Quinoline carboxamide for use in the treatment of MPN

Abstract

This specification describes specific quinoline carboxamides for use in the treatment of myeloproliferative neoplasms (MPNs). Quinoline carboxamides may be used more specifically in the treatment of advanced stages of MPN, including acute myeloid leukemia progressing from progenitor myeloproliferative neoplasms (post-MPN AML), in combination with further compounds optionally selected from Janus kinase (JAK) inhibitors, bromodomain and extraterminal motif protein (BET) inhibitors, B-cell lymphoma 2 (Bcl-2) inhibitors, and combinations thereof. Also included are pharmaceutical combinations of quinoline carboxamides with a second agent such as a BET inhibitor or a Bcl-2 inhibitor. Furthermore, specific quinoline carboxamides for use in combination with a BET inhibitor or a Bcl-2 inhibitor in the treatment of myeloproliferative neoplasms (MPNs) are included.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority and interest with respect to U.S. Provisional Patent Application No. 63 / 510,726, filed on 28 June 2023 and titled "Quinoline Carboxamides for Use in the Treatment of MPN," U.S. Provisional Patent Application No. 63 / 514,844, filed on 21 July 2023 and titled "Quinoline Carboxamides for Use in the Treatment of MPN," and U.S. Provisional Patent Application No. 63 / 594,235, filed on 30 October 2023, each of which is incorporated herein by reference in whole for all purposes.

[0002] The present invention relates to the treatment of myeloproliferative neoplasms (MPNs) using specific quinoline carboxamides. Quinoline carboxamides may be used more specifically in the treatment of accelerated-phase MPNs and secondary acute myeloid leukemias, i.e., advanced stages of MPNs such as acute myeloid leukemia progressing from progenitor myeloproliferative neoplasms (post-MPN AML), and may be used in combination with further compounds optionally selected from JAK (Janus kinase) inhibitors, BET (bromodomain and extraterminal motif protein) inhibitors, Bcl-2 (B-cell lymphoma 2) inhibitors, and combinations thereof. Also, pharmaceutical combinations of quinoline carboxamide with a second agent such as a BET inhibitor or a Bcl-2 inhibitor are also mentioned. The present invention further relates to specific quinoline carboxamides for use in combination with at least one of BET inhibitors and Bcl-2 inhibitors in the treatment of myeloproliferative neoplasms (MPNs). [Background technology]

[0003] Tascinimod and its preparation methods are described in WO99 / 55678 and WO00 / 03991, and the publication also discloses the usefulness of tascinimod and other quinoline carboxamides for the treatment of diseases in which pathological inflammation plays a major role, such as multiple sclerosis, insulin-dependent diabetes mellitus, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis, as well as autoimmune diseases such as asthma, atherosclerosis, stroke and Alzheimer's disease.

[0004] Processes for preparing tascinimod are also described in WO03 / 106424 and WO2012 / 004338. The deuterated form of tascinimod is described in WO2012 / 175541. WO2022 / 248401 discloses particles of tascinimod in free base form, or pharmaceutically acceptable salts, and the use of such particles having D(v,0.9) up to 30 μm and D(v,0.5) up to 15 μm. WO / 2023 / 275248 identifies degradation products of tascinimod in pharmaceutical formulations and uses them in a method for evaluating the suitability of such formulations for use.

[0005] The use of various quinoline carboxamides for the treatment of cancer, more specifically solid tumors such as prostate cancer and breast cancer, is disclosed in WO01 / 30758. These compounds have been found to bind to and inhibit the interaction of the immunomodulatory protein (S100A9), which promotes tumorigenesis, affects suppressor and pro-angiogenic cells within the tumor microenvironment, and is involved in the establishment of the pre-metastatic niche.

[0006] WO2016 / 078921 discloses tascinimod for use in the treatment of leukemias, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. WO2016 / 042112 discloses tascinimod for use in the treatment of multiple myeloma. WO2022 / 018240 discloses tascinimod for use in the prevention or treatment of myeloproliferative neoplasms associated with the fibrotic phase, such as primary myelofibrosis, essential thrombocythemia, or polycythemia vera. WO2022 / 152902 discloses tascinimod or a pharmaceutically acceptable salt thereof for use in the treatment of myelodysplastic syndromes.

[0007] WO2016 / 146329 discloses tascinimod for use in combination with PD-1 and / or PD-L1 inhibitors in the treatment of cancer, particularly bladder cancer. WO2021 / 175924 discloses tascinimod for use in combination with at least one further compound selected from proteasome inhibitors, immunomodulatory imides, and antibodies for use in the treatment of multiple myeloma.

[0008] Novel uses and therapeutic methods, including those involving tascinimod, are needed. Summary

[0009] The first embodiment is a compound of formula (I). [ka] (In the formula, R is selected from hydrogen and methyl.) or a pharmaceutically acceptable salt thereof, This relates to a combination of pharmaceuticals, including bromodomain and extra-terminal motif protein (BET) inhibitors, B-cell lymphoma 2 (Bcl-2) inhibitors, or combinations thereof.

[0010] Further embodiments relate to combinations of pharmaceuticals, including compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof, and BET inhibitors, Bcl-2 inhibitors, or combinations thereof.

[0011] Further embodiments relate to combinations of pharmaceutical products as defined herein for use in the treatment of myeloproliferative neoplasms (MPNs).

[0012] Further embodiments relate to compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in the treatment of MPN, wherein the treatment further comprises the administration of a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof.

[0013] Further embodiments relate to a kit comprising (i) a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, (ii) a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof, and (iii) instructions for the use thereof.

[0014] Further embodiments relate to the use of compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals in combination with BET inhibitors, Bcl-2 inhibitors, or combinations thereof, for the treatment of MPN.

[0015] Further embodiments relate to the use of (i) a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and (ii) a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof, in the manufacture of a drug or pharmaceutical kit for the treatment of MPN.

[0016] Further embodiments relate to methods for treating MPN by administering (i) a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and (ii) a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof, to a mammalian subject in need of such treatment.

[0017] The MPN can be selected from chronic myeloid leukemia (CML), polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. Philadelphia chromosome-negative MPNs (e.g., polycythemia vera, essential thrombocythemia, pre-fibrotic forms of primary myelofibrosis, or combinations thereof) often progress to more overt forms of myelofibrosis and advanced stages of MPN (e.g., accelerated-phase MPN, MPN-derived AML, or combinations thereof).

[0018] A further aspect relates to a compound of formula (I) as defined herein for use in the treatment of MPN, such as an advanced stage of MPN.

[0019] According to this aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be administered as monotherapy or in combination with a further therapeutic active agent such as a BET inhibitor, a JAK inhibitor, a Bcl-2 inhibitor, or a combination thereof.

[0020] Thus, a further aspect relates to a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of an advanced stage of MPN, the treatment further comprising administration of a therapeutic active agent selected from JAK inhibitors, BET inhibitors, Bcl-2 inhibitors, and combinations thereof.

[0021] A further aspect relates to a pharmaceutical combination comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and a therapeutic active agent selected from JAK inhibitors, BET inhibitors, Bcl-2 inhibitors, and combinations thereof for use in the treatment of an advanced stage of MPN.

[0022] A further aspect relates to a pharmaceutical composition for use in the treatment of an advanced stage of MPN, the pharmaceutical composition comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and optionally a therapeutic active agent selected from JAK inhibitors, BET inhibitors, Bcl-2 inhibitors, and combinations thereof, and optionally a pharmaceutically acceptable excipient.

[0023] A further aspect relates to a kit for use in the treatment of the advanced stage of MPN, the kit comprising a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, a therapeutic active agent selected from a JAK inhibitor, a BET inhibitor, a Bcl-2 inhibitor, and combinations thereof, and an accompanying document having instructions for use of the kit.

[0024] A further aspect relates to the use of a compound of formula (I) as defined herein above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of the advanced stage of MPN.

[0025] A further aspect relates to a method for the treatment of the advanced stage of MPN by administering a compound of formula (I) as defined herein above or a pharmaceutically acceptable salt thereof to a mammalian subject in need of such treatment.

[0026] A further aspect relates to the use of a compound of formula (I) as defined herein above or a pharmaceutically acceptable salt thereof, and a therapeutic active agent selected from a JAK inhibitor, a BET inhibitor, a Bcl-2 inhibitor, and combinations thereof in the manufacture of a medicament or a pharmaceutical kit for the treatment of the advanced stage of MPN.

[0027] A further aspect relates to a method for the treatment of the advanced stage of MPN by administering a compound of formula (I) as defined herein above or a pharmaceutically acceptable salt thereof, and a therapeutic active agent selected from a JAK inhibitor, a BET inhibitor, a Bcl-2 inhibitor, and combinations thereof to a mammalian subject in need of such treatment.

[0028] Further aspects and embodiments thereof are described herein below. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] [Figure 1]Figures 1A-1C show bar graphs of (Figure 1A) the apoptosis percentage of human MPN cell lines SET-2 and HEL92.1.7, (Figure 1B) the percentage of non-viable AML cells after MPN, and (Figure 1C) the percentage of non-viable normal CD34+ umbilical cord blood progenitor cells after treatment with different concentrations of tascinimod in vitro for 48 hours. [Figure 2] Figures 2A and 2B show bar graphs of relative mRNA expression of different genes compared to untreated cells (Figure 2A), and of the human MPN cell line SET-2 and (Figure 2B) patient-derived CD34+ MF-MPN cells after treatment with 50 μM tascinimod in vitro for 16 hours. [Figure 3] Figures 3A and 3B are Kaplan-Meier plots showing mouse survival rates in patient-derived xenograft (PDX) models for advanced MPN after treatment with tascinimod, ruxolitinib, virabrecib (OTX015), or vehicle in two independent studies. Irradiated NOD scid-gamma (NSG) mice were engrafted with mutant calreticulin (CALR) and telomerase reverse transcriptase (TERT) expressing patient-derived post-MPN AML cells. Treatment was initiated 15 days after infusion of post-MPN AML cells. In Figure 3A, the vehicle was 10 mg / kg tascinimod or 30 mg / kg tascinimod, and in Figure 3B, the vehicle was 30 mg / kg tascinimod, 30 mg / kg ruxolitinib, or 30 mg / kg virabrecib (OTX015). [Figure 4] Figures 4A-4D show (Figure 4A) the apoptosis percentage of the human MPN cell line SET-2, (Figure 4B) the delta synergy score of the same cell line after 48 hours of combination therapy with different concentrations of taskinimod and the JAK inhibitor ruxolitinib, (Figure 4C) the non-viability rate of post-MPN AML cells derived from patients, and (Figure 4D) the delta synergy score of the same cell line after 48 hours of combination therapy with different concentrations of taskinimod and the JAK inhibitor ruxolitinib. [Figure 5]Figures 5A–5F show the percentage of non-viable post-MPN AML cells from three different patients (Figures 5A, 5C, and 5E), as well as the delta synergy scores obtained from these cells after 48 hours of combined treatment with different concentrations of taskinimod and the BET inhibitor CPI-0610 (Figures 5B, 5D, and 5F). [Figure 6] Figures 6A–6F show the percentage of non-viable cells in (Figure 6A) the human MPN cell line SET-2 and (Figures 6C and 6E) post-MPN AML cells from two different patients after 72 hours of combination therapy with different concentrations of tascinimod and the BET inhibitor virabrecib (OTX015), and (Figures 6B, 6D, and 6F) the delta synergistic effect scores for the same cell lines. [Figure 7] Figures 7A–7C show (Figure 7A) survival and (Figures 7B and 7C) spleen size in patient-derived xenograft (PDX) models of progressive MPN after treatment with vehicle, tascinimod, ruxolitinib, or virabrecib (OTX015), or tascinimod (TQ) in combination with ruxolitinib or virabrecib (OTX015). Figure 7A is a Kaplan-Meier plot showing the survival rates of mice in different treatment groups, Figure 7B is a Kaplan-Meier plot showing the spleen length (mm) of treated mice, and Figure 7C shows representative spleen images from each treatment group. [Figure 8] Figures 8A–8D show (Figure 8A) the apoptosis percentage of the human MPN cell line SET-2 and (Figure 8B) the delta synergy score of the same cell line after 72 hours of combination therapy with different concentrations of tascinimod and the Bcl-2 inhibitor Navitoclax, and (Figure 8C) the percentage of patient-derived non-surviving post-MPN AML cells and (Figure 8D) the delta synergy score of the same cell line after 72 hours of combination therapy with different concentrations of tascinimod and the Bcl-2 inhibitor Navitoclax. [Figure 9]Figures 9A–9F show the percentage of non-viable cells in (Figure 9A) the human MPN cell line SET-2 and (Figures 9C and 9E) post-MPN AML cells from two different patients after 72 hours of combination therapy with different concentrations of tascinimod and the BCL-2 inhibitor venetoclax, and (Figures 9B, 9D, and 9F) the delta synergistic effect scores for the same cell line. [Modes for carrying out the invention]

