PIM1 inhibitors for the treatment of myeloproliferative neoplasms

Abstract

A method for treating myeloproliferative neoplasms is provided, particularly for treating human patients with poor bone marrow function and relapsed or refractory diseases that are difficult to treat. The disclosed method has the following structure: [Case 1] The method comprises administering a compound (1) having JPEG2026509318000030.jpg3762 or a pharmaceutically acceptable salt thereof, and optionally a JAK kinase inhibitor and / or an ACVR inhibitor, to a human subject in need.

Description

[Technical Field]

[0001] Relationship with prior applications This application claims priority to U.S. Provisional Patent Applications No. 63 / 381711 (filed October 31, 2022), No. 63 / 425522 (filed November 15, 2022), No. 63 / 501221 (filed May 10, 2023), and No. 63 / 506526 (filed June 6, 2023) (collectively, the "Prior Applications"). The contents of the Prior Applications are incorporated herein by reference as if they were fully described herein.

[0002] Technical field This technology relates to PIM kinase inhibitors, particularly selective PIM1 kinase inhibitors, for monotherapy and combination therapy for the treatment of myeloproliferative neoplasms such as myelofibrosis (MF). [Background technology]

[0003] Despite significant progress in the treatment of many hematological malignancies, major unmet needs remain. Drug resistance, toxicity, poor response, and poor overall survival persist as major challenges, necessitating the development and evaluation of new therapeutics.

[0004] Myelofibrosis ("MF") is the most severe form of myeloproliferative neoplasm ("MPN"), characterized by myelofibrosis, abnormal hematopoiesis, splenomegaly, symptom exacerbation, and frequent transformation to acute myeloid leukemia. The first-line standard treatment for MF is therapy with JAK2 inhibitors such as ruxolitinib. However, some patients do not respond adequately, their disease continues to progress, or they suffer from adverse events, particularly thrombocytopenia and other loss of bone marrow function.

[0005] To address these challenges, numerous molecules targeting various biological targets have been developed. Navitoclax (oral BCL-X) LMany of these drugs, such as BCL-2 inhibitors, parsaclisib (an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor), and pelabresib (an oral bromodomain and extraterminal domain (BET) inhibitor (BETi)), have shown efficacy in animal models, but subsequently failed or performed poorly in rigorous human clinical trials, particularly in relapsed or refractory patients previously treated with JAK inhibitors, or when evaluating the overall efficacy of the drugs in the most common symptom load reported by MPN human patients.

[0006] The PIM kinase family is involved in the regulation of cell proliferation, survival, and the cell cycle, and is overexpressed in various cancers. PIM1 kinase has been found to be significantly overexpressed in MF patients. TP-3654 is a highly selective oral PIM-1 kinase inhibitor. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] There remains a need for human therapeutic regimens that utilize the activity of both selective PIM1 kinase inhibitors in general, and especially TP-3654, to treat hematological malignancies such as MF.

[0008] Furthermore, there remains a need to treat the symptomatic burden of myeloproliferative neoplasms in humans, particularly the symptomatic burden measured by the Total Symptoms Score.

[0009] There is a further need to augment existing MPN treatments without causing or exacerbating hematological toxicity.

[0010] Further needs exist in groups that have previously been treated with JAK inhibitors and have experienced disease relapse, groups that have become refractory to treatment, groups that are intolerant to JAK inhibitors, or groups that are a combination of two or more of these.

[0011] Furthermore, there is a greater need in patients who suffer from poor bone marrow function as a result of previous drug treatments or the disease condition itself. [Means for solving the problem]

[0012] This disclosure is partly based on the finding that compound (1)(TP-3654) exhibits clinical activity in human myeloproliferative disorders (e.g., MF) with little to no hematological toxicity and poor bone marrow function associated with JAK inhibitors, as reported in the examples herein. These findings enable the treatment of patients with poor bone marrow function for whom other therapies are often unavailable. Furthermore, given that poor bone marrow function plays a prognostic role in disease progression, improved efficacy treatments are also possible.

[0013] Therefore, in one embodiment, the present disclosure provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, wherein the method provides the subject with a therapeutically effective amount of the following structure: [ka] The administration of a compound (1) having the above, or a pharmaceutically acceptable salt thereof, the subject being thrombocytopenia (e.g., platelet counts of 150, 100, 75, 50, or 25 × 10⁻¹⁰ 9 Poor bone marrow function characterized by: ≠ / L; anemia (e.g., Hgb levels ≠ 10, 9, or 8 g / dL); transfusion dependence; or a combination thereof, where treatment induces a clinically meaningful response in myeloproliferative neoplasms.

[0014] This disclosure further builds upon the finding that the absence of hematological toxicity observed with compound (1) is also observed with other selective PIM1 inhibitors, but these advantages are not observed with pan-PIM1 inhibitors, as shown in the examples herein.

[0015] Accordingly, in another aspect, the present disclosure provides a method for treating myeloproliferative neoplasms in a human subject requiring treatment, the method comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor, the subject having thrombocytopenia (e.g., platelet counts of 150, 100, 75, 50, or 25 × 10⁶). 9 Poor bone marrow function characterized by: ≠ / L; anemia (e.g., Hgb levels ≠ 10, 9, or 8 g / dL); transfusion dependence; or a combination thereof, where treatment induces a clinically meaningful response in myeloproliferative neoplasms.

[0016] This disclosure is further based on the finding that compound (1) is effective in human subjects who have previously failed with JAK inhibitor therapy and is effective against myeloproliferative neoplasms to a degree not seen with other treatments under development, as shown by the comparisons reported in the examples herein.

[0017] Therefore, in another aspect, the present disclosure provides a method for treating a myeloproliferative neoplasm in a human subject in need of treatment, the subject having been previously treated for the myeloproliferative neoplasm with a JAK inhibitor and, as appropriate, having a relapsed disease or being refractory to the JAK inhibitor, the method comprising administering to the subject a therapeutically effective amount of the following structure: [ka] The treatment comprises administering a compound (1) having the same, or a pharmaceutically acceptable salt thereof, which induces a clinically meaningful response in myeloproliferative neoplasms.

[0018] This disclosure is also based on the finding that compound (1) may treat the symptomatic burden of myeloproliferative neoplasms, particularly when other treatments under investigation have failed, as measured by a reduction of approximately 50% in the Total Symptoms Score ("TSS50").

[0019] Therefore, in another aspect, the present disclosure provides a method for treating myeloproliferative neoplasms by inducing TSS50 in a human subject in need of treatment, wherein the method involves administering to the subject a therapeutically effective amount of the following structure: [ka] Treatment of myeloproliferative neoplasms by inducing TSS50 in a subject comprises administering a compound (1) having or a pharmaceutically acceptable salt thereof, and optionally, treatment is performed at a time between approximately 12 weeks and approximately 100 weeks (e.g., a time between approximately 20 weeks and approximately 75 weeks, or a time between approximately 24 weeks and approximately 48 weeks).

[0020] This disclosure is also based on the finding that compound (1) or another selective PIM1 inhibitor, when administered in combination with other treatments for myeloproliferative neoplasms, such as JAK inhibitors and / or ACVR inhibitors (e.g., ruxolitinib and momerotinib), minimize or completely eliminate overlapping hematological toxicities, such as anemia, thrombocytopenia, transfusion dependence, or combinations of two or more thereof. At the same time, each molecule in the combination makes a meaningful contribution to the efficacy of the treatment, particularly in terms of improving TSS and / or reducing spleen volume.

[0021] Therefore, in another aspect, the present disclosure provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, wherein the subject has the following structure: [ka] The treatment comprises administering a compound (1) having the above, or a pharmaceutically acceptable salt thereof, and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof, in amounts that do not induce overlapping hematological toxicities (e.g., anemia and / or thrombocytopenia and / or transfusion dependence), wherein the treatment induces a clinically meaningful response in myeloproliferative neoplasms.

[0022] In another aspect, the Disclosure provides a method for treating myeloproliferative neoplasms in human subjects in need of treatment, the method comprising administering to the subject a selective PIM1 inhibitor and a JAK inhibitor and / or ACVR inhibitor (e.g., ruxolitinib or momerotinib) or a pharmaceutically acceptable salt thereof in a dose that does not induce overlapping hematological toxicities (e.g., anemia and / or thrombocytopenia and / or transfusion dependence), the treatment inducing a clinically meaningful response in the myeloproliferative neoplasm.

[0023] This disclosure is further based on the remarkable results observed from compound (1) compared to other treatments for myeloproliferative neoplasms in a human subject previously treated with a JAK inhibitor, and the potential for enhanced clinically meaningful improvement in SVR35 or TSS50.

[0024] Therefore, in another aspect, the present disclosure provides a method for inducing an SVR35 probability of approximately 15% or more, or approximately 20% or more, in human subjects suffering from myeloproliferative neoplasms, wherein the subjects have been previously treated with a JAK inhibitor for myeloproliferative neoplasms and may, as appropriate, have relapsed disease or be refractory to JAK inhibitors, and the method involves administering to the subjects a therapeutically effective amount of the following structure: [ka] The treatment comprises administering a compound (1) having the same, or a pharmaceutically acceptable salt thereof, which induces a probability of SVR35 of 15% or more or 20% or more in the subject.

[0025] In another aspect, the Disclosure provides a method for inducing a TSS50 probability of approximately 30% or more, approximately 35% or more, approximately 40% or more, approximately 45% or more, or approximately 50% or more in human subjects with myeloproliferative neoplasms, wherein the subjects have been previously treated with a JAK inhibitor for myeloproliferative neoplasm and may, as appropriate, have relapsed disease or be refractory to JAK inhibitors, and the Method provides the subjects with a therapeutically effective amount of the following structure: [ka] The treatment comprises administering a compound (1) having the same, or a pharmaceutically acceptable salt thereof, which induces a probability of TSS50 of approximately 30%, 35%, 40%, 45%, or 50% or more in the subjects.

[0026] These and other embodiments of the embodiments of this disclosure will become apparent from the following detailed description. For this purpose, various references that describe in more detail specific background information, methods, compounds and / or compositions are included herein, each incorporated herein in whole by reference.

[0027] In the diagram, the same reference number identifies similar elements. The size and relative position of elements in the diagram are not necessarily drawn to scale, and some of these elements have been enlarged and positioned to improve the readability of the diagram. Furthermore, the specific shapes of the depicted elements are not intended to convey information about the actual shape of the elements, but are selected solely for ease of recognition in the diagram. [Brief explanation of the drawing]

[0028] [Figure 1A] Figure 1A shows the in vitro effects of momerotinib, pacritinib, ruxolitinib, and the HCl salt of compound (1) on human erythrocytes (CFU-E, BFU-E) according to the examples. [Figure 1B] Figure 1B shows the in vitro effects of momerotinib, pacritinib, ruxolitinib, and the HCl salt of compound (1) in human megakaryocytes (CFU-MK) according to the examples. [Figure 1C] Figure 1C shows the in vitro effects of momerotinib, pacritinib, ruxolitinib, and the HCl salt of compound (1) in human granulocyte-monocytes (CFU-GM) according to the examples. [Figure 2A]Figure 2A shows the in vitro effects of ruxolitinib, the HCl salt of compound (1), and combinations thereof in human megakaryocytes (CFU-Mk) according to the examples. [Figure 2B] Figure 2B shows the in vitro effects of pacritinib, the HCl salt of compound (1), and combinations thereof in human megakaryocytes (CFU-MK) according to the examples. [Figure 2C] Figure 2C shows the in vitro effects of momerotinib, the HCl salt of compound (1), and combinations thereof in human megakaryocytes (CFU-MK) according to the examples. [Figure 3A] Figure 3A shows the in vitro effects of ruxolitinib, the HCl salt of compound (1), and combinations thereof in human erythrocytes (CFU-E, BFU-E) according to the examples. [Figure 3B] Figure 3B shows the in vitro effects of pacritinib, the HCl salt of compound (1), and combinations thereof in human erythrocytes (CFU-E, BFU-E) according to the examples. [Figure 3C] Figure 3C shows the in vitro effects of momerotinib, the HCl salt of compound (1), and combinations thereof in human erythrocytes (CFU-E, BFU-E) according to the examples. [Figure 4A] Figure 4A shows the in vitro effects of ruxolitinib, the HCl salt of compound (1), and combinations thereof in human granulocyte-monocytes (CFU-GM) according to the examples. [Figure 4B] Figure 4B shows the in vitro effects of pacritib, the HCl salt of compound (1), and combinations thereof in human granulocyte-monocytes (CFU-GM) according to the examples. [Figure 4C] Figure 4C shows the in vitro effects of momerotinib, the HCl salt of compound (1), and combinations thereof in human granulocyte-monocytes (CFU-GM) according to the examples. [Figure 5A] Figure 5A shows the platelet count of patients receiving monotherapy with the HCl salt of compound (1) according to the examples. [Figure 5B]Figure 5B shows patient hemoglobin during monotherapy treatment with the HCl salt of compound (1) according to the examples. [Figure 5C] Figure 5C shows neutrophils from patients undergoing monotherapy with the HCl salt of compound (1) according to the examples. [Figure 5D] Figure 5D shows the average blood cell counts (platelets, hemoglobin, and neutrophils) of patients undergoing monotherapy with the HCl salt of compound (1) according to the examples. [Figure 5E] Figure 5E shows the best percentage change in spleen volume reduction in patients treated with monotherapy using the HCl salt of compound (1) according to the examples. [Figure 5F] Figure 5F shows the best percentage change in overall symptom score reduction in patients receiving monotherapy with the HCl salt of compound (1) according to the examples. [Figure 5G] Figure 5G shows the best percentage change in spleen volume reduction and overall symptom score reduction in patients treated with monotherapy using the HCl salt of compound (1) according to the examples. [Figure 5H] Figure 5H shows cytokine regulation, spleen volume reduction, and overall symptom score reduction in patients treated with monotherapy using the HCl salt of compound (1) in the examples. [Figure 5I] Figure 5I shows the cytokine regulation and reduction in overall symptom scores in patients treated with the HCl salt of compound (1) at 4, 8, and 12 weeks, as in the example. [Figure 5J] Figure 5J shows the cytokine regulation and reduction in overall symptom scores in patients after 12 weeks of treatment with the HCl salt of compound (1) in the example. [Figure 5K] Figure 5K shows the mean hemoglobin and platelet counts over 24 weeks of treatment for 22 evaluable patients treated with the HCl salt of compound (1) in the examples. [Figure 5L] Figure 5L shows the cytokine regulation and reduction in overall symptom scores in patients at various time points following treatment with the HCl salt of compound (1) in the examples. [Modes for carrying out the invention]

[0029] The following description provides specific details to give a complete understanding of the various embodiments of this disclosure. However, those skilled in the art will understand that embodiments of this disclosure may be carried out without these details.

[0030] Definitions and Use of Terms Unless otherwise required by context, throughout this specification and the claims, the word “comprise” and its variations, such as “comprises” and “comprising,” should be interpreted in an open and comprehensive sense (i.e., “comprises, but not limited to”).

[0031] Throughout this specification, any reference to “one embodiment,” “an embodiment,” or “some embodiments” means that a particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment of this disclosure. Therefore, while the expressions “in one embodiment,” “in an embodiment,” or “in some embodiments” may appear in various places throughout this specification, they do not necessarily all refer to the same embodiment. Furthermore, certain features or characteristics can be combined in any suitable manner in one or more embodiments.

[0032] Myeloproliferative neoplasms (MPNs) refer to a group of disorders in which bone marrow stem cells abnormally proliferate and regenerate. Abnormal stem cells in MPNs produce an excess of one or more types of blood cells (e.g., red blood cells, white blood cells, and / or platelets). As disclosed herein, myeloproliferative neoplasms include, but are not limited to, polycythemia vera (PV), primary or essential thrombocythemia (ET), pre-MF, primary or idiopathic MF, and secondary MF (e.g., MF secondary to polycythemia vera or essential thrombocythemia). In some embodiments, MPN includes PV. In some embodiments, MPN includes primary or essential thrombocythemia. In some embodiments, MPN includes pre-MF. In some embodiments, MPN includes primary or idiopathic MF. In some embodiments, MPN includes secondary MF (e.g., MF secondary to polycythemia vera or essential thrombocythemia).

[0033] "Compounds of the Disclosure" or "Disclosed Compounds" means any of the active compounds disclosed herein, including compounds that target PIM kinase (i.e., Compound (1)), any of the compounds disclosed herein that target JAK and / or ACVR, or any compound known in the art to have any of these activities, all of which are incorporated herein by reference.

[0034] "Pharmaceuticals" or "Disclosed Pharmaceuticals" means compounds that target JAK and / or ACVR, such as ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, or pharmaceutically acceptable salts thereof, as well as lopeginterferon alpha-2b (interferon) and nabutemadeline (MDM2 inhibitors), or pharmaceutically acceptable salts thereof, or two or more combinations thereof.

[0035] As used herein, “PIM kinase inhibitor” refers to a compound that inhibits the activity of proviral insertion (PIM) kinases in mouse lymphoma. PIM kinases refer to a family of serine / threonine kinases that regulate several signaling pathways fundamental to cancer development and progression. The PIM family includes PIM1, PIM2, and PIM3. PIM inhibitors may be active against all members of the PIM family or one or more subtypes of the PIM family. PIM inhibitors may be selected to act on a specific subtype of the PIM family; for example, a PIM inhibitor may act on PIM1 of the PIM family at a lower concentration than on other members of the PIM family. More specifically, a PIM inhibitor may act selectively on PIM1 compared to, for example, PIM2. In some embodiments, a PIM inhibitor inhibits one or more PIM subtypes, including PIM1.

[0036] As used herein, “PIM1 inhibitor” or “PIM1 kinase inhibitor” refers to a compound that functions as an inhibitor of PIM1. In some embodiments, a PIM1 inhibitor is selective to PIM1 compared to other PIM subtypes, and particularly selective to PIM1 inhibitors (e.g., acts at lower concentrations), in which case it may be called a “selective PIM1 inhibitor” or “selective PIM1 kinase inhibitor.” Selective PIM1 inhibitors generally have a PIM1 / PIM2 IC5 ratio of less than approximately 0.05, 0.045, 0.04, 0.035, 0.03, or 0.025. 50 The ratio is shown and determined as described in Foulks, Neoplasia Vol. 16, No. 5, 2014. Alternatively, selective PIM1 inhibitors are used to achieve PIM1 / PIM2 IC5 ratios of approximately 0.001–0.05, 0.005–0.04, or 0.01–0.03. 50 Shows the ratio.

[0037] A specific example of a selective PIM1 kinase inhibitor is shown in the following structure: [ka] The compound (1) having the following structure, or a pharmaceutically acceptable salt thereof (also known as TP-3654 or cmpd 1). Another specific example of a selective PIM1 kinase inhibitor is shown below: [ka] Compound (2) having , or a pharmaceutically acceptable salt thereof (also known as SGI-1776 or cmpd 2). Additional examples are given by reference to publications mentioned in the text of this disclosure, which are incorporated herein by reference.

[0038] As used herein, “JAK inhibitor” refers to a compound that inhibits the activity of Janus kinases. Janus kinases refer to a family of intracellular non-receptor tyrosine kinases that transmit cytokine-mediated signals via the JAK-STAT pathway. The JAK family includes JAK1, JAK2, JAK3, and TYK2. JAK inhibitors may be active against all members of the JAK family, or against one or more subtypes of the JAK family. JAK inhibitors may be selected for their action against a specific subtype of the JAK family; for example, a JAK inhibitor may act against JAK2 of the JAK family at a lower concentration than against other members of the JAK family. More specifically, a JAK inhibitor may act selectively on JAK2 compared to, for example, its action against JAK1. In some embodiments, a JAK inhibitor inhibits one or more JAK subtypes, including JAK2. In some embodiments, a JAK inhibitor inhibits one or more JAK subtypes, including JAK1 and JAK2 (e.g., ruxolitinib).

[0039] In some embodiments, JAK inhibitors may include ruxolitinib, tofacitinib, oclacitinib, baricitinib, filgotinib, gandotinib, restaurtinib, momerotinib, pacritinib, PF-04965842, upacitinib, perficitinib, fedratinib, cucurbitacin I, CHZ868, desernotinib, CEP-33779, R348, fivotinib, ABT-494 (these compounds are known in the art), or two or more combinations thereof. In some embodiments, JAK inhibitors may include BMS-911543, ASN002, itacitinib, NS-018, AZD1480, gandotinib, or two or more combinations thereof. In some embodiments, the JAK inhibitor may include ruxolitinib, gandotinib, restaurtinib, momerotinib, pacritinib, fedratinib, or two or more combinations thereof. In some embodiments, the JAK inhibitor may include ruxolitinib, fedratinib, pacritinib, or momerotinib, or pharmaceutically acceptable salts thereof, or two or more combinations thereof. In some embodiments, the JAK inhibitor may include ruxolitinib or a pharmaceutically acceptable salt thereof (e.g., ruxolitinibulinate). In some embodiments, the JAK inhibitor may include fedratinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor may include pacritinib or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor may include momerotinib or a pharmaceutically acceptable salt thereof.

[0040] As used herein, "JAK1 inhibitor" refers to a compound that functions as an inhibitor of JAK1. In some embodiments, JAK1 inhibitors are selective for JAK1 compared to other JAK subtypes (e.g., they act at low concentrations).

[0041] As used herein, “JAK2 inhibitor” refers to a compound that functions as an inhibitor of JAK2. In some embodiments, JAK2 inhibitors are selective for JAK2 compared to other JAK subtypes (e.g., they act at low concentrations).

[0042] As used herein, "ACVR inhibitor" refers to a compound that inhibits the activity of activin receptors. Activin receptors are receptors that bind to activin and belong to the transforming growth factor beta superfamily (TGFβ) of ligands. They are involved in many physiological processes, including proliferation, cell differentiation, homeostasis, bone formation, apoptosis, and many other functions. There are two types of activin receptors: activin type 1 and activin type 2. Activin type 1 receptors transmit signals for various TGFβ ligands, while activin type 2 receptors modulate TGFβ ligand signaling. There are three types of activin type I receptors: ACVR1, ACVR1B, and ACVR1C, each binding to a specific type II receptor-ligand complex. There are two types of activin type 2 receptors: ACVR2A and ACVR2B. ACVR inhibitors can be active against all members of the activin receptor family, or against one or more subtypes of the activin receptor family. ACVR inhibitors may be selected for their action against specific subtypes of the activin receptor family; for example, an ACVR inhibitor may act on ACVR1 of the activin receptor family at a lower concentration than other members of the activin receptor family. In some embodiments, an ACVR inhibitor inhibits one or more activin receptors, including ACVR1. In some embodiments, an ACVR inhibitor may include momerotinib, pacritinib, ruspatercept, or a pharmaceutically acceptable salt thereof, or a combination of two or more of these. In some embodiments, an ACVR inhibitor may include momerotinib or a pharmaceutically acceptable salt thereof. In some embodiments, an ACVR inhibitor may include pacritinib or a pharmaceutically acceptable salt thereof. In some embodiments, an ACVR inhibitor may include ruspatercept or a pharmaceutically acceptable salt thereof.

[0043] As used herein, “ACVR1 inhibitor” refers to a compound that functions as an inhibitor of ACVR1. In some embodiments, ACVR1 inhibitors are selective for the type 1 kinase activin A receptor compared to other activin receptors (e.g., they act at low concentrations).

[0044] In some embodiments, the compound may be an ACVR inhibitor and a JAK inhibitor.

[0045] Embodiments of this disclosure also involve the administration of prodrugs of the disclosed compounds. “Prodrug” means a compound that can be converted to the biologically active compound of this disclosure under physiological conditions or by solvolysis. Therefore, the term “prodrug” refers to a pharmaceutically acceptable metabolic precursor of the compound of this disclosure. A prodrug may be inactive when administered to a human subject requiring administration, but is converted to the active compound of this disclosure in vivo. Prodrugs are typically rapidly converted in vivo, for example, by hydrolysis in the blood, to obtain the parent compound of this disclosure. Prodrug compounds often offer advantages in solubility, histocompatibility, or delayed release in the subject (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7 9, 21 24 (Elsevier, Amsterdam)). The prodrug study is available in Higuchi, T., et al., ACS Symposium Series, Vol. 14, and in *Bioreversible Carriers in Drug Design*, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0046] The term "prodrug" also means any covalently attached carrier that releases the active compound of the present disclosure in vivo when such a prodrug is administered to a subject. Prodrugs of the compounds of the present disclosure can be prepared by modifying the functional groups present in the compounds of the present disclosure so that they are cleaved to the parent compounds of the present disclosure either by routine manipulations or in vivo. Prodrugs include compounds of the present disclosure in which a hydroxy group, an amino group or a mercapto group is attached to any group that cleaves to form a free hydroxy group, a free amino group or a free mercapto group, respectively, when the prodrug of the compound of the present disclosure is administered to a subject. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols, or amide derivatives of amine functional groups in the compounds of the present disclosure.

[0047] Embodiments of the present disclosure also mean that the administration of all pharmaceutically acceptable compounds of the disclosed compounds that are isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers is included. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125This includes I. These radiolabeled compounds may be useful in determining or measuring the efficacy of a compound by characterizing, for example, the site or mode of action, or the binding affinity to a pharmacologically important site of action. Specific isotope-labeled compounds of structure (I), (II), or (III), e.g., compounds incorporating radioisotopes, are useful in tissue distribution studies of drugs and / or substrates. Tritium, a radioisotope, i.e. 3 H and carbon 14, that is 14 C is particularly useful for this purpose due to its ease of implementation and ease of detection.

[0048] Heavy isotopes such as deuterium, that 2 Substitution with H may offer certain therapeutic benefits resulting from greater metabolic stability, such as an increased half-life in vivo or a reduced required dose, and may therefore be preferred in certain situations.

[0049] 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 1N may be useful in positron-emitting topography (PET) studies to investigate substrate receptor occupancy. Isotope-labeled compounds of structures (I), (II), or (III) can generally be prepared by the prior art known to those skilled in the art, or by processes similar to those described in the preparations and examples below, using appropriate isotope-labeling reagents instead of unlabeled reagents.

[0050] Embodiments of the present disclosure also mean that they encompass in vivo metabolites of the disclosed compounds. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Thus, embodiments include compounds produced by processes that involve administering the compounds of the present disclosure to a human subject for a period of time sufficient to yield its metabolites. Such products are typically identified by administering the radiolabeled compounds of the present disclosure in detectable doses to animals such as rats, mice, guinea pigs, monkeys, or humans, giving them sufficient time for metabolism to occur, and then isolating the conversion products from urine, blood, or other biological samples.

[0051] "Optional" or "as appropriate" means that the event or situation described thereafter may or may not occur, and that the description includes examples where the event or situation occurs and examples where it does not. For example, "as appropriate substituted aryl" means that the aryl radical may or may not be substituted, and that it includes both substituted and unsubstituted aryl radicals.

[0052] "Pharmacologically acceptable carriers, diluents or excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, colorants, flavorings, surfactants, humectants, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are approved by the U.S. Food and Drug Administration as acceptable for use in humans.

[0053] "Pharmacologically acceptable salts" include both acid and base addition salts. Unless otherwise indicated (for example, by context), the use of the therapeutic agents described herein (e.g., PIM kinase inhibitors, JAK kinase inhibitors) may, as appropriate, include the use of pharmaceutically acceptable salts of the therapeutic agent in place of or in addition to the parent compound.

[0054] "Pharmacologically acceptable acid addition salts" refer to salts that retain the biological efficacy and properties of a free base and are not biologically or otherwise undesirable. These include, for example, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and, for example, but are not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonate, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, and gentisine. It is formed from acids and organic acids such as glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hypric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0055] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effects and properties of a free acid but is otherwise undesirable in a biological or other way. These salts are prepared by adding an inorganic or organic base to a free acid. Examples of salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0056] The compounds of this disclosure or their pharmaceutically acceptable salts may contain one or more chiral centers, and thus may give rise to enantiomers, diastereomers, and other stereoisomers, which may be defined from the viewpoint of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. This disclosure includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or can be resolved using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemics (or racemics of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). Where a compound described herein contains an olefinic double bond or other centers resulting in geometric asymmetry, and unless otherwise specified, the compound is intended to include both E and Z geometric isomers. Similarly, all tautomers are also intended to be included.

[0057] A "stereoisomer" refers to a compound in which the same atoms are bonded together by the same bonds but have different three-dimensional structures and are not interchangeable. This disclosure envisions various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers in which the molecules are non-superimposed mirror images of each other.

[0058] "Pharmaceutical composition" means a formulation of the compound of the Disclosure and a medium commonly accepted in the art for the delivery of the biologically active compound to humans. Such mediums include all pharmaceutically acceptable carriers, diluents, or excipients for the compound of the Disclosure.

[0059] “Effective dose” or “therapeutic effective dose” means the amount of the compound disclosed herein that, when administered to a human subject, is sufficient to treat a cancer such as MPN (as defined below) in that subject. The amount of the compound disclosed which constitutes a “therapeutic effective dose” will vary depending on the compound, the condition and its severity, the method of administration, and the age of the subject being treated, but can be routinely determined by a person skilled in the art, taking into account their knowledge and the disclosure.

[0060] Where “effective dose” or “therapeutic effective dose” is referred to herein, it is understood that it also includes “safe and effective dose” or “therapeutically safe and effective dose.” To be effective, it is understood that the intervention achieves a clinically meaningful response. Similarly, to be safe, it is understood that the intervention does not produce clinically meaningful adverse events, i.e., adverse events that would justify the suspension or discontinuation of treatment.

