Pharmaceutical combinations and uses thereof

Abstract

The present invention belongs to the field of medicine, specifically, to a pharmaceutical combination comprising a Bcl-2 inhibitor or a Bcl-2 / Bcl-xL inhibitor and one or more anti-cancer agents, and the use of said combination in the treatment of diseases such as cancer, in particular acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or multiple myeloma (MM) that are drug-resistant or insensitive to Bcl-2 inhibitors and / or have Bcl-2 mutations and / or TP53 mutations. The present invention further relates to a pharmaceutical composition or a reagent kit comprising said combination.

Description

[Technical field]

[0001] The present invention belongs to the pharmaceutical field, specifically, to a pharmaceutical combination comprising a Bcl-2 inhibitor or a Bcl-2 / Bcl-xL inhibitor and one or more anti-cancer agents, and the use of said combination in the treatment of diseases such as cancer. The present invention further relates to a pharmaceutical composition or a reagent kit comprising said combination. [Background technology]

[0002] Proliferative diseases pose a serious threat to modern society. Cancerous proliferations present serious challenges to modern medicine due to their unique characteristics, including uncontrolled cell proliferation, ability to invade local and even distant tissues, lack of differentiation, lack of detectable symptoms, and lack of effective treatment and prevention. Over 10 million people worldwide are diagnosed with cancer every year, and 6 million people die from cancer every year, accounting for 12% of the world's deaths.

[0003] Many cancer therapeutics against different targets have already been developed, including targeted drugs (e.g., drugs targeting Bcl-2, Bcl-xL, EED, ALK, CDK4 / 6, Mek, MDM2, HDAC, PD-1, PARP, VEGF, BCR-ABL, IAP inhibitors, etc.).

[0004] Taking Bcl-2 inhibitors as an example, cell apoptosis is a default mechanism that can eliminate potentially dangerous cells, such as cells with cancerous defects, and the Bcl-2 protein family is a vital regulator of the mitochondrial (also called "intrinsic") apoptosis pathway. In view of the important role of Bcl-2 family proteins in controlling apoptosis in cancerous and normal cells (i.e., non-cancerous cells), as well as the recognized variability of Bcl-2 family protein expression among cell types, it is therefore advantageous for small molecule inhibitors to selectively target and preferably bind one or subgroup of anti-apoptotic Bcl-2 proteins, for example, to bind anti-apoptotic Bcl-2 family members that are overexpressed in certain types of cancer. Several Bcl-2 small molecule inhibitors have been studied at different stages of pharmaceutical development, and the Bcl-2 / Bcl-xL inhibitor ABT-263 (navitoclax, WO2009155386) shows good clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. A new generation Bcl-2 selective inhibitor, Venetoclax (ABT-199 / GDC-0199), has been launched and shows potent activity in these cancers and can also protect platelets (Journal of Hematology & Oncology 2015, 8, 129; Clinical Advances in Hematology & Oncology 2017, 15, 210). Currently, Venetoclax (originally ABT-199) is approved by the FDA for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion.

[0005] However, there is still considerable uncertainty regarding which specific targeted agents and compounds of specific structures are more effective in cancer treatment. In addition, some single-agent drugs often suffer from problems such as ineffectiveness, overdosing, and drug resistance. For example, a novel Gly101Val (G101V) mutation was recently discovered in Bcl-2 after a patient had been treated with the Bcl-2 inhibitor Venetoclax (ABT-199) for 19-42 months (Cancer Discov. 2019, 9, 342-353). This mutation significantly reduces the binding affinity of Bcl-2 to Venetoclax (ABT-199) by approximately 180-fold in cell-based measurements.

[0006] Drug combinations have many potential advantages over the use of drugs alone. In particular, drug combinations against multiple different targets can reduce the dose of each drug, avoid the development of single drug resistance, and even produce synergistic effects through careful selection of the combination, thereby improving the efficacy of cancer treatment.

[0007] Therefore, overcoming drug resistance of targeted drugs and other anticancer drugs is one of the major goals of therapeutic efficacy and drug development, and there is always an urgent need for single agents and drug combinations to improve therapeutic efficacy and / or reduce drug resistance in the field of cancer treatment. Summary of the Invention

[0008] In one aspect, the present invention provides a pharmaceutical combination comprising a Bcl-2 inhibitor and one or more anti-cancer agents.

[0009] In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutical combination of the present invention, and optionally a pharma- ceutically acceptable vector.

[0010] In another aspect, the present invention provides a method for treating or inhibiting, reducing the severity, reducing the risk, or inhibiting metastasis of cancer in an individual, comprising administering to the individual a therapeutically effective amount of a Bcl-2 inhibitor, and optionally a therapeutically effective amount of one or more anti-cancer agents.

[0011] In another aspect, the present invention provides the use of a combination of a Bcl-2 inhibitor and one or more anti-cancer agents to treat or inhibit, reduce the severity of, reduce the risk of, or inhibit metastasis of cancer in an individual.

[0012] In another aspect, the present invention provides the use of a combination of a Bcl-2 inhibitor and one or more anti-cancer agents in the manufacture of a medicament for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual.

[0013] In another aspect, the present invention provides the use of an MDM2 inhibitor, alone or in combination with one or more anti-cancer agents, to treat or inhibit, reduce the severity of, reduce the risk of, or inhibit metastasis of cancer in an individual.

[0014] In another aspect, the present invention provides a method for the manufacture of a medicament for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual, using an MDM2 inhibitor alone or in combination with one or more anti-cancer agents.

[0015] In another aspect, the present invention provides a pharmaceutical combination for treating or inhibiting, reducing the severity, reducing the risk, or inhibiting metastasis of cancer in an individual comprising an MDM2 inhibitor and one or more anti-cancer agents.

[0016] In another aspect, the present invention provides the use of a Bcl-2 / Bcl-xL inhibitor, alone or in combination with one or more anti-cancer agents, to treat or inhibit, reduce the severity of, reduce the risk of, or inhibit metastasis of cancer in an individual.

[0017] In another aspect, the present invention provides the use of a Bcl-2 / Bcl-xL inhibitor, alone or in combination with one or more anti-cancer agents, in the manufacture of a medicament for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual.

[0018] In another aspect, the present invention provides a pharmaceutical combination for treating or inhibiting, reducing the severity, reducing the risk, or inhibiting metastasis of cancer in an individual comprising a Bcl-2 / Bcl-xL inhibitor and one or more anti-cancer agents.

[0019] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (a) a first component in a first container comprising a Bcl-2 inhibitor or a Bcl-2 / Bcl-xL inhibitor; (b) a second component in a second container comprising one or more anticancer drugs, and optionally a pharma- ceutically acceptable vector; and (c) Providing a reagent kit including optional specifications. [Brief description of the drawings]

[0020] [Figure 1-1] 1 shows that compound B can restore killing of RS4;11 cells harboring different Bcl-2 mutations. [Figure 1-2] 1 shows that compound B can restore killing of RS4;11 cells harboring different Bcl-2 mutations. [Figure 2-1] Figure 2 shows that the combination of the present invention is able to synergistically inhibit the proliferation of the RS4;11 Bcl2-G101V-Flag cell line. [Figure 2-2]Figure 2 shows that the combination of the present invention is able to synergistically inhibit the proliferation of the RS4;11 Bcl2-G101V-Flag cell line. [Figure 2-3] Figure 2 shows that the combination of the present invention is able to synergistically inhibit the proliferation of the RS4;11 Bcl2-G101V-Flag cell line. [Figure 2-4] Figure 2 shows that the combination of the present invention is able to synergistically inhibit the proliferation of the RS4;11 Bcl2-G101V-Flag cell line. [Figure 3-1] 1 shows that the combination of the present invention can synergistically inhibit the proliferation of the RS4;11 Bcl2-V156D-Flag cell line. [Figure 3-2] 1 shows that the combination of the present invention can synergistically inhibit the proliferation of the RS4;11 Bcl2-V156D-Flag cell line. [Figure 3-3] 1 shows that the combination of the present invention can synergistically inhibit the proliferation of the RS4;11 Bcl2-V156D-Flag cell line. [Diagram 3-4] 1 shows that the combination of the present invention can synergistically inhibit the proliferation of the RS4;11 Bcl2-V156D-Flag cell line. [Figure 4-1] We show that co-targeting BCL-2, MDM2, and IAPs is most effective in compound A-induced drug-resistant cell lines (AML and ALL). [Figure 4-2] We show that co-targeting BCL-2, MDM2, and IAPs is most effective in compound A-induced drug-resistant cell lines (AML and ALL). [Figure 4-3] We show that co-targeting BCL-2, MDM2, and IAPs is most effective in compound A-induced drug-resistant cell lines (AML and ALL). [Diagram 5] 1 shows that the combination of Compound A and Compound B overcomes Venetoclax drug resistance in a BCL-2 V156D mutated tumor model (RS4;11BCL-2-V156D-Flag cells). [Figure 6]1 shows combination treatment in a murine RS4;11BCL-2-G101V-Flag human ALL cancer xenograft model. [Figure 7-1] Mice show Compound A + Compound B + Aza vs. Compound A + Compound B + Compound C in the RS4;11-VEN-R human ALL cancer xenograft model. [Figure 7-2] Mice show Compound A + Compound B + Aza vs. Compound A + Compound B + Compound C in the RS4;11-VEN-R human ALL cancer xenograft model. [Figure 8-1] 1 shows the combined effect of Compound A + Compound C in AML cells (72 hours). [Figure 8-2] 1 shows the combined effect of Compound A + Compound C in AML cells (72 hours). [Figure 9-1] 1 shows that the combination of Compound A and Compound C produces synergistic effects in the treatment of subcutaneous MV-4-11 AML. [Figure 9-2] 1 shows that the combination of Compound A and Compound C produces synergistic effects in the treatment of subcutaneous MV-4-11 AML. [Figure 9-3] 1 shows that the combination of Compound A and Compound C produces synergistic effects in the treatment of subcutaneous MV-4-11 AML. [Figure 9-4] 1 shows that the combination of Compound A and Compound C produces synergistic effects in the treatment of subcutaneous MV-4-11 AML. [Figure 10-1] 1 shows the combined therapeutic effect of Compound A and Compound C in an orthotopic MOLM-13-luc human AML model. [Figure 10-2] 1 shows the combined therapeutic effect of Compound A and Compound C in an orthotopic MOLM-13-luc human AML model. [Figure 10-3] 1 shows the combined therapeutic effect of Compound A and Compound C in an orthotopic MOLM-13-luc human AML model. [Figure 11-1] 1 shows the efficacy of combination treatment with Compound A, Compound B and / or Compound C in the p53 WT systemic OCI-AML 3 AML model (intrinsic drug resistance to Venetoclax). [Figure 11-2] 1 shows the efficacy of combination treatment with Compound A, Compound B and / or Compound C in the p53 WT systemic OCI-AML 3 AML model (intrinsic drug resistance to Venetoclax). [Figure 11-3] 1 shows the efficacy of combination treatment with Compound A, Compound B and / or Compound C in the p53 WT systemic OCI-AML 3 AML model (intrinsic drug resistance to Venetoclax). [Figure 12-1] We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 12-2] We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 12-3] We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 12-4] We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 12-5] We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 12-6] We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 12-7] We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 12-8]We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 12-9] We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 12-10] We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 12-11] We show that intrinsic and extrinsic apoptosis are cotargeted to maximally induce cell death in Venetoclax drug-resistant AML cells. [Figure 13] 1 shows that Compound E exhibits single agent activity in BCL-2i insensitive cells RPMI 8226. [Figure 14-1] 1 shows that the combination of Compound E and Compound C sensitizes BCL-2i insensitive cells to growth inhibition. [Figure 14-2] 1 shows that the combination of Compound E and Compound C sensitizes BCL-2i insensitive cells to growth inhibition. [Figure 14-3] 1 shows that the combination of Compound E and Compound C sensitizes BCL-2i insensitive cells to growth inhibition. [Figure 14-4] 1 shows that the combination of Compound E and Compound C sensitizes BCL-2i insensitive cells to growth inhibition. [Figure 15-1] 1 shows that Compound C exhibits single agent activity in MM cells insensitive to BCL-2 inhibitors. [Figure 15-2] 1 shows that Compound C exhibits single agent activity in MM cells insensitive to BCL-2 inhibitors. [Figure 16-1]We show that Compound E / Compound D exhibit single-agent activity in both Venetoclax drug-resistant MM cells and xenograft models, with Compound E inhibiting the proliferation of drug-resistant clones (Figure 16A) and simultaneously inducing cell apoptosis (Figure 16B), with Compound E being the most effective in inducing cell death (Figure 16C). Compound E's prodrug Compound D was also effective in the CDX model of these two cell lines (Figures 16D and 16E), and we observed that Compound E was more active than Venetoclax in MM cells from four MM patients (Figure 16F). [Figure 16-2] We show that Compound E / Compound D exhibit single-agent activity in both Venetoclax drug-resistant MM cells and xenograft models, with Compound E inhibiting the proliferation of drug-resistant clones (Figure 16A) and simultaneously inducing cell apoptosis (Figure 16B), with Compound E being the most effective in inducing cell death (Figure 16C). Compound E's prodrug Compound D was also effective in the CDX model of these two cell lines (Figures 16D and 16E), and we observed that Compound E was more active than Venetoclax in MM cells from four MM patients (Figure 16F). [Figure 16-3] We show that Compound E / Compound D exhibit single-agent activity in both Venetoclax drug-resistant MM cells and xenograft models, with Compound E inhibiting the proliferation of drug-resistant clones (Figure 16A) and simultaneously inducing cell apoptosis (Figure 16B), with Compound E being the most effective in inducing cell death (Figure 16C). Compound E's prodrug Compound D was also effective in the CDX model of these two cell lines (Figures 16D and 16E), and we observed that Compound E was more active than Venetoclax in MM cells from four MM patients (Figure 16F). [Figure 16-4]We show that Compound E / Compound D exhibit single-agent activity in both Venetoclax drug-resistant MM cells and xenograft models, with Compound E inhibiting the proliferation of drug-resistant clones (Figure 16A) and simultaneously inducing cell apoptosis (Figure 16B), with Compound E being the most effective in inducing cell death (Figure 16C). Compound E's prodrug Compound D was also effective in the CDX model of these two cell lines (Figures 16D and 16E), and we observed that Compound E was more active than Venetoclax in MM cells from four MM patients (Figure 16F). [Figure 16-5] We show that Compound E / Compound D exhibit single-agent activity in both Venetoclax drug-resistant MM cells and xenograft models, with Compound E inhibiting the proliferation of drug-resistant clones (Figure 16A) and simultaneously inducing cell apoptosis (Figure 16B), with Compound E being the most effective in inducing cell death (Figure 16C). Compound E's prodrug Compound D was also effective in the CDX model of these two cell lines (Figures 16D and 16E), and we observed that Compound E was more active than Venetoclax in MM cells from four MM patients (Figure 16F). [Figure 16-6] We show that Compound E / Compound D exhibit single-agent activity in both Venetoclax drug-resistant MM cells and xenograft models, with Compound E inhibiting the proliferation of drug-resistant clones (Figure 16A) and simultaneously inducing cell apoptosis (Figure 16B), with Compound E being the most effective in inducing cell death (Figure 16C). Compound E's prodrug Compound D was also effective in the CDX model of these two cell lines (Figures 16D and 16E), and we observed that Compound E was more active than Venetoclax in MM cells from four MM patients (Figure 16F). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Unless otherwise defined below, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. References to techniques used in the present invention refer to techniques commonly understood in the art, including variations or technical equivalents that are obvious to those skilled in the art. Although the following terms are believed to be familiar to those skilled in the art, the following definitions are provided to better describe the present invention.

