Combination of loginolisib and BCL-2 inhibitors in the treatment of hematological malignancies

Abstract

A PI3K-delta inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of hematological malignancies in a subject, wherein the treatment comprises separate, sequential, or concurrent administration to the subject of i) the PI3K-delta inhibitor or a pharmaceutically acceptable salt thereof, and ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. The treatment may also further comprise iii) separate, sequential, or concurrent administration to the subject of iii) further chemotherapeutic agents.

Description

Technical Field

[0001] The present disclosure relates to a method of treating hematological malignancies in patients who require treatment.

[0002] This application claims the benefit of priority to UK Application No. 2303190.9, filed on 3 March 2023, and UK Application No. 2308119.3, filed on 31 May 2023, which are hereby incorporated by reference in their entirety.

Background Art

[0003] Hematological malignancies, also known as blood cancers, are malignant neoplasms mainly derived from the bone marrow and lymphoid cell lineages. Lymphomas, lymphocytic leukemias, and myelomas are derived from the lymphoid lineage, while acute and chronic myeloid leukemia, myelodysplastic syndromes, and myeloproliferative disorders are of bone marrow origin.

[0004] Hematological malignancies are a significant cause of morbidity and mortality worldwide, with nearly 1,000,000 new cases and over 600,000 deaths annually (Jephcote 2020). Several agents, including occupation, lifestyle, and genetic risk factors, contribute to the development of hematological cancers. Hematological malignancies are heterogeneous diseases with varying outcomes. Slow-chronic lymphomas and chronic leukemias, such as follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL), remain incurable chronic diseases that require patients to undergo repeated exposure to toxic treatments. For invasive lymphomas and acute leukemias, modern treatment regimens result in long-term survival rates ranging from >80% for Hodgkin lymphoma, approximately 60-65% for diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL), and <30% for peripheral T-cell lymphoma (PTCL) and acute myeloid leukemia (AML) (Intlekofer and Younes 2014, Kantarjian 2021). More effective treatments are needed to improve outcomes for patients with hematological malignancies. Furthermore, even in patients who are cured by combination chemotherapy, often used in conjunction with radiation, this treatment can result in long-term toxicity that impairs health, increases susceptibility to secondary malignancies, and negatively impacts quality of life.

[0005] Targeted therapies, including phosphatidylinositol 3-kinase (PI3K) inhibitors and B-cell lymphoma 2 (BCL-2) inhibitors, have transformed the treatment landscape for patients with hematological malignancies. PI3K plays a central role in regulating major intercellular pathways, including growth, proliferation, survival, migration, and differentiation, and PI3K pathway dysregulation is one of the most frequent pathogenic events in cancer (Kienle and Stilgenbauer 2020). BCL-2, a family of regulatory proteins, governs the mitochondrial pathway of apoptosis, and BCL-2 dysregulation generally arises from genetic abnormalities such as the t(14;18)(q32;q21) translocation in follicular lymphoma (FL) or a local deletion on chromosome 13 (del[13q14]) leading to the loss of negatively regulatory miRNA-15a / 16-1 in CLL (Kapoor 2020). Therefore, PI3K and BCL-2 are reasonable therapeutic targets in hematological malignancies.

[0006] While PI3K and BCL-2 inhibitors have shown impressive clinical outcomes across a variety of hematological malignancies, certain subtypes are characterized by significantly higher response rates than others, and resistance develops to these inhibitors, ultimately leading to clinical disease progression. Furthermore, both types of inhibitors are associated with serious adverse effects, limiting their therapeutic applicability and, in the case of PI3K inhibitors, even leading to drug withdrawal from the market (Hampel 2021, Richardson 2022).

[0007] BCL-2 as a therapeutic target for hematological malignancies was discussed in Pereini 2018.

[0008] Despite significant advances in the treatment of hematological malignancies, the demand for targeted therapies for these malignancies is increasing. Many patients with such cancers live with incurable diseases. Therefore, it is crucial to continue finding new and more effective treatments for patients with incurable diseases. [Overview of the Initiative]

[0009] The present invention relates to novel treatments for patients with hematological malignancies. In some embodiments, a method for treating a hematological malignancy in a subject requiring treatment, wherein the subject is given a first amount of a compound of formula I: [ka] A method is disclosed comprising administering a pharmaceutically acceptable salt thereof and a second amount of a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. In this method, both the first and second amounts constitute a therapeutically effective dose. The compound of formula I may be referred to herein as “compound 1”. In some of these embodiments, a third amount of an additional chemotherapeutic agent is administered.

[0010] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is disclosed for use in the treatment of hematological malignancies in a subject, the treatment comprising separate, sequential, or concurrent administration to the subject of i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises iii) separate, sequential, or concurrent administration to the subject of iii) further chemotherapeutic agents.

[0011] In some embodiments, a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is disclosed for use in the treatment of hematological malignancies in a subject, the treatment comprising separate, sequential, or concurrent administration to the subject of i) the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, and ii) compound 1 or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises iii) separate, sequential, or concurrent administration to the subject of iii) further chemotherapeutic agents.

[0012] In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a drug for use in the treatment of hematological malignancies is disclosed, the treatment comprising, i) separate, sequential, or concurrent administration to the subject of, the drug comprising compound 1 or a pharmaceutically acceptable salt thereof, and, ii) separate, sequential, or concurrent administration of a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises, iii) separate, sequential, or concurrent administration to the subject of, the pharmaceutically acceptable salt thereof.

[0013] In the above embodiments, hematological malignancies may be lymphoma, leukemia, myeloma, myelodysplastic syndrome, and myeloproliferative disorders.

[0014] In some embodiments, a pharmaceutical product is disclosed comprising i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the pharmaceutical product further comprises iii) an additional chemotherapeutic agent.

[0015] In some embodiments, a kit is disclosed comprising a first pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof, a second pharmaceutical composition comprising a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, and instructions for using the first and second pharmaceutical compositions in combination. In some of these embodiments, the kit further comprises a third pharmaceutical composition comprising an additional chemotherapeutic agent, and the instructions are for using the first, second, and third pharmaceutical compositions in combination.