[0061] A “clinically significant” or “clinically meaningful” response typically means both a statistically significant and meaningful response from the perspective of the patient, clinician, or caregiver, based on a static scale such as the CGI-S or a retrospective assessment of improvement such as the CGI-C, as commonly described in various publications of the U.S. Food and Drug Administration, including FDA2018, FDA2019, and FDA2020. Where a treatment or benefit is described herein, it is understood that the treatment or benefit preferably demonstrates clinically significant efficacy in a patient population to a statistically significant degree. A clinically “meaningful” response is synonymous with “improvement.”

[0062] In one embodiment, a clinically meaningful response in myeloproliferative neoplasms, or a clinically meaningful improvement in splenomegaly, means an SVR of 25. In another embodiment, a clinically meaningful response in myeloproliferative neoplasms, or a clinically meaningful improvement in splenomegaly, means an SVR of 35. In another embodiment, a clinically meaningful response in myeloproliferative neoplasms means a TSS of 50. In another embodiment, a clinically meaningful response in myeloproliferative neoplasms, or a clinically meaningful response in myelofibrosis, means a decrease of 1 or more in fibrosis grade. In another embodiment, a clinically meaningful response in myeloproliferative neoplasms means 50 × 10 9 This means an increase in platelet count of 1 / L or more. In another embodiment, a clinically meaningful response in myeloproliferative neoplasms means an increase in platelet count of grade 1 or higher. In another embodiment, a clinically meaningful response in myeloproliferative neoplasms means thrombocytopenia (generally 150 × 10⁻¹⁰). 9 This means the resolution of (defined as a platelet count of less than / L). In another embodiment, a clinically meaningful response in myeloproliferative neoplasms means an increase in Hgb of 2 g / dL or more. In another embodiment, a clinically meaningful response in myeloproliferative neoplasms means an increase in Hgb of grade 1 or more. In another embodiment, a clinically meaningful response in myeloproliferative neoplasms means the resolution of anemia (generally defined as Hgb less than 10 g / dL). In another embodiment, a clinically meaningful response in myeloproliferative disorders means a shift from transfusion dependence to transfusion independence.

[0063] In other embodiments, it is recognized that clinically meaningful improvement is based on the probability of achieving TSS50 or SVR35, and not all patients equally benefit. Therefore, in various embodiments, when compound (1) is administered as monotherapy, a clinically meaningful improvement in TSS50 includes the probability of achieving TSS50 ≥ 30, 35, or 40 percent, and a clinically meaningful improvement in SVR35 includes the probability of achieving SVR35 ≥ 20 or 25 percent. When compound (1) is administered in combination with momerotinib, a clinically meaningful improvement in TSS50 includes the probability of achieving TSS50 ≥ 40 or 45 percent, and a clinically meaningful improvement in SVR35 includes the probability of achieving SVR35 ≥ 20, 25, or 30 percent. When compound (1) is administered in combination with ruxolitinib, a clinically meaningful improvement in TSS50 includes the probability of achieving a TSS50 ≥ 50, 55, or 60 percent, and a clinically meaningful improvement in SVR35 includes the probability of achieving an SVR35 ≥ 40, 45, or 50 percent.

[0064] As used herein, “symptom burden” means constitutional or systemic ("systemic") symptoms (e.g., fatigue, night sweats, weight loss, itching, fever, bone pain, joint pain, or a combination of two or more of these).

[0065] Whenever a treatment method is performed in accordance with this disclosure, it is understood that the treatment method is performed with the aim of achieving a clinically meaningful response.

[0066] In various embodiments, any of the aforementioned clinically meaningful responses are observed for approximately 12 weeks or longer, approximately 24 weeks or longer, approximately 48 weeks or longer, approximately 72 weeks or longer, or approximately 96 weeks or longer.

[0067] As used herein, “to treat” or “to treat” refers to the treatment of a disease or condition in a person having the disease or condition of interest, and includes (i) preventing the development of the disease or condition in the subject, in particular, that the subject is predisposed to the condition but has not yet been diagnosed with the condition; (ii) suppressing the disease or condition, i.e., preventing its onset; (iii) alleviating the disease or condition, i.e., causing regression of the disease or condition; or (iv) alleviating all symptoms resulting from the disease or condition, i.e., relieving pain without addressing the underlying disease or condition.

[0068] With respect to MF, “treating” or “treatment” includes achieving complete or partial remission, cytogenetic or molecular remission of MF, as well as achieving clinical improvement, hematological response (e.g., platelets, red blood cells, and / or white blood cells), splenic response, overall symptom score response, or stable disease (collectively referred to as “improvement” of MF) (sometimes referred to as the IWG-MRT response criteria), these terms being defined in Tefferi, A., et al., Blood 2013, 122:1395-1398 (see in particular Table 1 of Tefferi), and the relevant teachings are incorporated herein by reference in their entirety. In various embodiments, any of the aforementioned improvements are observed for approximately 12 weeks or longer, approximately 24 weeks or longer, approximately 48 weeks or longer, approximately 72 weeks or longer, or approximately 96 weeks or longer (i.e., improvement is observed at the above points after the start of treatment, but not at all or any of the points prior to the above points). In some embodiments, any of the aforementioned improvements are observed after approximately 12 weeks, 24 weeks, 48 ​​weeks, 72 weeks, or 96 weeks of treatment (i.e., no improvement is observed until the aforementioned point in time after the start of treatment). In some embodiments, any of the aforementioned improvements are observed after approximately 26 weeks, 40 weeks, 52 weeks, or 80 weeks of treatment.

[0069] As used herein, the terms “disease” and “condition” may be interchangeable, or they may differ in that a particular disease or condition has no known causative agent (and therefore its etiology is not yet known), and is therefore not yet recognized as a disease, but is recognized by clinicians only as an undesirable condition or syndrome characterized by a more or less specific set of symptoms.

[0070] As used herein, the terms “JAK resistance” or “JAK inhibitor resistance” in relation to a disease or condition refer to a human subject having the disease or condition, being treated with a JAK inhibitor, and exhibiting an inadequate or no response. In some embodiments, MPN may be ruxolitinib resistant.

[0071] As used herein, the terms “inadequate” or “inadequate response” with respect to drug therapy refer to human subjects having a relapsed and / or refractory response to a drug (e.g., ruxolitinib and / or fedratinib), human subjects being unable to tolerate (i.e., intolerant to) the drug, or human subjects having a suboptimal response including poor reduction in spleen volume, reduction in overall symptoms, cytokine regulation, survival time, or a combination of two or more of these. In some embodiments, an inadequate response may refer to a lack of reduction in myelofibrosis and / or normalization or increase in platelet count and / or normalization or increase in neutrophil count and / or normalization or increase in hemoglobin count and / or transfusion improvement (including conversion to transfusion independence). In some embodiments, an inadequate response may refer to adverse effects requiring discontinuation of treatment with a JAK inhibitor.

[0072] "Bone marrow dysfunction" refers to a variety of conditions in which the bone marrow does not function properly, including myelosuppression, a state in which the bone marrow does not produce enough blood cells or platelets, and commonly manifests as conditions such as thrombocytopenia (low platelet count), anemia (low hemoglobin concentration), or transfusion dependence. Therefore, whenever a patient treated by the method of this disclosure is said to have poor bone marrow function, the patient may have thrombocytopenia (i.e., a platelet count of 150, 100, 75, or 50 × 10⁶). 9 It is understood that patients may have a combination of these symptoms, including blood glucose levels below 1 / L, anemia (i.e., Hgb levels below 10, 9, or 8), transfusion dependence, or poor bone marrow function.

[0073] "Transfusion-independent" refers to a patient who does not require a blood transfusion and has had an Hgb of 8 or higher for at least 12 weeks. "Transfusion-dependent" refers to a patient who is not transfusion-independent. For example, a transfusion-dependent patient may have required at least one transfusion in the past 12 weeks. In some embodiments, a transfusion-dependent patient may have required two or more transfusions in the past 12 weeks. In other embodiments, a patient may have required one, two, or more transfusions in the past 8 weeks. As used herein, "transfusion improvement" refers to a reduced need for blood transfusions or partial blood transfusions (e.g., red blood cells, white blood cells, and / or platelet transfusions). In some embodiments, a subject may become transfusion-independent (i.e., no longer require blood or partial blood transfusions (e.g., red blood cells, white blood cells, and / or platelet transfusions) based on the 12 weeks generally preceding treatment).

[0074] In some embodiments, subjects may have relapsed after treatment with the drug (e.g., ruxolitinib and / or fedratinib). In some embodiments, “relapsed” or “relapsed response” to the drug refers to human subjects who previously achieved a reduction of 35% or more in spleen volume (also known as “SVR35”) and / or a reduction of 50% or more in the overall symptom score (also known as “TSS50”) during treatment with the drug (e.g., ruxolitinib), but subsequently lost either of these responses during treatment. In some embodiments, subjects may have shown a refractory response to the drug (e.g., ruxolitinib and / or fedratinib). In some embodiments, “refractory” or “refractory response” to the drug refers to human subjects who have never achieved a reduction of 35% or more in spleen volume and / or a reduction of 50% or more in the overall symptom score during treatment with the drug.

[0075] In some embodiments, the subjects have received “prior treatment” with a JAK inhibitor. Prior treatment may have been continued for 3, 6, 9, or 12 months or longer before the decision to initiate administration of compound (1) was made.

[0076] If a patient has received "prior treatment" with a JAK inhibitor and administration of compound (1) is initiated, the administration of the JAK inhibitor may be continued or discontinued based on the medical judgment of the attending physician and the nature of the patient's response to the JAK inhibitor. For example, if the patient shows some response, and that response is suboptimal or plateaus, the physician may choose to continue administration of the JAK inhibitor in combination with compound (1). However, if the patient experiences significant hematological toxicity from the JAK inhibitor, the patient is refractory to the JAK inhibitor, or the patient's disease relapses, the physician may choose to discontinue administration of the JAK inhibitor and administer compound (1) as monotherapy or in combination with another JAK inhibitor and / or an ACVR inhibitor or other MPN treatment.

[0077] If the patient has previously received "prior treatment" with a JAK inhibitor, the most common JAK inhibitor is ruxolitinib. When discontinuing the JAK inhibitor and initiating compound (1) in combination with another JAK inhibitor, compound (1) is most commonly administered in combination with momerotinib.

[0078] In some embodiments, the subject may be resistant to the drug (i.e., drug intolerance) (e.g., ruxolitinib and / or fedratinib). In some embodiments, drug intolerance means that the subject cannot tolerate the side effects of the drug at or below a therapeutic dose. Side effects include, but are not limited to, anemia, thrombocytopenia, transfusion dependence, neutropenia, bruising, dizziness, headache, urinary tract infection, fatigue, shortness of breath, weight gain, gas, diarrhea, constipation, herpes zoster, or two or more of these in combination.

[0079] In some embodiments, subjects may have experienced inferior spleen volume reduction after treatment with the drug (e.g., ruxolitinib and / or fedratinib). In some embodiments, inferior spleen volume reduction may refer to a spleen volume reduction of less than 35% (e.g., less than approximately 30%, less than approximately 25%, less than approximately 20%, less than approximately 15%, less than approximately 10%, less than approximately 5%, less than approximately 1%, or no measurable reduction) based on the subject's baseline spleen volume (i.e., spleen volume before the start of treatment). In other words, the subject does not achieve SVR35. In some embodiments, spleen volume reduction may be measured 24 weeks after the first treatment dose.

[0080] In some embodiments, subjects may have experienced a poor overall symptom reduction after treatment with a drug (e.g., ruxolitinib and / or fedratinib). In some embodiments, a poor response to the drug or poor overall symptom reduction may refer to an overall symptom reduction of less than 50% (e.g., less than approximately 45%, less than approximately 40%, less than approximately 35%, less than approximately 30%, less than approximately 25%, less than approximately 20%, less than approximately 15%, less than approximately 10%, less than approximately 5%, less than approximately 1%, or no measurable reduction). That is, the subject does not achieve TSS50. In some embodiments, overall symptom reduction can be measured 24 weeks after the first treatment dose (i.e., at week 24).

[0081] In some embodiments, subjects may have poor cytokine regulation after treatment with a drug (e.g., ruxolitinib and / or fedratinib). In some embodiments, poor cytokine regulation may refer to a downregulation of less than 20%. In some embodiments, poor cytokine regulation may refer to a downregulation of 15% or less. In some embodiments, poor cytokine regulation may refer to a downregulation of 10% or less. In some embodiments, poor cytokine regulation may refer to the failure of cytokines to return to normal levels (i.e., cytokine levels in a sex-matched healthy cohort).

[0082] In some embodiments, subjects may have had a poor survival time after treatment with a drug (e.g., ruxolitinib and / or fedratinib). In some embodiments, poor survival time may refer to survival time of less than one year after the first treatment dose.

[0083] As used herein, “normal level” or “normalization” refers to the level of a measured component (e.g., platelets, white blood cells (e.g., neutrophils), red blood cells (e.g., hemoglobin), spleen volume, myelofibrosis reduction, overall symptom score, cytokine levels) in a sex-matched healthy cohort. In some embodiments, normalization may result in transfusion improvement (including conversion to transfusion independence).

[0084] As used herein, the terms “1-grade” or “1-grade” in relation to platelet count, hemoglobin count, neutrophil count, or myelofibrosis refer to a change in the grade from 1-grade to a subsequent grade. For example, a change from grade 1 to grade 2 is a 1-grade change, and a change from grade 1 to grade 3 is a 2-grade change. Thus, a 1-grade change may be a change from grade 1 to grade 2, a change from grade 2 to grade 3, or a change from grade 3 to grade 4.

[0085] As used herein, "Grade 1" with respect to the platelet count refers to a platelet count of 75 × 10⁶ 9 This refers to subjects with a platelet count of 75 × 10¹⁶ or higher, and "Grade 2" means that the platelet count is 75 × 10¹⁶. 9 / L is less than 50 x 10 9 This refers to subjects with a platelet count of 50 × 10¹⁶ or higher, and "Grade 3" means that the platelet count is 50 × 10¹⁶. 9 / L less than 25 x 10 9 This refers to subjects with a platelet count of 25 × 10¹⁶ or higher, and Grade 4 is defined as having a platelet count of 25 × 10¹⁶. 9 This refers to subjects with a platelet count of less than / L. Therefore, a higher platelet grade indicates a more severe condition. The term "upgrade" refers to a change from grade 1 to grade 2, 3, or 4, or from grade 2 to grade 3 or 4, or from grade 3 to grade 4. The term "upgrade" indicates a worsening of the condition from the perspective of platelet count. The term "downgrade" refers to a change from grade 4 to grade 3, 2, or 1, or from grade 3 to grade 2 or 1, or from grade 2 to 1. The term "downgrade" indicates an improvement in the condition from the perspective of platelet count.

[0086] As used herein, "Grade 1" for neutrophil count refers to a subject with a neutrophil count of 1500 / L or more, "Grade 2" refers to a subject with a neutrophil count of less than 1500 / L but 1000 / L or more, "Grade 3" refers to a subject with a neutrophil count of less than 1000 / L but 500 / L or more, and "Grade 4" refers to a subject with a neutrophil count of less than 500 / L. Therefore, a higher neutrophil grade indicates a more severe condition. The term "upgrade" refers to a change from Grade 1 to Grade 2, 3, or 4, or from Grade 2 to Grade 3 or 4, or from Grade 3 to Grade 4. The term "upgrade" indicates a worsening of the condition in terms of neutrophil count. The term "downgrade" refers to a change from Grade 4 to Grade 3, 2, or 1, or from Grade 3 to Grade 2 or 1, or from Grade 2 to Grade 1. The term "downgrade" refers to an improvement in the patient's condition as measured by the neutrophil count.

[0087] As used herein, "Grade 1" refers to a subject with a hemoglobin count of 10.0 g / dL or higher; "Grade 2" refers to a subject with a hemoglobin count of less than 10.0 g / dL but 8.0 g / dL or higher; and "Grade 3" refers to a subject with a hemoglobin count of less than 8.0 g / dL. Therefore, a higher hemoglobin grade indicates a more severe condition. The term "upgrade" refers to a change from Grade 1 to Grade 2 or 3, or from Grade 2 to Grade 3. The term "upgrade" indicates a worsening of the condition from the perspective of hemoglobin count. The term "downgrade" refers to a change from Grade 3 to Grade 2 or 1, or from Grade 2 to Grade 1. The term "downgrade" indicates an improvement in the condition from the perspective of hemoglobin count.

[0088] As used herein, “myelofibrosis reduction,” “BMFR,” or “myelofibrosis reduction” refers to an improvement or reduction in myelofibrosis of grade 1 or higher.

[0089] As used herein, “Grade 1” in relation to the myelofibrosis in question refers to a loose network of reticulans with many crossings, particularly in the perivascular region. “Grade 2” refers to a diffuse and dense increase in reticulans with extensive crossings, sometimes accompanied by localized bundles of thick fibers, primarily corresponding to collagen, and / or localized osteosclerosis. “Grade 3” refers to a diffuse and dense increase in reticulans with extensive crossings, accompanied by coarse bundles of thick fibers, primarily corresponding to collagen, and usually accompanied by osteosclerosis. Thus, a higher grade of myelofibrosis indicates a more severe condition. The term “upgrade” refers to a change from Grade 1 to Grade 2, 3, or 4, or from Grade 2 to Grade 3 or 4, or from Grade 3 to Grade 4. The term “upgrade” indicates a worsening of the condition from the perspective of myelofibrosis. The term “downgrade” refers to a change from Grade 4 to Grade 3, 2, or 1, or from Grade 3 to Grade 2 or 1, or from Grade 2 to Grade 1. The term "downgrade" refers to an improvement in the condition of myelofibrosis from a medical perspective.

[0090] As used herein, “spleen volume” is assessed using either a CT or MRI scan of the abdomen to determine the volume of the spleen during treatment. Subjects whose spleen volume has decreased by 20% or more (i.e., decreased spleen volume) at week 24 (i.e., week 24) compared to their spleen volume before the first treatment dose are designated as having decreased spleen volume in response to SVR20 treatment. In some embodiments, subjects may have a decrease of 35% or more in spleen volume at week 24 (i.e., week 24) compared to their spleen volume before the first treatment dose and are designated as having decreased spleen volume in response to SVR35 treatment. In some embodiments, subjects may have a decrease of at least about 35% (including at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, or at least about 65%) in spleen volume at week 24 (i.e., week 24) compared to their spleen volume before the first treatment dose.

[0091] In some embodiments, if the subject shows an insufficient response to the JAK inhibitor, the patient may have a spleen volume reduction of less than 35%, less than 25%, less than 20%, or less than 15% at week 24 (i.e., week 24) compared to the spleen volume before the first treatment with the JAK inhibitor.

[0092] As used herein, “cytokines” refers to small proteins (plural) that are important for cell signaling. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.

[0093] As used herein, “cytokine regulation” refers to an increase (i.e., upregulation) or decrease (i.e., downregulation) in the cytokine levels in the serum of the subject compared to the cytokine levels of the subject before the first therapeutic administration. In some embodiments, cytokine regulation in the subject may refer to a return of the cytokine levels of the subject to normal levels.

[0094] In some embodiments, cytokine regulation in the subject may be upcontrol. In some embodiments, upcontrol may refer to an increase in cytokine levels of approximately 20% or more, approximately 25% or more, approximately 35% or more, approximately 45% or more, approximately 50% or more, approximately 60% or more, approximately 75% or more, approximately 100% or more, approximately 150% or more, approximately 200% or more, approximately 250% or more, approximately 300% or more, or approximately 500% or more compared to the cytokine level before the first therapeutic dose. In some embodiments, upcontrol may refer to an increase in cytokine levels of approximately 25% or more compared to the cytokine level before the first therapeutic dose. In some embodiments, upcontrol may refer to an increase in cytokine levels of approximately 50% or more compared to the cytokine level before the first therapeutic dose. In some embodiments, cytokine upcontrol may be measured 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, or 20 hours after the first therapeutic dose (i.e., day 0). In some embodiments, cytokine upcontrol may be measured 6, 8, 10, or 12 hours after the first therapeutic dose (i.e., day 0). In some embodiments, cytokine upcontrol may be measured 24 hours after the first therapeutic dose (i.e., day 1). In some embodiments, cytokine upcontrol may be measured 4 weeks after the first therapeutic dose (i.e., week 4). In some embodiments, cytokine upcontrol may be measured 6 weeks after the first therapeutic dose (i.e., week 6). In some embodiments, cytokine upcontrol may be measured 8 weeks after the first therapeutic dose (i.e., week 8). In some embodiments, cytokine upcontrol may be measured 10 weeks after the first therapeutic dose (i.e., week 10). In some embodiments, cytokine upcontrol may be measured 12 weeks after the first therapeutic dose (i.e., week 12).

[0095] In some embodiments, cytokine regulation in the subject may be downregulation. In some embodiments, downregulation may refer to a decrease of approximately 20% or more, approximately 25% or more, approximately 35% or more, approximately 45% or more, approximately 50% or more, approximately 60% or more, approximately 75% or more, approximately 100% or more, approximately 150% or more, approximately 200% or more, approximately 250% or more, approximately 300% or more, or approximately 500% or more compared to the cytokine level before the first therapeutic administration. In some embodiments, downregulation may refer to a decrease of approximately 25% or more of cytokine compared to the cytokine level before the first therapeutic administration. In some embodiments, downregulation may refer to a decrease of approximately 30% or more of cytokine compared to the cytokine level before the first therapeutic administration. In some embodiments, downregulation may refer to a decrease of approximately 40% or more of cytokine compared to the cytokine level before the first therapeutic administration. In some embodiments, downregulation may refer to a decrease of approximately 50% or more of cytokine compared to the cytokine level before the first therapeutic administration. In some embodiments, downcontrol can refer to a reduction of approximately 60% or more in cytokine levels compared to the cytokine level before the first therapeutic dose. In some embodiments, downcontrol can refer to a reduction of approximately 70% or more in cytokine levels compared to the cytokine level before the first therapeutic dose. In some embodiments, downcontrol can refer to a reduction of approximately 80% or more in cytokine levels compared to the cytokine level before the first therapeutic dose. In some embodiments, downcontrol can refer to a reduction in cytokine levels such that they return to normal levels (i.e., cytokine levels in a sex-matched healthy cohort). In some embodiments, cytokine downcontrol can be measured 2, 4, 6, 8, 10, 12, 14, 16, 18, or 20 hours after the first therapeutic dose (i.e., day 0). In some embodiments, cytokine downcontrol can be measured 6, 8, 10, or 12 hours after the first therapeutic dose (i.e., day 0). In some embodiments, cytokine downcontrol can be measured 24 hours after the first therapeutic dose (i.e., day 1).In some embodiments, cytokine downcontrol can be measured 4 weeks after the first therapeutic dose (i.e., week 4). In some embodiments, cytokine downcontrol can be measured 6 weeks after the first therapeutic dose (i.e., week 6). In some embodiments, cytokine downcontrol can be measured 8 weeks after the first therapeutic dose (i.e., week 8). In some embodiments, cytokine downcontrol can be measured 10 weeks after the first therapeutic dose (i.e., week 10). In some embodiments, cytokine downcontrol can be measured 12 weeks after the first therapeutic dose (i.e., week 12). In some embodiments, cytokine downcontrol can be measured 6 months after the first therapeutic dose. In some embodiments, cytokine downcontrol can be measured 12 months after the first therapeutic dose. In some embodiments, cytokine downcontrol can be measured 18 months after the first therapeutic dose. In some embodiments, cytokine downcontrol can be measured 24 months after the first therapeutic dose.

[0096] In some embodiments, cytokine regulation in the subject may involve upregulation of specific cytokines and downregulation of other cytokines, as defined above.

[0097] In some embodiments, cytokines include adiponectin, angiopoietin 1, angiotensin II, beta-2 microglobulin, bone morphogenetic protein (BMP) and its subtypes (e.g., BMP1, BMP6, and BMP7), bone morphogenetic protein Rcp2, brain-derived neurotrophic factor (BDNF), CC-motif chemokine ligand (CCL) and its subtypes (e.g., CCL14 and CCL21), differentiation cluster 40 ligand (CD40L), differentiation cluster 40 (CD40), colony-stimulating factor (CSF1), complement factor D, C-reactive protein (CRP), C-X3-C-motif chemokine receptor 1 (CX3CR1), CXC-motif chemokine ligand (CXL) and its subtypes (e.g., CXL11, CXCL12, and CXCL16), and Dickkopf WNT signaling pathway inhibitor 1 (DKK1), endoglin, eotaxin and its subtypes (e.g., eotaxin-2 and eotaxin-3), epidermal growth factor (EGF), epidermal growth factor receptor (EGFR), erythropoietin (EPO), extracellular matrix protein tenacin-C (TN-C), extracellular newly identified receptor for advanced glycation end-products bindingProtein (EN-RAGE), ferritin, fibroblast growth factor (FGF), Fms-related receptor tyrosine kinase 3 (FLT3), Fms-related tyrosine kinase 3 ligand (FLT-3L), granulocyte-macrophage colony-stimulating factor (GM-CSF), growth colony-stimulating factor (G-CSF), growth regulatory protein alpha (GRO-alpha), heparin-binding EGF-like growth factor (HB-EGF), hepatocyte growth factor (HGF), insulin-like growth factor-binding protein 2 (IGFBP2), intercellular adhesion molecule 1 (ICAM-1), interferon (IFN) and its subtypes (e.g., interferon-gamma-inducible protein 9 (IP-9), interferon-alpha (IFN-alpha), interferon-ga Interferon-gamma-inducible protein (IFN-g-IP), interferon-gamma-inducible protein 10 (IP-10), interleukins (IL) and their subfactors (e.g., IL-1a, IL-1Ra, IL-2, IL-2R, IL-2Ra, IL-4, IL-5, IL-5a, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IL-17A, IL-17F, IL-18, IL-22, IL-23, IL-1B, and IL-1RA), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), latent-associated peptide transforming growth factor-β1 (LAP TGF-β1), leptin (LEP), LIF interleukin-6 family cytokines (LIF), macrophage colony-stimulating factor 1 (MCSF), macrophage-derived chemokines (MDCs), macrophage inflammatory proteins and their subtypes (e.g., MIP-1, MIP-1b, MIP-1a, MIP-3a, and MIP-3b), macrophage-derived chemokines (MDCs), matrix metalloproteinases and their subtypes (e.g., MMP-3 and MMP-9), monocyte chemotactic proteins and their subtypes (e.g., MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5), monokine-inducible gamma (MIG), myelin basic proteins and their subtypes (e.g., MBPR2 and MBP7), myeloperoxidase (MPO), myoglobin, osteoprotegerin (OPG), pentraxin (PTX) and its subtypes (e.g., PTX3), plasma protein factor VII (factor VII), plasminogen activator inhibitor-1 (PAI-1), platelet factor 4 (PF-4), platelet-derived growth factor BB (PDGF-BB), lung and activation-regulated chemokines (PARC), regulated on activation of normal T cells expressed and This may include secreted (RANTES), stem cell factor (SCF), 10-11 translocation 2 (TET2), thrombopoietin (TPO), thymic and activation-regulating chemokines (TARC), tissue metalloproteinase inhibitor-1 (TIMP-1), transforming growth factor β (TGF-β), transforming growth factor β1 (TGF-β1), tumor necrosis factor and its subtypes (TNF-1, TNF-α, TNF-RI, and TNF-RII), urokinase plasminogen activator receptor (uPAR), vascular adhesion molecule (VCAM-1), vascular endothelial growth factor (VEGF) and its subtype (VEGFb), vascular endothelial growth factor receptor (VGFR), α2-macroglobulin (A2M), or combinations of two or more of these. In some embodiments, cytokines may include EGFR, PDGF-BB, EPO, IP-10, TIMP-1, IL-2R-alpha, IL-1R-a, IL-12p40, IL-12p70, IL-15, MMP-3, MMP-9, VEGF, IL-2, IL-6, MIP-1beta, TNF-a, TGF-beta, or two or more combinations thereof. In some embodiments, cytokines may include IL-1Ra, IL-6, IL-10, IL-12, TGF-beta, EGFR, ferritin, GRO-a, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, VCAM-1, or two or more combinations thereof.

