Compounds for treating MDS-associated anemias and other conditions

Abstract

Provided herein is the use of particular dose levels or amounts of certain pyruvate kinase activators or pharmaceutically acceptable salts or compositions thereof, for treating anemia associated with low risk MDS, lower risk MDS and / or intermediate risk MDS (collectively, LRMDS) and other conditions.

Description

COMPOUNDS FOR TREATING MDS-ASSOCIATED ANEMIAS AND OTHER CONDITIONSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of and priority to U.S. Provisional Application Serial No. 63 / 703,641, filed October 4, 2024, which is incorporated by reference in its entirety herein.BACKGROUND

[0002] Myelodysplastic syndrome (MDS) is a heterogeneous group of rare hematological malignancies characterized by dysfunctional hematopoiesis, progressive cytopenia, and an increased risk of progression to acute myeloid leukemia (AML). MDS occurs when the blood- forming cells in the bone marrow become abnormal (dysplastic) and have problems making new blood cells. Many of the blood cells formed by the bone marrow cells often die or are destroyed by the body, thus leaving the individual without enough normal blood cells. Although different cell types are affected by this phenomenon, the most common finding in MDS is a shortage of red blood cells (anemia). However, hemolytic anemia has also been found to occur, albeit rarely, in patients suffering from MDS. See, for example, Leukemia Research Reports, Vol. 5, 2016, pp. 23-26.

[0003] With an average age at diagnosis of 71 years, MDS patients can be severely impacted by chronically low levels of hemoglobin. This can lead to fatigue, worsening cardiopulmonary function, increased falls, and significant cognitive decline. As such, treatment of anemia is essential for overall health and quality of life. Currently, transfusions of packed red blood cells (PRBC) is the standard of care for MDS-associated anemia. The problem with transfusion dependent MDS-associated anemia patients, however, is that these patients are at a higher risk of iron overload and transfusion reactions and report a decreased quality of life.

[0004] Certain activators of pyruvate kinase have been disclosed as having potential utility in treating MDS-associated anemia, particularly anemia associated with very low-risk MDS, low-risk MDS and / or intermediate-risk MDS (WO2023091414A1) which are collectively referred to herein as LR-MDS or lower-risk MDS. These activators include those having the following structure formulae:as well as pharmaceutically acceptable salts thereof.SUMMARY

[0005] Provided herein, are methods of treating MDS-associated anemias and other conditions in a subject in need thereof, comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof, wherein the MDS is very low-riskMDS, low-risk MDS or intermediate-risk MDS (LR-MDS). Also provided are methods of treating MDS-associated anemias and other conditions in a subject in need thereof, comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof, wherein the MDS is very low-risk MDS, low-risk MDS or intermediaterisk MDS (LR-MDS).

[0006] Further provided are methods of treating hemolytic anemia in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a compositionthereof. Also provided are methods of treating hemolytic anemia in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0007] Also provided are methods for increasing the hemoglobin level in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof. Also provided are methods for increasing the hemoglobin level in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0008] Also provided are methods of treating acquired PK deficiency (PKD) in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof. Also provided are methods of treating acquired PK deficiency (PKD) in asubject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0009] Also provided are methods of treating anemias associated with acquired PKD in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof. Also provided are methods of treating anemias associated with acquired PKD in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0010] Also provided are methods of treating cytopenia in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof. Also provided are methods of treating cytopenia in a subject suffering from very low-risk MDS, low- risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject theequivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0011] Further provided are methods of treating ineffective erythropoiesis in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof. Also provided are methods of treating ineffective erythropoiesis in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS), comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0012] Further provided are methods of reducing disease progression in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS) by administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of the compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof. Also provided are methods of reducing disease progression in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (LR-MDS) by administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of the compoundhaving the structural formula:■ wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0013] In some aspects, administering to the subject an amount that is the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of the compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof, reduces inflammation within the subject’s bone marrow thereby reducing disease progression in the subject. In other aspects, administering to the subject an amount that is the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of the compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof, reduces inflammation within the subject’s bone marrow thereby reducing disease progression in the subject.BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1 shows an overview of a Phase 2a study design with Compound 1 in subjects with anemia due to lower-risk myelodysplastic syndrome (LR-MDS).FIG. 2 shows an overview of a Phase 2b study design with Compound 1 in subjects with anemia due to lower-risk myelodysplastic syndrome (LR-MDS).FIG. 3 shows the average PK activity, HK activity. PK / HK ratio, and ATP levels of red blood cells of patients with lower-risk myelodysplastic syndrome (LR-MDS) compared to healthy controls.FIG. 4 shows the average PK activity, HK activity. PK / HK ratio, and ATP levels of red blood cells of patients with lower-risk myelodysplastic syndrome (LR-MDS) incubated for 24 hr with the indicated concentration of AG-946 (Compound 1) compared to healthy controls.FIG. 5 Shows decreased PK activity in MDS patients (N=10) compared to healthy controls (HCs) (N=6), as established based on the PK / hexokinase (HK) ratio of 6.1 vs 10.5. Error bars represent standard deviation ***p<0.001.FIG. 6 Shows a significant increase in PK activity after treatment of RBCs with AG-946 for 16 hours at 37 °C. Error bars represent standard deviation **p<0.01, ***p<0.001.FIG. 7 Shows an increase in PK thermostability after treatment of RBC lysates for 2 hours at 37 °C. Error bars represent standard deviation ****p<0.0001.FIG. 8 Shows an increase in ATP levels upon the increase in PK activity after ex vivo treatment of RBC’s. Error bars represent standard deviation **p<0.01.DETAILED DESCRIPTION

[0014] Provided herein are methods of treatment using a compound having the structural formula:(Compound 1); wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0015] Compound 1 is also known as tebapivat, AG-946 and 2-((lH-pyrazol-3- yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3- d] pyridazin-5 ( 6H) -one .

[0016] Throughout the embodiments and claims provided herein, the doses recited refer to the free base equivalent of the compound of formulawhether the compound is administered as the free base or as a pharmaceutically acceptable salt thereof or as a component of a composition (either as a free base or a pharmaceutically acceptable salt thereof). For example, use of the term “administration of 10 mg of Compound 1 as a free base or a pharmaceutically acceptable salt thereof “ refers to the administration of 10 mg of Compound 1 as the free base or the administration of the amount of a pharmaceutically acceptable salt of Compound 1 that provides 10 mg of Compound 1 as the free base equivalent of said pharmaceutically acceptable salt. Similarly, use of the term “administration of the equivalent of 10 mg of Compound 1” refers to the administration of the amount of a pharmaceutically acceptable salt of Compound 1 that provides 10 mg of Compound 1 as the free base equivalent of said pharmaceutically acceptable salt.

[0017] In a first embodiment, provided herein is a method for treating anemia associated with myelodysplastic syndrome (MDS) in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structuralformula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0018] In a second embodiment, provided herein is a method for treating anemia associated with myelodysplastic syndrome (MDS) in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0019] In a third embodiment, provided herein is a method for treating hemolytic anemia associated with myelodysplastic syndrome (MDS) in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0020] In a fourth embodiment, provided herein is a method for treating hemolytic anemia associated with myelodysplastic syndrome (MDS) in a subject suffering from very low- risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0021] In a fifth embodiment, provided herein is a method of increasing the hemoglobin level in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0022] In a sixth embodiment, provided herein is a method of increasing the hemoglobin level in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0023] In a seventh embodiment, provided herein is a method of treating acquired PK deficiency (PKD) in a subject suffering from very low-risk MDS, low-risk MDS or intermediaterisk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0024] In an eighth embodiment, provided herein is a method of treating acquired PK deficiency (PKD) in a subject suffering from very low-risk MDS, low-risk MDS or intermediaterisk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0025] In a ninth embodiment, provided herein is a method of treating anemia associated with acquired PK deficiency (PKD) in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:■ wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0026] In a tenth embodiment, provided herein is a method of treating anemia associated with acquired PK deficiency (PKD) in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0027] In an eleventh embodiment, provided herein is a method of treating cytopenia in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0028] In a twelfth embodiment, provided herein is a method of treating cytopenia in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS) comprising administering to the subject the equivalent of 25 mg daily,30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0029] In a thirteenth embodiment, provided herein is a method of treating ineffective erythropoiesis in a subject in need thereof comprising administering to the subject the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0030] In a fourteenth embodiment, provided herein is a method of treating ineffective erythropoiesis in a subject in need thereof comprising administering to the subject the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of a compound having the structural formula:■ wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0031] As used herein, the term “hemolytic anemia” refers to a sub-type of anemia where a subject’s low red blood cell count is caused by the destruction — rather than the underproduction — of red blood cells. Unless stated otherwise the term “anemia” as used herein refers to a low red blood cell count in a subject that is caused by underproduction of red blood cells, including ineffective erythropoiesis, and hemolytic anemia.

[0032] The terms “MDS-associated anemia”, “anemia associated with MDS”, and “anemia due to MDS” are used interchangeably herein and refer to anemia that has developed or has been acquired in a subject as a result of the subject having or suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-MDS).

[0033] The terms “anemia associated with acquired PK deficiency (PKD)” and “PKD- associated anemia” are used interchangeably herein and refer to anemia which has developed in a subject as a result of acquired PKD that arises in the subject as a consequence of having or suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR-AGS-131W0MDS). More specifically, the subject acquires PKD as a consequence of the subject having or suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR- MDS). In some embodiments, the anemia associated with acquired PK deficiency in a subject suffering from very low-risk MDS, low-risk MDS or intermediate-risk MDS (collectively, LR- MDS) is hemolytic anemia.

[0034] The terms “subject” and “patient” are used interchangeably herein and refer to a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). Unless stated to the contrary, the subject is a human in need of treatment. In some embodiments the subject is an adult human (e.g., > 18 years of age). In other embodiments the subject is a human child (e.g., < 18 years of age). In still other embodiments the subject is a human female (adult or child). In yet other embodiments the subject is a human male (adult or child). It should also be understood that the terms subject or patient includes both singular and plural forms of the terms. It should further be understood that the terms subject and patient (which may further include the term “in need thereof’) as used herein refer to individuals that have or are suffering from LR-MDS.

[0035] The terms “administer,” “administering,” or “administration” refer to providing, implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a pharmaceutically acceptable salt or composition thereof, to, in or on a subject.

[0036] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or one or more symptoms of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed (i.e., therapeutic treatment). In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (i.e., prophylactic treatment) (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. In certain embodiments, treatment includes delaying the onset of at least one symptom of the disorder for a period of time.

[0037] As used herein, the recitation of a range of values is intended to serve as a shorthand method of referring individually to each separate value falling within the range as well as the highest and lowest values that define the range and each value is incorporated into the specification as if it were individually recited herein, unless expressly stated to the contrary. ForAGS-131W0 example, a range of values from X to Y includes both X and Y and all the values in between X and Y.

[0038] The use of any and all examples, or exemplary language (e.g., “such as” or “for example”) provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0039] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art, for example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of Compound 1 include those derived from suitable inorganic and organic acids. Examples of pharmaceutically acceptable acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, gentisate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0040] Compound 1 or a pharmaceutically acceptable salt thereof may be formulated and administered as a pharmaceutical composition. Pharmaceutical compositions can be prepared by methods known in the art of pharmacology. In one aspect, the pharmaceutical compositions are orally administered in an orally acceptable dosage form including, but not limited to, granules or minitablets, capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. Unless expressly stated otherwise, the terms “composition” and “pharmaceutical composition” are used interchangeably herein and should be understood to refer to compositions comprising Compound 1 or a pharmaceutically acceptable salt of Compound 1. Similarly, unless expressly stated otherwise, the terms “composition thereof’ and “pharmaceutical composition thereof’ areused interchangeably herein and should be understood to refer to compositions comprising Compound 1 or a pharmaceutically acceptable salt of Compound 1.

[0041] In one aspect, as part of a fifteenth embodiment, a subject being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including those subjects described in any one of the first through fourth and seventh through fourteenth embodiments) experiences a hemoglobin response. Unless expressly stated to the contrary, the terms “a pharmaceutically acceptable salt” and “a pharmaceutically acceptable salt thereof’ are used interchangeably herein and should be understood to refer to a pharmaceutically acceptable salt of Compound 1.

[0042] As used herein, the term “hemoglobin response” refers to an increase in hemoglobin (Hb) from a baseline Hb level (i.e., Hb concentration) of the subject, where the subject’s hemoglobin response is measured over a period of time during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof or following administration of Compound 1 or a pharmaceutically acceptable salt or a composition thereof. Unless stated to the contrary, the terms “during treatment” or “following administration” when used in connection with Compound 1 or a pharmaceutically acceptable salt or a composition thereof refers to ongoing treatment or administration (i.e., the subject will continue to be treated with or administered Compound 1 or a pharmaceutically acceptable salt or a composition thereof). The terms hemoglobin (Hb) level and hemoglobin concentration are used interchangeably herein. As used herein, the term “baseline” refers to a level or concentration that is measured or established prior to treatment or during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. For example, as used herein the term “baseline hemoglobin level” refers to a subject’s hemoglobin (Hb) level that is measured or established prior to treatment or during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. In one aspect, “hemoglobin response” refers to an increase in hemoglobin from a baseline Hb level (i.e., Hb concentration) of the subject, where the subject’s hemoglobin response is measured over a period of time during treatment. In another aspect, “hemoglobin response” refers to an increase in hemoglobin from a baseline Hb level (i.e., Hb concentration) of the subject, where the subject’s hemoglobin response is measured over a period of time following administration of Compound 1 or a pharmaceutically acceptable salt or a composition thereof, e.g., after 1 week of treatment, 2 weeks of treatment, 3 weeks of treatment, 4 weeks of treatment, 3 months of treatment, 6 months of treatment or 1 year of treatment or longer.