[0016] The combination of compound 1 and a BCL-2 inhibitor (and, if present, further chemotherapeutic agents) may be synergistic and / or otherwise result in improved treatment outcomes or patient prognosis, such as reduced side effects and improved tolerability, compared to current monotherapy or combination therapy. This is due to compound 1 blocking survival pathways that are activated when a BCL-2 inhibitor is administered, and vice versa. [Brief explanation of the drawing]

[0017] [Figure 1] This shows dose-response data for the combination of compound 1 and venetoclax in the HH cell line, a cutaneous T-cell lymphoma cell line. [Figure 2] This shows dose-response data for the combination of compound 1 and venetoclax in the SP53 cell line, a mantle cell lymphoma cell line. [Modes for carrying out the invention]

[0018] Compound 1 is Example 339 of WO2011 / 058149, which is incorporated herein by reference in its entirety. Its structure is as follows: [ka]

[0019] In IUPAC nomenclature, compound 1 above may be called 6-fluoro-3-(morpholine-4-ylcarbonyl)-1-[4-(morpholine-4-ylmethyl)phenyl]-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide. Alternatively, the structural formula shown above may be written as [6-fluoro-1-(4-morpholine-4-ylmethylphenyl)-5,5-dioxo-4,5-dihydro-1H-5λ6-thiochromeno[4,3-C]pyrazole-3-yl]morpholine-4-ylmethanone.

[0020] Compound 1 can be prepared and characterized as described in the published patent application WO2011 / 058149A1 (see compound 339 on p.69, preparation on pp.303-307, and characterization on p.481 together with pp.414-418), the information of which is specifically incorporated herein by reference.

[0021] Based on the process disclosed in WO2011 / 058149A1, the authors of Haselmayer 2014 describe a five-step preparation procedure for a compound. This procedure starts with the reaction of 8-fluoro-2,3-dihydro-4H-thiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide. The intermediate is cyclized with 4-(4-hydrazinylbenzyl)morpholine to form a pyrazole ring. The thioether is then oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid, followed by saponification of the ethyl ester to the corresponding acid, and subsequent coupling with morpholine to obtain the compound of formula I.

[0022] Alternatively, the intermediate of the reaction of 8-fluoro-2,3-dihydro-4H-thiochromen-4-one with diethyl oxalate in the presence of sodium ethoxide is cyclized with 4-hydrazinobenzoic acid. This benzoic acid is reduced using a borane-THF complex, and the thioether is oxidized to the corresponding sulfone by reaction with meta-chloroperbenzoic acid. The ethyl ester is saponified to the corresponding acid, and both the acid and the alcohol are chlorinated with excess thionyl chloride in the presence of dimethylformamide, and then coupled with morpholine to obtain Compound 1.

[0023] Compound 1 may be provided as a pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salts are known in the art. Some pharmaceutically acceptable salts of Compound 1 are described in WO2014 / 121901, which is incorporated herein by reference in its entirety.

[0024] As used herein, Compound 1 is provided as the anhydrous hemifumarate (the formula is illustrated). Its synthesis and characterization are described in WO2014 / 121901 (page 4). This is designated as solid form A1. A hemifumarate hydrate (H1) has also been identified. The anhydrous hemifumarate used is crystalline and has the powder X-ray peak list described in WO2014 / 121901. The discovery of the present invention is not limited to the use of this solid form, although it is understood to be preferred.

[0025] Thus, in some cases, Compound 1 is administered as the hemifumarate (Formula Ia). However, it is understood that the present invention is not so limited and other solid forms (e.g., other pharmaceutically acceptable salts) are also contemplated.

Chemical Formula

[0026] Haselmayer 2014 also describes the characterization of the compound as a highly selective PI3Kδ inhibitor. Tarantelli 2022 further describes the activity of Compound 1 in lymphoma cell lines, and Carlo-Stella 2022 reports data on the first dose cohort of the clinical study of Compound 1 in FL patients (NCT04328844).

[0027] BCL-2 is a family of regulatory proteins encoded by the BCL-2 gene that regulates cell death. The BCL-2 family can be subclassified into different groups based on their forms and Bcl-2 homology (BH) domains and consists of anti-apoptotic and pro-apoptotic members (Ploumaki 2023). The term BCL-2 inhibitor includes agents that target and selectively inhibit anti-apoptotic protein members of the BCL-2 family such as BCL-2, BCL-W, BCL-XL, MCL-1, A1, and BFL-1.

[0028] Examples of BCL-2 inhibitors include, but are not limited to, navitoclax, obatoclax mesylate, venetoclax, lisafotoclax, LP-118, S55746, S64315, or parsitoclax.

[0029] Venetoclax (also known as ABT-199 and marketed under the brand names Venclexta and Venclyxto) is an orally administered, bioavailable BCL-2 inhibitor with high selectivity for the BCL-2 protein and significantly lower affinity for the BCL-W and BCL-XL proteins (Lasica 2021). It is used to treat patients with several hematological malignancies, including CLL, AML, small lymphocytic lymphoma, and multiple myeloma (MM).

[0030] The venetocracus has the following structure: [ka]

[0031] The IUPAC name for venetoclax is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide.

[0032] Navitoclax (also known as ABT-263) is an oral BCL-2 inhibitor that has high affinity for BCL-2 and BCL-XL proteins, but not for MCL-1 protein (Anuar 2020). Navitoclax treatment has been investigated in patients with several hematological malignancies, including CLL, DLBCL, MCL, FL, SLL, classical Hodgkin lymphoma, NK / T-cell lymphoma, and MZL. Common toxic effects observed with navigationoclax include gastrointestinal disorders, infections, fatigue thrombocytopenia, lymphopenia, and increased aminotransferases.

[0033] Navitocrax has the following structure: [ka]

[0034] Navitoclax has the preferred IUPAC name 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazine-1-yl)-N-(4-{[(2R)-4-(morpholine-4-yl)-1-(phenylsulfanyl)butan-2-yl]amino}-3-(trifluoromethanesulfonyl)benzene-1-sulfonyl)benzamide.

[0035] The compound and a method for producing it are disclosed in U.S. Patent Application Publication No. 2007 / 0027135 and WO2007 / 040650, which are incorporated herein by reference in their entirety.

[0036] Ovatoclax mesylate is an intravenously administered BCL-2 inhibitor that binds to several BCL-2 protein family members: BCL-2, BCL-XL, BCL-w, BCL-B, BFL-1, and MCL-1 (Goard 2013). Ovatoclax mesylate treatment has been investigated in patients with AML, ALL, CLL, myelodysplasia, and myelofibrosis. Neurological symptoms are the most common toxicity associated with ovatoclax mesylate. Other relatively common observed toxicities include gastrointestinal symptoms, dyspnea, and cough.

[0037] Obatocracus has the following structure: [ka]

[0038] The IUPAC name for ovatocracus is 2-(2-((3,5-dimethyl-1H-pyrrole-2-yl)methylene)-3-methoxy-2H-pyrrole-5-yl)-1H-indole.

