→400mg→600mg→800mg

[0320] 1200mg dose group: 20mg→50mg→100mg→200mg→400mg→600mg→800mg→1200mg.

[0321] 4. Effectiveness and safety indicators

[0322] Efficacy 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 change in target lesion SPD.

[0323] 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.

[0324] 5. Test results

[0325] Efficacy analyses demonstrated that the combination therapy exhibited antitumor activity in patients with MCL and CLL / SLL. Safety data showed that adverse events (TRAEs) associated with the combination therapy were primarily hematologic, mostly grade 1-2, with no major bleeding events.

[0326] For MCL patients,

[0327] 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.

[0328] For CLL / SLL patients,

[0329] 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.

[0330] The following table 2 is a representative case:

[0331] Table 2

[0332] Example 2 Single-drug clinical trial

[0333] 1. Trial Drug

[0334] Compound I: Specifications: 10 mg, 100 mg, tablets.

[0335] 2. Enrolled patients

[0336] Inclusion criteria:

[0337] 1) Hematologic malignancies clearly diagnosed by histology or cytology;

[0338] 2) Patient population: non-Hodgkin's lymphoma, etc.

[0339] 3) At least one lesion / measurable disease that can be evaluated for efficacy.

[0340] 3. Dosage regimen

[0341] Formula I compound tablets are administered orally with warm water within 30 minutes after the start of a meal. The dose is 20 mg to 1200 mg once daily for a 28-day dosing cycle. The duration of the lead-in period will depend on the therapeutic dose level. The day the therapeutic dose level is reached is considered C1D1 of the treatment period.

[0342] 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:

[0343] 100 mg dose group: 20 mg → 50 mg → 100 mg

[0344] 200mg dose group: 20mg→50mg→100mg→200mg

[0345] 400mg dose group: 20mg→50mg→100mg→200mg→400mg

[0346] 600mg dose group: 20mg→50mg→100mg→200mg→400mg→600mg

[0347] 800mg dose group: 20mg→50mg→100mg→200mg→400mg→600mg→800mg

[0348] 1200mg dose group: 20mg→50mg→100mg→200mg→400mg→600mg→800mg→1200mg.

[0349] 4. Effectiveness and safety indicators

[0350] Effectiveness indicators include CR rate, ORR, DOR, PFS, OS, etc.

[0351] 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.

[0352] 5. Test results

[0353] 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.

[0354] In patients with MCL, the ORR was 45% to 68%, with a CR rate of 15% to 50%. In the 200-600 mg dose group, the ORR was 45% to 68%, with a CR rate of 14% to 50%.

[0355] In patients with CLL / SLL, the ORR was 89% to 95%, with a CR rate of 45% to 55%. In the 200-600 mg dose group, the ORR was 89% to 95%, with a CR rate of 44% to 55%.

[0356] In patients with MCL, CLL / SLL, the number of complete remissions / (number of objective remissions + number of complete remissions) reached 25% to 100%.

[0357] Some efficacy data:

[0358] 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%.

[0359] In the 200-600 mg dose group, 27 patients with CLL / SLL were evaluated, 12 of whom achieved CR / CRi and 12 achieved PR, with an ORR of 89% and a CR rate of 44%.

[0360] For example, in evaluated MCL patients, the ratio of complete remission to (number of objective remissions + number of complete remissions) reached 27%; in evaluated CLL / SLL patients, the ratio of complete remission to (number of objective remissions + number of complete remissions) reached 50%.

[0361] Patients who have received previous treatment (including first-line, second-line, third-line or fourth-line treatment) or have not received treatment can show benefits (for example, they can show benefits for a longer period of time, have good efficacy and low side effects).

[0362] Table 3 below shows representative cases:

[0363] Table 3

[0364] Example 3 Animal or cell test

[0365] 1. MINO cell (MCL) proliferation inhibitory activity assay

[0366] Take MINO cells that are in good growth state, collect them into centrifuge tubes, and adjust the cell density to 5×10 4 The cells were inoculated with 100 μL / well of a 96-well plate and cultured overnight in a cell culture incubator. Compounds were added using a nanoliter pipette to a final concentration of 10,000 nM to 0.61 nM for Compound A and Compound I, with two replicates. A control was also set up. After 72 hours of incubation in a cell culture incubator, the detection reagent CCK-8 was added. After 4 hours of incubation in a cell culture incubator, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 The results are shown in Table 4.

[0367] 2. Jeko-1 cell (MCL) proliferation inhibitory activity assay

[0368] Take Jeko-1 cells that are in good growth state, collect them into a centrifuge tube, and adjust the cell density to 2×10 4 The cells were inoculated with 100 μL / well of a 96-well plate and cultured overnight in a cell culture incubator. Compounds were added using a nanoliter pipette to a final concentration of 10,000 nM to 0.61 nM for Compound A and Compound I, with two replicates. A control was also set up. After 72 hours of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 4 hours, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC. 50 .

