Compositions and methods for treating anemia

Abstract

To provide tablet formulations and pharmaceutical compositions for the treatment or prevention of anemia, such as anemia secondary to or associated with chronic kidney disease, anemia secondary to or associated with non-dialysis-dependent chronic kidney disease, anemia associated with or resulting from chemotherapy, or anemia associated with AIDS.SOLUTION: Provided is a tablet formulation comprising an intra-granular component, an extra-granular component, and a film coating component. Therein: the intra-granular component comprises: 55 to 75 wt.% of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or a salt thereof, 15 to 35 wt.% of microcrystalline cellulose, 2.0 to 4.0 wt.% of a disintegrant, and 1.8 to 3.8 wt.% of hydroxypropylmethylcellulose; the extra-granula component comprises 2.0 to 4.0 wt.% of a disintegrant, 0.15 to 0.35 wt.% of a glidant, and 0.35 to 1.15 wt.% of a lubricant; and the film coating component comprises 1.0 to 8 wt.% of a tablet coating.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] This application is a joint venture of U.S. Provisional Patent Application No. 62 / 270,168, filed December 21, 2015, and U.S. Provisional Patent Application No. 62 / 270,168, filed April 1, 2015. This application claims priority to and benefit of the filing date of U.S. Provisional Patent Application No. 62 / 141,420, filed on is incorporated herein in its entirety.

[0002] 1. Field of the Invention The present disclosure relates to anemia secondary to or associated with chronic kidney disease, non-dialysis dependent chronic kidney disease, chemotherapy, and the like. Treatment of anemia, such as drug-related or chemotherapy-related anemia or AIDS-related anemia The present disclosure further relates to the use of HIF prolyl hydroxylase inhibitors in the treatment or prevention of The present invention relates to a HIF prolyl hydroxylase inhibitor compound and a medicamentously acceptable salt thereof, Compositions containing hydroxylase inhibitor compounds, and methods for treating peripheral vascular disease (PVD), coronary artery disease (CAD) The present invention relates to a method for treating or preventing diseases such as heart failure, ischemia, hypoxia, and anemia. The present disclosure relates to anemia secondary to or associated with chronic kidney disease, chemotherapy-related or in the treatment or prevention of anemia, such as anemia resulting from therapy or associated with AIDS; Specific dosages and dosing regimens for the use of prolyl hydroxylase inhibitors do. [Background technology]

[0003] (2. Background of the Invention) 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 an α and a β subunit. HIF-α subunits are normally present in excess and are independent of oxygen tension, but they are upregulated in the hypoxic In this regard, accumulation of HIF-α is mainly due to the accumulation of HIF promoter. The enzymes in the prolyl hydroxylase family, known as prolyl hydroxylases, catalyze the synthesis of two proline residues. Hydroxylation of one or both proline residues regulates the function of HIF-α. Thus, inhibition of HIF prolyl hydroxylases leads to the stabilization and accumulation of HIF-α. (i.e., reduced degradation of HIF-α), which in turn favors the formation of HIF heterodimers. Increased amount of available HIF-α and upregulation of target genes such as the erythropoietin gene Conversely, activation of HIF prolyl hydroxylases leads to destabilization of HIF-α. (i.e., increased degradation of HIF-α), which leads to the formation of HIF heterodimers. This leads to a decrease in the amount of available HIF-α and downregulation of target genes such as VEGF. do.

[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 / 03099. 77, which is incorporated herein by reference in its entirety. Compounds such as these inhibit HIF prolyl hydroxylases, thereby stabilizing HIF-α. Stabilization of IFN-α results in increased endogenous erythropoietin (EPO) production. Similarly, appropriate dosages and dosing regimens for treating patients with disorders such as anemia are described in Achieving the desired or optimal therapeutic effect without adverse or unwanted side effects Indeed, many active compounds have been developed that are difficult to treat without finding effective and safe dosing regimens. have failed in clinical trials.

[0006] The use of prolyl hydroxylase inhibitors and specific dosing regimens to treat hypoxia-inducible factor (HIF) IF) Their use for the treatment or prevention of diseases ameliorated by modulation of prolyl hydroxylase This use is described in International Application No. WO / 2014 / 200773, which is incorporated herein by reference in its entirety. The present invention relates to a method for the treatment of a patient with a chronic condition in which the serum iron level is significantly increased relative to the baseline serum iron level. To increase the patient's total iron-binding capacity (TIBC) without increasing the The therapeutic regimen that modulates EPO and baseline hepcidin expression levels were compared. The results showed that the baseline serum hemoglobin level in patients was significantly reduced without significantly reducing gene expression. The administration of prolyl hydroxylase inhibitors to the bell, which increase serum hemoglobin levels, The method of administering the invention is also described therein. Summary of the Invention

[0007] (3. Summary of the invention) Oral dosage forms containing intragranular, extragranular and film-coated components e formulation), wherein the intragranular components are Compound 1, an insoluble diluent or carrier, a disintegrant, and and a diluent or filler; the extragranular component comprises a disintegrant, a glidant, and / or a lubricant. and wherein the film coating component comprises a tablet coating, the oral dosage formulation being It is described in.

[0008] An oral dosage formulation comprising an intragranular component, an extragranular component, and a film-coating component, The intragranular components were Compound 1, microcrystalline cellulose, sodium starch glycolate, and hyaluronan. The extragranular component contains sodium starch glycolate. , colloidal silicon dioxide, and magnesium stearate, and the film Described herein are oral dosage forms in which a coating component includes Opadry®.

[0009] A formulation comprising an intragranular component, an extragranular component, and a film-coating component, comprising Compound 1, an insoluble diluent or carrier, a disintegrant, and a diluent or filler; comprises a disintegrant, a glidant, and / or a lubricant, and the film coating component A method of treating anemia comprising administering to a patient a formulation comprising a tablet coating is provided herein. It is stated in the book.

[0010] A formulation comprising an intragranular component, an extragranular component, and a film-coating component, Compound 1, microcrystalline cellulose, sodium starch glycolate, and hydroxypropyl cellulose propyl methylcellulose, and the extragranular component is sodium starch glycolate, cobalt and magnesium stearate, and the film coating A method for treating anemia comprising administering to a patient a formulation in which the therapeutic ingredient comprises Opadry®. The methods are described herein.

[0011] A method for treating anemia secondary to non-dialysis dependent chronic kidney disease, comprising administering to said patient a Patients with anemia secondary to disease were administered an effective amount of {[5-(3-chlorophenyl)-3-hydroxypyridine Lysine-2-carbonyl]amino}acetic acid or a pharma- ceutical acceptable salt thereof, solvent and administering a daily dose of about 150 mg, about 300 mg, about 450 mg, Methods described herein include about 600 mg, or about 750 mg of the compound.

[0012] A method of treating anemia secondary to non-dialysis dependent chronic kidney disease comprising administering a sufficient number of consecutive A dose of HIF prolyl hydroxylase inhibitor or HIF-α stabilizer was administered to patients with non-dialysis-dependent chronic kidney disease. to a patient with secondary anemia, wherein the patient: (i) receives 60 mL / min / 1.73 m 2 Less than Estimated glomerular filtration rate (eGFR) (where the subject is dialysis-naïve and has a mean age of 3 months after initiation of treatment) (ii) a hemoglobin level of less than 10.0 g / dL prior to the start of treatment; Robin level, (iii) ferritin level of 100 ng / mL or more within 4 weeks of starting treatment, (iv) treatment (v) a transferrin saturation (TSAT) level of 20% or greater within 4 weeks of initiation of treatment; (vi) a folate measurement above the lower limit of normal within 4 weeks of starting treatment (vii) at least 2, 3, 4, and 5 of the 18 years of age or all of the methods described herein.

[0013] A method of treating anemia secondary to non-dialysis dependent chronic kidney disease comprising administering a sufficient number of consecutive A dose of HIF prolyl hydroxylase inhibitor or HIF-α stabilizer was administered to patients with non-dialysis-dependent chronic kidney disease. to a patient with secondary anemia, wherein the patient receives: (i) 65 mL / min / 1.73 m 2 Less than Estimated glomerular filtration rate (eGFR) (where the subject is dialysis-naïve and has a mean age of 3 months after initiation of treatment) (ii) hemoglobin levels less than 10.0 g / dL before treatment initiation; (iii) ferritin level of 50 ng / mL or more within 4 weeks of starting treatment; (iv) (v) a transferrin saturation (TSAT) level of 15% or greater within the first 4 weeks of treatment; (vi) a folate level above the lower limit of normal within 4 weeks of starting treatment Vitamin B12 measurements; and (vii) at least 2, 3, 4, or 5 of the following ages: at least 18 years; or any of the methods described herein.

[0014] A method for treating anemia in a patient having non-dialysis dependent chronic kidney disease, comprising: (i) administering to the patient (ii) administering to said subject an initial daily dose of Compound 1 for four weeks daily at said initial daily dose of Compound 1; If Hgb did not increase by more than 0.5 g / dL above baseline after each dose, the daily dose was increased to 15 The daily dose was increased by 150 mg / day of Compound 1 every 4 weeks until Hgb was greater than 10.0 g / dL. (iii) if Hgb rises rapidly during treatment, the daily dose should be increased to 150 mg / day. (iv) if Hgb falls below 10.0 g / dL, increase the daily dose by 150 mg / day (v) if Hgb level exceeds 11.0 g / dL, treat until Hgb is reduced to 10.5 g / dL or less. (vi) interrupting treatment and then resuming the medication at a daily dose reduced by 150 mg / day; and If a dosage adjustment is necessary to maintain the desired level, adjust the daily dose by 150 mg / day. Described herein are methods that include:

[0015] A method for treating anemia in a patient having non-dialysis dependent chronic kidney disease, comprising: (i) administering to the patient (ii) administering to said subject an initial daily dose of Compound 1 for four weeks daily at said initial daily dose of Compound 1; If Hgb did not increase by more than 0.5 g / dL above baseline after each dose, the daily dose was increased to 15 The daily dose was increased by 150 mg / day of Compound 1 every 4 weeks until Hgb was greater than 10.0 g / dL. (iii) if Hgb rises rapidly during treatment, the daily dose should be increased to 150 mg / day. (iv) if Hgb falls below 10.0 g / dL, increase the daily dose by 150 mg / day (v) if Hgb levels exceed 12.0 g / dL, reduce the daily dose by 150 mg / day and If Hgb levels exceed 13.0 g / dL, treatment should be interrupted until Hgb decreases to 12.5 g / dL or less. and (vi) resume dosing at a reduced daily dose of 150 mg / day; and If a dosage adjustment is necessary to maintain the normal dose, the daily dose should be adjusted by 150 mg / day. Methods are described herein.

[0016] A method for treating anemia in a patient having non-dialysis dependent chronic kidney disease, comprising: (i) administering to the patient (ii) administering to the subject an initial daily dose of Compound 1; If dosage adjustment is necessary, adjust the daily dose by 150 mg / day; (iii) Hgb should not increase rapidly during treatment. (iv) Hgb decreases to less than 10.0 g / dL. and (v) if Hgb levels exceed 11.0 g / dL, increase the daily dose by 150 mg / day. If this occurs, treatment should be interrupted until Hgb is reduced to 10.5 g / dL or less, then reduced by 150 mg / day. Methods described herein include reinstating dosing at a reduced daily dose.

[0017] A method for treating anemia in a patient having non-dialysis dependent chronic kidney disease, comprising: (i) administering to the patient (ii) administering to the subject an initial daily dose of Compound 1; If dosage adjustment is necessary, adjust the daily dose by 150 mg / day; (iii) Hgb should not increase rapidly during treatment. (iv) Hgb decreases to less than 10.0 g / dL. (v) if Hgb levels exceed 12.0 g / dL, increase the daily dose by 150 mg / day; and If Hgb levels are >13.0 g / dL, the daily dose should be reduced by 150 mg / day. If Hgb levels are >13.0 g / dL, the daily dose should be reduced by 150 mg / day. Withhold treatment until CSF levels are reduced to 0.5 g / dL or less, then reduce daily dose by 150 mg / day Described herein are methods that include resuming the

[0018] In certain embodiments, the baseline value is determined immediately prior to the first administration of Compound 1. do.

[0019] In certain embodiments, if Hgb rises by more than 1.0 g / dL in any two week period , Hgb rises rapidly.

[0020] In certain embodiments, the maximum daily dose is 600 mg / day.

[0021] In certain embodiments, the daily dose is increased more frequently than once every four weeks during the course of treatment. do not have.

[0022] In certain more specific embodiments, the reduction in the daily dose is no more than once every four weeks during the course of treatment. This does not happen very often.

[0023] In certain embodiments, the initial daily dosage is 300 mg / day.

[0024] In certain embodiments, the initial daily dose is in the form of two tablets of Compound 1, each of 150 mg. It is administered at .

[0025] In certain embodiments, the initial daily dose is 450 mg / day.

[0026] In certain embodiments, the initial daily dose is in the form of three tablets of Compound 1, each of 150 mg. It is administered at .

[0027] In certain embodiments, the initial daily dose is administered in the morning.

[0028] In certain embodiments, the initial daily dose is administered between 7 am and 2 pm.

[0029] In certain embodiments, Compound 1 is administered in the form of Formulation 1.

[0030] In certain embodiments, Compound 1 is administered in the form of Formulation 2. [Brief description of the drawings]

[0031] (4) BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1A]Relative bioavailability results - Plasma concentrations shown as a linear plot for Compound 1 administered as tablet Formulation 1 and Formulation 2 as described in Section 6.2.

[0032] [Figure 1B] Relative Bioavailability Results - Plasma concentrations shown as semi-log plots for Compound 1 administered as tablet Formulation 1 and Formulation 2 as described in Section 6.2.

[0033] [Figure 2A] Food Effect Results - Plasma concentrations of Compound 1 administered as tablet formulation 2 described in Section 6.2 in fed and fasted states shown as a linear plot.

[0034] [Figure 2B] Food Effect Results - Plasma concentrations shown as semi-log plots of Compound 1 administered as tablet formulation 2 described in Section 6.2 in the fed and fasted states. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] (5 Detailed Description) In certain embodiments, a method of treating or preventing anemia in a patient comprises administering to the patient A medicamentously effective amount of a compound having 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 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 certain embodiments, the patient is a non-dialysis dependent patient. In certain embodiments, the patient has anemia secondary to chronic kidney disease. a) restore or maintain the diurnal pattern of EPO serum levels; and / or b) increase total iron binding capacity. and / or c) increase total iron binding capacity without significantly increasing total iron levels; and / or or d) increasing hemoglobin levels in patients without significantly decreasing hepcidin levels. At least about 0.2 g / dL, 0.3 g / dL, 0.4 g / dL, 0.5 g / dL, or 1.0 g / dL above baseline hemoglobin level 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 , or at least about 1.5 g / dL.

[0036] General methods of treatment are described in Section 5.5. Compounds Described Herein Diseases treatable by the compounds and methods are described in Section 5.6. The treatments and dosing regimens used are described in Section 5.7. Combination therapy using the compositions is described in Section 5.8. Specific patient populations to be treated with the compounds and methods are described in Section 5.4. The specific formulations to be used in the dosing regimens for the patient populations described in the specification are set out in Section 1. This is explained in Section 5.3.

[0037] (5.1 Definitions and Abbreviations) In some embodiments, the word "including" as used throughout the description and claims of this specification "includes" and other forms of this word, such as "includes" and "comprises", are examples of other additives. Meaning the inclusion and exclusion of objects, ingredients, integers, or steps without limitation In some embodiments, the term "compound" used in the description and appended claims is not intended to be a compound that is As used herein, the singular forms "a," "an," and "the" are used unless the context clearly indicates otherwise. Thus, for example, reference to "a composition" includes two or more In some embodiments, the term "any" or "any mixture" refers to any of the compositions. "Intentionally" means that the subsequently described event or circumstance may or may not occur. and that this description includes instances where the event or circumstance will occur and instances where it will not occur. This means:

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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. .

[0042] 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.

[0043] 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, cyclopentyl, and cyclohexyl.

[0044] 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.

[0045] As used herein, a "cycloalkoxy" group refers to a cycloalkyl group as defined herein. Representative cycloalkoxy groups are cycloalkyl-O- groups, as defined below. Propyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy Includes shi.

[0046] As used herein, a "haloalkyl" group refers to an alkyl group having one or more (e.g., 1 to 5) hydrogen atoms. A, as defined herein above, in which an atom is replaced by a halogen atom. Representative haloalkyl groups are CF, CHF, CHF, CCl, CFCHCH, and CF. Includes 3CF2.

[0047] 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 Includes.

[0048] 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; The ring is a saturated ring of 5 or 6 ring atoms. There are no adjacent oxygen and / or sulfur atoms in the ring. Representative heterocycloalkyl groups are piperidyl, pyrrolidinyl, piperazinyl, Morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxa nyl, oxazolinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and tetrahydrophenyl. It is hydrothiopyranyl.

[0049] 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.

[0050] As used herein, "heteroaryl" refers to a heteroaryl group that is heterocyclic and / or heterocyclic, with adjacent oxygen and / or sulfur atoms. 2 to 9 carbon atoms and N, O, and S atoms, provided that they do not contain any 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 simple Cyclic heteroaryl groups include pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, aryl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl aryl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl, and Representative bicyclic heteroaryl groups include naphthyridyl (e.g., 1,5 or 1,7), imidazopyridyl, pyridopyrimidinyl, and 7-azaindolyl. The trifluoro-fused heteroaryl groups are indolyl, quinolyl, isoquinolyl, phthalazinyl, and phenyl. Benzothienyl (i.e. thianaphthenyl), benzimidazolyl, benzofuranyl, benzo Includes oxazolyl, benzisoxazolyl, benzothiazolyl, and benzofurazanyl. All positional isomers are understood, e.g., 2-pyridyl, 3-pyridyl, and 4-pyridyl. As shown in the figure.

[0051] For purposes of this disclosure, the terms "compound," "analog," and "composition" include all enantiomeric forms. The compounds described herein include isomers, diastereomeric forms, salts, tautomers, and the like. Equally well represented are inhibitors of HIF prolyl hydroxylases. Compounds disclosed herein The aryl groups include all salt forms, e.g. salts of basic groups, especially amines, as well as salts of acidic groups, especially carboxyl groups. The following are examples of anions that can form pharma- ceutically acceptable salts with basic groups: Non-limiting examples of ions are: chloride, bromide, iodide, sulfate, Hydrogen sulfate ion, carbonate ion, hydrogen carbonate ion, phosphate ion, formate ion, acetate ion , propionate ion, butyrate ion, pyruvate ion, lactate ion, oxalate ion, Malonate ion, maleate ion, succinate ion, tartrate ion, fumarate ion, citrate ion, and the like. The following are examples of anions of acidic substituents on the compounds described herein: Non-limiting examples of cations capable of forming pharma- ceutically acceptable salts of the on-type are: sodium , lithium, potassium, calcium, magnesium, zinc, bismuth, and the like. The following are examples of phenolic, aryl alcohol, or heteroaryl groups on the compounds described herein: Non-cations capable of forming pharma- ceutically acceptable salts of the anionic form of the diol alcohol substituent. Non-limiting examples are: sodium, lithium, and potassium. In some embodiments, The terms "compound," "analog," and "composition" are used interchangeably throughout this specification. .

[0052] If there is a discrepancy between a depicted structure and the name given to that structure, the depicted structure In addition, the standing of the structure or part of the structure Where the structure chemistry is not indicated, for example by a bold or dashed line, the structure or part of the structure is It should be understood that all stereoisomers thereof are encompassed.

[0053] 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, such as chemotherapy to treat bone marrow inflammation or other chronic diseases that reduce bone marrow production anemia), acute (e.g., blood loss during injury or surgery), nutrition-related (e.g., iron deficiency or Vitamin B12 deficiency), or hemoglobinopathies (e.g., sickle cell disease, thalassemia) etc.), or anemia due to premature puberty, or anemia due to autologous blood donation.

[0054] As used herein, the term "non-severe anemia" refers to an anemia in which the hemoglobin level is at least In some such embodiments, a patient with severe anemia is considered to have an anemia of 9.0 g / dL or less. Non-transfusion anemia refers to anemia in patients who do not require blood transfusions.

[0055] As used herein, the term "dose" refers to the amount of a compound, or a combination thereof, to be administered at one time. The dosage refers to the amount of a pharma- ceutically acceptable salt, solvate, or hydrate. The dosage form may contain two or more single unit dosage forms (e.g., two single doses). a single unit dosage form (e.g., a single dose may contain half a tablet) or less than one single unit dosage form (e.g., a single dose may contain half a tablet). Thus, when the compound is administered in a daily dose of 450 mg once a day, When administered once daily, the dosage of the compound is 3 tablets each containing 150 mg of the compound. It could be.

[0056] 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., a single daily dose) or the daily doses may be divided into The combination may be divided so that it 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 "continuous" dosage.

[0057] 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 providing a liquid dosage form suitable for oral or parenteral administration to a patient. and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to obtain a A unit dosage form does not necessarily have to be administered as a single dose, and a single unit dosage form is not necessarily It does not have to constitute the entire dose.

[0058] 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 compound equivalent sufficient to cause or delay or minimize symptoms associated with the disease. The amount of a pharma- ceutically acceptable salt, solvate or hydrate is referred to as the amount of the pharma- ceutically acceptable salt, solvate or hydrate. In some embodiments, the compound is a compound as described herein. The disclosed compounds are:

[0059] 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 that the subject may have a decreased ability to tolerate the composition compared to a subject who does not receive the composition. The present invention relates to a method for treating a disease comprising administering to a subject, comprising administering to said subject a therapeutically effective amount of ... The present invention includes administration of the compound 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

[0060] 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 the prevalence or increase of a disease as a result of the administration of the compound or its hydrate to a patient suffering from such a disease; It means minimizing evil.

[0061] 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 are described, for example, in "Remington's Pharmaceutical Sciences" (Remington's Pharmaceutical Sciences), 22nd ed., Pharmaceutical Press (2012) Please refer to.

[0062] 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. It does not cause any biological effect or interact with any of the other components of the pharmaceutical composition in which it is contained. Can be administered to an individual together with related active compounds without interacting in an adverse manner .

[0063] As used herein, the term "hydrate" refers to a compound bound by non-covalent intermolecular forces. The compounds provided herein, or their derivatives, further comprising a stoichiometric or non-stoichiometric amount of water. By pharma- ceutical acceptable salts is meant.

[0064] 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.

[0065] 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 present invention is important in the context of many of the disclosed and each value is also expressly incorporated herein by reference in its entirety as "about" that particular value in addition to the value itself. It is also understood that the disclosure in the specification is based on the value "10". For example, if the value "10" is disclosed, Also disclosed is "about 10". When a value is disclosed, it is understood by one of skill in the art that the value is It is also understood that "less than or equal to" a value and "greater than or equal to" that value, as well as possible ranges between the values, are also disclosed. For example, if the value "10" is disclosed, then "greater than or equal to 10" is also disclosed as well as "less than or equal to 10." Data is provided in many different formats and It is also understood that any combination of the data points represents endpoints and starting points and ranges. If a specific data point "10" and a specific data point "15" are disclosed, Between 10 and 15 are disclosed in addition to no more than, less than, less than, and equal to. It is understood that each unit amount between two particular unit amounts is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0066] In some embodiments, the term subject or patient refers to a human, mouse, dog, donkey, horse, In a specific embodiment, the term may refer to a mammal such as a rat, a guinea pig, or a monkey. The subject or patient is a human subject or patient.

[0067] In some embodiments, the compounds provided herein have the structure Product 1, i.e., {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid Acid: [ka] .

[0068] In some embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine Lysine-2-carbonyl]amino}acetic acid, while in some alternative embodiments The compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. In some alternative embodiments, the compound is , solvate of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid In some alternative embodiments, the compound may be {[5-(3-chlorophenyl)-3 Some preferred compounds include hydrates of 1-hydroxypyridine-2-carbonyl]amino}acetic acid. In certain embodiments, the present invention relates to a compound in its parent form (i.e., a salt, solvate, or hydrate). In some alternative preferred embodiments, the present invention relates to the compound or a pharma- ceutical acceptable salt thereof.

[0069] In certain embodiments, the compounds described herein are compounds having the structure: , i.e. {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid is [ka] .

[0070] In certain embodiments, the compound is {[5-(3-fluorophenyl)-3-hydroxypyridine In certain alternative embodiments, the compound may be dimethylamino-2-carbonylamino}acetic acid. The compound is {[5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid It may be a pharma- ceutically acceptable salt. In certain alternative embodiments, the compound is {[5-(3 -fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid solvate In certain alternative embodiments, the compound is {[5-(3-fluorophenyl)-3-hydro 2-[4-(2-pyridine-2-carbonyl)amino]acetic acid hydrate. In the present invention, the compound is provided in its parent form (i.e., not a salt, solvate, or hydrate). In certain alternative preferred embodiments, the present invention relates to the compound or its medicament. The present invention relates to acceptable salts thereof.

