Combining Loginolisib with HDAC Inhibitors in the Treatment of Hematologic Malignancies

Abstract

A PI3K delta inhibitor or a pharmaceutically acceptable salt thereof for use in treating a hematological malignancy in a subject, the treatment comprising administering to the subject i) the PI3K delta inhibitor or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof, separately, sequentially, or simultaneously. The treatment can also further comprise administering to the subject iii) a further chemotherapeutic agent, separately, sequentially, or simultaneously.

Description

[Technical Field]

[0001] The present disclosure relates to methods of treating hematological malignancies in a patient in need thereof.

[0002] This application claims the benefit of priority to UK Application No. 2303191.7, filed March 3, 2023, and UK Application No. 2308112.8, filed May 31, 2023, which are incorporated herein by reference in their entireties. [Background technology]

[0003] Hematologic malignancies, also known as blood cancers, are malignant neoplasms that originate primarily from the myeloid and lymphoid cell lineages. Lymphomas, lymphocytic leukemias, and myelomas are derived from the lymphoid system, while acute and chronic myeloid leukemias, myelodysplastic syndromes, and myeloproliferative disorders are of myeloid origin.

[0004] Hematological malignancies are a significant cause of morbidity and mortality worldwide, with approximately 1,000,000 new cases and over 600,000 deaths annually (Jephcote, 2020). Several factors, including occupational, lifestyle, and genetic risk factors, contribute to the development of hematological cancers. Hematological malignancies are heterogeneous diseases with variable outcomes. Indolent lymphomas and chronic leukemias, such as follicular lymphoma (FL), borderline zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL), remain incurable chronic diseases, requiring patients to undergo repeated exposure to toxic therapies. For aggressive lymphomas and acute leukemias, modern treatment regimens have resulted in long-term survival rates ranging from over 80% for Hodgkin lymphoma, approximately 60-65% for diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL), to less than 30% for peripheral T-cell lymphoma (PTCL) and acute myeloid leukemia (AML) (Intlekofer and Younges, 2014; Kantarjian, 2021). More effective treatments are needed to improve outcomes for patients with hematologic malignancies. Furthermore, even for patients who are cured by combination chemotherapy, often combined with radiation, this therapy can result in long-term toxicity, compromise health, predispose patients to secondary malignancies, and negatively impact quality of life.

[0005] Targeted therapies, including phosphatidylinositol 3-kinase (PI3K) inhibitors and histone deacetylase (HDAC) inhibitors, are transforming the treatment landscape for patients with hematological malignancies. PI3K plays a central role in regulating key cellular pathways, such as growth, proliferation, survival, migration, and differentiation, and dysregulation of the PI3K pathway is one of the most frequent pathogenic events in cancer (Kienle and Stilgenbauer, 2021). HDACs regulate cell proliferation and angiogenesis, play a key role in cell growth, and upregulated HDACs are present in many cancer types (Chen, 2020). Therefore, PI3K and HDACs are rational therapeutic targets in hematological malignancies.

[0006] While PI3K and HDAC inhibitors have demonstrated impressive clinical outcomes across a range of hematological malignancies, certain subtypes are characterized by significantly higher response rates than others, and resistance to these inhibitors develops, ultimately leading to clinical disease progression. Furthermore, both types of inhibitors are associated with severe side effects that limit their therapeutic applicability and, in the case of PI3K inhibitors, even lead to the drug's withdrawal from the market (Chen, 2020; Richardson, 2022).

[0007] While considerable progress has been made in the treatment of hematologic malignancies, there is an increasing demand for targeted therapies for these cancers. Many patients with such cancers live with intractable disease. Therefore, it is important to continue discovering new, more effective treatments for patients with intractable cancers. Summary of the Invention

[0008] The present invention is directed to new treatments for patients with hematological malignancies. In some embodiments, there is provided a method of treating a hematological malignancy in a subject in need thereof, comprising administering to the subject a first amount of a compound of Formula I [ka] or a pharmaceutically acceptable salt thereof, and a second amount of an HDAC inhibitor or a pharmaceutically acceptable salt thereof. In the method, the first amount and the second amount together comprise a therapeutically effective amount. 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.

[0009] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is disclosed for use in treating a hematological malignancy in a subject, the treatment comprising separately, sequentially, or simultaneously administering to the subject: i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises separately, sequentially, or simultaneously administering to the subject: iii) an additional chemotherapeutic agent.

[0010] In some embodiments, an HDAC inhibitor or a pharmaceutically acceptable salt thereof is disclosed for use in treating a hematological malignancy in a subject, the treatment comprising separately, sequentially, or simultaneously administering to the subject i) the HDAC 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 separately, sequentially, or simultaneously administering to the subject iii) an additional chemotherapeutic agent.

[0011] In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a hematological malignancy is disclosed, wherein the treatment comprises separately, sequentially, or simultaneously administering to the subject: i) the medicament comprising Compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises separately, sequentially, or simultaneously administering to the subject: iii) an additional chemotherapeutic agent.

[0012] In the above embodiments, the hematological malignancy may be lymphoma, leukemia, myeloma, myelodysplastic syndrome, and myeloproliferative disorder.

[0013] In some embodiments, disclosed are pharmaceutical products comprising: i) Compound 1 or a pharmaceutically acceptable salt thereof; and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the pharmaceutical product further comprises iii) an additional chemotherapeutic agent.

[0014] In some embodiments, a kit is disclosed that includes a first pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, a second pharmaceutical composition comprising an HDAC 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 includes a third pharmaceutical composition comprising an additional chemotherapeutic agent, and the instructions are for using the first, second, and third pharmaceutical compositions in combination.

[0015] The combination of Compound 1 with an HDAC inhibitor (and, if present, an additional chemotherapeutic agent) may be synergistic and / or otherwise result in improved treatment outcomes or patient prognosis, e.g., reduced side effects and improved tolerability, when compared to current monotherapy or combination therapies. This may be because Compound 1 blocks survival pathways that are activated when an HDAC inhibitor is administered, and vice versa. [Brief explanation of the drawings]

[0016] [Figure 1] 1 shows dose-response data for the combination of Compound 1 and vorinostat in the HH cell line, a cutaneous T-cell lymphoma cell line. [Figure 2] 1 shows dose-response data for the combination of Compound 1 and romidepsin in the HH cell line, a cutaneous T-cell lymphoma cell line. DETAILED DESCRIPTION OF THE INVENTION

[0017] Compound 1 is Example 339 of WO2011 / 058149, which is incorporated herein by reference in its entirety. Its structure is according to Formula I: [ka] In IUPAC nomenclature, compound 1 above can be referred to as 6-fluoro-3-(morpholin-4-ylcarbonyl)-1-[4-(morpholin-4-ylmethyl)phenyl]-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide. Alternatively, the above structure may be written as [6-fluoro-1-(4-morpholin-4-yl-methylphenyl)-5,5-dioxo-4,5-dihydro-1H-5λ6-thiochromeno[4,3-C]pyrazol-3-yl]-morpholin-4-yl-methanone.