[0043] In one aspect, as part of a sixteenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through fifteenth embodiments) increasesAGS-131W0 from baseline over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 30 weeks, at least 40 weeks, or at least 50 weeks during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. In one aspect, as part of a sixteenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through fifteenth embodiments) increases from baseline over a period of at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 30 weeks, at least 40 weeks, or at least 50 weeks during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. Alternatively, as part of a sixteenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through fifteenth embodiments) increases from baseline over a period of at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, or at least 20 weeks during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. In another alternative, as part of a sixteenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through fifteenth embodiments) increases from baseline from week 1 through week 20, from week 1 through week 18, from week 1 through week 16, from week 4 through week 20, from week 4 through week 18, from week 4 through week 16, from week 6 through week 20, from week 6 through week 18, from week 6 through week 16, from week 8 through week 20, from week 8 through week 18, from week 8 through week 16, from week 10 through week 20, from week 10 through week 18, or from week10 through week 16, during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. In another alternative, as part of a sixteenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through fifteenth embodiments) increases from baseline from week 8 through week 16 during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. In another alternative, as part of a sixteenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through fifteenth embodiments) increases from baseline at > 2, > 3, > 4, > 5, or > 6 consecutive time points from week 1 through week 20, from week 1 through week 18, from week 1 through week 16, from week 4 through week 20, from week 4 through week 18, from week 4 through week 16, from week 6 through week 20, from week 6 through week 18, from week 6 through week 16, from week 8 through week 20, from week 8 through week 18, from week 8 through week 16, from week 10 through week 20, from week 10 through week 18, or from week 10 through week 16, during treatment with Compound 1 or a pharmaceuticallyacceptable salt or a composition thereof. In another alternative, as part of a sixteenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through fifteenth embodiments) increases from baseline at > 2 consecutive time points from week 8 through week 16 during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. In another alternative, as part of a sixteenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through fifteenth embodiments) increases from baseline for > 1 consecutive week, for > 2 consecutive weeks, for > 3 consecutive weeks, for > 4 consecutive weeks, for > 5 consecutive weeks, for > 6 consecutive weeks, for > 7 consecutive weeks, for > 8 consecutive weeks, for > 9 consecutive weeks, or for > 10 consecutive weeks during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. In another alternative, as part of a sixteenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through fifteenth embodiments) increases from baseline for > 8 consecutive weeks during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof.

[0044] In one aspect, as part of a seventeenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through sixteenth embodiments) improves by at least 1.0 g / dL (e.g., > 1.0 g / dL increase from baseline) during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. Alternatively, as part of a seventeenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through sixteenth embodiments) improves by at least 1.5 g / dL (e.g., > 1.5 g / dL increase from baseline) during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. In another alternative, as part of a seventeenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through sixteenth embodiments) improves by at least 2.0 g / dL (e.g., > 2.0 g / dL increase from baseline) during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. In another alternative, as part of a seventeenth embodiment, the hemoglobin level of the subject being treated (including any one of the first through sixteenth embodiments) improves by more than 2.0 g / dL (e.g., > 2.0 g / dL increase from baseline) during treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof.

[0045] In one aspect, as part of an eighteenth embodiment, a subject being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth embodiments) is classified as a subject with LR-MDS who is non-transfusion dependent (NTD) prior to treatment.

[0046] As used herein, the terms “non-transfusion dependent (NTD)” and “nontransfused” refer to a subject with LR-MDS who does not require regular blood transfusionsAGS-131W0 prior to treatment with Compound 1 or a pharmaceutically acceptable salt or a composition thereof. In one aspect, NTD refers to a subject with LR-MDS who has <3 red blood cell (RBC) units in the 16-week period before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt or a composition thereof and no transfusions in the 8-week period before administration of the first dose of Compound 1 or a pharmaceutically acceptable salt or a composition thereof.

[0047] As used herein, the term “transfusion dependent (TD)” refers to a subject with LR-MDS who requires regular blood transfusions.

[0048] In one aspect, as part of a nineteenth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth embodiments) becomes transfusion independent during treatment. In some aspects, as part of a nineteenth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth embodiments) becomes transfusion independent for a period of time during treatment.

[0049] As used herein, the terms “transfusion independent” and “transfusion independence” and “transfusion free” are used interchangeably herein and refer to a subject with LR-MDS that is free of (i.e., have not had) a red blood cell transfusion for a period of time. In some aspects, the terms “transfusion independent” and “transfusion independence” and “transfusion free” refer to a subject with LR-MDS that has not had a red blood cell transfusion over a period of 16 consecutive weeks. In some aspects, a subject that has not had a red blood cell transfusion over a period of 16 consecutive weeks is referred to as being transfusion free. In other aspects, the terms “transfusion independent” and “transfusion independence” and “transfusion free” refer to a subject that has not had a red blood cell transfusion over a period of > 8 consecutive weeks. In some aspects, a subject that has not had a red blood cell transfusion over a period of > 8 consecutive weeks is referred to as being transfusion free.

[0050] In one aspect, as part of a twentieth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth or nineteenth embodiments) is classified as having a high transfusion burden (HTB). Alternatively, as part of a twentieth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth or nineteenth embodiments) is classified as having a high transfusion burden (HTB) prior to treatment. In another alternative, as part of a twentieth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including anyAGS-131W0 one of the first through seventeenth or nineteenth embodiments) is classified as having a high transfusion burden (HTB) which is characterized by the subject receiving at least 8 red blood cell ( RBC) units over the course of 16 weeks and having greater than or equal to 4 transfusion episodes over the course of 8 weeks. In another alternative, as part of a twentieth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth or nineteenth embodiments) is classified as having a high transfusion burden (HTB) which is characterized by the subject receiving at least 8 RBC units over the course of 16 weeks and having greater than or equal to 4 transfusion episodes over the course of 8 weeks prior to treatment. In another alternative, as part of a twentieth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth or nineteenth embodiments) is classified as having a high transfusion burden (HTB) which is characterized by the subject receiving at least 8 RBC units over the course of 16 weeks and receiving at least 4 RBC units over a period of 8 weeks during the course of the 16 weeks prior to treatment.

[0051] In one aspect, as part of a twenty-first embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth or nineteenth embodiments) is classified as having a low transfusion burden (LTB). Alternatively, as part of a twenty-first embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth or nineteenth embodiments) is classified as having a low transfusion burden (LTB) prior to treatment. In another alternative, as part of a twenty-first embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth or nineteenth embodiments) is classified as having a low transfusion burden (LTB) which is characterized by the subject receiving between 3-7 RBC units over the course of 16 weeks in at least 2 transfusion episodes with a maximum of 3 transfusion episodes over the course of 8 weeks prior to treatment. In another alternative, as part of a twenty- first embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through seventeenth or nineteenth embodiments) is classified as having a low transfusion burden (LTB) which is characterized by the subject receiving between 3-7 RBC units over the course of 16 weeks in at least 2 transfusion episodes with a maximum of 3 transfusion episodes over the course of 8 weeks at some point during treatment.

[0052] In one aspect, as part of a twenty-second embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-first embodiments) becomes transfusion independent for > 1 consecutive week, for > 2 consecutive weeks, for > 3 consecutive weeks, for> 4 consecutive weeks, for > 5 consecutive weeks, for > 6 consecutive weeks, for > 7 consecutive weeks, for > 8 consecutive weeks, for > 9 consecutive weeks, or for > 10 consecutive weeks during treatment. Alternatively, as part of a twenty-second embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-first embodiments) becomes transfusion independent for > 8 consecutive weeks during treatment. In another alternative, as part of a twenty-second embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-first embodiments) becomes transfusion independent for > 8 consecutive weeks during treatment, wherein the subject was classified as having a low transfusion burden (LTB) prior to treatment.

[0053] In one aspect, as part of a twenty-third embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-second embodiments) experiences a change from baseline in total transfused red blood cell (RBC) units during treatment. In one aspect, as part of a twenty-third embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-second embodiments) experiences a reduction in total transfused red blood cell (RBC) units during treatment in comparison to the subject’s baseline total transfused red blood cell (RBC) units.

[0054] In one aspect, as part of a twenty-fourth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-third embodiments) experiences a change from baseline in total transfused red blood cell (RBC) units which is characterized by a > 10%, > 20%, > 30%, > 40%, > 50%, > 60%, > 70%, or > 80% reduction in total transfused RBC units during treatment. Alternatively, as part of a twenty-fourth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-third embodiments) experiences a change from baseline in total transfused red blood cell (RBC) units characterized by a > 10%, > 20%, > 30%,> 40%, > 50%, > 60%, > 70%, or > 80% reduction in total transfused RBC units over a period of> 1 consecutive week, > 2 consecutive weeks, > 3 consecutive weeks, > 4 consecutive weeks, >AGS-131W05 consecutive weeks, > 6 consecutive weeks, > 7 consecutive weeks, > 8 consecutive weeks, > 9 consecutive weeks, or > 10 consecutive weeks during treatment. In another alternative, as part of a twenty-fourth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-third embodiments) experiences a change from baseline in total transfused red blood cell (RBC) units characterized by a > 50% reduction in total transfused RBC units during treatment. In another alternative, as part of a twenty-fourth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-third embodiments) experiences a change from baseline in total transfused red blood cell (RBC) units characterized by a > 50% reduction in total transfused RBC units over a period of > 1 consecutive week, > 2 consecutive weeks, > 3 consecutive weeks, > 4 consecutive weeks, > 5 consecutive weeks, > 6 consecutive weeks, > 7 consecutive weeks, > 8 consecutive weeks, > 9 consecutive weeks, or > 10 consecutive weeks during treatment. In another alternative, as part of a twenty-fourth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-third embodiments) experiences a change from baseline in total transfused red blood cell (RBC) units characterized by a > 50% reduction in total transfused RBC units over a period of > 8 consecutive weeks during treatment. In another alternative, as part of a twenty-fourth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-third embodiments) experiences a change from baseline in total transfused red blood cell (RBC) units characterized by a > 50% reduction in total transfused RBC units over a period of > 8 consecutive weeks during treatment, wherein the subject was classified as having a high transfusion burden (HTB) prior to treatment.

[0055] In one aspect, as part of a twenty-fifth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-fourth embodiments) experiences a reduction in 2,3-diphosphoglycerate (2,3-DPG) concentration during treatment as compared to the subject’s baseline 2,3-DPG concentration.

[0056] In one aspect, as part of a twenty-sixth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-fifth embodiments) experiences an increase in adenosine triphosphate (ATP) concentration during treatment as compared to the subject’s baseline ATP concentration. Alternatively, as part of a twenty-sixth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a compositionthereof (including any one of the first through twenty-fifth embodiments) experiences an increase in adenosine triphosphate (ATP) concentration of more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, and more than 75% during treatment as compared to the subject’s baseline ATP concentration. In another alternative, as part of a twenty-sixth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-fifth embodiments) experiences an increase in adenosine triphosphate (ATP) concentration of 68%, 71%, or 74% during treatment as compared to the subject’s baseline ATP concentration. In another alternative, as part of a twenty-sixth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-fifth embodiments) experiences an increase in adenosine triphosphate (ATP) concentration of more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, and more than 75% after 10, after 20, after 30, after 40, after 50, after 60, or after 65 days of daily dosing as compared to the subject’s baseline ATP concentration. In another alternative, as part of a twenty-sixth embodiment, a subject with LR-MDS being treated with Compound 1 or a pharmaceutically acceptable salt or a composition thereof (including any one of the first through twenty-fifth embodiments) experiences an increase in adenosine triphosphate (ATP) concentration of 68% after 56 days of daily dosing, 71% after 56 days of daily dosing, or 74% after 56 days of daily dosing as compared to the subject’s baseline ATP concentration.

[0057] In one aspect, as part of a twenty-seventh embodiment, the MDS described herein (including any one of the first to twelfth and sixteenth to twenty-sixth embodiments) is low risk MDS as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS. See, for example, Greenberg PL, Tuechler H, Schanz J, et al., Revised International Prognostic Scoring System for myelodysplastic syndromes. Blood. 2012;120:2454-2465. Low risk MDS includes, for example, an IPSS-R score of greater than 1.5 to 3. Alternatively, as part of a twenty-seventh embodiment, the MDS described herein (including any one of the first to twelfth and sixteenth to twenty-sixth embodiments) is very low risk MDS as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS. Very low risk MDS includes, for example, an IPSS-R score of less than or equal to 1.5. In another alternative, as part of a twenty-seventh embodiment, the MDS described herein (including any one of the first to twelfth and sixteenth to twenty-sixth embodiments) is intermediate risk MDS as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS. Intermediate risk MDS includes, for example, an IPSS-R score of greater than 3 to 4.5. In still another alternative, as part of a twenty-seventh embodiment, the MDS described herein (including any one of the firstto twelfth and sixteenth to twenty-sixth embodiments) is “lower risk MDS (LR-MDS)” which encompasses very low risk MDS and low risk MDS and intermediate risk MDS as described above.

[0058] In one aspect, as part of a twenty-eighth embodiment, the subject with LR-MDS described herein (including any one of the first to twenty-seventh embodiments) is male. Alternatively, as part of a twenty-eighth embodiment, the subject with LR-MDS described herein (including any one of the first to twenty-seventh embodiments) is female. Alternatively, as part of a twenty-eighth embodiment, the subject with LR-MDS described herein (including any one of the first to twenty-seventh embodiments) is an adult male. Alternatively, as part of a twentyeighth embodiment, the subject with LR-MDS described herein (including any one of the first to twenty-seventh embodiments) is an adult female. In another alternative, as part of a twentyeighth embodiment, the subject with LR-MDS described herein (including any one of the first to twenty-seventh embodiments) is a male child or a female child. Alternatively, as part of a twenty-eighth embodiment, the subject with LR-MDS described herein (including any one of the first to twenty-seventh embodiments) is an adult (i.e., > 18 years of age). In yet another alternative, as part of a twenty-eighth embodiment, the subject with LR-MDS described herein (including any one of the first to twenty-seventh embodiments) is a child (i.e., < 18 years of age).