[0071] 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, there are three distinct PHD isoforms: PHD1, PHD2, and PHD3. These are referred to as EGLN2, EGLN1, and EGLN3, or HPH3, HPH2, and HPH1, respectively. In embodiments, the HIF prolyl hydroxylase is an enzyme (e.g., HIF-1α prolyl hydroxylase). Specific targets of the enzymes HIF-2α prolyl hydroxylase, HIF-3α prolyl hydroxylase, and / or HIF-4α prolyl hydroxylase It can point to the target.

[0072] As used herein, "Formulation 1" and "Formulation 2" refer to the compounds described in Section 6.2. A pharmaceutical formulation of Compound 1.

[0073] Further abbreviations and acronyms are provided in the table below. [Table 2] TIFF2025069280000006.tif230170TIFF2025069280000007.tif159170

[0074] (5.2 Compounds) In certain embodiments, compounds for use in the methods and formulations provided herein is a modulator of HIF prolyl hydroxylase. The compounds for use in the methods provided herein are modulators of HIF-1-alpha prolyl hydroxylase. In another more specific embodiment, a compound for use in the methods provided herein is The compounds are modulators of HIF-2-α prolyl hydroxylase. In embodiments, the compounds for use in the methods provided herein contain 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% of HIF-1-α prolyl HIF-2α prolyl hydroxylase is more active against HIF-2α prolyl hydroxylase than against HIF-2α prolyl hydroxylase. Thus, in some embodiments, the compounds provided herein are modulators of oxidase. The compounds provided herein for use in the method of the present invention are capable of preferentially inhibiting HIF-2-α over HIF-1-α. To determine preferential stabilization of HIF-2-α versus HIF-1-α, test compounds were The concentrations of HIF-1-α and HIF-2-α in subjects with or without the drug were measured using the HIF-1-α and HIF-2-α The primary antibody of each kit cross-reacts with other HIFs. It should be noted that the primary antibody against HIF-1-α is not It reacts immunospecifically with HIF-1-α and does not cross-react with HIF-2-α; The secondary antibody reacts immunospecifically with HIF-2-α and does not cross-react with HIF-1-α.

[0075] In certain embodiments, the compound of the present invention is a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer. The disclosed compounds are heterocyclic carboxamides. In certain such embodiments, the heterocyclic The monocyclic carboxamides include pyridylcarboxamides, quinolinecarboxamides, and isocarboxamides. quinolinecarboxamides.

[0076] In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is of formula (I): or a pharma- ceutically acceptable salt, solvate or hydrate thereof. [ka] (In the formula, R and R 1 are, 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) the 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, independently: (i) hydrogen; (ii) C1-C4 alkyl; (iii) C3-C4 cycloalkyl; or (iv) R5a 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, 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 -[C(R 8a R 8b )] n - is a connected unit having the structure 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.

[0077] In certain, more specific embodiments, R and R in formula (I) 1 are both hydrogen That doesn't mean there is.

[0078] In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is a compound of formula (II): or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. : [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 cycloalkene. C2-C6 alkynyl, C4-C7 heterocycloalkyl, C6-C 10 Aryl, C5-C 10 Heteroa Reel, 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, C(CN)3; and R'' is C1-C6 alkyl, C3-C6 cycloalkyl, C4-C7 heterocycloalkyl, C6-C 10 Ants C5-C 10 heteroaryl; and wherein C1-C6 aryl is independently selected from the group consisting of 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)2NH R'', 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 where 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, N HC(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)NH R'', C(O)NR''2, CN, CH2CN, CF3, CHF2, CH2F, NH(CN), N(CN)2, CH(CN)2, or C(CN)3 and wherein the two R″ groups on the nitrogen together are 2 to 7 carbon atoms. and a nitrogen atom, including the nitrogen atom to which the two R″ groups are attached, selected from nitrogen, oxygen, and sulfur. can form a ring having 1 to 3 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, independently: (i) hydrogen; (ii) C1-C4 alkyl or C3-C4 cycloalkyl; or (iii)R7a and R 7b together form a ring having 3 to 7 atoms).

[0079] In certain embodiments, the HIF stabilizer is a compound having the structure of formula (III), or a pharmaceutical thereof: is an acceptable salt, solvate, or hydrate thereof [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, independently: (i) hydrogen; (ii) C1-C4 alkyl or C3-C4 cycloalkyl; or (iii)R 2 and R 3 Each of these has 2 to 7 carbon atoms and R 2 and R 3 Nitrogen containing a nitrogen atom to which can form a ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; and M 1 is a cation; and R 4 teeth: (i) -OH; or (ii)-OM 2 ; and M 2 is a cation).

[0080] In certain embodiments, the HIF stabilizer is a compound having the structure of formula (IV), or a pharmaceutical thereof: is an acceptable salt, solvate, or hydrate thereof [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, independently: (i) hydrogen; (ii) C1-C4 alkyl or C3-C4 cycloalkyl; or (iii)R 2 and R 3 Each of these has 2 to 7 carbon atoms and R 2 and R 3 Nitrogen containing a nitrogen atom to which can form a ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur; and M 1 is a cation; and R 4 teeth: (i) -OH; or (ii)-OM 2 ; and M 2 is a cation).

[0081] The HIF prolyl hydroxylase inhibitor compounds described herein have the structure shown in formula (V): Unsubstituted or substituted 3-hydroxy-pyridine-2-carboxamides having the structure, and their pharmaceutical uses Pharmaceutically acceptable salts and tautomers, wherein L is C 1-6 is alkyl; and R 1 and R 2 are independently H or C 1-6 (It is alkyl) [ka] .

[0082] In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer is {[5-(3- chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid (compound 1), or A pharma- ceutically acceptable salt, solvate, or hydrate of: [ka] .

[0083] In certain embodiments, the HIF stabilizer is Compound 2 having the structure: and optionally substituted salts, solvates, or hydrates thereof: [ka] .

[0084] In certain embodiments, the HIF stabilizer is compound 3 having the structure: and the like. [ka] .

[0085] In certain embodiments, the HIF stabilizer is compound 4 having the structure: and the like. [ka] .

[0086] In certain embodiments, the HIF stabilizer is compound 5 having the structure: and the like. [ka] .

[0087] In certain embodiments, the HIF stabilizer is compound 6 having the structure: and the like. [ka] .

[0088] In certain embodiments, the HIF prolyl hydroxylase inhibitor or HIF-α stabilizer has the structure Compound 7 has the structure: R: [ka] .

[0089] In certain embodiments, the HIF stabilizer is compound 8 having the structure: and optionally substituted salts, solvates, or hydrates thereof: [ka] .

[0090] In certain embodiments, the HIF stabilizer is compound 9 having the structure: and the like. [ka] .

[0091] In certain embodiments, the HIF stabilizer is compound 10 having the structure: and a salt, solvate, or hydrate thereof that is acceptable for [ka] .

[0092] In certain embodiments, the HIF stabilizer is compound 11 having the structure: and a salt, solvate, or hydrate thereof that is acceptable for [ka] .

[0093] In certain embodiments, the HIF stabilizer is compound 12 having the structure: and a salt, solvate, or hydrate thereof that is acceptable for [ka] .

[0094] In certain embodiments, the HIF stabilizer has the name N-(2-aminoethyl)-3-hydroxy-pyridine. Compound 13 has the following structure and has din-2-carboxamide, and its medicament is acceptable. Including salts and tautomers which may be [ka] . Tautomers of compound 13 include: [ka] .

[0095] In certain embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the formula: , Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, or Compound 13. Metabolites of the compounds can be used in the methods provided herein. In certain embodiments, such metabolites are phenol glucuronides or acyl glucuronides. It's Nido. [ka]

[0096] 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.

[0097] 5.3 Formulations 5.3.1 Compound 1 Formulation In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component comprises Compound 1, an insoluble diluent or carrier, a disintegrant, and a diluent or filler. the extragranular component comprises a disintegrant, a glidant, and / or a lubricant; and Provided herein are formulations in which the coating component comprises a tablet coating.

[0098] In certain embodiments, about 10% by weight, which is the total weight of the total intragranular and extragranular components of the tablet; About 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 7 Provided herein are oral dosage formulations comprising 0%, about 75%, about 80%, about 85%, or about 90% Compound 1. can be.

[0099] In certain embodiments, about 5% by weight, which is the total weight of the total intragranular and extragranular components of the tablet, 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% insoluble diluent or Provided herein are oral administration formulations that include a carrier.

[0100] In certain embodiments, about 1% by weight, which is the total weight of the total intragranular and extragranular components of the tablet, 1.5%, approx. 2.0%, approx. 2.5%, approx. 3%, approx. 3.5%, approx. 4%, approx. 4.5%, approx. 5.0%, approx. 5.5%, approx. 6.0%, approx. 6.5% , about 7%, about 7.5%, about 8%, about 8.5%, about 9.0%, about 9.5%, or about 10% disintegrant. Agents are provided herein.

[0101] In certain embodiments, about 0.05% by weight of the total intragranular and extragranular components of the tablet. , about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about Oral formulations containing 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, or about 0.8% of a glidant. Agents are provided herein.

[0102] In certain embodiments, about 0.1% by weight, which is the total weight of the total intragranular and extragranular components of the tablet. ,About 0.15%,About 0.2%,About 0.25%,About 0.3%,About 0.35%,About 0.4%,About 0.45%,About 0.5%,About 0.55%, About 0.6%, about 0.65%, about 0.7%, about 0.75%, or about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, About 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1. Provided herein are oral dosage formulations containing 45%, or about 1.5% lubricant.

[0103] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 50% by weight to about 80% by weight of compound 1, about 10% by weight to about 40% by weight of insoluble diluent a disintegrant or carrier, about 1.5% to about 4.5% by weight of a disintegrant, and about 1% to about 5% by weight of a diluent or filler. The extragranular component contains about 1.5% by weight to about 4.5% by weight of a disintegrant, about 0.1% by weight to about 0.4% by weight of a filler. a glidant, and about 0.15% to about 1.35% by weight of a lubricant; and The tablet coating comprises from about 1.0% to about 8% by weight of the tablet coating; and the weight is within the whole grain. Formulations are provided herein that are total weight of ingredients and extragranular ingredients.

[0104] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 55% by weight to about 75% by weight of Compound 1, about 15% by weight to about 35% by weight of an insoluble diluent % by weight of a disintegrant or carrier, about 2.0% to about 4.0% by weight of a disintegrant, and about 1.8% to about 3.8% by weight of a diluent or the extragranular component comprises about 2.0% by weight to about 4.0% by weight of a disintegrant, about 0.15% by weight to about 0.35% by weight of a filler; % by weight of a glidant, and about 0.35% to about 1.15% by weight of a lubricant; and The coating component comprises from about 1.0% by weight to about 8% by weight of the tablet coating; and Formulations are provided herein that are the total weight of intragranular and extragranular components.

[0105] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 60% by weight to about 70% by weight of compound 1, about 20% by weight to about 30% by weight of insoluble diluent % by weight of a disintegrant or carrier, about 2.5% to about 3.5% by weight of a disintegrant, and about 2.3% to about 3.3% by weight of a diluent or The extragranular component comprises about 2.5% by weight to about 3.5% by weight of a disintegrant, about 0.2% by weight to about 0.3% by weight of a granular component, and about 2.5% by weight to about 3.5% by weight of a disintegrant. % by weight of a glidant, and about 0.55% to about 0.95% by weight of a lubricant; and the tablet coating component comprises from about 1.0% to about 8% by weight of the tablet coating; and Formulations that are the total weight of the granular and extragranular ingredients are provided herein.

[0106] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 65% by weight of Compound 1, about 25% by weight of an insoluble diluent or carrier, about 3% by weight of disintegrant, and about 2.8% by weight of a diluent or filler; the extragranular component comprises about 3% by weight of a disintegrant, about 0.25% by weight of a glidant, about 0.75% by weight of a lubricant; and said film coating. the tablet coating comprises from about 2.0% to about 6.0% by weight of the total intragranular ingredients; and and the total weight of the extragranular components are provided herein.

[0107] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular components are Compound 1, microcrystalline cellulose, sodium starch glycolate, and and hydroxypropyl methylcellulose, and the extragranular component comprises sodium starch glycolate. thorium, colloidal silicon dioxide, and magnesium stearate; and Provided herein are formulations in which the film coating component comprises Opadry®.

[0108] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 50% by weight to about 80% by weight of Compound 1, about 10% by weight to about 40% by weight of microcrystalline sintered body. cellulose, about 1.5% to about 4.5% by weight of sodium starch glycolate, and about 1% to about 4.5% by weight of sodium starch glycolate. About 5% by weight of hydroxypropyl methylcellulose; and the extragranular component is about 1.5% by weight to about 4 0.5% by weight sodium starch glycolate, about 0.1% to about 0.4% by weight colloidal diacid silicon dioxide, and about 0.15% to about 1.35% by weight of magnesium stearate; the coating composition comprises about 1.0% to about 8% by weight of Opadry®; and wherein is the total weight of the total intragranular and extragranular components.

[0109] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 55% by weight to about 75% by weight of Compound 1, about 15% by weight to about 35% by weight of microcrystalline sintered body. cellulose, about 2.0% to about 4.0% by weight sodium starch glycolate, and about 1.8% by weight about 3.8% by weight hydroxypropyl methylcellulose; and the extragranular component is about 2.0% by weight ~ about 4.0% by weight sodium starch glycolate, about 0.15% by weight to about 0.35% by weight colloid silicon dioxide, and about 0.35% to about 1.15% by weight of magnesium stearate; the film coating component comprises about 1.0% to about 8% by weight Opadry®; and Formulations are provided herein in which the weight is the total weight of the intragranular and extragranular components.

[0110] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 60% by weight to about 70% by weight of compound 1, about 20% by weight to about 30% by weight of microcrystalline sintered body. cellulose, about 2.5% to about 3.5% by weight sodium starch glycolate, and about 2.3% by weight about 3.3% by weight hydroxypropyl methylcellulose; and the extragranular component is about 2.5% by weight ~About 3.5% by weight of sodium starch glycolate, about 0.2% by weight to about 0.3% by weight of colloidal silicon dioxide, and about 0.55% to about 0.95% by weight magnesium stearate; the film coating composition comprises about 1.0% to about 8% by weight Opadry®; and Formulations are provided herein in which the weight is the total weight of the intragranular and extragranular components.

[0111] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 60% by weight of Compound 1, about 30% by weight of microcrystalline cellulose, about 3% by weight of decanol, and about 10% by weight of cellulose acetate. sodium starch glycolate, and about 2.8% by weight hydroxypropyl methylcellulose the extragranular component being about 3% by weight sodium starch glycolate, about 0.25% by weight colophony % by weight of magnesium stearate; the coating composition comprises about 2.0% to about 6.0% by weight of Opadry®; and Formulations are provided herein that are the total weight of the intragranular and extragranular components.

[0112] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 65% by weight of Compound 1, about 25% by weight of microcrystalline cellulose, about 3% by weight of decanol, and about 10% by weight of cellulose acetate. sodium starch glycolate, and about 2.8% by weight hydroxypropyl methylcellulose the extragranular component being about 3% by weight sodium starch glycolate, about 0.25% by weight colophony % by weight of magnesium stearate; the coating composition comprises about 2.0% to about 6.0% by weight of Opadry®; and Formulations are provided herein that are the total weight of the intragranular and extragranular components.

[0113] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 70% by weight of Compound 1, about 20% by weight of microcrystalline cellulose, about 3% by weight of decanol, and about 10% by weight of cellulose acetate. sodium starch glycolate, and about 2.8% by weight hydroxypropyl methylcellulose the extragranular component being about 3% by weight sodium starch glycolate, about 0.25% by weight colophony % by weight of magnesium stearate; the coating composition comprises about 2.0% to about 6.0% by weight of Opadry®; and Formulations are provided herein that are the total weight of the intragranular and extragranular components.

[0114] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 75% by weight of Compound 1, about 15% by weight of microcrystalline cellulose, about 3% by weight of decanol, and about 10% by weight of cellulose acetate. sodium starch glycolate, and about 2.8% by weight hydroxypropyl methylcellulose the extragranular component being about 3% by weight sodium starch glycolate, about 0.25% by weight colophony % by weight of magnesium stearate; the coating composition comprises about 2.0% to about 6.0% by weight of Opadry®; and Formulations are provided herein that are the total weight of the intragranular and extragranular components.

[0115] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 80% by weight of Compound 1, about 10% by weight of microcrystalline cellulose, about 3% by weight of decanol, and about 10% by weight of cellulose acetate. sodium starch glycolate, and about 2.8% by weight hydroxypropyl methylcellulose the extragranular component being about 3% by weight sodium starch glycolate, about 0.25% by weight colophony % by weight of magnesium stearate; the coating composition comprises about 2.0% to about 6.0% by weight of Opadry®; and Formulations are provided herein that are the total weight of the intragranular and extragranular components.

[0116] In certain other embodiments, about 100 mg to about 1,200 mg, about 200 mg to about 1,000 mg, about 400 mg to about 1,200 mg, about 500 mg to about 1,000 mg, about 600 mg to about 1,200 mg, about 700 mg to about 1,000 mg, about 800 mg to about 1,200 mg, about 900 mg to about 1 About 800 mg, or about 450 mg to about 600 mg of the compound 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- ceutically acceptable salt, solvate, or Hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amine Units containing 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid Dosage forms are provided herein.

[0117] In certain other embodiments, about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg , 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1 2,000 mg, 1,050 mg, 1,100 mg, 1,150, or even about 1,200 mg 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 Compound 13, Metabolite 1, or Metabolite 2, or a medicament thereof. Salts, solvates, or hydrates of {[5-(3-chlorophenyl)-3-hydroxypyridine Lysine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinic acid Provided herein are unit dosage forms comprising benzodiazepine (benzoic acid) and benzoyl peroxidase (benzoic acid). Dosage forms may include about 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 of 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 Compound 9, 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-fluoro In certain such embodiments, the compound includes (3-(4-phenyl)-3-hydroxypicolinamido)acetic acid. In the present invention, the unit dosage form is about 40 mg, about 120 mg, about 185 mg, about 200 mg, about 200, about 250 mg, or more. In certain such embodiments, a single capsule contains about 300 mg of the compound. The dosage form is a tablet containing about 150 mg of the compound. In certain such embodiments, The unit dosage form is a tablet containing about 315 mg of the compound.

[0118] 5.3.2 Compound 7 formulation In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component comprises compound 7, an insoluble diluent or carrier, a disintegrant, and a diluent or filler. the extragranular component comprises a disintegrant, a glidant, and / or a lubricant; and Provided herein are formulations in which the coating component comprises a tablet coating.

[0119] In certain embodiments, about 10% by weight of the total intragranular and extragranular components of the tablet. ,About 15%,About 20%,About 25%,About 30%,About 35%,About 40%,About 45%,About 50%,About 55%,About 60%,About 65%, Provided herein are oral dosage formulations comprising about 70%, about 75%, about 80%, about 85%, or about 90% Compound 7. will be done.

[0120] In certain embodiments, about 5% by weight, which is the total weight of all intragranular and extragranular components of the tablet; About 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% insoluble diluent Oral administration formulations including the carrier are provided herein.

[0121] In certain embodiments, about 1% by weight, which is the total weight of all intragranular and extragranular components of the tablet; Approximately 1.5%, approximately 2.0%, approximately 2.5%, approximately 3%, approximately 3.5%, approximately 4%, approximately 4.5%, approximately 5.0%, approximately 5.5%, approximately 6.0%, approximately 6. Oral administration containing 5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9.0%, about 9.5%, or about 10% disintegrant. Formulations are provided herein.

[0122] In certain embodiments, the total weight of the total intragranular and extragranular components of the tablet is about 0.05 by weight. %, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, Oral administration containing about 0.55%, about 0.6%, about 0.65%, about 0.7%, about 0.75%, or about 0.8% of a glidant. Formulations are provided herein.

[0123] In certain embodiments, about 0.1% by weight of the total intragranular and extragranular components of the tablet. ,About 0.15%,About 0.2%,About 0.25%,About 0.3%,About 0.35%,About 0.4%,About 0.45%,About 0.5%,About 0.55%, About 0.6%, about 0.65%, about 0.7%, about 0.75%, or about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, About 1.05%, about 1.1%, about 1.15%, about 1.2%, about 1.2%, about 1.25%, about 1.3%, about 1.35%, about 1.4%, about 1. Provided herein are oral dosage formulations containing 45%, or about 1.5% lubricant.

[0124] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 50% by weight to about 80% by weight of compound 7, about 10% by weight to about 40% by weight of insoluble diluent a disintegrant or carrier, about 1.5% to about 4.5% by weight of a disintegrant, and about 1% to about 5% by weight of a diluent or filler. The extragranular component contains about 1.5% by weight to about 4.5% by weight of a disintegrant, about 0.1% by weight to about 0.4% by weight of a filler. a glidant, and about 0.15% to about 1.35% by weight of a lubricant; and The tablet coating comprises from about 1.0% to about 8% by weight of the tablet coating; and the weight is within the whole grain. Formulations are provided herein that are total weight of ingredients and extragranular ingredients.

[0125] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 55% by weight to about 75% by weight of compound 7, about 15% by weight to about 35% by weight of insoluble diluent % by weight of a disintegrant or carrier, about 2.0% to about 4.0% by weight of a disintegrant, and about 1.8% to about 3.8% by weight of a diluent or the extragranular component comprises about 2.0% by weight to about 4.0% by weight of a disintegrant, about 0.15% by weight to about 0.35% by weight of a filler; % by weight of a glidant, and about 0.35% to about 1.15% by weight of a lubricant; and The coating component comprises from about 1.0% by weight to about 8% by weight of the tablet coating; and Formulations are provided herein that are the total weight of intragranular and extragranular components.

[0126] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 60% by weight to about 70% by weight of compound 7, about 20% by weight to about 30% by weight of insoluble diluent % by weight of a disintegrant or carrier, about 2.5% to about 3.5% by weight of a disintegrant, and about 2.3% to about 3.3% by weight of a diluent or The extragranular component comprises about 2.5% by weight to about 3.5% by weight of a disintegrant, about 0.2% by weight to about 0.3% by weight of a granular component, and about 2.5% by weight to about 3.5% by weight of a disintegrant. % by weight of a glidant, and about 0.55% to about 0.95% by weight of a lubricant; and the tablet coating component comprises from about 1.0% to about 8% by weight of the tablet coating; and Formulations that are the total weight of the granular and extragranular ingredients are provided herein.

[0127] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 65% by weight of Compound 7, about 25% by weight of an insoluble diluent or carrier, about 3% by weight of disintegrant, and about 2.8% by weight of a diluent or filler; the extragranular component comprises about 3% by weight of a disintegrant, about 0.25% by weight of a glidant, about 0.75% by weight of a lubricant; and said film coating. the tablet coating comprises from about 2.0% to about 6.0% by weight of the total intragranular ingredients; and and the total weight of the extragranular components are provided herein.

[0128] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular components are Compound 7, microcrystalline cellulose, sodium starch glycolate, and and hydroxypropyl methylcellulose, and the extragranular component comprises sodium starch glycolate. thorium, colloidal silicon dioxide, and magnesium stearate; and Provided herein are formulations in which the film coating component comprises Opadry®.

[0129] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 50% by weight to about 80% by weight of compound 7, about 10% by weight to about 40% by weight of microcrystalline sintered body. cellulose, about 1.5% to about 4.5% by weight of sodium starch glycolate, and about 1% to about 4.5% by weight of sodium starch glycolate. About 5% by weight of hydroxypropyl methylcellulose; and the extragranular component is about 1.5% by weight to about 4 0.5% by weight sodium starch glycolate, about 0.1% to about 0.4% by weight colloidal diacid silicon dioxide, and about 0.15% to about 1.35% by weight of magnesium stearate; the coating composition comprises about 1.0% to about 8% by weight of Opadry®; and wherein is the total weight of the total intragranular and extragranular components.

[0130] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 55% by weight to about 75% by weight of compound 7, about 15% by weight to about 35% by weight of microcrystalline sintered body. cellulose, about 2.0% to about 4.0% by weight sodium starch glycolate, and about 1.8% by weight about 3.8% by weight hydroxypropyl methylcellulose; and the extragranular component is about 2.0% by weight ~ about 4.0% by weight sodium starch glycolate, about 0.15% by weight to about 0.35% by weight colloid silicon dioxide, and about 0.35% to about 1.15% by weight of magnesium stearate; the film coating component comprises about 1.0% to about 8% by weight Opadry®; and Formulations are provided herein in which the weight is the total weight of the intragranular and extragranular components.

[0131] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 60% by weight to about 70% by weight of compound 7, about 20% by weight to about 30% by weight of microcrystalline sintered body. cellulose, about 2.5% to about 3.5% by weight sodium starch glycolate, and about 2.3% by weight about 3.3% by weight hydroxypropyl methylcellulose; and the extragranular component is about 2.5% by weight ~About 3.5% by weight of sodium starch glycolate, about 0.2% by weight to about 0.3% by weight of colloidal silicon dioxide, and about 0.55% to about 0.95% by weight magnesium stearate; the film coating composition comprises about 1.0% to about 8% by weight Opadry®; and Formulations are provided herein in which the weight is the total weight of the intragranular and extragranular components.

