Compositions and methods for treating anemia

Abstract

To provide compositions comprising HIF prolyl hydroxylase inhibitors in treating or preventing anemia, such as anemia secondary to or associated with chronic kidney disease, anemia associated with or resulting from chemotherapy, or anemia associated with AIDS.SOLUTION: Disclosed is a pharmaceutical composition comprising a compound {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetate or a pharmaceutically acceptable salt thereof for use in a method for treating anemia secondary to dialysis of chronic kidney disease, where the compound is orally administered to a subject once a day at a dose of about 150 mg to about 600 mg.SELECTED DRAWING: None

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 Nov. 1, 2013; No. 61 / 898,890 filed on Nov. 1, 2013 No. 61 / 898,885, filed on 2011; and No. 61 / 912,185, filed on December 5, 2013. No. 6,313,635, filed on Oct. 13, 2003, and claims the benefit of prior art, each of which is incorporated herein by reference in its entirety. is incorporated into.

[0002] 1. FIELD OF THEINVENTION The present disclosure relates to anemia secondary to or associated with chronic kidney disease, anemia secondary to or associated with 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 pharma- ceutical compounds and pharma- ceutical acceptable salts thereof, HIF prolyl hydroxylase inhibitor compounds and a composition containing the same, as well as a composition for treating peripheral vascular disease (PVD), coronary artery disease (CAD), heart failure, ischemia, 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 The use of HIF prolyl hydroxylase inhibitors in the treatment or prevention of anemia, such as anemia associated with It concerns specific dosages and dosing regimes for use. [Background technology]

[0003] 2. BACKGROUND OF THEINVENTION (2.1 Hypoxia-inducible factor) 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 erythrocyte It upregulates the transcription of several target genes, including the gene encoding thrombopoietin. HIF is a heteroduplex that contains α and β subunits. The β subunit is normally present in excess and is independent of oxygen tension, whereas the HIF-α subunit In this regard, accumulation of HIF-α was observed only in cells under hypoxic conditions. The main mechanism is the bipartite synthesis of prolyl hydroxylases, a family of prolyl hydroxylases known as HIF prolyl hydroxylases. wherein the hydroxylation of one or both proline residues is This leads to rapid degradation of HIF-α. Therefore, inhibition of HIF prolyl hydroxylase reduces the stability of HIF-α. This results in the synthesis and accumulation of HIF-α (i.e., reduced degradation of HIF-α), thereby reducing HIF heterodimers. 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 results in 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 hydroxylase Their use to treat or prevent diseases ameliorated by modulation of metabolic enzymes is disclosed 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. 6,399,413, which is incorporated herein by reference in its entirety. The compounds inhibit HIF prolyl hydroxylase, 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 disorders such as anemia are important to prevent adverse effects. to achieve the desired or optimal therapeutic effect without undesirable 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 avoiding or reducing adverse or undesirable effects, provide an optimal therapeutic effect, i.e., provide 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) with erythropoiesis-stimulating agents is a long-term treatment option for This often results in erythropoietin (EPO) levels above normal levels, 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 thought to be essential for cell survival, but excess iron accumulation , is associated with the formation of toxic free radicals and progressive tissue destruction. Excess iron also It may 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 increased levels of hepcidin, but also leads to a parallel decrease in hepcidin gene expression. It blocks the action of ferroportin, which mobilizes iron outside of cells. Thus, when hepcidin expression is reduced in a subject, ferroportin action is blocked. Instead, iron is released from the cells, thereby increasing the risk of iron overload in the subject. In situations where iron overload is a concern, treatment of anemia without decreasing hepcidin levels is There is a need for novel therapeutics. 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 THEINVENTION) (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 the pharma- ceutical acceptable salts, solvates, or hydrates thereof are It is administered according to a specific dosing regimen that regulates hydroxylase enzyme activity, thereby stabilizing HIF-α. and thereby treat anemia (e.g., anemia secondary to chronic kidney disease). The description of these formulas and compounds is set forth 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 pharma- ceutically acceptable salt, solvate, or hydrate thereof. Specific dosage amounts and unit dosage forms of the products are further set forth herein. In an embodiment, 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 pharma- ceutically acceptable salt. In some specific embodiments, the compound is a solvate of Compound 1. It is.

[0011] In some embodiments, the disease ameliorated by modulation of HIF prolyl hydroxylase is administering to a patient having the disease 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 pharma- ceutically acceptable salt, solvate, or hydrate thereof. The present invention relates to a method for treating or preventing a disease that is ameliorated by modulation of HIF prolyl hydroxylase, comprising administering 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 compound of formula (I), formula (II), formula (III), formula (IV), formula (IV), formula (V ... 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 A compound selected from compound 12, compound 13, metabolite 1, and metabolite 2, or a pharmaceutical approved compound thereof. Acceptable daily amounts 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, / 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) Compound 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 pharma- ceutically acceptable salt, solvate, or 2. Treating anemia secondary to chronic kidney disease, comprising administering to a patient having anemia an effective amount of a hydrate. Methods for treating or preventing anemia, such as bronchitis, bronchitis, and bronchitis are provided herein. In some embodiments, 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 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, and Metabolite 2 Daily dose of the compound or a pharma- ceutically 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, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 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 In some such embodiments, the dosage is 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 amount may be administered orally once a day, twice a day, or three times a day, preferably once a day. 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, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, or 4 mg / kg. do.

[0014] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutically 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) Compound 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 pharma- ceutically 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, the hemoglobin level is increased by at least at least about 8.0 g / dL and no more than about 13.0 g / dL, at least about 8.5 g / dL and no more than 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, The method of maintaining blood glucose levels at 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 represented by the formula (I), (II), (III), (IV), or the like is provided. 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, A compound selected from Metabolite 1 and Metabolite 2, or a medicamentously acceptable salt or solvent thereof. The present invention relates to a method for treating anemia comprising administering an effective amount of Compound 1 to a patient suffering from anemia. and maintaining hemoglobin levels at least about 11.0 g / dL and no greater than about 13.0 g / dL in patients receiving the and maintaining the blood glucose level at a level of at least about 11.0 g / dL. In some such embodiments, the compound represented by Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure of , compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, compound 13, metabolite 1, and and metabolite 2, or a pharma- ceutical acceptable salt, solvate, or derivative thereof. or a hydrate, specifically, the daily dose of Compound 1 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. It may be administered orally once. 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) Compound 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 pharma- ceutically 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 hemoglobin level in the patient. At least about 0.1 g / dL, at least about 0.2 g / dL, or 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 represented by Formula (I), Formula (II), Formula (III), Formula (IV), 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 1 3, about 150 mg, about 300 mg, about 450 mg, about 600 mg, or a compound selected from metabolite 1 and metabolite 2; or about 750 mg. In some such embodiments, the daily dose is about 150 mg, about 300 mg, The daily dose is about 450 mg, or about 600 mg. Such a daily dose may be 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) Compound 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 pharma- ceutically acceptable salt, solvate, or and administering to the patient a medicament for treating anemia or anemia comprising ... Provided herein is a method for preventing, wherein the medicamentously effective amount is a hemoglobin The patient's hemoglobin level is increased by at least about 0.5 g / mL compared to the patient's baseline hemoglobin level. / 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 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 it is suitable for adding: a) restore or maintain the diurnal pattern of EPO serum levels; b) Increases 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 determined by measuring the baseline hemoglobin level. The diurnal variation of serum EPO levels in healthy individuals was also increased compared to globin levels. To mimic this, sequential doses of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers were administered in sufficient amounts. and administering the appropriate amount of EPO to a patient having a disease or condition 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, in which 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 pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0020] In some embodiments, the level of hemoglobin in the patient is determined by measuring the baseline hemoglobin level. HIF prolyl hydroxylase inhibitors or HIF-α stabilizers to increase HIF levels relative to globin levels A sufficient number of successive doses of the compound are administered to a subject suffering from 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 is a method for treating a disease or condition, comprising administering a small amount of the continuous dose to a subject. 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 return to approximately baseline serum EPO levels, where H The IF prolyl hydroxylase inhibitor or HIF-α stabilizer is represented by the 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, A compound selected from Metabolite 1 and Metabolite 2, or a medicamentously 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 determined by measuring the baseline hemoglobin level. HIF prolyl hydroxylase inhibitors or HIF-α stabilizers to increase HIF levels relative to globin levels A sufficient number of successive doses of the compound are administered to a subject suffering from 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 is a method 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 higher dose, serum EPO levels had returned to near baseline levels, The HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is represented by the formula (I), formula (II), formula (III), formula (IV) 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 1 A compound selected from 3, metabolite 1, and metabolite 2, or a pharma- ceutical acceptable salt thereof. In some such embodiments, the exogenous EPO is a solvate, 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. The hemoglobin levels in patients were increased to baseline hemoglobin levels without a significant increase in The combination of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers increased the levels of HIF-α compared to the control group. A patient with a disease or condition associated with reduced endogenous production of EPO is administered successive doses at sufficient frequency. The present invention relates to a method for treating a disease associated with decreased endogenous production of erythropoietin (EPO), including administering the method to a patient. Provided herein are methods for treating a disease or condition, comprising administering to a subject a therapeutically effective amount of 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 pharma- ceutically acceptable salt, solvate, or hydrate thereof. In some such embodiments, the cardiovascular The risk of side effects and thromboembolic events is minimized.

[0023] In some such embodiments, the level of serum EPO is determined according to the methods disclosed herein. About 1 week, about 6 days, about 5 days after administration of a dose of an IF prolyl hydroxylase inhibitor or a HIF-α stabilizer Within about 12 hours, 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 about 5 mIU / m L, within 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 determined to be 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 1 It rises by about 0.1 g / dL over a period of weeks.

[0026] In some embodiments, the level of hemoglobin is determined to be a baseline hemoglobin level. Compared to baseline, the serum creatinine concentration rises by about 0.1 to about 1.0 g / dL over a two-week period. In some embodiments, the hemoglobin level is increased by 2 to 4 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 determined to be a baseline hemoglobin level. Compared to baseline, the increase is 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 determined to be a baseline hemoglobin level. Compared to baseline, the increase is 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% 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 of chronic kidney disease. In such embodiments, the chronic renal disease is pre-dialysis chronic renal 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 stabiliser is administered orally.

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

[0033] In some embodiments, the disease, condition, or For the treatment of disorders, the dosages set forth in Section 5.5, specifically natural The compounds identified in Section 5.2, at doses appropriate to mimic the diurnal pattern of EPO in The subject matter is provided herein (see Section 5.3.1).

[0034] (3.3 Iron metabolism) Traditionally, the treatment for anemia or anemia secondary to chronic kidney disease has been limited to the treatment of reduced erythropoietin (EPO). 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 hepatitis or chronic kidney disease or a disease or condition associated with a deficiency in endogenous hemoglobin production. , which increases total iron binding capacity without increasing serum iron levels, thereby improving transferrin saturation. It has been found that the increased blood flow can be effectively treated by causing a decrease in Undesirable side effects associated with low iron levels can be reduced or avoided.

[0035] In some embodiments, the serum iron level is compared to a 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 a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer are administered. and administering the compound to a patient having a disease or condition associated with reduced endogenous production of EPO. To treat a disease or condition 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) Compound 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 pharma- ceutically acceptable salt, solvate, or The present invention relates to a method for treating anemia in a subject, comprising administering to the subject a medicamentously effective amount of a hydrate of In some more specific embodiments, methods of 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 medicamentously effective amount of a pharma- ceutical 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 least about 60 μg / dL, and / or maintain hemoglobin levels at baseline 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 pretreatment 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. Increase total iron-binding capacity (TIBC) in patients compared to baseline TIBC without a significant increase in Thus, a sufficient number of successive 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 reduced 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 decreased 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 / kg / day 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 one week. or for about 2 weeks, for about 3 weeks, for about 4 weeks, for about 5 weeks, or Occurs over a period of 6 weeks.

[0041] In some embodiments, the serum iron level is increased by about 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 certain 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 hydride is a heterocyclic carboxamide. Oxidase inhibitors or HIF-α stabilizers are pyridinecarboxamides, quinolinecarboxamides and isoquinolinecarboxamide. In some embodiments, the HI The F prolyl hydroxylase inhibitor or HIF-α stabilizer is represented by the 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, A compound selected from Metabolite 1 and Metabolite 2, or a medicamentously acceptable salt or solvent thereof. solvates or hydrates.

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

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

[0048] In some embodiments, hepcidin expression is measured using a baseline hepcidin expression level. The serum hemoglobin levels in patients were significantly reduced compared to baseline The serum hemoglobin level was increased by HIF prolyl hydroxylase inhibitors or HIF-α Sufficient doses of stabilisers should be administered to treat non-severe anemia secondary to chronic kidney disease, congestive heart failure, and chronic kidney disease. 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 The present invention provides 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. and provide it.