[0039] Palcitocrax (also known as APG-1252) is a novel intravenously administered BCL-2 inhibitor that binds to BCL-2 and BCL-XL proteins (Lakhani 2020). It is being investigated in patients with metastatic solid tumors. Thrombocytopenia and elevated liver enzymes are the most common observed toxicities.

[0040] The parsitocrax has the following structure: [ka]

[0041] The IUPAC name for palcitocrax is 3-[1-[(3R)-3-[4-[[4-[4-[3-[2-(4-chlorophenyl)-5-methyl-4-methylsulfonyl-1-propane-2-ylpyrrole-3-yl]-5-fluorophenyl]piperazine-1-yl]phenyl]sulfamoyl]-2-(trifluoromethylsulfonyl)anilino]-4-phenylsulfanylbutyl]piperidine-4-carbonyl]oxypropylphosphonic acid.

[0042] Lisaftoclax (also known as APG-2575) is a novel orally administered, bioavailable BCL-2 inhibitor that binds to BCL-2 and BCL-XL (Davids 2021). It is being investigated in patients with CLL, SLL, and other hematological malignancies (Ailawadhi 2021, NCT05147467). The most common toxicities include neutropenia, anemia, fatigue, diarrhea, and nausea.

[0043] Lisaftoclax has the following structure: [ka]

[0044] The IUPAC name for lisaftoclax is (S)-N-((4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridine-5-yl)oxy)-4-(4-((6-(4-chlorophenyl)spiro[3,5]non-6-en-7-yl)methyl)piperazine-1-yl)benzamide.

[0045] Lisaftoclax is compound 6 of WO2018 / 027097. Its synthesis and characterization are described in Example 6 (pages 87-89) of WO2018 / 027097.

[0046] LP-118 is a novel orally administered, bioavailable BCL-2 inhibitor that binds to BCL-2 and BCL-XL (Ravikrishnan 2021). It will be investigated in patients with multiple hematological malignancies, including non-Hodgkin lymphoma, Richter transformation, MM, T-cell lymphocytic leukemia, AML, ALL, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, MF, CLL, SLL, chronic myelomonocytic leukemia-2, and myelodysplastic neoplasms in the acute transformation phase (NCT04771572).

[0047] The structure of LP-118 has not yet been disclosed. It is likely to be covered by the following Markush structure described in U.S. Patent No. 10,377,755: [ka]

[0048] S55746 (also known as BCL201) is a novel orally administered, bioavailable BCL-2 inhibitor that binds to BCL-2. It has been investigated in FL and MCL (NCT02603445).

[0049] S55746 has the following structure: [ka]

[0050] The IUPAC name for S55746 is (S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindridine-1-carboxamide.

[0051] S64315 (also known as MIK665) is a novel intravenously administered BCL-2 inhibitor that binds to MCL-1. It is being investigated in patients with AML (NCT04629443). S64315 has the following structure: [ka]

[0052] The IUPAC name for S64315 is (R)-2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazine-1-yl)ethoxy)phenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-3-(2-((2-(2-methoxyphenyl)pyrimidine-4-yl)methoxy)phenyl)propanoic acid.

[0053] S63845 is a small molecule BCL-2 inhibitor that specifically binds to MCL-1 (Kotschy 2016). It is being investigated in patients with AML (NCT04629443). S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukemia, and lymphoma cells. S63845 has the following structure: [ka]

[0054] The IUPAC name for S63845 is (R)-2-((5-(3-chloro-2-methyl-4-(2-(4-methylpiperazine-1-yl)ethoxy)phenyl)-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidine-4-yl)oxy)-3-(2-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-yl)methoxy)phenyl)propanoic acid.

[0055] In some embodiments, a further chemotherapeutic agent may be a second BCL-2 inhibitor.

[0056] In other embodiments, further chemotherapeutic agents may be DNA methyltransferase inhibitors. DNA methylation, mediated by DNA methyltransferase, is a crucial epigenetic process that regulates gene expression and plays a vital role in the silencing of tumor suppressor genes in cancer. Therefore, it has become a promising therapeutic target for cancer treatment, particularly for hematological malignancies (Zhang 2022), and DNMT inhibitors can also enhance the immunogenicity of tumor cells by promoting tumor antigen presentation or by enhancing the function of cytotoxic T cells. Thus, DNMT is also a reasonable therapeutic target in hematological malignancies. However, first-generation DNMT inhibitors are characterized by high toxicity, low selectivity, and low bioavailability.

[0057] Examples of DNMT inhibitors include, but are not limited to, 5-azacitidine (azacitidine (AZA)), 5-aza-2'-deoxycytidine (decitabine (DAC)), clofarabine, gaudecitabine, and GSK3685032.

[0058] 5-Azacitidine (azacitidine (AZA)) has the following structure: [ka]

[0059] 5-Azacitidine is a cytarabine derivative synthesized in 1964 and first approved by the FDA in 2004.

[0060] Decitabine has the following structure: [ka]

[0061] Decitabine was approved by the FDA in 2006. Its inhibitory activity against DNMT is 30 times that of azacitidine (Zhang 2022).

[0062] Clopharabine has the following structure: [ka]

[0063] Clofarabine is a purine nucleoside DNMTi approved by the FDA in 2004.

[0064] Guadecitabine (SGI-110) has the following structure: [ka] It is a dinucleotide derivative of decitabine.

[0065] GSK3685032 has the following structure: [ka] It is described in Pappalardi 2021. It acts as a competitive inhibitor of DNMT1 by competing with the DNMT1 active site loop and target recognition domain for integration into semimethylated DNA.

[0066] Other DNMT inhibitors include, but are not limited to, RX-3117 (TV-1360), 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacitidine (DHAC), fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate (EGCG), hydralazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebralin, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, psammaprin A, psammaprin G, and UVI5008.

[0067] definition The term "pharmaceutical composition" includes a composition comprising an active ingredient and a pharmaceutically acceptable excipient, carrier, or diluent, wherein the active ingredient is compound 1 or a pharmaceutically acceptable salt thereof, or a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, or a further chemotherapeutic agent. The term "pharmaceutically acceptable excipient, carrier, or diluent" includes compounds, materials, compositions, and / or dosage forms that are within the range of sound medical judgment, as confirmed by those skilled in the art, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications. In some embodiments, the pharmaceutical composition is a solid dosage form such as a capsule, tablet, granule, powder, or pouch. In some embodiments, the pharmaceutical composition is in the form of a sterile injectable solution in one or more aqueous or non-aqueous non-toxic and parenterally acceptable buffer systems, diluents, solubilizers, co-solvents, or carriers. Sterile injection preparations may also be sterile injection-ready aqueous or oily suspensions, or suspensions in non-aqueous diluents, carriers, or co-solvents, which may be formulated according to known procedures using one or more suitable dispersants or wetting and suspending agents. Pharmaceutical compositions may be solutions for IV bolus / injection, or lyophilized systems (either alone or with excipients) for reconstitution using buffer systems with or without other excipients. Lyophilized materials may be prepared from non-aqueous or aqueous solvents. Dosage forms may also be concentrates for further dilution for subsequent injections.