[0018] Compound 1 can be prepared and characterized as described in published patent application WO 2011 / 058149 A1 (see compound 339 on page 69, preparation on pages 303-307, and characterization on pages 481 and 414-418), which information is specifically incorporated herein by reference.

[0019] Based on the process disclosed in WO2011 / 058149A1, author Haselmayer (2014) describes a five-step preparation procedure for the compound. The procedure begins 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 then 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, followed by coupling with morpholine to obtain the compound of Formula I.

[0020] Alternatively, the intermediate from 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. The benzoic acid is reduced using 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 alcohol are chlorinated with excess thionyl chloride in the presence of dimethylformamide, followed by coupling with morpholine to give compound 1.

[0021] Compound 1 can be provided as pharmaceutically acceptable salt.Suitable pharmaceutically acceptable salt is known in the art.Some pharmaceutically acceptable salts of Compound 1 are described in WO2014 / 121901, which is incorporated by reference in its entirety.

[0022] As used herein, compound 1 is provided as anhydrous hemifumarate (as shown in formula 1). Its synthesis and characterization are described in WO2014 / 121901 (page 4). This is referred to 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. It will be understood that the findings of the present invention are not limited to the use of this solid form, although it is preferred.

[0023] Thus, in some cases, Compound 1 is administered as the hemifumarate salt (Formula Ia). However, it will be understood that the invention is not so limited and that other solid forms (e.g., other pharmaceutically acceptable salts) are also contemplated. [ka]

[0024] Haselmayer et al., 2014, also describe the characterization of the compound as a highly selective PI3Kδ inhibitor. Talenti, 2022, further describes the activity of Compound 1 in lymphoma cell lines, and Carlo-Stella, 2022, reports data on the first dose cohort of a clinical study of Compound 1 in patients with FL (NCT04328844).

[0025] Histone deacetylases (HDACs) are enzymes that play a key role in the epigenetic regulation of gene expression by remodeling chromatin through the removal of acetyl groups from histones (Shanmume, 2022). To date, 18 HDACs have been identified in humans, and they are classified into different classes based on their homology with yeast HDACs. The term HDAC inhibitors includes targeted and selective inhibitors of one type of HDAC, or targeted inhibitors of two or more or all types of HDACs. HDAC inhibitors include, but are not limited to, abexinostat (PCI-24781), pracinostat (SB939), quisinostat (JNJ-26481585), tefinostat (CHR-2845), panobinostat (LBH589), belinostat (PXD101), divinostat (ITF2357), tushidinostat (CS-055, HBI-8000), vorinostat (suberoylanilide hydroxamic acid, SAHA), mocetinostat (MGCD0103), valproic acid (VAL), entinostat (MS275), romidepsin (depsipeptide, FK228), and trapoxin (TPX).

[0026] Vorinostat (also known as suberoylanilide hydroxamic acid - SAHA) is an orally bioavailable HDAC inhibitor approved by the FDA in 2006 for the treatment of cutaneous T-cell lymphoma (CTCL) (Bondaev, 2021). Clinically, vorinostat has been evaluated in patients with several hematological malignancies, including multiple myeloma, AML, ALL, myelodysplastic syndrome, diffuse large B-cell lymphoma (DBCL), CLL, SLL, leukemia, and lymphoma. The most common toxic effects observed with vorinostat include thrombocytopenia, anemia, diarrhea, fatigue, nausea, loss of appetite, weight loss, and stomach pain. Thromboembolic events, particularly pulmonary embolism (4%), were the most common life-threatening events observed.

[0027] Vorinostat has the following structure: [ka] Vorinostat's IUPAC name is N-hydroxy-N'-phenyloctanediamide. Its synthesis and characterization are described in US2008 / 0194692 A1.

[0028] Belinostat is an intravenous HDAC inhibitor approved by the FDA for peripheral T-cell lymphoma (PTCL) in 2014 (Bondaev, 2021). Belinostat has been investigated in patients with several hematologic malignancies, including non-Hodgkin lymphoma, DBCL, MCL (mantle cell lymphoma), PTCL, lymphoma, large cell lymphoma, myelodysplastic syndrome, AML, ALL (acute lymphoblastic leukemia), CML (chronic myeloid leukemia), and MM (multiple myeloma). The most common non-hematologic toxicities observed with belinostat are nausea, fatigue, fever, anemia, and vomiting.

[0029] Belinostat has the following structure: [ka] The IUPAC name for beliniostat is (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide. Belinostat is sold under the trade name Baleodaq and was formerly known as PXD101. Belinostat is disclosed in US 2004 / 0077726 A1, and its synthesis and characterization are described in Example 7.

[0030] Panobinostat (marketed under the name Farydak) is an orally bioavailable HDAC inhibitor approved by the FDA (2015) and EMA (2015) for MM (Bondaev, 2021). Panobinostat has been investigated in patients with several hematological malignancies, including AML, lymphoma, leukemia, MCL, MM, CTCL, PTCL, NK / T-cell lymphoma, ALL, DBCL, CML, MF (myelofibrosis), and myelodysplastic syndromes. The most common toxicities observed with panobinostat are hypophosphatemia, hypokalemia, hyponatremia, increased creatinine, thrombocytopenia, lymphopenia, leukopenia, neutropenia, anemia, diarrhea, fatigue, nausea, peripheral edema, decreased appetite, fever, and vomiting.

[0031] Panobinostat has the following structure: [ka] The IUPAC name for panobinostat is (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide. Methods for synthesizing this compound and its characterization are described in Example 200 of WO 02 / 22577.

[0032] Tucidinostat, also known as chidamide, is an orally bioavailable HDAC inhibitor approved by the China National Administration of Medical Products for use in PTCL in 2014 (Bondaev, 2021). The most common toxicities observed with tucidinostat are thrombocytopenia, leukopenia, neutropenia, prolonged QTc interval, fatigue, decreased appetite, diarrhea, nausea, elevated alanine aminotransferase levels, elevated gamma-glutamyltransferase levels, pulmonary infections, elevated aspartate aminotransferase levels, and vomiting.

[0033] Tucidinostat has the following structure: [ka] The IUPAC name for tucidinostat is N-(2-amino-4-fluorophenyl)-4-[[[(E)-3-pyridin-3-ylprop-2-enoyl]amino]methyl]benzamide. Tucidinostat is sold under the trade names Epidaza and Hiyasta.

[0034] Romidepsin is an intravenous cyclic depsipeptide approved by the FDA in 2009 for CTCL and in 2011 for PTCL (Bondaev, 2021). The most common toxicities observed with romidepsin are nausea, fatigue, infection, vomiting, anorexia, anemia, thrombocytopenia, ECG T-wave changes, neutropenia, and lymphopenia.