[0049] In some embodiments, the serum hemoglobin level is determined by measuring the baseline hemoglobin level. The levels are increased by about 0.1 to about 1.0 g / dL over a one-week period. In such embodiments, the serum hemoglobin level is adjusted to a 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 determined by measuring the baseline hemoglobin level. The levels are increased by about 0.1 to about 1.0 g / dL over a two-week period. In such embodiments, the serum hemoglobin level is adjusted to a 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 determined by measuring the baseline hemoglobin level. The levels are increased by about 0.1 to about 1.0 g / dL over a three-week period. In such embodiments, the serum hemoglobin level is adjusted to a baseline hemoglobin level. In comparison, over a three week period, it is elevated by approximately 0.5 g / dL.

[0052] In some embodiments, the serum hemoglobin level is determined by measuring the baseline hemoglobin level. Over a four week period, the levels are increased by about 0.1 to about 1.0 g / dL compared to normal levels. In such embodiments, the serum hemoglobin level is adjusted to a baseline hemoglobin level. In comparison, over a four week period, it is elevated by approximately 0.6 g / dL.

[0053] In some embodiments, the serum hemoglobin level is determined by measuring the baseline hemoglobin level. The levels are increased by about 0.1 to about 1.0 g / dL over a 5-week period. In such embodiments, the serum hemoglobin level is adjusted to a baseline hemoglobin level. In comparison, over a five week period, it is elevated by approximately 0.6 g / dL.

[0054] In some embodiments, the serum hemoglobin level is determined by measuring the baseline hemoglobin level. Over a 6-week period, the levels are increased by about 0.1 to about 1.0 g / dL compared to normal levels. In such embodiments, the serum hemoglobin level is adjusted to a baseline hemoglobin level. In comparison, over a six week period, it is elevated by approximately 0.6 g / dL.

[0055] In some embodiments, hepcidin expression is measured using a baseline hepcidin expression level. about 20% less, about 15% less, about 10% less, 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 hydride is a heterocyclic carboxamide. Oxidase inhibitors or HIF-α stabilizers are pyridinecarboxamides, quinolinecarboxamides 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 The compound is a pharma- ceutically acceptable salt, solvate, or hydrate thereof. The HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 1 or a pharmaceutical thereof. In a specific embodiment, the HIF protease is an acceptable salt, solvate, or hydrate. The aryl hydroxylase inhibitor or HIF-α stabilizer is Compound 7 or a pharma- ceutical 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 set forth in Section 5.5, specifically Section Reducing hepcidin levels as described in Section 5.3.3 and / or Suitable dosages for treating anemia without increasing erythroferon levels as described. Quantities of the compounds disclosed in Section 5.2 are provided herein. [Brief description 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 EPO responses in healthy male adults over a 24-hour period following administration of Compound 1.

[0063] [Diagram 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] [Diagram 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] [Diagram 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 an 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 baseline in patients with anemia secondary to chronic kidney disease over a 6-week period when treated with Compound 1.

[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 PREFERRED EMBODIMENTS

[0071] (5 Detailed Description) In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutically acceptable salt, solvate, or and administering to the patient a medicament for treating anemia or anemia comprising ... Provided herein is a method for preventing, wherein the medicamentously effective amount is a vein-dependent inhibitor of the pulmonary circulation of the patient. Compared to baseline hemoglobin levels, the dL, at least about 0.6 g / dL, at least about 0.7 g / dL, at least about 0.8 g / 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 "including" and "contains" are intended to be used interchangeably, e.g. The term "additives," "ingredients," "integers," or "steps" is intended to include, but not exclude, the following additives, ingredients, integers, or steps: In some embodiments, the present description and appended claims are not intended to The singular forms "a," "an," and "the" used herein are used unless the context clearly indicates otherwise. Thus, for example, reference to "a composition" includes reference to two or more such compositions. In some embodiments, the composition 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 is, for example, an alkyl group having 1 to 12 carbon atoms, 1 to 9 carbon atoms, , saturated linear or branched, 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; whereas branched alkyl includes -isopropyl. -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 the following non-limiting examples: methyl (C1), ethyl (C2), n-propyl. (C3), isopropyl (C3), n-butyl (C4), sec-butyl (C4), isobutyl (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, a partially unsaturated linear or branched acyclic alkyl group having 1 to 6 carbon atoms. Representative alkenyl groups include propenyl and the like.

[0076] As used herein, an "alkynyl" group is an alkynyl group having at least one carbon-carbon triple bond. and, for example, a partially unsaturated linear or branched acyclic alkyl group 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 are methoxy, ethoxy, n-propoxy, Includes siloxy, 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 6 carbon atoms. Representative cycloalkyl groups are cyclopropyl, ... Includes cyclobutyl and cyclopentyl.

[0079] As used herein, a "cycloalkenyl" group refers to an alkyl 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. Representative cycloalkoxy groups are cycloalkyl-O- groups, 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 hydrogen atoms are replaced by halogen atoms, as defined herein above. Representative haloalkyl groups are CF3, CHF2, CH2F, CCl3, CF3CH2CH2, and Includes 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 an alkyl group in which one or two ring members are O, S and NR″, and the remaining atoms are carbon, preferably 4 to 7 atoms. The ring is preferably a saturated ring of 5 or 6 ring atoms. Representative heterocycloalkyl groups are piperidyl, pyrrolidinyl, piperidyl, 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 monocyclic 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 substituted with adjacent oxygen and / or ion atoms. 2 to 9 carbon atoms and N, O and S, provided that they do not contain any C atoms. Monocyclic, bicyclic, 5-10 atom rings consisting of 1-4 heteroatoms selected from or benzo-fused heteroaromatic groups. N-oxides of the ring nitrogens are also included. Representative monocyclic Heteroaryl groups of the formula are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl , furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl 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 is indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothiyl, enyl (i.e. thianaphthalenyl), benzimidazolyl, benzofuranyl, benzoxa These include azolyl, 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 terms used herein include enantiomeric forms, diastereomeric forms, salts, tautomers, and the like. Equally representative are the enzyme inhibitors of HIF prolyl hydroxylases described herein. The compounds mentioned may take any salt form, for example salts of basic groups, especially amines, as well as salts of acidic groups, and The following compounds form pharma- ceutically acceptable salts with basic groups: Non-limiting examples of anions that may be used are: chloride, bromide, iodide, sulfur. Acid ion, hydrogen sulfate ion, carbonate ion, hydrogen carbonate ion, phosphate ion, formate ion, 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 pharma- ceutically 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 other amines on the compounds described herein: can form pharma- ceutically 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 aspects, the terms "compound," "analog," and "composition of matter" are used throughout this specification. are used interchangeably.

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

[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 secondary to aging, Idiopathic anemia, anemia due to 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 to treat bone marrow inflammation or other chronic diseases that reduce bone marrow production may be the cause. anemia due to injury or surgery), 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 pregnancy, pregnancy alone, or due to anemia caused by autologous blood donation.

[0089] As used herein, the term "non-severe anemia" refers to an anemia in which the hemoglobin level is at least In some such embodiments, the term refers to a patient with anemia greater than or equal to 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 pharma- ceutically acceptable salt, solvate, or hydrate thereof. The composition may contain a unit dosage form or may contain more than a unit dosage form (e.g., a single dose). may contain two tablets) or may be in a less than unit dosage form (e.g., a single dose may contain more than one tablet). Thus, the compound may be administered in a daily dose of 450 mg, once a day. When administered once daily, the compound dosage is comprised of three tablets, each containing 150 mg of the 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 means the amount of a pharma- ceutically 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 separate doses. The daily dose may be divided so that the compound is administered twice a day, three times a day, or even four times a day. When administered daily without interruption, the dosage is referred to as a "continuous" dosage.

[0092] As used herein, the term "unit dosage form" refers to any of the following: tablets; caplets; soft elastic gelatin Capsules, e.g. 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 obtain a A unit dosage form is not necessarily administered as a single dose, and may be any unit dosage form including: It does not necessarily have to constitute the entire dose.

[0093] As used herein, an "effective amount" refers to an amount sufficient to provide a therapeutic benefit in the treatment of a disease. or a compound or compounds sufficient to inhibit or delay or minimize symptoms associated with the disease. The present invention refers to the amount of a pharma- ceutically 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 that, as well as being useful in treating 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 condition, It is well understood in the art and is a method for treating a subject's condition, comprising administering to a subject a therapeutically effective amount of the composition, as compared to a subject who does not receive the composition. The compounds provided herein reduce the frequency or delay the onset of symptoms of a condition in or a pharma- ceutically 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). 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 symptoms, clinical signs and underlying pathology in a manner that improves or stabilises 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 pharma- ceutically acceptable salt, solvate or derivative thereof. the spread or aggravation of a disease as a result of the administration of the compound or hydrate to a patient suffering from such a disease; This refers to the minimization of

[0096] As used herein, the term "pharmaceutical acceptable salts" refers to inorganic acids and bases as well as and salts prepared from pharma- ceutically 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 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 pharma- ceutically acceptable base addition salts for Calcium, magnesium, zinc, bismuth, ammonium (alkyl substituted Ammonium), amino acids (e.g., lysine, ornithine, arginine, or glutathione, Examples of antidepressants include, but are not limited to, bromophenamine, tromethamine, and meglumine. Suitable non-toxic acids include inorganic and organic acids, such as acetic acid, alginic acid, anthracite, etc. 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, phosphoric acid 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 , sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Other examples of salts are well known in the art and can be found, for example, in Remington's Pharmaceutical Sciences. See "Mr. Emington's Pharmaceutical Sciences," 22nd ed., Pharmaceutical Press (2012). I want to be illuminated.

[0097] In some embodiments, "pharmaceutical acceptable" means biologically or otherwise is intended to mean a substance which is not undesirable in the above-mentioned cases, i.e. which is clinically unacceptable. 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 the relevant active compound without interacting in a deleterious manner with the 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 By "amines" is meant pharma- ceutical acceptable salts thereof.

[0099] As used herein, the term "solvate" refers to a compound that is 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 pharma- ceutical acceptable salt thereof.

[0100] Unless otherwise indicated, as used herein, the terms "about" or "approximately" refer to values. The specific characteristics, as determined by one of ordinary skill in the art, will depend in part on how they are 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 any value that is within the range of 50%, 20%, 15%, 10%, 9%, 8%, 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 "about" When values ​​are expressed as approximations, it will be understood that the particular value forms another embodiment. 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 set forth herein are important in determining the Note that there are many values, and that each value also represents "about" that particular value in addition to the value itself. It is also understood that the value "10" is set forth herein. When a value is given, "about 10" is also given. When a value is given, it is understood by those of ordinary skill in the art to be appropriate. "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 made clear 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 the 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, as well as 10 and 15 It is understood that the terms between two particular unit quantities are considered to be clearly defined. It is also understood that the quantities are also disclosed. For example, if 10 and 15 are disclosed, then 11, Numbers 12, 13, and 14 are also revealed.

[0101] In some embodiments, the term subject or patient refers to a human, mouse, dog, donkey, horse, The present invention may refer to a mammal, such as a rat, a guinea pig, a bird, or a monkey. In an embodiment, 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, although several alternative embodiments are possible. In the compound, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] In some alternative embodiments, the compound may be a pharma- ceutically acceptable salt of the 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 relates to compounds of the parent type. The present invention relates to a compound (i.e., not a salt, solvate, or hydrate). In an embodiment, the present invention relates to the present compounds or their pharma- ceutically acceptable salts.

[0104] As used herein, the term "HIF prolyl hydroxylase" refers to a protease that is known in the art. HIF prolyl hydroxylases are recognized as PHDs and can be abbreviated as "PHDs." Also known as "prolyl hydroxylase domain-containing protein," which can be abbreviated as "prolyl hydroxylase domain-containing protein." In this regard, three distinct PHD isoforms, PHD1, PHD2, and PHD3, respectively, There are three types of HPH1, 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 referred to as a target.

[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. 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 present invention, the compound for use in the methods provided herein is 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 hydroxylases than against the enzyme Thus, in some embodiments, the methods provided herein are The compounds provided herein for use in the methods of the present invention preferentially inhibit 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 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 Reacts immunospecifically with IF-1-α and does not cross-react with HIF-2-α; primary antibody against 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-alpha 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 pharma- ceutically 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 connected 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 pharma- ceutically 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 Haeta 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 H(CN), N(CN)2, CH(CN)2, C(CN)3; 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 represent a group having 2 to 7 carbon atoms. 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 containing 3 to 7 atoms.

[0110] In some embodiments, the HIF stabilizer is a compound having the structure of formula (III): and pharma- ceutically 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 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, they are made up of 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), or and pharma- ceutically 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 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, they are made up of 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 follows: 1-6 is alkyl; and Here, R 1 and R 2 are independently H or C 1-6 It is an alkyl group. [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 A pharma- ceutically acceptable salt, solvate or hydrate thereof: [ka] .

[0114] In some embodiments, the HIF stabilizer is Compound 2 having the structure: and the like. [ka] .

