ALK2 inhibitors for the treatment of anemia

Abstract

Provided herein are methods of treating anemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an ALK2 inhibitor.

Description

[Previous Technology]

[0001] Myelomectic dysplasia syndrome (MDS) is a pure stem cell disease characterized by ineffective hematopoiesis, morphological dysplasia, peripheral blood cytopenia, and a high risk of progression to acute myeloid leukemia. Most patients present with low-risk or intermediate-risk MDS, as defined by the International Prognostic Scoring System (IPS). Anemia is a major treatment challenge in these patients with MDS and is present in 85% of them. The pathophysiology of anemia in MDS can overlap with that of inflammatory anemia, specifically in early (i.e., low-risk) MDS. In many patients with MDS, levels of pro-inflammatory cytokines (e.g., IL-6) have been shown to induce hepcidin synthesis during inflammation. For these patients, the standard of care primarily includes supportive care addressing their symptoms: RBC infusion and ESA for anemic patients, and management of bleeding and infection risks. Chronic anemia and RBC infusion are independent risk factors affecting survival and are associated with iron overload, fatigue, impaired quality of life, and increased cardiovascular risk. ESA can provide clinical benefits for some patients with MDS. However, only about 30% of patients treated with ESA achieve improvement. This benefit is usually limited to a small number of patients with low erythropoietin levels at baseline. Most patients have elevated serum erythropoietin concentrations, and the anemia indicating MDS is due to ineffective red blood cell production that cannot usually be corrected by exogenous ESA. Treating anemia and reducing transfusion burden are the primary treatment goals for patients with low- or intermediate-risk MDS. There are few treatment options for these patients, especially after ESA failure.

[0002] Anemia also affects patients with multiple myeloma (MM): almost all patients with MM will be affected by anemia during the course of their disease. Multiple myeloma is a malignant plasma cell cachexia characterized by pure lineage proliferation of plasma cells in the bone marrow and simple lineage gamma globulinopathy. Symptomatic patients and their need for therapy are limited by the presence of hypercalcemia (C), renal insufficiency (R), anemia (A), and / or bone lesions (B) according to the CRAB criteria (Kyle, RA, Rajkumar, SVLeukemia 2009;23:3-9). In the United States, a retrospective study of 1,027 MM patients confirmed that 73% of patients had anemia (hemoglobin concentration < 120 g / L) at diagnosis (Kyle et al. 2003, Mayo Clin Proc. 2003;78:21-33). A broad European survey of 720 patients with multiple myeloma (MM) showed that 29.7% of patients had hemoglobin levels ≤ 9.9 g / dL at diagnosis, and 85.3% of these patients were anemic at any point during the survey period (Birgegard G et al., Eur J Haematol. 2006;77:378-386). Approximately 10% of MM patients had hemoglobin levels below 8 g / dL (VanderWall K et al., Crit. Rev. Oncog. 2013;18:449-461). Non-responsive patients and patients with relapsed myeloma typically continue to experience anemia.

[0003] Anemia also presents a challenge in managing patients with myelofibrosis (MF): 35% to 54% of patients with MF have reported hemoglobin levels <10 g / dL, and approximately 25% of these patients are dependent on red blood cell (RBC) transfusions at diagnosis. Elevated serum hepcidin levels in patients with MF have been shown to be associated with decreased hemoglobin, increased demand for RBC transfusions, and decreased overall survival. Anemia is also a common complication of chronic kidney disease (CKD). The current management of anemia in patients with CKD is controversial, with recent clinical trials demonstrating increased morbidity and mortality associated with erythropoiesis-stimulating agents.

[0004] There is still a need for novel treatments for anemia, especially anemia associated with MDS, MM, CKD or MF. [Summary of the Invention]

[0005] This article provides a method for treating anemia in an individual in need, comprising administering to the individual a compound of formula I: (I) or a pharmaceutically acceptable salt thereof, wherein such variables are defined herein.

[0006] In the method provided herein, R1 of compound I may be a hydroxylated bridged C8-cycloalkyl group. Additionally, R2 of compound I may be tetrahydropiperanone.

[0007] Compound I may be compound 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-(3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0008] Compound of Formula I may also be 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0009] Compound of Formula I may also be 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0010] Compound of Formula I may also be 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide fumarate dihydrate.

[0011] In the methods of treating anemia provided herein, the individual may suffer from myelomectomy syndrome (MDS). Myelomectomy syndrome (MDS) can be selected from a group consisting of MDS with multiple lineage dysplasia (MDS-MLD), MDS with single lineage dysplasia (MDS-SLD), MDS with excess blast cells (MDS-EB), MDS with individual (5q) loss, and unclassifiable MDS (MDS-U).

[0012] Furthermore, in the treatment of anemia provided herein, the individual may have multiple myeloma (MM). The individual may also be transfusion-dependent or transfusion-independent.

[0013] Individuals who are treated for anemia may also suffer from myelomectomy syndrome and myeloproliferative neoplasm (MDS / MPN) overlap syndrome, such as chronic myelomonocytic leukemia (CMML) and unclassified MDS / MPN overlap syndrome.

[0014] The anemia described in this article may be iron-refractory iron deficiency anemia (IRIDA).

[0015] In the methods of treating anemia provided herein, the individual may have myelofibrosis (MF). The individual with MF may be transfusion-dependent or transfusion-independent.

[0016] Compound of Formula I may be administered orally. Compound of Formula I may also be administered as a monotherapy for the treatment of anemia. This compound may be administered at a dose of about 5 mg to about 500 mg once daily (QD), or more specifically at a dose of about 50 mg once daily (QD). Compound of Formula I may be administered in tablet form of 5 mg, 25 mg or 50 mg or a combination thereof.

[0017] This article also provides a method for reducing hepcidin levels in individuals in need, which includes administering a compound of formula I or a pharmaceutically acceptable salt thereof to the individual.

[0018] Individuals who undergo methods to reduce hepcidin levels may develop anemia. This anemia may be iron-resistant iron deficiency anemia (IRIDA). This system may be transfusion-dependent or transfusion-independent.

[0019] This article also provides a method for reducing hepcidin levels in individuals with myelomectomy syndrome (MDS). The myelomectomy syndrome (MDS) can be selected from a group consisting of MDS with multiple lineage dysplasia (MDS-MLD), MDS with single lineage dysplasia (MDS-SLD), MDS with excess blasts (MDS-EB), MDS with individual (5q) loss, and unclassifiable MDS (MDS-U).

[0020] Individuals who undergo methods to lower hepcidin levels may develop multiple myeloma (MM). Individuals who undergo methods to lower hepcidin levels may develop myelofibrosis (MF). Individuals who undergo methods to lower hepcidin levels may develop myeloproliferative neoplasms (MPN). Individuals who undergo methods to lower hepcidin levels may develop chronic kidney disease (CKD).

[0021] When reducing hepcidin levels in individuals in need, the compound of formula I may be administered orally. The compound of formula I may also be administered as monotherapy for the treatment of anemia. This compound may be administered at a dose of about 5 mg to about 500 mg once daily (QD), or more specifically at a dose of about 50 mg once daily (QD). The compound of formula I may be administered in tablet form of 5 mg, 25 mg, or 50 mg, or in combination thereof.

Implementation Method

[0024] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 152,516, filed February 23, 2021; U.S. Provisional Application No. 63 / 056,761, filed July 27, 2020; and U.S. Provisional Application No. 63 / 039,742, filed June 16, 2020, the contents of which are incorporated herein by reference in their entirety.

[0025] This article provides a method for treating anemia in an individual in need, comprising administering to the individual a compound of formula I or a pharmaceutically acceptable salt thereof. Anemia is characterized by a decrease in the number of red blood cells or a lower than normal amount of hemoglobin in the blood. Anemia can also be caused by a decrease in the oxygen-binding capacity of hemoglobin.

[0026] This article also provides a method for reducing hepcidin levels in individuals in need, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to the individual. Hepcidin is a small peptide hormone primarily synthesized in hepatocytes that reduces duodenal iron absorption and iron export from monocytes and macrophages by binding to iron export ferrotransferrin and inducing its internalization and degradation (Nemeth E et al., Science. 2004;306:2090-2093; Theurl I et al., Haematologica. 2011;96:1761-1769; Zhao N, Zhang AS et al., J Clin Invest. 2013;123(6):2337-2343). Elevated serum hepcidin levels enhance iron storage within the reticuloendothelial system and lead to reduced iron utilization and iron-limiting erythropoiesis. Inappropriately increased hepcidin levels are of great importance in the pathophysiology of severe functional iron deficiency anemia in humans and anemia in chronic diseases (Weiss G, Goodnough LT.N Engl J Med 2005;352:1011-1023).

[0027] Inhibition of activator receptor kinase-2 (ALK2) (an upstream regulator of hepcidin) should increase circulating iron levels and improve anemia. The compounds presented herein have potent activity against ALK2 kinase and inhibit bone morphogenetic protein (BMP)-induced hepcidin production.

[0028] Hepcidin was observed to be disrupted in most MDS subtypes via iron homeostasis and almost completely lost in diseases with significant developmental disorders, such as refractory anemia with excessive blasts and chronic myeloid monocytic leukemia (CMML) (Santini V et al., PLoS ONE. 2011;6:e23109).

[0029] The causes of anemia in MM patients may be multifactorial: a decrease in the number of erythroid precursors due to BM infiltration of myeloma itself, erythropoietin deficiency (in patients with renal impairment), decreased response of erythropoietin to erythropoietin by erythropoietin-stimulating cells and CFU-E cells, impaired iron utilization due to increased hepcidin production caused by chronic inflammation, and increased plasma volume induced by paraproteins (König et al., Clin Lymphoma Myeloma Leuk. 2013;13:671-680).

