Pharmaceutical combination containing bcl-2 / bcl-xl inhibitor and use thereof

Abstract

The present invention relates to a pharmaceutical combination and the use thereof. The pharmaceutical combination contains a Bcl-2 / Bcl-xL inhibitor and a hypomethylated drug or a prodrug thereof. The pharmaceutical combination as described in the present invention achieves a good synergistic effect.

Description

Pharmaceutical combination containing a Bcl-2 / Bcl-xL inhibitor and use thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a pharmaceutical combination containing a Bcl-2 / Bcl-xL inhibitor and use thereof in the prevention and / or treatment of diseases. BACKGROUND

[0002] Myelodysplastic syndromes (MDS) correspond to different groups of hematologic malignancies associated with impaired bone marrow function, ineffective hematopoiesis, elevated bone marrow blasts, and persistent cytopenias in the peripheral blood. Anemia is one of the most common symptoms of MDS, and therefore, most MDS patients receive at least one red blood cell transfusion. MDS can also progress to acute myeloid leukemia (AML) (Heaney and Golde (1999) N. Engl, J. Med. 340(21): 1649-60). Although progression to AML can cause death in MDS patients, MDS-related deaths can also result from cytopenias and bone marrow failure in the absence of leukemic transformation. Prognosis of MDS is typically determined using the revised International Prognostic Scoring System (IPSS-R), which takes into account the percentage of bone marrow blasts, the number of cytopenias, and bone marrow cytogenetics. Untreated MDS patients are classified into five IPSS-R prognostic risk categories: very low, low, intermediate, high, and very high (Greenberg et al. (2012) Blood 108(11):2623).

[0003] Bcl-2 family proteins are important regulators of apoptosis. This protein family includes anti-apoptotic proteins, such as Bcl-2, Bcl-xL, and Mcl-1, and pro-apoptotic molecules, including Bid, Bim, Bad, Bak, and Bax. Although normal cells have low expression levels of anti-apoptotic Bcl-2 and Bcl-xL proteins, these proteins are found to be highly overexpressed in many different types of human tumors, which are believed to be associated with tumor generation, development, and drug resistance generation. Targeting Bcl-2 and / or Bcl-xL has been sought as a cancer treatment strategy. Combination therapy of anticancer drugs is sometimes employed in the treatment of cancer. There is still a need for a combination of a Bcl-2 / Bcl-xL inhibitor with other drugs that has high anticancer activity and low side effects. SUMMARY

[0004] The present application aims to provide a pharmaceutical combination having anticancer effect and use thereof, and a method for treating cancer.

[0005] In one aspect, the present application provides a pharmaceutical combination comprising a Bcl-2 / Bcl-xL inhibitor and a hypomethylating agent or a prodrug thereof; the Bcl-2 / Bcl-xL inhibitor has a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof, or a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof;

[0006] Further, the hypomethylating agent is selected from one or more of Azacitidine, Decitabine and Cytarabine.

[0007] In another aspect, the present application provides a use of a pharmaceutical combination in the manufacture of a medicament for the prevention and / or treatment of a disease selected from cancer, the pharmaceutical combination comprising a Bcl-2 / Bcl-xL inhibitor and a hypomethylating agent or a prodrug thereof; the Bcl-2 / Bcl-xL inhibitor has a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof, or a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof;

[0008] Further, the hypomethylating agent is selected from one or more of Azacitidine, Decitabine and Cytarabine.

[0009] In another aspect, the present application provides a use of a pharmaceutical combination in the manufacture of a medicament for the prevention and / or treatment of a disease selected from cancer, the pharmaceutical combination comprising a Bcl-2 / Bcl-xL inhibitor and a hypomethylating agent or a prodrug thereof; the Bcl-2 / Bcl-xL inhibitor has a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof, or a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof;

[0010] Further, the hypomethylating agent is selected from one or more of Azacitidine, Decitabine and Cytarabine.

[0011] In another aspect, the present application provides a method of treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a pharmaceutical combination comprising a Bcl-2 / Bcl-xL inhibitor and a hypomethylating agent or a prodrug thereof; the Bcl-2 / Bcl-xL inhibitor is a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof, or a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof;

[0012] Further, the hypomethylating agent is selected from one or more of Azacitidine, Decitabine and Cytarabine.

[0013] In another aspect, the present application provides a Bcl-2 / Bcl-xL inhibitor having a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof for use in the preparation of a medicament for the prevention and / or treatment of a disease selected from cancer.

[0014] In another aspect, the present application provides a use of a Bcl-2 / Bcl-xL inhibitor having a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof in the preparation of a medicament for the prevention and / or treatment of a disease selected from cancer.

[0015] In another aspect, the present application provides a method of treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a Bcl-2 / Bcl-xL inhibitor having a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof.

[0016] Effects of the Invention

[0017] The compound of Formula II of the present application exhibits excellent anti-cell proliferation activity against M6 (acute erytholeukemia) or M7 (acute megakaryocytic leukemia) type AML cell lines KG-1, MEG-01, HEL and TF-1a, and in particular, the anti-tumor cell proliferation effect is more significant in the TF-1a and HEL cell lines.

[0018] In addition, the pharmaceutical combination of the present application has excellent effects of treating MDS / AML, and in particular, the effect of the combination of the present application comprising a Bcl-2 / Bcl-xL inhibitor and a hypomethylating agent in treating MDS / AML is superior to the sum of the effects of using each component alone, that is, the pharmaceutical combination of the present application achieves excellent synergistic effects. Attached Figure Description

[0019] Figure 1 shows the growth inhibitory effect of the compound represented by Formula ii in combination with decitabine and azacitidine (AZA) on the TP53 mutant MDS cell line SKM-1. SKM-1 cells were treated with gradient concentrations of the compound represented by Formula ii, decitabine, and azacitidine, either alone or in combination, for 72 hours. Cell growth inhibition activity was detected by CellTiter-Glo luminescence assay. Growth inhibition curves were plotted using GraphPad Prism. Cell viability percentage is expressed as Mean ± SEM, n = 2.

[0020] Figure 2 shows that the compound shown in Formula ii, in combination with decitabine and azacitidine, can synergistically induce apoptosis in SKM-1 cells. SKM-1 cells were collected after being treated in vitro with 1 μM or 3 μM of the compound shown in Formula ii in combination with 1 μM decitabine (DEC) and 3 μM azacitidine (AZA) for 24-48 hours. Apoptosis was detected by Annenix V-FITC / PI staining and flow cytometry.

[0021] Figure 3 shows the growth inhibitory effects of the compound shown in Formula ii in combination with azacitidine (AZA) on the M6 / M7 AML cell lines KG-1, MEG-01, HEL, and TF-1a. Cell viability percentage is expressed as Mean ± SEM, n = 2–3.

