Ferroportin inhibitors for use in the treatment of myelodysplastic syndrome (MDS)

Abstract

The present invention relates to the use of ferroportin inhibitor compounds of general formula (I) for treating myelodysplastic syndromes (MDS). JPEG2024504349000030.jpg30123

Description

[Technical Field]

[0001] The present invention relates to the use of a compound of general formula (I) that acts as a ferroportin inhibitor for treating myelodysplastic syndrome (MDS) and related symptoms and pathological conditions. [Background technology]

[0002] Iron is an essential element for almost all living organisms, and its importance lies in its crucial role in red blood cell production and oxygen transport. The balance of iron metabolism is primarily regulated by the levels of iron recovered from hemoglobin in aged red blood cells, iron storage in the liver, and dietary iron absorbed in the duodenum. Elemental iron is taken up by intestinal cells in the duodenum via specific transport systems (DMT-1, ferroportin), enters the bloodstream, and is subsequently transported to appropriate tissues and organs by binding to its carrier, transferrin. In the human body, iron is crucial for oxygen transport, oxygen uptake, cellular functions such as mitochondrial electron transport and cognitive function, and ultimately for overall energy metabolism. Mammals cannot remove or excrete iron from their bodies through active systems. Iron homeostasis is regulated by the hepatic peptide hormone hepcidin, which modulates the activity of ferroportin, the only known iron efflux transporter, and thus releases iron from macrophages, hepatocytes, and intestinal cells. Hepcidin regulates iron absorption via the intestine and placenta, as well as iron recycling from the reticuloendothelial system. Hepcidin production is directly regulated by iron levels; that is, if an organism is supplied with sufficient or excess iron and oxygen, further hepcidin is produced; and if iron and oxygen levels are low, or if erythrocyte production is increased, hepcidin production decreases. When hepcidin binds to ferroportin in small intestinal mucosal cells and macrophages, its efflux function is blocked, and its internal translocation and degradation are promoted. Through this mechanism, hepcidin reduces the outflow of iron from cells into the bloodstream. The transport protein ferroportin is a transmembrane protein consisting of 571 amino acids and is expressed in the liver, spleen, kidneys, heart, intestines, and placenta. In particular, ferroportin is localized to the basement membrane of intestinal epithelial cells. Therefore, ferroportin acts to excrete dietary iron into the bloodstream. When hepcidin binds to ferroportin, ferroportin is transported into the cell, where it is broken down, and as a result, the release of iron from the cell is blocked.When ferroportin is inactivated or inhibited by hepcidin, preventing the excretion of iron stored in mucosal cells, iron absorption in the intestines is blocked. A decrease in hepcidin leads to an increase in active ferroportin, which in turn enhances dietary iron absorption and the release of stored iron, resulting in elevated serum iron levels.

[0003] In pathological cases, elevated iron levels lead to iron overload. For example, excessive iron uptake in organs such as the liver and heart leads to iron accumulation. Furthermore, iron accumulation in the brain has been observed in patients with neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. The majority of circulating iron is bound to transferrin, a classical iron transport molecule, which prevents the formation of free reactive iron. Iron portions that are not bound to transferrin (or other conventional iron-binding molecules such as heme, apoferritin, hemosiderin, etc.) are collectively called untransferrin-bound iron (NTBI). In further aspects of iron overload states and diseases, many problems and pathological conditions are caused by excessive levels of free iron in the circulation, i.e., NTBI.

[0004] A key harmful aspect of such excess free iron is the unwanted formation of radicals. In particular, iron(II) ions catalyze the formation of reactive oxygen species (ROS) (particularly via the Fenton reaction). ROS result in damage to DNA, lipids, proteins, and carbohydrates, and have widespread effects on cells, tissues, and organs. ROS formation is well known and has been documented in the literature as leading to so-called oxidative stress. NTBI has been widely documented as having a high tendency to induce ROS, which have potential toxicity to cells and major organs, including the heart, liver, pancreas, kidneys, and bone marrow. Therefore, iron overload is known to cause damage to tissues and organs, such as the heart, liver, and endocrine system (Vinchi, Hell, Platzbecker, "Controversies on the consequences of iron overload and chelation in MDS," Hemasphere, p. 27; Vol. 4 (No. 3), 2020; Patel M. et al., "Non-Transferrin Bound Iron: Nature, Manifestations and Analytical Approaches for Estimation," Ind. J. Clin. Biochem., 2012; Vol. 27 (No. 4): pp. 322-332, and Brissot P. et al., Review, "Non-transferrin bound iron: A key role in iron overload and iron toxicity," Biochimica et Biophysica Acta, 2012; Vol. 1820, pp. 403-410).

[0005] Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis, which leads to peripheral cytopenia, and an increased risk of leukemia. MDS is one of the most frequently encountered acquired bone marrow failure syndromes in adults. Genetic epigenetic changes affecting hematopoietic stem cells (HSCs), as well as changes in the hematopoietic niche that result in degeneration and apoptosis of hematopoietic stem cells and presumptive cells (HSPCs), are the primary causes of ineffective hematopoiesis.

[0006] MDS refers to a group of cancers in which HSPCs in the bone marrow fail to mature and do not become healthy blood cells. Typically, there are no symptoms in the early stages, but later symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, and frequent infections. Some types of MDS may develop into acute myeloid leukemia. In MDS, blood cell production is efficient, resulting in insufficient numbers of red blood cells, platelets, and white blood cells. Some types of MDS are characterized by an increase in immature blood cells called myeloblasts in the bone marrow and / or blood. Certain types of MDS are based on specific changes in blood cells and bone marrow.

[0007] The International Prognostic Scoring System (IPSS) and the Revised IPSS (IPSS-R) characterize different classes of MDS. Low-risk MDS are defined as low-risk or medium-risk 1 according to the IPSS, or as very low-risk, low-risk, or medium-risk according to the Revised IPSS [IPSS-R].

[0008] Low-risk myelodysplastic syndromes, as assessed by IPSS or IPSS-R, most commonly present with symptomatic anemia. Chronic anemia, particularly in older adults, is associated with multiple complications, including an increased risk of cardiovascular complications, falls, and fractures, as well as a shortened survival time. A high percentage of patients with low-risk myelodysplastic syndrome eventually become transfusion-dependent, a situation associated with reduced quality of life and overall survival.

[0009] As the feasibility of sequencing and identifying somatic gene mutations in clinical practice increases, it has become possible to identify further MDS subtypes defined by genetic abnormalities. Such subtypes include MDS with del(5q) alone or MDS with SF3B1 mutations, which are further described in the special report by L. Malcovati et al.: "SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS," Blood, Vol. 136, No. 2, pp. 157-170, 2020.

[0010] Common biological characteristics of low-risk MDS include defects in the self-renewal and differentiation of hematopoietic stem cells and presumptive cells, leading to cytopenia. Approximately 60% to 80% of patients with MDS experience symptomatic anemia, and 80% to 90% of anemic MDS patients require red blood cell (RBC) transfusions as supportive therapy.

[0011] Iron overload is common in MDS as a result of increased iron absorption in the intestines to support expanded red blood cell production, and chronic red blood cell transfusions are often essential to neutralize anemia in this patient population.

[0012] The main drivers of iron overload in MDS patients are ineffective erythropoiesis and blood transfusion therapy. Iron overload begins at the onset in MDS patients and becomes transfusion-dependent. That is, MDS patients may develop iron overload even before receiving transfusions, because it is underpinned by ineffective erythropoiesis, which leads to enhanced iron absorption to support the expansion of the red blood cell lineage in attempts to correct anemia. Improving anemia through RBC transfusion is a primary goal of supportive care in MDS, and typically, transfusions remain the primary cause of iron overload in this patient population. Ineffective erythropoiesis leads to the suppression of the iron hormone hepcidin, causing unrestrained iron absorption via duodenal intestinal cells. This mechanism enhances iron influx into the circulation, supports de novo erythropoiesis in the bone marrow, and thus iron overload accumulates in MDS. Therefore, correcting unbalanced iron absorption by inducing hepcidin synthesis or adding hepcidin mimes is being evaluated as an attractive therapeutic approach for normalizing dysregulated iron metabolism in MDS.

[0013] The necessity of chronic blood transfusion therapy in MDS patients often leads to secondary iron overload, ultimately resulting in life-threatening consequences. While transfusion dependence itself is a negative prognostic factor reflecting impaired bone marrow function, subsequent transfusion-induced iron overload has an additional dose-dependent adverse effect on the survival of patients with low-risk MDS. Recent data suggest that markers of iron overload are indeed relatively indicative of a poor prognosis, and retrospective analyses have demonstrated that iron chelation therapy is associated with long-term survival in transfusion-dependent MDS patients.

[0014] A diagnosis of suspected MDS is based on clinical and hematological analysis and supplemented by genetic analysis for the possibility of genetic abnormalities. Currently, treatment for MDS includes supportive care, drug therapy, and hematopoietic stem cell transplantation. Supportive care may include intermittent or routine blood transfusions, medications to increase red blood cell production, including erythropoietin stimulants, and antibiotics. Known drugs used in the treatment of MDS include lenalidomide, anti-thymocyte globulin, and azacitidine. Chemotherapy, followed by stem cell transplantation from a donor, is a further treatment option for MDS patients.

[0015] Iron accumulation is an early event in some MDS patients with potentially harmful effects, and iron chelating agents often exhibit undesirable side effects, including gastrointestinal symptoms. Therefore, there is a need for novel approaches to address iron overload conditions associated with MDS, improve quality of life and prognosis in this patient population, and implement currently available therapeutic strategies aimed at delaying disease progression to leukemia. Because MDS primarily affects the elderly population, the majority of patients cannot tolerate aggressive therapeutic approaches, such as allogeneic hematopoietic stem cell transplantation. The burden of regular blood transfusions is also difficult for elderly patients. Therefore, there is a need for novel therapeutic approaches that circumvent the shortcomings of available treatment methods.

[0016] In a novel therapeutic approach, luspatercept, a recombinant fusion protein that binds to ligands of the conversion growth factor β superfamily and reduces SMAD2 and SMAD3 signaling, showed promising results in a phase 2 trial (P. Fenaux et al., "Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes," N Engl J Med, vol. 382: pp. 140-151, 2020).

[0017] Ruspatercept is administered parenterally. Ruspatercept, and its use in the treatment of symptoms of beta-thalassemia, including incomplete erythrocyte production and ineffective erythrocyte production in the bone marrow, is described, for example, in WO2016183280.

[0018] Parenteral administration of drugs typically requires a physician's consultation, which can increase treatment costs, affect patient compliance, and impose an additional burden on the patient. Oral drug administration offers advantages over parenteral administration, such as ease of administration for patients, especially elderly patients, greater flexibility in dosage and formulation, cost-effectiveness, reduced sterility constraints and infection risk, injection site reactions, and anti-drug antibody generation.

[0019] Given the critical life-threatening situations faced by patients with MDS, it is clear that there is a need for new and improved treatment options that can extend survival and enhance quality of life for patients with MDS.

[0020] In addition to the ruspatercept treatment described above, MDS has traditionally been treated with regular blood transfusions (RBC transfusions), which involve regular concurrent treatment with iron chelate compounds aimed at the continuous removal of excess iron resulting from secondary iron overload caused by regular blood transfusions.

[0021] An established drug used in chelation therapy is deferoxamine (also known as desferrioxamine B; or Desferal®). Two novel drugs for iron chelation therapy approved for use in patients who develop iron overload as a result of receiving regular blood transfusions to treat thalassemia are deferasirox (also known as Exjade®) and deferipron (also known as Ferriprox®).

[0022] WO2013 / 086312A1 describes oral formulations containing desazadesferrithiocine polyether (DADFT-PE) analogs for treating iron overload, such as transfusion-dependent congenital and acquired anemia, via iron chelation as the basic mechanism of action.

[0023] A drawback of treating MDS with routine blood transfusions is the continued need for regular transfusions and chelation therapy to remove excess iron from the patient's system. Furthermore, established drugs for iron chelation therapy are known to exhibit potential toxicity, which poses a potential problem with long-term administration due to the long-term need for transfusion therapy.

[0024] Low molecular weight compounds having activity as ferroportin inhibitors are described in international applications WO2017 / 068089 and WO2017 / 068090. Furthermore, international application WO2018 / 192973 relates to specific salts of selected ferroportin inhibitors described in WO2017 / 068089 and WO2017 / 068090. The ferroportin inhibitors described in the aforementioned three international applications overlap with the compounds of formula (I) used in this application. In these, references to the potential treatment of MDS are merely general references in the list of possible indications without providing any data. The unpublished international application PCT / EP2020 / 070391 describes the use of a selected group of ferroportin inhibitors in the treatment of transfusion-dependent thalassemia.

[0025] In Manolova Vania et al., "Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of [beta]-thalassemia," The Journal of Clinical Investigation, Vol. 130, No. 1, January 2, 2020, pp. 491-506, XP055844753, experimental studies using a selected oral ferroportin inhibitor compound (VIT-2763, corresponding to Example Compound 127 of this application) are described, showing that VIT-2763 improves ineffective erythropoiesis, restores anemia, and prevents hepatic iron overload in a mouse model of β-thalassemia. The paper speculates on the potential (predicted) efficacy of VIT-2763 in neutralizing ineffective erythropoiesis and iron overload in various diseases, particularly with potential efficacy in restoring myeloproliferative / myelodysplastic disorders, such as MDS.

[0026] Frank Richard et al., "Oral ferroportin inhibitor VIT-2763: First-in-human, phase 1 study in healthy volunteers," American Journal of Hematology, Vol. 95, No. 1, November 19, 2019, pp. 68-77, XP055657378, presents the results of a first-in-human phase 1 trial evaluating the safety, tolerability, and pharmacokinetics of the oral ferroportin inhibitor compound VIT-2763 in healthy volunteers. Similar to the paper by Manolova et al. (2020) cited above, this paper also speculates in its discussion section on the potential of VIT-2763 to improve erythropoiesis and anemia in patients exhibiting ineffective erythropoiesis in MDS, for example, due to its ability to limit iron absorption.

[0027] The fundamental pathogenicity of MDS and β-thalassemia (bthal) differs significantly. There are prominent differences in the mechanisms of ineffective erythrocyte production between bthal and MDS, with some aspects being specific to MDS and absent in bthal.

[0028] Ineffective erythrocyte generation in MDS versus β-thalassemia: Invalid erythropoiesis is a characteristic of other diseases, such as thalassemia. Invalid erythropoiesis occurs under conditions in which progenitor precursors fail to mature, die during the process of becoming red blood cells, or develop into abnormal red blood cells that die prematurely. Both thalassemia and MDS exhibit invalid erythropoiesis, but their fundamental molecular mechanisms differ.