[0030] Serum hepcidin levels have been shown to be significantly higher in MM patients compared to healthy individuals and age-matched controls (Ibricevic-Balic et al., Med Arch. 2016 Dec;70: 429-432; Victor et al., Clin Lab. 2017;63:1273-1277; and Maes et al., Blood. 2010;116:3635-3644). Patients with stage III MM at diagnosis had higher urinary hepcidin levels than normal controls. Serum hepcidin levels in MM patients were inversely correlated with hemoglobin concentration (Katodritou et al., Am J Hematol. 2008;83:697-701), and in MM patients with normal renal function, increased hepcidin may contribute to the pathogenesis of MM anemia (Maes et al., 2010). Furthermore, in myeloma patients with normal renal function, urinary hepcidin was inversely correlated with hemoglobin levels at diagnosis, strongly suggesting a causal relationship between upregulated hepcidin and anemia. Urinary hepcidin was also significantly correlated with serum ferritin and C-reactive protein (Sharma et al., Clin Cancer Res. 2008;14: 3262-3267).

[0031] Iron-refractory iron deficiency anemia (IRIDA) is a rare inherited form of iron deficiency anemia. Iron deficiency anemia occurs when the red blood cell count is low due to iron deficiency. Although iron deficiency anemia is generally an acquired disease caused by insufficient iron in an individual's diet or long-term blood loss, IRIDA is an autosomal recessive disorder caused by a mutation in the TMPRSS6 gene, which causes iron deficiency (Bhatia, P et al., Pediatr. Hematol. Oncol. J. 2017; 2; 48-53). Common forms of acquired iron deficiency anemia are usually treated with oral iron supplements or intravenous (IV) iron infusions, but patients with IRIDA will not respond fully to these treatments.

[0032] Patients with myelofibrosis (MF) may develop splenomegaly (due to extramedullary hematopoiesis), symptoms of excessive catabolism (due to overexpression of inflammatory cytokines), and anemia (due to bone marrow failure and splenic sequestration). MF remains primarily curable with allogeneic hematopoietic stem cell transplantation (ASCT), a therapy considered suitable for a small number of MF patients. Therefore, the goal of treatment is usually palliative. JAK inhibitors can provide therapy for patients with MF; however, therapy-related anemia is often a drawback of this treatment. Therefore, anemia remains a challenge in managing MF and represents a major unmet need. Treatment-resistant anemia reduces quality of life, predicts poor outcomes, and may limit access to palliative JAK inhibitors in some patients. While therapies for MF-related anemia do exist, they are limited in their efficacy, duration, and tolerability.

[0033] Anemia in CKD is typically normocytic, normochromic, and hypoproliferative. Anemia management was reformed in the late 1980s with the introduction of recombinant human EPO. This, along with related erythropoiesis-stimulating agents (ESAs), has greatly benefited patients by improving debilitating symptoms and freeing them from dependence on transfusions and related complications (secondary iron overload, infection, and sensitivity hindering transplantation). However, even in initial studies, adverse effects were observed in patients receiving ESAs, including worsening hypertension, seizures, and dialysis-related clotting. Furthermore, prospective randomized controlled trials of ESAs did not reduce adverse outcomes associated with anemia, such as mortality, nonfatal cardiovascular events, left ventricular hypertrophy, hospitalization, and progression of kidney disease.

[0034] Therapies currently under development promise to improve anemia-specific outcomes; however, they are still in the early stages of the regulatory approval and routine clinical use pathway.

[0035] Definitions are provided below for the various terms used herein. Unless otherwise specified in particular instances, these definitions may apply to the terms as they are used individually or as part of the broader group throughout this specification and the claims. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention pertains. The compounds of this invention are described using standard nomenclature.

[0036] Unless otherwise specified, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. In general, the nomenclature and laboratory procedures used herein in cell culture, molecular genetics, organic chemistry and peptide chemistry are those well known and commonly used in this art.

[0037] As used herein, the article "a / an" refers to one or more of the grammatical objects of the article (i.e., at least one). For example, "an element" means one element or more elements. Furthermore, the use of the term "including" and other forms such as "include / includes / included" is non-restrictive.

[0038] As used herein, "medical combination" or "combination" refers to a formulation of separate compounds, with or without instructions for use in combination or as a combination product. Thus, combination compounds may be completely separate pharmaceutical dosage forms or pharmaceutical compositions that are sold separately from each other and in which instructions for use in combination are provided only in the packaging equipment (e.g., leaflets or the like) or in other information (e.g., oral, written or similar) provided to physicians and medical personnel for simultaneous or sequential synergistic action.

[0039] As used herein, the term “treating / treatment” means suppressing a disease; for example, suppressing the disease, symptoms or symptom of an individual experiencing or exhibiting the pathology or symptom of a disease, symptom or symptom (i.e., suppressing further development of the pathology and / or symptom) or improving the disease; for example, improving the disease, symptoms or symptom of an individual experiencing or exhibiting the pathology or symptom (i.e., reversing the pathology and / or symptom), such as reducing the severity of the disease.

[0040] As used herein, the term "prevent / preventing / prevention" includes the prevention of at least one symptom associated with or caused by a state, disease, or condition that is being prevented.

[0041] As used herein, the terms “patient,” “individual,” or “subject” refer to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets such as sheep, cattle, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is a human.

[0042] As used herein, the phrase “transfusion dependence” means that an individual receives routine platelet and / or red blood cell (RBC) transfusions more frequently than every 8 weeks due to persistently low platelet and / or RBC counts.

[0043] As used herein, the phrase “transfusion independence” means that an individual does not receive platelet and / or red blood cell (RBC) transfusions for at least eight consecutive weeks.

[0044] As used herein, the term "monotherapy" means treatment that uses a single active pharmaceutical ingredient to treat a disease or symptom. Monotherapy may still include treatment using a pharmaceutically acceptable carrier or excipient. In one embodiment of the methods provided herein, the single active pharmaceutical ingredient is a compound of formula I. In another embodiment, the compound of formula I is administered as monotherapy without binding to a Janus kinase inhibitor.

[0045] As used herein, the terms "effective amount," "medically effective amount," and "therapeutic effective amount" refer to a non-toxic but sufficient amount of a drug to provide the desired biological outcome. This outcome may be a reduction or alleviation of the signs, symptoms, or causes of disease, or any other desired change in a biological system. The appropriate therapeutic amount for any individual case can be determined by a person of ordinary skill using routine laboratory methods.

[0046] As used herein, the term “medically acceptable” means a material (such as a carrier or diluent) that does not negate the biological activity or properties of a compound and is relatively nontoxic, i.e., that the material can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any of the components of a composition containing it.

[0047] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include (but are not limited to) mineral acid or organic acid salts of basic residues (such as amines); basic or organic salts of acidic residues (such as carboxylic acids); and the like. Pharmaceutically acceptable salts as described herein include, for example, known nontoxic salts formed from parent compounds of nontoxic inorganic or organic acids. Pharmaceutically acceptable salts discussed herein can be synthesized from parent compounds containing basic or acidic moiety using known chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of such compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof; generally, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "medically acceptable salts" also includes bis-salts, such as dihydrochlorides. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), the full text of which is incorporated herein by reference.

[0048] As used herein, the term "composition" or "pharmaceutical composition" means a mixture of at least one compound and a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates the administration of the composition to a patient or individual. Various techniques for administering the compound are available in this art, including (but not limited to) intravenous, oral, aerosol, non-enteral, ocular, pulmonary, and topical administration.

[0049] As used herein, the term "medically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material that involves carrying or transporting a compound that can be used by a patient to achieve its intended function. Typically, such constructs carry or transport from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation (including the compounds disclosed herein) and harmless to the patient. Examples of materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate esters; powdered tragacanth gum; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations.

[0050] As used herein, "pharmaceutically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, absorption delay agents, and similar agents whose activity is compatible with and physiologically acceptable to patients as disclosed herein. Additional active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of the compounds(s) disclosed herein. Other additional ingredients that may be included in the pharmaceutical composition are known in the art and described, for example, in Remington's Pharmaceutical Sciences (edited by Genaro, Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0051] As used herein, the term "ALK2" or "ALK-2" refers to activin A receptor type I (ACVRI), also known as ACVRLK2, SKR1, ACVR1A, activin receptor type I, activin receptor kinase 2, serine / threonine protein kinase receptor R1, TGF-B superfamily receptor type I, ACTRI, TSRI, activin A receptor type II kinase 2, activin receptor type-1, hydroxyalkyl protein kinase, ACTR-I, TSR-I. Therefore, as used herein, "ALK2 inhibitor" refers to a compound that modulates the activity of ALK2.

[0052] As used herein, the term "single formulation" refers to a single carrier or mediator formulated to deliver an effective amount of two therapeutic agents to a patient. The single mediator is designed to deliver an effective amount of each of the pharmaceutical agents together with any pharmaceutically acceptable carrier or excipient. In some embodiments, the mediator is a tablet, capsule, pill, or patch. In other embodiments, the mediator is a solution or suspension.

[0053] As used herein, the term "unit dose" means the simultaneous administration of two pharmaceutical agents together in one dosage form to a patient being treated. In some embodiments, the unit dose is a single formulation. In some embodiments, the unit dose comprises one or more media such that each media contains an effective amount of at least one of the pharmaceutical agents along with a pharmaceutically acceptable carrier and excipient. In some embodiments, the unit dose is the simultaneous administration of one or more tablets, capsules, pills, or patches to a patient.

[0054] "Oral dosage form" includes unit dosage forms that are prescribed or intended for oral administration.

[0055] As used herein, unless otherwise specified, the term "alkyl" itself, or as part of another substituent, means a straight-chain or branched hydrocarbon having a specified number of carbon atoms (i.e., C1-C6 alkyl means an alkyl group having 1 to 6 carbon atoms) and includes both straight-chain and branched chains. In one embodiment, C1-C3, C1-C4, and C1-C6 alkyl groups are provided herein. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tributyl, pentyl, neopentyl, and hexyl.