[0098] In some embodiments, cytokine regulation involves adiponectin, angiopoietin 1, angiotensin II, beta-2-microglobulin, bone morphogenetic proteins (BMPs) and their subtypes (e.g., BMP1, BMP6, and BMP7), bone morphogenetic protein Rcp2, brain-derived neurotrophic factor (BDNF), CC-motif chemokine ligands (CCLs) and their subtypes (e.g., CCL14 and CCL21), differentiation cluster 40 ligand (CD40L), differentiation cluster 40 (CD40), colony-stimulating factor (CSF1), complement factor D, C-reactive protein (CRP), C-X3-C-motif chemokine receptor 1 (CX3CR1), CXC-motif chemokine ligands (CXLs) and their subtypes (e.g., CXL11, CXCL12, and CXCL16), and Dickkopf WNT signaling pathway inhibitor 1 (DKK1), endoglin, eotaxin and its subtypes (e.g., eotaxin-2 and eotaxin-3), epidermal growth factor (EGF), epidermal growth factor receptor (EGFR), erythropoietin (EPO), extracellular matrix protein tenacin-C (TN-C), extracellular newly identified receptor for advanced glycation end-products bindingProtein (EN-RAGE), ferritin, fibroblast growth factor (FGF), Fms-related receptor tyrosine kinase 3 (FLT3), Fms-related tyrosine kinase 3 ligand (FLT-3L), granulocyte-macrophage colony-stimulating factor (GM-CSF), growth colony-stimulating factor (G-CSF), growth regulatory protein alpha (GRO-alpha), heparin-binding EGF-like growth factor (HB-EGF), hepatocyte growth factor (HGF), insulin-like growth factor-binding protein 2 (IGFBP2), intercellular adhesion molecule 1 (ICAM-1), interferon (IFN) and its subtypes (e.g., interferon-gamma-inducible protein 9 (IP-9), interferon-alpha (IFN-alpha), interferon-ga Interferon-gamma-inducible protein (IFN-g-IP), interferon-gamma-inducible protein 10 (IP-10), interleukins (IL) and their subfactors (e.g., IL-1a, IL-1Ra, IL-2, IL-2R, IL-2Ra, IL-4, IL-5, IL-5a, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IL-17A, IL-17F, IL-18, IL-22, IL-23, IL-1B, and IL-1RA), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), latent-associated peptide transforming growth factor-β1 (LAP TGF-β1), leptin (LEP), LIF interleukin-6 family cytokines (LIF), macrophage colony-stimulating factor 1 (MCSF), macrophage-derived chemokines (MDCs), macrophage inflammatory proteins and their subtypes (e.g., MIP-1, MIP-1b, MIP-1a, MIP-3a, and MIP-3b), macrophage-derived chemokines (MDCs), matrix metalloproteinases and their subtypes (e.g., MMP-3 and MMP-9), monocyte chemotactic proteins and their subtypes (e.g., MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5), monokine-inducible gamma (MIG), myelin basic proteins and their subtypes (e.g., MBPR2 and MBP7), myeloperoxidase (MPO), myoglobin, osteoprotegerin (OPG), pentraxin (PTX) and its subtypes (e.g., PTX3), plasma protein factor VII (factor VII), plasminogen activator inhibitor-1 (PAI1), platelet factor 4 (PF-4), platelet-derived growth factor BB (PDGF-BB), lung and activation-regulated chemokines (PARC), regulated on activation of normal T cells expressed and This includes the downregulation of secreted (RANTES), stem cell factor (SCF), 10-11 translocation 2 (TET2), thrombopoietin (TPO), thymic and activation-regulating chemokines (TARC), tissue inhibitors of metalloproteinase-1 (TIMP1), transforming growth factor-β (TGF-beta), transforming growth factor-β1 (TGF-b1), tumor necrosis factor and its subtypes (TNF-1, TNF-α, TNF-RI, and TNF-RII), urokinase plasminogen activator receptor (uPAR), vascular adhesion molecule (VCAM1), vascular endothelial growth factor (VEGF) and its subtype (VEGFb), vascular endothelial growth factor receptor (VGFR), α2-macroglobulin (A2M), or two or more combinations thereof.

[0099] In some embodiments, downregulated cytokines include B2MICG, BMP1, BMP6, BMP7, BMP-Rcp2, CD40L, CRP, ferritin, FGF, GCSF, GM-CSF, HGF, IFN, IL-1, IL-10, IL-12, IL-13, IL-15, IL-17, IL-17A, IL-1B, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IFN, IFNa, IFNg, INF-g-IP, IP10, leptin, MBP R2, MBP7, MCP1, MIP1a, MIP1b, MCP2, MIG, MMP, PAL1, PDGF-BB, PTX, RANTES, TNF, TNF-1, TNF-a, TNF-RII, VCAM1, VEGF, VEGFb, VEGR, or two or more combinations thereof. In some embodiments, downregulated cytokines may include IL-6, IL-10, IL-12, IL-18, TGF-b, EGFR, ferritin, GRO-a, IL-1RA, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, VCAM-1, or two or more combinations thereof. In some embodiments, downregulated cytokines may include MIG, EN-RAGE, MMP-9, CD40, FRTN, ICAM-1, TIMP-1, IL-18, SCF, MPO, IP-10, IL-2R-alpha, IL-8, MIP-1β, IL-12p40, EPO, or two or more combinations thereof. In some embodiments, downregulated cytokines may include MCP-1, MIP-1-alpha, RANTES, IL-13, or two or more combinations thereof. In some embodiments, downregulated cytokines may include IL-8, MMP-9, PAI-1, IL-2, CXL11, CSF1, UPAR, CRP, FLT-3L, EPO, INF-a, LEP, or two or more combinations thereof. In some embodiments, downregulated cytokines may include IL-8, MMP-9, PAI-1, IL-2, or two or more combinations thereof. In some embodiments, downregulated cytokines may include CXL11, CSF1, UPAR, or a combination of two or more of these.In some embodiments, downregulated cytokines may include IL-1Ra, IL-6, IL-10, IL-12, TGF-beta, EGFR, ferritin, GRO-α, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, VCAM-1, or two or more combinations thereof. In some embodiments, downregulated cytokines may include IL-6, IL-12p40, MMP9, EN-RAGE, or two or more combinations thereof. In some embodiments, IL-6 may be downregulated by about 60% or more, IL-12p40 may be downregulated by about 75% or more, MMP9 may be downregulated by about 50% or more, EN-RAGE may be downregulated by about 60% or more, or two or more combinations thereof.

[0100] As used herein, “increasing” or “increasing” means increasing the daily dose of a compound or drug disclosed herein. This may include increasing the amount of the compound or drug in any given dose (e.g., increasing the dose from 100 mg to 200 mg) and / or increasing the number of daily doses of the compound or drug (e.g., increasing the number of daily doses from once daily to twice daily). Increasing the dose and / or daily dose of compound (1) results in an increase in the total daily dose of compound (1) or a pharmaceutically acceptable salt thereof. Elevating the dose and / or frequency of daily administration of ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, or nabutemadeline results in an increase in the total daily dose of ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof. In some embodiments, the elevation can be initiated from a predetermined starting dose. In some embodiments, the elevation can be performed every four weeks. In some embodiments, dose escalation may be continued until the maximum tolerable dose level is reached, or sooner if the subject shows MNP (e.g., MF) improvement, such as a decrease in myelofibrosis, a decrease in overall symptoms, cytokine regulation (e.g., a decrease or normalization of cytokines), normalization or increase in platelet count, normalization or increase in neutrophil count, normalization or increase in hemoglobin count, transfusion improvement (including conversion to transfusion independence), a decrease in spleen volume, or a combination of two or more of these. In some embodiments, myelofibrosis, overall symptom score, cytokine levels, platelet count, neutrophil count, hemoglobin count, and / or spleen volume may be measured every 2-4 weeks during treatment.

[0101] As used herein, “tasting” or “tasting” means reducing the daily dose of a compound or drug disclosed herein. This may include reducing the amount of the compound or drug in any given dose, and / or reducing the number of daily doses of the compound or drug. For example, the amount of the compound or drug may be reduced by half (e.g., reducing a dose from 200 mg to 100 mg), and / or the number of daily doses may be reduced by half (e.g., reducing the number of daily doses from twice a day to once a day). Tasting the dose and / or daily dose of compound (1) results in a reduction in the total daily dose of compound (1) or a pharmaceutically acceptable salt thereof. Gradually reducing the dose and / or frequency of daily administration of ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, or nabutemadeline results in a reduction in the total daily dose of ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, or nabutemadeline, or their pharmaceutically acceptable salts. Sometimes it may be necessary to interrupt the administration of compound (1). For example, administration may be stopped and then resumed after a certain period. The interruption may last for a number of days, until the side effect disappears and / or until the platelet count of the subject being treated exceeds a certain amount. In some embodiments, subjects being treated with a stable dose of a JAK inhibitor and compound (1) may have their administration of compound (1) interrupted if a new adverse event occurs. In some embodiments, administration of compound (1) may be resumed after the adverse event has disappeared. In some embodiments, if an adverse event recurs upon resumption of administration of compound (1), the total daily dose of compound (1) may be reduced. In some embodiments, if an adverse event recurs upon resumption of administration of compound (1), administration of compound (1) may be discontinued. In other embodiments, instead of discontinuation, the total daily dose of compound (1) may be reduced or kept the same, depending on the severity of the adverse event.In some embodiments, if the adverse event is a decrease in platelet count, the resolution of the adverse event may be achieved when the target platelet count increases to the platelet count that would have been achieved if treated with the JAK inhibitor alone (i.e., the baseline JAK inhibitor platelet count of the target). In some embodiments, if the adverse event is a decrease in platelet count, the resolution of the adverse event may be achieved when the target platelet count increases by one grade (e.g., from grade 4 to grade 3). In some embodiments, if the adverse event is a decrease in platelet count, the resolution of the adverse event may be achieved when the target platelet count increases by at least 25 × 10⁻⁶. 9 This can be achieved when the platelet count increases by 1 / L. In some embodiments, if the adverse event is a decrease in platelet count, the disappearance of the adverse event can be achieved when the target platelet count increases by at least 35%.

[0102] In this specification, the terms “substantial,” “substantial,” and “non-substantial” may be used to characterize the absence of side effects from the disclosed treatment. As used herein, “substantial,” “substantial,” or “non-substantial” means about 45% or less. In some embodiments, “substantial” means about 40% or less. In some embodiments, “substantial” means about 35% or less. In some embodiments, “substantial” means about 30% or less, about 25% or less, about 20% or less, about 15% or less, or about 10% or less. For example, in some embodiments, a decrease of 35% or less in the platelet count of the subject is not a substantial decrease (including about 34% or less, about 33% or less, about 32% or less, about 31% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, or about 5% or less). In some embodiments, a substantial decrease in the platelet count of the subject is less than one grade (i.e., a decrease in the platelet count such that the subject remains at the same grade). In contrast, as used herein, “substantial” or “effectively” means about 25% or more. In some embodiments, “substantial” means about 30% or more, about 35% or more, about 40% or more, about 45% or more, about 50% or more, or about 55% or more.

[0103] As used herein, “stable” means little to no change, such as a change of about ±10% or less. In some embodiments, stable means about ±8%. In some embodiments, stable means about ±5%, about ±2%, or about ±1%. For example, in some embodiments, if the platelet count of a subject remains stable (i.e., ±10%), it does not substantially decrease. In some embodiments, the platelet count, hemoglobin, neutrophil count, or myelofibrosis of a subject is stable if the subject remains at the same grade (e.g., the platelet count decreases, but the subject remains at grade 2). In some embodiments, if disease stability is achieved, monotherapy with compound (1) or combination therapy including compound (1) is continued at the dose at which stability was achieved.

[0104] As used herein, “overall symptom reduction” and similar terms mean a reduction of approximately 50% or more (also known as TSS50) from the subject’s overall symptom score immediately prior to the initiation of treatment (including approximately 55% or more, approximately 60% or more, approximately 65% ​​or more, approximately 70% or more, approximately 75% or more, approximately 80% or more, approximately 85% or more, approximately 90% or more, approximately 95% or more, approximately 99% or more, or approximately 100%). The symptoms used to determine the overall symptom score are provided in the MPN Symptom Assessment Form (MPN-SAF) (Scherber R et al., Blood (2011) 118 (2): 401-408), the Myelofibrosis Symptom Assessment Form (MFSAF or MF-SAF) (Mesa RA et al, Res 2009, vol. 33(9) (pg. 1199-1203)), and the MPN-SAF TSS abbreviated version of MPN-SAF (Emanuel R. et al., Journal of Clinical Oncology 30, no. 33 (November 20, 2012) 4098-4103) (all incorporated herein by reference).

[0105] All of these questionnaires require subjects to numerically score their symptoms and include questions about symptoms such as fatigue, early satiety, abdominal discomfort, lethargy, difficulty concentrating, night sweats, pruritus, diffuse bone pain, left subcostal pain, fever, and unintentional weight loss. If accuracy of the above questionnaires is required, the applicable versions of MPN-SAF and MPN-SAF TSS50 are the versions effective as of October 30, 2022. Version 4 is the applicable version of MFSAF. As with any other tests administered in this disclosure, a subject who has achieved TSS50 with version 4 of MFSAF does not need to be administered version 4 again, as long as the subject experiences TSS50 with version 4, if administered.

[0106] If the embodiment is based on a reduction in all symptoms in MF subjects in MFSAF, it is understood that a similar reduction may be achieved in MPN-SAF or MPN-SAF TSS in MPN subjects (particularly ET, PV, and MF subjects), and vice versa. In some embodiments, the reduction in all symptoms is measured about 4 weeks after the first therapeutic dose, at which point a TSS of 50 may be observed. In some embodiments, the reduction in all symptoms is measured about 12 weeks after the first therapeutic dose, at which point a TSS of 50 may be observed. In some embodiments, the reduction in all symptoms is measured about 24 weeks after the first therapeutic dose, at which point a TSS of 50 may be observed. In some embodiments, the reduction in all symptoms is measured about 36 weeks after the first therapeutic dose, at which point a TSS of 50 may be observed.

[0107] Where used herein, when two drugs are said to have “non-overlapping” toxicities, it means that, based on the toxicity profiles of each drug when administered individually, a person skilled in the art would expect that no particular toxicity would be clinically significant when the two drugs are combined. One or more toxicities can be evaluated, but the toxicities particularly relevant to this disclosure are hematological toxicities such as platelet count, hemoglobin concentration, and transfusion dependence. As thus defined, compound (1), when used in combination with the drugs at the dose levels reported in Table V, does not have overlapping hematological toxicities with ruxolitinib or momerotinib in terms of thrombocytopenia, neutropenia, or anemia.

[0108] As used herein, “increased neutrophil count” or “increased neutrophils” refers to an increase in neutrophils or an increase in white blood cells.

[0109] As used herein, “increase in hemoglobin count” or “increase in hemoglobin” means an increase in hemoglobin or an increase in red blood cells.

[0110] As used herein, “approximately” means ±10% of a given value. In some embodiments, “approximately” may be ±5% of a given value. In some embodiments, “approximately” may be ±2% of a given value. All numerical values ​​reported herein may be modified by the term “approximately” and further expressed based on the aforementioned positive or negative percentages.

[0111] I. Medical treatment In one embodiment, the present disclosure provides a method for treating myeloproliferative neoplasms in a human subject requiring treatment, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, the subject having thrombocytopenia (e.g., platelet count of 150, 100, 75, 50, or 25 × 10⁶). 9Poor bone marrow function characterized by: ≠ / L; anemia (e.g., Hgb levels ≠ 10, 9, or 8 g / dL); transfusion dependence; or a combination thereof, where treatment induces a clinically meaningful response in myeloproliferative neoplasms.

[0112] In another aspect, the Disclosure provides a method for treating myeloproliferative neoplasms in a human subject requiring treatment, the method comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor, the subject having thrombocytopenia (e.g., platelet counts of 150, 100, 75, 50, or 25 × 10⁶). 9 Poor bone marrow function characterized by: ≠ / L; anemia (e.g., Hgb levels ≠ 10, 9, or 8 g / dL); transfusion dependence; or a combination thereof, where treatment induces a clinically meaningful response in myeloproliferative neoplasms.

[0113] In another aspect, the Disclosure provides a method for treating a myeloproliferative neoplasm in a human subject requiring treatment, the subject having been previously treated for the myeloproliferative neoplasm with a JAK inhibitor and, as appropriate, having recurrent lesions or being refractory to the JAK inhibitor, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, the treatment inducing a clinically meaningful response in the myeloproliferative neoplasm.

[0114] In another aspect, the Disclosure provides a method for treating a myeloproliferative neoplasm by inducing TSS50 in a human subject in need of treatment, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, the myeloproliferative neoplasm being treated by inducing TSS50 in the subject, and optionally, at a time between those times, including 24 weeks and 48 weeks.

[0115] In another aspect, the Disclosure provides a method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject compound (1) or a pharmaceutically acceptable salt thereof, and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof, in amounts that do not induce overlapping hematological toxicities (e.g., anemia and / or thrombocytopenia and / or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.

[0116] In another aspect, the Disclosure provides a method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a selective PIM1 inhibitor and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof in a dose that does not induce overlapping hematological toxicities (e.g., anemia and / or thrombocytopenia and / or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.

[0117] In another aspect, the Disclosure provides a method for inducing a probability of SVR35 of 15% or more or 20% or more in human subjects with myeloproliferative neoplasms, the subjects having previously received treatment with a JAK inhibitor for myeloproliferative neoplasms and, as appropriate, having relapsed disease or being refractory to JAK inhibitors, the method comprising administering to the subjects a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, the treatment inducing a probability of SVR35 of 15% or more or 20% or more in human subjects. The aforementioned probabilities are absolute probabilities and do not refer to any comparator. The aforementioned probabilities further assume that the subjects continue treatment.

[0118] In another aspect, the Disclosure provides a method for inducing a probability of TSS50 in human subjects with myeloproliferative neoplasms of 30%, 35%, 40%, 45%, or 50% or more, the subjects having previously received treatment with a JAK inhibitor for myeloproliferative neoplasms and, as appropriate, having relapsed disease or being refractory to JAK inhibitors, the method comprising administering to the subjects a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, the treatment inducing a probability of TSS50 in human subjects of 30%, 35%, 40%, 45%, or 50% or more. The aforementioned probabilities are absolute probabilities without reference to any comparator. The aforementioned probabilities further assume that the subjects are continuing treatment.

[0119] In one embodiment, the technology provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is approximately 200 × 10 9 Less than / L (for example, about 150, 100, 75, 50, or 25 × 10) 9 / L less; 150, 100, 75, 50, or 25 x 10 9 / L less; 50 or 25 x 10 9 / L less; or 25 × 10 9 The patient has a platelet count of less than / L.

[0120] In another embodiment, the technology is a method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, the subject having received one or more prior treatments including compound (1) or a pharmaceutically acceptable salt thereof. In response to treatment, the subject has (a) a platelet count reduction of less than 1 grade compared to the baseline platelet grade, and (b) a reduction of 25 × 10⁶ platelets compared to the baseline platelet count. 9(c) A decrease in platelet count of less than 1 / L and / or a decrease of 35% or less compared to the baseline platelet count. The decrease in platelet count is determined by the change between the baseline platelet count and the second platelet count. The baseline platelet count is the platelet count determined within one week prior to administration of compound (1) or a pharmaceutically acceptable salt thereof. The second platelet count is determined at least two weeks after administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0121] In another embodiment, the technology provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising a combination therapy comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; as well as a JAK inhibitor or a pharmaceutically acceptable salt thereof and / or an ACVR inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the JAK inhibitor and the ACVR inhibitor may be the same compound. In some embodiments, the subject is approximately 10 × 10 9 It has a platelet count of 15 × 10¹⁶ or more. In some embodiments, the target is approximately 15 × 10¹⁶. 9 It has a platelet count of 1 / L or more. In some embodiments, the target is approximately 20 × 10 9 It has a platelet count of 1 / L or more. In some embodiments, the subject is approximately 25 × 10 9 Having a platelet count of 1 / L or more. In some embodiments, the subject is approximately 200 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 150 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 100 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 50 × 10 9 Having a platelet count of less than / L. In some embodiments, the subject is 25 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 10 × 10 9 / L or more, approximately 200 x 10 9 Having a platelet count of less than / L.

[0122] In another embodiment, the technology provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising a combination therapy comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeg interferon alpha-2b, nabutemadeline, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is approximately 10 × 10 9 It has a platelet count of 15 × 10¹⁶ or more. In some embodiments, the target is approximately 15 × 10¹⁶. 9 It has a platelet count of 1 / L or more. In some embodiments, the target is approximately 20 × 10 9 It has a platelet count of 1 / L or more. In some embodiments, the subject is approximately 25 × 10 9 Having a platelet count of 1 / L or more. In some embodiments, the subject is approximately 200 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 150 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 100 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 50 × 10 9 Having a platelet count of less than / L. In some embodiments, the subject is 25 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 10 × 10 9 / L or more, approximately 200 x 10 9 Having a platelet count of less than / L.

[0123] In another embodiment, the technology provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to a subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, nabutemadeline, or a pharmaceutically acceptable salt thereof, the subject having a baseline platelet count of 200 × 10⁶ 9 / L or less and / or 10×10 9The dosage is ≥ / L. Ruxolitinib or its pharmaceutically acceptable salt is approximately 5 mg to 25 mg; fedratinib or its pharmaceutically acceptable salt is approximately 200 mg to 500 mg; pacritinib or its pharmaceutically acceptable salt is approximately 100 mg to 200 mg; momerotinib or its pharmaceutically acceptable salt is approximately 50 mg to 200 mg; ruspatercept or its pharmaceutically acceptable dosage is approximately 0.5 mg / kg to 1. The dosage is 75 mg / kg (based on the subject's body weight); the dosage of lopeg interferon alpha-2b or a pharmaceutically acceptable salt is approximately 50-500 μg (e.g., approximately 50-150 μg, approximately 100-300 μg, approximately 200-400 μg, or approximately 300-500 μg); and the dosage of nabutemadeline or a pharmaceutically acceptable salt is approximately 100-300 mg (e.g., approximately 100-150 mg, approximately 150-300 mg, or approximately 120-240 mg).

[0124] In some embodiments, the target is approximately 10 × 10 9 It has a platelet count of 15 × 10¹⁶ or more. In some embodiments, the target is approximately 15 × 10¹⁶. 9 It has a platelet count of 1 / L or more. In some embodiments, the target is approximately 20 × 10 9 It has a platelet count of 1 / L or more. In some embodiments, the subject is approximately 25 × 10 9 Having a platelet count of 1 / L or more. In some embodiments, the subject is approximately 200 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 150 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 100 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 50 × 10 9 Having a platelet count of less than / L. In some embodiments, the subject is 25 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 10 × 10 9 / L or more, approximately 200 x 10 9 Having a platelet count of less than / L.

[0125] In another aspect, the present technology provides a method for treating myeloproliferative neoplasms in a human subject in need of treatment without causing a clinically significant risk of adverse events, the method comprising administering to the subject ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, pegylated interferon alpha-2b, nabumetone, or a pharmaceutically acceptable salt thereof for up to about 36 months; determining or having determined whether the subject had an adverse event during the treatment period; reducing the dosage by from about 33% to about 80%, or temporarily discontinuing the administration; and administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a platelet count of about 10×10 9 / L or more. In some embodiments, the subject has a platelet count of about 15×10 9 / L or more. In some embodiments, the subject has a platelet count of about 20×10 9 / L or more. In some embodiments, the subject has a platelet count of about 25×10 9 / L or more. In some embodiments, the subject has a platelet count of about 200×10 9 / L or less. In some embodiments, the subject has a platelet count of about 150×10 9 / L or less. In some embodiments, the subject has a platelet count of about 100×10 9 / L or less. In some embodiments, the subject has a platelet count of about 50×10 9 / L or less. In some embodiments, the subject has a platelet count of 25×10 9 / L or less. In some embodiments, the subject has a platelet count of about 10×10 9 / L or more and about 200×10 9 / L or less.

[0126] In another aspect, the present technology is a method for treating myeloproliferative neoplasms in a human subject who requires treatment while undergoing therapy with ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, pegylated interferon alpha-2b, or nab-paclitaxel, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and continuing to administer to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, during which the subject (a) does not receive therapy (e.g., JAK therapy such as ruxolitinib) or (b) receives a reduced therapy (e.g., JAK therapy such as ruxolitinib). In some embodiments, the subject has a platelet count of about 10×10 9 / L or more. In some embodiments, the subject has a platelet count of about 15×10 9 / L or more. In some embodiments, the subject has a platelet count of about 20×10 9 / L or more. In some embodiments, the subject has a platelet count of about 25×10 9 / L or more. In some embodiments, the subject has a platelet count of about 200×10 9 / L or less. In some embodiments, the subject has a platelet count of about 150×10 9 / L or less. In some embodiments, the subject has a platelet count of about 100×10 9 / L or less. In some embodiments, the subject has a platelet count of about 50×10 9 / L or less. In some embodiments, the subject has a platelet count of 25×10 9 / L or less. In some embodiments, the subject has a platelet count of about 10×10 9 / L or more and about 200×10 9 / L or less.

[0127] In another aspect, the present technology provides a method for treating myeloproliferative neoplasms in a human subject who requires treatment, the method comprising administering to the subject compound (1) or a pharmaceutically acceptable salt thereof; and an ACVR inhibitor (e.g., an ACVR1 inhibitor), wherein the subject has less than 200×10 9 / L and / or 10×10 9The patient has a platelet count of 10 / L or more. The ACVR1 inhibitor may be administered at a dose of approximately 50 mg to approximately 250 mg. In some embodiments, the patient is approximately 10 × 10 9 It has a platelet count of 15 × 10¹⁶ or more. In some embodiments, the target is approximately 15 × 10¹⁶. 9 It has a platelet count of 1 / L or more. In some embodiments, the target is approximately 20 × 10 9 It has a platelet count of 1 / L or more. In some embodiments, the subject is approximately 25 × 10 9 Having a platelet count of 1 / L or more. In some embodiments, the subject is approximately 200 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 150 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 100 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 50 × 10 9 Having a platelet count of less than / L. In some embodiments, the subject is 25 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 10 × 10 9 / L or more, approximately 200 x 10 9 Having a platelet count of less than / L.

[0128] In another aspect, the technology provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to a subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and a JAK inhibitor, the subject being approximately 10 × 10 9 Platelet counts of 10¹⁰ or more and / or approximately 200 × 10¹⁰ 9 The patient has a platelet count of less than 10 / L. The JAK inhibitor may be administered in doses of approximately 5 mg to 25 mg, 200 mg to 500 mg, or 100 mg to 200 mg. In some embodiments, the patient is approximately 10 × 10 9 It has a platelet count of 15 × 10¹⁶ or more. In some embodiments, the target is approximately 15 × 10¹⁶. 9 It has a platelet count of 1 / L or more. In some embodiments, the target is approximately 20 × 10 9 It has a platelet count of 1 / L or more. In some embodiments, the subject is approximately 25 × 10 9Having a platelet count of 1 / L or more. In some embodiments, the subject is approximately 200 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 150 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 100 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 50 × 10 9 Having a platelet count of less than / L. In some embodiments, the subject is 25 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 10 × 10 9 / L or more, approximately 200 x 10 9 Having a platelet count of less than / L.

[0129] In another embodiment, the technology provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient; compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alpha-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof.

[0130] In another embodiment, the Technology provides a kit comprising instructions for administering compound (1) or a pharmaceutically acceptable salt thereof; ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable salt thereof for the treatment of myeloproliferative neoplasms (e.g., MF).

[0131] In some embodiments, as a result of any of the methods disclosed herein, subjects may exhibit a reduction in myelofibrosis and / or a reduction in overall symptom score and / or cytokine regulation (e.g., reduction or normalization of cytokines), and / or normalization or increase in platelet count and / or normalization or increase in neutrophil count and / or normalization or increase in hemoglobin count and / or improved transfusion (including conversion to transfusion independence) and / or a reduction in spleen volume. In some embodiments, as a result of any of the methods disclosed herein, subjects may exhibit an increase in survival rate (more than one year) and / or a decrease in leukemia transformation rate and / or transplant eligibility.

[0132] In some embodiments, as a result of any of the methods disclosed herein, the subject exhibits (a) a reduction in platelet count of 1 grade or less compared to the baseline platelet grade, and (b) a reduction of 25 × 10 compared to the baseline platelet count. 9 A decrease in platelet count of less than / L and / or (c) a decrease in platelet count of 35% or less compared to the baseline platelet count may be observed. The decrease in platelet count is determined by the change between the baseline platelet count and the second platelet count. The baseline platelet count is the platelet count determined within one week prior to administration of compound (1) or a pharmaceutically acceptable salt thereof. The second platelet count is determined at least two weeks after administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, as a result of any of the methods disclosed herein, the subject may exhibit (a) a decrease in neutrophil count of less than one grade compared to the baseline neutrophil grade, (b) a decrease in neutrophil count of 500 / L or less compared to the baseline neutrophil count, and / or (c) a decrease in neutrophil count of 35% or less compared to the baseline neutrophil count. The decrease in neutrophil count is determined by the change between the baseline neutrophil count and the second neutrophil count. The baseline neutrophil count is the neutrophil count determined within one week prior to administration of compound (1) or a pharmaceutically acceptable salt thereof. The second neutrophil count is determined at least two weeks after administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, as a result of any of the methods disclosed herein, the subject may exhibit (a) a decrease in hemoglobin number of less than one grade compared to the baseline hemoglobin grade, (b) a decrease in hemoglobin number of 5.0 g / dL or less compared to the baseline hemoglobin number, and / or (c) a decrease in hemoglobin number of 35% or less compared to the baseline hemoglobin number. The decrease in hemoglobin number is determined by the change between the baseline hemoglobin number and the second hemoglobin number. The baseline hemoglobin number is the hemoglobin number determined within one week prior to administration of compound (1) or a pharmaceutically acceptable salt thereof. The second hemoglobin number is determined at least two weeks after administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0135] Accordingly, one embodiment provides a method for treating myeloproliferative neoplasms in a human subject requiring treatment, the method comprising administering an effective amount of a PIM kinase inhibitor to the subject. Another embodiment provides a method for reducing the proliferation of hematopoietic cells in a subject, the method comprising contacting cells with a PIM kinase inhibitor (e.g., an effective amount of a PIM kinase inhibitor).

[0136] Another embodiment provides a method for treating subjects having or at risk of developing MPN, such as MF, the method comprising administering to the subject a composition comprising a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the methods described herein involve identifying subjects at risk of developing MPN, such as MF. In some embodiments, the methods described herein further include administering compound 1 or a pharmaceutically acceptable salt thereof (e.g., an effective amount of compound 1 or a pharmaceutically acceptable salt thereof) to subjects identified as at risk of developing MPN, such as MF. In some embodiments, the methods further include administering compound 1 or a pharmaceutically acceptable salt thereof (e.g., an effective amount of compound 1 or a pharmaceutically acceptable salt thereof) to subjects suspected of having MPN, such as MF.

[0138] In some embodiments, a method is provided for the prophylactic treatment of MPNs such as MF, which comprises administering compound 1 or a pharmaceutically acceptable salt thereof (e.g., an effective amount of compound 1 or a pharmaceutically acceptable salt thereof) to a human subject in need of treatment.