[0029] In β-thalassemia, ineffective erythrocyte formation is characterized by restricted proliferation, differentiation, and premature death of erythrocyte precursors, processes mediated by factors involved in the cell cycle, iron uptake, and heme synthesis. In particular, an imbalance in the production of α- and β-globin chains leads to the accumulation of excess heme and α-globin elements as hemichrome. Hemichrome is a toxic aggregate that increases oxidative stress and leads to cell death due to the presence of a reactive iron moiety. Hemichrome precipitates on the erythrocyte (RBC) membrane, causing changes in membrane structure, inducing lipid peroxidation, and leading to exposure to anionic phospholipids, which together result in premature RBC clearance from circulation. In β-thalassemia, iron restriction in erythrocyte precursors acts as a compensatory mechanism, thereby reducing cellular iron, leading to decreased heme synthesis and reduced hemichrome. The delivery of small amounts of iron to many erythrocyte precursors leads to decreased mean cellular hemoglobin (MCH) and reduced hemichrome. Since hemichrome and ROS lead to ineffective erythropoiesis in β-thalassemia, iron restriction and reduced iron uptake by red blood cells lead to more effective erythropoiesis, normalization of RBC structure and lifespan, increased Hb circulation, and recovery of splenomegaly. Therefore, the use of drugs that reduce iron uptake from the diet improves erythropoiesis in β-thalassemia.

[0030] Ineffective erythropoiesis is characterized in both β-thalassemia and MDS by erythropoietin-led proliferation of early-stage erythrocyte precursors associated with apoptosis of erythrocyte precursors; however, the proliferation of the erythroid lineage is more severe in β-thalassemia, and the underlying cellular and molecular mechanisms of ineffective erythropoiesis, as well as its exacerbation by iron overload, differ between β-thalassemia and MDS. In contrast to β-thalassemia, where iron is central to disease pathogenesis via hemichrome deposition, MDS is an HSC disease that can be exacerbated by iron—though not directly driven—and is characterized by both ineffective erythropoiesis and hematopoiesis. In β-thalassemia, ineffective erythropoiesis is due to the premature death of erythrocyte precursors due to hemichrome formation, whereas in MDS, it is due to the arrest of erythrocyte precursor differentiation and increased apoptosis induced by genetic lesions originating from HSPCs and excessive pro-inflammatory cytokines and immune dysfunction in the bone marrow niche, independent of hemichrome production in MDS.

[0031] Therefore, iron overload is likely to worsen, and restricting it improves the following mechanisms:

[0032] (1) The contribution of iron to the generation of ineffective red blood cells in MDS: Due to the lack of hemichrome formation, the way in which iron contributes to the production of ineffective erythrocytes in MDS differs from that in β-thalassemia. Iron directly affects HSPC, This likely contributes to HSPC depletion and, consequently, to the production of ineffective erythrocytes. ROS is deeply involved in hematopoiesis: a certain amount of ROS is important for the coordinated proliferation and differentiation of HSPCs, but excessive ROS increases stem cell turnover, ultimately leading to HSC depletion. Therefore, HSC exposure to excess iron in the bone marrow niche promotes ROS formation in HSCs, inducing apoptosis in hematopoietic precursors and contributing to the production of ineffective erythrocytes. Iron directly affects the red blood cell lineage.Exposure of erythrocyte precursors to increased iron induces dysplastic changes, significantly impairing erythroblast differentiation and RBC maturation, leading to the formation of burst-forming unit colonies and an overall decrease in erythroblast apoptosis. These events are reversed by chelating agents and antioxidants. Consistent with these observations, HSCs from iron-treated MDS animals and from MDS patients exhibiting moderately elevated serum ferritin (≥250 μg / l) show reduced proliferation—exclusively in the erythrocyte lineage. Recent findings suggest that intracellular oxidative stress impairs erythrocyte development, which may be actively improved by modulating ferroportin expression on these cells. Enhanced sensitivity of erythrocyte precursors to iron toxicity may be attributable to the direct effects of exposure to unstable iron and / or mitochondrial iron retention, particularly in MDS-RS (MDS with ring sideroblasts). In MDS-RS, erythrocyte precursors accumulate iron in the mitochondria (appearing as ring sideroblasts). As a result of mitochondrial iron retention, iron uptake into heme is reduced, contributing to oxidative stress and hypoxia, which stimulates increased erythropoiesis in MDS, but it is ineffective. Iron in ring sideroblasts is plausibly deposited in mitochondrial ferritin, and its levels have been shown to correlate with early apoptosis in MDS-RS erythroblasts. Overall, this suggests that iron overload exacerbates ineffective erythropoiesis through differentiation defects and a tendency towards apoptosis in MDS erythroid precursors.

[0033] (2) The contribution of iron to the progression of leukemia: In addition to ineffective erythrocyte generation, the presence of unstable plasma iron, as well as associated increases in unstable cellular iron and ROS production, has been hypothesized to play a role in disease pathogenesis in MDS through increased apoptosis and genomic instability in HSPCs, alterations in the bone marrow microenvironment, and disease progression to acute myeloid leukemia (AML) exhibiting MDS-related features. ROS formation and oxidative DNA damage markers are elevated and further exacerbated by transfusion-induced iron overload in the bone marrow of MDS patients and neutralized by iron chelation therapy. Iron overload is also involved in the induction of epigenetic abnormalities and telomere erosion. Overall iron-induced oxidative stress, DNA damage, and telomere shortening likely contribute to bone marrow mutagenesis, highlighting iron as a potential additional driver of genomic instability and malignant transformation in MDS. Although iron overload itself cannot induce leukemic transformation of stem cells, it may accelerate leukemia progression by mediating genotoxic stress in highly proliferating HSPCs. Furthermore, the depletion of normal HSCs resulting from their emergence from quiescence induced by iron-led ROS elevation likely contributes to the selective proliferation of MDS clones. This suggests that iron may play a role in clonal proliferation and the progression of myeloid leukemia by promoting malignant transformation and normal HSC depletion.

[0034] (3) The contribution of iron to the abnormal bone marrow microenvironment: An abnormal bone marrow microenvironment plays a crucial role in the pathogenesis of MDS and the progression from low-risk MDS to more malignant disease. Due to the vital functions of the bone marrow microenvironment in the maintenance, self-renewal, and differentiation of hematopoietic cells (HSCs), changes in the microenvironment have been implicated in hematopoietic disorders, as well as apoptosis and dysplasia of presumptive cells. Iron likely contributes to the reduced survival and dysfunction of multiple cell types within the bone marrow microenvironment, including mesenchymal stromal cells (MSCs), osteocytes, immune cells, and vascular endothelial cells. Iron-driven changes in the mesenchymal cell compartment affect its supporting function for hematopoiesis. Indeed, the expression of several adhesion molecules and cytokine secretion are altered in bone marrow stromal cells under iron-overload conditions, impairing their ability to support hematopoietic cell growth. Furthermore, the role of iron and transfusion in immune modulation through altered cellular function and induction of cytokine production in immune cells likely plays a role in bone marrow niche dysfunction and abnormal hematopoiesis in MDS patients, where a pro-inflammatory niche is often present.

[0035] (4) The contribution of iron overload to organ toxicity: In addition to bone marrow, changes in iron metabolism can also affect other organs. Similar to β-thalassemia, iron overload resulting from multiple transfusions in MDS has been shown to be toxic to various organs such as the liver, heart, pancreas, thyroid, and pituitary gland, leading to increased morbidity and mortality.

[0036] To our surprise, the inventors of the present invention have found that ferroportin inhibitor compounds, as defined herein, not only act to block ferroportin, but also further improve the following aspects of steady-state MDS: • Ineffective red blood cell production • Survival of HSC • Myeloid proliferation • Inflammation in the bone marrow microenvironment • Iron overload in tissues.

[0037] Ineffective erythropoiesis is improved by ferroportin inhibitor-mediated iron restriction in both β-thalassemia and MDS. However, the basic mechanism in β-thalassemia is primarily a decrease in hemichrome formation of erythrocyte precursors, while in MDS, it is primarily a multifactorial improvement in the quality and quantity of HSCs and preerythrocyte material (e.g., reduced apoptosis, improved maturation) resulting from a decrease in ROS when iron utilization is reduced.

[0038] Surprisingly, efficacy has also been demonstrated in MDS, including the limitation of HSC pool depletion, reduced myeloid proliferation and leukemia progression, and improvements in MDS-specific aspects, including reduced inflammation in the bone marrow microenvironment, which is based on an additional, different mode of action compared to β-thalassemia.

[0039] Importantly, the inventors of this application have found that enhanced iron absorption is pathologically relevant, and that its inhibition via the ferroportin inhibitors described herein provides a therapeutic benefit in steady-state MDS through the modulation of fundamental pathophysiological mechanisms, including ineffective erythropoiesis, HSC depletion, and myeloid clonal proliferation. [Overview of the project] [Problems that the invention aims to solve]

[0040] The object of the present invention is to provide a novel method for treating myelodysplastic syndrome (MDS). A particular object of the present invention may be considered to be to provide a novel drug compound for effectively treating MDS and its associated symptoms and pathological conditions, or for improving the burden associated with conventional MDS treatment methods. In particular, a novel drug compound for treating MDS and its associated symptoms and pathological conditions, or for improving the burden associated with conventional MDS treatment methods using an improved route of administration, e.g., oral administration, should be provided to simplify administration, reduce side effects resulting from parenteral administration, enhance patient compliance, eliminate concerns about treatment costs, and reduce the treatment burden on patients. In a further embodiment, the object of the present invention may be considered to be to provide a compound for treating MDS and its associated symptoms and pathological conditions that is easier and less expensive to prepare than recombinant protein-based drugs or genetically modified drug compounds. [Means for solving the problem]

[0041] The inventors of the present invention have surprisingly found that compounds of general formula (I) as defined herein, acting as ferroportin inhibitors (FpnIs), can be used to treat MDS and its associated symptoms and pathological conditions, such as, in particular, incomplete erythropoiesis in the bone marrow, ineffective hematopoiesis, such as particularly ineffective erythropoiesis, decreased hemoglobin levels / anemia, iron overload and multiple organ dysfunction, iron overload of the liver and kidneys, and iron overload of the heart. In a further embodiment, ferroportin inhibitor compounds as defined herein can be used to reduce immature cells and myeloblasts in the bone marrow in MDS patients, and therefore to reduce myeloid proliferation, to prevent or delay the progression of leukemia in MDS patients if possible, to reduce the production of inflammatory cytokines such as TNFα and IL-1β by macrophages, and / or to improve the bone marrow microenvironment. In particular, the novel and surprising result showing delay in the progression of leukemia provides a novel approach to treating leukemia with ferroportin inhibitor compounds as defined herein.

[0042] Therefore, a first aspect of the present invention relates to compounds of the following formula (I), including pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof, for use in the treatment of myelodysplastic syndrome (MDS):

[0043] [ka] (In the formula, X 1 is N or O; X 2 is N, S, or O; However, X 1 and X 2 They are different; R 1 teeth, - Hydrogen, and - Optionally substituted alkyl groups Selected from the group consisting of; n is an integer from 1 to 3; A 1 and A 2 is independently selected from the group of alkanediyl, R 2 is - hydrogen, or - optionally substituted alkyl or; or A 1 and R 2 together with the nitrogen atom to which they are attached form an optionally substituted 4- to 6-membered ring; R 3 represents one, two or three optional substituents, which are - halogen, - cyano, - optionally substituted alkyl, - optionally substituted alkoxy, and - carboxyl group may be independently selected from the group consisting of; R 4 is - hydrogen, - halogen, - C1-C3-alkyl, and - halogen-substituted alkyl selected from the group consisting of) relates to.

[0044] Adaptation The present invention relates to the selected pharmaceutical use of the compounds of formula (I) described herein, as well as salts, solvates, hydrates, and polymorphs thereof, for treating MDS.

[0045] The treatment of myelodysplastic syndromes (MDS) and / or related symptoms involves the treatment of ineffective hematopoiesis, particularly ineffective erythropoiesis.

[0046] Treatment of MDS and / or related symptoms further includes improving, preventing, or delaying the progression of leukemia, reducing myeloid cells and myeloid proliferation, reducing the production of inflammatory cytokines such as TNFα and IL-1β by macrophages, and / or improving the myeloid microenvironment.

[0047] As mentioned above, several subtypes of MDS are classified in the International Prognostic Scoring System (IPSS) and the Revised IPSS (IPSS-R). Low-risk MDS are defined as low-risk or medium-risk 1 according to the IPSS, or as very low-risk, low-risk, or medium-risk according to the Revised IPSS [IPSS-R].

[0048] In a further embodiment, the present invention relates to compounds of formula (I), or salts, solvates, hydrates, and polymorphs thereof for treating MDS, wherein MDS patients are selected from individuals suffering from very low-risk, low-risk, or intermediate-risk myelodysplastic syndrome according to the IPSS / IPSS-R scoring system. Treatment of low-risk MDS (IPSS) is preferred.

[0049] Furthermore, genetic MDS subtypes, such as MDS with del(5q) alone or MDS with SF3B1 mutations, are defined. The report by Malcovati et al. (2020), cited above, further defines diagnostic criteria for the MDS subtypes and MDS entities listed in Table 1 below:

[0050] [Table 1]

[0051] Further aspects of the present invention relate to compounds of formula (I), or salts, solvates, hydrates, and polymorphs thereof, for treating MDS selected from one of the MDS entities defined in Table 1 above.

[0052] In a further embodiment of the present invention, the MDS patients to be treated are selected from one or more of the following patient groups, and the individuals are characterized by one or more of the following: - Having ring sideroblasts (RS) as defined by the World Health Organization criteria, characterized by 15% or more ring sideroblasts, or 5% or more ring sideroblasts if an SF3B1 mutation is present, or having myelodysplastic syndrome with less than 5% myeloblasts; - Having myelodysplastic syndrome with erythropoietin levels exceeding 200 U per liter; - Having erythrocyte dysplasia; - Having a cytopenia, especially a peripheral cytopenia; - Less than 5% myeloblasts; - Peripheral hemoblasts less than 1%; - Having a myelodysplastic syndrome characterized by a reduced or absent response to erythropoiesis-stimulating agents; - The patient has myelodysplastic syndrome with chromosome 5q deletion (del[5q]); - SF3B1 mutation patient; - Patients in whom PPOX and / or ABCB7 genes are significantly downregulated compared to healthy individuals; - The person is transfusion-dependent or receives regular red blood cell transfusions of 2 units or more every 8 weeks.

[0053] In one embodiment, the present invention relates to compounds of formula (I), or salts, solvates, hydrates, and polymorphs thereof, for treating transfusion-independent MDS.

[0054] In a further embodiment, the present invention relates to compounds of formula (I), or salts, solvates, hydrates, and polymorphs thereof for treating transfusion-dependent MDS, i.e., for treating MDS according to the present invention, wherein a selected group of patients is characterized by requiring regular blood transfusions or being transfusion-dependent. Such regular blood transfusions or transfusion dependence are a) Repeated transfusions of the same number of red blood cells (RBCs) at different time intervals thereafter, or b) Repeated transfusions of equal RBC units at equal time intervals thereafter, or c) Repeated transfusions of different RBC units at equal time intervals thereafter, or d) Repeated blood transfusions of different RBC units at different time intervals thereafter. It is characterized by:

[0055] The terms “to treat,” “treatment,” or “to treat” in the context of use of the present invention include improvement of at least one symptom or pathological condition associated with MDS. Non-limiting examples of symptoms or pathological conditions associated with MDS include incomplete erythropoiesis in the bone marrow, ineffective hematopoiesis, e.g., ineffective erythropoiesis in particular, decreased hemoglobin levels, multiple organ failure, iron overload, anemia, hepatic iron overload and cardiac iron overload, as well as the symptoms described above and below.