[0035] Romidepsin has the following structure: [ka] The IUPAC name for romidepsin is (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricho-16-ene-3,6,9,19,22-pentone. Romidepsin is also known as Istodax. The synthesis of romidepsin is disclosed in Li, 1996.

[0036] Avexinostat is an orally bioavailable experimental cancer drug candidate that is being used in trials investigating the treatment of, among others, sarcoma, lymphoma, leukemia, lymphoma, and Hodgkin's disease. Avexinostat has the following structure: [ka] The IUPAC name for abexinostat is 3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamide.

[0037] Pracinostat is an orally bioavailable HDAC inhibitor with potential antineoplastic activity and is currently in clinical trials for acute myeloid leukemia. Pracinostat has the following structure: [ka] The IUPAC name for pracinostat is (E)-3-[2-butyl-1-[2-(diethylamino)ethyl]benzimidazol-5-yl]-N-hydroxyprop-2-enamide. The dosing schedule for pracinostat is 60 mg per day.

[0038] Quisinostat is an experimental drug candidate for the treatment of cancer. Quisinostat is being used in trials investigating the treatment of lymphomas, neoplasms, myelodysplastic syndromes, and advanced or refractory leukemias. Quisinostat has the following structure: [ka] The IUPAC name for Quisinostat is N-hydroxy-2-[4-({[(1-methyl-1H-indol-3-yl)methyl]amino}methyl)-1-piperidinyl]-5-pyrimidinecarboxamide.

[0039] Tefinostat is an HDAC inhibitor with potential antineoplastic activity and is being investigated in clinical trial NCT02759601 for the treatment of liver cancer. Tefinostat has the following structure: [ka] The IUPAC name for tefinostat is cyclopentyl(2S)-2-[[4-[[8-(hydroxyamino)-8-oxooctanoyl]amino]phenyl]methylamino]-2-phenylacetate.

[0040] Givinostat (also known as gabinostat or ITF-2357) is an HDAC inhibitor in clinical trials for the treatment of a number of cancers. Givinostat has the following structure: [ka] The IUPAC name for divinostat is {6-[(diethylamino)methyl]naphthalen-2-yl}methyl[4-(hydroxycarbamoyl)phenyl]carbamate.

[0041] Entinostat (also known as SNDX-275 or MS-275) is an HDAC inhibitor currently in clinical trials for various cancers. The structure of entinostat is: [ka] The IUPAC name for entinostat is (pyridin-3-yl)methyl({4[2-aminophenyl)carbamoyl]phenyl}methyl)carbamate.

[0042] Trapoxin (cyclo-(L-phenylalanyl-L-phenylalanyl-D-pipecolinyl-L-2-amino-8-oxo-9,10-epoxy-decanoyl)) is a cyclotetrapeptide isolated from the fungus Helicoma ambiens. Trapoxin is an HDAC inhibitor. There are two forms of trapoxin: A and B. Trapoxin A has the following structure: [ka]

[0043] Trapoxin B has the following structure: [ka] Valproic acid (also known as valproic acid, sodium valproate, and hemisodium valproate) is a well-established treatment for seizures and bipolar disorder and has also been shown to be an HDAC inhibitor. First used medically in the 1960s, valproic acid has become widely available and is included on the World Health Organization's list of essential medicines.

[0044] Valproic acid has the following structure: [ka] Valproic acid has the IUPAC name 2-propylpentanoic acid.

[0045] Mocetinostat (also known as MDCD0103) is an HDAC inhibitor currently undergoing clinical trials for the treatment of various cancers, including follicular lymphoma, Hodgkin's lymphoma, and acute myeloid leukemia. Clinical and pharmacodynamic data support a fixed dose of 90 mg administered three times weekly. Mocetinostat has shown promising antitumor activity in several hematological disorders.

[0046] Mocetinostat has the following structure: [ka] The IUPAC name for mocetinostat is N-(2-amino-4-fluorophenyl)-4-({[4-(pyridin-3-yl)pyrimidin-2-yl]amino}methyl)benzamide.

[0047] In some embodiments, the additional chemotherapeutic agent can be a second HDAC inhibitor.

[0048] In other embodiments, the additional chemotherapeutic agent may be a DNA methyltransferase inhibitor. DNA methylation, mediated by DNA methyltransferases, is an important epigenetic process that regulates gene expression and plays a key role in silencing tumor suppressor genes in cancer. Therefore, it has become a promising therapeutic target for cancer treatment, particularly for hematological tumors (Zhang, 2022). DNMT inhibitors can also enhance the immunogenicity of tumor cells by promoting tumor antigen presentation or enhancing cytotoxic T cell function. Therefore, DNMT inhibitors are also a rational therapeutic target for hematological malignancies. However, first-generation DNMT inhibitors are characterized by high toxicity, low selectivity, and low bioavailability.

[0049] DNMT inhibitors include, but are not limited to, 5-azacytidine (azacytidine (AZA)), 5-aza-2'-deoxycytidine (decitabine (DAC)), clofarabine, gaudecitabine, and GSK3685032. 5-Azacytidine (azacytidine (AGA)) has the following structure: [ka] 5-Azacytidine is a cytarabine derivative that was synthesized in 1964 and first approved by the FDA in 2004.

[0050] Decitabine has the following structure: [ka] Decitabine was approved by the FDA in 2006. Its inhibitory activity against DNMTs is 30-fold greater than that of azacitidine (Zhang, 2022).

[0051] Clofarabine has the following structure: [ka] Clofarabine is a purine nucleoside DNMTi that was approved by the FDA in 2004.

[0052] Guadecitabine (SGI-110) has the following structure: [ka] It is a dinucleotide derivative of decitabine.

[0053] GSK3685032 has the following structure: [ka] It is also described in Pappulardi, 2021. It acts as a competitive inhibitor of DNMT1 through competition with the DNMT1 active site loop and target recognition domain as it is incorporated into hemimethylated DNA.

[0054] Other DNMT inhibitors include, but are not limited to, RX-3117 (TV-1360), 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacytidine (DHAC), fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate (EGCG), hydrazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebularine, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, psammaplin A, psammaplin G, and UVI5008.

[0055] definition The term "pharmaceutical composition" includes compositions 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 an HDAC inhibitor or a pharmaceutically acceptable salt thereof, or even a chemotherapeutic agent. The term "pharmaceutically acceptable excipient, carrier, or diluent" includes compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problems or complications, as determined by one of ordinary skill in the art within the scope of sound medical judgment. In some embodiments, the pharmaceutical composition is a solid dosage form such as a capsule, tablet, granule, powder, or sachet. 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, parenterally acceptable buffer systems, diluents, solubilizers, cosolvents, or carriers. Sterile injectable preparations can also be sterile injectable aqueous or oily suspensions or suspensions in non-aqueous diluents, carriers, or cosolvents, and can be formulated according to known procedures using one or more suitable dispersing or wetting agents and suspending agents.The pharmaceutical composition can be a solution for IV bolus / infusion injection, or a lyophilized system (alone or with excipients) for reconstitution with a buffer system with or without other excipients.Lyophilized freeze-dried materials can be prepared from non-aqueous or aqueous solvents.The dosage form can also be a concentrate for further dilution for subsequent injection.