[0139] In some embodiments, a method is provided for preventing MPN such as MF, which comprises administering compound 1 or a pharmaceutically acceptable salt thereof (e.g., an effective amount of compound 1 or a pharmaceutically acceptable salt thereof) to a human subject in need of treatment.

[0140] In some embodiments, a method is provided for inhibiting the formation or deposition of MF tissue, which comprises contacting MF tissue with a sufficient amount of compound 1 or a pharmaceutically acceptable salt thereof to inhibit the formation or deposition of MF tissue.

[0141] In some embodiments, this specification provides a method for treating subjects having or at risk of developing MPN, such as MF, the method comprising administering a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0142] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering an effective dose of a PIM kinase inhibitor. In some embodiments, the PIM kinase inhibitor is a PIM1 kinase inhibitor.

[0143] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to a subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, the subject being 200 × 10 9 The baseline platelet count is less than / L.

[0144] In some embodiments, the baseline platelet count is approximately 150 × 10⁶ 9 It is less than or equal to / L. In some embodiments, the baseline platelet count is approximately 100 × 10⁶ 9 In some embodiments, the baseline platelet count is approximately 50 × 10⁶ / L or less. 9 In some embodiments, the baseline platelet count is approximately 25 × 10⁶. 9 The value is less than or equal to / L. In some embodiments, the baseline platelet count is approximately 5, 10, 15, 20, 25, or 35 × 10 9 It is / L or higher.

[0145] In some embodiments, the target is approximately 10 × 10 9 It has a platelet count of 15 × 10¹⁶ or more. In some embodiments, the target is approximately 15 × 10¹⁶. 9 It has a platelet count of 1 / L or more. In some embodiments, the target is approximately 20 × 10 9 It has a platelet count of 1 / L or more. In some embodiments, the subject is approximately 25 × 10 9Having a platelet count of 1 / L or more. In some embodiments, the subject is approximately 200 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 150 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 100 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 50 × 10 9 Having a platelet count of less than / L. In some embodiments, the subject is 25 × 10 9 The platelet count is less than / L. In some embodiments, the subject is approximately 10 × 10 9 / L or more, approximately 200 x 10 9 Having a platelet count of less than / L.

[0146] In some embodiments, the method comprises administering to a subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the subject is (a) less than grade 1, or (b) 25 × 10 9 (c) having a platelet count reduction of ≤ / L and / or ≤35%, the platelet count reduction being determined by the change in baseline platelet count determined within one week prior to administration of compound (1) or a pharmaceutically acceptable salt thereof, and the second platelet count determined at least two weeks after administration. In some embodiments, subjects have a platelet count reduction of (a) less than grade 1. In some embodiments, subjects have a platelet count reduction of (b) 25 × 10 9 The subject has a platelet count reduction of less than / L. In some embodiments, the subject has a platelet count reduction of 35% or less (c).

[0147] In some embodiments, the method involves continuously administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof to a subject, wherein the subject has a neutropenia of (a) less than 1 grade compared to baseline neutrophil count, (b) less than 500 / L compared to baseline neutrophil count, and / or (c) less than 35% compared to baseline neutrophil count, the neutropenia being determined by the change in baseline neutrophil count determined within one week prior to administration of compound (1) or a pharmaceutically acceptable salt thereof, and a change in a second neutrophil count determined at least two weeks after administration. In some embodiments, the subject has a neutropenia of (a) less than 1 grade. In some embodiments, the subject has a neutropenia of (b) less than 500 / L. In some embodiments, the subject has a neutropenia of (c) less than 35%.

[0148] In some embodiments, the method involves continuously administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof to a subject, wherein the subject has a hemoglobin reduction of (a) less than 1 grade compared to the baseline hemoglobin grade, (b) 5.0 g / dL or less compared to the baseline hemoglobin number, and / or (c) 35% or less compared to the baseline hemoglobin number, the hemoglobin reduction being determined by the baseline hemoglobin number determined within one week prior to administration of compound (1) or a pharmaceutically acceptable salt thereof, and the change in a second hemoglobin number determined at least two weeks after administration. In some embodiments, the subject has (a) a hemoglobin reduction of less than 1 grade. In some embodiments, the subject has (b) a hemoglobin reduction of 5.0 g / dL or less. In some embodiments, the subject has (c) a hemoglobin reduction of 35% or less.

[0149] In some embodiments, the results of this method include a reduction in myelofibrosis, a reduction in all symptoms, cytokine regulation, or a combination of two or more of these.

[0150] In some embodiments, the results of this method include normalization or increase in platelet count, normalization or increase in neutrophil count, normalization or increase in hemoglobin count, improved transfusion performance (including conversion to transfusion independence), or a combination of two or more of these.

[0151] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to a subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the subject has received one or more prior treatments consisting of compound (1) or a pharmaceutically acceptable salt thereof, and (a) is less than grade 1, and (b) is 25 × 10 9less than or equal to / L, and / or (c) a platelet count decrease of 35% or less, where the platelet count decrease is determined by the change in the baseline platelet count determined within one week before administration of compound (1) or its pharmaceutically acceptable salt, and a second platelet count determined at least two weeks after administration, and as a result of the method, the subject exhibits a decrease in myelofibrosis, a decrease in all symptoms, cytokine modulation, or a combination of two or more thereof. In some embodiments, as a result of the method, the subject exhibits a decrease in myelofibrosis. In some embodiments, as a result of the method, the subject exhibits a decrease in all symptoms. In some embodiments, as a result of the method, the subject exhibits cytokine modulation. In some embodiments, as a result of the method, the subject exhibits a decrease in myelofibrosis, a decrease in all symptoms, and cytokine modulation.

[0152] In some embodiments, the subject has not been treated with a JAK inhibitor for at least two weeks prior to administration of compound (1) or its pharmaceutically acceptable salt.

[0153] In some embodiments, the decrease in all symptoms is a symptom selected from the group consisting of fever, night sweats, early satiety, weight loss, fatigue, weakness, shortness of breath, splenomegaly or hepatomegaly, left upper quadrant pain, bone or joint pain, easy bruising, easy bleeding, and combinations of two or more thereof.

[0154] In some embodiments, the decrease in all symptoms refers to minimizing, reducing, or alleviating fever, night sweats, early satiety, weight loss, fatigue, weakness, shortness of breath, splenomegaly or hepatomegaly, left upper quadrant pain, bone or joint pain, easy bruising, easy bleeding, or combinations of two or more thereof.

[0155] In some embodiments, as a result of the method, the subject exhibits a decrease in spleen volume.

[0156] In some embodiments, the method results in a decrease in myelofibrosis.

[0157] In some embodiments, the method results in an improvement in overall survival.

[0158] In some embodiments, the results of this method include normalization or increase in platelet count, normalization or increase in neutrophil count, normalization or increase in hemoglobin count, improvement in blood transfusion (including conversion to transfusion independence), or a combination of two or more of these.

[0159] In some embodiments, the methods of this disclosure result in a sustained response based on one or more efficacy measures described herein. A sustained response may be defined based on the satisfaction of a measure of efficacy at various time points, including 12 weeks, 24 weeks, 48 ​​weeks, 72 weeks, or 96 weeks.

[0160] In some embodiments, when compound (1) is co-administered with ruxolitinib or momerotinib, the therapeutically effective dose of the drug does not induce any overlapping hematological toxicities. That is, compound (1) does not exacerbate anemia, thrombocytopenia, or transfusion dependence induced by ruxolitinib or momerotinib.

[0161] Other embodiments are based on the probability of achieving a specific therapeutic endpoint. Thus, in one embodiment, the method induces a probability of SVR35 of 15% or more or 20% or more in subjects, where the subjects have previously been treated with a JAK inhibitor for myeloproliferative neoplasm and, as appropriate, have relapsed disease or are refractory to JAK inhibitors. In another embodiment, the method induces a probability of TSS50 of 30%, 35%, 40%, 45%, or 50% or more in subjects, where the subjects have previously been treated with a JAK inhibitor for myeloproliferative neoplasm and, as appropriate, have relapsed disease or are refractory to JAK inhibitors.

[0162] In some embodiments, the subjects had an inadequate response to JAK inhibitor therapy.

[0163] In some embodiments, the subjects are either intolerant to JAK inhibitor therapy, resistant to JAK inhibitor therapy, or unsuitable for JAK inhibitor therapy.

[0164] In some embodiments, the subjects experience a relapse from previous JAK inhibitor therapy.

[0165] In some embodiments, the subject has experienced a relapse from a previous bone marrow transplant.

[0166] In some embodiments, the method further comprises administering to a subject an effective amount of a JAK inhibitor and / or an ACVR inhibitor or a pharmaceutically acceptable salt thereof (i.e., the PIM kinase inhibitor is administered concurrently or sequentially with the JAK inhibitor and / or ACVR inhibitor or a pharmaceutically acceptable salt thereof). In some embodiments, the JAK inhibitor is a JAK2 inhibitor. In some embodiments, the JAK inhibitor is a JAK1 inhibitor.

[0167] In some specific embodiments, the myeloproliferative neoplasm is polycythemia vera. In some other specific embodiments, the myeloproliferative neoplasm is essential thrombocythemia. In yet another embodiment, the myeloproliferative neoplasm is MF. The structures of PIM kinase inhibitors, JAK inhibitors, and / or ACVR inhibitors are not particularly limited, as long as the inhibitors have satisfactory activity against the desired targets (i.e., PIM and JAK, respectively). Exemplary PIM kinase inhibitors included within the scope of embodiments of this disclosure are PCT applications published WO2016 / 161248; WO2015 / 019320; WO2014 / 033530; WO2014 / 033631; WO2014 / 0200216; WO2013 / 175388; WO2013 / 013188; WO2013 / 02 0371; WO2012 / 154274; WO2012 / 129338; WO2012 / 080990; WO2012 / 120415; WO2012 / 004 No. 217; WO2011 / 057784; WO2011 / 079274; WO2010 / 0148351; WO2010 / 135581; WO2010 / 0261 No. 21; WO2010 / 026122; WO2010 / 026124; WO2010 / 022076; WO2010 / 0000978; WO2010 / 0220 No. 81; WO2009 / 064486; WO2009 / 109576; WO2008 / 082839; WO2008 / 106692; WO2008 / 058126 General and specific compounds disclosed in U.S. Patent Nos. WO2007 / 041712, U.S. Patent No. 7,750,007, 8,168,794, and U.S. Patent Publication Nos. 2015 / 0057265, 2014 / 0200227, 2014 / 0329807, and 2008 / 0261988 are examples, the full disclosures of which are incorporated herein by reference. In some embodiments, the PIM kinase inhibitor is PIM447 or INCB053914. Other PIM kinase inhibitors are known in the art, and such inhibitors are also included in certain embodiments of this disclosure.

[0168] The structures of JAK inhibitors and / or ACVR inhibitors for use in the methods of the present invention are also not particularly limited, as long as they have sufficient activity against JAK when used in combination with a PIM inhibitor. In some embodiments, the JAK inhibitor has sufficient activity against JAK2 when used in combination with a PIM inhibitor. In some embodiments, the JAK inhibitor has sufficient activity against JAK1 when used in combination with a PIM inhibitor. All exemplary JAK inhibitors are included within the scope of the specific embodiments of this disclosure and are referred to in PCT publications WO2015 / 157257; WO2014 / 151871; WO2014 / 026595; WO2014 / 025128; WO2014 / 025486; WO2014 / 130411; and WO2014 / 130411. O2014 / 124230; WO2011 / 101161; WO2011 / 076519; WO2010 / 071885; WO2010 / 017122; WO2009 / 080638; WO2009 / 143389; WO2009 / 158571; WO2009 / 0179 No. 54; WO2009 / 085913; WO2009 / 155565; WO2008 / 106635; WO2008 / 128072; WO2008 / 092199; WO2005 / 026026130; WO2004 / 046118; WO2004 / 074244; W This is described in U.S. Patent Application Publications O2001 / 060816; 97 / 019065, and U.S. Patent Application Publications 2015 / 0306112; 2013 / 0018034; 2012 / 0053208; 2008 / 0260754; and 2008 / 0214558, the full disclosures thereof being incorporated herein by reference.

[0169] Additional therapeutic agents may be used in combination with a PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof) for the treatment of myeloproliferative neoplasms according to embodiments of the present disclosure. The combination of additional therapeutic agents may be administered simultaneously with (e.g., in the same formulation or different formulations) or sequentially with the PIM kinase inhibitor. For example, the PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof) may be administered before the JAK inhibitor or before the ACVR inhibitor. Alternatively, the PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof) may be administered after the JAK inhibitor or after the ACVR inhibitor. In some of these embodiments, the JAK or ACVR inhibitor may be administered in combination with the PIM kinase inhibitor and additional therapeutic agents, as appropriate. That is, in some embodiments, the method includes administering the PIM kinase inhibitor and additional therapeutic agents.

[0170] In some embodiments, additional therapeutic agents include hydroxyurea, interferon alpha, cladribine, thalidomide (including its derivatives, e.g., pomalidomide, lenoridamide), corticosteroids (e.g., prednisone), everolimus, androgens (e.g., testosterone), and combinations thereof. In some embodiments, additional therapeutic agents may be used for supportive therapy, such as corticosteroids, nonsteroidal anti-inflammatory drugs, and / or analgesics, to control symptoms.

[0171] In addition, the methods described herein can be performed in combination with other medical procedures. Therefore, in some embodiments, the method further includes performing blood transfusions, radiotherapy, splenectomy, or stem cell transplantation. In some specific embodiments, the method further includes administering an angiotensin mimetic (e.g., TXA127).

[0172] Various different myeloproliferative neoplasms (MPNs) can be treated by the methods disclosed herein. In some embodiments, MPN is polycythemia vera. In some embodiments, MPN is essential thrombocythemia. In other embodiments, MPN is MF.

[0173] Some embodiments provide a method for reducing the proliferation of hematopoietic cells in a subject, the method comprising contacting cells with a PIM kinase inhibitor. In some more specific embodiments, the method further comprises administering an effective amount of an ACVR inhibitor to the subject. In some more specific embodiments, the method further comprises administering an effective amount of an ACVR1 inhibitor to the subject. In some more specific embodiments, the method further comprises administering an effective amount of a JAK inhibitor to the subject. In some embodiments, the JAK inhibitor is a JAK2, or JAK1, or JAK1 / 2 inhibitor.

[0174] In some embodiments, this disclosure relates to a method for restoring hematological balance. In some different embodiments, this disclosure relates to a method for reducing the proliferation of cells expressing JAK2 V617F in human cells, the method comprising contacting cells with a PIM kinase inhibitor and optionally a JAK inhibitor disclosed herein. In some different embodiments, the present invention relates to a method for reducing the proliferation of cells expressing MPL W515L in human cells, the method comprising contacting cells with a PIM kinase inhibitor and optionally a JAK inhibitor disclosed herein. In some different embodiments, this technology relates to a method for reducing the proliferation of cells expressing calreticulin (CALR) mutations in human cells, the method comprising contacting cells with a PIM kinase inhibitor and optionally a JAK inhibitor or ACVR disclosed herein. In some different embodiments, this disclosure relates to methods for reducing the proliferation or overproduction of erythrocytes, leukocytes, or platelets in human cells, the methods comprising contacting cells with a PIM kinase inhibitor and, optionally, a JAK inhibitor or ACVR disclosed herein. In some embodiments, the human cells are bone marrow cells.

[0175] In some specific embodiments, the myeloproliferative neoplasms treated according to the embodiments described herein include JAK2 mutations, thrombopoietin receptor (MPL) mutations, or calreticulin (CALR) mutations. In some embodiments, the MPN includes JAK2 mutations and MPL mutations. In some embodiments, the MPN includes JAK2 mutations and CALR mutations. In some embodiments, the MPN includes MPL and CALR mutations. In some embodiments, the MPN includes JAK2, MPL, and CALR mutations.

[0176] In some embodiments, the JAK2 mutation includes the JAK2 V617 mutation. JAK2 V617F refers to a mutant JAK2 having a V→F amino acid substitution at position 617 with respect to wild-type human JAK2 (UniProt.060674). In some embodiments, the MPL mutation includes the MPL W515L mutation. MPL W515L refers to a mutant thrombopoietin receptor (MPL) having a W→L substitution at position 515 with respect to wild-type human MPL (UniProt.P40238). In some embodiments, the CALR mutation includes an indel in CALR exon 9.

[0177] In some embodiments, provided herein is a method for treating a myeloproliferative neoplasm in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momelotinib, luspatercept, pegylated interferon alpha-2b, or nabumetadrine, or a pharmaceutically acceptable salt thereof; wherein the subject has a baseline platelet count of 200×10 9 / L or less. Ruxolitinib or a pharmaceutically acceptable salt thereof is generally administered at a dosage of about 5 mg to about 25 mg. Fedratinib or a pharmaceutically acceptable salt thereof is at a dosage of about 200 mg to about 500 mg; pacritinib or a pharmaceutically acceptable salt thereof is at a dosage of about 100 mg to about 200 mg; momelotinib or a pharmaceutically acceptable salt thereof is at a dosage of about 50 mg to about 200 mg; luspatercept is at a dosage of about 0.5 mg / kg to 1.75 mg / kg based on the subject's body weight, pegylated interferon alpha-2b or a pharmaceutically acceptable salt thereof is at a dosage of 50 - 500 μg, and nabumetadrine or a pharmaceutically acceptable salt thereof is at a dosage of 120 - 240 mg.

[0178] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alpha-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof; the subject is 25 × 10 9 Patients have a baseline platelet count of ≥ / L. Ruxolitinib or a pharmaceutically acceptable salt thereof is generally administered in doses of approximately 5 mg to approximately 25 mg. Fedratinib or a pharmaceutically acceptable salt thereof is administered in doses of approximately 200 mg to approximately 500 mg; pacritinib or a pharmaceutically acceptable salt thereof is administered in doses of approximately 100 mg to approximately 200 mg; momerotinib or a pharmaceutically acceptable salt thereof is administered in doses of approximately 50 mg to approximately 200 mg; ruspatercept is administered in doses of approximately 0.6 mg / kg or 1.75 mg / kg based on the patient's body weight; lopeg interferon alfa-2b or a pharmaceutically acceptable salt thereof is administered in doses of 50 to 500 μg; and nabutemadeline or a pharmaceutically acceptable salt thereof is administered in doses of 120 to 240 mg.

[0179] In some embodiments, the baseline platelet count in combination therapy is approximately 150 × 10⁶ 9 It is less than or equal to / L. In some embodiments, the baseline platelet count in combination therapy is approximately 100 × 10⁶ 9 In some embodiments, the baseline platelet count in combination therapy is approximately 75 × 10⁶ / L or less. 9 The baseline platelet count in combination therapy is less than or equal to / L. 9 The baseline platelet count in combination therapy is less than or equal to / L. 9 The baseline platelet count in combination therapy is ≥ / L. In some embodiments, the baseline platelet count in combination therapy is approximately 25 × 10⁶. 9 The value is ≥ / L. In some embodiments, the baseline platelet count in combination therapy is approximately 35 × 10⁶. 9 It is / L or higher.

[0180] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib or a pharmaceutically acceptable salt thereof. The subject is 200 × 10 9 Patients with a baseline platelet count of less than 1 / L; the appropriate dose of ruxolitinib or a pharmaceutically acceptable salt thereof is approximately 5 mg to 25 mg.

[0181] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and fedratinib or a pharmaceutically acceptable salt thereof. The subject is 200 × 10 9 The following baseline platelet counts and / or 25 × 10⁻⁶ 9 Patients with a baseline platelet count of ≥ / L; the dose of fedratinib or a pharmaceutically acceptable salt thereof is approximately 200 mg to approximately 500 mg.

[0182] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and pacritinib or a pharmaceutically acceptable salt thereof. The subject is 200 × 10 9 Baseline platelet count below / L and / or 25 × 10 9 Patients with a baseline platelet count of ≥ / L; the dosage of pacritinib or a pharmaceutically acceptable salt thereof is approximately 100 mg to 200 mg.

[0183] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and momerotinib or a pharmaceutically acceptable salt thereof. The subject is 200 × 10 9 Baseline platelet count below / L and / or 25 × 10 9 Patients with a baseline platelet count of ≥ / L; momerotinib or a pharmaceutically acceptable salt thereof is administered at a dose of approximately 50 mg to approximately 200 mg.

[0184] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and ruspatercept. The subject is 200 × 10 9 Baseline platelet count below / L and / or 25 × 10 9 Patients with a baseline platelet count of ≥ / L are given ruspatercept at a dose of approximately 0.5 mg / kg or 1.75 mg / kg based on the patient's body weight.

[0185] In some embodiments, the baseline platelet count is measured within one week prior to the initiation of administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments of the combination therapy, the subject has not received any JAK inhibitor therapy for at least two weeks prior to administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, the method comprising: administering to the subject a dose of approximately 5 mg to approximately 25 mg of ruxolitinib or a pharmaceutically acceptable salt thereof for a period of up to approximately 36 months; determining or having determined whether the subject has had an adverse event during the treatment period; reducing the dose by approximately 33% to approximately 80% or temporarily discontinuing the dose; and administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, adverse events in combination therapy with compound (1) or a pharmaceutically acceptable salt thereof and ruxolitinib include thrombocytopenia, anemia, bruising, dizziness, headache, diarrhea, or a combination of two or more of these.

[0189] In some embodiments, the Specified provides a method for treating myeloproliferative neoplasms in a human subject requiring treatment while the subject is receiving ruxolitinib therapy comprising about 5 mg to about 25 mg of ruxolitinib or a pharmaceutically acceptable salt thereof, the method comprising: administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; continuing to administer to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, during which the subject (a) does not receive therapy (e.g., JAK therapy such as ruxolitinib) or (b) receives a reduced amount of therapy (JAK therapy such as ruxolitinib).

[0190] In some embodiments, the reduced amount of therapy comprises less than about 80% of the therapy or a pharmaceutically acceptable salt thereof. In some embodiments, the reduced amount of therapy comprises less than about 75% of the therapy or a pharmaceutically acceptable salt thereof. In some embodiments, the reduced amount of therapy comprises less than about 50% of the therapy or a pharmaceutically acceptable salt thereof. In some embodiments, the reduced amount of therapy comprises less than about 25% of the therapy or a pharmaceutically acceptable salt thereof. In some embodiments, the reduced amount of therapy comprises less than about 20% of the therapy or a pharmaceutically acceptable salt thereof. In some embodiments, the reduced amount of therapy comprises about 10% to about 80% of the therapy or a pharmaceutically acceptable salt thereof. In some embodiments, the reduced amount of therapy comprises about 30% to about 70% of the therapy or a pharmaceutically acceptable salt thereof. In some embodiments, the reduced amount of therapy comprises about 40% to about 60% of the therapy or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, the method comprising: administering to a subject a dose of approximately 200 mg to approximately 500 mg of fedratinib or a pharmaceutically acceptable salt thereof for a period of up to approximately 36 months; determining or having determined whether the subject has had an adverse event during the treatment period; reducing the dose to approximately 33% to approximately 80% or temporarily discontinuing administration; and administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, adverse events in combination therapy with compound (1) or a pharmaceutically acceptable salt thereof and fedratinib include thrombocytopenia, anemia, diarrhea, nausea, vomiting, encephalopathy, or a combination of two or more of these.

[0193] In some embodiments, the reduced-dose fedratinib therapy comprises 50% or less of a fedratinib dose, or 75% or less of a pharmaceutically acceptable salt thereof.

[0194] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, the method comprising: administering to the subject a dose of pacritinib or a pharmaceutically acceptable salt thereof in a dose of about 100 mg to about 200 mg for a period of up to about 36 months; determining or having determined whether the subject has had an adverse event during the treatment period; reducing the dose to about 33% to about 80% or temporarily discontinuing administration; and administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, adverse events in combination therapy with compound (1) or a pharmaceutically acceptable salt thereof and pacritinib include thrombocytopenia, anemia, diarrhea, nausea, peripheral edema, or a combination of two or more of these.

[0196] In some embodiments, the reduced-dose pacritinib therapy comprises 50% or less of a pacritinib dose, or 75% or less of a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, the method comprising: administering to the subject about 50 mg to about 200 mg of momerotinib or a pharmaceutically acceptable salt thereof for a period of up to about 36 months; determining or having determined whether the subject has had an adverse event during the treatment period; reducing the dose to about 33% to about 80% or temporarily discontinuing administration; and administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, adverse events in combination therapy with compound (1) or a pharmaceutically acceptable salt thereof and momerotinib include thrombocytopenia, anemia, diarrhea, nausea, dizziness, or a combination of two or more of these.

[0199] In some embodiments, the Specified provides a method for treating myeloproliferative neoplasms in a human subject requiring treatment while the subject is receiving momerotinib therapy comprising about 50 mg to about 200 mg of momerotinib or a pharmaceutically acceptable salt thereof, the method comprising: administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and continuing to administer to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, during which the subject (a) does not receive momerotinib therapy, or (b) receives a reduced amount of momerotinib therapy.

[0200] In some embodiments, the subject receives a reduced dose of momerotinib therapy. In some embodiments, the reduced dose of momerotinib therapy comprises 50% or less or 75% or less of momerotinib or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, this specification provides a method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, the method comprising: administering ruspatercept to a subject at a dose of about 0.6 mg / kg or 1.75 mg / kg for a period of up to about 36 months; determining or having determined whether the subject has had an adverse event during the treatment period; reducing the dose to about 33% to about 80% or temporarily discontinuing administration; and administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, adverse events in combination therapy with compound (1) or a pharmaceutically acceptable salt thereof and ruspatercept include fatigue, headache, musculoskeletal pain, arthralgia, dizziness / vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, hypersensitivity, or a combination of two or more of these.

[0203] In some embodiments, the Specified provides a method for treating myeloproliferative neoplasms in a human subject requiring treatment while the subject is receiving ruspatercept therapy comprising about 0.5 mg / kg or 1.75 mg / kg of ruspatercept, the method comprising: administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; continuing to administer to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, during which the subject (a) does not receive ruspatercept therapy, or (b) receives a reduced amount of ruspatercept therapy.

[0204] In some embodiments, the reduced amount of ruspatercept therapy includes 50% or less of the amount of ruspatercept, or 75% or less.

[0205] In some embodiments, the combination of administrations minimizes, reduces, or mitigates adverse events in the subject.

[0206] In some embodiments, the combination administration reduces myelofibrosis in the subjects.

[0207] In some embodiments, the combination administration reduces the spleen capacity in the subject.

[0208] In some embodiments, the combined administration results in the subject exhibiting normalization or increase in platelet count, normalization or increase in neutrophil count, normalization or increase in hemoglobin count, improvement in transfusion (including conversion to transfusion independence), or a combination of two or more of these.

[0209] In some embodiments, the subjects show normalization or increase in platelet count as a result of the combined administration.

[0210] In some embodiments, the subjects show normalization or increase in neutrophil count as a result of the combination administration.

[0211] In some embodiments, the subjects show normalization or increase in hemoglobin levels as a result of the combined administration.

[0212] In some embodiments, as a result of the combined administration, subjects show transfusion improvement (including conversion to transfusion independence).

[0213] In some embodiments, the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 120 mg to about 1500 mg.

[0214] In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is about 240 mg to about 1440 mg per day. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is about 240 mg to about 1000 mg. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is about 240 mg to about 900 mg. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is about 240 mg to about 800 mg. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is about 240 mg to about 700 mg. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is about 240 mg to about 600 mg. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is about 240 mg to about 500 mg.

[0215] In some embodiments, the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 350 mg to about 1350 mg. In some embodiments, the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 400 mg to about 1150 mg. In some embodiments, the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 500 mg to about 1050 mg.

[0216] In some embodiments, the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 350 mg to about 1000 mg. In some embodiments, the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 450 mg to about 900 mg. In some embodiments, the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 450 mg to about 800 mg. In some embodiments, the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 450 mg to about 750 mg. In some embodiments, the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 470 mg to about 730 mg.

[0217] In some embodiments, the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 120 mg to about 580 mg, about 581 mg to about 1040 mg, or about 1041 mg to about 1500 mg.

[0218] In some embodiments, the administration of a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is at least once daily. In some embodiments, the administration of a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is at least twice daily. In some embodiments, the administration of a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is at least three times daily. In some embodiments, the administration of a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is at least four times daily.

[0219] In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof ranges from about 120 mg / day to about 3000 mg / day. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof ranges from about 350 mg / day to about 2100 mg / day. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof ranges from about 550 mg / day to about 2000 mg / day. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof ranges from about 700 mg / day to about 1950 mg / day.

[0220] In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is about 120 mg / day to about 800 mg / day. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is about 200 mg / day to about 750 mg / day. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is about 250 mg / day to about 650 mg / day.

[0221] In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is approximately 240 mg to approximately 1440 mg twice daily. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is approximately 360 mg to approximately 1440 mg twice daily. In some embodiments, a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof is approximately 1440 mg twice daily.

[0222] In some embodiments, the dose of ruxolitinib or a pharmaceutically acceptable salt thereof is about 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, or 25 mg. In some embodiments, the dose of ruxolitinib or a pharmaceutically acceptable salt thereof may be about 2.5 mg. In some embodiments, the dose of ruxolitinib or a pharmaceutically acceptable salt thereof may be about 5 mg. In some embodiments, the dose of ruxolitinib or a pharmaceutically acceptable salt thereof may be about 7.5 mg. In some embodiments, the dose of ruxolitinib or a pharmaceutically acceptable salt thereof may be about 10 mg. In some embodiments, the dose of ruxolitinib or a pharmaceutically acceptable salt thereof may be about 12.5 mg. In some embodiments, the dose of ruxolitinib or a pharmaceutically acceptable salt thereof may be about 15 mg. In some embodiments, the dose of ruxolitinib or a pharmaceutically acceptable salt thereof may be about 20 mg. In some embodiments, the dose of ruxolitinib or a pharmaceutically acceptable salt thereof may be about 25 mg.