[0056] In the context of the present invention, the terms “to treat,” “treatment,” or “to treat” further include, for example, prevention by administering the compounds of the present invention before or concurrently with blood transfusion in transfusion-dependent MDS patients to prevent or mitigate the appearance of a transfusion-induced pathological condition.

[0057] Patients presenting with MDS may have severe iron overload due to routine blood transfusions (BT). The primary goal of blood transfusion therapy in the treatment of MDS is to neutralize the anemic state and suppress red blood cell production. This is thought to be achieved when the Hb level is 9 g / dL or higher. Therefore, in a further embodiment of the treatment of MDS patients, administration of a ferroportin inhibitor compound of formula (I) according to the present invention helps prevent iron absorption in the intestinal tract during the interval between transfusions, which helps reduce further iron burden in MDS patients.

[0058] Elevated levels of non-transferrin-bound iron (NTBI) have been observed in MDS patients. NTBI is released by macrophages recycling damaged RBCs resulting from the formation of immature RBCs in the bone marrow and / or transfused RBC units, leading to oxidative stress, vascular damage, and organ iron overload (Baek JH et al., "Iron accelerates hemoglobin oxidation increasing mortality in vascular diseased guinea pigs following transfusion of stored blood." JCI Insight, 2017; Vol. 2 (No. 9)).

[0059] The inventors of the present invention have found that the compound of formula (I) is particularly suitable for treating MDS by improving ineffective erythropoiesis through the restriction of iron overload mediated by the compound of formula (I). It is further assumed that the compound of formula (I) is particularly suitable for treating MDS by restricting reactive oxygen species (ROS) in erythrocyte precursors and thus improving erythropoiesis in patients suffering from MDS. Consequently, anemia in MDS patients is improved and tissue oxygenation is enhanced by many RBCs with extended lifespan. In MDS, the compound of formula (I) further efficiently reduces elevated NTBI levels and helps prevent the development of pathological conditions resulting therefrom, such as iron overload of the liver, kidneys, and heart, and thus organ dysfunction, as well as other diseases.

[0060] NTBI encompasses all forms of serum iron that do not strongly bind to transferrin or other molecules and is chemically and functionally heterogeneous. LPI (unstable plasma iron) represents a component of NTBI that also exhibits redox activity and is chelateable, can penetrate organs and induce tissue iron overload. The compound of formula (I) has the potential to efficiently reduce elevated NTBI, and therefore LPI, levels in MDS.

[0061] The following parameters may be determined to evaluate the efficacy of the compounds of the present invention in pharmaceutical applications treating MDS: serum iron, NTBI level, LPI (unstable plasma iron) level, erythropoietin, TSAT (transferrin saturation), Hb (hemoglobin), Hct (hematocrit), MCV (mean cell volume), MCH (mean cellular hemoglobin), RDW (red blood cell distribution width), and reticulocyte count, whole blood count, myeloblasts in bone marrow and peripheral blood, spleen weight, erythropoiesis in bone marrow and spleen, and iron content in the liver, spleen, and kidneys. Determination can be carried out using conventional methods of the art, particularly those described in more detail below. Compound (I) of the present invention is suitable for improving at least one of these parameters.

[0062] As explained by Patel et al. (2012; cited above), under normal physiological conditions, transferrin levels are sufficient to completely capture absorbed and recycled iron, ensuring the absence of NTBI, and therefore NTBI levels in normal healthy individuals do not exceed 0.1 μmol / L and are virtually undetectable by common methods. NTBI levels up to 20 μmol / L have been reported in the absence of transferrin, and up to 10 μmol / L have been observed in the presence of insufficient or highly saturated transferrin. However, as described by Patel et al. (2012) and Brissot et al. (2012), the determination is highly dependent on the method applied and the assay used, and the technical difficulties arising from the determination of heterogeneous chemical forms of circulating NTBI should be considered. For example, fluorescence measurements with reproducible accuracy of a minimum of 0.1 μmol / L have been described by Hider et al. (2010), cited in Brissot et al. (2012). According to Patel et al. (2012; Table 1), NTBI levels in elevated clinical iron overload range from 0.25 to 4.0 μmol / L (with varying accuracy and determination methods). Considering this, in the sense of the present invention, an elevated NTBI level is considered to exist if it is detectable by known methods (e.g., those described by Patel et al. (2012) or Brissot et al. (2012)), preferably exceeding 0.1 μmol / L.

[0063] In certain embodiments, the treatment of MDS according to the present invention reduces the patient's NTBI level by at least 100%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100% when determined at any point within a period of up to 72 hours, 60 hours, 48 ​​hours, 36 hours, 5%, 4, 3, 2, 1, and 0.5 hours after administration and compared to the patient's NTBI level determined at any point within 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, or 48 hours, or up to less than 1 week, prior to the commencement of the treatment according to the present invention. NTBI may be determined according to the assays described in the following examples.

[0064] In certain embodiments, the treatment of MDS according to the present invention reduces the patient's LPI level by at least 100%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100% when the LPI level is determined at any point within a period of up to 72 hours, 60 hours, 48 ​​hours, 36 hours, 5%, 4, 3, 2, 1, and 0.5 hours after administration and compared to the patient's total LPI level determined at any point within 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, or 48 hours, or up to less than 1 week, prior to the commencement of the treatment according to the present invention. The LPI may be determined according to the assay described in the following examples.

[0065] Reactive oxygen species (ROS) can lead to shortened lifespan of red blood cell cells (RBCs), anemia, and tissue hypoxia. The effect of the compounds of the present invention on ROS levels in RBCs may be monitored, for example, by commercially available far-infrared or green-emitting ROS-sensitive sensors as described in the following examples.

[0066] In a further embodiment, the treatment of MDS according to the present invention is determined at any point within a period of up to 5 days, up to 6 days, up to 7 days, up to 8 days, up to 9 days, up to 10 days, up to 11 days, up to 12 days, up to 13 days, up to 14 days, up to 15 days, up to 16 days, up to 17 days, up to 18 days, up to 19 days, up to 20 days, up to 21 days and up to 1 month after the first dose and / or ischemic event, and 12 hours, 24 hours, 3 hours before initiating the treatment of the present invention When compared to the ROS level in the patient's RBCs determined at any point within 6 hours, 48 ​​hours, 1 week, 2 weeks, 3 weeks, or 4 weeks, the ROS level in the patient's RBCs is reduced by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%. The ROS level in the RBCs may be determined according to the assay described in the following examples.

[0067] As explained above, the decrease in elevated NTBI and LPI levels helps to reduce iron concentrations in the liver, kidneys, and myocardium.

[0068] Accordingly, in a further embodiment, treatment for MDS according to the present invention may reduce the patient's hepatic iron concentration by at least 1%, 2%, 3%, 4%, 3 months, or at least 100%, when determined at any point within a period of up to 1, 2, 3, or 4 weeks after the initial administration and compared to the patient's hepatic iron concentration level determined at any point within 1, 2, 3, or 4 weeks prior to the commencement of treatment according to the present invention. The hepatic iron concentration may be determined according to the assay described in the following examples.

[0069] Accordingly, in a further embodiment, treatment for MDS according to the present invention may reduce the renal iron concentration in a patient by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%, when determined at any point within a period of up to 1, 2, 3, 4, or 3 months after the initial administration and compared with the level of renal iron concentration in the patient determined at any point within 1, 2, 3, or 4 weeks prior to the commencement of treatment according to the present invention. The renal iron concentration may be determined according to the assay described in the following examples.

[0070] In a further embodiment, treatment for MDS according to the present invention may reduce the myocardial iron concentration in a patient by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%, when determined at any point within a period of up to 1, 2, 3, or 4 weeks after the initial administration and compared with the myocardial iron concentration in the subject determined at any point within 1, 2, 3, or 4 weeks prior to the commencement of treatment according to the present invention. The myocardial iron concentration may be determined according to the assay described in the following examples.

[0071] In a further embodiment, the treatment for MDS according to the present invention may improve at least one of the patient's parameters, Hb, Hct, RBC count, MCV, MCH, RDW, and reticulocyte count, by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%, when determined at any point within a period of up to 1 week, 2 weeks, 3 weeks, or 4 weeks after the first administration and compared with the individual parameters in the subject determined at any point within 1, 2, 3, or 4 weeks prior to the commencement of the treatment according to the present invention. The parameters may be determined according to conventional methods.

[0072] In a further embodiment, the treatment of MDS according to the present invention may result in a red blood cell response, which may include a reduction in the transfusion burden in the patient by at least 33%, preferably at least 50%. In principle, the red blood cell response may include a reduction in the transfusion burden in the patient by at least 10%, 15%, 20%, 25%, 30%, 33%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100%. In a further embodiment, the treatment of MDS according to the present invention may result in a red blood cell response, which may include reducing the transfusion burden in the patient by at least 10%, 15%, 20%, 25%, 30%, 33%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 100% over a period of at least 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 months, up to 18 months, up to 24 months, or further beyond until transfusion independence. In a further embodiment, treatment of MDS according to the present invention may result in a red blood cell response, which may include a reduction in red blood cell transfusions in the patient by at least 1, 2, 3, or 4 red blood cell units, or more. In a further embodiment, treatment of MDS according to the present invention may result in a red blood cell response, which may include a reduction in red blood cell transfusions in the patient by at least 1, 2, 3, or 4 red blood cell units, or more, over a period of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, up to 18 months, up to 24 months, or further beyond, until the patient becomes independent of red blood cell unit transfusions. The red blood cell response may also include one or more of the improvements described above. The red blood cell response may be determined as described in the following embodiments.

[0073] Within this context, one unit of red blood cells refers to approximately 200-500 mL of concentrated red blood derived from donated blood. Blood transfusions are typically adjusted according to age, disease severity, and the patient's initial blood parameters. Guidelines for selecting the amount of blood transfusion include, for example:

[0074] [Table 2] They recommend it.

[0075] The formula for individual blood transfusion volumes is as follows: (Desired Hb - Actual Hb) × Body weight [kg] × 3 / Hematocrit value of transfused units = ml of blood transfused Further calculations can be performed using [this method].

[0076] According to the recommended transfusion scheme for MDS, the amount of blood transfused per kg of body weight is equivalent to 100 to 200 ml of pure red blood cells (RBCs) per year.

[0077] In a further embodiment, the treatment of MDS according to the present invention may reduce the transfusion burden on the patient compared to the patient's transfusion burden within 1, 2, 3, or 4 weeks, 2 months, 3 months, 4 months, 6 months, 8 months, 9 months, 12 months, or 24 months prior to initiating the treatment of the present invention.

[0078] In a further embodiment, the treatment of MDS according to the present invention can achieve that MDS patients treated according to the method of the present invention will be free from the need for red blood cell transfusions for at least 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 24 months, or even longer after treatment until they become independent of red blood cell transfusions.

[0079] In a further embodiment, the treatment of MDS according to the present invention may result in a reduction in daily iron chelating therapy in MDS patients receiving blood transfusions, for example, in the dose or frequency of one or more iron chelating agents administered to the patient. Non-limiting examples of iron chelating agents are those described above.

[0080] In a further embodiment, the treatment of MDS according to the present invention may result in a reduction in the use of erythropoietin stimulants, such as erythropoietin (EPO), for example, in the dose or frequency of erythropoietin stimulants administered to MDS patients.

[0081] In a further embodiment, treatment for MDS according to the present invention may reduce the patient's serum ferritin level by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or at least 100%, when determined at any point within a period of up to 1 week, 2 weeks, 3 weeks, or 4 weeks after the initial administration and compared to the patient's serum ferritin level determined at any point within 1 week, 2 weeks, 3 weeks, or 4 weeks prior to the commencement of treatment according to the present invention. Serum ferritin levels may be determined according to conventional assays.

[0082] In a further embodiment, treatment of MDS according to the present invention may result in a reduction of one or more clinical MDS complications and associated symptoms. Non-limiting examples of MDS symptoms include pallor, jaundice, fatigue, and chronic red blood cell transfusions, e.g., clinical complications of hepatitis B virus infection, hepatitis C virus infection, and human immunodeficiency virus infection, alloimmunity, and organ damage resulting from iron overload, e.g., liver damage, heart damage, and endocrine gland damage.

[0083] In a further embodiment, treatment for MDS according to the present invention may improve the quality of life in patients compared to the quality of life in patients assessed within 1, 2, 3, or 4 weeks prior to the initiation of the treatment according to the present invention. The improvement in quality of life is assessed within 3, 6, 9, 12, 15, 18, 21, or 24 months after the initiation of treatment. Quality of life may be assessed according to the assays described in the following examples.

[0084] One or more of the aforementioned improvements can be achieved by treating MDS according to the present invention.

[0085] patient group The present invention relates to compounds of formula (I) as described herein, as well as their salts, solvates, hydrates, and polymorphs, for pharmaceutical applications of MDS, particularly one or more of the MDS entities / subtypes defined above.

[0086] In principle, the subject treated in the use of the present invention may be any mammal, such as rodents and primates, and in a preferred embodiment, the pharmaceutical use relates to the treatment of humans. A subject suffering from MDS and treated using the method of the present invention may also be referred to as a “patient” or “individual.”

[0087] In particular, MDS patients treated according to the present invention are characterized by the basic pathophysiological mechanisms described in detail above, including the affliction of ineffective erythrocytes, HSC depletion, and myeloid clonal proliferation.

[0088] The subjects treated may be of any age. A preferred embodiment of the present invention relates to the treatment of elderly persons. Accordingly, in a preferred embodiment of the present invention, the subjects treated with the novel method described herein are over 25 years of age. In a further embodiment of the present invention, the subjects treated with the novel method described herein are between 25 and 30 years of age, or over 30 years of age, for example, preferably 25 to 30 years, 30 to 35 years, 35 to 40 years, 40 to 45 years, 45 to 50 years, 50 to 55 years, 55 to 60 years, or over 60 years of age. In a preferred case of treating elderly patients, the subjects treated with the novel method described herein are between 60 and 65 years of age, 65 to 70 years, 70 to 75 years, 75 to 80 years, or over 80 years of age.

[0089] Treatment of elderly patients is particularly preferred due to the significant advantages provided by treatment with the ferroportin inhibitor compound of formula (I) of the present invention. The compound may be administered orally, which is advantageous over parenteral administration of currently available drugs (e.g., ruspatercept). Furthermore, the orally bioavailable ferroportin inhibitors of the present invention have been found to have moderate bioavailability and half-life in the body and are therefore washed out relatively quickly. This leads to reduced adverse effects and rapid reversibility of the drug, which is particularly important in the treatment of elderly patients.

[0090] The patient group or population suffering from MDS and treated using the method according to the present invention is selected from subjects (patients) characterized as defined above. In a further embodiment of the present invention, the patient group or population suffering from MDS and treated using the method according to the present invention is selected from subjects (patients) with elevated NTBI levels. NTBI levels are considered elevated if they are detectable using known methods as discussed above. Preferably, NTBI levels of 0.1 μmol / L or higher are considered elevated in MDS patients. More preferably, the elevation of NTBI levels in MDS patients according to the present invention is an NTBI value exceeding the value determined in healthy individuals using individual determination methods such as those described by de Swart et al., "Second international round robin for the quantification of serum non-transferrin-bound iron and labile plasma iron in patients with iron-overload disorders," Haematologica, 2016; Vol. 101 (No. 1): pp. 38-45.