[0022] For example, as used herein, the terms "including," "comprising," "having," "containing," or "comprising," as well as other variations, are inclusive or open-ended and do not exclude other unrecited elements or method steps.

[0023] Unless otherwise stated, the terms "a", "an", "the" and similar uses should be construed as including the singular and the plural when used in the context of describing the present invention (especially in the context of the claims). Unless otherwise stated, the recitation of numerical ranges in the present invention is merely a shorthand way of reciting each individual value within the range, and each individual value is incorporated into the specification as if it were individually recited in the present invention. Unless otherwise stated, the use of any and all examples or exemplary language (e.g., "for example") provided in the present invention is intended to better describe the content disclosed in the present invention, and does not limit the scope of the disclosed invention. No language in this specification should be construed as indicating any non-claimed element essential to the practice of the disclosed invention.

[0024] For example, the terms "treat", "treating", "treatment" and the like as used herein refer to the elimination, reduction or amelioration of a disease or disorder and / or symptoms associated therewith. Treatment of a disease or disorder does not require the complete elimination of the disease, disorder or symptoms associated therewith, although it cannot eliminate them. The term "treatment" and synonyms contemplate administering a therapeutically effective amount of a compound disclosed in the present invention to a subject in need of such treatment. Treatment can be symptomatic, e.g., inhibition of symptoms. It can be effective within the short term, can be mid-term, or can be a long-term treatment, such as in the case of maintenance therapy.

[0025] For example, the terms "prevent", "preventing" and "prevention" as used herein refer to a method of preventing the onset of a disease or disorder and / or its associated symptoms or preventing a subject from contracting a disease. As used herein, "prevent", "preventing" and "prevention" further include delaying the onset of a disease and / or its associated symptoms and reducing a subject's risk of contracting a disease. The terms "prevent", "preventing" and "prevention" may include "prophylactic treatment", which refers to reducing the probability of a disease or condition relapse or recurrence in a subject who is not at risk of or susceptible to a disease or condition relapse or recurrence that has previously been controlled.

[0026] For example, the term "synergistic effect" used in the present invention refers to the effect of two therapeutic agents, for example, alleviating the progression of symptoms of proliferative disease, particularly cancer or its symptoms, which is greater than the simple sum of the effects of each agent by itself.For example, synergistic effect can be calculated using various methods and equations known in the art, such as those described in the examples of the present invention.

[0027] For example, the term "halogen" as used herein, by itself or as part of another group, refers to -Cl, -F, -Br, or -I.

[0028] For example, the term "nitro group" as used herein, by itself or as part of another group, represents -NO 2 Refers to...

[0029] For example, the term "cyano" as used herein, by itself or as part of another group, refers to --CN.

[0030] For example, the term "hydroxy group" as used herein, by itself or as part of another group, refers to --OH.

[0031] For example, the term "alkyl group" as used herein, alone or as part of another group, refers to an unsubstituted straight or branched chain aliphatic hydrocarbon group containing 1 to 12 carbon atoms or a specified number of carbon atoms (i.e., C 1-12 alkyl), e.g., methyl group, 1 C such as alkyl group and ethyl group 2 C such as alkyl group, n-propyl group or isopropyl group 3 C such as alkyl, methyl, ethyl, n-propyl or isopropyl groups 1-3 In one embodiment, the alkyl group is a C 1-4 It is an alkyl group. 1-12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl groups. 1-4 Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a t-butyl group and an isobutyl group.

[0032] For example, the term "alkenyl group" as used herein, by itself or as part of another group, refers to an alkyl group that contains one, two, or three carbon-carbon double bonds. In one embodiment, an alkenyl group is 2 -C 6 In another embodiment, the alkenyl group is C 2 -C 4 In another embodiment, the alkenyl group has one carbon-carbon double bond. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0033] For example, the term "alkynyl group" as used herein, by itself or as part of another group, refers to an alkyl group that contains one, two, or three carbon-carbon triple bonds. In one embodiment, an alkynyl group is 2 -C 6 In another embodiment, the alkynyl group is C 2 -C 4 In another embodiment, the alkynyl group has one carbon-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0034] The term "haloalkyl group" as used herein, by itself or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In one embodiment, the alkyl group is substituted with one, two or three fluorine and / or chlorine atoms. In another embodiment, the alkyl group is substituted with one, two or three fluorine atoms. In another embodiment, the alkyl group is C 1 -C 6 In another embodiment, the alkyl group is C 1 -C 4 In another embodiment, the alkyl group is C 1 or C2 Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1 difluoroethyl, 2,2-difluoroethyl, 2,2,2 trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4 trifluorobutyl, and trichloromethyl.

[0035] For example, the term "alkoxy group" as used herein, by itself or as part of another group, refers to an alkyl group linked to a terminal oxygen atom. In one embodiment, the alkyl group is 1 -C 6 alkyl group, and therefore the resulting alkoxy group is "C 1 -C 6 In another embodiment, the alkyl group is a C 1 -C 4 Alkyl groups. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and t-butoxy groups.

[0036] For example, the term "cycloalkyl group" as used herein, alone or as part of another group, refers to one or two rings having 3 to 12 carbon atoms or the indicated number of carbon atoms (i.e., C 3-12 In one embodiment, the cycloalkyl group has two rings. In one embodiment, the cycloalkyl group has one ring. In another embodiment, the cycloalkyl group has C 3-8 In another embodiment, the cycloalkyl group is selected from the group consisting of C 3-6 Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decahydronaphthalene, adamantyl, cyclohexenyl, and cyclopentenyl groups.

[0037] For example, the term "heterocycle" or "heterocyclyl group" as used herein, alone or as part of another group, refers to a saturated or partially unsaturated (e.g., containing one or two double bonds) cyclic group consisting of one, two or three cyclic groups and containing 3 to 14 rings (i.e., 3 to 14 heterocyclyl groups), in which at least one carbon atom of one ring is replaced with one heteroatom. Each heteroatom is independently selected from the group consisting of oxygen, sulfur (including sulfoxide and sulfone), and / or nitrogen (which may be oxidized or quaternized) atoms. The term "heterocycle" is intended to include groups in which -CH2- in the ring is replaced with -C(=O)-, such as cyclic ureido groups (e.g., 2-imidazolidinone) and cyclic amides (e.g., β-lactam, γ-lactam, δ-lactam, ε-lactam) and piperazine-2-one. In one embodiment, the heterocyclyl group is a 3- to 8-membered ring group containing one ring and one or two oxygen and / or nitrogen atoms. In one embodiment, the heterocyclyl group is a 4-, 5-, or 6-membered ring group containing one ring and one or two oxygen and / or nitrogen atoms. In one embodiment, the heterocyclyl group is a 4- or 6-membered ring group containing one ring and one or two oxygen and / or nitrogen atoms. The heterocycle can be linked to the remainder of the molecule through any available carbon or nitrogen atom. Non-limiting examples of heterocyclyl groups include dioxyacyl, tetrahydropyranyl, 2-oxopyrrolidin-3-yl, piperazin-2-one, piperazin-2,6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolyl.

[0038] For example, the term "aryl group" as used herein, by itself or as part of another group, refers to an aromatic ring system having 6 to 14 carbon atoms, i.e., C 6 -C 14Refers to an aryl group. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenyl, and fluorenyl. In one embodiment, the aryl group is a phenyl or naphthyl group. In another embodiment, the aryl group is a phenyl group.