[0056] As used herein, the term "alkenyl" refers to a monovalent group derived from a hydrocarbon moiety, which in some embodiments contains 2 to 4, 2 to 6, or 2 to 8 carbon atoms having at least one carbon-carbon double bond. The alkenyl group may or may not be a linking point to another group. The term "alkenyl" includes (but is not limited to) vinyl, 1-propenyl, 1-butenyl, heptenyl, octenyl, and the like.

[0057] As used herein, the term "alkynyl" refers to a monovalent group derived from a hydrocarbon moiety, in some embodiments of which contains 2 to 4, 2 to 6, or 2 to 8 carbon atoms having at least one carbon-carbon triple bond. The alkynyl group may or may not be a linking point to another group. The term "alkynyl" includes (but is not limited to) ethynyl, 1-propynyl, 1-butynyl, heptynyl, octyynyl, and the like.

[0058] As used herein, the term "alkoxy" refers to a -O-alkyl group, wherein the alkyl group is as defined herein. For example, alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, dibutoxy, terbutoxy, and the like. In one embodiment, C1-C3, C1-C4, and C1-C6 alkoxy groups are provided herein.

[0059] As used herein, unless otherwise specified, the terms “halogen” or “halogen” alone or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

[0060] As used herein, the term "hydroxyl group" refers to the group -OH, wherein the oxygen atom is solely bonded to the substituent and the hydrogen atom.

[0061] As used herein, the term "cyano" refers to the group -CN, which has a single bond between a carbon atom and a substituent and a triple bond between a carbon atom and a nitrogen atom.

[0062] As used herein, the term "cycloalkyl" means a partially or fully saturated non-aromatic carbocyclic system having one, two, or three rings, wherein such rings may be fused. The term "fused" means that a second ring is connected or formed by having two common (i.e., shared) adjacent atoms with the first ring. Cycloalkyl also includes bicyclic structures, which may be inherently bridged or spirocyclic, wherein the individual rings within the bicyclic vary from 3 to 10, 3 to 8, 3 to 7, 3 to 6, and 5 to 10 atoms. The term "cycloalkyl" includes (but is not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, bicyclo[2.2.2]octyl, and bicyclo[1.1.1]pentyl. In one embodiment, 3 to 10-membered cycloalkyl is provided herein. In another embodiment, C8 cycloalkyl is provided herein. In yet another embodiment, a bicyclic C8 cycloalkyl group is provided herein. In still another embodiment, a bridged C8 cycloalkyl group is provided herein.

[0063] As used herein, the term "heterocyclic alkyl" means a non-aromatic carbocyclic system containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having 1, 2, or 3 rings, wherein such rings may be fused, wherein fusion is as defined above. Heterocyclic alkyl also includes bicyclic structures that may be essentially bridged or spirocyclic, wherein the individual rings within the bicyclic vary in number from 3 to 8, 5 to 10, 4 to 6, or 3 to 10 atoms and contain 0, 1, or 2 N, O, or S atoms. The term "heterocyclic alkyl" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactamines) and also specifically includes (but is not limited to) epoxide groups, oxetane groups, tetrahydrofuranyl, tetrahydropiperanyl (i.e., oxetane propane), piperanyl, dioxane, azironeyl, azironeyl, pyrrolidyl, 2,5-dihydro-1H-pyrrolidyl, oxazolidinyl, thiazodinyl, piperidinyl, morpholinyl, piperazineyl, thiomorpholinyl, 1,3-oxazinyl, 1,3-thiazodinyl, 2-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.1.1]hexyl, 6-azabicyclo[3.1.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 2-azabicyclo[3.1.1]heptyl, Hexabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-7-azabicyclo[3.3.1]nonyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, 2-oxa- -5-azabicyclo[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 2-oxaspiro[3.5]nonyl, 3-oxaspiro[5.3]nonyl, and 8-oxabicyclo[3.2.1]octyl. In one embodiment, 3 to 10-membered heterocyclic alkyl groups are provided herein. In another embodiment, 5 to 10-membered heterocyclic alkyl groups are provided herein. In yet another embodiment, 4 to 6-membered heterocyclic alkyl groups are provided herein.

[0064] It should be understood that if a cycloalkyl or heterocycloalkyl moiety is connected to a specified moiety by different ring atom bonds or otherwise (i.e., no specific connection point is indicated as shown or described), then all possible points are expected, whether or not they are connected by a carbon atom, or, for example, a trivalent nitrogen atom. For example, the term "pyridinyl" means 2-, 3-, or 4-pyridinyl, the term "thienyl" means 2-, or 3-thienyl, and so on.

[0065] As used herein, the term "nitro" refers to the group -NO2, in which the nitrogen atom is individually bonded to the substituent, double-bonded to the first oxygen atom, and individually bonded to the second oxygen atom. Thus, the nitrogen atom is positively charged and the second oxygen atom is negatively charged.

[0066] As used herein, the term “substitution” means that an atom or a group of atoms has a substituted hydrogen as a substituent attached to another group.

[0067] The compounds described herein, their synthesis and their bioactivity against ALK2 can be found in PCT / CN2017 / 093385 (WO2018014829), which is incorporated herein by reference in its entirety.

[0068] In one embodiment, this article provides a method for treating anemia in an individual in need, comprising administering to the individual a compound of formula I: (I) or a pharmaceutically acceptable salt thereof; wherein R1 is, as appropriate, a 5 to 10-membered cycloalkyl group substituted once, twice, or three times with a hydroxyl or C1-C3 alkoxy group; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3 to 6-membered cycloalkyl, and 3 to 6-membered heterocycloalkyl, all of which are, as appropriate, substituted with R3; and R3 is selected from the group consisting of hydroxyl, halogen, cyano, nitro, SO2-C1-C3 alkyl, and SO3H.

[0069] In one embodiment, R1 is a hydroxylated bridged C8-cycloalkyl group.

[0070] In another embodiment, R2 is tetrahydropiperanone.

[0071] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-(3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0072] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0073] In one embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0074] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide fumarate dihydrate.

[0075] In another embodiment, the individual suffers from myelomectomy syndrome (MDS).

[0076] In another embodiment, the myelomectomy syndrome (MDS) is selected from the group consisting of MDS with multi-lineage dysplasia (MDS-MLD), MDS with single-lineage dysplasia (MDS-SLD), MDS with excess blast cells (MDS-EB), MDS with individual (5q) loss, and unclassifiable MDS (MDS-U).

[0077] In another embodiment, the myelomectic dysplasia syndrome (MDS) is MDS with multiple lineage dysplasia (MDS-MLD). In one embodiment, the myelomectic dysplasia syndrome (MDS) is MDS with single lineage dysplasia (MDS-SLD). In another embodiment, the myelomectic dysplasia syndrome (MDS) is MDS with excess blasts (MDS-EB). In yet another embodiment, the myelomectic dysplasia syndrome (MDS) is MDS with individual (5q) loss. In yet another embodiment, the myelomectic dysplasia syndrome (MDS) is unclassifiable MDS (MDS-U).

[0078] In one embodiment, the individual has multiple myeloma (MM).

[0079] In another embodiment, the individual suffers from myelomectomy syndrome and myeloproliferative neoplasm (MDS / MPN) overlap syndrome. In yet another embodiment, the MDS / MPN overlap syndrome is chronic myelomonocytic leukemia (CMML) or an unclassifiable MDS / MPN overlap syndrome.

[0080] In another embodiment, the individual suffers from myelofibrosis (MF). In yet another embodiment, the anemia is characterized as MF-induced anemia.

[0081] In another embodiment, the anemia is iron-refractory iron deficiency anemia (IRIDA).

[0082] In yet another embodiment, the system is transfusion-dependent. In still another embodiment, the individual is transfusion-independent.

[0083] In one embodiment, the compound of formula I is administered orally.

[0084] In another embodiment, the compound of formula I is administered as a monotherapy for the treatment of anemia. In another embodiment, the compound of formula I is administered as a monotherapy without binding to a Jenners kinase inhibitor.

[0085] In yet another embodiment, the compound of formula I is administered at a dose of about 5 mg to about 500 mg once daily (QD). In still another embodiment, the compound of formula I is administered at a dose of about 50 mg once daily (QD).

[0086] In one embodiment, the compound of formula I is administered in doses selected from the group consisting of: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg and 500 mg.

[0087] In another embodiment, the compound of formula I is administered at a dose of 5 mg. In yet another embodiment, the compound of formula I is administered at a dose of 10 mg. In still another embodiment, the compound of formula I is administered at a dose of 15 mg. In one embodiment, the compound of formula I is administered at a dose of 20 mg. In another embodiment, the compound of formula I is administered at a dose of 25 mg. In yet another embodiment, the compound of formula I is administered at a dose of 50 mg. In another embodiment, the compound of formula I is administered at a dose of 75 mg. In still another embodiment, the compound of formula I is administered at a dose of 100 mg. In another embodiment, the compound of formula I is administered at a dose of 125 mg. In another embodiment, the compound of formula I is administered at a dose of 150 mg. In another embodiment, the compound of formula I is administered at a dose of 175 mg. In another embodiment, the compound of formula I is administered at a dose of 200 mg. In another embodiment, the compound of formula I is administered at a dose of 225 mg. In another embodiment, the compound of formula I is administered at a dose of 250 mg. In another embodiment, the compound of formula I is administered at a dose of 275 mg. In yet another embodiment, the compound of formula I is administered at a dose of 300 mg. In another embodiment, the compound of formula I is administered at a dose of 325 mg. In another embodiment, the compound of formula I is administered at a dose of 350 mg. In another embodiment, the compound of formula I is administered at a dose of 375 mg. In another embodiment, the compound of formula I is administered at a dose of 400 mg. In another embodiment, the compound of formula I is administered at a dose of 425 mg. In yet another embodiment, the compound of formula I is administered at a dose of 450 mg. In another embodiment, the compound of formula I is administered at a dose of 475 mg. In yet another embodiment, the compound of formula I is administered at a dose of 500 mg.