[0091] In a further embodiment of the present invention, the group of patients or population suffering from MDS and treated using the method according to the present invention is selected from subjects (patients) with elevated LPI levels. LPI levels are considered elevated if they can be detected using known methods as discussed above. Preferably, the elevation of LPI levels in MDS patients according to the present invention exceeds the values ​​determined in healthy individuals using individual assessment methods, such as those described by de Swart et al., "Second international round robin for the quantification of serum non-transferrin-bound iron and labile plasma iron in patients with iron-overload disorders," Haematologica, 2016; Vol. 101 (No. 1): pp. 38-45.

[0092] In a further embodiment of the present invention, the patient group or population suffering from MDS and treated using the method according to the present invention is selected from subjects (patients) with elevated TSAT levels. Preferably, an elevated TSAT level in MDS patients according to the present invention is a TSAT level that exceeds the mean “normal” TSAT level determined in healthy individuals by an individual assessment method. Approximately 25% TSAT can be considered the mean. However, the reference range depends on several factors such as age, sex, race, and the test device. Most laboratories define “normal” as up to 30% for women and up to 45% for men. Above 50%, the risk of toxic non-transferrin-bound iron (NTBI) increases exponentially, potentially causing organ damage. TSAT levels can be further used to indirectly reflect NTBI and therefore can be used as a translation marker.

[0093] In a further embodiment of the present invention, the patient population or group suffering from MDS and treated using the method according to the present invention is selected from subjects (patients) having dysfunctional and pro-apoptotic hematopoietic stem cells and pre-cell (HSPCs) carrying MDS mutations.

[0094] Typically, one or more of the following diagnostic criteria for MDS apply: (1) Cytopenia as defined by standard hematological values (2) Genetic analysis of somatic SF3B1 mutations, (3) Morphological dysplasia (with or without RSV), (4) Less than 5% myeloblasts and less than 1% peripheral hematoblasts, (5) Progression of leukemia, onset of AML.

[0095] One of the most important hematological values ​​is hemoglobin level (Hb). Patients with MDS maintain Hb levels between 5 and 10 g / dl. Patients with MDS are usually classified as anemic if their Hb level is below 9 g / dL or below 8 g / dL. Hb levels in MDS patients can be as low as 4 to 5 g / dL. International guidelines recommend transfusions for patients who have reached the hemoglobin range of 9-10 g / dL, with the optimal range after transfusion being 13-14 g / dL. However, in clinical practice, Hb levels above 7 g / dL are generally considered sufficient without regular transfusions, and the usual goal of transfusion is to maintain the patient's hemoglobin level between 9.5 and 10 g / dL. However, depending on the condition, patients with Hb levels between 7 and 8 g / dL may be deemed to require transfusions. Achieving the recommended high Hb level of 13-14 g / dL would likely require an excessive increase in transfusion burden. However, the amount of blood needed varies greatly among patients and is heavily influenced by the patient's weight and target hemoglobin level.

[0096] In consideration of this, in a further embodiment of the present invention, the group of patients or population suffering from MDS and treated using the method according to the present invention may be selected from subjects (patients) whose hemoglobin (Hb) levels are below 8 g / dL.

[0097] In a further embodiment of the present invention, the group of patients or population suffering from MDS and treated using the method according to the present invention may be selected from subjects (patients) with an MCV between 50 and 70 fL.

[0098] In a further embodiment of the present invention, the group of patients or population suffering from MDS and treated using the method according to the present invention may be selected from subjects (patients) with MCH between 12 and 20 pg.

[0099] In a further embodiment, the patient group or population suffering from MDS and treated using the method according to the present invention may be selected from subjects (patients) having one or more of the following characteristics: a) an Hb level below 8 g / dL, b) an MCV between 50 and 70 fL, and c) an MCH between 12 and 20 pg.

[0100] In a further embodiment of the present invention, the patient group or population suffering from MDS and treated using the method according to the present invention receives regular blood transfusions. However, as discussed in detail above, further clinical symptoms and parameters also play an important role in determining MDS.

[0101] Routine blood transfusion further means repeated transfusions of red blood cell (RBC) units more than once within a time interval of at least two months or less. The intervals may be of equal length or may be modified depending on the individual patient, disease progression, severity, and treatment response. Routine blood transfusion may further include repeated transfusions of equal or different transfusion units at subsequent transfusion points. Examples of routine blood transfusion include: - Repeated transfusions of the same number of RBCs at different time intervals thereafter, or - Repeated blood transfusions of the same number of RBCs at equal time intervals thereafter, or - Repeated transfusions of different RBC units at equal time intervals thereafter, or - Repeated blood transfusions of different RBC units at different time intervals thereafter. It is possible.

[0102] In a further embodiment of the present invention, regular blood transfusions mean a period of three months or less, preferably two months or less, during which no blood transfusions are given.

[0103] In a further embodiment of the present invention, the patient group or population suffering from MDS and treated using the method according to the present invention is selected from subjects (patients) who require regular iron chelation therapy. Such patient group or population requiring regular iron chelation therapy may be further characterized by one or more of the characteristics defined above.

[0104] Dosage Form In a further embodiment of the present invention, treatment for MDS involves orally administering one or more of the compounds of formula (I), salts, solvates, hydrates, or polymorphs thereof, as described in any of the foregoing, to a patient in need.

[0105] For this purpose, the compounds of formula (I) according to the present invention are preferably provided in the form of pharmaceuticals or pharmaceutical compositions in the form of oral administration, including, for example, pills, tablets, such as enteric-coated tablets, film tablets and layered tablets, sustained-release formulations for oral administration, depot formulations, sugar-coated tablets, granules, emulsions, dispersants, microcapsules, micro formulations, nano formulations, liposome formulations, capsules, such as enteric-coated capsules, powders, microcrystalline formulations, sprays, drops, ampoules, liquids and suspensions for oral administration.

[0106] In a preferred embodiment of the present invention, the compound of formula (I) according to the present invention is administered in the form of tablets or capsules as defined above. These may be present, for example, as an acid-resistant form or with a pH-dependent coating.

[0107] Accordingly, further aspects of the present invention relate to compounds of formula (I) according to the present invention, including pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof, for use in the treatment of MDS in oral administration form, as well as pharmaceuticals, compositions, and combination preparations comprising them.

[0108] Medication regimen Further aspects of the present invention relate to compounds of formula (I) according to the present invention for use in accordance with the present invention, wherein the treatment is characterized by one of the following drug regimens:

[0109] In one embodiment, the compound of formula (I) according to the present invention may be administered in doses of 0.001 to 500 mg to patients who require it, for example, once to four times a day. However, the dose may be increased or decreased depending on age, weight, patient condition, severity of disease, or type of administration. In a further embodiment of the present invention, the compound of formula (I) is available in amounts of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 1 It may be administered in doses of 15 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg.

[0110] The preferred dose is between 0.5 and 500 mg, more preferably between 1 and 300 mg or 3 and 300 mg, and more preferably between 1 and 250 mg or 5 and 250 mg.

[0111] The most preferred doses are 5 mg, 15 mg, 60 mg, 120 mg, or 240 mg.

[0112] The dosage amount defined above is the total daily dose, and it can be administered as a single daily dose or divided into multiple doses for administration two or more times a day.

[0113] In further embodiments, doses between 0.001 and 35 mg / kg body weight, between 0.01 and 35 mg / kg body weight, between 0.1 and 25 mg / kg body weight, or between 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 up to a maximum of 20 mg / kg body weight may be administered. Particularly preferred are doses of 120 mg for patients weighing more than 50 kg and 60 mg for patients weighing less than 50 kg, in either case once or twice daily.

[0114] In a further embodiment, one of the dosages defined above may be selected as the initial dose, and thereafter, the same or different doses defined above may be administered once or multiple times at repeating intervals of 1 to 7 days, 1 to 5 days, preferably 1 to 3 days, or every 2 days.

[0115] The initial dose and subsequent doses may be selected from the dosages defined above and adjusted / modified according to the needs of the MDS patient within the provided range.

[0116] In particular, the amount of subsequent doses can be appropriately selected according to the individual patient, the progression of the disease, and the response to treatment. Subsequent doses can be administered 1, 2, 3, 4, 5, 6, 7 times, or more.

[0117] The initial dose may be equal to or different from one or more subsequent doses. Furthermore, subsequent doses may be equal to or different from those.

[0118] The repetition interval may be the same length, or it may be changed according to the individual patient, disease progression, and treatment response.

[0119] Preferably, the subsequent dose is such that it decreases as the number of subsequent doses increases.

[0120] Preferably, a dose between 3 mg and 300 mg, more preferably between 5 mg and 300 mg, most preferably 5 mg, 15 mg, 60 mg, 120 mg, or 240 mg is administered once daily over a treatment period of at least 3 days, at least 5 days, or at least 7 days. In a further preferred embodiment, a dose of 60 mg or 120 mg is administered once daily. In a further preferred embodiment, a total daily dose of 120 mg is administered by administering a dose of 60 mg twice daily.

[0121] In a further preferred embodiment, a total daily dose of 240 mg is administered by administering a 120 mg dose twice daily. This dose has been found to be safe and tolerable.

[0122] The preferred dosing regimen further demonstrated rapid oral absorption to detectable levels within 15 to 30 minutes after administration. Absorption levels could be maintained stably even with repeated dosing, and no significant accumulation was observed.

[0123] The preferred drug regimen was further found to efficiently reduce mean serum iron levels and mean calculated transferrin saturation, and to shift the mean serum hepcidin peak, demonstrating its effectiveness in treating MDS.

[0124] In a further embodiment of the present invention, the initial and one or more subsequent doses are adjusted according to the hemoglobin concentration of the patient being treated. The hemoglobin concentration is determined using a conventional method.

[0125] Ferroportin (Fpn) inhibitor compounds The present invention relates to a compound of formula (I) as defined herein:

[0126] [ka] Regarding new pharmaceutical applications.

[0127] Within this and throughout the invention, substituents have meanings as defined in detail in any part of this specification.

[0128] The optionally substituted alkyls are preferably linear or branched alkyls containing 1 to 8 carbon atoms, more preferably 1 to 6, particularly preferably 1 to 4, and even more preferably 1, 2, or 3 carbon atoms, and are also represented as C1-C4-alkyl or C1-C3-alkyl.

[0129] The optionally substituted alkyl groups are further cycloalkyl groups preferably containing 3 to 8 carbon atoms, more preferably 5 or 6 carbon atoms.

[0130] Examples of alkyl residues containing 1 to 8 carbon atoms include: methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, n-pentyl group, i-pentyl group, sec-pentyl group, t-pentyl group, 2-methylbutyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 3-ethylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethyl-1-methylpropyl group, n-heptyl group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 1-ethyl methyl Examples include pentyl group, 2-ethylpentyl group, 3-ethylpentyl group, 4-ethylpentyl group, 1,1-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 4,4-dimethylpentyl group, 1-propylbutyl group, n-octyl group, 1-methylheptyl group, 2-methylheptyl group, 3-methylheptyl group, 4-methylheptyl group, 5-methylheptyl group, 6-methylheptyl group, 1-ethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 5-ethylhexyl group, 1,1-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 5,5-dimethylhexyl group, 1-propylpentyl group, 2-propylpentyl group, etc. Alkyl groups containing 1 to 4 carbon atoms (C1-C4 alkyl), for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl are particularly preferred. C1-C3 alkyl groups, particularly methyl, ethyl, propyl, and i-propyl are more preferred. The most preferred are C1 and C2 alkyl groups, for example, methyl and ethyl.

[0131] The cycloalkyl residues containing 3 to 8 carbon atoms are preferably: cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, and cyclooctyl group. Cyclopropyl group, cyclobutyl group, cyclopentyl group, and cyclohexyl group are preferred. Cyclopropyl group is particularly preferred.

[0132] The optionally substituted alkyl substituents defined above are preferably, for example: halogens as defined below, for example preferably F; cycloalkyls as defined above, for example preferably cyclopropyl; optionally substituted heteroaryls as defined below, for example preferably a benzimidazolyl group; optionally substituted aminos as defined below, for example preferably an amino group or benzyloxycarbonylamino; carboxyl groups, for example aminocarbonyl groups as defined below; and alkylene groups, for example particularly, for example a methylene-substituted ethyl group (CH3-(C=CH2)- or

[0133] [ka] There are one, two, or three identical or different substituents selected from the group consisting of methylene groups that form a bond site (wherein * indicates a bonding site).

[0134] Within the scope of the present invention, halogens include fluorine, chlorine, bromine, and iodine, preferably fluorine or chlorine, and most preferably fluorine.

[0135] Examples of linear or branched alkyl residues substituted with halogens and containing 1 to 8 carbon atoms include:

[0136] Fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, bromomethyl group, dibromomethyl group, tribromomethyl group, 1-fluoroethyl group, 1-chloroethyl group, 1-bromoethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2-bromoethyl group, difluoroethyl group, for example, 1,2-difluoroethyl group, 1,2-dichloroethyl group, 1,2-dibromoethyl group, 2,2-difluoroethyl group, 2 ,2-dichloroethyl group, 2,2-dibromoethyl group, 2,2,2-trifluoroethyl group, heptafluoroethyl group, 1-fluoropropyl group, 1-chloropropyl group, 1-bromopropyl group, 2-fluoropropyl group, 2-chloropropyl group, 2-bromopropyl group, 3-fluoropropyl group, 3-chloropropyl group, 3-bromopropyl group, 1,2-difluoropropyl group, 1,2-dichloropropyl group, 1,2-dibromopropyl group, 2,3-difluoropropyl group, 2 ,3-dichloropropyl group, 2,3-dibromopropyl group, 3,3,3-trifluoropropyl group, 2,2,3,3,3-pentafluoropropyl group, 2-fluorobutyl group, 2-chlorobutyl group, 2-bromobutyl group, 4-fluorobutyl group, 4-chlorobutyl group, 4-bromobutyl group, 4,4,4-trifluorobutyl group, 2,2,3,3,4,4,4-heptafluorobutyl group, perfluorobutyl group, 2-fluoropentyl group, 2-chloropentyl group, 2-bromopen Examples include tyl group, 5-fluoropentyl group, 5-chloropentyl group, 5-bromopentyl group, perfluoropentyl group, 2-fluorohexyl group, 2-chlorohexyl group, 2-bromohexyl group, 6-fluorohexyl group, 6-chlorohexyl group, 6-bromohexyl group, perfluorohexyl group, 2-fluoroheptyl group, 2-chloroheptyl group, 2-bromoheptyl group, 7-fluoroheptyl group, 7-chloroheptyl group, 7-bromoheptyl group, and perfluoroheptyl group. Fluoroalkyl, difluoroalkyl, and trifluoroalkyl groups are particularly mentioned, with trifluoromethyl and mono- and difluoroethyl being preferred. Trifluoromethyl is particularly preferred.

