Compositions and methods for treating anemia

Abstract

To provide dosing regimens for administering a HIF prolyl hydroxylase inhibitor in the treatment or prevention of anemia, such as anemia secondary to or associated with chronic kidney disease, or anemia associated with or resulting from chemotherapy.SOLUTION: A pharmaceutical composition in a form of a tablet or capsule comprising Compound 1 having the following structure, for use in a method of increasing hemoglobin levels in a patient in need thereof relative to a baseline hemoglobin level, wherein the patient has a hemoglobin level of ≤10.5 g / dL or ≥9.5 g / dL and ≤12 g / dL at a start of treatment, a serum hemoglobin level increases by at least about 0.1 to about 1.0 g / dL relative to the baseline hemoglobin level, and the pharmaceutical composition is used such that Compound 1 is administered to the patient once daily, for example at a dose of about 150 mg.SELECTED DRAWING: Figure 1a

Description

[Technical Field]

[0001] This application is a continuation of U.S. Provisional Patent Application No. 61 / 834,808, filed June 13, 2013; No. 61 / 889,478 filed on November 1, 2013; No. 61 / 898,890 filed on November 1, 2013 No. 61 / 898,885, filed on December 5, 2013; and No. 61 / 912,185, filed on December 5, 2013. The benefit of prior art is claimed, and each of these applications is incorporated herein by reference in its entirety. It is incorporated into.

[0002] 1. FIELD OF THE INVENTION The present disclosure relates to anemia secondary to or associated with chronic kidney disease, anemia associated with or resulting from chemotherapy, or in the treatment or prevention of anemia, such as anemia associated with AIDS. The present disclosure further relates to the use of HIF prolyl hydroxylase inhibitors. and pharmaceutically acceptable salts thereof, HIF prolyl hydroxylase inhibitor compounds. and a composition containing the same, as well as peripheral vascular disease (PVD), coronary artery disease (CAD), heart failure, ischemia, and hypoxia. In addition, the present disclosure relates to methods for treating or preventing diseases such as chronic kidney disease and anemia. anemia associated with or resulting from chemotherapy, or anemia associated with AIDS of the use of HIF prolyl hydroxylase inhibitors in the treatment or prevention of anemia, such as anemia associated with Specific dosages and dosing regimens for use are described. [Background technology]

[0003] 2. BACKGROUND OF THE INVENTION (2.1 Hypoxia-inducible factors) Hypoxia-inducible factors (HIFs) are transcription factors that are key regulators of the response to hypoxia. In response to hypoxia, i.e., reduced oxygen levels in the cellular environment, HIF is activated by the elimination of It upregulates the transcription of several target genes, including those encoding thrombin. HIF is a heteroduplex containing α and β subunits. The β subunit is normally present in excess and is independent of oxygen tension, whereas the HIF-α subunit HIF-α accumulation is only detectable in cells under hypoxic conditions. The two main pathways are mediated by a family of prolyl hydroxylases known as HIF prolyl hydroxylases. wherein the hydroxylation of one or both proline residues is regulated by This leads to rapid degradation of HIF-α. Therefore, inhibition of HIF prolyl hydroxylases reduces the stability of HIF-α. This results in the synthesis and accumulation of HIF-α (i.e., reduced degradation of HIF-α), thereby and upregulation of target genes such as the erythropoietin gene. Conversely, activation of HIF prolyl hydroxylases increases the amount of HIF-α available. (i.e., increased degradation of HIF-α), which leads to the destabilization of HIF heterodimers and the amount of HIF-α available for downregulation of target genes such as VEGF. This leads to a decrease.

[0004] The family of hypoxia-inducible factors includes HIF-1-α, HIF-2-α, and HIF-3-α.

[0005] A novel class of prolyl hydroxylase inhibitors and their role in hypoxia-inducible factor (HIF) prolyl hydroxylation Their use to treat or prevent diseases ameliorated by modulation of metabolic enzymes is described in U.S. Pat. No. 7,811,595, which is incorporated herein by reference in its entirety. The synthesis of such prolyl hydroxylase inhibitors is described in U.S. Patent Publication No. 2012 / 0309977. No. 6,299,499, which is incorporated herein by reference in its entirety. The compounds inhibit HIF prolyl hydroxylases, thereby stabilizing HIF-α. As a result of stabilization, endogenous erythropoietin (EPO) production is increased. As with all drugs, Appropriate dosages and dosing regimens for treating patients with diseases such as anemia are important to prevent adverse effects. to achieve the desired or optimal therapeutic effect without excessive or unwanted side effects Indeed, for many active compounds, it is difficult to find an effective and safe dosing regimen. It has failed in clinical trials.

[0006] Thus, either adverse or unwanted effects are avoided or reduced, providing optimal therapeutic efficacy, i.e., providing a desirable therapeutic profile, or both; There is a need for safe, effective and non-toxic dosages and dosing regimens. Summary of the Invention

[0007] (2.2 Erythropoietin) Treatment of anemia associated with chronic kidney disease (CKD) using erythropoiesis-stimulating agents is a long-term physiological treatment. This often results in erythropoietin (EPO) levels above normal, which can lead to high blood pressure and It is associated with an increase in undesirable cardiovascular side effects, including thromboembolic events. Chronic kidney disease (CKD) without prolonged supraphysiological erythropoietin (EPO) levels D) There is a need for treatment of the anemia associated with

[0008] (2.3 Iron Metabolism) HIF inhibits several targets, including genes encoding proteins involved in iron metabolism. It regulates gene transcription. Iron is considered essential for cell survival, but excessive iron accumulation can lead to , is associated with the formation of toxic free radicals and progressive tissue destruction. Excess iron also It can also lead to a higher risk of cardiovascular and thromboembolic events. Iron overload can be caused by, for example, It can be caused by anemia resulting from blood transfusions or inadequate red blood cell production. There is a need to treat anemia without increasing the risk of disease.

[0009] (2.4 Hepcidin) Under conditions of anemia or hypoxia, erythropoietin expression increases, stimulating erythropoietic activity. This not only leads to a decrease in hepcidin gene expression, but also leads to a parallel decrease in hepcidin gene expression. It blocks the action of ferroportin, which mobilizes iron outside the cell. Thus, when hepcidin expression is reduced in a subject, ferroportin action is blocked. Instead, iron is released from the cells, increasing the risk of iron overload in the subject. In situations where iron overload is a concern, treatment of anemia without reducing hepcidin levels is needed. There is a need for treatments for hepcidin-related inflammatory bowel disease. Erythroferon has been identified as an inhibitor of hepcidin. (Kautz et al., 2014, Nature Genetics, Advance Online Publication on June 1, 2 014, "Identification of erythroferon as an erythroid regulator of iron metabolism" ythroferrone as an erythroid regulator of iron metabolism).

[0010] (3. Summary of the Invention) (3.1 Medication) A compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or compound 1 , compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2; or Specific dosages of their pharmaceutically acceptable salts, solvates, or hydrates are It is administered according to a specific dosing regimen that regulates hydroxylase activity, thereby stabilizing HIF-α. and thereby treating anemia (e.g., anemia secondary to chronic kidney disease). The formulas and compounds are disclosed herein. See Section 5.2. The structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the formula (I), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and Compound 7 , Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Specific dosage amounts and unit dosage forms of the products are further set forth herein. In embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl In some specific embodiments, the compound is a pharmaceutical equivalent of Compound 1. In some specific embodiments, the compound is a pharmaceutically acceptable salt. In some specific embodiments, the compound is a solvate of Compound 1. is.

[0011] In some embodiments, the disease ameliorated by modulation of HIF prolyl hydroxylase is administering to a patient having a steroid drug, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V) , or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2. an effective amount of the compound, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and administering to a subject a therapeutically effective amount of a compound selected from the group consisting of hydroxybenzoates, hydroxybenzoates, benzoyl peroxidases, hydroxybenzoates ... Methods for preventing the same are described herein. In specific embodiments, the compound comprises: Compound 1. In a specific embodiment, the compound is Compound 7.

[0012] In some embodiments, the compounds of formula (I), formula (II), formula (III), formula (IV ... III), a compound having the structure of formula (IV) or formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound Compound 12, compound 13, metabolite 1, and metabolite 2, or a pharmaceutical approved compound thereof. Acceptable daily doses of salts, solvates, or hydrates are about 100 mg, about 110 mg, about 120 mg, about 130 mg, and about 140 mg. g, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220 mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 31 0mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 4 00 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 600 mg, or about 750 mg. In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. g. Such a daily dose may be administered orally once a day, twice a day, or three times a day, preferably once a day. In some embodiments, the daily dose is 2 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3mg / kg, 3.1mg / kg g, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / k g, or 4 mg / kg.

[0013] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or 2. The method of claim 1, wherein the hydrate is administered to a patient suffering from anemia. Methods for treating or preventing anemia, such as steroid therapy, are provided herein. In embodiments, a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 Daily dose of the compound or a pharmaceutically acceptable salt, solvate, or hydrate thereof Specifically, the daily dose of Compound 1 is about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 160 mg. mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 24 0mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 3 30mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 600 mg, or about 750 mg. In embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. The dose may be administered orally once daily, twice daily, or three times daily, preferably once daily. In one embodiment, the daily dose is 2 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2. 5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3m g / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, or 4mg / kg do.

[0014] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or Provided herein is a unit dosage form containing the hydrate, specifically Compound 1, in an amount of about 150 mg. In some such embodiments, the unit dosage form is a tablet or capsule. be.

[0015] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or hydrate, specifically Compound 1, to a patient suffering from anemia. In patients with anemia, such as anemia secondary to renal disease, hemoglobin levels are increased by at least at least about 8.0 g / dL and less than or equal to about 13.0 g / dL, at least about 8.5 g / dL and less than or equal to 13.0 g / dL, at least about 9.0 g / dL and no more than 13.0 g / dL, at least about 9.5 g / dL and no more than 13.0 g / dL, and The method for maintaining blood glucose levels at levels of at least about 10.0 g / dL and no greater than about 13.0 g / dL is described herein. In some such embodiments, a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or or a compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 , Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, A compound selected from Metabolite 1 and Metabolite 2, or a pharmaceutically acceptable salt or solvent thereof. and administering to a patient suffering from anemia an effective amount of Compound 1, a solute or hydrate, or a hydrate, specifically Compound 1. and maintaining hemoglobin levels at least about 11.0 g / dL and less than or equal to about 13.0 g / dL in patients receiving and maintaining a level of at least about 11.0 g / dL. In some such embodiments, the compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) ) or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6 , compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, metabolite 1, and and metabolite 2, or a pharmaceutically acceptable salt, solvate, or the like thereof. or hydrate, specifically Compound 1, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 750 mg. Such a daily dose may be administered once a day, twice a day, or three times a day, preferably once a day. In some embodiments, the daily dose is 2 mg / kg, 2.1 mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3. 8mg / kg, 3.9mg / kg, or 4mg / kg.

[0016] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or hydrate, preferably Compound 1, to a patient suffering from anemia. The level of hemoglobin in a patient with anemia, such as anemia of disease, is measured by measuring the level of hemoglobin in the patient. At least about 0.1 g / dL, at least about 0.2 g / dL, or less than baseline hemoglobin level at least about 0.3 g / dL, at least about 0.4 g / dL, at least about 0.5 g / dL, at least about 0.6 g / dL , at least about 0.7 g / dL, at least about 0.8 g / dL, at least about 0.9 g / dL, at least about 1.0 g / dL, at least about 1.1 g / dL, at least about 1.2 g / dL, at least about 1.3 g / dL, at least Provided herein are methods for increasing by about 1.4 g / dL, or at least about 1.5 g / dL. In some such embodiments, the daily dose comprises a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or a compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 1 3, about 150 mg, about 300 mg, about 450 mg, about 600 mg of a compound selected from Metabolite 1 and Metabolite 2, In some such embodiments, the daily dose is about 150 mg, about 300 mg, or about 750 mg. Such a daily dose is about 450 mg, or about 600 mg, and is administered once a day, twice a day, or three times a day, preferably may be administered orally once daily.

[0017] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or and administering to the patient a pharmaceutically effective amount of a hydrate of the compound of formula (I) or (II). Provided herein are methods for preventing, wherein the pharmaceutically effective amount is a hemoglobin The patient's hemoglobin level is increased by at least about 0.5 g compared to the patient's baseline hemoglobin level. / dL, at least about 0.6g / dL, at least about 0.7g / dL, at least about 0.8g / dL, at least about an increase of at least about 0.9 g / dL, at least about 1.0 g / dL, at least about 1.2 g / dL, or at least about 1.5 g / dL While suitable for adding: a) restore or maintain the diurnal pattern of EPO serum levels; b) Increase total iron-binding capacity; c) increasing total iron binding capacity without a significant increase in total iron levels; and / or c) does not significantly reduce hepcidin levels.

[0018] In some embodiments, the disease, condition, or Section 5.2 of the dosages set forth in Section 5.5 for the treatment of disorders The compounds disclosed in are provided herein.

[0019] (3.2 Erythropoietin) In some embodiments, the level of hemoglobin in the patient is measured using a baseline hemoglobin level. The diurnal variation of serum EPO levels in healthy individuals was also increased compared to globin levels. Successive doses of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers were administered to mimic the and administering an appropriate number of doses to patients with diseases or conditions associated with reduced endogenous production of EPO. and treating a disease or condition associated with decreased endogenous production of erythropoietin (EPO), including Various methods are provided herein, wherein a HIF prolyl hydroxylase inhibitor or H The IF-α stabilizer is a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V). , or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0020] In some embodiments, the level of hemoglobin in the patient is measured using a baseline hemoglobin level. HIF prolyl hydroxylase inhibitors or HIF-α stabilizers to increase globin levels A sufficient number of successive doses of EPO are administered to treat a disease or condition associated with reduced endogenous production of EPO. associated with decreased endogenous production of erythropoietin (EPO), including administration to patients with Provided herein are methods for treating a disease or condition, wherein the continuous administration of small doses of At least one dose and the period between the administration of the immediately preceding dose should be sufficient to maintain serum EPO levels in the patient. , for a period of time sufficient to allow a return to near baseline serum EPO levels, where H The IF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound represented by formula (I), formula (II), formula (III), formula (IV), or or a compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 , Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, A compound selected from Metabolite 1 and Metabolite 2, or a pharmaceutically acceptable salt or solvent thereof. In some such embodiments, administration of exogenous EPO is The risk of associated cardiovascular side effects and thromboembolic events is minimized.

[0021] In some embodiments, the level of hemoglobin in the patient is measured using a baseline hemoglobin level. HIF prolyl hydroxylase inhibitors or HIF-α stabilizers to increase globin levels A sufficient number of successive doses of EPO are administered to treat a disease or condition associated with reduced endogenous production of EPO. associated with decreased endogenous production of erythropoietin (EPO), including administration to patients with Provided herein are methods for treating a disease or condition, comprising administering one or more doses of the compound after an initial dose. Prior to the addition of the above dose, serum EPO levels returned to near baseline levels, The HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is represented by formula (I), formula (II), formula (III), formula (IV): or a compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 1 3, a compound selected from Metabolite 1 and Metabolite 2, or a pharmaceutically acceptable salt thereof. In some such embodiments, the exogenous EPO is a hydroxybenzoate, a solvate, or a hydrate. The risk of cardiovascular side effects and thromboembolic events associated with administration is minimized.

[0022] In some embodiments, the level of serum EPO is compared to the baseline level of serum EPO. Hemoglobin levels were increased to baseline hemoglobin levels in patients without a significant increase in The combination of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers increased the levels of HIF compared to the control group. A sufficient number of consecutive doses are administered to a patient with a disease or condition associated with reduced endogenous production of EPO. and administering to a patient a dose of erythropoietin (EPO) to treat a disease associated with reduced endogenous production of erythropoietin (EPO).

[0010] Provided herein are methods for treating a disease or condition, wherein a HIF prolyl hydroxylase The inhibitor or HIF-α stabilizer has the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V). Compounds having the formula (I), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and Compound 7 , Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some such embodiments, the cardiovascular effects associated with administration of exogenous EPO are The risk of side effects and thromboembolic events is minimized.

[0023] In some such embodiments, the level of serum EPO is determined by the H About 1 week, about 6 days, about 5 days of administration of a dose of an IF prolyl hydroxylase inhibitor or a HIF-α stabilizer Within about 12 hours, about 24 hours, about 18 hours, or about 4 days, about 3 days, about 2 days, about 24 hours, about 18 hours, or about 12 hours, Return to baseline level.

[0024] In some embodiments, the serum EPO level is greater than or equal to a baseline EPO level of about 5 mIU / m L, about 4 mIU / mL, about 3 mIU / mL, about 2 mIU / mL, or about 1 mIU / mL.

[0025] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a one-week period. In some embodiments, the hemoglobin level is increased by 100% compared to the baseline hemoglobin level. It rises by about 0.1 g / dL over a period of weeks.

[0026] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a two-week period. In embodiments, the hemoglobin level is increased by 2 to 10 times compared to the baseline hemoglobin level. It rises by about 0.1 g / dL over a period of weeks.

[0027] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a 3-week period. In some embodiments, the hemoglobin level is increased by 3 to 10% compared to the baseline hemoglobin level. It rises by about 0.5 g / dL over a period of weeks.

[0028] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a 4-week period. In some embodiments, the hemoglobin level is increased by 4 to 10 times compared to the baseline hemoglobin level. It rises by about 0.6 g / dL over a period of weeks.

[0029] In some embodiments, the disease or condition is anemia. In some embodiments, the anemia is secondary to chronic kidney disease (CKD). In some embodiments, the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease. In such embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease.

[0030] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is administered daily. In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α The stabilizer is administered orally.

[0031] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a Compound 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0032] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a Compound 7, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0033] In some embodiments, the disease, condition, or is used in the treatment of disorders, particularly in the dosages set forth in Section 5.5, The compounds identified in Section 5.2 were administered at doses suitable to mimic the diurnal pattern of EPO. The products are provided herein (see Section 5.3.1).

[0034] (3.3 Iron Metabolism) Traditionally, the treatment of anemia due to reduced erythropoietin (EPO), such as anemia or anemia secondary to chronic kidney disease, has been In order to effectively treat diseases or conditions associated with endogenous iron production, it is necessary to increase serum iron levels and It has been thought that increasing transferrin saturation (TSAT) is desirable. Decreased endogenous production of erythropoietin (EPO), such as anemia secondary to blood or chronic kidney disease or a disease or condition associated with a defect in endogenous hemoglobin production , increases total iron binding capacity without increasing serum iron levels, thereby improving transferrin saturation Therefore, it has been found that the increased blood pressure can be effectively treated by causing a decrease in Undesirable side effects associated with elevated iron levels can be reduced or avoided.

[0035] In some embodiments, the serum iron level is measured relative to the baseline serum iron level. Increased total iron binding capacity (TIBC) in patients compared to baseline TIBC without significant increase To achieve this, sufficient doses of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers are administered. and administering the compound to a patient having a disease or condition associated with reduced endogenous production of EPO. to treat diseases or conditions associated with decreased endogenous production of erythropoietin (EPO), including Methods are provided herein.

[0036] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or and administering to the subject a pharmaceutically effective amount of a hydrate of the compound of formula (I) to treat or cure anemia in a subject. In some more specific embodiments, methods for preventing , a compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or compound 1 , compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2; or A pharmaceutically effective amount of a pharmaceutically acceptable salt, solvate, or hydrate thereof is: In the patient, the TIBC is increased by at least about 10 μg / dL, at least about 20 μg / dL, compared to the baseline TIBC. μg / dL, at least about 30 μg / dL, at least about 40 μg / dL, at least about 50 μg / dL, or and / or maintain hemoglobin levels at or above about 60 μg / dL, and / or maintain hemoglobin levels at or above baseline hemoglobin levels. at least about 0.5 g / dL, at least about 0.6 g / dL, at least about 0.7 g / dL, At least about 0.8 g / dL, at least about 0.9 g / dL, at least about 1.0 g / dL, at least about 1.2 g / dL dL, or at least about 1.5 g / dL, while: a) restoring or maintaining the diurnal pattern of EPO serum levels; and / or b) maintaining pre-treatment levels of total iron (i.e., no significant increase in total iron levels); and / or teeth, c) does not significantly reduce hepcidin levels.

[0037] In some embodiments, the serum iron level is significantly increased compared to the baseline serum iron level. Increased total iron-binding capacity (TIBC) compared to baseline TIBC in patients without significant increase in TIBC To achieve this, a sufficient number of consecutive doses of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers are administered. to a patient having a disease or condition associated with reduced endogenous production of EPO. Minimizing the risk of cardiovascular side effects and thromboembolic events associated with increased serum iron levels while treating diseases or conditions associated with decreased endogenous production of erythropoietin (EPO). Methods for treating the disease are provided herein.

[0038] In some embodiments, transferrin saturation (TSAT) is measured relative to baseline TSAT. In some embodiments, the serum iron level is reduced compared to the baseline serum iron level. It is reduced compared to the previous model.

[0039] In some embodiments, the TIBC is at least about 10 μg / mL compared to baseline TIBC. dL, at least about 20 μg / dL, at least about 30 μg / dL, at least about 40 μg / dL, at least An increase of about 50 μg / dL, or at least about 60 μg / dL.

[0040] In some embodiments, the increase in TIBC compared to baseline TIBC is observed over a period of about 1 week. or for about 2 weeks, for about 3 weeks, for about 4 weeks, for about 5 weeks, or for about Occurs over a 6 week period.

[0041] In some embodiments, the serum iron level is increased by about 100 mg / kg compared to the baseline serum iron level. The increase is by less than 20 μg / dL, less than about 15 μg / dL, less than about 10 μg / dL, or less than about 5 μg / dL.

[0042] In some embodiments, the disease or condition is anemia. In some embodiments, the anemia is secondary to chronic kidney disease (CKD). In some embodiments, the chronic kidney disease is chronic kidney disease stage 3, 4, or 5. In some embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease.

[0043] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is It is administered once daily.

[0044] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is It is administered orally.

[0045] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is In some such embodiments, the HIF prolyl hydroxyl group is a heterocyclic carboxamide. Oxidase inhibitors or HIF-α stabilizers include pyridine carboxamides and quinoline carboxamides. and isoquinolinecarboxamide. In some embodiments, the HI The F prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound represented by formula (I), formula (II), formula (III), formula (IV), or or a compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 , Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, A compound selected from Metabolite 1 and Metabolite 2, or a pharmaceutically acceptable salt or solvent thereof. solvates or hydrates.

[0046] In some embodiments, the disease, condition, or for the treatment of disorders, the dosages identified in Section 5.5, specifically Section The doses appropriate for increasing total iron-binding capacity as described in Section 5.3.2 are as specified in Section 5.2. The compounds identified are provided herein.

[0047] (3.4 Hepcidin) Surprisingly, there are cases of non-severe anemia secondary to chronic kidney disease and severe anemia secondary to chronic heart failure. Some types of anemia, such as idiopathic anemia of aging, decrease hepcidin expression. can be treated by increasing serum hemoglobin levels without Therefore, hepcidin expression was similar to that in healthy adults and iron-dependent. It functions to regulate normal transport.

[0048] In some embodiments, hepcidin expression is measured using a baseline hepcidin expression level. Serum hemoglobin levels were increased in patients without a significant decrease compared to baseline blood pressure. HIF prolyl hydroxylase inhibitors or HIF-α inhibitors were administered to increase serum hemoglobin levels compared with normal serum hemoglobin levels. Sufficient continuous doses of stabilizers are administered to treat non-severe anemia secondary to chronic kidney disease, congestive heart failure, and It is recommended that this drug be administered to patients with non-severe anemia secondary to heart failure or idiopathic anemia of aging. Non-severe anemia secondary to chronic kidney disease, including non-severe anemia secondary to congestive heart failure A method for treating a disease or condition selected from the group consisting of idiopathic anemia of aging, idiopathic anemia of aging, and idiopathic anemia of aging is provided herein. and provide it.

[0049] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. Over a one-week period, blood levels rise by about 0.1 to about 1.0 g / dL compared to normal blood levels. In such embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In comparison, over a one-week period, it is elevated by approximately 0.1 g / dL.