[0115] In some embodiments, the HIF stabilizer is Compound 3, having the structure: and the like. [ka] .

[0116] In some embodiments, the HIF stabilizer is Compound 4, having the structure: and the like. [ka] .

[0117] In some embodiments, the HIF stabilizer is Compound 5, having the structure: and the like. [ka] .

[0118] In some embodiments, the HIF stabilizer is Compound 6, having the structure: and the like. [ka] .

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

[0120] In some embodiments, the HIF stabilizer is Compound 8, having the structure: and the like. [ka] .

[0121] In some embodiments, the HIF stabilizer is compound 9 having the structure: and the like. [ka] .

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

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

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

[0125] In some embodiments, the HIF stabilizer is named N-(2-aminoethyl)-3-hydroxy- Compound 13 has the following structure and has pyridine-2-carboxamide. Including acceptable salts and tautomers thereof: [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) Compound 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 thus obtained can be used in the methods provided herein. In a more specific embodiment, such metabolites are phenolic glucuronides or acyl It is a glucuronide. [ka]

[0127] Compound 13 is disclosed in 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) Compound 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 pharma- ceutical acceptable salt, solvate, or and administering to the patient an effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer, such as a hydrate thereof, to treat anemia. wherein the daily dose comprises administering to a patient having the compound, a pharmacologic agent thereof, The amount of the salt, solvate, or hydrate that can be obtained by the method 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, such as anemia caused by 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, 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 , 3.9 mg / kg, or 4 mg / kg. In some embodiments, the HIF-α stabilizer is A daily dose of about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of a hydroxylase inhibitor is administered. 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 pharmaceutical preparations, and and administering the compound in the form of a salt, solvate, or hydrate thereof, which is acceptable for administering to a patient suffering from chronic kidney disease secondary to chronic kidney disease. A compound represented by the formula (I), (II), (III), (IV), (VIII) or (VIII) 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 medicament thereof. and a salt, solvate, or hydrate thereof capable of inhibiting HIF prolyl hydroxylase or HIF-α. Stabilizing agents 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-chlorophenyl)amino}acetic acid. Pharmaceutically acceptable 3-hydroxypyridine-2-carbonylamino}acetic acid In some embodiments, the compound is a {[5-(3-chlorophenyl)-3-hydroxyphenyl]- In some embodiments, the compound is a solvate of 2-methoxypyridine-2-carbonylamino}acetic acid. The compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amine In some embodiments, the compound is 2-(5-(3-fluoro-2-(2-methyl-1,2-dioxane))-1,2-dioxane. 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-(phenyl)-1,1-dihydro-2-(trifluoro ... In some embodiments, the compound is a solvate of 3-(3-hydroxypicolinamido)-1,3-dihydro ... The compound is a hydrate of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. It is an object.

[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 obtained by the method according to the present invention. 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 rituximab secondary to chronic kidney disease. In some embodiments, the patient is being treated for anemia, such as anemia associated with 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 or decreased for more than 42 consecutive days or even for more than 90 consecutive days. In some alternative embodiments, the daily dose is administered for at least one week and up to The drug 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 a day. 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 certain embodiments, the patient is receiving a daily dose in the early afternoon. Those with renal disease and who were administered the compound (see Section 5.2) at the same times of day, specifically in the late morning in the early afternoon, more specifically just before lunch, just after lunch, between lunch and 2 p.m., Between 10:00 and 2:00 p.m., 10:00 a.m., 11:00 a.m., 12:00 p.m., 1:00 p.m., or 2:00 p.m. do.

[0132] In some embodiments, the patient's hemoglobin level is between about 8.0 g / dL and about 13.0 g / dL. 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 serum 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 altitude, 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 ketamine resulted 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 The amount administered is such that the blood glucose level is maintained at 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. In these cases, 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 stimulating agent (ESA). 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 on an irregular basis.

[0136] In some such embodiments, the compound of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the structure of , Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, Young or metabolite 2, or a pharma- ceutical 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 comprises administering to the subject compounds, about 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 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 initiate the treatment. The daily dose is then 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 pharma- ceutically acceptable form thereof. In some embodiments, the compound is a salt, solvate, or hydrate. Compound 7, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0137] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutical acceptable salt, solvate, or or a daily dose of the hydrate thereof 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 less than about 10.0 g / dL and the hemoglobin level is or the patient's hemoglobin level is decreased by less than about 0.5 g / dL compared to the level measured previously; If the bottle level is less than about 10.0 g / dL and the hemoglobin level is greater than or equal to 10.0 g / dL, or the patient's hemoglobin level is changed by a maximum of about 0.4 g / dL compared to the level measured; The blood glucose level 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 from the prescribed level; a decrease of more than 150 mg from the prescribed daily amount administering a controlled daily dose of the compound; 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 pharma- ceutically acceptable salt thereof. In a specific embodiment, the compound is a salt, solvate, or hydrate thereof. Compound 7, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0138] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutical acceptable salt, solvate, or or a daily dose of the hydrate thereof 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 less than about 10.0 g / dL and the hemoglobin level is or if the patient's hemoglobin level is increased by approximately 1.5 g / dL compared to the level measured The hemoglobin level is between about 10.0 and about 10.9 g / dL and the hemoglobin level is higher than that of the earlier stage. or hemoglobin is increased by approximately 1.5 g / dL compared to the level measured between levels between about 11.0 and about 12.2 g / dL and the hemoglobin level is or if the hemoglobin level is increased by about 1.0 to about 1.4 g / dL compared to the measured level; levels between about 12.3 and about 12.9 g / dL and hemoglobin levels are higher for an earlier period The level is 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 has a hemoglobin level 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 in the earlier period. g / dL; the adjusted daily dose of the compound is 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 In some embodiments, the compound is {lysine-2-carbonyl]amino}acetic acid. [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid as a medicine In some embodiments, the compound is {[5-(3-chlorophenyl)- It is a solvate of 3-hydroxypyridine-2-carbonylamino- acetic acid. In an embodiment, 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 a 2-(5-(3-fluorophenyl)-2-(phenyl)-1,2-dihydro-1,2-trifluoro ... In some embodiments, the compound is a solvate of (3-(phenyl)-3-hydroxypicolinamido)acetic acid. In this manner, 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, 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or a daily dose of the hydrate thereof 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 is increased by about 1.5 g / dL compared to levels measured in an earlier period; or Hemoglobin levels between about 12.3 and about 12.9 g / dL and or if the patient's blood levels increase by about 1.0 to about 1.4 g / dL compared to levels measured in an earlier period; The hemoglobin level in the subject is between about 12.3 and about 12.9 g / dL, and If the level is increased by about 1.5 g / dL compared to the level measured in the earlier period; 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 cardiovascular disease, 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-hydroxyphenyl] It is a pharma- ceutical acceptable salt of 2-pyridine-2-carbonylaminoacetic acid. In an embodiment, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbo In some embodiments, the compound is a solvate of {[5-(3-phenyl]amino}acetic acid. 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-hydro In some embodiments, the compound is a pharma- ceutical acceptable salt of methoxypicolinamido)acetic 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, the compound 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. It is.

[0140] In some embodiments, the present invention provides a compound comprising {[5-(3-chlorophenyl)-3-hydroxypyridine; or a medicament for use as a medicament for treating a disease comprising administering to said patient a medicament a compound which is a compound selected from the group consisting of dimethylaminoethyl ether, ... 2. The method of claim 1, further comprising administering a daily dose of a solute or hydrate of said compound to a patient suffering from anemia. For a method of treating anemia, such as anemia secondary to bronchitis, wherein the daily dose is about 450 mg.

[0141] In some such embodiments, the daily dose is such that the daily dose of the compound is about 600 mg. In some embodiments, the daily dose is increased by about 150 mg to about 100 mg 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 In some embodiments, the compound is {lysine-2-carbonyl]amino}acetic acid. [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid as a medicine In some embodiments, the compound is {[5-(3-chlorophenyl)- It is a solvate of 3-hydroxypyridine-2-carbonylamino- acetic acid. In an embodiment, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbo It is a hydrate of 1,3-diphenylamino}acetic acid.

[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 rituximab secondary to chronic kidney disease. Being treated for anemia, such as anemia.

[0144] In some embodiments, the present invention provides a compound comprising {[5-(3-chlorophenyl)-3-hydroxypyridine; or a medicament for use as a medicament for treating a disease comprising administering to said patient a medicament a compound which is a compound selected from the group consisting of dimethylaminoethyl ether, ... 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 the hemoglobin level is increased by 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 has a hemoglobin level 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 in earlier periods administering an adjusted daily dose of the compound that is 300 mg less than said 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 it can increase serum hemoglobin levels, serum EPO levels remain elevated 24 hours after administration. Unexpectedly, the results showed that the ANEA and chronic inflammatory bowel disease were reversed to near baseline levels within a short time. associated with reduced endogenous production of erythropoietin (EPO), such as anemia secondary to chronic renal disease. or a disease or condition associated with a deficiency in endogenous hemoglobin production. In a patient suffering from mimicking the diurnal variation of serum EPO levels in healthy individuals through the administration of successive doses of and inducing a blood EPO increase in the patient without significantly increasing the patient's baseline serum EPO level. It has subsequently been 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. Thus, 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 The adverse side effects typically associated with administration of exogenous EPO and EPO levels above normal. In addition, these results suggest that the kidney may be involved in the development of This was surprising because erythropoietin is the major source of erythropoietin production in the In particular, for patients with diseases or conditions associated with impaired renal function, those skilled in the art will be able to Administration of the compounds provided herein causes an increase in the patient's serum hemoglobin level, It also mimics the diurnal variation of serum EPO levels in healthy individuals and is consistent with the patient's baseline serum EPO It is unexpected that the levels of β-lactamase were not increased in healthy individuals. The aim of this study was to mimic the diurnal variation of serum EPO levels in the 10-day period and to measure baseline serum erythropoietin (EPO) levels. The results showed that the hemoglobin level increased to baseline in patients without significantly increasing the creatine levels. Compounds disclosed herein, such as Compound 1, are used to increase hemoglobin levels relative to 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 (HEMO) This allows for administration to patients with a disease or condition associated with robin production.

[0146] In some embodiments, the pharmaceutical agent is a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer. The present invention includes administering to a subject a medicamentously effective amount of a medicament comprising a serum endothelial cell line comprising a medicament ... Suitable for mimicking the diurnal variation of rithropoietin, for treating anemia in a subject and / or Provided herein are methods for preventing. More specifically, provided herein are methods for preventing. Administration of a pharma- ceutical effective amount of the compound results in increased levels of EPO mRNA and / or EPO protein in the trachea. and / or EPO mRNA and / or EPO protein trough levels before treatment. or trough levels of EPO mRNA and / or EPO protein in subjects without anemia. Compared to the 100% limit, the 150% limit is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%. 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 pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0147] More specifically, a medicamentously effective amount is one that reduces serum erythropoietin levels to baseline levels. This is suitable for mimicking the diurnal variation of serum erythropoietin without increasing it above 100 mg / kg / day. wherein the baseline level is the diurnal EPO level in healthy volunteers without anemia. This is the baseline.

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

[0149] In some embodiments, the hemoglobin level is increased relative to the baseline hemoglobin level in the patient. While increasing the levels of erythropoietin, it mimics the diurnal variation of serum erythropoietin levels in healthy individuals. To mimic the effects of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers, sufficient consecutive doses were administered. administering the dose to a patient having a disease or condition associated with reduced endogenous production of EPO. The present invention relates to a method for treating a disease or condition associated with decreased endogenous production of erythropoietin (EPO), including the treatment of In some embodiments, methods are provided herein for isolating HIF prolyl hydroxylase. The enzyme inhibitor or HIF-α stabilizer is a compound represented by formula (I), (II), (III), (IV), or (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 pharma- ceutical acceptable salt, solvate, or the like thereof. In a specific embodiment, the HIF prolyl hydroxylase inhibitor or HIF- The alpha stabilizer is Compound 1 or a pharma- ceutically 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 pharma- ceutically acceptable salt, solvate, or hydrate thereof. In such embodiments, the cardiovascular side effects and thromboembolic events associated with administration of exogenous EPO are The risk of is minimized.

[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 increases the expression 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 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 measured using pre-treatment EPO mRNA and / or EPO protein levels. and / or EPO mRNA and / or EPO protein levels in subjects without anemia. or at least 10%, 15%, 20%, 25%, 30% or more lower than 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 medicamentously effective amount is a dose that reduces endogenous erythropoietin (EPO) levels. In subjects with a disease or condition related to sex production, the serum erythropoietin level was increased by 100 mg / kg / day. Mimicking the diurnal variation of serum erythropoietin without increasing it above in-line levels wherein the baseline level is in a healthy volunteer without anemia. The diurnal baseline of EPO. 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%, The trough level is increased by 90%, or at least 95%, or 100%, but not significantly. is not increased.