[0039] For example, the term "heteroaryl group" as used herein, by itself or as part of another group, refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 tetracyclic ring members, i.e., 5 to 14 membered heteroaryl groups containing 1, 2, 3 or 4 heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl group has 3 heteroatoms. In another embodiment, the heteroaryl group has 2 heteroatoms. In another embodiment, the heteroaryl group has 1 heteroatom. In another embodiment, the heteroaryl group is a 5- to 10-membered heteroaryl group. In another embodiment, the heteroaryl group has 5 ring atoms, e.g., a thienyl group is a 5-membered heteroaryl group having 4 carbon atoms and 1 sulfur atom. In another embodiment, the heteroaryl group has 6 ring atoms, e.g., a pyridyl group is a 6-membered heteroaryl group having 5 carbon atoms and 1 nitrogen atom.

[0040] For example, the term "cancer" as used herein refers to a neoplasm or tumor caused by abnormal, uncontrolled cell proliferation. Non-limiting examples include the exemplary cancers described in the detailed description of the invention. The term "cancer" includes diseases associated with pre-cancerous and malignant cancerous cells.

[0041] The term "cancer metastasis" as used in the present invention refers to the spread (metastasis) of cancer from its original site to another area of ​​the body. Almost all cancers can metastasize. Whether metastasis occurs depends on the complex interactions between multiple tumor cell elements, including the type of cancer, the degree of maturation (differentiation) of the tumor cells, the location and age of the cancer, and other factors that have not yet been fully understood. Metastasis has three modes: locally from the tumor to surrounding tissues, through the bloodstream to distant sites, or through the lymphatic system to nearby or distant lymph nodes. Each cancer has its own representative route of spread. Tumors are named according to their original site (e.g., breast cancer that metastasizes to the brain is called metastatic breast cancer that metastasizes to the brain).

[0042] For example, the terms "individual", "patient" or "subject" as used in the present invention refer to humans (e.g., patients) and animals (e.g., mice, rats, dogs, cats, rabbits, chickens, monkeys, etc.). When the subject is a human patient (usually calculated based on a body weight of 60 kg), the dose described in the present invention can be obtained by converting it into a conversion factor for experimental animals (e.g., human dose = mouse dose / 12.3) unless otherwise specified (Kin Tam. "Estimating the "First in human" dose-a revisit with special evidence on the oncology drug, ADMET & DMPK1 (4) (2013) 63-75). A person skilled in the art can reasonably adjust the dose based on common sense and factors such as the weight of the subject, the type and severity of the disease, and any of these adjusted technical proposals are within the scope of the technical proposals required by the present invention.

[0043] For example, the term "effective amount" or "prophylactically and / or therapeutically effective amount" as used herein refers to the amount (e.g., dose) of a pharmaceutical or compound to be administered that is treated to a sufficient degree to alleviate one or more symptoms of a disease or disorder. The result may be to reduce and / or alleviate the cause of the disorder or the cause of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound or drug (e.g., a combination product claimed in the present invention) that significantly alleviates the clinical symptoms of a disease or disorder without causing excessive toxic side effects.

[0044] For example, the term "dose" as used herein refers to the weight (eg, milligrams (mg)) of active agent per kilogram (kg) of subject body weight.

[0045] For example, the term "IC 50 " refers to the amount, concentration or dose of a particular test compound or pharmaceutical agent that achieves 50% maximal inhibition of the effect in an assay that measures such effect.

[0046] For example, the term "room temperature" used in the present invention refers to 25° C.±1° C. At the same time, the experimental temperature is room temperature unless otherwise specified.

[0047] For example, the term "pharmaceutically acceptable salts" as used herein includes acid addition salts and base addition salts of compounds.

[0048] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclohexylsulfamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, benzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodate. , isethionate, lactate malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, aldonate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate and octinoxate salts.

[0049] Suitable base addition salts are formed from bases which form non-toxic salts, examples include aluminum salts, arginine salts, benzylpenicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.

[0050] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth, Wiley-VCH, 2002. Methods for preparing pharma- ceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0051] For example, the term "solvate" as used in the present invention refers to a substance formed by combining, physically combining and / or solvating a compound of the present invention with a solvent molecule, for example, a disolvate, a monosolvate or a hemisolvate, in which the ratio of the solvent molecule to the compound of the present invention is about 2:1, about 1:1 or about 1:2, respectively. This physical combining involves, to different degrees, ionization and covalent bonding (including hydrogen bonding). In some cases (for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid), the solvate can be isolated. Thus, the solvent includes both solution phase and separable solvent. The compound of the present invention can exist in a solvated form with a pharma- ceutically acceptable solvent (for example, water, methanol, and ethanol), and the present application is intended to include the solvated and unsolvated forms of the compound of the present invention.

[0052] One type of solvate is a hydrate. "Hydrate" refers to a specific subset of solvates in which the solvent molecule is water. Solvates usually function in the form of pharmacological equivalents. The preparation of solvates is known in the art, see for example M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of a solvate of fluconazole with ethyl acetate and water. Van Tonder et al, AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004) and ALBingham et al, Chem. Commun. 603-604 (2001) describe similar methods for preparing solvates, hemisolvates, hydrates, and the like. An exemplary, non-limiting method for preparing the solvent involves dissolving the compound of the present invention in a desired solvent (organic solvent, water, or a mixture thereof) at a temperature greater than 20° C. to about 25° C., then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods (e.g., filtration). Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in the crystals.

[0053] A "pharmacologically acceptable vector" in the context of the present invention refers to a diluent, adjuvant, excipient, or vector for use with a therapeutic agent that is suitable, within the scope of reasonable medical judgment, for contact with the tissues of humans and / or other animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0054] Pharmaceutically acceptable vectors that can be used in the pharmaceutical composition or reagent kit of the present invention include, but are not limited to, sterile liquids, such as water, and oils derived from petroleum, animal, vegetable, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary vector. Saline and aqueous solutions of glucose and glycerin can also be used as liquid vectors, particularly for injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, nonfat dry milk, glycerin, propylene, water, ethanol, and the like. If necessary, the pharmaceutical composition may further contain small amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard vectors, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharma- ceutically acceptable vectors are described in Remington's Pharmaceutical Sciences (1990).

[0055] The components of the pharmaceutical composition and reagent kit of the present invention can act systemically and / or locally.To this end, they can be administered by a suitable route, for example, by injection (including, for example, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, instillation) or transdermal, or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic formulation or by inhalation.

[0056] For these administration routes, the pharmaceutical compositions and components of the reagent kit of the present invention can be administered in appropriate dosage forms.

[0057] Such dosage forms include, but are not limited to, tablets, capsules, troches, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, salves, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0058] For example, the term "container" as used herein refers to a container for housing pharmaceutical ingredients, which may be used for manufacturing, storing, shipping, and / or individual / batch sales, and is intended to include bottles, cans, vials, flasks, syringes, tubes (e.g., those used in cream products), or any other container for manufacturing, housing, storage, or dispensing pharmaceuticals.

[0059] For example, the term "instructions / instructions" as used herein refers to an insert, label, tag, etc. that records information about the pharmaceutical ingredient in the container. The recorded information is usually determined by a regulatory agency (e.g., the U.S. Food and Drug Administration) that has jurisdiction over the region in which the product is sold. Preferably, the packaging instructions specifically list the indications for which the pharmaceutical ingredient is approved for use. The packaging instructions can be made of any material that allows the information therein or thereon to be read. Preferably, the packaging leaflet is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which desired information can be formed (e.g., printed or applied).

[0060] For example, the term "drug resistance" as used herein refers to the development of drug resistance in cancer cells to chemotherapy. Cancer cells can acquire chemotherapy drug resistance through a range of mechanisms, including mutation or overexpression of the drug target, inactivation of the drug, or removal of the drug from the cell.

[0061] For example, the term "about" as used herein refers to ±10%, preferably ±5%, and most preferably ±2% of the modified value of the term, thereby allowing a person skilled in the art to clearly determine the range of "about" based on the modified value. Pharmaceutical Combinations and Uses

[0062] In one aspect, the present invention provides a pharmaceutical combination comprising a Bcl-2 inhibitor and one or more anti-cancer agents.

[0063] In one preferred embodiment, the one or more anti-cancer agents are selected from an MDM2 inhibitor, an IAP inhibitor, and other anti-cancer agents.

[0064] In one preferred embodiment, the one or more anti-cancer agents are selected from an MDM2 inhibitor, an IAP inhibitor, and combinations thereof.

[0065] In one embodiment, the Bcl-2 inhibitor is a compound of formula V: [ka] or a pharma- ceutically acceptable salt or solvate thereof, A 3 teeth [ka] Selected from E 3 is a nitrogen atom, and [ka] is a single bond, X 31 , X 32 , and X 33 are -CR, respectively. 38 = and -N=, R 31a and R 31b together with the carbon atom to which they are attached form a 3-, 4-, or 5-membered cycloalkyl group; R 32-NO 2 , -SO 2 CH 3 , and -SO 2 CF 3 Selected from R 32a is selected from hydrogen and halogens; R 33 -N(R 34a )(R 34b ) are selected, R 34a is an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-6 selected from cycloalkyl groups, heterocyclyl groups, heteroalkyl groups, (cycloalkyl)alkyl groups and (heterocyclyl)alkyl groups; R 34b is hydrogen and C 1-4 selected from alkyl groups, R 38 is selected from hydrogen and halogen.

[0066] In one preferred embodiment, the Bcl-2 inhibitor is [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0067] In one preferred embodiment, the Bcl-2 inhibitor is [ka] Compound A is (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide (Compound A) or a pharma- ceutically acceptable salt or solvate thereof.

[0068] In one embodiment, the MDM2 inhibitor is a compound of formula (VI) or a pharma- ceutically acceptable salt or solvate thereof: [ka] Among them, [ka] [ka] [ka] R 62 , R 63 , R 64 , R 65 , R 67 , R 68 , R 69 and R 70 is independently selected from the group consisting of H, F and Cl; [ka] And R 6c and R 6d is a substituent on one carbon atom of ring B, R 6c is H, C 1-3 is an alkyl group or a halogen; R 6d is H, C 1-3 is an alkyl group or a halogen; R 6e -C(=O)OR 6a and R 6a is hydrogen or unsubstituted C 1-4 It is an alkyl group.

[0069] In one preferred embodiment, R 62 is H and R 63 is F or Cl, and R 64 and R 65 is H and R 67 is fluorine, R 68 , R69 and R 70 Each of is H and R 6c is H, CH 3 or halogen, and R 6d is H, CH 3 Or a halogen.

[0070] In one preferred embodiment, the MDM2 inhibitor is [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0071] In one embodiment, the IAP inhibitor is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof: [ka] Among them, [ka] Y is selected from -NH-, -O-, -S-, and is absent; R is selected from the following:

[0072] [ka] R 1 teeth, [ka] Selected from.

[0073] In one preferred embodiment, the IAP inhibitor is: [ka]

[0074] or a pharma- ceutically acceptable salt or solvate thereof. In one preferred embodiment, the IAP inhibitor is: [ka]

[0075] 1,3-phenylenebis[7-(3S,5S,9aR)-5-((S)-2-methylamino-propionamido)-3-diphenylcarbamoyl-4-oxo-3a,7-diaza-decahydrocyclopentacyclooctene)]-sulfonamide (Compound C), or a pharma- ceutically acceptable salt or solvate thereof.

[0076] In a preferred embodiment, the pharmaceutical combination is used to treat or inhibit, reduce the severity of, reduce the risk of, or inhibit metastasis in an individual of cancer, preferably bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and lung squamous cell carcinoma), mesothelial carcinoma tumors, melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroturbinoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer, squamous cell carcinoma, spindle cell carcinoma, gastric cancer, seminal tract cancer, thyroid cancer, ovarian cancer, thyroid ... The cancer is selected from: focal carcinoma, thyroid cancer, uterine cancer, mesothelioma, neuroblastoma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma tumor, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, metastasis from spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma and hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma (MM), uveal melanoma, pleural mesothelioma, peritoneal mesothelioma.

[0077] In a preferred embodiment, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM).