[0050] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. Over a two-week period, blood levels rise by about 0.1 to about 1.0 g / dL compared to normal blood levels. In such embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In comparison, over a two-week period, it is elevated by approximately 0.1 g / dL.

[0051] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. Over a 3-week period, blood levels rise by about 0.1 to about 1.0 g / dL compared to normal blood levels. In such embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In comparison, over a 3-week period, it is elevated by approximately 0.5 g / dL.

[0052] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. Over a 4-week period, blood levels rise by about 0.1 to about 1.0 g / dL compared to normal blood levels. In such embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In comparison, over a 4-week period, it is elevated by approximately 0.6 g / dL.

[0053] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. Over a 5-week period, blood levels rise by about 0.1 to about 1.0 g / dL compared to normal blood levels. In such embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In comparison, over a 5-week period, it is elevated by approximately 0.6 g / dL.

[0054] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. The levels are elevated by about 0.1 to about 1.0 g / dL over a 6-week period. In such embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In comparison, over a 6-week period, it is elevated by approximately 0.6 g / dL.

[0055] In some embodiments, hepcidin expression is measured at a baseline hepcidin expression level. less than about 20%, less than about 15%, and less than about 10% compared to baseline hepcidin expression levels The decrease is less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1%.

[0056] In some embodiments, the disease or condition is non-severe poverty secondary to chronic kidney disease. In some embodiments, the disease or condition is non-severe congestive heart failure. In some embodiments, the disease or condition is idiopathic anemia of aging.

[0057] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF- Alpha stabilizers are administered orally.

[0058] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is In some such embodiments, the HIF prolyl hydroxyl group is a heterocyclic carboxamide. Oxidase inhibitors or HIF-α stabilizers include pyridine carboxamides and quinoline carboxamides. and isoquinolinecarboxamide.

[0059] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is A compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10 a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2, or and pharmaceutically acceptable salts, solvates, or hydrates thereof. The HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 1 or a pharmaceutical thereof. In a specific embodiment, the HIF protease inhibitor is an acceptable salt, solvate, or hydrate thereof. The hydroxylase inhibitor or HIF-α stabilizer may be Compound 7 or a pharmaceutically acceptable salt thereof; It is a solvate or a hydrate.

[0060] In some embodiments, the disease, condition, or for the treatment of disorders, the dosages identified in Section 5.5, specifically Section Decreasing hepcidin levels as described in Section 5.3.3 and / or Suitable dosages for treating anemia without increasing erythroferon levels as described Amounts of the compounds disclosed in Section 5.2 are provided herein. [Brief explanation of the drawings]

[0061] [Figure 1a] FIG. 1a shows serum concentrations of Compound 1 in healthy male adults over a 24-hour period.

[0062] [Figure 1b] FIG. 1b shows the EPO response in healthy male adults over a 24-hour period following administration of Compound 1.

[0063] [Figure 2] FIG. 2 shows EPO levels over a 24-hour period in patients with anemia secondary to chronic kidney disease following administration of Compound 1.

[0064] [Figure 3] FIG. 3 shows the concentration of Compound 1 in patients with anemia secondary to chronic kidney disease over a 24-hour period.

[0065] [Figure 4] FIG. 4 shows the change in hemoglobin from baseline in patients with anemia secondary to chronic kidney disease when Compound 1 is administered at various doses.

[0066] [Figure 5] FIG. 5 shows hemoglobin, reticulocyte, and EPO levels in patients with anemia secondary to chronic kidney disease over 6 weeks of treatment with Compound 1.

[0067] [Figure 6] FIG. 6 shows the mean (±SE) absolute change from mean baseline in hemoglobin and ferritin in a dose escalation study in patients with anemia secondary to chronic kidney disease.

[0068] [Figure 7] FIG. 7 shows the increase in total iron binding capacity in patients with anemia secondary to chronic kidney disease who do not show a significant increase in serum iron levels when treated with Compound 1 over a 6-week period.

[0069] [Figure 8] FIG. 8 shows the increase in serum hemoglobin levels over 6 weeks in patients with anemia secondary to chronic kidney disease when treated with Compound 1 compared to baseline.

[0070] [Figure 9] FIG. 9 shows that hepcidin expression does not decrease compared to baseline in patients with anemia secondary to chronic kidney disease when treated with low doses of Compound 1 over a 6-week period. DETAILED DESCRIPTION OF THE INVENTION

[0071] (5 detailed explanation) In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or and administering to the patient a pharmaceutically effective amount of a hydrate of the compound of formula (I) or (II). Provided herein are methods for preventing, wherein the pharmaceutically effective amount is Compared to baseline hemoglobin levels, at least approximately 0.2g / dL, 0.3g / dL, 0.4g / dL, 0.5g / dL dL, at least about 0.6g / dL, at least about 0.7g / dL, at least about 0.8g / dL by at least about 0.9 g / dL, by at least about 1.0 g / dL, by at least about 1.2 g / dL, or suitable for increasing hemoglobin levels by at least about 1.5 g / dL, while: a) restoring or maintaining the diurnal pattern of EPO serum levels; and / or b) increasing total iron-binding capacity; and / or c) increasing total iron binding capacity without significantly increasing total iron levels; and / or c) does not significantly reduce hepcidin levels.

[0072] 5.1 Definitions and Abbreviations In some embodiments, the word "including" as used throughout the description and claims of this specification "Consists of" and other forms of this word, such as "includes" and "comprises," are examples of other The term "additives," "ingredients," "integer numbers," or "steps" is intended to include, but not be limited to, and does not exclude, any of the following additives, ingredients, integers, or steps: In some embodiments, the present description and appended claims The singular forms "a," "an," and "the" used herein shall apply unless the context clearly indicates otherwise. Thus, for example, reference to "a composition" includes reference to two or more such compositions. In some embodiments, "any" or "optionally" includes a mixture of compositions such as " indicates that the subsequently described event or circumstance may or may not occur, and This description is meant to include instances where the event or circumstance occurs and instances where it does not occur. do.

[0073] As used herein, an "alkyl" group includes, for example, an alkyl group having 1 to 12 carbon atoms, an alkyl group having 1 to 9 carbon atoms, and an alkyl group having 1 to 9 carbon atoms. , saturated straight-chain or branched chain having 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 2 to 6 carbon atoms Representative alkyl groups are -methyl, -ethyl, -n-propyl, -n- butyl, -n-pentyl and -n-hexyl; while branched alkyl includes -isopropyl -butyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl, 2-methylpentyl, 3- Includes methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like.

[0074] C 1-6 Alkyl units include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), iso-propyl (C3), n-butyl (C4), sec-butyl (C4), iso-butyl (C4), tert-butyl pentyl (C4), n-pentyl (C5), tert-pentyl (C5), neo-pentyl (C5), iso-pentyl (C5), s ec-pentyl (C5), 3-pentyl (C5), n-hexyl (C6), iso-hexyl (C6), neo-hexyl ( C6), 3-methylpentyl (C6), 4-methylpentyl (C6), 3-methylpentan-2-yl (C6), 4- Methylpentan-2-yl (C6), 2,3-dimethylbutyl (C6), 3,3-dimethylbutan-2-yl (C6) , 2,3-dimethylbutan-2-yl (C6), and the like.

[0075] As used herein, an "alkenyl" group is an alkyl group having at least one carbon-carbon double bond. and, for example, partially unsaturated, straight-chain or branched acyclic alkyl groups having 1 to 6 carbon atoms. is a hydrocarbon of the formula: Representative alkenyl groups include propenyl and the like.

[0076] As used herein, an "alkynyl" group is an alkyl group having at least one carbon-carbon triple bond. and, for example, partially unsaturated, linear or branched acyclic alkyl groups having 2 to 6 carbon atoms. Representative alkynyl groups include propynyl, butynyl, and the like. .

[0077] As used herein, an "alkoxy" group refers to an alkyl group as defined herein. Representative alkoxy groups include methoxy, ethoxy, n-propoxy, and methyl. Includes silyl, isopropoxy and n-butoxy.

[0078] As used herein, a "cycloalkyl" group refers to a group having one ring and three carbon atoms. A saturated cyclic alkyl group having up to six carbon atoms. Representative cycloalkyl groups include cyclopropyl, ... Includes cyclobutyl and cyclopentyl.

[0079] As used herein, a "cycloalkenyl" group refers to a group having at least one ring. Partially unsaturated cyclic alkyl groups containing at least one carbon-carbon double bond and 3 to 6 carbon atoms Representative cycloalkenyl groups include cyclopropenyl and cyclobutenyl.

[0080] As used herein, a "cycloalkoxy" group refers to a cycloalkyl group as defined herein. A representative cycloalkoxy group is a cycloalkyl-O- group, as defined below. Includes propyloxy, cyclobutyloxy and cyclopentyloxy.

[0081] As used herein, a "haloalkyl" group refers to an alkyl group having one or more (e.g., 1 to 5) hydrogen atoms. wherein an atom is replaced by a halogen atom, as defined herein above. Representative haloalkyl groups are CF3, CHF2, CH2F, CCl3, CF3CH2CH2, and Contains CF3CF2.

[0082] As used herein, a "halocycloalkyl" group refers to one or more (e.g., 1 to 5) cycloalkyl groups. ) a hydrogen atom is replaced by a halogen atom, as defined herein above Representative halocycloalkyl groups include 2,2-difluorocyclopropane, 2,2-difluorocyclopropane, and 2,2-difluorocyclopropane. 2,2-dichlorocyclopropyl, 2,2-dibromocyclopropyl, tetrafluorocyclopropyl cyclopropyl, 3,3-difluorocyclobutyl and 2,2,3,3-tetrafluorocyclobutyl include.

[0083] As used herein, a "heterocycloalkyl" group is a group in which one or two ring members are O, S and NR″, and the remaining atoms are carbon, preferably 4 to 7 atoms. It is a saturated ring of 5 or 6 ring atoms. Representative heterocycloalkyl groups include piperidyl, pyrrolidinyl, piperidinyl, and Razinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1, 4-dioxanyl, oxazolinyl, tetrahydrofuranyl, tetrahydrothiophenyl and and tetrahydrothiopyranyl.

[0084] As used herein, an "aryl" group refers to an aromatic mono- or di-substituted group containing 6 to 10 carbon atoms. It is a ring or polycyclic ring system. Representative aryl groups include phenyl and naphthyl.

[0085] As used herein, "heteroaryl" refers to a heteroaryl group in which the ring is free of adjacent oxygen and / or ion atoms. 2 to 9 carbon atoms and a group consisting of N, O and S, provided that no carbon atoms are contained Monocyclic, bicyclic rings of 5 to 10 atoms, consisting of 1 to 4 heteroatoms selected from or benzo-fused heterocyclic aromatic groups. N-oxides of ring nitrogens are also included. Representative monocyclic Heteroaryl groups of the formula include pyridyl, oxazolyl, isoxazolyl, oxadiazolyl , furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl thiadiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and trimethylsilyl Representative bicyclic heteroaryl groups include naphthyridyl (e.g., 1,5 or 1,7). , imidazopyridyl, pyridopyrimidinyl, and 7-azaindolyl. The heteroaryl group includes indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothiyl, and the like. enyl (i.e., thianaphthenyl), benzimidazolyl, benzofuranyl, benzoxa This includes benzothiazolyl, benzisoxazolyl, benzothiazolyl and benzofurazanyl. All positional isomers are contemplated, for example, 2-pyridyl, 3-pyridyl and 4-pyridyl. do.

[0086] For purposes of this disclosure, the terms "compound," "analog," and "composition of matter" refer to all The compounds referred to herein include enantiomeric forms, diastereomeric forms, salts, tautomers, and the like. Equally representative are the enzyme inhibitors of HIF prolyl hydroxylases disclosed herein. The compounds mentioned may be in all salt forms, for example salts of basic groups, especially amines, as well as salts of acidic groups and The following compounds form pharmaceutically acceptable salts with basic groups: Non-limiting examples of anions that can be used are: chloride, bromide, iodide, sulfur Acid ions, hydrogen sulfate ions, carbonate ions, hydrogen carbonate ions, phosphate ions, formate ions, Acetate ion, propionate ion, butyrate ion, pyruvate ion, lactate ion, oxalate Acid ion, malonate ion, maleate ion, succinate ion, tartrate ion, fumarate ion acid ions, citrate ions, and the like. The following are examples of acidic substituents on the compounds described herein: Non-limiting examples of cations that can form pharmaceutically acceptable salts with the anionic form of the substituent are: : Sodium, lithium, potassium, calcium, magnesium, zinc, bismuth, and The following are examples of phenolic, aryl alcohol, or can form pharmaceutically acceptable salts with the anionic form of the heteroaryl alcohol substituent. Non-limiting examples of cations that can be used are: sodium, lithium, and potassium. In some embodiments, the terms "compound," "analog," and "composition of matter" are used throughout this specification. are used interchangeably.

[0087] If a discrepancy exists between a described structure and the name given to that structure, the described structure It should be noted that weight is given to the structure. In addition, Where the stereochemistry is not indicated, for example by a bold or dashed line, the structure or portion of the structure is , should be construed as encompassing all stereoisomers thereof.

[0088] The term "anemia" as used herein is art-recognized and means It is defined by the following hemoglobin thresholds: [Table 1] Anemia can be chronic (e.g., anemia secondary to chronic kidney disease, anemia secondary to chronic heart failure, anemia of aging, Idiopathic anemia, anemia of chronic diseases such as inflammatory bowel disease or rheumatoid arthritis, myelodysplastic syndrome group, myelofibrosis, and other aplastic or dysplastic anemias), subacute (e.g., cancer, hepatitis C, chemotherapy-induced leukemia, such as chemotherapy to treat bone marrow inflammation or other chronic diseases that reduce bone marrow production anemia), acute (e.g., blood loss during injury or surgery), nutrition-related (e.g., iron deficiency or Vitamin B12 deficiency), or hemoglobinopathies (e.g., sickle cell disease, thalassemia, etc.) The anemia may be due to anemia caused by a genetic disorder, such as anemia caused by a genetic disorder, or anemia caused by autologous blood donation.

[0089] As used herein, the term "non-severe anemia" refers to anemia in which hemoglobin is at least In some such embodiments, a patient with anemia greater than 9.0 g / dL is referred to as having anemia greater than 9.0 g / dL. Mild anemia refers to anemia in a patient such that the patient does not require a blood transfusion.

[0090] As used herein, the term "dose" refers to the amount of a compound or compound(s) administered at one time. The dosage refers to the amount of a pharmaceutically acceptable salt, solvate, or hydrate thereof. The composition may contain a single unit dosage form or may contain more than a unit dosage form (e.g., a single dose). may contain two tablets), or even in a unit dosage form (e.g., a single dose may contain more than one tablet Therefore, if the compound is administered at a daily dose of 450 mg once a day, When administered, the compound dose is three tablets each containing 150 mg of compound administered once daily. It may be a tablet.

[0091] As used herein, the term "daily dose" refers to the amount of a compound or compound administered during a 24-hour period. means the amount of a pharmaceutically acceptable salt, solvate, or hydrate thereof. The daily dose may be administered all at once (i.e., once-daily dosing) or the daily dose may be administered in a compound The daily dose may be divided so that the product is administered twice a day, three times a day, or even four times a day. When administered daily without interruption, the medication is referred to as "continuous" medication.

[0092] As used herein, the term "unit dosage form" refers to tablets; caplets; soft elastic gelatin tablets; Capsules such as capsules; sachets; cachets; lozenges; dispersibles; powders; liquids gels; suspensions (e.g., aqueous or non-aqueous liquid suspensions), emulsions (e.g., oil-in-water emulsions) or water-in-oil liquid emulsions), solutions, and elixirs, and liquid dosage forms suitable for oral or parenteral administration to a patient. a sterile solid (e.g., a crystalline or amorphous solid) that can be reconstituted to A unit dosage form is not necessarily administered as a single dose, and a unit dosage form may be: It does not necessarily have to make up the entire dose.

[0093] As used herein, an "effective amount" refers to an amount that provides a therapeutic benefit in the treatment of a disease. or a compound or compounds thereof sufficient to cause or delay or minimize symptoms associated with the disease. The term "amount" refers to the amount of a pharmaceutically acceptable salt, solvate or hydrate thereof. Effective amounts are described herein. In some embodiments, the compound is administered in a dose as described herein. It is a compound revealed in the book.

[0094] As used herein, the terms "prevent," "preventing," and "prevention" refer to It is recognized in the art and is used to treat conditions such as local recurrence (e.g., pain), cancer, etc. When used in connection with a complex syndrome such as a disease of the art, heart failure, or other pathology, It is well understood in the art and is intended to provide a therapeutic effect on subjects compared to subjects who do not receive the composition. the compounds provided herein reduce the frequency or delay the onset of symptoms of a condition in or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments, the compound is a compound not disclosed herein. In some embodiments, the condition is associated with reduced endogenous production of erythropoietin (EPO). diseases or conditions associated with endogenous hemoglobin levels, such as anemia or anemia secondary to chronic kidney disease; It is a disease or condition associated with a deficiency in the production of

[0095] As used herein, the terms "treat," "treating," and "treatment" refer to Identifying the symptoms, clinical signs and underlying pathology of the condition in a manner that improves or stabilizes the elephant's condition The terms "treat" and "treatment" also refer to the reversal, alleviation, or cessation of a disease or its It also refers to the eradication or amelioration of symptoms associated with a disease. The term refers to a compound provided herein, or a pharmaceutically acceptable salt, solvate, or the like thereof. the spread or exacerbation of such diseases as a result of the administration of the compound or its hydrate to patients with such diseases This refers to the minimization of

[0096] As used herein, the term "pharmaceutically acceptable salts" refers to salts of inorganic acids and bases, as well as and salts prepared from pharmaceutically acceptable non-toxic acids or bases, including organic acids and bases. A compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 Suitable pharmaceutically acceptable base addition salts for ammonium, calcium, magnesium, zinc, bismuth, ammonium (alkyl substituted ammonium), amino acids (e.g., lysine, ornithine, arginine, or glutathione), amine), tromethamine, and meglumine. Suitable non-toxic acids include inorganic and organic acids, such as acetic acid, alginic acid, anthracite, and the like. acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamine Acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, phosphorus acetic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenyl Acetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid Acids include, but are not limited to, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Other examples of salts are well known in the art and are described, for example, in Remington's Pharmaceutical Sciences. See "Miller's Pharmaceutical Sciences," 22nd ed., Pharmaceutical Press (2012). I want to be illuminated.

[0097] In some embodiments, "pharmaceutically acceptable" means biologically or otherwise means a substance that is not undesirable in the case of without causing any biological effect or any other component of the pharmaceutical composition in which it is contained. can be administered to an individual together with related active compounds without interacting in a deleterious manner with the compound. Cut.

[0098] As used herein, the term "hydrate" refers to a compound in which water is bound by non-covalent intermolecular forces. The compounds provided herein further comprise a stoichiometric or non-stoichiometric amount of The term "amyloid" refers to a pharmaceutically acceptable salt thereof.

[0099] As used herein, the term "solvate" refers to a compound bound by non-covalent intermolecular forces. The compounds provided herein further comprise a stoichiometric or non-stoichiometric amount of a solvent other than water. or a pharmaceutically acceptable salt thereof.

[0100] Unless otherwise indicated, the terms "about" or "approximately" as used herein refer to values. The specific characteristics, as determined by one skilled in the art, will depend in part on how the value is measured or determined. In some embodiments, the term "about" or "Approximately" means within 1, 2, 3, or 4 standard deviations. The term "about" or "approximately" means 50%, 20%, 15%, 10%, 9%, 8%, 10% of a given value or range. This means within 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05%. In embodiments, ranges may be from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another embodiment is the same as Similarly, the use of the antecedent "about" includes from one particular value and / or to another particular value. When values are expressed as approximations, it will be understood that the particular value forms another aspect. The endpoints of each range may be expressed both in relation to the other endpoint, and independently of the other endpoint. It will be further understood that the numbers disclosed herein are important in It is understood that there are many values, and that each value may also be used in addition to the value itself to be "about" that particular value. It is also understood that the value "10" is defined herein as "10" and "20." When a value is given, "about 10" is also given. When a value is given, it is understood appropriately by those skilled in the art. "less than or equal to," "greater than or equal to," and "between values" are used to indicate It is also understood that a possible range of values is also disclosed. For example, if a value of "10" is disclosed, In this case, "greater than or equal to 10" is also specified in addition to "less than or equal to 10." Throughout this document, data may be provided in a number of different formats and this data It is also understood that the values represent endpoints and starting points and ranges for any combination of data points. For example, if a specific data point "10" and a specific data point "15" are identified, Greater than, greater than, less than, less than, and equal to 10 and 15, plus 10 and 15 It is understood that the difference between two specific unit quantities is considered to be It is also understood that quantities are also revealed. For example, if 10 and 15 are revealed, 11, 12, 13, and 14 are also revealed.

[0101] In some embodiments, the term subject or patient refers to a human, mouse, dog, donkey, horse, or The term may refer to a mammal, such as a rat, a guinea pig, a bird, or a monkey. In embodiments, the subject or patient is a human subject or patient.

[0102] In some embodiments, the compounds provided herein have the structure Compound 1, i.e., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} Acetic acid: [ka] .

[0103] In some embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine] lysine-2-carbonyl]amino}acetic acid, while some alternative embodiments In the formula, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] In some alternative embodiments, the compound may be a pharmaceutically acceptable salt of amino}acetic acid. In this case, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] a In some alternative embodiments, the compound may be a solvate of methylamino}acetic acid. is a hydrate of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid In some preferred embodiments, the present invention provides compounds of the parent type. Some alternative preferred forms of the compound are: In an embodiment, the present invention relates to the present compounds or their pharmaceutically acceptable salts.

[0104] The term "HIF prolyl hydroxylase" as used herein is defined in the art as a HIF prolyl hydroxylases are recognized as PHDs and can be abbreviated as "PHDs." It is also known as "prolyl hydroxylase domain-containing protein," which can be abbreviated as "prolyl hydroxylase domain-containing protein." In this regard, three different PHD isoforms, PHD1, PHD2, and PHD3, respectively, There are those called EGLN1, EGLN2, EGLN1, and EGLN3, or HPH3, HPH2, and HPH1. In some embodiments, the HIF prolyl hydroxylase is an enzyme (e.g., HIF-1α prolyl hydroxylase). hydroxylase, HIF-2α prolyl hydroxylase, and / or HIF-3α prolyl hydroxylase) A specific target can be mentioned.

[0105] (5.2 Compounds) In some embodiments, the compounds for use in the methods provided herein are In a more specific embodiment, the compounds provided herein are modulators of HIF prolyl hydroxylases. The compounds for use in the provided methods are modulators of HIF-1-α prolyl hydroxylase. In another more specific embodiment, the compound for use in the methods provided herein is a modulator of HIF-2-α prolyl hydroxylase. In the compounds for use in the methods provided herein, at least 10%, 20% , 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 125%, 150%, 175 %, 200%, 250%, 500%, 750%, or at least 1000% HIF-1-α prolyl hydroxylation HIF-2-α prolyl hydroxylase is more active against HIF-2-α prolyl hydroxylase than against HIF-2-α prolyl hydroxylase. Thus, in some embodiments, the methods provided herein The compounds provided herein for use in the methods preferentially stimulate HIF-2-α over HIF-1-α. To determine preferential stabilization of HIF-2-α over HIF-1-α, test compounds were The concentrations of HIF-1-α and HIF-2-α in subjects with or without HIF-1-α and HIF-2-α were measured. It can be determined using an ELISA kit. The primary antibody in each kit cross-reacts with other HIFs. It should be noted that the primary antibody against HIF-1-α is not specific for HIF-1-α. Reacts immunospecifically with IF-1-α and does not cross-react with HIF-2-α; primary target for HIF-2-α The antibody reacts immunospecifically with HIF-2-α and does not cross-react with HIF-1-α).

[0106] In some embodiments, the inhibitor is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer. The compounds of the invention are heterocyclic carboxamides. In some such embodiments, , heterocyclic carboxamides include pyridyl carboxamides, quinoline carboxamides, and isoquinolinecarboxamides.