[0369] 3. Determination of MEC-1 cell (CLL) proliferation inhibitory activity

[0370] Take MEC-1 cells that are in good growth state, collect them into centrifuge tubes, and adjust the cell density to 8×10 4 The cells were inoculated with 100 μL / well of a 96-well plate and cultured overnight in a cell culture incubator. Compounds were added using a nanoliter pipette to a final concentration of 10,000 nM to 0.61 nM for Compound A and Compound I, with two replicates. A control was also set up. After 72 hours of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 4 hours, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, and the dose-effect curve was fitted to calculate the IC. 50 .

[0371] 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.

[0372] Table 4

[0373] For MINO cells, according to CompuSyn software analysis, compound A and compound I had obvious synergistic effects. At different final concentrations, the synergistic index CI was between 0.04 and 0.7, and was <0.3 at most concentrations.

Claims

1. Combination of BCL-2 inhibitor and BTK inhibitor, in, The BCL-2 inhibitor is selected from a compound of formula I-1 or a pharmaceutically acceptable salt thereof, Among them, R 11 Selected from hydrogen, halogen or C 1-6 alkyl; Ring A is selected from 5-6 membered heterocycloalkyl, R 22 are independently selected from 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, -COR aa 、-SO2R bb , or C optionally substituted by halogen 1-6 alkyl; R aa or R bb are independently selected from H, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with halogen, CN, -N(C 1-6 Alkyl)2, -NHC 1-6 Alkyl, or -OC 1-6 Alkyl substitution; p is selected from 0, 1, 2 or 3; Wherein, the BTK inhibitor is selected from the compound of formula II-1 or a pharmaceutically acceptable salt thereof Among them, R 1 are independently selected from halogen or C optionally substituted by fluorine 1-3 alkyl; m is selected from 0, 1 or 2; R 2 are independently selected from halogen, -OH, -NH2 or C 1-3 alkyl; n is selected from 0, 1 or 2; R 3 Selected from R a C(O)-,R a Selected from C 2-3 Alkynyl, C 2-3 Alkenyl, C 1-3 Alkyl or C 3-4 Cycloalkyl.

2. The combination according to claim 1, for use in the treatment of hematological tumors.

3. The combination according to claim 1 or 2, wherein: Structure fragment Selected from and / or, R 11 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 are independently selected from 4-6 membered heterocycloalkyl, C 4-6 Cycloalkyl, -COR aa 、-SO2R bb , or C optionally substituted by halogen 1-4 alkyl; R aa or R bb are independently selected from H, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with halogen, CN, -N(C 1-4 Alkyl)2, -NHC 1-4 Alkyl, or -OC 1-4 Alkyl substitution; and / or, R 22 Each independently selected from -C(O)H, -COC(CH3)3, -COCF3, -COCH2CN, -COCH2N(CH3)2, -SO2CH2CH3, -SO2CF3, -SO2C2F5, -CF3, -C2F5, tetrahydropyran, monooxetane, -SO 2- Cyclopropane, -CO-cyclopropane, -CO-monooxetane, -SO 2- Monooxetane, or -SO 2- Cyclobutane; and / or, p is selected from 0 or 1.

4. 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, 5. 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, R 1 is trifluoromethyl; and / or, R 2 are independently selected from halogen; and / or, R 2 are independently fluorine; and / or, n is selected from 0 or 1; and / or, n is 0; and / or, n is 1, R 2 is fluorine; and / or, R a Selected from propynyl, C 2-3 alkenyl or cyclopropyl; and / or, R a Selected from CH3C≡C-, CH2=CH- or cyclopropyl.

6. 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:

7. 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.

8. 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 lymphomas that are cyclin D1 positive and / or have t(11;14) translocation.

9. 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 the presence of 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.

10. The combination of any one of claims 1 to 9, wherein the daily or per dose of the compound of formula I-1 or a pharmaceutically acceptable salt thereof is selected from 10-5000 mg, 20-5000 mg, or 20-4000 mg, or 20-3000 mg, or 20-2000 mg, or 50-1500 mg, or 100-1200 mg, or 200-1000 mg, or 200-800 mg, or 200-600 mg, or 200-400 mg; 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 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.

11. The combination of any one of claims 1 to 10, wherein the daily or per 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.

12. 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.

13. Use of the combination according to any one of claims 1 to 11 in the preparation of a medicament for treating blood tumors.

14. Use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating blood tumors in combination with Compound A or a pharmaceutically acceptable salt thereof.

15. 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.

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