[0132] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 60% by weight of Compound 7, about 30% by weight of microcrystalline cellulose, about 3% by weight of decanol, and about 10% by weight of cellulose acetate. sodium starch glycolate, and about 2.8% by weight hydroxypropyl methylcellulose the extragranular component being about 3% by weight sodium starch glycolate, about 0.25% by weight colophony % by weight of magnesium stearate; the coating composition comprises about 2.0% to about 6.0% by weight of Opadry®; and Formulations are provided herein that are the total weight of the intragranular and extragranular components.

[0133] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 65% by weight of Compound 7, about 25% by weight of microcrystalline cellulose, about 3% by weight of decanol, and about 10% by weight of cellulose acetate. sodium starch glycolate, and about 2.8% by weight hydroxypropyl methylcellulose the extragranular component being about 3% by weight sodium starch glycolate, about 0.25% by weight colophony % by weight of magnesium stearate; the coating composition comprises about 2.0% to about 6.0% by weight of Opadry®; and Formulations are provided herein that are the total weight of the intragranular and extragranular components.

[0134] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 70% by weight of Compound 7, about 20% by weight of microcrystalline cellulose, about 3% by weight of decanol, and about 10% by weight of cellulose acetate. sodium starch glycolate, and about 2.8% by weight hydroxypropyl methylcellulose the extragranular component being about 3% by weight sodium starch glycolate, about 0.25% by weight colophony % by weight of magnesium stearate; the coating composition comprises about 2.0% to about 6.0% by weight of Opadry®; and Formulations are provided herein that are the total weight of intragranular and extragranular components.

[0135] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 75% by weight of Compound 7, about 15% by weight of microcrystalline cellulose, about 3% by weight of decanol, and about 10% by weight of cellulose acetate. sodium starch glycolate, and about 2.8% by weight hydroxypropyl methylcellulose the extragranular component being about 3% by weight sodium starch glycolate, about 0.25% by weight colophony % by weight of magnesium stearate; the coating composition comprises about 2.0% to about 6.0% by weight of Opadry®; and Formulations are provided herein that are the total weight of the intragranular and extragranular components.

[0136] In certain embodiments, the composition includes an intragranular component, an extragranular component, and a film coating component. The intragranular component is about 80% by weight of Compound 7, about 10% by weight of microcrystalline cellulose, about 3% by weight of decanol, and about 10% by weight of cellulose acetate. sodium starch glycolate, and about 2.8% by weight hydroxypropyl methylcellulose the extragranular component being about 3% by weight sodium starch glycolate, about 0.25% by weight colophony % by weight of magnesium stearate; the coating composition comprises about 2.0% to about 6.0% by weight of Opadry®; and Formulations are provided herein that are the total weight of the intragranular and extragranular components.

[0137] In certain other embodiments, about 25 mg to about 2000 mg, about 50 mg to about 1500 mg, about 100 mg to about 1,2 00 mg, about 200 mg to about 1,000 mg, about 400 mg to about 800 mg, or about 450 mg to about 600 mg of formula (I) or formula (II). Compounds having the structure of formula (III), formula (IV), or formula (V), or Compound 1, Compound 2, Compound Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, A compound selected from compound 12, compound 13, metabolite 1, or metabolite 2, or a pharmaceutical agent thereof. and acceptable salts, solvates, or hydrates thereof (specifically, {[5-(3-fluorophenyl)- Provided herein are unit dosage forms comprising 3-hydroxypyridine-2-carbonyl]amino}acetic acid. can be.

[0138] In certain other embodiments, about 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg , 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 7 50mg, 800mg, 850mg, 900mg, 950mg, 1,000mg, 1,050mg, 1,100mg, 1,150 or even Approximately 1,200 mg of a compound having the structure of formula (I), formula (II), formula (III), formula (IV), or formula (V), or is Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, 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-fluorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid) In certain embodiments, the unit dosage form is about 25 mg, about 40 mg, or about 50 mg. , about 120 mg, about 150 mg, about 185 mg, about 200 mg, about 250 mg, about 300 mg, or even about 315 mg of 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 A pharma- ceutical acceptable salt, solvate, or hydrate thereof (specifically, {[5-(3-fluoro phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid). In embodiments, the unit dosage form is about 25 mg, about 40 mg, about 120 mg, about 185 mg, about 200 mg, about 200, A capsule containing about 250 mg, or even about 300 mg, of the compound. In an embodiment, the unit dosage form is a tablet containing about 150 mg of the compound. In an embodiment, the unit dosage form is a tablet containing about 315 mg of the compound. In an embodiment, the unit dosage form is a tablet containing about 25 mg of the compound. In embodiments, the unit dosage form is about 25 mg, about 40 mg, about 120 mg, about 185 mg, about 200 mg, about 200, A pharma- ceutically acceptable emulsion, microemulsion, or emulsion formulation, comprising about 250 mg, or even about 300 mg, of the compound. The free acid may be in the form of an emulsion, solution, suspension, syrup, or elixir. In certain such embodiments, the unit dosage form contains about 150 mg of the compound. Acceptable emulsions, microemulsions, solutions, suspensions, syrups, or elixirs In certain such embodiments, the unit dosage form contains about 315 mg of the free acid. Pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, etc., containing the compound. In certain such embodiments, the compound is the free acid in the form of a drop, capsule, or elixir. The unit dosage form is a pharma- ceutically acceptable emulsion, microemulsion, or the like, containing about 25 mg of the compound. The compound is preferably a free acid in the form of a concentrate, solution, suspension, syrup, or elixir.

[0139] 5.3.3 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.

[0140] In certain embodiments, pharmaceutical compositions and dosage forms contain one or more excipients. Such excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. The suitability of a particular excipient for inclusion in a pharmaceutical composition or dosage form is provided in the The dosage form may be administered in any manner 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. The suitability of a particular excipient depends on the specific activity of the formulation. For example, the degradation of some active ingredients can be influenced by some This may be accelerated by the presence of excipients such as primary or secondary amines or on exposure to water. Active ingredients containing Nevertheless, pharmaceutical compositions and dosage forms are provided that contain only small amounts of lactose other mono- or disaccharides. As used herein, the term "lactose-free" refers to any lactose-free food that is present, if any. This means that the amount of lactose is insufficient to substantially increase the decomposition rate of the active ingredient. .

[0141] Lactose-free compositions are well known in the art and are described, for example, in the United States Pharmacopeia (USP) 25 May contain excipients listed in 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. It contains hydrolyzed cellulose, pregelatinized starch, and magnesium stearate.

[0142] 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. 3 79-80. 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.

[0143] 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.

[0144] Also, pharmaceutical 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 are useful in treating and / or preventing the development of inflammatory bowel disorders. These include, but are not limited to, antioxidants such as scorbic acid, pH buffers, or salt buffers. It is not.

[0145] 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. may vary depending on factors such as the route by which it is administered to a patient.

[0146] 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 by methods of pharmacy well known to those skilled in the art. Generally, the Remington's The Science and Practice of Pharmacy Science and Practice of Pharmacy), 21st edition, Lippincott Williams & Wilkins (2005 ) for more information.

[0147] 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 excipient. These may take a wide variety of forms, depending on the form of preparation desired for administration. For example, oral liquids or aerosols. Excipients suitable for use in pharmaceutical dosage forms include water, glycols, oils, alcohols, flavoring agents, preservatives, and the like. Solid oral dosage forms (e.g., powders, tablets ... Examples of suitable excipients for use in the pharmaceutical formulations (tablets, capsules, and caplets) include starch. These include, but are not limited to, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants. , but is not limited to these.

[0148] In one embodiment, the oral dosage form is a tablet or capsule, in which case solid excipients are used. 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 in which the active ingredient is uniformly and intimately mixed with liquid carriers, finely divided solid carriers, or both. The product is then prepared by mixing directly into the desired shape and appearance if necessary.

[0149] 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.

[0150] Examples of excipients that can be used in the oral dosage forms provided herein include insoluble diluents, binders, These include, but are not limited to, agents, fillers, disintegrants, glidants, carriers, and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include corn starch, Potato starch or other starches, gelatin, gum acacia, sodium alginate Natural and artificial ingredients such as thorium, alginic acid, other alginates, powdered tragacanth, and guar gum Synthetic rubber, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, Calcium carboxymethylcellulose, sodium carboxymethylcellulose), poly Vinylpyrrolidone, methylcellulose, alpha-starch, hydroxypropylmethylcellulose cellulose (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. However, the present invention is not limited to these.

[0151] Insoluble diluents and carriers suitable for use in the pharmaceutical compositions and dosage forms provided herein Examples include, but are not limited to, dibasic calcium phosphate and microcrystalline cellulose. Preferred forms of microcrystalline cellulose are AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581 , AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales (Markus Hook, P A) available from FDA (Food and Drug Administration), and mixtures thereof. An exemplary binder is a microcrystalline cellulosic acid binder sold as AVICEL RC-581. A mixture of sodium carboxymethylcellulose and sodium carboxymethylcellulose is preferred. Excipients or additives include AVICEL-PH-103™ and Starch 1500 LM. Other microcrystalline cells A suitable form of cellulose is microcrystalline cellulose containing silica, e.g. PROSOLV 50, PROSOLV 90, This includes substances marketed as PROSOLV HD90, PROSOLV 90 LM, and mixtures thereof. However, the present invention is not limited to these.

[0152] Examples of suitable diluents / fillers for use in the pharmaceutical compositions and dosage forms provided herein include Talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose Rosin, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, Pregelatinized starch, hydroxypropyl methylcellulose (e.g., Methocel E5 Premium) um LV), and mixtures thereof.

[0153] In certain embodiments, the filler is a block copolymer of ethylene oxide and propylene oxide. Such block copolymers may include, but are not limited to, block copolymers. The compound is sold as Poloxamer or Pluronic and is available as Poloxamer 188 NF, ... Poloxamer 237 NF, Poloxamer 338 NF, Poloxamer 437 NF, and mixtures thereof. However, the present invention is not limited to these.

[0154] 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.

[0155] 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 based upon the type of formulation, and is readily discernible to one of ordinary skill in the art.

[0156] Disintegrants that can be used in pharmaceutical compositions and dosage forms include agar, alginic acid, calcium carbonate, microcrystalline cellulose, and the like. Crystalline cellulose, croscarmellose sodium, povidone, crospovidone, polak Lilin potassium, sodium starch glycolate (e.g., Explotab®), tortarch or tapioca starch, other starches, pregelatinized starch, other starches, These include, but are not limited to, clays, other algins, other celluloses, gums, and mixtures thereof. Not determined.

[0157] Glidants that can be used in pharmaceutical compositions and dosage forms include fumed silica, magnesium carbonate, , magnesium stearate, colloidal silicon dioxide (e.g., Aerosil, Cab-O-Sil) , starch and talc.

[0158] Lubricants that can be used in pharmaceutical compositions and dosage forms include calcium stearate, stearic acid Magnesium (e.g., Hyqual® 5712), mineral oil, light mineral oil , glycerin, sorbitol, mannitol, polyethylene glycol, other glycols , stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, talc, Hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil) locomotive oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate ( ethyl laureate), agar, and mixtures thereof. Additional lubricants include, for example, Silica Gel (AEROSIL 200, WR Grace, Inc. (Boltzmann) (manufactured by Degussa, Plano, TX) a synthetic silica coagulated aerosol (commercially available from Degussa, Plano, TX) and CAB - O-SIL, a pyrogenic colloidal silicon dioxide product sold by Cabot Corporation, Boston, Mass.; and mixtures thereof.

[0159] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, microemulsions, liquid Liquid dosage forms include preparations, suspensions, syrups, and elixirs. Inert diluents, solubilizing agents, such as water or other solvents, commonly used in the art. and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol Recalls: Oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, Castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene Glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0160] Oral compositions can include, in addition to inert diluents, wetting agents, emulsifying and suspending agents, sweetening, flavoring agents, Adjuvants such as colorants, flavors and preservatives may also be included.

[0161] Suspending agents, in addition to the active inhibitor, may include, for example, ethoxylated isostearyl alcohol. , polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, meta Aluminum hydroxide, bentonite, agar and tragacanth, and mixtures thereof, etc. The suspension may include a suspending agent.

[0162] 5.4 Patient Population In certain embodiments, the method comprises treating and / or preventing anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering a sufficient number of consecutive doses of a HIF prolyl hydroxylase inhibitor or a HIF -alpha stabilizers to patients with anemia secondary to non-dialysis-dependent chronic kidney disease (i) 60 mL / min / 1.73 m 2 An estimated glomerular filtration rate (eGFR) of less than (not undergoing dialysis and not expected to start dialysis within 3 months of initiating treatment), ii) hemoglobin level less than 10.0 g / dL before initiating treatment, (iii) hemoglobin level less than 100 ng / dL within 4 weeks of initiating treatment (iv) ferritin level of ≥20% transferrin saturation within 4 weeks of starting treatment (v) folate measurements above the lower limit of normal within 4 weeks of starting treatment; (vi) (vii) a vitamin B12 level at or above the lower limit of normal within 4 weeks of starting treatment; and Provided herein are methods for treating a subject having at least two, three, four, five, or all of the following ages: .

[0163] In certain embodiments, the method comprises treating and / or preventing anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering a sufficient number of consecutive doses of a HIF prolyl hydroxylase inhibitor or a HIF -alpha stabilizers to patients with anemia secondary to non-dialysis-dependent chronic kidney disease The patient was: (i) 65 mL / min / 1.73 m 2 An estimated glomerular filtration rate (eGFR) of less than (not undergoing dialysis and not expected to start dialysis within 3 months of initiating treatment), ii) hemoglobin level less than 10.0 g / dL before initiating treatment; (iii) hemoglobin level less than 50 ng / ferritin levels of ≥ 15% within 4 weeks of initiating treatment; (v) folate measurement above the lower limit of normal within 4 weeks of starting treatment; (vi) treatment (vii) a vitamin B12 measurement at or above the lower limit of normal within 4 weeks of initiation of Provided herein are methods having at least two, three, four, five, or all of the following: age.

[0164] In certain embodiments, the method comprises treating and / or preventing anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering a sufficient number of consecutive doses of a HIF prolyl hydroxylase inhibitor or a HIF -alpha stabilizers to patients with anemia secondary to non-dialysis-dependent chronic kidney disease Provided herein are methods for treating a patient who is not, and does not have, any of the following: (i) Pregnant or breastfeeding women, or those who are unable or unwilling to use acceptable contraception, (ii) women who are unable or unwilling to use an acceptable method of contraception; (iii) anemia due to causes other than CKD; e.g., sickle disease Erythrocytosis, myelodysplastic syndrome, myelofibrosis, hematological malignancies, myeloma, hemolytic anemia, sara (iv) 4–8 days before the start of any treatment (v) intravenous iron administration within 4 to 8 weeks prior to initiation of treatment; (vi) initiation of any treatment Use of any erythropoietin stimulating agent (e.g., rHuEPO; protease inhibitor) within the previous 8 to 12 weeks Locrit (registered trademark), Eplex (registered trademark), Neorecormon (registered trademark), Epoje (vii) Current status of acute infections (viii) any major surgery within 8 to 12 weeks prior to the start of any treatment; (ix) liver dysfunction within 4 weeks prior to the initiation of any treatment Evidence (AST or ALT > 3.0 x ULN or total bilirubin > 2.0 x ULN), (x) initiation of any treatment Insufficient control of hypertension (diastolic blood pressure > 110mmHg or systolic blood pressure > 180mmHg) within 4 weeks prior to the start of treatment. xi) New York Heart Association Class IV congestive heart failure, (xii) 8 to 12 weeks prior to initiation of any treatment (xiii) Myocardial infarction, acute coronary syndrome, hospitalization for congestive heart failure, or stroke within the last 24 hours; History of active malignancy within 2 years prior to screening, except for curatively resected skin tumors basal cell carcinoma of the skin, squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, or benign resected colon polyps (xiv) recent severe acute myocardial infarction requiring active treatment within 12 weeks prior to Screening (xv) history of deep vein thrombosis (DVT) or pulmonary embolism, (xvi) hemosiderosis or hemoglobinuria (xvi) History of previous or planned organ transplantation (kidney transplant) transplant waiting list are not excluded), or stem cell or bone marrow transplant (corneal transplants are not excluded) (xvii) prior to the 4 weeks prior to the initiation of any treatment; Use of an investigational drug or participation in a clinical trial within 0 days or 5 half-lives of the investigational drug (whichever is longer) (xviii) receiving the compound in a separate test or in a separate test for a hypoxia-inducible factor prolyl-hydroxylase; (xix) previous participation in a trial with a hyperactivating phosphoinositide (HIF-PHI) enzyme inhibitor; or 4. Any other reason that makes the patient less suitable for treatment.

[0165] In certain embodiments, the method comprises treating and / or preventing anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering a sufficient number of consecutive doses of a HIF prolyl hydroxylase inhibitor or a HIF -alpha stabilizers to patients with anemia secondary to non-dialysis-dependent chronic kidney disease Provided herein are methods for treating a patient who is not, and does not have, any of the following: (i) Women who are pregnant or breastfeeding or who are unable or unwilling to use acceptable contraception; (ii) women of childbearing age who are unable or unwilling to use acceptable contraceptive methods; or unwilling non-vasectomized men; (iii) BMI > 50.0 kg / m 2 , (iv) hemolysis (hemolysis anemia due to causes other than chronic kidney disease, such as chronic anemia, active bleeding, or recent blood loss; (v) (vi) History of myelodysplastic syndrome or myelofibrosis, (vii) Red blood cell transfusion within 8 weeks prior to the start of treatment (vii) intravenous iron therapy within 4 weeks prior to initiation of treatment; (viii) any red blood cell count within 10 weeks prior to initiation of treatment. Human erythropoietin stimulators (rHuEPO; Procrit®, Eprex, Neorecormon, Epoje (ix) administering treatment to the subject if the subject is suitable for treatment; (x) evidence of active infection, unless otherwise deemed necessary by a physician; (x) known chronic liver disease within 4 weeks prior to initiation of treatment; History of disease or evidence of liver dysfunction (AST or ALT > 3.0 × ULN, or total bilirubin > 2 (xi) insufficient control of hypertension (diastolic blood pressure >110 mmHg or systolic blood pressure >180 mmHg), (xii) New York Heart Association Class IV congestive heart failure within 4 weeks prior to the start of treatment (xiii) myocardial infarction, acute coronary syndrome, or stroke within 12 weeks prior to the start of treatment, (x iv) Any history of active malignancy or treatment for malignancy within 2 years prior to initiation of treatment; However, in cases of curatively excised basal cell carcinoma of the skin, squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, or (xv) Patients who required active treatment within 12 weeks prior to initiating treatment, excluding benign colonic polyps that had been resected (xvi) recent history of deep vein thrombosis (DVT) or pulmonary embolism; (xvii) medical history, including previous or planned organ transplantation (kidney transplant waiting list) (xviii) stem cell or bone marrow transplants (corneal transplants are not excluded); Use of an investigational drug within 45 days or 5 half-lives of the investigational drug (whichever is longer) prior to treatment (xix) previous participation in this study or in another clinical trial of 5-(3-chlorophenyl) Previous receipt of 4-phenyl-3-hydroxypyridine-2-carbonylamino}acetic acid had previously received another hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), and (xx) may increase the risks associated with treatment and may, in the physician's opinion, render the patient unsuitable for treatment. Other severe acute or chronic medical or psychiatric conditions or laboratory findings that Abnormal.

[0166] In certain embodiments, a method for treating anemia, such as anemia secondary to chronic kidney disease (CKD) A patient having anemia is administered an effective amount of a compound of formula (I), formula (II), formula (III), formula (IV), or formula (IV). A compound having the structure of (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 pharma- ceutically acceptable salt or solvate thereof; or hydrate (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) The formulations and dosages and / or or a dosing regimen, wherein the patient is at least 18 years of age and at least Both are 50 years old, at least 60 years old, at least 65 years old, at least 70 years old or even at least 80 years of age. In certain embodiments, the patient is an elderly patient. In certain embodiments, the patient is under 18 years of age. In certain embodiments, the patient is a pediatric patient. In certain such embodiments, the daily dose is about 150 mg, about 3 00 mg, about 450 mg, about 600 mg, or about 750 mg of a compound of formula (I), formula (II), formula (III), formula (IV), or formula (IV) V) or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6 , Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, Young or a pharma- ceutical acceptable salt, solvate, or derivative thereof. or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) In certain 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 once a day, twice a day, or three times a day, preferably once a day. , may be administered orally.

[0167] In certain embodiments, a method for treating anemia, such as anemia secondary to chronic kidney disease (CKD) A patient having anemia is administered an effective amount of a compound of formula (I), formula (II), formula (III), formula (IV), or formula (IV). A compound having the structure of (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 pharma- ceutically acceptable salt or solvate thereof; or hydrate (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) The formulations and dosages and / or or a dosing regimen, wherein the patient is white, Hispanic, black, Provided herein are methods for identifying individuals who are members of a subpopulation selected from the group consisting of: In an embodiment, the patient is a member of a subpopulation selected from males and females. In such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 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-fluoro In certain such embodiments, In such cases, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. may be administered orally once daily, twice daily, or three times daily, preferably once daily.

[0168] In certain embodiments, a method for treating anemia, such as anemia secondary to chronic kidney disease (CKD) A patient having anemia is administered an effective amount of a compound of formula (I), formula (II), formula (III), formula (IV), or formula (IV). A compound having the structure of (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 pharma- ceutically acceptable salt or solvate thereof; or hydrate (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) The formulations and dosages and / or or a dosing regimen, wherein the patient is suffering from cancer, AIDS, congestive heart failure, left ventricular dysfunction, Ventricular hypertrophy, diabetes, hypertension, dyslipidemia, chronic heart failure, stroke, fatigue, depression, and cognition or any combination thereof. In certain such embodiments, the daily dose is about 150 mg, about 3 00 mg, about 450 mg, about 600 mg, or about 750 mg of a compound of formula (I), formula (II), formula (III), formula (IV), or formula (IV) V) or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6 , Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, Young or a pharma- ceutical acceptable salt, solvate, or derivative thereof. or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) In certain 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 once a day, twice a day, or three times a day, preferably once a day. , may be administered orally.

[0169] In certain embodiments, a method of treating anemia, such as anemia secondary to CKD, comprising administering to the patient and administering to a patient having a blood clot an effective amount of a compound represented by formula (I), (II), (III), (IV), or (V). Compounds having the formula: , 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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. and administering to the patient an erythropoietin mimetic, such as an erythropoietin mimetic, in accordance with the method of the present invention. Provided herein are methods for treating refractory disease to treatment with an esophageal stimulating agent ("ESA"). In embodiments, the ESA is epoetin alfa, epoetin beta, darbepoetin, or pegine. In certain such embodiments, rhEPO products include, but are not limited to, sacide. In this case, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of the compound of formula (I), formula (II), A compound having a structure of formula (III), formula (IV), or formula (V), or compound 1, compound 2, compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Chemical A compound selected from compound 12, compound 13, metabolite 1, or metabolite 2, or a pharmaceutical thereof. and its acceptable salts, solvates, or hydrates, particularly {[5-(3-chlorophenyl)-3-phenyl hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypyridine In certain such embodiments, the daily dose is about 15 mg / kg. Such daily doses may be administered once a day, twice a day, or in a single dose of about 0 mg, about 300 mg, about 450 mg, or about 600 mg. may be administered orally three times a day, preferably once a day.

[0170] In certain embodiments, a method of treating anemia, such as anemia secondary to CKD, comprising administering to the patient and administering to a patient having a blood clot an effective amount of a compound represented by formula (I), (II), (III), (IV), or (V). Compounds having the formula: , 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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. and administering the same in accordance with any one of the methods described above, wherein the patient is less than 85, less than 80, less than 75, less than 70, less than 65, Over, under 60, under 55, or 50mL / min / 1.73m 2 The method described herein has a glomerular filtration rate of less than 100%. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 500 mg. g, about 600 mg, or about 750 mg of 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 A compound selected from compound 2, or a pharma- ceutically 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). In 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 orally once a day, twice a day, or three times a day, preferably once a day. It is possible.

[0171] In certain embodiments, a method of treating anemia, such as anemia secondary to CKD, comprising administering to the patient and administering to a patient having a blood clot an effective amount of a compound represented by formula (I), (II), (III), (IV), or (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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. and administering the drug according to the formula: Provided herein are methods for achieving hemoglobin levels of at least 5%. In embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of formula (I). , a compound having a structure of formula (II), formula (III), formula (IV), or formula (V), or compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound A compound selected from Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2, or A pharma- ceutical acceptable salt, solvate, or hydrate of {[5-(3-chlorophenyl)- 2-(5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl)amino}acetic acid or In certain such embodiments, the compound is selected from the group consisting of 1-3-hydroxypicolinamido)acetic acid. The amount is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such a daily dose is administered once a day. It may be administered orally twice a day, or three times a day, preferably once a day.