[0068] The terms “to treat,” “to treat,” and “treatment” include reducing or inhibiting tumor cells of a hematological malignancy in a subject, improving one or more symptoms of a hematological malignancy in a subject, or slowing or delaying the progression of a hematological malignancy in a subject. The terms “to treat,” “to treat,” and “treatment” also include reducing or inhibiting tumor growth or proliferation of cancer cells in a subject.

[0069] The terms “to treat,” “to treat,” and “treatment” include a reduction in the baseline activity of a biological activity or process.

[0070] The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, such as a human. In some embodiments, the subject suffers from a hematological malignancy.

[0071] The term "therapeutic dose" includes the amount of Compound 1 and the BCL-2 inhibitor that together induce a biological or medical response in a subject, such as a reduction or inhibition of tumor cells, improvement of symptoms of a hematological malignancy, or slowing or delaying the progression of a hematological malignancy. In some embodiments, the term "therapeutic dose" includes the amount of Compound 1 and the BCL-2 inhibitor that together are effective in at least partially mitigating, inhibiting and / or improving a hematological malignancy in a subject, or in inhibiting tumor cells and / or reducing or inhibiting the proliferation of cancer cells. In some embodiments, the term "therapeutic dose" includes the amount of Compound 1, the BCL-2 inhibitor, and further chemotherapeutic agents that together are effective in at least partially mitigating, inhibiting and / or improving a hematological malignancy in a subject, or in inhibiting tumor cells and / or reducing or inhibiting the proliferation of cancer cells.

[0072] In some embodiments, a method for treating hematological malignancies in a subject requiring treatment is disclosed, comprising administering to the subject a first amount of compound 1 or a pharmaceutically acceptable salt thereof, and a second amount of a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. In this method, both the first and second amounts constitute a therapeutically effective dose. In some of these embodiments, a third amount of an additional chemotherapeutic agent is administered.

[0073] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is disclosed for use in the treatment of hematological malignancies in a subject, the treatment comprising separate, sequential, or concurrent administration to the subject of i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises iii) separate, sequential, or concurrent administration to the subject of iii) further chemotherapeutic agents.

[0074] In some embodiments, a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is disclosed for use in the treatment of hematological malignancies in a subject, the treatment comprising separate, sequential, or concurrent administration to the subject of i) the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, and ii) compound 1 or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises iii) separate, sequential, or concurrent administration to the subject of iii) further chemotherapeutic agents.

[0075] In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a drug for use in the treatment of hematological malignancies in a subject is disclosed, the treatment comprising separate, sequential, or concurrent administration to the subject of i) the drug comprising compound 1 or a pharmaceutically acceptable salt thereof, and ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises iii) separate, sequential, or concurrent administration to the subject of iii) further chemotherapeutic agents.

[0076] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof, and a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof (and, if present, further chemotherapeutic agents) are administered separately, sequentially, or concurrently in a treatment cycle. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered sequentially in a treatment cycle, and the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is also administered sequentially in a treatment cycle. In some of these embodiments, further chemotherapeutic agents are also administered sequentially in a treatment cycle.

[0077] In some embodiments, the BCL-2 inhibitor is selected from venetoclax, navitoclax, ovatoclax mesylate, palcitoclax, risaftoclax, LP-118, S55746, or S64315. In further embodiments, the BCL-2 inhibitor is venetoclax.

[0078] The terms "continuous" or "sequentially" refer to administering the therapeutic agent, e.g., compound 1, at regular intervals without interruption or cessation, i.e., without gap days. A "gap day" means a day on which the therapeutic agent is not administered.

[0079] As used herein, “cycle,” “treatment cycle,” or “medication schedule” refers to a period of combination therapy repeated on a regular schedule. For example, treatment may be administered over one, two, or three weeks in which compound 1 and the BCL-2 inhibitor are administered in coordination. In some embodiments, the treatment cycle is approximately one week to three months. In some embodiments, the treatment cycle is approximately five days to one month. In some embodiments, the treatment cycle is approximately one week to three weeks. In some embodiments, the treatment cycle is approximately one week, ten days, two weeks, three weeks, four weeks, two months, or three months.

[0080] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof, and a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof (and, if present, further chemotherapeutic agents) are administered to a human subject in one or more treatment cycles, e.g., a treatment course. A “treatment course” includes multiple treatment cycles that can be repeated on a regular schedule or adjusted as a tapering schedule as the patient’s disease progression is monitored. For example, a patient’s treatment cycles may have longer treatment periods and / or shorter rest periods at the start of the treatment course (e.g., when the patient is first diagnosed), and as the cancer goes into remission, the rest periods are extended, thereby increasing the length of a single treatment cycle. The duration of treatment and rest in a treatment cycle, the number of treatment cycles, and the length of time of a treatment course can be determined and adjusted throughout the treatment course by those skilled in the art, based on the patient’s disease progression, treatment resistance, and prognosis. In some embodiments, the method includes 1 to 10 treatment cycles. In some embodiments, the method includes 2 to 8 treatment cycles.

[0081] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered for 28 days in a 28-day treatment cycle.

[0082] Dosage In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, compound 1 as hemi-fumarate is administered at a dose of 40 mg per day. In some embodiments, compound 1 as hemi-fumarate is administered at a dose of 80 mg per day.

[0083] In some embodiments, the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is in capsule form. In some embodiments, the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day.

[0084] In some embodiments, the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is administered as an intravenous (IV) infusion.

[0085] In some embodiments, the further chemotherapeutic agent is administered orally. In some embodiments, the further chemotherapeutic agent is in tablet form. In some embodiments, the further chemotherapeutic agent is in capsule form. In some embodiments, the further chemotherapeutic agent is administered at a dose of 10 mg to 1 g per day.

[0086] In some embodiments, compound 1 and the BCL-2 inhibitor are taken together on an empty stomach, 2 hours prior and 1 hour after eating.

[0087] In some embodiments, compound 1 is taken on an empty stomach without food 2 hours prior and 1 hour after, while the BCL-2 inhibitor is taken with a meal, so at least 2 hours prior or 1 hour after compound 1.

[0088] In some embodiments, the BCL-2 inhibitor is administered weekly.