[0078] In a preferred embodiment, the cancer is resistant or insensitive to Bcl-2 inhibitors such as Compound A or Venetoclax, and more preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM), which is resistant or insensitive to Bcl-2 inhibitors such as Compound A or Venetoclax.

[0079] In a preferred embodiment, the cancer has a Bcl-2 mutation (e.g., G101V, D103E, V156D, and combinations thereof) and / or a TP53 mutation (e.g., R248Q, R175H, R282W, Y220C, and combinations thereof).More preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM) with a Bcl-2 mutation and / or a TP53 mutation.

[0080] In a preferred embodiment, the weight ratio of the Bcl-2 inhibitor to the one or more anticancer agents is 0.005-5000:0.005-5000, for example, 0.05-1500:0.005-5000, 0.1-6:0.005-4, 100:0.5-400, 100:1-350, 100:2-300, 100:5-200, 100:10-150, 100:10-100, 100:10-90 or 100:20-80.

[0081] In one preferred embodiment, the molar ratio of the Bcl-2 inhibitor to the one or more anti-cancer agents is 10 to 1:1 to 10, such as 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, and any range between the above values.

[0082] In one preferred embodiment, the Bcl-2 inhibitor is [ka] (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide (Compound A) or a pharma- ceutically acceptable salt or solvate thereof; and / or MDM2 inhibitors [ka] or a pharma- ceutically acceptable salt or solvate thereof; and / or IAP inhibitors are: [ka]

[0083] 1,3-phenylenebis[7-(3S,5S,9aR)-5-((S)-2-methylamino-propionamido)-3-diphenylcarbamoyl-4-oxo-3a,7-diaza-decahydrocyclopentacyclooctene)]-sulfonamide (Compound C), or a pharma- ceutically acceptable salt or solvate thereof.

[0084] In another aspect, the present invention provides a pharmaceutical combination comprising any of the pharmaceutical combinations of the present invention, and optionally a pharma- ceutically acceptable vector.

[0085] In a preferred embodiment, the pharmaceutical composition may be in any form, for example, the composition is a tablet, capsule, granule, syrup, powder, troche, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol, ointment, cream and injectable.

[0086] The pharmaceutical combinations are typically administered in admixture with a pharmaceutical vector to provide a pharmaceutical composition selected according to a given route of administration and standard pharmaceutical practice. The pharmaceutical compositions used in the present invention are formulated in a conventional manner using one or more physiologically acceptable vectors, including excipients and / or adjuvants that facilitate processing of the pharmaceutical composition. These pharmaceutical compositions may be prepared, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, embedding, or lyophilizing processes. Appropriate formulations depend on the chosen route of administration. When a therapeutically effective amount of the pharmaceutical combination is administered orally, the composition is usually in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition may further comprise a solid vector such as gelatin or an adjuvant. The tablets, capsules, and powders contain about 0.01% to about 95%, preferably about 1% to about 50%, of the pharmaceutical combination. When administered in liquid form, a liquid vector such as water, petroleum, or oil of animal or vegetable origin may be added. The liquid form of the composition may further comprise saline, glucose or other carbohydrate solution, or ethylene glycol. When administered in liquid form, the composition contains about 0.1% to about 90%, preferably about 1% to about 50%, of the pharmaceutical combination by weight.

[0087] When the therapeutically effective amount of the pharmaceutical combination is administered by intravenous, cutaneous or subcutaneous injection, the composition is in the form of a pyrogen-free parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, taking into account appropriate pH, isotonicity, stability, etc., is within the skill of the art. A preferred composition for intravenous, cutaneous or subcutaneous injection usually contains an isotonic vector.

[0088] The pharmaceutical combination can be easily combined with pharma- ceutically acceptable vectors well known in the art. Standard pharmaceutical vectors are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed.1995. Such vectors allow the active agent to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like for oral ingestion by the subject. Oral pharmaceutical preparations can be prepared by adding the pharmaceutical combination to a solid excipient, optionally grinding the resulting mixture, and processing the granulated mixture after adding appropriate pharmaceuticals as necessary, thereby obtaining tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations, and disintegrants may be added as necessary.

[0089] The pharmaceutical combination can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion.The preparation for injection can be in unit dosage form, for example, in ampoules or multi-dose containers, with preservative added.The composition can take the form of suspension, solution or emulsion in oily or aqueous vector, and can contain compounding agents such as suspending agents, stabilizers and / or powders.

[0090] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agents in water-soluble form. Furthermore, suspensions of the pharmaceutical combinations may be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vectors include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may further contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, the compositions of the present invention may be in powder form for constitution with a suitable vector (e.g., sterile pyrogen-free water) before use.

[0091] The pharmaceutical combination can also be formulated as rectal composition, for example, suppository containing conventional suppository matrix or retention enema.In addition to the above-mentioned formulation, the compound of the present invention can be formulated as long-acting preparation.Such long-acting preparation can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.Thus, for example, the compound of the present invention can be formulated with suitable polymer or hydrophobic material (for example, as emulsion in acceptable oil) or ion exchange resin.

[0092] Specifically, the pharmaceutical combination may be administered orally, bucally or sublingually in the form of a tablet containing an excipient (e.g., starch or lactose), or in the form of a capsule or ovule, or may be administered alone or mixed with an excipient, or in the form of a suspension containing a flavoring or coloring agent. Such liquid preparations can be prepared using pharma- ceutically acceptable additives such as suspending agents. The pharmaceutical combination may be injected by intravenous injection, intramuscular injection, subcutaneous injection or intracoronary injection. For parenteral administration, the pharmaceutical combination is usually used in the form of a sterile aqueous solution, which may contain other substances, such as salts or simple sugars such as mannitol or glucose, to make the solution isotonic with blood.

[0093] In another aspect, the present invention provides a method for treating or inhibiting, reducing the severity, reducing the risk, or inhibiting metastasis of cancer in an individual, comprising administering to the individual a therapeutically effective amount of a Bcl-2 inhibitor, and optionally a therapeutically effective amount of one or more anti-cancer agents.

[0094] In one preferred embodiment, the one or more anti-cancer agents are selected from an MDM2 inhibitor, an IAP inhibitor, and other anti-cancer agents.

[0095] In a preferred embodiment, said Bcl-2, MDM2 and / or IAP inhibitor is as defined above and said cancer is as defined above.

[0096] In one preferred embodiment, the dosage of the Bcl-2 inhibitor is from about 0.005 mg / day to about 5000 mg / day, for example, about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 4000, 4500, or 5000 milligrams / day.

[0097] In a preferred embodiment, the dosage of the Bcl-2 inhibitor is about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg per unit dose. For example, the dosage is about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg per unit dose. g, approximately 375μg / kg, approximately 400μg / kg, approximately 425μg / kg, approximately 450μg / kg, approximately 475μg / kg, approximately 500μg / kg, approximately 525μg / kg, approximately 550μg / kg , about 575μg / kg, about 600μg / kg, about 625μg / kg, about 650μg / kg, about 675μg / kg, about 700μg / kg, about 725μg / kg, about 750μg / kg, about 775μg / kg, about 800μg / kg, about 825μg / kg, about 850μg / kg, about 875μg / kg, about 900μg / kg, about 925μg / kg, about 950μg / kg, about 9 75μg / kg, approximately 1mg / kg, approximately 5mg / kg, approximately 10mg / kg, approximately 15mg / kg, approximately 20mg / kg, approximately 25mg / kg, approximately 30mg / kg, approximately 35mg / kg, approximately 40m g / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, and administered in one or multiple (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) unit doses per day.

[0098] In a preferred embodiment, the one or more anti-cancer agents are administered in an amount of 0.005 mg / day to about 5000 mg / day, e.g., about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 milligrams / day.

[0099] In a preferred embodiment, the dosage of the one or more anticancer agents is about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg per unit dose. For example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg per unit dose. g, approximately 375μg / kg, approximately 400μg / kg, approximately 425μg / kg, approximately 450μg / kg, approximately 475μg / kg, approximately 500μg / kg, approximately 525μg / kg, approximately 550μg / kg , about 575μg / kg, about 600μg / kg, about 625μg / kg, about 650μg / kg, about 675μg / kg, about 700μg / kg, about 725μg / kg, about 750μg / kg, about 775μg / kg, about 800μg / kg, about 825μg / kg, about 850μg / kg, about 875μg / kg, about 900μg / kg, about 925μg / kg, about 950μg / kg, about 9 75μg / kg, approximately 1mg / kg, approximately 5mg / kg, approximately 10mg / kg, approximately 15mg / kg, approximately 20mg / kg, approximately 25mg / kg, approximately 30mg / kg, approximately 35mg / kg, approximately 40m g / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, and administered in one or multiple (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) unit doses per day.

[0100] In one preferred embodiment, the Bcl-2 inhibitor and one or more anti-cancer agents are administered together, simultaneously, sequentially, or alternatingly.

[0101] In a preferred embodiment, the Bcl-2 inhibitor and the one or more anti-cancer agents are administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.

[0102] In one preferred embodiment, the Bcl-2 inhibitor and one or more anti-cancer agents are administered in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment courses, wherein each treatment course is for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least lasting for 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days, with an interval of 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, 3 weeks, or 4 weeks between every two treatment courses.

[0103] In a preferred embodiment, when there are multiple therapeutic courses, the amount of Bcl-2 inhibitor and / or anticancer drug administered in each therapeutic course is the same or different. In a more preferred embodiment, the amount of Bcl-2 inhibitor and / or anticancer drug administered during a previous therapeutic course is 1-10 times, preferably 1-5 times, for example, 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times or 5 times the amount used in a subsequent therapeutic course.

[0104] In a preferred embodiment, the Bcl-2 inhibitor and one or more anti-cancer agents are administered by the same (eg, orally) or different routes (eg, orally and parenterally (eg, by injection), respectively).

[0105] In one preferred embodiment, the anti-cancer agent is administered at a lower dose compared to the dose of the anti-cancer agent administered alone or without the administration of one or more Bcl-2 inhibitors.

[0106] In one preferred embodiment, said Bcl-2 inhibitor enhances the therapeutic effect of said anti-cancer agent in the treatment of cancer and / or reduces the side effects of said anti-cancer agent in the treatment of cancer.

[0107] In a preferred embodiment, the one or more anti-cancer agents are capable of reducing or overcoming drug resistance or insensitivity of the cancer to a Bcl-2 inhibitor.

[0108] In a preferred embodiment, the Bcl-2 inhibitor and one or more anti-cancer agents (e.g., selected from an MDM2 inhibitor, an IAP inhibitor, and other inhibitors) reduce the side effects of the anti-cancer agents in the treatment of cancer and / or the treatment of cancer.

[0109] In another aspect, the present invention provides the use of a combination of a Bcl-2 inhibitor and one or more anti-cancer agents (e.g., selected from an MDM2 inhibitor, an IAP inhibitor, and other anti-cancer agents) to treat or inhibit cancer, reduce its severity, reduce its risk, or inhibit metastasis in an individual.

[0110] In a preferred embodiment, said Bcl-2, MDM2 and / or IAP inhibitor is as defined above and / or said cancer is as defined above.

[0111] In a preferred embodiment, the individual has a cancer that is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax. More preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM), which is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax.

[0112] In another aspect, the present invention provides the use of a combination of a Bcl-2 inhibitor and one or more anti-cancer agents (e.g., selected from an MDM2 inhibitor, an IAP inhibitor, and other anti-cancer agents) in the manufacture of a medicament for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual.

[0113] In a preferred embodiment, said Bcl-2, MDM2 and / or IAP inhibitor is as defined above and / or said cancer is as defined above.

[0114] In a preferred embodiment, the individual has a cancer that is resistant or insensitive to Bcl-2 inhibitors such as Compound A or Venetoclax, and more preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM), which is resistant or insensitive to Bcl-2 inhibitors such as Compound A or Venetoclax.

