Ferroportin inhibitors for use in the treatment of myelodysplastic syndromes (MDS) - Patent Application 20070233334

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 compounds of general formula (I), which act as ferroportin inhibitors, for the treatment of myelodysplastic syndromes (MDS) and symptoms and pathological conditions associated therewith. [Background technology]

[0002] Iron is an essential element for almost all living organisms, and its importance lies in its crucial role in erythropoiesis and oxygen transport. The balance of iron metabolism is mainly regulated by the iron levels recovered from hemoglobin of aged erythrocytes, iron stores in the liver, and duodenal absorption of dietary iron. Elemental iron is taken up by duodenal enterocytes via specific transport systems (DMT-1, ferroportin) and enters the blood circulation, where it is subsequently bound to its carrier transferrin for delivery to the appropriate tissues and organs. In the human body, iron is crucial for, among other things, oxygen transport, oxygen uptake, cellular functions, e.g., mitochondrial electron transport, cognitive function, and ultimately for the entire energy metabolism. Mammalian organisms cannot remove or excrete iron from the body via active systems. Iron homeostasis is controlled by the hepatic peptide hormone hepcidin, which regulates the activity of the only known iron efflux transporter, ferroportin, thus releasing iron from macrophages, hepatocytes, and enterocytes. Hepcidin controls iron absorption through the intestine and placenta, as well as iron recycling from the reticuloendothelial system. Hepcidin production is directly regulated by iron levels; if the organism is provided with sufficient or excess iron and oxygen, more hepcidin is produced; if iron and oxygen levels are low or erythropoiesis increases, hepcidin production decreases. When hepcidin binds to ferroportin in small intestinal mucosal cells and macrophages, it blocks its excretory function and promotes its internalization and degradation. Through this mechanism, hepcidin reduces the efflux of iron from cells into the bloodstream. The transport protein ferroportin is a transmembrane protein of 571 amino acids that is expressed in the liver, spleen, kidney, heart, intestine, and placenta. In particular, ferroportin is localized in the basement membrane of intestinal epithelial cells. Thus, ferroportin acts to excrete dietary iron into the blood. When hepcidin binds to ferroportin, ferroportin is transported to the interior of the cell where it is degraded, thereby blocking the release of iron from the cell.Intestinal iron absorption is blocked when ferroportin is inactivated or inhibited by hepcidin and is unable to release iron stored in mucosal cells. A decrease in hepcidin leads to an increase in active ferroportin, thus enhancing dietary iron absorption and release of stored iron, resulting in elevated serum iron levels.

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

[0004] A key detrimental 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 cause damage to DNA, lipids, proteins, and carbohydrates, with widespread effects on cells, tissues, and organs. The formation of ROS is well known and has been documented to result in the so-called oxidative stress. NTBI has been extensively documented to exhibit a high propensity for the induction of ROS, which are potentially toxic to cells and major organs, including the heart, liver, pancreas, kidneys, and bone marrow. Thus, iron overload is known to result in tissue and organ damage, e.g., cardiac, hepatic, and endocrine damage (Vinchi, Hell, Platzbecker, "Controversies on the consequences of iron overload and chelation in MDS," Hemasphere, 27; 4(3), 2020; Patel M. et al., "Non-Transferrin Bound Iron: Nature, Manifestations and Analytical Approaches for Estimation," Ind. J. Clin. Biochem., 2012; 27(4):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; 1820, 403-410).

[0005] Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and a risk of leukemic transformation. MDS are one of the most frequently encountered acquired bone marrow failure syndromes in adults. Genetic and epigenetic alterations affecting hematopoietic stem cells (HSCs) and alterations in the hematopoietic niche leading to degeneration and apoptosis of hematopoietic stem and progenitor cells (HSPCs) primarily contribute to ineffective hematopoiesis.

[0006] MDS refers to a group of cancers in which HSPCs in the bone marrow do not mature and become healthy blood cells. Although there are typically no symptoms in the early stages, 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 inefficient, resulting in insufficient numbers of red blood cells, platelets, and white blood cells. Some MDS types 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 is defined as low or intermediate risk according to the IPSS, or as very low, low, or intermediate risk according to the revised IPSS [IPSS-R].

[0008] Low-risk myelodysplastic syndromes by IPSS or IPSS-R most commonly present with symptomatic anemia. Chronic anemia, especially in the elderly, is associated with multiple comorbidities, including increased risk of cardiovascular complications, falls, and fractures, as well as reduced survival. A high percentage of patients presenting with low-risk myelodysplastic syndromes eventually become dependent on red blood cell transfusions (transfusion dependent), a condition associated with reduced quality of life and overall survival.

[0009] As sequencing and identification of somatic gene mutations becomes more feasible in clinical practice, it has become possible to identify additional MDS subtypes defined by genetic abnormalities. Such subtypes are 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] A common biological feature of lower-risk MDS is a defect in the self-renewal and differentiation of hematopoietic stem and progenitor cells, resulting in cytopenias. Approximately 60% to 80% of patients presenting with MDS experience symptomatic anemia, and 80% to 90% of anemic MDS patients require red blood cell (RBC) transfusions as supportive care.

[0011] Iron overload is common in MDS as a result of enhanced intestinal iron absorption to support expanded erythropoiesis, and chronic RBC 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 onset in MDS patients and becomes transfusion dependent. That is, MDS patients may develop iron overload even before receiving blood transfusions due to underlying ineffective erythropoiesis that results in enhanced iron absorption to support the expansion of the erythroid lineage in an attempt to reverse anemia. Correction of anemia via RBC transfusions is the primary goal of supportive care in MDS, and typically blood transfusions remain the primary cause of iron overload in this patient population. Ineffective erythropoiesis leads to suppression of the iron hormone hepcidin, causing unlimited iron absorption via duodenal enterocytes. This mechanism enhances iron influx into the circulation and supports de novo erythropoiesis in the bone marrow, thus accumulating iron overload in MDS. Therefore, correcting the unbalanced iron absorption by inducing hepcidin synthesis or adding hepcidin mimetics is being evaluated as an attractive therapeutic approach to normalize dysregulated iron metabolism in MDS.

[0013] The mandatory requirement of chronic transfusion therapy in MDS patients frequently leads to secondary iron overload, ultimately of life-threatening consequence, in this patient population. Although transfusion dependence is itself a negative prognostic factor reflecting a decline in bone marrow function, subsequent transfusion-induced iron overload has an additional dose-dependent adverse effect on the survival of patients presenting with low-risk MDS. Recent data suggest that markers of iron overload are, in fact, harbingers of a relatively poor prognosis, and retrospective analyses have demonstrated that iron chelation therapy is associated with prolonged survival in patients with transfusion-dependent MDS.

[0014] The diagnosis of suspected MDS is based on clinical and hematological analysis, supplemented by genetic analysis for possible genetic abnormalities. Currently, treatment of MDS includes supportive care, drug therapy, and hematopoietic stem cell transplantation. Supportive care can include intermittent or regular blood transfusions, medicines to increase red blood cell production, including erythropoietin stimulators, and antibiotics. 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 additional treatment option for MDS patients.

[0015] Since iron accumulation is an early event in some MDS patients with potentially deleterious effects, and iron chelators often show undesirable side effects, including gastrointestinal symptoms, novel approaches are needed to address the iron overload conditions associated with MDS, improve the quality of life and prognosis of this patient population, and delay the progression of the disease to leukemia with the currently available therapeutic strategies. As MDS mainly affects the elderly population, the majority of patients are unable to tolerate intensive therapeutic approaches, such as allogeneic hematopoietic stem cell transplantation. The burden of regular blood transfusions is also difficult for elderly patients. Therefore, novel treatment approaches are needed that avoid the shortcomings of available treatment methods.

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

[0017] Luspatercept is administered parenterally. Luspatercept and its use in treating symptoms of beta-thalassemia, including defective and ineffective erythropoiesis in the bone marrow, are described, for example, in WO2016183280.

[0018] Parenteral administration of drugs usually requires a doctor's consultation, which may increase the cost of treatment, affect patient compliance, and impose additional burden on patients. Oral drug administration offers advantages over parenteral administration, such as ease of administration by patients, especially elderly patients, high flexibility in terms of dosage and formulation, cost-effectiveness, reduced sterility constraints and risk of infection, injection site reaction, and anti-drug antibody generation.

[0019] Given the significant life-threatening consequences for patients with MDS, it is clear that new and improved treatment options are needed to achieve extended survival and improved quality of life for patients with MDS.

[0020] In addition to the described treatment with luspatercept, MDS is traditionally treated routinely with regular blood transfusions (RBC transfusions), with regular co-treatment with iron chelators for 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 newer drugs for iron chelation therapy approved for use in patients who receive regular blood transfusions to treat thalassemia and who have developed iron overload as a result are deferasirox (also known as Exjade®) and deferiprone (also known as Ferriprox®).

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

[0023] The drawback of treating MDS with regular blood transfusions is the continued need for regular blood transfusions for the patient and regular removal of excess iron by chelation therapy. Furthermore, established drugs for iron chelation therapy are known to exhibit potential toxicity, posing potential problems with long-term administration due to the prolonged need for blood 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 certain salts of selected ferroportin inhibitors described in WO2017 / 068089 and WO2017 / 068090. The ferroportin inhibitors described in said three international applications overlap with the compounds according to formula (I) used in this application. Therein, reference to the potential treatment of MDS is only mentioned generally in a list of possible indications, without providing any data. Unpublished international application PCT / EP2020 / 070391 describes the use of selected groups of ferroportin inhibitors in the treatment of transfusion-dependent thalassemia.

[0025] 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, describes experimental studies carried out with a selected oral ferroportin inhibitor compound (VIT-2763, corresponding to Example compound 127 of the present application), which shows that VIT-2763 improves ineffective erythropoiesis, reverses anemia, and prevents hepatic iron overload in a mouse model of β-thalassemia. The paper speculates regarding the potential (predicted) efficacy of VIT-2763 in neutralizing ineffective erythropoiesis and iron overload in various diseases, including, inter alia, potential efficacy in reversing myeloproliferative / myelodysplastic disorders, e.g., 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 study evaluating the safety, tolerability, pharmacokinetics, etc. of the oral ferroportin inhibitor compound VIT-2763 in healthy volunteers. Similar to the above-cited paper by Manolova et al. (2020), this paper also speculates in the discussion section regarding the potential of VIT-2763 to improve erythropoiesis and anemia in patients exhibiting ineffective erythropoiesis, for example in MDS, due to its ability to limit iron absorption.

[0027] The underlying pathogenesis of MDS and β-thalassemia (bthal) is significantly different. There are notable differences in the mechanisms of ineffective erythropoiesis in bthal versus MDS, with some aspects unique to MDS and absent in bthal.

[0028] Ineffective erythropoiesis in MDS versus β-thalassemia: Ineffective erythropoiesis is a feature of other diseases, such as thalassemia. Ineffective erythropoiesis occurs under conditions in which red blood cell progenitor precursors fail to mature and die during the process of becoming red blood cells, or develop into abnormal red blood cells and die prematurely. Although thalassemia and MDS both exhibit ineffective erythropoiesis, the underlying molecular mechanisms are different.