[0022] Figure 4 shows the inhibitory effects of the compound of formula ii on the growth of M6 / M7 AML cell lines KG-1, MEG-01, HEL, and TF-1a. Cell viability percentage is expressed as Mean ± SEM, n = 2–3. Detailed Implementation

[0023] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly show the details of the local features; unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application pertains.

[0024] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor of the present application is preferably (R)-2-(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-(trifluoromethylsulfanyl)phenylamino)-4-(phenylthio)butyl)piperidine-4-carbonyloxy)ethylphosphonic acid (i.e. the compound of Formula I) or a pharmaceutically acceptable salt thereof, as represented by the following structural formula:

[0025] The compound of Formula I binds selectively to Bcl-2, Bcl-xL, Bcl-w proteins with high affinity, with IC50values of 1.6 nM, 4.4 nM, 9.3 nM, respectively. The compound of Formula I binds weakly to Mcl-1. The compound of Formula I effectively reduces the platelet toxicity defect of the first generation BCL-2 inhibitors in the blood circulation by chemical structural modification, but can obtain specific enzyme activation in the tissue to effectively kill tumor cells. Its platelet toxicity is reduced by 10-30 times, but the activity is about 10 times that of the first generation BCL-2 inhibitors. The compound of Formula I is a second generation new target BCL-2 protein inhibitor. 50 The compound of Formula I binds selectively to Bcl-2, Bcl-xL, Bcl-w proteins with high affinity, with IC50values of 1.6 nM, 4.4 nM, 9.3 nM, respectively. The compound of Formula I binds weakly to Mcl-1. The compound of Formula I effectively reduces the platelet toxicity defect of the first generation BCL-2 inhibitors in the blood circulation by chemical structural modification, but can obtain specific enzyme activation in the tissue to effectively kill tumor cells. Its platelet toxicity is reduced by 10-30 times, but the activity is about 10 times that of the first generation BCL-2 inhibitors. The compound of Formula I is a second generation new target BCL-2 protein inhibitor.

[0026] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor of the present application is preferably (R)-2-(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-(trifluoromethylsulfanyl)phenylamino)-4-(phenylthio)butyl)piperidine-4-carbonyloxy)ethylphosphonic acid (i.e. the compound of Formula I) or a pharmaceutically acceptable salt thereof, as represented by the following structural formula:

[0027] The above-mentioned Bcl-2 / Bcl-xL inhibitor in the pharmaceutical combination of the present application can be synthesized according to the method described in WO2014 / 113413A1.

[0028] The present application provides a pharmaceutical combination comprising a Bcl-2 / Bcl-xL inhibitor and a hypomethylating agent or a prodrug thereof; the Bcl-2 / Bcl-xL inhibitor has a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof, or a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof;

[0029] In certain embodiments, the hypomethylating drug is selected from one or more of Azacitidine, Decitabine, and Cytarabine.

[0030] In certain embodiments, the hypomethylating drug is Azacitidine.

[0031] Azacitidine, CAS No.: 320-67-2,

[0032] In certain embodiments, the hypomethylating drug is Decitabine.

[0033] Decitabine, CAS No.: 2353-33-5,

[0034] In certain embodiments, the hypomethylating drug is Cytarabine.

[0035] Cytarabine, CAS No.: 147-94-4,

[0036] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or an active metabolite thereof, and Azacitidine.

[0037] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or an active metabolite thereof, and Decitabine.

[0038] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or an active metabolite thereof, and Cytarabine.

[0039] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, or an active metabolite thereof, and Azacitidine.

[0040] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, or an active metabolite thereof, and Decitabine.

[0041] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, or active metabolite thereof, and Cytarabine.

[0042] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day.

[0043] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week.

[0044] In certain embodiments, the fixed dose of the Bcl-2 / Bcl-xL inhibitor is 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg / kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg / kg, 550 pg / kg, 575 pg / kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

[0045] In certain embodiments, the administered dose of the hypomethylating drug is 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day;

[0046] In certain embodiments, the hypomethylating drug is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week.

[0047] In certain embodiments, the hypomethylating drug is administered at a dose of 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg kg, 550 pg / kg, 575 pg kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

[0048] In certain embodiments, the drug combination is in the form of a pharmaceutical composition.

[0049] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor and the hypomethylating agent are each in a separate formulation.

[0050] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor and the hypomethylating agent are administered simultaneously or sequentially.

[0051] In certain embodiments, the Bcl-2 inhibitor or Bcl-2 / Bcl-xL inhibitor and the additional agent are administered sequentially with an interval of about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks.

[0052] In certain embodiments, the combination of the present application containing the Bcl-2 inhibitor or Bcl-2 / Bcl-xL inhibitor and the additional agent in the form of a pharmaceutical composition, preferably each in the form of a separate dosage unit, can be administered daily as needed including but not limited to 1, 2, 3, 4, 5, or 6 times.

[0053] In certain embodiments, the combination of the present application containing the Bcl-2 inhibitor or Bcl-2 / Bcl-xL inhibitor and the additional agent in the form of a pharmaceutical composition, preferably each in the form of a separate dosage unit, can be administered daily as needed including but not limited to 1, 2, 3, 4, 5, or 6 times.

[0054] In certain embodiments, the combination product can be administered orally, buccally, by inhalation spray, sublingually, rectally, transdermally, transmucosally, topically, nasally, or enterally; by injection, such as intramuscularly, subcutaneously, intramedullary, and intrathecally, direct brain administration, in situ, subcutaneously, intraperitoneally, intravenously, intraarticular synovial, intrastemally, intrahepatically, intralesionally, intracranially, intraperitoneally, intranasally, or intraocularly, or other drug delivery means.

[0055] In certain embodiments, the pharmaceutical combination further comprises a pharmaceutically acceptable carrier.

[0056] In certain embodiments, the pharmaceutical combination is in the form of a tablet, capsule, granule, syrup, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol, ointment, cream, or injection.

[0057] The present application provides the above pharmaceutical combination for use in the preparation of a medicament for the prevention and / or treatment of a disease selected from a cancer.

[0058] In certain embodiments, the cancer is a hematological malignancy.

[0059] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myelogenous leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer, or NK / T-cell lymphoma.

[0060] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, or myelodysplastic syndrome.

[0061] The present application provides the above pharmaceutical combination for use in the preparation of a medicament for the prevention and / or treatment of a disease selected from a cancer.

[0062] In certain embodiments, the cancer is a hematological malignancy.

[0063] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myelogenous leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer, or NK / T-cell lymphoma.

[0064] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, or myelodysplastic syndrome.

[0065] The present application provides a method of treating a cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a pharmaceutical combination comprising a Bcl-2 / Bcl-xL inhibitor and a hypomethylating drug or a prodrug thereof.