[0030] definition Unless otherwise defined or clearly indicated in the context, all technical and scientific terms and abbreviations used in this disclosure have the same meaning as those commonly understood by those skilled in the art of the field to which this disclosure belongs. However, some definitions of terms used in this disclosure are provided below in this disclosure.

[0031] The terms "a," "an," and "the" encompass multiple cases unless otherwise specified or clearly evident from the context. Therefore, the indefinite article "a" or "an" usually means "at least one."

[0032] When referring to measurable values ​​such as quantity, duration, or time, the term "approximately" is intended to encompass variations of ±20%, ±15%, ±10%, ±5%, ±2%, ±1%, ±0.5%, or ±0.1% from the specified value.

[0033] As used herein, “administer,” “dosage,” etc., means giving, distributing, or applying a drug, agent, or relief to a subject (e.g., a mammalian subject, preferably a human) to alleviate or cure a medical condition. Oral administration is one method of administering the compound to a subject.

[0034] For the purposes of this specification, the term TASQ may be used to refer to the compound of formula (I).

[0035] As used in this disclosure, “combination” means that TASQ and further therapeutic activators, such as BET inhibitors, JAK inhibitors, Bcl-2 inhibitors, or combinations thereof, may be administered simultaneously or separately, in the same formulation, or in separate formulations. Combinations of TASQ and further therapeutic activators include administering each compound separately, for example, sequentially or at different time points. In some embodiments, TASQ and further therapeutic activators are administered essentially simultaneously, for example, simultaneously or sequentially. In some embodiments, TASQ is administered over a first treatment period, followed by the administration of the further therapeutic activator over a second treatment period, and optionally, TASQ and the further therapeutic activator are administered together over a third treatment period. In some embodiments, the further therapeutic activator is administered over a first treatment period, followed by the administration of TASQ over a second treatment period, and optionally, TASQ and the further therapeutic activator are administered together over a third treatment period. In some embodiments, the further therapeutic activator is a BET inhibitor or a Bcl-2 inhibitor. In some embodiments, a further therapeutic agent is a BET inhibitor. In some embodiments, a further therapeutic agent is a Bcl-2 inhibitor.

[0036] Where used herein, when referring to the quantity or combination of therapeutic activators, “effective” means, as used in the manner of the present invention, an amount sufficient to produce a desired therapeutic response without excessive adverse side effects (such as toxicity, irritation, or allergic reactions) that are commensurate with a reasonable benefit / risk ratio.

[0037] As used herein, “excipient” refers to a substance formulated together with the active ingredient of a drug to provide bulk to a solid formulation, for purposes such as long-term stabilization, or to impart therapeutic enhancement to the active ingredient in the final dosage form, for example, by promoting absorption, reducing viscosity, or enhancing solubility. Excipients may also be useful in the manufacturing process, for example, by promoting powder flowability or providing non-stick properties. Examples of excipients include anti-adhesives, binders, coatings, colorants, disintegrants, flavorings, lubricants, preservatives, absorbents, sweeteners, vehicles (carriers), and combinations thereof.

[0038] The terms “to include,” “to contain,” and “to include” (or other forms such as, for example, “to include,” “to contain,” “to include,” and similar) are to be interpreted as inclusive and open-ended. Specifically, the terms and variations mean that a specified feature, step, or component is included, but not that other features, steps, or components are excluded unless they are not specified as such or are evident from the context.

[0039] As used herein, “mammals” may include animals such as dogs, horses, cats, monkeys, rats, sheep, cows, goats, rabbits, or humans. It is preferable that the mammal is a human.

[0040] The term "tumor" refers to an abnormal mass of tissue that forms when cells grow and divide more than necessary, and when they do not die.

[0041] The term "myeloproliferative neoplasm" (MPN) refers to a type of disease in which the bone marrow produces an excessive amount of red blood cells, platelets, or certain white blood cells. Examples of MPNs are described herein.

[0042] The term "advanced stage of MPN" refers to a stage of MPN in which the number of myeloblasts in the peripheral blood or bone marrow is at least 10%. For example, the term "advanced stage MPN" refers to MPN that is in the advanced stage (has reached the advanced stage), i.e., the number of myeloblasts in the peripheral blood or bone marrow is at least 10%.

[0043] The term "accelerated MPN" refers to a stage of MPN where the peripheral blood or bone marrow myeloblast count is at least 10% but less than 20%.

[0044] The term secondary acute myeloid leukemia arising from MPN (or post-MPN AML) refers to the stage of MPN in which the number of myeloblasts in the peripheral blood or bone marrow is at least 20%. Post-MPN AML may also be called blast-stage MPN.

[0045] The term "Philadelphia chromosome" refers to a genetically abnormal chromosome 22 that contains a reciprocal translocation of genetic material between the chromosome and chromosome 9, t(9;22)(q34;q11), and contains the fusion gene BCR-ABL1.

[0046] The term "Philadelphia chromosome negative" indicates the absence of the genetically abnormal Philadelphia chromosome.

[0047] The term "Philadelphia chromosome-negative MPN" refers to MPN in which the Philadelphia chromosome is absent in the cells of an MPN patient.

[0048] "Optional (at will, at will)" or "at will (at will, at will)" means that the events or situations described below may occur, but are not required to occur, and that the explanation includes both cases in which the events or situations occur and cases in which they do not.

[0049] "Pharmacologically acceptable" means that a substance is generally safe, non-toxic, and useful in the preparation of a medicinal composition that is not undesirable for biological or other reasons, and is acceptable for veterinary and human medicinal use.

[0050] Examples of pharmaceutically acceptable salts include alkali metal ions, such as Li. + , Na+, or K + A salt (as a counterion) containing, or an alkaline earth metal ion, such as Mg 2+ Or Ca 2+ A salt containing, or any other pharmaceutically acceptable metal ion, such as Zn 2+ Or Al 3+ Examples of pharmaceutically acceptable salts include salts having or formed with organic bases, such as diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, or tromethamine. Further examples of pharmaceutically acceptable salts include acid addition salts having strong mineral acids, such as hydrochloric acid.

[0051] The terms "simultaneous" or "concurrently" (or "at the same time" or "concurrently"), in relation to the administration of two or more active ingredients to a subject, mean that the active ingredients are administered essentially at the same time, whether via the same or different routes of administration.

[0052] In relation to the administration of two or more active ingredients to a target, the term “separate” (or “separately”) refers to the administration of the active ingredients in separate forms and / or at separate points in time, whether via the same or different routes of administration.

[0053] The term “sequential” (or “continuously”) in relation to the administration of two or more active ingredients to a target indicates that the administration of a second active ingredient follows the administration of a first active ingredient, whether immediately after or after a certain period of time.

[0054] References to TASQ or any other active ingredients prepared herein (e.g., any specific BET inhibitor, JAK inhibitor, or Bcl-2 inhibitor) should be interpreted as references to their pharmaceutically acceptable salts or solvates (e.g., hydrates), unless otherwise specified in the context.

[0055] The therapeutically effective dose means the amount of the therapeutically active ingredient, e.g., TASQ or a pharmaceutically acceptable salt thereof, which, when administered in combination with further compounds as defined herein, is sufficient to treat the condition of interest and to produce such treatment for the condition. The therapeutically effective dose varies depending, for example, on the age and relative health status of the subject being treated, the stage of disease progression, the route and form of administration, the specific combination of TASQ, and one or more further compounds.

[0056] As used herein, the term "treatment" refers to an approach to obtain beneficial or desirable outcomes, including clinical outcomes. Beneficial or desirable clinical outcomes may include, but are not limited to, reduction or improvement of one or more symptoms of the treated disease, reduction in the severity of the disease, stabilization of the disease state (i.e., no worsening), prevention, delay, or slowing of disease progression, improvement or mitigation of the disease state, and remission (partial or total), whether detectable or undetectable. The term may also mean an extension of survival compared to expected survival without treatment.

[0057] Myeloproliferative neoplasms include chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera (PV) with predominantly erythrocytosis, primary and idiopathic myelofibrosis (MF) with megakaryocyte proliferation and progressive myelofibrosis, essential thrombocythemia (ET) with marked thrombocytosis, chronic eosinophilic leukemia, and mastocytosis. MPN also includes the progressive stages of MPN, namely accelerated MPN, which is defined as a myeloblast count of ≥10% to <20% in peripheral blood or bone marrow, and secondary acute myeloid leukemia arising from MPN (post-MPN AML) is defined as ≥20% myeloblasts in the peripheral blood or bone marrow of patients with preceding Philadelphia chromosome-negative MPN.

[0058] Compound of formula (1) In some embodiments, in the compound of formula (I), R is methyl, i.e., the compound is 4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide (tascinimod), which has the following structural formula. [ka]

[0059] As described herein, taschinimod, its pharmaceutically acceptable salts, its deuterated form, its crystalline salts, and pharmaceutical compositions containing taschinimod or its salts, as well as methods for preparing taschinimod, its salts, deuterated forms containing taschinimod and taschinimod salts, and pharmaceutical compositions are described in WO99 / 55678, and as described in WO00 / 03991, WO03 / 106424, WO2012 / 004338 and WO2012 / 175541, the entire document is incorporated into this application by reference.

[0060] In some embodiments, any reference to a compound of formula (I) also includes its deuterated form. As described above herein, the deuterated form of tascinimod is described in WO2012 / 175541. Thus, in some embodiments, tascinimod has a deuterium concentration of at least 70%, more preferably at least 90%, in the amide-N-methyl. In some other embodiments, the compound of formula (I) is dedeuterated, having a deuterium content corresponding to the natural abundance of deuterium.