[0029] In β-thalassemia, ineffective erythropoiesis is characterized by limited proliferation, differentiation, and premature death of erythroid precursors, a process 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 hemichromes. Hemichromes are toxic aggregates that increase oxidative stress and result in cell death due to the presence of reactive iron moieties. Hemichromes precipitate on the red blood cell (RBC) membrane, leading to changes in membrane structure, inducing lipid peroxidation, and exposure of anionic phospholipids, which together result in premature RBC clearance from the circulation. In β-thalassemia, iron restriction in erythroid precursors acts as a compensatory mechanism, thereby reducing cellular iron, leading to reduced heme synthesis and reduced hemichromes. The delivery of small amounts of iron to many erythroid precursors leads to reduced mean cellular hemoglobin (MCH) and reduced hemichromes. Because hemichromes and ROS result in ineffective erythropoiesis in β-thalassemia, iron restriction and reduced erythrocyte iron uptake leads to more effective erythropoiesis, normalizing RBC structure and lifespan, increasing Hb circulation, and reversing splenomegaly. Thus, the use of drugs that reduce dietary iron uptake improves erythropoiesis in β-thalassemia.

[0030] Ineffective erythropoiesis is characterized by erythropoietin-driven proliferation of early-stage erythroid precursors associated with apoptosis of erythroid precursors in both β-thalassemia and MDS, but erythroid proliferation is more severe in β-thalassemia, and the cellular and molecular mechanisms underlying ineffective erythropoiesis, as well as its exacerbation by iron overload, are different in β-thalassemia and MDS. In contrast to β-thalassemia, where iron is central to disease pathogenesis through hemichrome deposition, MDS is an HSC disorder that can be exacerbated - although not directly driven - by iron and is characterized by both ineffective erythropoiesis and hematopoiesis. In β-thalassemia, ineffective erythropoiesis is due to premature death of erythroid precursors due to hemichrome formation, whereas in MDS it is due to genetic lesions originating from HSPCs and to arrest of differentiation and increased apoptosis of erythroid precursors induced by excess proinflammatory cytokines and immune disturbances in the bone marrow niche, independent of hemichromes that are not produced in MDS.

[0031] Therefore, iron overload is likely to be exacerbated and its restriction improves the following mechanisms:

[0032] (1) Contribution of iron to ineffective erythropoiesis in MDS: Due to the lack of hemichrome formation, the way in which iron contributes to ineffective erythropoiesis in MDS differs from that in β-thalassemia. Iron has a direct effect on HSPC, ROS are deeply involved in hematopoiesis: a certain amount of ROS is important for the coordinated proliferation and differentiation of HSPCs, whereas excessive ROS enhances stem cell turnover and ultimately leads to HSC exhaustion. Thus, exposure of HSCs to excess iron in the bone marrow niche promotes ROS formation in HSCs and induces apoptosis in hematopoietic precursors, contributing to ineffective erythropoiesis. Iron has a direct effect on the red blood cell lineage.Exposure of erythroid precursors to increased iron induces dysplastic changes, resulting in marked impairment of erythroblast differentiation and RBC maturation, and an overall reduction in burst-forming unit colony formation and erythroblast apoptosis. These events are reversed by chelators and antioxidants. Consistent with these observations, HSCs from iron-treated MDS animals and from MDS patients exhibiting moderate elevations of serum ferritin (>250 μg / l) show reduced proliferation - exclusively in the erythroid lineage. Recent findings suggest that intracellular oxidative stress impairs erythroid development, which may be actively ameliorated by modulating the expression of ferroportin on these cells. The enhanced susceptibility of erythroid precursors to iron toxicity may be due to a direct effect of exposure to labile iron and / or mitochondrial iron retention, especially in MDS-RS (MDS with ringed sideroblasts). In MDS-RS, erythroid precursors accumulate iron in mitochondria (appearing as ringed sideroblasts). As a consequence of mitochondrial iron retention, iron incorporation into heme is reduced, which contributes to oxidative stress and hypoxia, stimulating the expansion of erythropoiesis in MDS, which is ineffective. Iron in ringed sideroblasts is plausibly deposited in mitochondrial ferritin, the levels of which were correlated with early apoptosis in MDS-RS erythroblasts. Overall, this suggests that iron overload exacerbates ineffective erythropoiesis via defective differentiation of MDS erythroid precursors and a propensity for apoptosis.

[0033] (2) Contribution of iron to leukemia progression: In addition to ineffective erythropoiesis, in MDS, the presence of labile plasma iron and associated increased labile cellular iron and production of ROS have been hypothesized to play a role in disease pathogenesis via increased apoptosis rates and genomic instability of HSPCs, alterations in the bone marrow microenvironment, and disease progression to acute myeloid leukemia (AML) that exhibits 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 are neutralized by iron chelation therapy. Iron overload has also been implicated in the induction of epigenetic abnormalities and telomere erosion. Global 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. Despite being unable to induce leukemic transformation of stem cells by itself, iron overload may accelerate leukemic progression by mediating genotoxic stress in highly proliferating HSPCs. Furthermore, depletion of normal HSCs due to their escape from quiescence induced by iron-driven ROS elevation likely contributes to the selective expansion of MDS clones, indicating that iron may play a role in clonal expansion and progression of myeloid leukemia by promoting malignant transformation and depletion of normal HSCs.

[0034] (3) Contribution of iron to the abnormal bone marrow microenvironment: The abnormal bone marrow microenvironment plays a key role in the pathogenesis of MDS and the progression from low-risk MDS to more malignant disease. Due to the critical functions of the bone marrow microenvironment in the maintenance, self-renewal, and differentiation of HSCs, its alterations were implicated in impaired hematopoiesis, as well as apoptosis and dysplasia of presegmental cells. Iron likely contributes to the reduced survival and impaired function of multiple cell types within the bone marrow microenvironment, including mesenchymal stromal cells (MSCs), bone cells, immune cells, and vascular endothelial cells. Iron-driven alterations of the mesenchymal cell compartment affect its supportive function on hematopoiesis. Indeed, the expression and cytokine secretion of several adhesion molecules are altered in bone marrow stromal cells under iron overload conditions, compromising their ability to support hematopoietic cell growth. Furthermore, the immune-modulating role of iron and blood transfusions, via altered cell 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 proinflammatory niche is often present.

[0035] (4) Contribution of iron overload to organ toxicity: In addition to the bone marrow, alterations in iron metabolism may also affect other organs. As in β-thalassemia, iron overload resulting from multiple transfusions in MDS has been demonstrated to be toxic to various organs such as the liver, heart, pancreas, thyroid, and pituitary gland, causing increased morbidity and mortality.

[0036] The inventors of the present invention have surprisingly found that ferroportin inhibitor compounds as defined herein not only act to block ferroportin, but also further improve the following aspects in steady-state MDS: Ineffective erythropoiesis Survival of HSCs Myeloid proliferation Inflammation in the bone marrow microenvironment -Tissue iron overload.

[0037] Ineffective erythropoiesis is improved by ferroportin inhibitor-mediated iron restriction in both β-thalassemia and MDS, but the underlying mechanism is centered on reduced hemichrome formation in erythroid precursors in β-thalassemia, whereas in MDS it is centered on multifactorial improvement in the quality and quantity of HSC and preerythroid material (e.g., reduced apoptosis, improved maturation) due to reduced ROS upon reduced iron availability.

[0038] It has also surprisingly shown efficacy in MDS by improving MDS-specific aspects including limiting the depletion of the HSC pool, reducing myeloid proliferation and leukemic progression, as well as reducing inflammation in the bone marrow microenvironment, based on additional and distinct modes of action compared to β-thalassemia.

[0039] Importantly, the inventors' findings of the present application demonstrate that enhanced iron absorption is pathologically relevant and that its inhibition via the ferroportin inhibitors described herein is of therapeutic benefit in steady-state MDS through modulation of fundamental pathophysiological mechanisms including ineffective erythropoiesis, HSC depletion, and myeloid clonal expansion. Summary of the Invention [Problem to be solved by the invention]

[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 administration route, such as oral administration in particular, should be provided to simplify administration, reduce side effects caused by parenteral administration, enhance patient compliance, eliminate concerns about treatment costs, and reduce patient treatment burden. In a further aspect, 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 cheaper to prepare than drugs based on recombinantly engineered proteins or genetically engineered 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 (FpnI) can be used to treat MDS and its associated symptoms and pathological conditions, such as incomplete erythropoiesis in bone marrow, ineffective hematopoiesis, such as ineffective erythropoiesis, reduced hemoglobin levels / anemia, iron overload and multiple organ dysfunction, liver and kidney iron load, and cardiac iron overload. In a further embodiment, ferroportin inhibitor compounds as defined herein can be used to reduce bone marrow immature cells and myeloblasts in MDS patients, thus reducing myeloid proliferation, possibly preventing or delaying leukemia progression in MDS patients, reducing the production of inflammatory cytokines such as TNFα and IL-1β by macrophages, and / or improving the bone marrow microenvironment. In particular, the novel surprising results showing the delay in leukemia progression provide a novel approach to treat leukemia with ferroportin inhibitor compounds as defined herein.

[0042] Thus, a first aspect of the present invention provides a compound according to the following formula (I), including pharma- ceutically acceptable salts, solvates, hydrates and polymorphs thereof, for use in the treatment of myelodysplastic syndromes (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 is different; R 1 teeth, - Hydrogen, and - optionally substituted alkyl 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 alkanediyls; R 2 teeth, - Hydrogen, or - optionally substituted alkyl Is it; 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 teeth, - Hydrogen, - halogen, - C1-C3-alkyl, and - Halogen-substituted alkyl (selected from the group consisting of Regarding.

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

[0045] Treatment of myelodysplastic syndromes (MDS) and / or conditions associated therewith involves treatment of ineffective hematopoiesis, in particular ineffective erythropoiesis.

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

[0047] As mentioned above, several subtypes of MDS have been classified in the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R). Low-risk MDS is defined as low or intermediate risk according to the IPSS, or very low, low, or intermediate risk according to the revised IPSS [IPSS-R].

[0048] In a further embodiment, the present invention relates to the compound of formula (I) or its salts, solvates, hydrates and polymorphs thereof for treating MDS, wherein the MDS patient is 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] Additionally, genetic MDS subtypes have been defined, such as MDS with del(5q) alone or MDS with SF3B1 mutations. The above cited report by Malcovati et al. (2020) further defines diagnostic criteria for MDS subtypes and MDS entities, which are listed in Table 1 below:

[0050] [Table 1]

[0051] A further aspect of the invention relates to a compound of formula (I), or a salt, solvate, hydrate, or polymorph thereof, for treating MDS selected from one of the MDS entities defined in Table 1 above.