[0172] In certain embodiments, a method of treating anemia, such as anemia secondary to CKD, comprising administering to the patient and administering to a patient having a blood clot an effective amount of a compound represented by formula (I), (II), (III), (IV), or (V). Compounds having the formula: , 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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. wherein the patient has a folate level at or above the lower limit of normal. Methods are provided herein. In certain such embodiments, the daily dose is about 150 mg. , about 300 mg, about 450 mg, about 600 mg, or about 750 mg of a compound of formula (I), formula (II), formula (III), formula (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 1, or metabolite 2, or a pharma- ceutical acceptable salt or solvate thereof. , or a hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbamate 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) In certain 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 once a day, twice a day, or three times a day, preferably once a day. It may be administered orally once.

[0173] In certain embodiments, a method of treating anemia, such as anemia secondary to CKD, comprising administering to the patient and administering to a patient having a blood clot an effective amount of a compound represented by formula (I), (II), (III), (IV), or (V). Compounds having the formula: , 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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. and administering the same in accordance with the regimen when the patient has a vitamin B12 level at or above the lower limit of normal. Provided herein are methods of administering the composition of claim 1, wherein the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg 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 pharma- ceutically 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 In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about Such daily doses are preferably administered once a day, twice a day, or three times a day. It may be administered orally, preferably once daily.

[0174] In certain embodiments, a method of treating anemia, such as anemia secondary to CKD, comprising administering to the patient and administering to a patient having a blood clot an effective amount of a compound represented by formula (I), (II), (III), (IV), or (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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. and administering the compound according to formula (I) in accordance with claim 1, wherein the patient has at least 15%, at least 18%, or more Also provided herein are methods having a transferrin saturation (TSAT) of at least 20%. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 6 00 mg, or about 750 mg of a compound having 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 8 , Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 The compound selected, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof (specifically Specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid). In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally once daily, twice daily, or three times daily, preferably once daily.

[0175] In certain embodiments, a method of treating anemia, such as anemia secondary to CKD, comprising administering to the patient and administering to a patient having a blood clot an effective amount of a compound represented by formula (I), (II), (III), (IV), or (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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. and administering to the patient a dose of at least 50 ng / mL or even less in accordance with the method of claim 1. Provided herein are methods for obtaining ferritin levels of at least 100 ng / mL. In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. 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, or Metabolite 2; or or a pharma- ceutical acceptable salt, solvate, or hydrate thereof (specifically, {[5-(3-chloro phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl) In certain such embodiments, The daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses are about 100 mg, about 200 mg, about 300 mg, about 450 mg, or about 600 mg. The dosage may be administered orally once a day, twice a day, or three times a day, preferably once a day.

[0176] In certain embodiments, a method of treating anemia, such as anemia secondary to CKD, comprising administering to the patient and administering to a patient having a blood clot an effective amount of a compound represented by formula (I), (II), (III), (IV), or (V). Compounds having the formula: , 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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. wherein the patient has at least 18% transferrin saturation. A ferritin level of at least 50ng / mL with serum glucose or a transferrin level of at least 15% Provided herein are methods for obtaining a ferritin level of at least 100 ng / mL along with ferritin saturation. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 6 00 mg, or about 750 mg of a compound having 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 8 , Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or Metabolite 2 The compound selected, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof (specifically Specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid). In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally once daily, twice daily, or three times daily, preferably once daily.

[0177] In certain embodiments, a method of treating anemia, such as anemia secondary to CKD, comprising administering to the patient and administering to a patient having a blood clot an effective amount of a compound represented by formula (I), (II), (III), (IV), or (V). Compounds having the formula: , 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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. and administering the same to the patient according to the formula (I) above, 2 Less than or equal to 44kg / m 2 Less than or 50 kg / m 2 Provided herein are methods for having a body mass index (BMI) of less than 100 mg / kg. In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. 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, or Metabolite 2; or or a pharma- ceutical acceptable salt, solvate, or hydrate thereof (specifically, {[5-(3-chloro phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl) In certain such embodiments, The daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses are about 100 mg, about 200 mg, about 300 mg, about 450 mg, or about 600 mg. The dosage may be administered orally once daily, twice daily, or three times daily, preferably once daily.

[0178] In certain embodiments, a method of treating anemia, such as anemia secondary to CKD, comprising administering to the patient and administering to a patient having a blood clot an effective amount of a compound represented by formula (I), (II), (III), (IV), or (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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. wherein the patient is administered 11 weeks or more prior to initiation of treatment with the compound according to the present invention. Provided herein are methods for treating a patient who has had a red blood cell transfusion within 12 weeks. and the patient has not had a red blood cell transfusion within 11 or 12 weeks of initiating treatment with the compound. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, , about 600 mg, or about 750 mg of 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 A compound selected from compound 2, or a pharma- ceutically 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). In 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 orally once a day, twice a day, or three times a day, preferably once a day. It is possible.

[0179] In certain embodiments, non-severe anemia secondary to chronic kidney disease, A method for treating non-severe anemia caused by idiopathic anemia of aging, comprising administering to a patient having anemia: The method comprises administering a daily dose of a compound disclosed herein, such as Compound 1, Provided herein are methods of continuous and / or indefinite administration.

[0180] In certain embodiments, the present invention relates to a method for treating and / or preventing iron overload in a patient. and administering to the patient an effective amount of 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}acetic acid or includes administering 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid Methods are provided herein. In certain embodiments, the administering step is described in Section 5. 3 and the formulations and dosages and / or dosing regimens described herein in Sections 5.7. This will be carried out in accordance with the guidelines.

[0181] 5.5 Treatment and Prevention Methods In certain embodiments, anemia secondary to non-dialysis-dependent chronic kidney disease, such as anemia in accordance with Section 5. 4. A method for treating and / or preventing anemia in a subject according to claim 4, comprising administering to a patient having anemia The present invention relates to 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. an effective amount of HIF, such as a compound or a pharma- ceutically acceptable salt, solvate, or hydrate thereof; The method includes administering a prolyl hydroxylase inhibitor or a HIF-α stabilizer, the daily dose of which is about 100 mg. , about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190m g, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280 mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 37 0mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 6 00 mg, or about 750 mg of the compound, a pharma- ceutically acceptable salt, solvate, or hydrate thereof. Provided herein are methods comprising administering to the patient a daily dose of about 15 mg / kg or more of the active ingredient, or to the patient in need thereof. In certain such embodiments, the daily dose is about 15 mg / kg or more of the active ingredient, or to the patient in need thereof. 0 mg, about 300 mg, about 450 mg, or about 600 mg. Specifically, such methods include administering to a patient: Such a daily dose may include administering the formulations described in Section 5.3 once daily. It may be administered orally twice daily or three times daily, preferably once daily. The daily doses are 2mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, and 2. 7mg / kg, 2.8mg / kg, 2.9mg / kg, 3mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5m g / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, or 4 mg / kg.

[0182] In certain embodiments, the HIF-α stabilizer HIF prolyl hydroxylase inhibitor is administered in an amount of about 100 mg, Approximately 110mg, approximately 120mg, approximately 130mg, approximately 140mg, approximately 150mg, approximately 160mg, approximately 170mg, approximately 180mg, approximately 190mg , about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280m g, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 60 1.0 mg, or about 750 mg of the compound, a pharma- ceutically acceptable salt, solvate, or hydrate thereof. 2. A method for treating anemia, such as anemia secondary to chronic kidney disease, comprising administering to a subject in a daily dose a compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V) for 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. Certain such embodiments are provided herein as inhibitors of hydroxylase or HIF-α stabilizers. In embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. A suitable daily dose 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. In certain embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine In certain embodiments, the compound is {[5-(3- Pharmaceutically acceptable salts of chlorophenyl-3-hydroxypyridine-2-carbonylamino}acetic acid In certain embodiments, the compound is a salt obtained by In certain embodiments, the compound is a solvate of 2-hydroxypyridine-2-carbonyl]amino}acetic acid. The compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. In certain embodiments, the compound is a hydrate of the acid. 3-hydroxypicolinamido)acetic acid. In certain embodiments, the compound is 2-(5- A pharma- ceutical acceptable salt of (3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain embodiments, the compound is 2-(5-(3-fluorophenyl)-3-hydroxypyridine. In certain embodiments, the compound is a solvate of 2-(5-(3- Fluorophenyl)-3-hydroxypicolinamido)acetic acid hydrate. In the present invention, the compound is administered in a formulation as described in Section 5.3.

[0183] In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 6 00 mg of the compound, a pharma- ceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the daily dose comprises about 150 mg. In certain embodiments, the daily dose comprises about 450 mg. Thus, the daily dose contains approximately 600 mg.

[0184] In certain embodiments, the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease. In certain such embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. In such embodiments, the chronic kidney disease is non-dialysis dependent chronic kidney disease. In some embodiments, the patient has previously been treated for anemia, such as anemia secondary to chronic kidney disease. In certain alternative embodiments, the patient has previously been diagnosed with anemia, such as anemia secondary to chronic kidney disease. In certain embodiments, the patient is treated for anemia with recombinant erythropoietin. The disease is refractory to treatment with

[0185] In certain embodiments, the daily dose is administered continuously. The daily dose may be administered indefinitely, such as for more than 42 consecutive days, or even for more than 90 consecutive days. In certain alternative embodiments, the daily dose is administered for at least one week and up to 30 consecutive days. The administration may be for up to 35 consecutive days, or even up to 40 consecutive days. In certain embodiments, the daily dose is administered orally once daily. In certain embodiments, the daily dose is administered orally in divided doses. In an even more specific embodiment, the daily dose is administered in the early afternoon. In a specific embodiment, the patient has chronic kidney disease and the compound (see Section 5.2) at the same time, specifically before noon, in the early afternoon, or more specifically just before lunch immediately after lunch, between lunch and 2 p.m., between 10 a.m. and 2 p.m., at 10 a.m., at 11 a.m. In certain embodiments, the dose is administered at 12 p.m., 1 p.m., or 2 p.m. Doses are administered in the formulations described in Section 5.3.

[0186] In certain embodiments, the daily dose is administered twice a week, three times a week, four times a week, five times a week, six times a week, or , daily, once every 2 weeks, once every 3 weeks, once every 4 weeks, or once every 2 months, or once every 3 months In certain such embodiments, the dosages are as set forth in Section 5.3. It is administered in the formulations described.

[0187] In certain embodiments, the patient's hemoglobin level is below 8.0 g / dL and about 13.0 g / dL. at least about 8.5 g / dL and less than or equal to 13.0 g / dL, at least about 9.0 g / dL and less than or equal to 13.0 g / dL , 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 certain such embodiments, the hemoglobin level is maintained at a level below 100 mg / kg / day. In particular, the blood glucose level is maintained at a level of at least about 11.0 g / dL and no greater than about 13.0 g / dL. In embodiments, the hemoglobin level is at least about 11.0 g / dL and no greater than about 12.0 g / dL. In certain embodiments, these values ​​are maintained at a constant level depending on the altitude, the sex and age of the patient. is adjusted.

[0188] In certain embodiments, the compositions provided herein in the formulations described in Section 5.3. Administration of the compound results in an increase in the level of hemoglobin, at least about 0.1 g / dL, at least about 0.2 g / dL, at least about By 0.3 g / dL, by at least about 0.4 g / dL, by at least about 0.5 g / dL, by at least about 0.6 g / dL dL, at least about 0.7 g / dL, at least about 0.8 g / dL, at least about 0.9 g / dL by at least about 1.0 g / dL, by at least about 1.1 g / dL, by at least about 1.2 g / dL, Increased by at least about 1.3 g / dL, at least about 1.4 g / dL, or at least about 1.5 g / dL Add.

[0189] In certain embodiments, the compound is optionally administered in combination with another pharmaceutical agent. In certain such embodiments, the other medicament is ferrous sulfate, ferrous gluconate, or An iron supplement, such as ferrous fumarate, which is administered at least 2 hours after administration of the compound. In certain embodiments, the iron supplement may be administered to a patient having a ferritin level of about 50 ng / mL to about 300 ng / mL. In certain embodiments, the iron supplement is administered in an amount to maintain the iron concentration at levels below ng / mL. The agent is orally administered in a daily dose of about 50 mg of elemental iron. is administered as needed, while in certain alternative embodiments, the iron supplement is administered continuously. In certain embodiments, the compound is administered in a therapeutically effective amount and / or indefinitely. It is administered in the formulation described in .3.

[0190] In certain embodiments, the other medicament is an erythropoiesis stimulator, such as an erythropoietin mimetic. In certain embodiments, the other medicament is epoetin alpha, epoetin beta, In certain embodiments, the EPO product is rhEPO, such as darbepoetin, or peginesatide. SA is administered as salvage therapy, while in certain alternative embodiments, ESA is administered concomitantly. In certain embodiments, the compound is administered continuously and / or indefinitely. The drug will be administered in the formulation described in Section 5.3.

[0191] In certain 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 a pharma- ceutical acceptable salt, solvate, or derivative thereof. The daily dose of the drug or hydrate is adjusted during the course of treatment. Routine tests such as blood pressure, hematocrit, hemoglobin level, and / or red blood cell count Depending on the results of these studies, the daily dose may be adjusted, i.e. increased. In more specific embodiments, the treatment is at about 50 mg, 60 mg, 70 mg, 80 mg, , 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 20 0mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg , 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 4 30 mg, 440 mg, or 500 mg of the compound, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof per day. or about 450 mg of the compound, a pharma- ceutically acceptable salt, solvate, or In certain embodiments, the daily dose is then increased to about 50 mg / kg or 100 mg / kg. In certain embodiments, the daily dose is increased by 100 mg, 100 mg, 150 mg, or 200 mg. is then decreased by about 50 mg, 100 mg, 150 mg, or 200 mg. The compound is Compound 1, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. In certain embodiments, the compound is Compound 7, or a pharma- ceutically acceptable form thereof. In certain embodiments, the compound is a salt, solvate, or hydrate. In certain embodiments, the dosage is administered in a formulation as described in Section 5.3. The amount of the bonus will be adjusted as described in Section 5.7.

[0192] In certain embodiments, anemia secondary to non-dialysis-dependent chronic kidney disease, such as anemia in accordance with Section 5. A method of treating anemia in a subject as described in Section 4 with a formulation as described in Section 5.3. A patient having anemia is administered a daily dose of a compound of formula (I), (II), (III), (IV), or (IV). A compound having the structure of (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 pharma- ceutically acceptable salt or solvate thereof; or a hydrate thereof; administering the compound to a subject after administration of the daily amount of the compound and again after a period of time. and determining a hemoglobin level of the patient, and the hemoglobin level is less than about 10.0 g / dL, and the hemoglobin level is lower than the level measured prior to the period. or if the hemoglobin level of the patient is decreased by less than about 10 g / dL compared to about 0.0 g / dL, and the hemoglobin level is less than the level measured prior to the period or the patient's hemoglobin level changes by about 10.0 to about 20.0 g / dL; 10.9 g / dL, and said hemoglobin level is compared to the level measured prior to said period If the daily dose is decreased by less than about 0.5 g / dL, the adjusted daily dose of the compound is 150 mg greater than the daily dose. Provided herein are methods comprising administering. In certain embodiments, the period of time is: For example, about 2 weeks to about 7 weeks, about 3 weeks to about 6 weeks, or about 4 weeks, for example, about 1 week to about 8 weeks. In a specific embodiment, the compound is Compound 1, or a pharma- ceutically acceptable salt, solubilizer, or the like thereof. In a specific embodiment, the compound is Compound 7, is a pharma- ceutical acceptable salt, solvate, or hydrate thereof.

[0193] In certain embodiments, anemia secondary to non-dialysis-dependent chronic kidney disease, such as anemia in accordance with Section 5. 5. A method for treating anemia in a subject according to claim 4, comprising administering to a patient having anemia a daily dose of 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- ceutically acceptable salt, solvate, or hydrate thereof; The patient's hemoglobin level is measured after administration of the compound and again after a period of time. wherein the patient has a hemoglobin level of less than about 10.0 g / dL, and If the level of ketamine increases by more than about 1.5 g / dL compared to the level measured prior to the period Alternatively, the patient's hemoglobin level is about 10.0 to about 10.9 g / dL, and the hemoglobin If the level of ketamine increases by more than about 1.5 g / dL compared to the level measured prior to the period Alternatively, the hemoglobin level is about 11.0 to about 12.2 g / dL, bell increases by about 1.0 to about 1.4 g / dL compared to the level measured prior to the period; Alternatively, the hemoglobin level is about 12.3 to about 12.9 g / dL, and the hemoglobin level has decreased by up to about 0.4 g / dL compared to the level measured prior to the period, or or the patient's hemoglobin level increases by about 12.3 to about 12.9 g / dL; g / dL, and the hemoglobin level is about 0. 5 to about 0.9 g / dL; adjusted daily dose of the compound 150 mg less than the daily dose Provided herein are methods comprising administering to a subject a compound comprising the steps of: The daily amount of is about 450 mg. In certain embodiments, the compound is {[5-(3-chlorophenyl)- In certain embodiments, The compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} In certain embodiments, the compound is a pharma- ceutically acceptable salt of acetic acid. chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid solvate. In certain embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine- 2-carbonyl]amino}acetic acid hydrate. In certain embodiments, the compound is In certain embodiments, the compound is 3-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. The compound is a pharmaceutical composition of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain embodiments, the compound is 2-(5-(3-fluorophenyl)-2-(phenyl)-1,1-dihydro-1,1-triazol-2-yl)-1,1-di ... In certain embodiments, the compound is a solvate of phenyl-3-hydroxypicolinamido)acetic acid. The compound is a hydrate of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain embodiments, the compound is administered in a formulation as described in Section 5.3. In certain embodiments, the period is from about 2 weeks to about 7 weeks, from about 3 weeks to about 6 weeks, Or from about 1 week to about 8 weeks, such as about 4 weeks.

[0194] In certain embodiments, anemia secondary to non-dialysis-dependent chronic kidney disease, such as anemia in accordance with Section 5. 5. A method for treating anemia in a subject according to claim 4, comprising administering to a patient having anemia a daily dose of 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- ceutically acceptable salt, solvate, or hydrate thereof; The patient's hemoglobin level is measured after administration of the compound and again after a period of time. wherein the patient has a hemoglobin level of about 11.0 to about 12.2 g / dL, and Globin levels increase by more than about 1.5 g / dL compared to levels measured prior to the time period or the patient's hemoglobin level is about 12.3 to about 12.9 g / dL, The omegaly level increases by about 1.0 to about 1.4 g / dL compared to the level measured before the period. or the patient's hemoglobin level is about 12.3 to about 12.9 g / dL; The hemoglobin level is greater than about 1.5 g / dL compared to the level measured prior to the period. or administer an adjusted daily dose of the compound that is 300 mg less than the daily dose. In certain embodiments, the compound is The daily dose is about 450 mg. In certain embodiments, the compound is {[5-(3-chlorophenyl)- 3-hydroxypyridine-2-carbonyl]amino}acetic acid. In certain embodiments, The compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. In certain embodiments, the compound is a pharma- ceutically acceptable salt. phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid solvate. In an embodiment, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxamide In certain embodiments, the daily dose of the compound is about In certain embodiments, the compound is 2-(5-(3-fluorophenyl)-3-phenylenediamine). In certain embodiments, the compound is 2-(5-(3-hydroxypicolinamido)acetic acid. Fluorophenyl)-3-hydroxypicolinamido)acetic acid is a pharma- ceutical acceptable salt. In certain embodiments, the compound is 2-(5-(3-fluorophenyl)-3-hydroxypico In certain embodiments, the compound is a solvate of phosphoamido)acetic acid. In certain embodiments, the compound is administered in the formulation described in .3. In certain embodiments, the compound is a hydrate of (3-(phenyl)-3-hydroxypicolinamido)acetic acid. In this case, the period is about 1 week to about 7 weeks, about 3 weeks to about 6 weeks, or about 4 weeks. It's 8 weeks.

[0195] In certain embodiments, the present invention provides a method for treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. A method of treating anemia in a subject as described in Section 5.4, comprising administering to a patient having anemia A daily dose of about 450 mg of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxamide or a pharma- ceutically acceptable salt, solvate, or In certain embodiments, the compound is a sec- The drug will be administered in the formulation described in Section 5.3.

[0196] In certain such embodiments, the daily dose is such that the daily dose of the compound is about 600 mg. In certain embodiments, the daily dose is increased by about 150 mg, such that the daily amount of the compound is In certain embodiments, the daily dose is reduced by about 150 mg to about 300 mg. The daily dose of the combination is reduced by about 300 mg so that it is about 150 mg. The compounds are administered in the formulations described in Section 5.3.

[0197] In certain embodiments, the compound is {[5-(3-chlorophenyl)-3-hydroxypyridinyl In certain embodiments, the compound is {[5-(3-chloro-2-carbonyl]amino}acetic acid. Pharmaceutically acceptable 3-hydroxypyridine-2-carbonylamino}acetic acid In certain embodiments, the compound is a salt of {[5-(3-chlorophenyl)-3-hydro In certain embodiments, the compound is a solvate of 2-(2-pyridine-2-carbonyl)amino}acetic acid. The compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid In certain embodiments, the compound is a hydrate of the formula described in Section 5.3. It is administered as a drug.

[0198] In certain embodiments, the chronic kidney disease is stage 3, 4, or 5 chronic kidney disease. In certain such embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease. In such embodiments, the chronic kidney disease is non-dialysis dependent chronic kidney disease. In some embodiments, the patient has previously been treated for anemia, such as anemia secondary to chronic kidney disease. In certain alternative embodiments, the patient has previously been diagnosed with anemia, such as anemia secondary to chronic kidney disease. He was treated for anemia.

[0199] In certain embodiments, the present invention provides a method for treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. A method of treating anemia in a subject as described in Section 5.4, comprising administering to a patient having anemia 1 daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid The compound is administered as an acid, or as a pharma- ceutically acceptable salt, solvate, or hydrate thereof. administering said daily dose of said compound to said patient and again after a period of time; and measuring the hemoglobin level of the patient, the hemoglobin level being between about 11.0 and about 12.2 g / mL. dL, and the hemoglobin level is about 1.5 g / mL or lower compared to the level measured prior to the period. or the patient's hemoglobin level increases by more than about 12.3 to about 12.9 g / dL; dL, and the hemoglobin level is about 1.0 or if the hemoglobin level of the patient increases by about 12.3 to about 12. 0.9 g / dL, and said hemoglobin level is about if the daily dose of the compound is increased by more than 1.5 g / dL; or if the daily dose of the compound is adjusted to 300 mg less than the daily dose of the compound. In certain embodiments, the daily amount of the compound is administered to a subject. The amount is about 450 mg. In certain embodiments, the compound is It is administered in a formulation.

[0200] 5.6 Diseases Associated with HIF Prolyl Hydroxylase Regulation The formulations provided herein in Section 5.3 may be any of the formulations described, for example, in Section 5.4. In patients with, among others, peripheral vascular disease (PVD); coronary artery disease (CAD); heart failure; ischemia; anemia; wound healing Wound healing; Ulcers; Ischemic ulcers; Inadequate blood supply; Poor capillary circulation; Atherosclerotic arterial disease Arteriosclerosis; venous congestion; atherosclerotic lesions (e.g., in the coronary arteries); angina pectoris; myocardial infarction; diabetes Hypertension; Buerger's disease; diseases associated with abnormal levels of VEGF, GAPDH, and / or EPO; Rohn's disease;Ulcerative colitis;Psoriasis;Sarcoidosis;Rheumatoid arthritis;Hemangioma;Osler-Wayne disease Barr vasculitis disease; hereditary hemorrhagic telangiectasia; solid or blood-borne tumors and acquired immune deficiencies atrial arrhythmia; cardiac tissue such as myocardium and ventricle, skeletal muscle, nerves derived from the cerebellum, etc. tissues, internal organs such as stomach, intestines, pancreas, liver, spleen, and lungs; and distal attachments such as fingers and toes. The present invention relates to a method for treating and / or preventing and / or controlling ischemic tissue damage in tissues, such as organs. Specifically, it can be used to treat peripheral vascular disease (PVD); coronary artery disease (CAD); heart failure; ischemia; Anemia; Wound healing; Ulcers; Ischemic ulcers; Inadequate blood supply; Poor capillary circulation; Atherosclerosis of small arteries atherosclerosis; venous congestion; atherosclerotic lesions (e.g., in the coronary arteries); angina pectoris; cardiac Myocardial infarction; diabetes; hypertension; Buerger's disease; associated with abnormal levels of VEGF, GAPDH, and / or EPO Crohn's disease;Ulcerative colitis;Psoriasis;Sarcoidosis;Rheumatoid arthritis;Hemangioma;Osteoarthritis Lahr-Weber vasculitis disease; hereditary hemorrhagic telangiectasia; solid or blood-borne tumors and acquired immune deficiency syndrome; atrial arrhythmias; cardiac tissue such as the myocardium and ventricles, skeletal muscle, and the cerebellum. nervous tissue from the stomach, intestines, pancreas, liver, spleen, and lungs; and internal organs such as the fingers and toes. and / or to treat and / or prevent and / or inhibit ischemic tissue damage in tissues such as distal appendages, The method of claim 1, further comprising administering to said patient a medicament for which said medicament is ... The method comprises administering an effective amount of a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer to a patient. Effective amounts as: 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 suitable for reducing the severity or frequency of at least one symptom of these diseases. is provided herein.