[0061] In some embodiments, in the compound of formula (I), R is hydrogen, i.e., the compound is 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide having the following structural formula. [ka]

[0062] As used herein, the term TASQ generally refers to the compound of formula (I). In some preferred embodiments, TASQ refers to 4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide (Taskinimod). In some other embodiments, TASQ refers to 4-hydroxy-5-methoxy-1-methyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide.

[0063] In some embodiments, TASQ refers to a pharmaceutically acceptable salt of the compound of formula (I), such as a salt having a monovalent metal cation, like a sodium salt or a potassium salt.

[0064] BET inhibitor The bromodomain and extraterminal (BET) protein families, including the ubiquitously expressed BRD2, BRD3, and BRD4 proteins, as well as the testis-limited BRDT protein, play crucial roles in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cell proliferation and differentiation processes. However, BET proteins have also been reported to be involved in tumorigenesis, and therefore, compounds that can inhibit BET proteins are being developed for use as anticancer agents. Therefore, BET inhibitors are, for example, WO1998 / 011111, WO2006 / 129623, WO2008 / 092231, WO2009 / 158404, WO2009 / 084693, WO2010 / 123975, WO2011 / 143669, WO2011 / 143660, WO2011 / 143651, WO2011 / 054845, WO2011 / 054844, WO2011 / 161031, WO2011 Disclosed in / 054848, WO2011 / 054846, WO2011 / 054843, WO2012 / 174487, WO2012 / 075383, WO2012 / 151512, WO2012 / 116170, WO2013 / 030150, WO2013 / 027168, WO2013 / 024104, WO2013 / 097601, and WO2013 / 033268, the contents of which are incorporated herein by reference.

[0065] Some specific examples of BET inhibitors are listed below, with alternative names in parentheses, and include CAS and IUPAC names. Perabrecib (CPI-0610), CAS number 1380087-89-7, IUPAC name: 2-[(4S)-6-(4-chlorophenyl)-1-methyl-4H-[1,2]oxazolo[5,4-d][2]benzoazepine-4-yl]acetamide, Virabrecib (OTX-015, MK-8628), CAS number 202590-98-5, IUPAC name: 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6Trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(4-hydroxyphenyl)acetamide, Molicib (I-BET 762, GSK525762; GSK525762A), CAS number 1260907-17-2, IUPAC name: 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide, I-BET 151 (GSK1210151A), CAS number 1300031-49-5, IUPAC name: 7-(3,5-dimethyl-1,2-oxazol-4-yl)-8-methoxy-1-[(1R)-1-pyridin-2-yl-ethyl]-3H-imidazo[4,5-c]quinolin-2-one); TEN-010 ((S)-JQ-35), CAS number 1446144-04-2, IUPAC name: 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6 Trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[3-(4-methylpiperazin-1-yl)propyl]acetamide, JQ1 ((+)-JQ-1), CAS number 1268524-70-4, IUPAC name: 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6 tert-Butyl trideca-2(6),4,7,10,12-pentaenoate, ABBV-744 (ABBV744, ABBV 744), CAS number 2138861-99-9, IUPAC name: N-ethyl-4-[2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl]-6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-2-carboxamide; Mibeblesib (ABBV-075, ABBV075), CAS number 1445993-26-9, IUPAC name: N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridine-4-yl)phenyl]ethanesulfonamide, Apabetalone (RVX-208, RVX-000222), CAS number 1044870-39-4, IUPAC name: 2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3H-quinazolin-4-one BMS-986158 (BMS986158), CAS number 1800340-40-2, IUPAC name: 2-[3-(3,5-dimethyltriazol-4-yl)-5-[(S)-oxan-4-yl(phenyl)methyl]pyrido[3,2-b]indole-7-yl]propan-2-ol, MS417 (GTPL7512), CAS number 916489-36-6, IUPAC name: 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0 2,6 ]Trideca-2(6),4,7,10,12-pentaen-9-yl]methyl acetate, AZD-5153 (AZD5153), CAS number 1869912-39-9, IUPAC name: (3R)-4-[2-[4-[1-(3-methoxy-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidine-4-yl]phenoxy]ethyl]-1,3-dimethylpiperazine-2-one, and INCB054329 (INCB54329), CAS number 1628607-64-6, IUPAC name: (11S)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-11-pyridine-2-yl-9-oxa-1,3-diazatricyclo[6.3.1.0 4,12 Dodeca-4(12),5,7-triene-2-one.

[0066] The BET inhibitors disclosed herein may be bromodomain-containing protein 2 (BRD2) inhibitors, bromodomain-containing protein 3 (BRD3) inhibitors, and / or bromodomain-containing protein 4 (BRD4) inhibitors. In some embodiments, the BET inhibitor is a BRD2 inhibitor. In some embodiments, the BET inhibitor is a BRD3 inhibitor. In some embodiments, the BET inhibitor is a BRD4 inhibitor.

[0067] In some embodiments, the BET inhibitor is selected from the BET inhibitors disclosed in any one of the WO brochures referenced above herein.

[0068] In some embodiments, the BET inhibitor is selected from perabrecib, virabrecib, morirecib, I-BET 151, TEN-010, JQ1, ABBV-744, mibebresib, apabetalone, BMS-986158, MS417, AZD-5153, and INCB054329, as well as pharmaceutically acceptable salts thereof.

[0069] In some embodiments, the BET inhibitor is selected from perabrecib or a pharmaceutically acceptable salt thereof, virabrecib or a pharmaceutically acceptable salt thereof, and combinations thereof.

[0070] In some embodiments, the BET inhibitor is vilabrecib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is perabrecib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is molybrecib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is I-BET 151 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is TEN-010 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is JQ1 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is ABBV-744 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is mibeblecib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is apavetalone or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is BMS-986158 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is MS417 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is AZD-5153 or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is INCB054329 or a pharmaceutically acceptable salt thereof.

[0071] BCL-2 inhibitor The Bcl-2 protein family includes several family members, including Bcl-2 (B-cell lymphoma 2), Bcl-xL (B-cell lymphoma - superlarge), Bcl-w (Bcl-2-like protein 2 or BCL2L2), Mcl-1 (inducible myeloid leukemia cell differentiation protein), and A1 (Bcl-2-related protein A1 or BCL2A1). This family is involved in regulating apoptosis in mitochondria and has been found to play important roles in a variety of diseases, including cancer, immune diseases, and autoimmune diseases.

[0072] As used herein, the term Bcl-2 inhibitor refers to an inhibitor of one or more Bcl-2 family proteins, such as Bcl-2, Bcl-xL, Bcl-w, Mcl-1, A1, or combinations thereof. Thus, as referred to herein, a Bcl-2 inhibitor may, but is not limited to, inhibitors of Bcl-2, Bcl-xL, and Bcl-w, or inhibitors of Bcl-2 and Bcl-xL.

[0073] Some specific examples of Bcl-2 inhibitors are listed below, with alternative names in parentheses, and include their CAS number and IUPAC name. Navitocrax (ABT263, ABT-263), CAS number 923564-51-6, IUPAC name: 4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohexa-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, Lisaftoclax, (APG2575, APG-2575), CAS number 2180923-05-9, IUPAC name: 4-[4-[[8-(4-chlorophenyl)spiro[3.5]non-7-en-7-yl]methyl]piperazin-1-yl]-N-[4-[[(2S)-1,4-dioxan-2-yl]methylamino]-3-nitrophenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)benzamide, Obatocracks, (GX15-070), CAS number 803712-67-6, IUPAC name: 2-(2-((3,5-dimethyl-1H-pyrrole-2-yl)methylene)-3-methoxy-2H-pyrrole-5-yl)-1H-indole, and Venetoclax (ABT-199, GDC-0199, G-7601), CAS number 1257044-40-8, IUPAC name: 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.

[0074] In some embodiments, the Bcl-2 inhibitor is navitocrax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is risaftocrax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is ovatocrax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is ovatocrax mesylate or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is navitocrax or a pharmaceutically acceptable salt thereof.

[0075] TASQ and further therapeutic agents Also provided herein are combinations of TASQ with further therapeutic activators, which are BET inhibitors, Bcl-2 inhibitors, or combinations thereof. In some embodiments, the further therapeutic activator is or includes a BET inhibitor. In some embodiments, the further therapeutic activator is or includes a Bcl-2 inhibitor (e.g., navitocrax or a pharmaceutically acceptable salt thereof, or venetoclax or a pharmaceutically acceptable salt thereof). In some embodiments, the BET inhibitor may be selected from, for example, perabrecib, virabrecib, molybrecib, I-BET-151, TEN-010, JQ1, apavetalone, and INCB054329, or pharmaceutically acceptable salts thereof (e.g., perabrecib or a pharmaceutically acceptable salt thereof, virabrecib or a pharmaceutically acceptable salt thereof, or combinations thereof). In some embodiments, the Bcl-2 inhibitor may be selected from, for example, navitocrax, risaftocrax, ovatocrax, and venetoclax, or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is navitocrax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is navitocrax. In some embodiments, the Bcl-2 inhibitor is venetoclax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is venetoclax.

[0076] TASQ and further therapeutic activators may be administered simultaneously in the same formulation, or simultaneously or separately in separate formulations. The combination of TASQ and further therapeutic activators may involve the sequential or different time points of administration of each agent. In some embodiments, TASQ and further agents are administered essentially simultaneously, concurrently, or sequentially.

[0077] In some embodiments, TASQ is administered over a first treatment period, followed by the administration of a further therapeutic activator over a second treatment period, and optionally, a combination of TASQ and the further therapeutic activator over a third treatment period. In some embodiments, the further therapeutic activator is administered over a first treatment period, followed by the administration of TASQ over a second treatment period, and optionally, a combination of TASQ and the further therapeutic activator over a third treatment period. In some embodiments, TASQ is administered over a first treatment period, optionally, followed by the administration of a further therapeutic activator over a second treatment period, and then a combination of TASQ and the further therapeutic activator over a third treatment period. In some embodiments, the further therapeutic activator is administered over a first treatment period, optionally, followed by the administration of TASQ over a second treatment period, and then a combination of TASQ and the further therapeutic activator over a third treatment period. Further modalities are intended to be determined by the treating physician. For example, additional and / or different treatment periods may be required depending on the number and type of further therapeutic activators.

[0078] In some of these embodiments, each treatment period may extend over 1 to 8 weeks, or over 1 to 6 weeks, or over 1 to 4 weeks, for example, over 2 to 4 weeks, thereby the length of each subsequent period may be the same or different.

[0079] In some embodiments, treatment is chronic, i.e., continues for several years, or has no predictable endpoint, i.e., is continued as needed, taking into account the condition of the treated patient. In some embodiments, treatment is intermittent, i.e., is administered for a certain period, as may be determined by the treating physician, then discontinued and resumed at will, as needed, or according to pre-scheduled criteria.

[0080] In some embodiments, TASQ and further therapeutic agents are administered simultaneously or at different times of the day.

[0081] TASQ is preferably administered orally, for example, as a capsule or tablet. Similarly, further therapeutic agents are preferably administered orally, for example, as capsules or tablets.

[0082] However, it should be understood that the present invention is not limited to oral administration, and that, if necessary, either TASQ or any further therapeutic activator, or both, may be administered by another route, such as injection.

[0083] Generally, the active ingredients used in the combination of the present invention are administered in therapeutically effective doses by any of the acceptable modes of administration for drugs that provide similar utility.