[0223] In some embodiments, the dose of fedratinib or a pharmaceutically acceptable salt thereof may be about 100 mg. In some embodiments, the dose of fedratinib or a pharmaceutically acceptable salt thereof may be about 200 mg. In some embodiments, the dose of fedratinib or a pharmaceutically acceptable salt thereof may be about 400 mg. In some embodiments, the dose of fedratinib or a pharmaceutically acceptable salt thereof may be about 500 mg.

[0224] In some embodiments, the dose of pacritinib or a pharmaceutically acceptable salt thereof may be about 50 mg. In some embodiments, the dose of pacritinib or a pharmaceutically acceptable salt thereof may be about 100 mg. In some embodiments, the dose of pacritinib or a pharmaceutically acceptable salt thereof may be about 200 mg.

[0225] In some embodiments, the dose of momerotinib or a pharmaceutically acceptable salt thereof may be about 25 mg. In some embodiments, the dose of momerotinib or a pharmaceutically acceptable salt thereof may be about 50 mg. In some embodiments, the dose of momerotinib or a pharmaceutically acceptable salt thereof may be about 100 mg. In some embodiments, the dose of momerotinib or a pharmaceutically acceptable salt thereof may be about 200 mg.

[0226] In some embodiments, the dose of ruspatercept may be about 0.6 mg / kg based on the subject's body weight. In some embodiments, the dose of ruspatercept may be about 0.8 mg / kg based on the subject's body weight. In some embodiments, the dose of ruspatercept may be about 1.0 mg / kg based on the subject's body weight. In some embodiments, the dose of ruspatercept may be about 1.25 mg / kg based on the subject's body weight. In some embodiments, the dose of ruspatercept may be about 1.33 mg / kg based on the subject's body weight. In some embodiments, the dose of ruspatercept may be about 1.50 mg / kg based on the subject's body weight. In some embodiments, the dose of ruspatercept may be about 1.75 mg / kg based on the subject's body weight. In some embodiments, ruspatercept is administered by subcutaneous injection once every three weeks for at least 21 weeks.

[0227] In some embodiments, administration of ruxolitinib, fedratinib, pacritinib, or momerotinib, or a pharmaceutically acceptable salt thereof, is at least once per day. In some embodiments, administration of ruxolitinib, fedratinib, pacritinib, or momerotinib, or a pharmaceutically acceptable salt thereof, is at least twice per day.

[0228] In some embodiments, compound (1) or a pharmaceutically acceptable salt thereof is administered simultaneously with ruxolitinib, fedratinib, pacritinib, or momerotinib, or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof with ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alpha-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof, is sequential.

[0230] In some embodiments, the myeloproliferative neoplasm is a myeloproliferative neoplasm resistant to JAK inhibitors.

[0231] In some embodiments, the subjects had previously been treated with JAK inhibitors and showed an insufficient response.

[0232] In some embodiments, an inadequate response includes tolerance or intolerance to a JAK inhibitor, loss or absence of a significant splenic response or overall symptom response, and / or development of a clinically significant decrease in blood cell count, neutropenia, or thrombocytopenia.

[0233] In some embodiments, the subjects have not been previously treated with a JAK inhibitor.

[0234] In some embodiments, the technique further includes monitoring the total blood count of the subject and progressively adjusting the dosage of compound (1) or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, monitoring assesses the platelet count and, based on the baseline platelet count (i.e., the platelet count before the start of treatment), determines if the change in platelet count is (a) less than 1 grade, or (b) 25 × 10 9 If the dose decreases to less than / L and / or (c) decreases to less than 35%, this includes increasing the dose or frequency of administration (i.e., escalating).

[0236] In some embodiments, monitoring evaluates the platelet count, and if the change in platelet count is (a) an increase of 1 grade or more, (b) 25 × 10 9 If the dose decreases by more than / L and / or (c) 35% or more, this includes reducing the dose or decreasing the frequency of administration (i.e., tapering).

[0237] In some embodiments, the platelet count increased from grade 1 to grade 2, 3, or 4, or from grade 2 to grade 3 or 4, or from grade 3 to grade 4.

[0238] In some embodiments, monitoring includes evaluating the neutrophil count and reducing the dose or reducing the frequency of administration (i.e., tapering) if the change in the neutrophil count is (a) an increase of one grade or more, (b) a decrease of 500 / L or more, and / or (c) a decrease of 35% or more.

[0239] In some embodiments, the neutrophil count increased from grade 1 to grade 2, 3, or 4, or from grade 2 to grade 3 or 4, or from grade 3 to grade 4.

[0240] In some embodiments, monitoring includes evaluating the hemoglobin count and reducing the dose or reducing the frequency of administration (i.e., tapering) if the change in hemoglobin count is (a) an increase of one grade or more, (b) a decrease of 5.0 g / dL or more, and / or (c) a decrease of 35% or more.

[0241] In some embodiments, the hemoglobin count increased from grade 1 to grade 2 or 3, or from grade 2 to grade 3.

[0242] In some embodiments, monitoring is performed before, during, and / or after treatment.

[0243] In some embodiments, monitoring is performed once a week or once every 2 to 4 weeks. In some embodiments, monitoring is performed once a week. In some embodiments, monitoring is performed every two weeks. In some embodiments, monitoring is performed every three weeks. In some embodiments, monitoring is performed every four weeks.

[0244] In some embodiments, monitoring further includes continuing to adjust the dosage or frequency of administration in stages until a desired stable clinical state is achieved.

[0245] In some embodiments, the method further includes monitoring the total blood count in the subject and gradually adjusting the dosage of ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof.

[0246] In some embodiments, the method further includes monitoring the total blood count in the subject and gradually adjusting the dose of ruxolitinib or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the method further includes monitoring the total blood count in the subject and gradually adjusting the dose of fedratinib or a pharmaceutically acceptable salt thereof.

[0248] In some embodiments, the method further includes monitoring the total blood count in the subject and gradually adjusting the dosage of pacritinib or a pharmaceutically acceptable salt thereof.

[0249] In some embodiments, the method further includes monitoring the total blood count in the subject and gradually adjusting the dose of momerotinib or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the method further includes monitoring the total blood count in the subject and adjusting the dose of ruspatercept in stages.

[0251] In some embodiments, monitoring of this method includes evaluating the platelet count in the subject before, during, and / or after treatment.

[0252] In some embodiments, when administered in combination with compound (1), stepwise adjustment is used when the baseline platelet count reaches 200 × 10 9 If the baseline platelet count is greater than / L, administer ruxolitinib or a pharmaceutically acceptable salt thereof at 20 mg twice daily, until the baseline platelet count reaches 100 × 10⁶. 9 / L~200×10 9 For / L, 10 mg twice daily, with a baseline platelet count of 50 × 10 9 / L~100×10 9 If the dose is less than / L, the treatment should be initiated in the subject with a dose of 5 mg twice daily.

[0253] In some embodiments, the method includes increasing the dose of ruxolitinib if the subject's response is insufficient and the platelet and neutrophil counts are appropriate.

[0254] In some embodiments, when administered in combination with compound (1), the method includes increasing the dose of ruxolitinib or a pharmaceutically acceptable salt thereof by 5 mg twice daily, up to a maximum of 25 mg twice daily.

[0255] In some embodiments, the method includes increasing the dose of ruxolitinib or a pharmaceutically acceptable salt thereof in subjects who meet all of the following conditions: (a) no reduction from baseline from pretreatment is achieved in either a 50% reduction in palpable spleen length or a 35% reduction in spleen volume, as measured by computed tomography (CT) or magnetic resonance imaging (MRI); (b) platelet count at 4 weeks is 125 × 10⁶ 9 Platelet count exceeds / L, platelet count is 100 × 10 9 (c) The ANC level must not fall below / L; and (c) the ANC level must not fall below 0.75 × 10 9 It must be greater than / L.

[0256] In some embodiments, this method is performed when a) the platelet count is at least 40 × 10 9 a) The patient maintains a low / L level, b) the platelet count has not decreased by more than 20% in the past four weeks, and c) the ANC is 1 × 10⁻¹⁶. 9 The dosage of ruxolitinib or a pharmaceutically acceptable salt in the subject is increased by 5 mg twice daily up to a maximum of 10 mg, provided that the dosage is ≥ / L and d) the dosage has not been reduced or interrupted due to adverse events or hematological toxicity in the past four weeks.

[0257] In some embodiments, the dosage of ruxolitinib or a pharmaceutically acceptable salt thereof is graded to increase the platelet count to 100 × 10⁶ 9 For thrombocytopenia in patients who initiated treatment with a level of / L or higher, follow Table (a):

[0258] [Table 1]

[0259] In some embodiments, the stepwise adjustment of the dosage of ruxolitinib or a pharmaceutically acceptable salt thereof is used to increase the platelet count to 50 × 10 9 / L~100×10 9 For patients with thrombocytopenia who initiated treatment with a level below / L, follow Table (b):

[0260] [Table 2]

[0261] In some embodiments, this method is used when the baseline platelet count is 50 × 10 9 For patients with a blood alcohol content of 1 / L or higher, initiation may involve administering 200, 300, or 400 mg of fedratinib or a pharmaceutically acceptable salt thereof once daily.

[0262] In some embodiments, the method includes reducing the dose of fedratinib to 100 mg or less, or temporarily discontinuing the drug if side effects occur.

[0263] In some embodiments, side effects of fedratinib therapy include anemia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with active bleeding, grade 3 or higher nausea, vomiting, diarrhea, anemia, or elevated alanine transaminase (ALT), aspartate aminotransferase (AST), or bilirubin.

[0264] In some embodiments, this method is used when the baseline platelet count is 50 × 10 9 For patients with a dose of less than 1 / L, the treatment involves initiating treatment with 100 mg or 200 mg of pacritinib or a pharmaceutically acceptable salt thereof twice daily.

[0265] In some embodiments, this method includes reducing the dose of pacritinib to 100 mg or less if side effects occur.

[0266] In some embodiments, side effects of pacritinib therapy include diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema.

[0267] In some embodiments, the method further includes temporarily discontinuing the dose of pacritinib if there is a clinically significant worsening of thrombocytopenia lasting for more than 7 days until toxicity disappears, and then restarting pacritinib or a pharmaceutically acceptable salt thereof at 50% of the last administered dose.

[0268] In some embodiments, the method involves administering ruspatercept subcutaneously to the subject, starting at 0.5 mg / kg or 1 mg / kg, once every three weeks.

[0269] In some embodiments, if the subject's response is insufficient or adverse effects occur, the dosage of ruspatercept is adjusted in stages.

[0270] In some embodiments, the dosage of ruspatercept is further adjusted in stages based on the response according to Table (c):

[0271] [Table 3]

[0272] In some embodiments, the dosage of ruspatercept is adjusted in stages based on the response according to Table (d):

[0273] [Table 4]

[0274] In some embodiments, the method involves administering momerotinib or a pharmaceutically acceptable salt thereof to subjects suffering from moderate-risk or high-risk primary or secondary (post-PV or post-ET) myelofibrosis with hemoglobin levels less than 10, at doses of approximately 50 mg to approximately 200 mg.

[0275] In some embodiments, the subject exhibits overall symptom stability as a result of this method.

[0276] In some embodiments, the subject shows a reduction in all symptoms as a result of this method.

[0277] In some embodiments, the subject shows a partial reduction in symptoms as a result of this method.

[0278] In some embodiments, the subject shows a decrease in spleen volume as a result of this method.

[0279] In some embodiments, the results of this method include normalization or increase in platelet count, normalization or increase in neutrophil count, normalization or increase in hemoglobin count, improvement in blood transfusion (including conversion to transfusion independence), or a combination of two or more of these.

[0280] In some embodiments, the subject exhibits cytogenetic remission, molecular partial remission, or complete remission as a result of this method.

[0281] In some embodiments, this method improves clinically meaningful overall survival in the subjects.

[0282] In some embodiments, this method alleviates anemia in the subject.

[0283] In some embodiments, this method results in an increase in hemoglobin levels of 20 g / L or more, or a change from transfusion dependence to transfusion independence in the subjects.

[0284] In some embodiments, this method results in improvement (at least a 1-point increase) on the Patient Global Change Impression (PGIC) questionnaire at week 24.

[0285] In some embodiments, the myeloproliferative neoplasm is myelofibrosis.

[0286] In some embodiments, the myelofibrosis is a moderate-risk myelofibrosis.

[0287] In some embodiments, myelofibrosis is a high-risk myelofibrosis.

[0288] In some embodiments, the myelofibrosis is primary myelofibrosis.

[0289] In some embodiments, the myelofibrosis is secondary myelofibrosis (e.g., post-PV myelofibrosis and post-ET myelofibrosis).

[0290] In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt.

[0291] In some embodiments, the hydrochloride salt of compound (1) is in crystalline form.

[0292] In some embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof is for a period of about one week to about two years.

[0293] In some embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof is for a period of about 15 weeks to about 1 year.

[0294] In some embodiments, the administration of compound (1) or a pharmaceutically acceptable salt thereof is for approximately 24 weeks to approximately 1 year.

[0295] In some embodiments, subjects with MF are stratified into risk groups using the Dynamic International Prognostic Scoring System (DIPSS), the Mutation-enhanced International Prognostic Scoring System plus karyotype (MIPSS70+), or other systems. Risk factors using DIPSS include age, symptom burden (e.g., weight loss, fever, excessive sweating), white blood cell count, hemoglobin, and peripheral blast count. Patients with low-risk MF have a DIPSS score of 0. In some embodiments, MF is considered low-risk MF.

[0296] Patients with moderate-risk MF have a DIPSS score of 1–4. A DIPSS score of 1–2 is also called moderate-1 risk and is typically associated with a median survival time of approximately 14.2 years. A DIPSS score of 3 or 4 is also called moderate-2 risk and is typically associated with a median survival time of 4 years. In some embodiments, MF is moderate-risk MF (e.g., moderate-1 risk MF, moderate-2 risk MF).

[0297] High-risk MF patients have a DIPSS score of 5 or 6 and are associated with a median survival time of 1.5 years. In some embodiments, MF is high-risk MF.

[0298] In some embodiments, MPN is ruxolitinib-resistant MPN (e.g., ruxolitinib-resistant MF). In some embodiments, MPN (e.g., MF) has been previously treated with ruxolitinib in the absence of a PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof).

[0299] In some embodiments, treating MPN according to the methods described herein results in complete remission of the subject. When used to refer to human subjects with MPN, such as MF, “complete remission” means that the subject meets the following criteria for at least 12 weeks: the bone marrow is age-adjusted normal cellularity, blasts are less than 5%, MF is grade 1 or less according to the European classification, peripheral blood hemoglobin is ≥ 100 g / L and below the upper limit of normal (UNL), and the neutrophil count is 1 × 10⁶ 9 The platelet count is above / L, below the upper limit of normal (UNL), and 100 × 10⁶ 9 The myelocyte count is greater than / L, less than UNL, and less than 2% are immature myelocytes. However, in splenectomy patients, less than 5% are immature myelocytes, there is no disappearance of disease symptoms (e.g., all symptoms), no palpable spleen or liver, and no findings of extramedullary hematopoiesis (EMH).

[0300] In some embodiments, treating MPN according to the methods described herein results in partial remission in the subject. When used to refer to human subjects having MPN, such as MF, “partial remission” means that the subject meets the following criteria for at least 12 weeks: hemoglobin is ≥ 100 g / L, < UNL, and peripheral blood neutrophil count is 1 × 10⁶ 9 The platelet count is greater than or equal to / L, less than UNL, and 100 × 10⁶ 9 The myelocyte count is greater than or equal to 1 / L, less than 100 g / L, and less than 2% are immature myelocytes. However, in splenectomized patients, less than 5% are immature myelocytes, there is no resolution of disease symptoms (e.g., all symptoms), no palpable spleen or liver, and no findings of extramedullary hematopoiesis (EMH). Alternatively, "partial remission" is defined as bone marrow showing age-adjusted normal cells, less than 5% blasts, MF grade 1 or less according to the European classification, hemoglobin ≥ 85 but less than 100 g / L, and peripheral blood neutrophil count 1 × 10⁶ 9 The platelet count is greater than or equal to / L and less than UNL; and the platelet count is greater than or equal to 50, and 100 × 10 9A value of less than / L and less than 2% indicates immature myelocytes. However, in splenectomy patients, less than 5% of myelocytes are found, along with the absence of disease symptoms (e.g., all symptoms), palpable spleen and liver, and findings of extramedullary hematopoiesis (EMH).

[0301] In some embodiments, treating MPN according to the methods described herein results in complete cytogenetic remission, partial cytogenetic remission, complete molecular remission, or partial molecular remission in the subject. In some embodiments, treating MPN according to the methods described herein results in cytogenetic remission or molecular remission in the subject.

[0302] As used herein, “cytogenetic complete remission” or “molecular complete remission” refers to a subject in whom the pre-existing abnormality has disappeared for six months or longer.

[0303] As used herein, “cytogenetic partial remission” means a patient who has at least 10 abnormal metaphasias prior to treatment and whose abnormal metaphasias have decreased by 50% or more.

[0304] In some embodiments, subjects may have progenitor cells with acquired mutations in the JAK2, CALR, and MPL genes. For example, common mutations in JAK2 include the V617F mutation and mutations in exon 12 (e.g., substitutions, deletions, insertions, and duplications). Common mutations in CALR include mutations in exon 9. Common mutations in MPL include mutations in exon 10 (e.g., W515L and W515K). Cytogenetic and molecular testing is typically performed using allele-specific quantitative PCR (qPCR), digital PCR, or next-generation sequencing. The methods described above are outlined in Haslam, K. and Langabeer, SE, “Monitoring Residual Disease in the Myeloproliferative Neoplasms: Current Applications and Emerging Approaches,” Biomed. Res. Intl. 2016:7241591, and the relevant teachings therein are incorporated herein by reference in their entirety.

[0305] This method can be defined based on other baseline characteristics. Therefore, in some embodiments, subjects have moderate or severe splenomegaly at baseline. In some embodiments, subjects have imaging findings of, for example, 450, 600, 750, 1,000, 1,500, or 2,000 cm². 3 The subjects have the baseline spleen size described above. In some embodiments, the subjects have a total symptom score (TSS) greater than 15, 20, 25, 30, 35, 40, 45, or 50 at baseline. In some embodiments, the subjects require cytokine regulation. In other embodiments, the subjects have the JAK2V16F mutation. In some embodiments, the subjects have the CALR mutation. In some embodiments, the subjects have the MPLW515L mutation.

[0306] In some embodiments, subjects are characterized by poor bone marrow function at baseline. Therefore, in some embodiments, subjects are characterized by thrombocytopenia at baseline (e.g., platelet counts of 150, 100, 75, 50, or 25 × 10⁶). 9 Subjects are characterized by baseline anemia (e.g., Hgb levels ≤ 10, 9, or 8 g / dL). In some embodiments, subjects are characterized by baseline transfusion dependence. In some embodiments, subjects are characterized by baseline severe thrombocytopenia or anemia (i.e., platelet count ≤ 50 × 10⁶ g / dL). 9 Characterized by being below / L or having an Hgb level of 8 g / dL or less.

[0307] In some embodiments, subjects have fibrosis of grade 2 or higher at baseline. In some embodiments, subjects have 1 × 10 at baseline. 9 The subject has an absolute neutrophil count greater than / L. In some embodiments, the subject has fewer than 10% peripheral hemoblasts at baseline.

[0308] In some embodiments, myeloproliferative neoplasms are responsive to selective PIM1 inhibition. For example, myeloproliferative neoplasms respond to PIM1 / PIM2 IC2 values ​​less than 0.05, 0.045, 0.035, 0.03, or 0.025. 50 Responsive to selective PIM1 kinase inhibitors with a ratio, IC 50 This is determined to be described in Foulks, Neoplasia Vol. 16, No. 5, 2014.

[0309] Pharmaceutical composition Other embodiments relate to pharmaceutical compositions. PIM kinase inhibitors (i.e., compound (1) or a pharmaceutically acceptable salt thereof) and / or JAK inhibitors (e.g., ruxolitinib, fedratinib, pacritinib, momerotinib, or ruspatercept, or a pharmaceutically acceptable salt thereof) and / or ACVR inhibitors (e.g., momerotinib, pacritinib, ruspatercept, or a pharmaceutically acceptable salt thereof), lopeg interferon alpha-2b, nabutemadeline, or other therapeutic agents can be formulated together or separately according to methods known in the art. Certain embodiments include a pharmaceutically acceptable carrier or excipient, a PIM kinase inhibitor and / or a JAK inhibitor and / or an ACVR inhibitor. In some embodiments, the pharmaceutical composition includes a PIM kinase inhibitor and / or a JAK inhibitor and / or an ACVR inhibitor according to any of the embodiments described above.

[0310] In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection.

[0311] Appropriate routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, ophthalmic, nasal, and topical administration. Furthermore, as merely an example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal, intrathecal, intraventricular, intraperitoneal, lymphatic, and nasal administration routes.

[0312] In certain embodiments, the compounds described herein are administered topically rather than systemically, for example, by direct injection of the compound into an organ, often in the form of depot or sustained-release formulations. In specific embodiments, long-acting formulations are administered by transplantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered by a targeted drug delivery system, for example, liposomes coated with organ-specific antibodies. In such embodiments, the liposomes are targeted to an organ and selectively taken up by the organ. In yet another embodiment, the compounds described herein are provided in the form of a rapid-release formulation, a sustained-release formulation, or a moderate-release formulation. In yet another embodiment, the compounds described herein are administered topically.

[0313] In some embodiments, PIM kinase inhibitors and / or JAK kinase inhibitors and / or ACVR inhibitors are administered in a single dose. Typically, such administration is carried out by injection, e.g., intravenous injection, to rapidly deliver the drug. However, other routes may be used as appropriate. Thus, in some embodiments, PIM kinase inhibitors (i.e., compound (1) or a pharmaceutically acceptable salt thereof) and / or JAK kinase inhibitors (e.g., ruxolitinib, fedratinib, pacritinib, momerotinib, or a pharmaceutically acceptable salt thereof) and / or ACVR inhibitors (e.g., momerotinib, pacritinib, ruspatercept, or a pharmaceutically acceptable salt thereof) or lopeg interferon alpha-2b or nabutemadeline are administered orally.

[0314] In some embodiments, a PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof), a JAK kinase inhibitor, and / or ACVR are administered in multiple doses. In some embodiments, administration is approximately once, twice, three times, four times, five times, six times, or six or more times per day. In other embodiments, administration is approximately once a month, once every two weeks, once a week, or once every other day. In yet another embodiment, a PIM kinase inhibitor and another drug (e.g., a JAK2 inhibitor) are administered together approximately once to six times per day. In yet another embodiment, administration of a PIM kinase inhibitor and another drug (e.g., a JAK inhibitor) continues for less than seven days. In yet another embodiment, administration continues for approximately six, ten, fourteen, or twenty-eight days, two months, six months, or more than one year. In yet another embodiment, administration continues for approximately seven days to approximately five years (e.g., approximately seven days to approximately two years, or approximately seven days to approximately one year). In another embodiment, administration continues for 28 days. In yet another embodiment, administration continues for one year. In some cases, continuous administration is achieved and maintained for as long as necessary.

[0315] Administration of PIM kinase inhibitors and, optionally, JAK or ACVR inhibitors may be continued for as long as necessary. In some embodiments, PIM kinase inhibitors and, optionally, JAK or ACVR inhibitors are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, PIM kinase inhibitors and, optionally, JAK or ACVR inhibitors are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, PIM kinase inhibitors and, optionally, JAK or ACVR inhibitors are administered continuously and chronically, for example, to treat chronic effects.

[0316] In some embodiments, one or more cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 cycles, etc.) of a PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof) and / or a JAK kinase inhibitor (e.g., ruxolitinib or a pharmaceutically acceptable salt thereof) and / or an ACVR inhibitor are administered. In some embodiments, the PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof) and / or a JAK kinase inhibitor (e.g., ruxolitinib or a pharmaceutically acceptable salt thereof) and / or an ACVR inhibitor are administered in one cycle, for example, a 28-day cycle. Thus, in some embodiments, one or more cycles of the PIM kinase inhibitor and / or a JAK kinase inhibitor (e.g., the PIM kinase inhibitor) are each administered independently once or twice daily for 28 days in a 28-day cycle.

[0317] In some embodiments, PIM kinase inhibitors, and optionally JAK or ACVR inhibitors, are administered in doses. Due to within-subject variability in the pharmacokinetics of the compounds, individualization of the dosing regimen is provided in certain embodiments. The dosages of the compounds in embodiments of this disclosure may be found by routine experiments in light of this disclosure and / or derived by those skilled in the art.

[0318] In some embodiments, PIM kinase inhibitors and, optionally, JAK or ACVR inhibitors are formulated into pharmaceutical compositions. In specific embodiments, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable formulation. Appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients suitable for formulating the pharmaceutical compositions described herein may be used: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0319] As used herein, pharmaceutical compositions refer to (1) PIM kinase inhibitors, (2) combinations of PIM kinase inhibitors and JAK kinase inhibitors, (3) combinations of PIM kinase inhibitors and ACVR inhibitors, or (4) combinations of PIM kinase inhibitors and JAK kinase inhibitors with other chemical components. Other chemical components may include carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates the administration of the compound(s) to a living organism. In some embodiments, when performing the treatment or method of use provided herein, a therapeutically effective dose of a PIM kinase inhibitor, and optionally a JAK kinase inhibitor or ACVR inhibitor, is administered in the pharmaceutical composition to a human subject having the disease, disorder or condition to be treated provided herein. In certain embodiments, the therapeutically effective dose varies depending on the severity of the disease, the age and relative health status of the subject, the potency of the compound used, and other factors.

[0320] In one embodiment, the inhibitor(s) are formulated in an aqueous solution. In a specific embodiment, the aqueous solution is selected, simply as an example, from a physiologically suitable buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In another embodiment, the inhibitor, targeting at least two super-enhancer components, is formulated for transmucosal administration. In a particular embodiment, the transmucosal formulation includes a suitable permeation agent for the barrier to which the substance is to be permeated. In yet another embodiment in which the compounds described herein are formulated for other parenteral injections, the suitable formulation includes an aqueous or non-aqueous solution. In a specific embodiment, such a solution includes a physiologically suitable buffer and / or excipient.

[0321] In another embodiment, the compounds described herein are formulated for oral administration. The compounds described herein are formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient. In various embodiments, the compounds described herein are formulated in oral dosage forms, including, but not limited to, tablets, powders, pills, sugar-coated tablets, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0322] In certain embodiments, pharmaceutical formulations for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and, if desired, adding appropriate adjuvants, and then processing the granular mixture to obtain a core for a tablet or sugar-coated tablet. Suitable excipients include, in particular, fillers such as sugars, e.g., lactose, sucrose, mannitol, or sorbitol; cellulose preparations, e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others, e.g., polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In certain embodiments, disintegrants may be added as appropriate. Disintegrants include, just one example, crosslinked croscarmellose sodium, polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate.

[0323] In one embodiment, the dosage form, such as a sugar-coated tablet core and tablets, is provided with one or more suitable coatings. In a specific embodiment, a concentrated sugar solution is used for coating the dosage form. The sugar solution may optionally include additional components such as, for example, just one example, gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes and / or pigments may also be optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments may be optionally used to characterize different combinations of dosages of the active compound.

[0324] In certain embodiments, inhibitors targeting PIM kinase, JAK kinase, and / or ACVR may be formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, and soft-seal capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In specific embodiments, the push-fit capsule contains the active ingredient mixed with one or more fillers. The fillers include, as merely one example, binders such as lactose and starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In other embodiments, the soft capsule contains one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, as merely one example, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. Further stabilizers may be added.

[0325] The specific composition comprises a PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof) and a polyglycolated glyceride.

[0326] "Polyglycolized glycerides" refer to mixtures of glycerol monoesters, diesters, and triesters with polyethylene glycol monoesters and diesters having an average relative molecular weight of about 200 to 6000. Polyglycolized glycerides can be obtained by partially transesterifying triglycerides with polyethylene glycol, or by esterifying glycerol and polyethylene glycol with fatty acids. In some embodiments, the fatty acid component contains 8 to 22 carbon atoms, for example, 10 to 18 carbon atoms. Examples of natural vegetable oils from which polyglycolized glycerides can be derived include palm kernel oil and palm oil. Suitable polyol compounds generally have a molecular weight in the range of about 200 to about 6000 g / mol and preferably contain polyethylene glycol, but other polyols such as polyglycerin or sorbitol can be used. Polyglycolized glycerides are commercially available under the trade name Gelucire®. Examples of polyglycolized glycerides useful in various embodiments include WL 2514CS, LABRASOL, LABRAFIL, Gelucire 44 / 14 (lauroyl polyoxy-32 glyceride), Gelucire 33 / 01, Gelucire 35 / 10, Gelucire 37 / 02, Gelucire 50 / 13, Gelucire 44 / 11, and mixtures thereof.

[0327] "Gelucire® 44 / 14" or "Gelucire 44 / 14" is a lipid-based excipient manufactured by Gattefosse Corporation, Westwood, NJ, containing a mixture of pegylated fatty acid esters and glycerides. The number 44 indicates the melting point of the compound, and 14 indicates the hydrophilic / lipophilic balance (HLB) value. Other Gelucire excipients similarly indicate melting points and HLB values, such as Gelucire 33 / 01, Gelucire 35 / 10, Gelucire 37 / 02, Gelucire 50 / 13, and Gelucire 44 / 11.