[0201] 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 pulmonary embolism (PEM).

[0202] The present disclosure relates to a method for controlling blood flow, oxygen transport, and / or energy utilization in ischemic tissue. The method comprises administering to a human an effective amount of one or more compounds disclosed herein or a pharmaceutical formulation thereof. The present invention also relates to methods that can include administering a compound or an acceptable salt or tautomer thereof.

[0203] The formulations listed herein in Section 5.3 have numerous uses, and Specifically, it addresses several unmet medical needs: 1) To provide a composition effective as an inhibitor of HIF prolyl hydroxylase, thereby inhibiting HIF prolyl hydroxylase in human tissues. Stimulates angiogenic responses in ischemic tissues, thereby improving blood flow, oxygen transport, and energy 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 enhancing cellular response to hypoxia. Maintaining various biological pathways that are normal responses to disease; 3) To provide compositions effective for stimulating an EPO response in cells, thereby increasing the production of erythrocyte progenitors. Enhancement of red blood cell maintenance by controlling proliferation and differentiation of cells into red blood cells; 4) providing compositions effective in stimulating angiogenic responses, thereby increasing the number and density of blood vessels; Increases the risk of developing chronic obstructive pulmonary disease and may result in increased risk of complications from hypertension and diabetes, including, inter alia, claudication, ischemic ulcers, and Relieving hypertension, hypertension, and renal failure; 5) providing a composition that activates vascular endothelial growth factor (VEGF) gene transcription in hypoxic cells; As a result, stimulation of important biological responses, particularly vasodilation, vascular permeability, and endothelial cell increasing migration and proliferation of; 6) Providing compositions that induce the production of soluble VEGF and inhibitors of VEGF in hypoxic cells, resulting in The stimulation of important biological responses, in particular increasing anti-angiogenic activity.

[0204] Therefore, these and other unmet medical needs are addressed by the present disclosure of HIF prolyl hydrochloride. This is due to insufficient regulation of HIF prolyl hydroxylases, which can be resolved by oxidase inhibitors. Regulating 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 may have other effects on human tissue. and the favorable medical effects of those conditions or diseases specifically pointed out in this disclosure. However, it will be appreciated that the angiogenic process may have other effects on the alleviation of symptoms and conditions other than the vascularization process. As more details emerge about the diseases and conditions associated with Unknown or as yet unknown conditions include hypoxia and other low blood oxygen conditions They will be favorably influenced by compositions that stimulate the body's own responses.

[0205] In certain embodiments, a disease or disorder that is ameliorated by modulation of HIF prolyl hydroxylase. A method for treating or preventing a disease that is ameliorated by modulation of HIF prolyl hydroxylase. and administering to a patient having the disease an effective amount of a compound represented by formula (I), (II), (III), (IV), or (V). Compounds having the formula: , 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 water hydrate thereof. Solvates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino }acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) Formulations and dosages and / or administration as described herein in Sections 5.3 and 5.7. Methods are provided herein that include administering the compound according to the regimen. In an embodiment, the compound is administered 1 to 3 times, for example 1, 2 or 3 times, over the course of a 24 hour period. In certain such embodiments, the improved condition is due to modulation of HIF prolyl hydroxylase. The present invention relates to a method for treating or preventing a disease which is improved by regulating HIF prolyl hydroxylase. A patient having a disease or disorder is administered an effective amount of {[5-(3-chlorophenyl)-3-hydroxypyridine Provided herein are methods for administering a compound comprising administering once daily to a subject In certain such embodiments, the daily dose is as provided herein in Section 5.3. About 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of {[5-(3-chlorophenyl)- The compound is 3-hydroxypyridine-2-carbonylamino-2-phenylacetic acid. In one embodiment, the method comprises treating or preventing a disease that is ameliorated by modulation of HIF prolyl hydroxylase. The present invention relates to a method for preventing a disease or disorder that is ameliorated by modulation of HIF prolyl hydroxylase. Patients were administered an effective amount of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid for 1 hour. Methods are provided herein that include administering the compound once daily. In certain such embodiments, In this case, the daily dose is about 150 mg, about 300 mg, or about 500 mg in the formulations provided herein in Section 5.3. g, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicoline In certain such embodiments, the daily dose is about 150 mg, about 300 mg Such daily doses may be administered once a day, twice a day, or three times a day, preferably. It may be administered orally, preferably once a day.

[0206] In certain embodiments, the HIF proliferative disorder is characterized in that the patient is either a patient with a HIF proliferative disorder, e.g., a patient described in Section 5.4. Diseases ameliorated by inhibition of hydroxylase (e.g., PHD1, PHD2, and / or PHD3) A method for treating or preventing a disease or disorder comprising inhibiting HIF prolyl hydroxylase. A patient having a disease or disorder to be improved is administered an effective amount of a compound represented by formula (I), (II), (III), or (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, 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 acetic acid) in the formulations and Methods are provided herein that include administering according to the dosage and / or dosing regimen. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg. or about 750 mg of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 500 mg. g, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamide) acetic acid In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 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 daily. In certain such embodiments, inhibiting PHD1 The present invention relates to a method for treating or preventing a disease or disorder that is improved by inhibiting PHD1. administering to a patient having a disease or disorder that can be improved by administering to said patient an effective amount of 5-(3-chlorophenyl)-3-hydroxybenzoate

[0036] 2-(2-pyridine-2-carbonyl)amino}acetic acid was prepared as described in Sections 5.3 and 5.7. This includes administering the compound according to the formulations and dosages and / or dosing regimens described herein. In certain such embodiments, methods are provided herein that include inhibiting PHD1. A method for treating or preventing a disease or disorder ameliorated by inhibiting PHD1, comprising: administering to a patient having a disease or disorder that can be improved by administering to said patient an effective amount of 2-(5-(3-fluorophenyl)-3- Hydroxypicolinamido)acetic acid is described herein in Sections 5.3 and 5.7. and administering the composition in accordance with the dosage and / or dosing regimen described in In certain such embodiments, inhibition of PHD2 results in A method for treating or preventing a disease or disorder that is ameliorated by inhibiting PHD2, comprising: A patient having a disease or disorder to be ameliorated is administered an effective amount of 5-(3-chlorophenyl)-3-hydroxybenzoic acid. The pyridine-2-carbonyl]amino}acetic acid section is now described in Section 5.3 and Section 5.7. and administering the composition in accordance with the formulations and dosages and / or dosing regimens described herein. Methods are provided herein. In certain such embodiments, inhibiting PHD2 A method for treating or preventing a disease or disorder ameliorated by inhibition of PHD2. administering to a patient having a disease or disorder that can be improved by administering to said patient an effective amount of 2-(5-(3-fluorophenyl)-3-hydroxybenzoate hydroxypicolinamido)acetic acid is described herein in Sections 5.3 and 5.7. Methods comprising administering according to the formulations and dosages and / or dosing regimens described herein. In certain such embodiments, by inhibiting PHD3, A method of treating or preventing a disease or disorder that is ameliorated by inhibiting PHD3. A patient having a disease or disorder to be improved is administered an effective amount of 5-(3-chlorophenyl)-3-hydroxypyridine. Lysine-2-carbonyl]amino}acetic acid is prepared as described herein in Sections 5.3 and 5.7. and administering the composition in accordance with the formulations and dosages and / or dosing regimens described in the literature. Methods are provided herein for inhibiting PHD3. The present invention relates to a method for treating or preventing a disease or disorder that is improved by inhibiting PHD3. administering to a patient having a disease or disorder that can be improved by administering an effective amount of 2-(5-(3-fluorophenyl)-3-hydroxybenzoate The acetamide (roxypicolinamide) acetic acid is as described herein in Sections 5.3 and 5.7. The method includes administering the composition according to the formulations and dosages and / or dosing regimens described herein. Provided in the specification.

[0207] In certain embodiments, HIF-α (e.g., For example, diseases that are ameliorated by stabilizing HIF-1-α, HIF-2-α, and / or HIF-3-α. A method for treating or preventing a disease or disorder, the disease or disorder being ameliorated by stabilizing HIF-α. administering to a patient having a disease or disorder an effective amount of a compound represented by formula (I), (II), (III), (IV), or (V) or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or a pharma- ceutical acceptable salt, solvate, or derivative thereof. or hydrate (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]a 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) The formulations and dosages and / or Methods are provided herein that include administering the drug according to a dosing regimen. In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. In such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 6 00 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain 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 once a day, twice a day, or three times a day, preferably once a day. In certain such embodiments, the stabilization of HIF-1-α may be achieved by administering the compound orally. A method for treating or preventing a disease or disorder that is improved by stabilizing HIF-1-α. administering to a patient having a disease or disorder that can be improved by administering to said patient an effective amount of 5-(3-chlorophenyl)-3-phenyl Hydroxypyridine-2-carbonylamino}acetic acid was prepared as described in Sections 5.3 and 5.7. and administering the same in accordance with the formulations and dosages and / or dosing regimens described herein. In certain such embodiments, HIF-1-α is administered to a subject. A method for treating or preventing a disease or disorder that is ameliorated by stabilizing HIF-1- A patient having a disease or disorder that can be improved by stabilizing α is administered an effective amount of 2-(5-(3-furan) (fluorophenyl)-3-hydroxypicolinamido)acetic acid was prepared as described in Section 5.3 and Section 5. 7. In certain such embodiments, a method is provided herein comprising: α, comprising administering to said subject a subject a subject in need thereof a therapeutically effective amount of HI A patient having a disease or disorder that is ameliorated by inhibiting F-2-α is administered an effective amount of 5-(3-chlorophenyl) (phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid as described in Section 5.3 and The formulations and dosages and / or dosing regimens described herein in Section 5.7 Thus, methods are provided herein that include administering. and a method for treating or preventing a disease or disorder that is ameliorated by stabilizing HIF-2-α. and wherein the compound is effective in treating a patient having a disease or disorder that is ameliorated by inhibiting HIF-2-α. 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid in an amount and the formulations and dosages and / or dosing regimens described herein in Section 5.7. Provided herein are methods comprising administering according to

[0208] In certain such embodiments, e.g., in a patient as described in Section 5.4. and a method for treating or preventing a disease or disorder that is ameliorated by stabilizing HIF-3-α. Thus, an effective amount of the compound is administered to a patient having a disease or disorder that is improved by stabilizing HIF-3-α. 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid Formulations and dosages and / or administration as described herein in Sections 5.3 and 5.7. Methods are provided herein that include administering the compound according to the regimen. In an embodiment, a patient having a disease or disorder that is ameliorated by stabilizing HIF-3-α. An effective amount of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid is added to the The formulations and dosages and / or administration methods described herein in Sections 5.3 and 5.7. and administering to said patient a therapeutically effective amount of the compound according to the present invention in accordance with a therapeutically effective amount of the compound. Provided herein is the treatment or prevention of a disease or disorder.

[0209] In certain embodiments, reduced serotonin levels in patients, e.g., as described in Section 5.4. Methods for treating or preventing diseases or conditions associated with the endogenous production of erythropoietin (EPO) The present invention relates to a method for treating a disease or disorder associated with decreased endogenous production of EPO, the method comprising administering to a patient an effective amount of a compound of the formula (I). 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 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 3-Hydroxypicolinamido)acetic acid) as described herein in Sections 5.3 and 5.7. and administering the composition in accordance with the formulations and dosages and / or dosing regimens described herein. Methods are provided herein. In certain such embodiments, the daily dose is about 150 mg. , about 300 mg, about 450 mg, about 600 mg, or about 750 mg of {[5-(3-chlorophenyl)-3-hydroxypyridine In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3 -hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is Such daily doses are about 150 mg, about 300 mg, about 450 mg, or about 600 mg. It may be administered orally once or three times daily, preferably once daily.

[0210] In certain embodiments, anemia (e.g., anemia secondary to or associated with chronic kidney disease, chronic cardiac Anemia secondary to liver disease, idiopathic anemia of aging, anemia of chronic disease, myelodysplastic syndrome, bone marrow fibrosis Fibrosis, other aplastic or dysplastic anemias, chemotherapy-induced anemia (treating cancer, hepatitis C) chemotherapy to reduce bone marrow production, or other long-term drug therapy to reduce bone marrow production, anemia due to iron deficiency, anemia due to vitamin B12 deficiency, sickle cell disease or thalassemia, comprising administering to a patient having anemia an effective amount of a compound of formula (I). 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 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 3-Hydroxypicolinamido)acetic acid) as described herein in Sections 5.3 and 5.7. and administering the composition in accordance with the formulations and dosages and / or dosing regimens described herein. Methods are provided herein. In certain embodiments, the method comprises administering to a patient suffering from anemia, such as anemia secondary to chronic kidney disease. A method for treating anemia comprising administering to a patient having anemia an effective amount of 5-(3-chlorophenyl)-3

[0023] The method described herein includes administering 1-hydroxypyridine-2-carbonyl]amino}acetic acid to In certain embodiments, the method is for treating anemia, such as anemia secondary to chronic kidney disease. The method comprises administering to a patient having anemia an effective amount of 2-(5-(3-fluorophenyl)-3-hydroxyphenyl)- Methods are provided herein that include administering picolinamido)acetic acid to a subject. A method of treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease, In one embodiment, a patient suffering from anemia is administered an effective amount of 2-(5-(3-fluorophenyl)-3-hydroxypicoline amine. Methods are provided herein that include administering acetic acid to a subject in need thereof. In the present invention, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of {[5-(3-chlorophenyl) The compound is 3-hydroxypyridine-2-carbonylamino-2-phenylacetic acid. In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. -(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses may be administered orally once daily, twice daily, or three times daily, preferably once daily.

[0211] In certain embodiments, a patient with anemia secondary to chronic kidney disease (CKD) is administered an effective amount of 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)- phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl) (Nyl)-3-hydroxypicolinamido)acetic acid) as described in Sections 5.3 and 5.7 Administering the compositions and dosages and / or dosing regimens described herein following CKD, including non-dialysis-dependent CKD, in patients described in Section 5.4. Provided herein are methods for treating or preventing anemia resulting from In the present invention, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of {[5-(3-chlorophenyl) The compound is 3-hydroxypyridine-2-carbonylamino-2-phenylacetic acid. In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. -(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses can be administered orally once a day, twice a day, or three times a day, preferably once a day. In certain embodiments, the daily dose is administered once a day. In certain such embodiments, the patient is diagnosed with chronic kidney disease at stage 1, 2, 3, 4, or 5. KD is chronic kidney disease at stage 3, 4, or 5. In certain embodiments, CKD is stage In certain embodiments, the CKD is stage 1 chronic kidney disease. In certain embodiments, the CKD is stage 3 chronic kidney disease. In certain embodiments, the CKD is stage 4 chronic kidney disease. In certain embodiments, the chronic kidney disease is pre-dialysis chronic kidney disease stage 5. In certain embodiments, the patient is a dialysis patient, and these patients are end stage renal disease. In certain such embodiments, CKD or For anemia secondary to ESRD, epoetin alpha, epoetin beta, darbepoetin, or The disease is refractory to treatment with erythropoiesis-stimulating agents, including rhEPO products such as peginesatide. In certain embodiments, the patient has previously been treated for anemia, while In certain alternative embodiments, the patient has not previously been treated for anemia.

[0212] In certain embodiments, the angiogenesis, e.g., in a patient described in Section 5.4. A method for treating or preventing a disease or disorder associated with angiogenesis, comprising administering to said patient a therapeutically effective amount of administering to a patient having a disorder an effective amount of 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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the The formulations and dosages and / or dosing regimens described herein in Sections 5.3 and 5.7. Methods are provided herein that include administering in accordance with the method of the present invention. A method for controlling angiogenesis by administering to a patient an effective amount of 5-(3-chlorophenyl)-3-hydroxybenzoate. 1,2-dioxypyridine-2-carbonyl]amino}acetic acid in the dosages and / or doses described herein. Provided herein are methods comprising administering to said subject a subject a drug regimen. A method for controlling angiogenesis in a patient comprising administering to the patient an effective amount of 2-(5-(3-fluorophenyl )-3-hydroxypicolinamido)acetic acid in the dosages and / or dosing regimens described herein. Methods are provided herein that include administering in accordance with certain such embodiments. In such cases, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of {[5-(3-chlorophenyl)- The specific compound is 3-hydroxypyridine-2-carbonylamino-1-phenylacetic acid. In such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. The compound is 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In 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 orally once a day, twice a day, or three times a day, preferably once a day. .

[0213] In certain embodiments, VEGF or G A method for treating or preventing a disease or disorder affected by the level of APDH, comprising administering to the patient a VEGF or A patient having a disease or disorder affected by the level of GADPH is administered an effective amount of a compound of formula (I), formula (II), A compound having a structure of formula (III), formula (IV), or formula (V), or compound 1, compound 2, compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Chemical A compound selected from compound 12, compound 13, metabolite 1, or metabolite 2, or a pharmaceutical thereof. and its acceptable salts, solvates, or hydrates (specifically, 5-(3-chlorophenyl)-3-hydro 2-(5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl)amino}acetic acid or Cypicolinamide (acetic acid) is prepared as described herein in Sections 5.3 and 5.7. The method includes administering the compound according to the formulation dosage and / or dosing regimen provided herein. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 500 mg. , about 600 mg, or about 750 mg of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl In certain such embodiments, the daily dose is about 150 mg, about 300 mg , about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicoline In certain such embodiments, the daily dose is about 150 mg, about 300 mg Such daily doses may be administered once a day, twice a day, or three times a day, preferably. It may be administered orally, preferably once a day.

[0214] In certain embodiments, a method for promoting wound healing includes, for example, a method as described in Section 5.4. A patient having a wound is administered an effective amount of a compound represented by formula (I), (II), (III), (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 pharma- ceutical acceptable salt or solvate thereof. , or a hydrate (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxime 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) and the formulations and dosages and and / or a dosing regimen. In such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 75 0 mg of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg. , or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. Such daily doses are administered orally once a day, twice a day, or three times a day, preferably once a day. It can be administered.

[0215] In certain embodiments, the damaged tissue in a patient is, for example, as described in Section 5.4. A method for enhancing revascularization or increasing vasculature in a tissue having damaged tissue, comprising: and administering to a patient having the disease an effective amount of 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 The compound selected, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof (specifically Specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2- (5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was prepared as described in Section 5.3 and Section 5. According to the formulations and dosages and / or dosing regimens described herein in Section 5.7. In certain embodiments, methods are provided herein that include administering to an ischemic A method for vascularizing tissue, comprising administering to a patient having ischemic tissue an effective amount of 5-(3-chloroform) (phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid was added to the Methods are provided herein that include administering according to a dosage and / or dosing regimen. In certain embodiments, a method of vascularizing an ischemic tissue comprises administering to a subject having an ischemic tissue a The patient is administered an effective amount of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. The formulations and dosages and / or Methods are provided herein that include administering the compound according to a dosing regimen. In such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg. The compound is {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or is approximately 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In 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 orally once a day, twice a day, or three times a day, preferably once a day. It can be done.

[0216] In certain embodiments, the growth of skin graft replacements is promoted. A method of promoting the growth of a patient having a skin graft, e.g., as described in Section 5.4, comprising administering to the patient: an effective amount of a compound having the structure of formula (I), (II), (III), (IV), or (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 compound, 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-fluoro (3-O-phenyl)-3-hydroxypicolinamido)acetic acid) in accordance with Sections 5.3 and 5.7. and administered according to the formulations and dosages and / or dosing regimens described herein. In certain such embodiments, a daily dose of about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of {[5-(3-chlorophenyl)-3-phenylpropanediol] In certain such embodiments, The daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluoro In certain such embodiments, For example, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. It may be administered orally once daily, twice daily, or three times daily, preferably once daily.

[0217] In certain embodiments, a method for promoting tissue repair in the context of guided tissue regeneration (GTR) For example, a patient as described in Section 5.4 is administered an effective amount of a compound represented by formula (I), (II), (III) , a compound having a structure of formula (IV) or formula (V), or compound 1, compound 2, compound 3, compound Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, A compound selected from compound 13, metabolite 1, or metabolite 2, or a medicament thereof. The salts, solvates, or hydrates obtained by the above process (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine) Lysine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinic acid amide) acetic acid) in the formulations described herein in Sections 5.3 and 5.7. and administering the compound according to the dosage and / or dosing regimen provided herein. In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, About 600 mg or about 750 mg of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] In certain such embodiments, the daily dose is about 150 mg, about 300 mg , about 450 mg, about 600 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicoline In certain such embodiments, the daily dose is about 150 mg, about 300 mg Such daily doses may be administered once a day, twice a day, or three times a day, preferably. It may be administered orally, preferably once a day.

[0218] In certain embodiments, the therapeutic target of the present invention is diabetic retinopathy, macular degeneration, cancer, sickle cell anemia, sarcoid , syphilis, pseudoxanthoma elasticum, Paget's disease, venous occlusion, arterial occlusion, carotid artery obstructive disease chronic uveitis / vitreous inflammation, mycobacterial infection, Lyme disease, systemic lupus erythematosus -Desmia, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing retinitis or choroiditis disease, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stahl's disease Gardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, traumatic Post-laser complications, rubeosis-related diseases, proliferative vitreoretinopathy, and Crohn's disease and ulcerative colitis, psoriasis, sarcoidosis, rheumatoid arthritis, hemangioma, Osler-Weber's disease -Rendu's disease or hereditary hemorrhagic telangiectasia, solid tumors or blood-borne tumors, acquired Immunodeficiency syndrome, skeletal and myocardial ischemia, stroke, coronary artery disease, peripheral vascular disease, and coronary A method for treating or preventing a disease or disorder selected from the group consisting of diseases, administering to a patient having a disorder an effective amount of 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 water hydrate thereof. solvates (specifically, 5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino) Acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was added to the Formulations and / or doses and / or administration amounts as described herein in Sections 5.3 and 5.7 and / or a dosing regimen. In such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or Approximately 750 mg of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 6 00 mg, or about 750 mg of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid. In certain 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 once a day, twice a day, or three times a day, preferably once a day. , may be administered orally.

[0219] 5.7 Dosage and Dosage Regimens For the use of the HIF prolyl hydroxylase inhibitors or HIF-α stabilizers described in this section, The specific dosage for administration can be administered by any method known to those of skill in the art. The dosage of the compound described herein may be taken orally, topically, or intravenously. The doses of compounds described may be taken while fasting, with fluids, or with any type of food. In a specific embodiment, the dosage of the compounds described herein is administered once a meal. , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after a meal, or 1, 2, 3, 4, 5, or 6 hours after a meal The compound described herein may be administered 7, 8, 9, 10, 11, or 12 hours prior to administration. Doses may be taken at any time of day. In certain embodiments, multiple doses are administered during the day. In certain embodiments, the doses are administered at the same time in the morning. In certain embodiments, dosages are administered at 4:00 A.M., near noon, or in the evening. In certain embodiments, dosages are administered between 5.00 a.m. and 1.00 p.m. In certain embodiments, dosages are administered between 6.00 am and 12.00 noon. In certain embodiments, doses are administered between 7.00 am and 11.00 am. In certain embodiments, the dose is administered between 8.00 am and 10.00 am. In an embodiment, the dose is administered before, during, or after breakfast. The regimen may be adjusted as described herein.

[0220] In a specific embodiment, subjects are initially treated with three tablets of 150 mg Compound 1 daily. The dose levels of the compound include 150, 300, 450, and 600 mg. The drug is to be taken once daily for the course of treatment. Subjects will be The drug should be taken with 4 ounces (113 g) of water or other oral fluid. The dosage is: It is taken at approximately the same time each day, preferably between 7 am and 2 pm.

[0221] Anemia (e.g., secondary to non-dialysis-dependent chronic kidney disease), as described in Section 5.6 and / or a combination of HIF prolyl hydroxylase inhibitors and / or Various parameters that guide the dosing regimen of the HIF-α stabilizer are described herein. The present invention relates to a method for the treatment of HIF prolyl hydroxylase inhibitors or HIF-α stabilizers. Some specific dosage amounts are provided. In certain embodiments, such dosage amounts are In other embodiments, such doses are administered over the course of treatment. In certain embodiments, the HIF prolyl hydroxylase is administered intravenously or intramuscularly. The HIF-α inhibitor or stabilizer has 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 water hydrate thereof. In a specific embodiment, the compound is Compound 1, or a pharma- ceutically acceptable salt thereof. In a specific embodiment, the compound is an acceptable salt, solvate, or hydrate. , Compound 7, or a pharma- ceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the compound is administered in a formulation described in Section 5.3.