[0052] In a further embodiment of the invention, the MDS patient to be treated is selected from one or more of the following patient groups, the individual being characterized by one or more of the following: - Having myelodysplastic syndrome with ringed sideroblasts (RS) according to the World Health Organization criteria characterized by ≥15% ringed sideroblasts, or ≥5% ringed sideroblasts if a SF3B1 mutation is present, or with <5% myeloblasts; - Having myelodysplastic syndrome with erythropoietin levels greater than 200 U per liter; - Having erythrocytic dysplasia; - Having cytopenias, especially peripheral cytopenias; - Less than 5% myeloblasts; - less than 1% peripheral blood blasts; - suffer from myelodysplastic syndrome with reduced or absent response to erythropoiesis-stimulating agents; -Having myelodysplastic syndrome with chromosome 5q deletion (del[5q]); - Patients with SF3B1 mutations; - Patients with significantly downregulated PPOX and / or ABCB7 genes compared to healthy individuals; - Being transfusion dependent or receiving regular red blood cell transfusions of 2 or more units per 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 their salts, solvates, hydrates and polymorphs thereof for treating transfusion-dependent MDS, i.e. for treating MDS according to the present invention, wherein the selected patient group is characterized by the need for regular blood transfusions or being transfusion-dependent patients. Such regular blood transfusions or transfusion dependency are characterized by: a) Subsequent repeated transfusions of equal red blood cell (RBC) units at different time intervals, or b) Repeated blood transfusions of equal RBC units at equal time intervals thereafter; or c) Subsequent repeated transfusions of different RBC units at equal time intervals; or d) Subsequent repeated transfusions of different RBC units at different time intervals. It is characterized by:

[0055] The terms "treat", "treatment" or "treating" in the context of the use of the present invention include the amelioration of at least one symptom or pathological condition associated with MDS. Non-limiting examples of symptoms or pathological conditions associated with MDS include incomplete red blood cell production in the bone marrow, ineffective hematopoiesis, including in particular ineffective erythropoiesis, reduced hemoglobin levels, multiple organ dysfunction, iron overload, anemia, hepatic iron overload and cardiac iron overload, as well as the symptoms described above and in the examples below.

[0056] The terms "treat", "treatment" or "treating" in the context of the present invention further include prophylaxis, e.g. by administering a compound of the present invention prior to or simultaneously with a blood transfusion in a transfusion-dependent MDS patient, to prevent or at least reduce the appearance of one or more pathological conditions caused by a blood transfusion.

[0057] Patients with MDS may have severe iron overload due to regular blood transfusions (BT). The main goal of blood transfusion therapy in the treatment of MDS is to neutralize the anemic state and suppress erythropoiesis. This is believed to be achieved at Hb levels of 9 g / dL or higher. Thus, in a further embodiment of the treatment of MDS patients, administration of the ferroportin inhibitor compound of formula (I) according to the present invention helps to prevent intestinal iron absorption in the interval between transfusions, which helps to reduce further iron load in MDS patients.

[0058] It has been observed that patients with MDS have elevated levels of non-transferrin-bound iron (NTBI). NTBI is released by macrophages recycling damaged RBCs resulting from the formation of immature RBCs in the bone marrow and / or in transfused RBC units, leading to oxidative stress, vascular injury, 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;2(9)).

[0059] The inventors of the present invention have found that the compound of formula (I) of the present invention is particularly suitable for treating MDS by improving ineffective erythropoiesis through the limitation of iron overload mediated by the compound of formula (I).It is further assumed that the compound of formula (I) of the present invention is particularly suitable for treating MDS by limiting reactive oxygen species (ROS) in erythrocyte precursors, thus improving erythropoiesis in patients suffering from MDS.As a result, anemia is improved in MDS patients by many RBCs with extended life span, and tissue oxygenation is improved.In MDS, the compound of formula (I) further effectively reduces elevated NTBI levels, helping to prevent pathological conditions resulting therefrom, such as iron overload in the liver, kidney, and heart, and thus organ dysfunction, as well as the appearance of other diseases.

[0060] NTBI encompasses all forms of serum iron that are not tightly bound to transferrin or other molecules, and is chemically and functionally heterogeneous. LPI (labile plasma iron) represents a component of NTBI that is both redox active and chelatable, and can penetrate into organs and induce tissue iron overload. Compounds of formula (I) have the potential to effectively reduce elevated NTBI and thus LPI levels in MDS.

[0061] The following parameters may be measured to evaluate the effectiveness of the compound of the present invention in the medical use of treating MDS: serum iron, NTBI level, LPI (labile plasma iron) level, erythropoietin, TSAT (transferrin saturation), Hb (hemoglobin), Hct (hematocrit), MCV (mean cell volume), MCH (mean cell hemoglobin), RDW (red blood cell distribution width), and reticulocyte count, total blood count, bone marrow blasts in bone marrow and peripheral blood, spleen weight, erythropoiesis in bone marrow and spleen, iron content of liver, spleen and kidney. Measurement can be carried out by using conventional methods in the art, especially by the ones 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), in normal physiological conditions, the level of transferrin is 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 nearly undetectable by routine methods. In the absence of transferrin, NTBI levels of up to 20 μmol / L have been reported, and in the presence of insufficient or highly saturated transferrin, NTBI levels of up to 10 μmol / L have been observed. 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, taking into account the technical difficulties resulting from the determination of the heterogeneous chemical forms of circulating NTBI. For example, fluorescent measurements with a reproducible precision of down to 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), elevated NTBI levels in clinical iron overload conditions range between 0.25 and 4.0 μmol / L (with different accuracy and determination methods). With this in mind, in the sense of the present invention, NTBI levels are considered as elevated if they are detectable by known methods (e.g., those described in Patel et al. (2012) or Brissot et al. (2012)), preferably if they are above 0.1 μmol / L.

[0063] In certain embodiments, treatment of MDS according to the invention reduces NTBI levels 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 time within a period of up to 72 hours, up to 60 hours, up to 48 hours, up to 36 hours, up to 24 hours, or up to 12, 8, 6, 5, 4, 3, 2, 1, and 0.5 hours after administration and compared to NTBI levels in the patient determined at any time 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 initiating treatment of the invention. NTBI may be determined according to the assays described in the Examples below.

[0064] In certain embodiments, the treatment of MDS according to the present invention reduces the LPI level in the 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 time within a period of up to 72 hours, up to 60 hours, up to 48 hours, up to 36 hours, up to 24 hours, or up to 12, 8, 6, 5, 4, 3, 2, 1, and 0.5 hours after administration, and compared to the total LPI level in the patient determined at any time within 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, or 48 hours, or up to less than 1 week before starting the treatment of the present invention. LPI may be determined according to the assay described in the Examples below.

[0065] Reactive oxygen species (ROS) lead to shortened RBC life span, anemia, and tissue hypoxia. The effect of the compounds of the present invention on RBC ROS levels may be monitored, for example, by commercially available far-red or green-emitting ROS-sensitive sensors as described in the Examples below.

[0066] In a further embodiment, treatment of MDS according to the invention is determined at any time 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 one month after the first administration and / or after the ischemic event, and within 12 hours, 24 hours, 3 hours, 5 days, 10 days, 12 hours, 14 hours, 16 days, 18 days, 19 days, 20 days, 21 days and up to one month before starting the treatment of the invention. 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% when compared to the ROS level in the patient's RBCs determined at any time within 6 hours, 48 ​​hours, 1 week, 2 weeks, 3 weeks, or 4 weeks. The ROS level in RBCs may be determined according to the assays described in the Examples below.

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

[0068] Thus, in further embodiments, treatment of MDS according to the invention may reduce liver 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 time within a period of up to 1 week, up to 2 weeks, up to 3 weeks, up to 3 months after the first administration and compared to the level of liver iron concentration in the patient determined at any time within 1 week, 2 weeks, 3 weeks, or 4 weeks prior to beginning treatment of the invention. Liver iron concentration may be determined according to the assays described in the Examples below.

[0069] Thus, in further embodiments, treatment of MDS according to the invention may reduce 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 time within a period of up to 1 week, up to 2 weeks, up to 3 weeks, up to 3 months after the first administration and compared to the level of renal iron concentration in the patient determined at any time within 1 week, 2 weeks, 3 weeks, or 4 weeks prior to beginning treatment of the invention. Renal iron concentration may be determined according to the assays described in the Examples below.

[0070] In further embodiments, treatment of MDS according to the invention may reduce 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 time within a period of up to 1 week, up to 2 weeks, up to 3 weeks, up to 3 months after the first administration and compared to myocardial iron concentration in the subject determined at any time within 1 week, 2 weeks, 3 weeks, or 4 weeks prior to beginning treatment of the invention. Myocardial iron concentration may be determined according to the assays described in the Examples below.

[0071] In further embodiments, treatment of MDS according to the invention may improve at least one of the parameters Hb, Hct, RBC count, MCV, MCH, RDW, and reticulocyte count in a patient 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 assessed at any time within a period of up to 1 week, up to 2 weeks, up to 3 weeks, up to 4 weeks, up to 3 months after the first administration and compared to the respective parameter in the subject assessed at any time within 1 week, 2 weeks, 3 weeks, or 4 weeks prior to beginning treatment of the invention. The parameters may be assessed according to conventional methods.

[0072] In a further embodiment, treatment of MDS according to the invention may result in an erythroid response, which may include reducing the transfusion burden in a patient by at least 33%, preferably at least 50%. In principle, an erythroid response may include reducing the transfusion burden in a 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 further embodiments, treatment of MDS according to the present invention may result in an erythroid response, which may include reducing transfusion burden in a 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% 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, up to 18 months, up to 24 months, or even longer, leading to transfusion independence. In further embodiments, the treatment of MDS according to the present invention may result in an erythrocytic response, which may include a reduction in erythrocytic transfusions in the patient by at least 1, 2, 3, 4 erythrocytic units, or more. In further embodiments, the treatment of MDS according to the present invention may result in an erythrocytic response, which may include a reduction in erythrocytic transfusions in the patient by at least 1, 2, 3, 4 erythrocytic units, or more, 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, up to 18 months, up to 24 months, or even more, leading to independence from transfusion of erythrocytic units. The erythrocytic response may include one or more of the above improvements. The erythrocytic response may be determined as described in the examples below.

[0073] Among them, one unit of red blood cells refers to the amount of packed red blood cells derived from approximately 200-500 mL of donated blood. Usually, blood transfusions are adjusted according to the age, severity of the disease, and the patient's starting blood parameters. Guidelines for selecting the amount of blood transfusion are, for example:

[0074] [Table 2] is recommended.

[0075] The individual blood transfusion volumes are calculated using the following formula: (Desired Hb - Actual Hb) x body weight [kg] x 3 / hematocrit value of unit transfused = ml transfused It can be further calculated using:

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

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

[0078] In further embodiments, treatment of MDS according to the invention can achieve that MDS patients treated according to the methods of the invention are 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, post-treatment from red blood cell transfusion to independence.

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

[0080] In further embodiments, treatment of MDS according to the present invention may result in a reduction in therapy with an erythropoietin stimulating agent, such as erythropoietin (EPO), for example a reduction in the dose or frequency of the erythropoietin stimulating agent administered to an MDS patient.

[0081] In further embodiments, treatment of MDS according to the present invention may reduce serum ferritin levels in a patient 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 time within a period of up to 1 week, up to 2 weeks, up to 3 weeks, up to 3 months after the first administration, and compared to serum ferritin levels in the patient determined at any time within 1 week, 2 weeks, 3 weeks, or 4 weeks before starting treatment according to the present invention. Serum ferritin levels may be determined according to conventional assays.

[0082] In further embodiments, treatment of MDS according to the present invention may result in a reduction in symptoms associated with one or more clinical MDS complications, non-limiting examples of MDS symptoms include pallor, jaundice, fatigue, and organ damage, e.g., liver damage, cardiac damage, and endocrine gland damage, due to chronic red blood cell transfusions, clinical complications such as Hepatitis B virus infection, Hepatitis C virus infection, and human immunodeficiency virus infection, alloimmunization, and iron overload.