[0115] In another aspect, the present invention provides the use of an MDM2 inhibitor alone or in combination with one or more anti-cancer agents (e.g., selected from a Bcl-2 inhibitor, an IAP inhibitor, and other anti-cancer agents) to treat or inhibit, reduce the severity of, reduce the risk of, or inhibit metastasis of cancer in an individual.

[0116] In a preferred embodiment, said MDM2, Bcl-2 and / or IAP inhibitor is as defined above and / or said cancer is as defined above.

[0117] In a preferred embodiment, the individual has a cancer that is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax. More preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM), which is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax.

[0118] In another aspect, the present invention provides the use of an MDM2 inhibitor, alone or in combination with one or more anti-cancer agents (e.g., selected from a Bcl-2 inhibitor, an IAP inhibitor and other anti-cancer agents), in the manufacture of a medicament for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual.

[0119] In a preferred embodiment, said MDM2, Bcl-2 and / or IAP inhibitor is as defined above and / or said cancer is as defined above.

[0120] In a preferred embodiment, the individual has a cancer that is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax. More preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM), which is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax.

[0121] In another aspect, the present invention provides a pharmaceutical combination for treating or inhibiting, reducing the severity, reducing the risk, or inhibiting metastasis of cancer in an individual comprising an MDM2 inhibitor and one or more anti-cancer agents (e.g., selected from a Bcl-2 inhibitor, an IAP inhibitor, and other anti-cancer agents).

[0122] In a preferred embodiment, said MDM2, Bcl-2 and / or IAP inhibitor is as defined above and / or said cancer is as defined above.

[0123] In a preferred embodiment, the individual has a cancer that is resistant or insensitive to Bcl-2 inhibitors such as Compound A or Venetoclax, and more preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM), which is resistant or insensitive to Bcl-2 inhibitors such as Compound A or Venetoclax.

[0124] In another aspect, the present invention provides the use of a Bcl-2 / Bcl-xL inhibitor alone or in combination with one or more anti-cancer agents (e.g., selected from an MDM2 inhibitor, an IAP inhibitor and other anti-cancer agents) to treat or inhibit, reduce the severity of, reduce the risk of, or inhibit metastasis of cancer in an individual.

[0125] In a preferred embodiment, said MDM2 inhibitor and / or said IAP inhibitor are as defined above and / or said cancer is as defined above.

[0126] In a preferred embodiment, the individual has a cancer that is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax. More preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM), which is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax.

[0127] In one preferred embodiment, the Bcl-2 / Bcl-xL inhibitor is [ka] (3R)-1-(3-(4-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-4-methylsulfonyl-5-methyl-1H-pyrrol-3-yl))-5-fluorophenyl)piperazin-1-yl)-phenylaminosulfonyl)-2-trifluoromethylsulfonyl-anilino)-4-phenylthio-butyl)-piperidine-4-carboxylic acid 3-phosphonopropyl ester (Compound D), or a pharma- ceutically acceptable salt or solvate thereof; or [ka] It is selected from ((R)-1-(3-((4-(N-(4-(4-(3-(2-(4-chlorophenyl))-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H))-pyrrol-3-yl)-5-fluorophenyl)piperazin-1-yl)phenyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperidine-4-carboxylic acid (Compound E) or a pharma- ceutically acceptable salt or solvate thereof.

[0128] In another aspect, the present invention provides the use of a Bcl-2 / Bcl-xL inhibitor, alone or in combination with one or more anti-cancer agents (e.g., selected from an MDM2 inhibitor, an IAP inhibitor and other anti-cancer agents), in the manufacture of a medicament for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual.

[0129] In a preferred embodiment, said Bcl-2 / Bcl-xL, MDM2 and / or IAP inhibitor is as defined above and / or said cancer is as defined above.

[0130] In a preferred embodiment, the individual has a cancer that is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax. More preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM), which is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax.

[0131] In another aspect, the present invention provides a pharmaceutical combination for treating or inhibiting, reducing the severity, reducing the risk of, or inhibiting metastasis of cancer in an individual comprising a Bcl-2 / Bcl-xL inhibitor and one or more anti-cancer agents (e.g., selected from an MDM2 inhibitor, an IAP inhibitor, and other anti-cancer agents).

[0132] In a preferred embodiment, said Bcl-2 / Bcl-xL, MDM2 and / or IAP inhibitor is as defined above and / or said cancer is as defined above.

[0133] In a preferred embodiment, the individual has a cancer that is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax. More preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM), which is resistant or insensitive to a Bcl-2 inhibitor, such as Compound A or Venetoclax.

[0134] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (a) a first component in a first container comprising a Bcl-2 inhibitor (preferably a Bcl-2 inhibitor as defined above) or a Bcl-2 / Bcl-xL inhibitor (preferably a Bcl-2 / Bcl-xL inhibitor as defined above), and optionally a pharma- ceutically acceptable vector; (b) a second component in a second container comprising one or more anti-cancer agents, preferably as defined above, and an optional pharma- ceutically acceptable vector; and (c) Optional specifications included The present invention provides a reagent kit, wherein the first container and the second container may be the same or different. Specific Examples

[0135] In order to more clearly show the purpose and technical solution of the present invention, the present invention will be further described below in combination with specific examples. It should be understood that these examples are not intended to limit the scope of the present invention. In addition, the specific experimental methods not described in the following examples were carried out according to conventional experimental methods. Compound synthesis

[0136] Example 1: Preparation of exemplary compounds A-E.

[0137] Compound A is prepared according to methods known in the art, for example, the methods described in WO2018 / 027097A1.

[0138] Compound B is prepared according to methods known in the art, for example, the methods described in WO2015 / 161032A1.

[0139] Compound C is prepared according to methods known in the art, for example, the methods described in WO2014 / 031487A1.

[0140] Compounds D and E are prepared according to methods known in the art, for example, the methods described in WO2014 / 113413A1.

[0141] The disclosures of the above references are incorporated herein by reference. biometrics

[0142] The general experimental method used in the present invention is as follows: WST experiment Seeding of cells into plates: Antiproliferative effects were detected by CCK-8 (Cell Counting Kit-8) measurement based on water-soluble tetrazolium salts (WST). Cells were seeded into 96-well plates, and only 95 μL of complete medium was added to each negative control group. 95 μL of cell suspension in complete culture medium was added to each well waiting for testing, and the cell density was (5~10)×10^4 / well.

[0143] Addition of drugs (avoid light): In a 96-well culture plate, depending on the sensitivity of different cells to different drugs, we chose the highest concentration of 10 μM and serially diluted it in a 1:3 ratio to obtain 9 concentrations. Add 5 μL of compound to each well, with 2-3 replicate wells for each concentration. After compound addition, the 96-well plate was incubated at 4°C for 1 h in 5% CO. 2 The cells were cultured in an incubator at 37° C. Nine different concentrations of drugs and three fixed doses of compounds were administered for 72 hours, after which the combined effects of the compounds and drugs were measured.

[0144] Reading: At the end of incubation, remove the old solution from the wells waiting to be tested and add 100 μL / well of CCK-8 measurement solution (corresponding medium contained 10% CCK-8, 5% FBS). Plates were incubated in a CO 2 The cells were continuously cultured in an incubator at 37°C for 2 to 4 hours.

[0145] The OD values ​​were measured at A450 nm using a microplate reader (SpectraMax Plus384, Molecular Devices, LLC., US). The average OD values ​​of three replicate wells were obtained and the percentage of cell viability was calculated according to the following formula:

[0146] (Outer diameter of measurement well-Outer diameter of blank control well) / (Outer diameter of cell control well-Outer diameter of blank control well) x 100%.

[0147] For combination experiments, cell viability was calculated by normalizing the mean OD values ​​of triplicate wells to the single-agent control. Comparison of IC50 values ​​obtained from combination and single-agent treatment curves indicated that the two compounds achieved synergistic effects (combination treatment curve was shifted to the left). Cell viability measurement (CTG)

[0148] Cell viability was measured using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega) or WST assay (Cell counting Kit-8, Shanghai life iLab, China) according to the manufacturer's instructions. Cell viability was calculated as cell viability = (average RLU sample - average RLU blank) / (RLU cell control - RLU blank) x 100. IC 50Values ​​were calculated using GraphPad Prism. Combination index (CI) values ​​were calculated by CalcuSyn software (BIOSOFT, UK). CI<0.9 indicated a synergistic combination effect. A score of CI<0.1 indicated a very strong synergistic combination effect, a score of CI 0.1-0.3 indicated a strong synergistic combination effect, and a score of CI 0.3-0.7 indicated a moderate synergistic combination effect, with a score of 5+. In vivo drug efficacy evaluation method

[0149] A cell inoculation method was adopted to establish a human tumor-implanted subcutaneous tumor model in immunodeficient mice. Tumor cells in the logarithmic growth phase were collected, counted, and resuspended in 1× PBS, with the concentration of the cell suspension ranging from 2.5 to 5×10. 7 Using a 1 mL syringe (No. 4 needle), 5–10 × 10 6 All animal experiments were carried out in strict accordance with the regulations for the use and management of experimental animals of GenePharma Co., Ltd. and Suzhou Ascentage Pharma Co., Ltd., and the calculation of relevant parameters was based on the Technical Guidelines for Nonclinical Research of Cytotoxic Antitumor Drugs of the China National Medical Products Administration (NMPA).

[0150] During the experimental process, the animals' weights and tumor sizes were measured twice a week. The animals' condition and death were observed every day. The effects of tumor growth and treatment on the normal behavior of the animals were regularly monitored, including the activity of the experimental animals, feeding and drinking, weight gain or loss, and abnormal conditions of the eyes, clothes, hair, etc. Mortality and clinical symptoms observed during the experimental period were recorded in the raw data. All administration and mouse weight and tumor volume measurements were performed on a clean workbench. According to the requirements of the experimental protocol, plasma and tumor tissues were collected, weighed, and photographed after the end of the final administration. Plasma and tumor samples were frozen at -80°C and kept for future use.

[0151] The formula for calculating tumor volume (TV) is TV=a×b 2 / 2, where a and b represented the length and width of the tumor pending measurement, respectively.

[0152] The formula for calculating relative tumor volume (RTV) is RTV=V t / V 1 Wherein V 1 is the tumor volume at the start of treatment in each group, V t was the tumor volume measured on day t after administration.

[0153] The evaluation index of antitumor activity is the tumor relative proliferation rate T / C (%), and its calculation formula is tumor relative proliferation rate T / C (%) = (T RTV / C RTV )×100%, T RTV is the treatment group RTV, C RTV was the RTV of the vehicle control group.

[0154] The formula for calculating the tumor regression rate (%) was the number of tumor-bearing mice that showed SD (stable disease), PR (partial regression), and CR (complete regression) after treatment / total number of mice in this group × 100%.

[0155] Body weight change (%)=(actual body weight−body weight at the start of grouping) / body weight at the start of grouping×100%.

[0156] Therapeutic effect evaluation criteria: According to China NMPA "Technical Guideline for Nonclinical Research of Cytotoxic Antitumor Drugs" (November 2006), the therapeutic effect was confirmed when the T / C(%) value was ≦40% and statistical analysis p<0.05. If the mice lost more than 20% of their body weight or the drug-related death rate exceeded 20%, the drug at that dose was considered to have severe toxicity.