[0084] In some preferred and advantageous embodiments, the combinations provided in this disclosure will produce a synergistic effect, which may offer the possibility of dose reduction. However, as is usually the case, when determining an appropriate treatment regimen, the appropriate dose must typically be determined by the treating physician, taking into account factors such as the age, weight, and condition of the patient being treated.

[0085] In some embodiments, the combination involves administering additional therapeutic agents on an outpatient basis, for example, on days 1, 4, 8, and 11 of a 3-week cycle, for a total of up to 8 cycles. While injection or rectal administration of the active ingredient may be considered, oral administration is generally considered most convenient, if necessary.

[0086] In some embodiments, TASQ and further therapeutic activators are administered in separate formulations, for example, each as an oral preparation in the form of a capsule or tablet. In such cases, the above description of preferred pharmaceutical preparations can be applied independently to each such formulation. For example, in some embodiments, TASQ is administered orally to an individual, and simultaneously, sequentially, or separately, further therapeutic activators or drugs are administered orally or by some other mode of administration (if multiple therapeutic activators are used, they may be administered simultaneously, sequentially, or separately).

[0087] In some embodiments, TASQ is administered orally to the individual, for example, as a capsule or tablet, before, after, or during the injection or intravenous administration of further therapeutic activators.

[0088] In some embodiments, the administration of TASQ and the administration of further therapeutic activators are carried out within the same 24-hour period, more preferably within the same 12-hour period, the same 10-hour period, the same 8-hour period, the same 6-hour period, the same 3-hour period, the same 2-hour period, or the same 1-hour period, for example, with one administration occurring immediately after the other.

[0089] In some embodiments, TASQ is administered daily, but further therapeutic activators may be administered on the same or different treatment schedule as TASQ, for example, daily, weekly, or at any other preferred interval.

[0090] Generally, the daily dose of TASQ is expected to range from a minimum of 0.001 mg / kg body weight, or 0.002 mg / kg body weight, or 0.005 mg / kg body weight, or 0.008 mg / kg body weight, or a maximum of 0.2 mg / kg body weight, or 0.1 mg / kg body weight, or 0.05 mg / kg body weight, or 0.02 mg / kg body weight, or 0.01 mg / kg body weight.

[0091] In some embodiments, TASQ is administered in amounts of 0.1–0.3 mg / day, or 0.15–0.3 mg / day, for example, 0.2–0.3 mg / day (or the corresponding amount of a pharmaceutically acceptable salt of TASQ).

[0092] In some embodiments, TASQ is administered in doses of 0.1–6 mg / day, 0.2–6 mg / day, or 0.5–6 mg / day (or in corresponding doses of pharmaceutically acceptable salts of TASQ).

[0093] In some embodiments, TASQ is administered in doses of 0.1–1 mg / day, 0.2–1 mg / day, or 0.5–1 mg / day (or in corresponding doses of pharmaceutically acceptable salts of TASQ).

[0094] In some embodiments, TASQ is administered in doses of 0.2–1.5 mg / day, 0.4–1.5 mg / day, or 0.8–1.5 mg / day (or in corresponding doses of pharmaceutically acceptable salts of TASQ).

[0095] In some embodiments, TASQ is administered in doses of 0.5–2 mg / day, or 0.8–2 mg / day, for example, 1–2 mg / day (or the corresponding dose of a pharmaceutically acceptable salt of TASQ).

[0096] In some embodiments, TASQ is administered in doses of 0.8–3 mg / day, or 1–3 mg / day, for example, 1.5–3 mg / day (or the corresponding amount of a pharmaceutically acceptable salt of TASQ).

[0097] In some embodiments, TASQ is administered in doses of 1–6 mg / day, or 2–6 mg / day, for example, 3–6 mg / day (or the corresponding dose of a pharmaceutically acceptable salt of TASQ).

[0098] In some embodiments, the dose of one or both of the active ingredients may be gradually adjusted to reach an optimal result, a so-called dose titration. For example, the dose titration may be configured to begin with a low daily dose of, for example, 0.25 mg of the active ingredient as defined herein, and maintain this dose level for a period of one or two weeks. If no significant side effects that would contraindicate dose increases are encountered, the level may then be increased, for example, to 0.5 mg / day for one or two weeks, after which another increase may be planned to reach a daily dose of 1 mg. In this manner, if any significant side effects occur after a gradual increase in the dose, the dose may be reduced again to the previous level.

[0099] In some embodiments, each of the further therapeutic activators may be administered to a mammalian patient, such as a human, in any dose, for example, 0.005 to 50 mg per kg of body weight, 0.01 to 50 mg per kg of body weight, 0.05 to 50 mg per kg of body weight, 0.1 to 50 mg per kg of body weight, 0.2 to 50 mg per kg of body weight, 0.5 to 50 mg per kg of body weight, 1 to 50 mg per kg of body weight, 2 to 50 mg per kg of body weight, 5 to 50 mg per kg of body weight, 10 to 50 mg per kg of body weight, 15 to 50 mg per kg of body weight, 20 to 50 mg per kg of body weight, or 25 to 50 mg per kg of body weight, during the treatment period, for example, once every other day, once a day, or twice a day.

[0100] In some embodiments, each of the further therapeutic activators may be administered to a mammalian patient, such as a human, in any dose, for example, 0.005 to 30 mg per kg of body weight, 0.01 to 30 mg per kg of body weight, 0.05 to 30 mg per kg of body weight, 0.1 to 30 mg per kg of body weight, 0.2 to 30 mg per kg of body weight, 0.5 to 30 mg per kg of body weight, 1 to 30 mg per kg of body weight, 2 to 30 mg per kg of body weight, 5 to 30 mg per kg of body weight, 10 to 30 mg per kg of body weight, 15 to 30 mg per kg of body weight, 20 to 30 mg per kg of body weight, or 25 to 30 mg per kg of body weight, during the treatment period, for example, once every day, once daily, or twice daily.

[0101] In some embodiments, each of the further therapeutic activators may be administered to a mammalian patient, such as a human, in any dose, for example, 0.005 to 20 mg per kg of body weight, 0.01 to 20 mg per kg of body weight, 0.05 to 20 mg per kg of body weight, 0.1 to 20 mg per kg of body weight, 0.2 to 20 mg per kg of body weight, 0.5 to 20 mg per kg of body weight, 1 to 20 mg per kg of body weight, 2 to 20 mg per kg of body weight, 5 to 20 mg per kg of body weight, 10 to 20 mg per kg of body weight, or 15 to 20 mg per kg of body weight, during the treatment period, for example, once or twice a day, every other day.

[0102] In some embodiments, each of the further therapeutic activators may be administered to mammalian patients, such as humans, in any dose, for example, 0.005 to 10 mg per kg of body weight, 0.01 to 10 mg per kg of body weight, 0.05 to 10 mg per kg of body weight, 0.1 to 10 mg per kg of body weight, 0.2 to 10 mg per kg of body weight, 0.5 to 10 mg per kg of body weight, 1 to 10 mg per kg of body weight, 2 to 10 mg per kg of body weight, or 5 to 10 mg / kg of body weight, every other day, once daily, or twice daily during the treatment period.

[0103] In some embodiments, each of the further therapeutic activators may be administered to a mammalian patient, such as a human, in doses of, for example, 0.005–5 mg / kg body weight, 0.01–5 mg / kg body weight, 0.05–5 mg / kg body weight, 0.1–5 mg / kg body weight, 0.2–5 mg / kg body weight, 0.5–5 mg / kg body weight, 1–5 mg / kg body weight, or 2–5 mg / kg body weight, for a period of treatment, for example, once daily, every other day, or twice daily.

[0104] In some embodiments, each of the further therapeutic activators may be administered to a mammalian patient, such as a human, in doses of, for example, 0.005–3 mg / kg body weight, 0.01–3 mg / kg body weight, 0.05–3 mg / kg body weight, 0.1–3 mg / kg body weight, 0.2–3 mg / kg body weight, 0.5–3 mg / kg body weight, 1–3 mg / kg body weight, or 2–3 mg / kg body weight, for a period of treatment, for example, once daily, every other day, or twice daily.

[0105] In some embodiments, each of the further therapeutic activators may be administered to a mammalian patient, such as a human, in doses of, for example, 0.005–2 mg / kg body weight, 0.01–2 mg / kg body weight, 0.05–2 mg / kg body weight, 0.1–2 mg / kg body weight, 0.2–2 mg / kg body weight, 0.5–2 mg / kg body weight, or 1–2 mg / kg body weight, for a period of treatment, for example, once daily, every other day, or twice daily.

[0106] In some embodiments, further therapeutic activators are or comprise perabrecib, virabrecib, molybrecib, I-BET-151, TEN-010, JQ1, apabetalone, and INCB054329, as well as pharmaceutically acceptable salts thereof (e.g., from perabrecib and virabrecib), administered in doses of 5 mg to 300 mg, or 10 mg to 300 mg, 25 mg to 300 mg, 50 mg to 300 mg, or 100 mg to 300 mg over a period of treatment.

[0107] In some of these embodiments, each of the additional therapeutic agents is administered over the course of treatment in doses of 5 mg to 200 mg, or 10 mg to 200 mg, 25 mg to 200 mg, 50 mg to 200 mg, or 100 mg to 200 mg.

[0108] In some of these embodiments, each of the additional therapeutic agents is administered over the course of treatment in doses of 5 mg to 150 mg, or 10 mg to 150 mg, 25 mg to 150 mg, or 50 mg to 150 mg.

[0109] In some of these embodiments, each of the additional therapeutic agents is administered over the course of treatment in doses of 5 mg to 100 mg, or 10 mg to 100 mg, 25 mg to 100 mg, or 50 mg to 100 mg.

[0110] In some of these embodiments, each of the additional therapeutic agents is administered over the course of treatment in doses of 5 mg to 80 mg, 10 mg to 80 mg, 25 mg to 80 mg, or 50 mg to 80 mg.

[0111] In some of these embodiments, each of the additional therapeutic agents is administered over the course of treatment in doses of 5 mg to 50 mg, 10 mg to 50 mg, or 25 mg to 50 mg.

[0112] In some embodiments, each of the further therapeutic compounds may be administered over the course of treatment in doses of 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, or 0.1 to 5 mg.

[0113] In some of these embodiments, each of the additional therapeutic agents may be configured to be administered over the course of treatment in doses of 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 to 15 mg, 1 to 10 mg, or 1 to 5 mg.

[0114] In some of these embodiments, each of the additional therapeutic agents may be configured to be administered over a period of treatment in doses of 2 mg to 100 mg, 2 mg to 50 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 to 15 mg, 2 to 10 mg, or 1 to 5 mg.

[0115] In some of these embodiments, each of the additional therapeutic agents may be configured to be administered over a period of treatment in doses of 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 5 mg to 20 mg, 5 to 15 mg, or 5 to 10 mg.

[0116] In some of these embodiments, each of the additional therapeutic agents may be configured to be administered over the course of treatment in doses of 10 mg to 100 mg, 10 mg to 50 mg, 10 mg to 25 mg, 10 mg to 20 mg, or 10 to 15 mg.

[0117] In the embodiments described above, the dosage may be administered, for example, once every two days, daily, or twice daily. In some embodiments, administration is daily. Preferably, administration is by oral route.