[0066] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor of the present application is preferably (R)-2-(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-(trifluoromethylsulfanyl)phenylamino)-4-(phenylthio)butyl)piperidine-4-carbonyloxy)ethylphosphonic acid (i.e., the compound of Formula I) or a pharmaceutically acceptable salt thereof, as represented by the following structural formula:

[0067] The compound of Formula I selectively binds to Bcl-2, Bcl-xL, Bcl-w proteins with high affinity, with IC 50 1.6 nM, 4.4 nM, 9.3 nM, respectively. The compound of Formula I binds weakly to Mcl-1. The compound of Formula I effectively reduces the platelet toxicity defect of the first generation BCL-2 inhibitors in the blood circulation by chemical structural modification, but can obtain specific enzyme activation in the tissue to effectively kill tumor cells. The platelet toxicity is reduced by 10-30 times, but the activity is about 10 times that of the first generation BCL-2 inhibitors. The compound of Formula I is a second generation new target BCL-2 protein inhibitor.

[0068] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor of the present application is preferably (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-(trifluoromethylsulfanyl)phenylamino)-4-(phenylthio)butyl)piperidine-4-carboxylic acid (i.e., the compound of Formula II) or a pharmaceutically acceptable salt thereof, which is an active metabolite of the compound of Formula I. The compound of Formula II is represented by the following structural formula:

[0069] The present application provides a method for treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a pharmaceutical combination comprising a Bcl-2 / Bcl-xL inhibitor and a hypomethylating drug or a prodrug thereof; the Bcl-2 / Bcl-xL inhibitor has a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof, or a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof;

[0070] In certain embodiments, the hypomethylating drug is selected from one or more of Azacitidine, Decitabine, and Cytarabine.

[0071] In certain embodiments, the hypomethylating drug is Azacitidine.

[0072] Azacitidine, CAS Number: 320-67-2,

[0073] In certain embodiments, the hypomethylating drug is Decitabine.

[0074] Decitabine, CAS Number: 2353-33-5,

[0075] In certain embodiments, the hypomethylating drug is Cytarabine.

[0076] Cytarabine, CAS Number: 147-94-4,

[0077] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or an active metabolite thereof, and Azacitidine.

[0078] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or an active metabolite thereof, and Decitabine.

[0079] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or an active metabolite thereof, and Cytarabine.

[0080] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, or an active metabolite thereof, and Azacitidine.

[0081] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, or an active metabolite thereof, and Decitabine.

[0082] In certain embodiments, the pharmaceutical combination of the present application comprises a combination of a compound of Formula II, or a pharmaceutically acceptable salt or solvate thereof, or active metabolite thereof, and Cytarabine.

[0083] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day;

[0084] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week;

[0085] In certain embodiments, the fixed dose of the Bcl-2 / Bcl-xL inhibitor is 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg / kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg / kg, 550 pg / kg, 575 pg / kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

[0086] In certain embodiments, the administered dose of the hypomethylating drug is 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day;

[0087] In certain embodiments, the hypomethylating drug is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week.

[0088] In certain embodiments, the hypomethylating drug is administered at a dose of 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg kg, 550 pg / kg, 575 pg kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

[0089] In certain embodiments, the drug combination is in the form of a pharmaceutical composition.

[0090] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor and the hypomethylating agent are each in a separate formulation.

[0091] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor and the hypomethylating agent are administered simultaneously or sequentially.

[0092] In certain embodiments, the Bcl-2 inhibitor or Bcl-2 / Bcl-xL inhibitor and the additional agent are administered sequentially with an interval of about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 8 weeks, or about 12 weeks.

[0093] In certain embodiments, the combination of the present application containing the Bcl-2 inhibitor or Bcl-2 / Bcl-xL inhibitor and the additional agent in the form of a pharmaceutical composition (preferably, each in a separate dosage unit form) can be administered daily as needed including but not limited to 1, 2, 3, 4, 5, or 6 times.

[0094] In certain embodiments, the combination of the present application containing the Bcl-2 inhibitor or Bcl-2 / Bcl-xL inhibitor and the additional agent in the form of a pharmaceutical composition (preferably, dosage unit form) can be administered daily as needed including but not limited to 1, 2, 3, 4, 5, or 6 times.

[0095] In certain embodiments, the combination product can be administered orally, buccally, by inhalation spray, sublingually, rectally, transdermally, transmucosally, topically, nasally, or enterally; by injection, such as intramuscularly, subcutaneously, intramedullary, and intrathecally, direct brain administration, in situ, subcutaneously, intraperitoneally, intravenously, intraarticular synovial, intrastemally, intrahepatically, intralesionally, intracranially, intraperitoneally, intranasally, or intraocularly, or other drug delivery means.

[0096] In certain embodiments, the pharmaceutical combination further comprises a pharmaceutically acceptable carrier.

[0097] In certain embodiments, the pharmaceutical combination is in the form of a tablet, capsule, granule, syrup, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol, ointment, cream, or injection.

[0098] In certain embodiments, the cancer is a hematologic malignancy.

[0099] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myeloid leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer, or NK / T-cell lymphoma.

[0100] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, or myelodysplastic syndrome.

[0101] The present application provides a Bcl-2 / Bcl-xL inhibitor for use in the preparation of a medicament for the prevention and / or treatment of a disease selected from a cancer.

[0102] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor of the present application is preferably (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- (trifluoromethylsulfonyl)anilino)-4-(phenylsulfanyl)butyl)piperidine-4-carboxylic acid (i.e., the compound of Formula II) or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof. This is represented by the following structural formula:

[0103] In certain embodiments, the cancer is a hematologic malignancy.

[0104] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myeloid leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer, or NK / T-cell lymphoma.

[0105] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, or myelodysplastic syndrome.

[0106] In certain embodiments, the prevention and / or treatment is the administration of the Bcl-2 / Bcl-xL inhibitor.

[0107] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day;

[0108] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week;

[0109] In certain embodiments, the fixed dose of the Bcl-2 / Bcl-xL inhibitor is 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 75 μg / kg, 100 μg / kg, 125 μg / kg, 150 μg / kg, 175 μg / kg, 200 μg / kg, 225 μg / kg, 250 μg / kg, 275 μg / kg, 300 μg / kg, 325 μg / kg, 350 μg / kg, 375 μg / kg, 400 μg / kg, 425 μg / kg, 450 μg / kg, 475 μg / kg, 500 μg / kg, 525 μg / kg, 550 μg / kg, 575 μg / kg, 600 μg / kg, 625 μg / kg, 650 μg / kg, 675 μg / kg, 700 μg / kg, 725 μg / kg, 750 μg / kg, 775 μg / kg, 800 μg / kg, 825 μg / kg, 850 μg / kg, 875 μg / kg, 900 μg / kg, 925 μg / kg, 950 μg / kg, 975 μg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

[0110] The present application provides the use of a Bcl-2 / Bcl-xL inhibitor in the manufacture of a medicament for the prevention and / or treatment of a disease selected from a cancer.

[0111] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor of the present application is preferably (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- (trifluoromethylsulfonyl)anilino)-4-(phenylsulfanyl)butyl)piperidine-4-carboxylic acid (i.e., the compound of Formula II) or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof. This is represented by the following structural formula:

[0112] In certain embodiments, the cancer is a hematologic malignancy.