[0083] In further embodiments, treatment of MDS according to the invention may improve quality of life in a patient as compared to quality of life in the patient determined within 1, 2, 3, or 4 weeks prior to initiating treatment of the invention. The improved quality of life is determined within 3, 6, 9, 12, 15, 18, 21, or 24 months after initiating treatment. Quality of life may be determined according to the assays described in the Examples below.

[0084] Treatment of MDS according to the present invention may result in one or more of the aforementioned improvements.

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

[0086] In principle, the subject to be treated in the use according to the invention may be any mammal, such as rodents and primates, and in a preferred embodiment, the medical use concerns the treatment of humans. The subject suffering from MDS and treated using the method according to the invention is also referred to as "patient" or "individual".

[0087] In particular, MDS patients treated according to the present invention are characterized by the underlying pathophysiological mechanisms detailed above, including the involvement of ineffective erythropoiesis, HSC depletion, and myeloid clonal expansion.

[0088] The subject to be treated may be of any age. A preferred embodiment of the present invention relates to the treatment of elderly people. Thus, in a preferred embodiment of the present invention, the subject to be treated using the novel method described herein is over 25 years old. In a further embodiment of the present invention, the subject to be treated using the novel method described herein is 25-30 years old, or over 30 years old, such as, preferably, 25-30 years old, 30-35 years old, 35-40 years old, 40-45 years old, 45-50 years old, 50-55 years old, 55-60 years old, or over 60 years old. In the preferred case of treating elderly patients, the subject to be treated using the novel method described herein is 60-65 years old, 65-70 years old, 70-75 years old, 75-80 years old, or over 80 years old.

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

[0090] The group or population of patients suffering from MDS and treated with the method according to the invention is selected from subjects (patients) characterized as defined above. In a further embodiment of the invention, the group or population of patients suffering from MDS and treated with the method according to the invention is selected from subjects (patients) with elevated NTBI levels. NTBI levels are considered elevated if they are detectable using known methods such as those discussed above. Preferably, NTBI levels of 0.1 μmol / L or more are considered elevated in MDS patients. More preferably, elevated NTBI levels in MDS patients according to the invention are NTBI values ​​that exceed the values ​​determined in healthy individuals in a separate determination method such as that described in 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(1): pp. 38-45.

[0091] In a further embodiment of the present invention, the patient group or population suffering from MDS and treated with the method according to the present invention is selected from subjects (patients) with elevated LPI levels. LPI levels are considered elevated when they are detectable using known methods such as those discussed above. Preferably, the elevated LPI levels in MDS patients according to the present invention exceed the values ​​determined in healthy individuals in a separate determination method such as that described in 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;101(1):38-45.

[0092] In a further embodiment of the present invention, the patient group or population suffering from MDS and treated with the method according to the present invention is selected from subjects (patients) with elevated TSAT levels.Preferably, the elevated TSAT level in MDS patients according to the present invention is a TSAT level that exceeds the average "normal" TSAT level determined in healthy individuals in a separate determination method.A TSAT level of about 25% is considered as the average. However, the reference range depends on several factors such as age, sex, race, and 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, which may cause organ damage.TSAT level can further be used to indirectly reflect NTBI, and therefore can be used as a translational marker.

[0093] In a further embodiment of the invention, the patient group or population suffering from MDS and treated with the method according to the invention is selected from subjects (patients) with dysfunctional and proapoptotic hematopoietic stem and progenitor cells (HSPCs) carrying an MDS mutation.

[0094] Usually, one or more of the following diagnostic criteria for MDS apply: (1) Cytopenia defined by standard hematological values (2) genetic analysis for somatic SF3B1 mutations; (3) morphological dysplasia (with or without RS); (4) less than 5% bone marrow blasts and less than 1% peripheral blood blasts; (5) Progression of leukemia or development of AML.

[0095] One of the most important hematological values ​​is the hemoglobin level (Hb). Patients suffering from MDS maintain Hb levels between 5 and 10 g / dl. Patients suffering from MDS are usually classified as anemic by having Hb levels less than 9 g / dL or less than 8 g / dL. Hb levels in MDS patients can be as low as 4 to 5 g / dl. Although international guidelines recommend transfusing patients who reach a hemoglobin range of 9 to 10 g / dL, with an optimal range after transfusion being 13 to 14 g / dL, in clinical practice Hb levels above 7 g / dL are usually considered sufficient without regular transfusions, and the usual aim under transfusion is to maintain the patient's hemoglobin level between 9.5 and 10 g / dL. However, depending on the condition, patients presenting with Hb levels between 7 and 8 g / dL may be found to require transfusion. Reaching the recommended high Hb level of 13-14 g / dL would require a disproportionate increase in transfusion burden, but the amount of blood required varies widely between patients and is heavily influenced by the patient's weight and the target hemoglobin level.

[0096] With this in mind, in a further embodiment of the present invention, the patient group or population suffering from MDS and treated with the method according to the present invention may be selected from subjects (patients) with a hemoglobin (Hb) level below 8 g / dL.

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

[0098] In a further embodiment of the invention, the patient group or population suffering from MDS and treated with the method according to the invention may be selected from subjects (patients) with an 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 invention may be selected from subjects (patients) having one or more of the following characteristics: a) Hb level below 8 g / dL, b) MCV between 50 and 70 fL, and c) 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 with 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] Regular blood transfusion further means more than one repeated transfusion of red blood cell (RBC) units within a time interval of at least up to two months or less. The interval may be of equal length or may vary depending on the individual patient, the progression of the disease, its severity, and treatment response. Regular blood transfusion may further include repeated transfusions of equal or different transfusion units at subsequent transfusion times. Regular blood transfusion includes: - Subsequent repeated transfusions of equal RBC units at different time intervals, or - Subsequent repeated transfusions of equal RBC units at equal time intervals, or - Subsequent repeated transfusions of different RBC units at equal time intervals, or - Subsequent repeated transfusions of different RBC units at different time intervals is possible.

[0102] In a further embodiment of the invention, regular blood transfusion means a transfusion-free period of less than 3 months, preferably less than 2 months.

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

[0104] Dosage form In a further aspect of the invention, the treatment of MDS comprises orally administering to a patient in need thereof one or more of the compounds of formula (I), salts, solvates, hydrates, or polymorphs thereof, each as described anywhere herein.

[0105] For this purpose, the compounds of formula (I) according to the invention are preferably provided in medicaments or pharmaceutical compositions in the form of oral dosage forms, including, for example, pills, tablets, e.g. enteric coated tablets, film tablets and layered tablets, oral sustained release formulations, depot preparations, dragees, granules, emulsions, dispersions, microcapsules, microformulations, nanoformulations, liposomal preparations, capsules, e.g. enteric coated capsules, powders, microcrystalline preparations, dusting powders, drops, ampoules, solutions and suspensions for oral administration.

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

[0107] Thus, a further aspect of the present invention relates to compounds of formula (I) according to the present invention, including their pharma- ceutically acceptable salts, solvates, hydrates and polymorphs, as well as medicaments, compositions and combined preparations containing them, for use in the treatment of MDS in the form of oral dosage forms.

[0108] Medication Regimen A further aspect of the invention relates to a compound of formula (I) according to the invention for use according to the invention, wherein the treatment is characterized by one of the following dosage regimens:

[0109] In one embodiment, the compound of formula (I) according to the present invention may be administered to a patient in need thereof at a dose of 0.001 to 500 mg, for example 1 to 4 times a day. However, the dose may be increased or decreased depending on the age, weight, condition of the patient, severity of the disease, or type of administration. In a further aspect of the invention, the compound of formula (I) is present in an amount 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, It may be administered in doses of 15mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg.

[0110] Preferred dosages are between 0.5 and 500 mg, more preferably between 1 and 300 mg or 3 and 300 mg, 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 dosages defined above can be administered as a total daily dose in a single dose each day or divided into separate doses to be administered two or more times a day.

[0113] In further embodiments, doses of 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, 10 and up to 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 each case once or twice daily.

[0114] In a further embodiment, one of the dosages defined above is selected as an initial dose, followed by one or more administrations of the same or different doses as defined above, at repeat intervals of 1 to 7 days, 1 to 5 days, preferably 1 to 3 days, or every second day.

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

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

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

[0118] The repetition intervals may be of the same length or may vary depending on the individual patient, the progression of the disease, and the treatment response.

[0119] Preferably, the subsequent doses are of decreasing amounts as the frequency of subsequent doses increases.

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

[0121] In a further preferred embodiment, a total daily dose of 240 mg is administered by administering a dose of 120 mg twice daily, said dose having been shown to be safe and well tolerated.

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

[0123] The preferred dosing regimen was further found to effectively reduce mean serum iron levels and mean calculated transferrin saturation and shift the mean serum hepcidin peak, indicating its effectiveness for treating MDS.

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

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

[0126] [ka] The present invention relates to a novel medicinal use of the compound.

[0127] Therein and throughout the present invention, the substituents have the meanings as specifically defined elsewhere in this specification.

[0128] Optionally substituted alkyl is preferably: linear or branched alkyl, preferably containing 1 to 8, more preferably 1 to 6, particularly preferably 1 to 4, even more preferably 1, 2 or 3 carbon atoms, also designated C1-C4-alkyl or C1-C3-alkyl.

[0129] Optionally substituted alkyl further includes cycloalkyl, preferably containing from 3 to 8, more preferably 5 or 6 carbon atoms.

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

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

[0132] Substituents for the optionally substituted alkyl as defined above are preferably, for example: halogen as defined below, such as preferably F, cycloalkyl as defined above, such as preferably cyclopropyl, optionally substituted heteroaryl as defined below, such as preferably a benzimidazolyl group, optionally substituted amino as defined below, such as preferably an amino group or a benzyloxycarbonylamino, carboxyl groups, aminocarbonyl groups as defined below, as well as alkylene groups, such as in particular methylene substituted ethyl groups (CH3-(C=CH2)- or

[0133] [ka] wherein * indicates a bonding site, there are one, two or three of the same or different substituents selected from the group consisting of methylene groups forming

[0134] Within the meaning of the present invention, halogen includes fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine, most preferably fluorine.

[0135] Examples of linear or branched alkyl residues containing 1 to 8 carbon atoms and substituted by halogen are:

[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, e.g., 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-bromopentyl group, Examples of the fluoroalkyl groups include ethyl, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, perfluoropentyl, 2-fluorohexyl, 2-chlorohexyl, 2-bromohexyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, perfluorohexyl, 2-fluoroheptyl, 2-chloroheptyl, 2-bromoheptyl, 7-fluoroheptyl, 7-chloroheptyl, 7-bromoheptyl, and perfluoroheptyl. Fluoroalkyl, difluoroalkyl, and trifluoroalkyl are particularly mentioned, with trifluoromethyl and mono- and difluoroethyl being preferred. Particularly preferred is trifluoromethyl.

[0137] Examples of cycloalkyl-substituted alkyl groups are the abovementioned alkyl residues containing 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. Preference is given to cyclopropylmethyl.