[0118] The duration of treatment may be determined by the treating physician and may range, for example, from one week to six months, one week to two months, or two weeks to two months, or for example, from two to four weeks. The duration of treatment may also be, for example, one year or several years. Treatment may also be structured to continue throughout the patient's lifetime, i.e., chronically, or as determined by the treating physician.

[0119] In some embodiments, TASQ is administered concurrently with the additional therapeutic agent or drug during the entire treatment period or during a portion of the treatment period. In some embodiments, the additional therapeutic agent or drug and TASQ are administered in separate (non-overlapping) treatment periods, optionally during intermediate periods without administration of either TASQ or the additional therapeutic agent or drug.

[0120] Generally, each active ingredient may be administered daily, for example, 1 to 3 times, or 1 to 2 times, for example, once a day. In some embodiments, administration is performed on a less frequent basis, for example, every other day, once a week, etc. Administration may follow an established treatment cycle, for example, over 3 to 6 weeks.

[0121] In some embodiments, TASQ and further therapeutic agents (e.g., BET inhibitors, Bcl-2 inhibitors, or combinations thereof) are administered according to different dosing schedules and, possibly, different modes of administration. However, preferably, both TASQ and further therapeutic agents or drugs are administered orally (e.g., as capsule or tablet preparations). In some embodiments, both TASQ and further therapeutic agents or multiple drugs are provided as capsule formulations suitable for oral administration.

[0122] In some embodiments, the use of TASQ in combination with further therapeutic agents selected from BET inhibitors, Bcl-2 inhibitors, and combinations thereof can very advantageously provide a synergistic therapeutic effect (i.e., more than an additive effect).

[0123] One aspect of the present invention is a pharmaceutical composition comprising TASQ or a pharmaceutically acceptable salt thereof for use in the treatment of MPN, the treatment also comprising administration of the pharmaceutical composition comprising a further therapeutic activator which is a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof.

[0124] In one embodiment, a method for treating myeloproliferative neoplasms (MPNs) in a subject in need includes administering to the subject TASQ and further therapeutic activators, which are BET inhibitors, Bcl-2 inhibitors, or combinations thereof.

[0125] Pharmaceutical composition TASQ and one or more further therapeutic agents (e.g., BET inhibitors, JAK inhibitors, Bcl-2 inhibitors, or combinations thereof such as BET inhibitors and Bcl-2 inhibitors) are provided in one identical pharmaceutical composition, or separately, in different compositions used in combination, each pharmaceutical composition may be configured to be suitable for enteral administration, such as rectal or oral administration, or parenteral administration to mammals (particularly humans), and may contain, in a therapeutically effective amount, one or more active ingredients, optionally accompanied by pharmaceutically acceptable excipients, such as pharmaceutically acceptable carriers. The therapeutically effective amount of each active ingredient is as defined herein above and depends, for example, on the mammalian species, body weight, age, individual condition, individual pharmacokinetic data, and mode of administration.

[0126] For enteral administration, such as oral administration, each active ingredient can be formulated in a wide variety of dosage forms. A pharmaceutically acceptable carrier may be either solid or liquid. Solid preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that also act as diluents, flavorings, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is generally a finely divided solid, a mixture with the finely divided active ingredient. In tablets, the active ingredient is generally mixed in appropriate proportions with a carrier having the required binding capacity and compressed into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-solubility waxes, and cocoa butter.

[0127] Other forms suitable for oral administration include emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or liquid preparations containing solid preparations, which are intended to be converted to liquid preparations immediately before use. Emulsions may be prepared in solution, for example, in an aqueous solution of propylene glycol, or may contain emulsifiers, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding appropriate colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing the micronized active ingredient in water using viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Solid preparations may include solutions, suspensions, and emulsions and may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0128] Examples of compositions for rectal administration include suppositories that are solid at normal temperatures but may contain suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters, or polyethylene glycol, which liquefy and / or dissolve in the rectal lumen to release the drug.

[0129] The active ingredient may also be administered parenterally by injection or infusion, for example, intravenously, intraarterially, intraosseously, intramuscularly, intracerebrally, intraventricularly, synovially, intrasternally, subarachnoidally, intralesionally, intracranially, intratumorally, intradermally, and subcutaneously. Therefore, for parenteral administration, the pharmaceutical composition may be in the form of sterile injection or injection preparations, for example, sterile aqueous solutions or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents (e.g., Tween® 80) and suspending agents, using techniques known in the art. Sterile injection or injection preparations may be sterile injection or injection solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as a 1,3-butanediol solution. For example, the pharmaceutical composition may be a solution in 1,3-butanediol. Other examples of acceptable vehicles and solvents that may be used in the compositions of the present invention include, but are not limited to, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterilized fixative oils are conventionally used as solvents or suspension media. For this purpose, any fixative oil may be employed, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectable preparations, as there are naturally pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.

[0130] Solutions for parenteral use may also contain appropriate stabilizers and, if necessary, buffering agents. Suitable stabilizers include antioxidants such as sodium bisulfate, sodium sulfite, or ascorbic acid, either alone or in combination, citric acid and its salts, and sodium EDTA. Parenteral solutions may also contain preservatives such as benzalkonium chloride, methylparaben or propylparaben, and chlorobutanol.

[0131] Conventional procedures for the selection and preparation of appropriate pharmaceutical formulations are described, for example, in “Pharmaceutics - The Science of Dosage Form Design”, MB Aulton, Churchill Livingstone, 2nd ed. 2002 (ISBN 0443055173, 9780443055171). Methods for preparing pharmaceutical excipients, such as carriers, and pharmaceutical dosage forms are also described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in the art of drug formulation.

[0132] The pharmaceutical composition may consist of one or more active ingredients totaling about 1% to about 95% by weight of the composition, with the remainder being at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains at least 5%, at least 10%, at least 15%, or at least 20% of one or more active ingredients. In some embodiments, the pharmaceutical composition contains up to 90%, up to 85%, or up to 80% of one or more active ingredients. For example, in some embodiments, the pharmaceutical composition contains about 20% to about 90% of one or more active ingredients and at least one pharmaceutically acceptable excipient.

[0133] Furthermore, pharmaceutical compositions (or formulations) are disclosed herein that, as active ingredients, include TASQ or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent described herein (e.g., a BET inhibitor, a JAK inhibitor, and a Bcl-2 inhibitor, or a combination thereof such as a BET inhibitor, a Bcl-2 inhibitor, or a combination of a BET inhibitor and a Bcl-2 inhibitor), together with a pharmaceutically acceptable excipient, such as a carrier.

[0134] kit Further embodiments disclosed herein include a kit comprising TASQ or a pharmaceutically acceptable salt thereof, further therapeutic agents described herein (e.g., BET inhibitors, JAK inhibitors, Bcl-2 inhibitors, or combinations thereof such as BET inhibitors, Bcl-2 inhibitors, or combinations thereof), and a package insert having instructions for their use.

[0135] In the kit, TASQ and additional therapeutic activators may be present in a form that allows for separate administration or administration of the components together.

[0136] In some embodiments, the kit includes a pharmaceutical formulation containing TASQ or a pharmaceutically acceptable salt thereof, a pharmaceutical formulation containing a further therapeutic agent, and a package insert having instructions for their use.

[0137] In some embodiments, the kit includes an orally administered pharmaceutical formulation containing TASQ or a pharmaceutically acceptable salt thereof, an orally administered pharmaceutical formulation containing a further therapeutic activator, and a package insert having instructions for their use.

[0138] Any particular embodiment of such kits includes configurations defined herein in relation to specific combinations, uses, and pharmaceutical formulations (or compositions).

[0139] treatment Further embodiments disclosed herein are methods for treating MPN, comprising administering TASQ or a pharmaceutically acceptable salt thereof to an individual in need of such treatment in combination with further therapeutic agents described herein (e.g., BET inhibitors, JAK inhibitors, Bcl-2 inhibitors, or BET inhibitors, Bcl-2 inhibitors, or a combination of BET inhibitors and Bcl-2 inhibitors). Specific embodiments of such methods include configurations defined herein in relation to specific combinations, pharmaceutical compositions (or formulations), uses, and kits.

[0140] Treatment indications The combinations provided herein are useful for the treatment of myeloproliferative neoplasms (MPNs).

[0141] In some embodiments, the combinations disclosed herein are provided for use in the treatment of MPN, including myelofibrosis (including primary myelofibrosis and myelofibrosis arising from essential thrombocytosis or polycythemia vera), essential thrombocytosis, polycythemia vera, chronic neutrophilic leukemia, chronic myeloid leukemia, chronic eosinophilic leukemia, and advanced-stage MPN such as accelerated-stage MPN or post-MPN AML. In some embodiments, MPN is Philadelphia chromosome-negative MPN (e.g., advanced-stage, Philadelphia chromosome-negative MPN). In some embodiments, Philadelphia chromosome-negative MPN is selected from myelofibrosis, essential thrombocytosis, and polycythemia vera. In some embodiments, MPN is myelofibrosis. In some embodiments, myelofibrosis is primary myelofibrosis.

[0142] Essential thrombocythemia (ET) is characterized by excessive production of platelets by megakaryocytes in the bone marrow. Essential thrombocythemia can develop into myelofibrosis.

[0143] In polycythemia vera, the bone marrow produces excessive red blood cells, and the disorder can also lead to excessive production of white blood cells and platelets. Polycythemia vera can develop into myelofibrosis.

[0144] In some embodiments, MPN is myelofibrosis. Myelofibrosis is a disorder in which normal bone marrow tissue is gradually replaced by fibrous, scar-like material. Over time, this can lead to progressive bone marrow failure. Approximately one-third of patients with myelofibrosis are diagnosed with polycythemia (post-erythropoiesis myelofibrosis) or essential thrombocythemia (post-ET myelofibrosis).

[0145] In some embodiments, MPN is selected from the progression stages of MPN having a precursor Philadelphia chromosome-negative MPN. In some of these embodiments, MPN is an accelerated MPN. In some of these embodiments, MPN is post-MPN AML.

[0146] Compound of formula (I) for use in post-MPN AML, In a further embodiment, a compound of formula (I) as defined herein (e.g., TASQ) is provided for use, for example, in the treatment of secondary acute myeloid leukemia (AML) progressing from a precursor myeloproliferative neoplasm (MPN) of post-MPN AML.

[0147] In this embodiment, the compound of formula (I) (e.g., TASQ) may be administered as monotherapy using the doses and pharmaceutical compositions described above for TASQ in conjunction with a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof. Accordingly, specific embodiments of this embodiment include the same configurations discussed herein in relation to TASQ in embodiments of the combination therapy embodiment, unless otherwise specified or evident from the context.

[0148] Combination of TASQ with additional therapeutic agents selected from JAK inhibitors, BET inhibitors, and BCL-2 inhibitors. Further embodiments relate to combinations of TASQ with a therapeutic activator selected from JAK inhibitors, BET inhibitors, and Bcl-2 inhibitors, or combinations of TASQ with two or more such inhibitors, for use in the treatment of post-MPN AML. In these embodiments, TASQ may be administered as a combination therapy for the treatment of MPN, in connection with combination therapy with a BET inhibitor, a Bcl-2 inhibitor, or a combination thereof, using the doses and pharmaceutical compositions described above for TASQ. Thus, specific embodiments of these embodiments include the same configurations as defined in relation to TASQ in embodiments of the earlier combination therapy embodiments described above, unless otherwise specified or evident from the context.