[0107] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer has the formula: I) or a pharmaceutically acceptable salt, solvate or hydrate thereof. be: [ka] (In the formula: R and R 1 are, each independently: (i) hydrogen, (ii) substituted or unsubstituted phenyl; or (iii) substituted or unsubstituted heteroaryl; The substitution is: (i) C1-C4 alkyl; (ii) C3-C4 cycloalkyl; (iii) C1-C4 alkoxy; (iv) C3-C4 cycloalkoxy; (v) C1-C4 haloalkyl; (vi) C3-C4 halocycloalkyl; (vii) halogens; (viii) cyano; (ix) NHC(O)R 4 ; (x)C(O)NR 5a R 5b and (xi) heteroaryl; or (xii) two substituents together form a fused ring having 5 to 7 atoms; R 4 is C1-C4 alkyl or C3-C4 cycloalkyl; R 5a and R 5b are, each independently: (i) Hydrogen; (ii) C1-C4 alkyl; (iii) C3-C4 cycloalkyl; or (iv)R 5a and R 5b together form a ring having 3 to 7 atoms; R 2 teeth, (i) OR 6 (ii)NR 7a R 7b and R 6 is selected from hydrogen and C1-C4 alkyl or C3-C4 cycloalkyl; R 7a and R 7b are, each independently: (i) Hydrogen; (ii) C1-C4 alkyl or C3-C4 cycloalkyl; or (iii)R 7a and R 7b together form a ring having 3 to 7 atoms; R 3 is selected from hydrogen, methyl, and ethyl; L is a group having the structure -[C(R 8a R 8b )] n - a concatenated unit having; R 8a and R 8b are each independently selected from hydrogen, methyl, and ethyl; n is an integer from 1 to 3; and R 9 is selected from hydrogen and methyl.

[0108] In some more specific embodiments, R and R in Formula (I) 1 are both hydrogen That doesn't mean there is.

[0109] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer has the formula: II) or a pharmaceutically acceptable salt, solvate or hydrate thereof. is: [ka] (In the formula: A is CR', N, N + -O - , and N + (C1-C6 alkyl); R' is H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloa alkenyl, C2-C6 alkynyl, C4-C7 heterocycloalkyl, C6-C 10 Aryl, C5-C 10 Haitai aryl, NH2, NHR”, N(R”)2, NHC(O)R”, NR”C(O)R”, F, Cl, Br, I, OH, OR” , SH, SR”, S(O)R”, S(O)2R”, S(O)NHR”, S(O)2NHR”, S(O)NR”2, S(O)2NR”2, C(O )R”, CO2H, CO2R”, C(O)NH2, C(O)NHR”, C(O)NR”2, CN, CH2CN, CF3, CHF2, CH2F, N selected from the group consisting of H(CN), N(CN), CH(CN), C(CN); and R" is C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 heterocycloalkyl, C6-C 10 Aryl and C5-C 10 heteroaryl; and wherein C1 -C6 alkyl, C3-C6 cycloalkyl, or C4-C7 heterocycloalkyl is oxo, NH2, NHR”, N(R”)2, F, Cl, Br, I, OH, OR”, SH, SR”, S(O)R”, S(O)2R”, S(O)NHR”, S(O)2NHR”, S(O)NR”2, S(O)2NR”2, C(O)R”, CO2H, CO2R”, C(O)NH2, C(O)NHR”, C( O)NR”2, CN, CH2CN, CF3, CHF2, CH2F, NH(CN), N(CN)2, CH(CN)2, C(CN)3 and wherein C6-C 10 Aryl or C5-C 10 Heteroaryl is C1-C6 alkyl , C3-C6 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, C4-C7 heterocycloalkyl, C6 aryl, C5-C6 heteroaryl, NH2, NHR”, N(R”)2 , NHC(O)R”, NR”C(O)R”, F, Cl, Br, I, OH, OR”, SH, SR”, S(O)R”, S(O)2R”, S (O)NHR”, S(O)2NHR”, S(O)NR”2, S(O)2NR”2, C(O)R”, CO2H, CO2R”, C(O)NH2, C(O )NHR”, C(O)NR”2, CN, CH2CN, CF3, CHF2, CH2F, NH(CN), N(CN)2, CH(CN)2, or C(CN and wherein the two R groups on the nitrogen together form a group of carbon atoms 2 to 7. and a nitrogen atom having two R" groups attached thereto, forming a ring having 1 to 3 selected heteroatoms; R 2 teeth, (i) OR 6 (ii)NR 7a R 7b and R 6 is selected from hydrogen and C1-C4 alkyl or C3-C4 cycloalkyl; R 7a and R 7b are, each independently: (i) Hydrogen; (ii) C1-C4 alkyl or C3-C4 cycloalkyl; or (iii)R 7a and R 7b together form a ring with 3 to 7 atoms.

[0110] In some embodiments, the HIF stabilizer is a compound having the structure of Formula (III): and pharmaceutically acceptable salts, solvates or hydrates of: [ka] (In the formula: R is: (i)-OR 1 or (ii)-NR 2 R 3 or (iii)-OM 1 : is selected from, R 1 teeth; (i) hydrogen; or (ii) C1-C6 alkyl or C3-C6 cycloalkyl; R 2 and R 3 are, each independently: (i) Hydrogen; (ii) C1-C4 alkyl or C3-C4 cycloalkyl; or (iii)R 2 and R 3 together with 2 to 7 carbon atoms and R 2 and R 3 is bonded a ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, including a nitrogen atom; can be formed; and M 1 is a cation; and R 4 teeth: (i) —OH; or (ii) -OM 2 and M 2 is a positive ion.

[0111] In some embodiments, the HIF stabilizer is a compound having the structure of Formula (IV): and pharmaceutically acceptable salts, solvates or hydrates of: [ka] (In the formula: R is: (i)-OR 1 or (ii)-NR 2 R 3 or (iii)-OM 1 : is selected from, R 1 teeth; (i) hydrogen; or (ii) C1-C6 alkyl or C3-C6 cycloalkyl; R 2 and R 3 are, each independently: (i) Hydrogen; (ii) C1-C4 alkyl or C3-C4 cycloalkyl; or (iii)R 2 and R 3 together with 2 to 7 carbon atoms and R 2 and R 3 is bonded a ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, including a nitrogen atom can be formed; and M 1 is a cation; and R 4 teeth: (i) —OH; or (ii) -OM 2 and M 2 is a positive ion.

[0112] The HIF prolyl hydroxylase inhibitor compounds described herein have the structure shown in formula (V): Unsubstituted or substituted 3-hydroxy-pyridine-2-carboxamides and pharmaceutical compositions thereof and acceptable salts and tautomers thereof as: 1-6 alkyl; and where R 1 and R 2 are independently H or C 1-6 It is alkyl.) [ka] .

[0113] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is -(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (Compound 1), or and pharmaceutically acceptable salts, solvates or hydrates thereof: [ka] .

[0114] In some embodiments, the HIF stabilizer is Compound 2, having the structure: and the like, as acceptable salts, solvates or hydrates thereof: [ka] .

[0115] In some embodiments, the HIF stabilizer is Compound 3, having the structure: and the like, as acceptable salts, solvates or hydrates thereof: [ka] .

[0116] In some embodiments, the HIF stabilizer is Compound 4, having the structure: and the like, as acceptable salts, solvates or hydrates thereof: [ka] .

[0117] In some embodiments, the HIF stabilizer is Compound 5, having the structure: and the like, as acceptable salts, solvates or hydrates thereof: [ka] .

[0118] In some embodiments, the HIF stabilizer is Compound 6, having the structure: and the like, as acceptable salts, solvates or hydrates thereof: [ka] .

[0119] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 7 has the following structure: : [ka] .

[0120] In some embodiments, the HIF stabilizer is Compound 8, having the structure: and the like, as acceptable salts, solvates or hydrates thereof: [ka] .

[0121] In some embodiments, the HIF stabilizer is Compound 9, having the structure: and the like, as acceptable salts, solvates or hydrates thereof: [ka] .

[0122] In some embodiments, the HIF stabilizer is Compound 10, having the structure: A pharmaceutically acceptable salt, solvate or hydrate of: [ka] .

[0123] In some embodiments, the HIF stabilizer is Compound 11, having the structure: A pharmaceutically acceptable salt, solvate or hydrate of: [ka] .

[0124] In some embodiments, the HIF stabilizer is Compound 12, having the structure: A pharmaceutically acceptable salt, solvate or hydrate of: [ka] .

[0125] In some embodiments, the HIF stabilizer is designated N-(2-aminoethyl)-3-hydroxy- Compound 13 has the following structure and has pyridine-2-carboxamide, and its pharmaceutical use is and its acceptable salts and tautomers: [ka] . Tautomers of compound 13 include: [ka] .

[0126] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, or Compound 13. Metabolites of the compounds isolated can be used in the methods provided herein. In more specific embodiments, such metabolites are phenolic glucuronides or acyl It is a glucuronide. [ka]

[0127] Compound 13 was prepared according to the Chinese Patent Application Publication No. CN 85107182 A, published on April 8, 1987, and This includes the method provided in German Patent Application Publication No. DE 3530046 A1, published March 13, 1986. Each of these can be prepared using reagents and methods known in the art. The entire contents of this application are incorporated herein by reference.

[0128] 5.3 Treatment and Prevention Methods In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or an effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer, such as a hydrate thereof, is administered to a subject in need of treatment with anemia. wherein the daily dose comprises administering to a patient having the compounds, their pharmaceutically acceptable salts, The amount of a salt, solvate, or hydrate that can be obtained by the method of the present invention is about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 1 50mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, Approx. 330mg, approx. 340mg, approx. 350mg, approx. 360mg, approx. 370mg, approx. 380mg, approx. 390mg, approx. 400mg, approx. 410mg , about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 600 mg, or about 750 mg, secondary to chronic kidney disease Provided herein are methods for treating and / or preventing anemia, including anemia caused by steroids. In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such a daily dose may be administered orally once a day, twice a day, or three times a day, preferably once a day. In some embodiments, the daily dose is 2 mg / kg, 2.1 mg / kg, 2.2 mg / kg, or g, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3mg / kg , 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg In some embodiments, the HIF-α stabilizer is at a concentration of 1000 mg / kg, 3.9 mg / kg, or 4 mg / kg. A hydroxylase inhibitor is administered at a daily dose of approximately 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg. g, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 33 0mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 4 20 mg, about 430 mg, about 440 mg, about 450 mg, about 600 mg, or about 750 mg of the present compound, their pharmaceuticals, and and administering the compound in the form of a salt, solvate, or hydrate thereof, which is acceptable to the patient. A compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VII) or formula (VII) for use in a method for treating anemia, such as anemia. (IV) or a compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4 , Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Chemical a compound selected from Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt thereof; HIF prolyl hydroxylase inhibitors or HIF-α, such as salts, solvates, or hydrates that can Stabilizers are provided herein. In some such embodiments, the daily dose is , about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered once a day, twice a day, Alternatively, it can be administered orally three times a day, preferably once a day. The daily doses are 2mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, and 2.6mg. / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg g, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, or 4 mg / kg. In one embodiment, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylate] In some embodiments, the compound is {[5-(3-chloro- Pharmaceutically acceptable 3-hydroxyphenyl-3-hydroxypyridine-2-carbonylamino}acetic acid In some embodiments, the compound is a salt of {[5-(3-chlorophenyl)-3-hydroxybenzoate]. In some embodiments, the compound is a solvate of 2-hydroxypyridine-2-carbonylamino}acetic acid. In this case, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amine In some embodiments, the compound is 2-(5-(3-fluoro-2-methyl-2-propanol)-2-one. In some embodiments, the compound is phenyl-3-hydroxypicolinamido)acetic acid. The compound is a pharmaceutical compound of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In some embodiments, the compound is 2-(5-(3-fluorophenyl)-2-methyl-2-propanol, or an acceptable salt thereof. In some embodiments, the compound is a solvate of (3-hydroxypicolinamido)acetic acid. This compound is a hydrate of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. It is a thing.

[0129] In some such embodiments, the daily dose is The compound contains about 150 mg, about 300 mg, about 450 mg, or about 600 mg of a salt, solvate, or hydrate thereof. In some embodiments, the daily dose comprises about 150 mg. In some embodiments, the daily dose comprises about 300 mg. In some embodiments, the daily dose comprises about 450 mg. In an embodiment, the daily dose comprises about 600 mg.

[0130] In some embodiments, the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease. In some such embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. In some embodiments, the patient has previously received treatment for anemia, such as anemia secondary to chronic kidney disease. In some alternative embodiments, the patient has not previously undergone treatment with steroids secondary to chronic kidney disease. In some embodiments, the patient is being treated for anemia, such as anemia associated with steroid therapy. It is refractory to treatment with recombinant erythropoietin.

[0131] In some embodiments, the daily dose is administered continuously. In this case, the daily dose may be increased by more than 42 consecutive days or even more than 90 consecutive days. In some alternative embodiments, the daily dose is administered for at least one week and for a maximum of one week. It may be administered for as long as 30 consecutive days, up to 35 consecutive days, or even up to 40 consecutive days. In some embodiments, the daily dose is administered orally once daily. In some embodiments, the daily dose is administered orally as divided doses administered twice daily. In an embodiment, the daily dose is administered at a particular time during the day. In a specific embodiment, the patient is receiving chronic If you have renal disease and the compound (see section 5.2) is administered at the same time during the day, specifically in the late morning, early afternoon, more specifically just before lunch, just after lunch, between lunch and 2 p.m., Between 10:00 AM and 2:00 PM, 10:00 AM, 11:00 AM, 12:00 PM, 1:00 PM, or 2:00 PM do.

[0132] In some embodiments, the patient's hemoglobin level is between 8.0 g / dL and about 13.0 g / dL. or less, at least about 8.5 g / dL and at least about 13.0 g / dL, at least about 9.0 g / dL and at least about 13.0 g / dL or less, at least about 9.5 g / dL and no more than 13.0 g / dL, or at least about 10.0 g / dL and no more than about 13.0 g / dL. In some such embodiments, the hemoglobin level is maintained at or below 1 / dL. The blood glucose level is maintained at a level of at least about 11.0 g / dL and no greater than about 13.0 g / dL. In certain embodiments, the hemoglobin level is at least about 11.0 g / dL and no more than about 12.0 g / dL. In some embodiments, these values are maintained at a level of Adjustments are made for patient sex and age.

[0133] In some embodiments, administration of a compound provided herein (see Section 5.2) The administration of acetaminophen results in an increase in hemoglobin levels, with a small increase compared to baseline hemoglobin levels. at least about 0.1 g / dL, at least about 0.2 g / dL, at least about 0.3 g / dL, at least about 0.4 g / dL , at least about 0.5 g / dL, at least about 0.6 g / dL, at least about 0.7 g / dL, at least about 0.8 g / dL, at least about 0.9 g / dL, at least about 1.0 g / dL, at least about 1.1 g / dL, at least by about 1.2 g / dL, at least about 1.3 g / dL, at least about 1.4 g / dL, or at least about 1.5 g / dL Increase.

[0134] In some embodiments, the compound is administered, optionally in combination with other pharmaceutical agents. In some such embodiments, the other pharmaceutical agent is ferrous sulfate, ferrous gluconate, or is an iron supplement, such as ferrous fumarate, which is administered for at least 2 hours after administration of the compound. In some embodiments, the iron supplement can be administered at a dose of about It is administered in an amount to maintain a level between 50 ng / mL and about 300 ng / mL. In some embodiments, the iron supplement is administered orally at a daily dose of about 50 mg of elemental iron. In some alternative embodiments, iron supplements are administered as needed, whereas in others, iron supplements are administered as needed. In this setting, iron supplements are administered continuously and / or irregularly.

[0135] In some embodiments, the other pharmaceutical agent is an erythropoietin mimetic, such as an erythropoietin mimetic. In some embodiments, the other pharmaceutical agent is an epoetin alfa. rhEPO products such as pharmacokinetics, epoetin beta, darbepoetin, and peginesatide In some embodiments, the ESA is administered as a salvage therapy, whereas in some In an alternative embodiment, the ESA is administered continuously and / or irregularly.

[0136] In some such embodiments, the compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) ) or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6 , Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, Young or metabolite 2, or a pharmaceutically acceptable salt or solvate thereof The daily dose of the compound or hydrate is adjusted during the course of treatment. blood pressure, hematocrit, hemoglobin level, and / or red blood cell count. Depending on the results of these tests, the daily dose may be adjusted. In a more specific embodiment, the treatment is with the compounds, about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg of a pharmaceutically acceptable salt, solvate, or hydrate thereof, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210 mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg , 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 4 A daily dose of 40 mg or a daily dose of about 450 mg is used to start. The daily dose is subsequently increased by about 50 mg, 100 mg, 150 mg, or 200 mg. In embodiments, the daily dose is subsequently reduced by about 50 mg, 100 mg, 150 mg, or 200 mg. In some embodiments, the compound is Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound Compound 7, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0137] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or a hydrate of the compound to a patient suffering from anemia; and then again after a period of time, wherein the patient's hemoglobin level is measured. and hemoglobin levels are less than about 10.0 g / dL and the hemoglobin levels are higher than or the patient's hemoglobin level is decreased by less than about 0.5 g / dL compared to the level measured in the previous study; If the bottle level is less than about 10.0 g / dL and the hemoglobin level is measured at an earlier time or the patient's hemoglobin level is changed by a maximum of about 0.4 g / dL compared to the level measured. If the blood pressure is between about 10.0 and about 10.9 g / dL and the hemoglobin level is measured earlier, A decrease of less than about 0.5 g / dL compared to the established level; more than 150 mg above the daily dose administering a controlled daily dose of the compound to treat anemia, such as anemia secondary to chronic kidney disease, including: Methods for treating anemia are provided herein. In some embodiments, the The period is about 1 week to about 8 weeks, for example, about 2 weeks to about 7 weeks, about 3 weeks to about 6 weeks, or about 4 weeks. In a specific embodiment, the compound is Compound 1, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the compound is a salt, solvate, or hydrate thereof. Compound 7, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0138] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or a hydrate of the compound to a patient suffering from anemia; and then again after a period of time, wherein the patient's hemoglobin level is measured. and hemoglobin levels are less than about 10.0 g / dL and the hemoglobin levels are higher than or if the patient's hemoglobin level is increased by approximately 1.5 g / dL compared to the level measured previously; The hemoglobin level is between about 10.0 and about 10.9 g / dL, and the hemoglobin level is higher than the or hemoglobin increases by approximately 1.5 g / dL compared to the level measured between levels between about 11.0 and about 12.2 g / dL, and hemoglobin levels are higher in the early If the hemoglobin level is increased by about 1.0 to about 1.4 g / dL compared to the measured level; or levels between about 12.3 and about 12.9 g / dL, and hemoglobin levels are higher than decreased by up to about 0.4 g / dL or increased by up to about 0.4 g / dL compared to the level measured or the patient's hemoglobin level is between about 12.3 and about 12.9 g / dL. and the hemoglobin level is about 0.5 to about 0.9 times lower than the level measured at an earlier time point. g / dL; if the adjusted daily dose of the compound is increased by 150 mg less than the daily dose, The present disclosure provides a method for treating anemia, such as anemia secondary to chronic kidney disease, comprising administering: In some embodiments, the daily dose of the compound is about 450 mg. In some embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine]. lysine-2-carbonyl]amino}acetic acid. In some embodiments, the compound is { [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid as a medicine In some embodiments, the compound is {[5-(3-chlorophenyl)-2-methyl-2-propanol, ... It is a solvate of [(3-hydroxypyridine-2-carbonyl)amino]acetic acid. In embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbo In some embodiments, the compound is a hydrate of 2-(5-(3- In some embodiments, the compound is fluorophenyl-3-hydroxypicolinamido)acetic acid. The compound is a pharmaceutical compound of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In some embodiments, the compound is 2-(5-(3-fluoromethyl-2-methyl-2-phenylpropanol). A solvate of (3-hydroxyphenyl)-3-hydroxypicolinamido)acetic acid is also available. In this regard, the compound is 2-(5-(3-fluorophenyl)-3-hydroxypicolinamide)acetic acid. In some embodiments, the period is from about 1 week to about 8 weeks, e.g., For example, it is about 2 weeks to about 7 weeks, about 3 weeks to about 6 weeks, or about 4 weeks.

[0139] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or a hydrate of the compound to a patient suffering from anemia; and then again after a period of time, wherein the patient's hemoglobin level is measured. and the hemoglobin level is between about 11.0 and about 12.2 g / dL, and the hemoglobin level is If the level increases by more than about 1.5 g / dL compared to levels measured earlier; or Hemoglobin levels between about 12.3 and about 12.9 g / dL, and If the level is increased by about 1.0 to about 1.4 g / dL compared to the level measured in an earlier period; or The hemoglobin level in the subject is between about 12.3 and about 12.9 g / dL, and If the level is increased by more than about 1.5 g / dL compared to the level measured at an earlier time point; administering an adjusted daily dose of the compound 300 mg less than the daily dose of: Methods for treating anemia, such as anemia secondary to steroids, are provided herein. In some embodiments, the daily dose of the compound is about 450 mg. The compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. In some embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxybenzoyl] It is a pharmaceutically acceptable salt of 2-[2-pyridine-2-carbonyl]amino]acetic acid. In embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbo In some embodiments, the compound is a solvate of {[5-(3 1-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid hydrate. In some embodiments, the daily dose of the compound is about 450 mg. In this case, the compound is 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In some embodiments, the compound is 2-(5-(3-fluorophenyl)-3-hydrophenyl). In some embodiments, the compound is a pharmaceutically acceptable salt of hydroxypicolinamidoacetic acid. This compound is a solvent of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In some embodiments, the compound is 2-(5-(3-fluorophenyl)-3- In some embodiments, this stage is a hydrate of hydroxypicolinamido)acetic acid. The period is about 1 week to about 8 weeks, for example, about 2 weeks to about 7 weeks, about 3 weeks to about 6 weeks, or about 4 weeks. is.

[0140] In some embodiments, the present invention provides {[5-(3-chlorophenyl)-3-hydroxypyridine] a compound which is dimethyl-2-carbonylamino}acetic acid, or a pharmaceutically acceptable salt thereof, a solvent 2. Therapy for treating chronic kidney disease, comprising administering a daily dose of a solute or hydrate thereof to a patient with anemia. and a method for treating anemia, such as anemia secondary to steroids, wherein the daily dose is about 450 mg.

[0141] In some such embodiments, the daily dose is about 600 mg of the compound. In some embodiments, the daily dose is increased by about 150 mg to a daily dose of the compound. In some embodiments, the daily dose is reduced by about 150 mg, such that the daily dose is about 300 mg. is reduced by about 300 mg so that the daily dose of the compound is about 150 mg.

[0142] In some embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine] lysine-2-carbonyl]amino}acetic acid. In some embodiments, the compound is { [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid as a medicine In some embodiments, the compound is {[5-(3-chlorophenyl)-2-methyl-2-propanol, ... It is a solvate of [(3-hydroxypyridine-2-carbonyl)amino]acetic acid. In embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbo methylamino}acetic acid hydrate.

[0143] In some embodiments, the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease. In some such embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. In some embodiments, the patient has previously been treated for anemia, such as anemia secondary to chronic kidney disease. In some alternative embodiments, the patient has not previously undergone treatment with steroids secondary to chronic kidney disease. Being treated for anemia, such as anemia.

[0144] In some embodiments, the present invention provides {[5-(3-chlorophenyl)-3-hydroxypyridine] a compound which is dimethyl-2-carbonylamino}acetic acid, or a pharmaceutically acceptable salt thereof, a solvent Administering a daily dose of the compound to a patient suffering from anemia; measuring hemoglobin levels in the patient after administration and again after a period of time thereafter, The patient's hemoglobin level is between about 11.0 and about 12.2 g / dL, and is increased by more than about 1.5 g / dL compared to levels measured at an earlier time point; or the patient's hemoglobin level is between about 12.3 and about 12.9 g / dL, and If the level is increased by about 1.0 to about 1.4 g / dL compared to levels measured at an earlier time point; or or the patient's hemoglobin level is between about 12.3 and about 12.9 g / dL and Bottle levels are increased by approximately 1.5 g / dL compared to levels measured at earlier periods administering an adjusted daily dose of the compound that is 300 mg less than the daily dose, In some embodiments, the present invention relates to a method for treating anemia, such as anemia secondary to chronic kidney disease. In this case, the daily dose of the compound is about 450 mg.