[0059] In one aspect, as part of a twenty-ninth embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 10 mg once daily (QD), 15 mg once daily (QD) or 20 mg once daily (QD) of 2- ((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof. Alternatively, as part of a twenty-ninth embodiment, a subject with LR- MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 10 mg once daily (QD), 15 mg once daily (QD) or 20 mg once daily (QD) of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as part of a composition comprising 2- ((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0060] In one aspect, as part of a thirtieth embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of 2-((lH-pyrazol-3- yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3- d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof.Alternatively, as part of a thirtieth embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 25 mg daily, 30 mg daily, 35 mg daily or 40 mg daily of 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as part of a composition comprising 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)- 4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0061] In one aspect, as part of a thirty-first embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 10 mg once daily (QD) of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2- yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof. Alternatively, as part of a thirty-first embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 10 mg once daily (QD) of2-((lH-pyrazol-3- yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3- d]pyridazin-5(6H)-one, as part of a composition comprising 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0062] In one aspect, as part of a thirty-second embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 15 mg once daily (QD) of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2- yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof. Alternatively, as part of a thirty-second embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 15 mg once daily (QD) of 2-((lH-pyrazol-3- yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3- d]pyridazin-5(6H)-one, as part of a composition comprising 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0063] In one aspect, as part of a thirty-third embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 20 mg once daily (QD) of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2- yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or aAGS-131W0 pharmaceutically acceptable salt thereof. Alternatively, as part of a thirty-third embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 20 mg once daily (QD) of2-((lH-pyrazol-3- yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3- d]pyridazin-5(6H)-one, as part of a composition comprising 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0064] In one aspect, as part of a thirty-fourth embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 25 mg once daily (QD) of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2- yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof. Alternatively, as part of a thirty-fourth embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 25 mg once daily (QD) of2-((lH-pyrazol-3- yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3- d]pyridazin-5(6H)-one, as part of a composition comprising 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0065] In one aspect, as part of a thirty-fifth embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 30 mg once daily (QD) of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2- yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof. Alternatively, as part of a thirty-fifth embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 30 mg once daily (QD) of2-((lH-pyrazol-3- yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3- d]pyridazin-5(6H)-one, as part of a composition comprising 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0066] In one aspect, as part of a thirty-sixth embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 35 mg once daily (QD) of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-AGS-131W0 yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof. Alternatively, as part of a thirty-sixth embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 35 mg once daily (QD) of2-((lH-pyrazol-3- yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3- d]pyridazin-5(6H)-one, as part of a composition comprising 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0067] In one aspect, as part of a thirty-seventh embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 40 mg once daily (QD) of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2- yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof. Alternatively, as part of a thirty-seventh embodiment, a subject with LR-MDS described herein (including any one of the first to twenty-eighth embodiments) is administered the equivalent of 40 mg once daily (QD) of2-((lH-pyrazol-3- yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3- d]pyridazin-5(6H)-one, as part of a composition comprising 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0068] In one aspect, as part of a thirty-eighth embodiment, a subject with LR-MDS described herein (including any one of the first to thirty-seventh embodiments) is administered 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base.

[0069] In one aspect, as part of a thirty-ninth embodiment, a subject with LR-MDS described herein (including any one of the first to thirty-seventh embodiments) is administered 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a pharmaceutically acceptable salt.

[0070] In one aspect, as part of a fortieth embodiment, a subject with LR-MDS as described herein, (including any one of the first to thirty-ninth embodiments) is treated (i.e., administered Compound 1 or a pharmaceutically acceptable salt or a composition thereof as described herein) for a period of at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 24 weeks, at least 30 weeks, or at least 6 weeks. Alternatively, as part of a fortieth embodiment, a subject with LR-MDS as described herein (including any one of the first to thirty-ninthAGS-131W0 embodiments) is treated (i.e., administered Compound 1 or a pharmaceutically acceptable salt or a composition thereof as described herein) for a period of up to 12 weeks, up to 14 weeks, up to 16 weeks, up to 24 weeks, up to 30 weeks, up to 36 weeks, up to 50 weeks, up to 100 weeks, or up to 160 weeks. In another alternative, as part of a fortieth embodiment, a subject with LR- MDS as described herein (including any one of the first to thirty-ninth embodiments) is treated (i.e., administered Compound 1 or a pharmaceutically acceptable salt or a composition thereof as described herein) for a period of 16 weeks, of 24 weeks, or of 156 weeks. In another alternative, as part of a fortieth embodiment, a subject with LR-MDS as described herein (including any one of the first to thirty-ninth embodiments) is treated (i.e., administered Compound 1 or a pharmaceutically acceptable salt or a composition thereof as described herein) indefinitely or for the remainder of the subject’s life.

[0071] In one aspect, provided is the use of 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one or a pharmaceutically acceptable salt or a composition thereof, for the manufacture of a medicament for treating LR-MDS (e.g., as in any one of the embodiments disclosed above), wherein the medicament is configured to administer an amount that is equivalent to 10 mg, 15 mg or 20 mg of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or as a pharmaceutically acceptable salt.

[0072] In one aspect, provided is the use of 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one or a pharmaceutically acceptable salt or a composition thereof, for the manufacture of a medicament for treating LR-MDS (e.g., as in any one of the embodiments disclosed above), wherein the medicament is configured to administer an amount that is equivalent to 25 mg, 30 mg, 35 mg or 40 mg of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl- 4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or as a pharmaceutically acceptable salt.

[0073] In another aspect, also provided is the use of 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one or a pharmaceutically acceptable salt or a composition thereof, for treating LR-MDS (e.g., as in any one of the embodiments disclosed above), wherein treating LR-MDS comprises administering to a subject in need thereof an amount that is equivalent to 10 mg, 15 mg, or 20 mg of 2-((lH- pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or as a pharmaceutically acceptable salt.

[0074] In another aspect, also provided is the use of 2-((lH-pyrazol-3-yl)methyl)-6-((6- aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one or a pharmaceutically acceptable salt or a composition thereof, for treating LR-MDS (e.g., as in any one of the embodiments disclosed above), wherein treating LR-MDS comprises administering to a subject in need thereof an amount that is equivalent to 25 mg, 30 mg, 35 mg, or 40 mg of 2- ((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, as a free base or as a pharmaceutically acceptable salt.