[0152] In some such embodiments, the level of serum EPO is determined 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 dosage 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 determined to be a baseline hemoglobin level. Compared to baseline, blood levels rise by about 0.1 to about 1.0 g / dL over a one-week period. In certain embodiments, the level of hemoglobin is , elevated by approximately 0.1 g / dL over a one week period.

[0155] In some embodiments, the level of hemoglobin is determined to be 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 certain embodiments, the level of hemoglobin is , elevated by approximately 0.1 g / dL over a two week period.

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

[0157] In some embodiments, the level of hemoglobin is determined to be a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a four-week period. In certain embodiments, the level of hemoglobin is , elevated by approximately 0.6 g / dL over a four 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 stabiliser 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 HIF levels relative to the The present invention relates to a method for treating a patient having a disease or condition associated with reduced endogenous production of EPO, the method comprising administering the patient to a hospital or clinic for treatment of a patient having 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 remains at approximately the baseline serum EPO level. Reduced endogenous erythropoietin (EPO) levels 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 of the present invention, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer has the formula: Compounds 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 The present invention relates to medicaments, solvates, or hydrates thereof. In an embodiment, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 1 or its derivatives. In yet a more specific embodiment, the compound is a pharma- ceutically acceptable salt, solvate, or hydrate. In this regard, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 7 or its medicament-approved compound. In some such embodiments, the compound is an acceptable salt, solvate, or hydrate. The risk of cardiovascular side effects and thromboembolic events associated with administration of endogenous EPO is minimized. .

[0161] In some such embodiments, the level of serum EPO is determined 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 dosage 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 determined to be a baseline hemoglobin level. Compared to baseline, blood levels rise by about 0.1 to about 1.0 g / dL over a one-week period. In certain embodiments, the level of hemoglobin is , elevated by approximately 0.1 g / dL over a one week period.

[0164] In some embodiments, the level of hemoglobin is determined to be 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 certain embodiments, the level of hemoglobin is , elevated by approximately 0.1 g / dL over a two week period.

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

[0166] In some embodiments, the level of hemoglobin is determined to be a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a four-week period. In certain embodiments, the level of hemoglobin is , elevated by approximately 0.6 g / dL over a four 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 stabiliser 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 HIF levels relative to the The present invention relates to a method for treating a patient having a disease or condition associated with reduced endogenous production of EPO, the method comprising administering the patient to a hospital or clinic for treatment of a patient having a disease or condition associated with reduced endogenous production of EPO. wherein prior to one or more additional doses following the initial dose, serum EPO The levels of erythropoietin (EPO) in the blood are restored to approximately baseline levels. Methods for treating diseases or conditions associated with sex production are provided herein. In a more specific embodiment of the present invention, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer has the formula: Compounds 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 pharma- ceutically 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, following administration of exogenous EPO The associated risk of cardiovascular side effects and thromboembolic events is minimized.

[0170] In some such embodiments, the level of serum EPO is determined 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 dosage 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 determined to be a baseline hemoglobin level. Compared to baseline, blood levels rise by about 0.1 to about 1.0 g / dL over a one-week period. In certain embodiments, the level of hemoglobin is , elevated by approximately 0.1 g / dL over a one week period.

[0173] In some embodiments, the level of hemoglobin is determined to be 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 certain embodiments, the level of hemoglobin is , elevated by approximately 0.1 g / dL over a two week period.

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

[0175] In some embodiments, the level of hemoglobin is determined to be a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a four-week period. In certain embodiments, the level of hemoglobin is , elevated by approximately 0.6 g / dL over a four 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 stabiliser is administered orally.

[0178] In some embodiments, the level of serum EPO is compared to the baseline level of serum EPO. The hemoglobin level was 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 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 1 Compound 1, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or any of them. A pharmaceutical acceptable salt, solvate, or hydrate of Provided herein are methods for treating a disease or condition associated with endogenous production of erythropoietin (EPO). In a specific embodiment, the compound is Compound 1, or a pharma- ceutically acceptable form thereof. In a specific embodiment, the compound is a salt, solvate, or hydrate. or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the reduction in cardiovascular side effects and thromboembolic events associated with administration of exogenous EPO is The risk is minimized.

[0179] In some such embodiments, the level of serum EPO is determined 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 dosage 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 determined to be a baseline hemoglobin level. Compared to baseline, blood levels rise by about 0.1 to about 1.0 g / dL over a one-week period. In certain embodiments, the level of hemoglobin is , elevated by approximately 0.1 g / dL over a one week period.

[0182] In some embodiments, the level of hemoglobin is determined to be 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 certain embodiments, the level of hemoglobin is , elevated by approximately 0.1 g / dL over a two week period.

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

[0184] In some embodiments, the level of hemoglobin is determined to be a baseline hemoglobin level. Compared to baseline, blood glucose levels rise by about 0.1 to about 1.0 g / dL over a four-week period. In certain embodiments, the level of hemoglobin is , elevated by approximately 0.6 g / dL over a four 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 stabiliser is administered orally.

[0187] In normal, healthy adults, there is an increase in serum levels of EPO that subsequently rises above baseline Normal diurnal variation in serum levels of erythropoietin (EPO) with return to normal serum EPO levels That is, EPO is detectable in serum and is at its highest level in the afternoon. and then recover to baseline levels that vary among individuals in a well-characterized rhythm. It shows fluctuations over a 24 hour period.

[0188] Serum EPO levels can be measured, for example, by in vivo bioassays, in vitro bioassays, and In some embodiments, the determination can be made 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 can be 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. 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 increasing relative 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 a disease or condition associated with hemoglobin production. In some such embodiments, the cardiovascular side effects and adverse events associated with 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. Provided herein are methods for administering the compound to a patient in need thereof. In a specific embodiment, the compound is 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. In such a manner, the compound is Compound 7, or a pharma- ceutical acceptable salt, solvate, or the like thereof. Most of the compounds are 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 HIF levels relative to the The present invention relates to a method for treating a patient having a disease or condition associated with reduced endogenous production of EPO, the method comprising administering the patient to a hospital or clinic for treatment of a patient having 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 restores the patient's serum EPO levels to approximately baseline serum EPO levels. The endogenous production of reduced erythropoietin (EPO) is sufficient to allow or a disease or condition associated with reduced hemoglobin production. In some such embodiments, methods of treating the inflammatory bowel disease 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 a disease or condition associated with the production of globin. In a specific embodiment, the compound is Compound 1, or a pharma- ceutically acceptable salt, dissolution medium, or the like. In a specific embodiment, the compound is Compound 7, A pharma- ceutical 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 HIF levels relative to the The present invention relates to a method for treating a patient having a disease or condition associated with reduced endogenous production of EPO, the method comprising administering the patient to a hospital or clinic for treatment of a patient having a disease or condition associated with reduced endogenous production of EPO. wherein prior to one or more additional doses following the initial dose, serum EPO levels are Levels return to near baseline levels, indicating that endogenous erythropoietin (EPO) is reduced Diseases or conditions associated with reduced hemoglobin production or diseases or conditions associated with reduced hemoglobin production In some such embodiments, methods of treating a condition include the steps of: 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 a disease or condition associated with the production of hemoglobin. In a specific embodiment, the compound is Compound 1, or a pharma- ceutically acceptable salt thereof. , solvates, or hydrates. In a specific embodiment, the compound is Compound 7, or a pharma- ceutical 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 Methods for treating a disease or condition associated with reduced hemoglobin production, or a disorder associated with reduced hemoglobin production, are provided herein. In some such embodiments, 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 endogenous production of EPO or with reduced hemoglobin production In a specific embodiment, a method for treating a disease or condition is provided herein. The compound is Compound 1, or a pharma- ceutical acceptable salt, solvate, or hydrate thereof. In a specific embodiment, the compound is Compound 7, or a pharma- ceutically acceptable analog thereof. The compound is a salt, solvate, or hydrate thereof.

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

[0195] In some embodiments, the level of serum EPO is determined by administering a HIF prolyl hydroxylase inhibitor or Within 1 week, 6 days, 5 days, 4 days, 3 days, 2 days or less of administration of the HIF-α stabilizer Recovery to near baseline levels within 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 determined to be a baseline hemoglobin level. For a period of about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks, etc., the .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 levels are measured at 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 determined to be 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 level. In the study, hemoglobin levels were increased over a 2-week period compared to baseline hemoglobin levels. 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 about 0.5 g / dL over a three-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 four 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. to a patient having EPO blood, wherein the diurnal pattern of EPO expression is as previously described. anemia (e.g., secondary 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; bone marrow dysplasia Syndromes of advanced stage, myelofibrosis, other aplastic or dysplastic anemias, chemotherapy-induced anemias ( including chemotherapy to treat cancer, hepatitis C, or other long-term drug therapies that reduce bone marrow production. anemia due to blood loss, anemia due to iron deficiency, anemia due to vitamin B12 deficiency Provided herein are methods for treating or preventing erythrocyte segregation syndrome, sickle cell disease, or thalassemia. In some embodiments, an effective amount of a compound disclosed herein, such as Compound 1, to a patient having 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 to treat patients with anemia secondary to chronic kidney disease (CKD). Methods for treating or preventing the same are provided herein. Such daily doses are administered orally, preferably In some embodiments, the daily dose is administered once a day. 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 epothane. rhEPO, such as ethinyl alpha, 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 manner, 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) are ) suggests that the normal and endogenous expression of EPO occurs between 6 p.m. and midnight. In some implementations, the circadian pattern is administered to mimic the normal (i.e., healthy) circadian pattern. In embodiments, the compound is administered at a time point such that the EPO peak occurs earlier than the cortisol peak. Specifically, the EPO peak occurs about 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 a.m., 9:00 a.m., 10:00 a.m., 11:00 a.m., 12:00 p.m., or is administered at 2 p.m. In some embodiments, the compound is administered after breakfast. In some embodiments, the compound is administered at breakfast, 8:00 a.m., 9:00 a.m., 10:00 a.m., 11:00 a.m., 12:00 a.m., 13:00 a.m., and 14:00 a.m. 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 lunch. In some embodiments, the compound is administered between lunch and 2 p.m. In some embodiments, the compound is administered at or about the same time each day. In particular embodiments, the daily dose is about 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 simultaneously between the morning and 2 p.m. The present disclosure provides a method for treating anemia in a subject with chronic kidney disease, comprising administering a medicament for treatment with an anemia inhibitor, the ... This document provides:

[0202] 5.3.2 Total iron-binding capacity A Phase 2a clinical trial is evaluating Compound 1, HIF prolyl, in patients with CKD stages 3, 4, or 5. Hydroxylase inhibitors increased TIBC levels after 6 weeks of treatment compared to placebo-treated patients Unexpectedly, the increase in TIBC levels was associated with a significant increase in serum iron levels. Furthermore, Compound 1 produced dose-related increases in TIBC and decreases 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 disclosed herein A medicamentously effective amount of a HIF-α inhibitor or HIF-α stabilizer is administered to a subject in need of treatment with reduced endogenous production of EPO. wherein the HIF prolyl hydroxylase inhibitor is administered to a patient having a disease or condition. A medicamentously effective amount of the 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 The present invention relates to a method for treating a disease or condition associated with decreased endogenous production of erythropoietin (EPO), In a more specific embodiment, a method for treating or preventing the condition is provided herein. A medicamentously effective amount is one that reduces the total iron binding capacity of 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 represented by Formula (I), Formula (II), Formula (III), 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 agent thereof. Specifically, the HIF prolyl hydroxylate is a salt, solvate, or hydrate that is acceptable for the treatment of osteoarthritis. The enzyme inhibitor or HIF-α stabilizer is Compound 1, or a pharma- ceutically acceptable salt or solvate thereof. or a hydrate. Specifically, a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer is compound 7, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0204] In some embodiments, the HIF prolyl hydroxylase disclosed herein The present invention relates to a method for treating a patient with a rheumatoid arthritis syndrome (HIT) by administering a medicamentous amount of a HIF-α inhibitor or HIF-α stabilizer to a patient with a rheumatoid arthritis syndrome (HIT) that is a therapeutic agent for treating a patient with a rheumatoid arthritis syndrome (HIT). and administering to a patient having a disease or condition in which HIF prolyl hydroxylation is possible. A medicamentously effective amount of an enzyme inhibitor or HIF-α stabilizer reduces the total iron binding capacity in a patient by at least At least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% It is suitable for increasing endogenous erythropoietin (EPO) production, which is a key factor in treating Methods for treating a treatable disease or condition are provided herein. In embodiments, the medicamentously effective amount 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 On the other hand, total serum iron levels either did not increase or increased by at most 1%, 2%, 3%, 4%, 5%, or 6%. %, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or at most 25% increase 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 pharma- ceutical acceptable salt, solvate, or hydrate thereof. The HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 1, or a pharma- ceutical acceptable derivative thereof. Specifically, the compound is a salt, solvate, or hydrate of a HIF prolyl hydroxylase inhibitor. or the HIF-α stabilizer is Compound 7, or a pharma- ceutically acceptable salt, solvate, or It is a hydrate.