[0145] 5.3.1 Circadian variation of serum erythropoietin A Phase I clinical trial in healthy adult males demonstrated that Compound 1, an inhibitor of HIF prolyl hydroxylase, While serum hemoglobin levels can be increased, serum EPO levels remain elevated at 24 hours after administration. Unexpectedly, the results showed that the blood pressure returned to near baseline levels within a short time. associated with reduced endogenous production of erythropoietin (EPO), such as anemia secondary to chronic kidney disease. or a disease or condition associated with a defect in endogenous hemoglobin production. a HIF prolyl hydroxylase inhibitor compound of the type disclosed herein in a patient mimicking the diurnal variation of serum EPO levels in healthy individuals through the administration of successive doses of and without significantly increasing the patient's baseline serum EPO level. It was subsequently discovered that it is possible to increase serum hemoglobin levels. This was a surprising result for a number of reasons. For example, the efficacy of the compound in such unhealthy patients Due to the fact that the half-life of the compound is approximately twice as long as that in healthy adult males, This result was surprising. Therefore, one skilled in the art would be able to assess the recovery of baseline EPO levels. takes significantly longer in patients with impaired kidneys, which may be due to long-term physiological EPO levels exceeding the normal range and the undesirable side effects typically associated with the administration of exogenous EPO. In addition, this result suggests that the kidney is This was surprising because it is the primary source of erythropoietin production in the liver. Therefore, those skilled in the art will be able to readily understand the nature of the present invention, particularly with respect to patients with diseases or conditions associated with impaired renal function. Administration of the compounds provided herein causes an increase in serum hemoglobin levels in patients, It also mimics the diurnal variation of serum EPO levels in healthy individuals and is consistent with the patient's baseline serum EPO Such surprising results are unexpected because they are not accompanied by elevated levels of ATP in healthy individuals. This mimics the diurnal variation of serum EPO levels in the circadian rhythm and also measures the baseline serum erythropoietin (EPO). The hemoglobin level was increased to baseline in patients without significantly increasing the ATP level. Compounds disclosed herein, such as Compound 1, are used to increase hemoglobin levels relative to normal hemoglobin levels. Sufficient consecutive doses of the compound are administered to treat anemia, such as anemia or anemia secondary to chronic kidney disease, Diseases or conditions associated with endogenous production of erythropoietin (EPO) or endogenous hemoglobin This allows for administration to patients with diseases or conditions associated with robin production.

[0146] In some embodiments, the medicament is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer. and administering to a subject a pharmaceutically effective amount of a compound selected from the group consisting of acetaminophen, ... and / or a method for treating anemia in a subject, the method being adapted to mimic the diurnal variation of rithropoietin. Provided herein are methods for preventing or preventing the use of the method provided herein. More specifically, Administration of a pharmaceutically effective amount of the compound increases the tracheal level of EPO mRNA and / or EPO protein. The levels were compared to pre-treatment trough levels of EPO mRNA and / or EPO protein, and / or or trough levels of EPO mRNA and / or EPO protein in subjects without anemia Compared to the or at most 50% increase, while at the same time increasing the peak serum EPO levels during the circadian cycle. at least 1% higher than the peak serum EPO level before treatment (or compared to healthy non-anemic subjects) 0%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75 %, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, or at least 150 In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF- The alpha stabilizer is a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V): or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0147] More specifically, a pharmaceutically effective amount is a dose that increases serum erythropoietin to baseline levels. This is suitable for mimicking the diurnal variation of serum erythropoietin without increasing it above 400kJ / day. wherein the baseline level is the diurnal EPO level in healthy volunteers without anemia. It's the baseline.

[0148] In some embodiments, a pharmaceutically effective amount is EPO tamoxifen administered over a 24 hour period. to increase EPO levels as measured by the area under the curve plotting protein levels , suitable. During this time, EPO protein levels are at their lowest diurnal levels (trough) The period of time is the "trough period"; during which EPO protein levels reach their highest diurnal The 12-hour period during which the level (peak) is the "peak period." Increase in EPO levels by at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% , 90%, or at least 95%, or 100% increase occurs during this peak period.

[0149] In some embodiments, the hemoglobin level in the patient is increased relative to the baseline hemoglobin level in the patient. While increasing serum EPO levels, it mimics the diurnal variation of serum EPO levels in healthy individuals. To mimic the effects of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers, sufficient continuous administration administering the dose to a patient having a disease or condition associated with reduced endogenous production of EPO. to treat diseases or conditions associated with decreased endogenous production of erythropoietin (EPO), including In some embodiments, methods are provided herein for the production of HIF prolyl hydroxylase. The enzyme inhibitor or HIF-α stabilizer is a compound represented by formula (I), formula (II), formula (III), formula (IV), or formula (V): Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or or a compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or In a specific embodiment, the HIF prolyl hydroxylase inhibitor or HIF- The alpha stabilizer is Compound 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In a specific embodiment, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound Compound 7 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In such embodiments, the cardiovascular side effects and thromboembolic events associated with the administration of exogenous EPO are The risk of

[0150] More specifically, diseases or conditions associated with reduced endogenous production of erythropoietin (EPO). Administration of the compounds provided herein to a subject with the condition results in increased levels of EPO mRNA and / or EPO protein. Trough levels of EPO protein were compared with pretreatment trough levels of EPO mRNA and / or EPO protein. levels of EPO mRNA and / or EPO protein in subjects without anemia Compared to the trough level of quality, it is only about 0%, at most 5%, 10%, 15%, 20%, 25%, 30%, 35% %, 40%, 45%, or at most 50% increase in EPO mR during the circadian cycle Peak EPO mRNA and / or EPO protein levels were compared with pre-treatment EPO mRNA and / or EPO protein levels. and / or EPO mRNA in subjects without anemia compared to peak protein levels. or at least 10%, 15%, 20%, 25%, 30% or more of the trough level of EPO protein %, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% The dose is increased by at least 100%.

[0151] More specifically, the pharmaceutically effective amount is a dose of erythropoietin (EPO) that is reduced by endogenous erythropoietin (EPO). In subjects with a disease or condition related to sex production, serum erythropoietin was elevated to a baseline level. mimicking the diurnal variation of serum erythropoietin without increasing it above the normal level wherein the baseline level is a value measured in healthy volunteers without anemia. In some such embodiments, the circadian cycle is mimicked. However, the amplitude of the diurnal variation of serum EPO levels is increased. Bell will be at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, Increased by 90%, or at least 95%, or 100%, but trough levels are not significantly is not increased.

[0152] In some such embodiments, serum EPO levels are measured by HIF prolyl hydroxylase inhibition. about 1 week, about 6 days, about 5 days, about 4 days, about 3 days of administration of the agent or HIF-α stabilizer dose, Recovery to near baseline levels within about 2 days, about 24 hours, about 18 hours, or about 12 hours do.

[0153] In some embodiments, the serum EPO level is about 5 mIU above the baseline level of EPO. / mL, about 4mIU / mL, about 3mIU / mL, about 2mIU / mL, or within about 1mIU / mL.

[0154] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. It increases by about 0.1 to about 1.0 g / dL over a one-week period compared to baseline. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.1 g / dL over a one week period.

[0155] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a two-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.1 g / dL over a two-week period.

[0156] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a 3-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.5 g / dL over a 3-week period.

[0157] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by approximately 0.1 to 1.0 g / dL over a 4-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.6 g / dL over a 4-week period.

[0158] In some embodiments, the disease or condition is anemia. In some embodiments, the anemia is secondary to chronic kidney disease (CKD). In embodiments, the chronic kidney disease is stage 3, 4, or 5 of chronic kidney disease. In an embodiment, the chronic kidney disease is pre-dialysis chronic kidney disease.

[0159] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is administered daily. In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α The stabilizer is administered orally.

[0160] In some embodiments, the hemoglobin level is determined by measuring the patient's baseline hemoglobin level. The use of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers increases the levels of HIF-α compared to the control group. A suitable number of consecutive doses are administered to patients with a disease or condition associated with reduced endogenous production of EPO. wherein at least one of the successive doses and the immediately preceding dose are administered to a subject. The period between doses of EPO is such that the serum EPO level in the patient is approximately the baseline serum EPO level. Endogenous production of reduced erythropoietin (EPO) for a period of time sufficient to allow the body to return to normal Methods for treating diseases or conditions associated with sex production are provided herein. In a more specific embodiment, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer has the formula: a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2; or Pharmaceutically acceptable salts, solvates, or hydrates thereof are also included. In embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 1 or its derivatives. A pharmaceutically acceptable salt, solvate, or hydrate. In this regard, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 7 or its pharmaceutically acceptable salts. In some such embodiments, the compound is an acceptable salt, solvate, or hydrate. The risk of cardiovascular side effects and thromboembolic events associated with the administration of endogenous EPO is minimized. .

[0161] In some such embodiments, serum EPO levels are measured by HIF prolyl hydroxylase inhibition. about 1 week, about 6 days, about 5 days, about 4 days, about 3 days of administration of the agent or HIF-α stabilizer dose, Recovery to near baseline levels within about 2 days, about 24 hours, about 18 hours, or about 12 hours do.

[0162] In some embodiments, the serum EPO level is about 5 mIU above the baseline level of EPO. / mL, about 4mIU / mL, about 3mIU / mL, about 2mIU / mL, or within about 1mIU / mL.

[0163] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. It increases by about 0.1 to about 1.0 g / dL over a one-week period compared to baseline. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.1 g / dL over a one week period.

[0164] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a two-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.1 g / dL over a two-week period.

[0165] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a 3-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.5 g / dL over a 3-week period.

[0166] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by approximately 0.1 to 1.0 g / dL over a 4-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.6 g / dL over a 4-week period.

[0167] In some embodiments, the disease or condition is anemia. In some embodiments, the anemia is secondary to chronic kidney disease (CKD). In embodiments, the chronic kidney disease is stage 3, 4, or 5 of chronic kidney disease. In an embodiment, the chronic kidney disease is pre-dialysis chronic kidney disease.

[0168] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is administered daily. In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α The stabilizer is administered orally.

[0169] In some embodiments, the hemoglobin level is determined by measuring the patient's baseline hemoglobin level. The use of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers increases the levels of HIF-α compared to the control group. A suitable number of consecutive doses are administered to patients with a disease or condition associated with reduced endogenous production of EPO. wherein prior to one or more additional doses after the initial dose, serum EPO The level of erythropoietin (EPO) is reduced and the endogenous level of erythropoietin (EPO) is restored to approximately baseline levels. Methods for treating diseases or conditions associated with sex production are provided herein. In a more specific embodiment, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer has the formula: a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2; or and pharmaceutically acceptable salts, solvates, or hydrates thereof. In embodiments, the compound is Compound 1. In some specific embodiments, The compound is Compound 7. In some such embodiments, administration of exogenous EPO The risk of associated cardiovascular side effects and thromboembolic events is minimized.

[0170] In some such embodiments, serum EPO levels are measured by HIF prolyl hydroxylase inhibition. about 1 week, about 6 days, about 5 days, about 4 days, about 3 days of administration of the agent or HIF-α stabilizer dose, Recovery to near baseline levels within about 2 days, about 24 hours, about 18 hours, or about 12 hours do.

[0171] In some embodiments, the serum EPO level is about 5 mIU above the baseline level of EPO. / mL, about 4mIU / mL, about 3mIU / mL, about 2mIU / mL, or within about 1mIU / mL.

[0172] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. It increases by about 0.1 to about 1.0 g / dL over a one-week period compared to baseline. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.1 g / dL over a one week period.

[0173] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a two-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.1 g / dL over a two-week period.

[0174] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a 3-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.5 g / dL over a 3-week period.

[0175] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by approximately 0.1 to 1.0 g / dL over a 4-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.6 g / dL over a 4-week period.

[0176] In some embodiments, the disease or condition is anemia. In some embodiments, the anemia is secondary to chronic kidney disease (CKD). In embodiments, the chronic kidney disease is stage 3, 4, or 5 of chronic kidney disease. In an embodiment, the chronic kidney disease is pre-dialysis chronic kidney disease.

[0177] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is administered daily. In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α The stabilizer is administered orally.

[0178] In some embodiments, the level of serum EPO is compared to the baseline level of serum EPO. Hemoglobin levels were increased to the patient's baseline hemoglobin level without significant increase. A sufficient number of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers were administered to increase the to a patient having a disease or condition associated with reduced endogenous production of EPO. wherein the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound of formula (I), (II), a compound having the structure of formula (III), formula (IV), or formula (V), or compound 1, compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 1 Compound 1, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or any of them. a pharmaceutically acceptable salt, solvate, or hydrate of Provided herein are methods for treating diseases or conditions associated with the endogenous production of erythropoietin (EPO). In a specific embodiment, the compound is Compound 1, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the compound is a salt, solvate, or hydrate of Compound 7. or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the cardiovascular side effects and thromboembolic events associated with the administration of exogenous EPO are reduced. The risk is minimized.

[0179] In some such embodiments, serum EPO levels are measured by HIF prolyl hydroxylase inhibition. about 1 week, about 6 days, about 5 days, about 4 days, about 3 days of administration of the agent or HIF-α stabilizer dose, Recovery to near baseline levels within about 2 days, about 24 hours, about 18 hours, or about 12 hours do.

[0180] In some embodiments, the serum EPO level is about 5 mIU above the baseline level of EPO. / mL, about 4mIU / mL, about 3mIU / mL, about 2mIU / mL, or within about 1mIU / mL.

[0181] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. It increases by about 0.1 to about 1.0 g / dL over a one-week period compared to baseline. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.1 g / dL over a one week period.

[0182] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a two-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.1 g / dL over a two-week period.

[0183] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a 3-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.5 g / dL over a 3-week period.

[0184] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by approximately 0.1 to 1.0 g / dL over a 4-week period. In some embodiments, the level of hemoglobin is measured relative to the baseline hemoglobin level. , elevated by approximately 0.6 g / dL over a 4-week period.

[0185] In some embodiments, the disease or condition is anemia. In some embodiments, the anemia is secondary to chronic kidney disease (CKD). In embodiments, the chronic kidney disease is stage 3, 4, or 5 of chronic kidney disease. In an embodiment, the chronic kidney disease is pre-dialysis chronic kidney disease.

[0186] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is administered daily. In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α The stabilizer is administered orally.

[0187] In normal, healthy adults, there is an increase in serum levels of EPO, which then rises above baseline Normal diurnal variation in serum levels of erythropoietin (EPO) with recovery to serum EPO levels That is, EPO is detectable in serum and has the highest levels in the afternoon. and then recover to a baseline level that varies between individuals, resulting in a well-characterized rhythm It shows fluctuations over a 24-hour period, accompanied by

[0188] Serum EPO levels can be measured, for example, by in vivo bioassays, in vitro bioassays, and It can be determined using an immunological assay. The serum EPO levels described herein are determined using an immunological assay, such as an ELISA assay. do.

[0189] Serum hemoglobin levels are determined, for example, by lysing red blood cells and administering potassium ferricyanide. However, it oxidizes hemoglobin to methemoglobin, which combines with potassium cyanide to form cyanide. This can be determined using a standard CBC. The color is measured spectrophotometrically and the corresponding hemoglobin is reported.

[0190] In some embodiments, the hemoglobin level is determined by measuring the patient's baseline hemoglobin level. While elevated compared to serum EPO levels, it mimics the diurnal variation of serum EPO levels in healthy individuals. To achieve this, sufficient consecutive doses of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers are administered. to a patient having a disease or condition associated with reduced endogenous production of EPO. , a disease or condition associated with reduced endogenous production of erythropoietin (EPO), or reduced Provided herein are methods for treating diseases or conditions associated with hemoglobin production. In some such embodiments, the cardiovascular side effects and side effects associated with the administration of exogenous EPO are reduced. Reduced endogenous production of erythropoietin (EPO) while minimizing the risk of thromboembolic events or a disease or condition associated with reduced hemoglobin production In a specific embodiment, the compound is 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In this manner, the compound is Compound 7, or a pharmaceutically acceptable salt, solvate, or Mostly hydrates.

[0191] In some embodiments, the hemoglobin level is determined by measuring the patient's baseline hemoglobin level. The use of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers increases the levels of HIF-α compared to the control group. A suitable number of consecutive doses are administered to patients with a disease or condition associated with reduced endogenous production of EPO. wherein at least one of the successive doses and the immediately preceding dose are administered to a subject. The period between doses restores the patient's serum EPO levels to approximately baseline serum EPO levels. Reduced endogenous production of erythropoietin (EPO) for a period sufficient to allow or a disease or condition associated with reduced hemoglobin production. In some such embodiments, methods of treating exogenous factors are provided herein. The aim of this study was to reduce, while minimizing, the risk of cardiovascular side effects and thromboembolic events associated with the administration of oral EPO. Diseases or conditions associated with decreased endogenous production of erythropoietin (EPO) or decreased hemoglobin Provided herein are methods for treating diseases or conditions associated with the production of globin. In a specific embodiment, the compound is Compound 1, or a pharmaceutically acceptable salt, dissolution medium, or a pharmaceutically acceptable salt thereof. In a specific embodiment, the compound is Compound 7, or It is a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0192] In some embodiments, the hemoglobin level is determined by measuring the patient's baseline hemoglobin level. The use of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers increases the levels of HIF-α compared to the control group. A suitable number of consecutive doses are administered to patients with a disease or condition associated with reduced endogenous production of EPO. and administering to a subject, prior to one or more additional doses after the initial dose, a serum EPO level Levels return to near baseline levels, and endogenous erythropoietin (EPO) levels are reduced. Diseases or conditions associated with decreased hemoglobin production In some such embodiments, methods for treating a condition include: While minimizing the risk of cardiovascular side effects and thromboembolic events associated with the administration of exogenous EPO , a disease or condition associated with reduced endogenous production of erythropoietin (EPO), or reduced Provided herein are methods for treating diseases or conditions associated with the production of hemoglobin. In a specific embodiment, the compound is Compound 1, or a pharmaceutically acceptable salt thereof. , solvate, or hydrate. In a specific embodiment, the compound is Compound 7, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0193] In some embodiments, the level of serum EPO is increased relative to the baseline level of serum EPO. The hemoglobin level was increased to the patient's baseline hemoglobin level without a significant increase in A sufficient number of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers were administered to increase the to a patient having a disease or condition associated with reduced endogenous production of EPO. Diseases or conditions associated with reduced endogenous production of erythropoietin (EPO), including administering The present disclosure provides methods for treating diseases or conditions associated with impaired hemoglobin production, including but not limited to, steroid therapy, steroid therapy, or reduced hemoglobin production. In some such embodiments, the administration of exogenous EPO is accompanied by Reduced erythropoietin while minimizing the risk of cardiovascular side effects and thromboembolic events Diseases or conditions associated with the endogenous production of EPO or with reduced hemoglobin production Provided herein are methods for treating a disease or condition. The compound is Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In a specific embodiment, the compound is Compound 7, or a pharmaceutically acceptable salt thereof. The compound is a salt, solvate, or hydrate thereof.

[0194] In some such embodiments, the cardiovascular side effects and side effects associated with the administration of exogenous EPO are reduced. Reduced endogenous production of erythropoietin (EPO) while minimizing the risk of thromboembolic events or a disease or condition associated with reduced hemoglobin production. Methods of treating the disease are provided herein.

[0195] In some embodiments, serum EPO levels are measured by administering a HIF prolyl hydroxylase inhibitor or Within 1 week, 6 days, 5 days, 4 days, 3 days, 2 days or more of administration of the HIF-α stabilizer Recovery to near baseline levels within 12 hours, 24 hours, 18 hours, or 12 hours .

[0196] In some embodiments, the serum EPO level is about 5 mIU above the baseline level of EPO. / mL, about 4mIU / mL, about 3mIU / mL, about 2mIU / mL, or within about 1mIU / mL.

[0197] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. Compared to the baseline, the difference is about 0.1 to about 1 over a period of about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks. .0g / dL, about 0.1 to about 0.9g / dL, about 0.1 to about 0.8g / dL, about 0.1 to about 0.7g / dL, about 0.1 to about 0.6g / dL, or by about 0.1 to about 0.5 g / dL. The level may be increased by about 1 week, about 2 weeks, about 3 weeks, or At least about 0.1 g / dL, about 0.2 g / dL, about 0.3 g / dL, about 0.4 g / dL over a period of time, such as about 4 weeks , about 0.5 g / dL, about 0.6 g / dL, about 0.7 g / dL, about 0.8 g / dL, about 0.9, or about 1.0 g / dL. .

[0198] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. In some embodiments, the blood glucose level is increased by about 0.1 g / dL over a one week period compared to the baseline. In this study, hemoglobin levels were significantly higher than baseline hemoglobin levels over a 2-week period. In some embodiments, the hemoglobin level is increased by about 0.1 g / dL over a period of time. Bell reported that his baseline hemoglobin levels increased by approximately 0.5 g / dL over a 3-week period. In some embodiments, the hemoglobin level is increased relative to baseline hemoglobin. Compared to globin levels, they are elevated by approximately 0.6 g / dL over a 4-week period.

[0199] In some embodiments, an effective amount of a compound disclosed herein, such as Compound 1, is administered to a patient in need thereof. and administering to a patient having EPO blood, wherein the diurnal pattern of EPO expression is as previously described. anemia (e.g., secondary to or associated with chronic kidney disease) that is mimicked in patients in response to said administration; anemia due to chronic heart disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplasia Syndrome, myelofibrosis, other aplastic or dysplastic anemia, chemotherapy-induced anemia ( including chemotherapy to treat cancer, hepatitis C, or other long-term drug therapy that reduces bone marrow production. anemia resulting from blood loss, anemia resulting from iron deficiency, anemia resulting from vitamin B12 deficiency Provided herein are methods for treating or preventing erythrocyte segregation syndrome (ESS), sickle cell disease, or thalassemia. In some embodiments, an effective amount of a compound disclosed herein, such as Compound 1, to a patient with anemia, wherein the diurnal pattern of EPO expression is anemia, such as anemia secondary to chronic kidney disease, that is mimicked in patients in response to the administration of Provided herein are methods for treating

[0200] In some embodiments, an effective amount of a compound disclosed herein, such as Compound 1, is administered to treat CKD. to treat anemia secondary to chronic kidney disease (CKD), including administering to patients with anemia secondary to Methods for treating or preventing the disease are provided herein. Such daily doses are administered orally, preferably In some embodiments, the daily dose is administered once daily. In some embodiments, the CKD is stage 1, 2, 3, 4, or 5 of chronic kidney disease. In some such embodiments, the CKD is stage 3, 4, or 5 of chronic kidney disease. In some embodiments, the CKD is stage 1 chronic kidney disease. In some embodiments, the CKD is stage 2 chronic kidney disease. In some embodiments, the CKD is stage 3 of chronic kidney disease. In some embodiments, the CKD is stage 5 chronic kidney disease. In some embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. Dialysis patients, and these patients are sometimes referred to as having end-stage renal disease (ESRD) In some such embodiments, anemia, such as anemia secondary to CKD or ESRD, is treated with epothecin. rhEPO, such as ethin alfa, epoetin beta, darbepoetin, or peginesatide In some embodiments, the patient may be refractory to treatment with erythropoiesis-stimulating agents, including the erythropoiesis-stimulating agent. In some alternative embodiments, the patient is previously treated for anemia. In this case, the patient has not been previously treated for anemia.