[0113] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myelogenous leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer, or NK / T-cell lymphoma.

[0114] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, or myelodysplastic syndrome.

[0115] In certain embodiments, the prevention and / or treatment is administration of the Bcl-2 / Bcl-xL inhibitor.

[0116] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day;

[0117] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week;

[0118] In certain embodiments, the fixed dose of the Bcl-2 / Bcl-xL inhibitor is 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 75 μg / kg, 100 μg / kg, 125 μg / kg, 150 μg / kg, 175 μg / kg, 200 μg / kg, 225 μg / kg, 250 μg / kg, 275 μg / kg, 300 μg / kg, 325 μg / kg, 350 μg / kg, 375 μg / kg, 400 μg / kg, 425 μg / kg, 450 μg / kg, 475 μg / kg, 500 μg / kg, 525 μg / kg, 550 μg / kg, 575 μg / kg, 600 μg / kg, 625 μg / kg, 650 μg / kg, 675 μg / kg, 700 μg / kg, 725 μg / kg, 750 μg / kg, 775 μg / kg, 800 μg / kg, 825 μg / kg, 850 μg / kg, 875 μg / kg, 900 μg / kg, 925 μg / kg, 950 μg / kg, 975 μg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

[0119] The present application provides a method of treating cancer, comprising administering to an individual in need thereof a therapeutically effective amount of a Bcl-2 / Bcl-xL inhibitor.

[0120] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor of the present application is preferably (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- (trifluoromethylsulfonyl)anilino)-4-(phenylsulfanyl)butyl)piperidine-4-carboxylic acid (i.e., the compound of Formula II) or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof. This is represented by the following structural formula:

[0121] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day;

[0122] In certain embodiments, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week;

[0123] In certain embodiments, the fixed dose of the Bcl-2 / Bcl-xL inhibitor is 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg / kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg / kg, 550 pg / kg, 575 pg / kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

[0124] In certain embodiments, the combination product can be administered orally, buccally, by inhalation spray, sublingually, rectally, transdermally, transmucosally, topically, nasally, or enterally; by injection, such as intramuscularly, subcutaneously, intramedullary, and intrathecally, direct brain administration, in situ, subcutaneously, intraperitoneally, intravenously, intraarticular synovial, intrastemally, intrahepatically, intralesionally, intracranially, intraperitoneally, intranasally, or intraocularly, or by other means of drug delivery.

[0125] In certain embodiments, the cancer is a hematologic malignancy.

[0126] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myelogenous leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer, or NK / T-cell lymphoma.

[0127] In certain embodiments, the cancer is acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, or myelodysplastic syndrome.

[0128] Glossary

[0129] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0130] The term "pharmaceutically acceptable salt" means a salt of a compound of the disclosure that is safe and effective for use in a mammal and possesses the desirable biological activity. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate moiety with a suitable base or acid. Alkali metal (e.g., sodium and potassium) and alkaline earth metal (e.g., magnesium) salts are in particular useful for forming pharmaceutically acceptable salts. Salts of organic anions such as amines are also useful.

[0131] The term "therapeutically effective amount" with respect to a pharmaceutical or pharmacological agent means a sufficient amount of the agent to provide the desired effect, without being toxic to the recipient. The determination of an effective amount is dependent on the age and general condition of the recipient, as well as the particular active agent, and an appropriate effective amount for a given case can be determined by one of ordinary skill in the art according to routine testing.

[0132] The term "solvate" means a physical association between a compound of the disclosure and one or more, preferably 1 to 3, solvent molecules, either organic or inorganic. This physical association can include hydrogen bonding. In certain instances, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods for solvation are generally known in the art.

[0133] The term "prodrug" means a compound that can be converted in vivo to yield an active parent compound, for example, by hydrolysis in blood.

[0134] The term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0135] The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of the processes by which a particular substance is changed by an organism (including, but not limited to, hydrolysis and enzyme-catalyzed reactions, such as oxidation). Further information on metabolism can be found in The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill (1996). Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with liver cells in vitro and analyzing the resulting compounds. Both of these methods are known in the art. In some embodiments, a metabolite of a compound is formed by an oxidation process and corresponds to a hydroxyl-containing compound. In some embodiments, a compound is metabolized to a pharmacologically active metabolite.

[0136] The terms "comprise," "comprises," and "comprising," or any variation thereof, are open-ended, and include the presence of the recited elements, components, and steps, as well as the possibility of additional, unrecited elements, components, and steps.

[0137] Examples

[0138] The concept of the present application and the technical effects produced will be further illustrated below in conjunction with examples, so that those skilled in the art can fully understand the purpose, features and effects of the present application. It should be understood that the following examples are only illustrative and do not constitute a limitation on the scope of the present application.

[0139] Example 1

[0140] 1. Cell lines

[0141] MDS cell line SKM-1 was purchased from Japan Cancer Research Resources Bank (JCRB Cell Bank), and the culture conditions were 90% RPMI 1640 (#C11875500BT, GIBCO) medium + 10% fetal bovine serum (FBS) (#1943609-65-1, Sigma) + 1% penicillin / streptomycin (P / S) (#15140-122, GIBCO), and the cells were cultured in a 37°C, 5% CO2 incubator.

[0142] In the cell proliferation activity experiment, the cells were plated into a 96-well plate, and the number of cells was 8000 cells / well / cell line. In the apoptosis detection experiment, the cells were plated into a 24-well plate, and the number of cells was 20000 cells / well / cell line.

[0143] 2. Test substance

[0144] The compound of formula II was independently developed by Jiangsu Yasheng Pharmaceutical Development Co., Ltd. The demethylating drugs azacitidine (AZA) and decitabine (DEC) were purchased from Selleck Company.

[0145] The above-mentioned compounds were respectively dissolved in dimethyl sulfoxide (DMSO) (#D8418, Sigma) to a concentration of 10 mM as a stock solution. The stock solution was stored at -20°C in the dark when not in use. The stock solution was diluted to the required working concentration using serum-free medium as a diluent.

[0146] 3. Instruments

[0147] The instruments used in this experiment include: biological safety cabinet (ESCO, model AC2-4S1); CO2 incubator (ESCO, model CLM-170B-8-NF); inverted microscope (COIC INDUSTRIAL, model: XDS-1B); Schman peak electric aspirator (Shanghai Baogia Medical Instrument Co., Ltd., model YX930D); balance (Mettler-Toledo, AB135-S); low-speed centrifuge (Shanghai Luxiang Instrument Co., Ltd., model L600); microplate reader (Bio-Tek, model Synergy H1); 10 μL, 20 μL, 100 μL, 200 μL, 1000 μL single-channel pipettor (Eppendorf); multichannel pipettor (Eppendorf); electric suction device (INTEGRA PIPETBOY2, 155000 classic); constant temperature water bath (Shanghai Yiheng Scientific Instrument Co., Ltd., DK-8AX); vortex shaker (Haimen Qilinbell Instrument Manufacturing Co., Ltd., Kylin-Bell 5); sterilization pot (Shanghai Shen'an Medical Instrument Co., Ltd., LDZM-60KCS); flow cytometer (Life technology, model Attune NxT).