[0075] Throughout the description herein, references to a “method” of treating are intended to also cover compounds for use in said treating, uses of compounds in said treating, and uses of compounds for the manufacture of medicaments for said treating. References to a medicament orally administered to deliver a certain dose of compound are intended to also cover a medicament configured for oral administration, and configured to comprise and / or to deliver said dose of compound.Selected embodimentsEmbodiment 1. A method of treating anemia associated with lower-risk myelodysplastic syndrome (MDS) or LR-MDS in a subject suffering from lower-risk MDS (LR-MDS) comprising orally administering to the subject an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 2. A method of treating anemia associated with lower-risk myelodysplastic syndrome (MDS) or LR-MDS in a subject suffering from lower-risk MDS (LR-MDS) comprising orally administering to the subject an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 3. A method of treating hemolytic anemia in a subject suffering from lower- risk MDS (LR-MDS) comprising orally administering to the subject an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 4. A method of treating hemolytic anemia in a subject suffering from lower- risk MDS (LR-MDS) comprising orally administering to the subject an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 5. A method of increasing the hemoglobin level in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS comprising orally administering to the subject an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 6. A method of increasing the hemoglobin level in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS comprising orally administering to the subject an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 7. A method of treating acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS comprising orally administering to the subject an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 8. A method of treating acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS comprising orally administering to the subject an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 9. A method of treating anemia associated with acquired PK deficiency(PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS comprising orally administering to the subject an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 10. A method of treating anemia associated with acquired PK deficiency(PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS comprising orally administering to the subject an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 11. A method of treating cytopenia in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS comprising orally administering to the subject an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 12. A method of treating cytopenia in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS comprising orally administering to the subject an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 13. A method of treating a disease or disorder associated with ineffective erythropoiesis in a subject in need thereof comprising orally administering to the subject an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 14. A method of treating a disease or disorder associated with ineffective erythropoiesis in a subject in need thereof comprising orally administering to the subject an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.AGS-131W0Embodiment 15. The method of any one of embodiments 1 to 14, wherein the hemoglobin level of the subject improves over a period of at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, or at least 20 weeks of treatment.Embodiment 16. The method of any one of embodiments 1 to 15, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL.Embodiment 17. The method of any one of embodiments 1 to 15, wherein the hemoglobin level of the subject increases from baseline by > 1.5 g / dL.Embodiment 18. The method of any one of embodiments 1 to 15, wherein the hemoglobin level of the subject increases from baseline by > 2.0 g / dL.Embodiment 19. The method of any one of embodiments 1 to 18, wherein the subject becomes transfusion independent.Embodiment 20. The method of any one of embodiments 1 to 19, wherein the subject is classified as having a low transfusion burden prior to treatment.Embodiment 21. The method of any one of embodiments 1 to 20, wherein the subject becomes transfusion independent for > 1 consecutive week, for > 2 consecutive weeks, for > 3 consecutive weeks, for > 4 consecutive weeks, for > 5 consecutive weeks, for > 6 consecutive weeks, for > 7 consecutive weeks, for > 8 consecutive weeks, for > 9 consecutive weeks, or for > 10 consecutive weeks.Embodiment 22. The method of any one of embodiments 1 to 21, wherein the subject becomes transfusion independent for > 8 consecutive weeks.Embodiment 23. The method of any one of embodiments 1 to 22, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 10%, > 20%, > 30%, > 40%, > 50%, > 60%, > 70%, or > 80%.Embodiment 24. The method of any one of embodiments 1 to 23, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50%.Embodiment 25. The method of any one of embodiments 1 to 24, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 1 consecutive week, > 2 consecutive weeks, > 3 consecutive weeks, > 4 consecutive weeks, > 5 consecutive weeks, > 6 consecutive weeks, > 7 consecutive weeks, > 8 consecutive weeks, > 9 consecutive weeks, or > 10 consecutive weeks.Embodiment 26. The method of any one of embodiments 1 to 25, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 8 consecutive weeks.Embodiment 27. The method of any one of embodiments 1 to 26, wherein the LR-MDS is low risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS- R) for MDS).Embodiment 28. The method of any one of embodiments 1 to 26, wherein the LR-MDS is very low risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS).Embodiment 29. The method of any one of embodiments 1 to 26, wherein the LR-MDS is intermediate risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS).Embodiment 30. The method of any one of embodiments 1 to 29, wherein the subject is male.Embodiment 31. The method of any one of embodiments 1 to 29, wherein the subject is female.Embodiment 32. The method of any one of embodiments 1 to 31, wherein the compound or pharmaceutically acceptable salt is administered as a pharmaceutical composition.Embodiment 33. The method of embodiment 32 wherein the pharmaceutical composition is in the form of a tablet or one or more granules.Embodiment 34. The method of any one of embodiments 1 to 32, wherein the pharmaceutical composition is in the form of one or more granules.Embodiment 35. The method of any one of embodiments 1 to 32 wherein the pharmaceutical composition is in the form of a tablet.Embodiment 36. A method of treating anemia associated with lower-risk myelodysplastic syndrome (LR-MDS) in a subject comprising orally administering to the subject an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof, wherein the subject is classified as being non-transfused, of low transfusion burden, or of high transfusion burden prior to administration.Embodiment 37. A method of treating anemia associated with lower-risk myelodysplastic syndrome (LR-MDS) in a subject comprising orally administering to the subject an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of a compound having the structural formula:wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof, wherein the subject is classified as being non-transfused, of low transfusion burden, or of high transfusion burden prior to administration.Embodiment 38. The method of embodiment 37, wherein the subject is classified as having a low transfusion burden prior to treatment.Embodiment 39. The method of embodiment 38, wherein the subject becomes transfusion independent for > 8 consecutive weeks.Embodiment 40. The method of embodiment 38 or 39, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL, > 1.5 g / dL or > 2.0 g / dL.Embodiment 41. The method of embodiment 37, wherein the subject is classified as being non-transfused prior to treatment.Embodiment 42. The method of embodiment 41, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL, > 1.5 g / dL or > 2.0 g / dL.Embodiment 43. The method of embodiment 37, wherein the subject is classified as having a high transfusion burden prior to treatment.Embodiment 44. The method of embodiment 43, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 8 consecutive weeks.Embodiment 45. The method of any of embodiments 9, 10 and 15 to 35, wherein the anemia associated with acquired PK deficiency (PKD) is hemolytic anemia.Embodiment 46. The method of any one of embodiments 1 to 45, wherein the method comprises administering to the subject an amount that is equivalent to 10 mg once daily (QD) of the compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 47. The method of any one of embodiments 1 to 45, wherein the method comprises administering to the subject an amount that is equivalent to 15 mg once daily (QD) of the compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 48. The method of any one of embodiments 1 to 45, wherein the method comprises administering to the subject an amount that is equivalent to 20 mg once daily (QD) of the compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 49. The method of any one of embodiments 1 to 45, wherein the method comprises administering to the subject an amount that is equivalent to 25 mg once daily (QD) of the compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 50. The method of any one of embodiments 1 to 45, wherein the method comprises administering to the subject an amount that is equivalent to 30 mg once daily (QD) of the compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 51. The method of any one of embodiments 1 to 45, wherein the method comprises administering to the subject an amount that is equivalent to 35 mg once daily (QD) of the compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 52. The method of any one of embodiments 1 to 45, wherein the method comprises administering to the subject an amount that is equivalent to 40 mg once daily (QD) of the compound having the structural formula:; wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 53. The method of any one of embodiments 1 to 52, wherein the amount of the compound administered is either maintained or is modified if the subject experiences a platelet count decrease.Embodiment 54. The method of embodiment 53, wherein the amount of the compound administered is not modified for a grade 1 platelet count decrease (platelet count between 75,000 / pL and lower limit of normal (LLN)).Embodiment 55. The method of embodiment 53, wherein the amount of the compound administered is not modified for a grade 2 platelet count decrease (platelet count of 25,000 / pL to <75,000 / pL).Embodiment 56. The method of embodiment 55, wherein a subject’s platelet count is monitored weekly for 4 weeks, then monitored every 2 weeks for 4 weeks, then monitored every 4 weeks for 12 weeks, provided that the platelet count is stable.Embodiment 57. The method of embodiment 53, wherein at a first occurrence of a grade 4 platelet count decrease (platelet count <25,000 / pL): a) administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of a platelet count decrease; b) administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally c) administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.Embodiment 58. The method of embodiment 53, wherein at a second occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL): a) administration of the compound is discontinued for subjects that were receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; b) administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally c) administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.Embodiment 59. The method of embodiment 57 or 58, wherein in optional step c administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, or at an amount equivalent to 15 mg of the compoundadministered as a free base or pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 60. The method of any one of embodiments 1 to 52, wherein the amount of the compound administered is either maintained or is modified for events of platelet count decrease as follows: a) the amount of the compound administered is not modified for grade 1 platelet count decreases (platelet count between 75,000 / pL and lower limit of normal (LLN)); b) the amount of the compound administered is not modified for grade 2 platelet count decreases (platelet count of 25,000 / pL to <75,000 / pL) and platelet count is monitored weekly for 4 weeks, then monitored every 2 weeks for 4 weeks, then monitored every 4 weeks for 12 weeks, provided that the platelet count is stable; c) the amount of the compound administered is modified at a first occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL) as follows: i. administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; ii. administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally iii. administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks; d) the amount of the compound administered is modified at a second occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL) as follows: i. administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; ii. administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally iii. administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.Embodiment 61. The method of embodiment 60, wherein in optional step c(iii) administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 62. The method of embodiment 60, wherein in optional step d(iii) administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 63. The method of embodiment 60, wherein in optional step c(iii) administration is restarted at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 64. The method of embodiment 60, wherein in optional step d(iii) administration is restarted at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 65. The method of embodiment 60, wherein in optional step c(iii) administration is restarted at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 66. The method of embodiment 60, wherein in optional step d(iii) administration is restarted at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 67. The method of embodiment 60, wherein in optional step c(iii) administration is restarted at an amount equivalent to 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 40 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 68. The method of embodiment 60, wherein in optional step d(iii) administration is restarted at an amount equivalent to 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if theprevious amount was the equivalent of 40 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 69. A compound having the structural formula:for use in treating anemia associated with lower-risk myelodysplastic syndrome (MDS) or LR-MDS in a subject suffering from lower-risk MDS (LR-MDS), said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 70. A compound having the structural formula:for use in treating anemia associated with lower-risk myelodysplastic syndrome (MDS) or LR- MDS in a subject suffering from lower-risk MDS (LR-MDS), said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 71. A compound having the structural formula:for use in treating hemolytic anemia in a subject suffering from lower-risk MDS (LR-MDS), said use comprising orally administering to the subject an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 72. A compound having the structural formula:for use in treating hemolytic anemia in a subject suffering from lower-risk MDS (LR-MDS), said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 73. A compound having the structural formula:for use in increasing the hemoglobin level in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 74. A compound having the structural formula:for use in increasing the hemoglobin level in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 75. A compound having the structural formula:for use in treating acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 76. A compound having the structural formula:for use in treating acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 77. A compound having the structural formula:for use in treating anemia associated with acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 78. A compound having the structural formula:for use in treating anemia associated with acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 79. A compound having the structural formula:for use in treating cytopenia in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 80. A compound having the structural formula:for use in treating cytopenia in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 81. A compound having the structural formula:for use in treating a disease or disorder associated with ineffective erythropoiesis in a subject in need thereof, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 82. A compound having the structural formula:for use in treating a disease or disorder associated with ineffective erythropoiesis in a subject in need thereof, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 83. The compound for use of any one of embodiments 69 to 82, wherein the hemoglobin level of the subject improves over a period of at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, or at least 20 weeks of treatment.Embodiment 84. The compound for use of any one of embodiments 69 to 83, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL.Embodiment 85. The compound for use of any one of embodiments 69 to 83, wherein the hemoglobin level of the subject increases from baseline by > 1.5 g / dL.Embodiment 86. The compound for use of any one of embodiments 69 to 83, wherein the hemoglobin level of the subject increases from baseline by > 2.0 g / dL.Embodiment 87. The compound for use of any one of embodiments 69 to 86, wherein the subject becomes transfusion independent.Embodiment 88. The compound for use of any one of embodiments 69 to 87, wherein the subject is classified as having a low transfusion burden prior to treatment.Embodiment 89. The compound for use of any one of embodiments 69 to 88, wherein the subject becomes transfusion independent for > 1 consecutive week, for > 2 consecutive weeks, for > 3 consecutive weeks, for > 4 consecutive weeks, for > 5 consecutive weeks, for > 6 consecutive weeks, for > 7 consecutive weeks, for > 8 consecutive weeks, for > 9 consecutive weeks, or for > 10 consecutive weeks.Embodiment 90. The compound for use of any one of embodiments 69 to 89, wherein the subject becomes transfusion independent for > 8 consecutive weeks.Embodiment 91. The compound for use of any one of embodiments 69 to 90, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 10%, >20%, > 30%, > 40%, > 50%, > 60%, > 70%, or > 80%Embodiment 92. The compound for use of any one of embodiments 69 to 91, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50%.Embodiment 93. The compound for use of any one of embodiments 69 to 92, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 1 consecutive week, > 2 consecutive weeks, > 3 consecutive weeks, > 4 consecutive weeks, > 5 consecutive weeks, > 6 consecutive weeks, > 7 consecutive weeks, > 8 consecutive weeks, > 9 consecutive weeks, or > 10 consecutive weeks.Embodiment 94. The compound for use of any one of embodiments 69 to 93, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 8 consecutive weeks.Embodiment 95. The compound for use of any one of embodiments 69 to 94, wherein the LR-MDS is low risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS).Embodiment 96. The compound for use of any one of embodiments 69 to 94, wherein the LR-MDS is very low risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS).Embodiment 97. The compound for use of any one of embodiments 69 to 94, wherein the LR-MDS is intermediate risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS).Embodiment 98. The compound for use of any one of embodiments 69 to 97, wherein the subject is male.Embodiment 99. The compound for use of any one of embodiments 69 to 97, wherein the subject is female.Embodiment 100. The compound for use of any one of embodiments 69 to 99, wherein the compound or pharmaceutically acceptable salt is administered as a pharmaceutical composition.Embodiment 101. The compound for use of embodiment 100, wherein the pharmaceutical composition is in the form of a tablet or one or more granules.Embodiment 102. The compound for use of any one of embodiments 69 to 100, wherein the pharmaceutical composition is in the form of one or more granules.Embodiment 103. The compound for use of any one of embodiments 69 to 100, wherein the pharmaceutical composition is in the form of a tablet.Embodiment 104. A compound having the structural formula:for use in treating anemia associated with lower-risk myelodysplastic syndrome (LR-MDS) in a subject, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof, and wherein the subject is classified as being non-transfused, of low transfusion burden, or of high transfusion burden prior to administration.Embodiment 105. A compound having the structural formula:for use in treating anemia associated with lower-risk myelodysplastic syndrome (LR-MDS) in a subject, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof, and wherein the subject is classified as being non-transfused, of low transfusion burden, or of high transfusion burden prior to administration.Embodiment 106. The compound for use of embodiment 105, wherein the subject is classified as having a low transfusion burden prior to treatment.Embodiment 107. The compound for use of embodiment 106, wherein the subject becomes transfusion independent for > 8 consecutive weeks.Embodiment 108. The compound for use of embodiment 106 or 107, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL, > 1.5 g / dL or > 2.0 g / dL.Embodiment 109. The compound for use of embodiment 105, wherein the subject is classified as being non-transfused prior to treatment.Embodiment 110. The compound for use of embodiment 109, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL, > 1.5 g / dL or > 2.0 g / dL.Embodiment 111. The compound for use of embodiment 105, wherein the subject is classified as having a high transfusion burden prior to treatment.Embodiment 112. The compound for use of embodiment 111, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 8 consecutive weeks.Embodiment 113. The compound for use of any of embodiments 77, 78 and 83 to 103, wherein the anemia associated with acquired PK deficiency (PKD) is hemolytic anemia.Embodiment 114. The compound for use of any one of embodiments 69 to 113, wherein the use comprises administering the compound in an amount that is equivalent to 10 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 115. The compound for use of any one of embodiments 69 to 113, wherein the use comprises administering the compound in an amount that is equivalent to 15 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 116. The compound for use of any one of embodiments 69 to 113, wherein the use comprises administering the compound in an amount that is equivalent to 20 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 117. The compound for use of any one of embodiments 69 to 113, wherein the use comprises administering the compound in an amount that is equivalent to 25 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 118. The compound for use of any one of embodiments 69 to 113, wherein the use comprises administering the compound in an amount that is equivalent to 30 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 119. The compound for use of any one of embodiments 69 to 113, wherein the use comprises administering the compound in an amount that is equivalent to 35 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 120. The compound for use of any one of embodiments 69 to 113, wherein the use comprises administering the compound in an amount that is equivalent to 40 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 121. The compound for use of any one of embodiments 69 to 120, wherein the amount of the compound administered is either maintained or is modified if the subject experiences a platelet count decrease.Embodiment 122. The compound for use of embodiment 121, wherein the amount of the compound administered is not modified for a grade 1 platelet count decrease (platelet count between 75,000 / pL and lower limit of normal (LLN)).Embodiment 123. The compound for use of embodiment 121, wherein the amount of the compound administered is not modified for a grade 2 platelet count decrease (platelet count of 25,000 / pL to <75,000 / pL).Embodiment 124. The compound for use of embodiment 123, wherein a subject’s platelet count is monitored weekly for 4 weeks, then monitored every 2 weeks for 4 weeks, then monitored every 4 weeks for 12 weeks, provided that the platelet count is stable.Embodiment 125. The compound for use of embodiment 121, wherein at a first occurrence of a grade 4 platelet count decrease (platelet count <25,000 / pL): a) administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of a platelet count decrease; b) administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally c) administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.Embodiment 126. The compound for use of embodiment 121, wherein at a second occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL): a) administration of the compound is discontinued for subjects that were receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; b) administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally c) administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.Embodiment 127. The compound for use of embodiment 125 or 126, wherein in optional step c administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, or at an amount equivalent to 15 mg of the compound administered as a free base or pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 128. The compound for use of any one of embodiments 69 to 120, wherein the amount of the compound administered is either maintained or is modified for events of platelet count decrease as follows:a) the amount of the compound administered is not modified for grade 1 platelet count decreases (platelet count between 75,000 / pL and lower limit of normal (LLN)); b) the amount of the compound administered is not modified for grade 2 platelet count decreases (platelet count of 25,000 / pL to <75,000 / pL) and platelet count is monitored weekly for 4 weeks, then monitored every 2 weeks for 4 weeks, then monitored every 4 weeks for 12 weeks, provided that the platelet count is stable; c) the amount of the compound administered is modified at a first occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL) as follows: i. administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; ii. administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally iii. administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks; d) the amount of the compound administered is modified at a second occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL) as follows: i. administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; ii. administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally iii. administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.Embodiment 129. The compound for use of embodiment 128, wherein in optional step c(iii) administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.AGS-131W0 Embodiment 130. The compound for use of embodiment 128, wherein in optional step d(iii) administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 131. The compound for use of embodiment 128, wherein in optional step c(iii) administration is restarted at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 132. The compound for use of embodiment 128, wherein in optional step d(iii) administration is restarted at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 133. The compound for use of embodiment 128, wherein in optional step c(iii) administration is restarted at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 134. The compound for use of embodiment 128, wherein in optional step d(iii) administration is restarted at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 135. The compound for use of embodiment 128, wherein in optional step c(iii) administration is restarted at an amount equivalent to 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 40 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 136. The compound for use of embodiment 128, wherein in optional step d(iii) administration is restarted at an amount equivalent to 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 40 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 137. Use of a compound having the structural formula:in the manufacture of a medicament for treating anemia associated with lower-risk myelodysplastic syndrome (MDS) or LR-MDS in a subject suffering from lower-risk MDS (LR- MDS), wherein the medicament is orally administered to deliver the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 138. Use of a compound having the structural formula:in the manufacture of a medicament for treating anemia associated with lower-risk myelodysplastic syndrome (MDS) or LR-MDS in a subject suffering from lower-risk MDS (LR- MDS), wherein the medicament is orally administered to deliver the equivalent of 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 139. Use of a compound having the structural formula:in the manufacture of a medicament for treating hemolytic anemia in a subject suffering from lower-risk MDS (LR-MDS), wherein the medicament is orally administered to deliver the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 140. Use of a compound having the structural formula:in the manufacture of a medicament for treating hemolytic anemia in a subject suffering from lower-risk MDS (LR-MDS), wherein the medicament is orally administered to deliver theequivalent of 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 141. Use of a compound having the structural formula:in the manufacture of a medicament for increasing the hemoglobin level in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, wherein the medicament is orally administered to deliver the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 142. Use of a compound having the structural formula:in the manufacture of a medicament for increasing the hemoglobin level in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, wherein the medicament is orally administered to deliver the equivalent of 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 143. Use of a compound having the structural formula:in the manufacture of a medicament for treating acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, wherein themedicament is orally administered to deliver the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 144. Use of a compound having the structural formula:in the manufacture of a medicament for treating acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, wherein the medicament is orally administered to deliver the equivalent of 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 145. Use of a compound having the structural formula:in the manufacture of a medicament for treating anemia associated with acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, wherein the medicament is orally administered to deliver the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 146. Use of a compound having the structural formula:in the manufacture of a medicament for treating anemia associated with acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS,wherein the medicament is orally administered to deliver the equivalent of 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 147. Use of a compound having the structural formula:in the manufacture of a medicament for treating cytopenia in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, wherein the medicament is orally administered to deliver the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 148. Use of a compound having the structural formula:in the manufacture of a medicament for treating cytopenia in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, wherein the medicament is orally administered to deliver the equivalent of 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 149. Use of a compound having the structural formula:in the manufacture of a medicament for treating a disease or disorder associated with ineffective erythropoiesis in a subject in need thereof, wherein the medicament is orally administered todeliver the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 150. Use of a compound having the structural formula:in the manufacture of a medicament for treating a disease or disorder associated with ineffective erythropoiesis in a subject in need thereof, wherein the medicament is orally administered to deliver the equivalent of 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 151. The use of any one of embodiments 137 to 150, wherein the hemoglobin level of the subject improves over a period of at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, or at least 20 weeks of treatment.Embodiment 152. The use of any one of embodiments 137 to 151, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL.Embodiment 153. The use of any one of embodiments 137 to 151, wherein the hemoglobin level of the subject increases from baseline by > 1.5 g / dL.Embodiment 154. The use of any one of embodiments 137 to 151, wherein the hemoglobin level of the subject increases from baseline by > 2.0 g / dL.Embodiment 155. The use of any one of embodiments 137 to 154, wherein the subject becomes transfusion independent.Embodiment 156. The use of any one of embodiments 137 to 155, wherein the subject is classified as having a low transfusion burden prior to treatment.Embodiment 157. The use of any one of embodiments 137 to 156, wherein the subject becomes transfusion independent for > 1 consecutive week, for > 2 consecutive weeks, for > 3 consecutive weeks, for > 4 consecutive weeks, for > 5 consecutive weeks, for > 6 consecutive weeks, for > 7 consecutive weeks, for > 8 consecutive weeks, for > 9 consecutive weeks, or for > 10 consecutive weeks.Embodiment 158. The use of any one of embodiments 137 to 157, wherein the subject becomes transfusion independent for > 8 consecutive weeks.Embodiment 159. The use of any one of embodiments 137 to 158, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 10%, > 20%,> 30%, > 40%, > 50%, > 60%, > 70%, or > 80%Embodiment 160. The use of any one of embodiments 137 to 159, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50%.Embodiment 161. The use of any one of embodiments 137 to 160, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 1 consecutive week, > 2 consecutive weeks, > 3 consecutive weeks, > 4 consecutive weeks, > 5 consecutive weeks, > 6 consecutive weeks, > 7 consecutive weeks, > 8 consecutive weeks, > 9 consecutive weeks, or > 10 consecutive weeks.Embodiment 162. The use of any one of embodiments 137 to 161, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 8 consecutive weeks.Embodiment 163. The use of any one of embodiments 137 to 162, wherein the LR-MDS is low risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS- R) for MDS).AGS-131W0Embodiment 164. The use of any one of embodiments 137 to 162, wherein the LR-MDS is very low risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS).Embodiment 165. The use of any one of embodiments 137 to 162, wherein the LR-MDS is intermediate risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS).Embodiment 166. The use of any one of embodiments 137 to 165, wherein the subject is male.Embodiment 167. The use of any one of embodiments 137 to 165, wherein the subject is female.Embodiment 168. The use of any one of embodiments 137 to 167, wherein the compound or pharmaceutically acceptable salt is administered as a pharmaceutical composition.Embodiment 169. The use of embodiment 168, wherein the pharmaceutical composition is in the form of a tablet or one or more granules.Embodiment 170. The use of any one of embodiments 137 to 168, wherein the pharmaceutical composition is in the form of one or more granules.Embodiment 171. The use of any one of embodiments 137 to 168, wherein the pharmaceutical composition is in the form of a tablet.Embodiment 172. Use of a compound having the structural formula:in the manufacture of a medicament for treating anemia associated with lower-risk myelodysplastic syndrome (LR-MDS) in a subject, wherein the medicament is administeredorally to the subject to deliver the equivalent of 10 mg daily, 15 mg daily, or 20 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof, and wherein the subject is classified as being non-transfused, of low transfusion burden, or of high transfusion burden prior to administration.Embodiment 173. Use of a compound having the structural formula:in the manufacture of a medicament for treating anemia associated with lower-risk myelodysplastic syndrome (LR-MDS) in a subject, wherein the medicament is administered orally to the subject to deliver the equivalent of 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof, and wherein the subject is classified as being non-transfused, of low transfusion burden, or of high transfusion burden prior to administration.Embodiment 174. The use of embodiment 173, wherein the subject is classified as having a low transfusion burden prior to treatment.Embodiment 175. The use of embodiment 174, wherein the subject becomes transfusion independent for > 8 consecutive weeks.Embodiment 176. The use of embodiment 174 or 175, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL, > 1.5 g / dL or > 2.0 g / dL.Embodiment 177. The use of embodiment 173, wherein the subject is classified as being non-transfused prior to treatment.Embodiment 178. The use of embodiment 177, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL, > 1.5 g / dL or > 2.0 g / dL.AGS-131W0Embodiment 179. The use of embodiment 173, wherein the subject is classified as having a high transfusion burden prior to treatment.Embodiment 180. The use of embodiment 179, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 8 consecutive weeks.Embodiment 181. The use of any of embodiments 145, 146 and 151 to 171, wherein the anemia associated with acquired PK deficiency (PKD) is hemolytic anemia.Embodiment 182. The use of any one of embodiments 137 to 181, wherein the medicament is administered to deliver the equivalent of 10 mg once daily (QD) of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 183. The use of any one of embodiments 137 to 181, wherein the medicament is administered to deliver the equivalent of 15 mg once daily (QD) of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 184. The use of any one of embodiments 137 to 181, wherein the medicament is administered to deliver the equivalent of 20 mg once daily (QD) of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 185. The use of any one of embodiments 137 to 181, wherein the medicament is administered to deliver the equivalent of 25 mg once daily (QD) of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 186. The use of any one of embodiments 137 to 181, wherein the medicament is administered to deliver the equivalent of 30 mg once daily (QD) of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.AGS-131W0 Embodiment 187. The use of any one of embodiments 137 to 181, wherein the medicament is administered to deliver the equivalent of 35 mg once daily (QD) of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 188. The use of any one of embodiments 137 to 181, wherein the medicament is administered to deliver the equivalent of 40 mg once daily (QD) of the compound, wherein the compound is present in the medicament as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 189. The use of any one of embodiments 137 to 188, wherein the amount of the compound administered is either maintained or is modified if the subject experiences a platelet count decrease.Embodiment 190. The use of embodiment 189, wherein the amount of the compound administered is not modified for a grade 1 platelet count decrease (platelet count between 75,000 / pL and lower limit of normal (LLN)).Embodiment 191. The use of embodiment 189, wherein the amount of the compound administered is not modified for a grade 2 platelet count decrease (platelet count of 25,000 / pL to <75,000 / pL).Embodiment 192. The use of embodiment 191, wherein a subject’s platelet count is monitored weekly for 4 weeks, then monitored every 2 weeks for 4 weeks, then monitored every 4 weeks for 12 weeks, provided that the platelet count is stable.Embodiment 193. The use of embodiment 189, wherein at a first occurrence of a grade 4 platelet count decrease (platelet count <25,000 / pL): a) administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of a platelet count decrease; b) administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionallyc) administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.Embodiment 194. The use of embodiment 189, wherein at a second occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL): a) administration of the compound is discontinued for subjects that were receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; b) administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally c) administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.Embodiment 195. The use of embodiment 193 or 194, wherein in optional step c administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, or at an amount equivalent to 15 mg of the compound administered as a free base or pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 196. The use of any one of embodiments 137 to 188, wherein the amount of the compound administered is either maintained or is modified for events of platelet count decrease as follows: a) the amount of the compound administered is not modified for grade 1 platelet count decreases (platelet count between 75,000 / pL and lower limit of normal (LLN)); b) the amount of the compound administered is not modified for grade 2 platelet count decreases (platelet count of 25,000 / pL to <75,000 / pL) and platelet count is monitored weekly for 4 weeks, then monitored every 2 weeks for 4 weeks, then monitored every 4 weeks for 12 weeks, provided that the platelet count is stable;c) the amount of the compound administered is modified at a first occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL) as follows: i. administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; ii. administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally iii. administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks; d) the amount of the compound administered is modified at a second occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL) as follows: i. administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; ii. administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally iii. administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.Embodiment 197. The use of embodiment 196, wherein in optional step c(iii) administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 198. The use of embodiment 196, wherein in optional step d(iii) administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if theprevious amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 199. The use of embodiment 196, wherein in optional step c(iii) administration is restarted at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 200. The use of embodiment 196, wherein in optional step d(iii) administration is restarted at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 201. The use of embodiment 196, wherein in optional step c(iii) administration is restarted at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 202. The use of embodiment 196, wherein in optional step d(iii) administration is restarted at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 25 mg of the compoundAGS-131W0 administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 203. The use of embodiment 196, wherein in optional step c(iii) administration is restarted at an amount equivalent to 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 40 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.Embodiment 204. The use of embodiment 196, wherein in optional step d(iii) administration is restarted at an amount equivalent to 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 40 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