[0328] In some embodiments, the PIM kinase inhibitor and polyglycolated glyceride composition is formulated for oral administration, for example, in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.

[0329] Compound (1) as used herein may be in the form of a free base or a pharmaceutically acceptable salt. In some embodiments, compound (1) exists as a free base. In some embodiments, compound (1) exists as a salt. In some embodiments, compound (1) exists as a hydrochloride salt.

[0330] Compositions comprising PIM kinase inhibitors and polyglycolated glycerides disclosed herein may optionally be used in place of the PIM kinase inhibitor in any of the methods disclosed herein.

[0331] In other embodiments, PIM kinase inhibitors and / or JAK kinase inhibitors and / or ACVR inhibitors are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, but are not limited to, tablets, lozenges, or gels. In yet other embodiments, the compounds described herein are formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, the injectable formulation is presented in unit dose form (e.g., in an ampoule) or in a multi-dose container. Preservatives may be added to the injectable formulation as appropriate. In yet other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in an oily or aqueous medium. The parenteral injectable formulation may optionally include compounding agents such as suspending agents, stabilizers, and / or dispersants. In specific embodiments, the parenteral pharmaceutical formulation includes an aqueous solution of the active compound in a water-soluble form. In further embodiments, a suspension of the active compound (e.g., a PIM kinase inhibitor and / or a JAK kinase inhibitor and / or an ACVR inhibitor) is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or media for use in the pharmaceutical compositions described herein include, but are not limited to, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, the aqueous injection suspension contains a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may contain a suitable stabilizer or agent that increases the solubility of the compound to enable the preparation of high-concentration solutions. Alternatively, in other embodiments, the active ingredient is in powder form to be prepared in a suitable medium, e.g., sterile pyrogen-free water, before use.

[0332] In further embodiments, PIM kinase inhibitors and / or JAK kinase inhibitors and / or ACVR inhibitors are administered topically. The compounds described herein are formulated into a variety of topically administered compositions, such as solutions, suspensions, lotions, gels, pastes, medicinal sticks, balms, creams, or ointments. Such pharmaceutical compositions may optionally contain solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0333] In further embodiments, PIM kinase inhibitors and / or JAK kinase inhibitors and / or ACVR inhibitors are formulated for transdermal administration. In specific embodiments, the transdermal formulation may be a lipophilic emulsion or buffered aqueous solution dissolved and / or dispersed in a polymer or adhesive, employing a transdermal delivery device and / or transdermal delivery patch. In various embodiments, such patches are constructed for continuous, pulsatile, or on-demand delivery of the pharmaceutical agent. In further embodiments, transdermal delivery of the inhibitor is achieved by iontophoresis patches, etc. In certain embodiments, the transdermal patch provides controlled delivery of the inhibitor. In certain embodiments, the absorption rate is slowed by using a rate-controlled membrane or by encapsulating the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. The absorption enhancer or carrier contains an absorbable, pharmaceutically acceptable solvent that aids skin passage. For example, in one embodiment, the transdermal device is in the form of a bandage comprising a backing member, a reservoir containing the compound optionally together with a carrier, an optional rate-controlled barrier for delivering the compound to the host skin at a controlled predetermined rate over a long period of time, and means for securing the device to the skin.

[0334] In other embodiments, PIM kinase inhibitors and / or JAK kinase inhibitors and / or ACVR inhibitors are formulated for inhalation administration. Various forms suitable for inhalation administration include, but are not limited to, aerosols, mists, or powders. The pharmaceutical composition of the inhibitor is conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer, using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In certain embodiments, the dosage unit of the pressurized aerosol is determined by providing a valve for delivering the measured amount. In certain embodiments, capsules and cartridges, such as gelatin, for use in inhalers or inflators, are formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch, as merely one example.

[0335] In yet another embodiment, PIM kinase inhibitors and / or JAK kinase inhibitors and / or ACVR inhibitors are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, comprising conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone and PEG. In the suppository form of the composition, a low-melting-point wax, such as a mixture of fatty acid glycerides, optionally combined with cocoa butter, is melted first.

[0336] In certain embodiments, the pharmaceutical composition is formulated by any conventional method using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally and suitably used. The pharmaceutical composition containing the inhibitor is manufactured by conventional methods, for example, by conventional mixing, dissolution, granulation, dragéing, powdering, emulsification, encapsulation, encapsulation, or compression processes, for example, as merely one example.

[0337] A pharmaceutical composition comprises at least one pharmaceutically acceptable carrier, diluent, or excipient, and an inhibitor described herein as an active ingredient. The active ingredient is in the form of a free acid or free base, or a pharmaceutically acceptable salt. Furthermore, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having similar activity. All tautomers of the compounds described herein fall within the range of compounds presented herein. Furthermore, the compounds described herein include non-solvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water and ethanol. The solvated forms of the inhibitors presented herein are also considered to be disclosed herein. Furthermore, the pharmaceutical composition may optionally include other pharmacokinetics or pharmaceuticals, adjuvants such as carriers, preservatives, stabilizers, wetting agents or emulsifiers, solution enhancers, salts for adjusting osmotic pressure, buffers, and / or other substances of therapeutic value.

[0338] Methods for preparing compositions comprising PIM kinase inhibitors and / or JAK kinase inhibitors and / or ACVR inhibitors as described herein include formulating the compound with one or more inert and pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing the compound disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. Forms of pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solutions or suspensions in liquid before use, or emulsions. These compositions may also optionally contain small amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers and pH buffers.

[0339] In some embodiments, pharmaceutical compositions comprising PIM kinase inhibitors and / or JAK kinase inhibitors and / or ACVR inhibitors take exemplary form as liquids in which the drug is present in a solution, a suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the drug is present in the solution, and a second portion of the drug is present as particulate matter in a suspension within a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0340] In certain embodiments, a useful aqueous suspension comprises one or more polymers as suspending agents. Useful polymers include cellulosic polymers, such as water-soluble polymers like hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Specific pharmaceutical compositions described herein include, for example, adhesive polymers selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0341] Useful pharmaceutical compositions may also include, as appropriate, solubilizers to aid in the solubility of the inhibitor. The term “solubilizer” generally includes agents that result in the formation of micelles or true solutions of the drug. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizers, as are ophthalmologically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

[0342] Furthermore, useful pharmaceutical compositions may optionally include one or more pH adjusters or buffers, one or more salts in amounts necessary to bring the osmotic pressure of the composition within an acceptable range, one or more preservatives for inhibiting microbial activity, one or more surfactants for enhancing physical stability or for other purposes, one or more antioxidants for enhancing chemical stability as needed, or a combination of two or more of these.

[0343] In certain embodiments, the aqueous suspension composition is packaged in a resealable container for single doses. Alternatively, a resealable container for multiple doses is used, in which case the composition typically contains a preservative.

[0344] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of useful delivery media or carriers as described herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In further embodiments, the compounds described herein are delivered using a sustained-release system.

[0345] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelating agents, thiol-containing compounds, and / or other common stabilizers.

[0346] PIM kinase inhibitors and any JAK inhibitors and / or ACVR inhibitors may be administered simultaneously or separately. When multiple therapeutic agents that are not presented in the same dosing form are administered, the administration of various therapeutic agents (e.g., PIM kinase inhibitors and / or JAK inhibitors and / or ACVR inhibitors) may be carried out simultaneously in separate dosing forms, concurrently in separate dosing forms, sequentially in separate dosing forms, or according to a protocol schedule. For example, one inhibitor may be administered as a bolus, followed by a second inhibitor in a separate bolus after an appropriate period. Slower administration, such as longer infusions, may be used for one or both inhibitors. An experienced clinician may determine the appropriate method and order of administration, but these are all within the scope of this disclosure.

[0347] Accordingly, some embodiments provide a different dosage form comprising a PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof) and an additional therapeutic agent (e.g., an additional therapeutic agent as described herein), wherein the PIM kinase inhibitor and the additional therapeutic agent are related to each other. The term “related to each other” as used herein means that the different dosage forms are packaged together or otherwise attached to each other so that it is readily apparent that they are intended to be sold and / or administered together, for example, in accordance with the methods described herein. In some embodiments, the dosage form comprises a PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof) and a JAK kinase inhibitor (e.g., ruxolitinib or a pharmaceutically acceptable salt thereof) and / or an ACVR inhibitor. In some embodiments, the PIM kinase inhibitor is as described herein. In some embodiments, the JAK inhibitor is as described herein. In some embodiments, the ACVR inhibitor is as described herein.

[0348] In some relevant embodiments, a kit is provided comprising a PIM kinase inhibitor (i.e., compound (1) or a pharmaceutically acceptable salt thereof) and instructions for administering the PIM kinase inhibitor for the treatment of myeloproliferative neoplasms. In more specific embodiments, the kit further comprises a JAK inhibitor and instructions for administering the JAK inhibitor in combination with the PIM kinase inhibitor. In more specific embodiments, the kit further comprises an ACVR inhibitor and instructions for administering the JAK inhibitor in combination with the PIM kinase inhibitor. In some embodiments, the PIM kinase inhibitor is as described herein. In some embodiments, the JAK inhibitor is as described herein. In some embodiments, the ACVR inhibitor is as described herein. In some embodiments, the myeloproliferative neoplasm is as described herein.

[0349] PIM kinase inhibitors, such as compound (1) or a pharmaceutically acceptable salt thereof, as well as any JAK inhibitor and / or any ACVR, can be prepared according to methods known in the art.Exemplary preparation methods are described in PCT publications WO2016 / 161248; WO2014 / 052365; WO2015 / 048689; WO2015 / 002894; WO2014 / 168975; WO2014 / 159745; WO2014 / 130693; WO2014 / 078578; WO2014 / 018567; WO2013 / 184572; WO2013 / 173518; WO2013 / 116382; WO2013 / 102059; and WO2013 / 059738; same WO2013 / 010136; same WO2013 / 013188; same WO2011 / 153514; same WO2011 / 046964; same WO2010 / 009342; same WO2008 / 121742; same WO2008 / 054827; same WO2008 / 039218; same WO2008 / 058126; same WO2007 / 087068, and US Patent Application Publication No. 2015 / 0018336; same 2014 / 0336206; same 2014 / 0329807; same 2014 / 0 No. 243355; No. 2014 / 0212485; No. 2014 / 0194446 / 2014 / 0187564; No. 2014 / 0 No. 135347; No. 2014 / 0128414; No. 2014 / 0187565; No. 2014 / 0171453; No. 201 4 / 0163027; 2014 / 01663046; 2014 / 0142126; 2014 / 0142123; No. 2014 / 0128413; No. 2014 / 0079690; No. 2014 / 0080844; No. 2014 / 0057907 ; as provided in US Patent Nos. 2014 / 0039168; 2013 / 0338172; 2013 / 0310402; 2013 / 0273030; 2013 / 0197014; 2013 / 0035334; 2013 / 0012525; 2012 / 0283277; 2012 / 0283276; 2012 / 0277254; 2012 / 0252821; 2010 / 0331350, and US Patent No. 7,750,007, the full content of which is incorporated herein by reference.

[0350] This technical embodiment Embodiment 1. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the subject (a) has thrombocytopenia (e.g., platelet count of 150, 100, 75, 50, or 25 × 10⁻¹⁰ 9 (b) having poor bone marrow function characterized by having an Hgb level of 10, 9, or 8 g / dL or less; (c) being transfusion-dependent; or (d) having a combination thereof, and the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.

[0351] Embodiment 2. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor, wherein the subject (a) has thrombocytopenia (e.g., platelet count of 150, 100, 75, 50, or 25 × 10⁶). 9 (b) having poor bone marrow function characterized by having an Hgb level of 10, 9, or 8 g / dL or less; (c) being transfusion-dependent; or (d) having a combination thereof, and the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.

[0352] Embodiment 3. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, wherein the subject has been previously treated for the myeloproliferative neoplasm with a JAK inhibitor and may, as appropriate, have a relapsed disease or be refractory to the JAK inhibitor, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.

[0353] Embodiment 4. A method for treating a myeloproliferative neoplasm in a human subject in need of treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the myeloproliferative neoplasm is treated by inducing TSS50 in the subject, and optionally treated at a time between those times, including 24 weeks and 48 weeks.

[0354] Embodiment 5. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject compound (1) or a pharmaceutically acceptable salt thereof, and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof, in amounts that do not induce overlapping hematological toxicity (e.g., anemia and / or thrombocytopenia and / or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.

[0355] Embodiment 6. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a selective PIM1 inhibitor and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof in a dose that does not induce overlapping hematological toxicities (e.g., anemia and / or thrombocytopenia and / or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.

[0356] Embodiment 7. A method for inducing an SVR35 probability of 15% or more or 20% or more in a human subject with myeloproliferative neoplasm, wherein the subject has been previously treated with a JAK inhibitor for myeloproliferative neoplasm and may, as appropriate, have a relapsed disease or be refractory to the JAK inhibitor, the method comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, the treatment inducing an SVR35 probability of 15% or more or 20% or more in the human subject.

[0357] Embodiment 8. A method for inducing a TSS50 probability in human subjects with myeloproliferative neoplasms of 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more, wherein the subjects have previously received treatment with a JAK inhibitor for myeloproliferative neoplasms and may, as appropriate, have relapsed disease or be refractory to JAK inhibitors, the method comprising administering to the subjects a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, the treatment inducing a TSS50 probability in human subjects of 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more.

[0358] Embodiment 9. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering a therapeutically effective dose of a selective PIM1 inhibitor to the subject, wherein the subject is 200 × 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 A method having a baseline platelet count of less than or equal to / L.

[0359] Embodiment 10. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the subject is 200 × 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 A method having a baseline platelet count of less than or equal to / L.

[0360] Embodiment 11. A method for treating myeloproliferative neoplasms in human subjects requiring treatment, The subjects will be administered a therapeutically effective dose of a selective PIM1 inhibitor, and The patient will be continuously administered a therapeutically effective dose of a selective PIM1 inhibitor. This includes, and the target is (a) below Grade 1, or (b) 25 × 10 9 Having a platelet count of less than / L and / or (c) 35% or less, A decrease in platelet count is determined by the change in baseline platelet count determined within one week prior to administration of a selective PIM1 inhibitor, and by a second platelet count determined at least two weeks after administration.

[0361] Embodiment 12. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and The subject is to continue administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof to the subject. This includes, and the target is (a) below Grade 1, or (b) 25 × 10 9 Having a platelet count of less than / L and / or (c) 35% or less, A method in which a decrease in platelet count is determined by the change in baseline platelet count determined within one week prior to administration of compound (1) or a pharmaceutically acceptable salt thereof, and by a second platelet count determined at least two weeks after administration.

[0362] Embodiment 13. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering a selective PIM1 inhibitor to the subject, The subjects were those who had received one or more prior treatments including a selective PIM1 inhibitor and who (a) had a grade of 1 or lower, or (b) had 25 × 10 9 Having a platelet count of less than / L and / or (c) 35% or less, A decrease in platelet count is determined by the change in baseline platelet count determined within one week prior to administration of a selective PIM1 inhibitor, and by the second platelet count determined at least two weeks after administration. The method results in subjects exhibiting a reduction in myelofibrosis, a reduction in overall symptoms, cytokine regulation, or a combination of two or more of these.

[0363] Embodiment 14. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, The subjects had received one or more prior treatments containing compound (1) or a pharmaceutically acceptable salt thereof, and (a) had a grade of 1 or lower, and (b) 25 × 10 9 Having a platelet count of less than / L and / or (c) 35% or less, A decrease in platelet count is determined by the change in baseline platelet count determined within one week prior to administration of compound (1) or a pharmaceutically acceptable salt thereof, and by the second platelet count determined at least two weeks after administration. The method results in subjects exhibiting a reduction in myelofibrosis, a reduction in overall symptoms, cytokine regulation, or a combination of two or more of these.

[0364] Embodiment 15. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor and ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, nabutemadeline, or pharmaceutically acceptable salts thereof, or a combination of two or more thereof. The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; Ruxolitinib or its pharmaceutically acceptable salts are administered in doses of approximately 5 mg to approximately 25 mg; The dosage of fedratinib or its pharmaceutically acceptable salts is approximately 200 mg to approximately 500 mg; Pacritinib or its pharmaceutically acceptable salts are administered in doses of approximately 100 mg to 200 mg; Momerotinib or its pharmaceutically acceptable salts are administered in doses of approximately 50 mg to approximately 200 mg; Ruspatercept is administered at a dose of approximately 0.5 mg / kg to 1.75 mg / kg based on the patient's body weight; Lopeg interferon alpha-2b or its pharmaceutically acceptable salts are administered in doses of 50-500 μg; Nabutemadeline or a pharmaceutically acceptable salt thereof is administered in doses of 120-240 mg, according to the method.

[0365] Embodiment 16. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alpha-2b, nabutemadeline, or a pharmaceutically acceptable salt thereof, or a combination of two or more thereof. The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; Ruxolitinib or its pharmaceutically acceptable salts are administered in doses of approximately 5 mg to approximately 25 mg; The dosage of fedratinib or its pharmaceutically acceptable salts is approximately 200 mg to approximately 500 mg; Pacritinib or its pharmaceutically acceptable salts are administered in doses of approximately 100 mg to 200 mg; Momerotinib or its pharmaceutically acceptable salts are administered in doses of approximately 50 mg to approximately 200 mg; Ruspatercept is administered at a dose of approximately 0.5 mg / kg to 1.75 mg / kg based on the patient's body weight; Lopeg interferon alpha-2b or its pharmaceutically acceptable salts are administered in doses of 50-500 μg; Nabutemadeline or a pharmaceutically acceptable salt thereof is administered in doses of 120-240 mg, according to the method.

[0366] Embodiment 17. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9A method having a baseline platelet count of less than or equal to / L.

[0367] Embodiment 18. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor and ruxolitinib or a pharmaceutically acceptable salt thereof. The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; Ruxolitinib or its pharmaceutically acceptable salts are administered in doses of approximately 5 mg to approximately 25 mg.

[0368] Embodiment 19. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib or a pharmaceutically acceptable salt thereof, The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; Ruxolitinib or its pharmaceutically acceptable salts are administered in doses of approximately 5 mg to approximately 25 mg.

[0369] Embodiment 20. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor and fedratinib or a pharmaceutically acceptable salt thereof, The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; The dosage of fedratinib or a pharmaceutically acceptable salt thereof is approximately 200 mg to approximately 500 mg.

[0370] Embodiment 21. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and fedratinib or a pharmaceutically acceptable salt thereof. The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; The dosage of fedratinib or a pharmaceutically acceptable salt thereof is approximately 200 mg to approximately 500 mg.

[0371] Embodiment 22. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor and pacritinib or a pharmaceutically acceptable salt thereof, The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; Pacritinib or a pharmaceutically acceptable salt thereof is administered in doses of approximately 100 mg to approximately 200 mg.

[0372] Embodiment 23. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and pacritinib or a pharmaceutically acceptable salt thereof, The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; Pacritinib or a pharmaceutically acceptable salt thereof is administered in doses of approximately 100 mg to approximately 200 mg.

[0373] Embodiment 24. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor and momerotinib or a pharmaceutically acceptable salt thereof, The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; Momerotinib or its pharmaceutically acceptable salts are administered in doses of approximately 50 mg to approximately 200 mg.

[0374] Embodiment 25. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and momerotinib or a pharmaceutically acceptable salt thereof. The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; Momerotinib or its pharmaceutically acceptable salts are administered in doses of approximately 50 mg to approximately 200 mg.

[0375] Embodiment 26. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor and ruspatercept, The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L Ruspatercept is administered in doses of approximately 0.5 mg / kg or 1.75 mg / kg based on the subject's body weight.

[0376] Embodiment 27. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and ruspatercept, The target is 200 x 10 9 / L or less (for example, 150, 100, 75, 50, or 25 x 10) 9 Having a baseline platelet count of less than / L; Ruspatercept is administered in doses of approximately 0.5 mg / kg or 1.75 mg / kg based on the subject's body weight.

[0377] Embodiment 28. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor and ruxolitinib or a pharmaceutically acceptable salt thereof, The target area is 10x10 9 / L or more (for example, 15, 20, 50, 75, or 100 x 10) 9 Having a baseline platelet count of ≥ / L; Ruxolitinib or its pharmaceutically acceptable salts are administered in doses of approximately 5 mg to approximately 25 mg.

[0378] Embodiment 29. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and ruxolitinib or a pharmaceutically acceptable salt thereof. The target area is 10x10 9 / L or more (for example, 15, 20, 50, 75, or 100 x 10) 9 Having a baseline platelet count of ≥ / L; Ruxolitinib or its pharmaceutically acceptable salts are administered in doses of approximately 5 mg to approximately 25 mg.

[0379] Embodiment 30. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor and fedratinib or a pharmaceutically acceptable salt thereof, The target area is 10x10 9 / L or more (for example, 15, 20, 50, 75, or 100 x 10) 9Having a baseline platelet count of ≥ / L; The dosage of fedratinib or a pharmaceutically acceptable salt thereof is approximately 200 mg to approximately 500 mg.

[0380] Embodiment 31. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and fedratinib or a pharmaceutically acceptable salt thereof. The target area is 10x10 9 / L or more (for example, 15, 20, 50, 75, or 100 x 10) 9 Having a baseline platelet count of ≥ / L; The dosage of fedratinib or a pharmaceutically acceptable salt thereof is approximately 200 mg to approximately 500 mg.

[0381] Embodiment 32. A method for treating myeloproliferative neoplasms in human subjects requiring treatment, comprising administering a therapeutically effective dose of a selective PIM1 inhibitor and pacritinib or a pharmaceutically acceptable salt thereof to the subject. The target area is 10x10 9 / L or more (for example, 15, 20, 50, 75, or 100 x 10) 9 Having a baseline platelet count of ≥ / L; Pacritinib or a pharmaceutically acceptable salt thereof is administered in doses of approximately 100 mg to approximately 200 mg.

[0382] Embodiment 33. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and pacritinib or a pharmaceutically acceptable salt thereof, The target area is 10x10 9 / L or more (for example, 15, 20, 50, 75, or 100 x 10) 9 Having a baseline platelet count of ≥ / L; Pacritinib or a pharmaceutically acceptable salt thereof is administered in doses of approximately 100 mg to approximately 200 mg.

[0383] Embodiment 34. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor and momerotinib or a pharmaceutically acceptable salt thereof. The target area is 10x10 9 / L or more (for example, 15, 20, 50, 75, or 100 x 10) 9 Having a baseline platelet count of ≥ / L; Momerotinib or its pharmaceutically acceptable salts are administered in doses of approximately 50 mg to approximately 200 mg.

[0384] Embodiment 35. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and momerotinib or a pharmaceutically acceptable salt thereof, The target area is 10x10 9 / L or more (for example, 15, 20, 50, 75, or 100 x 10) 9 Having a baseline platelet count of ≥ / L; Momerotinib or its pharmaceutically acceptable salts are administered in doses of approximately 50 mg to approximately 200 mg.

[0385] Embodiment 36. A method for treating myeloproliferative neoplasms in a human subject requiring treatment, comprising administering to the subject a therapeutically effective dose of a selective PIM1 inhibitor and ruspatercept, The target area is 10x10 9 / L or more (for example, 15, 20, 50, 75, or 100 x 10) 9 Having a baseline platelet count of ≥ / L; Ruspatercept is administered in doses of approximately 0.5 mg / kg or 1.75 mg / kg based on the subject's body weight.

[0386] Embodiment 37. A method for treating myeloproliferative neoplasms in human subjects requiring treatment, comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof to the subject; and ruspatercept. The target area is 10x10 9 / L or more (for example, 15, 20, 50, 75, or 100 x 10) 9 Having a baseline platelet count of ≥ / L; Ruspatercept is administered in doses of approximately 0.5 mg / kg or 1.75 mg / kg based on the subject's body weight.

[0387] Embodiment 38. A method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, The subjects will be administered ruxolitinib or a pharmaceutically acceptable salt in doses of approximately 5 mg to 25 mg for a period of up to approximately 36 months. To determine or to have determined whether the subject experienced adverse events during the treatment period; Reduce the dosage by approximately 33% to approximately 80%, or temporarily discontinue administration; and The patient will be administered a therapeutically effective dose of a selective PIM1 inhibitor. A method that includes this.

[0388] Embodiment 39. A method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, The subjects will be administered ruxolitinib or a pharmaceutically acceptable salt in doses of approximately 5 mg to 25 mg for a period of up to approximately 36 months. To determine or to have determined whether the subject experienced adverse events during the treatment period; Reduce the dosage by approximately 33% to approximately 80%, or temporarily discontinue administration; and The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof. A method that includes this.

[0389] Embodiment 40. The method according to Embodiment 38 or 39, wherein the adverse event is thrombocytopenia, anemia, bruising, dizziness, headache, diarrhea, or a combination of two or more of these.

[0390] Embodiment 41. A method for treating myeloproliferative neoplasms in human subjects requiring treatment while the subject is receiving ruxolitinib therapy containing approximately 5 mg to approximately 25 mg of ruxolitinib or a pharmaceutically acceptable salt thereof, The target group will be administered a therapeutically effective dose of a selective PIM1 inhibitor; and The subject will continue to receive a therapeutically effective dose of a selective PIM1 inhibitor, during which time the subject will either (a) not receive ruxolitinib therapy, or (b) receive ruxolitinib therapy at a reduced dose. A method that includes this.

[0391] Embodiment 42. A method for treating myeloproliferative neoplasms in human subjects requiring treatment while the subjects are receiving ruxolitinib therapy containing approximately 5 mg to approximately 25 mg of ruxolitinib or a pharmaceutically acceptable salt thereof, The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and The subject is to be continuously administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, during which time the subject either (a) does not receive ruxolitinib therapy or (b) receives ruxolitinib therapy at a reduced dose. A method that includes this.

[0392] Embodiment 43. The method according to Embodiment 41 or 42, wherein the reduced amount of ruxolitinib therapy is 50% or less or 75% or less of ruxolitinib therapy.

[0393] Embodiment 44. A method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, The subjects will be administered approximately 200 mg to 500 mg of fedratinib or a pharmaceutically acceptable salt thereof for a period of up to approximately 36 months. To determine or to have determined whether the subject experienced adverse events during the treatment period; Reduce the dosage by approximately 33% to approximately 80%, or temporarily discontinue administration; and The patient will be administered a therapeutically effective dose of a selective PIM1 inhibitor. A method that includes this.

[0394] Embodiment 45. A method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, The subjects will be administered approximately 200 mg to 500 mg of fedratinib or a pharmaceutically acceptable salt thereof for a period of up to approximately 36 months. To determine or to have determined whether the subject experienced adverse events during the treatment period; Reduce the dosage by approximately 33% to approximately 80%, or temporarily discontinue administration; and The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof. A method that includes this.

[0395] Embodiment 46. The method according to Embodiment 44 or 45, wherein the adverse event is thrombocytopenia, anemia, diarrhea, nausea, vomiting, encephalopathy, or a combination of two or more thereof.

[0396] Embodiment 47. A method for treating myeloproliferative neoplasms in human subjects requiring treatment while the subject is receiving fedratinib therapy comprising approximately 200 mg to approximately 500 mg of fedratinib or a pharmaceutically acceptable salt thereof, The target group will be administered a therapeutically effective dose of a selective PIM1 inhibitor; and The subject will continue to receive a therapeutically effective dose of a selective PIM1 inhibitor, during which time the subject will either (a) not receive fedratinib therapy or (b) receive a reduced dose of fedratinib therapy. A method that includes this.

[0397] Embodiment 48. A method for treating myeloproliferative neoplasms in human subjects requiring treatment while the subjects are receiving fedratinib therapy containing approximately 200 mg to approximately 500 mg of fedratinib or a pharmaceutically acceptable salt thereof, The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and The subject is to be continuously administered a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof, during which time the subject either (a) does not receive fedratinib therapy or (b) receives fedratinib therapy at a reduced dose. A method that includes this.

[0398] Embodiment 49. The method according to Embodiment 47 or 48, wherein the reduced amount of fedratinib therapy is 50% or less or 75% or less of the fedratinib therapy.

[0399] Embodiment 50. A method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, The subjects will be administered approximately 100 mg to 200 mg of pacritinib or a pharmaceutically acceptable salt thereof for a period of up to approximately 36 months. To determine or to have determined whether the subject experienced adverse events during the treatment period; Reduce the dosage by approximately 33% to approximately 80%, or temporarily discontinue administration; and The patient will be administered a therapeutically effective dose of a selective PIM1 inhibitor. A method that includes this.

[0400] Embodiment 51. A method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, The subjects will be administered approximately 100 mg to 200 mg of pacritinib or a pharmaceutically acceptable salt thereof for a period of up to approximately 36 months. To determine or to have determined whether the subject experienced adverse events during the treatment period; Reduce the dosage by approximately 33% to approximately 80%, or temporarily discontinue administration; and The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof. A method that includes this.

[0401] Embodiment 52. The method according to Embodiment 50 or 51, wherein the adverse event is thrombocytopenia, anemia, diarrhea, nausea, peripheral edema, or a combination of two or more of these.

[0402] Embodiment 53. A method for treating myeloproliferative neoplasms in human subjects requiring treatment while the subject is receiving pacritinib therapy containing approximately 100 mg to approximately 200 mg of pacritinib or a pharmaceutically acceptable salt thereof, The target group will be administered a therapeutically effective dose of a selective PIM1 inhibitor; and The subject will continue to receive a therapeutically effective dose of a selective PIM1 inhibitor, during which time the subject will either (a) not receive pacritinib therapy or (b) receive a reduced dose of pacritinib therapy. A method that includes this.