[0148] 4. CTG experiment

[0149] Using The luminescence method cell viability detection kit was used to determine the anti-proliferation effect of the test substance MDS cell line by quantifying ATP. Cells were seeded in a 96-well plate and treated with different concentrations of test substances for 72 hours. The combined effect of the compound of formula II and the combination therapy drugs was tested by using 8 serial concentrations of the compound of formula II and other demethylating drugs (HMA) including standard AML treatment standard drugs decitabine and azacitidine for 72 hours. Each test concentration was done in duplicate.

[0150] First, collect cells in log phase growth, centrifuge, count the cell suspension and dilute to the desired concentration. After mixing, add 90 μL of cell suspension to each well of a 96-well plate. The number of cells per well is 8 x 10 3 Incubate overnight in an incubator at 37°C with 5% CO2. Set up 3 or more blank control wells containing only medium (100 μL / well) without cells on the same plate to obtain background luminescence values.

[0151] According to the sensitivity of different cells to different drugs, select the appropriate initial highest concentration, dilute it in a ratio of 1:3 to obtain 8 serial concentrations, and add 10 μL / well to the 96-well plate. For combination experiments, the final volume of the two test substances is 10 μL / well. Incubate the plate in a 37°C, 5% CO2incubator for 24 or 72 hours. Observe the cell growth under an inverted microscope every day. At the end of the incubation, remove the 96-well plate and its contents from the incubator and equilibrate to room temperature. Then add 30 μL of reagent (protected from light) to each well. Place the 96-well plate on a orbital shaker to mix the contents for 2 minutes to fully lyse the cells. Place the 96-well plate in an incubator at room temperature for 10 minutes to stabilize the fluorescence signal value. Incubate the plate in a 37°C, 5% CO2incubator for 24 or 72 hours. Observe the cell growth under an inverted microscope every day. At the end of the incubation, remove the 96-well plate and its contents from the incubator and equilibrate to room temperature. Then add 30 μL of reagent (protected from light) to each well. Place the 96-well plate on a orbital shaker to mix the contents for 2 minutes to fully lyse the cells. Place the 96-well plate in an incubator at room temperature for 10 minutes to stabilize the fluorescence signal value.

[0152] Use the Biotek synergy H1 microplate reader to detect the luminescence signal. Use the average fluorescence signal value of 3 replicate wells to calculate the percentage of cell survival by the following formula:

[0153] Percentage of cell survival (%) = (fluorescence signal value of test well - fluorescence signal value of negative control well) / (fluorescence signal value of cell control well - fluorescence signal value of negative control well) x 100%

[0154] Use the non-linear regression data analysis method of Graphpad Prism 6.0 software (Golden software, Golden, Colorado, USA) to calculate IC50 and draw the cell survival curve.

[0155] For combination experiments, the results were further analyzed by the method of calculating combination index (CI) using CalcuSyn program (Chou, 2010). CalcuSyn is a professional software for analyzing mixed drugs. It can accurately analyze the effects of drug combination, quickly calculate and analyze the interactions of various drugs, including synergistic, additive, and antagonistic effects. CI value <1 indicates synergistic effect of two drugs; CI value =1 indicates additive effect of two drugs; CI value >1 indicates antagonistic effect of two drugs. CI <0.1 is marked as 5+, indicating very strong synergistic combination effect; CI between 0.1 and 0.3 is marked as 4+, indicating strong synergistic combination effect; CI between 0.3 and 0.7 is marked as 3+, indicating moderate synergistic combination effect.

[0156] 5. Flow cytometry analysis

[0157] SKM-1 cells were collected after 24 hours or 48 hours of single drug treatment with the compound of Formula II or combination treatment with the compound of Formula II and standard therapeutic drug decitabine or azacitidine, and washed once with pre-cooled 1x PBS (#U10017B, Keygen Biotech). According to the instructions of the FITC Annexin V Apoptosis Detection Kit I (#556547, BD Pharmingen), resuspend the cells with 100 μL 1x binding buffer, add 5 μL Annexin V-FITC, mix well, add 5 μL propidium iodide (PI), mix well, incubate at room temperature for 20 minutes in the dark, add 400 μL 1x PBS, mix well, and then place in ice bath. Flow cytometry (Attune NxT, Thermo) was used to detect apoptosis. Flow Jo analysis software (version number: Flow Jo 10.4.2, Treestar) was used to process the data, and apoptosis profiles were obtained by analyzing 20,000 cells under each experimental condition.

[0158] 6. Results

[0159] The combination effect of the compound of Formula II and demethylation therapeutic drug azacitidine or decitabine was tested in TP53 mutant MDS cell line SKM-1. As shown in Figure 1, when the compound of Formula II was combined with the standard demethylation drugs decitabine and azacitidine in the treatment, the response curve was shifted to the left compared with single drug, suggesting that the anti-proliferation effect of the compound of Formula II in SKM-1 cell line was enhanced. Synergy analysis showed that the combination index (CI value) was less than 1 at multiple combination concentrations, indicating that the combination had synergistic effect. The specific CI values and the original dose-effect growth inhibition curves of the combination of the compound of Formula II and demethylation drugs are shown in Figure 1.

[0160] Example 2

[0161] Previous studies have reported that azacitidine and decitabine have an effect of inducing apoptosis on AML cells. Therefore, we further evaluated the effect of the combination of the compound of Formula II and demethylation drugs (decitabine, azacitidine) on apoptosis in SKM-1 cells using Annexin V-PI fluorescent probe and flow cytometry analysis. SKM-1 cells were treated with 1 μM or 3 μM of the compound of Formula II and appropriate concentrations of azacitidine, decitabine for 24-48 hours, and then analyzed for the proportion of apoptotic cells by flow cytometry. As shown in the results of Figure 2, compared with the control group and the single drug treatment group, the combination of the compound of Formula II and azacitidine, decitabine significantly increased the proportion of apoptotic cells, and the combination of the two drugs produced a synergistic pro-apoptotic effect.

[0162] Example 3

[0163] 1. Cell lines

[0164] The present application is selected from KG-1 cell line, MEG-01 cell line, HEL cell line, TF-1a cell line. The culture conditions of MEG-01, HEL, TF-1a are 90% RPMI 1640 (#C11875500BT, GIBCO) medium + 10% fetal bovine serum (FBS) (#1943609-65-1, Sigma) + 1% penicillin / streptomycin (P / S) (#15140-122, GIBCO), and the culture conditions of KG-1 are 90% IMDM (#C12440500BRT, GIBCO) medium + 10% fetal bovine serum (FBS) (#1943609-65-1, Sigma) + 1% penicillin / streptomycin (P / S) (#15140-122, GIBCO). The cells are all cultured in a 37°C, 5% CO2 incubator.