[0089] In some embodiments, a pharmaceutical product is disclosed comprising i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof, and the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, exist in a single dosage form. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof, and the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, exist as separate dosage forms. In some of these embodiments, the pharmaceutical product further comprises iii) an additional chemotherapeutic agent.

[0090] In some embodiments, a kit is disclosed comprising a first pharmaceutical composition comprising compound 1 or a pharmaceutically acceptable salt thereof, a second pharmaceutical composition comprising a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, and instructions for using the first and second pharmaceutical compositions in combination. In some of these embodiments, the kit further comprises a third pharmaceutical composition comprising an additional chemotherapeutic agent, and the instructions are for using the first, second, and third pharmaceutical compositions in combination.

[0091] In some embodiments, the BCL-2 inhibitor is selected from venetoclax, navitoclax, ovatoclax mesylate, palcitoclax, lisaftoclax, LP-118, S55746, or S64315.

[0092] The dosing schedule for venetoclax as monotherapy, administered once daily, is tumor-dependent but typically involves increasing the dose over the first few days or weeks of treatment (Juarez-Salcedo 2019). For example, in patients with CLL, venetoclax is started at a 20 mg dose level in week 1, and the dose level is increased to 50 mg in week 2, 100 mg in week 3, 200 mg in week 4, and up to 400 mg from week 5 onward. In AML, venetoclax dosing is increased depending on concomitant medications, starting from 100 mg on day 1, up to 200 mg on day 2, up to 400 mg on day 3, and up to 400 mg or 600 mg from day 4 onward. Dose reduction of venetoclax may be necessary to manage venetoclax-related toxicities such as oncolytic syndrome and grade 3 neutropenia and / or non-hematological toxicities. Venetoclax tablets are available in three strengths (10, 50, and 100 mg) and are recommended to be taken daily at approximately the same time with water and food.

[0093] In some embodiments, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. Venetoclax is administered orally, for example, in tablet or capsule form. In some embodiments, venetoclax is administered in doses of 10 mg to 400 mg per day, 10 mg to 200 mg per day, 20 mg to 400 mg per day, or 10 mg to 100 mg per day. In some embodiments, venetoclax is administered in doses of 20 mg, 50 mg, 100 mg, 200 mg, or 400 mg per day. In some embodiments, venetoclax is administered once daily in doses of 20 mg, 50 mg, 100 mg, 200 mg, or 400 mg. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered, for example, starting at 20 mg per day in the first week, with increasing doses over the first few weeks of treatment, with dose levels increasing to 50 mg per day in the second week, 100 mg per day in the third week, 200 mg per day in the fourth week, and up to 400 mg per day from the fifth week onward. In another embodiment, venetoclax or a pharmaceutically acceptable salt thereof is administered at 100 mg on day 1, up to 200 mg on day 2, up to 400 mg on day 3, and up to 400 mg or 600 mg from day 4 onward. In some embodiments, venetoclax or a pharmaceutically acceptable salt thereof is administered at 400 mg per day.

[0094] In some embodiments, a pharmaceutical product is disclosed comprising i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) venetoclax or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and venetoclax or a pharmaceutically acceptable salt thereof exist in a single dosage form. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and venetoclax or a pharmaceutically acceptable salt thereof exist as separate dosage forms.

[0095] In some embodiments, the BCL-2 inhibitor is navitoclax. Navitoclax is administered orally, for example, as a tablet or capsule. The dosing schedule for navitoclax as monotherapy taken daily also typically consists of a dose-escalation regimen over one or two weeks, reaching a final dose of 250 mg or 325 mg per day. In some embodiments, navitoclax is administered in doses of 125–325 mg per day, or 250–325 mg per day. In some embodiments, navitoclax is administered in a dose of 250 mg per day. In some embodiments, navitoclax is administered in a dose of 325 mg per day. In some embodiments, the daily dose of navitoclax is increased from an initial starting dose to a final dose level.

[0096] In some embodiments, a pharmaceutical product is disclosed comprising i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) navitoclax or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and navitoclax or a pharmaceutically acceptable salt thereof exist in a single dosage form. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and navitoclax or a pharmaceutically acceptable salt thereof exist as separate dosage forms.

[0097] In some embodiments, the BCL-2 inhibitor is ovatoclax mesylate. Ovatoclax mesylate is administered intravenously. The ovatoclax mesylate infusion is typically given over a 24-hour period, and a typical dosing schedule for ovatoclax mesylate infusion consists of a set dose of 28 mg per square meter of body surface area per day for up to 4 days every two weeks, or 60 mg every two weeks. In some embodiments, ovatoclax mesylate is administered at a dose of 28 mg per square meter of body surface area per day. In some embodiments, ovatoclax mesylate is administered at a dose of 60 mg every two weeks.

[0098] In some embodiments, the BCL-2 inhibitor is palcitoclax. Palcitoclax is administered intravenously, and its recommended phase 2 dose is determined to be 240 mg administered once weekly. In some embodiments, palcitoclax is administered intravenously at doses of 100–300 mg once weekly. In some embodiments, palcitoclax is administered at doses of 120 or 240 mg once weekly.

[0099] In some embodiments, the BCL-2 inhibitor is lisaftoclax. Lisaftoclax is administered orally, for example, as a tablet or capsule. In some embodiments, lisaftoclax is administered daily in doses of 200–600 mg, 200–400 mg, 300–600 mg, 300 mg, or 600 mg.

[0100] In some embodiments, a pharmaceutical product is disclosed comprising i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) lisaftoclax or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and lisaftoclax or a pharmaceutically acceptable salt thereof exist in a single dosage form. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and lisaftoclax or a pharmaceutically acceptable salt thereof exist as separate dosage forms.

[0101] In some embodiments, the BCL-2 inhibitor is LP-118. LP-118 is administered orally, for example, in tablet or capsule form. In some embodiments, LP-118 is administered in doses of 10 to 600 mg per day. In some embodiments, LP-118 is administered in doses of 20 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, or 600 mg per day. In some embodiments, LP-118 is administered in doses of 100 mg or 200 mg per day.

[0102] In some embodiments, the BCL-2 inhibitor is S55746. S55746 is administered orally, for example, as a tablet or capsule. In some embodiments, S55746 is administered in doses of 50 to 1500 mg per day. In some embodiments, S55746 is administered in doses of up to approximately 100 mg, up to approximately 200 mg, up to approximately 300 mg, up to approximately 400 mg, or up to approximately 500 mg per day. In some embodiments, S55746 is administered once daily in doses of 50 to 1500 mg.