[0056] The terms "treat," "treating," and "treatment" include reducing or inhibiting tumor cells of a hematological malignancy in a subject, ameliorating 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 "treat," "treating," and "treatment" also include reducing or inhibiting tumor growth or cancerous cell proliferation in a subject.

[0057] The terms "inhibit," "inhibition," or "inhibiting" include a decrease in the baseline activity of a biological activity or process.

[0058] 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 is suffering from a hematological malignancy.

[0059] The phrase "therapeutically effective amount" includes an amount of Compound 1 and an amount of HDAC inhibitor that together cause a biological or medical response in a subject, such as a reduction or inhibition of tumor cells, an improvement in symptoms of a hematological malignancy, or a slowing or delay in the progression of a hematological malignancy. In some embodiments, the phrase "therapeutically effective amount" includes an amount of Compound 1 and an HDAC inhibitor, combined, that is effective to at least partially alleviate, inhibit, and / or ameliorate a hematological malignancy, or inhibit tumor cells, and / or reduce or inhibit the proliferation of cancerous cells in a subject. In some embodiments, the phrase "therapeutically effective amount" includes an amount of Compound 1, an HDAC inhibitor, and an additional chemotherapeutic agent, combined, that is effective to at least partially alleviate, inhibit, and / or ameliorate a hematological malignancy, or inhibit tumor cells, and / or reduce or inhibit the proliferation of cancerous cells in a subject.

[0060] In some embodiments, methods of treating a hematological malignancy in a subject in need thereof are disclosed, comprising administering to the subject a first amount of Compound 1 or a pharmaceutically acceptable salt thereof and a second amount of an HDAC inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount. In some of these embodiments, a third amount of an additional chemotherapeutic agent is administered.

[0061] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is disclosed for use in treating a hematological malignancy in a subject, the treatment comprising separately, sequentially, or simultaneously administering to the subject: i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises separately, sequentially, or simultaneously administering to the subject: iii) an additional chemotherapeutic agent.

[0062] In some embodiments, an HDAC inhibitor or a pharmaceutically acceptable salt thereof is disclosed for use in treating a hematological malignancy in a subject, the treatment comprising separately, sequentially, or simultaneously administering to the subject i) the HDAC 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 separately, sequentially, or simultaneously administering to the subject iii) an additional chemotherapeutic agent.

[0063] In some embodiments, the use of Compound 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a hematological malignancy in a subject is disclosed, wherein the treatment comprises separately, sequentially, or simultaneously administering to the subject: i) the medicament comprising Compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof. In some of these embodiments, the treatment further comprises separately, sequentially, or simultaneously administering to the subject iii) an additional chemotherapeutic agent.

[0064] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and the HDAC inhibitor or a pharmaceutically acceptable salt thereof (and, if present, the additional chemotherapeutic agent) are administered separately, sequentially, or simultaneously in a treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered sequentially in a treatment cycle, and the HDAC inhibitor or a pharmaceutically acceptable salt thereof is also administered sequentially in a treatment cycle. In some of these embodiments, the additional chemotherapeutic agent is also administered sequentially in a treatment cycle.

[0065] In some embodiments, the HDAC inhibitor is selected from abexinostat (PCI-24781), pracinostat (SB939), quisinostat (JNJ-26481585), tefinostat (CHR-2845), panobinostat (LBH589), belinostat (PXD101), divinostat (ITF2357), tushidinostat (CS-055, HBI-8000), vorinostat (suberoylanilide hydroxamic acid, SAHA), mocetinostat (MGCD0103), valproic acid (VAL), entinostat (MS275), romidepsin (depsipeptide, FK228), and trapoxin (TPX).

[0066] In some embodiments, the HDAC inhibitor is selected from vorinostat, belinstat, panobinostat, tucidinostat, or romidepsin.

[0067] In some embodiments, the HDAC inhibitor is selected from vorinostat or romidepsin.

[0068] The terms "continuous" or "sequentially" refer to the administration of a therapeutic agent, e.g., Compound 1, on a regular basis without stopping or interruption, i.e., without a dead day. A "dead day" refers to a day on which the therapeutic agent is not administered.

[0069] As used herein, a "cycle," "treatment cycle," or "dosing schedule" refers to a period of combination treatment that is repeated on a regular schedule. For example, treatment can be administered for 1 week, 2 weeks, or 3 weeks, with Compound 1 and the HDAC inhibitor administered in a coordinated manner. In some embodiments, the treatment cycle is from about 1 week to about 3 months. In some embodiments, the treatment cycle is from about 5 days to about 1 month. In some embodiments, the treatment cycle is from about 1 week to about 3 weeks. In some embodiments, the treatment cycle is from about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months.

[0070] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and an HDAC inhibitor or a pharmaceutically acceptable salt thereof (and, if present, an additional chemotherapeutic agent) are administered to a human subject in one or more treatment cycles, e.g., a treatment course. A "treatment course" includes multiple treatment cycles and can be repeated on a regular schedule or can be adjusted as a schedule that is gradually adjusted as the patient's disease progression is monitored. For example, a patient's treatment cycle may have a longer treatment period and / or a shorter rest period at the beginning of the treatment course (e.g., when the patient is first diagnosed), and as the cancer enters remission, the rest period becomes longer, 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 the treatment course can be determined and adjusted by one skilled in the art throughout the treatment course 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.

[0071] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered for 28 days in a 28-day treatment cycle, and the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered for 28 days in a 28-day treatment cycle.

[0072] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered for 28 days in a 28-day treatment cycle, and the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered on days 1, 8, and 15 of the 28-day treatment cycle.

[0073] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered for 28 days in a 28-day treatment cycle, and the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered on days 1, 3, 8, 10, and 12 in a 21-day treatment cycle.

[0074] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered on 28 days in a 28-day treatment cycle, and the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered on days 1-5 in a 21-day treatment cycle.

[0075] dose In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is orally administered. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is in the form of a tablet. In some embodiments, Compound 1 as the hemifumarate salt is administered at a dose of 40 mg per day. In some embodiments, Compound 1 as the hemifumarate salt is administered at a dose of 80 mg per day.

[0076] In some embodiments, the HDAC inhibitor or a pharmaceutically acceptable salt thereof is orally administered. In some embodiments, the HDAC inhibitor or a pharmaceutically acceptable salt thereof is in tablet form. In some embodiments, the HDAC inhibitor or a pharmaceutically acceptable salt thereof is in capsule form. In some embodiments, the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day.