[0201] In some embodiments, the patient is a patient with chronic kidney disease. In a more specific embodiment, the patient does not have a circadian cycling expression pattern of endogenous EPO. In some embodiments, the compounds (i.e., compounds disclosed in Section 5.2) ) indicates that the normal and endogenous production of EPO is such that peak EPO expression occurs between 6 PM and midnight. The circadian pattern is administered in a way that mimics the normal (i.e., normal) circadian pattern. In embodiments, the compound is administered at a time such that the EPO peak occurs earlier than the cortisol peak. Specifically, the EPO peak occurs approximately 1 hour, 2 hours, 3 hours, or 4 hours after the cortisol peak. The administration may occur at a time such that the administration precedes the administration of the active ingredient by about 5 hours, about 6 hours, about 7 hours, or about 8 hours. In some embodiments, the cortisol peak is in the morning. The compound was administered at 8:00 AM, 9:00 AM, 10:00 AM, 11:00 AM, 12:00 PM, or is administered at 2:00 PM. In some embodiments, the compound is administered after breakfast. In some embodiments, the compound is administered at breakfast, 8:00 AM, 9:00 AM, 10:00 AM, 11:00 AM, 12:00 AM, 13:00 AM, 14:00 AM, 15:00 AM, 16:00 AM, 17:00 AM, 18:00 AM, 19:00 AM, 20:00 AM, 21:00 AM, 22:00 The dose is administered between 11:00 AM, 12:00 PM, 1:00 PM, or 2:00 PM. In some embodiments, the compound is administered before breakfast. In some embodiments, the compound is administered between lunch and dinner. In some embodiments, the compound is administered between lunch and 2:00 PM. In some embodiments, the compound is administered at or about the same time each day. In particular embodiments, the daily dose is 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, Approximately 160mg, approximately 170mg, approximately 180mg, approximately 190mg, approximately 200mg, approximately 210mg, approximately 220mg, approximately 230mg, approximately 240mg , about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330m g, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 600 mg, or about 750 mg taken at the same time between the morning and 2 p.m. The present disclosure provides a method for treating anemia in a subject with chronic kidney disease, wherein the method comprises administering a dose of 100 mg of acetaminophen daily at 200 mg / kg / day. This document provides:

[0202] (5.3.2 Total iron-binding capacity) A Phase 2a clinical trial is evaluating Compound 1, a HIF prolyl agonist, in patients with CKD stages 3, 4, or 5. Hydroxylase inhibitors increased TIBC levels after 6 weeks of treatment compared with placebo-treated patients Unexpectedly, the increase in TIBC levels was associated with an increase in serum iron levels. Furthermore, Compound 1 produced a dose-related increase in TIBC and a decrease in TSAT. It was also discovered that administration of Compound 1 resulted in enhanced iron mobilization. It suggests.

[0203] In some embodiments, the HIF prolyl hydroxylase enzymes disclosed herein A pharmaceutically effective amount of a HIF-α inhibitor or HIF-α stabilizer is administered to a subject in need thereof, the subject being treated with a medicament for treating ... and administering to a patient having a disease or condition characterized by a HIF prolyl hydroxylase inhibitor. A pharmaceutically effective amount of an agent or HIF-α stabilizer is one that increases the total iron binding capacity in a patient by at least 5 %, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% increase a disease or condition associated with reduced endogenous production of erythropoietin (EPO), suitable for In a more specific embodiment, methods for treating or preventing the condition are provided herein. A pharmaceutically effective amount is a dose that reduces the total iron binding capacity in a patient by at least 5%, 10%, 15%, 20%, or 30%. %, 25%, 30%, 35%, 40%, 45%, or at least 50% increase in total serum iron The level will not increase or will increase by at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, It is suitable to increase by 9%, 10%, 15%, 20%, or at most 25%. In embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (IV), Formula (V), Formula (VI), Formula (VII ... (III), a compound having the structure of formula (IV), or formula (V), or Compound 1, Compound 2, Compound 3 , compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound a compound selected from Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutical thereof; and the like. Specifically, HIF prolyl hydroxylates are also suitable salts, solvates, or hydrates thereof. The enzyme inhibitor or HIF-α stabilizer is Compound 1, or a pharmaceutically acceptable salt or solvate thereof. or a hydrate thereof. Specifically, a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer is compound 7, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0204] In some embodiments, the HIF prolyl hydroxylase enzymes disclosed herein A pharmaceutically effective amount of a HIF-α inhibitor or HIF-α stabilizer is administered to treat the disease by increasing the endogenous production of EPO. and administering to a patient having a disease or condition in which HIF prolyl hydroxylation is possible. A pharmaceutically effective amount of an enzyme inhibitor or HIF-α stabilizer reduces the total iron binding capacity in a patient by at least 100%. At least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% It is suitable for increasing endogenous erythropoietin (EPO) production. Methods for treating treatable diseases or conditions are provided herein. In embodiments, the pharmaceutically effective amount is sufficient to increase the total iron binding capacity in a patient by at least 5 %, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% increase whereas total serum iron levels either did not increase or decreased by at most 1%, 2%, 3%, 4%, 5%, or Suitable for increases of 6%, 7%, 8%, 9%, 10%, 15%, 20%, or at most 25% In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer , a compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or compound 1 , compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. The HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 1, or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a salt, solvate, or hydrate of a HIF prolyl hydroxylase inhibitor. Alternatively, the HIF-α stabilizer is Compound 7, or a pharmaceutically acceptable salt, solvate, or It is a hydrate.

[0205] In some embodiments, the HIF prolyl hydroxylase enzymes disclosed herein and administering a pharmaceutically effective amount of a HIF-α inhibitor or HIF-α stabilizer to a patient suffering from anemia. wherein a pharmaceutically effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer comprises Increase the total iron-binding capacity of patients to at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, %, 45%, or at least 50%. In a more specific embodiment, the medicament is The effective dose for each agent is to increase the total iron-binding capacity in a patient by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, Total serum iron levels increase by 0%, 35%, 40%, 45%, or at least 50%. No increase or at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% It is suitable to increase the ion exchange rate by 15%, 20%, or at most 25%. The HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VII). IV), or a compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound a compound selected from Metabolite 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt thereof; Specifically, the present invention relates to a salt, solvate, or hydrate of a HIF prolyl hydroxylase inhibitor. Alternatively, the HIF-α stabilizer may be Compound 1, or a pharmaceutically acceptable salt, solvate, or Specifically, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 7. or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0206] In some embodiments, the anemia is, for example, anemia secondary to or associated with chronic kidney disease, chronic kidney disease, Anemia secondary to cardiac disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplastic syndrome, bone Myelofibrosis, other aplastic or dysplastic anemias, chemotherapy-induced anemia (cancer, hepatitis C, etc.) chemotherapy to treat bone marrow disorders, or other long-term medications that reduce bone marrow production), blood loss anemia resulting from iron deficiency, anemia resulting from vitamin B12 deficiency, sickle cell disease Hemocytosis or thalassemia.

[0207] In some more specific embodiments, the anemia is anemia secondary to chronic kidney disease (CKD). and the daily dose of the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is administered orally, preferably In some embodiments, the daily dose is administered once daily. In some embodiments, the CKD is stage 1, 2, 3, 4, or 5 chronic kidney disease. In some such embodiments, the CKD is stage 3, 4, or 5 chronic kidney disease. In some embodiments, the CKD is stage 1 chronic kidney disease. In some embodiments, the CKD is stage 2 chronic kidney disease. The CKD is stage 3 of the disease. In some embodiments, the CKD is stage 4 of chronic kidney disease. In some embodiments, the CKD is stage 5 chronic kidney disease. In some embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. Some are dialysis patients, and these patients are said to have end-stage renal disease (ESRD). In some such embodiments, anemia, such as anemia secondary to CKD or ESRD, is treated with epoetin. rhEPO products such as alpha, epoetin beta, darbepoetin, or peginesatide In some embodiments, the patient may be refractory to treatment with erythropoiesis-stimulating agents, including In some alternative embodiments, the patient has previously been treated for anemia. In this case, the patient has not been previously treated for anemia.

[0208] In some embodiments, the disease or condition associated with decreased endogenous EPO production is In some embodiments, the anemia is anemia secondary to chronic kidney disease. Diseases or conditions that can be treated by increasing O production include anemia secondary to chronic kidney disease. is anemia.

[0209] In some embodiments, the HIF prolyl hydroxylase enzymes disclosed herein A pharmaceutically effective amount of a HIF-α inhibitor or HIF-α stabilizer is administered to a subject with reduced endogenous hemoglobin production. wherein the HIF prolyl hydroxylase is administered to a patient having a disease or condition associated with A pharmaceutically effective amount of an enzyme inhibitor or HIF-α stabilizer reduces the total iron binding capacity in a patient by at least 100%. At least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% associated with reduced endogenous hemoglobin production in patients suitable for increasing Methods for treating or preventing a disease or condition are provided herein. In such cases, the pharmaceutically effective amount is sufficient to increase the total iron binding capacity in a patient by at least 5%, 1 Increase by 0%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% On the other hand, total serum iron levels either did not increase or decreased by at most 1%, 2%, 3%, 4%, 5%, 6%, or 7%. Suitable for increases of 7%, 8%, 9%, 10%, 15%, 20%, or at most 25% In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer has the formula: a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2; or Pharmaceutically acceptable salts, solvates, or hydrates thereof. The prolyl hydroxylase inhibitor or HIF-α stabilizer may be Compound 1, or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a salt, solvate, or hydrate of a HIF prolyl hydroxylase inhibitor or The HIF-α stabilizer is Compound 7, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. It is a Japanese product.

[0210] In some embodiments, the HIF prolyl hydroxylase enzymes disclosed herein A pharmaceutically effective amount of a HIF-α inhibitor or HIF-α stabilizer is administered to increase endogenous hemoglobin production. to a patient having a disease or condition treatable by administering HIF A pharmaceutically effective amount of a prolyl hydroxylase inhibitor or HIF-α stabilizer is Binding capacity is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or less. By increasing endogenous hemoglobin production, which is suitable for increasing by at least 50% Provided herein are methods for treating diseases or conditions treatable by the method. In one embodiment, the pharmaceutically effective amount is sufficient to increase the total iron binding capacity in a patient by at least Increase by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% While the total serum iron level does not increase or increases by at most 1%, 2%, 3%, or 4% , 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or at most 25% increase. In some embodiments, a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizing agent is The agent is a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a chemical Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof. The HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 1, or a pharmaceutical thereof. and acceptable salts, solvates, or hydrates thereof. Specifically, HIF prolyl hydroxylases The inhibitor or HIF-α stabilizer is Compound 7, or a pharmaceutically acceptable salt, solvate, or or a hydrate.

[0211] In some embodiments, the present invention relates to a disease associated with reduced endogenous hemoglobin production or The condition is anemia, such as anemia secondary to chronic kidney disease. Diseases or conditions that can be treated by increasing endogenous hemoglobin production include chronic Anemia, such as anemia secondary to renal disease.

[0212] In some embodiments, serum iron is measured using a method based on the Ferrozine method without deproteinization. The specimens were analyzed using Roche Diagnostics Reagents. Analyzed on a Roche Modular Instrument. Under acidic conditions, iron is released from transferrin. Detergents clarify lipid samples. Ascorbate is released. The reacted Fe3+ ions are reduced to Fe2+ ions, which then react with ferrozine to form a colored complex. The intensity of this color is directly proportional to the iron concentration and can be measured photometrically. do.

[0213] In some embodiments, the unsaturated iron-binding capacity (UIBC) is the available iron on transferrin. Alkaline buffer / reducing agent containing a known concentration of iron to saturate available binding sites This can be determined by adding serum to the solution. 2 +; consequently, to ensure that all iron is present in the ferrous state, An iron reducing agent is added. Excess unbound divalent iron reacts with the ferrozine chromogen to form magenta. The unsaturated iron-binding capacity (UIBC) is the iron-binding capacity of the iron-containing iron complexes added to the iron-containing iron complexes, which is measured spectrophotometrically. Serum TIBC is equal to the measured difference between the iron solution concentration and the excess unbound iron concentration. Serum TIBC is the sum of total serum iron + UIBC. and consequently the results of the UIBC and serum iron determination can be used to calculate:

[0214] Total iron binding capacity (TIBC) is a measure of the blood's ability to bind iron to transferrin. performed by drawing blood and measuring the maximum amount of iron the blood can carry Therefore, TIBCs have two binding sites for transporting iron from iron stores to erythroid precursor cells. This represents the amount of circulating transferrin contained in the blood.

[0215] Serum iron level measurements determine how much iron is present in the blood plasma. The amount of iron absorbed depends on the ability to mobilize iron stored in cells. The oxidative process involves the interaction of ferroportin with erythropoietin, which works together to regulate the amount of iron transported into the plasma. It is regulated by hepcidin. Ferroportin moves iron in and out of cells, while Hepcidin regulates the action of ferroportin, thereby releasing iron into the plasma or determines whether iron is retained within the cell. Although it is possible that serum iron levels are influenced by the activity of ferroportin and hepcidin, The bell is relatively low.

[0216] In some embodiments, a significant increase in serum iron levels compared to baseline HIF prolyl hydroxylase inhibitors were used to increase TIBC compared to baseline TIBC in patients without HIF prolyl hydroxylase inhibitors. Sufficient continuous doses of enzyme inhibitors or HIF-α stabilizers are administered to reduce the endogenous production of EPO. and administering to patients with a disease or condition associated with reduced erythropoietin production. Provided herein are methods for treating diseases or conditions associated with the endogenous production of erythropoietin (EPO). In some such embodiments, the cardiovascular system associated with increased serum iron levels associated with reduced endogenous production of EPO while minimizing the risk of side effects and thromboembolic events Methods for treating a disease or condition are provided herein. Some such embodiments In the above, the disease or condition is anemia, such as anemia secondary to chronic kidney disease.

[0217] In some embodiments, a significant increase in serum iron levels compared to baseline HIF prolyl hydroxylase inhibitors were used to increase TIBC compared to baseline TIBC in patients without HIF prolyl hydroxylase inhibitors. Sufficient consecutive doses of enzyme inhibitors or HIF-α stabilizers are administered to increase endogenous EPO production. Administration to patients with diseases or conditions associated with reduced endogenous production of EPO that are more treatable It can be treated by increasing endogenous erythropoietin (EPO) production, including administering Methods for treating certain diseases or conditions are provided herein. In embodiments, the risk of cardiovascular side effects and thromboembolic events associated with increased serum iron levels is reduced. Diseases or conditions that can be treated by increasing the endogenous production of EPO while minimizing the risk In some such embodiments, methods for treating a condition include: The disease or condition is anemia, such as anemia secondary to chronic kidney disease.

[0218] In some embodiments, the TIBC is increased by about 10 μg / dL, about 20 μg / dL, or about 30 μg / dL compared to baseline TIBC. g / dL, approx. 30 μg / dL, approx. 40 μg / dL, approx. 50 μg / dL, approx. 60 μg / dL, approx. 70 μg / dL, approx. 80 μg / dL, approx. In some embodiments, the TIBC increases by at least 90 μg / dL or about 100 μg / dL. All levels are approximately 10 μg / dL, at least approximately 20 μg / dL, at least approximately 30 μg / dL, and at least approximately 40 μg / dL. , at least about 50 μg / dL, at least about 60 μg / dL, at least about 70 μg / dL, at least about 80 μg / dL, at least about 90 μg / dL, or at least about 100 μg / dL. In an embodiment, the TIBC is between about 10 μg / dL and about 60 μg / dL, between about 10 μg / dL and about 50 μg / dL, or between about 10 μg / dL and about 60 μg / dL. g / dL to about 40 μg / dL, about 10 μg / dL to about 30 μg / dL, or about 10 μg / dL to about 20 μg / dL In some embodiments, the TIBC is between 20 μg / dL and about 60 μg / dL, between about 30 μg / dL and about 60 μg / dL. dL, 40 μg / dL to about 60 μg / dL, or about 50 μg / dL to about 60 μg / dL.

[0219] In some such embodiments, the increase in TIBC is greater than or equal to about 1 week after administration compared to baseline TIBC. The period may be about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks.

[0220] In some embodiments, the serum iron level is increased by about 100 mg / kg compared to the baseline serum iron level. An increase of less than 20 μg / dL, less than about 15 μg / dL, less than about 10 μg / dL, or less than about 5 μg / dL. In some embodiments, the serum iron level is between about 0 μg / dL and about 20 μg / dL, between about 0 μg / dL and about 15 μg / dL, μg / dL, about 0 μg / dL to about 10 μg / dL, or about 0 μg / dL to about 5 μg / dL.

[0221] (5.3.3 Hepcidin Levels) A Phase 2a clinical trial is evaluating Compound 1, a HIF prolyl esterase inhibitor, in patients with stages 3, 4, or 5 CKD. Hydroxylase inhibitors were associated with a significant improvement in schizophrenia compared to baseline and placebo-treated patients at 6 weeks post-treatment. Unexpectedly, it was shown that steroids can increase serum hemoglobin levels in This increase in hemoglobin levels is not associated with a decrease in hepcidin levels.

[0222] In some embodiments, the medicament is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer. to a patient having a disease or condition associated with decreased endogenous production of EPO. wherein a pharmaceutically effective amount is a HIF prolyl hydroxylase inhibitor or a HIF -Compared to hepcidin levels before administration of α-stabilizers, 1%, 2%, 3%, 4%, 5%, 6%, 7%, and 8% %, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or more on serum EPO trough levels without reducing serum hepcidin levels by more than 20% Compared to at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% ,65%,70%,75%,80%,85%,90%,95%,100%,110%,120%,130%,140%, or suitable for increasing the peak serum EPO level during the circadian cycle by at least 150%. to treat or prevent diseases or conditions associated with decreased endogenous production of erythropoietin (EPO). In some embodiments, a method for preventing HIF prolyl The hydroxylase inhibitor or HIF-α stabilizer is a compound represented by formula (I), formula (II), formula (III), formula (IV), or formula (V). ) or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6 , Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, Young or metabolite 2, or a pharmaceutically acceptable salt or solvate thereof or a hydrate thereof. Specifically, a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer is Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Specifically, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 7, or a combination thereof. In some embodiments, the compound is a suitably acceptable salt, solvate, or hydrate. Diseases or conditions associated with impaired endogenous EPO production include non-severe impoverishment secondary to chronic kidney disease. anemia, including non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging. .

[0223] In some embodiments, the medicament is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer. and administering an effective amount as a medicament for treating a disease or condition that is treatable by increasing the endogenous production of EPO. to a patient having HIF prolyl hydroxylation, wherein a pharmaceutically effective amount of Compared to hepcidin levels before administration of the enzyme inhibitor or HIF-α stabilizer, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 1 and serum EPO levels without decreasing serum hepcidin levels by more than 9% or 20%. At least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more of the trough level %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 1 Increase the peak serum EPO levels during the circadian cycle by 30%, 140%, or at least 150%. can be treated by increasing the endogenous production of erythropoietin (EPO), which is suitable for Provided herein are methods for treating or preventing a disease or condition in which In embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound represented by Formula (I), Formula (II), A compound having a structure of formula (III), formula (IV), or formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Chemical Compound 12, compound 13, metabolite 1, or metabolite 2, or a pharmaceutical composition thereof. Specifically, HIF prolyl hydroxylase is an acceptable salt, solvate, or hydrate thereof. The enzyme inhibitor or HIF-α stabilizer is Compound 1, or a pharmaceutically acceptable salt or solvate thereof. Specifically, the compound is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer. The agent is Compound 7, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, a disease or condition treatable by increasing endogenous EPO production is non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, and anemia such as idiopathic anemia of aging.

[0224] In some embodiments, the medicament is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer. to a patient having a disease or condition associated with endogenous hemoglobin production. wherein the pharmaceutically effective amount is a HIF prolyl hydroxylase inhibitor or a HIF- 1%, 2%, 3%, 4%, 5%, 6%, 7%, and 8% higher hepcidin levels compared to pre-administration of alpha stabilizers , 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or more without decreasing serum hepcidin levels by more than 0% to pre-treatment hepcidin levels Compared to at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, Increase the peak hemoglobin level by 14%, 15%, 16%, 17%, 18%, or at least 20% and treating a disease or condition associated with endogenous hemoglobin production, suitable for increasing hemoglobin levels. In some embodiments, methods for preventing or treating HIF proliferative disorders are provided herein. The hydroxylase inhibitor or HIF-α stabilizer is a compound represented by formula (I), (II), (III), (IV), or is a compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite a compound selected from 1 or metabolite 2, or a pharmaceutically acceptable salt or solvent thereof Specifically, the compound is a HIF prolyl hydroxylase inhibitor or a HIF-α inhibitor. The fixed agent is Compound 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Specifically, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 7, or its derivatives. In some embodiments, the compound is a pharmaceutically acceptable salt, solvate, or hydrate. , a disease or condition associated with reduced endogenous hemoglobin production secondary to chronic kidney disease Non-severe anemia, non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging is anemia.

[0225] In some embodiments, the medicament is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer. and administering an effective amount as a steroid to a patient suffering from a disease or condition treatable by increasing endogenous hemoglobin production. to a patient having the condition, wherein a pharmaceutically effective amount of HIF prolyl Compared to hepcidin levels before administration of hydroxylase inhibitors or HIF-α stabilizers, ,4%,5%,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16%,17%, Treatment without a decrease in serum hepcidin levels of more than 18%, 19%, or 20% At least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, or at least 20% hemoglobin Increases endogenous hemoglobin production, suitable for increasing peak globin levels Methods for treating or preventing diseases or conditions treatable by adding In some embodiments, a HIF prolyl hydroxylase inhibitor or a HIF-α The stabilizer may be a compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Specifically, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 1, or a combination thereof. and the like. Specifically, HIF prolyl hydroxylates are also suitable salts, solvates, or hydrates thereof. The enzyme inhibitor or HIF-α stabilizer is Compound 7, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is a compound that is therapeutically effective by increasing endogenous EPO production. Treatable diseases or conditions include non-severe anemia secondary to chronic kidney disease, congestive heart failure, These include secondary non-severe anemia and idiopathic anemia of aging.

[0226] In some embodiments, the medicament is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer. to a patient suffering from anemia, wherein the pharmaceutically effective amount compared with hepcidin levels before administration of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers ,1%,2%,3%,4%,5%,6%,7%,8%,9%,10%,11%,12%,13%,14%,15 Reduce hepcidin serum levels by more than 16%, 17%, 18%, 19%, or 20% without any significant changes in hepcidin levels, and at least 2%, 3%, 4%, 5%, or 6% improvement compared to pre-treatment hepcidin levels , 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, or less In patients with steroid use, the dose is sufficient to increase the peak hemoglobin level by at least 20%. Provided herein are methods for treating or preventing anemia in a patient. In the present invention, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound represented by formula (I), formula (II), formula (III), A compound having a structure of formula (IV) or formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Chemical a compound selected from Compound 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt thereof; Specifically, the compound is a salt, solvate, or hydrate capable of inhibiting HIF prolyl hydroxylase. The agent or HIF-α stabilizer is Compound 1, or a pharmaceutically acceptable salt, solvate, or Specifically, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound Compound 7, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In an embodiment, the disease or condition treatable by increasing endogenous EPO production is , non-severe anemia secondary to chronic kidney disease (CKD), non-severe anemia secondary to congestive heart failure In some embodiments, the anemia is, for example, idiopathic anemia of aging, and idiopathic anemia of aging. For example, anemia secondary to or associated with chronic kidney disease, anemia secondary to chronic heart disease, and idiopathic anemia associated with aging. Anemia, anemia of chronic disease, myelodysplastic syndrome, myelofibrosis, other aplastic or dysplastic Anemia, chemotherapy-induced anemia (such as chemotherapy to treat cancer, hepatitis C, or bone marrow regeneration) (including other long-term medications that decrease blood pressure), anemia resulting from blood loss, anemia resulting from iron deficiency, Anemia resulting from vitamin B12 deficiency, sickle cell disease, or thalassemia.

[0227] In some embodiments, such a daily dose is administered orally, preferably once daily. In some embodiments, the daily dose is administered once a day. In some such embodiments, the CKD is stage 1, 2, 3, 4, or 5 of chronic kidney disease. In some embodiments, the CKD is stage 3, 4, or 5 chronic kidney disease. In some embodiments, the CKD is stage 1 chronic kidney disease. In some embodiments, the CKD is stage 2 of chronic kidney disease. In some embodiments, the CKD is stage 4 chronic kidney disease. In some embodiments, the CKD is stage 5 chronic kidney disease. In some embodiments, the patient is a dialysis patient, and These patients are sometimes referred to as having end-stage renal disease (ESRD). In embodiments, anemia, such as anemia secondary to CKD or ESRD, is treated with epoetin alfa, epoetin alfa, or epoetin alfa. Erythropoiesis inhibitors, including rhEPO products such as etin beta, darbepoetin, or peginesatide In some embodiments, the patient may be refractory to treatment with a growth stimulating agent. Whereas the patient has previously been treated for anemia, in some alternative embodiments, the patient: Anemia not previously treated.