[0103] In some embodiments, the BCL-2 inhibitor is S64315. S64315 is administered intravenously. In some embodiments, S64315 is administered once per week in doses of 50 to 250 mg. In some embodiments, S64315 is administered once per week in doses of up to 100 mg. In some embodiments, S64315 is administered once per week in doses of up to 200 mg.

[0104] In some embodiments, hematological malignancies include lymphomas such as cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenström macroglobulinemia.

[0105] In some embodiments, hematological malignancies are leukemias, including ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorders, and myelofibrosis.

[0106] In some embodiments, hematological malignancies include myelomas, including multiple myeloma.

[0107] While we do not wish to be constrained by theory, the combination of compound 1 and a BCL-2 inhibitor may be beneficial for patients who do not respond to or are refractory to either compound 1 or the BCL-2 inhibitor. In addition, the combination of compound 1 and the BCL-2 inhibitor may deepen or make the response to either compound 1 or the BCL-2 inhibitor more sustained. Furthermore, the combination of compound 1 and the BCL-2 inhibitor may allow for dose reduction of the BCL-2 inhibitor, resulting in improved tolerability and quality of life.

[0108] Furthermore, the above reasoning can be equally applied if the additional chemotherapeutic agent is a second BCL-2 inhibitor. If the additional chemotherapeutic agent is a DNA methyltransferase inhibitor, the combination may be beneficial for patients who do not respond to or are refractory to any of compound 1, the BCL-2 inhibitor, and the DNMT inhibitor. In addition, the combination of compound 1, the BCL-2 inhibitor, and the DNMT inhibitor may deepen or make the response to compound 1, the BCL-2 inhibitor, or the DNMT inhibitor more sustained. Moreover, the combination of compound 1, the BCL-2 inhibitor, and the DNMT inhibitor may allow for dose reduction of the BCL-2 inhibitor or the DNMT inhibitor, resulting in improved tolerability and quality of life.

[0109] Method of the present invention As will be described in more detail below, the inventors have surprisingly found that the combination of compound 1 and a BCL-2 inhibitor has a synergistic effect on the proliferation of hematological malignant cell lines. Therefore, a combination therapy with improved antiproliferative activity can be provided.

[0110] Secondly, the inventors have surprisingly found that the synergistic antitumor activity of the combination of compound 1 and the BCL-2 inhibitor is not limited to specific hematological malignancies. Therefore, it is possible to provide a combination therapy with improved therapeutic activity across multiple hematological malignancies.

[0111] Furthermore, the inventors have surprisingly found that the combination of compound 1 and a BCL-2 inhibitor results in tumor cell death that is not observed with either inhibitor alone. Therefore, a combination that can reduce tumor volume can be provided.

[0112] Furthermore, the inventors have surprisingly found that the combination of compound 1 and the BCL-2 inhibitor already exhibits a synergistic effect at doses below therapeutic levels. Therefore, a combination with improved tolerability may be provided. [Examples]

[0113] The compounds of this application will be further described here with reference to the following non-limiting examples.

[0114] Example 1. Efficacy of Compound 1 in combination with the BCL-2 inhibitor venetoclax in an in vitro assay using cutaneous T-cell lymphoma (CTCL) cell line HH and mantle cell lymphoma (MCL) cell line SP53. HH(CRL-2105) and SP53 cells were exposed to increasing doses of compound 1, increasing doses of venetoclax, and increasing doses of a combination of compound 1 and venetoclax. Venetoclax was used at a maximum concentration of 10 μM according to an 8x dose-response design based on a 1:4 compound dilution + untreated control. Compound 1 was used at a maximum concentration of 10 μM according to an 8x dose-response design based on a 1:3 compound dilution + untreated control.

[0115] Cells were incubated at 37°C and 5% CO2 for 72 hours. The antiproliferative effects of single and combination therapies were determined by adding 20 μL of MTT[3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] reagent (Sigma Aldrich, Buchs, Switzerland) to each well. The plates were incubated at 37°C for 4 hours, followed by the addition of 50 μL of sodium dodecyl sulfate (SDS) (250 μM SDS, 0.21% fuming HCl) lysis buffer. Lysized cells were held overnight, and absorbance was read at 570 nm using a Cytation 3 instrument (BioTek, Winoosku, VT, USA). The combined effects were determined according to the Chou-Talalay combination index (CI) (Chou 2008, Chou 2010) and calculated using the Synergy R package (Lee 2007). The effects of combinations were defined as follows: strongly synergistic for CI values ​​below <0.3, synergistic for CI values ​​between 0.3 and 0.9, additive for CI values ​​between 0.9 and 1.1, and antagonistic for CI values ​​>1.1.

[0116] Data from two representative experiments are shown in Figures 1 and 2.

[0117] The combination of compound 1 and venetoclax in HH is strongly synergistic with a median CI of 0.006. The combination of compound 1 and venetoclax in SP53 is strongly synergistic with a median CI of 0.77.

[0118] Example 2. Efficacy of Compound 1 in combination with a BCL-2 inhibitor in an in vitro assay using several different blood cell lines. Cell lines from different hematological malignancies were exposed to increasing doses of compound 1, increasing doses of BCL-2 inhibitors, and increasing doses of combinations of compound 1 and BCL-2 inhibitors. Venetoclax, S55746, S64315, and S63845 were used at a maximum concentration of 10 μM according to an 8-fold dose response based on a 1:4 compound dilution + untreated control. Compound 1 was used at a maximum concentration of 10 μM according to an 8-fold dose response based on a 1:3 compound dilution + untreated control.

[0119] Cells were incubated at 37°C and 5% CO2 for 72 hours. The antiproliferative effects of single and combination therapies were determined by adding 20 μL of MTT[3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] reagent (Sigma Aldrich, Buchs, Switzerland) to each well. The plates were incubated at 37°C for 4 hours, followed by the addition of 50 μL of sodium dodecyl sulfate (SDS) (250 μM SDS, 0.21% fuming HCl) lysis buffer. Lysized cells were held overnight, and absorbance was read at 570 nm using a Cytation 3 instrument (BioTek, Winoosku, VT, USA). The combined effects were determined according to the Chou-Talalay combination index (CI) (Chou 2008, Chou 2010) and calculated using the Synergy R package (Lee 2007). The effects of combinations were defined as follows: strongly synergistic for CI values ​​below <0.3, synergistic for CI values ​​between 0.3 and 0.9, additive for CI values ​​between 0.9 and 1.1, and antagonistic for CI values ​​>1.1.