[0157] According to Clarke R., Experimental Design Issues and Endpoint Analysis in In Vivo Experimental Cytotoxicity Studies of Breast Cancer and Other Models [J]. Breast Cancer Research & Treatment, 1997, 46(2-3):255-278, synergy analysis was evaluated using the following formula: Synergy coefficient = ((A / C) x (B / C)) / (AB / C), where A = RTV value of drug A alone, B = RTV value of drug B alone, C = RTV value of solvent control, and AB = RTV value of A and B combined. A synergy coefficient > 1 indicates that synergy is achieved, a synergy coefficient = 1 indicates that additive effects are achieved, and a synergy coefficient < 1 indicates that antagonism is achieved.

[0158] Tumor response was measured using mRECIST (Gao et al., 2015) and included stable disease (SD), partial tumor regression (PR), and complete regression (CR), and tumor volume change at day t was compared to baseline to determine tumor volume change (%) = (Vt-V1 / V1). The best response was the minimum tumor volume change (%) at t >= 10. For each time t, the average tumor volume change from t = 1 to t was also calculated. The best average response (BestAvgResponse) was defined as the minimum of this average at t >= 10. Response criteria (mRECIST) were adapted from RECIST criteria (Gao et al., 2015; Therasse et al., 2000) and were defined as follows: for mCR, best response <-95% and best mean response <-40%, for mPR, best response <-50% and best mean response <-20%, for mSD, best response <35% and best mean response <30%, and for mPD, not otherwise classified. SD, PR, and CR were considered as responders and were used to calculate the response rate (%). Animal body weights were monitored simultaneously. Body weight changes were calculated based on the body weight of the animals on the first day of treatment (day 1). Tumor volume and body weight changes (%) were expressed as mean ± standard error of the mean (SEM). Orthotopic / systemic xenotransplantation methods

[0159] MOLM 13-Luc tumor cells were plated in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum (Gibco), 100 U / mL penicillin, and 100 μg / mL streptomycin and incubated at 37°C, 5% CO 2 The tumor cells were cultured in suspension at 1000 x g of air. The tumor cells were routinely subcultured twice a week. Cells growing in the exponential phase were harvested and the tumor inoculum was counted.

[0160] To establish a xenograft model by inhibiting the immune system, female NOD SCID mice were pretreated with 150 mg / kg cyclophosphamide twice, once per day (qd), 24 h before cell inoculation. Each mouse was inoculated with MOLM13-luc tumor cells (2 × 10 6 10 mice (100 / mouse) were inoculated via the tail vein for tumor development. Three days after tumor implantation, the mean bioluminescence reading was 3.18 × 10 7 When photons / sec was reached, animals were selected for group allocation. An Excel-based randomization software was used to group animals and perform stratified randomization according to their bioluminescence intensity. Treatment was started immediately on the same day (defined as d1).

[0161] The first end point was to evaluate whether tumor growth rate could be slowed and / or metastasis could be prevented compared to the pharmaceutical treatment group. For this, surgically inoculated mice were weighed and intraperitoneally injected with fluorescein at a dose of 150 mg / kg. 10 min after fluorescein injection, the animals were anesthetized with a mixture of oxygen and isoflurane gas. When the animals were fully anesthetized, they were transferred to the imaging chamber of the IVIS (Lumina II) imaging system for bioluminescence measurement. Bioluminescence was measured and recorded twice a week. Tumor growth curves were plotted using bioluminescence intensity (photons / sec). Tumor bioluminescence was then used to calculate T / C values ​​(%), where T and C were the relative bioluminescence growth rates of the treatment and control groups on a particular day, respectively. One-way ANOVA was performed on the tumor bioluminescence data, resulting in a significant F-statistic (ratio of treatment variance to error variance) (P<0.001), and Games-Howell was employed to perform comparisons between groups.

[0162] The secondary endpoint was animal survival. Animals were examined daily and animals with signs of deterioration and moribundity (including 20% ​​weight loss, paralysis of the limbs, protruding eyes, increased abdominal circumference due to tumor growth and metastasis) and / or inability to obtain sufficient food or water were treated with CO 2 All animals were euthanized by euthanasia. The survival time of each animal was recorded, and the median survival time (MST) of each group was calculated. Survival times were analyzed by employing the Kaplan-Meier method. The relevant event was the death of the animal. Survival time was defined as the time (in days) from the start of treatment to death. The median survival time of each group and the corresponding 95% confidence interval were calculated. Kaplan-Meier curves were plotted for each group, and the log-rank method was used to compare the survival curves between groups. Statistical differences in survival times between the control group and all treatment groups, and between treatment groups, were analyzed.

[0163] All data were analyzed using SPSS 17.0. P values ​​<0.05 were considered statistically significant. Example 2: Compound B can restore killing of RS4;11 cells harboring different Bcl-2 mutations

[0164] Cell viability was measured by adopting the CTG method. RS4;11 cells were established from the bone marrow of an acute lymphoblastic leukemia (ALL) patient.

[0165] As shown in Figure 1A and Figure 1B, compound B could effectively reduce the cell viability of RS4;11 cells, including RS4;11-wt (wild type) and RS4;11 cells with different Bcl-2 mutations, such as G101V, D103E, V156D, and G101V-D103E. In all cell lines, the IC 50 (CTG72h) values ​​were all lower than those of ABT-199 (Venetoclax).

[0166] Conclusion: Compound B can restore killing of RS4;11 cells with different Bcl-2 mutations. Because BCL2 mutations have been widely reported in patients with Venetoclax drug resistance, the above results suggest that compound B may be used alone or in combination with other drugs to overcome Venetoclax drug resistance in cancers such as AML and ALL. Example 3: The combination of the present invention is able to synergistically inhibit the proliferation of the RS4;11 Bcl2-G101V-Flag cell line

[0167] Cell viability was measured by adopting the CTG method. The RS4;11 BCL2-G101V-Flag cell line was RS4;11 cells carrying the Bcl2-G101V-Flag mutation.

[0168] As shown in Figures 2A to 2D, in the CTG measurements (72 h), the combined use of compound A and compound B resulted in lower cell viability than the use of compound A or compound B alone, the combined use of compound A and compound C resulted in lower cell viability than the use of compound A or compound C alone, the combined use of compound B and compound C resulted in lower cell viability than the use of compound B or compound C alone, and the combined use of compound A, compound B, and compound C resulted in lower cell viability than the use of compound A, compound B, or compound C alone.

[0169] Conclusion: The combinations of the present invention (Compound A+Compound B, Compound A+Compound C, and Compound B+Compound C) had relatively strong anti-proliferative activity against RS4;11 Bcl2-G101V-Flag cells. Because BCL2 mutations are widely reported in patients with Venetoclax drug resistance, the above results indicated the potential use of the combinations of the present invention in overcoming Venetoclax drug resistance in cancers such as AML and ALL. Example 4: The combination of the present invention is able to synergistically inhibit the proliferation of the RS4;11 BCL2-V156D-Flag cell line

[0170] Cell viability was measured by employing the CTG method. The RS4;11 BCL2-V156D-Flag cell line was RS4;11 cells carrying the Bcl2-V156D-Flag mutation.

[0171] As shown in Figures 3A to 3D, in the CTG measurements (72 h), the combined use of compound A and compound B resulted in lower cell viability than the use of compound A or compound B alone, the combined use of compound A and compound C resulted in lower cell viability than the use of compound A or compound C alone, the combined use of compound B and compound C resulted in lower cell viability than the use of compound B or compound C alone, and the combined use of compound A, compound B, and compound C resulted in lower cell viability than the use of compound A, compound B, or compound C alone.

[0172] Conclusion: The combinations of the present invention (compound A + compound B, compound A + compound C, and compound B + compound C) had relatively strong anti-proliferative activity against RS4;11 BCL2-V156D-Flag cells.Because BCL2 mutations are widely reported in patients with Venetoclax drug resistance, the above results indicated the potential use of the combinations of the present invention in overcoming Venetoclax drug resistance in cancers such as AML and ALL. Example 5: Combined targeting of BCL-2, MDM2 and IAP was most effective in drug-resistant cell lines (AML and ALL) induced by Compound A

[0173] Cell viability was measured by CTG method. Before the experiment, compound A was used to treat long-term drug-resistant cell lines induced by compound A (MV-4-11, RS4;11, and MOLM-13).

[0174] As shown in FIG. 4A to FIG. 4C, the combination of Compound A, Compound B, and Compound C showed the lowest cell viability in the CTG measurement (72 h).

[0175] Conclusion: The triple combination of compound A (Bcl-2 inhibitor), compound B (MDM2 inhibitor), and compound C (IAP inhibitor) was most effective against the drug-resistant cell lines (MV-4-11, RS4;11, and MOLM-13) induced by compound A. Thus, the combined targeting of BCL-2, MDM2, and IAP was most effective against the drug-resistant cell lines (AML and ALL) induced by compound A. The above results indicated the potential use of triple combination therapy in overcoming compound A drug resistance in cancers such as AML and ALL. Example 6: Combination treatment of Compound A and Compound B can overcome Venetoclax drug resistance in BCL-2 mutant tumor models

[0176] A subcutaneous xenograft method was used. The RS4;11 BCL2-V156D-Flag cell line was RS4;11 cells carrying the Bcl2-V156D-Flag mutation.

[0177] As shown in FIG. 5, in subcutaneous xenograft experiments, tumor growth curves demonstrated that the combination of Compound A and Compound B was superior to each agent alone in inhibiting tumor growth (based on tumor volume).

[0178] Conclusion: The antitumor effect of the combination of Compound A and Compound B was superior to that of the single agent. Because Bcl2-V156D is a mutation reported in patients with Venetoclax drug resistance, the above results indicated that the combination of Compound A and Compound B has potential application value in overcoming Venetoclax drug resistance in cancers such as AML and ALL. Example 7: RS4;11 BCL-2-G101V-Flag Combination treatment of human ALL cancer mouse xenograft models

[0179] A subcutaneous xenograft method was used. The RS4;11 BCL2-G101V-Flag cell line was RS4;11 cells carrying the Bcl2-G101V-Flag mutation.

[0180] As shown in Figure 6, in the subcutaneous xenograft experiment, the combination of Compound A and Compound B, the combination of Compound A and Compound C, the combination of Compound B and Compound C, and the triple combination of Compound A, Compound B, and Compound C all had lower tumor growth rates (based on tumor volume) than each of the individual drugs. Among them, the triple combination of Compound A, Compound B, and Compound C had the lowest tumor growth.

[0181] Conclusion: The combinations of the present invention (Compound A + Compound B, Compound A + Compound C, Compound B + Compound C and Compound A + Compound B + Compound C) are RS4;11 BCL-2-G101V-Flag It has relatively strong anti-proliferative activity against human ALL cancer mouse transplant tumor model.Because BCL2 mutation (including BCL2-G101V mutation) is widely reported in Venetoclax drug resistance patients, the above results show that the combination of the present invention can be used to overcome Venetoclax drug resistance in cancer such as AML and ALL. Example 8: Comparison of Compound A + Compound B + Aza and Compound A + Compound B + Compound C in the RS4;11-VEN-R human ALL cancer mouse xenograft model

[0182] The method was a xenograft experiment. A RS4;11-VEN-R human ALL cancer mouse xenograft tumor model was established. The model was resistant to the drug Venetoclax (VEN).

[0183] As shown in Figures 7A and 7B, in xenograft experiments, the combination of Compound A and Compound B achieved a reduction in tumor volume compared to the vector control. Also, the three combinations of Compound A, Compound B, and Azacitidine, and the three combinations of Compound A, Compound B, and Compound C were all superior to the combination of Compound A and Compound B and the vector control. Specifically, the antiproliferative activity of the combination of Compound A, Compound B, and Compound C was equivalent to that of the combination of Compound A, Compound B, and Azacitidine.