[0138] Examples of heteroaryl-substituted alkyl groups are the above-mentioned alkyl residues containing one to three, preferably one, (optionally substituted) heteroaryl group, such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, benzimidazolyl, thiophenyl, or oxazolyl groups, such as pyridin-2-yl-methyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl, 2-pyridin-2-yl-ethyl, 2-pyridin-1-yl-ethyl ... Lysin-3-yl-ethyl, pyridazin-3-yl-methyl, pyrimidin-2-yl-methyl, pyrimidin-4-yl-methyl, pyrazin-2-yl-methyl, pyrazol-3-yl-methyl, pyrazol-4-yl-methyl, pyrazol-5-yl-methyl, imidazol-2-yl-methyl, imidazol-5-yl-methyl, benzimidazol-2-yl-methyl, thiophen-2-yl-methyl, thiophen-3-yl-methyl, 1,3-oxazol-2-yl-methyl.

[0139] Preferred are alkyl groups substituted with benzimidazolyl groups, such as benzimidazol-2-yl-methyl and benzimidazol-2-yl-ethyl. Examples of amino-substituted alkyl residues are the above-mentioned alkyl residues containing one to three, preferably one, (optionally substituted) amino group, as defined below, such as aminoalkyl (NH2-alkyl) or mono- or dialkylaminoalkyl, such as aminomethyl, 2-aminoethyl, 2- or 3-aminopropyl, methylaminomethyl, methylaminoethyl, methylaminopropyl, 2-ethylaminomethyl, 3-ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminoethyl, 3-aminopropyl, or optionally substituted alkyloxycarbonylamino groups, such as those of the formula

[0140] [ka] Preferred are alkyl groups optionally substituted with groups according to the formula: (wherein R defines a phenyl group, forming a benzyloxycarbonylaminopropyl group).

[0141] Optionally substituted amino according to the present invention preferably includes: amino (-NH2), optionally substituted mono- or dialkylamino (alkyl-NH-, (alkyl)2N-), for "alkyl" reference may be made to the above definition of optionally substituted alkyl. 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, a carboxyl group designates the group [-(C=O)-OH] and an aminocarbonyl group designates the group [NH2-(C=O)-].

[0143] Optionally substituted alkoxy includes optionally substituted alkyl-O- groups, which may refer to the above definition of alkyl group. Preferred alkoxy groups are straight-chain or branched alkoxy groups containing up to 6 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, ethoxy, n-propyloxy, and i-propyloxy groups are preferred. Methoxy and ethoxy groups are more preferred. Particularly preferred is the methoxy group.

[0144] Throughout the present invention, optionally substituted alkanediyl is preferably a divalent linear or branched alkanediyl radical having 1 to 6, preferably 1 to 4, more preferably 1, 2 or 3 carbon atoms, optionally bearing 1 to 3, preferably 1 or 2, substituents selected from the group consisting of halogen, hydroxyl (-OH), oxo group (C=O; forming a carbonyl or acyl group [-(C=O)-]), and alkyl groups as defined above, e.g., preferably methyl. The following may be mentioned 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 are hydroxy-substituted alkanediyl, such as hydroxy-substituted ethanediyl, oxo-substituted alkanediyl, such as oxo-substituted methylene or ethanediyl groups forming carbonyl or acyl (acetyl) groups, halogen-substituted alkanediyl groups, such as alkanediyl groups substituted with one or two halogen atoms selected from F and Cl, preferably 2,2-di-fluoro-ethanediyl, or alkanediyl groups substituted with methyl groups.

[0146] According to the invention, A has the meaning of a linear or branched alkanediyl radical as defined above. 1 and R having the meaning of an optionally substituted alkyl group as defined above. 2may further be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4- to 6-membered ring, which may be substituted with 1 to 3 substituents as defined above. Thus, A 1 and R 2 may together form a group according to the formula:

[0147] [ka]

[0148] Among these, (substituted or unsubstituted) four-membered ring formations are preferred, for example very specifically

[0149] [ka] In this case, the left-hand binding site is preferably the X 1 and X 2 The right-hand bond indicates the direct bond site between A and the 5-membered heterocyclic ring, which has the meaning of an alkanediyl group as defined herein. 2 The site of attachment to the group is indicated.

[0150] In formula (I) as defined anywhere herein, n has the meaning of an integer from 1 to 3, inclusive, 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 context of the present invention, the individual substituents of 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 is different; Therefore, the formula

[0152] [ka] It forms a five-membered heterocyclic ring (In the formula, * indicates the bonding site to the aminocarbonyl group, and ** indicates the bonding site to the A 1 (indicating the site of attachment to the group). 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 (as defined above); selected from the group consisting of; Preferably, R 1 is hydrogen or methyl, more preferably R 1 is hydrogen. D)R 2 teeth, - Hydrogen, and - optionally substituted alkyl (as defined above); selected from the group consisting of; Preferably, R 2 is hydrogen or C1-C4-alkyl, more preferably R 2 is hydrogen or methyl, and even more preferably, R 2 is hydrogen. E)R 3 represents one, two or three optional substituents, which are halogen (as defined above), - Cyano, optionally substituted alkyl (as defined above); - optionally substituted alkoxy (as defined above), and - a carboxyl group (as defined above) may be independently selected from the group consisting of: Preferably, R 3represents one or two optional substituents, which are - halogen, - Cyano, - alkyl (as defined above), optionally substituted by 1, 2 or 3 halogen atoms (as defined above), optionally substituted alkoxy (as defined above); and Carboxyl group (as defined above) may be independently selected from the group consisting of: More preferably, R 3 represents one or two optional substituents, which are - F and Cl, - Cyano, - trifluoromethyl, - methoxy, and - Carboxyl group may be independently selected from the group consisting of: Even more preferably, R 3 is hydrogen and represents 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; More preferably, R 4 teeth, - Hydrogen, -Cl, - methyl, and - Trifluoromethyl selected from the group consisting of; More preferably, R 4 teeth, - Hydrogen, - Cl, and - Methyl selected from the group consisting of; Even more preferably, R 4 is hydrogen. G)A 1 is an alkanediyl; Preferably, A 1 is methylene or ethane-1,2-diyl, more preferably A 1 is ethane-1,2-diyl. H)A 2 is an alkanediyl; Preferably, A 2 is methylene, ethane-1,2-diyl, or propane-1,3-diyl; More preferably, A 2 is methylene or ethane-1,2-diyl; Even more preferably, A 2 is ethane-1,2-diyl. I) 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 as defined above; Among them, A 1 and R 2 together with the nitrogen atom to which they are attached, preferably form a four-membered ring, optionally substituted as defined above; Among them, A 1 and R 2 together with the nitrogen atom to which they are attached more preferably form an unsubstituted 4-membered ring (azetidinyl ring).

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

[0154] In a preferred embodiment of the invention, the compound of general formula (I) is defined by: X 1 is N or O; X 2 is N, S, or O; However, X 1 and X 2 is 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 hydrogen or C1-C4-alkyl; or A 1 and R 2 together with the nitrogen atom to which they are attached form an optionally substituted four-membered ring; R 3 represents one or two optional substituents, which are - halogen, - Cyano, - alkyl optionally substituted by 1, 2 or 3 halogen atoms, - optionally substituted alkoxy, and - Carboxyl group may be independently selected from the group consisting of: R 4 teeth, - Hydrogen -Cl, - Methyl, ethyl, isopropyl, and - Trifluoromethyl is selected from the group consisting of:

[0155] In a further preferred embodiment of the invention, the compound of general formula (I) is defined by: X 1 is N or O; X 2 is N, S, or O; However, X 1 and X 2 is different; R 1 is hydrogen; n is 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 form together with the nitrogen atom to which they are attached an unsubstituted four-membered ring; R 3 represents one or two optional substituents, which are - F and Cl, - Cyano, - trifluoromethyl, - methoxy, and - Carboxyl group may be independently selected from the group consisting of: R 4 teeth, - Hydrogen, -Cl, - methyl, and - Trifluoromethyl is selected from the group consisting of:

[0156] In a further preferred embodiment of the invention, the compound of general formula (I) is defined by X 1 is N or O; X 2 is N, S, or O; However, X 1 and X 2 is 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 form together with the nitrogen atom to which they are attached an unsubstituted four-membered ring; R 3 represents hydrogen, thus forming an unsubstituted terminal benzimidazolyl ring; R 4 teeth, - Hydrogen, - Cl, and - Methyl is selected from the group consisting of:

[0157] In a further preferred embodiment of the invention, the compound of general formula (I) is defined by X 1 is N or O; X 2 is N, S, or O; However, X 1 and X 2 is 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 form together with the nitrogen atom to which they are attached an unsubstituted four-membered ring; R 3 represents hydrogen, thus forming an unsubstituted terminal benzimidazolyl ring; and R 4 is hydrogen.

[0158] In a further aspect, the present invention relates to novel uses and methods of treatment as defined herein, wherein the compound according to formula (I) or salts, solvates, hydrates and polymorphs 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 A 1 and R 2 together with the nitrogen atom to which they are attached form an optionally substituted four-membered ring; Forming a compound according to formula (II) or (III):

[0159] [ka] In the formula (II) and / or (III), l is 0 or 1; m is an integer of 1, 2, or 3; X 1 , X 2 , R 1 and R 2 has the meaning as defined for compounds of formula (I) anywhere herein Uses and methods.

[0160] Preferably, in formulas (II) and (III), X 1 and X 2 has the meaning as defined above in A).

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

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

[0163] In a further preferred embodiment of the invention, the compound of general formula (II) X 1 and X 2 is selected from N and O and is different; R 1 = hydrogen; R 2 = hydrogen; l=1; and m=2 is defined as follows:

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

[0165] For suitable pharma- ceutically acceptable salts of compounds of formulae (I), (II), and (III) as defined anywhere herein, see International Applications WO2017 / 068089, WO2017 / 068090, and in particular WO2018 / 192973, the definitions of pharma- ceutically acceptable salts as disclosed therein are hereby incorporated by reference.

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

[0167] [Table 3] It may be selected from the group consisting of:

[0168] In a further preferred embodiment, the present invention relates to uses and methods of treatment as defined herein, wherein the pharma- ceutically acceptable salt of a compound of formula (I), (II) or (III) or of a compound according to WO2020 / 123850A1 is selected from salts with an acid 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. Preferred acids are 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 the pharma- ceutically acceptable salts of the compounds of formula (I), (II), or (III) are selected from mono salts (1:1 salts), triple salts (1:3 salts), and salts characterized by a ratio of compound (I), (II), or (III) to the acid of 1-2:1-3; including solvates, hydrates, and polymorphs thereof.

[0170] Therein, the salts of compounds (I), (II), or (III) may be characterized by the selected ratio of base:acid, i.e., compound (I), (II), or (III):acid as defined above, ranging from 1.0 to 2.0 (mol base):1.0 to 3.0 (mol acid). In certain embodiments, the selected ratio of base:acid is 1.0 to 2.0 (mol base):1.0 to 2.0 (mol acid).

[0171] Particular examples include the following ratios of base:acid, i.e., compound (I), (II), or (III):acid as defined above: 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, a salt with a 1:1 ratio of base:acid is also referred to as a "mono salt" or a "1:1 salt." For example, a mono HCl salt is also referred to as monoHCl or a monoHCl salt.

[0173] Among them, a salt with a base:acid ratio of 1:2 is also called a "di-salt" or a "1:2 salt." For example, a di-HCl salt is also called diHCl or a diHCl 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, tri-HCl salts are also referred to as 3HCl or 3HCl salts.

[0175] A salt with a base:acid ratio of 1:1.25 is also called a "1:1.25 salt."

[0176] A salt with a base:acid ratio of 1:1.35 is also called a "1:1.35 salt."