[0165] 2. Test substance

[0166] The compound of formula II is independently developed by Jiangsu Yasheng Pharmaceutical Development Co., Ltd. The demethylated drug azacitidine (Azacitidine, AZA) is purchased from Selleck Company.

[0167] The above-mentioned compounds are respectively dissolved in dimethyl sulfoxide (Dimethyl sulfoxide, DMSO) (#D8418, Sigma) to a concentration of 10 mM as a stock solution. The stock solution is stored at -20°C in the dark when not in use. The stock solution is diluted to the required working concentration using serum-free medium as a diluent.

[0168] 3. Instruments

[0169] The instruments used in the experiment include: biological safety cabinet (ESCO, model AC2-4S1); CO2 incubator (ESCO, model CLM-170B-8-NF); inverted microscope (COIC INDUSTRIAL, model: XDS-1B); Sman peak electric aspirator (Shanghai Baogia Medical Instrument Co., Ltd., model YX930D); balance (Mettler-Toledo, AB135-S); low-speed centrifuge (Shanghai Luxiang Instrument Co., Ltd., model L600); microplate reader (Bio-Tek, model Synergy H1); 10 μL, 20 μL, 100 μL, 200 μL, 1000 μL single-channel pipette (Eppendorf); multichannel pipette (Eppendorf); electric suction device (INTEGRA PIPETBOY2, 155000 classic); constant temperature water bath (Shanghai Yiheng Scientific Instrument Co., Ltd., DK-8AX); vortex shaker (Haimen Qilinbell Instrument Manufacturing Co., Ltd., Kylin-Bell 5); sterilization pot (Shanghai Shen'an Medical Instrument Co., Ltd., LDZM-60KCS).

[0170] 4. CTG experiment

[0171] Using The luminescence method cell viability detection kit was used to determine the anti-proliferation effect of the test substance on M6 or M7 type AML cell lines by quantifying ATP. Cells were inoculated in a 96-well plate and treated with different concentrations of test substances for 24 hours. The combined effect of the compound of formula II and the combination therapy drug was tested by using 8 serial concentrations of the compound of formula II and azacitidine (Azacitidine) for 24 hours. Each test concentration was made in 2-3 replicates.

[0172] First, logarithmic growth phase cells were collected, centrifuged, and the cell suspension was counted and diluted to the desired concentration. After mixing, 90 μL of cell suspension was added to each well of a 96-well plate. The number of cells in each well was 10,000-15,000 cells, and the plate was incubated overnight in a 5% CO2, 37°C incubator. More than 3 blank control wells containing only medium (100 μL / well) without cells were set up on the same culture plate to obtain the background luminescence value.

[0173] According to the sensitivity of different cells to different drugs, the appropriate initial highest concentration was selected, and 8 serial concentrations were obtained by serial dilution at a ratio of 1:3. For the combination experiment, the final volume of 2 test substances was 10 μL / well. The culture plate was incubated in a 37°C, 5% CO2 incubator for 24 hours. At the end of the culture, the 96-well plate and its contents were removed from the incubator and equilibrated to room temperature at room temperature, and then 30 μL of Reagents (protected from light). Place the 96-well plate on an orbital shaker for 2 minutes to mix the contents and to lyse the cells completely. Incubate the 96-well plate at room temperature for 10 minutes to stabilize the fluorescence signal.

[0174] The luminescent signal was detected using a Biotek synergy H1 microplate reader. The average fluorescence signal value of 2-3 replicates was used to calculate the percentage of cell survival by the following formula:

[0175] Percentage of cell survival (%) = (fluorescence signal value of test well - fluorescence signal value of negative control well) / (fluorescence signal value of cell control well - fluorescence signal value of negative control well) x 100%

[0176] Cell survival curves were plotted using Graphpad Prism 6.0 software (Golden software, Golden, Colorado, USA).

[0177] For combination experiments, the results were further analyzed using the CalcuSyn program to calculate the combination index (CI) (Chou, 2010). CalcuSyn is a professional software for mixed drug analysis. Using CalcuSyn software, the effects of drug combinations can be accurately analyzed, and the interactions of various drugs, including synergistic, additive, and antagonistic effects, can be quickly calculated and analyzed. When the CI value of two drugs is <1, it indicates that the combination of the two drugs has a synergistic effect; when the CI value is =1, it indicates that the combination of the two drugs has an additive effect; and when the CI value is >1, it indicates that the combination of the two drugs has an antagonistic effect. CI <0.1 is marked as 5+, indicating a very strong synergistic combination effect; CI between 0.1 and 0.3 is marked as 4+, indicating a strong synergistic combination effect; and CI between 0.3 and 0.7 is marked as 3+, indicating a moderate synergistic combination effect.

[0178] 5. Results

[0179] The combination of the compound of formula II and the demethylation therapeutic drug azacitidine was tested in M6 or M7 type AML cell lines KG-1, MEG-01, HEL and TF-1a. As shown in Figure 3, when the compound of formula II is combined with the demethylation drug azacitidine, the combination drug response curve shifts to the left compared to single drug, indicating that the anti-proliferative effect of the compound of formula II in KG-1, MEG-01, HEL and TF-1a cell lines is enhanced. Synergistic analysis showed that the combination index (CI value) was less than 1 at multiple combination drug concentrations, indicating that the combination had a synergistic effect. The specific CI values and the original dose-dependent growth inhibition curves of the combination of the compound of formula II and the demethylation drug are shown in Figure 3.

[0180] Example 4

[0181] 1. Cell lines

[0182] KG-1, MEG-01, HEL cell lines were purchased from Nanjing Cobioer, TF-1a cell line was a gift from Professor Wang Shaomeng, University of Michigan. MEG-01, HEL, TF-1a culture conditions were 90% RPMI 1640 (#C11875500BT, GIBCO) medium + 10% fetal bovine serum (FBS) (#1943609-65-1, Sigma) + 1% penicillin / streptomycin (P / S) (#15140-122, GIBCO), KG-1 culture conditions were 90% IMDM (#C12440500BRT, GIBCO) medium + 10% fetal bovine serum (FBS) (#1943609-65-1, Sigma) + 1% penicillin / streptomycin (P / S) (#15140-122, GIBCO). Cells were all placed in a 37°C, 5% CO2 incubator for culture.

[0183] 2. Test substances

[0184] The compound of formula II was independently developed by Jiangsu Yasheng Pharmaceutical Development Co., Ltd.

[0185] The above compound was dissolved in dimethyl sulfoxide (Dimethyl sulfoxide, DMSO) (#D8418, Sigma) to a concentration of 10 mM as a stock solution. The conventional concentration was 10 -2 M. The stock solution was stored at -20°C in the dark when not in use. Serum-free medium was used as a diluent to dilute the stock solution to the required working concentration.