[0205] In some embodiments, the HIF prolyl hydroxylase disclosed herein The present invention relates to a method for treating anemia, the method comprising administering to a patient suffering from anemia a medicamentously effective amount of a HIF-α inhibitor or a HIF-α stabilizer. wherein a pharma- tically 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 comprises a The effective dose for each compound is 0.01 mg / kg / day, and is 0.01 mg / kg / day. 0%, 35%, 40%, 45%, or at least 50% increase while total serum iron levels are No increase or at most 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% In some embodiments, the increase may be 15%, 20%, or at most 25%. The HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is represented by the formula (I), the formula (II), the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII ... IV), 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 medicament thereof. Specifically, the compound is a salt, solvate, or hydrate of a HIF prolyl hydroxylase inhibitor. or the HIF-α stabilizer is Compound 1, or a pharma- ceutically acceptable salt, solvate, or Specifically, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is compound 7. or a pharma- ceutically 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 Anemia secondary to cardiac disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplastic syndromes, bone Myelofibrosis, other aplastic or dysplastic anemias, chemotherapy-induced anemias (cancer, hepatitis C, etc.) chemotherapy to treat osteoporosis, osteoporosis, 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 anemia Hemophilia 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 a day. 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. The CKD is at stage 3 of the disease. In some embodiments, the CKD is at 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. Most of these patients 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 is previously 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 reduced 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. of anemia.

[0209] In some embodiments, the HIF prolyl hydroxylase disclosed herein A medicamentously effective amount of a HIF-α inhibitor or HIF-α stabilizer is administered to a subject having reduced endogenous hemoglobin production. wherein the HIF prolyl hydroxylase is administered to a patient having a disease or condition associated with A medicamentously effective amount of an enzyme inhibitor or HIF-α stabilizer reduces the total iron binding capacity in a patient by at least At least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% associated with decreased endogenous hemoglobin production in patients suitable for increasing Methods for treating or preventing a disease or condition are provided herein. In such a case, the medicamentously effective amount is a dose that reduces 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 increased by at most 1%, 2%, 3%, 4%, 5%, 6%, or 7%, respectively. %, 7%, 8%, 9%, 10%, 15%, 20%, or at most 25% increase In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer has the formula: Compounds 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 The present invention relates to a medicament for treating HIF. The prolyl hydroxylase inhibitor or HIF-α stabilizer is Compound 1, or a pharma- ceutical acceptable salt thereof. Specifically, the compound is a salt, solvate, or hydrate of a HIF prolyl hydroxylase inhibitor or The HIF-α stabilizer is Compound 7, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. It is a Japanese product.

[0210] In some embodiments, the HIF prolyl hydroxylase disclosed herein A medicamentously effective amount of a HIF-α inhibitor or HIF-α stabilizer is administered to increase endogenous hemoglobin production. wherein the HIF A medicamentously effective amount of a prolyl hydroxylase inhibitor or a HIF-α stabilizer is The 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 medicamentously effective amount is sufficient to increase the total iron binding capacity in a patient to at least Increase by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or at least 50% While the total serum iron level either did not increase or increased by at most 1%, 2%, 3%, or 4%. , 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or at most 25% increase. In some embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizing The agent is 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, or Metabolite 2. or a pharma- ceutically 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. In particular, HIF prolyl hydroxylases The inhibitor or HIF-α stabilizer may be Compound 7, or a pharma- ceutically acceptable salt, solvate, or derivative thereof. 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 determined based on the Ferrozine method without deproteinization. The specimens were prepared using the Roche Diagnostics Reagents. Analyzed on a Roche Modular Instrument. Under acidic conditions, iron is released from transferrin Detergents clarify lipid samples. Ascorbate releases The reduced Fe3+ ions are converted 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 known concentrations of iron to saturate available binding sites The ferrozine chromogen can be used to determine the amount of Fe in the serum. 2 +; thus, to ensure that all iron is present in the ferrous state, An iron reducing agent is added. Excess free divalent iron reacts with the ferrozine chromogen to produce magenta. The unsaturated iron-binding capacity (UIBC) is the iron-binding capacity of the iron-binding protein that is determined by the amount of added iron. The serum TIBC is equal to the measured difference between the concentration of iron in the iron solution and the concentration of excess unbound iron. and consequently the results of the UIBC and serum iron determinations can be used and calculated.

[0214] Total iron binding capacity (TIBC) is a measure of the blood's ability to bind iron to transferrin. This is done by taking a blood sample and measuring the maximum amount of iron that the blood can carry. Thus, TIBC has two binding sites for the transport of iron from iron stores to erythroid precursor cells. This represents the amount of circulating transferrin that

[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 ferroportin, which works together to regulate the amount of iron transported to the plasma. It is regulated by hepcidin. Ferroportin moves iron in and out of cells, while Hepcidin regulates the action of ferroportin, thereby increasing or decreasing the release of iron into the plasma. determines whether iron is retained in the cell or not. However, serum iron levels are dependent on the activity of ferroportin and hepcidin. The bell is relatively low.

[0216] In some embodiments, the serum iron level is significantly increased compared to baseline. To increase TIBC compared to baseline TIBC in patients without Sufficient consecutive doses of enzyme inhibitors or HIF-α stabilizers were administered to reduce endogenous production of EPO. The present invention relates to a method for treating reduced erythropoietin production, including administering the method to a patient having a disease or condition associated with reduced erythropoietin production. Provided herein are methods for treating a disease or condition associated with endogenous production of erythropoietin (EPO). In some such embodiments, cardiovascular events associated with increased serum iron levels are 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, the serum iron level is significantly increased compared to baseline. To increase TIBC compared to baseline TIBC in patients without Sufficient consecutive doses of enzyme inhibitors or HIF-α stabilizers were administered to increase endogenous EPO production. Administration to patients with diseases or conditions associated with reduced endogenous production of EPO that are more treatable This can be treated by increasing endogenous erythropoietin (EPO) production, including by administering Methods for treating a disease or condition 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 of treating a condition include the steps of: 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 about 90 μg / dL or about 100 μg / dL. About 10 μg / dL, at least about 20 μg / dL, at least about 30 μg / dL, at least about 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 about 10 μg / dL to about 60 μg / dL, about 10 μg / dL to about 50 μg / dL, ...60 μg / d 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 about 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 baseline TIBC. The period may be about 1 to 6 weeks, 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 Increase by less than about 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, HIF prolyl, in patients with stages 3, 4, or 5 of CKD. Hydroxylase inhibitors were associated with a 6-week improvement in schizophrenia compared to baseline and placebo-treated patients. Unexpectedly, the results showed that the drug can increase serum hemoglobin levels in a 10-mg dose of 100 mg / kg / day. This increase in hemoglobin levels is not associated with a decrease in hepcidin levels.

[0222] In some embodiments, the pharmaceutical agent is a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer. to a patient having a disease or condition associated with reduced endogenous production of EPO. wherein a medicamentously effective amount is a HIF prolyl hydroxylase inhibitor or a HIF -Compared to hepcidin levels before administration of alpha 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 decreasing 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 a circadian cycle by at least 150%. and treating or preventing a disease or condition associated with decreased endogenous production of erythropoietin (EPO). In some embodiments, a method for preventing HIF prolyl cleavage is provided herein. The hydroxylase 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 of , Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, Young or metabolite 2, or a pharma- ceutical acceptable salt or solvate thereof. or a hydrate. Specifically, a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer is Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. Specifically, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is compound 7, or a pharmaceutical thereof. In some embodiments, the compound is a hydrochloride, a hydrochloride, or a hydrochloride that is a hydrochloride or a hydrochloride that is a hydrochloride. A disease or condition associated with impaired endogenous EPO production may be a non-severe form of 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 pharmaceutical agent is a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer. and administering to a subject a disease or condition treatable by increasing the endogenous production of EPO. and administering to a patient having HIF prolyl hydroxylase, 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 The serum EPO level was increased by 1.0% without decreasing the serum hepcidin level by more than 9% or 20%. At least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more below trough levels %, 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 an embodiment, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is 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 A compound selected from compound 12, compound 13, metabolite 1, or metabolite 2, or a pharmaceutical composition thereof. Specifically, the HIF prolyl hydroxyl group is an acceptable salt, solvate, or hydrate thereof. The enzyme inhibitor or HIF-α stabilizer is Compound 1, or a pharma- ceutical acceptable salt, solvate or the like thereof. Specifically, the compound is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizing agent. The agent is Compound 7, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. In some embodiments, the disease or condition is 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 pharmaceutical agent is a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer. to a patient having a disease or condition associated with endogenous hemoglobin production. wherein the medicamentously effective amount is a HIF prolyl hydroxylase inhibitor or a HIF- Compared to hepcidin levels before administration of alpha stabilizers, , 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or more 0% reduction in serum hepcidin levels to pre-treatment hepcidin levels Compared to at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, or at least 20% higher peak hemoglobin levels and (b) treating a disease or condition associated with endogenous hemoglobin production, the disease or condition being suitable for increasing hemoglobin production. In some embodiments, methods for preventing or preventing 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 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, Metabolite A compound selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, Specifically, the compound is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizing agent. The fixed agent is Compound 1, or a pharma- ceutically 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 pharma- ceutically acceptable salt, solvate, or hydrate. A disease or condition associated with reduced endogenous hemoglobin production is secondary to chronic kidney disease. Non-severe anemia, non-severe anemia secondary to congestive heart failure, and idiopathic anemia of aging of anemia.

[0225] In some embodiments, the pharmaceutical agent is a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer. The present invention relates to a method for treating a disease or condition that can be treated by increasing endogenous hemoglobin production. to a patient having the condition, wherein a medicamentously effective amount is a 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 was performed without decreasing serum levels of hepcidin by more than 18%, 19%, or 20%. At least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% higher than pre-treatment hepcidin levels 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, or at least 20% hemoglobinuria Increases endogenous hemoglobin production, suitable for increasing peak globin levels Methods for treating or preventing a disease or condition 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), (II), (III), (IV), or (V), is 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 pharma- ceutically acceptable salt, solvate, or hydrate thereof. Specifically, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound 1 or a pharmaceutical thereof. Specifically, the HIF prolyl hydroxylate is a salt, solvate, or hydrate that is acceptable for the treatment of osteoarthritis. The enzyme inhibitor or HIF-α stabilizer is compound 7, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the therapeutic agent is an EPO inhibitor, a hydrate thereof, or a hydrate thereof. 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 ageing.

[0226] In some embodiments, the pharmaceutical agent is a HIF prolyl hydroxylase inhibitor or a HIF-alpha stabilizer. to a patient having anemia, wherein the medicamentically 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 %, 16%, 17%, 18%, 19%, or 20% reduction in serum hepcidin levels without any reduction in hepcidin levels, and at least 2%, 3%, 4%, 5%, or 6% higher than pretreatment hepcidin levels , 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18% or less In patients with 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 represented by the formula (I), the formula (II), the 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 medicament 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 pharma- ceutical acceptable salt, solvate, or Specifically, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound Compound 7, or a pharma- ceutically 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 syndromes, myelofibrosis, other aplastic or dysplastic Anemia, chemotherapy-induced anemia (from chemotherapy to treat cancer, Hepatitis C, or to reduce bone marrow production) 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 daily doses are administered orally, preferably once a day. 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 of 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, Erythropoietin-producing drugs, including rhEPO products, such as ethinyl 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 Staphylococcus aureus were purified on a Staphylococcus aureus protein A column according to the manufacturer's protocol. 96-well plates were coated with the antibody and buffered with Tris-Buffer 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 Incubated with 200 μL (a sample containing very low concentrations of hepcidin) and 10 ng / mL Biotinylated hepcidin-25 was added as a tracer. A standard curve was generated using the 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 , 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 -peroxidase and tetramethylbenzidine. This enzyme reaction was carried out in the presence of sulfuric acid. The reaction was stopped by 500 rpm and the plates were read at 450 nm on a DTX 880 microplate reader. Standard curves were generated using GraphPad Prism software with a 12-point fit. The fitted curve was then used to convert the absorbance measurements of the samples to Hepsisy Convert to concentration.

[0229] Serum hemoglobin levels can be 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 the standard CBC method, which is the formation of methaemoglobin. The brown color is measured spectrophotometrically and the corresponding hemoglobin is reported.