[0088] In one embodiment, the compound of formula I is administered orally as a tablet. In another embodiment, the compound of formula I is administered as a 5 mg, 25 mg, or 50 mg tablet, or any combination thereof.

[0089] In another embodiment, this document provides a method for treating anemia in an individual in need, comprising administering to the individual 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide fumarate dihydrate.

[0090] In another embodiment, this document provides a method for reducing the hepcidin content in an individual in need, comprising administering to the individual a compound of formula I: (I) or a pharmaceutically acceptable salt thereof; wherein R1 is, as appropriate, a 5 to 10-membered cycloalkyl group substituted once, twice, or three times with a hydroxyl or C1-C3 alkoxy group; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3 to 6-membered cycloalkyl, and 3 to 6-membered heterocycloalkyl, all of which are substituted with R3 as appropriate; and R3 is selected from the group consisting of hydroxyl, halogen, cyano, nitro, SO2-C1-C3 alkyl, and SO3H.

[0091] In one embodiment, R1 is a hydroxylated bridged C8-cycloalkyl group.

[0092] In another embodiment, R2 is tetrahydropiperanone.

[0093] In yet another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-(3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0094] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0095] In one embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0096] In another embodiment, the individual suffers from anemia. In yet another embodiment, the anemia is iron-refractory iron deficiency anemia (IRIDA).

[0097] In one embodiment, the system is transfusion-dependent. In another embodiment, the individual is transfusion-independent.

[0098] In another embodiment, the individual suffers from myelomectomy syndrome (MDS).

[0099] In another embodiment, the myelomectomy syndrome (MDS) is selected from the group consisting of MDS with multi-lineage dysplasia (MDS-MLD), MDS with single-lineage dysplasia (MDS-SLD), MDS with excess blast cells (MDS-EB), MDS with individual (5q) loss, and unclassifiable MDS (MDS-U).

[0100] In another embodiment, the myelomectic dysplasia syndrome (MDS) is MDS with multiple lineage dysplasia (MDS-MLD). In one embodiment, the myelomectic dysplasia syndrome (MDS) is MDS with single lineage dysplasia (MDS-SLD). In another embodiment, the myelomectic dysplasia syndrome (MDS) is MDS with excess blasts (MDS-EB). In yet another embodiment, the myelomectic dysplasia syndrome (MDS) is MDS with individual (5q) loss. In yet another embodiment, the myelomectic dysplasia syndrome (MDS) is unclassifiable MDS (MDS-U).

[0101] In one embodiment, the individual has multiple myeloma (MM).

[0102] In another embodiment, the individual suffers from myelomectomy syndrome and myeloproliferative neoplasm (MDS / MPN) overlap syndrome. In yet another embodiment, the MDS / MPN overlap syndrome is chronic myeloid monocytic leukemia (CMML) or an unclassifiable MDS / MPN overlap syndrome.

[0103] In another embodiment, the individual suffers from myelofibrosis (MF). In yet another embodiment, the anemia is characterized as MF-induced anemia. In still another embodiment, the MF-induced anemia is iron-refractory iron deficiency anemia (IRIDA).

[0104] In one embodiment, the compound of formula I was administered orally.

[0105] In another embodiment, the compound of formula I is administered as a monotherapy to reduce hepcidin levels. In another embodiment, the compound of formula I is administered as a monotherapy without binding to a Jenners kinase inhibitor.

[0106] In another embodiment, this document provides a method for treating chronic kidney disease (CKD)-induced anemia in an individual in need, comprising administering to the individual a compound of formula I: (I) or a pharmaceutically acceptable salt thereof; wherein R1 is, as appropriate, a 5 to 10-membered cycloalkyl group substituted once, twice, or three times with a hydroxyl or C1-C3 alkoxy group; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3 to 6-membered cycloalkyl, and 3 to 6-membered heterocycloalkyl, all of which are, as appropriate, substituted with R3; and R3 is selected from the group consisting of hydroxyl, halogen, cyano, nitro, SO2-C1-C3 alkyl, and SO3H.

[0107] In one embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-(3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0108] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0109] In one embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0110] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide fumarate dihydrate.

[0111] In yet another embodiment, the compound of formula I is administered as a monotherapy to treat anemia induced by chronic kidney disease (CKD).

[0112] In another embodiment, this document provides a method for treating anemia in an individual in need, comprising administering to the individual a compound of formula I: (I) or a pharmaceutically acceptable salt thereof; wherein R1 is, as appropriate, a 5 to 10-membered cycloalkyl group substituted once, twice, or three times with a hydroxyl or C1-C3 alkoxy group; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3 to 6-membered cycloalkyl, and 3 to 6-membered heterocycloalkyl, all of which are, as appropriate, substituted with R3; and R3 is selected from the group consisting of hydroxyl, halogen, cyano, nitro, SO2-C1-C3 alkyl, and SO3H; wherein the individual suffers from myelofibrosis (MF) and has previously been treated with a JAK inhibitor or is ineligible for JAK inhibitor treatment.

[0113] In one embodiment, the individual had previously been treated with a JAK inhibitor. In another embodiment, the individual was ineligible for JAK inhibitor treatment. In yet another embodiment, the individual was ineligible for JAK inhibitor treatment because the individual was intolerant to JAK inhibitor treatment.

[0114] In one embodiment, R1 is a hydroxylated bridged C8-cycloalkyl group.

[0115] In another embodiment, R2 is tetrahydropiperanone.

[0116] In yet another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-(3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0117] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0118] In one embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0119] In one embodiment of these methods, the compound of formula I is administered at a dose of about 5 mg to about 500 mg once daily (QD). In yet another embodiment, the compound of formula I is administered at a dose of about 50 mg once daily (QD).

[0120] In one embodiment, the compound of formula I is administered in doses selected from the group consisting of: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg and 500 mg.

[0121] In another embodiment, the compound of formula I is administered at a dose of 5 mg. In yet another embodiment, the compound of formula I is administered at a dose of 10 mg. In still another embodiment, the compound of formula I is administered at a dose of 15 mg. In one embodiment, the compound of formula I is administered at a dose of 20 mg. In another embodiment, the compound of formula I is administered at a dose of 25 mg. In yet another embodiment, the compound of formula I is administered at a dose of 50 mg. In another embodiment, the compound of formula I is administered at a dose of 75 mg. In still another embodiment, the compound of formula I is administered at a dose of 100 mg. In another embodiment, the compound of formula I is administered at a dose of 125 mg. In another embodiment, the compound of formula I is administered at a dose of 150 mg. In another embodiment, the compound of formula I is administered at a dose of 175 mg. In another embodiment, the compound of formula I is administered at a dose of 200 mg. In another embodiment, the compound of formula I is administered at a dose of 225 mg. In another embodiment, the compound of formula I is administered at a dose of 250 mg. In another embodiment, the compound of formula I is administered at a dose of 275 mg. In yet another embodiment, the compound of formula I is administered at a dose of 300 mg. In another embodiment, the compound of formula I is administered at a dose of 325 mg. In another embodiment, the compound of formula I is administered at a dose of 350 mg. In another embodiment, the compound of formula I is administered at a dose of 375 mg. In another embodiment, the compound of formula I is administered at a dose of 400 mg. In another embodiment, the compound of formula I is administered at a dose of 425 mg. In yet another embodiment, the compound of formula I is administered at a dose of 450 mg. In another embodiment, the compound of formula I is administered at a dose of 475 mg. In yet another embodiment, the compound of formula I is administered at a dose of 500 mg.

[0122] In one embodiment, the compound of formula I is administered orally as a tablet. In another embodiment, the compound of formula I is administered as a 5 mg, 25 mg, or 50 mg tablet, or any combination thereof.

[0123] In another state, this article provides a method for reducing the hepcidin content in an individual in need, comprising administering to the individual 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide fumarate dihydrate.

[0124] In one embodiment, this article provides a method for treating myelomectic dysplasia syndrome (MDS) in an individual in need, comprising administering to the individual a compound of formula I: (I) or a pharmaceutically acceptable salt thereof; wherein R1 is, as appropriate, a 5 to 10-membered cycloalkyl group substituted once, twice, or three times with a hydroxyl or C1-C3 alkoxy group; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3 to 6-membered cycloalkyl, and 3 to 6-membered heterocycloalkyl, all of which are substituted with R3 as appropriate; and R3 is selected from the group consisting of hydroxyl, halogen, cyano, nitro, SO2-C1-C3 alkyl, and SO3H.

[0125] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-(3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0126] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0127] In one embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0128] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide fumarate dihydrate.

[0129] In another embodiment, this document provides a method for treating multiple myeloma (MM) in an individual in need, comprising administering to the individual a compound of formula I: (I) or a pharmaceutically acceptable salt thereof; wherein R1 is, as appropriate, a 5 to 10-membered cycloalkyl group substituted once, twice, or three times with a hydroxyl or C1-C3 alkoxy group; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3 to 6-membered cycloalkyl, and 3 to 6-membered heterocycloalkyl, all of which are substituted with R3 as appropriate; and R3 is selected from the group consisting of hydroxyl, halogen, cyano, nitro, SO2-C1-C3 alkyl, and SO3H.

[0130] In yet another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-(3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0131] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0132] In one embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0133] In another embodiment, the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide fumarate dihydrate.

[0134] In another embodiment of these methods, the individual is a human being.