[0177] A salt with a base:acid ratio of 1:1.5 is also called a "1:1.5 salt."

[0178] A salt with a base:acid ratio of 1:1.75 is also called a "1:1.75 salt."

[0179] Salts with a 2:1 ratio of base:acid are also called "hemisalts" or "2:1 salts."

[0180] The salts of the compounds of formula (I), (II) or (III) according to the invention may exist in amorphous, polymorphic, crystalline and / or semi-crystalline (partially crystalline) form, 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 invention exist in crystalline and / or semi-crystalline (partially crystalline) form, and / or in the form of solvates thereof.

[0181] The preferred crystallinity of salts or salt solvates may be determined by using conventional analytical methods, for example by using various X-ray methods, which allow clear and easy analysis of salt compounds. In particular, the grade of crystallinity may be determined or confirmed by using powder X-ray diffraction (reflection) or by using powder X-ray diffraction (transmission) (PXRD). For crystalline solids with the same chemical composition, the differently obtained crystal lattices are summarized by the term polymorphs. For solvates, hydrates, and polymorphs and salts with specific 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 uses and methods of treatment as defined herein, wherein a compound of formula (I), (II) or (III) is:

[0183] [Table 4] and uses and methods selected from the group consisting of pharma- ceutically 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] and uses and methods selected from the group consisting of pharma- ceutically 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] The present invention relates to uses and methods selected from the group consisting of:

[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] and uses and methods selected from the group consisting of pharma- ceutically acceptable salts, solvates, hydrates, and polymorphs thereof.

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

[0191] [ka] and pharma- ceutically acceptable salts, solvates, hydrates, and polymorphs thereof.

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

[0193] [ka] 1:1 sulfate salt with formula

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

[0195] [ka] formula

[0196] [ka] 1:3 HCl salt with and these polymorphs is selected from the group consisting of:

[0197] As described in WO2017 / 068089, WO2017 / 068090, and WO2018 / 192973, the compounds of formula (I) act as ferroportin inhibitors. Please refer to said international applications for the ferroportin inhibitor activity of the compounds.

[0198] Pharmaceuticals containing ferroportin inhibitor compounds A further aspect of the present invention relates to medicaments or pharmaceutical compositions comprising one or more of the compounds of formula (I), (II), or (III) as defined anywhere herein for novel uses and methods of treatment of MDS as defined anywhere herein.

[0199] Such medicaments may further comprise one or more pharmaceutical carriers and / or one or more auxiliary agents and / or one or more solvents.

[0200] Preferably the medicament is in the form of an oral dosage form, for example as defined above.

[0201] Preferably, the pharmaceutical carriers and / or auxiliary agents and / or solvents are selected from among the compounds suitable for preparing oral dosage forms.

[0202] Said pharmaceutical compositions comprise, 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 being formed by pharmacologically acceptable carriers and / or auxiliary agents and / or solvents and / or optionally further pharma- ceutical active compounds, respectively.

[0203] Among these, pharma- ceutically acceptable carriers, auxiliary substances, or solvents are common pharmaceutical carriers, auxiliary substances, or solvents, and include various organic or inorganic carriers and / or auxiliary materials as are customarily used for pharmaceutical purposes, especially in solid pharmaceutical formulations. Examples include excipients such as saccharose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talcum, calcium phosphate, calcium carbonate; binders such as cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethylene glycol, saccharose, starch; disintegrants such as starch, hydrolyzed starch, carboxymethylcellulose, calcium salt of carboxymethylcellulose, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate; lubricants such as magnesium stearate, talcum, sodium lauryl sulfate; flavorings such as citric acid, menthol, glycine, orange powder; preservatives such as sodium benzoate, sodium bisulfite, parabens (e.g. methylparaben, ethylparaben, propylparaben, butylparaben); stabilizers such as citric acid, sodium citrate, acetic acid, and multicarboxylic acids from the titriplex series, e.g. diethylenediaminetetraacetic acid (DTPA). acids); suspending agents, for example, methylcellulose, polyvinylpyrrolidone, aluminum stearate; dispersing agents; diluents, for example, water, organic solvents; waxes, fats, and oils, for example, beeswax, cocoa butter; polyethylene glycols; white petrolatum; and the like.

[0204] Liquid pharmaceutical formulations, such as solutions, suspensions, and gels, usually contain a liquid carrier, such as water and / or a pharma- ceutically acceptable organic solvent. In addition, such liquid formulations may also contain pH adjusting agents, emulsifying or dispersing agents, buffers, preservatives, wetting agents, gelling agents (e.g., methylcellulose), dyes, and / or flavoring agents, such as those defined above. The composition may be isotonic, i.e., have the same osmotic pressure as blood. The isotonicity of the composition may be adjusted by using sodium chloride and other pharma- ceutically acceptable agents, such as 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 pharma- ceutically acceptable thickening agent, such as methylcellulose. Other suitable thickening agents include, for example, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, and the like. The preferred concentration of the thickening agent will depend on the drug selected.

[0205] Pharmaceutically acceptable preservatives may be used to extend the shelf life of the liquid composition. Benzyl alcohol may be suitable, but a number of preservatives may also be used, including, for example, parabens, thimerosal, chlorobutanol, and benzalkonium chloride.

[0206] Combination Therapy A further object of the present invention relates to a medicament or combination preparation comprising one or more of the ferroportin inhibitor compounds as defined anywhere herein and at least one further pharma- ceutical active compound ("combination therapy compound"), preferably an additional active compound useful in the treatment of MDS as defined herein. Preferred combination therapy compounds are specific compounds used in the prevention and treatment of ineffective erythropoiesis, including erythropoietin stimulating agents, 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 additional treatment option for MDS patients. Further preferred combination therapy compounds are selected from medicaments for treating iron overload and associated symptoms. Most preferred combination therapy compounds are iron chelating compounds or compounds for preventing and treating any of the conditions, disorders, or diseases associated with or caused by iron overload and MDS. Suitable combination therapy drug compounds (co-drugs) may be selected from pharmacologic active compounds for preventing and treating MDS and related conditions. In particular, co-drugs for treating ineffective hematopoiesis, especially ineffective erythropoiesis, such as erythropoietin stimulators or erythropoietin are preferred. In a further embodiment, at least one additional pharmacologic active combination therapy compound is selected from drugs for reducing iron overload (e.g., Tmprss6-ASO), and iron chelators, especially curcumin, SSP-004184, deferithrine, deferasirox, deferoxamine, and deferiprone, and hydroxyurea, and JAK2 inhibitors.

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

[0208] Further possible codrugs include erythrocyte maturation agents such as luspatercept, or other erythrocyte maturation agents / erythrocyte stimulating agents such as EPO, epoetin, or darbepoetin, or synthetic human hepcidin (LJPC-401), the hepcidin peptidomimetic PTG-300, and antisense oligonucleotides targeting Tmprss6 (IONIS-TMPRSS6-LRX).

[0209] In a further aspect, the present invention relates to a use in the medical treatment of MDS as defined herein, in which a ferroportin inhibitor compound as defined herein is administered to a patient in need thereof in combination therapy with one or more of the combination therapy compounds (codrugs) defined above, in fixed dose or non-fixed dose combination for continuous use. Such combination therapy comprises the simultaneous administration of a ferroportin inhibitor compound as defined herein and at least one additional pharmacologic active compound (drug / combination therapy compound).

[0210] Combination therapy in fixed dose combination therapy involves the co-administration of a ferroportin inhibitor compound, as defined herein, and at least one additional pharma- ceutical active compound in a fixed dose formulation.

[0211] Combination therapy in the context of non-fixed dose combination therapy includes the co-administration of a ferroportin inhibitor compound as defined herein with at least one additional pharma- ceutical active compound in non-fixed doses of the individual compounds, either by co-administration of the individual compounds given separately over a period of time (Distributed) or by sequential use of the individual compounds.

[0212] In a preferred embodiment, the combination therapy involves the co-administration of an oral ferroportin inhibitor according to Example Compound No. 127 described herein with erythropoietin.

[0213] In a further embodiment, the combination therapy comprises co - administration of an oral ferroportin inhibitor according to Example Compound No. 127 described herein and luspatercept.

[0214] In a further embodiment, the combination therapy comprises co - administration of an oral ferroportin inhibitor according to Example Compound No. 127 described herein and deferasirox, an iron chelating agent.

[0215] A further embodiment of the present invention is the combination therapy described herein, wherein the ferroportin inhibitor compound is selected from those described in WO2020 / 123850A1, particularly one of the specific example compounds as described above. Preferably, such a combination therapy comprises co - administration of the ferroportin inhibitor compound and deferasirox, an iron chelating agent.