[0230] In some embodiments, the hepcidin level is significantly increased compared to baseline levels. Increase serum hemoglobin levels compared to baseline serum hemoglobin levels without The present invention provides a method for treating HIF-α deficiency by administering a sufficient number of consecutive doses of a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer to a patient having a deficiency. to a patient having a disease or condition associated with reduced endogenous production of EPO. Methods for treating diseases or conditions associated with reduced endogenous production of erythropoietin (EPO) In some embodiments, the method comprises administering to the subject a therapeutically effective amount of endogenous EPO. Diseases or conditions related to the 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 level is significantly increased compared to baseline levels. Increase serum hemoglobin levels compared to baseline serum hemoglobin levels without The present invention provides a method for treating HIF-α deficiency by administering a sufficient number of consecutive doses of a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer to a patient having a deficiency. to a patient having a disease or condition that is treatable by increasing endogenous EPO production. Can be treated by increasing endogenous production of erythropoietin (EPO), including by administering Provided herein are methods for treating a disease or condition that is In 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 chronic obstructive pulmonary disease, or idiopathic anemia of aging. In an embodiment, the disease or condition treatable by increasing endogenous EPO production is chronic non-severe anemia secondary to chronic renal disease, non-severe anemia secondary to congestive heart failure, and and idiopathic anemia of the elderly.

[0232] In some embodiments, the level of serum hemoglobin is determined by measuring the baseline hemoglobin level. Compared to the standard level, the expected 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 patients with pulmonary embolism, hemoglobin levels increased by approximately 2% for approximately 1 week 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 determined to be 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 baseline. Hemoglobin levels were increased 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 three week period. In some embodiments, the level of hemoglobin is measured using a method according to claim 1, wherein the level of hemoglobin is greater than or equal to the baseline hemoglobin level. In some embodiments, the IL-10 level is increased by about 0.6 g / dL over a four week period compared to the IL-10 level. Hemoglobin levels were compared to baseline hemoglobin levels over a 5-week period In some embodiments, the hemoglobin level is increased by about 0.6 g / dL. Over a 6-week period, baseline hemoglobin levels are increased by approximately 0.6 g / dL.

[0234] In some embodiments, hepcidin expression is measured using 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%. Compared to the baseline hepcidin expression level, %, 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 100%. about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, or about 1% relative to 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 The present invention relates to a method for treating chronic kidney disease in which a patient is given sufficient continuous doses of a steroid or HIF-α stabilizer to treat non-severe kidney problems secondary to chronic kidney disease. Injection into patients with severe anemia secondary to hepatitis, 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, idiopathic anemia of aging, and idiopathic anemia of aging. Provided in the specification.

[0236] In some embodiments, the serum hemoglobin level is determined by measuring the baseline hemoglobin level. The levels are increased by about 0.1 to about 1.0 g / dL over a one-week period. In certain embodiments, the serum hemoglobin level is compared to the baseline hemoglobin level. Thus, it would increase by approximately 0.1 g / dL over a one-week period.

[0237] In some embodiments, the serum hemoglobin level is determined by measuring the baseline hemoglobin level. The levels are increased by about 0.1 to about 1.0 g / dL over a two-week period. In certain embodiments, the serum hemoglobin level is compared to the baseline hemoglobin level. Therefore, it will increase by approximately 0.1 g / dL over a two-week period.

[0238] In some embodiments, the serum hemoglobin level is determined by measuring the baseline hemoglobin level. The levels are increased by about 0.1 to about 1.0 g / dL over a three-week period. In certain embodiments, the serum hemoglobin level is compared to the baseline hemoglobin level. Thus, it is increased by approximately 0.5 g / dL over a three week period.

[0239] In some embodiments, the serum hemoglobin level is determined by measuring the baseline hemoglobin level. The levels are increased by about 0.1 to about 1.0 g / dL over a four-week period. In certain embodiments, the serum hemoglobin level is compared to the baseline hemoglobin level. Thus, it would increase by approximately 0.6 g / dL over a four-week period.

[0240] In some embodiments, the serum hemoglobin level is determined by measuring the baseline hemoglobin level. The levels are increased by about 0.1 to about 1.0 g / dL over a 5-week period. In certain embodiments, the serum hemoglobin level is compared to the baseline hemoglobin level. Overall, the increase is approximately 0.6 g / dL over a 5-week period.

[0241] In some embodiments, the serum hemoglobin level is determined by measuring the baseline hemoglobin level. The levels are increased by about 0.1 to about 1.0 g / dL over a 6-week period. In certain embodiments, the serum hemoglobin level is compared to the baseline hemoglobin level. Thus, it is increased by approximately 0.6 g / dL over a six-week period.

[0242] In some embodiments, erythroferon transcription is at 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 qRT-PCR product of RNA. Relative to baseline erythropoietin 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 erythropoietin expression. The expression level of Sloferon is increased by less than about 20%, less than about 15%, or less than about 10%, e.g., Erythroferon protein was measured by Western blot (see SEQ ID NO:2) , less than about 5%, less than about 4%, or less than about 3% compared to baseline erythropoietin 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 stabiliser is administered orally.

[0246] 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. 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: Compounds 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 pharma- ceutically 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 is a hydrochloride, a hydrochloride, or a hydrochloride that is acceptable for use in treating a patient. The aryl hydroxylase inhibitor or HIF-α stabilizer is Compound 7, or a pharma- ceutical acceptable salt thereof. , a solvate, or a hydrate.

[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;improper 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 associated 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 disorders such as the myocardium and ventricles Internal organs such as liver tissue, skeletal muscle, nerve tissue derived from the cerebellum, 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 medicamentously 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; Ulcer; Ischemic Ulcer ;Inadequate blood supply;Poor capillary circulation;Atherosclerosis of small arteries;Venous congestion; Atherosclerotic lesions (e.g., in the coronary arteries); angina pectoris; myocardial infarction; diabetes; hypertension; biliary Urger'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 · Rendue's disease; hereditary hemorrhagic telangiectasia; solid or blood-borne tumors and acquired Immunodeficiency syndrome; atrial arrhythmia; originating from cardiac tissues such as the myocardium and ventricles, skeletal muscle, cerebellum, etc. nervous tissue, internal organs such as the stomach, intestines, pancreas, liver, spleen, and lungs, and the fingers and toes Ischemic tissue damage in tissues such as distal appendages of the body: for the treatment and / or prevention and / or vascular and a method for treating at least one of these diseases, wherein a medicamentously 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 be manifested in three ways: 1) asymptomatic PVD diagnosed on the basis of non-invasive 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 progressive 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 patient with a disease comprising administering to the patient one or more of the compounds disclosed herein or to a human. .

[0251] The compounds and compositions listed herein have numerous uses, and are particularly useful in the following areas: Addresses several unmet medical needs: 1) To provide compositions effective as inhibitors of HIF prolyl hydroxylase, thereby Stimulates angiogenic responses in tissues, thereby improving blood flow, oxygen delivery and metabolism in ischemic tissues. 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 3) To provide a composition effective for 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 angiogenic responses, thereby increasing the number and density of blood vessels. This increases the risk of heart failure and, consequently, the deleterious consequences of hypertension and diabetes, especially claudication, ischemic ulcers, and ulcers. Alleviating advanced hypertension and renal failure; 5) Provide a composition that activates vascular endothelial growth factor (VEGF) gene transcription in hypoxic cells and consequently the stimulation of important biological responses, notably vasodilation, vascular permeability, and endothelial Increasing cell migration and proliferation; 6) providing a composition that induces the production of soluble VEGF and inhibitors of VEGF in hypoxic cells; The result is stimulation of important biological responses, in particular increasing anti-angiogenic activity.

[0252] Accordingly, these and other unmet medical needs are addressed by the present disclosure of HIF prolyl hydroxylase inhibitors. This is due to insufficient regulation of HIF prolyl hydroxylases, which can be resolved by enzyme inhibitors. It is possible to regulate blood flow, oxygen transport and energy utilization in ischemic tissues. Those skilled in the art will also recognize 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 angiogenic process may have a beneficial effect on the relief of other symptoms and conditions. As more details emerge about the associated diseases 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 a physical response.

[0253] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to the 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 / day over the course of a 24 hour period. In some such embodiments, the {[5-(3-chlorophenyl)-p-tolylaminophenyl]phenylamine is administered once, for example, 1, 2 or 3 times. An effective dose of phenyl-3-hydroxypyridine-2-carbonyl]amino}acetic acid is administered once daily to the HIF prostate. and administering the compound to a patient having a disease or disorder that is ameliorated by modulation of aryl hydroxylase. The present invention provides a method for treating or preventing a disease that is ameliorated by modulation of HIF prolyl hydroxylase. In some such embodiments, the daily dose is 150mg, 300mg, 450mg of phenyl-3-hydroxypyridine-2-carbonylamino}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 Provided herein are methods for treating or preventing diseases that are ameliorated by modulation of hydroxylase. 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, taken orally once a day, twice a day, or three times a day, preferably once a day. It can be administered.

[0254] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to the 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 a disease or disorder that is improved are provided herein. In such embodiments, the daily dose is {[5-(3-chlorophenyl)-3-hydroxypyridine-2 -carbonyl]amino}acetic acid, about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. In some such embodiments, the daily dose is 2-(5-(3-fluorophenyl)-3-hydroxyphenyl)- The amount of cypicolinamide) acetate 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 and / or according to the dosing regimen, and administering to a patient having a disease or disorder that is improved by inhibiting PHD1 an effective amount of 1,3-diaminoethyl ether. The present invention relates to a method for treating or preventing a disease or disorder ameliorated by inhibiting PHD1, comprising administering to a patient Provided herein are methods for preventing the development of a pulmonary edema. In some such embodiments, the According to the dosages and / or dosing regimens described herein, 2-(5-(3-fluorophenyl)- The present invention relates to a method for treating a disease that is improved by inhibiting PHD1, the method comprising administering an effective amount of 3-hydroxypicolinamido)acetic acid to a subject. 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, An effective amount of chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid is added to PHD2. to a patient having a disease or disorder that is ameliorated by inhibiting PHD2. Methods for treating or preventing a disease or disorder that is ameliorated by inhibition are provided herein. In some such embodiments, the dosages and / or Followed the dosing regimen and received 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 include According to the dosage and / or dosing regimen prescribed, A disease that is improved by inhibiting PHD3 by administering an effective amount of dimethylsulfate (2-carbonyl)amino)acetic acid. or a disorder that is ameliorated by inhibiting PHD3, including administering the same to a patient having the same disorder. Methods for treating or preventing a cancer or disorder are provided herein. In embodiments, 2-(5-(3-furan) is administered according to the dosages and / or dosing regimens described herein. The effective dose of fluorophenyl-3-hydroxypicolinamidoacetic acid was determined to inhibit PHD3. and administering the compound to a patient having a disease or disorder that can be improved by inhibiting PHD3. Provided herein are methods for treating or preventing a disease or disorder, the method comprising:

[0255] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to stabilize HIF-α. to a patient having a disease or disorder that is ameliorated by administering HIF-α (e.g. Diseases or conditions that can be improved by stabilizing HIF-1-α, HIF-2-α, and / or HIF-3-α. 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 In some cases, the amount of acetylcholine in the solution is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of amino acid acetic acid. 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. About 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of cholinesteric acid. 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 According to the dosing regimen, 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. The present invention relates to a method for treating a disease or disorder that is ameliorated by stabilizing HIF-1α, the method comprising administering the method to a patient suffering from the disease or disorder. Methods for treating or preventing the harm of a cancer are provided herein. In some such embodiments, In accordance with the dosage and / or dosing regimen described herein, An effective amount of phenyl-3-hydroxypicolinamido)acetic acid was administered to stabilize HIF-1-α. and stabilizing HIF-1α, including administering to a patient having a disease or disorder that is to be improved. Provided herein are methods for treating or preventing a disease or disorder that is ameliorated by administering 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. The present invention relates to a method for treating or preventing a disease or disorder that is 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 Provided herein are methods for treating or preventing a disease or disorder as described above.

[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. The present invention relates to a method for treating or preventing a disease or disorder that is 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 hydroxypicolinamido)acetic acid was improved by stabilizing HIF-3-α. and administering the compound to a patient having a disease or disorder characterized by the inactivation of HIF-3-α. Provided herein are methods for treating or preventing a disease or disorder that is ameliorated.

[0257] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid was administered to the The method includes administering to a patient having a disease or disorder associated with sex production a reduced erythropoietin-producing cell. 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 about 600 mg, or about 750 mg. (fluorophenyl)-3-hydroxypicolinamido)acetic acid, about 150 mg, about 300 mg, about 450 mg, about 60 In some such embodiments, the daily dose is about 150 mg, about 300 mg, or about 750 mg. Such daily doses are preferably administered once a day, twice a day, or three times a day. It can be administered orally once daily.

[0258] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to a patient suffering from 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 anemias (for treating cancer, hepatitis C) chemotherapy for bone marrow deficiency 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 In some embodiments, methods for treating or preventing rhabdomyolysis, including rhabdomyolysis, 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. Provided herein are methods for treating 2-(5-(3- An effective amount of fluorophenyl-3-hydroxypicolinamido)acetic acid is administered to a patient suffering from anemia. Described herein is a method 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 0 mg, or about 750 mg. In some such embodiments, the daily dose is 2-(5-(3-fluroyl) Approximately 150 mg, approximately 300 mg, approximately 450 mg, approximately 600 mg of (3-hydroxypicolinamido)acetic acid 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, usually once daily.