[0135] In some embodiments, the method or treatment reduces the serum hepcidin level in a patient relative to baseline or compared to levels in a healthy individual. The serum hepcidin level may be reduced by more than about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100%. In some embodiments, the serum hepcidin level is reduced by about 50% or more relative to baseline. In some embodiments, the serum hepcidin level is reduced to less than about 150 ng / mL, 140, 130, 120, 110, 100, 90, 80, 70, 60, or about 50 ng / mL. The hepcidin level may be measured using standard techniques, including radioimmunoassay, ELISA, ligand binding assay, or mass spectrometry.

[0136] In some embodiments, the method or treatment increases serum iron concentration in patients relative to baseline or compared to levels in healthy individuals. Serum iron concentration may increase by more than about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100%. Serum iron concentration can be tested using standard techniques.

[0137] In some embodiments, the method or treatment increases the serum hemoglobin level in a patient relative to baseline or compared to levels in a healthy individual. The serum hemoglobin level may increase by more than about 5%, 10%, 15%, 20%, 25%, or about 30%. The hemoglobin level can be tested using standard techniques.

[0138] In some embodiments, the method or treatment increases transferrin saturation (TSAT) in patients relative to baseline or compared to levels in healthy individuals. TSAT may increase by more than about 5%, 10%, 15%, 20%, 25%, or about 30%. TSAT can be tested using standard techniques.

[0139] In some embodiments, the method or treatment reduces the ferritin level in a patient relative to baseline or compared to levels in a healthy individual. The ferritin level may be reduced by more than about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100%. The ferritin level can be tested using standard techniques.

[0140] The pharmaceutical composition or combination thereof provided herein contains the compounds disclosed herein together with a pharmaceutically acceptable carrier.

[0141] Administration of a combination includes administration of the combination in a single formulation or unit dosage form, administration of individual agents of the combination simultaneously but separately, or administration of individual agents of the combination sequentially by any suitable route. The dosage of an individual agent in a combination may require that one of the agents(s) be administered more frequently than the other agents(s) in the combination. Therefore, to permit appropriate administration, packaged pharmaceutical products may contain one or more dosage forms of a combination containing agents, and one or more dosage forms of one of the other agents(s) in a combination but not in the combination.

[0142] The actual dosage level of the active ingredient in the pharmaceutical composition can be changed to obtain an amount of active ingredient that is effective in achieving the therapeutic response required for a specific patient, composition and administration mode, but is non-toxic to the patient.

[0143] Specifically, the selected dose level will depend on a variety of factors, including the activity of the particular compound used, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and previous medical history of the patient being treated and similar factors known in medical technology.

[0144] A physician (e.g., a doctor or veterinarian) with general skills can easily determine and prescribe the effective amount of a pharmaceutical composition. For example, a physician or veterinarian can begin administering the pharmaceutical composition to deliver the disclosed compound at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0145] In certain embodiments, it is particularly advantageous to prepare the compound in unit dosage forms to facilitate administration and uniformity of dosage. As used herein, a unit dosage form refers to a physically discrete unit suitable as a unit dose for a patient to be treated; each unit contains a predetermined amount of the disclosed compound calculated to produce the desired therapeutic effect associated with the desired pharmaceutical medium. The unit dosage form is governed by and directly dependent on: (a) the unique characteristics of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the techniques for mixing / preparing the disclosed compound for treating a patient's pain, depression, or drug addiction.

[0146] In one embodiment, the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0147] The routes of administration of any of the compositions discussed herein include oral, nasal, rectal, vaginal, non-enteric, buccal, sublingual, or topical. The compounds can be formulated for administration via any suitable route, such as oral or non-enteric, for example, transdermal, transmucosal (e.g., sublingual, lingual, buccal, urethral, ​​vaginal (e.g., vaginal and periceric), nasal (internal) and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrasacral, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral.

[0148] Suitable compositions and dosage forms include, for example, tablets, capsules, granules, pills, gel pills, sugar tablets, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, pastes, lozenges, creams, ointments, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or nebulized formulations for inhalation, compositions and formulations for intravesical administration, and the like. It should be understood that formulations and compositions are not limited to the specific formulations and compositions described herein.

[0149] For oral application, tablets, sugar-coated pills, liquids, drops, suppositories, capsules, sachets, and gel pills are particularly suitable. Compositions intended for oral use may be prepared according to any method known in this art, and such compositions may contain one or more agents selected from the group of inert, non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated by known techniques for perfecting or delaying the release of the active ingredient. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0150] For non-enteral administration, the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for single-dose administration or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous media containing other formulations, such as suspending agents, stabilizers, or dispersants, may be used, as appropriate.

[0151] The present invention also includes, for example, pharmaceutical kits for treating or preventing diseases or conditions (such as anemia) associated with the activity of ALK2, comprising containers containing one or more pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I or any of the embodiments thereof. Such kits may further comprise one or more of various known pharmaceutical kit components, such as, for example, containers having one or more pharmaceutically acceptable carriers, as well as other containers readily apparent to those skilled in the art. Instructions indicating the amount of component to be administered, administration guidelines, and / or guidelines for mixing the components may also be included in the kit.

[0152] Those skilled in the art will know or be able to determine many equivalents of the specific procedures, embodiments, claims, and examples described herein using no more conventional experiments. These equivalents are considered to be within the scope of this invention and covered by the appended claims. For example, it should be understood that reaction conditions, including (but not limited to) reaction time, reaction size / volume, and experimental reagents (such as solvents, catalysts, pressure, atmospheric conditions (e.g., nitrogen atmosphere), and reducing / oxidizing agents), utilizing technically recognized substitutions and modifications not exceeding those of conventional experiments, are within the scope of this application.

[0153] It should be understood that wherever values ​​and ranges are provided herein, all values ​​and ranges contained therein are intended to be included within the scope of this invention. Furthermore, all values ​​falling within such ranges, as well as the upper or lower limits of the ranges of values, are also included in this application.

[0154] The following examples further illustrate the nature of the invention. However, they do not in any way limit the teachings of the invention as set forth.

[0155] Examples The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limitations. Unless otherwise specified, practice of this invention will be carried out using the skills of the art in organic synthesis, cell biology, cell culture and molecular biology.

[0156] The process for preparing the compounds disclosed herein can be found at least in WO 2018 / 014829, the full text of which is incorporated herein.

[0157] Example 1: A clinical protocol was used to conduct a phase 1a, double-blind, randomized, placebo-controlled, single-dose, dose-escalation, and food effect study of 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide (“Compound A”) to assess the safety, tolerability, and pharmacokinetics (PK) of Compound A when administered orally in a single dose to healthy adult participants.

[0158] Compound A was administered to nine healthy participants at single dose levels of 10 mg, 25 mg, 50 mg, 100 mg, and 175 mg. No serious adverse events (SAEs) were observed at any dose level, and all adverse events (AEs) were mild and self-limiting.

[0159] 1.1. Benefit / Risk Assessment: The study design will maximize participant safety while collecting important pharmacokinetic (PK) information. Dose escalation will continue using safety information and PK data collected as the study progresses. All adverse events (AEs), including hematological, blood chemistry, and liver function test abnormalities, will be monitored in all participants to identify any safety signals.

[0160] In a 28-day repeated-dose toxicity study of compound A in rats and dogs, findings at the no-observed adverse effect level (NOAEL) in both species were limited to a slight increase in iron staining in the liver, with no associated increase in liver function tests (LFT) or microscopic findings of the liver; these findings were attributed to ALK2-mediated alterations in iron metabolism. At higher doses, increases in serum alanine transaminase (ALT) and aspartate transaminase (AST) and microscopic findings of the liver were observed, considered secondary to hepatic iron accumulation. Iron parameters and liver function tests will be monitored clinically.

[0161] Other adverse findings associated with ALK3 inhibition at higher doses include gastrointestinal mucosal hypertrophy and hyperplasia, associated changes in mesenteric lymph nodes, anagen arrest in hair follicles, and further alterations in iron metabolism. Additionally, increased heart rate was observed in dogs at higher doses. Potential increases in heart rate, skin / hair, and gastrointestinal tract were also clinically monitored.

[0162] All adverse findings in non-clinical toxicology studies were associated with exposures exceeding the participants’ expected exposure within the planned dose range.

[0163] 1.2. Details of Objectives and Endpoints Table 1 shows the research objectives and endpoints. Table 1: Objectives and Endpoints Target end main Determining the safety and tolerability of compound A in MDS and MM participants. ● Frequency and severity of adverse events (AEs) and severe analgesics (SAEs), including changes in vital signs, ECG, physical examination, and clinical blood and urine laboratory parameters. ● Identification of DLT, MTD and RDE. secondary Determining the efficacy of compound A in participants with MDS and MM. For both MDS and MM disease groups: - For participants with infusion independence (TI) at baseline: - Anemia response, defined as an increase in Hgb of at least 1.5 g / dL from baseline lasting for any 8-week period during the 24 weeks prior to treatment (where each assessment meets this requirement). - The duration of anemia response, which is defined as the interval from the first onset of anemia response to the earliest date of loss of anemia response (which lasts at least 4 weeks) or death from any cause. - For participants with transfusion dependence (TD) at baseline: - Red blood cell transfusion independence (RBC-TI) is defined as the absence of any RBC transfusion for at least 8 consecutive weeks during the 24 weeks prior to treatment. - The duration of RBC-TI in participants who achieved at least 8 consecutive weeks of RBC-TI during the 24 weeks prior to treatment. - The rate of RBC infusion from week 12 to week 24 was defined as the average number of RBC units per participant per month during the treatment period. - The maximum increase in mean Hgb value from baseline during any rolling 8-week treatment period in the 24 weeks prior to treatment. For MDS participants only: - Overall response, defined as the proportion of participants with CR or PR, if applicable, according to the definition of MDS by Cheson et al. 2006 and the definition of MDS / MPN overlap syndrome by Savona et al. 2015. - Progression-free survival (PFS) is defined as the interval from the first dose of the investigational drug to the first registered progression or death, according to the definition of MDS by Cheson et al. 2006 and the definition of MDS / MPN overlap syndrome by Savona et al. 2015. - Leukemia-free survival (LFS) is defined as the interval from the first dose of the investigational drug until the first registered leukemia transformation or death from any cause. For MM participants only: - The overall response rate was defined as the proportion of participants with strict complete response, complete response, excellent partial response, and partial response, according to Kumar S et al., Lancet Oncol 2016;17:e328-46. - Progression-free survival (PFS) is defined as the interval from the first dose of the investigational drug to the first registered progression or death, according to Kumar et al. 2016. Evaluation of the pharmacokinetic (PK) of compound A among MDS and MM participants Pharmacokinetic (PK) parameters: C max T max and AUC 0-t . To evaluate the effects of compound A on iron homeostasis and erythrocyte production in MDS and MM participants. Blood samples were drawn for evaluation: - Blood levels of hepcidin - Iron steady-state parameters, - Red blood cell production parameters ECG = Electrocardiogram; DLT = Dose-limiting toxicity; MTD = Maximum tolerated dose; RDE = Recommended dose for extension; Hgb = Hemoglobin; TI = Transfusion independence; CR = Complete response; PR = Partial response