[0137] Examples of cycloalkyl-substituted alkyl groups include the alkyl residues described above, which contain one to three, preferably one, cycloalkyl group, such as: cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethylcyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl2-cyclohexylethyl, 2- or 3-cyclopropylpropyl, 2- or 3-cyclobutylpropyl, 2- or 3-cyclopentylpropyl, 2- or 3-cyclohexylpropyl, etc. Cyclopropylmethyl is preferred.

[0138] Examples of heteroaryl-substituted alkyl groups include the alkyl residues described above containing one to three, preferably one (optionally substituted) heteroaryl groups, such as pyridinyl, pyridadinyl, pyrimidinyl, pyrazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiophenyl, or oxazolyl groups, such as pyridine-2-ylmethyl, pyridine-3-ylmethyl, pyridine-4-ylmethyl, 2-pyridine-2-ylethyl, 2-pyridine-1-ylethyl, 2-pyridine-1-ylethyl, 2-pyridine-2-ylethyl, 2-pyridine-1-ylethyl. These include lysine-3-ylethyl, pyridazine-3-ylmethyl, pyrimidine-2-ylmethyl, pyrimidine-4-ylmethyl, pyrazine-2-ylmethyl, pyrazole-3-ylmethyl, pyrazole-4-ylmethyl, pyrazole-5-ylmethyl, imidazole-2-ylmethyl, imidazole-5-ylmethyl, benzimidazole-2-ylmethyl, thiophene-2-ylmethyl, thiophene-3-ylmethyl, and 1,3-oxazole-2-ylmethyl.

[0139] Preferred alkyl groups are those substituted with a benzimidazolyl group, such as benzimidazole-2-ylmethyl and benzimidazole-2-ylethyl. Examples of amino-substituted alkyl residues include the alkyl residues described above, which contain one to three, preferably one (optionally substituted) amino groups, as defined below, for example, aminoalkyl (NH2-alkyl) or mono- or dialkylaminoalkyl groups, such as aminomethyl, 2-aminoethyl, 2- or 3-aminopropyl, methylaminomethyl, methylaminoethyl, methylaminopropyl, 2-ethylaminomethyl, 3-ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminoethyl, etc., and 3-aminopropyl, or optionally substituted alkyloxycarbonylamino groups, for example, formula

[0140] [ka] A alkyl group may be substituted with a group defined by (wherein R defines a phenyl group and forms a benzyloxycarbonylaminopropyl group).

[0141] The optionally substituted aminos according to the present invention are preferably amino(-NH2), optionally substituted mono- or dialkylaminos (alkyl-NH-, (alkyl)2N-), and for "alkyl", refer to the definition of optionally substituted alkyl above. Preferred are mono- or dimethylamino, mono- or diethylamino, and monopropylamino. Most preferred are the amino group (-NH2) and monopropylamino.

[0142] Furthermore, in the sense of the present invention, the carboxyl group represents a [-(C=O)-OH] group, and the aminocarbonyl group represents a [NH2-(C=O)-] group.

[0143] Optionally substituted alkoxys include optionally substituted alkyl-O- groups, and the above definition of alkyl groups may be referenced. Preferred alkoxy groups include linear or branched alkoxy groups containing up to six carbon atoms, such as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy, t-butyloxy, n-pentyloxy, i-pentyloxy, sec-pentyloxy, t-pentyloxy, 2-methylbutoxy, n-hexyloxy, i-hexyloxy, t-hexyloxy, sec-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethyl-1-methylpropyloxy, and cycloalkyloxy groups, such as cyclopentyloxy or cyclohexyloxy. Methoxy groups, ethoxy groups, n-propyloxy groups, and i-propyloxy groups are preferred. Methoxy and ethoxy groups are more preferred. Methoxy groups are particularly preferred.

[0144] Throughout the present invention, optionally substituted alkanediyls are preferably divalent linear or branched alkanediyl groups having 1 to 6 carbon atoms, preferably 1 to 4, more preferably 1, 2, or 3, and optionally having 1 to 3 substituents, preferably 1 or 2 substituents, selected from the group consisting of halogens, hydroxyl (-OH), oxo groups (C=O; forming a carbonyl or acyl group [-(C=O)-]), and alkyl groups as defined above, for example, preferably methyl. The following can be given as preferred examples: methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,2-diyl, butane-1,3-diyl, butane-2,3-diyl, butane-1,1-diyl, butane-2,2-diyl, butane-3,3-diyl, pentane-1,5-diyl, etc. Particularly preferred are methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, and butane-2,2-diyl. Most preferred are methylene, ethane-1,2-diyl, and propane-1,3-diyl.

[0145] Preferred substituted alkanediyl groups include hydroxy-substituted alkanediyl groups, such as hydroxy-substituted ethanediyl; oxo-substituted alkanediyl groups, such as oxo-substituted methylene or ethanediyl groups that form a carbonyl or acyl (acetyl) group; halogen-substituted alkanediyl groups, such as alkanediyl groups substituted with one or two halogen atoms selected from F and Cl, preferably 2,2-di-fluoroethanediyl; or alkanediyl groups substituted with a methyl group.

[0146] According to the present invention, A has the meaning of a linear or branched alkanediyl group as defined above. 1 , and R having the meaning of an optionally substituted alkyl group as defined above. 2Furthermore, along with the nitrogen atoms to which they are bonded, they can optionally form a 4 to 6 membered ring which may be substituted with 1 to 3 substituents as defined above. Therefore, A 1 and R 2 It may also form a group with the following formula.

[0147] [ka]

[0148] Among these, the formation of a (substituted or unsubstituted) four-membered ring is preferred, for example, very specifically,

[0149] [ka] The base is preferred. Among them, the bonding site on the left is X in formula (I) of the present invention. 1 and X 2 This shows the direct bonding site to the heterocyclic five-membered ring between and . The bonding site on the right has the meaning of an alkanediyl group as defined herein. 2 This shows the binding site to the group.

[0150] In formula (I) as defined in any part of this specification, n has the meaning of an integer from 1 to 3, including 1, 2, or 3, and thus represents a methylene group, an ethane-1,2-diyl group, or a propane-1,3-diyl group. More preferably, n is 1 or 2, and even more preferably, n is 1, representing a methylene group.

[0151] In the present invention, each substituent in formula (I) above may have the following meanings: A)X 1 is N or O; X 2 is N, S, or O; However, X 1 and X 2 They are different; Therefore, the formula

[0152] [ka] It forms a 5-membered heterocycle. (In the formula, * indicates the site of attachment to the aminocarbonyl group, and ** indicates A 1 (Indicates the binding site to the base.) B) n is an integer of 1, 2, or 3; preferably n is 1 or 2, and more preferably n is 1. C)R 1 teeth, - Hydrogen, and - Optionally substituted alkyl groups (as defined above) Selected from the group consisting of; Preferably, R 1 is hydrogen or methyl, more preferably R 1 It is hydrogen. D)R 2 teeth, - Hydrogen, and - Optionally substituted alkyl groups (as defined above) Selected from the group consisting of; Preferably, R 2 is hydrogen or a C1-C4 alkyl group, more preferably R 2 is hydrogen or methyl, and more preferably R 2 It is hydrogen. E)R 3 This represents one, two, or three optionally selected substituents, which are, - Halogens (as defined above), - Cyano, - Optionally substituted alkyl (as defined above), - Optionally substituted alkoxys (as defined above), and - Carboxyl group (as defined above) They may be independently selected from the group consisting of; Preferably, R 3This represents one or two optionally selected substituents, which are, - Halogen, - Cyano, - Alkyl (as defined above) which may be substituted with 1, 2, or 3 halogen atoms (as defined above), Optionally substituted alkoxys (as defined above), and Carboxyl group (as defined above) They may be selected independently from the following; Comfortable, R 3 This represents one or two optionally selected substituents, which are, - F and Cl, - Cyano, - Trifluoromethyl, - Methoxy, and - Carboxyl group They may be independently selected from the group consisting of; Furthermore, R 3 This is hydrogen, representing the unsubstituted terminal benzimidazolyl ring in formula (I). F)R 4 teeth, - Hydrogen, - Halogens (as defined above), - C1~C3-alkyl, and - Halogen-substituted alkyl (as defined above) Selected from the group consisting of; Preferably R 4 teeth, - Hydrogen - Cl, - Methyl, ethyl, isopropyl, and - Trifluoromethyl Selected from the group consisting of; Comfortable, R 4 teeth, - Hydrogen, - Cl, - Methyl, and - Trifluoromethyl Selected from the group consisting of; Comfortable, R 4 teeth, - Hydrogen, - Cl, and - Methyl Selected from the group consisting of; Furthermore, R 4 It is hydrogen. G)A 1 is Arcaneil; Preferably, A 1 is methylene or ethane-1,2-diyl, more preferably A 1 It is ethane-1,2-diyl. H)A 2 is Arcaneil; Preferably, A 2 is methylene, ethane-1,2-diyl, or propane-1,3-diyl; more, A 2 is methylene or ethane-1,2-diyl; Even more comfortably, A 2 It is ethane-1,2-diyl. I) or A 1 and R 2 Together with the nitrogen atoms to which they are bonded, they form a 4- to 6-membered ring that is optionally substituted as defined above; Among them, A 1 and R 2 These, together with the nitrogen atoms to which they are bonded, preferably form an optionally substituted four-membered ring as defined above; Among them, A 1 and R 2 These, along with the nitrogen atoms to which they are bonded, more preferably form an unsubstituted four-membered ring (azetidinyl ring).

[0153] The substituents of the compound (I) below may have the following meanings in particular: n may have any of the meanings defined in B) above, and the remaining substituents may have any of the meanings defined in A) and C) through I). R 1The substituents may have any of the meanings defined in C) above, and the remaining substituents may have any of the meanings defined in A), B), and D) through I). R 2 The substituents may have any of the meanings defined in D) above, and the remaining substituents may have any of the meanings defined in A) through C) and E) through H) or I). R 3 The substituents may have any of the meanings defined in E) above, and the remaining substituents may have any of the meanings defined in A) through D) and F) through I). R 4 The substituents may have any of the meanings defined in F) above, and the remaining substituents may have any of the meanings defined in A) through E) and G) through I). A 1 The substituents may have any of the meanings defined in G) above, and the remaining substituents may have any of the meanings defined in A) through F) and H) or I). A 2 The substituents may have any of the meanings defined in H) above, and the remaining substituents may have any of the meanings defined in A) through G) and I). R 2 and A 1 The substituents may have any of the meanings defined in I), and the remaining substituents may have any of the meanings defined in A) through C), E), F), and H).

[0154] In a preferred embodiment of the present invention, a compound of general formula (I) is defined as follows: X 1 is N or O; X 2 is N, S, or O; However, X 1 and X 2 They are different; R 1 is hydrogen; n is 1, 2, or 3; A 1is methylene or ethane-1,2-diyl; A 2 is methylene, ethane-1,2-diyl, or propane-1,3-diyl; R 2 is either hydrogen or a C1-C4 alkyl group; or A 1 and R 2 These, along with the nitrogen atoms to which they are bonded, form a optionally substituted four-membered ring; R 3 This represents one or two optionally selected substituents, which are, - Halogen, - Cyano, - Alkyl which may be substituted with 1, 2, or 3 halogen atoms, - Optionally substituted alkoxys, and - Carboxyl group They may be independently selected from the group consisting of; R 4 teeth, - Hydrogen - Cl, - Methyl, ethyl, isopropyl, and - Trifluoromethyl It is selected from the group consisting of the following.

[0155] In a further preferred embodiment of the present invention, a compound of general formula (I) is defined as follows: X 1 is N or O; X 2 is N, S, or O; However, X 1 and X 2 They are different; R 1 is hydrogen; n is either 1 or 2; A 1 is methylene or ethane-1,2-diyl; A 2is methylene, ethane-1,2-diyl, or propane-1,3-diyl; R 2 is hydrogen or methyl; or A 1 and R 2 together with the nitrogen atom to which they are attached form an unsubstituted 4-membered ring; R 3 represents one or two optional substituents, which are - F and Cl, - cyano, - trifluoromethyl, - methoxy, and - carboxyl group and may be independently selected from the group consisting of; R 4 is - hydrogen, - Cl, - methyl, and - trifluoromethyl and is selected from the group consisting of.

[0156] In a further preferred embodiment of the present invention, the compound of general formula (I) is defined by X 1 is N or O; X 2 is N, S, or O; provided that X 1 and X 2 are different; R 1 is hydrogen; n is 1; A 1 is methylene or ethane-1,2-diyl; A 2 is methylene, ethane-1,2-diyl, or propane-1,3-diyl; R 2 is hydrogen; or A 1 and R 2 together with the nitrogen atom to which they are attached form an unsubstituted 4-membered ring; R 3 represents hydrogen and thus forms an unsubstituted terminal benzimidazolyl ring; R 4 is - hydrogen, - Cl, and - methyl selected from the group consisting of.

[0157] In a further preferred embodiment of the present invention, the compound of general formula (I) is defined by X 1 is N or O; X 2 is N, S, or O; provided that X 1 and X 2 are different; R 1 is hydrogen; n is 1; A 1 is methylene or ethane-1,2-diyl; A 2 is methylene, ethane-1,2-diyl, or propane-1,3-diyl; R 2 is hydrogen; or or A 1 and R 2 together with the nitrogen atom to which they are attached form an unsubstituted 4-membered ring; R 3 represents hydrogen and thus forms an unsubstituted terminal benzimidazolyl ring; and<000089\0>R 4 is hydrogen.

[0158] In a further aspect, the present invention is a novel use and method of treatment as defined herein, wherein a compound of formula (I), or a salt, solvate, hydrate, and polymorph thereof, is selected from the compounds of formula (I) as shown above, n = 1; R 3 = hydrogen; R 4 = hydrogen; A 1 = methylene or ethane-1,2-diyl; A 2 = methylene, ethane-1,2-diyl, or propane-1,3-diyl; or or A 1 and R 2 together with the nitrogen atom to which they are attached form an optionally substituted 4-membered ring, forming a compound according to formula (II) or (III):

[0159]

Chemical formula

[0160] Preferably, in formula (II) and (III), X 1 and X 2 have the meanings as defined above in (A).

[0161] In formula (II), R 1 and R 2 are preferably hydrogen.

[0162] In formula (III), R 1 is preferably hydrogen and m is preferably 2.

[0163] In a further preferred embodiment of the present invention, the compound of general formula (II) is X 1 and X 2 are selected from N and O and are different; R 1 = Hydrogen; R 2 = Hydrogen; l=1; and m=2 Defined by:

[0164] In a further preferred embodiment, the present invention relates to novel uses and methods of treatment as defined herein, wherein the compound according to formula (I) is used in the form of its pharmaceutically acceptable salt, or its solvates, hydrates, and polymorphs.

[0165] For preferred pharmaceutically acceptable salts of the compounds of formulas (I), (II), and (III) as defined in any of these Specifications, please refer to international applications WO2017 / 068089, WO2017 / 068090, and in particular WO2018 / 192973. The definitions of pharmaceutically acceptable salts disclosed therein are incorporated herein by reference.