[0077] In some embodiments, the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered as an intravenous (IV) infusion.

[0078] In some of these embodiments, the additional chemotherapeutic agent is administered orally. In some of these embodiments, the additional chemotherapeutic agent is in tablet form. In some of these embodiments, the additional chemotherapeutic agent is in capsule form. In some of these embodiments, the additional chemotherapeutic agent is administered by injection. In some of these embodiments, the additional chemotherapeutic agent is administered by intravenous (IV) injection. In some of these embodiments, the additional chemotherapeutic agent is administered at a dose of 10 mg to 1 g per day.

[0079] In some embodiments, Compound 1 and the HDAC inhibitor are taken together on an empty stomach, with no food ingested 2 hours before and 1 hour after.

[0080] In some embodiments, Compound 1 is taken on an empty stomach, with no food ingested 2 hours before and 1 hour after, and the HDAC inhibitor is taken with food, such that it is taken either at least 2 hours before or 1 hour after Compound 1.

[0081] In some embodiments, the HDAC inhibitor is dosed weekly.

[0082] In some embodiments, pharmaceutical products are disclosed that include i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof are present in a single dosage form. In some embodiments, i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof are present in separate dosage forms. In some of these embodiments, the pharmaceutical product further includes iii) an additional chemotherapeutic agent.

[0083] In some embodiments, a kit is disclosed that includes a first pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, a second pharmaceutical composition comprising an HDAC 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 includes a third pharmaceutical composition comprising an additional chemotherapeutic agent, and the instructions are for using the first, second, and third pharmaceutical compositions in combination.

[0084] In some embodiments, the HDAC inhibitor is abexinostat (PCI-24781), pracinostat (SB939), quisinostat (JNJ-26481585), tefinostat (CHR-2845), panobinostat (LBH589), belinostat (PXD101), divinostat (ITF2357), tushidinostat (CS-055, HBI-8000), vorinostat (suberoylanilide hydroxamic acid, SAHA), mocetinostat (MGCD0103), valproic acid (VAL), entinostat (MS275), romidepsin (depsipeptide, FK228), and trapoxin (TPX).

[0085] In some embodiments, the HDAC inhibitor is vorinostat. Vorinostat as monotherapy is administered orally, for example, via tablets or capsules. The dosing schedule for vorinostat is 400 mg or 300 mg once daily taken with food, with vorinostat capsules available in 100 mg strengths. In some embodiments, vorinostat is administered at a dose of 100 mg to 500 mg per day. In some embodiments, vorinostat is administered at a dose of 200 mg, 300 mg, or 400 mg per day. In some embodiments, vorinostat is administered at a dose of 300 mg per day. In some embodiments, vorinostat is administered at a dose of 400 mg per day. In some embodiments, vorinostat is administered orally in the form of three or four 100 mg capsules per day. In further embodiments, vorinostat is administered daily with food.

[0086] In some embodiments, pharmaceutical products are disclosed that include i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) vorinostat or a pharmaceutically acceptable salt thereof. In some embodiments, i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) vorinostat or a pharmaceutically acceptable salt thereof are present in a single dosage form. In some embodiments, i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) vorinostat or a pharmaceutically acceptable salt thereof are present in separate dosage forms.

[0087] In some embodiments, the HDAC inhibitor is belinostat. Belinostat is administered intravenously. The recommended dose of belinostat is 1000 mg per square meter of body surface area administered by intravenous infusion over 30 minutes once daily on days 1-5 of a 21-day cycle. Cycles may be repeated until disease progression or unacceptable toxicity occurs. Dose adjustments for thrombocytopenia and neutropenia based on absolute platelet and neutrophil nadirs are common. Belinostat for injection is available in vials containing 500 mg of lyophilized powder for reconstitution. In some embodiments, belinostat is administered at a dose of 500-1200 mg per square meter of body surface area administered by intravenous infusion over 20-40 minutes once daily. In a further embodiment, belinostat is administered at a dose of 500-1200 mg per square meter of body surface area by intravenous infusion over 20-40 minutes once daily on days 1-5 of a 21-day cycle.

[0088] In some embodiments, the HDAC inhibitor is panobinostat. Panobinostat is administered orally, for example, via tablets or capsules. The recommended starting dose of panobinostat is 20 mg, taken orally once daily on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle. Panobinostat capsules are available in three strengths: 10 mg, 15 mg, and 20 mg. In some embodiments, panobinostat is administered at a dose of 5-40 mg once daily. In some embodiments, panobinostat is administered at a dose of 20 mg once daily. In some embodiments, panobinostat is administered at a dose of 5-40 mg once daily every 2-3 days for 2 weeks. In further embodiments, panobinostat is administered at a dose of 5-40 mg once daily on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle.

[0089] In some embodiments, the HDAC inhibitor is tucidinostat. Tucidinostat is administered orally, for example, via tablets or capsules. The recommended dose and dosing schedule for tucidinostat is 40 mg twice weekly. In some embodiments, tucidinostat is administered at a dose of 20-60 mg twice weekly. In some embodiments, tucidinostat is administered at a dose of 40 mg twice weekly. In some embodiments, 40 mg of tucidinostat is administered every three days.

[0090] In some embodiments, the HDAC inhibitor is romidepsin. Romidepsin is administered intravenously. The recommended dose and dosing schedule for romidepsin is 14 mg per square meter of body surface area administered over 4 hours on days 1, 8, and 15 of a 28-day cycle. Discontinuation or interruption of treatment, with or without a dose reduction to 10 mg per square meter of body surface area, may be required to manage adverse drug reactions. Romidepsin for injection is available in 10 mg vials for reconstitution. In some embodiments, romidepsin is administered at a dose of 5-30 mg per square meter of body surface area administered over a 2-6 hour period. In a further embodiment, romidepsin is administered at a dose of 5-30 mg per square meter of body surface area administered once weekly. In a further embodiment, romidepsin is administered at a dose of 5-30 mg per square meter of body surface area administered over a period of 2-6 hours on days 1, 8, and 15 of a 28-day cycle. In some embodiments, romidepsin is administered at a dose of 10 mg or 14 mg per square meter of body surface area administered over a period of 2-6 hours. In a further embodiment, romidepsin is administered once weekly. In a further embodiment, romidepsin is administered over a period of about 4 hours.

[0091] In some embodiments, pharmaceutical products are disclosed that include i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) romidepsin or a pharmaceutically acceptable salt thereof. In some embodiments, i) Compound 1 or a pharmaceutically acceptable salt thereof, and ii) romidepsin or a pharmaceutically acceptable salt thereof are present in separate dosage forms. In some embodiments, Compound 1 is administered orally as a tablet or capsule, and romidepsin is administered intravenously. In some embodiments, the oral and intravenous administrations are administered sequentially or simultaneously.

[0092] In some embodiments, the hematological malignancy is a lymphoma, including cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom's macroglobulinemia.