Brief Description of the Drawings

[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. [Diagram 2] MDS mice show very mild, mild, and moderate anemia at 3 months of age. Blood parameters (hemoglobin, red blood cell count, hematocrit, and white blood cell count) in 3 - month - old wild - type (WT) control mice and myelodysplastic (MDS) mice according to anemia levels (no anemia / very 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). [Diagram 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 serum of 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Figure 4] Fpn127 treatment prevents iron loading in MDS mice. Liver, kidney, and spleen iron content in 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Diagram 5] Fpn127 treatment ameliorates anemia in MDS mice. Erythrocyte parameters (hemoglobin, red blood cell count, hematocrit, mean cell volume, mean cellular hemoglobin, and reticulocyte count) in 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Figure 6] Fpn127 treatment shows a trend towards reduced progression to leukemia in MDS mice. White blood cell parameters (white blood cell, platelet, neutrophil, lymphocyte, and monocyte counts) in 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Figure 7] Fpn127 treatment improves bone marrow erythroid maturation in MDS mice. Immature to mature erythroid populations were monitored by progressive loss of CD71 expression on bone marrow Ter119+ erythroid cells in 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Figure 8]Fpn127 treatment improves bone marrow erythroid maturation in MDS mice. Erythroid maturation was assessed by assessing erythroid populations I to V (I: proerythroblasts; II: basophilic erythroblasts; III: polychromatic erythroblasts; IV: normochromatic erythroblasts / reticulocytes; V: erythrocytes) via progressive loss of CD44 expression on bone marrow Ter119+ erythroid cells in 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Figure 9] Fpn127 treatment improves splenic erythrocyte maturation in MDS mice. Immature to mature erythrocyte populations were monitored by progressive loss of CD71 expression on splenic Ter119+ erythroid cells in 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [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: normochromatic erythroblasts / reticulocytes; V: erythrocytes) via progressive loss of CD44 expression on splenic Ter119+ erythrocyte cells in 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Figure 11] Fpn127 treatment improves erythrocyte maturation in MDS mice. Improvement of erythrocyte maturation by Fpn127 was confirmed by monitoring the loss of CD71 expression on bone marrow and splenic Ter119+ erythroid cells in 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice that were untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Figure 12]Fpn127 treatment ameliorates anemia by reducing oxidative stress and apoptosis of erythroid precursors in MDS mice.Iron accumulation (labile iron), oxidative stress (ROS), and apoptosis (Annexin V) were monitored by flow cytometry in bone marrow and splenic Ter119+ erythroid cells from 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice that were untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Figure 13] Fpn127 treatment improves the overall status of hematopoietic LSK cells in MDS mice. Cell percentage, iron accumulation (labile iron), oxidative stress (ROS), and apoptosis (Annexin V), and double-stranded strand breaks (γH2AX) were monitored by flow cytometry in bone marrow hematopoietic Lin- Sca-1+ ckit+ (LSK) cells from 6-month-old wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated for 3 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Figure 14] Fpn127 treatment ameliorates anemia in aged MDS mice. Erythroid parameters (hemoglobin, red blood cell count, hematocrit) in 8-10 month old wild type (WT) control and myelodysplastic (MDS) mice untreated or treated for 3-5 months with 0.5 mg / ml Fpn127 (MDS+VIT). [Figure 15] Fpn127 treatment reduces leukemia-related deaths in aged MDS mice. WBC counts in 8-10 month old wild type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5mg / ml Fpn127 (MDS+VIT) for 3-5 months. As shown, two untreated MDS mice died of leukemia while two Fpn127-treated MDS mice died of MDS, as indicated by the lower WBC counts. [Figure 16]VIT-2763 treatment ameliorates anemia in MDS mice. Longitudinal monitoring of blood parameters (hemoglobin - Hb, hematocrit - HCT, red blood cells - RBC) in wild-type (WT) control and myelodysplastic (MDS) mice untreated or 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. Improvement in Hb (Δ, delta), HCT and RBC in myelodysplastic (MDS) mice untreated or treated with 0.5mg / ml VIT-2763 (MDS+VIT) starting at 3 months of age. Δ is shown after 2, 3 and 4 months of treatment (5, 6 and 7 months of age). [Figure 18] VIT-2763 treatment delays leukemia progression in MDS mice. Longitudinal monitoring of total leukocytes, monocytes, and neutrophils in wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 months of age. [Figure 19] VIT-2763 treatment improves survival in MDS mice. Kaplan-Meier curves in wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 months of age. [Figure 20] VIT-2763 treatment reduces bone marrow immature cells in MDS mice. Percentage of cKit+ and Lin+ cKit+ cells in bone marrow of wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 to 6 months of age. Immature blasts are within the Lin+ cKit+ population. [Figure 21]VIT-2763 treatment reduces myeloid proliferation in the bone marrow of MDS mice. Percentages of CD45+ immune cells, CD11b+ myeloid cells, and CD3+ CD19+ lymphoid cells in the bone marrow of wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 to 6 months of age. [Figure 22] VIT-2763 treatment reduces myeloid proliferation in the bone marrow of MDS mice. Percentages of total CD11b+Ly6C+Ly6G+ myeloid-derived suppressor cells (MDSCs), CD11b+ Ly6C+ monocytes, and CD11b+ Ly6G+ granulocyte MDSCs in the bone marrow of wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 to 6 months of age. [Figure 23] VIT-2763 treatment improves macrophage numbers in the bone marrow of MDS mice. Percentages of total macrophages, erythroblastic islands, and HSC macrophages in the bone marrow of wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 to 6 months of age. [Figure 24] VIT-2763 treatment limits bone marrow macrophage-mediated inflammation in MDS mice. TNFa and IL-1b production in total bone marrow macrophages from wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 3 to 6 months of age. [Diagram 25] VIT-2763 treatment ameliorates anemia in MDS mice. Longitudinal monitoring of blood parameters (hemoglobin - Hb, hematocrit - HCT, red blood cells - RBC) in wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 5 months of age. [Figure 26]VIT-2763 treatment delays leukemia progression in MDS mice. Longitudinal monitoring of leukocytes in wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 5 months of age. [Figure 27] VIT-2763 treatment improves survival in MDS mice. Kaplan-Meier curves in wild-type (WT) control and myelodysplastic (MDS) mice untreated or treated with 0.5 mg / ml VIT-2763 (MDS+VIT) from 5 months of age. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0217] In the figure, "VIT-2763" or "VIT" refers to the test compound Fpn127 (Example Compound No. 127). EXAMPLES

[0218] The present invention is illustrated in more detail by the following examples, which are merely illustrative and one skilled in the art can extend the specific examples to additional ferroportin inhibitor compounds according to the present invention.

[0219] I. Ferroportin inhibitor example compounds For the preparation of specific ferroportin inhibitor example compounds Nos. 1, 2, 4, 40, 94, 118, 126, 127, 193, 206, 208, and 233 described herein, as well as the preparation of pharma- ceutically acceptable salts thereof, see International Applications WO2017 / 068089, WO2017 / 068090, and WO2018 / 192973.

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

[0221] II. Pharmacological assays II.1 Introduction Orally bioavailable ferroportin inhibitors, such as the clinical stage compound Example Compound No. 127 (Fpn127), have been shown to improve ineffective erythropoiesis, improve anemia, and prevent NTBI formation and liver iron loading in mouse MDS models. Ferroportin inhibitors, such as the clinical stage Example Compound No. 127, further limit iron availability and reactive oxygen species (ROS) in erythrocyte precursors, thus preventing their apoptosis and improving ineffective erythropoiesis. As a result, anemia is improved with more RBCs with an extended life span, and tissue oxygenation is improved.

[0222] Based on this, the inventors of the present invention have found that the described ferroportin inhibitors are particularly efficient in the treatment of MDS, especially in the treatment of ineffective erythropoiesis. Patients with MDS suffering from ineffective erythropoiesis have reduced Hb levels, which are usually treated with blood transfusions (BT), causing severe iron overload. In a further embodiment, the prevention of intestinal iron absorption by ferroportin inhibitors in the interval between transfusions helps to 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 found to have elevated NTBI levels, which applies to transfused and non-transfused MDS patients.

[0223] It has now been found that oral ferroportin inhibitors according to the present invention, such as ferroportin inhibitor example compound No. 127, have the potential to prevent these deleterious effects by sequestering iron in macrophages. In line with the beneficial effects achieved with ferroportin inhibition 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 in MDS patients.

[0224] II.2 Evaluation of the ferroportin inhibitor compound Fpn127 in preclinical MDS mouse models Background Summary Patients with myelodysplastic syndromes (MDS) are prone to iron overload due to ineffective erythropoiesis that promotes increased iron absorption, and chronic blood transfusions are often essential to reverse anemia in this patient population. The effect of the ferroportin inhibitor compounds of the present invention in transfusion-independent and transfusion-dependent MDS has been evaluated using the example compound Fpn127, with the aim of showing 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 overall iron burden in transfusion-independent MDS by reducing iron influx into the body through erythropoiesis-driven hepcidin inhibition. The reduction of iron levels and NTBI is believed 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 erythropoiesis, and limiting oxidative damage to hematopoietic stem cells (HSCs). In transfusion-dependent MDS, in addition to reducing iron absorption, FPN inhibition is believed to provide a strategy to limit RBC-driven iron and cause its redistribution from iron-sensitive tissues to recycling macrophages.This is believed to provide beneficial effects in transfusion-dependent MDS by reducing NTBI levels and thus reducing the exposure of bone marrow to NTBI in particular.Furthermore, the combination of ferroportin inhibitors according to the present invention administered in combination therapy with iron chelation is believed to provide a new and more effective strategy to remove body iron in transfusion-dependent MDS conditions.

[0225] Determining the steady-state effects of iron restriction induced by administration of Fpn127 in a mouse model of MDS The ferroportin inhibitor compound Fpn127 was tested in NUP98-HOXD13 MDS mice. Fpn127 was administered at a concentration of 0.5 mg / ml in drinking water containing 1% glucose.

[0226] Preventive effects: 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 three-month-old MDS mice were treated with the example compound Fpn127 and compared with 15 untreated MDS mice and wild-type controls that matched in age and gender (a total of three repeated experiments). Mice aged three to six months were treated for three months. During the treatment period, two untreated and one treated MDS mouse died.

[0227] Three-month-old MDS mice already show a certain degree of anemia, which supports starting the ferroportin inhibitor in the treatment from three months until erythropoiesis and anemia are improved (Figure 1).

[0228] Approximately 60 - 70% of MDS mice show mild to moderate anemia at three months of age. According to the Hb level, three-month-old MDS mice can be divided into three 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 three months of age. This reflects the situation of MDS patients, about 70 - 80% of whom show anemia of varying severity at the time of diagnosis.

[0229] In MDS mice treated with Fpn127 from three to six months of age for three months, the following parameters were monitored: · Serum iron level 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 to 15 show results obtained as the average of three independent experiments.

[0231] Serum iron levels and NTBI: Serum iron and NTBI levels are elevated in MDS mice compared with control mice and are significantly reduced by Fpn127 treatment (FIG. 3).

[0232] Hepatic iron accumulation: Liver and kidney iron content is elevated in MDS mice compared to controls and is significantly reduced by Fpn127 treatment (both males and females) (Figure 4). In contrast, splenic iron is slightly, but not significantly, elevated in MDS mice due to enhanced iron absorption and slight erythroid proliferation, and is further elevated upon VIT treatment, consistent with VIT-mediated FPN inhibition and splenic macrophage iron accumulation (Figure 4).

[0233] Anemia and blood parameters: Hb, RBC, and HCT are decreased in MDS mice compared to control animals and are significantly improved by Fpn127 treatment. Reticulocytes show a tendency to improve after Fpn127 treatment. MCV and MCH remain unchanged (Figure 5).

[0234] Leukocyte parameters: WBC counts are decreased in MDS mice. Only MDS mice that developed a form of leukemia show a significant increase in WBC counts, both lymphoid or myeloid lineages. Three mice in the untreated group show an increase in WBC counts (one developed leukemia), while only one mouse in the Fpn127-treated group shows a trend toward increased WBC counts. Reticulocytes show a trend toward improvement after Fpn127 treatment. Platelet counts in MDS mice are decreased and remain unchanged after Fpn127 treatment (Figure 6).

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

[0236] Erythropoiesis: Amelioration of anemia following Fpn127 treatment was associated with reduced ROS formation and apoptosis in Ter119+ erythroid precursors, suggesting that limiting oxidative stress and improving cell survival mechanistically contribute to improved erythropoiesis (Figure S12).

[0237] Hematopoietic stem cells: Iron restriction by Fpn127 treatment is associated with an overall improvement in hematopoietic LSK stem cell status (Figure 13). The pool of LSK cells is reduced in MDS mice and may be prevented by Fpn127 treatment. LSK cells from Fpn127-treated MDS mice show reduced iron accumulation, reduced ROS production, and improved cell survival (reduced apoptosis), suggesting that changes in these events increase the preservation of the HSC pool. Furthermore, LSK cells show reduced double-stranded strand breaks (DSBs; reduced γH2AX) in Fpn127-treated MDS mice compared to untreated animals. DSBs may contribute to leukemia progression via the accumulation of mutations in HSPCs that acquire an increased propensity for proliferation and clonogenic potential.

[0238] Rescue Effects: To study the rescue effect of ferroportin inhibitors according to the invention on 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 with eight age- and sex-matched MDS untreated mice and wild-type controls (one experiment). Mice were treated from 5 months of age onwards. During the treatment period, three untreated and three treated MDS mice died. In this cohort of mice, no improvement of anemia was observed after 3 months of treatment (from 5 to 8 months of age). However, the results of mice aged 9 and 10 months suggest that some of the mice were able to obtain the benefit of Fpn127 treatment with partial improvement of anemia (Figure 14). Mice died of different causes - two untreated MDS mice died of AML and TLL; two Fpn127-treated MDS mice died of MDS without obvious progression to leukemia (Figure 15). The other two mice died without the opportunity to monitor the parameters. Molecular analysis of treated mice at 5 months of age was not available, as this cohort was kept for further observation and monitoring. To better track the modulation of individual blood parameters, two cohorts of mice, treated at 3 and 5 months of age, respectively, will be longitudinally analyzed monthly along with the treatment.