[0166] Further compounds that act as ferroportin inhibitors and are suitable for the treatment of MDS as defined herein are those described in WO2020 / 123850A1, which is incorporated herein by reference in its entirety. Specific compounds from WO2020 / 123850A1 that are suitable for the treatment of MDS as defined herein include:

[0167] [Table 3] You may choose from the group consisting of the following:

[0168] In a further preferred embodiment, the present invention relates to a use and method of treatment as defined herein, wherein a pharmaceutically acceptable salt of a compound of formula (I), (II), or (III), or a compound according to WO2020 / 123850A1, is selected from salts with acids from the group consisting of benzoic acid, citric acid, fumaric acid, hydrochloric acid, lactic acid, malic acid, maleic acid, methanesulfonic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and toluenesulfonic acid. A preferred acid is selected from the group consisting of citric acid, hydrochloric acid, maleic acid, phosphoric acid, and sulfuric acid.

[0169] In a further preferred embodiment, the present invention relates to novel uses and methods of treatment as defined herein, wherein a pharmaceutically acceptable salt of a compound of formula (I), (II), or (III) is selected from monosalts (1:1 salts), triplesalts (1:3 salts), and salts characterized by a ratio of compound (I), (II), or (III) to an acid of 1 to 2:1 to 3; and uses and methods thereof, including solvates, hydrates, and polymorphs.

[0170] Among these, salts of compound (I), (II), or (III) may be characterized by a base:acid ratio, i.e., compound (I), (II), or (III):acid as defined above, being in the range of 1.0 to 2.0 (mol, base):1.0 to 3.0 (mol, acid). In a particular embodiment, the selected base:acid ratio is 1.0 to 2.0 (mol, base):1.0 to 2.0 (mol, acid).

[0171] Specific examples include base:acid, i.e., compound (I), (II), or (III):acid as defined above, in the following ratios: 1.0 (mol, base): 1.0 (mol, acid); 1.0 (mol, base): 1.25 (mol, acid): 1.0 (mol, base) : 1.35 (mol, acid); 1.0 (mol, base): 1.5 (mol, acid); 1.0 (mol, base) : 1.75 (mol, acid); 1.0 (mol, base) : 2.0 (mol, acid); 1.0 (mol, base) : 3.0 (mol, acid); and 2.0 (mol, base) : 1.0 (mol, acid).

[0172] Among them, salts with a base:acid ratio of 1:1 are also referred to as "mono-salts" or "1:1 salts". For example, the mono-HCl salt is also referred to as 1HCl or 1HCl salt.

[0173] Among them, salts with a base:acid ratio of 1:2 are also referred to as "di-salts" or "1:2 salts". For example, the di-HCl salt is also referred to as 2HCl or 2HCl salt.

[0174] Among them, salts with a base:acid ratio of 1:3 are also referred to as "tri-salts", "triple salts", or "1:3 salts". For example, the tri-HCl salt is also referred to as 3HCl or 3HCl salt.

[0175] Salts with a base:acid ratio of 1:1.25 are also referred to as "1:1.25 salts".

[0176] Salts with a base:acid ratio of 1:1.35 are also referred to as "1:1.35 salts".

[0177] Salts with a base:acid ratio of 1:1.5 are also referred to as "1:1.5 salts".

[0178] Salts with a base:acid ratio of 1:1.75 are also referred to as "1:1.75 salts".

[0179] Salts with a base:acid ratio of 2:1 are also referred to as "hemi-salts" or "2:1 salts".

[0180] Salts of the compounds of formula (I), (II), or (III) according to the present invention may exist in amorphous, polymorphic, crystalline, and / or semicrystalline (partially crystalline) forms, as well as in the form of solvates of the salts. Preferred salts of the compounds of formula (I), (II), or (III) according to the present invention exist in crystalline and / or semicrystalline (partially crystalline) forms, as well as in the form of these solvates.

[0181] The preferred degree of crystallinity of a salt or salt solvate may be determined by conventional analytical methods, for example, by various X-ray methods that allow for clear and simple analysis of salt compounds. In particular, the grade of crystallinity may be determined or confirmed by powder X-ray diffraction (reflection) or powder X-ray diffraction (transfer) (PXRD). With respect to crystalline solids having the same chemical composition, differently obtained crystal lattices are summarized by the term polymorph. With respect to solvates, hydrates, and polymorphs and salts having a specific degree of crystallinity, please refer to international application WO2018 / 192973, which is incorporated herein by reference.

[0182] In a further preferred embodiment, the present invention relates to the use and method of treatment as defined herein, wherein a compound of formula (I), (II), or (III) is:

[0183] [Table 4] The present invention relates to the use and methods of selecting from the group consisting of pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof.

[0184] In a further preferred embodiment, the present invention relates to novel uses and methods of treatment as defined herein, wherein a compound of formula (I), (II), or (III) is:

[0185] [Table 5] The present invention relates to the use and methods of selecting from the group consisting of pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof.

[0186] In a further preferred embodiment, the present invention relates to novel uses and methods of treatment as defined herein, wherein a compound of formula (I), (II), or (III) is:

[0187] [Table 6] This relates to uses and methods selected from the group consisting of the following.

[0188] In a further preferred embodiment, the present invention relates to novel uses and methods of treatment as defined herein, wherein a compound of formula (I), (II), or (III) is:

[0189] [Table 7] The present invention relates to the use and methods of selecting from the group consisting of pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof.

[0190] In a more preferred embodiment of the present invention, the compound of formula (I), (II), or (III) is:

[0191] [ka] Furthermore, a selection is made from the group consisting of pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof.

[0192] In a further preferred embodiment of the present invention, the compound of formula (I), (II), or (III) is a salt of the following: formula

[0193] [ka] A 1:1 sulfate salt containing; formula

[0194] [ka] A 1:1 phosphate containing; 2:1 phosphate (hemiphosphate);

[0195] [ka] formula

[0196] [ka] HCl salt having a 1:3 ratio and these polymorphs It is selected from the group consisting of the following.

[0197] As described in WO2017 / 068089, WO2017 / 068090, and WO2018 / 192973, the compound of formula (I) acts as a ferroportin inhibitor. For the ferroportin inhibitory activity of the compound, please refer to the aforementioned international applications.

[0198] Pharmaceuticals containing ferroportin inhibitor compounds Further aspects of the present invention relate to pharmaceuticals or pharmaceutical compositions comprising one or more compounds of formula (I), (II), or (III) as defined herein, for novel uses and methods of treating MDS as defined herein.

[0199] Such pharmaceuticals may further comprise one or more pharmaceutical carriers and / or one or more excipients and / or one or more solvents.

[0200] Preferably, the pharmaceutical product is in the form of an oral medication, as defined above.

[0201] Preferably, the pharmaceutical carrier and / or auxiliary agent and / or solvent is selected from compounds suitable for preparing an oral medication form.

[0202] The pharmaceutical composition comprises, for example, up to 99% by weight, or up to 90% by weight, or up to 80% by weight, or up to 70% by weight of the ferroportin inhibitor compound of the present invention, the remainder of which is formed by a pharmacokinetically acceptable carrier and / or adjutant and / or solvent and / or optionally further pharmaceutically active compound.

[0203] Among these, pharmaceutically acceptable carriers, auxiliary substances, or solvents are common pharmaceutical carriers, auxiliary substances, or solvents, and include a variety of organic or inorganic carriers and / or auxiliary materials that are conventionally used for pharmaceutical purposes, particularly in solid pharmaceutical formulations. Examples include excipients, e.g., saccharose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talcum, calcium phosphate, calcium carbonate; binders, e.g., cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, acacia gum, polyethylene glycol, saccharose, starch; disintegrants, e.g., starch, hydrolyzed starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate; lubricants, e.g., magnesium stearate, talcum, sodium lauryl sulfate; flavorings, e.g., citric acid, menthol, glycine, orange powder; preservatives, e.g., sodium benzoate, sodium bisulfite, parabens (e.g., methylparaben, ethylparaben, propylparaben, butylparaben); stabilizers, e.g., citric acid, sodium citrate, acetic acid, and the titriplex series, e.g., polycarboxylic acids from diethylene pentaacetic acid (DTPA) Acids; suspending agents, e.g., methylcellulose, polyvinylpyrrolidone, aluminum stearate; dispersants; diluents, e.g., water, organic solvents; waxes, fats, and oils, e.g., beeswax, cocoa butter; polyethylene glycol; white petrolatum; and so on.

[0204] Liquid pharmaceutical formulations, such as solutions, suspensions, and gels, typically contain a liquid carrier, e.g., water and / or a pharmaceutically acceptable organic solvent. Furthermore, such liquid formulations may also contain pH adjusters, emulsifiers or dispersants, buffers, preservatives, wetting agents, gelling agents (e.g., methylcellulose), dyes, and / or flavoring agents, e.g., those defined above. The composition may be isotonic, i.e., it may have the same osmotic pressure as blood. The isotonicity of the composition may be adjusted by using sodium chloride and other pharmaceutically acceptable agents, e.g., dextrose, maltose, boric acid, sodium tartrate, propylene glycol, and other inorganic or organic soluble substances. The viscosity of the liquid composition may be adjusted using a pharmaceutically acceptable thickener, e.g., methylcellulose. Other suitable thickeners include, for example, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, and carbomer. The preferred concentration of the thickener will depend on the chosen agent.

[0205] A pharmaceutically acceptable preservative may be used to extend the shelf life of the liquid composition. Benzyl alcohol may be preferred, but several other preservatives, including, for example, parabens, thimerosal, chlorobutanol, and benzalkonium chloride, may also be used.

[0206] Combination therapy A further object of the present invention relates to a pharmaceutical or combination preparation comprising one or more ferroportin inhibitor compounds as defined herein and at least one further pharmaceutically active compound ("combination therapy compound"), preferably an additional active compound useful in the treatment of MDS as defined herein. Preferred combination therapy compounds are certain compounds used in the prevention and treatment of ineffective erythropoiesis, including erythropoietin stimulants, erythropoietin (EPO), and antibiotics, as well as immunosuppressants. Known drugs used in the treatment of MDS include lenalidomide, antithymocyte globulin, and azacitidine. Chemotherapy, followed by stem cell transplantation from a donor, is an option for further treatment for MDS patients. Further preferred combination therapy compounds are selected from pharmaceuticals for treating iron overload and related symptoms. Most preferred combination therapy compounds are iron chelates, or compounds for preventing and treating any of the conditions, disorders, or diseases associated with or resulting from iron overload and MDS. A suitable combination therapeutic drug compound (co-drug) may be selected from pharmaceutically active compounds for preventing and treating MDS and related symptoms. Particularly preferred are co-drugs for treating ineffective hematopoiesis, especially ineffective erythropoiesis, such as erythropoietin stimulants or erythropoietin. In further embodiments, at least one additional pharmaceutically active combination therapeutic compound may be selected from drugs for alleviating iron overload (e.g., Tmprss6-ASO), as well as iron chelators, particularly curcumin, SSP-004184, deferritrin, deferasirox, deferoxamine, and deferipron, as well as hydroxyurea, and JAK2 inhibitors.

[0207] Further preferred combination therapeutic compounds may be selected from drugs for treating MDS, such as lenalidomide, antithymocyte globulin, and azacitidine, or antibiotics, as well as immunosuppressants.

[0208] Further possible codrugs include erythrocyte maturators, e.g., ruspatercept, or other erythrocyte maturators / erythrocyte stimulants, e.g., EPO, epoetin, or darbepoetin, or synthetic human hepcidin (LJPC-401), hepcidin peptide mimetic PTG-300, and antisense oligonucleotides targeting Tmprss6 (IONIS-TMPRSS6-LRX).

[0209] In further embodiments, the present invention relates to the use of a ferroportin inhibitor compound as defined herein in the medical treatment of MDS, wherein a ferroportin inhibitor compound as defined herein is administered to a patient in need of it in combination therapy with one or more of the combination therapy compounds (codrugs) defined above, in fixed or non-fixed dose combinations for continuous use. Such combination therapy includes co-administration of a ferroportin inhibitor compound as defined herein with at least one additional pharmaceutically active compound (drug / combination therapy compound).

[0210] In fixed-dose combination therapy, the combination therapy includes co-administration of a fixed-dose formulation of a ferroportin inhibitor compound as defined herein and at least one additional pharmaceutically active compound.

[0211] In free-dose combination therapy, combination therapy includes co-administration of a ferroportin inhibitor compound as defined herein and at least one additional pharmaceutically active compound, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds, at free doses of the individual compounds.

[0212] In a preferred embodiment, the combination therapy includes concurrent administration of an oral ferroportin inhibitor and erythropoietin, as described herein by example compound number 127.

[0213] In further embodiments, the combination therapy includes concurrent administration of an oral ferroportin inhibitor and ruspatercept, as described herein by example compound number 127.

[0214] In further embodiments, the combination therapy includes concurrent administration of an oral ferroportin inhibitor according to Example Compound No. 127 described herein and the iron chelating agent deferasirox.