[0093] In some embodiments, the hematological malignancy is a leukemia, including ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndromes, myeloproliferative disorders, and myelofibrosis.

[0094] In some embodiments, the hematological malignancy is a myeloma, including multiple myeloma.

[0095] Without wishing to be bound by theory, the combination of Compound 1 with an HDAC inhibitor may be beneficial for patients who are unresponsive or refractory to either Compound 1 or an HDAC inhibitor. Furthermore, the combination of Compound 1 with an HDAC inhibitor may deepen or make the response to either Compound 1 or an HDAC inhibitor more durable. Furthermore, the combination of Compound 1 with an HDAC inhibitor may allow for a reduction in the dose of the HDAC inhibitor, leading to improved tolerability and quality of life.

[0096] Furthermore, when the additional chemotherapeutic agent is a second HDAC inhibitor, the above reasoning can be similarly applied. When the additional chemotherapeutic agent is a DNA methyltransferase inhibitor, this combination may be beneficial for patients who are unresponsive or refractory to Compound 1, HDAC inhibitors, and DNMT inhibitors. Furthermore, the combination of Compound 1 with an HDAC inhibitor and a DNMT inhibitor may deepen or make the response to either Compound 1, an HDAC inhibitor, or a DNMT inhibitor more durable. Furthermore, the combination of Compound 1 with an HDAC inhibitor and a DNMT inhibitor may allow for a reduction in the dose of the HDAC inhibitor or DNMT inhibitor, leading to improved tolerability and quality of life.

[0097] Methods of the Invention As described in more detail below, the present inventors have surprisingly found that the combination of Compound 1 with an HDAC inhibitor has a synergistic effect on the proliferation of hematological malignant cell lines, thus providing a combination therapy with improved antiproliferative activity.

[0098] Second, the inventors surprisingly found that the synergistic antitumor activity of the combination of Compound 1 and an HDAC inhibitor is not limited to a specific hematological malignancy, thus providing a combination therapy with improved therapeutic activity across multiple hematological malignancies.

[0099] Furthermore, the inventors have surprisingly found that the combination of Compound 1 with an HDAC inhibitor results in tumor cell killing not observed with either inhibitor alone, thus providing a combination that can reduce tumor burden.

[0100] Furthermore, the present inventors have surprisingly found that the combination of Compound 1 with an HDAC inhibitor has a synergistic effect even at subtherapeutic doses, which may result in improved tolerability. [Example]

[0101] The compounds of the present application will now be further described by reference to the following non-limiting examples.

[0102] Example 1. Efficacy of Compound 1 in Combination with the HDAC Inhibitors Vorinostat and Romidepsin in an In Vitro Assay Using the Cutaneous T-Cell Lymphoma (CTCL) Cell Line HH HH (CRL-2105) cells were exposed to increasing doses of Compound 1, increasing doses of vorinostat or romidepsin, and increasing doses of Compound 1 in combination with vorinostat or romidepsin. Compound 1 and vorinostat were used at concentrations up to 10 μM in an 8-fold dose-response design based on a 1:3 compound dilution and untreated controls. Romidepsin was used at concentrations up to 20 μM in an 8-fold dose-response design based on a 1:2 compound dilution and untreated controls.

[0103] Cells were incubated at 37°C and 5% CO2 for 72 hours. The antiproliferative effects of single-agent and combination treatments were determined by adding 20 μL of MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] reagent (Sigma-Aldrich, Bachs, Switzerland) to each well. After 4 hours of incubation at 37°C, 50 μL of sodium dodecyl sulfate (SDS) lysis buffer (250 μM SDS, 0.21% fuming hydrochloric acid) was added. Lysed cells were kept overnight, and then absorbance was read at 570 nm using a Cytation 3 instrument (BioTek, Winoosku, VT, USA). The effect of combination treatments was determined according to the Chou-Talalay Combination Index (CI) (Chou, 2008; Chou, 2010) and calculated using the Synergy R package (Lee, 2007). The effect of the combination was defined as strongly synergistic for CI values ​​less than 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 ​​greater than 1.1.

[0104] Data from two representative experiments are shown in Figures 1 and 2.

[0105] The combination of Compound 1 and vorinostat in HH is synergistic with a median CI of 0.64. The combination of Compound 1 and romidepsin in HH is synergistic with a median CI of 0.89.

[0106] Example 2. Efficacy of Compound 1 in combination with HDAC inhibitors in in vitro assays using several different hematological cell lines Cell lines derived from various hematological malignancies were exposed to increasing doses of Compound 1, increasing doses of HDAC inhibitors, and the combination of Compound 1 and HDAC inhibitors at increasing doses. Compound 1 and vorinostat were used at concentrations up to 10 μM according to an 8-fold dose-response design based on a 1:3 compound dilution and untreated controls. Belinostat was used at concentrations up to 10 μM according to an 8-fold dose-response design based on a 1:4 compound dilution and untreated controls.

[0107] Cells were incubated at 37°C and 5% CO2 for 72 hours. The antiproliferative effects of single-agent and combination treatments were determined by adding 20 μL of MTT [3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide] reagent (Sigma-Aldrich, Bachs, Switzerland) to each well. After 4 hours of incubation at 37°C, 50 μL of sodium dodecyl sulfate (SDS) lysis buffer (250 μM SDS, 0.21% fuming hydrochloric acid) was added. Lysed cells were kept overnight, and then absorbance was read at 570 nm using a Cytation 3 instrument (BioTek, Winoosku, VT, USA). The effect of combination treatments was determined according to the Chou-Talalay Combination Index (CI) (Chou, 2008; Chou, 2010) and calculated using the Synergy R package (Lee, 2007). The effect of the combination was defined as strongly synergistic for CI values ​​less than 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 ​​greater than 1.1.

[0108] CI values ​​from a representative experiment are shown in Table 1. [Table 1] References Numerous publications have been cited above in order to more fully describe and disclose the invention and the state of the art to which it pertains. Full citations for these references are provided below. Each of these references is incorporated herein in its entirety. [Table 2]

[0109] statement 1. A method of treating a hematological malignancy in a subject in need thereof, comprising administering to the subject a first amount of a compound of formula I. [ka] or a pharmaceutically acceptable salt thereof, and a second amount of an HDAC inhibitor or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

[0110] 2. The method of statement 1, wherein the hematological malignancy is lymphoma, leukemia, myeloma, myelodysplastic syndrome, or myeloproliferative disorder.

[0111] 3. The method of statement 2, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom's macroglobulinemia.

[0112] 4. The method of statement 2, wherein the leukemia is ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

[0113] 5. The method of any one of statements 1 to 4, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, guisinostat, tefinostat, panobinostat, belinostat, divinostat, tucidinostat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trapoxin.

[0114] 6. The method of any of statements 1 to 5, wherein compound 1 is administered at a dose of 40 mg or 80 mg per day as the hemifumarate salt.