[0228] In some embodiments, hepcidin expression is measured using the method of Ganz, T. et al., "Human Serum Hepcidin Expression." Immunoassay for human serum hepcidin,” Blood, 112: 4292-4 297 (2008). Briefly, human hepcidin Antibodies against staphylococcal protein A were purified on a staphylococcal protein A column according to the manufacturer's protocol. 96-well plates were coated with this antibody and buffered in Tris-buffered saline containing 0.05% Tween-20. 100 μL of a 1:20 dilution of serum or a 1:10 dilution of urine in buffered saline (TBS-Tween 20) (standard samples) or Incubation with 200 μL (sample containing very low concentrations of hepcidin) and 10 ng / mL Biotinylated hepcidin-25 was added as a tracer. A standard curve was prepared using the tracer. Serial 2-fold dilutions of synthetic hepcidin at 4000 ng / mL in TBS-Tween 20 buffer containing The integrity and bioactivity of synthetic hepcidin and biotinylated hepcidin were investigated. , and ferroportin-green fluorescent protein-expressing HEK-293 cells by mass spectrometry. After washing, the assay was performed using streptavidin The color was developed using β-peroxidase and tetramethylbenzidine. This enzyme reaction was carried out in the presence of sulfuric acid. The reaction was stopped by 500 rpm and the plate was read at 450 nm on a DTX 880 microplate reader. Standard curves were generated using GraphPad Prism software by 12-point fitting. The fitted curve was then used to calculate the absorbance readings of the samples. Convert to ion concentration.

[0229] Serum hemoglobin levels are determined, for example, by lysing red blood cells and administering potassium ferricyanide. However, it oxidizes hemoglobin to methemoglobin, which combines with potassium cyanide to form cyanide. This can be determined using standard CBC methods, which involves the formation of methemoglobin. The brown color is measured spectrophotometrically and the corresponding hemoglobin is reported.

[0230] In some embodiments, the hepcidin is significantly increased compared to baseline levels. Increase serum hemoglobin levels compared to baseline serum hemoglobin levels without A sufficient number of consecutive doses of a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer are administered to to a patient having a disease or condition associated with reduced endogenous production of EPO. A method for treating a disease or condition associated with decreased endogenous production of erythropoietin (EPO). In some embodiments, the reduced endogenous EPO level is Diseases or conditions related to its production include non-severe anemia secondary to chronic kidney disease, congestive heart failure, The anemia is selected from non-severe anemia secondary to idiopathic anemia of aging.

[0231] In some embodiments, the hepcidin is significantly increased compared to baseline levels. Increase serum hemoglobin levels compared to baseline serum hemoglobin levels without A sufficient number of consecutive doses of a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer are administered to to a patient having a disease or condition that can be treated by increasing endogenous EPO production. Can be treated by increasing the endogenous production of erythropoietin (EPO), including administering Provided herein are methods for treating a disease or condition that is In some embodiments, the disease or condition is non-severe anemia secondary to chronic kidney disease, congestive heart failure, The anemia is a non-severe anemia secondary to a genetic disorder, or an idiopathic anemia of aging. In embodiments, the disease or condition treatable by increasing endogenous EPO production is chronic urinary tract infection (CUP). non-severe anemia secondary to chronic kidney disease, non-severe anemia secondary to congestive heart failure, and It is selected from idiopathic anemia of the elderly.

[0232] In some embodiments, the level of serum hemoglobin is measured using a baseline hemoglobin level. Compared to the standard level, the period is about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks. Over the course of the period, the levels were approximately 0.1 to approximately 1.0 g / dL, approximately 0.1 to approximately 0.9 g / dL, approximately 0.1 to approximately 0.8 g / dL, and approximately 0.1 to approximately 0.7 g / dL. In some embodiments, the blood glucose level is increased by about 0.1 to about 0.6 g / dL, or by about 0.1 to about 0.5 g / dL. In this study, hemoglobin levels increased by approximately 2 weeks compared to baseline hemoglobin levels. at least about 0.1 g for a period of about 1 week, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks, / dL, approx. 0.2g / dL, approx. 0.3g / dL, approx. 0.4g / dL, approx. 0.5g / dL, approx. 0.6g / dL, approx. 0.7g / dL, approx. 0.8g / dL , about 0.9, or about 1.0 g / dL.

[0233] In some embodiments, the level of hemoglobin is measured using a baseline hemoglobin level. In some embodiments, the blood glucose level is increased by about 0.1 g / dL over a one week period compared to the baseline. Hemoglobin levels were significantly higher over a 2-week period compared to baseline hemoglobin levels. In some embodiments, the hemoglobin level is increased by about 0.1 g / dL. Baseline hemoglobin levels are elevated by approximately 0.5 g / dL over a 3-week period. In some embodiments, the level of hemoglobin is measured using a 2000 mg / kg hemoglobin test. In some embodiments, the IL-16 level is increased by about 0.6 g / dL over a 4-week period compared to the IL-16 level. Hemoglobin levels were measured over a 5-week period compared to baseline hemoglobin levels. In some embodiments, the hemoglobin level is increased by about 0.6 g / dL. The baseline hemoglobin level is elevated by approximately 0.6 g / dL over a 6-week period.

[0234] In some embodiments, hepcidin expression is measured at a baseline hepcidin expression level. Compared to, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% In some embodiments, hepcidin expression is decreased by less than about 1% or by less than about 1%. Compared to the baseline hepcidin expression level, the %, or about 0% to about 5%, about 0% to about 4%, about 0% to about 3%, about 0% to about 2%, or about 0% to about 1% In some embodiments, hepcidin expression is decreased by more than baseline hepcidin. about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, or about 1% of the expression level of the target gene. % decrease.

[0235] (5.3.4 Erythroferon Levels) In some embodiments, the erythropoietin expression level is increased relative to the baseline erythropoietin expression level. without significantly increasing Roferon expression, baseline serum hemoglobin in patients HIF prolyl hydroxylase inhibition to increase serum hemoglobin levels relative to normal levels and administering sufficient consecutive doses of a drug or HIF-α stabilizer to patients with non-severe kidney problems secondary to chronic kidney disease. Administered to patients with severe anemia secondary to hemoglobinuria, congestive heart failure, or idiopathic anemia of aging. non-severe anemia secondary to chronic kidney disease, severe anemia secondary to congestive heart failure, including administration of The present invention provides a method for treating a disease or condition selected from non-severe anemia and idiopathic anemia of aging. Provided in the specification.

[0236] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. The blood glucose level rises by about 0.1 to about 1.0 g / dL over a one-week period. In certain embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In total, it increases by approximately 0.1 g / dL over a one-week period.

[0237] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. The blood glucose level rises by about 0.1 to about 1.0 g / dL over a two-week period. In certain embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In total, it will rise by approximately 0.1 g / dL over a two-week period.

[0238] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. The level is elevated by about 0.1 to about 1.0 g / dL over a 3-week period. In certain embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In total, it is increased by approximately 0.5 g / dL over a 3-week period.

[0239] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. The level is elevated by about 0.1 to about 1.0 g / dL over a 4-week period. In certain embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In total, it is increased by approximately 0.6 g / dL over a 4-week period.

[0240] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. The level is elevated by about 0.1 to about 1.0 g / dL over a 5-week period. In certain embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. Overall, it increases by approximately 0.6 g / dL over a 5-week period.

[0241] In some embodiments, the serum hemoglobin level is measured by measuring the baseline hemoglobin level. The level is elevated by about 0.1 to about 1.0 g / dL over a 6-week period. In certain embodiments, the serum hemoglobin level is measured relative to the baseline hemoglobin level. In total, it is increased by approximately 0.6 g / dL over a 6-week period.

[0242] In some embodiments, erythroferon transcription is measured using baseline erythroferon. The level of transcription is increased by less than about 20%, less than about 15%, or less than about 10% compared to the level of transcription of the RNA. Relative to baseline erythroferon transcript levels (see SEQ ID NO: 3) as measured by CR In general, the increase is less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1%.

[0243] In some embodiments, erythroferon protein expression is measured at baseline erythroferon protein expression. The expression level of serotonin is increased by less than about 20%, less than about 15%, or less than about 10% compared to the expression level of serotonin, e.g., Erythroferon protein was measured by Western blot (see SEQ ID NO: 2) , less than about 5%, less than about 4%, and less than about 3% compared to baseline erythroferon expression levels , by less than about 2%, or by less than about 1%.

[0244] In some embodiments, the disease or condition is non-severe anemia secondary to chronic kidney disease. In some embodiments, the disease or condition is non-severe congestive heart failure. In some embodiments, the disease or condition is idiopathic anemia of aging.

[0245] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is administered daily. In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α The stabilizer is administered orally.

[0246] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a In some such embodiments, the HIF prolyl hydroxyl group is a heterocyclic carboxamide. Enzyme inhibitors or HIF-α stabilizers include pyridine carboxamides, quinoline carboxamides, and and isoquinolinecarboxamide.

[0247] In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer has the formula: a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2; or and pharmaceutically acceptable salts, solvates, or hydrates thereof. In the present invention, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 1, or a pharmaceutical thereof. In a specific embodiment, the HIF protease inhibitor is a soluble form of the HIF protease inhibitor. The hydroxylase inhibitor or HIF-α stabilizer is Compound 7, or a pharmaceutically acceptable salt thereof. , solvates, or hydrates.

[0248] 5.4 Diseases Associated with HIF Prolyl Hydroxylase Regulation The present disclosure also relates to, among other things, peripheral vascular disease (PVD); coronary artery disease (CAD); heart failure; ischemia; and anemia. wound healing; ulcers; ischemic ulcers; inadequate blood supply; poor capillary circulation; atherosclerosis of small arteries atherosclerosis; venous congestion; atherosclerotic lesions (e.g., in the coronary arteries); angina pectoris; Myocardial infarction; diabetes; hypertension; Buerger's disease; abnormal levels of VEGF, GAPDH, and / or EPO Concomitant diseases; Crohn's disease; ulcerative colitis; psoriasis; sarcoidosis; rheumatoid arthritis; Hemangioma; Osler-Weber-Rendu disease; Hereditary hemorrhagic telangiectasia; Solid tumors or blood-borne tumors and acquired immune deficiency syndrome; atrial arrhythmias; cardiac conditions such as the myocardium and ventricles liver tissue, skeletal muscle, nerve tissue derived from the cerebellum, etc., internal organs such as the stomach, intestines, pancreas, liver, spleen, and lungs Treating ischemic tissue damage in tissues such as the liver and distal appendages, such as the fingers and toes The present invention also relates to methods for treating and / or preventing and / or managing HIF prolyl hydroxylation. and administering a pharmaceutically effective amount of an enzyme inhibitor or HIF-α stabilizer to, among others, Peripheral vascular disease (PVD); coronary artery disease (CAD); heart failure; ischemia; anemia; wound healing; ulcers; ischemic ulcers ; inadequate blood supply; poor capillary circulation; atherosclerosis of small arteries; venous congestion; Atherosclerotic lesions (e.g., in the coronary arteries); angina; myocardial infarction; diabetes; hypertension; Jurgen's disease; diseases associated with abnormal levels of VEGF, GAPDH, and / or EPO; Crohn's disease; Ulcerative colitis; psoriasis; sarcoidosis; rheumatoid arthritis; hemangioma; Osler-Weber Rendu's disease; hereditary hemorrhagic telangiectasia; solid or blood-borne tumors and acquired Immunodeficiency syndrome; atrial arrhythmia; derived from cardiac tissues such as the myocardium and ventricles, skeletal muscle, and cerebellum nervous tissue, internal organs such as the stomach, intestines, pancreas, liver, spleen, and lungs, and fingers and toes Ischemic tissue damage in tissues such as distal appendages: for the treatment and / or prevention and / or vascular and a method for treating at least one of these diseases, wherein a pharmaceutically effective amount is While suitable for reducing the severity or frequency of symptoms: a) restore or maintain the diurnal pattern of EPO serum levels; b) Increases total iron-binding capacity; c) increasing total iron binding capacity without significantly increasing total iron levels; and / or d) Does not significantly reduce hepcidin levels: Methods are provided herein.

[0249] Atherosclerotic PVD can present in three ways: 1) asymptomatic PVD diagnosed on the basis of noninvasive tests (usually physiological tests); 2) Intermittent claudication with symptoms of leg pain on exertion; and 3) Leg pain at rest and limb-threatening ischemic changes (usually non-healing or infected skin ulcers) Critical limb ischemia with ulcer formation.

[0250] The present disclosure also provides a method for regulating blood flow, oxygen transport and / or energy utilization in ischemic tissue. The present invention also relates to a method of treating a cancer, comprising administering to a patient a therapeutically effective amount of one or more of the compounds disclosed herein or their derivatives. to a human an effective amount of a pharmaceutically acceptable salt or tautomer of .

[0251] The compounds and compositions listed herein have numerous uses, and are particularly useful in: Addressing several unmet medical needs: 1) To provide compositions effective as inhibitors of HIF prolyl hydroxylases, thereby inhibiting the activity of HIF in human tissues. stimulates angiogenic responses in tissues, thereby improving blood flow, oxygen transport, and Providing ways to increase energy utilization; 2) To provide a composition effective as an inhibitor of human protein HIF prolyl hydroxylase, This increases the concentration of HIF-1α, leading to greater activation and cellular response to hypoxia. Maintaining various biological pathways that are normal responses to disease; 3) To provide a composition effective in stimulating an EPO response in cells, thereby increasing the production of red blood cells. Enhancement of red blood cell maintenance by controlling the proliferation and differentiation of progenitor cells into red blood cells ; 4) To provide compositions effective in stimulating an angiogenic response, thereby increasing the number and density of blood vessels. Increased blood pressure and consequent adverse consequences of hypertension and diabetes, especially claudication, ischemic ulcers, and urticaria Alleviating advanced high blood pressure and renal failure; 5) Provide a composition that activates vascular endothelial growth factor (VEGF) gene transcription in hypoxic cells. This results in the stimulation of important biological responses, particularly vasodilation, vascular permeability, and endothelial increasing cell migration and proliferation; 6) Providing compositions that induce the production of soluble VEGF, inhibitors of VEGF in hypoxic cells; The result is stimulation of important biological responses, in particular an increased anti-angiogenic activity.

[0252] Therefore, these and other unmet medical needs are addressed by the HIF prolyl hydroxylation compounds of the present disclosure. This is caused by insufficient regulation of HIF prolyl hydroxylases and is resolved by enzyme inhibitors. Can regulate blood flow, oxygen transport, and energy utilization in affected ischemic tissues Those skilled in the art will also appreciate that inhibition of HIF-1-α prolyl hydroxylase has other positive effects on human tissue. The medical effects of the present invention, as well as those symptoms or conditions specifically pointed out in this disclosure, However, it will be appreciated that the angiogenesis process may have other beneficial effects on the patient's condition and symptoms. As more details emerge concerning the associated pathologies and conditions, these as yet uncovered Unknown or as yet unknown conditions include the body's own response to hypoxia and other low blood oxygen conditions. You will be positively affected by compositions that stimulate your body's response.

[0253] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- an effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid (HIF prolyl hydroxylase); and administering to a patient having a disease that is ameliorated by modulation of the HIF prolyl hydroxylase enzyme. Methods for treating or preventing diseases or disorders ameliorated by modulation of metabolic enzymes are provided herein. In some such embodiments, the compound is administered in an amount of 1 to 3 mg / kg over the course of a 24-hour period. In some such embodiments, the {[5-(3-chloro- phenyl-3-hydroxypyridine-2-carbonyl]amino}acetic acid once daily in an effective dose of HIF protease inhibitors. and administering the compound to a patient having a disease or disorder that is ameliorated by modulation of hydroxylase. The present invention provides a method for treating or preventing diseases that are ameliorated by modulation of HIF prolyl hydroxylases. In some such embodiments, the daily dose is Approximately 150 mg, approximately 300 mg, and approximately 450 mg of (phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid , about 600 mg, or about 750 mg. In some such embodiments, the 2-(5-(3-fluoro An effective dose of (phenyl)-3-hydroxypicolinamido)acetic acid was administered once daily to treat HIF prolyl hydroxylase to a patient having a disease or disorder that is ameliorated by modulation of HIF prolyl Methods for treating or preventing diseases ameliorated by modulation of hydroxylases are provided herein. In some such embodiments, the daily dose is 2-(5-(3-fluorophenyl)-3- About 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of hydroxypicolinamido)acetic acid In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or Such a daily dose is about 600 mg orally once a day, twice a day, or three times a day, preferably once a day. can be administered.

[0254] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- an effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid (HIF prolyl hydroxylase); administering to a patient having a disease or disorder that is ameliorated by inhibiting the enzyme. by inhibiting HIF prolyl hydroxylases (e.g., PHD1, PHD2, and / or PHD3). Methods for treating or preventing diseases or disorders of the invention are provided herein. In such embodiments, the daily dose is {[5-(3-chlorophenyl)-3-hydroxypyridine-2 about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of [-carbonyl]amino}acetic acid. In some such embodiments, the daily dose is 2-(5-(3-fluorophenyl)-3-hydroxybenzoyl)- The dosage is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of cispicolinamide acetate. In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such a daily dose may be administered orally once a day, twice a day, or three times a day, preferably once a day. In some such embodiments, the dosages and and / or according to the dosing regimen, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl an effective amount of phenyl]amino}acetic acid, and administering to a patient a compound of formula (I) or (II) ... to treat or treat a disease or disorder ameliorated by inhibiting PHD1. In some such embodiments, the present invention provides a method for preventing the 2-(5-(3-fluorophenyl)- An effective amount of 3-hydroxypicolinamidoacetic acid is administered to a subject suffering from a disease improved by inhibiting PHD1. and administering to a patient having a disease or disorder that is ameliorated by inhibiting PHD1. Methods for treating or preventing a disease or disorder are provided herein. In embodiments, the dosages and / or dosing regimens described herein are followed by administration of {[5-(3- an effective amount of chlorophenyl-3-hydroxypyridine-2-carbonylamino}acetic acid, to a patient having a disease or disorder that is ameliorated by inhibiting PHD2. Methods for treating or preventing diseases or disorders ameliorated by inhibiting In some such embodiments, the dosages and / or followed the dosing regimen and administered 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. to a patient having a disease or disorder that is ameliorated by inhibiting PHD2. A method for treating or preventing a disease or disorder ameliorated by inhibiting PHD2, comprising: In some such embodiments, the methods described herein are According to the prescribed dosage and / or dosing regimen, A disease that is improved by inhibiting PHD3, wherein an effective amount of benzo[a]diazine-2-carbonyl]amino}acetic acid is administered. or a disease ameliorated by inhibiting PHD3, including administering to a patient having the disorder. Methods for treating or preventing a cancer or disorder are provided herein. In embodiments, 2-(5-(3-furan)-2-one is administered according to the dosages and / or dosing regimens described herein. The effective dose of (fluorophenyl)-3-hydroxypicolinamido)acetic acid was determined to inhibit PHD3. and administering to a patient having a disease or disorder that can be improved by inhibiting PHD3. Provided herein are methods for treating or preventing diseases or disorders that are more ameliorated.

[0255] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- an effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid to stabilize HIF-α; and administering to a patient having a disease or disorder that is ameliorated by administering HIF-α (e.g., Diseases or conditions that are ameliorated by stabilizing HIF-1α, HIF-2α, and / or HIF-3α Methods for treating or preventing a disorder are provided herein. In such cases, the daily dose is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] a The amount of hydroxybenzoate is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of hydroxybenzoate. In some embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. In some such embodiments, the daily dose is 2-(5-(3-fluorophenyl)-3-hydroxypyridine). The amount of cholinesterase inhibitor is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such a daily dose may be administered orally once a day, twice a day, or three times a day, preferably once a day. In some such embodiments, the dosages and / or followed the medication regimen and administered {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] and administering an effective amount of amino}acetic acid to a subject having a disease or disorder that is improved by stabilizing HIF-1-α. and administering to a patient suffering from a disease or disorder that is ameliorated by stabilizing HIF-1α. Methods for treating or preventing harm are provided herein. In some such embodiments, in accordance with the dosages and / or dosing regimens described herein, An effective amount of (phenyl)-3-hydroxypicolinamido)acetic acid is administered to stabilize HIF-1-α. and stabilizing HIF-1α, including administering to a patient having a disease or disorder to be improved. Provided herein are methods for treating or preventing diseases or disorders ameliorated by administering the compound of formula (I) to a subject. In some such embodiments, the dosages and / or dosing regimens described herein are used. According to dimen- {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid An effective amount of the acid is administered to a patient having a disease or disorder that is ameliorated by inhibiting HIF-2-α. and treating or preventing a disease or disorder ameliorated by stabilizing HIF-2-α, including administering Methods for preventing are provided herein. In some such embodiments, the present invention 2-(5-(3-fluorophenyl)-3- The effective dose of hydroxypicolinamido)acetic acid is improved by inhibiting HIF-2-α. stabilizing HIF-2-α, including administering to a patient having a disease or disorder

[0010] Provided herein are methods for treating or preventing diseases or disorders associated with:

[0256] In some such embodiments, the dosages and / or dosing regimens described herein are According to the method of the present invention, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid to a patient having a disease or disorder that is ameliorated by stabilizing HIF-3-α. and treating or preventing a disease or disorder ameliorated by stabilizing HIF-3-α, including administering Methods for preventing are provided herein. In some such embodiments, the present invention 2-(5-(3-fluorophenyl)-3- The effective dose of hydroxypicolinamidoacetic acid was improved by stabilizing HIF-3-α. and administering the compound to a patient having a disease or disorder characterized by stabilizing HIF-3-α. Provided herein are methods for treating or preventing diseases or disorders that are ameliorated.

[0257] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective dose of (fluorophenyl)-3-hydroxypicolinamido)acetic acid was administered to the patient after the endogenous production of EPO was reduced. and administering to a patient suffering from a disease or disorder associated with sex production a reduced erythropoietin-producing agent. Methods for treating or preventing diseases or conditions associated with the endogenous production of ethine (EPO) are provided herein. In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about In some such embodiments, the daily dose is 2-(5-(3-furan)-2-yl)-2-propanol, 600 mg, or about 750 mg. (Fluorophenyl)-3-hydroxypicolinamido)acetic acid, approximately 150 mg, approximately 300 mg, approximately 450 mg, approximately 60 In some such embodiments, the daily dose is about 150 mg, about 30 mg, or about 750 mg. Such a daily dose may be administered once a day, twice a day, or three times a day, preferably at a dose of about 0 mg, about 450 mg, or about 600 mg. It can be administered orally once daily.

[0258] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. anemia (e.g., anemia secondary to or associated with chronic kidney disease, chronic heart disease, anemia secondary to idiopathic anemia of aging, anemia of chronic disease, myelodysplastic syndrome, myelofibrosis, Other aplastic or dysplastic anemias, chemotherapy-induced anemia (for treating cancer, hepatitis C) chemotherapy for bone marrow atrophy or other long-term drug therapy that reduces bone marrow production), anemia resulting from blood loss , anemia resulting from iron deficiency, anemia resulting from vitamin B12 deficiency, sickle cell disease, or Methods for treating or preventing racemia are provided herein. In the case of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid anemia, such as anemia secondary to chronic kidney disease, comprising administering an effective amount to a patient having anemia. In some embodiments, a method for treating 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. Provided herein are methods for treating anemia, such as anemia secondary to chronic kidney disease, comprising administering In some such embodiments, the daily dose is )-3-hydroxypyridine-2-carbonyl]amino}acetic acid, about 150 mg, about 300 mg, about 450 mg, about 60 In some such embodiments, the daily dose is 2-(5-(3-fluro[pi]pyridinyl)-2-hydroxybenzoates, or about 750 mg. (3-hydroxyphenyl)-3-hydroxypicolinamido)acetic acid in approximately 150 mg, approximately 300 mg, approximately 450 mg, and approximately 600 mg g, or about 750 mg. In some such embodiments, the daily dose is about 150 mg, about 300 mg, or about 750 mg. g, about 450 mg, or about 600 mg. Such daily doses may be administered once a day, twice a day, or three times a day, preferably It can be administered orally once daily.