[0149] In some embodiments, further therapeutic agents are BET inhibitors, Bcl-2 inhibitors, or combinations thereof. In some embodiments, further therapeutic agents are BET inhibitors or Bcl-2 inhibitors. In some embodiments, further therapeutic agents include or are BET inhibitors. In some embodiments, further therapeutic agents include Bcl-2 inhibitors.

[0150] In some embodiments, the BET inhibitor may be selected from any BET inhibitor, such as any of the BET inhibitors described herein. In some embodiments, the BET inhibitor is perabrecib or a pharmaceutically acceptable salt thereof, or virabrecib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is perabrecib or a pharmaceutically acceptable salt thereof. In some embodiments, the BET inhibitor is virabrecib or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the Bcl-2 inhibitor may be selected from any Bcl-2 inhibitor, such as any of the Bcl-2 inhibitors described herein. In some embodiments, the Bcl-2 inhibitor is selected from navitocrax or a pharmaceutically acceptable salt thereof, risafthocrax or a pharmaceutically acceptable salt thereof, ovatocrax or a pharmaceutically acceptable salt thereof (e.g., ovatocrax mesylate), or venetocrax or a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is selected from navitocrax, risafthocrax, ovatocrax (or ovatocrax mesylate), and venetocrax.

[0152] In some embodiments, the Bcl-2 inhibitor is a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is a pharmaceutically acceptable salt thereof. In some embodiments, the Bcl-2 inhibitor is a pharmaceutically acceptable salt of any of the Bcl-2 inhibitors described herein (e.g., ovatoclax mesylate).

[0153] Janus kinase (JAK) is a protein tyrosine kinase that phosphorylates a group of proteins called signaling and transcription activators or STATs. When phosphorylated, STATs dimerize and translocate to the nucleus, activating the expression of genes that, among other things, lead to cell proliferation. Due to the central role that the JAK family plays in cytokine-dependent regulation of both proliferation and terminal function in several important cell types, drugs that can inhibit JAK kinases are being developed for use in the prevention and chemotherapy of these enzyme-dependent conditions, including various myeloproliferative neoplasms (MPNs), a group of bone marrow diseases characterized by the overproduction of cells. Some examples of JAK inhibitors include ruxolitinib (CAS number 941678-49-5, IUPAC name: (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)pyrazole-1-yl]propannitrile) and fedratinib (CAS number 936091-26-8, IUPAC name: N-tert-butyl-3-{5-methyl-2-[4-(2-pyrrolidine-1-ylethoxy)-pheni There are pacritinib (CAS number 937272-79-2, IUPAC name: (16E)-11-[2-(1-pyrrolidinyl)ethoxy]-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene).

[0154] In some embodiments, further therapeutic agents are BET inhibitors, JAK inhibitors, or combinations thereof (e.g., BET inhibitors or JAK inhibitors). In some embodiments, further therapeutic agents are Bcl-2 inhibitors, JAK inhibitors, or combinations thereof (Bcl-2 inhibitors or JAK inhibitors). In some embodiments, further therapeutic agents are JAK inhibitors. In some embodiments, the JAK inhibitor is preferably selected from JAK1 inhibitors and JAK2 inhibitors. In some embodiments, the JAK inhibitor is an inhibitor of JAK1 and JAK2. In some embodiments, the JAK inhibitor is ruxolitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is an inhibitor of JAK2. In some embodiments, the JAK inhibitor is fedratinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor is pacritinib or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the JAK inhibitor is selected from ruxolitinib, fedratinib, pacritinib, and pharmaceutically acceptable salts thereof.

[0156] In some embodiments, the JAK inhibitor may be administered to mammalian patients, such as humans, in any dose, for example, 0.005 to 50 mg per kg of body weight, 0.01 to 50 mg per kg of body weight, 0.05 to 50 mg per kg of body weight, 0.1 to 50 mg per kg of body weight, 0.2 to 50 mg per kg of body weight, 0.5 to 50 mg per kg of body weight, 1 to 50 mg per kg of body weight, 2 to 50 mg per kg of body weight, 5 to 50 mg per kg of body weight, 10 to 50 mg per kg of body weight, 15 to 50 mg per kg of body weight, 20 to 50 mg per kg of body weight, or 25 to 50 mg per kg of body weight, for example, every other day, once a day, or twice a day, during the treatment period.

[0157] In some embodiments, the JAK inhibitor may be administered to mammalian patients, such as humans, in any dose, for example, 0.005 to 30 mg per kg of body weight, 0.01 to 30 mg per kg of body weight, 0.05 to 30 mg per kg of body weight, 0.1 to 30 mg per kg of body weight, 0.2 to 30 mg per kg of body weight, 0.5 to 30 mg per kg of body weight, 1 to 30 mg per kg of body weight, 2 to 30 mg per kg of body weight, 5 to 30 mg per kg of body weight, 10 to 30 mg per kg of body weight, 15 to 30 mg per kg of body weight, 20 to 30 mg per kg of body weight, or 25 to 30 mg per kg of body weight, for example, every other day, once a day, or twice a day during the treatment period.

[0158] In some embodiments, the JAK inhibitor may be administered to mammalian patients, such as humans, at any dose, for example, 0.005 to 20 mg per kg of body weight, 0.01 to 20 mg per kg of body weight, 0.05 to 20 mg per kg of body weight, 0.1 to 20 mg per kg of body weight, 0.2 to 20 mg per kg of body weight, 0.5 to 20 mg per kg of body weight, 1 to 20 mg per kg of body weight, 2 to 20 mg per kg of body weight, 5 to 20 mg per kg of body weight, 10 to 20 mg per kg of body weight, or 15 to 20 mg per kg of body weight, for the duration of treatment, for example, once every day, once daily, or twice daily.

[0159] In some embodiments, the JAK inhibitor may be administered to mammalian patients, such as humans, at any dose, for example, 0.005–10 mg / kg body weight, 0.01–10 mg / kg body weight, 0.05–10 mg / kg body weight, 0.1–10 mg / kg body weight, 0.2–10 mg / kg body weight, 0.5–10 mg / kg body weight, 1–10 mg / kg body weight, 2–10 mg / kg body weight, or 5–10 mg / kg body weight, for the duration of treatment, for example, once daily, every other day, or twice daily.

[0160] In some embodiments, the JAK inhibitor may be administered, for example, during the treatment period, in doses of 0.005–5 mg / kg body weight, 0.01–5 mg / kg body weight, 0.05–5 mg / kg body weight, 0.1–5 mg / kg body weight, 0.2–5 mg / kg body weight, 0.5–5 mg / kg body weight, 1–5 mg / kg body weight, or 2–5 mg / kg body weight, for example, every two days, once daily, or twice daily.

[0161] In some embodiments, the JAK inhibitor may be administered to mammalian patients, such as humans, during the treatment period in doses of, for example, 0.005–3 mg / kg body weight, 0.01–3 mg / kg body weight, 0.05–3 mg / kg body weight, 0.1–3 mg / kg body weight, 0.2–3 mg / kg body weight, 0.5–3 mg / kg body weight, 1–3 mg / kg body weight, or 2–3 mg / kg body weight, for example, once daily, every other day, or twice daily.

[0162] In some embodiments, the JAK inhibitor may be administered, for example, during the treatment period, in doses of 0.005–2 mg / kg body weight, 0.01–2 mg / kg body weight, 0.05–2 mg / kg body weight, 0.1–2 mg / kg body weight, 0.2–2 mg / kg body weight, 0.5–2 mg / kg body weight, or 1–2 mg / kg body weight, for example, every two days, once daily, or twice daily.

[0163] In some embodiments, a JAK inhibitor, such as ruxolitinib, fedratinib, pacritinib, and pharmaceutically acceptable salts thereof, particularly ruxolitinib, is administered over the course of treatment in doses of 5 mg to 300 mg, or 10 mg to 300 mg, 25 mg to 300 mg, 50 mg to 300 mg, or 100 mg to 300 mg.

[0164] In some of these embodiments, the JAK inhibitor is administered over the course of treatment in doses of 5 mg to 200 mg, or 10 mg to 200 mg, 25 mg to 200 mg, 50 mg to 200 mg, or 100 mg to 200 mg.

[0165] In some of these embodiments, the JAK inhibitor is administered over the course of treatment in doses of 5 mg to 150 mg, or 10 mg to 150 mg, 25 mg to 150 mg, or 50 mg to 150 mg.

[0166] In some of these embodiments, the JAK inhibitor is administered over the course of treatment in doses of 5 mg to 100 mg, or 10 mg to 100 mg, 25 mg to 100 mg, or 50 mg to 100 mg.

[0167] In some of these embodiments, the JAK inhibitor is administered over the course of treatment in doses of 5 mg to 80 mg, 10 mg to 80 mg, 25 mg to 80 mg, or 50 mg to 80 mg.

[0168] In some of these embodiments, the JAK inhibitor is administered in doses of 5 mg to 50 mg, 10 mg to 50 mg, or 25 mg to 50 mg over the course of treatment.

[0169] In some of these embodiments, the JAK inhibitor is administered over the course of treatment in doses of 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 to 15 mg, 1 to 10 mg, or 1 to 5 mg.

[0170] In some of these embodiments, the JAK inhibitor is administered over the course of treatment in doses of 2 mg to 100 mg, 2 mg to 50 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 to 15 mg, 2 to 10 mg, or 1 to 5 mg.

[0171] In some of these embodiments, the JAK inhibitor is administered over the course of treatment in doses of 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 5 mg to 20 mg, 5 to 15 mg, or 5 to 10 mg.

[0172] In some of these embodiments, the JAK inhibitor is administered over the course of treatment in doses of 10 mg to 100 mg, 10 mg to 50 mg, 10 mg to 25 mg, 10 mg to 20 mg, or 10 to 15 mg.

[0173] In the embodiments described above, the dosage may be administered, for example, once every two days, daily, or twice daily. In some embodiments, administration is daily. Preferably, administration is by oral route.

[0174] The duration of treatment may be determined by the treating physician and may range, for example, from one week to six months, one week to two months, or two weeks to two months, or even from two to four weeks. The duration of treatment may also be, for example, one year or several years. Treatment may also continue throughout the patient's lifetime, i.e., chronically, or as determined by the treating physician.

[0175] In some embodiments, TASQ is administered concurrently with the JAK inhibitor during the entire JAK inhibitor treatment period or during a portion of the JAK inhibitor treatment period. In some embodiments, the JAK inhibitor and TASQ are administered in separate (non-overlapping) treatment periods, optionally, during an intermediate period without administration of either drug.

[0176] Generally, each active ingredient may be administered daily, for example, 1 to 3 times, or 1 to 2 times, for example, once a day. In some embodiments, administration is performed on a less frequent basis, for example, every other day, once a week, etc. Administration may follow an established treatment cycle, for example, over 3 to 6 weeks.

[0177] In some embodiments, TASQ and JAK inhibitors are administered according to different dosing schedules and, possibly, different modes of administration. However, both TASQ and JAK inhibitors are preferably administered orally, for example, as capsule or tablet preparations. In some embodiments, both TASQ and JAK inhibitors are provided as capsule preparations suitable for oral administration.