[0120] Table 1 shows the CI values ​​from representative experiments. [Table 1]

[0121] References Numerous publications have been cited above in order to more fully describe and disclose the present invention and the state of the art to which it pertains. A complete citation of these references is provided below. The entirety of each of these references is incorporated herein. [Table 2-1] [Table 2-2] [Table 2-3]

[0122] Description 1. A method for treating a hematological malignancy in a subject requiring treatment, wherein the subject is given a first amount of a compound of formula I: [ka] The method comprising administering a pharmaceutically acceptable salt thereof and a second amount of a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, wherein both the first and second amounts constitute a therapeutically effective dose. 2. The method according to Description 1, wherein the hematological malignancy is lymphoma, leukemia, myeloma, myelodysplastic syndrome, or myeloproliferative disorder. 3. The method according to Description 2, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, or Waldenström macroglobulinemia. 4. The method according to Description 2, wherein the leukemia is ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis. 5. The method according to any one of descriptions 1 to 4, wherein the BCL-2 inhibitor is selected from navitoclax, ovatoclax mesylate, venetoclax, risaftoclax, LP-118, S55746, S64315, or palcitoclax. 6. The method according to any one of descriptions 1 to 5, wherein compound 1 is administered at a dose of 40 mg or 80 mg per day as hemifumarate. 7. The method according to any one of descriptions 1 to 6, wherein the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day. 8. The method according to any one of descriptions 1 to 7, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. 9. The method according to any one of descriptions 1 to 8, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, administered in doses of 20 mg, 50 mg, 100 mg, 200 mg, or 400 mg per day. 10. The method according to any one of descriptions 1 to 7, wherein the BCL-2 inhibitor is navitoclax. 11. The method according to any one of descriptions 1 to 10, wherein a third dose of an additional chemotherapeutic agent is administered. 12. The method according to description 11, wherein the further chemotherapeutic agent is a second BCL-2 inhibitor. 13. The method according to description 11, wherein the further chemotherapeutic agent is a DNA methyltransferase inhibitor. 14. The DNA methyltransferase inhibitors include 5-azacitidine, 5-aza-2'-deoxycytidine, clofarabine, gaudecitabine, and GSK3685032. The method according to Description 13, selected from RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacitidine, fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate, hydralazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebralin, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, psammaprin A, psammaprin G, and UVI5008. 15. Compounds of formula I for use in the treatment of hematological malignancies in the subject: [ka] or a pharmaceutically acceptable salt thereof, for use in the treatment, wherein the treatment comprises separate, sequential, or concurrent administration to the subject of i) compound 1 or a pharmaceutically acceptable salt thereof, and ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. 16. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Description 15, wherein the hematological malignancy is lymphoma, leukemia, myeloma, myelodysplastic syndrome, or myeloproliferative disorder. 17. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Description 16, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, or Waldenström macroglobulinemia. 18. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Description 16, wherein the leukemia is ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis. 19. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of descriptions 15 to 18, wherein the BCL-2 inhibitor is selected from navitoclax, ovatoclax mesylate, venetoclax, risaftoclax, LP-118, S55746, S64315, or palcitoclax. 20. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of descriptions 15-19, administered in doses of 40 mg or 80 mg per day as hemi-fumarate. 21. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of descriptions 15 to 20, wherein the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day. 22. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of descriptions 15 to 21, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. 23. The BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, administered in doses of 20 mg, 50 mg, 100 mg, 200 mg, or 400 mg per day, for use as described in any one of descriptions 15 to 22. 24. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of descriptions 15 to 23, wherein the BCL-2 inhibitor is navitoclax. 25. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of descriptions 15 to 24, wherein the treatment further comprises iii) separate, sequential, or concurrent administration of further chemotherapeutic agents to the subject. 26. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Description 25, wherein the further chemotherapeutic agent is a second BCL-2 inhibitor. 27. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Description 25, wherein the further chemotherapeutic agent is a DNA methyltransferase inhibitor. 28. The DNA methyltransferase inhibitors include 5-azacitidine, 5-aza-2'-deoxycytidine, clofarabine, gaudecitabine, and GSK3685032. Compound 1 or a pharmaceutically acceptable salt thereof for use as described in Description 27, selected from RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacitidine, fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate, hydralazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebralin, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, psammaprin A, psammaprin G, and UVI5008. 29. A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of hematological malignancies in a subject, wherein the treatment involves i) the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, and ii) a compound of formula I to the subject: [ka] A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment thereof, comprising separate, sequential, or concurrent administration of such pharmaceutically acceptable salt thereof. 30. The BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use as described in Description 29, wherein the hematological malignancy is lymphoma, leukemia, myeloma, myelodysplastic syndrome, or myeloproliferative disorder. 31. A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use as described in Description 30, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, or Waldenström macroglobulinemia. 32. The BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use as described in Description 30, wherein the leukemia is ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis. 33. A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of descriptions 29 to 32, wherein the BCL-2 inhibitor is selected from navitoclax, ovatoclax mesylate, venetoclax, risaftoclax, LP-118, S55746, S64315, or palcitoclax. 34. Compound 1 is administered in doses of 40 mg or 80 mg per day as a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use as described in any one of descriptions 29-33. 35. The BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of descriptions 29 to 34, wherein the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose of 10 mg to 1 g per day. 36. A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of descriptions 29 to 35, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. 37. The BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, administered in doses of 20 mg, 50 mg, 100 mg, 200 mg, or 400 mg per day, for use as described in any one of descriptions 29 to 36. 38. The BCL-2 inhibitor for use according to any one of descriptions 29 to 36, wherein the BCL-2 inhibitor is navitoclax, or a pharmaceutically acceptable salt thereof. 39. A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of descriptions 29 to 38, wherein the treatment further comprises iii) separate, sequential, or concurrent administration of further chemotherapeutic agents to the subject. 40. The BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use as described in Description 39, wherein the further chemotherapeutic agent is a second BCL-2 inhibitor. 41. The BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use as described in Description 39, wherein the further chemotherapeutic agent is a DNA methyltransferase inhibitor. 42. The DNA methyltransferase inhibitors include 5-azacitidine, 5-aza-2'-deoxycytidine, clofarabine, gaudecitabine, and GSK3685032. BCL-2 inhibitors or pharmaceutically acceptable salts thereof for use as described in Description 41, selected from RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacitidine, fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate, hydralazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebralin, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, pusanmaprin A, pusanmaprin G, and UVI5008. 43. Compounds of formula I in the manufacture of drugs for use in the treatment of hematological malignancies: [ka] or use of a pharmaceutically acceptable salt thereof, wherein the treatment comprises separate, sequential, or simultaneous administration to the subject of: i) the agent comprising compound 1 or a pharmaceutically acceptable salt thereof; and ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof. 44. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in description 43, wherein the hematological malignancy is lymphoma, leukemia, myeloma, myelodysplastic syndrome, or myeloproliferative disorder. 45. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in description 44, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, or Waldenström macroglobulinemia. 46. ​​Use of compound 1 or a pharmaceutically acceptable salt thereof as described in description 44, wherein the leukemia is ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis. 47. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of descriptions 43 to 46, wherein the BCL-2 inhibitor is selected from navitoclax, ovatoclax mesylate, venetoclax, lisaftoclax, LP-118, S55746, S64315, or palcitoclax. 48. Use of Compound 1 or a pharmaceutically acceptable salt thereof as described in any one of descriptions 43-47, administered in doses of 40 mg or 80 mg per day as hemi-fumarate. 49. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of descriptions 43 to 48, wherein the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day. 50. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of descriptions 43 to 49, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. 51. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of descriptions 43 to 50, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, administered in doses of 20 mg, 50 mg, 100 mg, 200 mg, or 400 mg per day. 52. Use of compound 1 or a pharmaceutically acceptable salt thereof as described in any one of descriptions 43 to 49, wherein the BCL-2 inhibitor is navitoclax. 53. Use of compound 1 or a pharmaceutically acceptable salt thereof for use as described in any one of descriptions 43 to 52, wherein the treatment further comprises iii) separate, sequential, or concurrent administration of further chemotherapeutic agents to the subject. 54. Use of compound 1 or a pharmaceutically acceptable salt thereof for the use described in description 53, wherein the further chemotherapeutic agent is a second BCL-2 inhibitor. 55. Use of compound 1 or a pharmaceutically acceptable salt thereof for use as described in description 53, wherein the further chemotherapeutic agent is a DNA methyltransferase inhibitor. 56. The DNA methyltransferase inhibitor is 5-azacitidine, 5-aza-2'-deoxycytidine, clofarabine, gaudecitabine, GSK3685032 Use of compound 1 or a pharmaceutically acceptable salt thereof for the use described in description 55, selected from RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacitidine, fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate, hydralazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebralin, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, psammaprin A, psammaprin G, and UVI5008. 57.i) Compounds of formula I: [ka] a pharmaceutical product comprising: ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutically acceptable salt thereof. 58. The pharmaceutical product described in description 57, wherein the pharmaceutical product further comprises (iii) a further chemotherapeutic agent. 59. Compounds of formula I: [ka] A kit comprising: a first pharmaceutical composition comprising a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination. 60. The kit according to description 59, wherein the kit further comprises a third pharmaceutical composition comprising a further chemotherapeutic agent, and the instructions are for the combined use of the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition.