[0164] 2. Study Design 2.1. Overall Design This phase 1 / 2 open-label, multicenter dose-finding study aims to evaluate the safety, tolerability, pharmacokinetics, PD and preliminary efficacy of compound A as a monotherapy in participants with MDS or MM who are transfusion-dependent or present with symptomatic anemia.

[0165] 2.2. Overall Study Duration The study begins when the first participant signs an informed consent form (ICF). The study ends when all participants complete up to 6 months of treatment or discontinue treatment early and complete an applicable safety follow-up assessment, or when the sponsor terminates the study. Participants who are still receiving compound A at the time of study closure, who have experienced clinical benefit, and who do not have any evidence of progressive disease may have the option to continue receiving treatment with compound A in accordance with this trial or transfer agreement.

[0166] If a participant has completed all phases of the study (including safety follow-up), the participant is considered to have completed the study.

[0167] For each participant, the study will include the following: ● Screening for up to 28 days. ● Continuous treatment with the study drug for up to 6 months during the 28-day treatment cycle, the same length as the participant has benefited from the study drug and has not met any criteria for discontinuing the study drug. ● An additional 30-day safety follow-up period. ● Follow-up every 6 months after treatment.

[0168] 2.3. Research Termination The researcher reserves the right to terminate research participation at any time in accordance with the terms specified in the research contract. The researcher shall notify the Institutional Review Board / Independent Ethics Committee (IRB / IEC) of the completion or early termination of the research, send a copy of the notification to the sponsor or the sponsor's appointee, and retain one copy of the on-site research normative documents.

[0169] The sponsor may choose to terminate the study if required by regulatory decision or recommendation of the Data Monitoring Committee (DMC). If the study is terminated early, the sponsor will notify the researchers of the IRB / IEC and the regulatory body’s decision and the reasons for termination. If a guarantee is provided, the DMC may recommend termination of the study.

[0170] 3. Deviations from eligibility criteria are not permitted for the research community, as they could potentially jeopardize the scientific integrity, regulatory acceptability, and / or participant safety of the research. Therefore, compliance with the criteria specified in the agreement is essential. The anticipated approval of deviations from the agreement regarding recruitment and enrollment criteria is also referred to as an agreement waiver or exemption.

[0171] 3.1. Inclusion Criteria A participant is eligible for inclusion in the study only if all of the following criteria apply: 1. The ability to understand and sign a written informed consent (ICF) for the study. 2. Being 18 years of age or older at the time of signing the ICF. 3. The following Eastern Cooperative Oncology Group (ECOG) performance status scores: a. For the dose escalation phase, 0 or 1. b. For the dose extension phase, 0, 1, or 2. 4. Life expectancy greater than 6 months. 5. Consent to contraception or childbearing based on the following criteria: a. Male participants of reproductive potential must consent to taking appropriate precautions to avoid pregnancy from screening to the last study drug dose within 90 days and must refrain from donating sperm during this period. The method of pregnancy prevention should be communicated to participants and their understanding confirmed. b. Female participants of woman of reproductive age (WOCBP) must have a negative serum pregnancy test at screening prior to the first dose (within 3 days of the first study drug dose) and must consent to taking appropriate precautions to avoid pregnancy from screening to safety follow-up (see Table 2). Participants should be informed of the methods for preventing pregnancy and their understanding confirmed. c. Female participants who are not expected to become pregnant are not considered eligible. Table 2 filter Treatment period Follow-up D-28 to D0 Cycle 1 Cycle 2 ≥3rd cycle EOT Security After treatment Day 1 Day 8 Day 15 Day 22 Day 1 Day 15 Day 1 Day 15 Laboratory assessment Pregnancy test X X X X X hematology X X X X X X X X X Hemoglobin only X X Serum Chemistry X X X X X X X X HbA1c, Vitamin B12 and MMA X Q. 3 cycles (Day 1) X Serological screening X Blood lipid group X X X X X X Coagulation Team X X X C3D1 only X X Urine analysis X X PK Sampling Schedule Blood PK Samples X X PD sampling time schedule Plasma PD X X X X Iron metabolism, erythropoiesis parameters and EPO X X X X X X X X Plasma-related substances (before drug administration) X X C4DI only BM smear* X Post-treatment assessment Leukemia progression / disease progression / novel anticancer treatments X C3D1 - 3rd cycle, day 1; C4DI - 4th cycle, day 1; one cycle is 28 days.

[0172] Inclusion criteria for defining disease characteristics: 6. Participants with transfusion dependence or symptomatic anemia, defined as follows: a. Anemia: Hgb levels < 10 g / dL recorded in three separate instances during the screening period, at least 7 days between measurements (Note: RBC infusions must have occurred at least 2 weeks prior to Hgb measurement during the screening period). b. Transfusion dependence: For Hgb levels < 8.5 g / dL, in the absence of bleeding or treatment-induced anemia, participants have received at least 4 units of RBC infusions within the 28 days immediately preceding Day 1 of Cycle 1, or at least 4 units of RBC infusions within the 8 weeks immediately preceding Day 1 of Cycle 1. Furthermore, the most recent transfusion must have occurred within 28 days prior to Day 1 of Cycle 1.

[0173] For MDS participants: 7. Those who are ineligible for or unresponsive to available therapies for anemia (such as ESA or lenalidomide). 8. Those who do not require cytoreductive therapy other than hydroxyurea. 9. Those with BM and peripheral blood myeloblast counts <10%. 10. The following histologically confirmed diagnoses (according to the 2016 WHO criteria [Swerdlow et al. 2017]): a. MDS. b. CMML. c. Unclassifiable MDS / MPN overlap syndrome. Note: This excludes participants presenting with MDS-RS or atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, or MDS / MPN with ring sideroblasts and thrombocytosis.

[0174] For MM participants: 11. Histologically confirmed diagnosis of multiple myeloma (according to the 2016 WHO criteria [Swerdlow et al. 2017]): 12. After failure of available standard treatments; standard treatment options include the following: alkylating agents, glucocorticoids, immunomodulatory drugs IMiD (lenalidomide, pomalidomide or thalidomide)), proteasome inhibitors (bortezomib or carfilzomib) and daratumumab.