[0259] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective dose of (fluorophenyl)-3-hydroxypicolinamido)acetic acid was administered to treat anemia secondary to CKD. for treating or preventing anemia secondary to chronic kidney disease (CKD), including administering to patients with In some such embodiments, the daily dose is Approximately 150 mg of [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, approximately In some such embodiments, the amount is about 300 mg, about 450 mg, about 600 mg, or about 750 mg. The daily dose is approximately 150 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, approximately 30 mg of In some such embodiments, the daily dose is about 0 mg, about 450 mg, about 600 mg, or about 750 mg. The amount is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such a daily dose is administered once a day, twice a day. It can be administered orally once or three times a day, preferably once a day. In some embodiments, the daily dose is administered once daily. In some embodiments, the CKD is chronic kidney disease. In some such embodiments, CKD is stage 1, 2, 3, 4, or 5 of chronic kidney disease. In some embodiments, the CKD is stage 3, 4, or 5 of chronic kidney disease. In some embodiments, the CKD is stage 2 chronic kidney disease. In some embodiments, the CKD is stage 3 chronic kidney disease. is stage 4 of chronic kidney disease. In some embodiments, CKD is stage 1 of chronic kidney disease. In some embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. In some embodiments, the patient is a dialysis patient, and these patients have end-stage renal disease. In some such embodiments, a patient may be referred to as having CKD or ESR. Anemia, such as that secondary to D, can be treated with epoetin alfa, epoetin beta, and darbepoetin. for treatment with erythropoiesis-stimulating agents, including rhEPO products, such as erythropoietin or peginesatide, In some embodiments, the patient has been previously treated for anemia and may be refractory. whereas in some alternative embodiments, the patient has previously been treated for anemia. not present.

[0260] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid was administered to and treating a disease or disorder associated with angiogenesis, including administering the compound to a patient having the disease or disorder. In some embodiments, methods for treating or preventing the disease are provided herein. [5-(3-chlorophenyl)-3-hydroxybenzoates] according to the dosage and / or dosing regimen described in the product leaflet. administering to a patient an effective amount of hydroxypyridine-2-carbonylamino}acetic acid. Provided herein are methods for modulating angiogenesis. 2-(5-(3-fluorophenyl)- A method for modulating angiogenesis, comprising administering to a patient an effective amount of 3-hydroxypicolinamidoacetic acid. In some such embodiments, a daily dose of is approximately 150mM of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. g, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. In some such embodiments, The daily dose is approximately 150 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In some such embodiments, the amount is about 300 mg, about 450 mg, about 600 mg, or about 750 mg. The daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such a daily dose is administered once a day. It can be administered orally twice a day or three times a day, preferably once a day.

[0261] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- an effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid to inhibit the level of VEGF or GADPH VEGF or GAPDH, including administering to a patient having a disease or disorder affected by the Provided herein are methods for treating or preventing diseases or disorders affected by the level of In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg of hydroxypyridine-2-carbonylamino}acetic acid, or In some such embodiments, the daily dose is about 750 mg. about 150 mg, about 300 mg, about 450 mg, or about 600 mg of (3-hydroxypicolinamido)-3-hydroxypicolinamido)acetic acid, or In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 750 mg. Such a daily dose may be administered once a day, twice a day, or three times a day, preferably once a day. It can be administered orally once.

[0262] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient having a wound. Provided herein are methods for promoting wound healing, comprising administering In such embodiments, the daily dose is {[5-(3-chlorophenyl)-3-hydroxypyridine-2 about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of [-carbonyl]amino}acetic acid. In some such embodiments, the daily dose is 2-(5-(3-fluorophenyl)-3-hydroxybenzoyl)- The dosage is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of cispicolinamide acetate. In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such a daily dose may be administered orally once a day, twice a day, or three times a day, preferably once a day. It is possible.

[0263] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- an effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid and enhancing revascularization or increasing vasculature in damaged tissue, including administering to a patient In some embodiments, methods of administering the method described herein are provided. and administering to a subject a dose and / or regimen prescribed by the administering an effective amount of lysine-2-carbonyl]amino}acetic acid to a patient having ischemic tissue. Provided herein are methods for vascularizing ischemic tissue, including: In embodiments, 2-(5-(3-furan)-2-one is administered according to the dosages and / or dosing regimens described herein. an effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid to a patient having ischemic tissue; Provided herein are methods for vascularizing ischemic tissue, comprising administering to a subject In some such embodiments, the daily dose is {[5-(3-chlorophenyl)-3-hydroxybenzoyl] about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of pyridine-2-carbonyl]amino}acetic acid In some such embodiments, the daily dose is 2-(5-(3-fluorophenyl)-3 mg. about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 1-hydroxypicolinamido)acetic acid In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or Such a daily dose can be administered once a day, twice a day, or three times a day, preferably once a day, or twice a day. It can be administered orally.

[0264] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid was administered to a subject having a skin graft. A method for promoting the growth of a skin graft substitute comprising administering to a patient a ... In some such embodiments, the daily dose is Approximately 150 mg, approximately 300 mg, approximately 450 mg, and approximately 600 mg of hydroxypyridine-2-carbonyl]amino}acetic acid or about 750 mg. In some such embodiments, the daily dose is 2-(5-(3-fluoro- Approximately 150 mg, approximately 300 mg, approximately 450 mg, and approximately 600 mg of (phenyl)-3-hydroxypicolinamido)acetic acid, In some such embodiments, the daily dose is about 150 mg, about 300 mg, or about 750 mg. Such a daily dose is about 450 mg, or about 600 mg, and is administered once a day, twice a day, or three times a day, preferably It can be administered orally once daily.

[0265] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- administering to a patient an effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid Methods for promoting tissue repair in the context of guided tissue regeneration (GTR) are described herein, including: In some such embodiments, the daily dose is {[5-(3-chlorophenyl)- Approximately 150 mg, approximately 300 mg, approximately 450 mg, and approximately 600 mg of 3-hydroxypyridine-2-carbonyl]amino}acetic acid g, or about 750 mg. In some such embodiments, the daily dose is 2-(5-(3-fluoro- (3-Hydroxypicolinamido)acetic acid (approx. 150 mg, approx. 300 mg, approx. 450 mg, approx. 600 mg) In some such embodiments, the daily dose is about 150 mg, about 300 mg, or about 750 mg. Such a daily dose may be administered once a day, twice a day, or three times a day, preferably It can be administered orally once daily.

[0266] In some embodiments, the method further comprises administering to the patient a therapeutically effective amount of ... Coid, syphilis, pseudoxanthoma elasticum, Paget's disease, venous occlusion, arterial occlusion, carotid artery occlusion Sexual disorders, chronic uveitis / vitreous inflammation, mycobacterial infections, Lyme disease, systemic erythematous lupus causes ulcers, retinopathy of prematurity, Eales' disease, Behcet's disease, retinitis or choroiditis Infections, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stahl Gardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, traumatic Post-laser complications, diseases associated with rubeosis, proliferative vitreoretinopathy, and Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangioma, Osler-Way Bar-Rendu disease, or hereditary hemorrhagic telangiectasia, solid tumors or blood-borne tumors, Acquired immune deficiency syndrome, skeletal and cardiac ischemia, stroke, coronary artery disease, peripheral vascular disease, and Methods for treating or preventing a disease or disorder selected from the group consisting of steroids, steroids, and coronary artery disease are provided herein. wherein the method comprises administering to a subject a dose and / or dosage and / or administration rate as described herein. According to the dimen, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V) , or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 The compounds or their pharmaceutically acceptable salts, solvates, or hydrates (specifically Specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or An effective amount of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) is administered to a patient suffering from such a disease. In some such embodiments, the method comprises administering the compound to a patient having a disorder or a condition, the compound being administered daily. The amount is about 15% of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. In some such embodiments, the amount of hydroxybenzoate is about 0 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. The daily dose is approximately 150 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. g, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. In some such embodiments, Thus, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such a daily dose is administered once a day. The compound can be administered orally once a day, twice a day, or three times a day, preferably once a day.

[0267] 5.5 Dosage and Dosage Regimen Various conditions listed in Section 5.4, including anemia (e.g., anemia secondary to chronic kidney disease) and HIF prolyl hydroxylase inhibitors or HIF-alpha stabilizers for the prevention and / or treatment of disorders - Patents.com Various parameters that guide the dosing regimen of an agent are described herein. This section provides information regarding such uses of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers. In some embodiments, such dosages are In other embodiments, such doses are administered over the course of treatment. In some embodiments, the HIF promoter is an adjusted dose at a later time point in the process. The hydroxylase inhibitor or HIF-α stabilizer is a compound represented by formula (I), (II), (III), (IV), or is a compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite a compound selected from 1 or metabolite 2, or a pharmaceutically acceptable salt or solvent thereof In a specific embodiment, the compound is Compound 1, or a solvate or hydrate thereof. In a specific embodiment, the compound is a pharmaceutically acceptable salt, solvate, or hydrate of The compound is Compound 7, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. is.

[0268] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] about 1% of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) 00mg to about 1,200mg, about 200mg to about 1,000mg, about 400mg to about 800mg, or about 450mg to about 600mg, or and administering a daily dose of about 300 mg to about 600 mg to a patient with anemia. Methods for treating anemia, including anemia secondary to disease, are provided herein. In some embodiments, a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds that are the same as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. compounds (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} The daily dose of acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) is approximately 1 In some embodiments, the daily dose of the compound is from about 150 mg to about 300 mg. In some embodiments, the dose is about 00 mg, between about 300 and about 600 mg, or between about 600 mg and about 750 mg. The daily dose is a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5 -(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) in approximately 100 mg, 150 mg, 200 mg, and 2 50mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800m g, 850 mg, 900 mg, 950 mg, 1,000 mg, 1,050 mg, 1,100 mg, 1,150 mg, or even about 1,200 mg In some embodiments, the daily dose is at least about 300 mg, at least about 450 mg g, or even at least about 600 mg.

[0269] In some embodiments, the daily dose is a dose of Formula (I), Formula (II), Formula (III), Formula (IV), or A compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1 or metabolite 2, or a pharmaceutically acceptable salt thereof, or a solvent thereof monohydrate or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamide) In some embodiments, the amount of hydroxybenzoates (hydroxybenzoates) is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of hydroxybenzoates (acetic acid). In some embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. In embodiments, the daily dose is not 240 mg, 370 mg, 500 mg, or 630 mg of Compound 1. In an embodiment, the daily dose comprises a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V). Compounds having the formula (I), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and Compound 7 , Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or a substitute A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or is a hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] acetone) Approximately 240 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid , 370 mg, 500 mg or about 630 mg.

[0270] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid). anemia secondary to chronic kidney disease, comprising administering a daily dose of a compound to a patient having anemia. Provided herein are methods for treating anemia, such as administering the compound sequentially and / or administered irregularly.

[0271] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) to a patient with anemia, such as anemia secondary to chronic kidney disease. Methods of treating are provided herein, wherein the daily dose is about 450 mg. In such embodiments, the daily dose of about 450 mg is a compound of Formula (I), Formula (II), Formula (III), Formula (I V), or a compound having a structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound a compound selected from Metabolite 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt thereof; The resulting salts, solvates, or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxy pyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypico Some examples include a three-unit dosage form, such as three tablets containing approximately 150 mg of (phosphoramido)acetic acid. In embodiments, a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 The selected compounds or their pharmaceutically acceptable salts, solvates, or hydrates (including Specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or A daily dose of approximately 450 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid is The daily dose of the compound can be increased by about 150 mg so that it is about 600 mg. In some embodiments, a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds that are the same as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. compounds (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} 450 mg daily dose of acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) can be reduced by about 150 mg so that the daily dose of the compound is about 300 mg. In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the formula (I), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, and Compound 7 , Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or a substitute A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or is a hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] acetone) The daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid In some cases, the daily dose of the compound may be reduced by about 300 mg so that it is about 150 mg. In some embodiments, the daily dose is about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 2 The dose can be increased or decreased by about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg. In some embodiments, the daily dose is about 75 mg to 300 mg, about 100 mg to about 300 mg, about 125 mg to Approximately 300mg, approximately 150mg to approximately 300mg, approximately 175mg to approximately 300mg, approximately 200mg to approximately 300mg, approximately 225mg to approximately 300mg , about 250 mg to about 300 mg, or about 275 mg to about 300 mg. In some embodiments, the daily dose is from about 75 mg to about 250 mg, from about 100 mg to about 225 mg, or from about 12 It may be increased or decreased by an amount of 5 mg to about 200 mg. In such cases, the daily dose does not exceed about 600 mg or about 750 mg.

[0272] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) to a patient having anemia, wherein the compound is administered for 42 or more consecutive days. anemia secondary to chronic kidney disease, which can be administered continuously and / or irregularly, such as Provided herein are methods for treating anemia, such as: wherein the daily dose of the compound is a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V). or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or a substitute A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or is a hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] acetone) Approximately 150 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid In some such embodiments, the amount is about 300 mg, about 450 mg, about 600 mg, or about 750 mg. The daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.

[0273] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) to a patient having anemia, wherein the patient's hemoglobin level is Poor circulation secondary to chronic kidney disease, maintained at levels below about 10.0 g / dL and about 13.0 g / dL Provided herein are methods for treating anemia, such as anaemia. In such cases, the hemoglobin level is at least about 11.0 g / dL and not more than about 13.0 g / dL. In some such embodiments, the hemoglobin level is maintained at at least The blood glucose level is maintained at levels below about 11.0 g / dL and about 12.0 g / dL. In some such embodiments, Thus, the daily dose of the compound is a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V). Compounds that are the same as Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. compounds (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} Approximately 150 mg of acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid), approximately 3 In some such embodiments, the daily dose is about 100 mg, about 450 mg, about 600 mg, or about 750 mg. The amount is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.

[0274] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) to a patient having anemia, wherein the patient's hemoglobin level is Chronic kidney disease, with an increase in hemoglobin level of at least approximately 1.2 g / dL compared to baseline Methods for treating anemia, such as anemia secondary to certain diseases, are provided herein. In such embodiments, the daily dose of the compound is a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or or a compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5 , compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, a compound selected from Metabolite 1 or Metabolite 2, or a pharmaceutically acceptable salt thereof; Solvates or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine -2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicoline amine The dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of acetic acid. In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg.

[0275] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] administration of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) may be temporarily suspended if hemoglobin levels are 13.0 g / dL or higher. In some such embodiments, administration of the compound is continued once hemoglobin levels have reached a It may be resumed once blood pressure drops below 12.5 g / dL.

[0276] In some embodiments, hemoglobin levels are monitored and a compound represented by Formula (I): A compound having a structure of formula (II), formula (III), formula (IV), or formula (V), or compound 1, compound 2 , compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or Pharmaceutically acceptable salts, solvates, or hydrates thereof (specifically, {[5-(3-chlorophenyl)methyl]-2-propanol; phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid The dose of (hydroxy)-3-hydroxypicolinamido)acetic acid (HPA) administered may affect hemoglobin levels and / or hemoglobin levels. In some embodiments, the amount of ATP in the blood can be adjusted based on changes in the level of ATP. The dosage is a compound having a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. The compounds or their pharmaceutically acceptable salts, solvates, or hydrates (specifically {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2- (5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) by 150 mg, or Furthermore, it can be adjusted by either increasing or decreasing by 300 mg. .

[0277] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) may be increased after a period of time, starting on the day the patient receives a daily dose of the compound. In some embodiments, this period is from about 1 week to about 8 weeks, for example, about 2 weeks. For example, the period is from about 1 week to about 7 weeks, from about 3 weeks to about 6 weeks, or about 4 weeks.

[0278] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) can be adjusted once for a period of time. In some embodiments, this period of time is About 1 week to about 8 weeks, for example, about 2 weeks to about 7 weeks, about 3 weeks to about 6 weeks, or about 4 weeks. do.

[0279] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) is when hemoglobin levels are greater than 1.2 g / dL compared to baseline hemoglobin levels. If it increases, it does not increase.

[0280] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid). administering a daily dose of a compound to a patient having anemia; and again measuring hemoglobin levels in the patient after a period of time has elapsed since said measurement, wherein the hemoglobin level in the patient is less than about 10.0 g / dL, and If the level of thrombin is reduced by less than about 0.5 g / dL compared with the level measured at an earlier time point, or the patient has a hemoglobin level of less than about 10.0 g / dL, and Robin levels changed by a maximum of approximately 0.4 g / dL compared to levels measured in earlier periods. or the patient has a hemoglobin level of about 10.0 to about 10.9 g / dL, and This hemoglobin level was approximately 0.5 g / dL lower than the levels measured at an earlier time point. If the daily dose is decreased by more than about 150 mg, the adjusted daily dose of the compound may be increased by about 150 mg. Provided herein are methods for treating anemia, such as anemia secondary to chronic kidney disease, by administering In some such embodiments, the compound is administered once daily and is administered orally. In some embodiments, the daily dose is about 450 mg, As a result, if the daily dose is increased by about 150 mg, the adjusted daily dose is about 600 mg. In some embodiments, the period is from about 1 week to about 8 weeks, for example, from about 2 weeks to about 7 weeks, or from about 3 weeks to about 8 weeks. In some embodiments, the daily dose is about 75 ml to about 6 weeks, or about 4 weeks. g, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or In some embodiments, the daily dose can be increased or decreased by about 300 mg. Approximately 75mg to 300mg, approximately 100mg to approximately 300mg, approximately 125mg to approximately 300mg, approximately 150mg to approximately 300mg, approximately 175mg to approximately 300 mg, about 200 mg to about 300 mg, about 225 mg to about 300 mg, about 250 mg to about 300 mg, or about 275 mg to about 300 mg In some embodiments, the daily dose can be increased or decreased by an amount of Increased or decreased by about 75 mg to about 250 mg, about 100 mg to about 225 mg, or about 125 mg to about 200 mg. In some embodiments, the adjusted daily dose is 600 mg or 750 mg. does not exceed.

[0281] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] administering a daily dose of a compound which is a hydroxybenzoate (amino)acetic acid to a patient suffering from anemia; Hemoglobin levels are measured in the patient after administration of the dose and again after a period of time. wherein the hemoglobin level in the patient is less than about 10.0 g / dL; And this hemoglobin level is about 1.5 g / dL higher than the level measured earlier. or if the hemoglobin level in the patient is increased by about 10.0 to about 10.9 g / dL, and this hemoglobin level was similar to that measured at an earlier time point. or if the hemoglobin level in the patient is increased by more than about 1.5 g / dL compared to the normal blood glucose level; The hemoglobin level is about 11.0 to about 12.2 g / dL, and this hemoglobin level is measured at an earlier time point. an increase of about 1.0 to about 1.4 g / dL compared to the established level; or The hemoglobin level is about 12.3 to about 12.9 g / dL, and this hemoglobin level is A decrease of up to about 0.4 g / dL compared to levels measured in an earlier period or a decrease of up to about 0.4 g / dL compared to levels measured in an earlier period or if the hemoglobin level in the patient is increased by about 12.3 to about 12.9 g / dL; g / dL, and this hemoglobin level is higher than the level measured at an earlier time point. When the daily dose is increased by about 0.5 to about 0.9 g / dL, the daily dose is about 150 mg less than the daily dose of the compound. 20. A method for treating anemia, such as anemia secondary to chronic kidney disease, comprising administering a controlled daily dose of In some such embodiments, the compound is administered once daily. In some embodiments, the daily dose is , about 450 mg, so that if the daily dose is reduced by about 150 mg, the adjusted daily dose is In some embodiments, the period is about 1 week to about 8 weeks, e.g., about 300 mg. For example, about 2 weeks to about 7 weeks, about 3 weeks to about 6 weeks, or about 4 weeks. The daily dose is approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, It can be increased or decreased by about 250 mg, about 275 mg, or about 300 mg. In some embodiments, the daily dose is about 75 mg to 300 mg, about 100 mg to about 300 mg, about 125 mg to about 300 mg, or about 150 mg. g ~ about 300mg, about 175mg - about 300mg, about 200mg - about 300mg, about 225mg - about 300mg, about 250mg - about 300 The amount of the active ingredient may be increased or decreased by about 275 mg to about 300 mg. In embodiments, the daily dose is from about 75 mg to about 250 mg, from about 100 mg to about 225 mg, or from about 125 mg to about 200 mg. In some embodiments, the amount of the adjusted 1 The daily dose should not exceed 600 mg or 750 mg.

[0282] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid). administering a daily dose of a compound to a patient having anemia; and again measuring hemoglobin levels in the patient after a period of time has elapsed since said measurement, Here, the hemoglobin level in the patient is about 11.0 to about 12.2 g / dL, and Robin levels increased by more than approximately 1.5 g / dL compared to levels measured at earlier times. or the patient has a hemoglobin level of about 12.3 to about 12.9 g / dL. and this hemoglobin level is approximately 1.0 to 1.5 times higher than the level measured at an earlier time point. or if the hemoglobin level in the patient is increased by about 12.3 to 1.4 g / dL; The hemoglobin level was approximately 12.9 g / dL, and this hemoglobin level was higher than that measured at an earlier time point. If the increase is more than about 1.5 g / dL compared to the daily dose, the daily dose should be less than about 300 mg. administering a controlled daily dose of the compound to treat anemia, such as anemia secondary to chronic kidney disease; In some embodiments, the compound is administered once daily. In some embodiments, the daily dose is 4 50 mg, so that the initial daily dose is reduced by about 300 mg, the adjusted daily dose is about 150 In some embodiments, the period is from about 1 week to about 8 weeks, for example, about 2 weeks. In some embodiments, the period is from about 1 to about 7 weeks, from about 3 to about 6 weeks, or about 4 weeks. , daily doses are approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, and approximately 250 mg The amount of hydroxybenzoate may be increased or decreased by about 275 mg, about 275 mg, or about 300 mg. The daily dose is approximately 75 mg to 300 mg, approximately 100 mg to 300 mg, approximately 125 mg to 300 mg, approximately 150 mg to 300 mg. mg, about 175 mg to about 300 mg, about 200 mg to about 300 mg, about 225 mg to about 300 mg, about 250 mg to about 300 mg, or It can be increased or decreased by an amount of about 275 mg to about 300 mg. In this case, the daily dose is about 75 mg to about 250 mg, about 100 mg to about 225 mg, or about 125 mg to about 200 mg. In some embodiments, the adjusted daily dose is 6 Not to exceed 00mg or 750mg.

[0283] In some embodiments, the hemodialysis treatment is performed about 8 hours, 7 hours, 6 hours, or 8 hours prior to the start of the hemodialysis session. , 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour, or about 7 to 8 hours, 6 to 7 hours , 5 to 6 hours, 4 to 5 hours, 3 to 4 hours, 2 to 3 hours, 1 to 2 hours, or has a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) for up to about 1 hour. Compound, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 A method for treating hemodialysis comprising administering to a patient a pharmaceutically effective amount of a compound selected from the group consisting of: Provided herein are methods for treating anemia associated with CKD in patients receiving CKD. .

[0284] In some embodiments, the hemodialysis session is stopped within about 8 hours, 7 hours, 6 hours, or 8 hours after completion of the hemodialysis session. , 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour, or about 7 to 8 hours, 6 to 7 hours , 5 to 6 hours, 4 to 5 hours, 3 to 4 hours, 2 to 3 hours, 1 to 2 hours, or has a structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) for up to about 1 hour. Compound, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 A method for treating hemodialysis comprising administering to a patient a pharmaceutically effective amount of a compound selected from the group consisting of: Provided herein are methods for treating anemia associated with CKD in patients receiving CKD. .

[0285] In some embodiments, the methods provided herein comprise the step of reacting a compound of Formula (I), Formula (II), Formula (III), A compound having a structure of formula (IV) or formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Chemical Determine the serum concentration of a metabolite of a compound selected from Compound 13, Metabolite 1, or Metabolite 2. In a more specific embodiment, the method further comprises a monitoring step. A compound having a structure of formula (IV) or formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Chemical a phenolic glucuronide of a compound selected from Compound 13, Metabolite 1, or Metabolite 2; and / or the serum concentration of the acyl glucuronide is determined. The phenolic glucuronide and / or acyl glucuronide of compound 1, i.e., metabolite 1 or The serum concentration of Metabolite 2 (see Section 5.2) is determined. In embodiments, the daily dose is adjusted according to the serum concentration of the metabolite.