[0178] In some embodiments, the use of a combination of TASQ and a JAK inhibitor can very advantageously provide a synergistic therapeutic effect, i.e., a therapeutic effect greater than the additive effect.

[0179] One aspect of the present invention is a pharmaceutical composition comprising TASQ or a pharmaceutically acceptable salt thereof for use in the treatment of post-MPN AML, the treatment also comprising administration of a pharmaceutical composition comprising a JAK inhibitor, a BET inhibitor, or a Bcl-2 inhibitor, or a combination thereof.

[0180] As described herein, a combination of at least two inhibitors selected from JAK inhibitors, BET inhibitors, and Bcl-2 inhibitors may, for example, be a combination of a BET inhibitor and one further inhibitor selected from JAK inhibitors and Bcl-2 inhibitors. In some embodiments, the inhibitor combination includes a Bcl-2 inhibitor. In some embodiments, the inhibitor combination includes a JAK inhibitor.

[0181] Further embodiments of the present invention are pharmaceutical compositions and kits for use in the treatment of post-MPN AML, comprising TASQ and JAK inhibitors, BET inhibitors, or Bcl-2 inhibitors. The features of embodiments of these embodiments are generally described herein with respect to the treatment of other indications, such as MPN.

[0182] A method for treating the progressive stages of MPN in subjects such as mammals, comprising a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (wherein R is selected from hydrogen and methyl), This includes administering JAK inhibitors, BET inhibitors, Bcl-2 inhibitors, or combinations thereof to the target population.

[0183] In one embodiment, the treatment regimen is: For patients requiring treatment for MPN, preleukemic state, or myeloproliferative neoplasms, administering a JAK inhibitor, BET inhibitor, or Bcl-2 inhibitor is recommended. The drug should be administered in accordance with the stage of progression to the JAK inhibitor, the BET inhibitor, or the Bcl-2 inhibitor, the stage of advanced MPN, the stage of MPN with excessive blast cells, or the stage of progression to accelerated or secondary acute myeloid leukemia. The subject is given TASQ, This includes optionally continuing to administer the JAK inhibitor, BET inhibitor, Bcl-2 inhibitor, or a combination thereof, together with the TASQ. [Examples]

[0184] The present invention is further illustrated in the following non-limiting embodiments.

[0185] Example 1: Use of Taskinimodo Human MPN cell line SET-2 (DSMZ catalog number ACC 608 (Brunschweig, Germany), RRID: CVCL_2187), and human post-MPN AML cells isolated from whole blood by density centrifugation (Ficoll®) from four different patients with HEL92.1.7, advanced MPN (with JAK2V617F or calreticulin mutation), as well as human normal CD34 derived from umbilical cord blood. + Progenitor cells were cultured in RPMI-1640 medium supplemented with 20% fetal bovine serum (FBS) and treated with different concentrations of tascinimod for 48 hours. At the end of treatment, the cells were washed in 1×PBS and treated with Annexin-V-FITC (BD Bioscience) and / or TO-PRO. TM Staining was performed with -3 iodide (Invitrogen). The percentage of apoptotic cells (Annexin-V positive) or the percentage of non-viable cells (TO-PRO TM(-3 Iodide positive) was determined by flow cytometry. Figures 1A-1C show that treatment with tascinimod induced apoptosis and reduced cell viability in human MPN and post-MPN AML cells. However, tascinimod did not affect the survival of normal CD34+ hematopoietic progenitor cells.

[0186] Human MPN cell lines SET-2 (triple) and CD34 were isolated from patients with advanced MPN and myelofibrosis (duplication) using an RNA isolation kit from Ambion, Inc. (catalog number AM1914) according to the manufacturer's instructions, after being treated with 50 μM tascinimod for 16 hours. + Total RNA was isolated from MF-MPN cells. The RNA was reverse transcribed using a kit purchased from Invitrogen (catalog number 4368814), and the resulting cDNA was used for quantitative real-time PCR with a StepOne® Plus QPCR instrument and Taqman® reagents purchased from ThermoFisher, along with primers specific to different genes. The expression of each gene was normalized to GAPDH expression and compared to the corresponding untreated control cells. The results, shown in Figures 2A and 2B, demonstrate that tascinimod induces a reduction in the expression of cell proliferation and survival genes, including MYCgene, in both SET-2 and MF-MPN cells. Increased p21 expression, known to induce cell cycle arrest, was also observed in both cell types. These data support the idea that tascinimod has a direct effect on the cell proliferation and survival of MPN cells while preserving normal hematopoietic progenitor cells. This is related to the induction of gene expression cell cycle inhibitory proteins and the reduction in the expression of genes that promote cell growth and survival.

[0187] The effect of tascinimod on the progression of MPN is further supported by survival data in in vivo xenograft PDX models from two independent studies, as illustrated in Figures 3A and 3B. Disease-specific mutations in the JAK2, myeloproliferative leukemia virus (MPL), telomerase reverse transcriptase (TERT), or calreticulin (CALR) genes in hematopoietic stem cells / progenitor cells (HSCs) cause the chronic phase of Philadelphia chromosome-negative myeloproliferative neoplasms. HSCs with any of these mutations increase JAK-STAT 3 / 5 and NFκB signaling, leading to myeloproliferation and extramedullary hematopoiesis, splenomegaly, constructive symptoms, and myelofibrosis. All of these can be partially ameliorated by JAK inhibitors (JAKi), including ruxolitinib, pacritinib, and fedalitinib. However, JAKi treatment does not prevent the accumulation of additional “epimutations” in HSCs, leading to the progression of chronic MPN to progressive MPN with differentiation arrest, resulting in MPN with excess blast cells (5–9% blast cells, EB), accelerated-phase MPN (10–19% blast cells, MPN-AP), and blast-stage or secondary AML MPN (≥20% blast cells, MPN secondary acute myeloid leukemia (sAML)). MPN-EB / AP / sAML patients have a poor prognosis, losing their response to JAKi and exhibiting poor survival after standard AML therapy, with a mean survival time of less than 6 months. This highlights the clear need to develop and test novel effective agents, such as taskinimod, administered alone or in combination with JAKi or other activators, which would lead to superior clinical outcomes.

[0188] In short, female NOD.Cg-Prkdcscid Il2rgtm1Wjl / SzJ (NSG(trademark)) mice (stock number: 005557; 4-6 weeks old) [Jackson Labs, Bar Harbor, Maine; RRID: IMSR_JAX:005557] (n=6) received a pre-adjusted dose (2.5 Gy) from a cesium-137 irradiator, and via the transverse tail vein, mice with mutations in their CALR and TER genes, 2.5-3.0 × 10⁻¹⁶. 6Individual sAML patient-derived xenograft (PDX) cells were injected. Mice were monitored for 2 weeks. After confirmation of engraftment, mice were randomized and treatment was initiated, thereby treating mice with either vehicle (3:1 Labrasol®: ethanol) or tascinimod (10 or 30 mg / kg, PO, daily x 5 days / week) for 8 weeks, after which treatment was discontinued. Separately, mice were treated with vehicle (3:1 Labrasol®: ethanol), tascinimod (10 mg / kg (Figure 3A) or 30 mg / kg (Figures 3A and 3B), PO, daily x 5 days / week), ruxolitinib (30 mg / kg, daily x 5 days / week via oral gastric tube feeding), or virabrecib (OTX015) (30 mg / kg, daily x 5 days / week via oral gastric tube feeding) for 10 weeks. Mouse survival is illustrated in Kaplan-Meier plots (Figures 3A and 3B). The results show a significant improvement in survival in mice treated with 10 mg / kg and 30 mg / kg of tascinimod compared to vehicle-treated mice. Furthermore, mice treated with 30 mg / kg of tascinimod showed improved survival compared to mice treated with ruxolitinib or OTX015. Significance was determined by the Mantelcox log-rank test. Significance was assigned to p-values ​​less than 0.05. *=p<0.05, **=p<0.01, ***=p<0.005, ***=p<0.001.

[0189] Example 2: Use of tascinimod in combination with ruxolitinib Human SET-2 MPN cell lines and human post-MPN AML cells isolated from one patient were cultured in RPMI-1640 medium supplemented with 20% fetal bovine serum (FBS), treated in vitro with different concentrations of tascinimod and ruxolitinib for 48 hours, then washed with 1× phosphate-buffered saline, and treated with Annexin-V-FITC and / or TO-PRO as described above. TM Stained with -3 iodide, BD Accuri TMFlow cytometry analysis was performed on a CFlow-6 flow cytometer (BD Biosciences, San Jose, California). Drug synergies were evaluated using the SynergyFinder V2 online web application tool. Delta synergy scores were determined according to the zero interaction potency (ZIP) model (Bhagwan Yadav et al., Comput Struct Biotechnol J. 2015; 13: 504-513). A delta synergy score greater than 1.0 indicates a synergistic interaction between the two drugs in the combination. Figures 4A-4D show that co-treatment with tascinimod and the JAK inhibitor ruxolitinib induced synergistic lethal activity in human MPN cells and post-MPN AML cells.

[0190] Example 3: Use of Taskinimod in combination with perabrecib The protocol of Example 2 was repeated with tascinimod and the BET inhibitor perabrecib (CPI-0610). Figures 5A–5F show that co-treatment with tascinimod and perabrecib induced synergistic lethal activity in human MPN and post-MPN AML cells.

[0191] Example 4: Use of Taskinimod in combination with vilabrecib The protocol of Example 2 was repeated with tascinimod and the BET inhibitor virabrecib (OTX015). Figures 6A-6F show that co-treatment with tascinimod and the BET inhibitor virabrecib induced synergistic lethal activity in human MPN cells and post-MPN AML cells.

[0192] Example 5: Use of tascinimod alone or in combination with ruxolitinib or virabrecib The synergistic interaction between tascinimod and the JAK inhibitor ruxolitinib or the BET inhibitor virabrecib in the progressive stages of MPN was further supported by a combination study in an in vivo xenograft MPN PDX model described in Example 1. Briefly, mice were randomized to different treatment groups (n=6-7) and treatment was initiated two weeks after injection of either vehicle (3:1 Labrasol®:ethanol), tascinimod (30 mg / kg, PO, daily x 5 days / week), ruxolitinib (30 mg / kg, oral gastric tube feeding, daily x 5 days / week), virabrecib (OTX015) (30 mg / kg, oral gastric tube feeding, daily x 5 days / week), or tascinimod (30 mg / kg) and either ruxolitinib (30 mg / kg) or virabrecib (OTX015) (30 mg / kg).

[0193] The results, as shown in Figure 7A, indicated that the survival of mice treated with a combination of tascinimod and either ruxolitinib or virabrecib was improved compared to mice treated with monotherapy or vehicle therapy.

[0194] Since splenic enlargement is a common finding in MPN, spleen size in each treatment group was analyzed using this PDX model. Figures 7B and 7C show the effect on spleen size after 6 weeks of treatment with vehicle, tascinimod, ruxolitinib, virabrecib, or a combination of tascinimod and either ruxolitinib or virabrecib.

[0195] The results show that tascinimod and virabrecib as monotherapy significantly reduced spleen size compared to vehicle, while ruxolitinib had no effect. However, in this MPN model, the combination of tascinimod with either ruxolitinib or virabrecib was superior to vehicle and monotherapy with either drug. Significance was determined by the Mantelcox log-rank test. Significance was assigned to p-values ​​less than 0.05. *=p<0.05, **=p<0.01, ***=p<0.005; ****=p<0.001.