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

[0240] Prevention effect - additional results: To study the protective effect of the compound against the progressive development of iron overload and associated toxicity, MDS mice at 3 months of age were treated and compared with age- and sex-matched untreated MDS mice and wild-type controls. Mice were treated with VIT-2763 from 3 months of age and followed longitudinally for blood parameters and survival (Figures 16-19) or from 3 to 6 months of age for 3 months, and cellular and biochemical analyses were performed (Figures 20-24).

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

[0242] White blood cell parameters - additional results: The WBC count in MDS mice was initially decreased. 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 WBC in peripheral blood in the VIT-2763 treated group was not observed or was delayed (Figure 18).

[0243] Consistent with the trend toward reduced / delayed leukemia onset, immature Lin, including myeloblasts, were identified in MDS mice. + cKit + The cells increased and then 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 decreased percentages of bone marrow CD11b+ myeloid cells and monocytic and granulocytic myeloid-derived suppressor cells (MDSCs) (Figures 21 and 22).

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

[0246] Rescue Effect - Additional Results: To study the rescue effect of the compounds on established iron overload and associated toxicity 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 from 5 months of age onwards. In this cohort of mice, improvement of anemia was observed after 5 months of treatment (10 months of age). Anemia in MDS mice tends to worsen from 5 months of age onwards. The results suggest that while initially, most mice do not benefit from treatment, some mice may benefit with partial improvement of anemia at around 10 months of age (Figure 25).

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

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

[0249] Overall, VIT treatment in aged MDS mice resulted in a small change in median survival improvement of about 16 days compared to untreated mice (Figure 27). However, this clearly demonstrates that some mice can derive special benefit from VIT treatment, with all untreated MDS animals dying within 400 days of birth and MDS benefiting from VIT treatment reaching up to 600 days.

[0250] III. Blood transfusion burden Transfusion burden in a subject treated according to the methods of the invention may be assessed by determining the patient's transfusion requirements, e.g., via the required amount and / or frequency of red blood cell transfusions by conventional clinically accepted assessments.

[0251] IV. Iron levels Iron levels, e.g., liver, kidney, or myocardial iron levels, may be determined using conventional assays. For example, iron levels (e.g., liver iron concentration, kidney 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. Erythroid response The duration of the erythroid response may be calculated for subjects who achieved a response using the following algorithm: First day of response = first day of the first 12-week interval showing a response. Last day of response = last day of the last consecutive 129-week interval showing an interval response. Last Assessment Date = either the date of last visit for subjects still on drug or the date of discontinuation for subjects who discontinued treatment.

[0254] Duration of erythroid response may be calculated depending on whether the response terminates before the last assessment date as follows: 1. For subjects whose response is not sustained through the end of the treatment period, duration of response will not be censored and will be calculated as follows: Response duration = last day of response - first day of response + 1; 2. For subjects who continue to show an erythroid response through the end of the treatment period, the last day of response will be censored and the duration of response will be calculated as follows: Duration of response = date of last response assessment - date of first response + 1.

[0255] The time to first red blood cell response may be calculated as follows: The days from first dose of study drug to the date of onset of response will be calculated using the following: Time to response = day of first response - day of first study drug + 1.

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

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

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

[0259] The experiments described therein were performed by intravenous administration of a small molecule ferroportin inhibitor, VIT-2653, which corresponds to Example Compound No. 40 of the present invention, and further confirm some of the findings of the present invention.

[0260] NTBI and Hb levels after exchange transfusion were significantly improved by administration of a ferroportin inhibitor.

[0261] Additionally, total iron in the kidney after transfusion can be reduced by administering a ferroportin inhibitor. We assessed the contribution of circulating Hb to renal iron loading and the subsequent effect on oxidative stress and cellular damage and found that administering a ferroportin inhibitor to transfused guinea pigs significantly reduced the occurrence of changes in plasma creatinine >0.3 mg / dL, which is used as an indicator of early acute kidney injury (AKI).

[0262] Experimental details and study conditions and specific study results can be derived from the cited papers.

Claims

1. A compound according to formula (I) for use in the prevention or treatment of myelodysplastic syndrome (MDS) and / or symptoms associated therewith. 【Chemical 1】 (In the formula, X １ is N or O; X ２ is N, S, or O; However, X １ and X ２ is different; R １ teeth, - hydrogen, and - optionally substituted alkyl selected from the group consisting of: n is an integer from 1 to 3; A １ and A ２ are independently selected from the group of alkanediyls, R ２ teeth, - hydrogen, or - optionally substituted alkyl Is it; 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 - halogens, - Cyano, optionally substituted alkyl, optionally substituted alkoxy, and - carboxyl group may be independently selected from the group consisting of: R ４ teeth, - hydrogen, - halogens, - C １ ~C ３ - alkyl, and - Halogen-substituted alkyl selected from the group consisting of and pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof.

2. 2. The compound of formula (I), or salts, solvates, hydrates, and polymorphs thereof, for use according to claim 1, wherein the treatment of myelodysplastic syndromes (MDS) and / or symptoms associated therewith includes treatment of ineffective hematopoiesis, in particular ineffective erythropoiesis.

3. 2. The compound of formula (I), or salts, solvates, hydrates, and polymorphs thereof, for use according to claim 1, wherein the treatment of myelodysplastic syndromes (MDS) and / or symptoms associated therewith comprises reducing, preventing, or slowing the progression of leukemia, reducing bone marrow immature cells, reducing myeloid proliferation, reducing the production of inflammatory cytokines such as TNFα and IL-1β by macrophages, and / or improving the bone marrow microenvironment.

4. 4. The compound of formula (I), or salts, solvates, hydrates, and polymorphs thereof, for use according to any one of claims 1 to 3, 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 IPSS scoring system.

5. 5. The compound of formula (I), or salts, solvates, hydrates and polymorphs thereof, for use according to any one of claims 1 to 4, wherein the patient to be treated is selected from individuals characterized by one or more of the following: - Myelodysplastic syndrome with ring sideroblasts according to 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 with less than 5% myeloblasts; - Myelodysplastic syndrome with erythropoietin levels greater than 200 U per liter; - Suffering from erythroid dysplasia; - Cytopenia, especially peripheral cytopenia; - less than 5% myeloblasts; - less than 1% peripheral blood blasts; - Having myelodysplastic syndrome with reduced or absent response to erythropoiesis-stimulating agents; - suffer from myelodysplastic syndrome with chromosome 5q deletion (del[5q]); - SF3B1 mutated patients; - patients in which the PPOX and / or ABCB7 genes are significantly downregulated compared to healthy individuals; - Transfusion dependent or receiving regular red blood cell transfusions of 2 or more units per 8 weeks.

6. The patient, a) exhibiting detectable levels of NTBI; and / or b) Hb levels below 8 g / dL, and / or c) having an MCV between 50 and 70 10 fL; and / or d) having between 12 and 20 pg of MCH; and / or e) having a TSAT level greater than 45% 6. The compound of formula (I), or a salt, solvate, hydrate, or polymorph thereof, for use according to any one of claims 1 to 5, characterized by:

7. The patient to be treated is selected from transfusion-dependent patients characterized by receiving blood transfusions on a regular basis, and receiving blood transfusions on a regular basis is a) Subsequent repeated transfusions of equal red blood cell (RBC) units at different time intervals; or b) Repeated transfusions of equal RBC units at subsequent equal time intervals; or c) Subsequent repeated transfusions of different RBC units at equal time intervals; or d) Subsequent repeated transfusions of different RBC units at different time intervals.

7. The compound of formula (I), or salts, solvates, hydrates, and polymorphs thereof, for use according to any one of claims 1 to 6, comprising:

8. 8. The compound of formula (I), or a salt, solvate, hydrate, or polymorph thereof, for use according to any one of claims 1 to 7, wherein the treatment comprises orally administering one or more of the compound of formula (I), a salt, solvate, hydrate, or polymorph thereof to a patient in need thereof.

9. 9. The compound of formula (I), or a salt, solvate, hydrate, or polymorph thereof, for use according to any one of claims 1 to 8, wherein treatment comprises administering once or twice daily to a patient in need thereof a dose of 5 mg, 15 mg, 60 mg, 120 mg, or 240 mg; preferably 120 mg for patients weighing more than 50 kg and 60 mg for patients weighing less than 50 kg.

10. In formula (I), 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 A １ and R ２ together with the nitrogen atom to which they are attached form an optionally substituted four-membered ring to form a compound according to formula (II) or (III): 【Chemistry 2】 wherein in formulas (II) and (III): l is 0 or 1; m is an integer of 1, 2, or 3; X １ , X ２ , and R １ has the meaning as defined in claim 1, 10. A compound according to formula (I), or a salt, solvate, hydrate, or polymorph thereof, for use according to any one of claims 1 to 9.

11. with an acid 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; Preferably, with an acid selected from the group consisting of citric acid, hydrochloric acid, maleic acid, phosphoric acid, and sulfuric acid.

11. A compound for use according to any one of claims 1 to 10 in the form of a pharmaceutically acceptable salt; and solvates, hydrates, and polymorphs thereof.

12. When the compound of formula (I) is: 【Table 1】 is selected from the group consisting of Preferably, the compound of formula (I) is: 【Table 2】 12. The compound for use according to any one of claims 1 to 11, selected from the group consisting of: and pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof.

13. When the compound of formula (I) is: 【Chemistry 3】 A group consisting of and pharmaceutically acceptable salts, solvates, hydrates, and polymorphs thereof; or the following salts: formula 【Chemistry 4】 1:1 sulfate having formula 【Chemistry 5】 1:1 phosphate salt having formula 【Chemistry 6】 1:3 HCl salt with group of and these polymorphs Selected from:

13. A compound for use according to any one of claims 1 to 12.

14. 14. A medicament comprising one or more of the compounds as defined in any one of claims 1 and 9 to 13 for a use as defined in any one of claims 1 to 13, further comprising one or more pharmaceutical carriers and / or adjuvants and / or solvents, and / or one or more additional pharmaceutically active compounds.

15. 15. A compound of formula (I), or salts, solvates, hydrates and polymorphs thereof, as defined in any one of claims 1 to 14, for use in combination therapy for treating myelodysplastic syndrome, wherein the combination therapy comprises the co-administration of a compound as defined in any one of claims 1 to 14, including salts, solvates, hydrates and polymorphs thereof, with one or more other additional pharmaceutically active compounds; The co-administration of the combination therapy may be carried out in a fixed dose combination therapy by co-administering a compound as defined in any one of claims 1 to 14, including salts, solvates, hydrates, and polymorphs thereof, and one or more other additional pharmaceutically active compounds in a fixed dose formulation; or The simultaneous administration of the combination therapy may be carried out in a non-fixed dose combination therapy by co-administering the compound as defined in any one of claims 1 to 14, including its salts, solvates, hydrates, and polymorphs, with one or more other additional pharmaceutically active compounds, with non-fixed doses of the individual compounds, by simultaneous administration of the individual compounds administered over a period of time or by sequential use of the individual compounds, or the compound of formula (I), or its salts, solvates, hydrates, and polymorphs.

Images