[0215] Further embodiments of the present invention relate to combination therapies described herein, wherein the ferroportin inhibitor compound is selected from those described in WO2020 / 123850A1, particularly from one of the specific example compounds described above. Preferably, such combination therapy comprises concurrent administration of the ferroportin inhibitor compound and the iron chelating agent deferasirox. [Brief explanation of the drawing]

[0216] [Figure 1] Anemia in 3-month-old MDS mice. Blood parameters (hemoglobin, red blood cell count, hematocrit, mean cell volume, and white blood cell count) in 3-month-old wild-type (WT) control mice and myelodysplastic (MDS) mice. [Figure 2]MDS mice show ultra - mild, mild, and moderate anemia at 3 months of age. Blood parameters (hemoglobin, red blood cell count, hematocrit, and white blood cell count) in wild - type (WT) control mice and myelodysplastic (MDS) mice at 3 months of age according to anemia levels (no anemia / ultra - mild anemia: Hb > 13 g / dl; mild anemia: 10 g / dl < Hb < 13 g / dl; moderate anemia: 8 g / dl < Hb < 10 g / dl; severe anemia: Hb < 8 g / dl). [Figure 3] Fpn127 treatment reduces serum iron levels and NTBI formation in MDS mice. Measurement of total iron (SFBC) and non - transferrin - bound iron (NTBI) in sera of wild - type (WT) control mice and myelodysplastic (MDS) mice at 6 months of age untreated or treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3 months. [Figure 4] Fpn127 treatment prevents iron overload in MDS mice. Iron contents in the liver, kidney, and spleen of wild - type (WT) control mice and myelodysplastic (MDS) mice at 6 months of age untreated or treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3 months. [Figure 5] Fpn127 treatment improves anemia in MDS mice. Red blood cell parameters (hemoglobin, red blood cell count, hematocrit, mean cell volume, mean cell hemoglobin, and reticulocyte count) in wild - type (WT) control mice and myelodysplastic (MDS) mice at 6 months of age untreated or treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3 months. [Figure 6] Fpn127 treatment shows a tendency to reduce the progression to leukemia in MDS mice. White blood cell parameters (white blood cell, platelet, neutrophil, lymphocyte, and monocyte counts) in wild - type (WT) control mice and myelodysplastic (MDS) mice at 6 months of age untreated or treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3 months. [Figure 7]Fpn127 treatment improves bone marrow erythrocyte maturation in MDS mice. The progression from immature to mature erythrocytes was monitored by progressive loss of CD71 expression on bone marrow Ter119+ erythrocytes in untreated or 6-month-old wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3 months. [Figure 8] Fpn127 treatment improves bone marrow erythrocyte maturation in MDS mice. Erythrocyte maturation was assessed by assessing erythrocyte populations I to V (I: proerythroblasts; II: basophilic erythroblasts; III: polychromatic erythroblasts; IV: orthochromatic erythroblasts / reticulocytes; V: erythrocytes) via progressive loss of CD44 expression on bone marrow Ter119+ erythrocytes in untreated or 6-month-old wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3 months. [Figure 9] Fpn127 treatment improves splenic erythrocyte maturation in MDS mice. The progression from immature to mature erythrocytes was monitored by progressive loss of CD71 expression on splenic Ter119+ erythrocytes in untreated or 6-month-old wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3 months. [Figure 10] Fpn127 treatment improves splenic erythrocyte maturation in MDS mice. Erythrocyte maturation was assessed by assessing erythrocyte populations I to V (I: proerythroblasts; II: basophilic erythroblasts; III: polychromatic erythroblasts; IV: orthochromatic erythroblasts / reticulocytes; V: erythrocytes) via progressive loss of CD44 expression on splenic Ter119+ erythrocytes in untreated or 6-month-old wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3 months. [Figure 11]Treatment with Fpn127 improves erythrocyte maturation in MDS mice. The improvement in erythrocyte maturation by Fpn127 was confirmed by monitoring the loss of CD71 expression on bone marrow and spleen Ter119+ erythrocytes in untreated or 6-month-old wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3 months. [Figure 12] Fpn127 treatment improves anemia in MDS mice by reducing oxidative stress and apoptosis in erythrocyte precursors. Iron accumulation (unstable iron), oxidative stress (ROS), and apoptosis (annexin V) were monitored by flow cytometry in bone marrow and spleen Ter119+ erythrocytes of untreated or 6-month-old wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3 months. [Figure 13] Fpn127 treatment improves the overall status of hematopoietic LSK cells in MDS mice. Cell percentage, iron accumulation (unstable iron), oxidative stress (ROS), apoptosis (annexin V), and double-strand breaks (γH2AX) were monitored by flow cytometry in bone marrow hematopoietic Lin-Sca-1+ ckit+ (LSK) cells from untreated or 6-month-old wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml Fpn127 (MDS+VIT) for 3 months. [Figure 14] Fpn127 treatment improves anemia in aged MDS mice. Red blood cell parameters (hemoglobin, red blood cell count, hematocrit) in untreated or 8-10 month old wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3-5 months. [Figure 15]Fpn127 treatment reduces leukemia-related deaths in aged MDS mice. WBC counts in untreated or 8-10 month old wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml Fpn127 (MDS + VIT) for 3-5 months. As shown, two untreated MDS mice died from leukemia, and simultaneously, two Fpn127-treated MDS mice died from MDS, which was also suggested by lower WBC counts. [Figure 16] VIT-2763 treatment improves anemia in MDS mice. Long-term monitoring of blood parameters (hemoglobin - Hb, hematocrit - HCT, red blood cells - RBC) in untreated or myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 months of age. [Figure 17] VIT-2763 treatment improves anemia in MDS mice. Improvements in Hb (Δ, delta), HCT, and RBC in untreated or treated myelodysplastic (MDS) mice initiated with 0.5 mg / ml VIT-2763 (MDS+VIT) at 3 months of age. Δ is shown at 2, 3, and 4 months after treatment (5, 6, and 7 months of age). [Figure 18] Treatment with VIT-2763 delays the progression of leukemia in MDS mice. Long-term monitoring of total leukocytes, monocytes, and neutrophils in untreated or myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 months of age. [Figure 19] VIT-2763 treatment improves the survival of MDS mice. Kaplan-Meier curves in untreated or myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 months of age. [Figure 20]Treatment with VIT-2763 reduces immature cells in the bone marrow of MDS mice. Percentages of cKit+ and Lin+ cKit+ cells in the bone marrow of untreated or wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 to 6 months of age. Immature blasts are within the range of the Lin+ cKit+ population. [Figure 21] Treatment with VIT-2763 reduces myeloid proliferation in the bone marrow of MDS mice. Percentages of CD45+ immune cells, CD11b+ myeloid cells, and CD3+ CD19+ lymphocyte cells in the bone marrow of untreated or wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 to 6 months of age. [Figure 22] Treatment with VIT-2763 reduces myeloid proliferation in the bone marrow of MDS mice. Percentage of total CD11b+Ly6C+Ly6G+ myeloid-derived suppressor cells (MDSCs), CD11b+Ly6C+ monocytes, and CD11b+Ly6G+ granulocyte MDSCs in the bone marrow of untreated or wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 to 6 months of age. [Figure 23] Treatment with VIT-2763 improves macrophage counts in the bone marrow of MDS mice. Percentages of total macrophages, erythroblasts, and HSC macrophages in the bone marrow of untreated or wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 to 6 months of age. [Figure 24] Treatment with VIT-2763 limits myelomacrophage-mediated inflammation in MDS mice. TNFα and IL-1β production in total myelomacrophage macrophages in untreated or wild-type (WT) control mice and myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 to 6 months of age. [Figure 25]VIT-2763 treatment improves anemia in MDS mice. Long-term monitoring of blood parameters (hemoglobin - Hb, hematocrit - HCT, red blood cells - RBC) in untreated or myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 5 months of age. [Figure 26] Treatment with VIT-2763 delays the progression of leukemia in MDS mice. Long-term monitoring of leukocytes in untreated or myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 5 months of age. [Figure 27] VIT-2763 treatment improves the survival of MDS mice. Kaplan-Meier curves in untreated or myelodysplastic (MDS) mice treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 5 months of age. [Modes for carrying out the invention]

[0217] In the figure, "VIT-2763" or "VIT" refers to the test compound Fpn127 (Example Compound Number 127). [Examples]

[0218] The present invention is illustrated in more detail by the following examples. The examples are for illustrative purposes only, and those skilled in the art can extend the application of specific examples to further ferroportin inhibitor compounds according to the present invention.

[0219] I. Examples of ferroportin inhibitor compounds For the preparation of the specific ferroportin inhibitors described herein, example compound numbers 1, 2, 4, 40, 94, 118, 126, 127, 193, 206, 208, and 233, and for the preparation of pharmaceutically acceptable salts thereof, please refer to international applications WO2017 / 068089, WO2017 / 068090, and WO2018 / 192973.

[0220] For the preparation of specific ferroportin inhibitor compounds described in WO2020 / 123850A1, please refer to the preparation method described in the aforementioned international application WO2020 / 123850A1.

[0221] II. Pharmacological assay II.1 Introduction Orally bioavailable ferroportin inhibitors, such as the clinical-stage compound Example No. 127 (Fpn127), have been shown to improve ineffective erythropoiesis, alleviate anemia, and prevent NTBI formation and hepatic iron overload in a mouse MDS model. The ferroportin inhibitor, e.g., the clinical-stage compound Example No. 127, further restricts iron utilization and reactive oxygen species (ROS) in erythrocyte precursors, thus preventing apoptosis and improving ineffective erythropoiesis. Consequently, anemia is improved by a greater number of RBCs with extended lifespan, and tissue oxygenation is enhanced.

[0222] Based on this, the inventors of the present invention have found that the described ferroportin inhibitors are particularly efficient in treating MDS, especially in the treatment of ineffective erythropoiesis. Patients presenting with MDS suffering from ineffective erythropoiesis have reduced Hb levels, which are usually treated with blood transfusions (BT) and lead to severe iron overload. In a further embodiment, prevention of intestinal iron absorption by ferroportin inhibitors during the interval between transfusions helps reduce further iron load in MDS patients. Furthermore, non-transferrin-bound iron (NTBI) is released by macrophages recycling damaged RBCs, causing oxidative stress and vascular damage. MDS patients have been observed to have elevated NTBI levels, and this applies to transfused and non-transfused MDS patients.

[0223] The oral ferroportin inhibitor according to the present invention, for example, compound number 127, a ferroportin inhibitor, has been found to have the potential to prevent these harmful effects by sequestering iron in macrophages. Given the beneficial effects achieved with ferroportin inhibitor therapy on hemoglobin, NTBI, and LPI levels in MDS patients, the ferroportin inhibitor compounds of the present invention have the potential to improve hematological values ​​in MDS patients and, in a further embodiment, can achieve a reduction in transfused RBC units, thus reducing the transfusion burden on MDS patients.

[0224] II.2 Evaluation of the ferroportin inhibitor compound Fpn127 in a preclinical MDS mouse model Summary of background Patients with myelodysplastic syndrome (MDS) tend to develop iron overload due to ineffective erythrocyte formation, which promotes increased iron absorption, and restoring anemia in this patient population is often essential for chronic transfusions. The effects of the ferroportin inhibitor compounds according to the present invention in transfusion-independent and transfusion-dependent MDS were evaluated using the example compound Fpn127, with the aim of demonstrating that iron restriction limits iron absorption, reduces the formation of non-transferrin-bound iron (NTBI) and tissue iron deposition, and mediates its redistribution, and whether the ferroportin inhibitors of the present invention are beneficial in reducing the overall iron burden in transfusion-independent MDS by reducing iron influx into the body through erythrocyte-driven hepcidin inhibition. Lower iron levels and NTBI are thought to affect MDS by reducing iron-driven cytotoxicity (cell death, ROS production) and organ damage, improving bone marrow function with positive effects on the microenvironment and erythrocyte formation, and limiting oxidative damage to hematopoietic stem cells (HSCs). In transfusion-dependent MDS, in addition to reduced iron absorption, FPN inhibition is thought to offer a strategy to limit RBC-led iron redistribution, causing its redistribution from iron-sensitive tissues to recycling macrophages. This is thought to reduce NTBI levels and consequently provide beneficial effects in transfusion-dependent MDS by reducing NTBI exposure, particularly in the bone marrow. Furthermore, the combination of ferroportin inhibitors according to the present invention, administered in combination therapy using iron chelation, is thought to provide a novel and more effective strategy for removing iron from the body in transfusion-dependent MDS conditions.

[0225] Determination of the steady-state effect of Fpn127 administration on iron restriction in a mouse model of MDS. The ferroportin inhibitor compound Fpn127 was tested in NUP98-HOXD13MDS mice. Fpn127 was administered at a concentration of 0.5 mg / ml in drinking water containing 1% glucose.

[0226] Preventive effect: To study the protective effect of the ferroportin inhibitor according to the present invention against the progressive development of iron overload and related toxicities, all 15 MDS mice at 3 months of age were treated with the example compound Fpn127 and compared with 15 untreated MDS mice and wild-type controls that matched in age and gender (total of 3 replicate experiments). Mice at 3 to 6 months of age were treated for 3 months. During the treatment period, 2 untreated and 1 treated MDS mice died.

[0227] MDS mice at 3 months of age already show some anemia, which supports starting the ferroportin inhibitor in treatment from 3 months until erythropoiesis and anemia are improved (Figure 1).

[0228] Approximately 60 - 70% of MDS mice show mild to moderate anemia at 3 months of age. According to Hb levels, MDS mice at 3 months of age can be divided into 3 groups showing ultra-mild, mild, and moderate anemia (no anemia / ultra-mild anemia: Hb > 13 g / dl; mild anemia: 10 g / dl < Hb < 13 g / dl; moderate anemia: 8 g / dl < Hb < 10 g / dl) (Figure 2). Rarely, MDS mice show severe anemia (severe anemia: Hb < 8 g / dl) at 3 months of age. This reflects the situation of MDS patients in which 70 - 80% show anemia of varying severity at the time of diagnosis.

[0229] In MDS mice treated with Fpn127 from 3 to 6 months of age for 3 months, the following parameters were monitored: · Serum iron levels and NTBI; · Iron accumulation in the liver; · Anemia and blood parameters; · Erythropoiesis - including RBC maturation, erythroid progenitor apoptosis, and ROS; · Hematopoietic stem cells - including apoptosis, ROS, and DNA damage; · Bone marrow macrophages and myeloid-derived suppressor cells (not shown).

[0230] Figures 3 through 15 show the results obtained as the average of three independent experiments.

[0231] Serum iron levels and NTBI: Serum iron and NTBI levels were elevated in MDS mice compared to control mice and significantly decreased with Fpn127 treatment (Figure 3).

[0232] Iron accumulation in the liver: Iron content in the liver and kidneys was elevated in MDS mice compared to controls and significantly decreased with Fpn127 treatment (both males and females) (Figure 4). In contrast, splenic iron was slightly elevated, though not significantly, in MDS mice, due to enhanced iron absorption and slight erythrocyte proliferation, and further elevated with VIT treatment, consistent with VIT-mediated FPN inhibition and splenic macrophage iron accumulation (Figure 4).

[0233] Anemia and blood parameters: Hb, RBC, and HCT levels were decreased in MDS mice compared to control animals and were significantly improved by Fpn127 treatment. Reticulocytes showed an improving trend after Fpn127 treatment. MCV and MCH remained unchanged (Figure 5).

[0234] White blood cell parameters: WBC count decreases in MDS mice. Only MDS mice that develop a specific type of leukemia show a significant increase in WBC count in both lymphocytes and myeloid lineages. Three mice in the untreated group show an increase in WBC count (one of which developed leukemia), but only one mouse in the Fpn127-treated group shows an increasing trend in WBC count. Reticulocyte count shows an improving trend after Fpn127 treatment. Platelet count decreases in MDS mice and remains unchanged after Fpn127 treatment (Figure 6).

[0235] Erythropoiesis: Erythropoiesis was significantly reduced in both the bone marrow and spleen of MDS mice compared to controls and was significantly improved by Fpn127 treatment. Erythrocyte maturation was improved by iron restriction, as assessed through both CD71 and CD44 loss to Ter119+ cells, resulting in a decrease in cell percentage in the immature population and an increase in that of the mature population (Figures 7 to 10). Overall, this indicates improved RBC maturation and reduced ineffective erythropoiesis (in both bone marrow and spleen). This is confirmed by a significant decrease in CD71 expression on Ter119+ erythrocyte precursors, particularly in the bone marrow (Figure 11).

[0236] Erythropoiesis: The improvement in anemia after Fpn127 treatment is associated with a reduction in ROS formation and apoptosis in Ter119+ erythrocyte precursors, suggesting that the limitation of oxidative stress and improved cell viability mechanistically contribute to improved erythropoiesis (Figure 12).

[0237] Hematopoietic stem cells: Iron restriction by Fpn127 treatment is associated with an overall improvement in the status of hematopoietic LSK stem cells (Figure 13). The LSK cell pool is reduced in MDS mice and may be preventable by Fpn127 treatment. LSK cells in Fpn127-treated MDS mice show reduced iron accumulation, reduced ROS production, and improved cell survival (reduced apoptosis), and these changes in events suggest increased preservation of the HSC pool. Furthermore, LSK cells in Fpn127-treated MDS mice show reduced double-strand breaks (DSBs; decreased γH2AX) compared to untreated animals. DSBs may contribute to leukemia progression through the accumulation of mutations in HSPCs, which acquire an increased tendency towards proliferation and clonality.