[0196] Example 6: Use of Taskinimod in combination with Navitocrax The protocol of Example 2 was repeated with taskinimod and the Bcl-2 inhibitor Navitocrax. Figures 8A–8D show that 72 hours of co-treatment with taskinimod and Navitocrax induces synergistic lethal activity in human MPN and post-MPN AML cells.

[0197] Example 7: Use of Tascinimod in combination with Venetocrax The protocol of Example 2 was repeated with tascinimod and the BCL-2 inhibitor venetoclax. Venetoclax was obtained from MedChem Express (Monmouth Junction, New Jersey). For the in vitro study, venetoclax was prepared as a 10 mM stock in 100% DMSO and frozen in 5-10 μL aliquots at -80°C to enable single use. This avoids multiple freeze-thaw cycles that could lead to compound degradation and loss of activity. Results shown in Figures 9A-9F indicate that co-treatment with tascinimod and the BCL-2 inhibitor venetoclax induced synergistic lethal activity in human MPN and post-MPN AML cells.

Claims

1. It is a combination of pharmaceuticals, Compound of formula (I) 【Chemistry 1】 ， (wherein R is selected from hydrogen and methyl), or a pharmaceutically acceptable salt thereof, A combination of pharmaceuticals comprising a further therapeutic activator, including a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

2. The aforementioned further therapeutic activator, The BET inhibitor perabrecib or a pharmaceutically acceptable salt thereof, or virabrecib or a pharmaceutically acceptable salt thereof, The Bcl-2 inhibitor Navitocrax or a pharmaceutically acceptable salt thereof, or Venetoclax or a pharmaceutically acceptable salt thereof, A combination of pharmaceuticals according to claim 1, including those combinations.

3. The combination of pharmaceuticals according to claim 1 or 2, wherein the further therapeutic activator comprises a BET inhibitor.

4. The combination of pharmaceuticals according to claim 1 or 2, wherein the further therapeutic activator comprises a Bcl-2 inhibitor.

5. A pharmaceutical composition, Compound of formula (I) 【Chemistry 2】 ， (wherein R is selected from hydrogen and methyl), or a pharmaceutically acceptable salt thereof, Further therapeutic activators, including bromodomain and extra-terminal motif protein (BET) inhibitors, B-cell lymphoma 2 (Bcl-2) inhibitors, or combinations thereof. A pharmaceutical composition comprising a pharmaceutically acceptable excipient.

6. The aforementioned further therapeutic activator, The BET inhibitor perabrecib or a pharmaceutically acceptable salt thereof, or virabrecib or a pharmaceutically acceptable salt thereof, The Bcl-2 inhibitor Navitocrax or a pharmaceutically acceptable salt thereof, or Venetoclax or a pharmaceutically acceptable salt thereof, The pharmaceutical composition according to claim 5, comprising a combination thereof.

7. The pharmaceutical composition according to claim 5 or 6, wherein the further therapeutic agent comprises a BET inhibitor.

8. The pharmaceutical composition according to claim 5 or 6, wherein the further therapeutic activator comprises a Bcl-2 inhibitor.

9. It's a kit, Compound of formula (I) 【Transformation 3】 ， (wherein R is selected from hydrogen and methyl), or a pharmaceutically acceptable salt thereof, Further therapeutic activators including bromodomain and extra-terminal motif protein (BET) inhibitors, B-cell lymphoma 2 (Bcl-2) inhibitors, or combinations thereof, A kit comprising: an accompanying document containing instructions for using the aforementioned kit;

10. The aforementioned further therapeutic activator, The BET inhibitor perabrecib or a pharmaceutically acceptable salt thereof, or virabrecib or a pharmaceutically acceptable salt thereof, The Bcl-2 inhibitor Navitocrax or a pharmaceutically acceptable salt thereof, or Venetoclax or a pharmaceutically acceptable salt thereof, The kit according to claim 9, which is at least one of those combinations.

11. The kit according to claim 9 or 10, wherein the further therapeutic agent comprises a BET inhibitor.

12. The kit according to claim 9 or 10, wherein the further therapeutic agent comprises a Bcl-2 inhibitor.

13. A combination of pharmaceuticals according to any one of claims 1 to 4, or a pharmaceutical composition according to any one of claims 5 to 8, or a kit according to any one of claims 9 to 12, for use in the treatment of myeloproliferative neoplasms (MPNs).

14. Compound of formula (I), 【Chemistry 4】 ， (wherein R is selected from hydrogen and methyl), or a pharmaceutically acceptable salt thereof It is intended for use in the treatment of myeloproliferative neoplasms (MPNs), The treatment comprises administering a further therapeutic agent, including a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof, the compound or a pharmaceutically acceptable salt thereof.

15. The aforementioned further therapeutic activator, The BET inhibitor perabrecib or a pharmaceutically acceptable salt thereof, or virabrecib or a pharmaceutically acceptable salt thereof, The Bcl-2 inhibitor Navitocrax or a pharmaceutically acceptable salt thereof, Venetoclax or a pharmaceutically acceptable salt thereof, A compound according to claim 14, including a combination thereof, or a pharmaceutically acceptable salt thereof.

16. The compound for use according to claim 14 or 15, wherein the further therapeutic agent comprises a BET inhibitor, or a pharmaceutically acceptable salt thereof.

17. The compound for use according to claim 14 or 15, wherein the further therapeutic agent comprises a Bcl-2 inhibitor, or a pharmaceutically acceptable salt thereof.

18. Compound of formula (I) 【Transformation 5】 ， Use of a combination of agents for the treatment of myeloproliferative neoplasms (MPNs), wherein the combination comprises a bromodomain and an extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof, in the manufacture of such combinations.

19. The aforementioned further therapeutic activator, The BET inhibitor perabrecib or a pharmaceutically acceptable salt thereof, or virabrecib or a pharmaceutically acceptable salt thereof, The Bcl-2 inhibitor Navitocrax or a pharmaceutically acceptable salt thereof, or Venetoclax or a pharmaceutically acceptable salt thereof, The use according to claim 18, including combinations thereof.

20. The use according to claim 18 or 19, wherein the further therapeutic agent comprises a BET inhibitor.

21. The use according to claim 18 or 19, wherein the further therapeutic agent comprises a Bcl-2 inhibitor.

22. A combination of pharmaceuticals, pharmaceutical compositions, or kits for use according to claim 13, or a compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 14 to 17, or a use according to any one of claims 18 to 21, wherein the MPN is selected from chronic myeloid leukemia (CML), polycythemia vera, myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, Philadelphia chromosome-negative MPN, a more obvious form of myelofibrosis, and progression to an advanced stage of MPN.

23. Compound of formula (I) for use in the treatment of advanced myeloproliferative neoplasms (MPNs) 【Transformation 6】 ， (wherein R is selected from hydrogen and methyl), or a pharmaceutically acceptable salt thereof.

24. The compound for use according to claim 23, wherein the treatment comprises the administration of a further therapeutic activator, including a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

25. A compound for use according to claim 24, wherein the further therapeutic agent is The JAK inhibitor ruxolitinib or a pharmaceutically acceptable salt thereof, The BET inhibitor perabrecib or a pharmaceutically acceptable salt thereof, or virabrecib or a pharmaceutically acceptable salt thereof, The Bcl-2 inhibitor Navitocrax or a pharmaceutically acceptable salt thereof, or Venetoclax or a pharmaceutically acceptable salt thereof, Compounds, including combinations of those compounds.

26. The compound for use according to claim 24 or 25, wherein the further therapeutic agent comprises a JAK inhibitor.

27. The compound for use according to claim 24 or 25, wherein the further therapeutic agent comprises a BET inhibitor.

28. The compound for use according to claim 24 or 25, wherein the further therapeutic activator comprises a Bcl-2 inhibitor.

29. It is a combination of pharmaceuticals, Compound of formula (I) 【Transformation 7】 ， (wherein R is selected from hydrogen and methyl), or a pharmaceutically acceptable salt thereof. Further therapeutic activators include Janus kinase (JAK) inhibitors, bromodomain and extra-terminal motif protein (BET) inhibitors, B-cell lymphoma 2 (Bcl-2) inhibitors, or combinations thereof. A combination of drugs for use in the treatment of advanced myeloproliferative neoplasms (MPNs).

30. The aforementioned further therapeutic activator, The JAK inhibitor ruxolitinib or a pharmaceutically acceptable salt thereof, The BET inhibitor perabrecib or a pharmaceutically acceptable salt thereof, or virabrecib or a pharmaceutically acceptable salt thereof, The Bcl-2 inhibitor Navitocrax or a pharmaceutically acceptable salt thereof, or Venetoclax or a pharmaceutically acceptable salt thereof, A combination of pharmaceuticals for use according to claim 29, including those combinations.

31. The combination of pharmaceuticals for use according to claim 29 or 30, wherein the further therapeutic agent comprises a JAK inhibitor.

32. The combination of pharmaceuticals for use according to claim 29 or 30, wherein the further therapeutic activator comprises a BET inhibitor.

33. The combination of pharmaceuticals for use according to claim 29 or 30, wherein the further therapeutic activator comprises a Bcl-2 inhibitor.

34. A pharmaceutical composition for use in the treatment of advanced myeloproliferative neoplasms (MPNs), Compound of formula (I) 【Transformation 8】 ， (wherein R is selected from hydrogen and methyl), or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising a pharmaceutically acceptable excipient.

35. The pharmaceutical composition for use according to claim 34, further comprising a further therapeutic activator, comprising a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

36. A kit for use in the treatment of advanced myeloproliferative neoplasms (MPNs), Compound of formula (I) 【Chemistry 9】 ， (wherein R is selected from hydrogen and methyl), or a pharmaceutically acceptable salt thereof, Further therapeutic activators, including Janus kinase (JAK) inhibitors, bromodomain and extraterminal motif protein (BET) inhibitors, B-cell lymphoma 2 (Bcl-2) inhibitors, or combinations thereof. A kit comprising: an accompanying document containing instructions for using the aforementioned kit;

37. Compound of formula (I) 【Chemistry 10】 ， Use of a compound (wherein R is selected from hydrogen and methyl), or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product for the treatment of advanced myeloproliferative neoplasms (MPNs).

38. The use according to claim 37, wherein the treatment is combined with a further therapeutic activator, including a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

39. A method for treating myeloproliferative neoplasms (MPNs) in subjects requiring such treatment, wherein the subject (mammals, etc.) Compound of formula (I) 【Chemistry 11】 ， (wherein R is selected from hydrogen and methyl), or a pharmaceutically acceptable salt thereof, A method comprising administering a further therapeutic activator, including a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

40. A method for treating advanced myeloproliferative neoplasms (MPNs) in patients in need, comprising the compound of formula (I). 【Chemistry 12】 ， A method comprising administering (wherein R is selected from hydrogen and methyl) or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.

41. The method according to claim 40, comprising administering to the mammal a further therapeutic agent, including a Janus kinase (JAK) inhibitor, a bromodomain and extra-terminal motif protein (BET) inhibitor, a B-cell lymphoma 2 (Bcl-2) inhibitor, or a combination thereof.

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