[0186] 3. Instruments

[0187] The instruments used in the experiment include: biological safety cabinet (ESCO, model AC2-4S1); CO2 incubator (ESCO, model CLM-170B-8-NF); inverted microscope (COIC INDUSTRIAL, model: XDS-1B); Sman peak electric aspirator (Shanghai Baogia Medical Instrument Co., Ltd., model YX930D); balance (Mettler-Toledo, AB135-S); low-speed centrifuge (Shanghai Luxiang Instrument Co., Ltd., model L600); microplate reader (Bio-Tek, model Synergy H1); 10 μL, 20 μL, 100 μL, 200 μL, 1000 μL single-channel pipette (Eppendorf); multichannel pipette (Eppendorf); electric suction device (INTEGRA PIPETBOY2, 155000 classic); constant temperature water bath (Shanghai Yiheng Scientific Instrument Co., Ltd., DK-8AX); vortex shaker (Haimen Qilinbell Instrument Manufacturing Co., Ltd., Kylin-Bell 5); sterilization pot (Shanghai Shen'an Medical Instrument Co., Ltd., LDZM-60KCS).

[0188] 4. CTG experiment

[0189] Using The luminescence cell viability assay kit was used to determine the anti-proliferative effect of the test substance on M6 or M7 type AML cell lines by quantifying ATP. Cells were seeded in 96-well plates and treated with different concentrations of test substance for 24 hours. The anti-proliferative effect of the compound of formula II on M6 or M7 type AML cell lines was tested by using 8 serial concentrations of the compound of formula II for 24 hours. 2-3 replicates were performed for each test concentration.

[0190] First, logarithmic growth phase cells were collected, centrifuged, and the cell suspension was counted and diluted to the desired concentration. After mixing, 90 μL of cell suspension was added to each well of a 96-well plate. The number of cells in each well was 10,000-15,000 cells, and the plate was incubated overnight in a 5% CO2, 37°C incubator. More than 3 blank control wells containing only medium (100 μL / well) without cells were set up on the same culture plate to obtain the background luminescence value.

[0191] According to the sensitivity of different cells to different drugs, the appropriate initial maximum concentration was selected, and 8 serial concentrations were obtained by serial dilution at a ratio of 1:3. For this experiment, the final volume of the test substance was 10 μL / well. The culture plate was incubated at 37°C in a 5% CO2 incubator for 24 hours. At the end of the culture, the 96-well plate and its contents were removed from the incubator and equilibrated to room temperature, and then 30 μL of CellTiter-Glo® reagent was added to each well. The plate was mixed thoroughly for 10 minutes at room temperature to allow the reagent to react with the cells. The luminescence signal was measured using a microplate reader. Reagents (protected from light). Place the 96-well plate on an orbital shaker for 2 minutes to mix the contents and to fully lyse the cells. Incubate the 96-well plate at room temperature for 10 minutes to stabilize the fluorescence signal values.

[0192] The luminescence signal was detected using a Biotek synergy H1 microplate reader. The mean fluorescence signal values of 3 replicates were used to calculate the percentage of cell survival by the following formula:

[0193] Percentage of cell survival (%) = (fluorescence signal value of test well - fluorescence signal value of negative control well) / (fluorescence signal value of cell control well - fluorescence signal value of negative control well) x 100%

[0194] Cell survival curves were plotted using Graphpad Prism 6.0 software (Golden software, Golden, Colorado, USA).

[0195] 5. Results

[0196] The in vitro anti-proliferative activity of the compound of formula II was tested in M6 or M7 type AML cell lines KG-1, MEG-01, HEL and TF-1a. As can be seen from Figure 4, the results show that the compound of formula II exhibited significant anti-tumor proliferative effects in all cell lines. Among them, the TF-1a and HEL cell lines were the most sensitive to the compound of formula II with IC 50 values of 95.61 nM and 127.7 nM, respectively; the IC 50 values of the MEG-01 and KG-1 cell lines were 847 nM and 2561 nM, respectively. Overall, the compound of formula II exhibited effective anti-proliferative activity of varying degrees in M6 or M7 type AML cell lines, especially in the TF-1a and HEL cell lines.

[0197] It should be understood that the above examples are exemplary and are not intended to limit all possible implementations encompassed by the claims. Various modifications and alterations can also be made on the basis of the above examples without departing from the scope of the present disclosure. Similarly, any of the individual technical features of the above examples can be arbitrarily combined to form additional embodiments of the present disclosure that can not have been explicitly described. Therefore, the above examples merely express several embodiments of the present disclosure and do not limit the scope of protection of the present patent.

Claims

1. A pharmaceutical combination, characterized in that, The pharmaceutical combination comprises a Bcl-2 / Bcl-xL inhibitor and a hypomethylating drug or a prodrug thereof; the Bcl-2 / Bcl-xL inhibitor has a compound shown in formula i or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof, or a compound shown in formula ii or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof; 2. The pharmaceutical combination according to claim 1, characterized in that, The hypomethylating agent is selected from one or more of Azacitidine, Decitabine, and Cytarabine.

3. The pharmaceutical combination according to claim 2, characterized in that, The hypomethylating agent is selected from Azacitidine.

4. The pharmaceutical combination according to claim 2, characterized in that, The hypomethylating agent is selected from Decitabine.

5. The pharmaceutical combination according to claim 2, wherein The hypomethylating agent is selected from Cytarabine.

6. The pharmaceutical combination according to any one of claims 1-5, characterized in that, The Bcl-2 / Bcl-xL inhibitor is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day; Preferably, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week; Preferably, the fixed dose of the Bcl-2 / Bcl-xL inhibitor is 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg kg, 550 pg / kg, 575 pg kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

7. The pharmaceutical combination according to any one of claims 1-5, characterized in that, The hypomethylating agent is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day; Preferably, the hypomethylating agent is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week. Preferably, the hypomethylating agent is administered at a dose of 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg / kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg / kg, 550 pg / kg, 575 pg / kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

8. The pharmaceutical combination according to any one of claims 1-7, characterized in that, The pharmaceutical combination is in the form of a pharmaceutical composition.

9. The pharmaceutical combination according to any one of claims 1-7, characterized in that, The Bcl-2 / Bcl-xL inhibitor and the hypomethylating agent are each in a separate formulation.

10. The pharmaceutical combination according to any one of claims 1-7, characterized in that, The Bcl-2 / Bcl-xL inhibitor and the hypomethylating agent are administered simultaneously or sequentially.

11. The pharmaceutical combination according to any one of claims 1-7, characterized in that, The pharmaceutical combination further comprises a pharmaceutically acceptable carrier.

12. The pharmaceutical combination according to claim 11, characterized in that, The pharmaceutical combination is in the form of a tablet, capsule, granule, syrup, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol, ointment, cream or injection.

13. The pharmaceutical combination of any one of claims 1-12 for use in the preparation of a medicament for the prevention and / or treatment of a disease selected from cancer.

14. Use according to claim 13, characterized in that, The cancer is a hematological malignancy; preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myeloid leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer or NK / T-cell lymphoma; more preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia or myelodysplastic syndrome.