[0403] Embodiment 54. A method for treating myeloproliferative neoplasms in human subjects requiring treatment while the subject is receiving pacritinib therapy containing approximately 100 mg to approximately 200 mg of pacritinib or a pharmaceutically acceptable salt thereof, The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and The subject is to be continuously administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, during which time the subject either (a) does not receive pacritinib therapy or (b) receives pacritinib therapy at a reduced dose. A method that includes this.

[0404] Embodiment 55. The method according to Embodiment 53 or 54, wherein the reduced amount of pacritinib therapy is 50% or less or 75% or less of the amount of pacritinib therapy.

[0405] Embodiment 56. A method for treating myeloproliferative neoplasms in human subjects in need without causing a risk of clinically significant adverse events, The subjects will be administered momerotinib or a pharmaceutically acceptable salt in doses of approximately 50 mg to 200 mg for a period of up to approximately 36 months. To determine or to have determined whether the subject experienced adverse events during the treatment period; Reduce the dosage by approximately 33% to approximately 80%, or temporarily discontinue administration; and The patient will be administered a therapeutically effective dose of a selective PIM1 inhibitor. A method that includes this.

[0406] Embodiment 57. A method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, The subjects will be administered momerotinib or a pharmaceutically acceptable salt in doses of approximately 50 mg to 200 mg for a period of up to approximately 36 months. To determine or to have determined whether the subject experienced adverse events during the treatment period; Reduce the dosage by approximately 33% to approximately 80%, or temporarily discontinue administration; and The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof. A method that includes this.

[0407] Embodiment 58. The method according to Embodiment 56 or 57, wherein the adverse event is thrombocytopenia, anemia, diarrhea, nausea, dizziness, or a combination of two or more thereof.

[0408] Embodiment 59. A method for treating myeloproliferative neoplasms in human subjects requiring treatment while the subjects are receiving momerotinib therapy containing approximately 50 mg to approximately 200 mg of momerotinib or a pharmaceutically acceptable salt thereof, The target group will be administered a therapeutically effective dose of a selective PIM1 inhibitor; and The subject will continue to receive a therapeutically effective dose of a selective PIM1 inhibitor, during which time the subject will either (a) not receive momerotinib therapy, or (b) receive momerotinib therapy at a reduced dose. A method that includes this.

[0409] Embodiment 60. A method for treating myeloproliferative neoplasms in human subjects requiring treatment while the subjects are receiving momerotinib therapy comprising approximately 50 mg to approximately 200 mg of momerotinib or a pharmaceutically acceptable salt thereof, The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and The subject is to be continuously administered a therapeutically effective dose of compound (1) or a pharmaceutically acceptable salt thereof, during which time the subject either (a) does not receive momerotinib therapy or (b) receives momerotinib therapy at a reduced dose. A method that includes this.

[0410] Embodiment 61. The method according to Embodiment 59 or 60, wherein the reduced dose of momerotinib therapy comprises 50% or less or 75% or less of momerotinib therapy.

[0411] Embodiment 62. A method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, The target group will be administered ruspatercept at a dose of approximately 0.6 mg / kg or 1.75 mg / kg for a maximum period of approximately 36 months. To determine or to have determined whether the subject experienced adverse events during the treatment period; Reduce the dosage by approximately 33% to approximately 80%, or temporarily discontinue administration; and The patient will be administered a therapeutically effective dose of a selective PIM1 inhibitor. A method that includes this.

[0412] Embodiment 63. A method for treating myeloproliferative neoplasms in human subjects requiring treatment without causing a risk of clinically significant adverse events, The target group will be administered ruspatercept at a dose of approximately 0.6 mg / kg or 1.75 mg / kg for a maximum period of approximately 36 months. To determine or to have determined whether the subject experienced adverse events during the treatment period; Reduce the dosage by approximately 33% to approximately 80%, or temporarily discontinue administration; and The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof. A method that includes this.

[0413] Embodiment 64. The method according to Embodiment 62 or 63, wherein the adverse event is fatigue, headache, musculoskeletal pain, arthralgia, dizziness / vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, hypersensitivity, or a combination of two or more of these.

[0414] Embodiment 65. A method for treating myeloproliferative neoplasms in a human subject requiring treatment while the subject is receiving ruspatercept therapy containing approximately 0.5 mg / kg or 1.75 mg / kg of ruspatercept, The target group will be administered a therapeutically effective dose of a selective PIM1 inhibitor; and The subject will continue to receive a therapeutically effective dose of a selective PIM1 inhibitor, during which time the subject will either (a) not receive ruspatercept therapy, or (b) receive a reduced dose of ruspatercept therapy. A method that includes this.

[0415] Embodiment 66. A method for treating myeloproliferative neoplasms in a human subject requiring treatment while the subject is receiving ruspatercept therapy containing approximately 0.5 mg / kg or 1.75 mg / kg of ruspatercept, The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and The subject is administered a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, during which time the subject either (a) does not receive ruspatercept therapy or (b) receives ruspatercept therapy at a reduced dose. A method that includes this.

[0416] Embodiment 67. The method according to Embodiment 65 or 66, wherein the reduced amount of ruspatercept therapy is 50% or less or 75% or less of ruspatercept therapy.

[0417] Embodiment 67a. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment without causing a risk of clinically significant adverse events, comprising administering to the subject a therapeutically effective dose of lopeg interferon alpha-2b and compound (1) or a pharmaceutically acceptable salt thereof.

[0418] Embodiment 67b. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment without causing a risk of clinically significant adverse events, comprising administering to the subject a therapeutically effective dose of nabutemadeline and compound (1) or a pharmaceutically acceptable salt thereof.

[0419] Embodiment 68. The subject is thrombocytopenia (for example, platelet counts of 150, 100, 75, 50, or 25 × 10 9 The method according to any of the prior embodiments, having poor bone marrow function characterized by being less than or equal to / L.

[0420] Embodiment 69. The method according to any of the preceding embodiments, wherein the subject has poor bone marrow function characterized by anemia (e.g., Hgb level is 10, 9, or 8 g / dL or less).

[0421] Embodiment 70. The method according to any of the preceding embodiments, wherein the subject has poor bone marrow function characterized by transfusion dependence.

[0422] Embodiment 71. The object is 100 × 10 9 The method according to any of the prior embodiments, having poor bone marrow function characterized by a platelet count of less than / L.

[0423] Embodiment 72. The subject is 50 × 109 The method according to any of the prior embodiments, having poor bone marrow function characterized by a platelet count of less than / L.

[0424] Embodiment 73. The method according to any of the preceding embodiments, wherein the subject has poor bone marrow function characterized by an Hgb level of 10 g / dL or less.

[0425] Embodiment 74. The method according to any of the preceding embodiments, wherein the subject has poor bone marrow function characterized by an Hgb level of 8 g / dL or less.

[0426] Embodiment 75. The method according to any of the preceding embodiments, wherein the subject has poor bone marrow function characterized by transfusion dependence.

[0427] Embodiment 76. The subject is (a) with a platelet count of 50 × 10 9 The method according to any of the preceding embodiments, wherein (b) the Hgb level is less than or equal to 8 g / dL; (c) the Hgb level is transfusion-dependent; or (d) the Hgb function is poorly characterized by a combination thereof.

[0428] Embodiment 77. The method according to the preceding embodiment, wherein the subject has previously been treated with a JAK inhibitor for myeloproliferative neoplasm and has a relapsed disease or is refractory to JAK inhibitors.

[0429] Embodiment 78. A method according to any of the preceding embodiments for treating a myeloproliferative neoplasm by inducing TSS50 in a human subject in need of treatment, wherein the myeloproliferative neoplasm is treated by inducing TSS50 in the subject at a time between thereafter, including 24 weeks and 48 weeks.

[0430] Embodiment 79. The method according to any of the preceding embodiments, comprising administering to a subject compound (1) or a pharmaceutically acceptable salt thereof, and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof, in an amount that does not induce overlapping hematological toxicity selected from anemia, thrombocytopenia, and transfusion dependence.

[0431] Embodiment 80. The method according to any of the preceding embodiments, comprising administering to a subject compound (1) or a pharmaceutically acceptable salt thereof, and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof, in an amount that does not induce hematological toxicity that overlaps in terms of anemia, thrombocytopenia, and transfusion dependence.

[0432] Embodiment 81. The method according to any of the preceding embodiments for treating a myeloproliferative neoplasm, wherein the subject has been previously treated with a JAK inhibitor for a myeloproliferative neoplasm, has relapsed disease or is refractory to JAK inhibitors, and the treatment induces a probability of SVR35 of 15% or more or 20% in the subject, which would induce a probability of SVR35 of 20% or more or 25% in the human subject.

[0433] Embodiment 81a. The method according to any of the preceding embodiments for treating a myeloproliferative neoplasm, where the subject has been previously treated with a JAK inhibitor for a myeloproliferative neoplasm, has relapsed disease, or is refractory to a JAK inhibitor, and the treatment induces a probability of SVR35 of 20% or more or 25% in the subject, which is the probability of SVR35 in the human subject.

[0434] Embodiment 81b. The method according to any of the prior embodiments, for treating a myeloproliferative neoplasm by inducing a probability of SVR35 of 20% or more or 30% or more in a subject, where the subject has been previously treated with a JAK inhibitor for a myeloproliferative neoplasm, has relapsed disease or is refractory to a JAK inhibitor, and the treatment induces a probability of SVR35 of 20% or more or 30% in a human subject.

[0435] Embodiment 81c. The method according to any of the prior embodiments for treating a myeloproliferative neoplasm by inducing a probability of SVR35 in a subject to 40% or more or 50% or more, when administered in combination with ruxolitinib, the treatment induces a probability of SVR35 in a human subject to more than 40% or more or more or more than 50%.

[0436] Embodiment 82. The method according to any of the preceding embodiments for treating a myeloproliferative neoplasm, wherein the subject has previously received treatment with a JAK inhibitor for a myeloproliferative neoplasm, has relapsed disease or is refractory to JAK inhibitors, and the treatment induces a probability of 30%, 35%, 40%, 45%, or 50% or higher of TSS50 in the subject, or a probability of 30%, 35%, 40%, 45%, or 50% or higher of TSS50 in the subject.

[0437] Embodiment 82a. The method according to any of the preceding embodiments for treating myeloproliferative neoplasms, where the subject has been previously treated with a JAK inhibitor for myeloproliferative neoplasms, has relapsed disease, or is refractory to JAK inhibitors, and the treatment induces a TSS50 probability of 30% or 40% or more in human subjects.

[0438] Embodiment 82b. The method according to any of the prior embodiments for treating myeloproliferative neoplasms, in combination with momelotinib, wherein the subject has been previously treated with a JAK inhibitor for myeloproliferative neoplasms, has relapsed disease, or is refractory to JAK inhibitors, and the treatment induces a TSS50 probability of 40% or 45% or more in human subjects, or a TSS50 probability of 40% or 50% or more in subjects.

[0439] Embodiment 82c. The method according to any of the prior embodiments, for treating myeloproliferative neoplasms by inducing a TSS50 probability of 50% or 60% or more in subjects, when used in combination with ruxolitinib, wherein the subjects have been previously treated with a JAK inhibitor for myeloproliferative neoplasms, have relapsed disease or are refractory to JAK inhibitors, and the treatment induces a TSS50 probability of 50% or 60% or more in human subjects.

[0440] Embodiment 83. The method according to any of the preceding embodiments, wherein the subject has been previously treated with a JAK inhibitor for myeloproliferative neoplasm and has relapsed disease or is refractory to JAK inhibitors.

[0441] Embodiment 84. The method according to any of the preceding embodiments, wherein the subject has been treated with a JAK inhibitor for myeloproliferative neoplasm for 3, 6, 9, or 12 months or more prior to the present invention and has a relapsed disease or is refractory to JAK inhibitors.

[0442] Embodiment 85. The method according to any of the preceding embodiments, wherein the method involves inducing SVR35 and TSS50 in a subject, and the myeloproliferative neoplasm is treated by inducing SVR35 and TSS50 in the subject, and optionally, the treatment is performed at a time between those weeks, including 24 weeks and 48 weeks.

[0443] Embodiment 86. The method is (a) for example, by imaging diagnosis, 450 cm3 More than 600cm 3 More than 750cm 3 Over 1,000cm 3 Over 1,500cm 3 Above, or 2,000 cm 3 (b) A clinically meaningful reduction in splenomegaly from baseline spleen size; (c) A clinically meaningful reduction in elevated TSS from baseline TSS, for example, ≥15, ≥20, ≥25, ≥30, ≥35, ≥40, ≥45, or ≥50, based on the Myelofibrosis Symptom Assessment Scale (MFSAF) version 4.0; (d) Thrombocytopenia (e.g., platelet count of 150, 100, 75, 50, or 25 × 10¹⁰ 9 (d) a clinically meaningful improvement in poor bone marrow function selected from (i.e., Hgb levels ≤ 10, 9, or 8 g / dL), transfusion-dependent, or a combination thereof; (d) a clinically meaningful reduction in fibrosis from baseline, e.g., grade 2 or higher; (e) a clinically meaningful increase in overall survival, e.g., at 1, 2, or 3 years; and (f) the method of any of the preceding embodiments by inducing a clinically meaningful response in a subject selected from a combination thereof, wherein the clinically meaningful response is induced in response to administration.

[0444] Embodiment 87. The method is, for example, 450 cm by image diagnosis. 3 More than 600cm 3 More than 750cm 3 Over 1,000cm 3 Over 1,500cm 3 Above, or 2,000 cm 3 The method according to any of the preceding embodiments, wherein the above-described clinically meaningful reduction in splenomegaly (e.g., SVR35) from baseline spleen size is induced in response to administration.

[0445] Embodiment 88. The method according to any of the preceding embodiments, wherein the method is by inducing a clinically meaningful reduction in TSS (e.g., TSS50) from a baseline TSS of, for example, 15 or greater, 20 or greater, 25 or greater, 30 or greater, 35 or greater, 40 or greater, 45 or greater, or 50 or greater, based on the Myelofibrosis Symptom Assessment Scale (MFSAF) version 4.0, and the clinically meaningful reduction is induced in response to administration.

[0446] Embodiment 89. The method according to any of the preceding embodiments, wherein the method is by inducing a clinically meaningful reduction in fibrosis from baseline fibrosis (e.g., grade 1 or higher), for example, grade 2 or higher, and the clinically meaningful reduction is induced in response to administration.

[0447] Embodiment 90. The method according to any of the preceding embodiments, wherein the method is by inducing a clinically meaningful increase in overall survival probability, for example, at 1 year, 2 years, or 3 years, and the clinically meaningful increase is induced in response to administration.

[0448] Embodiment 91. The method according to any of the preceding embodiments, wherein the method is by inducing a clinically meaningful response in a subject, selected from (a) complete remission; (b) partial remission; (c) clinical improvement; and (d) stable disease, the clinically meaningful response being evaluated by the IWG-MRT response criteria, and the clinically meaningful response being induced in the subject in response to administration.

[0449] Embodiment 92. The subject at baseline had splenomegaly (for example, 450 cm² as determined by imaging). 3 More than 600cm 3 More than 750cm 3 Over 1,000cm 3 Over 1,500cm 3 Above, or 2,000 cm 3 A method according to any of the prior embodiments, having the above characteristics.

[0450] Embodiment 93. The method according to any of the preceding embodiments, wherein the baseline subject has an elevated TSS (for example, 15 or higher, 20 or higher, 25 or higher, 30 or higher, 35 or higher, 40 or higher, 45 or higher, or 50 or higher, based on the Myelofibrosis Symptom Assessment Scale (MFSAF) version 4.0).

[0451] Embodiment 94. The method according to any of the preceding embodiments, wherein the subject at baseline has fibrosis (e.g., grade 2 or higher).

[0452] Embodiment 95. The method according to any of the preceding embodiments, wherein the subject at baseline has poor bone marrow function.

[0453] Embodiment 96. The method according to any of the preceding embodiments, wherein the baseline subject has two or more measurable symptoms of myelofibrosis based on MFSAF v4.

[0454] Embodiment 97. The method according to any of the preceding embodiments, wherein the subject has been optionally treated for three months or more or six months or more previously with a BET inhibitor (e.g., perabrecib), an ACVR1 inhibitor (e.g., pacritinib), or a telomerase inhibitor (e.g., imetelstat).

[0455] Embodiment 98. The method according to any of the preceding embodiments, wherein the myeloproliferative neoplasm is moderate-1, moderate-2, or high-risk myelofibrosis according to the DIPSS scoring system.

[0456] Embodiment 99. The method according to any of the preceding embodiments, wherein the myeloproliferative neoplasm is low-risk myelofibrosis on the DIPSS scoring system.

[0457] Embodiment 100. The method according to any of the preceding embodiments, wherein the subject is positive for a mutation selected from JAK2V617F, MPLW515L, or CALR, or for a combination of two or three such mutations.

[0458] Embodiment 101. The method of any of the prior embodiments, further comprising monitoring the cytokine levels of the target, and (a) adjusting the dose of compound (1) or a pharmaceutically acceptable salt thereof based on changes in the cytokine levels of the target; and / or (b) correlating changes in cytokine levels with improvement in the fibrosis of the target.

[0459] Embodiment 102. The method according to any of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered as monotherapy for a myeloproliferative neoplasm, the subject having been previously treated with a JAK inhibitor.

[0460] Embodiment 103. The method according to any one of Embodiments 1 to 101, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in combination with momerotinib or a pharmaceutically acceptable salt thereof, and the subject has been previously treated with a JAK inhibitor other than momerotinib or a pharmaceutically acceptable salt thereof and has poor bone marrow function.

[0461] Embodiment 104. The method according to any one of Embodiments 1 to 101, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in combination with ruxolitinib or a pharmaceutically acceptable salt thereof, and prior to initiating the method, the subject is therapeutically naive to a JAK inhibitor.

[0462] Embodiment 105. The method according to any one of Embodiments 1 to 101, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in combination with ruxolitinib or a pharmaceutically acceptable salt thereof to a subject who has been administered ruxolitinib or a pharmaceutically acceptable salt thereof for more than 6 months, has been administered a stable dose for at least 8 weeks, and whose response to ruxolitinib or a pharmaceutically acceptable salt thereof is suboptimal, plateaued, or lost its response.

[0463] Embodiment 106. The method according to any of the prior embodiments, further comprising administering a BET inhibitor (e.g., perabrecib), an ACVR1 inhibitor (e.g., pacritinib), or a telomerase inhibitor (e.g., imetelstat).

[0464] Embodiment 107. The method of any of the prior embodiments, optionally comprising administering compound (1) or a pharmaceutically acceptable salt thereof in a BID.

[0465] Embodiment 108. comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof to a target, The target group is those who (a) have a grade below 1, or (b) have a 25x10 9 Having a platelet count of less than / L and / or (c) 35% or less, The method according to any of the preceding embodiments, wherein the decrease in platelet count is determined by a change in baseline platelet count determined within one week prior to administration of compound (1) or a pharmaceutically acceptable salt thereof, and a second platelet count determined at least two weeks after administration.

[0466] Embodiment 109. A method according to any one of the prior embodiments, wherein the method minimizes, reduces, or mitigates an adverse event in a subject.

[0467] Embodiment 110. The method according to any one of the preceding embodiments, wherein the method results in improvement of a symptom selected from the group consisting of fever, night sweats, early satiety, weight loss, fatigue, weakness, shortness of breath, spleen or hepatomegaly, left upper abdominal pain, bone or joint pain, bruising, bleeding, and two or more combinations thereof.

[0468] Embodiment 111. The method according to any one of the preceding embodiments, which results in the minimization, reduction, or mitigation of fever, night sweats, early satiety, weight loss, fatigue, weakness, shortness of breath, spleen or hepatomegaly, left upper abdominal pain, bone or joint pain, bruising, bleeding, or two or more combinations thereof.

[0469] Embodiment 112. The method involves adiponectin, angiopoietin 1, angiotension II, beta-2 microglobulin, bone morphogenetic protein (BMP) and its subtypes (e.g., BMP1, BMP6, and BMP7), bone morphogenetic protein Rcp2, brain-derived neurotrophic factor (BDNF), CC-motif chemokine ligand (CCL) and its subtypes (e.g., CCL14 and CCL21), differentiation cluster 40 ligand (CD40L), differentiation cluster 40 (CD40), colony-stimulating factor (CSF1), complement factor D, C-reactive protein (CRP), C-X3-C-motif chemokine receptor 1 (CX3CR1), CXC-motif chemokine ligand (CXL) and its subtypes (e.g., CXL11, CXCL12, and CXCL16), Dickkopf WNT signaling pathway inhibitor 1 (DKK1), endoglin, eotaxin and its subtypes (e.g., eotaxin-2 and eotaxin-3), epidermal growth factor (EGF), epidermal growth factor receptor (EGFR), erythropoietin (EPO), extracellular matrix protein tenacin-C (TN-C), extracellular newly identified receptor for advanced glycation end-products bindingProtein (EN-RAGE), ferritin, fibroblast growth factor (FGF), Fms-related receptor tyrosine kinase 3 (FLT3), Fms-related tyrosine kinase 3 ligand (FLT-3L), granulocyte-macrophage colony-stimulating factor (GM-CSF), growth colony-stimulating factor (G-CSF), growth regulatory protein alpha (GRO-alpha), heparin-binding EGF-like growth factor (HB-EGF), hepatocyte growth factor (HGF), insulin-like growth factor-binding protein 2 (IGFBP2), intercellular adhesion molecule 1 (ICAM-1), interferon (IFN) and its subtypes (e.g., interferon-gamma-inducible protein 9 (IP-9), interferon-alpha (IFN-alpha), interferon-gamma-inducible protein 9, interferon-gamma-inducible protein 9, interferon-alpha (IFN-alpha), interferon-gamma-inducible protein 9, interferon-alpha IFN-g, interferon-gamma-inducible protein (IFN-g-IP), interferon-gamma-inducible protein 10 (IP-10), interleukins (IL) and their subfactors (e.g., IL-1a, IL-1Ra, IL-2, IL-2R, IL-2Ra, IL-4, IL-5, IL-5a, IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, IL-17A, IL-17F, IL-18, IL-22, IL-23, IL-1B, and IL-1RA), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), latent-associated peptide transforming growth factor-β1 (LAP TGF-β1), leptin (LEP), LIF interleukin-6 family cytokines (LIF), macrophage colony-stimulating factor 1 (MCSF), macrophage-derived chemokines (MDCs), macrophage inflammatory proteins and their subtypes (e.g., MIP-1, MIP-1b, MIP-1a, MIP-3a, and MIP-3b), macrophage-derived chemokines (MDCs), matrix metalloproteinases and their subtypes (e.g., MMP-3 and MMP-9), monocyte chemotactic proteins and their subtypes (e.g., MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5), monokine-inducible gamma (MIG), myelin basic proteins and their subtypes (e.g., MBPR2 and MBP7), myeloperoxidase (MPO), myoglobin, osteoprotegerin (OPG), pentraxin (PTX) and its subtypes (e.g., PTX3), plasma protein factor VII (factor VII), plasminogen activator inhibitor-1 (PAI1), platelet factor 4 (PF-4), platelet-derived growth factor BB (PDGF-BB), lung and activation-regulated chemokines (PARC), regulated on activation of normal T cells expressed and The method according to any one of the preceding embodiments, which results in downregulation of secreted (RANTES), stem cell factor (SCF), 10-11 translocation 2 (TET2), thrombopoietin (TPO), thymic and activation-regulating chemokines (TARC), tissue inhibitor of metalloproteinase-1 (TIMP1), transforming growth factor-β (TGF-beta), transforming growth factor-β1 (TGF-b1), tumor necrosis factor and its subtypes (TNF-1, TNF-α, TNF-RI, and TNF-RII), urokinase plasminogen activator receptor (uPAR), vascular adhesion molecule (VCAM1), vascular endothelial growth factor (VEGF) and its subtype (VEGFb), vascular endothelial growth factor receptor (VGFR), α2-macroglobulin (A2M), or a combination of two or more thereof.

[0470] Embodiment 113. A method according to any one of the preceding embodiments, wherein the method results in downcontrol of IL-1Ra, IL-6, IL-10, IL-12, IL-12, TGF-beta, EGFR, ferritin, GRO-a, MMP-9, PAI-1, RANTES, TIMP-1, TNFR-2, VCAM-1, or two or more combinations thereof.

[0471] Embodiment 114. A method according to any one of the prior embodiments, wherein the method improves clinically meaningful overall survival in a subject.

[0472] Embodiment 115. The method according to any one of the preceding embodiments, wherein the result of the method is normalization or increase of platelet count, normalization or increase of neutrophil count, normalization or increase of hemoglobin count, improvement of blood transfusion (including conversion to transfusion independence), or a combination of two or more of these.

[0473] Embodiment 116. The method according to any one of the preceding embodiments, wherein the result of the method is a reduction in myelofibrosis, a reduction in overall symptoms, cytokine regulation, or a combination of two or more of these.

[0474] Embodiment 117. A method according to any one of the prior embodiments, wherein the method results in a reduction of more than 50% in the Total Symptom Score (TSS).

[0475] Embodiment 119. A method according to any one of the prior embodiments, wherein the method results in a reduction of more than 70% in the Total Symptom Score (TSS).

[0476] Embodiment 120. A method according to any one of the prior embodiments, wherein the method reduces myelofibrosis in a subject.

[0477] Embodiment 121. A method according to any one of the prior embodiments, wherein the method results in a reduction of at least one grade of myelofibrosis in a subject.

[0478] Embodiment 122. A method according to any one of the preceding embodiments, wherein the method reduces the spleen volume in a subject.

[0479] Embodiment 123. A method according to any one of the preceding embodiments, wherein the method results in a clinical improvement in blood cell count or neutrophil count, and / or alleviation of thrombocytopenia.

[0480] Embodiment 124. A method according to any one of the prior embodiments, wherein the method results in cytogenetic remission, molecular partial remission, or complete remission in a subject.

[0481] Embodiment 125. A method according to any one of the prior embodiments, wherein the method results in partial remission or complete remission in a subject.

[0482] Embodiment 126. A method according to any one of the preceding embodiments, wherein the method alleviates anemia in a subject.

[0483] Embodiment 127. A method according to any one of the prior embodiments, wherein the method results in an increase in hemoglobin levels of 20 g / L or more or a change from transfusion dependence to transfusion independence in a subject.

[0484] Embodiment 128. The method according to any one of the prior embodiments, wherein the method results in an improvement (at least a 1-point increase) on the Patient Global Change Impression (PGIC) questionnaire at week 24.

[0485] Embodiment 129. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 120 mg to about 3000 mg.

[0486] Embodiment 130. The method according to any one of the prior embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of approximately 240 mg to approximately 1440 mg per day.

[0487] Embodiment 131. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 240 mg to about 1200 mg.

[0488] Embodiment 132. The method according to any one of the prior embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 240 mg to about 1000 mg.

[0489] Embodiment 133. The method according to any one of the prior embodiments, wherein the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 240 mg to about 900 mg.

[0490] Embodiment 134. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 240 mg to about 800 mg.

[0491] Embodiment 135. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 240 mg to about 700 mg.

[0492] Embodiment 136. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 240 mg to about 600 mg.

[0493] Embodiment 137. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 240 mg to about 500 mg.

[0494] Embodiment 138. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 350 mg to about 1350 mg.

[0495] Embodiment 139. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg to about 1250 mg.

[0496] Embodiment 140. The method according to any one of the prior embodiments, wherein the therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof is about 450 mg to about 1150 mg.

[0497] Embodiment 141. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 500 mg to about 1050 mg.

[0498] Embodiment 142. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 550 mg to about 1000 mg.

[0499] Embodiment 143. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 350 mg to about 1000 mg.

[0500] Embodiment 144. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 450 mg to about 900 mg.

[0501] Embodiment 145. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 450 mg to about 800 mg.

[0502] Embodiment 146. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 450 mg to about 750 mg.

[0503] Embodiment 147. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 470 mg to about 730 mg.

[0504] Embodiment 148. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 120 mg to about 580 mg, about 581 mg to about 1040 mg, or about 1041 mg to about 1500 mg.

[0505] Embodiment 149. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 120 mg / day to about 1500 mg / day.

[0506] Embodiment 150. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 350 mg / day to about 2100 mg / day.

[0507] Embodiment 151. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 550 mg / day to about 2000 mg / day.

[0508] Embodiment 152. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 700 mg / day to about 1950 mg / day.

[0509] Embodiment 153. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 120 mg / day to about 800 mg / day.

[0510] Embodiment 154. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 200 mg / day to about 750 mg / day.

[0511] Embodiment 155. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in an amount of about 250 mg / day to about 650 mg / day.

[0512] Embodiment 156. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of about 240 mg to about 1440 mg.

[0513] Embodiment 157. The method according to any one of Embodiments 1 to 128, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered twice daily in an amount of about 1440 mg.

[0514] Embodiment 158. The method according to any one of the prior embodiments, comprising administering a selective PIM1 inhibitor or compound (1) or a pharmaceutically acceptable salt thereof at least once daily.

[0515] Embodiment 159. The method according to any one of the prior embodiments, comprising administering a selective PIM1 inhibitor or compound (1) or a pharmaceutically acceptable salt thereof at least twice daily.

[0516] Embodiment 160. The method according to any one of the prior embodiments, comprising administering a selective PIM1 inhibitor or compound (1) or a pharmaceutically acceptable salt thereof twice daily.

[0517] Embodiment 161. The method according to any one of the prior embodiments, comprising administering a selective PIM1 inhibitor or compound (1) or a pharmaceutically acceptable salt thereof at least three times daily.