[0259] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid was administered to treat anemia secondary to CKD. The present invention relates to a method for treating or preventing anemia secondary to chronic kidney disease (CKD), including administering the same 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 about 150 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, about 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 daily doses are administered once a day, twice a day, or both. The drug may be administered orally once or three times daily, 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. 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 5 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 secondary to D and other conditions can be treated with epoetin alfa, epoetin beta, and darbepoetin. For treatment with erythropoiesis-stimulating agents, including rhEPO products, such as ribavirin 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 are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid was administered to and administering to a patient having the disease or disorder, Provided herein are methods for treating or preventing According to the dosage and / or dosing regimen explained in the specification, administering to a patient an effective amount of hydroxypyridine-2-carbonylamino}acetic acid. Provided herein are methods for modulating angiogenesis. In some embodiments, the According to the dosages and / or dosing regimens described herein, 2-(5-(3-fluorophenyl)- The method comprises administering to a patient an effective amount of 3-hydroxypicolinamido)acetic acid. Provided herein are methods for reducing the daily dose. 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. , 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 daily doses are 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 are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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 the VEGF or GAPDH, including administering to a patient having a disease or disorder affected by the VEGF or GAPDH receptor. Provided herein are methods for treating or preventing a disease or disorder 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, or In some such embodiments, the daily dose is about 750 mg. about 150 mg, about 300 mg, about 450 mg, about 600 mg of 3-(2-hydroxypicolinamido)-1,3-dihydro ... 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 are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic 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 -carbonyl]amino}acetic acid, about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. In some such embodiments, the daily dose is 2-(5-(3-fluorophenyl)-3-hydroxyphenyl)- The amount of cypicolinamide) acetate 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. It is possible.

[0263] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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 subject having damaged tissue. and enhancing revascularization or increasing vasculature in damaged tissue, including administering to a patient having In some embodiments, methods of administering the method described herein are provided. According to the prescribed dosage and / or dosing regimen, 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, comprising: In embodiments, 2-(5-(3-furan) is administered according to the dosages and / or dosing regimens described herein. An effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid is administered to a patient having ischemic tissue. Provided herein is a method for vascularizing ischemic tissue, comprising administering to a subject In some such embodiments, the daily dose is {[5-(3-chlorophenyl)-3-hydroxyphenyl 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 -hydroxypicolinamido)acetic acid, 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 The daily dose is 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 can be administered orally.

[0264] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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 of promoting the growth of a skin graft substitute comprising administering to a patient a method for ... In some such embodiments, the daily dose is provided by administering to the patient a dose of {[5-(3-chlorophenyl)-3- Hydroxypyridine-2-carbonyl]amino}acetic acid, about 150 mg, about 300 mg, about 450 mg, about 600 mg or about 750 mg. In some such embodiments, the daily dose is 2-(5-(3-fluoro about 150 mg, about 300 mg, about 450 mg, about 600 mg of phenyl)-3-hydroxypicolinamido)acetic acid, or about 750 mg. In some such embodiments, the daily dose is about 150 mg, about 300 mg, The daily dose is about 450 mg, or about 600 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.

[0265] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- administering to the patient an effective amount of (fluorophenyl)-3-hydroxypicolinamido)acetic acid; Provided herein are methods for promoting tissue repair in the context of guided tissue regeneration (GTR), comprising: 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 600 mg g, or about 750 mg. In some such embodiments, the daily dose is 2-(5-(3-fluorophenyl) (phenyl)-3-hydroxypicolinamido)acetic acid, about 150 mg, about 300 mg, about 450 mg, about 600 mg In some such embodiments, the daily dose is about 150 mg, about 300 mg, or about 750 mg. Such daily doses are preferably administered once a day, twice a day, or three times a day. It can be administered orally, usually once daily.

[0266] In some embodiments, the present invention relates to a method for treating diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, monkeys, or the like. Coid, syphilis, pseudoxanthoma elasticum, Paget's disease, venous occlusion, arterial occlusion, carotid occlusion Sexual disorders, chronic uveitis / vitreous inflammation, mycobacterial infections, Lyme disease, systemic erythematous lupus Causes acne, 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 pulmonary artery disease and coronary artery disease are provided herein. wherein the method comprises administering to the subject a dose and / or dosage and / or dosing regimen 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 pharma- ceutically 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 the patient suffering from such a disease. In some such embodiments, the method comprises administering the compound to a patient having a disorder or disorder. The amount is about 15% of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. In some such embodiments, the amount of glycerol in the formulation 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 daily doses are administered once a day. The compound may be administered orally, twice a day, or three times a day, preferably once a day.

[0267] 5.5 Dosage and Dosage Regimens Various conditions, such as anemia (e.g., secondary to chronic kidney disease), as described in Section 5.4 and HIF prolyl hydroxylase inhibitors or HIF-alpha stabilizers for the prevention and / or treatment of disorders. Various parameters that guide the dosing regimen of the agent are described herein. This section concerns such uses of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers. In some embodiments, such dosages are provided. In other embodiments, such doses are administered over the course of treatment. In some embodiments, the HIF promoter is a cytotoxic agent. The hydroxylase inhibitor or HIF-α stabilizer is a compound represented by formula (I), (II), (III), (IV), or is 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, Metabolite A compound selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, In a specific embodiment, the compound is Compound 1, or a hydrate thereof. In a specific embodiment, the compound is a pharma- ceutically acceptable salt, solvate, or hydrate of The compound is Compound 7, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. It is.

[0268] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid), 00 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, or A daily dose of about 300 mg to about 600 mg is administered to a patient with anemia. Methods for treating anemia, such as anemia secondary to disease, are provided herein. In some embodiments, the compound having the 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 or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. 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 100 mg, between about 300 mg and about 600 mg, or between about 600 mg and about 750 mg. The daily dose is a compound having a 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 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutically acceptable salt, solvate, or hydrate thereof (specifically is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5 -(3-fluorophenyl)-3-hydroxypicolinamide)acetic acid) at 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 compound represented by Formula (I), Formula (II), Formula (III), Formula (IV), 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, Metabolite 1 or metabolite 2, or a medicamentously acceptable salt or solvent thereof. solvates or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamide) 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 pharma- ceutical 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (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, the method comprising administering to the patient a daily dose of a compound comprising administering to the patient a daily dose of a compound to treat anemia secondary to chronic kidney disease; Provided herein is a method for treating anemia, such as administering the compound sequentially to and / or administered irregularly.

[0271] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or to a patient having 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 ... 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 medicament 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 three unit dosage forms, such as three tablets containing approximately 150 mg of phosphodiesterase (phosphorylamide) acetic acid. In some embodiments, 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 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 The selected compounds or their pharma- ceutically acceptable salts, solvates, or hydrates (including Specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or A daily dose of about 450 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid is The daily dose of the compound may be increased by about 150 mg so that the daily dose is about 600 mg. In some embodiments, the compound having the 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 or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. 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 pharma- ceutical 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 is In some cases, the daily dose of the compound may be reduced by about 300 mg, so that the daily dose 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 dosage may be increased or decreased by about 100 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 about 300 mg, or about 150 mg to about 300 mg. Approximately 300mg, approximately 150mg to approximately 300mg, approximately 175mg to approximately 300mg, approximately 200mg to approximately 300mg, approximately 225mg to approximately 300mg , from about 250 mg to about 300 mg, or from 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 from 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (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 may be administered continuously and / or irregularly, Provided herein are methods for treating anemia, such as by administering a medicament to a subject in need of treatment with an anemia inhibitor. 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 Substitute A compound selected from Compound 2, or a pharma- ceutical 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 , 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) The method includes administering a therapeutically effective amount of the therapeutically effective amount of the therapeutically effective amount to a patient having anemia, wherein the patient's hemoglobin level is at least and 4.3 g / dL or less. Provided herein are methods for treating anemia, such as hypercalcaemia. In the embodiment, 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 below about 12.0 g / dL. In some such embodiments, The daily dose of the compound is a compound having the 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 or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (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 Patients with chronic kidney disease who have an increase in hemoglobin level of at least about 1.2 g / dL compared to their baseline hemoglobin level Methods for treating anemia, such as anemia secondary to a disease, are provided herein. In such embodiments, the daily dose of the compound is a compound represented by 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, a compound selected from Metabolite 1 or Metabolite 2, or a pharma- ceutical 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 amount of acetic acid in the solution is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Administration of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid may be temporarily suspended if hemoglobin levels reach or exceed 13.0 g / dL. In some such embodiments, administration of the compound once hemoglobin levels have increased. It may be resumed once blood glucose levels are 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)phenyl]phenyl} phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl The dose of phenyl)-3-hydroxypicolinamido)acetic acid may be adjusted to control hemoglobin levels and / or hemoglobin levels. In some embodiments, the amount of phosphodiesterase (PDM) administered can be adjusted based on changes in the level of phosphodiesterase (PDM) in the blood. 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 pharma- ceutically acceptable salts, solvates, or hydrates (specifically The compound may be {[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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or can be increased after a period of time, starting on the day that the patient receives a daily dose of the compound. In some embodiments, the period is from about 1 week to about 8 weeks, for example about 2 weeks. For example, the period is from about 1 to about 7 weeks, from about 3 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or can be adjusted once for a period of time. In some embodiments, the 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or is when your hemoglobin level is more than 1.2 g / dL higher than your baseline hemoglobin level. If it does increase, it is not increased.

[0280] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (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 the hemoglobin level in the patient after a period of time following said measurement, wherein the hemoglobin level in the patient is less than about 10.0 g / dL, and If the serum glucose level is decreased by less than about 0.5 g / dL compared with the level measured at an earlier time point, or the hemoglobin level in the patient is 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 The hemoglobin level at this time was approximately 0.5 g / dL lower than that 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 is about 150 mg or more higher than the daily dose. 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 The daily dose may be increased or decreased by about 300 mg. In some embodiments, the daily dose is 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 an amount of 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. not exceed.

[0281] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] administering a daily amount of a compound which is a cyclic amine (amino)acetic acid to a patient suffering from anemia; The hemoglobin levels are measured in the patients 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 in the earlier period. 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 the hemoglobin level in the patient is increased by more than about 1.5 g / dL compared to the normal range; and the hemoglobin level is between about 11.0 and about 12.2 g / dL, and or a hemoglobin level in the patient is increased by about 1.0 to about 1.4 g / dL compared to the established level; and the hemoglobin level is about 12.3 to about 12.9 g / dL, and 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 of the compound. A method for treating anemia, such as anemia secondary to chronic kidney disease, comprising administering a controlled daily amount 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 from 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. In this case, the daily dose is about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, It may be increased or decreased by about 250 mg, about 275 mg, or about 300 mg. In one embodiment, 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 an embodiment, 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 modified 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (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 the hemoglobin level in the patient after a period of time following said measurement, The hemoglobin level in the patient is about 11.0 to about 12.2 g / dL, and Robin levels increased by approximately 1.5 g / dL compared to levels measured in earlier periods. 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 2.5 times lower than the level measured in the earlier period. or if the hemoglobin level in the patient increases by about 12.3 to 14.5 g / dL; 12.9 g / dL, and this hemoglobin level is higher than that measured at an earlier time point. If the increase is more than about 1.5 g / dL, the daily dose is about 300 mg less than the above. administering a regulated 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 dose is about 75mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg In some embodiments, the amount of the active ingredient may be increased or decreased by about 275 mg, about 275 mg, or about 300 mg. The daily dose is about 75 mg to 300 mg, about 100 mg to 300 mg, about 125 mg to 300 mg, about 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 may 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 00mg or 750mg.

[0283] In some embodiments, about 8 hours, 7 hours, 6 hours, or before 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 The method of the present invention comprises administering to a patient undergoing hemodialysis a medicamentously effective amount of a compound selected from the group consisting of Provided herein are methods for treating anemia associated with CKD in patients receiving .

[0284] In some embodiments, the hemodialysis session is completed within about 8 hours, 7 hours, 6 hours, or , 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 The method of the present invention comprises administering to a patient undergoing hemodialysis a medicamentously effective amount of a compound selected from the group consisting of Provided herein are methods for treating anemia associated with CKD in patients receiving .

[0285] In some embodiments, the methods provided herein comprise a method comprising administering to a patient 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 Compound 13, Metabolite 1, or Metabolite 2, and a phenol glucuronide thereof. In an even more specific embodiment, 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 metabolites.