[0175] 3.2. Exclusion Criteria A participant will be excluded from the study if any of the following criteria apply: 1. Underwent any prior allogeneic stem cell transplantation or is a candidate for such transplantation. 2. Underwent any major surgery within 28 days prior to the first dose of the study drug. 3. Underwent any prior chemotherapy, immunomodulatory therapy, immunosuppressive therapy, biotherapy, endocrine therapy, targeted therapy, antibody, or hypomethylating agent to treat the participant's disease within 5 half-lives or 28 days (whichever is shorter) prior to the first dose of the study drug. a. Except for permitted glucocorticoids (which may be continued during the study if the participant has a stable dose for 4 weeks immediately prior to C1D1 and does not exhibit any grade 2 or higher toxicity due to treatment) and hydroxyurea (which may be requested to treat hyperproliferative diseases from cycle 2 in the dose escalation group and from cycle 1 in the dose extension group). 4. Underwent or was treated with another study drug within 28 days prior to the first dose of the study drug. Note: The sponsor's medical guardian should be contacted in any event where a participant must receive any treatment to treat signs or symptoms of COVID-19. 5. Participants who have received treatment with ESA, G-CSF or GM-CSF, romiplostin, or eltrombopag at any time within 28 days prior to the first dose of the study drug. 6. Participants who have received treatment with a potent / strong inhibitor or inducer of CYP3A4 / 5 within 28 days or 5 half-lives (whichever is longer) prior to the first dose of the study drug, or who expect to receive such treatment during the study. 7. Any prior radiation therapy within 28 days prior to the first dose of the study drug. Single-site or small-area reduction in radiation therapy is permitted if washed out at least 1 week prior to the first dose of the study drug. 8. If applicable, any hematologic malignancy other than MDS or MM. 9. Active invasive malignancy within the previous 5 years. Exceptions include participants with early-stage basal or squamous cell skin cancer, completely excised cervical intraepithelial carcinoma, or completely excised papillary or follicular thyroid cancer, who may be eligible at the investigator's discretion. Participants with malignancies exhibiting indolent behavior (such as prostate cancer treated with radiation or surgery) may be recruited, provided they have a reasonable expectation of cure with the received treatment modality. 10. Known active disease involving the CNS. 11. History of clinically significant or uncontrolled cardiac events, including recent (within the last 12 months) unstable angina or acute myocardial infarction, or New York Heart Association Class III or IV congestive heart failure, or clinically significant arrhythmias uncontrolled by medication. Participants with a pacemaker and well-controlled rhythm for at least one month prior to the first dose of the study drug will be permitted. 12. History or presence of abnormal ECGs that are clinically significant at the investigator's discretion.Unless approved by the sponsor's medical guardian, participants with a QTc interval > 450 ms will be excluded from screening. For participants with intraventricular conduction delay (QRS interval 120 ms), a JTc interval may be used instead of a QTc interval with the sponsor's approval. Participants with left bundle branch block will be excluded. Participants with pacemaker-induced QTc prolongation may be recruited with prior approval from the sponsor's medical guardian. 13. Participants with a chronic or currently active infectious disease requiring systemic antibiotic, antifungal, or antiviral therapy should be screened / recruited using delayed screening until the cause of antibiotic, antifungal, or antiviral therapy is completed and the infection is no longer active. 14. Participants diagnosed with chronic liver disease (e.g., chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, nonalcoholic steatohepatitis). 15. Participants with known active hepatitis A, HBV, or HCV infection, or known HIV positivity. 16. Unwillingness to receive blood component transfusions containing RBC packs and platelets. 17. Any condition that would interfere with the investigator's judgment in full participation in the study (e.g., inability, unwillingness, or inability to adhere to the dosage schedule and study evaluation), including administration of the study drug and participation in required study visits; imposing significant risks on participants; or interfering with the interpretation of study data. 18. Active alcohol or drug addiction that would interfere with their ability to comply with study requirements. 19. Gastroesophageal reflux disease uncontrolled by medication (i.e., current symptoms or endoscopic evidence of esophagitis) within 28 days prior to the first dose of the study drug. 20. Any unresolved grade ≥ 2 toxicity from prior therapy, except for stable chronic toxicities (≤ 2) that are not expected to be resolved, such as stable grade 2 peripheral neuropathy. 21. Known hypersensitivity, serious reactions, or any known contraindications to the use of any of the active substance or excipients in a pharmaceutical composition containing compound A. 22. Pregnant or breastfeeding women. 23. Inability to swallow or retain oral medications. 24. Current use of prohibited medications. 25. Participants with laboratory values ​​as defined in Table 3 at the time of screening. Table 3: Exclusionary Laboratory Values. Laboratory parameters Exclusion criteria hematology a platelets < 50 × 10 9 / L without auxiliary growth factors, thrombotic factors or platelet transfusion b ANC < 0.75 × 10 9 / L liver c ALT ≥ 2.5 × ULN d AST ≥ 2.5 × ULN e Total bilirubin ≥ 2.0 ULN, unless conjugated (direct) bilirubin ≤ 1.5 ULN (if total bilirubin exceeds the ULN, only direct bilirubin needs to be tested; except in cases of known Gilbert's syndrome, in which case direct bilirubin is tested). If no institutional ULN exists, then direct bilirubin must be < 40% of total bilirubin. f ALP ≥ 3 × ULN kidney g Creatinine clearance According to the Cockcroft-Gault formula, < 30 mL / min. other h Iron metabolism Serum ferritin levels > 1000 ng / mL on liver MRI or biopsy and clinically significant iron overload on record. ANC = Absolute neutrophil count; ALP = Alkaline phosphatase; ULN = Upper limit of normal.

[0176] Primary Analysis and Study Closure: The primary analysis will be conducted after all participants have completed at least 6 months of treatment with the study drug and completed all safety assessments for Cycle 6 or have discontinued the study drug early. Participants who are still receiving compound A at study closure, are experiencing clinical benefit, and have no evidence of progressive disease may have the option to continue treatment with compound A. Study closure will occur when all participants have discontinued treatment and completed applicable safety follow-up assessments, or when the sponsor terminates the study.

[0177] Example 2: Clinical Protocol for MF-Induced Anemia This study is a phase 1 / 2, open-label, multicenter, dose-escalation, and expansion study evaluating compound A alone (treatment group A [TGA]) or in combination with ruxolitinib (treatment group B [TGB]) in patients with transfusion-dependent or symptomatic anemia and MF. For TGA, patients must have previously been treated with a JAK inhibitor (for at least 12 weeks and be resistant, refractory, or lost to response to a JAK inhibitor) or be intolerant, or be ineligible for JAK inhibitor treatment (e.g., participants who do not receive any JAK inhibitor treatment due to severe anemia and / or have no symptoms other than anemia and no splenomegaly) and have an intermediate-2 or high risk category according to the Dynamic International Prognostic Score (DIPSS); for TGB, patients must have received a therapeutic and stable regimen of ruxolitinib for ≥12 consecutive weeks prior to the first dose of the study treatment and have an intermediate-1 or -2 or high DIPSS risk category. To be eligible, patients must be ≥18 years old, have an Eastern Cooperative Oncology Group (ECOG) performance status for dose escalation phase 0 to 1 or for dose expansion phase 0 to 2, have a life expectancy > 6 months, and have histologically confirmed primary or secondary (post-polycythemia vera, post-escalation thrombocythemia) myocardial infarction (MF).

[0178] Patients are ineligible if they have any other hematologic malignancies; have undergone any previous allogeneic or autologous stem cell transplantation; have undergone major surgery within 28 days of the first dose of the investigational drug; or have received prior chemotherapy, immunomodulatory drugs, immunosuppressive drugs, biological, endocrine or targeted therapies, or antibodies / hypomethylating agents within 5 half-lives or 28 days prior to the first dose of the investigational drug.

[0179] In Part 1 (Dose Escalation) of the study, patients will be recruited to either the TGA or TGB. Compound A monotherapy will be administered orally at an initial dose of 50 mg / day (28-day cycle) in the TGA. The dose escalation phase will use a Bayesian optimal interval design to determine the maximum tolerated dose (MTD), with dose increases not exceeding 100% (2-fold) until a treatment-related toxicity grade ≥2 is observed. Dose escalation in the TGB will begin at two dose levels below the maximum evaluable dose (recommended dose extension [RDE]) determined to be safe and tolerable in the TGA; patients in the TGB will receive compound A in combination with ruxolitinib. In each treatment group in Part 1, ≤24 patients will be treated during the dose escalation phase. In Part 2 (Dose Extension), the RDE in the TGB will be evaluated in approximately 25 patients in combination with ruxolitinib. The patient will receive treatment for up to 12 months, and may continue treatment if the patient is experiencing clinical benefit and has no evidence of progressive disease.

[0180] The primary study objective is to determine the safety and tolerability of compound A as monotherapy or in combination with ruxolitinib (assessed by the frequency and severity of adverse events [AEs], physical examination and monitoring of vital signs and laboratory values, and identification of dose-limiting toxicities, MTD, and RDE against TGB). Secondary objectives are to determine the efficacy of compound A as monotherapy or in combination with ruxolitinib (assessed by anemia response, duration of anemia response, mean change in hemoglobin from baseline, and rate of RBC infusion from week 24 to week 48), evaluate the pharmacokinetics of compound A, and evaluate the effects of compound A as monotherapy or in combination with ruxolitinib on hepcidin levels, iron homeostasis, and erythropoiesis.

[0181] Example 3: A mouse model of adenine-induced chronic kidney disease. Anemia associated with chronic kidney disease has been associated with the hepatic hormone hepcidin (Akchurin et al., Am. J. Physiol. Renal Physiol., 2016). Therefore, reducing hepcidin levels through ALK2 inhibition would be a useful therapeutic strategy to combat this state of the disease. To test this hypothesis, a mouse model of chronic kidney disease that also causes anemia was used. Adenine was orally administered to the mouse, metabolized into 2,8-dihydroxyadenine, which crystallizes in the tubules of the kidney. The accumulation of this metabolite causes kidney damage (nephropathy), inflammation, and subsequently anemia. Adenine (maximum dose of 50 mg / kg QD) was administered orally to mice (typically male C57B / 6 mice aged 6 to 10 weeks) for 28 days. During this period, renal function and hematological changes in the mice were monitored weekly. Anemia onset is tracked by measuring complete blood count (CBC), including red blood cell count, hemoglobin content, and hematocrit. Decreases in these blood parameters indicate anemia. Anemia onset has been observed 28 days after adenine administration and several weeks after cessation of oral adenine (Rahman et al., PLoS One, 2018). Changes in renal function can be detected within 10 days of adenine administration (Jia et al., BMC Nephrology, 2013; Rahman et al., PLoS One, 2018) and monitored by analyzing plasma creatinine and blood urea nitrogen (BUN) levels (Rahman et al., PLoS One, 2018). Increases (>2-fold) in plasma creatinine, plasma BUN, and urinary protein indicate renal impairment. Weight is also monitored weekly as an indicator of overall health.

[0182] Preliminary internal studies indicate that kidney injury does occur within 10 days of adenine administration, hepcidin levels do increase within 3 to 4 weeks of adenine administration, and hemoglobin and hematocrit levels do decrease after 4 weeks of adenine administration, as described elsewhere (Rahman et al., PLoS One, 2018).

[0183] The research was conducted under the supervision of a veterinarian and in accordance with guidelines and agreements established and approved by Incyte IACUC.

[0184] To investigate the ability of ALK2 inhibitors to alleviate anemia caused by kidney injury, male C57BL / 6 mice (Charles River Laboratories) were orally administered adenine (45 mg / kg QD) for 28 days. A mediator solution was also administered to the mouse group to maintain a baseline of normal blood content for comparison (n = 10). Blood parameters were monitored weekly by changes in CBC and body weight. Starting on day 14 after the first adenine administration, mice receiving adenine were administered compound A at 30 mg / kg QD (n = 8) or 100 mg / kg QD (n = 9), or a mediator control (n = 10). Mice were administered the compound A for 21 days, including day 14 after cessation of adenine administration. Final analysis was performed one week after the last dose of compound A, and on day 42 after the start of adenine administration. Figure 1 shows the results from this experiment. The left panel shows hemoglobin levels on day 42 of the study. Mice administered adenine and a carton agent showed signs of anemia, indicated by decreased hemoglobin levels, while mice administered a carton agent without adenine showed normal hemoglobin levels. Compound A dose-dependently increased hemoglobin (HGB) levels in this model. In mice administered adenine, the change in HGB levels was significantly increased in mice treated with compound A compared to mice treated with a carton agent. Furthermore, reducing anemia with compound A resulted in increased overall health, as measured by body weight, as shown in the right panel of Figure 1. Mice administered compound A had increased weight compared to mice administered adenine without compound A.