[0076] Further details are described in the Exemplification section below and are included as part of the present invention.EXAMPLESPreparation of CompoundsExample 1: Preparation of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4- methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one (Compound 1).

[0077] 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one can be prepared following the procedures outline for compound E8-4 of Example 8A in U.S. Patent No. 11,040,036, the entire contents of which are incorporated herein by reference. Pharmaceutically acceptable salts of 2-(( IH-pyrazol- 3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one can also be prepared in view of the disclosure of U.S. Patent No. 11,040,036.

[0078] 2-((lH-pyrazol-3-yl)methyl)-4-methyl-6-((l-methyl-lH-pyrazol-3-yl)methyl)- 4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one can be prepared following the procedures outline for compound E8-41 in U.S. Patent No. 11,040,036, the entire contents of which are incorporated herein by reference. Pharmaceutically acceptable salts of 2-(( IH-pyrazol- 3-yl)methyl)-4-methyl-6-((l-methyl-lH-pyrazol-3-yl)methyl)-4H-thiazolo[5',4':4,5]pyrrolo[2,3- d]pyridazin-5(6H)-one can also be prepared in view of the disclosure of U.S. Patent No. 11,040,036.Example 2: Phase 2a / 2b, Study of 2-((lH-pyrazol-3-yl)methyl)-6-((6-aminopyridin-2- yl)methyl)-4-methyl-4H-thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one in Subject with Anemia Due to Lower-Risk Myelodysplastic Syndromes

[0079] A Phase 2a / 2b multicenter study evaluating the efficacy and safety of 2-((lH- pyrazol-3-yl)methyl)-6-((6-aminopyridin-2-yl)methyl)-4-methyl-4H- thiazolo[5',4':4,5]pyrrolo[2,3-d]pyridazin-5(6H)-one, referred to herein as Compound 1 in subjects with anemia due to lower-risk myelodysplastic syndromes (LR-MDS) is conducted. The Phase 2a portion of the study is completed. Throughout the clinical trial description, references to Compound 1 should be understood to mean Compound 1 or a pharmaceutically acceptable salt thereof, unless expressly stated otherwise, and mention of specific doses of Compound 1 should be understood as referring to a dose of the free base of Compound 1 or an amount of a pharmaceutically acceptable salt of Compound 1 that is equivalent to the dose of the free base .Study Design

[0080] The Phase 2a part of the study is a single-arm evaluation of 1 dose level of Compound 1 (5 mg once daily [QD]) to establish proof of concept of Compound 1 in LR-MDS. Eligible subjects will receive Compound 1 for oral administration for the 16-week Core Period. Subjects who complete the 16-week Core Period will be eligible to continue receiving the same dose of Compound 1 for up to 156 weeks in the Extension Period. An overview of the Phase 2a study design is illustrated in FIG. 1.

[0081] The Phase 2b part of the study is a double-blind, randomized, placebo-controlled evaluation of the efficacy and safety of Compound 1 (2 mg QD, 3 mg QD, and 5 mg QD) versus placebo. The initiation of the Phase 2b part of the study will be based on prespecified go / no-go criteria. Eligible subjects will be randomized in a 1 : 1 : 1 : 1 ratio to receive 2 mg QD Compound 1 (Dose Level 1), 3 mg Compound 1 (Dose Level 2), 5 mg QD Compound 1 (Dose Level 3) or matched placebo for QD oral administration. Subjects who complete the 24-week Double-blind Period will be eligible to receive Compound 1 for up to 156 weeks in the Extension Period.Randomization will be stratified by baseline transfusion burden (low transfusion burden [subjects who are NTD and subjects with LTB], high transfusion burden (HTB)). An overview of the Phase 2b study design is illustrated in FIG. 2.

[0082] During the Extension Period in Phase 2b, all subjects will receive Compound 1. Subjects who received placebo during the Double-blind Period will be randomized 1 : 1 : 1 to receive 2 mg QD Compound 1 (Dose Level 1), 3 mg QD Compound 1 (Dose Level 2), or 5 mg QD Compound 1 (Dose Level 3) to enable the assessment of the long-term safety and efficacy of these multiple doses of Compound 1. Subjects who received Compound 1 during the Doubleblind Period will be eligible to continue receiving the same dose of Compound 1.Study DesignPhase 2a

[0083] The Phase 2a part of the study was a single-arm evaluation of 1 dose level of Compound 1 (5 mg once daily [QD]) to establish proof of concept of Compound 1 in LR-MDS. Eligible subjects received Compound 1 for oral administration for the 16-week Core Period. Subjects who completed the 16-week Core Period will be eligible to continue receiving the same dose of Compound 1 for up to 156 weeks in the Extension Period. An overview of the Phase 2a study design is illustrated in FIG. 4.Phase 2a to Phase 2b Go / No-Go Decision

[0084] The decision to proceed to the Phase 2b part of the study was based on the data from the Core Period of the Phase 2a part of the study only, including the results of the analyses of the Phase 2a primary endpoint as well as additional considerations outlined below:1. If the observed Hb response rate is >40% (participants who are NTD and participants with LTB) or the observed TI rate is >40% (participants with LTB only) (see Section 9.2. 1), then the study will proceed to Phase 2b provided the benefit / risk profile is favorable.2. If the observed Hb response rate is <15% (participants who are NTD and participants with LTB) and no participants with LTB achieve TI (see Section 9.2.1), then the study will not proceed to Phase 2b.3. If neither 1 nor 2 are met, then the decision to proceed to Phase 2b will be based on the observed Hb 1.0+ response rate, the observed rate of participants with LTB who achieve >50% reduction in total transfused RBC units, pharmacodynamic data, including 2,3-DPG and ATP, and safety data.Phase 2a results:

[0085] Four of the 10 patients with low transfusion burden (LTB) included in Phase 2a achieved the transfusion independence endpoint, and one of the 22 patients treated in the study achieved the hemoglobin response endpoint in the 16-week treatment (core) period. The safetyprofile observed was consistent with data reported in the healthy volunteer study AG946-C-001 (NCT04536792).Phase 2b

[0086] The Phase 2b part of the study is a double-blind, randomized, placebo-controlled evaluation of the efficacy and safety of Compound 1 (10 mg QD, 15 mg QD, and 20 mg QD) versus placebo. The initiation of the Phase 2b part of the study was based on accomplishing prespecified go / no-go criteria in Phase 2a.

[0087] Eligible subjects will be randomized in a 1 : 1 : 1 : 1 ratio to receive 10 mg QD Compound 1 (Dose Level 1), 15 mg Compound 1 (Dose Level 2), 20 mg QD Compound 1 (Dose Level 3), or matched placebo for QD oral administration. Subjects who complete the 24- week Double-blind Period will be eligible to receive Compound 1 for up to 156 weeks in the Extension Period. Randomization will be stratified by baseline transfusion burden (low transfusion burden [subjects who are NTD and subjects with LTB], high transfusion burden (HTB)). An overview of the Phase 2b study design is illustrated in FIG. 1.