[0286] 5.6 Combination Therapy In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid), to treat anemia, such as that secondary to chronic kidney disease, including when administered in combination with other medications Such combination therapy may be administered in combination with the administration of the individual components of the treatment. This can be achieved simultaneously, sequentially, or separately. When administered as a single dose, the compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V) Compounds corresponding to the above, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or Hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amine 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) and other medicines The products can be synergistic, so that the daily dose of either or both of these ingredients is: The dosage of either component can be reduced compared to the dosage normally administered as monotherapy. Alternatively, when administered as a component of such a combination therapy, V), or a compound having a structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound a compound selected from Metabolite 13, Metabolite 1, or Metabolite 2, or a pharmaceutically acceptable salt thereof; The resulting salts, solvates, or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxy pyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypico The effects of benzodiazepines (phosphoramido)acetic acid and other drugs can be additive, resulting in the The daily dose should be similar to the dose of either component normally administered as monotherapy or It's the same.

[0287] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or HIF proteins, such as hydroxybenzoates or hydrates (e.g., compounds disclosed herein, such as Compound 1), A daily dose of a loryl hydroxylase inhibitor or HIF-α stabilizer should be administered to patients with anemia. Non-severe anemia secondary to chronic kidney disease, including non-severe anemia secondary to congestive heart failure and a method for treating idiopathic anemia of aging, wherein the compound is , continuously and / or intermittently, and the compound is administered in conjunction with another pharmaceutical agent. .

[0288] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) for anemia to a patient having a steroid hormone, wherein the compound is optionally administered in the presence of ferrous sulfate, gluconate, or the like. Secondary to chronic kidney disease, administered in combination with iron supplements, such as ferrous iron or ferrous fumarate Methods for treating anemia, such as anemia caused by steroids, are provided herein. In some embodiments, the iron supplement is administered at least 1 hour, at least 2 hours, or It can be administered over at least 3 hours, at least 4 hours, or even at least 6 hours. In some embodiments, the iron supplement provides a ferritin concentration of about 50 ng / mL to about 300 ng / mL. In some embodiments, the iron supplement is administered in an amount such that the iron level is maintained at a level of L. is orally administered in a daily dose of at least about 50 mg of elemental iron. The iron supplement is administered orally at a dosage of about 50 mg of elemental iron. The supplement is administered intravenously. In some embodiments, the iron supplement is administered intravenously for 42 consecutive days. The administration may be continuous and / or irregular, such as for days or more. Therefore, iron supplements are necessary to maintain ferritin at a level of approximately 50 ng / mL to approximately 300 ng / mL. In some such embodiments, the daily dose of the compound is a dose of a compound of formula (I) , a compound having a structure of formula (II), formula (III), formula (IV), or formula (V), or compound 1, compound compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or Pharmaceutically acceptable salts, solvates, or hydrates thereof (specifically, {[5-(3-chloro- phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)- about 150 mg, about 300 mg, about 450 mg, about 600 mg of (3-hydroxypicolinamido)acetic acid), or In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 750 mg. Such a daily dose may be administered once a day, twice a day, or three times a day, preferably once a day. It is administered orally once.

[0289] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) for anemia to a patient having anemia secondary to chronic kidney disease, such as those administered in combination with erythropoiesis-stimulating agents (ESAs) Provided herein are methods for treating anemia. In some such embodiments, ESAs include, but are not limited to, epoetin alfa, epoetin beta, darbepoetin, or is a rhEPO product that includes peginesatide. In some such embodiments, the ESA is In some alternative embodiments, the ESA is administered for 42 consecutive days as rescue therapy. In some such embodiments, the dose is administered continuously and / or irregularly, such as over a period of time. The daily dose of the compound has the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V). Compound, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 or a pharmaceutically acceptable salt, solvate, or hydrate thereof. (Specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid), about 150 mg, about 300 In some such embodiments, the daily dose is about 450 mg, about 600 mg, or about 750 mg. The daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such a daily dose can be administered once a day, twice a day, or both. or three times a day, preferably once a day, or orally.

[0290] (5.7 Patient Population) In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. wherein the patient is at least 50 years old, at least 60 years old, at least 65 years old, age, at least 70 years old, or even at least 80 years old, and suffering from poverty secondary to chronic kidney disease (CKD) Provided herein are methods for treating anemia, such as anaemia. In some embodiments, the patient is an elderly patient. In some embodiments, the patient is under 18 years of age. In some embodiments, the patient is a pediatric patient. wherein the patient is at least 18 years of age. In some such embodiments, the daily dose is , a compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or compound 1 , compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2; or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, {[5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (3-Hydroxyphenyl)-3-hydroxypicolinamido)acetic acid) approximately 150 mg, approximately 300 mg, approximately 450 mg, approximately 600 mg In some such embodiments, the daily dose is about 150 mg, about 300 mg, or about 750 mg. Such a daily dose may be administered once a day, twice a day, or three times a day, preferably It is usually administered orally once daily.

[0291] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. administering, wherein the patient is selected from Caucasian, Hispanic, Black, and Asian. Those who treat anemia, including anemia secondary to chronic kidney disease (CKD), who are part of a select subpopulation In some embodiments, the patient is a male or female. In some such embodiments, the daily dose is: A compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10 a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, {[5-(3-chloro- 2-(5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid about 150 mg, about 300 mg, about 450 mg, about 600 mg of (phenyl)-3-hydroxypicolinamido)acetic acid, In some such embodiments, the daily dose is about 150 mg, about 300 mg, or about 750 mg. Such a daily dose is about 450 mg, or about 600 mg, and is administered once a day, twice a day, or three times a day, preferably is administered orally once daily.

[0292] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. wherein the patient is suffering from cancer, AIDS, congestive heart failure, left ventricular hypertrophy, diabetes, Selected from hypertension, dyslipidemia, chronic heart failure, stroke, fatigue, depression, and cognitive impairment Chronic kidney disease (CKD) with an additional disease or condition, or any combination thereof Methods for treating anemia, including secondary anemia, are provided herein. In some embodiments, the daily dose comprises a compound having the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V). or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or a substitute A compound selected from Compound 2, or a pharmaceutically acceptable salt, solvate, or is a hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] acetone) Approximately 150 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid In some such embodiments, the amount is about 300 mg, about 450 mg, about 600 mg, or about 750 mg. The daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such a daily dose is administered once a day. It is administered orally twice or three times a day, preferably once a day.

[0293] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. wherein the patient is receiving treatment with an ESA, such as an erythropoietin mimetic. Methods for treating anemia, such as anemia secondary to CKD, that is refractory to steroids are provided herein. In some embodiments, the ESA includes, but is not limited to, epoetin alfa, rhEPO products, including epoetin beta, darbepoetin, or peginesatide. In some such embodiments, the daily dose is a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or A compound having the structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1 or metabolite 2, or a pharmaceutically acceptable salt thereof, or a solvent thereof monohydrate or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamide) acetic acid) is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. In embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. The dose is administered orally once daily, twice daily, or three times daily, preferably once daily.

[0294] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. wherein the patient has a transferrin saturation (TSAT) of at least 15% anemia, such as anemia secondary to CKD, having a CKD of at least 18% or even at least 20% In some such embodiments, methods of treating The amount is a compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- about 150 mg, about 300 mg, about 450 mg of (fluorophenyl)-3-hydroxypicolinamido)acetic acid, In some such embodiments, the daily dose is about 150 mg, about 600 mg, or about 750 mg. Such daily doses are about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered once a day, twice a day, or three times a day. It is preferably administered orally once a day.

[0295] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. wherein the patient has a ferritin level of at least 50 ng / mL or more The present invention provides a method for treating anemia, such as anemia secondary to CKD, having a serum creatine nitrate concentration of at least 100 ng / mL. In some such embodiments, the daily dose comprises a compound of Formula (I), Formula (II), A compound having a structure of formula (III), formula (IV), or formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Chemical Compound 12, compound 13, metabolite 1, or metabolite 2, or a pharmaceutical composition thereof. and an acceptable salt, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypyridine About 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of hydroxypicolinamide (acetic acid) In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or Such a daily dose is about 600 mg orally once a day, twice a day, or three times a day, preferably once a day. It is administered.

[0296] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. wherein the patient has a ferritin level of at least 50 ng / mL and trans A ferrin saturation of at least 18% or a ferritin level of at least 100 ng / mL and trans Methods for treating anemia, such as anemia secondary to CKD, with a ferrin saturation of at least 15% In some such embodiments, the daily dose comprises a compound of formula (I): A compound having a structure of formula (II), formula (III), formula (IV), or formula (V), or compound 1, compound 2 , compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound a compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or Pharmaceutically acceptable salts, solvates, or hydrates thereof (specifically, {[5-(3-chlorophenyl)methyl]-2-propanol; phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about In some such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 750 mg. g, or about 600 mg. Such a daily dose may be administered once a day, twice a day, or three times a day, preferably once a day. It is administered orally once.

[0297] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. wherein the patient has a body mass index (BMI) of 42 kg / m 2 Less than or 44 kg / m 2 Less than Provided herein are methods for treating anemia, such as anemia secondary to CKD, having In some such embodiments, the daily dose is a dose of Formula (I), Formula (II), Formula (III), Formula (IV), or or a compound having a structure of formula (V), or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolism a compound selected from Metabolite 1 or Metabolite 2, or a pharmaceutically acceptable salt or solution thereof; Solvates or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2 -carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamide) acetic acid) is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. In embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. The dose is administered orally once daily, twice daily, or three times daily, preferably once daily.

[0298] In some embodiments, the dosages and / or dosing regimens described herein Therefore, a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or a compound Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharmaceutically acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient with anemia. wherein the patient is administered within 11 or 12 weeks of initiating treatment with the compound. The present disclosure provides a method for treating anemia, such as anemia secondary to CKD, in patients receiving red blood cell transfusions. In some alternative embodiments, the patient is treated with the compound. No red blood cell transfusions within 11 or 12 weeks of initiation. wherein the daily dose is a compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V). compound, or compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8 , Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 Selected compounds or their pharmaceutically acceptable salts, solvates, or hydrates ( Specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or about 150 mg, about 300 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) In some such embodiments, the daily dose is about 450 mg, about 600 mg, or about 750 mg. , about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered once a day, twice a day, Alternatively, it is administered orally three times a day, preferably once a day.

[0299] In some embodiments, a daily dose of a compound disclosed herein, such as Compound 1, is administered. to a patient with anemia, wherein the compound is administered sequentially and / or Irregularly administered, non-severe anemia secondary to chronic kidney disease, secondary to congestive heart failure Provided herein are methods for treating non-severe anemia and idiopathic anemia of aging.

[0300] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) and a method for treating and / or preventing iron overload in a patient, comprising administering to the patient an amount of In some embodiments, the administering step comprises administering a compound as described herein. The dosage and / or administration regimen described is followed.

[0301] 5.8 Pharmaceutical Compositions The pharmaceutical compositions can be used in the preparation of individual, single unit dosage forms. The pharmaceutical compositions and dosage forms provided herein are intended to be used in combination with the compounds provided herein or their pharmaceutical equivalents. and a pharmaceutical composition comprising a compound selected from the group consisting of a pharmaceutically acceptable salt, solvate, or hydrate of the parent compound. The products and dosage forms may further contain one or more excipients.

[0302] In some embodiments, pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are set forth in the present application. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form is provided in the specification. Whether a dosage form is suitable for a patient is well known in the art, including, but not limited to, the manner in which the dosage form is administered to a patient. For example, oral dosage forms such as tablets are determined by a variety of factors, including the use of The suitability of a particular excipient may depend on the specific It can also depend on the active ingredient. For example, the degradation of some active ingredients can be affected by certain sugars, such as lactose. This may be accelerated by some excipients or on exposure to water. Active ingredients containing benzophenone are particularly susceptible to such accelerated degradation. However, pharmaceutical compositions and dosage forms containing only trace amounts of lactose and other mono- or disaccharides are provided. As used herein, the term "lactose-free" refers to lactose-free sugars, if any, present. This means that the amount of lactose present is insufficient to substantially increase the decomposition rate of the active ingredient. do.

[0303] Lactose-free compositions are well known in the art and are described, for example, in the United States Pharmacopoeia (USP) 25 NF20 (2002). Generally, lactose-free compositions The product comprises the active ingredient, a pharmaceutically compatible amount and a pharmaceutically acceptable amount of a binder / filler. In one embodiment, the lactose-free dosage form contains the active ingredient, microcrystalline Contains cellulose, pregelatinized starch, and magnesium stearate.

[0304] Anhydrous pharmaceutical compositions and dosage forms are also provided, as water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) determines characteristics such as shelf life or stability of the formulation over time. It has gained widespread acceptance in the pharmaceutical industry as a means of simulating long-term storage to determine For example, Jens T. Carstensen's article, "Drug Stability: Principles and Practice" g Stability: Principles & Practice), 2nd edition, Marcel Dekker, NY, NY, 1995, pp. See pp. 379-80. In fact, water and heat accelerate the decomposition of some compounds. and / or humidity levels commonly experienced during the manufacture, handling, packaging, storage, shipping, and use of the formulation. As encountered, the effect of water on a formulation can be very significant.

[0305] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Thus, anhydrous compositions, in one embodiment, are found to prevent exposure to water. The materials used are packaged so that they can be included in a suitable prescription kit. Examples of suitable packaging include hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and the like. Packaging includes, but is not limited to, box packaging, and strip packaging.

[0306] Also included are pharmaceutical compositions and compositions containing one or more compounds that reduce the rate at which the active ingredient decomposes. Such compounds are referred to herein as "stabilizers" and include ascorbic acid, benzodiazepines, and benzoyl peroxides. Antioxidants such as acetic acid, pH buffers, or salt buffers are examples of additives that may be used. do not have.

[0307] The amounts and specific types of active ingredients in a dosage form, as well as the amounts and types of excipients, can also be used, but are not limited to, The dose varies depending on factors such as the route by which it is administered to the patient.

[0308] 5.8.1 Oral Dosage Forms Pharmaceutical compositions suitable for oral administration include, but are not limited to, tablets (e.g., chewable tablets), caplets, and the like. provided as individual dosage forms such as tablets, capsules, and liquids (e.g., flavored syrups) Such dosage forms contain predetermined amounts of active ingredients and can be prepared by methods of preparation well known to those skilled in the art. Generally, the formula is prepared by the method described in "Remington's Science and Practice of Pharmaceuticals." s The Science and Practice of Pharmacy), 21st edition, Lippincott Williams & Wilkins (2005).

[0309] The oral dosage forms provided herein may be formulated according to conventional pharmaceutical compounding techniques to contain at least one These preparations are prepared by combining the active ingredients in an intimate admixture with excipients such as: Depending on the form of preparation desired for administration, it may take a wide variety of forms, for example, oral liquid or aerosol. Suitable excipients for use in sol dosage forms include water, glycols, oils, alcohols, flavoring agents, preservatives, and the like. Solid oral dosage forms (e.g., Examples of excipients suitable for use in pharmaceutical formulations (powders, tablets, capsules, and caplets) include denatured or undenatured ... Contains starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants. However, the present invention is not limited to these.

[0310] In one embodiment, the oral dosage form is a tablet or capsule, in which case the solid excipient is In another embodiment, tablets are coated by standard aqueous or nonaqueous techniques. Such dosage forms may be prepared by any method of pharmacy. The compositions and dosage forms comprise the active ingredient in a liquid carrier, a finely divided solid carrier, or both. Prepared by uniform and intimate mixing, if necessary, followed by shaping of the product to the desired appearance. do.

[0311] For example, tablets can be prepared by compression or molding. Compressed tablets can be prepared by compressing or molding powder or granules. The active ingredient in a free-flowing form such as PEG-100, optionally mixed with an excipient, is compressed in a suitable machine. Molded tablets can be prepared by suspending the powder in an inert liquid diluent. It can be produced by molding a mixture of compounds in a suitable machine.

[0312] Examples of excipients that can be used in oral dosage forms provided herein include binders, These include, but are not limited to, fillers, disintegrants, and lubricants. Suitable binders for use in the dosage form include corn starch, potato starch, or or other starches, gelatin, acacia gum, sodium alginate, alginic acid, Other natural and synthetic gums such as alginate, tragacanth powder, guar gum, cellulose, and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose) Calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., No. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. It's not that.

[0313] Suitable forms of microcrystalline cellulose are AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL CEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marx Hook, PA) This includes, but is not limited to, substances sold as A specific binder is a microcrystalline cellulose sold as AVICEL RC-581. A suitable anhydrous or low moisture excipient is a mixture of sodium carboxymethylcellulose and sodium carboxymethylcellulose. Examples of additives include AVICEL-PH-103™ and Starch 1500 LM. Other microcrystalline cellulose Suitable forms include silica-containing microcrystalline cellulose, e.g., PROSOLV 50, PROSOLV 90, PROSOLV HD. including, but not limited to, substances sold as PROSOLV 90, PROSOLV 90 LM, and mixtures thereof It is not something that is done.

[0314] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include: Talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, Dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized denatured In pharmaceutical compositions, the compounds include, but are not limited to, lactic acid bacteria ... The binder or filler, in one embodiment, is present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form. There is.

[0315] In some embodiments, the filler is a bridgehead of ethylene oxide and propylene oxide. Such block copolymers include, but are not limited to, , sold as Poloxamer or Pluronic, Poloxamer 188 NF, Poloxamer Poloxamer 237 NF, Poloxamer 338 NF, Poloxamer 437 NF, and mixtures thereof, It is not limited to these.

[0316] In some embodiments, the filler is isomalt, lactose, lactitol, mannitol, or the like. sorbitol, xylitol, erythritol, and mixtures thereof. However, the present invention is not limited to these.

[0317] Disintegrants are used in the composition to provide tablets that disintegrate when exposed to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage. Conversely, those that contain too little disintegrant will not disintegrate at a desired rate or under the desired conditions. Therefore, it is important to choose a dosage that is neither too much nor too little so as not to adversely alter the release of the active ingredient. Any suitable amount of disintegrant may be used to form the solid oral dosage form. The amount of agent varies depending on the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical composition contains about 0.5 to about 15% by weight of a disintegrant, or about 1 to about 5% by weight of a disintegrant. .

[0318] Disintegrants that can be used in pharmaceutical compositions and dosage forms are agar, alginic acid, carbonate Calcium, microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone Don, polacrilin potassium, sodium starch glycolate, potato or Pioca starch, other starches, pregelatinized starch, other starches, clay, other algae including, but not limited to, cellulose, other cellulosics, gums, and mixtures thereof. isn't it.

[0319] Lubricants that can be used in pharmaceutical compositions and dosage forms include calcium stearate. , magnesium stearate, mineral oil, light mineral oil, glycerin, Carboxymethylcellulose, mannitol, polyethylene glycol, other glycols, stearic acid , Sodium Stearyl Fumarate, Sodium Lauryl Sulfate, Talc, Hydrogenated Vegetable Oil (e.g. For example, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and da Oil), zinc stearate, ethyl oleate, ethyl laureate Additional lubricants include, but are not limited to, glycerin, agar, and mixtures thereof. Examples of silica gel include siloid silica gel (AEROSIL 200, manufactured by W.R. Grace, Inc., Baltimore, MD), Synthetic silica coagulated aerosol (commercially available from Degussa, Plano, TX), CAB-O-SIL (commercially available from Cabot Corporation), Pyrogenic colloidal silicon dioxide products sold by Pharmacia, Inc. of Boston, MA, and Lubricants, if used at all, are used in the pharmaceutical compositions or formulations in which they are incorporated. It may be used in an amount of less than about 1% by weight of the dosage form.

[0320] In some embodiments, the oral dosage form comprises the compound, silica-containing microcrystalline cellulose, Sodium starch glycolate, ethylene oxide and propylene oxide block copolymer Contains polymer, sodium stearyl fumarate and colloidal silicon dioxide. In some embodiments, the oral dosage form contains the compound in an amount of about 5% to about 75% by weight of the oral dosage form. About 15% to about 85% of microcrystalline cellulose containing sodium starch glycolate is used. 2% to about 10%, and ethylene oxide and propylene oxide block copolymers in an amount of about 2% to about 10%. about 10%, sodium stearyl fumarate in an amount of 0.2% to about 2%, and colloidal dioxide The silicon content is about 0.2% to about 2% by weight.

[0321] In some embodiments, the oral dosage form comprises the compound, microcrystalline cellulose, isomalt , Sodium starch glycolate, Sodium lauryl sulfate, Povidone, Colloidal diglyceride In some embodiments, the composition contains silicon oxide and magnesium stearate. The oral dosage form contains the compound in an amount of about 40% to about 50% of the oral dosage form, and microcrystalline cellulose in an amount of about 40% to about 50% of the total amount, isomalt at 0% to about 5%, sodium starch glycolate at about 5% to about 1% 0% of sodium lauryl sulfate, 0.2% to about 2% of sodium lauryl sulfate, and about 2% to about 10% of povidone. Colloidal silicon dioxide in an amount of 0.1% to about 1% and magnesium stearate in an amount of about 0.1% It contains about 1% by weight.

[0322] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) Contains about 1,200 mg to about 1,200 mg, about 200 mg to about 1,000 mg, about 400 mg to about 800 mg, or about 450 mg to about 600 mg. Such unit dosage forms are provided herein.

[0323] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or A compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg , 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1,000mg, 1,050mg, 1,100mg, 1,150, or Additionally provided herein is a unit dosage form containing about 1,200 mg. In embodiments, the unit dosage form comprises a compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V). Compounds having the structure, or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or or a compound selected from Metabolite 2, or a pharmaceutically acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) containing 40 mg, about 120 mg, about 150 mg, about 185 mg, about 200 mg, about 250 mg, about 300 mg, or even about 315 mg In some such embodiments, the unit dosage form contains about 40 mg of the compound, about 12 mg of the compound, and about 16 mg of the compound. and capsules containing about 0 mg, about 185 mg, about 200 mg, about 200, about 250 mg, or even about 300 mg. In some such embodiments, the unit dosage form is a tablet containing about 150 mg of the compound. In some such embodiments, the unit dosage form contains about 315 mg of the compound. It is a tablet having the following properties.

[0324] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, liquid L...

Claims

1. Baseline hemoglobin levels in patients who need it 2. For use in a method for increasing the yield of a compound having the structure: 【Chemical 1】 {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid having the formula 1. A pharmaceutical composition comprising a tablet or capsule containing Compound 1, The patient must have a hemoglobin (Hb) of ≦10.5 g / dL or ≧9.5 g / dL and ≦12 g / dL at the start of treatment. HGB) level, The level of serum hemoglobin is at least about 100 mg / kg / day compared to the baseline hemoglobin level. elevated by 0.1 to about 1.0 g / dL, and The pharmaceutical composition may comprise administering Compound 1 to the patient in an amount of about 150 mg, about 300 mg, about 450 mg, or about 600 mg. The pharmaceutical composition is used to be administered once a day.

2. The serum hemoglobin level is increased by about 1% compared to the baseline hemoglobin level.

10. The pharmaceutical composition of claim 1, wherein the blood glucose level is increased by about 0.1 to about 1.0 g / dL for up to 6 weeks.

3. The serum hemoglobin level is compared to the baseline hemoglobin level at 4 weeks 3. The pharmaceutical composition of claim 2, wherein the blood glucose level is increased by about 0.1 to about 1.0 g / dL over a period of time.

4. The serum hemoglobin level is increased by 6 weeks compared to the baseline hemoglobin level.

3. The pharmaceutical composition of claim 2, wherein the blood glucose level is increased by about 0.1 to about 1.0 g / dL over a period of time.

5. The serum hemoglobin level is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 5. The pharmaceutical composition of claim 1, wherein the blood glucose level is increased by 1.0 g / dL or 1.0 g / dL.

6. Claims: The patient has a hemoglobin (HGB) level that is ≦10.5 g / dL at the start of treatment. The pharmaceutical composition according to any one of claims 1 to 5.

7. The patient has a hemoglobin (HGB) level of ≥ 9.5 g / dL and ≤ 12 g / dL at the start of treatment. The pharmaceutical composition according to any one of claims 1 to 5, comprising:

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