[0222] Dosage Formulation

[0223] In certain specific embodiments, the dosages described in this Section 5.7 are Formulations containing intragranular, extragranular and film-coated components as described in Section 5.3. In a specific embodiment, the intragranular component is about 60% by weight of Compound 1, about 20% by weight microcrystalline cellulose, about 3% by weight sodium starch glycolate, and about 2.8% by weight % by weight of hydroxypropyl methylcellulose; the extragranular component is about 3% by weight of starch. sodium glycolate, about 0.25% by weight colloidal silicon dioxide, and about 0.75% by weight magnesium tearate; the film coating component comprises from about 2.0% to about 6.0% by weight % Opadry®; and the weight is the total weight of the intragranular and extragranular ingredients.

[0224] In certain specific embodiments, the dosages described in this Section 5.7 are Formulations containing intragranular, extragranular and film-coated components as described in Section 5.3. In a specific embodiment, the intragranular component is about 65% by weight of Compound 1, about 25% by weight microcrystalline cellulose, about 3% by weight sodium starch glycolate, and about 2.8% by weight % by weight of hydroxypropyl methylcellulose; the extragranular component is about 3% by weight of starch. sodium glycolate, about 0.25% by weight colloidal silicon dioxide, and about 0.75% by weight magnesium tearate; the film coating component comprises from about 2.0% to about 6.0% by weight % Opadry®; and the weight is the total weight of the intragranular and extragranular ingredients.

[0225] In certain specific embodiments, the dosages described in this Section 5.7 are Formulations containing intragranular, extragranular and film-coated components as described in Section 5.3. In a specific embodiment, the intragranular component is about 70% by weight of Compound 1, about 20% by weight microcrystalline cellulose, about 3% by weight sodium starch glycolate, and about 2.8% by weight % by weight of hydroxypropyl methylcellulose; the extragranular component is about 3% by weight of starch. sodium glycolate, about 0.25% by weight colloidal silicon dioxide, and about 0.75% by weight magnesium tearate; the film coating component comprises from about 2.0% to about 6.0% by weight % Opadry®; and the weight is the total weight of the intragranular and extragranular ingredients.

[0226] In certain specific embodiments, the dosages described in this Section 5.7 are Formulations containing intragranular, extragranular and film-coated components as described in Section 5.3. In a specific embodiment, the intragranular component is about 75% by weight of Compound 1, about 15% by weight microcrystalline cellulose, about 3% by weight sodium starch glycolate, and about 2.8% by weight % by weight of hydroxypropyl methylcellulose; the extragranular component is about 3% by weight of starch. sodium glycolate, about 0.25% by weight colloidal silicon dioxide, and about 0.75% by weight magnesium tearate; the film coating component comprises from about 2.0% to about 6.0% by weight % Opadry®; and the weight is the total weight of the intragranular and extragranular ingredients.

[0227] In certain specific embodiments, the dosages described in this Section 5.7 are Formulations containing intragranular, extragranular and film-coated components as described in Section 5.3. In a specific embodiment, the intragranular component is about 80% by weight of Compound 1, about 10% by weight microcrystalline cellulose, about 3% by weight sodium starch glycolate, and about 2.8% by weight % by weight of hydroxypropyl methylcellulose; the extragranular component is about 3% by weight of starch. sodium glycolate, about 0.25% by weight colloidal silicon dioxide, and about 0.75% by weight magnesium tearate; the film coating component comprises from about 2.0% to about 6.0% by weight % Opadry®; and the weight is the total weight of the intragranular and extragranular ingredients.

[0228] 5.7.1 Dosing Regimen In certain embodiments, the present invention is directed to treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering to a patient having anemia as described in Section 5.4 between about 100 mg and about 1,200 mg of , about 200 mg to about 1,000 mg, about 400 mg to about 800 mg, about 450 mg to about 600 mg, or about 300 mg to about 600 mg mg of 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 The compound or a pharma- ceutically acceptable salt, solvate, or hydrate thereof (specifically The compound may be {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2- (5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) In certain embodiments, the 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 pharma- ceutically 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 daily dose of acetone is about 150 mg to about 600 mg. The daily dose is about 150 mg to about 300 mg, about 300 mg to about 600 mg, or about 600 mg to about 750 mg. In embodiments, the daily dose is about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1,000m g, 1,050 mg, 1,100 mg, 1,150 mg, or even about 1,200 mg of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), 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 pharma- ceutically acceptable salt thereof. Salts, solvates, or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine 2-(5-(3-fluorophenyl)-3-hydroxypicoline In certain embodiments, the daily dose is at least about 300 mg, at least about 500 mg, In certain specific embodiments, the amount of the glycerol in the formulation is at least about 450 mg, or even at least about 600 mg. The doses are administered in the formulations described in Section 5.3.

[0229] In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 75 0 mg of 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 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) In certain embodiments, the compound is administered daily. The amount is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. The amount is not 240 mg, 370 mg, 500 mg, or 630 mg of Compound 1. In certain embodiments, The amount is about 240 mg, 370 mg, 500 mg, or about 630 mg of the compound of formula (I), formula (II), formula (III), formula (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 1, or metabolite 2, or a pharma- ceutical acceptable salt or solvate thereof. , or a hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbamate 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) In certain specific embodiments, the dosage is the formulation described in Section 5.3. It is administered at .

[0230] In certain embodiments, the present invention is directed to treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering to a patient having anemia a daily dose of a compound of formula (I), (II), (III), (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, Chemical Compound 13, Metabolite 1, or Metabolite 2, or a medicament thereof. Salts, solvates, or hydrates of {[5-(3-chlorophenyl)-3-hydroxypyridine Lysine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinic acid The method includes administering a compound (aminobutyric acid) to a subject, the compound being administered continuously and / or indefinitely. Provided herein are methods for administering the same to a patient in need thereof. In certain specific embodiments, the dosage is It is administered in the formulations described in Section 5.3.

[0231] In certain embodiments, the present invention is directed to treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering to a patient having anemia as described in Section 5.4 a daily dose of a compound of formula (I), I), a compound having the structure of formula (III), formula (IV), or formula (V), or compound 1, compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11 , 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 wherein the daily dose is about 450 mg. As provided herein. In certain such embodiments, a daily dose of about 450 mg is about 150 mg of 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 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) Three tablets each containing (3-phenyl)-3-hydroxypicolinamide (acetic acid) were In certain embodiments, the dosage form includes a daily dose of about 450 mg of 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 Compound 13, Metabolite 1, or Metabolite 2, or a medicament thereof. Salts, solvates, or hydrates of {[5-(3-chlorophenyl)-3-hydroxypyridine Lysine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinic acid The amount of acetaminophen (acetate) may be increased by about 150 mg so that the daily dose of the compound is about 600 mg. In certain embodiments, a daily dose of 450 mg of Formula (I), Formula (II), Formula (III), Formula (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 1, or metabolite 2, or a pharma- ceutical acceptable salt or solvate thereof. , or a hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbamate 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) may be reduced by about 150 mg, such that the daily dose of the compound is about 300 mg. In the above, a daily amount of a compound having a structure of formula (I), formula (II), formula (III), formula (IV), or formula (V) is administered. 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 (including Specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) is the daily dose of the compound In certain embodiments, the daily dose may be reduced by about 300 mg, such that the daily dose is about 150 mg. , about 75mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg, about 275mg or may be increased or decreased by about 300 mg. In certain embodiments, the daily dose is about 75 mg. ~300mg, about 100mg to about 300mg, about 125mg to about 300mg, about 150mg to about 300mg, about 175mg to about 300mg , 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 certain embodiments, the daily dose may be increased or decreased by about 75 mg to about 250 mg, about 1 The amount of the active ingredient may be increased or decreased by an amount of about 0.00 mg to about 225 mg, or about 125 mg to about 200 mg. In certain embodiments, the daily dose does not exceed about 600 mg or about 750 mg. In such cases, the dose is administered in the formulations described in Section 5.3.

[0232] In certain embodiments, the present invention is directed to treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering to a patient having anemia as described in Section 5.4 an effective amount of a compound of formula (I), I), a compound having the structure of formula (III), formula (IV), or formula (V), or compound 1, compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11 , 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 The method includes administering 1,2-dihydroxypicolinamide (hydroxypicolinamide acetic acid) to a subject for more than 42 consecutive days. Provided herein are methods in which the drug may be administered continuously and / or indefinitely, such as by administering the drug continuously and / or indefinitely. In such embodiments, the daily dose of compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or About 750 mg of 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 compound, 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- Specific such embodiments are In certain embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. In an embodiment, the dose is administered in a formulation described in Section 5.3.

[0233] In certain embodiments, the present invention is directed to treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering to a patient having anemia as described in Section 5.4 an effective amount of a compound of formula (I), I), a compound having the structure of formula (III), formula (IV), or formula (V), or compound 1, compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11 , 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 The method includes administering hydroxypicolinamide (acetate) to a patient, the patient's hemoglobin level being reduced by Provided herein are methods for maintaining blood glucose levels at or below about 10.0 g / dL and below about 13.0 g / dL. In certain such embodiments, the hemoglobin level is at least about 11.0 g / dL. and is maintained at a level of about 13.0 g / dL or less. The riboflavin level is maintained at a level of at least about 11.0 g / dL and no greater than about 12.0 g / dL. In such embodiments, the daily dose of compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 700 mg. mg, or about 750 mg of 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 The compound or a pharma- ceutically acceptable salt, solvate, or hydrate thereof (specifically The compound may be {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2- (5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid). In embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 600 mg. In specific embodiments, the dose is administered in a formulation described in Section 5.3.

[0234] In certain embodiments, the present invention is directed to treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering to a patient having anemia as described in Section 5.4 an effective amount of a compound of formula (I), I), a compound having the structure of formula (III), formula (IV), or formula (V), or compound 1, compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11 , 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 and administering to the patient a medicament for treating hemoglobinuria, Methods for increasing baseline hemoglobin levels by at least about 1.2 g / dL are described herein. In certain such embodiments, the daily dose of the compound is about 150 mg, about 300 mg, or mg, about 450 mg, about 600 mg, or about 750 mg of a compound of formula (I), formula (II), formula (III), formula (IV), or formula (V). or Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 13, Metabolite 1, or a pharma- ceutical acceptable salt, solvate, or derivative thereof. or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid). In certain such embodiments, the daily dose is about 150 mg, about 300 mg, about 450 mg, or about 6 In certain specific embodiments, the dosage is as described in Section 5.3. It is administered in a formulation.

[0235] In certain embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the formula: , 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 water hydrate thereof. Solvates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino Administration of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid Treatment may be discontinued if the alpha-globin level is 13.0 g / dL or higher. In the present study, administration of the compound was resumed once the hemoglobin level was below 12.5 g / dL. In certain specific embodiments, the compound is obtained in the formulation described in Section 5.3. It is administered at .

[0236] In certain embodiments, hemoglobin levels are monitored and a compound represented by Formula (I), Formula (II), Formula (II Compounds having the structure of formula (I), 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, or a medicament thereof. A salt, solvate, or hydrate thereof (specifically, {[5-(3-chlorophenyl)-3-hydroxyphenyl] 2-(5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl)amino}acetic acid or The dosage of choline amidoacetate is determined based on the hemoglobin level and / or In certain embodiments, the dosage may be adjusted based on changes in the dosage of the compound of formula (I), formula (II), Compounds having the structure of formula (III), formula (IV), or formula (V), or Compound 1, Compound 2, Compound Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, A compound selected from compound 12, compound 13, metabolite 1, or metabolite 2, or a pharmaceutical agent thereof. and acceptable salts, solvates, or hydrates thereof (specifically, {[5-(3-chlorophenyl)-3- Hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypyridine The amount of propyloxypicolinamide acetate was increased or decreased by 150 mg or even by 300 mg. In certain specific embodiments, the dosage can be adjusted by adjusting the It is administered in the formulation described in 5.3.

[0237] 5.7.2 Dose Adjustments In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. An initial daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylate] or a pharma- ceutically acceptable salt, solvate or the like thereof, administering a hydrate or hydrated drug to the patient; taking a first measurement of the patient's hemoglobin level, and then administering the performing a second measurement of the hemoglobin level of the patient; a hemoglobin level of less than about 10.0 g / dL, and the hemoglobin level is less than about 10.0 g / dL in the first measurement; or if the level of said patient in said second measurement is decreased by less than about 0.5 g / dL compared to the level of said patient in said second measurement; and a hemoglobin level of less than about 10.0 g / dL in the first measurement. or the hemoglobin concentration of the patient in the second measurement changes by a maximum of about 0.4 g / dL compared to the hemoglobin concentration of the patient in the second measurement. the hemoglobin level is about 10.0 to about 10.9 g / dL in the first measurement, if the level is decreased by less than about 0.5 g / dL compared to the initial daily amount; then, The amount of the compound administered may be adjusted by administering an adjusted daily amount of the compound. In the adjusted daily dose of the compound is about 150 mg higher than the initial daily dose.

[0238] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. An initial daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylate] or a pharma- ceutically acceptable salt, solvate or the like thereof, administering a hydrate or hydrated drug to the patient; taking a first measurement of the patient's hemoglobin level, and then administering the performing a second measurement of the hemoglobin level of the patient; a hemoglobin level of less than about 10.0 g / dL, and the hemoglobin level is less than about 10.0 g / dL in the first measurement; or if the level of said patient in said second measurement increases by more than about 1.5 g / dL compared to the level of said patient in said second measurement; and a hemoglobin level of about 10.0 to about 10.9 g / dL, and the hemoglobin level is measured by a first measurement. or if the level in said patient in the second measurement is increased by more than about 1.5 g / dL compared to the level in said patient in the first measurement; A hemoglobin level of about 11.0 to about 12.2 g / dL, and the hemoglobin level is a first or if the level in the second measurement is increased by about 1.0 to about 1.4 g / dL compared to the level in the first measurement; The hemoglobin level of the subject is about 12.3 to about 12.9 g / dL, and the hemoglobin level is a decrease of up to about 0.4 g / dL or an increase of up to about 0.4 g / dL compared to the first measurement; or the patient's hemoglobin level in the second measurement is about 12.3 to about 12.9 g / dL; The hemoglobin level is increased by about 0.5 to about 0.9 g / dL compared to the level in the first measurement. then administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, the adjusted daily dose of the compound may be The amount is about 150 mg less than the initial daily amount. In certain embodiments, the lowest dose level is 1 150 mg per day. Patients already on the lowest dose level should expect their Hgb to increase to 13.0 g / dL or higher. The patient will continue at 150 mg per day until this occurs.

[0239] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. An initial daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylate] or a pharma- ceutically acceptable salt, solvate or the like thereof, administering a hydrate or hydrated drug to the patient; taking a first measurement of the patient's hemoglobin level, and then administering the performing a second measurement of the hemoglobin level of the patient; A hemoglobin level of about 11.0 to about 12.2 g / dL, and the hemoglobin level is a first or if the patient has a second measurement, The hemoglobin level is about 12.3 to about 12.9 g / dL, and the hemoglobin level is an increase of about 1.0 to about 1.4 g / dL compared to the level in the first measurement; or The patient's hemoglobin level is about 12.3 to about 12.9 g / dL, and the hemoglobin level increases by more than about 1.5 g / dL compared to the level in the first measurement; then, The amount of the compound administered may be adjusted by administering a daily dose of the compound that is less than the amount of the compound administered. In such embodiments, the adjusted daily amount of the compound is about 30% lower than the initial daily amount. In certain embodiments, the lowest dose level is 150 mg per day. Patients in the low dose phase were treated with 150 mg / day until their Hgb increased to 13.0 g / dL or higher. It will continue.

[0240] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbamyl]- or a pharma- ceutically acceptable salt, solvate, or administering hydration to said patient; taking a first measurement of said patient's hemoglobin level, thereafter and performing a second measurement of the hemoglobin level of the patient, If the omegaloglobin level is 13.0 g / dL or greater, then a dose of the compound less than the initial daily dose is administered. The amount of the compound administered may be adjusted by administering an adjusted daily amount of the compound. In certain such embodiments, dosing is discontinued when Hgb is below 13 g / d If Hgb rises above 12.5 g / dL, treatment will be discontinued and not resumed until Hgb falls below 12.5 g / dL. Before discontinuing the dose, factors that may temporarily alter Hgb levels should be considered. Hgb will be assessed every 2 weeks during this period.

[0241] In certain embodiments, the dosage comprises an initial daily dose of, 3-hydroxypyridine-2-carbonyl]amino}acetic acid, or administering to said patient a pharma- ceutically acceptable salt, solvate, or hydrate of A first measurement of hemoglobin level is taken, followed by a second measurement of the hemoglobin level of the patient. wherein the hemoglobin level of the patient in the second measurement is 12.5 g / dL or greater. then administering an adjusted daily amount of the compound that is less than the initial daily amount. In certain such embodiments, dosing is discontinued. In such embodiments, dosing is discontinued if Hgb rises above 12.5 g / dL, It will not be resumed until Hgb levels have fallen to 12.0 g / dL or less. Factors that may be temporally variable must be considered. Hgb should be assessed every 2 weeks during this period. It is valued.

[0242] In certain embodiments, the dosage is an initial daily dose of {[5-(3-chlorophenyl)- (phenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, or administering a pharma- ceutically acceptable salt, solvate, or hydrate of said A first measurement of the hemoglobin level is taken, followed by a second measurement of the hemoglobin level of the patient. and wherein the hemoglobin level of the patient in the second measurement is or 13.0 g / dL or more in some cases, or 12.5 g / dL or more if the patient is an adult female In some cases, an adjusted daily dose of the compound is then administered that is less than the initial daily dose. In certain such embodiments, dosing is discontinued. In such embodiments, dosing is performed to maintain Hgb below 13.0 g / d if the patient is an adult male. If the patient is an adult female, the Hgb is 12.5 g / dL or less if the patient is an adult male, or is 12.5 g / dL or less if the patient is an adult female It will not be resumed until Hgb levels have fallen to 12.0 g / dL or less. Factors that may be temporally variable must be considered. Hgb should be assessed every 2 weeks during this period. It is valued.

[0243] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbamyl]- or a pharma- ceutically acceptable salt, solvate, or administering hydration to said patient; taking a first measurement of said patient's hemoglobin level, thereafter and performing a second measurement of the hemoglobin level of the patient, and the hemoglobin level is less than about 9.5 to 10.5 g / dL or about 9.75 to 10.25 g / dL, the level is about 0.2 to 0.8, about 0.3 to 0.7, or about 0.4 to 0.6 g higher than the level in the first measurement or if the hemoglobin level of the patient in the second measurement is decreased by less than about 9.5 / dL; or about 9.75 to 10.25 g / dL, and the hemoglobin level is less than about 9.75 to 10.5 g / dL in the first measurement. If the level changes by a maximum of about 0.1 to 0.7, about 0.2 to 0.6, or about 0.3 to 0.5 g / dL compared to the Alternatively, the hemoglobin level of the patient in the second measurement is about 9.5 to 10.5 g / dL or about 9.7 5 to 10.25 g / dL, about 10.4 to 11.4 g / dL, or about 10.65 to 11.15 g / dL, The level is about 0.2 to 0.8, about 0.3 to 0.7, or about 0.4 to 0.6 g / dL compared to the level in the first measurement. if the initial daily amount is decreased by less than 0.5 mg / kg; then, an adjusted daily amount of the compound greater than the initial daily amount is In certain such embodiments, the compound can be administered The daily dose is about 150 mg more than the initial daily dose.

[0244] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbamyl]- or a pharma- ceutically acceptable salt, solvate, or administering hydration to said patient; taking a first measurement of said patient's hemoglobin level, thereafter and performing a second measurement of the hemoglobin level of the patient, The hemoglobin level is less than about 9.5 to 10.5 g / dL or about 9.75 to 10.25 g / dL, The level of the amine is about 1.2 to 1.8, about 1.3 to 1.7, or about 1.4 to 1.5 compared to the level in the first measurement. or if the hemoglobin level of the patient in a second measurement is increased by more than 6 g / dL; About 9.5 to 10.5 or about 9.75 to 10.25 g / dL and about 10.4 to 11.4 g / dL or about 10.65 to 11.15 g / dL , the hemoglobin level is about 1.2 to 1.8, about 1.3 to 1.7, or or if the hemoglobin level of the patient in the second measurement increases by more than about 1.4 to 1.6 g / dL; Bottle levels are about 10.5-11.5 g / dL or about 10.75-11.25 g / dL and about 11.7-12.7 g / dL or about 11 0.95 to 12.45 g / dLg / dL, and the hemoglobin level is greater than or equal to the level in the first measurement. , about 0.7 to 1.3, about 0.8 to 1.2, or about 0.9 to 1.1 g / dL and about 1.1 to 1.7, about 1.2 to 1.6, or about 1. or the hemoglobin level of the patient in a second measurement is increased by: Approximately 11.8 to 12.8 g / dL or approximately 12.05 to 12.55 g / dL and approximately 12.4 to 13.9 g / dL or approximately 12.65 to 13.15 g / dL and the hemoglobin level is up to about 0.1 to 0.7, about 0.2 to 0.6, or or decreased by about 0.3 to 0.5 g / dL, or by up to about 0.1 to 0.7, about 0.2 to 0.6, or about or if the hemoglobin level of the patient in a second measurement increases by 0.3 to 0.5 g / dL; , about 11.8 to 12.8 g / dL or about 12.05 to 12.55 g / dL and about 12.4 to 13.9 g / dL or about 12.65 to 13.15 g / dL dLg / dL, and the hemoglobin level is about 0.2 to 0.8 compared to the level in the first measurement. , or from about 0.3 to 0.7, or from about 0.4 to 0.6, or from about 0.6 to 1.2, or from about 0.7 to 1.1, or from about 0.8 to 1.0 g / dL. then administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, the adjusted The daily dose is about 150 mg less than the initial daily dose. In certain embodiments, the lowest dose level is 1 Patients already on the lowest dose level should be on the lowest dose level if their Hgb is 12.0, 12.5, or This will be continued at 150 mg per day until increased to 13.0 g / dL or greater.

[0245] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbamyl]- or a pharma- ceutically acceptable salt, solvate, or administering hydration to said patient; taking a first measurement of said patient's hemoglobin level, thereafter and performing a second measurement of the hemoglobin level of the patient, Myoglobin level is about 10.5 to 11.5 g / dL or about 10.75 to 11.25 g / dL and about 11.7 to 12.7 g / dL or and the hemoglobin level is about 11.95 to 12.45 g / dLg / dL, and the hemoglobin level is the same as the level in the first measurement. or an increase of more than about 1.2-1.8, about 1.3-1.7, or about 1.4-1.6 g / dL compared to The hemoglobin level of the patient in the second measurement is about 11.8 to 12.8 g / dL or about 12.05 to 12.55 g / dL. / dL and about 12.4 to 13.9 g / dL or about 12.65 to 13.15 g / dL / dL, is about 0.7 to 1.3, about 0.8 to 1.2, or about 0.9 to 1.1 g / dL compared to the level in the first measurement, and or an increase of about 1.1 to 1.7, about 1.2 to 1.6, or about 1.3 to 1.5 g / dL in the second measurement; The hemoglobin level of the patient is about 11.8 to 12.8 g / dL or about 12.05 to 12.55 g / dL and about 12.4 13.9 g / dL or about 12.65 to 13.15 g / dL, and the hemoglobin level is If the level is increased by more than about 1.2 to 1.8, about 1.3 to 1.7, or about 1.4 to 1.6 g / dL compared to the level at then administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, the adjusted daily dose of the compound is In certain embodiments, the lowest dose level is about 300 mg per day less than the initial daily dose. Patients already on the lowest dose level will be required to maintain their Hgb at 12.0, 12.5, or 13.0 g / mL. This will be continued at 150 mg per day until the blood flow increases to ≥ 150 dL.

[0246] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbamyl]- or a pharma- ceutically acceptable salt, solvate, or administering hydration to said patient; taking a first measurement of said patient's hemoglobin level, thereafter and performing a second measurement of the hemoglobin level of the patient, If your DMARD level is 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, or 14.0 g / dL or higher, then administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, dosing is discontinued. In such embodiments, dosing is initiated when Hgb is below 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, or 14. If Hgb rises above 10.0 g / dL, treatment will be discontinued. 0.5 g / dL. Before discontinuing the dose, monitor Hgb levels. Factors that may change over time must be considered. Hgb should be assessed every 2 weeks during this period. will be done.

[0247] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbamyl]- or a pharma- ceutically acceptable salt, solvate, or administering hydration to said patient; taking a first measurement of said patient's hemoglobin level, thereafter and performing a second measurement of the hemoglobin level of the patient, If your DMARD level is 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, or 13.5 g / dL or higher, by administering an adjusted daily dose of the compound that is less than the initial daily dose. In certain such embodiments, dosing is discontinued. In embodiments, dosing is performed to determine whether Hgb is below 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, or 13.5 g / dL. If Hgb rises above 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, or 13.0 g / kg, treatment will be discontinued. / dL. Before discontinuing the dose, the Hgb level should be temporarily altered. Factors that may be contributing to the decline in Hgb should be considered. Hgb will be assessed every 2 weeks during this period.