[0115] 7. The method of any one of statements 1 to 6, wherein the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day.

[0116] 8. The method of any one of statements 1 to 7, wherein the HDAC inhibitor is selected from vorinostat or a pharmaceutically acceptable salt thereof.

[0117] 9. The method of any one of statements 1 to 8, wherein the HDAC inhibitor is vorinostat or a pharmaceutically acceptable salt thereof and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

[0118] 10. The method of any one of statements 1 to 7, wherein the HDAC inhibitor is romidepsin.

[0119] 11. The method of any one of statements 1 to 10, wherein a third amount of an additional chemotherapeutic agent is administered.

[0120] 12. The method of statement 11, wherein the additional chemotherapeutic agent is a second HDAC inhibitor.

[0121] 13. The method of statement 11, wherein the additional chemotherapeutic agent is a DNA methyltransferase inhibitor.

[0122] 14. The DNA methyltransferase inhibitor is 5-azacytidine, 5-aza-2'-deoxycytidine, clofarabine, gaudecitabine, or GSK3685032. 14. The method of statement 13, wherein the anti-inflammatory drug is selected from RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacytidine, fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate, hydrazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebularine, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, psammaplin A, psammaplin G, and UVI5008.

[0123] 15. A compound of formula I for use in treating a hematological malignancy in a subject. [ka] or a pharmaceutically acceptable salt thereof, wherein said treatment comprises administering to said subject i) said compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously.

[0124] 16. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 15, wherein the hematological malignancy is lymphoma, leukemia, myeloma, myelodysplastic syndrome, or myeloproliferative disorder.

[0125] 17. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 16, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom's macroglobulinemia.

[0126] 18. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 16, wherein the leukemia is ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

[0127] 19. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 18, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, guisinostat, tefinostat, panobinostat, belinostat, divinostat, tucidinostat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trapoxin.

[0128] 20. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 19, wherein compound 1 is administered at a dose of 40 mg or 80 mg per day as the hemifumarate salt.

[0129] 21. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 20, wherein the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day.

[0130] 22. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 21, wherein the HDAC inhibitor is selected from vorinostat or a pharmaceutically acceptable salt thereof.

[0131] 23. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 22, wherein the HDAC inhibitor is vorinostat or a pharmaceutically acceptable salt thereof and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

[0132] 24. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 21, wherein the HDAC inhibitor is romidepsin.

[0133] 25. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 15 to 24, wherein the treatment further comprises iii) administering to the subject separately, sequentially, or simultaneously an additional chemotherapeutic agent.

[0134] 26. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 25, wherein the further chemotherapeutic agent is a second HDAC inhibitor.

[0135] 27. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to statement 25, wherein the further chemotherapeutic agent is a DNA methyltransferase inhibitor.

[0136] 28. The DNA methyltransferase inhibitor is 5-azacytidine, 5-aza-2'-deoxycytidine, clofarabine, gaudecitabine, or GSK3685032. 28. Compound 1 for use in accordance with statement 27, wherein the compound is selected from RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacytidine, fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate, hydrazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebularine, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, psammaplin A, psammaplin G, and UVI5008, or a pharmaceutically acceptable salt thereof.

[0137] 29. An HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating a hematological malignancy in a subject, said treatment comprising: i) said HDAC inhibitor or a pharmaceutically acceptable salt thereof; and ii) a compound of Formula I [ka] or a pharmaceutically acceptable salt thereof to said subject separately, sequentially or simultaneously administering an HDAC inhibitor or a pharmaceutically acceptable salt thereof.

[0138] 30. The HDAC inhibitor for use according to statement 29, or a pharmaceutically acceptable salt thereof, wherein the hematological malignancy is lymphoma, leukemia, myeloma, myelodysplastic syndrome, or myeloproliferative disorder.

[0139] 31. The HDAC inhibitor for use according to statement 30, or a pharmaceutically acceptable salt thereof, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenström's macroglobulinemia.

[0140] 32. The HDAC inhibitor for use according to statement 30, or a pharmaceutically acceptable salt thereof, wherein the leukemia is ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

[0141] 33. The HDAC inhibitor for use according to any one of statements 29 to 32, or a pharmaceutically acceptable salt thereof, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, guisinostat, tefinostat, panobinostat, belinostat, divinostat, tucidinostat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trapoxin.

[0142] 34. The HDAC inhibitor for use according to any one of statements 29 to 33, or a pharmaceutically acceptable salt thereof, wherein compound 1 is administered at a dose of 40 mg or 80 mg per day as the hemifumarate salt.

[0143] 35. An HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 29 to 34, wherein the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day.

[0144] 36. The HDAC inhibitor for use according to any one of statements 29 to 35, wherein the HDAC inhibitor is selected from vorinostat or a pharmaceutically acceptable salt thereof.

[0145] 37. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of statements 29 to 36, wherein the HDAC inhibitor is vorinostat or a pharmaceutically acceptable salt thereof and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

[0146] 38. The HDAC inhibitor for use according to any one of statements 29 to 37, or a pharmaceutically acceptable salt thereof, wherein the HDAC inhibitor is romidepsin.

[0147] 39. The HDAC inhibitor for use according to any one of statements 29 to 38, or a pharmaceutically acceptable salt thereof, wherein said treatment further comprises iii) administering to said subject separately, sequentially, or simultaneously an additional chemotherapeutic agent.

[0148] 40. The HDAC inhibitor for use according to statement 39, or a pharmaceutically acceptable salt thereof, wherein the further chemotherapeutic agent is a second HDAC inhibitor.

[0149] 41. The HDAC inhibitor for use according to statement 39, or a pharmaceutically acceptable salt thereof, wherein the further chemotherapeutic agent is a DNA methyltransferase inhibitor.

[0150] 42. The DNA methyltransferase inhibitor is 5-azacytidine, 5-aza-2'-deoxycytidine, clofarabine, gaudecitabine, or GSK3685032. 42. The HDAC inhibitor for use according to statement 41 selected from RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacytidine, fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate, hydrazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebularine, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, psammaplin A, psammaplin G, and UVI5008, or a pharmaceutically acceptable salt thereof.

[0151] 43. A compound of formula I in the manufacture of a medicament for use in the treatment of hematological malignancies. [ka] or a pharmaceutically acceptable salt thereof, wherein the treatment comprises administering to the subject i) the drug comprising Compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof, separately, sequentially, or simultaneously.

[0152] 44. Use of compound 1, or a pharmaceutically acceptable salt thereof, according to statement 43, wherein the hematological malignancy is lymphoma, leukemia, myeloma, myelodysplastic syndrome, or myeloproliferative disorder.

[0153] 45. The use of compound 1, or a pharmaceutically acceptable salt thereof, according to statement 44, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom's macroglobulinemia.