[0238] Rescue effect: To study the rescue effect of the ferroportin inhibitor according to the present invention against established iron overload and associated toxicity in MDS, a total of eight 5-month-old MDS mice were treated with the example compound Fpn127 and compared to eight age- and sex-matched untreated MDS mice and wild-type controls (one experiment). Mice were treated from 5 months of age onward. During the treatment period, three untreated and three treated MDS mice died. In this cohort of mice, no improvement in anemia was observed 3 months after treatment (5 to 8 months of age). However, the results for mice at 9 and 10 months of age suggest that some mice were able to benefit from Fpn127 treatment with partial improvement in anemia (Figure 14). The mice died from different causes—two untreated MDS mice died from AML and TLL; and two Fpn127-treated MDS mice died from MDS without apparent progression to leukemia (Figure 15). The other two mice died without an opportunity to monitor their parameters. This cohort was preserved for further observation and monitoring, therefore molecular analysis of the 5-month-old treated mice was not obtained. To better track the modulation of individual blood parameters, two cohorts of mice, treated at 3 and 5 months of age respectively, will be analyzed monthly over the long term, along with their treatment.

[0239] Additional results: Similar to the MDS mouse model described above, the pharmacokinetic effects of VIT-2763 administered in drinking water (0.5 mg / ml) were investigated in the NUP98-HOXD13 model of MDS.

[0240] Preventive effect - additional results: To study the protective effects of the compound against the progressive development of iron overload and associated toxicity, 3-month-old MDS mice were treated and compared to age- and sex-matched untreated MDS mice and wild-type controls. Mice were treated with VIT-2763 from 3 months of age, and blood parameters and survival were tracked over the long term (Figures 16-19), or cytochemical analyses were performed from 3 to 6 months of age for 3 months (Figures 20-24).

[0241] Anemia and blood parameters - additional results: Hb, HCT, and RBC levels were reduced in MDS mice compared to control animals and were significantly improved by VIT-2763 treatment between 5 and 7 months of age (Figure 16). VIT treatment improved Hb levels in MDS mice to approximately 2 g / dl (Figure 17).

[0242] White blood cell parameters - additional results: In MDS mice, the WBC count was the first to decrease. Only MDS mice that developed leukemia showed a significant increase in WBC count. Interestingly, some MDS mice in the untreated group showed an increase in WBC count and developed leukemia, but such WBCs in peripheral blood were not observed or were delayed in the VIT-2763 treated group (Figure 18).

[0243] Consistent with the trend of decreased / delayed leukemia onset, immature Lin including myeloblasts in MDS mice + cKit + The cell count increased and decreased after a 3-month period of VIT treatment (Figure 20).

[0244] Myeloid proliferation was reduced in MDS mice after VIT treatment, as suggested by a decrease in the percentage of bone marrow CD11b+ myeloid cells and monocyte and granulocyte myeloid-derived suppressor cells (MDSCs) (Figures 21 and 22).

[0245] Bone marrow macrophages were significantly reduced in MDS mice. This is a result of insufficient myeloid terminal differentiation and can contribute to ineffective erythropoiesis and HSC loss. VIT treatment improved the number of macrophages in the bone marrow of MDS mice (Figure 23). Along with this, VIT treatment reduced the production of inflammatory cytokines such as TNFα and IL-1β by macrophages (Figure 24), resulting in potentially beneficial effects on erythropoiesis, HSPCs, and the bone marrow microenvironment.

[0246] Rescue effect - additional results: To study the rescue effect of compounds against iron overload and associated toxicity established in MDS, 5-month-old MDS mice were treated and compared with age- and sex-matched untreated MDS mice and wild-type controls. Mice were treated starting at 5 months of age. In this cohort of mice, improvement in anemia was observed 5 months after treatment (10 months of age). Anemia in MDS mice tends to worsen from 5 months of age. The results suggest that while mice initially showed little benefit from treatment, some mice could benefit with partial improvement in anemia around 10 months of age (Figure 25).

[0247] Interestingly, MDS mice treated with VIT showed a delay in the onset of leukemia, similar to what was observed in mice treated from 3 months of age (Figure 26).

[0248] Most MDS mice died at approximately 12 / 13 months of age, but two MDS mice treated with VIT a total of 10 times were still alive at 15 months of age, with stable blood parameters (Hb approximately 9 g / dl), and one of them reached 20 months of age (Figure 25).

[0249] Overall, VIT treatment in aged MDS mice resulted in a slight change in the median survival improvement to approximately 16 days compared to untreated mice (Figure 27). However, this clearly demonstrates that some mice can derive a particular benefit from VIT treatment; all untreated MDS animals died within 400 days of birth, while MDS mice that benefited from VIT treatment lived up to 600 days.

[0250] III. Blood transfusion burden The transfusion burden in subjects treated according to the method of the present invention may be assessed by determining the patient's transfusion requirements, for example, through the amount and / or frequency of red blood cell transfusions required by conventional clinically recognized assessments.

[0251] IV. Iron level Iron levels, such as those in the liver, kidneys, or myocardium, may be determined using conventional assays. For example, iron levels (e.g., hepatic iron concentration, renal iron concentration, or myocardial iron concentration) may be determined by magnetic resonance imaging.

[0252] V. Serum ferritin level determination Serum ferritin levels may be determined using conventional assays.

[0253] VI. Red blood cell response The duration of the red blood cell response may be calculated for subjects that achieved the response using the following algorithm: Response Day 1 = The first day of the first 12-week interval showing a response. Response Day 2 = The last day of the last consecutive 129-week interval showing an interval response. Final evaluation date = either the last visit date for patients still taking medication (On drug) or the discontinuation date for patients who have discontinued treatment.

[0254] The duration of the red blood cell response may be calculated as follows, depending on whether the response ends before the final evaluation date: 1. If the response did not continue until the end of the treatment period, the duration of the response is not terminated, and is calculated as follows: Response duration = Last day of response - First day of response + 1; 2. For subjects that continue to show a red blood cell response until the end of the treatment period, the last day of response is terminated, and the duration of the response is calculated as follows: Response duration = Last response evaluation date - First response day + 1.

[0255] The time to the first red blood cell response can be calculated as follows: The number of days from the first dose of the test drug to the response start date is calculated using the following: Time to response = Day 1 of response - Day 1 of first test drug administration + 1.

[0256] VII. Hemoglobin test Hemoglobin levels may be determined using conventional assays.

[0257] VIII. Quality of Life Quality of life may be assessed using the Short Form(36) Health Survey(SF-26) and / or using the Functional Assessment of Cancer Therapy-Anemia (FACT-An), as described in, for example, WO2016 / 183280.

[0258] IX. Efficacy of the ferroportin inhibitor VIT-2653 (Example Compound No. 40) to reduce plasma iron, oxidative stress, and kidney damage after red blood cell transfusion in guinea pigs. The efficacy of the ferroportin inhibitor compound of the present invention in the treatment of MDS is further supported by the results of JHBaek et al., "Ferroportin inhibition attenuates plasma iron, oxidant stress, and renal injury following red blood cell transfusion in guinea pigs," Transfusion, March 2020; Vol. 60 (No. 3): pp. 513-523.

[0259] The experiments described therein were conducted by intravenous administration of the small molecule ferroportin inhibitor VIT-2653, which corresponds to compound number 40 in the example of the present invention, and further confirmed some of the discoveries of the present invention.

[0260] NTBI and Hb levels after exchange transfusion are significantly improved by the administration of ferroportin inhibitors.

[0261] Furthermore, total iron in the kidney after transfusion can be reduced by administering ferroportin inhibitors. Evaluating the contribution of circulating hemoglobin (Hb) to renal iron load and its subsequent effects on oxidative stress and cell damage, it was found that administration of ferroportin inhibitors to transfused guinea pigs significantly reduced the occurrence of changes in plasma creatinine levels above 0.3 mg / dL, which is used as an indicator of early acute kidney injury (AKI).

[0262] The details of the experiment, the research conditions, and the specific research results can be derived from the cited papers.

Claims

1. For use in the prevention or treatment of myelodysplastic syndrome (MDS) and / or related conditions, comprising one or more of the following compounds, or pharmaceutically acceptable salts, solvates, hydrates, and / or polymorphs thereof, wherein the patient to be treated is selected from individuals suffering from very low-risk, low-risk, or intermediate-risk myelodysplastic syndrome according to the International Prognostic Scoring System (IPSS scoring system). A pharmaceutical composition comprising a reduction in myeloid proliferation for the treatment of myelodysplastic syndrome (MDS) and / or related symptoms. 【Chemistry 1】

2. For use in the prevention or treatment of myelodysplastic syndrome (MDS) and / or related conditions, comprising one or more of the following compounds, or pharmaceutically acceptable salts, solvates, hydrates, and / or polymorphs thereof, wherein the patient to be treated is selected from individuals suffering from very low-risk, low-risk, or intermediate-risk myelodysplastic syndrome according to the International Prognostic Scoring System (IPSS scoring system). A pharmaceutical composition for the treatment of myelodysplastic syndrome (MDS) and / or related symptoms, including delaying the progression of leukemia. 【Chemistry 2】

3. For use in the prevention or treatment of myelodysplastic syndrome (MDS) and / or related conditions, comprising one or more of the following compounds, or pharmaceutically acceptable salts, solvates, hydrates, and / or polymorphs thereof, wherein the patient to be treated is selected from individuals suffering from very low-risk, low-risk, or intermediate-risk myelodysplastic syndrome according to the International Prognostic Scoring System (IPSS scoring system), A pharmaceutical composition for the treatment of myelodysplastic syndrome (MDS) and / or related symptoms, comprising reducing the production of inflammatory cytokines TNFα and / or IL-1β by macrophages. 【Transformation 3】

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the treatment of myelodysplastic syndrome (MDS) and / or related symptoms includes treatment of ineffective hematopoiesis.

5. The pharmaceutical composition according to claim 4, wherein the treatment of myelodysplastic syndrome (MDS) and / or related symptoms comprises treatment of ineffective red blood cell production.

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the treatment for myelodysplastic syndrome (MDS) and / or related symptoms comprises one or more selected from the group consisting of a reduction in immature cells in the bone marrow and improvement of the bone marrow microenvironment.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the patient to be treated is selected from individuals characterized by one or more of the following: - Having sideroblasts with rings as defined by the World Health Organization criteria, characterized by 15% or more ring sideroblasts, or 5% or more ring sideroblasts if an SF3B1 mutation is present, or having myelodysplastic syndrome with less than 5% myeloblasts; - Having myelodysplastic syndrome with erythropoietin levels exceeding 200 U per liter; - Having erythrocyte dysplasia; - Having a cytopenia, especially a peripheral cytopenia; - Less than 5% myeloblasts; - Peripheral hemoblasts less than 1%; - Having a myelodysplastic syndrome characterized by a reduced or absent response to erythropoiesis-stimulating agents; - Having myelodysplastic syndrome with chromosome 5q deletion (del[5q]); - SF3B1 mutant patient; - Patients in whom PPOX and / or ABCB7 genes are significantly downregulated compared to healthy individuals; - The patient is transfusion-dependent or receives regular red blood cell transfusions of two or more units every eight weeks.

8. The patient, a) It indicates a detectable NTBI level, and / or b) Hb level is below 8 g / dL, and / or c) Having an MCV between 50 and 70 10 fL, and / or d) Having MCH between 12 and 20 pg, and / or e) Having a TSAT level of over 45% A pharmaceutical composition according to any one of claims 1 to 7, characterized by the above.

9. Patients to be treated are selected from transfusion-dependent patients characterized by receiving regular blood transfusions, and the fact that they receive regular blood transfusions is a) Repeated transfusions of the same number of red blood cells (RBCs) at different time intervals thereafter, or b) Repeated blood transfusions of the same RBC units at equal time intervals thereafter, or c) Repeated transfusions of different RBC units at equal time intervals thereafter, or d) Repeated blood transfusions of different RBC units at different time intervals thereafter. A pharmaceutical composition according to any one of claims 1 to 8, comprising:

10. The pharmaceutical composition according to any one of claims 1 to 9, which is in an oral administration form.

11. A pharmaceutical composition according to any one of claims 1 to 10, for use in administering the compound, or a pharmaceutically acceptable salt, solvate, hydrate, and / or polymorph thereof, in doses of 5 mg, 15 mg, 60 mg, 120 mg, or 240 mg, to a patient in need thereof.

12. A pharmaceutical composition according to any one of claims 1 to 11, for use in administering a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, and / or polymorph thereof, to patients in need, in doses of 120 mg for patients weighing more than 50 kg and 60 mg for patients weighing less than 50 kg, once or twice daily.

13. A pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutically acceptable salt is selected from pharmaceutically acceptable salts of an acid selected from the group consisting of benzoic acid, citric acid, fumaric acid, hydrochloric acid, lactic acid, malic acid, maleic acid, methanesulfonic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and toluenesulfonic acid, as well as solvates, hydrates, and / or polyforms thereof.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the pharmaceutically acceptable salt is selected from pharmaceutically acceptable salts with an acid selected from the group consisting of citric acid, hydrochloric acid, maleic acid, phosphoric acid, and sulfuric acid, as well as solvates, hydrates, and / or polyforms thereof.

15. The compound is formula 【Chemistry 4】 A 1:1 sulfate represented by; formula 【Transformation 5】 A 1:1 phosphate represented by; formula 【Transformation 6】 HCl salts in a 1:3 ratio, as shown above. and groups consisting of these polymorphs A pharmaceutical composition according to any one of claims 1 to 14, wherein the salt form is selected from the following.

16. A pharmaceutical product comprising a compound as defined in any one of claims 1 to 3 and 13 to 15 for use in the uses defined in any one of claims 1 to 12, further comprising one or more pharmaceutical carriers and / or excipients and / or solvents, and / or one or more additional pharmaceutically active compounds.

17. The pharmaceutical product according to claim 16, further comprising ruspatercept as an additional pharmaceutically active compound.

18. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 3 and 13 to 15, for use in a combination therapy for treating myelodysplastic syndrome as defined in any one of claims 1 to 12, The combination therapy comprises the combined administration of a compound specified in any one of claims 1 to 3 and 13 to 15, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, with one or more additional pharmaceutically active compounds. The combination therapy may be carried out as a fixed-dose combination therapy by co-administering a compound specified in any one of claims 1 to 3 and 13 to 15, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, with one or more additional pharmaceutically active compounds in a fixed-dose formulation, or A pharmaceutical composition in which combination therapy may be carried out in a non-fixed-dose combination therapy by co-administering a compound specified in any one of claims 1 to 3 and 13 to 15, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, and one or more additional pharmaceutically active compounds, in non-fixed doses of the individual compounds, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds administered over a period of time.

19. The pharmaceutical composition according to claim 18, wherein the combination therapy comprises the combined administration of a compound specified in any one of claims 1 to 3 and 13 to 15 and ruspatercept as an additional pharmaceutically active compound.

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