[0248] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily dose of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbamyl]- or a pharma- ceutically acceptable salt, solvate, or administering hydration to said patient; taking a first measurement of said patient's hemoglobin level, thereafter and performing a second measurement of the hemoglobin level of the patient, If the patient is an adult male, the alpha-globin level is 11.0, 11.5, 12.0, 12.5, 13.0, 13 0.5, 10.0, 11.0, 12.0, or 14.0 g / dL or more if the patient is an adult female , 12.5, 13.0, or 13.5 g / dL or more, then less than the initial daily amount; This can be adjusted by administering an adjusted daily amount of the compound. In embodiments, dosing is discontinued. In certain such embodiments, dosing is discontinued when Hgb , 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, or 14.0 g / kg if the patient is an adult male or 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, or 14.0 dL if the patient is an adult female. If the patient is an adult male, the treatment is discontinued if the Hgb rises to 10.5, 1 or less than 1.0, 11.5, 12.0, 12.5, 13.0, or 13.5 g / dL, or the patient is an adult female If necessary, resume treatment until blood glucose levels decrease to 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, or 13.0 g / dL or less. Before discontinuing the dose, consider factors that may temporarily alter Hgb levels. Hgb should be assessed every 2 weeks during this period. The dosage adjustment method includes administering any of the compounds described herein or any combination thereof. It may be applied in the therapeutic regimen utilized.

[0249] Medication Algorithm

[0250] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily doses are given in the appropriate formulation (specifically, Formulation 1 or 2; see Section 6.2). administering a compound described in Section 5.2 to said patient; and performing a first measurement of said patient's hemoglobin level. and then performing a second measurement of said hemoglobin level in said patient, and In certain embodiments, the first measurement may be adjusted by adjusting the dosage. The measurement is a baseline measurement. In certain embodiments, the dosage is administered to a patient with anemia. Administer an initial daily dose of a compound, Compound 1, administered in the formulation described in Section 5.3. administering the hemoglobin to the patient, taking a first measurement of the patient's hemoglobin level, and then administering the hemoglobin to the patient. A second measurement of globin level should be taken and dosage adjusted as described below. It can be adjusted by.

[0251] In certain embodiments, hemoglobin levels are measured using HemoCue® point-of-care ELISA. Hgb was measured and monitored throughout the study using a Hgb monitoring system. It can be determined whether the dose is adjusted. In certain embodiments, Hgb is measured using HemoCue (registered trademark). A registered trademark can be obtained every two weeks for monitoring purposes for dosage adjustments. In certain embodiments, more frequent monitoring may be required as clinically indicated based on dosage changes. Hgb should be obtained every 4 weeks via HemoCue® unless otherwise indicated or justified. In certain embodiments, Hgb can be measured by HemoCue® at levels of 4, 6, 8, 10, 12 or 20. can be obtained every 16 weeks. In certain embodiments, hemoglobin is used to assess efficacy and Safety assessment may also be performed by a central laboratory using a complete blood count (CBC); however, Dose adjustments are based on the facility's HemoCue® Hgb values. The goal is to increase Hgb levels and maintain them at 10-11 g / dL. In one embodiment, the goal is to increase Hgb levels and maintain levels between 10 and 12 g / dL. In certain embodiments, the goal is to increase Hgb levels to a level of 10-13 g / dL. The aim is to maintain this.

[0252] In certain embodiments, Compound 1 is administered in the formulations described in Section 5.3, specifically in the formulation 1 or 2 (see section 6.2) and follow the dose adjustment algorithm guidelines below. Medications are administered. Rate of rise, rate of fall, and variability of Hgb are considered when adjusting therapy. A single Hgb deviation may not require a medication change.

[0253] 5.7.3 Dosage Adjustment Procedures in Patients with Chronic Kidney Disease In certain embodiments, dosing of Compound 1 is administered over the course of a patient's treatment, as described below. In certain specific embodiments, the dosage is adjusted to correct anemia in the patient. In certain specific embodiments, the patient is a patient with non-dialysis dependent chronic kidney disease. In a specific embodiment, Compound 1 is formulated as Formulation 1 or Formulation 2. will be done.

[0254] In certain embodiments, the baseline value is determined immediately prior to the first administration of Compound 1. In certain embodiments, the initial daily dosage administered to a patient is 300 mg / day. In certain embodiments, the initial daily dose is administered in the form of two tablets of 150 mg each. In one embodiment, the initial daily dose administered to a patient is 450 mg / day. In one embodiment, the initial daily dose is administered in the form of three tablets of 150 mg each. In certain specific embodiments, the initial daily dose is administered in the morning. The initial daily dose is administered between 7 am and 2 pm.

[0255] In certain embodiments, the daily dose of Compound 1 is administered more frequently than once every four weeks during the course of treatment. Daily dose reductions may occur more frequently, but frequent dose adjustments should be avoided. It should be.

[0256] In certain embodiments, Hgb is greater than or equal to 0.5 g / dL above baseline after 4 weeks of treatment. If the Hgb concentration does not increase by more than 100 mg / day, the daily dose of the compound is increased by 150 mg / day. It is increased by 150 mg / day every 4 weeks until it exceeds 10.0 g / dL (maximum dose is 600 mg / day). In certain specific embodiments, Hgb is measured in NDD-CKD patients after 4 weeks of daily doses of Compound 1. If the daily dose of compound did not increase by more than 0.5 g / dL above baseline after treatment, In certain specific embodiments, the daily dose of Compound 1 is increased by 150 mg / day. -Increased by 150 mg / day every 4 weeks until Hgb is >10.0 g / dL in CKD patients ( The maximum dose is 600 mg / day.

[0257] In certain embodiments, if Hgb rises rapidly during treatment (e.g., within any 2 week period), For periods of time greater than 1.0 g / dL), the daily dose is reduced by 150 mg / day. Therefore, if Hgb in NDD-CKD patients increases rapidly during treatment with a daily dose of Compound 1 (e.g. For example, >1.0 g / dL in any 2-week period), the daily dose is reduced by 150 mg / day.

[0258] In certain embodiments, if Hgb falls below 10.0 g / dL, the daily dose is only 150 mg / day. In certain specific embodiments, Hgb in NDD-CKD patients is increased by Compound 1. If the dose falls below 10.0 g / dL during treatment, the daily dose is increased by 150 mg / day. .

[0259] In certain embodiments, if Hgb levels are above 11.0 g / dL, Hgb is reduced to 10.5 g / dL or less. Treatment is then suspended until the patient is cured. The medication is then resumed at a reduced daily dose of 150 mg / day. In certain specific embodiments, Hgb levels in NDD-CKD patients are greater than 11.0 g / dL. If so, Compound 1 treatment is discontinued until Hgb decreases to 10.5 g / dL or less. Compound 1 dosing is resumed at a reduced daily dose of 150 mg / day.

[0260] In certain embodiments, if Hgb levels exceed 12.0 g / dL, the daily dose is reduced by 150 mg. In certain embodiments, if the Hgb level is greater than 13.0 g / dL, then the Hgb level is increased to 12.5 g / dL or less. Treatment is discontinued until the daily dose is reduced to 150 mg / day. In certain specific embodiments, Hgb levels in NDD-CKD patients are resumed at 1 day If the amount exceeds 12.0 g / dL during treatment with Compound 1, the dosage will be reduced by 150 mg / day. In certain specific embodiments, when Hgb levels in NDD-CKD patients are greater than 13.0 g / dL, If so, Compound 1 treatment will be discontinued until Hgb decreases to 12.5 g / dL or less. Dosing of substance 1 is resumed at a reduced daily dose of 150 mg / day.

[0261] In certain embodiments, dosage adjustments are necessary to maintain Hgb at desired levels. In certain specific embodiments, the daily dose is adjusted by 150 mg / day. If a dose adjustment of Compound 1 is necessary to maintain Hgb at the desired level in the patient , the daily dose is adjusted by 150 mg / day.

[0262] In certain embodiments, dosing of Compound 1 is administered over the course of a patient's treatment, as described below. In certain specific embodiments, the daily dose is adjusted to maintain anemia in the patient. In certain specific embodiments, the patient is treated with chronic non-dialysis-dependent In a specific embodiment, Compound 1 is administered in Formulation 1 or Formulation 2. It is formulated as follows.

[0263] In certain embodiments, the baseline value is determined immediately prior to the first administration of Compound 1. In certain embodiments, the initial daily dose administered to the patient is 300 mg / day. In a typical embodiment, the initial daily dose is administered in the form of two tablets of 150 mg each. In certain embodiments, the initial daily dose administered to a patient is 450 mg / day. In an embodiment, the initial daily dose is administered in the form of three tablets of 150 mg each. In a specific embodiment, the initial daily dose is administered in the morning. The initial daily dose is administered between 7 am and 2 pm.

[0264] In certain embodiments, the daily dose of Compound 1 administered in the formulation described in Section 5.3 is The amount will not be increased more frequently than once every 4 weeks during the course of treatment. Reductions in daily doses may be made more frequently. however, frequent dosage adjustments should be avoided.

[0265] In certain embodiments, dose adjustments are required to maintain Hgb at desired levels. If the compound is administered intravenously, the daily dose of the compound is adjusted by 150 mg / day (maximum daily dose is 600 mg / day). In certain specific embodiments, to maintain Hgb at a desired level in NDD-CKD patients If a dose adjustment is required, the daily dose of Compound 1 is adjusted by 150 mg / day (maximum dose is 600 mg / day). mg / day).

[0266] In certain embodiments, if Hgb falls below 10.0 g / dL, the daily dose is only 150 mg / day. In certain specific embodiments, Hgb in NDD-CKD patients is increased by Compound 1. If the dose falls below 10.0 g / dL during treatment, the daily dose is increased by 150 mg / day. .

[0267] In certain embodiments, if the Hgb level is above 11.0 g / dL, the Hgb is reduced to 10.5 g / dL or less. Treatment is interrupted until the patient has recovered from the condition. The medication is then resumed at a reduced daily dose of 150 mg / day. In certain specific embodiments, Hgb levels in NDD-CKD patients are greater than 11.0 g / dL. If so, Compound 1 treatment will be discontinued until Hgb is reduced to 10.5 g / dL or less. Then, Compound 1 dosing is resumed at a reduced daily dose of 150 mg / day.

[0268] In certain embodiments, if Hgb levels are above 12.0 g / dL, the daily dose is only 150 mg / day. In certain embodiments, if the Hgb level is greater than 13.0 g / dL, the Hgb is reduced to 12.5 g / dL. Treatment is discontinued until the blood glucose level is reduced to below 150 mg / day. In certain specific embodiments, Hgb levels in NDD-CKD patients are resumed at During treatment with a daily dose of Compound 1, if the daily dose exceeds 12.0 g / dL, the daily dose will be reduced by 150 mg / day. In certain specific embodiments, Hgb levels in NDD-CKD patients are greater than 13.0 g / dL. If so, Compound 1 treatment will be discontinued until Hgb is reduced to 12.5 g / dL or less. Then, Compound 1 dosing is resumed at a reduced daily dose of 150 mg / day.

[0269] In certain embodiments, the compound of formula (I), formula (II) is administered in a formulation as described in Section 5.3. Compounds having the structure of formula (III), formula (IV), or formula (V), or Compound 1, Compound 2, Compound Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, A compound selected from compound 12, compound 13, metabolite 1, or metabolite 2, or a pharmaceutical agent thereof. and acceptable salts, solvates, or hydrates thereof (specifically, {[5-(3-chlorophenyl)-3- Hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypyridine roxypicolinamide) acetic acid) or a pharma- ceutically acceptable salt, solvate, or hydrate thereof During administration of the drug, the dosage may not be increased more than once every four weeks, but frequent dosage adjustments are permitted. In certain embodiments, the dosage may be reduced more frequently while avoiding anemia. administering to the patient an initial daily dose of a compound; and a first measurement of the patient's hemoglobin level. and then performing a second measurement of said hemoglobin level in said patient four weeks later; and If the Hgb and Hgb did not increase by more than 0.5 g / dL from the first value after 4 weeks, then the initial daily dose was A higher adjusted daily dose of the compound, e.g., 150 mg higher than the initial dose. The dosage can be adjusted by administering the dose to the patient. taking 1, 2, 3, 4, 5, or more consecutive measurements of said hemoglobin level; and If the blood glucose and Hgb did not increase by more than 0.5 g / dL from the previous value, the patient was given a higher daily dose than the previous This can be further adjusted by administering a daily dose of the compound. This adjustment process continues until Hgb is greater than 10.0 g / dL. This adjustment process continues until Hgb reaches 8.0g / dL, 8.5, g / dL, 9.0g / dL, 9.5g / dL, 10.0g / dL, and 1 0.5g / dL, 11.0g / dL, 11.5g / dL, 12.0g / dL, 12.5g / dL, 13.0g / dL, 13.5g / dL, or 14.0g / d In certain embodiments, the maximum daily dose of the compound is 600 mg / L. In certain embodiments, the maximum daily dose of the compound is 400 mg / day, 450 mg / day, 500 mg / day, g / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, or 800 mg / day.

[0270] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily dose of a compound of formula (I), formula (II), formula (III), formula (IV), or formula (V) administered in a formulation comprising 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- ceutically acceptable salt, solvate, or Hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amine 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) or its derivatives administering a pharma- ceutically acceptable salt, solvate, or hydrate thereof to said patient; and then performing a second measurement of the hemoglobin level of the patient. and if Hgb rises rapidly (e.g., >1 g / dL in any 2-week period), then: An adjusted daily dose of the compound that is lower than the initial daily dose, for example, 150 mg lower than the initial dose. This can be adjusted by administering a tailored dose.

[0271] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily dose of a compound of formula (I), formula (II), formula (III), formula (IV), or formula (V) administered in a formulation comprising 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- ceutically acceptable salt, solvate, or Hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amine 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) or its derivatives administering a pharma- ceutically acceptable salt, solvate, or hydrate thereof to said patient; and then performing a second measurement of the hemoglobin level of the patient. and if the Hgb level exceeds 11.0 g / dL, then administer a lower daily dose of the compound than the initial daily dose. In certain embodiments, the dosage may be adjusted by administering an adjusted daily amount of the compound. The dosage may be administered to a patient having anemia by administering an initial daily amount of the compound to the patient, A first measurement of the hemoglobin level is taken, followed by a second measurement of the hemoglobin level of the patient. and if Hgb levels exceed 11.0 g / dL, then reduce Hgb to 10.5 g / dL or less. and then administering a daily dose of the compound lower than the initial daily dose. by administering an adjusted daily dose of 10 mg / kg / day, followed by resuming treatment. In certain embodiments, the adjusted daily dose of the compound is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg. In embodiments, the adjusted daily dose is 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times 5-fold, 4-fold, 4.5-fold, or 5-fold higher. In certain embodiments, the initial dose is adjusted 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 times higher than the administered dose.

[0272] In certain embodiments, the dosage is administered to a patient with anemia using a method as described in Section 5.3. The initial daily dose of a compound of formula (I), formula (II), formula (III), formula (IV), or formula (V) administered in a formulation comprising 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- ceutically acceptable salt, solvate, or Hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amine 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid), or administering a pharma- ceutical acceptable salt, solvate, or hydrate thereof to said patient; A first measurement of the hemoglobin level is taken, followed by a second measurement of the hemoglobin level of the patient. and if the Hgb level exceeds 12.0 g / dL, then administer a lower daily dose of the compound than the initial daily dose. In certain embodiments, the dosage may be adjusted by administering an adjusted daily amount of the compound. The dosage may be administered to a patient having anemia by administering an initial daily amount of the compound to the patient, A first measurement of the hemoglobin level is taken, followed by a second measurement of the hemoglobin level of the patient. and if Hgb levels exceed 13.0 g / dL, then reduce Hgb to 12.5 g / dL or less. discontinuing administration of the daily dose until a dose lower than the initial daily dose is administered; The daily dose of the compound may be adjusted by reinitiating treatment. In certain embodiments, the adjusted daily dose is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, , 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg. The adjusted daily dose is 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0, 20.0, 2 5-fold, or 5-fold higher. In certain embodiments, the initial dose is 1. 5x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, or 5x higher.

[0273] (5.7.4 Daily dose) In certain 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 water hydrate thereof. Solvates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino The daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid was The dose may be increased after a period of time beginning on the day the subject is given a daily dose of the compound. In such a case, the period may be about 1 week, such as about 2 weeks to about 7 weeks, about 3 weeks to about 6 weeks, or about 4 weeks. In certain specific embodiments, the compound is administered in a dose-dependent manner as described in Section 5.3. It is administered in the formulation described herein.

[0274] In certain embodiments, the structure of Formula (I), Formula (II), Formula (III), Formula (IV), or Formula (V) Compounds having the formula: , 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 water hydrate thereof. Solvates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino The daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid is The adjustment may be made once for a period of time. In certain embodiments, the period of time is from about 2 weeks to about 7 weeks. For example, about 1 week to about 8 weeks, about 3 weeks to about 6 weeks, or about 4 weeks. In embodiments, the compound is administered in a formulation described in Section 5.3.

[0275] In certain 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 water hydrate thereof. Solvates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino The daily dose of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid is The hemoglobin level increases by more than 1.2 g / dL above the baseline hemoglobin level In certain specific embodiments, the compound is not increased when the compound is added to the medium as described in Section 5. It is administered in the formulation described in 3.

[0276] 5.7.5 Medication and Methods of Treating Anemia In certain embodiments, the present invention is directed to treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering to a patient having anemia a daily dose of a compound of formula (I), (II), (III), (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, metabolite 2, and a pharma- ceutical acceptable salt or solvate thereof. or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylate 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid administering a compound that is a medicament for treating atopic dermatitis (such as atopic dermatitis); after administering a daily dose of the compound and again after a period of time; measuring a hemoglobin level of the patient, is less than about 10.0 g / dL, and said hemoglobin level is less than about 10.0 g / dL compared to the level measured prior to said period. or if the hemoglobin level of the patient decreases by less than about 10.0 g / dL; dL, and the hemoglobin level is up to 100% relative to the level measured before the period. or if the patient's hemoglobin level changes by about 10.0 to about 10.9 g / dL; dL, and the hemoglobin level is about 0.5 g / dL compared to the level measured prior to the period. If the daily dose of the compound is decreased by less than about 150 mg, administer an adjusted daily dose of the compound that is greater than about 150 mg. In certain such embodiments, the method comprises administering The compound is administered once daily and may be administered orally. In certain embodiments, the daily dose is about 450 ml. g, so if the daily dose is increased by about 150 mg, the adjusted daily dose is about 600 mg. In certain embodiments, the period is from about 2 weeks to about 7 weeks, from about 3 weeks to about 6 weeks, or from about 4 weeks to about 8 weeks. In certain embodiments, the daily dose is about 75 mg, about 10 mg, or about 8 weeks. 0 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg In certain embodiments, the daily dose can be increased or decreased by about 75 mg to 300 mg, about 100 mg to 300 mg, or about 100 mg to 300 mg. mg ~ approx. 300 mg, approx. 125 mg ~ approx. 300 mg, approx. 150 mg ~ approx. 300 mg, approx. 175 mg ~ approx. 300 mg, approx. 200 mg ~ approx. 30 Increase or decrease by 0 mg, about 225 mg to about 300 mg, about 250 mg to about 300 mg, or about 275 mg to about 300 mg. In certain embodiments, the daily dose is from about 75 mg to about 250 mg, from about 100 mg to about 225 mg. In certain embodiments, the amount of the adjusted dose may be increased or decreased by about 125 mg to about 200 mg. The administered daily amount does not exceed 600 mg or 750 mg. In certain specific embodiments, the dosage is administered in the formulations described in Section 5.3.

[0277] In certain embodiments, the present invention is directed to treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering to a patient having anemia a daily dose of a compound of formula (I), (II), (III), (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, metabolite 2, and a pharma- ceutical acceptable salt or solvate thereof. or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylate administering a compound which is a medicament for treating a patient having a pulmonary artery disease, the compound being an agonist, a benzo[a]pyridinyl]amino}acetic acid; after administration of a daily dose of the compound, measuring the hemoglobin level of the patient again after a period of time; a hemoglobin level of less than about 10.0 g / dL, and said hemoglobin level was less than about 10.0 g / dL prior to said period or if the hemoglobin level of the patient increases by more than about 1.5 g / dL compared to the level measured and the hemoglobin level is about 10.0 to about 10.9 g / dL, and the hemoglobin level was measured before the period. or if the hemoglobin level of the patient increases by more than about 1.5 g / dL compared to a level determined by the The hemoglobin level is about 11.0 to about 12.2 g / dL, and the hemoglobin level was measured before the period. or the patient's hemoglobin level is increased by about 1.0 to about 1.4 g / dL compared to the normal level; the hemoglobin level is about 12.3 to about 12.9 g / dL, and the hemoglobin level is Decreased by up to about 0.4 g / dL or increased by up to about 0.4 g / dL compared to levels measured or the patient's hemoglobin level is about 12.3 to about 12.9 g / dL, Hemoglobin levels are about 0.5 to about 0.9 g / dL higher than the levels measured before the period If the patient is increased in the amount of 150 mg of the compound, an adjusted daily dose of the compound may be administered that is 150 mg less than the daily dose. and (c) administering to said patient a compound comprising: It is administered once daily and can be administered orally. In certain embodiments, the daily dose is about 450 mg. So, if the daily dose is reduced by about 150 mg, the adjusted daily dose is about 300 mg. In this embodiment, the period is about 2 weeks to about 7 weeks, about 3 weeks to about 6 weeks, or about 4 weeks, etc. In certain embodiments, the daily dose is about 75 mg, about 100 mg, Increase by about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg In certain embodiments, the daily dose is from about 75 mg to about 300 mg, from about 100 mg to about 300mg, about 125mg to about 300mg, about 150mg to about 300mg, about 175mg to about 300mg, about 200mg to about 300mg, The amount may be increased or decreased by about 225 mg to about 300 mg, about 250 mg to about 300 mg, or about 275 mg to about 300 mg. In certain embodiments, the daily dose is from about 75 mg to about 250 mg, from about 100 mg to about 225 mg, or from about The amount of the adjusted 1 The daily dose does not exceed 600 mg or 750 mg. In certain specific embodiments, the dosage is It is administered in the formulations described in Section 5.3.

[0278] In certain embodiments, the present invention is directed to treating anemia, such as anemia secondary to non-dialysis dependent chronic kidney disease. The method comprises administering to a patient having anemia a daily dose of a compound of formula (I), (II), (III), (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, metabolite 2, and a pharma- ceutical acceptable salt or solvate thereof. or hydrate (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylate 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid administering a compound that is a medicament for treating atopic dermatitis (such as atopic dermatitis); after administering a daily dose of the compound and again after a period of time; measuring a hemoglobin level of the patient, and the hemoglobin level is about 11.0 to about 12.2 g / dL, and the hemoglobin level is lower than that measured before the period. or the hemoglobin level of the patient is increased by more than about 1.5 g / dL compared to the normal hemoglobin level; and the hemoglobin level is about 12.3 to about 12.9 g / dL, and the hemoglobin level is lower than that measured before the period. or the patient's hemoglobin level increases by about 1.0 to about 1.4 g / dL compared to the normal baseline; or and the hemoglobin level is about 12.3 to about 12.9 g / dL, the hemoglobin level being measured prior to the period. If the level increases by more than about 1.5 g / dL compared to the level obtained by Provided herein are methods comprising administering a regulated daily amount of the compound. In certain embodiments, the compound is administered once daily and may be administered orally. The daily dose is 450 mg, so if the initial daily dose is reduced by about 300 mg, the adjusted daily dose is In certain embodiments, the period is about 2 weeks to about 7 weeks, about 3 weeks to about 5 weeks, about 6 weeks to about 7 weeks, about 8 weeks to about 9 weeks, about 10 weeks to about 15 weeks, about 15 weeks to about 2 weeks, about 10 weeks to about 3 weeks, about 15 weeks to about 5 weeks, about 10 weeks to about 15 weeks, about 15 weeks to about 2 ... From about 1 week to about 8 weeks, such as about 6 weeks, or about 4 weeks. is about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg In certain embodiments, the daily dose is about 75 mg, or about 300 mg. g~300mg, about 100mg~about 300mg, about 125mg~about 300mg, about 150mg~about 300mg, about 175mg~about 300mg , 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 certain embodiments, the daily dose may be increased or decreased by about 75 mg to about 250 mg, about 1 The amount of the active ingredient may be increased or decreased by an amount of from about 100 mg to about 225 mg, or from about 125 mg to about 200 mg. In certain specific embodiments, the adjusted daily dose does not exceed 600 mg or 750 mg. In this case, the dose is administered in the formulation described in Section 5.3.