[0088] During the Extension Period in Phase 2b, all subjects will receive Compound 1. Subjects who received placebo during the double-blind period will be randomized 1 : 1 : 1 to receive 10 mg QD Compound 1 (Dose Level 1), 15 mg QD Compound 1 (Dose Level 2), or 20 mg QD Compound 1 (Dose Level 3) to enable the assessment of the long-term safety and efficacy of these multiple doses of Compound 1. Subjects who received Compound 1 during the double-blind period will be eligible to continue receiving the same dose or a higher dose of Compound 1. Dose expansion arms may be opened to include patients receiving 25 mg QD Compound 1 (Dose Level 4), 30 mg QD Compound 1 (Dose Level 5), 35 mg QD Compound 1 (Dose Level 6), or 40 mg QD Compound 1 (Dose Level 7).Rationale for Dose SelectionPhase 2a

[0089] In the Phase 2a part of the study, participants received 5 mg QD AG-946(Compound 1). The selected Phase 2a dose was one that was approximately equal to the dose that resulted in near maximal pharmacodynamic activity and was considered safe and tolerable in normal, healthy volunteers (NHV) in the single -ascending dose / multiple ascending dose (SAD / MAD) Study AG946-C-001 (NCT04536792). The results of this study have been published in Xiaoshu Dai Gurov et al. ; “Results from the Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AG-946 in Healthy Volunteers” Blood 2022; 140 (Supplement 1) (hereinafter “Dai”), incorporated herein by reference.AGS-131W0

[0090] Wild-type PKR is expressed in healthy individuals as well as in majority of subjects with LR-MDS; therefore, preliminary pharmacokinetic, pharmacodynamic, and safety results (available as of May 2022) from completed SAD and MAD cohorts of the healthy volunteer portion of the Phase 1 study AG946-C-001 (NCT04536792) were used to inform the dose selected for the Phase 2a part of the study. Six dose levels of AG-946 (Compound 1) have been evaluated in the completed single ascending dose (SAD) cohorts under fasted conditions. The starting dose level was 1 mg (Cohort 1) and subsequent dose levels were 3, 10, 30, 60 and 100 mg (Cohorts 2, 3, 4, 5 and 6 respectively). Four dose levels of AG-946 have been evaluated in the completed multiple ascending dose cohorts under fasted conditions. The starting dose level was 1 mg QD (Cohort 1) and subsequent dose levels were 2 mg QD, 5 mg QD, 10 mg QD, and 20 mg QD (Cohorts 2, 3, 4, and 5 respectively). One participant on the 10 mg cohort of the MAD experienced platelet count decrease that led to study drug discontinuation. Patients in the 20 mg cohort who received AG-946 experienced platelet count decreases that led to study drug discontinuation starting on Day 9, with all subjects discontinuing by Day 13. As a result, steady state PKPD data at this dose level were not available to support the PKPD modeling. Thus far, events of thrombocytopenia related to AG-946 have occurred within the first two weeks after drug initiation and have been asymptomatic and reversible after stopping study drug.

[0091] In the SAD and MAD cohorts of Study AG946-C-001 (NCT04536792) activation of PKR by AG-946 led to dose-dependent increases in ATP concentrations and dose-dependent decreases in 2,3 -DPG.

[0092] Literature suggests that there is dysfunction in the glycolytic pathway of patients with LR-MDS, as demonstrated by decreased PK / HK ratio and low baseline ATP values. A hallmark of anemia due to LR-MDS is ineffective erythropoiesis in the bone marrow. AG-946 is expected to provide benefit to subjects with LR-MDS by increasing ATP, improving RBC health, and improving erythroblast maturation in the bone marrow. Preliminary pharmacokinetic assessments from Healthy Volunteers in Phase la suggest increasing doses of AG-946 following SAD resulted in over-proportional increases in AG-946 exposure, however increasing doses of AG-946 following MAD resulted in near proportional increases in AG-946 exposure.

[0093] Preliminary pharmacodynamic assessments suggested that ATP concentrations were close to plateau at doses of 30 to 100 mg in SAD and 5 to 10 mg QD in MAD. Maximum increase from baseline was ~70% in SAD and ~40 to 60% in MAD. An indirect response model has been developed to describe the relationship between AG-946 pharmacokinetics and ATP. The model predicted -53% mean change from baseline at the dose of 5 mg QD after 14 days of continuous dosing in ATP. Model-based simulations indicate there is a potential for further increase in ATP, with a prediction of -74% mean change from baseline at 5 mg QD after 56AGS-131W0 days of continuous dosing which corresponds to -95% of the predicted maximal pharmacological effect. The AG-946 dose of 5 mg QD selected for the Phase 2a portion of the study was found to be safe and tolerable in healthy volunteers.

[0094] In SAD, 8 / 55 (14.5%) of subjects experienced >1 treatment-emergent adverse event (TEAE). There were no serious AEs (SAEs) or Grade >3 AEs. No events were assessed as treatment related by the investigator in SAD.

[0095] In MAD, 16 / 40 (40%) of subjects experienced >1 TEAE. There was 1 SAE (Grade 2) of rhabdomyolysis reported in the 2 mg QD cohort that was unrelated to study treatment. A total of 6 decreased platelet events (5 Grade 1, 1 Grade 3) were reported in cohorts receiving doses >10 mg QD ([n=l] 10 mg QD; [n=5] 20 mg QD) that were assessed as treatment related by the investigator. The Grade 3 event occurred in the 20 mg QD cohort. No AEs of platelet decrease were observed in other QD cohorts. All 6 decreased platelet events were asymptomatic and reversible with treatment discontinuation. All other AEs reported were nonserious, unrelated to study treatment, and less than Grade 3.4.3.2. Phase 2b

[0096] The Core Period of the Phase 2a part of the study has been completed and the go criteria for initiation of Phase 2b were met.

[0097] Data from the Phase 2a part of the study indicated that administration of AG-946 5 mg QD in participants with LR-MDS was well tolerated and proof-of-concept was established.

[0098] Preliminary results from a population PK model suggested MDS patients exhibit a 76% higher clearance CL compared to SCD and NHV (normal healthy volunteer) patients.

[0099] The mean observed exposure (AUCo-s) after 8 weeks of 5 mg QD dosing in participants with LR-MDS (238 h*ng / mL) was 40% lower compared to the predicted steady state (D56) AUCo-s (385 h*ng / mL) based on the data obtained in healthy participants.

[0100] Model derived exposures across a range of concentrations in MDS patients and NHV are shown in Table 1 The simulated mean steady state exposure after 8 weeks of 5 mg QD dosing in participants with LR-MDS corresponded with the observed exposure. The simulated mean steady state in MDS patients was 40% lower compared to exposures in healthy participants at 8 weeks. Exposure at 8 mg / day in MDS patients should be equivalent to 5 mg / day in NHV. Based on these calculations, the mean exposure of AG-946 (Compound 1) in participants with LR-MDS receiving 10 mg or 15 mg QD is likely to be similar to the exposure in healthy participants receiving 6 mg or 9 mg QD.AGS-131W0Table 1 Comparison of Mean NCA parameters in NHV and MDS after 8 weeks of AG-946 administration

[0101] Considering a dose-dependent response was observed in NHV according to the data published in Dai, it was hypothesized that a dose-dependent response could be expected in LR-MDS subjects.

[0102] As noted above, treatment-related TEAEs of platelet count decreased (PTs of Platelet count decreased or Thrombocytopenia) were reported in 6 healthy participants who received >10 mg QD of AG-946 in the MAD cohorts of Study AG946-C-001; the majority of events were of Grade 1 and 1 event was of Grade 3. After treatment discontinuation, the platelet decreases were reversible with no clinical sequelae reported. Thrombocytopenia is common in LR-MDS patients as part of the disease pathology of ineffective hematopoiesis in the bone marrow causing dysplastic blood cells and cytopenia in the blood cell lineages. In the Phase 2a part of Study AG946-C-002, three participants experienced decreases in platelets throughout the study. Two participants experienced grade 1 events, which resolved without any alteration to dose. One participant receiving AG-946 5 mg QD experienced an event of Grade 3 Platelet count decrease. The exposure of AG-946 in this participant was comparable to exposures of other participants with LR-MDS who received the same dose. Upon discontinuation of AG-946 theparticipant’s platelet count recovered to baseline levels. Such decreases in platelet counts are identifiable, monitorable, and reversible through the measures set forth in the clinical trial protocol. The clinical trial protocol contains instructions for monitoring of platelet counts in the first weeks after treatment initiation, dose escalation, or restarting treatment, along with recommendations for stopping drug or dose reduction. Because platelet count is both clinically measurable and proactively monitorable and AEs of decreased platelet count have been clinically asymptomatic and reversible upon discontinuation in Phase 1 -healthy volunteers and in Phase 2a, the benefits of increasing the dose of AG-946 in participants with MDS appear to outweigh the risks.

[0103] Based on the efficacy, pharmacokinetic, and safety data, and considerations outlined above, in the Core Period of the Phase 2b part of the study, participants will receive AG-946 at 10 mg QD, 15 mg QD, or 20 mg QD for 24 weeks; enrollment will be sequential, starting with Dose Level 1 (10 mg QD) and enrollment in subsequent dose levels will begin once the last participant has enrolled in the prior dose level. The efficacy and safety of AG-946 10 mg, 15 mg, and 20 mg QD in participants with LR-MDS will guide further development of AG- 946 for the treatment of MDS.Inclusion CriteriaPhase 2a

[0104] Subjects were eligible to be included in the Phase 2a part of the study if all the following criteria apply:1. At least 18 years of age at the time of providing informed consent.2. Documented diagnosis of MDS according to World Health Organization (WHO) classification, that meets IPSS-R classification of lower-risk disease (risk score: <3.5) and <5% blasts as determined by the participant’s bone marrow biopsy / aspirate during the Screening Period.3. Nontransfiised (NTD) or with low transfusion burden (LTB), based on transfusion history from the participant’s medical record, according to revised IWG 2018 criteria: a. NTD: <3 RBC units in the 16-week period before administration of the first dose of study drug and no transfusions in the 8-week period before administration of the first dose of study drug, or b. LTB: 3 to 7 RBC units in the 16-week period before administration of the first dose of study drug and <4 RBC units in the 8-week period before administration of the first dose of study drug.4. A hemoglobin (Hb) concentration <11.0 g / dL during the 4-week Screening Period.5. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2.AGS-131W06. If taking iron chelation therapy, the iron chelation therapy dose must have been stable and started >56 days before administration of the first dose of study drug.7. For women of childbearing potential (WOCBP) and men with partners who are WOCBP, must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, 1 of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug for women and 90 days after the last dose of study drug for men. The second form of contraception can be an acceptable barrier method.8. Written informed consent from the participant before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.Phase 2b

[0105] Subjects are eligible to be included in the Phase 2b part of the study if all the following criteria apply:1. At least 18 years of age at the time of providing informed consent.2. Documented diagnosis of MDS according to WHO classification that meets IPSS-R classification of lower-risk disease (risk score: <3.5) and <5% blasts as determined by the participant’s bone marrow biopsy / aspirate during the Screening Period.3. With LTB, or high transfusion burden (HTB), based on transfusion history from the participant’s medical record, according to revised IWG 2018 criteria: a. LTB: 3 to 7 RBC units from at least 2 transfusion episodes in the 16-week period before administration of the first dose of study drug AND <4 RBC units in the 8-week period before administration of the first dose of study drug, or b. HTB: >8 RBC units in the 16-week period before administration of the first dose of study drug AND >4 RBC units in the 8-week period before administration of the first dose of study drug.If a participant’s transfusion burden does not fall into either the LTB or HTB category, as defined per IWG 2018 criteria, then the transfusion burden will be categorized based on their transfusion history in the 16-week period before administration of the first dose of study drug.4. Pretransfiision Hb concentration available for a minimum of 2 and at least half (50%) of the transfusions received in the 16-week period before administration of the first dose of study drug.5. An Hb concentration < 10.0 g / dL during the 4-week Screening Period.6. Up to 2 prior therapies including erythropoiesis-stimulating agents (ESAs) (e.g, erythropoietin [EPO], EPO + granulocyte colony-stimulating factor [G-CSF]) and / or luspatercept.7. ECOG Performance Status score of 0, 1, or 2.8. If taking iron chelation therapy, the iron chelation therapy dose must have been stable and started >56 days before administration of the first dose of study drug.AGS-131W09. WOCBP must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use a highly effective, from the time of providing informed consent throughout the study and for 28 days after the last dose of study drug; if the highly effective method of contraception is hormonal contraception, then an acceptable barrier method must be used. Men with partners who are WOCBP must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use a condom from the time of providing informed consent throughout the study and for 28 days after the last dose of study drug.10. Written informed consent from the participant before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.Exclusion Criteria:Phase 2a