[0184] Conclusion: The combination of Compound A and Compound B has a growth inhibitory effect on the RS4;11-VEN-R human ALL cancer xenograft tumor model, and the growth inhibitory effect can be further enhanced by the addition of Compound C. The above results demonstrated the potential use of the combination of the present invention in overcoming Venetoclax drug resistance (VEN-R) in cancers such as AML and ALL. Example 9: Effect of the combination of Compound A + Compound C in AML cells (72 hours)

[0185] Cell viability was measured by WST method. MOLM-13WAT assay and MV-4-11WST assay were performed, respectively.

[0186] The combination index (CI) method was based on that described by Chou and Talalay, and CI values ​​were calculated using CalsuSyn software.

[0187] As shown in Figures 8A and 8B, the synergistic effect of Compound A and Compound C in AML cell lines MOLM-13 and MV-4-11 was demonstrated according to the CI value in cell viability WST assays. Specifically, a CI value of <0.9 indicated synergy.

[0188] Conclusion: The combination of Compound A and Compound C achieved synergistic effects in AML cell lines MOLM-13 and MV-4-11. The above results indicated that the combination treatment of Compound A and Compound C has potential application value in the treatment of cancers such as AML. Example 10: Combination of Compound A and Compound C achieved synergistic effects in the treatment of subcutaneous MV-4-11 AML

[0189] The method used was subcutaneous xenograft transplantation. In this example, the subcutaneous MV-4-11 AML model was used.

[0190] As shown in Figures 9A-9D, the synergistic effect of Compound A and Compound C in the AML MV-4-11 xenograft model was reflected by the enhancement of tumor inhibition effects by T / C and tumor volume. Furthermore, the synergistic ratio >1 also showed synergistic antitumor activity.

[0191] Conclusion: The combination of Compound A and Compound C achieved synergistic effects in the AML MV-4-11 xenograft model. The above results indicated that the combination treatment of Compound A and Compound C has potential application value in the treatment of cancers such as AML.

[0192] Example 11: Combination treatment of Compound A and Compound C in an orthotopic MOLM-13-luc human AML model The method was orthotopic / systemic xenotransplantation. In this example, the orthotopic MOLM-13-luc human AML model was used.

[0193] Referring to Figure 10A-C, Figure 10A shows the animal tumor burden bioluminescence, Figure 10B shows the survival curve, and Figure 10C shows the median survival time and survival extension time. As shown in Figure 10A-C, in the orthotopic MOLM-13-luc human AML model, the combination treatment of Compound A and Compound C was more effective than each single agent.

[0194] Conclusion: The combination of Compound A and Compound C was beneficial in the orthotopic MOLM-13-luc human AML model. The above results demonstrated the potential use of the combination of Compound A and Compound C in the treatment of cancers such as AML.

[0195] Example 12: Combination Treatment of Compound A, Compound B and / or Compound C in p53 WT Systemic OCI-AML3AML Model (Venetoclax Intrinsic Drug Resistance) The method was orthotopic / systemic xenograft. In this example, the p53 WT systemic OCI-AML3AML model, which is an intrinsic drug resistance model for Venetoclax, was used.

[0196] Referring to Figures 11A to 11C, Figure 11A shows tumor volume, Figure 11B shows body weight change, and Figure 11C shows RTV and T / C values. As shown in Figures 11A to 11C, in the p53 WT systemic OCI-AML3AML model, the combination treatment of Compound A + Compound B or Compound A + Compound B + Compound C was superior to the control group treatment.

[0197] Conclusion: Combinations of Compound A and Compound B, and Compound A, Compound B, and Compound C, obtained benefit in the p53 WT systemic OCI-AML3AML model (ventoclax intrinsic drug resistance). The above results demonstrated the potential use of the combinations of the present invention in the treatment of cancers such as AML that are drug resistant to venetoclax. Example 13: Combined targeting of intrinsic and extrinsic apoptosis to maximally induce cell death in Venetoclax drug-resistant AML cells

[0198] We used these three drugs and their combinations to treat Molm13 cells lacking TP53 or harboring TP53 mutations (R248W, KO, R175H, R282W, Y220C, R248Q) generated by CRISPR (Boettcher S et al., Science 2019). As shown in Figure 12A-K, all mutant cells were insensitive to either single drug. When two drugs were combined, the activity of Bcl-2, IAPs, and MDM2 was enhanced, and the combination of Bcl-2, IAPs, and MDM2 was the most effective against cell death induced by TP53 knockout and all TP53 mutant cells (triple drug combination was P<0.05 compared to any two-drug or single-drug treatment, and two-drug combination was P<0.05 compared to each single-drug treatment). Western blot analysis showed that a decrease in cIAP1, cIAP2, XIAP, or p21 was observed in cells treated with either single or combination therapy. Only in the triple-drug group, there was an obvious decrease in cIAP1, cIAP2, XIAP, and MDM2, and a notable decrease in p21.

[0199] Taken together, these studies demonstrated that combined targeting of endogenous and exogenous apoptosis could maximally induce AML cell death with acquired resistance to VEN or TP53 mutations by antagonizing Bcl-2 and ablation of cIAPs and XIAP, as well as MDM2 and p21. Example 14: Compound E exhibits single agent activity in BCL-2 inhibitor (BCL-2i) insensitive cells RPMI 8226

[0200] Cell viability was measured by employing the CTG method. The construction of a BCL-2i-insensitive multiple myeloma (MM) model RPMI 8226 cells was performed to evaluate the IC 50 was 5.58 μM (non-sensitive).

[0201] As shown in FIG. 13, in MM cells insensitive to BCL-2 inhibitors (including Venetoclax), Compound E demonstrated single agent activity in inhibiting cell proliferation (RPMI 8226 model).

[0202] Conclusion: Compound E showed single agent activity in BCL-2i insensitive cells RPMI 8226, and the above results indicated the potential use of Compound E alone or in combination with other drugs to overcome drug resistance of Compound A against cancers such as Venetoclax or MM. Example 15: The combination of Compound E and Compound C synergistically sensitizes BCL-2i anti-proliferative inhibitor cells

[0203] Cell viability was measured by adopting the CTG method. A BCL-2i-resistant MM model, KMS-26, was established.

[0204] As shown in Figures 14A-14D, in MM cells that were insensitive or resistant to BCL-2 inhibitors (including Venetoclax), Compound E, in combination with Compound B (an MDM2 inhibitor) or Compound C (an IAP inhibitor), sensitized KMS-26 cells to growth inhibition.

[0205] Conclusion: The combination of Compound E with Compound C / Compound B could synergistically enhance the sensitivity of BCL-2i-insensitive cells to growth inhibition, and the above results indicated that Compound E could be combined with other drugs to overcome drug resistance to Venetoclax or Compound A in tumors such as MM. Example 16: Compound C exhibits single-agent activity in MM cells insensitive to BCL-2 inhibitors

[0206] Cell viability was measured by CTG method. BCL-2i-resistant MM mold NCI-H929 was constructed.

[0207] As shown in Figures 15A and 15B, Compound C demonstrated single agent activity in inhibiting cell proliferation in MM cells that were insensitive or resistant to BCL-2 inhibitors (including Venetoclax) (NCI-H929 model).

[0208] Conclusion: Compound C demonstrated single-agent activity in MM cells insensitive to BCL-2 inhibitors, demonstrating that Compound C can be used alone or in combination with other drugs to overcome drug resistance in tumors such as MM to Venetoclax or Compound A. Example 17: Compound E / Compound D show single agent activity in both Venetoclax drug-resistant MM cells and xenograft models

[0209] KMS27-sensitive MM cell lines were treated with high concentrations of Venetoclax to establish the acquired drug resistance phenotype of MM. To generate monoclonal drug resistance-amplifying-persistent (DTEP) clones, colonies arising from surviving cells were cultured in high doses of Venetoclax. The IC50 was increased at least 3-10 fold compared to parental cells. Compared to Venetoclax, the BCL-2 / BCL-xL / BCL-w inhibitor compound E successfully inhibited the proliferation of drug-resistant clones (Figure 16A) and simultaneously induced cell apoptosis (Figure 16B).

[0210] To determine whether Compound E is effective in cases of Venetoclax intrinsic drug resistance, Venetoclax drug-resistant MM cell lines (MM1.S and KMS34) were treated with Venetoclax, Compound E, or Navitoclax. As shown in Figure 16C, Compound E was the most effective at inducing cell death. Compound D, a prodrug of Compound E with relatively low platelet toxicity, was also effective in the CDX model in both cell lines, as shown in Figures 16D and 16E.

[0211] The activity of Compound E was confirmed in primary MM cells in vitro. As shown in Figure 16F, we treated MM cells from four MM patients and observed that the activity of Compound E was higher than that of Venetoclax.

[0212] As described above, Compound E / Compound D showed single-agent activity in both Venetoclax-resistant MM cells and xenograft models.

[0213] After the method, compound and composition of the present invention have been fully described, a person skilled in the art should understand that the method, compound and composition of the present invention or any embodiment thereof can be similarly carried out within a wide range of equivalent conditions, formulations and other parameters without affecting the method, compound and composition of the present invention or any embodiment thereof.

[0214] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A pharmaceutical combination comprising a Bcl-2 inhibitor and one or more anti-cancer agents.

2. 2. The pharmaceutical combination of claim 1, wherein the one or more anti-cancer agents are selected from an MDM2 inhibitor, an IAP inhibitor, and other anti-cancer agents.

3. 2. The pharmaceutical combination of claim 1, wherein the one or more anti-cancer agents are selected from an MDM2 inhibitor, an IAP inhibitor, and combinations thereof.

4. The Bcl-2 inhibitor is a compound of formula V: 【Chemical 1】 or a pharmaceutically acceptable salt or solvate thereof, A ３ teeth 【Chemistry 2】 Selected from E ３ is a nitrogen atom, and 【Chemistry 3】 is a single bond, X ３１ , X ３２ , and X ３３ are -CR ３８ independently selected from -N= and -N=; R ３１ａ and R ３１ｂ together with the carbon atom to which they are attached form a 3-, 4-, or 5-membered cycloalkyl group; R ３２ Ha-NO ２ , -SO ２ CH ３ , and -SO ２ CF ３ Selected from R ３２ａ is selected from hydrogen and halogens, R ３３ HA-N(R ３４ａ ) (R ３４ｂ ) are selected from R ３４ａ is an optionally substituted C １－６ alkyl group, optionally substituted C ３－６ selected from cycloalkyl groups, heterocyclyl groups, heteroalkyl groups, (cycloalkyl)alkyl groups and (heterocyclyl)alkyl groups; R ３４ｂ is hydrogen and C １－４ selected from alkyl groups, R ３８ The pharmaceutical combination according to any one of claims 1 to 3, wherein is selected from hydrogen and halogen.

5. The Bcl-2 inhibitor is 【Chemistry 4】 5. The pharmaceutical combination according to claim 4, which is selected from: or a pharmaceutically acceptable salt or solvate thereof.

6. The Bcl-2 inhibitor is 【Chemistry 5】 5. The pharmaceutical combination of claim 4, which is (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide (Compound A) or a pharmaceutically acceptable salt or solvate thereof.

7. The MDM2 inhibitor is a compound of formula (VI) or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 6】 Among them, 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 R ６２ , R ６３ , R ６４ , R ６５ , R ６７ , R ６８ , R ６９ and R ７０ are independently selected from the group consisting of H, F and Cl; 【Chemistry 10】 R ６ｃ and R ６ｄ is a substituent on one carbon atom of ring B, R ６ｃ is H, C １－３ is an alkyl group or a halogen; R ６ｄ is H, C １－３ is an alkyl group or a halogen; R ６ｅ is -C(=O)OR ６ａ and R ６ａ is hydrogen or unsubstituted C １－４ The pharmaceutical combination according to claim 2 or 3, wherein the alkyl group is an alkyl group.