[0185] A study was conducted to investigate the effect of compound A administration at approximately the time of adenine administration during the later stages of kidney disease progression when hepcidin levels increased. Male C57BL / 6 mice were orally administered adenine (45 mg / kg QD) for 28 days. A mediator solution was also administered to a control group of mice to maintain a baseline of normal blood levels for comparison (n = 8). Blood parameters in mice were monitored weekly by changes in CBC and body weight. Mice receiving adenine were administered compound A at 30 mg / kg QD (n = 8) or 100 mg / kg QD (n = 8) or a mediator control (n = 8). Compound A administration was initiated on day 14 or 21 after the start of adenine administration and continued for 21 days, followed by another week until blood analysis. Administration initiated on day 14 was referred to as "prophylactic" because it was initiated before the increase in hepcidin occurred. The administration starting on day 21 is referred to as "concomitant" because the administration coincides with an increase in hepcidin levels. Figure 2 shows the results of prophylactic administration (left panel) and concomitant administration (right panel). Prophylactic administration of compound A resulted in a dose-dependent increase in hemoglobin levels, indicating an improvement in anemia in these animals. In C57BL / 6 mice, a QD dose of 100 mg / kg of compound A also returned hemoglobin levels to the normal range. Similarly, concomitant administration of compound A also resulted in a significant dose-dependent increase in hemoglobin levels. In conclusion, compound A improves the anemia observed in this model. Increased hemoglobin levels can be achieved when administered before or concurrently with an increase in hepcidin, the cause of anemia in this model.

[0186] The subject matter disclosed herein is not limited to the specific embodiments and examples described herein. Indeed, various modifications to the invention other than those described will become apparent to those skilled in the art from the foregoing description and drawings. Such modifications are intended to fall within the scope of the appended claims.

[0187] All references cited herein (e.g., publications, patents, or patent applications) are incorporated herein by reference in their entirety and for all purposes, as if the entirety of each individual reference (e.g., publications, patents, or patent applications) were expressly and individually incorporated by reference. Other embodiments are within the scope of the following patent applications. [Simplified Explanation of the Diagram]

[0022] Figure 1 shows the results of the mouse adenine-induced chronic kidney disease model, where *p < 0.05; **p < 0.01; ***p < 0.001. Single-factor ANOVA and Tukey's multiple comparison test were used, and LLN = lower limit of normal.

[0023] Figure 2 shows the results of prophylactic administration in the left figure and concomitant administration in the right figure of the nephropathy-anemia model, where ** p < 0.01; *** p < 0.001. Single-factor ANOVA and Tukey's multiple comparison test, LLN = lower limit of normal.

Claims

1. A method for treating anemia in an individual in need, comprising administering to the individual a compound of formula I: (I) or a pharmaceutically acceptable salt thereof; wherein R1 is, as appropriate, a 5 to 10-membered cycloalkyl group substituted once, twice, or three times with a hydroxyl or C1-C3 alkoxy group; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3 to 6-membered cycloalkyl, and 3 to 6-membered heterocycloalkyl, all of which are, as appropriate, substituted with R3; and R3 is selected from the group consisting of hydroxyl, halogen, cyano, nitro, SO2-C1-C3 alkyl, and SO3H.

2. The method of claim 1, wherein R1 is a hydroxylated bridged C8-cycloalkyl group.

3. The method of request item 1 or 2, wherein R2 is tetrahydropiperanone.

4. The method of any one of claims 1 to 3, wherein the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-(3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

6. The method of claim 4, wherein the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

7. The method of any of the requests 1 to 6, wherein the individual suffers from myelodysplastic syndrome (MDS).

8. The method of claim 7, wherein the myelomectic dysplasia syndrome (MDS) is selected from the group consisting of MDS with multilineage dysplasia (MDS-MLD), MDS with single lineage dysplasia (MDS-SLD), MDS with excess blast (MDS-EB), MDS with individual (5q) loss, and unclassifiable MDS (MDS-U).

9. The method of any one of claims 1 to 6, wherein the individual has multiple myeloma (MM).

10. The method of any one of claims 1 to 6, wherein the individual suffers from myelofibrosis (MF).

11. The method of any one of claims 1 to 6, wherein the anemia is iron-refractory iron deficiency anemia (IRIDA).

12. The method of any one of requests 1 to 11, wherein the system is transfusion dependent.

13. The method of any of requests 1 to 11, wherein the individual is not transfusion dependent.

14. The method of any one of claims 1 to 13, wherein the compound of formula I is administered orally.

15. The method of any one of claims 1 to 14, wherein the compound of formula I is administered as a monotherapy for the treatment of anemia.

16. The method of any one of claims 1 to 15, wherein the compound of formula I is administered at a dose of about 5 mg to about 500 mg once daily (QD).

17. The method of any one of claims 1 to 16, wherein the compound of formula I is administered at a dose of about 50 mg once daily (QD).

18. The method of any one of claims 1 to 17, wherein the compound of formula I is administered in the form of 5 mg, 25 mg or 50 mg tablets or a combination thereof.

19. A method for reducing hepcidin levels in an individual in need, comprising administering to the individual a compound of formula I: (I) or a pharmaceutically acceptable salt thereof; wherein R1 is, as appropriate, a 5- to 10-membered cycloalkyl group substituted once, twice, or three times with a hydroxyl or C1-C3 alkoxy group; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl, all of which are substituted with R3 as appropriate; and R3 is selected from the group consisting of hydroxyl, halogen, cyano, nitro, SO2-C1-C3 alkyl, and SO3H.

20. The method of claim 19, wherein R1 is a hydroxylated bridged C8-cycloalkyl group.

21. The method of claim 19 or 20, wherein R2 is tetrahydropiperanone.

22. The method of any one of claims 19 to 21, wherein the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-(3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

24. The method of claim 22, wherein the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

25. The method of any of claims 19 to 24, wherein the individual suffers from anemia.

26. The method of claim 25, wherein the anemia is iron-refractory iron deficiency anemia (IRIDA).

27. The method of any of requests 19 to 26, wherein the system is transfusion dependent.

28. The method of any of claims 19 to 26, wherein the individual is not transfusion dependent.

29. The method of any of claims 19 to 28, wherein the individual suffers from myelomectomy syndrome (MDS).

30. The method of claim 29, wherein the myelomectic dysplasia syndrome (MDS) is selected from a group consisting of MDS with multi-lineage dysplasia (MDS-MLD), MDS with single-lineage dysplasia (MDS-SLD), MDS with excess blasts (MDS-EB), MDS with individual (5q) loss, and unclassifiable MDS (MDS-U).

31. The method of any of claims 19 to 28, wherein the individual has multiple myeloma (MM).

32. The method of any of claims 19 to 28, wherein the individual suffers from myelofibrosis (MF).

33. The method of any one of claims 19 to 32, wherein the compound of formula I is administered orally.

34. The method of any one of claims 19 to 33, wherein the compound of formula I is administered as a monotherapy to reduce hepcidin content.

35. The method of any one of claims 19 to 34, wherein the compound of formula I is administered at a dose of about 5 mg to about 500 mg once daily (QD).

36. The method of any one of claims 19 to 35, wherein the compound of formula I is administered at a dose of about 50 mg once daily (QD).

37. The method of any one of claims 19 to 36, wherein the compound of formula I is administered in the form of a 5 mg, 25 mg or 50 mg tablet or a combination thereof.

38. A method for treating chronic kidney disease (CKD)-induced anemia in an individual in need, comprising administering to the individual a compound of formula I: (I) or a pharmaceutically acceptable salt thereof; wherein R1 is, as appropriate, a 5- to 10-membered cycloalkyl group substituted once, twice, or three times with a hydroxyl or C1-C3 alkoxy group; R2 is selected from the group consisting of C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C3 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl, all of which are, as appropriate, substituted with R3; and R3 is selected from the group consisting of hydroxyl, halogen, cyano, nitro, SO2-C1-C3 alkyl, and SO3H.

39. The method of claim 38, wherein R1 is a hydroxylated bridged C8-cycloalkyl group.

40. The method of claim 38 or 39, wherein R2 is tetrahydropiperanone.

41. The method of any one of claims 38 to 40, wherein the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-(3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

42. The method of claim 41, wherein the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

43. The method of claim 41, wherein the compound of formula I is 2-amino-N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-5-(4-((1S,5R)-3-(tetrahydro-2H-piperan-4-yl)-3-azabicyclo[3.1.0]hex-1-yl)phenyl)nicotinamide or a pharmaceutically acceptable salt thereof.

44. The method of any one of claims 38 to 43, wherein the compound of formula I is administered orally.

45. The method of any one of claims 38 to 44, wherein the compound of formula I is administered as a monotherapy to treat anemia induced by chronic kidney disease (CKD).

46. ​​The method of any one of claims 38 to 45, wherein the compound of formula I is administered at a dose of about 5 mg to about 500 mg once daily (QD).

47. The method of any one of claims 38 to 45, wherein the compound of formula I is administered at a dose of about 50 mg once daily (QD).

48. The method of any one of claims 38 to 47, wherein the compound of formula I is administered in the form of a 5 mg, 25 mg or 50 mg tablet or a combination thereof.

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