[0106] Participants are excluded from the Phase 2a part of the study if any of the following criteria apply:1. Known history of acute myeloid leukemia (AML);2. Secondary MDS, defined as MDS that is known to have arisen as a result of chemical injury or treatment with chemotherapy and / or radiation for other diseases;3. Prior exposure to a pyruvate kinase activator and / or disease-modifying agents for underlying MDS:• Immunomodulatory drugs (IMiDs) such as lenalidomide; at the Investigator’s discretion and in consultation with the Medical Monitor, participants who received <1 week of treatment with IMiDs may not be excluded, provided their last dose was >8 weeks before administration of the first dose of study drug• Hypomethylating agents (HMAs); at the Investigator’s discretion and in consultation with the Medical Monitor, participants who received <2 doses of HMAs may not be excluded, provided that their last dose was >8 weeks before administration of the first dose of study drug• Isocitrate dehydrogenase (IDH) inhibitors• Immunosuppressive therapy (1ST)• Allogeneic or autologous stem cell transplant;4. Currently receiving treatment with ESAs±G-CSF and / or luspatercept. Treatment with ESAs±G-CSF must have been stopped for >28 days before administration of the first dose of study drug; treatment with luspatercept must have been stopped for >65 days before administration of the first dose of study drug;5. History of active and / or uncontrolled cardiac or pulmonary disease within 6 months before providing informed consent, including but not limited to:a) New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia b) Myocardial infarction, unstable angina pectoris, or unstable hypertension; high risk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism c) Heart rate-corrected QT interval using Fridericia’s method of >470 milliseconds for female participants and >450 milliseconds for male participants, except for right or left bundle branch block d) Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50% e) Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right-sided heart failure, and oxygen indicated;6. History of hepatobiliary disorders, as defined by: a) Serum aspartate aminotransferase (AST) >2.5 x upper limit of normal (ULN) (unless due to hemolysis and / or hepatic iron deposition) and alanine aminotransferase (ALT) >2.5 x ULN (unless due to hepatic iron deposition) b) Serum bilirubin >ULN, if the elevation is associated with clinically symptomatic choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease;7. Renal dysfunction, as defined by an estimated glomerular filtration rate (eGFR) <45 milliliters per minute (mL / min) / 1.73 m2;8. Active infection requiring systemic antimicrobial therapy at the time of providing informed consent. If antimicrobial therapy is required during the Screening Period, screening procedures should not be performed while antimicrobial therapy is being administered, and the last dose of antimicrobial therapy must be administered >7 days before administration of the first dose of study drug;9. Major surgery within 12 weeks before administration of the first dose of study drug. Participants must have completely recovered from any previous surgery before administration of the first dose of study drug;10. For any malignancy except MDS: History of malignancy (active or treated) <5 years before providing informed consent for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;11. Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg);12 Positive test for HIV-1 Ab or HIV-2 Ab;13. Absolute neutrophil count (ANC) <500 / microliter (pL) (0.5 x 109 / L);14. Platelet count <75,000 / pL during Screening (75 x 109 / L) platelet transfusions within 28 days before Screening or during Screening;15. Nonfasting triglyceride concentration >500 mg / dL;16. Receiving inhibitors of P-glycoprotein (P-gp) that have not been stopped for >5 days or a time frame equivalent to 5 half-lives (whichever is longer) before administration of the first dose of study drug;17. Current enrollment or past participation (within 4 weeks or a time frame equivalent to 5 half-lives of the investigational study drug before administration of the first dose of study drug or, whichever is longer) in any other clinical study involving an investigational treatment or device;18. Known allergy to AG-946 or its excipients;19. Pregnant or breastfeeding;20. Any medical, hematologic, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and / or could confound the interpretation of the study data. Also excluded are:• Participants who are institutionalized by regulatory or court order;• Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).Phase 2b1. Known history of AML;2. Secondary MDS, defined as MDS that is known to have arisen as a result of chemical injury or treatment with chemotherapy and / or radiation for other diseases;3. Prior exposure to a pyruvate kinase activator, including exposure to AG- 946 in the Phase 2a part of this study, and / or disease -modifying agents for underlying MDS:• Imetelstat; at the Investigator’s discretion and in consultation with the Medical Monitor, participants who received <2 doses of imetelstat may not be excluded, provided that their last dose was >8 weeks before administration of the first dose of study drug• IMiDs such as lenalidomide; at the Investigator’s discretion and in consultation with the Medical Monitor, participants who received <1 week of treatment withIMiDs may not be excluded, provided their last dose was >8 weeks before administration of the first dose of study drug• HMAs; at the Investigator’s discretion and in consultation with the Medical Monitor, participants who received <2 doses of HMAs may not be excluded, provided that their last dose was >8 weeks before administration of the first dose of study drug• IDH inhibitors• 1ST• Allogeneic or autologous stem cell transplant;4. Currently receiving treatment with ESAs±G-CSF and / or luspatercept. Treatment with ESAs±G-CSF must have been stopped for >28 days before administration of the first dose of study drug; treatment with luspatercept must have been stopped for >65 days before administration of the first dose of study drug;5. History of active and / or uncontrolled cardiac or pulmonary disease within 6 months before providing informed consent, including but not limited to: a. New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia b. Myocardial infarction, unstable angina pectoris, or unstable hypertension; high risk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism c. Heart rate-corrected QT interval using Fridericia’s method of >470 milliseconds for female participants and >450 milliseconds for male participants, except for right or left bundle branch block d. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50% e. Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right-sided heart failure, and oxygen indicated6. History of hepatobiliary disorders, as defined by: a. Serum AST >2.5 x ULN (unless due to hemolysis and / or hepatic iron deposition) and ALT >2.5 x ULN (unless due to hepatic iron deposition) b. Serum bilirubin >ULN, if the elevation is associated with clinically symptomatic choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease7. Renal dysfunction, as defined by an eGFR <45 mL / min / 1.73 m2;8. Active infection requiring systemic antimicrobial therapy at the time of providing informed consent. If antimicrobial therapy is required during the Screening Period, screeningprocedures should not be performed while antimicrobial therapy is being administered, and the last dose of antimicrobial therapy must be administered >7 days before administration of the first dose of study drug;9. Major surgery within 12 weeks before administration of the first dose of study drug. Participants must have completely recovered from any previous surgery before administration of the first dose of study drug;10. For any malignancy except MDS: History of malignancy (active or treated) <5 years before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;11. Positive test for HCV Ab with evidence of active HCV infection, or positive test for HBsAg;12. Positive test for HIV-1 Ab or HIV-2 Ab;13. ANC <500 / pL (0.5 x 109 / L);14. Platelet count < 75,000 / pL (75 x 10A9 / L) during Screening; platelet transfusions within 28 days before Screening or during Screening15. Nonfasting triglyceride concentration >500 mg / dL16. Receiving inhibitors of P-gp that have not been stopped for >5 days or a time frame equivalent to 5 half-lives (whichever is longer) before administration of the first dose of study drug17. Current enrollment or past participation (within 4 weeks or a time frame equivalent to 5 half-lives of the investigational study drug before administration of the first dose of study drug or, whichever is longer) in any other clinical study involving an investigational treatment or device18. Known allergy to AG-946 or its excipients19. Pregnant or breastfeeding20. Any medical, hematologic, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and / or could confound the interpretation of the study data. Also excluded are:• Participants who are institutionalized by regulatory or court order• Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).AGS-131W021. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, autoimmune or hereditary hemolytic anemia, hypothyroidism, or any type of known clinically significant bleeding.EndpointsPhase 2aPrimary endpoints

[0107] Primary endpoints for Phase 2a include:1. Proportion of Participants With Hemoglobin (Hb) ResponseHb response is defined as a >1.5-grams per deciliter (g / dL) increase from baseline in the average Hb concentration from Week 8 through Week 16. [Time Frame: Baseline, Week 8 through Week 16]2. Proportion of Participants With Transfusion Independence During the Core Period Transfusion Independence is defined as transfusion-free for >8 consecutive weeks during the Core Period (participants With Low Transfusion Burden [LTB] only). [Time Frame: Up to 16 weeks].Secondary endpoints:

[0108] Secondary endpoints for Phase 2a include:• AEs, SAEs, discontinuations due to AEs, and laboratory abnormalities during the Core Period.• Hb 1.0+ response, defined as a >1.0-g / dL increase from baseline in the average Hb concentration from Week 8 through Week 16• Change from baseline in Hb concentration during the Core Period• >1 ,5-g / dL increase from baseline in the Hb concentration at >2 consecutive time points from Week 8 through Week 16• Change from baseline in total transfused red blood cell (RBC) units during the Core Period• >50% reduction in total transfused RBC units for >8 consecutive weeks during the Core Period compared with baseline• Plasma concentration and pharmacokinetic parameters of AG-946 during the Core Period• Whole blood concentrations of pharmacodynamics parameters, including 2,3-DPG and ATP during the Core Period.AGS-131W0Exploratory Endpoints

[0109] Exploratory endpoints for Phase 2a include:• Change from baseline in exploratory biomarkers, including hepcidin, erythroferrone, soluble transferrin receptor, and GDF11 during the Core Period• Change from baseline in iron, serum ferritin, total iron binding capacity, and transferrin saturation during the Core Period• Change from baseline in markers of erythropoiesis, including absolute and percent reticulocytes, and erythropoietin during the Core Period• Change from baseline in bone marrow-derived biomarkers, including erythroid precursors, during the Core Period• Change from baseline in markers of hemolysis, including indirect bilirubin, lactate dehydrogenase, and haptoglobin during the Core Period• Change from baseline in PKR activity during the Core Period• Change from baseline during the Extension Period in:- Total transfused RBC units (participants with LTB only)- Hb concentration- Markers of iron metabolism- Markers of erythropoiesis and hemolysis- Bone marrow-derived biomarkers, including erythroid precursors- Exploratory biomarkers• AEs, SAEs, discontinuations due to AEs, and laboratory abnormalities during the Extension PeriodPhase 2bPrimary endpoint Phase 2b

[0110] Primary endpoint for phase to be is:1. Proportion of Participants With Transfusion IndependenceTransfusion independence, defined as transfusion-free for >8 consecutive weeks (TI8) during theCore Period. [Time Frame: Up to 24 weeks]Secondary Endpoints Phase 2b

[0111] Secondary endpoints for Phase 2b include:• AEs, SAEs, discontinuations due to AEs, and laboratory abnormalities during the Core Period.• Change from baseline in Hb concentration during the Core Period.• Change from baseline in total transfused RBC units from Week 8 through Week 24.AGS-131W0• >50% Reduction in Total Transfused Red Blood Units for >8 Consecutive Weeks CellDuring the Core Period (Participants With HTB Only) Compared With Baseline• Time to first Th (transfusion free for >8 Consecutive Weeks) during the Core Period• Transfusion-Free for >12 Consecutive Weeks During the Core Period• >50% reduction in total transfused RBC units for >12 consecutive weeks during the Core Period (Participants With HTB Only) Compared With Baseline• Plasma concentration and pharmacokinetic parameters of AG-946 during the Core Period• Time to first Tin during the Core Period• Duration of TI, defined as the longest transfusion-free period during the Core Period.• Whole blood concentrations of pharmacodynamics parameters, including 2,3-DPG and ATP during the Core Period.Exploratory Endpoints Phase 2b

[0112] Exploratory endpoints for Phase 2b include:• Change from baseline in the frequency of RBC transfusions during the Core Period• Tin during the study• Time to first Tin during the study• Transfusion-free for >16 consecutive weeks (Tlie) during the Core Period• Time to first Tlie during the Core Period• Tlie during the study• Time to first Tlie during the study• Duration of TI, defined as the longest transfusion-free period during the study• Change from baseline in exploratory biomarkers, including hepcidin, erythroferrone, soluble transferrin receptor, and GDF11 during the Core Period• Change from baseline in iron, serum ferritin, total iron binding capacity, and transferrin saturation during the Core Period• Change from baseline in markers of erythropoiesis, including absolute and percent reticulocytes, and erythropoietin during the Core Period• Change from baseline in bone marrow-derived biomarkers, including erythroid precursors, during the Core Period• Change from baseline in markers of hemolysis, including indirect bilirubin, lactate dehydrogenase, and haptoglobin during the Core PeriodAGS-131W0• Exposure-response (or pharmacokinetic / pharmacodynamic) relationship between relevant pharmacokinetic parameters and endpoints that are indicators of clinical activity and safety during the Core Period• Change from baseline during the Extension Period in:- Total transfused RBC units- The frequency of RBC transfusions- Hb concentration- Markers of iron metabolism- Markers of erythropoiesis and hemolysis- Bone marrow-derived biomarkers, including erythroid precursors- Exploratory biomarkers• AEs, SAEs, discontinuations due to AEs, and laboratory abnormalities during the Extension PeriodDose Modifications

[0113] Excessive Hb response is defined as an increase in Hb concentration that is >ULN (upper limit of normal) (by sex), in the absence of RBC transfusions. In the event of an excessive Hb response, in the absence of RBC transfusions for >4 weeks, study drug must be interrupted. If the event resolves, and in the opinion of the Investigator, reintroduction of study drug is justified, the Medical Monitor should be consulted before any further study drug is administered.

[0114] Dose modifications for events of platelet count decreased (PTs of Platelet count decreased and Thrombocytopenia) are provided in Table 2.Table 2 Dose Modifications for Events of Platelet Count DecreasedAGS-131W0Abbreviations: LLN=lower limit of normal; QD=once daily; SOA=schedule of assessments.Example 3: Enzymatic activity of the glycolytic pathway in pts with anemia due to LR- MDS and effect of ex vivo treatment with PK activator (AG-946 (Compound 1)) in Red Blood Cells in Subjects with low-risk myelodysplastic syndromes (LR-MDS)

[0115] An ex- vivo study was conducted to measure the activity of hexokinase and pyruvate kinase in the red blood cells of patients (pts) with low-risk myelodysplastic syndromes (LR-MDS).

[0116] In part A, 66 anemic pts (i.e., Hb <11 g / dL) diagnosed with MDS according to WHO 2022 were enrolled in the study and a peripheral blood sample was taken more than 4 weeks after the last red blood cell (RBC) unit administration to reduce blood donor contamination. The determination of activities of RBC enzymes hexokinase (HK) and PK, the initial and terminal steps of glycolytic pathway, and of ATP levels was performed by standard spectrophotometric methods according to Beutler et al, 1984. 2,3 DPG levels were tested by (2,3-DPG) ELISA kit. The glycolytic pathway is a metabolic pathway responsible for the conversion of glucose to pyruvate.

[0117] The patients were mainly elderly males (median age :80 yr, range: 58-92 yr), and mostly belonged to international prognostic scoring system (IPSS-R) low (78%) and very low / low groups (85%). The PK activity (median: 13.7 lU / gHb, range: 7.5-35.9 lU / gHb) was reduced in 35% of cases and the HK activity (median: 2.3 lU / gHb, range: 0.8-8.1) was increased in 91% of patients, resulting in an abnormally reduced PK / HK ratio in the majority of LR-MDS patients (95%). Notably, ATP levels (median 3.4 pmol / gHb, range: 1.3-6.5 pmol / gHb) were also reduced in 33 / 56 tested LR-MDS patients (59%), while 2,3 DPG levels were close to the upper limit of the normal range (median 389 nmol / gHb, range: 318-639).

[0118] In part B, purified RBC or whole blood of 10 LR-MDS patients and 5 healthy controls (HC) were incubated for 6 h and 24 h at 37°C in the presence or absence of AG-946 (Compound 1) in phosphate-buffered saline containing 1% glucose, 170 mg / L adenine, and 5.25 g / L mannitol (AGAM, pH 7.40). RBCs were incubated with 1, 5, and 50 uM of AG-946 (Compound 1) for up to 24 h at 37°C. After 6 and 24 h, the enzymatic activities of HK and PK, and ATP levels were measured.

[0119] 10 MDS pts (all IPSS-R low, 6 MDS-RS / SF3B1, 3 MDS-MLD / LB, and 1 MDS- del5q) were included, 9 male / 1 female, median age 82 years (range: 58-87). The baseline (BL) PK activity, HK activity, PK / HK ratio, and ATP levels were confirmed to be reduced in LR- MDS patients compared to HC (FIG. 3). After an ex vivo incubation of 24 hr with AG-946 (Compound 1), 5 / 10 pts (3 MDS-RS / SF3B1, 1 MDS-MLD / LB, 1 MDS-del5q) had a significant increase in mean PK activity from baseline (BL) across all AG-946 (Compound 1) concentrations evaluated (FIG. 4; BL: mean 9.68 lU / gHb [SD 1.4], 1 pM: 11.68 lU / gHb [SDAGS-131W0 0.9], 5 pM: 11.2 lU / gHb [SD 0.89], 50 pM: 11.54 lU / gHb [SD 0.8]; p<0.0I). LR-MDS patients who demonstrated an increase in PK activity also had higher HK levels at BL. LR-MDS patients who demonstrated an increase in PK activity maintained stable ATP levels across all evaluated concentrations of AG-946 (Compound 1).