[0286] 5.6 Combination Therapy In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (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 anemia secondary to chronic kidney disease, including when administered in combination with other medications Such combination therapy may be achieved by administering the individual components of the treatment in a controlled manner. This can be accomplished simultaneously, sequentially, or in a separate manner. When administered as a single component, the compound has the 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 A compound selected from compound 2, or a pharma- ceutically acceptable salt, solvate, or Hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amine 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) and other medicines The products may be synergistic, so that the daily dosage of either or both of these ingredients is: The dosage of either component may 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 medicament 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 phosphodiesterase (phosphorylamide) and other drugs can be additive, so that the effects of each of these 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) Compound 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 pharma- ceutical acceptable salt, solvate, or and / or hydrates (e.g., compounds disclosed herein, such as Compound 1). A daily dose of a 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 age-related idiopathic anemia, 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) for anemia wherein the compound is optionally administered to a patient having 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 In some embodiments, the iron supplement is administered at least 1 hour, at least 2 hours, or at least 2 hours after administration of the compound. It may 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 concentration 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 about 50 ng / mL to about 300 ng / mL. In some such embodiments, the daily dose of the compound is a dose of 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)- 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-(2-hydroxypicolinamido)-1,3-dihydro-1,3-dihydro-2,4-triazabicyclo[4.1.1]phenyl)-3-hydroxypicolinamido)acetic acid, 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] Amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) for anemia wherein the compound is optionally administered to a patient having an erythropoietin mimetic In combination with erythropoietin-stimulating agents (ESAs), such as anemia secondary to chronic kidney disease Provided herein are methods for treating anemia in a subject. 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, and so on. 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 pharma- ceutically acceptable salt, solvate, or hydrate thereof. (Specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid about 150 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, about 300 mg of 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 daily doses are administered once a day, twice a day, or both. or three times a day, preferably once a day.

[0290] 5.7 Patient Population In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to a patient suffering from 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 / or have poverty secondary to chronic kidney disease (CKD) Provided herein are methods for treating anemia, such as anemia. In some embodiments, 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. In some such embodiments, the patient is at least 18 years of age. 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 pharma- ceutical acceptable salt, solvate, or hydrate thereof (specifically, {[5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl) (phenyl)-3-hydroxypicolinamide) acetic acid) about 150mg, about 300mg, about 450mg, about 600mg In some such embodiments, the daily dose is about 150 mg, about 300 mg, or about 750 mg. Such daily doses are preferably administered once a day, twice a day, or three times a day. It is usually administered orally once daily.

[0291] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to a patient suffering from anemia. administering to the patient, wherein the patient is selected from the group consisting of 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 pharma- ceutical acceptable salt, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)- 2-(5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or about 150 mg, about 300 mg, about 450 mg, about 600 mg of (phenyl)-3-hydroxypicolinamido)acetic acid, or about 750 mg. In some such embodiments, the daily dose is about 150 mg, about 300 mg, The daily dose is about 450 mg, or about 600 mg. Such a daily dose may be 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 are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to a patient suffering from 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 any of the additional diseases or conditions listed above, or any combination thereof Methods for treating anemia, such as 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 Substitute A compound selected from Compound 2, or a pharma- ceutical 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 , 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 daily doses are 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 are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to a patient suffering from 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 comprises a compound of Formula (I), Formula (II), Formula (III), Formula (IV), 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, Metabolite 1 or metabolite 2, or a medicamentously acceptable salt or solvent thereof. solvates or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamide) acetic acid) in an amount of 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 amount 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 are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to a patient suffering from anemia. administering to the patient a saturation of at least 15% of transferrin saturation (TSAT), , at least 18% or even at least 20% anemia, such as anemia secondary to CKD. Methods of treating the same are provided herein. In some such embodiments, The amount of the 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical acceptable salt, solvate, or hydrate thereof (specifically, [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3- Fluorophenyl)-3-hydroxypicolinamido)acetic acid) about 150 mg, about 300 mg, about 450 mg, In some such embodiments, the daily dose is about 150 mg, about 600 mg, or about 750 mg. The daily dose is about 300 mg, about 450 mg, or about 600 mg. Such daily doses can be administered once a day, twice a day, or three times a day. It is preferably administered orally once daily.

[0295] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to a patient suffering from anemia. wherein the patient has a ferritin level of at least 50 ng / mL or even The present invention provides a method for treating anemia, such as anemia secondary to CKD, having a serum creatinine concentration of at least 100 ng / mL. In some such embodiments, the daily dose comprises 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 A compound selected from compound 12, compound 13, metabolite 1, or metabolite 2, or a pharmaceutical composition thereof. and the like. 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, taken orally once a day, twice a day, or three times a day, preferably once a day. is administered.

[0296] In some embodiments, the dosages and / or dosing regimens described herein are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to a patient suffering from anemia. wherein the patient has a ferritin level of at least 50 ng / mL and A ferritin 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, having an ferric saturation of at least 15% In some such embodiments, the daily dose comprises 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)phenyl]phenyl} 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, 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 daily doses 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 are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to a patient suffering from anemia. wherein the patient has a body mass index (BMI) of 42 kg / m 2 Less than or equal to 44kg / m 2 Less than Provided herein are methods for treating anemia, such as anemia secondary to CKD, comprising administering to the patient a therapeutically effective amount of creatine phosphate ... In some such embodiments, the daily dose comprises a compound represented by 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 the group consisting of metabolite 1 and metabolite 2, or a medicamentously 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) in an amount of 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 amount 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 are Accordingly, 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, A compound selected from Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2. or a pharma- ceutical 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-hydroxypicolinamidoacetic acid is administered to a patient suffering from 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 have been received 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 pharma- ceutically acceptable salts, solvates, or hydrates (e.g., 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 , 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 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 compound disclosed herein, such as Compound 1, is administered daily. to a patient having anemia, wherein the compound is administered continuously and / or Non-severe anemia secondary to chronic kidney disease, secondary to congestive heart failure, administered irregularly Provided herein are methods for treating non-severe anemia and idiopathic anemia of age.

[0300] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (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 to a subject a subject comprising a subject comprising a subject, the subject being administered a therapeutically effective amount of the ... The dosage and / or dosing 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 useful for administering to a subject in need thereof a compound provided herein, or a pharmaceutical combination thereof. The pharmaceutical composition includes a suitable salt, solvate, or hydrate thereof (e.g., 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 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 use in 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 The decomposition of some active ingredients can also be influenced by the active ingredient. For example, the decomposition of some active ingredients can be influenced by certain sugars such as lactose. This may be accelerated by some excipients or on exposure to water. Active ingredients containing amines are particularly susceptible to such accelerated decomposition. 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 foods that are free of lactose, if any. 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 Pharmacopeia (USP) 25 NF20 (2002). Generally, lactose-free compositions. The article comprises the active ingredient, a pharma- ceutically compatible amount and a pharma- ceutically acceptable amount of a binder / filler. In one embodiment, the lactose-free dosage form contains the active ingredient, microcrystalline cellulose, and a lubricant. Contains cellulose, pregelatinized starch, and magnesium stearate.

[0304] Anhydrous pharmaceutical compositions and dosage forms are also provided since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) may determine 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 (Dru g Stability: Principles & Practice), 2nd edition, Marcel Dekker, NY, NY, 1995, pp. See, e.g., 379-80. In fact, water and heat accelerate the decomposition of some compounds. and / or humidity are typically present during manufacture, handling, packaging, storage, shipping, and use of the drug product. 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, have been found to prevent exposure to water. The materials used are packaged as described above 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), bliss Packaging includes, but is not limited to, box packaging, box wrap, and strip packaging.

[0306] Also included are pharmaceutical compositions and compositions containing one or more compounds that reduce the rate at which an 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, but are not limited to these. 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, those listed above. The dosage range 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, They are provided as separate dosage forms, such as tablets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients and can be formulated according to formulating methods well known to those skilled in the art. Generally, the Remington's Science and Practice of Pharmaceutical Preparations 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 include at least one The formulation is prepared by combining the active ingredient in an intimate mixture with the excipients. Depending on the preparation desired for administration, it may take a wide variety of forms, for example, oral liquid or aerosol. Excipients suitable 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 the formulations (powders, tablets, capsules, and caplets) are denatured cellulose, sorbitol, sorbitol-based cellulose, sorbitol-based cellulose acetate ... Contains punch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants. , but 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 include those comprising the active ingredient with liquid carriers, with finely divided solid carriers, or with both. The mixture is prepared by uniform and intimate mixing, followed, if necessary, by shaping the product into 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 granules, optionally mixed with an excipient, is compressed in a suitable machine. Molded tablets can be prepared by mixing the powder with an inert liquid diluent. It may be produced by molding a mixture of the 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. Binders suitable for use in the formulation include corn starch, potato starch, or other starch. or other starches, gelatin, gum acacia, sodium alginate, alginic acid, Other natural and synthetic gums such as alginates, tragacanth, guar gum, cellulose and and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose, calcium, sodium carboxymethylcellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., No. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. It is not.

[0313] Preferred forms of microcrystalline cellulose are AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL PH-102, AVICEL PH-103, AVICEL PH-101, AVICEL PH-103, AVICEL PH-102 ... CEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marx Hook, PA) This includes, but is not limited to, substances sold as "chemicals" or "chemical mixtures" (e.g., An exemplary binder is microcrystalline cellulose sold as AVICEL RC-581. A mixture of sodium carboxymethylcellulose and sodium carboxymethylcellulose. Excipients include AVICEL-PH-103™ and Starch 1500 LM. Other microcrystalline celluloses Suitable forms include silica-containing microcrystalline cellulose, e.g. PROSOLV 50, PROSOLV 90, PROSOLV HD. Includes, but is 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, alpha-density In the pharmaceutical composition, The binder or filler, in one embodiment, is present in about 50 to about 99 weight percent of the pharmaceutical composition or dosage form. There is.

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

[0316] In some embodiments, the bulking agent is isomalt, lactose, lactitol, mannitol, These include, but are not limited to, sorbitol, xylitol, erythritol, and mixtures thereof. However, the present invention is not limited to these.

[0317] Disintegrants are used in the composition to provide a tablet that disintegrates 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 use a sufficient amount, 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 a solid oral dosage form. The amount of agent varies depending on the type of formulation and is readily discernible by 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 the pharmaceutical compositions and dosage forms include agar, alginic acid, carbonate, etc. Calcium, microcrystalline cellulose, croscarmellose sodium, povidone, crospovidone Don, polacrilin potassium, sodium starch glycolate, potato or ta Pioca starch, other starches, pregelatinized starch, other starches, clay, other algae Including, but not limited to, polyesters, 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, Soybean Oil Glycol, 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, agar, agar, and mixtures thereof. Examples of silica gel include siloid silica gel (AEROSIL 200, manufactured by WR Grace, Inc., Baltimore, MD), Synthetic silica coagulated aerosol (commercially available from Degussa, Plano, TX), CAB-O-SIL (commercially available from Cabot, Inc.), Pyrogenic colloidal silicon dioxide products sold by Epson Corporation of Boston, Mass., and Lubricants, when used at all, are a part of the pharmaceutical composition or formulation in which they are incorporated. They 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 ricin, about 15% to about 85% of sodium starch glycolate 2% to about 10%, and block copolymers of ethylene oxide and propylene oxide at 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, isomaltulose, , Sodium Starch Glycolate, Sodium Lauryl Sulfate, Povidone, Colloidal Diglyceride In some embodiments, the composition further comprises: 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% in an amount of sodium lauryl sulfate, 0.2% to about 2% in an amount of sodium lauryl sulfate, and about 2% to about 10% in an amount of povidone. Colloidal silicon dioxide in an amount of 0.1% to about 1%, and magnesium stearate in an amount of about 0.1% about 1% by weight.

[0322] In some embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] 100 ml of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 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) Compound 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 pharma- ceutical acceptable salt, solvate, or or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] 100 ml of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 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 pharma- ceutical acceptable salt, solvate, or the like thereof. or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) 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, or about 20 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 ...

Claims

1. 2. For use in a method for increasing the level of hemoglobin in a patient in need thereof relative to baseline hemoglobin levels, comprising administering to said patient a compound having the structure: 【Chemistry 1】 1. A pharmaceutical composition comprising a tablet or capsule containing compound 1, which is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid having the formula: The patient has a hemoglobin (HGB) level at the start of treatment that is ≦10.5 g / dL or ≧9.5 g / dL and ≦12 g / dL, the level of serum hemoglobin is elevated by at least about 0.1 to about 1.0 g / dL compared to the baseline hemoglobin level; and The pharmaceutical composition is used such that Compound 1 is administered to the patient once daily in an amount of about 150 mg, about 300 mg, about 450 mg, or about 600 mg.

2. 2. The pharmaceutical composition of claim 1, wherein the serum hemoglobin level is increased by about 0.1 to about 1.0 g / dL compared to the baseline hemoglobin level for about 1 to 6 weeks.

3. 3. The method of claim 2, wherein the serum hemoglobin level is increased by about 0.1 to about 1.0 g / dL compared to the baseline hemoglobin level for four weeks.

4. 3. The pharmaceutical composition of claim 2, wherein the serum hemoglobin level is increased by about 0.1 to about 1.0 g / dL compared to the baseline hemoglobin level for six weeks.

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

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

7. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the patient has a hemoglobin (HGB) level of ≧9.5 g / dL and ≦12 g / dL at the start of treatment.

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