8. R ６２ is H and R ６３ is F or Cl, and R ６４ and R ６５ is H and R ６７ is fluorine, and R ６８ , R ６９ and R ７０ is H, and R ６ｃ is H, CH ３ or halogen, and R ６ｄ is H, CH ３ or a halogen.

9. The MDM2 inhibitor is 【Chemistry 11】 8. The pharmaceutical combination of claim 7, which is: or a pharmaceutically acceptable salt or solvate thereof.

10. The IAP inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: 【Chemistry 12】 Among them, 【Chemistry 13】 Y is selected from —NH—, —O—, —S—, and is absent; R is 【Chemistry 14】 Selected from R １ teeth, 【Chemistry 15】 The pharmaceutical combination according to claim 2 or 3, selected from:

11. The IAP inhibitor is 【Chemistry 16】 11. The pharmaceutical combination of claim 10, which is: or a pharmaceutically acceptable salt or solvate thereof.

12. The IAP inhibitor is 【Chemistry 17】 11. The pharmaceutical combination of claim 10, which is 1,3-phenylenebis[7-(3S,5S,9aR)-5-((S)-2-methylamino-propionamido)-3-diphenylcarbamoyl-4-oxo-3a,7-diaza-decahydrocyclopentacyclooctene)]-sulfonamide (Compound C), or a pharmaceutically acceptable salt or solvate thereof.

13. It is used to treat or inhibit, reduce the severity of, reduce the risk of, or inhibit metastasis of cancer in an individual, wherein the cancer is preferably bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer, and lung squamous cell carcinoma), mesothelial carcinoma tumor, melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroturbinoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer, squamous cell carcinoma, spindle cell carcinoma, stomach cancer, testicular cancer, thyroid cancer, selected from uterine cancer, mesothelioma, neuroblastoma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma tumor, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, metastasis from spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma and hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma (MM), uveal melanoma, pleural mesothelioma, peritoneal mesothelioma, More preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM).

14. 14. The pharmaceutical combination of claim 13, wherein the cancer is resistant to or insensitive to Bcl-2 inhibitors such as Compound A or Venetoclax, more preferably, the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM), which is resistant to or insensitive to Bcl-2 inhibitors such as Compound A or Venetoclax.

15. The pharmaceutical combination according to claim 13, wherein the cancer has a Bcl-2 mutation (e.g., G101V, D103E, V156D, and a combination thereof) and / or a TP53 mutation (e.g., R248Q, R175H, R282W, Y220C, and a combination thereof), and more preferably the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or multiple myeloma (MM) with a Bcl-2 mutation and / or a TP53 mutation.

16. 4. The pharmaceutical combination of claim 1, wherein the weight ratio of the Bcl-2 inhibitor to the one or more anticancer agents is 0.005-5000:0.005-5000, e.g., 0.05-1500:0.005-5000, 0.1-6:0.005-4, 100:0.5-400, 100:1-350, 100:2-300, 100:5-200, 100:10-150, 100:10-100, 100:10-90, or 100:20-80.

17. 4. The pharmaceutical combination of any one of claims 1 to 3, wherein the molar ratio of the Bcl-2 inhibitor to the one or more anti-cancer agents is 10 to 1:1 to 10, such as 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, and any ranges between the above values are also included.

18. The Bcl-2 inhibitor is 【Chemistry 18】 (S)—N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3.5]non-6-en-7-yl)methyl)piperazin-1-yl)benzamide (Compound A) or a pharmaceutically acceptable salt or solvate thereof; and / or The MDM2 inhibitor is 【Chemistry 19】 or a pharmaceutically acceptable salt or solvate thereof, and / or The IAP inhibitor is 【Chemistry 20】 4. The pharmaceutical combination according to claim 2 or 3, which is 1,3-phenylenebis[7-(3S,5S,9aR)-5-((S)-2-methylamino-propionamido)-3-diphenylcarbamoyl-4-oxo-3a,7-diaza-decahydrocyclopentacyclooctene)]-sulfonamide (Compound C), or a pharmaceutically acceptable salt or solvate thereof.

19. A pharmaceutical combination comprising the pharmaceutical combination of any one of claims 1 to 3 and an optional pharmaceutically acceptable vector.

20. 20. The pharmaceutical combination of claim 19, which is a tablet, capsule, granule, syrup, powder, troche, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol, ointment, cream, and injectable.

21. 1. A method for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual, comprising administering to the individual a therapeutically effective amount of a Bcl-2 inhibitor, and optionally a therapeutically effective amount of one or more anti-cancer agents; Preferably, the Bcl-2 inhibitor is as defined in claim 4, and the anti-cancer agent is selected from MDM2 inhibitors, IAP inhibitors and other anti-cancer agents, as defined in any one of claims 7, and Preferably, the cancer is as defined in claim 13.

22. 22. The method of claim 21, wherein the dosage of the Bcl-2 inhibitor is from about 0.005 mg / day to about 5000 mg / day, e.g., about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 4000, 4500, or 5000 milligrams / day.

23. The dosage of the Bcl-2 inhibitor is about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg per unit dose, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225μg / kg, about 250μg / kg, about 275μg / kg, about 300μg / kg, about 325μg / kg, about 350μg / kg, about 375μg / kg, about 400μg / kg, about 425μg / kg, about 450 μg / kg, approximately 475 μg / kg, approximately 500 μg / kg, approximately 525 μg / kg, approximately 550 μg / kg, approximately 575 μg / kg, approximately 600 μg / kg, approximately 625 μg / kg, approximately 650 μg / kg, approximately 675 μg / kg kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, About 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 3 22. The method of claim 21, wherein the compound is administered at 5 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, and in one or multiple (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) unit doses per day.

24. 22. The method of claim 21, wherein the one or more anti-cancer agents are administered in an amount of 0.005 mg / day to about 5000 mg / day, e.g., about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 5000 milligrams / day.

25. The dosage of the one or more anticancer agents is about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg per unit dose, e.g., about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg per unit dose. , about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 4 50μg / kg, about 475μg / kg, about 500μg / kg, about 525μg / kg, about 550μg / kg, about 575μg / kg, about 600μg / kg, about 625μg / kg, about 650μg / kg, about 675μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg , about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 22. The method of claim 21, wherein the compound is administered at 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, and in one or multiple (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) unit doses per day.

26. 22. The method of claim 21, wherein the Bcl-2 inhibitor and one or more anti-cancer agents are administered together, simultaneously, sequentially, or alternatingly.

27. 22. The method of claim 21, wherein the Bcl-2 inhibitor and the one or more anti-cancer agents are administered continuously for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.

28. The Bcl-2 inhibitor and one or more anti-cancer agents are administered in one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment courses, wherein each treatment course lasts for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, 22. The method of claim 21, wherein the two treatment courses last for at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days, with an interval of 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 2 weeks, 3 weeks, or 4 weeks between every two treatment courses.

29. 22. The method of claim 21, wherein the Bcl-2 inhibitor and the one or more anti-cancer agents are administered by the same (e.g., orally) or by different routes (e.g., orally and parenterally (e.g., by injection) respectively).

30. 1. Use of a combination of a Bcl-2 inhibitor and one or more anti-cancer agents to treat or inhibit, reduce the severity of, reduce the risk of, or inhibit metastasis of cancer in an individual, comprising: Preferably, the Bcl-2 inhibitor is as defined in claim 4, and the anti-cancer agent is selected from MDM2 inhibitors, IAP inhibitors and other anti-cancer agents, as defined in claim 7; and Preferably, the cancer is as defined in claim 13.

31. 1. Use of a combination of a Bcl-2 inhibitor and one or more anti-cancer agents in the manufacture of a medicament for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual, comprising: Preferably, the Bcl-2 inhibitor is as defined in claim 4, and the anti-cancer agent is selected from MDM2 inhibitors, IAP inhibitors and other anti-cancer agents, as defined in claim 7; and Preferably, the cancer is as defined in claim 13.

32. 1. Use of an MDM2 inhibitor, alone or in combination with one or more anti-cancer agents, to treat or inhibit, reduce the severity of, reduce the risk of, or inhibit metastasis of cancer in an individual, comprising: Preferably, the MDM2 inhibitor is as defined in claim 7, and the anti-cancer agent is selected from Bcl-2 inhibitors, IAP inhibitors and other anti-cancer agents, as defined in claim 4; and Preferably, the cancer is as defined in claim 13.

33. 1. Use of an MDM2 inhibitor, alone or in combination with one or more anti-cancer agents, in the manufacture of a medicament for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual, comprising: Preferably, the MDM2 inhibitor is as defined in claim 7, and the anti-cancer agent is selected from Bcl-2 inhibitors, IAP inhibitors and other anti-cancer agents, as defined in claim 4; and Preferably, the cancer is as defined in claim 13.

34. 1. A pharmaceutical combination for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual, comprising an MDM2 inhibitor and one or more anti-cancer agents, Preferably, the MDM2 inhibitor is as defined in claim 7, and the anti-cancer agent is selected from Bcl-2 inhibitors, IAP inhibitors and other anti-cancer agents, as defined in claim 4; and Preferably, the cancer is as defined in claim 13.

35. 1. Use of a Bcl-2 / Bcl-xL inhibitor, alone or in combination with one or more anti-cancer agents, to treat or inhibit, reduce the severity of, reduce the risk of, or inhibit metastasis of cancer in an individual, comprising: Preferably, the anti-cancer agent is selected from MDM2 inhibitors, IAP inhibitors and other anti-cancer agents, as defined in claim 7; and Preferably, the cancer is as defined in claim 13.

36. 1. Use of a Bcl-2 / Bcl-xL inhibitor, alone or in combination with one or more anti-cancer agents, in the manufacture of a medicament for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual, comprising: Preferably, the anti-cancer agent is selected from MDM2 inhibitors, IAP inhibitors and other anti-cancer agents, as defined in claim 7; and Preferably, the cancer is as defined in claim 13.

37. 1. A pharmaceutical combination for treating or inhibiting, reducing the severity of, reducing the risk of, or inhibiting metastasis of cancer in an individual, comprising a Bcl-2 / Bcl-xL inhibitor and one or more anti-cancer agents, Preferably, the anti-cancer agent is selected from MDM2 inhibitors, IAP inhibitors and other anti-cancer agents, as defined in claim 7; and Preferably, the cancer is as defined in claim 13.

38. The Bcl-2 / Bcl-xL inhibitor is 【Chemical 21】 (3R)-1-(3-(4-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-4-methylsulfonyl-5-methyl-1H-pyrrol-3-yl))-5-fluorophenyl)piperazin-1-yl)-phenylaminosulfonyl)-2-trifluoromethylsulfonyl-anilino)-4-phenylthio-butyl)-piperidine-4-carboxylic acid 3-phosphonopropyl ester (Compound D), or a pharmaceutically acceptable salt or solvate thereof; 【Chemical 22】 The use according to claim 35, wherein the compound is selected from ((R)-1-(3-((4-(N-(4-(4-(3-(2-(4-chlorophenyl))-1-isopropyl-5-methyl-4-(methylsulfonyl)-1H))-pyrrol-3-yl)-5-fluorophenyl)piperazin-1-yl)phenyl)sulfamoyl)-2-((trifluoromethyl)sulfonyl)phenyl)amino)-4-(phenylthio)butyl)piperidine-4-carboxylic acid (Compound E) or a pharmaceutically acceptable salt or solvate thereof.

39. (a) a first component in a first container comprising a Bcl-2 inhibitor (preferably a Bcl-2 inhibitor as defined above) or a Bcl-2 / Bcl-xL inhibitor (preferably a Bcl-2 / Bcl-xL inhibitor as defined above), and optionally a pharmaceutically acceptable vector; (b) a second component in a second container comprising one or more anti-cancer agents (preferably as defined above), and an optional pharmaceutically acceptable vector; and (c) including optional specifications, The first container and the second container may be the same or different.

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