[0154] 46. ​​The use of compound 1, or a pharmaceutically acceptable salt thereof, according to statement 44, wherein the leukemia is ALL, AML, CLL, chronic myeloid leukemia, hairy cell leukemia, myelodysplastic syndrome, myeloproliferative disorder, and myelofibrosis.

[0155] 47. Use of compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 46, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, guisinostat, tefinostat, panobinostat, belinostat, divinostat, tucidinostat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trapoxin.

[0156] 48. Use of compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 47, wherein compound 1 is administered at a dose of 40 mg or 80 mg per day as the hemifumarate salt.

[0157] 49. Use of compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 48, wherein the HDAC inhibitor or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg to 1 g per day.

[0158] 50. Use of compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 49, wherein the HDAC inhibitor is selected from vorinostat or a pharmaceutically acceptable salt thereof.

[0159] 51. The use of compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 50, wherein the HDAC inhibitor is vorinostat or a pharmaceutically acceptable salt thereof, administered at a dose of 200 mg, 300 mg, or 400 mg per day.

[0160] 52. Use of compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 51, wherein the HDAC inhibitor is romidepsin.

[0161] 53. The use of compound 1, or a pharmaceutically acceptable salt thereof, according to any one of statements 43 to 52, wherein the treatment further comprises iii) administering to the subject separately, sequentially, or simultaneously an additional chemotherapeutic agent.

[0162] 54. The use of compound 1, or a pharmaceutically acceptable salt thereof, according to statement 53, wherein the additional chemotherapeutic agent is a second HDAC inhibitor.

[0163] 55. The use of compound 1, or a pharmaceutically acceptable salt thereof, according to statement 53, wherein the additional chemotherapeutic agent is a DNA methyltransferase inhibitor.

[0164] 56. The DNA methyltransferase inhibitor is 5-azacytidine, 5-aza-2'-deoxycytidine, clofarabine, gaudecitabine, or GSK3685032. 56. The use of compound 1 in accordance with statement 55, or a pharmaceutically acceptable salt thereof, selected from RX-3117, 5-fluoro-2-deoxycytidine, 6-dihydro-5-azacytidine, fazarabine, cladribine, fludarabine, procaine, epigallocatechin gallate, hydrazine, genistein, equol, curcumin, disulfiram, resveratrol, caffeic acid, CP-4200, zebularine, NPEOC-DAC, T-dCyd, 5-aza-t-dCyd, RG108, DC-05, DC-501, DC-517, SGI-1027, CM-272, CM-579, psammaplin A, psammaplin G, and UVI5008.

[0165] 57. i) Compound of Formula I [ka] or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof.

[0166] 58. The pharmaceutical product of statement 57, wherein the pharmaceutical product further comprises iii) an additional chemotherapeutic agent.

[0167] 59. Compound of Formula I [ka] or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising an HDAC inhibitor, or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

[0168] 60. The kit of statement 59, wherein 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.

Claims

1. A compound of formula I for use in treating a hematological malignancy in a subject 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein said treatment comprises administering to said subject i) said compound 1 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof, separately, sequentially or simultaneously.

2. 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. 3. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to claim 2, wherein the lymphoma comprises cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom's macroglobulinemia.

4. 3. 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. 5. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 4, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, guisinostat, tefinostat, panobinostat, belinostat, divinostat, tucidinostat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trapoxin.

6. 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 at a dose of 40 mg or 80 mg per day as the hemifumarate salt.

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

8. 8. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 7, wherein the HDAC inhibitor is selected from vorinostat or a pharmaceutically acceptable salt thereof.

9. 9. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 8, wherein the HDAC inhibitor is vorinostat or a pharmaceutically acceptable salt thereof and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

10. 8. Compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 7, wherein the HDAC inhibitor is romidepsin.

11. 11. The compound 1, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 10, wherein the treatment further comprises iii) administering to the subject an additional chemotherapeutic agent separately, sequentially, or simultaneously, wherein the additional chemotherapeutic agent is a second HDAC inhibitor or a DNA methyltransferase inhibitor.

12. 1. An HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating a hematological malignancy in a subject, said treatment comprising administering to a subject a compound of formula I, i) the HDAC inhibitor or a pharmaceutically acceptable salt thereof, and ii) a compound of formula I 【Chemistry 2】 or a pharmaceutically acceptable salt thereof to said subject separately, sequentially or simultaneously administering to said subject a compound or a pharmaceutically acceptable salt thereof.

13. 13. The HDAC 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. 14. The HDAC inhibitor for use according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the lymphoma is cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, FL, mantle cell lymphoma (MCL), MZL, DLBCL, SLL, PTCL, and Waldenstrom's macroglobulinemia.

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

16. 16. The HDAC inhibitor for use according to any one of claims 12 to 15, or a pharmaceutically acceptable salt thereof, wherein the HDAC inhibitor is selected from abexinostat, pracinostat, guisinostat, tefinostat, panobinostat, belinostat, divinostat, tucidinostat, vorinostat, mocetinostat, valproic acid, entinostat, romidepsin, and trapoxin.

17. 17. The HDAC inhibitor for use according to any one of claims 12 to 16, or a pharmaceutically acceptable salt thereof, wherein compound 1 is administered at a dose of 40 mg or 80 mg per day as the hemifumarate salt.

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

19. 19. The HDAC inhibitor for use according to any one of claims 12 to 18, wherein the HDAC inhibitor is selected from vorinostat or a pharmaceutically acceptable salt thereof.

20. 20. The HDAC inhibitor, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 12 to 19, wherein the HDAC inhibitor is vorinostat or a pharmaceutically acceptable salt thereof and is administered at a dose of 200 mg, 300 mg, or 400 mg per day.

21. 21. The HDAC inhibitor for use according to any one of claims 12 to 20, wherein the HDAC inhibitor is romidepsin, or a pharmaceutically acceptable salt thereof.

22. 22. The HDAC inhibitor for use according to any one of claims 12 to 21, or a pharmaceutically acceptable salt thereof, wherein the treatment further comprises iii) administering to the subject a further chemotherapeutic agent separately, sequentially, or simultaneously, wherein the further chemotherapeutic agent is a second HDAC inhibitor or a DNA methyltransferase inhibitor.

23. i) a compound of formula I 【Transformation 3】 or a pharmaceutically acceptable salt thereof, and ii) an HDAC inhibitor or a pharmaceutically acceptable salt thereof.

24. 24. The pharmaceutical product of claim 23, wherein the pharmaceutical product further comprises iii) an additional chemotherapeutic agent.

25. Compounds of Formula I 【Chemistry 4】 or a pharmaceutically acceptable salt thereof; a second pharmaceutical composition comprising an HDAC inhibitor, or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination.

26. 26. The kit of claim 25, wherein the kit further comprises a third pharmaceutical composition comprising an additional chemotherapeutic agent, and wherein the instructions are for the combined use of the first, second, and third pharmaceutical compositions.

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