15. The pharmaceutical combination of any one of claims 1-12 for use in the preparation of a medicament for the prevention and / or treatment of a disease selected from cancer.

16. Use according to claim 15, characterized in that, The cancer is a hematological malignancy; preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myeloid leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer or NK / T-cell lymphoma; more preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia or myelodysplastic syndrome.

17. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-16. comprising administering to an individual in need thereof a therapeutically effective amount of a pharmaceutical combination comprising a Bcl-2 / Bcl-xL inhibitor and a hypomethylating drug or prodrug thereof; the Bcl-2 / Bcl-xL inhibitor having a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof or active metabolite thereof, or a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or active metabolite thereof; 18. The method of claim 17, wherein, The hypomethylating agent is selected from one or more of Azacitidine, Decitabine and Cytarabine.

19. The method of claim 18, wherein, The hypomethylating agent is selected from Azacitidine.

20. The method of claim 18, wherein, The hypomethylating agent is selected from Decitabine.

21. The method of claim 18, wherein, The hypomethylating agent is selected from Cytarabine.

22. The method of any one of claims 17-21, wherein, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day; Preferably, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week; Preferably, the fixed dose of the Bcl-2 / Bcl-xL inhibitor is 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg kg, 550 pg / kg, 575 pg kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

23. The method of any one of claims 17-21, wherein, The hypomethylating agent is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day; Preferably, the hypomethylating agent is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week. Preferably, the hypomethylating agent is administered at a dose of 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg / kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg / kg, 550 pg / kg, 575 pg / kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

24. The method of any one of claims 17-23, wherein, The pharmaceutical combination is in the form of a pharmaceutical composition.

25. The method of any one of claims 17-23, wherein, The Bcl-2 / Bcl-xL inhibitor and the hypomethylating agent are each in a separate formulation.

26. The method of any one of claims 17-23, wherein, The Bcl-2 / Bcl-xL inhibitor and the hypomethylating agent are administered simultaneously or sequentially.

27. The method of any one of claims 17-23, wherein, The pharmaceutical combination further comprises a pharmaceutically acceptable carrier.

28. The method of claim 27, wherein, The pharmaceutical combination is in the form of a tablet, a capsule, a granule, a syrup, a powder, a lozenge, a sachet, a cachet, an elixir, a suspension, an emulsion, a solution, a syrup, an aerosol, an ointment, a cream or an injection.

29. The method of any one of claims 17-23, wherein, The cancer is a hematological malignancy; preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myelogenous leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer or NK / T-cell lymphoma; more preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia or myelodysplastic syndrome.

30. Use of a Bcl-2 / Bcl-xL inhibitor having a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof in the manufacture of a medicament for the prevention and / or treatment of a disease selected from the group consisting of cancer; 31. Use according to claim 30, characterized in that, The cancer is a hematological malignancy; preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myelogenous leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer or NK / T-cell lymphoma; more preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia or myelodysplastic syndrome.

32. Use according to claim 30 or 31, characterized in that, The prevention and / or treatment is the administration of the Bcl-2 / Bcl-xL inhibitor; preferably, the administration dose of the Bcl-2 / Bcl-xL inhibitor is 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day or 5000 mg / day; Preferably, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week; Preferably, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg / kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg / kg, 550 pg / kg, 575 pg / kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

33. Use of a Bcl-2 / Bcl-xL inhibitor having a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof in the manufacture of a medicament for the prevention and / or treatment of a disease selected from the group consisting of cancer; 34. Use according to claim 33, characterized in that, The cancer is a hematologic malignancy; preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myeloid leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer, or NK / T-cell lymphoma; more preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, or myelodysplastic syndrome.

35. Use according to claim 33 or 34, characterized in that, the prevention and / or treatment is the administration of the Bcl-2 / Bcl-xL inhibitor; preferably the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day; preferably the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week; Preferably, the fixed dose of the Bcl-2 / Bcl-xL inhibitor is 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg kg, 550 pg / kg, 575 pg kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

36. A method for treating cancer, characterized in that, comprising administering to an individual in need thereof a therapeutically effective amount of a Bcl-2 / Bcl-xL inhibitor having a compound of Formula II or a pharmaceutically acceptable salt or solvate thereof or an active metabolite thereof; 37. The method of claim 36, wherein, The Bcl-2 / Bcl-xL inhibitor is administered at a dose of 0.005 mg / day, 0.05 mg / day, 0.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 40 mg / day, 50 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1500 mg / day, 2000 mg / day, 2500 mg / day, 3000 mg / day, 3500 mg / day, 4000 mg / day, 4500 mg / day, or 5000 mg / day; Preferably, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 10 mg / week, 15 mg / week, 20 mg / week, 25 mg / week, 30 mg / week, 35 mg / week, 40 mg / week, 50 mg / week, 55 mg / week, 60 mg / week, 65 mg / week, 70 mg / week, 75 mg / week, 80 mg / week, 85 mg / week, 90 mg / week, 95 mg / week, 100 mg / week, 150 mg / week, 200 mg / week, 250 mg / week, 300 mg / week, 350 mg / week, 400 mg / week, 450 mg / week, 500 mg / week, 550 mg / week, 600 mg / week, 650 mg / week, 700 mg / week, 750 mg / week, 800 mg / week, 850 mg / week, 900 mg / week, 950 mg / week, or 1000 mg / week; Preferably, the Bcl-2 / Bcl-xL inhibitor is administered at a dose of 1 pg / kg, 10 pg / kg, 25 pg / kg, 50 pg / kg, 75 pg / kg, 100 pg / kg, 125 pg / kg, 150 pg / kg, 175 pg / kg, 200 pg / kg, 225 pg / kg, 250 pg / kg, 275 pg / kg, 300 pg / kg, 325 pg / kg, 350 pg / kg, 375 pg / kg, 400 pg / kg, 425 pg / kg, 450 pg / kg, 475 pg / kg, 500 pg / kg, 525 pg / kg, 550 pg / kg, 575 pg / kg, 600 pg / kg, 625 pg / kg, 650 pg / kg, 675 pg / kg, 700 pg / kg, 725 pg / kg, 750 pg / kg, 775 pg / kg, 800 pg / kg, 825 pg / kg, 850 pg / kg, 875 pg / kg, 900 pg / kg, 925 pg / kg, 950 pg / kg, 975 pg / kg, 1 mg / kg, 4 mg / kg, 5 mg / kg, 8 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, or 200 mg / kg.

38. The method of claim 36 or 37, wherein, The cancer is a hematologic malignancy; preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphoma, chronic myeloid leukemia, mantle cell lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, T-prolymphocytic leukemia, small cell lung cancer, or NK / T-cell lymphoma; more preferably acute erythroid leukemia, acute megakaryocytic leukemia, acute myeloid leukemia, or myelodysplastic syndrome.

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