[0279] In certain embodiments, a patient described in Section 5.4 who is undergoing hemodialysis 20. A method for treating anemia associated with CKD in a patient, comprising administering to the patient as a pharmaceutical an effective amount of 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 compounds were administered at approximately 8, 7, 6, 5, 4, 3, and 2 hours after the start of hemodialysis. or 1 hour, or about 7 to 8 hours, 6 to 7 hours, 5 to 6 hours, 4 to 5 hours, 3 hours Including administration up to 4 hours, 2 to 3 hours, 1 to 2 hours, or up to about 1 hour before In certain specific embodiments, the compound is a compound according to Section 1. It will be administered in the formulation described in 5.3.

[0280] In certain embodiments, a patient described in Section 5.4 who is undergoing hemodialysis 20. A method for treating anemia associated with CKD in a patient, comprising administering to the patient as a pharmaceutical an effective amount of 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 compound was administered twice a week, three times a week, four times a week, five times a week, six times a week, daily, once every two weeks, once every three weeks, This includes administering the drug once every 4 weeks, once every 2 months, or once every 3 months. Provided herein are methods for treating a variety of conditions, including the administration of a compound comprising the steps of: The drug will be administered in the formulation described in Section 5.3.

[0281] In certain embodiments, a patient described in Section 5.4 who is undergoing hemodialysis 20. A method for treating anemia associated with CKD in a patient, comprising administering to the patient as a pharmaceutical an effective amount of 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 compounds were administered at approximately 8, 7, 6, 5, 4, 3, 2, and 4-hour intervals after the completion of hemodialysis. or 1 hour, or about 7 to 8 hours, 6 to 7 hours, 5 to 6 hours, 4 to 5 hours, or 3 hours This includes administering the drug within 4 hours, 2 hours to 3 hours, 1 hour to 2 hours, or up to about 1 hour after the administration. Provided herein are methods for treating a variety of conditions, including the administration of a compound comprising the steps of: The drug will be administered in the formulation described in Section 5.3.

[0282] In certain embodiments, the methods provided herein comprise the step of reacting a compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII ... (IV) or a compound having the structure of formula (V), or compound 1, compound 2, compound 3, compound 4 , Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Chemical The serum concentration of a metabolite of a compound selected from Compound 13, Metabolite 1, or Metabolite 2 is determined. In a more specific embodiment, the compound of formula (I), formula (II), formula (III), 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, Compound 13, Metabolite 1, or Metabolite 2. In yet another more specific embodiment, the serum concentration of the acyl glucuronide and / or the acyl glucuronide is determined. In the present invention, the phenol glucuronide and / or acyl glucuronide of compound 1, i.e., The serum concentration of metabolite 1 or metabolite 2 is determined. In certain specific embodiments, the daily dose is adjusted according to the serum concentration of the metabolite. Doses are administered in the formulations described in Section 5.3.

[0283] 5.8 Combination Therapy In certain embodiments, the present invention relates to a method for treating chronic kidney disease secondary to chronic kidney disease in a patient as described in Section 5.4. A method of treating anemia, such as anemia caused by anemia of the present invention, comprising administering to a subject an anemia-causing agent or an anti-anemia agent, the anemia being treated by an anti-anemia agent or an anti-inflammatory agent ... the anemia being caused by an anti-anemia agent or an anti-inflammatory agent, the anemia being caused by an anti The formulation comprises a compound having a structure of formula (I), (II), (III), (IV), or (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- ceutical acceptable salt, solvate, or hydrate thereof (specifically , {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-( 3-Fluorophenyl-3-hydroxypicolinamidoacetic acid) in combination with another drug Such combination therapy may comprise administering to a subject the individual components of the treatment. This can be achieved by simultaneous, sequential, or separate administration of such combination therapy. When administered as one component, the compound of formula (I) in the formulations described herein in Section 5.3 ), 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 A pharma- ceutical acceptable salt, solvate, or hydrate of {[5-(3-chlorophenyl)- 2-(5-(3-fluorophenyl)-3-hydroxypyridine-2-carbonyl)amino}acetic acid or Since 1-hydroxypicolinamidoacetate can be synergistic with other drugs, it is not recommended as a monotherapy. of either or both of the ingredients compared to the dosage of either ingredient that would normally be given The daily dosage may be reduced. Alternatively, when administered as one component of such a combination therapy, Formula (I), Formula (II), Formula (III), Formula (IV) in the formulations described herein in Section 5.3. 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 pharma- ceutically acceptable salt thereof; Solvates or hydrates (specifically, {[5-(3-chlorophenyl)-3-hydroxypyridine-2- carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypicolinamide) Acetic acid) and other medications may be additive, so the daily dose of each component should be The dosage is similar or the same as the dosage of either component that would normally be given in a single dose.

[0284] In certain embodiments, a patient as described in Section 5.4 is treated with a steroid therapy following chronic kidney disease. non-severe anemia secondary to non-dialysis-dependent chronic kidney disease; non-severe anemia secondary to congestive heart failure A method for treating idiopathic anemia of aging and idiopathic anemia of aging, comprising administering to a patient having anemia a sexual In the formulations described herein in Section 5.3, 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 medicamentously acceptable salt or solvent thereof. hydrates, solvates, or hydrates (e.g., compounds disclosed herein, such as Compound 1) and administering to the patient a HIF prolyl hydroxylase inhibitor or a HIF-α stabilizer of Methods in which the compound is administered continuously and / or indefinitely and in which the compound is administered with another medicament are disclosed herein. Provided in the fine print.

[0285] In certain embodiments, a patient as described in Section 5.4 is treated with a steroid therapy following chronic kidney disease. A method for treating anemia, such as anemia caused by In the formulation, 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 compound or a pharma- ceutically acceptable salt, solvate, or hydrate thereof (specifically The compound may be {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2- (5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) was administered to patients with anemia. and optionally providing the compound ferrous sulfate, ferrous gluconate, or ferrous fumarate. Provided herein are methods for administering the compound in combination with an iron supplement, such as ferrous iron. In such embodiments, the iron supplement is administered at least one hour after administration of the compound. at least 2 hours, at least 3 hours, at least 4 hours, or even at least 6 hours. In certain embodiments, the iron supplement provides iron levels of ferritin between about 50 ng / mL and about 300 ng / mL. In certain embodiments, the iron supplement is administered in an amount that maintains the iron intake at about 50 mg / kg / day. In certain embodiments, the iron supplement is administered orally at a daily dose of about 50 mg of elemental iron. The dose of elemental iron is administered orally. In certain embodiments, the iron supplement is administered intravenously. In certain embodiments, iron supplements are administered continuously and / or daily, such as for 42 or more consecutive days. In certain alternative embodiments, the iron supplement provides an iron level of about 50 ng ferritin. The dose is administered as needed to maintain a level between about 1 / mL and about 300 ng / mL. In such embodiments, the daily dose of the compound is In the formulation, about 150 mg, about 300 mg, about 450 mg, about 600 mg, or about 750 mg of the compound of formula (I), formula (II), formula (II) II), 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, or metabolite 2, or a pharmaceutical approved compound thereof. Acceptable salts, solvates, or hydrates, particularly {[5-(3-chlorophenyl)-3-hydro xypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxy In certain such embodiments, the daily dose is about 150 mg Such daily doses may be administered once a day, twice a day, or once a day. It may be administered orally three times a day, preferably once a day.

[0286] In certain embodiments, a patient as described in Section 5.4 is treated with a steroid therapy following chronic kidney disease. A method for treating anemia, such as anemia caused by In the formulation, 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 compound or a pharma- ceutically acceptable salt, solvate, or hydrate thereof (specifically The compound may be {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid or 2- (5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid) as described in Section 5.4 and administering to a patient having anemia, the compound optionally inhibiting erythropoietin. Provided herein are methods in which the antibody is administered in combination with an erythropoiesis stimulating agent (ESA), such as an erythropoietin mimetic. In certain such embodiments, the ESA is epoetin alfa, epoetin beta, dal rhEPO products, including but not limited to bepoetin or peginesatide. In such embodiments, the ESA is administered as salvage therapy. In certain embodiments, the ESA is administered continuously and / or indefinitely, such as for 42 or more consecutive days. In such embodiments, the daily dose of the compound is about 150 mg, about 300 mg, about 450 mg, about 600 mg or about 750 mg of Formula (I), Formula (II) in the formulations described herein in Section 5.3. Compounds having the structure of formula (III), formula (IV), or formula (V), or Compound 1, Compound 2, Compound Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, A compound selected from compound 12, compound 13, metabolite 1, or metabolite 2, or a pharmaceutical agent thereof. and acceptable salts, solvates, or hydrates thereof (specifically, {[5-(3-chlorophenyl)-3- Hydroxypyridine-2-carbonyl]amino}acetic acid or 2-(5-(3-fluorophenyl)-3-hydroxypyridine In certain such embodiments, the daily dose is about Such daily doses may be administered once a day, twice a day, Alternatively, it may be administered orally three times a day, preferably once a day. EXAMPLES

[0287] (6 Examples) 6.1 Example 1: Compounds for Correction of Anemia in Subjects with Non-Dialysis-Dependent Chronic Kidney Disease Item 1) This example shows the effect of dialysis on the survival of approximately 1,000 subjects with non-dialysis-dependent chronic kidney disease (NDD-CKD). Phase 3 to evaluate the efficacy and safety of oral Compound 1 for the correction of anemia in subjects This is a randomized, open-label, active-controlled study to evaluate the efficacy and safety of Compound 1 in patients with NDD-CKD secondary to Compared with darbepoetin alfa for correction and maintenance of Hgb in subjects with anemia Sticky.

[0288] The study population consisted of patients with erythropoietin-stimulating agents (ESAs)-naïve, non-CKD, estimated glomerular filtration rate (GFP) Excess (eGFR)≦60mL / min / 1.73m 2 and those aged 18 years or older with hemoglobin (Hgb) < 10.0 g / dL It consists of elephants.

[0289] After a screening period of up to 4 weeks, subjects who met all of the inclusion criteria listed below were Subjects who did not meet any of the exclusion criteria were randomized 1:1 to either Compound 1 or darbepoetin alfa. Randomization will be stratified by: · Geographic region (United States [US] vs. European Union [EU] vs. Rest of the World [ROW]). New York Heart Association Congestive Heart Failure (CHF) Class 0 or I vs. II or III. · Study entry Hgb (<9.5 vs. ≥9.5 g / dL).

[0290] After randomization, there are four periods during the trial: Correction period (weeks 0-23): the initial period of study treatment for correction of Hbg Maintenance period (weeks 24-52): the period of study treatment during which efficacy is evaluated (primary evaluation period: weeks 24-36; Secondary evaluation period: Weeks 40-52) Long-term treatment period (week 53 to end of treatment) Continued study treatment to evaluate long-term safety Follow-up period (end of treatment + 4 weeks): Post-treatment visit for safety (either in person or by phone) Either one.

[0291] The estimated time to complete enrollment of approximately 1,000 randomized subjects is 20 months, with an average The estimated follow-up period is 1.8 years. Approximately 631 major adverse cardiovascular events (M They remained in the study until ACE occurred across two separate NDD-CKD studies, at which point At this point, subjects will be scheduled for their final visit and the study will end. The inter-institutional study end date was announced (based on the increase in MACE across the two studies) and then will inform active subjects of the international clinical trial end date.

[0292] (Selection and Withdrawal of Subjects)

[0293] Subjects are selected for the study based on the following inclusion and exclusion criteria.

[0294] Inclusion Criteria. To be eligible, subjects must meet all of the following inclusion criteria: Not: 1. 18 years of age or older (including 18 years of age); 2. Use of the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine formula at screening , estimated glomerular filtration rate (eGFR) ≤ 60 mL / min / 1.73 m at the screening visit 2 Chronic kidney disease are not expected to initiate dialysis within 6 months of diagnosis and screening; 3. Determined by the average of two Hgb values ​​measured by a central laboratory during screening Mean screening Hgb<10.0g / dL; 4. Serum ferritin ≥ 100ng / mL and transferrin saturation during screening (TSAT) ≥ 20%; 5. Folate and vitamin B12 measurements ≥ lower limit of normal during screening; 6. Understand the procedures and requirements of this study and provide written informed consent; Authorizing Disclosure of Protected Health Information.

[0295] Exclusion Criteria. Subjects who complain of any of the following are ineligible for entry into the study: 1.Subjects with anemia or active bleeding or recent blood loss due to causes other than CKD; 2. Sickle cell disease, myelodysplastic syndrome, myelofibrosis, hematological malignancies, myeloma, hemolytic anemia subjects with thalassemia, or pure red cell aplasia; 3. Red blood cell (RBC) transfusion within 4 weeks prior to or during screening. 4. Intravenous (IV) iron within 4 weeks prior to screening; 5. Any ESA (e.g., recombinant human erythropoietin [ rhEPO] or darbepoetin alfa); 6. Aspartate aminotransferase (AST) / serum glutamine at screening Serum oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT) / blood Serum glutamic pyruvic transaminase (SGPT) or total bilirubin > 2.0 x normal Upper limit of normal (ULN). Subjects with a history of Gilbert syndrome are not excluded; 7. At screening, insufficiently controlled hypertension (confirmed diastolic blood pressure >110mmHg or systolic blood pressure >110mmHg) blood pressure >180mmHg); 8. Severe heart failure (New York Heart Association class IV) at screening; 9. Acute coronary syndrome (hospitalization for unstable angina or myocardial infarction) within 12 weeks prior to screening , impending coronary revascularization, hospitalization for CHF, or stroke; 10. History of active malignancy within 2 years prior to screening, except for curatively removed skin tumors Basal cell carcinoma, squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, or resected benign colon polyps except; 11. Deep vein thrombosis (DVT) or pulmonary embolism requiring active treatment within 8 weeks prior to screening History of pulmonary embolism (PE); 12. History of hemosiderosis or hemochromatosis; 13. History of previous or planned organ transplant (excluding subjects on the kidney transplant waiting list) previous stem cell or bone marrow transplant (corneal transplants are not excluded); 14. Within 30 days or 5 half-lives of an investigational drug (whichever is longer) prior to the screening visit Use of an investigational drug or participation in a clinical trial; 15. Previous participation in this study, receipt of Compound 1 in another study, or another hypoxia-inducing agent previous participation in a trial with a high-intensity prolyl hydroxylase inhibitor (HIF PHI); 16. Pregnant or breastfeeding women who are unable or unwilling to use acceptable methods of contraception unwilling childbearing women; 17. Non-vasectomized individuals who are unable or unwilling to use an acceptable method of contraception Male target; 18. Any other condition that, in the opinion of the Investigator, makes the subject unsuitable for participation in the study. reason.

[0296] (Efficacy endpoint)

[0297] The efficacy endpoints of this study are defined as follows:

[0298] primary Hgb between baseline (mean pretreatment Hgb) and primary evaluation period (mean Hgb from weeks 24-36) Average change.

[0299] primary secondary Hgb between baseline (mean pretreatment Hgb) and primary evaluation period (mean Hgb from weeks 24-36) Mean change; Subjects with a mean Hgb of 10.0-12.0 g / dL (inclusive) during the primary evaluation period (weeks 24-36) ratio; · Mean weekly dose of intravenous (IV) elemental iron administered from baseline to week 52; Proportion of subjects receiving RBC transfusion(s) from baseline to week 52.

[0300] Other secondary · CKD progression based on changes in GFR; · Proportion of Hgb values ​​within the target range during the maintenance phase (weeks 24–52); · Hgb increase from baseline >1.0 g / dL; Confirmed Hgb <10.0 or >12.0 g / dL; ·ESA relief; Dosage adjustments; ·Maintaining iron sufficiency (defined as ferritin ≥ 100ng / mL and TSAT ≥ 20%); · Receiving IV iron therapy.

[0301] (Safety endpoint)

[0302] The safety endpoints of this study are defined as follows: MACE, defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke; · Individual components of MACE; o All-cause mortality; o Non-fatal myocardial infarction; o Non-fatal stroke; Thromboembolic events: arterial thrombosis, DVT, PE, or vascular access thrombosis; Hgb>12.0g / dL, >13.0g / dL, or >14.0g / dL; Hgb increase >1.0 g / dL in any 2-week interval or Hgb increase >2.0 g / dL in any 4-week interval; Adverse events (AEs) and serious adverse events (SAEs); -Vital signs and laboratory values.

[0303] (Target treatment) ...

Claims

1. 1. A tablet formulation comprising an intragranular component, an extragranular component, and a film coating component, The intragranular component is 55% to 75% by weight of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] a Amino}acetic acid: 【Chemistry 1】 (Compound 1), or a pharma- ceutical acceptable salt thereof; 15% to 35% by weight of microcrystalline cellulose, 2.0% to 4.0% by weight of a disintegrant, and comprising 1.8% to 3.8% by weight of hydroxypropyl methylcellulose; The extragranular component is 2.0% to 4.0% by weight of a disintegrant; 0.15% to 0.35% by weight of a glidant, and comprising 0.35% to 1.15% by weight of a lubricant; the film coating component comprises 1.0% to 8% by weight of the tablet coating; the weight being the total weight of all intra- and extra-grain components; Disintegrants include agar, alginic acid, calcium carbonate, microcrystalline cellulose, and croscarmellose. sodium, polacrilin potassium, sodium starch glycolate, potato starch starch or tapioca starch, pregelatinized starch, other starches, clays, other algins, selected from other celluloses, gums, and mixtures thereof; The glidants are fumed silica, magnesium carbonate, magnesium stearate, cobalt. selected from loidal silicon dioxide, starch, and talc; Lubricants include calcium stearate, magnesium stearate, mineral oil, and lauryl stearate. Mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol ole, other glycols, stearic acid, sodium stearyl fumarate, talc, hydrogenated plants Oil, zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof and The tablet formulation is used to administer 150 mg to 600 mg of Compound 1 once a day. Drug formulation.

2. The intragranular component is 60% to 70% by weight of compound 1, 20% to 30% by weight of microcrystalline cellulose, 2.5% to 3.5% by weight of a disintegrant, and comprising 2.3% to 3.3% by weight of hydroxypropyl methylcellulose; The extragranular component is 2.5% to 3.5% by weight of a disintegrant; 0.2% to 0.3% by weight of a glidant, and 10. The tablet formulation of claim 1 comprising from 0.55% to 0.95% by weight of a lubricant.

3. In the intragranular component, the disintegrant is sodium starch glycolate; and In the extragranular component, the disintegrant is sodium starch glycolate, The glidant is colloidal silicon dioxide and the lubricant is magnesium stearate. and 2. The tablet formulation of claim 1, wherein the film coating component comprises Opadry®. 。

4. 1. A tablet formulation comprising an intragranular component, an extragranular component, and a film coating component, The intragranular component is 55% to 75% by weight of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] a Amino}acetic acid: 【Chemistry 2】 (Compound 1), or a pharma- ceutical acceptable salt thereof; 15% to 35% by weight of microcrystalline cellulose, 2.0% to 4.0% by weight of sodium starch glycolate, and comprising 1.8% to 3.8% by weight of hydroxypropyl methylcellulose; The extragranular component is 2.0% to 4.0% by weight of sodium starch glycolate, 0.15% to 0.35% by weight of colloidal silicon dioxide, and containing 0.35% to 1.15% by weight of magnesium stearate; the film coating component comprises 1.0% to 8% by weight of the tablet coating; the weight being the total weight of all intra- and extra-grain components; and The tablet formulation is used to administer 75 mg to 600 mg of Compound 1 once a day. Drug formulation.

5. The intragranular component is 60% to 70% by weight of compound 1, 20% to 30% by weight of microcrystalline cellulose, 2.5% to 3.5% by weight of sodium starch glycolate, and comprising 2.3% to 3.3% by weight of hydroxypropyl methylcellulose; The extragranular component is 2.5% to 3.5% by weight of sodium starch glycolate, 0.2% to 0.3% by weight of colloidal silicon dioxide, and containing 0.55% to 0.95% by weight of magnesium stearate; the film coating component comprises 1.0% to 8% by weight of the tablet coating; t 5. The tablet formulation of claim 4, wherein said weight is the total weight of all intragranular and extragranular components.

6. 1. A pharmaceutical composition for treating anemia, which is a tablet, comprising an intragranular component, Contains an extragranular component and a film coating component, The intragranular component is 55% to 75% by weight of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] a Amino}acetic acid: 【Chemistry 3】 (Compound 1), or a pharma- ceutically acceptable salt thereof; 15% to 35% by weight of microcrystalline cellulose, 2.0% to 4.0% by weight of a disintegrant, and comprising 1.8% to 3.8% by weight of hydroxypropyl methylcellulose; The extragranular component is 2.0% to 4.0% by weight of a disintegrant; 0.15% to 0.35% by weight of a glidant, and comprising 0.35% to 1.15% by weight of a lubricant; the film coating component comprises 1.0% to 8% by weight of the tablet coating; the weight being the total weight of all intra- and extra-grain components; Disintegrants include agar, alginic acid, calcium carbonate, microcrystalline cellulose, and croscarmellose. sodium, polacrilin potassium, sodium starch glycolate, potato starch starch or tapioca starch, pregelatinized starch, other starches, clays, other algins, selected from other celluloses, gums, and mixtures thereof; The glidants are fumed silica, magnesium carbonate, magnesium stearate, cobalt. selected from loidal silicon dioxide, starch, and talc; Lubricants include calcium stearate, magnesium stearate, mineral oil, and lauryl stearate. Mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol ole, other glycols, stearic acid, sodium stearyl fumarate, talc, hydrogenated plants Oil, zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof and The tablet is used to administer 150 mg to 600 mg of compound 1 once a day. Composition.

7. The intragranular component is 60% to 70% by weight of compound 1, 20% to 30% by weight of microcrystalline cellulose, 2.5% to 3.5% by weight of a disintegrant, and comprising 2.3% to 3.3% by weight of hydroxypropyl methylcellulose; The extragranular component is 2.5% to 3.5% by weight of a disintegrant; 0.2% to 0.3% by weight of a glidant, and 7. The pharmaceutical composition of claim 6, comprising 0.55% to 0.95% by weight of a lubricant.

8. In the intragranular component, the disintegrant is sodium starch glycolate; and In the extragranular component, the disintegrant is sodium starch glycolate, The glidant is colloidal silicon dioxide and the lubricant is magnesium stearate. is sodium; and 7. The pharmaceutical composition of claim 6, wherein the film coating component comprises Opadry®. thing.

9. 1. A pharmaceutical composition for treating anemia, which is a tablet, comprising an intragranular component, Contains an extragranular component and a film coating component, The intragranular component is 55% to 75% by weight of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] a Amino}acetic acid: 【Chemistry 4】 (Compound 1), or a pharma- ceutically acceptable salt thereof; 15% to 35% by weight of microcrystalline cellulose, 2.0% to 4.0% by weight of sodium starch glycolate, and comprising 1.8% to 3.8% by weight of hydroxypropyl methylcellulose; The extragranular component is 2.0% to 4.0% by weight of sodium starch glycolate, 0.15% to 0.35% by weight of colloidal silicon dioxide, and containing 0.35% to 1.15% by weight of magnesium stearate; the film coating component comprises 1.0% to 8% by weight of the tablet coating; the weight being the total weight of all intra- and extra-grain components; and The tablet is used to administer 75 mg to 600 mg of compound 1 once a day. Composition.

10. The intragranular component is 60% to 70% by weight of compound 1, 20% to 30% by weight of microcrystalline cellulose, 2.5% to 3.5% by weight of sodium starch glycolate, and comprising 2.3% to 3.3% by weight of hydroxypropyl methylcellulose; The extragranular component is 2.5% to 3.5% by weight of sodium starch glycolate, 0.2% to 0.3% by weight of colloidal silicon dioxide, and 0.55% to 0.95% by weight of magnesium stearate; and The film coating composition comprises 1.0% to 8% by weight of Opadry®. The pharmaceutical composition according to claim 9.

11. The anemia is anemia secondary to or associated with non-dialysis dependent chronic kidney disease. The pharmaceutical composition according to any one of items 6 to 10.

12. 2. The method of claim 1, wherein the anemia is secondary to or associated with dialysis-dependent chronic kidney disease. The pharmaceutical composition according to any one of claims 6 to 10.

13. 6. The tablet formulation of claim 1, wherein the intragranular component contains 75 mg of compound 1. Or the pharmaceutical composition according to any one of claims 6 to 10.

14. The tablet formulation according to any one of claims 1 to 5, wherein the intragranular component contains 150 mg of compound 1. or the pharmaceutical composition according to any one of claims 6 to 10.

15. The tablet formulation according to any one of claims 1 to 5, wherein the intragranular component contains 300 mg of compound 1. or the pharmaceutical composition according to any one of claims 6 to 10.

16. The tablet formulation according to any one of claims 1 to 5, wherein the intragranular component contains 450 mg of compound 1. or the pharmaceutical composition according to any one of claims 6 to 10.

17. The tablet formulation according to any one of claims 1 to 5, wherein the intragranular component contains 600 mg of compound 1. or the pharmaceutical composition according to any one of claims 6 to 10.

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