[0120] The data demonstrate decreased glycolytic activity in a large cohort of anemic pts with LR-MDS versus HC, with reduced PK activity in 1 / 3 of cases, decreased PK / HK ratio in nearly all LR-MDS subjects, and reduced ATP in 2 / 3 of LR-MDS patients. Furthermore, ex-vivo treatment with AG-946 (Compound 1) led to an increase in PK activity, PK / HK ratio, and stable ATP levels in RBCs of LR-MDS pts across all WHO classifications. Notably, a dose-dependent response was observed in the LR-MDS RBCs. These data support clinical investigation of AG- 946 in LR-MDS patients.Example 4: AG-946, improves PK properties and RBC metabolism upon ex-vivo treatment of RBCs from patients with myelodysplastic syndromes

[0121] Ten non-transfusion dependent MDS patients and six healthy controls (HCs) were studied. Baseline PK activity and PK thermostability were measured in purified RBCs and RBC lysates, respectively. Hexokinase (HK) activity was included to evaluate PK activity in relation to mean RBC age. Ex vivo treatment was performed by incubating MDS RBCs for 16 hours at 37 °C in presence or absence of the PK activator AG-946 (lOpM or 5pM) using dimethylsulfoxide (DMSO) as a blank. Effect of treatment was assessed by measuring PK activity and levels of adenosine triphosphate (ATP) (LC-MS / MS). Functional RBC analysis was performed by osmotic gradient ektacytometry (LoRRca MaxSis). To investigate the effect on PK thermostability RBC lysates were incubated with AG-946 (2pM or IpM, DMSO as blank). The effect of ex vivo treatment of AG-946 on erythroid development was studied using peripheral blood mononuclear cells, cultured in MethoCult™ H4434 medium for 14 days in the presence or absence of AG-946 (lOpM, 625nM or 0.97nM, DMSO as blank).

[0122] Mean PK / HK ratio was significantly lower in RBCs from MDS patients compared to HCs (6.1 versus 10.5, p<Q.001, FIG. 5). Upon ex vivo treatment, PK activity significantly increased in a non-dose-related manner compared to DMSO (lOpM AG-946, mean increase 29%; 5pM, 27%, FIG. 6). MDS RBCs displayed decreased PK thermostability at baseline (not shown), which could be restored by ex vivo treatment with AG-946 (DMSO, 32% residual activity, 2pM AG-946, 84%; IpM, 86%, FIG. 7). Increase in activity was accompanied by significantly increased ATP levels (FIG. 8). On a functional level, RBC properties improved as reflected by the modest yet significant increase in Ohyper obtained by osmotic gradient ektacytometry, indicating improved hydration status (lOpM AG-946, mean increase 2.3%; 5pM, 2.8%). To date, culture assays were performed for 4 / 10 patients to investigate the effect of PKAGS-131W0 activation at the level of erythroid development; 1 / 4 showed a 36% increase (non-dose-related) in number of burst-forming units-erythroid (BFU-Es) upon treatment with AG-946 (lOpM, 625nM and 0.97nM) compared to DMSO.

[0123] These findings suggest that RBCs from MDS patients show a decrease in PK activity and thermostability. Furthermore, ex vivo treatment with AG-946 increases PK activity, ATP levels and stabilizes PK. Moreover, ex vivo treatment with AG-946 improves RBC hydration, suggesting that improved energy status directly improves RBC functional properties.

[0124] The scope of this invention is to be determined by the appended claims in view of, but not limited to, the specific embodiments and illustrative examples described herein. The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

LISTING OF CLAIMS:WHAT IS CLAIMED IS:

1. A compound having the structural formula:for use in treating anemia associated with lower-risk myelodysplastic syndrome (MDS) or LR-MDS in a subject suffering from lower-risk MDS (LR-MDS), said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

2. A compound having the structural formula:for use in treating anemia associated with lower-risk myelodysplastic syndrome (MDS) or LR-MDS in a subject suffering from lower-risk MDS (LR-MDS), said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

3. A compound having the structural formula:for use in treating hemolytic anemia in a subject suffering from lower-risk MDS (LR-MDS), said use comprising orally administering to the subject an amount that is equivalent to 10mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

4. A compound having the structural formula:for use in treating hemolytic anemia in a subject suffering from lower-risk MDS (LR-MDS), said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

5. A compound having the structural formula:for use in increasing the hemoglobin level in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

6. A compound having the structural formula:for use in increasing the hemoglobin level in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

7. A compound having the structural formula:for use in treating acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

8. A compound having the structural formula:for use in treating acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

9. A compound having the structural formula:for use in treating anemia associated with acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

10. A compound having the structural formula:for use in treating anemia associated with acquired PK deficiency (PKD) in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

11. A compound having the structural formula:for use in treating cytopenia in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

12. A compound having the structural formula:for use in treating cytopenia in a subject suffering from lower risk myelodysplastic syndrome (MDS) or LR-MDS, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

13. A compound having the structural formula:for use in treating a disease or disorder associated with ineffective erythropoiesis in a subject in need thereof, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

14. A compound having the structural formula:for use in treating a disease or disorder associated with ineffective erythropoiesis in a subject in need thereof, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

15. The compound for use of any one of claims 1 to 14, wherein the hemoglobin level of the subject improves over a period of at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, or at least 20 weeks of treatment.

16. The compound for use of any one of claims 1 to 15, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL.

17. The compound for use of any one of claims 1 to 15, wherein the hemoglobin level of the subject increases from baseline by > 1.5 g / dL.

18. The compound for use of any one of claims 1 to 15, wherein the hemoglobin level of the subject increases from baseline by > 2.0 g / dL.

19. The compound for use of any one of claims 1 to 18, wherein the subject becomes transfusion independent.

20. The compound for use of any one of claims 1 to 19, wherein the subject is classified as having a low transfusion burden prior to treatment.

21. The compound for use of any one of claims 1 to 20, wherein the subject becomes transfusion independent for > 1 consecutive week, for > 2 consecutive weeks, for > 3 consecutive weeks, for > 4 consecutive weeks, for > 5 consecutive weeks, for > 6 consecutive weeks, for > 7 consecutive weeks, for > 8 consecutive weeks, for > 9 consecutive weeks, or for > 10 consecutive weeks.

22. The compound for use of any one of claims 1 to 21, wherein the subject becomes transfusion independent for > 8 consecutive weeks.

23. The compound for use of any one of claims 1 to 22, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 10%, > 20%, > 30%, > 40%,> 50%, > 60%, > 70%, or > 80%.

24. The compound for use of any one of claims 1 to 23, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50%.

25. The compound for use of any one of claims 1 to 24, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 1 consecutive week, > 2 consecutive weeks, > 3 consecutive weeks, > 4 consecutive weeks, > 5 consecutive weeks, > 6 consecutive weeks, > 7 consecutive weeks, > 8 consecutive weeks,> 9 consecutive weeks, or > 10 consecutive weeks.

26. The compound for use of any one of claims 1 to 25, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 8 consecutive weeks.

27. The compound for use of any one of claims 1 to 26, wherein the LR-MDS is low risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS).

28. The compound for use of any one of claims 1 to 26, wherein the LR-MDS is very low risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS-R) for MDS).

29. The compound for use of any one of claims 1 to 26, wherein the LR-MDS is intermediate risk MDS (as characterized by the Revised International Prognostic Scoring System (IPSS- R) for MDS).

30. The compound for use of any one of claims 1 to 29, wherein the subject is male.

31. The compound for use of any one of claims 1 to 29, wherein the subject is female.

32. The compound for use of any one of claims 1 to 31, wherein the compound or pharmaceutically acceptable salt is administered as a pharmaceutical composition.

33. The compound for use of claim 32, wherein the pharmaceutical composition is in the form of a tablet or one or more granules.

34. The compound for use of any one of claims 1 to 32, wherein the pharmaceutical composition is in the form of one or more granules.

35. The compound for use of any one of claims 1 to 32, wherein the pharmaceutical composition is in the form of a tablet.

36. A compound having the structural formula:for use in treating anemia associated with lower-risk myelodysplastic syndrome (LR-MDS) in a subject, said use comprising orally administering the compound to the subject in an amount that is equivalent to 10 mg daily, 15 mg daily, or 20 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof, and wherein the subject is classified as being non-transfused, of low transfusion burden, or of high transfusion burden prior to administration.

37. A compound having the structural formula:for use in treating anemia associated with lower-risk myelodysplastic syndrome (LR-MDS) in a subject, said use comprising orally administering the compound to the subject in an amount that is equivalent to 25 mg daily, 30 mg daily, 35 mg daily, or 40 mg daily, wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof, and wherein the subject is classified as being non-transfused, of low transfusion burden, or of high transfusion burden prior to administration.

38. The compound for use of claim 37, wherein the subject is classified as having a low transfusion burden prior to treatment.

39. The compound for use of claim 38, wherein the subject becomes transfusion independent for > 8 consecutive weeks.

40. The compound for use of claim 38 or 39, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL, > 1.5 g / dL or > 2.0 g / dL.

41. The compound for use of claim 37, wherein the subject is classified as being non-transfused prior to treatment.

42. The compound for use of claim 41, wherein the hemoglobin level of the subject increases from baseline by > 1.0 g / dL, > 1.5 g / dL or > 2.0 g / dL.

43. The compound for use of claim 37, wherein the subject is classified as having a high transfusion burden prior to treatment.

44. The compound for use of claim 43, wherein the total transfused red blood cell (RBC) units of the subject are reduced from baseline by > 50% over a period of > 8 consecutive weeks.

45. The compound for use of any of claims 9, 10 and 15 to 35, wherein the anemia associated with acquired PK deficiency (PKD) is hemolytic anemia.

46. The compound for use of any one of claims 1 to 45, wherein the use comprises administering the compound in an amount that is equivalent to 10 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

47. The compound for use of any one of claims 1 to 45, wherein the use comprises administering the compound in an amount that is equivalent to 15 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

48. The compound for use of any one of claims 1 to 45, wherein the use comprises administering the compound in an amount that is equivalent to 20 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

49. The compound for use of any one of claims 1 to 45, wherein the use comprises administering the compound in an amount that is equivalent to 25 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

50. The compound for use of any one of claims 1 to 45, wherein the use comprises administering the compound in an amount that is equivalent to 30 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

51. The compound for use of any one of claims 1 to 45, wherein the use comprises administering the compound in an amount that is equivalent to 35 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

52. The compound for use of any one of claims 1 to 45, wherein the use comprises administering the compound in an amount that is equivalent to 40 mg once daily (QD), wherein the compound is administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

53. The compound for use of any one of claims 1 to 52, wherein the amount of the compound administered is either maintained or is modified if the subject experiences a platelet count decrease.

54. The compound for use of claim 53, wherein the amount of the compound administered is not modified for a grade 1 platelet count decrease (platelet count between 75,000 / pL and lower limit of normal (LLN)).

55. The compound for use of claim 53, wherein the amount of the compound administered is not modified for a grade 2 platelet count decrease (platelet count of 25,000 / pL to <75,000 / pL).

56. The compound for use of claim 55, wherein a subject’s platelet count is monitored weekly for 4 weeks, then monitored every 2 weeks for 4 weeks, then monitored every 4 weeks for 12 weeks, provided that the platelet count is stable.

57. The compound for use of claim 53, wherein at a first occurrence of a grade 4 platelet count decrease (platelet count <25,000 / pL): a) administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of a platelet count decrease; b) administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally c) administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.

58. The compound for use of claim 53, wherein at a second occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL): a) administration of the compound is discontinued for subjects that were receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; b) administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionallyc) administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.

59. The compound for use of claim 57 or 58, wherein in optional step c administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, or at an amount equivalent to 15 mg of the compound administered as a free base or pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

60. The compound for use of any one of claims 1 to 52, wherein the amount of the compound administered is either maintained or is modified for events of platelet count decrease as follows: a) the amount of the compound administered is not modified for grade 1 platelet count decreases (platelet count between 75,000 / pL and lower limit of normal (LLN)); b) the amount of the compound administered is not modified for grade 2 platelet count decreases (platelet count of 25,000 / pL to <75,000 / pL) and platelet count is monitored weekly for 4 weeks, then monitored every 2 weeks for 4 weeks, then monitored every 4 weeks for 12 weeks, provided that the platelet count is stable; c) the amount of the compound administered is modified at a first occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL) as follows: i. administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; ii. administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally iii. administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks; d) the amount of the compound administered is modified at a second occurrence of grade 4 platelet count decrease (platelet count <25,000 / pL) as follows:i. administration of the compound is discontinued for subjects receiving <10 mg of compound QD prior to the occurrence of platelet count decrease; ii. administration of the compound is interrupted and platelet count is monitored weekly until the count increases to >75,000 / pL for subjects receiving >10 mg of compound; and optionally iii. administration of the compound is restarted at the next lower amount provided that restarting is medically justified, and platelet count is monitored weekly for 4 weeks, then every 2 weeks for 4 weeks, then every 4 weeks for 12 weeks.

61. The compound for use of claim 60, wherein in optional step c(iii) administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

62. The compound for use of claim 60, wherein in optional step d(iii) administration is restarted at an amount equivalent to 10 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

63. The compound for use of claim 60, wherein in optional step c(iii) administration is restarted at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

64. The compound for use of claim 60, wherein in optional step d(iii) administration is restarted at an amount equivalent to 15 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

65. The compound for use of claim 60, wherein in optional step c(iii) administration is restarted at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

66. The compound for use of claim 60, wherein in optional step d(iii) administration is restarted at an amount equivalent to 20 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 25 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

67. The compound for use of claim 60, wherein in optional step c(iii) administration is restarted at an amount equivalent to 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 40 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

8. The compound for use of claim 60, wherein in optional step d(iii) administration is restarted at an amount equivalent to 30 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof; or at an amount equivalent to 35 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof, if the previous amount was the equivalent of 40 mg of the compound administered as a free base or a pharmaceutically acceptable salt or a composition thereof.

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