Claims

1. Compound of formula I for use in the treatment of hematological malignancies in the subject: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, for use in the treatment, wherein the treatment comprises separate, sequential, or concurrent administration to the subject of i) the compound 1 or a pharmaceutically acceptable salt thereof, and ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof.

2. Compound 1 or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the hematological malignancy is lymphoma, leukemia, myeloma, myelodysplastic syndrome, or myeloproliferative disorder.

3. Compound 1 or a pharmaceutically acceptable salt thereof for use according to claim 2, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, or Waldenström macroglobulinemia.

4. Compound 1 or a pharmaceutically acceptable salt thereof for use according to claim 2, wherein the leukemia is ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

5. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 4, wherein the BCL-2 inhibitor is selected from navitoclax, ovatoclax mesylate, venetoclax, risaftoclax, LP-118, S55746, S64315, or palcitoclax.

6. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 5, wherein Compound 1 is administered in a dose of 40 mg or 80 mg per day as hemifumarate.

7. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 6, wherein the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose of 10 mg to 1 g per day.

8. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 7, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

9. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 8, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, administered in doses of 20 mg, 50 mg, 100 mg, 200 mg, or 400 mg per day.

10. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 7, wherein the BCL-2 inhibitor is venetoclax.

11. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 10, wherein the treatment further comprises a separate, sequential, or concurrent administration of iii) a further chemotherapeutic agent to the subject, the further chemotherapeutic agent being a second BCL-2 inhibitor or a DNA methyltransferase inhibitor.

12. A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of hematological malignancies in a subject, wherein the treatment involves i) the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof, and ii) a compound of formula I to the subject: 【Chemistry 2】 A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment thereof, comprising separate, sequential, or concurrent administration of such pharmaceutically acceptable salt thereof.

13. The BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to claim 12, wherein the hematological malignancy is lymphoma, leukemia, myeloma, myelodysplastic syndrome, or myeloproliferative disorder.

14. The BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to claim 13, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, or Waldenström macroglobulinemia.

15. The BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to claim 13, wherein the leukemia is ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

16. A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 12 to 15, wherein the BCL-2 inhibitor is selected from navitoclax, ovatoclax mesylate, venetoclax, risaftoclax, LP-118, S55746, S64315, or palcitoclax.

17. A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 12 to 16, wherein compound 1 is administered in a dose of 40 mg or 80 mg per day as hemifumarate.

18. The BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 12 to 17, wherein the BCL-2 inhibitor or a pharmaceutically acceptable salt thereof is administered in a dose of 10 mg to 1 g per day.

19. The BCL-2 inhibitor for use according to any one of claims 12 to 18, wherein the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof.

20. The BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof, administered in doses of 20 mg, 50 mg, 100 mg, 200 mg, or 400 mg per day, for use according to any one of claims 12 to 19.

21. Compound 1 or a pharmaceutically acceptable salt thereof for use according to any one of claims 12 to 18, wherein the BCL-2 inhibitor is navitoclax.

22. A BCL-2 inhibitor or a pharmaceutically acceptable salt thereof for use according to any one of claims 12 to 21, wherein the treatment further comprises a separate, sequential, or concurrent administration of iii) a further chemotherapeutic agent to the subject, the further chemotherapeutic agent being a second BCL-2 inhibitor or a DNA methyltransferase inhibitor.

23. i) Compounds of formula I: 【Transformation 3】 A pharmaceutical product comprising: ii) a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof; and ii) a pharmaceutically acceptable salt thereof.

24. The pharmaceutical product according to claim 23, wherein the pharmaceutical product further comprises iii) a further chemotherapeutic agent.

25. Compound of formula I: 【Chemistry 4】 A kit comprising: a first pharmaceutical composition comprising a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising a BCL-2 inhibitor or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

26. The kit according to claim 25, further comprising a third pharmaceutical composition comprising a further chemotherapeutic agent, wherein the instructions are for using the first pharmaceutical composition, the second pharmaceutical composition, and the third pharmaceutical composition in combination.

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