[0518] Embodiment 162. The method according to any one of the prior embodiments, comprising administering a selective PIM1 inhibitor or compound (1) or a pharmaceutically acceptable salt thereof at least four times daily.

[0519] Embodiment 163. The method according to any one of the prior embodiments, further comprising administering ruxolitinib or a pharmaceutically acceptable salt thereof in an amount of about 5 mg, about 10 mg, about 15 mg, or about 25 mg.

[0520] Embodiment 164. The method according to any one of the prior embodiments, further comprising administering fedratinib or a pharmaceutically acceptable salt thereof in an amount of about 200 mg or about 400 mg.

[0521] Embodiment 165. The method according to any one of the prior embodiments, further comprising administering pacritinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg or about 200 mg.

[0522] Embodiment 166. The method according to any one of the prior embodiments, further comprising administering momerotinib or a pharmaceutically acceptable salt thereof in an amount of about 100 mg or about 200 mg.

[0523] Embodiment 167. The method according to any one of the prior embodiments, further comprising administering ruspatercept in an amount of at least about 1 mg / kg or 1.25 mg / kg based on the subject's body weight.

[0524] Embodiment 168. The method according to Embodiment 167, wherein ruspatercept is administered by subcutaneous injection once every three weeks for at least 21 weeks.

[0525] Embodiment 169. The method according to any one of Embodiments 163 to 166, wherein ruxolitinib, fedratinib, pacritinib, or momerotinib, or a pharmaceutically acceptable salt thereof, is administered at least once daily.

[0526] Embodiment 170. The method according to any one of Embodiments 163 to 166, wherein ruxolitinib, fedratinib, pacritinib, or momerotinib, or a pharmaceutically acceptable salt thereof, is administered at least twice a day.

[0527] Embodiment 171. The method according to any one of Embodiments 163 to 168, comprising administering compound (1) or a pharmaceutically acceptable salt thereof simultaneously with ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alpha-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof.

[0528] Embodiment 172. The method according to any one of Embodiments 163 to 168, comprising sequentially administering compound (1) or a pharmaceutically acceptable salt thereof with ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alpha-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof.

[0529] Embodiment 173. The method according to any one of the preceding embodiments, wherein, when referring to baseline platelet count, the baseline platelet count is measured within one week prior to the initiation of administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0530] Embodiment 174. The method according to any one of the prior embodiments, further comprising monitoring the total blood count in a subject and progressively adjusting the dosage of compound (1) or a pharmaceutically acceptable salt thereof.

[0531] Embodiment 175. The platelet count is monitored, and based on the baseline platelet count of the subject (i.e., the platelet count before the start of treatment), the change in platelet count is (a) less than grade 1, (b) 25 × 10 9 The method according to any one of the prior embodiments, further comprising increasing (i.e., escalating) the dose or frequency if the decrease is less than / L and / or (c) less than 35%.

[0532] Embodiment 176. The platelet count is monitored, and if the change in platelet count is (a) an increase of 1 grade or more, (b) 25 × 10 9 The method according to any one of the prior embodiments, further comprising reducing the dose or reducing the frequency of administration (collectively, tapering) if the decrease is greater than or equal to / L and / or (c) greater than or equal to 35%.

[0533] Embodiment 177. The method according to claim 175, wherein the platelet count increases from grade 1 to grade 2, 3, or 4, or from grade 2 to grade 3 or 4, or from grade 3 to grade 4.

[0534] Embodiment 178. The method according to any one of Embodiments 164 to 177, wherein monitoring is performed before, during, and / or after treatment.

[0535] Embodiment 179. The method according to any one of Embodiments 174 to 178, wherein monitoring is performed once a week or once every 2 to 4 weeks.

[0536] Embodiment 180. The method according to any one of Embodiments 174 to 179, further comprising continuing to adjust the dosage or frequency in stages until a desired stable clinical state is achieved.

[0537] Embodiment 181. The method according to any one of the preceding embodiments, further comprising monitoring the total blood count in a subject when ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof, is administered, and gradually adjusting the dose of ruxolitinib, fedratinib, pacritinib, momerotinib, ruspatercept, lopeginterferon alfa-2b, or nabutemadeline, or a pharmaceutically acceptable salt thereof.

[0538] Embodiment 182. The method according to any one of the prior embodiments, further comprising monitoring including evaluating the platelet count in a subject before, during, and / or after treatment.

[0539] Embodiment 183. When ruxolitinib or a pharmaceutically acceptable salt thereof is administered, the following dosages of ruxolitinib or a pharmaceutically acceptable salt thereof are used: Baseline platelet count: 200 × 10⁶ 9 If the value exceeds / L, take 20 mg twice a day. Baseline platelet count: 100 × 10 9 / L to 200 x 10 9 If the dose is up to / L, take 10 mg twice a day. Baseline platelet count: 50 × 10 9 / L to 100x10 9 If the value is less than / L, take 5 mg twice a day. A method according to any one of the prior embodiments, further comprising starting with

[0540] Embodiment 184. The method according to Embodiment 183, further comprising increasing the dose when the subject's response is insufficient and the platelet and neutrophil counts are appropriate.

[0541] Embodiment 185. The method according to Embodiment 184, comprising increasing the dosage by 5 mg twice daily, up to a maximum of 25 mg twice daily.

[0542] Embodiment 186. The following conditions: As measured by computed tomography (CT) or magnetic resonance imaging (MRI), the palpable spleen length decreases by 50% from the baseline before treatment, or the spleen volume does not decrease by 35%; Platelet count increased to 125 x 10 in 4 weeks. 9 Platelet count exceeds / L, platelet count is 100 × 10 9 Not less than / L; and ANC level 0.75×10 9 / L exceeds The method according to Embodiment 184 or 185, comprising increasing the dose of ruxolitinib or a pharmaceutically acceptable salt thereof in subjects who satisfy all of the following conditions.

[0543] Embodiment 187. Platelet count is at least 40 × 10 9 If you maintain / L, If your platelet count has not decreased by more than 20% in the past four weeks, ANC 1×10 9 If / L or more, and If the dosage has not been reduced or interrupted due to adverse events or hematological toxicity in the past four weeks. The method according to Embodiment 184 or 185, comprising increasing the dose of ruxolitinib or a pharmaceutically acceptable salt thereof in the subject by 5 mg twice daily, up to a maximum of 10 mg.

[0544] Embodiment 188. Platelet count 100 × 10 9For patients whose treatment was initiated at a level of / L or higher, due to thrombocytopenia, Table (a):

[0545] [Table 5] The method according to Embodiment 184 or 185, comprising graded adjustment of the dosage of ruxolitinib or a pharmaceutically acceptable salt thereof according to [the specified method].

[0546] Embodiment 189. Platelet count of 50 × 10 9 / L~100×10 9 Table (b): For patients with thrombocytopenia who initiated treatment with a level less than / L:

[0547] [Table 6] The method according to Embodiment 184 or 185, comprising graded adjustment of the dosage of ruxolitinib or a pharmaceutically acceptable salt thereof according to [the specified method].

[0548] Embodiment 190. When fedratinib is administered, the baseline platelet count is 50 × 10 9 The method according to any one of Embodiments 1 to 182, further comprising initiating a patient with a cephalically acceptable level of ≥ / L with fedratinib or a pharmaceutically acceptable salt thereof once daily at a dose of 200, 300, or 400 mg.

[0549] Embodiment 191. The method according to Embodiment 190, comprising reducing the dose of fedratinib to 100 mg or less, or temporarily discontinuing administration if an adverse event occurs.

[0550] Embodiment 192. The method according to Embodiment 191, wherein the side effects are anemia, grade 4 thrombocytopenia, grade 3 thrombocytopenia with active bleeding, grade 3 or higher nausea, vomiting, diarrhea, anemia, or elevated alanine transaminase (ALT), aspartate aminotransferase (AST), or bilirubin.

[0551] Embodiment 193. When pacritinib is administered, the baseline platelet count is 50 × 10⁶. 9 The method according to any one of Embodiments 1 to 182, further comprising initiating a patient with a pharmaceutically acceptable salt thereof at 100 mg or 200 mg twice daily in the subject.

[0552] Embodiment 194. The method according to Embodiment 183, further comprising reducing the dose of pacritinib to 100 mg or less if an adverse reaction occurs.

[0553] Embodiment 195. The method according to Embodiment 194, wherein the side effects are diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema.

[0554] Embodiment 196. The method according to Embodiment 194 or 195, further comprising temporarily discontinuing administration if there is any clinically significant worsening of thrombocytopenia lasting more than 7 days until toxicity is resolved, and restarting pacritinib or a pharmaceutically acceptable salt thereof at 50% of the last administered dose.

[0555] Embodiment 197. The method according to any one of Embodiments 1 to 182, further comprising initiating ruspatercept in a subject by subcutaneous injection at a dose of 0.5 mg / kg or 1 mg / kg once every three weeks.

[0556] Embodiment 198. The method according to Embodiment 197, further comprising adjusting the dosage of ruspatercept in stages if the subject's response is insufficient or adverse effects occur.

[0557] Embodiment 199. Table (c):

[0558] [Table 7] The method according to Embodiment 198, further comprising adjusting the dosage in stages based on the response thereto.

[0559] Embodiment 200. Table (d):

[0560] [Table 8] The method according to Embodiment 198, comprising adjusting the dosage in stages based on the response thereto.

[0561] Embodiment 201. The method according to any one of Embodiments 1 to 182, further comprising administering momerotinib to a subject in a dose of approximately 50 mg to approximately 200 mg of momerotinib or a pharmaceutically acceptable salt thereof, when the subject has moderate-risk or high-risk primary or secondary (post-PV or post-ET) myelofibrosis with a hemoglobin level of <10.

[0562] Embodiment 202. The method according to any one of the prior embodiments, wherein the myeloproliferative neoplasm is responsive to selective PIM1 inhibition.

[0563] Embodiment 203. The method according to any one of the prior embodiments, wherein the myeloproliferative neoplasm is a JAK inhibitor-resistant myeloproliferative neoplasm.

[0564] Embodiment 204. The method according to any one of the preceding embodiments, wherein the myeloproliferative neoplasm is myelofibrosis.

[0565] Embodiment 205. The method according to any one of Embodiments 1 to 203, wherein the myeloproliferative neoplasm is moderate-risk myelofibrosis or high-risk myelofibrosis.

[0566] Embodiment 206. The method according to any one of Embodiments 1 to 203, wherein the myeloproliferative neoplasm is primary myelofibrosis or idiopathic myelofibrosis.

[0567] Embodiment 207. The method according to any one of Embodiments 1 to 203, wherein the myeloproliferative neoplasm is a secondary myelofibrosis (e.g., post-PV myelofibrosis and post-ET myelofibrosis).

[0568] Embodiment 208. The method according to any one of Embodiments 1 to 203, wherein the myeloproliferative neoplasm is selected from polycythemia vera (PV), primary or essential thrombocythemia (ET), or pre-myelofibrosis.

[0569] Embodiment 209. The method according to any one of the prior embodiments, wherein the subject has not been previously treated with a JAK inhibitor.

[0570] Embodiment 210. The method according to any one of the preceding embodiments, wherein the subject has not been treated with a JAK inhibitor for at least two weeks prior to administration of compound (1) or a pharmaceutically acceptable salt thereof.

[0571] Embodiment 211. The method according to any one of the prior embodiments, wherein the subject has been previously treated with a JAK inhibitor and has shown an insufficient response.

[0572] Embodiment 212. The method according to any one of the preceding embodiments, wherein the subject has been previously treated with a JAK inhibitor and has shown an inadequate response, defined as resistance or intolerance to the JAK inhibitor, loss or absence of a significant splenic response or overall symptom response, and / or development of a clinically significant decrease in blood cell count, neutropenia, or thrombocytopenia.

[0573] Embodiment 213. A method according to any one of the prior embodiments, wherein the subject is intolerant to JAK inhibitor therapy, resistant to JAK inhibitor therapy, or unsuitable for JAK inhibitor therapy.

[0574] Embodiment 214. The method according to any one of the preceding embodiments, wherein the subject has experienced a relapse from previous JAK inhibitor therapy.

[0575] Embodiment 215. The method according to any one of the preceding embodiments, wherein the subject has experienced a relapse from a previous bone marrow transplant.

[0576] Embodiment 216. The method according to any one of the preceding embodiments, wherein the subject has moderate or severe splenomegaly at baseline.

[0577] Embodiment 217. The method according to any one of the preceding embodiments, wherein the subject has a Total Symptom Score (TSS) greater than 15, 20, 25, 30, 35, 40, 45, or 50 at baseline.

[0578] Embodiment 218. A method according to any one of the prior embodiments, wherein the subject requires cytokine regulation.

[0579] Embodiment 219. The method according to any one of the prior embodiments, wherein the subject has the JAK2V16F mutation.

[0580] Embodiment 220. The method according to any one of the prior embodiments, wherein the subject has a CALR mutation.

[0581] Embodiment 221. The method according to any one of the prior embodiments, wherein the subject has fibrosis of grade 2 or higher.

[0582] Embodiment 222. The subject is 1 × 10 9 The method according to any one of the prior embodiments, having an absolute neutrophil count greater than / L.

[0583] Embodiment 223. The method according to any one of the preceding embodiments, wherein the subject has less than 10% peripheral hemoblasts.

[0584] Embodiment 224. The target is 200 × 10 9 The method according to any one of the prior embodiments, having a baseline platelet count of less than / L.

[0585] Embodiment 225. The target is 150 × 10 9 The method according to any one of the prior embodiments, having a baseline platelet count of less than / L.

[0586] Embodiment 226. The object is 100 × 10 9 The method according to any one of the prior embodiments, having a baseline platelet count of less than / L.

[0587] Embodiment 227. The subject is 50 × 10 9 The method according to any one of the prior embodiments, having a baseline platelet count of less than / L.

[0588] Embodiment 228. The object is 10 × 10 9 The method according to any one of the prior embodiments, having a baseline platelet count greater than / L.

[0589] Embodiment 229. The subject is 25 × 10 9 The method according to any one of the prior embodiments, having a baseline platelet count greater than / L.

[0590] Embodiment 230. The subject is 35 × 10 9 The method according to any one of the prior embodiments, having a baseline platelet count greater than / L.

[0591] Embodiment 231. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered for about 1 week to about 2 years.

[0592] Embodiment 232. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered for about 15 weeks to about 1 year.

[0593] Embodiment 233. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered for about 24 weeks to about 1 year.

[0594] Embodiment 234. The method according to any one of the preceding embodiments, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered orally.

[0595] Embodiment 235. The method according to any one of the preceding embodiments, wherein the hydrochloride salt of compound (1) is administered orally.

[0596] Embodiment 236. The method according to any one of the preceding embodiments, wherein the crystalline hydrochloride of compound (1) is administered orally.

[0597] Embodiment 237. The method according to any one of the preceding embodiments, wherein a selective PIM1 inhibitor is administered, and the selective PIM1 inhibitor has a PIM1 / PIM-2 IC50 ratio of less than 0.05, less than 0.045, less than 0.04, less than 0.035, less than 0.03, or less than 0.025. [Examples]

[0598] Example 1: Individual in vitro hematological tolerability of compound (1), ruxolitinib, pacritinib, and momerotinib. The potential effects of compound (1), ruxolitinib, pacritinib, and momerotinib (collectively referred to as the test compounds) on the proliferation of human myeloid, erythroid, and megakaryocytic progenitor cells were evaluated using colony-forming cell assays. 50 The value was calculated.

[0599] Cloning progenitor cells of human erythrocytes (CFU-E, BFU-E), granulocytes (CFU-GM), and pluripotent (CFU-GEMM) lineages were evaluated in methylcellulose-based semi-solid medium preparations containing rhIL-3 (10 ng / mL), rhGM-SCF (10 ng / mL), r...

Claims

1. A method for treating myeloproliferative neoplasms in human subjects requiring treatment, wherein the subject has the following structure: 【Chemistry 1】 The procedure involves administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the subject is a. Thrombocytopenia (for example, platelet counts of 150, 100, 75, 50, or 25 × 10) ９ (It is less than or equal to / L); b. Anemia (for example, Hgb levels below 10, 9, or 8 g / dL); c. Blood transfusion dependence; or d. Combinations of those It has poor bone marrow function characterized by, A method of treatment that induces a clinically meaningful response in myeloproliferative neoplasms.

2. A method for treating myeloproliferative neoplasms in human subjects requiring treatment, comprising administering a therapeutically effective dose of a selective PIM1 inhibitor to the subject, wherein the subject is a. Thrombocytopenia (for example, platelet counts of 150, 100, 75, 50, or 25 × 10) ９ (It is less than or equal to / L); b. Anemia (for example, Hgb levels below 10, 9, or 8 g / dL); c. Blood transfusion dependence; or d. Combinations of those It has poor bone marrow function characterized by, A method of treatment that induces a clinically meaningful response in myeloproliferative neoplasms.

3. A method for treating myeloproliferative neoplasms in human subjects requiring treatment, wherein the subjects have been previously treated for myeloproliferative neoplasms with a JAK inhibitor and may, as appropriate, have relapsed disease or be refractory to JAK inhibitors, and the method involves applying the following structure to the subjects: 【Chemistry 2】 A method comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the treatment induces a clinically meaningful response in a myeloproliferative neoplasm.

4. A method for treating myeloproliferative neoplasms in human subjects requiring treatment by inducing TSS50, wherein the subject has the following structure: 【Transformation 3】 A method comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein a myeloproliferative neoplasm is treated by inducing TSS50 in the subject, and optionally, at a time between those times, including about 24 weeks and about 48 weeks.

5. A method for treating myeloproliferative neoplasms in human subjects requiring treatment, wherein the subject has the following structure: 【Chemistry 4】 A method comprising administering a compound (1) having the above-mentioned property or a pharmaceutically acceptable salt thereof, and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof, in an amount that does not induce overlapping hematological toxicities (e.g., anemia and / or thrombocytopenia and / or transfusion dependence), wherein the treatment induces a clinically meaningful response in myeloproliferative neoplasms.

6. A method for treating a myeloproliferative neoplasm in a human subject requiring treatment, comprising administering to the subject a selective PIM1 inhibitor and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof in a dose that does not induce overlapping hematological toxicities (e.g., anemia and / or thrombocytopenia and / or transfusion dependence), wherein the treatment induces a clinically meaningful response in the myeloproliferative neoplasm.

7. A method for inducing an SVR35 probability of 15% or more, or 20% or more, in human subjects with myeloproliferative neoplasms, wherein the subjects have been previously treated with a JAK inhibitor for myeloproliferative neoplasms and may, as appropriate, have relapsed disease or be refractory to JAK inhibitors, and the method involves applying the following structure to the subjects: 【Transformation 5】 A method comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the treatment induces a probability of SVR35 in a human subject to about 15% or more or about 20% or more.

8. A method for inducing a TSS50 probability in human subjects with myeloproliferative neoplasms of approximately 30% or more, approximately 35% or more, approximately 40% or more, approximately 45% or more, or approximately 50% or more, wherein the subjects have been previously treated with a JAK inhibitor for myeloproliferative neoplasms and may, as appropriate, have relapsed disease or be refractory to JAK inhibitors, and the method involves applying the following structure to the subjects: 【Transformation 6】 A method comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof, wherein the treatment induces a probability of TSS50 in human subjects of about 30% or more, about 35% or more, about 40% or more, about 45% or more, or about 50% or more.

9. The target is, a. Thrombocytopenia (for example, platelet counts of 150, 100, 75, 50, or 25 × 10) ９ (It is less than or equal to / L); b. Anemia (e.g., Hgb level ≤ 10, 9, or 8 g / dL); c. Blood transfusion dependence; or d. Combinations of those The method according to claim 3, 4, 5, 6, 7, or 8, having poor bone marrow function characterized by...

10. The method according to claim 1, 2, 4, 5, 6, 7, or 8, wherein the subject has been previously treated with a JAK inhibitor for myeloproliferative neoplasm and may, as appropriate, have a relapsed disease or be refractory to JAK inhibitors.

11. The method according to claim 1, 2, 3, 5, 6, or 7 for treating myeloproliferative neoplasms by inducing TSS50 in a human subject in need of treatment, wherein the myeloproliferative neoplasm is treated by optionally inducing TSS50 in the subject at a time between therein, including about 24 weeks and about 48 weeks.

12. The method according to claim 1, 2, 3, 4, 7, or 8, comprising administering to a subject compound (1) or a pharmaceutically acceptable salt thereof, and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof, in an amount that does not induce overlapping hematological toxicity (e.g., anemia and / or thrombocytopenia and / or transfusion dependence).

13. The method according to claim 1, 2, 3, 4, 5, 6, or 8, for treating a myeloproliferative neoplasm by inducing an SVR35 probability of approximately 15% or more or approximately 20% or more in a subject, wherein the subject has been previously treated with a JAK inhibitor for a myeloproliferative neoplasm and may, as appropriate, have a relapsed disease or be refractory to JAK inhibitors, and the treatment induces an SVR35 probability of approximately 15% or more or approximately 20% or more in a human subject.

14. The method according to claim 1, 2, 3, 4, 5, 6, or 7, for treating myeloproliferative neoplasms by inducing a TSS50 probability in human subjects of approximately 30%, approximately 35%, approximately 40%, approximately 45%, or approximately 50% or more, where the subjects have been previously treated with a JAK inhibitor for myeloproliferative neoplasms and may, as appropriate, have relapsed disease or be refractory to JAK inhibitors.

15. The method according to any one of claims 1 to 8, wherein the subject has been previously treated with a JAK inhibitor for myeloproliferative neoplasm and has a relapsed disease or is refractory to JAK inhibitors.

16. The method according to any one of claims 1 to 8, comprising administering to a subject a compound (1) or a pharmaceutically acceptable salt thereof, and ruxolitinib or momerotinib or a pharmaceutically acceptable salt thereof, in an amount that does not induce hematological toxicity that overlaps in terms of anemia, thrombocytopenia, and transfusion dependence.

17. The target is, a. Platelet count 50 × 10 ９ / L or less; b. The Hgb level is 8 g / dL or less; c. Blood transfusion dependence; or d. Combinations of those The method according to any one of claims 1 to 8, having poor bone marrow function characterized by...

18. The method according to any one of claims 1 to 8, wherein the method involves inducing SVR35 and TSS50 in a subject, and the myeloproliferative neoplasm is treated by inducing SVR35 and TSS50 in the subject, and optionally treated at a time between therein, including about 24 weeks and about 48 weeks.

19. The method according to any one of claims 1 to 8, wherein the subject has been previously treated with a JAK inhibitor for myeloproliferative neoplasm, and has been treated for approximately 3 months or more, 6 months or more, 9 months or more, or 12 months or more at the discretion of the subject, and has a relapsed disease or is refractory to JAK inhibitors.

20. The method is a. For example, a clinically significant decrease in splenomegaly from the baseline spleen size of about 450 cm ３ or more, about 600 cm ３ or more, about 750 cm ３ or more, about 1,000 cm ３ or more, about 1,500 cm ３ or more, or about 2,000 cm ３ or more; b. A clinically significant increase in TSS from baseline, for example, based on the Myelofibrosis Symptom Assessment Scale (MFSAF) version 4.0, of approximately 15 or more, approximately 20 or more, approximately 25 or more, approximately 30 or more, approximately 35 or more, approximately 40 or more, approximately 45 or more, or approximately 50 or more; c. Thrombocytopenia (for example, platelet counts of 150, 100, 75, 50, or 25 × 10⁻¹⁰) ９ Clinically meaningful improvement in poor bone marrow function, selected from anemia (e.g., Hgb levels below 10, 9, or 8 g / dL), transfusion dependence, or a combination thereof; d. For example, a clinically meaningful reduction in fibrosis from baseline fibrosis of grade 2 or higher; e. For example, a clinically meaningful increase in overall survival probability at one, two, or three years; and f. Combinations of those This involves inducing clinically meaningful responses in subjects selected from the following: The method according to any one of claims 1 to 8, wherein a clinically meaningful response is induced in response to administration.

21. The method involves imaging diagnostics, for example, approximately 450 cm ３ Above, approximately 600cm ３ Above, approximately 750cm ３ Approximately 1,000cm or more ３ Above, approximately 1,500cm ３ Above, or approximately 2,000 cm ３ The method according to any one of claims 1 to 8, wherein the above is achieved by inducing a clinically meaningful reduction in splenomegaly (e.g., SVR35) from baseline spleen size, and the clinically meaningful reduction is induced in response to administration.

22. The method according to any one of claims 1 to 8, wherein the method is by inducing a clinically meaningful decrease in TSS (e.g., TSS 50) from a baseline TSS of, for example, about 15 or more, about 20 or more, about 25 or more, about 30 or more, about 35 or more, about 40 or more, about 45 or more, or about 50 or more, and the clinically meaningful decrease is induced in response to administration.

23. The method according to any one of claims 1 to 8, wherein the method is, for example, by inducing a clinically meaningful reduction in fibrosis from baseline fibrosis of grade 2 or higher (e.g., grade 1 or higher), and the clinically meaningful reduction is induced in response to administration.

24. The method according to any one of claims 1 to 8, wherein the method is, for example, by inducing a clinically meaningful increase in the probability of overall survival over a period of about one year, about two years, or about three years, and the clinically meaningful increase is induced in response to administration.

25. The method is a. Complete remission; b. Partial remission; c. Clinical improvement; and d. Stable illness This involves inducing a clinically meaningful response in the subject, selected from among the following: The method according to any one of claims 1 to 8, wherein a clinically meaningful response is evaluated by the IWG-MRT response criteria, and a clinically meaningful response is induced in the subject in response to administration.

26. The baseline subject had splenomegaly (for example, approximately 450 cm as detected by imaging). ３ Above, approximately 600cm ３ Above, approximately 750cm ３ Approximately 1,000cm or more ３ Above, approximately 1,500cm ３ Above, or approximately 2,000 cm ３ The method according to any one of claims 1 to 8, having the above characteristics.

27. The method according to any one of claims 1 to 8, wherein the baseline subject has an elevated TSS (for example, approximately 15 or higher, approximately 20 or higher, approximately 25 or higher, approximately 30 or higher, approximately 35 or higher, approximately 40 or higher, approximately 45 or higher, or approximately 50 or higher, based on the Myelofibrosis Symptom Assessment Scale (MFSAF) version 4.0).

28. The method according to any one of claims 1 to 8, wherein the subject at baseline has fibrosis (e.g., grade 2 or higher).

29. The method according to any one of claims 1 to 8, wherein the subject at baseline has poor bone marrow function.

30. The method according to any one of claims 1 to 8, wherein the baseline subject has two or more measurable symptoms of myelofibrosis based on MFSAF v4.

31. The method according to any one of claims 1 to 8, wherein the subject has been optionally previously treated with a BET inhibitor (e.g., perabrecib), an ACVR1 inhibitor (e.g., pacritinib), or a telomerase inhibitor (e.g., imetelstat) for about three months or more or six months or more.

32. The method according to any one of claims 1 to 8, wherein the myeloproliferative neoplasm is selected from myelofibrosis (MF), polycythemia vera (PV), primary or essential thrombocythemia (ET), and chronic myelomonocytic leukemia (CMML).

33. The method according to any one of claims 1 to 8, wherein the myeloproliferative neoplasm is a myelofibrosis (MF) selected from pre-fibrotic myelofibrosis (pre-PMF), primary or idiopathic MF (PMF), post-ET MF (post-ET MF), and post-PV MF (post-polycythemia vera).

34. The method according to any one of claims 1 to 8, wherein the myeloproliferative neoplasm is classified as moderate-1, moderate-2, or high-risk myelofibrosis in the DIPSS scoring system.

35. The method according to any one of claims 1 to 8, wherein the myeloproliferative neoplasm is low-risk myelofibrosis in the DIPSS scoring system.

36. The method according to any one of claims 1 to 8, wherein the subject is positive for a mutation selected from JAK2V617F, MPLW515L, or CALR, or for a combination of two or three of said mutations.

37. Monitoring the target cytokine levels, and a. Adjusting the dosage of compound (1) or a pharmaceutically acceptable salt thereof based on changes in the target cytokine levels; and / or b. Correlating changes in cytokine levels with improvement in the target fibrosis. The method according to any one of claims 1 to 8, further comprising:

38. The method according to any one of claims 1 to 8, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered as monotherapy for a myeloproliferative neoplasm, the subject having been previously treated with a JAK inhibitor.

39. The method according to any one of claims 1 to 8, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in combination with momerotinib or a pharmaceutically acceptable salt thereof, and the subject has been previously treated with a JAK inhibitor other than momerotinib or a pharmaceutically acceptable salt thereof and has poor bone marrow function.

40. The method according to any one of claims 1 to 8, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in combination with ruxolitinib or a pharmaceutically acceptable salt thereof, and the subject is therapeutically naive to a JAK inhibitor prior to initiating the method.

41. The method according to any one of claims 1 to 8, wherein compound (1) or a pharmaceutically acceptable salt thereof is administered in combination with ruxolitinib or a pharmaceutically acceptable salt thereof to a subject who has been administered ruxolitinib or a pharmaceutically acceptable salt thereof for about six months or more, has been administered a stable dose for at least eight weeks, and whose response to ruxolitinib or a pharmaceutically acceptable salt thereof is suboptimal, plateaued, or lost its response.

42. The method according to any one of claims 1 to 8, further comprising administering a BET inhibitor (e.g., perabrecib), an ACVR1 inhibitor (e.g., pacritinib), or a telomerase inhibitor (e.g., imetelstat).

43. The method according to any one of claims 1 to 8, comprising administering compound (1) or a pharmaceutically acceptable salt thereof in a BID.

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